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Friedman, Henry Seth

Overview:

Overview: Our laboratory is pursuing a comprehensive analysis of the biology and therapy of adult and childhood central nervous system malignancies, particularly high-grade medulloblastoma, glioma, and ependymoma.

Laboratory Studies: Active programs, using human adult and pediatric CNS tumor continuous cell lines, transplantable xenografts growing subcutaneously and intracranially in athymic nude mice and rats, and as well as in the subarachnoid space of the athymic nude rats, and patients tumor specimens, are defining:

1) the chemotherapeutic profile of medulloblastoma, adult and childhood glioma and ependymoma
2) mechanisms of resistance to classical bifunctional alkylators, nitrosoureas and methylators operational in malignant glioma and medulloblastoma, particularly DNA adduct and crosslink repair, O6-alkylguanine-DNA alkyltransferase elevation and DNA mismatch repair deficiency.
3) modulations designed to over come or circumvent specific mechanisms of resistance
4) the activity of signal pathway inhibitors of EGFR, m-tor and other targets
5) the therapeutic advantages of intrathecal and intratumoral drug delivery in the treatment of neoplastic meningitis and intracranial malignancies, respectively.

The results of the therapeutic studies to date have demonstrated the marked activity of alkylating agents, particularly melphalan and cyclophosphamide and the role of glutathione, AGT glutathione-S-transferase, abnormal drug transport and alterations in formation and repair of DNA-DNA crosslinks in modulating cytotoxicity of these agents. Modulations shown to be effective in enhancing alkylator activity/reversing alkylator resistance include BSO-mediated glutathione depletion, inhibition of DNA-DNA crosslink repair and inhibition of 06-alkylguanine-DNA alkyltransferase by 06-benzylguanine. Recent studies have demonstrated profound activity of temozolomide, CPT-11 topotecan, irofulven, and karenitecin as well as the combination of CPT-11 or topotecan plus BCNU or temozolomide. Successful treatment of neoplastic meningitis in nude rats with intrathecal 4-hydroperoxycyclophosphamide, melphalan, temozolomide and busulfan, and intracranial glioma in nude rats with intratumoral temozolomide has also been demonstrated. More recent studies have revealed cyclophosphamide resistance secondary to DNA interstrand crosslink repair. Additional studies have shown that cyclophosphamide crosslinks are formed at the 1,3 N7 position, serving as the basis for construction of a defined crosslink in a plasmid vector to assay for crosslink repair and allowing demonstration of the lack of a role of nucleotide excision repair. Mismatch repair deficiency has been shown as a mechanism mediating acquired methylator (procarbazine and temozolomide) resistance in an adult glioblastoma xenograft.

Clinical Studies: Clinical investigations are designed to translate laboratory programs into successful treatment for adults and children with malignant brain tumors, particularly medulloblastoma. Clinical trials for adults include phase II trials of temozolomide, ZD1839 (Iressa), karenitecin, and temozolomide plus O6-BG as well as phase I trials of topotecan plus BCNU, CPT-11 plus temozolomide, and PTK787 ± temozolomide or CCNU. Studies are in progress in children evaluating the activity CPT-11 plus temozolomide, intrathecal busulfan and cyclophosphamide/melphalan or cyclophosphamide/busulfan plus autologous bone marrow support . Extension of these studies to a larger cohort of patients is being performed nationally under the auspices of the Pediatric Brain Tumor Consortium (Henry S. Friedman -- Head of New Agents Committee).

Future studies will address the role of agents designed to decrease repair of interstrand crosslinks when given in combination with alkylating agents, as well as newer signal pathway inhibitors such as RAD001, PKI166, and DB-67.

Positions:

James B. Powell, Jr. Professor of Pediatric Oncology, in the School of Medicine

Neurosurgery, Neuro-Oncology
School of Medicine

Professor of Neurosurgery

Neurosurgery, Neuro-Oncology
School of Medicine

Professor of Pediatrics

Pediatrics
School of Medicine

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1977

M.D. — SUNY Upstate Medical University

News:

Grants:

Oncolytic Polovirus, Immunotoxin, and Checkpoint Inhibitor Therapy of Gliomas

Administered By
Neurosurgery, Neuro-Oncology Clinical Research
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 2015
End Date
July 31, 2022

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1998
End Date
August 31, 2016

Adoptive Immunotherapy for GBM During Hematopoietic Recovery from Temozolomide

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 23, 2009
End Date
July 31, 2014

Gene Targeted Therapy of Brain Tumors

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 30, 2009
End Date
February 29, 2012

Targeting Brain Tumor Stem Cells

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 08, 2009
End Date
August 07, 2011

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 15, 2005
End Date
August 31, 2010

Temodar Resistance in CNS Tumors

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 22, 1992
End Date
April 30, 2010

Changes in Functional Status Across Therapy for Primary Gilioma

Administered By
Radiation Oncology
AwardedBy
National Cancer Institute
Role
Consultant
Start Date
September 21, 2006
End Date
August 31, 2009

TGFbeta-PTEN Interactions in Glioma Biology & Therapy

Administered By
Neurology, General & Community Neurology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
August 01, 2006
End Date
September 30, 2008

Molecular Mechanisms of SPARC Mediated Glioma Invasion

Administered By
Neurology, General & Community Neurology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
February 15, 2006
End Date
September 30, 2008

DNA Methylation and GSTP1 Gene Regulation in Gliomas

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 01, 2002
End Date
June 30, 2008

Biomarker Studies for Novel Anti-Cancer Agents

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
May 28, 2003
End Date
February 29, 2008

Imaging of O6-Alkylguianine-DNA Alkyltransferase

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
September 30, 2002
End Date
August 31, 2007

Phase II Study of 44Gy from 131I-81C6 for CNS Tumors

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 29, 2003
End Date
August 31, 2006

Astatine-211 & Radioiodine Labeled Octreotide Conjugates

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
July 01, 2001
End Date
June 30, 2006

Regional AGT Depletion of CNS and Leptomeningeal Tumors

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 2002
End Date
January 31, 2006

AGT Depletion for therapy of CNS tumors

Administered By
Neurology, General & Community Neurology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 30, 2000
End Date
August 31, 2005

GCRC CAP

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 2000
End Date
August 31, 2005

Therapy of Temodar plus O6-BG in Malignant Glioma

Administered By
Neurology, General & Community Neurology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 01, 2003
End Date
March 31, 2005

A Molecular Classification of Brain Tumors

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 29, 2000
End Date
August 31, 2003

ZD1839 Therapy of Glioblastoma Multiforme

Administered By
Pediatrics
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2001
End Date
March 31, 2003

Intrathecal Busulfan Therapy of Neoplastic Meningitis

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
Food and Drug Administration
Role
Principal Investigator
Start Date
September 30, 1998
End Date
September 29, 2002

GRT-Photo-Documentary/Patients/Brain Tumors

Administered By
Pediatrics
Role
Principal Investigator
Start Date
February 01, 1999
End Date
August 31, 2002

Temozolomide Resistance in CNS Tumors

Administered By
Pediatrics
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1999
End Date
March 31, 2001

Src On Primary And Matastatic Tumors Of The Cns

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
May 01, 1994
End Date
March 31, 1999

Src On Primary And Metastatic Tumors Of The Cns

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
March 01, 1997
End Date
February 28, 1999

Cyclophosphamide Resistance In Medulloblastoma

Administered By
Pediatrics
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1996
End Date
June 30, 1998

Phase I Trial Of 06-Benzylguanine Plus Bcnu In Glioma

Administered By
Pediatrics
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1996
End Date
June 30, 1998

Cyclophosphamide Resistance In Medulloblastoma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 1995
End Date
June 30, 1998

Cyclophoshamide Resistance In Medulloblastoma

Administered By
Pediatrics
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 22, 1992
End Date
June 30, 1998

Phase I Trial Of 06-Benzylguanine Plus Bcnu In Glioma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 07, 1995
End Date
June 30, 1997

Pediatric Oncology Group Studies

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 1995
End Date
December 31, 1995

Gluathione Modulation Of Alkylators In Medulloblastoma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 22, 1992
End Date
June 30, 1995

Glutathione Modulation Of Alkylators In Medulloblastoma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 01, 1993
End Date
May 31, 1995

Pediatric Oncology Group Studies

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 1991
End Date
December 31, 1994

Src On Malignant Human Gliomas And Medulloblastomas

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1993
End Date
March 31, 1994

Melphalan Cytotoxicity And Resistance In Medulloblastoma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 1990
End Date
April 30, 1991

Neurobiology And Rational Therapy Of Human Medulloblastoma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1987
End Date
March 01, 1990

Neurobiology And Rational Therapy Of Human Medulloblasto

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1986
End Date
March 01, 1990
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Publications:

Complementary and integrative health interventions and their association with health-related quality of life in the primary brain tumor population.

BACKGROUND AND PURPOSE: Little is known about complementary and integrative health intervention usage in the primary brain tumor population. We aimed to identify the percentage of patients using these practices and explore the impact on quality of life. MATERIALS AND METHODS: Clinical records from patients seen in clinic between December 16, 2013 and February 28, 2014 were reviewed retrospectively. The questionnaires used were a modified version of the International Complementary and Alternative Medicine Questionnaire, the Functional Assessment of Cancer Therapy- Brain Cancer and the Functional Assessment of Chronic Illness Therapy- Fatigue. RESULTS: 76% of patients utilized a complementary and integrative health modality. The most frequently reported modalities used were vitamins, massage, and spiritual healing, prayer, diet and meditation. CONCLUSION: These results confirm the usage of complementary and integrative health practices within the primary brain tumor population; however, there was no evidence of association between use and quality of life.

Authors
Randazzo, DM; McSherry, F; Herndon, JE; Affronti, ML; Lipp, ES; Flahiff, C; Miller, E; Woodring, S; Boulton, S; Desjardins, A; Ashley, DM; Friedman, HS; Peters, KB
MLA Citation
Randazzo, Dina M., et al. “Complementary and integrative health interventions and their association with health-related quality of life in the primary brain tumor population..” Complement Ther Clin Pract, vol. 36, Aug. 2019, pp. 43–48. Pubmed, doi:10.1016/j.ctcp.2019.05.002.
PMID
31383442
Source
pubmed
Published In
Complement Ther Clin Pract
Volume
36
Publish Date
2019
Start Page
43
End Page
48
DOI
10.1016/j.ctcp.2019.05.002

MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation.

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic alterations in glioblastoma (GBM), but its pathologic consequences remain unclear. In this study, we report that loss of MTAP results in profound epigenetic reprogramming characterized by hypomethylation of PROM1/CD133-associated stem cell regulatory pathways. MTAP deficiency promotes glioma stem-like cell (GSC) formation with increased expression of PROM1/CD133 and enhanced tumorigenicity of GBM cells and is associated with poor prognosis in patients with GBM. As a combined consequence of purine production deficiency in MTAP-null GBM and the critical dependence of GSCs on purines, the enriched subset of CD133+ cells in MTAP-null GBM can be effectively depleted by inhibition of de novo purine synthesis. These findings suggest that MTAP loss promotes the pathogenesis of GBM by shaping the epigenetic landscape and stemness of GBM cells while simultaneously providing a unique opportunity for GBM therapeutics. SIGNIFICANCE: This study links the frequently mutated metabolic enzyme MTAP to dysregulated epigenetics and cancer cell stemness and establishes MTAP status as a factor for consideration in characterizing GBM and developing therapeutic strategies.

Authors
Hansen, LJ; Sun, R; Yang, R; Singh, SX; Chen, LH; Pirozzi, CJ; Moure, CJ; Hemphill, C; Carpenter, AB; Healy, P; Ruger, RC; Chen, C-PJ; Greer, PK; Zhao, F; Spasojevic, I; Grenier, C; Huang, Z; Murphy, SK; McLendon, RE; Friedman, HS; Friedman, AH; Herndon, JE; Sampson, JH; Keir, ST; Bigner, DD; Yan, H; He, Y
MLA Citation
Hansen, Landon J., et al. “MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation..” Cancer Res, vol. 79, no. 13, July 2019, pp. 3383–94. Pubmed, doi:10.1158/0008-5472.CAN-18-1010.
PMID
31040154
Source
pubmed
Published In
Cancer Res
Volume
79
Issue
13
Publish Date
2019
Start Page
3383
End Page
3394
DOI
10.1158/0008-5472.CAN-18-1010

Single-institution retrospective review of patients with recurrent glioblastoma treated with bevacizumab in clinical practice.

Background and aims: This retrospective review of patients with recurrent glioblastoma treated at the Preston Robert Tisch Brain Tumor Center investigated treatment patterns, survival, and safety with bevacizumab in a real-world setting. Methods: Adult patients with glioblastoma who initiated bevacizumab at disease progression between January 1, 2009, and May 14, 2012, were included. A Kaplan-Meier estimator was used to describe overall survival (OS), progression-free survival (PFS), and time to greater than or equal to 20% reduction in Karnofsky Performance Status (KPS). The effect of baseline demographic and clinical factors on survival was examined using a Cox proportional hazards model. Adverse event (AE) data were collected. Results: Seventy-four patients, with a median age of 59 years, were included in this cohort. Between bevacizumab initiation and first failure, defined as the first disease progression after bevacizumab initiation, biweekly bevacizumab and bevacizumab/irinotecan were the most frequently prescribed regimens. Median duration of bevacizumab treatment until failure was 6.4 months (range, 0.5-58.7). Median OS and PFS from bevacizumab initiation were 11.1 months (95% confidence interval [CI], 7.3-13.4) and 6.4 months (95% CI, 3.9-8.5), respectively. Median time to greater than or equal to 20% reduction in KPS was 29.3 months (95% CI, 13.8-∞). Lack of corticosteroid usage at the start of bevacizumab therapy was associated with both longer OS and PFS, with a median OS of 13.2 months (95% CI, 8.6-16.6) in patients who did not initially require corticosteroids versus 7.2 months (95% CI, 4.8-12.5) in those who did (P = 0.0382, log-rank), while median PFS values were 8.6 months (95% CI, 4.6-9.7) and 3.7 months (95% CI, 2.7-6.6), respectively (P = 0.0243, log-rank). Treatment failure occurred in 70 patients; 47 of whom received salvage therapy, and most frequently bevacizumab/carboplatin (7/47; 14.9%). Thirteen patients (18%) experienced a grade 3 AE of special interest for bevacizumab. Conclusions: Treatment patterns and outcomes for patients with recurrent glioblastoma receiving bevacizumab in a real-world setting were comparable with those reported in prospective clinical trials.

Authors
Desjardins, A; Herndon, JE; McSherry, F; Ravelo, A; Lipp, ES; Healy, P; Peters, KB; Sampson, JH; Randazzo, D; Sommer, N; Friedman, AH; Friedman, HS
MLA Citation
Desjardins, Annick, et al. “Single-institution retrospective review of patients with recurrent glioblastoma treated with bevacizumab in clinical practice..” Health Sci Rep, vol. 2, no. 4, Apr. 2019. Pubmed, doi:10.1002/hsr2.114.
PMID
31049419
Source
pubmed
Published In
Health Science Reports
Volume
2
Issue
4
Publish Date
2019
Start Page
e114
DOI
10.1002/hsr2.114

MGMT: Immunohistochemical Detection in High-Grade Astrocytomas.

Glioma therapeutic resistance to alkylating chemotherapy is mediated via O6-methylguanine-DNA methyltransferase (MGMT). We hypothesized that a CD45/HAM56/MGMT double-stained cocktail would improve MGMT discrimination in tumor cells versus inflammatory and endothelial cells (IEC). Total MGMT protein was quantified by IHC on 982 glioblastomas (GBM) and 199 anaplastic astrocytomas. Correcting for IEC was done by a CD45/HAM56/MGMT 2-color cocktail. Lowest IEC infiltrates (IEC "cold spots") were identified to quantitate MGMT as well as the percentage of IEC% in the IEC cold spots. MGMT promoter methylation (PM) was also determined. Among the GBM biopsies, mean uncorrected and corrected MGMT% were 19.87 (range 0-90) and 16.67; mean IEC% was 18.65 (range 1-80). Four hundred and fifty one (45.9%) GBM biopsies were positive MGMT PM. Both uncorrected and corrected MGMT% positivity correlated with PM. All 3 MGMT scores correlated with overall survival (OS) in GBM's. Cold spot IEC% was also positively associated with OS. These effects remained in a multivariate model after adjusting for age and disease status. Prognosis determined by correcting MGMT% score for IEC% is not improved in this analysis. However, IEC COLD SPOT score does provide additional prognostic information that can be gained from this correction method.

Authors
Lipp, ES; Healy, P; Austin, A; Clark, A; Dalton, T; Perkinson, K; Herndon, JE; Friedman, HS; Friedman, AH; Bigner, DD; McLendon, RE
MLA Citation
Lipp, Eric S., et al. “MGMT: Immunohistochemical Detection in High-Grade Astrocytomas..” J Neuropathol Exp Neurol, vol. 78, no. 1, Jan. 2019, pp. 57–64. Pubmed, doi:10.1093/jnen/nly110.
PMID
30500933
Source
pubmed
Published In
J Neuropathol Exp Neurol
Volume
78
Issue
1
Publish Date
2019
Start Page
57
End Page
64
DOI
10.1093/jnen/nly110

Pilot Study to Describe the Trajectory of Symptoms and Adaptive Strategies of Adults Living with Low-grade Glioma.

OBJECTIVES: To describe the adaptability to the patterns in symptoms and quality of life (QoL) during 6 months post low-grade glioma diagnosis by valid and reliable tools; to identify through qualitative interviews patient/provider adaptive techniques and strategies; and to assess associations among patient characteristics, symptoms and QoL, and adaptive techniques or strategies. DATA SOURCES: Demographic, clinical and pathologic data from medical records. Validated instruments that assess QoL, fatigue, depression, and distress were completed at 2, 4, and 6 months post diagnosis. Qualitative interviews identifying the symptoms, challenges, adaptive techniques and strategies were conducted at 4 and 6 months. CONCLUSION: The most frequently used adaptive strategies included: obtaining community support (87%), managing expectations (73%) and support systems (67%), and seeking out knowledge about physical (67%) and behavioral symptoms (53%). Seizures were reported with IDH1mut (11%) but not IDH1wildtype. Patients with either IDH1mut or TERTmut consistently reported lower QoL and higher distress, depression, and fatigue scores. IDH1/TERTmut may be related to lower QoL because of IDH1mut-related seizures. IMPLICATIONS FOR NURSING PRACTICE: Findings provide a list of adaptive strategies and characteristics to address the problems and symptoms that may improve overall QoL in patients with low-grade glioma.

Authors
Affronti, ML; Randazzo, D; Lipp, ES; Peters, KB; Herndon, SC; Woodring, S; Healy, P; Cone, CK; Herndon, JE; Schneider, SM
MLA Citation
Affronti, Mary Lou, et al. “Pilot Study to Describe the Trajectory of Symptoms and Adaptive Strategies of Adults Living with Low-grade Glioma..” Semin Oncol Nurs, vol. 34, no. 5, 2018, pp. 472–85. Pubmed, doi:10.1016/j.soncn.2018.10.006.
PMID
30409554
Source
pubmed
Published In
Semin Oncol Nurs
Volume
34
Issue
5
Publish Date
2018
Start Page
472
End Page
485
DOI
10.1016/j.soncn.2018.10.006

Phase II Study to Evaluate the Efficacy and Safety of Rilotumumab and Bevacizumab in Subjects with Recurrent Malignant Glioma.

LESSONS LEARNED: Due to evolving imaging criteria in brain tumors and variation in magnetic resonance imaging evaluation, it is not ideal to use response rate as a primary objective. Future studies involving antiangiogenic agents should use overall survival.Disease-expected toxicities should be considered when defining the clinical significance of an adverse event. For example, vascular thromboembolic events are common in brain tumor patients and should not be attributed to the study drug in the safety analysis. BACKGROUND: Recurrent malignant glioma (rMG) prognosis is poor, with a median patient survival of 3-11 months with bevacizumab (BEV)-containing regimens. BEV in rMG has 6-month progression free survival (PFS-6) of ∼40% and an objective response rate of 21.2%. BEV-containing regimens improve PFS-6 to 42.6%-50.3%, indicating that BEV combination therapies may be superior to single agent. Rilotumumab, a hepatocyte growth factor (HGF) antibody, inhibits angiogenesis and expression of angiogenic autocrine factors (e.g., vascular endothelial growth factor [VEGF]) by c-Met inhibition. Combination of rilotumumab with BEV to block vascular invasion and tumor proliferation may synergistically inhibit tumor growth. METHODS: Thirty-six BEV-naïve rMG subjects received rilotumumab (20 mg/kg and BEV (10 mg/kg) every 2 weeks. Endpoints included objective response rate (using Response Assessment in Neuro-Oncology [RANO] criteria), PFS-6, overall survival (OS), and toxicity. RESULTS: Median patient follow-up was 65.0 months. Objective response rate was 27.8% (95% confidence interval [CI]: 15.7%-44.1%). Median OS was 11.2 months (95% CI: 7-17.5). PFS-6 was 41.7% (95% CI: 25.6%-57.0%). Most frequent treatment-related grade ≤2 events included weight gain, fatigue, allergic rhinitis, and voice alteration; grade ≥3 events included venous thromboembolism (four patients), including one death from pulmonary embolism. CONCLUSION: Rilotumumab with BEV did not significantly improve objective response compared with BEV alone, and toxicity may preclude the use of rilotumumab in combination BEV regimens.

Authors
Affronti, ML; Jackman, JG; McSherry, F; Herndon, JE; Massey, EC; Lipp, E; Desjardins, A; Friedman, HS; Vlahovic, G; Vredenburgh, J; Peters, KB
MLA Citation
Affronti, Mary Lou, et al. “Phase II Study to Evaluate the Efficacy and Safety of Rilotumumab and Bevacizumab in Subjects with Recurrent Malignant Glioma..” Oncologist, vol. 23, no. 8, Aug. 2018, pp. 889-e98. Pubmed, doi:10.1634/theoncologist.2018-0149.
PMID
29666296
Source
pubmed
Published In
Oncologist
Volume
23
Issue
8
Publish Date
2018
Start Page
889
End Page
e98
DOI
10.1634/theoncologist.2018-0149

Recurrent Glioblastoma Treated with Recombinant Poliovirus.

BACKGROUND: The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment. METHODS: We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 107 and 1010 50% tissue-culture infectious doses (TCID50), first in a dose-escalation phase and then in a dose-expansion phase. RESULTS: From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level -1 (5.0×107 TCID50) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (1010 TCID50) was administered had a grade 4 intracranial hemorrhage immediately after the catheter was removed. To mitigate locoregional inflammation of the infused tumor with prolonged glucocorticoid use, dose level 5 was deescalated to reach the phase 2 dose. In the dose-expansion phase, 19% of the patients had a PVSRIPO-related adverse event of grade 3 or higher. Overall survival among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11 to 33) at 24 months that was sustained at 36 months. CONCLUSIONS: Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls. (Funded by the Brain Tumor Research Charity and others; ClinicalTrials.gov number, NCT01491893 .).

Authors
Desjardins, A; Gromeier, M; Herndon, JE; Beaubier, N; Bolognesi, DP; Friedman, AH; Friedman, HS; McSherry, F; Muscat, AM; Nair, S; Peters, KB; Randazzo, D; Sampson, JH; Vlahovic, G; Harrison, WT; McLendon, RE; Ashley, D; Bigner, DD
MLA Citation
Desjardins, Annick, et al. “Recurrent Glioblastoma Treated with Recombinant Poliovirus..” N Engl J Med, vol. 379, no. 2, July 2018, pp. 150–61. Pubmed, doi:10.1056/NEJMoa1716435.
PMID
29943666
Source
pubmed
Published In
The New England Journal of Medicine
Volume
379
Issue
2
Publish Date
2018
Start Page
150
End Page
161
DOI
10.1056/NEJMoa1716435

Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models.

BACKGROUND: Sym004 is a mixture of two monoclonal antibodies (mAbs), futuximab and modotuximab, targeting non-overlapping epitopes on the epidermal growth factor receptor (EGFR). Previous studies have shown that Sym004 is more efficient at inducing internalization and degradation of EGFR than individual components, which translates into superior cancer cell inhibition. We investigated whether Sym004 induces removal of EGFRvIII and if this removal translates into tumor growth inhibition in hard-to-treat glioblastomas (GBMs) harboring the mutated, constitutively active EGFR variant III (EGFRvIII). METHODS: To address this question, we tested the effect of Sym004 versus cetuximab in eight patient-derived GBM xenograft models expressing either wild-type EGFR (EGFRwt) and/or mutant EGFRvIII. All models were tested as both subcutaneous and orthotopic intracranial xenograft models. RESULTS: In vitro studies demonstrated that Sym004 internalized and removed EGFRvIII more efficiently than mAbs, futuximab, modotuximab, and cetuximab. Removal of EGFRvIII by Sym004 translated into significant in vivo anti-tumor activity in all six EGFRvIII xenograft models. Furthermore, the anti-tumor activity of Sym004 in vivo was superior to that of its individual components, futuximab and modotuximab, suggesting a clear synergistic effect of the mAbs in the mixture. CONCLUSION: These results demonstrate the broad activity of Sym004 in patient-derived EGFRvIII-expressing GBM xenograft models and provide a clear rationale for clinical evaluation of Sym004 in EGFRvIII-positive adult GBM patients.

Authors
Keir, ST; Chandramohan, V; Hemphill, CD; Grandal, MM; Melander, MC; Pedersen, MW; Horak, ID; Kragh, M; Desjardins, A; Friedman, HS; Bigner, DD
MLA Citation
Keir, Stephen T., et al. “Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models..” J Neurooncol, vol. 138, no. 3, July 2018, pp. 489–98. Pubmed, doi:10.1007/s11060-018-2832-6.
PMID
29564747
Source
pubmed
Published In
J Neurooncol
Volume
138
Issue
3
Publish Date
2018
Start Page
489
End Page
498
DOI
10.1007/s11060-018-2832-6

PHASE 1B STUDY POLIO VACCINE SABIN-RHINOVIRUS POLIOVIRUS (PVSRIPO) FOR RECURRENT MALIGNANT GLIOMA IN CHILDREN

Authors
Ashley, DM; Thompson, EM; Landi, D; Desjardins, A; Friedman, AH; Threatt, S; Herndon, JE; Boulton, S; McSherry, F; Lipp, ES; Sampson, JH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Ashley, David M., et al. “PHASE 1B STUDY POLIO VACCINE SABIN-RHINOVIRUS POLIOVIRUS (PVSRIPO) FOR RECURRENT MALIGNANT GLIOMA IN CHILDREN.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 93–93.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
93
End Page
93

The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma.

The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, about 20% of glioblastomas lack alterations in TERTp and IDH. These tumors, designated TERTpWT-IDHWT glioblastomas, do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we report the genetic landscape of TERTpWT-IDHWT glioblastoma and identify SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT. Furthermore, we identify a novel mechanism of telomerase activation in glioblastomas that occurs via chromosomal rearrangements upstream of TERT. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDHWT-TERTSV), and an ALT-positive subgroup (IDHWT-ALT) with mutations in ATRX or SMARCAL1.

Authors
Diplas, BH; He, X; Brosnan-Cashman, JA; Liu, H; Chen, LH; Wang, Z; Moure, CJ; Killela, PJ; Loriaux, DB; Lipp, ES; Greer, PK; Yang, R; Rizzo, AJ; Rodriguez, FJ; Friedman, AH; Friedman, HS; Wang, S; He, Y; McLendon, RE; Bigner, DD; Jiao, Y; Waitkus, MS; Meeker, AK; Yan, H
MLA Citation
Diplas, Bill H., et al. “The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma..” Nat Commun, vol. 9, no. 1, May 2018. Pubmed, doi:10.1038/s41467-018-04448-6.
PMID
29802247
Source
pubmed
Published In
Nature Communications
Volume
9
Issue
1
Publish Date
2018
Start Page
2087
DOI
10.1038/s41467-018-04448-6

Phase I/II trial of vorinostat, bevacizumab, and daily temozolomide for recurrent malignant gliomas.

Prognosis of recurrent glioblastoma (GBM) is poor with 6-month progression-free survival (PFS6) ranging from 9 to 48% depending on the treatment regimen and use of anti-angiogenic therapies. We sought to study vorinostat (VOR), a histone deacetylase inhibitor, in combination with bevacizumab (BEV) and daily metronomic temozolomide (TMZ) in a Phase I/II trial in recurrent high-grade gliomas (HGGs). This was a Phase I/II open-label, single-arm study in recurrent HGG patients. Phase I primary endpoint was to determine the maximum tolerated dose (MTD) of VOR with BEV and daily TMZ. Phase II primary endpoint was PFS6. Regimen was BEV 10 mg/kg iv every 2 weeks, TMZ 50 mg/m2 po daily, and VOR 200 or 400 mg po alternating 7 days on then 7 days off throughout a 28-day cycle. Phase I portion enrolled nine subjects with three receiving VOR 200 mg and 6 receiving VOR 400 mg. With no dose-limiting toxicities (DLTs) at 200 mg and one DLT (thrombocytopenia, Grade 3) at 400 mg, the MTD was 400 mg. Phase II portion enrolled 39 GBM subjects, and PFS6 was 53.8% (95% CI 37.2-67.9%). Of note, 14 subjects had received prior BEV and all had received prior 5-day TMZ. Combination therapy with VOR, BEV, and daily TMZ was well tolerated and safe. While PFS6 was not statistically improved beyond historical controls, it is important to note that this was a heavily pretreated GBM population and further consideration is warranted in a less pretreated group.

Authors
Peters, KB; Lipp, ES; Miller, E; Herndon, JE; McSherry, F; Desjardins, A; Reardon, DA; Friedman, HS
MLA Citation
Peters, Katherine B., et al. “Phase I/II trial of vorinostat, bevacizumab, and daily temozolomide for recurrent malignant gliomas..” J Neurooncol, vol. 137, no. 2, Apr. 2018, pp. 349–56. Pubmed, doi:10.1007/s11060-017-2724-1.
PMID
29264836
Source
pubmed
Published In
J Neurooncol
Volume
137
Issue
2
Publish Date
2018
Start Page
349
End Page
356
DOI
10.1007/s11060-017-2724-1

Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma.

LESSONS LEARNED: Combination regimen with bevacizumab (BEV) and vorinostat is well tolerated in patients with recurrent glioblastoma.Treatment of recurrent glioblastoma remains challenging as this study and others attempt to improve progression-free survival and overall survival with BEV-containing regimens. BACKGROUND: Recurrent glioblastoma (GBM; World Health Organization grade 4) continues to have a very poor prognosis. Bevacizumab (BEV) has been shown to improve progression-free survival (PFS) in recurrent GBM and is approved by the U.S. Food and Drug Administration for the treatment of recurrent GBM. Combination regimens have been explored, and in this phase II nonrandomized trial, we evaluated the efficacy of BEV combined with histone deacetylase inhibitor vorinostat (VOR) in recurrent GBM. MATERIALS AND METHODS: In this phase II, single-center, nonrandomized study, subjects with recurrent GBM received BEV 10 mg/kg intravenously (IV) every 2 weeks combined with VOR 400 mg p.o. daily for 7 days on, 7 days off, in a 28-day cycle. The primary endpoint was 6-month PFS (PFS6). RESULTS: Forty patients with recurrent GBM were enrolled and evaluated. PFS6 was 30.0% (95% confidence interval [CI] 16.8%-44.4%). Median overall survival (OS) was 10.4 months (95% CI 7.6-12.8 months). Overall radiographic response rate was 22.5% based on 9 partial responses. The most common grade 2 and above treatment-related adverse events were lymphopenia (55%), leukopenia (45%), neutropenia (35%), and hypertension (33%). Grade 4 adverse events were leukopenia (3%), neutropenia (3%), sinus bradycardia (3%), and venous thromboembolism (3%). Two deaths occurred in this study, with one due to tumor progression and another possibly related as death not otherwise specified. CONCLUSION: Combination treatment of BEV and VOR was well tolerated. This combination therapy for this study population did not improve PFS6 or median OS when compared with BEV monotherapy.

Authors
Ghiaseddin, A; Reardon, D; Massey, W; Mannerino, A; Lipp, ES; Herndon, JE; McSherry, F; Desjardins, A; Randazzo, D; Friedman, HS; Peters, KB
MLA Citation
Ghiaseddin, Ashley, et al. “Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma..” Oncologist, vol. 23, no. 2, Feb. 2018, pp. 157-e21. Pubmed, doi:10.1634/theoncologist.2017-0501.
PMID
29133513
Source
pubmed
Published In
Oncologist
Volume
23
Issue
2
Publish Date
2018
Start Page
157
End Page
e21
DOI
10.1634/theoncologist.2017-0501

Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma.

Median survival for glioblastoma (GBM) remains <15 months. Human cytomegalovirus (CMV) antigens have been identified in GBM but not normal brain, providing an unparalleled opportunity to subvert CMV antigens as tumor-specific immunotherapy targets. A recent trial in recurrent GBM patients demonstrated the potential clinical benefit of adoptive T-cell therapy (ATCT) of CMV phosphoprotein 65 (pp65)-specific T cells. However, ex vivo analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8+ T-cell polyfunctionality in vivo when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DCs would enhance the frequency of polyfunctional CMV pp65-specific CD8+ T cells after ATCT. Here, we report prospective results of a pilot trial in which 22 patients with newly diagnosed GBM were initially enrolled, of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFNγ+, TNFα+, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8+ T cells correlated (R = 0.7371, P = 0.0369) with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study.Significance: A randomized pilot trial in patients with GBM implicates polyfunctional T-cell responses as a biomarker for effective antitumor immunotherapy. Cancer Res; 78(1); 256-64. ©2017 AACR.

Authors
Reap, EA; Suryadevara, CM; Batich, KA; Sanchez-Perez, L; Archer, GE; Schmittling, RJ; Norberg, PK; Herndon, JE; Healy, P; Congdon, KL; Gedeon, PC; Campbell, OC; Swartz, AM; Riccione, KA; Yi, JS; Hossain-Ibrahim, MK; Saraswathula, A; Nair, SK; Dunn-Pirio, AM; Broome, TM; Weinhold, KJ; Desjardins, A; Vlahovic, G; McLendon, RE; Friedman, AH; Friedman, HS; Bigner, DD; Fecci, PE; Mitchell, DA; Sampson, JH
MLA Citation
Reap, Elizabeth A., et al. “Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma..” Cancer Res, vol. 78, no. 1, Jan. 2018, pp. 256–64. Pubmed, doi:10.1158/0008-5472.CAN-17-0469.
PMID
29093005
Source
pubmed
Published In
Cancer Res
Volume
78
Issue
1
Publish Date
2018
Start Page
256
End Page
264
DOI
10.1158/0008-5472.CAN-17-0469

Adaptive Evolution of the GDH2 Allosteric Domain Promotes Gliomagenesis by Resolving IDH1R132H-Induced Metabolic Liabilities.

Hotspot mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in a number of human cancers and confer a neomorphic enzyme activity that catalyzes the conversion of α-ketoglutarate (αKG) to the oncometabolite D-(2)-hydroxyglutarate (D2HG). In malignant gliomas, IDH1R132H expression induces widespread metabolic reprogramming, possibly requiring compensatory mechanisms to sustain the normal biosynthetic requirements of actively proliferating tumor cells. We used genetically engineered mouse models of glioma and quantitative metabolomics to investigate IDH1R132H-dependent metabolic reprogramming and its potential to induce biosynthetic liabilities that can be exploited for glioma therapy. In gliomagenic neural progenitor cells, IDH1R132H expression increased the abundance of dipeptide metabolites, depleted key tricarboxylic acid cycle metabolites, and slowed progression of murine gliomas. Notably, expression of glutamate dehydrogenase GDH2, a hominoid-specific enzyme with relatively restricted expression to the brain, was critically involved in compensating for IDH1R132H-induced metabolic alterations and promoting IDH1R132H glioma growth. Indeed, we found that recently evolved amino acid substitutions in the GDH2 allosteric domain conferred its nonredundant, glioma-promoting properties in the presence of IDH1 mutation. Our results indicate that among the unique roles for GDH2 in the human forebrain is its ability to limit IDH1R132H-mediated metabolic liabilities, thus promoting glioma growth in this context. Results from this study raise the possibility that GDH2-specific inhibition may be a viable therapeutic strategy for gliomas with IDH mutations.Significance: These findings show that the homonid-specific brain enzyme GDH2 may be essential to mitigate metabolic liabilities created by IDH1 mutations in glioma, with possible implications to leverage its therapeutic management by IDH1 inhibitors. Cancer Res; 78(1); 36-50. ©2017 AACR.

Authors
Waitkus, MS; Pirozzi, CJ; Moure, CJ; Diplas, BH; Hansen, LJ; Carpenter, AB; Yang, R; Wang, Z; Ingram, BO; Karoly, ED; Mohney, RP; Spasojevic, I; McLendon, RE; Friedman, HS; He, Y; Bigner, DD; Yan, H
MLA Citation
Waitkus, Matthew S., et al. “Adaptive Evolution of the GDH2 Allosteric Domain Promotes Gliomagenesis by Resolving IDH1R132H-Induced Metabolic Liabilities..” Cancer Res, vol. 78, no. 1, Jan. 2018, pp. 36–50. Pubmed, doi:10.1158/0008-5472.CAN-17-1352.
PMID
29097607
Source
pubmed
Published In
Cancer Res
Volume
78
Issue
1
Publish Date
2018
Start Page
36
End Page
50
DOI
10.1158/0008-5472.CAN-17-1352

Adjunctive perampanel for glioma-associated epilepsy.

Glioma-associated epilepsy is associated with excessive glutamate signaling. We hypothesized that perampanel, an amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor antagonist, would treat glioma-related epilepsy. We conducted a single-arm study of adjunctive perampanel for patients with focal-onset glioma-associated seizures. The most common related adverse events were fatigue and dizziness. Three out of 8 participants had self-reported seizure reduction and an additional 3 reported improved control. Of these 6, 5 had isocitrate dehydrogenase 1 mutant gliomas. We conclude that perampanel is safe for patients with glioma-related focal-onset epilepsy. Further study into the association between AMPA signaling, IDH1 status and seizures is warranted.

Authors
Dunn-Pirio, AM; Woodring, S; Lipp, E; Herndon, JE; Healy, P; Weant, M; Randazzo, D; Desjardins, A; Friedman, HS; Peters, KB
MLA Citation
Dunn-Pirio, Anastasie M., et al. “Adjunctive perampanel for glioma-associated epilepsy..” Epilepsy Behav Case Rep, vol. 10, 2018, pp. 114–17. Pubmed, doi:10.1016/j.ebcr.2018.09.003.
PMID
30377587
Source
pubmed
Published In
Epilepsy & Behavior Case Reports
Volume
10
Publish Date
2018
Start Page
114
End Page
117
DOI
10.1016/j.ebcr.2018.09.003

A SINGLE INSTITUTION'S EXPERIENCE EXPLORING THE ASSOCIATION OF INTEGRATIVE MEDICINE AND SURVIVORSHIP IN GLIOBLASTOMA

Authors
Randazzo, D; McSherry, F; Herndon, JE; Affronti, ML; Healy, P; Lipp, ES; Desjardins, A; Friedman, HS; Peters, KB
MLA Citation
Randazzo, Dina, et al. “A SINGLE INSTITUTION'S EXPERIENCE EXPLORING THE ASSOCIATION OF INTEGRATIVE MEDICINE AND SURVIVORSHIP IN GLIOBLASTOMA.” Neuro Oncology, vol. 19, OXFORD UNIV PRESS INC, 2017, pp. 202–202.
Source
wos
Published In
Neuro Oncology
Volume
19
Publish Date
2017
Start Page
202
End Page
202

INCREASED FATIGUE ASSOCIATED WITH TUMOR PROGRESSION IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PATIENTS

Authors
Peters, KB; Affronti, ML; Threatt, S; Healy, P; Herndon, JE; Lipp, ES; Panta, S; Randazzo, D; Friedman, HS; Desjardins, A
MLA Citation
Peters, Katherine B., et al. “INCREASED FATIGUE ASSOCIATED WITH TUMOR PROGRESSION IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PATIENTS.” Neuro Oncology, vol. 19, OXFORD UNIV PRESS INC, 2017, pp. 170–170.
Source
wos
Published In
Neuro Oncology
Volume
19
Publish Date
2017
Start Page
170
End Page
170

MAINTENANCE OF HEALTH RELATED QUALITY OF LIFE (QOL) BEYOND PROGRESSION IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS TREATED WITH BEVACIZUMAB

Authors
Peters, KB; Affronti, ML; Threatt, S; Healy, P; Herndon, JE; Lipp, ES; Panta, S; Randazzo, D; Friedman, HS; Desjardins, A
MLA Citation
Peters, Katherine B., et al. “MAINTENANCE OF HEALTH RELATED QUALITY OF LIFE (QOL) BEYOND PROGRESSION IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS TREATED WITH BEVACIZUMAB.” Neuro Oncology, vol. 19, OXFORD UNIV PRESS INC, 2017, pp. 206–206.
Source
wos
Published In
Neuro Oncology
Volume
19
Publish Date
2017
Start Page
206
End Page
206

PATTERNS OF RELAPSE AFTER SUCCESSFUL COMPLETION OF INITIAL THERAPY IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

Authors
Weant, MP; Kirkpatrick, J; Johnson, M; Dunn-Pirio, A; Healy, P; Herndon, JE; Lipp, ES; Fountain, E; Desjardins, A; Randazzo, D; Friedman, HS; Peters, KB
MLA Citation
Weant, Mallika P., et al. “PATTERNS OF RELAPSE AFTER SUCCESSFUL COMPLETION OF INITIAL THERAPY IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA.” Neuro Oncology, vol. 19, OXFORD UNIV PRESS INC, 2017, pp. 217–217.
Source
wos
Published In
Neuro Oncology
Volume
19
Publish Date
2017
Start Page
217
End Page
217

PHASE 2 STUDY OF SYM004 FOR ADULT PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM)

Authors
Desjardins, A; Randazzo, D; Peters, KB; Johnson, MO; Massey, W; Herndon, JE; McSherry, F; Lipp, ES; Nadler, P; Horak, ID; Friedman, HS
MLA Citation
Desjardins, Annick, et al. “PHASE 2 STUDY OF SYM004 FOR ADULT PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM).” Neuro Oncology, vol. 19, OXFORD UNIV PRESS INC, 2017, pp. 14–14.
Source
wos
Published In
Neuro Oncology
Volume
19
Publish Date
2017
Start Page
14
End Page
14

A RETROSPECTIVE, SINGLE INSTITUTION STUDY OF CENTRAL NEUROCYTOMA (2004-2016): SURVIVAL, TREATMENT, AND SUPPORTIVE CARE

Authors
Johnson, MO; Kirkpatrick, JP; Weant, MP; Dunn-Pirio, A; Desjardins, A; Randazzo, D; Friedman, HS; Peters, KB
MLA Citation
Johnson, Margaret O., et al. “A RETROSPECTIVE, SINGLE INSTITUTION STUDY OF CENTRAL NEUROCYTOMA (2004-2016): SURVIVAL, TREATMENT, AND SUPPORTIVE CARE.” Neuro Oncology, vol. 19, OXFORD UNIV PRESS INC, 2017, pp. 215–16.
Source
wos
Published In
Neuro Oncology
Volume
19
Publish Date
2017
Start Page
215
End Page
216

PERAMPANEL FOR TREATMENT OF REFRACTORY SEIZURES IN PATIENTS WITH GLIOMAS

Authors
Dunn-Pirio, A; Woodring, S; Panta, S; Lipp, ES; Healy, P; Herndon, JE; Fountain, E; Desjardins, A; Randazzo, D; Friedman, HS; Peters, KB
MLA Citation
Dunn-Pirio, Anastasie, et al. “PERAMPANEL FOR TREATMENT OF REFRACTORY SEIZURES IN PATIENTS WITH GLIOMAS.” Neuro Oncology, vol. 19, OXFORD UNIV PRESS INC, 2017, pp. 168–168.
Source
wos
Published In
Neuro Oncology
Volume
19
Publish Date
2017
Start Page
168
End Page
168

A cross sectional analysis from a single institution's experience of psychosocial distress and health-related quality of life in the primary brain tumor population.

Primary brain tumor patients experience high levels of distress. The purpose of this cross-sectional, retrospective study is to evaluate the level and different sources of psychosocial distress and how these pertain to health-related quality of life (HRQoL). The Primary and Recurrent Glioma registry at Duke's The Preston Robert Tisch Brain Tumor Center was queried retrospectively for demographic and clinical information on patients seen between December 2013 and February 2014. Data also included the National Comprehensive Cancer Network's Distress Thermometer (NCCN-DT), Functional Assessment of Cancer Therapy-Brain Cancer (FACT-Br), and Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F). 829 subjects completed questionnaires. 54% were male; 96% completed the NCCN-DT; 33.3% had a DT score ≥4 (moderate/severe distress). Women reported DT ≥ 4 more often than men (38.6 vs 29.0%; p = 0.005). Patients within 1 year of diagnosis reported DT ≥ 4 more often than those 1+ years after diagnosis (38.8 vs 30.9%; p = 0.034). 73.0% reported physical problems; the most frequent being fatigue (43.2%) and memory/concentration (40.9%). 42.0% complained of emotional problems with worry (29.4%) and nervousness (22.4%) being the most common. Patients who reported at least one practical, family, emotional or physical problem had significantly lower HRQoL scores (p < 0.001). Primary brain tumor patients experience memory dysfunction, fatigue, nervousness, worry, and financial concerns, which have a negative effect on the patient's HRQoL. By identifying and addressing these stressors, it may be possible to improve patient HRQoL.

Authors
Randazzo, DM; McSherry, F; Herndon, JE; Affronti, ML; Lipp, ES; Flahiff, C; Miller, E; Woodring, S; Freeman, M; Healy, P; Minchew, J; Boulton, S; Desjardins, A; Vlahovic, G; Friedman, HS; Keir, S; Peters, KB
MLA Citation
Randazzo, Dina M., et al. “A cross sectional analysis from a single institution's experience of psychosocial distress and health-related quality of life in the primary brain tumor population..” J Neurooncol, vol. 134, no. 2, Sept. 2017, pp. 363–69. Pubmed, doi:10.1007/s11060-017-2535-4.
PMID
28669010
Source
pubmed
Published In
J Neurooncol
Volume
134
Issue
2
Publish Date
2017
Start Page
363
End Page
369
DOI
10.1007/s11060-017-2535-4

A Phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma (protocol POG 9631): A report from the Children's Oncology Group.

BACKGROUND: Children with high-risk medulloblastoma historically have had a poor prognosis. The Children's Oncology Group completed a Phase II study using oral etoposide given with radiotherapy followed by intensive chemotherapy. PROCEDURE: Patients enrolled in the study had high-risk disease defined as ≥1.5 cm2 of residual disease postsurgery or definite evidence of central nervous metastasis. All patients underwent surgery followed by radiotherapy. During radiation, the patients received oral etoposide (21 days on, 7 off) at an initial dose of 50 mg/m2 per day (treatment 1), which was reduced to 35 mg/m2 per day (treatment 2) due to toxicity. After radiotherapy, the patients received chemotherapy with three cycles of cisplatin and oral etoposide, followed by eight courses of cyclophosphamide and vincristine. RESULTS: Between November 1998 and October 2002, 53 patients were accrued; 15 received treatment 1 and 38 treatment 2. Forty-seven patients (89%) were eligible. Response to radiation was excellent, with 19 (40.4%) showing complete response, 24 (51.1%) partial response, and four (8.5%) no recorded response. The overall 2- and 5-year progression-free survival (PFS) was 76.6 ± 6% and 70.2 ± 7%, respectively. The 2- and 5-year overall survival (OS) was 80.9 ± 6% and 76.6 ± 6%, respectively. Clinical response postradiation and PFS/OS were not significantly different between the treatment groups. There was a trend toward a difference in 5-year PFS between those without and with metastatic disease (P = 0.072). CONCLUSIONS: Oral etoposide was tolerable at 35 mg/m2 (21 days on and 7 days off) when given during full-dose irradiation in patients with high-risk medulloblastoma with encouraging survival data.

Authors
Esbenshade, AJ; Kocak, M; Hershon, L; Rousseau, P; Decarie, J-C; Shaw, S; Burger, P; Friedman, HS; Gajjar, A; Moghrabi, A
MLA Citation
Esbenshade, Adam J., et al. “A Phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma (protocol POG 9631): A report from the Children's Oncology Group..” Pediatr Blood Cancer, vol. 64, no. 6, June 2017. Pubmed, doi:10.1002/pbc.26373.
PMID
28000417
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
64
Issue
6
Publish Date
2017
DOI
10.1002/pbc.26373

Dose finding study of the intratumoral administration of the oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG).

Authors
Desjardins, A; Sampson, JH; Vlahovic, G; Peters, KB; Randazzo, D; Threatt, S; Herndon, JE; Bullock, CA; Miller, ES; Boulton, S; Lally-Goss, D; McSherry, F; Lipp, ES; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, Annick, et al. “Dose finding study of the intratumoral administration of the oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG)..” Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. e13533–e13533. Crossref, doi:10.1200/jco.2017.35.15_suppl.e13533.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
15_suppl
Publish Date
2017
Start Page
e13533
End Page
e13533
DOI
10.1200/jco.2017.35.15_suppl.e13533

Reductions in exercise behavior and tumor progression in newly diagnosed glioblastoma (GBM) patients.

Authors
Peters, KB; Threatt, S; Healy, P; Herndon, JE; Lipp, ES; Panta, S; Randazzo, D; Vlahovic, G; Friedman, HS; Desjardins, A
MLA Citation
Peters, Katherine B., et al. “Reductions in exercise behavior and tumor progression in newly diagnosed glioblastoma (GBM) patients..” Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. e21636–e21636. Crossref, doi:10.1200/jco.2017.35.15_suppl.e21636.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
15_suppl
Publish Date
2017
Start Page
e21636
End Page
e21636
DOI
10.1200/jco.2017.35.15_suppl.e21636

Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination.

Purpose: Patients with glioblastoma have less than 15-month median survival despite surgical resection, high-dose radiation, and chemotherapy with temozolomide. We previously demonstrated that targeting cytomegalovirus pp65 using dendritic cells (DC) can extend survival and, in a separate study, that dose-intensified temozolomide (DI-TMZ) and adjuvant granulocyte macrophage colony-stimulating factor (GM-CSF) potentiate tumor-specific immune responses in patients with glioblastoma. Here, we evaluated pp65-specific cellular responses following DI-TMZ with pp65-DCs and determined the effects on long-term progression-free survival (PFS) and overall survival (OS).Experimental Design: Following standard-of-care, 11 patients with newly diagnosed glioblastoma received DI-TMZ (100 mg/m2/d × 21 days per cycle) with at least three vaccines of pp65 lysosome-associated membrane glycoprotein mRNA-pulsed DCs admixed with GM-CSF on day 23 ± 1 of each cycle. Thereafter, monthly DI-TMZ cycles and pp65-DCs were continued if patients had not progressed.Results: Following DI-TMZ cycle 1 and three doses of pp65-DCs, pp65 cellular responses significantly increased. After DI-TMZ, both the proportion and proliferation of regulatory T cells (Tregs) increased and remained elevated with serial DI-TMZ cycles. Median PFS and OS were 25.3 months [95% confidence interval (CI), 11.0-∞] and 41.1 months (95% CI, 21.6-∞), exceeding survival using recursive partitioning analysis and matched historical controls. Four patients remained progression-free at 59 to 64 months from diagnosis. No known prognostic factors [age, Karnofsky performance status (KPS), IDH-1/2 mutation, and MGMT promoter methylation] predicted more favorable outcomes for the patients in this cohort.Conclusions: Despite increased Treg proportions following DI-TMZ, patients receiving pp65-DCs showed long-term PFS and OS, confirming prior studies targeting cytomegalovirus in glioblastoma. Clin Cancer Res; 23(8); 1898-909. ©2017 AACR.

Authors
Batich, KA; Reap, EA; Archer, GE; Sanchez-Perez, L; Nair, SK; Schmittling, RJ; Norberg, P; Xie, W; Herndon, JE; Healy, P; McLendon, RE; Friedman, AH; Friedman, HS; Bigner, D; Vlahovic, G; Mitchell, DA; Sampson, JH
MLA Citation
Batich, Kristen A., et al. “Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination..” Clin Cancer Res, vol. 23, no. 8, Apr. 2017, pp. 1898–909. Pubmed, doi:10.1158/1078-0432.CCR-16-2057.
PMID
28411277
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
23
Issue
8
Publish Date
2017
Start Page
1898
End Page
1909
DOI
10.1158/1078-0432.CCR-16-2057

A Phase II single-arm trial of palonosetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting in malignant glioma patients receiving multidose irinotecan in combination with bevacizumab.

PURPOSE: Given that the prognosis of recurrent malignant glioma (MG) remains poor, improving quality of life (QoL) through symptom management is important. Meta-analyses establishing antiemetic guidelines have demonstrated the superiority of palonosetron (PAL) over older 5-hydroxytryptamine 3-receptor antagonists in chemotherapy-induced nausea and vomiting (CINV) prevention, but excluded patients with gliomas. Irinotecan plus bevacizumab is a treatment frequently used in MG, but is associated with low (55%) CINV complete response (CR; no emesis or use of rescue antiemetic) with commonly prescribed ondansetron. A single-arm Phase II trial was conducted in MG patients to determine the efficacy of intravenous PAL (0.25 mg) and dexamethasone (DEX; 10 mg) received in conjunction with biweekly irinotecan-bevacizumab treatment. The primary end point was the proportion of subjects achieving acute CINV CR (no emesis or antiemetic ≤24 hours postchemotherapy). Secondary end points included delayed CINV CR (days 2-5), overall CINV CR (days 1-5), and QoL, fatigue, and toxicity. MATERIALS AND METHODS: A two-stage design of 160 patients was planned to differentiate between CINV CR of 55% and 65% after each dose of PAL-DEX. Validated surveys assessed fatigue and QoL. RESULTS: A total of 63 patients were enrolled, after which enrollment was terminated due to slow accrual; 52 patients were evaluable for the primary outcome of acute CINV CR. Following PAL-DEX dose administrations 1-3, acute CINV CR rates were 62%, 68%, and 70%; delayed CINV CR rates were 62%, 66%, and 70%, and overall CINV CR rates were 47%, 57%, and 62%, respectively. Compared to baseline, there was a clinically meaningful increase in fatigue during acute and overall phases, but not in the delayed phase. There were no grade ≥3 PAL-DEX treatment-related toxicities. CONCLUSION: Data suggest that PAL-DEX is effective in preventing CINV in MG patients, which ultimately maintains the QoL of patients with glioma.

Authors
Affronti, ML; Woodring, S; Peters, KB; Herndon, JE; McSherry, F; Healy, PN; Desjardins, A; Vredenburgh, JJ; Friedman, HS
MLA Citation
Affronti, Mary Lou, et al. “A Phase II single-arm trial of palonosetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting in malignant glioma patients receiving multidose irinotecan in combination with bevacizumab..” Ther Clin Risk Manag, vol. 13, 2017, pp. 33–40. Pubmed, doi:10.2147/TCRM.S122480.
PMID
28096679
Source
pubmed
Published In
Therapeutics and Clinical Risk Management
Volume
13
Publish Date
2017
Start Page
33
End Page
40
DOI
10.2147/TCRM.S122480

Long-Term Outcomes for Patients With Atypical or Malignant Meningiomas Treated With Radiation Therapy: A Single-Institution Retrospective Analysis.

Authors
Kent, CL; Mowery, YM; Wright, AO; Kim, GJ; Desjardins, A; Peters, KB; Vlahovic, G; Friedman, HS; Cummings, TJ; McLendon, RE; Friedman, AH; Sampson, JH; Kirkpatrick, JP
MLA Citation
Kent, C. L., et al. “Long-Term Outcomes for Patients With Atypical or Malignant Meningiomas Treated With Radiation Therapy: A Single-Institution Retrospective Analysis..” Int J Radiat Oncol Biol Phys, vol. 96, no. 2S, Oct. 2016, pp. E83–84. Pubmed, doi:10.1016/j.ijrobp.2016.06.802.
PMID
27675478
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
96
Issue
2S
Publish Date
2016
Start Page
E83
End Page
E84
DOI
10.1016/j.ijrobp.2016.06.802

Psychosocial distress and its effects on the health-related quality of life of primary brain tumor patients.

All cancer patients experience distress from the diagnosis, the effects of the disease or the treatment. Clinically significant distress decreases overall quality of life and the recognition of distress with prompt intervention is essential. The National Comprehensive Cancer Network distress thermometer (NCCN-DT) is a validated measuring tool that has been utilized in the primary brain tumor population to detect psychologic distress thereby provoking a referral process to the appropriate support system. Brain tumor patients commonly reported emotional and physical distress encompassing: fatigue, fears, memory and concentration and worry. More research is needed to identify the stressors of all primary brain tumor patients and their caretakers and integrate appropriate interventions to improve health-related quality of life in both groups.

Authors
Randazzo, D; Peters, KB
MLA Citation
Randazzo, Dina, and Katherine B. Peters. “Psychosocial distress and its effects on the health-related quality of life of primary brain tumor patients..” Cns Oncol, vol. 5, no. 4, 2016, pp. 241–49. Pubmed, doi:10.2217/cns-2016-0010.
PMID
27397796
Source
pubmed
Published In
Cns Oncology
Volume
5
Issue
4
Publish Date
2016
Start Page
241
End Page
249
DOI
10.2217/cns-2016-0010

Phase II study to evaluate the safety and efficacy of intravenous palonosetron (PAL) in primary malignant glioma (MG) patients receiving standard radiotherapy (RT) and concomitant temozolomide (TMZ).

BACKGROUND: In malignant glioma (MG) patients undergoing radiation therapy (RT) with concomitant temozolomide, chemoradiation-induced nausea and vomiting (cRINV) degrades quality of life (QoL) and reduces treatment adherence, which thereby potentially compromises cancer control. METHODS: We conducted a 6-week phase II single-arm trial of PAL, a second-generation 5-HT3RA antiemetic, for cRINV prevention in MG patients receiving radiation therapy (RT; 54-60 Gy) and concomitant daily temozolomide (TMZ; 75 mg/m(2)/dX42d). Each week before radiation, patients received single-dose palonosetron (PAL) 0.25 mg IV (total = 6 doses). With safety/tolerability as the primary endpoint, the study was designed to differentiate between toxicity rates of 25 % (unacceptable) and 10 % (acceptable) toxicity rates. Secondary endpoints included the percentage of patients achieving cRINV complete response (CR: no emesis or rescue antiemetic) and QoL. Patients reported adverse effects in Common Toxicity Criteria for Adverse Events diaries; recorded vomiting, nausea, and rescue medication use in diaries (which were used to assess cRINV-CR); and reported QoL 4 days/week using the Modified Functional Living Index-Emesis (M-FLIE) and Osoba nausea and vomiting/retching modules. RESULTS: We enrolled 38 patients (mean age 59 years, 55 % female, 95 % white, 68 % used oral corticosteroids, 76 % reported low alcohol use). Four patients (10.5 %) experienced unacceptable treatment-related toxicity, defined as any grade 3, 4, or 5 non-hematologic toxicity. M-FLIE and Osoba scores showed no evidence of treatment impact on QoL. Overall, cRINV-CR rates for 6 weeks ranged from 67-79 %. CONCLUSION: Single-dose weekly PAL is a safe and tolerable antiemetic for cRINV prevention in MG patients receiving standard RT and concomitant TMZ.

Authors
Affronti, ML; Woodring, S; Allen, K; Kirkpatrick, J; Peters, KB; Herndon, JE; McSherry, F; Healy, PN; Desjardins, A; Vredenburgh, JJ; Friedman, HS
MLA Citation
Affronti, Mary Lou, et al. “Phase II study to evaluate the safety and efficacy of intravenous palonosetron (PAL) in primary malignant glioma (MG) patients receiving standard radiotherapy (RT) and concomitant temozolomide (TMZ)..” Support Care Cancer, vol. 24, no. 10, 2016, pp. 4365–75. Pubmed, doi:10.1007/s00520-016-3276-1.
PMID
27271867
Source
pubmed
Published In
Support Care Cancer
Volume
24
Issue
10
Publish Date
2016
Start Page
4365
End Page
4375
DOI
10.1007/s00520-016-3276-1

Patient survival on the dose escalation phase of the Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG) clinical trial compared to historical controls.

Authors
Desjardins, A; Sampson, JH; Peters, KB; Vlahovic, G; Randazzo, D; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Lipp, ES; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, Annick, et al. “Patient survival on the dose escalation phase of the Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG) clinical trial compared to historical controls..” Journal of Clinical Oncology, vol. 34, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2016, pp. 2061–2061. Crossref, doi:10.1200/jco.2016.34.15_suppl.2061.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
15_suppl
Publish Date
2016
Start Page
2061
End Page
2061
DOI
10.1200/jco.2016.34.15_suppl.2061

Phase I trial of combination of antitumor immunotherapy targeted against cytomegalovirus (CMV) plus regulatory T-cell inhibition in patients with newly-diagnosed glioblastoma multiforme (GBM).

Authors
Vlahovic, G; Archer, GE; Reap, E; Desjardins, A; Peters, KB; Randazzo, D; Healy, P; Herndon, JE; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Vlahovic, Gordana, et al. “Phase I trial of combination of antitumor immunotherapy targeted against cytomegalovirus (CMV) plus regulatory T-cell inhibition in patients with newly-diagnosed glioblastoma multiforme (GBM)..” Journal of Clinical Oncology, vol. 34, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2016, pp. e13518–e13518. Crossref, doi:10.1200/jco.2016.34.15_suppl.e13518.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
15_suppl
Publish Date
2016
Start Page
e13518
End Page
e13518
DOI
10.1200/jco.2016.34.15_suppl.e13518

The Duke glioma handbook: Pathology, diagnosis, and management

© Cambridge University Press 2016. All rights reserved. The management of patients with a glioma is challenging and best achieved by a team approach encompassing a combination of chemotherapy, radiotherapy, immunotherapy, and surgical excision in a specialist Cancer Center - the balance of treatment depending on the site and grade of tumor. Survival rates are improving and care of patients with or recovering from gliomas is increasingly handled in the community under the care of local physicians. This book provides an authoritative, multi-disciplinary summary of glioma biology, genetics, management and social issues, based on the world-leading program at the Duke University Preston Robert Tisch Brain Tumor Center, one of the world's largest and most successful Centers to offer brain cancer treatment and translational research. The text is written by specialists from this Center, giving it a consistent approach and style. This is an important educational resource for neurologists, neurosurgeons, oncologists, psychiatrists, neurohospitalists and ancillary members of neuro-oncology teams.

Authors
Sampson, JH; Bigner, DD; Friedman, AH; Friedman, HS; McLendon, R
MLA Citation
Sampson, J. H., et al. The Duke glioma handbook: Pathology, diagnosis, and management. 2016, pp. 1–210. Scopus, doi:10.1017/CBO9781107588721.
Source
scopus
Publish Date
2016
Start Page
1
End Page
210
DOI
10.1017/CBO9781107588721

Chemotherapy for gliomas

Authors
Desjardins, A; Friedman, HS
MLA Citation
Desjardins, A., and H. S. Friedman. “Chemotherapy for gliomas.” The Duke Glioma Handbook: Pathology, Diagnosis, and Management, 2016, pp. 76–90. Scopus, doi:10.1017/CBO9781107588721.005.
Source
scopus
Publish Date
2016
Start Page
76
End Page
90
DOI
10.1017/CBO9781107588721.005

Vaccine Therapy, Oncolytic Viruses, and Gliomas.

After years of active research and refinement, vaccine therapy and oncolytic viruses are becoming part of the arsenal in the treatment of gliomas. In contrast to standard treatment with radiation therapy and chemotherapy, vaccines are more specific to the patient and the tumor. The majority of ongoing vaccine trials are investigating peptide, heat shock protein, and dendritic cell vaccines. The immunosuppression triggered by the tumor itself and by its treatment is a major obstacle to vaccine and oncolytic virus therapy. Thus, combination therapy with different agents that affect the immune system will probably be necessary.

Authors
Desjardins, A; Vlahovic, G; Friedman, HS
MLA Citation
Desjardins, Annick, et al. “Vaccine Therapy, Oncolytic Viruses, and Gliomas..” Oncology (Williston Park), vol. 30, no. 3, Mar. 2016, pp. 211–18.
PMID
26984213
Source
pubmed
Published In
Oncology (Williston Park, N.Y.)
Volume
30
Issue
3
Publish Date
2016
Start Page
211
End Page
218

Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells.

Under normal physiologic conditions, the glutathione S-transferase P1 (GSTP1) protein exists intracellularly as a dimer in reversible equilibrium with its monomeric subunits. In the latter form, GSTP1 binds to the mitogen-activated protein kinase, JNK, and inhibits JNK downstream signaling. In tumor cells, which frequently are characterized by constitutively high GSTP1 expression, GSTP1 undergoes phosphorylation by epidermal growth factor receptor (EGFR) at tyrosine residues 3, 7, and 198. Here we report on the effect of this EGFR-dependent GSTP1 tyrosine phosphorylation on the interaction of GSTP1 with JNK, on the regulation of JNK downstream signaling by GSTP1, and on tumor cell survival. Using in vitro and in vivo growing human brain tumors, we show that tyrosine phosphorylation shifts the GSTP1 dimer-monomer equilibrium to the monomeric state and facilitates the formation of the GSTP1-JNK complex, in which JNK is functionally inhibited. Targeted mutagenesis and functional analysis demonstrated that the increased GSTP1 binding to JNK results from phosphorylation of the GSTP1 C-terminal Tyr-198 by EGFR and is associated with a >2.5-fold decrease in JNK downstream signaling and a significant suppression of both spontaneous and drug-induced apoptosis in the tumor cells. The findings define a novel mechanism of regulatory control of JNK signaling that is mediated by the EGFR/GSTP1 cross-talk and provides a survival advantage for tumors with activated EGFR and high GSTP1 expression. The results lay the foundation for a novel strategy of dual EGFR/GSTP1 for treating EGFR+ve, GSTP1 expressing GBMs.

Authors
Okamura, T; Antoun, G; Keir, ST; Friedman, H; Bigner, DD; Ali-Osman, F
MLA Citation
Okamura, Tatsunori, et al. “Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells..” J Biol Chem, vol. 290, no. 52, Dec. 2015, pp. 30866–78. Pubmed, doi:10.1074/jbc.M115.656140.
PMID
26429914
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
290
Issue
52
Publish Date
2015
Start Page
30866
End Page
30878
DOI
10.1074/jbc.M115.656140

Outcomes for Patients With Intracranial Meningiomas Treated With Radiation therapy and Bevacizumab: A Single-Institution Retrospective Analysis

Authors
Mowery, YM; Kim, GJ; Wright, A; Desjardins, A; Peters, KB; Vlahovic, G; Friedman, HS; Sampson, JH; Kirkpatrick, JP
MLA Citation
Mowery, Y. M., et al. “Outcomes for Patients With Intracranial Meningiomas Treated With Radiation therapy and Bevacizumab: A Single-Institution Retrospective Analysis.” International Journal of Radiation Oncology*Biology*Physics, vol. 93, no. 3, Elsevier BV, 2015, pp. E104–E104. Crossref, doi:10.1016/j.ijrobp.2015.07.813.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
93
Issue
3
Publish Date
2015
Start Page
E104
End Page
E104
DOI
10.1016/j.ijrobp.2015.07.813

Identification and treatment data of xenografts representing TCGA-defined glioblastoma subtypes

Authors
Keir, ST; Rasheed, BA; Hoadley, KA; Roskoski, MA; Gasinski, D; Kwatra, MM; Friedman, HS; Bigner, DD
MLA Citation
Keir, Stephen T., et al. “Identification and treatment data of xenografts representing TCGA-defined glioblastoma subtypes.” Cancer Research, vol. 75, 2015. Wos-lite, doi:10.1158/1538-7445.AM2015-2435A.
Source
wos-lite
Published In
Cancer Research
Volume
75
Publish Date
2015
DOI
10.1158/1538-7445.AM2015-2435A

Phase II Trial of Upfront Bevacizumab, Irinotecan, and Temozolomide for Unresectable Glioblastoma.

LESSONS LEARNED: Trials focusing on unresectable multifocal glioblastoma are needed because of the extremely poor prognosis and challenges in receiving standard therapy, such as concurrent radiation and chemotherapy.Developing a strategy to chemically debulk tumors before radiation and/or surgery is warranted. BACKGROUND: Extent of resection remains a key prognostic factor in glioblastoma (GBM), with gross total resection providing a better prognosis than biopsy or subtotal resection. We conducted a phase II trial of upfront therapy with bevacizumab (BV), irinotecan (CPT-11), and temozolomide (TMZ) prior to chemoradiation in patients with unresectable, subtotally resected, and/or multifocal GBM. METHODS: Patients received up to 4 cycles of TMZ at 200 mg/m(2) per day on days 1-5 (standard dosing) and BV at 10 mg/kg every 2 weeks on a 28-day cycle. CPT-11 was given every 2 weeks on a 28-day cycle at 125 mg/m(2) or 340 mg/m(2) depending on antiepileptic drugs. Magnetic resonance imaging of the brain was done every 4 weeks, and treatment continued as long as there was no tumor progression or unmanageable toxicity. The primary endpoint was tumor response rate, with a goal of 26% or greater. RESULTS: Forty-one patients were enrolled from December 2009 to November 2010. Radiographic responses were as follows: 9 patients (22.0%) had partial response, 25 (61.0%) had stable disease, and 2 (4.9%) had progression; 5 patients were not assessed. Cumulative response rate was 22%. Median overall survival was 12 months (95% confidence interval: 7.2-13.5 months). CONCLUSION: Upfront treatment with BV, TMZ, and CPT-11 is tolerable and can lead to radiographic response in unresectable and/or subtotally resected GBM.

Authors
Peters, KB; Lou, E; Desjardins, A; Reardon, DA; Lipp, ES; Miller, E; Herndon, JE; McSherry, F; Friedman, HS; Vredenburgh, JJ
MLA Citation
Peters, Katherine B., et al. “Phase II Trial of Upfront Bevacizumab, Irinotecan, and Temozolomide for Unresectable Glioblastoma..” Oncologist, vol. 20, no. 7, July 2015, pp. 727–28. Pubmed, doi:10.1634/theoncologist.2015-0135.
PMID
26025933
Source
pubmed
Published In
Oncologist
Volume
20
Issue
7
Publish Date
2015
Start Page
727
End Page
728
DOI
10.1634/theoncologist.2015-0135

Secondary cancers in long-term survivors of primary glioblastoma.

Authors
Kim, J-Y; Woodring, S; Affronti, ML; Randazzo, D; McSherry, F; Herndon, JE; Lipp, ES; Desjardins, A; Vlahovic, G; Friedman, HS; Peters, KB
MLA Citation
Kim, Jung-Young, et al. “Secondary cancers in long-term survivors of primary glioblastoma..” Journal of Clinical Oncology, vol. 33, no. 15, AMER SOC CLINICAL ONCOLOGY, 2015.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Phase II study of bevacizumab and vorinostat for recurrent glioblastoma.

Authors
Ghiaseddin, A; Reardon, DA; Massey, W; Mannerino, A; Lipp, ES; Herndon, JE; McSherry, F; Desjardins, A; Randazzo, DM; Vlahovic, G; Friedman, HS; Peters, KB
MLA Citation
Ghiaseddin, Ashley, et al. “Phase II study of bevacizumab and vorinostat for recurrent glioblastoma..” Journal of Clinical Oncology, vol. 33, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2015, pp. 2034–2034. Crossref, doi:10.1200/jco.2015.33.15_suppl.2034.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15_suppl
Publish Date
2015
Start Page
2034
End Page
2034
DOI
10.1200/jco.2015.33.15_suppl.2034

Phase I study of combination of antitumor immunotherapy targeted against cytomegalovirus (CMV) plus regulatory T-cell inhibition in patients with newly diagnosed glioblastoma multiforme (GBM).

Authors
Vlahovic, G; Archer, GE; Lally-Goss, D; Reap, E; Desjardins, A; Peters, KB; Randazzo, D; Healy, P; Herndon, JE; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Vlahovic, Gordana, et al. “Phase I study of combination of antitumor immunotherapy targeted against cytomegalovirus (CMV) plus regulatory T-cell inhibition in patients with newly diagnosed glioblastoma multiforme (GBM)..” Journal of Clinical Oncology, vol. 33, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2015, pp. e13030–e13030. Crossref, doi:10.1200/jco.2015.33.15_suppl.e13030.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15_suppl
Publish Date
2015
Start Page
e13030
End Page
e13030
DOI
10.1200/jco.2015.33.15_suppl.e13030

Oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma (GBM): Optimal dose determination.

Authors
Desjardins, A; Sampson, JH; Peters, KB; Vlahovic, G; Randazzo, D; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Lipp, ES; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, Annick, et al. “Oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma (GBM): Optimal dose determination..” Journal of Clinical Oncology, vol. 33, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2015, pp. 2068–2068. Crossref, doi:10.1200/jco.2015.33.15_suppl.2068.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15_suppl
Publish Date
2015
Start Page
2068
End Page
2068
DOI
10.1200/jco.2015.33.15_suppl.2068

Carboxyamidotriazole orotate (CTO) in combination with bevacizumab (BEV) for adult patients with recurrent malignant glioma post-BEV failure: Phase 1.

Authors
Desjardins, A; Peters, KB; Vlahovic, G; Randazzo, D; Boulton, S; Massey, WC; Lipp, ES; Herndon, JE; Healy, P; Miller, E; Karmali, RA; Friedman, HS
MLA Citation
Desjardins, Annick, et al. “Carboxyamidotriazole orotate (CTO) in combination with bevacizumab (BEV) for adult patients with recurrent malignant glioma post-BEV failure: Phase 1..” Journal of Clinical Oncology, vol. 33, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2015, pp. 2067–2067. Crossref, doi:10.1200/jco.2015.33.15_suppl.2067.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15_suppl
Publish Date
2015
Start Page
2067
End Page
2067
DOI
10.1200/jco.2015.33.15_suppl.2067

Phase 1 clinical trial of carboxyamidotriazole orotate (CTO) in combination with lomustine (CCNU) for adult patients with recurrent malignant glioma (MG).

Authors
Friedman, HS; Peters, KB; Vlahovic, G; Randazzo, D; Boulton, S; Woodring, S; Lipp, ES; Herndon, JE; Healy, P; Miller, E; Karmali, RA; Desjardins, A
MLA Citation
Friedman, Henry S., et al. “Phase 1 clinical trial of carboxyamidotriazole orotate (CTO) in combination with lomustine (CCNU) for adult patients with recurrent malignant glioma (MG)..” Journal of Clinical Oncology, vol. 33, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2015, pp. e13004–e13004. Crossref, doi:10.1200/jco.2015.33.15_suppl.e13004.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
33
Issue
15_suppl
Publish Date
2015
Start Page
e13004
End Page
e13004
DOI
10.1200/jco.2015.33.15_suppl.e13004

Severe adverse immunologic reaction in a patient with glioblastoma receiving autologous dendritic cell vaccines combined with GM-CSF and dose-intensified temozolomide.

Therapeutic vaccination of patients with cancer-targeting tumor-associated antigens is a promising strategy for the specific eradication of invasive malignancies with minimal toxicity to normal tissues. However, as increasingly potent modalities for stimulating immunologic responses are developed for clinical evaluation, the risk of inflammatory and autoimmune toxicities also may be exacerbated. In this report, we describe the induction of a severe (grade 3) immunologic reaction in a patient with newly diagnosed glioblastoma (GBM) receiving autologous RNA-pulsed dendritic cell (DC) vaccines admixed with GM-CSF and administered coordinately with cycles of dose-intensified temozolomide. Shortly after the eighth administration of the admixed intradermal vaccine, the patient experienced dizziness, flushing, conjunctivitis, headache, and the outbreak of a disseminated macular/papular rash and bilateral indurated injection sites. Immunologic workup of patient reactivity revealed sensitization to the GM-CSF component of the vaccine and the production of high levels of anti-GM-CSF autoantibodies during vaccination. Removal of GM-CSF from the DC vaccine allowed continued vaccination without incident. Despite the known lymphodepletive and immunosuppressive effects of temozolomide, these observations demonstrate the capacity for the generation of severe immunologic reactivity in patients with GBM receiving DC-based therapy during adjuvant dose-intensified temozolomide.

Authors
Mitchell, DA; Sayour, EJ; Reap, E; Schmittling, R; DeLeon, G; Norberg, P; Desjardins, A; Friedman, AH; Friedman, HS; Archer, G; Sampson, JH
MLA Citation
Mitchell, Duane A., et al. “Severe adverse immunologic reaction in a patient with glioblastoma receiving autologous dendritic cell vaccines combined with GM-CSF and dose-intensified temozolomide..” Cancer Immunol Res, vol. 3, no. 4, Apr. 2015, pp. 320–25. Pubmed, doi:10.1158/2326-6066.CIR-14-0100.
PMID
25387895
Source
pubmed
Published In
Cancer Immunol Res
Volume
3
Issue
4
Publish Date
2015
Start Page
320
End Page
325
DOI
10.1158/2326-6066.CIR-14-0100

Prognostic marker analysis in pediatric intracranial ependymomas.

Histologic grading methods dependent upon H&E staining review have not been shown to reliably predict survival in children with intracranial ependymomas due to the subjectivity of the analytical methods. We hypothesized that the immunohistochemical detection of MIB-1, Tenascin C, CD34, VEGF, and CA IX may represent objective markers of post-operative survival (Progression Free and Overall Survival; PFS, OS) in these patients. Intracranial ependymomas from patients aged 22 years or less were studied. The original histologic grade was recorded, H&E sections were reviewed for vascular proliferation status, and immunohistochemistry was used to determine MIB-1, Tenascin C, CD34, VEGF, and CA IX status. Based upon the World Health Organization (WHO) grading system, 3 Grade I, 18 Grade II and 9 Grade III ependymomas were studied. Median follow-up time was 9.0 years; median PFS was, 6.1 years. Original WHO grade did not correlate with PFS or OS. Peri-necrotic CA IX localization correlated with PFS (Log rank = 0.0181) and OS (Log rank p = 0.0015). All patients with a CA IX ≤ 5 % total area localization were alive at last follow-up. Perinecrotic CA IX staining was also associated with vascular proliferation (p = 0.006), though not with VEGF expression score. MIB-1 labeling index (LI) correlated with OS (HR 1.06, 95 % CI 1.01, 1.12) and PFS (HR 1.08, 95 % CI 1.02, 1.14). MIB-1 LI and perinecrotic CA IX individually correlated with PFS. The effect of perinecrotic CA IX remained when grade was added to a Cox model predicting PFS. Immunodetection of CA IX and MIB-1 expression are predictive biomarkers for survival in children with posterior fossa ependymomas. These markers represent objective indicators of survival that supplement H&E grading alone.

Authors
McLendon, RE; Lipp, E; Satterfield, D; Ehinger, M; Austin, A; Fleming, D; Perkinson, K; Lefaivre, M; Zagzag, D; Wiener, B; Gururangan, S; Fuchs, H; Friedman, HS; Herndon, JE; Healy, P
MLA Citation
McLendon, Roger E., et al. “Prognostic marker analysis in pediatric intracranial ependymomas..” J Neurooncol, vol. 122, no. 2, Apr. 2015, pp. 255–61. Pubmed, doi:10.1007/s11060-014-1711-z.
PMID
25563815
Source
pubmed
Published In
J Neurooncol
Volume
122
Issue
2
Publish Date
2015
Start Page
255
End Page
261
DOI
10.1007/s11060-014-1711-z

Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.

After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

Authors
Mitchell, DA; Batich, KA; Gunn, MD; Huang, M-N; Sanchez-Perez, L; Nair, SK; Congdon, KL; Reap, EA; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; Coan, A; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, Duane A., et al. “Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients..” Nature, vol. 519, no. 7543, Mar. 2015, pp. 366–69. Pubmed, doi:10.1038/nature14320.
Website
http://hdl.handle.net/10161/16099
PMID
25762141
Source
pubmed
Published In
Nature
Volume
519
Issue
7543
Publish Date
2015
Start Page
366
End Page
369
DOI
10.1038/nature14320

Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas.

Adoptive cellular therapy (ACT) after lymphodepletive conditioning can induce dramatic clinical responses, but this approach has been largely limited to melanoma due to a lack of reliable methods for expanding tumor-specific lymphocytes from the majority of other solid cancers. We have employed tumor RNA-pulsed dendritic cells (DCs) to reliably expand CD4+ and CD8+ tumor-reactive T lymphocytes for curative ACT in a highly-invasive, chemotherapy- and radiation-resistant malignant glioma model. Curative treatment of established intracranial tumors involved a synergistic interaction between myeloablative (MA) conditioning, adoptively transferred tumor-specific T cells, and tumor RNA-pulsed DC vaccines. Hematopoietic stem cells (HSCs), administered for salvage from MA conditioning, rapidly migrated to areas of intracranial tumor growth and facilitated the recruitment of tumor-specific lymphocytes through HSC-elaborated chemokines and enhanced immunologic rejection of intracranial tumors during ACT. Furthermore, HSC transplant under non-myeloablative (NMA) conditions also enhanced immunologic tumor rejection, indicating a novel role for the use of HSCs in the immunologic treatment of malignant gliomas and possibly other solid tumors.

Authors
Flores, C; Pham, C; Snyder, D; Yang, S; Sanchez-Perez, L; Sayour, E; Cui, X; Kemeny, H; Friedman, H; Bigner, DD; Sampson, J; Mitchell, DA
MLA Citation
Flores, Catherine, et al. “Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas..” Oncoimmunology, vol. 4, no. 3, Mar. 2015. Pubmed, doi:10.4161/2162402X.2014.994374.
PMID
25949916
Source
pubmed
Published In
Oncoimmunology
Volume
4
Issue
3
Publish Date
2015
Start Page
e994374
DOI
10.4161/2162402X.2014.994374

Impact of health-related quality of life and fatigue on survival of recurrent high-grade glioma patients.

Quality of life (QoL) impairment and fatigue are frequently experienced during treatment for recurrent high-grade glioma (HGG). Fatigue and QoL impairments can be due to primary neurological dysfunction, cytotoxic treatments, mood disturbances, and supportive medications. We now seek to understand how QoL and fatigue impacts survival in recurrent HGG. Using a prospective observational design, 237 patients with recurrent HGG and KPS ≥70 completed a self-administered questionnaire that evaluated QoL and fatigue. QoL was assessed with Functional Assessment of Cancer Therapy-General (FACT-G) and FACT-Brain (FACT-Br) scales while fatigue was assessed using Functional Assessment of Chronic Illness Therapy (FACIT-F) scale. Cox proportional hazard models were utilized to evaluate the association between QoL and fatigue and survival. Seventy-three (31 %) subjects had recurrent WHO grade III gliomas and 164 (69 %) had recurrent WHO grade IV gliomas. Median follow-up analysis was 27.60 months. In univariate Cox analyses, the FACT-Br specific subscale (HR 0.88; CI 95 %, 0.77-1; p = 0.048) and FACIT-F (HR 0.82; CI 95 %, 0.68-0.99; p = 0.045) were both significant predictors of survival. Fatigue added prognostic information beyond that provided by KPS, age, sex, tumor grade, and number of prior progressions (HR 0.80; CI 95 %, 0.68-0.9; p = 0.031). A greater degree of fatigue was associated with poorer survival in recurrent HGG patients. In multivariable analyses, FACT-G and FACT-Br are not independent predictors of prognosis. Fatigue is a strong independent predictor of survival that provides incremental prognostic value to the traditional markers of prognosis in recurrent HGG. Pharmacological or non-pharmacological strategies to treat fatigue warrant investigation.

Authors
Peters, KB; West, MJ; Hornsby, WE; Waner, E; Coan, AD; McSherry, F; Herndon, JE; Friedman, HS; Desjardins, A; Jones, LW
MLA Citation
Peters, Katherine B., et al. “Impact of health-related quality of life and fatigue on survival of recurrent high-grade glioma patients..” J Neurooncol, vol. 120, no. 3, Dec. 2014, pp. 499–506. Pubmed, doi:10.1007/s11060-014-1574-3.
PMID
25115739
Source
pubmed
Published In
J Neurooncol
Volume
120
Issue
3
Publish Date
2014
Start Page
499
End Page
506
DOI
10.1007/s11060-014-1574-3

Profiling Hsp90 differential expression and the molecular effects of the Hsp90 inhibitor IPI-504 in high-grade glioma models.

Retaspimycin hydrochloride (IPI-504), an Hsp90 (heat shock protein 90) inhibitor, has shown activity in multiple preclinical cancer models, such as lung, breast and ovarian cancers. However, its biological effects in gliomas and normal brain derived cellular populations remain unknown. In this study, we profiled the expression pattern of Hsp90α/β mRNA in stable glioma cell lines, multiple glioma-derived primary cultures and human neural stem/progenitor cells. The effects of IPI-504 on cell proliferation, apoptosis, motility and expression of Hsp90 client proteins were evaluated in glioma cell lines. In vivo activity of IPI-504 was investigated in subcutaneous glioma xenografts. Our results showed Hsp90α and Hsp90β expression levels to be patient-specific, higher in high-grade glioma-derived primary cells than in low-grade glioma-derived primary cells, and strongly correlated with CD133 expression and differentiation status of cells. Hsp90 inhibition by IPI-504 induced apoptosis, blocked migration and invasion, and significantly decreased epidermal growth factor receptor levels, mitogen-activated protein kinase and/or Akt activities, and secretion of vascular endothelial growth factor in glioma cell lines. In vivo study showed that IPI-504 could mildly attenuate tumor growth in immunocompromised mice. These findings suggest that targeting Hsp90 by IPI-504 has the potential to become an active therapeutic strategy in gliomas in a selective group of patients, but further research into combination therapies is still needed.

Authors
Di, K; Keir, ST; Alexandru-Abrams, D; Gong, X; Nguyen, H; Friedman, HS; Bota, DA
MLA Citation
Di, Kaijun, et al. “Profiling Hsp90 differential expression and the molecular effects of the Hsp90 inhibitor IPI-504 in high-grade glioma models..” J Neurooncol, vol. 120, no. 3, Dec. 2014, pp. 473–81. Pubmed, doi:10.1007/s11060-014-1579-y.
PMID
25115740
Source
pubmed
Published In
J Neurooncol
Volume
120
Issue
3
Publish Date
2014
Start Page
473
End Page
481
DOI
10.1007/s11060-014-1579-y

Oncolytic polio virotherapy of cancer.

Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct tumor cytotoxicity (oncolytic virotherapy), recently, the proinflammatory and immunogenic effects of viral tumor infection (oncolytic immunotherapy) have come into focus. Indeed, a capacity for eliciting broad, sustained antineoplastic effects stemming from combined direct viral cytotoxicity, innate antiviral activation, stromal proinflammatory stimulation, and recruitment of adaptive immune effector responses is the greatest asset of oncolytic viruses. However, it also is the source for enormous mechanistic complexity that must be considered for successful clinical translation. Because of fundamentally different relationships with their hosts (malignant or not), diverse replication strategies, and distinct modes of tumor cytotoxicity/killing, oncolytic viruses should not be referred to collectively. These agents must be evaluated based on their individual merits. In this review, the authors highlight key mechanistic principles of cancer treatment with the polio:rhinovirus chimera PVSRIPO and their implications for oncolytic immunotherapy in the clinic.

Authors
Brown, MC; Dobrikova, EY; Dobrikov, MI; Walton, RW; Gemberling, SL; Nair, SK; Desjardins, A; Sampson, JH; Friedman, HS; Friedman, AH; Tyler, DS; Bigner, DD; Gromeier, M
MLA Citation
Brown, Michael C., et al. “Oncolytic polio virotherapy of cancer..” Cancer, vol. 120, no. 21, Nov. 2014, pp. 3277–86. Pubmed, doi:10.1002/cncr.28862.
PMID
24939611
Source
pubmed
Published In
Cancer
Volume
120
Issue
21
Publish Date
2014
Start Page
3277
End Page
3286
DOI
10.1002/cncr.28862

Intratumoral administration of an Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) in recurrent glioblastoma(GBM): Preliminary results of the Phase I clinical trial

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Friedman, A; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, Annick, et al. “Intratumoral administration of an Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) in recurrent glioblastoma(GBM): Preliminary results of the Phase I clinical trial.” Cancer Research, vol. 74, no. 19, 2014. Wos-lite, doi:10.1158/1538-7445.AM2014-CT416.
Source
wos-lite
Published In
Cancer Research
Volume
74
Issue
19
Publish Date
2014
DOI
10.1158/1538-7445.AM2014-CT416

Establishment, identification and treatment data of TCGA glioblatoma xenograft subtypes

Authors
Keir, ST; Rasheed, BA; Hoadley, KA; Roskoski, MA; Gasinski, D; Killela, PJ; Yan, H; Kwatra, MM; Friedman, HS; Bigner, DD
MLA Citation
Keir, Stephen T., et al. “Establishment, identification and treatment data of TCGA glioblatoma xenograft subtypes.” Cancer Research, vol. 74, no. 19, 2014. Wos-lite, doi:10.1158/1538-7445.AM2014-838.
Source
wos-lite
Published In
Cancer Research
Volume
74
Issue
19
Publish Date
2014
DOI
10.1158/1538-7445.AM2014-838

Adherence to antiemetic guidelines in patients with malignant glioma: a quality improvement project to translate evidence into practice.

PURPOSE: A quality improvement project was implemented to improve adherence to evidence-based antiemetic guidelines for malignant glioma patients treated with moderately emetic chemotherapy (MEC). Poorly controlled chemotherapy-induced nausea and vomiting (CINV) reduce cancer treatment efficacy and significantly impair cancer patients' quality of life (QOL). A review of Duke University Preston Robert Tisch Brain Tumor Center (PRTBTC)'s usual practice demonstrates a high incidence (45%) of CINV, despite premedication with short-acting 5-HT3-serotonin-receptor antagonists (5-HT3-RAs). National Comprehensive Cancer Network (NCCN)'s evidence-based guidelines recommend the combination of the long-acting 5-HT3-RA palonosetron (PAL) and dexamethasone (DEX) for the prevention of acute and delayed CINV with MEC. Low adherence (58%) to antiemetic guidelines may have explained our high CINV incidence. METHODS: One-sample binomial test, quasi-experimental design, evaluated a combination intervention that included a provider education session; implementation of risk-assessment tool with computerized, standardized antiemetic guideline order sets; and a monthly audit-feedback strategy. Post-implementation adherence to evidence-based antiemetic order sets and patient outcomes were measured and compared to baseline and historical data. Primary outcome was the guideline order set adherence rate. Secondary outcomes included nausea/vomiting rates and QOL. RESULTS: Adherence to ordering MEC guideline antiemetics increased significantly, from 58% to a sustained 90%, with associated improvement in nausea/vomiting. In acute and delayed phases, 75 and 84% of patients, respectively, did not experience CINV. There was no significant change in QOL. CONCLUSION: Combination intervention and audit-feedback strategy to translate evidence into oncology practice improved and sustained adherence to antiemetic guidelines. Adherence corresponded with effective nausea/vomiting control and preserved QOL in patients with malignant gliomas.

Authors
Affronti, ML; Schneider, SM; Herndon, JE; Schlundt, S; Friedman, HS
MLA Citation
Affronti, Mary Lou, et al. “Adherence to antiemetic guidelines in patients with malignant glioma: a quality improvement project to translate evidence into practice..” Support Care Cancer, vol. 22, no. 7, July 2014, pp. 1897–905. Pubmed, doi:10.1007/s00520-014-2136-0.
PMID
24570103
Source
pubmed
Published In
Support Care Cancer
Volume
22
Issue
7
Publish Date
2014
Start Page
1897
End Page
1905
DOI
10.1007/s00520-014-2136-0

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.

Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.

Authors
Zhang, L; Chen, LH; Wan, H; Yang, R; Wang, Z; Feng, J; Yang, S; Jones, S; Wang, S; Zhou, W; Zhu, H; Killela, PJ; Zhang, J; Wu, Z; Li, G; Hao, S; Wang, Y; Webb, JB; Friedman, HS; Friedman, AH; McLendon, RE; He, Y; Reitman, ZJ; Bigner, DD; Yan, H
MLA Citation
Zhang, Liwei, et al. “Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas..” Nat Genet, vol. 46, no. 7, July 2014, pp. 726–30. Pubmed, doi:10.1038/ng.2995.
PMID
24880341
Source
pubmed
Published In
Nat Genet
Volume
46
Issue
7
Publish Date
2014
Start Page
726
End Page
730
DOI
10.1038/ng.2995

Oncolytic polio/rhinovirus recombinant (pvsripo) in recurrent glioblastoma (gbm): first phase I clinical trial evaluating the intratumoral administration.

PVSRIPO is the live attenuated, oral (SABIN) serotype 1 poliovirus vaccine containing a heterologous internal ribosomal entry site stemming from human rhinovirus type 2. PVSRIPO recognizes nectin-like molecule-5, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. Within, we report on the ongoing phase I study evaluating the intratumoral convection-enhanced delivery (CED) of PVSRIPO.

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, A., et al. “Oncolytic polio/rhinovirus recombinant (pvsripo) in recurrent glioblastoma (gbm): first phase I clinical trial evaluating the intratumoral administration..” Neuro Oncol, vol. 16 Suppl 3, July 2014. Pubmed, doi:10.1093/neuonc/nou209.5.
PMID
25165331
Source
pubmed
Published In
Neuro Oncol
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii43
DOI
10.1093/neuonc/nou209.5

Identification and preliminary treatment data of xenografts representing tcga-defined subtypes.

The Cancer Genome Atlas (TCGA) Network recently catalogued recurrent genomic abnormalities in glioblastoma (GBM). This genomic profiling lead to the molecular classification of GBMs into four subtypes: Proneural, Neural, Classical and Mesenchymal. The importance of identifying these subtypes stands to help researchers and clinicians to better understand GBMs with the potential to personalize treatment options and explore different therapeutic approaches that each subtype may require. As such, the development of preclinical xenograft models that represent each TCGA subtype serves to expedite the evaluation of targeted therapeutic strategies for the treatment of GBMs.

Authors
Keir, ST; Roskoski, MA; Gasinski, D; Kwatra, MK; Friedman, HS; Bigner, DD
MLA Citation
Keir, S. T., et al. “Identification and preliminary treatment data of xenografts representing tcga-defined subtypes..” Neuro Oncol, vol. 16 Suppl 3, July 2014. Pubmed, doi:10.1093/neuonc/nou208.45.
PMID
25165298
Source
pubmed
Published In
Neuro Oncol
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii35
DOI
10.1093/neuonc/nou208.45

Phase I study of the intratumoral administration of an oncolytic polio/rhinovirus recombinant (PVSRIPO) in recurrent glioblastoma (GBM).

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Watts, J; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, Annick, et al. “Phase I study of the intratumoral administration of an oncolytic polio/rhinovirus recombinant (PVSRIPO) in recurrent glioblastoma (GBM)..” Journal of Clinical Oncology, vol. 32, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2014, pp. TPS2106–TPS2106. Crossref, doi:10.1200/jco.2014.32.15_suppl.tps2106.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15_suppl
Publish Date
2014
Start Page
TPS2106
End Page
TPS2106
DOI
10.1200/jco.2014.32.15_suppl.tps2106

Long-term survivorship in adult primary glioblastoma: Clinical and neurological outcomes of a large, single-center study.

Authors
Peters, KB; Woodring, S; Affronti, ML; McSherry, F; Herndon, JE; Desjardins, A; Ranjan, T; Vlahovic, G; Friedman, AH; Friedman, HS
MLA Citation
Peters, Katherine B., et al. “Long-term survivorship in adult primary glioblastoma: Clinical and neurological outcomes of a large, single-center study..” Journal of Clinical Oncology, vol. 32, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2014, pp. 9519–9519. Crossref, doi:10.1200/jco.2014.32.15_suppl.9519.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15_suppl
Publish Date
2014
Start Page
9519
End Page
9519
DOI
10.1200/jco.2014.32.15_suppl.9519

Regulatory T-cell inhibition plus antitumor immunotherapy targeted against cytomegalovirus (CMV) in patients with newly diagnosed glioblastoma multiforme (GBM).

Authors
Vlahovic, G; Archer, GE; Lally-Goss, D; Norman, S; Desjardins, A; Peters, KB; Ranjan, T; Watts, J; Healy, P; Herndon, JE; Friedman, HS; Friedman, AH; Bigner, DD; Sampson, JH
MLA Citation
Vlahovic, Gordana, et al. “Regulatory T-cell inhibition plus antitumor immunotherapy targeted against cytomegalovirus (CMV) in patients with newly diagnosed glioblastoma multiforme (GBM)..” Journal of Clinical Oncology, vol. 32, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2014, pp. 3069–3069. Crossref, doi:10.1200/jco.2014.32.15_suppl.3069.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15_suppl
Publish Date
2014
Start Page
3069
End Page
3069
DOI
10.1200/jco.2014.32.15_suppl.3069

Single-institution retrospective review of newly diagnosed glioblastoma (GBM) patients (pts) treated on bevacizumab (BEV) in clinical practice.

Authors
Friedman, HS; Herndon, JE; McSherry, F; Ravelo, A; Lipp, ES; Healy, P; Peters, KB; Ranjan, T; Vlahovic, G; Watts, J; Sampson, JH; Friedman, AH; Desjardins, A
MLA Citation
Friedman, Henry S., et al. “Single-institution retrospective review of newly diagnosed glioblastoma (GBM) patients (pts) treated on bevacizumab (BEV) in clinical practice..” Journal of Clinical Oncology, vol. 32, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2014, pp. 2082–2082. Crossref, doi:10.1200/jco.2014.32.15_suppl.2082.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15_suppl
Publish Date
2014
Start Page
2082
End Page
2082
DOI
10.1200/jco.2014.32.15_suppl.2082

Randomized phase IIb study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) alone or in combination with ipilimumab versus bevacizumab in patients (pts) with recurrent glioblastoma (GBM).

Authors
Sampson, JH; Vlahovic, G; Desjardins, A; Friedman, HS; Baehring, JM; Hafler, D; Rollin, L; Coric, V; Perez, SN; Reardon, DA
MLA Citation
Sampson, John Howard, et al. “Randomized phase IIb study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) alone or in combination with ipilimumab versus bevacizumab in patients (pts) with recurrent glioblastoma (GBM)..” Journal of Clinical Oncology, vol. 32, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2014, pp. TPS2101–TPS2101. Crossref, doi:10.1200/jco.2014.32.15_suppl.tps2101.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
32
Issue
15_suppl
Publish Date
2014
Start Page
TPS2101
End Page
TPS2101
DOI
10.1200/jco.2014.32.15_suppl.tps2101

Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas.

Frequent mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and the promoter of telomerase reverse transcriptase (TERT) represent two significant discoveries in glioma genomics. Understanding the degree to which these two mutations co-occur or occur exclusively of one another in glioma subtypes presents a unique opportunity to guide glioma classification and prognosis. We analyzed the relationship between overall survival (OS) and the presence of IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas. We hypothesized and show that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of cases. Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS (11.5 months). Patients whose Grade III-IV gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months. Analyzing gliomas based on their genetic signatures allows for the stratification of these patients into distinct cohorts, with unique prognosis and survival.

Authors
Killela, PJ; Pirozzi, CJ; Healy, P; Reitman, ZJ; Lipp, E; Rasheed, BA; Yang, R; Diplas, BH; Wang, Z; Greer, PK; Zhu, H; Wang, CY; Carpenter, AB; Friedman, H; Friedman, AH; Keir, ST; He, J; He, Y; McLendon, RE; Herndon, JE; Yan, H; Bigner, DD
MLA Citation
Killela, Patrick J., et al. “Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas..” Oncotarget, vol. 5, no. 6, Mar. 2014, pp. 1515–25. Pubmed, doi:10.18632/oncotarget.1765.
Website
http://hdl.handle.net/10161/16105
PMID
24722048
Source
pubmed
Published In
Oncotarget
Volume
5
Issue
6
Publish Date
2014
Start Page
1515
End Page
1525
DOI
10.18632/oncotarget.1765

The genetic landscape of anaplastic astrocytoma.

Anaplastic astrocytoma WHO grade III (A3) is a lethal brain tumor that often occurs in middle aged patients. Clinically, it is challenging to distinguish A3 from glioblastoma multiforme (GBM) WHO grade IV. To reveal the genetic landscape of this tumor type, we sequenced the exome of a cohort of A3s (n=16). For comparison and to illuminate the genomic landscape of other glioma subtypes, we also included in our study diffuse astrocytoma WHO grade II (A2, n=7), oligoastrocytoma WHO grade II (OA2, n=2), anaplastic oligoastrocytoma WHO grade III (OA3, n=4), and GBM (n=28). Exome sequencing of A3s identified frequent mutations in IDH1 (75%, 12/16), ATRX (63%, 10/16), and TP53 (82%, 13/16). In contrast, the majority of GBMs (75%, 21/28) did not contain IDH1 or ATRX mutations, and displayed a distinct spectrum of mutations. Finally, our study also identified novel genes that were not previously linked to this tumor type. In particular, we found mutations in Notch pathway genes (NOTCH1, NOTCH2, NOTCH4, NOTCH2NL), including a recurrent NOTCH1-A465Tmutation, in 31% (5/16) of A3s. This study suggests genetic signatures will be useful for the classification of gliomas.

Authors
Killela, PJ; Pirozzi, CJ; Reitman, ZJ; Jones, S; Rasheed, BA; Lipp, E; Friedman, H; Friedman, AH; He, Y; McLendon, RE; Bigner, DD; Yan, H
MLA Citation
Killela, Patrick J., et al. “The genetic landscape of anaplastic astrocytoma..” Oncotarget, vol. 5, no. 6, Mar. 2014, pp. 1452–57. Pubmed, doi:10.18632/oncotarget.1505.
PMID
24140581
Source
pubmed
Published In
Oncotarget
Volume
5
Issue
6
Publish Date
2014
Start Page
1452
End Page
1457
DOI
10.18632/oncotarget.1505

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas

Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.© 2014 Nature America, Inc. All rights reserved.

Authors
Zhang, L; Chen, LH; Wan, H; Yang, R; Wang, Z; Feng, J; Yang, S; Jones, S; Wang, S; Zhou, W; Zhu, H; Killela, PJ; Zhang, J; Wu, Z; Li, G; Hao, S; Wang, Y; Webb, JB; Friedman, HS; Friedman, AH; McLendon, RE; He, Y; Reitman, ZJ; Bigner, DD; Yan, H
MLA Citation
Zhang, L., et al. “Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.” Nature Genetics, vol. 46, no. 7, Jan. 2014, pp. 726–30. Scopus, doi:10.1038/ng.2995.
Source
scopus
Published In
Nature Genetics
Volume
46
Issue
7
Publish Date
2014
Start Page
726
End Page
730
DOI
10.1038/ng.2995

Bevacizumab therapy for glioblastoma: a passionate discussion.

Authors
Desjardins, A; Friedman, HS
MLA Citation
Desjardins, Annick, and Henry S. Friedman. “Bevacizumab therapy for glioblastoma: a passionate discussion..” Cns Oncol, vol. 3, no. 1, Jan. 2014, pp. 1–3. Pubmed, doi:10.2217/cns.13.53.
PMID
25054891
Source
pubmed
Published In
Cns Oncology
Volume
3
Issue
1
Publish Date
2014
Start Page
1
End Page
3
DOI
10.2217/cns.13.53

Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas--a Pediatric Brain Tumor Consortium study.

BACKGROUND: A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent low-grade glioma to measure sustained response and/or stable disease lasting ≥6 months and progression-free survival. METHODS: Thirty-five evaluable patients received 2 doses (10 mg/kg each) of single-agent BVZ intravenously 2 weeks apart and then BVZ + CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included neuroimaging and expression of tumor angiogenic markers (vascular endothelial growth factor [VEGF], VEGF receptor 2, hypoxia-inducible factor 2α, and carbonic anhydrase 9). RESULTS: Thirty-five evaluable patients (median age 8.4 y [range, 0.6-17.6]) received a median of 12 courses of BVZ + CPT-11 (range, 2-26). Twenty-nine of 35 patients (83%) received treatment for at least 6 months. Eight patients progressed on treatment at a median time of 5.4 months (range, 1-17.8). Six patients (17.7%) still in follow-up have had stable disease without receiving additional treatment for a median of 40.1 months (range, 30.6-49.3) from initiating therapy. The 6-month and 2-year progression-free survivals were 85.4% (SE ± 5.96%) and 47.8% (SE ± 9.27%), respectively. The commonest toxicities related to BVZ included grades 1-2 hypertension in 24, grades 1-2 fatigue in 23, grades 1-2 epistaxis in 18, and grades 1-4 proteinuria in 15. The median volume of enhancement decreased significantly between baseline and day 15 (P < .0001) and over the duration of treatment (P < .037). CONCLUSION: The combination of BVZ + CPT-11 appears to produce sustained disease control in some children with recurrent low-grade gliomas.

Authors
Gururangan, S; Fangusaro, J; Poussaint, TY; McLendon, RE; Onar-Thomas, A; Wu, S; Packer, RJ; Banerjee, A; Gilbertson, RJ; Fahey, F; Vajapeyam, S; Jakacki, R; Gajjar, A; Goldman, S; Pollack, IF; Friedman, HS; Boyett, JM; Fouladi, M; Kun, LE
MLA Citation
Gururangan, Sridharan, et al. “Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas--a Pediatric Brain Tumor Consortium study..” Neuro Oncol, vol. 16, no. 2, Jan. 2014, pp. 310–17. Pubmed, doi:10.1093/neuonc/not154.
PMID
24311632
Source
pubmed
Published In
Neuro Oncol
Volume
16
Issue
2
Publish Date
2014
Start Page
310
End Page
317
DOI
10.1093/neuonc/not154

Bevacizumab (BVZ)-associated toxicities in children with recurrent central nervous system tumors treated with BVZ and irinotecan (CPT-11): a Pediatric Brain Tumor Consortium Study (PBTC-022).

BACKGROUND: The incidence and spectrum of acute toxicities related to the use of bevacizumab (BVZ)-containing regimens in children are largely unknown. This report describes the adverse events in a recently completed large phase 2 trial of BVZ plus irinotecan (CPT-11) in children with recurrent central nervous system tumors. METHODS: Pediatric Brain Tumor Consortium trial-022 evaluated the efficacy and toxicity of BVZ (10 mg/kg administered intravenously) as a single agent for 2 doses given 2 weeks apart and then combined with CPT-11 every 2 weeks (1 course = 4 weeks) in children with recurrent central nervous system tumors. Children were treated until they experienced progressive disease, unacceptable toxicity or completed up to a maximum of 2 years of therapy. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Patients who received at least 1 dose of BVZ were included for toxicity assessment. RESULTS: Between October 2006 and June 2010, 92 patients evaluable for toxicity were enrolled and received 687 treatment courses. The most common toxicities attributable to BVZ included grade I-III hypertension (38% of patients), grade I-III fatigue (30%), grade I-II epistaxis (24%), and grade I-IV proteinuria (22%). Twenty-two patients (24%) stopped therapy due to toxicity. CONCLUSIONS: The combination of BVZ and CPT-11 was fairly well-tolerated, and most severe BVZ-related toxicities were rare, self-limiting, and manageable.

Authors
Fangusaro, J; Gururangan, S; Poussaint, TY; McLendon, RE; Onar-Thomas, A; Warren, KE; Wu, S; Packer, RJ; Banerjee, A; Gilbertson, RJ; Jakacki, R; Gajjar, A; Goldman, S; Pollack, IF; Friedman, HS; Boyett, JM; Kun, LE; Fouladi, M
MLA Citation
Fangusaro, Jason, et al. “Bevacizumab (BVZ)-associated toxicities in children with recurrent central nervous system tumors treated with BVZ and irinotecan (CPT-11): a Pediatric Brain Tumor Consortium Study (PBTC-022)..” Cancer, vol. 119, no. 23, 2013, pp. 4180–87. Pubmed, doi:10.1002/cncr.28343.
PMID
24104527
Source
pubmed
Published In
Cancer
Volume
119
Issue
23
Publish Date
2013
Start Page
4180
End Page
4187
DOI
10.1002/cncr.28343

Proteasome inhibition with bortezomib induces cell death in GBM stem-like cells and temozolomide-resistant glioma cell lines, but stimulates GBM stem-like cells' VEGF production and angiogenesis.

OBJECT: Recurrent malignant gliomas have inherent resistance to traditional chemotherapy. Novel therapies target specific molecular mechanisms involved in abnormal signaling and resistance to apoptosis. The proteasome is a key regulator of multiple cellular functions, and its inhibition in malignant astrocytic lines causes cell growth arrest and apoptotic cell death. The proteasome inhibitor bortezomib was reported to have very good in vitro activity against malignant glioma cell lines, with modest activity in animal models as well as in clinical trials as a single agent. In this paper, the authors describe the multiple effects of bortezomib in both in vitro and in vivo glioma models and offer a novel explanation for its seeming lack of activity. METHODS: Glioma stem-like cells (GSCs) were obtained from resected glioblastomas (GBMs) at surgery and expanded in culture. Stable glioma cell lines (U21 and D54) as well as temozolomide (TMZ)-resistant glioma cells derived from U251 and D54-MG were also cultured. GSCs from 2 different tumors, as well as D54 and U251 cells, were treated with bortezomib, and the effect of the drug was measured using an XTT cell viability assay. The activity of bortezomib was then determined in D54-MG and/or U251 cells using apoptosis analysis as well as caspase-3 activity and proteasome activity measurements. Human glioma xenograft models were created in nude mice by subcutaneous injection. Bevacizumab was administered via intraperitoneal injection at a dose of 5 mg/kg daily. Bortezomib was administered by intraperitoneal injection 1 hour after bevacizumab administration in doses of at a dose of 0.35 mg/kg on days 1, 4, 8, and 11 every 21 days. Tumors were measured twice weekly. RESULTS: Bortezomib induced caspase-3 activation and apoptotic cell death in stable glioma cell lines and in glioma stem-like cells (GSCs) derived from malignant tumor specimens Furthermore, TMZ-resistant glioma cell lines retained susceptibility to the proteasome inhibition. The bortezomib activity was directly proportional with the cells' baseline proteasome activity. The proteasome inhibition stimulated both hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) production in malignant GSCs. As such, the VEGF produced by GSCs stimulated endothelial cell growth, an effect that could be prevented by the addition of bevacizumab (VEGF antibody) to the media. Similarly, administration of bortezomib and bevacizumab to athymic mice carrying subcutaneous malignant glioma xenografts resulted in greater tumor inhibition and greater improvement in survival than administration of either drug alone. These data indicate that simultaneous proteasome inhibition and VEGF blockade offer increased benefit as a strategy for malignant glioma therapy. CONCLUSIONS: The results of this study indicate that combination therapies based on bortezomib and bevacizumab might offer an increased benefit when the two agents are used in combination. These drugs have a complementary mechanism of action and therefore can be used together to treat TMZ-resistant malignant gliomas.

Authors
Bota, DA; Alexandru, D; Keir, ST; Bigner, D; Vredenburgh, J; Friedman, HS
MLA Citation
Bota, Daniela A., et al. “Proteasome inhibition with bortezomib induces cell death in GBM stem-like cells and temozolomide-resistant glioma cell lines, but stimulates GBM stem-like cells' VEGF production and angiogenesis..” J Neurosurg, vol. 119, no. 6, Dec. 2013, pp. 1415–23. Pubmed, doi:10.3171/2013.7.JNS1323.
PMID
24093630
Source
pubmed
Published In
J Neurosurg
Volume
119
Issue
6
Publish Date
2013
Start Page
1415
End Page
1423
DOI
10.3171/2013.7.JNS1323

ADOPTIVE LYMPHOCYTE THERAPY (ALT) PLUS DENDRITIC CELL VACCINATION (DCV) AFTER MYELOABLATIVE (MA) OR NON-MYELOABLATIVE (NMA) CONDITIONING IN PATIENTS WITH RECURRENT CENTRAL PNET (C-PNET)

Authors
Gururangan, S; Grant, GA; Driscoll, T; Archer, G; Sayour, EJ; Herndon, JE; Friedman, HS; Kurtzberg, J; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Gururangan, S., et al. “ADOPTIVE LYMPHOCYTE THERAPY (ALT) PLUS DENDRITIC CELL VACCINATION (DCV) AFTER MYELOABLATIVE (MA) OR NON-MYELOABLATIVE (NMA) CONDITIONING IN PATIENTS WITH RECURRENT CENTRAL PNET (C-PNET).” Pediatric Blood & Cancer, vol. 60, WILEY-BLACKWELL, Sept. 2013, pp. 13–13.
Source
wos
Published In
Pediatric Blood & Cancer
Volume
60
Publish Date
2013
Start Page
13
End Page
13

High-risk medulloblastoma: a pediatric oncology group randomized trial of chemotherapy before or after radiation therapy (POG 9031).

PURPOSE: To compare event-free survival (EFS) in children with high-risk medulloblastoma randomly assigned to receive either chemotherapy before radiation or chemotherapy after radiation. PATIENTS AND METHODS: One hundred twelve patients were randomly assigned to each arm. Criteria used to categorize patients as high risk included M1-4 disease by modified Chang staging classification, T3b/T4 disease, or greater than 1.5 cm3 of residual tumor after surgery. Postoperatively, children with high-risk medulloblastoma were randomly assigned to two arms, either chemotherapy entailing three cycles of cisplatin and etoposide before radiation (chemotherapy first [CT1]) or the same chemotherapy regimen after radiation (radiation therapy first [RT1]). Both groups received consolidation chemotherapy consisting of vincristine and cyclophosphamide. RESULTS: The median follow-up time was 6.4 years. Five-year EFS was 66.0% in the CT1 arm and 70.0% in the RT1 arm (P = .54), and 5-year overall survival in the two groups was 73.1% and 76.1%, respectively (P = .47). In the CT1 arm, 40 of the 62 patients with residual disease achieved either complete or partial remission. CONCLUSION: Five-year EFS did not differ significantly whether, after surgery, patients received chemotherapy before or after radiotherapy.

Authors
Tarbell, NJ; Friedman, H; Polkinghorn, WR; Yock, T; Zhou, T; Chen, Z; Burger, P; Barnes, P; Kun, L
MLA Citation
Tarbell, Nancy J., et al. “High-risk medulloblastoma: a pediatric oncology group randomized trial of chemotherapy before or after radiation therapy (POG 9031)..” J Clin Oncol, vol. 31, no. 23, Aug. 2013, pp. 2936–41. Pubmed, doi:10.1200/JCO.2012.43.9984.
PMID
23857975
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
31
Issue
23
Publish Date
2013
Start Page
2936
End Page
2941
DOI
10.1200/JCO.2012.43.9984

Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: a prospective trial.

PURPOSE: Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. METHODS AND MATERIALS: Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. RESULTS: One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. CONCLUSIONS: Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach.

Authors
Cabrera, AR; Cuneo, KC; Desjardins, A; Sampson, JH; McSherry, F; Herndon, JE; Peters, KB; Allen, K; Hoang, JK; Chang, Z; Craciunescu, O; Vredenburgh, JJ; Friedman, HS; Kirkpatrick, JP
MLA Citation
Cabrera, Alvin R., et al. “Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: a prospective trial..” Int J Radiat Oncol Biol Phys, vol. 86, no. 5, Aug. 2013, pp. 873–79. Pubmed, doi:10.1016/j.ijrobp.2013.04.029.
PMID
23725997
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
86
Issue
5
Publish Date
2013
Start Page
873
End Page
879
DOI
10.1016/j.ijrobp.2013.04.029

O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma.

Temozolomide, an alkylating agent, has shown promise in treating primary central nervous system lymphoma (PCNSL). The enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) repairs alkylating damage, such as that induced by temozolomide. We hypothesized that MGMT immunohistochemistry would predict resistance to temozolomide in PCNSL. A retrospective study of newly-diagnosed and recurrent PCNSL patients treated at our institution was conducted to study the predictive value of MGMT immunohistochemistry for response to temozolomide. 20 patients who were treated with temozolomide as a single agent were identified during the study time period. 6/20 patients demonstrated a response, corresponding to an objective response rate of 30 % (95 % CI 8-52). Five patients with low MGMT level (<30 %) showed a response to temozolomide. Only one of 10 patients (10 %) with high MGMT level (≥30 %) exhibited a response to temozolomide. Small sample numbers precluded formal statistical comparisons. Two patients with complete response remain alive without progressive disease 6.7 and 7.2 years after temozolomide initiation. Immunohistochemistry can be performed on small biopsies to selectively assess MGMT status in tumor versus surrounding inflammation. MGMT analysis by immunohistochemistry may predict response to temozolomide in PCNSL and should be prospectively investigated.

Authors
Jiang, X; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Quinn, JA; Austin, AD; Herndon, JE; McLendon, RE; Friedman, HS
MLA Citation
Jiang, Xiaoyin, et al. “O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma..” J Neurooncol, vol. 114, no. 1, Aug. 2013, pp. 135–40. Pubmed, doi:10.1007/s11060-013-1162-y.
PMID
23686298
Source
pubmed
Published In
J Neurooncol
Volume
114
Issue
1
Publish Date
2013
Start Page
135
End Page
140
DOI
10.1007/s11060-013-1162-y

Dose-finding and safety study of an oncolytic polio/rhinovirus recombinant against recurrent glioblastoma.

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Threatt, S; Herndon, JE; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, Annick, et al. “Dose-finding and safety study of an oncolytic polio/rhinovirus recombinant against recurrent glioblastoma..” Journal of Clinical Oncology, vol. 31, no. 15, AMER SOC CLINICAL ONCOLOGY, 2013.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Phase II trial for patients with newly diagnosed glioblastoma (GBM) treated with carmustine wafers followed by concurrent radiation therapy (RT), temozolomide (TMZ), and bevacizumab (BV), then followed by TMZ and BV post-RT.

Authors
Ranjan, T; Peters, KB; Vlahovic, G; Alderson, LM; Herndon, JE; McSherry, F; Threatt, S; Sampson, JH; Friedman, AH; Bigner, DD; Friedman, HS; Vredenburgh, JJ; Desjardins, A
MLA Citation
Ranjan, Tulika, et al. “Phase II trial for patients with newly diagnosed glioblastoma (GBM) treated with carmustine wafers followed by concurrent radiation therapy (RT), temozolomide (TMZ), and bevacizumab (BV), then followed by TMZ and BV post-RT..” Journal of Clinical Oncology, vol. 31, no. 15, AMER SOC CLINICAL ONCOLOGY, 2013.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Dose-finding and safety study of an oncolytic polio/rhinovirus recombinant against recurrent glioblastoma.

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Threatt, S; Herndon, JE; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, Annick, et al. “Dose-finding and safety study of an oncolytic polio/rhinovirus recombinant against recurrent glioblastoma..” Journal of Clinical Oncology, vol. 31, no. 15, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Analysis of high-dose methotrexate with rituximab versus other treatment regimens for primary central nervous system (CNS) lymphoma.

Authors
Lindhorst, SM; McSherry, F; Desjardins, A; Friedman, HS; Peters, KB
MLA Citation
Lindhorst, Scott Michael, et al. “Analysis of high-dose methotrexate with rituximab versus other treatment regimens for primary central nervous system (CNS) lymphoma..” Journal of Clinical Oncology, vol. 31, no. 15, AMER SOC CLINICAL ONCOLOGY, 2013.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Efficacy of Sym004, a novel anti-EGFR antibody mixture, against EGFRvIII positive glioblastoma xenografts.

Authors
Keir, ST; Roskoski, MA; Kragh, M; Pederson, MW; Jacobsen, HJ; Horak, ID; Friedman, HS; Bigner, DD
MLA Citation
Keir, Stephen T., et al. “Efficacy of Sym004, a novel anti-EGFR antibody mixture, against EGFRvIII positive glioblastoma xenografts..” Cancer Research, vol. 73, no. 8, 2013. Wos-lite, doi:10.1158/1538-7445.AM2013-4322.
Source
wos-lite
Published In
Cancer Research
Volume
73
Issue
8
Publish Date
2013
DOI
10.1158/1538-7445.AM2013-4322

Abstract 2079: Antitumoral activity of INC280 against adult glioblastoma brain tumors xenografts.

Authors
Keir, ST; Roskoski, MA; Wagner, S; Tiedt, R; Bigner, DD; Friedman, HS
MLA Citation
Keir, Stephen T., et al. “Abstract 2079: Antitumoral activity of INC280 against adult glioblastoma brain tumors xenografts..” Experimental and Molecular Therapeutics, American Association for Cancer Research, 2013. Crossref, doi:10.1158/1538-7445.am2013-2079.
Source
crossref
Published In
Experimental and Molecular Therapeutics
Publish Date
2013
DOI
10.1158/1538-7445.am2013-2079

TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.

Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (≥15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.

Authors
Killela, PJ; Reitman, ZJ; Jiao, Y; Bettegowda, C; Agrawal, N; Diaz, LA; Friedman, AH; Friedman, H; Gallia, GL; Giovanella, BC; Grollman, AP; He, T-C; He, Y; Hruban, RH; Jallo, GI; Mandahl, N; Meeker, AK; Mertens, F; Netto, GJ; Rasheed, BA; Riggins, GJ; Rosenquist, TA; Schiffman, M; Shih, I-M; Theodorescu, D; Torbenson, MS; Velculescu, VE; Wang, T-L; Wentzensen, N; Wood, LD; Zhang, M; McLendon, RE; Bigner, DD; Kinzler, KW; Vogelstein, B; Papadopoulos, N; Yan, H
MLA Citation
Killela, Patrick J., et al. “TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal..” Proc Natl Acad Sci U S A, vol. 110, no. 15, Apr. 2013, pp. 6021–26. Pubmed, doi:10.1073/pnas.1303607110.
PMID
23530248
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
110
Issue
15
Publish Date
2013
Start Page
6021
End Page
6026
DOI
10.1073/pnas.1303607110

ONCOLYTIC POLIOVIRUS IMMUNOTHERAPY OF PRIMARY CNS TUMORS

Authors
Gromeier, M; Desjardins, A; Sampson, JH; Threatt, SJE; Herndon, JE; Friedman, A; Friedman, HS; Bigner, DD
MLA Citation
Gromeier, Matthias, et al. “ONCOLYTIC POLIOVIRUS IMMUNOTHERAPY OF PRIMARY CNS TUMORS.” Neuro Oncology, vol. 15, OXFORD UNIV PRESS INC, 2013, pp. 20–20.
Source
wos
Published In
Neuro Oncology
Volume
15
Publish Date
2013
Start Page
20
End Page
20

Phase II trial of upfront bevacizumab and temozolomide for unresectable or multifocal glioblastoma.

Patients with unresectable glioblastomas have a poor prognosis, with median survival of 6-10 months. We conducted a phase II trial of upfront 5-day temozolomide (TMZ) and bevacizumab (BV) in patients with newly diagnosed unresectable or multifocal glioblastoma. Patients received up to four cycles of TMZ at 200 mg/m(2) on days 1-5, and BV at 10 mg/kg on days 1 and 15 of a 28-day cycle. Brain magnetic resonance imaging (MRI) was performed monthly. Therapy was continued as long as there was no tumor progression, grade 4 nonhematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary end point was best tumor response as measured on MRI. Forty-one patients were accrued over 12 months; 39 had a full set of MRI scans available for evaluation. Assessment for best radiographic responses was as follows: partial responses in 24.4%, stable disease in 68.3%, and progressive disease in 2.4%. Treatment-related toxicities included seven grade 4 toxicities and one grade 5 toxicity (myocardial infarction). From this study, it was concluded that an upfront regimen of TMZ and BV for unresectable glioblastoma was well tolerated and provided a significant level of disease stabilization. Therapeutic toxicities were consistent with those seen in the adjuvant setting using these agents. The upfront approach to treatment of glioblastoma in the unresectable population warrants further investigation in randomized controlled phase III trials.

Authors
Lou, E; Peters, KB; Sumrall, AL; Desjardins, A; Reardon, DA; Lipp, ES; Herndon, JE; Coan, A; Bailey, L; Turner, S; Friedman, HS; Vredenburgh, JJ
MLA Citation
Lou, Emil, et al. “Phase II trial of upfront bevacizumab and temozolomide for unresectable or multifocal glioblastoma..” Cancer Med, vol. 2, no. 2, Apr. 2013, pp. 185–95. Pubmed, doi:10.1002/cam4.58.
Website
http://hdl.handle.net/10161/16113
PMID
23634286
Source
pubmed
Published In
Cancer Medicine
Volume
2
Issue
2
Publish Date
2013
Start Page
185
End Page
195
DOI
10.1002/cam4.58

Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model.

Glioblastoma multiforme (GBM) is a devastating disease with a dismal prognosis and a very limited response to treatment. The current standard of care for GBM usually consists of surgery, radiation and chemotherapy with the alkylating agent temozolomide, although resistance to this drug is common. The predominant mechanism of action of temozolomide is methylation of guanine residues although this can be reversed by methylguanine methyltransferase (MGMT) as well as other DNA repair systems. The presence of methylguanine causes abortive DNA synthesis with subsequent apoptosis. This suggests that the closer a particular cell is to S phase when it is exposed to temozolomide the more likely it is to die since repair enzymes will have had less time to reverse the damage. T type calcium channel inhibitors can stop the entry of extracellular calcium that is necessary for transit past the G1/S boundary. As a result, T type calcium channel blockers can slow the growth of cancer cells, but do not generally kill them. Though slowing the growth of cancer cells is important in its own right, it also provides a therapeutic strategy in which a T type channel blocker is administered then withdrawn followed by the administration of temozolomide. We show here that imposing this cell cycle restriction increases the efficacy of subsequently administered temozolomide in immunodeficient mice bearing various human GBM xenograft lines. We also present data that MGMT expressing GBM tumors, which are temozolomide resistant, may be rendered more sensitive by this strategy.

Authors
Keir, ST; Friedman, HS; Reardon, DA; Bigner, DD; Gray, LA
MLA Citation
Keir, Stephen T., et al. “Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model..” J Neurooncol, vol. 111, no. 2, Jan. 2013, pp. 97–102. Pubmed, doi:10.1007/s11060-012-0995-0.
PMID
23086436
Source
pubmed
Published In
J Neurooncol
Volume
111
Issue
2
Publish Date
2013
Start Page
97
End Page
102
DOI
10.1007/s11060-012-0995-0

MISMATCH REPAIR DEFICIENCY: A TEMOZOLOMIDE RESISTANCE FACTOR IN MEDULLOBLASTOMA CELL LINES WHICH IS UNCOMMON IN PRIMARY MEDULLOBLASTOMA TUMORS

Authors
von Bueren, AO; Bacolod, MD; Hagel, C; Heinimann, K; Fedier, A; Kordes, U; Pietsch, T; Koster, J; Grotzer, MA; Friedman, HS; Marra, G; Kool, M; Rutkowski, S
MLA Citation
von Bueren, Andre O., et al. “MISMATCH REPAIR DEFICIENCY: A TEMOZOLOMIDE RESISTANCE FACTOR IN MEDULLOBLASTOMA CELL LINES WHICH IS UNCOMMON IN PRIMARY MEDULLOBLASTOMA TUMORS.” Pediatric Blood & Cancer, vol. 59, no. 6, WILEY PERIODICALS, INC, Dec. 2012, pp. 1083–1083.
Source
wos
Published In
Pediatric Blood & Cancer
Volume
59
Issue
6
Publish Date
2012
Start Page
1083
End Page
1083

Lack of efficacy of bevacizumab + irinotecan in cases of pediatric recurrent ependymoma--a Pediatric Brain Tumor Consortium study.

A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in cases of pediatric recurrent ependymoma (EPN) to estimate sustained objective response rate and progression-free survival (PFS). Eligible patients received 2 doses of single-agent BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ + CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion-weighted and T1 dynamic contrast enhanced permeability imaging and tumor immunohistochemistry for vascular endothelial growth factor (VEGF)-A and -B, hypoxia inducible factor-2α, VEGF receptor (R)-2, and carbonic anhydrase (CA)-9. Thirteen evaluable patients received a median of 3 courses (range, 2-12) of BVZ + CPT-11. No sustained response was observed in any patient. Median time to progression in 10 patients was 2.2 months (range, 1.9-6.3). Two patients had stable disease for 10 months and 12 months, respectively. Six-month PFS was 25.7% (SE = 11.1%). Grades I-III toxicities related to BVZ treatment included fatigue in 4 patients, systemic hypertension in 2, epistaxis in 1, headache in 1, and avascular necrosis of bone in 1. Although there was a decrease in the mean diffusion ratio following 2 doses of BVZ, it did not correlate with PFS. BVZ + CPT-11 was well tolerated but had minimal efficacy in cases of recurrent EPN.

Authors
Gururangan, S; Fangusaro, J; Young Poussaint, T; Onar-Thomas, A; Gilbertson, RJ; Vajapeyam, S; Gajjar, A; Goldman, S; Friedman, HS; Packer, RJ; Boyett, JM; Kun, LE; McLendon, R
MLA Citation
Gururangan, Sridharan, et al. “Lack of efficacy of bevacizumab + irinotecan in cases of pediatric recurrent ependymoma--a Pediatric Brain Tumor Consortium study..” Neuro Oncol, vol. 14, no. 11, Nov. 2012, pp. 1404–12. Pubmed, doi:10.1093/neuonc/nos213.
PMID
23019233
Source
pubmed
Published In
Neuro Oncol
Volume
14
Issue
11
Publish Date
2012
Start Page
1404
End Page
1412
DOI
10.1093/neuonc/nos213

Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients.

BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial.

Authors
Reardon, DA; Herndon, JE; Peters, KB; Desjardins, A; Coan, A; Lou, E; Sumrall, AL; Turner, S; Lipp, ES; Sathornsumetee, S; Rich, JN; Sampson, JH; Friedman, AH; Boulton, ST; Bigner, DD; Friedman, HS; Vredenburgh, JJ
MLA Citation
Reardon, D. A., et al. “Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients..” Br J Cancer, vol. 107, no. 9, Oct. 2012, pp. 1481–87. Pubmed, doi:10.1038/bjc.2012.415.
Website
http://hdl.handle.net/10161/16115
PMID
23037712
Source
pubmed
Published In
Br J Cancer
Volume
107
Issue
9
Publish Date
2012
Start Page
1481
End Page
1487
DOI
10.1038/bjc.2012.415

Mismatch repair deficiency: a temozolomide resistance factor in medulloblastoma cell lines that is uncommon in primary medulloblastoma tumours.

BACKGROUND: Tumours are responsive to temozolomide (TMZ) if they are deficient in O(6)-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient. METHODS: The effect of TMZ on medulloblastoma (MB) cell killing was analysed with clonogenic survival assays. Expression of DNA repair genes and enzymes was investigated using microarrays, western blot, and immunohistochemistry. DNA sequencing and promoter methylation analysis were employed to investigate the cause of loss of the expression of MMR gene MLH1. RESULTS: Temozolomide exhibited potent cytotoxic activity in D425Med (MGMT deficient, MLH1 proficient; IC(50)=1.7 μM), moderate activity against D341Med (MGMT proficient, MLH1 deficient), and DAOY MB cells (MGMT proficient, MLH1 proficient). MGMT inhibitor O(6)-benzylguanine sensitised DAOY, but not D341Med cells to TMZ. Of 12 MB cell lines, D341Med, D283Med, and 1580WÜ cells exhibited MMR deficiency due to MLH1 promoter hypermethylation. DNA sequencing of these cells provided no evidence for somatic genetic alterations in MLH1. Expression analyses of MMR and MGMT in MB revealed that all patient specimens (n=74; expression array, n=61; immunostaining, n=13) are most likely MMR proficient, whereas some tumours had low MGMT expression levels (according to expression array) or were totally MGMT deficient (3 out of 13 according to immunohistochemistry). CONCLUSION: A subset of MB may respond to TMZ as some patient specimens are MGMT deficient, and tumours appear to be MMR proficient.

Authors
von Bueren, AO; Bacolod, MD; Hagel, C; Heinimann, K; Fedier, A; Kordes, U; Pietsch, T; Koster, J; Grotzer, MA; Friedman, HS; Marra, G; Kool, M; Rutkowski, S
MLA Citation
von Bueren, A. O., et al. “Mismatch repair deficiency: a temozolomide resistance factor in medulloblastoma cell lines that is uncommon in primary medulloblastoma tumours..” Br J Cancer, vol. 107, no. 8, Oct. 2012, pp. 1399–408. Pubmed, doi:10.1038/bjc.2012.403.
PMID
22976800
Source
pubmed
Published In
Br J Cancer
Volume
107
Issue
8
Publish Date
2012
Start Page
1399
End Page
1408
DOI
10.1038/bjc.2012.403

Phase II study of Gleevec plus hydroxyurea in adults with progressive or recurrent low-grade glioma.

BACKGROUND: We evaluated the efficacy of imatinib plus hydroxyurea in patients with progressive/recurrent low-grade glioma. METHODS: A total of 64 patients with recurrent/progressive low-grade glioma were enrolled in this single-center study that stratified patients into astrocytoma and oligodendroglioma cohorts. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg per day for patients not on enzyme-inducing antiepileptic drugs (EIAEDs) and at 500 mg twice a day if on EIAEDs. The primary endpoint was progression-free survival at 12 months (PFS-12) and secondary endpoints were safety, median progression-free survival, and radiographic response rate. RESULTS: Thirty-two patients were enrolled into each cohort. Eleven patients (17%) had before radiotherapy and 24 (38%) had received before chemotherapy. The median PFS and PFS-12 were 11 months and 39%, respectively. Outcome did not differ between the histologic cohorts. No patient achieved a radiographic response. The most common grade 3 or greater adverse events were neutropenia (11%), thrombocytopenia (3%), and diarrhea (3%). CONCLUSIONS: Imatinib plus hydroxyurea was well tolerated among recurrent/progressive LGG patients but this regimen demonstrated negligible antitumor activity.

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Herndon, JE; Coan, A; Gururangan, S; Peters, KB; McLendon, R; Sathornsumetee, S; Rich, JN; Lipp, ES; Janney, D; Friedman, HS
MLA Citation
Reardon, David A., et al. “Phase II study of Gleevec plus hydroxyurea in adults with progressive or recurrent low-grade glioma..” Cancer, vol. 118, no. 19, Oct. 2012, pp. 4759–67. Pubmed, doi:10.1002/cncr.26541.
PMID
22371319
Source
pubmed
Published In
Cancer
Volume
118
Issue
19
Publish Date
2012
Start Page
4759
End Page
4767
DOI
10.1002/cncr.26541

A PHASE II SINGLE-ARM TRIAL OF PALONOSETRON FOR THE PREVENTION OF ACUTE AND DELAYED CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING IN MALIGNANT GLIOMA PATIENTS RECEIVING IRINOTECAN IN COMBINATION WITH BEVACIZUMAB

Authors
Affronti, ML; Woodring, S; Herndon, JE; McSherry, F; Peters, KB; Friedman, HS; Desjardins, A; Freeman, W; Cheshire, S; Cone, C; Kalinowski, KH; Kim, J-Y; Lay, HH; Poillucci, V; Southerland, C; Tetterton, J; Vredenburgh, JJ
MLA Citation
Affronti, Mary Lou, et al. “A PHASE II SINGLE-ARM TRIAL OF PALONOSETRON FOR THE PREVENTION OF ACUTE AND DELAYED CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING IN MALIGNANT GLIOMA PATIENTS RECEIVING IRINOTECAN IN COMBINATION WITH BEVACIZUMAB.” Neuro Oncology, vol. 14, OXFORD UNIV PRESS INC, 2012, pp. 156–156.
Website
http://hdl.handle.net/10161/16098
Source
wos
Published In
Neuro Oncology
Volume
14
Publish Date
2012
Start Page
156
End Page
156

NEWLY DIAGNOSED GLIOBLASTOMA TREATED WITH GLIADEL (R) FOLLOWED BY RADIATION THERAPY (RT), TEMOZOLOMIDE AND BEVACIZUMAB, AND POST-RT BEVACIZUMAB AND TEMOZOLOMIDE: A PHASE II STUDY

Authors
Desjardins, A; Peters, KB; Herndon, JE; Bailey, LA; Alderson, LM; Ranjan, T; Sampson, JH; Friedman, AH; Bigner, DD; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, Annick, et al. “NEWLY DIAGNOSED GLIOBLASTOMA TREATED WITH GLIADEL (R) FOLLOWED BY RADIATION THERAPY (RT), TEMOZOLOMIDE AND BEVACIZUMAB, AND POST-RT BEVACIZUMAB AND TEMOZOLOMIDE: A PHASE II STUDY.” Neuro Oncology, vol. 14, OXFORD UNIV PRESS INC, 2012, pp. 104–104.
Source
wos
Published In
Neuro Oncology
Volume
14
Publish Date
2012
Start Page
104
End Page
104

EZN-2208, A NOVEL PEGYLATED SN38 DRUG CONJUGATE, MARKEDLY INHIBITS TUMOR GROWTH IN COMPARISON TO IRINOTECAN

Authors
Keir, ST; Friedman, HS; Bigner, DD
MLA Citation
Keir, Stephen T., et al. “EZN-2208, A NOVEL PEGYLATED SN38 DRUG CONJUGATE, MARKEDLY INHIBITS TUMOR GROWTH IN COMPARISON TO IRINOTECAN.” Neuro Oncology, vol. 14, OXFORD UNIV PRESS INC, 2012, pp. 29–29.
Source
wos
Published In
Neuro Oncology
Volume
14
Publish Date
2012
Start Page
29
End Page
29

BEVACIZUMAB GIVEN WITH TEMOZOLOMIDE AND RADIATION THERAPY (RT) IN NEWLY DIAGNOSED PATIENTS WITH GLIOBLASTOMA MULTIFORME (GBM) REDUCES THE CHANCE OF EARLY RADIOLOGIC PROGRESSION

Authors
Alderson, LM; Desjardins, A; Ranjan, T; Peters, KB; Friedman, HS; Vredenburgh, JJ
MLA Citation
Alderson, Lloyd M., et al. “BEVACIZUMAB GIVEN WITH TEMOZOLOMIDE AND RADIATION THERAPY (RT) IN NEWLY DIAGNOSED PATIENTS WITH GLIOBLASTOMA MULTIFORME (GBM) REDUCES THE CHANCE OF EARLY RADIOLOGIC PROGRESSION.” Neuro Oncology, vol. 14, OXFORD UNIV PRESS INC, 2012, pp. 81–81.
Source
wos
Published In
Neuro Oncology
Volume
14
Publish Date
2012
Start Page
81
End Page
81

LONG-TERM SURVIVORSHIP IN PRIMARY GLIOBLASTOMA: A FOCUS ON NEUROCOGNITION

Authors
Peters, KB; Woodring, S; Herndon, JE; McSherry, F; Vredenburgh, JJ; Desjardins, A; Friedman, HS
MLA Citation
Peters, Katherine B., et al. “LONG-TERM SURVIVORSHIP IN PRIMARY GLIOBLASTOMA: A FOCUS ON NEUROCOGNITION.” Neuro Oncology, vol. 14, OXFORD UNIV PRESS INC, 2012, pp. 62–62.
Source
wos
Published In
Neuro Oncology
Volume
14
Publish Date
2012
Start Page
62
End Page
62

VORINOSTAT, BEVACIZUMAB, AND METRONOMIC TEMOZOLOMIDE FOR RECURRENT HIGH-GRADE GLIOMA: A PHASE I/II CLINICAL TRIAL

Authors
Peters, KB; Reardon, DA; Vredenburgh, JJ; Desjardins, A; Herndon, JE; Coan, A; McSherry, F; Lipp, E; Brickhouse, A; Massey, W; Friedman, HS
MLA Citation
Peters, Katherine B., et al. “VORINOSTAT, BEVACIZUMAB, AND METRONOMIC TEMOZOLOMIDE FOR RECURRENT HIGH-GRADE GLIOMA: A PHASE I/II CLINICAL TRIAL.” Neuro Oncology, vol. 14, OXFORD UNIV PRESS INC, 2012, pp. 81–81.
Source
wos
Published In
Neuro Oncology
Volume
14
Publish Date
2012
Start Page
81
End Page
81

LONG-TERM SURVIVORSHIP IN PRIMARY GLIOBLASTOMA: A FOCUS ON QUALITY OF LIFE

Authors
Peters, KB; Woodring, S; Herndon, JE; McSherry, F; Vredenburgh, JJ; Desjardins, A; Friedman, HS
MLA Citation
Peters, Katherine B., et al. “LONG-TERM SURVIVORSHIP IN PRIMARY GLIOBLASTOMA: A FOCUS ON QUALITY OF LIFE.” Neuro Oncology, vol. 14, OXFORD UNIV PRESS INC, 2012, pp. 158–158.
Source
wos
Published In
Neuro Oncology
Volume
14
Publish Date
2012
Start Page
158
End Page
158

Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series.

Intracranial meningiomas are often indolent tumors which typically grow over years to decades. Nonetheless, meningiomas that progress after maximum safe resection and radiation therapy pose a significant therapeutic challenge and effective therapies have yet to be identified. Preclinical studies implicate angiogenesis in the pathophysiology of more aggressive meningiomas, suggesting that anti-angiogenic therapies may be of utility in this setting. We performed a retrospective review of fourteen patients with recurrent meningioma treated at Duke University Medical Center with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, administered either alone or in combination with chemotherapy. Most patients were heavily pre-treated. Progression-free survival at 6 months was 86 % and was comparable regardless of meningioma grade and whether bevacizumab was administered as monotherapy or in combination with chemotherapy. Most toxicities were mild however single patients developed CNS hemorrhage (grade 1) and intestinal perforation (grade 4), respectively. Bevacizumab can be administered safely to patients with meningioma and appears to be associated with encouraging anti-tumor effect when administered as either a single agent or in combination with chemotherapy. Phase II trials investigating bevacizumab in patients with progressive/recurrent meningioma are warranted.

Authors
Lou, E; Sumrall, AL; Turner, S; Peters, KB; Desjardins, A; Vredenburgh, JJ; McLendon, RE; Herndon, JE; McSherry, F; Norfleet, J; Friedman, HS; Reardon, DA
MLA Citation
Lou, Emil, et al. “Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series..” Journal of Neuro Oncology, vol. 109, no. 1, Aug. 2012, pp. 63–70. Epmc, doi:10.1007/s11060-012-0861-0.
PMID
22535433
Source
epmc
Published In
Journal of Neuro Oncology
Volume
109
Issue
1
Publish Date
2012
Start Page
63
End Page
70
DOI
10.1007/s11060-012-0861-0

Adjuvant PCV chemo hikes oligodendroglioma survival: Commentary

Authors
Friedman, HS; Desjardins, A
MLA Citation
Friedman, H. S., and A. Desjardins. “Adjuvant PCV chemo hikes oligodendroglioma survival: Commentary.” Oncology Report, no. JULY, July 2012.
Source
scopus
Published In
Oncology Report
Issue
JULY
Publish Date
2012
Start Page
6

Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma.

To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib, an inhibitor of the Src family kinase proteins, with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, among recurrent malignant glioma patients. Once daily dasatinib was escalated in successive cohorts while erlotinib was administered daily at established doses based on concurrent CYP3A-inducing anticonvulsant (EIAEDS) use. Dasatinib pharmacokinetic analyzes were performed. Forty-seven patients enrolled including 37 (79 %) with grade IV and 10 (21 %) with grade III malignant glioma. Thirty patients (64 %) were at ≥second recurrence, while 27 (57 %) had received prior bevacizumab. The dasatinib MTD was 180 mg when combined with either 150 mg of erlotinib for patients not on EIAEDs, or 450 mg of erlotinib for patients on EIAEDs. The most common DLTs were diarrhea and fatigue, while most adverse events were grade 2. Pharmacokinetic data suggests that dasatinib exposure increased with increased dasatinib dose and concurrent erlotinib administration, while concurrent EIAED use diminished dasatinib exposure. No radiographic responses were observed, and only one patient (2 %) remained progression-free at 6 months. We demonstrate that dasatinib plus erlotinib can be safely co-administered on a continuous, daily dosing schedule with erlotinib, and established the recommended dose level of this combination.

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Peters, KB; Sathornsumetee, S; Threatt, S; Sampson, JH; Herndon, JE; Coan, A; McSherry, F; Rich, JN; McLendon, RE; Zhang, S; Friedman, HS
MLA Citation
Reardon, David A., et al. “Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma..” J Neurooncol, vol. 108, no. 3, July 2012, pp. 499–506. Pubmed, doi:10.1007/s11060-012-0848-x.
PMID
22407177
Source
pubmed
Published In
J Neurooncol
Volume
108
Issue
3
Publish Date
2012
Start Page
499
End Page
506
DOI
10.1007/s11060-012-0848-x

Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.

Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.

Authors
Jiao, Y; Killela, PJ; Reitman, ZJ; Rasheed, AB; Heaphy, CM; de Wilde, RF; Rodriguez, FJ; Rosemberg, S; Oba-Shinjo, SM; Nagahashi Marie, SK; Bettegowda, C; Agrawal, N; Lipp, E; Pirozzi, C; Lopez, G; He, Y; Friedman, H; Friedman, AH; Riggins, GJ; Holdhoff, M; Burger, P; McLendon, R; Bigner, DD; Vogelstein, B; Meeker, AK; Kinzler, KW; Papadopoulos, N; Diaz, LA; Yan, H
MLA Citation
Jiao, Yuchen, et al. “Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas..” Oncotarget, vol. 3, no. 7, July 2012, pp. 709–22. Pubmed, doi:10.18632/oncotarget.588.
Website
https://hdl.handle.net/10161/17849
PMID
22869205
Source
pubmed
Published In
Oncotarget
Volume
3
Issue
7
Publish Date
2012
Start Page
709
End Page
722
DOI
10.18632/oncotarget.588

Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients.

PURPOSE: Vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) play a significant role in glioblastoma angiogenesis and proliferation, making tyrosine kinase (TK) receptors logical targets for treatment. We evaluated AEE788, a reversible TK inhibitor that inhibits EGFR and VEGFR, in recurrent glioblastoma patients. METHODS: In this dose-escalation, phase I study, patients with recurrent glioblastoma received AEE788 once daily in 28-day cycles in stratified subgroups: those receiving (1) non-enzyme-inducing anticonvulsants drugs or no anticonvulsants (Group A) and (2) enzyme-inducing anticonvulsant drugs (Group B). A dose-expansion phase stratified patients by surgical eligibility. Primary objectives were to determine dose-limiting toxicity (DLT) and maximum tolerated dose; secondary objectives included evaluating (1) safety/tolerability, (2) pharmacokinetics, and (3) preliminary antitumor activity. RESULTS: Sixty-four glioblastoma patients were enrolled. Two Group A patients experienced DLTs (proteinuria and stomatitis) at 550 mg; 550 mg was, therefore, the highest dose evaluated and dose limiting. One Group B patient receiving 800 mg experienced a DLT (diarrhea). The initially recommended dose for dose-expansion phase for Group A was 400 mg; additional patients received 250 mg to assess the hepatotoxicity. Most frequently reported adverse events (AEs) included diarrhea and rash. Serious AEs, most commonly grade 3/4 liver function test elevations, were responsible for treatment discontinuation in 17% of patients. AEE788 concentrations were reduced by EIACD. The best overall response was stable disease (17%). CONCLUSIONS: Continuous, once-daily AEE788 was associated with unacceptable toxicity and minimal activity for the treatment of recurrent glioblastoma. The study was, therefore, discontinued prematurely.

Authors
Reardon, DA; Conrad, CA; Cloughesy, T; Prados, MD; Friedman, HS; Aldape, KD; Mischel, P; Xia, J; DiLea, C; Huang, J; Mietlowski, W; Dugan, M; Chen, W; Yung, WKA
MLA Citation
Reardon, David A., et al. “Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients..” Cancer Chemother Pharmacol, vol. 69, no. 6, June 2012, pp. 1507–18. Pubmed, doi:10.1007/s00280-012-1854-6.
PMID
22392572
Source
pubmed
Published In
Cancer Chemother Pharmacol
Volume
69
Issue
6
Publish Date
2012
Start Page
1507
End Page
1518
DOI
10.1007/s00280-012-1854-6

Phase II study of bevacizumab plus irinotecan and carboplatin for recurrent WHO grade 3 malignant gliomas with no prior bevacizumab failure.

Authors
Desjardins, A; Vredenburgh, JJ; Peters, KB; Threatt, S; Herndon, JE; Sampson, JH; Friedman, AH; Friedman, HS; Reardon, DA
MLA Citation
Desjardins, Annick, et al. “Phase II study of bevacizumab plus irinotecan and carboplatin for recurrent WHO grade 3 malignant gliomas with no prior bevacizumab failure..” Journal of Clinical Oncology, vol. 30, no. 15, AMER SOC CLINICAL ONCOLOGY, 2012.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

The addition of bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide, and oral topotecan for newly diagnosed glioblastoma multiforme (GBM).

Authors
Friedman, HS; Desjardins, A; Peters, KB; Reardon, DA; Kirkpatrick, J; Herndon, JE; Coan, AD; Bailey, L; Sampson, JH; Friedman, AH; Vredenburgh, JJ
MLA Citation
Friedman, Henry S., et al. “The addition of bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide, and oral topotecan for newly diagnosed glioblastoma multiforme (GBM)..” Journal of Clinical Oncology, vol. 30, no. 15, AMER SOC CLINICAL ONCOLOGY, 2012.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Vorinostat, temozolomide, and bevacizumab for patients with recurrent glioblastoma: A phase I/II trial

Authors
Peters, KB; Vredenburgh, JJ; Desjardins, A; Friedman, HS; Herndon, JE; Coan, AD; McSherry, F; Lipp, ES; Brickhouse, A; Massey, WC; Reardon, DA
MLA Citation
Peters, Katherine B., et al. “Vorinostat, temozolomide, and bevacizumab for patients with recurrent glioblastoma: A phase I/II trial.” Journal of Clinical Oncology, vol. 30, no. 15, AMER SOC CLINICAL ONCOLOGY, 2012.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Safety and efficacy of the addition of bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma multiforme

Authors
Vredenburgh, JJ; Desjardins, A; Peters, KB; Reardon, DA; Herndon, JE; Coan, AD; Kirkpatrick, J; Bailey, L; Threatt, S; Sampson, JH; Friedman, AH; Friedman, HS
MLA Citation
Vredenburgh, James J., et al. “Safety and efficacy of the addition of bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma multiforme.” Journal of Clinical Oncology, vol. 30, no. 15, AMER SOC CLINICAL ONCOLOGY, 2012.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Abstract LB-76: Mibefradil, a novel therapy for glioblastoma: An interlaced therapy approach

Authors
Keir, ST; Gray, L; Friedman, HS
MLA Citation
Keir, Stephen T., et al. “Abstract LB-76: Mibefradil, a novel therapy for glioblastoma: An interlaced therapy approach.” Molecular and Cellular Biology, American Association for Cancer Research, Apr. 2012. Crossref, doi:10.1158/1538-7445.am2012-lb-76.
Source
crossref
Published In
Molecular and Cellular Biology
Publish Date
2012
DOI
10.1158/1538-7445.am2012-lb-76

Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas.

PURPOSE: Patients with recurrent malignant gliomas treated with stereotactic radiosurgery (SRS) and multiagent systemic therapies were reviewed to determine the effects of patient- and treatment-related factors on survival and toxicity. METHODS AND MATERIALS: A retrospective analysis was performed on patients with recurrent malignant gliomas treated with salvage SRS from September 2002 to March 2010. All patients had experienced progression after treatment with temozolomide and radiotherapy. Salvage SRS was typically administered only after multiple postchemoradiation salvage systemic therapies had failed. RESULTS: 63 patients were treated with SRS for recurrent high-grade glioma; 49 patients had World Health Organization (WHO) Grade 4 disease. Median follow-up was 31 months from primary diagnosis and 7 months from SRS. Median overall survival from primary diagnosis was 41 months for all patients. Median progression-free survival (PFS) and overall survival from SRS (OS-SRS) were 6 and 10 months for all patients, respectively. The 1-year OS-SRS for patients with Grade 4 glioma who received adjuvant (concurrent with or after SRS) bevacizumab was 50% vs. 22% for patients not receiving adjuvant bevacizumab (p = 0.005). Median PFS for patients with a WHO Grade 4 glioma who received adjuvant bevacizumab was 5.2 months vs. 2.1 months for patients who did not receive adjuvant bevacizumab (p = 0.014). Karnofsky performance status (KPS) and age were not significantly different between treatment groups. Treatment-related Grade 3/4 toxicity for patients receiving and not receiving adjuvant BVZ was 10% and 14%, respectively (p = 0.58).On multivariate analysis, the relative risk of death and progression with adjuvant bevacizumab was 0.37 (confidence interval [CI] 0.17-0.82) and 0.45 (CI 0.21-0.97). KPS >70 and age <50 years were significantly associated with improved survival. CONCLUSIONS: The combination of salvage radiosurgery and bevacizumab to treat recurrent malignant gliomas is well tolerated and seems to be associated with improved outcomes. Prospective multiinstitutional studies are required to determine efficacy and long-term toxicity with this approach.

Authors
Cuneo, KC; Vredenburgh, JJ; Sampson, JH; Reardon, DA; Desjardins, A; Peters, KB; Friedman, HS; Willett, CG; Kirkpatrick, JP
MLA Citation
Cuneo, Kyle C., et al. “Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas..” Int J Radiat Oncol Biol Phys, vol. 82, no. 5, Apr. 2012, pp. 2018–24. Pubmed, doi:10.1016/j.ijrobp.2010.12.074.
PMID
21489708
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
82
Issue
5
Publish Date
2012
Start Page
2018
End Page
2024
DOI
10.1016/j.ijrobp.2010.12.074

A change in the apparent diffusion coefficient after treatment with bevacizumab is associated with decreased survival in patients with recurrent glioblastoma multiforme.

OBJECTIVES: The aim of this study was to determine the prognostic significance of changes in parameters derived from diffusion tensor imaging (DTI) that occur in response to treatment with bevacizumab and irinotecan in patients with recurrent glioblastoma multiforme. METHODS: 15 patients with recurrent glioblastoma multiforme underwent serial 1.5 T MRI. Axial single-shot echo planar DTI was obtained on scans performed 3 days and 1 day prior to and 6 weeks after initiation of therapy with bevacizumab and irinotecan. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were registered to whole brain contrast-enhanced three-dimensional (3D) spoiled gradient recalled and 3D fluid attenuation inversion recovery (FLAIR) image volumes. Anatomic image volumes were segmented to isolate regions of interest defined by tumour-related enhancement (TRE) and FLAIR signal abnormality (FSA). Mean ADC and mean FA were calculated for each region. A Bland-Altman repeatability coefficient was also calculated for each parameter based on the two pre-treatment studies. A patient was considered to have a change in FA or ADC after therapy if the difference between the pre- and post-treatment values was greater than the repeatability coefficient for that parameter. Survival was compared using a Cox proportional hazard model. RESULTS: DTI detected a change in ADC within FSA after therapy in nine patients (five in whom ADC was increased; four in whom it was decreased). Patients with a change in ADC within FSA had significantly shorter overall survival (p=0.032) and progression free survival (p=0.046) than those with no change. CONCLUSION: In patients with recurrent glioblastoma multiforme treated with bevacizumab and irinotecan, a change in ADC after therapy in FSA is associated with decreased survival.

Authors
Paldino, MJ; Desjardins, A; Friedman, HS; Vredenburgh, JJ; Barboriak, DP
MLA Citation
Paldino, M. J., et al. “A change in the apparent diffusion coefficient after treatment with bevacizumab is associated with decreased survival in patients with recurrent glioblastoma multiforme..” Br J Radiol, vol. 85, no. 1012, Apr. 2012, pp. 382–89. Pubmed, doi:10.1259/bjr/24774491.
PMID
21224297
Source
pubmed
Published In
The British Journal of Radiology
Volume
85
Issue
1012
Publish Date
2012
Start Page
382
End Page
389
DOI
10.1259/bjr/24774491

Neuro-oncology: Glioblastoma--community adjusts to new standard of care.

Authors
Desjardins, A; Friedman, HS
MLA Citation
Desjardins, Annick, and Henry S. Friedman. “Neuro-oncology: Glioblastoma--community adjusts to new standard of care..” Nat Rev Neurol, vol. 8, no. 5, Mar. 2012, pp. 244–46. Pubmed, doi:10.1038/nrneurol.2012.42.
PMID
22430106
Source
pubmed
Published In
Nat Rev Neurol
Volume
8
Issue
5
Publish Date
2012
Start Page
244
End Page
246
DOI
10.1038/nrneurol.2012.42

Bevacizumab and daily temozolomide for recurrent glioblastoma.

BACKGROUND: The authors performed a phase 2 trial of combined protracted daily temozolomide and biweekly bevacizumab for patients with recurrent glioblastoma who had previously received radiation therapy and temozolomide. METHODS: There was no limit on the number of previous disease progressions or previous regimens allowed. Thirty-two adult patients were enrolled. Patients received temozolomide 50 mg/m(2) daily and bevacizumab 10 mg/kg intravenously every 14 days. Patients underwent physical examination and brain magnetic resonance imaging every 8 weeks. RESULTS: The authors observed a 6-month progression-free survival (PFS) rate of 18.8% (95% confidence interval [CI], 7.6%-33.7%) and a median PFS of 15.8 weeks. The median overall survival (OS) was 37 weeks, the 6-month OS rate was 62.5% (95% CI, 43.5%-76.7%), and the 12-month OS rate was 31.3% (95% CI, 16.4%-47.3%). Nine patients (28%) had a radiographic response, and 7 patients (22%) had disease progression within the first 8 weeks of treatment. Patterns of progression were available for 21 patients. The authors observed that 52% of patients (n = 11) progressed locally, 38% (n = 8) progressed with a diffuse pattern, and 10% (n = 2) progressed at a distant site. Two patients discontinued therapy secondary to toxicity (prolonged thrombocytopenia and grade 4 pancreatitis). One patient experienced grade 5 pneumonia. CONCLUSIONS: The current study demonstrated that a regimen of combined daily temozolomide and biweekly bevacizumab had some activity and was well tolerated. However, the results obtained in this study were inferior to those observed in studies of bevacizumab monotherapy and of combined irinotecan and bevacizumab therapy. The current patient population was more heterogeneous and was pretreated more heavily than patients in previous studies.

Authors
Desjardins, A; Reardon, DA; Coan, A; Marcello, J; Herndon, JE; Bailey, L; Peters, KB; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, Annick, et al. “Bevacizumab and daily temozolomide for recurrent glioblastoma..” Cancer, vol. 118, no. 5, Mar. 2012, pp. 1302–12. Pubmed, doi:10.1002/cncr.26381.
PMID
21792866
Source
pubmed
Published In
Cancer
Volume
118
Issue
5
Publish Date
2012
Start Page
1302
End Page
1312
DOI
10.1002/cncr.26381

Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naïve, recurrent glioblastoma.

We evaluated the efficacy of carboplatin, irinotecan, and bevacizumab among bevacizumab-naïve, recurrent glioblastoma (GBM) patients in a phase 2, open-label, single arm trial. Forty eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day one, while bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A-enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first two cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, non-compliance, or voluntary withdrawal. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints included safety and median overall survival (OS). All patients had progression after standard therapy. The median age was 51 years. Sixteen patients (40%) had a KPS of 90-100, while 27 (68%) were at first progression. The median time from original diagnosis was 11.4 months. The PFS-6 rate was 46.5% (95% CI: 30.4, 61.0%) and the median OS was 8.3 months [95% confidence interval (CI): 5.9, and 10.7 months]. Grade 4 events were primarily hematologic and included neutropenia and thrombocytopenia in 20 and 10%, respectively. The most common grade 3 events were neutropenia, thrombocytopenia, fatigue, and infection in 25, 20, 13, and 10%, respectively. Eleven patients (28%) discontinued study therapy due to toxicity and 17 patients (43%) required dose modification. One patient died due to treatment-related intestinal perforation. The addition of carboplatin and irinotecan to bevacizumab significantly increases toxicity but does not improve anti-tumor activity to that achieved historically with single-agent bevacizumab among bevacizumab-naïve, recurrent GBM patients. (ClinicalTrials.gov number NCT00953121).

Authors
Reardon, DA; Desjardins, A; Peters, KB; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Bulusu, A; Threatt, S; Friedman, AH; Vredenburgh, JJ; Friedman, HS
MLA Citation
Reardon, David A., et al. “Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naïve, recurrent glioblastoma..” J Neurooncol, vol. 107, no. 1, Mar. 2012, pp. 155–64. Pubmed, doi:10.1007/s11060-011-0722-2.
PMID
21986722
Source
pubmed
Published In
J Neurooncol
Volume
107
Issue
1
Publish Date
2012
Start Page
155
End Page
164
DOI
10.1007/s11060-011-0722-2

Outcome after bevacizumab clinical trial therapy among recurrent grade III malignant glioma patients.

Although outcome following bevacizumab among recurrent grade IV malignant glioma patients is documented as poor by several analyses, outcome for recurrent grade III patients following bevacizumab therapy has not been specifically evaluated. We performed a pooled analysis of 96 recurrent grade III malignant glioma patients enrolled on three consecutive phase II bevacizumab salvage trials to evaluate overall outcome following bevacizumab trial discontinuation. Outcome on the three bevacizumab trials, which included similar eligibility, treatment and assessment criteria, was comparable. Forty-nine patients who progressed on bevacizumab trial therapy and remained alive for at least 30 days elected to receive additional therapy. These patients achieved a median PFS-6 and OS of 30.6% (95% CI: 18.4, 43.6) and 10.3 months (95% CI: 5.2, 11.7), respectively. Among patients who continued bevacizumab therapy (n = 23) after study progression, PFS-6 and median OS were 39.1% (95% CI: 19.9, 58.0) and 9.2 months (95% CI: 5.2, 13.6), respectively, compared to 23.1% (95% CI: 9.4, 40.3; P = 0.51) and 10.3 months (95% CI: 2.5, 14.4; P = 0.91) for patients who initiated non-bevacizumab containing therapy (n = 26). Outcome after discontinuation of bevacizumab therapy for recurrent grade III malignant glioma patients is associated with improved outcome compared to historical data for recurrent grade IV malignant glioma patients. Salvage therapies following bevacizumab failure have modest activity for grade III malignant glioma patients that is independent of further bevacizumab continuation.

Authors
Reardon, DA; Herndon, JE; Peters, K; Desjardins, A; Coan, A; Lou, E; Sumrall, A; Turner, S; Sathornsumetee, S; Rich, JN; Boulton, S; Lipp, ES; Friedman, HS; Vredenburgh, JJ
MLA Citation
Reardon, David A., et al. “Outcome after bevacizumab clinical trial therapy among recurrent grade III malignant glioma patients..” J Neurooncol, vol. 107, no. 1, Mar. 2012, pp. 213–21. Pubmed, doi:10.1007/s11060-011-0740-0.
PMID
21997879
Source
pubmed
Published In
J Neurooncol
Volume
107
Issue
1
Publish Date
2012
Start Page
213
End Page
221
DOI
10.1007/s11060-011-0740-0

Addition of bevacizumab to standard radiation therapy and daily temozolomide is associated with minimal toxicity in newly diagnosed glioblastoma multiforme.

PURPOSE: To determine the safety of the addition of bevacizumab to standard radiation therapy and daily temozolomide for newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS: A total of 125 patients with newly diagnosed GBM were enrolled in the study, and received standard radiation therapy and daily temozolomide. All patients underwent a craniotomy and were at least 2 weeks postoperative. Radiation therapy was administered in 1.8-Gy fractions, with the clinical target volume for the primary course treated to a dose of 45 to 50.4 Gy, followed by a boost of 9 to 14.4 Gy, to a total dose of 59.4 Gy. Patients received temozolomide at 75 mg/m(2) daily throughout the course of radiation therapy. Bevacizumab was given at 10 mg/kg intravenously every 14 days, beginning a minimum of 4 weeks postoperatively. RESULTS: Of the 125 patients, 120 (96%) completed the protocol-specified radiation therapy. Five patients had to stop the protocol therapy, 2 patients with pulmonary emboli, and 1 patient each with a Grade 2 central nervous system hemorrhage, Grade 4 pancytopenia, and wound dehiscence requiring surgical intervention. All 5 patients ultimately finished the radiation therapy. After radiation therapy, 3 patients had progressive disease, 2 had severe fatigue and decreased performance status, 1 patient had a colonic perforation, and 1 had a rectal fissure; these 7 patients therefore did not proceed with the protocol-specified adjuvant temozolomide, bevacizumab, and irinotecan. However, 113 patients (90%) were able to continue on study. CONCLUSIONS: The addition of bevacizumab to standard radiation therapy and daily temozolomide was found to be associated with minimal toxicity in patients newly diagnosed with GBM.

Authors
Vredenburgh, JJ; Desjardins, A; Kirkpatrick, JP; Reardon, DA; Peters, KB; Herndon, JE; Marcello, J; Bailey, L; Threatt, S; Sampson, J; Friedman, A; Friedman, HS
MLA Citation
Vredenburgh, James J., et al. “Addition of bevacizumab to standard radiation therapy and daily temozolomide is associated with minimal toxicity in newly diagnosed glioblastoma multiforme..” Int J Radiat Oncol Biol Phys, vol. 82, no. 1, Jan. 2012, pp. 58–66. Pubmed, doi:10.1016/j.ijrobp.2010.08.058.
PMID
21036490
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
82
Issue
1
Publish Date
2012
Start Page
58
End Page
66
DOI
10.1016/j.ijrobp.2010.08.058

Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma.

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥ 10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication.

Authors
Reardon, DA; Norden, AD; Desjardins, A; Vredenburgh, JJ; Herndon, JE; Coan, A; Sampson, JH; Gururangan, S; Peters, KB; McLendon, RE; Norfleet, JA; Lipp, ES; Drappatz, J; Wen, PY; Friedman, HS
MLA Citation
Reardon, David A., et al. “Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma..” J Neurooncol, vol. 106, no. 2, Jan. 2012, pp. 409–15. Pubmed, doi:10.1007/s11060-011-0687-1.
PMID
21938530
Source
pubmed
Published In
J Neurooncol
Volume
106
Issue
2
Publish Date
2012
Start Page
409
End Page
415
DOI
10.1007/s11060-011-0687-1

A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma.

BACKGROUND: Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells. OBJECTIVE: To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses. METHODOLOGY: A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ). RESULTS AND CONCLUSIONS: Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00626015.

Authors
Sampson, JH; Schmittling, RJ; Archer, GE; Congdon, KL; Nair, SK; Reap, EA; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; Coan, A; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Mitchell, DA
MLA Citation
Sampson, John H., et al. “A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma..” Plos One, vol. 7, no. 2, 2012. Pubmed, doi:10.1371/journal.pone.0031046.
Website
http://hdl.handle.net/10161/16110
PMID
22383993
Source
pubmed
Published In
Plos One
Volume
7
Issue
2
Publish Date
2012
Start Page
e31046
DOI
10.1371/journal.pone.0031046

Alkylating agents: Part B. methylating agents

Authors
Friedman, HS; Averbuch, SD; Kurtzberg, J
MLA Citation
Friedman, H. S., et al. “Alkylating agents: Part B. methylating agents.” Cancer Chemotherapy and Biotherapy: Principles and Practice, 2011, pp. 732–68.
Source
scopus
Publish Date
2011
Start Page
732
End Page
768

Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy.

BACKGROUND: The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open-label, single-arm trial was evaluated. METHODS: Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression-free survival at 6 months (PFS-6), and secondary end points included safety and median overall survival (OS). RESULTS: All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0-7.0 months) and PFS-6 rate was 16% (95% CI, 5.0%-32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment-related deaths. CONCLUSIONS: Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously.

Authors
Reardon, DA; Desjardins, A; Peters, KB; Vredenburgh, JJ; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Coan, A; Threatt, S; Friedman, AH; Friedman, HS
MLA Citation
Reardon, David A., et al. “Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy..” Cancer, vol. 117, no. 23, Dec. 2011, pp. 5351–58. Pubmed, doi:10.1002/cncr.26188.
PMID
21590689
Source
pubmed
Published In
Cancer
Volume
117
Issue
23
Publish Date
2011
Start Page
5351
End Page
5358
DOI
10.1002/cncr.26188

Phase I study of sunitinib and irinotecan for patients with recurrent malignant glioma.

We determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, sunitinib, when administered with irinotecan among recurrent malignant glioma (MG) patients. For each 42-day cycle, sunitinib was administered once a day for four consecutive weeks followed by a 2 week rest. Irinotecan was administered intravenously every other week. Each agent was alternatively escalated among cohorts of 3-6 patients enrolled at each dose level. Patients on CYP3A-inducing anti-epileptic drugs were not eligible. Twenty-five patients with recurrent MG were enrolled, including 15 (60%) with glioblastoma (GBM) and 10 (40%) with grade 3 MG. Five patients progressed previously on bevacizumab and two had received prior VEGFR tyrosine kinase inhibitor therapy. The MTD was 50 mg of sunitinib combined with 75 mg/m(2) of irinotecan. DLT were primarily hematologic and included grade 4 neutropenia in 3 patients and one patient with grade 4 thrombocytopenia. Non-hematologic DLT included grade 3 mucositis (n = 1) and grade 3 dehydration (n = 1). Progression-free survival (PFS)-6 was 24% and only one patient achieved a radiographic response. The combination of sunitinib and irinotecan was associated with moderate toxicity and limited anti-tumor activity. Further studies with this regimen using the dosing schedules evaluated in this study are not warranted.

Authors
Reardon, DA; Vredenburgh, JJ; Coan, A; Desjardins, A; Peters, KB; Gururangan, S; Sathornsumetee, S; Rich, JN; Herndon, JE; Friedman, HS
MLA Citation
Reardon, David A., et al. “Phase I study of sunitinib and irinotecan for patients with recurrent malignant glioma..” J Neurooncol, vol. 105, no. 3, Dec. 2011, pp. 621–27. Pubmed, doi:10.1007/s11060-011-0631-4.
PMID
21744079
Source
pubmed
Published In
J Neurooncol
Volume
105
Issue
3
Publish Date
2011
Start Page
621
End Page
627
DOI
10.1007/s11060-011-0631-4

A phase I trial of the farnesyl transferase inhibitor, SCH 66336, with temozolomide for patients with malignant glioma.

We conducted a phase I clinical trial of the combination of SCH 66336 with temozolomide administered on the standard 5-day dosing schedule. The primary objective was to determine the maximum tolerated dose and dose limiting toxicity (DLT) of twice daily SCH 66336 when administered with temozolomide to adults with malignant glioma previously treated with radiation therapy. Patients were enrolled to two strata: stratum A, patients not on enzyme-inducing antiepileptic drugs (EIAEDs); stratum B, patients receiving EIAEDs. Temozolomide was administered at a dose of 150 mg/m(2) daily for five days for the first 28-day cycle and escalated to 200 mg/m(2), during subsequent cycles. SCH 66336 was administered twice daily on a continuous daily dosing schedule. The starting dose of SCH 66336 was 75 mg twice daily for stratum A and 125 mg twice daily for stratum B. Cohorts of 3-6 patients were treated per dose level until DLT was observed. Thirty six patients were enrolled on study, including 21 patients on stratum A and 15 on stratum B. All DLTs were grade 3 events and included hepatic, gastrointestinal, renal, thrombotic and constitutional events. No grade 4 or 5 toxicities were observed. The phase II dose of SCH 66336 when combined with temozolomide is 150 mg twice daily for patients not on EIAEDs and 175 mg twice daily for patients on EIAEDs.

Authors
Desjardins, A; Reardon, DA; Peters, KB; Threatt, S; Coan, AD; Herndon, JE; Friedman, AH; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, Annick, et al. “A phase I trial of the farnesyl transferase inhibitor, SCH 66336, with temozolomide for patients with malignant glioma..” J Neurooncol, vol. 105, no. 3, Dec. 2011, pp. 601–06. Pubmed, doi:10.1007/s11060-011-0627-0.
PMID
21735117
Source
pubmed
Published In
J Neurooncol
Volume
105
Issue
3
Publish Date
2011
Start Page
601
End Page
606
DOI
10.1007/s11060-011-0627-0

DENDRITIC CELL VACCINES TARGETING CYTOMEGALOVIRUS IN GLIOBLASTOMA

Authors
Mitchell, DA; Archer, GE; Friedman, HS; Herndon, JE; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, Duane A., et al. “DENDRITIC CELL VACCINES TARGETING CYTOMEGALOVIRUS IN GLIOBLASTOMA.” Neuro Oncology, vol. 13, OXFORD UNIV PRESS INC, Nov. 2011, pp. 39–39.
Source
wos
Published In
Neuro Oncology
Volume
13
Publish Date
2011
Start Page
39
End Page
39

MIBEFRADIL, A NOVEL THERAPY FOR GLIOBLATOMA MULTIFORME: INTERLACED THERAPY IN A MURINE MODEL

Authors
Keir, ST; Reardon, DA; Saling, JR; Gray, LS; Bigner, DD; Friedman, HS
MLA Citation
Keir, Stephen T., et al. “MIBEFRADIL, A NOVEL THERAPY FOR GLIOBLATOMA MULTIFORME: INTERLACED THERAPY IN A MURINE MODEL.” Neuro Oncology, vol. 13, OXFORD UNIV PRESS INC, Nov. 2011, pp. 108–09.
Source
wos
Published In
Neuro Oncology
Volume
13
Publish Date
2011
Start Page
108
End Page
109

ACTIVITY OF THE PAN-HER INHIBITOR PF-00299804 AGAINST A PANEL OF BRAIN TUMOR XENOGRAFTS

Authors
Keir, ST; Reardon, DA; Friedman, HS; Bigner, DD
MLA Citation
Keir, Stephen T., et al. “ACTIVITY OF THE PAN-HER INHIBITOR PF-00299804 AGAINST A PANEL OF BRAIN TUMOR XENOGRAFTS.” Neuro Oncology, vol. 13, OXFORD UNIV PRESS INC, Nov. 2011, pp. 164–164.
Source
wos
Published In
Neuro Oncology
Volume
13
Publish Date
2011
Start Page
164
End Page
164

PHASE II STUDY OF PANITUMUMAB IN COMBINATION WITH IRINOTECAN FOR MALIGNANT GLIOMA PATIENTS

Authors
Desjardins, A; Reardon, DA; Peters, KB; Herndon, JE; Gururangan, S; Norfleet, J; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, Annick, et al. “PHASE II STUDY OF PANITUMUMAB IN COMBINATION WITH IRINOTECAN FOR MALIGNANT GLIOMA PATIENTS.” Neuro Oncology, vol. 13, OXFORD UNIV PRESS INC, Nov. 2011, pp. 90–90.
Source
wos
Published In
Neuro Oncology
Volume
13
Publish Date
2011
Start Page
90
End Page
90

PROGNOSTIC IMPORTANCE OF QUALITY OF LIFE AND FATIGUE IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA

Authors
Peters, KB; Coan, AD; West, MJ; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Friedman, HS; Jones, LW
MLA Citation
Peters, Katherine B., et al. “PROGNOSTIC IMPORTANCE OF QUALITY OF LIFE AND FATIGUE IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA.” Neuro Oncology, vol. 13, OXFORD UNIV PRESS INC, Nov. 2011, pp. 123–123.
Source
wos
Published In
Neuro Oncology
Volume
13
Publish Date
2011
Start Page
123
End Page
123

THE ADDITION OF BEVACIZUMAB TO TEMOZOLOMIDE AND RADIATION THERAPY FOLLOWED BY BEVACIZUMAB, TEMOZOLOMIDE, AND ORAL TOPOTECAN FOR NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Peters, KB; Kirkpatrick, JP; Herndon, JE; Coan, AD; Bailey, L; Janney, D; Lu, C; Friedman, HS
MLA Citation
Vredenburgh, James J., et al. “THE ADDITION OF BEVACIZUMAB TO TEMOZOLOMIDE AND RADIATION THERAPY FOLLOWED BY BEVACIZUMAB, TEMOZOLOMIDE, AND ORAL TOPOTECAN FOR NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME.” Neuro Oncology, vol. 13, OXFORD UNIV PRESS INC, Nov. 2011, pp. 89–90.
Source
wos
Published In
Neuro Oncology
Volume
13
Publish Date
2011
Start Page
89
End Page
90

Bevacizumab-induced reversible posterior leukoencephalopathy syndrome and successful retreatment in a patient with glioblastoma.

Authors
Lou, E; Turner, S; Sumrall, A; Reardon, DA; Desjardins, A; Peters, KB; Sampson, JH; Friedman, HS; Vredenburgh, JJ
MLA Citation
Lou, Emil, et al. “Bevacizumab-induced reversible posterior leukoencephalopathy syndrome and successful retreatment in a patient with glioblastoma..” J Clin Oncol, vol. 29, no. 28, Oct. 2011, pp. e739–42. Pubmed, doi:10.1200/JCO.2011.36.1865.
PMID
21900098
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
28
Publish Date
2011
Start Page
e739
End Page
e742
DOI
10.1200/JCO.2011.36.1865

Everolimus tablets for patients with subependymal giant cell astrocytoma.

INTRODUCTION: Better understanding of aberrantly active molecular pathways in tumors offers potential to develop more specific and less toxic therapies. Abnormal mammalian target of rapamycin (mTOR) complex signaling and defects in TSC1 and TSC2 have been associated with the development of subependymal giant cell astrocytomas (SEGAs) in tuberous sclerosis complex (TSC) patients. Recently, mTOR inhibitors such as everolimus have shown encouraging benefit for patients with SEGAs. AREAS COVERED: The authors discuss a molecular genetic pathway linked with TSC, specifically the role of two proteins whose functional absence is responsible for most SEGA tumors that arise in TSC patients. The authors also examine the rationale for targeted agents against this pathway therapeutically and describe the clinical evidence underlying the FDA approval of everolimus for patients with inoperable SEGAs. EXPERT OPINION: Everolimus (Afinitor) selectively targets a molecular defect of SEGAs in TSC patients. Although surgery is effective, most SEGAs recur. An agent that inhibits an underlying molecular abnormality represents a particularly attractive therapeutic option for patients with inoperable or recurrent tumors. Studies are also underway to assess everolimus in treating other sequelae of TSC, and other gliomas. Finally, additional research aimed at better understanding aberrant cell signaling pathways may lead to the development of more effective therapeutics.

Authors
Turner, SG; Peters, KB; Vredenburgh, JJ; Desjardins, A; Friedman, HS; Reardon, DA
MLA Citation
Turner, Scott G., et al. “Everolimus tablets for patients with subependymal giant cell astrocytoma..” Expert Opin Pharmacother, vol. 12, no. 14, Oct. 2011, pp. 2265–69. Pubmed, doi:10.1517/14656566.2011.601742.
PMID
21806479
Source
pubmed
Published In
Expert Opin Pharmacother
Volume
12
Issue
14
Publish Date
2011
Start Page
2265
End Page
2269
DOI
10.1517/14656566.2011.601742

Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans.

Lymphodepletion augments adoptive cell transfer during antitumor immunotherapy, producing dramatic clinical responses in patients with malignant melanoma. We report that the lymphopenia induced by the chemotherapeutic agent temozolomide (TMZ) enhances vaccine-driven immune responses and significantly reduces malignant growth in an established model of murine tumorigenesis. Unexpectedly, despite the improved antitumor efficacy engendered by TMZ-induced lymphopenia, there was a treatment related increase in the frequency of immunosuppressive regulatory T cells (T(Regs); P = .0006). Monoclonal antibody (mAb)-mediated inhibition of the high-affinity IL-2 receptor α (IL-2Rα/CD25) during immunotherapy in normal mice depleted T(Regs) (73% reduction; P = .0154) but also abolished vaccine-induced immune responses. However, during lymphodepletion, IL-2Rα blockade decreased T(Regs) (93% reduction; P = .0001) without impairing effector T-cell responses, to augment therapeutic antitumor efficacy (66% reduction in tumor growth; P = .0024). Of clinical relevance, we also demonstrate that anti-IL-2Rα mAb administration during recovery from lymphodepletive TMZ in patients with glioblastoma reduced T(Reg) frequency (48% reduction; P = .0061) while permitting vaccine-stimulated antitumor effector cell expansion. To our knowledge, this is the first report of systemic antibody-mediated T(Reg) depletion during lymphopenia and the consequent synergistic enhancement of vaccine-driven cellular responses, as well as the first demonstration that anti-IL-2Rα mAbs function differentially in nonlymphopenic versus lymphopenic contexts.

Authors
Mitchell, DA; Cui, X; Schmittling, RJ; Sanchez-Perez, L; Snyder, DJ; Congdon, KL; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, Duane A., et al. “Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans..” Blood, vol. 118, no. 11, Sept. 2011, pp. 3003–12. Pubmed, doi:10.1182/blood-2011-02-334565.
PMID
21768296
Source
pubmed
Published In
Blood
Volume
118
Issue
11
Publish Date
2011
Start Page
3003
End Page
3012
DOI
10.1182/blood-2011-02-334565

Exercise behavior, functional capacity, and survival in adults with malignant recurrent glioma.

PURPOSE: Identifying strong markers of prognosis are critical to optimize treatment and survival outcomes in patients with malignant recurrent glioma. We investigated the prognostic significance of exercise behavior and functional capacity in this population. PATIENTS AND METHODS: Using a prospective design, 243 patients with WHO grades 3 to 4 recurrent malignant glioma and Karnofsky performance status (KPS) ≥ 70 completed a self-administered questionnaire that assessed exercise behavior and performed a 6-minute walk test (6MWT) to assess functional capacity. Cox proportional models were used to estimate the risk of all-cause mortality according to 6MWT distance (6MWD; < 390 meters, 390-489 meters, > 489 meters) and exercise behavior (metabolic equivalent [MET] -h/wk) adjusted for KPS and other important clinical factors. RESULTS: Median follow-up was 27.43 months. During this period, 149 deaths were recorded (61% of the total sample). Exercise behavior was an independent predictor of survival (P = .0081). Median survival was 13.03 months for patients reporting < 9 MET-h/wk relative to 21.84 months for those reporting ≥ 9 MET-h/wk. Exercise behavior added incremental prognostic value beyond that provided by KPS, age, sex, grade, and number of prior progressions (P < .001). Compared with patients reporting < 9 MET-h/wk, the adjusted hazard ratio for mortality was 0.64 (95% CI, 0.46 to 0.91) for patients reporting ≥ 9 MET-h/wk. Functional capacity was not an independent predictor of prognosis. CONCLUSION: Exercise behavior is a strong independent predictor of survival that provides incremental prognostic value to KPS as well as traditional markers of prognosis in malignant recurrent glioma.

Authors
Ruden, E; Reardon, DA; Coan, AD; Herndon, JE; Hornsby, WE; West, M; Fels, DR; Desjardins, A; Vredenburgh, JJ; Waner, E; Friedman, AH; Friedman, HS; Peters, KB; Jones, LW
MLA Citation
Ruden, Emily, et al. “Exercise behavior, functional capacity, and survival in adults with malignant recurrent glioma..” J Clin Oncol, vol. 29, no. 21, July 2011, pp. 2918–23. Pubmed, doi:10.1200/JCO.2011.34.9852.
PMID
21690470
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
21
Publish Date
2011
Start Page
2918
End Page
2923
DOI
10.1200/JCO.2011.34.9852

Intensified temozolomide fails to hike glioblastoma survival: Commentary

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Intensified temozolomide fails to hike glioblastoma survival: Commentary.” Oncology Report, no. JULY-AUGUST, July 2011.
Source
scopus
Published In
Oncology Report
Issue
JULY-AUGUST
Publish Date
2011
Start Page
6

The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma.

PURPOSE: To determine if the addition of bevacizumab to radiation therapy and temozolomide, followed by bevacizumab, temozolomide, and irinotecan, for newly diagnosed glioblastoma patients is safe and effective. EXPERIMENTAL DESIGN: A total of 75 patients with newly diagnosed glioblastoma were enrolled in the phase II trial that investigated the addition of bevacizumab to standard radiation therapy and daily temozolomide followed by the addition of bevacizumab and irinotecan to adjuvant temozolomide. The bevacizumab was given at 10 mg/kg every 14 days beginning a minimum of 4 weeks postcraniotomy. Two weeks after radiation therapy, the patients began 6 to 12 cycles of 5-day temozolomide with bevacizumab and irinotecan every 14 days. The primary endpoint was the proportion of patients alive 16 months after informed consent. RESULTS: The therapy had moderate toxicity. Three patients, one of whom had a grade 2 central nervous system hemorrhage, came off study during radiation therapy. Seventy patients started the postradiation therapy, and 16 (23%) terminated this adjuvant therapy early because of toxicity. The median overall survival was 21.2 months (95% CI: 17.2-25.4), and 65% of the patients were alive at 16 months (95% CI: 53.4-74.9). The median progression-free survival was 14.2 months (95% CI: 12-16). CONCLUSION: The addition of bevacizumab to standard radiation therapy and temozolomide, followed by bevacizumab, irinotecan, and temozolomide, for the treatment of newly diagnosed glioblastoma has moderate toxicity and may improve efficacy compared with historical controls. The results from phase III trials are required before the role of bevacizumab for newly diagnosed glioblastoma is established.

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Peters, KB; Herndon, JE; Marcello, J; Kirkpatrick, JP; Sampson, JH; Bailey, L; Threatt, S; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Vredenburgh, James J., et al. “The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma..” Clin Cancer Res, vol. 17, no. 12, June 2011, pp. 4119–24. Pubmed, doi:10.1158/1078-0432.CCR-11-0120.
PMID
21531816
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
17
Issue
12
Publish Date
2011
Start Page
4119
End Page
4124
DOI
10.1158/1078-0432.CCR-11-0120

Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy.

We evaluated the efficacy of metronomic etoposide or temozolomide administered with bevacizumab among recurrent glioblastoma (GBM) patients who progressed on prior bevacizumab therapy in a phase 2, open-label, two-arm trial. Twenty-three patients received bevacizumab (10 mg/kg) every 2 weeks with either oral etoposide (50 mg/m2) daily for 21 consecutive days each month or daily temozolomide (50 mg/m2). The primary endpoint was 6-month progression-free survival (PFS-6) and secondary endpoints included safety and overall survival. Both the etoposide and temozolomide arms of the study closed at the interim analysis due to lack of adequate anti-tumor activity. No radiographic responses were observed. Although 12 patients (52%) achieved stable disease, PFS-6 was 4.4% and the median PFS was 7.3 weeks. The only grade 4 adverse event was reversible neutropenia. Grade 3 toxicities included fatigue (n = 2) and infection (n = 1). Metronomic etoposide or temozolomide is ineffective when administered with bevacizumab among recurrent GBM patients who have progressed on prior bevacizumab therapy. Alternative treatment strategies remain critically needed for this indication.

Authors
Reardon, DA; Desjardins, A; Peters, K; Gururangan, S; Sampson, J; Rich, JN; McLendon, R; Herndon, JE; Marcello, J; Threatt, S; Friedman, AH; Vredenburgh, JJ; Friedman, HS
MLA Citation
Reardon, David A., et al. “Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy..” J Neurooncol, vol. 103, no. 2, June 2011, pp. 371–79. Pubmed, doi:10.1007/s11060-010-0403-6.
PMID
20853132
Source
pubmed
Published In
J Neurooncol
Volume
103
Issue
2
Publish Date
2011
Start Page
371
End Page
379
DOI
10.1007/s11060-010-0403-6

Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab.

Neurocognitive decline is a frequent adverse effect of glioblastoma. Antitumor therapies that are efficacious, as measured by traditional endpoints such as objective response (OR) and progression-free survival (PFS), and have beneficial effects on neurocognitive function (NCF) are of clinical benefit to these patients. We evaluated neurocognitive changes across time in 167 patients with recurrent glioblastoma treated with bevacizumab-based therapy in BRAIN, a phase II, randomized, multicenter trial. All patients underwent MRI and neurocognitive testing at baseline and every 6 weeks thereafter. Memory, visuomotor scanning speed, and executive function were evaluated using the Hopkins Verbal Learning Test-Revised, the Trail Making Test, and the Controlled Oral Word Association test, respectively. NCF relative to baseline for patients with an OR, PFS >6 months, or disease progression was evaluated at time of OR, 24 weeks, and time of progression, respectively. For patients with an OR or PFS >6 months, median standardized test scores were examined from baseline to week 24. Most patients with an OR or PFS >6 months had poorer NCF performance compared to the general population at baseline and had improved or stable NCF at the time of response or at the 24-week assessment, respectively; most patients with progressive disease had neurocognitive decline at the time of progression. For patients with an OR or PFS >6 months, median standardized test scores were largely stable across the first 24 weeks on study. Neurocognitive testing was an objective, valid, and feasible method of monitoring NCF in patients with recurrent glioblastoma.

Authors
Wefel, JS; Cloughesy, T; Zazzali, JL; Zheng, M; Prados, M; Wen, PY; Mikkelsen, T; Schiff, D; Abrey, LE; Yung, WKA; Paleologos, N; Nicholas, MK; Jensen, R; Vredenburgh, J; Das, A; Friedman, HS
MLA Citation
Wefel, Jeffrey S., et al. “Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab..” Neuro Oncol, vol. 13, no. 6, June 2011, pp. 660–68. Pubmed, doi:10.1093/neuonc/nor024.
PMID
21558074
Source
pubmed
Published In
Neuro Oncol
Volume
13
Issue
6
Publish Date
2011
Start Page
660
End Page
668
DOI
10.1093/neuonc/nor024

Bevacizumab, temozolomide, and radiation therapy followed by bevacizumab, temozolomide, and oral topotecan for newly-diagnosed glioblastoma multiforme (GBM).

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Peters, K; Kirkpatrick, J; Coan, AD; Bailey, L; Janney, D; Lu, C; Friedman, HS
MLA Citation
Vredenburgh, J. J., et al. “Bevacizumab, temozolomide, and radiation therapy followed by bevacizumab, temozolomide, and oral topotecan for newly-diagnosed glioblastoma multiforme (GBM)..” Journal of Clinical Oncology, vol. 29, no. 15, AMER SOC CLINICAL ONCOLOGY, May 2011.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15
Publish Date
2011

Upfront bevacizumab with temozolomide or with temozolomide and irinotecan for unresectable or multifocal glioblastoma.

Authors
Lou, E; Reardon, DA; Peters, K; Desjardins, A; Herndon, JE; Coan, AD; Turner, SG; Sumrall, AL; Bailey, L; Friedman, HS; Vredenburgh, JJ
MLA Citation
Lou, E., et al. “Upfront bevacizumab with temozolomide or with temozolomide and irinotecan for unresectable or multifocal glioblastoma..” Journal of Clinical Oncology, vol. 29, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2011, pp. 2055–2055. Crossref, doi:10.1200/jco.2011.29.15_suppl.2055.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
2055
End Page
2055
DOI
10.1200/jco.2011.29.15_suppl.2055

Phase II clinical trial of bortezomib and bevacizumab combination in recurrent glioblastoma.

Authors
Bota, DA; Eroglu, Z; Reardon, DA; Fu, BD; Norfleet, J; Desjardins, A; Linskey, ME; Peters, K; Friedman, HS; Vredenburgh, JJ
MLA Citation
Bota, D. A., et al. “Phase II clinical trial of bortezomib and bevacizumab combination in recurrent glioblastoma..” Journal of Clinical Oncology, vol. 29, no. 15, AMER SOC CLINICAL ONCOLOGY, May 2011.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15
Publish Date
2011

A pharmacokinetic (PK) study of AC480 administered twice daily in patients with surgically resectable, recurrent malignant glioma (MG) not on enzyme-inducing antiepileptic drug (EIAED).

Authors
Desjardins, A; Reardon, DA; Vredenburgh, JJ; Peters, K; Trikha, M; James, J; Gardner, M; Brickhouse, A; Herndon, JE; Friedman, HS
MLA Citation
Desjardins, A., et al. “A pharmacokinetic (PK) study of AC480 administered twice daily in patients with surgically resectable, recurrent malignant glioma (MG) not on enzyme-inducing antiepileptic drug (EIAED)..” Journal of Clinical Oncology, vol. 29, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2011, pp. 2070–2070. Crossref, doi:10.1200/jco.2011.29.15_suppl.2070.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
2070
End Page
2070
DOI
10.1200/jco.2011.29.15_suppl.2070

Bevacizumab (BV) continuation following BV progression: Meta-analysis of five consecutive recurrent glioblastoma (GBM) trials.

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Peters, K; Coan, AD; Herndon, JE; Friedman, HS
MLA Citation
Reardon, D. A., et al. “Bevacizumab (BV) continuation following BV progression: Meta-analysis of five consecutive recurrent glioblastoma (GBM) trials..” Journal of Clinical Oncology, vol. 29, no. 15, AMER SOC CLINICAL ONCOLOGY, May 2011.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15
Publish Date
2011

Bevacizumab (BV) continuation following BV progression: Meta-analysis of five consecutive recurrent glioblastoma (GBM) trials.

2030 Background: Although BV benefits most recurrent GBM patients, the duration of benefit is limited and subsequent survival after BV progression is poor due to lack of effective therapeutic options. METHODS: We performed a meta-analysis of five consecutive phase II BV salvage trials conducted at our institution to evaluate potential prognostic factors and to assess outcome following BV trial progression for recurrent GBM patients. RESULTS: The five BV salvage trials included similar eligibility, treatment and assessment criteria and enrolled 172 recurrent GBM patients. Outcome across the trials was comparable and traditional prognostic factors including age, KPS and degree of prior treatment did not predict outcome. Following progression on BV trial therapy, 95 patients (68%) received additional therapy including 42 patients who were initially treated with a non-BV regimen and 53 who received a BV regimen. Patients who received non-BV therapy did not differ from those who received BV therapy with regard to age, number of prior episodes of progression, time from original diagnosis or duration on BV trial therapy. The median overall survival (OS) and OS at 6 months (OS-6) for patients who received a BV regimen after progression on a BV trial was 6.1 months (95% CI: 5.2, 7.6) and 51.1% (95% CI: 36.7, 63.8), while the median OS and OS-6 for patients treated with a non-BV regimen were 4.5 months (95% CI: 2.5, 5.4) and 31.0% (95% CI: 17.8, 45.0), respectively (p=0.0135). After adjusting for known risk factors, BV therapy was the only factor associated with OS for patients undergoing further therapy after BV trial progression (hazard ratio 0.564; p-value 0.0287). CONCLUSIONS: Among recurrent GBM patients, clinical factors may poorly predict outcome for BV therapy. Outcome following BV failure is poor, but continuation of BV improves OS compared to available non-BV therapy.

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Peters, K; Coan, AD; Herndon, JE; Friedman, HS
MLA Citation
Reardon, D. A., et al. “Bevacizumab (BV) continuation following BV progression: Meta-analysis of five consecutive recurrent glioblastoma (GBM) trials..” J Clin Oncol, vol. 29, no. 15_suppl, May 2011.
PMID
28023816
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
2030

Venous thromboembolic complications in patients with malignant glioma treated on a bevacizumab clinical trial.

9090 Background: Although the prognosis for malignant glioma remains poor, the introduction of bevacizumab has improved survival for patients with this devastating illness. Bevacizumab is a humanized monoclonal antibody to vascular endothelial growth factor (VEGF). Patients with malignant gliomas are felt to have an incidence of thromboembolism in 20-30%. As patients with malignant gliomas are at increased risk for venous thrombosis by nature of their diagnosis, one worries about potentially increasing this risk with the addition of bevacizumab. Previous reports have shown an incidence of approximately 25% of venous thromboembolic disease in cancer patients receiving concurrent chemotherapy and bevacizumab. METHODS: We performed a retrospective analysis of all clinical trial participants receiving bevacizumab for malignant glioma from April 2005 to January 2011. 617 patients with malignant glioma were included: 529 with glioblastoma (GBM) and 88 with anaplastic glioma (AG). Of those, 204 patients were newly diagnosed. This group was treated with standard temozolomide and radiation, combined with bevacizumab and a topoisomerase I inhibitor. 413 patients with recurrent tumors were included. Their treatment regimens varied, but all had progressed on standard therapy. After being diagnosed with a venous thromboembolic complication, patients were started on anticoagulation with heparin, low molecular weight heparin, or warfarin. They were followed until death or progression of disease. RESULTS: The incidence of venous thrombosis was 7% (n=43), and incidence of pulmonary embolism was 2.9% (n=18). Of those, 1.3% (n=8) were patients with anaplastic glioma. Newly diagnosed patients represented only 2.3% (n=14). Of those patients, 0.6% (n=4) had a history of previous venous thrombosis but were no longer on anticoagulation. The mean time on treatment prior to diagnosis of the venous thromboembolic complication was 105.8 days; and a median time of 87 days. Of the patients treated for thromboembolic disease, 0.5% (n=3) had intracranial hemorrhage. CONCLUSIONS: Use of bevacizumab does not increase the risk of venous thromboembolic complications in patients with malignant gliomas.

Authors
Sumrall, AL; Reardon, DA; Desjardins, A; Peters, K; Lou, E; Turner, SG; Bailey, L; Friedman, HS; Vredenburgh, JJ
MLA Citation
Sumrall, A. L., et al. “Venous thromboembolic complications in patients with malignant glioma treated on a bevacizumab clinical trial..” J Clin Oncol, vol. 29, no. 15_suppl, May 2011.
PMID
28021530
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
9090

Upfront bevacizumab with temozolomide or with temozolomide and irinotecan for unresectable or multifocal glioblastoma.

2055 Background: Patients with unresectable or multifocal glioblastomas (GBs) have a poor prognosis with median survival of 6-10 months. Given the angiogenic phenotype of GB, we conducted two phase II trials of upfront 5-day temozolomide (TMZ) and Bevacizumab (BV) with or without Irinotecan in patients with newly diagnosed unresectable or multifocal GB. METHODS: Before radiation, patients received up to 4 cycles of temozolomide at 200 mg/m(2)/d days 1-5 and BV at 10 mg/kg on days 1 and 15 in each 28-day cycle. In the second trial, Irinotecan was added on days 1 and 15 at 125 mg/M(2) for patients not on an enzyme-inducing anti-epileptic drug (EIAED), or 340 mg/M(2) for patients on an EIAED. An MRI was performed monthly and therapy continued as long as there was no tumor progression, grade 4 non-hematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary endpoint was tumor response using the RANO criteria. RESULTS: In the initial trial of TMZ and BV, 41 patients were enrolled from 10/07 to 9/08. MRI's were available from 31 patients. There were 8 (25.8%) partial responses, 19 (61.3 %) patients with stable disease, and 4 (12.9 %) had disease progression. 19 of the 41 patients enrolled completed four cycles without tumor progression. The regimen was tolerable, with three grade 4 hematologic toxicities. There were 3 venous thromboembolic complications. There were 2 CNS hemorrhages. The median PFS was 5.2 mos (3.2, 9.0 months) and the median OS was 11.7 months (7.1, 15.6 months). In the second trial, Irinotecan was added to TMZ and BV and 41 patients were enrolled between 12/09 and 11/10. The partial response rate was 41%, 44% had stable disease and 15% had progression. 16 of 41 patients completed four cycles without tumor progression. There were 4 patients with grade 4 hematologic toxicity, 7 patients with venous thromboembolic complications and 1 with CNS hemorrhage. The median PFS was 6.7 months (2.0, 10.5 months) and median OS was 10.5 months (7.2, ND months). CONCLUSIONS: Upfront TMZ and BV was well tolerated. Adding Irinotecan to TMZ and BV does not appear to improve survival. Upfront therapy for unresectable or multifocal GB is an excellent platform to determine clinical activity.

Authors
Lou, E; Reardon, DA; Peters, K; Desjardins, A; Herndon, JE; Coan, AD; Turner, SG; Sumrall, AL; Bailey, L; Friedman, HS; Vredenburgh, JJ
MLA Citation
Lou, E., et al. “Upfront bevacizumab with temozolomide or with temozolomide and irinotecan for unresectable or multifocal glioblastoma..” J Clin Oncol, vol. 29, no. 15_suppl, May 2011.
PMID
28019946
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
2055

Phase II clinical trial of bortezomib and bevacizumab combination in recurrent glioblastoma.

2056 Background: The only approved 2nd-line treatment for glioblastoma is Bevacizumab (Avastin), with estimated 6-month progression-free survival (PFS) rate of 42.6% and overall survival (OS) of 9.2 months. Laboratory data show Bortezomib (Velcade) is an effective agent in glioma models. We evaluated the combination of Avastin and Velcade in patients with recurrent GBM in a phase II, 2 center, open-label trial. METHODS: Eligible patients were over 18 years of age, with WHO grade 4 glioma, Karnofsky score 70%. Bevacizumab was given 15 mg/kg IV every 3 weeks, and Bortezomib was given on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42 day cycle, at 1.7 mg/m2 for patients on non-enzyme-inducing antiepileptic drugs (EIAED) and 2.5 mg/m2 for patients on EIAED. Primary end points were 6-month PFS; secondary endpoints were toxicity, PFS, OS and radiographic response. RESULTS: There were a total of 61 patients enrolled, 32 patients on non-EIAEDs, and 29 patients on EIADs. Median age was 55.2. Six-month PFS was 40.6% for patients on non-EIAEDs, and 24.1% for patients on EIAEDs (p=0.17). Eleven patients are still alive; median OS was 9.1 months, with 8.8 months for non-EIAED patients, and 9.6 months for EIAED patients (p = 0.9). Of the patients on non-EIAEDs, best radiographic response included 11 patients (34.4%) with partial response, 13 with stable disease (40.6%), and 8 with progressive disease. Of patients on EIAEDs, 3 patients (10.3%) had a partial response, 18 (62.1%) with stable disease, and 6 with progression. On comparison of partial response rates between the 2 groups, p=0.03 was obtained. Most frequent grade 3 non-hematologic toxicities included fatigue (15.9%), sensory neuropathy (10.2%), diarrhea (9%), and thrombosis (8%). There were 2 episodes of grade 4 hyponatremia and 1 episode of epistaxis from a nasal septal ulcer. 14 patients eventually had to be taken off of Velcade and continued Avastin alone, due to sensory neuropathy. CONCLUSIONS: Bevacizumab and Bortezomib appear to be an effective treatment for recurrent malignant gliomas with a moderate toxicity profile. However, this phase II clinical study suggests that the combination is not superior to single-agent Bevacizumab and that the response may be blunted in the presence of EIAEDs.

Authors
Bota, DA; Eroglu, Z; Reardon, DA; Fu, BD; Norfleet, J; Desjardins, A; Linskey, ME; Peters, K; Friedman, HS; Vredenburgh, JJ
MLA Citation
Bota, D. A., et al. “Phase II clinical trial of bortezomib and bevacizumab combination in recurrent glioblastoma..” J Clin Oncol, vol. 29, no. 15_suppl, May 2011.
PMID
28019947
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
2056

A pharmacokinetic (PK) study of AC480 administered twice daily in patients with surgically resectable, recurrent malignant glioma (MG) not on enzyme-inducing antiepileptic drug (EIAED).

2070 Background: AC480 is a novel oral tyrosine kinase inhibitor of the human epidermal growth factor receptor family, especially EGFR and HER2. EGFR is an important therapeutic target in MG. We performed a pilot study to evaluate the tumor and plasma PK of AC480 among patients with recurrent MG. METHODS: Eligibility included: adult patients with < three recurrences of a WHO grade 3 or 4 MG; candidate to surgical resection; prior treatment with radiotherapy and chemotherapy; Karnofsky >60%; adequate hematologic, renal and liver function. Exclusion included use of EIAED and prior targeted therapies to EGFR and HER2. FDG-PET was obtained at baseline, then AC480 was initiated at 300 mg orally BID. FDG-PET was repeated on day 14. Patients remained on treatment until surgery (day16). Plasma PK were obtained on days 1, 14 and 16. Tumor specimen for tumor PK was obtained at surgery. Patients resumed AC480 7 to 21 days post-surgery. RESULTS: As planned, 5 patients were enrolled on study (WHO grade 4, n=4; WHO grade 3, n=1). Median age was 58 (range, 36-65). All patients completed FDG-PET and surgery. Three patients had same or decreased metabolic activity on day 14 FDG-PET; two had increased metabolic activity. Following surgery, 4 patients resumed therapy, one patient refused, as pathology showed WHO grade 2. One patient remains on therapy after 45+ weeks. Two patients progressed 4 weeks after resuming AC480 and one after 8 weeks. One patient each experienced grade 3 proteinuria and leukopenia. Tumor PK levels were variable, but AC480 was present in all samples. Concentrations ranged from 2561 to 8703 ng/mL (5 to 16 uM). Tumor/Plasma PK ratios ranged from 3 to 11, indicating tumor levels exceeded plasma levels in all patients. CONCLUSIONS: AC480 is well tolerated and reaches the brain with tumor PK levels exceeding plasma. Further trials combining AC480 with chemotherapy or other targeted therapies are warranted.

Authors
Desjardins, A; Reardon, DA; Vredenburgh, JJ; Peters, K; Trikha, M; James, J; Gardner, M; Brickhouse, A; Herndon, JE; Friedman, HS
MLA Citation
Desjardins, A., et al. “A pharmacokinetic (PK) study of AC480 administered twice daily in patients with surgically resectable, recurrent malignant glioma (MG) not on enzyme-inducing antiepileptic drug (EIAED)..” J Clin Oncol, vol. 29, no. 15_suppl, May 2011.
PMID
28019891
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
2070

Bevacizumab, temozolomide, and radiation therapy followed by bevacizumab, temozolomide, and oral topotecan for newly-diagnosed glioblastoma multiforme (GBM).

2098 Background: The prognosis for newly-diagnosed GBM remains poor. Adding temozolomide to radiation therapy improved the median event-free survival (EFS) to 6.9 months and median overall survival to 14.6 months. The five year survival remains < 10%. GBM's have abundant neo-vascularization and the highest level of vascular endothelial growth factor (VEGF). Bevacizumab is an antibody to VEGF and is the most active agent for recurrent GBM. Hypoxia inducing factor-1 α (HIF-1 α) is an important regulator of VEGF, and topotecan may inhibit HIF-1 α. We performed a phase II trial in newly diagnosed GBM patients, adding bevacizumab and topotecan to standard therapy. METHODS: Eighty newly diagnosed GBM patients were enrolled after their craniotomy between December 2009 and December 2010. Patients received standard radiation therapy and temozolomide at 75 mg/m(2)/d beginning between 2-6 weeks post-craniotomy. Bevacizumab, 10 mg/kg every 14 days was added a minimum of 4 weeks post-op. Two weeks after radiation therapy was completed, 12 monthly cycles of temozolomide at 150-200 mg/m(2)/d days 1-5, oral topotecan at 1.5 mg/m(2/)day days 2-6 for patients not on an enzyme inducing anti-epileptic drug (EIAED) and 2.0 mg/m(2)/day days 2-6 for patients on an EIAED bevacizumab at 10 mg/kg on days 1 and 15. RESULTS: Adding bevacizumab and topotecan to standard therapy resulted in a 6-month EFS of 90%. The median overall survival has not been reached, but 96% of the patients are alive at 8 months. The regimen was tolerable, 96% completed radiation therapy. Eight patients came off due to toxicity, there were 2 CNS hemorrhages, 2 grade 4 thrombocytopenias, 1 pulmonary embolus, 1 colon perforation, 1 craniotomy bone flap infection, and 1 CMV pneumonitis. There were 2 toxic deaths, 1 from CMV pneumonits and 1 from CNS hemorrhage. There are 10 progressions. A comprehensive analysis of tumor biomarkers is underway. CONCLUSIONS: Adding bevacizumab to temozolomide and radiation followed by temozolomide, bevacizumab and oral topotecan is tolerable. The 6-month EFS is encouraging. Randomized phase III trials of the addition of bevacizumab to the treatments of newly diagnosed GBM patients are essential.

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Peters, K; Kirkpatrick, J; Coan, AD; Bailey, L; Janney, D; Lu, C; Friedman, HS
MLA Citation
Vredenburgh, J. J., et al. “Bevacizumab, temozolomide, and radiation therapy followed by bevacizumab, temozolomide, and oral topotecan for newly-diagnosed glioblastoma multiforme (GBM)..” J Clin Oncol, vol. 29, no. 15_suppl, May 2011.
PMID
28019863
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
2098

A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma.

Glioblastoma, the most common primary malignant brain tumor among adults, is a highly angiogenic and deadly tumor. Angiogenesis in glioblastoma, driven by hypoxia-dependent and independent mechanisms, is primarily mediated by vascular endothelial growth factor (VEGF), and generates blood vessels with distinctive features. The outcome for patients with recurrent glioblastoma is poor because of ineffective therapies. However, recent encouraging rates of radiographic response and progression-free survival, and adequate safety, led the FDA to grant accelerated approval of bevacizumab, a humanized monoclonal antibody against VEGF, for the treatment of recurrent glioblastoma in May 2009. These results have triggered significant interest in additional antiangiogenic agents and therapeutic strategies for patients with both recurrent and newly diagnosed glioblastoma. Given the potent antipermeability effect of VEGF inhibitors, the Radiologic Assessment in Neuro-Oncology (RANO) criteria were recently implemented to better assess response among patients with glioblastoma. Although bevacizumab improves survival and quality of life, eventual tumor progression is the norm. Better understanding of resistance mechanisms to VEGF inhibitors and identification of effective therapy after bevacizumab progression are currently a critical need for patients with glioblastoma.

Authors
Reardon, DA; Turner, S; Peters, KB; Desjardins, A; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Jones, LW; Kirkpatrick, JP; Friedman, AH; Vredenburgh, JJ; Bigner, DD; Friedman, HS
MLA Citation
Reardon, David A., et al. “A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma..” J Natl Compr Canc Netw, vol. 9, no. 4, Apr. 2011, pp. 414–27.
PMID
21464146
Source
pubmed
Published In
J Natl Compr Canc Netw
Volume
9
Issue
4
Publish Date
2011
Start Page
414
End Page
427

Prognostic significance of parameters derived from co-registered 18F-fluorodeoxyglucose PET and contrast-enhanced MRI in patients with high-grade glioma.

OBJECTIVE: The aim of this study was to determine the prognostic significance of the volume and intensity of abnormal (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) accumulation within areas of contrast enhancement on post-therapeutic volumetric MRI. METHODS: A total of 10 patients with Grade III or IV glioma were treated with resection followed by intracavitary radiation therapy with (131)I-labelled antitenascin monoclonal antibody. Patients underwent serial FDG-PET and 1.5 T MR imaging. For each patient, MR and FDG-PET image volumes at each time point were aligned using a rigid-body normalised mutual information algorithm. Contrast-enhancing regions of interest (ROIs) were defined using a semi-automated k-means clustering technique. Activity within the ROI on the co-registered PET scan was calculated as a ratio (mean activity ratio; MAR) to activity in contralateral normal-appearing white matter (NAWM). The PET lesion was defined as the portion of the ROI associated with activity greater than two standard deviations above the mean in NAWM. Survival was assessed using the logrank test. RESULTS: Larger contrast-enhancing ROIs were strongly associated with an increased MAR (r = 0.51; p<0.002). Enhancing lesions with an MAR >1.2 were associated with decreased survival (p<0.016). In nine patients who died, the MAR on PET correlated inversely with survival duration (r = -0.43; p<0.01), whereas PET lesion volume did not. CONCLUSION: Following intracavitary radiation therapy, the development of contrast-enhancing lesions that are associated with high mean FDG-PET accumulation suggests poor prognosis.

Authors
Paldino, MJ; Wong, TZ; Reardon, DA; Friedman, HS; Barboriak, DP
MLA Citation
Paldino, M. J., et al. “Prognostic significance of parameters derived from co-registered 18F-fluorodeoxyglucose PET and contrast-enhanced MRI in patients with high-grade glioma..” Br J Radiol, vol. 84, no. 1000, Apr. 2011, pp. 327–33. Pubmed, doi:10.1259/bjr/48528504.
PMID
20959370
Source
pubmed
Published In
The British Journal of Radiology
Volume
84
Issue
1000
Publish Date
2011
Start Page
327
End Page
333
DOI
10.1259/bjr/48528504

Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma.

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m(2) per 5 days) or dose-intensified (DI) TMZ (100 mg/m(2) per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3(+) T-cell (P = .005) and B-cell (P = .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (T(Reg); P = .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P = .037) and delayed-type hypersensitivity responses (P = .036) of greater magnitude. EGFRvIII-expressing tumor cells were also eradicated in nearly all patients (91.6%; CI(95): 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI(95): 11.0-18.5 months; hazard ratio [HR] = 0.35; P = .024) and overall survival (23.6 months; CI(95): 18.5-33.1 months; HR = 0.23; P = .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIII-targeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.

Authors
Sampson, JH; Aldape, KD; Archer, GE; Coan, A; Desjardins, A; Friedman, AH; Friedman, HS; Gilbert, MR; Herndon, JE; McLendon, RE; Mitchell, DA; Reardon, DA; Sawaya, R; Schmittling, R; Shi, W; Vredenburgh, JJ; Bigner, DD; Heimberger, AB
MLA Citation
Sampson, John H., et al. “Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma..” Neuro Oncol, vol. 13, no. 3, Mar. 2011, pp. 324–33. Pubmed, doi:10.1093/neuonc/noq157.
PMID
21149254
Source
pubmed
Published In
Neuro Oncol
Volume
13
Issue
3
Publish Date
2011
Start Page
324
End Page
333
DOI
10.1093/neuonc/noq157

O6-Methylguanine-DNA Methytransferase (MGMT) Immunohistochemistry as a Predictor of Resistance to Temozolomide in Primary CNS Lymphoma

Authors
Jiang, X; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Quinn, JA; Austin, AD; Herndon, JE; McLendon, RE; Friedman, HS
MLA Citation
Jiang, X., et al. “O6-Methylguanine-DNA Methytransferase (MGMT) Immunohistochemistry as a Predictor of Resistance to Temozolomide in Primary CNS Lymphoma.” Laboratory Investigation, vol. 91, NATURE PUBLISHING GROUP, 2011, pp. 382A-382A.
Source
wos
Published In
Laboratory Investigation
Volume
91
Publish Date
2011
Start Page
382A
End Page
382A

The genetic landscape of the childhood cancer medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

Authors
Parsons, DW; Li, M; Zhang, X; Jones, S; Leary, RJ; Lin, JC-H; Boca, SM; Carter, H; Samayoa, J; Bettegowda, C; Gallia, GL; Jallo, GI; Binder, ZA; Nikolsky, Y; Hartigan, J; Smith, DR; Gerhard, DS; Fults, DW; VandenBerg, S; Berger, MS; Marie, SKN; Shinjo, SMO; Clara, C; Phillips, PC; Minturn, JE; Biegel, JA; Judkins, AR; Resnick, AC; Storm, PB; Curran, T; He, Y; Rasheed, BA; Friedman, HS; Keir, ST; McLendon, R; Northcott, PA; Taylor, MD; Burger, PC; Riggins, GJ; Karchin, R; Parmigiani, G; Bigner, DD; Yan, H; Papadopoulos, N; Vogelstein, B; Kinzler, KW; Velculescu, VE
MLA Citation
Parsons, D. Williams, et al. “The genetic landscape of the childhood cancer medulloblastoma..” Science, vol. 331, no. 6016, Jan. 2011, pp. 435–39. Pubmed, doi:10.1126/science.1198056.
PMID
21163964
Source
pubmed
Published In
Science
Volume
331
Issue
6016
Publish Date
2011
Start Page
435
End Page
439
DOI
10.1126/science.1198056

Cediranib falls short in phase III recurrent glioblastoma study: Commentary

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Cediranib falls short in phase III recurrent glioblastoma study: Commentary.” Oncology Report, no. JANUARY, Jan. 2011.
Source
scopus
Published In
Oncology Report
Issue
JANUARY
Publish Date
2011
Start Page
11

Frail elderly benefit from post-op temozolomide for glioblastoma: Commentary

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Frail elderly benefit from post-op temozolomide for glioblastoma: Commentary.” Oncology Report, no. JANUARY, Jan. 2011.
Source
scopus
Published In
Oncology Report
Issue
JANUARY
Publish Date
2011
Start Page
11

Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma.

Sorafenib, an oral VEGFR-2, Raf, PDGFR, c-KIT and Flt-3 inhibitor, is active against renal cell and hepatocellular carcinomas, and has recently demonstrated promising activity for lung and breast cancers. In addition, various protracted temozolomide dosing schedules have been evaluated as a strategy to further enhance its anti-tumor activity. We reasoned that sorafenib and protracted, daily temozolomide may provide complementary therapeutic benefit, and therefore performed a phase 2 trial among recurrent glioblastoma patients. Adult glioblastoma patients at any recurrence after standard temozolomide chemoradiotherapy received sorafenib (400 mg twice daily) and continuous daily temozolomide (50 mg/m²/day). Assessments were performed every eight weeks. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary end points were radiographic response, overall survival (OS), safety and sorafenib pharmacokinetics. Of 32 enrolled patients, 12 (38%) were on CYP3-A inducing anti-epileptics (EIAEDs), 17 (53%) had 2 or more prior progressions, 15 had progressed while receiving 5-day temozolomide, and 12 (38%) had failed either prior bevacizumab or VEGFR inhibitor therapy. The most common grade ≥ 3 toxicities were palmer-planter erythrodysesthesia (19%) and elevated amylase/lipase (13%). Sorafenib pharmacokinetic exposures were comparable on day 1 regardless of EIAED status, but significantly lower on day 28 for patients on EIAEDs (P = 0.0431). With a median follow-up of 93 weeks, PFS-6 was 9.4%. Only one patient (3%) achieved a partial response. In conclusion, sorafenib can be safely administered with daily temozolomide, but this regimen has limited activity for recurrent GBM. Co-administration of EIAEDs can lower sorafenib exposures in this population.

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Peters, K; Gururangan, S; Sampson, JH; Marcello, J; Herndon, JE; McLendon, RE; Janney, D; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Reardon, David A., et al. “Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma..” J Neurooncol, vol. 101, no. 1, Jan. 2011, pp. 57–66. Pubmed, doi:10.1007/s11060-010-0217-6.
PMID
20443129
Source
pubmed
Published In
J Neurooncol
Volume
101
Issue
1
Publish Date
2011
Start Page
57
End Page
66
DOI
10.1007/s11060-010-0217-6

Ulceration of Striae distensae in high-grade glioma patients on concurrent systemic corticosteroid and bevacizumab therapy.

Striae distensae (stretch marks) are a common complication seen in patients on chronic corticosteroid therapy. Under certain circumstances, primary brain tumor patients require chronic corticosteroid therapy and can suffer from striae distensae. Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor-A (VEGF-A) is now more widely used for the treatment of primary brain tumors. In this paper, we present four cases of ulcerated striae distensae in primary brain tumor patients on concurrent corticosteroid and bevacizumab therapy. Because of bevacizumab's effects on wound healing and its recent accelerated approval for recurrent glioblastoma multiforme (GBM), the most common malignant primary brain tumor in adults, this novel skin complication should be considered in patients on concurrent corticosteroid and bevacizumab therapy.

Authors
Peters, KB; Coyle, TE; Vredenburgh, JJ; Desjardins, A; Friedman, HS; Reardon, DA
MLA Citation
Peters, Katherine B., et al. “Ulceration of Striae distensae in high-grade glioma patients on concurrent systemic corticosteroid and bevacizumab therapy..” Journal of Neuro Oncology, vol. 101, no. 1, Jan. 2011, pp. 155–59. Epmc, doi:10.1007/s11060-010-0239-0.
PMID
20524043
Source
epmc
Published In
Journal of Neuro Oncology
Volume
101
Issue
1
Publish Date
2011
Start Page
155
End Page
159
DOI
10.1007/s11060-010-0239-0

Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab.

Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm. Hazard ratios (HRs) and P-values for survival between responders and nonresponders were calculated. Additional analyses were performed to test robustness, validity, fit, and accuracy of the models. The relationships between progression-free survival (PFS) and survival and between OR and PFS were also explored. There were 55 responders and 112 nonresponders across the 2 treatment arms in BRAIN. OR status at 9, 18, and 26 weeks was a statistically significant predictor of survival (HR ≤ 0.52, P < .01). PFS was also a statistically significant predictor of survival at each landmark (HR ≤ 0.25, P < .0001). The association between OR and PFS was not statistically significant, likely due to inadequate statistical power for the analysis. Clarifying the relationship of OR and survival is important for determining whether OR can be a reliable predictor of the benefit of a therapeutic agent in patients with recurrent GBM.

Authors
Prados, M; Cloughesy, T; Samant, M; Fang, L; Wen, PY; Mikkelsen, T; Schiff, D; Abrey, LE; Yung, WKA; Paleologos, N; Nicholas, MK; Jensen, R; Vredenburgh, J; Das, A; Friedman, HS
MLA Citation
Prados, Michael, et al. “Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab..” Neuro Oncol, vol. 13, no. 1, Jan. 2011, pp. 143–51. Pubmed, doi:10.1093/neuonc/noq151.
PMID
21084434
Source
pubmed
Published In
Neuro Oncol
Volume
13
Issue
1
Publish Date
2011
Start Page
143
End Page
151
DOI
10.1093/neuonc/noq151

Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling

The clinical manifestations of Fanconi's anemia, an autosomal recessive disorder, include progressive pancyto-penia, a predisposition to neoplasia, and nonhematopoietic developmental anomalies [1-3]. Hypersensitivity to the clastogenic effect of DNA-cross-linking agents such as diepoxybutane acts as a diagnostic indicator of the genotype of Fanconi's anemia, both prenatally and postnatally [3-6]. Prenatal HLA typing has made it possible to ascertain whether a fetus is HLA-identical to an affected sibling [7]. We report here on hematopoietic reconstitution in a boy with severe Fanconi's anemia who received cryo-pre-served umbilical-cord blood from a sister shown by prenatal testing to be unaffected by the disorder, to have a normal karyotype, and to be HLA-identical to the patient. We used a pretransplantation conditioning procedure developed specifcally for the treatment of such patients [8]; this technique makes use of the hypersensitivity of the abnormal cells to alkylating agents that cross-link DNA [9,10] and to irradiation [11] In this case, the availability of cord blood obviated the need for obtaining bone marrow from the infant sibling. This use of cord blood followed the suggestion of one of us that blood retrieved from umbilical cord at delivery, usually discarded, might restore hematopoiesis - a proposal supported by preparatory studies by some of us [12] and consistent with reports on the presence of hematopoietic stem and multipotential (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells in human umbilical-cord blood (see the references cited by Broxmeyer et al. [12]). © 1989 Massachusetts Medical Society. All rights reserved.

Authors
Gluckman, E; Broxmeyer, HE; Auerbach, AD; Friedman, HS; Douglas, GW; Devergie, A; Esperou, H; Thierry, D; Socie, G; Lehn, P; Cooper, S; English, D; Kurtzberg, J; Bard, J; Boyse, EA
MLA Citation
Gluckman, E., et al. “Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling.” Cellular Therapy and Transplantation, vol. 2, no. 7, Dec. 2010. Scopus, doi:10.3205/ctt-2010-en-000079.01.
Source
scopus
Published In
Cellular Therapy and Transplantation
Volume
2
Issue
7
Publish Date
2010
DOI
10.3205/ctt-2010-en-000079.01

Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma.

Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling are established contributors to malignant glioma (MG) biology. We, therefore, evaluated bevacizumab, a humanized anti-VEGF monoclonal antibody, in combination with the EGFR tyrosine kinase inhibitor erlotinib, in this phase 2 study for recurrent MG patients (www.ClinicalTrials.gov, NCT00671970). Fifty-seven patients (n = 25, glioblastoma [GBM]; n = 32, anaplastic glioma [AG]) were enrolled. The primary endpoint was 6-month progression-free survival (PFS-6). Overall survival (OS), radiographic response, pharmacokinetics, and correlative biomarkers were the secondary endpoints. Patients were stratified based on the concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). Bevacizumab (10 mg/kg) was given intravenously every 2 weeks. Erlotinib was orally administered daily at 200 mg/day for patients not on EIAEDs and 500 mg/day for patients on EIAEDs. PFS-6 and median OS were 28% and 42 weeks for GBM patients and 44% and 71 weeks for AG patients, respectively. Twelve (48%) GBM patients and 10 (31%) AG patients achieved a radiographic response. Erlotinib pharmacokinetic exposures were comparable between EIAED and non-EIAED groups. Rash, mucositis, diarrhea, and fatigue were common but mostly grades 1 and 2. Among GBM patients, grade 3 rash, observed in 32%, was associated with survival benefit, whereas elevated hypoxia-inducible factor-2 alpha and VEGF receptor-2 levels were associated with poor survival. Bevacizumab plus erlotinib was adequately tolerated in recurrent MG patients. However, this regimen was associated with similar PFS benefit and radiographic response when compared with other historical bevacizumab-containing regimens.

Authors
Sathornsumetee, S; Desjardins, A; Vredenburgh, JJ; McLendon, RE; Marcello, J; Herndon, JE; Mathe, A; Hamilton, M; Rich, JN; Norfleet, JA; Gururangan, S; Friedman, HS; Reardon, DA
MLA Citation
Sathornsumetee, Sith, et al. “Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma..” Neuro Oncol, vol. 12, no. 12, Dec. 2010, pp. 1300–10. Pubmed, doi:10.1093/neuonc/noq099.
PMID
20716591
Source
pubmed
Published In
Neuro Oncol
Volume
12
Issue
12
Publish Date
2010
Start Page
1300
End Page
1310
DOI
10.1093/neuonc/noq099

Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma.

PURPOSE: Immunologic targeting of tumor-specific gene mutations may allow precise eradication of neoplastic cells without toxicity. Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively activated and immunogenic mutation not expressed in normal tissues but widely expressed in glioblastoma multiforme (GBM) and other neoplasms. PATIENTS AND METHODS: A phase II, multicenter trial was undertaken to assess the immunogenicity of an EGFRvIII-targeted peptide vaccine and to estimate the progression-free survival (PFS) and overall survival (OS) of vaccinated patients with newly diagnosed EGFRvIII-expressing GBM with minimal residual disease. Intradermal vaccinations were given until toxicity or tumor progression was observed. Sample size was calculated to differentiate between PFS rates of 20% and 40% 6 months after vaccination. RESULTS: There were no symptomatic autoimmune reactions. The 6-month PFS rate after vaccination was 67% (95% CI, 40% to 83%) and after diagnosis was 94% (95% CI, 67% to 99%; n = 18). The median OS was 26.0 months (95% CI, 21.0 to 47.7 months). After adjustment for age and Karnofsky performance status, the OS of vaccinated patients was greater than that observed in a control group matched for eligibility criteria, prognostic factors, and temozolomide treatment (hazard ratio, 5.3; P = .0013; n = 17). The development of specific antibody (P = .025) or delayed-type hypersensitivity (P = .03) responses to EGFRvIII had a significant effect on OS. At recurrence, 82% (95% CI, 48% to 97%) of patients had lost EGFRvIII expression (P < .001). CONCLUSION: EGFRvIII-targeted vaccination in patients with GBM warrants investigation in a phase III, randomized trial.

Authors
Sampson, JH; Heimberger, AB; Archer, GE; Aldape, KD; Friedman, AH; Friedman, HS; Gilbert, MR; Herndon, JE; McLendon, RE; Mitchell, DA; Reardon, DA; Sawaya, R; Schmittling, RJ; Shi, W; Vredenburgh, JJ; Bigner, DD
MLA Citation
Sampson, John H., et al. “Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma..” J Clin Oncol, vol. 28, no. 31, Nov. 2010, pp. 4722–29. Pubmed, doi:10.1200/JCO.2010.28.6963.
PMID
20921459
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
31
Publish Date
2010
Start Page
4722
End Page
4729
DOI
10.1200/JCO.2010.28.6963

ACTIVITY OF GMX1777 AGAINST A PANEL OF BRAIN TUMOR XENOGRAFTS

Authors
Keir, ST; Reardon, DA; Watson, M; Shore, GC; Bigner, DD; Friedman, HS
MLA Citation
Keir, Stephen T., et al. “ACTIVITY OF GMX1777 AGAINST A PANEL OF BRAIN TUMOR XENOGRAFTS.” Neuro Oncology, vol. 12, OXFORD UNIV PRESS INC, 2010, pp. 99–99.
Source
wos
Published In
Neuro Oncology
Volume
12
Publish Date
2010
Start Page
99
End Page
99

EFFICACY OF LBH589 (PANOBINOSTAT) AGAINST A PANEL OF PEDIATRIC BRAIN TUMOR XENOGRAFTS

Authors
Keir, ST; Gururangan, S; Reardon, DA; Bigner, DD; Friedman, HS
MLA Citation
Keir, Stephen T., et al. “EFFICACY OF LBH589 (PANOBINOSTAT) AGAINST A PANEL OF PEDIATRIC BRAIN TUMOR XENOGRAFTS.” Neuro Oncology, vol. 12, OXFORD UNIV PRESS INC, 2010, pp. 99–99.
Source
wos
Published In
Neuro Oncology
Volume
12
Publish Date
2010
Start Page
99
End Page
99

CHARACTERIZATION OF LONG-TERM SURVIVORS OF PRIMARY GLIOBLASTOMA MULTIFORME AND THEIR USE OF PSYCHOACTIVE MEDICATIONS

Authors
Peters, KB; Reardon, DA; Vredenburgh, JJ; Desjardins, A; Friedman, HS
MLA Citation
Peters, Katherine B., et al. “CHARACTERIZATION OF LONG-TERM SURVIVORS OF PRIMARY GLIOBLASTOMA MULTIFORME AND THEIR USE OF PSYCHOACTIVE MEDICATIONS.” Neuro Oncology, vol. 12, OXFORD UNIV PRESS INC, 2010, pp. 59–60.
Source
wos
Published In
Neuro Oncology
Volume
12
Publish Date
2010
Start Page
59
End Page
60

DASATINIB (SPRYCEL) AND ERLOTINIB (TARCEVA) FOR PATIENTS WITH RECURRENT MALIGNANT GLIOMA: A PHASE 1 TRIAL

Authors
Desjardins, A; Peters, KB; Vredenburgh, JJ; Friedman, HS; Reardon, DA
MLA Citation
Desjardins, Annick, et al. “DASATINIB (SPRYCEL) AND ERLOTINIB (TARCEVA) FOR PATIENTS WITH RECURRENT MALIGNANT GLIOMA: A PHASE 1 TRIAL.” Neuro Oncology, vol. 12, OXFORD UNIV PRESS INC, 2010, pp. 51–51.
Source
wos
Published In
Neuro Oncology
Volume
12
Publish Date
2010
Start Page
51
End Page
51

A PHASE I/II STUDY OF VORINOSTAT PLUS DAILY TEMOZOLOMIDE AND BEVACIZUMAB IN THE TREATMENT OF PATIENTS WITH RECURRENT MALIGNANT GLIOMA

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Janney, DE; Peters, K; Sampson, J; Gururangan, S; Friedman, HS
MLA Citation
Reardon, David A., et al. “A PHASE I/II STUDY OF VORINOSTAT PLUS DAILY TEMOZOLOMIDE AND BEVACIZUMAB IN THE TREATMENT OF PATIENTS WITH RECURRENT MALIGNANT GLIOMA.” Neuro Oncology, vol. 12, OXFORD UNIV PRESS INC, 2010, pp. 73–73.
Source
wos
Published In
Neuro Oncology
Volume
12
Publish Date
2010
Start Page
73
End Page
73

FINAL RESULTS OF A PHASE II STUDY OF IMATINIB MESYLATE (GLEEVEC) PLUS HYDROXYUREA FOR ADULTS WITH RECURRENT/PROGRESSIVE LOW-GRADE GLIOMA

Authors
Reardon, DA; Peters, K; Desjardins, A; Sampson, J; Vredenburgh, JJ; Gururangan, S; Friedman, HS
MLA Citation
Reardon, David A., et al. “FINAL RESULTS OF A PHASE II STUDY OF IMATINIB MESYLATE (GLEEVEC) PLUS HYDROXYUREA FOR ADULTS WITH RECURRENT/PROGRESSIVE LOW-GRADE GLIOMA.” Neuro Oncology, vol. 12, OXFORD UNIV PRESS INC, 2010, pp. 49–49.
Source
wos
Published In
Neuro Oncology
Volume
12
Publish Date
2010
Start Page
49
End Page
49

RETROSPECTIVE ANALYSIS OF INSOMNIA IN RECURRENT GLIOMA PATIENTS AND ITS ASSOCIATION WITH DEXAMETHASONE AND ANTI-EPILEPTICS

Authors
Peters, KB; Reardon, DA; Vredenburgh, JJ; Desjardins, A; Friedman, HS
MLA Citation
Peters, Katherine B., et al. “RETROSPECTIVE ANALYSIS OF INSOMNIA IN RECURRENT GLIOMA PATIENTS AND ITS ASSOCIATION WITH DEXAMETHASONE AND ANTI-EPILEPTICS.” Neuro Oncology, vol. 12, OXFORD UNIV PRESS INC, 2010, pp. 104–104.
Source
wos
Published In
Neuro Oncology
Volume
12
Publish Date
2010
Start Page
104
End Page
104

SURVIVAL AND TOXICITY UPDATE OF THE PHASE 2 TRIAL OF BEVACIZUMAB (BV) IN COMBINATION WITH TEMOZOLOMIDE (TMZ) AND RADIATION THERAPY (RT) FOLLOWED BY BV, TMZ, AND IRINOTECAN (CPT-11) FOR NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) PATIENTS

Authors
Desjardins, A; Reardon, DA; Peters, KB; Herndon, JE; Kirkpatrick, JP; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, Annick, et al. “SURVIVAL AND TOXICITY UPDATE OF THE PHASE 2 TRIAL OF BEVACIZUMAB (BV) IN COMBINATION WITH TEMOZOLOMIDE (TMZ) AND RADIATION THERAPY (RT) FOLLOWED BY BV, TMZ, AND IRINOTECAN (CPT-11) FOR NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) PATIENTS.” Neuro Oncology, vol. 12, OXFORD UNIV PRESS INC, 2010, pp. 77–77.
Source
wos
Published In
Neuro Oncology
Volume
12
Publish Date
2010
Start Page
77
End Page
77

Decoupling of DNA damage response signaling from DNA damages underlies temozolomide resistance in glioblastoma cells.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults. Current therapy includes surgery, radiation and chemotherapy with temozolomide (TMZ). Major determinants of clinical response to TMZ include methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter and mismatch repair (MMR) status. Though the MGMT promoter is methylated in 45% of cases, for the first nine months of follow-up, TMZ does not change survival outcome. Furthermore, MMR deficiency makes little contribution to clinical resistance, suggesting that there exist unrecognized mechanisms of resistance. We generated paired GBM cell lines whose resistance was attributed to neither MGMT nor MMR. We show that, responding to TMZ, these cells exhibit a decoupling of DNA damage response (DDR) from ongoing DNA damages. They display methylation-resistant synthesis in which ongoing DNA synthesis is not inhibited. They are also defective in the activation of the S and G2 phase checkpoint. DDR proteins ATM, Chk2, MDC1, NBS1 and gammaH2AX also fail to form discrete foci. These results demonstrate that failure of DDR may play an active role in chemoresistance to TMZ. DNA damages by TMZ are repaired by MMR proteins in a futile, reiterative process, which activates DDR signaling network that ultimately leads to the onset of cell death. GBM cells may survive genetic insults in the absence of DDR. We anticipate that our findings will lead to more studies that seek to further define the role of DDR in ultimately determining the fate of a tumor cell in response to TMZ and other DNA methylators.

Authors
Cui, B; Johnson, SP; Bullock, N; Ali-Osman, F; Bigner, DD; Friedman, HS
MLA Citation
Cui, Bo, et al. “Decoupling of DNA damage response signaling from DNA damages underlies temozolomide resistance in glioblastoma cells..” J Biomed Res, vol. 24, no. 6, Nov. 2010, pp. 424–35. Pubmed, doi:10.1016/S1674-8301(10)60057-7.
PMID
23554659
Source
pubmed
Published In
Journal of Biomedical Research
Volume
24
Issue
6
Publish Date
2010
Start Page
424
End Page
435
DOI
10.1016/S1674-8301(10)60057-7

Poor drug distribution as a possible explanation for the results of the PRECISE trial.

OBJECT: Convection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. METHODS: Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. RESULTS: Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score. CONCLUSIONS: The potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

Authors
Sampson, JH; Archer, G; Pedain, C; Wembacher-Schröder, E; Westphal, M; Kunwar, S; Vogelbaum, MA; Coan, A; Herndon, JE; Raghavan, R; Brady, ML; Reardon, DA; Friedman, AH; Friedman, HS; Rodríguez-Ponce, MI; Chang, SM; Mittermeyer, S; Croteau, D; Puri, RK; PRECISE Trial Investigators,
MLA Citation
Sampson, John H., et al. “Poor drug distribution as a possible explanation for the results of the PRECISE trial..” J Neurosurg, vol. 113, no. 2, Aug. 2010, pp. 301–09. Pubmed, doi:10.3171/2009.11.JNS091052.
PMID
20020841
Source
pubmed
Published In
J Neurosurg
Volume
113
Issue
2
Publish Date
2010
Start Page
301
End Page
309
DOI
10.3171/2009.11.JNS091052

Inhibition of poly(ADP-ribose) polymerase enhances the effect of chemotherapy in an animal model of regional therapy for the treatment of advanced extremity malignant melanoma.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) is an important regulator of programmed cell death in response to alkylating agents such as temozolomide (TMZ). The goal of this study was to determine if a systemically administered PARP-inhibitor (INO-1001) could augment the efficacy of TMZ in a rat model of extremity malignant melanoma. MATERIALS AND METHODS: PARP activity was measured in vitro across a panel of 5 human malignant melanoma-derived cell lines. To evaluate tumor response to PARP inhibition in combination with regional isolated limb infusion (ILI) therapy with TMZ, two TMZ-resistant malignant melanoma cell lines were grown as xenografts in the hind limb of rats. INO-1001 (400 mg/kg) was injected intraperitoneally 7 times every 8 hours prior to ILI. Tumor volume was measured for up to 40 days. RESULTS: In vitro inhibition of PARP activity by INO-1001 ranged from 25.5% to 65.6%. In a mismatch repair (MMR)-deficient xenograft, treatment with INO-1001 prior to ILI significantly (P < .04) increased the efficacy of TMZ. The increase in tumor volume at day 40 following TMZ-ILI with INO-1001 was only 22.6% compared with 322.8% with TMZ-ILI alone. In a xenograft that was MMR-proficient and had high levels of O(6)-methylguanine-DNA methyltransferase (MGMT) activity, there was little improvement in TMZ efficacy with INO-1001 treatment. CONCLUSION: The PARP-inhibitor, INO-1001, can enhance the response of TMZ-resistant, MMR-deficient, malignant melanoma xenografts to intra-arterially administered TMZ in a regional treatment model of advanced extremity malignant melanoma.

Authors
Toshimitsu, H; Yoshimoto, Y; Augustine, CK; Padussis, JC; Yoo, JS; Angelica Selim, M; Pruitt, SK; Friedman, HS; Ali-Osman, F; Tyler, DS
MLA Citation
Toshimitsu, Hiroaki, et al. “Inhibition of poly(ADP-ribose) polymerase enhances the effect of chemotherapy in an animal model of regional therapy for the treatment of advanced extremity malignant melanoma..” Ann Surg Oncol, vol. 17, no. 8, Aug. 2010, pp. 2247–54. Pubmed, doi:10.1245/s10434-010-0971-x.
PMID
20182810
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
17
Issue
8
Publish Date
2010
Start Page
2247
End Page
2254
DOI
10.1245/s10434-010-0971-x

Bevacizumab-irinotecan data hold up in recurrent GBM: Comment

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Bevacizumab-irinotecan data hold up in recurrent GBM: Comment.” Oncology Report, no. JULY-AUGUST, July 2010.
Source
scopus
Published In
Oncology Report
Issue
JULY-AUGUST
Publish Date
2010
Start Page
4

Novel electric fields device may offer alternative to chemotherapy: Comment

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Novel electric fields device may offer alternative to chemotherapy: Comment.” Oncology Report, no. JULY-AUGUST, July 2010.
Source
scopus
Published In
Oncology Report
Issue
JULY-AUGUST
Publish Date
2010
Start Page
5

Bevacizumab fails to treat temporal paraganglioma: discussion and case illustration.

Temporal paragangliomas are highly vascular tumors treated primarily by surgical resection. However, surgery to remove these tumors is associated with significant morbidity, including cranial nerve dysfunction. Interestingly, these tumors have been shown to express vascular endothelial growth factor (VEGF). A variety of tumors expressing VEGF and the VEGF receptor have been shown to reduce in size and vascularity when treated with the VEGF-specific antibody, bevacizumab (Avastin). We hypothesized that paragangliomas may be treated noninvasively with bevacizumab, either as a primary treatment or as a useful adjuvant to surgical resection or radiation. Thus, our aim was to evaluate the effects of bevacizumab on this patient's paraganglioma. A 36-year-old female presented to us with a 3 month history of positional dizziness, light-headedness, and left ear pulsatile tinnitus and hearing loss. She was found to have a temporal paraganglioma (glomus jugulare tumor) on imaging. Histopathology confirmed significant staining for VEGF. This patient was treated with bevacizumab prior to surgical treatment; radiographic imaging at 3 months, however, showed no significant response. We discuss possible reasons for treatment failure.

Authors
Aliabadi, H; Vredenburgh, JJ; Everson, RG; Desjardins, A; Friedman, HS; McLendon, RE; Tucci, DL; Sampson, JH
MLA Citation
Aliabadi, Hamidreza, et al. “Bevacizumab fails to treat temporal paraganglioma: discussion and case illustration..” Journal of Neuro Oncology, vol. 98, no. 3, July 2010, pp. 427–30. Epmc, doi:10.1007/s11060-009-0091-2.
PMID
20020179
Source
epmc
Published In
Journal of Neuro Oncology
Volume
98
Issue
3
Publish Date
2010
Start Page
427
End Page
430
DOI
10.1007/s11060-009-0091-2

Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric Brain Tumor Consortium study.

PURPOSE: A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent malignant glioma (MG) and intrinsic brainstem glioma (BSG). PATIENTS AND METHODS: Eligible patients received two doses of BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ plus CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion weighted and T1 dynamic contrast-enhanced permeability imaging, BVZ pharmacokinetics, and estimation of vascular endothelial growth factor receptor 2 (VEGFR-2) phosphorylation in peripheral blood mononuclear cells (PBMC) after single-agent BVZ. RESULTS: Thirty-one evaluable patients received a median of two courses of BVZ plus CPT-11 (range, 1 to 19). No sustained responses were observed in either stratum. Median time to progression for all 34 eligible patients enrolled was 127 days for MG and 71 days for BSG. Progression-free survival rates at 6 months were 41.8% and 9.7% for MG and BSG, respectively. Toxicities related to BVZ included grade 1 to 3 fatigue in seven patients, grade 1 to 2 hypertension in seven patients, grade 1 CNS hemorrhage in four patients, and grade 4 CNS ischemia in two patients. The mean diffusion ratio decreased after two doses of BVZ in patients with MG only. Vascular permeability parameters did not change significantly after therapy in either stratum. Inhibition of VEGFR-2 phosphorylation in PBMC was detected in eight of 11 patients after BVZ exposure. CONCLUSION: BVZ plus CPT-11 was well-tolerated but had minimal efficacy in children with recurrent malignant glioma and brainstem glioma.

Authors
Gururangan, S; Chi, SN; Young Poussaint, T; Onar-Thomas, A; Gilbertson, RJ; Vajapeyam, S; Friedman, HS; Packer, RJ; Rood, BN; Boyett, JM; Kun, LE
MLA Citation
Gururangan, Sridharan, et al. “Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric Brain Tumor Consortium study..” J Clin Oncol, vol. 28, no. 18, June 2010, pp. 3069–75. Pubmed, doi:10.1200/JCO.2009.26.8789.
PMID
20479404
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
18
Publish Date
2010
Start Page
3069
End Page
3075
DOI
10.1200/JCO.2009.26.8789

Phase I trial of the addition of oral topotecan to standard 5-day temozolomide for malignant gliomas.

Authors
Kirkpatrick, J; Vredenburgh, JJ; Reardon, DA; Desjardins, A; Peters, K; Gururangan, S; Herndon, JE; Marcello, J; Woodring, S; Friedman, HS
MLA Citation
Kirkpatrick, J., et al. “Phase I trial of the addition of oral topotecan to standard 5-day temozolomide for malignant gliomas..” Journal of Clinical Oncology, vol. 28, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2010, pp. 2073–2073. Crossref, doi:10.1200/jco.2010.28.15_suppl.2073.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15_suppl
Publish Date
2010
Start Page
2073
End Page
2073
DOI
10.1200/jco.2010.28.15_suppl.2073

CYP3A-inducing antiepileptics decrease sorafenib exposures: Results of a phase II study in adults with recurrent glioblastoma.

Authors
Gururangan, S; Vredenburgh, JJ; Desjardins, A; Peters, K; Herndon, JE; McLendon, RE; Janney, D; Friedman, HS; Reardon, DA
MLA Citation
Gururangan, S., et al. “CYP3A-inducing antiepileptics decrease sorafenib exposures: Results of a phase II study in adults with recurrent glioblastoma..” Journal of Clinical Oncology, vol. 28, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2010, pp. 2089–2089. Crossref, doi:10.1200/jco.2010.28.15_suppl.2089.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15_suppl
Publish Date
2010
Start Page
2089
End Page
2089
DOI
10.1200/jco.2010.28.15_suppl.2089

Phase II trial of bevacizumab plus erlotinib for patients with recurrent malignant gliomas: Final results.

Authors
Sathornsumetee, S; Desjardins, A; Vredenburgh, JJ; McLendon, RE; Marcello, J; Herndon, JE; Norfleet, J; Gururangan, S; Friedman, HS; Reardon, DA
MLA Citation
Sathornsumetee, S., et al. “Phase II trial of bevacizumab plus erlotinib for patients with recurrent malignant gliomas: Final results..” Journal of Clinical Oncology, vol. 28, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2010, pp. 2055–2055. Crossref, doi:10.1200/jco.2010.28.15_suppl.2055.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15_suppl
Publish Date
2010
Start Page
2055
End Page
2055
DOI
10.1200/jco.2010.28.15_suppl.2055

Imatinib mesylate plus hydroxyurea for adults with recurrent/progressive low-grade glioma: Final phase II study results.

Authors
Peters, K; Desjardins, A; Vredenburgh, JJ; Dryman, B; Gururangan, S; Friedman, HS; Reardon, DA
MLA Citation
Peters, K., et al. “Imatinib mesylate plus hydroxyurea for adults with recurrent/progressive low-grade glioma: Final phase II study results..” Journal of Clinical Oncology, vol. 28, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2010, pp. 2060–2060. Crossref, doi:10.1200/jco.2010.28.15_suppl.2060.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15_suppl
Publish Date
2010
Start Page
2060
End Page
2060
DOI
10.1200/jco.2010.28.15_suppl.2060

Bevacizumab (BEV) in combination with temozolomide (TMZ) and radiation therapy (XRT) followed by BEV, TMZ, and irinotecan for newly diagnosed glioblastoma multiforme (GBM).

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Peters, K; Kirkpatrick, J; Herndon, JE; Marcello, J; Bailey, L; Threatt, S; Friedman, HS
MLA Citation
Vredenburgh, J. J., et al. “Bevacizumab (BEV) in combination with temozolomide (TMZ) and radiation therapy (XRT) followed by BEV, TMZ, and irinotecan for newly diagnosed glioblastoma multiforme (GBM)..” Journal of Clinical Oncology, vol. 28, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2010, pp. 2023–2023. Crossref, doi:10.1200/jco.2010.28.15_suppl.2023.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15_suppl
Publish Date
2010
Start Page
2023
End Page
2023
DOI
10.1200/jco.2010.28.15_suppl.2023

Phase I trial of vandetanib and oral etoposide (VP-16) for recurrent malignant gliomas (MG).

Authors
Brickhouse, A; Vredenburgh, JJ; Gururangan, S; Reardon, DA; Desjardins, A; Peters, K; Herndon, JE; Norfleet, J; Marcello, J; Friedman, HS
MLA Citation
Brickhouse, A., et al. “Phase I trial of vandetanib and oral etoposide (VP-16) for recurrent malignant gliomas (MG)..” Journal of Clinical Oncology, vol. 28, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2010, pp. 2038–2038. Crossref, doi:10.1200/jco.2010.28.15_suppl.2038.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15_suppl
Publish Date
2010
Start Page
2038
End Page
2038
DOI
10.1200/jco.2010.28.15_suppl.2038

Long-term survival from the initial trial of bevacizumab and irinotecan.

Authors
Desjardins, A; Vredenburgh, JJ; Reardon, DA; Herndon, JE; Marcello, J; Peters, K; Gururangan, S; Sathornsumetee, S; Rich, JN; Friedman, HS
MLA Citation
Desjardins, A., et al. “Long-term survival from the initial trial of bevacizumab and irinotecan..” Journal of Clinical Oncology, vol. 28, no. 15, AMER SOC CLINICAL ONCOLOGY, May 2010.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Updated safety and survival of patients with relapsed glioblastoma treated with bevacizumab in the BRAIN study

Authors
Cloughesy, T; Vredenburgh, JJ; Day, B; Das, A; Friedman, HS
MLA Citation
Cloughesy, T., et al. “Updated safety and survival of patients with relapsed glioblastoma treated with bevacizumab in the BRAIN study.” Journal of Clinical Oncology, vol. 28, no. 15, AMER SOC CLINICAL ONCOLOGY, May 2010.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Reply to W. Wick et al

Authors
Friedman, HS; Prados, MD; Wen, PY; Mikkelsen, T; Schiff, D; Abrey, LE; Yung, WKA; Paleologos, N; Nicholas, MK; Jensen, R; Vredenburgh, J; Huang, J; Zheng, M; Cloughesy, T
MLA Citation
Friedman, H. S., et al. “Reply to W. Wick et al.” Journal of Clinical Oncology, vol. 28, no. 12, Apr. 2010. Scopus, doi:10.1200/JCO.2009.26.9472.
Source
scopus
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
28
Issue
12
Publish Date
2010
DOI
10.1200/JCO.2009.26.9472

Gene expression signatures as a guide to treatment strategies for in-transit metastatic melanoma.

In-transit metastatic melanoma, which typically presents as multifocal lesions, provides a unique setting to evaluate the utility of gene signatures for defining optimal regional therapeutic strategies and assessing the efficacy of treatment. The goal of this study was to determine whether a single multifocal lesion is representative of residual tumor burden in terms of gene expression signatures predictive of response to therapy. Using microarray-based gene expression profiling, we examined 55 in-transit melanoma lesions across 29 patients with multifocal disease. Principal component analysis, unsupervised hierarchical clustering, one-way ANOVA, binary regression analysis, and gene signatures predictive of oncogenic pathway activation were used to compare patterns of gene expression across all multifocal lesions from a patient. Patterns of gene expression were highly similar (P < 0.006; average r = 0.979) across pretreatment lesions from a single patient compared with the significantly different patterns observed across patients (P < 0.05). The findings presented in this study show that individual melanoma tumor nodules in patients with multifocal disease harbor similar patterns of gene expression and a single lesion can be used to predict response to chemotherapy, evaluate the activation status of oncogenic signaling pathways, and characterize other aspects of the biology of an individual patient's disease. These results will facilitate the use of gene expression profiling in melanoma regional therapy clinical trials to not only select optimal regional chemotherapeutic agents but to also allow for a more rational identification of candidates for specific targeted therapies and evaluation of their therapeutic efficacy. Mol Cancer Ther; 9(4); 779-90. (c)2010 AACR.

Authors
Augustine, CK; Jung, S-H; Sohn, I; Yoo, JS; Yoshimoto, Y; Olson, JA; Friedman, HS; Ali-Osman, F; Tyler, DS
MLA Citation
Augustine, Christina K., et al. “Gene expression signatures as a guide to treatment strategies for in-transit metastatic melanoma..” Mol Cancer Ther, vol. 9, no. 4, Apr. 2010, pp. 779–90. Pubmed, doi:10.1158/1535-7163.MCT-09-0764.
PMID
20371714
Source
pubmed
Published In
Mol Cancer Ther
Volume
9
Issue
4
Publish Date
2010
Start Page
779
End Page
790
DOI
10.1158/1535-7163.MCT-09-0764

Quantitative assessment of cardiorespiratory fitness, skeletal muscle function, and body composition in adults with primary malignant glioma.

BACKGROUND: The study was undertaken to evaluate cardiorespiratory fitness, skeletal muscle function, and body composition of patients with newly diagnosed and untreated, postsurgical primary malignant glioma. METHODS: By using a cross-sectional design, patients with clinically stable (10 +/- 7 days postsurgery) high-grade glioma (HGG; n = 25) or low-grade glioma (LGG; n = 10) were studied. Participants performed a cardiopulmonary exercise test (CPET) with expired gas analysis to assess cardiorespiratory fitness (peak oxygen consumption, VO2peak). Other physiological outcomes included skeletal muscle cross-sectional area (CSA; magnetic resonance imaging), isokinetic muscle strength (isokinetic dynamometer), and body composition (air displacement plethysmography). Quality of life was assessed with the Functional Assessment of Cancer Therapy-Brain scale. RESULTS: CPET was a feasible and safe procedure to assess VO2peak, with no serious adverse events. VO2peak indexed to total body weight and lean body mass (LBM) for both groups was 13.0 mL x weight x min(-1) and 19 mL x LBM x min(-1), the equivalent to 59% and 38% below age- and sex-predicted normative values, respectively. Skeletal muscle strength and mid-thigh CSA were lower in HGG relative to LGG patients (83 vs 125 Nm, P = .025; 94 vs 119 cm2, P = .171, respectively). Skeletal muscle isokinetic strength, CSA, and body composition outcomes predicted VO2peak (r = -0.59 to 0.68, P < .05). CONCLUSIONS: Postsurgical glioma patients have markedly reduced cardiorespiratory fitness, isokinetic strength, and CSA. Prospective studies are now required to determine whether such abnormalities influence treatment toxicity and clinical outcome as well as to test the effect of appropriately selected interventions to prevent and/or mitigate dysfunction.

Authors
Jones, LW; Friedman, AH; West, MJ; Mabe, SK; Fraser, J; Kraus, WE; Friedman, HS; Tresch, MI; Major, N; Reardon, DA
MLA Citation
Jones, Lee W., et al. “Quantitative assessment of cardiorespiratory fitness, skeletal muscle function, and body composition in adults with primary malignant glioma..” Cancer, vol. 116, no. 3, Feb. 2010, pp. 695–704. Pubmed, doi:10.1002/cncr.24808.
PMID
20029975
Source
pubmed
Published In
Cancer
Volume
116
Issue
3
Publish Date
2010
Start Page
695
End Page
704
DOI
10.1002/cncr.24808

Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma.

We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade > or = 2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Friedman, AH; Herndon, JE; Marcello, J; Norfleet, JA; McLendon, RE; Sampson, JH; Friedman, HS
MLA Citation
Reardon, David A., et al. “Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma..” J Neurooncol, vol. 96, no. 2, Jan. 2010, pp. 219–30. Pubmed, doi:10.1007/s11060-009-9950-0.
PMID
19562254
Source
pubmed
Published In
J Neurooncol
Volume
96
Issue
2
Publish Date
2010
Start Page
219
End Page
230
DOI
10.1007/s11060-009-9950-0

Changes in functional performance measures in adults undergoing chemoradiation for primary malignant glioma: a feasibility study.

PURPOSE: To investigate the feasibility of longitudinal assessment of functional performance measures in newly diagnosed postsurgical malignant glioma patients. METHODS: Patients with histologically confirmed, clinically stable, postsurgical, and previously untreated high-grade glioma (HGG) or low-grade glioma (LGG) were studied. Using a prospective design, all participants performed a cardiopulmonary exercise test with expired gas analysis to assess cardiorespiratory function (VO(2peak)) immediately following surgical resection (mean, 10 days). Additional functional outcomes were skeletal muscle cross-sectional area (CSA) via magnetic resonance imaging, isokinetic muscle strength (isokinetic dynamometry), and body composition (air displacement plethysmography). Quality of life (QOL) was assessed by the Functional Assessment of Cancer Therapy-Brain scale. All study assessments were repeated at 6 and 24 weeks following surgery. RESULTS: Thirty-five patients (HGG, n = 25; LGG, n = 10) completed baseline assessments. Of these, 20 HGG (80%) and nine LGG (90%) and 15 HGG (60%) and nine LGG (90%) patients completed study assessments at 6 weeks and 24 weeks, respectively. Intention-to-treat analyses indicated several significant time-by-group interactions, with favorable improvements in functional and QOL endpoints from baseline to 24 weeks in the LGG cohort and unfavorable changes in the HGG cohort. Per-protocol analyses including participants assessed at all three study timepoints indicated significant improvements in VO(2peak) and fatigue from baseline to 24 weeks in the HGG cohort; peak workload, body composition, and muscle strength improved from baseline to 6 weeks (all p-values < .05). CONCLUSIONS: Longitudinal quantitative functional assessments are safe and feasible among select patients undergoing chemoradiation for primary malignant glioma. Large prospective studies investigating the clinical importance of these measures appear warranted.

Authors
Jones, LW; Mourtzakis, M; Peters, KB; Friedman, AH; West, MJ; Mabe, SK; Kraus, WE; Friedman, HS; Reardon, DA
MLA Citation
Jones, Lee W., et al. “Changes in functional performance measures in adults undergoing chemoradiation for primary malignant glioma: a feasibility study..” Oncologist, vol. 15, no. 6, 2010, pp. 636–47. Pubmed, doi:10.1634/theoncologist.2009-0265.
PMID
20484122
Source
pubmed
Published In
Oncologist
Volume
15
Issue
6
Publish Date
2010
Start Page
636
End Page
647
DOI
10.1634/theoncologist.2009-0265

Corticosteroid use in patients with glioblastoma at first or second relapse treated with bevacizumab in the BRAIN study.

BACKGROUND: Vascular endothelial growth factor inhibitors have corticosteroid-sparing effects in patients with high-grade gliomas. We assessed corticosteroid use in patients with recurrent glioblastoma treated with bevacizumab (BEV) in the BRAIN study (J Clin Oncol 2009;27:4733-4740). METHODS: BRAIN was a phase II, multicenter, randomized, noncomparative trial of BEV alone (n = 85) or in combination with irinotecan (CPT-11) (n = 82) in adults with recurrent glioblastoma. Median corticosteroid dose for patients who used corticosteroids at baseline was summarized by treatment arm; the percentage of patients who had sustained (≥50% corticosteroid dose reduction for ≥50% of time on study drug) or complete (discontinuation of corticosteroid for ≥25% of time on study drug) reduction in corticosteroid dose overall and by objective response and progression-free survival was calculated. The incidence of corticosteroid-related adverse events was summarized. RESULTS: In each treatment group, 50% of patients were using systemic corticosteroids at baseline. The majority of those experienced a reduction in dose while receiving BEV-based therapy. Thirteen (30.2%) BEV and 20 (46.5%) BEV + CPT-11 patients had a sustained reduction of corticosteroid dose; 7 (16.3%) BEV and 9 (20.9%) BEV + CPT-11 patients had a complete reduction of corticosteroid dose. The majority of patients who had an objective response or progression-free survival >6 months experienced corticosteroid dose reduction. Approximately 64% of patients who used corticosteroids while receiving BEV-based therapy experienced infection. CONCLUSION: BEV may have corticosteroid-sparing effects in patients with recurrent glioblastoma. Corticosteroid reduction may positively affect patient health-related quality of life. Given the exploratory nature of the analyses in a noncomparative study, these results should be interpreted cautiously.

Authors
Vredenburgh, JJ; Cloughesy, T; Samant, M; Prados, M; Wen, PY; Mikkelsen, T; Schiff, D; Abrey, LE; Yung, WKA; Paleologos, N; Nicholas, MK; Jensen, R; Das, A; Friedman, HS
MLA Citation
Vredenburgh, James J., et al. “Corticosteroid use in patients with glioblastoma at first or second relapse treated with bevacizumab in the BRAIN study..” Oncologist, vol. 15, no. 12, 2010, pp. 1329–34. Pubmed, doi:10.1634/theoncologist.2010-0105.
PMID
21147867
Source
pubmed
Published In
Oncologist
Volume
15
Issue
12
Publish Date
2010
Start Page
1329
End Page
1334
DOI
10.1634/theoncologist.2010-0105

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study.

BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Sampson, JH; Sathornsumetee, S; McLendon, RE; Herndon, JE; Marcello, JE; Norfleet, J; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Reardon, D. A., et al. “Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study..” Br J Cancer, vol. 101, no. 12, Dec. 2009, pp. 1986–94. Pubmed, doi:10.1038/sj.bjc.6605412.
Website
http://hdl.handle.net/10161/16102
PMID
19920819
Source
pubmed
Published In
Br J Cancer
Volume
101
Issue
12
Publish Date
2009
Start Page
1986
End Page
1994
DOI
10.1038/sj.bjc.6605412

PHASE II STUDY OF BEVACIZUMAB PLUS ETOPOSIDE AMONG RECURRENT MALIGNANT GLIOMA PATIENTS: FINAL STUDY RESULTS

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Peters, KB; Norfleet, JA; Friedman, AH; Friedman, HS
MLA Citation
Reardon, David A., et al. “PHASE II STUDY OF BEVACIZUMAB PLUS ETOPOSIDE AMONG RECURRENT MALIGNANT GLIOMA PATIENTS: FINAL STUDY RESULTS.” Neuro Oncology, vol. 11, no. 6, OXFORD UNIV PRESS INC, 2009, pp. 905–905.
Source
wos
Published In
Neuro Oncology
Volume
11
Issue
6
Publish Date
2009
Start Page
905
End Page
905

BEVACIZUMAB PLUS ERLOTINIB IN RECURRENT HIGH-GRADE GLIOMA: A PHASE II TRIAL

Authors
Sithornsumetee, S; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Janney, DE; Friedman, AH; Friedman, HS; Reardon, DA
MLA Citation
Sithornsumetee, Sith, et al. “BEVACIZUMAB PLUS ERLOTINIB IN RECURRENT HIGH-GRADE GLIOMA: A PHASE II TRIAL.” Neuro Oncology, vol. 11, no. 6, OXFORD UNIV PRESS INC, 2009, pp. 926–926.
Source
wos
Published In
Neuro Oncology
Volume
11
Issue
6
Publish Date
2009
Start Page
926
End Page
926

A PHASE I STUDY OF SUNITINIB PLUS IRINOTECAN IN THE TREATMENT OF PATIENTS WITH RECURRENT MALIGNANT GLIOMA

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Janney, DE; Peters, KB; Friedman, AH; Gururangan, S; Friedman, HS
MLA Citation
Reardon, David A., et al. “A PHASE I STUDY OF SUNITINIB PLUS IRINOTECAN IN THE TREATMENT OF PATIENTS WITH RECURRENT MALIGNANT GLIOMA.” Neuro Oncology, vol. 11, no. 6, OXFORD UNIV PRESS INC, 2009, pp. 946–946.
Source
wos
Published In
Neuro Oncology
Volume
11
Issue
6
Publish Date
2009
Start Page
946
End Page
946

BEVACIZUMAB PLUS ERLOTINIB IN RECURRENT HIGH-GRADE GLIOMA: A PHASE II TRIAL

Authors
Sathornsumetee, S; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Janney, DE; Friedman, AH; Friedman, HS; Reardon, DA
MLA Citation
Sathornsumetee, Sith, et al. “BEVACIZUMAB PLUS ERLOTINIB IN RECURRENT HIGH-GRADE GLIOMA: A PHASE II TRIAL.” Neuro Oncology, vol. 11, no. 6, OXFORD UNIV PRESS INC, 2009, pp. 906–906.
Source
wos
Published In
Neuro Oncology
Volume
11
Issue
6
Publish Date
2009
Start Page
906
End Page
906

Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy.

This phase II trial evaluated efficacy and safety of temozolomide (TMZ) in combination with irinotecan (CPT-11) before radiotherapy in patients with newly diagnosed glioblastoma multiforme (GBM). Prior to radiotherapy, patients were treated with a maximum of three 6-week cycles of TMZ and CPT-11. Patients received TMZ at a dose of 200 mg/m(2)/day on days 1-5 and CPT-11 on days 1, 8, 22, and 29, with a dose adjustment for enzyme-inducing antiepileptic drug use. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and tumor O(6)-methylguanine-DNA methyltransferase (MGMT) expression. Of the 42 patients treated, 8 (19%) patients achieved a partial response. Median PFS and median OS were 3.1 and 13.8 months, respectively. Grade 3 or 4 AEs were documented in 36% of patients, most of which were hematologic (29%). Twenty-four percent of patients had grade 3 or 4 non-hematologic AEs, with gastrointestinal AEs being the most common (12%) Two patients died, one of intracranial hemorrhage and one of treatment-related renal failure. Low MGMT expression, compared with high MGMT expression, showed no significant difference in ORR (25 vs. 8%), median PFS (14 vs. 5 months) or OS (21 vs. 15 months). Although TMZ plus CPT-11 is at least comparable in efficacy to TMZ alone, this combination appears more toxic and poorly tolerated. The lack of correlation of activity with MGMT expression is intriguing, but needs further evaluation in subsequent trials.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Friedman, AH; Sampson, JH; McLendon, RE; Herndon, JE; Friedman, HS
MLA Citation
Quinn, Jennifer A., et al. “Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy..” J Neurooncol, vol. 95, no. 3, Dec. 2009, pp. 393–400. Pubmed, doi:10.1007/s11060-009-9937-x.
PMID
19533023
Source
pubmed
Published In
J Neurooncol
Volume
95
Issue
3
Publish Date
2009
Start Page
393
End Page
400
DOI
10.1007/s11060-009-9937-x

Radiotherapy, Temozolomide and Bevacizumab followed by Irinotecan, Temozolomide and Bevacizumab Appears Well-tolerated and Efficacious in Newly Diagnosed Glioblastoma Multiforme: Results from a Phase II Trial

Authors
Kirkpatrick, JP; Desjardins, A; Reardon, DA; Friedman, AH; Friedman, HS; Vredenburgh, JJ
MLA Citation
Kirkpatrick, J. P., et al. “Radiotherapy, Temozolomide and Bevacizumab followed by Irinotecan, Temozolomide and Bevacizumab Appears Well-tolerated and Efficacious in Newly Diagnosed Glioblastoma Multiforme: Results from a Phase II Trial.” International Journal of Radiation Oncology*Biology*Physics, vol. 75, no. 3, Elsevier BV, 2009, pp. S102–03. Crossref, doi:10.1016/j.ijrobp.2009.07.250.
Source
crossref
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
75
Issue
3
Publish Date
2009
Start Page
S102
End Page
S103
DOI
10.1016/j.ijrobp.2009.07.250

Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma.

PURPOSE: We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial. PATIENTS AND METHODS: One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m(2) or 125 mg/m(2) (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival. RESULTS: In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade > or = 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively). CONCLUSION: Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.

Authors
Friedman, HS; Prados, MD; Wen, PY; Mikkelsen, T; Schiff, D; Abrey, LE; Yung, WKA; Paleologos, N; Nicholas, MK; Jensen, R; Vredenburgh, J; Huang, J; Zheng, M; Cloughesy, T
MLA Citation
Friedman, Henry S., et al. “Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma..” J Clin Oncol, vol. 27, no. 28, Oct. 2009, pp. 4733–40. Pubmed, doi:10.1200/JCO.2008.19.8721.
PMID
19720927
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
28
Publish Date
2009
Start Page
4733
End Page
4740
DOI
10.1200/JCO.2008.19.8721

Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients.

The purpose of this study was to determine the safety of tinzaparin for deep vein thrombosis prophylaxis in newly diagnosed grade III-IV malignant glioma patients. Patients were initiated on daily tinzaparin at a fixed dose of 4,500 IU subcutaneously between 48 h and 4 weeks post-operative for planned duration of 12 months. During chemotherapy cycles, blood counts were monitored weekly and tinzaparin was held if the platelet count decreased to <50,000 and was re-initiated at a platelet count >100,000. Forty patients were enrolled into the study, 35 with glioblastoma multiforme and 5 with anaplastic astrocytoma. Possible attributable toxicity was limited to two patients who developed CNS hemorrhages (one grade 1 and one grade 2) and one patient with an increase in liver enzymes (grade 3). There were no patients with a grade 4 or 5 CNS hemorrhages or systemic hemorrhages >or=grade 2. The median time on prophylactic tinzaparin was 161 days (range of 5 to 601 days). One patient developed a deep venous thrombosis while taking tinzaparin, and three patients developed thromboembolic complications while off tinzaparin. Tinzaparin at a fixed prophylactic dose is safe and may decrease the incidence of thromboembolic complications in brain tumor patients.

Authors
Perry, SL; Bohlin, C; Reardon, DA; Desjardins, A; Friedman, AH; Friedman, HS; Vredenburgh, JJ
MLA Citation
Perry, Stephanie L., et al. “Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients..” J Neurooncol, vol. 95, no. 1, Oct. 2009, pp. 129–34. Pubmed, doi:10.1007/s11060-009-9911-7.
PMID
19415455
Source
pubmed
Published In
J Neurooncol
Volume
95
Issue
1
Publish Date
2009
Start Page
129
End Page
134
DOI
10.1007/s11060-009-9911-7

A sphingosine kinase inhibitor induces cell death in temozolomide resistant glioblastoma cells.

PURPOSE: Sphingosine kinase is an oncogene that is up-regulated in several solid tumors. The product of the sphingosine kinase activity, sphingosine-1-phosphate is a potent mitogen involved in diverse cell processes such as cell survival and migration. Current standard therapy in the treatment of glioblastoma multiforme (GBM) is a combination of surgery, radiation, and chemotherapy using the drug temozolomide (TMZ). However, virtually all tumors become resistant to TMZ. Therefore, new drug targets are necessary. In this study, we investigated whether inhibiting sphingosine kinase could induce cell death in TMZ-resistant GBM cells. METHODS: To study TMZ resistance in vitro, we have generated TMZ-resistant cell lines from established GBM cells. We used a potent inhibitor of sphingosine kinase to study its effect on colony formation and cell growth in GBM cells with a limited dilution and WST assay. Moreover, cell death was determined by measuring caspase-3 activity using flow cytometry. RESULTS: A sphingosine kinase inhibitor reduced cell colony formation and activated caspase-3 in both TMZ-sensitive and resistant GBM cells. CONCLUSION: Addition of a sphingosine kinase inhibitor to the standard chemotherapy regimen against GBM may be beneficial.

Authors
Bektas, M; Johnson, SP; Poe, WE; Bigner, DD; Friedman, HS
MLA Citation
Bektas, Meryem, et al. “A sphingosine kinase inhibitor induces cell death in temozolomide resistant glioblastoma cells..” Cancer Chemother Pharmacol, vol. 64, no. 5, Oct. 2009, pp. 1053–58. Pubmed, doi:10.1007/s00280-009-1063-0.
PMID
19597728
Source
pubmed
Published In
Cancer Chemother Pharmacol
Volume
64
Issue
5
Publish Date
2009
Start Page
1053
End Page
1058
DOI
10.1007/s00280-009-1063-0

An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme.

Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by nonspecific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent and tumor-specific mutation widely expressed in GBMs and other neoplasms. The safety and immunogenicity of a dendritic cell (DC)-based vaccine targeting the EGFRvIII antigen was evaluated in this study. Adults with newly diagnosed GBM, who had undergone gross-total resection and standard conformal external beam radiotherapy, received three consecutive intradermal vaccinations with autologous mature DCs pulsed with an EGFRvIII-specific peptide conjugated to keyhole limpet hemocyanin. The dose of DCs was escalated in cohorts of three patients. Patients were monitored for toxicity, immune response, radiographic and clinical progression, and death. No allergic reactions or serious adverse events were seen. Adverse events were limited to grade 2 toxicities. The maximum feasible dose of antigen-pulsed mature DCs was reached at 5.7 x 10(7) +/- 2.9 x 10(7) SD without dose-limiting toxicity. EGFRvIII-specific immune responses were evident in most patients. The mean time from histologic diagnosis to vaccination was 3.6 +/- 0.6 SD months. Median time to progression from vaccination was 6.8 months [95% confidence interval (C.I.(95)), 2.5-8.8], and median survival time from vaccination was 18.7 months (C.I.(95), 14.5-25.6). Overall median survival from time of histologic diagnosis was 22.8 months (C.I.(95), 17.5-29). This study establishes the EGFRvIII mutation as a safe and immunogenic tumor-specific target for immunotherapy.

Authors
Sampson, JH; Archer, GE; Mitchell, DA; Heimberger, AB; Herndon, JE; Lally-Goss, D; McGehee-Norman, S; Paolino, A; Reardon, DA; Friedman, AH; Friedman, HS; Bigner, DD
MLA Citation
Sampson, John H., et al. “An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme..” Mol Cancer Ther, vol. 8, no. 10, Oct. 2009, pp. 2773–79. Pubmed, doi:10.1158/1535-7163.MCT-09-0124.
PMID
19825799
Source
pubmed
Published In
Mol Cancer Ther
Volume
8
Issue
10
Publish Date
2009
Start Page
2773
End Page
2779
DOI
10.1158/1535-7163.MCT-09-0124

Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma.

This phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with O(6)-benzylguanine (O(6)-BG). Both TMZ and O(6)-BG were administered on days 1-5 of a 28-day treatment cycle. A bolus infusion of O(6)-BG was administered at 120 mg/m(2) over 1 h on days 1, 3, and 5, along with a continuous infusion of O(6)-BG at 30 mg/m(2)/day. TMZ was administered at the end of the first bolus infusion of O(6)-BG and then every 24 h for 5 days during the continuous infusion of O(6)-BG. Patients were accrued to one of three 5-day dosing regimens of TMZ. Twenty-nine patients were enrolled into this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for TMZ for the three different 5-day dosing schedules was determined as follows: schedule 1, 200 mg/m(2) on day 1 and 50 mg/m(2)/day on days 2-5; schedule 2, 50 mg/m(2)/day on days 1-5; and schedule 3, 50 mg/m(2)/day on days 1-5 while receiving pegfilgrastim. Thus, the 5-day TMZ dosing schedule that maximized the total dose of TMZ when combined with O(6)-BG was schedule 1. This study provides the foundation for a phase II trial of O(6)-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Walker, A; Friedman, HS
MLA Citation
Quinn, Jennifer A., et al. “Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma..” Neuro Oncol, vol. 11, no. 5, Oct. 2009, pp. 556–61. Pubmed, doi:10.1215/15228517-2009-007.
PMID
19289491
Source
pubmed
Published In
Neuro Oncology
Volume
11
Issue
5
Publish Date
2009
Start Page
556
End Page
561
DOI
10.1215/15228517-2009-007

Bevacizumab, chemotherapy, and RT delay progression: Commentary

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Bevacizumab, chemotherapy, and RT delay progression: Commentary.” Oncology Report, no. FALL, Sept. 2009.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2009
Start Page
6

8721 Evaluation of objective response as a predictor of survival in bevacizumab-treated patients with glioblastoma at first or second relapse in the BRAIN Study

Authors
Prados, M; Cloughesy, T; Samant, MK; Fang, L; Das, A; Friedman, HS
MLA Citation
Prados, M., et al. “8721 Evaluation of objective response as a predictor of survival in bevacizumab-treated patients with glioblastoma at first or second relapse in the BRAIN Study.” European Journal of Cancer Supplements, vol. 7, no. 2, Elsevier BV, 2009, pp. 499–500. Crossref, doi:10.1016/s1359-6349(09)71695-7.
Source
crossref
Published In
European Journal of Cancer Supplements
Volume
7
Issue
2
Publish Date
2009
Start Page
499
End Page
500
DOI
10.1016/s1359-6349(09)71695-7

8707 Clinical assessment of corticosteroid use and neurocognitive function in patients with glioblastoma at first or second relapse treated with bevacizumab in the BRAIN study

Authors
Vredenburgh, JJ; Wefel, J; Cloughesy, T; Zazzali, J; Samant, MK; Zheng, M; Fang, L; Das, A; Friedman, HS
MLA Citation
Vredenburgh, J. J., et al. “8707 Clinical assessment of corticosteroid use and neurocognitive function in patients with glioblastoma at first or second relapse treated with bevacizumab in the BRAIN study.” European Journal of Cancer Supplements, vol. 7, no. 2, Elsevier BV, 2009, pp. 495–96. Crossref, doi:10.1016/s1359-6349(09)71681-7.
Source
crossref
Published In
European Journal of Cancer Supplements
Volume
7
Issue
2
Publish Date
2009
Start Page
495
End Page
496
DOI
10.1016/s1359-6349(09)71681-7

Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy.

BACKGROUND: Glioblastoma multiforme (GBM), the most lethal type of brain tumor, has a 1-year median survival. The effect of carmustine wafers on the survival of newly diagnosed GBM patients treated with radiotherapy (RT) and concurrent temozolomide (TMZ) plus RT plus rotational chemotherapy was investigated. METHODS: An institutional review board-approved retrospective study was conducted in 85 newly diagnosed GBM patients who received surgical resection with and without carmustine wafers followed by RT and concurrent TMZ plus rotational chemotherapy. Treatment group comparisons were conducted using the log-rank test. Survival experience of the Duke cohort was examined within specific patient subgroups defined by the original Radiation Therapy Oncology Group (RTOG) recursive partition analysis (RPA) class and compared with the European Organization for Research and Treatment of Cancer (Stupp) and RTOG trial. RESULTS: Overall 1- and 2-year survival for the noncarmustine wafer cohort were 69% and 29%, respectively, with a median survival of 72.7 weeks. One- and 2-year survival for the carmustine wafer cohort were 81% and 47%, with median survival of 89.5 weeks. Carmustine wafer was not an independent predictor (P=.110) of survival after adjustment for RPA class. The proportion of patients in the carmustine wafer cohort who lived longer than predicted based upon Stupp regimen results was significantly greater than 0.5 (P<.006); similar results based upon the RTOG trial data were observed (P<.001). CONCLUSIONS: Carmustine wafer with concurrent TMZ and radiation followed by rotational chemotherapy is a well tolerated, effective therapy, and has a survival benefit compared with radiation alone. Prospective randomized trials are needed to rigorously compare the carmustine wafer regimen to the Stupp and postradiation multimodality regimens.

Authors
Affronti, ML; Heery, CR; Herndon, JE; Rich, JN; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Affronti, Mary Lou, et al. “Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy..” Cancer, vol. 115, no. 15, Aug. 2009, pp. 3501–11. Pubmed, doi:10.1002/cncr.24398.
PMID
19514083
Source
pubmed
Published In
Cancer
Volume
115
Issue
15
Publish Date
2009
Start Page
3501
End Page
3511
DOI
10.1002/cncr.24398

Assessment of physical functioning in recurrent glioma: preliminary comparison of performance status to functional capacity testing.

BACKGROUND: Performance status (PS) scoring systems are tools of immense clinical importance in the management of patients with malignant disease but these tools are subjective and do not provide an objective evaluation of physical functioning. We conducted a pilot study to explore the feasibility and clinical utility of functional capacity testing to assess physical functioning in recurrent primary malignant glioma patients. PATIENTS AND METHODS: Using a cross-sectional design, consecutive patients with recurrent glioma performed a six minute walk (6MW) test to assess functional capacity. Performance status was assessed using Karnofsky Performance Status (KPS) scoring system. QOL was assessed by the Functional Assessment of Cancer Therapy-Brain scale. Self-reported exercise behavior was assessed using the Godin Leisure Time Exercise Questionnaire (GLTEQ). RESULTS: A total of 171 patients were recruited and tested. Seventy percent were diagnosed with glioblastoma multiforme (WHO grade IV) and 85% were undergoing therapy. Median KPS was 90% (range, 70-100%). Median 6MW distance was 400 m (range, 102-630 m), equivalent to 56 +/- 13% (range, 14-87%) of that predicted for age and sex. KPS, self-reported exercise, and QOL increased across 6MW distance quartiles (P < 0.05) although there was considerable variation within each category. 6MW distance and KPS were significantly correlated with each other (r = 0.34, P < 0.01) and several QOL domains (range, r = -0.43 to 0.46, P < 0.05). CONCLUSIONS: 6MW distance is a clinically feasible tool that provides an objective measure of physical functioning in select patients with recurrent glioma. Further research is required to investigate the prognostic value of these tests in patients with advanced malignancy.

Authors
Jones, LW; Cohen, R-R; Mabe, SK; West, MJ; Desjardins, A; Vredenburgh, JJ; Friedman, AH; Reardon, DA; Waner, E; Friedman, HS
MLA Citation
Jones, Lee W., et al. “Assessment of physical functioning in recurrent glioma: preliminary comparison of performance status to functional capacity testing..” J Neurooncol, vol. 94, no. 1, Aug. 2009, pp. 79–85. Pubmed, doi:10.1007/s11060-009-9803-x.
PMID
19212703
Source
pubmed
Published In
J Neurooncol
Volume
94
Issue
1
Publish Date
2009
Start Page
79
End Page
85
DOI
10.1007/s11060-009-9803-x

Phase 1 trial of temozolomide plus irinotecan plus O6-benzylguanine in adults with recurrent malignant glioma.

BACKGROUND: The current study was a phase 1 clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG). The trial was designed to determine the maximum tolerated dose (MTD) and toxicity of irinotecan (CPT-11) when administered with temozolomide (TMZ) and O(6)-benzylguanine (O(6)-BG). METHODS: All 3 drugs, CPT-11, TMZ, and O(6)-BG, were administered on Day 1 of a 21-day treatment. First, patients were treated with a 1-hour bolus infusion of O(6)-BG at a dose of 120 mg/m(2) followed immediately by a 48-hour continuous infusion of O(6)-BG at a dose of 30 mg/m(2)/d. Second, within 60 minutes of the end of the 1-hour bolus infusion of O(6)-BG, TMZ was administered orally at a dose of 355 mg/m(2). Third, 1 hour after administration of TMZ, CPT-11 was infused over 90 minutes. Patients were accrued to 1 of 2 strata based on CYP3A1- and CYP3A4-inducing antiepileptic drug (EIAED) use; dose escalation was conducted independently within these strata. RESULTS: Fifty-five patients were enrolled. In both strata, the dose-limiting toxicities were hematologic and included grade 4 neutropenia, febrile neutropenia, leukopenia, and/or thrombocytopenia. For Stratum 1 (EIAEDs), when TMZ was administered at a dose of 355 mg/m(2), the MTD of CPT-11 was determined to be 120 mg/m(2). In contrast, for Stratum 2 (no EIAEDs), when TMZ was administered at a dose of 200 mg/m(2), the MTD of CPT-11 was determined to be 80 mg/m(2). CONCLUSIONS: The authors believe that the results of the current study provide the foundation for a phase 2 trial of O(6)-BG in combination with CPT-11 and TMZ in patients with MG.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Friedman, HS
MLA Citation
Quinn, Jennifer A., et al. “Phase 1 trial of temozolomide plus irinotecan plus O6-benzylguanine in adults with recurrent malignant glioma..” Cancer, vol. 115, no. 13, July 2009, pp. 2964–70. Pubmed, doi:10.1002/cncr.24336.
PMID
19402172
Source
pubmed
Published In
Cancer
Volume
115
Issue
13
Publish Date
2009
Start Page
2964
End Page
2970
DOI
10.1002/cncr.24336

Tyrosine phosphorylation of the human glutathione S-transferase P1 by epidermal growth factor receptor.

Epidermal growth factor receptor (EGFR) gene amplification, mutations, and/or aberrant activation are frequent abnormalities in malignant gliomas and other human cancers and have been associated with an aggressive clinical course and a poor therapeutic outcome. Elevated glutathione S-transferase P1 (GSTP1), a major drug-metabolizing and stress response signaling protein, is also associated with drug resistance and poor clinical outcome in gliomas and other cancers. Here, we provide evidence that GSTP1 is a downstream EGFR target and that EGFR binds to and phosphorylates tyrosine residues in the GSTP1 protein in vitro and in vivo. Mass spectrometry and mutagenesis analyses in a cell-free system and in gliomas cells identified Tyr-7 and Tyr-198 as major EGFR-specific phospho-acceptor residues in the GSTP1 protein. The phosphorylation increased GSTP1 enzymatic activity significantly, and computer-based modeling showed a corresponding increase in electronegativity of the GSTP1 active site. In human glioma and breast cancer cells, epidermal growth factor stimulation rapidly increased GSTP1 tyrosine phosphorylation and decreased cisplatin sensitivity. Lapatinib, a clinically active EGFR inhibitor, significantly reversed the epidermal growth factor-induced cisplatin resistance. These data define phosphorylation and activation of GSTP1 by EGFR as a novel, heretofore unrecognized component of the EGFR signaling network and a novel mechanism of tumor drug resistance, particularly in tumors with elevated GSTP1 and/or activated EGFR.

Authors
Okamura, T; Singh, S; Buolamwini, J; Haystead, T; Friedman, H; Bigner, D; Ali-Osman, F
MLA Citation
Okamura, Tatsunori, et al. “Tyrosine phosphorylation of the human glutathione S-transferase P1 by epidermal growth factor receptor..” J Biol Chem, vol. 284, no. 25, June 2009, pp. 16979–89. Pubmed, doi:10.1074/jbc.M808153200.
PMID
19254954
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
284
Issue
25
Publish Date
2009
Start Page
16979
End Page
16989
DOI
10.1074/jbc.M808153200

Bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea activates the ATR-Chk1 pathway independently of the mismatch repair pathway.

The presence of DNA damage initiates signaling through the ataxia-telangiectasia mutated kinase (ATM) and the ATM- and the Rad3-related kinase (ATR), which phosphorylate, thus activating, the checkpoint kinases (Chk) 1 and 2, which leads to cell cycle arrest. The bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is cytotoxic primarily by inducing DNA monoadducts and ultimately, interstrand cross-links, which block DNA replication. In this study, we investigated the activation of the ATR-Chk1 pathway in response to BCNU treatment and the dependence of this response on the DNA mismatch repair (MMR) capacity. Medulloblastoma cells were exposed to low and moderate doses of BCNU, and the effects on this DNA damage signaling pathway were examined. In response to BCNU, Chk1 was found to be phosphorylated at serine 345 and exhibited increased kinase activity. Caffeine and wortmannin, which are broad-spectrum inhibitors of ATM and ATR, reduced this phosphorylation. Cell cycle analysis further revealed an accumulation of cells in the S phase in response to BCNU, an effect that was attenuated by caffeine. Small interfering RNA knockdown of ATR also reduced Chk1 phosphorylation after exposure to BCNU. However, knockdown of ATM had no effect on the observed Chk1 phosphorylation, suggesting that ATR was primarily responsible for Chk1 activation. Analysis of Chk1 activation in cells deficient in MMR proteins MutLalpha or MutSalpha indicated that the DNA damage response induced by BCNU was independent of the MMR apparatus. This MMR-independent activation seems to be the result of DNA interstrand cross-link formation.

Authors
Cui, B; Johnson, SP; Bullock, N; Ali-Osman, F; Bigner, DD; Friedman, HS
MLA Citation
Cui, B., et al. “Bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea activates the ATR-Chk1 pathway independently of the mismatch repair pathway..” Mol Pharmacol, vol. 75, no. 6, June 2009, pp. 1356–63. Pubmed, doi:10.1124/mol.108.053124.
PMID
19261750
Source
pubmed
Published In
Mol Pharmacol
Volume
75
Issue
6
Publish Date
2009
Start Page
1356
End Page
1363
DOI
10.1124/mol.108.053124

Neurocognitive function in patients with glioblastoma multiforme in first or second relapse treated with bevacizumab in the BRAIN study

Authors
Wefel, JS; Cloughesy, T; Zazzali, J; Yi, J; Friedman, HS
MLA Citation
Wefel, J. S., et al. “Neurocognitive function in patients with glioblastoma multiforme in first or second relapse treated with bevacizumab in the BRAIN study.” Journal of Clinical Oncology, vol. 27, no. 15, AMER SOC CLINICAL ONCOLOGY, 2009.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Phase I study of vandetanib, imatinib mesylate, and hydroxyurea for recurrent malignant glioma.

e13007 Background: Malignant glioma (MG), an incurable primary CNS tumor, is characterized by frequent aberrant activation of EGFR, VEGFR, and PDGFR. This study will determine the MTD and DLT of vandetanib (V), a once-daily, oral selective inhibitor of VEGFR and EGFR when combined with imatinib mesylate (IM), an inhibitor of multiple tyrosine kinases including PDGFR and hydroxyurea (H). METHODS: Adult recurrent MG patients with ≤ 3 prior recurrences, KPS ≥ 60% and adequate organ function were stratified based on concurrent enzyme-inducing anticonvulsant use (EIAC). Both strata were independently escalated using a "3+3" design. H is administered at 500 mg BID while IM is administered at 500 mg BID for patients on EIAC and 400 mg QD for those not on EIAC. V is increased by 100 mg in successive cohorts beginning at 100 mg and 200 mg for patients not on and on EIAC, respectively. Evaluations were after every other 28-day cycle. Pharmacokinetics of V and IM were obtained on days 1 and 28 of cycle 1. RESULTS: Twenty-six patients (grade 4 MG, n = 20; grade 3 MG, n = 6) have enrolled. Only 1 DLT (reversible grade 4 transaminase elevation; dose level 1) occurred among 22 non-EIAC patients and enrollment to this stratum is planned to continue at dose level 4. The MTD of V for patients on EIAC is 200 mg/day due to 2 of 3 patients developing grade 3 thrombocytopenia at the 300 mg/day dose level. Evidence of therapeutic benefit to date includes 1 partial response and 15 patients (58%) with stable disease for at least 4 weeks, including 4 patients for ≥4 months. CONCLUSIONS: Combination of V, IM, and H is well-tolerated in recurrent MG patients. Further accrual is ongoing and an update of outcome, toxicity, and pharmacokinetic analyses will be presented. No significant financial relationships to disclose.

Authors
Kirkpatrick, JP; Vredenburgh, JJ; Desjardins, A; Gururangan, S; Peters, KB; Boulton, ST; Friedman, AH; Friedman, HS; Reardon, DA
MLA Citation
Kirkpatrick, J. P., et al. “Phase I study of vandetanib, imatinib mesylate, and hydroxyurea for recurrent malignant glioma..” J Clin Oncol, vol. 27, no. 15_suppl, May 2009.
PMID
27962760
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
e13007

A phase I study of sunitinib plus irinotecan in the treatment of patients with recurrent malignant glioma.

e13024 Background: Malignant glioma (MG), an incurable primary CNS tumor, are highly angiogenic due to overexpression of VEGF/VEGFR. The current study was designed to determine the MTD and DLT of sunitinib (S), a once-daily, oral selective inhibitor of VEGFR when combined with irinotecan (I), a topoisomerase-1 inhibitor among recurrent MG patients. METHODS: We employed a '3+3' dose escalation design to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of S, administered once daily for the first 28 days of each 42 day cycle, with I, administered every 2 weeks. The initial S and I doses were 25 mg/day and 75 mg/m(2). Key eligibility criteria included KPS ≥ 70%, adequate organ function and no concurrent CYP3A-inducing anti-epileptics. Pharmacokinetic studies for S are obtained during cycle 1 among 6 additional patients treated at the MTD. RESULTS: Eleven patients (grade 4 MG, n = 6; grade 3 MG, n = 5) have enrolled. No DLTs were observed in cohort 1, but 2 patients experienced hematologic DLT (grade 3 thrombocytopenia, n = 2; grade 4 neutropenia, n = 1) in cohort 2. Therefore the MTD for this regimen is 25 mg of S plus 75 mg/m(2) of I. Evidence of therapeutic benefit to date includes 8 patients (73%) with stable disease including 3 who continue on therapy. CONCLUSIONS: Combination of sunitinib plus irinotecan is well tolerated in recurrent MG patients at the defined MTD dose level. Accrual to the PK dose expansion cohort continues. No significant financial relationships to disclose.

Authors
Friedman, HS; Vredenburgh, JJ; Desjardins, A; Janney, DE; Peters, KB; Friedman, AH; Gururangan, S; Reardon, DA
MLA Citation
Friedman, H. S., et al. “A phase I study of sunitinib plus irinotecan in the treatment of patients with recurrent malignant glioma..” J Clin Oncol, vol. 27, no. 15_suppl, May 2009.
PMID
27962793
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
e13024

Effect of daclizumab on TReg counts and EGFRvIII-specific immune responses in GBM.

2034 Background: TRegs are increased in patients with GBM and constitutively express the high affinity interleukin-2 receptor (IL-2Rα). Treatment with an antibody that blocks IL-2Rα signaling functionally inactivates and eliminates TRegs without inducing autoimmune toxicity in murine models. We hypothesized that daclizumab, a commercially-available, IL-2Rα-specific antibody would function identically. METHODS: A randomized phase II clinical trial assessed the effects of daclizumab in the context of the cancer vaccine, CDX-110, which is comprised of an EGFRvIII-specific peptide sequence linked to KLH. EGFRvIII is a constitutively activated and immunogenic mutation not expressed in normal tissues, but widely expressed in GBMs and other neoplasms. In patients with newly-diagnosed, EGFRvIII+ GBM, after resection and radiation/TMZ, patients received CDX-110 vaccinations biweekly x 3, then monthly until tumor progression in combination with TMZ (200 mg/m(2) x 5/28 days). Half the patients were randomized to receive daclizumab (1mg/Kg x1) at the first vaccine. The others received saline in a double-blinded fashion. RESULTS: There were no drug related SAEs. EGFRvIII-specific immune responses were generated in all patients, and all immune responses were sustained or enhanced during subsequent TMZ cycles. Preliminary analysis (n = 4) suggests that daclizumab reduces Treg (CD4(+)CD25(+)CD45RO(+)FOXP3(+)) numbers [change 82.4 ± 7.1% from baseline (p = 0.011; t-test)] without reducing overall CD8(+) or CD4(+) T-cell counts. Tregs decreased only 3.7 + 11.0% after vaccination in the saline treated group during the same interval. Preliminary analysis (n = 4) also suggest that daclizumab enhanced EGFRvIII-specific immune responses (p = 0.01; t-test) and enhanced the titer of cytotoxic EGFRvIII-specific IgG1 isotype antibodies compared to the saline treated group (p = 0.003; t-test) and compared to previously vaccinated patients who did not receive daclizumab (p = 0.0015; t-test). TTP and OS survival in both arms has not been reached. CONCLUSIONS: Daclizumab may reduce Treg counts in patients with GBM. TMZ and daclizumab may enhance EGFRvIII-targeted immune responses despite lymphodepletion. These combinations are currently under further investigation. [Table: see text].

Authors
Sampson, JH; Archer, GE; Bigner, DD; Schmittling, RJ; Herndon, JE; Davis, T; Friedman, HS; Keler, T; Reardon, DA; Mitchell, DA
MLA Citation
Sampson, J. H., et al. “Effect of daclizumab on TReg counts and EGFRvIII-specific immune responses in GBM..” J Clin Oncol, vol. 27, no. 15_suppl, May 2009.
PMID
27964629
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
2034

Epidermal growth factor receptor variant III (EGFRvIII) vaccine (CDX-110) in GBM.

2021 Background: Unlike conventional therapies for GBM, immunologic targeting of tumor-specific gene mutations allows precise eradication of neoplastic cells with reduced toxicity. EGFRvIII is a constitutively activated and immunogenic mutation not expressed in normal tissues, but widely expressed in GBM and other neoplasms. The cancer vaccine CDX-110 is comprised of an EGFRvIII-specific peptide sequence linked to keyhole limpet hemocyanin (KLH). METHODS: A phase II multi-center trial assessed the immunogenicity and efficacy of CDX-110 in patients with newly-diagnosed, EGFRvIII+ GBM. After resection and radiation / TMZ, patients received CDX-110 vaccinations biweekly x 3, then monthly until tumor progression. Sequential cohorts received CDX-110 alone [ACTIVATE (n = 18)] or in combination with TMZ (200 mg/m(2) x 5/28 days [ACT II A (n = 13)]) or (100 mg/m(2) x 21/28 days [ACT II B (n=10)]). RESULTS: Reversible systemic drug hypersensitivity reactions were seen in 1 ACTIVATE and 4 ACT II patients. Two patients had non-specific changes on MRI which were possibly due to the vaccine but which resolved. Despite grade 2 or 3 lymphopenia in all ACT II patients, EGFRvIII-specific immune responses were generated in all patients, and all immune responses were sustained or enhanced during subsequent TMZ cycles. Although ACT II B patients had more severe TMZ-induced lymphopenia, they developed greater EGFRvIII-specific immune responses (p = 0.028) when compared to ACT II A. EGFRvIII-specific IgG1 also increased in avidity with vaccination (Ka>2x10(9)M(-1)) in a randomly selected subset of 4 patients (p = 0.000068). Of the 23 recurrent tumors studied, 18 lost EGFRvIII expression (p = 0.001). There are no significant differences between ACT II A and B in estimated median TTP (18.5 vs. 14.9 months, p = 0.31) and OS (23.6 vs. 19.9 months, p = 0.75). ACTIVATE TTP (14.2 months) and OS (26.0 months) and ACT II TTP (15.2 months) and OS (23.6 months) compare favorably to a TMZ-treated, matched historical control group (TTP: 6.3 months; OS: 15.0 months). CONCLUSIONS: CDX-110 vaccination in patients with GBM appears very promising. TMZ enhances immune responses despite lymphodepletion. CDX-110 with simultaneous TMZ is under further investigation in a larger phase II trial. [Table: see text].

Authors
Heimberger, AB; Archer, GE; Mitchell, DA; Bigner, DD; Schmittling, RJ; Herndon, JE; Davis, T; Friedman, HS; Keler, T; Reardon, DA; Sampson, JH
MLA Citation
Heimberger, A. B., et al. “Epidermal growth factor receptor variant III (EGFRvIII) vaccine (CDX-110) in GBM..” J Clin Oncol, vol. 27, no. 15_suppl, May 2009.
PMID
27964605
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
2021

Prognostic significance of early changes in the apparent diffusion coefficient that occurs after treatment of patients with glioblastoma multiforme with bevacizumab.

2058 Background: To determine the prognostic significance of changes in parameters derived from diffusion tensor imaging (DTI) that occur in response to combination chemotherapy with the antiangiogenesis agent bevacizumab (BEV) in patients with recurrent glioblastoma multiforme (GBM). METHODS: 16 patients (10 men, 6 women; age range 38-62 years) with recurrent GBM underwent serial 1.5T MR imaging. Axial single-shot echo planar DTI (TR/TE 6000/100; flip angle 90 degrees; voxel: 1.72 x 1.72 x 5mm; b value of 1000 sec/mm(2); 12 directions) was obtained on scans performed 3 days and 1 day prior to and 1 day after initiation of therapy with BEV and irinotecan (CPT-11). Clinical follow-up and survival status was documented up to 20 months after the date of initial MR imaging. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were aligned to whole brain contrast-enhanced 3D FLASH and 3D FLAIR image volumes (1 mm isotropic voxels) using a rigid body normalized mutual information algorithm. Based on two pre-treatment scans, the 95% confidence limits for change (95%CL) in ADC and FA were calculated in volumes of tumor-related contrast-enhancement (TRE) and FLAIR signal abnormality (FSA). A patient was considered to have a change in FA or ADC after therapy if the difference between the pre- and post-treatment values was greater than the 95% CL for that parameter. Progression was defined on contrast-enhanced MRI using MacDonald criteria by neuro-oncologists blinded to the DTI findings. Survival was compared using the log rank test. RESULTS: DTI detected a change in ADC within FSA after therapy in three patients (2 increased, 1 decreased). Patients with a change in ADC within FSA had significantly shorter overall (p < 0.0012) and progression free (p < 0.015) survival than those with no change. Median survival in the patient group with a change in ADC was 24.7 (95% CI [17.3, 39.4]) weeks and 56.4 (95% CI [41.7, 96]) weeks in those patients with no change. CONCLUSIONS: In patients with GBM treated with BEV and CPT-11, a change in ADC after therapy in areas of FSA is associated with decreased survival. Parameters derived from DTI may, therefore, potentially serve as early markers of treatment failure in patients with GBM. [Table: see text].

Authors
Paldino, M; Desjardins, A; Friedman, HS; Vredenburgh, JJ; Barboriak, DP
MLA Citation
Paldino, M., et al. “Prognostic significance of early changes in the apparent diffusion coefficient that occurs after treatment of patients with glioblastoma multiforme with bevacizumab..” J Clin Oncol, vol. 27, no. 15_suppl, May 2009.
PMID
27964666
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
2058

Phase I trial of vendetanib and oral etoposide for recurrent malignant gliomas.

e13016 Background: Recurrent malignant gliomas have a poor prognosis, with a median survival of 6-15 months, with grade 4 glioblastomas more aggressive than grade 3 anaplastic astrocytomas or oligodendrogliomas. Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are critically important in glioma biology. Vandetanib is a multi-kinase inhibitor, predominantly of VEGF and EGF. We report a phase I trial of vandetanib in combination with oral etoposide for recurrent malignant glioma. METHODS: Patients with histologically documented recurrent grade 3 or grade 4 malignant glioma were eligible. Patients were treated with daily oral vandetanib and oral etoposide. The trial design was a modified 3 + 3 Phase I design, with the dose levels outlined below. RESULTS: Eighteen patients have been accrued. There was more hematologic toxicity than expected, with 3/6 of the patients enrolled at dose level 1 developing grade 4 neutropenia. There were no DLT's at the -1 dose level. The protocol was amended to decrease the dose of etoposide to 50 mg daily for 21 days, then 7 days off and dose escalation of vandetanib started again at 100 mg daily. Six patients had no dose limiting toxicity at the new dose level 1 of vandetanib 100 mg daily and etoposide 50 mg daily. Dose escalation continues. There has been clinical activity, with patients remaining stable on study for multiple cycles. CONCLUSIONS: Vandetanib and oral etoposide appear to interact to produce more marrow toxicity than expected. A phase II trial is planned when the MTD of vandetanib with reduced dose etoposide is determined. [Table: see text] No significant financial relationships to disclose.

Authors
Herndon, J; Vredenburgh, J; Reardon, D; Desjardins, A; Peters, K; Gururangan, S; Norfleet, J; Friedman, A; Bigner, D; Friedman, HS
MLA Citation
Herndon, J., et al. “Phase I trial of vendetanib and oral etoposide for recurrent malignant gliomas..” J Clin Oncol, vol. 27, no. 15_suppl, May 2009.
PMID
27962830
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
e13016

Temozolomide (TMZ) and bevacizumab (BV) as initial treatment for unresectable or multifocal glioblastoma multiforme (GBM).

e13025 Background: GBMs are vascular tumors and inherently resistant to therapy. The prognosis for patients is poor with a median survival of 9-15 months. Patients with unresectable or multifocal GBMs have an even poorer prognosis, with a median survival of 6-8 months. Given the angiogenic phenotype of GBM, we conducted a phase II trial of upfront BV and 5-day TMZ in newly diagnosed unresectable or multifocal GBMs. METHODS: Patients had histologically documented newly diagnosed GBMs that were unresectable or multifocal. Patients received up to 4 cycles of temozolomide at 200 mg/m(2)/d days 1-5 and BV at 10 mg/kg on days 1 and 14 in a 28 day cycle. An MRI was performed after every cycle and patients continued on therapy as long as there was no tumor progression, grade 4 non-hematologic toxicity or recurrent grade 4 hematologic toxicity after a dose reduction to 150 mg/m(2)/d. The primary endpoint was tumor response using the modified MacDonald criteria plus FLAIR and T2 sequences to evaluate non-enhancing tumor. Results were evaluated by two independent reviewers. RESULTS: 41 patients were enrolled between October 2007 and September 2008 and 31 patients were analyzed after completion of cycle 2. As the best response, there were 8 (25.8%) partial responses, 19 (61.3 %) patients with stable disease, and 4(12.9 %) had disease progression. 19 of the 41 patients enrolled completed four cycles without tumor progression. The regimen was tolerable, with 3 grade 4 hematologic toxicities including neutropenia and thrombocytopenia. There were 2 grade 4 non-hematologic toxicities, including pulmonary embolism. There were two CNS hemorrhages. The median PFS was 3.6 months (2.9 months, 4.4 months) and the median OS was 4.5 months (3.7 months, 5.3 months). CONCLUSIONS: Upfront temozolomide and bevacizumab was well tolerated, but synergistic chemotherapy or growth factor inhibitors need to be added to produce meaningful clinical benefit, particularly for unresectable or multifocal GBM. No significant financial relationships to disclose.

Authors
Peters, K; Desjardins, A; Reardon, DA; Perry, S; Herndon, JE; Bailey, L; Friedman, AH; Friedman, HS; Bigner, DD; Vredenburgh, JJ
MLA Citation
Peters, K., et al. “Temozolomide (TMZ) and bevacizumab (BV) as initial treatment for unresectable or multifocal glioblastoma multiforme (GBM)..” J Clin Oncol, vol. 27, no. 15_suppl, May 2009.
PMID
27962792
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
e13025

Neurocognitive function in patients with glioblastoma multiforme in first or second relapse treated with bevacizumab in the BRAIN study.

2056 Background: Patients with glioblastoma multiforme (GBM) suffer from neurocognitive decline due to both the disease and its treatment. We analyzed neurocognitive function of patients with recurrent GBM who participated in the BRAIN study, a phase II, multicenter, randomized, noncomparative clinical trial which assessed the efficacy and safety of bevacizumab alone or in combination with irinotecan. METHODS: Eighty-five patients who participated in the bevacizumab-only group of the BRAIN study were assessed with the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test parts A (TMTA) and B (TMTB), and the Controlled Oral Word Association (COWA) test. Assessments were conducted at baseline and then every 6 weeks while patients remained on study drug, up to 52 weeks. Change in neurocognitive function from baseline to Week 6 was categorized as improved, stable, or declined, using the reliable change index. Changes were confirmed at the next assessment, when available. Results were not adjusted for practice effects. RESULTS: Between 93 and 98% of patients completed each test at baseline and 73-78% completed each test at both baseline and Week 6. The majority of patients demonstrated stable performance on each test at Week 6, relative to baseline. With the exception of the COWA test, 18-25% of patients demonstrated improved performance on one or more tests at Week 6. CONCLUSIONS: Preliminary results suggest that the majority of patients with recurrent GBM who were treated with bevacizumab alone in the BRAIN study demonstrated stable or improved neurocognitive function during the first 6 weeks of treatment. Changes across tasks and associations with measures of clinical efficacy, patient characteristics, and concomitant medications will be explored. [Table: see text] [Table: see text].

Authors
Wefel, JS; Cloughesy, T; Zazzali, J; Yi, J; Friedman, HS; BRAIN Investigators,
MLA Citation
Wefel, J. S., et al. “Neurocognitive function in patients with glioblastoma multiforme in first or second relapse treated with bevacizumab in the BRAIN study..” J Clin Oncol, vol. 27, no. 15_suppl, May 2009.
PMID
27964669
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
2056

Phase II study of bevacizumab plus erlotinib for recurrent malignant gliomas.

2045 Background: Bevacizumab (B), a neutralizing VEGF monoclonal antibody, has anti-glioma activity as single agent and in combination with cytotoxic therapy. Erlotinib (E), an EGFR tyrosine kinase inhibitor, may exhibit anti-tumor activity in some malignant glioma (MG) patients. B plus E was associated with clinical benefit in several solid tumors. We performed a single-arm, phase II study to evaluate the efficacy of B and E in patients with recurrent MG. METHODS: The primary endpoint was 6-month progression-free survival (PFS-6). Radiographic response, pharmacokinetics and correlative biomarkers were secondary endpoints. E was orally administered daily at 200 mg/day for patients not on enzyme-inducing anticonvulsants (EIAC) and 500 mg/day for patients on EIAC. All patients received 10 mg/kg of B intravenously every two weeks. Key eligibility criteria included: age ≥ 18 years; KPS ≥ 60; > 4 weeks from prior surgery, XRT or chemotherapy. Patients with either > 3 prior progressions, requirement for therapeutic anti-coagulation or acute hemorrhage on pre-treatment imaging were excluded. RESULTS: Fifty-six patients with recurrent MG (n = 24 for glioblastoma multiforme [GBM] and n = 32 for anaplastic gliomas [AGs]) were assessable for outcome. The PFS-6 rates were 25% for GBM and 50% for AGs. There was no survival difference between EIAC and non-EIAC groups. Rash (54% grade 1-2 and 38% grade 3) was the most common side effect. Nausea, diarrhea, and fatigue were common but mostly grade 1-2. Serious side effects were rare and included two patients with pulmonary embolism, single patients with either intestinal perforation, ischemic stroke, gastric bleeding, or nasal septal perforation. Pharmacokinetic and tissue biomarker profiles are in preparation. CONCLUSIONS: Among heavily pretreated recurrent MG patients, bevacizumab plus erlotinib is tolerated and associated with encouraging anti-tumor benefit. No significant financial relationships to disclose.

Authors
Sathornsumetee, S; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Friedman, HS; Reardon, DA
MLA Citation
Sathornsumetee, S., et al. “Phase II study of bevacizumab plus erlotinib for recurrent malignant gliomas..” J Clin Oncol, vol. 27, no. 15_suppl, May 2009.
PMID
27964647
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
2045

Safety and efficacy of the addition of bevacizumab (BV) to temozolomide (TMZ) and radiation therapy (RT) followed by BV, TMZ, and irinotecan (CPT-11) for newly diagnosed glioblastoma multiforme (GBM).

2015 Background: Standard GBM treatment includes TMZ and RT, and results in a median progression-free survival and median survival of 6.9 and 15.8 months, respectively. GBM have high concentrations of vascular endothelial growth factor (VEGF), higher levels are associated with poorer prognosis. BV is a humanized antibody to VEGF with activity in recurrent GBMs. This study aims to improve the survival of newly diagnosed GBM patients by incorporating an anti-angiogenic agent with RT and TMZ, and adding a topoisomerase I inhibitor, and an anti-angiogenic agent to TMZ post-RT therapy. METHODS: Patients received standard RT and TMZ at 75 mg/m(2)/day, with BV at 10 mg/kg every 14 days beginning a minimum of 28 days post-operatively. Following the completion of RT, patients received 6 cycles of BV, TMZ and CPT-11. Each cycle was 28 days. BV was given at a dose of 10 mg/kg on days 1 and 15, TMZ at 200 mg/m(2) on days 1-5 and CPT-11 on days 1 and 15 at 125 mg/m(2) for patients not on an enzyme inducing anti-epileptic drug (EIAED) and 340 mg/m(2) for patients on an EIAED. The study was designed to differentiate between a 16-month survival rate of 45% and 60% with type I and II error rates of 0.05. RESULTS: 75 patients were enrolled between 8/07 and 9/08. All the patients have completed RT; 40 patients continue to receive BV, TMZ, and CPT-11. Twenty-two patients have completed 6 cycles of BV, TMZ, and CPT-11; 17 of them had a cold PET One patient developed a CNS hemorrhage (grade 2) necessitating stopping BV. Five patients developed thrombocytopenia for which TMZ was held (grade 3, n = 1; grade 4, n = 4). There were no other ≥ grade 3 toxicities, including no wound dehiscence during RT. Twelve patients had tumor progression, and 14 stopped because of toxicity, including: 6 with fatigue; 3 with PEs; 2 with grade 4 thrombocytopenia; the patient with CNS hemorrhage, and one each with a rectal abscess and sepsis. There have been 7 deaths: 5 from tumor progression; one each from sepsis and PEs. At a median follow-up of 9 months, 81% remain alive and progression-free. CONCLUSIONS: Adding BV to TMZ and RT followed by BV, TMZ with CPT-11 is tolerable and efficacious. No significant financial relationships to disclose.

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Peters, K; Herndon, JE; Kirkpatrick, J; Gururangan, S; Bailey, L; Friedman, AH; Friedman, HS
MLA Citation
Vredenburgh, J. J., et al. “Safety and efficacy of the addition of bevacizumab (BV) to temozolomide (TMZ) and radiation therapy (RT) followed by BV, TMZ, and irinotecan (CPT-11) for newly diagnosed glioblastoma multiforme (GBM)..” J Clin Oncol, vol. 27, no. 15_suppl, May 2009.
PMID
27964581
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
2015

Effect of daclizumab on T-Reg counts and EGFRvIII-specific immune responses in GBM

Authors
Sampson, JH; Archer, GE; Bigner, DD; Schmittling, RJ; Herndon, JE; Davis, T; Friedman, HS; Keler, T; Reardon, DA; Mitchell, DA
MLA Citation
Sampson, J. H., et al. “Effect of daclizumab on T-Reg counts and EGFRvIII-specific immune responses in GBM.” Journal of Clinical Oncology, vol. 27, no. 15, AMER SOC CLINICAL ONCOLOGY, 2009.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Epidermal growth factor receptor variant III (EGFRvIII) vaccine ( CDX-110) in GBM

Authors
Heimberger, AB; Archer, GE; Mitchell, DA; Bigner, DD; Schmittling, RJ; Herndon, JE; Davis, T; Friedman, HS; Keler, T; Reardon, DA; Sampson, JH
MLA Citation
Heimberger, A. B., et al. “Epidermal growth factor receptor variant III (EGFRvIII) vaccine ( CDX-110) in GBM.” Journal of Clinical Oncology, vol. 27, no. 15, AMER SOC CLINICAL ONCOLOGY, 2009.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Prognostic significance of early changes in the apparent diffusion coefficient that occurs after treatment of patients with glioblastoma multiforme with bevacizumab

Authors
Paldino, M; Desjardins, A; Friedman, HS; Vredenburgh, JJ; Barboriak, DP
MLA Citation
Paldino, M., et al. “Prognostic significance of early changes in the apparent diffusion coefficient that occurs after treatment of patients with glioblastoma multiforme with bevacizumab.” Journal of Clinical Oncology, vol. 27, no. 15, AMER SOC CLINICAL ONCOLOGY, 2009.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Temozolomide (TMZ) and bevacizumab (BV) as initial treatment for unresectable or multifocal glioblastoma multiforme (GBM)

Authors
Peters, K; Desjardins, A; Reardon, DA; Perry, S; Herndon, JE; Bailey, L; Friedman, AH; Friedman, HS; Bigner, DD; Vredenburgh, JJ
MLA Citation
Peters, K., et al. “Temozolomide (TMZ) and bevacizumab (BV) as initial treatment for unresectable or multifocal glioblastoma multiforme (GBM).” Journal of Clinical Oncology, vol. 27, no. 15, AMER SOC CLINICAL ONCOLOGY, 2009.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Safety and efficacy of the addition of bevacizumab (BV) to temozolomide (TMZ) and radiation therapy (RT) followed by BV, TMZ, and irinotecan (CPT-11) for newly diagnosed glioblastoma multiforme (GBM)

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Peters, K; Herndon, JE; Kirkpatrick, J; Gururangan, S; Bailey, L; Friedman, AH; Friedman, HS
MLA Citation
Vredenburgh, J. J., et al. “Safety and efficacy of the addition of bevacizumab (BV) to temozolomide (TMZ) and radiation therapy (RT) followed by BV, TMZ, and irinotecan (CPT-11) for newly diagnosed glioblastoma multiforme (GBM).” Journal of Clinical Oncology, vol. 27, no. 15, AMER SOC CLINICAL ONCOLOGY, 2009.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Phase I study of vandetanib, imatinib mesylate, and hydroxyurea for recurrent malignant glioma

Authors
Kirkpatrick, JP; Vredenburgh, JJ; Desjardins, A; Gururangan, S; Peters, KB; Boulton, ST; Friedman, AH; Friedman, HS; Reardon, DA
MLA Citation
Kirkpatrick, J. P., et al. “Phase I study of vandetanib, imatinib mesylate, and hydroxyurea for recurrent malignant glioma.” Journal of Clinical Oncology, vol. 27, no. 15, AMER SOC CLINICAL ONCOLOGY, 2009.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Phase II study of bevacizumab plus erlotinib for recurrent malignant gliomas

Authors
Sathornsumetee, S; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Friedman, HS; Reardon, DA
MLA Citation
Sathornsumetee, S., et al. “Phase II study of bevacizumab plus erlotinib for recurrent malignant gliomas.” Journal of Clinical Oncology, vol. 27, no. 15, AMER SOC CLINICAL ONCOLOGY, 2009.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Phase I trial of vendetanib and oral etoposide for recurrent malignant gliomas

Authors
Herndon, J; Vredenburgh, J; Reardon, D; Desjardins, A; Peters, K; Gururangan, S; Norfleet, J; Friedman, A; Bigner, D; Friedman, HS
MLA Citation
Herndon, J., et al. “Phase I trial of vendetanib and oral etoposide for recurrent malignant gliomas.” Journal of Clinical Oncology, vol. 27, no. 15, AMER SOC CLINICAL ONCOLOGY, 2009.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma.

BACKGROUND: This study determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients. METHODS: All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme-inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice-a-day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed. RESULTS: A total of 37 recurrent patients, 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice-a-day. DLTs were hematologic, gastrointestinal, renal, and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures. CONCLUSIONS: Vatalanib doses up to 1000 mg twice-a-day combined with imatinib and hydroxyurea were well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and platelet-derived growth factor, respectively, were safe among recurrent malignant glioma patients and may enhance antiangiogenesis activity.

Authors
Reardon, DA; Egorin, MJ; Desjardins, A; Vredenburgh, JJ; Beumer, JH; Lagattuta, TF; Gururangan, S; Herndon, JE; Salvado, AJ; Friedman, HS
MLA Citation
Reardon, David A., et al. “Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma..” Cancer, vol. 115, no. 10, May 2009, pp. 2188–98. Pubmed, doi:10.1002/cncr.24213.
PMID
19248046
Source
pubmed
Published In
Cancer
Volume
115
Issue
10
Publish Date
2009
Start Page
2188
End Page
2198
DOI
10.1002/cncr.24213

Correction: Article on genomic and molecular profiling to predict response to temozolomide (Clinical Cancer Research (2009) 15, (502-510))

Authors
Augustine, CK; Yoo, JS; Potti, A; Yoshimoto, Y; Zipfel, PA; Friedman, HS; Nevins, JR; Ali-Osman, F; Tyler, DS
MLA Citation
Augustine, C. K., et al. “Correction: Article on genomic and molecular profiling to predict response to temozolomide (Clinical Cancer Research (2009) 15, (502-510)).” Clinical Cancer Research, vol. 15, no. 9, 1 May 2009. Scopus, doi:10.1158/1078-0432.CCR-15-9-COR.
Source
scopus
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
15
Issue
9
Publish Date
2009
Start Page
3240
DOI
10.1158/1078-0432.CCR-15-9-COR

RNA Transfected Dendritic Cell Vaccines Targeting Human Cytomegalovirus Antigens in Patients with Glioblastoma

Authors
Mitchell, DA; Archer, GE; Bigner, DD; Friedman, HS; Lally-Goss, D; Perry, B; Herndon, JE; McGehee, S; McLendon, RE; Reardon, D; Sampson, JH
MLA Citation
Mitchell, Duane A., et al. “RNA Transfected Dendritic Cell Vaccines Targeting Human Cytomegalovirus Antigens in Patients with Glioblastoma.” Molecular Therapy, vol. 17, NATURE PUBLISHING GROUP, 2009, pp. S93–S93.
Source
wos
Published In
Molecular Therapy
Volume
17
Publish Date
2009
Start Page
S93
End Page
S93

Repeatability of quantitative parameters derived from diffusion tensor imaging in patients with glioblastoma multiforme.

PURPOSE: To quantify the repeatability of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in patients with glioblastoma multiforme. MATERIALS AND METHODS: IRB approval and informed consent were obtained for this Health Insurance Portability and Accountability Act-compliant study. Sixteen patients with glioblastoma multiforme underwent MR imaging at two time points without interval intervention. ADC and FA maps were registered to the contrast-enhanced and fluid-attenuated inversion recovery (FLAIR) image volumes. Volumes of tumor-related enhancement (TRE) and FLAIR signal abnormality (FSA) were defined using a semiautomated segmentation technique. RESULTS: Repeated observations of mean ADC and mean FA were highly consistent within both TRE (ADC: r = 0.947,P < 0.0001; FA: r = 0.947, P < 0.0001) and FSA (ADC: r = 0.979, P < 0.0001; FA: r = 0.972, P < 0.0001). Within TRE, repeatability coefficients and 95% confidence intervals (CIs) for change measured 0.104 x 10(-3) mm(2)S(-1) and 7.4% (ADC) and 0.0196 and 13.9% (FA), respectively. Within FSA, repeatability coefficients and 95% CI for change measured 0.071 x 10(-3) mm(2)S(-1) and 5.2% (ADC) and 0.0159 and 8.7% (FA), respectively. To detect 10% changes in mean ADC, sample sizes of nine (TRE) and six (FSA) patients would be required. The same change in mean FA would require sample sizes of 21 (TRE) and 10 (FSA) patients, respectively. CONCLUSION: Changes after therapy greater than the repeatability coefficient or 95% CI for change are unlikely to be related to variability in the measurement of ADC and FA.

Authors
Paldino, MJ; Barboriak, D; Desjardins, A; Friedman, HS; Vredenburgh, JJ
MLA Citation
Paldino, Michael J., et al. “Repeatability of quantitative parameters derived from diffusion tensor imaging in patients with glioblastoma multiforme..” Journal of Magnetic Resonance Imaging : Jmri, vol. 29, no. 5, May 2009, pp. 1199–205. Epmc, doi:10.1002/jmri.21732.
PMID
19388113
Source
epmc
Published In
Journal of Magnetic Resonance Imaging : Jmri
Volume
29
Issue
5
Publish Date
2009
Start Page
1199
End Page
1205
DOI
10.1002/jmri.21732

INDUCTION OF IMMUNOLOGIC AND CLINICAL RESPONSES WITH EGFRVIII-TARGETED VACCINE (CDX-110) WITH CYCLES OF TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED EGFRVIII-POSITIVE GBM

Authors
Archer, GE; Heimberger, AB; Bigner, DD; Davis, T; Friedman, HS; Keler, T; McLendon, RE; Mitchell, DA; Reardon, D; Sawaya, R; Vredenberg, J; Sampson, JH
MLA Citation
Archer, Gary E., et al. “INDUCTION OF IMMUNOLOGIC AND CLINICAL RESPONSES WITH EGFRVIII-TARGETED VACCINE (CDX-110) WITH CYCLES OF TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED EGFRVIII-POSITIVE GBM.” Neuro Oncology, vol. 11, no. 2, DUKE UNIV PRESS, Apr. 2009, pp. 224–224.
Source
wos
Published In
Neuro Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
224
End Page
224

PHASE II STUDY OF BEVACIZUMAB AND ERLOTINIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME

Authors
Reardon, DA; Sathornsumetee, S; Vredenburgh, JJ; Rich, JN; Desjardins, A; Quinn, JA; Mathe, A; Gururangan, S; Friedman, AH; Friedman, HS
MLA Citation
Reardon, David A., et al. “PHASE II STUDY OF BEVACIZUMAB AND ERLOTINIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME.” Neuro Oncology, vol. 11, no. 2, DUKE UNIV PRESS, Apr. 2009, pp. 231–231.
Source
wos
Published In
Neuro Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
231
End Page
231

EGF RECEPTOR TYROSINE KINASE MEDIATES A NOVEL PATHWAY OF DRUG RESISTANCE IN MALIGNANT GLIOMAS VIA TYROSINE PHOSPHORYLATION AND FUNCTIONAL ACTIVATION OF GLUTATHIONE S-TRANSFERASE P1

Authors
Okamura, T; Singh, S; Buolamwini, JK; Friedman, HS; Bigner, DD; Ali-Osman, F
MLA Citation
Okamura, Tatsunori, et al. “EGF RECEPTOR TYROSINE KINASE MEDIATES A NOVEL PATHWAY OF DRUG RESISTANCE IN MALIGNANT GLIOMAS VIA TYROSINE PHOSPHORYLATION AND FUNCTIONAL ACTIVATION OF GLUTATHIONE S-TRANSFERASE P1.” Neuro Oncology, vol. 11, no. 2, DUKE UNIV PRESS, Apr. 2009, pp. 218–218.
Source
wos
Published In
Neuro Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
218
End Page
218

In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs (British Journal of Cancer (2008) 99, (294-304) DOI: 10.1038/sj.bjc.6604459)

Authors
Ashley, DM; Riffkin, CD; Lovric, MM; Mikeska, T; Dobrovic, A; Maxwell, JA; Friedman, HS; Drummond, KJ; Kaye, AH; Gan, HK; Johns, TG; Hawkins, CJ
MLA Citation
Ashley, D. M., et al. “In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs (British Journal of Cancer (2008) 99, (294-304) DOI: 10.1038/sj.bjc.6604459).” British Journal of Cancer, vol. 100, no. 6, Mar. 2009. Scopus, doi:10.1038/sj.bjc.6604990.
Source
scopus
Published In
British Journal of Cancer
Volume
100
Issue
6
Publish Date
2009
Start Page
1012
DOI
10.1038/sj.bjc.6604990

Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma.

PURPOSE: This phase II trial was designed to define the role of O(6)-benzylguanine (O(6)-BG) in restoring temozolomide sensitivity in patients with recurrent or progressive, temozolomide-resistant malignant glioma and to evaluate the safety of administering O(6)-BG in combination with temozolomide. PATIENTS AND METHODS: Patients were accrued into two independent strata on the basis of histology: glioblastoma multiforme (GBM) and anaplastic glioma. Both temozolomide and O(6)-BG were administered on day 1 of a 28-day treatment cycle. Patients were administered a 1-hour O(6)-BG infusion at a dose of 120 mg/m(2) followed immediately by a 48-hour infusion at a dose of 30 mg/m(2)/d. Temozolomide was administered orally within 60 minutes of the end of the 1-hour O(6)-BG infusion at a dose of 472 mg/m(2). The primary end point was objective response rate. Secondary end points included progression-free survival, overall survival, and safety. RESULTS: Sixty-six of 67 patients who enrolled were treated with temozolomide and O(6)-BG. One of 34 patients (3%) with GBM (95% CI, 0.1% to 15%) and five of 32 assessable patients (16%) with anaplastic glioma (95% CI, 5% to 33%) were responders. The most commonly reported adverse events were grade 4 hematologic events experienced in 48% of the patients. CONCLUSION: O(6)-BG when added to a 1-day dosing regimen of temozolomide was able to restore temozolomide sensitivity in patients with temozolomide-resistant anaplastic glioma, but there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant GBM.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Walker, A; Friedman, HS
MLA Citation
Quinn, Jennifer A., et al. “Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma..” J Clin Oncol, vol. 27, no. 8, Mar. 2009, pp. 1262–67. Pubmed, doi:10.1200/JCO.2008.18.8417.
PMID
19204199
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
8
Publish Date
2009
Start Page
1262
End Page
1267
DOI
10.1200/JCO.2008.18.8417

BCNU-sequestration by metallothioneins may contribute to resistance in a medulloblastoma cell line.

PURPOSE: Resistance of neoplastic cells to the alkylating drug BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] has been correlated with expression of O (6)-methylguanine-DNA methyltransferase, which repairs the O (6)-chloroethylguanine produced by the drug. Other possible mechanisms of resistance include raised levels of glutathione or increased repair of the DNA interstrand cross-links formed by BCNU. Transcriptional profiling revealed the upregulation of several metallothionein (MT) genes in a BCNU-resistant medulloblastoma cell line [D341 MED (OBR)] relative to its parental line. Previous studies have shown that MTs, through their reactive thiol groups can quench nitrogen mustard-derived alkylating drugs. In this report, we evaluate whether MTs can also quench BCNU. METHODS: To demonstrate the binding of BCNU to MT, we used an assay that measured the release of the MT-bound divalent cations (Zn(2+), Cd(2+)) upon their displacement by the drug. We also measured the decomposition rates of BCNU at those reaction conditions. RESULTS: The rate of release of the cations was higher in pH 7.4 than at pH 7.0, which is likely a result of more rapid decomposition of BCNU (thus faster release of MT-binding intermediate) at pH 7.4 than at pH 7.0. CONCLUSION: We demonstrate that resistance to BCNU may be a result of elevated levels of MTs which act by sequestering the drug's decomposition product(s).

Authors
Bacolod, MD; Fehdrau, R; Johnson, SP; Bullock, NS; Bigner, DD; Colvin, M; Friedman, HS
MLA Citation
Bacolod, Manny D., et al. “BCNU-sequestration by metallothioneins may contribute to resistance in a medulloblastoma cell line..” Cancer Chemother Pharmacol, vol. 63, no. 4, Mar. 2009, pp. 753–58. Pubmed, doi:10.1007/s00280-008-0792-9.
PMID
18633619
Source
pubmed
Published In
Cancer Chemother Pharmacol
Volume
63
Issue
4
Publish Date
2009
Start Page
753
End Page
758
DOI
10.1007/s00280-008-0792-9

IDH1 and IDH2 mutations in gliomas.

BACKGROUND: A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). METHODS: We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. RESULTS: We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein. CONCLUSIONS: Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.

Authors
Yan, H; Parsons, DW; Jin, G; McLendon, R; Rasheed, BA; Yuan, W; Kos, I; Batinic-Haberle, I; Jones, S; Riggins, GJ; Friedman, H; Friedman, A; Reardon, D; Herndon, J; Kinzler, KW; Velculescu, VE; Vogelstein, B; Bigner, DD
MLA Citation
Yan, Hai, et al. “IDH1 and IDH2 mutations in gliomas..” N Engl J Med, vol. 360, no. 8, Feb. 2009, pp. 765–73. Pubmed, doi:10.1056/NEJMoa0808710.
PMID
19228619
Source
pubmed
Published In
The New England Journal of Medicine
Volume
360
Issue
8
Publish Date
2009
Start Page
765
End Page
773
DOI
10.1056/NEJMoa0808710

Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme.

PURPOSE: This phase II trial was designed to define the efficacy of Gliadel wafers in combination with an infusion of O6-benzylguanine (O6-BG) that suppresses tumor O6-alkylguanine-DNA alkyltransferase (AGT) levels in patients with recurrent glioblastoma multiforme for 5 days and to evaluate the safety of this combination therapy. EXPERIMENTAL DESIGN: This was a phase II, open-label, single center trial. On gross total resection of the tumor, up to eight Gliadel wafers were implanted. Bolus infusion of O6-BG was administered at 120 mg/m2 over 1 hour on days 1, 3, and 5, along with a continuous infusion at 30 mg/m2/d. The primary end points were 6-month overall survival (OS) and safety, and the secondary end points were 1-year, 2-year, and median OS. RESULTS: Fifty-two patients were accrued. The 6-month OS was 82% [95% confidence interval (95% CI), 72-93%]. The 1- and 2-year OS rates were 47% (95% CI, 35-63%) and 10% (95% CI, 3-32%), respectively. The median OS was 50.3 weeks (95% CI, 36.1-69.4 weeks). Treatment-related toxicity with this drug combination included grade 3 hydrocephalus (9.6%), grade 3 cerebrospinal fluid (CSF) leak (19.2%), and grade 3 CSF/brain infection (13.4%). CONCLUSION: The efficacy of implanted Gliadel wafers may be improved with the addition of O6-BG. Although systemically administered O6-BG can be coadministered with Gliadel wafers safely, it may increase the risk of hydrocephalus, CSF leak, and CSF/brain infection. Future trials are required to verify that inhibition of tumor AGT levels by O6-BG results in increased efficacy of Gliadel wafers without added toxicity.

Authors
Quinn, JA; Jiang, SX; Carter, J; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Threatt, S; Friedman, HS
MLA Citation
Quinn, Jennifer A., et al. “Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme..” Clin Cancer Res, vol. 15, no. 3, Feb. 2009, pp. 1064–68. Pubmed, doi:10.1158/1078-0432.CCR-08-2130.
PMID
19188181
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
15
Issue
3
Publish Date
2009
Start Page
1064
End Page
1068
DOI
10.1158/1078-0432.CCR-08-2130

Experience with irinotecan for the treatment of malignant glioma.

Malignant glioma is the most commonly occurring primary malignant brain tumor. It is difficult to treat and is usually associated with an inexorable, rapidly fatal clinical course. Chemotherapy, radiotherapy, and surgical excision are core components in the management of malignant glioma. However, chemotherapy, even with the most active regimens currently available, achieves only modest improvement in overall survival. Novel agents and new approaches to therapy are required to improve clinical outcomes. Irinotecan, a first-line treatment for metastatic colorectal cancer and an agent with high activity against solid tumors of the gastrointestinal tract, is an inhibitor of topoisomerase I, a critical enzyme needed for DNA transcription. Irinotecan crosses the blood-brain barrier and, in preclinical investigations, has demonstrated cytotoxic activity against central nervous system tumor xenografts. Its antitumor activity has also been demonstrated against glioblastoma cells with multidrug resistance. Studies in adult and pediatric patients with recurrent, intractable malignant glioma have evaluated irinotecan as monotherapy and in combination with other agents, including temozolomide, carmustine, thalidomide, and bevacizumab. Studies of irinotecan in combination with other medications, particularly temozolomide and bevacizumab, have yielded promising results. Irinotecan monotherapy has demonstrated efficacy; however, its efficacy appears to be enhanced when used in combination with other chemotherapeutic agents. When administered concurrently with enzyme-inducing antiepileptic drugs, the dosage must be increased to compensate for enhanced cytochrome CY3A4/5 enzyme activity. Toxicities associated with irinotecan have been manageable; the most important dose-limiting toxicities are neutropenia and diarrhea. Irinotecan-based chemotherapy of malignant glioma merits further study.

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Friedman, HS
MLA Citation
Vredenburgh, James J., et al. “Experience with irinotecan for the treatment of malignant glioma..” Neuro Oncol, vol. 11, no. 1, Feb. 2009, pp. 80–91. Pubmed, doi:10.1215/15228517-2008-075.
PMID
18784279
Source
pubmed
Published In
Neuro Oncology
Volume
11
Issue
1
Publish Date
2009
Start Page
80
End Page
91
DOI
10.1215/15228517-2008-075

Enterohepatic recirculation model of irinotecan (CPT-11) and metabolite pharmacokinetics in patients with glioma.

BACKGROUND: Enterohepatic recirculation of irinotecan and one of its metabolites, SN-38, has been observed in pharmacokinetic data sets from previous studies. A mathematical model that can incorporate this phenomenon was developed to describe the pharmacokinetics of irinotecan and its metabolites. PATIENTS AND METHODS: A total of 32 patients with recurrent malignant glioma were treated with weekly intravenous administration of irinotecan at a dose of 125 mg/m(2). Plasma concentrations of irinotecan and its three major metabolites were determined. Pharmacokinetic models were developed and tested for simultaneous fit of parent drug and metabolites, including a recirculation component. RESULTS: Rebound in the plasma concentration suggestive of enterohepatic recirculation at approximately 0.5-1 h post-infusion was observed in most irinotecan plasma concentration profiles, and in some plasma profiles of the SN-38 metabolite. A multi-compartment model containing a recirculation chain was developed to describe this process. The recirculation model was optimal in 22 of the 32 patients compared to the traditional model without the recirculation component. CONCLUSION: A recirculation chain incorporated in a multi-compartment pharmacokinetic model of irinotecan and its metabolites appears to improve characterization of this drug's disposition in patients with glioma.

Authors
Younis, IR; Malone, S; Friedman, HS; Schaaf, LJ; Petros, WP
MLA Citation
Younis, Islam R., et al. “Enterohepatic recirculation model of irinotecan (CPT-11) and metabolite pharmacokinetics in patients with glioma..” Cancer Chemother Pharmacol, vol. 63, no. 3, Feb. 2009, pp. 517–24. Pubmed, doi:10.1007/s00280-008-0769-8.
PMID
18496691
Source
pubmed
Published In
Cancer Chemother Pharmacol
Volume
63
Issue
3
Publish Date
2009
Start Page
517
End Page
524
DOI
10.1007/s00280-008-0769-8

Phase I study of SU5416, a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR) in refractory pediatric central nervous system tumors.

SU5416 is a novel small molecule tyrosine kinase inhibitor of the VEGF receptors 1 and 2. A phase I dose escalation study stratified by concurrent use (stratum II) or absence (stratum I) of enzyme-inducing anticonvulsant drugs was undertaken to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile of SU5416 in pediatric patients with refractory brain tumors. Dose escalations were conducted independently for stratum I starting at 110 mg/m(2) while stratum II started at 48 mg/m(2). Thirty-three eligible patients were treated on stratum I (n = 23) and stratum II (n = 10). Tumor types included 23 glial tumors, 4 neural tumors, 4 ependymomas, and 2 choroid plexus carcinomas. The MTD in stratum I was initially estimated to be 110 mg/m(2). The protocol was amended to determine the MTD after excluding transient AST elevation. Re-estimation of the MTD began at the 145 mg/m(2) dose level but due to development of SU5416 being stopped by the sponsor, the trial was closed before completion. The most serious drug-related toxicities were grade 3 liver enzyme abnormalities, arthralgia, and hallucinations. The plasma pharmacokinetics of SU5416 was not significantly affected by the concurrent administration of enzyme-inducing anticonvulsant drugs. Mean values of the total body clearance, apparent volume of distribution, and terminal phase half-life of SU5416 for the 19 patients in stratum I were 26.1 +/- 12.5 l/hr/m(2), 41.9 +/- 21.4 l/m(2), and 1.11 +/- 0.41 hr, respectively. The plasma pharmacokinetics of SU5416 in children was similar to previously reported findings in adult cancer patients. Prolonged disease stabilization was observed in 4 of 16 stratum I patients.

Authors
Kieran, MW; Supko, JG; Wallace, D; Fruscio, R; Poussaint, TY; Phillips, P; Pollack, I; Packer, R; Boyett, JM; Blaney, S; Banerjee, A; Geyer, R; Friedman, H; Goldman, S; Kun, LE; Macdonald, T; Pediatric Brain Tumor Consortium,
MLA Citation
Kieran, Mark W., et al. “Phase I study of SU5416, a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR) in refractory pediatric central nervous system tumors..” Pediatr Blood Cancer, vol. 52, no. 2, Feb. 2009, pp. 169–76. Pubmed, doi:10.1002/pbc.21873.
PMID
19065567
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
52
Issue
2
Publish Date
2009
Start Page
169
End Page
176
DOI
10.1002/pbc.21873

Genomic and molecular profiling predicts response to temozolomide in melanoma.

PURPOSE: Despite objective response rates of only approximately 13%, temozolomide remains one of the most effective single chemotherapy agents against metastatic melanoma, second only to dacarbazine, the current standard of care for systemic treatment of melanoma. The goal of this study was to identify molecular and/or genetic markers that correlate with, and could be used to predict, response to temozolomide-based treatment regimens and that reflect the intrinsic properties of a patient's tumor. EXPERIMENTAL DESIGN: Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O(6)-methylguanine-DNA methyltransferase (MGMT) activity, MGMT protein expression and promoter methylation status, and mismatch repair proficiency, as well as the expression profile of 38,000 genes using an oligonucleotide-based microarray platform. RESULTS: The results showed a broad spectrum of temozolomide sensitivity across the panel of cell lines, with IC(50) values ranging from 100 micromol/L to 1 mmol/L. There was a significant correlation between measured temozolomide sensitivity and a gene expression signature-derived prediction of temozolomide sensitivity (P < 0.005). Notably, MGMT alone showed a significant correlation with temozolomide sensitivity (MGMT activity, P < 0.0001; MGMT expression, P

Authors
Augustine, CK; Yoo, JS; Potti, A; Yoshimoto, Y; Zipfel, PA; Friedman, HS; Nevins, JR; Ali-Osman, F; Tyler, DS
MLA Citation
Augustine, Christina K., et al. “Genomic and molecular profiling predicts response to temozolomide in melanoma..” Clin Cancer Res, vol. 15, no. 2, Jan. 2009, pp. 502–10. Pubmed, doi:10.1158/1078-0432.CCR-08-1916.
PMID
19147755
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
15
Issue
2
Publish Date
2009
Start Page
502
End Page
510
DOI
10.1158/1078-0432.CCR-08-1916

Family appraisal of caregiving in a brain cancer model

Caregivers of patients with brain tumors frequently provide care to a patient with a potentially short terminal disease trajectory. Understanding the impact of caregiving is important because caregivers are often called upon to make difficult decisions regarding the patient for whom they provide care. The goal of this study was to document caregiver appraisal of providing care to persons with brain tumors. Using 70 patient and caregiver dyads, levels of caregiver strain, distress, family well-being, and positive appraisal were assessed in caregivers of patients with brain cancer using the Family Appraisal of Caregiving Questionnaire for Palliative Care. Patient quality of life and stress were assessed using the Functional Assessment of Cancer Therapy-Brain and the Perceived Stress Scale. Participants indicated high levels of positive caregiver appraisal (mean [SD], 4.3 [0.53]) and low levels of strain (mean [SD], 2.72 [0.88]). Of the four domains assessed by the Family Appraisal of Caregiving Questionnaire for Palliative Care, only caregiver distress correlated (r = -0.245, P = .04) with patients' overall Functional Assessment of Cancer Therapy-Brain score. Higher patient Perceived Stress Scale scores were associated with caregiver strain and burden, whereas lower scores were associated with family well-being and positive caregiving appraisal. Despite the challenges that caregivers of patients with brain tumors must address, this study documented that respondents experienced higher levels of positive appraisal and family well-being over caregiver distress and strain. The data also indicated a clear relationship between caregiver appraisal and patient quality of life and more so regarding patient stress.

Authors
Keir, ST; Farland, MM; Lipp, ES; Friedman, HS
MLA Citation
Keir, S. T., et al. “Family appraisal of caregiving in a brain cancer model.” Journal of Hospice and Palliative Nursing, vol. 11, no. 1, Jan. 2009, pp. 60–66. Scopus, doi:10.1097/NJH.0b013e3181917e35.
Source
scopus
Published In
Journal of Hospice & Palliative Nursing
Volume
11
Issue
1
Publish Date
2009
Start Page
60
End Page
66
DOI
10.1097/NJH.0b013e3181917e35

Distress persists in long-term brain tumor survivors with glioblastoma multiforme.

INTRODUCTION: Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor. The prognosis for GBM patients is extremely poor with an estimated median survival of 12 months. Despite this statistic, a number of GBM patients are living longer than in the past as new detection and treatment approaches are used. However, little is known about the psychological correlates of this disease. To address this issue we investigated distress and its sources in long-term survivors (LTS) of this disease. MATERIALS AND METHODS: Participants were asked to complete the National Comprehensive Cancer Network's (NCCN) Distress Thermometer, a single-item rapid screening tool for distress. Participants were also asked to designate sources of distress from a 34-item list developed by the NCCN. Distress scores and sources of distress for long-term GBM survivors (>18 months) were compared to patients diagnosed within the last 18 months (<18 months). RESULTS: Eight-three brain tumor patients participated in this study. Fifty-nine percent of LTS met the > or = 4 cut-off score for distress (M = 4.61, SD 3.12) as compared to 49% of patients diagnosed less than 18 months (M = 3.93, SD = 2.21; x(2) = 0.406, NS), LTS reported fewer items of concern while more LTS reported being distressed. CONCLUSIONS: This study indicates that LTS of GBM report experiencing distress at similar levels to other brain tumor patients. Level of distress for LTS is directly related to the total number of concerns in both emotional and physical domains. IMPLICATIONS FOR CANCER SURVIVORS: Regardless of LTS status, distress continues to be a part of the disease trajectory for many GBM patients. As such, attention to distress in these survivors of a major life threatening disease is warranted in follow up surveillance visits.

Authors
Keir, ST; Farland, MM; Lipp, ES; Friedman, HS
MLA Citation
Keir, Stephen T., et al. “Distress persists in long-term brain tumor survivors with glioblastoma multiforme..” J Cancer Surviv, vol. 2, no. 4, Dec. 2008, pp. 269–74. Pubmed, doi:10.1007/s11764-008-0069-7.
PMID
18958627
Source
pubmed
Published In
J Cancer Surviv
Volume
2
Issue
4
Publish Date
2008
Start Page
269
End Page
274
DOI
10.1007/s11764-008-0069-7

Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines.

The epidermal growth factor receptor variant III (EGFRvIII) is a consistent tumor-specific mutation that is widely expressed in glioblastoma multiforme (GBM) and other neoplasms. As such it represents a truly tumor-specific target for antitumor immunotherapy. Although endogenous humoral responses to EGFRvIII have been reported in patients with EGFRvIII-expressing breast cancer, it is not known whether de novo responses can be generated or endogenous responses enhanced with an EGFRvIII-specific vaccine. To assess this in clinical trials, we have developed and validated an immunoassay to measure and isolate anti-EGFRvIII and anti-KLH antibodies from the serum of patients vaccinated with an EGFRvIII-specific peptide (PEPvIII) conjugated to keyhole limpet hemocyanin (KLH). Using magnetic beads with immobilized antigen we captured and detected anti-EGFRvIII and anti-KLH antibodies in serum from patients before and after vaccinations. Using this assay, we found that significant levels of antibody for tumor-specific antigen EGFRvIII (>4 microg/mL) and KLH could be induced after vaccination with PEPvIII-KLH.

Authors
Schmittling, RJ; Archer, GE; Mitchell, DA; Heimberger, A; Pegram, C; Herndon, JE; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Schmittling, Robert J., et al. “Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines..” J Immunol Methods, vol. 339, no. 1, Nov. 2008, pp. 74–81. Pubmed, doi:10.1016/j.jim.2008.08.004.
PMID
18775433
Source
pubmed
Published In
Journal of Immunological Methods
Volume
339
Issue
1
Publish Date
2008
Start Page
74
End Page
81
DOI
10.1016/j.jim.2008.08.004

In reply

Authors
Vredenburgh, JJ; Rich, JN; Reardon, DA; Desjardins, A; Friedman, HS
MLA Citation
Vredenburgh, J. J., et al. “In reply.” Journal of Clinical Oncology, vol. 26, no. 32, Nov. 2008. Scopus, doi:10.1200/JCO.2008.18.0372.
Source
scopus
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
32
Publish Date
2008
Start Page
5305
DOI
10.1200/JCO.2008.18.0372

Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas.

PURPOSE: Although patients with newly diagnosed WHO grade 3 malignant glioma have a more favorable prognosis than those with WHO grade 4 malignant glioma, salvage therapies following recurrence offer essentially palliative benefit. We did a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan for patients with recurrent grade 3 malignant glioma. EXPERIMENTAL DESIGN: Upon documentation of adequate safety among an initial cohort of nine patients treated with bevacizumab (10 mg/kg) and irinotecan every 14 days, a second cohort (n=24) was treated with bevacizumab (15 mg/kg) every 3 weeks with irinotecan on days 1, 8, 22, and 29 of each 42-day cycle. For both cohorts, the dose of irinotecan was 340 mg/m(2) for patients on enzyme-inducing antiepileptic drugs (EIAED) and 125 mg/m(2) for patients not on EIAEDs. After each 6-week cycle, patients were evaluated with a physical examination and magnetic resonance imaging. RESULTS: The 6-month progression-free survival was 55% (95% confidence interval, 36-70%). The 6-month overall survival was 79% (95% confidence interval, 61-89%). Twenty patients (61%) had at least a partial response. Outcome did not differ between the two treatment cohorts. Significant adverse events were infrequent and included a central nervous system hemorrhage in one patient, and one patient who developed thrombotic thrombocytopenic purpura. CONCLUSION: Bevacizumab and irinotecan is an active regimen with acceptable toxicity for patients with recurrent WHO grade 3 malignant glioma.

Authors
Desjardins, A; Reardon, DA; Herndon, JE; Marcello, J; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Sampson, J; Bailey, L; Bigner, DD; Friedman, AH; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, Annick, et al. “Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas..” Clin Cancer Res, vol. 14, no. 21, Nov. 2008, pp. 7068–73. Pubmed, doi:10.1158/1078-0432.CCR-08-0260.
PMID
18981004
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
14
Issue
21
Publish Date
2008
Start Page
7068
End Page
7073
DOI
10.1158/1078-0432.CCR-08-0260

Dose intensive melphalan and cyclophosphamide with autologous hematopoietic stem cells for recurrent medulloblastoma or germinoma.

PURPOSE: To determine the response, toxicity, and survival for children with progressive or recurrent medulloblastoma and germinoma using a single myeloablative course of chemotherapy supported by autologous hematopoietic stem cells. PATIENTS AND METHODS: Subjects were in second remission or had minimal residual disease at the time of study entry. The conditioning regimen consisted of cyclophosphamide 6,000 mg/m(2) plus melphalan 180 mg/m(2). RESULTS: Twenty-nine evaluable pediatric patients were accrued. The most frequent major toxicities were myelosuppression, infections, and stomatitis, but no toxic deaths were recorded. Best responses were: CR = 6, CCR = 13, PR = 6, SD = 2, and PD = 2. There were 6 medulloblastoma and 3 germinoma survivors with a median follow-up of 7.5 years (range = 2.8-10). Two germinoma survivors received radiotherapy after autografting for presumptive progressive disease. CONCLUSION: Myeloablative chemotherapy consisting of cyclophosphamide and melphalan was tolerable in the relapsed brain tumor setting with 19/29 cases achieving CR or CCR status and 9/29 becoming long-term survivors.

Authors
Kadota, RP; Mahoney, DH; Doyle, J; Duerst, R; Friedman, H; Holmes, E; Kun, L; Zhou, T; Pollack, IF
MLA Citation
Kadota, Richard P., et al. “Dose intensive melphalan and cyclophosphamide with autologous hematopoietic stem cells for recurrent medulloblastoma or germinoma..” Pediatr Blood Cancer, vol. 51, no. 5, Nov. 2008, pp. 675–78. Pubmed, doi:10.1002/pbc.21655.
PMID
18623206
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
51
Issue
5
Publish Date
2008
Start Page
675
End Page
678
DOI
10.1002/pbc.21655

Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma.

The efficacy of high-dose chemotherapy (HDC) or standard salvage therapy was evaluated in patients with recurrent medulloblastoma (MBL) using retrospective chart review of all patients with recurrent MBL treated at Duke University Medical Center between 1995 and 2005 and who had undergone HDC with or without radiotherapy (RT) or standard salvage therapy after relapse. A total of 30 patients were diagnosed with recurrent MBL after standard RT alone or chemotherapy with RT. Nineteen patients (7 who received no RT before recurrence [group A] and 12 who received definitive RT before recurrence [group B]) underwent surgery and/or induction chemotherapy followed by HDC plus autologous stem-cell rescue. Eleven patients (group C) underwent standard salvage therapy. Six of seven group A patients also received standard RT just before or after recovery from HDC, and 5 of 12 group B patients received adjuvant palliative focal RT post-HDC. At a median follow-up of 28 months, three of seven patients in group A are alive and disease-free at >or=34, >or=110, and >or=116 months, respectively, post-HDC. All patients in groups B and C have died of tumor, at a median of 35 months and 26 months from HDC and standard salvage therapy, respectively. HDC or standard salvage therapy was ineffective in our patients with recurrent MBL who had received standard RT before recurrence. The favorable impact of HDC on disease control in the two long-term survivors cannot be clearly established due to the cofounding effect of definitive RT postrecurrence.

Authors
Gururangan, S; Krauser, J; Watral, MA; Driscoll, T; Larrier, N; Reardon, DA; Rich, JN; Quinn, JA; Vredenburgh, JJ; Desjardins, A; McLendon, RE; Fuchs, H; Kurtzberg, J; Friedman, HS
MLA Citation
Gururangan, Sridharan, et al. “Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma..” Neuro Oncol, vol. 10, no. 5, Oct. 2008, pp. 745–51. Pubmed, doi:10.1215/15228517-2008-044.
PMID
18755919
Source
pubmed
Published In
Neuro Oncology
Volume
10
Issue
5
Publish Date
2008
Start Page
745
End Page
751
DOI
10.1215/15228517-2008-044

558 POSTER Pediatric Preclinical Testing Program (PPTP) evaluation of the fully human anti-IGF-1R antibody IMC-A12

Authors
Kolb, EA; Morton, C; Houghton, PJ; Maris, JM; Friedman, HS; Kier, ST; Gorlick, RG; Kang, MH; Reynolds, CP; Smith, MA
MLA Citation
Kolb, E. A., et al. “558 POSTER Pediatric Preclinical Testing Program (PPTP) evaluation of the fully human anti-IGF-1R antibody IMC-A12.” European Journal of Cancer Supplements, vol. 6, no. 12, Elsevier BV, 2008, pp. 176–176. Crossref, doi:10.1016/s1359-6349(08)72492-3.
Source
crossref
Published In
European Journal of Cancer Supplements
Volume
6
Issue
12
Publish Date
2008
Start Page
176
End Page
176
DOI
10.1016/s1359-6349(08)72492-3

Bevacizumab drove 6-month survival in glioblastoma: Commentary

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Bevacizumab drove 6-month survival in glioblastoma: Commentary.” Oncology Report, no. FALL, Sept. 2008.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2008
Start Page
9

Blocking p-STAT-3 restored in vitro T-cell function in glioblastoma: Commentary

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Blocking p-STAT-3 restored in vitro T-cell function in glioblastoma: Commentary.” Oncology Report, no. FALL, Sept. 2008.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2008
Start Page
11

Mismatch repair deficiency does not mediate clinical resistance to temozolomide in malignant glioma.

PURPOSE: A major mechanism of resistance to methylating agents, including temozolomide, is the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT). Preclinical data indicates that defective DNA mismatch repair (MMR) results in tolerance to temozolomide regardless of AGT activity. The purpose of this study was to determine the role of MMR deficiency in mediating resistance in samples from patients with both newly diagnosed malignant gliomas and those who have failed temozolomide therapy. EXPERIMENTAL DESIGN: The roles of AGT and MMR deficiency in mediating resistance in glioblastoma multiforme were assessed by immunohistochemistry and microsatellite instability (MSI), respectively. The mutation status of the MSH6 gene, a proposed correlate of temozolomide resistance, was determined by direct sequencing and compared with data from immunofluorescent detection of MSH6 protein and reverse transcription-PCR amplification of MSH6 RNA. RESULTS: Seventy percent of newly diagnosed and 78% of failed-therapy glioblastoma multiforme samples expressed nuclear AGT protein in > or = 20% of cells analyzed, suggesting alternate means of resistance in 20% to 30% of cases. Single loci MSI was observed in 3% of patient samples; no sample showed the presence of high MSI. MSI was not shown to correlate with MSH6 mutation or loss of MSH6 protein expression. CONCLUSIONS: Although high AGT levels may mediate resistance in a portion of these samples, MMR deficiency does not seem to be responsible for mediating temozolomide resistance in adult malignant glioma. Accordingly, the presence of a fraction of samples exhibiting both low AGT expression and MMR proficiency suggests that additional mechanisms of temozolomide resistance are operational in the clinic.

Authors
Maxwell, JA; Johnson, SP; McLendon, RE; Lister, DW; Horne, KS; Rasheed, A; Quinn, JA; Ali-Osman, F; Friedman, AH; Modrich, PL; Bigner, DD; Friedman, HS
MLA Citation
Maxwell, Jill A., et al. “Mismatch repair deficiency does not mediate clinical resistance to temozolomide in malignant glioma..” Clin Cancer Res, vol. 14, no. 15, Aug. 2008, pp. 4859–68. Pubmed, doi:10.1158/1078-0432.CCR-07-4807.
PMID
18676759
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
14
Issue
15
Publish Date
2008
Start Page
4859
End Page
4868
DOI
10.1158/1078-0432.CCR-07-4807

In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs.

TRAIL/Apo-2L has shown promise as an anti-glioma drug, based on investigations of TRAIL sensitivity in established glioma cell lines, but it is not known how accurately TRAIL signalling pathways of glioma cells in vivo are reproduced in these cell lines in vitro. To replicate as closely as possible the in vivo behaviour of malignant glioma cells, 17 early passage glioma cell lines and 5 freshly resected gliomas were exposed to TRAIL-based agents and/or chemotherapeutic drugs. Normal human hepatocytes and astrocytes and established glioma cell lines were also tested. Cross-linked TRAIL, but not soluble TRAIL, killed both normal cell types and cells from three tumours. Cells from only one glioma were killed by soluble TRAIL, although only inefficiently. High concentrations of cisplatin were lethal to glioma cells, hepatocytes and astrocytes. Isolated combinations of TRAIL and chemotherapy drugs were more toxic to particular gliomas than normal cells, but no combination was generally selective for glioma cells. This study highlights the widespread resistance of glioma cells to TRAIL-based agents, but suggests that a minority of high-grade glioma patients may benefit from particular combinations of TRAIL and chemotherapy drugs. In vitro sensitivity assays may help identify effective drug combinations for individual glioma patients.

Authors
Ashley, DM; Riffkin, CD; Lovric, MM; Mikeska, T; Dobrovic, A; Maxwell, JA; Friedman, HS; Drummond, KJ; Kaye, AH; Gan, HK; Johns, TG; Hawkins, CJ
MLA Citation
Ashley, D. M., et al. “In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs..” Br J Cancer, vol. 99, no. 2, July 2008, pp. 294–304. Pubmed, doi:10.1038/sj.bjc.6604459.
PMID
18594532
Source
pubmed
Published In
Br J Cancer
Volume
99
Issue
2
Publish Date
2008
Start Page
294
End Page
304
DOI
10.1038/sj.bjc.6604459

Molecular characterization of the pediatric preclinical testing panel.

PURPOSE: Identifying novel therapeutic agents for the treatment of childhood cancers requires preclinical models that recapitulate the molecular characteristics of their respective clinical histotypes. EXPERIMENTAL DESIGN AND RESULTS: Here, we have applied Affymetrix HG-U133Plus2 profiling to an expanded panel of models in the Pediatric Preclinical Testing Program. Profiling led to exclusion of two tumor lines that were of mouse origin and five osteosarcoma lines that did not cluster with human or xenograft osteosarcoma samples. We compared expression profiles of the remaining 87 models with profiles from 112 clinical samples representing the same histologies and show that model tumors cluster with the appropriate clinical histotype, once "immunosurveillance" genes (contributed by infiltrating immune cells in clinical samples) are eliminated from the analysis. Analysis of copy number alterations using the Affymetrix 100K single nucleotide polymorphism GeneChip showed that the models have similar copy number alterations to their clinical counterparts. Several consistent copy number changes not reported previously were found (e.g., gain at 22q11.21 that was observed in 5 of 7 glioblastoma samples, loss at 16q22.3 that was observed in 5 of 9 Ewing's sarcoma and 4 of 12 rhabdomyosarcoma models, and amplification of 21q22.3 that was observed in 5 of 7 osteosarcoma models). We then asked whether changes in copy number were reflected by coordinate changes in gene expression. We identified 493 copy number-altered genes that are nonrandom and appear to identify histotype-specific programs of genetic alterations. CONCLUSIONS: These data indicate that the preclinical models accurately recapitulate expression profiles and genetic alterations common to childhood cancer, supporting their value in drug development.

Authors
Neale, G; Su, X; Morton, CL; Phelps, D; Gorlick, R; Lock, RB; Reynolds, CP; Maris, JM; Friedman, HS; Dome, J; Khoury, J; Triche, TJ; Seeger, RC; Gilbertson, R; Khan, J; Smith, MA; Houghton, PJ
MLA Citation
Neale, Geoffrey, et al. “Molecular characterization of the pediatric preclinical testing panel..” Clin Cancer Res, vol. 14, no. 14, July 2008, pp. 4572–83. Pubmed, doi:10.1158/1078-0432.CCR-07-5090.
PMID
18628472
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
14
Issue
14
Publish Date
2008
Start Page
4572
End Page
4583
DOI
10.1158/1078-0432.CCR-07-5090

Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors.

The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of (123)I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused (123)I-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5-102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of (123)I-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses

Authors
Sampson, JH; Akabani, G; Archer, GE; Berger, MS; Coleman, RE; Friedman, AH; Friedman, HS; Greer, K; Herndon, JE; Kunwar, S; McLendon, RE; Paolino, A; Petry, NA; Provenzale, JM; Reardon, DA; Wong, TZ; Zalutsky, MR; Pastan, I; Bigner, DD
MLA Citation
Sampson, John H., et al. “Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors..” Neuro Oncol, vol. 10, no. 3, June 2008, pp. 320–29. Pubmed, doi:10.1215/15228517-2008-012.
PMID
18403491
Source
pubmed
Published In
Neuro Oncology
Volume
10
Issue
3
Publish Date
2008
Start Page
320
End Page
329
DOI
10.1215/15228517-2008-012

Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: phase 1 trial in adults with malignant glioma.

We determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate, an inhibitor of the receptor tyrosine kinases platelet-derived growth factor receptor (PDGFR), the proto-oncogene product c-kit, and the fusion protein Bcr-Abl, when administered for 8 days in combination with temozolomide (TMZ) to malignant glioma (MG) patients. MG patients who had not failed prior TMZ were eligible to receive TMZ at a dose of 150-200 mg/m(2) per day on days 4-8 plus imatinib mesylate administered orally on days 1-8 of each 4-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing antiepileptic drugs (EIAEDs). The imatinib dose was escalated in successive cohorts of patients independently for each stratum. Imatinib, at doses ranging from 400 mg to 1,200 mg, was administered with TMZ to 65 patients: 52 (80%) with glioblastoma multiforme (GBM) and 13 (20%) with grade III MG. At enrollment, 34 patients (52%) had stable disease, and 33 (48%) had progressive disease; 30 patients (46%) were on EIAEDs. The MTD of imatinib for patients concurrently receiving or not receiving EIAEDs was 1,000 mg. DLTs were hematologic, gastrointestinal, renal, and hepatic. Pharmacokinetic analyses revealed lowered exposures and enhanced clearance among patients on EIAEDs. Among GBM patients with stable disease at enrollment (n=28), the median progression-free and overall survival times were 41.7 and 56.1 weeks, respectively. Imatinib doses up to 1,000 mg/day for 8 consecutive days are well tolerated when combined with standard TMZ dosing for MG patients. A subsequent phase 2 study is required to further evaluate the efficacy of this regimen for this patient population.

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Sathornsumetee, S; Rich, JN; Quinn, JA; Lagattuta, TF; Egorin, MJ; Gururangan, S; McLendon, R; Herndon, JE; Friedman, AH; Salvado, AJ; Friedman, HS
MLA Citation
Reardon, David A., et al. “Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: phase 1 trial in adults with malignant glioma..” Neuro Oncol, vol. 10, no. 3, June 2008, pp. 330–40. Pubmed, doi:10.1215/15228517-2008-003.
PMID
18359865
Source
pubmed
Published In
Neuro Oncology
Volume
10
Issue
3
Publish Date
2008
Start Page
330
End Page
340
DOI
10.1215/15228517-2008-003

Screening for distress in patients with brain cancer using the NCCN's rapid screening measure.

GOALS OF WORK: Patients with brain cancer are at a risk of experiencing elevated levels of distress due to the severe functional, neurocognitive, and neuropsychological sequelae of the disease. Using the National Comprehensive Cancer Network's Distress Thermometer, we evaluated the extent and sources of distress within a population of patients with brain cancer. PATIENTS AND METHODS: Participants were asked to complete the Distress Thermometer, a single-item rapid screening tool for distress. The Distress Thermometer is a visual analog scale on which participants rate their level of distress from '0' (none) to '10' (extreme). Participants were also asked to designate which items from a 34-item list constitute sources of distress. MAIN RESULTS: Fifty-two percent of participants met the > or =4 cut-off score for distress. The scores were positively correlated with patient-reported emotional sources of distress (r = 0.444, p < 0.001), physical sources of stress (r = 0.231, p < 0.05), and total number of concerns (r = 0.368, p < 0.001). On average, brain tumor patients reported 5.8 cancer-related items of concern. CONCLUSION: Brain cancer patients are likely to experience distress at some point during their disease trajectory. Patient-reported emotional sources of distress should be targeted and interventions should be designed to address sources of distress such as worry, sadness, and depression.

Authors
Keir, ST; Calhoun-Eagan, RD; Swartz, JJ; Saleh, OA; Friedman, HS
MLA Citation
Keir, Stephen T., et al. “Screening for distress in patients with brain cancer using the NCCN's rapid screening measure..” Psychooncology, vol. 17, no. 6, June 2008, pp. 621–25. Pubmed, doi:10.1002/pon.1271.
PMID
17973236
Source
pubmed
Published In
Psychooncology
Volume
17
Issue
6
Publish Date
2008
Start Page
621
End Page
625
DOI
10.1002/pon.1271

A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM)

Authors
Cloughesy, TF; Prados, MD; Wen, PY; Mikkelsen, T; Abrey, LE; Schiff, D; Yung, WK; Maoxia, Z; Dimery, I; Friedman, HS
MLA Citation
Cloughesy, T. F., et al. “A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM).” Journal of Clinical Oncology, vol. 26, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2008, pp. 2010b-2010b. Crossref, doi:10.1200/jco.2008.26.15_suppl.2010b.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
2010b
End Page
2010b
DOI
10.1200/jco.2008.26.15_suppl.2010b

Final report: Phase I trial of imatinib mesylate, hydroxyurea, and vatalanib for patients with recurrent malignant glioma (MG).

2057 Background: Angiogenesis is a hallmark of MG with VEGF as a key regulator. Imatinib mesylate (IM) and hydroxyurea (H) have recently demonstrated promising anti-glioma activity. We attempt to extend the efficacy of IM and H by adding a VEGF receptor inhibitor, vatalanib (V; PTK787). METHODS: We employed a "3+3" dose escalation design to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of V when administered with established doses of IM and H in adult recurrent MG patients with < 3 prior recurrences, KPS ≥ 70% and adequate organ function. Patients were stratified based on concurrent enzyme-inducing anticonvulsant (EIAC) administration, and both strata (A- not on EIAC and B- on EIAC) were independently dose-escalated. Response was evaluated after every other 28-day cycle. Pharmacokinetic (PK) studies were performed during cycle 1. RESULTS: Thirty-seven recurrent MG patients enrolled including 34 (92%) with glioblastoma multiforme and 3 (8%) with WHO grade 3 MG. The median age is 53 (range 26 to 76) and 51% are on EIAC. The MTD of V is 1,000 mg bid. DLTs included grade 3 thrombocytopenia, rash, fatigue, hypertension and transaminase elevation. Best responses include partial response (n=8, 22%) and stable disease (n=19, 51%). With a median follow-up of 82 weeks, 6-month progression-free survival is 27%. PK results are pending. CONCLUSIONS: Combination of imatinib, hydroxyurea and vatalanib is safe and well tolerated with an encouraging rate of radiographic response. MTD is 1,000 mg of V bid with standard imatinib and hydroxyurea dosing for recurrent MG patients. [Table: see text].

Authors
Kirkpatrick, JP; Rich, JN; Vredenburgh, JJ; Desjardins, A; Quinn, JA; Gururangan, S; Sathornsumetee, S; Egorin, MJ; Friedman, HS; Reardon, DA
MLA Citation
Kirkpatrick, J. P., et al. “Final report: Phase I trial of imatinib mesylate, hydroxyurea, and vatalanib for patients with recurrent malignant glioma (MG)..” J Clin Oncol, vol. 26, no. 15_suppl, May 2008.
PMID
27948101
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
2057

Effect of EGFRvIII-targeted vaccine (CDX-110) on immune response and TTP when given with simultaneous standard and continuous temozolomide in patients with GBM

Authors
Sampson, JH; Archer, GE; Bigner, DD; Davis, T; Friedman, HS; Keler, T; Mitchell, DA; Reardon, DA; Sawaya, R; Heimberger, AB
MLA Citation
Sampson, J. H., et al. “Effect of EGFRvIII-targeted vaccine (CDX-110) on immune response and TTP when given with simultaneous standard and continuous temozolomide in patients with GBM.” Journal of Clinical Oncology, vol. 26, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2008, pp. 2011–2011. Crossref, doi:10.1200/jco.2008.26.15_suppl.2011.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
2011
End Page
2011
DOI
10.1200/jco.2008.26.15_suppl.2011

Efficacy of a phase II vaccine targeting Cytomegalovirus antigens in newly diagnosed GBM

Authors
Mitchell, D; Archer, GE; Bigner, DD; Friedman, HS; Lally-Goss, D; Herndon, JE; McGehee, S; McLendon, R; Reardon, DA; Sampson, JH
MLA Citation
Mitchell, D., et al. “Efficacy of a phase II vaccine targeting Cytomegalovirus antigens in newly diagnosed GBM.” Journal of Clinical Oncology, vol. 26, no. 15, AMER SOC CLINICAL ONCOLOGY, May 2008.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Effect of bevacizumab (BEV) and irinotecan (CPT-11) on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in glioblastoma (GBM) patients

Authors
Desjardins, A; Barboriak, DP; Herndon, JE; Marcello, J; Reardon, DA; Quinn, JA; Rich, JN; Sathornsumetee, S; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, A., et al. “Effect of bevacizumab (BEV) and irinotecan (CPT-11) on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in glioblastoma (GBM) patients.” Journal of Clinical Oncology, vol. 26, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2008, pp. 2026–2026. Crossref, doi:10.1200/jco.2008.26.15_suppl.2026.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
2026
End Page
2026
DOI
10.1200/jco.2008.26.15_suppl.2026

Update on survival from the original phase II trial of bevacizumab and irinotecan in recurrent malignant gliomas

Authors
Wagner, SA; Desjardins, A; Reardon, DA; Marcello, J; Herndon, JE; Quinn, JA; Rich, JN; Sathornsumetee, S; Friedman, HS; Vredenburgh, JJ
MLA Citation
Wagner, S. A., et al. “Update on survival from the original phase II trial of bevacizumab and irinotecan in recurrent malignant gliomas.” Journal of Clinical Oncology, vol. 26, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2008, pp. 2021–2021. Crossref, doi:10.1200/jco.2008.26.15_suppl.2021.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
2021
End Page
2021
DOI
10.1200/jco.2008.26.15_suppl.2021

Phase II study of bevacizumab and erlotinib in patients with recurrent glioblastoma multiforme

Authors
Sathornsumetee, S; Vredenburgh, JJ; Rich, JN; Desjardins, A; Quinn, JA; Mathe, AE; Gururangan, S; Friedman, AH; Friedman, HS; Reardon, DA
MLA Citation
Sathornsumetee, S., et al. “Phase II study of bevacizumab and erlotinib in patients with recurrent glioblastoma multiforme.” Journal of Clinical Oncology, vol. 26, no. 15, AMER SOC CLINICAL ONCOLOGY, May 2008.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Final report: Phase I trial of imatinib mesylate, hydroxyurea, and vatalanib for patients with recurrent malignant glioma (MG)

Authors
Kirkpatrick, JP; Rich, JN; Vredenburgh, JJ; Desjardins, A; Quinn, JA; Gururangan, S; Sathornsumetee, S; Egorin, MJ; Friedman, HS; Reardon, DA
MLA Citation
Kirkpatrick, J. P., et al. “Final report: Phase I trial of imatinib mesylate, hydroxyurea, and vatalanib for patients with recurrent malignant glioma (MG).” Journal of Clinical Oncology, vol. 26, no. 15, AMER SOC CLINICAL ONCOLOGY, May 2008.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Treatment of adults with recurrent progressive low-grade glioma using imatinib mesylate and hydroxyurea

Authors
Salacz, ME; Desjardins, A; Quinn, JA; Rich, JN; Vredenburgh, JJ; Sathornsumetee, S; Goli, K; Friedman, HS; Reardon, DA
MLA Citation
Salacz, M. E., et al. “Treatment of adults with recurrent progressive low-grade glioma using imatinib mesylate and hydroxyurea.” Journal of Clinical Oncology, vol. 26, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2008, pp. 2071–2071. Crossref, doi:10.1200/jco.2008.26.15_suppl.2071.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
2071
End Page
2071
DOI
10.1200/jco.2008.26.15_suppl.2071

Phase I trial of temozolomide plus O6-benzylguanine on three different 5-day temozolomide regimens for patients with progressive glioblastoma multiforme

Authors
Quinn, JA; Jiang, XS; Rich, JN; Desjardins, A; Vredenburgh, JJ; Reardon, DA; Gururangan, S; Walker, AR; Birch, R; Friedman, AH; Friedman, HS
MLA Citation
Quinn, J. A., et al. “Phase I trial of temozolomide plus O6-benzylguanine on three different 5-day temozolomide regimens for patients with progressive glioblastoma multiforme.” Journal of Clinical Oncology, vol. 26, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2008, pp. 2084–2084. Crossref, doi:10.1200/jco.2008.26.15_suppl.2084.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
2084
End Page
2084
DOI
10.1200/jco.2008.26.15_suppl.2084

Bevacizumab and daily temozolomide for recurrent glioblastoma multiforme (GBM)

Authors
Maron, R; Vredenburgh, JJ; Desjardins, A; Reardon, DA; Quinn, JA; Rich, JN; Gururangan, S; Wagner, SA; Salacz, ME; Friedman, HS
MLA Citation
Maron, R., et al. “Bevacizumab and daily temozolomide for recurrent glioblastoma multiforme (GBM).” Journal of Clinical Oncology, vol. 26, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2008, pp. 2074–2074. Crossref, doi:10.1200/jco.2008.26.15_suppl.2074.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
2074
End Page
2074
DOI
10.1200/jco.2008.26.15_suppl.2074

Phase II study of bevacizumab and etoposide in patients with recurrent malignant glioma

Authors
Rich, JN; Desjardins, A; Sathornsumetee, S; Vredenburgh, JJ; Quinn, JA; Gururangan, S; Friedman, AH; Friedman, HS; Reardon, DA
MLA Citation
Rich, J. N., et al. “Phase II study of bevacizumab and etoposide in patients with recurrent malignant glioma.” Journal of Clinical Oncology, vol. 26, no. 15, AMER SOC CLINICAL ONCOLOGY, May 2008.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Phase II trial of erlotinib plus sirolimus for recurrent glioblastoma multiforme (GBM)

Authors
Friedman, HS; Desjardins, A; Vredenburgh, JJ; Rich, JN; Sathornsumetee, S; Gururangan, S; Quinn, JA; Reardon, DA
MLA Citation
Friedman, H. S., et al. “Phase II trial of erlotinib plus sirolimus for recurrent glioblastoma multiforme (GBM).” Journal of Clinical Oncology, vol. 26, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2008, pp. 2062–2062. Crossref, doi:10.1200/jco.2008.26.15_suppl.2062.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
2062
End Page
2062
DOI
10.1200/jco.2008.26.15_suppl.2062

The gene expression profiles of medulloblastoma cell lines resistant to preactivated cyclophosphamide.

The total expression profiles of two medulloblastoma cell lines resistant to the preactivated form of cyclophosphamide (4-hydroperoxycyclophosphamide, 4-HC) were examined using the Affymetrix GeneChip U133A array. Our primary objective was to look for possible genes, other than the well-studied aldehyde dehydrogenases (ALDH) that may be involved in cyclophosphamide (CP) resistance in medulloblastomas. We present here the lists of the most highly upregulated [30 for D341 MED (4-HCR); 20 for D283 MED (4-HCR)] and downregulated [19 for D341 MED (4-HCR); 15 for D283 MED (4-HCR)] genes which may be involved in conferring CP-resistance to the two medullobalstoma cell lines. The lists of genes from the two sublines almost had no overlap, suggesting different mechanisms of CP-resistance. One of the most noteworthy upregulated gene is TAP1 [90-fold increase in D341 MED (4-HCR) relative to D341 MED]. TAP1, a protein belonging to the ABC transporter family is normally involved in major histocompatibility class I (MHC I) antigen processing. This suggests the possible role of multidrug resistance (MDR), albeit atypical (which means it does not involve the usual MDR1 and MRP glycoproteins), in medulloblastoma's CP-resistance. Apart from TAP1, a number of other genes involved in MHC1 processing were upregulated in D341 MED (4HCR). D341 MED (4-HCR) also had a 20-fold increase in the expression of the aldo-keto reductase gene, AKR1B10, which may deactivate the reactive cyclophosphamide metabolite, aldophosphamide. For D283 MED (4-HCR), the most notable increase in expression is that of ALDH1B1, a member of the aldehyde dehydrogenase (ALDH) family of proteins.

Authors
Bacolod, MD; Lin, SM; Johnson, SP; Bullock, NS; Colvin, M; Bigner, DD; Friedman, HS
MLA Citation
Bacolod, M. D., et al. “The gene expression profiles of medulloblastoma cell lines resistant to preactivated cyclophosphamide..” Curr Cancer Drug Targets, vol. 8, no. 3, May 2008, pp. 172–79.
PMID
18473730
Source
pubmed
Published In
Curr Cancer Drug Targets
Volume
8
Issue
3
Publish Date
2008
Start Page
172
End Page
179

Immunotherapy against angiogenesis-associated targets: evidence and implications for the treatment of malignant glioma.

Angiogenesis, the growth of new blood vessels from previously existing vasculature, is a requirement for tumor growth and metastasis. The first US FDA-approved drugs targeting angiogenesis have shown potential in the treatment of malignant gliomas. Immunotherapy as a treatment modality lends itself well to specifically targeting angiogenesis in tumors and may represent a powerful tool in the treatment of malignant gliomas. This review focuses on developments in immunotherapy targeting angiogenesis and tumor-vascular-specific endothelial cells using a variety of immunotherapeutic strategies including monoclonal antibodies and conjugated immunotoxins, as well as cellular, peptide, DNA and dendritic cell vaccines.

Authors
Everson, RG; Graner, MW; Gromeier, M; Vredenburgh, JJ; Desjardins, A; Reardon, DA; Friedman, HS; Friedman, AH; Bigner, DD; Sampson, JH
MLA Citation
Everson, Richard G., et al. “Immunotherapy against angiogenesis-associated targets: evidence and implications for the treatment of malignant glioma..” Expert Rev Anticancer Ther, vol. 8, no. 5, May 2008, pp. 717–32. Pubmed, doi:10.1586/14737140.8.5.717.
PMID
18471045
Source
pubmed
Published In
Expert Rev Anticancer Ther
Volume
8
Issue
5
Publish Date
2008
Start Page
717
End Page
732
DOI
10.1586/14737140.8.5.717

A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost.

The purpose of this study was to determine the feasibility and assess the efficacy and toxicity, among newly diagnosed malignant glioma patients, of administering (131)I-labeled murine antitenascin monoclonal antibody 81C6 ((131)I-81C6) into a surgically created resection cavity (SCRC) to achieve a patient-specific, 44-Gy boost to the 2-cm SCRC margin. A radioactivity dose of (131)I-81C6 calculated to achieve a 44-Gy boost to the SCRC was administered, followed by conventional external beam radiotherapy (XRT) and chemotherapy. Twenty-one patients were enrolled in the study: 16 with glioblastoma multiforme (GBM) and 5 with anaplastic astrocytoma. Twenty patients received the targeted 44-Gy boost (+/-10%) to the SCRC. Attributable toxicity was mild and limited to reversible grade 3 neutropenia or thrombocytopenia (n = 3; 14%), CNS wound infections (n = 3; 14%), and headache (n = 2; 10%). With a median follow-up of 151 weeks, median overall survival times for all patients and those with GBM are 96.6 and 90.6 weeks, respectively; 87% of GBM patients are alive at 1 year. It is feasible to consistently achieve a 44-Gy boost dose to the SCRC margin with patient-specific dosing of (131)I-81C6. Our study regimen ((131)I-81C6 + XRT + temozolomide) was well tolerated and had encouraging survival. To determine if selection of good-prognosis patients affects outcome associated with this approach, the U.S. Food and Drug Administration has approved a trial randomizing newly diagnosed GBM patients to either our study regimen or standard XRT plus temozolomide.

Authors
Reardon, DA; Zalutsky, MR; Akabani, G; Coleman, RE; Friedman, AH; Herndon, JE; McLendon, RE; Pegram, CN; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Guruangan, S; Boulton, S; Raynor, RH; Dowell, JM; Wong, TZ; Zhao, X-G; Friedman, HS; Bigner, DD
MLA Citation
Reardon, David A., et al. “A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost..” Neuro Oncol, vol. 10, no. 2, Apr. 2008, pp. 182–89. Pubmed, doi:10.1215/15228517-2007-053.
PMID
18287339
Source
pubmed
Published In
Neuro Oncology
Volume
10
Issue
2
Publish Date
2008
Start Page
182
End Page
189
DOI
10.1215/15228517-2007-053

In reply

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Friedman, HS
MLA Citation
Vredenburgh, J. J., et al. “In reply.” Journal of Clinical Oncology, vol. 26, no. 6, Feb. 2008. Scopus, doi:10.1200/JCO.2007.15.1746.
Source
scopus
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
6
Publish Date
2008
Start Page
1013
DOI
10.1200/JCO.2007.15.1746

Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors: a pediatric brain tumor consortium study.

PURPOSE: VNP40101M (Cloretazine), a novel DNA alkylating agent, was evaluated in a phase I study in children with recurrent brain tumors. EXPERIMENTAL DESIGN: VNP40101M was given i.v. daily for 5 consecutive days every 6 weeks for up to eight cycles. Dose escalation was done independently in patients stratified based on intensity of prior therapy (moderately pretreated, stratum I; heavily pretreated, stratum II). Correlative studies included pharmacokinetics and measurement of O(6)-alkylguanine-DNA alkyl transferase levels in peripheral blood mononuclear cells before and after treatment. RESULTS: Forty-one eligible patients (stratum I, 19; stratum II, 22) were enrolled on this study. The dose-limiting toxicity in 35 evaluable patients was myelosuppression, which occurred in 4 of 16 patients in stratum I and 3 of 19 patients in stratum II. Pharmacokinetic studies showed a median terminal half-life of 30 min (range, 14-39.5). The maximum tolerated dose in stratum I and II were 45 and 30 mg/m(2)/d daily for 5 days every 6 weeks, respectively. Peripheral blood mononuclear cells alkylguanine alkyl transferase levels did not decrease significantly after VNP40101M treatment. Central imaging review confirmed that three patients had stable disease for a median of 45 weeks (range, 37-61+) after therapy. CONCLUSIONS: The recommended dose of VNP40101M for phase II studies in children with brain tumors is 45 mg/m(2)/d in moderately pretreated and 30 mg/m(2)/d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks.

Authors
Gururangan, S; Turner, CD; Stewart, CF; O'Shaughnessy, M; Kocak, M; Poussaint, TY; Phillips, PC; Goldman, S; Packer, R; Pollack, IF; Blaney, SM; Karsten, V; Gerson, SL; Boyett, JM; Friedman, HS; Kun, LE
MLA Citation
Gururangan, Sridharan, et al. “Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors: a pediatric brain tumor consortium study..” Clin Cancer Res, vol. 14, no. 4, Feb. 2008, pp. 1124–30. Pubmed, doi:10.1158/1078-0432.CCR-07-4242.
PMID
18281546
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
14
Issue
4
Publish Date
2008
Start Page
1124
End Page
1130
DOI
10.1158/1078-0432.CCR-07-4242

Multifocal anaplastic astrocytoma in a patient with hereditary colorectal cancer, transcobalamin II deficiency, agenesis of the corpus callosum, mental retardation, and inherited PMS2 mutation.

We describe the case of a patient with transcobalamin II deficiency, hypogammaglobulinemia, absent corpus callosum, and mental retardation who presented at an early age with colorectal cancer and multifocal anaplastic astrocytoma. He was found to have a possible germline mutation of the PMS2 gene, as evidenced by absent protein expression in both normal and tumor tissues. His parents were found to be carriers of a nonsense mutation of the PMS2 gene.

Authors
Gururangan, S; Frankel, W; Broaddus, R; Clendenning, M; Senter, L; McDonald, M; Eastwood, J; Reardon, D; Vredenburgh, J; Quinn, J; Friedman, HS
MLA Citation
Gururangan, Sridharan, et al. “Multifocal anaplastic astrocytoma in a patient with hereditary colorectal cancer, transcobalamin II deficiency, agenesis of the corpus callosum, mental retardation, and inherited PMS2 mutation..” Neuro Oncology, vol. 10, no. 1, Feb. 2008, pp. 93–97. Epmc, doi:10.1215/15228517-2007-037.
PMID
17993636
Source
epmc
Published In
Neuro Oncology
Volume
10
Issue
1
Publish Date
2008
Start Page
93
End Page
97
DOI
10.1215/15228517-2007-037

Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan.

PURPOSE: The combination of a vascular endothelial growth factor (VEGF) -neutralizing antibody, bevacizumab, and irinotecan is associated with high radiographic response rates and improved survival outcomes in patients with recurrent malignant gliomas. The aim of these retrospective studies was to evaluate tumor vascularity and expression of components of the VEGF pathway and hypoxic responses as predictive markers for radiographic response and survival benefit from the bevacizumab and irinotecan therapy. PATIENTS AND METHODS: In a phase II trial, 60 patients with recurrent malignant astrocytomas were treated with bevacizumab and irinotecan. Tumor specimens collected at the time of diagnosis were available for further pathologic studies in 45 patients (75%). VEGF, VEGF receptor-2, CD31, hypoxia-inducible carbonic anhydrase 9 (CA9), and hypoxia-inducible factor-2alpha were semiquantitatively assessed by immunohistochemistry. Radiographic response and survival outcomes were correlated with these angiogenic and hypoxic markers. RESULTS: Of 45 patients, 27 patients had glioblastoma multiforme, and 18 patients had anaplastic astrocytoma. Twenty-six patients (58%) had at least partial radiographic response. High VEGF expression was associated with increased likelihood of radiographic response (P = .024) but not survival benefit. Survival analysis revealed that high CA9 expression was associated with poor survival outcome (P = .016). CONCLUSION: In this patient cohort, tumor expression levels of VEGF, the molecular target of bevacizumab, were associated with radiographic response, and the upstream promoter of angiogenesis, hypoxia, determined survival outcome, as measured from treatment initiation. Validation in a larger clinical trial is warranted.

Authors
Sathornsumetee, S; Cao, Y; Marcello, JE; Herndon, JE; McLendon, RE; Desjardins, A; Friedman, HS; Dewhirst, MW; Vredenburgh, JJ; Rich, JN
MLA Citation
Sathornsumetee, Sith, et al. “Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan..” J Clin Oncol, vol. 26, no. 2, Jan. 2008, pp. 271–78. Pubmed, doi:10.1200/JCO.2007.13.3652.
PMID
18182667
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
2
Publish Date
2008
Start Page
271
End Page
278
DOI
10.1200/JCO.2007.13.3652

Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6.

UNLABELLED: alpha-Particle-emitting radionuclides, such as (211)At, with a 7.2-h half-life, may be optimally suited for the molecularly targeted radiotherapy of strategically sensitive tumor sites, such as those in the central nervous system. Because of the much shorter range and more potent cytotoxicity of alpha-particles than of beta-particles, (211)At-labeled agents may be ideal for the eradication of tumor cells remaining after surgical debulking of malignant brain tumors. The main goal of this study was to investigate the feasibility and safety of this approach in patients with recurrent malignant brain tumors. METHODS: Chimeric antitenascin monoclonal antibody 81C6 (ch81C6) (10 mg) was labeled with 71-347 MBq of (211)At by use of N-succinimidyl 3-[(211)At]astatobenzoate. Eighteen patients were treated with (211)At-labeled ch81C6 ((211)At-ch81C6) administered into a surgically created resection cavity (SCRC) and then with salvage chemotherapy. Serial gamma-camera imaging and blood sampling over 24 h were performed. RESULTS: A total of 96.7% +/- 3.6% (mean +/- SD) of (211)At decays occurred in the SCRC, and the mean blood-pool percentage injected dose was < or = 0.3. No patient experienced dose-limiting toxicity, and the maximum tolerated dose was not identified. Six patients experienced grade 2 neurotoxicity within 6 wk of (211)At-ch81C6 administration; this neurotoxicity resolved fully in all but 1 patient. No toxicities of grade 3 or higher were attributable to the treatment. No patient required repeat surgery for radionecrosis. The median survival times for all patients, those with glioblastoma multiforme, and those with anaplastic astrocytoma or oligodendroglioma were 54, 52, and 116 wk, respectively. CONCLUSION: This study provides proof of concept for regional targeted radiotherapy with (211)At-labeled molecules in oncology. Specifically, the regional administration of (211)At-ch81C6 is feasible, safe, and associated with a promising antitumor benefit in patients with malignant central nervous system tumors.

Authors
Zalutsky, MR; Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; McLendon, RE; Wong, TZ; Bigner, DD
MLA Citation
Zalutsky, Michael R., et al. “Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6..” J Nucl Med, vol. 49, no. 1, Jan. 2008, pp. 30–38. Pubmed, doi:10.2967/jnumed.107.046938.
PMID
18077533
Source
pubmed
Published In
Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
Volume
49
Issue
1
Publish Date
2008
Start Page
30
End Page
38
DOI
10.2967/jnumed.107.046938

Pediatric preclinical testing program (PPTP) evaluation of the EGFR and ErbB2 inhibitor lapatinib

Authors
Houghton, PJ; Maris, JM; Courtright, J; Friedman, HS; Keir, ST; Lock, RB; Carol, H; Gorlick, R; Kolb, EA; Keshelava, N; Reynolds, CP; Morton, CL; Smith, MA
MLA Citation
Houghton, Peter J., et al. “Pediatric preclinical testing program (PPTP) evaluation of the EGFR and ErbB2 inhibitor lapatinib.” Molecular Cancer Therapeutics, vol. 6, no. 12, AMER ASSOC CANCER RESEARCH, Dec. 2007, pp. 3471S-3471S.
Source
wos
Published In
Molecular Cancer Therapeutics
Volume
6
Issue
12
Publish Date
2007
Start Page
3471S
End Page
3471S

Pediatric preclinical testing program (PPTP) evaluation of the fully human anti-IGF-1R antibody SCH 717454

Authors
Houghton, PJ; Maris, JM; Friedman, HS; Keir, ST; Lock, RB; Carol, H; Gorlick, R; Kolb, EA; Keshlava, N; Reynolds, CP; Morton, CL; Smith, MA
MLA Citation
Houghton, Peter J., et al. “Pediatric preclinical testing program (PPTP) evaluation of the fully human anti-IGF-1R antibody SCH 717454.” Molecular Cancer Therapeutics, vol. 6, no. 12, AMER ASSOC CANCER RESEARCH, Dec. 2007, pp. 3405S-3405S.
Source
wos
Published In
Molecular Cancer Therapeutics
Volume
6
Issue
12
Publish Date
2007
Start Page
3405S
End Page
3405S

Stress and long-term survivors of brain cancer.

INTRODUCTION: Adult brain tumor patients are joining the ranks of cancer survivors in increasing numbers in the United States. As a result, health care providers are faced with new challenges to address the need for psychosocial support in this population. METHODS: Using the Perceived Stress Scale and the National Comprehensive Cancer Network's Distress Thermometer, levels of stress and cancer-related items of concern were assessed in adult long-term survivors of brain cancer. RESULTS: Sixty-one percent of the sample population experienced elevated levels of stress. Scores were not significantly associated with age, gender, treatment status, or tumor grade. Long-term survivors were just as likely to report being stressed (chi(2) = 0.032, NS), while reporting fewer numbers of items of concern (5.02, SD = 3.509), compared to brain tumor patients diagnosed 18 months (M = 6.82, SD = 3.737, t = 2.467, p 0.05). DISCUSSION/CONCLUSION: Despite their long-term survival status, long-term survivors of brain cancer continue to experience elevated levels of stress. Predictors of stress in this population are related to familial, emotional, and practical concerns. While the scientific community continues to examine the specific impact of stress on both the physical and mental outcomes of cancer patients, understanding the sources of stress within cancer populations is key in designing targeted interventions to help patients manage the stress associated with this disease. IMPLICATIONS FOR BRAIN TUMOR SURVIVORS: This study provides a better understanding of the unique needs of long-term survivors of brain cancer. An awareness of the sources and levels of stress experienced by this population could lead to the development of effective supportive care interventions to improve the quality of life of the survivor.

Authors
Keir, ST; Swartz, JJ; Friedman, HS
MLA Citation
Keir, Stephen T., et al. “Stress and long-term survivors of brain cancer..” Support Care Cancer, vol. 15, no. 12, Dec. 2007, pp. 1423–28. Pubmed, doi:10.1007/s00520-007-0292-1.
PMID
17609991
Source
pubmed
Published In
Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer
Volume
15
Issue
12
Publish Date
2007
Start Page
1423
End Page
1428
DOI
10.1007/s00520-007-0292-1

The pediatric preclinical testing program: description of models and early testing results.

BACKGROUND: The Pediatric Preclinical Testing Program (PPTP) is an initiative supported by the National Cancer Institute (NCI) to identify novel therapeutic agents that may have significant activity against childhood cancers. The PPTP has established panels of childhood cancer xenografts and cell lines to be used for in vivo and in vitro testing. These include panels for Wilms tumor, sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), neuroblastoma, brain tumors (glioblastoma, ependymoma, and medulloblastoma), rhabdoid tumors (CNS and renal), and acute lymphoblastic leukemia (ALL). Here, we describe the characteristics of the in vivo tumor panels and report results for the in vivo evaluation of two standard agents, vincristine and cyclophosphamide. PROCEDURES: Solid tumors were grown subcutaneously in immune-deficient mice and tumor dimensions were measured weekly. ALL xenografts were inoculated intravenously and human CD45-positive cells were enumerated weekly. RESULTS: Vincristine-induced objective responses in 6 of 24 (25%) and cyclophosphamide-induced objective responses in 18 of 28 (64%) solid tumor models. Comparable assessments of high levels of activity for these two agents were obtained using a tumor growth delay (TGD) measure. Both agents induced regressions in each of the ALL models evaluated. CONCLUSIONS: We have established 51 solid tumor and 10 ALL in vivo models. The models identify vincristine and cyclophosphamide as having broad-spectrum activity. The PPTP tumor panels appear to generally recapitulate the activity of these agents against specific childhood cancers and to have the potential for identifying novel agents having significant clinical activity.

Authors
Houghton, PJ; Morton, CL; Tucker, C; Payne, D; Favours, E; Cole, C; Gorlick, R; Kolb, EA; Zhang, W; Lock, R; Carol, H; Tajbakhsh, M; Reynolds, CP; Maris, JM; Courtright, J; Keir, ST; Friedman, HS; Stopford, C; Zeidner, J; Wu, J; Liu, T; Billups, CA; Khan, J; Ansher, S; Zhang, J; Smith, MA
MLA Citation
Houghton, Peter J., et al. “The pediatric preclinical testing program: description of models and early testing results..” Pediatr Blood Cancer, vol. 49, no. 7, Dec. 2007, pp. 928–40. Pubmed, doi:10.1002/pbc.21078.
PMID
17066459
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
49
Issue
7
Publish Date
2007
Start Page
928
End Page
940
DOI
10.1002/pbc.21078

Phase I trial of single-dose temozolomide and continuous administration of o6-benzylguanine in children with brain tumors: a pediatric brain tumor consortium report.

PURPOSE: To estimate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of temozolomide combined with O(6)-benzylguanine in patients < or =21 years with recurrent brain tumors. EXPERIMENTAL DESIGN: Treatment strata consisted of patients who had previously received no or local radiotherapy (Str1) and patients who had undergone craniospinal radiotherapy or myeloablative chemotherapy (Str2). One-hour i.v. administration of O(6)-benzylguanine at 120 mg/m(2) was followed by 48-h continuous infusion at 30 mg/m(2)/day. Single-dose temozolomide at five dosage levels (267, 355, 472, 628, and 835 mg/m(2)) was given at least 6 h after completion of O(6)-benzylguanine bolus. Treatment was repeated after recovery from toxicities at least 4 weeks apart for a maximum of 12 courses. Dose escalation followed the modified continual reassessment method. Pharmacokinetic analyses of temozolomide and 5-triazeno imidazole carboxamide (MTIC) were done in 28 patients. RESULTS: A total of 44 and 26 eligible patients were enrolled on Str1 and Str2, respectively. Median age at study entry in each stratum was 8.6 and 11.3 years, respectively. Predominant diagnoses were high-grade/brainstem glioma in Str1 and medulloblastoma in Str2. Whereas the estimated MTDs of temozolomide for Str1 and Str2 were 562 and 407 mg/m(2), respectively, the doses recommended for phase II investigations are 472 and 355 mg/m(2), respectively. DLTs were predominantly neutropenia and thrombocytopenia. Three patients with gliomas experienced centrally confirmed partial responses to therapy. Four patients completed all planned therapy. Temozolomide and MTIC exposures were statistically associated with temozolomide dosage. CONCLUSIONS: The current schedule of temozolomide and O(6)-benzylguanine is safe and showed modest activity against recurrent brain tumors in children.

Authors
Broniscer, A; Gururangan, S; MacDonald, TJ; Goldman, S; Packer, RJ; Stewart, CF; Wallace, D; Danks, MK; Friedman, HS; Poussaint, TY; Kun, LE; Boyett, JM; Gajjar, A
MLA Citation
Broniscer, Alberto, et al. “Phase I trial of single-dose temozolomide and continuous administration of o6-benzylguanine in children with brain tumors: a pediatric brain tumor consortium report..” Clin Cancer Res, vol. 13, no. 22 Pt 1, Nov. 2007, pp. 6712–18. Pubmed, doi:10.1158/1078-0432.CCR-07-1016.
PMID
18006772
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
13
Issue
22 Pt 1
Publish Date
2007
Start Page
6712
End Page
6718
DOI
10.1158/1078-0432.CCR-07-1016

O (4)-benzylfolic acid inactivates O (6)-alkylguanine-DNA alkyltransferase in brain tumor cell lines.

PURPOSE: The DNA repair protein, O (6)-alkylguanine-DNA alkyltransferase (AGT), is a primary source of tumor resistance to agents such as temozolomide and chloroethylnitrosoureas that form DNA lesions at the O (6)-position of guanines. To increase the efficacy of these drugs, pseudosubstrate inactivators of AGT such as O (6)-benzylguanine have been developed. A novel inactivator of AGT, O (4)-benzylfolic acid (O(4)-BFA), has been reported which is more potent and water soluble than O (6)-benzylguanine. Previous studies have suggested that uptake of O(4)-BFA is mediated by the folate receptor (FR), and, thus, its use may be limited to cells expressing FR. METHODS: We measured AGT activity in cell extracts from a panel of brain tumor cells exposed to O(4)-BFA. Inactivation of AGT by O(4)-BFA was measured in cells grown without folic acid as well as in cells grown in folic acid-containing media. Competitive binding studies were performed using purified FR to determine its affinity for O(4)-BFA. RESULTS: The observed IC(50) for O(4)-BFA in brain tumor cell lines ranged from 0.2 to 1.3 microM for cells grown in media containing 2.3 microM folic acid. At this concentration, folic acid would saturate the FR and the FR would be unable to take up O(4)-BFA. When cells were grown in folic acid free media, there was at most a 50% decrease in the observed IC(50)s, indicating that the FR was not essential for O(4)-BFA uptake. Competitive binding studies using purified FR confirmed that the IC(50) for O(4)-BFA is approximately 180 times greater than folic acid, i.e., it has a very weak affinity for FR. CONCLUSION: These results indicate that O(4)-BFA has potentially broad use as an inactivator of AGT as its use is not limited to tumors expressing high levels of FR.

Authors
Johnson, SP; Kamen, BA; Bigner, DD; Friedman, HS
MLA Citation
Johnson, Stewart P., et al. “O (4)-benzylfolic acid inactivates O (6)-alkylguanine-DNA alkyltransferase in brain tumor cell lines..” Cancer Chemother Pharmacol, vol. 60, no. 6, Nov. 2007, pp. 883–89. Pubmed, doi:10.1007/s00280-007-0435-6.
PMID
17333191
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
60
Issue
6
Publish Date
2007
Start Page
883
End Page
889
DOI
10.1007/s00280-007-0435-6

Bevacizumab plus irinotecan in recurrent glioblastoma multiforme.

PURPOSE: The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan. PATIENTS AND METHODS: This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs received 125 mg/m2. After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging. RESULTS: The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli). CONCLUSION: Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.

Authors
Vredenburgh, JJ; Desjardins, A; Herndon, JE; Marcello, J; Reardon, DA; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Sampson, J; Wagner, M; Bailey, L; Bigner, DD; Friedman, AH; Friedman, HS
MLA Citation
Vredenburgh, James J., et al. “Bevacizumab plus irinotecan in recurrent glioblastoma multiforme..” J Clin Oncol, vol. 25, no. 30, Oct. 2007, pp. 4722–29. Pubmed, doi:10.1200/JCO.2007.12.2440.
PMID
17947719
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
30
Publish Date
2007
Start Page
4722
End Page
4729
DOI
10.1200/JCO.2007.12.2440

Cyclophosphamide (CPM) and melphalan (MEL) for recurrent medulloblastoma (MB) and intracranial germinoma (GCT) - A Children's Oncology Group (COG) study

Authors
Kadota, R; Mahoney, DH; Doyle, J; Duerst, R; Friedman, HS; Holmes, EJ; Kun, LE; Zhou, T; Pollack, IE
MLA Citation
Kadota, Richard, et al. “Cyclophosphamide (CPM) and melphalan (MEL) for recurrent medulloblastoma (MB) and intracranial germinoma (GCT) - A Children's Oncology Group (COG) study.” Pediatric Blood & Cancer, vol. 49, no. 4, WILEY-LISS, Oct. 2007, pp. 422–422. Wos, doi:10.1002/pbc.
Source
wos
Published In
Pediatric Blood & Cancer
Volume
49
Issue
4
Publish Date
2007
Start Page
422
End Page
422
DOI
10.1002/pbc

Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group.

BACKGROUND: Effective chemotherapy is lacking for most types of central nervous system (CNS) tumors in children. Temozolomide, an agent with activity against adult brain tumors, was investigated in children and adolescents with recurrent CNS tumors. METHODS: Temozolomide was administered orally as monthly 5-day courses at doses of 200 mg/m(2)/d (patients with no prior craniospinal irradiation [CSI]) or 180 mg/m(2)/d (prior CSI). Patients with a complete (CR) or partial (PR) response or stable disease (SD) could continue temozolomide for up to 12 cycles. RESULTS: The cohort comprised 122 patients, including 113 with CNS tumors. Median age was 11 years (range, 1-23 years). Among 104 evaluable patients with CNS tumors, 5 PRs and 1 CR were observed. PRs occurred in 1 of 23 evaluable patients with high-grade astrocytoma, 1 of 21 with low-grade astrocytoma, and 3 of 25 with medulloblastoma/primitive neuroectodermal tumor (PNET). The CR occurred in an additional patient with medulloblastoma/PNET. No responses were observed in patients with ependymoma, brain-stem glioma, or other CNS tumors. Notably, 41% of patients with low-grade astrocytoma had SD through 12 courses. The most frequent toxicities were grade 3 or 4 neutropenia (19%) and thrombocytopenia (25%); nonhematologic toxicity was infrequent. CONCLUSIONS: Although overall objective responses were limited, further exploration of temozolomide may be warranted in children with medulloblastoma and other PNETs, or in patients with low-grade astrocytoma, perhaps in a setting of less pretreatment than the patients in the current study, or in the context of multiagent therapy.

Authors
Nicholson, HS; Kretschmar, CS; Krailo, M; Bernstein, M; Kadota, R; Fort, D; Friedman, H; Harris, MB; Tedeschi-Blok, N; Mazewski, C; Sato, J; Reaman, GH
MLA Citation
Nicholson, H. Stacy, et al. “Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group..” Cancer, vol. 110, no. 7, Oct. 2007, pp. 1542–50. Pubmed, doi:10.1002/cncr.22961.
PMID
17705175
Source
pubmed
Published In
Cancer
Volume
110
Issue
7
Publish Date
2007
Start Page
1542
End Page
1550
DOI
10.1002/cncr.22961

Interstitial chemotherapy with biodegradable BCNU (Gliadel) wafers in the treatment of malignant gliomas.

Malignant gliomas represent the majority of primary brain tumors, and the prognosis of the patients afflicted with these tumors has been historically dismal, with almost uniform progressive neurologic impairment and rapid death. Even with multimodal treatment using surgery, focal radiation, and chemotherapy, no major strides were made until recently. The development of interstitial BCNU wafers (carmustine wafers, Gliadel((R))) has led to promising results in the treatment of a selected patients with malignant gliomas, as well as with other intracranial malignancies.BCNU is one of the first systemic chemotherapies which had obtained United States Food and Drug Administration (FDA) approval for the treatment of brain tumors. However, systemic use has been hampered by the modest prolongation of survival and by the prolonged myelosuppression and potentially fatal pulmonary toxicity. The development of interstitial therapies with BCNU represented a great step forward, allowing direct delivery to the tumor bed, with virtually no systemic toxicities. Clinical studies of BCNU wafers have showed good efficacy in both newly diagnosed and recurrent gliomas, as well as a possible therapeutic role in other primary or secondary intracranial malignancies. New studies are currently underway trying to improve the efficacy of the BCNU wafers (Gliadel((R))) by combining them with different systemic chemotherapies. An overview of the current knowledge ranging from the preclinical developments, to the efficacy and safety seen in the clinical trials and in clinical practice following the drug approval to the future avenues of research is therefore timely.

Authors
Bota, DA; Desjardins, A; Quinn, JA; Affronti, ML; Friedman, HS
MLA Citation
Bota, Daniela A., et al. “Interstitial chemotherapy with biodegradable BCNU (Gliadel) wafers in the treatment of malignant gliomas..” Therapeutics and Clinical Risk Management, vol. 3, no. 5, Oct. 2007, pp. 707–15.
PMID
18472995
Source
epmc
Published In
Therapeutics and Clinical Risk Management
Volume
3
Issue
5
Publish Date
2007
Start Page
707
End Page
715

Dendritic cell vaccine shows promise in glioblastoma: Commentary

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Dendritic cell vaccine shows promise in glioblastoma: Commentary.” Oncology Report, no. FALL, Sept. 2007.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2007
Start Page
11

Motexafin gadolinium delays progression in NSCLC brain metastases: Commentary

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Motexafin gadolinium delays progression in NSCLC brain metastases: Commentary.” Oncology Report, no. FALL, Sept. 2007.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2007
Start Page
10

Bevacizumab plus irinotecan stalls recurrent gliomas: Commentary

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Bevacizumab plus irinotecan stalls recurrent gliomas: Commentary.” Oncology Report, no. FALL, Sept. 2007.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2007
Start Page
9

VEGF inhibitor cediranib active in recurrent glioblastoma: Commentary

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “VEGF inhibitor cediranib active in recurrent glioblastoma: Commentary.” Oncology Report, no. FALL, Sept. 2007.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2007
Start Page
10

Temozolomide and vaccination can work together to treat GBM: Commentary

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Temozolomide and vaccination can work together to treat GBM: Commentary.” Oncology Report, no. FALL, Sept. 2007.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2007
Start Page
11

Stress levels and sources of stress in an adult brain tumor population

Authors
Keir, ST; Swartz, JJ; Friedman, HS
MLA Citation
Keir, S. T., et al. “Stress levels and sources of stress in an adult brain tumor population.” Psycho Oncology, vol. 16, no. 9, JOHN WILEY & SONS LTD, Sept. 2007, pp. S140–41.
Source
wos
Published In
Psycho Oncology
Volume
16
Issue
9
Publish Date
2007
Start Page
S140
End Page
S141

The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion.

Monotherapies have proven largely ineffective for the treatment of glioblastomas, suggesting that increased patient benefit may be achieved by combining therapies. Two protumorigenic pathways known to be active in glioblastoma include RAS/RAF/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT/target of rapamycin (TOR). We investigated the efficacy of a combination of novel low molecular weight inhibitors LBT613 and RAD001 (everolimus), which were designed to target RAF and TOR, respectively. LBT613 decreased phosphorylation of extracellular signal-regulated kinase 1 and 2, downstream effectors of RAF, in a human glioma cell line. RAD001 resulted in decreased phosphorylation of the TOR effector S6. To determine if targeting RAF and TOR activities could result in decreased protumorigenic glioma cellular behaviors, we evaluated the abilities of LBT613 and RAD001 to affect the proliferation, migration, and invasion of human glioma cells. Treatment with either LBT613 or RAD001 alone significantly decreased the proliferation of multiple human glioma cell lines. Furthermore, LBT613 and RAD001 in combination synergized to decrease glioma cell proliferation in association with G(1) cell cycle arrest. Glioma invasion is a critical contributor to tumor malignancy. The combination of LBT613 and RAD001 inhibited the invasion of human glioma cells through Matrigel to a greater degree than treatment with either drug alone. These data suggest that the combination of LBT613 and RAD001 reduces glioma cell proliferation and invasion and support examination of the combination of RAF and TOR inhibitors for the treatment of human glioblastoma patients.

Authors
Hjelmeland, AB; Lattimore, KP; Fee, BE; Shi, Q; Wickman, S; Keir, ST; Hjelmeland, MD; Batt, D; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Hjelmeland, Anita B., et al. “The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion..” Mol Cancer Ther, vol. 6, no. 9, Sept. 2007, pp. 2449–57. Pubmed, doi:10.1158/1535-7163.MCT-07-0155.
PMID
17766837
Source
pubmed
Published In
Molecular Cancer Therapeutics
Volume
6
Issue
9
Publish Date
2007
Start Page
2449
End Page
2457
DOI
10.1158/1535-7163.MCT-07-0155

The fallacy of single-agent chemotherapy for cancer.

Authors
Friedman, HS; Maxwell, J
MLA Citation
Friedman, Henry S., and Jill Maxwell. “The fallacy of single-agent chemotherapy for cancer..” J Clin Oncol, vol. 25, no. 23, Aug. 2007. Pubmed, doi:10.1200/JCO.2007.12.3596.
PMID
17687162
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
23
Publish Date
2007
Start Page
3550
DOI
10.1200/JCO.2007.12.3596

Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice.

VNP40101M, or 1,2-bis(methylsulfonyl)-1-(2-choloroethyl)-2-(methylamino)carbonylhydrazine (Cloretazine), is a bifunctional prodrug that belongs to a class of DNA-modifying agents-the sulfonylhydrazines-that has been synthesized and been shown to have activity against a wide spectrum of xenografts. The current study was designed to assess the activity of VNP40101M administered at a dose of 18 mg/kg daily for five days against a panel of human adult and pediatric CNS tumors growing subcutaneously or intracranially in athymic nude mice. The results demonstrated statistically significant (p < 0.05) growth delays of 15.0, 8.3, 51.0, 60+, 60+, and 60+ days in subcutaneous xenografts derived from childhood glioblastoma multiforme (D-456 MG), childhood ependymoma (D-528 EP and D-612 EP), childhood medulloblastoma (D-425 MED), and adult malignant glioma (D-245 MG and D-54 MG), respectively, with corresponding tumor regressions in 10 of 10, 4 of 10, 8 of 10, 9 of 10, 9 of 10, and 10 of 10 treated mice, respectively. Delayed toxicity was seen more than 60 days after treatment, with 23 deaths in 100 treated animals, despite a median weight loss of only 0.06%. In mice bearing intracranial D-245 MG xenografts, treatment with VNP40101M at a dose of 18 mg/kg daily for five days produced a 50% increase in median survival compared with controls. Additional experiments conducted against subcutaneous D-245 MG xenografts by using reduced doses of 13.5 or 9.0 mg/kg daily for five days demonstrated tumor growth delays of 82.2 and 53.5 days, with corresponding tumor regressions in 8 of 9 and 9 of 10 treated mice, respectively (all values, p < 0.001), with one toxic death. These findings suggest that VNP40101M is active in the treatment of a wide range of human central nervous system tumors and warrants translation to the clinic.

Authors
Badruddoja, MA; Keir, ST; King, I; Zeidner, J; Vredenburgh, JJ; Muhlbaier, LH; Bigner, DD; Friedman, HS
MLA Citation
Badruddoja, Michael A., et al. “Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice..” Neuro Oncol, vol. 9, no. 3, July 2007, pp. 240–44. Pubmed, doi:10.1215/15228517-2007-011.
PMID
17522334
Source
pubmed
Published In
Neuro Oncology
Volume
9
Issue
3
Publish Date
2007
Start Page
240
End Page
244
DOI
10.1215/15228517-2007-011

Prevalence of osteoporosis in glioma patients on enzyme inducing anticonvulsants (EIAC) and/or glucocorticoids

Authors
Jones, L; Affronti, ML; Bohlin, CW; Herndon, JE; Quinn, JA; Reardon, DA; Rich, JN; Friedman, HS; Vredenburgh, JJ
MLA Citation
Jones, L., et al. “Prevalence of osteoporosis in glioma patients on enzyme inducing anticonvulsants (EIAC) and/or glucocorticoids.” Journal of Clinical Oncology, vol. 25, no. 18, AMER SOC CLINICAL ONCOLOGY, 2007.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
18
Publish Date
2007

Radiation and concurrent temozolomide followed by rotational multi-agent chemotherapy for glioblastoma (GBM) patients

Authors
Affronti, ML; Day, JM; Herndon, JE; Rich, JN; Quinn, JA; Reardon, DA; Vredenburgh, JJ; Desjardins, A; McLendon, RE; Friedman, HS
MLA Citation
Affronti, M. L., et al. “Radiation and concurrent temozolomide followed by rotational multi-agent chemotherapy for glioblastoma (GBM) patients.” Journal of Clinical Oncology, vol. 25, no. 18, AMER SOC CLINICAL ONCOLOGY, 2007.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
18
Publish Date
2007

Overall survival of primary glioblastoma (GBM) patients (pts) receiving carmustine (BCNU) wafers followed by radiation (RT) and concurrent temozolomide (TMZ) plus rotational multi-agent

Authors
Rich, JN; Affronti, ML; Day, JM; Herndon, JE; Quinn, JA; Reardon, DA; Vredenburgh, JJ; Desjardins, A; Friedman, HS
MLA Citation
Rich, J. N., et al. “Overall survival of primary glioblastoma (GBM) patients (pts) receiving carmustine (BCNU) wafers followed by radiation (RT) and concurrent temozolomide (TMZ) plus rotational multi-agent.” Journal of Clinical Oncology, vol. 25, no. 18, AMER SOC CLINICAL ONCOLOGY, 2007.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
18
Publish Date
2007

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) evaluation in glioblastoma (GBM) patients treated with bevacizumab (BEV) and irinotecan (CPT-11)

Authors
Desjardins, A; Barboriak, DP; Herndon, JE; Reardon, DA; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, A., et al. “Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) evaluation in glioblastoma (GBM) patients treated with bevacizumab (BEV) and irinotecan (CPT-11).” Journal of Clinical Oncology, vol. 25, no. 18, AMER SOC CLINICAL ONCOLOGY, 2007.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
18
Publish Date
2007

Phase II trial of Gliadel plus O-6-benzylguanic (O-6-BG) for patients with recurrent glioblastoma multiforme

Authors
Quinn, JA; Vredenburgh, JJ; Rich, JN; Reardon, DA; Desjardins, A; Gururangan, S; Friedman, AH; Carter, JH; Threatt, S; Friedman, HS
MLA Citation
Quinn, J. A., et al. “Phase II trial of Gliadel plus O-6-benzylguanic (O-6-BG) for patients with recurrent glioblastoma multiforme.” Journal of Clinical Oncology, vol. 25, no. 18, AMER SOC CLINICAL ONCOLOGY, 2007.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
18
Publish Date
2007

Phase I trial of imatinib mesylate, hydroxyurea and vatalanib for patients with recurrent glioblastoma multiforme (GBM)

Authors
Sathornsumetee, S; Rich, JN; Vredenburgh, JJ; Desjardins, A; Quinn, JA; Gururangan, S; Egorin, MJ; Salvado, AJ; Friedman, HS; Reardon, DA
MLA Citation
Sathornsumetee, S., et al. “Phase I trial of imatinib mesylate, hydroxyurea and vatalanib for patients with recurrent glioblastoma multiforme (GBM).” Journal of Clinical Oncology, vol. 25, no. 18, AMER SOC CLINICAL ONCOLOGY, 2007.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
18
Publish Date
2007

Phase II trial of imatinib mesylate and hydroxyurea for adults with recurrent/progressive low-grade glioma

Authors
Bota, DA; Desjardins, A; Quinn, JA; Rich, JN; Vredenburgh, JJ; Sathornsumetee, S; Goli, K; Salvado, A; Friedman, HS; Reardon, DA
MLA Citation
Bota, D. A., et al. “Phase II trial of imatinib mesylate and hydroxyurea for adults with recurrent/progressive low-grade glioma.” Journal of Clinical Oncology, vol. 25, no. 18, AMER SOC CLINICAL ONCOLOGY, 2007.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
18
Publish Date
2007

Phase I trial of VNP40101M in children with recurrent brain tumors-A Pediatric Brain Tumor Consortium (PBTC) study

Authors
Gururangan, S; Turner, C; Stewart, CF; Kocak, M; Poussaint, TY; Boyett, JM; Kun, LE; Karsten, V; Gerson, SL; Friedman, HS
MLA Citation
Gururangan, S., et al. “Phase I trial of VNP40101M in children with recurrent brain tumors-A Pediatric Brain Tumor Consortium (PBTC) study.” Journal of Clinical Oncology, vol. 25, no. 18, AMER SOC CLINICAL ONCOLOGY, 2007.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
18
Publish Date
2007

Pilot study of dronabinol for adult patients with primary malignant gliomas

Authors
Vredenburgh, JJ; Bohlin, CH; Reardon, DA; Desjardins, A; Quinn, JA; Rich, JN; Bota, DA; Goli, KJ; Friedman, HS; Allen, DH
MLA Citation
Vredenburgh, J. J., et al. “Pilot study of dronabinol for adult patients with primary malignant gliomas.” Journal of Clinical Oncology, vol. 25, no. 18, AMER SOC CLINICAL ONCOLOGY, 2007.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
18
Publish Date
2007

Phase II trial of bevacizumab and irinotecan in the treatment of malignant gliomas

Authors
Goli, KJ; Desjardins, A; Herndon, JE; Rich, JN; Reardon, DA; Quinn, JA; Sathornsumetee, S; Bota, DA; Friedman, HS; Vredenburgh, JJ
MLA Citation
Goli, K. J., et al. “Phase II trial of bevacizumab and irinotecan in the treatment of malignant gliomas.” Journal of Clinical Oncology, vol. 25, no. 18, AMER SOC CLINICAL ONCOLOGY, 2007.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
18
Publish Date
2007

Tinzaparin prophylaxis in brain tumor patients

Authors
Bohlin, CW; Reardon, DA; Desjardins, A; Quinn, JA; Rich, JN; Bota, DA; Goli, K; Friedman, HS; Vredenburgh, JJ
MLA Citation
Bohlin, C. W., et al. “Tinzaparin prophylaxis in brain tumor patients.” Journal of Clinical Oncology, vol. 25, no. 18, AMER SOC CLINICAL ONCOLOGY, 2007.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
25
Issue
18
Publish Date
2007

A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth.

Glioblastomas are highly lethal cancers that resist current therapies. Novel therapies under development target molecular mechanisms that promote glioblastoma growth. In glioblastoma patient specimens, the non-receptor tyrosine kinase focal adhesion kinase (FAK) is overexpressed. Upon growth factor receptor stimulation or integrin engagement, FAK is activated by phosphorylation on critical tyrosine residues. Activated FAK initiates a signal transduction cascade which promotes glioma growth and invasion by increasing cellular adhesion, migration, invasion, and proliferation. We find that human glioma cell lines express different levels of total FAK protein and activating phosphorylation of tyrosine residues Tyr397, Tyr861, and Tyr925. As all glioma cell lines examined expressed phosphorylated FAK, we examined the efficacy of a novel low-molecular weight inhibitor of FAK, TAE226, against human glioma cell lines. TAE226 inhibited the phosphorylation of FAK as well as the downstream effectors AKT, extracellular signal-related kinase, and S6 ribosomal protein in multiple glioma cell lines. TAE226 induced a concentration-dependent decrease in cellular proliferation with an associated G(2) cell cycle arrest in every cell line and an increase in apoptosis in a cell-line-specific manner. TAE226 also decreased glioma cell adhesion, migration, and invasion through an artificial extracellular matrix. Together, these data demonstrate the potential benefit of TAE226 for glioma therapy.

Authors
Shi, Q; Hjelmeland, AB; Keir, ST; Song, L; Wickman, S; Jackson, D; Ohmori, O; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Shi, Qing, et al. “A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth..” Mol Carcinog, vol. 46, no. 6, June 2007, pp. 488–96. Pubmed, doi:10.1002/mc.20297.
PMID
17219439
Source
pubmed
Published In
Molecular Carcinogenesis
Volume
46
Issue
6
Publish Date
2007
Start Page
488
End Page
496
DOI
10.1002/mc.20297

Tumor resection cavity administered iodine-131-labeled antitenascin 81C6 radioimmunotherapy in patients with malignant glioma: neuropathology aspects.

INTRODUCTION: The neurohistological findings in patients treated with targeted beta emitters such as (131)I are poorly described. We report a histopathologic analysis from patients treated with combined external beam therapy and a brachytherapy consisting of a (131)I-labeled monoclonal antibody (mAb) injected into surgically created resection cavities during brain tumor resections. METHODS: Directed tissue samples of the cavity walls were obtained because of suspected tumor recurrence from 28 patients. Samples and clinical follow-up were evaluated on all patients (Group A) based on total radiation dose received and a subset of these (n=18; Group B, proximal therapy subset) who had received external beam therapy within

Authors
McLendon, RE; Akabani, G; Friedman, HS; Reardon, DA; Cleveland, L; Cokgor, I; Herndon, JE; Wikstrand, C; Boulton, ST; Friedman, AH; Bigner, DD; Zalutsky, MR
MLA Citation
McLendon, Roger E., et al. “Tumor resection cavity administered iodine-131-labeled antitenascin 81C6 radioimmunotherapy in patients with malignant glioma: neuropathology aspects..” Nucl Med Biol, vol. 34, no. 4, May 2007, pp. 405–13. Pubmed, doi:10.1016/j.nucmedbio.2007.01.009.
PMID
17499730
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
34
Issue
4
Publish Date
2007
Start Page
405
End Page
413
DOI
10.1016/j.nucmedbio.2007.01.009

Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents.

Five different human melanoma xenografts were used in a xenograft model of extremity melanoma to evaluate the variability of tumor response to regionally administered melphalan or temozolomide and to determine if various components of pertinent drug resistance pathways for melphalan [glutathione S-transferase (GST)/glutathione] and temozolomide [O(6)-alkylguanine DNA alkyltranferase (AGT)/mismatch repair (MMR)] could be predictive of tumor response. Xenograft-bearing rats underwent regional isolated limb infusion with either melphalan (90 mg/kg) or temozolomide (2,000 mg/kg). The levels of AGT activity, GST activity, glutathione level, and GST/AGT expression were examined in this group of xenografts and found to be quite heterogeneous. No correlation was identified between melphalan sensitivity and the GST/glutathione cellular detoxification pathway. In contrast, a strong correlation between the levels of AGT activity and percentage increase in tumor volume on day 30 (r = 0.88) was noted for tumors treated with temozolomide. Regional therapy with temozolomide was more effective when compared with melphalan for the xenograft with the lowest AGT activity, whereas melphalan was more effective than temozolomide in another xenograft that had the highest AGT activity. In three other xenografts, there was no significant difference in response between the two chemotherapy agents. This study shows that AGT activity may be useful in predicting the utility of temozolomide-based regional therapy for advanced extremity melanoma tumors. Our observations also point out the limited ability of analysis of the GST/glutathione pathway to predict response to chemotherapies like melphalan whose resistance is primarily mediated through a complex mechanism of detoxification.

Authors
Yoshimoto, Y; Augustine, CK; Yoo, JS; Zipfel, PA; Selim, MA; Pruitt, SK; Friedman, HS; Ali-Osman, F; Tyler, DS
MLA Citation
Yoshimoto, Yasunori, et al. “Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents..” Mol Cancer Ther, vol. 6, no. 5, May 2007, pp. 1492–500. Pubmed, doi:10.1158/1535-7163.MCT-06-0718.
PMID
17483437
Source
pubmed
Published In
Molecular Cancer Therapeutics
Volume
6
Issue
5
Publish Date
2007
Start Page
1492
End Page
1500
DOI
10.1158/1535-7163.MCT-06-0718

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas.

PURPOSE: Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG). PATIENTS AND METHOD: Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate. RESULTS: Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1-7) and the median number of prior treatment regimens was 3 (range, 1-8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses. CONCLUSION: Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG.

Authors
Desjardins, A; Quinn, JA; Vredenburgh, JJ; Sathornsumetee, S; Friedman, AH; Herndon, JE; McLendon, RE; Provenzale, JM; Rich, JN; Sampson, JH; Gururangan, S; Dowell, JM; Salvado, A; Friedman, HS; Reardon, DA
MLA Citation
Desjardins, Annick, et al. “Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas..” J Neurooncol, vol. 83, no. 1, May 2007, pp. 53–60. Pubmed, doi:10.1007/s11060-006-9302-2.
PMID
17245623
Source
pubmed
Published In
Journal of Neuro Oncology
Volume
83
Issue
1
Publish Date
2007
Start Page
53
End Page
60
DOI
10.1007/s11060-006-9302-2

Pilot phase II study of metrenomic oral cyclophosphamide plus thalidomide in children with recurrent malignant brain tumors

Authors
Gururangan, S; Provenzale, J; Friedman, HS
MLA Citation
Gururangan, S., et al. “Pilot phase II study of metrenomic oral cyclophosphamide plus thalidomide in children with recurrent malignant brain tumors.” Neuro Oncology, vol. 9, no. 2, DUKE UNIV PRESS, 2007, pp. 203–203.
Source
wos
Published In
Neuro Oncology
Volume
9
Issue
2
Publish Date
2007
Start Page
203
End Page
203

Phase I trial of oral temozolomide and intravenous O-6-benzylguanine (O-6-BG), a methylguanine methyltransferase inhibitor, in pediatric patients with recurrent brain tumors

Authors
Broniscer, A; Gururangan, S; Goldman, S; MacDonald, T; Wallace, D; Stewart, CF; Jakacki, R; Kieran, MW; Chintagumpala, M; Banerjee, A; Geyer, JR; Phillips, P; Friedman, HS; Gajjar, A
MLA Citation
Broniscer, A., et al. “Phase I trial of oral temozolomide and intravenous O-6-benzylguanine (O-6-BG), a methylguanine methyltransferase inhibitor, in pediatric patients with recurrent brain tumors.” Neuro Oncology, vol. 9, no. 2, DUKE UNIV PRESS, 2007, pp. 189–189.
Source
wos
Published In
Neuro Oncology
Volume
9
Issue
2
Publish Date
2007
Start Page
189
End Page
189

Temozolomide in children with progressive low-grade glioma.

We conducted a phase II study to assess the efficacy of oral temozolomide (TMZ) in children with progressive low-grade glioma. Thirty eligible patients were enrolled on this study. Median age at enrollment was 10 years (range, 4-18 years). Eligible patients received TMZ (200 mg/m(2) per day) by mouth for five days every four weeks. Patients received a median of nine cycles (range, 2-12 cycles) of treatment. Best responses in the 26 patients (86%) with optic pathway glioma (OPG)/pilocytic astrocytoma (PA) included partial response in 3 patients (11%), minor response in 1 (4%), stable disease in 10 (38%), and progressive disease in 12 (46%). Only one of four patients with fibrillary astrocytoma had stable disease for 29 months after TMZ. The overall disease stabilization rate in patients with OPG/PA was 54%, and disease control was maintained for a median interval of 34 months. Seventeen of 26 patients had progressive disease either on or off therapy, and three have died of disease. The two-year progression-free and overall survivals in patients with OPG/PA were 49% (95% CI, 30%-67%) and 96% (95% CI, 89%-100%), respectively. Worst toxicity related to TMZ in all 30 patients included grade 2-4 thrombocytopenia in seven patients, grade 2-4 neutropenia in seven, grade 2 skin rash in one, and intratumor hemorrhage in one. TMZ given in this schedule was successful in stabilizing disease in a significant proportion of the patients with OPG/PA, with manageable toxicity.

Authors
Gururangan, S; Fisher, MJ; Allen, JC; Herndon, JE; Quinn, JA; Reardon, DA; Vredenburgh, JJ; Desjardins, A; Phillips, PC; Watral, MA; Krauser, JM; Friedman, AH; Friedman, HS
MLA Citation
Gururangan, Sridharan, et al. “Temozolomide in children with progressive low-grade glioma..” Neuro Oncol, vol. 9, no. 2, Apr. 2007, pp. 161–68. Pubmed, doi:10.1215/15228517-2006-030.
PMID
17347491
Source
pubmed
Published In
Neuro Oncology
Volume
9
Issue
2
Publish Date
2007
Start Page
161
End Page
168
DOI
10.1215/15228517-2006-030

Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report.

This study estimated the maximum tolerated dose (MTD) of imatinib with irradiation in children with newly diagnosed brainstem gliomas, and those with recurrent malignant intracranial gliomas, stratified according to use of enzyme-inducing anticonvulsant drugs (EIACDs). In the brainstem glioma stratum, imatinib was initially administered twice daily during irradiation, but because of possible association with intratumoral hemorrhage (ITH) was subsequently started two weeks after irradiation. The protocol was also amended to exclude children with prior hemorrhage. Twenty-four evaluable patients received therapy before the amendment, and three of six with a brainstem tumor experienced dose-limiting toxicity (DLT): one had asymptomatic ITH, one had grade 4 neutropenia and, one had renal insufficiency. None of 18 patients with recurrent glioma experienced DLT. After protocol amendment, 3 of 16 patients with brainstem glioma and 2 of 11 patients with recurrent glioma who were not receiving EIACDs experienced ITH DLTs, with three patients being symptomatic. In addition to the six patients with hemorrhages during the DLT monitoring period, 10 experienced ITH (eight patients were symptomatic) thereafter. The recommended phase II dose for brainstem gliomas was 265 mg/m(2). Three of 27 patients with brainstem gliomas with imaging before and after irradiation, prior to receiving imatinib, had new hemorrhage, excluding their receiving imatinib. The MTD for recurrent high-grade gliomas without EIACDs was 465 mg/m(2), but the MTD was not established with EIACDs, with no DLTs at 800 mg/m(2). In summary, recommended phase II imatinib doses were determined for children with newly diagnosed brainstem glioma and recurrent high-grade glioma who were not receiving EIACDs. Imatinib may increase the risk of ITH, although the incidence of spontaneous hemorrhages in brainstem glioma is sufficiently high that this should be considered in studies of agents in which hemorrhage is a concern.

Authors
Pollack, IF; Jakacki, RI; Blaney, SM; Hancock, ML; Kieran, MW; Phillips, P; Kun, LE; Friedman, H; Packer, R; Banerjee, A; Geyer, JR; Goldman, S; Poussaint, TY; Krasin, MJ; Wang, Y; Hayes, M; Murgo, A; Weiner, S; Boyett, JM
MLA Citation
Pollack, Ian F., et al. “Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report..” Neuro Oncol, vol. 9, no. 2, Apr. 2007, pp. 145–60. Pubmed, doi:10.1215/15228517-2006-031.
PMID
17293590
Source
pubmed
Published In
Neuro Oncology
Volume
9
Issue
2
Publish Date
2007
Start Page
145
End Page
160
DOI
10.1215/15228517-2006-031

Using the theory of planned behavior to understand the determinants of exercise intention in patients diagnosed with primary brain cancer.

The purpose of the present study was to examine the demographic, medical, and social cognitive determinants of exercise intentions in a institution-based cohort of primary brain tumor patients. Using a cross-sectional survey, 100 primary brain tumor patients completed a mailed survey that assessed medical and demographic characteristics, past exercise behavior using the Godin Leisure Time Exercise Questionnaire (GLTEQ), and social cognitive beliefs towards exercise using Aizen's theory of planned behavior (TPB; i.e. intention, perceived behavioral control, subjective norm, affective and instrumental attitude). Descriptive statistics indicated that participants had positive social cognitive beliefs towards exercise. In support of the tenets of the TPB, we found moderate to large (>0.40) positive correlations between the majority of TPB constructs. Moreover, the TPB constructs combined to explain 32% of the variance in exercise intentions with affective attitude (beta = 0.24; p = 0.020) and perceived behavioral control (beta = 0.36; p<0.001) being the most important determinants. Except past exercise behavior, medical and demographic variables were not consistently correlated with any TPB constructs. Finally, participant's gender and body mass index influenced the association between instrumental attitude and exercise intention with male and overweight/obese patients (> or =25 kg/m(2)) considering the health benefits of exercise to be more important than their female and normal weight (<25 kg/m(2)) counterparts. Information gained from this study suggests that the TPB is a useful framework to design and implement theoretically based interventions to promote exercise in primary brain cancer patients.

Authors
Jones, LW; Guill, B; Keir, ST; Carter, K; Friedman, HS; Bigner, DD; Reardon, DA
MLA Citation
Jones, Lee W., et al. “Using the theory of planned behavior to understand the determinants of exercise intention in patients diagnosed with primary brain cancer..” Psychooncology, vol. 16, no. 3, Mar. 2007, pp. 232–40. Pubmed, doi:10.1002/pon.1077.
PMID
16929468
Source
pubmed
Published In
Psycho Oncology
Volume
16
Issue
3
Publish Date
2007
Start Page
232
End Page
240
DOI
10.1002/pon.1077

Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma.

PURPOSE: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available salvage therapy. This study was conducted to determine if the combination of a novel antiangiogenic therapy, bevacizumab, and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma. EXPERIMENTAL DESIGN: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma. Patients with evidence of intracranial hemorrhage on initial brain magnetic resonance imaging were excluded. Patients were scheduled to receive bevacizumab and irinotecan i.v. every 2 weeks of a 6-week cycle. Bevacizumab was administered at 10 mg/kg. The dose of irinotecan was determined based on antiepileptic use: patients taking enzyme-inducing antiepileptic drugs received 340 mg/m(2), whereas patients not taking enzyme-inducing antiepileptic drugs received 125 mg/m(2). Toxicity and response were assessed. RESULTS: Thirty-two patients were assessed (23 with grade IV glioma and 9 with grade III glioma). Radiographic responses were noted in 63% (20 of 32) of patients (14 of 23 grade IV patients and 6 of 9 grade III patients). The median progression-free survival was 23 weeks for all patients (95% confidence interval, 15-30 weeks; 20 weeks for grade IV patients and 30 weeks for grade III patients). The 6-month progression-free survival probability was 38% and the 6-month overall survival probability was 72%. No central nervous system hemorrhages occurred, but three patients developed deep venous thromboses or pulmonary emboli, and one patient had an arterial ischemic stroke. CONCLUSIONS: The combination of bevacizumab and irinotecan is an active regimen for recurrent grade III-IV glioma with acceptable toxicity.

Authors
Vredenburgh, JJ; Desjardins, A; Herndon, JE; Dowell, JM; Reardon, DA; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Wagner, M; Bigner, DD; Friedman, AH; Friedman, HS
MLA Citation
Vredenburgh, James J., et al. “Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma..” Clin Cancer Res, vol. 13, no. 4, Feb. 2007, pp. 1253–59. Pubmed, doi:10.1158/1078-0432.CCR-06-2309.
PMID
17317837
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
13
Issue
4
Publish Date
2007
Start Page
1253
End Page
1259
DOI
10.1158/1078-0432.CCR-06-2309

Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: descriptive effects of target anatomy and catheter positioning.

OBJECTIVE: Convection-enhanced delivery (CED) holds tremendous potential for drug delivery to the brain. However, little is known about the volume of distribution achieved within human brain tissue or how target anatomy and catheter positioning influence drug distribution. The primary objective of this study was to quantitatively describe the distribution of a high molecular weight agent by CED relative to target anatomy and catheter position in patients with malignant gliomas. METHODS: Seven adult patients with recurrent malignant gliomas underwent intracerebral infusion of the tumor-targeted cytotoxin, cintredekin besudotox, concurrently with 123I-labeled human serum albumin. High-resolution single-photon emission computed tomographic images were obtained at 24 and 48 hours and were coregistered with magnetic resonance imaging scans. The distribution of 123I-labeled human serum albumin relative to target anatomy and catheter position was analyzed. RESULTS: Intracerebral CED infusions were well-tolerated and some resulted in a broad distribution of 123I-labeled human serum albumin, but target anatomy and catheter positioning had a significant influence on infusate distribution even within non-contrast-enhancing areas of brain. Intratumoral infusions were anisotropic and resulted in limited coverage of the enhancing tumor area and adjacent peritumoral regions. CONCLUSIONS: CED has the potential to deliver high molecular weight agents into tumor-infiltrated brain parenchyma with volumes of distribution that are clinically relevant. Target tissue anatomy and catheter position are critical parameters in optimizing drug delivery.

Authors
Sampson, JH; Brady, ML; Petry, NA; Croteau, D; Friedman, AH; Friedman, HS; Wong, T; Bigner, DD; Pastan, I; Puri, RK; Pedain, C
MLA Citation
Sampson, John H., et al. “Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: descriptive effects of target anatomy and catheter positioning..” Neurosurgery, vol. 60, no. 2 Suppl 1, Feb. 2007, pp. ONS89–98. Pubmed, doi:10.1227/01.NEU.0000249256.09289.5F.
PMID
17297371
Source
pubmed
Published In
Neurosurgery
Volume
60
Issue
2 Suppl 1
Publish Date
2007
Start Page
ONS89
End Page
ONS98
DOI
10.1227/01.NEU.0000249256.09289.5F

Phase II study of Cloretazine for the treatment of adults with recurrent glioblastoma multiforme.

Cloretazine (VNP40101M) is a newly synthesized alkylating agent belonging to a novel class of alkylating agents called 1,2-bis(sulfonyl)hydrazines. Agents that belong to this class do not produce vinylating and chloroethylating species, and hence this class of alkylating agents is thought to have minimal systemic toxicity. Cloretazine produces two short-lived active species: 1,2-bis(methylsulfonyl)-1-(2-chloroethyl) hydrazine (a chloroethylating species) and a thiophilic carbamoylating methylisocyanate species. The chloroethylating species preferentially produces lesions at the O(6) position of guanine. The methylisocyanate species may inhibit O(6)-alkylguanine-DNA alkyltransferase, an important mechanism of resistance against alkylating agents. The purpose of this study was to determine the efficacy and tolerability of Cloretazine in patients with recurrent glioblastoma multiforme. The basis for the determination of efficacy was the proportion of patients alive without evidence of disease progression six months after initiation of treatment. Patients with recurrent glioblastoma multiforme received Cloretazine (300 mg/m(2)) intravenously every six weeks. Radiographic response, survival data, and toxicity were assessed. Thirty-two patients were enrolled. Median age was 56 years; 24 patients (75%) were men. At six months, two patients were alive and progression free, so the six-month progression-free survival (PFS) was 6%. The median PFS was 6.3 weeks. There were no objective radiographic responses. Twelve patients had stable disease for at least one cycle, but only two patients received more than three cycles. Nine patients experienced grade 4 thrombocytopenia and three patients experienced grade 4 neutropenia. Cloretazine administered every six weeks was relatively well tolerated, although this schedule has insignificant activity for patients with recurrent glioblastoma multiforme.

Authors
Badruddoja, MA; Penne, K; Desjardins, A; Reardon, DA; Rich, JN; Quinn, JA; Sathornsumetee, S; Friedman, AH; Bigner, DD; Herndon, JE; Cahill, A; Friedman, HS; Vredenburgh, JJ
MLA Citation
Badruddoja, Michael A., et al. “Phase II study of Cloretazine for the treatment of adults with recurrent glioblastoma multiforme..” Neuro Oncol, vol. 9, no. 1, Jan. 2007, pp. 70–74. Pubmed, doi:10.1215/15228517-2006-022.
PMID
17108065
Source
pubmed
Published In
Neuro Oncology
Volume
9
Issue
1
Publish Date
2007
Start Page
70
End Page
74
DOI
10.1215/15228517-2006-022

Exercise interest and preferences among patients diagnosed with primary brain cancer.

GOALS OF THE WORK: The purpose of the present investigation was to examine the interest and exercise preferences of an institution-based sample of brain tumor patients. Secondary aims were to examine potential differences in participant's interest and preferences by exercise behavior and select demographic/medical variables. MATERIALS AND METHODS: Using a cross-sectional design, 106 brain tumor patients (age range, 32 to 83 years) who received treatment at the Preston Robert Tisch Brain Tumor Center (BTC) at Duke completed a questionnaire that assessed self-reported exercise behavior, exercise interest and preferences during active and off-treatment periods. MAIN RESULTS: For exercise program preferences, participants were significantly more interested and felt more capable of participating in an exercise program following compared to during adjuvant therapy. Approximately equal proportions of brain tumor patients preferred to exercise at home with their spouse or other family members. These preferences were consistent across both cancer treatment-related time periods. For exercise information preferences, a higher proportion of respondents preferred receiving information via technologically based approaches (i.e., Internet, CD-ROM, and mailed correspondence) compared with more traditional methods (i.e., mail or face-to-face counseling). Chi-square analyses revealed that a small number of exercise program and information preferences were modified by exercise, medical, and demographic variables. CONCLUSIONS: Brain tumor patients may have unique and varied preferences compared with other cancer populations. Incorporating patient's preferences into rehabilitation programs and clinical exercise investigations may optimize the potential benefits of this modality for patients with neurologic malignancies.

Authors
Jones, LW; Guill, B; Keir, ST; Carter, K; Friedman, HS; Bigner, DD; Reardon, DA
MLA Citation
Jones, Lee W., et al. “Exercise interest and preferences among patients diagnosed with primary brain cancer..” Support Care Cancer, vol. 15, no. 1, Jan. 2007, pp. 47–55. Pubmed, doi:10.1007/s00520-006-0096-8.
PMID
16819629
Source
pubmed
Published In
Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer
Volume
15
Issue
1
Publish Date
2007
Start Page
47
End Page
55
DOI
10.1007/s00520-006-0096-8

Stress and intervention preferences of patients with brain tumors.

BACKGROUND: Despite advances in diagnosis, treatment, and management of brain tumors, a brain tumor (BT) can significantly disrupt a person's life and create stress. To design effective stress reduction interventions, it is essential to have an understanding of the beliefs, past experiences, and preferences concerning stress reduction techniques and programs among patients with BTs. MATERIALS AND METHODS: Using a convenience sample, 60 adult patients with primary BTs completed the study questionnaire. Demographic information and patient preferences were collected using self-reported measures, medical information was collected via medical chart review, and stress was assessed using Perceived Stress Scale. RESULTS: Sixty-three percent of the population sampled experienced elevated levels of stress. Eighty-six percent wanted to learn about techniques to reduce stress and 78% believed stress reduction techniques can help reduce stress. However, only 56% indicated they would be able to participate in a stress reduction program twice a week and only 40% of the sample wanted to participate in the various stress reduction programs presented to them in this study. Furthermore, only 26% of the sample actually wanted to receive information about stress reduction programs and only 25% would participate in programs using the various modes presented. CONCLUSION: The results of this study clearly indicate that patients with BTs experience stress. Furthermore, the data is encouraging in regard to the patients' desire to learn about stress reduction techniques. However, the lack of interest in actually receiving information and the inability to envision themselves participating in programs present a major challenge.

Authors
Keir, ST; Guill, AB; Carter, KE; Friedman, HS
MLA Citation
Keir, Stephen T., et al. “Stress and intervention preferences of patients with brain tumors..” Support Care Cancer, vol. 14, no. 12, Dec. 2006, pp. 1213–19. Pubmed, doi:10.1007/s00520-006-0087-9.
PMID
16733656
Source
pubmed
Published In
Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer
Volume
14
Issue
12
Publish Date
2006
Start Page
1213
End Page
1219
DOI
10.1007/s00520-006-0087-9

Differential levels of stress in caregivers of brain tumor patients--observations from a pilot study.

OBJECTIVE: Caregivers of patients with brain tumors (BT) experience elevated levels of stress. Using pilot data, we sought to determine which caregivers are at risk for experiencing elevated levels of stress based on caregiver-demographic and patient-medical information. METHODS: Using a convenience sample of 60 caregivers, participants were asked to complete the Perceived Stress Scale and to provide demographic information. The Perceived Stress Scale is a 10-item scale designed to measure the degree to which situations in life are perceived as stressful. Demographic information was collected using self-reported measures. Medical data concerning tumor grade of patient were obtained from most recent medical note. Data for study were standardized using z-scores and analyzed using SPSS software. RESULTS: Seventy-two percent (n=43) of caregivers reported experiencing elevated levels of stress within the last 30 days. Thirty-five percent (n=21) of the sample scored at least one standard deviation above the mean. A statistical trend [F(1, 57)=3.12, p=0.08] exists between caregiver stress and tumor grade of patients for which they are providing care. CONCLUSIONS: Caregivers of patients with BT experience significant stress. Furthermore, this data provide an indication of the profound levels of stress these caregivers experience. Caregivers of patients with grade I/II tumors are at increased risk for experiencing stress. Younger caregiver age and higher levels of education were also found to correlate to higher levels of stress.

Authors
Keir, ST; Guill, AB; Carter, KE; Boole, LC; Gonzales, L; Friedman, HS
MLA Citation
Keir, Stephen T., et al. “Differential levels of stress in caregivers of brain tumor patients--observations from a pilot study..” Support Care Cancer, vol. 14, no. 12, Dec. 2006, pp. 1258–61. Pubmed, doi:10.1007/s00520-006-0090-1.
PMID
16775683
Source
pubmed
Published In
Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer
Volume
14
Issue
12
Publish Date
2006
Start Page
1258
End Page
1261
DOI
10.1007/s00520-006-0090-1

322 POSTER Pediatric Preclinical Testing Program (PPTP) evaluation of the Src-Abl inhibitor dasatinib (BMS-354825)

Authors
Smith, MA; Maris, JM; Keir, ST; Friedman, HS; Lock, RB; Kolb, EA; Keshelava, N; Reynolds, CP; Morton, C; Houghton, PJ
MLA Citation
Smith, M. A., et al. “322 POSTER Pediatric Preclinical Testing Program (PPTP) evaluation of the Src-Abl inhibitor dasatinib (BMS-354825).” European Journal of Cancer Supplements, vol. 4, no. 12, Elsevier BV, Nov. 2006, pp. 101–101. Crossref, doi:10.1016/s1359-6349(06)70327-5.
Source
crossref
Published In
European Journal of Cancer Supplements
Volume
4
Issue
12
Publish Date
2006
Start Page
101
End Page
101
DOI
10.1016/s1359-6349(06)70327-5

313 POSTER Pediatric preclinical testing program (PPTP) evaluation of the KSP inhibitor Ispinesib (SB-715992)

Authors
Houghton, PJ; Maris, JM; Friedman, HS; Keir, ST; Lock, RB; Gorlick, R; Kolb, EA; Reynolds, CP; Morton, C; Smith, MA
MLA Citation
Houghton, P. J., et al. “313 POSTER Pediatric preclinical testing program (PPTP) evaluation of the KSP inhibitor Ispinesib (SB-715992).” European Journal of Cancer Supplements, vol. 4, no. 12, Elsevier BV, Nov. 2006, pp. 98–98. Crossref, doi:10.1016/s1359-6349(06)70318-4.
Source
crossref
Published In
European Journal of Cancer Supplements
Volume
4
Issue
12
Publish Date
2006
Start Page
98
End Page
98
DOI
10.1016/s1359-6349(06)70318-4

Neurocognitive deficits according to hemisphere and diagnosis among patients with high-grade CNS tumors

Authors
Brigidi, BD; Raynor, RH; Friedman, HS
MLA Citation
Brigidi, Bart D., et al. “Neurocognitive deficits according to hemisphere and diagnosis among patients with high-grade CNS tumors.” Neuro Oncology, vol. 8, no. 4, DUKE UNIV PRESS, 2006, pp. 476–77.
Source
wos
Published In
Neuro Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
476
End Page
477

Development of the duke cancer cognitions inventory-brain tumor version (DCCI-BT)

Authors
Brigidi, BD; Raynor, RH; Bonner, M; Schweitzer, H; Carter, K; Guill, B; Friedman, HS
MLA Citation
Brigidi, Bart D., et al. “Development of the duke cancer cognitions inventory-brain tumor version (DCCI-BT).” Neuro Oncology, vol. 8, no. 4, DUKE UNIV PRESS, 2006, pp. 476–476.
Source
wos
Published In
Neuro Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
476
End Page
476

AAL881, a novel small molecule inhibitor of RAF and VEGFR activities, blocks growth of malignant glioma

Authors
Sathornsumetee, S; Hjelmeland, AB; Keir, ST; McLendon, RE; Batt, D; Ramsey, T; Yusuff, N; Ahmed Rasheed, BK; Kieran, MW; Laforme, A; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Sathornsumetee, Sith, et al. “AAL881, a novel small molecule inhibitor of RAF and VEGFR activities, blocks growth of malignant glioma.” Neuro Oncology, vol. 8, no. 4, DUKE UNIV PRESS, 2006, pp. 417–417.
Source
wos
Published In
Neuro Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
417
End Page
417

The combination of novel low-molecular-weight inhibitors of Raf (LBT 613) and TOR (RAD001, everolimus) decreases glioma proliferation and invasion

Authors
Hjelmeland, AB; Lattimore, K; Fee, B; Wickman, S; Keir, ST; Hjelmeland, MD; Batt, D; Lane, H; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Hjelmeland, Anita B., et al. “The combination of novel low-molecular-weight inhibitors of Raf (LBT 613) and TOR (RAD001, everolimus) decreases glioma proliferation and invasion.” Neuro Oncology, vol. 8, no. 4, DUKE UNIV PRESS, 2006, pp. 412–412.
Source
wos
Published In
Neuro Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
412
End Page
412

A novel low-molecular-weight inhibitor of focal adhesion kinase, inhibits glioma growth

Authors
Shi, Q; Hjelmeland, AB; Keir, ST; Wickman, SK; Wu, G; Jackson, D; Ohmori, O; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Shi, Qing, et al. “A novel low-molecular-weight inhibitor of focal adhesion kinase, inhibits glioma growth.” Neuro Oncology, vol. 8, no. 4, DUKE UNIV PRESS, 2006, pp. 417–417.
Source
wos
Published In
Neuro Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
417
End Page
417

Phase I trial of Temodar plus O-6-benzylguanine 5-day regimen for patients with progressive glioblastoma multiforme

Authors
Quinn, JA; Desjardins, A; Rich, JN; Vredenburgh, JJ; Reardon, DA; Gururangan, S; Sathornsumetee, S; Walker, A; Lavin, KN; Birch, R; Friedman, AH; Friedman, HS
MLA Citation
Quinn, J. A., et al. “Phase I trial of Temodar plus O-6-benzylguanine 5-day regimen for patients with progressive glioblastoma multiforme.” Neuro Oncology, vol. 8, no. 4, DUKE UNIV PRESS, 2006, pp. 450–450.
Source
wos
Published In
Neuro Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
450
End Page
450

Phase I trial of temozolomide plus dose-escalating imatinib mesylate for patients with malignant glioma

Authors
Sathornsumetee, S; Rich, JN; Vredenburgh, JJ; Desjardins, A; Quinn, JA; Gururangan, S; Friedman, AH; Egorin, MJ; Salvado, A; Friedman, HS; Reardon, DA
MLA Citation
Sathornsumetee, Sith, et al. “Phase I trial of temozolomide plus dose-escalating imatinib mesylate for patients with malignant glioma.” Neuro Oncology, vol. 8, no. 4, DUKE UNIV PRESS, 2006, pp. 451–451.
Source
wos
Published In
Neuro Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
451
End Page
451

A phase I trial of imatinib (GLEEVEC), hydroxyurea and RAD001 for patients with recurrent malignant glioma

Authors
Desjardins, A; Quinn, JA; Rich, JN; Vredenburgh, JJ; Sathornsumetee, S; Gururangan, S; Friedman, AH; Berg, W; Egorin, MJ; Salvado, A; Friedman, HS; Reardon, DA
MLA Citation
Desjardins, A., et al. “A phase I trial of imatinib (GLEEVEC), hydroxyurea and RAD001 for patients with recurrent malignant glioma.” Neuro Oncology, vol. 8, no. 4, DUKE UNIV PRESS, 2006, pp. 441–441.
Source
wos
Published In
Neuro Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
441
End Page
441

Overall survival of primary glioblastoma (GBM) patients receiving radiation and concurrent temozolomide followed by rotational multi-agent chemotherapy

Authors
Affronti, ML; Dowell, JM; Herndon, JE; Cahill, J; Rich, JN; Quinn, JA; Reardon, DA; Vredenburgh, JJ; Desjardins, A; Gururangan, S; Friedman, HS
MLA Citation
Affronti, Mary Lou, et al. “Overall survival of primary glioblastoma (GBM) patients receiving radiation and concurrent temozolomide followed by rotational multi-agent chemotherapy.” Neuro Oncology, vol. 8, no. 4, DUKE UNIV PRESS, 2006, pp. 437–437.
Source
wos
Published In
Neuro Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
437
End Page
437

Treatment of neoplastic meningitis with intrathecal 9-nitro-camptothecin.

The topoisomerase I inhibitor, 9-nitro-camptothecin (9NC), is highly tumoricidal against glioblastoma multiforme (GBM) in vitro. However, systemic administration of 9NC has not shown the expected efficacy in clinical trials. This failure may be due to the rapid hydrolysis of 9NC in plasma from the active form to the inactive and myelosuppressive form in the presence of human albumin at physiologic pH. Concurrent treatment with anticonvulsants and dexamethasone, drugs indispensable for the supportive therapy of patients with GBM, has also been shown to decrease plasma concentrations of these drugs. Intrathecal drug delivery circumvents the blood-brain barrier and minimizes systemic toxicity. Intrathecal delivery of 9NC may also have the more specific advantage of significantly reducing the hydrolysis of 9NC that occurs after systemic delivery due to the more favorable pH and reduced albumin content in cerebrospinal fluid. The present study evaluated the toxicity and efficacy of intrathecal delivery of 9NC in an athymic rat model of neoplastic meningitis. Toxicity tests showed that 0.3 micromol (5000 microM), 0.03 micromol (500 microM), 0.003 micromol (50 microM), or 0.0003 micromol (5 microM) of 9NC administered intrathecally to the athymic rats caused no evidence of clinical or histological toxicity. Intrathecal administration of 0.3 micromol (5000 microM) of 9NC twice a week for three doses to athymic rats with neoplastic meningitis induced by the GBM cell line, U87MGDeltaEGFR, resulted in a 26% increase of median survival compared to the control group (p < 0.005). These results suggest that intrathecal treatment with 9NC may be useful for patients with GBM neoplastic meningitis.

Authors
Ochiai, H; Pernell, CT; Archer, GE; Chewning, TA; McLendon, RE; Friedman, HS; Sampson, JH
MLA Citation
Ochiai, Hidenobu, et al. “Treatment of neoplastic meningitis with intrathecal 9-nitro-camptothecin..” Neurol Med Chir (Tokyo), vol. 46, no. 10, Oct. 2006, pp. 485–89. Pubmed, doi:10.2176/nmc.46.485.
PMID
17062987
Source
pubmed
Published In
Neurologia Medico Chirurgica
Volume
46
Issue
10
Publish Date
2006
Start Page
485
End Page
489
DOI
10.2176/nmc.46.485

Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma.

Promoter hypermethylation of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) has been associated with an enhanced response to chloroethylating and methylating agents in patients with malignant glioma. The purpose of this study was to compare three distinct yet related indices for measuring AGT to determine if these assays could be used interchangeably when AGT status is to be used to guide chemotherapeutic decisions. Real-time methylation-specific PCR (MSP), assessed as the ratio of methylated AGT copies to internal beta-actin control, was used to quantitate AGT hypermethylation in 32 glioma samples. Data were compared with AGT enzyme activity as well as immunohistochemical detection of AGT protein from the same samples. Hypermethylation of the AGT promoter was detected in 19 of 31 (61%) samples evaluable by MSP. Low-level AGT, defined as <20% nuclear AGT staining by immunohistochemistry, was found in 10 of 32 samples (31%), whereas 12 of 32 (38%) had low levels of AGT activity. Correlation of immunohistochemistry to AGT activity was statistically significant (P = 0.014) as was the correlation of immunohistochemistry to MSP (P = 0.043), whereas MSP compared with AGT activity (P = 0.246) was not significant. Cross-tabulation of immunohistochemistry and MSP data based on prognostic groups, where good prognosis was represented by an immunohistochemistry of <20% and an MSP ratio >12, showed no significant relationship (P = 0.214), suggesting that one assay cannot be used interchangeably for another. The observed discordance between respective measures of AGT based on prognosis supports further standardization of AGT assays designed to guide therapeutic practice. The data also suggest that consideration be given to the large population of AGT-expressing cells within samples when therapeutic strategies based on tumor methylation are used.

Authors
Maxwell, JA; Johnson, SP; Quinn, JA; McLendon, RE; Ali-Osman, F; Friedman, AH; Herndon, JE; Bierau, K; Bigley, J; Bigner, DD; Friedman, HS
MLA Citation
Maxwell, Jill A., et al. “Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma..” Mol Cancer Ther, vol. 5, no. 10, Oct. 2006, pp. 2531–39. Pubmed, doi:10.1158/1535-7163.MCT-06-0106.
PMID
17041097
Source
pubmed
Published In
Molecular Cancer Therapeutics
Volume
5
Issue
10
Publish Date
2006
Start Page
2531
End Page
2539
DOI
10.1158/1535-7163.MCT-06-0106

AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma.

Malignant gliomas are highly proliferative and angiogenic cancers resistant to conventional therapies. Although RAS and RAF mutations are uncommon in gliomas, RAS activity is increased in gliomas. Additionally, vascular endothelial growth factor and its cognate receptors are highly expressed in gliomas. We now report that AAL881, a novel low-molecular weight inhibitor of the kinase activities associated with B-RAF, C-RAF (RAF-1), and VEGF receptor-2 (VEGFR2), showed activity against glioma cell lines and xenografts. In culture, AAL881 inhibited the downstream effectors of RAF in a concentration-dependent manner, with inhibition of proliferation associated with a G(1) cell cycle arrest, induction of apoptosis, and decreased colony formation. AAL881 decreased the proliferation of bovine aortic endothelial cells as well as the tumor cell secretion of vascular endothelial growth factor and inhibited the invasion of glioma cells through an artificial extracellular matrix. Orally administered AAL881 was well tolerated with minimal weight loss in non-tumor-bearing mice. Established s.c. human malignant glioma xenografts grown in immunocompromised mice treated with a 10-day course of oral AAL881 exhibited growth delays relative to control tumors, frequently resulting in long-term complete regressions. AAL881 treatment extended the survival of immunocompromised mice bearing orthotopic glioma xenografts compared with placebo controls. The intraparenchymal portions of orthotopic AAL881-treated tumors underwent widespread necrosis consistent with vascular disruption compared with the subarachnoid elements. These effects are distinct from our prior experience with VEGFR2 inhibitors, suggesting that targeting RAF itself or in combination with VEGFR2 induces profound tumor responses in gliomas and may serve as a novel therapeutic approach in patients with malignant gliomas.

Authors
Sathornsumetee, S; Hjelmeland, AB; Keir, ST; McLendon, RE; Batt, D; Ramsey, T; Yusuff, N; Rasheed, BKA; Kieran, MW; Laforme, A; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Sathornsumetee, Sith, et al. “AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma..” Cancer Res, vol. 66, no. 17, Sept. 2006, pp. 8722–30. Pubmed, doi:10.1158/0008-5472.CAN-06-0284.
PMID
16951188
Source
pubmed
Published In
Cancer Res
Volume
66
Issue
17
Publish Date
2006
Start Page
8722
End Page
8730
DOI
10.1158/0008-5472.CAN-06-0284

Spontaneous necrosis influences the accuracy of glioma grading: Comment

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Spontaneous necrosis influences the accuracy of glioma grading: Comment.” Oncology Report, no. FALL, Sept. 2006, pp. 13–14.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2006
Start Page
13
End Page
14

Bevacizumab-irinotecan combination shows activity in recurrent glioma: Comment

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Bevacizumab-irinotecan combination shows activity in recurrent glioma: Comment.” Oncology Report, no. FALL, Sept. 2006.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2006
Start Page
11

Chromosomal translocation confers favorable prognosis in brain tumors: Comment

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Chromosomal translocation confers favorable prognosis in brain tumors: Comment.” Oncology Report, no. FALL, Sept. 2006, pp. 12–13.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2006
Start Page
12
End Page
13

Age, resection status fail to define risk in glioma: Comment

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Age, resection status fail to define risk in glioma: Comment.” Oncology Report, no. FALL, Sept. 2006.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2006
Start Page
14

Modafinil improves neurocognitive function in brain tumor patients: Comment

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Modafinil improves neurocognitive function in brain tumor patients: Comment.” Oncology Report, no. FALL, Sept. 2006, pp. 11–12.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2006
Start Page
11
End Page
12

Chimeric murine/human IgG(2) anti-tenascin 81C6 monoclonal antibody: phase I trial in patients with malignant glioma of a construct with improved stability

Authors
Zalutsky, MR; Reardon, DA; Quinn, JA; Coleman, RE; Akabani, G; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Wong, TZ; Bigner, DD
MLA Citation
Zalutsky, M. R., et al. “Chimeric murine/human IgG(2) anti-tenascin 81C6 monoclonal antibody: phase I trial in patients with malignant glioma of a construct with improved stability.” European Journal of Nuclear Medicine and Molecular Imaging, vol. 33, SPRINGER, Sept. 2006, pp. S194–S194.
Source
wos
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S194
End Page
S194

Radioimmunotherapy of patients with malignant brain tumors: patient-specific dosing of I-131-labeled anti-tenacin antibody to achieve 44 Gy boost dose to resection cavity margins

Authors
Reardon, DA; Zalutsky, MR; Akabani, G; Coleman, RE; Friedman, AH; McLendon, RE; Friedman, HS; Herndon, JE; Kirkpatrick, J; Bigner, DD
MLA Citation
Reardon, D. A., et al. “Radioimmunotherapy of patients with malignant brain tumors: patient-specific dosing of I-131-labeled anti-tenacin antibody to achieve 44 Gy boost dose to resection cavity margins.” European Journal of Nuclear Medicine and Molecular Imaging, vol. 33, SPRINGER, Sept. 2006, pp. S194–S194.
Source
wos
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S194
End Page
S194

A phase II study of temozolomide and oral VP-16 for adults with recurrent glioma - Final results.

Authors
Korones, DN; Benita-Weiss, M; Coyle, T; Bushunow, P; Mechtler, L; Friedman, HS
MLA Citation
Korones, D. N., et al. “A phase II study of temozolomide and oral VP-16 for adults with recurrent glioma - Final results..” Journal of Clinical Oncology, vol. 24, no. 18, AMER SOC CLINICAL ONCOLOGY, 2006, pp. 74S-74S.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
74S
End Page
74S

A novel low molecular weight inhibitor of focal adhesion kinase and insulin-like growth factor-1 receptor, TAE226, inhibits glioma growth.

11505 Background: Glioblastomas are highly lethal cancers that resist current therapies. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase overexpressed in glioblastoma patient specimens that may promote glioma growth and invasion by increasing cellular adhesion, migration, invasion, proliferation. TAE226 is a novel low molecular weight inhibitor of several kinases that demonstrates in vitro activity primarily against FAK with activity against insulin-like growth factor-1 receptor (IGF1R) at higher concentrations. METHODS: As FAK and IGF1R are potential molecular targets in glioblastomas, we examined the efficacy of TAE226 against human glioma cell lines and xenografts. RESULTS: TAE226 inhibited the activating phosphorylation of FAK at submicromolar concentrations with residue specific preference. Downstream effectors (Akt and ERK) were inhibited at slightly higher concentrations. TAE226 demonstrated a concentration-dependent decrease in cellular proliferation with an associated G2 cell cycle arrest in multiple glioma cell lines, whereas TAE226 potently induced apoptosis in a concentration-dependent manner in only one of four cell lines tested. TAE226 also induced a concentration-dependent decrease in cellular adhesion, migration, and invasion. In preliminary animal studies, a limited course of orally administered TAE226 (100 mg/kg qd 5 days on/2 days off/5 days) was well tolerated with minimal weight loss. TAE226 induced a modest growth delay of human glioma xenografts grown in a subcutaneous location in athymic mice (3 to 4 days delay, p < 0.001). In addition, mice bearing orthotopic intracranial human glioma xenografts demonstrated a modest increase in median survival (3.5 days, p = 0.078). Despite the modest degree of the tumor responses, these results are superior to other low molecular weight inhibitors, such as epidermal growth factor receptor (EGFR) inhibitors. As glioma xenografts often grow without invasion, these results may underestimate the efficacy of targeting FAK as FAK plays a major role in tumor invasion. CONCLUSION: TAE226 demonstrates modest activity as monotherapy against malignant gliomas and warrants further investigation, potentially in combination with other therapies. [Table: see text].

Authors
Rich, JN; Shi, Q; Hjelmeland, AB; Keir, ST; Wickman, S; Wu, G; Jackson, D; Ohmori, O; Bigner, DD; Friedman, HS
MLA Citation
Rich, J. N., et al. “A novel low molecular weight inhibitor of focal adhesion kinase and insulin-like growth factor-1 receptor, TAE226, inhibits glioma growth..” J Clin Oncol, vol. 24, no. 18_suppl, June 2006.
PMID
27954359
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
11505

Combination of bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and temozolomide: Study of cases.

11522 Background: The prognosis for glioblastoma multiforme remains poor. Survival is generally limited to less than 1 year. Currently available standard treatments have not allowed, thus far, to prolong survival significantly. Response rates observed in clinical trials evaluating glioblastoma multiforme are usually less than 20%. Knowing that malignant gliomas have high concentrations of VEGF receptors, and the higher the VEGF receptor concentration, the worse the prognosis, we decided to evaluate the efficacy of bevacizumab in malignant brain tumor patients. Bevacizumab is a humanized IgG1 monoclonal antibody to VEGF, which is synergistic with chemotherapy for most malignancies. We performed a phase II study combining bevacizumab with irinotecan for patient with malignant gliomas and observed an unprecedented response rate of 63%. METHODS: Building of those results, we decided to treat a number of our patients with voluminous unresectable disease with bevacizumab and temozolomide as an upfront regimen. Temozolomide is an oral methylating agent known effective for primary malignant brain tumor patients. A phase III trial, first presented at the ASCO meeting of 2003, demonstrated the efficacy of temozolomide for newly diagnosed glioblastoma multiforme patients, establishing temozolomide as the new standard of care. Given the known results with temozolomide as monotherapy and the combination of bevacizumab with irinotecan, we treated patients with temozolomide and bevacizumab upfront. RESULTS: With this new combination, some patients demonstrated dramatic improvement clinically and radiographically. The combination has been well tolerated thus far, with no incidence of hemorrhage or arterial thrombosis observed. CONCLUSIONS: Results will be updated at the time of presentation. [Table: see text].

Authors
Kirkpatrick, J; Desjardins, A; Vredenburgh, JJ; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Friedman, AH; Friedman, HS; Reardon, DA
MLA Citation
Kirkpatrick, J., et al. “Combination of bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and temozolomide: Study of cases..” J Clin Oncol, vol. 24, no. 18_suppl, June 2006.
PMID
27954538
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
11522

Acute toxicity analysis of patients receiving surgery, Gliadel wafer implantation, and postoperative daily temozolomide with radiation therapy for primary high-grade glioma.

11504 Background: Treatment of patients with newly diagnosed malignant glioma using Gliadel wafer implantation at initial surgery has been shown to increase survival (Westphal et al 2003). Similarly, administration of temozolomide during and after radiotherapy has also been shown to increase survival in this patient population (Stupp et al 2005). Accordingly use of both Gliadel and temozolomide may be advantageous for these patients although it is possible that the toxicity of these two approaches used together might be prohibitive. METHODS: The Preston Robert Tisch Brain Tumor Center at Duke has occasionally treated with this approach over the last several years, and we now present an analysis of the observed acute toxicity. We retrospectively reviewed the Duke patients treated with surgery plus Gliadel wafer placement followed by daily temozolomide (75 mg/m(2)-150 mg/m(2)) and radiation therapy. RESULTS: Of 28 patients reviewed, four patients were diagnosed with AA (WHO grade III), two patients were diagnosed with AO (WHO grade III) and the remaining 22 patients were diagnosed with glioblastoma multiforme (WHO grade IV). Two of the 28 7.1%) patients experienced grade 3 or 4 hematologic toxicity during radiation and daily temozolomide therapy. This is similar to the 7% of patients found to have hematologic toxicity reported by Stupp et al (2005). Three patients (10.7%) had grade 3 or 4 seizure activity. Two patients (7.1%) had grade 4 pulmonary emboli. No events of cerebral edema or wound complications were noted in this review of patient events following Gliadel wafer placement. CONCLUSIONS: In summary, the addition of Gliadel wafer placement at the time of surgery followed by radiation therapy with concurrent daily low dose temozolomide does not appear to have significant acute toxicity over that observed with radiation therapy and daily temozolomide. Future formal trials combining these therapeutic strategies may allow evaluation of the possible survival advantage associated with this approach. [Table: see text].

Authors
Heery, CR; Desjardins, A; Quinn, JA; Rich, JN; Gururangan, S; Vredenburgh, JJ; Friedman, AH; Reardon, DA; Friedman, HS
MLA Citation
Heery, C. R., et al. “Acute toxicity analysis of patients receiving surgery, Gliadel wafer implantation, and postoperative daily temozolomide with radiation therapy for primary high-grade glioma..” J Clin Oncol, vol. 24, no. 18_suppl, June 2006.
PMID
27954360
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
11504

A phase I trial of imatinib, hydroxyurea and RAD001 for patients with recurrent malignant glioma.

1580 Background: This study attempts to extend the anti-glioma activity of imatinib mesylate (Gleevec, IM) plus hydroxyurea (H), by adding RAD001 (R), an orally bioavailable inhibitor of mTOR, a critical intracellular mediator of signal transduction and metabolism. METHODS: We employ a "3+3" dose escalation design to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of IM + H + R administered daily among adult recurrent malignant glioma patients s with ≤ 3 prior recurrences, KPS > 60% and adequate organ function. Patients are stratified based on concurrent enzyme-inducing anticonvulsant use (EIAC), and both strata are independently escalated. Initial dose level for each stratum: IM - 400 mg/day; H - 500 mg bid; R - 2.5 mg/day. Each treatment cycle is 28 days. Response is evaluated every other cycle. Pharmacokinetic (PK) studies are performed on days 1 and 28 of cycle 1. RESULTS: Twenty-two recurrent GBM patients have enrolled. The median age is 53 (range 37 to 75), 41% are male, and 45% are on EIAC. Two DLTs (grade 4 hypercholesterolemia and thrombocytopenia) occurred among 5 patients on dose level one (non-EIAC stratum). No other DLTs have occurred. The dose escalation schema has been amended to include alternate day R dosing. IM PK were consistent with those previously reported for patients on IM and HU. IM clearance on day 1 was 492 ± 247 ml/min in the EIAC stratum and 231 ± 100 ml/min in the non-EIAC stratum. On day 28, IM clearance was decreased in both strata (243 ± 93 ml/min in the EIAC stratum and 116 ± 47 ml/min in the non-EIAC stratum) PK results for HU and R are pending. Nine patients continue on study having received 2-8 cycles of therapy. Four partial responses have been observed and accrual is ongoing. CONCLUSIONS: Further accrual is warranted. An update of outcome, toxicity and pharmacokinetic analyses will be presented. [Table: see text].

Authors
Reardon, D; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Sathornsumetee, S; Gururangan, S; Egorin, MJ; Salvado, A; Friedman, HS
MLA Citation
Reardon, D., et al. “A phase I trial of imatinib, hydroxyurea and RAD001 for patients with recurrent malignant glioma..” J Clin Oncol, vol. 24, no. 18_suppl, June 2006.
PMID
27952508
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
1580

Phase II trial of imatinib mesylate and hydroxyurea for grade III malignant gliomas.

1573 Background: We evaluated the combination of imatinib mesylate (Gleevec) and hydroxyurea in WHO grade III malignant gliomas following the encouraging response of this combination demonstrated in glioblastoma multiforme. METHODS: Eligibility: adult patients with recurrent/relapsing AA or AO with measurable disease; 2 weeks since surgical resection or 4 weeks since radiotherapy or chemotherapy; Karnofsky 60% and adequate organ function. Imatinib and hydroxyurea were given orally daily. Imatinib was administered at 400 mg daily to patients not on enzyme inducing antiepileptic drugs (EIAED) while those on EIAED received 500 mg twice a day. Hydroxyurea was administered to all patients at 500 mg twice a day. Each cycle was 28 days of therapy. RESULTS: Thirty-nine patients with recurrent AA (n= 32) or AO (n=7), following prior radiation therapy and chemotherapy, have been enrolled, including 21 (54%) not on EIAED and 18 (46%) on EIAED. Patient characteristics were comparable between both strata. Median age was 39 years (range, 21-59 years). The most frequent grade III-IV toxicities were neutropenia (n=11), leukopenia (n=8), thrombocytopenia (n=6), deep venous thrombosis (n=3), fatigue (n=2) and pulmonary edema (n=2). One patient presented grade V brain hemorrhage at the time of disease progression. Four patients achieved a partial response, for an overall response rate of 10%. Thirteen patients (33%) achieved disease stabilization. Twelve patients (67%) not on EIAED had progressive disease as their best response compared to only 4 patients (27%) on EIAED. The median time to progression for all patients, and for those not on EAIED and on EIAED was 14.1 weeks, 10.9 weeks and 26.0 weeks, respectively. CONCLUSIONS: Daily imitanib mesylate plus hydroxyurea demonstrates encouraging activity and is well tolerated among patients with recurrent AA or AO. As observed with glioblastoma multiforme patients, patients on EAIED seem to demonstrate a better response. [Table: see text].

Authors
Desjardins, A; Reardon, DA; Quinn, JA; Rich, JN; Vredenburgh, JJ; Sathornsumetee, S; Salvado, A; Friedman, HS
MLA Citation
Desjardins, A., et al. “Phase II trial of imatinib mesylate and hydroxyurea for grade III malignant gliomas..” J Clin Oncol, vol. 24, no. 18_suppl, June 2006.
PMID
27952528
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
1573

A phase II study of temozolomide and oral VP-16 for adults with recurrent glioma-Final results.

1565 Background: Although temozolomide has proven activity in patients with high and low grade gliomas, many patients do not respond, and for those who do, responses are often short-lived. We therefore undertook a trial of temozolomide in combination with oral VP-16 (etoposide) for patients with recurrent glioma. METHODS: Patients were eligible for the study if they had recurrence of a glioma (glioblastoma [GBM], anaplastic glioma, or low-grade glioma), were ≥ 18 years of age, had a WHO score of 0-2, and had not received prior therapy with temozolomide or oral VP-16. All patients received temozolomide, 150 mg/m(2)/d days 1-5 and oral VP-16, 50 mg/m(2)/d days 1-12 (based on the maximum tolerated dose established in a previous phase 1 study [Cancer 2003, 97 (8); 1963-68.]). Cycles were repeated every 28 days for up to 12 cycles. All patients received prophylaxis for pneumocystis. RESULTS: Fifty-one patients were enrolled - 32 with glioblastoma, 12 with anaplastic gliomas, and 7 with low-grade glioma. Median age was 52 years (21-76), and 67% were male. Forty-one were enrolled at first and 10 at second recurrence. Fifty had had prior radiation, and 30 of these 50 patients had also received prior chemotherapy. Of the 32 subjects with GBM, 4 had a PR (12.5%), 13 (41%) SD, 13 (41%) PD, and 2 were not evaluable because of deterioration prior to imaging. The median progression-free survival (PFS) was 2 mo. (0-51+ mo), and the 6 mo. PFS was 19%. Of the 12 patients with anaplastic gliomas, 2 had a PR (16%), 7 SD (58%), 2 PD (16%) and one was not evaluable. Their median PFS was 5.5 mo, and the 6 mo. PFS was 50%. Of the seven subjects with low grade gliomas, 4 had a PR, 2 SD, and 1 PD. Their median PFS was 5 mo. (0-12) and 6 mo. PFS was 57%. Of the entire cohort, two patients developed fever and neutropenia and died of pseudomonas sepsis. Another two patients were prematurely withdrawn from the study due to toxicity (one for grade 4 neutropenia and a second for grade 2 diarrhea). CONCLUSIONS: In this population of previously treated patients with recurrent glioma, the combination of oral VP-16 and temozolomide has only modest efficacy and significant toxicity. The results of this study suggest that in this setting, the combination offers no advantage over either agent used alone. [Table: see text].

Authors
Korones, DN; Benita-Weiss, M; Coyle, T; Bushunow, P; Mechtler, L; Friedman, HS
MLA Citation
Korones, D. N., et al. “A phase II study of temozolomide and oral VP-16 for adults with recurrent glioma-Final results..” J Clin Oncol, vol. 24, no. 18_suppl, June 2006.
PMID
27952501
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
1565

An update on phase I study of dose-escalating imatinib mesylate plus standard-dosed temozolomide for the treatment of patients with malignant glioma.

1560 Background: Imatinib mesylate, a kinase inhibitor of the PDGF receptor has been shown to decrease tumor interstitial pressure resulting in enhanced delivery of cytotoxic therapy. Recent phase II trial demonstrated promising anti-glioma activity of imatinib mesylate in combination with chemotherapy, hydroxyurea. METHODS: The current phase I study is designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate when combined with temozolomide, a DNA methylator with established efficacy against gliomas. Eligibility criteria include: histologically confirmed malignant glioma; age of at least 18 years; KPS of at least 60%; less than grade 2 intratumoral hemorrhage; adequate hepatic, renal, and bone marrow function and lack of prior failure or significant toxicity following treatment with either imatinib mesylate or temozolomide. Temozolomide is dosed at 200 mg/m(2) on days 4-8 of each 28-day cycle. Imatinib mesylate is administered on days 1-8 of each cycle and the dose is escalated in successive cohorts of 3-6 patients via a standard "3+3" dose escalation design. Patients are stratified based on concurrent use of enzyme-inducing anticonvulsants (EIAC) and both strata are independently escalated. RESULTS: To date 47 patients have been enrolled including 40 with GBM and 7 with anaplastic gliomas. Median age is 53.9 years (range 28 to 72); 66% are male and 51% are on EIAC. The MTD has yet to be defined for either stratum. To date DLT of ALT elevation has been observed in one patient from non-EIAC stratum. Two patients discontinued therapy due to toxicities with one asymptomatic intracerebral hemorrhage and one severe hematologic toxicity. Pharmacokinetic sampling has been performed in approximately half of the patients. One patient completed the study (12 cycles) with stable disease. Eleven patients remain on study with one partial response and three patients have undergone more than 10 cycles of therapy with stable disease. Twenty-eight patients (59%) have developed progressive disease and discontinued therapy. CONCLUSIONS: Combination of imatinib mesylate and temozolomide is safe and well tolerated. Further accrual and dose escalation are ongoing. [Table: see text].

Authors
Sathornsumetee, S; Reardon, DA; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Gururangan, S; Egorin, M; Salvado, A; Friedman, HS
MLA Citation
Sathornsumetee, S., et al. “An update on phase I study of dose-escalating imatinib mesylate plus standard-dosed temozolomide for the treatment of patients with malignant glioma..” J Clin Oncol, vol. 24, no. 18_suppl, June 2006.
PMID
27952499
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
1560

Phase II trial of Gliadel plus O(6)-benzylguanine (O(6)-BG) for patients with recurrent glioblastoma multiforme.

1568 Background. The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) which removes chloroethylation or methylation damage from the O(6)-position of guanine. O(6)-BG is an AGT substrate that inhibits AGT by suicide inactivation. A previous phase III randomized, placebo-controlled trial has shown that Gliadel wafer significantly prolongs 6-month survival (55.5% for Gliadel vs. 35.6% for placebo) and median survival (28 weeks for Gliadel vs. 20 weeks for placebo) in patients with recurrent glioblastoma multiforme (GBM) (Brem et al 1995). Despite the success of Gliadel in prolonging survival we may be able to improve on this success by depleting AGT. METHODS: Thus, we have designed a phase 2 trial where we define the activity and the toxicity of Gliadel in combination with a 5-day infusion of O(6)-BG in patients with recurrent GBM. In a prior study the O(6)-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m(2) over 1 hour followed by a continuous infusion of 30 mg/m(2)/d for 48 hours. In order to guarantee depletion of tumor AGT activity for at least 5 days after Gliadel placement, this O(6)-BG bolus was repeated on days 3 and 5 while continuing the infusion. RESULTS: To date, 24 patients have been enrolled out of a planned accrual of 50 patients. Seventeen of these patients received prior nitrosourea therapy. The 6-month survival is 68% and the median survival is 36 weeks. The adverse events include the following: 2 episodes of CSF leak (8%), 4 episodes of wound infection at craniotomy site (16%), 5 episodes of grade ≥ 3 seizures (21%) and 3 episodes of hyponatremia (12%). These adverse events were similar in frequency to those seen in patients receiving Gliadel in prior placebo-controlled Gliadel trials. CONCLUSIONS: Thus far, this data demonstrates an increase in the efficacy of Gliadel when combined with O(6)-BG. Twenty-six additional patients will be enrolled for a total accrual of 50 patients. [Table: see text].

Authors
Quinn, JA; Vredenburgh, JJ; Rich, JN; Reardon, DA; Desjardins, A; Gururangan, S; Friedman, AH; Lavin, K; Sathornsumetee, S; Threatt, S; Friedman, HS
MLA Citation
Quinn, J. A., et al. “Phase II trial of Gliadel plus O(6)-benzylguanine (O(6)-BG) for patients with recurrent glioblastoma multiforme..” J Clin Oncol, vol. 24, no. 18_suppl, June 2006.
PMID
27952495
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
1568

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and irinotecan for treatment of malignant gliomas.

1506 Background: The prognosis for recurrent malignant gliomas is poor, with a median survival <12 months, median progression-free survival <12 weeks and response rates <20%. Malignant gliomas have high concentrations of VEGF receptors, and the higher the VEGF receptor concentration, the worse the prognosis. Bevacizumab is a humanized IgG1 monoclonal antiblody to VEGF, which is synergistic with chemotherapy for most malignancies. Irinotecan is a topoisomerase 1 inhibitor, and has modest activity against recurrent malignant gliomas. METHODS: We report a FDA approved phase II trial of bevacizumab and irinotecan for the treatment of recurrent malignant gliomas. 32 patients were enrolled, 23 with grade IV tumors (glioblastoma multiforme) and 9 with grade III tumors (anaplastic astrocytomas or oligodendrogliomas). All the patients had progressive disease and every patient had received prior radiation therapy and chemotherapy. Patients were treated every other week with bevacizumab 10 mg/kg and irinotecan 125 mg/m(2) for patients not taking enzyme inducing anti-epileptic drugs or 340 mg/m(2) for patients taking enzyme inducing anti-epileptic drugs. RESULTS: The regimen was well tolerated with no CNS hemorrhages or >grade 1 systemic hemorrhages. Four patients were taken off study for thrombotic complications, 2 pulmonary emboli, 1 deep venous thrombus, and one thrombotic stroke. Two patients were discontinued secondary to grade 2 proteinuria and three were discontinued because they required non-neurosurgical surgery, appendectomy, repair of anal fissures and hip stabilization. The response rate was 63% (19 PRs and 1 CR). The median progression-free survival is 24 weeks. The median overall survival has not been reached, and exceeds 6 months. There have been ten deaths due to disease progression. CONCLUSIONS: The combination of bevacizumab and irinotecan is safe and one of the most active regimens against malignant gliomas. [Table: see text].

Authors
Vredenburgh, JJ; Desjardins, A; Herndon, JE; Quinn, J; Rich, J; Sathornsumetee, S; Friedman, HS; Reardon, D; Gururangan, S; Friedman, A
MLA Citation
Vredenburgh, J. J., et al. “Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and irinotecan for treatment of malignant gliomas..” J Clin Oncol, vol. 24, no. 18_suppl, June 2006.
PMID
27952313
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
1506

Tinzaparin prophylaxis against thromboembolic complications in brain tumor patients.

1539 Background: Thromboembolic complications are common in brain tumor patients, contribute to the morbidity and mortality and complicate treatment. Twenty to 40% of brain tumor patients develop a deep venous thrombosis and/or pulmonary embolus during their course. Thromboembolic complications are the second leading cause of death in brain tumor patients. One of the low molecular weight heparins, tinzaparin, has increased factor Xa activity as opposed to thrombin inhibition, which may improve the therapeutic:toxicity ratio. METHODS: We report a phase II trial of prophylactic tinzaparin for newly diagnosed brain tumor patients. Twenty-seven of the planned 40 patients have been accrued. Patients received daily tinzaparin at a fixed dose of 4500 IU subcutaneously beginning a minimum of 48 hours post-operatively and a maximum of 4 weeks post-operatively. Patients were scheduled to receive tinzaparin for 12 months. During chemotherapy cycles, the blood counts were monitored weekly. If the platelet count was <50,000, the tinzaparin was held until the platelets were >100,000. RESULTS: One of the patients developed a grade 3 CNS hemorrhage, necessitating cessation of the tinzaparin, there have been no grade 4 or 5 CNS hemorrhages or treatment associated mortality. Also, there have been no ≥ grade 2 systemic hemorrhages. One patient developed a deep venous thrombosis while taking tinzaparin, and three patients developed thromboembolic complications while off tinzaparin secondary to thrombocytopenia. One patient was taken off study for increased liver function tests, possibly secondary to tinzaparin. The patients have taken the tinzaparin for 4-52 weeks, with a median of 18 weeks. CONCLUSIONS: Tinzaparin at a fixed prophylactic dose is safe and may decrease the incidence of thromboembolic complications in brain tumor patients. If the completed phase II study yields similar results, a phase III trial is warranted. No significant financial relationships to disclose.

Authors
Vredenburgh, JJ; Bohlin, C; Reardon, DA; Desjardins, A; Quinn, J; Rich, J; Sathornsumetee, S; Marks, LB; Friedman, AH; Friedman, HS
MLA Citation
Vredenburgh, J. J., et al. “Tinzaparin prophylaxis against thromboembolic complications in brain tumor patients..” J Clin Oncol, vol. 24, no. 18_suppl, June 2006.
PMID
27952290
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
1539

A phase I trial of imatinib, hydroxyurea and RAD001 for patients with recurrent malignant glioma.

Authors
Reardon, D; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Sathornsumetee, S; Gururangan, S; Egorin, MJ; Salvado, A; Friedman, HS
MLA Citation
Reardon, D., et al. “A phase I trial of imatinib, hydroxyurea and RAD001 for patients with recurrent malignant glioma..” Journal of Clinical Oncology, vol. 24, no. 18, AMER SOC CLINICAL ONCOLOGY, 2006, pp. 77S-77S.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
77S
End Page
77S

Phase II trial of Gliadel plus 0(6)-benzylguanine (0(6) -BG) for patients with recurrent glioblastoma multiforme.

Authors
Quinn, JA; Vredenburgh, JJ; Rich, JN; Reardon, DA; Desjardins, A; Gururangan, S; Friedman, AH; Lavin, K; Sathornsumetee, S; Threatt, S; Friedman, HS
MLA Citation
Quinn, J. A., et al. “Phase II trial of Gliadel plus 0(6)-benzylguanine (0(6) -BG) for patients with recurrent glioblastoma multiforme..” Journal of Clinical Oncology, vol. 24, no. 18, AMER SOC CLINICAL ONCOLOGY, 2006, pp. 74S-74S.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
74S
End Page
74S

An update on phase I study of dose-escalating imatinib mesylate plus standard-dosed temozolomide for the treatment of patients with malignant glioma.

Authors
Sathornsumetee, S; Reardon, DA; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Gururangan, S; Egorin, M; Salvado, A; Friedman, HS
MLA Citation
Sathornsumetee, S., et al. “An update on phase I study of dose-escalating imatinib mesylate plus standard-dosed temozolomide for the treatment of patients with malignant glioma..” Journal of Clinical Oncology, vol. 24, no. 18, AMER SOC CLINICAL ONCOLOGY, 2006, pp. 72S-72S.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
72S
End Page
72S

Phase II trial of imatinib mesylate and hydroxyurea for grade III malignant gliomas.

Authors
Desjardins, A; Reardon, DA; Quinn, JA; Rich, JN; Vredenburgh, JJ; Sathornsumetee, S; Salvado, A; Friedman, HS
MLA Citation
Desjardins, A., et al. “Phase II trial of imatinib mesylate and hydroxyurea for grade III malignant gliomas..” Journal of Clinical Oncology, vol. 24, no. 18, AMER SOC CLINICAL ONCOLOGY, 2006, pp. 76S-76S.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
76S
End Page
76S

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and irinotecan for treatment of malignant gliomas.

Authors
Vredenburgh, JJ; Desjardins, A; Herndon, JE; Quinn, J; Rich, J; Sathornsumetee, S; Friedman, HS; Reardon, D; Gururangan, S; Friedman, A
MLA Citation
Vredenburgh, J. J., et al. “Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and irinotecan for treatment of malignant gliomas..” Journal of Clinical Oncology, vol. 24, no. 18, AMER SOC CLINICAL ONCOLOGY, 2006, pp. 59S-59S.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
59S
End Page
59S

Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results.

UNLABELLED: Results from animal experiments have shown that human IgG2/mouse chimeric antitenascin 81C6 (ch81C6) monoclonal antibody exhibited higher tumor accumulation and enhanced stability compared with its murine parent. Our objective was to determine the effect of these differences on the maximum tolerated dose (MTD), pharmacokinetics, dosimetry, and antitumor activity of (131)I-ch81C6 administered into the surgically created resection cavity (SCRC) of malignant glioma patients. METHODS: In this phase I trial, eligible patients received a single injection of (131)I-ch81C6 administered through a Rickham catheter into the SCRC. Patients were stratified as newly diagnosed and untreated (stratum A), newly diagnosed after external beam radiotherapy (XRT) (stratum B), and recurrent (stratum C). (131)I-ch81C6 was administered either before (stratum A) or after (stratum B) conventional XRT for newly diagnosed patients. In addition, chemotherapy was prescribed for all patients after (131)I-ch81C6 administration. Dose escalation was performed independently for each stratum. Patients were observed for toxicity and response until death or progressive disease. RESULTS: We treated 47 patients with (131)I-ch81C6 doses up to 4.44 GBq (120 mCi), including 35 with newly diagnosed tumors (strata A and B) and 12 with recurrent disease (stratum C). Dose-limiting hematologic toxicity defined the MTD to be 2.96 GBq (80 mCi) for all patients, regardless of treatment strata. Neurologic dose-limiting toxicity developed in 3 patients; however, none required further surgery to debulk radiation necrosis. Median survival was 88.6 wk and 65.0 wk for newly diagnosed and recurrent patients, respectively. CONCLUSION: The MTD of (131)I-ch81C6 is 2.96 GBq (80 mCi) because of dose-limiting hematologic toxicity. Although encouraging survival was observed, (131)I-ch81C6 was associated with greater hematologic toxicity, probably due to the enhanced stability of the IgG2 construct, than previously observed with (131)I-murine 81C6.

Authors
Reardon, DA; Quinn, JA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Pegram, CN; Provenzale, JM; Dowell, JM; Rich, JN; Vredenburgh, JJ; Desjardins, A; Sampson, JH; Gururangan, S; Wong, TZ; Badruddoja, MA; Zhao, X-G; Bigner, DD; Zalutsky, MR
MLA Citation
Reardon, David A., et al. “Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results..” J Nucl Med, vol. 47, no. 6, June 2006, pp. 912–18.
PMID
16741299
Source
pubmed
Published In
Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
Volume
47
Issue
6
Publish Date
2006
Start Page
912
End Page
918

Patterns of exercise across the cancer trajectory in brain tumor patients.

BACKGROUND: Exercise may represent a supportive intervention that may complement existing neurooncologic therapies and address a multitude of therapy-induced debilitating side effects in patients with brain tumors. Given the limited evidence, the authors conducted a survey to examine the exercise patterns of brain tumor patients across the cancer trajectory. METHODS: Using a cross-sectional design, 386 brain tumor patients who received treatment at the Brain Tumor Center at Duke University were sent a questionnaire that assessed self-reported exercise behavior prior to diagnosis, during adjuvant therapy, and after the completion of therapy. RESULTS: The response rate was 28% (106 of 383 patients). Descriptive analyses indicated that 42%, 38%, and 41% of participants, respectively, met national exercise prescription guidelines prior to diagnosis, during treatment, and after the completion of adjuvant therapy. Repeated measures analyses indicated no significant changes in the majority of exercise behavior outcomes over the cancer trajectory. However, exploratory analyses indicated that males and younger participants may be at the greatest risk of reducing exercise levels after a brain tumor diagnosis. These analyses remained unchanged after controlling for relevant demographic and medical covariates. CONCLUSIONS: A relatively high percentage of brain tumor patients are exercising at recommended levels across the cancer trajectory. Moreover, these patients have unique exercise patterns that may be modified by select demographic variables. This preliminary study provides important informative data for future studies examining the potential role of exercise in patients diagnosed with neurologic malignancies.

Authors
Jones, LW; Guill, B; Keir, ST; Carter B S, K; Friedman, HS; Bigner, DD; Reardon, DA
MLA Citation
Jones, Lee W., et al. “Patterns of exercise across the cancer trajectory in brain tumor patients..” Cancer, vol. 106, no. 10, May 2006, pp. 2224–32. Pubmed, doi:10.1002/cncr.21858.
PMID
16586497
Source
pubmed
Published In
Cancer
Volume
106
Issue
10
Publish Date
2006
Start Page
2224
End Page
2232
DOI
10.1002/cncr.21858

O-6-alkylguanine-DNA alkyltransferase (AGT) and microsatellite instability (MSI) analyses in malignant glioma

Authors
Maxwell, JA; Johnson, SP; McLendon, RE; Ali-Osman, F; Quinn, JA; Friedman, AH; Herndon, JE; Bierau, K; Bigley, J; Bigner, DD; Friedman, HS
MLA Citation
Maxwell, Jill A., et al. “O-6-alkylguanine-DNA alkyltransferase (AGT) and microsatellite instability (MSI) analyses in malignant glioma.” Cancer Research, vol. 66, no. 8, AMER ASSOC CANCER RESEARCH, 2006.
Source
wos
Published In
Cancer Research
Volume
66
Issue
8
Publish Date
2006

Constitutive phosphorylation of Chk1 at serine 317 in a medulloblastoma cell line is sensitive to the inhibition of the phosphatidyalinositol-3-kinase-related kinase (PIKK) pathway

Authors
Cui, B; Johnson, SP; Ali-Osman, F; Bigner, DD; Friedman, HS
MLA Citation
Cui, Bo, et al. “Constitutive phosphorylation of Chk1 at serine 317 in a medulloblastoma cell line is sensitive to the inhibition of the phosphatidyalinositol-3-kinase-related kinase (PIKK) pathway.” Cancer Research, vol. 66, no. 8, AMER ASSOC CANCER RESEARCH, 2006.
Source
wos
Published In
Cancer Research
Volume
66
Issue
8
Publish Date
2006

Evaluation of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG, KOS-1022) against Childhood Cancer Models by the Pediatric Preclinical Testing Program (PPTP)

Authors
Houghton, PJ; Maris, J; Friedman, HS; Kier, ST; Lock, RB; Gorlick, R; Kolb, EA; Reynolds, CP; Morton, C; Smith, MA
MLA Citation
Houghton, Peter J., et al. “Evaluation of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG, KOS-1022) against Childhood Cancer Models by the Pediatric Preclinical Testing Program (PPTP).” Cancer Research, vol. 66, no. 8, AMER ASSOC CANCER RESEARCH, 2006.
Source
wos
Published In
Cancer Research
Volume
66
Issue
8
Publish Date
2006

Characterization of membrane transport of the novel O-6-alkylguanine-DNA alkyltransferase inactivator, O-4-benzylfolic acid

Authors
Johnson, SP; Kamen, BA; Moschel, RC; Friedman, HS
MLA Citation
Johnson, Stewart P., et al. “Characterization of membrane transport of the novel O-6-alkylguanine-DNA alkyltransferase inactivator, O-4-benzylfolic acid.” Cancer Research, vol. 66, no. 8, AMER ASSOC CANCER RESEARCH, 2006.
Source
wos
Published In
Cancer Research
Volume
66
Issue
8
Publish Date
2006

Radiotherapy in pediatric medulloblastoma: quality assessment of Pediatric Oncology Group Trial 9031.

PURPOSE: To evaluate the potential influence of radiotherapy quality on survival in high-risk pediatric medulloblastoma patients. METHODS AND MATERIALS: Trial 9031 of the Pediatric Oncology Group (POG) aimed to study the relative benefit of cisplatin and etoposide randomization of high-risk patients with medulloblastoma to preradiotherapy vs. postradiotherapy treatment. Two-hundred and ten patients were treated according to protocol guidelines and were eligible for the present analysis. Treatment volume (whole brain, spine, posterior fossa, and primary tumor bed) and dose prescription deviations were assessed for each patient. An analysis of first site of failure was undertaken. Event-free and overall survival rates were calculated. A log-rank test was used to determine the significance of potential survival differences between patients with and without major deviations in the radiotherapy procedure. RESULTS: Of 160 patients who were fully evaluable for all treatment quality parameters, 91 (57%) had 1 or more major deviations in their treatment schedule. Major deviations by treatment site were brain (26%), spinal (7%), posterior fossa (40%), and primary tumor bed (17%). Major treatment volume or total dose deviations did not significantly influence overall and event-free survival. CONCLUSIONS: Despite major treatment deviations in more than half of fully evaluable patients, underdosage or treatment volume misses were not associated with a worse event-free or overall survival.

Authors
Miralbell, R; Fitzgerald, TJ; Laurie, F; Kessel, S; Glicksman, A; Friedman, HS; Urie, M; Kepner, JL; Zhou, T; Chen, Z; Barnes, P; Kun, L; Tarbell, NJ
MLA Citation
Miralbell, Raymond, et al. “Radiotherapy in pediatric medulloblastoma: quality assessment of Pediatric Oncology Group Trial 9031..” Int J Radiat Oncol Biol Phys, vol. 64, no. 5, Apr. 2006, pp. 1325–30. Pubmed, doi:10.1016/j.ijrobp.2005.11.002.
PMID
16413699
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
64
Issue
5
Publish Date
2006
Start Page
1325
End Page
1330
DOI
10.1016/j.ijrobp.2005.11.002

A phase II window trial of procarbazine and topotecan in children with high-grade glioma: a report from the children's oncology group.

The role of chemotherapy in the treatment of high-grade gliomas in children is unclear. Early reports were suggestive of improved outcome in children with high-grade glioma with the addition of chemotherapy after surgery and radiation therapy. Subsequent studies did not show similar favorable contribution of chemotherapy to the outcome of these children. Further efforts to identify active chemotherapy agents in children include use of agents that have shown efficacy in adult patients with high-grade glioma and agents that have shown promise in mice bearing human xenografts of brain tumors. A Pediatric Oncology Group (POG 9431) trial tested the activity of two such agents, procarbazine and topotecan in newly diagnosed patients with high-grade glioma who had measurable disease after diagnostic surgery. Neither agent showed efficacy within the confines of the statistical design of the study. This study showed that children with high-grade glioma have an innate resistance to alkylating agents based on mismatch repair deficiency and high levels of alkyguanine transferase (AGT). Future trials should consider strategies to overcome the resistance mechanisms in children with high-grade glioma.

Authors
Chintagumpala, MM; Friedman, HS; Stewart, CF; Kepner, J; McLendon, RE; Modrich, PL; McCluggage, C; Burger, P; Holmes, E; Thompson, S; Rutka, J; Michalski, J; Woo, S; Blaney, SM; Kun, LE; Horowitz, ME; Pediatric Oncology Group Study,
MLA Citation
Chintagumpala, Murali M., et al. “A phase II window trial of procarbazine and topotecan in children with high-grade glioma: a report from the children's oncology group..” J Neurooncol, vol. 77, no. 2, Apr. 2006, pp. 193–98. Pubmed, doi:10.1007/s11060-005-9024-x.
PMID
16314955
Source
pubmed
Published In
Journal of Neuro Oncology
Volume
77
Issue
2
Publish Date
2006
Start Page
193
End Page
198
DOI
10.1007/s11060-005-9024-x

Incidence and patterns of neuraxis metastases in children with diffuse pontine glioma.

PURPOSE: We performed a retrospective study of patients with diffuse pontine glioma (DPG) who suffered neuraxis metastasis (NM) and characterized the incidence, clinical features, radiologic findings, and patterns of disease dissemination. METHODS: Magnetic resonance imaging (MRI) of brain and spine was used to assess NM. Some patients also underwent magnetic resonance spectroscopy (MRS) (6 patients) and fluorodeoxyglucose positron emission tomography (FDG-PET) scans (13 patients) to further evaluate areas of metastatic disease. Three patients had histologic confirmation of disease at the site of NM. RESULTS: Between 1986 and 2003, 18 of 96 patients (17.3%) with DPG developed NM. The median age at diagnosis was 8 years (range, 4-17). All patients had adjuvant chemotherapy and/or focal radiotherapy at diagnosis. The NM occurred at a median of 15 months from diagnosis of DPG (range, 3-96). Three patterns of NM were seen on MRI of brain and spine in these patients; 8 (39%) had parenchymal (PM), 4 (22%) leptomeningeal (PM), 2 (11%) subependymal, and in 5 a combination of two or more patterns. The MRS and FDG-PET scan of suspected areas of metastatic disease was consistent with tumor in 6 of 6 and 12 of 13 patients who underwent these procedures respectively. Three patients also had histologic confirmation of malignant glioma at the site of NM. Despite salvage therapy, all 18 patients have died of disease at a median of 5 months (range, 0.5-20) from diagnosis of neuraxis spread. CONCLUSION: Our study emphasizes the need for screening patients with DPG for NM at the time of recurrence.

Authors
Gururangan, S; McLaughlin, CA; Brashears, J; Watral, MA; Provenzale, J; Coleman, RE; Halperin, EC; Quinn, J; Reardon, D; Vredenburgh, J; Friedman, A; Friedman, HS
MLA Citation
Gururangan, Sridharan, et al. “Incidence and patterns of neuraxis metastases in children with diffuse pontine glioma..” J Neurooncol, vol. 77, no. 2, Apr. 2006, pp. 207–12. Pubmed, doi:10.1007/s11060-005-9029-5.
PMID
16568209
Source
pubmed
Published In
Journal of Neuro Oncology
Volume
77
Issue
2
Publish Date
2006
Start Page
207
End Page
212
DOI
10.1007/s11060-005-9029-5

Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine.

PURPOSE: An inverse correlation has been established between tumor levels of the DNA repair protein alkylguanine-DNA alkyltransferase (AGT) and a positive outcome after alkylator chemotherapy. Quantitative imaging of AGT could provide important information for patient-specific cancer treatment. Several radiolabeled analogues of O6-benzylguanine (BG), a potent AGT inactivator, have been developed and shown to be capable of labeling pure AGT protein. Herein, two of these analogues--O6-3-[*I]iodobenzylguanine ([*I]IBG) and O6-3-[*I]iodobenzyl-2'-deoxyguanosine ([*I]IBdG)--were further evaluated in two murine xenograft models. (AcO)2-[131I]IBdG, a peracetylated derivative of IBdG, also was investigated as an alternative agent. METHODS: Several biodistribution studies of radioiodinated IBG and IBdG were performed in TE-671 human rhabdomyosarcoma and DAOY human medulloblastoma murine xenograft models. Mice were treated with BG or its nucleoside analogue dBG to deplete the tumor AGT content. The effect of unlabeled IBG and that of 7,8-benzoflavone (BF), an inhibitor of the cytochrome P-450 isozyme CYP1A2, on the tumor uptake of the tracers was determined. The uptake of (AcO)2-[131I]IBdG along with that of [125I]IBdG in DAOY cells in vitro was determined in the presence and absence of a nucleoside transporter inhibitor, dipyridamole. RESULTS: Pretreatment of mice either with BG or dBG failed to reduce tumor levels of [*I]IBG or [*I]IBdG even though such treatments completely depleted tumor AGT content. Treatment of mice with BF increased tumor uptake of [125I]IBG by 56%; however, differentiation of tumors with and without AGT still was not possible. (AcO)2-[131I]IBdG, a peracetylated derivative of IBdG, had a higher uptake in vitro in DAOY tumor cells. However, its uptake, like that of [125I]IBdG, was blocked by dipyridamole. CONCLUSIONS: Taken together, these results suggest that labeled agents that are more specific for cellular AGT and that are more metabolically stable are needed.

Authors
Shankar, S; Zalutsky, MR; Friedman, H; Vaidyanathan, G
MLA Citation
Shankar, Sriram, et al. “Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine..” Nucl Med Biol, vol. 33, no. 3, Apr. 2006, pp. 399–407. Pubmed, doi:10.1016/j.nucmedbio.2005.12.015.
PMID
16631089
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
33
Issue
3
Publish Date
2006
Start Page
399
End Page
407
DOI
10.1016/j.nucmedbio.2005.12.015

Recent advances in the treatment of malignant astrocytoma.

Malignant gliomas, including the most common subtype, glioblastoma multiforme (GBM), are among the most devastating of neoplasms. Their aggressive infiltration in the CNS typically produces progressive and profound disability--ultimately leading to death in nearly all cases. Improvement in outcome has been elusive despite decades of intensive clinical and laboratory research. Surgery and radiotherapy, the traditional cornerstones of therapy, provide palliative benefit, while the value of chemotherapy has been marginal and controversial. Limited delivery and tumor heterogeneity are two fundamental factors that have critically hindered therapeutic progress. A novel chemoradiotherapy approach, consisting of temozolomide administered concurrently during radiotherapy followed by adjuvant systemic temozolomide, has recently demonstrated a meaningful, albeit modest, improvement in overall survival for newly diagnosed GBM patients. As cell-signaling alterations linked to the development and progression of gliomas are being increasingly elucidated, targeted therapies have rapidly entered preclinical and clinical evaluation. Responses to therapies that function via DNA damage have been associated with specific mediators of resistance that may also be subject to targeted therapies. Other approaches include novel locoregional delivery techniques to overcome barriers of delivery. The simultaneous development of multiple advanced therapies based on specific tumor biology may finally offer glioma patients improved survival.

Authors
Reardon, DA; Rich, JN; Friedman, HS; Bigner, DD
MLA Citation
Reardon, David A., et al. “Recent advances in the treatment of malignant astrocytoma..” J Clin Oncol, vol. 24, no. 8, Mar. 2006, pp. 1253–65. Pubmed, doi:10.1200/JCO.2005.04.5302.
PMID
16525180
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
8
Publish Date
2006
Start Page
1253
End Page
1265
DOI
10.1200/JCO.2005.04.5302

Phase I trial of intrathecal spartaject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004).

PURPOSE: A phase I trial of intrathecal Spartaject Busulfan (SuperGen, Inc., San Ramon, CA) was conducted in children with neoplastic meningitis following recurrent primary brain tumors to describe toxicities, estimate the maximum tolerated dose (MTD), and document evidence of responses to this agent. EXPERIMENTAL DESIGN: The continuous reassessment method was used to assign cohorts of patients to doses of intrathecal Spartaject Busulfan via an Ommaya reservoir and/or lumbar puncture twice weekly for 2 weeks followed by an assessment of toxicity and response. Patients with stable disease or an objective response continued to receive intrathecal Spartaject Busulfan plus systemic chemotherapy at regular intervals. Cerebrospinal fluid and blood were obtained for pharmacokinetic studies in patients with Ommaya reservoirs after the first dose of intrathecal Spartaject Busulfan. Seven evaluable patients were assigned to the starting dose of 5 mg, two patients to 7.5 mg, three patients to 10 mg, seven patients to 13 mg, and four patients to 17 mg. RESULTS: Between September 2000 and May 2003, 28 patients were enrolled in this study. Twenty-three patients (median age, 8.8 years; range, 2.5-19.5 years) were evaluable for estimating the MTD, and dose-limiting toxicities were observed in three and included grade 3 vomiting (n = 1 at 5 mg), grade 3 headache (n = 1 at 17 mg), and grade 3 arachnoiditis (n = 1 at 17 mg). Pharmacokinetic data showed that post-infusion concentrations of busulfan ranged from 50 to 150 microg/mL and declined to <1 microg/mL within 5 hours. CONCLUSIONS: Intrathecal Spartaject Busulfan was well tolerated in children with neoplastic meningitis from brain tumors, and the recommended dose for future phase II studies is 13 mg.

Authors
Gururangan, S; Petros, WP; Poussaint, TY; Hancock, ML; Phillips, PC; Friedman, HS; Bomgaars, L; Blaney, SM; Kun, LE; Boyett, JM
MLA Citation
Gururangan, Sridharan, et al. “Phase I trial of intrathecal spartaject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004)..” Clin Cancer Res, vol. 12, no. 5, Mar. 2006, pp. 1540–46. Pubmed, doi:10.1158/1078-0432.CCR-05-2094.
PMID
16533779
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
12
Issue
5
Publish Date
2006
Start Page
1540
End Page
1546
DOI
10.1158/1078-0432.CCR-05-2094

Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic O6-benzylguanine.

This study investigated whether the therapeutic index of regional melanoma therapy using parenteral temozolomide could be improved by chemomodulation with O6-benzylguanine (O6BG), an inhibitor of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT). Using a nude rat s.c. human melanoma xenograft model of the extremity, tumors were analyzed for AGT level 2 to 3 hours after the i.p. injection of 3.5 to 70.0 mg/kg O6BG to inhibit AGT activity. Survival studies were conducted using animals that were treated with a 15-minute isolated limb infusion with 10% DMSO in PBS (control), temozolomide alone, or temozolomide in conjunction with single or multiple doses of i.p. O6BG. Tumor volume and toxicity level were monitored every other day. Administration of 3.5 mg/kg O6BG depleted tumor AGT activity by 93.5% (P < 0.01). Groups treated with regional temozolomide alone (350 mg/kg), systemic temozolomide with O6BG, or vehicle combined with O6BG showed no significant tumor responses compared with controls. Whereas use of regional temozolomide alone at a higher dose (750 mg/kg) showed some degree of tumor response, regional temozolomide given in conjunction with multiple dosages of O6BG showed a marked (P < 0.01) reduction in tumor growth with minimal toxicity. Our findings suggest that AGT modulation by the administration of O6BG in combination with temozolomide regional chemotherapy leads to a significant improvement in melanoma antitumor responses. Clinical trials using chemotherapy modulation may improve response rates in future regional infusion and perfusion drug trials.

Authors
Ueno, T; Ko, SH; Grubbs, E; Yoshimoto, Y; Augustine, C; Abdel-Wahab, Z; Cheng, T-Y; Abdel-Wahab, OI; Pruitt, SK; Friedman, HS; Tyler, DS
MLA Citation
Ueno, Tomio, et al. “Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic O6-benzylguanine..” Mol Cancer Ther, vol. 5, no. 3, Mar. 2006, pp. 732–38. Pubmed, doi:10.1158/1535-7163.MCT-05-0098.
PMID
16546988
Source
pubmed
Published In
Molecular Cancer Therapeutics
Volume
5
Issue
3
Publish Date
2006
Start Page
732
End Page
738
DOI
10.1158/1535-7163.MCT-05-0098

Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma.

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent malignant glioma. PATIENTS AND METHODS: Gefitinib and sirolimus were administered on a continuous daily dosing schedule at dose levels that were escalated in successive cohorts of malignant glioma patients at any recurrence who were stratified based on concurrent use of CYP3A-inducing anticonvulsants [enzyme-inducing antiepileptic drugs, (EIAED)]. Pharmacokinetic and archival tumor biomarker data were also assessed. RESULTS: Thirty-four patients with progressive disease after prior radiation therapy and chemotherapy were enrolled, including 29 (85%) with glioblastoma multiforme and 5 (15%) with anaplastic glioma. The MTD was 500 mg of gefitinib plus 5 mg of sirolimus for patients not on EIAEDs and 1,000 mg of gefitinib plus 10 mg of sirolimus for patients on EIAEDs. DLTs included mucositis, diarrhea, rash, thrombocytopenia, and hypertriglyceridemia. Gefitinib exposure was not affected by sirolimus administration but was significantly lowered by concurrent EIAED use. Two patients (6%) achieved a partial radiographic response, and 13 patients (38%) achieved stable disease. CONCLUSION: We show that gefitinib plus sirolimus can be safely coadministered on a continuous, daily dosing schedule, and established the recommended dose level of these agents in combination for future phase 2 clinical trials.

Authors
Reardon, DA; Quinn, JA; Vredenburgh, JJ; Gururangan, S; Friedman, AH; Desjardins, A; Sathornsumetee, S; Herndon, JE; Dowell, JM; McLendon, RE; Provenzale, JM; Sampson, JH; Smith, RP; Swaisland, AJ; Ochs, JS; Lyons, P; Tourt-Uhlig, S; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Reardon, David A., et al. “Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma..” Clin Cancer Res, vol. 12, no. 3 Pt 1, Feb. 2006, pp. 860–68. Pubmed, doi:10.1158/1078-0432.CCR-05-2215.
PMID
16467100
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
12
Issue
3 Pt 1
Publish Date
2006
Start Page
860
End Page
868
DOI
10.1158/1078-0432.CCR-05-2215

The role of chemoresistance in regional infusion therapy for melanoma

Authors
Yoshimoto, Y; Yoo, JS; Augustine, CK; Pruitt, SK; Friedman, HS; Tyler, DS
MLA Citation
Yoshimoto, Y., et al. “The role of chemoresistance in regional infusion therapy for melanoma.” Annals of Surgical Oncology, vol. 13, no. 2, SPRINGER, 2006, pp. 82–82.
Source
wos
Published In
Annals of Surgical Oncology
Volume
13
Issue
2
Publish Date
2006
Start Page
82
End Page
82

Caregivers of brain tumor patients: Stress and intervention preferences

Authors
Keir, ST; Guill, AB; Carter, KE; Friedman, HS
MLA Citation
Keir, S. T., et al. “Caregivers of brain tumor patients: Stress and intervention preferences.” Psycho Oncology, vol. 15, no. 1, JOHN WILEY & SONS LTD, Feb. 2006, pp. S52–S52.
Source
wos
Published In
Psycho Oncology
Volume
15
Issue
1
Publish Date
2006
Start Page
S52
End Page
S52

Brain tumor patients: Stress and intervention preferences

Authors
Keir, ST; Guill, AB; Carter, KE; Friedman, HS
MLA Citation
Keir, S. T., et al. “Brain tumor patients: Stress and intervention preferences.” Psycho Oncology, vol. 15, no. 1, JOHN WILEY & SONS LTD, Feb. 2006, pp. S77–78.
Source
wos
Published In
Psycho Oncology
Volume
15
Issue
1
Publish Date
2006
Start Page
S77
End Page
S78

Moxifloxacin versus levofloxacin for treatment of acute rhinosinusitis: a retrospective database analysis of treatment duration, outcomes, and charges

Authors
Keating, KN; Friedman, HS; Perfetto, EM
MLA Citation
Keating, Karen N., et al. “Moxifloxacin versus levofloxacin for treatment of acute rhinosinusitis: a retrospective database analysis of treatment duration, outcomes, and charges.” Current Medical Research and Opinion, vol. 22, no. 2, Informa Healthcare, Feb. 2006, pp. 327–33. Crossref, doi:10.1185/030079906x80620.
Source
crossref
Published In
Current Medical Research and Opinion
Volume
22
Issue
2
Publish Date
2006
Start Page
327
End Page
333
DOI
10.1185/030079906x80620

Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity.

PURPOSE: Previous preclinical studies have shown that regional temozolomide therapy via isolated limb infusion is more effective than melphalan, the current drug of choice for regional chemotherapy for advanced extremity melanoma. The aim of this study was to determine whether hyperthermia could further augment the efficacy of temozolomide, an alkylating agent, against melanoma and improve its therapeutic index in a rat model of isolated limb infusion. EXPERIMENTAL DESIGN: Athymic rats bearing s.c. human melanoma xenografts (DM6) in their hind limbs were randomized to a 15-minute isolated limb infusion procedure with or without temozolomide at room temperature, normothermic (37.5 degrees C), or hyperthermic (43 degrees C) conditions. RESULTS: The concomitant administration of hyperthermia during an infusion with temozolomide led to the greatest increase in tumor growth delay, decreased proliferative index, and increased cell death. Isolated limb infusion treatment with a low dose (350 mg/kg) of temozolomide was ineffective at producing tumor growth delay (P = 0.07). Similarly, temozolomide infusion under normothermia yielded minimal tumor growth delay (P = 0.08). In contrast, the combination of hyperthermia plus temozolomide treatment produced marked tumor growth delay of 10.4 days (P = 0.02) with minimal toxicity. The addition of heat to temozolomide treatment yielded the smallest proliferative index (P = 0.001), while markedly increasing the level of apoptosis 48 hours after isolated limb infusion. CONCLUSION: This study, the first to examine the interaction between hyperthermia and temozolomide, shows a strong, synergistic antitumor effect when hyperthermia is combined with temozolomide for regional treatment of melanoma confined to an extremity. The mechanism of this synergy seems to be through an augmentation, by hyperthermia, of the antiproliferative and proapoptotic effects of temozolomide.

Authors
Ko, SH; Ueno, T; Yoshimoto, Y; Yoo, JS; Abdel-Wahab, OI; Abdel-Wahab, Z; Chu, E; Pruitt, SK; Friedman, HS; Dewhirst, MW; Tyler, DS
MLA Citation
Ko, Sae Hee, et al. “Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity..” Clin Cancer Res, vol. 12, no. 1, Jan. 2006, pp. 289–97. Pubmed, doi:10.1158/1078-0432.CCR-05-0210.
PMID
16397054
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
12
Issue
1
Publish Date
2006
Start Page
289
End Page
297
DOI
10.1158/1078-0432.CCR-05-0210

Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results.

PURPOSE: To assess the efficacy and toxicity of intraresection cavity iodine-131-labeled murine antitenascin monoclonal antibody 81C6 (131I-m81C6) among recurrent malignant brain tumor patients. PATIENTS AND METHODS: In this phase II trial, 100 mCi of 131I-m81C6 was injected directly into the surgically created resection cavity (SCRC) of 43 patients with recurrent malignant glioma (glioblastoma multiforme [GBM], n = 33; anaplastic astrocytoma [AA], n = 6; anaplastic oligodendroglioma [AO], n = 2; gliosarcoma [GS], n = 1; and metastatic adenocarcinoma, n = 1) followed by chemotherapy. RESULTS: With a median follow-up of 172 weeks, 63% and 59% of patients with GBM/GS and AA/AO tumors were alive at 1 year. Median overall survival for patients with GBM/GS and AA/AO tumors was 64 and 99 weeks, respectively. Ten patients (23%) developed acute hematologic toxicity. Five patients (12%) developed acute reversible neurotoxicity. One patient (2%) developed irreversible neurotoxicity. No patients required reoperation for radionecrosis. CONCLUSION: In this single-institution phase II study, administration of 100 mCi of 131I-m81C6 to recurrent malignant glioma patients followed by chemotherapy is associated with a median survival that is greater than that of historical controls treated with surgery plus iodine-125 brachytherapy. Furthermore, toxicity was acceptable. Administration of a fixed millicurie dose resulted in a wide range of absorbed radiation doses to the SCRC. We are now conducting a phase II trial, approved by the US Food and Drug Administration, using patient-specific 131I-m81C6 dosing, to deliver 44 Gy to the SCRC followed by standardized chemotherapy. A phase III multicenter trial with patient-specific dosing is planned.

Authors
Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Pegram, CN; Provenzale, JM; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Gururangan, S; Badruddoja, M; Dowell, JM; Wong, TZ; Zhao, X-G; Zalutsky, MR; Bigner, DD
MLA Citation
Reardon, David A., et al. “Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results..” J Clin Oncol, vol. 24, no. 1, Jan. 2006, pp. 115–22. Pubmed, doi:10.1200/JCO.2005.03.4082.
PMID
16382120
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
1
Publish Date
2006
Start Page
115
End Page
122
DOI
10.1200/JCO.2005.03.4082

Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor.

Carbohydration of N-terminus and substitution of a threonine for the threoninol residue at the C-terminus of Tyr3-octreotide (TOC) has resulted in improved pharmacokinetics and tumor targeting of its radioiodinated derivatives. Yet, these peptides are very susceptible to in vivo deiodination due to the similarity of monoiodotyrosine (MIT) to thyroid hormone. The goal of this work was to develop octreotate analogues containing both a sugar moiety and a nontyrosine prosthetic group on which a radioiodine or 211At can be introduced. Solid-phase synthesis and subsequent modifications delivered an iodo standard of the target peptide N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-(3-iodobenzoyl)-Lys0-octreotate (GIBLO) and the corresponding tin precursor N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-[(3-tri-n-butylstannyl)benzoyl]-Lys0-octreotate (GTBLO). GIBLO displaced [125I]TOC from somatostatin receptor subtype 2 (SSTR2)-positive AR42J rat pancreatic tumor cell membranes with an IC50 of 0.46 +/- 0.05 nM suggesting that GIBLO retained affinity to SSTR2. GTBLO was radiohalogenated to [131I]GIBLO and N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-(3-[211At]astatobenzoyl)-Lys0-octreotate ([211At]GABLO) in 21.2 +/- 4.9% and 46.8 +/- 9.5% radiochemical yields, respectively. From a paired-label internalization assay using D341 Med medulloblastoma cells, the maximum specific internalized radioactivity from [131I]GIBLO was 1.78 +/- 0.8% of input dose compared to 9.67 +/- 0.43% for N(alpha)-(1-deoxy-D-fructosyl)-[125I]iodo-Tyr3-octreotate ([125I]I-Gluc-TOCA). Over a 4 h period, the extent of internalization of [131I]GIBLO and [211At]GABLO was similar in this cell line. In D341 Med murine subcutaneous xenografts, the uptake of [125I]I-Gluc-TOCA at 0.5, 1 and 4 h was 21.5 +/- 4.0% ID/g, 18.8 +/- 7.7% ID/g, and 0.9 +/- 0.4% ID/g, respectively. In comparison, these values for [131I]GIBLO were 6.9 +/- 1.2% ID/g, 4.7 +/- 1.4% ID/g, and 0.8 +/- 0.5% ID/g. Both in vitro and in vivo catabolism studies did not suggest the severance of the lys0 along with its appendages from the peptide. Taken together, although GIBLO maintained affinity to SSTR2, its tumor uptake both in vitro and in vivo was substantially lower than that of I-Gluc-TOCA suggesting other factors such as net charge and overall geometry of the peptide may be important.

Authors
Vaidyanathan, G; Affleck, DJ; Schottelius, M; Wester, H; Friedman, HS; Zalutsky, MR
MLA Citation
Vaidyanathan, G., et al. “Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor..” Bioconjug Chem, vol. 17, no. 1, Jan. 2006, pp. 195–203. Pubmed, doi:10.1021/bc0502560.
PMID
16417269
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
17
Issue
1
Publish Date
2006
Start Page
195
End Page
203
DOI
10.1021/bc0502560

Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.

PURPOSE: We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). RESULTS: Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. CONCLUSION: Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

Authors
Reardon, DA; Egorin, MJ; Quinn, JA; Rich, JN; Gururangan, S; Vredenburgh, JJ; Desjardins, A; Sathornsumetee, S; Provenzale, JM; Herndon, JE; Dowell, JM; Badruddoja, MA; McLendon, RE; Lagattuta, TF; Kicielinski, KP; Dresemann, G; Sampson, JH; Friedman, AH; Salvado, AJ; Friedman, HS
MLA Citation
Reardon, David A., et al. “Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme..” J Clin Oncol, vol. 23, no. 36, Dec. 2005, pp. 9359–68. Pubmed, doi:10.1200/JCO.2005.03.2185.
PMID
16361636
Source
pubmed
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
23
Issue
36
Publish Date
2005
Start Page
9359
End Page
9368
DOI
10.1200/JCO.2005.03.2185

A phase I trial of AP23573, a novel mTOR inhibitor, in patients (Pts) with recurrent malignant glioma.

Authors
Reardon, DA; Wen, PY; Lyons, P; Rich, JN; Berk, L; Knowles, HL; Rivera, VM; Bedrosian, CL; Friedman, HS
MLA Citation
Reardon, D. A., et al. “A phase I trial of AP23573, a novel mTOR inhibitor, in patients (Pts) with recurrent malignant glioma..” Clinical Cancer Research, vol. 11, no. 24, AMER ASSOC CANCER RESEARCH, 2005, pp. 9012S-9012S.
Source
wos
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
11
Issue
24
Publish Date
2005
Start Page
9012S
End Page
9012S

Evaluation of bortezomib against childhood tumor models by the pediatric preclinical testing program (PPTP)

Authors
Houghton, PJ; Maris, JM; Friedman, HS; Keir, ST; Lock, RB; Gorlick, R; Kolb, EA; Reynolds, CP; Morton, C; Smith, MA
MLA Citation
Houghton, P. J., et al. “Evaluation of bortezomib against childhood tumor models by the pediatric preclinical testing program (PPTP).” Clinical Cancer Research, vol. 11, no. 24, AMER ASSOC CANCER RESEARCH, 2005, pp. 8987S-8988S.
Source
wos
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
11
Issue
24
Publish Date
2005
Start Page
8987S
End Page
8988S

Ependymoma

Authors
Friedman, AH; McLendon, RE; Provenzale, JN; Friedman, HS
MLA Citation
Friedman, A. H., et al. Ependymoma. Dec. 2005, pp. 190–98. Scopus, doi:10.1016/B978-0-7216-8148-1.50028-0.
Source
scopus
Publish Date
2005
Start Page
190
End Page
198
DOI
10.1016/B978-0-7216-8148-1.50028-0

ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors.

PURPOSE: Primary central nervous system (CNS) tumors represent a diverse group of tumor types with heterogeneous molecular mechanisms that underlie their formation and maintenance. CNS tumors depend on angiogenesis and often display increased activity of ErbB-associated pathways. Current nonspecific therapies frequently have poor efficacy in many of these tumor types, so there is a pressing need for the development of novel targeted therapies. EXPERIMENTAL DESIGN: ZD6474 is a novel, orally available low molecular weight inhibitor of the kinase activities associated with vascular endothelial growth factor receptor-2 and epidermal growth factor receptor. We hypothesized that ZD6474 may provide benefit in the treatment of several CNS tumor types. RESULTS: In mice bearing established s.c. tumor xenografts of CNS tumors (malignant glioma and ependymoma) or rhabdomyosarcoma, a limited course of ZD6474 treatment produced significant tumor growth delays and a high rate of partial tumor regression in most models examined. Mice with i.c. malignant glioma xenografts treated with ZD6474 experienced a significant prolongation of survival. Tumors from mice treated with ZD6474 displayed a lower proliferative index and disrupted tumor vascularity. Notably, some of these models are insensitive to low molecular weight kinase inhibitors targeting only vascular endothelial growth factor receptor-2 or epidermal growth factor receptor functions, suggesting that the combined disruption of both epidermal growth factor receptor and vascular endothelial growth factor receptor-2 activities may significantly increase tumor control. CONCLUSIONS: In conclusion, ZD6474 shows significant activity against xenograft models of several primary human CNS tumor types. Consideration for clinical development in this disease setting seems warranted.

Authors
Rich, JN; Sathornsumetee, S; Keir, ST; Kieran, MW; Laforme, A; Kaipainen, A; McLendon, RE; Graner, MW; Rasheed, BKA; Wang, L; Reardon, DA; Ryan, AJ; Wheeler, C; Dimery, I; Bigner, DD; Friedman, HS
MLA Citation
Rich, Jeremy N., et al. “ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors..” Clin Cancer Res, vol. 11, no. 22, Nov. 2005, pp. 8145–57. Pubmed, doi:10.1158/1078-0432.CCR-05-0319.
PMID
16299247
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
11
Issue
22
Publish Date
2005
Start Page
8145
End Page
8157
DOI
10.1158/1078-0432.CCR-05-0319

Glioblastoma multiforme and the epidermal growth factor receptor.

Authors
Friedman, HS; Bigner, DD
MLA Citation
Friedman, Henry S., and Darell D. Bigner. “Glioblastoma multiforme and the epidermal growth factor receptor..” N Engl J Med, vol. 353, no. 19, Nov. 2005, pp. 1997–99. Pubmed, doi:10.1056/NEJMp058186.
PMID
16282174
Source
pubmed
Published In
The New England Journal of Medicine
Volume
353
Issue
19
Publish Date
2005
Start Page
1997
End Page
1999
DOI
10.1056/NEJMp058186

Longevity following the experience of parental divorce

Authors
Martin, LR; Friedman, HS; Clark, KM; Tucker, JS
MLA Citation
Martin, Leslie R., et al. “Longevity following the experience of parental divorce.” Social Science & Medicine, vol. 61, no. 10, Elsevier BV, Nov. 2005, pp. 2177–89. Crossref, doi:10.1016/j.socscimed.2005.04.027.
Source
crossref
Published In
Social Science & Medicine
Volume
61
Issue
10
Publish Date
2005
Start Page
2177
End Page
2189
DOI
10.1016/j.socscimed.2005.04.027

Survival analysis of presumptive prognostic markers among oligodendrogliomas.

BACKGROUND: Allelic losses of 1p and 19q arms correlate with the oligodendroglial phenotype as well as with sensitivity to radiotherapy and chemotherapy. Furthermore, the DNA repair gene, methylguanine methyltransferase (MGMT), is diminished in 80% of oligodendroglial tumors and represents a possible mechanism for this therapeutic sensitivity. However, the authors questioned the relevance of genetic testing and measuring MGMT levels in tumors that were diagnostic of oligodendroglioma. METHODS: The authors performed a retrospective analysis of 1p, 19q, 9p21, TP53, and MGMT status in 46 patients with oligodendrogliomas to address any relations that may exist among these markers with regard to progression-free survival (PFS) and total survival. Methodologies included comparative genomic hybridization; loss of heterozygosity (LOH) on 1p, 19q, and 9p21; TP53 mutational analysis; and immunohistochemistry for MGMT. RESULTS: The authors found that survival among patients with light microscopically diagnosed oligodendroglial tumors demonstrating LOH of 1p and 19q trended toward statistical significance (P = 0.102 and P = 0.058, respectively). 9p21 LOH was significant as a predictor of PFS only among anaplastic oligodendrogliomas in this cohort (P = 0.033). TP53 mutation was found to be significantly predictive of a shorter survival (P = 0.027) among all patients and exhibited a strong trend toward a shorter PFS (P = 0.060). Low-level MGMT labeling index (LI) (< 20%) was noted in 86% of all oligodendroglial tumors. MGMT LI was not found to correlate with an improved PFS or total survival in this cohort, recognizing that median survival was not reached after a median follow-up of 104 months. CONCLUSIONS: 9p21 and TP53 mutational status assisted in developing a stricter subclassification of these tumors with prognostic significance. MGMT levels were decreased in a majority of oligodendrogliomas.

Authors
McLendon, RE; Herndon, JE; West, B; Reardon, D; Wiltshire, R; Rasheed, BKA; Quinn, J; Friedman, HS; Friedman, AH; Bigner, DD
MLA Citation
McLendon, Roger E., et al. “Survival analysis of presumptive prognostic markers among oligodendrogliomas..” Cancer, vol. 104, no. 8, Oct. 2005, pp. 1693–99. Pubmed, doi:10.1002/cncr.21362.
PMID
16116609
Source
pubmed
Published In
Cancer
Volume
104
Issue
8
Publish Date
2005
Start Page
1693
End Page
1699
DOI
10.1002/cncr.21362

Etoposide, vincristine, and cyclosporin A with standard-dose radiation therapy in newly diagnosed diffuse intrinsic brainstem gliomas: a pediatric oncology group phase I study.

BACKGROUND: Brainstem gliomas (BSGs) are resistant to all therapy. Based on their imaging characteristics, we postulated that inhibition of P-glycoprotein (P-gp) associated with endothelial cells of the blood-brain barrier might enhance penetration of xenobiotic antineoplastics. PROCEDURE: Seven patients were enrolled in a Phase I study of etoposide, continuous infusion cyclosporine A given with and escalating doses of vincristine and concomitant standard-dose irradiation. RESULTS: Six patients were entered at the first level and one at the second. Closure of the study was mandated by dose-limiting neurotoxicity, consisting of seizures associated with white-matter changes, and alteration of consciousness with bulbar signs. One patient had tumor necrosis at 6 weeks, suggesting some tumor effect. Median survival for the group was 11 months, and for the patients who completed more than 1 month of therapy it was 11 months. CONCLUSION: This regimen proved excessively toxic.

Authors
Greenberg, ML; Fisher, PG; Freeman, C; Korones, DN; Bernstein, M; Friedman, H; Blaney, S; Hershon, L; Zhou, T; Chen, Z; Kretschmar, C
MLA Citation
Greenberg, Mark L., et al. “Etoposide, vincristine, and cyclosporin A with standard-dose radiation therapy in newly diagnosed diffuse intrinsic brainstem gliomas: a pediatric oncology group phase I study..” Pediatr Blood Cancer, vol. 45, no. 5, Oct. 2005, pp. 644–48. Pubmed, doi:10.1002/pbc.20382.
PMID
16110498
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
45
Issue
5
Publish Date
2005
Start Page
644
End Page
648
DOI
10.1002/pbc.20382

Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma.

BACKGROUND: The authors determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan (CPT-11), a topoisomerase I inhibitor, when administered with temozolomide among patients with recurrent malignant glioma (MG). METHODS: Patients with MG at any recurrence received temozolomide (TMZ) at a dose of 200 mg/m(2)/day on Days 1-5 plus CPT-11 administered as a 90-minute intravenous infusion during Weeks 1, 2, 4, and 5 of each 6-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing anticonvulsants (enzyme-inducing antiepileptic drugs [EIAEDs]). The CPT-11 dose was escalated in successive cohorts of patients independently for each stratum. RESULTS: CPT-11, at doses ranging from 40 mg/m(2) to 375 mg/m(2), was administered with TMZ to 107 patients. Ninety-one patients (85%) had recurrent glioblastoma multiforme (GBM) and 16 (15%) had recurrent anaplastic glioma. Sixty-eight patients (64%) were given EIAEDs. The MTD of CPT-11 for patients concurrently receiving and not receiving EIAEDs was 325 mg/m(2) and 125 mg/m(2), respectively. The DLTs were hematologic, gastrointestinal, and hepatic. Fifteen patients (14%) achieved either a radiographic complete (n = 5) or partial (n = 10) response across a wide range of CPT-11 dose levels. Patients with recurrent GBM who achieved radiographic response had a median time to disease progression of 54.9 weeks. CONCLUSIONS: The current study built on preclinical observations designed to increase the clinical activity of topoisomerase I inhibitors. CPT-11, administered at full dose levels, was well tolerated in combination with TMZ. Furthermore, durable responses were observed in this recurrent population. Ongoing Phase II studies will evaluate the efficacy of this regimen and its application to other malignancies.

Authors
Reardon, DA; Quinn, JA; Rich, JN; Desjardins, A; Vredenburgh, J; Gururangan, S; Sathornsumetee, S; Badruddoja, M; McLendon, R; Provenzale, J; Herndon, JE; Dowell, JM; Burkart, JL; Newton, HB; Friedman, AH; Friedman, HS
MLA Citation
Reardon, David A., et al. “Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma..” Cancer, vol. 104, no. 7, Oct. 2005, pp. 1478–86. Pubmed, doi:10.1002/cncr.21316.
PMID
16088964
Source
pubmed
Published In
Cancer
Volume
104
Issue
7
Publish Date
2005
Start Page
1478
End Page
1486
DOI
10.1002/cncr.21316

Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG. PATIENTS AND METHODS: For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined. RESULTS: The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression. CONCLUSION: This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.

Authors
Quinn, JA; Desjardins, A; Weingart, J; Brem, H; Dolan, ME; Delaney, SM; Vredenburgh, J; Rich, J; Friedman, AH; Reardon, DA; Sampson, JH; Pegg, AE; Moschel, RC; Birch, R; McLendon, RE; Provenzale, JM; Gururangan, S; Dancey, JE; Maxwell, J; Tourt-Uhlig, S; Herndon, JE; Bigner, DD; Friedman, HS
MLA Citation
Quinn, Jennifer A., et al. “Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma..” J Clin Oncol, vol. 23, no. 28, Oct. 2005, pp. 7178–87. Pubmed, doi:10.1200/JCO.2005.06.502.
PMID
16192602
Source
pubmed
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
23
Issue
28
Publish Date
2005
Start Page
7178
End Page
7187
DOI
10.1200/JCO.2005.06.502

Chemotherapy and novel therapeutic approaches in malignant glioma.

Glial neoplasms represent 0.5-1% of all cancers in most Western countries. Malignant gliomas are among the most devastating cancers, leading to death in most cases. They present unique challenges due to their location, aggressive biological behavior and diffuse infiltrative growth. Notwithstanding the development of new surgical and radiation techniques in the last thirty years, a cure for malignant gliomas remains elusive. In this article, we will review the standard and new therapies used for malignant gliomas. As standard therapies, surgery, radiation therapy and systemic chemotherapy, are in a continuous process of evolution. Multiple chemotherapies have been used in malignant gliomas, as single agents, in combination, or with different modes of administration, including high-dose chemotherapy with stem cell rescue and intra-arterial chemotherapy. The last decade has been noticeable for the advent of a better understanding of the biology of malignant gliomas. This has stimulated active research in multiples areas and the advent of new treatment strategies. Techniques to circumvent the resistance mechanisms to chemotherapy have been evaluated, tyrosine kinase inhibitors have shown activity in malignant primary brain tumors and radioimmunotherapy remains an area of active research. In this article, we review the past, present and future treatments of malignant gliomas with a special interest on chemotherapy, resistance mechanisms and tyrosine kinase inhibitors.

Authors
Desjardins, A; Rich, JN; Quinn, JA; Vredenburgh, J; Gururangan, S; Sathornsumetee, S; Reardon, DA; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Desjardins, Annick, et al. “Chemotherapy and novel therapeutic approaches in malignant glioma..” Front Biosci, vol. 10, Sept. 2005, pp. 2645–68.
PMID
15970525
Source
pubmed
Published In
Frontiers in Bioscience : a Journal and Virtual Library
Volume
10
Publish Date
2005
Start Page
2645
End Page
2668

Can PFS predict overall survival. Comment

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Can PFS predict overall survival. Comment.” Oncology Report, no. FALL, Sept. 2005.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2005
Start Page
14

Peritumoral administration best way to deliver ILI3PE. Comment

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Peritumoral administration best way to deliver ILI3PE. Comment.” Oncology Report, no. FALL, Sept. 2005.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2005
Start Page
12

Thalidomide does not improve survival. Comment

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Thalidomide does not improve survival. Comment.” Oncology Report, no. FALL, Sept. 2005, pp. 14–15.
Source
scopus
Published In
Oncology Report
Issue
FALL
Publish Date
2005
Start Page
14
End Page
15

Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft.

Temozolomide is a DNA-methylating agent used in the treatment of malignant gliomas. In this study, we have examined if inhibition of poly(ADP-ribose) polymerase (PARP) could increase the cytotoxicity of temozolomide, particularly in cells deficient in DNA mismatch repair. Athymic mice, transplanted with mismatch repair-proficient [D-245 MG] or deficient [D-245 MG (PR)] xenografts, were treated with a combination of temozolomide and the PARP inhibitor, INO-1001. For the tumors deficient in mismatch repair, the most effective dose of INO-1001 was found to be 150 mg/kg, given i.p. thrice at 4-hour intervals with the first injection in combination with 262.5 mg/kg temozolomide (0.75 LD(10)). This dose of temozolomide by itself induced no partial regressions and a 4-day growth delay. In two separate experiments, the combination therapy increased the growth delay by 21.6 and 9.7 days with partial regressions observed in four of eight and three of nine mice, respectively. The addition of INO-1001 had a more modest, yet statistically significant, increase in tumor growth delay in the mismatch repair-proficient xenografts. In these experiments, mice were treated with a lower amount of temozolomide (88 mg/kg), which resulted in growth delays of 43.1 and 39.2 days. When the temozolomide treatment was in combination with 200 mg/kg INO-1001, there was an increase in growth delay to 48.9 and 45.7 days, respectively. These results suggest that inhibition of PARP may increase the efficacy of temozolomide in the treatment of malignant gliomas, particularly in tumors deficient in DNA mismatch repair.

Authors
Cheng, CL; Johnson, SP; Keir, ST; Quinn, JA; Ali-Osman, F; Szabo, C; Li, H; Salzman, AL; Dolan, ME; Modrich, P; Bigner, DD; Friedman, HS
MLA Citation
Cheng, C. Lynn, et al. “Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft..” Mol Cancer Ther, vol. 4, no. 9, Sept. 2005, pp. 1364–68. Pubmed, doi:10.1158/1535-7163.MCT-05-0128.
PMID
16170028
Source
pubmed
Published In
Molecular Cancer Therapeutics
Volume
4
Issue
9
Publish Date
2005
Start Page
1364
End Page
1368
DOI
10.1158/1535-7163.MCT-05-0128

A phase I trial of gefitinib (ZD1 839) plus rapamycin for patients with recurrent malignant glioma.

Authors
Rich, JN; Reardon, DA; Quinn, JA; Vredenburgh, JJ; Desjardins, A; Sathornsumetee, S; Gururangan, S; Lyons, P; Bigner, DD; Friedman, HS
MLA Citation
Rich, J. N., et al. “A phase I trial of gefitinib (ZD1 839) plus rapamycin for patients with recurrent malignant glioma..” Journal of Clinical Oncology, vol. 23, no. 16, AMER SOC CLINICAL ONCOLOGY, 2005, pp. 130S-130S.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
130S
End Page
130S

Efficacy of imatinib mesylate plus hydroxyurea regimen in the treatment of recurrent malignant glioma: Phase II study results

Authors
Friedman, HS; Quinn, J; Rich, J; Vredenburgh, J; Desjardins, A; Sathornsumetee, S; Salvado, A; Nikolova, Z; Bigner, D; Reardon, D
MLA Citation
Friedman, H. S., et al. “Efficacy of imatinib mesylate plus hydroxyurea regimen in the treatment of recurrent malignant glioma: Phase II study results.” Journal of Clinical Oncology, vol. 23, no. 16, AMER SOC CLINICAL ONCOLOGY, 2005, pp. 117S-117S.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
117S
End Page
117S

A phase 1 dose escalation study of imatinib mesylate plus standard-dosed temozolomide in the treatment of patients with malignant glioma

Authors
Sathornsumetee, S; Reardon, DA; Quinn, J; Rich, JN; Vredenburgh, JJ; Desjardins, A; Gururangan, S; Lyons, P; Salvado, A; Friedman, HS
MLA Citation
Sathornsumetee, S., et al. “A phase 1 dose escalation study of imatinib mesylate plus standard-dosed temozolomide in the treatment of patients with malignant glioma.” Journal of Clinical Oncology, vol. 23, no. 16, AMER SOC CLINICAL ONCOLOGY, 2005, pp. 124S-124S.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
124S
End Page
124S

Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant gliomas: a phase II study.

UNLABELLED: The objective was to perform dosimetry and evaluate dose-response relationships in newly diagnosed patients with malignant brain tumors treated with direct injections of (131)I-labeled anti-tenascin murine 81C6 monoclonal antibody (mAb) into surgically created resection cavities (SCRCs) followed by conventional external-beam radiotherapy and chemotherapy. METHODS: Absorbed doses to the 2-cm-thick shell, measured from the margins of the resection cavity interface, were estimated for 33 patients with primary brain tumors. MRI/SPECT registrations were used to assess the distribution of the radiolabeled mAb in brain parenchyma. Results from biopsies obtained from 15 patients were classified as tumor, radionecrosis, or tumor and radionecrosis, and these were correlated with absorbed dose and dose rate. Also, MRI/PET registrations were used to assess radiographic progression among patients. RESULTS: This therapeutic strategy yielded a median survival of 86 and 79 wk for all patients and glioblastoma multiforme (GBM) patients, respectively. The average SCRC residence time of (131)I-mu81C6 mAb was 76 h (range, 34-169 h). The average absorbed dose to the 2-cm cavity margins was 48 Gy (range, 25-116 Gy) for all patients and 51 Gy (range, 27-116 Gy) for GBM patients. In MRI/SPECT registrations, we observed a preferential distribution of (131)I-mu81C6 mAb through regions of vasogenic edema. An analysis of the relationship between the absorbed dose and dose rate and the first biopsy results yielded a most favorable absorbed dose of 44 Gy. A correlation between decreased survival and irreversible neurotoxicity was noted. A comparative analysis, in terms of median survival, was performed with previous brachytherapy clinical studies, which showed a proportional relationship between the average boost absorbed dose and the median survival. CONCLUSION: This study shows that (131)I-mu81C6 mAb increases the median survival of GBM patients. An optimal absorbed dose of 44 Gy to the 2-cm cavity margins is suggested to reduce the incidence of neurologic toxicity. Further clinical studies are warranted to determine the effectiveness of (131)I-mu81C6 mAb based on a target dose of 44 Gy rather than a fixed administered activity.

Authors
Akabani, G; Reardon, DA; Coleman, RE; Wong, TZ; Metzler, SD; Bowsher, JE; Barboriak, DP; Provenzale, JM; Greer, KL; DeLong, D; Friedman, HS; Friedman, AH; Zhao, X-G; Pegram, CN; McLendon, RE; Bigner, DD; Zalutsky, MR
MLA Citation
Akabani, Gamal, et al. “Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant gliomas: a phase II study..” J Nucl Med, vol. 46, no. 6, June 2005, pp. 1042–51.
PMID
15937318
Source
pubmed
Published In
Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
Volume
46
Issue
6
Publish Date
2005
Start Page
1042
End Page
1051

Radiation sensitizer shows promise in breast cancer patients with brain metastases

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Radiation sensitizer shows promise in breast cancer patients with brain metastases.” Oncology Report, no. SPRING, Mar. 2005, pp. 14–16.
Source
scopus
Published In
Oncology Report
Issue
SPRING
Publish Date
2005
Start Page
14
End Page
16

'Encouraging news': Vaccine increases survival in phase I brain cancer trial

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “'Encouraging news': Vaccine increases survival in phase I brain cancer trial.” Oncology Report, no. SPRING, Mar. 2005, pp. 13–14.
Source
scopus
Published In
Oncology Report
Issue
SPRING
Publish Date
2005
Start Page
13
End Page
14

Promising results in overcoming temozolomide resistance

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Promising results in overcoming temozolomide resistance.” Oncology Report, no. SPRING, Mar. 2005, pp. 12–13.
Source
scopus
Published In
Oncology Report
Issue
SPRING
Publish Date
2005
Start Page
12
End Page
13

Adding temozolomide to radiation improves survival in patients with glioblastoma

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Adding temozolomide to radiation improves survival in patients with glioblastoma.” Oncology Report, no. SPRING, Mar. 2005, pp. 11–12.
Source
scopus
Published In
Oncology Report
Issue
SPRING
Publish Date
2005
Start Page
11
End Page
12

Carotid-artery stenting versus endarterectomy.

Authors
Friedman, HS
MLA Citation
Friedman, H. S. “Carotid-artery stenting versus endarterectomy..” The New England Journal of Medicine, vol. 352, no. 6, Feb. 2005, pp. 624–27.
Source
manual
Published In
The New England Journal of Medicine
Volume
352
Issue
6
Publish Date
2005
Start Page
624
End Page
627

Phase I clinical trial of mafosfamide in infants and children aged 3 years or younger with newly diagnosed embryonal tumors: a pediatric brain tumor consortium study (PBTC-001).

PURPOSE: A phase I trial of intrathecal (IT) mafosfamide was performed to determine the optimal dose, dose-limiting toxicities, and incidence and severity of other toxicities when administered in association with concomitant multiagent systemic chemotherapy to children younger than 3 years with newly diagnosed embryonal tumors. PATIENTS AND METHODS: Twenty-five assessable patients received IT mafosfamide at one of six dose levels ranging from 5 mg to 17 mg. Patients were premedicated with dexamethasone (0.15 mg/kg) and morphine (0.1 mg/kg) before receiving IT mafosfamide. Serial samples of CSF for pharmacokinetic studies were obtained in a subset of patients with Ommaya reservoirs. RESULTS: Irritability, presumably secondary to pain or headache during mafosfamide administration, was dose limiting in two of three patients at the 17-mg dose level. The maximum-tolerated dose of IT mafosfamide following premedication with dexamethasone and morphine was 14 mg. CONCLUSION: The maximum tolerated dose and recommended phase II dose of IT mafosfamide in patients younger than 3 years with newly diagnosed embryonal CNS tumors is 14 mg. A trial to assess the efficacy of regional therapy with IT mafosfamide administered with intensive systemic chemotherapy in children younger than 3 years with primary intracranial embryonal tumors is now in progress.

Authors
Blaney, SM; Boyett, J; Friedman, H; Gajjar, A; Geyer, R; Horowtiz, M; Hunt, D; Kieran, M; Kun, L; Packer, R; Phillips, P; Pollack, IF; Prados, M; Heideman, R
MLA Citation
Blaney, Susan M., et al. “Phase I clinical trial of mafosfamide in infants and children aged 3 years or younger with newly diagnosed embryonal tumors: a pediatric brain tumor consortium study (PBTC-001)..” J Clin Oncol, vol. 23, no. 3, Jan. 2005, pp. 525–31. Pubmed, doi:10.1200/JCO.2005.06.544.
PMID
15659498
Source
pubmed
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
23
Issue
3
Publish Date
2005
Start Page
525
End Page
531
DOI
10.1200/JCO.2005.06.544

Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma.

BACKGROUND: In the current study, the authors report a Phase II trial of irinotecan (CPT-11), a topoisomerase I inhibitor active against malignant glioma (MG), with celecoxib, a selective COX-2 inhibitor, among MG patients with recurrent disease. METHODS: Patients with MG at any type of recurrence received CPT-11, administered as a 90-minute intravenous infusion on Weeks 1, 2, 4, and 5 of each 6-week cycle plus celecoxib, which was administered continuously at a dose of 400 mg twice a day. CPT-11 was given at a dose of 350 mg/m(2) for patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and at a dose of 125 mg/m(2) for those patients not receiving EIAEDs. Assessments were performed after every cycle. The primary endpoint was radiographic response and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and therapeutic safety. RESULTS: Thirty-four of the 37 patients enrolled in the current study (92%) were diagnosed with recurrent GBM and 3 patients (8%) were diagnosed with recurrent anaplastic astrocytoma (AA). Twenty-one patients were receiving EIAEDs and 16 patients were not. The median follow-up time was 76.9 weeks. Concomitant CPT-11 plus celecoxib was found to be well tolerated and safe. Hematologic toxicities of >/= Grade 3 (according the second version of the Common Toxicity Criteria of the National Cancer Institute) reportedly complicated 8.6% of treatment courses. Grade 3 diarrhea, the most commonly reported nonhematologic toxicity, occurred with equal frequency (8%), regardless of whether the patient was receiving EIAED. Six patients (16%), all whom were diagnosed with recurrent GBM, achieved an objective radiographic response whereas an additional 13 patients (35%) achieved stable disease. The median PFS was 11.0 weeks and the 6-month PFS was reported to be 25.1%. The median OS was 31.5 weeks. CONCLUSIONS: The results of the current study confirm that CPT-11 plus celecoxib can be safely administered concurrently at full dose levels, and that this regimen has encouraging activity among heavily pretreated patients with recurrent MG.

Authors
Reardon, DA; Quinn, JA; Vredenburgh, J; Rich, JN; Gururangan, S; Badruddoja, M; Herndon, JE; Dowell, JM; Friedman, AH; Friedman, HS
MLA Citation
Reardon, David A., et al. “Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma..” Cancer, vol. 103, no. 2, Jan. 2005, pp. 329–38. Pubmed, doi:10.1002/cncr.20776.
PMID
15558802
Source
pubmed
Published In
Cancer
Volume
103
Issue
2
Publish Date
2005
Start Page
329
End Page
338
DOI
10.1002/cncr.20776

Sustained radiographic and clinical response in patient with bifrontal recurrent glioblastoma multiforme with intracerebral infusion of the recombinant targeted toxin TP-38: case study.

Glioblastoma multiforme remains refractory to conventional therapy, and novel therapeutic modalities are desperately needed. TP-38 is a recombinant chimeric protein containing a genetically engineered form of the cytotoxic Pseudomonas exotoxin fused to transforming growth factor (TGF)-alpha. TGF-alpha binds with high affinity to the epidermal growth factor receptor, which is uniformly overexpressed in malignant gliomas, often because of gene amplification. Prior to therapy with TP-38, the patient described here was completely refractory to multiple other therapies, with radiographic and pathologic evidence of tumor progression. After therapy, she improved clinically, was weaned off steroids and anti-convulsants, and experienced a progressive decrease in enhancing tumor volume. Despite multiple prior recurrences, she has not progressed for >43 months after TP-38 therapy. Small remaining areas of enhancement demonstrate no evidence of tumor histologically and are hypometabolic on positron emission tomography. This report describes a dramatic and sustained clinical and radiographic response in a patient with a bifrontal glioblastoma multiforme treated with intratumoral infusion of a novel targeted toxin, TP-38.

Authors
Sampson, JH; Reardon, DA; Friedman, AH; Friedman, HS; Coleman, RE; McLendon, RE; Pastan, I; Bigner, DD
MLA Citation
Sampson, John H., et al. “Sustained radiographic and clinical response in patient with bifrontal recurrent glioblastoma multiforme with intracerebral infusion of the recombinant targeted toxin TP-38: case study..” Neuro Oncol, vol. 7, no. 1, Jan. 2005, pp. 90–96. Pubmed, doi:10.1215/S1152851703000589.
PMID
15701286
Source
pubmed
Published In
Neuro Oncology
Volume
7
Issue
1
Publish Date
2005
Start Page
90
End Page
96
DOI
10.1215/S1152851703000589

Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition.

Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a single molecular target may slow tumor progression, but tumors are likely not dependent on a signal transduction pathway. Rather, malignant gliomas exhibit sustained mitogenesis and cell growth mediated in part through the effects of receptor tyrosine kinases and the mammalian target of rapamycin (mTOR). AEE788 is a novel orally active tyrosine kinase inhibitor that decreases the kinase activity associated with the epidermal growth factor receptor and, at higher concentrations, the vascular endothelial growth factor receptor 2 (kinase domain region). RAD001 (everolimus) is an orally available mTOR inhibitor structurally related to rapamycin. We hypothesized that combined inhibition of upstream epidermal growth factor receptor and kinase domain region receptors with AEE788 and inhibition of the downstream mTOR pathway with RAD001 would result in increased efficacy against gliomas compared with single-agent therapy. In vitro experiments showed that the combination of AEE788 and RAD001 resulted in increased rates of cell cycle arrest and apoptosis and reduced proliferation more than either agent alone. Combined AEE788 and RAD001 given orally to athymic mice bearing established human malignant glioma tumor xenografts resulted in greater tumor growth inhibition and greater increases in median survival than monotherapy. These studies suggest that simultaneous inhibition of growth factor receptor and mTOR pathways offer increased benefit in glioma therapy.

Authors
Goudar, RK; Shi, Q; Hjelmeland, MD; Keir, ST; McLendon, RE; Wikstrand, CJ; Reese, ED; Conrad, CA; Traxler, P; Lane, HA; Reardon, DA; Cavenee, WK; Wang, X-F; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Goudar, Ranjit K., et al. “Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition..” Mol Cancer Ther, vol. 4, no. 1, Jan. 2005, pp. 101–12.
PMID
15657358
Source
pubmed
Published In
Molecular Cancer Therapeutics
Volume
4
Issue
1
Publish Date
2005
Start Page
101
End Page
112

Secreted protein acidic, rich in cysteine (SPARC), mediates cellular survival of gliomas through AKT activation.

Secreted protein acidic, rich in cysteine (SPARC), is an extracellular matrix protein expressed in many advanced cancers, including malignant gliomas. We and others have previously shown that human glioma cell lines engineered to overexpress SPARC adopt an invasive phenotype. We now show that SPARC expression increases cell survival under stress initiated by serum withdrawal through a decrease in apoptosis. Phosphatidylinositol 3-OH kinase/AKT is a potent pro-survival pathway that contributes to the malignancy of gliomas. Cells expressing SPARC display increased AKT activation with decreased caspase 3/7 activity. Exogenous SPARC rapidly induces AKT phosphorylation, an effect that is blocked by a neutralizing SPARC antibody. Furthermore, AKT activation is essential for the anti-apoptotic effects of SPARC as the decreased apoptosis and caspase activity associated with SPARC expression can be blocked with dominant-negative AKT or a specific AKT inhibitor. As tumor cells face stressful microenvironments particularly during the process of invasion, these results suggest that SPARC functions, in part, to promote tumor progression by enabling tumor cells to survive under stressful conditions.

Authors
Shi, Q; Bao, S; Maxwell, JA; Reese, ED; Friedman, HS; Bigner, DD; Wang, X-F; Rich, JN
MLA Citation
Shi, Qing, et al. “Secreted protein acidic, rich in cysteine (SPARC), mediates cellular survival of gliomas through AKT activation..” J Biol Chem, vol. 279, no. 50, Dec. 2004, pp. 52200–09. Pubmed, doi:10.1074/jbc.M409630200.
PMID
15469933
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
279
Issue
50
Publish Date
2004
Start Page
52200
End Page
52209
DOI
10.1074/jbc.M409630200

Temozolomide is a novel regional infusion agent for the treatment of advanced extremity melanoma.

BACKGROUND: Regional infusion therapy with melphalan (LPAM) is an accepted treatment for advanced extremity melanoma. However, much room exists for improving the therapeutic index of this type of therapy. METHODS: Isolated limb infusion (ILI) with temozolomide (TMZ), a novel methylating agent, was performed using a nude rat bearing human melanoma xenograft. Additional rats were treated systemically with TMZ, or regionally with LPAM or 10% dimethyl sulfoxide (DMSO; control) using ILI. RESULTS: Rats that received systemic TMZ showed a poor tumor response and no tumor regression. In contrast, intra-arterial TMZ demonstrated a prolongation of tumor growth delay in a dose-responsive manner. In comparison with LPAM of equitoxic dose, TMZ provided both longer tumor growth delay and a greater number of tumor regressions. CONCLUSIONS: These data suggest that ILI with TMZ is an effective treatment for advanced extremity melanoma and may be better than LPAM in this setting.

Authors
Ueno, T; Ko, SH; Grubbs, E; Pruitt, SK; Friedman, HS; Tyler, DS
MLA Citation
Ueno, Tomio, et al. “Temozolomide is a novel regional infusion agent for the treatment of advanced extremity melanoma..” Am J Surg, vol. 188, no. 5, Nov. 2004, pp. 532–37. Pubmed, doi:10.1016/j.amjsurg.2004.07.014.
PMID
15546565
Source
pubmed
Published In
American Journal of Surgery
Volume
188
Issue
5
Publish Date
2004
Start Page
532
End Page
537
DOI
10.1016/j.amjsurg.2004.07.014

Recent advances in the treatment of pediatric brain tumors.

Central nervous system (CNS) cancers are the second most frequent malignancy (and the most common solid tumor) in childhood. In recent years, significant advances in surgery, radiotherapy, and chemotherapy have improved survival in children with these tumors. However, a significant proportion of patients with CNS tumors suffer progressive disease despite such treatment. Advances in the understanding of the nature of the blood-brain/tumor barrier, chemotherapy resistance, tumor biology, and the role of angiogenesis in tumor progression and metastases have led to the advent of newer therapeutic strategies that circumvent these obstacles or target specific receptors that control signal transduction and/or angiogenesis in tumor cells. Ongoing clinical trials will determine whether these novel treatment modalities will improve outcomes for children with brain tumors.

Authors
Gururangan, S; Friedman, HS
MLA Citation
Gururangan, Sri, and Henry S. Friedman. “Recent advances in the treatment of pediatric brain tumors..” Oncology (Williston Park), vol. 18, no. 13, Nov. 2004, pp. 1649–61.
PMID
15648297
Source
pubmed
Published In
Oncology (Williston Park, N.Y.)
Volume
18
Issue
13
Publish Date
2004
Start Page
1649
End Page
1661

ZD6474, a vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor, inhibits growth of multiple primary central nervous system tumor types

Authors
Rich, JN; Loncar, D; Sathornsumetee, S; Keir, S; Wheeler, C; Dimery, I; Bigner, DD; Friedman, HS
MLA Citation
Rich, J. N., et al. “ZD6474, a vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor, inhibits growth of multiple primary central nervous system tumor types.” Neuro Oncology, vol. 6, no. 4, DUKE UNIV PRESS, 2004, pp. 413–413.
Source
wos
Published In
Neuro Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
413
End Page
413

Inhibition of receptor tyrosine kinases and mammalian target of rapamycin offers combinatorial benefit in tumor control

Authors
Gondar, RK; Hjelmeland, MD; Keir, ST; Conrad, CA; McLendon, RE; Wikstrand, CJ; Traxler, P; Lane, HA; Reardon, DA; Cavenee, WK; Wang, XF; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Gondar, R. K., et al. “Inhibition of receptor tyrosine kinases and mammalian target of rapamycin offers combinatorial benefit in tumor control.” Neuro Oncology, vol. 6, no. 4, DUKE UNIV PRESS, 2004, pp. 407–407.
Source
wos
Published In
Neuro Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
407
End Page
407

Extraosseous Ewings sarcoma (EES) of the central nervous system (CNS) - Case reports and molecular diagnosis

Authors
Gururangan, S; Bridge, JA; Cummings, TJ; Halperin, EC; Friedman, HS
MLA Citation
Gururangan, S., et al. “Extraosseous Ewings sarcoma (EES) of the central nervous system (CNS) - Case reports and molecular diagnosis.” Neuro Oncology, vol. 6, no. 4, DUKE UNIV PRESS, 2004, pp. 457–457.
Source
wos
Published In
Neuro Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
457
End Page
457

Phase I trial of adults with primary malignant glioma with irinotecan (CPT-11) plus temozolomide (Temodar)

Authors
Desjardins, A; Reardon, D; Vredenburgh, J; Rich, J; Gururangan, S; Friedman, A; Sampson, J; Provenzale, J; McLendon, R; Herndon, J; Badruddoja, M; Amara, J; Tourt-Uhlig, S; Newton, H; Friedman, HS; Quinn, JA
MLA Citation
Desjardins, A., et al. “Phase I trial of adults with primary malignant glioma with irinotecan (CPT-11) plus temozolomide (Temodar).” Neuro Oncology, vol. 6, no. 4, DUKE UNIV PRESS, 2004, pp. 373–74.
Source
wos
Published In
Neuro Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
373
End Page
374

Phase II upfront CPT-11 plus celecoxib for adults with glioblastoma multiforme

Authors
Badruddoja, MA; Reardon, DA; Vredenburgh, JJ; Quinn, JA; Rich, JN; Desjardins, A; Friedman, A; Walker, A; Bailey, P; Jex, R; Friedman, HS
MLA Citation
Badruddoja, M. A., et al. “Phase II upfront CPT-11 plus celecoxib for adults with glioblastoma multiforme.” Neuro Oncology, vol. 6, no. 4, DUKE UNIV PRESS, 2004, pp. 369–70.
Source
wos
Published In
Neuro Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
369
End Page
370

Phase I trial of temozolomide (Temodar) plus irinotecan (CPT-11) plus O6-benzylguanine (O6-BG) in the treatment of recurrent or progressive cerebral anaplastic gliomas

Authors
Quinn, JA; Desjardins, A; Reardon, D; Vredenburgh, J; Rich, J; Gururangan, S; Friedman, A; Sampson, J; Provenzale, J; McLendon, R; Herndon, J; Dolan, ME; Badruddoja, M; Walker, A; Tourt-Uhlig, S; Friedman, HS
MLA Citation
Quinn, J. A., et al. “Phase I trial of temozolomide (Temodar) plus irinotecan (CPT-11) plus O6-benzylguanine (O6-BG) in the treatment of recurrent or progressive cerebral anaplastic gliomas.” Neuro Oncology, vol. 6, no. 4, DUKE UNIV PRESS, 2004, pp. 380–380.
Source
wos
Published In
Neuro Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
380
End Page
380

Phase II trial of temozolomide (Temodar) plus O6-benzylguanine (O6-BG) in the treatment of patients with Temodar-resistant malignant glioma

Authors
Quinn, JA; Desjardins, A; Reardon, D; Vredenburgh, J; Rich, J; Gururangan, S; Friedman, A; Sampson, J; Provenzale, J; McLendon, R; Herndon, J; Dolan, ME; Badruddoja, M; Walker, A; Tourt-Uhlig, S; Friedman, HS
MLA Citation
Quinn, J. A., et al. “Phase II trial of temozolomide (Temodar) plus O6-benzylguanine (O6-BG) in the treatment of patients with Temodar-resistant malignant glioma.” Neuro Oncology, vol. 6, no. 4, DUKE UNIV PRESS, 2004, pp. 380–380.
Source
wos
Published In
Neuro Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
380
End Page
380

Somatostatin targeted radiotherapeuiccs for medulloblastoma

Authors
Vaidyanathan, G; Boskovitz, A; Friedman, HS; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G., et al. “Somatostatin targeted radiotherapeuiccs for medulloblastoma.” Neuro Oncology, vol. 6, no. 4, DUKE UNIV PRESS, 2004, pp. 416–416.
Source
wos
Published In
Neuro Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
416
End Page
416

Phase II study of oral temozolomide (TMZ) in children with progressive low-grade gliomas (LGG)

Authors
Gururangan, S; Allen, JC; Phillips, PC; Dillard, E; Friedman, HS
MLA Citation
Gururangan, S., et al. “Phase II study of oral temozolomide (TMZ) in children with progressive low-grade gliomas (LGG).” Neuro Oncology, vol. 6, no. 4, DUKE UNIV PRESS, 2004, pp. 457–457.
Source
wos
Published In
Neuro Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
457
End Page
457

Incidence and patterns of neuraxis metastasis (NM) in patients (PTS) with diffuse pon'ine glioma (DPG)

Authors
Brashears, J; Gururangan, S; McLaughlin, C; Morgan, M; Provenzale, J; Halperin, EC; Friedman, HS
MLA Citation
Brashears, J., et al. “Incidence and patterns of neuraxis metastasis (NM) in patients (PTS) with diffuse pon'ine glioma (DPG).” Neuro Oncology, vol. 6, no. 4, DUKE UNIV PRESS, 2004, pp. 417–417.
Source
wos
Published In
Neuro Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
417
End Page
417

A 4-methyl-substituted meta-iodobenzylguanidine analogue with prolonged retention in human neuroblastoma cells.

PURPOSE: As a part of our efforts to develop a meta-iodobenzylguanidine (MIBG) analogue with improved characteristics for the diagnosis and treatment of neuroendocrine tumours, 3-[131I]iodo-4-methyl-benzylguanidine ([131I]MeIBG) has been developed. The purpose of this study was to evaluate [131I]MeIBG in vitro using the uptake-1 positive SK-N-SH neuroblastoma cell line and in vivo in normal mice and mice bearing human neuroblastoma xenografts. METHODS: The ability of SK-N-SH human neuroblastoma cells to retain [131I]MeIBG in vitro over a period of 4 days, in comparison to [125I]MIBG, was determined by a paired-label assay. Paired-label biodistributions of [131I]MeIBG and [125I]MIBG were performed in normal mice as well as in athymic mice bearing SK-N-SH and IMR-32 human neuroblastoma xenografts. RESULTS: Retention of [131I]MeIBG by SK-N-SH cells in vitro was increased by factors of 1.2, 1.5, 2.0, 2.5 and 3.1 compared with [125I]MIBG at 8, 24, 48, 72 and 96 h, respectively. In normal mice, the uptake of [131I]MeIBG in the heart was similar to that of [125I]MIBG at 1 and 4 h; in contrast, myocardial uptake of [131I]MeIBG was 1.6-fold higher than that of [125I]MIBG (p<0.05) at 24 h. When mice were pre-treated with the uptake-1 inhibitor desipramine (DMI), the heart uptake of both tracers was reduced to about half that in untreated controls at 1 h post injection (p<0.05). The hepatic uptake of [131I]MeIBG was two- to threefold lower than that of [125I]MIBG. On the other hand, blood levels of [131I]MeIBG were substantially higher (up to sixfold), especially at early time points. Uptake of [131I]MeIBG in heart and tumour at 1 h in the murine SK-N-SH model was specific and comparable to that of [125I]MIBG. However, [131I]MeIBG uptake was 1.6- to 1.7-fold lower than that of [125I]MIBG over 4-48 h. While the uptake of both tracers in IMR32 xenografts was similar, it was not uptake-1 mediated. CONCLUSION: Introduction of a methyl group at the 4-position of MIBG seems to be advantageous in terms of higher tumour retention in vitro and lower hepatic uptake in vivo. However, the slower blood clearance of MeIBG may be problematic for some applications.

Authors
Vaidyanathan, G; Welsh, PC; Vitorello, KC; Snyder, S; Friedman, HS; Zalutsky, MR
MLA Citation
Vaidyanathan, Ganesan, et al. “A 4-methyl-substituted meta-iodobenzylguanidine analogue with prolonged retention in human neuroblastoma cells..” Eur J Nucl Med Mol Imaging, vol. 31, no. 10, Oct. 2004, pp. 1362–70. Pubmed, doi:10.1007/s00259-004-1596-8.
PMID
15205923
Source
pubmed
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
31
Issue
10
Publish Date
2004
Start Page
1362
End Page
1370
DOI
10.1007/s00259-004-1596-8

Brain tumor cell lines resistant to O6-benzylguanine/1,3-bis(2-chloroethyl)-1-nitrosourea chemotherapy have O6-alkylguanine-DNA alkyltransferase mutations.

The chemotherapeutic activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU or carmustine) may be improved by the addition of O6-benzylguanine (O6-BG). The reaction of O6-BG with O6-alkylguanine-DNA alkyltransferase (AGT) prevents the repair of O6-chloroethyl lesions caused by BCNU. In clinics, the combination of O6-BG and BCNU is now being tested for the treatment of brain tumors. However, the effectiveness of this drug regimen may be limited by drug resistance acquired during treatment. To understand the possible mechanisms of resistance of brain tumor cells to the O6-BG/BCNU combination, we generated medulloblastoma cell lines (D283 MED, D341 MED, and Daoy) resistant to the combination of O6-BG and BCNU [O6-BG/BCNU resistant (OBR)]. DNA sequencing showed that all of the parent cell lines express wild-type AGTs, whereas every OBR cell line exhibited mutations that potentially affected the binding of O6-BG to the protein as evidenced previously by in vitro mutagenesis and structural studies of AGT. The D283 MED (OBR), Daoy (OBR), and D341 MED (OBR) cell lines expressed G156C, Y114F, and K165T AGT mutations, respectively. We reported previously that rhabdomyosarcoma TE-671 (OBR) also expresses a G156C mutation. These data suggest that the clonal selection of AGT mutants during treatment with O6-BG plus an alkylator may produce resistance to this intervention in clinical settings.

Authors
Bacolod, MD; Johnson, SP; Pegg, AE; Dolan, ME; Moschel, RC; Bullock, NS; Fang, Q; Colvin, OM; Modrich, P; Bigner, DD; Friedman, HS
MLA Citation
Bacolod, Manny D., et al. “Brain tumor cell lines resistant to O6-benzylguanine/1,3-bis(2-chloroethyl)-1-nitrosourea chemotherapy have O6-alkylguanine-DNA alkyltransferase mutations..” Mol Cancer Ther, vol. 3, no. 9, Sept. 2004, pp. 1127–35.
PMID
15367707
Source
pubmed
Published In
Molecular Cancer Therapeutics
Volume
3
Issue
9
Publish Date
2004
Start Page
1127
End Page
1135

In-transit melanoma: the role of alkylating-agent resistance in regional therapy.

BACKGROUND: Regional perfusion treatments for melanoma, using the alkylating agent melphalan, show variable responses in magnitude and duration. Surprisingly, the potential contribution of alkylating-agent resistance mechanisms to diminish tumor responses, especially the crucial cellular detoxifying system formed by glutathione (GSH) and its associated enzyme glutathione-S-transferase (GST), has remained unexplored. Objectives of this study were to characterize GSH levels and GST activity in melanoma of patients undergoing regional perfusion and examine the effect of melphalan concentration in both an in vitro human melanoma cell line and in the extremity melanoma of an in vivo rodent limb infusion model. STUDY DESIGN: Human in-transit melanoma, muscle, subcutaneous tissue, and skin (n = 9) and metastatic regional lymph nodes (n = 7) were evaluated for GSH level and GST activity. Effects of increasing melphalan exposure on GSH and GST were studied in an in vitro human melanoma cell line. A survival human melanoma xenograft model of isolated limb infusion using increasing dosages of melphalan was used, with evaluation of GSH and GST in the recurrent tumor. RESULTS: GSH levels in human in-transit lesions and muscle were significantly higher than that of skin and subcutaneous tissue. Four of 9 patients had tumor-to-muscle GSH ratio > 1. A strong correlation was seen between in vitro melphalan dose and resultant GSH level and GST activity. In vivo recurrent tumor GSH levels correlated with increasing melphalan infusion dose. CONCLUSIONS: A GSH-based resistance pathway may play a role in effecting response and toxicity to regional melphalan perfusion.

Authors
Grubbs, EG; Abdel-Wahab, O; Cheng, T-Y; Abdel-Wahab, Z; Peterson, B; Pruitt, SK; Colvin, OM; Friedman, HS; Tyler, DS
MLA Citation
Grubbs, Elizabeth G., et al. “In-transit melanoma: the role of alkylating-agent resistance in regional therapy..” J Am Coll Surg, vol. 199, no. 3, Sept. 2004, pp. 419–27. Pubmed, doi:10.1016/j.jamcollsurg.2004.05.271.
PMID
15325612
Source
pubmed
Published In
Journal of the American College of Surgeons
Volume
199
Issue
3
Publish Date
2004
Start Page
419
End Page
427
DOI
10.1016/j.jamcollsurg.2004.05.271

Comparative genomic hybridization analysis of astrocytomas: prognostic and diagnostic implications.

Astrocytoma is comprised of a group of common intracranial neoplasms that are classified into four grades based on the World Health Organization histological criteria and patient survival. To date, histological grade, patient age, and clinical performance, as reflected in the Karnofsky score, are the most reliable prognostic predictors. Recently, there has been a significant effort to identify additional prognostic markers using objective molecular genetic techniques. We believe that the identification of such markers will characterize new chromosomal loci important in astrocytoma progression and aid clinical diagnosis and prognosis. To this end, our laboratory used comparative genomic hybridization to identify DNA sequence copy number changes in 102 astrocytomas. Novel losses of 19p loci were detected in low-grade pilocytic astrocytomas and losses of loci on 9p, 10, and 22 along with gains on 7, 19, and 20 were detected in a significant proportion of high-grade astrocytomas. The Cox proportional hazards statistical modeling showed that the presence of +7q and -10q comparative genomic hybridization alterations significantly increased a patient's risk of dying, independent of histological grade. This investigation demonstrates the efficacy of comparative genomic hybridization for identifying tumor suppressor and oncogene loci in different astrocytic grades. The cumulative effect of these loci is an important consideration in their diagnostic and prognostic implications.

Authors
Wiltshire, RN; Herndon, JE; Lloyd, A; Friedman, HS; Bigner, DD; Bigner, SH; McLendon, RE
MLA Citation
Wiltshire, Rodney N., et al. “Comparative genomic hybridization analysis of astrocytomas: prognostic and diagnostic implications..” J Mol Diagn, vol. 6, no. 3, Aug. 2004, pp. 166–79. Pubmed, doi:10.1016/S1525-1578(10)60507-7.
PMID
15269292
Source
pubmed
Published In
The Journal of Molecular Diagnostics
Volume
6
Issue
3
Publish Date
2004
Start Page
166
End Page
179
DOI
10.1016/S1525-1578(10)60507-7

Modulation of resistance to regional chemotherapy in the extremity melanoma model.

BACKGROUND: The presence of resistance to chemotherapy is associated with poor tumor response and patient survival in a variety of tumors. Attempts to modulate resistance in conjunction with systemic chemotherapy have been limited by the toxicity of combined therapy, particularly gastrointestinal or hematopoetic toxicity. This study explored systemic modulation of resistance in conjunction with intra-arterial regional therapy to determine if tumor responses to melphalan could be improved with acceptable toxicity. METHODS: Using a nude rat human xenograft model of extremity melanoma,we analyzed tumors for glutathione (GSH), the main protein in the melphalan resistance pathway. Modulation of GSH was performed with intraperitoneal buthionine sulfoximine (BSO). In parallel, BSO-modulated and nonmodulated animals underwent survival studies after regional intra-arterial perfusion with melphalan or saline. Rats were monitored daily for tumor growth and toxicity. RESULTS: BSO depleted tumor GSH levels by 71.8% with minimal toxicity. Survival studies using increasing melphalan concentrations demonstrated similar tumor growth. The combined use of modulator and chemotherapeutic agent showed a significant tumor growth delay as compared to control and drug-alone group without enhanced toxicity. CONCLUSIONS: Modulation of resistance in conjunction with regional chemotherapy allows for improved tumor responses with minimal toxicity. These results demonstrate that BSO can potentiate the cytotoxic effects of regional melphalan therapy in the setting of extremity melanoma.

Authors
Grubbs, EG; Ueno, T; Abdel-Wahab, O; Cheng, T-Y; Pruitt, SK; Michael Colvin, O; Friedman, HS; Tyler, DS
MLA Citation
Grubbs, Elizabeth G., et al. “Modulation of resistance to regional chemotherapy in the extremity melanoma model..” Surgery, vol. 136, no. 2, Aug. 2004, pp. 210–18. Pubmed, doi:10.1016/j.surg.2004.04.021.
PMID
15300182
Source
pubmed
Published In
Surgery
Volume
136
Issue
2
Publish Date
2004
Start Page
210
End Page
218
DOI
10.1016/j.surg.2004.04.021

Phase II trial of iodine 131-labeled murine anti-tenascin monoclonal anti-body 81C6 (M81C6) via surgically created resection cavity in the treatment of patients with recurrent malignant brain tumors.

1569 Background: In a prior phase I study we established the dose of 100mCi as the maximum tolerated dose of iodine 131-labeled murine anti-tenascin antibody 81C6 (131I-81C6) injected into a surgically created resection cavity (SCRC) for the treatment of recurrent malignant glioma in adult patients. METHODS: In the current phase II study we have treated 42 patients with recurrent brain tumors (GBM=32, AA=6, AO=2, infiltrating glioma = 1, metastatic =1). Patients were included into study if they had: 1) gross total resection, 2) KPS > 60%, 3) normal bone marrow and normal hepatic and renal function. All patients had received standard external beam radiation and 14 (33%) patients had received prior chemotherapy. RESULTS: The median age was 54.5 years and 27 patients (64%) were males. All patients received 100mCi except for two patients that received 67mCi and 75mCi respectively due to the limited size of the SCRC. Toxicities were divided into acute (< 4 weeks), subacute (4-16 weeks) and delayed (>16 weeks) periods. Acute and sub-acute reversible, grade 4 hematologic toxicity was seen in 2 patients (4%) and 3 (7%) patients, respectively. Delayed grade 3 or 4 neurotoxicity was seen in 2 patients (4%). The median survival of all patients and GBM patients was 59 weeks for both groups, respectively. For patients with GBM the probability of 1-year survival is 0.56 (CI-95%; 0.41-0.78). As of December 16, 2003, 15 patients remain alive with a median follow up of 81.9 weeks for GBMs and 78.9 weeks for all patients. CONCLUSIONS: I(131)- labeled murine anti-tenascin antibody 81C6 is associated with minimal hematologic toxicity and provides an improvement in survival in patients with recurrent malignant glioma that have failed conventional therapy. No significant financial relationships to disclose.

Authors
Badruddoja, MA; Reardon, DA; Akabani, G; Friedman, AH; Friedman, HS; Rich, JN; Quinn, JA; Penne, K; Vredenburgh, JJ; Bigner, DD
MLA Citation
Badruddoja, M. A., et al. “Phase II trial of iodine 131-labeled murine anti-tenascin monoclonal anti-body 81C6 (M81C6) via surgically created resection cavity in the treatment of patients with recurrent malignant brain tumors..” J Clin Oncol, vol. 22, no. 14_suppl, July 2004.
PMID
28015735
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
1569

Phase II study of thalidomide and daily cyclophosphamide for adults with malignant glioma.

1554 Background: We performed a phase II study to determine the activity and toxicity of thalidomide plus daily cyclophosphamide in patients with recurrent anaplastic astrocytomas (AA) and anaplastic oligodendrogliomas (AO). METHODS: Eligibility: adult patients with AA or AO in first relapse with measurable disease; interval of at least 3 weeks between surgical resection or 6 weeks between radiotherapy or chemotherapy; Karnofsky ≥ 60%; negative pregnancy test; and adequate marrow, renal, and hepatic function. Thalidomide was begun at 100 mg at bedtime and increased by 100 mg weekly to a maximum dose of 400 mg. Cyclophosphamide was administered at 100 mg daily. Responses were assessed every eight weeks and patients remained on study for up to one year or until disease progression or unacceptable toxicity. RESULTS: To date, 11 patients with recurrent AA (n = 10) or AO (n=1) have been enrolled (planned accrual=30). Median age is 38 years (range: 27 to 51). All patients received prior radiation therapy and chemotherapy (median: 2, range: 1 to 3). Grade 3 or greater toxicities included neutropenia (grade 3, n=3; grade 4, n=2), and hyponatremia (grade 3, n=1). Responses include one complete and one partial, both of these patients completed one year of treatment and remain off therapy with no evidence of disease progression. One patient achieved stable disease and is in the 21(st) week of therapy. Five patients progressed after cycle one. Two patients are too early for evaluation and one patient died of intratumoral hemorrhage after six days on protocol. CONCLUSIONS: Thalidomide plus daily cyclophosphamide demonstrates encouraging activity and is well tolerated among patients with recurrent AA or AO. [Table: see text].

Authors
Desjardins, A; Quinn, JA; Reardon, DA; Rich, JN; Vredenburgh, JJ; Efird, C; Friedman, HS
MLA Citation
Desjardins, A., et al. “Phase II study of thalidomide and daily cyclophosphamide for adults with malignant glioma..” J Clin Oncol, vol. 22, no. 14_suppl, July 2004.
PMID
28015449
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
1554

Phase II trial of iodine 131-labeled murine anti-tenascin monoclonal anti-body 81C6 (M81C6) via surgically created resection cavity in the treatment of patients with recurrent malignant brain tumors.

Authors
Badruddoja, MA; Reardon, DA; Akabani, G; Friedman, AH; Friedman, HS; Rich, JN; Quinn, JA; Penne, K; Vredenburgh, JJ; Bigner, DD
MLA Citation
Badruddoja, M. A., et al. “Phase II trial of iodine 131-labeled murine anti-tenascin monoclonal anti-body 81C6 (M81C6) via surgically created resection cavity in the treatment of patients with recurrent malignant brain tumors..” Journal of Clinical Oncology, vol. 22, no. 14, AMER SOC CLINICAL ONCOLOGY, 2004, pp. 124S-124S.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
124S
End Page
124S

Phase II study of thalidomide and daily cyclophosphamide for adults with malignant glioma.

Authors
Desjardin, A; Quinn, JA; Reardon, DA; Rich, JN; Vredenburgh, JJ; Efird, C; Friedman, HS
MLA Citation
Desjardin, A., et al. “Phase II study of thalidomide and daily cyclophosphamide for adults with malignant glioma..” Journal of Clinical Oncology, vol. 22, no. 14, AMER SOC CLINICAL ONCOLOGY, 2004, pp. 120S-120S.
Source
wos
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
120S
End Page
120S

SB-431542, a small molecule transforming growth factor-beta-receptor antagonist, inhibits human glioma cell line proliferation and motility.

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that promotes malignant glioma invasion, angiogenesis, and immunosuppression. Antisense oligonucleotide suppression of TGF-beta(2) ligand expression has shown promise in preclinical and clinical studies but at least two ligands mediate the effects of TGF-beta in gliomas. Therefore, we examined the effects of SB-431542, a novel, small molecule inhibitor of the type I TGF-beta receptor, on a panel of human malignant glioma cell lines. SB-431542 blocked the phosphorylation and nuclear translocation of the SMADs, intracellular mediators of TGF-beta signaling, with decreased TGF-beta-mediated transcription. Furthermore, SB-431542 inhibited the expression of two critical effectors of TGF-beta-vascular endothelial growth factor and plasminogen activator inhibitor-1. SB-431542 treatment of glioma cultures inhibited proliferation, TGF-beta-mediated morphologic changes, and cellular motility. Together, our results suggest that small molecule inhibitors of TGF-beta receptors may offer a novel therapy for malignant gliomas by reducing cell proliferation, angiogenesis, and motility.

Authors
Hjelmeland, MD; Hjelmeland, AB; Sathornsumetee, S; Reese, ED; Herbstreith, MH; Laping, NJ; Friedman, HS; Bigner, DD; Wang, X-F; Rich, JN
MLA Citation
Hjelmeland, Mark D., et al. “SB-431542, a small molecule transforming growth factor-beta-receptor antagonist, inhibits human glioma cell line proliferation and motility..” Mol Cancer Ther, vol. 3, no. 6, June 2004, pp. 737–45.
PMID
15210860
Source
pubmed
Published In
Molecular Cancer Therapeutics
Volume
3
Issue
6
Publish Date
2004
Start Page
737
End Page
745

Resistance to tyrosine kinase inhibition by mutant epidermal growth factor receptor variant III contributes to the neoplastic phenotype of glioblastoma multiforme.

PURPOSE: We have reported previously that tumors expressing wild-type epidermal growth factor receptor (EGFR) in a murine model are sensitive to the EGFR tyrosine kinase inhibitor gefitinib, whereas tumors expressing mutant