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Ashley, David

Overview:

Dr. Ashley's primary research focus is laboratory based, investigating the role of immunotherapy as a novel approach to the treatment of tumors of the central nervous system (CNS). Since beginning his appointment at the faculty level at Duke in August of 1995 his activities have centered on two main areas of investigation. The first involves both in vivo and in vitro studies of the use of molecular therapeutics to target a CNS tumor associated antigen. The second area of interest comprises a detailed analysis of the role of TGF beta, a protein messenger produced by tumors of the CNS, both in the pathogenesis of disease and as a possible target for immunotherapy.

In addition to his laboratory role Dr. Ashely is involved in the design and application of a variety of clinical research protocols in the treatment of children with malignant brain tumors.

Positions:

The Rory David Deutsch Professor of Neuro-Oncology

Neurosurgery
School of Medicine

Professor of Neurosurgery

Neurosurgery
School of Medicine

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Professor in Pediatrics

Pediatrics, Neurology
School of Medicine

Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

F.R.A.C.P. 1993

F.R.A.C.P. — Royal Australian College of Physicians

M.B.B.S. 1994

M.B.B.S. — University of Melbourne (Australia)

Ph.D. 1998

Ph.D. — University of Melbourne (Australia)

Grants:

Clinical Brain Tumor Development of a Cytomegalovirus-targeted Therapeutic with Vaccine pre-conditioning to Validate Novel Predictors of Vaccine Efficacy

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
December 01, 2018
End Date
November 30, 2023

LGG-14C03: A Phase III study comparing two carboplatin containing regimens for children and young adults with previously untreated low grade glioma

Administered By
Duke Cancer Institute
AwardedBy
Ann & Robert H. Lurie Children's Hospital of Chicago
Role
Principal Investigator
Start Date
January 26, 2018
End Date
November 30, 2021

A Randomized, Multicenter, Phase 2 Study of PVSRIPO alone or in combination with Lomustine

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
November 06, 2018
End Date
October 31, 2021

Poliovirus-Instigated APC Responses Against BRaf(V600E) for Pediatric Brain Tumor Immunotherapy

Administered By
Neurosurgery, Neuro-Oncology Clinical Research
AwardedBy
V Foundation for Cancer Research
Role
Principal Investigator
Start Date
March 01, 2018
End Date
March 01, 2021

Recombinant Attenuated Poliovirus Immunization Vectors Targeting H3.3(K27M) in DIPG

Administered By
Neurosurgery, Neuro-Oncology Clinical Research
Role
Principal Investigator
Start Date
January 08, 2018
End Date
January 07, 2019

SJMB12: A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
St. Jude Children's Research Hospital
Role
Principal Investigator
Start Date
January 01, 2014
End Date
December 31, 2018
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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

BEVACIZUMAB, IRINOTECAN, TEMOZOLOMIDE, TYROSINE KINASE INHIBITION, AND MEK INHIBITION ARE EFFECTIVE AGAINST PLEOMORPHIC XANTHOASTROCYTOMA REGARDLESS OF V600E STATUS

Authors
Thompson, E; Landi, D; Ashley, D; Keir, S; Bigner, D
MLA Citation
Thompson, Eric, et al. “BEVACIZUMAB, IRINOTECAN, TEMOZOLOMIDE, TYROSINE KINASE INHIBITION, AND MEK INHIBITION ARE EFFECTIVE AGAINST PLEOMORPHIC XANTHOASTROCYTOMA REGARDLESS OF V600E STATUS.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 102–102.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
102
End Page
102

DYSFUNCTIONAL STING PATHWAY SIGNALING COMPROMISES INNATE IMMUNITY IN GLIOBLASTOMA

Authors
Bowie, M; Ashley, D; Hostettler, J; Brown, M; Bryant, J; Bigner, D; Gromeier, M; Nair, S
MLA Citation
Bowie, Michelle, et al. “DYSFUNCTIONAL STING PATHWAY SIGNALING COMPROMISES INNATE IMMUNITY IN GLIOBLASTOMA.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 127–28.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
127
End Page
128

DOSE ESCALATION TRIAL OF D2C7 IMMUNOTOXIN (D2C7-IT) ADMINISTERED INTRATUMORALLY VIA CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMA (MG)

Authors
Desjardins, A; Randazzo, D; Chandramohan, V; Peters, K; Johnson, M; Thomas, L; Threatt, S; Bullock, C; Herndon, J; Boulton, S; Healy, P; Lipp, E; Sampson, J; Friedman, A; Friedman, H; Ashley, D; Bigner, D
MLA Citation
Desjardins, Annick, et al. “DOSE ESCALATION TRIAL OF D2C7 IMMUNOTOXIN (D2C7-IT) ADMINISTERED INTRATUMORALLY VIA CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMA (MG).” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 9–9.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
9
End Page
9

INTRATUMORAL ADMINISTRATION OF AN ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) IN MALIGNANT GLIOMA PATIENTS: ASSESSMENT OF MUTATIONAL RESPONSE CORRELATES

Authors
Ashley, D; Desjardins, A; Gromeier, M; Muscat, A; Herndon, J; Friedman, A; Friedman, H; McSherry, F; Randazzo, D; Peters, K; Threatt, S; Bullock, C; Miller, E; Boulton, S; Lipp, E; Bigner, D; Sampson, J
MLA Citation
Ashley, David, et al. “INTRATUMORAL ADMINISTRATION OF AN ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) IN MALIGNANT GLIOMA PATIENTS: ASSESSMENT OF MUTATIONAL RESPONSE CORRELATES.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 7–7.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
7
End Page
7

ESTABLISHMENT AND PRELIMINARY EVALUATION OF BEVACIZUMAB-RESISTANT GLIOMA XENOGRAFT MODELS

Authors
Keir, S; Waitkus, M; Roskoski, M; Friedman, H; Bigner, D; Yan, H; Ashley, D
MLA Citation
Keir, Stephen, et al. “ESTABLISHMENT AND PRELIMINARY EVALUATION OF BEVACIZUMAB-RESISTANT GLIOMA XENOGRAFT MODELS.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 275–275.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
275
End Page
275

CLINICAL AND HISTOPATHOLOGICAL CHARACTERISTICS OF YOUNG ADULTS WITH GLIOBLASTOMA AT DIAGNOSIS

Authors
Vaslow, Z; Kirkpatrick, J; Affronti, M; Healy, P; Herndon, J; Lipp, E; Thomas, L; Johnson, M; Randazzo, D; Desjardins, A; Friedman, H; Ashley, D; Peters, K
MLA Citation
Vaslow, Zachary, et al. “CLINICAL AND HISTOPATHOLOGICAL CHARACTERISTICS OF YOUNG ADULTS WITH GLIOBLASTOMA AT DIAGNOSIS.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 239–239.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
239
End Page
239

PHASE 1 DOSE ESCALATION TRIAL OF THE SAFETY OF BMX-001 CONCURRENT WITH RADIATION THERAPY AND TEMOZOLOMIDE IN NEWLY DIAGNOSED PATIENTS WITH HIGH-GRADE GLIOMAS

Authors
Peters, K; Kirkpatrick, J; Batinic-Haberle, I; Affronti, M; Woodring, S; Iden, D; Panta, S; Lipp, E; Healy, P; Herndon, J; Spasojevic, I; Penchev, S; Gad, S; Siberstein, D; Johnson, M; Randazzo, D; Desjardins, A; Friedman, H; Ashley, D; Crapo, J
MLA Citation
Peters, Katherine, et al. “PHASE 1 DOSE ESCALATION TRIAL OF THE SAFETY OF BMX-001 CONCURRENT WITH RADIATION THERAPY AND TEMOZOLOMIDE IN NEWLY DIAGNOSED PATIENTS WITH HIGH-GRADE GLIOMAS.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 17–17.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
17
End Page
17

ENHANCING VACCINE RESPONSES WITH DOSE-INTENSIFIED TEMOZOLOMIDE IN GLIOBLASTOMA: INITIATION OF THE I-ATTAC TRIAL

Authors
Batich, K; Ashley, D; Archer, G; Sanchez-Perez, L; Norberg, P; Congdon, K; Herndon, J; McSherry, F; Gemberling, S; Hesler, R; Jaggers, D; Van, R; Parker, J; Peters, K; Desjardins, A; Friedman, H; Sampson, J
MLA Citation
Batich, Kristen, et al. “ENHANCING VACCINE RESPONSES WITH DOSE-INTENSIFIED TEMOZOLOMIDE IN GLIOBLASTOMA: INITIATION OF THE I-ATTAC TRIAL.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 234–234.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
234
End Page
234

TREATMENT PATTERNS, OUTCOMES, AND PROGNOSTIC INDICATORS IN ELDERLY PATIENTS WITH GLIOBLASTOMA: A RETROSPECTIVE SINGLE INSTITUTION ANALYSIS

Authors
Johnson, M; Kirkpatrick, J; Weant, M; Vaslow, Z; Lipp, E; Herndon, J; McSherry, F; Desjardins, A; Randazzo, D; Friedman, H; Ashley, D; Peters, K
MLA Citation
Johnson, Margaret, et al. “TREATMENT PATTERNS, OUTCOMES, AND PROGNOSTIC INDICATORS IN ELDERLY PATIENTS WITH GLIOBLASTOMA: A RETROSPECTIVE SINGLE INSTITUTION ANALYSIS.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 117–117.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
117
End Page
117

MOLECULAR EVOLUTION OF DIFFUSE GLIOMAS AND THE GLIOMA LONGITUDINAL ANALYSIS CONSORTIUM

Authors
Verhaak, R; Aldape, K; Amin, S; Ashley, D; Barnholtz-Sloan, J; Bates, A; Beroukhim, R; Bock, C; Brat, D; Claus, E; Costello, J; de Groot, J; Finocchiaro, G; French, P; Gan, H; Griffith, B; Herold-Mende, C; Horbinski, C; Iavarone, A; Kalkanis, S; Karabatsou, K; Kim, H; Kouwenhoven, M; McDonald, K; Miletic, H; Nam, D-H; Ng, HK; Niclou, S; Noushmehr, H; Ormond, D; Poisson, L; Reifenberger, G; Roncaroli, F; Sa, JK; Smitt, PS; Smits, M; Souza, CF; Tabatabai, G; van Meir, E; Watts, C; Wesseling, P; Woehrer, A; Yung, WKA; Jungk, C; van Dyck, E; Westerman, BA; Abiola, O; Zeps, N; Grimmond, S
MLA Citation
Verhaak, Roel, et al. “MOLECULAR EVOLUTION OF DIFFUSE GLIOMAS AND THE GLIOMA LONGITUDINAL ANALYSIS CONSORTIUM.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 76–76.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
76
End Page
76

Bevacizumab, irinotecan, temozolomide, tyrosine kinase inhibition, and MEK inhibition are effective against pleomorphic xanthoastrocytoma regardless of V600E status.

INTRODUCTION: Pleomorphic xanthoastrocytoma (PXA) is a rare Grade II and III glioma. Surgical resection is the mainstay of treatment, however, adjuvant therapy is sometimes necessary. Given the rarity of PXA, chemotherapeutic efficacy data is limited. The importance of the BRAF V600E mutation in the context of MAP kinase pathway inhibition is unknown. The purpose of this study was to perform an in vivo screen of a variety to agents to determine efficacy against both V600E mutant and non-mutant PXA. METHODS: The efficacy of bevacizumab, temozolomide, lomustine (CCNU), irinotecan (CPT 11), a tyrosine kinase inhibitor (sorafenib), a selective MEK1/2 inhibitor (cobimetinib), and a BRAF inhibitor (vemurafenib) were assessed in two subcutaneous xenografts: D645 PXA (V600E-mutant) and D2363 PXA (V600E-non-mutant) (n = 5-10 mice). Select agents were also assessed in an intracranial model of D2363 PXA (n = 6-9). Subcutaneous tumor growth and survival were the endpoints. RESULTS: Temozolomide, bevacizumab, CPT 11, and sorafenib significantly inhibited subcutaneous tumor growth in both V600E-mutant and V600E-non-mutant models (P < 0.05). MEK inhibition (cobimetinib) but not BRAF inhibition (vemurafenib) also inhibited tumor growth regardless of V600E mutation (P < 0.05). Temozolomide, CPT 11, and bevacizumab also prolonged survival in a V600E-non-mutant intracranial model (median overall survival (OS) 68.5, 62.5, and 42.5 days, respectively) in contrast to controls (31.5 days, P < 0.001). CONCLUSIONS: These findings suggest that when adjuvant treatment is clinically indicated for PXA, temozolomide, CPT 11, or bevacizumab may be considered. Additionally, a trial of a MEK inhibitor or tyrosine kinase inhibitor could be considered for PXA regardless of V600E mutation status.

Authors
Thompson, EM; Landi, D; Ashley, D; Keir, ST; Bigner, D
MLA Citation
Thompson, Eric M., et al. “Bevacizumab, irinotecan, temozolomide, tyrosine kinase inhibition, and MEK inhibition are effective against pleomorphic xanthoastrocytoma regardless of V600E status..” J Neurooncol, vol. 140, no. 2, Nov. 2018, pp. 261–68. Pubmed, doi:10.1007/s11060-018-2975-5.
PMID
30120661
Source
pubmed
Published In
J Neurooncol
Volume
140
Issue
2
Publish Date
2018
Start Page
261
End Page
268
DOI
10.1007/s11060-018-2975-5

A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors.

PURPOSE: This was an open label, phase I (3 + 3 design), multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumors. METHODS: Primary endpoints were to establish MTD, define and describe associated toxicities, including dose limiting toxicities (DLT) and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and its biologic activity, by measuring acetylation of histones in peripheral blood mononuclear cells. RESULTS: Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15 mg/m2 which was tolerated. Six were evaluable for adverse events. Two (33%) patients experienced Grade 3-4 thrombocytopenia, 1 (17%) experienced Grade 3 anemia, and 2 (33%) experienced Grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (33%) of the patients studied. Two (33%) patients experienced a Grade 2 QTcF change (0.478 ± 0.006 ms). One cardiac DLT (T wave changes) was reported. PK values for 15 mg/m2 (n = 9) dosing were: Tmax 0.8 h, Cmax 235.2 ng/mL, AUC0-t 346.8 h ng/mL and t1/2 7.3 h. Panobinostat significantly induced acetylation of histone H3 and H4 at all time points measured when compared to pre-treatment samples (p < 0.05). Pooled quantitative Western blot data confirmed that panobinostat significantly induced acetylation of histone H4 at 6 h (p < 0.01), 24 h (p < 0.01) and 28-70 h (p < 0.01) post dose. CONCLUSION: A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15 mg/m2. PK data and drug tolerability at 15 mg/m2 was similar to that previously published.

Authors
Wood, PJ; Strong, R; McArthur, GA; Michael, M; Algar, E; Muscat, A; Rigby, L; Ferguson, M; Ashley, DM
MLA Citation
Wood, Paul J., et al. “A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors..” Cancer Chemother Pharmacol, vol. 82, no. 3, Sept. 2018, pp. 493–503. Pubmed, doi:10.1007/s00280-018-3634-4.
PMID
29987369
Source
pubmed
Published In
Cancer Chemother Pharmacol
Volume
82
Issue
3
Publish Date
2018
Start Page
493
End Page
503
DOI
10.1007/s00280-018-3634-4

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

Glioma through the looking GLASS: molecular evolution of diffuse gliomas and the Glioma Longitudinal Analysis Consortium.

Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal Analysis Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities and, ultimately, improved outcomes for a patient population in need.

MLA Citation
Glioma through the looking GLASS: molecular evolution of diffuse gliomas and the Glioma Longitudinal Analysis Consortium..” Neuro Oncol, vol. 20, no. 7, June 2018, pp. 873–84. Pubmed, doi:10.1093/neuonc/noy020.
PMID
29432615
Source
pubmed
Published In
Neuro Oncol
Volume
20
Issue
7
Publish Date
2018
Start Page
873
End Page
884
DOI
10.1093/neuonc/noy020

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

TARGETING EGFR IN HYPOMUTATED PEDIATRIC BRAIN TUMORS USING THE D2C7 IMMUNOTOXIN

Authors
Landi, D; Thompson, E; McLendon, R; Desjardins, A; Chandramohan, V; Ashley, D; Bigner, D
MLA Citation
Landi, Daniel, et al. “TARGETING EGFR IN HYPOMUTATED PEDIATRIC BRAIN TUMORS USING THE D2C7 IMMUNOTOXIN.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 103–103.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
103
End Page
103

CMV PP65 RNA-PULSED DENDRITIC CELL VACCINES FOR PEDIATRIC GLIOBLASTOMA AND MEDULLOBLASTOMA: A PHASE I TRIAL

Authors
Landi, D; Thompson, E; Herndon, J; Sampson, J; Ashley, D
MLA Citation
Landi, Daniel, et al. “CMV PP65 RNA-PULSED DENDRITIC CELL VACCINES FOR PEDIATRIC GLIOBLASTOMA AND MEDULLOBLASTOMA: A PHASE I TRIAL.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 103–103.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
103
End Page
103

A PHASE II STUDY OF PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH SOLID TUMORS INCLUDING MALIGNANT RHABDOID TUMOR/ATYPICAL TERATOID RHABDOID TUMOURS

Authors
Wood, P; Desai, J; Gottardo, N; Cain, J; Ashley, D
MLA Citation
Wood, Paul, et al. “A PHASE II STUDY OF PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH SOLID TUMORS INCLUDING MALIGNANT RHABDOID TUMOR/ATYPICAL TERATOID RHABDOID TUMOURS.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 33–33.
Source
wos
Published In
Neuro Oncology
Volume
20
Publish Date
2018
Start Page
33
End Page
33

Adult Pilocytic Astrocytoma: Clinical Management and Prognostic Factors

Authors
Inamullah, O; Kirkpatrick, J; Healy, P; Lipp, E; Johnson, M; Ashley, D; Randazzo, D; Friedman, H; Peters, K
MLA Citation
Inamullah, Ovais, et al. “Adult Pilocytic Astrocytoma: Clinical Management and Prognostic Factors.” Neurology, vol. 90, LIPPINCOTT WILLIAMS & WILKINS, 2018.
Source
wos
Published In
Neurology
Volume
90
Publish Date
2018

Efficacy of a telephone outcall program to reduce caregiver burden among caregivers of cancer patients [PROTECT]: a randomised controlled trial.

BACKGROUND: Informal caregivers provide extended support to people with cancer but they receive little support from the health care system to assist them in their caring role. The aim of this single-blind, multi-centre, randomised controlled trial was to test the efficacy of a telephone outcall program to reduce caregiver burden and unmet needs, and improve psychological well-being among cancer caregivers, as well as evaluating the potential impact on patient outcomes. METHODS: Cancer patient/caregiver dyads (N = 216) were randomised to a telephone outcall program (n = 108) or attention control group (n = 108). The primary outcome was self-reported caregiver burden. Secondary endpoints included depressive symptoms, unmet needs, self-esteem, self-empowerment, and health literacy. Data were collected at baseline and at both 1 and 6 months post-intervention. An intention to treat analysis was performed. RESULTS: The intervention had no effect on the primary outcome (caregiver burden), but reduced the number of caregiver unmet needs (intervention group baseline, mean = 2.66, 95% confidence interval (CI) [1.91-3.54]; intervention group 1 month post intervention, mean = 0.85, 95%CI [0.42-1.44]; control group baseline, mean = 1.30 95%CI [0.80-1.94], control group 1 month post intervention, mean = 1.02 95%CI [0.52-1.69]; p = 0.023). For caregivers at risk for depression, the intervention had a significant effect on caregivers' confidence in having sufficient information to manage their health (p = 0.040). No effects were found for patients' depressive symptoms, unmet needs, self-empowerment, and other health literacy domains. CONCLUSIONS: While caregiver burden was not reduced, the outcall program was effective in reducing unmet needs in caregivers. Provision of cancer information and support via a telephone service may represent a feasible approach to reducing unmet needs among cancer caregiver populations. TRIAL REGISTRATION: ACTRN12613000731796 ; prospectively registered on 02/07/2013.

Authors
Heckel, L; Fennell, KM; Reynolds, J; Boltong, A; Botti, M; Osborne, RH; Mihalopoulos, C; Chirgwin, J; Williams, M; Gaskin, CJ; Ashley, DM; Livingston, PM
MLA Citation
Heckel, Leila, et al. “Efficacy of a telephone outcall program to reduce caregiver burden among caregivers of cancer patients [PROTECT]: a randomised controlled trial..” Bmc Cancer, vol. 18, no. 1, Jan. 2018. Pubmed, doi:10.1186/s12885-017-3961-6.
PMID
29310613
Source
pubmed
Published In
Bmc Cancer
Volume
18
Issue
1
Publish Date
2018
Start Page
59
DOI
10.1186/s12885-017-3961-6

The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection

© Muscat et al. Glioblastoma presents as a heterogeneous disease with poor prognosis despite the use of multimodal therapy. Analysis of genomic DNA changes between initial diagnosis and recurrence in response to standard treatment protocols would enhance understanding of disease progression and better inform new treatment strategies. A cohort of 21 patients with primary glioblastoma were examined between diagnosis and first recurrence. This study presented a rare opportunity to characterize molecular alterations in tumors observed in three patients who received no therapeutic intervention, other than surgery, offering a unique control. We focused this study by comparing the dynamic mutation profiles between the primary tumors and their matched recurrent counterparts. Molecular profiling of tumors was performed using multiplexed targeted deep sequencing of 409 well characterized cancer-associated genes, achieving a mean read depth of 1272 x. Three levels of evidence suggested an evolutionary pattern consistent with a response to therapy-mediated selection pressures exists in treated patients: 1) variant burden was reduced in recurrent tumors, 2) neutral evolutionary dynamics apparent in untreated tumors shifted toward a non-neutral mode of evolution in treated patients at recurrence, and 3) the recurrent tumor of one patient displayed an increased mutation rate attributable to a temozolomide-associated hypermutator phenotype. Our observations suggest that current treatment modalities are likely to fail in achieving long term remission with the majority of relapse samples containing distinct mutations when compared to primary diagnostic samples.

Authors
Muscat, AM; Wong, NC; Drummond, KJ; Algar, EM; Khasraw, M; Verhaak, R; Field, K; Rosenthal, MA; Ashley, DM
MLA Citation
Muscat, A. M., et al. “The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection.” Oncotarget, vol. 9, no. 8, Jan. 2018, pp. 7844–58. Scopus, doi:10.18632/oncotarget.23541.
Source
scopus
Published In
Oncotarget
Volume
9
Issue
8
Publish Date
2018
Start Page
7844
End Page
7858
DOI
10.18632/oncotarget.23541

Comparison of outcomes for cancer patients discussed and not discussed at a multidisciplinary meeting.

OBJECTIVES: Comparison of outcomes for cancer patients discussed and not discussed at a multidisciplinary meeting (MDM). STUDY DESIGN: Retrospective analysis of the association of MDM discussion with survival. METHODS: All newly diagnosed cancer patients from 2009 to 2012, presenting to a large regional cancer service in South West Victoria, Australia (620 colorectal, 657 breast, 593 lung and 511 haematological) were recorded and followed up to 5 years after diagnosis. Treatment patterns and survival of patients whose treatment was discussed at an MDM compared to those who were not, were explored. RESULTS: The proportion of patients presented to an MDM within 60 days after diagnosis was 56% (n = 366) for breast cancer, 59% (n = 363) for colorectal cancer, 27% (n = 137) for haematological malignancies and 60% (n = 355) for lung cancer. Seventy-three percent (n = 886) of patients discussed at an MDM had their tumour stage recorded in their medical records while only 52% (n = 604) of patients not discussed had their tumour stage recorded (P < 0.01). We found for haematological and lung cancer patients that those presented to an MDM prior to treatment had a significant reduction in mortality (lung cancer hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50-0.76, P < 0.01) (haematological cancer HR 0.58, 95% CI 0.35-0.96, P = 0.03) compared to patients whose cases were not discussed at an MDM after adjusting for the potential cofounders of age, stage, comorbidities and treatment. This was not the case for colorectal and breast cancer patients where there was no significant difference. CONCLUSION: MDM discussion has been recommended as best practice in the management of cancer patients, however, from a public health perspective this creates potential issues around access and resources. It is likely that MDM presentation patterns and outcomes across tumour streams are linked in complex ways. We believe that our data would demonstrate that these patterns differ across tumour streams and that more detailed work is required to better allocate relatively scarce and potentially costly MDM resources to tumour streams and patient groups that may get the most benefit.

Authors
Rogers, MJ; Matheson, L; Garrard, B; Maher, B; Cowdery, S; Luo, W; Reed, M; Riches, S; Pitson, G; Ashley, DM
MLA Citation
Rogers, M. J., et al. “Comparison of outcomes for cancer patients discussed and not discussed at a multidisciplinary meeting..” Public Health, vol. 149, 2017, pp. 74–80. Pubmed, doi:10.1016/j.puhe.2017.04.022.
PMID
28575751
Source
pubmed
Published In
Public Health
Volume
149
Publish Date
2017
Start Page
74
End Page
80
DOI
10.1016/j.puhe.2017.04.022

TARGETED CATALYTIC INHIBITION OF EZH2 SYNERGIZES WITH LOW-DOSE PANOBINOSTAT IN MALIGNANT RHABDOID TUMOR

Authors
Popovski, D; Cochrane, C; Algar, E; Szczepny, A; Jayasekara, S; Ashley, D; Downie, P; Watkins, N; Cain, J
MLA Citation
Popovski, Dean, et al. “TARGETED CATALYTIC INHIBITION OF EZH2 SYNERGIZES WITH LOW-DOSE PANOBINOSTAT IN MALIGNANT RHABDOID TUMOR.” Neuro Oncology, vol. 19, OXFORD UNIV PRESS INC, 2017, pp. 1–1.
Source
wos
Published In
Neuro Oncology
Volume
19
Publish Date
2017
Start Page
1
End Page
1

Condition-specific or generic preference-based measures in oncology? A comparison of the EORTC-8D and the EQ-5D-3L.

PURPOSE: It has been argued that generic health-related quality of life measures are not sensitive to certain disease-specific improvements; condition-specific preference-based measures may offer a better alternative. This paper assesses the validity, responsiveness and sensitivity of a cancer-specific preference-based measure, the EORTC-8D, relative to the EQ-5D-3L. METHODS: A longitudinal prospective population-based cancer genomic cohort, Cancer 2015, was utilised in the analysis. EQ-5D-3L and the EORTC QLQ-C30 (which gives EORTC-8D values) were asked at baseline (diagnosis) and at various follow-up points (3 months, 6 months, 12 months). Baseline values were assessed for convergent validity, ceiling effects, agreement and sensitivity. Quality-adjusted life-years (QALYs) were estimated and similarly assessed. Multivariate regression analyses were employed to understand the determinants of the difference in QALYs. RESULTS: Complete case analysis of 1678 patients found that the EQ-5D-3L values at baseline were significantly lower than the EORTC-8D values (0.748 vs 0.829, p < 0.001). While the correlation between the instruments was high, agreement between the instruments was poor. The baseline health state values using both instruments were found to be sensitive to a number of patient and disease characteristics, and discrimination between disease states was found to be similar. Mean generic QALYs (estimated using the EQ-5D-3L) were significantly lower than condition-specific QALYs (estimated using the EORTC-8D) (0.860 vs 0.909, p < 0.001). The discriminatory power of both QALYs was similar. CONCLUSIONS: When comparing a generic and condition-specific preference-based instrument, divergences are apparent in both baseline health state values and in the estimated QALYs over time for cancer patients. The variability in sensitivity between the baseline values and the QALY estimations means researchers and decision makers are advised to be cautious if using the instruments interchangeably.

Authors
Lorgelly, PK; Doble, B; Rowen, D; Brazier, J; Cancer 2015 investigators,
MLA Citation
Lorgelly, Paula K., et al. “Condition-specific or generic preference-based measures in oncology? A comparison of the EORTC-8D and the EQ-5D-3L..” Qual Life Res, vol. 26, no. 5, May 2017, pp. 1163–76. Pubmed, doi:10.1007/s11136-016-1443-y.
PMID
27830513
Source
pubmed
Published In
Qual Life Res
Volume
26
Issue
5
Publish Date
2017
Start Page
1163
End Page
1176
DOI
10.1007/s11136-016-1443-y

Cancer diagnosed in the Emergency Department of a Regional Health Service.

OBJECTIVE: Patients diagnosed with cancer in the Emergency Department (ED) have more advanced disease at diagnosis and poorer outcomes. High rates of initial presentation to ED suggest potential problems with access to care. The aim of this project was to interpret findings in regional/rural Victoria and explore implications for practice. DESIGN: Cross-sectional study linking two independent data sets. SETTING: Regional city of Geelong and surrounding rural areas in south-west Victoria. PARTICIPANTS: All newly diagnosed cancer patients in 2009. MAIN OUTCOME MEASURES: Number of cancer patients diagnosed in the ED. RESULTS: One in five newly diagnosed cancer patients present to ED 6 months prior to cancer diagnosis. One in 10 is diagnosed as a result of their ED visit. Patients presenting to ED were older, more often men and from disadvantaged areas. Symptoms on presentation included chest complaints, bowel obstruction, abdominal pain, anaemia and generalised weakness. Cancer diagnosed in the ED is associated with advanced stage and shorter survival. CONCLUSION: Reasons for presentation to ED would be multifactorial and include complex cases with coexisting symptoms making diagnosis difficult. The general public appear to have a low level of awareness of alternative primary care services or difficulty accessing such information. Some of the changes towards reducing the number of patients presenting to ED will include patient education.

Authors
Rogers, MJ; Matheson, LM; Garrard, B; Mukaro, V; Riches, S; Sheridan, M; Ashley, D; Pitson, G
MLA Citation
Rogers, Margaret J., et al. “Cancer diagnosed in the Emergency Department of a Regional Health Service..” Aust J Rural Health, vol. 24, no. 6, Dec. 2016, pp. 409–14. Pubmed, doi:10.1111/ajr.12280.
PMID
26833693
Source
pubmed
Published In
Aust J Rural Health
Volume
24
Issue
6
Publish Date
2016
Start Page
409
End Page
414
DOI
10.1111/ajr.12280

M-HEALTH: THE IMPACT OF SMARTPHONE TECHNOLOGY TO IMPROVE QUALITY OF LIFE OUTCOMES AMONG PEOPLE WITH CANCER: A RANDOMISED CONTROLLED TRIAL

Authors
Livingston, PM; Ashley, D; Chambers, S; Whites, V; Heckel, L; Lavelle, B; Parente, P; Krishnasamy, M; Chirgwin, J; Botti, M; Reynolds, J; Mihalopoulos, C; O'Meagher, C; Woollett, A; Boltong, A; Simons, K; Ugalde, A; Riches, S; Byrne, J; Sutton, J; Lau, D; Wickramasinghe, N
MLA Citation
Livingston, P. M., et al. “M-HEALTH: THE IMPACT OF SMARTPHONE TECHNOLOGY TO IMPROVE QUALITY OF LIFE OUTCOMES AMONG PEOPLE WITH CANCER: A RANDOMISED CONTROLLED TRIAL.” International Journal of Behavioral Medicine, vol. 23, SPRINGER, 2016, pp. S168–S168.
Source
wos
Published In
International Journal of Behavioral Medicine
Volume
23
Publish Date
2016
Start Page
S168
End Page
S168

Low-Dose Histone Deacetylase Inhibitor Treatment Leads to Tumor Growth Arrest and Multi-Lineage Differentiation of Malignant Rhabdoid Tumors.

PURPOSE: Malignant rhabdoid tumor (MRT) and atypical teratoid rhabdoid tumors (ATRT) are rare aggressive undifferentiated tumors primarily affecting the kidney and CNS of infants and young children. MRT are almost exclusively characterized by homozygous deletion or inactivation of the chromatin remodeling gene SMARCB1 SMARCB1 protein loss leads to direct impairment of chromatin remodeling and we have previously reported a role for this protein in histone acetylation. This provided the rationale for investigating the therapeutic potential of histone deactylase inhibitors (HDACi) in MRT. EXPERIMENTAL DESIGN: Whereas previously HDACis have been used at doses and schedules that induce cytotoxicity, in the current studies we have tested the hypothesis, both in vitro and in vivo, that sustained treatment of human MRT with low-dose HDACi can lead to sustained cell growth arrest and differentiation. RESULTS: Sustained low-dose panobinostat (LBH589) treatment led to changes in cellular morphology associated with a marked increase in the induction of neural, renal, and osteoblast differentiation pathways. Genome-wide transcriptional profiling highlighted differential gene expression supporting multilineage differentiation. Using mouse xenograft models, sustained low-dose LBH589 treatment caused tumor growth arrest associated with tumor calcification detectable by X-ray imaging. Histological analysis of LBH589-treated tumors revealed significant regions of ossification, confirmed by Alizarin Red staining. Immunohistochemical analysis showed increased TUJ1 and PAX2 staining suggestive of neuronal and renal differentiation, respectively. CONCLUSIONS: Low-dose HDACi treatment can terminally differentiate MRT tumor cells and reduce their ability to self-renew. The use of low-dose HDACi as a novel therapeutic approach warrants further investigation. Clin Cancer Res; 22(14); 3560-70. ©2016 AACR.

Authors
Muscat, A; Popovski, D; Jayasekara, WSN; Rossello, FJ; Ferguson, M; Marini, KD; Alamgeer, M; Algar, EM; Downie, P; Watkins, DN; Cain, JE; Ashley, DM
MLA Citation
Muscat, Andrea, et al. “Low-Dose Histone Deacetylase Inhibitor Treatment Leads to Tumor Growth Arrest and Multi-Lineage Differentiation of Malignant Rhabdoid Tumors..” Clin Cancer Res, vol. 22, no. 14, July 2016, pp. 3560–70. Pubmed, doi:10.1158/1078-0432.CCR-15-2260.
PMID
26920892
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
22
Issue
14
Publish Date
2016
Start Page
3560
End Page
3570
DOI
10.1158/1078-0432.CCR-15-2260

Use of targeted therapy in cancer patients in the end-of-life period: results from an Australian centre.

PURPOSE: Data on the use of targeted therapies at the end of life are scarce. This study reviews the pattern of use of targeted and potentially futile, toxic, or costly therapies at an Australian cancer centre. METHODS: This retrospective single-centre review of data from patients who died within 3 months of having targeted therapy examined demographic characteristics, types of cancers, types of therapy, age, and lines of prior therapy. RESULTS: Over 24 months, two groups were analysed. Firstly, 889 patients died with 107 patients who were prescribed targeted therapy. Secondly, 457 patients were treated with targeted therapies with 52 patients, (11 %) dying within 3 months. To focus on the 52 patients: median age was 69 years, 65 % were men and 35 % were women, 50 % had haematologic cancers and 50 % had solid tumours. Ten therapeutic agents were represented: a higher total number of deaths among those prescribed erlotinib, bevacizumab, and rituximab. There were no deaths within 3 months of treatment with trastuzumab, ipilimumab, or vemurafenib. The targeted therapy was the first-line treatment in 54 %, second in 15 %, and third and beyond in 15 %. The patient's sex and type of cancer had no statistically significant influence on death within 3 months of targeted treatment. CONCLUSIONS: The use of targeted therapy at the end of life in this single-centre descriptive study was lower than documented in other studies. There is a need to prospectively document the factors leading to this prescribing behaviour to guide future protocols.

Authors
Wann, A; Ashley, D; Khasraw, M
MLA Citation
Wann, Alysson, et al. “Use of targeted therapy in cancer patients in the end-of-life period: results from an Australian centre..” Support Care Cancer, vol. 24, no. 7, July 2016, pp. 3023–28. Pubmed, doi:10.1007/s00520-016-3124-3.
PMID
26887377
Source
pubmed
Published In
Support Care Cancer
Volume
24
Issue
7
Publish Date
2016
Start Page
3023
End Page
3028
DOI
10.1007/s00520-016-3124-3

Retrospective analysis of cancer survival across South-Western Victoria in Australia.

OBJECTIVE: This paper aims to describe cancer survival and examine association between survival and socio-demographic characteristics across Barwon South-Western region (BSWR) in Victoria, Australia. DESIGN: This study is based on the retrospective cohort database of patients accessing oncology services across BSWR. SETTING: Six rural and three urban hospital settings across the BSWR. PARTICIPANTS: The participants were patients who were diagnosed with cancer in 2009. MAIN OUTCOME MEASURES: Overall survival (OS) of participants was the main outcome measure. RESULTS: Total of 1778 eligible patients had four-year OS for all cancers combined of 59.7% (95% CI, 57.4-62.0). Improved OS was observed for patients in the upper socio-economic tertile (64.2%; 95% CI, 60.9-67.5) compared to the middle (59.3%; 95% CI, 55.5-63.1) and lowest tertiles (49.6%; 95% CI, 44.2-54.9) (P < 0.01). On multivariate analyses, higher socio-economic status remained a significant predictor of OS adjusting for gender, remoteness and age (HR [hazard ratio] 0.81; 95% CI 0.74-0.89; P < 0.01). Remoteness was significantly associated with improved OS after adjusting for age, gender and socio-economic status (HR 0.86; 95% CI, 0.77-0.97; P = 0.01). Older age ≥70 years compared to <70 years conferred inferior OS (HR 3.08; 95% CI, 2.64-3.59; P < 0.01). CONCLUSIONS: Our study confirmed improved survival outcomes for patients of higher socio-economic status and younger age. Future research to explain the unexpected survival benefit in patients who lived in more remote areas should examine factors including the correlation between geographical residence and eventual treatment facility as well as compare the BSWR care model to other regions' approaches.

Authors
Wong, SF; Matheson, L; Morrissy, K; Pitson, G; Ashley, DM; Khasraw, M; Lorgelly, PK; Henry, MJ
MLA Citation
Wong, Shu Fen, et al. “Retrospective analysis of cancer survival across South-Western Victoria in Australia..” Aust J Rural Health, vol. 24, no. 2, Apr. 2016, pp. 79–84. Pubmed, doi:10.1111/ajr.12203.
PMID
26122852
Source
pubmed
Published In
Aust J Rural Health
Volume
24
Issue
2
Publish Date
2016
Start Page
79
End Page
84
DOI
10.1111/ajr.12203

A Discrete Choice Experiment to Examine the Preferences of Patients With Cancer and Their Willingness to Pay for Different Types of Health Care Appointments.

BACKGROUND: This study sought to understand the preferences of patients with cancer and the trade-offs between appointment attributes using discrete choice experiment (DCE). METHODS AND STUDY DESIGN: Patients with cancer at 3 hospitals completed a self-administered DCE. Each scenario described 6 attributes: expertise of health care professionals (HCPs), familiarity of doctors with patients' medical history, waiting time, accompaniment by family/friends, travel time, and out-of-pocket costs. Patient preferences were estimated using logistic regression. Willingness to pay (WTP) estimates were derived from regression coefficients. RESULTS: Of 512 patients contacted, 185 returned the questionnaire. The mean age was 61 years, and 60% of respondents were female. The mean time since cancer diagnosis was 34 months, 90% had received treatment; and 61% had early-stage disease. The most important attributes were expertise and familiarity of doctors with patients' medical history; distance traveled was least likely to influence patient preferences. The WTP analysis estimated that patients were willing to pay $680 (95% CI, 470-891) for an appointment with a specialist, $571 (95% CI, 388-754) for doctors familiar with their history, $422 (95% CI, 262-582) for shorter waiting times, $399 (95% CI, 249-549) to be accompanied by family/friends, and $301 (95% CI, 162-441) for shorter traveling times. Male patients had a stronger preference for accompaniment by family/friends. The expertise of HCP was the most important attribute for patients regardless of geographic remoteness. CONCLUSIONS: Our study can assist the development of patient-centered health care models that improve patient access to experienced HCPs, support the role of primary care providers during the cancer journey, and educate patients about the roles of non-oncology HCPs to cope with increasing demand for cancer care.

Authors
Wong, SF; Norman, R; Dunning, TL; Ashley, DM; Khasraw, M; Hayes, TM; Collins, I; Lorgelly, PK
MLA Citation
Wong, Shu Fen, et al. “A Discrete Choice Experiment to Examine the Preferences of Patients With Cancer and Their Willingness to Pay for Different Types of Health Care Appointments..” J Natl Compr Canc Netw, vol. 14, no. 3, Mar. 2016, pp. 311–19.
PMID
26957617
Source
pubmed
Published In
J Natl Compr Canc Netw
Volume
14
Issue
3
Publish Date
2016
Start Page
311
End Page
319

Realising the Value of Linked Data to Health Economic Analyses of Cancer Care: A Case Study of Cancer 2015.

There is a growing appetite for large complex databases that integrate a range of personal, socio-demographic, health, genetic and financial information on individuals. It has been argued that 'Big Data' will provide the necessary catalyst to advance both biomedical research and health economics and outcomes research. However, it is important that we do not succumb to being data rich but information poor. This paper discusses the benefits and challenges of building Big Data, analysing Big Data and making appropriate inferences in order to advance cancer care, using Cancer 2015 (a prospective, longitudinal, genomic cohort study in Victoria, Australia) as a case study. Cancer 2015 has been linked to State and Commonwealth reimbursement databases that have known limitations. This partly reflects the funding arrangements in Australia, a country with both public and private provision, including public funding of private healthcare, and partly the legislative frameworks that govern data linkage. Additionally, linkage is not without time delays and, as such, achieving a contemporaneous database is challenging. Despite these limitations, there is clear value in using linked data and creating Big Data. This paper describes the linked Cancer 2015 dataset, discusses estimation issues given the nature of the data and presents panel regression results that allow us to make possible inferences regarding which patient, disease, genomic and treatment characteristics explain variation in health expenditure.

Authors
Lorgelly, PK; Doble, B; Knott, RJ; Cancer 2015 Investigators,
MLA Citation
Lorgelly, Paula K., et al. “Realising the Value of Linked Data to Health Economic Analyses of Cancer Care: A Case Study of Cancer 2015..” Pharmacoeconomics, vol. 34, no. 2, Feb. 2016, pp. 139–54. Pubmed, doi:10.1007/s40273-015-0343-2.
PMID
26547307
Source
pubmed
Published In
Pharmacoeconomics
Volume
34
Issue
2
Publish Date
2016
Start Page
139
End Page
154
DOI
10.1007/s40273-015-0343-2

Multiple adverse effects prediction in longitudinal cancer treatment

© 2016 IEEE. Adverse effects, such as voice change and fatigue, are prevalent in cancer treatment duration. These adverse effects have been significant burden for patients physically and emotionally. Predicting multiple adverse effects becomes important for patients and oncologists. In this paper, we formulate the prediction of multiple adverse effects in cancer treatment as a longitudinal multiple-output regression problem. The correlated multiple outputs are first decoupled to uncorrelated ones in a new output space. We then propose a comprehensive framework to capture the empirical loss between the predicted value and the ground truth in the transformed space and the temporal smoothness at neighboring prediction points. Experiments were performed on one synthetic data and two real-world datasets including radiotherapy and chemotherapy treatments. Results in terms of root mean square errors (RMSE) and R-value show that our proposed approach is promising for the longitudinal multiple-output regression problem.

Authors
Li, C; Gupta, S; Rana, S; Nguyen, V; Venkatesh, S; Ashley, D; Livingston, T
MLA Citation
Li, C., et al. “Multiple adverse effects prediction in longitudinal cancer treatment.” Proceedings  International Conference on Pattern Recognition, vol. 0, 2016, pp. 3156–61. Scopus, doi:10.1109/ICPR.2016.7900120.
Source
scopus
Published In
Proceedings International Conference on Pattern Recognition
Volume
0
Publish Date
2016
Start Page
3156
End Page
3161
DOI
10.1109/ICPR.2016.7900120

Cancer 2015: a longitudinal whole-of-system study of genomic cancer medicine.

Genomic cancer medicine promises revolutionary change in oncology. The impacts of 'personalized medicine', based upon a molecular classification of cancer and linked to targeted therapies, will extend from individual patient outcomes to the health economy at large. To address the 'whole-of-system' impact of genomic cancer medicine, we have established a prospective cohort of patients with newly diagnosed cancer in the state of Victoria, Australia, about whom we have collected a broad range of clinical, demographic, molecular, and patient-reported data, as well as data on health resource utilization. Our goal is to create a model for investigating public investment in genomic medicine that maximizes the cost:benefit ratio for the Australian community at large.

Authors
Thomas, DM; Fox, S; Lorgelly, PK; Ashley, D; Richardson, G; Lipton, L; Parisot, JP; Lucas, M; McNeil, J; Wright, M; Cancer 2015 Investigators,
MLA Citation
Thomas, David M., et al. “Cancer 2015: a longitudinal whole-of-system study of genomic cancer medicine..” Drug Discov Today, vol. 20, no. 12, Dec. 2015, pp. 1429–32. Pubmed, doi:10.1016/j.drudis.2015.10.009.
PMID
26494144
Source
pubmed
Published In
Drug Discov Today
Volume
20
Issue
12
Publish Date
2015
Start Page
1429
End Page
1432
DOI
10.1016/j.drudis.2015.10.009

Implementing novel models of posttreatment care for cancer survivors: Enablers, challenges and recommendations.

AIM: The American Society of Clinical Oncology and US Institute of Medicine emphasize the need to trial novel models of posttreatment care, and disseminate findings. In 2011, the Victorian State Government (Australia) established the Victorian Cancer Survivorship Program (VCSP), funding six 2-year demonstration projects, targeting end of initial cancer treatment. Projects considered various models, enrolling people of differing cancer types, age and residential areas. We sought to determine common enablers of success, as well as challenges/barriers. METHODS: Throughout the duration of the projects, a formal "community of practice" met regularly to share experiences. Projects provided regular formal progress reports. An analysis framework was developed to synthesize key themes and identify critical enablers and challenges. Two external reviewers examined final project reports. Discussion with project teams clarified content. RESULTS: Survivors reported interventions to be acceptable, appropriate and effective. Strong clinical leadership was identified as a critical success factor. Workforce education was recognized as important. Partnerships with consumers, primary care and community organizations; risk stratified pathways with rapid re-access to specialist care; and early preparation for survivorship, self-management and shared care models supported positive project outcomes. Tailoring care to individual needs and predicted risks was supported. Challenges included: lack of valid assessment and prediction tools; limited evidence to support novel care models; workforce redesign; and effective engagement with community-based care and issues around survivorship terminology. CONCLUSION: The VCSP project outcomes have added to growing evidence around posttreatment care. Future projects should consider the identified enablers and challenges when designing and implementing survivorship care.

Authors
Jefford, M; Kinnane, N; Howell, P; Nolte, L; Galetakis, S; Bruce Mann, G; Naccarella, L; Lai-Kwon, J; Simons, K; Avery, S; Thompson, K; Ashley, D; Haskett, M; Davies, E; Whitfield, K
MLA Citation
Jefford, Michael, et al. “Implementing novel models of posttreatment care for cancer survivors: Enablers, challenges and recommendations..” Asia Pac J Clin Oncol, vol. 11, no. 4, Dec. 2015, pp. 319–27. Pubmed, doi:10.1111/ajco.12406.
PMID
26245952
Source
pubmed
Published In
Asia Pac J Clin Oncol
Volume
11
Issue
4
Publish Date
2015
Start Page
319
End Page
327
DOI
10.1111/ajco.12406

M-HEALTH: THE IMPACT OF SMARTPHONE TECHNOLOGY TO IMPROVE QUALITY OF LIFE OUTCOMES AMONG PEOPLE WITH CANCER: A RANDOMISED CONTROLLED TRIAL

Authors
Livingston, P; Ashley, D; Chambers, S; White, V; Heckel, L; Lavelle, B; Parente, P; Krishnasamy, M; Chirgwin, J; Botti, M; Reynolds, J; Mihalopoulos, C; O'Meagher, C; Woollett, A; Boltong, A; Simons, K; Ugalde, A; Riches, S; Byrne, J; Sutton, J; Lau, D; Wickramasinghe, N
MLA Citation
Livingston, Patricia, et al. “M-HEALTH: THE IMPACT OF SMARTPHONE TECHNOLOGY TO IMPROVE QUALITY OF LIFE OUTCOMES AMONG PEOPLE WITH CANCER: A RANDOMISED CONTROLLED TRIAL.” Asia Pacific Journal of Clinical Oncology, vol. 11, WILEY-BLACKWELL, 2015, pp. 161–161.
Source
wos
Published In
Asia Pacific Journal of Clinical Oncology
Volume
11
Publish Date
2015
Start Page
161
End Page
161

"Cancer 2015": A Prospective, Population-Based Cancer Cohort-Phase 1: Feasibility of Genomics-Guided Precision Medicine in the Clinic.

"Cancer 2015" is a longitudinal and prospective cohort. It is a phased study whose aim was to pilot recruiting 1000 patients during phase 1 to establish the feasibility of providing a population-based genomics cohort. Newly diagnosed adult patients with solid cancers, with residual tumour material for molecular genomics testing, were recruited into the cohort for the collection of a dataset containing clinical, molecular pathology, health resource use and outcomes data. 1685 patients have been recruited over almost 3 years from five hospitals. Thirty-two percent are aged between 61-70 years old, with a median age of 63 years. Diagnostic tumour samples were obtained for 90% of these patients for multiple parallel sequencing. Patients identified with somatic mutations of potentially "actionable" variants represented almost 10% of those tumours sequenced, while 42% of the cohort had no mutations identified. These genomic data were annotated with information such as cancer site, stage, morphology, treatment and patient outcomes and health resource use and cost. This cohort has delivered its main objective of establishing an upscalable genomics cohort within a clinical setting and in phase 2 aims to develop a protocol for how genomics testing can be used in real-time clinical decision-making, providing evidence on the value of precision medicine to clinical practice.

Authors
Parisot, JP; Thorne, H; Fellowes, A; Doig, K; Lucas, M; McNeil, JJ; Doble, B; Dobrovic, A; John, T; James, PA; Lipton, L; Ashley, D; Hayes, T; McMurrick, P; Richardson, G; Lorgelly, P; Fox, SB; Thomas, DM
MLA Citation
Parisot, John P., et al. “"Cancer 2015": A Prospective, Population-Based Cancer Cohort-Phase 1: Feasibility of Genomics-Guided Precision Medicine in the Clinic..” J Pers Med, vol. 5, no. 4, Oct. 2015, pp. 354–69. Pubmed, doi:10.3390/jpm5040354.
PMID
26529019
Source
pubmed
Published In
Journal of Personalized Medicine
Volume
5
Issue
4
Publish Date
2015
Start Page
354
End Page
369
DOI
10.3390/jpm5040354

Unmet needs and depression among carers of people newly diagnosed with cancer.

AIMS: The aims of this analysis were to examine levels of unmet needs and depression among carers of people newly diagnosed with cancer and to identify groups who may be at higher risk, by examining relationships with demographic characteristics. METHODS: One hundred and fifty dyads of people newly diagnosed with cancer and their carers, aged 18 years and older, were recruited from four Australian hospitals. People with cancer receiving adjuvant cancer treatment with curative intent, were eligible to participate. Carers completed the Supportive Care Needs Survey-Partners & Caregivers (SCNS-P&C45), and both carers and patients completed the Centre of Epidemiologic-Depression Scale (CES-D). RESULTS: Overall, 57% of carers reported at least one, 37% at least three, 31% at least five, and 15% at least 10 unmet needs; the most commonly endorsed unmet needs were in the domains of information and health care service needs. Thirty percent of carers and 36% of patients were at risk of clinical depression. A weak to moderate positive relationship was observed between unmet needs and carer depression (r=0.30, p<0.001). Carer levels of unmet needs were significantly associated with carer age, hospital type, treatment type, cancer type, living situation, relationship status (in both uni- and multi-factor analysis); person with cancer age and carer level of education (in unifactor analysis only); but not with carer gender or patient gender (in both uni- and multi-factor analyses). CONCLUSION: Findings highlight the importance of developing tailored programmes to systematically assist carers who are supporting patients through the early stages of cancer treatment.

Authors
Heckel, L; Fennell, KM; Reynolds, J; Osborne, RH; Chirgwin, J; Botti, M; Ashley, DM; Livingston, PM
MLA Citation
Heckel, L., et al. “Unmet needs and depression among carers of people newly diagnosed with cancer..” Eur J Cancer, vol. 51, no. 14, Sept. 2015, pp. 2049–57. Pubmed, doi:10.1016/j.ejca.2015.06.129.
PMID
26208461
Source
pubmed
Published In
Eur J Cancer
Volume
51
Issue
14
Publish Date
2015
Start Page
2049
End Page
2057
DOI
10.1016/j.ejca.2015.06.129

Accepting risk in the acceleration of drug development for rare cancers.

Rare cancers collectively contribute a disproportionate fraction of the total burden of cancer. The oncology community is increasingly facing small numbers of patients with each cancer subtype, requiring cooperation and collaboration to complete multicentre trials that advance knowledge and patient care. At the same time, new insights into the biology of rare cancers have led to an explosion in knowledge and development of targeted agents. These insights and techniques are set to revolutionise the care of patients with cancer. However, drug development strategies and the availability of new agents for rare cancers are at risk of stalling owing to the ever-increasing complexity and costs of clinical trials. Finding solutions to these problems is imperative to the future of cancer care. We propose that a greater degree of risk sharing is needed than is currently accepted to enable the use of new methods with confidence, and to keep pace with scientific advancement.

Authors
Ashley, D; Thomas, D; Gore, L; Carter, R; Zalcberg, JR; Otmar, R; Savulescu, J
MLA Citation
Ashley, David, et al. “Accepting risk in the acceleration of drug development for rare cancers..” Lancet Oncol, vol. 16, no. 4, Apr. 2015, pp. e190–94. Pubmed, doi:10.1016/S1470-2045(14)71153-2.
PMID
25846099
Source
pubmed
Published In
Lancet Oncol
Volume
16
Issue
4
Publish Date
2015
Start Page
e190
End Page
e194
DOI
10.1016/S1470-2045(14)71153-2

A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma.

PURPOSE: Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated medulloblastoma. EXPERIMENTAL DESIGN: Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed. RESULTS: Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded. CONCLUSIONS: This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment.

Authors
Shou, Y; Robinson, DM; Amakye, DD; Rose, KL; Cho, Y-J; Ligon, KL; Sharp, T; Haider, AS; Bandaru, R; Ando, Y; Geoerger, B; Doz, F; Ashley, DM; Hargrave, DR; Casanova, M; Tawbi, HA; Rodon, J; Thomas, AL; Mita, AC; MacDonald, TJ; Kieran, MW
MLA Citation
Shou, Yaping, et al. “A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma..” Clin Cancer Res, vol. 21, no. 3, Feb. 2015, pp. 585–93. Pubmed, doi:10.1158/1078-0432.CCR-13-1711.
PMID
25473003
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
21
Issue
3
Publish Date
2015
Start Page
585
End Page
593
DOI
10.1158/1078-0432.CCR-13-1711

Oncology service initiatives and research in regional Australia.

OBJECTIVE: This paper reflects on the recent growth of cancer research being conducted through some of Australia's rural centres. It encompasses work being done across the fields of clinical, translational and health services research. DESIGN: This is a collaborative piece with contributions from rural health researchers, clinical and cancer services staff from several different regions. CONCLUSION: The past decade has seen an expansion in cancer research in rural and regional Australia driven in part by the recognition that cancer patients in remote areas experience poorer outcomes than their metropolitan counterparts. This work has led to the development of more effective cancer networks and new models of care designed to meet the particular needs of the rural cancer patient. It is hoped that the growth of cancer research in regional centres will, in time, reduce the disparity between rural and urban communities and improve outcomes for cancer patients across both populations.

Authors
Murphy, C; Sabesan, S; Steer, C; Yates, P; Booms, A; Jones, V; Simpson, A; Clarke, K; Eek, R; Ashley, D; Goldstein, D; Packer, C; Tuthill, F; Boyce, A; Underhill, C
MLA Citation
Murphy, Caitlin, et al. “Oncology service initiatives and research in regional Australia..” Aust J Rural Health, vol. 23, no. 1, Feb. 2015, pp. 40–48. Pubmed, doi:10.1111/ajr.12173.
PMID
25689382
Source
pubmed
Published In
Aust J Rural Health
Volume
23
Issue
1
Publish Date
2015
Start Page
40
End Page
48
DOI
10.1111/ajr.12173

PULMONARY FUNCTION AFTER TREATMENT FOR EMBRYONAL BRAIN TUMORS ON SJMB03 THAT INCLUDED CRANIOSPINAL IRRADIATION

Authors
Green, D; Merchant, TE; Billups, C; Stokes, DC; Broniscer, A; Bartels, U; Chintagumpala, M; Hassall, TE; Gururangan, S; McCowage, GB; Heath, JA; Cohn, RJ; Fisher, MJ; Srinivasan, A; Robinson, GW; Gajjar, A
MLA Citation
Green, D., et al. “PULMONARY FUNCTION AFTER TREATMENT FOR EMBRYONAL BRAIN TUMORS ON SJMB03 THAT INCLUDED CRANIOSPINAL IRRADIATION.” Pediatric Blood & Cancer, vol. 61, WILEY-BLACKWELL, 2014, pp. S305–S305.
Source
wos
Published In
Pediatric Blood & Cancer
Volume
61
Publish Date
2014
Start Page
S305
End Page
S305

DEVELOPING A SERVICE CAPABILITY FRAMEWORK: A GUIDE FOR HEALTH SERVICES PROVIDING CARE TO CHILDREN AND ADOLESCENTS WITH CANCER

Authors
Williams, C; Shelly, A; Williamson, J; Downie, P; Mechinaud, F; Wheeler, G; Ashley, D; Whitfield, K
MLA Citation
Williams, C., et al. “DEVELOPING A SERVICE CAPABILITY FRAMEWORK: A GUIDE FOR HEALTH SERVICES PROVIDING CARE TO CHILDREN AND ADOLESCENTS WITH CANCER.” Pediatric Blood & Cancer, vol. 61, WILEY-BLACKWELL, 2014, pp. S356–S356.
Source
wos
Published In
Pediatric Blood & Cancer
Volume
61
Publish Date
2014
Start Page
S356
End Page
S356

DEVELOPING A SERVICE CAPABILITY FRAMEWORK: A GUIDE FOR HEALTH SERVICES PROVIDING CARE TO CHILDREN AND ADOLESCENTS WITH CANCER

Authors
Williams, C; Williamson, J; Mechinaud, F; Downie, P; Wheeler, G; Ashley, D
MLA Citation
Williams, Chris, et al. “DEVELOPING A SERVICE CAPABILITY FRAMEWORK: A GUIDE FOR HEALTH SERVICES PROVIDING CARE TO CHILDREN AND ADOLESCENTS WITH CANCER.” Asia Pacific Journal of Clinical Oncology, vol. 10, WILEY-BLACKWELL, 2014, pp. 75–75.
Source
wos
Published In
Asia Pacific Journal of Clinical Oncology
Volume
10
Publish Date
2014
Start Page
75
End Page
75

A protocol for a discrete choice experiment: understanding preferences of patients with cancer towards their cancer care across metropolitan and rural regions in Australia.

INTRODUCTION: Medical decision-making in oncology is a complicated process and to date there are few studies examining how patients with cancer make choices with respect to different features of their care. It is also unknown whether patient choices vary by geographical location and how location could account for observed rural and metropolitan cancer differences. This paper describes an ongoing study that aims to (1) examine patient and healthcare-related factors that influence choices of patients with cancer; (2) measure and quantify preferences of patients with cancer towards cancer care using a discrete choice experiment (DCE) and (3) explore preference heterogeneity between metropolitan and rural locations. METHODS AND ANALYSIS: A DCE is being conducted to understand how patients with cancer choose between two clinical scenarios accounting for different patient and healthcare-related factors (and levels). Preliminary qualitative research was undertaken to guide the development of an appropriate DCE design including characteristics that are important and relevant to patients with cancer. A fractional factorial design using the D-efficiency criteria was used to estimate interactions among attributes. Multinomial logistic regression will be used for the primary DCE analysis and to control for sociodemographic and clinical characteristics. ETHICS AND DISSEMINATION: The Barwon Health Human Research Ethics Committee approved the study. Findings from the study will be presented in national/international conferences and peer-reviewed journals. Our results will form the basis of a feasibility study to inform the development of a larger scale study into preferences of patients with cancer and their association with cancer outcomes.

Authors
Wong, SF; Norman, R; Dunning, TL; Ashley, DM; Lorgelly, PK
MLA Citation
Wong, Shu Fen, et al. “A protocol for a discrete choice experiment: understanding preferences of patients with cancer towards their cancer care across metropolitan and rural regions in Australia..” Bmj Open, vol. 4, no. 10, Oct. 2014. Pubmed, doi:10.1136/bmjopen-2014-006661.
PMID
25344489
Source
pubmed
Published In
Bmj Open
Volume
4
Issue
10
Publish Date
2014
Start Page
e006661
DOI
10.1136/bmjopen-2014-006661

Characteristics of cancer diagnoses and staging in South Western Victoria: a rural perspective.

OBJECTIVE: Australian states and territories have legislation mandating reporting of cancer diagnoses; however, tumour stage at diagnosis, treatment plan and associated outcomes are not routinely recorded in cancer registries for all tumour types. This study describes the Evaluation of Cancer Outcomes study that collects detailed information for patients diagnosed with cancer in south-western Victoria. DESIGN: Retrospective data collection. SETTING: Population based. PARTICIPANTS: New cancer patients within the Barwon South Western region. MAIN OUTCOME MEASURES: Cancer incidence and staging data for a regional and rural area. RESULTS: In 2009, there were 1778 primary tumours. Prominent tumour streams included prostate, breast, colon, lung, lymphoma, melanoma and rectum. Stage at diagnosis was recorded for more than 50% of patients for the tumour streams of testis, breast, bowel, renal, lung, and head and neck. Patients reporting to health centres with an on-site oncologist as part of their team had a higher rate of staging recorded at diagnosis (48.0 versus 36.9%, P=0.01). More women (55.4%) than men (41.4%) had stage-recorded. CONCLUSION: The Evaluation of Cancer Outcomes study is an important initiative that collects information about newly diagnosed cases of cancer more detailed than is currently collected by the Cancer Council of Victoria. Future studies will build on this base dataset and provide valuable insight into the regional and rural experience of treatment pathways after diagnosis. More work is needed to bring more services to our rural patients, or more education is needed to encourage the recording of tumour staging.

Authors
Banks, P; Matheson, LM; Morrissy, K; Olesen, I; Pitson, G; Chapman, A; Ashley, DM; Henry, MJ
MLA Citation
Banks, Patricia, et al. “Characteristics of cancer diagnoses and staging in South Western Victoria: a rural perspective..” Aust J Rural Health, vol. 22, no. 5, Oct. 2014, pp. 257–63. Pubmed, doi:10.1111/ajr.12112.
PMID
25303418
Source
pubmed
Published In
Aust J Rural Health
Volume
22
Issue
5
Publish Date
2014
Start Page
257
End Page
263
DOI
10.1111/ajr.12112

Radiotherapy in the Barwon South Western Region: a rural perspective.

INTRODUCTION: Cancer-related mortality rates are higher in rural areas compared with urban regions. Whether there are corresponding geographical variations in radiotherapy utilisation rates (RURs) is the subject of this study. METHODS: RURs for the regional centre of Geelong and rural areas of the Barwon South Western Region were calculated using a population-based database (2009). RESULTS: Lower RURs were observed for rural patients compared with the Geelong region for prostate cancer (15.7% vs 25.8%, P = 0.02), rectal cancer (32.8% vs 44.7%, P = 0.11), lymphoma (9.4% vs 26.2%, P = 0.05), and all cancers overall (25.6% vs 28.9%, P = 0.06). This lower rate was significant in men (rural, 19.9%; Geelong, 28.3%; P = 0.00) but not in women (rural, 33.6%; Geelong, 29.7%; P = 0.88). Time from diagnosis to radiotherapy was not significantly different for patients from the two regions. Tumour staging within the rural and Geelong regions was not significantly different for the major tumour streams of rectal, prostate and lung cancer (P = 0.61, P = 0.79, P = 0.43, respectively). A higher proportion of tumours were unstaged or unstageable in the rural region for lung (44% vs 18%, P < 0.01) and prostate (73% vs 57%, P < 0.01) cancer. CONCLUSION: Lower RURs were observed in our rural region. Differences found within tumour streams and in men suggest a complexity of relationships that will require further study.

Authors
Henry, MJ; Jones, P; Morrissy, K; Matheson, LM; Pitson, G; Healy, P; Coory, M; Lynch, R; Chapman, A; Ashley, D
MLA Citation
Henry, Margaret J., et al. “Radiotherapy in the Barwon South Western Region: a rural perspective..” J Med Imaging Radiat Oncol, vol. 58, no. 5, Oct. 2014, pp. 612–17. Pubmed, doi:10.1111/1754-9485.12208.
PMID
25091019
Source
pubmed
Published In
J Med Imaging Radiat Oncol
Volume
58
Issue
5
Publish Date
2014
Start Page
612
End Page
617
DOI
10.1111/1754-9485.12208

Outpatient versus inpatient IV antibiotic management for pediatric oncology patients with low risk febrile neutropenia: a randomised trial.

BACKGROUND: Febrile neutropenia (FN) is a frequent, serious complication of intensive pediatric chemotherapy regimens. The aim of this trial was to compare quality of life (QOL) between inpatient and outpatient intravenous antibiotic management of children and adolescents with low risk febrile neutropenia (LRFN). PROCEDURE: In this randomised non-blinded trial, patients between 1 and 21 years old, receiving low/moderate intensity chemotherapy were pre-consented and, on presentation to emergency (ED) with FN satisfying low risk criteria, randomised to either outpatient or inpatient care with intravenous cefepime 50 mg/kg (12 hourly). All patients continued antibiotics for at least 48 hours, until afebrile for 24 hours and demonstrating a rising absolute neutrophil count ≥200/mm(3). Several domains of QOL were examined by daily questionnaire. RESULTS: Eighty-one patients presented to ED with 159 episodes of fever. Thirty-seven FN presentations involving 27 patients were randomised to inpatient (18) and outpatient (19) management. Combined QOL mean scores for parents were higher for the outpatient group and scores for three specific parent variables (keeping up with household tasks/time spent with partner/time spent with other children) were higher among outpatients. There was no difference in parent confidence/satisfaction in care between groups. Patients scored better in the outpatient group overall and for sleep and appetite. The mean length of fever was equivalent between groups and there were no serious adverse events attributable to cefepime or outpatient care. CONCLUSION: Outpatient cefepime management of LRFN provided significant benefit to parents and patients across several QOL domains and appeared both feasible and safe.

Authors
Orme, LM; Babl, FE; Barnes, C; Barnett, P; Donath, S; Ashley, DM
MLA Citation
Orme, Lisa M., et al. “Outpatient versus inpatient IV antibiotic management for pediatric oncology patients with low risk febrile neutropenia: a randomised trial..” Pediatr Blood Cancer, vol. 61, no. 8, Aug. 2014, pp. 1427–33. Pubmed, doi:10.1002/pbc.25012.
PMID
24604835
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
61
Issue
8
Publish Date
2014
Start Page
1427
End Page
1433
DOI
10.1002/pbc.25012

Validation of DNA methylation biomarkers for diagnosis of acute lymphoblastic leukemia.

BACKGROUND: DNA methylation biomarkers capable of diagnosis and subtyping have been found for many cancers. Fifteen such markers have previously been identified for pediatric acute lymphoblastic leukemia (ALL). Validation of these markers is necessary to assess their clinical utility for molecular diagnostics. Substantial efficiencies could be achieved with these DNA methylation markers for disease tracking with potential to replace patient-specific genetic testing. METHODS: We evaluated DNA methylation of promoter regions of TLX3 (T-cell leukemia homeobox) and FOXE3 (forkhead box E3) in bone marrow biopsies from 197 patients classified as leukemic (n = 95) or clear of the disease (n = 102) by MALDI-TOF. Using a single nucleotide extension assay (methylSABER), we tested 10 bone marrow biopsies collected throughout the course of patient chemotherapy. Using reference materials, diagnostic thresholds and limits of detection were characterized for both methods. RESULTS: Reliable detection of DNA methylation of TLX3 and FOXE3 segregated ALL from those clear of disease with minimal false-negative and false-positive results. The limit of detection with MALDI-TOF was 1000-5000 copies of methylated allele. For methylSABER, the limit of detection was 10 copies of methylated TLX3, which enabled monitoring of minimal residual disease in ALL patients. CONCLUSIONS: Mass spectrometry procedures can be used to regionally multiplex and detect rare DNA methylation events, establish DNA methylation loci as clinically applicable biomarkers for disease diagnosis, and track pediatric ALL.

Authors
Chatterton, Z; Burke, D; Emslie, KR; Craig, JM; Ng, J; Ashley, DM; Mechinaud, F; Saffery, R; Wong, NC
MLA Citation
Chatterton, Zac, et al. “Validation of DNA methylation biomarkers for diagnosis of acute lymphoblastic leukemia..” Clin Chem, vol. 60, no. 7, July 2014, pp. 995–1003. Pubmed, doi:10.1373/clinchem.2013.219956.
PMID
24829271
Source
pubmed
Published In
Clin Chem
Volume
60
Issue
7
Publish Date
2014
Start Page
995
End Page
1003
DOI
10.1373/clinchem.2013.219956

LOW DOSE HISTONE DEACETYLASE INHIBITOR TREATMENT HALTS RHABDOID TUMOUR GROWTH AND INDUCES OSTEOGENESIS AND NEURONAL DIFFERENTIATION

Authors
Muscat, A; Cain, J; Ferguson, M; Popovski, D; Algar, E; Rossello, FJ; Jayasekara, S; Watkins, DN; Hodge, J; Ashley, D
MLA Citation
Muscat, Andrea, et al. “LOW DOSE HISTONE DEACETYLASE INHIBITOR TREATMENT HALTS RHABDOID TUMOUR GROWTH AND INDUCES OSTEOGENESIS AND NEURONAL DIFFERENTIATION.” Neuro Oncology, vol. 16, OXFORD UNIV PRESS INC, 2014, pp. 1–1.
Source
wos
Published In
Neuro Oncology
Volume
16
Publish Date
2014
Start Page
1
End Page
1

Machine-learning prediction of cancer survival: a retrospective study using electronic administrative records and a cancer registry.

OBJECTIVES: Using the prediction of cancer outcome as a model, we have tested the hypothesis that through analysing routinely collected digital data contained in an electronic administrative record (EAR), using machine-learning techniques, we could enhance conventional methods in predicting clinical outcomes. SETTING: A regional cancer centre in Australia. PARTICIPANTS: Disease-specific data from a purpose-built cancer registry (Evaluation of Cancer Outcomes (ECO)) from 869 patients were used to predict survival at 6, 12 and 24 months. The model was validated with data from a further 94 patients, and results compared to the assessment of five specialist oncologists. Machine-learning prediction using ECO data was compared with that using EAR and a model combining ECO and EAR data. PRIMARY AND SECONDARY OUTCOME MEASURES: Survival prediction accuracy in terms of the area under the receiver operating characteristic curve (AUC). RESULTS: The ECO model yielded AUCs of 0.87 (95% CI 0.848 to 0.890) at 6 months, 0.796 (95% CI 0.774 to 0.823) at 12 months and 0.764 (95% CI 0.737 to 0.789) at 24 months. Each was slightly better than the performance of the clinician panel. The model performed consistently across a range of cancers, including rare cancers. Combining ECO and EAR data yielded better prediction than the ECO-based model (AUCs ranging from 0.757 to 0.997 for 6 months, AUCs from 0.689 to 0.988 for 12 months and AUCs from 0.713 to 0.973 for 24 months). The best prediction was for genitourinary, head and neck, lung, skin, and upper gastrointestinal tumours. CONCLUSIONS: Machine learning applied to information from a disease-specific (cancer) database and the EAR can be used to predict clinical outcomes. Importantly, the approach described made use of digital data that is already routinely collected but underexploited by clinical health systems.

Authors
Gupta, S; Tran, T; Luo, W; Phung, D; Kennedy, RL; Broad, A; Campbell, D; Kipp, D; Singh, M; Khasraw, M; Matheson, L; Ashley, DM; Venkatesh, S
MLA Citation
Gupta, Sunil, et al. “Machine-learning prediction of cancer survival: a retrospective study using electronic administrative records and a cancer registry..” Bmj Open, vol. 4, no. 3, Mar. 2014. Pubmed, doi:10.1136/bmjopen-2013-004007.
PMID
24643167
Source
pubmed
Published In
Bmj Open
Volume
4
Issue
3
Publish Date
2014
Start Page
e004007
DOI
10.1136/bmjopen-2013-004007

Epigenetic deregulation in pediatric acute lymphoblastic leukemia.

Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the EPO-receptor, while Hyperdiploid patients (> 50 chr) displayed upregulation of B-cell lymphoma (BCL) members and repression of PTPRG and FHIT. In combination, these data indicate genetically distinct B-cell ALL subtypes contain cooperative epimutations and genome-wide epigenetic deregulation is common across all B-cell ALL subtypes.

Authors
Chatterton, Z; Morenos, L; Mechinaud, F; Ashley, DM; Craig, JM; Sexton-Oates, A; Halemba, MS; Parkinson-Bates, M; Ng, J; Morrison, D; Carroll, WL; Saffery, R; Wong, NC
MLA Citation
Chatterton, Zac, et al. “Epigenetic deregulation in pediatric acute lymphoblastic leukemia..” Epigenetics, vol. 9, no. 3, Mar. 2014, pp. 459–67. Pubmed, doi:10.4161/epi.27585.
PMID
24394348
Source
pubmed
Published In
Epigenetics : Official Journal of the Dna Methylation Society
Volume
9
Issue
3
Publish Date
2014
Start Page
459
End Page
467
DOI
10.4161/epi.27585

Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group.

Medulloblastoma is curable in approximately 70% of patients. Over the past decade, progress in improving survival using conventional therapies has stalled, resulting in reduced quality of life due to treatment-related side effects, which are a major concern in survivors. The vast amount of genomic and molecular data generated over the last 5-10 years encourages optimism that improved risk stratification and new molecular targets will improve outcomes. It is now clear that medulloblastoma is not a single-disease entity, but instead consists of at least four distinct molecular subgroups: WNT/Wingless, Sonic Hedgehog, Group 3, and Group 4. The Medulloblastoma Down Under 2013 meeting, which convened at Bunker Bay, Australia, brought together 50 leading clinicians and scientists. The 2-day agenda included focused sessions on pathology and molecular stratification, genomics and mouse models, high-throughput drug screening, and clinical trial design. The meeting established a global action plan to translate novel biologic insights and drug targeting into treatment regimens to improve outcomes. A consensus was reached in several key areas, with the most important being that a novel classification scheme for medulloblastoma based on the four molecular subgroups, as well as histopathologic features, should be presented for consideration in the upcoming fifth edition of the World Health Organization's classification of tumours of the central nervous system. Three other notable areas of agreement were as follows: (1) to establish a central repository of annotated mouse models that are readily accessible and freely available to the international research community; (2) to institute common eligibility criteria between the Children's Oncology Group and the International Society of Paediatric Oncology Europe and initiate joint or parallel clinical trials; (3) to share preliminary high-throughput screening data across discovery labs to hasten the development of novel therapeutics. Medulloblastoma Down Under 2013 was an effective forum for meaningful discussion, which resulted in enhancing international collaborative clinical and translational research of this rare disease. This template could be applied to other fields to devise global action plans addressing all aspects of a disease, from improved disease classification, treatment stratification, and drug targeting to superior treatment regimens to be assessed in cooperative international clinical trials.

Authors
Gottardo, NG; Hansford, JR; McGlade, JP; Alvaro, F; Ashley, DM; Bailey, S; Baker, DL; Bourdeaut, F; Cho, Y-J; Clay, M; Clifford, SC; Cohn, RJ; Cole, CH; Dallas, PB; Downie, P; Doz, F; Ellison, DW; Endersby, R; Fisher, PG; Hassall, T; Heath, JA; Hii, HL; Jones, DTW; Junckerstorff, R; Kellie, S; Kool, M; Kotecha, RS; Lichter, P; Laughton, SJ; Lee, S; McCowage, G; Northcott, PA; Olson, JM; Packer, RJ; Pfister, SM; Pietsch, T; Pizer, B; Pomeroy, SL; Remke, M; Robinson, GW; Rutkowski, S; Schoep, T; Shelat, AA; Stewart, CF; Sullivan, M; Taylor, MD; Wainwright, B; Walwyn, T; Weiss, WA; Williamson, D; Gajjar, A
MLA Citation
Gottardo, Nicholas G., et al. “Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group..” Acta Neuropathol, vol. 127, no. 2, 2014, pp. 189–201. Pubmed, doi:10.1007/s00401-013-1213-7.
PMID
24264598
Source
pubmed
Published In
Acta Neuropathol
Volume
127
Issue
2
Publish Date
2014
Start Page
189
End Page
201
DOI
10.1007/s00401-013-1213-7

Efficacy and cost-effectiveness of an outcall program to reduce carer burden and depression among carers of cancer patients [PROTECT]: rationale and design of a randomized controlled trial.

BACKGROUND: Carers provide extended and often unrecognized support to people with cancer. The aim of this study is to test the hypothesis that excessive carer burden is modifiable through a telephone outcall intervention that includes supportive care, information and referral to appropriate psycho-social services. Secondary aims include estimation of changes in psychological health and quality of life. The study will determine whether the intervention reduces unmet needs among patient dyads. A formal economic program will also be conducted. METHODS/DESIGN: This study is a single-blind, multi-centre, randomized controlled trial to determine the efficacy and cost-efficacy of a telephone outcall program among carers of newly diagnosed cancer patients. A total of 230 carer/patient dyads will be recruited into the study; following written consent, carers will be randomly allocated to either the outcall intervention program (n = 115) or to a minimal outcall / attention control service (n = 115). Carer assessments will occur at baseline, at one and six months post-intervention. The primary outcome is change in carer burden; the secondary outcomes are change in carer depression, quality of life, health literacy and unmet needs. The trial patients will be assessed at baseline and one month post-intervention to determine depression levels and unmet needs. The economic analysis will include perspectives of both the health care sector and broader society and comprise a cost-consequences analysis where all outcomes will be compared to costs. DISCUSSION: This study will contribute to our understanding on the potential impact of a telephone outcall program on carer burden and provide new evidence on an approach for improving the wellbeing of carers.

Authors
Livingston, PM; Osborne, RH; Botti, M; Mihalopoulos, C; McGuigan, S; Heckel, L; Gunn, K; Chirgwin, J; Ashley, DM; Williams, M
MLA Citation
Livingston, Patricia M., et al. “Efficacy and cost-effectiveness of an outcall program to reduce carer burden and depression among carers of cancer patients [PROTECT]: rationale and design of a randomized controlled trial..” Bmc Health Serv Res, vol. 14, Jan. 2014. Pubmed, doi:10.1186/1472-6963-14-5.
PMID
24393305
Source
pubmed
Published In
Bmc Health Services Research
Volume
14
Publish Date
2014
Start Page
5
DOI
10.1186/1472-6963-14-5

The oncogenic properties of EWS/WT1 of desmoplastic small round cell tumors are unmasked by loss of p53 in murine embryonic fibroblasts.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is characterized by the presence of a fusion protein EWS/WT1, arising from the t (11;22) (p13;q12) translocation. Here we examine the oncogenic properties of two splice variants of EWS/WT1, EWS/WT1-KTS and EWS/WT1 + KTS. METHODS: We over-expressed both EWS/WT1 variants in murine embryonic fibroblasts (MEFs) of wild-type, p53+/- and p53-/- backgrounds and measured effects on cell-proliferation, anchorage-independent growth, clonogenicity after serum withdrawal, and sensitivity to cytotoxic drugs and gamma irradiation in comparison to control cells. We examined gene expression profiles in cells expressing EWS/WT1. Finally we validated our key findings in a small series of DSRCT. RESULTS: Neither isoform of EWS/WT1 was sufficient to transform wild-type MEFs however the oncogenic potential of both was unmasked by p53 loss. Expression of EWS/WT1 in MEFs lacking at least one allele of p53 enhanced cell-proliferation, clonogenic survival and anchorage-independent growth. EWS/WT1 expression in wild-type MEFs conferred resistance to cell-cycle arrest after irradiation and daunorubicin induced apoptosis. We show DSRCT commonly have nuclear localization of p53, and copy-number amplification of MDM2/MDMX. Expression of either isoform of EWS/WT1 induced characteristic mRNA expression profiles. Gene-set enrichment analysis demonstrated enrichment of WNT pathway signatures in MEFs expressing EWS/WT1 + KTS. Wnt-activation was validated in cell lines with over-expression of EWS/WT1 and in DSRCT. CONCLUSION: In conclusion, we show both isoforms of EWS/WT1 have oncogenic potential in MEFs with loss of p53. In addition we provide the first link between EWS/WT1 and Wnt-pathway signaling. These data provide novel insights into the function of the EWS/WT1 fusion protein which characterize DSRCT.

Authors
Bandopadhayay, P; Jabbour, AM; Riffkin, C; Salmanidis, M; Gordon, L; Popovski, D; Rigby, L; Ashley, DM; Watkins, DN; Thomas, DM; Algar, E; Ekert, PG
MLA Citation
Bandopadhayay, Pratiti, et al. “The oncogenic properties of EWS/WT1 of desmoplastic small round cell tumors are unmasked by loss of p53 in murine embryonic fibroblasts..” Bmc Cancer, vol. 13, Dec. 2013. Pubmed, doi:10.1186/1471-2407-13-585.
PMID
24321497
Source
pubmed
Published In
Bmc Cancer
Volume
13
Publish Date
2013
Start Page
585
DOI
10.1186/1471-2407-13-585

Case report of interstitial nephritis induced by bevacizumab therapy for glioblastoma multiforme.

Glioblastoma multiforme is an aggressive malignant brain tumor. The monoclonal antibody, bevacizumab, is active in recurrent disease via inhibition of angiogenesis. Proteinuria and renal thrombotic microangiopathy are known complications. We report a case of a patient developing acute renal failure with biopsy-proven interstitial nephritis while receiving bevacizumab for recurrent disease. The patient was otherwise well with a history of controlled hypertension. Renal function improved with discontinuation of bevacizumab and the administration of corticosteroid therapy.

Authors
Lomax, AJ; Hill, PA; Ashley, DM
MLA Citation
Lomax, Anna J., et al. “Case report of interstitial nephritis induced by bevacizumab therapy for glioblastoma multiforme..” J Oncol Pharm Pract, vol. 19, no. 4, Dec. 2013, pp. 365–68. Pubmed, doi:10.1177/1078155212466421.
PMID
23235917
Source
pubmed
Published In
J Oncol Pharm Pract
Volume
19
Issue
4
Publish Date
2013
Start Page
365
End Page
368
DOI
10.1177/1078155212466421

Emerging pharmacotherapy for cancer patients with cognitive dysfunction.

Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae of therapy, including that of cognitive dysfunction. The cytotoxic nature of chemotherapeutic agents may also reduce neurogenesis, a key component of the physiology of memory and cognition, with ramifications for the patient's mood and other cognition disorders. Similarly radiotherapy employed as a therapeutic or prophylactic tool in the treatment of primary or metastatic disease may significantly affect cognition. A number of emerging pharmacotherapies are under investigation for the treatment of cognitive dysfunction experienced by cancer patients. Recent data from clinical trials is reviewed involving the stimulants modafinil and methylphenidate, mood stabiliser lithium, anti-Alzheimer's drugs memantine and donepezil, as well as other agents which are currently being explored within dementia, animal, and cell culture models to evaluate their use in treating cognitive dysfunction.

Authors
Davis, J; Ahlberg, FM; Berk, M; Ashley, DM; Khasraw, M
MLA Citation
Davis, Justin, et al. “Emerging pharmacotherapy for cancer patients with cognitive dysfunction..” Bmc Neurol, vol. 13, Oct. 2013. Pubmed, doi:10.1186/1471-2377-13-153.
PMID
24156319
Source
pubmed
Published In
Bmc Neurology
Volume
13
Publish Date
2013
Start Page
153
DOI
10.1186/1471-2377-13-153

THE ONCOGENIC PROPERTIES OF THE EWS/WT1 FUSION PROTEIN OF DESMOPLASTIC SMALL ROUND CELL TUMOUR

Authors
Bandopadhayay, P; Jabbour, A; Riffkin, C; Salmanidis, M; Gordon, L; Popovski, D; Rigby, L; Ashley, D; Watkins, D; Thomas, D; Algar, E; Ekert, P
MLA Citation
Bandopadhayay, P., et al. “THE ONCOGENIC PROPERTIES OF THE EWS/WT1 FUSION PROTEIN OF DESMOPLASTIC SMALL ROUND CELL TUMOUR.” Pediatric Blood & Cancer, vol. 60, WILEY-BLACKWELL, 2013, pp. 8–8.
Source
wos
Published In
Pediatric Blood & Cancer
Volume
60
Publish Date
2013
Start Page
8
End Page
8

A phase II single-arm study of irinotecan in combination with temozolomide (TEMIRI) in children with newly diagnosed high grade glioma: a joint ITCC and SIOPE-brain tumour study.

A multicenter, two stage phase II study, investigated irinotecan plus temozolomide in children with newly diagnosed high grade glioma. The primary endpoint was tumor response during a two-cycle treatment window, confirmed by external review committee. Patients received oral temozolomide 100 mg/(m(2) day) (days 1-5) and intravenous irinotecan 10 mg/(m(2) day) (days 1-5 and 8-12) for two 21-day cycles (three cycles for patients exhibiting objective tumor response). Standard treatment was then administered according to local investigator choice. In total 17 patients were enrolled and treated by local investigators. However, central pathology review found three patients did not have a diagnosis of high grade glioma and another four patients did not have evaluable disease according to independent central radiological review. The primary endpoint was based on the first ten evaluable patients as determined by the external review committee. Recruitment was stopped for futility after there were no complete or partial responses during the two-cycle treatment window in the first ten evaluable patients. Five patients had stable disease, and five progressed. Data for secondary endpoints including; time to tumor progression, time to treatment failure, and overall survival is reported. The safety profile of the treatment showed the combination was tolerable with two patients (11.8 %) having grade three nausea, and one (5.9 %) experiencing a grade four neutropenia, leading to permanent discontinuation from adjuvant treatment. Irinotecan plus temozolomide, although well tolerated did not improve outcome over historical controls in this setting.

Authors
Hargrave, D; Geoerger, B; Frappaz, D; Pietsch, T; Gesner, L; Cisar, L; Breazna, A; Dorman, A; Cruz-Martinez, O; Fuster, JL; Rialland, X; Icher, C; Leblond, P; Ashley, D; Perilongo, G; Elliott, M; English, M; Clausen, N; Grill, J
MLA Citation
Hargrave, Darren, et al. “A phase II single-arm study of irinotecan in combination with temozolomide (TEMIRI) in children with newly diagnosed high grade glioma: a joint ITCC and SIOPE-brain tumour study..” J Neurooncol, vol. 113, no. 1, May 2013, pp. 127–34. Pubmed, doi:10.1007/s11060-013-1098-2.
PMID
23459995
Source
pubmed
Published In
J Neurooncol
Volume
113
Issue
1
Publish Date
2013
Start Page
127
End Page
134
DOI
10.1007/s11060-013-1098-2

Sustained low-dose treatment with the Histone deacetylase inhibitor LBH589 induces terminal differentiation of osteosarcoma cells

Histone deacetylase inhibitors (HDACi) were identified nearly four decades ago based on their ability to induce cellular differentiation. However, the clinical development of these compounds as cancer therapies has focused on their capacity to induce apoptosis in hematologic and lymphoid malignancies, often in combination with conventional cytotoxic agents. In many cases, HDACi doses necessary to induce these effects result in significant toxicity. Since osteosarcoma cells express markers of terminal osteoblast differentiation in response to DNA methyltransferase inhibitors, we reasoned that the epigenetic reprogramming capacity of HDACi might be exploited for therapeutic benefit. Here, we show that continuous exposure of osteosarcoma cells to low concentrations of HDACi LBH589 (Panobinostat) over a three-week period induces terminal osteoblast differentiation and irreversible senescence without inducing cell death. Remarkably, transcriptional profiling revealed that HDACi therapy initiated gene signatures characteristic of chondrocyte and adipocyte lineages in addition to marked upregulation of mature osteoblast markers. In a mouse xenograft model, continuous low dose treatment with LBH589 induced a sustained cytostatic response accompanied by induction of mature osteoblast gene expression. These data suggest that the remarkable capacity of osteosarcoma cells to differentiate in response to HDACi therapy could be exploited for therapeutic benefit without inducing systemic toxicity. © 2013 Jason E. Cain et al.

Authors
Cain, JE; McCaw, A; Jayasekara, WSN; Rossello, FJ; Marini, KD; Irving, AT; Kansara, M; Thomas, DM; Ashley, DM; Watkins, DN
MLA Citation
Cain, J. E., et al. “Sustained low-dose treatment with the Histone deacetylase inhibitor LBH589 induces terminal differentiation of osteosarcoma cells.” Sarcoma, vol. 2013, Apr. 2013. Scopus, doi:10.1155/2013/608964.
Source
scopus
Published In
Sarcoma
Volume
2013
Publish Date
2013
DOI
10.1155/2013/608964

New drugs for children and adolescents with cancer: the need for novel development pathways.

Despite major progress in the past 40 years, 20% of children with cancer die from the disease, and 40% of survivors have late adverse effects. Innovative, safe, and effective medicines are needed. Although regulatory initiatives in the past 15 years in the USA and Europe have been introduced, new drug development for children with cancer is insufficient. Children and families face major inequity between countries in terms of access to innovative drugs in development. Hurdles and bottlenecks are well known-eg, small numbers of patients, the complexity of developing targeted agents and their biomarkers for selected patients, limitations of US and EU regulations for paediatric medicines, insufficient return on investment, and the global economic crisis facing drug companies. New drug development pathways could efficiently address the challenges with innovative methods and trial designs, investment in biology and preclinical research, new models of partnership and funding including public-private partnerships and precompetitive research consortia, improved regulatory requirements, initiatives and incentives that better address these needs, and increased collaboration between paediatric oncology cooperative groups worldwide. Increased cooperation between all stakeholders-academia, parents' organisations and advocacy groups, regulatory bodies, pharmaceutical companies, philanthropic organisations, and government-will be essential.

Authors
Vassal, G; Zwaan, CM; Ashley, D; Le Deley, MC; Hargrave, D; Blanc, P; Adamson, PC
MLA Citation
Vassal, Gilles, et al. “New drugs for children and adolescents with cancer: the need for novel development pathways..” Lancet Oncol, vol. 14, no. 3, Mar. 2013, pp. e117–24. Pubmed, doi:10.1016/S1470-2045(13)70013-5.
PMID
23434337
Source
pubmed
Published In
Lancet Oncol
Volume
14
Issue
3
Publish Date
2013
Start Page
e117
End Page
e124
DOI
10.1016/S1470-2045(13)70013-5

Acute pain associated with oxaliplatin infusion: case report and literature review.

Both acute and chronic neurotoxicities are well-described with the use of oxaliplatin. We describe the case of a 50-year-old man with Dukes C colon carcinoma being treated with an adjuvant FOLFOX4 (5-fluorouracil, leucovorin and oxaliplatin (85 mg/m(2) per cycle)) who developed a widespread acute pain 5 min after commencing his twelfth cycle of chemotherapy. The pain was disabling and distressing, and remained for 16 h despite multimodality analgesia. The patient was not rechallenged with oxaliplatin. We believe this presentation represents an acute neurological phenomenon relating to oxaliplatin. Of note, this acute reaction occurred after 11 cycles of treatment, significantly later in the treatment course than other reports of atypical acute reactions.

Authors
Clay, TD; Ashley, DA
MLA Citation
Clay, Timothy D., and David A. Ashley. “Acute pain associated with oxaliplatin infusion: case report and literature review..” J Oncol Pharm Pract, vol. 18, no. 4, Dec. 2012, pp. 421–24. Pubmed, doi:10.1177/1078155211428999.
PMID
22080592
Source
pubmed
Published In
J Oncol Pharm Pract
Volume
18
Issue
4
Publish Date
2012
Start Page
421
End Page
424
DOI
10.1177/1078155211428999

Using lithium as a neuroprotective agent in patients with cancer.

Neurocognitive impairment is being increasingly recognized as an important issue in patients with cancer who develop cognitive difficulties either as part of direct or indirect involvement of the nervous system or as a consequence of either chemotherapy-related or radiotherapy-related complications. Brain radiotherapy in particular can lead to significant cognitive defects. Neurocognitive decline adversely affects quality of life, meaningful employment, and even simple daily activities. Neuroprotection may be a viable and realistic goal in preventing neurocognitive sequelae in these patients, especially in the setting of cranial irradiation. Lithium is an agent that has been in use for psychiatric disorders for decades, but recently there has been emerging evidence that it can have a neuroprotective effect.This review discusses neurocognitive impairment in patients with cancer and the potential for investigating the use of lithium as a neuroprotectant in such patients.

Authors
Khasraw, M; Ashley, D; Wheeler, G; Berk, M
MLA Citation
Khasraw, Mustafa, et al. “Using lithium as a neuroprotective agent in patients with cancer..” Bmc Med, vol. 10, Nov. 2012. Pubmed, doi:10.1186/1741-7015-10-131.
PMID
23121766
Source
pubmed
Published In
Bmc Medicine
Volume
10
Publish Date
2012
Start Page
131
DOI
10.1186/1741-7015-10-131

Predictors of acute and posttraumatic stress symptoms in parents following their child's cancer diagnosis.

This longitudinal study aimed to examine acute and posttraumatic stress symptoms and predictors of traumatic stress symptoms in parents of children recently diagnosed with cancer. The sample comprised 220 parents of 143 children who completed questionnaires at diagnosis (T1) focused on acute stress disorder (ASD); of these, 145 parents of 97 children completed questionnaires 6-8 months later (T2) focused on posttraumatic stress disorder (PTSD). Demographic, psychosocial, and treatment and illness variables were predictors. Results were that 63% of mothers and 60% of fathers met criteria for ASD at T1. At T2, 21% of mothers and 16% of fathers met criteria for PTSD, with 40% of parents reporting significant subthreshold symptoms. Predictors of ASD symptoms were female gender, presence of psychosocial risk factors, trait anxiety, family functioning, and central nervous system tumor diagnosis. Risk factors for PTSD symptoms were younger maternal age, severity of ASD symptoms, and trait anxiety at T1, and parent-reported quality of life of the child at T2. The results suggest that screening for ASD may help identify parents at increased risk of persistent traumatic stress symptoms who could benefit from preventative, evidence-based psychosocial interventions.

Authors
McCarthy, MC; Ashley, DM; Lee, KJ; Anderson, VA
MLA Citation
McCarthy, Maria C., et al. “Predictors of acute and posttraumatic stress symptoms in parents following their child's cancer diagnosis..” J Trauma Stress, vol. 25, no. 5, Oct. 2012, pp. 558–66. Pubmed, doi:10.1002/jts.21745.
PMID
23055298
Source
pubmed
Published In
Journal of Traumatic Stress
Volume
25
Issue
5
Publish Date
2012
Start Page
558
End Page
566
DOI
10.1002/jts.21745

Induction chemotherapy and conformal radiation therapy for very young children with nonmetastatic medulloblastoma: Children's Oncology Group study P9934.

PURPOSE: P9934 was a prospective trial of systemic chemotherapy, second surgery, and conformal radiation therapy (CRT) limited to the posterior fossa and primary site for children between 8 months and 3 years old with nonmetastatic medulloblastoma. The study was open from June 2000 until June 2006. PATIENTS AND METHODS: After initial surgery, children received four cycles of induction chemotherapy, followed by age- and response-adjusted CRT to the posterior fossa (18 or 23.4 Gy) and tumor bed (cumulative 50.4 or 54 Gy) and maintenance chemotherapy. Neurodevelopmental outcomes were evaluated and event-free survival (EFS) results were directly compared with a previous study of multiagent chemotherapy without irradiation (Pediatric Oncology Group [POG] trial 9233). RESULTS: Seventy-four patients met eligibility requirements. The 4-year EFS and overall survival probabilities were 50% ± 6% and 69% ± 5.5%, respectively, which compared favorably to the results from POG 9233. Analysis showed that the desmoplastic/nodular subtype was a favorable factor in predicting survival. Our 4-year EFS rate was 58% ± 8% for patients with desmoplasia. Whereas seven of 10 patients who had disease progression before CRT had primary-site failure, 15 of 19 patients who progressed after CRT had distant-site failure. Neurodevelopmental assessments did not show a decline in cognitive or motor function after protocol-directed chemotherapy and CRT. CONCLUSION: The addition of CRT to postoperative chemotherapy in young children with nonmetastatic medulloblastoma increased event-free survival compared with the use of postoperative chemotherapy alone. Future studies will use histopathologic typing (desmoplastic/nodular versus nondesmoplastic/nodular) to stratify patients for therapy by risk of relapse.

Authors
Ashley, DM; Merchant, TE; Strother, D; Zhou, T; Duffner, P; Burger, PC; Miller, DC; Lyon, N; Bonner, MJ; Msall, M; Buxton, A; Geyer, R; Kun, LE; Coleman, L; Pollack, IF
MLA Citation
Ashley, David M., et al. “Induction chemotherapy and conformal radiation therapy for very young children with nonmetastatic medulloblastoma: Children's Oncology Group study P9934..” J Clin Oncol, vol. 30, no. 26, Sept. 2012, pp. 3181–86. Pubmed, doi:10.1200/JCO.2010.34.4341.
PMID
22851568
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
26
Publish Date
2012
Start Page
3181
End Page
3186
DOI
10.1200/JCO.2010.34.4341

Methods for the analysis of histone H3 and H4 acetylation in blood.

LBH589 is one of the many histone deacetylase inhibitors (HDACi) that are currently in clinical trial. Despite their wide-spread use, there is little literature available describing the typical levels of histone acetylation in untreated peripheral blood, the treatment and storage of samples to retain optimal measurement of histone acetylation nor methods by which histone acetylation analysis may be monitored and measured during the course of a patient's treatment. In this study, we have used cord or peripheral blood as a source of human leukocytes, performed a comparative analysis of sample processing methods and developed a flow cytometric method suitable for monitoring histone acetylation in isolated lymphocytes and liquid tumors. Western blotting and immunohistochemistry techniques have also been addressed. We have tested these methods on blood samples collected from four patients treated with LBH589 as part of an Australian Children's Cancer Clinical Trial (CLBH589AAU03T) and show comparable results when comparing in vitro and in vivo data. This paper does not seek to correlate histone acetylation levels in peripheral blood with clinical outcome but describes methods of analysis that will be of interest to clinicians and scientists monitoring the effects of HDACi on histone acetylation in blood samples in clinical trials or in related research studies.

Authors
Rigby, L; Muscat, A; Ashley, D; Algar, E
MLA Citation
Rigby, Lin, et al. “Methods for the analysis of histone H3 and H4 acetylation in blood..” Epigenetics, vol. 7, no. 8, Aug. 2012, pp. 875–82. Pubmed, doi:10.4161/epi.20983.
PMID
22772164
Source
pubmed
Published In
Epigenetics : Official Journal of the Dna Methylation Society
Volume
7
Issue
8
Publish Date
2012
Start Page
875
End Page
882
DOI
10.4161/epi.20983

Feasibility of neurobehavioral screening following diagnosis of pediatric cancer.

BACKGROUND: Neurobehavioral deficits will affect up to 50% of pediatric cancer survivors treated with central nervous system (CNS)-directed therapies. Guidelines suggest assessment of neurobehavioral skills at diagnosis be extended from patients with brain tumors to include all patients requiring CNS-directed therapies. However, comprehensive neuropsychological assessment at diagnosis is difficult to implement and resource intensive. A screening assessment targeted at the neurobehavioral domains known to be impacted by cancer treatments may be more feasible. This study aimed to assess the feasibility of implementing baseline neurobehavioral screening following childhood cancer diagnosis. PROCEDURE: A consecutive sample of 59 recently diagnosed patients requiring CNS-directed therapies, and 49 healthy controls were assessed using a targeted neurobehavioral screen, which included measures of developmental, cognitive, academic, behavioral, and psychosocial functioning. Feasibility was assessed using a formal feasibility framework, with criteria of brevity, simplicity, relevance, acceptability, and value. Neurobehavioral assessment was compared to standard care to determine the quality of information acquired from the screen. RESULTS: Mean time from diagnosis to assessment was 5.17 weeks. Assessments were completed within 1 hour for 87% of patients. Participant and researcher evaluation indicated the screen was acceptable across a range of criteria, with no differences between clinical and control groups. Compared to standard medical record documentation, the screen provided significant additional information on developmental and neurobehavioral status of patients at diagnosis. CONCLUSION: A brief neurobehavioral screen in the early period following cancer diagnosis is feasible and provides valuable baseline data for children at risk of neurobehavioral late-effects of cancer treatments.

Authors
Pejnovic, LP; De Luca, CR; Gentle, E; Anson, K; Ashley, DM; Anderson, VA; McCarthy, MC
MLA Citation
Pejnovic, Laura P., et al. “Feasibility of neurobehavioral screening following diagnosis of pediatric cancer..” Pediatr Blood Cancer, vol. 59, no. 2, Aug. 2012, pp. 295–300. Pubmed, doi:10.1002/pbc.24056.
PMID
22238124
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
59
Issue
2
Publish Date
2012
Start Page
295
End Page
300
DOI
10.1002/pbc.24056

A distinct DNA methylation signature defines pediatric pre-B cell acute lymphoblastic leukemia.

Pre-B cell acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy and remains one of the highest causes of childhood mortality. Despite this, the mechanisms leading to disease remain poorly understood. We asked if recurrent aberrant DNA methylation plays a role in childhood ALL and have defined a genome-scale DNA methylation profile associated with the ETV6-RUNX1 subtype of pediatric ALL. Archival bone marrow smears from 19 children collected at diagnosis and remission were used to derive a disease specific DNA methylation profile. The gene signature was confirmed in an independent cohort of 86 patients. A further 163 patients were analyzed for DNA methylation of a three gene signature. We found that the DNA methylation signature at diagnosis was unique from remission. Fifteen loci were sufficient to discriminate leukemia from disease-free samples and purified CD34+ cells. DNA methylation of these loci was recurrent irrespective of cytogenetic subtype of pre-B cell ALL. We show that recurrent aberrant genomic methylation is a common feature of pre-B ALL, suggesting a shared pathway for disease development. By revealing new DNA methylation markers associated with disease, this study has identified putative targets for development of novel epigenetic-based therapies.

Authors
Wong, NC; Ashley, D; Chatterton, Z; Parkinson-Bates, M; Ng, HK; Halemba, MS; Kowalczyk, A; Bedo, J; Wang, Q; Bell, K; Algar, E; Craig, JM; Saffery, R
MLA Citation
Wong, Nicholas C., et al. “A distinct DNA methylation signature defines pediatric pre-B cell acute lymphoblastic leukemia..” Epigenetics, vol. 7, no. 6, June 2012, pp. 535–41. Pubmed, doi:10.4161/epi.20193.
PMID
22531296
Source
pubmed
Published In
Epigenetics : Official Journal of the Dna Methylation Society
Volume
7
Issue
6
Publish Date
2012
Start Page
535
End Page
541
DOI
10.4161/epi.20193

Genome-scale DNA methylation analyses of cancer in children

© Cambridge University Press 2012. Introduction Although rare, cancer is a leading cause of disease mortality in children after accidents, homicides, and suicides (Ries et al., 1999). The biology of cancer in children is markedly different to cancer in adults. This is highlighted by the disparate incidence and etiology of common cancers found between children and adults (AIHW and AACR, 2004). In children, leukemia and brain tumors predominate in newly diagnosed cases, while breast, colorectal, melanoma, and lung cancer are common cancers in adults. While there seems to be a genetic basis for adult cancers, where familial cases of breast (reviewed in Narod and Foulkes, 2004) and colorectal (reviewed in Jasperson et al., 2010) cancer have identified mutations of candidate risk genes, the same can not be said for childhood cancer. The precise causes of childhood cancer still remain unknown. With the scarce number of cases of familial or inherited cancers in children, it would seem that genetics plays a minor role in childhood cancer. Tumours acquire somatic mutation during their progression to cancer and it has long been hypothesized that selected environmental exposures can accelerate mutation rate in tumours that have given rise to their presentation as cancer in children (Knudson, 1976). There is a proposed list of high-risk exposures including radiation, infection, and pesticides associated with childhood cancer (reviewed in Anderson, 2006); however, the small study numbers used to identify these factors have led to small effect sizes and have been difficult to reproduce. Large, multi-center prospective cohort studies have begun to address this issue (Brown et al., 2007).

Authors
Wong, NC; Ashley, DM
MLA Citation
Wong, N. C., and D. M. Ashley. “Genome-scale DNA methylation analyses of cancer in children.” Epigenomics: From Chromatin Biology to Therapeutics, 2012, pp. 338–46. Scopus, doi:10.1017/CBO9780511777271.030.
Source
scopus
Publish Date
2012
Start Page
338
End Page
346
DOI
10.1017/CBO9780511777271.030

Enhanced lithium-induced brain recovery following cranial irradiation is not impeded by inflammation

Radiation-induced brain injury occurs in many patients receiving cranial radiation therapy, and these deleterious effects are most profound in younger patients. Impaired neurocognitive functions in both humans and rodents are associated with inflammation, demyelination, and neural stem cell dysfunction. Here we evaluated the utility of lithium and a synthetic retinoid receptor agonist in reducing damage in a model of brain-focused irradiation in juvenile mice. We found that lithium stimulated brain progenitor cell proliferation and differentiation following cranial irradiation while also preventing oligodendrocyte loss in the dentate gyrus of juvenile mice. In response to inflammation induced by radiation, which may have encumbered the optimal reparative action of lithium, we used the anti-inflammatory synthetic retinoid Am80 that is in clinical use in the treatment of acute promyelocytic leukemia. Although Am80 reduced the number of cyclooxygenase-2-positive microglial cells following radiation treatment, it did not enhance lithium-induced neurogenesis recovery, and this alone was not significantly different from the effect of lithium on this proinflammatory response. Similarly, lithium was superior to Am80 in supporting the restoration of new doublecortin-positive neurons following irradiation. These data suggest that lithium is superior in its restorative effects to blocking inflammation alone, at least in the case of Am80. Because lithium has been in routine clinical practice for 60 years, these preclinical studies indicate that this drug might be beneficial in reducing post-therapy late effects in patients receiving cranial radiotherapy and that blocking inflammation in this context may not be as advantageous as previously suggested. © AlphaMed Press.

Authors
Malaterre, J; McPherson, CS; Denoyer, D; Lai, E; Hagekyriakou, J; Lightowler, S; Shudo, K; Ernst, M; Ashley, DM; Short, JL; Wheeler, G; Ramsay, RG
MLA Citation
Malaterre, J., et al. “Enhanced lithium-induced brain recovery following cranial irradiation is not impeded by inflammation.” Stem Cells Translational Medicine, vol. 1, no. 6, Jan. 2012, pp. 469–79. Scopus, doi:10.5966/sctm.2011-0046.
Source
scopus
Published In
Stem Cells Translational Medicine
Volume
1
Issue
6
Publish Date
2012
Start Page
469
End Page
479
DOI
10.5966/sctm.2011-0046

Evaluation of microRNA expression in patient bone marrow aspirate slides.

Like formalin fixed paraffin embedded (FFPE) tissues, archived bone marrow aspirate slides are an abundant and untapped resource of biospecimens that could enable retrospective molecular studies of disease. Historically, RNA obtained from slides is limited in utility because of their low quality and highly fragmented nature. MicroRNAs are small (≈ 22 nt) non-coding RNA that regulate gene expression, and are speculated to preserve well in FFPE tissue. Here we investigate the use of archived bone marrow aspirate slides for miRNA expression analysis in paediatric leukaemia. After determining the optimal method of miRNA extraction, we used TaqMan qRT-PCR to identify reference miRNA for normalisation of other miRNA species. We found hsa-miR-16 and hsa-miR-26b to be the most stably expressed between lymphoblastoid cell lines, primary bone marrow aspirates and archived samples. We found the average fold change in expression of hsa-miR-26b and two miRNA reportedly dysregulated in leukaemia (hsa-miR-128a, hsa-miR-223) was <0.5 between matching archived slide and bone marrow aspirates. Differential expression of hsa-miR-128a and hsa-miR-223 was observed between leukaemic and non-leukaemic bone marrow from archived slides or flash frozen bone marrow. The demonstration that archived bone marrow aspirate slides can be utilized for miRNA expression studies offers tremendous potential for future investigations into the role miRNA play in the development and long term outcome of hematologic, as well as non-hematologic, diseases.

Authors
Morenos, L; Saffery, R; Mechinaud, F; Ashley, D; Elwood, N; Craig, JM; Wong, NC
MLA Citation
Morenos, Leah, et al. “Evaluation of microRNA expression in patient bone marrow aspirate slides..” Plos One, vol. 7, no. 8, 2012. Pubmed, doi:10.1371/journal.pone.0042951.
PMID
22912766
Source
pubmed
Published In
Plos One
Volume
7
Issue
8
Publish Date
2012
Start Page
e42951
DOI
10.1371/journal.pone.0042951

ANZCCSG BabyBrain99; intensified systemic chemotherapy, second look surgery and involved field radiation in young children with central nervous system malignancy.

BACKGROUND: ANZCCSG BabyBrain99 is a trial of intensive systemic chemotherapy with dual stem cell supported treatment, second look surgery and involved field radiation for children less than four years of age with malignant central nervous system tumours. PROCEDURE: Following primary resection, treatment included two courses of cisplatin and oral etoposide, a third course of mobilising chemotherapy (vincristine, etoposide, cyclophosphamide) with stem cell harvest, followed by intensive stem cell supported chemotherapy with high dose cyclophosphamide, etoposide and vincristine. Children were evaluated for second resection before proceeding to a second stem cell supported consolidation therapy consisting of melphalan and carboplatin. Patients then received involved field radiation therapy. RESULTS: Thirty three children with a range of diagnoses were enrolled. Nine percent of children had metastatic disease at diagnosis. Eighteen children completed treatment including irradiation. At the end of induction the event free survival was 70% (54-86). Forty eight percent of children had a complete response, 18% had stable disease and 3% had a partial response. Five year overall survival was 40% (22-56) and event free survival was 33% (17-50). Children in whom a complete resection were achieved had a significantly superior outcome compared to those children without a complete resection, 5 year EFS 60% (45-75), as compared to 22% (13-30), P-value <0.05. CONCLUSIONS: BabyBrain99 confirms that intensive stem cell supported chemotherapy can be safely administered to infants with CNS tumours however overall prognosis remains poor. Importantly, the study reinforces a complete surgical resection as an important favourable prognostic indicator. Pediatr Blood Cancer 2011;56:1055-1061. © 2011 Wiley-Liss, Inc.

Authors
Bandopadhayay, P; Hassall, TE; Rosenfeld, JV; Wheeler, GC; Downie, PA; Kirby, ML; Cohn, RJ; Sullivan, MJ; Ashley, DM
MLA Citation
Bandopadhayay, Pratiti, et al. “ANZCCSG BabyBrain99; intensified systemic chemotherapy, second look surgery and involved field radiation in young children with central nervous system malignancy..” Pediatr Blood Cancer, vol. 56, no. 7, July 2011, pp. 1055–61. Pubmed, doi:10.1002/pbc.22942.
PMID
21298769
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
56
Issue
7
Publish Date
2011
Start Page
1055
End Page
1061
DOI
10.1002/pbc.22942

Effects of the roller feed ratio on wrinkling failure in conventional spinning of a cylindrical cup

In this study, wrinkling failure in conventional spinning of a cylindrical cup has been investigated by using both finite element (FE) analysis and experimental methods. FE simulation models of a spinning experiment have been developed using the explicit finite element solution method provided by the software Abaqus. The severity of wrinkles is quantified by calculating the standard deviation of the radial coordinates of element nodes on the edge of the workpiece obtained from the FE models. The results show that the severity of wrinkles tends to increase when increasing the roller feed ratio. A forming limit study for wrinkling has been carried out and shows that there is a feed ratio limit beyond which the wrinkling failure will take place. Provided that the feed ratio is kept below this limit, the wrinkling failure can be prevented. It is believed that high compressive tangential stresses in the local forming zone are the causes of the wrinkling failure. Furthermore, the computational performance of the solid and shell elements in simulating the spinning process are examined and the tool forces obtained from wrinkling and wrinkle-free models are compared. Finally, the effects of the feed ratio on variations of the wall thickness of the spun cylindrical cup are investigated. © 2011 Authors.

Authors
Wang, L; Long, H; Ashley, D; Roberts, M; White, P
MLA Citation
Wang, L., et al. “Effects of the roller feed ratio on wrinkling failure in conventional spinning of a cylindrical cup.” Proceedings of the Institution of Mechanical Engineers, Part B: Journal of Engineering Manufacture, vol. 225, no. 11, Jan. 2011, pp. 1991–2006. Scopus, doi:10.1177/0954405410396024.
Source
scopus
Published In
Proceedings of the Institution of Mechanical Engineers, Part B: Journal of Engineering Manufacture
Volume
225
Issue
11
Publish Date
2011
Start Page
1991
End Page
2006
DOI
10.1177/0954405410396024

DEVELOPMENTAL AND FUNCTIONAL OUTCOME FOLLOWING POST-OPERATIVE CHEMOTHERAPY AND LOCAL CONFORMAL RADIATION IN INFANTS WITH MEDULLOBLASTOMA USING A CENTRALLY ADMINISTERED PHONE BASED INTERVIEW TECHNIQUE, FOLLOW UP REPORT: A CHILDRENS ONCOLOGY GROUP STUDY

Authors
Ashley, DM; Lyon, N; Bonner, M; Msall, M; Tianni, Z; Strother, D; Merchant, T; Geyer, R; Pollack, IE; Kun, L; Duffner, P
MLA Citation
Ashley, D. M., et al. “DEVELOPMENTAL AND FUNCTIONAL OUTCOME FOLLOWING POST-OPERATIVE CHEMOTHERAPY AND LOCAL CONFORMAL RADIATION IN INFANTS WITH MEDULLOBLASTOMA USING A CENTRALLY ADMINISTERED PHONE BASED INTERVIEW TECHNIQUE, FOLLOW UP REPORT: A CHILDRENS ONCOLOGY GROUP STUDY.” Neuro Oncology, vol. 12, no. 6, OXFORD UNIV PRESS INC, 2010, pp. II8–II8.
Source
wos
Published In
Neuro Oncology
Volume
12
Issue
6
Publish Date
2010
Start Page
II8
End Page
II8

RISK-ADAPTED CRANIOSPINAL RADIOTHERAPY FOLLOWED BY HIGH DOSE CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL RESCUE IN CHILDREN WITH LARGE CELL/ANAPLASTIC MEDULLOBLASTOMA: RESULTS FROM ST. JUDE MEDULLOBLASTOMA 96 (SJMB96) AND ST. JUDE MEDULLOBLASTOMA 03 (SJMB03)

Authors
Wright, KD; Chintagumpala, M; Hassall, T; Ashley, DM; Bouffet, E; Kellie, SJ; Gururangan, S; Cohn, R; Fisher, M; Broniscer, A; Qaddoumi, I; Morris, EB; Armstrong, G; Merchant, TE; Panandiker, AP; Ellison, DW; Lesh, S; Wallace, D; Gajjar, A
MLA Citation
Wright, K. D., et al. “RISK-ADAPTED CRANIOSPINAL RADIOTHERAPY FOLLOWED BY HIGH DOSE CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL RESCUE IN CHILDREN WITH LARGE CELL/ANAPLASTIC MEDULLOBLASTOMA: RESULTS FROM ST. JUDE MEDULLOBLASTOMA 96 (SJMB96) AND ST. JUDE MEDULLOBLASTOMA 03 (SJMB03).” Neuro Oncology, vol. 12, no. 6, OXFORD UNIV PRESS INC, 2010, pp. II5–6.
Source
wos
Published In
Neuro Oncology
Volume
12
Issue
6
Publish Date
2010
Start Page
II5
End Page
II6

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

The role of social support in families coping with childhood brain tumor.

Previous studies suggest that support from social networks is a protective factor buffering the negative effects of stressful events, such as having a child with a chronic illness. The literature highlights the need for more systematic examination of parents' social support networks across the disease trajectory, to obtain a more complete understanding of how a family's support system affects adjustment over time. This was attempted in this study of 88 parents of children with brain tumors, recruited from hospitals in Australia, Singapore, and New Zealand. It employed a longitudinal design, tracking families for 2 years postdiagnosis to examine the relationship between social support and coping. As in previous research this study showed that different types of support are needed at different stages in the illness trajectory. The study also identified the use of various coping strategies by families, directed at the maintenance and enhancement of existing supports and the securing of new supports. The study failed to establish a statistically significant relationship between level of coping and social support, however, suggesting that parents were using primarily "internal" familial modes of coping, including preexisting patterns of coping, with external social support being an adjunct to their coping rather than being a major contributor.

Authors
Jackson, AC; Enderby, K; O'Toole, M; Thomas, SA; Ashley, D; Rosenfeld, JV; Simos, E; Tokatlian, N; Gedye, R
MLA Citation
Jackson, Alun C., et al. “The role of social support in families coping with childhood brain tumor..” J Psychosoc Oncol, vol. 27, no. 1, 2009, pp. 1–24. Pubmed, doi:10.1080/07347330802614634.
PMID
19197676
Source
pubmed
Published In
J Psychosoc Oncol
Volume
27
Issue
1
Publish Date
2009
Start Page
1
End Page
24
DOI
10.1080/07347330802614634

Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma.

PURPOSE: To determine the role of amifostine as a protectant against cisplatin-induced ototoxicity in patients with average-risk (AR) medulloblastoma treated with craniospinal radiotherapy and four cycles of cisplatin-based, dose-intense chemotherapy and stem-cell rescue. PATIENTS AND METHODS: The primary objective was to determine whether, in patients with AR medulloblastoma (n = 62), amifostine would decrease the need for hearing aids (defined as >or= grade 3 ototoxicity in one ear) compared with a control group (n = 35), 1 year from initiating treatment. Ninety-seven patients received craniospinal irradiation (23.4 Gy) followed by 55.8 Gy to the primary tumor bed using three-dimensional conformal technique, and four cycles of high-dose cyclophosphamide (4,000 mg/m(2)/cycle), cisplatin (75 mg/m(2)/cycle), and vincristine (two 1.5 mg/m(2) doses/cycle) and stem-cell rescue. When used, amifostine (600 mg/m(2)/dose) was administered as a bolus immediately before and 3 hours into the cisplatin infusion. RESULTS: The median age of the 97 patients was 8.7 years (range, 3.2 to 20.2 years). The study and control groups were similar in age and sex distribution. Amifostine was well-tolerated. One year after treatment initiation, 13 patients (37.1%) in the control group versus nine (14.5%; one-sided chi(2) test P = .005) of the amifostine-treated patients had at least grade 3 ototoxicity, requiring hearing aid in at least one ear. CONCLUSION: Amifostine administered before and during the cisplatin infusion can significantly reduce the risk of severe ototoxicity in patients with AR medulloblastoma receiving dose-intense chemotherapy.

Authors
Fouladi, M; Chintagumpala, M; Ashley, D; Kellie, S; Gururangan, S; Hassall, T; Gronewold, L; Stewart, CF; Wallace, D; Broniscer, A; Hale, GA; Kasow, KA; Merchant, TE; Morris, B; Krasin, M; Kun, LE; Boyett, JM; Gajjar, A
MLA Citation
Fouladi, Maryam, et al. “Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma..” J Clin Oncol, vol. 26, no. 22, Aug. 2008, pp. 3749–55. Pubmed, doi:10.1200/JCO.2007.14.3974.
PMID
18669462
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
22
Publish Date
2008
Start Page
3749
End Page
3755
DOI
10.1200/JCO.2007.14.3974

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

Developmental and functional outcome following postoperative chemotherapy and local conformal radiation in infants with medulloblastoma using a centrally administered phone-based interview technique, initial report: A children's oncology group study

Authors
Ashley, D; Nancy, L; Melanie, B; Michael, M; Zhou, T; Strother, D; Merchant, T; Geyer, R; Pollack, I; Duffner, P
MLA Citation
Ashley, David, et al. “Developmental and functional outcome following postoperative chemotherapy and local conformal radiation in infants with medulloblastoma using a centrally administered phone-based interview technique, initial report: A children's oncology group study.” Neuro Oncology, vol. 10, no. 3, DUKE UNIV PRESS, 2008, pp. 434–434.
Source
wos
Published In
Neuro Oncology
Volume
10
Issue
3
Publish Date
2008
Start Page
434
End Page
434

Temozolomide in pediatric low-grade glioma.

BACKGROUND: We describe a retrospective series of children with low-grade glioma who received temozolomide. PROCEDURE: Eligible patients had had a diagnosis of low-grade glioma with or without histological confirmation. Temozolomide was administered at a dose of 200 mg/m(2) daily for 5 days, in a 4-week cycle. Therapy was stopped on completion of the targeted 12 cycles of chemotherapy or on evidence of tumor progression. RESULTS: Thirteen eligible patients were identified, eight male and five female. Median age at diagnosis was 5.5 years (range 2.6-15.0 years) and at commencement of temozolomide treatment was 9.0 years (range 3.8-15.2 years). Nine patients had a histological diagnosis of pilocytic astrocytoma. Twelve patients had received carboplatin prior to temozolomide, including three in combination with vincristine. A total of 111 cycles of therapy have been administered. Hematological toxicity and nausea were the most common adverse effects. Median time to progression was 6.7 months (range 1.5-41.8 months). Event-free survival rate at 3 years was 57%. Twelve of 13 patients remain alive at the time of report. Eleven have stable disease (SD). CONCLUSION: Temozolomide appears to be active in pediatric low-grade glioma, with the advantage of oral administration and excellent tolerability.

Authors
Khaw, SL; Coleman, LT; Downie, PA; Heath, JA; Ashley, DM
MLA Citation
Khaw, Seong L., et al. “Temozolomide in pediatric low-grade glioma..” Pediatr Blood Cancer, vol. 49, no. 6, Nov. 2007, pp. 808–11. Pubmed, doi:10.1002/pbc.21270.
PMID
17588234
Source
pubmed
Published In
Pediatric Blood & Cancer
Volume
49
Issue
6
Publish Date
2007
Start Page
808
End Page
811
DOI
10.1002/pbc.21270

Multiple factors contribute to neuropsychological outcome in children with posterior fossa tumors.

Cognitive deficits are frequently reported in children treated for posterior fossa (PF) tumors. A range of tumor, treatment, medical and treatment complications have been implicated in causing a variety of cognitive deficits. The aim of this study is to identify factors that influence intelligence, attention and information processing in these children. Thirty-five children (aged 4-16) with PF tumors attending the Royal Children's Hospital Melbourne, Australia, were enrolled into a prospective, repeated measures design. Neuropsychological assessments were conducted at diagnosis and at 12 month intervals for three years. The results find that the PF tumor, hydrocephalus, white matter injury and radiation therapy have various impacts on intelligence, attention and information processing skills, and contribute to the long term outcome in children treated for PF tumor. The neurological structures that subserve the efficient function of attention and information processing are particularly vulnerable to those factors.

Authors
Stargatt, R; Rosenfeld, JV; Maixner, W; Ashley, D
MLA Citation
Stargatt, Robyn, et al. “Multiple factors contribute to neuropsychological outcome in children with posterior fossa tumors..” Dev Neuropsychol, vol. 32, no. 2, 2007, pp. 729–48. Pubmed, doi:10.1080/87565640701376151.
PMID
17931127
Source
pubmed
Published In
Developmental Neuropsychology
Volume
32
Issue
2
Publish Date
2007
Start Page
729
End Page
748
DOI
10.1080/87565640701376151

Intelligence and adaptive function in children diagnosed with brain tumour during infancy.

BACKGROUND: Late effects of treatment in children diagnosed and treated for brain tumours in infancy is a major concern. Assessment of infants presenting with brain tumours is difficult and there is little information available regarding the development of infants prior to treatment and hence the impact of the tumour itself on developmental outcomes. AIM: To describe the development of children diagnosed with brain tumours in infancy and to document their cognitive and adaptive function at school entry. METHOD: Infants were psychologically evaluated at the time of diagnosis of a brain tumour and during their fifth or sixth year in preparation for school entry. RESULTS: Children diagnosed with brain tumours in infancy display developmental delays in a number of areas of adaptive function. By the time these children are school age they display further compromise in cognitive and academic skills and adaptive behaviour. Higher levels of deficit at follow-up were associated with tumour location in the supratentorium, younger age at diagnosis and longer time since diagnosis. The effect of radiotherapy could not be determined because of differing degrees of developmental compromise in the treatment groups at baseline. CONCLUSION: Brain tumours in infancy confer a risk of poor developmental progress at the time of diagnosis. These children display additional compromise of development by the time they reach school age. Research protocols evaluating the impact of treatment in infants diagnosed with brain tumours need to take account of the developmental status of the child at diagnosis.

Authors
Stargatt, R; Rosenfeld, JV; Anderson, V; Hassall, T; Maixner, W; Ashley, D
MLA Citation
Stargatt, Robyn, et al. “Intelligence and adaptive function in children diagnosed with brain tumour during infancy..” J Neurooncol, vol. 80, no. 3, Dec. 2006, pp. 295–303. Pubmed, doi:10.1007/s11060-006-9187-0.
PMID
16807781
Source
pubmed
Published In
Journal of Neuro Oncology
Volume
80
Issue
3
Publish Date
2006
Start Page
295
End Page
303
DOI
10.1007/s11060-006-9187-0

Phase II study of carboplatin in children with progressive low-grade gliomas.

PURPOSE: To assess the rate of tumor response and activity of carboplatin in stabilizing the growth of progressive low-grade gliomas. PATIENTS AND METHODS: Eligible patients received carboplatin 560 mg/m(2) intravenously every 4 weeks for 1 year after maximum tumor response or until disease progression or unacceptable toxicity. RESULTS: Between October 1993 and October 2000, 81 children (median age, 79 months; range, 6 to 204) were enrolled onto this study. Patients received a median of 11 cycles of carboplatin (range, one to 29). Median follow-up from the time of enrollment was 55 months (range, 10 to 93). The overall objective response (complete response [CR] + partial response [PR] + minor response [MR]) and disease stabilization (CR + PR + stable disease + MR) rates to carboplatin treatment were 28% (95% confidence interval [CI], 18% to 38%) and 85% (95% CI, 74% to 93%), respectively. Eleven and 14 patients suffered progressive disease on study and after stopping therapy, respectively. Toxicity was predominantly myelosuppression and included grade 3/4 neutropenia in 56 patients and grade 3/4 thrombocytopenia in 40 patients. The 3-year failure-free survival (FFS) and overall survival (OS) for all patients were 64% (95% CI, 54% to 76%) and 84% (95% CI, 76% to 93%), respectively. Patients with diencephalic tumors had inferior FFS and OS compared with those with tumor at other sites (38% v 74% for FFS, P =.011; 54% v 91% for OS, P =.004). Neurofibromatosis type 1 patients with progressive low-grade glioma had a significantly better OS (95% v 80%; P =.052). CONCLUSION: Carboplatin, in the schedule used in this study, produced disease stabilization or improvement in a majority of children with progressive low-grade glioma, with manageable toxicity. Improved treatment strategies are particularly required for patients with diencephalic tumors.

Authors
Gururangan, S; Cavazos, CM; Ashley, D; Herndon, JE; Bruggers, CS; Moghrabi, A; Scarcella, DL; Watral, M; Tourt-Uhlig, S; Reardon, D; Friedman, HS
MLA Citation
Gururangan, Sridharan, et al. “Phase II study of carboplatin in children with progressive low-grade gliomas..” J Clin Oncol, vol. 20, no. 13, July 2002, pp. 2951–58. Pubmed, doi:10.1200/JCO.2002.12.008.
PMID
12089224
Source
pubmed
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
20
Issue
13
Publish Date
2002
Start Page
2951
End Page
2958
DOI
10.1200/JCO.2002.12.008

Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: 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)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration. RESULTS: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.

Authors
Friedman, HS; Pluda, J; Quinn, JA; Ewesuedo, RB; Long, L; Friedman, AH; Cokgor, I; Colvin, OM; Haglund, MM; Ashley, DM; Rich, JN; Sampson, J; Pegg, AE; Moschel, RC; McLendon, RE; Provenzale, JM; Stewart, ES; Tourt-Uhlig, S; Garcia-Turner, AM; Herndon, JE; Bigner, DD; Dolan, ME
MLA Citation
Friedman, H. S., et al. “Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma..” J Clin Oncol, vol. 18, no. 20, Oct. 2000, pp. 3522–28. Pubmed, doi:10.1200/JCO.2000.18.20.3522.
PMID
11032594
Source
pubmed
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
18
Issue
20
Publish Date
2000
Start Page
3522
End Page
3528
DOI
10.1200/JCO.2000.18.20.3522

Chemotherapy is useful in the treatment of gliomas. Discussant.

Authors
Ashley, DM
MLA Citation
Ashley, D. M. “Chemotherapy is useful in the treatment of gliomas. Discussant..” J Clin Neurosci, vol. 7, no. 5, Sept. 2000, pp. 467–68. Pubmed, doi:10.1054/jocn.2000.0689.
PMID
10942679
Source
pubmed
Published In
Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia
Volume
7
Issue
5
Publish Date
2000
Start Page
467
End Page
468
DOI
10.1054/jocn.2000.0689

Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors.

The epidermal growth factor receptor (EGFR) is often amplified and rearranged structurally in tumors of the brain, breast, lung, and ovary. The most common mutation, EGFRvIII, is characterized by an in-frame deletion of 801 base pairs, resulting in the generation of a novel tumor-specific epitope at the fusion junction. A murine homologue of the human EGFRvIII mutation was created, and an IgG2a murine mAb, Y10, was generated that recognizes the human and murine equivalents of this tumor-specific antigen. In vitro, Y10 was found to inhibit DNA synthesis and cellular proliferation and to induce autonomous, complement-mediated, and antibody-dependent cell-mediated cytotoxicity. Systemic treatment with i.p. Y10 of s.c. B16 melanomas transfected to express stably the murine EGFRvIII led to long-term survival in all mice treated (n = 20; P < 0.001). Similar therapy with i.p. Y10 failed to increase median survival of mice with EGFRvIII-expressing B16 melanomas in the brain; however, treatment with a single intratumoral injection of Y10 increased median survival by an average 286%, with 26% long-term survivors (n = 117; P < 0.001). The mechanism of action of Y10 in vivo was shown to be independent of complement, granulocytes, natural killer cells, and T lymphocytes through in vivo complement and cell subset depletions. Treatment with Y10 in Fc receptor knockout mice demonstrated the mechanism of Y10 to be Fc receptor-dependent. These data indicate that an unarmed, tumor-specific mAb may be an effective immunotherapy against human tumors and potentially other pathologic processes in the "immunologically privileged" central nervous system.

Authors
Sampson, JH; Crotty, LE; Lee, S; Archer, GE; Ashley, DM; Wikstrand, CJ; Hale, LP; Small, C; Dranoff, G; Friedman, AH; Friedman, HS; Bigner, DD
MLA Citation
Sampson, J. H., et al. “Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors..” Proc Natl Acad Sci U S A, vol. 97, no. 13, June 2000, pp. 7503–08. Pubmed, doi:10.1073/pnas.130166597.
PMID
10852962
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
97
Issue
13
Publish Date
2000
Start Page
7503
End Page
7508
DOI
10.1073/pnas.130166597

Evaluation of pre-radiotherapy cyclophosphamide in patients with newly diagnosed glioblastoma multiforme. Writing Committee for The Brain Tumor Center at Duke.

Cyclophosphamide is an alkylating agent that has shown activity in the treatment of pediatric brain tumors, including high-grade gliomas. This study was designed to evaluate the response of patients with newly diagnosed glioblastoma multiforme to pre-radiotherapy cyclophosphamide. Fourteen patients with glioblastoma multiforme were treated with high-dose cyclophosphamide (2 g/m2/day for 2 doses every 28 days) followed by either sargramostim or filgrastin. Sargramostim was given 250 microg/m2 subcutaneously twice a day continuing through the leukocyte nadir until the absolute neutrophil count was more than 1000 cells/microl for 2 consecutive days. The filgrastin dose was 10 microg/kg given subcutaneously once daily until the post nadir absolute neutrophil count was > or = 10,000 cells/microl. A total of 46 courses was given. Four patients received a total of 3 courses, 7 patients completed 4 courses and 3 patients received 2 courses. Three patients demonstrated complete response; 3 stable disease; and 8 progressive disease. The most common toxicity was hematologic, requiring platelet and packed red blood cell transfusions, with 13 admissions for neutropenia with fever. There were no deaths related to infection or bleeding. These results suggest that high-dose cyclophosphamide has modest activity with acceptable toxicity against newly diagnosed glioblastoma multiforme.

Authors
Bottom, KS; Ashley, DM; Friedman, HS; Longee, DC
MLA Citation
Bottom, K. S., et al. “Evaluation of pre-radiotherapy cyclophosphamide in patients with newly diagnosed glioblastoma multiforme. Writing Committee for The Brain Tumor Center at Duke..” J Neurooncol, vol. 46, no. 2, 2000, pp. 151–56.
PMID
10894368
Source
pubmed
Published In
Journal of Neuro Oncology
Volume
46
Issue
2
Publish Date
2000
Start Page
151
End Page
156

Irinotecan therapy in adults with recurrent or progressive malignant glioma.

PURPOSE: To determine the activity, toxicity, and pharmacokinetics of irinotecan (CPT-11, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI) in the treatment of adults with progressive, persistent, or recurrent malignant glioma. PATIENTS AND METHODS: Patients with progressive or recurrent malignant gliomas were enrolled onto this study between October 1996 and August 1997. CPT-11 was given as a 90-minute intravenous (i.v.) infusion at a dose of 125 mg/m2 once weekly for 4 weeks followed by a 2-week rest, which comprised one course. Plasma concentrations of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were determined in a subset of patients. RESULTS: All 60 patients who enrolled (36 males and 24 females) were treated with CPT-11 and all were assessable for toxicity, response, and survival. Pharmacokinetic data were available in 32 patients. Nine patients (15%; 95% confidence interval, 6% to 24%) had a confirmed partial response, and 33 patients (55%) achieved stable disease lasting more than two courses (12 weeks). Toxicity observed during the study was limited to infrequent neutropenia, nausea, vomiting, and diarrhea. CPT-11, SN-38, and SN-38G area under the plasma concentration-time curves through infinite time values in these patients were approximately 40%, 25%, and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer not receiving antiepileptics or chronic dexamethasone treatment. CONCLUSION: Response results document that CPT-11, given with a standard starting dose and treatment schedule, has activity in patients with recurrent malignant glioma. However, the low incidence of severe toxicity and low plasma concentrations of CPT-11 and SN-38 achieved in this patient population suggest that concurrent treatment with anticonvulsants and dexamethasone enhances drug clearance.

Authors
Friedman, HS; Petros, WP; Friedman, AH; Schaaf, LJ; Kerby, T; Lawyer, J; Parry, M; Houghton, PJ; Lovell, S; Rasheed, K; Cloughsey, T; Stewart, ES; Colvin, OM; Provenzale, JM; McLendon, RE; Bigner, DD; Cokgor, I; Haglund, M; Rich, J; Ashley, D; Malczyn, J; Elfring, GL; Miller, LL
MLA Citation
Friedman, H. S., et al. “Irinotecan therapy in adults with recurrent or progressive malignant glioma..” J Clin Oncol, vol. 17, no. 5, May 1999, pp. 1516–25. Pubmed, doi:10.1200/JCO.1999.17.5.1516.
PMID
10334539
Source
pubmed
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
17
Issue
5
Publish Date
1999
Start Page
1516
End Page
1525
DOI
10.1200/JCO.1999.17.5.1516

DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma.

PURPOSE: We evaluated the response to Temodal (Schering-Plough Research Institute, Kenilworth, NJ) of patients with newly diagnosed malignant glioma, as well as the predictive value of quantifying tumor DNA mismatch repair activity and O6-alkylguanine-DNA alkyltransferase (AGT). PATIENTS AND METHODS: Thirty-three patients with newly diagnosed glioblastoma multiforme (GBM) and five patients with newly diagnosed anaplastic astrocytoma (AA) were treated with Temodal at a starting dose of 200 mg/m2 daily for 5 consecutive days with repeat dosing every 28 days after the first daily dose. Immunochemistry for the detection of the human DNA mismatch repair proteins MSH2 and MLH1 and the DNA repair protein AGT was performed with monoclonal antibodies and characterized with respect to percent positive staining. RESULTS: Of the 33 patients with GBM, complete responses (CRs) occurred in three patients, partial responses (PRs) occurred in 14 patients, stable disease (SD) was seen in four patients, and 12 patients developed progressive disease (PD). Toxicity included infrequent grades 3 and 4 myelosuppression, constipation, nausea, and headache. Thirty tumors showed greater than 60% cells that stained for MSH2 and MLH1, with three CRs, 12 PRs, three SDs, and 12 PDs. Eight tumors showed 60% or less cells that stained with antibodies to MSH2 and/or MLH1, with 3 PRs, 3 SDs, and 2 PDs. Eleven tumors showed 20% or greater cells that stained with an antibody to AGT, with 1 PR, 2 SDs, and 8 PDs. Twenty-five tumors showed less than 20% cells that stained for AGT, with 3 CRs, 12 PRs, 4 SDs, and 6 PDs. CONCLUSION: These results suggest that Temodal has activity against newly diagnosed GBM and AA and warrants continued evaluation of this agent. Furthermore, pretherapy analysis of tumor DNA mismatch repair and, particularly, AGT protein expression may identify patients in whom tumors are resistant to Temodal.

Authors
Friedman, HS; McLendon, RE; Kerby, T; Dugan, M; Bigner, SH; Henry, AJ; Ashley, DM; Krischer, J; Lovell, S; Rasheed, K; Marchev, F; Seman, AJ; Cokgor, I; Rich, J; Stewart, E; Colvin, OM; Provenzale, JM; Bigner, DD; Haglund, MM; Friedman, AH; Modrich, PL
MLA Citation
Friedman, H. S., et al. “DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma..” J Clin Oncol, vol. 16, no. 12, Dec. 1998, pp. 3851–57. Pubmed, doi:10.1200/JCO.1998.16.12.3851.
PMID
9850030
Source
pubmed
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
16
Issue
12
Publish Date
1998
Start Page
3851
End Page
3857
DOI
10.1200/JCO.1998.16.12.3851

Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma.

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy is the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which removes chlorethylation or methylation damage from the O6-position of guanine. O6-benzylguanine (O6-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial to define the presurgical dose required for depletion of tumor AGT activity in patients with malignant glioma. MATERIALS AND METHODS: Patients were to be treated 18 hours before craniotomy with intravenous doses that ranged between 40 and 100 mg/m2 given over 1 hour. Resected tumor was snap-frozen in liquid nitrogen and AGT activity analyzed by high-pressure liquid chromatography (HPLC). Up to 13 patients were treated at a specific dose of O6-BG, with a target end point of > or = 11 of 13 patients with undetectable tumor AGT levels (< 10 fmol/mg protein). RESULTS: Thirty patients with malignant gliomas were enrolled, with 11 of 11 patients treated at 100 mg/m2 O6-BG demonstrating tumor AGT levels less than 10 fmol/mg protein. No toxicity was noted in any patient treated. CONCLUSION: These results indicate that 100 mg/m2 of O6-BG can maintain tumor AGT levels less than 10 fmol/mg protein for at least 18 hours after treatment, a time interval in which bis(2-chloroethyl)nitrosourea (BCNU)-induced chloroethyl adducts are fully converted into interstrand cross-links. A 100-mg/m2 dose of O6-BG will be used in combination with BCNU in another phase I trial designed to determine the maximal-tolerated dose of BCNU.

Authors
Friedman, HS; Kokkinakis, DM; Pluda, J; Friedman, AH; Cokgor, I; Haglund, MM; Ashley, DM; Rich, J; Dolan, ME; Pegg, AE; Moschel, RC; McLendon, RE; Kerby, T; Herndon, JE; Bigner, DD; Schold, SC
MLA Citation
Friedman, H. S., et al. “Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma..” J Clin Oncol, vol. 16, no. 11, Nov. 1998, pp. 3570–75. Pubmed, doi:10.1200/JCO.1998.16.11.3570.
PMID
9817277
Source
pubmed
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
16
Issue
11
Publish Date
1998
Start Page
3570
End Page
3575
DOI
10.1200/JCO.1998.16.11.3570

Local production of TGF beta1 inhibits cerebral edema, enhances TNF-alpha induced apoptosis and improves survival in a murine glioma model.

We have previously reported that local secretion of either TNF-alpha or TGF beta1 by intracerebral SMA-560 malignant glioma tumor cells can reduce or eliminate tumor growth in mice. However, the use of TNF-alpha, while improving the overall survival of tumor bearing animals, was associated with early toxic deaths due to cerebral edema. In the present study, we demonstrate that TNF-alpha induces apoptosis of the SMA 560 cell line, as does TGF beta1, and that these two cytokines act in an additive fashion to enhance apoptosis and thus, to inhibit SMA 560 cell growth in vitro. Next, we show that the production of TGF beta1 when added to TNF-alpha production by central nervous system tumors in vivo abrogates any early deaths seen due to TNF-alpha toxicity and leads to a larger percentage of animals surviving CNS tumor challenge. Finally, we demonstrate that the production of TGF beta1 by tumor cells is associated with the abolition of tumor-associated cerebral edema in both TNF-alpha and in non-TNF-alpha producing tumors. These results are important for the development of effective and less toxic therapies for brain tumors, as well as for examining the pathogenesis of tumor-related cerebral edema.

Authors
Ashley, DM; Sampson, JH; Archer, GE; Hale, LP; Bigner, DD
MLA Citation
Ashley, D. M., et al. “Local production of TGF beta1 inhibits cerebral edema, enhances TNF-alpha induced apoptosis and improves survival in a murine glioma model..” J Neuroimmunol, vol. 86, no. 1, June 1998, pp. 46–52.
PMID
9655471
Source
pubmed
Published In
Journal of Neuroimmunology
Volume
86
Issue
1
Publish Date
1998
Start Page
46
End Page
52

Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas.

In this study, the authors sought to investigate the response rate and toxicity of carboplatin in patients with progressive low-grade glioma (LGG). Thirty-two patients with progressive LGG were treated with carboplatin at a dosage of 560 mg/m(2). Treatment was given at 4-week intervals and continued until the disease progressed, unacceptable toxicity supervened, or for 12 additional courses after achieving maximal response. Patients with stable disease were treated with a total of 12 cycles. All patients were treated as outpatients. Patients were evaluated for response to treatment and toxicity. All patients received a minimum of two cycles of carboplatin, and were examined for response. A partial response was achieved in nine patients (28%) and a minimal response in two (6%), for an overall response rate of 34% (11 of 32 patients). Eighteen patients (56%) had stable disease. A partial response was achieved in the nine patients after a median of six cycles (range 4-11 cycles), a minimal response was achieved in the two patients after five cycles. Glioma progression was noted in three patients after three, five, and five cycles, respectively. The 11 patients in whom some response was achieved had either an optic pathway tumor or a juvenile pilocytic astrocytoma. Twenty-six of the 32 patients had those characteristics, making the response rate in that group 42% (11 of 26 patients). Thirty-two patients received a total of 387 cycles of chemotherapy. Hematological toxicity was moderate. Twenty-one patients developed thrombocytopenia (platelet count < 50,000/microl); three patients required one platelet transfusion each. Nine patients developed neutropenia (absolute neutrophil count < 500/microl); one developed fever and required administration of antibiotic agents. One dose adjustment in each of the patients prevented further thrombocytopenia and neutropenia. Two patients with stable disease died of respiratory complications. One patient developed Grade III ototoxicity after receiving five cycles, one patient developed hypersensitivity to carboplatin, and none developed nephrotoxicity. Carboplatin given at a dosage of 560 mg/m(2) every 4 weeks has activity in patients with progressive LGG. This drug regimen is relatively simple and well tolerated. Further investigation and longer follow-up study are warranted.

Authors
Moghrabi, A; Friedman, HS; Ashley, DM; Bottom, KS; Kerby, T; Stewart, E; Bruggers, C; Provenzale, JM; Champagne, M; Hershon, L; Watral, M; Ryan, J; Rasheed, K; Lovell, S; Korones, D; Fuchs, H; George, T; McLendon, RE; Friedman, AH; Buckley, E; Longee, DC
MLA Citation
Moghrabi, A., et al. “Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas..” Neurosurg Focus, vol. 4, no. 4, Apr. 1998.
PMID
17168503
Source
pubmed
Published In
Neurosurgical Focus
Volume
4
Issue
4
Publish Date
1998
Start Page
e3

Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas.

Seventeen patients less than or equal to 20 years of age with newly diagnosed (n = 10) or recurrent (n = 7) malignant gliomas (anaplastic astrocytoma and glioblastoma multiforme) were treated with cyclophosphamide in association with hematopoietic cytokines (GM-CSF or G-CSF). Cyclophosphamide was given at a dose of 2 g/m2 daily for 2 days at 4-week intervals. Toxicity consisted of grade IV neutropenia and thrombocytopenia in 95% and 48% of cycles, respectively. There were no cyclophosphamide-related cardiac, pulmonary, or urothelial toxicities observed. Four of 10 patients with newly diagnosed disease demonstrated responses (three complete and one partial responses; one CR was only of 2 months duration). None of the seven patients with recurrent tumors demonstrated a response. We conclude that high-dose cyclophosphamide warrants further evaluation in children with newly diagnosed malignant glioma.

Authors
McCowage, GB; Friedman, HS; Moghrabi, A; Kerby, T; Ferrell, L; Stewart, E; Duncan-Brown, M; Fuchs, HE; Tien, R; McLendon, RE; Meier, L; Kurtzberg, J; Ashley, D; Colvin, OM; Longee, DC
MLA Citation
McCowage, G. B., et al. “Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas..” Med Pediatr Oncol, vol. 30, no. 2, Feb. 1998, pp. 75–80.
PMID
9403013
Source
pubmed
Published In
Medical and Pediatric Oncology
Volume
30
Issue
2
Publish Date
1998
Start Page
75
End Page
80

Endogenous expression of transforming growth factor beta1 inhibits growth and tumorigenicity and enhances Fas-mediated apoptosis in a murine high-grade glioma model.

It has been hypothesized that transforming growth factor beta (TGF-beta) may prevent immune-mediated glioma cell elimination; however, previous work has also indicated that increased TGF-beta may lead to reduced proliferation, induction of apoptosis, and enhancement of Fas-induced apoptosis. We have investigated the role of TGF-beta in the progression of malignant glioma using an immunocompetent murine model. SMA 560 malignant glioma cells were stably transfected with constructs that resulted in over- or underproduction of active TGF-beta1. Using these cell lines, we have shown that (a) TGF-beta1 inhibits induction of antitumor cytotoxicity when the tumor cells are given s.c. but not when they are given intracranially; (b) Fas/APO-1 is expressed on SMA 560 cells in vitro and in vivo, SMA 560 cells are susceptible to TGF-beta1- and Fas-induced apoptosis in vitro, and TGF-beta1 and Fas act synergistically to induce glioma cell death; (c) increased levels of endogenous TGF-beta1 production by SMA 560 cells lead to increased sensitivity to Fas-mediated apoptosis; (d) overproduction of endogenous TGF-beta1 reduces the rate of s.c. SMA 560 tumor growth and also reduces the tumorigenicity of tumors located in the central nervous system, with opposite effects observed with underproduction of TGF-beta1 using antisense cell lines; and (e) the observed changes in growth parameters in vivo were associated with increased rates of apoptosis in TGF-beta1-overproducing cells. Taken together, these results indicate that, despite decreased induction of CTL responses, the dominant net effect of TGF-beta1 on the growth of the SMA 560 murine high-grade glioma in vivo is growth inhibition. This contrasts with results seen with non-central nervous system malignant tumors in immunocompetent animals, in which TGF-beta1 production provides a major growth advantage.

Authors
Ashley, DM; Kong, FM; Bigner, DD; Hale, LP
MLA Citation
Ashley, D. M., et al. “Endogenous expression of transforming growth factor beta1 inhibits growth and tumorigenicity and enhances Fas-mediated apoptosis in a murine high-grade glioma model..” Cancer Res, vol. 58, no. 2, Jan. 1998, pp. 302–09.
PMID
9443409
Source
pubmed
Published In
Cancer Research
Volume
58
Issue
2
Publish Date
1998
Start Page
302
End Page
309

Monoclonal antibodies to growth factors and growth factor receptors: their diagnostic and therapeutic potential in brain tumors.

Authors
Ashley, DM; Batra, SK; Bigner, DD
MLA Citation
Ashley, D. M., et al. “Monoclonal antibodies to growth factors and growth factor receptors: their diagnostic and therapeutic potential in brain tumors..” J Neurooncol, vol. 35, no. 3, Dec. 1997, pp. 259–73.
PMID
9440024
Source
pubmed
Published In
Journal of Neuro Oncology
Volume
35
Issue
3
Publish Date
1997
Start Page
259
End Page
273

Recent advances in the biology of central nervous system tumors.

The failure of conventional therapies for many malignant brain tumors has led to a search for more promising alternatives. Recent advances have elucidated a variety of biological factors that act to determine the growth and invasiveness of central nervous system tumors. Such factors include aberrations in the regulation of the cell cycle, apoptosis, and interactions with the host microenvironment. Such insights should translate into novel interventions so that more meaningful outcomes can be achieved in patient care in the future.

Authors
Ashley, DM; Bigner, DD
MLA Citation
Ashley, D. M., and D. D. Bigner. “Recent advances in the biology of central nervous system tumors..” Curr Opin Neurol, vol. 10, no. 6, Dec. 1997, pp. 445–51.
PMID
9425557
Source
pubmed
Published In
Current Opinion in Neurology
Volume
10
Issue
6
Publish Date
1997
Start Page
445
End Page
451

Characterization of a spontaneous murine astrocytoma and abrogation of its tumorigenicity by cytokine secretion.

OBJECTIVE: The promise of immunotherapies developed against brain tumors in animal models has not been realized in human clinical trials. This may be because of the routine use of rodent tumors artificially induced by chemicals or viruses that do not accurately portray the intrinsic qualities of spontaneously arising human tumors and that often fail to incorporate the role of immunosuppressants, such as transforming growth factor-beta, that are secreted by human gliomas. From an astrocytoma that arose spontaneously in inbred VM/Dk mice, we have characterized a highly tumorigenic spontaneous murine astrocytoma cell line (SMA-560) that retains features of glial differentiation and naturally produces high levels of biologically active transforming growth factor-beta. We have used this model to determine whether cytokine production by tumor cells will inhibit intracerebral astrocytoma growth. METHODS: Packaging cell lines producing replication-incompetent retroviral vectors were used to transfect the SMA-560 cell line in vitro with the genes encoding the murine cytokines interleukin (IL)-2, IL-3, IL-4, IL-6, tumor necrosis factor-alpha, gamma-interferon, or granulocyte-macrophage colony-stimulating factor or the costimulatory molecule B7.1 (CD80). RESULTS: Mice challenged intracerebrally with 5000 untransfected SMA-560 cells all succumbed to tumor within 30 days, with a median survival of 25 days. In contrast, mice challenged with SMA-560 cells producing IL-2, IL-4, or tumor necrosis factor-alpha each had a more than 400% increase in median survival (P < 0.0001). In these groups, 78.3% (18 of 23 mice), 66.7% (10 of 15 mice), and 60% (6 of 10 mice) of the mice, respectively, remained alive without evidence of tumor for longer than 100 days after the initial tumor challenge. All other cytokines tested and the expression of B7.1 failed to result in an increase in median survival. CONCLUSION: Using a spontaneous astrocytoma model in an inbred mouse strain, we have shown that cytokine production by glial tumors can abrogate their tumorigenicity in vivo despite production of transforming growth factor-beta. These results predict that approaches directed at cytokine production within intracerebral astrocytomas may be efficacious in human trials and that the "immunological privilege" of the brain may not be absolute under such conditions.

Authors
Sampson, JH; Ashley, DM; Archer, GE; Fuchs, HE; Dranoff, G; Hale, LP; Bigner, DD
MLA Citation
Sampson, J. H., et al. “Characterization of a spontaneous murine astrocytoma and abrogation of its tumorigenicity by cytokine secretion..” Neurosurgery, vol. 41, no. 6, Dec. 1997, pp. 1365–72. Pubmed, doi:10.1097/00006123-199712000-00024.
PMID
9402588
Source
pubmed
Published In
Neurosurgery
Volume
41
Issue
6
Publish Date
1997
Start Page
1365
End Page
1372
DOI
10.1097/00006123-199712000-00024

Bone marrow-generated dendritic cells pulsed with tumor extracts or tumor RNA induce antitumor immunity against central nervous system tumors.

Recent studies have shown that the brain is not a barrier to successful active immunotherapy that uses gene-modified autologous tumor cell vaccines. In this study, we compared the efficacy of two types of vaccines for the treatment of tumors within the central nervous system (CNS): dendritic cell (DC)-based vaccines pulsed with either tumor extract or tumor RNA, and cytokine gene-modified tumor vaccines. Using the B16/F10 murine melanoma (B16) as a model for CNS tumor, we show that vaccination with bone marrow-generated DCs, pulsed with either B16 cell extract or B16 total RNA, can induce specific cytotoxic T lymphocytes against B16 tumor cells. Both types of DC vaccines were able to protect animals from tumors located in the CNS. DC-based vaccines also led to prolonged survival in mice with tumors placed before the initiation of vaccine therapy. The DC-based vaccines were at least as effective, if not more so, as vaccines containing B16 tumor cells in which the granulocytic macrophage colony-stimulating factor gene had been modified. These data support the use of DC-based vaccines for the treatment of patients with CNS tumors.

Authors
Ashley, DM; Faiola, B; Nair, S; Hale, LP; Bigner, DD; Gilboa, E
MLA Citation
Ashley, D. M., et al. “Bone marrow-generated dendritic cells pulsed with tumor extracts or tumor RNA induce antitumor immunity against central nervous system tumors..” J Exp Med, vol. 186, no. 7, Oct. 1997, pp. 1177–82. Pubmed, doi:10.1084/jem.186.7.1177.
PMID
9314567
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
186
Issue
7
Publish Date
1997
Start Page
1177
End Page
1182
DOI
10.1084/jem.186.7.1177

A genetically modified allogeneic cellular vaccine generates MHC class I-restricted cytotoxic responses against tumor-associated antigens and protects against CNS tumors in vivo.

An active immunotherapeutic strategy using transfected allogeneic cells for targeting the mutant epidermal growth factor receptor (EGFRvIII) on intracranial tumors was examined. Immunization with allogeneic 300.19/EGFRvIII cells induced CD8+ cytotoxic T-lymphocytes against EGFRvIII bearing syngeneic B16-F10 melanoma or 560 astrocytoma cells (H-2b), but not against allogeneic NR6 cells (H-2q) also bearing EGFRvIII significant NK cell activity was also noted in vitro. Vaccination protected against intracranial challenge with EGFRvIII-positive tumor, with 50% long term survival. In vivo depletions of effector cell subsets demonstrated the requirements for both CD8+ and CD4+ T-cells but not NK cells in producing this protective effect. These data demonstrate the generation of significant, antigen-specific and MHC class I-restricted cytotoxic immune responses which are effective against tumors present in the CNS.

Authors
Ashley, DM; Sampson, JH; Archer, GE; Batra, SK; Bigner, DD; Hale, LP
MLA Citation
Ashley, D. M., et al. “A genetically modified allogeneic cellular vaccine generates MHC class I-restricted cytotoxic responses against tumor-associated antigens and protects against CNS tumors in vivo..” J Neuroimmunol, vol. 78, no. 1–2, Sept. 1997, pp. 34–46.
PMID
9307226
Source
pubmed
Published In
Journal of Neuroimmunology
Volume
78
Issue
1-2
Publish Date
1997
Start Page
34
End Page
46

Chronic CSF leak into the peritoneal cavity shown by radionuclide cisternography. Successful treatment with an epidural blood patch.

Authors
Ashley, DM; Coleman, RE; Fuchs, H; Dear, G; Ginsberg, B; Zalduondo, FM; Friedman, HS; Longee, D
MLA Citation
Ashley, D. M., et al. “Chronic CSF leak into the peritoneal cavity shown by radionuclide cisternography. Successful treatment with an epidural blood patch..” Clin Nucl Med, vol. 22, no. 6, June 1997, pp. 390–92. Pubmed, doi:10.1097/00003072-199706000-00010.
PMID
9193811
Source
pubmed
Published In
Clinical Nuclear Medicine
Volume
22
Issue
6
Publish Date
1997
Start Page
390
End Page
392
DOI
10.1097/00003072-199706000-00010

Subcutaneous vaccination with irradiated, cytokine-producing tumor cells stimulates CD8+ cell-mediated immunity against tumors located in the "immunologically privileged" central nervous system.

Vaccination with cytokine-producing tumor cells generates potent immune responses against tumors outside the central nervous system (CNS). The CNS, however, is a barrier to allograft and xenograft rejection, and established tumors within the CNS have failed to respond to other forms of systemic immunotherapy. To determine what barriers the "immunologically privileged" CNS would pose to cytokine-assisted tumor vaccines and what cytokines would be most efficacious against tumors within the CNS, we irradiated B16 murine melanoma cells producing murine interleukin 2 (IL-2), IL-3, IL-4, IL-6, gamma-interferon, or granulocyte-macrophage colony stimulating factor (GM-CSF) and used these cells as subcutaneous vaccines against tumors within the brain. Under conditions where untransfected B16 cells had no effect, cells producing IL-3, IL-6, or GM-CSF increased the survival of mice challenged with viable B16 cells in the brain. Vaccination with B16 cells producing IL-4 or gamma-interferon had no effect, and vaccination with B16 cells producing IL-2 decreased survival time. GM-CSF-producing vaccines were also able to increase survival in mice with pre-established tumors. The response elicited by GM-CSF-producing vaccines was found to be specific to tumor type and to be abrogated by depletion of CD8+ cells. Unlike the immunity generated against subcutaneous tumors by GM-CSF, however, the effector responses generated against tumors in the CNS were not dependent on CD4+ cells. These data suggest that cytokine-producing tumor cells are very potent stimulators of immunity against tumors within the CNS, but effector responses in the CNS may be different from those obtained against subcutaneous tumors.

Authors
Sampson, JH; Archer, GE; Ashley, DM; Fuchs, HE; Hale, LP; Dranoff, G; Bigner, DD
MLA Citation
Sampson, J. H., et al. “Subcutaneous vaccination with irradiated, cytokine-producing tumor cells stimulates CD8+ cell-mediated immunity against tumors located in the "immunologically privileged" central nervous system..” Proc Natl Acad Sci U S A, vol. 93, no. 19, Sept. 1996, pp. 10399–404. Pubmed, doi:10.1073/pnas.93.19.10399.
PMID
8816812
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
93
Issue
19
Publish Date
1996
Start Page
10399
End Page
10404
DOI
10.1073/pnas.93.19.10399

Response of recurrent medulloblastoma to low-dose oral etoposide.

PURPOSE: The outcome for patients with recurrent medulloblastoma has historically been poor, with most patients dying of disseminated disease. Here, we report on seven patients with recurrent medulloblastoma, most heavily pretreated with a variety of chemotherapeutic agents, including parenteral etoposide (VP-16), who showed responses to the administration of repeated courses of low-dose oral VP-16. PATIENTS AND METHODS: Seven patients age 4 to 16 years were treated with VP-16 after neuroradiographic and clinical evidence of tumor progression. Six had received prior irradiation. All seven had been pretreated with a variety of chemotherapeutic agents and schedules, including parenteral VP-16. VP-16 was administered orally as repeated 21-day courses at 50 mg/m2/d with a 7-day interval between courses. Evaluation consisted of neuroradiographic and clinical examination after completion of every two courses of therapy. Complete blood cell counts were performed weekly. RESULTS: The major toxicity of oral VP-16 was hematologic, with two patients requiring platelet transfusions due to thrombocytopenia and two requiring RBC transfusions. All seven patients developed treatment-related neutropenia. Two patients were supported with granulocyte colony-stimulating factor (G-CSF) between courses. One patient developed infectious epididymitis after course 2 and required intravenous antibiotics; this illness was complicated by Clostridium difficile colitis. There was one episode of fever associated with neutropenia. There were no treatment-related deaths. Of seven patients assessed, six have demonstrated partial responses (PRs) and the remaining patient had stable disease (SD). CONCLUSION: This report demonstrates the activity of oral VP-16 in the treatment of a small cohort of pretreated patients with recurrent medulloblastoma. This form of administration of oral VP-16 was well tolerated and produced modest toxicity.

Authors
Ashley, DM; Meier, L; Kerby, T; Zalduondo, FM; Friedman, HS; Gajjar, A; Kun, L; Duffner, PK; Smith, S; Longee, D
MLA Citation
Ashley, D. M., et al. “Response of recurrent medulloblastoma to low-dose oral etoposide..” J Clin Oncol, vol. 14, no. 6, June 1996, pp. 1922–27. Pubmed, doi:10.1200/JCO.1996.14.6.1922.
PMID
8656261
Source
pubmed
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
14
Issue
6
Publish Date
1996
Start Page
1922
End Page
1927
DOI
10.1200/JCO.1996.14.6.1922

Treatment of patients with pineoblastoma with high dose cyclophosphamide.

The outcome for patients with pineoblastoma has historically been very poor, with most patients dying of disseminated disease despite irradiation. Furthermore, the low incidence of this tumor has hindered progress toward defining better treatment strategies. Here we report the activity and toxicity of cyclophosphamide administered as a single agent at a dose schedule of 2 g/m2/day for 2 successive days at monthly intervals for a maximum of four courses. Eight patients were evaluated, six newly diagnosed and two recurrent. Amongst the six newly diagnosed patients, there were three patients demonstrating partial responses, and three had stable disease throughout the cyclophosphamide treatment period. All six patients are alive and disease free after further therapy. One patient with recurrent disease demonstrated tumor progression on cyclophosphamide, and the other had stable disease throughout the cyclophosphamide treatment period. Both patients subsequently died of progressive disease. The major toxicity of high dose cyclophosphamide was hematopoietic, with one patient requiring a dose reduction after three courses due to prolonged thrombocytopenia. One patient was also withdrawn from treatment with cyclophosphamide due to impaired pulmonary function. This study demonstrates the activity of high dose cyclophosphamide in the treatment of pineoblastoma and may serve as basis for the design of future studies of this tumor.

Authors
Ashley, DM; Longee, D; Tien, R; Fuchs, H; Graham, ML; Kurtzberg, J; Casey, J; Olson, J; Meier, L; Ferrell, L; Kerby, T; Duncan-Brown, M; Stewart, E; Colvin, OM; Pipas, JM; McCowage, G; McLendon, R; Bigner, DD; Friedman, HS
MLA Citation
Ashley, D. M., et al. “Treatment of patients with pineoblastoma with high dose cyclophosphamide..” Med Pediatr Oncol, vol. 26, no. 6, June 1996, pp. 387–92. Pubmed, doi:10.1002/(SICI)1096-911X(199606)26:6<387::AID-MPO3>3.0.CO;2-D.
PMID
8614374
Source
pubmed
Published In
Medical and Pediatric Oncology
Volume
26
Issue
6
Publish Date
1996
Start Page
387
End Page
392
DOI
10.1002/(SICI)1096-911X(199606)26:6<387::AID-MPO3>3.0.CO;2-D

Flow cytometric analysis of intercellular adhesion between B-cell precursor acute lymphoblastic leukemic cells and bone marrow stromal cells.

The growth of B-cell precursor acute lymphoblastic leukemic (BCP ALL) cells in vitro is dependent on interactions with bone marrow (BM) stromal cells. We have recently demonstrated that the rate of cell division of BCP ALL cells increases when cultured in direct contact with BM stromal cells. In this study we describe a new method for examining the direct binding of BM stromal cells and BCP ALL cells at a cellular level. For this binding assay, BCP ALL cells from six patient samples were first stained with the lipophilic fluorescent probe PKH 26 GL and mixed with BM stromal cells in suspension. In all cases, aggregates between BCP ALL and BM stromal cells were identified by flow cytometry and isolated. Using this assay we have examined some of the mechanisms involved in this binding process. The pattern of aggregate formation at various leukemic/stromal cell ratios showed that the aggregate formation increased by increasing the number of either cell type and that the binding could not be saturated. This suggests that the interaction between these cells is an equilibrium reaction. Functional studies showed that the majority of BCP ALL-BM stromal cell binding is dependent on the presence of divalent cations and requires active cellular metabolism. Finally, by use of inhibitory monoclonal antibodies (moAbs) directed against cell adhesion molecules including anti-CD29, VCAM and CD18, we have demonstrated that the involvement of these molecules in the direct cellular interactions could be detected by this method. However, the maximum inhibition observed was 36% which suggests either that the avidity is low or that other adhesion molecules are involved. The data show that the use of flow cytometric analysis of aggregate formation (rather than cell binding to intact cell layers) allows the study of cell interactions at the individual cell level which can reveal additional cellular adhesion mechanisms.

Authors
Ashley, DM; Bol, SJ; Tucker, DP; Waugh, CM; Kannourakis, G
MLA Citation
Ashley, D. M., et al. “Flow cytometric analysis of intercellular adhesion between B-cell precursor acute lymphoblastic leukemic cells and bone marrow stromal cells..” Leukemia, vol. 9, no. 1, Jan. 1995, pp. 58–67.
PMID
7845030
Source
pubmed
Published In
Leukemia
Volume
9
Issue
1
Publish Date
1995
Start Page
58
End Page
67
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