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Hyslop, Terry

Positions:

Professor of Biostatistics & Bioinformatics

Biostatistics & Bioinformatics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2001

Ph.D. — Temple University

Grants:

Smartphone Enabled Point-of-Care Detection of Serum Markers of Liver Cancer

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
June 01, 2017
End Date
June 30, 2022

Comparison of Operative to Medical Endocrine Therapy (COMET) for Low Risk DCIS

Administered By
Surgical Oncology
Role
Investigator
Start Date
June 01, 2016
End Date
December 01, 2021

Translational Research in Surgical Oncology

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
January 01, 2002
End Date
August 31, 2021

Intergovernmental Personnel Agreements (IPA) Han

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
June 05, 2019
End Date
June 04, 2021

Targeting RNA splicing in race-related aggressive and lethal prostate cancer

Administered By
Duke Cancer Institute
Role
Biostatistician
Start Date
October 12, 2018
End Date
October 12, 2020

Helicobacter pylori blood biomarker for gastric cancer risk in East Asia

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Biostatistician Investigator
Start Date
July 01, 2017
End Date
June 30, 2020

Smartphone Enabled Point-of-Care Detection of Serum Markers of Liver Cancer

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
June 01, 2017
End Date
April 30, 2020

Innovative Biomarker-Integrated Clinical Trial Design and Analysis

Administered By
Biostatistics & Bioinformatics
AwardedBy
University of North Carolina - Chapel Hill
Role
Co Investigator
Start Date
May 15, 2015
End Date
March 31, 2020

Personal Service Agreement (PSA) Gu

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
November 20, 2018
End Date
November 19, 2019

IPA - Terry Hyslop

Administered By
Biostatistics & Bioinformatics
Role
Research Associate
Start Date
October 01, 2017
End Date
July 31, 2019

Epigenetic damage in women living in LA food-desert zip codes

Administered By
Biostatistics & Bioinformatics
Role
Principal Investigator
Start Date
August 01, 2017
End Date
July 31, 2019

Combined breast MRI/biomarker strategies to identify aggressive biology

Administered By
Biostatistics & Bioinformatics
Role
Principal Investigator
Start Date
October 01, 2015
End Date
July 31, 2019

Microscaled Proteogenomics for Cancer Clinical Trials

Administered By
Duke Cancer Institute
AwardedBy
Baylor College of Medicine
Role
Principal Investigator
Start Date
June 07, 2017
End Date
May 31, 2019

IPA - Lin Gu

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
October 01, 2017
End Date
November 19, 2018

The Mathematics of Breast Cancer Overtreatment: Improving Treatment Choice through Effective Communication of Personalized Cancer Risk

Administered By
Surgical Oncology
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
September 01, 2016
End Date
August 31, 2018

Tension-Stat3-miR-mediated Metastasis

Administered By
Biostatistics & Bioinformatics
Role
Principal Investigator
Start Date
October 01, 2015
End Date
March 31, 2018

Breast Cancer Research Foundation

Administered By
Duke Cancer Institute
Role
Principal Investigator
Start Date
October 01, 2015
End Date
September 30, 2017

National Clinical Trials Network - Network Group Statistics and DMCs

Administered By
Duke Cancer Institute
AwardedBy
Mayo Clinic
Role
Statistician
Start Date
April 17, 2014
End Date
August 31, 2017

Tension-Stat3-miR-mediated Metastasis

Administered By
Biostatistics & Bioinformatics
Role
Principal Investigator
Start Date
October 01, 2015
End Date
March 31, 2017

Single cell analysis of intratumoral heterogeneity in parathyroid neoplasia

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Biostatistician
Start Date
January 16, 2015
End Date
February 28, 2017

Small RNA Sequencing and prospective evaluation of HCC risk in HBV patients

Administered By
Biostatistics & Bioinformatics
AwardedBy
Thomas Jefferson University
Role
Principal Investigator
Start Date
April 01, 2014
End Date
December 31, 2016

Combined breast MRI/biomarker strategies to identify aggressive biology

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Biostatistician
Start Date
August 01, 2015
End Date
September 30, 2015

Tension-Stat3-miR-mediated metastasis

Administered By
Medicine, Medical Oncology
AwardedBy
University of California, San Francisco
Role
Biostatistician
Start Date
April 01, 2015
End Date
September 30, 2015

Structural Models of Breast Cancer Outcomes Disparities

Administered By
Biostatistics & Bioinformatics
Role
Principal Investigator
Start Date
August 05, 2014
End Date
July 31, 2015

Therapy-relevant stratification of breast cancer patients: Integrating pathology and biomarkers analysis

Administered By
Biostatistics & Bioinformatics
AwardedBy
Thomas Jefferson University
Role
Principal Investigator
Start Date
January 08, 2014
End Date
January 07, 2015

Occult tumor burden as a marker stratifying therapy to eliminate racial disparities in colon cancer

Administered By
Biostatistics & Bioinformatics
AwardedBy
Thomas Jefferson University
Role
Principal Investigator
Start Date
April 01, 2014
End Date
August 29, 2014

Tumor MicroRNA Signatures as Prognostic Biomarkers of Colorectal Cancer

Administered By
Biostatistics & Bioinformatics
AwardedBy
Thomas Jefferson University
Role
Principal Investigator
Start Date
April 01, 2014
End Date
June 30, 2014

Therapeutic vaccine bridging the gap in racial disparities in colorectal cancer

Administered By
Biostatistics & Bioinformatics
AwardedBy
Thomas Jefferson University
Role
Principal Investigator
Start Date
April 01, 2014
End Date
May 31, 2014
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Awards:

Fellow. American Statistical Association.

Type
International
Awarded By
American Statistical Association
Date
January 01, 2016

Publications:

The Influence of Age on the Histopathology and Prognosis of Atypical Breast Lesions.

BACKGROUND: Although several prognostic variables and risk factors for breast cancer are age-related, the association between age and risk of cancer with breast atypia is controversial. This study aimed to compare the type of breast atypia and risk of underlying or subsequent breast cancer by age. METHODS: Adult women with breast atypia (atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ) at a single institution from 2008 to 2017 were stratified by age at initial diagnosis: <50 y, 50-70 y, and >70 y. Regression modeling was used to estimate the association of age with risk of underlying carcinoma or subsequent cancer diagnosis. RESULTS: A total of 530 patients with atypia were identified: 31.1% < 50 y (n = 165), 58.1% 50-70 y (n = 308), and 10.8% > 70 y (n = 57). The proportion of women with atypical ductal hyperplasia steadily increased with age, compared with atypical lobular proliferations (P = 0.04). Of those with atypia on needle biopsy, the overall rate of underlying carcinoma was 17.5%. After adjustment, older age was associated with a greater risk of underlying carcinoma (odds ratio: 1.028, 95% confidence interval: 1.003-1.053; P = 0.03). Of those confirmed to have atypia on surgical excision, the overall rate of a subsequent cancer diagnosis was 15.7%. Age was not associated with a long-term risk for breast cancer (P = 0.48) or the time to a subsequent diagnosis of carcinoma (log-rank P = 0.41). CONCLUSIONS: Although atypia diagnosed on needle biopsy may be sufficient to warrant surgical excision, older women may be at a greater risk for an underlying carcinoma, albeit the long-term risk for malignancy associated with atypia does not appear to be affected by age.

Authors
Sergesketter, AR; Thomas, SM; Fayanju, OM; Menendez, CS; Rosenberger, LH; Greenup, RA; Hyslop, T; Parrilla Castellar, ER; Hwang, ES; Plichta, JK
MLA Citation
Sergesketter, Amanda R., et al. “The Influence of Age on the Histopathology and Prognosis of Atypical Breast Lesions..” J Surg Res, vol. 241, Sept. 2019, pp. 188–98. Pubmed, doi:10.1016/j.jss.2019.03.047.
PMID
31028940
Source
pubmed
Published In
J Surg Res
Volume
241
Publish Date
2019
Start Page
188
End Page
198
DOI
10.1016/j.jss.2019.03.047

Growth Dynamics of Mammographic Calcifications: Differentiating Ductal Carcinoma in Situ from Benign Breast Disease.

Background Most ductal carcinoma in situ (DCIS) lesions are first detected on screening mammograms as calcifications. However, false-positive biopsy rates for calcifications range from 30% to 87%. Improved methods to differentiate benign from malignant calcifications are thus needed. Purpose To quantify the growth rates of DCIS and benign breast disease that manifest as mammographic calcifications. Materials and Methods All calcifications (n = 2359) for which a stereotactic biopsy was performed from 2008 through 2015 at Duke University Medical Center were retrospectively identified. Mammograms from all cases of DCIS (n = 404) were reviewed for calcifications that were visible on mammograms taken at least 6 months before biopsy. Women with at least one prior mammogram with visible calcifications were age- and race-matched 1:2 to women with a benign breast biopsy and calcifications visible on prior mammograms. The long axis of the calcifications was measured on all mammograms. Multivariable adjusted linear mixed-effects models estimated the association of calcification growth rates with patholo findings. Hierarchical clustering accounted for matching benign and DCIS groups. Results A total of 74 DCIS calcifications and 148 benign calcifications were included for final analysis. The median patient age was 62 years (interquartile range, 51-71 years). No significant difference in breast density (P > .05) or number of available mammograms (P > .05) was detected between groups. Calcifications associated with DCIS were larger than those associated with benign breast disease at biopsy (median, 10 mm vs 6 mm, respectively; P < .001). After adjustment, the relative annual increase in the long-axis length of DCIS calcifications was greater than that of benign breast calcifications (96% [95% confidence interval: 72%, 224%] vs 68% [95% confidence interval: 56%, 80%] per year, respectively; P < .001). Conclusion Ductal carcinoma in situ calcifications are more extensive at diagnosis and grow faster in extent than those associated with benign breast disease. The rate of calcification change may help to discriminate benign from malignant calcifications. © RSNA, 2019 Online supplemental material is available for this article.

Authors
Grimm, LJ; Miller, MM; Thomas, SM; Liu, Y; Lo, JY; Hwang, ES; Hyslop, T; Ryser, MD
MLA Citation
Grimm, Lars J., et al. “Growth Dynamics of Mammographic Calcifications: Differentiating Ductal Carcinoma in Situ from Benign Breast Disease..” Radiology, vol. 292, no. 1, July 2019, pp. 77–83. Pubmed, doi:10.1148/radiol.2019182599.
PMID
31112087
Source
pubmed
Published In
Radiology
Volume
292
Issue
1
Publish Date
2019
Start Page
77
End Page
83
DOI
10.1148/radiol.2019182599

Incidence of Ductal Carcinoma in Situ in the United States, 2000-2014.

BACKGROUND: In absence of definitive molecular risk markers, clinical management of patients diagnosed with ductal carcinoma in situ (DCIS) remains largely guided by patient and tumor characteristics. In this study, we analyzed recent trends in DCIS incidence and compared them against trends in mammography use. METHODS: The Surveillance, Epidemiology and End Results (SEER) registry was queried for patients diagnosed with DCIS from 2000 to 2014 (18 registries). Joinpoint regression analyses were used to compute age- and race-stratified trends in age-adjusted incidence of DCIS. The patterns of DCIS incidence were compared against mammography utilization data from the National Health Interview Survey. RESULTS: Between 2000 and 2014, overall DCIS incidence in the US population was stable (P=0.24). Among age groups 20-44 years and 45-55 years DCIS incidence increased by 1.3% (P=0.001) and 0.6% (P=0.02) per year, respectively. While stable among white women, DCIS incidence increased among black women and women of other races by 1.6% (P<0.001) and 1.0% (P=0.002) per year, respectively. Mammography uptake correlated well with DCIS incidence, with the exception of women aged 40-49 years and black women who experienced an increase in DCIS incidence despite stagnating and decreasing mammography uptake, respectively. CONCLUSIONS: Overall DCIS incidence rates have remained stable between 2000 and 2014. However, subgroup analyses revealed an increase in incidence among both younger women and black women. IMPACT: DCIS incidence trends did not correlate with the mammography uptake patterns, suggesting that etiologic factors other than screening may be leading to an increased DCIS incidence in these groups.

Authors
Ryser, MD; Hendrix, LH; Worni, M; Liu, Y; Hyslop, T; Hwang, ES
MLA Citation
Ryser, Marc D., et al. “Incidence of Ductal Carcinoma in Situ in the United States, 2000-2014..” Cancer Epidemiol Biomarkers Prev, June 2019. Pubmed, doi:10.1158/1055-9965.EPI-18-1262.
PMID
31186262
Source
pubmed
Published In
Cancer Epidemiol Biomarkers Prev
Publish Date
2019
DOI
10.1158/1055-9965.EPI-18-1262

Low-Risk Thyroid Cancer in Elderly: Total Thyroidectomy/RAI Predominates but Lacks Survival Advantage.

BACKGROUND: Papillary thyroid cancer (PTC) is the fastest increasing cancer in the United States; incidence increases with age. It generally has a favorable prognosis but may behave more aggressively in older patients. This study aims to describe national treatment patterns for low-risk PTC in older adults. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results-Medicare database was used to identify patients ≥66 y treated for clinical T1N0M0 PTC between 1996 and 2011. Multivariable logistic regression was used to identify factors associated with extent of surgery (total thyroidectomy versus lobectomy) and radioactive iodine (RAI) administration. Cox proportional hazards modeling was used to estimate the effect of treatment type on disease-specific survival (DSS). RESULTS: Three thousand two hundred and fourteen patients met inclusion criteria; 77.6% were women, median age was 72 y, and mean tumor size was 0.7 cm. 42.7% had preoperatively diagnosed PTC (versus incidental). 65.4% underwent total thyroidectomy, 29.0% lobectomy, and 5.6% lobectomy followed by completion thyroidectomy; 33.4% received postoperative RAI. Five- and 10-year DSS were 98.9% and 98.3%, respectively. After adjustment, larger tumor size (1.1-2 cm), multifocality, and a preoperative PTC diagnosis were associated with greater odds of undergoing more extensive surgery and receiving RAI (P < 0.0001). DSS was not associated with extent of surgery or RAI administration (P > 0.05). CONCLUSIONS: Most older adults with PTC underwent total thyroidectomy and a third received RAI; neither treatment improved DSS. In the growing elderly population, less extensive interventions for PTC may reduce morbidity and improve quality of life while preserving an excellent prognosis.

Authors
Zambeli-Ljepović, A; Wang, F; Dinan, MA; Hyslop, T; Roman, SA; Sosa, JA; Scheri, RP
MLA Citation
Zambeli-Ljepović, Alan, et al. “Low-Risk Thyroid Cancer in Elderly: Total Thyroidectomy/RAI Predominates but Lacks Survival Advantage..” J Surg Res, vol. 243, June 2019, pp. 189–97. Pubmed, doi:10.1016/j.jss.2019.05.029.
PMID
31185435
Source
pubmed
Published In
J Surg Res
Volume
243
Publish Date
2019
Start Page
189
End Page
197
DOI
10.1016/j.jss.2019.05.029

The impact of chemotherapy sequence on survival in node-positive invasive lobular carcinoma.

BACKGROUND AND OBJECTIVES: We sought to evaluate the impact of chemotherapy sequence on survival by comparing node-positive invasive lobular carcinoma (ILC) patients who received neoadjuvant (NACT) and adjuvant (ACT) chemotherapy. METHODS: cT1-4c, cN1-3 ILC patients in the National Cancer Data Base (2004-2013) who underwent surgery and chemotherapy were divided into NACT and ACT cohorts. Kaplan-Meier curves and Cox proportional hazards modeling were used to estimate unadjusted and adjusted overall survival (OS), respectively. RESULTS: Five thousand five hundred fifty-one (35.6%) of 15 573 ILC patients treated with chemotherapy received NACT. NACT patients had similar rates of pT3/4 disease (26.6% vs 26.2%), nodal involvement (median 3 vs 4), and number of lymph nodes examined (median 13 vs 14) but higher rates of mastectomy (81.8% vs 74.5%, P < 0.001) vs ACT patients. 3.4% of NACT patients experienced pathologic complete response (pCR). Unadjusted 10-year OS was worse for NACT vs ACT patients (65.1% vs 54.4%, log-rank P < 0.001). After adjustment for known covariates, NACT continued to be associated with worse OS (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.25-1.52). CONCLUSIONS: In node-positive ILC, NACT yielded low rates of pCR, was not associated with lower rates of mastectomy or less extensive axillary surgery, and was associated with worse survival vs ACT, suggesting limited benefit for these patients.

Authors
Tamirisa, N; Williamson, HV; Thomas, SM; Westbrook, KE; Greenup, RA; Plichta, JK; Rosenberger, LH; Hyslop, T; Hwang, E-SS; Fayanju, OM
MLA Citation
Tamirisa, Nina, et al. “The impact of chemotherapy sequence on survival in node-positive invasive lobular carcinoma..” J Surg Oncol, May 2019. Pubmed, doi:10.1002/jso.25492.
PMID
31062375
Source
pubmed
Published In
J Surg Oncol
Publish Date
2019
DOI
10.1002/jso.25492

Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study.

PURPOSE: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). PATIENTS AND METHODS: In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and antitumor function were evaluated. We tested VRP-HER2 in a phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. RESULTS: Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n = 4) and 32.7 months in cohort 2 (n = 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. CONCLUSIONS: VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T-cell activity by combining with anti-PD-1.

Authors
Crosby, EJ; Gwin, W; Blackwell, K; Marcom, PK; Chang, S; Maecker, HT; Broadwater, G; Hyslop, T; Kim, S; Rogatko, A; Lubkov, V; Snyder, JC; Osada, T; Hobeika, AC; Morse, MA; Lyerly, HK; Hartman, ZC
MLA Citation
Crosby, Erika J., et al. “Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study..” Clin Cancer Res, vol. 25, no. 9, May 2019, pp. 2725–36. Pubmed, doi:10.1158/1078-0432.CCR-18-3102.
Website
https://hdl.handle.net/10161/17931
PMID
30635338
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
25
Issue
9
Publish Date
2019
Start Page
2725
End Page
2736
DOI
10.1158/1078-0432.CCR-18-3102

Breast cancer biology, stage of presentation, and treatment in the extremes of age

Authors
Plichta, J; Thomas, S; DeChant, C; Fayanju, O; Rosenberger, L; Gupta, A; Hyslop, T; Hwang, E; Greenup, R
MLA Citation
Plichta, Jennifer, et al. “Breast cancer biology, stage of presentation, and treatment in the extremes of age.” Annals of Surgical Oncology, vol. 26, SPRINGER, 2019, pp. 184–85.
Source
wos
Published In
Annals of Surgical Oncology
Volume
26
Publish Date
2019
Start Page
184
End Page
185

Neoadjuvant endocrine therapy vs chemotherapy in node-positive invasive lobular carcinoma

Authors
Fayanju, O; Thornton, M; Williamson, H; Westbrook, K; Greenup, R; Plichta, J; Rosenberger, L; Gupta, A; Hyslop, T; Hwang, E-S
MLA Citation
Fayanju, Oluwadamilola, et al. “Neoadjuvant endocrine therapy vs chemotherapy in node-positive invasive lobular carcinoma.” Annals of Surgical Oncology, vol. 26, SPRINGER, 2019, pp. 41–42.
Source
wos
Published In
Annals of Surgical Oncology
Volume
26
Publish Date
2019
Start Page
41
End Page
42

Perspectives on the costs of cancer care: A survey of the American Society of Breast Surgeons

Authors
Greenup, R; Rushing, C; Fish, L; Lane, W; Peppercorn, J; Tolnitch, L; Hyslop, T; Myers, E; Zafar, SY; Hwang, ES
MLA Citation
Greenup, Rachel, et al. “Perspectives on the costs of cancer care: A survey of the American Society of Breast Surgeons.” Annals of Surgical Oncology, vol. 26, SPRINGER, 2019, pp. 20–21.
Source
wos
Published In
Annals of Surgical Oncology
Volume
26
Publish Date
2019
Start Page
20
End Page
21

HELICOBACTER PYLORI INFECTION DOES NOT MODIFY THE PROTECTIVE EFFECT OF REGULAR ASPIRIN USE ON COLORECTAL CANCER RISK IN A POPULATION OF US ADULTS

Authors
Varga, MG; Hendrix, L; Blot, W; Butt, J; Sesso, HD; Peek, RM; Potter, JD; Cover, T; Hyslop, T; Grodstein, F; Song, M; Berndt, S; Hildesheim, A; Waterboer, T; Pawlita, M; Epplein, M
MLA Citation
Varga, Matthew G., et al. “HELICOBACTER PYLORI INFECTION DOES NOT MODIFY THE PROTECTIVE EFFECT OF REGULAR ASPIRIN USE ON COLORECTAL CANCER RISK IN A POPULATION OF US ADULTS.” Gastroenterology, vol. 156, no. 6, W B SAUNDERS CO-ELSEVIER INC, 2019, pp. S821–22.
Source
wos
Published In
Gastroenterology
Volume
156
Issue
6
Publish Date
2019
Start Page
S821
End Page
S822

HELICOBACTER PYLORI ANTIBODY PREVALENCE BY YEAR OF BIRTH AND DEMOGRAPHIC FACTORS IN A CONSORTIUM OF US ADULTS

Authors
Varga, MG; Butt, J; Blot, W; La Marchand, L; Haiman, C; Chen, Y; Wassertheil-Smoller, S; Ho, GY; Tinker, L; Peek, RM; Potter, JD; Cover, T; Hendrix, L; Hyslop, T; Zeleniuch-Jacquotte, A; Berndt, S; Hildesheim, A; Waterboer, T; Pawlita, M; Epplein, M
MLA Citation
Varga, Matthew G., et al. “HELICOBACTER PYLORI ANTIBODY PREVALENCE BY YEAR OF BIRTH AND DEMOGRAPHIC FACTORS IN A CONSORTIUM OF US ADULTS.” Gastroenterology, vol. 156, no. 6, W B SAUNDERS CO-ELSEVIER INC, 2019, pp. S523–24.
Source
wos
Published In
Gastroenterology
Volume
156
Issue
6
Publish Date
2019
Start Page
S523
End Page
S524

Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients.

BACKGROUND: The colorectal cancer antigen GUCY2C exhibits unique split tolerance, evoking antigen-specific CD8+, but not CD4+, T-cell responses that deliver anti-tumor immunity without autoimmunity in mice. Here, the cancer vaccine Ad5-GUCY2C-PADRE was evaluated in a first-in-man phase I clinical study of patients with early-stage colorectal cancer to assess its safety and immunological efficacy. METHODS: Ten patients with surgically-resected stage I or stage II (pN0) colon cancer received a single intramuscular injection of 1011 viral particles (vp) of Ad5-GUCY2C-PADRE. Safety assessment and immunomonitoring were carried out for 6 months following immunization. This trial employed continual monitoring of both efficacy and toxicity of subjects as joint primary outcomes. RESULTS: All patients receiving Ad5-GUCY2C-PADRE completed the study and none developed adverse events greater than grade 1. Antibody responses to GUCY2C were detected in 10% of patients, while 40% exhibited GUCY2C-specific T-cell responses. GUCY2C-specific responses were exclusively CD8+ cytotoxic T cells, mimicking pre-clinical studies in mice in which GUCY2C-specific CD4+ T cells are eliminated by self-tolerance, while CD8+ T cells escape tolerance and mediate antitumor immunity. Moreover, pre-existing neutralizing antibodies (NAbs) to the Ad5 vector were associated with poor vaccine-induced responses, suggesting that Ad5 NAbs oppose GUCY2C immune responses to the vaccine in patients and supported by mouse studies. CONCLUSIONS: Split tolerance to GUCY2C in cancer patients can be exploited to safely generate antigen-specific cytotoxic CD8+, but not autoimmune CD4+, T cells by Ad5-GUCY2C-PADRE in the absence of pre-existing NAbs to the viral vector. TRIAL REGISTRATION: This trial (NCT01972737) was registered at ClinicalTrials.gov on October 30th, 2013. https://clinicaltrials.gov/ct2/show/NCT01972737.

Authors
Snook, AE; Baybutt, TR; Xiang, B; Abraham, TS; Flickinger, JC; Hyslop, T; Zhan, T; Kraft, WK; Sato, T; Waldman, SA
MLA Citation
Snook, Adam E., et al. “Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients..” J Immunother Cancer, vol. 7, no. 1, Apr. 2019. Pubmed, doi:10.1186/s40425-019-0576-2.
PMID
31010434
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
7
Issue
1
Publish Date
2019
Start Page
104
DOI
10.1186/s40425-019-0576-2

The COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial: a phase III randomised controlled clinical trial for low-risk ductal carcinoma in situ (DCIS).

INTRODUCTION: Ductal carcinoma in situ (DCIS) is a non-invasive non-obligate precursor of invasive breast cancer. With guideline concordant care (GCC), DCIS outcomes are at least as favourable as some other early stage cancer types such as prostate cancer, for which active surveillance (AS) is a standard of care option. However, AS has not yet been tested in relation to DCIS. The goal of the COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial for low-risk DCIS is to gather evidence to help future patients consider the range of treatment choices for low-risk DCIS, from standard therapies to AS. The trial will determine whether there may be some women who do not substantially benefit from current GCC and who could thus be safely managed with AS. This protocol is version 5 (11 July 2018). Any future protocol amendments will be submitted to Quorum Centralised Institutional Review Board/local institutional review boards for approval via the sponsor of the study (Alliance Foundation Trials). METHODS AND ANALYSIS: COMET is a phase III, randomised controlled clinical trial for patients with low-risk DCIS. The primary outcome is ipsilateral invasive breast cancer rate in women undergoing GCC compared with AS. Secondary objectives will be to compare surgical, oncological and patient-reported outcomes. Patients randomised to the GCC group will undergo surgery as well as radiotherapy when appropriate; those in the AS group will be monitored closely with surgery only on identification of invasive breast cancer. Patients in both the GCC and AS groups will have the option of endocrine therapy. The total planned accrual goal is 1200 patients. ETHICS AND DISSEMINATION: The COMET trial will be subject to biannual formal review at the Alliance Foundation Data Safety Monitoring Board meetings. Interim analyses for futility/safety will be completed annually, with reporting following Consolidated Standards of Reporting Trials (CONSORT) guidelines for non-inferiority trials. TRIAL REGISTRATION NUMBER: NCT02926911; Pre-results.

Authors
Hwang, ES; Hyslop, T; Lynch, T; Frank, E; Pinto, D; Basila, D; Collyar, D; Bennett, A; Kaplan, C; Rosenberg, S; Thompson, A; Weiss, A; Partridge, A
MLA Citation
Hwang, E. Shelley, et al. “The COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial: a phase III randomised controlled clinical trial for low-risk ductal carcinoma in situ (DCIS)..” Bmj Open, vol. 9, no. 3, Mar. 2019. Pubmed, doi:10.1136/bmjopen-2018-026797.
PMID
30862637
Source
pubmed
Published In
Bmj Open
Volume
9
Issue
3
Publish Date
2019
Start Page
e026797
DOI
10.1136/bmjopen-2018-026797

Surgical Resection of the Primary Tumor in Women With De Novo Stage IV Breast Cancer: Contemporary Practice Patterns and Survival Analysis.

OBJECTIVE: We evaluated patterns of surgical care and their association with overall survival among a contemporary cohort of women with stage IV breast cancer. BACKGROUND: Surgical resection of the primary tumor remains controversial among women with stage IV breast cancer. METHODS: Women diagnosed with clinical stage IV breast cancer from 2003 to 2012 were identified from the American College of Surgeons National Cancer Database. Those with intact primary tumors who were alive 12 months after diagnosis were categorized by treatment sequence: (1) surgery before systemic therapy, (2) systemic therapy before surgery, and (3) systemic therapy alone. Multivariate logistic regression was used to estimate the association of treatment sequence with surgery type. Overall survival was estimated using multivariate Cox proportional hazards models. RESULTS: Among 24,015 women, 56.2% (13,505) underwent systemic therapy alone and 43.8% (10,510) underwent surgical resection. Rates of surgery decreased slightly over time (43.1% in 2003 to 41.9% in 2011). Treatment with systemic therapy before surgery was associated with larger tumor size (median 4.5 vs 3.1 cm, P < 0.001) and receipt of mastectomy (81.4% vs 52.2%, P < 0.001) when compared to those who underwent surgery first. Receipt of surgery, whether before or after systemic therapy (Hazard Ratio, 0.68; 95% confidence interval, 0.62-0.73; Hazard Ratio, 0.56; 95% confidence interval, 0.52-0.61; P < 0.001), was independently associated with improved adjusted overall survival when compared to systemic therapy alone. CONCLUSIONS: Surgical resection of the primary tumor occurs in almost half of women with stage IV breast cancer alive 1 year after diagnosis, and is increasingly occurring after systemic therapy. Coordinated multidisciplinary care remains highly relevant in the setting of metastatic breast cancer, where surgical decisions should be made on an individual basis and may affect survival in select women.

Authors
Lane, WO; Thomas, SM; Blitzblau, RC; Plichta, JK; Rosenberger, LH; Fayanju, OM; Hyslop, T; Hwang, ES; Greenup, RA
MLA Citation
Lane, Whitney O., et al. “Surgical Resection of the Primary Tumor in Women With De Novo Stage IV Breast Cancer: Contemporary Practice Patterns and Survival Analysis..” Ann Surg, vol. 269, no. 3, Mar. 2019, pp. 537–44. Pubmed, doi:10.1097/SLA.0000000000002621.
PMID
29227346
Source
pubmed
Published In
Ann Surg
Volume
269
Issue
3
Publish Date
2019
Start Page
537
End Page
544
DOI
10.1097/SLA.0000000000002621

Cancer Outcomes in DCIS Patients Without Locoregional Treatment.

Background: The vast majority of women diagnosed with ductal carcinoma in situ (DCIS) undergo treatment. Therefore, the risks of invasive progression and competing death in the absence of locoregional therapy are uncertain. Methods: We performed survival analyses of patient-level data from DCIS patients who did not receive definitive surgery or radiation therapy as recorded in the US National Cancer Institute's Surveillance, Epidemiology, and End Results program (1992-2014). Kaplan-Meier curves were used to estimate the net risk of subsequent ipsilateral invasive cancer. The cumulative incidences of ipsilateral invasive cancer, contralateral breast cancer, and death were estimated using competing risk methods. Results: A total of 1286 DCIS patients who did not undergo locoregional therapy were identified. Median age at diagnosis was 60 years (inter-quartile range = 51-74 years), with median follow-up of 5.5 years (inter-quartile range = 2.3-10.6 years). Among patients with tumor grade I/II (n = 547), the 10-year net risk of ipsilateral invasive breast cancer was 12.2% (95% confidence interval [CI] = 8.6% to 17.1%) compared with 17.6% (95% CI = 12.1% to 25.2%) among patients with tumor grade III (n = 244) and 10.1% (95% CI = 7.4% to 13.8%) among patients with unknown grade (n = 495). Among all patients, the 10-year cumulative incidences of ipsilateral invasive cancer, contralateral breast cancer, and all-cause mortality were 10.5% (95% CI = 8.5% to 12.4%), 3.9% (95% CI = 2.6% to 5.2%), and 24.1% (95% CI = 21.2% to 26.9%), respectively. Conclusion: Despite limited data, our findings suggest that DCIS patients without locoregional treatment have a limited risk of invasive progression. Although the cohort is not representative of the general population of patients diagnosed with DCIS, the findings suggest that there may be overtreatment, especially among older patients and patients with elevated comorbidities.

Authors
Ryser, MD; Weaver, DL; Zhao, F; Worni, M; Grimm, LJ; Gulati, R; Etzioni, R; Hyslop, T; Lee, SJ; Hwang, ES
MLA Citation
Ryser, Marc D., et al. “Cancer Outcomes in DCIS Patients Without Locoregional Treatment..” J Natl Cancer Inst, Feb. 2019. Pubmed, doi:10.1093/jnci/djy220.
PMID
30759222
Source
pubmed
Published In
J Natl Cancer Inst
Publish Date
2019
DOI
10.1093/jnci/djy220

Adjuvant Chemotherapy Improves Survival Following Resection of Locally Advanced Rectal Cancer with Pathologic Complete Response.

BACKGROUND: Controversy exists over the use of adjuvant chemotherapy for locally advanced (stages II-III) rectal cancer (LARC) patients who demonstrate pathologic complete response (pCR) following neoadjuvant chemoradiation. We conducted a retrospective analysis to determine whether adjuvant chemotherapy imparts survival benefit among this population. METHODS: The National Cancer Database (NCDB) was queried to identify LARC patients with pCR following neoadjuvant chemoradiation. The cohort was stratified by receipt of adjuvant chemotherapy. Multiple imputation and a Cox proportional hazards model were employed to estimate the effect of adjuvant chemotherapy on overall survival. RESULTS: There were 24,418 patients identified in the NCDB with clinically staged II or III rectal cancer who received neoadjuvant chemoradiation. Of these, 5606 (23.0%) had pCR. Among patients with pCR, 1401 (25%) received adjuvant chemotherapy and 4205 (75%) did not. Patients who received adjuvant chemotherapy were slightly younger, more likely to have private insurance, and more likely to have clinically staged III disease, but did not differ significantly in comparison to patients who did not receive adjuvant chemotherapy with respect to race, sex, facility type, Charlson comorbidity score, histologic tumor grade, procedure type, length of stay, or rate of 30-day readmission following surgery. On adjusted analysis, receipt of adjuvant chemotherapy was associated with a lower risk of death at a given time compared to patients who did not receive adjuvant chemotherapy (HR 0.808; 95% CI 0.679-0.961; p = 0.016). CONCLUSION: Supporting existing NCCN guidelines, the findings from this study suggest that adjuvant chemotherapy improves survival for LARC with pCR following neoadjuvant chemoradiation.

Authors
Turner, MC; Keenan, JE; Rushing, CN; Gulack, BC; Nussbaum, DP; Benrashid, E; Hyslop, T; Strickler, JH; Mantyh, CR; Migaly, J
MLA Citation
Turner, Megan C., et al. “Adjuvant Chemotherapy Improves Survival Following Resection of Locally Advanced Rectal Cancer with Pathologic Complete Response..” J Gastrointest Surg, 2019. Pubmed, doi:10.1007/s11605-018-04079-8.
PMID
30635829
Source
pubmed
Published In
J Gastrointest Surg
Publish Date
2019
DOI
10.1007/s11605-018-04079-8

Serologic Response to Helicobacter pylori Proteins Associated With Risk of Colorectal Cancer Among Diverse Populations in the United States.

BACKGROUND & AIMS: Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States. METHODS: We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression. RESULTS: Overall, 40% of controls and 41% of cases were H pylori-seropositive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007). CONCLUSIONS: In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.

Authors
Butt, J; Varga, MG; Blot, WJ; Teras, L; Visvanathan, K; Le Marchand, L; Haiman, C; Chen, Y; Bao, Y; Sesso, HD; Wassertheil-Smoller, S; Ho, GYF; Tinker, LE; Peek, RM; Potter, JD; Cover, TL; Hendrix, LH; Huang, L-C; Hyslop, T; Um, C; Grodstein, F; Song, M; Zeleniuch-Jacquotte, A; Berndt, S; Hildesheim, A; Waterboer, T; Pawlita, M; Epplein, M
MLA Citation
Butt, Julia, et al. “Serologic Response to Helicobacter pylori Proteins Associated With Risk of Colorectal Cancer Among Diverse Populations in the United States..” Gastroenterology, vol. 156, no. 1, 2019, pp. 175-186.e2. Pubmed, doi:10.1053/j.gastro.2018.09.054.
PMID
30296434
Source
pubmed
Published In
Gastroenterology
Volume
156
Issue
1
Publish Date
2019
Start Page
175
End Page
186.e2
DOI
10.1053/j.gastro.2018.09.054

Loss of Nuclear Localized Parathyroid Hormone-Related Protein in Primary Breast Cancer Predicts Poor Clinical Outcome and Correlates with Suppressed Stat5 Signaling.

PURPOSE: Parathyroid hormone-related protein (PTHrP) is required for normal mammary gland development and biology. A PTHLH gene polymorphism is associated with breast cancer risk, and PTHrP promotes growth of osteolytic breast cancer bone metastases. Accordingly, current dogma holds that PTHrP is upregulated in malignant primary breast tumors, but solid evidence for this assumption is missing. EXPERIMENTAL DESIGN: We used quantitative IHC to measure PTHrP in normal and malignant breast epithelia, and correlated PTHrP levels in primary breast cancer with clinical outcome. RESULTS: PTHrP levels were markedly downregulated in malignant compared with normal breast epithelia. Moreover, low levels of nuclear localized PTHrP in cancer cells correlated with unfavorable clinical outcome in a test and a validation cohort of breast cancer treated at different institutions totaling nearly 800 cases. PTHrP mRNA levels in tumors of a third cohort of 737 patients corroborated this association, also after multivariable adjustment for standard clinicopathologic parameters. Breast cancer PTHrP levels correlated strongly with transcription factors Stat5a/b, which are established markers of favorable prognosis and key mediators of prolactin signaling. Prolactin stimulated PTHrP transcript and protein in breast cancer cell lines in vitro and in vivo, effects mediated by Stat5 through the P2 gene promoter, producing transcript AT6 encoding the PTHrP 1-173 isoform. Low levels of AT6, but not two alternative transcripts, correlated with poor clinical outcome. CONCLUSIONS: This study overturns the prevailing view that PTHrP is upregulated in primary breast cancers and identifies a direct prolactin-Stat5-PTHrP axis that is progressively lost in more aggressive tumors.

Authors
Tran, TH; Utama, FE; Sato, T; Peck, AR; Langenheim, JF; Udhane, SS; Sun, Y; Liu, C; Girondo, MA; Kovatich, AJ; Hooke, JA; Shriver, CD; Hu, H; Palazzo, JP; Bibbo, M; Auer, PW; Flister, MJ; Hyslop, T; Mitchell, EP; Chervoneva, I; Rui, H
MLA Citation
Tran, Thai H., et al. “Loss of Nuclear Localized Parathyroid Hormone-Related Protein in Primary Breast Cancer Predicts Poor Clinical Outcome and Correlates with Suppressed Stat5 Signaling..” Clin Cancer Res, vol. 24, no. 24, Dec. 2018, pp. 6355–66. Pubmed, doi:10.1158/1078-0432.CCR-17-3280.
PMID
30097435
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
24
Issue
24
Publish Date
2018
Start Page
6355
End Page
6366
DOI
10.1158/1078-0432.CCR-17-3280

Financial Burden Related to Decisions for Breast Cancer Surgery

Authors
Greenup, RA; Rushing, C; Fish, L; Campbell, BM; Tolnitch, L; Hyslop, T; Peppercorn, J; Wheeler, S; Zafar, Y; Myers, ER; Hwang, ES
MLA Citation
Greenup, Rachel A., et al. “Financial Burden Related to Decisions for Breast Cancer Surgery.” Journal of Womens Health, vol. 27, no. 11, MARY ANN LIEBERT, INC, 2018, pp. 1422–23.
Source
wos
Published In
Journal of Women'S Health (2002)
Volume
27
Issue
11
Publish Date
2018
Start Page
1422
End Page
1423

Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer.

Purpose: Response to a complex trastuzumab-based regimen is affected by multiple features of the tumor and its microenvironment. Developing a predictive algorithm is key to optimizing HER2-targeting therapy.Experimental Design: We analyzed 137 pretreatment tumors with mRNA-seq and DNA exome sequencing from CALGB 40601, a neoadjuvant phase III trial of paclitaxel plus trastuzumab with or without lapatinib in stage II to III HER2-positive breast cancer. We adopted an Elastic Net regularized regression approach that controls for covarying features within high-dimensional data. First, we applied 517 known gene expression signatures to develop an Elastic Net model to predict pCR, which we validated on 143 samples from four independent trials. Next, we performed integrative analyses incorporating clinicopathologic information with somatic mutation status, DNA copy number alterations (CNA), and gene signatures.Results: The Elastic Net model using only gene signatures predicted pCR in the validation sets (AUC = 0.76). Integrative analyses showed that models containing gene signatures, clinical features, and DNA information were better pCR predictors than models containing a single data type. Frequently selected variables from the multiplatform models included amplifications of chromosome 6p, TP53 mutation, HER2-enriched subtype, and immune signatures. Variables predicting resistance included Luminal/ER+ features.Conclusions: Models using RNA only, as well as integrated RNA and DNA models, can predict pCR with improved accuracy over clinical variables. Somatic DNA alterations (mutation, CNAs), tumor molecular subtype (HER2E, Luminal), and the microenvironment (immune cells) were independent predictors of response to trastuzumab and paclitaxel-based regimens. This highlights the complexity of predicting response in HER2-positive breast cancer. Clin Cancer Res; 24(21); 5292-304. ©2018 AACR.

Authors
Tanioka, M; Fan, C; Parker, JS; Hoadley, KA; Hu, Z; Li, Y; Hyslop, TM; Pitcher, BN; Soloway, MG; Spears, PA; Henry, LN; Tolaney, S; Dang, CT; Krop, IE; Harris, LN; Berry, DA; Mardis, ER; Winer, EP; Hudis, CA; Carey, LA; Perou, CM
MLA Citation
Tanioka, Maki, et al. “Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer..” Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, vol. 24, no. 21, Nov. 2018, pp. 5292–304. Epmc, doi:10.1158/1078-0432.ccr-17-3431.
PMID
30037817
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
24
Issue
21
Publish Date
2018
Start Page
5292
End Page
5304
DOI
10.1158/1078-0432.ccr-17-3431

The costs of breast cancer care: Patient-reported experiences and preferences for transparency.

Authors
Greenup, RA; Rushing, C; Fish, L; Hyslop, T; Peppercorn, JM; Wheeler, SB; Zafar, Y; Myers, E; Hwang, E-SS
MLA Citation
Greenup, Rachel Adams, et al. “The costs of breast cancer care: Patient-reported experiences and preferences for transparency..” Journal of Clinical Oncology, vol. 36, no. 30_suppl, American Society of Clinical Oncology (ASCO), 2018, pp. 207–207. Crossref, doi:10.1200/jco.2018.36.30_suppl.207.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
36
Issue
30_suppl
Publish Date
2018
Start Page
207
End Page
207
DOI
10.1200/jco.2018.36.30_suppl.207

Implications for Breast Cancer Restaging Based on the 8th Edition AJCC Staging Manual.

OBJECTIVE:: We assessed the changes that have resulted from the latest breast cancer staging guidelines and the potential impact on prognosis. BACKGROUND: Contemporary data suggest that combining anatomic staging and tumor biology yields a predictive synergy for determining breast cancer prognosis. This forms the basis for the American Joint Committee on Cancer's (AJCC) Staging Manual, 8th edition. We assessed the changes that have resulted from the new staging guidelines and the potential impact on prognosis. METHODS: Women with stages I to III breast cancer from 2010 to 2014 in the National Cancer Data Base were pathologically staged according to the 7th and 8th editions of the AJCC Staging Manual. Patient characteristics and restaging outcomes were summarized. Unadjusted overall survival (OS) was estimated, and differences were assessed. Cox proportional-hazards models were utilized to estimate the adjusted association of stage with OS. RESULTS: After restaging the 493,854 women identified, 6.8% were upstaged and 29.7% were downstaged. The stage changes varied by tumor histology, receptor status, tumor grade, and Oncotype DX scores (all P < 0.0001). Applying the 8th edition criteria yielded an incremental reduction in survival for each increase in stage, which was not consistently seen in the 7th edition. In a subgroup analysis based on hormone receptor (HR) status, those with stages II and III, and HR- disease had a worse OS than those with HR+ disease. CONCLUSIONS: Applying the 8th edition staging criteria resulted in a stage change for >35% of patients diagnosed with invasive breast cancer and refined OS estimates. Overall, the transition to the 8th edition is expected to better drive clinical care, treatment recommendations, and future research.

Authors
Plichta, JK; Ren, Y; Thomas, SM; Greenup, RA; Fayanju, OM; Rosenberger, LH; Hyslop, T; Hwang, ES
MLA Citation
Plichta, Jennifer K., et al. “Implications for Breast Cancer Restaging Based on the 8th Edition AJCC Staging Manual..” Ann Surg, Oct. 2018. Pubmed, doi:10.1097/SLA.0000000000003071.
PMID
30312199
Source
pubmed
Published In
Ann Surg
Publish Date
2018
DOI
10.1097/SLA.0000000000003071

Axillary Nodal Evaluation in Elderly Breast Cancer Patients: Potential Effects on Treatment Decisions and Survival

© 2018, Society of Surgical Oncology. Background: Recent studies suggest that surgical lymph node (LN) evaluation may be omitted in select elderly breast cancer patients as it may not influence adjuvant therapy decisions. To evaluate differences in adjuvant therapy receipt and overall survival (OS), we compared clinically node-negative (cN0) elderly patients who did and did not undergo axillary surgery. Methods: Patients aged ≥70 years in the National Cancer Database (2004–2014) with cT1-3, cN0 breast cancer were divided into two cohorts—those with surgical LN evaluation (one or more nodes removed) and those without (no nodes removed). Propensity scores were used to match patients based on age, year of diagnosis, tumor grade, cT stage, estrogen receptor status, and Charlson–Deyo comorbidity score. A Cox proportional hazards model was used to estimate the effect of LN surgery on OS. Results: Overall, 133,778 patients were matched, of whom 102,247 patients (76.4%) underwent nodal surgery. Patients undergoing nodal surgery were more likely to receive chemotherapy (pN1-3: 22.2%; pN0: 5.8%; cN0-no nodal surgery: 2.8%; p < 0.001), radiation (pN1-3: 49.7%; pN0: 47.5%; cN0-no nodal surgery: 26%; p < 0.001), and endocrine therapy (pN1-3: 72%; pN0: 58.5%; cN0-no nodal surgery: 46.5%; p < 0.001). After adjustment for known covariates, patients who did not undergo nodal surgery had a worse OS (hazard ratio 1.66, 95% confidence interval 1.61–1.70). Conclusions: For elderly cN0 breast cancer patients, axillary surgery was associated with higher rates of adjuvant therapy and improved OS. A selective approach to omitting nodal surgery should be considered in elderly patients with cN0 breast cancer as axillary staging may influence subsequent treatment decisions and long-term outcomes.

Authors
Tamirisa, N; Thomas, SM; Fayanju, OM; Greenup, RA; Rosenberger, LH; Hyslop, T; Hwang, ES; Plichta, JK
MLA Citation
Tamirisa, N., et al. “Axillary Nodal Evaluation in Elderly Breast Cancer Patients: Potential Effects on Treatment Decisions and Survival.” Annals of Surgical Oncology, vol. 25, no. 10, Oct. 2018, pp. 2890–98. Scopus, doi:10.1245/s10434-018-6595-2.
Source
scopus
Published In
Annals of Surgical Oncology
Volume
25
Issue
10
Publish Date
2018
Start Page
2890
End Page
2898
DOI
10.1245/s10434-018-6595-2

Early Stage HER2-Positive Breast Cancers Not Achieving a pCR From Neoadjuvant Trastuzumab- or Pertuzumab-Based Regimens Have an Immunosuppressive Phenotype.

BACKGROUND: Stromal tumor-infiltrating lymphocytes (TILs) might predict pathologic complete response (pCR) in patients with HER2-positive (HER2+) breast cancer treated with trastuzumab (H). Docetaxel (T), carboplatin (C), H, and pertuzumab (P) have immune-modulating effects. Pre- and post-treatment immune biomarkers in cancers treated with neoadjuvant TCH with or without P are lacking. In this study we quantified baseline and changes in TILs, cluster of differentiation (CD) 4+, CD8+, FoxP3+, and PD-L1+ cells using immunohistochemistry (IHC) and quantified productive T-cell receptor β (TCRβ) rearrangements and TCRβ clonality using next-generation sequencing (NGS) in 30 HER2+ breast cancer tissues treated with neoadjuvant H with or without P regimens. MATERIALS AND METHODS: Thirty pre- and post-neoadjuvant TCH (n = 4) or TCHP (n = 26) breast cancer tissues were identified. TILs were quantified manually using hematoxylin and eosin. CD4, CD8, FoxP3, and PD-L1 were stained using IHC. TCRβ was evaluated using NGS. Immune infiltrates were compared between pCR and non-pCR groups using the Wilcoxon rank sum test. RESULTS: A pCR occurred in 15 (n = 15; 50%) cancers (TCH n = 2; TCHP, n = 13). Pretreatment TILs, CD4+, CD8+, FoxP3+, and PD-L1+ cells were not associated with response (P = .42, P = .55, P = .19, P = .66, P = .87, respectively. Pretreatment productive TCRβ and TCRβ clonality did not predict response, P = .84 and P = .40, respectively). However, post-treatment CD4+ and FoxP3+ cells (T-regulatory cells) were elevated in the non-pCR cohort (P = .042 and P = .082, respectively). CONCLUSION: An increase in regulatory T cells in non-pCR tissues suggests the development of an immunosuppressive phenotype. Further investigation in a larger cohort of samples is warranted to validate these findings.

Authors
Force, J; Howie, LJ; Abbott, SE; Bentley, R; Marcom, PK; Kimmick, G; Westbrook, K; Sammons, SL; Parks, M; Topping, DL; Emerson, R; Broadwater, G; Hyslop, T; Blackwell, KL; Nair, SK
MLA Citation
Force, Jeremy, et al. “Early Stage HER2-Positive Breast Cancers Not Achieving a pCR From Neoadjuvant Trastuzumab- or Pertuzumab-Based Regimens Have an Immunosuppressive Phenotype..” Clin Breast Cancer, vol. 18, no. 5, Oct. 2018, pp. 410–17. Pubmed, doi:10.1016/j.clbc.2018.02.010.
PMID
29615305
Source
pubmed
Published In
Clin Breast Cancer
Volume
18
Issue
5
Publish Date
2018
Start Page
410
End Page
417
DOI
10.1016/j.clbc.2018.02.010

Axillary Nodal Evaluation in Elderly Breast Cancer Patients: Potential Effects on Treatment Decisions and Survival.

BACKGROUND: Recent studies suggest that surgical lymph node (LN) evaluation may be omitted in select elderly breast cancer patients as it may not influence adjuvant therapy decisions. To evaluate differences in adjuvant therapy receipt and overall survival (OS), we compared clinically node-negative (cN0) elderly patients who did and did not undergo axillary surgery. METHODS: Patients aged ≥70 years in the National Cancer Database (2004-2014) with cT1-3, cN0 breast cancer were divided into two cohorts-those with surgical LN evaluation (one or more nodes removed) and those without (no nodes removed). Propensity scores were used to match patients based on age, year of diagnosis, tumor grade, cT stage, estrogen receptor status, and Charlson-Deyo comorbidity score. A Cox proportional hazards model was used to estimate the effect of LN surgery on OS. RESULTS: Overall, 133,778 patients were matched, of whom 102,247 patients (76.4%) underwent nodal surgery. Patients undergoing nodal surgery were more likely to receive chemotherapy (pN1-3: 22.2%; pN0: 5.8%; cN0-no nodal surgery: 2.8%; p < 0.001), radiation (pN1-3: 49.7%; pN0: 47.5%; cN0-no nodal surgery: 26%; p < 0.001), and endocrine therapy (pN1-3: 72%; pN0: 58.5%; cN0-no nodal surgery: 46.5%; p < 0.001). After adjustment for known covariates, patients who did not undergo nodal surgery had a worse OS (hazard ratio 1.66, 95% confidence interval 1.61-1.70). CONCLUSIONS: For elderly cN0 breast cancer patients, axillary surgery was associated with higher rates of adjuvant therapy and improved OS. A selective approach to omitting nodal surgery should be considered in elderly patients with cN0 breast cancer as axillary staging may influence subsequent treatment decisions and long-term outcomes.

Authors
Tamirisa, N; Thomas, SM; Fayanju, OM; Greenup, RA; Rosenberger, LH; Hyslop, T; Hwang, ES; Plichta, JK
MLA Citation
Tamirisa, Nina, et al. “Axillary Nodal Evaluation in Elderly Breast Cancer Patients: Potential Effects on Treatment Decisions and Survival..” Ann Surg Oncol, vol. 25, no. 10, 2018, pp. 2890–98. Pubmed, doi:10.1245/s10434-018-6595-2.
PMID
29968029
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
25
Issue
10
Publish Date
2018
Start Page
2890
End Page
2898
DOI
10.1245/s10434-018-6595-2

The Association of Extent of Axillary Surgery and Survival in Women with N2-3 Invasive Breast Cancer.

BACKGROUND: Although surgical management of the axilla for breast cancer continues to evolve, axillary lymphadenectomy remains the standard of care for women with advanced nodal disease. We sought to evaluate national patterns of care in axillary surgery, and its association with overall survival (OS) among women with N2-3 invasive breast cancer. METHODS: Women (18-90 years) with clinical N2-3 invasive breast cancer who underwent axillary surgery were identified from the National Cancer Data Base (NCDB) from 2004 to 2013. Axillary surgery was categorized as sentinel lymph node biopsy (SLNB, 1-5 nodes) or axillary lymph node dissection (ALND, ≥ 10 nodes). Patient and treatment characteristics, trends over time, and overall survival (OS) were compared by surgical treatment. RESULTS: Overall, 22,156 patients were identified. At diagnosis, 68.5% had cN2 and 31.5% had cN3 disease. Treatment included: lumpectomy (27%), mastectomy (73%), adjuvant chemotherapy (53.4%), neoadjuvant chemotherapy (NAC) (39.7%), radiation (74%), and endocrine therapy (54.4%). In total, 9.9% (n = 2190) underwent SLNB and 90.1% (n = 19,966) underwent ALND. Receipt of SLNB was associated with private insurance, grade 3 disease, invasive ductal cancer, NAC, and lumpectomy (all p < 0.001). After adjustment for known covariates, including chemotherapy use, ALND was associated with improved survival [hazard ratio (HR) 0.68, p < 0.001] and this effect was similar for N2 and N3 patients (axillary surgery × cN-stage interaction p = 0.29). CONCLUSIONS: Axillary lymphadenectomy was associated with improved survival in patients presenting with clinical N2-3 invasive breast cancer. Further studies, particularly in the neoadjuvant setting, are needed to identify breast cancer patients with advanced nodal disease who may safely avoid a lesser extent of axillary surgery.

Authors
Park, TS; Thomas, SM; Rosenberger, LH; Fayanju, OM; Plichta, JK; Blitzblau, RC; Ong, CT; Hyslop, T; Hwang, ES; Greenup, RA
MLA Citation
Park, Tristen S., et al. “The Association of Extent of Axillary Surgery and Survival in Women with N2-3 Invasive Breast Cancer..” Ann Surg Oncol, vol. 25, no. 10, Oct. 2018, pp. 3019–29. Pubmed, doi:10.1245/s10434-018-6587-2.
PMID
29978365
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
25
Issue
10
Publish Date
2018
Start Page
3019
End Page
3029
DOI
10.1245/s10434-018-6587-2

The Clinical Significance of Breast-only and Node-only Pathologic Complete Response (pCR) After Neoadjuvant Chemotherapy (NACT): A Review of 20,000 Breast Cancer Patients in the National Cancer Data Base (NCDB).

OBJECTIVE: To determine whether the association between overall survival (OS) and response to neoadjuvant chemotherapy (NACT) in breast cancer patients varies with tumor subtype and anatomic extent of pathologic complete response (pCR). BACKGROUND: pCR after NACT predicts improved OS in breast cancer, but it is unclear whether pCR limited to the breast or axilla is also associated with OS. METHODS: Women with cT1-3/cN0-1 breast cancer diagnosed in 2010 to 2014 who underwent surgery following NACT were identified in the NCDB and divided into 4 subtypes based on reported hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Kaplan-Meier curves and Cox proportional hazards models were used to estimate OS. Multivariate logistic regression was used to identify factors associated with post-NACT response, defined as upstage (yp stage>clinical stage); no change (clinical stage = yp stage); overall (breast+axilla, ypT0N0), breast-only (ypT0N1/N1mic), or node-only (ypT1-3N0) pCR. RESULTS: Of 33,162 identified patients, 20,265 experienced overall pCR (n = 6370, 19.2%), breast-only pCR (n = 494, 1.5%), node-only pCR (n = 1133, 3.4%), no stage change (n = 9641, 29.1%), or upstage (n = 2627, 7.9%). Compared with no stage change, breast-only pCR was associated with improved OS in triple-negative disease [hazard ratio = 0.58, 95% confidence interval (95% CI) = 0.37-0.89], and node-only pCR was associated with improved OS in both triple-negative (hazard ratio = 0.55,95% CI = 0.39-0.76) and HR+/HER2- disease (hazard ratio = 0.54, 95% CI = 0.33-0.89). For patients achieving overall (breast+axilla) pCR, unadjusted 5-year OS was 0.94 (95% CI = 0.93-0.95), with no difference between patients who were cN0 (hazard ratio = 0.95, 95% CI = 0.93-0.96) or cN1 (hazard ratio = 0.94, 95% CI = 0.92-0.96) at diagnosis. CONCLUSIONS: In node-positive patients, pCR limited to either the breast or axilla predicts survival for select receptor subtypes. In patients achieving pCR in both the breast and axilla, survival is driven by response to NACT rather than presenting cN stage.

Authors
Fayanju, OM; Ren, Y; Thomas, SM; Greenup, RA; Plichta, JK; Rosenberger, LH; Tamirisa, N; Force, J; Boughey, JC; Hyslop, T; Hwang, ES
MLA Citation
Fayanju, Oluwadamilola M., et al. “The Clinical Significance of Breast-only and Node-only Pathologic Complete Response (pCR) After Neoadjuvant Chemotherapy (NACT): A Review of 20,000 Breast Cancer Patients in the National Cancer Data Base (NCDB)..” Ann Surg, vol. 268, no. 4, Oct. 2018, pp. 591–601. Pubmed, doi:10.1097/SLA.0000000000002953.
PMID
30048319
Source
pubmed
Published In
Ann Surg
Volume
268
Issue
4
Publish Date
2018
Start Page
591
End Page
601
DOI
10.1097/SLA.0000000000002953

Total Thyroidectomy and Radioactive Iodine for Elderly Patients with Low-Risk Papillary Thyroid Cancer Confers No Survival Benefit over Lobectomy Alone

Authors
Zambeli-Ljepovic, A; Wang, F; Hyslop, T; Roman, SA; Sosa, JA; Scheri, RP
MLA Citation
Zambeli-Ljepovic, Alan, et al. “Total Thyroidectomy and Radioactive Iodine for Elderly Patients with Low-Risk Papillary Thyroid Cancer Confers No Survival Benefit over Lobectomy Alone.” Journal of the American College of Surgeons, vol. 227, no. 4, Elsevier BV, 2018, pp. S88–89. Crossref, doi:10.1016/j.jamcollsurg.2018.07.176.
Source
crossref
Published In
Journal of the American College of Surgeons
Volume
227
Issue
4
Publish Date
2018
Start Page
S88
End Page
S89
DOI
10.1016/j.jamcollsurg.2018.07.176

Modeling qRT-PCR dynamics with application to cancer biomarker quantification.

Quantitative reverse transcription polymerase chain reaction (qRT-PCR) is widely used for molecular diagnostics and evaluating prognosis in cancer. The utility of mRNA expression biomarkers relies heavily on the accuracy and precision of quantification, which is still challenging for low abundance transcripts. The critical step for quantification is accurate estimation of efficiency needed for computing a relative qRT-PCR expression. We propose a new approach to estimating qRT-PCR efficiency based on modeling dynamics of polymerase chain reaction amplification. In contrast, only models for fluorescence intensity as a function of polymerase chain reaction cycle have been used so far for quantification. The dynamics of qRT-PCR efficiency is modeled using an ordinary differential equation model, and the fitted ordinary differential equation model is used to obtain effective polymerase chain reaction efficiency estimates needed for efficiency-adjusted quantification. The proposed new qRT-PCR efficiency estimates were used to quantify GUCY2C (Guanylate Cyclase 2C) mRNA expression in the blood of colorectal cancer patients. Time to recurrence and GUCY2C expression ratios were analyzed in a joint model for survival and longitudinal outcomes. The joint model with GUCY2C quantified using the proposed polymerase chain reaction efficiency estimates provided clinically meaningful results for association between time to recurrence and longitudinal trends in GUCY2C expression.

Authors
Chervoneva, I; Freydin, B; Hyslop, T; Waldman, SA
MLA Citation
Chervoneva, Inna, et al. “Modeling qRT-PCR dynamics with application to cancer biomarker quantification..” Stat Methods Med Res, vol. 27, no. 9, Sept. 2018, pp. 2581–95. Pubmed, doi:10.1177/0962280216683204.
PMID
28504051
Source
pubmed
Published In
Stat Methods Med Res
Volume
27
Issue
9
Publish Date
2018
Start Page
2581
End Page
2595
DOI
10.1177/0962280216683204

Metaplastic Breast Cancer Treatment and Outcomes in 2500 Patients: A Retrospective Analysis of a National Oncology Database.

BACKGROUND: Metaplastic breast cancer (MBC) is characterized by chemoresistance and hematogenous spread. We sought to identify factors associated with improved MBC outcomes and increased likelihood of MBC diagnosis. METHODS: Women ≥ 18 years of age with stage I-III MBC and non-MBC diagnosed between 2010 and 2014 were identified in the National Cancer Data Base. Kaplan-Meier and multivariate Cox proportional hazards models were used to estimate associations with overall survival (OS). Multivariate logistic regression identified factors associated with MBC diagnosis. RESULTS: Overall, 2451 MBC and 568,057 non-MBC patients were included; 70.3% of MBC vs. 11.3% of non-MBC patients were triple negative (p < 0.001). Five-year OS was reduced among MBC vs. non-MBC patients for the entire cohort (72.7 vs. 87.5%) and among triple-negative patients (71.1 vs. 77.8%; both p < 0.001). In MBC, triple-negative (vs. luminal) subtype was not associated with worse OS (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.88-1.54, p = 0.28). Compared with non-MBC patients, MBC patients were more likely to receive mastectomy (59.0 vs. 44.9%), chemotherapy (74.1 vs. 43.1%), and axillary lymph node dissection (ALND; 35.2 vs. 32.2%, all p ≤ 0.001). MBC patients more frequently had negative ALND (pN0) than non-MBC patients (20.0 vs. 10.6%, p < 0.001). Among MBC patients, chemotherapy (HR 0.69, 95% CI 0.53-0.89, p = 0.004) and radiotherapy (HR 0.52, 95% CI 0.39-0.69, p < 0.001) were associated with improved survival, while ALND was associated with decreased survival (HR 1.37, 95% CI 1.06-1.77, p = 0.02). CONCLUSIONS: MBC patients had worse survival than non-MBC patients, independent of receptor status, suggesting that MBC may confer an additional survival disadvantage. Multimodal therapy was associated with improved outcomes, but ALND was not and may be overutilized in MBC.

Authors
Ong, CT; Campbell, BM; Thomas, SM; Greenup, RA; Plichta, JK; Rosenberger, LH; Force, J; Hall, A; Hyslop, T; Hwang, ES; Fayanju, OM
MLA Citation
Ong, Cecilia T., et al. “Metaplastic Breast Cancer Treatment and Outcomes in 2500 Patients: A Retrospective Analysis of a National Oncology Database..” Ann Surg Oncol, vol. 25, no. 8, Aug. 2018, pp. 2249–60. Pubmed, doi:10.1245/s10434-018-6533-3.
PMID
29855830
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
25
Issue
8
Publish Date
2018
Start Page
2249
End Page
2260
DOI
10.1245/s10434-018-6533-3

Single-nucleotide polymorphisms of stemness genes predicted to regulate RNA splicing, microRNA and oncogenic signaling are associated with prostate cancer survival.

Prostate cancer (PCa) is a clinically and molecularly heterogeneous disease, with variation in outcomes only partially predicted by grade and stage. Additional tools to distinguish indolent from aggressive disease are needed. Phenotypic characteristics of stemness correlate with poor cancer prognosis. Given this correlation, we identified single-nucleotide polymorphisms (SNPs) of stemness-related genes and examined their associations with PCa survival. SNPs within stemness-related genes were analyzed for association with overall survival of PCa in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Significant SNPs predicted to be functional were selected for linkage disequilibrium analysis and combined and stratified analyses. Identified SNPs were evaluated for association with gene expression. SNPs of CD44 (rs9666607), ABCC1 (rs35605 and rs212091) and GDF15 (rs1058587) were associated with PCa survival and predicted to be functional. A role for rs9666607 of CD44 and rs35605 of ABCC1 in RNA splicing regulation, rs212091 of ABCC1 in miRNA binding site activity and rs1058587 of GDF15 in causing an amino acid change was predicted. These SNPs represent potential novel prognostic markers for overall survival of PCa and support a contribution of the stemness pathway to PCa patient outcome.

Authors
Freedman, JA; Wang, Y; Li, X; Liu, H; Moorman, PG; George, DJ; Lee, NH; Hyslop, T; Wei, Q; Patierno, SR
MLA Citation
Freedman, Jennifer A., et al. “Single-nucleotide polymorphisms of stemness genes predicted to regulate RNA splicing, microRNA and oncogenic signaling are associated with prostate cancer survival..” Carcinogenesis, vol. 39, no. 7, July 2018, pp. 879–88. Pubmed, doi:10.1093/carcin/bgy062.
Website
https://hdl.handle.net/10161/18503
PMID
29726910
Source
pubmed
Published In
Carcinogenesis
Volume
39
Issue
7
Publish Date
2018
Start Page
879
End Page
888
DOI
10.1093/carcin/bgy062

Tips for Analyzing Large Data Sets From the JAMA Surgery Statistical Editors.

Authors
Kaji, AH; Rademaker, AW; Hyslop, T
MLA Citation
Kaji, Amy H., et al. “Tips for Analyzing Large Data Sets From the JAMA Surgery Statistical Editors..” Jama Surg, vol. 153, no. 6, June 2018, pp. 508–09. Pubmed, doi:10.1001/jamasurg.2018.0647.
PMID
29617520
Source
pubmed
Published In
Jama Surg
Volume
153
Issue
6
Publish Date
2018
Start Page
508
End Page
509
DOI
10.1001/jamasurg.2018.0647

Extent of axillary surgery in women with Stage IV breast cancer

Authors
Lane, W; Thomas, S; Plichta, J; Rosenberger, L; Fayanju, O; Hyslop, T; Hwang, ES; Greenup, R
MLA Citation
Lane, Whitney, et al. “Extent of axillary surgery in women with Stage IV breast cancer.” Annals of Surgical Oncology, vol. 25, SPRINGER, 2018, pp. 291–92.
Source
wos
Published In
Annals of Surgical Oncology
Volume
25
Publish Date
2018
Start Page
291
End Page
292

Overall health at diagnosis predicts the risk of complications within the first year after breast cancer diagnosis and treatment

Authors
Ong, C; Ren, Y; Thomas, S; Stashko, I; Hyslop, T; Goode, V; Kimmick, G; Blitzblau, R; Hwang, E; Grimm, L; Greenup, R
MLA Citation
Ong, Cecilia, et al. “Overall health at diagnosis predicts the risk of complications within the first year after breast cancer diagnosis and treatment.” Annals of Surgical Oncology, vol. 25, SPRINGER, 2018, pp. 314–15.
Source
wos
Published In
Annals of Surgical Oncology
Volume
25
Publish Date
2018
Start Page
314
End Page
315

Immune profiling of BRCA-mutated breast cancers.

Authors
Force, JM; Abbott, S; Broadwater, G; Stashko, I; Westbrook, KE; Kimmick, GG; Sammons, SL; Hyslop, T; Brauer, HA; Mashadi-Hossein, A; Plichta, JK; Hwang, E-SS; Kauff, ND; Weinhold, KJ; Nair, S; Castellar, E; Marcom, PK
MLA Citation
Force, Jeremy Meyer, et al. “Immune profiling of BRCA-mutated breast cancers..” Journal of Clinical Oncology, vol. 36, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2018, pp. 585–585. Crossref, doi:10.1200/jco.2018.36.15_suppl.585.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
36
Issue
15_suppl
Publish Date
2018
Start Page
585
End Page
585
DOI
10.1200/jco.2018.36.15_suppl.585

Restaging de novo metastatic breast cancer to refine prognostic estimates.

Authors
Plichta, JK; Thomas, SM; Sergesketter, AR; Fayanju, OM; Greenup, RA; Rosenberger, LH; Kimmick, GG; Hyslop, T; Hwang, E-SS
MLA Citation
Plichta, Jennifer Kay, et al. “Restaging de novo metastatic breast cancer to refine prognostic estimates..” Journal of Clinical Oncology, vol. 36, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2018, pp. e13083–e13083. Crossref, doi:10.1200/jco.2018.36.15_suppl.e13083.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
36
Issue
15_suppl
Publish Date
2018
Start Page
e13083
End Page
e13083
DOI
10.1200/jco.2018.36.15_suppl.e13083

The impact of chemotherapy sequence on survival in node-positive invasive lobular carcinoma.

Authors
Tamirisa, NP; Vernia, H; Thomas, SM; Westbrook, KE; Greenup, RA; Plichta, JK; Rosenberger, LH; Hyslop, T; Hwang, E-SS; Fayanju, OM
MLA Citation
Tamirisa, Nina Prabha, et al. “The impact of chemotherapy sequence on survival in node-positive invasive lobular carcinoma..” Journal of Clinical Oncology, vol. 36, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2018, pp. 587–587. Crossref, doi:10.1200/jco.2018.36.15_suppl.587.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
36
Issue
15_suppl
Publish Date
2018
Start Page
587
End Page
587
DOI
10.1200/jco.2018.36.15_suppl.587

HIGH RISK ADENOMAS AT BASELINE COLONOSCOPY ASSOCIATED WITH FUTURE ADVANCED ADENOMA DESPITE AN INTERVENING NEGATIVE COLONOSCOPY

Authors
Sullivan, B; Redding, TS; Hauser, ER; Gellad, ZF; Qin, X; Gupta, S; Robertson, DJ; Weiss, DG; O'Leary, MC; Madison, A; Bullard, J; Hyslop, T; Musselwhite, L; Sims, K; Thomas, R; Williams, C; Hong, J; Johnson, M; Turner, M; Provenzale, D; Lieberman, DA
MLA Citation
Sullivan, Brian, et al. “HIGH RISK ADENOMAS AT BASELINE COLONOSCOPY ASSOCIATED WITH FUTURE ADVANCED ADENOMA DESPITE AN INTERVENING NEGATIVE COLONOSCOPY.” Gastroenterology, vol. 154, no. 6, W B SAUNDERS CO-ELSEVIER INC, 2018, pp. S29–S29.
Source
wos
Published In
Gastroenterology
Volume
154
Issue
6
Publish Date
2018
Start Page
S29
End Page
S29

Reply to: "Surgeon Volume Threshold for Total Thyroidectomy".

Authors
Adam, MA; Thomas, S; Youngwirth, L; Hyslop, T; Reed, SD; Scheri, RP; Roman, SA; Sosa, JA
MLA Citation
Adam, Mohamed A., et al. “Reply to: "Surgeon Volume Threshold for Total Thyroidectomy"..” Ann Surg, vol. 267, no. 4, Apr. 2018, pp. e78–79. Pubmed, doi:10.1097/SLA.0000000000002161.
PMID
29517563
Source
pubmed
Published In
Ann Surg
Volume
267
Issue
4
Publish Date
2018
Start Page
e78
End Page
e79
DOI
10.1097/SLA.0000000000002161

Expanded Genomic Profiling of Circulating Tumor Cells in Metastatic Breast Cancer Patients to Assess Biomarker Status and Biology Over Time (CALGB 40502 and CALGB 40503, Alliance).

Purpose: We profiled circulating tumor cells (CTCs) to study the biology of blood-borne metastasis and to monitor biomarker status in metastatic breast cancer (MBC).Methods: CTCs were isolated from 105 patients with MBC using EPCAM-based immunomagnetic enrichment and fluorescence-activated cells sorting (IE/FACS), 28 of whom had serial CTC analysis (74 samples, 2-5 time points). CTCs were subjected to microfluidic-based multiplex QPCR array of 64 cancer-related genes (n = 151) and genome-wide copy-number analysis by array comparative genomic hybridization (aCGH; n = 49).Results: Combined transcriptional and genomic profiling showed that CTCs were 26% ESR1-ERBB2-, 48% ESR1+ERBB2-, and 27% ERBB2+ Serial testing showed that ERBB2 status was more stable over time compared with ESR1 and proliferation (MKI67) status. While cell-to-cell heterogeneity was observed at the single-cell level, with increasingly stable expression in larger pools, patient-specific CTC expression "fingerprints" were also observed. CTC copy-number profiles clustered into three groups based on the extent of genomic aberrations and the presence of large chromosomal imbalances. Comparative analysis showed discordance in ESR1/ER (27%) and ERBB2/HER2 (23%) status between CTCs and matched primary tumors. CTCs in 65% of the patients were considered to have low proliferation potential. Patients who harbored CTCs with high proliferation (MKI67) status had significantly reduced progression-free survival (P = 0.0011) and overall survival (P = 0.0095) compared with patients with low proliferative CTCs.Conclusions: We demonstrate an approach for complete isolation of EPCAM-positive CTCs and downstream comprehensive transcriptional/genomic characterization to examine the biology and assess breast cancer biomarkers in these cells over time. Clin Cancer Res; 24(6); 1486-99. ©2018 AACR.

Authors
Magbanua, MJM; Rugo, HS; Wolf, DM; Hauranieh, L; Roy, R; Pendyala, P; Sosa, EV; Scott, JH; Lee, JS; Pitcher, B; Hyslop, T; Barry, WT; Isakoff, SJ; Dickler, M; Van't Veer, L; Park, JW
MLA Citation
Magbanua, Mark Jesus M., et al. “Expanded Genomic Profiling of Circulating Tumor Cells in Metastatic Breast Cancer Patients to Assess Biomarker Status and Biology Over Time (CALGB 40502 and CALGB 40503, Alliance)..” Clin Cancer Res, vol. 24, no. 6, Mar. 2018, pp. 1486–99. Pubmed, doi:10.1158/1078-0432.CCR-17-2312.
PMID
29311117
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
24
Issue
6
Publish Date
2018
Start Page
1486
End Page
1499
DOI
10.1158/1078-0432.CCR-17-2312

Role of Preoperative Variables in Reducing the Rate of Occult Invasive Disease for Women Considering Active Surveillance for Ductal Carcinoma In Situ.

Authors
Grimm, LJ; Ryser, MD; Hyslop, T
MLA Citation
Grimm, Lars J., et al. “Role of Preoperative Variables in Reducing the Rate of Occult Invasive Disease for Women Considering Active Surveillance for Ductal Carcinoma In Situ..” Jama Surg, vol. 153, no. 3, Mar. 2018, pp. 290–91. Pubmed, doi:10.1001/jamasurg.2017.5566.
PMID
29344621
Source
pubmed
Published In
Jama Surg
Volume
153
Issue
3
Publish Date
2018
Start Page
290
End Page
291
DOI
10.1001/jamasurg.2017.5566

Incidence and mortality among breast cancer patients < 40 years old: US trends from 1992-2014

Authors
Oyekunle, TO; Thomas, SM; Greenup, RA; Hyslop, T; Blackwell, K
MLA Citation
Oyekunle, Taofik O., et al. “Incidence and mortality among breast cancer patients < 40 years old: US trends from 1992-2014.” Cancer Research, vol. 78, no. 4, AMER ASSOC CANCER RESEARCH, 2018.
Source
wos
Published In
Cancer Research
Volume
78
Issue
4
Publish Date
2018

Quantifying the natural history and overtreatment rate of ductal carcinoma in situ

Authors
Ryser, MD; Weaver, DL; Marks, JR; Hyslop, T; Hwang, ES
MLA Citation
Ryser, Marc D., et al. “Quantifying the natural history and overtreatment rate of ductal carcinoma in situ.” Cancer Research, vol. 78, no. 4, AMER ASSOC CANCER RESEARCH, 2018.
Source
wos
Published In
Cancer Research
Volume
78
Issue
4
Publish Date
2018

Primary endocrine therapy for ER-positive ductal carcinoma in situ (DCIS) CALGB 40903 (Alliance)

Authors
Hwang, ES; Duong, S; Bedrosian, I; Allred, J; Wisner, D; Hyslop, T; Caudle, A; Guenther, J; Hudis, C; Winer, E; Esserman, L; Hylton, N
MLA Citation
Hwang, E. Shelley, et al. “Primary endocrine therapy for ER-positive ductal carcinoma in situ (DCIS) CALGB 40903 (Alliance).” Cancer Research, vol. 78, no. 4, AMER ASSOC CANCER RESEARCH, 2018.
Source
wos
Published In
Cancer Research
Volume
78
Issue
4
Publish Date
2018

Trajectory patterns of circulating tumor cells (CTC) in chemotherapy-treated metastatic breast cancer (MBC) patients predict poor clinical outcomes: CALGB 40502 (Alliance)/NCCTG N063H study

Authors
Magbanua, MJ; Hendrix, L; Hyslop, T; Barry, WT; Winer, EP; Hudis, C; Toppmeyer, D; Burnstein, H; Qadir, M; Ma, C; Scott, JH; Park, JW; Rugo, HS
MLA Citation
Magbanua, Mark J., et al. “Trajectory patterns of circulating tumor cells (CTC) in chemotherapy-treated metastatic breast cancer (MBC) patients predict poor clinical outcomes: CALGB 40502 (Alliance)/NCCTG N063H study.” Cancer Research, vol. 78, no. 4, AMER ASSOC CANCER RESEARCH, 2018.
Source
wos
Published In
Cancer Research
Volume
78
Issue
4
Publish Date
2018

Treatment Patterns and Outcomes for Breast Cancer with Isolated Supraclavicular Metastases

Authors
Thomas, SM; Fayanju, OM; Plichta, JK; Rosenberger, LH; Force, J; Hyslop, T; Hwang, ES; Greenup, RA
MLA Citation
Thomas, S. M., et al. “Treatment Patterns and Outcomes for Breast Cancer with Isolated Supraclavicular Metastases.” Annals of Surgical Oncology, vol. 25, SPRINGER, 2018, pp. S26–S26.
Source
wos
Published In
Annals of Surgical Oncology
Volume
25
Publish Date
2018
Start Page
S26
End Page
S26

Clinical and Pathologic Stage Discordance is Associated with Breast Cancer Prognosis

Authors
Plichta, JK; Thomas, SM; Greenup, RA; Fayanju, OM; Rosenberger, LH; Tamirisa, N; Hyslop, T; Hwang, ES
MLA Citation
Plichta, J. K., et al. “Clinical and Pathologic Stage Discordance is Associated with Breast Cancer Prognosis.” Annals of Surgical Oncology, vol. 25, SPRINGER, 2018, pp. S94–S94.
Source
wos
Published In
Annals of Surgical Oncology
Volume
25
Publish Date
2018
Start Page
S94
End Page
S94

Breast Cancer Treatment Costs: Surgical Decisions and Preferences for Transparency

Authors
Greenup, RA; Rushing, CN; Fish, LJ; Campbell, B; Hyslop, T; Peppercorn, JM; Myers, ER; Zafar, Y; Hwang, ES
MLA Citation
Greenup, R. A., et al. “Breast Cancer Treatment Costs: Surgical Decisions and Preferences for Transparency.” Annals of Surgical Oncology, vol. 25, SPRINGER, 2018, pp. S15–S15.
Source
wos
Published In
Annals of Surgical Oncology
Volume
25
Publish Date
2018
Start Page
S15
End Page
S15

The Effect of Hospital Volume on Breast Cancer Mortality.

OBJECTIVE: The aim of this study was to determine whether hospital volume was associated with mortality in breast cancer, and what thresholds of case volume impacted survival. BACKGROUND: Prior literature has demonstrated improved survival with treatment at high volume centers among less common cancers requiring technically complex surgery. METHODS: All adults (18 to 90 years) with stages 0-III unilateral breast cancer diagnosed from 2004 to 2012 were identified from the American College of Surgeons National Cancer Data Base (NCDB). A multivariable Cox proportional hazards model with restricted cubic splines was used to examine the association of annual hospital volume and overall survival, after adjusting for measured covariates. Intergroup comparisons of patient and treatment characteristics were conducted with X and analysis of variance (ANOVA). The log-rank test was used to test survival differences between groups. A multivariable Cox proportional hazards model was used to estimate hazard ratios (HRs) associated with each volume group. RESULTS: One million sixty-four thousand two hundred and fifty-one patients met inclusion criteria. The median age of the sample was 60 (interquartile range 50 to 70). Hospitals were categorized into 3 groups using restricted cubic spline analysis: low-volume (<148 cases/year), moderate-volume (148 to 298 cases/year), and high-volume (>298 cases/year). Treatment at high volume centers was associated with an 11% reduction in overall mortality for all patients (HR 0.89); those with stage 0-I, ER+/PR+ or ER+/PR- breast cancers derived the greatest benefit. CONCLUSIONS: Treatment at high volume centers is associated with improved survival for breast cancer patients regardless of stage. High case volume could serve as a proxy for the institutional infrastructure required to deliver complex multidisciplinary breast cancer treatment.

Authors
Greenup, RA; Obeng-Gyasi, S; Thomas, S; Houck, K; Lane, WO; Blitzblau, RC; Hyslop, T; Hwang, ES
MLA Citation
Greenup, Rachel A., et al. “The Effect of Hospital Volume on Breast Cancer Mortality..” Ann Surg, vol. 267, no. 2, Feb. 2018, pp. 375–81. Pubmed, doi:10.1097/SLA.0000000000002095.
PMID
27893532
Source
pubmed
Published In
Ann Surg
Volume
267
Issue
2
Publish Date
2018
Start Page
375
End Page
381
DOI
10.1097/SLA.0000000000002095

Genetic variants in the metzincin metallopeptidase family genes predict melanoma survival.

Metzincins are key molecules in the degradation of the extracellular matrix and play an important role in cellular processes such as cell migration, adhesion, and cell fusion of malignant tumors, including cutaneous melanoma (CM). We hypothesized that genetic variants of the metzincin metallopeptidase family genes would be associated with CM-specific survival (CMSS). To test this hypothesis, we first performed Cox proportional hazards regression analysis to evaluate the associations between genetic variants of 75 metzincin metallopeptidase family genes and CMSS using the dataset from the genome-wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC) which included 858 non-Hispanic white patients with CM, and then validated using the dataset from the Harvard GWAS study which had 409 non-Hispanic white patients with invasive CM. Four independent SNPs (MMP16 rs10090371 C>A, ADAMTS3 rs788935 T>C, TLL2 rs10882807 T>C and MMP9 rs3918251 A>G) were identified as predictors of CMSS, with a variant-allele attributed hazards ratio (HR) of 1.73 (1.32-2.29, 9.68E-05), 1.46 (1.15-1.85, 0.002), 1.68 (1.31-2.14, 3.32E-05) and 0.67 (0.51-0.87, 0.003), respectively, in the meta-analysis of these two GWAS studies. Combined analysis of risk genotypes of these four SNPs revealed a decreased CMSS in a dose-response manner as the number of risk genotypes increased (Ptrend  < 0.001). An improvement was observed in the prediction model (area under the curve [AUC] = 81.4% vs. 78.6%), when these risk genotypes were added to the model containing non-genotyping variables. Our findings suggest that these genetic variants may be promising prognostic biomarkers for CMSS.

Authors
Xu, Y; Wang, Y; Liu, H; Shi, Q; Zhu, D; Amos, CI; Fang, S; Lee, JE; Hyslop, T; Li, X; Han, J; Wei, Q
MLA Citation
Xu, Yinghui, et al. “Genetic variants in the metzincin metallopeptidase family genes predict melanoma survival..” Mol Carcinog, vol. 57, no. 1, Jan. 2018, pp. 22–31. Pubmed, doi:10.1002/mc.22716.
Website
https://hdl.handle.net/10161/18518
PMID
28796414
Source
pubmed
Published In
Molecular Carcinogenesis
Volume
57
Issue
1
Publish Date
2018
Start Page
22
End Page
31
DOI
10.1002/mc.22716

Patient Age and Tumor Subtype Predict the Extent of Axillary Surgery Among Breast Cancer Patients Eligible for the American College of Surgeons Oncology Group Trial Z0011.

BACKGROUND: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial established the safety of omitting axillary lymph node dissection (ALND) for early-stage breast cancer patients with limited nodal disease undergoing lumpectomy. We examined the extent of axillary surgery among women eligible for Z0011 based on patient age and tumor subtype. METHODS: Patients with cT1-2, cN0 breast cancers and one or two positive nodes diagnosed from 2009 to 2014 and treated with lumpectomy were identified in the National Cancer Data Base. Sentinel lymph node biopsy (SLNB) was defined as the removal of 1-5 nodes and ALND as the removal of 10 nodes or more. Tumor subtype was categorized as luminal, human epidermal growth factor 2-positive (HER2+), or triple-negative. Logistic regression was used to estimate the odds of receiving SLNB alone versus ALND. RESULTS: The inclusion criteria were met by 28,631 patients (21,029 SLNB-alone and 7602 ALND patients). Patients 70 years of age or older were more likely to undergo SLNB alone than ALND (27.0% vs 20.1%; p < 0.001). The radiation therapy use rate was 89.4% after SLNB alone and 89.7% after ALND. In the multivariate analysis, the uptake of Z0011 recommendations increased over time (2014 vs 2009: odds ratio [OR] 13.02; p < 0.001). Younger patients were less likely to undergo SLNB alone than older patients (age <40 vs ≥70: OR 0.59; p < 0.001). Patients with HER2+ (OR 0.89) or triple-negative disease (OR 0.79) (p < 0.001) were less likely to undergo SLNB alone than those with luminal subtypes. CONCLUSIONS: Among women potentially eligible for ACOSOG Z0011, the use of SLNB alone increased over time in all groups, but the extent of axillary surgery differed by patient age and tumor subtype.

Authors
Ong, CT; Thomas, SM; Blitzblau, RC; Fayanju, OM; Park, TS; Plichta, JK; Rosenberger, LH; Hyslop, T; Shelley Hwang, E; Greenup, RA
MLA Citation
Ong, Cecilia T., et al. “Patient Age and Tumor Subtype Predict the Extent of Axillary Surgery Among Breast Cancer Patients Eligible for the American College of Surgeons Oncology Group Trial Z0011..” Ann Surg Oncol, vol. 24, no. 12, Nov. 2017, pp. 3559–66. Pubmed, doi:10.1245/s10434-017-6075-0.
PMID
28879416
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
24
Issue
12
Publish Date
2017
Start Page
3559
End Page
3566
DOI
10.1245/s10434-017-6075-0

GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.

High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. Eliminating GUCY2C signaling exacerbated RIGS, amplifying radiation-induced mortality, weight loss, mucosal bleeding, debilitation, and intestinal dysfunction. Durable expression of GUCY2C, guanylin, and uroguanylin mRNA and protein by intestinal epithelial cells was preserved following lethal irradiation inducing RIGS. Oral delivery of the heat-stable enterotoxin (ST), an exogenous GUCY2C ligand, opposed RIGS, a process requiring p53 activation mediated by dissociation from MDM2. In turn, p53 activation prevented cell death by selectively limiting mitotic catastrophe, but not apoptosis. These studies reveal a role for the GUCY2C paracrine hormone axis as a novel compensatory mechanism opposing RIGS, and they highlight the potential of oral GUCY2C agonists (Linzess; Trulance) to prevent and treat RIGS in cancer therapy and nuclear disasters. Cancer Res; 77(18); 5095-106. ©2017 AACR.

Authors
Li, P; Wuthrick, E; Rappaport, JA; Kraft, C; Lin, JE; Marszalowicz, G; Snook, AE; Zhan, T; Hyslop, TM; Waldman, SA
MLA Citation
Li, Peng, et al. “GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome..” Cancer Res, vol. 77, no. 18, Sept. 2017, pp. 5095–106. Pubmed, doi:10.1158/0008-5472.CAN-17-0859.
PMID
28916678
Source
pubmed
Published In
Cancer Res
Volume
77
Issue
18
Publish Date
2017
Start Page
5095
End Page
5106
DOI
10.1158/0008-5472.CAN-17-0859

Rethinking the Current American Joint Committee on Cancer TNM Staging System for Medullary Thyroid Cancer.

Importance: Controversy exists around the American Joint Committee on Cancer (AJCC) TNM staging system for medullary thyroid cancer (MTC). Because of the rarity of the disease and limited available data, the staging system for MTC has been largely extrapolated from staging for differentiated thyroid cancer. Objectives: To evaluate how well the current (seventh and eighth editions) AJCC TNM staging system correlates with survival for patients with MTC and to suggest a possible revision. Design, Setting, and Participants: This population-based retrospective cohort analysis used the National Cancer Database to select patients aged 18 years or older diagnosed with MTC in the United States between 1998 and 2012. Patient demographic and tumor characteristics were assessed, and pathologic tumor stages were provided as T, N, and M categories. Recursive partitioning with bootstrapping was used to divide patients by TNM stages into groups with similar survival. The newly identified groupings were validated in a Surveillance, Epidemiology, and End Results (SEER) cohort. Data analysis was conducted between July 17, 2016, and November 11, 2016. Main Outcomes and Measures: Overall survival and disease-specific survival. Results: Of the 3315 patients with MTC included in the analysis, 1941 (58.6%) were women. The median (interquartile range) age was 54 (42-65) years, and 2839 (85.6%) self-reported their race/ethnicity as white. The current AJCC TNM staging system classified 941 of these patients (28.4%) as stage I, 907 (27.4%) as stage II, 424 (12.9%) as stage III, and 1043 (31.5%) as stage IV. Recursive partitioning analysis yielded 4 TNM groups: stage I (T1N0-1aM0, T2N0M0), stage II (T1N1bM0, T2N1a-bM0, and T3N0M0), stage III (T3N1a-bM0, T4N0-1bM0), and stage IV (T1-4N0-1bM1). Based on these proposed TNM groupings, 1797 of the 3315 patients (54.2%) were classified as stage I, 684 (20.6%) as stage II, 669 (20.2%) as stage III, and 165 (5.0%) as stage IV. Under the proposed TNM groupings, survival differences across TNM groups were more distinct than under the current AJCC TNM staging system. With stage I as the reference, the hazard ratios of the proposed TNM groupings and the current AJCC TNM staging system were 2.19 (95% CI, 1.37-3.12) vs 1.45 (95% CI, 1.09-1.92) for stage II, 4.20 (95% CI, 2.75-5.75) vs 2.17 (95% CI, 1.59-2.89) for stage III, and 10.97 (95% CI, 5.52-18.57) vs 5.33 (95% CI, 4.13-6.86) for stage IV. In a SEER cohort, the proposed TNM groupings were better at discriminating survival than was the current AJCC TNM staging system. Conclusions and Relevance: The current AJCC TNM staging system for MTC appears to be less than optimal in distinguishing risk of mortality among stage groups, upstaging a significant number of patients to stage IV. The current AJCC TNM staging system could be improved with the new TNM groupings proposed here for more accurate risk stratification and potential treatment selection.

Authors
Adam, MA; Thomas, S; Roman, SA; Hyslop, T; Sosa, JA
MLA Citation
Adam, Mohamed Abdelgadir, et al. “Rethinking the Current American Joint Committee on Cancer TNM Staging System for Medullary Thyroid Cancer..” Jama Surg, vol. 152, no. 9, Sept. 2017, pp. 869–76. Pubmed, doi:10.1001/jamasurg.2017.1665.
PMID
28636692
Source
pubmed
Published In
Jama Surg
Volume
152
Issue
9
Publish Date
2017
Start Page
869
End Page
876
DOI
10.1001/jamasurg.2017.1665

The Financial Burden of Breast Cancer Treatment

Authors
Greenup, RA; Fish, L; Rushing, C; Peppercorn, J; Hyslop, T; Zafar, Y; Hwang, ES
MLA Citation
Greenup, Rachel Adams, et al. “The Financial Burden of Breast Cancer Treatment.” Journal of Womens Health, vol. 26, no. 9, MARY ANN LIEBERT, INC, 2017, pp. 1022–1022.
Source
wos
Published In
Journal of Women'S Health (2002)
Volume
26
Issue
9
Publish Date
2017
Start Page
1022
End Page
1022

Associations between RNA splicing regulatory variants of stemness-related genes and racial disparities in susceptibility to prostate cancer.

Evidence suggests that cells with a stemness phenotype play a pivotal role in oncogenesis, and prostate cells exhibiting this phenotype have been identified. We used two genome-wide association study (GWAS) datasets of African descendants, from the Multiethnic/Minority Cohort Study of Diet and Cancer (MEC) and the Ghana Prostate Study, and two GWAS datasets of non-Hispanic whites, from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the Breast and Prostate Cancer Cohort Consortium (BPC3), to analyze the associations between genetic variants of stemness-related genes and racial disparities in susceptibility to prostate cancer. We evaluated associations of single-nucleotide polymorphisms (SNPs) in 25 stemness-related genes with prostate cancer risk in 1,609 cases and 2,550 controls of non-Hispanic whites (4,934 SNPs) and 1,144 cases and 1,116 controls of African descendants (5,448 SNPs) with correction by false discovery rate ≤0.2. We identified 32 SNPs in five genes (TP63, ALDH1A1, WNT1, MET and EGFR) that were significantly associated with prostate cancer risk, of which six SNPs in three genes (TP63, ALDH1A1 and WNT1) and eight EGFR SNPs showed heterogeneity in susceptibility between these two racial groups. In addition, 13 SNPs in MET and one in ALDH1A1 were found only in African descendants. The in silico bioinformatics analyses revealed that EGFR rs2072454 and SNPs in linkage with the identified SNPs in MET and ALDH1A1 (r2  > 0.6) were predicted to regulate RNA splicing. These variants may serve as novel biomarkers for racial disparities in prostate cancer risk.

Authors
Wang, Y; Freedman, JA; Liu, H; Moorman, PG; Hyslop, T; George, DJ; Lee, NH; Patierno, SR; Wei, Q
MLA Citation
Wang, Yanru, et al. “Associations between RNA splicing regulatory variants of stemness-related genes and racial disparities in susceptibility to prostate cancer..” Int J Cancer, vol. 141, no. 4, Aug. 2017, pp. 731–43. Pubmed, doi:10.1002/ijc.30787.
PMID
28510291
Source
pubmed
Published In
Int J Cancer
Volume
141
Issue
4
Publish Date
2017
Start Page
731
End Page
743
DOI
10.1002/ijc.30787

Genetic variants in the genes encoding rho GTPases and related regulators predict cutaneous melanoma-specific survival.

Rho GTPases control cell division, motility, adhesion, vesicular trafficking and phagocytosis, which may affect progression and/or prognosis of cancers. Here, we investigated associations between genetic variants of Rho GTPases-related genes and cutaneous melanoma-specific survival (CMSS) by re-analyzing a published melanoma genome-wide association study (GWAS) and validating the results in another melanoma GWAS. In the single-locus analysis of 36,018 SNPs in 129 Rho-related genes, 427 SNPs were significantly associated with CMSS (p < 0.050 and false-positive report probability <0.2) in the discovery dataset, and five SNPs were replicated in the validation dataset. Among these, four SNPs (i.e., RHOU rs10916352 G > C, ARHGAP22 rs3851552 T > C, ARHGAP44 rs72635537 C > T and ARHGEF10 rs7826362 A > T) were independently predictive of CMSS (a meta-analysis derived p = 9.04 × 10-4 , 9.58 × 10-4 , 1.21 × 10-4 and 8.47 × 10-4 , respectively). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had markedly reduced CMSS in both discovery dataset and validation dataset (ptrend =1.47 × 10-7 and 3.12 × 10-5 ). The model including the NUGs and clinical variables demonstrated a significant improvement in predicting the five-year CMSS. Moreover, rs10916352C and rs3851552C alleles were significantly associated with an increased mRNA expression levels of RHOU (p = 1.8 × 10-6 ) and ARHGAP22 (p = 5.0 × 10-6 ), respectively. These results may provide promising prognostic biomarkers for CM personalized management and treatment.

Authors
Liu, S; Wang, Y; Xue, W; Liu, H; Xu, Y; Shi, Q; Wu, W; Zhu, D; Amos, CI; Fang, S; Lee, JE; Hyslop, T; Li, Y; Han, J; Wei, Q
MLA Citation
Liu, Shun, et al. “Genetic variants in the genes encoding rho GTPases and related regulators predict cutaneous melanoma-specific survival..” Int J Cancer, vol. 141, no. 4, Aug. 2017, pp. 721–30. Pubmed, doi:10.1002/ijc.30785.
PMID
28510328
Source
pubmed
Published In
Int J Cancer
Volume
141
Issue
4
Publish Date
2017
Start Page
721
End Page
730
DOI
10.1002/ijc.30785

Transplantation of Ex Vivo Expanded Umbilical Cord Blood (NiCord) Decreases Early Infection and Hospitalization.

Delayed hematopoietic recovery contributes to increased infection risk following umbilical cord blood (UCB) transplantation. In a Phase 1 study, adult recipients of UCB stem cells cultured ex vivo for 3 weeks with nicotinamide (NiCord) had earlier median neutrophil recovery compared with historical controls. To evaluate the impact of faster neutrophil recovery on clinically relevant early outcomes, we reviewed infection episodes and hospitalization during the first 100 days in an enlarged cohort of 18 NiCord recipients compared with 86 standard UCB recipients at our institution. The median time to neutrophil engraftment was shorter in NiCord recipients compared with standard UCB recipients (12.5 days versus 26 days; P < .001). Compared with standard UCB recipients, NiCord recipients had a significantly reduced risk for total infection (RR, 0.69; P = .01), grade 2-3 (moderate to severe) infection (RR, 0.36; P < .001), bacterial infection (RR, 0.39; P = .003), and grade 2-3 bacterial infection (RR, 0.21; P = .003) by Poisson regression analysis; this effect persisted after adjustment for age, disease stage, and grade II-IV acute GVHD. NiCord recipients also had significantly more time out of the hospital in the first 100 days post-transplantation after adjustment for age and Karnofsky Performance Status (69.9 days versus 49.7 days; P = .005). Overall, transplantation of NiCord was associated with faster neutrophil engraftment, fewer total and bacterial infections, and shorter hospitalization in the first 100 days compared with standard UCB transplantation. In conclusion, rapid hematopoietic recovery from an ex vivo expanded UCB transplantation approach is associated with early clinical benefit.

Authors
Anand, S; Thomas, S; Hyslop, T; Adcock, J; Corbet, K; Gasparetto, C; Lopez, R; Long, GD; Morris, AK; Rizzieri, DA; Sullivan, KM; Sung, AD; Sarantopoulos, S; Chao, NJ; Horwitz, ME
MLA Citation
Anand, Sarah, et al. “Transplantation of Ex Vivo Expanded Umbilical Cord Blood (NiCord) Decreases Early Infection and Hospitalization..” Biol Blood Marrow Transplant, vol. 23, no. 7, July 2017, pp. 1151–57. Pubmed, doi:10.1016/j.bbmt.2017.04.001.
PMID
28392378
Source
pubmed
Published In
Biol Blood Marrow Transplant
Volume
23
Issue
7
Publish Date
2017
Start Page
1151
End Page
1157
DOI
10.1016/j.bbmt.2017.04.001

Evaluating the addition of bevacizumab (Bev) to endocrine therapy as first-line treatment for hormone-receptor positive (HR+)/HER2-negative advanced breast cancer (ABC): Pooled-analysis from the LEA (GEICAM/2006-11_GBG51) and CALGB 40503 (Alliance) trials.

Authors
Martin, M; Loibl, S; Hyslop, T; de la Haba-Rodriguez, J; Aktas, B; Cirrincione, C; Carrasco, EM; Mehta, K; Barry, WT; Morales, S; Carey, LA; Garcia Saenz, JA; Partridge, A; Martinez, N; Hahn, OM; Winer, EP; Guerrero, A; Hudis, C; Casas, M; Dickler, MN
MLA Citation
Martin, Miguel, et al. “Evaluating the addition of bevacizumab (Bev) to endocrine therapy as first-line treatment for hormone-receptor positive (HR+)/HER2-negative advanced breast cancer (ABC): Pooled-analysis from the LEA (GEICAM/2006-11_GBG51) and CALGB 40503 (Alliance) trials..” Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. 1012–1012. Crossref, doi:10.1200/jco.2017.35.15_suppl.1012.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
15_suppl
Publish Date
2017
Start Page
1012
End Page
1012
DOI
10.1200/jco.2017.35.15_suppl.1012

A population-based analysis of treatment and outcomes in 2,500 metaplastic breast cancer patients.

Authors
Ong, CT; Thomas, SM; Campbell, BM; Greenup, RA; Plichta, JK; Rosenberger, LH; Force, JM; Hyslop, T; Hwang, E-SS; Fayanju, OM
MLA Citation
Ong, Cecilia Tuongquang, et al. “A population-based analysis of treatment and outcomes in 2,500 metaplastic breast cancer patients..” Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. 532–532. Crossref, doi:10.1200/jco.2017.35.15_suppl.532.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
15_suppl
Publish Date
2017
Start Page
532
End Page
532
DOI
10.1200/jco.2017.35.15_suppl.532

The epidemiology of metaplastic breast cancer: A review of 2,500 cases from the national cancer database.

Authors
Campbell, BM; Thomas, SM; Ong, CT; Greenup, RA; Plichta, JK; Rosenberger, LH; Force, JM; Hyslop, T; Hwang, E-SS; Fayanju, OM
MLA Citation
Campbell, Brittany Morgan, et al. “The epidemiology of metaplastic breast cancer: A review of 2,500 cases from the national cancer database..” Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. 1570–1570. Crossref, doi:10.1200/jco.2017.35.15_suppl.1570.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
15_suppl
Publish Date
2017
Start Page
1570
End Page
1570
DOI
10.1200/jco.2017.35.15_suppl.1570

Number of tumor-infiltrating lymphocytes in breast cancer brain metastases compared to matched breast primaries.

Authors
Narloch, J; Luedke, C; Broadwater, G; Priedigkeit, N; Hall, A; Hyslop, T; Sammons, SL; Huggins-Puhalla, SL; Leone, JP; Ramirez, J; Kirkpatrick, JP; Ewend, MG; Fecci, PE; Brufsky, A; Lee, AV; Anders, CK; Blackwell, KL
MLA Citation
Narloch, Jessie, et al. “Number of tumor-infiltrating lymphocytes in breast cancer brain metastases compared to matched breast primaries..” Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. 2049–2049. Crossref, doi:10.1200/jco.2017.35.15_suppl.2049.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
15_suppl
Publish Date
2017
Start Page
2049
End Page
2049
DOI
10.1200/jco.2017.35.15_suppl.2049

Temporal associations between prognostic indicators and overall survival after breast cancer.

Authors
Plichta, JK; Thomas, SM; Fayanju, OM; Rosenberger, LH; Park, TS; Hyslop, T; Greenup, RA; Hwang, E-SS
MLA Citation
Plichta, Jennifer Kay, et al. “Temporal associations between prognostic indicators and overall survival after breast cancer..” Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. e18144–e18144. Crossref, doi:10.1200/jco.2017.35.15_suppl.e18144.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
15_suppl
Publish Date
2017
Start Page
e18144
End Page
e18144
DOI
10.1200/jco.2017.35.15_suppl.e18144

Impact of insurance status on treatment for stage 0-IV breast cancer.

Authors
Greenup, RA; Thomas, SM; Fayanju, OM; Hyslop, T; Hwang, E-SS
MLA Citation
Greenup, Rachel Adams, et al. “Impact of insurance status on treatment for stage 0-IV breast cancer..” Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. 6532–6532. Crossref, doi:10.1200/jco.2017.35.15_suppl.6532.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
15_suppl
Publish Date
2017
Start Page
6532
End Page
6532
DOI
10.1200/jco.2017.35.15_suppl.6532

Validation of the NCI colorectal cancer risk assessment tool in the CSP 380 veterans cohort.

Authors
Musselwhite, LW; Redding, TS; Sims, KJ; O'Leary, M; Hauser, ER; Hyslop, T; Lieberman, DA; Provenzale, DT
MLA Citation
Musselwhite, Laura W., et al. “Validation of the NCI colorectal cancer risk assessment tool in the CSP 380 veterans cohort..” Journal of Clinical Oncology, vol. 35, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. e15135–e15135. Crossref, doi:10.1200/jco.2017.35.15_suppl.e15135.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
35
Issue
15_suppl
Publish Date
2017
Start Page
e15135
End Page
e15135
DOI
10.1200/jco.2017.35.15_suppl.e15135

The Impact of Axillary Surgery on Women with N2-N3 Invasive Breast Cancer

Authors
Park, T; Thomas, S; Rosenberger, L; Fayanju, O; Plichta, J; Ong, C; Hyslop, T; Hwang, ES; Greenup, R
MLA Citation
Park, Tristen, et al. “The Impact of Axillary Surgery on Women with N2-N3 Invasive Breast Cancer.” Annals of Surgical Oncology, vol. 24, SPRINGER, 2017, pp. 162–63.
Source
wos
Published In
Annals of Surgical Oncology
Volume
24
Publish Date
2017
Start Page
162
End Page
163

Surgical resection of the primary tumor in women with stage IV breast cancer: Contemporary practice patterns and survival analysis

Authors
Lane, W; Thomas, SM; Plichta, JK; Fayanju, OM; Rosenberger, LH; Hyslop, T; Hwang, ES; Greenup, RA
MLA Citation
Lane, Whitney, et al. “Surgical resection of the primary tumor in women with stage IV breast cancer: Contemporary practice patterns and survival analysis.” Annals of Surgical Oncology, vol. 24, SPRINGER, 2017, pp. 46–46.
Source
wos
Published In
Annals of Surgical Oncology
Volume
24
Publish Date
2017
Start Page
46
End Page
46

Patient age and tumor subtype predicts adherence to ACOSOG Z0011 recommendations: Analysis of national practice patterns

Authors
Ong, C; Thomas, S; Rosenberger, L; Park, T; Plichta, J; Fayanju, O; Hyslop, T; Hwang, ES; Greenup, R
MLA Citation
Ong, Cecilia, et al. “Patient age and tumor subtype predicts adherence to ACOSOG Z0011 recommendations: Analysis of national practice patterns.” Annals of Surgical Oncology, vol. 24, SPRINGER, 2017, pp. 164–65.
Source
wos
Published In
Annals of Surgical Oncology
Volume
24
Publish Date
2017
Start Page
164
End Page
165

A novel integrative risk index of papillary thyroid cancer progression combining genomic alterations and clinical factors.

Although the majority of papillary thyroid cancer (PTC) is indolent, a subset of PTC behaves aggressively despite the best available treatment. A major clinical challenge is to reliably distinguish early on between those patients who need aggressive treatment from those who do not. Using a large cohort of PTC samples obtained from The Cancer Genome Atlas (TCGA), we analyzed the association between disease progression and multiple forms of genomic data, such as transcriptome, somatic mutations, and somatic copy number alterations, and found that genes related to FOXM1 signaling pathway were significantly associated with PTC progression. Integrative genomic modeling was performed, controlling for demographic and clinical characteristics, which included patient age, gender, TNM stages, histological subtypes, and history of other malignancy, using a leave-one-out elastic net model and 10-fold cross validation. For each subject, the model from the remaining subjects was used to determine the risk index, defined as a linear combination of the clinical and genomic variables from the elastic net model, and the stability of the risk index distribution was assessed through 2,000 bootstrap resampling. We developed a novel approach to combine genomic alterations and patient-related clinical factors that delineates the subset of patients who have more aggressive disease from those whose tumors are indolent and likely will require less aggressive treatment and surveillance (p = 4.62 × 10-10, log-rank test). Our results suggest that risk index modeling that combines genomic alterations with current staging systems provides an opportunity for more effective anticipation of disease prognosis and therefore enhanced precision management of PTC.

Authors
Cheng, Q; Li, X; Acharya, CR; Hyslop, T; Sosa, JA
MLA Citation
Cheng, Qing, et al. “A novel integrative risk index of papillary thyroid cancer progression combining genomic alterations and clinical factors..” Oncotarget, vol. 8, no. 10, Mar. 2017, pp. 16690–703. Pubmed, doi:10.18632/oncotarget.15128.
PMID
28187428
Source
pubmed
Published In
Oncotarget
Volume
8
Issue
10
Publish Date
2017
Start Page
16690
End Page
16703
DOI
10.18632/oncotarget.15128

Abstract P5-08-12: HER2 status remains the primary predictor of improved survival in patients with BCBM over the past 2 decades (1996-2015)

Authors
Narloch, JL; Harnden, K; Broadwater, G; Peterson, B; Hyslop, T; Kirkpatrick, J; Fecci, P; Kim, G; Blackwell, KL
MLA Citation
Narloch, J. L., et al. “Abstract P5-08-12: HER2 status remains the primary predictor of improved survival in patients with BCBM over the past 2 decades (1996-2015).” Poster Session Abstracts, American Association for Cancer Research, 2017. Crossref, doi:10.1158/1538-7445.sabcs16-p5-08-12.
Source
crossref
Published In
Poster Session Abstracts
Publish Date
2017
DOI
10.1158/1538-7445.sabcs16-p5-08-12

Abstract PD1-03: Multivariate analysis of subtype and gene expression signatures predictive of pathologic complete response (pCR) in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance)

Authors
Hoadley, KA; Hyslop, T; Fan, C; Berry, DA; Hahn, O; Tolaney, SM; Sikov, WM; Perou, CM; Carey, LA
MLA Citation
Hoadley, K. A., et al. “Abstract PD1-03: Multivariate analysis of subtype and gene expression signatures predictive of pathologic complete response (pCR) in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance).” Poster Discussion Abstracts, American Association for Cancer Research, 2017. Crossref, doi:10.1158/1538-7445.sabcs16-pd1-03.
Source
crossref
Published In
Poster Discussion Abstracts
Publish Date
2017
DOI
10.1158/1538-7445.sabcs16-pd1-03

Abstract P2-04-19: Elucidating the tumor immune microenvironment phenotype in early stage untreated BRCA mutated breast cancer patients

Authors
Force, J; Abbott, S; Broadwater, G; Kimmick, G; Westbrook, K; Hwang, S; Kauff, N; Stashko, I; Weinhold, K; Nair, S; Hyslop, T; Blackwell, K; Castellar, E; Marcom, PK
MLA Citation
Force, J., et al. “Abstract P2-04-19: Elucidating the tumor immune microenvironment phenotype in early stage untreated BRCA mutated breast cancer patients.” Poster Session Abstracts, American Association for Cancer Research, 2017. Crossref, doi:10.1158/1538-7445.sabcs16-p2-04-19.
Source
crossref
Published In
Poster Session Abstracts
Publish Date
2017
DOI
10.1158/1538-7445.sabcs16-p2-04-19

Abstract S3-05: Integrated analysis of multidimensional genomic data on CALGB 40601 (Alliance), a randomized neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for HER2-positive breast cancer

Authors
Tanioka, M; Fan, C; Carey, LA; Hyslop, T; Pitcher, BN; Parker, JA; Hoadley, KA; Henry, NL; Tolaney, S; Dang, C; Krop, IE; Harris, L; Berry, DA; Mardis, E; Perou, CM; Winer, EP; Hudis, CA
MLA Citation
Tanioka, M., et al. “Abstract S3-05: Integrated analysis of multidimensional genomic data on CALGB 40601 (Alliance), a randomized neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for HER2-positive breast cancer.” General Session Abstracts, American Association for Cancer Research, 2017. Crossref, doi:10.1158/1538-7445.sabcs16-s3-05.
Source
crossref
Published In
General Session Abstracts
Publish Date
2017
DOI
10.1158/1538-7445.sabcs16-s3-05

Is There a Minimum Number of Thyroidectomies a Surgeon Should Perform to Optimize Patient Outcomes?

OBJECTIVE: To determine the number of total thyroidectomies per surgeon per year associated with the lowest risk of complications. BACKGROUND: The surgeon volume-outcome association has been established for thyroidectomy; however, a threshold number of cases defining a "high-volume" surgeon remains unclear. METHODS: Adults undergoing total thyroidectomy were identified from the Health Care Utilization Project-National Inpatient Sample (1998-2009). Multivariate logistic regression with restricted cubic splines was utilized to examine the association between the number of annual total thyroidectomies per surgeon and risk of complications. RESULTS: Among 16,954 patients undergoing total thyroidectomy, 47% had thyroid cancer and 53% benign disease. Median annual surgeon volume was 7 cases; 51% of surgeons performed 1 case/y. Overall, 6% of the patients experienced complications. After adjustment, the likelihood of experiencing a complication decreased with increasing surgeon volume up to 26 cases/y (P < 0.01). Among all patients, 81% had surgery by low-volume surgeons (≤25 cases/y). With adjustment, patients undergoing surgery by low-volume surgeons were more likely to experience complications (odds ratio 1.51, P = 0.002) and longer hospital stays (+12%, P = 0.006). Patients had an 87% increase in the odds of having a complication if the surgeon performed 1 case/y, 68% for 2 to 5 cases/y, 42% for 6 to 10 cases/y, 22% for 11 to 15 cases/y, 10% for 16 to 20 cases/y, and 3% for 21 to 25 cases/y. CONCLUSIONS: This is the first study to identify a surgeon volume threshold (>25 total thyroidectomies/y) that is associated with improved patient outcomes. Identifying a threshold number of cases defining a high-volume thyroid surgeon is important, as it has implications for quality improvement, criteria for referral and reimbursement, and surgical education.

Authors
Adam, MA; Thomas, S; Youngwirth, L; Hyslop, T; Reed, SD; Scheri, RP; Roman, SA; Sosa, JA
MLA Citation
Adam, Mohamed Abdelgadir, et al. “Is There a Minimum Number of Thyroidectomies a Surgeon Should Perform to Optimize Patient Outcomes?.” Ann Surg, vol. 265, no. 2, Feb. 2017, pp. 402–07. Pubmed, doi:10.1097/SLA.0000000000001688.
PMID
28059969
Source
pubmed
Published In
Ann Surg
Volume
265
Issue
2
Publish Date
2017
Start Page
402
End Page
407
DOI
10.1097/SLA.0000000000001688

Abstract B58: Single-nucleotide polymorphisms of race-related alternatively spliced genes associate with prostate cancer risk, aggressiveness and/or survival

Authors
Freedman, J; Wang, Y; Liu, H; Moorman, P; Hyslop, T; George, D; Lee, N; Wei, Q; Patierno, S
MLA Citation
Freedman, Jennifer, et al. “Abstract B58: Single-nucleotide polymorphisms of race-related alternatively spliced genes associate with prostate cancer risk, aggressiveness and/or survival.” Epidemiology, Lifestyle, and Genetics, American Association for Cancer Research, 2017. Crossref, doi:10.1158/1538-7755.disp16-b58.
Source
crossref
Published In
Epidemiology, Lifestyle, and Genetics
Publish Date
2017
DOI
10.1158/1538-7755.disp16-b58

Exploring the Relationship Between Patient Age and Cancer-Specific Survival in Papillary Thyroid Cancer: Rethinking Current Staging Systems.

Purpose Patient age is considered to play a unique prognostic role in papillary thyroid cancer (PTC), with a distinct staging dichotomization at 45 years of age. This is based on older, limited data demonstrating a marked rise in mortality around the ages of 40 to 50 years. We hypothesized that age is associated with compromised survival from cancer, with no cutoff denoting survival difference. Patients and Methods Patients with PTC who had surgery were identified from the SEER database (1998 to 2012). Multivariable proportional hazards modeling utilizing several flexible smoothing approaches were used to examine the association between age and cancer-specific survival (CSS) and to determine whether there is an age cut point that is associated with CSS decrement. Results A total of 31,802 patients with PTC were included. Median age was 45 years (range, 2 to 105 years). Ten-year CSS according to age was as follows: 2 to 19 years, 99.8%; 20 to 29 years, 99.9%; 30 to 39 years, 99.8%; 40 to 49 years, 99.5%; 50 to 59 years, 98.1%; 60 to 69 years, 94.8%; 70 to 79 years, 91.5%; 80 to 89 years, 79.2%; and ≥ 90 years, 73.9%. After adjustment for patient demographic and clinicopathologic characteristics, increasing age was associated with increasing mortality from the disease in a dose-dependent fashion, without an apparent cut point. Each of the smoothing approaches demonstrated a similar linearity of risk over all ages and provided close measures of goodness of fit to the data. Conclusion Patient age is significantly associated with death from PTC in a linear fashion, without an apparent age cut point demarcating survival difference. These results challenge the appropriateness of a patient age cut point in current staging systems for PTC and argue for considering a revision in how we anticipate prognosis for patients with PTC.

Authors
Adam, MA; Thomas, S; Hyslop, T; Scheri, RP; Roman, SA; Sosa, JA
MLA Citation
Adam, Mohamed Abdelgadir, et al. “Exploring the Relationship Between Patient Age and Cancer-Specific Survival in Papillary Thyroid Cancer: Rethinking Current Staging Systems..” J Clin Oncol, vol. 34, no. 36, Dec. 2016, pp. 4415–20. Pubmed, doi:10.1200/JCO.2016.68.9372.
PMID
27998233
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
34
Issue
36
Publish Date
2016
Start Page
4415
End Page
4420
DOI
10.1200/JCO.2016.68.9372

Reply to J. Heil et al.

Authors
Hwang, ES; Hyslop, T
MLA Citation
Hwang, E. Shelley, and Terry Hyslop. “Reply to J. Heil et al..” J Clin Oncol, vol. 34, no. 34, Dec. 2016. Pubmed, doi:10.1200/JCO.2016.69.1121.
PMID
27621401
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
34
Issue
34
Publish Date
2016
Start Page
4192
DOI
10.1200/JCO.2016.69.1121

Preclinical Evaluation of a Replication-Deficient Recombinant Adenovirus Serotype 5 Vaccine Expressing Guanylate Cyclase C and the PADRE T-helper Epitope.

There is an unmet need for improved therapeutics for colorectal cancer, the second leading cause of cancer mortality worldwide. Adjuvant chemotherapy only marginally improves survival in some patients and has no benefit in others, underscoring the clinical opportunity for novel immunotherapeutic approaches to improve survival in colorectal cancer. In that context, guanylate cyclase C (GUCY2C) is an established biomarker and therapeutic target for metastatic colorectal cancer with immunological characteristics that promote durable antitumor efficacy without autoimmunity. Preliminary studies established non-replicating human type 5 adenovirus (Ad5) expressing GUCY2C as safe and effective to induce GUCY2C-specific immune responses and antitumor immunity in mice. This study characterized the biodistribution, immunogenicity, and safety of a vector expressing GUCY2C fused with the human CD4+ T helper cell epitope PADRE (Ad5-GUCY2C-PADRE) to advance this vaccine into clinical trials in colorectal cancer patients. Ad5-GUCY2C-PADRE levels were highest in the injection site and distributed in vivo primarily to draining lymph nodes, the liver, spleen and, unexpectedly, to the bone marrow. Immune responses following Ad5-GUCY2C-PADRE administration were characterized by PADRE-specific CD4+ T-cell and GUCY2C-specific B-cell and CD8+ T-cell responses, producing antitumor immunity targeting GUCY2C-expressing colorectal cancer metastases in the lungs, without acute or chronic autoimmune or other toxicities. Collectively, these data support Ad5-GUCY2C-PADRE as a safe and effective vaccination strategy in preclinical models and position Ad5-GUCY2C-PADRE for Phase I clinical testing in colorectal cancer patients.

Authors
Snook, AE; Baybutt, TR; Hyslop, T; Waldman, SA
MLA Citation
Snook, Adam E., et al. “Preclinical Evaluation of a Replication-Deficient Recombinant Adenovirus Serotype 5 Vaccine Expressing Guanylate Cyclase C and the PADRE T-helper Epitope..” Hum Gene Ther Methods, vol. 27, no. 6, Dec. 2016, pp. 238–50. Pubmed, doi:10.1089/hgtb.2016.114.
PMID
27903079
Source
pubmed
Published In
Hum Gene Ther Methods
Volume
27
Issue
6
Publish Date
2016
Start Page
238
End Page
250
DOI
10.1089/hgtb.2016.114

Registry for the EVolution Of LUng Cancer Therapy Implementation and Outcomes Now (REVOLUTION): Registry Study in Progress

Authors
Kim, E; Dinan, M; Islam, KMM; Fernandes, A; Schwartzberg, L; Croft, E; Brahmer, J; Mansfield, A; Hyslop, T; Burke, L; Crawford, J
MLA Citation
Kim, Edward, et al. “Registry for the EVolution Of LUng Cancer Therapy Implementation and Outcomes Now (REVOLUTION): Registry Study in Progress.” Journal of Thoracic Oncology, vol. 11, no. 11, ELSEVIER SCIENCE INC, 2016, pp. S308–09.
Source
wos
Published In
Journal of Thoracic Oncology
Volume
11
Issue
11
Publish Date
2016
Start Page
S308
End Page
S309

PS01.61: Registry for the EVolution Of LUng Cancer Therapy Implementation and Outcomes Now (REVOLUTION): Registry Study in Progress: Topic: Medical Oncology.

Authors
Kim, E; Dinan, M; Islam, KM; Fernandes, A; Schwartzberg, L; Croft, E; Brahmer, J; Mansfield, A; Hyslop, T; Burke, L; Crawford, J
MLA Citation
Kim, Edward, et al. “PS01.61: Registry for the EVolution Of LUng Cancer Therapy Implementation and Outcomes Now (REVOLUTION): Registry Study in Progress: Topic: Medical Oncology..” J Thorac Oncol, vol. 11, no. 11S, Nov. 2016, pp. S308–09. Pubmed, doi:10.1016/j.jtho.2016.09.096.
PMID
27969528
Source
pubmed
Published In
J Thorac Oncol
Volume
11
Issue
11S
Publish Date
2016
Start Page
S308
End Page
S309
DOI
10.1016/j.jtho.2016.09.096

Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial.

BACKGROUND: Respiratory viral infections (RVIs) are frequent complications of hematopoietic stem cell transplant (HSCT). Surgical masks are a simple and inexpensive intervention that may reduce nosocomial spread. METHODS: In this prospective single-center study, we instituted a universal surgical mask policy requiring all individuals with direct contact with HSCT patients to wear a surgical mask, regardless of symptoms or season. The primary endpoint was the incidence of RVIs in the mask period (2010-2014) compared with the premask period (2003-2009). RESULTS: RVIs decreased from 10.3% (95/920 patients) in the premask period to 4.4% (40/911) in the mask period (P < .001). Significant decreases occurred after both allogeneic (64/378 [16.9%] to 24/289 [8.3%], P = .001) and autologous (31/542 [5.7%] to 16/622 [2.6%], P = .007) transplants. After adjusting for multiple covariates including season and year in a segmented longitudinal analysis, the decrease in RVIs remained significant, with risk of RVI of 0.4 in patients in the mask group compared with the premask group (0.19-0.85, P = .02). In contrast, no decrease was observed during this same period in an adjacent hematologic malignancy unit, which followed the same infection control practices except for the mask policy. The majority of this decrease was in parainfluenza virus 3 (PIV3) (8.3% to 2.2%, P < .001). CONCLUSIONS: Requiring all individuals with direct patient contact to wear a surgical mask is associated with a reduction in RVIs, particularly PIV3, during the most vulnerable period following HSCT.

Authors
Sung, AD; Sung, JAM; Thomas, S; Hyslop, T; Gasparetto, C; Long, G; Rizzieri, D; Sullivan, KM; Corbet, K; Broadwater, G; Chao, NJ; Horwitz, ME
MLA Citation
Sung, Anthony D., et al. “Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial..” Clin Infect Dis, vol. 63, no. 8, Oct. 2016, pp. 999–1006. Pubmed, doi:10.1093/cid/ciw451.
PMID
27481873
Source
pubmed
Published In
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Volume
63
Issue
8
Publish Date
2016
Start Page
999
End Page
1006
DOI
10.1093/cid/ciw451

How Many Lymph Nodes Are Enough? Assessing the Adequacy of Lymph Node Yield for Papillary Thyroid Cancer.

PURPOSE: Patients who undergo surgery for papillary thyroid cancer with only a limited lymph node examination are thought to be at risk for potentially harboring occult disease. However, this risk has not been objectively quantified and may have implications for subsequent management and surveillance. METHODS: Data from the National Cancer Database (1998 to 2012) were used to characterize the distribution of nodal positivity of adult patients diagnosed with localized ≥ 1-cm papillary thyroid cancer who underwent thyroidectomy with one or more lymph nodes (LNs) examined. A β-binomial distribution was used to estimate the probability of occult nodal disease as a function of total number of LNs examined and pathologic tumor stage. RESULTS: A total of 78,724 patients met study criteria; 38,653 patients had node-positive disease. The probability of falsely identifying a patient as node negative was estimated to be 53% for patients with a single node examined and decreased to less than 10% when more than six LNs were examined. To rule out occult nodal disease with 90% confidence, six, nine, and 18 nodes would need to be examined for patients with T1b, T2, and T3 disease, respectively. Sensitivity analyses limited to patients likely undergoing prophylactic central neck dissection resulted in three, four, and eight nodes needed to provide comparable adequacy of LN evaluation. CONCLUSION: To our knowledge, our study provides the first empirically based estimates of occult nodal disease risk in patients after surgery for papillary thyroid cancer as a function of primary tumor stage and number of LNs examined. Our estimates provide an objective guideline for evaluating adequacy of LN yield for surgeons and pathologists in the treatment of papillary thyroid cancer, and especially intermediate-risk disease, for which use of adjuvant radioactive iodine and surveillance intensity are not currently standardized.

Authors
Robinson, TJ; Thomas, S; Dinan, MA; Roman, S; Sosa, JA; Hyslop, T
MLA Citation
Robinson, Timothy J., et al. “How Many Lymph Nodes Are Enough? Assessing the Adequacy of Lymph Node Yield for Papillary Thyroid Cancer..” J Clin Oncol, vol. 34, no. 28, Oct. 2016, pp. 3434–39. Pubmed, doi:10.1200/JCO.2016.67.6437.
PMID
27528716
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
34
Issue
28
Publish Date
2016
Start Page
3434
End Page
3439
DOI
10.1200/JCO.2016.67.6437

Validation of tumor protein marker quantification by two independent automated immunofluorescence image analysis platforms.

Protein marker levels in formalin-fixed, paraffin-embedded tissue sections traditionally have been assayed by chromogenic immunohistochemistry and evaluated visually by pathologists. Pathologist scoring of chromogen staining intensity is subjective and generates low-resolution ordinal or nominal data rather than continuous data. Emerging digital pathology platforms now allow quantification of chromogen or fluorescence signals by computer-assisted image analysis, providing continuous immunohistochemistry values. Fluorescence immunohistochemistry offers greater dynamic signal range than chromogen immunohistochemistry, and combined with image analysis holds the promise of enhanced sensitivity and analytic resolution, and consequently more robust quantification. However, commercial fluorescence scanners and image analysis software differ in features and capabilities, and claims of objective quantitative immunohistochemistry are difficult to validate as pathologist scoring is subjective and there is no accepted gold standard. Here we provide the first side-by-side validation of two technologically distinct commercial fluorescence immunohistochemistry analysis platforms. We document highly consistent results by (1) concordance analysis of fluorescence immunohistochemistry values and (2) agreement in outcome predictions both for objective, data-driven cutpoint dichotomization with Kaplan-Meier analyses or employment of continuous marker values to compute receiver-operating curves. The two platforms examined rely on distinct fluorescence immunohistochemistry imaging hardware, microscopy vs line scanning, and functionally distinct image analysis software. Fluorescence immunohistochemistry values for nuclear-localized and tyrosine-phosphorylated Stat5a/b computed by each platform on a cohort of 323 breast cancer cases revealed high concordance after linear calibration, a finding confirmed on an independent 382 case cohort, with concordance correlation coefficients >0.98. Data-driven optimal cutpoints for outcome prediction by either platform were reciprocally applicable to the data derived by the alternate platform, identifying patients with low Nuc-pYStat5 at ~3.5-fold increased risk of disease progression. Our analyses identified two highly concordant fluorescence immunohistochemistry platforms that may serve as benchmarks for testing of other platforms, and low interoperator variability supports the implementation of objective tumor marker quantification in pathology laboratories.

Authors
Peck, AR; Girondo, MA; Liu, C; Kovatich, AJ; Hooke, JA; Shriver, CD; Hu, H; Mitchell, EP; Freydin, B; Hyslop, T; Chervoneva, I; Rui, H
MLA Citation
Peck, Amy R., et al. “Validation of tumor protein marker quantification by two independent automated immunofluorescence image analysis platforms..” Mod Pathol, vol. 29, no. 10, Oct. 2016, pp. 1143–54. Pubmed, doi:10.1038/modpathol.2016.112.
PMID
27312066
Source
pubmed
Published In
Modern Pathology
Volume
29
Issue
10
Publish Date
2016
Start Page
1143
End Page
1154
DOI
10.1038/modpathol.2016.112

Patient-Reported Outcomes After Choice for Contralateral Prophylactic Mastectomy.

PURPOSE: The rate of contralateral prophylactic mastectomies (CPMs) continues to rise, although there is little evidence to support improvement in quality of life (QOL) with CPM. We sought to ascertain whether patient-reported outcomes and, more specifically, QOL differed according to receipt of CPM. METHODS: Volunteers recruited from the Army of Women with a history of breast cancer surgery took an electronically administered survey, which included the BREAST-Q, a well-validated breast surgery outcomes patient-reporting tool, and demographic and treatment-related questions. Descriptive statistics, hypothesis testing, and regression analysis were used to evaluate the association of CPM with four BREAST-Q QOL domains. RESULTS: A total of 7,619 women completed questionnaires; of those eligible, 3,977 had a mastectomy and 1,598 reported receipt of CPM. Women undergoing CPM were younger than those who did not choose CPM. On unadjusted analysis, mean breast satisfaction was higher in the CPM group (60.4 v 57.9, P < .001) and mean physical well-being was lower in the CPM group (74.6 v 76.6, P < .001). On multivariable analysis, the CPM group continued to report higher breast satisfaction (P = .046) and psychosocial well-being (P = .017), but no difference was reported in the no-CPM group in the other QOL domains. CONCLUSION: Choice for CPM was associated with an improvement in breast satisfaction and psychosocial well-being. However, the magnitude of the effect may be too small to be clinically meaningful. Such patient-reported outcomes data are important to consider when counseling women contemplating CPM as part of their breast cancer treatment.

Authors
Hwang, ES; Locklear, TD; Rushing, CN; Samsa, G; Abernethy, AP; Hyslop, T; Atisha, DM
MLA Citation
Hwang, E. Shelley, et al. “Patient-Reported Outcomes After Choice for Contralateral Prophylactic Mastectomy..” J Clin Oncol, vol. 34, no. 13, 2016, pp. 1518–27. Pubmed, doi:10.1200/JCO.2015.61.5427.
PMID
26951322
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
34
Issue
13
Publish Date
2016
Start Page
1518
End Page
1527
DOI
10.1200/JCO.2015.61.5427

Patient-Reported Outcomes After Choice for Contralateral Prophylactic Mastectomy

Authors
Hwang, ES; Locklear, TD; Rushing, CN; Samsa, G; Abernethy, AP; Hyslop, T; Atisha, DM
MLA Citation
Hwang, E. Shelley, et al. “Patient-Reported Outcomes After Choice for Contralateral Prophylactic Mastectomy.” Journal of Clinical Oncology, vol. 34, no. 13, May 2016, pp. 1518-+. Wos-lite, doi:10.1200/JCO.2015.61.5427.
Source
wos-lite
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
34
Issue
13
Publish Date
2016
Start Page
1518
End Page
+
DOI
10.1200/JCO.2015.61.5427

Effects of Cancer Stage and Treatment Differences on Racial Disparities in Survival From Colon Cancer: A United States Population-Based Study.

BACKGROUND & AIMS: We evaluated differences in treatment of black vs white patients with colon cancer and assessed their effects on survival, based on cancer stage. METHODS: We collected data from the Surveillance, Epidemiology, and End Results-Medicare database and identified 6190 black and 61,951 white patients with colon cancer diagnosed from 1998 through 2009 and followed up through 2011. Three sets of 6190 white patients were matched sequentially, using a minimum distance strategy, to the same set of 6190 black patients based on demographic (age; sex; diagnosis year; and Surveillance, Epidemiology, and End Results registry), tumor presentation (demographic plus comorbidities, tumor stage, grade, and size), and treatment (presentation plus therapies) variables. We conducted sensitivity analyses to explore the effects of socioeconomic status in a subcohort that included 2000 randomly selected black patients. Racial differences in treatment were assessed using a logistic regression model; their effects on racial survival disparity were evaluated using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: After patients were matched for demographic variables, the absolute 5-year difference in survival between black and white patients was 8.3% (white, 59.2% 5-y survival; blacks, 50.9% 5-y survival) (P < .0001); this value decreased significantly, to 5.0% (P < .0001), after patients were matched for tumor presentation, and decreased to 4.9% (P < .0001) when patients were matched for treatment. Differences in treatment therefore accounted for 0.1% of the 8.3% difference in survival between black and white patients. After patients were matched for tumor presentation, racial disparities were observed in almost all types of treatment; the disparities were most prominent for patients with advanced-stage cancer (stages III or IV, up to an 11.1% difference) vs early stage cancer (stages I or II, up to a 4.3% difference). After patients were matched for treatment, there was a greater reduction in disparity for black vs white patients with advanced-stage compared with early-stage cancer. In sensitivity analyses, the 5-year racial survival disparity was 7.7% after demographic match, which was less than the 8.3% observed in the complete cohort. This reduction likely was owing to the differences between the subcohort and the complete cohort in those variables that were not included in the demographic match. This value was reduced to 6.5% (P = .0001) after socioeconomic status was included in the demographic match. The difference decreased significantly to 2.8% (P = .090) after tumor presentation match, but was not reduced further after treatment match. CONCLUSIONS: We observed significant disparities in treatment and survival of black vs white patients with colon cancer. The disparity in survival appears to have been affected more strongly by tumor presentation at diagnosis than treatment. The effects of treatment differences on disparities in survival were greater for patients with advanced-stage vs early-stage cancer.

Authors
Lai, Y; Wang, C; Civan, JM; Palazzo, JP; Ye, Z; Hyslop, T; Lin, J; Myers, RE; Li, B; Jiang, B; Sama, A; Xing, J; Yang, H
MLA Citation
Lai, Yinzhi, et al. “Effects of Cancer Stage and Treatment Differences on Racial Disparities in Survival From Colon Cancer: A United States Population-Based Study..” Gastroenterology, vol. 150, no. 5, May 2016, pp. 1135–46. Pubmed, doi:10.1053/j.gastro.2016.01.030.
PMID
26836586
Source
pubmed
Published In
Gastroenterology
Volume
150
Issue
5
Publish Date
2016
Start Page
1135
End Page
1146
DOI
10.1053/j.gastro.2016.01.030

Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism.

Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERα-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERα+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERα-positive breast cancers.

Authors
Goodman, CR; Sato, T; Peck, AR; Girondo, MA; Yang, N; Liu, C; Yanac, AF; Kovatich, AJ; Hooke, JA; Shriver, CD; Mitchell, EP; Hyslop, T; Rui, H
MLA Citation
Goodman, C. R., et al. “Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism..” Oncogene, vol. 35, no. 11, Mar. 2016, pp. 1373–85. Pubmed, doi:10.1038/onc.2015.193.
PMID
26096934
Source
pubmed
Published In
Oncogene
Volume
35
Issue
11
Publish Date
2016
Start Page
1373
End Page
1385
DOI
10.1038/onc.2015.193

Is There a Minimum Number of Thyroidectomies a Surgeon Should Perform to Optimize Patient Outcomes?

: Supplemental Digital Content is available in the text OBJECTIVE:: To determine the number of total thyroidectomies per surgeon per year associated with the lowest risk of complications. BACKGROUND: The surgeon volume-outcome association has been established for thyroidectomy; however, a threshold number of cases defining a "high-volume" surgeon remains unclear. METHODS: Adults undergoing total thyroidectomy were identified from the Health Care Utilization Project-National Inpatient Sample (1998-2009). Multivariate logistic regression with restricted cubic splines was utilized to examine the association between the number of annual total thyroidectomies per surgeon and risk of complications. RESULTS: Among 16,954 patients undergoing total thyroidectomy, 47% had thyroid cancer and 53% benign disease. Median annual surgeon volume was 7 cases; 51% of surgeons performed 1 case/y. Overall, 6% of the patients experienced complications. After adjustment, the likelihood of experiencing a complication decreased with increasing surgeon volume up to 26 cases/y (P < 0.01). Among all patients, 81% had surgery by low-volume surgeons (≤25 cases/y). With adjustment, patients undergoing surgery by low-volume surgeons were more likely to experience complications (odds ratio 1.51, P = 0.002) and longer hospital stays (+12%, P = 0.006). Patients had an 87% increase in the odds of having a complication if the surgeon performed 1 case/y, 68% for 2 to 5 cases/y, 42% for 6 to 10 cases/y, 22% for 11 to 15 cases/y, 10% for 16 to 20 cases/y, and 3% for 21 to 25 cases/y. CONCLUSIONS: This is the first study to identify a surgeon volume threshold (>25 total thyroidectomies/y) that is associated with improved patient outcomes. Identifying a threshold number of cases defining a high-volume thyroid surgeon is important, as it has implications for quality improvement, criteria for referral and reimbursement, and surgical education.

Authors
Adam, MA; Thomas, S; Youngwirth, L; Hyslop, T; Reed, SD; Scheri, RP; Roman, SA; Sosa, JA
MLA Citation
Adam, Mohamed Abdelgadir, et al. “Is There a Minimum Number of Thyroidectomies a Surgeon Should Perform to Optimize Patient Outcomes?.” Ann Surg, Mar. 2016. Pubmed, doi:10.1097/SLA.0000000000001688.
PMID
26967630
Source
pubmed
Published In
Ann Surg
Publish Date
2016
DOI
10.1097/SLA.0000000000001688

Latent class model characterization of neighborhood socioeconomic status.

PURPOSE: Neighborhood-level socioeconomic status (NSES) can influence breast cancer mortality and poorer health outcomes are observed in deprived neighborhoods. Commonly used NSES indexes are difficult to interpret. Latent class models allow for alternative characterization of NSES for use in studies of cancer causes and control. METHODS: Breast cancer data was from a cohort of women diagnosed at an academic medical center in Philadelphia, PA. NSES variables were defined using Census data. Latent class modeling was used to characterize NSES. RESULTS: Complete data was available for 1,664 breast cancer patients diagnosed between 1994 and 2002. Two separate latent variables, each with 2-classes (LC2) best represented NSES. LC2 demonstrated strong associations with race and tumor stage and size. CONCLUSIONS: Latent variable models identified specific characteristics associated with advantaged or disadvantaged neighborhoods, potentially improving our understanding of the impact of socioeconomic influence on breast cancer prognosis. Improved classification will enhance our ability to identify vulnerable populations and prioritize the targeting of cancer control efforts.

Authors
Palumbo, A; Michael, Y; Hyslop, T
MLA Citation
Palumbo, Aimee, et al. “Latent class model characterization of neighborhood socioeconomic status..” Cancer Causes Control, vol. 27, no. 3, Mar. 2016, pp. 445–52. Pubmed, doi:10.1007/s10552-015-0711-4.
PMID
26797452
Source
pubmed
Published In
Cancer Causes Control
Volume
27
Issue
3
Publish Date
2016
Start Page
445
End Page
452
DOI
10.1007/s10552-015-0711-4

Abstract S3-06: Treatment outcomes in patients with invasive breast cancer treated with neoadjuvant systemic therapy and breast MR imaging: Results of a secondary analysis of TBCRC 017

Authors
Hyslop, T; Alvarado, M; Forero, A; Golshan, M; Hieken, T; Horton, J; Hudis, C; McGuire, K; Meric-Bernstam, F; Nanda, R; Zagar, T; Hwang, S
MLA Citation
Hyslop, T., et al. “Abstract S3-06: Treatment outcomes in patients with invasive breast cancer treated with neoadjuvant systemic therapy and breast MR imaging: Results of a secondary analysis of TBCRC 017.” General Session Abstracts, American Association for Cancer Research, 2016. Crossref, doi:10.1158/1538-7445.sabcs15-s3-06.
Source
crossref
Published In
General Session Abstracts
Publish Date
2016
DOI
10.1158/1538-7445.sabcs15-s3-06

Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis.

Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide.

Authors
Lin, JE; Colon-Gonzalez, F; Blomain, E; Kim, GW; Aing, A; Stoecker, B; Rock, J; Snook, AE; Zhan, T; Hyslop, TM; Tomczak, M; Blumberg, RS; Waldman, SA
MLA Citation
Lin, Jieru E., et al. “Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis..” Cancer Res, vol. 76, no. 2, Jan. 2016, pp. 339–46. Pubmed, doi:10.1158/0008-5472.CAN-15-1467-T.
PMID
26773096
Source
pubmed
Published In
Cancer Res
Volume
76
Issue
2
Publish Date
2016
Start Page
339
End Page
346
DOI
10.1158/0008-5472.CAN-15-1467-T

Component-wise gradient boosting and false discovery control in survival analysis with high-dimensional covariates.

MOTIVATION: Technological advances that allow routine identification of high-dimensional risk factors have led to high demand for statistical techniques that enable full utilization of these rich sources of information for genetics studies. Variable selection for censored outcome data as well as control of false discoveries (i.e. inclusion of irrelevant variables) in the presence of high-dimensional predictors present serious challenges. This article develops a computationally feasible method based on boosting and stability selection. Specifically, we modified the component-wise gradient boosting to improve the computational feasibility and introduced random permutation in stability selection for controlling false discoveries. RESULTS: We have proposed a high-dimensional variable selection method by incorporating stability selection to control false discovery. Comparisons between the proposed method and the commonly used univariate and Lasso approaches for variable selection reveal that the proposed method yields fewer false discoveries. The proposed method is applied to study the associations of 2339 common single-nucleotide polymorphisms (SNPs) with overall survival among cutaneous melanoma (CM) patients. The results have confirmed that BRCA2 pathway SNPs are likely to be associated with overall survival, as reported by previous literature. Moreover, we have identified several new Fanconi anemia (FA) pathway SNPs that are likely to modulate survival of CM patients. AVAILABILITY AND IMPLEMENTATION: The related source code and documents are freely available at https://sites.google.com/site/bestumich/issues. CONTACT: yili@umich.edu.

Authors
He, K; Li, Y; Zhu, J; Liu, H; Lee, JE; Amos, CI; Hyslop, T; Jin, J; Lin, H; Wei, Q; Li, Y
MLA Citation
He, Kevin, et al. “Component-wise gradient boosting and false discovery control in survival analysis with high-dimensional covariates..” Bioinformatics, vol. 32, no. 1, Jan. 2016, pp. 50–57. Pubmed, doi:10.1093/bioinformatics/btv517.
Website
http://hdl.handle.net/10161/10678
PMID
26382192
Source
pubmed
Published In
Bioinformatics
Volume
32
Issue
1
Publish Date
2016
Start Page
50
End Page
57
DOI
10.1093/bioinformatics/btv517

Prospective assessment of the prognostic value of circulating tumor cells and their clusters in patients with advanced-stage breast cancer.

The enumeration of circulating tumor cells (CTCs) provides important prognostic values in patients with metastatic breast cancer. Recent studies indicate that individual CTCs form clusters and these CTC-clusters play an important role in tumor metastasis. We aimed to assess whether quantification of CTC-clusters provides additional prognostic value over quantification of individual CTCs alone. In 115 prospectively enrolled advanced-stage (III and IV) breast cancer patients, CTCs and CTC-clusters were counted in 7.5 ml whole blood using the CellSearch system at baseline before first-line therapy. The individual and joint effects of CTC and CTC cluster counts on patients' progression-free survival (PFS) were analyzed using Cox proportional hazards modeling. Of the 115 patients, 36 (31.3 %) had elevated baseline CTCs (≥5 CTCs/7.5 ml) and 20 (17.4 %) had CTC-clusters (≥2 CTCs/7.5 ml). Patients with elevated CTCs and CTC-clusters both had worse PFS with a hazard ratio (HR) of 2.76 [95 % confidence interval (CI) 1.57-4.86, P log-rank = 0.0005] and 2.83 (1.48-5.39, P log-rank = 0.001), respectively. In joint analysis, compared with patients with <5 CTCs and without CTC-clusters, patients with elevated CTCs but without clusters, and patients with elevated CTCs and with clusters, had an increasing trend of progression risk, with an HR of 2.21 (1.02-4.78) and 3.32 (1.68-6.55), respectively (P log-rank = 0.0006, P trend = 0.0002). The additional prognostic value of CTC-clusters appeared to be more pronounced in patients with inflammatory breast cancer (IBC), the most aggressive form of breast cancer with the poorest survival. Baseline counts of both individual CTCs and CTC-clusters were associated with PFS in advanced-stage breast cancer patients. CTC-clusters might provide additional prognostic value compared with CTC enumeration alone, in patients with elevated CTCs.

Authors
Mu, Z; Wang, C; Ye, Z; Austin, L; Civan, J; Hyslop, T; Palazzo, JP; Jaslow, R; Li, B; Myers, RE; Jiang, J; Xing, J; Yang, H; Cristofanilli, M
MLA Citation
Mu, Zhaomei, et al. “Prospective assessment of the prognostic value of circulating tumor cells and their clusters in patients with advanced-stage breast cancer..” Breast Cancer Res Treat, vol. 154, no. 3, Dec. 2015, pp. 563–71. Pubmed, doi:10.1007/s10549-015-3636-4.
PMID
26573830
Source
pubmed
Published In
Breast Cancer Res Treat
Volume
154
Issue
3
Publish Date
2015
Start Page
563
End Page
571
DOI
10.1007/s10549-015-3636-4

Presence and Number of Lymph Node Metastases Are Associated With Compromised Survival for Patients Younger Than Age 45 Years With Papillary Thyroid Cancer.

PURPOSE: Cervical lymph node metastases are recognized as a prognostic indicator only in patients age 45 years or older with papillary thyroid cancer (PTC); patients younger than age 45 years are perceived to have low-risk disease. The current American Joint Committee on Cancer staging for PTC in patients younger than age 45 years does not include cervical lymph node metastases. Our objective was to test the hypothesis that the presence and number of cervical lymph node metastases have an adverse impact on overall survival (OS) in patients younger than age 45 years with PTC. PATIENTS AND METHODS: Adult patients younger than age 45 years undergoing surgery for stage I PTC (no distant metastases) were identified from the National Cancer Data Base (NCDB; 1998-2006) and from SEER 1988-2006 data. Multivariable models were used to examine the association of OS with the presence of lymph node metastases and number of metastatic nodes. RESULTS: In all, 47,902 patients in NCDB (11,740 with and 36,162 without nodal metastases) and 21,855 in the SEER database (5,188 with and 16,667 without nodal metastases) were included. After adjustment, OS was compromised for patients with nodal metastases compared with patients who did not have them (NCDB: hazard ratio (HR), 1.32; 95% CI, 1.04 to 1.67; P = .021; SEER: HR, 1.29; 95% CI, 1.08 to 1.56; P = .006). After adjustment, increasing number of metastatic lymph nodes was associated with decreasing OS up to six metastatic nodes (HR, 1.12; 95% CI, 1.01 to 1.25; P = .03), after which more positive nodes conferred no additional mortality risk (HR, 0.99; 95% CI, 0.99 to 1.05; P = .75). CONCLUSION: Our results suggest that cervical lymph node metastases are associated with compromised survival in young patients, warranting consideration of revised American Joint Committee on Cancer staging. A change point of six or fewer metastatic lymph nodes seems to carry prognostic significance, thus advocating for rigorous preoperative screening for nodal metastases.

Authors
Adam, MA; Pura, J; Goffredo, P; Dinan, MA; Reed, SD; Scheri, RP; Hyslop, T; Roman, SA; Sosa, JA
MLA Citation
Adam, Mohamed Abdelgadir, et al. “Presence and Number of Lymph Node Metastases Are Associated With Compromised Survival for Patients Younger Than Age 45 Years With Papillary Thyroid Cancer..” J Clin Oncol, vol. 33, no. 21, July 2015, pp. 2370–75. Pubmed, doi:10.1200/JCO.2014.59.8391.
PMID
26077238
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
33
Issue
21
Publish Date
2015
Start Page
2370
End Page
2375
DOI
10.1200/JCO.2014.59.8391

Assessing adverse events of postprostatectomy radiation therapy for prostate cancer: evaluation of outcomes in the Regione Emilia-Romagna, Italy.

PURPOSE: Although the likelihood of radiation-related adverse events influences treatment decisions regarding radiation therapy after prostatectomy for eligible patients, the data available to inform decisions are limited. This study was designed to evaluate the genitourinary, gastrointestinal, and sexual adverse events associated with postprostatectomy radiation therapy and to assess the influence of radiation timing on the risk of adverse events. METHODS: The Regione Emilia-Romagna Italian Longitudinal Health Care Utilization Database was queried to identify a cohort of men who received radical prostatectomy for prostate cancer during 2003 to 2009, including patients who received postprostatectomy radiation therapy. Patients with prior radiation therapy were excluded. Outcome measures were genitourinary, gastrointestinal, and sexual adverse events after prostatectomy. Rates of adverse events were compared between the cohorts who did and did not receive postoperative radiation therapy. Multivariable Cox proportional hazards models were developed for each class of adverse events, including models with radiation therapy as a time-varying covariate. RESULTS: A total of 9876 men were included in the analyses: 2176 (22%) who received radiation therapy and 7700 (78%) treated with prostatectomy alone. In multivariable Cox proportional hazards models, the additional exposure to radiation therapy after prostatectomy was associated with increased rates of gastrointestinal (rate ratio [RR] 1.81; 95% confidence interval [CI] 1.44-2.27; P<.001) and urinary nonincontinence events (RR 1.83; 95% CI 1.83-2.80; P<.001) but not urinary incontinence events or erectile dysfunction. The addition of the time from prostatectomy to radiation therapy interaction term was not significant for any of the adverse event outcomes (P>.1 for all outcomes). CONCLUSION: Radiation therapy after prostatectomy is associated with an increase in gastrointestinal and genitourinary adverse events. However, the timing of radiation therapy did not influence the risk of radiation therapy-associated adverse events in this cohort, which contradicts the commonly held clinical tenet that delaying radiation therapy reduces the risk of adverse events.

Authors
Showalter, TN; Hegarty, SE; Rabinowitz, C; Maio, V; Hyslop, T; Dicker, AP; Louis, DZ
MLA Citation
Showalter, Timothy N., et al. “Assessing adverse events of postprostatectomy radiation therapy for prostate cancer: evaluation of outcomes in the Regione Emilia-Romagna, Italy..” Int J Radiat Oncol Biol Phys, vol. 91, no. 4, Mar. 2015, pp. 752–59. Pubmed, doi:10.1016/j.ijrobp.2014.11.038.
PMID
25752388
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
91
Issue
4
Publish Date
2015
Start Page
752
End Page
759
DOI
10.1016/j.ijrobp.2014.11.038

Modeling the overall survival of patients with advanced-stage non-small cell lung cancer using data of routine laboratory tests

© 2014 UICC. Cancer patients undergo routine clinical monitoring with an array of blood tests that may carry long-term prognostic information. We aimed to develop a new prognostic model predicting survival for patients with advanced non-small cell lung cancer (NSCLC), based on laboratory tests commonly performed in clinical practice. A cohort of 1,161 stage IIIB or IV NSCLC patients was divided into training (n = 773) and testing (n = 388) cohorts. We analyzed the associations of 32 commonly tested laboratory variables with patient survival in the training cohort. We developed a model based on those significant laboratory variables, together with important clinical variables. The model was then evaluated in the testing cohort. Five variables, including albumin, total protein, alkaline phosphatase, blood urea nitrogen and international normalized ratio, were significantly associated with patient survival after stepwise selection. A model incorporating these variables classified patients into low-, medium- and high-risk groups with median survival of 16.9, 7.2 and 2.1 months, respectively (p < 0.0001). Compared with low-risk group, patients in the medium- and high-risk groups had a significantly higher risk of death at 1 year, with hazard ratio (HR) of 1.95 (95% CI 1.62-2.36) and 5.22 (4.30-6.34), respectively. These results were validated in the testing cohort. Overall, we developed a prognostic model relying entirely on readily available variables, with similar predictive power to those which depend on more specialized and expensive molecular assays. Further study is necessary to validate and further refine this model, and compare its performance to models based on more specialized and expensive testing. What's new? Blood-based variables, such as albumin and white blood cell levels, are associated with lung cancer prognosis, raising the possibility that a panel of variables considered jointly might increase their predictive power. Here, analysis of the results of routine laboratory tests and survival for patients with advanced non-small cell lung cancer (NSCLC) uncovered five blood-based variables associated specifically with survival. Patients could be classified according to mortality using a model that incorporated the variables. The findings could inform the development of a cost-effective predictive model for survival in lung cancer patients.

Authors
Zhang, K; Lai, Y; Axelrod, R; Campling, B; Hyslop, T; Civan, J; Solomides, C; Myers, RE; Lu, B; Bar Ad, V; Li, B; Ye, Z; Yang, H
MLA Citation
Zhang, K., et al. “Modeling the overall survival of patients with advanced-stage non-small cell lung cancer using data of routine laboratory tests.” International Journal of Cancer, vol. 136, no. 2, Jan. 2015, pp. 382–91. Scopus, doi:10.1002/ijc.28995.
Source
scopus
Published In
International Journal of Cancer
Volume
136
Issue
2
Publish Date
2015
Start Page
382
End Page
391
DOI
10.1002/ijc.28995

An open label randomized phase II study of pasireotide with or without everolimus in castrate-resistant chemotherapy-naïve prostate cancer patients

© 2015 Elsevier Ltd. New areas of research continue to examine the role of non-androgen receptor pathways in prostate cancer treatment. The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway may be a target for prostate cancer therapy. Somatostatin receptor signaling inhibits intracellular PI3K/Akt signaling, making it an attractive target for combination therapy. We conducted a phase II open label clinical trial examining the use of somatostatin receptor agonist, pasireotide (SOM230) in combination with mTOR inhibitor, everolimus in metastatic castrate-resistant chemotherapy-naïve prostate cancer patients. Of the 6 patients enrolled in the study, only 1 patient had >50% PSA reduction from baseline. Three patients withdrew due to grade 3 adverse events. The study was closed early due to toxicity profiles and no further development was planned for this combination treatment in prostate cancer.

Authors
Lin, J; Deng, A; Hoffman-Censits, J; Gibney, G; Hyslop, T; Miller, B; Kilpatrick, D; Jabbour, S; Kevin Kelly, W
MLA Citation
Lin, J., et al. “An open label randomized phase II study of pasireotide with or without everolimus in castrate-resistant chemotherapy-naïve prostate cancer patients.” Cancer Treatment Communications, vol. 4, Jan. 2015, pp. 192–95. Scopus, doi:10.1016/j.ctrc.2015.11.003.
Source
scopus
Published In
Cancer Treatment Communications
Volume
4
Publish Date
2015
Start Page
192
End Page
195
DOI
10.1016/j.ctrc.2015.11.003

Impact of extent of surgery on survival for papillary thyroid cancer patients younger than 45 years.

CONTEXT: Papillary thyroid cancer (PTC) patients <45 years old are considered to have an excellent prognosis; however, current guidelines recommend total thyroidectomy for PTC tumors >1.0 cm, regardless of age. OBJECTIVE: Our objective was to examine the impact of extent of surgery on overall survival (OS) in patients <45 years old with stage I PTC of 1.1 to 4.0 cm. DESIGN, SETTING, AND PATIENTS: Adult patients <45 years of age undergoing surgery for stage I PTC were identified from the National Cancer Data Base (NCDB, 1998-2006) and the Surveillance, Epidemiology, and End RESULTS dataset (SEER, 1988-2006). MAIN OUTCOME MEASURE: Multivariable modeling was used to compare OS for patients undergoing total thyroidectomy vs lobectomy. RESULTS: In total, 29 522 patients in NCDB (3151 lobectomy, 26 371 total thyroidectomy) and 13 510 in SEER (1379 lobectomy, 12 131 total thyroidectomy) were included. Compared with patients undergoing lobectomy, patients having total thyroidectomy more often had extrathyroidal and lymph node disease. At 14 years, unadjusted OS was equivalent between total thyroidectomy and lobectomy in both databases. After adjustment, OS was similar for total thyroidectomy compared with lobectomy across all patients with tumors of 1.1 to 4.0 cm (NCDB: hazard ratio = 1.45 [confidence interval = 0.88-2.51], P = 0.19; SEER: 0.95 (0.70-1.29), P = 0.75) and when stratified by tumor size: 1.1 to 2.0 cm (NCDB: 1.12 [0.50-2.51], P = 0.78; SEER: 0.95 [0.56-1.62], P = 0.86) and 2.1 to 4.0 cm (NCDB: 1.93 [0.88-4.23], P = 0.10; SEER: 0.94 [0.60-1.49], P = 0.80). CONCLUSIONS: After adjusting for patient and clinical characteristics, total thyroidectomy compared with thyroid lobectomy was not associated with improved survival for patients <45 years of age with stage I PTC of 1.1 to 4.0 cm. Additional clinical and pathologic factors should be considered when choosing extent of resection.

Authors
Adam, MA; Pura, J; Goffredo, P; Dinan, MA; Hyslop, T; Reed, SD; Scheri, RP; Roman, SA; Sosa, JA
MLA Citation
Adam, Mohamed Abdelgadir, et al. “Impact of extent of surgery on survival for papillary thyroid cancer patients younger than 45 years..” J Clin Endocrinol Metab, vol. 100, no. 1, Jan. 2015, pp. 115–21. Pubmed, doi:10.1210/jc.2014-3039.
PMID
25337927
Source
pubmed
Published In
The Journal of Clinical Endocrinology and Metabolism
Volume
100
Issue
1
Publish Date
2015
Start Page
115
End Page
121
DOI
10.1210/jc.2014-3039

Racial disparity in breast cancer survival: the impact of pre-treatment hematologic variables.

PURPOSE: A survival disparity of black versus white breast cancer patients has been extensively documented but not adequately explained. Blacks and whites also have significant differences in hematologic traits including hemoglobin (HGB). However, a link between survival disparity and hematologic differences has not been reported. We aimed to explore the effect of pre-treatment hematologic variables on this survival disparity. METHODS: We sequentially matched 443 black patients, using a minimum distance approach, to four different sets of 443 whites on demographics (age, year of diagnosis, smoking, and drinking status), tumor presentation (all demographic variables plus tumor stage, grade, and hormone receptor status), treatment (all presentation variables plus surgery, chemotherapy, radiation therapy, and hormone therapy), and presentation plus pre-treatment hematologic variables. Racial survival for each matched dataset was analyzed by Cox proportional hazards model. RESULTS: We found that white patients matched on demographic characteristics had more favorable survival than blacks [hazard ratio (HR) 0.57, 95 % confidence interval (CI) 0.42-0.77, p log-rank = 0.0002]. Presentation match diminished this disparity [HR 0.72 (0.54-0.95), p log-rank = 0.0199], which was not further reduced in treatment match [HR 0.73 (0.55-0.96), p log-rank = 0.0249]. However, the survival disparity was largely reduced when pre-treatment level of HGB or red blood cell distribution width was further matched in addition to presentation match [HR 0.83 (0.64-1.09), p log-rank = 0.1819 and HR 0.83 (0.64-1.09), p log-rank = 0.1760, respectively]. CONCLUSIONS: We found that in our patient population, differences in tumor presentation and certain pre-treatment hematologic traits, but not treatment, were associated with the survival disparity between black and white breast cancer patients.

Authors
Wang, C; Civan, J; Lai, Y; Cristofanilli, M; Hyslop, T; Palazzo, JP; Myers, RE; Li, B; Ye, Z; Zhang, K; Xing, J; Yang, H
MLA Citation
Wang, Chun, et al. “Racial disparity in breast cancer survival: the impact of pre-treatment hematologic variables..” Cancer Causes Control, vol. 26, no. 1, Jan. 2015, pp. 45–56. Pubmed, doi:10.1007/s10552-014-0481-4.
PMID
25359303
Source
pubmed
Published In
Cancer Causes Control
Volume
26
Issue
1
Publish Date
2015
Start Page
45
End Page
56
DOI
10.1007/s10552-014-0481-4

Radiation therapy after radical prostatectomy for prostate cancer: evaluation of complications and influence of radiation timing on outcomes in a large, population-based cohort.

PURPOSE: To evaluate the influence of timing of salvage and adjuvant radiation therapy on outcomes after prostatectomy for prostate cancer. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified prostate cancer patients diagnosed during 1995-2007 who had one or more adverse pathological features after prostatectomy. The final cohort of 6,137 eligible patients included men who received prostatectomy alone (n = 4,509) or with adjuvant (n = 894) or salvage (n = 734) radiation therapy. Primary outcomes were genitourinary, gastrointestinal, and erectile dysfunction events and survival after treatment(s). RESULTS: Radiation therapy after prostatectomy was associated with higher rates of gastrointestinal and genitourinary events, but not erectile dysfunction. In adjusted models, earlier treatment with adjuvant radiation therapy was not associated with increased rates of genitourinary or erectile dysfunction events compared to delayed salvage radiation therapy. Early adjuvant radiation therapy was associated with lower rates of gastrointestinal events that salvage radiation therapy, with hazard ratios of 0.80 (95% CI, 0.67-0.95) for procedure-defined and 0.70 (95% CI, 0.59, 0.83) for diagnosis-defined events. There was no significant difference between ART and non-ART groups (SRT or RP alone) for overall survival (HR = 1.13 95% CI = (0.96, 1.34) p = 0.148). CONCLUSIONS: Radiation therapy after prostatectomy is associated with increased rates of gastrointestinal and genitourinary events. However, earlier radiation therapy is not associated with higher rates of gastrointestinal, genitourinary or sexual events. These findings oppose the conventional belief that delaying radiation therapy reduces the risk of radiation-related complications.

Authors
Hegarty, SE; Hyslop, T; Dicker, AP; Showalter, TN
MLA Citation
Hegarty, Sarah E., et al. “Radiation therapy after radical prostatectomy for prostate cancer: evaluation of complications and influence of radiation timing on outcomes in a large, population-based cohort..” Plos One, vol. 10, no. 2, 2015. Pubmed, doi:10.1371/journal.pone.0118430.
PMID
25706657
Source
pubmed
Published In
Plos One
Volume
10
Issue
2
Publish Date
2015
Start Page
e0118430
DOI
10.1371/journal.pone.0118430

Impact of extent of surgery on survival for papillary thyroid cancer patients younger than 45 years

© 2015 by the Endocrine Society.Context: Papillary thyroid cancer (PTC) patients <45 years old are considered to have an excellent prognosis; however, current guidelines recommend total thyroidectomy for PTC tumors 1.0 cm, regardless of age. Objective: Our objective was to examine the impact of extent of surgery on overall survival (OS) in patients <45 years old with stage I PTC of 1.1 to 4.0 cm. Design, Setting, and Patients: Adult patients <45 years of age undergoing surgery for stage I PTC were identified from the National Cancer Data Base (NCDB, 1998-2006) and the Surveillance, Epidemiology, and End Results dataset (SEER, 1988-2006). Main Outcome Measure: Multivariable modeling was used to compare OS for patients undergoing total thyroidectomy vs lobectomy. Results: In total, 29 522 patients in NCDB (3151 lobectomy, 26 371 total thyroidectomy) and 13 510 in SEER (1379 lobectomy, 12 131 total thyroidectomy) were included. Compared with patients undergoing lobectomy, patients having total thyroidectomy more often had extrathyroidal and lymph node disease. At 14 years, unadjusted OS was equivalent between total thyroidectomy and lobectomy in both databases. After adjustment, OS was similar for total thyroidectomy compared with lobectomy across all patients with tumors of 1.1 to 4.0 cm (NCDB: hazard ratio = 1.45 [confidence interval = 0.88-2.51], P = 0.19; SEER: 0.95 (0.70 -1.29), P = 0.75) and when stratified by tumor size: 1.1 to 2.0 cm (NCDB: 1.12 [0.50 -2.51], P=0.78; SEER: 0.95 [0.56 -1.62], P=0.86) and 2.1 to 4.0 cm (NCDB: 1.93 [0.88-4.23], P = 0.10; SEER: 0.94 [0.60 -1.49], P = 0.80). Conclusions: After adjusting for patient and clinical characteristics, total thyroidectomy compared with thyroid lobectomy was not associated with improved survival for patients <45 years of age with stage I PTC of 1.1 to 4.0 cm. Additional clinical and pathologic factors should be considered when choosing extent of resection.

Authors
Adam, MA; Pura, J; Goffredo, P; Dinan, MA; Hyslop, T; Reed, SD; Scheri, RP; Roman, SA; Sosa, JA
MLA Citation
Adam, M. A., et al. “Impact of extent of surgery on survival for papillary thyroid cancer patients younger than 45 years.” Journal of Clinical Endocrinology and Metabolism, vol. 100, no. 1, 2015, pp. 115–21. Scival, doi:10.1210/jc.20143039.
Source
scival
Published In
The Journal of Clinical Endocrinology and Metabolism
Volume
100
Issue
1
Publish Date
2015
Start Page
115
End Page
121
DOI
10.1210/jc.20143039

The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer.

BACKGROUND: Although colorectal cancer is a disease characterized by sequential accumulation of mutations in epithelial cells, mechanisms leading to genomic vulnerability contributing to tumor initiation remain undefined. GUCY2C has emerged as an intestine-specific tumor suppressor controlling epithelial homeostasis through circuits canonically disrupted in cancer. Surprisingly, the GUCY2C tumor suppressor is universally overexpressed by human colorectal cancer cells. This apparent paradox likely reflects silencing of GUCY2C through loss of its paracrine hormone guanylin. Here, we quantified expression of guanylin mRNA and protein in tumors and normal epithelia from patients with colorectal cancer. METHODS: Guanylin mRNA was quantified in tumors and normal adjacent epithelia from 281 patients by the reverse transcriptase-polymerase chain reaction. Separately, the guanylin protein was quantified by immunohistochemistry in 54 colorectal tumors and 30 specimens of normal intestinal epithelium. RESULTS: Guanylin mRNA in colorectum varied more than a 100-fold across the population. Guanylin mRNA was reduced 100- to 1,000-fold in >85% of tumors compared with matched normal adjacent mucosa (P < 0.001). Loss of guanylin mRNA was greatest in tumors from patients <50 years old (P < 0.005) and with the highest expression in normal adjacent mucosa (Spearman correlation coefficient = 0.61; P < 0.001). In a separate validation cohort, guanylin protein was detected in all 30 normal colorectal mucosa specimens, but in none of 54 colorectal tumors. CONCLUSIONS: Colorectal cancer may initiate as a disease of paracrine hormone insufficiency through loss of guanylin expression, silencing the GUCY2C tumor suppressor and disrupting homeostatic mechanisms regulating colorectal epithelia cells. IMPACT: Intestinal tumorigenesis may be prevented by oral GUCY2C hormone replacement therapy.

Authors
Wilson, C; Lin, JE; Li, P; Snook, AE; Gong, J; Sato, T; Liu, C; Girondo, MA; Rui, H; Hyslop, T; Waldman, SA
MLA Citation
Wilson, Chantell, et al. “The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer..” Cancer Epidemiol Biomarkers Prev, vol. 23, no. 11, Nov. 2014, pp. 2328–37. Pubmed, doi:10.1158/1055-9965.EPI-14-0440.
PMID
25304930
Source
pubmed
Published In
Cancer Epidemiol Biomarkers Prev
Volume
23
Issue
11
Publish Date
2014
Start Page
2328
End Page
2337
DOI
10.1158/1055-9965.EPI-14-0440

Abstract 4137: Latent class model characterization of neighborhood SES

Authors
Palumbo, A; Michael, Y; Hyslop, T
MLA Citation
Palumbo, Aimee, et al. “Abstract 4137: Latent class model characterization of neighborhood SES.” Epidemiology, American Association for Cancer Research, 2014. Crossref, doi:10.1158/1538-7445.am2014-4137.
Source
crossref
Published In
Epidemiology
Publish Date
2014
DOI
10.1158/1538-7445.am2014-4137

Abstract P4-06-09: HER2+ and HER2- luminal B subtypes have similar overall survival and histologic grade distributions

Authors
Chen, Y; Kovatich, AJ; Fantacone-Campbell, JL; Hooke, JA; Kvecher, L; Kovatich, AW; Gallagher, CM; Hueman, MT; Hyslop, T; Mural, RJ; Shriver, CD; Rui, H; Hu, H
MLA Citation
Chen, Y., et al. “Abstract P4-06-09: HER2+ and HER2- luminal B subtypes have similar overall survival and histologic grade distributions.” Poster Session Abstracts, American Association for Cancer Research, Dec. 2013. Crossref, doi:10.1158/0008-5472.sabcs13-p4-06-09.
Source
crossref
Published In
Poster Session Abstracts
Publish Date
2013
DOI
10.1158/0008-5472.sabcs13-p4-06-09

Abstract P4-06-03: Assays on core biopsies and surgically resected tumors may result in different subtyping of the invasive breast cancer from the same patient

Authors
Kovatich, AJ; Chen, Y; Fantacone-Campbell, JL; Wareham, JA; Tafra, L; Kvecher, L; Hyslop, T; Hooke, JA; Rui, H; Shriver, CD; Mural, RJ; Hu, H
MLA Citation
Kovatich, A. J., et al. “Abstract P4-06-03: Assays on core biopsies and surgically resected tumors may result in different subtyping of the invasive breast cancer from the same patient.” Poster Session Abstracts, American Association for Cancer Research, Dec. 2013. Crossref, doi:10.1158/0008-5472.sabcs13-p4-06-03.
Source
crossref
Published In
Poster Session Abstracts
Publish Date
2013
DOI
10.1158/0008-5472.sabcs13-p4-06-03

Abstract P1-08-20: Increased risk of hormone therapy failure in breast cancers expressing low phospho-Stat5: Validation of quantitative immunofluorescence assay parameters

Authors
Girondo, MA; Peck, AR; Freydin, B; Chervoneva, I; Hyslop, T; Kovatich, AJ; Hooke, JA; Shriver, CD; Mitchell, EP; Rui, H
MLA Citation
Girondo, M. A., et al. “Abstract P1-08-20: Increased risk of hormone therapy failure in breast cancers expressing low phospho-Stat5: Validation of quantitative immunofluorescence assay parameters.” Poster Session Abstracts, American Association for Cancer Research, Dec. 2013. Crossref, doi:10.1158/0008-5472.sabcs13-p1-08-20.
Source
crossref
Published In
Poster Session Abstracts
Publish Date
2013
DOI
10.1158/0008-5472.sabcs13-p1-08-20

Population and target considerations for triple-negative breast cancer clinical trials.

Triple-negative breast cancer (TNBC) is an aggressive disease subtype that has a poor prognosis. Extensive epidemiological evidence demonstrates clear socioeconomic and demographic associations with increased likelihood of TNBC in both poorer and minority populations. Thus, biological aggressiveness with few known therapeutic directions generates disparities in breast cancer outcomes for vulnerable populations. Emerging molecular evidence of potential targets in triple-negative subpopulations offers great potential for future clinical trial directions. However, trials must appropriately consider populations at risk for aggressive subtypes of disease in order to address this disparity most completely. New US FDA draft guidance documents provide both flexible outcomes for accelerated approvals as well as flexibility in design with adaptive trials. Careful planning with design, potential patient population and choices of molecular targets informed by biomarkers will be critical to address TNBC clinical care.

Authors
Hyslop, T; Michael, Y; Avery, T; Rui, H
MLA Citation
Hyslop, Terry, et al. “Population and target considerations for triple-negative breast cancer clinical trials..” Biomark Med, vol. 7, no. 1, Feb. 2013, pp. 11–21. Pubmed, doi:10.2217/bmm.12.114.
PMID
23387481
Source
pubmed
Published In
Biomark Med
Volume
7
Issue
1
Publish Date
2013
Start Page
11
End Page
21
DOI
10.2217/bmm.12.114

GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity.

The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c(-/-)) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated with increased spontaneous and carcinogen-induced systemic tumorigenesis in Gucy2c(-/-) mice. GUCY2C regulated barrier integrity by repressing AKT1, associated with increased junction proteins occludin and claudin 4 in mice and Caco2 cells in vitro. Thus, GUCY2C defends the intestinal barrier, opposing colitis and systemic genotoxicity and tumorigenesis. The therapeutic potential of this observation is underscored by the emerging clinical development of oral GUCY2C ligands, which can be used for chemoprophylaxis in inflammatory bowel disease and cancer.

Authors
Lin, JE; Snook, AE; Li, P; Stoecker, BA; Kim, GW; Magee, MS; Garcia, AVM; Valentino, MA; Hyslop, T; Schulz, S; Waldman, SA
MLA Citation
Lin, Jieru Egeria, et al. “GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity..” Plos One, vol. 7, no. 2, 2012. Pubmed, doi:10.1371/journal.pone.0031686.
PMID
22384056
Source
pubmed
Published In
Plos One
Volume
7
Issue
2
Publish Date
2012
Start Page
e31686
DOI
10.1371/journal.pone.0031686

P1-06-24: Nuclear Localization of Stat5a Predicts Response to Antiestrogen Therapy and Prognosis of Clinical Breast Cancer Outcome.

Authors
Peck, AR; Witkiewicz, AK; Liu, C; Klimowicz, AC; Stringer, GA; Pequignot, E; Freydin, B; Yang, N; Tran, TH; Rosenberg, AL; Hooke, JA; Kovatich, AJ; Shriver, CD; Rimm, DL; Magliocco, AM; Hyslop, T; Rui, H
MLA Citation
Peck, A. R., et al. “P1-06-24: Nuclear Localization of Stat5a Predicts Response to Antiestrogen Therapy and Prognosis of Clinical Breast Cancer Outcome..” Poster Session Abstracts, American Association for Cancer Research, Dec. 2011. Crossref, doi:10.1158/0008-5472.sabcs11-p1-06-24.
Source
crossref
Published In
Poster Session Abstracts
Publish Date
2011
DOI
10.1158/0008-5472.sabcs11-p1-06-24

Bayesian Belief Network Mortality Analysis of a Breast Cancer Registry Data Set.

Authors
Eberhardt, JS; Hyslop, T; Mitchell, E; Hu, H; Rui, H
MLA Citation
Eberhardt, J. S., et al. “Bayesian Belief Network Mortality Analysis of a Breast Cancer Registry Data Set..” Cancer Research, vol. 71, AMER ASSOC CANCER RESEARCH, 2011. Wos, doi:10.1158/0008-5472.5ABCS11-P5-14-12.
Source
wos
Published In
Cancer Research
Volume
71
Publish Date
2011
DOI
10.1158/0008-5472.5ABCS11-P5-14-12

Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure.

PURPOSE: To investigate nuclear localized and tyrosine phosphorylated Stat5 (Nuc-pYStat5) as a marker of prognosis in node-negative breast cancer and as a predictor of response to antiestrogen therapy. PATIENTS AND METHODS: Levels of Nuc-pYStat5 were analyzed in five archival cohorts of breast cancer by traditional diaminobenzidine-chromogen immunostaining and pathologist scoring of whole tissue sections or by immunofluorescence and automated quantitative analysis (AQUA) of tissue microarrays. RESULTS: Nuc-pYStat5 was an independent prognostic marker as measured by cancer-specific survival (CSS) in patients with node-negative breast cancer who did not receive systemic adjuvant therapy, when adjusted for common pathology parameters in multivariate analyses both by standard chromogen detection with pathologist scoring of whole tissue sections (cohort I; n = 233) and quantitative immunofluorescence of a tissue microarray (cohort II; n = 291). Two distinct monoclonal antibodies gave concordant results. A progression array (cohort III; n = 180) revealed frequent loss of Nuc-pYStat5 in invasive carcinoma compared to normal breast epithelia or ductal carcinoma in situ, and general loss of Nuc-pYStat5 in lymph node metastases. In cohort IV (n = 221), loss of Nuc-pYStat5 was associated with increased risk of antiestrogen therapy failure as measured by univariate CSS and time to recurrence (TTR). More sensitive AQUA quantification of Nuc-pYStat5 in antiestrogen-treated patients (cohort V; n = 97) identified by multivariate analysis patients with low Nuc-pYStat5 at elevated risk for therapy failure (CSS hazard ratio [HR], 21.55; 95% CI, 5.61 to 82.77; P < .001; TTR HR, 7.30; 95% CI, 2.34 to 22.78; P = .001). CONCLUSION Nuc-pYStat5 is an independent prognostic marker in node-negative breast cancer. If confirmed in prospective studies, Nuc-pYStat5 may become a useful predictive marker of response to adjuvant hormone therapy.

Authors
Peck, AR; Witkiewicz, AK; Liu, C; Stringer, GA; Klimowicz, AC; Pequignot, E; Freydin, B; Tran, TH; Yang, N; Rosenberg, AL; Hooke, JA; Kovatich, AJ; Nevalainen, MT; Shriver, CD; Hyslop, T; Sauter, G; Rimm, DL; Magliocco, AM; Rui, H
MLA Citation
Peck, Amy R., et al. “Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure..” J Clin Oncol, vol. 29, no. 18, June 2011, pp. 2448–58. Pubmed, doi:10.1200/JCO.2010.30.3552.
PMID
21576635
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
18
Publish Date
2011
Start Page
2448
End Page
2458
DOI
10.1200/JCO.2010.30.3552

Abstract 2277: Loss of nuclear localized and tyrosine phosphorylated Stat5: A predictor of poor clinical outcome and increased risk of antiestrogen therapy failure in breast cancer

Authors
Peck, AR; Witkiewicz, AK; Liu, C; Stringer, GA; Klimowicz, AC; Pequignot, E; Freydin, B; Tran, TH; Yang, N; Rosenberg, AL; Hooke, JA; Kovatich, AJ; Nevalainen, MT; Shriver, CD; Hyslop, T; Sauter, G; Rimm, DL; Magliocco, AM; Rui, H
MLA Citation
Peck, Amy R., et al. “Abstract 2277: Loss of nuclear localized and tyrosine phosphorylated Stat5: A predictor of poor clinical outcome and increased risk of antiestrogen therapy failure in breast cancer.” Clinical Research, American Association for Cancer Research, Apr. 2011. Crossref, doi:10.1158/1538-7445.am2011-2277.
Source
crossref
Published In
Clinical Research
Publish Date
2011
DOI
10.1158/1538-7445.am2011-2277

Selection of optimal reference genes for normalization in quantitative RT-PCR.

BACKGROUND: Normalization in real-time qRT-PCR is necessary to compensate for experimental variation. A popular normalization strategy employs reference gene(s), which may introduce additional variability into normalized expression levels due to innate variation (between tissues, individuals, etc). To minimize this innate variability, multiple reference genes are used. Current methods of selecting reference genes make an assumption of independence in their innate variation. This assumption is not always justified, which may lead to selecting a suboptimal set of reference genes. RESULTS: We propose a robust approach for selecting optimal subset(s) of reference genes with the smallest variance of the corresponding normalizing factors. The normalizing factor variance estimates are based on the estimated unstructured covariance matrix of all available candidate reference genes, adjusting for all possible correlations. Robustness is achieved through bootstrapping all candidate reference gene data and obtaining the bootstrap upper confidence limits for the variances of the log-transformed normalizing factors. The selection of the reference gene subset is optimized with respect to one of the following criteria: (A) to minimize the variability of the normalizing factor; (B) to minimize the number of reference genes with acceptable upper limit on variability of the normalizing factor, (C) to minimize the average rank of the variance of the normalizing factor. The proposed approach evaluates all gene subsets of various sizes rather than ranking individual reference genes by their stability, as in the previous work. In two publicly available data sets and one new data set, our approach identified subset(s) of reference genes with smaller empirical variance of the normalizing factor than in subsets identified using previously published methods. A small simulation study indicated an advantage of the proposed approach in terms of sensitivity to identify the true optimal reference subset in the presence of even modest, especially negative correlation among the candidate reference genes. CONCLUSIONS: The proposed approach performs comprehensive and robust evaluation of the variability of normalizing factors based on all possible subsets of candidate reference genes. The results of this evaluation provide flexibility to choose from important criteria for selecting the optimal subset(s) of reference genes, unless one subset meets all the criteria. This approach identifies gene subset(s) with smaller variability of normalizing factors than current standard approaches, particularly if there is some nontrivial innate correlation among the candidate genes.

Authors
Chervoneva, I; Li, Y; Schulz, S; Croker, S; Wilson, C; Waldman, SA; Hyslop, T
MLA Citation
Chervoneva, Inna, et al. “Selection of optimal reference genes for normalization in quantitative RT-PCR..” Bmc Bioinformatics, vol. 11, May 2010. Pubmed, doi:10.1186/1471-2105-11-253.
PMID
20470420
Source
pubmed
Published In
Bmc Bioinformatics
Volume
11
Publish Date
2010
Start Page
253
DOI
10.1186/1471-2105-11-253

Abstract 5061: Induction of B cell acute lymphoblastic leukemia by BCR/ABL requires c-Myb and its activation of Bmi-1

Authors
Waldron, TJ; Soliera, AR; Zhang, Y; Martinez, R; Hyslop, T; Bender, T; Calabretta, B
MLA Citation
Waldron, Todd J., et al. “Abstract 5061: Induction of B cell acute lymphoblastic leukemia by BCR/ABL requires c-Myb and its activation of Bmi-1.” Cellular and Molecular Biology, American Association for Cancer Research, Apr. 2010. Crossref, doi:10.1158/1538-7445.am10-5061.
Source
crossref
Published In
Cellular and Molecular Biology
Publish Date
2010
DOI
10.1158/1538-7445.am10-5061

The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling.

BACKGROUND & AIMS: GUCY2C is the intestinal receptor for the paracrine hormones guanylin and uroguanylin that converts guanosine-5'-triphosphate to cyclic guanosine monophosphate (cGMP). It functions as a tumor suppressor; its loss disrupts intestinal homeostasis and promotes tumorigenesis. We investigated the effects of GUCY2C loss on intestinal cell proliferation, metabolism, signaling, and tumorigenesis in mice. METHODS: Intestinal cell proliferation and metabolism were examined in Gucy2c(-/-) and colon cancer cells by microscopy, immunoblot, and functional analyses. Microarray analyses compared gene expression profiles of intestine cell from Gucy2c(-/-) and wild-type mice. v akt murine thymoma viral oncogene homolog (AKT) regulation and signaling were examined, and the role of AKT in GUCY2C-dependent tumorigenesis was defined in Gucy2c(-/-)Akt1(-/-) mice. RESULTS: The size and number of intestinal crypts increased in Gucy2c(-/-) mice; the associated epithelial cells showed accelerated proliferation, increased glycolysis, and reduced oxidative phosphorylation, which was reversed by oral administration of cGMP. Conversely, activating guanylyl cyclase C in human colon cancer cells delayed cell-cycle progression, decreased DNA synthesis and colony formation, reduced glycolysis, and increased mitochondrial adenosine triphosphate production. AKT signaling pathways were activated in intestines of Gucy2c(-/-) mice, associated with increased AKT phosphorylation. Disruption of AKT activity, pharmacologically or genetically, reduced DNA synthesis, proliferation, and glycolysis, and increased mitochondrial biogenesis. Intestinal tumorigenesis increased after administration of azoxymethane to Gucy2c(-/-) mice, compared with wild-type mice, but was eliminated in Gucy2c(-/-)Akt1(-/-) mice. CONCLUSIONS: GUCY2C is a tumor suppressor that controls proliferation and metabolism of intestinal epithelial cells by inactivating AKT signaling. This receptor and its ligands, which are paracrine hormones, might be novel candidates for anticolorectal cancer therapy.

Authors
Lin, JE; Li, P; Snook, AE; Schulz, S; Dasgupta, A; Hyslop, TM; Gibbons, AV; Marszlowicz, G; Pitari, GM; Waldman, SA
MLA Citation
Lin, Jieru Egeria, et al. “The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling..” Gastroenterology, vol. 138, no. 1, Jan. 2010, pp. 241–54. Pubmed, doi:10.1053/j.gastro.2009.08.064.
PMID
19737566
Source
pubmed
Published In
Gastroenterology
Volume
138
Issue
1
Publish Date
2010
Start Page
241
End Page
254
DOI
10.1053/j.gastro.2009.08.064

Nuclear expression of transcription factors Stat5a and Stat5b confers favorable prognosis in breast cancer

Authors
Witkiewicz, A; Thai, T; Er, O; Hyslop, T; Rui, H
MLA Citation
Witkiewicz, Agnieszka, et al. “Nuclear expression of transcription factors Stat5a and Stat5b confers favorable prognosis in breast cancer.” Cancer Research, vol. 69, AMER ASSOC CANCER RESEARCH, 2009.
Source
wos
Published In
Cancer Research
Volume
69
Publish Date
2009

Association of GUCY2C expression in lymph nodes with time to recurrence and disease-free survival in pN0 colorectal cancer.

CONTEXT: The established relationship between lymph node metastasis and prognosis in colorectal cancer suggests that recurrence in 25% of patients with lymph nodes free of tumor cells by histopathology (pN0) reflects the presence of occult metastases. Guanylyl cyclase 2C (GUCY2C) is a marker expressed by colorectal tumors that could reveal occult metastases in lymph nodes and better estimate recurrence risk. OBJECTIVE: To examine the association of occult lymph node metastases detected by quantifying GUCY2C messenger RNA, using the reverse transcriptase-polymerase chain reaction, with recurrence and survival in patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 257 patients with pN0 colorectal cancer enrolled between March 2002 and June 2007 at 9 US and Canadian centers (7 academic medical centers and 2 community hospitals) provided 2570 fresh lymph nodes measuring 5 mm or larger for histopathology and GUCY2C messenger RNA analysis. Patients were followed up for a median of 24 months (range, 2-63 months) for disease recurrence or death. MAIN OUTCOME MEASURES: Time to recurrence (primary outcome) and disease-free survival (secondary outcome) relative to expression of GUCY2C in lymph nodes. RESULTS: Thirty-two patients (12.5%) had lymph nodes negative for GUCY2C (pN0 [mol-]), and all but 2 remained free of disease during follow-up (recurrence rate, 6.3%; 95% confidence interval [CI], 0.8%-20.8%). Conversely, 225 patients (87.5%) had lymph nodes positive for GUCY2C (pN0 [mol+]), and 47 developed recurrent disease (20.9%; 95% CI, 15.8%-26.8%) (P = .006). Multivariate analyses revealed that GUCY2C in lymph nodes was an independent marker of prognosis. Patients who were pN0 (mol+) exhibited earlier time to recurrence (adjusted hazard ratio, 4.66; 95% CI, 1.11-19.57; P = .04) and reduced disease-free survival (adjusted hazard ratio, 3.27; 95% CI, 1.15-9.29; P = .03). CONCLUSION: Expression of GUCY2C in histologically negative lymph nodes appears to be independently associated with time to recurrence and disease-free survival in patients with pN0 colorectal cancer.

Authors
Waldman, SA; Hyslop, T; Schulz, S; Barkun, A; Nielsen, K; Haaf, J; Bonaccorso, C; Li, Y; Weinberg, DS
MLA Citation
Waldman, Scott A., et al. “Association of GUCY2C expression in lymph nodes with time to recurrence and disease-free survival in pN0 colorectal cancer..” Jama, vol. 301, no. 7, Feb. 2009, pp. 745–52. Pubmed, doi:10.1001/jama.2009.141.
PMID
19224751
Source
pubmed
Published In
Jama
Volume
301
Issue
7
Publish Date
2009
Start Page
745
End Page
752
DOI
10.1001/jama.2009.141

A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation.

Decreased expression of specific microRNAs (miRNAs) occurs in human tumors, which suggests a function for miRNAs in tumor suppression. Herein, levels of the miR-17-5p/miR-20a miRNA cluster were inversely correlated to cyclin D1 abundance in human breast tumors and cell lines. MiR-17/20 suppressed breast cancer cell proliferation and tumor colony formation by negatively regulating cyclin D1 translation via a conserved 3' untranslated region miRNA-binding site, thereby inhibiting serum-induced S phase entry. The cell cycle effect of miR-17/20 was abrogated by cyclin D1 siRNA and in cyclin D1-deficient breast cancer cells. Mammary epithelial cell-targeted cyclin D1 expression induced miR-17-5p and miR-20a expression in vivo, and cyclin D1 bound the miR-17/20 cluster promoter regulatory region. In summary, these studies identify a novel cyclin D1/miR-17/20 regulatory feedback loop through which cyclin D1 induces miR-17-5p/miR-20a. In turn, miR-17/20 limits the proliferative function of cyclin D1, thus linking expression of a specific miRNA cluster to the regulation of oncogenesis.

Authors
Yu, Z; Wang, C; Wang, M; Li, Z; Casimiro, MC; Liu, M; Wu, K; Whittle, J; Ju, X; Hyslop, T; McCue, P; Pestell, RG
MLA Citation
Yu, Zuoren, et al. “A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation..” J Cell Biol, vol. 182, no. 3, Aug. 2008, pp. 509–17. Pubmed, doi:10.1083/jcb.200801079.
PMID
18695042
Source
pubmed
Published In
The Journal of Cell Biology
Volume
182
Issue
3
Publish Date
2008
Start Page
509
End Page
517
DOI
10.1083/jcb.200801079

Transcription factors Stat5a and Stat5b: Favorable prognostic markers in breast cancer.

22071 Background: We have previously reported that presence of nuclear localized, tyrosine phosphorylated Stat5 in breast carcinoma cells is associated with a highly favorable prognosis in a material of 209 patients with node-negative breast cancer. This initial analysis was performed on tissue array sections and not on whole sections. Furthermore, the initial study did not distinguish between Stat5a and Stat5b, since the phosphotyrosine-motif recognized by the antibody is the same in Stat5a and Stat5b. Stat5a and Stat5b are highly homologous transcription factors with overlapping but distinct regulation and biological effects. It has remained unclear whether both Stat5a and Stat5b contribute to the favorable prognosis associated with positive anti-phospho-Stat5 status. METHODS: We have now performed a retrospective follow-up analysis of nuclear localized, tyrosine phosphorylated Stat5 in whole sections of breast cancer from an independent material of 400 node-negative breast cancer specimens with outcome data provided by the National Cancer Institute's Cooperative Breast Cancer Tissue Resource (CBCTR). We also analyzed levels of Stat5a and Stat5b individually and performed survival analyses. RESULTS: Nuclear localized, tyrosine phosphorylated Stat5 remained a significant favorable prognostic marker in this independent follow-up material of human breast cancer, validating our previous data. Furthermore, nuclear localized Stat5a and Stat5b both correlated with favorable prognosis. In contrast, nuclear localized phosphorylated Stat3 did not significantly correlate with prognosis. CONCLUSIONS: Levels of nuclear localized, tyrosine phosphorylated Stat5a/b, alone or in conjunction with levels of nuclear Stat5a or Stat5b proteins, could be a cost-effective test identifying a subset of node-negative breast cancer patients with excellent prognosis who may be managed less aggressively following surgery. No significant financial relationships to disclose.

Authors
Witkiewicz, A; Ryder, A; Neilson, LM; Utama, FE; Tran, TH; Hyslop, T; Rui, H
MLA Citation
Witkiewicz, A., et al. “Transcription factors Stat5a and Stat5b: Favorable prognostic markers in breast cancer..” J Clin Oncol, vol. 26, no. 15_suppl, May 2008.
PMID
27950536
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
22071

A prospective multicenter study of guanylyl cyclase C (GCC), quantified by the reverse transcriptase-polymerase chain reaction (qRT-PCR), as a prognostic marker of occult metastases in lymph nodes of pN0 colorectal cancer patients.

11011 Background: Patients with pN0 colorectal cancer have a ∼25% risk of disease recurrence reflecting, in part, under-diagnosis of lymph node metastases at staging. Improved methods that predict recurrence would identify patients who could benefit from adjuvant chemotherapy. GCC, expressed selectively by intestinal cells and universally in colorectal tumors, is a marker whose detection in lymph nodes could enhance staging. METHODS: At staging, 356 patients with pN0 colorectal cancer from 9 hospitals were enrolled. Fresh lymph nodes >5 mm were bisected for histopathology and GCC qRT-PCR. Three hundred patients provided lymph nodes, of which 261 provided tissues with sufficient mRNA for analysis. Categorical GCC expression, normalized to beta-actin, was estimated in 2,452 lymph nodes from these patients, who were followed to assess time to recurrence. RESULTS: Median follow-up of patients was 45 months (range 1-75 months). Of the 261 patients, 13% (34 patients) had lymph nodes free of occult metastases by GCC qRT-PCR and all but 2 remained free of disease (5.8% raw recurrence rate). Conversely, 20.7% (47 patients) with lymph nodes containing occult metastases by GCC qRT-PCR developed recurrent disease (p=0.029, log-rank test). In multivariable Cox models, controlling for T stage, tumor location, lymphovascular invasion, and tumor differentiation, occult metastases in lymph nodes by GCC qRT-PCR was the most powerful independent predictor of recurrence (adjusted Hazard Ratio=4.51, p=0.039, 95%CI=1.07, 18.90). CONCLUSIONS: GCC qRT-PCR identifies occult metastases in lymph nodes that independently predict time to recurrence in pN0 colorectal cancer patients. Thus, GCC may serve as a prognostic and predictive marker, identifying pN0 patients at minimum risk for disease recurrence and, conversely, who might benefit from adjuvant chemotherapy, respectively. [Table: see text].

Authors
Waldman, SA; Hyslop, T; Schulz, S; Nielsen, K; Haaf, J; Bonaccorso, C; Li, Y; Barkun, A; Weinberg, D
MLA Citation
Waldman, S. A., et al. “A prospective multicenter study of guanylyl cyclase C (GCC), quantified by the reverse transcriptase-polymerase chain reaction (qRT-PCR), as a prognostic marker of occult metastases in lymph nodes of pN0 colorectal cancer patients..” J Clin Oncol, vol. 26, no. 15_suppl, May 2008.
PMID
27948328
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
11011

Relative quantification based on logistic models for individual polymerase chain reactions.

The quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) technology measures molecular variations in specific biomarkers. Relative quantification determines the target expression relative to an external standard or reference sample and should be adjusted for the PCR efficiencies actually achieved. More accurate methods of estimating PCR efficiency require a number of serial dilutions of the target sample, which is not generally feasible for clinical specimens. Alternatively, the efficiency of a single reaction may be estimated by considering kinetic data from this reaction. The current methods of estimating individual reaction efficiency require finding its exponential phase, which may affect the accuracy and precision of efficiency estimates. Thus, a model adequately representing all available kinetic RT-PCR data is preferable, but no such model is currently in use for relative quantification. In this work, we use a logistic model for all kinetic data from each RT-PCR and propose a new method of efficiency-adjusted relative quantification based on the estimates from the fitted logistic models. This method allows incorporating multiple replicates and possibly multiple reference ('housekeeping') genes for estimating relative expression and corresponding confidence interval. Real kinetic RT-PCR data are used to compare the proposed and standard methods. The methods are applied to the clinical data from the ongoing study of guanylyl cyclase C as a biomarker for colorectal cancer.

Authors
Chervoneva, I; Li, Y; Iglewicz, B; Waldman, S; Hyslop, T
MLA Citation
Chervoneva, Inna, et al. “Relative quantification based on logistic models for individual polymerase chain reactions..” Stat Med, vol. 26, no. 30, Dec. 2007, pp. 5596–611. Pubmed, doi:10.1002/sim.3127.
PMID
17968873
Source
pubmed
Published In
Statistics in Medicine
Volume
26
Issue
30
Publish Date
2007
Start Page
5596
End Page
5611
DOI
10.1002/sim.3127

Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas.

Noncoding RNA (ncRNA) transcripts are thought to be involved in human tumorigenesis. We report that a large fraction of genomic ultraconserved regions (UCRs) encode a particular set of ncRNAs whose expression is altered in human cancers. Genome-wide profiling revealed that UCRs have distinct signatures in human leukemias and carcinomas. UCRs are frequently located at fragile sites and genomic regions involved in cancers. We identified certain UCRs whose expression may be regulated by microRNAs abnormally expressed in human chronic lymphocytic leukemia, and we proved that the inhibition of an overexpressed UCR induces apoptosis in colon cancer cells. Our findings argue that ncRNAs and interaction between noncoding genes are involved in tumorigenesis to a greater extent than previously thought.

Authors
Calin, GA; Liu, C-G; Ferracin, M; Hyslop, T; Spizzo, R; Sevignani, C; Fabbri, M; Cimmino, A; Lee, EJ; Wojcik, SE; Shimizu, M; Tili, E; Rossi, S; Taccioli, C; Pichiorri, F; Liu, X; Zupo, S; Herlea, V; Gramantieri, L; Lanza, G; Alder, H; Rassenti, L; Volinia, S; Schmittgen, TD; Kipps, TJ; Negrini, M; Croce, CM
MLA Citation
Calin, George A., et al. “Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas..” Cancer Cell, vol. 12, no. 3, Sept. 2007, pp. 215–29. Pubmed, doi:10.1016/j.ccr.2007.07.027.
PMID
17785203
Source
pubmed
Published In
Cancer Cell
Volume
12
Issue
3
Publish Date
2007
Start Page
215
End Page
229
DOI
10.1016/j.ccr.2007.07.027

A general approach for two-stage analysis of multilevel clustered non-Gaussian data.

In this article, we propose a two-stage approach to modeling multilevel clustered non-Gaussian data with sufficiently large numbers of continuous measures per cluster. Such data are common in biological and medical studies utilizing monitoring or image-processing equipment. We consider a general class of hierarchical models that generalizes the model in the global two-stage (GTS) method for nonlinear mixed effects models by using any square-root-n-consistent and asymptotically normal estimators from stage 1 as pseudodata in the stage 2 model, and by extending the stage 2 model to accommodate random effects from multiple levels of clustering. The second-stage model is a standard linear mixed effects model with normal random effects, but the cluster-specific distributions, conditional on random effects, can be non-Gaussian. This methodology provides a flexible framework for modeling not only a location parameter but also other characteristics of conditional distributions that may be of specific interest. For estimation of the population parameters, we propose a conditional restricted maximum likelihood (CREML) approach and establish the asymptotic properties of the CREML estimators. The proposed general approach is illustrated using quartiles as cluster-specific parameters estimated in the first stage, and applied to the data example from a collagen fibril development study. We demonstrate using simulations that in samples with small numbers of independent clusters, the CREML estimators may perform better than conditional maximum likelihood estimators, which are a direct extension of the estimators from the GTS method.

Authors
Chervoneva, I; Iglewicz, B; Hyslop, T
MLA Citation
Chervoneva, Inna, et al. “A general approach for two-stage analysis of multilevel clustered non-Gaussian data..” Biometrics, vol. 62, no. 3, Sept. 2006, pp. 752–59. Pubmed, doi:10.1111/j.1541-0420.2005.00512.x.
PMID
16984317
Source
pubmed
Published In
Biometrics
Volume
62
Issue
3
Publish Date
2006
Start Page
752
End Page
759
DOI
10.1111/j.1541-0420.2005.00512.x

Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.

A large number of tiny noncoding RNAs have been cloned and named microRNAs (miRs). Recently, we have reported that miR-15a and miR-16a, located at 13q14, are frequently deleted and/or down-regulated in patients with B cell chronic lymphocytic leukemia, a disorder characterized by increased survival. To further investigate the possible involvement of miRs in human cancers on a genome-wide basis, we have mapped 186 miRs and compared their location to the location of previous reported nonrandom genetic alterations. Here, we show that miR genes are frequently located at fragile sites, as well as in minimal regions of loss of heterozygosity, minimal regions of amplification (minimal amplicons), or common breakpoint regions. Overall, 98 of 186 (52.5%) of miR genes are in cancer-associated genomic regions or in fragile sites. Moreover, by Northern blotting, we have shown that several miRs located in deleted regions have low levels of expression in cancer samples. These data provide a catalog of miR genes that may have roles in cancer and argue that the full complement of miRs in a genome may be extensively involved in cancers.

Authors
Calin, GA; Sevignani, C; Dumitru, CD; Hyslop, T; Noch, E; Yendamuri, S; Shimizu, M; Rattan, S; Bullrich, F; Negrini, M; Croce, CM
MLA Citation
Calin, George Adrian, et al. “Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers..” Proc Natl Acad Sci U S A, vol. 101, no. 9, Mar. 2004, pp. 2999–3004. Pubmed, doi:10.1073/pnas.0307323101.
PMID
14973191
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
101
Issue
9
Publish Date
2004
Start Page
2999
End Page
3004
DOI
10.1073/pnas.0307323101

Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study.

The role that maternal and fetal human leukocyte antigen (HLA) genes play in pregnancy is unknown, but it has been suggested that fetuses whose HLA alleles do not differ from maternal alleles (i.e. histocompatible fetuses) are more likely to be aborted than fetuses with HLA alleles that differ from maternal alleles (i.e. histoincompatible fetuses). To elucidate the role of HLA compatibility in pregnancy, we tested the hypothesis that couples who match for HLA alleles or haplotypes would have reduced fertility because only these couples could produce histocompatible fetuses. We conducted a 10 year prospective study of HLA matching and pregnancy outcome in 111 Hutterite couples, providing information on 251 pregnancies. A logistic regression analysis was performed to determine the effects of HLA matching at HLA regions and loci on pregnancy outcome (fetal loss versus delivery). Significantly increased fetal loss rates were observed among couples matching for the entire 16-locus haplotype (P = 0.002). Among the individual loci, loss rates were increased among couples matching for HLA-B (P = 0.019), HLA-C (P = 0.033) and the complement component, C4 (P = 0.043). We interpret these results as evidence that matching for the entire 16-locus haplotype and/or alleles at an HLA-B-linked locus confers significant risk for fetal loss.

Authors
Ober, C; Hyslop, T; Elias, S; Weitkamp, LR; Hauck, WW
MLA Citation
Ober, C., et al. “Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study..” Hum Reprod, vol. 13, no. 1, Jan. 1998, pp. 33–38. Pubmed, doi:10.1093/humrep/13.1.33.
PMID
9512225
Source
pubmed
Published In
Human Reproduction
Volume
13
Issue
1
Publish Date
1998
Start Page
33
End Page
38
DOI
10.1093/humrep/13.1.33
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Research Areas:

  • Breast Neoplasms
  • Cohort Studies
  • Colorectal Neoplasms
  • Gastrointestinal Hormones
  • Gastrointestinal Tract
  • Italy
  • Lung Neoplasms
  • Models, Statistical
  • Neoplasm Invasiveness
  • Prognosis
  • Socioeconomic Factors
  • Survival Analysis
  • Thyroid Neoplasms
  • Thyroidectomy
  • Urogenital System