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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:

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

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

Administered By
Surgery, Advanced Oncologic and Gastrointestinal Surgery
AwardedBy
Alliance for Clinical Trials in Oncology Foundation
Role
Investigator
Start Date
June 01, 2016
End Date
February 28, 2021

City of Hope / Contract to continue work on 1U01CA189283-01A1

Administered By
Biostatistics & Bioinformatics
AwardedBy
City of Hope
Role
Principal Investigator
Start Date
October 01, 2015
End Date
July 31, 2020

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

Administered By
Surgery, Advanced Oncologic and Gastrointestinal Surgery
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
September 01, 2016
End Date
August 31, 2018

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, 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

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
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

Breast Cancer Research Foundation

Administered By
Duke Cancer Institute
AwardedBy
Alliance for Clinical Trials in Oncology Foundation
Role
Principal Investigator
Start Date
October 01, 2015
End Date
September 30, 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
AwardedBy
Susan G Komen for the Cure
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:

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, Q, Li, X, Acharya, CR, Hyslop, T, and Sosa, JA. "A novel integrative risk index of papillary thyroid cancer progression combining genomic alterations and clinical factors." Oncotarget (February 6, 2017).
PMID
28187428
Source
epmc
Published In
Oncotarget
Publish Date
2017
DOI
10.18632/oncotarget.15128

Reply to J. Heil et al.

Authors
Hwang, ES; Hyslop, T
MLA Citation
Hwang, ES, and Hyslop, T. "Reply to J. Heil et al." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34.34 (December 2016): 4192-.
PMID
27621401
Source
epmc
Published In
Journal of Clinical Oncology
Volume
34
Issue
34
Publish Date
2016
Start Page
4192

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, AE, Baybutt, TR, Hyslop, T, and Waldman, SA. "Preclinical Evaluation of a Replication-Deficient Recombinant Adenovirus Serotype 5 Vaccine Expressing Guanylate Cyclase C and the PADRE T-helper Epitope." Human gene therapy methods 27.6 (December 2016): 238-250.
PMID
27903079
Source
epmc
Published In
Human gene therapy methods
Volume
27
Issue
6
Publish Date
2016
Start Page
238
End Page
250
DOI
10.1089/hgtb.2016.114

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, MA, Thomas, S, Hyslop, T, Scheri, RP, Roman, SA, and Sosa, JA. "Exploring the Relationship Between Patient Age and Cancer-Specific Survival in Papillary Thyroid Cancer: Rethinking Current Staging Systems." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34.36 (December 2016): 4415-4420.
PMID
27998233
Source
epmc
Published In
Journal of Clinical Oncology
Volume
34
Issue
36
Publish Date
2016
Start Page
4415
End Page
4420

The Effect of Hospital Volume on Breast Cancer Mortality.

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.Prior literature has demonstrated improved survival with treatment at high volume centers among less common cancers requiring technically complex surgery.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.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.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, RA, Obeng-Gyasi, S, Thomas, S, Houck, K, Lane, WO, Blitzblau, RC, Hyslop, T, and Hwang, ES. "The Effect of Hospital Volume on Breast Cancer Mortality." Annals of surgery (November 23, 2016).
PMID
27893532
Source
epmc
Published In
Annals of Surgery
Publish Date
2016

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, AR, Girondo, MA, Liu, C, Kovatich, AJ, Hooke, JA, Shriver, CD, Hu, H, Mitchell, EP, Freydin, B, Hyslop, T, Chervoneva, I, and Rui, H. "Validation of tumor protein marker quantification by two independent automated immunofluorescence image analysis platforms." Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 29.10 (October 2016): 1143-1154.
PMID
27312066
Source
epmc
Published In
Modern Pathology
Volume
29
Issue
10
Publish Date
2016
Start Page
1143
End Page
1154
DOI
10.1038/modpathol.2016.112

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

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.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).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).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, AD, Sung, JAM, Thomas, S, Hyslop, T, Gasparetto, C, Long, G, Rizzieri, D, Sullivan, KM, Corbet, K, Broadwater, G, Chao, NJ, and Horwitz, ME. "Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial." Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 63.8 (October 2016): 999-1006.
PMID
27481873
Source
epmc
Published In
Clinical Infectious Diseases
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.

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.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.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.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, TJ, Thomas, S, Dinan, MA, Roman, S, Sosa, JA, and Hyslop, T. "How Many Lymph Nodes Are Enough? Assessing the Adequacy of Lymph Node Yield for Papillary Thyroid Cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34.28 (October 2016): 3434-3439.
PMID
27528716
Source
epmc
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

Patient-Reported Outcomes After Choice for Contralateral Prophylactic Mastectomy.

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.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.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.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, ES, Locklear, TD, Rushing, CN, Samsa, G, Abernethy, AP, Hyslop, T, and Atisha, DM. "Patient-Reported Outcomes After Choice for Contralateral Prophylactic Mastectomy." May 2016.
PMID
26951322
Source
epmc
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

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

We evaluated differences in treatment of black vs white patients with colon cancer and assessed their effects on survival, based on cancer stage.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.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.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, Y, Wang, C, Civan, JM, Palazzo, JP, Ye, Z, Hyslop, T, Lin, J, Myers, RE, Li, B, Jiang, B, Sama, A, Xing, J, and Yang, H. "Effects of Cancer Stage and Treatment Differences on Racial Disparities in Survival From Colon Cancer: A United States Population-Based Study." Gastroenterology 150.5 (May 2016): 1135-1146.
PMID
26836586
Source
epmc
Published In
Gastroenterology
Volume
150
Issue
5
Publish Date
2016
Start Page
1135
End Page
1146
DOI
10.1053/j.gastro.2016.01.030

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.The surgeon volume-outcome association has been established for thyroidectomy; however, a threshold number of cases defining a "high-volume" surgeon remains unclear.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.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.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, MA, Thomas, S, Youngwirth, L, Hyslop, T, Reed, SD, Scheri, RP, Roman, SA, and Sosa, JA. "Is There a Minimum Number of Thyroidectomies a Surgeon Should Perform to Optimize Patient Outcomes?." Annals of surgery (March 8, 2016).
PMID
26967630
Source
epmc
Published In
Annals of Surgery
Publish Date
2016

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, CR, Sato, T, Peck, AR, Girondo, MA, Yang, N, Liu, C, Yanac, AF, Kovatich, AJ, Hooke, JA, Shriver, CD, Mitchell, EP, Hyslop, T, and Rui, H. "Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism." Oncogene 35.11 (March 2016): 1373-1385.
PMID
26096934
Source
epmc
Published In
Oncogene: Including Oncogene Reviews
Volume
35
Issue
11
Publish Date
2016
Start Page
1373
End Page
1385
DOI
10.1038/onc.2015.193

Latent class model characterization of neighborhood socioeconomic status.

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.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.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.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, A, Michael, Y, and Hyslop, T. "Latent class model characterization of neighborhood socioeconomic status." Cancer causes & control : CCC 27.3 (March 2016): 445-452.
PMID
26797452
Source
epmc
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

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

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.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.The related source code and documents are freely available at https://sites.google.com/site/bestumich/issues.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, K, Li, Y, Zhu, J, Liu, H, Lee, JE, Amos, CI, Hyslop, T, Jin, J, Lin, H, Wei, Q, and Li, Y. "Component-wise gradient boosting and false discovery control in survival analysis with high-dimensional covariates." Bioinformatics (Oxford, England) 32.1 (January 2016): 50-57.
Website
http://hdl.handle.net/10161/10678
PMID
26382192
Source
epmc
Published In
Bioinformatics
Volume
32
Issue
1
Publish Date
2016
Start Page
50
End Page
57
DOI
10.1093/bioinformatics/btv517

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, JE, Colon-Gonzalez, F, Blomain, E, Kim, GW, Aing, A, Stoecker, B, Rock, J, Snook, AE, Zhan, T, Hyslop, TM, Tomczak, M, Blumberg, RS, and Waldman, SA. "Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis." Cancer research 76.2 (January 2016): 339-346.
PMID
26773096
Source
epmc
Published In
Cancer Research
Volume
76
Issue
2
Publish Date
2016
Start Page
339
End Page
346
DOI
10.1158/0008-5472.can-15-1467-t

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, 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, and Cristofanilli, M. "Prospective assessment of the prognostic value of circulating tumor cells and their clusters in patients with advanced-stage breast cancer." Breast cancer research and treatment 154.3 (December 2015): 563-571.
PMID
26573830
Source
epmc
Published In
Breast Cancer Research and Treatment
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, MA, Pura, J, Goffredo, P, Dinan, MA, Reed, SD, Scheri, RP, Hyslop, T, Roman, SA, and Sosa, JA. "Presence and Number of Lymph Node Metastases Are Associated With Compromised Survival for Patients Younger Than Age 45 Years With Papillary Thyroid Cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.21 (July 2015): 2370-2375.
PMID
26077238
Source
epmc
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, TN, Hegarty, SE, Rabinowitz, C, Maio, V, Hyslop, T, Dicker, AP, and Louis, DZ. "Assessing adverse events of postprostatectomy radiation therapy for prostate cancer: evaluation of outcomes in the Regione Emilia-Romagna, Italy." International journal of radiation oncology, biology, physics 91.4 (March 2015): 752-759.
PMID
25752388
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
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, Lai, Y, Axelrod, R, Campling, B, Hyslop, T, Civan, J, Solomides, C, Myers, RE, Lu, B, Bar Ad, V, Li, B, Ye, Z, and Yang, H. "Modeling the overall survival of patients with advanced-stage non-small cell lung cancer using data of routine laboratory tests." International Journal of Cancer 136.2 (January 1, 2015): 382-391.
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

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

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.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.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).Multivariable modeling was used to compare OS for patients undergoing total thyroidectomy vs lobectomy.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).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, MA, Pura, J, Goffredo, P, Dinan, MA, Hyslop, T, Reed, SD, Scheri, RP, Roman, SA, and Sosa, JA. "Impact of extent of surgery on survival for papillary thyroid cancer patients younger than 45 years." The Journal of clinical endocrinology and metabolism 100.1 (January 2015): 115-121.
PMID
25337927
Source
epmc
Published In
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.

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.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.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].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, C, Civan, J, Lai, Y, Cristofanilli, M, Hyslop, T, Palazzo, JP, Myers, RE, Li, B, Ye, Z, Zhang, K, Xing, J, and Yang, H. "Racial disparity in breast cancer survival: the impact of pre-treatment hematologic variables." Cancer causes & control : CCC 26.1 (January 2015): 45-56.
PMID
25359303
Source
epmc
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.

To evaluate the influence of timing of salvage and adjuvant radiation therapy on outcomes after prostatectomy for prostate cancer.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).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).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, SE, Hyslop, T, Dicker, AP, and Showalter, TN. "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 10.2 (January 2015): e0118430-.
PMID
25706657
Source
epmc
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, MA, Pura, J, Goffredo, P, Dinan, MA, Hyslop, T, Reed, SD, Scheri, RP, Roman, SA, and Sosa, JA. "Impact of extent of surgery on survival for papillary thyroid cancer patients younger than 45 years." Journal of Clinical Endocrinology and Metabolism 100.1 (2015): 115-121.
Source
scival
Published In
Journal of Clinical Endocrinology and Metabolism
Volume
100
Issue
1
Publish Date
2015
Start Page
115
End Page
121
DOI
10.1210/jc.20143039

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

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, Deng, A, Hoffman-Censits, J, Gibney, G, Hyslop, T, Miller, B, Kilpatrick, D, Jabbour, S, and Kevin Kelly, W. "An open label randomized phase II study of pasireotide with or without everolimus in castrate-resistant chemotherapy-naïve prostate cancer patients." Cancer Treatment Communications 4 (2015): 192-195.
Source
crossref
Published In
Cancer Treatment Communications
Volume
4
Publish Date
2015
Start Page
192
End Page
195
DOI
10.1016/j.ctrc.2015.11.003

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

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.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.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.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.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, C, Lin, JE, Li, P, Snook, AE, Gong, J, Sato, T, Liu, C, Girondo, MA, Rui, H, Hyslop, T, and Waldman, SA. "The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 23.11 (November 2014): 2328-2337.
PMID
25304930
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
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: Table 1.

Authors
Palumbo, A; Michael, Y; Hyslop, T
MLA Citation
Palumbo, A, Michael, Y, and Hyslop, T. "Abstract 4137: Latent class model characterization of neighborhood SES: Table 1." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
4137
End Page
4137
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, Kovatich, AJ, Fantacone-Campbell, JL, Hooke, JA, Kvecher, L, Kovatich, AW, Gallagher, CM, Hueman, MT, Hyslop, T, Mural, RJ, Shriver, CD, Rui, H, and Hu, H. "Abstract P4-06-09: HER2+ and HER2- luminal B subtypes have similar overall survival and histologic grade distributions." Cancer Research 73.24 Supplement (December 15, 2013): P4-06-09-P4-06-09.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
24 Supplement
Publish Date
2013
Start Page
P4-06-09
End Page
P4-06-09
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, AJ, Chen, Y, Fantacone-Campbell, JL, Wareham, JA, Tafra, L, Kvecher, L, Hyslop, T, Hooke, JA, Rui, H, Shriver, CD, Mural, RJ, and Hu, H. "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:." Cancer Research 73.24 Supplement (December 15, 2013): P4-06-03-P4-06-03.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
24 Supplement
Publish Date
2013
Start Page
P4-06-03
End Page
P4-06-03
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, MA, Peck, AR, Freydin, B, Chervoneva, I, Hyslop, T, Kovatich, AJ, Hooke, JA, Shriver, CD, Mitchell, EP, and Rui, H. "Abstract P1-08-20: Increased risk of hormone therapy failure in breast cancers expressing low phospho-Stat5: Validation of quantitative immunofluorescence assay parameters." Cancer Research 73.24 Supplement (December 15, 2013): P1-08-20-P1-08-20.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
24 Supplement
Publish Date
2013
Start Page
P1-08-20
End Page
P1-08-20
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, T, Michael, Y, Avery, T, and Rui, H. "Population and target considerations for triple-negative breast cancer clinical trials." Biomarkers in medicine 7.1 (February 2013): 11-21. (Review)
PMID
23387481
Source
epmc
Published In
Biomarkers in medicine
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, JE, Snook, AE, Li, P, Stoecker, BA, Kim, GW, Magee, MS, Garcia, AVM, Valentino, MA, Hyslop, T, Schulz, S, and Waldman, SA. "GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity." PloS one 7.2 (January 2012): e31686-.
PMID
22384056
Source
epmc
Published In
PloS one
Volume
7
Issue
2
Publish Date
2012
Start Page
e31686
DOI
10.1371/journal.pone.0031686

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

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.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.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, 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, and Rui, H. "Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.18 (June 2011): 2448-2458.
PMID
21576635
Source
epmc
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

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

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.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.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, I, Li, Y, Schulz, S, Croker, S, Wilson, C, Waldman, SA, and Hyslop, T. "Selection of optimal reference genes for normalization in quantitative RT-PCR." BMC bioinformatics 11 (May 14, 2010): 253-.
PMID
20470420
Source
epmc
Published In
BMC Bioinformatics
Volume
11
Publish Date
2010
Start Page
253
DOI
10.1186/1471-2105-11-253

The Hormone Receptor GUCY2C Suppresses Intestinal Tumor Formation by Inhibiting AKT Signaling

Authors
Lin, JE; Li, P; Snook, AE; Schulz, S; Dasgupta, A; Hyslop, TM; Gibbons, AV; Marszlowicz, G; Pitari, GM; Waldman, SA
MLA Citation
Lin, JE, Li, P, Snook, AE, Schulz, S, Dasgupta, A, Hyslop, TM, Gibbons, AV, Marszlowicz, G, Pitari, GM, and Waldman, SA. "The Hormone Receptor GUCY2C Suppresses Intestinal Tumor Formation by Inhibiting AKT Signaling." GASTROENTEROLOGY 138.1 (January 2010): 241-254.
PMID
19737566
Source
wos-lite
Published In
Gastroenterology
Volume
138
Issue
1
Publish Date
2010
Start Page
241
End Page
254
DOI
10.1053/j.gastro.2009.08.064

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

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.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.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.Time to recurrence (primary outcome) and disease-free survival (secondary outcome) relative to expression of GUCY2C in lymph nodes.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).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, SA, Hyslop, T, Schulz, S, Barkun, A, Nielsen, K, Haaf, J, Bonaccorso, C, Li, Y, and Weinberg, DS. "Association of GUCY2C expression in lymph nodes with time to recurrence and disease-free survival in pN0 colorectal cancer." JAMA 301.7 (February 2009): 745-752.
PMID
19224751
Source
epmc
Published In
JAMA : the journal of the American Medical Association
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, Z, Wang, C, Wang, M, Li, Z, Casimiro, MC, Liu, M, Wu, K, Whittle, J, Ju, X, Hyslop, T, McCue, P, and Pestell, RG. "A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation." The Journal of cell biology 182.3 (August 2008): 509-517.
PMID
18695042
Source
epmc
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

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, I, Li, Y, Iglewicz, B, Waldman, S, and Hyslop, T. "Relative quantification based on logistic models for individual polymerase chain reactions." Statistics in medicine 26.30 (December 2007): 5596-5611.
PMID
17968873
Source
epmc
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, 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, and Croce, CM. "Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas." Cancer cell 12.3 (September 2007): 215-229.
PMID
17785203
Source
epmc
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, I, Iglewicz, B, and Hyslop, T. "A general approach for two-stage analysis of multilevel clustered non-Gaussian data." Biometrics 62.3 (September 2006): 752-759.
PMID
16984317
Source
epmc
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, GA, Sevignani, C, Dumitru, CD, Hyslop, T, Noch, E, Yendamuri, S, Shimizu, M, Rattan, S, Bullrich, F, Negrini, M, and Croce, CM. "Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers." Proceedings of the National Academy of Sciences of the United States of America 101.9 (March 2004): 2999-3004.
PMID
14973191
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
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, Hyslop, T, Elias, S, Weitkamp, LR, and Hauck, WW. "Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study." Human reproduction (Oxford, England) 13.1 (January 1998): 33-38.
PMID
9512225
Source
epmc
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