73 results on '"Covington KR"'
Search Results
2. P1-12-04: EBP50 – A Novel Biomarker for Resistance to Endocrine and HER2−Targeted Therapies in Breast Cancer.
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Gu, G, primary, Covington, KR, additional, Fernandez, NM, additional, Ando’, S, additional, and Fuqua, SAW, additional
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- 2011
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3. Abstract P5-06-14: Ezrin Binding Protein Ebp50 Negatively Regulates HER2 and Alters Tamoxifen Sensitivity
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Gu, G, primary, Covington, KR, additional, Fernandez, NM, additional, Ando, S, additional, and Fuqua, SAW., additional
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- 2010
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4. Abstract P5-06-01: MTA2 and AR Overexpression in ER-Negative Breast Cancer Cells: Roles in Invasion and Metastasis
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Morales, SF, primary, Covington, KR, additional, Ciupek, A, additional, Brusco, L, additional, Weigel, NL, additional, Lu, Y, additional, Mills, G, additional, and Fuqua, SAW., additional
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- 2010
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5. Abstract P5-06-08: Role of Androgen Receptor in Metastasis and Hormone Resistance of Estrogen Receptor Positive Breast Cancer
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Ciupek, A, primary, Brusco, L, additional, Covington, KR, additional, Weigel, NL, additional, Lu, Y, additional, Mills, G, additional, and Fuqua, SAW., additional
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- 2010
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6. MTA2 is a metastasis promoter in breast cancer cells.
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Covington, KR, primary, Barone, I, additional, Cui, Y, additional, Tsimelzon, A, additional, Rodriguez, A, additional, Wang, T, additional, and Fuqua, SA, additional
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- 2009
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7. Predicting adjuvant radiation therapy benefit in cutaneous squamous cell carcinoma with the 40-gene expression profile.
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Ruiz ES, Brito K, Karn EE, Vidimos AT, Campbell SR, Wang DM, Siegel JJ, Covington KR, Cook RW, Goldberg MS, and Koyfman SA
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Aim: To independently confirm that the 40-gene expression profile (40-GEP) test can identify patients with high-risk cutaneous squamous cell carcinoma who are more or less likely to benefit from adjuvant radiation therapy (ART). Materials & methods: Primary cutaneous squamous cell carcinoma tumors from two academic centers received retrospective 40-GEP testing and were analyzed for 5-year metastasis-free survival and projected time to event. Results: Random sampling of matched patient pairs ( n = 52 ART-treated; 371 no ART) showed a median 50% decrease in 5-year progression rate for ART-treated patients (vs no ART) with 40-GEP Class 2B. Class 2A was associated with a modest ART benefit, but not Class 1. Conclusion: The 40-GEP identified patients most likely to benefit from ART (Class 2B) and those that can consider deferring treatment (Class 1).
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- 2024
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8. 31-Gene Expression Profile Testing in Cutaneous Melanoma and Survival Outcomes in a Population-Based Analysis: A SEER Collaboration.
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Bailey CN, Martin BJ, Petkov VI, Schussler NC, Stevens JL, Bentler S, Cress RD, Doherty JA, Durbin EB, Gomez SL, Gonsalves L, Hernandez BY, Liu L, Morawski BM, Schymura MJ, Schwartz SM, Ward KC, Wiggins C, Wu XC, Goldberg MS, Siegel JJ, Cook RW, Covington KR, and Kurley SJ
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- Humans, Transcriptome, Kaplan-Meier Estimate, Melanoma, Cutaneous Malignant, Melanoma genetics, Skin Neoplasms genetics
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Purpose: The DecisionDx-Melanoma 31-gene expression profile (31-GEP) test is validated to classify cutaneous malignant melanoma (CM) patient risk of recurrence, metastasis, or death as low (class 1A), intermediate (class 1B/2A), or high (class 2B). This study aimed to examine the effect of 31-GEP testing on survival outcomes and confirm the prognostic ability of the 31-GEP at the population level., Methods: Patients with stage I-III CM with a clinical 31-GEP result between 2016 and 2018 were linked to data from 17 SEER registries (n = 4,687) following registries' operation procedures for linkages. Melanoma-specific survival (MSS) and overall survival (OS) differences by 31-GEP risk category were examined using Kaplan-Meier analysis and the log-rank test. Crude and adjusted hazard ratios (HRs) were calculated using Cox regression model to evaluate variables associated with survival. 31-GEP tested patients were propensity score-matched to a cohort of non-31-GEP tested patients from the SEER database. Robustness of the effect of 31-GEP testing was assessed using resampling., Results: Patients with a 31-GEP class 1A result had higher 3-year MSS and OS than patients with a class 1B/2A or class 2B result (MSS: 99.7% v 97.1% v 89.6%, P < .001; OS: 96.6% v 90.2% v 79.4%, P < .001). A class 2B result was an independent predictor of MSS (HR, 7.00; 95% CI, 2.70 to 18.00) and OS (HR, 2.39; 95% CI, 1.54 to 3.70). 31-GEP testing was associated with a 29% lower MSS mortality (HR, 0.71; 95% CI, 0.53 to 0.94) and 17% lower overall mortality (HR, 0.83; 95% CI, 0.70 to 0.99) relative to untested patients., Conclusion: In a population-based, clinically tested melanoma cohort, the 31-GEP stratified patients by their risk of dying from melanoma.
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- 2023
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9. Author Correction: The repertoire of mutational signatures in human cancer.
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Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Tian Ng AW, Wu Y, Boot A, Covington KR, Gordenin DA, Bergstrom EN, Islam SMA, Lopez-Bigas N, Klimczak LJ, McPherson JR, Morganella S, Sabarinathan R, Wheeler DA, Mustonen V, Getz G, Rozen SG, and Stratton MR
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- 2023
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10. Optimizing treatment approaches for patients with cutaneous melanoma by integrating clinical and pathologic features with the 31-gene expression profile test.
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Jarell A, Gastman BR, Dillon LD, Hsueh EC, Podlipnik S, Covington KR, Cook RW, Bailey CN, Quick AP, Martin BJ, Kurley SJ, Goldberg MS, and Puig S
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- Humans, Transcriptome, Retrospective Studies, Sentinel Lymph Node Biopsy, Prognosis, Melanoma, Cutaneous Malignant, Melanoma pathology, Skin Neoplasms pathology
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Background: Many patients with low-stage cutaneous melanoma will experience tumor recurrence, metastasis, or death, and many higher staged patients will not., Objective: To develop an algorithm by integrating the 31-gene expression profile test with clinicopathologic data for an optimized, personalized risk of recurrence (integrated 31 risk of recurrence [i31-ROR]) or death and use i31-ROR in conjunction with a previously validated algorithm for precise sentinel lymph node positivity risk estimates (i31-SLNB) for optimized treatment plan decisions., Methods: Cox regression models for ROR were developed (n = 1581) and independently validated (n = 523) on a cohort with stage I-III melanoma. Using National Comprehensive Cancer Network cut points, i31-ROR performance was evaluated using the midpoint survival rates between patients with stage IIA and stage IIB disease as a risk threshold., Results: Patients with a low-risk i31-ROR result had significantly higher 5-year recurrence-free survival (91% vs 45%, P < .001), distant metastasis-free survival (95% vs 53%, P < .001), and melanoma-specific survival (98% vs 73%, P < .001) than patients with a high-risk i31-ROR result. A combined i31-SLNB/ROR analysis identified 44% of patients who could forego sentinel lymph node biopsy while maintaining high survival rates (>98%) or were restratified as being at a higher or lower risk of recurrence or death., Limitations: Multicenter, retrospective study., Conclusion: Integrating clinicopathologic features with the 31-GEP optimizes patient risk stratification compared to clinicopathologic features alone., Competing Interests: Conflicts of interest Dillon, Covington, Goldberg, Bailey, Quick, Martin, Kurley, and Cook are employees and stock and options holders at Castle Biosciences, Inc. Jarell and Hsueh are on the speaker’s bureau for Castle Biosciences, Inc. Podlipnik and Puig have no conflicts of interest to disclose., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)
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- 2022
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11. Expanded evidence that the 31-gene expression profile test provides clinical utility for melanoma management in a multicenter study.
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Dillon LD, McPhee M, Davidson RS, Quick AP, Martin B, Covington KR, Zolochevska O, Cook RW, Vetto JT, Jarell AD, and Fleming MD
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- Gene Expression Profiling methods, Humans, Neoplasm Staging, Prognosis, Transcriptome, Melanoma, Cutaneous Malignant, Melanoma genetics, Melanoma therapy, Skin Neoplasms diagnosis, Skin Neoplasms genetics, Skin Neoplasms therapy
- Abstract
Objective: National Comprehensive Cancer Network (NCCN) guidelines for cutaneous melanoma (CM) recommend physicians consider increased surveillance for patients who typically have lower melanoma survival rates (stages IIB-IV as determined by the American Joint Committee on Cancer (AJCC), 8th edition). However, up to 15% of patients identified as having a low recurrence risk (stages I-IIA) experience disease recurrence, and some patients identified as having a high recurrence risk will not experience any recurrence. The 31-gene expression profile test (31-GEP) stratifies patient recurrence risk into low (Class 1) and high (Class 2) and has demonstrated risk-appropriate impact on disease management and clinical decisions., Methods: Five-year plans for lab work, frequency of clinical visits, and imaging pre- and post-31-GEP test results were assessed for a cohort of 509 stage I-III patients following an interim subset analysis of 247 patients., Results: After receiving 31-GEP results, 50.6% of patients had a change in management plans in at least one of the following categories-clinical visits, lab work, or surveillance imaging. The changes aligned with the risk predicted by the 31-GEP for 76.1% of patients with a Class 1 result and 78.7% of patients with a Class 2 result. A Class 1 31-GEP result was associated with changes toward low-intensity management recommendations, while a Class 2 result was associated with changes toward high-intensity management recommendations., Conclusion: The 31-GEP can stratify patient recurrence risk in patients with CM, and clinicians understand and apply the prognostic ability of the 31-GEP test to alter patient management in risk-appropriate directions.
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- 2022
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12. Development and validation of a nomogram incorporating gene expression profiling and clinical factors for accurate prediction of metastasis in patients with cutaneous melanoma following Mohs micrographic surgery.
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Thorpe RB, Covington KR, Caruso HG, Quick AP, Zolochevska O, Bricca GM, Campoli M, DeBloom JR Jr, Fazio MJ, Greenhaw BN, Kirkland EB, Machan ML, Brodland DG, and Zitelli JA
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- Bayes Theorem, Gene Expression Profiling methods, Humans, Mohs Surgery, Nomograms, Prognosis, Melanoma, Cutaneous Malignant, Melanoma genetics, Melanoma pathology, Melanoma surgery, Skin Neoplasms genetics, Skin Neoplasms pathology, Skin Neoplasms surgery
- Abstract
Background: There is a need to improve prognostic accuracy for patients with cutaneous melanoma. A 31-gene expression profile (31-GEP) test uses the molecular biology of primary tumors to identify individual patient metastatic risk., Objective: Develop a nomogram incorporating 31-GEP with relevant clinical factors to improve prognostic accuracy., Methods: In an IRB-approved study, 1124 patients from 9 Mohs micrographic surgery centers were prospectively enrolled, treated with Mohs micrographic surgery, and underwent 31-GEP testing. Data from 684 of those patients with at least 1-year follow-up or a metastatic event were included in nomogram development to predict metastatic risk., Results: Logistic regression modeling of 31-GEP results and T stage provided the simplest nomogram with the lowest Bayesian information criteria score. Validation in an archival cohort (n = 901) demonstrated a significant linear correlation between observed and nomogram-predicted risk of metastasis. The resulting nomogram more accurately predicts the risk for cutaneous melanoma metastasis than T stage or 31-GEP alone., Limitations: The patient population is representative of Mohs micrographic surgery centers. Sentinel lymph node biopsy was not performed for most patients and could not be used in the nomogram., Conclusions: Integration of 31-GEP and T stage can gain clinically useful prognostic information from data obtained noninvasively., Competing Interests: Conflicts of interest Drs Covington, Caruso, Quick, and Zolochevska are employees and stockholders at Castle Biosciences. Drs Thorpe, Bricca, Campoli, DeBloom, Fazio, Greenhaw, Kirkland, Machan, Brodland, and Zitelli have no conflicts of interest to disclose., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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13. Improved cutaneous melanoma survival stratification through integration of 31-gene expression profile testing with the American Joint Committee on Cancer 8th Edition Staging.
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Wisco OJ, Marson JW, Litchman GH, Brownstone N, Covington KR, Martin BJ, Quick AP, Siegel JJ, Caruso HG, Cook RW, Winkelmann RR, and Rigel DS
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- Gene Expression Profiling methods, Humans, Neoplasm Staging, Prognosis, Retrospective Studies, Transcriptome, United States, Melanoma, Cutaneous Malignant, Melanoma pathology, Skin Neoplasms pathology
- Abstract
Cutaneous melanoma (CM) survival is assessed using averaged data from the American Joint Committee on Cancer 8th edition (AJCC8). However, subsets of AJCC8 stages I-III have better or worse survival than the predicted average value. The objective of this study was to determine if the 31-gene expression profile (31-GEP) test for CM can further risk-stratify melanoma-specific mortality within each AJCC8 stage. This retrospective multicenter study of 901 archival CM samples obtained from patients with stages I-III CM assessed 31-GEP test predictions of 5-year melanoma-specific survival (MSS) using Kaplan-Meier and Cox proportional hazards. In stage I-III CM population, patients with a Class 2B result had a lower 5-year MSS (77.8%) than patients with a Class 1A result (98.7%) and log-rank testing demonstrated significant stratification of MSS [χ2 (2df, n = 901) = 99.7, P < 0.001). Within each stage, 31-GEP data provided additional risk stratification, including in stage I [χ2 (2df, n = 415) = 11.3, P = 0.004]. Cox regression multivariable analysis showed that the 31-GEP test was a significant predictor of melanoma-specific mortality (MSM) in patients with stage I-III CM [hazard ratio: 6.44 (95% confidence interval: 2.61-15.85), P < 0.001]. This retrospective study focuses on Class 1A versus Class 2B results. Intermediate results (Class 1B/2A) comprised 21.6% of cases with survival rates between Class 1A and 2B, and similar to 5-year MSS AJCC stage values. Data from the 31-GEP test significantly differentiates MSM into lower (Class 1A) and higher risk (Class 2B) groups within each AJCC8 stage. Incorporating 31-GEP results into AJCC8 survival calculations has the potential to more precisely assess survival and enhance management guidance., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2022
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14. Enhanced metastatic risk assessment in cutaneous squamous cell carcinoma with the 40-gene expression profile test.
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Ibrahim SF, Kasprzak JM, Hall MA, Fitzgerald AL, Siegel JJ, Kurley SJ, Covington KR, Goldberg MS, Farberg AS, Trotter SC, Reed K, Brodland DG, Koyfman SA, Somani AK, Arron ST, and Wysong A
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- Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell pathology, Humans, Male, Middle Aged, Prognosis, Risk Factors, Skin Neoplasms pathology, Carcinoma, Squamous Cell genetics, Gene Expression Profiling methods, Risk Assessment methods, Skin Neoplasms genetics
- Abstract
Aim: To clinically validate the 40-gene expression profile (40-GEP) test for cutaneous squamous cell carcinoma patients and evaluate coupling the test with individual clinicopathologic risk factor-based assessment methods. Patients & methods: In a 33-site study, primary tumors with known patient outcomes were assessed under clinical testing conditions (n = 420). The 40-GEP results were integrated with clinicopathologic risk factors. Kaplan-Meier and Cox regression analyses were performed for metastasis. Results: The 40-GEP test demonstrated significant prognostic value. Risk classification was improved via integration of 40-GEP results with clinicopathologic risk factor-based assessment, with metastasis rates near the general cutaneous squamous cell carcinoma population for class 1 and ≥50% for class 2B. Conclusion: Combining molecular profiling with clinicopathologic risk factor assessment enhances stratification of cutaneous squamous cell carcinoma patients and may inform decision-making for risk-appropriate management strategies.
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- 2022
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15. Analytical validity of DecisionDx-SCC, a gene expression profile test to identify risk of metastasis in cutaneous squamous cell carcinoma (SCC) patients.
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Borman S, Wilkinson J, Meldi-Sholl L, Johnson C, Carter K, Covington KR, Fitzgerald AL, Kurley SJ, Farberg AS, Goldberg MS, Monzon FA, Oelschlager K, and Cook RW
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- Gene Expression Profiling methods, Humans, Prognosis, Reproducibility of Results, Transcriptome, Carcinoma, Squamous Cell diagnosis, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Skin Neoplasms diagnosis, Skin Neoplasms genetics, Skin Neoplasms pathology
- Abstract
Background: To improve identification of patients with cutaneous squamous cell carcinoma (SCC) at high risk for metastatic disease, the DecisionDx-SCC assay, a prognostic 40-gene expression profile (40-GEP) test, was developed and validated. The 40-GEP assay utilizes RT-PCR gene expression analysis on primary tumor biopsy tissue to evaluate the expression of 34 signature gene targets and 6 normalization genes. The test provides classifications of low risk (Class 1), moderate risk (Class 2A), and high risk (Class 2B) of metastasis within 3 years of diagnosis. The primary objective of this study was to validate the analytical performance of the 40-gene expression signature., Methods: The repeatability and reproducibility of the 40-GEP test was evaluated by performance of inter-assay, intra-assay, and inter-operator precision experiments along with monitoring the reliability of sample and reagent stability for class call concordance. The technical performance of clinical orders from September 2020 through July 2021 for the 40-GEP test was assessed., Results: Patient hematoxylin and eosin (H&E) stained slides were reviewed by a board-certified pathologist to assess minimum acceptable tumor content. Class specific controls (Class 1 and Class 2B) were evaluated with Levey-Jennings analysis and demonstrated consistent and reproducible results. Inter-assay, inter-operator and intra-assay concordance were all ≥90%, with short-term and long-term RNA stability also meeting minimum concordance requirements. Of the 2586 orders received, 93.5% remained eligible for testing, with 97.1% of all tested samples demonstrating actionable class call results., Conclusion: DecisionDx-SCC demonstrates a high degree of analytical precision, yielding high concordance rates across multiple performance experiments, along with exhibiting robust technical reliability on clinical samples., (© 2022. The Author(s).)
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- 2022
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16. Gene expression profiling for metastatic risk in head and neck cutaneous squamous cell carcinoma.
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Arron ST, Wysong A, Hall MA, Bailey CN, Covington KR, Kurley SJ, Goldberg MS, Kasprzak JM, Somani AK, Ibrahim SF, Brodland DG, Cleaver NJ, Maher IA, Xia Y, Koyfman SA, and Newman JG
- Abstract
Objective: Over 50% of newly diagnosed cutaneous squamous cell carcinoma (cSCC) lesions occur in the head and neck (cSCC-HN), and metastasis to nodal basins in this region further complicates surgical and adjuvant treatment. The current study addressed whether the 40-gene expression profile (40-GEP) test can predict metastatic risk in cSCC-HN with improved accuracy and provide independent prognostic value to complement current risk assessment methods., Study Design: Multicenter, retrospective cohort study., Methods: Formalin-fixed paraffin-embedded primary tumor tissue and associated clinical data from patients with cSCC-HN ( n = 278) were collected from 33 independent centers. Samples were analyzed via the 40-GEP test. Cases were staged per American Joint Committee on Cancer, Eighth Edition (AJCC8) and Brigham and Women's Hospital (BWH) criteria after comprehensive medical record and pathology report review. Metastasis-free survival (MFS) rates were determined, and risk factors were analyzed via Cox regression., Results: The 40-GEP test classified the cohort into low (Class 1, n = 126; 45.3%), moderate (Class 2A, n = 134; 48.2%), and high (Class 2B, n = 18; 6.5%) metastatic risk at 3 years postdiagnosis. Regional/distant metastasis occurred in 54 patients (19.4%). MFS rates were 92.1% (Class 1), 76.1% (Class 2A), and 44.4% (Class 2B; p < .0001). Multivariate analysis of 40-GEP results with AJCC8 or BWH tumor stage, or clinicopathologic risk factors, demonstrated independent prognostic value of the 40-GEP test ( p < .03). Accuracy of predicting metastatic risk was also improved using 40-GEP classification ( p < .02)., Conclusions: Improved metastatic risk stratification through the 40-GEP test could complement cSCC-HN risk assessment for better-informed decision-making for treatment and surveillance and ultimately improve patient outcomes., Level of Evidence: 3., Competing Interests: Sarah T. Arron is an employee of Rakuten Medical and is a consultant for Castle Biosciences and Enspectra Health. Ashley Wysong is a board member for the American College of Mohs Surgery, Women's Dermatologic Society, and Dermatology Foundation and is the principal investigator on an institutional research grant from Castle Biosciences. Mary A. Hall, Christine N. Bailey, Kyle R. Covington, Sarah J. Kurley, and Matthew S. Goldberg are employees and option holders for Castle Biosciences, Inc. Sherrif F. Ibrahim has received advisor fees from Castle Biosciences, Regeneron Pharmaceuticals, and Sun Pharmaceutical Industries; research funding from Castle Biosciences, Galderma, and Regeneron Pharmaceuticals; and speaker fees from Castle Biosciences, Galderma, Genentech, Regeneron Pharmaceuticals, and Sun Pharmaceutical Industries. Shlomo A. Koyfman received research funding and consulting fees from Merck, research funding from Bristol Myers Squibb, and honoraria from UpToDate. Jason G. Newman is a consultant for Bolder Surgical, Inc. and Medtronic, Inc. and a steering committee member for Castle Biosciences The remaining authors served as investigators for this study, and there are no further conflicts to disclose., (© 2022 Castle Biosciences, Inc. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)
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- 2022
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17. Analytical Validation and Performance of a 7-Gene Next-Generation Sequencing Panel in Uveal Melanoma.
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Alsina KM, Sholl LM, Covington KR, Arnal SM, Durante MA, Decatur CL, Stone JF, Oelschlager KM, Harbour JW, Monzon FA, Cook RW, and Borman S
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Introduction: Gene expression profiling (GEP) is widely used for prognostication in patients with uveal melanoma (UM). Because biopsy tissue is limited, it is critical to obtain as much genomic information as possible from each sample. Combined application of both GEP and next-generation sequencing (NGS) allows for analysis of RNA and DNA from a single biopsy sample, offers additional prognostic information, and can potentially inform therapy selection. This study evaluated the analytical performance of a targeted custom NGS panel for mutational profiling of 7 genes commonly mutated in UM., Methods: One hundred five primary UM tumors were analyzed, including 37 formalin-fixed paraffin-embedded (FFPE) and 68 fine-needle aspiration biopsy specimens. Sequencing was performed on the Ion GeneStudio S5 platform to an average read depth of >500X per region of interest., Results: The 7-gene panel achieved a positive percent agreement of 100% for detection of both single-nucleotide variants and insertions/deletions, with a technical positive predictive value of 98.8% and 100%, respectively. Intra-assay and inter-assay concordance studies confirmed the assay's reproducibility and repeatability., Discussion/conclusion: The 7-gene panel is a robust, highly accurate NGS test that can be successfully performed, along with GEP, from a single small-gauge needle biopsy sample or FFPE specimen., Competing Interests: K.M.A., L.M.S., K.R.C., S.M.A., J.K.W., J.F.S., S.B., K.M.O., F.A.M., and R.W.C. were employees and stockholders of Castle Biosciences, Inc. at the time of this study. J.W.H. is the inventor of intellectual property related to prognostic testing for uveal melanoma. He is a paid consultant for Castle Biosciences, Inc., Friendswood, TX, USA licensee of this intellectual property, and he receives royalties from its commercialization., (Copyright © 2021 by S. Karger AG, Basel.)
- Published
- 2021
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18. Development of the Exercise in Cancer Evaluation and Decision Support (EXCEEDS) algorithm.
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Covington KR, Marshall T, Campbell G, Williams GR, Fu JB, Kendig TD, Howe N, Alfano CM, and Pergolotti M
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- Algorithms, Exercise Therapy, Humans, Survivors, Neoplasms therapy
- Abstract
Purpose: Participation in exercise or rehabilitation services is recommended to optimize health, functioning, and well-being across the cancer continuum of care. However, limited knowledge of individual needs and complex decision-making are barriers to connect the right survivor to the right exercise/rehabilitation service at the right time. In this article, we define the levels of exercise/rehabilitation services, provide a conceptual model to improve understanding of individual needs, and describe the development of the Exercise in Cancer Evaluation and Decision Support (EXCEEDS) algorithm., Methods: From literature review, we synthesized defining characteristics of exercise/rehabilitation services and individual characteristics associated with safety and efficacy for each service. We developed a visual model to conceptualize the need for each level of specialized care, then organized individual characteristics into a risk-stratified algorithm. Iterative review with a multidisciplinary expert panel was conducted until consensus was reached on algorithm content and format., Results: We identified eight defining features of the four levels of exercise/rehabilitation services and provide a conceptual model of to guide individualized navigation for each service across the continuum of care. The EXCEEDS algorithm includes a risk-stratified series of eleven dichotomous questions, organized in two sections and ten domains., Conclusions: The EXCEEDS algorithm is an evidence-based decision support tool that provides a common language to describe exercise/rehabilitation services, a practical model to understand individualized needs, and step-by-step decision support guidance. The EXCEEDS algorithm is designed to be used at point of care or point of need by multidisciplinary users, including survivors. Thus, implementation may improve care coordination for cancer exercise/rehabilitation services., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2021
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19. Integrating 31-Gene Expression Profiling With Clinicopathologic Features to Optimize Cutaneous Melanoma Sentinel Lymph Node Metastasis Prediction.
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Whitman ED, Koshenkov VP, Gastman BR, Lewis D, Hsueh EC, Pak H, Trezona TP, Davidson RS, McPhee M, Guenther JM, Toomey P, Smith FO, Beitsch PD, Lewis JM, Ward A, Young SE, Shah PK, Quick AP, Martin BJ, Zolochevska O, Covington KR, Monzon FA, Goldberg MS, Cook RW, Fleming MD, Hyams DM, and Vetto JT
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- Gene Expression Profiling methods, Gene Expression Profiling statistics & numerical data, Humans, Lymphatic Metastasis diagnosis, Lymphatic Metastasis prevention & control, Melanoma surgery, Sentinel Lymph Node pathology, Sentinel Lymph Node physiopathology, Sentinel Lymph Node Biopsy methods, Sentinel Lymph Node Biopsy standards, Sentinel Lymph Node Biopsy statistics & numerical data, Gene Expression Profiling standards, Melanoma diagnosis
- Abstract
National guidelines recommend sentinel lymph node biopsy (SLNB) be offered to patients with > 10% likelihood of sentinel lymph node (SLN) positivity. On the other hand, guidelines do not recommend SLNB for patients with T1a tumors without high-risk features who have < 5% likelihood of a positive SLN. However, the decision to perform SLNB is less certain for patients with higher-risk T1 melanomas in which a positive node is expected 5%-10% of the time. We hypothesized that integrating clinicopathologic features with the 31-gene expression profile (31-GEP) score using advanced artificial intelligence techniques would provide more precise SLN risk prediction., Methods: An integrated 31-GEP (i31-GEP) neural network algorithm incorporating clinicopathologic features with the continuous 31-GEP score was developed using a previously reported patient cohort (n = 1,398) and validated using an independent cohort (n = 1,674)., Results: Compared with other covariates in the i31-GEP, the continuous 31-GEP score had the largest likelihood ratio (G
2 = 91.3, P < .001) for predicting SLN positivity. The i31-GEP demonstrated high concordance between predicted and observed SLN positivity rates (linear regression slope = 0.999). The i31-GEP increased the percentage of patients with T1-T4 tumors predicted to have < 5% SLN-positive likelihood from 8.5% to 27.7% with a negative predictive value of 98%. Importantly, for patients with T1 tumors originally classified with a likelihood of SLN positivity of 5%-10%, the i31-GEP reclassified 63% of cases as having < 5% or > 10% likelihood of positive SLN, for a more precise, personalized, and clinically actionable SLN-positive likelihood estimate., Conclusion: These data suggest the i31-GEP could reduce the number of SLNBs performed by identifying patients with likelihood under the 5% threshold for performance of SLNB and improve the yield of positive SLNBs by identifying patients more likely to have a positive SLNB., Competing Interests: John T. Vetto Employment: Gilead Sciences (I) Stock and Other Ownership Interests: Gilead Sciences (I), Roche/Genentech (I) Speakers' Bureau: Castle Biosciences Travel, Accommodations, Expenses: Castle Biosciences No other potential conflicts of interest were reported. John T. Vetto Employment: Gilead Sciences (I) Stock and Other Ownership Interests: Gilead Sciences (I), Roche/Genentech (I) Speakers' Bureau: Castle Biosciences Travel, Accommodations, Expenses: Castle Biosciences No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)- Published
- 2021
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20. Risk Stratification of Patients with Stage I Cutaneous Melanoma Using 31-Gene Expression Profiling.
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Martin BJ, Covington KR, Quick AP, and Cook RW
- Abstract
Background: While patients with localized cutaneous melanoma (CM) generally have good five-year melanoma-specific survival rates, identifying patients with localized disease at a high risk of recurrence could allow them access to additional follow-up or surveillance., Objective: We sought to examine the prognostic value of the 31-gene expression profile (31-GEP) test for the risk of recurrence in stage I CM patients according to 31-GEP main class (low risk: Class 1 vs. high-risk: Class 2) and the lowest and highest risk 31-GEP subclasses (Class 1A vs. Class 2B)., Methods: Data from a previously described meta-analysis detailing the 31-GEP results for patients with stage I CM (N = 623) were re-analyzed to determine 31-GEP accuracy., Results: Patients with stage I CM and a Class 1 31-GEP result were less likely to have a recurrence (15/556; 2.7% vs. 6/67; 9.0%; p =0.018) than patients with a Class 2 result and had a higher five-year recurrence-free survival (RFS) (96% vs. 85%). Patients with a Class 2 result were 2.8 times as likely to experience a recurrence (positive likelihood ratio: 2.82; 95% confidence interval: 1.38-5.77). In a subset of patients with stage I CM stratified further into 31-GEP subclasses (n = 206), patients with a Class 1A result had a higher five-year RFS than those with a Class 2B result (98% vs. 73%). Patients with a Class 2B result were also 6.5 times as likely to experience a recurrence (positive likelihood ratio: 6.45; 95% confidence interval: 2.44-17.00) than those with a Class 1A result, and the 31-GEP had a negative predictive value of 96.3% (95% confidence interval: 92.3%-98.4%)., Conclusion: The 31-GEP test significantly differentiates between low and high recurrence risk in patients with stage I CM., Competing Interests: DISCLOSURES: All authors are employees with Castle Biosciences, Inc. in Friendswood, Texas., (Copyright © 2021. Matrix Medical Communications. All rights reserved.)
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- 2021
21. Long-Term Outcomes in a Multicenter, Prospective Cohort Evaluating the Prognostic 31-Gene Expression Profile for Cutaneous Melanoma.
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Hsueh EC, DeBloom JR, Lee JH, Sussman JJ, Covington KR, Caruso HG, Quick AP, Cook RW, Slingluff CL Jr, and McMasters KM
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- Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Middle Aged, Prognosis, Prospective Studies, Time Factors, Treatment Outcome, Young Adult, Gene Expression Profiling, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Purpose: Current guidelines for postoperative management of patients with stage I-IIA cutaneous melanoma (CM) do not recommend routine cross-sectional imaging, yet many of these patients develop metastases. Methods that complement American Joint Committee on Cancer (AJCC) staging are needed to improve identification and treatment of these patients. A 31-gene expression profile (31-GEP) test predicts metastatic risk as low (class 1) or high (class 2). Prospective analysis of CM outcomes was performed to test the hypotheses that the 31-GEP provides prognostic value for patients with stage I-III CM, and that patients with stage I-IIA melanoma and class 2 31-GEP results have metastatic risk similar to patients for whom surveillance is recommended., Materials and Methods: Two multicenter registry studies, INTEGRATE (ClinicalTrials.gov identifier:NCT02355574) and EXPAND (ClinicalTrials.gov identifier:NCT02355587), were initiated under institutional review board approval, and 323 patients with stage I-III CM and median follow-up time of 3.2 years met inclusion criteria. Primary end points were 3-year recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS)., Results: The 31-GEP was significant for RFS, DMFS, and OS in a univariate analysis and was a significant, independent predictor of RFS, DMFS, and OS in a multivariable analysis. GEP class 2 results were significantly associated with lower 3-year RFS, DMFS, and OS in all patients and those with stage I-IIA disease. Patients with stage I-IIA CM and a class 2 result had recurrence, distant metastasis, and death rates similar to patients with stage IIB-III CM. Combining 31-GEP results and AJCC staging enhanced sensitivity over each approach alone., Conclusion: These data provide a rationale for using the 31-GEP along with AJCC staging, and suggest that patients with stage I-IIA CM and a class 2 31-GEP signature may be candidates for more intense follow-up., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Eddy C. Hsueh Speakers' Bureau: Amgen, Castle BiosciencesJeffrey J. Sussman Consulting or Advisory Role: Castle BiosciencesKyle R. Covington Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Gene expression profile tests Travel, Accommodations, Expenses: Castle BiosciencesHillary G. Caruso Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Chimeric antigen receptors (CARs) and CAR-expressing T cells are provided that can specifically target cells that express an elevated level of a target antigen. Likewise, methods for specifically targeting cells that express elevated levels of antigen (eg, cancer cells) with CAR T-cell therapies are provided Travel, Accommodations, Expenses: Castle BiosciencesAnn P. Quick Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Travel, Accommodations, Expenses: Castle BiosciencesRobert W. Cook Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Castle Biosciences related patents Travel, Accommodations, Expenses: Castle BiosciencesCraig L. Slingluff Consulting or Advisory Role: Immatics, Polynoma, CureVac Research Funding: GlaxoSmithKline, Merck Sharp & Dohme, 3M, Theraclion, Celldex Patents, Royalties, Other Intellectual Property: Licensing and Ventures Group of the University of Virginia Travel, Accommodations, Expenses: Polynoma Uncompensated Relationships: Agenus No other potential conflicts of interest were reported.Eddy C. Hsueh Speakers' Bureau: Amgen, Castle Biosciences Jeffrey J. Sussman Consulting or Advisory Role: Castle Biosciences Kyle R. Covington Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Gene expression profile tests Travel, Accommodations, Expenses: Castle Biosciences Hillary G. Caruso Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Chimeric antigen receptors (CARs) and CAR-expressing T cells are provided that can specifically target cells that express an elevated level of a target antigen. Likewise, methods for specifically targeting cells that express elevated levels of antigen (eg, cancer cells) with CAR T-cell therapies are provided Travel, Accommodations, Expenses: Castle Biosciences Ann P. Quick Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Travel, Accommodations, Expenses: Castle Biosciences Robert W. Cook Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Castle Biosciences related patents Travel, Accommodations, Expenses: Castle Biosciences Craig L. Slingluff Consulting or Advisory Role: Immatics, Polynoma, CureVac Research Funding: GlaxoSmithKline, Merck Sharp & Dohme, 3M, Theraclion, Celldex Patents, Royalties, Other Intellectual Property: Licensing and Ventures Group of the University of Virginia Travel, Accommodations, Expenses: Polynoma Uncompensated Relationships: Agenus No other potential conflicts of interest were reported.Eddy C. Hsueh Speakers' Bureau: Amgen, Castle Biosciences Jeffrey J. Sussman Consulting or Advisory Role: Castle Biosciences Kyle R. Covington Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Gene expression profile tests Travel, Accommodations, Expenses: Castle Biosciences Hillary G. Caruso Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Chimeric antigen receptors (CARs) and CAR-expressing T cells are provided that can specifically target cells that express an elevated level of a target antigen. Likewise, methods for specifically targeting cells that express elevated levels of antigen (eg, cancer cells) with CAR T-cell therapies are provided Travel, Accommodations, Expenses: Castle Biosciences Ann P. Quick Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Travel, Accommodations, Expenses: Castle Biosciences Robert W. Cook Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Castle Biosciences related patents Travel, Accommodations, Expenses: Castle Biosciences Craig L. Slingluff Consulting or Advisory Role: Immatics, Polynoma, CureVac Research Funding: GlaxoSmithKline, Merck Sharp & Dohme, 3M, Theraclion, Celldex Patents, Royalties, Other Intellectual Property: Licensing and Ventures Group of the University of Virginia Travel, Accommodations, Expenses: Polynoma Uncompensated Relationships: Agenus No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)
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- 2021
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22. Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma.
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Wysong A, Newman JG, Covington KR, Kurley SJ, Ibrahim SF, Farberg AS, Bar A, Cleaver NJ, Somani AK, Panther D, Brodland DG, Zitelli J, Toyohara J, Maher IA, Xia Y, Bibee K, Griego R, Rigel DS, Meldi Plasseraud K, Estrada S, Sholl LM, Johnson C, Cook RW, Schmults CD, and Arron ST
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- Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell diagnosis, Carcinoma, Squamous Cell epidemiology, Carcinoma, Squamous Cell genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Staging methods, Predictive Value of Tests, Prognosis, Prospective Studies, Risk Assessment methods, Skin pathology, Skin Neoplasms diagnosis, Skin Neoplasms epidemiology, Skin Neoplasms genetics, Survival Rate, Biomarkers, Tumor genetics, Carcinoma, Squamous Cell secondary, Gene Expression Profiling methods, Skin Neoplasms pathology
- Abstract
Background: Current staging systems for cutaneous squamous cell carcinoma (cSCC) have limited positive predictive value for identifying patients who will experience metastasis., Objective: To develop and validate a gene expression profile (GEP) test for predicting risk for metastasis in localized, high-risk cSCC with the goal of improving risk-directed patient management., Methods: Archival formalin-fixed paraffin-embedded primary cSCC tissue and clinicopathologic data (n = 586) were collected from 23 independent centers in a prospectively designed study. A GEP signature was developed using a discovery cohort (n = 202) and validated in a separate, nonoverlapping, independent cohort (n = 324)., Results: A prognostic 40-GEP test was developed and validated, stratifying patients with high-risk cSCC into classes based on metastasis risk: class 1 (low risk), class 2A (high risk), and class 2B (highest risk). For the validation cohort, 3-year metastasis-free survival rates were 91.4%, 80.6%, and 44.0%, respectively. A positive predictive value of 60% was achieved for the highest-risk group (class 2B), an improvement over staging systems, and negative predictive value, sensitivity, and specificity were comparable to staging systems., Limitations: Potential understaging of cases could affect metastasis rate accuracy., Conclusion: The 40-GEP test is an independent predictor of metastatic risk that can complement current staging systems for patients with high-risk cSCC., (Copyright © 2020 American Academy of Dermatology, Inc. All rights reserved.)
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- 2021
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23. Integrating the melanoma 31-gene expression profile test with surgical oncology practice within national guideline and staging recommendations.
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Hyams DM, Covington KR, Johnson CE, Plasseraud KM, and Cook RW
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- Adult, Aged, Aged, 80 and over, Clinical Decision-Making, Female, Follow-Up Studies, Gene Expression Profiling, Humans, Male, Melanoma genetics, Melanoma secondary, Melanoma therapy, Middle Aged, Neoplasm Staging standards, Prognosis, Prospective Studies, Retrospective Studies, Skin Neoplasms genetics, Skin Neoplasms pathology, Skin Neoplasms therapy, United States, Watchful Waiting standards, Biomarkers, Tumor genetics, Melanoma diagnosis, Practice Guidelines as Topic, Skin Neoplasms diagnosis, Surgical Oncology standards
- Abstract
Aim: Define changes in clinical management resulting from the use of the prognostic 31-gene expression profile (31-GEP) test for cutaneous melanoma in a surgical oncology practice. Patients & methods: Management plans for 112 consecutively tested patients with stage I-III melanoma were evaluated for duration and number of clinical visits, blood work and imaging. Results: 31-GEP high-risk (class 2; n = 46) patients received increased management compared with low-risk (class 1; n = 66) patients. Test results were most closely associated with follow-up and imaging. Of class 1 patients, 65% received surveillance intensity within guidelines for stage I-IIA patients; 98% of class 2 patients received surveillance intensity equal to stage IIB-IV patients. Conclusion: We suggest clinical follow-up and metastatic screening be adjusted according to 31-GEP test results.
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- 2021
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24. NF-κB and STAT3 co-operation enhances high glucose induced aggressiveness of cholangiocarcinoma cells.
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Saengboonmee C, Phoomak C, Supabphol S, Covington KR, Hampton O, Wongkham C, Gibbs RA, Umezawa K, Seubwai W, Gingras MC, and Wongkham S
- Subjects
- Cell Line, Tumor, Cell Movement physiology, Gene Expression Regulation, Neoplastic, Glucose metabolism, Humans, Interleukin-1beta genetics, Neoplasm Invasiveness, Bile Duct Neoplasms pathology, Cholangiocarcinoma pathology, NF-kappa B metabolism, STAT3 Transcription Factor metabolism
- Abstract
Aims: The present report aimed to investigate the underlying genes and pathways of high glucose driving cholangiocarcinoma (CCA) aggressiveness., Main Methods: We screened and compared the gene expression profiles obtained by RNA sequencing, of CCA cells cultured in high and normal glucose. Results from the transcriptomic analysis were confirmed in additional cell lines using in vitro migration-invasion assay, Western blotting and immunocytofluorescence., Key Findings: Data indicated that high glucose increased the expression of interleukin-1β (IL-1β), an upstream regulator of nuclear factor-κB (NF-κB) pathway, through the nuclear localization of NF-κB. High glucose-induced NF-κB increased the migration and invasion of CCA cells and the expression of downstream NF-κB targeted genes associated with aggressiveness, including interleukin-6, a potent triggering signal of the signal transducer and activator of transcription 3 (STAT3) pathway. Such effects were reversed by inhibiting NF-κB nuclear translocation which additionally reduced the phosphorylation of STAT3 at Y705., Significance: These results indicate that NF-κB is activated by high glucose and they suggest that NF-κB interaction with STAT3 enhances CCA aggressiveness. Therefore, targeting multiple pathways such as STAT3 and NF-κB might improve CCA treatment outcome especially in condition such as hyperglycemia., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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25. Reply to Problematic methodology in a systematic review and meta-analysis of DecisionDx-Melanoma.
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Greenhaw BN, Covington KR, Kurley SJ, Yeniay Y, Cao NA, Plasseraud KM, Cook RW, Hsueh EC, Gastman BR, and Wei ML
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- Gene Expression Profiling, Humans, Prognosis, Transcriptome, Melanoma, Skin Neoplasms
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- 2020
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26. Gene Expression Profiling in Uveal Melanoma: Five-Year Prospective Outcomes and Meta-Analysis.
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Aaberg TM, Covington KR, Tsai T, Shildkrot Y, Plasseraud KM, Alsina KM, Oelschlager KM, and Monzon FA
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Introduction: The prognostic 15-gene expression profile (15-GEP) test for uveal melanoma (UM) predicts metastatic risk based on primary tumor biology. Here we report outcomes from a prospective registry of 15-GEP-tested patients, and a meta-analysis with published cohorts., Objectives: Management and 5-year clinical outcomes following 15-GEP testing were evaluated., Methods: Eighty-nine patients with 15-GEP results were prospectively enrolled at four centers. Physician-recommended management plans were collected, and clinical outcomes tracked every 6 months., Results: Eighty percent of Class 1 (low-risk) patients underwent low-intensity management; all Class 2 (high-risk) patients underwent high-intensity management ( p < 0.0001). Median follow-up for event-free patients was 4.9 years. Five Class 1 (10%) and 23 Class 2 (58%) tumors metastasized ( p < 0.0001). Five-year Class 1 and 2 metastasis-free survival rates were 90% (81-100%) and 41% (27-62%; p < 0.0001), and melanoma-specific survival rates were 94% (87-100%) and 63% (49-82%; p = 0.0007). Class 2 was the only independent predictor of metastasis and was associated with increased risk for metastasis and mortality by meta-analysis., Conclusions: UM patient management is guided by 15-GEP testing. Class 2 patients were managed more intensely, in accordance with an observed metastatic rate of >50%; Class 1 patients were safely spared intensive surveillance, resulting in appropriate utilization of healthcare resources., Competing Interests: K.R.C., K.M.P., K.M.A., K.M.O., and F.A.M. are employees and shareholders of Castle Biosciences, Inc., (Copyright © 2020 by S. Karger AG, Basel.)
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- 2020
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27. Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression.
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Midorikawa Y, Yamamoto S, Tatsuno K, Renard-Guillet C, Tsuji S, Hayashi A, Ueda H, Fukuda S, Fujita T, Katoh H, Ishikawa S, Covington KR, Creighton CJ, Sugitani M, Wheeler DA, Shibata T, Nagae G, Takayama T, and Aburatani H
- Subjects
- Carcinoma, Hepatocellular pathology, DNA Methylation, DNA, Neoplasm isolation & purification, Disease Progression, Epigenesis, Genetic, Gene Dosage, Gene Drive Technology, Gene Expression, Genes, cdc, Histone-Lysine N-Methyltransferase genetics, Humans, Liver Neoplasms pathology, Mutation, Myeloid-Lymphoid Leukemia Protein genetics, Oncogene Protein v-akt genetics, Phosphatidylinositol 3-Kinases genetics, Probability, RNA, Neoplasm isolation & purification, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA, Telomerase genetics, Transcriptional Activation, Up-Regulation, beta Catenin genetics, Carcinoma, Hepatocellular genetics, Genes, p53, Liver Neoplasms genetics, Wnt Proteins genetics
- Abstract
Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLL protein family, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53 , early HCC was a separate molecular entity from overt HCC, as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC regardless of CTNNB1 mutation status because β-catenin did not translocate into the nucleus due to the E-cadherin/β-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC, with CTNNB1 mutation associated with downregulation of CDH1 and hypomethylation of CpG islands in target genes. Similarly, cell-cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC, with TP53 or RB1 gene mutations associated with chromosomal deletion of 4q or 16q. HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Collectively, these data show that as HCC progresses, additional molecular events exclusive of driver gene mutations cooperatively contribute to transcriptional activation of downstream targets according to methylation status. SIGNIFICANCE: In addition to driver gene mutations in the WNT and p53 pathways, further molecular events are required for aberrant transcriptional activation of these pathways as HCC progresses., (©2020 American Association for Cancer Research.)
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- 2020
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28. Molecular risk prediction in cutaneous melanoma: A meta-analysis of the 31-gene expression profile prognostic test in 1,479 patients.
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Greenhaw BN, Covington KR, Kurley SJ, Yeniay Y, Cao NA, Plasseraud KM, Cook RW, Hsueh EC, Gastman BR, and Wei ML
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- Disease-Free Survival, Feasibility Studies, Humans, Kaplan-Meier Estimate, Melanoma diagnosis, Melanoma genetics, Melanoma therapy, Neoplasm Recurrence, Local genetics, Neoplasm Staging, Predictive Value of Tests, Prognosis, Risk Assessment methods, Skin Neoplasms diagnosis, Skin Neoplasms genetics, Skin Neoplasms therapy, Survival Rate, Biomarkers, Tumor genetics, Gene Expression Profiling, Melanoma mortality, Neoplasm Recurrence, Local epidemiology, Skin Neoplasms mortality
- Abstract
Background: Multiple studies have reported on the accuracy of the prognostic 31-gene expression profile test for cutaneous melanoma. Consistency of the test results across studies has not been systematically evaluated., Objective: To assess the robustness of the prognostic value of the 31-gene expression profile., Methods: Raw data were obtained from studies identified from systematic review. A meta-analysis was performed to determine overall effect of the 31-gene expression profile. Clinical outcome metrics for the 31-gene expression profile were compared with American Joint Committee on Cancer staging., Results: Three studies met inclusion criteria; data from a novel cohort of 211 patients were included (n = 1,479). Five-year recurrence-free and distant metastasis-free survival rates were 91.4% and 94.1% for Class 1A patients and 43.6% and 55.5% for Class 2B patients (P < .0001). Meta-analysis results showed that Class 2 was significantly associated with recurrence (hazard ratio 2.90; P < .0001) and distant metastasis (hazard ratio 2.75; P < .0001). The 31-gene expression profile identified American Joint Committee on Cancer stage I to III patient subsets with high likelihood for recurrence and distant metastasis. Sensitivity was 76% (95% confidence interval 71%-80%) and 76% (95% confidence interval 70%-82%) for each end point, respectively. When 31-gene expression profile and sentinel lymph node biopsy results were considered together, sensitivity and negative predictive value for distant metastasis-free survival were both improved., Conclusion: The 31-gene expression profile test consistently and accurately identifies melanoma patients at increased risk of metastasis, is independent of other clinicopathologic covariates, and augments current risk stratification by reclassifying patients for heightened surveillance who were previously designated as being at low risk., (Published by Elsevier Inc.)
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- 2020
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29. Integrating gene expression profiling into NCCN high-risk cutaneous squamous cell carcinoma management recommendations: impact on patient management.
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Farberg AS, Hall MA, Douglas L, Covington KR, Kurley SJ, Cook RW, and Dinehart SM
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- Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Cohort Studies, Female, Humans, Male, Middle Aged, Neoplasm Staging, Practice Guidelines as Topic, Skin Neoplasms genetics, Skin Neoplasms pathology, Carcinoma, Squamous Cell therapy, Gene Expression Profiling, Skin Neoplasms therapy
- Abstract
Objective: To integrate gene expression profiling into the management of high-risk cutaneous squamous cell carcinoma (cSCC) within the National Comprehensive Cancer Network (NCCN) guidelines to improve risk-aligned management recommendations. Methods: A cohort of 300 NCCN-defined high-risk cSCC patients, along with the American Joint Committee on Cancer (AJCC) T stage, Brigham and Women's Hospital (BWH) T stage, and known patient outcomes were analyzed. Risk classifications using a validated 40-gene expression profile (40-GEP) test and T stage were applied to NCCN patient management guidelines. Risk-directed patient management recommendations within the NCCN guidelines framework were aligned based on risk for metastasis. Results: Of the 300 NCCN high-risk cSCC patients, 159 (53.0%) were 40-GEP Class 1 and AJCC T1-T2, and 173 (57.7%) were Class 1 and BWH T1-2a, indicating low risk for metastasis and, thereby, suggesting low management intensity. The 40-GEP integration suggested high intensity management for only 24 (8.0%) patients (all Class 2B), and moderate intensity management for the remainder of the cohort. Conclusions: The 40-GEP test can be integrated within existing NCCN guideline recommendations for managing cSCC patients to help refine risk-directed management decisions. Integration of the 40-GEP test would allow >50% of this NCCN-defined high-risk cohort to be managed with the lowest intensity recommendations within the broad NCCN guidelines. High intensity management was deemed risk-appropriate for a small subpopulation (8.0%). This study demonstrates that the 40-GEP test, in combination with T stage, has clinical utility to impact patient management decisions in NCCN high-risk cSCC for improving risk-aligned management within the NCCN guidelines framework.
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- 2020
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30. An exercise oncology clinical pathway: Screening and referral for personalized interventions.
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Stout NL, Brown JC, Schwartz AL, Marshall TF, Campbell AM, Nekhlyudov L, Zucker DS, Basen-Engquist KM, Campbell G, Meyerhardt J, Cheville AL, Covington KR, Ligibel JA, Sokolof JM, Schmitz KH, and Alfano CM
- Subjects
- Age Factors, Cancer Survivors, Comorbidity, Decision Making, Humans, Medical Oncology, Neoplasms epidemiology, Neoplasms etiology, Patient Education as Topic, Telemedicine methods, Critical Pathways, Exercise, Neoplasms therapy, Precision Medicine methods, Referral and Consultation
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- 2020
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31. Women's Experiences After Ovarian Cancer Surgery: Distress, Uncertainty, and the Need for Occupational Therapy.
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Pergolotti M, Bailliard A, McCarthy L, Farley E, Covington KR, and Doll KM
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- Cross-Sectional Studies, Female, Humans, Interviews as Topic, Patient Reported Outcome Measures, Quality of Life, Occupational Therapy, Ovarian Neoplasms rehabilitation, Psychological Distress, Uncertainty
- Abstract
Importance: Despite the growing literature on the association of functional, physical, and quality-of-life (QOL) deficits with poor postoperative outcomes, there is a gap in the literature identifying women's occupational performance needs after ovarian cancer surgery., Objective: To describe the experiences of women hospitalized after ovarian cancer surgery to identify potential areas for intervention. Goals were to (1) identify functional needs and limitations at time of discharge as measured by the typical acute care occupational therapy evaluation and semistructured interview and (2) understand the women's perspectives of their needs for occupational therapy and a safe return to home., Design: Single-arm, cross-sectional descriptive study. Mixed-methods data collection and analysis., Setting: Academic cancer center., Participants: Women with ovarian cancer (N = 11) who had completed surgery., Intervention: Semistructured interviews and patient-reported outcome measures (PROMs) completed postsurgery., Outcomes and Measures: PROMs included the National Comprehensive Cancer Network (NCCN) Distress Thermometer and Problem List, the PROMIS
® Global Physical Health (GPH) and Global Mental Health (GMH) scales, and the Possibilities for Activity Scale-Women (PActS-W)., Results: The mean NCCN Distress score was 6.0 (standard deviation [SD] = 3.1, with the top three concerns being pain (80%), worry (80%), and fatigue (78%). Mean GPH and GMH T scores were 38.0 (SD = 8.8) and 48.2 (SD = 8.4), respectively. Women scored a mean of 39.2 (SD = 11.2, range = 26-58) on the PActS-W. Thematic analyses found that the women were uncertain about potential functional limitations and significantly distressed., Conclusion and Relevance: Women with ovarian cancer experienced high levels of uncertainty and distress after surgery. Integrating in-home or community-based occupational therapy into routine care could decrease functional distress and uncertainty and help women manage concerns related to pain, worry, and fatigue., What This Article Adds: This study suggests that occupational therapy evaluation and intervention are needed to decrease distress and improve QOL of women upon discharge after ovarian cancer surgery., (Copyright © 2020 by the American Occupational Therapy Association, Inc.)- Published
- 2020
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32. Embracing the complexity: Older adults with cancer-related cognitive decline-A Young International Society of Geriatric Oncology position paper.
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Pergolotti M, Battisti NML, Padgett L, Sleight AG, Abdallah M, Newman R, Van Dyk K, Covington KR, Williams GR, van den Bos F, Pollock Y, Salerno EA, Magnuson A, Gattás-Vernaglia IF, and Ahles TA
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- Aged, Geriatric Assessment, Humans, Mass Screening, Medical Oncology, Quality of Life, Cognitive Dysfunction etiology, Cognitive Dysfunction therapy, Neoplasms complications, Neoplasms therapy
- Abstract
Cancer-related cognitive decline (CRCD) may have particularly significant consequences for older adults, impacting their functional and physical abilities, level of independence, ability to make decisions, treatment adherence, overall quality of life, and ultimately survival. In honor of Dr. Hurria's work we explore and examine multiple types of screening, assessment and non-pharmacologic treatments for CRCD. We then suggest future research and clinical practice questions to holistically appreciate the complexity of older adults with cancer's experiences and fully integrate the team-based approach to best serve this population., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2020
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33. Understanding fall risk for older adults with cancer: An evaluation of experts' perceptions.
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Covington KR, Atler KE, Schmid AA, and Pergolotti M
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- Aged, Geriatric Assessment, Humans, Perception, Risk Factors, Accidental Falls, Neoplasms epidemiology
- Abstract
Objective: Older adults with cancer have elevated risk of falling. However, cancer-specific fall risk factors are not well understood., Methods: A pragmatic, qualitative study utilized semi-structured interviews to investigate expert's perceptions of fall risk for older adults with cancer. Interview questions were guided by the International Classification of Functioning and Disability (ICF) constructs and the Cancer Aging Research Group's model of fall risk factors. Themes were identified deductively from interview transcriptions. Transcripts were coded using Nvivo software., Results: Ten multidisciplinary experts participated (n = 5 clinical, n = 5 research). Two themes in fall risk factors emerged from interview data: 1) cancer-specific factors aligned with each ICF construct: body function and structures (BF&S), activity and participation (A&P), personal and environmental factors; and 2) a cycle among factors. Experts described that treatment-related limitations in A&P produced or exacerbated impairments in BF&S (physical and mental), leading to falls and further limitations in A&P. Personal and environmental factors influencing this cycle included: cancer-related distress, social support, and perceptions of aging and treatment., Conclusion: Experts identified a cycle among cancer-specific fall risk factors for older adults and emphasized the importance of a "holistic" view of the patient to evaluate fall risk. Cancer-related distress, social support and expectations of aging and treatment may influence the cycle between risk factors, with potential negative or protective effects. Future prospective, longitudinal implementation of geriatric assessments and analysis of data may inform risk factors and relationships among factors. Patient interviews could further inform the understanding of fall risk for older adults with cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2020
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34. The repertoire of mutational signatures in human cancer.
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Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Tian Ng AW, Wu Y, Boot A, Covington KR, Gordenin DA, Bergstrom EN, Islam SMA, Lopez-Bigas N, Klimczak LJ, McPherson JR, Morganella S, Sabarinathan R, Wheeler DA, Mustonen V, Getz G, Rozen SG, and Stratton MR
- Subjects
- Age Factors, Base Sequence, Exome genetics, Genome, Human genetics, Humans, Sequence Analysis, DNA, Mutation genetics, Neoplasms genetics
- Abstract
Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature
1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses3-15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.- Published
- 2020
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35. Community-based exercise programs for cancer survivors: a scoping review of practice-based evidence.
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Covington KR, Hidde MC, Pergolotti M, and Leach HJ
- Subjects
- Community Health Services methods, Community Health Services organization & administration, Evidence-Based Medicine, Exercise physiology, Exercise Therapy organization & administration, Humans, Program Evaluation, Quality of Life, Randomized Controlled Trials as Topic, Cancer Survivors, Exercise Therapy methods, Neoplasms rehabilitation
- Abstract
Purpose: Based on randomized controlled trials, exercise is an efficacious strategy to improve quality of life (QOL) among cancer survivors. However, the effectiveness of exercise programs to improve QOL in real-world settings is unknown, as are factors related to external validity. This hinders dissemination and scalability. This scoping review synthesized published research on community-based exercise programs for cancer survivors and reported on the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM)., Methods: A systematic literature search identified community-based exercise programs for adult cancer survivors (1980-March 2018), that met the following inclusion criteria: at least one face-to-face exercise session, the primary aim of program evaluation (i.e., feasibility/effectiveness), and pre/post measure of QOL. Data were coded using the RE-AIM framework. The effect size was calculated for overall QOL., Results: Electronic database search yielded 553 articles; 31 studies describing unique programs were included for review. All studies described at least one element of implementation and most (80.6%) reported a significant (p < .05) improvement in at least one subscale, or total QOL. Few studies reported on indicators of reach (16.1%), adoption (6.5%), individual (16.1%), or system-level maintenance (32.3%)., Conclusions: Community-based exercise programs are effective for improving QOL in adult cancer survivors. Recommendations are provided to improve reporting across RE-AIM dimensions, which is an important step to enhance the scalability of programs and thus, the potential for exercise to be fully integrated into system-level standard care for cancer survivors., Implications for Cancer Survivors: Community-based exercise programs are a resource to improve QOL for adult cancer survivors.
- Published
- 2019
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36. Genomic evolution of uveal melanoma arising in ocular melanocytosis.
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Durante MA, Field MG, Sanchez MI, Covington KR, Decatur CL, Dubovy SR, and Harbour JW
- Subjects
- Exome, Eye metabolism, Female, Genetic Predisposition to Disease genetics, Genomics, High-Throughput Nucleotide Sequencing, Humans, Melanosis genetics, Middle Aged, Mutation, Phospholipase C beta metabolism, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Ubiquitin Thiolesterase genetics, Ubiquitin Thiolesterase metabolism, Exome Sequencing, Melanoma genetics, Phospholipase C beta genetics, Uveal Neoplasms genetics
- Abstract
Ocular melanocytosis is the most important predisposing condition for the eye cancer uveal melanoma (UM). Here, we present a patient who developed UM arising within ocular melanocytosis who was treated with enucleation (eye removal), which provided an invaluable opportunity to interrogate both the UM and adjacent uveal tissue containing the melanocytosis using whole-exome and deep-targeted sequencing. This analysis revealed a clonal PLCB4 mutation in the melanocytosis, confirming that this is indeed a neoplastic condition and explaining why it predisposes to UM. This mutation was present in 100% of analyzed UM cells, indicating that a PLCB4 -mutant cell gave rise to the UM. The earliest aberrations specific to the tumor were loss of Chromosomes 1p, 3, and 9p, which were present in virtually all tumor cells. A mutation in BAP1 arose later on the other copy of Chromosome 3 in a tumor subclone, followed by a gain of Chromosome 8q. These findings provide a mechanistic explanation for the well-known clinical association between ocular melanocytosis and UM by showing that this predisposing condition introduces the first "hit" and thereby increases the stochastic likelihood of acquiring further aberrations leading to UM., (© 2019 Durante et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2019
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37. Older Adults with Cancer: A Randomized Controlled Trial of Occupational and Physical Therapy.
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Pergolotti M, Deal AM, Williams GR, Bryant AL, McCarthy L, Nyrop KA, Covington KR, Reeve BB, Basch E, and Muss HB
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Incidence, Male, Neoplasm Recurrence, Local epidemiology, Neoplasms physiopathology, Treatment Outcome, United States epidemiology, Exercise physiology, Geriatric Assessment methods, Health Status, Neoplasms rehabilitation, Occupational Therapy methods, Physical Therapy Modalities
- Abstract
Objectives: The impact of occupational therapy (OT) and physical therapy (PT) on functional outcomes in older adults with cancer is unknown., Design: Two-arm single-institution randomized controlled trial of outpatient OT/PT., Setting: Comprehensive cancer center with two off-site OT/PT clinics., Participants: We recruited adults 65 years and older with a recent diagnosis or recurrence of cancer within 5 years, with at least one functional limitation as identified by a geriatric assessment. Participants were randomized to OT/PT or usual care., Intervention: Rehabilitation consisted of individualized OT and PT that addressed functional activities and strength/endurance needs., Measurements: Primary outcome was functional status as measured by the Nottingham Extended Activities of Daily Living scale. Secondary outcomes were Patient-Reported Outcomes Measurement Information System-Global Mental Health (GMH) and Global Physical Health (GPH), ability to participate in Social Roles (SR), physical function, and activity expectations and self-efficacy (Possibilities for Activity Scale [PActS])., Results: Among those recruited (N = 63), only 45 patients (71%) were evaluable due to loss of follow-up and/or nonreceipt of intervention. The median age was 74 years; 53% were female, and 91% were white. Overall, 30% patients had hematologic malignancies, 30% breast cancer, and 16% colorectal cancers. A total of 65% were in active treatment; 49% had stage 3 or 4 disease. At follow-up, both OT/PT (P = .02) and usual care (P = .03) groups experienced a decline in functional status. PActS scores between groups (P = .04) was significantly improved in the intervention group. GMH and SR met criteria for minimally important clinical difference favoring the intervention, but not statistical significance. Several barriers were noted in the implementation of the intervention program: recruitment, concerns about cost, distance, scheduling, and limited treatment provided., Conclusion: OT/PT may positively influence activity expectations and self-efficacy. Future research needs to address significant barriers to implementation to increase use of OT/PT services and access to quality care. J Am Geriatr Soc 67:953-960, 2019., (© 2019 The American Geriatrics Society.)
- Published
- 2019
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38. Performance of a 31-gene expression profile test in cutaneous melanomas of the head and neck.
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Gastman BR, Zager JS, Messina JL, Cook RW, Covington KR, Middlebrook B, Gerami P, Wayne JD, Leachman S, and Vetto JT
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Disease-Free Survival, Female, Head and Neck Neoplasms mortality, Humans, Kaplan-Meier Estimate, Lymph Node Excision methods, Lymph Nodes surgery, Lymphatic Metastasis, Male, Melanoma mortality, Melanoma pathology, Middle Aged, Multivariate Analysis, Neoplasm Invasiveness pathology, Neoplasm Staging, Proportional Hazards Models, Retrospective Studies, Risk Assessment, Sentinel Lymph Node Biopsy, Skin Neoplasms mortality, Skin Neoplasms pathology, Survival Analysis, United States, Gene Expression Profiling, Head and Neck Neoplasms genetics, Head and Neck Neoplasms pathology, Lymph Nodes pathology, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Background: We report the performance of a gene expression profile test to classify the recurrence risk of cutaneous melanoma tumors of the head and neck as low-risk Class 1 or high-risk Class 2., Methods: Of note, 157 primary head and neck cutaneous melanoma tumors were identified. Survival analyses were performed using Kaplan-Meier and Cox methods., Results: Gene expression profile class and node status stratified tumors into significantly different 5-year survival groups by Kaplan-Meier method (P < .0001 for all end points), and both were independent predictors of recurrence in multivariate analysis. Overall, 74% of distant metastases and 88% of melanoma-specific deaths had Class 2 risk., Conclusion: The gene expression profile test identifies cases at increased risk for metastasis and death independent of a clinically or pathologically negative nodal status, suggesting that incorporation of this molecular tool could improve clinical management of patients with head and neck cutaneous melanoma, especially in those with a negative sentinel lymph node biopsy., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2019
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39. Effect of Group Dynamics-Based Exercise Versus Personal Training in Breast Cancer Survivors.
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Leach HJ, Covington KR, Voss C, LeBreton KA, Harden SM, and Schuster SR
- Subjects
- Adult, Aged, Female, Humans, Middle Aged, Surveys and Questionnaires, Breast Neoplasms rehabilitation, Cancer Survivors psychology, Exercise Therapy methods, Psychotherapy, Group methods, Quality of Life psychology
- Abstract
Objectives: To determine the feasibility and preliminary effectiveness of a group dynamics-based exercise intervention versus a personal training intervention for increasing physical activity (PA), physical fitness, and quality of life (QOL) in post-treatment breast cancer survivors., Sample & Setting: 26 women with stage I or II breast cancer who attended intervention activities at a local academic institution., Methods & Vriables: Participants were randomly assigned to receive an eight-week intervention in either a group dynamics-based exercise or a personal training setting. Both intervention arms received supervised exercise twice per week, as well as PA education and discussion sessions., Results: Significant increases were noted in both intervention arms for vigorous PA, chest press, and leg press. Increases in overall QOL and total PA were significant only in the group dynamics-based exercise intervention arm., Implications for Nursing: The group dynamics-based exercise intervention produced similar improvements in PA and physical fitness compared to the personal training intervention, and it may have facilitated greater improvements in overall QOL.
- Published
- 2019
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40. APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa.
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Cho RJ, Alexandrov LB, den Breems NY, Atanasova VS, Farshchian M, Purdom E, Nguyen TN, Coarfa C, Rajapakshe K, Prisco M, Sahu J, Tassone P, Greenawalt EJ, Collisson EA, Wu W, Yao H, Su X, Guttmann-Gruber C, Hofbauer JP, Hashmi R, Fuentes I, Benz SC, Golovato J, Ehli EA, Davis CM, Davies GE, Covington KR, Murrell DF, Salas-Alanis JC, Palisson F, Bruckner AL, Robinson W, Has C, Bruckner-Tuderman L, Titeux M, Jonkman MF, Rashidghamat E, Lwin SM, Mellerio JE, McGrath JA, Bauer JW, Hovnanian A, Tsai KY, and South AP
- Subjects
- DNA Copy Number Variations genetics, DNA Repair genetics, Gene Expression Regulation, Neoplastic, Humans, Mutagenesis genetics, Mutation Rate, Transcriptome genetics, APOBEC Deaminases genetics, Carcinoma, Squamous Cell enzymology, Carcinoma, Squamous Cell genetics, Cytosine Deaminase genetics, Epidermolysis Bullosa Dystrophica enzymology, Epidermolysis Bullosa Dystrophica genetics, Mutation genetics, Skin Neoplasms enzymology, Skin Neoplasms genetics
- Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCCs). The molecular etiology of RDEB SCC, which arises at sites of sustained tissue damage, is unknown. We performed detailed molecular analysis using whole-exome, whole-genome, and RNA sequencing of 27 RDEB SCC tumors, including multiple tumors from the same patient and multiple regions from five individual tumors. We report that driver mutations were shared with spontaneous, ultraviolet (UV) light-induced cutaneous SCC (UV SCC) and head and neck SCC (HNSCC) and did not explain the early presentation or aggressive nature of RDEB SCC. Instead, endogenous mutation processes associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) deaminases dominated RDEB SCC. APOBEC mutation signatures were enhanced throughout RDEB SCC tumor evolution, relative to spontaneous UV SCC and HNSCC mutation profiles. Sixty-seven percent of RDEB SCC driver mutations was found to emerge as a result of APOBEC and other endogenous mutational processes previously associated with age, potentially explaining a >1000-fold increased incidence and the early onset of these SCCs. Human papillomavirus-negative basal and mesenchymal subtypes of HNSCC harbored enhanced APOBEC mutational signatures and transcriptomes similar to those of RDEB SCC, suggesting that APOBEC deaminases drive other subtypes of SCC. Collectively, these data establish specific mutagenic mechanisms associated with chronic tissue damage. Our findings reveal a cause for cancers arising at sites of persistent inflammation and identify potential therapeutic avenues to treat RDEB SCC., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
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41. Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.
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McMillan EA, Ryu MJ, Diep CH, Mendiratta S, Clemenceau JR, Vaden RM, Kim JH, Motoyaji T, Covington KR, Peyton M, Huffman K, Wu X, Girard L, Sung Y, Chen PH, Mallipeddi PL, Lee JY, Hanson J, Voruganti S, Yu Y, Park S, Sudderth J, DeSevo C, Muzny DM, Doddapaneni H, Gazdar A, Gibbs RA, Hwang TH, Heymach JV, Wistuba I, Coombes KR, Williams NS, Wheeler DA, MacMillan JB, Deberardinis RJ, Roth MG, Posner BA, Minna JD, Kim HS, and White MA
- Subjects
- Carcinoma, Non-Small-Cell Lung metabolism, Cell Line, Tumor, Cytochrome P450 Family 4 deficiency, Cytochrome P450 Family 4 genetics, Drug Discovery, G1 Phase Cell Cycle Checkpoints drug effects, Glucocorticoids pharmacology, Glucose Transport Proteins, Facilitative antagonists & inhibitors, Glucose Transport Proteins, Facilitative genetics, Glucose Transport Proteins, Facilitative metabolism, Humans, Kelch-Like ECH-Associated Protein 1 genetics, Kelch-Like ECH-Associated Protein 1 metabolism, Lung Neoplasms metabolism, Microtubule-Associated Proteins genetics, Microtubule-Associated Proteins metabolism, Mutation, NF-E2-Related Factor 2 antagonists & inhibitors, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, RNA Interference, RNA, Small Interfering metabolism, Receptor, Notch2 genetics, Receptor, Notch2 metabolism, Receptors, Glucocorticoid antagonists & inhibitors, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism, Small Molecule Libraries chemistry, Small Molecule Libraries metabolism, Carcinoma, Non-Small-Cell Lung pathology, Cell Proliferation drug effects, Lung Neoplasms pathology, Small Molecule Libraries pharmacology
- Abstract
Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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42. Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines.
- Author
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Ellrott K, Bailey MH, Saksena G, Covington KR, Kandoth C, Stewart C, Hess J, Ma S, Chiotti KE, McLellan M, Sofia HJ, Hutter C, Getz G, Wheeler D, and Ding L
- Subjects
- Algorithms, Exome, High-Throughput Nucleotide Sequencing methods, Humans, Information Dissemination methods, Mutation, Software, Exome Sequencing methods, Genomics methods, Neoplasms genetics, Sequence Analysis, DNA methods
- Abstract
The Cancer Genome Atlas (TCGA) cancer genomics dataset includes over 10,000 tumor-normal exome pairs across 33 different cancer types, in total >400 TB of raw data files requiring analysis. Here we describe the Multi-Center Mutation Calling in Multiple Cancers project, our effort to generate a comprehensive encyclopedia of somatic mutation calls for the TCGA data to enable robust cross-tumor-type analyses. Our approach accounts for variance and batch effects introduced by the rapid advancement of DNA extraction, hybridization-capture, sequencing, and analysis methods over time. We present best practices for applying an ensemble of seven mutation-calling algorithms with scoring and artifact filtering. The dataset created by this analysis includes 3.5 million somatic variants and forms the basis for PanCan Atlas papers. The results have been made available to the research community along with the methods used to generate them. This project is the result of collaboration from a number of institutes and demonstrates how team science drives extremely large genomics projects., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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43. Analytic validity of DecisionDx-Melanoma, a gene expression profile test for determining metastatic risk in melanoma patients.
- Author
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Cook RW, Middlebrook B, Wilkinson J, Covington KR, Oelschlager K, Monzon FA, and Stone JF
- Subjects
- Humans, Melanoma pathology, Real-Time Polymerase Chain Reaction methods, Risk Factors, Transcriptome genetics, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic genetics, Melanoma genetics, Neoplasm Metastasis genetics
- Abstract
Background: The DecisionDx-Melanoma test provides prognostic information for patients with cutaneous melanoma (CM). Using formalin-fixed paraffin-embedded primary tumor tissue, the RT-PCR-based test classifies patients into a low- (Class 1) or high-risk (Class 2) category for recurrence based on expression of 31 genes. The current study was designed to assess the analytical validity of this test., Methods: Inter-assay, inter-instrument, and inter-operator studies were performed to evaluate reliability of the 31-gene expression test results, sample stability and reagent stability. From March 2013 through June 2016, the gene expression test was performed on 8244 CM tumors. De-identified data from Pathology Reports were used to assess technical success., Results: Robust sample and reagent stability was observed. Inter-assay concordance on 168 specimens run on 2 consecutive days was 99% and matched probability scores were significantly correlated (R
2 = 0.96). Inter-instrument concordance was 95%, and probability scores had a correlation R2 of 0.99 (p < 0.001). From 8244 CM specimens submitted since 2013, 85% (7023) fulfilled pre-specified tumor content parameters. In these samples with sufficient tumor requirements, the technical success of the test was 98%., Conclusion: DecisionDx-Melanoma is a robust gene expression profile test that demonstrates strong reproducibility between experiments and has high technical reliability on clinical samples.- Published
- 2018
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44. Performance of a prognostic 31-gene expression profile in an independent cohort of 523 cutaneous melanoma patients.
- Author
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Zager JS, Gastman BR, Leachman S, Gonzalez RC, Fleming MD, Ferris LK, Ho J, Miller AR, Cook RW, Covington KR, Meldi-Plasseraud K, Middlebrook B, Kaminester LH, Greisinger A, Estrada SI, Pariser DM, Cranmer LD, Messina JL, Vetto JT, Wayne JD, Delman KA, Lawson DH, and Gerami P
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, Gene Expression Profiling statistics & numerical data, Humans, Kaplan-Meier Estimate, Lymphatic Metastasis, Melanoma pathology, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Prognosis, Proportional Hazards Models, Sentinel Lymph Node Biopsy, Skin Neoplasms pathology, Young Adult, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Background: The heterogeneous behavior of patients with melanoma makes prognostication challenging. To address this, a gene expression profile (GEP) test to predict metastatic risk was previously developed. This study evaluates the GEP's prognostic accuracy in an independent cohort of cutaneous melanoma patients., Methods: This multi-center study analyzed primary melanoma tumors from 523 patients, using the GEP to classify patients as Class 1 (low risk) and Class 2 (high risk). Molecular classification was correlated to clinical outcome and assessed along with AJCC v7 staging criteria. Primary endpoints were recurrence-free (RFS) and distant metastasis-free (DMFS) survival., Results: The 5-year RFS rates for Class 1 and Class 2 were 88% and 52%, respectively, and DMFS rates were 93% versus 60%, respectively (P < 0.001). The GEP was a significant predictor of RFS and DMFS in univariate analysis (hazard ratio [HR] = 5.4 and 6.6, respectively, P < 0.001 for each), along with Breslow thickness, ulceration, mitotic rate, and sentinel lymph node (SLN) status (P < 0.001 for each). GEP, tumor thickness and SLN status were significant predictors of RFS and DMFS in a multivariate model that also included ulceration and mitotic rate (RFS HR = 2.1, 1.2, and 2.5, respectively, P < 0.001 for each; and DMFS HR = 2.7, 1.3 and 3.0, respectively, P < 0.01 for each)., Conclusions: The GEP test is an objective predictor of metastatic risk and provides additional independent prognostic information to traditional staging to help estimate an individual's risk for recurrence. The assay identified 70% of stage I and II patients who ultimately developed distant metastasis. Its role in consideration of patients for adjuvant therapy should be examined prospectively.
- Published
- 2018
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45. Impact of Gene Expression Profiling on Decision-Making in Clinically Node Negative Melanoma Patients after Surgical Staging.
- Author
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Schuitevoerder D, Heath M, Cook RW, Covington KR, Fortino J, Leachman S, and Vetto JT
- Subjects
- Female, Follow-Up Studies, Gene Expression Profiling trends, Humans, Male, Melanoma diagnosis, Neoplasm Staging, Prospective Studies, Skin Neoplasms diagnosis, Melanoma, Cutaneous Malignant, Clinical Decision-Making methods, Gene Expression Profiling methods, Melanoma genetics, Melanoma surgery, Skin Neoplasms genetics, Skin Neoplasms surgery
- Abstract
Introduction: The surgeon's role in the follow-up of pathologic stage I and II melanoma patients has traditionally been minimal. Melanoma genetic expression profile (GEP) testing provides binary risk assessment (Class 1-low risk, Class 2-high risk), which can assist in predicting metastasis and formulating appropriate follow up. We sought to determine the impact of GEP results on the management of clinically node negative cutaneous melanoma patients staged with sentinel lymph node biopsy (SLNB)., Methods: A retrospective review of prospectively gathered data consisting of patients seen from September 2015 - August 2016 was performed to determine whether GEP class influenced follow-up recommendations. Patients were stratified into four groups based on recommended follow-up plan: Dermatology alone, Surgical Oncology, Surgical Oncology with recommendation for adjuvant clinical trial, or Medical and Surgical Oncology., Results: Of ninety-one patients, 38 were pathologically stage I, 42 stage II, 10 stage III, and 1 stage IV. Combining all stages, GEP Class 1 patients were more likely to be followed by Dermatology alone and less like to be followed by Surgical Oncology with recommendation for adjuvant trial compared to Class 2 patients (P less than 0.001). Among stage 1 patients, Class 1 were more likely to follow up with Dermatology alone compared to Class 2 patients (82 vs. 0%; P less than 0.001). Among stage II patients, GEP Class 1 were more likely to follow up with Dermatology alone (21 vs 0%) and more Class 2 patients followed up with surgery and recommendations for adjuvant trial (36 vs 64%; P less than 0.05). There was no difference in follow up for stage III patients based on the GEP results (P=0.76)., Conclusion: GEP results were significantly associated with the management of stage I-II melanoma patients after staging with SLNB. For node negative patients, Class 2 results led to more aggressive follow up and management. J Drugs Dermatol. 2018;17(2):196-199.
- Published
- 2018
46. Erratum to: Interim analysis of survival in a prospective, multi-center registry cohort of cutaneous melanoma tested with a prognostic 31-gene expression profile test.
- Author
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Hsueh EC, DeBloom JR, Lee J, Sussman JJ, Covington KR, Middlebrook B, Johnson C, Cook RW, Slingluff CL Jr, and McMasters KM
- Published
- 2017
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47. Interim analysis of survival in a prospective, multi-center registry cohort of cutaneous melanoma tested with a prognostic 31-gene expression profile test.
- Author
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Hsueh EC, DeBloom JR, Lee J, Sussman JJ, Covington KR, Middlebrook B, Johnson C, Cook RW, Slingluff CL Jr, and McMasters KM
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Melanoma mortality, Melanoma pathology, Middle Aged, Neoplasm Metastasis, Prognosis, Prospective Studies, Registries, Skin Neoplasms mortality, Skin Neoplasms pathology, Survival Rate, Young Adult, Melanoma, Cutaneous Malignant, Gene Expression Profiling methods, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Background: A 31-gene expression profile (GEP) test that provides risk classification of cutaneous melanoma (CM) patients has been validated in several retrospective studies. The objective of the reported study was a prospective evaluation of the GEP performance in patients enrolled in two clinical registries., Methods: Three-hundred twenty two CM patients enrolled in the EXPAND (NCT02355587) and INTEGRATE (NCT02355574) registries met the criteria of age ≥ 16 years, successful GEP result and ≥1 follow-up visit for inclusion in this interim analysis. Primary endpoints were recurrence-free (RFS), distant metastasis-free (DMFS), and overall survival (OS)., Results: Median follow-up was 1.5 years for event-free patients. Median age for subjects was 58 years (range 18-87) and median Breslow thickness was 1.2 mm (range 0.2-12.0). Eighty-eight percent (282/322) of cases had stage I/II disease and 74% (237/322) had a SLN biopsy. Seventy-seven percent (248/322) had class 1 molecular profiles. 1.5-year RFS, DMFS, and OS rates were 97 vs. 77%, 99 vs. 89%, and 99 vs. 92% for class 1 vs. class 2, respectively (p < 0.0001 for each). Multivariate Cox regression showed Breslow thickness, mitotic rate, and GEP class to significantly predict recurrence (p < 0.01), while tumor thickness was the only significant predictor of distant metastasis and overall survival in this interim analysis., Conclusions: Interim analysis of patient outcomes from a combined prospective cohort supports the 31-gene GEP's ability to stratify early-stage CM patients into two groups with significantly different metastatic risk. RFS outcomes in this real-world cohort are consistent with previously published analyses with retrospective specimens. GEP testing complements current clinicopathologic features and increases identification of high-risk patients., Trial Registration: ClinicalTrials.gov, NCT02355574 and NCT02355587.
- Published
- 2017
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48. Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.
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Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J, Robertson AG, Hinoue T, Hoadley KA, Gibb EA, Roszik J, Covington KR, Wu CC, Shinbrot E, Stransky N, Hegde A, Yang JD, Reznik E, Sadeghi S, Pedamallu CS, Ojesina AI, Hess JM, Auman JT, Rhie SK, Bowlby R, Borad MJ, Zhu AX, Stuart JM, Sander C, Akbani R, Cherniack AD, Deshpande V, Mounajjed T, Foo WC, Torbenson MS, Kleiner DE, Laird PW, Wheeler DA, McRee AJ, Bathe OF, Andersen JB, Bardeesy N, Roberts LR, and Kwong LN
- Published
- 2017
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49. Non-malignant respiratory epithelial cells preferentially proliferate from resected non-small cell lung cancer specimens cultured under conditionally reprogrammed conditions.
- Author
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Gao B, Huang C, Kernstine K, Pelekanou V, Kluger Y, Jiang T, Peters-Hall JR, Coquelin M, Girard L, Zhang W, Huffman K, Oliver D, Kinose F, Haura E, Teer JK, Rix U, Le AT, Aisner DL, Varella-Garcia M, Doebele RC, Covington KR, Hampton OA, Doddapaneni HV, Jayaseelan JC, Hu J, Wheeler DA, Shay JW, Rimm DL, Gazdar A, and Minna JD
- Subjects
- A549 Cells, Adult, Aged, Aged, 80 and over, Base Sequence, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cells, Cultured, DNA Copy Number Variations, DNA Mutational Analysis methods, Epithelial Cells cytology, Female, Gene Expression Profiling methods, Genetic Predisposition to Disease genetics, Humans, Lung Neoplasms pathology, Male, Middle Aged, Mutation, Respiratory Mucosa cytology, Respiratory Mucosa metabolism, Tumor Cells, Cultured, Carcinoma, Non-Small-Cell Lung genetics, Cell Proliferation genetics, Coculture Techniques methods, Epithelial Cells metabolism, Lung Neoplasms genetics
- Abstract
The "conditionally reprogrammed cells" (CRC) method, using a Rho kinase inhibitor and irradiated mouse fibroblast cells has been described for the efficient growth of cells from malignant and non-malignant samples from primary tumor and non-malignant sites. Using the CRC method, four institutions independently cultured tumor tissues from 48 non-small cell lung cancers (NSCLC, mostly from primary resected tumors) and 22 non-malignant lungs. We found that epithelial cells could be cultured from tumor and non-malignant lung. However, epithelial cells cultured from tumors had features of non-malignant respiratory epithelial cells which include: 1) among 22 mutations found in the original tumors only two mutations were found in the CRC cultures with reduced frequency (31% to 13% and 92% to 15% from original tumor and CRC culture respectively); 2) copy number variation was analyzed in 9 tumor and their CRC cultures and only diploid patterns were found in CRC cultures; 3) mRNA expression profiles were similar to those of normal respiratory epithelial cells; and 4) co-culture of tumor and non-malignant lung epithelial cells resulted in mostly non-malignant cells. We conclude that CRC method is a highly selective and useful method for the growth of non-malignant respiratory epithelial cells from tumor specimens and only occasionally do such CRC cultures contain a small subpopulation of cancer cells marked by oncogenic mutations. While our findings are restricted to resected primary NSCLC, they indicated the necessity to fully characterize all CRC cultures and the need to develop culture technology that facilitates the growth of primary lung cancers.
- Published
- 2017
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50. Cross-species identification of genomic drivers of squamous cell carcinoma development across preneoplastic intermediates.
- Author
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Chitsazzadeh V, Coarfa C, Drummond JA, Nguyen T, Joseph A, Chilukuri S, Charpiot E, Adelmann CH, Ching G, Nguyen TN, Nicholas C, Thomas VD, Migden M, MacFarlane D, Thompson E, Shen J, Takata Y, McNiece K, Polansky MA, Abbas HA, Rajapakshe K, Gower A, Spira A, Covington KR, Xiao W, Gunaratne P, Pickering C, Frederick M, Myers JN, Shen L, Yao H, Su X, Rapini RP, Wheeler DA, Hawk ET, Flores ER, and Tsai KY
- Subjects
- Animals, Carcinogenesis genetics, Carcinoma, Squamous Cell etiology, Carcinoma, Squamous Cell prevention & control, DNA Mutational Analysis, Disease Progression, Female, Gene Expression Profiling, Genomics, High-Throughput Nucleotide Sequencing, Humans, Mice, Mice, Hairless, Molecular Targeted Therapy methods, Precancerous Conditions genetics, Sequence Analysis, RNA, Skin pathology, Skin Neoplasms etiology, Skin Neoplasms prevention & control, Ultraviolet Rays adverse effects, Exome Sequencing, Antineoplastic Agents therapeutic use, Carcinoma, Squamous Cell genetics, Keratosis, Actinic pathology, Precancerous Conditions pathology, Skin Neoplasms genetics
- Abstract
Cutaneous squamous cell carcinoma (cuSCC) comprises 15-20% of all skin cancers, accounting for over 700,000 cases in USA annually. Most cuSCC arise in association with a distinct precancerous lesion, the actinic keratosis (AK). To identify potential targets for molecularly targeted chemoprevention, here we perform integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar ultraviolet radiation-driven Hairless mouse model. We identify the major transcriptional drivers of this progression sequence, showing that the key genomic changes in cuSCC development occur in the normal skin to AK transition. Our data validate the use of this ultraviolet radiation-driven mouse cuSCC model for cross-species analysis and demonstrate that cuSCC bears deep molecular similarities to multiple carcinogen-driven SCCs from diverse sites, suggesting that cuSCC may serve as an effective, accessible model for multiple SCC types and that common treatment and prevention strategies may be feasible.
- Published
- 2016
- Full Text
- View/download PDF
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