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Melanoma: HELP
Articles by David W. Ollila
Based on 39 articles published since 2010
(Why 39 articles?)
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Between 2010 and 2020, D. Ollila wrote the following 39 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Time may Heal All Wounds, but While It Does, Melanoma Marches on. 2019

Ollila, David W / Meyers, Michael O. ·Department of Surgery, Division of Surgical Oncology, University of North Carolina, Chapel Hill, NC, USA. david_ollila@med.unc.edu. · Department of Surgery, Division of Surgical Oncology, University of North Carolina, Chapel Hill, NC, USA. ·Ann Surg Oncol · Pubmed #31468216.

ABSTRACT: -- No abstract --

2 Editorial Another brick in the wall: toward a better understanding of melanoma of unknown primary. 2014

Ollila, David W / Meyers, Michael O. ·Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, david_ollila@med.unc.edu. ·Ann Surg Oncol · Pubmed #25201497.

ABSTRACT: -- No abstract --

3 Editorial A phase 2 trial of complete resection for stage IV melanoma: results of Southwest Oncology Group Clinical Trial S9430. 2011

Ollila, David W. · ·Cancer · Pubmed #21455996.

ABSTRACT: -- No abstract --

4 Review Metastasectomy for Stage IV Melanoma in the Era of Effective Systemic Agents. 2016

Ollila, David W / Lopez, Nicole E / Hsueh, Eddy C. ·The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. · Saint Louis University Hospital, Saint Louis, Missouri. ·Crit Rev Oncog · Pubmed #27481001.

ABSTRACT: There is an increasing body of literature that strongly suggests that complete metastasectomy for stage IV melanoma can improve overall survival. Before 2011, the efficacy of systemic therapy for melanoma was poor, making surgical resection the mainstay for treatment and the only realistic chance for cure. Now, in just a short time span (2011-2014), we have six Food & Drug Administration (FDA)-approved drugs for patients with stage IV metastatic melanoma. In the absence of prospective clinical trials evaluating the most advantageous sequence and timing for systemic therapy and surgical resection in the setting of stage IV melanoma, the treating surgical and medical oncologists must jointly devise individual treatment plans that take into account the advantages and disadvantages of each modality. This multidisciplinary approach gives the patient the best chance for prolonged survival. This article briefly reviews the FDA-approved systemic therapy options, discusses the data for site-specific metastasectomy, critiques the previous stage IV metastasectomy trials, and presents a view for moving forward with a multidisciplinary approach in mind.

5 Review Systematic review: surgery for patients with metastatic melanoma during active treatment with ipilimumab. 2014

Baker, Justin J / Stitzenberg, Karyn B / Collichio, Frances A / Meyers, Michael O / Ollila, David W. ·Division of Surgical Oncology, Department of Surgery, Maine Medical Center, Portland, Maine, USA. ·Am Surg · Pubmed #25105403.

ABSTRACT: Studies of ipilimumab have shown improved overall survival in patients with metastatic cutaneous melanoma. As a result, use of ipilimumab in patients with Stage IV melanoma is rapidly increasing. Patients with Stage IV melanoma often require urgent operations for complications from metastases, but little is known about the safety of surgical intervention for patients receiving ipilimumab. We performed a systematic review of the literature using PubMed. Our search terms were melanoma and ipilimumab. We excluded foreign language articles, review articles, and those not addressing cutaneous melanoma. We identified 194 publications matching the search criteria. Only six of those met the inclusion criteria. In these six publications, seven patients who had undergone surgical intervention during treatment with ipilimumab were described. There were no documented surgical complications. We reviewed our institutional experience and identified an additional three patients. No postoperative complications could be attributed directly to ipilimumab. There are limited data on the safety of surgical intervention during treatment with ipilimumab. Preliminary reports suggest there is no reason to withhold or delay surgery for patients receiving ipilimumab therapy.

6 Review Historical review of melanoma treatment and outcomes. 2013

Lee, Carrie / Collichio, Frances / Ollila, David / Moschos, Stergios. ·Department of Medicine, The University of North Carolina School of Medicine, Physician's Office Building, 3rd Floor 170 Manning Drive CB# 7305, Chapel Hill, NC 27599, USA. carrie_lee@med.unc.edu ·Clin Dermatol · Pubmed #23438377.

ABSTRACT: The surgical and medical management of melanoma has changed dramatically since the first description of melanoma as a disease entity more than 200 years ago. Refinement of surgical techniques, including evaluation of optimal surgical margins, utility of elective lymph node dissection, and incorporation of sentinel lymph node mapping as both a prognostic tool and guide for selective lymphadenectomy have lessened surgical morbidity and improved outcomes for early-stage and locally advanced melanoma. Astute clinical observations of the integrated roles of the immune system and oncogenic mutations have more recently led to improvements in survival and quality of life for advanced melanoma. Herein, we provide an overview of the most significant surgical and medical milestones in the treatment of melanoma over the past 2 centuries.

7 Review Rationale for complete metastasectomy in patients with stage IV metastatic melanoma. 2011

Ollila, David W / Gleisner, Ana L / Hsueh, Eddy C. ·Division of Surgical Oncology and Endocrine Surgery, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA. david_ollila@med.unc.edu ·J Surg Oncol · Pubmed #21858837.

ABSTRACT: Patients with stage IV melanoma have usually been treated with systemic therapies; however, the overall survival for patients with this approach is disappointing. A complete surgical resection of metastatic disease to stage IV sites offers the best chance to maximize survival. This review article will present data supporting the position that if a complete metastasectomy is technically feasible, then surgery should be strongly considered the first option for properly selected patients with stage IV melanoma.

8 Clinical Trial Cutaneous head and neck melanoma in OPTiM, a randomized phase 3 trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/IIIC/IV melanoma. 2016

Andtbacka, Robert H I / Agarwala, Sanjiv S / Ollila, David W / Hallmeyer, Sigrun / Milhem, Mohammed / Amatruda, Thomas / Nemunaitis, John J / Harrington, Kevin J / Chen, Lisa / Shilkrut, Mark / Ross, Merrick / Kaufman, Howard L. ·University of Utah Huntsman Cancer Institute, Salt Lake City, Utah. · St. Luke's University Hospital and Temple University, Philadelphia, Pennsylvania. · University of North Carolina, Chapel Hill, North Carolina. · Advocate Lutheran General Hospital, Park Ridge, Illinois. · University of Iowa Hospitals and Clinics, Iowa City, Iowa. · Minnesota Oncology, Fridley, Minnesota. · Mary Crowley Cancer Research Center, Dallas, Texas. · The Institute of Cancer Research/The Royal Marsden Hospital, London, UK. · Amgen, Inc, Thousand Oaks, California. · The University of Texas MD Anderson Cancer Center, Houston, Texas. · Rutgers Cancer Institute of New Jersey, Rutgers, New Jersey. ·Head Neck · Pubmed #27407058.

ABSTRACT: BACKGROUND: Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS: Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM-CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma. RESULTS: DRR was higher for talimogene laherparepvec-treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM-CSF. Among talimogene laherparepvec-treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with talimogene laherparepvec. CONCLUSION: Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1752-1758, 2016.

9 Clinical Trial Targeted next generation sequencing identifies clinically actionable mutations in patients with melanoma. 2014

Jeck, William R / Parker, Joel / Carson, Craig C / Shields, Janiel M / Sambade, Maria J / Peters, Eldon C / Burd, Christin E / Thomas, Nancy E / Chiang, Derek Y / Liu, Wenjin / Eberhard, David A / Ollila, David / Grilley-Olson, Juneko / Moschos, Stergios / Neil Hayes, D / Sharpless, Norman E. ·Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA. ·Pigment Cell Melanoma Res · Pubmed #24628946.

ABSTRACT: Somatic sequencing of cancers has produced new insight into tumorigenesis, tumor heterogeneity, and disease progression, but the vast majority of genetic events identified are of indeterminate clinical significance. Here, we describe a NextGen sequencing approach to fully analyzing 248 genes, including all those of known clinical significance in melanoma. This strategy features solution capture of DNA followed by multiplexed, high-throughput sequencing and was evaluated in 31 melanoma cell lines and 18 tumor tissues from patients with metastatic melanoma. Mutations in melanoma cell lines correlated with their sensitivity to corresponding small molecule inhibitors, confirming, for example, lapatinib sensitivity in ERBB4 mutant lines and identifying a novel activating mutation of BRAF. The latter event would not have been identified by clinical sequencing and was associated with responsiveness to a BRAF kinase inhibitor. This approach identified focal copy number changes of PTEN not found by standard methods, such as comparative genomic hybridization (CGH). Actionable mutations were found in 89% of the tumor tissues analyzed, 56% of which would not be identified by standard-of-care approaches. This work shows that targeted sequencing is an attractive approach for clinical use in melanoma.

10 Article Real-World Outcomes of Talimogene Laherparepvec Therapy: A Multi-Institutional Experience. 2019

Louie, Raphael J / Perez, Matthew C / Jajja, Mohammad Raheel / Sun, James / Collichio, Frances / Delman, Keith A / Lowe, Michael / Sarnaik, Amod A / Zager, Jonathan S / Ollila, David W. ·Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC. · Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL. · Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine, Atlanta, GA. · Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC. · Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC. Electronic address: david_ollila@med.unc.edu. ·J Am Coll Surg · Pubmed #30690076.

ABSTRACT: BACKGROUND: Talimogene laherparepvec (TVEC) is an FDA-approved oncolytic herpes virus used to treat unresectable stage IIIB to IV metastatic melanoma via intralesional injection. This study aims to characterize the efficacy TVEC in patients with unresectable stage IIIB to IV melanoma. METHODS: We performed a multi-institutional, IRB-approved review of all patients who received TVEC at 3 centers from October 2015 to October 2018. Clinicopathologic characteristics, TVEC treatment data, and outcomes were assessed. RESULTS: One hundred and twenty-one patients received TVEC, of which 80 patients had available treatment response data with at least 3-month follow-up. Anatomic sites treated were 19 (24%) head and neck, 9 (11%) upper extremity, 12 (15%) torso, and 40 (50%) lower extremity. Thirty-four (42.5%) patients did not receive therapy before TVEC. Side effects were mild and self-limited, most commonly flu-like symptoms seen in 22 (28%) patients. Median follow-up was 9 months (range 3 to 28 months), with complete local response in 31 (39%) and partial response in 14 (18%) patients. Of complete responders, 29 (37%) had no evidence of disease at last follow-up and received a median of 6 (range 2 to 12) cycles of therapy. CONCLUSIONS: Talimogene laherparepvec is a well-tolerated, durable treatment option for patients with unresectable locoregional melanoma, particularly in stage IIIB/C disease. Additionally, we found that TVEC can be administered safely across anatomic sites that are otherwise not amenable to other local therapies.

11 Article Relationship of Chromosome Arm 10q Variants to Occurrence of Multiple Primary Melanoma in the Population-Based Genes, Environment, and Melanoma (GEM) Study. 2019

Miles, Jonathan A / Orlow, Irene / Kanetsky, Peter A / Luo, Li / Cust, Anne E / Armstrong, Bruce K / Kricker, Anne / Anton-Culver, Hoda / Gruber, Stephen B / Gallagher, Richard P / Zanetti, Roberto / Rosso, Stefano / Sacchetto, Lidia / Dwyer, Terence / Gibbs, David C / Busam, Klaus J / Mavinkurve, Vikram / Ollila, David W / Begg, Colin B / Berwick, Marianne / Thomas, Nancy E / Anonymous13431193. ·Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. · Department of Internal Medicine, University of New Mexico Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA. · Sydney School of Public Health, The University of Sydney, Sydney, Australia; Melanoma Institute Australia, The University of Sydney, North Sydney, Australia. · School of Public and Global Health, The University of Western Australia, Perth, Australia. · Sydney School of Public Health, The University of Sydney, Sydney, Australia. · Department of Epidemiology, University of California, Irvine, California, USA. · Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA. · British Columbia Cancer and Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada. · Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy. · Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy; Politecnico di Torino, Turin, Italy. · George Institute for Global Health, Nuffield Department of Obstetrics and Gynecology, University of Oxford, Oxford, UK. · Department of Epidemiology, Emory University, Atlanta, Georgia, USA. · Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Department of Surgery, University of North Carolina, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. Electronic address: nthomas@med.unc.edu. ·J Invest Dermatol · Pubmed #30571972.

ABSTRACT: -- No abstract --

12 Article Identification of a Robust Methylation Classifier for Cutaneous Melanoma Diagnosis. 2019

Conway, Kathleen / Edmiston, Sharon N / Parker, Joel S / Kuan, Pei Fen / Tsai, Yi-Hsuan / Groben, Pamela A / Zedek, Daniel C / Scott, Glynis A / Parrish, Eloise A / Hao, Honglin / Pearlstein, Michelle V / Frank, Jill S / Carson, Craig C / Wilkerson, Matthew D / Zhao, Xiaobei / Slater, Nathaniel A / Moschos, Stergios J / Ollila, David W / Thomas, Nancy E. ·Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina, USA; Department of Dermatology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center (LCCC), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Electronic address: kconway@med.unc.edu. · Lineberger Comprehensive Cancer Center (LCCC), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. · Lineberger Comprehensive Cancer Center (LCCC), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, USA. · Department of Dermatology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA; Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA; Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine, Rochester, New York, USA. · Department of Dermatology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. · Lineberger Comprehensive Cancer Center (LCCC), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. · Lineberger Comprehensive Cancer Center (LCCC), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Surgery, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Dermatology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center (LCCC), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. ·J Invest Dermatol · Pubmed #30529013.

ABSTRACT: Early diagnosis improves melanoma survival, yet the histopathological diagnosis of cutaneous primary melanoma can be challenging, even for expert dermatopathologists. Analysis of epigenetic alterations, such as DNA methylation, that occur in melanoma can aid in its early diagnosis. Using a genome-wide methylation screening, we assessed CpG methylation in a diverse set of 89 primary invasive melanomas, 73 nevi, and 41 melanocytic proliferations of uncertain malignant potential, classified based on interobserver review by dermatopathologists. Melanomas and nevi were split into training and validation sets. Predictive modeling in the training set using ElasticNet identified a 40-CpG classifier distinguishing 60 melanomas from 48 nevi. High diagnostic accuracy (area under the receiver operator characteristic curve = 0.996, sensitivity = 96.6%, and specificity = 100.0%) was independently confirmed in the validation set (29 melanomas, 25 nevi) and other published sample sets. The 40-CpG melanoma classifier included homeobox transcription factors and genes with roles in stem cell pluripotency or the nervous system. Application of the 40-CpG melanoma classifier to the diagnostically uncertain samples assigned melanoma or nevus status, potentially offering a diagnostic tool to assist dermatopathologists. In summary, the robust, accurate 40-CpG melanoma classifier offers a promising assay for improving primary melanoma diagnosis.

13 Article Utility of TERT Promoter Mutations for Cutaneous Primary Melanoma Diagnosis. 2019

Thomas, Nancy E / Edmiston, Sharon N / Tsai, Yihsuan S / Parker, Joel S / Googe, Paul B / Busam, Klaus J / Scott, Glynis A / Zedek, Daniel C / Parrish, Eloise A / Hao, Honglin / Slater, Nathaniel A / Pearlstein, Michelle V / Frank, Jill S / Kuan, Pei Fen / Ollila, David W / Conway, Kathleen. ·Department of Dermatology, School of Medicine, University of North Carolina, Chapel Hill, NC. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC. · Departments of Genetics, and. · Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC. · Department of Pathology, Memorial Sloan-Kettering Cancer Center, Manhattan, NY. · Departments of Dermatology, and. · Pathology and Laboratory Medicine, University of Rochester School of Medicine, Rochester, NY. · Department of Surgery, School of Medicine, University of North Carolina, Chapel Hill, NC. · Department of Applied Mathematics and Statistics, State University of New York, Stony Brook, NY. · Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC. ·Am J Dermatopathol · Pubmed #30211730.

ABSTRACT: Telomerase reverse transcriptase (TERT) promoter mutations are commonly found in malignant melanomas but rare in melanocytic nevi. To assess its potential diagnostic utility for the distinction of melanoma from nevus, we determined the TERT promoter mutation status of 86 primary melanomas, 72 melanocytic nevi, and 40 diagnostically problematic melanocytic proliferations. Of the 86 melanomas, 67 (77.9%) were TERT-positive, defined as harboring a hotspot TERT promoter mutation at positions -124C>T, -124_125CC>TT, -138_139CC>TT, or -146C>T. Of the 72 nevi, only 1 (1.4%) was TERT-positive. Of the 40 diagnostically uncertain melanocytic proliferations, 2 (5.0%) were TERT-positive. TERT positivity as a test for melanoma versus nevus had an accuracy of 87.3% [95% confidence interval (CI), 81.1-92.1], a sensitivity of 77.9% (95% CI, 68.9-85.4), a specificity of 98.6% (95% CI, 95.8-100), a positive predictive value of 98.5% (95% CI, 95.6-100), and a negative predictive value of 78.9% (95% CI, 72.6-85.4). Our results indicate that hotspot TERT promoter mutation status may be a useful ancillary parameter for the diagnosis of melanoma. In particular, the high specificity of these mutations for melanoma indicates the presence of a TERT promoter mutation in a melanocytic neoplasm associated with diagnostic controversy, or uncertainty should increase concern for a melanoma.

14 Article The Prognostic Significance of Low-Frequency Somatic Mutations in Metastatic Cutaneous Melanoma. 2018

Zhao, Xiaobei / Little, Paul / Hoyle, Alan P / Pegna, Guillaume J / Hayward, Michele C / Ivanova, Anastasia / Parker, Joel S / Marron, David L / Soloway, Matthew G / Jo, Heejoon / Salazar, Ashley H / Papakonstantinou, Michael P / Bouchard, Deeanna M / Jefferys, Stuart R / Hoadley, Katherine A / Ollila, David W / Frank, Jill S / Thomas, Nancy E / Googe, Paul B / Ezzell, Ashley J / Collichio, Frances A / Lee, Carrie B / Earp, H Shelton / Sharpless, Norman E / Hugo, Willy / Wilmott, James S / Quek, Camelia / Waddell, Nicola / Johansson, Peter A / Thompson, John F / Hayward, Nicholas K / Mann, Graham J / Lo, Roger S / Johnson, Douglas B / Scolyer, Richard A / Hayes, D Neil / Moschos, Stergios J. ·Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. · Department of Biostatistics, Gillings School of Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. · Division of Hematology/Oncology, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. · Division of Surgical Oncology, Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. · Melanoma Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. · Department of Dermatology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. · Department of Cell Biology & Physiology, Histology Research Core Facility, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. · Division of Dermatology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, United States. · Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. · Queensland Institute of Medical Research-QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. · Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, United States. ·Front Oncol · Pubmed #30662871.

ABSTRACT:

15 Article Inherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes. 2018

Thomas, Nancy E / Edmiston, Sharon N / Orlow, Irene / Kanetsky, Peter A / Luo, Li / Gibbs, David C / Parrish, Eloise A / Hao, Honglin / Busam, Klaus J / Armstrong, Bruce K / Kricker, Anne / Cust, Anne E / Anton-Culver, Hoda / Gruber, Stephen B / Gallagher, Richard P / Zanetti, Roberto / Rosso, Stefano / Sacchetto, Lidia / Dwyer, Terence / Ollila, David W / Begg, Colin B / Berwick, Marianne / Conway, Kathleen / Anonymous5160946. ·Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. Electronic address: nthomas@med.unc.edu. · Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, USA. · Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. · Department of Internal Medicine, University of New Mexico Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA. · Department of Epidemiology, Emory University, Atlanta, Georgia, USA. · Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA. · School of Public and Global Health, The University of Western Australia, Perth, Australia. · Sydney School of Public Health, The University of Sydney, Sydney, Australia. · Sydney School of Public Health, The University of Sydney, Sydney, Australia; Melanoma Institute Australia, The University of Sydney, North Sydney, Australia. · Department of Epidemiology, University of California, Irvine, California, USA. · USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA. · British Columbia Cancer and Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada. · Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy. · Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy; Politecnico di Torino, Turin, Italy. · George Institute for Global Health, Nuffield Department of Obstetrics and Gynecology, University of Oxford, Oxford, UK. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Department of Surgery, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA. ·J Invest Dermatol · Pubmed #29753029.

ABSTRACT: BRAF and NRAS mutations arise early in melanoma development, but their associations with low-penetrance melanoma susceptibility loci remain unknown. In the Genes, Environment and Melanoma Study, 1,223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRAS mutations and germline DNA genotyped for 47 single-nucleotide polymorphisms identified as low-penetrant melanoma-risk variants. We used multinomial logistic regression to simultaneously examine each single-nucleotide polymorphism's relationship to BRAF V600E, BRAF V600K, BRAF other, and NRAS+ relative to BRAF-/NRAS- melanoma adjusted for study features. IRF4 rs12203592*T was associated with BRAF V600E (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.43-0.79) and V600K (OR = 0.65, 95% CI = 0.41-1.03), but not BRAF other or NRAS+ melanoma. A global test of etiologic heterogeneity (P

16 Article Implementing a Program of Talimogene laherparepvec. 2018

Collichio, Frances / Burke, Lauren / Proctor, Amber / Wallack, Diana / Collichio, Anthony / Long, Patricia K / Ollila, David W. ·Division of Hematology-Oncology, Department of Medicine, The University of North Carolina, Chapel Hill, NC, USA. fcollich@med.unc.edu. · Department of Radiology, The University of North Carolina, Chapel Hill, NC, USA. · Department of Pharmacy, The University of North Carolina, Chapel Hill, NC, USA. · The Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. · Boston University, Boston, MA, USA. · Division of Surgical Oncology, The University of North Carolina, Chapel Hill, NC, USA. ·Ann Surg Oncol · Pubmed #29417403.

ABSTRACT: BACKGROUND: Oncolytic viruses are genetically engineered or naturally occurring viruses that selectively replicate in cancer cells without harming normal cells. Talimogene laherparepvec (Imlygic PURPOSE: As a biologic product, use of T. laherparepvec in the clinical setting requires pretreatment planning and a unique systematic approach to deliver the therapy. The processes we describe herein could be adopted by other centers that choose to prescribe T. laherparepvec. METHODS: We studied our clinical trial experience with T. laherparepvec before we embarked on using commercially available T. laherparepvec. We created a standard operating procedure (SOP) with multidisciplinary buy-in and oversight from leadership in Infection Control at our institution. We reflected on clinical cases and the actual procedures of administering T. laherparepvec to create the SOP. RESULTS: The preimplementation planning, patient selection, identification of lesions to treat, the actual procedure, and ongoing assessment of patients are described. Tumoral-related factors that lead to unique challenges are described. CONCLUSIONS: A process to ensure safe and responsible implementation of a program to administer T. laherparepvec for treatment of melanoma may improve the quality of treatment for patients who suffer from advanced melanoma.

17 Article Tumor Mitotic Rate and Association with Recurrence in Sentinel Lymph Node Negative Stage II Melanoma Patients. 2017

Laks, Shachar / Meyers, Michael O / Deal, Allison M / Frank, Jill S / Stitzenberg, Karyn B / Yeh, Jen Jen / Thomas, Nancy E / Ollila, David W. · ·Am Surg · Pubmed #28958277.

ABSTRACT: Tumor mitotic rate (TMR) is a known prognostic variable in thin melanoma patients. Its significance in stage II melanoma patients is yet to be demonstrated. Retrospective analysis of a prospective melanoma database from 9/1997 to 7/2015 was performed. All stage II melanoma, with documented TMR, and six months of follow-up were included. We evaluated the association of clinicopathologic variables, TMR, as a continuous and categorical variable with recurrence-free survival (RFS) and overall survival (OS) using Cox proportional hazards modeling. We used a statistical model, X-tile, to develop optimal categorizations of TMR. A total of 265 patient characteristics are included in this study. Recurrences occurred in 82 (30.9%) patients, including 5 local, 41 regional, and 36 distant patients. In multivariate model, ulceration, Breslow, and continuous TMR were associated with worse RFS\OS. Continuous TMR demonstrated worse RFS (hazards ratio [HR] 1.02 (1.00-1.05)) and OS (HR 1.02 (1.00-1.04)), whereas dichotomized TMR (≥1 vs <1) was not significant. TMR >10.4 mitoses/mm2 has a 5-year RFS\OS of 27.2 and 44.3 per cent, respectively, compared with 57.4 and 71.4 per cent, respectively, for TMR <3.2 mitoses/mm2. Continuous TMR predicts incidence of recurrence in stage II melanoma. We propose a new categorization method developed by statistical modeling for optimal stratification that may guide surveillance for this disparate patient population.

18 Article Associations of MC1R Genotype and Patient Phenotypes with BRAF and NRAS Mutations in Melanoma. 2017

Thomas, Nancy E / Edmiston, Sharon N / Kanetsky, Peter A / Busam, Klaus J / Kricker, Anne / Armstrong, Bruce K / Cust, Anne E / Anton-Culver, Hoda / Gruber, Stephen B / Luo, Li / Orlow, Irene / Reiner, Anne S / Gallagher, Richard P / Zanetti, Roberto / Rosso, Stefano / Sacchetto, Lidia / Dwyer, Terence / Parrish, Eloise A / Hao, Honglin / Gibbs, David C / Frank, Jill S / Ollila, David W / Begg, Colin B / Berwick, Marianne / Conway, Kathleen / Anonymous2060917. ·Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. Electronic address: nthomas@med.unc.edu. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA. · Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA. · Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia. · Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia; Melanoma Institute Australia, North Sydney, Australia. · Department of Epidemiology, University of California, Irvine, California, USA. · Univeristy of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA. · Department of Internal Medicine, University of New Mexico Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA. · Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, USA. · British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy. · Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA; Politecnico di Torino, Turin, Italy. · George Institute for Global Health, Nuffield Department of Obstetrics and Gynecology, University of Oxford. · Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA; Department of Epidemiology, Emory University, Atlanta, Georgia, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Department of Surgery, University of North Carolina, Chapel Hill, North Carolina, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA; Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA. ·J Invest Dermatol · Pubmed #28842324.

ABSTRACT: Associations of MC1R with BRAF mutations in melanoma have been inconsistent between studies. We sought to determine for 1,227 participants in the international population-based Genes, Environment, and Melanoma (GEM) study whether MC1R and phenotypes were associated with melanoma BRAF/NRAS subtypes. We used logistic regression adjusted by age, sex, and study design features and examined effect modifications. BRAF

19 Article Association of Incident Amelanotic Melanoma With Phenotypic Characteristics, MC1R Status, and Prior Amelanotic Melanoma. 2017

Vernali, Steven / Waxweiler, Weston T / Dillon, Patrick M / Kanetsky, Peter A / Orlow, Irene / Luo, Li / Busam, Klaus J / Kricker, Anne / Armstrong, Bruce K / Anton-Culver, Hoda / Gruber, Stephen B / Gallagher, Richard P / Zanetti, Roberto / Rosso, Stefano / Sacchetto, Lidia / Dwyer, Terence / Cust, Anne E / Ollila, David W / Begg, Colin B / Berwick, Marianne / Thomas, Nancy E / Anonymous850914. ·Department of Dermatology, University of North Carolina, Chapel Hill. · Department of Medicine, University of Virginia, Charlottesville. · Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York. · Department of Internal Medicine, University of New Mexico Cancer Center, University of New Mexico, Albuquerque. · Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia. · Department of Epidemiology, University of California, Irvine. · USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles. · Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy. · Politecnico di Torino, Turin, Italy. · Universitá degli Studi di Torino, Turin, Italy. · George Institute for Global Health, Nuffield Department of Obstetrics and Gynecology, University of Oxford, England. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. · Department of Surgery, University of North Carolina, Chapel Hill. ·JAMA Dermatol · Pubmed #28746718.

ABSTRACT: Importance: We previously reported that survival is poorer from histopathologically amelanotic than pigmented melanoma because of more advanced stage at diagnosis. Identifying patients at risk of amelanotic melanoma might enable earlier diagnosis and improved survival; however, the phenotypic characteristics and underlying genetics associated with amelanotic melanoma are unknown. Objective: To determine whether phenotypic characteristics, carriage of MC1R variants, and history of amelanotic melanoma are associated with histopathologically amelanotic melanoma. Design, Setting, and Participants: The Genes, Environment, and Melanoma (GEM) study is an international cohort study that enrolled patients with incident primary cutaneous melanomas from population-based and hospital-based cancer registries (1998 to 2003). The GEM participants included here were 2387 patients with data for phenotypes, MC1R genotype, and primary melanomas scored for histopathologic pigmentation. Of these 2387 patients with incident melanomas scored for pigmentation, 527 had prior primary melanomas also scored for pigmentation. Main Outcomes and Measures: Associations of phenotypic characteristics (freckles, nevi, phenotypic index) and MC1R status with incident amelanotic melanomas were evaluated using logistic regression models adjusted for age, sex, study center, and primary status (single or multiple primary melanoma); odds ratios (ORs) and 95% CIs are reported. Association of histopathologic pigmentation between incident and prior melanomas was analyzed using an exact logistic regression model. Results: This study included 2387 patients (1065 women, 1322 men; mean [SD] age at diagnosis, 58.3 [16.1] years) and 2917 primary melanomas. In a multivariable model including phenotypic characteristics, absence of back nevi, presence of many freckles, and a sun-sensitive phenotypic index were independently associated with amelanotic melanoma. Carriage of MC1R variants was associated with amelanotic melanoma but lost statistical significance in a model with phenotype. Further, patients with incident primary amelanotic melanomas were more likely to have had a prior primary amelanotic melanoma (OR, 4.62; 95% CI, 1.25-14.13) than those with incident primary pigmented melanomas. Conclusions and Relevance: Absence of back nevi, presence of many freckles, a sun-sensitive phenotypic index, and prior amelanotic melanoma increase odds for development of amelanotic melanoma. An increased index of suspicion for melanoma in presenting nonpigmented lesions and more careful examination for signs of amelanotic melanoma during periodic skin examination in patients at increased odds of amelanotic melanoma might lead to earlier diagnosis and improved survival.

20 Article Functional melanoma-risk variant IRF4 rs12203592 associated with Breslow thickness: a pooled international study of primary melanomas. 2017

Gibbs, D C / Ward, S V / Orlow, I / Cadby, G / Kanetsky, P A / Luo, L / Busam, K J / Kricker, A / Armstrong, B K / Cust, A E / Anton-Culver, H / Gallagher, R P / Zanetti, R / Rosso, S / Sacchetto, L / Ollila, D W / Begg, C B / Berwick, M / Thomas, N E / Anonymous4580911. ·Department of Epidemiology, Emory University, Atlanta, GA, U.S.A. · Centre for Genetic Origins of Health and Disease, The University of Western Australia, Crawley, Western Australia, Australia. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, NY, U.S.A. · Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, U.S.A. · Department of Internal Medicine, University of New Mexico Cancer Center, University of New Mexico, Albuquerque, NM, U.S.A. · Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia. · Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. · Department of Epidemiology, University of California, Irvine, CA, U.S.A. · Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy. · Politecnico di Torino, Turin, Italy. · Department of Surgery, University of North Carolina, Chapel Hill, NC, U.S.A. · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, U.S.A. · Department of Dermatology, University of North Carolina, Chapel Hill, NC, U.S.A. ·Br J Dermatol · Pubmed #28667740.

ABSTRACT: -- No abstract --

21 Article Patient Symptoms Are the Most Frequent Indicators of Recurrence in Patients with American Joint Committee on Cancer Stage II Melanoma. 2017

Berger, Adam C / Ollila, David W / Christopher, Adrienne / Kairys, John C / Mastrangelo, Michael J / Feeney, Kendra / Dabbish, Nooreen / Leiby, Benjamin / Frank, Jill A / Stitzenberg, Karyn B / Meyers, Michael O. ·Department of Surgery, Thomas Jefferson University, Philadelphia, PA. Electronic address: adam.berger@jefferson.edu. · Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA. · Department of Surgery, Thomas Jefferson University, Philadelphia, PA. · Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA. · Department of Surgery, University of North Carolina, Chapel Hill, NC. ·J Am Coll Surg · Pubmed #28189663.

ABSTRACT: BACKGROUND: Patients with stage II melanoma have a considerable risk for recurrence. Current guidelines are imprecise as to optimal follow-up. We hypothesized that by examining recurrence patterns, we could help to better inform guidelines. STUDY DESIGN: We queried IRB-approved melanoma databases of Thomas Jefferson University and University of North Carolina, identifying 581 patients with stage II melanoma between 1996 and 2015 with at least 1 year of follow-up. Data included location of first recurrence and how recurrence was detected (ie patient symptom, physician examination, or routine surveillance imaging). Cox regression with backward elimination was used for multivariable analysis. RESULTS: One hundred and seventy-one patients had a recurrence (29.4%), the incidence increased considerably by stage sub-group. Significant predictors of recurrence included male sex (p = 0.003), ulceration (p = 0.03), and stage (p < 0.001). On multivariable analysis, male sex and stage continued to be significant (p < 0.01). For overall survival, regression, ulceration, stage, and age were significant predictors of survival. Stage, regression, and age remained significant by multivariable analysis. Patient symptoms were the most frequent mode of detection (40%), followed by physician examination (30%) and surveillance imaging (26%)-this did not differ significantly by stage. Regional nodes were the most common site of recurrence (30%), followed by lung (27%) and in-transit (18%). CONCLUSIONS: The majority of recurrences in stage II melanoma are detected by patients and their physicians and rarely by routine imaging. As such, clinical follow-up and patient education are critical factors in detection of recurrence. With the prevalence of regional nodal recurrences, ultrasound might prove to be an important strategy in early recurrence detection.

22 Article Association of Interferon Regulatory Factor-4 Polymorphism rs12203592 With Divergent Melanoma Pathways. 2016

Gibbs, David C / Orlow, Irene / Bramson, Jennifer I / Kanetsky, Peter A / Luo, Li / Kricker, Anne / Armstrong, Bruce K / Anton-Culver, Hoda / Gruber, Stephen B / Marrett, Loraine D / Gallagher, Richard P / Zanetti, Roberto / Rosso, Stefano / Dwyer, Terence / Sharma, Ajay / La Pilla, Emily / From, Lynn / Busam, Klaus J / Cust, Anne E / Ollila, David W / Begg, Colin B / Berwick, Marianne / Thomas, Nancy E / Anonymous5210857. ·Department of Dermatology, University of North Carolina, Chapel Hill, NC (DCG, NET) · Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC (NET, DWO) · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, NY (IO, AS, ELP, KJB, CBB) · Department of Surgery, University of North Carolina, Chapel Hill, NC (JIB, DWO) · Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL (PAK) · Department of Internal Medicine, University of New Mexico Cancer Center, University of New Mexico, Albuquerque, NM (LL, MB) · Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia (AEC, AK, BKA) · Department of Epidemiology, University of California, Irvine, CA (HAC) · USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA (SBG) · Department of Population Studies and Surveillance, Cancer Care Ontario, Toronto, Ontario, Canada (LDM) · Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada (RPG) · Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy (RZ, SR) · The George Institute for Global Health, Oxford Martin School of Public Health, University of Oxford, Oxford, UK (TD) · Department of Pathology, Women's College Hospital, Toronto, Ontario, Canada (LF). ·J Natl Cancer Inst · Pubmed #26857527.

ABSTRACT: BACKGROUND: Solar elastosis and neval remnants are histologic markers characteristic of divergent melanoma pathways linked to differences in age at onset, host phenotype, and sun exposure. However, the association between these pathway markers and newly identified low-penetrance melanoma susceptibility loci remains unknown. METHODS: In the Genes, Environment and Melanoma (GEM) Study, 2103 Caucasian participants had first primary melanomas that underwent centralized pathology review. For 47 single-nucleotide polymorphisms (SNPs) previously identified as low-penetrant melanoma risk variants, we used multinomial logistic regression to compare melanoma with solar elastosis and melanoma with neval remnants simultaneously to melanoma with neither of these markers, excluding melanomas with both markers. All statistical tests were two-sided. RESULTS: IRF4 rs12203592 was the only SNP to pass the false discovery threshold in baseline models adjusted for age, sex, and study center. rs12203592*T was associated positively with melanoma with solar elastosis (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.18 to 1.82) and inversely with melanoma with neval remnants (OR = 0.65, 95% CI = 0.48 to 0.87) compared with melanoma with neither marker (P global = 3.78 x 10(-08)). Adjusting for phenotypic characteristics and total sun exposure hours did not materially affect rs12203592's associations. Distinct early- and late-onset age distributions were observed in patients with IRF4 rs12203592 [CC] and [TT] genotypes, respectively. CONCLUSIONS: Our findings suggest a role of IRF4 rs12203592 in pathway-specific risk for melanoma development. We hypothesize that IRF4 rs12203592 could underlie in part the bimodal age distribution reported for melanoma and linked to the divergent pathways.

23 Article Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma. 2015

Thomas, Nancy E / Edmiston, Sharon N / Alexander, Audrey / Groben, Pamela A / Parrish, Eloise / Kricker, Anne / Armstrong, Bruce K / Anton-Culver, Hoda / Gruber, Stephen B / From, Lynn / Busam, Klaus J / Hao, Honglin / Orlow, Irene / Kanetsky, Peter A / Luo, Li / Reiner, Anne S / Paine, Susan / Frank, Jill S / Bramson, Jennifer I / Marrett, Lorraine D / Gallagher, Richard P / Zanetti, Roberto / Rosso, Stefano / Dwyer, Terence / Cust, Anne E / Ollila, David W / Begg, Colin B / Berwick, Marianne / Conway, Kathleen / Anonymous2890835. · ·JAMA Oncol · Pubmed #26146664.

ABSTRACT: IMPORTANCE: NRAS and BRAF mutations in melanoma inform current treatment paradigms, but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. OBJECTIVE: To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. DESIGN, SETTING, AND PARTICIPANTS: A population-based study with a median follow-up of 7.6 years (through 2007), including 912 patients from the United States and Australia in the Genes, Environment, and Melanoma (GEM) Study, with first primary cutaneous melanoma diagnosed in the year 2000 and analyzed for NRAS and BRAF mutations. MAIN OUTCOMES AND MEASURES: Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. RESULTS: The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype [WT]). In a multivariable model including clinicopathologic characteristics, relative to WT melanoma (with results reported as odds ratios [95% CIs]), NRAS+ melanoma was associated with presence of mitoses (1.8 [1.0-3.3]), lower tumor-infiltrating lymphocyte (TIL) grade (nonbrisk, 0.5 [0.3-0.8]; and brisk, 0.3 [0.5-0.7] [vs absent TILs]), and anatomic site other than scalp/neck (0.1 [0.01-0.6] for scalp/neck vs trunk/pelvis), and BRAF+ melanoma was associated with younger age (ages 50-69 years, 0.7 [0.5-1.0]; and ages >70 years, 0.5 [0.3-0.8] [vs <50 years]), superficial spreading subtype (nodular, 0.5 [0.2-1.0]; lentigo maligna, 0.4 [0.2-0.7]; and unclassified/other, 0.2 [0.1-0.5] [vs superficial spreading]), and presence of mitoses (1.7 [1.1-2.6]) (P < .05 for all). There was no significant difference in melanoma-specific survival (reported as hazard ratios [95% CIs]) for melanoma harboring mutations in NRAS (1.7 [0.8-3.4]) or BRAF (1.5 [0.8-2.9]) compared with WT melanoma, as adjusted for age, sex, site, American Joint Committee on Cancer (AJCC) tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher-risk (T2b or higher stage) tumors with NRAS (2.9 [1.1-7.7]) or BRAF (3.1 [1.2-8.5]) mutations (P = .04) but not for lower-risk (T2a or lower) tumors with NRAS (0.9 [0.3-3.0]) or BRAF (0.6 [0.2-1.7]) (P = .65), as adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. CONCLUSIONS AND RELEVANCE: Lower TIL grade for NRAS+ melanoma suggests it has a more immunosuppressed microenvironment, which may affect its response to immunotherapies. The approximate 3-fold increased risk of death for higher-risk tumors harboring NRAS or BRAF mutations after adjusting for other prognostic factors compared with WT melanomas indicates that the prognostic implication of these mutations deserves further investigation, particularly in higher–AJCC stage primary melanomas.

24 Article IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma. 2015

Carson, Craig C / Moschos, Stergios J / Edmiston, Sharon N / Darr, David B / Nikolaishvili-Feinberg, Nana / Groben, Pamela A / Zhou, Xin / Kuan, Pei Fen / Pandey, Shaily / Chan, Keefe T / Jordan, Jamie L / Hao, Honglin / Frank, Jill S / Hopkinson, Dennis A / Gibbs, David C / Alldredge, Virginia D / Parrish, Eloise / Hanna, Sara C / Berkowitz, Paula / Rubenstein, David S / Miller, C Ryan / Bear, James E / Ollila, David W / Sharpless, Norman E / Conway, Kathleen / Thomas, Nancy E. ·Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina. · Department of Medicine, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. · Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, North Carolina. · Department of Biostatistics, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Biostatistics, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina. · Department of Surgery, The University of North Carolina, Chapel Hill, North Carolina. · Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, North Carolina. Department of Neurology, The University of North Carolina, Chapel Hill, North Carolina. Neuroscience Center, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Surgery, The University of North Carolina, Chapel Hill, North Carolina. · Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Epidemiology, The University of North Carolina, Chapel Hill, North Carolina. · Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. nthomas@med.unc.edu. ·Clin Cancer Res · Pubmed #25934889.

ABSTRACT: PURPOSE: IL2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared with nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation. EXPERIMENTAL DESIGN: An ITK-specific monoclonal antibody was used to probe sections from deidentified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by IHC. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined. RESULTS: ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacologic inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0-G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Pten(null)/Braf(V600E)) melanomas. CONCLUSIONS: We conclude that ITK, formerly considered an immune cell-specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small-molecule ITK inhibitor in the Tyr-Cre/Pten(null)/Braf(V600E) mouse melanoma model supports this possibility.

25 Article Inherited genetic variants associated with occurrence of multiple primary melanoma. 2015

Gibbs, David C / Orlow, Irene / Kanetsky, Peter A / Luo, Li / Kricker, Anne / Armstrong, Bruce K / Anton-Culver, Hoda / Gruber, Stephen B / Marrett, Loraine D / Gallagher, Richard P / Zanetti, Roberto / Rosso, Stefano / Dwyer, Terence / Sharma, Ajay / La Pilla, Emily / From, Lynn / Busam, Klaus J / Cust, Anne E / Ollila, David W / Begg, Colin B / Berwick, Marianne / Thomas, Nancy E / Anonymous6630825. ·Departments of Dermatology and Surgery, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. · Departments of Epidemiology and Biostatistics and Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. · Department of Internal Medicine, University of New Mexico Cancer Center, University of New Mexico, Albuquerque, New Mexico. · Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia. · Department of Epidemiology, University of California, Irvine, California. · USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. · Cancer Care Ontario, Toronto, Ontario, Canada. · British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy. · The George Institute for Global Health, Oxford Martin School & Nuffield Department of Population Health, Oxford University, United Kingdom. · Women's College Hospital, Toronto, Ontario, Canada. · Departments of Dermatology and Surgery, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. nancy_thomas@med.unc.edu. ·Cancer Epidemiol Biomarkers Prev · Pubmed #25837821.

ABSTRACT: Recent studies, including genome-wide association studies, have identified several putative low-penetrance susceptibility loci for melanoma. We sought to determine their generalizability to genetic predisposition for multiple primary melanoma in the international population-based Genes, Environment, and Melanoma (GEM) Study. GEM is a case-control study of 1,206 incident cases of multiple primary melanoma and 2,469 incident first primary melanoma participants as the control group. We investigated the odds of developing multiple primary melanoma for 47 SNPs from 21 distinct genetic regions previously reported to be associated with melanoma. ORs and 95% confidence intervals were determined using logistic regression models adjusted for baseline features (age, sex, age by sex interaction, and study center). We investigated univariable models and built multivariable models to assess independent effects of SNPs. Eleven SNPs in 6 gene neighborhoods (TERT/CLPTM1L, TYRP1, MTAP, TYR, NCOA6, and MX2) and a PARP1 haplotype were associated with multiple primary melanoma. In a multivariable model that included only the most statistically significant findings from univariable modeling and adjusted for pigmentary phenotype, back nevi, and baseline features, we found TERT/CLPTM1L rs401681 (P = 0.004), TYRP1 rs2733832 (P = 0.006), MTAP rs1335510 (P = 0.0005), TYR rs10830253 (P = 0.003), and MX2 rs45430 (P = 0.008) to be significantly associated with multiple primary melanoma, while NCOA6 rs4911442 approached significance (P = 0.06). The GEM Study provides additional evidence for the relevance of these genetic regions to melanoma risk and estimates the magnitude of the observed genetic effect on development of subsequent primary melanoma.

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