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Melanoma: HELP
Articles by David W. Ollila
Based on 33 articles published since 2008
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Between 2008 and 2019, D. Ollila wrote the following 33 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 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 --

2 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 --

3 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.

4 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.

5 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.

6 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.

7 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.

8 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.

9 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.

10 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.

11 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 / Anonymous401127. ·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

12 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 / Anonymous281025. ·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.

13 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 / Anonymous691029. ·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 --

14 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.

15 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 / Anonymous5620857. ·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.

16 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 / Anonymous2880835. · ·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.

17 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.

18 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 / Anonymous6640825. ·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.

19 Article Prognostic significance of tumor mitotic rate in T2 melanoma staged with sentinel lymphadenectomy. 2015

Baker, Justin J / Meyers, Michael O / Deal, Allison M / Frank, Jill F / Stitzenberg, Karyn B / Ollila, David W. ·Department of Surgery, Maine Medical Center, Portland, Maine. ·J Surg Oncol · Pubmed #25663414.

ABSTRACT: BACKGROUND AND OBJECTIVES: Tumor mitotic rate (TMR) is an important prognostic variable for patients with thin melanoma. However it remains unclear what the significance of TMR is for more deeply invasive melanoma pathologically staged with a sentinel lymph node biopsy. We sought to determine the prognostic value of TMR in clinically node-negative T2 melanoma patients staged with sentinel lymphadenectomy. METHODS: A prospective IRB-approved database of cutaneous melanoma patients treated from 09/01/1997-03/01/2011 was used to identify patients with T2 melanoma staged with a SLN. Associations were evaluated using Fisher's Exact test, and Kaplan-Meier analysis. RESULTS: Three hundred thirteen T2 patients were included. 19% had ulceration, 11% a positive sentinel node (SLN), and 10% recurred. 44% of patients had TMR ≥ 1/mm(2). TMR ≥ 1/mm(2) did not predict SLN status. TMR ≥ 1/mm(2) was significantly associated with recurrence in SLN negative patients; only 3% of those with TMR < 1/mm(2) developed a recurrence compared to 16% of those with TMR ≥ 1/mm(2) (P < 0.0001). CONCLUSIONS: Although TMR ≥ 1/mm(2) is not associated with risk of SLN involvement in T2 melanoma, it is a significant risk factor for recurrence when SLN negative. As such, TMR could be used to stratify follow-up regimens in SLN negative T2 patients.

20 Article Vascular channels formed by subpopulations of PECAM1+ melanoma cells. 2014

Dunleavey, James M / Xiao, Lin / Thompson, Joshua / Kim, Mi Mi / Shields, Janiel M / Shelton, Sarah E / Irvin, David M / Brings, Victoria E / Ollila, David W / Brekken, Rolf A / Dayton, Paul A / Melero-Martin, Juan M / Dudley, Andrew C. ·Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. · Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina 27599, USA. · Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. · Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. · Departments of Surgery and Pharmacology, UT Southwestern Medical Center, Dallas, Texas 75235, USA. · Department of Cardiac Surgery, Harvard Medical School and Children's Hospital Boston, Boston, Massachusetts 02115, USA. · 1] Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA [2] Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA [3] McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ·Nat Commun · Pubmed #25335460.

ABSTRACT: Targeting the vasculature remains a promising approach for treating solid tumours; however, the mechanisms of tumour neovascularization are diverse and complex. Here we uncover a new subpopulation of melanoma cells that express the vascular cell adhesion molecule PECAM1, but not VEGFR-2, and participate in a PECAM1-dependent form of vasculogenic mimicry (VM). Clonally derived PECAM1(+) tumour cells coalesce to form PECAM1-dependent networks in vitro and they generate well-perfused, vascular endothelial growth factor (VEGF)-independent channels in mice. The neural crest specifier AP-2α is diminished in PECAM1(+) melanoma cells and is a transcriptional repressor of PECAM1. Re-introduction of AP-2α into PECAM1(+) tumour cells represses PECAM1 and abolishes tube-forming ability, whereas AP-2α knockdown in PECAM1(-) tumour cells upregulates PECAM1 expression and promotes tube formation. Thus, VM-competent subpopulations, rather than all cells within a tumour, may instigate VM, supplant host-derived endothelium, and form PECAM1-dependent conduits that are not diminished by neutralizing VEGF.

21 Article Comparison of clinicopathologic features and survival of histopathologically amelanotic and pigmented melanomas: a population-based study. 2014

Thomas, Nancy E / Kricker, Anne / Waxweiler, Weston T / Dillon, Patrick M / Busman, Klaus J / From, Lynn / Groben, Pamela A / Armstrong, Bruce K / Anton-Culver, Hoda / Gruber, Stephen B / Marrett, Loraine D / Gallagher, Richard P / Zanetti, Roberto / Rosso, Stefano / Dwyer, Terence / Venn, Alison / Kanetsky, Peter A / Orlow, Irene / Paine, Susan / Ollila, David W / Reiner, Anne S / Luo, Li / Hao, Honglin / Frank, Jill S / Begg, Colin B / Berwick, Marianne / Anonymous4450804. · ·JAMA Dermatol · Pubmed #25162299.

ABSTRACT: IMPORTANCE Previous studies have reported that histopathologically amelanotic melanoma is associated with poorer survival than pigmented melanoma; however, small numbers of amelanotic melanomas, selected populations, lack of centralized pathologic review, or no adjustment for stage limit the interpretation or generalization of results from prior studies.OBJECTIVE To compare melanoma-specific survival between patients with histopathologically amelanotic and those with pigmented melanoma in a large international population-based study.DESIGN, SETTING, AND PARTICIPANTS Survival analysis with a median follow-up of 7.6 years.The study population comprised 2995 patients with 3486 invasive primary melanomas centrally scored for histologic pigmentation from the Genes, Environment, and Melanoma(GEM) Study, which enrolled incident cases of melanoma diagnosed in 1998 through 2003 from international population-based cancer registries.MAIN OUTCOMES AND MEASURES Clinicopathologic predictors and melanoma-specific survival of histologically amelanotic and pigmented melanoma were compared using generalized estimating equations and Cox regression models, respectively.RESULTS Of 3467 melanomas, 275 (8%) were histopathologically amelanotic. Female sex,nodular and unclassified or other histologic subtypes, increased Breslow thickness, presence of mitoses, severe solar elastosis, and lack of a coexisting nevus were independently associated with amelanotic melanoma (each P < .05). Amelanotic melanoma was generally ofa higher American Joint Committee on Cancer (AJCC) tumor stage at diagnosis (odds ratios[ORs] [95%CIs] between 2.9 [1.8-4.6] and 11.1 [5.8-21.2] for tumor stages between T1b and T3b and ORs [95%CIs] of 24.6 [13.6-44.4] for T4a and 29.1 [15.5-54.9] for T4b relative to T1a;P value for trend, <.001) than pigmented melanoma. Hazard of death from melanoma was higher for amelanotic than for pigmented melanoma (hazard ratio [HR], 2.0; 95%CI, 1.4-3.0)(P < .001), adjusted for age, sex, anatomic site, and study design variables, but survival did not differ once AJCC tumor stage was also taken into account (HR, 0.8; 95%CI, 0.5-1.2)(P = .36).CONCLUSIONS AND RELEVANCE At the population level, survival after diagnosis of amelanotic melanoma is poorer than after pigmented melanoma because of its more advanced stage at diagnosis. It is probable that amelanotic melanomas present at more advanced tumor stages because they are difficult to diagnose. The association of amelanotic melanoma with presence of mitoses independently of Breslow thickness and other clinicopathologic characteristics suggests that amelanotic melanomas might also grow faster than pigmented melanomas. New strategies for early diagnosis and investigation of the biological properties of amelanotic melanoma are warranted.

22 Article DNA methylation profiles in primary cutaneous melanomas are associated with clinically significant pathologic features. 2014

Thomas, Nancy E / Slater, Nathaniel A / Edmiston, Sharon N / Zhou, Xin / Kuan, Pei-Fen / Groben, Pamela A / Carson, Craig C / Hao, Honglin / Parrish, Eloise / Moschos, Stergios J / Berwick, Marianne / Ollila, David W / Conway, Kathleen. ·Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. ·Pigment Cell Melanoma Res · Pubmed #24986547.

ABSTRACT: DNA methylation studies have elucidated a methylation signature distinguishing primary melanomas from benign nevi and provided new insights about genes that may be important in melanoma development. However, it is unclear whether methylation differences among primary melanomas are related to tumor pathologic features with known clinical significance. We utilized the Illumina GoldenGate Cancer Panel array to investigate the methylation profiles of 47 primary cutaneous melanomas. Arraywide methylation patterns revealed a positive association of methylation with Breslow thickness and mutated BRAF, a negative association with mitotic rate, and a weak association with ulceration. Hierarchical clustering on CpG sites exhibiting the most variable methylation (n = 235) divided the melanoma samples into three clusters, including a highly methylated cluster that was positively associated with Breslow thickness and an intermediately methylated cluster associated with Breslow thickness and mitotic rate. Our findings provide support for the existence of methylation-defined subsets in melanomas with increased methylation associated with Breslow thickness.

23 Article Validation of the VE1 immunostain for the BRAF V600E mutation in melanoma. 2014

Pearlstein, Michelle V / Zedek, Daniel C / Ollila, David W / Treece, Amanda / Gulley, Margaret L / Groben, Pamela A / Thomas, Nancy E. ·Department of Dermatology, UNC School of Medicine, Chapel Hill, NC, USA. ·J Cutan Pathol · Pubmed #24917033.

ABSTRACT: BACKGROUND: BRAF mutation status, and therefore eligibility for BRAF inhibitors, is currently determined by sequencing methods. We assessed the validity of VE1, a monoclonal antibody against the BRAF V600E mutant protein, in the detection of mutant BRAF V600E melanomas as classified by DNA pyrosequencing. METHODS: The cases were 76 metastatic melanoma patients with only one known primary melanoma who had had BRAF codon 600 pyrosequencing of either their primary (n = 19), metastatic (n = 57) melanoma, or both (n = 17). All melanomas (n = 93) were immunostained with the BRAF VE1 antibody using a red detection system. The staining intensity of these specimens was scored from 0 to 3+ by a dermatopathologist. Scores of 0 and 1+ were considered as negative staining while scores of 2+ and 3+ were considered positive. RESULTS: The VE1 antibody showed a sensitivity of 85% and a specificity of 100% as compared to DNA pyrosequencing results. There was 100% concordance between VE1 immunostaining of primary and metastatic melanomas from the same patient. V600K, V600Q, and V600R BRAF melanomas did not positively stain with VE1. CONCLUSIONS: This hospital-based study finds high sensitivity and specificity for the BRAF VE1 immunostain in comparison to pyrosequencing in detection of BRAF V600E in melanomas.

24 Article Routine restaging PET/CT and detection of initial recurrence in sentinel lymph node positive stage III melanoma. 2014

Baker, Justin J / Meyers, Michael O / Frank, Jill / Amos, Keith D / Stitzenberg, Karyn B / Ollila, David W. ·Division of Surgical Oncology and Endocrine Surgery and The Lineberger Comprehensive Cancer Center, Department of Surgery, University of North Carolina at Chapel Hill, Campus Box 7213, 170 Manning Drive, 1150 POB, Chapel Hill, NC 27599, USA. · Division of Surgical Oncology and Endocrine Surgery and The Lineberger Comprehensive Cancer Center, Department of Surgery, University of North Carolina at Chapel Hill, Campus Box 7213, 170 Manning Drive, 1150 POB, Chapel Hill, NC 27599, USA. Electronic address: david_ollila@med.unc.edu. ·Am J Surg · Pubmed #24674829.

ABSTRACT: BACKGROUND: Follow-up of patients with sentinel lymph node-positive stage III melanoma uses history, physical exam, and cross-sectional imaging. The aim of this study was to evaluate positron emission tomographic (PET)/computed tomographic (CT) scans in the detection of recurrence. METHODS: From 2003 to 2009, a single-institution prospective database of all cutaneous melanoma patients was used to identify sentinel lymph node-positive stage III patients with disease-free survival >1 year and 1 restaging PET/CT scan. RESULTS: Thirty-eight patients were identified, with a median follow-up period of 27.5 months. Seven (18%) developed recurrence (median time to recurrence, 25 months). Recurrences were detected as follows: 3 by patients, 1 by physician, 1 by PET/CT scan and lactate dehydrogenase, 1 by PET/CT scan, and 1 by brain magnetic resonance imaging. One hundred eight follow-up PET/CT scans were performed. Two of 38 patients had asymptomatic metastases detected by routine restaging PET/CT scan, and there were 9 scans with false-positive results. CONCLUSIONS: With short follow-up, the utility of routine PET/CT scans in identifying unsuspected recurrence in patients with sentinel lymph node-positive stage III melanoma appears minimal.

25 Article Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. 2013

Thomas, Nancy E / Busam, Klaus J / From, Lynn / Kricker, Anne / Armstrong, Bruce K / Anton-Culver, Hoda / Gruber, Stephen B / Gallagher, Richard P / Zanetti, Roberto / Rosso, Stefano / Dwyer, Terence / Venn, Alison / Kanetsky, Peter A / Groben, Pamela A / Hao, Honglin / Orlow, Irene / Reiner, Anne S / Luo, Li / Paine, Susan / Ollila, David W / Wilcox, Homer / Begg, Colin B / Berwick, Marianne. ·Nancy E. Thomas, Pamela A. Groben, Honglin Hao, and David W. Ollila, University of North Carolina, Chapel Hill, NC · Klaus J. Busam, Irene Orlow, Anne S. Reiner, and Colin B. Begg, Memorial Sloan-Kettering Cancer Center, New York, NY · Lynn From, Women's College Hospital, Toronto, Ontario · Richard P. Gallagher, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada · Anne Kricker and Bruce K. Armstrong, The University of Sydney, Sydney, New South Wales · Alison Venn, Menzies Research Institute, Tasmania, Australia · Hoda Anton-Culver, University of California, Irvine · Stephen B. Gruber, University of Southern California, Los Angeles, CA · Roberto Zanetti and Stefano Rosso, Center for Cancer Prevention, Torino, Italy · Terence Dwyer, International Agency for Research on Cancer, Lyon, France · Peter A. Kanetsky, University of Pennsylvania, Philadelphia, PA · Li Luo, Susan Paine, and Marianne Berwick, University of New Mexico, Albuquerque, NM · and Homer Wilcox, New Jersey Department of Health, Trenton, NJ. ·J Clin Oncol · Pubmed #24127443.

ABSTRACT: PURPOSE: Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas. PATIENTS AND METHODS: On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined. RESULTS: Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (P(trend) < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage. CONCLUSION: At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.

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