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Melanoma: HELP
Articles by Marc S. Ernstoff
Based on 32 articles published since 2008
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Between 2008 and 2019, M. Ernstoff wrote the following 32 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. 2016

Coit, Daniel G / Thompson, John A / Algazi, Alain / Andtbacka, Robert / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / DiMaio, Dominick / Ernstoff, Marc / Fields, Ryan C / Fleming, Martin D / Gonzalez, Rene / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Joseph, Richard W / Lange, Julie R / Martini, Mary C / Materin, Miguel A / Olszanski, Anthony J / Ross, Merrick I / Salama, April K / Skitzki, Joseph / Sosman, Jeff / Swetter, Susan M / Tanabe, Kenneth K / Torres-Roca, Javier F / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Engh, Anita. · ·J Natl Compr Canc Netw · Pubmed #27059193.

ABSTRACT: This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

2 Guideline The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. 2013

Kaufman, Howard L / Kirkwood, John M / Hodi, F Stephen / Agarwala, Sanjiv / Amatruda, Thomas / Bines, Steven D / Clark, Joseph I / Curti, Brendan / Ernstoff, Marc S / Gajewski, Thomas / Gonzalez, Rene / Hyde, Laura Jane / Lawson, David / Lotze, Michael / Lutzky, Jose / Margolin, Kim / McDermott, David F / Morton, Donald / Pavlick, Anna / Richards, Jon M / Sharfman, William / Sondak, Vernon K / Sosman, Jeffrey / Steel, Susan / Tarhini, Ahmad / Thompson, John A / Titze, Jill / Urba, Walter / White, Richard / Atkins, Michael B. ·Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA. ·Nat Rev Clin Oncol · Pubmed #23982524.

ABSTRACT: Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts--including physicians, nurses, and patient advocates--to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

3 Editorial Is pediatric melanoma always malignant? 2013

Coit, Daniel G / Ernstoff, Marc S / Busam, Klaus J. ·Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York. ·Cancer · Pubmed #24022827.

ABSTRACT: -- No abstract --

4 Editorial Been there, not done that--melanoma in the age of molecular therapy. 2011

Ernstoff, Marc S. · ·N Engl J Med · Pubmed #21639809.

ABSTRACT: -- No abstract --

5 Review Primary melanoma of the spinal cord: a case report, molecular footprint, and review of the literature. 2011

Fuld, Alexander D / Speck, Maren E / Harris, Brent T / Simmons, Nathan E / Corless, Christopher L / Tsongalis, Gregory J / Pastel, David A / Hartford, Alan C / Ernstoff, Marc S. ·Dartmouth Hitchcock Medical Center and Dartmouth Medical School, Lebanon, NH, USA. ·J Clin Oncol · Pubmed #21444862.

ABSTRACT: -- No abstract --

6 Clinical Trial Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. 2018

Tawbi, Hussein A / Forsyth, Peter A / Algazi, Alain / Hamid, Omid / Hodi, F Stephen / Moschos, Stergios J / Khushalani, Nikhil I / Lewis, Karl / Lao, Christopher D / Postow, Michael A / Atkins, Michael B / Ernstoff, Marc S / Reardon, David A / Puzanov, Igor / Kudchadkar, Ragini R / Thomas, Reena P / Tarhini, Ahmad / Pavlick, Anna C / Jiang, Joel / Avila, Alexandre / Demelo, Sheena / Margolin, Kim. ·From the University of Texas M.D. Anderson Cancer Center, Houston (H.A.T.) · Moffitt Cancer Center and Research Institute, Tampa, FL (P.A.F., N.I.K.) · University of California-San Francisco, San Francisco (A. Algazi), the Angeles Clinic and Research Institute, Los Angeles (O.H.), Stanford University Hospital, Palo Alto (R.P.T.), and the Department of Medical Oncology, City of Hope, Duarte (K.M.) - all in California · Dana-Farber Cancer Institute, Boston (F.S.H., D.A.R.) · University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (S.J.M.) · University of Colorado Comprehensive Cancer Center, Aurora (K.L.) · University of Michigan, Ann Arbor (C.D.L.) · Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (M.A.P.), Roswell Park Cancer Institute, Buffalo (M.S.E., I.P.), and New York University, Lake Success (A.C.P.) - all in New York · Georgetown-Lombardi Comprehensive Cancer Center, Washington DC (M.B.A.) · Winship Cancer Institute of Emory University, Atlanta (R.R.K.) · University of Pittsburgh Medical Center, Pittsburgh (A.T.) · Bristol-Myers Squibb, Princeton, NJ (J.J., A. Avila, S.D.) · and Cleveland Clinic-Taussig Cancer Institute, Cleveland (A.T.). ·N Engl J Med · Pubmed #30134131.

ABSTRACT: BACKGROUND: Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases. METHODS: In this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response. RESULTS: Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases. CONCLUSIONS: Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).

7 Clinical Trial Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. 2016

Hodi, F Stephen / Chesney, Jason / Pavlick, Anna C / Robert, Caroline / Grossmann, Kenneth F / McDermott, David F / Linette, Gerald P / Meyer, Nicolas / Giguere, Jeffrey K / Agarwala, Sanjiv S / Shaheen, Montaser / Ernstoff, Marc S / Minor, David R / Salama, April K / Taylor, Matthew H / Ott, Patrick A / Horak, Christine / Gagnier, Paul / Jiang, Joel / Wolchok, Jedd D / Postow, Michael A. ·Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_hodi@dfci.harvard.edu. · University of Louisville, Louisville, KY, USA. · New York University, New York, NY, USA. · Gustave Roussy, INSERM U981, Paris, France. · Huntsman Cancer Institute, Salt Lake City, UT, USA. · Beth Israel Deaconess Medical Center, Boston, MA, USA. · Washington University School of Medicine, St Louis, MO, USA. · Institut Universitaire du Cancer, Toulouse, France. · Greenville Health System Cancer Institute, Greenville, SC, USA. · St Luke's Cancer Center and Temple University, Bethlehem, PA, USA. · University of New Mexico, Albuquerque, NM, USA. · Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. · California Pacific Center for Melanoma Research, San Francisco, CA, USA. · Duke University Medical Center, Durham, NC, USA. · Oregon Health & Science University, Portland, OR, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Bristol-Myers Squibb, Princeton, NJ, USA. · Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. ·Lancet Oncol · Pubmed #27622997.

ABSTRACT: BACKGROUND: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. METHODS: In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAF FINDINGS: Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1-25·7), 2-year overall survival was 63·8% (95% CI 53·3-72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1-66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43-1·26; p=0·26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. INTERPRETATION: Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. FUNDING: Bristol-Myers Squibb.

8 Clinical Trial Randomized, Placebo-Controlled, Phase III Trial of Yeast-Derived Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With No Evidence of Disease After Complete Surgical Resection of Locally Advanced and/or Stage IV Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E4697). 2015

Lawson, David H / Lee, Sandra / Zhao, Fengmin / Tarhini, Ahmad A / Margolin, Kim A / Ernstoff, Marc S / Atkins, Michael B / Cohen, Gary I / Whiteside, Theresa L / Butterfield, Lisa H / Kirkwood, John M. ·David H. Lawson, Winship Cancer Institute of Emory University, Atlanta, GA · Sandra Lee and Fengmin Zhao, Dana-Farber Cancer Institute · Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA · Ahmad A. Tarhini, Theresa L. Whiteside, Lisa H. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, PA · Kim A. Margolin, Seattle Cancer Care Alliance, Seattle, WA · Marc S. Ernstoff, Dartmouth-Hitchcock Medical Center, Lebanon, NH · and Gary I. Cohen, Greater Baltimore Medical Center, Baltimore, MD. ·J Clin Oncol · Pubmed #26351350.

ABSTRACT: PURPOSE: We conducted a double-blind, placebo-controlled trial to evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in patients with resected high-risk melanoma. PATIENTS AND METHODS: Patients with completely resected stage IV or high-risk stage III melanoma were grouped by human leukocyte antigen (HLA) -A2 status. HLA-A2-positive patients were randomly assigned to receive GM-CSF, PV, both, or placebo; HLA-A2-negative patients, GM-CSF or placebo. Treatment lasted for 1 year or until recurrence. Efficacy analyses were conducted in the intent-to-treat population. RESULTS: A total of 815 patients were enrolled. There were no significant improvements in OS (stratified log-rank P = .528; hazard ratio, 0.94; 95% repeated CI, 0.77 to 1.15) or RFS (P = .131; hazard ratio, 0.88; 95% CI, 0.74 to 1.04) in the patients assigned to GM-CSF (n = 408) versus those assigned to placebo (n = 407). The median OS times with GM-CSF versus placebo treatments were 69.6 months (95% CI, 53.4 to 83.5 months) versus 59.3 months (95% CI, 44.4 to 77.3 months); the 5-year OS probability rates were 52.3% (95% CI, 47.3% to 57.1%) versus 49.4% (95% CI, 44.3% to 54.3%), respectively. The median RFS times with GM-CSF versus placebo were 11.4 months (95% CI, 9.4 to 14.8 months) versus 8.8 months (95% CI, 7.5 to 11.2 months); the 5-year RFS probability rates were 31.2% (95% CI, 26.7% to 35.9%) versus 27.0% (95% CI, 22.7% to 31.5%), respectively. Exploratory analyses showed a trend toward improved OS in GM-CSF-treated patients with resected visceral metastases. When survival in HLA-A2-positive patients who received PV versus placebo was compared, RFS and OS were not significantly different. Treatment-related grade 3 or greater adverse events were similar between GM-CSF and placebo groups. CONCLUSION: Neither adjuvant GM-CSF nor PV significantly improved RFS or OS in patients with high-risk resected melanoma. Exploratory analyses suggest that GM-CSF may be beneficial in patients with resected visceral metastases; this observation requires prospective validation.

9 Clinical Trial Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. 2013

Hodi, F Stephen / Corless, Christopher L / Giobbie-Hurder, Anita / Fletcher, Jonathan A / Zhu, Meijun / Marino-Enriquez, Adrian / Friedlander, Philip / Gonzalez, Rene / Weber, Jeffrey S / Gajewski, Thomas F / O'Day, Steven J / Kim, Kevin B / Lawrence, Donald / Flaherty, Keith T / Luke, Jason J / Collichio, Frances A / Ernstoff, Marc S / Heinrich, Michael C / Beadling, Carol / Zukotynski, Katherine A / Yap, Jeffrey T / Van den Abbeele, Annick D / Demetri, George D / Fisher, David E. ·F. Stephen Hodi, Anita Giobbie-Hurder, Philip Friedlander, Jason J. Luke, Katherine A. Zukotynski, Jeffrey T. Yap, Annick D. Van den Abbeele, and George D. Demetri, Dana-Farber Cancer Institute · Jonathan A. Fletcher, Meijun Zhu, and Adrian Marino-Enriquez, Brigham and Women's Hospital · Donald Lawrence, Keith T. Flaherty, and David E. Fisher, Massachusetts General Hospital, Boston, MA · Christopher L. Corless, Michael C. Heinrich, and Carol Beadling, Portland Veterans Administration Medical Center and Oregon Health & Science University, Portland, OR · Philip Friedlander, Mount Sinai Medical Center, New York, NY · Rene Gonzalez, University of Colorado Cancer Center, Aurora, CO · Jeffrey S. Weber, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL · Thomas F. Gajewski, University of Chicago, Chicago, IL · Steven J. O'Day, Beverly Hills Cancer Center, Beverly Hills, CA · Kevin B. Kim, The University of Texas MD Anderson Cancer Center, Houston, TX · Frances A. Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC · and Marc S. Ernstoff, Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH. ·J Clin Oncol · Pubmed #23775962.

ABSTRACT: PURPOSE: Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities. PATIENTS AND METHODS: We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy. RESULTS: Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment. CONCLUSION: Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.

10 Clinical Trial Phase I trial of bortezomib and dacarbazine in melanoma and soft tissue sarcoma. 2013

Poklepovic, Andrew / Youssefian, Leena E / Winning, Mary / Birdsell, Christine A / Crosby, Nancy A / Ramakrishnan, Viswanathan / Ernstoff, Marc S / Roberts, John D. ·Massey Cancer Center and the Division of Hematology, Oncology & Palliative Care, Virginia Commonwealth University, Richmond, VA 23298-0037, USA. ·Invest New Drugs · Pubmed #23315028.

ABSTRACT: PURPOSE: Preclinical studies in human melanoma cell lines and murine xenograft tumor models suggest that the proteasome inhibitor bortezomib enhances the activity of the cytotoxic agent dacarbazine. We performed a phase I trial of bortezomib and dacarbazine in melanoma, soft tissue sarcoma, and amine precursor uptake and decarboxylation tumors. The primary objective was to identify recommended phase II doses for the combination. EXPERIMENTAL DESIGN: Bortezomib and dacarbazine were both administered intravenously once weekly. All patients received prophylactic antiemetics. Dose escalation proceeded using a standard 3 + 3 design. Response was assessed according to NCI RECIST v1.0. RESULTS: Twenty eight patients were enrolled to six dose levels. Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) are the recommended phase II weekly doses. The combination was generally well tolerated. Among 15 patients with melanoma there was one durable complete response in a patient with an exon-11 cKIT mutation, and one partial response. Among 12 patients with soft tissue sarcoma there was one partial response. CONCLUSIONS: Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) administered intravenously once weekly is well tolerated and has at least minimal activity in melanoma and soft tissue sarcoma.

11 Clinical Trial Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. 2012

Margolin, Kim / Ernstoff, Marc S / Hamid, Omid / Lawrence, Donald / McDermott, David / Puzanov, Igor / Wolchok, Jedd D / Clark, Joseph I / Sznol, Mario / Logan, Theodore F / Richards, Jon / Michener, Tracy / Balogh, Agnes / Heller, Kevin N / Hodi, F Stephen. ·University of Washington, Seattle, WA 98109, USA. kmargoli@seattlecca.org ·Lancet Oncol · Pubmed #22456429.

ABSTRACT: BACKGROUND: Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases. METHODS: Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766. FINDINGS: We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0·1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0·1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis. INTERPRETATION: Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population. FUNDING: Bristol-Myers Squibb.

12 Clinical Trial Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. 2011

Bedikian, A Y / DeConti, R C / Conry, R / Agarwala, S / Papadopoulos, N / Kim, K B / Ernstoff, M. ·Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. abedikia@mdanderson.org ·Ann Oncol · Pubmed #20855467.

ABSTRACT: BACKGROUND: Docosahexaenoic acid-paclitaxel (DHA-paclitaxel, Taxoprexin(®)) is made by covalently conjugating the essential fatty acid DHA to the paclitaxel molecule. Preclinical studies of DHA-paclitaxel have demonstrated increased activity relative to paclitaxel and the potential for an improved therapeutic ratio. In the present study, the efficacy and toxicity profiles of DHA-paclitaxel were compared with those of dacarbazine. METHODS: In this study, 393 chemonaive patients with metastatic melanoma were randomly assigned to receive either DHA-paclitaxel at a starting dose of 900 mg/m(2) IV on day 1 every 3 weeks or dacarbazine at a starting dose of 1000 mg/m(2) IV on day 1 every 3 weeks. The primary end point of the study was the comparison of overall survival (OS). RESULTS: No significant difference in OS was noted between patients in the DHA-paclitaxel and dacarbazine arms. Similarly, there were no significant differences in response rate, duration of response, time to progression, and time to treatment failure between the two drugs. Safety results of the two drugs were as predicted from prior studies. Myelosuppression was more common with DHA-paclitaxel. CONCLUSIONS: DHA-paclitaxel was not superior to dacarbazine. We conclude that further studies with the drug on an every 3-week schedule in melanoma are not warranted.

13 Clinical Trial Cytokine working group study of lymphodepleting chemotherapy, interleukin-2, and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma: clinical outcomes and peripheral-blood cell recovery. 2010

Gunturu, Krishna S / Meehan, Kenneth R / Mackenzie, Todd A / Crocenzi, Todd S / McDermott, David / Usherwood, Edward J / Margolin, Kim A / Crosby, Nancy A / Atkins, Michael B / Turk, Mary Jo / Ahonen, Cory / Fuse, Shinichiro / Clark, Joseph I / Fisher, Jan L / Noelle, Randolph J / Ernstoff, Marc S. ·Section of Hematology/Oncology, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756, USA. ·J Clin Oncol · Pubmed #20124177.

ABSTRACT: PURPOSE: Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma. PATIENTS AND METHODS: This was a two-stage phase II trial design. Patients with measurable metastatic melanoma were treated with intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m(2), day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 microg/m(2)/d beginning day 8) was given until granulocyte recovery. Lymphocyte recovery profiles were determined by flow cytometric phenotyping at regular intervals, and clinical outcome was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: The trial was stopped at the end of stage 1 with four of 18 objective responses noted. Twelve patients had detailed lymphocyte subcompartments evaluated. After lymphodepletion, we observed an induction of regulatory cells (CD4+ T regulatory cells; CD8+ T suppressor cells) and of T memory cells (CD8+ T central memory cells; T effector memory RA+ cells). Expansion of circulating melanoma-specific CD8(+) cells was observed in one of four HLA-A2-positive patients. CONCLUSION: Chemotherapy-induced lymphodepletion modulates the homeostatic repopulation of the lymphocyte compartment and influences recovering lymphocyte subpopulations. Clinical activity seems similar to standard high-dose aldesleukin alone.

14 Clinical Trial Temozolomide, thalidomide, and whole brain radiation therapy for patients with brain metastasis from metastatic melanoma: a phase II Cytokine Working Group study. 2008

Atkins, Michael B / Sosman, Jeffrey A / Agarwala, Sanjiv / Logan, Theodore / Clark, Joseph I / Ernstoff, Marc S / Lawson, David / Dutcher, Janice P / Weiss, Geoffrey / Curti, Brendan / Margolin, Kim A. ·Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. Matkins@bidmc.harvard.edu ·Cancer · Pubmed #18792064.

ABSTRACT: BACKGROUND: The combination of temozolomide (TMZ) and thalidomide was reported to produce a high response rate, including shrinkage of brain metastases, in patients with metastatic melanoma. The authors tested the efficacy of a regimen including TMZ, thalidomide, and whole brain radiation therapy (WBRT) in patients with brain (CNS) metastases from melanoma. METHODS: Patients with melanoma, CNS metastases documented by magnetic resonance imaging, and no prior systemic chemotherapy received WBRT, 30 Gray in 10 fractions, Days 1 to 5 and 8 to 12; TMZ, 75 mg/m(2)/day, Weeks 1 to 6; and thalidomide, 100 mg/day, Weeks 1 to 4, then escalated by 100 mg/day at Weeks 5, 7, and 9 as tolerated to a maximum of 400 mg/day. CNS and systemic tumor response was assessed at Week 10. Patients without CNS or clinically significant systemic disease progression received additional cycles of TMZ at 10-week intervals. RESULTS: Thirty-nine patients received treatment, and 3 exhibited CNS response (1 complete response, 2 partial responses) (response rate, 7.6%; 95% confidence interval, 0.7%-16.1%), all unconfirmed by repeat imaging. Seven patients had stable CNS disease at 10 weeks. No patient exhibited a systemic response. Only 4 patients received 2 cycles of therapy, and just 1 received 3. Median time to progression was 7 weeks, and median overall survival was 4 months. Grade 3-4 side effects included deep venous thrombosis (3), pulmonary embolism (1), and CNS events (12). Eighteen (45%) patients required admission for side effects (7) and/or symptomatic disease progression (11). CONCLUSIONS: The efficacy of TMZ, thalidomide, and WBRT in the treatment of CNS metastatic melanoma is low. Other treatment approaches should be considered for this patient population.

15 Clinical Trial Three phase II cytokine working group trials of gp100 (210M) peptide plus high-dose interleukin-2 in patients with HLA-A2-positive advanced melanoma. 2008

Sosman, Jeffrey A / Carrillo, Carole / Urba, Walter J / Flaherty, Lawrence / Atkins, Michael B / Clark, Joseph I / Dutcher, Janet / Margolin, Kim A / Mier, James / Gollob, Jarod / Kirkwood, John M / Panka, David J / Crosby, Nancy A / O'Boyle, Kevin / LaFleur, Bonnie / Ernstoff, Marc S. ·Vanderbilt-Ingram Cancer Center Vanderbilt, University Medical Center, Section of Hematology/Oncology, 777 Preston Research Bldg, Nashville, TN 37232-6307, USA. jeff.sosman@vanderbilt.edu ·J Clin Oncol · Pubmed #18467720.

ABSTRACT: PURPOSE: High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2-restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial. PATIENTS AND METHODS: In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment. RESULTS: From 1998 to 2003, 131 patients with HLA-A2-positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at >or= 30 months. Immune studies including assays of CD3-zeta expression and numbers of CD4(+)/CD25(+)/FoxP3(+) regulatory T cells, CD15(+)/CD11b(+)/CD14(-) immature myeloid-derived cells, and CD8(+)gp100 tetramer-positive cells in the blood did not correlate with clinical benefit. CONCLUSION: The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.

16 Article Identification of gene expression levels in primary melanoma associated with clinically meaningful characteristics. 2018

Gorlov, Ivan / Orlow, Irene / Ringelberg, Carol / Hernando, Eva / Ernstoff, Marc S / Cheng, Chao / Her, Stephanie / Parker, Joel S / Thompson, Cheryl L / Gerstenblith, Meg R / Berwick, Marianne / Amos, Christopher. ·Department of Biomedical Data Science, The Geisel School of Medicine, Dartmouth College, Dartmouth-Hitchcock Medical Center, Lebanon. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center. · Department of Pathology, NYU School of Medicine, New York City. · Roswell Park Cancer Institute, Elm & Carlton, Buffalo, New York. · Department of Computer Science, Dartmouth College, Hanover, New Hampshire. · Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. · School of Medicine, Case Western Reserve University, Cleveland, Ohio. · Department of Internal Medicine and Dermatology, University of New Mexico, Albuquerque, New Mexico. · Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. ·Melanoma Res · Pubmed #29975213.

ABSTRACT: Factors influencing melanoma survival include sex, age, clinical stage, lymph node involvement, as well as Breslow thickness, presence of tumor-infiltrating lymphocytes based on histological analysis of primary melanoma, mitotic rate, and ulceration. Identification of genes whose expression in primary tumors is associated with these key tumor/patient characteristics can shed light on molecular mechanisms of melanoma survival. Here, we show results from a gene expression analysis of formalin-fixed paraffin-embedded primary melanomas with extensive clinical annotation. The Cancer Genome Atlas data on primary melanomas were used for validation of nominally significant associations. We identified five genes that were significantly associated with the presence of tumor-infiltrating lymphocytes in the joint analysis after adjustment for multiple testing: IL1R2, PPL, PLA2G3, RASAL1, and SGK2. We also identified two genes significantly associated with melanoma metastasis to the regional lymph nodes (PIK3CG and IL2RA), and two genes significantly associated with sex (KDM5C and KDM6A). We found that LEF1 was significantly associated with Breslow thickness and CCNA2 and UBE2T with mitosis. RAD50 was the gene most significantly associated with survival, with a higher level of expression associated with worse survival.

17 Article VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. 2018

Kuklinski, Lawrence F / Yan, Shaofeng / Li, Zhongze / Fisher, Jan L / Cheng, Chao / Noelle, Randolph J / Angeles, Christina V / Turk, Mary Jo / Ernstoff, Marc S. ·Geisel School of Medicine at Dartmouth, Hanover, NH, USA. · Department of Medicine, Santa Barbara Cottage Hospital, Santa Barbara, CA, USA. · Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. · Biostatistics Shared Resource, Norris Cotton Cancer Center, Dartmouth-Hitchock Medical Center, Lebanon, NH, USA. · Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. · Departments of Biomedical Data Sciences, Molecular and Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, USA. · Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. · Department of Surgery, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. · Roswell Park Cancer Institute, University of Buffalo, The State University of New York, Elm and Carlton, Buffalo, NY, 14263, USA. marc.ernstoff@roswellpark.org. ·Cancer Immunol Immunother · Pubmed #29737375.

ABSTRACT: Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.

18 Article Epithelial-Mesenchymal Expression Phenotype of Primary Melanoma and Matched Metastases and Relationship with Overall Survival. 2016

Yan, Shaofeng / Holderness, Britt M / Li, Zhongze / Seidel, Gregory D / Gui, Jiang / Fisher, Jan L / Ernstoff, Marc S. ·Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, U.S.A. · Department of Hematology/Oncology, Dartmouth Hitchcock Medical Center, Lebanon, NH, U.S.A. · Biostatistics Shared Resource, Geisel School of Medicine at Dartmouth, Lebanon, NH, U.S.A. · Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH, U.S.A. · Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, U.S.A. · Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, U.S.A. marc.ernstoff@RoswellPark.org. ·Anticancer Res · Pubmed #27919967.

ABSTRACT: E-Cadherin and N-cadherin are important components of epithelial-mesenchymal transition (EMT). The majority of studies on EMT in melanoma have been performed with cultured cell lines or pooled melanoma samples. The goal of our study was to evaluate the expression of E-cadherin and N-cadherin in matched tissue samples from primary and metastatic sites of melanoma and to determine the correlation with survival outcome. We analyzed tissues from 42 melanoma primary lesions and their corresponding metastases, as well as 53 benign nevi, for expression levels of E-cadherin and N-cadherin using immunohistochemical methods. There were heterogenous expression patterns of E- and N-cadherin in both primary and metastatic melanomas. Overall, metastatic tumor showed a decrease in E-cadherin expression and an increase in N-cadherin expression compared to the primary tumor, although the difference did not reach statistical significance (p=0.24 and 0.28 respectively). A switch of membranous expression from E-cadherin to N-cadherin from primary to metastatic melanoma was seen in eight patients (19%). Aberrant E-cadherin expression (defined as negative to weak membranous E-cadherin or positive nuclear E-cadherin expression) was more frequently observed in metastatic than in primary melanomas (p=0.03). Multivariate analysis showed that absence of N-cadherin expression in primary melanomas and the presence of aberrant E-cadherin expression in primary melanomas and metastatic melanomas was associated with a significantly worse overall survival. Our data support the importance of E-cadherin and N-cadherin proteins in melanoma progression and patient survival.

19 Article The mitogen-activated protein kinase pathway plays a critical role in regulating immunological properties of BRAF mutant cutaneous melanoma cells. 2016

Whipple, Chery A / Boni, Andrea / Fisher, Jan L / Hampton, Thomas H / Tsongalis, Gregory J / Mellinger, Diane L / Yan, Shaofeng / Tafe, Laura J / Brinckerhoff, Constance E / Turk, Mary J / Mullins, David W / Fadul, Camilo E / Ernstoff, Marc S. ·aDepartment of Medicine, Norris Cotton Cancer Center bDepartment of Microbiology and Immunology, Geisel School of Medicine at Dartmouth cMedical Oncology Immunotherapy Group dDepartment of Pathology, Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire eDepartment of Pathology, College of Medicine, University of Arizona, Tucson, Arizona, USA. ·Melanoma Res · Pubmed #26974965.

ABSTRACT: The advent of drugs targeting the mitogen-activated protein kinase (MAPK) pathway has markedly changed the treatment of advanced-stage melanoma harboring BRAF mutations. However, drug resistance, through mechanisms not well elucidated, often occurs. A better understanding of how melanoma-derived immunologically active molecules change in response to MAPK inhibition of BRAF mutated (BRAF) and BRAF wild type (BRAF) melanomas could help identify promising treatment combinations of small molecule inhibitors and immunotherapy. To this aim, we treated 13 BRAF and 13 BRAF mutated human melanoma cell lines with either a specific BRAF inhibitor or an MEK1/2 inhibitor and analyzed changes in the secretion of 42 selected cytokines, chemokines, and growth factors. We also measured changes in the expression levels of immunologically relevant melanoma cell surface markers. The BRAF melanomas showed minimal changes in response to the inhibitors, whereas the BRAF cell lines showed, on average, a significant decrease in IFNα2, interleukin-7, Fractalkine, GCSF, GRO, TGFα2, interleukin-8, and VEGF, as well as a reduction in pERK and pMEK protein levels, upon MAPK pathway blockade. BRAF inhibition in BRAF cell lines also resulted in significant changes in the expression of several surface markers including upregulation of β2-microglobulin as well as a decrease in MIC A/B and TRAIL-R2. These results indicate that MAPK pathway inhibition leads to changes in the immunological properties of mutant BRAF melanoma cells and lends support for future studies aimed at designing effective treatment strategies that combine BRAF and MEK inhibition with immunotherapy.

20 Article Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. 2015

Postow, Michael A / Chesney, Jason / Pavlick, Anna C / Robert, Caroline / Grossmann, Kenneth / McDermott, David / Linette, Gerald P / Meyer, Nicolas / Giguere, Jeffrey K / Agarwala, Sanjiv S / Shaheen, Montaser / Ernstoff, Marc S / Minor, David / Salama, April K / Taylor, Matthew / Ott, Patrick A / Rollin, Linda M / Horak, Christine / Gagnier, Paul / Wolchok, Jedd D / Hodi, F Stephen. ·From Memorial Sloan Kettering Cancer Center (M.A.P., J.D.W.), Weill Cornell Medical College (M.A.P., J.D.W.), and New York University, Perlmutter Cancer Center (A.C.P.) - all in New York · J. Graham Brown Cancer Center, University of Louisville, Louisville, KY (J.C.) · Institute Gustave Roussy, Villejuif (C.R.), Paris-Sud University, Orsay (C.R.), and Institut Universitaire du Cancer, Toulouse (N.M.) - all in France · Huntsman Cancer Institute, Salt Lake City (K.G.) · Beth Israel Deaconess Medical Center (D. McDermott) and Dana-Farber Cancer Institute (P.A.O., F.S.H.) - both in Boston · Washington University in St. Louis, St. Louis (G.P.L.) · Greenville Health System, Greenville, SC (J.K.G.) · St. Luke's Cancer Center, Bethlehem, PA (S.S.A.) · University of New Mexico, Albuquerque (M.S.) · Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland (M.S.E.) · California Pacific Center for Melanoma Research, San Francisco (D. Minor) · Duke University, Durham, NC (A.K.S.) · Oregon Health and Science University, Portland (M.T.) · Bristol-Myers Squibb, Lawrenceville, NJ (C.H.) · and Bristol-Myers Squibb, Wallingford, CT (L.M.R., P.G.). ·N Engl J Med · Pubmed #25891304.

ABSTRACT: BACKGROUND: In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma. METHODS: In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors. RESULTS: Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P<0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P<0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication. CONCLUSIONS: The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01927419.).

21 Article Development and validation of a melanoma risk score based on pooled data from 16 case-control studies. 2015

Davies, John R / Chang, Yu-mei / Bishop, D Timothy / Armstrong, Bruce K / Bataille, Veronique / Bergman, Wilma / Berwick, Marianne / Bracci, Paige M / Elwood, J Mark / Ernstoff, Marc S / Green, Adele / Gruis, Nelleke A / Holly, Elizabeth A / Ingvar, Christian / Kanetsky, Peter A / Karagas, Margaret R / Lee, Tim K / Le Marchand, Loïc / Mackie, Rona M / Olsson, Håkan / Østerlind, Anne / Rebbeck, Timothy R / Reich, Kristian / Sasieni, Peter / Siskind, Victor / Swerdlow, Anthony J / Titus, Linda / Zens, Michael S / Ziegler, Andreas / Gallagher, Richard P / Barrett, Jennifer H / Newton-Bishop, Julia. ·Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. J.R.Davies@leeds.ac.uk. · Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. · Sax Institute and Sydney School of Public Health, The University of Sydney, Sydney, Australia. · Twin Research and Genetic Epidemiology Unit, St. Thomas' Campus, Kings College London, London, United Kingdom. Dermatology Department, West Herts NHS Trust, Hemel Hempstead General Hospital, Herts, United Kingdom. · Department of Dermatology, Leiden University Medical Centre, Leiden, the Netherlands. · Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico. · Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California. · Department of Epidemiology and Biostatistics, School of Population Health, University of Auckland, Auckland, New Zealand. · Department of Medicine, Geisel School of Medicine and the Norris Cotton Cancer Center, Dartmouth University, Lebanon, New Hampshire. · Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, Australia. · Department of Surgery, University Hospital, Lund, Sweden. · Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. · Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, New Hampshire. · B.C. Cancer Research Centre, Vancouver, British Columbia, Canada. · University of Hawaii Cancer Center, Honolulu, Hawaii. · Department of Public Health and Health Policy, University of Glasgow, Glasgow, United Kingdom. · Department of Oncology, University Hospital, Lund, Sweden. · Kobenhaausevej 35, Hillerød, Denmark. · Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania. · Dermatologikum Hamburg, Hamburg, Germany. · Wolfson Institute of Preventive Medicine, Barts & The London School of Medicine, London, United Kingdom. · Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom. Division of Breast Cancer Research, Institute of Cancer Research, London, United Kingdom. · Institute of Medical Biometry and Statistics, University of Lübeck, University Hospital Schleswig-Holstein, Campus Lübeck, Germany. Center for Clinical Trials, University of Lübeck, Lübeck, Germany. ·Cancer Epidemiol Biomarkers Prev · Pubmed #25713022.

ABSTRACT: BACKGROUND: We report the development of a cutaneous melanoma risk algorithm based upon seven factors; hair color, skin type, family history, freckling, nevus count, number of large nevi, and history of sunburn, intended to form the basis of a self-assessment Web tool for the general public. METHODS: Predicted odds of melanoma were estimated by analyzing a pooled dataset from 16 case-control studies using logistic random coefficients models. Risk categories were defined based on the distribution of the predicted odds in the controls from these studies. Imputation was used to estimate missing data in the pooled datasets. The 30th, 60th, and 90th centiles were used to distribute individuals into four risk groups for their age, sex, and geographic location. Cross-validation was used to test the robustness of the thresholds for each group by leaving out each study one by one. Performance of the model was assessed in an independent UK case-control study dataset. RESULTS: Cross-validation confirmed the robustness of the threshold estimates. Cases and controls were well discriminated in the independent dataset [area under the curve, 0.75; 95% confidence interval (CI), 0.73-0.78]. Twenty-nine percent of cases were in the highest risk group compared with 7% of controls, and 43% of controls were in the lowest risk group compared with 13% of cases. CONCLUSION: We have identified a composite score representing an estimate of relative risk and successfully validated this score in an independent dataset. IMPACT: This score may be a useful tool to inform members of the public about their melanoma risk.

22 Article BRAF inhibition alleviates immune suppression in murine autochthonous melanoma. 2014

Steinberg, Shannon M / Zhang, Peisheng / Malik, Brian T / Boni, Andrea / Shabaneh, Tamer B / Byrne, Katelyn T / Mullins, David W / Brinckerhoff, Constance E / Ernstoff, Marc S / Bosenberg, Marcus W / Turk, Mary Jo. ·Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. · Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. · Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. · Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. · Department of Dermatology and Pathology, Yale School of Medicine, New Haven, Connecticut. · Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. mary.jo.turk@dartmouth.edu. ·Cancer Immunol Res · Pubmed #25183499.

ABSTRACT: A growing body of evidence suggests that BRAF inhibitors, in addition to their acute tumor growth-inhibitory effects, can also promote immune responses to melanoma. The present study aimed to define the immunologic basis of BRAF-inhibitor therapy using the Braf/Pten model of inducible, autochthonous melanoma on a pure C57BL/6 background. In the tumor microenvironment, BRAF inhibitor PLX4720 functioned by on-target mechanisms to selectively decrease both the proportions and absolute numbers of CD4(+)Foxp3(+) regulatory T cells (Treg) and CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSC), while preserving numbers of CD8(+) effector T cells. In PLX4720-treated mice, the intratumoral Treg populations decreased significantly, demonstrating enhanced apopotosis. CD11b(+) myeloid cells from PLX4720-treated tumors also exhibited decreased immunosuppressive function on a per-cell basis. In accordance with a reversion of tumor immune suppression, tumors that had been treated with PLX4720 grew with reduced kinetics after treatment was discontinued, and this growth delay was dependent on CD8 T cells. These findings demonstrate that BRAF inhibition selectively reverses two major mechanisms of immunosuppression in melanoma and liberates host-adaptive antitumor immunity.

23 Article Multiple murine BRaf(V600E) melanoma cell lines with sensitivity to PLX4032. 2014

Jenkins, Molly H / Steinberg, Shannon M / Alexander, Matthew P / Fisher, Jan L / Ernstoff, Marc S / Turk, Mary Jo / Mullins, David W / Brinckerhoff, Constance E. ·Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA; Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. ·Pigment Cell Melanoma Res · Pubmed #24460976.

ABSTRACT: -- No abstract --

24 Article The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics. 2014

Ribas, Antoni / Zhang, Weijiang / Chang, Ilsung / Shirai, Keisuke / Ernstoff, Marc S / Daud, Adil / Cowey, C Lance / Daniels, Gregory / Seja, Elizabeth / O'Laco, Elizabeth / Glaspy, John A / Chmielowski, Bartosz / Hill, Todd / Joe, Andrew K / Grippo, Joseph F. ·Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA. ·J Clin Pharmacol · Pubmed #24374975.

ABSTRACT: Vemurafenib is an orally bioavailable BRAF inhibitor approved for the treatment of BRAF(V600) -mutant metastatic melanoma. It is important to understand the effects of a high-fat meal on the pharmacokinetics (PK) of vemurafenib in humans because it is a Biopharmaceutics Classification System Class IV drug and its PK can be altered by food. An open-label, multicenter, randomized, 2-period crossover study was performed to evaluate the effect of food (high-fat meal) on the PK of a single oral dose of vemurafenib. Secondary objectives were safety and tolerability, efficacy with best overall response rate, and overall survival during the treatment period. The concomitant intake of food (high-fat meal) increased mean Cmax 3.5 to 7.5 µg/mL and mean AUC0-∞ 119 to 360 µg·h/mL after a single 960 mg dose of vemurafenib (N = 13-15 patients). An effect of food on single-dose exposure is suggested by point estimates and 90% CI of geometric mean ratios for vemurafenib plasma AUC0-∞ (4.7) and Cmax (2.5). Toxicity and response rate of vemurafenib in this study were consistent with prior experience in patients with BRAF(V600) -mutant metastatic melanoma. A high-fat meal increased the exposure to vemurafenib without altering the mean terminal half-life.

25 Article Recent skin self-examination and doctor visits in relation to melanoma risk and tumour depth. 2013

Titus, L J / Clough-Gorr, K / Mackenzie, T A / Perry, A / Spencer, S K / Weiss, J / Abrahams-Gessel, S / Ernstoff, M S. ·Department of Community and Family Medicine, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, NH 03756, USA. linda.titus@dartmouth.edu ·Br J Dermatol · Pubmed #22897437.

ABSTRACT: BACKGROUND: Little is known about the potential benefit of skin self-examination for melanoma prevention and early detection. OBJECTIVES: To determine whether skin self-examination is associated with reduced melanoma risk, self-detection of tumours, and reduced risk of deeper melanomas. METHODS: We used data from a population-based case-control study (423 cases, 678 controls) to assess recent skin self-examination in relation to self-detection, melanoma risk and tumour depth ( ≤1 mm; > 1 mm). Logistic regression was used to estimate odds ratios (ORs) and confidence intervals (CIs) for associations of interest. RESULTS: Skin self-examination conducted 1-11 times during a recent year was associated with a possible decrease in melanoma risk (OR 0·74; 95% CI 0·54-1·02). Melanoma risk was decreased for those who conducted skin self-examination and saw a doctor (OR 0·52; 95% CI 0·30-0·90). Among cases, those who examined their skin were twice as likely to self-detect the melanoma (OR 2·23; 95% CI 1·47-3·38), but self-detection was not associated with shallower tumours. Tumour depth was reduced for those who conducted skin self-examination 1-11 times during a recent year (OR 0·39; 95% CI 0·18-0·81), but was not influenced by seeing a doctor, or by conducting skin self-examination and seeing a doctor. CONCLUSIONS: Risk of a deeper tumour and possibly risk of melanoma were reduced by skin self-examination 1-11 times annually. Melanoma risk was markedly reduced by skin self-examination coupled with a doctor visit. We cannot, however, exclude the possibility that our findings reflect bias or confounding. Additional studies are needed to elucidate the potential benefits of skin self-examination for melanoma prevention and early detection.

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