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Melanoma: HELP
Articles by Dr. John Kirkwood
Based on 172 articles published since 2010
(Why 172 articles?)
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Between 2010 and 2020, J. Kirkwood wrote the following 172 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7
1 Guideline An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0. 2018

Sullivan, Ryan J / Atkins, Michael B / Kirkwood, John M / Agarwala, Sanjiv S / Clark, Joseph I / Ernstoff, Marc S / Fecher, Leslie / Gajewski, Thomas F / Gastman, Brian / Lawson, David H / Lutzky, Jose / McDermott, David F / Margolin, Kim A / Mehnert, Janice M / Pavlick, Anna C / Richards, Jon M / Rubin, Krista M / Sharfman, William / Silverstein, Steven / Slingluff, Craig L / Sondak, Vernon K / Tarhini, Ahmad A / Thompson, John A / Urba, Walter J / White, Richard L / Whitman, Eric D / Hodi, F Stephen / Kaufman, Howard L. ·Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. · Georgetown University, Washington, DC, 20057, USA. · University of Pittsburgh, Pittsburgh, PA, 15213, USA. · St. Luke's Cancer Center and Temple University, Center Valley, PA, 18034, USA. · Loyola University Medical Center, Maywood, IL, 60153, USA. · Roswell Park Cancer Institute, Buffalo, NY, 14263, USA. · University of Michigan, Ann Arbor, MI, 48109, USA. · University of Chicago Medical Center, Chicago, IL, 60637, USA. · Cleveland Clinic, Cleveland, OH, 44195, USA. · Emory Winship Cancer Institute, Atlanta, GA, 30322, USA. · Mt. Sinai Medical Center, Miami Beach, FL, 33140, USA. · Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. · City of Hope, Duarte, CA, 91010, USA. · Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. · New York University Cancer Institute, New York, NY, 10016, USA. · Lutheran General Hospital, Park Ridge, IL, 60068, USA. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21231, USA. · Melanoma Research Foundation, Woodcliff Lake, NJ, 07077, USA. · University of Virginia, Charlottesville, VA, 22908, USA. · H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. · Cleveland Clinic Taussig Cancer Center, Cleveland, OH, 44195, USA. · Seattle Cancer Care Alliance, Seattle, WA, 98109, USA. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, 97213, USA. · Carolinas Medical Center, Charlotte, NC, 28204, USA. · Carol G. Simon Cancer Center, Morristown, NJ, 07046, USA. · Dana-Farber Cancer Institute, Boston, MA, 02215, USA. · Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. howardkaufman6@gmail.com. ·J Immunother Cancer · Pubmed #29848375.

ABSTRACT: BACKGROUND: Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. METHODS: To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. RESULTS: The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. CONCLUSION: These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy.

2 Guideline Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update. 2018

Wong, Sandra L / Faries, Mark B / Kennedy, Erin B / Agarwala, Sanjiv S / Akhurst, Timothy J / Ariyan, Charlotte / Balch, Charles M / Berman, Barry S / Cochran, Alistair / Delman, Keith A / Gorman, Mark / Kirkwood, John M / Moncrieff, Marc D / Zager, Jonathan S / Lyman, Gary H. ·Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. · The Angeles Clinic and Research Institute, Santa Monica, CA, USA. · American Society of Clinical Oncology, Alexandria, VA, USA. guidelines@asco.org. · St Luke's Cancer Center, Easton, PA, USA. · Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · MD Anderson Cancer Center, Houston, TX, USA. · Broward Health, Fort Lauderdale, FL, USA. · Los Angeles Center for Health Services, University of California, Los Angeles, CA, USA. · Emory University, Atlanta, GA, USA. · , Silver Spring, MD, USA. · University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. · Norfolk and Norwich University Hospital, Norwich, UK. · H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. · Fred Hutchinson Cancer Research Center, Seattle, WA, USA. ·Ann Surg Oncol · Pubmed #29236202.

ABSTRACT: PURPOSE: To update the American Society of Clinical Oncology (ASCO)-Society of Surgical Oncology (SSO) guideline for sentinel lymph node (SLN) biopsy in melanoma. METHODS: An ASCO-SSO panel was formed, and a systematic review of the literature was conducted regarding SLN biopsy and completion lymph node dissection (CLND) after a positive sentinel node in patients with melanoma. RESULTS: Nine new observational studies, two systematic reviews and an updated randomized controlled trial (RCT) of SLN biopsy, as well as two randomized controlled trials of CLND after positive SLN biopsy, were included. RECOMMENDATIONS: Routine SLN biopsy is not recommended for patients with thin melanomas that are T1a (non-ulcerated lesions < 0.8 mm in Breslow thickness). SLN biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or <0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure. SLN biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of >1.0 to 4.0 mm). SLN biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm. In the case of a positive SLN biopsy, CLND or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathological factors. For higher risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. Important qualifying statements outlining relevant clinicopathological factors, and details of the reference patient populations are included within the guideline.

3 Guideline Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update. 2018

Wong, Sandra L / Faries, Mark B / Kennedy, Erin B / Agarwala, Sanjiv S / Akhurst, Timothy J / Ariyan, Charlotte / Balch, Charles M / Berman, Barry S / Cochran, Alistair / Delman, Keith A / Gorman, Mark / Kirkwood, John M / Moncrieff, Marc D / Zager, Jonathan S / Lyman, Gary H. ·Sandra L. Wong, Dartmouth-Hitchcock Medical Center, Lebanon, NH · Mark B. Faries, The Angeles Clinic and Research Institute, Santa Monica · Alistair Cochran, University of California, Los Angeles Center for Health Services, Los Angeles, CA · Erin B. Kennedy, American Society of Clinical Oncology, Alexandria, VA · Sanjiv S. Agarwala, St Luke's Cancer Center, Easton · John M. Kirkwood, University of Pittsburgh Cancer Institute, Pittsburgh, PA · Timothy J. Akhurst, Peter MacCallum Cancer Centre, Victoria, Australia · Charlotte Ariyan, Memorial Sloan Kettering Cancer Center, New York, NY · Charles M. Balch, MD Anderson Cancer Center, Houston, TX · Barry S. Berman, Broward Health, Fort Lauderdale · Jonathan S. Zager, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL · Keith A. Delman, Emory University, Atlanta, GA · Mark Gorman, Silver Spring, MD · Marc D. Moncrieff, Norfolk and Norwich University Hospital, Norwich, United Kingdom · and Gary H. Lyman, Fred Hutchinson Cancer Research Center, Seattle, WA. ·J Clin Oncol · Pubmed #29232171.

ABSTRACT: Purpose To update the American Society of Clinical Oncology (ASCO)-Society of Surgical Oncology (SSO) guideline for sentinel lymph node (SLN) biopsy in melanoma. Methods An ASCO-SSO panel was formed, and a systematic review of the literature was conducted regarding SLN biopsy and completion lymph node dissection (CLND) after a positive sentinel node in patients with melanoma. Results Nine new observational studies, two systematic reviews, and an updated randomized controlled trial of SLN biopsy, as well as two randomized controlled trials of CLND after positive SLN biopsy, were included. Recommendations Routine SLN biopsy is not recommended for patients with thin melanomas that are T1a (nonulcerated lesions < 0.8 mm in Breslow thickness). SLN biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or < 0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure. SLN biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of > 1.0 to 4.0 mm). SLN biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm. In the case of a positive SLN biopsy, CLND or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathological factors. For higher-risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. Important qualifying statements outlining relevant clinicopathological factors and details of the reference patient populations are included within the guideline. Additional information is available at www.asco.org/melanoma-guidelines and www.asco.org/guidelineswiki .

4 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.

5 Editorial Developing agents for the therapeutic prevention of melanoma: can the assessment of cutaneous precursor lesions help? 2020

Maguire, William F / Kirkwood, John M. ·Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA. ·Future Oncol · Pubmed #32100570.

ABSTRACT: -- No abstract --

6 Editorial Targeting the MAPK pathway in advanced BRAF wild-type melanoma. 2019

Massa, R C / Kirkwood, J M. ·UPMC Division of Hematology/Oncology, Pittsburgh. · Dermatology and Translational Science, Department of Medicine, University of Pittsburgh, Pittsburgh; Melanoma Program, University of Pittsburgh Cancer Institute, Pittsburgh, USA. Electronic address: KirkwoodJM@upmc.edu. ·Ann Oncol · Pubmed #30821319.

ABSTRACT: -- No abstract --

7 Editorial BRAF Inhibitors and IFNα: Plus, Minus, or Indeterminate? 2016

Davar, Diwakar / Fuchs, Serge Y / Kirkwood, John M. ·Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA (DD, JMK) · Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA (SYF). ·J Natl Cancer Inst · Pubmed #26851801.

ABSTRACT: -- No abstract --

8 Editorial How much of a good thing? What duration for interferon alfa-2b adjuvant therapy? 2012

Tarhini, Ahmad A / Kirkwood, John M. · ·J Clin Oncol · Pubmed #23008298.

ABSTRACT: -- No abstract --

9 Editorial The role of BRAF V600 mutation in melanoma. 2012

Ascierto, Paolo A / Kirkwood, John M / Grob, Jean-Jacques / Simeone, Ester / Grimaldi, Antonio M / Maio, Michele / Palmieri, Giuseppe / Testori, Alessandro / Marincola, Francesco M / Mozzillo, Nicola. ·Department of Melanoma, Istituto Nazionale Tumori Fondazione G, Pascale, Naples, Italy. paolo.ascierto@gmail.com ·J Transl Med · Pubmed #22554099.

ABSTRACT: BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.

10 Review Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials. 2019

Jeter, Joanne M / Bowles, Tawnya L / Curiel-Lewandrowski, Clara / Swetter, Susan M / Filipp, Fabian V / Abdel-Malek, Zalfa A / Geskin, Larisa J / Brewer, Jerry D / Arbiser, Jack L / Gershenwald, Jeffrey E / Chu, Emily Y / Kirkwood, John M / Box, Neil F / Funchain, Pauline / Fisher, David E / Kendra, Kari L / Marghoob, Ashfaq A / Chen, Suephy C / Ming, Michael E / Albertini, Mark R / Vetto, John T / Margolin, Kim A / Pagoto, Sherry L / Hay, Jennifer L / Grossman, Douglas / Ellis, Darrel L / Kashani-Sabet, Mohammed / Mangold, Aaron R / Markovic, Svetomir N / Meyskens, Frank L / Nelson, Kelly C / Powers, Jennifer G / Robinson, June K / Sahni, Debjani / Sekulic, Aleksandar / Sondak, Vernon K / Wei, Maria L / Zager, Jonathan S / Dellavalle, Robert P / Thompson, John A / Weinstock, Martin A / Leachman, Sancy A / Cassidy, Pamela B. ·Department of Medicine, Divisions of Genetics and Oncology, The Ohio State University, Columbus, Ohio. · Department of Surgery, Intermountain Health Care, Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah. · Department of Medicine, The University of Arizona Cancer Center, Tucson, Arizona. · Department of Dermatology, Pigmented Lesion and Melanoma Program, Stanford University Medical Center Cancer Institute, Veterans Affairs Palo Alto Health Care System, Palo Alto, California. · Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California Merced, Merced, California. · Department of Dermatology, University of Cincinnati, Cincinnati, Ohio. · Department of Dermatology, Cutaneous Oncology Center, Columbia University Medical Center, New York, New York. · Department of Dermatologic Surgery, Mayo Clinic Minnesota, Rochester, Minnesota. · Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia. · Division of Dermatology, Veterans Affairs Medical Center, Atlanta, Georgia. · Departments of Surgical Oncology and Cancer Biology, Melanoma and Skin Cancer Center, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. · Melanoma and Skin Cancer Program, Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. · Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. · Dermatology Service, U.S. Department of Veterans Affairs, Eastern Colorado Health Care System, Denver, Colorado. · Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado. · Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. · Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts. · Department of Internal Medicine, Medical Oncology Division, The Ohio State University, Columbus, Ohio. · Memorial Sloan Kettering Skin Cancer Center and Department of Dermatology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Medicine, University of Wisconsin, School of Medicine and Public Health, University of Wisconsin Carbone Cancer Center, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin. · Division of Surgical Oncology, Oregon Health & Science University, Portland, Oregon. · Department of Medical Oncology, City of Hope National Medical Center, Duarte, California. · Department of Allied Health Sciences, UConn Institute for Collaboration in Health, Interventions, and Policy, University of Connecticut, Storrs, Connecticut. · Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, New York. · Departments of Dermatology and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. · Department of Dermatology, Vanderbilt University Medical Center and Division of Dermatology, Vanderbilt Ingram Cancer Center, Nashville, Tennessee. · Department of Medicine, Tennessee Valley Healthcare System, Nashville Veterans Affairs Medical Center, Nashville, Tennessee. · Center for Melanoma Research and Treatment, California Pacific Medical Center, San Francisco, California. · Department of Dermatology, Mayo Clinic, Scottsdale, Arizona. · Department of Hematology and Oncology, Mayo Clinic, Rochester, Minnesota. · Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Dermatology, University of Iowa, Iowa City, Iowa. · Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. · Department of Dermatology, Boston Medical Center, Boston, Massachusetts. · Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida. · Departments of Oncologic Sciences and Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida. · Department of Dermatology, University of California, San Francisco, San Francisco, California. · Dermatology Service, San Francisco Veterans Affairs Medical Center, San Francisco, California. · Department of Sarcoma, H. Lee Moffitt Cancer Center, Tampa, Florida. · Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington. · Center for Dermatoepidemiology, Veterans Affairs Medical Center, Providence, Rhode Island. · Department of Dermatology, Brown University, Providence, Rhode Island. · Department of Epidemiology, Brown University, Providence, Rhode Island. · Department of Dermatology, Rhode Island Hospital, Providence, Rhode Island. · Department of Dermatology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon. ·Cancer · Pubmed #30281145.

ABSTRACT: Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

11 Review Relapse-Free Survival as a Surrogate for Overall Survival in the Evaluation of Stage II-III Melanoma Adjuvant Therapy. 2018

Suciu, Stefan / Eggermont, Alexander M M / Lorigan, Paul / Kirkwood, John M / Markovic, Svetomir N / Garbe, Claus / Cameron, David / Kotapati, Srividya / Chen, Tai-Tsang / Wheatley, Keith / Ives, Natalie / de Schaetzen, Gaetan / Efendi, Achmad / Buyse, Marc. ·European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Gustave Roussy Cancer Campus Grand Paris, Villejuif, France; The Christie NHS Foundation Trust, Manchester, UK; University of Pittsburgh Cancer Institute and School of Medicine, Pittsburgh, PA; Mayo Clinic Rochester, Rochester, MN; University of Tubingen, Tubingen, Germany; University of Edinburgh, Western General Hospital, Edinburgh, UK; Bristol-Myers Squibb, Wallingford, CT; Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK; Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK; Universitas Brawijaya, Malang, Indonesia; IDDI, Louvain-la-Neuve, Belgium. ·J Natl Cancer Inst · Pubmed #28922786.

ABSTRACT: Background: We assessed whether relapse-free survival (RFS; time until recurrence/death) is a valid surrogate for overall survival (OS) among resected stage II-III melanoma patients through a meta-analysis of randomized controlled trials. Methods: Individual patient data (IPD) on RFS and OS were collected from 5826 patients enrolled in 11 randomized adjuvant trials comparing interferon (IFN) to observation. In addition, IPD from two studies comparing IFN and vaccination in 989 patients were included. A two-level modeling approach was used for assessing Spearman's patient-level correlation (rho) of RFS and OS and the trial-level coefficient of determination (R²) of the treatment effects on RFS and on OS. The results were validated externally in 13 adjuvant studies without available IPD. We then tested the results on the European Organisation for Research and Treatment of Cancer (EORTC) 18071 double-blind trial comparing ipilimumab 10 mg/kg with placebo, which showed a statistically significant impact of the checkpoint inhibitor on RFS and OS. All statistical tests were two-sided. Results: With a median follow-up of seven years, 12 of 13 trials showed a consistency between the IFN vs No IFN differences regarding RFS (hazard ratio [HR]RFS = 0.88) and OS (HROS = 0.91), but the small trial, Eastern Cooperative Oncology Group 2696, was an outlier (HRRFS = 0.72 vs HROS = 1.11). Therefore, even if rho was high, R² was low and could not reliably be estimated. Based on the 12 trials, rho remained high (0.89), and the hazard ratios for RFS and OS were strongly correlated (R² = 0.91). The surrogate threshold effect for RFS was estimated to be 0.77. For the EORTC 18071 trial, the hazard ratio for RFS was 0.75, predicting an effect of ipilimumab on OS. This was subsequently confirmed (HROS = 0.72, 95.1% confidence interval = 0.58 to 0.88, P = .001). Conclusions: In high-risk stage II-III melanoma, RFS appeared to be a valid surrogate end point for OS for adjuvant randomized studies assessing interferon or a checkpoint inhibitor. In future similar adjuvant studies, a hazard ratio for RFS of 0.77 or less would predict a treatment impact on OS.

12 Review Skin cancer screening: recommendations for data-driven screening guidelines and a review of the US Preventive Services Task Force controversy. 2017

Johnson, Mariah M / Leachman, Sancy A / Aspinwall, Lisa G / Cranmer, Lee D / Curiel-Lewandrowski, Clara / Sondak, Vernon K / Stemwedel, Clara E / Swetter, Susan M / Vetto, John / Bowles, Tawnya / Dellavalle, Robert P / Geskin, Larisa J / Grossman, Douglas / Grossmann, Kenneth F / Hawkes, Jason E / Jeter, Joanne M / Kim, Caroline C / Kirkwood, John M / Mangold, Aaron R / Meyskens, Frank / Ming, Michael E / Nelson, Kelly C / Piepkorn, Michael / Pollack, Brian P / Robinson, June K / Sober, Arthur J / Trotter, Shannon / Venna, Suraj S / Agarwala, Sanjiv / Alani, Rhoda / Averbook, Bruce / Bar, Anna / Becevic, Mirna / Box, Neil / E Carson, William / Cassidy, Pamela B / Chen, Suephy C / Chu, Emily Y / Ellis, Darrel L / Ferris, Laura K / Fisher, David E / Kendra, Kari / Lawson, David H / Leming, Philip D / Margolin, Kim A / Markovic, Svetomir / Martini, Mary C / Miller, Debbie / Sahni, Debjani / Sharfman, William H / Stein, Jennifer / Stratigos, Alexander J / Tarhini, Ahmad / Taylor, Matthew H / Wisco, Oliver J / Wong, Michael K. ·Department of Dermatology, Oregon Health & Science University, 3303 SW Bond Ave., Portland, OR, USA. · University of Utah, Salt Lake City, UT, USA. · University of Washington, Seattle, WA, USA. · University of Arizona Cancer Center, Tucson, AZ, USA. · Moffitt Cancer Center, Tampa, FL, USA. · Oregon Health & Science University, Portland, OR, USA. · Stanford University Medical Center & VA Palo Alto Health Care System, Palo Alto, CA, USA. · Intermountain Healthcare & University of Utah, Salt Lake City, UT, USA. · University of Colorado, Aurora, CO, USA. · Columbia University, New York, NY, USA. · The Ohio State University, Columbus, OH, USA. · Harvard Medical School, Boston, MA, USA. · University of Pittsburgh, Pittsburgh, PA, USA. · Mayo Clinic Arizona, Scottsdale, AZ, USA. · University of California, Irvine, Orange, CA, USA. · University of Pennsylvania, Philadelphia, PA, USA. · The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Emory University & Atlanta VA Medical Center, Atlanta, GA, USA. · Northwestern University Feinberg School of Medicine, Chicago, IL USA. · Inova Medical Group, Fairfax, VA, USA. · St Luke's University Hospital & Temple University, Bethlehem, PA, USA. · Boston University, Boston, MA, USA. · Case Western Reserve University, Cleveland, OH, USA. · University of Missouri, Columbia, MO, USA. · Vanderbilt University, Nashville, TN, USA. · Harvard Medical School & Massachusetts General Hospital, Charlestown, MA, USA. · Winship Cancer Institute of Emory University, Atlanta, GA, USA. · The Christ Hospital, Cincinnati, OH, USA. · City of Hope National Cancer Center, Duarte, CA, USA. · Mayo Clinic Rochester, MN, USA. · Johns Hopkins University, Baltimore, MD. · NYU Langone Medical Center, New York, NY, USA. · Department of Dermatology, University of Athens, Andreas Sygros Hospital, Athens, Greece. · Bend Memorial Clinic, Bend, OR, USA. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. ·Melanoma Manag · Pubmed #28758010.

ABSTRACT: Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is no national consensus on skin cancer screening in the USA, but dermatologists and primary care providers are routinely confronted with making the decision about when to recommend total body skin examinations and at what interval. The objectives of this paper are: to propose rational, risk-based, data-driven guidelines commensurate with the US Preventive Services Task Force screening guidelines for other disorders; to compare our proposed guidelines to recommendations made by other national and international organizations; and to review the US Preventive Services Task Force's 2016 Draft Recommendation Statement on skin cancer screening.

13 Review Adjuvant interferon-α for the treatment of high-risk melanoma: An individual patient data meta-analysis. 2017

Ives, Natalie J / Suciu, Stefan / Eggermont, Alexander M M / Kirkwood, John / Lorigan, Paul / Markovic, Svetomir N / Garbe, Claus / Wheatley, Keith / Anonymous2250912. ·Birmingham Clinical Trials Unit, College of Medical and Dental Sciences, Public Health Building, University of Birmingham, Birmingham, B15 2TT, UK. · EORTC Headquarters, Avenue Emmanuel Mounier 83/11, 1200 Brussels, Belgium. · Gustave Roussy Cancer Campus Grand Paris, 114 Rue Edouard Vaillant, 94800, Villejuif, France. · University of Pittsburgh Cancer Institute and School of Medicine, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. · The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester, M20 4BX, UK. · Mayo Clinic Rochester, 200 First St. SW, Rochester, MN, 55905, USA. · University of Tubingen, Liebermeisterstraße 25, 72076, Tübingen, Germany. · Cancer Research UK Clinical Trials Unit, College of Medical and Dental Sciences, Robert Aitken Institute, University of Birmingham, Birmingham, B15 2TT, UK. Electronic address: k.wheatley@bham.ac.uk. ·Eur J Cancer · Pubmed #28692949.

ABSTRACT: BACKGROUND: Many randomised trials assessing interferon-α (IFN-α) as adjuvant therapy for high-risk malignant melanoma have been undertaken. To better assess the role of IFN-α, an individual patient data (IPD) meta-analysis of these trials was undertaken. METHODS: IPD was sought from all randomised trials of adjuvant IFN-α versus no IFN-α for high-risk melanoma. Primary outcomes were event-free survival (EFS) and overall survival (OS). Standard methods for quantitative IPD meta-analysis were used. Subgroup analyses by dose, duration of treatment and various patient and disease-specific parameters were performed. FINDINGS: Fifteen trials were included in the analysis (eleven with IPD). EFS was significantly improved with IFN-α (hazard ratio [HR] = 0.86, CI 0.81-0.91; P < 0.00001), as was OS (HR = 0.90, CI 0.85-0.97; P = 0.003). The absolute differences in EFS at 5 and 10 years were 3.5% and 2.7%, and for OS were 3.0% and 2.8% respectively in favour of IFN-α. There was no evidence that the benefit of IFN-α differed depending on dose or duration of treatment, or by age, gender, site of primary tumour, disease stage, Breslow thickness, or presence of clinical nodes. Only for ulceration was there evidence of an interaction (test for heterogeneity: P = 0.04 for EFS; P = 0.002 for OS); only patients with ulcerated tumours appeared to obtain benefit from IFN-α. CONCLUSION: This meta-analysis provides clear evidence that adjuvant IFN-α significantly reduces the risk of relapse and improves survival and shows no benefit for higher doses compared to lower doses. The increased benefit in patients with ulcerated tumours, and lack of benefit in patients without ulceration, needs further investigation.

14 Review Neoadjuvant treatment for melanoma: current challenges and future perspectives. 2016

Najjar, Yana G / Kirkwood, John M. ·Division of Hematology-Oncology, University of Pittsburgh, 5150 Centre Avenue, Fourth Floor, Pittsburgh, PA 15232, USA. · Medicine, Dermatology & Translational Science, University of Pittsburgh School of Medicine, Melanoma & Skin Cancer Program, UPCI, Hillman Cancer Center, 5115 Centre Avenue, Pittsburgh, PA 15232, USA. ·Melanoma Manag · Pubmed #30190883.

ABSTRACT: There will be an estimated 76,100 new cases of melanoma diagnosed in 2015 and 9710 deaths. Patients with stage I/II disease have excellent outcomes, and the treatment landscape for patients with metastatic disease has been transformed by the approval of several immune checkpoint inhibitors and molecular targeted therapies. Patients with stage III disease, however, continue to have very limited options, as the only agent shown to improve survival in the adjuvant setting is high-dose IFN-α. Neoadjuvant trials of chemotherapy and chemobiotherapy have not been successful, and while neoadjuvant ipilimumab and high-dose interferon have shown promise in small trials, neither agent has been approved. Current trials are testing immune therapy and targeted therapy combinations in the neoadjuvant setting.

15 Review Adjuvant Therapy of Melanoma. 2016

Davar, Diwakar / Kirkwood, John M. ·Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, 5150 Centre Avenue, Pittsburgh, PA, 15232, USA. davard@upmc.edu. · Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, 5150 Centre Avenue, Pittsburgh, PA, 15232, USA. kirkwoodjm@upmc.edu. ·Cancer Treat Res · Pubmed #26601863.

ABSTRACT: The incidence of melanoma is rapidly increasing, especially in younger female and older male patients. Recent fundamental advances in our knowledge of melanoma tumorigenesis have established roles for inhibitors of the MAPK pathway and regulatory immune checkpoints CTLA-4 and PD-1/PD-L1. However, the majority of patients continue to present with non-metastatic disease-typically managed with surgical resection and adjuvant therapy. High-dose IFN-α2b (HDI) is the main adjuvant therapeutic mainstay in high-risk disease following definitive resection. In this chapter, we review the evidence supporting the use of adjuvant HDI in high-risk melanoma. We also discuss some of the other treatment modalities that have been evaluated including vaccines, chemotherapy, and radiotherapy.

16 Review Immune checkpoint blockade and interferon-α in melanoma. 2015

Rafique, Imran / Kirkwood, John M / Tarhini, Ahmad A. ·University of Pittsburgh Medical Center, Pittsburgh, PA. · University of Pittsburgh Medical Center, Pittsburgh, PA; University of Pittsburgh Cancer Institute, Pittsburgh, PA. · University of Pittsburgh Medical Center, Pittsburgh, PA; University of Pittsburgh Cancer Institute, Pittsburgh, PA. Electronic address: tarhiniaa@upmc.edu. ·Semin Oncol · Pubmed #25965362.

ABSTRACT: The quality of the host immune response in patients with advanced melanoma is compromised with a bias towards Th2-type polarization and a tumor microenvironment that facilitates disease progression. Overcoming tumor-induced immune suppression through strategies that build upon the immunomodulatory qualities and clinical activity of interferon-α as demonstrated in the melanoma adjuvant setting is a major clinical need. The recent advances in the field of immune checkpoint modulation and the unprecedented clinical activity in advanced melanoma opens the door on novel combinations that may overcome tumor tolerogenic mechanisms that are known to suppress the potent anti-tumor impact of interferon (IFN)-α. Promising preliminary data suggest that such combinations may move the clinical management of advanced melanoma into the next level, beyond what is currently seen with immune checkpoint blockers alone.

17 Review Intermediate-grade meningeal melanocytoma associated with nevus of Ota: a case report and review of the literature. 2015

Shin, Donghoon / Sinha, Milind / Kondziolka, Douglas S / Kirkwood, John M / Rao, Uma N M / Tarhini, Ahmad A. ·University of Pittsburgh, Pittsburgh, Pennsylvania, USA. ·Melanoma Res · Pubmed #25933209.

ABSTRACT: Meningeal melanocytomas are rare melanin-producing tumors that are often found to be benign. However, a small subset of these tumors can present as intermediate-grade melanocytomas (IGMs) that have histopathological features that are between those of benign melanocytomas and malignant melanomas. IGMs have the potential to recur and metastasize or progress to a more histologically high grade melanoma. Melanocytomas appear to differ from primary and metastatic melanoma by their prolonged clinical course and they appear to have different driver mutations (i.e. mutation of GNAQ gene). The association of a meningeal melanocytoma with nevus of Ota is extremely rare. To our knowledge, there have been only 10 reported cases of synchronous occurrence and only one of the cases involved an IGM. We report the second case of intermediate-grade meningeal melanocytoma that is associated with congenital nevus of Ota. Histopathological work-up confirmed the intermediate grade of the lesion and a driver GNAQ mutation was identified consistent with previous reports.

18 Review Tenascin-C Signaling in melanoma. 2015

Shao, Hanshuang / Kirkwood, John M / Wells, Alan. ·a Department of Pathology. ·Cell Adh Migr · Pubmed #25482624.

ABSTRACT: Tenascin-C (TNC), a multifunctional matricellular glyco-protein, is highly expressed in the majority of melanoma cell lines and has been implicated in the progression of melanoma. A growing body of evidence has implicated the role of TNC in the process of invasion and metastasis for melanoma. However, the mechanism and individual signaling pathways by which TNC drives melanoma progression have not been illuminated. Herein we provide perspectives from the investigation of TNC in other settings that may hint at the mechanistic role of TNC in this disease.

19 Review Addressing the knowledge gap in clinical recommendations for management and complete excision of clinically atypical nevi/dysplastic nevi: Pigmented Lesion Subcommittee consensus statement. 2015

Kim, Caroline C / Swetter, Susan M / Curiel-Lewandrowski, Clara / Grichnik, James M / Grossman, Douglas / Halpern, Allan C / Kirkwood, John M / Leachman, Sancy A / Marghoob, Ashfaq A / Ming, Michael E / Nelson, Kelly C / Veledar, Emir / Venna, Suraj S / Chen, Suephy C. ·Pigmented Lesion Clinic and Cutaneous Oncology Program, Department of Dermatology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Pigmented Lesion and Melanoma Program, Department of Dermatology, Stanford University Medical Center, Palo Alto, California3Dermatology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California. · Pigmented Lesion Clinic and Multidisciplinary Cutaneous Oncology Program, Division of Dermatology, Department of Medicine, University of Arizona, Tucson. · Melanoma Program, Department of Dermatology, Miller School of Medicine, University of Miami, Miami, Florida. · Pigmented Lesion Clinic, Departments of Dermatology and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City. · Pigmented Lesion Clinic, Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Melanoma Program, University of Pittsburgh Cancer Institute, Department of Medicine, Dermatology and Translational Science, University of Pittsburgh, Pittsburgh, Pennsylvania. · Melanoma and Cutaneous Oncology Program, Department of Dermatology, Oregon Health and Science University, Portland. · Pigmented Lesion Clinic, Department of Dermatology, University of Pennsylvania, Philadelphia. · Pigmented Lesion Clinic, Department of Dermatology, Duke University Medical Center, Durham, North Carolina. · Center for Research and Grants, Baptist Health South Florida, Miami. · Skin Oncology and Melanoma Center, Department of Medicine, MedStar Washington Cancer Institute and Georgetown University Medical Center, Washington, DC. · Melanoma and Pigmented Lesion Clinic, Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia15Division of Dermatology, Atlanta Veterans Administration Medical Center, Decatur, Georgia. ·JAMA Dermatol · Pubmed #25409291.

ABSTRACT: IMPORTANCE: The management of clinically atypical nevi/dysplastic nevi (CAN/DN) is controversial, with few data to guide the process. Management recommendations for DN with positive histologic margins were developed by the Delphi method to achieve consensus among members of the Pigmented Lesion Subcommittee (PLS) of the Melanoma Prevention Working Group (MPWG) after reviewing the current evidence. OBJECTIVES: To outline key issues related to the management of CAN/DN: (1) biopsies of CAN and how positive margins arise, (2) whether incompletely excised DN evolve into melanoma, (3) current data on the outcomes of DN with positive histologic margins, (4) consensus recommendations, and (5) a proposal for future studies, including a large-scale study to help guide the management of DN with positive margins. EVIDENCE REVIEW: The literature, including recent studies examining management and outcomes of DN with positive margins between 2009 to 2014, was reviewed. FINDINGS: A consensus statement by the PLS of the MPWG following review of the literature, group discussions, and a structured Delphi method consensus. CONCLUSIONS AND RELEVANCE: This consensus statement reviews the complexities of management of CAN/DN. A review of the literature and 2 rounds of a structured Delphi consensus resulted in the following recommendations: (1) mildly and moderately DN with clear margins do not need to be reexcised, (2) mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than reexcised, and (3) observation may be a reasonable option for management of moderately DN with positive histologic margins without clinically apparent residual pigmentation; however, more data are needed to make definitive recommendations in this clinical scenario.

20 Review Atypical Spitzoid neoplasms: a review of potential markers of biological behavior including sentinel node biopsy. 2014

McCormack, Christopher J / Conyers, Rachel K / Scolyer, Richard A / Kirkwood, John / Speakman, David / Wong, Nick / Kelly, John W / Henderson, Michael A. ·aPeter Macallum Cancer Institute, East Melbourne bVictorian Melanoma Service, Alfred Hospital, Prahran cDepartment of Paediatrics, Murdoch Children's Research Institute, Royal Children's Hospital, The University of Melbourne, Parkville dThe Royal Children's Hospital, Flemington Road, Parkville, Victoria eMelanoma Institute Australia , Royal Prince Alfred Hospital, The University of Sydney, Sydney, New South Wales, Australia fDepartment of Medicine, Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA. ·Melanoma Res · Pubmed #24892957.

ABSTRACT: Atypical cutaneous melanocytic lesions, including those with Spitzoid features, can be difficult to categorize as benign or malignant. This can lead to suboptimal management, with potential adverse patient outcomes. Recent studies have enhanced knowledge of the molecular and genetic biology of these lesions and, combined with clinicopathological findings, is further defining their biological spectrum, classification, and behavior. Sentinel node biopsy provides important prognostic information in patients with cutaneous melanoma, but its role in the management of melanocytic lesions of uncertain malignant potential (MELTUMP) is controversial. This paper examines the role of molecular testing and sentinel node biopsy in MELTUMPs, particularly atypical Spitzoid tumors.

21 Review State of melanoma: an historic overview of a field in transition. 2014

Gorantla, Vikram C / Kirkwood, John M. ·Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, 5150 Centre Avenue, Pittsburgh, PA 15232, USA. · Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, 5150 Centre Avenue, Pittsburgh, PA 15232, USA; Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, 5115 Centre Avenue, Suite 1.32, Pittsburgh, PA 15232, USA. Electronic address: kirkwoodjm@upmc.edu. ·Hematol Oncol Clin North Am · Pubmed #24880939.

ABSTRACT: The last 30 years has seen a revolution in melanoma. Fundamental elements of the surgical, adjuvant medical, and systemic therapy for the disease have been significantly altered toward improved management and better outcomes. The intent of this article is to reflect on past efforts and research in melanoma and the current landscape of treatment of melanoma. The authors also hope to capture the excitement currently rippling through the field and the hope for a cure. The intent of treatment of advanced melanoma, which was once considered incurable, has changed from palliative to potentially curative.

22 Review Advances in adjuvant therapy: potential for prognostic and predictive biomarkers. 2014

Davar, Diwakar / Tarhini, Ahmad A / Gogas, Helen / Kirkwood, John M. ·Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ·Methods Mol Biol · Pubmed #24258973.

ABSTRACT: Melanoma is the third most common skin cancer but accounts for the majority of skin cancer-related mortality. The rapidly rising incidence and younger age at diagnosis has made melanoma a leading cause of lost productive years of life and has increased the urgency of finding improved adjuvant therapy for melanoma. Interferon-α was approved for the adjuvant treatment of resected high-risk melanoma following studies that demonstrated improvements in relapse-free survival and overall survival that were commenced nearly 30 years ago. The clinical benefits associated with this agent have been consistently observed across multiple studies and meta-analyses in terms of relapse rate, and to a smaller and less-consistent degree, mortality. However, significant toxicity and lack of prognostic and/or predictive biomarkers that would allow greater risk-benefit ratio have limited the more widespread adoption of this modality.Recent success with targeted agents directed against components of the MAP-kinase pathway and checkpoint inhibitors have transformed the treatment landscape in metastatic disease. Current research efforts are centered around discovering predictive/prognostic biomarkers and exploring the options for more effective regimens, either singly or in combination.

23 Review Melanoma brain metastases: an unmet challenge in the era of active therapy. 2013

Gorantla, Vikram / Kirkwood, John M / Tawbi, Hussein A. ·Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. ·Curr Oncol Rep · Pubmed #23954973.

ABSTRACT: Metastatic disease to the brain is a frequent manifestation of melanoma and is associated with significant morbidity and mortality and poor prognosis. Surgery and stereotactic radiosurgery provide local control but less frequently affect the overall outcome of melanoma brain metastases (MBM). The role of systemic therapies for active brain lesions has been largely underinvestigated, and patients with active brain lesions are excluded from the vast majority of clinical trials. The advent of active systemic therapy has revolutionized the care of melanoma patients, but this benefit has not been systematically translated into intracranial activity. In this article, we review the biology and clinical outcomes of patients with MBM, and the evidence supporting the use of radiation, surgery, and systemic therapy in MBM. Prospective studies that included patients with active MBM have shown clinical intracranial activity that parallels systemic activity and support the inclusion of patients with active MBM in clinical trials involving novel agents and combination therapies.

24 Review Immunotherapy for advanced melanoma: fulfilling the promise. 2013

Gogas, Helen / Polyzos, Aristidis / Kirkwood, John. ·1st Department of Medicine, University of Athens, Medical School, Laikon General Hospital, Athens, Greece. Electronic address: hgogas@hol.gr. ·Cancer Treat Rev · Pubmed #23725878.

ABSTRACT: The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past thirty years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimes failed to show significant improvement in overall survival. Recent advances and in-depth understanding of the biology of melanoma, have contributed in the development of new agents. Based on the molecular and immunological background of the disease, the new drugs have shown benefit in overall and progression free survival. As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma.

25 Review Adjuvant immunotherapy of melanoma and development of new approaches using the neoadjuvant approach. 2013

Davar, Diwakar / Tarhini, Ahmad A / Kirkwood, John M. ·Division of General Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. ·Clin Dermatol · Pubmed #23608443.

ABSTRACT: Melanoma is the third most common skin cancer but the leading cause of death from cutaneous malignancies. Although early-stage disease is frequently cured by surgical resection with excellent long-term survival, patients with deeper primary lesions (AJCC stage IIB-C) and those with microscopic (IIIA) or clinically evident regional lymph node or in-transit metastases (IIIB-C) have an increased risk of relapse and death, the latter approaching 70% or more at 5 years. In patients at high risk of recurrence/metastases, adjuvant therapy with high-dose interferon alpha-2b (HDI) following definitive surgical resection has been shown to improve relapse-free and overall survival. Neoadjuvant chemotherapy and/or radiotherapy have offered the prospect to improve regional recurrence risk and overall survival in several solid tumors. The advent of effective new molecularly targeted therapies for metastatic disease and new immunotherapies that overcome checkpoints of immune response have augmented the range of new options that are in current trial evaluation to determine their role as potential adjuvant therapies, alone and in combination with one another, and the established modality of IFN-α. The differential characteristics of the host immune response between early and advanced melanoma provide a strong mechanistic rationale for the use of neoadjuvant immunotherapeutic approaches in melanoma, and the opportunity to evaluate the mechanism of action suggest neoadjuvant trial evaluation for each of the new candidate agents and combinations of interest. Several neoadjuvant trials have been conducted in the phase II setting, which have illuminated the mechanism of IFN-α, as well as providing insight to the effects of anti-CTLA4 blocking antibodies. These agents (anti-CTLA4 blocking antibody ipilimumab, and BRAF inhibitor vemurafenib) are likely to be followed by other immunotherapies that may overcome the PD-1 checkpoint (anti-PD1 and anti-PDL-1) as well as other molecularly targeted agents such as the BRAF inhibitor dabrafenib and the MEK inhibitors trametinib, selumetinib, and MEK162 in the near future. Evaluation of the clinical role of these agents as adjuvant therapy will take years to accomplish to ascertain the relapse-free survival benefits and overall survival benefits of these agents, but neoadjuvant exploration may provide early critical evidence of the therapeutic benefits, as well as clarifying the mechanisms of these agents alone and in combination.

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