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Melanoma: HELP
Articles from University of Pittsburgh
Based on 286 articles published since 2008
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These are the 286 published articles about Melanoma that originated from University of Pittsburgh during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11 · 12
1 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.

2 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 --

3 Review Subungual Melanoma. 2019

Littleton, Travis W / Murray, Peter M / Baratz, Mark E. ·Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15237, USA. Electronic address: littletontw@upmc.edu. · Department of Orthopedic Surgery, Mayo Clinic, 4500 San Pablo Road South #378, Jacksonville, FL 32224, USA; Neurosurgery, Mayo Clinic, 4500 San Pablo Road South #378, Jacksonville, FL 32224, USA. · Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15237, USA. ·Orthop Clin North Am · Pubmed #31084838.

ABSTRACT: Subungual melanoma is a rare form of melanoma that presents a unique set of challenges largely based on the complex anatomy of the nail unit. Subungual melanoma often first appears with longitudinal melanonychia. Thus, practitioners must have a high clinical suspicion in any patient with longitudinal melanonychia and a low threshold for a biopsy. The "ABCDEF" guide can be a useful tool to aid in screening any lesion of the nail bed. The authors recommend that biopsies of the nail unit be performed by a surgeon with an in-depth understanding of the pathoanatomy of subungual melanoma.

4 Review MEK inhibitors for the treatment of NRAS mutant melanoma. 2018

Sarkisian, Saro / Davar, Diwakar. ·Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, PA, USA. · Division of Hematology-Oncology, Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA, USA, davard@upmc.edu. ·Drug Des Devel Ther · Pubmed #30154648.

ABSTRACT: Melanoma is increasing rapidly in incidence and prevalence, especially in younger females and older males. Treatment options have expanded beyond high-dose interleukin 2 and adoptive T-cell therapy to include inhibitors of immune checkpoints programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and small molecular inhibitors of pathways activated in melanoma, in particular the mitogen-activated protein kinase (MAPK) pathway. PD-1/CTLA-4 inhibitors and inhibitors of MAPK such as BRAF/MEK inhibitors have significantly improved survival in both the metastatic and, more recently, adjuvant settings. In this review, we discuss the preclinical data, clinical development, and potential use of novel MEK inhibitor binemetinib, particularly in the setting of

5 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.

6 Review Smartphone-Based Applications for Skin Monitoring and Melanoma Detection. 2017

Chao, Elizabeth / Meenan, Chelsea K / Ferris, Laura K. ·Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. · School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. · Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. Electronic address: ferrislk@upmc.edu. ·Dermatol Clin · Pubmed #28886812.

ABSTRACT: With the advancement of mobile technologies, smartphone applications (apps) have become widely available and gained increasing attention as a novel tool to deliver dermatologic care. This article presents a review of various apps for skin monitoring and melanoma detection and a discussion of current limitations in the field of dermatology. Concerns regarding quality, transparency, and reliability have emerged because there are currently no established quality standards or regulatory oversight of mobile medical apps. Only a few apps have been evaluated clinically. Further research is needed to evaluate the utility and efficacy of smartphone apps in skin cancer screening and early melanoma detection.

7 Review Understanding Mohs Micrographic Surgery: A Review and Practical Guide for the Nondermatologist. 2017

Tolkachjov, Stanislav N / Brodland, David G / Coldiron, Brett M / Fazio, Michael J / Hruza, George J / Roenigk, Randall K / Rogers, Howard W / Zitelli, John A / Winchester, Daniel S / Harmon, Christopher B. ·Surgical Dermatology Group, Birmingham, AL. Electronic address: Stan.tolkachjov@gmail.com. · Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA; Department of Plastic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA; Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, PA; Zitelli & Brodland, P.C., Pittsburgh, PA. · The Skin Cancer Center, Cincinnati, OH; Department of Dermatology, University of Cincinnati, Cincinnati, OH. · Skin Cancer Surgery Center, Sacramento, CA. · Department of Dermatology, St Louis University, St Louis, MO; Laser & Dermatologic Surgery Center, Chesterfield, MO. · Department of Dermatology, Mayo Clinic, Rochester, MN; Division of Dermatologic Surgery, Mayo Clinic, Rochester, MN. · Advanced Dermatology, Norwich, CT. · Surgical Dermatology Group, Birmingham, AL. ·Mayo Clin Proc · Pubmed #28778259.

ABSTRACT: The incidence and diagnosis of cutaneous malignancies are steadily rising. In addition, with the aging population and increasing use of organ transplant and immunosuppressive medications, subsets of patients are now more susceptible to skin cancer. Mohs micrographic surgery (MMS) has become the standard of care for the treatment of high-risk nonmelanoma skin cancers and is increasingly used to treat melanoma. Mohs micrographic surgery has the highest cure rates, spares the maximal amount of normal tissue, and is cost-effective for the treatment of cutaneous malignancies. As in other medical fields, appropriate use criteria were developed for MMS and have become an evolving guideline for determining which patients and tumors are appropriate for referral to MMS. Patients with cutaneous malignancies often require multidisciplinary care. With the changing landscape of medicine and the rapidly increasing incidence of skin cancer, primary care providers and specialists who do not commonly manage cutaneous malignancies will need to have an understanding of MMS and its role in patient care. This review better familiarizes the medical community with the practice of MMS, its utilization and capabilities, differences from wide excision and vertical section pathology, and cost-effectiveness, and it guides practitioners in the process of appropriately evaluating and determining when patients with skin cancer might be appropriate candidates for MMS.

8 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 / Anonymous3260912. ·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.

9 Review Operable Melanoma: Screening, Prognostication, and Adjuvant and Neoadjuvant Therapy. 2017

Tarhini, Ahmad A / Lorigan, Paul / Leachman, Sancy. ·From the University of Pittsburgh, Pittsburgh, PA; University of Manchester, Manchester, United Kingdom; Oregon Health & Science University, Portland, OR. ·Am Soc Clin Oncol Educ Book · Pubmed #28561661.

ABSTRACT: The importance of reducing the numbers of patients with late-stage melanoma, identifying which patients are most likely to progress, and treating these patients at the earliest possible stage cannot be overemphasized. Improved screening of patients prior to diagnosis has the advantage of identifying early-stage disease that is for the most part treatable by surgical methods. The process of melanoma screening is rapidly evolving through population-based programs, mobile health technologies, and advanced imaging tools. For patients with newly diagnosed melanoma, accurately estimating disease prognosis has important implications for management and follow-up. Prognostic factors are individual host- or tumor-related factors or molecules that correlate with genetic predisposition and clinical course. These include clinical covariates and host and tumor proteomic/genomic markers that allow the prognostic subclassification of patients. Adjuvant therapy for high-risk surgically resected melanoma targets residual micrometastatic disease with the goal of reducing the risk of relapse and mortality. In the United States, three regimens have achieved regulatory approval for adjuvant therapy, including high-dose interferon alpha, pegylated interferon alpha, and ipilimumab at 10 mg/kg. Phase III trials have reported benefits in relapse-free survival (all regimens) and overall survival (high-dose interferon alpha and ipilimumab). The management of locally/regionally advanced melanoma may benefit from neoadjuvant therapy, which is the subject of several ongoing studies. Recent studies have shown promising clinical activity and yielded important biomarker findings and mechanistic insights.

10 Review The use of immunotherapy in the treatment of melanoma. 2017

Achkar, Tala / Tarhini, Ahmad A. ·University of Pittsburgh, Pittsburgh, PA, USA. · University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Room 555, Pittsburgh, PA, 15232, USA. · University of Pittsburgh, Pittsburgh, PA, USA. tarhiniaa@upmc.edu. · University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Room 555, Pittsburgh, PA, 15232, USA. tarhiniaa@upmc.edu. ·J Hematol Oncol · Pubmed #28434398.

ABSTRACT: Patients with advanced melanoma have a compromised anti-tumor immune response leading to tumor immune tolerance and a tumor microenvironment conducive to disease progression. Immunotherapy that successfully overcomes this tumor-mediated immune suppression has made the greatest impact in the management of this disease over the past few years. This progress through immunotherapy builds upon earlier successes that interferon-α had in the treatment of melanoma in the adjuvant setting, as well as that of high-dose interleukin-2 in advanced melanoma. The development of immune checkpoint inhibitors has led to dramatic clinical activity in advanced melanoma. In particular, anti-CTLA4 and anti-PD1 monoclonal antibodies have taken us forward into the realm of longer survival and durable responses with the possibility of cure in a continuously increasing proportion of patients. Combination immunotherapeutic strategies and novel immunotherapeutic agents are being tested at an accelerated pace where the outlook for long-term survival benefits for the majority of patients appears brighter than ever.

11 Review Adjuvant Therapy for Melanoma. 2017

Agha, Aya / Tarhini, Ahmad A. ·University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. · University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. tarhiniaa@upmc.edu. · University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Room 555, Pittsburgh, PA, 15232, USA. tarhiniaa@upmc.edu. ·Curr Oncol Rep · Pubmed #28417343.

ABSTRACT: Systemic adjuvant therapy for surgically resected cutaneous melanoma that is at high risk for disease recurrence and death targets residual micrometastatic disease which is the source of future local or distant relapse. Interferon-alfa (IFNα) has been the most extensively studied in regimens that varied by dosage, route of administration, formulation, and duration of therapy. Most regimens have demonstrated improvements in relapse-free survival (RFS), while the regimen administered at high dosage (HDI) showed improvements in overall survival (OS) in two out of three RCTs. HDI benefits as measured by the hazard ratios (HR) in E1684 (vs. observation), E1690 (vs. observation), and E1694 (vs. vaccine) trials were estimated at 0.61, 0.78, and 0.67 (RFS) and 0.67, 1.0, and 0.72 (OS) when first reported with lesser estimates on later updates. Pegylated IFNα (peg-IFN) as studied in the European Organisation for Research and Treatment of Cancer (EORTC) 18991 trial in patients with stage III melanoma significantly reduced the risk of relapse (HR 0.87) with no impact on OS. More recently (EORTC 18071), ipilimumab at the high dose of 10 mg/kg was shown to significantly improve RFS (HR 0.76) and OS (HR 0.72) of stage III melanoma patients but at a significant cost in terms of immune-related toxicities. Ongoing adjuvant studies are testing ipilimumab at 3 or 10 mg/kg versus HDI (E1609) and the anti-PD-1 antibodies nivolumab (CheckMate 238) and pembrolizumab (KEYNOTE-054 and S1404).

12 Review Gamma Knife Radiosurgery for Uveal Metastases: Report of Three Cases and a Review of the Literature. 2017

Ares, William J / Tonetti, Daniel / Yu, Jenny Y / Monaco, Edward A / Flickinger, John C / Lunsford, L Dade. ·Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address: areswj@upmc.edu. · Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Ophthalmology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. ·Am J Ophthalmol · Pubmed #27889503.

ABSTRACT: PURPOSE: Uveal metastases are ophthalmologic tumors that have historically been treated by fractionated external beam radiation therapy or invasive brachytherapy. The need for rapid response and less invasive management options led the authors to explore the use of Gamma Knife stereotactic radiosurgery (SRS) for this common problem. DESIGN: Interventional case series. METHODS: To prevent eye movement during the procedure, all 3 patients underwent a retrobulbar anesthetic block followed by magnetic resonance imaging to detect the target. All tumors were treated in a single procedure using the 4C or Perfexion Gamma Knife. The tumors received a minimal tumor dose of 14-20 Gy. Two patients also underwent SRS for additional intracranial metastases. RESULTS: At follow-up, performed between 4 and 15 months after SRS, all 3 patients demonstrated a reduction in uveal tumor volumes. One patient developed decreased visual acuity secondary to radiation retinopathy. CONCLUSION: In this early experience, SRS was found to be an effective management option for uveal metastases associated with systemic cancer. Patients can be screened and treated effectively early after diagnosis using a joint approach between ophthalmologists and neurosurgeons. Systemic oncologic care can continue without interruption.

13 Review Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. 2016

Boutros, Celine / Tarhini, Ahmad / Routier, Emilie / Lambotte, Olivier / Ladurie, Francois Leroy / Carbonnel, Franck / Izzeddine, Hassane / Marabelle, Aurelien / Champiat, Stephane / Berdelou, Armandine / Lanoy, Emilie / Texier, Matthieu / Libenciuc, Cristina / Eggermont, Alexander M M / Soria, Jean-Charles / Mateus, Christine / Robert, Caroline. ·Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · University of Pittsburgh, 4200 Fifth Avenue, Pittsburgh, Pennsylvania 15260, USA. · AP-HP, Internal Medicine Department, University Hospital of Bicêtre, 78 Rue du General Leclerc, 94270 Le Kremlin-Bicetre, France. · Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicêtre, France. · INSERM Unit U1184, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicêtre, France. · Thoracic and Vascular Surgery Service, Centre Chirurgical Marie Lannelongue, 133 Avenue de la Resistance, 92350 Le Plessis-Robinson, France. · AP-HP, Department of Gastroenterology, University Hospital of Bicêtre, Paris Sud University, 78 Rue du General Leclerc, 94270 Le Kremlin-Bicetre, France. · Department of Nephrology, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l'hopital, 75013 Paris, France. · Drug Development Department (DITEP), Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · INSERM Unit U981, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · Biostatistic and Epidemiology Unit, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. ·Nat Rev Clin Oncol · Pubmed #27141885.

ABSTRACT: Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.

14 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.

15 Review Immunotherapy of Melanoma. 2016

Tarhini, Ahmad A. ·University of Pittsburgh Cancer Institute, 5150 Centre Avenue (555), Pittsburgh, PA 15232, USA. tarhiniaa@upmc.edu. ·Curr Mol Pharmacol · Pubmed #26177647.

ABSTRACT: The host antitumor immune response in patients with advanced melanoma is compromised with a bias towards tumor immune tolerance and a tumor microenvironment that facilitates disease survival and progression. Overcoming tumor-induced immune suppression has been one of the most significant advances in cancer therapy, making a cure an ever closer and achievable goal. Immunotherapeutic strategies in melanoma have been built upon the immunomodulatory qualities and the early successes of interferon-α in the melanoma adjuvant setting and interleukin-2 in the treatment of inoperable advanced melanoma. The recent advances in the field of immune checkpoint modulation and the unprecedented clinical activity in advanced melanoma opened the doors for novel agents and combinations that may potently overcome tumor tolerogenic mechanisms. Recent data with immune anti-CTLA4 and anti-PD1 monoclonal antibodies have moved the clinical management of advanced melanoma into a new era, an era of long-term survival and potential cures.

16 Review Neoadjuvant therapy for melanoma: a promising therapeutic approach and an ideal platform in drug development. 2015

Tarhini, Ahmad A. ·From the University of Pittsburgh School of Medicine and Cancer Institute, Pittsburgh, PA. ·Am Soc Clin Oncol Educ Book · Pubmed #25993220.

ABSTRACT: Patients with locoregionally advanced but surgically operable melanoma continue to carry a high risk of relapse and death despite the best available standard management approaches. Neoadjuvant studies targeting this patient population tested chemotherapy with temozolomide and biochemotherapy (BCT), in which BCT demonstrated high tumor response rates but was eventually abandoned with the failure of BCT to deliver survival benefits in randomized trials of metastatic disease. Smaller neoadjuvant immunotherapy studies with interferon (IFN) alfa and ipilimumab have yielded promising clinical activity and important mechanistic insights and biomarker findings. Newer targeted and immunotherapeutic agents and combinations currently are being translated into the neoadjuvant setting at an accelerated pace and carry significant clinical promise. In drug development, the neoadjuvant approach allows access to blood and tumor tissue before and after initiation of systemic therapy, which allows for the conduct of novel mechanistic and biomarker studies in the circulation and the tumor microenvironment. Such studies may guide drug development and allow for the discovery of predictive biomarkers selected on the basis of their capacity to classify patients according to the degree of benefit from treatment or the risk for significant toxicity.

17 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.

18 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.

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 Mitotic rate for thin melanomas: should a single mitotic figure warrant a sentinel lymph node biopsy? 2014

Kirkland, E Brent / Zitelli, John A. ·*Both the authors are affiliated with Shadyside Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania. ·Dermatol Surg · Pubmed #25072127.

ABSTRACT: BACKGROUND: The seventh edition of the American Joint Committee on Cancer guidelines recognize mitotic rate (MR) as a component of the staging criteria for cutaneous melanomas with a Breslow depth ≤1 mm. OBJECTIVE: This review discusses the evidence behind the threshold of 1 mitosis per square millimeter as a prognostic variable in thin melanomas, particularly because it relates to the decision to pursue a sentinel lymph node biopsy (SLNB). MATERIALS AND METHODS: We performed a systematic review using the PubMed database to identify articles that contain prognostic information for thin melanomas based on MR and sentinel lymph node (SLN) status. RESULTS: Although the threshold of a single mitosis correlates with a statistically significant decrease in survival rates for patients with thin melanomas, the clinical relevance remains questionable particularly because it relates to the decision to pursue an SLNB. CONCLUSION: A single mitosis in thin melanomas does not increase the risk of a positive SLN so much that SLN biopsy should be routinely performed for this cohort.

21 Review Screening for melanoma. 2014

Collins, Mary-Katharine M / Secrest, Aaron M / Ferris, Laura K. ·aDepartment of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA bDepartment of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA. ·Melanoma Res · Pubmed #24999755.

ABSTRACT: Although melanoma is a deadly cancer that is rising in incidence, the USA does not have uniform guidelines for melanoma screening. Screening for melanoma requires no specialized equipment and has little associated morbidity. However, screening has the greatest impact when performed among patients with the highest risk for melanoma incidence and mortality. Screening lower-risk patients may result in prohibitively high costs, unnecessary biopsies of benign lesions, and decreased access to a dermatologic specialist for patients who are actually at a higher risk. We advocate targeting melanoma screening efforts toward those patients at high risk of developing and dying from melanoma, as well as toward those at-risk patients who are least likely to detect their own melanoma.

22 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.

23 Review Melanoma adjuvant therapy. 2014

Tarhini, Ahmad A / Thalanayar, Prashanth M. ·Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue (555), Pittsburgh, PA 15232, USA. Electronic address: tarhiniaa@upmc.edu. · Department of Internal Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA. ·Hematol Oncol Clin North Am · Pubmed #24880942.

ABSTRACT: Adjuvant therapy targets melanoma micrometastases in patients with surgically resected disease that carry a high risk of death from melanoma recurrence. In this setting, adjuvant therapy provides the greatest opportunity for cure before progression into advanced inoperable stages. In randomized clinical trials, interferon-alfa has been shown to have a significant impact on relapse-free survival and, at high dosage, on overall survival compared with observation (E1684) and the GMK vaccine (E1694). This article reviews melanoma adjuvant therapy along with the ongoing and planned clinical trials.

24 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.

25 Review The role of sentinel lymph node biopsy for thin cutaneous melanomas of the head and neck. 2014

Kupferman, Michael E / Kubik, Mark W / Bradford, Carol R / Civantos, Francisco J / Devaney, Kenneth O / Medina, Jesus E / Rinaldo, Alessandra / Stoeckli, Sandro J / Takes, Robert P / Ferlito, Alfio. ·Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: mekupfer@mdanderson.org. · Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA. · Department of Otolaryngology-Head and Neck Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA. · Department of Pathology, Allegiance Health, Jackson, MI, USA. · Department of Otorhinolaryngology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. · ENT Clinic, University of Udine, Udine, Italy. · Department of Otorhinolaryngology-Head and Neck Surgery, Kantonsspital St. Gallen, St. Gallen, Switzerland. · Department of Otolaryngology-Head and Neck Surgery, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands. ·Am J Otolaryngol · Pubmed #24439782.

ABSTRACT: From 18% to 35% of cutaneous melanomas are located in the head and neck, and nearly 70% are thin (Breslow thickness ≤ 1 mm). Sentinel lymph node biopsy (SLNB) has an established role in staging of intermediate-thickness melanomas, however its use in thin melanomas remains controversial. In this article, we review the literature regarding risk factors for occult nodal metastasis in thin cutaneous melanoma of the head and neck (CMHN). Based on the current literature, we recommend SLNB for all lesions with Breslow thickness ≥ 0.75 mm, particularly when accompanied by adverse features including mitotic rate ≥ 1 per mm(2), ulceration, and extensive regression. SLNB should also be strongly considered in younger patients (e.g. < 40 years old), especially in the presence of additional adverse features. All patients who do not proceed with sentinel lymph node biopsy must be carefully followed to monitor for regional relapse.

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