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Melanoma: HELP
Articles by Martin C. Mihm
Based on 64 articles published since 2008

Between 2008 and 2019, M. Mihm wrote the following 64 articles about Melanoma.
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline EANM-EORTC general recommendations for sentinel node diagnostics in melanoma. 2009

Chakera, Annette H / Hesse, Birger / Burak, Zeynep / Ballinger, James R / Britten, Allan / Caracò, Corrado / Cochran, Alistair J / Cook, Martin G / Drzewiecki, Krzysztof T / Essner, Richard / Even-Sapir, Einat / Eggermont, Alexander M M / Stopar, Tanja Gmeiner / Ingvar, Christian / Mihm, Martin C / McCarthy, Stanley W / Mozzillo, Nicola / Nieweg, Omgo E / Scolyer, Richard A / Starz, Hans / Thompson, John F / Trifirò, Giuseppe / Viale, Giuseppe / Vidal-Sicart, Sergi / Uren, Roger / Waddington, Wendy / Chiti, Arturo / Spatz, Alain / Testori, Alessandro / Anonymous1200637. ·Department of Plastic Surgery and Burns Unit, Rigshospitalet, Copenhagen, Denmark. annette.hougaard.chakera@live.dk ·Eur J Nucl Med Mol Imaging · Pubmed #19714329.

ABSTRACT: The accurate diagnosis of a sentinel node in melanoma includes a sequence of procedures from different medical specialities (nuclear medicine, surgery, oncology, and pathology). The items covered are presented in 11 sections and a reference list: (1) definition of a sentinel node, (2) clinical indications, (3) radiopharmaceuticals and activity injected, (4) dosimetry, (5) injection technique, (6) image acquisition and interpretation, (7) report and display, (8) use of dye, (9) gamma probe detection, (10) surgical techniques in sentinel node biopsy, and (11) pathological evaluation of melanoma-draining sentinel lymph nodes. If specific recommendations given cannot be based on evidence from original, scientific studies, referral is given to "general consensus" and similar expressions. The recommendations are designed to assist in the practice of referral to, performance, interpretation and reporting of all steps of the sentinel node procedure in the hope of setting state-of-the-art standards for good-quality evaluation of possible spread to the lymphatic system in intermediate-to-high risk melanoma without clinical signs of dissemination.

2 Editorial Advances in melanoma: revolutionary progress delivering improved patient management and outcomes. 2016

Scolyer, Richard A / Vilain, Ricardo E / Mihm, Martin C. ·Melanoma Institute Australia, North Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia. Electronic address: richard.scolyer@sswahs.nsw.gov.au. · School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, Australia; Hunter Cancer Research Alliance (HCRA), Calvary Mater Newcastle, Waratah, Australia; Division of Anatomical Pathology, Pathology North (Hunter), New Lambton Heights, NSW, Australia. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. ·Pathology · Pubmed #27020382.

ABSTRACT: -- No abstract --

3 Review Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy. 2016

Lee, Nayoung / Zakka, Labib R / Mihm, Martin C / Schatton, Tobias. ·Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA. Electronic address: tschatton@bwh.harvard.edu. ·Pathology · Pubmed #27020390.

ABSTRACT: The field of systemic cancer therapy for metastatic disease has entered an exciting era with the advent of novel immunomodulatory strategies targeting immune checkpoints. At the heart of these promising efforts are the tumour-infiltrating lymphocytes (TILs). As the reports demonstrating efficacy of modulating TIL effector function in patients with advanced stage cancer continue to accrue, it has become essential to better understand TIL immunobiology in order to further improve clinical outcome. In addition to providing an overview of the current immunotherapies available for metastatic melanoma, this review will briefly introduce the history and classification of TILs. Moreover, we will dissect the multifaceted roles of TILs in tumour-specific immunity and melanoma immune escape. The significance of TILs in melanoma prognosis and cancer immunotherapy will also be discussed, with a particular focus on their potential utility as biomarkers of patient response. The goal of personalised medicine appears to be in realistic sight, as new immunomodulatory techniques and technological innovations continue to advance the field of cancer immunotherapy. In light of recent studies highlighting the possible utility of TILs in determining therapeutic outcome, further characterisation of TIL phenotype and function has the potential to help translate individualised care into current medical practice.

4 Review Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy. 2016

Wiesner, Thomas / Kutzner, Heinz / Cerroni, Lorenzo / Mihm, Martin C / Busam, Klaus J / Murali, Rajmohan. ·Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria. Electronic address: wiesnert@me.com. · Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria; Dermatopathologie Friedrichshafen, Friedrichshafen, Germany. · Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria. · Melanoma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, United States. ·Pathology · Pubmed #27020384.

ABSTRACT: Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas common acquired naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion and may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are usually capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour progression will refine the classification of spitzoid melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy.

5 Review Reflections on the Histopathology of Tumor-Infiltrating Lymphocytes in Melanoma and the Host Immune Response. 2015

Mihm, Martin C / Mulé, James J. ·Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. mmihm@partners.org James.Mule@moffitt.org. · Translational Science, Melanoma Research and Treatment, Moffitt Cancer Center, Tampa, Florida. mmihm@partners.org James.Mule@moffitt.org. ·Cancer Immunol Res · Pubmed #26242760.

ABSTRACT: In the past five decades, the role for lymphocytes in host immune response to tumors has been shown, at least in some patients, to be a critical component in disease prognosis. Also, the heterogeneity of lymphocytes has been documented, including the existence of regulatory T cells that suppress the immune response. As the functions of lymphocytes have become better defined in terms of antitumor immunity, specific targets on lymphocytes have been uncovered. The appreciation of the role of immune checkpoints has also led to therapeutic approaches that illustrate the effectiveness of blocking negative regulators of the antitumor immune response. In this Masters of Immunology article, we trace the evolution of our understanding of tumor-infiltrating lymphocytes and discuss their role in melanoma prognosis from the very basic observation of their existence to the latest manipulation of their functions with the result of improvement of the host response against the tumor.

6 Review Tumor-infiltrating lymphocytes and their significance in melanoma prognosis. 2014

Schatton, Tobias / Scolyer, Richard A / Thompson, John F / Mihm, Martin C. ·Department of Dermatology, Brigham and Women's Hospital and Transplantation Research Center, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA. ·Methods Mol Biol · Pubmed #24258985.

ABSTRACT: The role of the tumor-infiltrating lymphocyte (TIL) and its relationship to prognosis has been most extensively studied in malignant melanoma. The purpose of this chapter is to discuss in depth the immunobiology and molecular aspects of lymphocyte function in general and particularly TIL function in the context of antimelanoma immunity. Emphasis is placed upon the role of these inflammatory mediators in the enhancement and impairment of progression of this often fatal human cancer. In addition, the analysis of TILs in melanoma and their direct relationship to prognosis as well as their effect on the positivity of the sentinel lymph node will be discussed. Furthermore, details of lymph node responses to metastatic melanomas and their prognostic significance will be clarified. Finally, the importance of TILs for the evaluation of therapeutic response and how TIL immunobiology could critically inform the design of novel melanoma immunotherapeutic protocols will be elucidated.

7 Review Progression of cutaneous melanoma: implications for treatment. 2012

Leong, Stanley P L / Mihm, Martin C / Murphy, George F / Hoon, Dave S B / Kashani-Sabet, Mohammed / Agarwala, Sanjiv S / Zager, Jonathan S / Hauschild, Axel / Sondak, Vernon K / Guild, Valerie / Kirkwood, John M. ·Center for Melanoma Research and Treatment and Department of Surgery, California Pacific Medical Center, San Francisco, CA, USA. leongsx@cpmcri.org ·Clin Exp Metastasis · Pubmed #22892755.

ABSTRACT: The survival rates of melanoma, like any type of cancer, become worse with advancing stage. Spectrum theory is most consistent with the progression of melanoma from the primary site to the in-transit locations, regional or sentinel lymph nodes and beyond to the distant sites. Therefore, early diagnosis and surgical treatment before its spread is the most effective treatment. Recently, new approaches have revolutionized the diagnosis and treatment of melanoma. Genomic profiling and sequencing will form the basis for molecular taxonomy for more accurate subgrouping of melanoma patients in the future. New insights of molecular mechanisms of metastasis are summarized in this review article. Sentinel lymph node biopsy has become a standard of care for staging primary melanoma without the need for a more morbid complete regional lymph node dissection. With recent developments in molecular biology and genomics, novel molecular targeted therapy is being developed through clinical trials.

8 Review AJCC melanoma staging update: impact on dermatopathology practice and patient management. 2011

Piris, Adriano / Mihm, Martin C / Duncan, Lyn M. ·Dermatopathology Unit, Pathology Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. ·J Cutan Pathol · Pubmed #21385199.

ABSTRACT: Changes in the 2010 American Joint Commission on Cancer melanoma staging guidelines include the evaluation of primary tumor mitotic index (mitogenicity) and the recognized prognostic significance of a single melanoma cell in a sentinel lymph node. These revised criteria have important practice implications for dermatopathologists as well as for dermatologists, oncologists and surgeons who treat patients with cutaneous melanoma.

9 Review Expert opinion in melanoma: the sentinel node; EORTC Melanoma Group recommendations on practical methodology of the measurement of the microanatomic location of metastases and metastatic tumour burden. 2009

van Akkooi, Alexander C J / Spatz, Alain / Eggermont, Alexander M M / Mihm, Martin / Cook, Martin G. ·Erasmus University Medical Centre - Daniel den Hoed Cancer Centre, Department of Surgical Oncology, Groene Hilledijk 301 - Kamer A1-41, 3075 EA Rotterdam, The Netherlands. a.vanakkooi@erasmusmc.nl ·Eur J Cancer · Pubmed #19767199.

ABSTRACT: The sentinel node (SN) status has been recognised to be the most important prognostic factor in melanoma. Many studies have investigated additional factors to further predict survival/lymph node involvement. The EORTC Melanoma Group (MG) has formulated the following question: How should we report the microanatomic location and SN tumour burden? The EORTC MG recommends the following: the EORTC MG SN pathology protocol or a similarly extensive protocol, which has also been proven to be accurate, should be used. Only measure what you can see not what you presume. Cumulative measurements decrease the accuracy and reproducibility of measuring. The most reproducible measure is a single measurement of the maximum diameter of the largest lesion in any direction (1-D). If there is any infiltration into the parenchyma, this lesion can no longer be considered solely subcapsular. Reporting of the microanatomic location of metastases should be an assessment of the entire sentinel node, not only of the largest lesion. Multifocality reflects a scattered metastatic pattern, not to be confused with multiple cohesive foci, which fall under the regular location system. A subcapsular metastasis should have a smooth usually curved outline, not ragged or irregular. We recommend all pathologists to report the following items per positive SN for melanoma patients: the microanatomic location of the metastases according to Dewar et al. for the entire node, the SN Tumour Burden according to the Rotterdam Criteria for the maximum diameter of the largest metastasis expressed as an absolute number, and the SN Tumour Burden stratified per category; <0.1mm or 0.1-1.0mm or >1.0mm.

10 Review Progress in melanoma histopathology and diagnosis. 2009

Piris, Adriano / Mihm, Martin C. ·Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Warren 820, Boston, MA 02114, USA. apiris@partners.org ·Hematol Oncol Clin North Am · Pubmed #19464597.

ABSTRACT: This article reviews the main aspects of the histopathology of cutaneous melanoma with emphasis on recent advances in the morphological evaluation of these lesions. The limitations of morphology for the "so called" borderline lesions are briefly discussed, with a list of diagnostic criteria to help predict behavior for these challenging lesions. The prognostic factors are described with emphasis on the ones that are currently being used by the American Joint Committee on Cancer staging system. Ancillary tests, such as immunohistochemistry and molecular techniques, are also briefly touched upon as complimentary tools to help understand the biology of malignant melanoma. The conclusion is that an accurate morphological evaluation remains the most efficient approach to establish the diagnosis and predict behavior of this challenging neoplasm.

11 Review Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. 2009

Oble, Darryl A / Loewe, Robert / Yu, Ping / Mihm, Martin C. ·Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Warren 827, Boston, MA 02114, USA. ·Cancer Immun · Pubmed #19338264.

ABSTRACT: Tumors contain variable numbers of lymphocytes, referred to as tumor infiltrating lymphocytes (TILs). In melanoma, the intensity of this lymphocytic infiltrate is believed to correlate with outcome, though there is some debate about the applicability of this finding for all melanomas. Much research has gone into classifying TILs with respect to antigen receptor structure and the antigen to which melanoma-specific T cells react. However, these studies for the most part did not immunophenotype TILs, and recent data has revealed that the composition of tumoral lymphocytes is not homogenous, but rather represents varying contributions from many lymphocytic subsets. Furthermore, the function of TILs is often compromised as a result of the accumulation of immunoregulatory cells and various tumor escape mechanisms. These recent insights stress the need to collect more data on the composition and function of TIL infiltrates before definitive conclusions about the prognostic significance of TILs can be drawn. Advances in immunology have also facilitated the development of immunotherapeutic strategies, examples of which will be discussed with a special emphasis on blocking antibodies against CTLA-4, which are prototypical immunotherapeutic agents. This flurry of novel "biological" therapies will undoubtedly complicate our already incomplete understanding of TIL immunobiology as each of these agents has the potential to uniquely distort the series of immunological events which normally occur in untreated melanoma. Therefore, considerable research is needed to better elucidate the function and prognostic significance of TILs in both untreated melanoma and tumors treated with "biological" therapy.

12 Clinical Trial Bevacizumab plus ipilimumab in patients with metastatic melanoma. 2014

Hodi, F Stephen / Lawrence, Donald / Lezcano, Cecilia / Wu, Xinqi / Zhou, Jun / Sasada, Tetsuro / Zeng, Wanyong / Giobbie-Hurder, Anita / Atkins, Michael B / Ibrahim, Nageatte / Friedlander, Philip / Flaherty, Keith T / Murphy, George F / Rodig, Scott / Velazquez, Elsa F / Mihm, Martin C / Russell, Sara / DiPiro, Pamela J / Yap, Jeffrey T / Ramaiya, Nikhil / Van den Abbeele, Annick D / Gargano, Maria / McDermott, David. ·Authors' Affiliations: Departments of Medical Oncology, Stephen_Hodi@dfci.harvard.edu. · Massachusetts General Hospital Cancer Center; Departments of. · University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; · Authors' Affiliations: Departments of Medical Oncology. · Biostatistics, and. · Lombardi Cancer Center Georgetown University, Washington, District of Columbia; and. · Mount Sinai Medical Center, New York, New York. · Pathology and. · Tufts University; Miraca Life Sciences, Newton, Massachusetts; · Surgery, Brigham and Women's Hospital; · Imaging, Dana-Farber Cancer Institute; · Beth Israel-Deaconess Medical Center, Boston; ·Cancer Immunol Res · Pubmed #24838938.

ABSTRACT: Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade.

13 Clinical Trial Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells. 2011

Butler, Marcus O / Friedlander, Philip / Milstein, Matthew I / Mooney, Mary M / Metzler, Genita / Murray, Andrew P / Tanaka, Makito / Berezovskaya, Alla / Imataki, Osamu / Drury, Linda / Brennan, Lisa / Flavin, Marisa / Neuberg, Donna / Stevenson, Kristen / Lawrence, Donald / Hodi, F Stephen / Velazquez, Elsa F / Jaklitsch, Michael T / Russell, Sara E / Mihm, Martin / Nadler, Lee M / Hirano, Naoto. ·Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. marcus_butler@dfci.harvard.edu ·Sci Transl Med · Pubmed #21525398.

ABSTRACT: Although advanced-stage melanoma patients have a median survival of less than a year, adoptive T cell therapy can induce durable clinical responses in some patients. Successful adoptive T cell therapy to treat cancer requires engraftment of antitumor T lymphocytes that not only retain specificity and function in vivo but also display an intrinsic capacity to survive. To date, adoptively transferred antitumor CD8(+) T lymphocytes (CTLs) have had limited life spans unless the host has been manipulated. To generate CTLs that have an intrinsic capacity to persist in vivo, we developed a human artificial antigen-presenting cell system that can educate antitumor CTLs to acquire both a central memory and an effector memory phenotype as well as the capacity to survive in culture for prolonged periods of time. We examined whether antitumor CTLs generated using this system could function and persist in patients. We showed that MART1-specific CTLs, educated and expanded using our artificial antigen-presenting cell system, could survive for prolonged periods in advanced-stage melanoma patients without previous conditioning or cytokine treatment. Moreover, these CTLs trafficked to the tumor, mediated biological and clinical responses, and established antitumor immunologic memory. Therefore, this approach may broaden the availability of adoptive cell therapy to patients both alone and in combination with other therapeutic modalities.

14 Clinical Trial The performance of MelaFind: a prospective multicenter study. 2011

Monheit, Gary / Cognetta, Armand B / Ferris, Laura / Rabinovitz, Harold / Gross, Kenneth / Martini, Mary / Grichnik, James M / Mihm, Martin / Prieto, Victor G / Googe, Paul / King, Roy / Toledano, Alicia / Kabelev, Nikolai / Wojton, Maciej / Gutkowicz-Krusin, Dina. ·Total Skin and Beauty Dermatology, Birmingham, Alabama, USA. ·Arch Dermatol · Pubmed #20956633.

ABSTRACT: OBJECTIVE: To demonstrate the safety and effectiveness of MelaFind, a noninvasive and objective computer-vision system designed to aid in detection of early pigmented cutaneous melanoma. DESIGN: A prospective, multicenter, blinded study. The diagnostic performance of MelaFind and of study clinicians was evaluated using the histologic reference standard. Standard images and patient information for a subset of 50 randomly selected lesions (25 melanomas) were used in a reader study of 39 independent dermatologists to estimate clinicians' biopsy sensitivity to melanoma. SETTING: Three academic and 4 community practices in the United States with expertise in management of pigmented skin lesions. PATIENTS: A total of 1383 patients with 1831 lesions enrolled from January 2007 to July 2008; 1632 lesions (including 127 melanomas-45% in situ-with median Breslow thickness of invasive lesions, 0.36 mm) were eligible and evaluable for the study end points. MAIN OUTCOME MEASURES: Sensitivity of MelaFind; specificities and biopsy ratios for MelaFind and the study investigators; and biopsy sensitivities of independent dermatologists in the reader study. RESULTS: The measured sensitivity of MelaFind was 98.4% (125 of 127 melanomas) with a 95% lower confidence bound at 95.6% and a biopsy ratio of 10.8:1; the average biopsy sensitivity of dermatologists was 78% in the reader study. Including borderline lesions (high-grade dysplastic nevi, atypical melanocytic proliferations, or hyperplasias), MelaFind's sensitivity was 98.3% (172 of 175), with a biopsy ratio of 7.6:1. On lesions biopsied mostly to rule out melanoma, MelaFind's average specificity (9.9%) was superior to that of clinicians (3.7%) (P=.02). CONCLUSION: MelaFind is a safe and effective tool to assist in the evaluation of pigmented skin lesions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00434057.

15 Clinical Trial Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis. 2008

Oble, Darryl A / Mino-Kenudson, Mari / Goldsmith, Jeffrey / Hodi, F Stephen / Seliem, Rania M / Dranoff, Glenn / Mihm, Martin / Hasserjian, Robert / Lauwers, Gregory Y. ·Department of Pathology, Massachusetts General Hospital, Boston, MA 02114-2696, USA. ·Am J Surg Pathol · Pubmed #18545145.

ABSTRACT: Monoclonal antibodies (mAbs) against the cytotoxic T lymphocyte antigen-4 (CTLA-4) molecule are used as an adjuvant to experimental tumor immunization protocols in the treatment of malignant melanomas and ovarian cancers. Aside from noted early therapeutic successes, a spectrum of adverse effects, including severe gastroenteritis, has been reported. We report herein our observations of 5 patients who developed severe gastrointestinal toxicity affecting the gastric, small intestinal, and colonic mucosa. The endoscopic findings were variable, ranging from normal to diffusely erythematous and ulcerated mucosa. The constant histologic findings included a lymphoplasmacytic expansion of the lamina propria with increase in intraepithelial lymphocytes. Increased epithelial apoptosis was also a distinctive feature. Cryptitis and glandular inflammation were observed in the colon, ileum, and stomach, whereas villous blunting was present in the ileal and duodenal mucosa. Immunohistochemical analysis revealed a marked increase of all T-cell subsets (CD3+, CD4+, and CD8+) and of CD4CD25 regulatory T cells. We conclude that the panenteritis associated with injection of alpha-CTLA-4 mAbs demonstrates histology resembling autoimmune enteropathy. Furthermore, although the pathogenesis of immune dysregulation after the infusion of alpha-CTLA-4 mAbs remains unclear, we suspect that the increased number of regulatory T cells in the gastrointestinal mucosa may play a role in the pathogenicity.

16 Clinical Trial Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. 2008

Hodi, F Stephen / Butler, Marcus / Oble, Darryl A / Seiden, Michael V / Haluska, Frank G / Kruse, Andrea / Macrae, Suzanne / Nelson, Marybeth / Canning, Christine / Lowy, Israel / Korman, Alan / Lautz, David / Russell, Sara / Jaklitsch, Michael T / Ramaiya, Nikhil / Chen, Teresa C / Neuberg, Donna / Allison, James P / Mihm, Martin C / Dranoff, Glenn. ·Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. stephen_hodi@dfci.harvard.edu ·Proc Natl Acad Sci U S A · Pubmed #18287062.

ABSTRACT: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as a negative regulator of endogenous and vaccine-induced antitumor immunity. The administration of fully human anti-CTLA-4 blocking monoclonal antibodies to advanced-cancer patients increases immune-mediated tumor destruction in some subjects. Nonetheless, patients that respond also frequently manifest serious inflammatory pathologies, raising the possibility that the therapeutic and toxic effects of CTLA-4 blockade might be linked. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. The application of this sequential immunotherapy to advanced ovarian carcinoma patients also revealed that tumor destruction and severe inflammatory pathology could be dissociated, although further refinements are required to increase clinical responses and to minimize toxicity in this population. The extent of therapy-induced tumor necrosis was linearly related to the natural logarithm of the ratio of intratumoral CD8(+) effector T cells to FoxP3(+) regulatory T cells (Tregs) in posttreatment biopsies. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy.

17 Article New insights into naevoid melanomas: a clinicopathological reassessment. 2017

Cook, Martin G / Massi, Daniela / Blokx, Willeke A M / Van den Oord, Joost / Koljenović, Senada / De Giorgi, Vincenzo / Kissin, Eleanor / Grant, Megan / Mandal, Amit / Gremel, Gabriela / Gaudy, Caroline / Viros, Amaya / Dhomen, Nathalie / Khosrotehrani, Kiarash / Marais, Richard / Green, Adele C / Mihm, Martin C. ·Histopathology, Royal Surrey County Hospital, Guildford, UK. · Molecular Oncology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK. · Division of Clinical Medicine, University of Surrey, Guildford, Surrey, UK. · Members of EORTC Melanoma Group Pathology Working Group, Florence, Italy. · Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. · Department of Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands. · Translational Cell and Tissue Research, Department of Imaging and Pathology, University of Leuven (KU Leuven), Leuven, Belgium. · Department of Pathology, Erasmus University Medical Centre, Rotterdam, the Netherlands. · Department of Dermatology, University of Florence, Florence, Italy. · Eleanor Kissin, Department of Plastic Surgery, St George's Hospital, London, UK. · Department of Dermatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia. · The University of Queensland, UQ Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · Brigham and Women's Hospital, Boston, MA, USA. ·Histopathology · Pubmed #28741688.

ABSTRACT: AIMS: Because the term 'naevoid melanoma' has variable clinical and pathological interpretations, we aimed to clarify the features of melanomas referred to as naevoid. METHODS AND RESULTS: A review was undertaken of 102 melanomas diagnosed histopathologically as naevoid melanomas and ascertained by European Organization for Research and Treatment of Cancer Melanoma Group Subcommittee pathologists from their records. We found these could be classified morphologically into three groups. Thirteen melanomas were overlying genuine naevi and were therefore excluded. Of the 89 melanomas considered to be naevoid, 11 presented clinically as exophytic papillomatous nodules with little junctional component and composed of small atypical cells showing numerous mitoses and no change with depth; we termed these 'papillomatous naevoid' melanomas. The other 78 were flat or only slightly raised, and had a superficial spreading melanoma-like component with maturation to a small cell, but still an atypical, dermal component; we termed these 'maturing naevoid' melanomas. We showed that papillomatous and maturing naevoid melanomas also have differing immunochemical profiles. Preliminary clinical follow-up suggested different outcomes for these two naevoid melanoma types. CONCLUSIONS: Melanomas that have been classified as naevoid melanomas comprise two types with distinct clinical, histopathological and immunohistochemical features that may also be prognostically significant.

18 Article The correlation of the standard 5 probe FISH assay with melanocytic tumors of uncertain malignant potential. 2017

Muhlbauer, Aaron / Momtahen, Shabnam / Mihm, Martin C / Wang, James / Magro, Cynthia M. ·Department of Pathology, Loyola University Medical Center, Maywood, IL, USA. · Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. · Department of Pathology, Brigham and Women's Cancer Center, Harvard Medical School, USA. · Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. Electronic address: cym2003@med.cornell.edu. ·Ann Diagn Pathol · Pubmed #28648937.

ABSTRACT: BACKGROUND: FISH has recently emerged as a technique to better assess the malignant potential of histologically ambiguous melanocytic lesions. However, the usefulness of FISH has not been conclusively established. The purpose of this study was to further explore the diagnostic value of FISH in distinguishing the borderline melanocytic tumor (BMT) from melanoma. METHOD: 73 cases with BMT were analyzed retrospectively from a dermatopathology database between 2010-2015. FISH studies were conducted in each case using probes targeting 5 loci including CCND1 on 11q13, RREB1 on 6p25, MYB on 6q23, CDKN2A on 9p21, and CEP 6 control probe for chromosome 6. RESULTS: The study was composed of 50 females and 23 males with an age range of 1-73 and a mean age of 35years. Of the 6 cases in the superficial atypical Spitz tumor (AST) category, 2 had indeterminate results due to polyploidy. In the conventional atypical Spitz tumor cases, FISH was positive in 3 of 15 cases. Of the 27 cases in the borderline nevoid tumor (BNM) category, 3 showed positive FISH and 3 were equivocal due to the possibility of polyploidy. 3 of 13 cases of the borderline tumor of deep penetrating nevus variant (B-DPN) were positive for FISH. Neither of the 2 pigmented epithelioid melanocytoma (PEM) cases had positive FISH result. Of the 4 cases in the superficial atypical dermoepidermal nevomelanocytic proliferation group, only 1 met the FISH diagnostic criteria for melanoma. None of the 6 borderline tumors with overlapping features met FISH criteria diagnostic of melanoma. Clinical follow up was available on 55 patients. None of the patients had recurrence nor died of the disease. Lymph node biopsy was performed on five patients without evidence of metastasis. CONCLUSION: Despite the benefits of FISH, it is limited by the fact that melanomas are not genetically identical whereby certain genetic abnormalities are only seen in specific subtypes. Additionally, FISH only targets specific chromosomes resulting in limitations in sensitivity and specificity. Although FISH has proven to be highly sensitive and specific in distinguishing unequivocally benign from malignant lesions, in cases of histopathological ambiguity, these parameters cannot be assessed with great confidence because the histopathological diagnosis (gold standard) is not without uncertainty. The 4-probe set (excluding 9p21) consistently showed chromosomal aberrations throughout all groups, but only 10 of the 73 total cases (13%) met the diagnostic criteria for melanoma. Moreover, it would be wise to establish new cytogenetic reference values that incorporate these borderline lesions in an effort to better assess the possibility of malignant behavior and or define a cytogenetic profile supportive of its categorization as an indeterminate proliferation. Polyploidy is another inherent limitation, which leads to false positives due to the absolute signal counts incorrectly reflecting relative imbalances in the tumor genome.

19 Article 5-Hydroxymethylcytosine is a nuclear biomarker to assess biological potential in histologically ambiguous heavily pigmented melanocytic neoplasms. 2017

Lee, Jonathan J / Vilain, Ricardo E / Granter, Scott R / Hu, Nina R / Bresler, Scott C / Xu, Shuyun / Frank, Alexander H / Mihm, Martin C / Saw, Robyn P M / Fletcher, Christopher D / Scolyer, Richard A / Murphy, George F / Lian, Christine G. ·Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Melanoma Institute Australia, North Sydney, Australia. · Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. · Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Discipline of Surgery, Royal Prince Alfred Hospital, Sydney, NSW, Australia. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. ·J Cutan Pathol · Pubmed #28032662.

ABSTRACT: BACKGROUND: 5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker detectable through immunohistochemistry (IHC) that has been shown to distinguish benign nevi from melanoma with high sensitivity and specificity. The purpose of the study was to explore its diagnostic utility in a subset of histologically challenging, heavily pigmented cutaneous melanocytic neoplasms. METHODS: 5-hmC IHC was performed on 54 heavily pigmented melanocytic tumors. Semi-quantitative analysis of immunoreactivity was correlated with clinical, pathologic and follow-up data. RESULTS: Benign melanocytic neoplasms (4 of 4 blue nevi with epithelioid change; 12 of 12 combined nevi; 5 of 5 deep penetrating nevi, DPN) exhibited strong 5-hmC nuclear reactivity. Eight heavily pigmented blue nevus-like melanomas and 7 of 8 pigmented epithelioid melanocytomas (PEM) showed significant 5-hmC loss. Five of 7 atypical DPN cases and 8 of 10 melanocytic tumors of uncertain malignant potential (MELTUMP) showed low to intermediate 5-hmC immunoreactivity. These differences were statistically significant (P-value <.0001). CONCLUSIONS: Loss of 5-hmC may be helpful in differentiating benign, diagnostically challenging, heavily pigmented melanocytic tumors from those with malignant potential. The intermediate to low 5-hmC immunoreactivity in atypical DPNs, PEMs and so-called MELTUMP categories further underscores the need to consider these neoplasms as having some potential for lethal biological behavior.

20 Article Neuropeptide Y expression in primary cutaneous melanoma. 2017

Pérez Tato, B / Juarranz, Á / Nájera, L / Mihm, M C / Fernández, P / Gilaberte, Y / González, S. ·Dermatology Service, Mostoles University Hospital, Madrid, Spain. · Department of Biology, Faculty of Sciences, Autonomous University of Madrid, Madrid, Spain. · Pathology Service, Puerta de Hierro University Hospital, Madrid, Spain. · Dermatology Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Dermatology Service, San Jorge Hospital, Huesca, Spain. · Department of Medicine and Medical Specialities, Alcalá University, Madrid, Spain. · Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. ·J Eur Acad Dermatol Venereol · Pubmed #27427400.

ABSTRACT: BACKGROUND: Neuropeptide Y (NPY) is involved in the carcinogenesis of different tumours, especially neural crest-derived tumours. OBJECTIVE: The aim of our study is to investigate the expression of NPY on melanoma and its relation with prognostic histological parameters and survival. METHODS: This is a retrospective observational study of two independent series, with a total of 79 primary melanomas, diagnosed in two independent University Hospitals in Spain, from January 2000 to December 2004. RESULTS: We found a significant higher expression of NPY on superficial spreading melanoma and lentigo maligna (40%) (P = 0.030). Thinner tumours were associated with higher NPY expression (Clark level, P = 0.003; Breslow level, P = 0.012). Melanomas with low NPY expression were associated with intense cell proliferation (Ki-67, P = 0.034), high density of peritumoral mast cell infiltrates (P = 0.033) and low E-cadherin expression (P = 0.031). Melanomas with high NPY expression exhibited significant differences in terms of relapse time (median: 114 vs. 68 months, P = 0.008) and overall survival (114 vs. 74 months, P = 0.004). CONCLUSION: High expression of NPY was associated with better prognostic histological parameters, low peritumoral mast cells density, presence of adhesion proteins and better outcome.

21 Article Lethal melanoma in children: a clinicopathological study of 12 cases. 2016

Prieto-Granada, Carlos N / Lezcano, Cecilia / Scolyer, Richard A / Mihm, Martin C / Piris, Adriano. ·Department of Pathology and Dermatology, Moffitt Cancer Center/University of South Florida, Tampa, FL, United States. Electronic address: Carlos.prietogranada@gmail.com. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. · Melanoma Institute Australia, North Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. · Dermatology Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States. ·Pathology · Pubmed #27956274.

ABSTRACT: Melanoma in children is rare, representing 3% of paediatric malignancies and <1% of all melanomas. Very few detailed descriptions of bona fide lethal childhood melanomas exist in the literature. We performed a retrospective clinicopathological review of 12 paediatric (≤16 years) melanoma patients who died of metastatic disease, including detailed assessment of architectural and cytomorphological features. There were nine prepubertal patients (median age 7 years old) and three postpubertal cases (median age 15 years old). The patients died on average 45.7 months after diagnosis with the prepubertal subcohort showing a relatively longer time from diagnosis to death. The tumours were bulky (average tumour thickness=10mm), showed brisk mitotic activity (average mitotic count per mm

22 Article Evaluation of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) classification scheme for diagnosis of cutaneous melanocytic neoplasms: Results from the International Melanoma Pathology Study Group. 2016

Lott, Jason P / Elmore, Joann G / Zhao, Ge A / Knezevich, Stevan R / Frederick, Paul D / Reisch, Lisa M / Chu, Emily Y / Cook, Martin G / Duncan, Lyn M / Elenitsas, Rosalie / Gerami, Pedram / Landman, Gilles / Lowe, Lori / Messina, Jane L / Mihm, Martin C / van den Oord, Joost J / Rabkin, Michael S / Schmidt, Birgitta / Shea, Christopher R / Yun, Sook Jung / Xu, George X / Piepkorn, Michael W / Elder, David E / Barnhill, Raymond L / Anonymous2520868. ·Cornell Scott-Hill Health Center, New Haven, Connecticut. · Department of Internal Medicine, University of Washington School of Medicine, Seattle, Washington. Electronic address: jelmore@u.washington.edu. · Division of Dermatology, University of Washington School of Medicine, Seattle, Washington. · Pathology Associates, Clovis, California. · Department of Internal Medicine, University of Washington School of Medicine, Seattle, Washington. · Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. · University of Surrey Division of Clinical Medicine, Surrey, United Kingdom. · Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. · Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. · Department of Pathology, Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, Brazil. · Department of Pathology and Dermatology, University of Michigan Hospital and Health Systems, Ann Arbor, Michigan. · Departments of Anatomic Pathology and Cutaneous Oncology, Moffitt Center, and Department of Pathology and Cell Biology, University of South Florida Morsani College of Medicine, Tampa, Florida. · Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Pathology, University Hospitals Katholieke Universiteit Leuven, Leuven, Belgium. · Rabkin Dermatopathology Laboratory PC, Tarentum, Pennsylvania. · Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. · Section of Dermatology, University of Chicago Medicine, Chicago, Illinois. · Department of Dermatology, Chonnam National University School of Medicine, Gwangju, Korea. · Department of Pathology and Lab Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. · Department of Pathology, Institut Curie and Faculty of Medicine, University of Paris Descartes, Paris, France. ·J Am Acad Dermatol · Pubmed #27189823.

ABSTRACT: BACKGROUND: Pathologists use diverse terminology when interpreting melanocytic neoplasms, potentially compromising quality of care. OBJECTIVE: We sought to evaluate the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) scheme, a 5-category classification system for melanocytic lesions. METHODS: Participants (n = 16) of the 2013 International Melanoma Pathology Study Group Workshop provided independent case-level diagnoses and treatment suggestions for 48 melanocytic lesions. Individual diagnoses (including, when necessary, least and most severe diagnoses) were mapped to corresponding MPATH-Dx classes. Interrater agreement and correlation between MPATH-Dx categorization and treatment suggestions were evaluated. RESULTS: Most participants were board-certified dermatopathologists (n = 15), age 50 years or older (n = 12), male (n = 9), based in the United States (n = 11), and primary academic faculty (n = 14). Overall, participants generated 634 case-level diagnoses with treatment suggestions. Mean weighted kappa coefficients for diagnostic agreement after MPATH-Dx mapping (assuming least and most severe diagnoses, when necessary) were 0.70 (95% confidence interval 0.68-0.71) and 0.72 (95% confidence interval 0.71-0.73), respectively, whereas correlation between MPATH-Dx categorization and treatment suggestions was 0.91. LIMITATIONS: This was a small sample size of experienced pathologists in a testing situation. CONCLUSION: Varying diagnostic nomenclature can be classified into a concise hierarchy using the MPATH-Dx scheme. Further research is needed to determine whether this classification system can facilitate diagnostic concordance in general pathology practice and improve patient care.

23 Article Decreased tumor-infiltrating lymphocytes in nodular melanomas compared with matched superficial spreading melanomas. 2016

Lin, Richard L / Wang, Thomas J / Joyce, Cara J / Mihm, Martin C / Murphy, George F / Lian, Christine G / Lin, Jennifer Y. ·aHarvard Medical School bMihm Cutaneous Pathology Consultative Service cProgram in Dermatopathology, Department of Pathology dDepartment of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts eDepartment of Biostatistics, Tulane University, New Orleans, Louisiana, USA. ·Melanoma Res · Pubmed #26974966.

ABSTRACT: Melanoma causes over 9000 deaths annually in the USA. Among its subtypes, nodular melanoma leads to a disproportionate number of fatalities compared with superficial spreading melanoma, the most common subtype. Recent breakthroughs in melanoma research have indicated a strong connection between melanoma virulence and the immune system. We hypothesize that the aggression of nodular melanoma may, in part, be because of decreased recognition by the immune system, as represented by a decreased presence of tumor-infiltrating lymphocytes (TILs), compared with its superficial spreading counterpart. Indeed, TILs on a primary melanoma have been used as a marker for immune response and have prognostic value for survival and sentinel lymph node status. After matching melanoma cases by age, sex, and Breslow thickness, we found significantly fewer TILs in nodular melanomas than in superficial spreading melanomas. This association was prominent in thin (≤2 mm) melanomas and was no longer significant in thick (>2 mm) melanomas. In addition, this difference in TILs was only present in men and not in women. Our finding suggests that nodular melanomas are more frequently associated with absent TILs, providing an avenue for further investigation into differences in immunogenicity of the primary melanoma and whether they underlie the unique virulence of nodular melanoma.

24 Article Loss of the epigenetic mark, 5-Hydroxymethylcytosine, correlates with small cell/nevoid subpopulations and assists in microstaging of human melanoma. 2015

Lee, Jonathan J / Cook, Martin / Mihm, Martin C / Xu, Shuyun / Zhan, Qian / Wang, Thomas J / Murphy, George F / Lian, Christine G. ·Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Department of Histopathology, Royal Surrey County Hospital, Guildford, United Kingdom. · Cancer Research UK, Manchester Institute, Manchester, United Kingdom. · Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ·Oncotarget · Pubmed #26462027.

ABSTRACT: Melanomas in the vertical growth phase (VGP) not infrequently demonstrate cellular heterogeneity. One commonly encountered subpopulation displays small cell/nevoid morphology. Although its significance remains unknown, such subpopulations may pose diagnostic issues when faced with differentiating such changes from associated nevus or mistaking such regions for nevic maturation (pseudomaturation). That 'loss' of the epigenetic biomarker, 5-hydroxymethylcytosine (5-hmC), is a hallmark for melanoma and correlates with virulence prompted us to explore the diagnostic utility and biological implications of 5-hmC immunohistochemistry (IHC) in melanomas with small cell/nevoid subpopulations. Fifty-two cases were included in this study, including melanomas with small cell/nevoid subpopulations (MSCN) or melanomas with pre-existing nevus (MPEN). Semiquantitative and computer-validated immunohistochemical analyses revealed invariable, uniform loss of 5-hmC in the conventional melanoma component. By contrast, the nevic components in MPEN cases demonstrated strong nuclear immunopositivity. In MSCN cases, there was partial to complete loss of 5-hmC restricted to these nevoid areas. Based on recent data supporting tight correlation between 5-hmC loss and malignancy, our findings indicate a potential 'intermediate' biological nature for small cell/nevoid subpopulations. Because 5-hmC assisted in differentiating such regions from associated nevus, the use of 5-hmC as an adjunct to microstaging in difficult cases showing VGP heterogeneity should be further explored.

25 Article Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. 2015

Kleffel, Sonja / Posch, Christian / Barthel, Steven R / Mueller, Hansgeorg / Schlapbach, Christoph / Guenova, Emmanuella / Elco, Christopher P / Lee, Nayoung / Juneja, Vikram R / Zhan, Qian / Lian, Christine G / Thomi, Rahel / Hoetzenecker, Wolfram / Cozzio, Antonio / Dummer, Reinhard / Mihm, Martin C / Flaherty, Keith T / Frank, Markus H / Murphy, George F / Sharpe, Arlene H / Kupper, Thomas S / Schatton, Tobias. ·Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Dermatology, The Rudolfstiftung Hospital, 1030 Vienna, Austria. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Dermatology, Innsbruck Medical University, 6020 Innsbruck, Austria. · Department of Dermatology, University of Bern, 3010 Bern, Switzerland. · Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA; School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. Electronic address: tschatton@bwh.harvard.edu. ·Cell · Pubmed #26359984.

ABSTRACT: Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy.