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Background: While the prognostic role of tertiary lymphoid structures (TLS) has been well studied in solid cancers, the prevalence and impact of immature precursor lymphoid structures known as lymphoid aggregates (LA) remain unresolved in relation to the disease process. In this study, we examined characteristics and the prognostic utility of LA and TLS status in histological samples from patients with melanoma., Methods: We assessed The Cancer Genomic Atlas-skin cutaneous melanoma digital slides and melanoma specimens from the University of Pittsburgh for the presence of LA and TLS using H&E staining, multiplex immunofluorescence (mIF) and transcriptomic analyses. Cox proportional hazard regression models were used to assess the prognostic value associated with the presence of lymphoid structures in melanomas., Results: A total of 278 evaluable samples were analyzed and split into primary melanomas in skin (N=195) and metastatic melanomas involving skin/subcutaneous/soft tissue sites (N=83). 72% of tumor specimens contained histologically defined LA located in peritumoral (34%), intratumoral (5.6%) or stromal (6.1%) locations, with the remaining samples (54.3%) exhibiting LA in multiple locations. In contrast to LA which tended to form more commonly in primary melanoma samples, TLS with germinal centers predominantly formed in peritumoral (45.2%) or stromal (35.5%) locations in metastatic melanomas (p=0.02), with TLS observed in 11% of all melanoma specimens evaluated. mIF analyses revealed cellular heterogeneity of lymphoid structures, with CD20 + (B) cells present in nodule-shaped and stromal locations where they exhibited a high degree of colocalization with CD4 + and CD8 + T cells. A previously defined 12-chemokine gene expression score was significantly higher in samples with evidence of LA versus none (p<0.001), and samples without LA/TLS were enriched with pigmentation/neural network gene signatures. The presence of LA was significantly associated with tumor-free regional lymph node status (p=0.002). In multivariable analysis, after adjusting for age, sex, sample type, and stage, the presence of LA was associated with improved patient overall survival (OS) (HR=0.52, 95% CI 0.31 to 0.87, p=0.01)., Conclusion: Melanoma frequently contains LA, which tends to form in diverse locations in the tumor microenvironment in association with improved overall survival and tumor-free regional lymph node status in patients with primary disease., Competing Interests: Competing interests: JMK: consultation with Amgen (with Davar and Najjar), Ankyra Therapeutics, Applied Clinical Intelligence, Axio Research, Becker Pharmaceutical Consulting, Bristol Myers Squibb, Cancer Network, Cancer Study Group, Checkmate Pharmaceuticals, CytomX Therapeutics, DermTech, Fenix Group International, Harbour BioMed, Immunocore, iOnctura, Iovance Biotherapeutics, IQVIA, Istari Oncology, Jazz Pharmaceuticals, Lytix Biopharma AS, Magnolia Innovation, Merck, Natera, Novartis Pharmaceuticals, OncoCyte Corporation, OncoSec Medical, PathAI, Pfizer, Piper Sandler & Co., PyrOjas Corporation, Regeneron Pharmaceuticals, Replimune, Scopus BioPharma, SR One Capital Management, Takeda, Valar Labs. JJM is Associate Center Director at Moffitt Cancer Center, has ownership interest in Aleta Biotherapeutics, CG Oncology, Turnstone Biologics, Ankyra Therapeutics, and AffyImmune Therapeutics, and is a paid consultant/paid advisory board member for ONCoPEP, CG Oncology, Turnstone Biologics, Vault Pharma, Ankyra Therapeutics, AffyImmune Therapeutics, UbiVac, Vycellix, and Aleta Biotherapeutics., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Difficulty obtaining a dermatological consultation is an obstacle to the early diagnosis of melanoma. On the one hand, patients survival depends on the lesion thickness at the time of diagnosis. On the other hand, dermatologists treat many patients with benign lesions. Optimizing patient care pathways is a major concern. The aim of the present study was to assess whether the e-mail transmission of photographs of suspected melanoma lesions between general practitioners (GPs) and dermatologists reduces the time to dermatological consultation for patients whose suspicious skin lesions ultimately require resection., Methods: We conducted a cluster-randomized controlled study in primary care involving 51 French GPs between April 2017 and August 2019. A total of 250 patients referred to a dermatologist for a suspected melanoma lesion were included GPs were randomized to either the smartphone arm or the usual care arm. In the smartphone arm, the GPs referred patients to the dermatologist by sending 2 photographs of the suspicious lesion using their smartphone. The dermatologist then had to set up an appointment at an appropriate time. In the usual care arm, GPs referred patients to a dermatologist according to their usual practice. The primary outcome was the time to dermatological consultation for patients whose lesion ultimately required resection., Results: 57 GPs volunteered were randomized (27 to the smartphone arm, and 30 to the usual care arm). A total of 125 patients were included in each arm (mean age: 49.8 years; 53% women) and followed 8 months. Twenty-three dermatologists participated in the study. The time to dermatological consultation for patients whose suspicious skin lesion required resection was 56.5 days in the smartphone arm and 63.7 days in the usual care arm (mean adjusted time reduction: -18.5 days, 95% CI [-74.1;23.5], p = .53)., Conclusions: The e-mail transmission of photographs from GPs to dermatologists did not improve the dermatological management of patients whose suspicious skin lesions ultimately required resection. Further research is needed to validate quality criteria that might be useful for tele-expertise in dermatology., Trial Registration: Registered on ClinicalTrials.gov under reference number NCT03137511 (May 2, 2017)., (© 2024. The Author(s).)

Background: Pediatric melanoma presents with distinct clinical features compared to adult disease., Objective: Characterize risk factors and negative outcomes in pediatric melanoma., Methods: Multicenter retrospective study of patients under 20 years diagnosed with melanoma between January 1, 1995 and June 30, 2015 from 11 academic medical centers., Results: Melanoma was diagnosed in 317 patients, 73% of whom were diagnosed in adolescence (age ≥11). Spitzoid (31%) and superficial spreading (26%) subtypes were most common and 11% of cases arose from congenital nevi. Sentinel lymph node biopsy was performed in 68% of cases and positive in 46%. Fatality was observed in 7% of cases. Adolescent patients with melanoma were more likely to have family history of melanoma (P = .046) compared to controls., Limitations: Retrospective nature, cohort size, control selection, and potential referral bias., Conclusion: Pediatric melanoma has diverse clinical presentations. Better understanding of these cases and outcomes may facilitate improved risk stratification of pediatric melanoma., Competing Interests: Conflicts of interest SH reports honorarium from Elsevier and past consulting for Novan Pharmaceuticals., (Copyright © 2024. Published by Elsevier Inc.)

Melanoma is the leading cause of skin cancer-related death. As prognosis of patients with melanoma remains problematic, identification of new therapeutic targets remains essential. Matricellular proteins are nonstructural extracellular matrix proteins. They are secreted into the tumor microenvironment to coordinate behavior among different cell types, yet their contribution to melanoma is underinvestigated. Examples of matricellular proteins include those comprising the CCN family. The CCN family member, CCN1, is highly proangiogenic. Herein, we show that, in human patients with melanoma, although found in several tumor cell types, CCN1 is highly expressed by a subset of cancer-associated fibroblasts (CAF) in patients with melanoma and this expression correlates positively with expression of proangiogenic genes and progressive disease/resistance to anti-PD1 checkpoint inhibitors. Consistent with these observations, in a syngeneic C57BL6 mouse model of melanoma, loss of CCN1 expression from Col1A2-Cre-, herein identified as "universal," fibroblasts, impaired metastasis of subcutaneously injected B16F10 tumor cells to lung, concomitant with disrupted neovascularization and collagen organization. Disruption of the extracellular matrix in the loss of CCN1 was validated using a novel artificial intelligence-based image analysis platform that revealed significantly decreased phenotypic fibrosis and composite morphometric collagen scores. As drug resistance is linked to matrix deposition and neoangiogenesis, these data suggest that CCN1, due to its multifaceted role, may represent a novel therapeutic target for drug-resistant melanoma. Our data further emphasize the essential role that cancer-associated, (universal) Col1A2-Cre-fibroblasts and extracellular matrix remodeling play in coordinating behavior among different cell types within the tumor microenvironment., Significance: In human patients, the expression of proangiogenic matricellular protein CCN1 in CAFs correlates positively with expression of stroma and angiogenic markers and progressive disease/resistance to checkpoint inhibitor therapy. In an animal model, loss of CCN1 from CAFs impaired metastasis of melanoma cells, neovascularization, and collagen deposition, emphasizing that CAFs coordinate cellular behavior in a tumor microenvironment and that CCN1 may be a novel target., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Competing Interests: Conflicts of interest C Felmingham was supported by a Monash University Research Training Program Scholarship. Y Pan has previously reported for MoleMap Ltd. A Chamberlain was a reporting teledermatologist for MoleMap Ltd from 2009 to 2010. A Chamberlain has honoraria from Proctor & Gamble, Schering-Plough, CSL, Leo-Pharma; a consulting/advisory role for L'Oreal (La Roche Posay); and is on the Speakers Bureau for Novartis, Janssen, HealthCert International, Cancer Council of Victoria, Merck Sharp & Dohme. A Oakley is a diagnosing consultant for MoleMap Ltd; and was involved in another study of the MoleMap AI system (abstract published https://www.iproc.org/themes/1158-9th-world-congress-of-teledermatology-imaging-and-ai-for-skin-diseases-abstracts-2021). S Tucker is a diagnosing consultant for MoleMap Ltd and Dermatology Solutions. A Robinson is a sub-Investigator for Dermira, Galderma, Pfizer, Arcutis, Bristol Myers Squib, Leo Pharma, Argenx, Genesis Care; has had sponsored conference attendance from Lilly, and Janssen was on the steering committee for conference for Novartis; and on the Advisory Board for Lilly. P Foley has received grant support from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, Merck, Novartis, Pfizer, Sanofi, and Sun Pharma; has served as an investigator for AbbVie, Amgen, Arcutis, Argenx, Aslan, AstraZeneca, Boehringer Ingelheim, Botanix, Bristol-Myers Squibb, Celgene, Celtaxsys, CSL, Cutanea, Dermira, Eli Lilly, Evelo, Galderma, Genentech, Geneseq, GlaxoSmithKline, Hexima, Janssen, Kymab, Leo, Merck, MedImmune, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, Reistone, Roche, Sanofi, Sun Pharma, Teva, UCB Pharma, and Valeant; has served on advisory boards for AbbVie, Amgen, Aslan, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galderma, GlaxoSmithKline, Janssen, Leo, Mayne Pharma, Merck, Novartis, Pfizer, Sanofi, Sun Pharma, UCB Pharma, and Valeant; has served as a consultant for Aslan, Bristol-Myers Squibb, Eli Lilly, Galderma, GenesisCare, Hexima, Janssen, Leo Pharma, MedImmune, Mayne Pharma, Novartis, Pfizer, Roche, and UCB Pharma; has received travel grants from AbbVie, Eli Lilly, Galderma, Janssen, Leo Pharma, Merck, Novartis, Pfizer, Roche, Sun Pharma, and Sanofi; and has served as a speaker for or received honoraria from AbbVie, Amgen, Celgene, Eli Lilly, Galderma, GlaxoSmithKline, Janssen, Leo Pharma, Merck, Novartis, Pfizer, Roche, Sanofi, Sun Pharma, and Valeant. A Bowling is a shareholder, founder and consultant to MoleMap Ltd. Z Ge has received personal fees from MoleMap Ltd. M Haskett has received personal fees from MoleMap Ltd and is a shareholder in MoleMap Ltd. V Mar is supported by a National Health and Medical Research Council Early Career Fellowship; and has honoraria from Novartis, Merck, Bristol-Myers-Squibb, Janssen, and Eli Lily; and has had sponsored conference attendance from L'Oreal.

Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs); thus, effective strategies to safely increase itICs are needed. We report that dietary administration of L-fucose induces fucosylation and cell surface enrichment of the major histocompatibility complex (MHC)-II protein HLA-DRB1 in melanoma cells, triggering CD4 + T cell-mediated increases in itICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance and anti-programmed cell death protein 1 (PD1) responder status in patient melanoma specimens, suggesting the potential use of melanoma fucosylation as a strategy for stratifying patients for immunotherapies. Our findings demonstrate that fucosylation is a key mediator of anti-tumor immunity and, importantly, suggest that L-fucose is a powerful agent for safely increasing itICs and immunotherapy efficacy in melanoma., (© 2023. The Author(s).)

Background/objectives: Sequential digital dermoscopic imaging (SDDI) and total body photography (TBP) are recommended as a two-step surveillance method for individuals at high-risk of developing cutaneous melanoma. Dermoscopic features specific to melanoma have been well described, however, dynamic changes on serial imaging are less understood. This study aims to identify and compare dermoscopic features in developing melanomas and benign naevi that underwent SDDI and TBP to understand which dermoscopic features may be associated with a malignant change., Method: Histopathology reports from a private specialist dermatology clinic from January 2007 to December 2019 were reviewed. Histopathologically confirmed melanoma and benign naevi that underwent SDDI and TBP with a minimum follow-up interval of 3 months were included., Results: Eighty-nine melanomas (38.2% invasive, median Breslow thickness 0.35 mm, range: 0.2-1.45 mm) and 48 benign naevi were evaluated by three experienced dermatologists for dermoscopic changes. Features most strongly associated with melanoma included the development of neovascularisation, asymmetry and growth in pigment network, additional colours, shiny white structures, regression, structureless areas and change to a multi-component pattern. The presence of atypical vessels (p = 0.02) and shiny white structures (p = 0.02) were significantly associated with invasive melanoma., Conclusion: Evaluation for certain evolving dermoscopic features in melanocytic lesions monitored by SDDI and TBP is efficient in assisting clinical decision making. SDDI with TBP is an effective tool for early detection of melanoma., (© 2023 The Australasian College of Dermatologists.)

Dermatologists often diagnose or rule out early melanoma by evaluating the follow-up dermoscopic images of skin lesions. However, existing algorithms for early melanoma diagnosis are developed using single time-point images of lesions. Ignoring the temporal, morphological changes of lesions can lead to misdiagnosis in borderline cases. In this study, we propose a framework for automated early melanoma diagnosis using sequential dermoscopic images. To this end, we construct our method in three steps. First, we align sequential dermoscopic images of skin lesions using estimated Euclidean transformations, extract the lesion growth region by computing image differences among the consecutive images, and then propose a spatio-temporal network to capture the dermoscopic changes from aligned lesion images and the corresponding difference images. Finally, we develop an early diagnosis module to compute probability scores of malignancy for lesion images over time. We collected 179 serial dermoscopic imaging data from 122 patients to verify our method. Extensive experiments show that the proposed model outperforms other commonly used sequence models. We also compared the diagnostic results of our model with those of seven experienced dermatologists and five registrars. Our model achieved higher diagnostic accuracy than clinicians (63.69% vs. 54.33%, respectively) and provided an earlier diagnosis of melanoma (60.7% vs. 32.7% of melanoma correctly diagnosed on the first follow-up images). These results demonstrate that our model can be used to identify melanocytic lesions that are at high-risk of malignant transformation earlier in the disease process and thereby redefine what is possible in the early detection of melanoma.

Our purpose was to investigate the prognostic value of 18 F-FDG PET/CT parameters in melanoma patients before beginning therapy with antibodies to the programmed cell death 1 receptor (anti-PD-1). Methods: Imaging parameters including SUV max , metabolic tumor volume, and the ratio of bone marrow to liver SUV mean (BLR) were measured from baseline PET/CT in 92 patients before the start of anti-PD-1 therapy. The association with survival and imaging parameters combined with clinical factors was evaluated. Clinical and laboratory data were compared between the high-BLR group (>median) and the low-BLR group (≤median). Results: Multivariate analyses demonstrated that BLR was an independent prognostic factor for progression-free and overall survival ( P = 0.017 and P = 0.011, respectively). The high-BLR group had higher white blood cell counts and neutrophil counts and a higher level of C-reactive protein than the low-BLR group ( P < 0.05). Conclusion: Patients with a high BLR were associated with poor progression-free and overall survival, potentially explained by evidence of systemic inflammation known to be associated with immunosuppression., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background/objective: Diagnostic tools such as dermoscopy, sequential digital dermoscopy imaging (SDDI), total body photography (TBP) and automated diagnostic tools are available to assist in early melanoma diagnosis. The use, accessibility and barriers of dermoscopy have been well studied; however, there are few similar studies regarding SDDI, TBP and automated diagnostic tools. We aim to understand the use of these diagnostic aids amongst Australian general practitioners (GPs) and dermatologists., Methods: Between June 2019 and January 2020, GPs and dermatologists across Australia were invited to participate in an online survey. Surveys were distributed through GP and dermatology organisations., Results: A total of 227 survey responses were received, 175 from GPs and 52 from dermatologists. Amongst GPs, 44.6% worked in a skin cancer clinic. Dermoscopy was used at least occasionally by 98.9% of all GPs. SDDI was used by 93.6% of skin cancer GPs, 80.8% of dermatologists and 45.3% of generalist GPs. TBP was used or recommended by 77.1% of generalist GPs, 82.3% of skin cancer GPs and 86.5% of dermatologists. The most common barriers to the use of TBP were cost, limited accessibility, poor patient compliance, and time required for both patients and doctors. Very few clinicians reported using automated diagnostic tools. There was an interest in future diagnostic aids for melanoma in 88% of GPs and dermatologists., Conclusion: Dermoscopy, SDDI and TBP were commonly used by responding Australian skin cancer GPs and dermatologists in this survey. Automated diagnostic tools were not reported to be used routinely. Several barriers were identified for use of TBP., (© 2021 The Australasian College of Dermatologists.)

Abstract: We report an unusual case of a 59-year-old man with recurrent right ear melanoma resulting in perineural spread to the right greater auricular nerve. Direct perineural spread to the greater auricular nerve is not commonly reported in melanoma. Our case demonstrates perineural spread along the greater auricular nerve on 18F-FDG PET/CT and MRI. This finding was supported by intraneural invasion noted at the surgical margin of the wide local excision of the right helix melanoma. Resolution of FDG activity and improved MRI appearances of the right greater auricular nerve were seen after immunotherapy treatment., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: We investigated the ability of baseline 2-deoxy-2-[ 18 F]fluoro-D-glucose PET/CT parameters, acquired before the start of immunotherapy, to predict development of hyperprogressive disease (HPD) in melanoma patients. We also evaluated the diagnostic performances of ratios of baseline and first restaging PET/CT parameters to diagnose HPD without information of the tumor growth kinetic ratio (TGKR) that requires pre-baseline imaging before baseline imaging (3 timepoint imaging)., Procedures: Seventy-six patients who underwent PET/CT before and approximately 3 months following initiation of immunotherapy were included. PET/CT parameters, including metabolic tumor volume (MTV) for all melanoma lesions and total measured tumor burden (TMTB) based on irRECIST, were measured from baseline PET/CT (MTV base and TMTB base ) and first restaging PET/CT (MTV post and TMTB post ). The ratios of MTV (MTV post /MTV base , MTVr) and TMTB (TMTB post /TMTB base , TMTBr) were calculated., Results: MTV base of HPD patients (n = 9, TGKR ≥ 2) was larger than that of non-HPD (n = 67, TGKR < 2) patients (P < 0.05), and HPD patients demonstrated shorter median overall survival (7 vs. more than 60 months, P < 0.05). The area under the curve (AUC) of MTV base (≥ 155.5 ml) to predict the risk of HPD was 0.703, with a sensitivity of 66.7 % and specificity of 81.2 %. The AUCs of MTVr (≥ 1.25) and TMTBr (≥ 1.27) to diagnose HPD without information of TGKR were 0.875 and 0.977 with both sensitivities of 100 %, and specificities of 79 % and 83.9 %, respectively., Conclusions: Patients at high risk of developing HPD could not be accurately identified based on baseline PET/CT parameters. The ratios of baseline and first restaging PET/CT parameters may be helpful to diagnose HPD, when patients do not undergo pre-baseline imaging.

Purpose: The purpose of this study was to investigate the prognostic value of whole-body metabolic tumor volume (MTV) and other metabolic tumor parameters, obtained from baseline and first restaging 18 F-FDG PET/CT scans in melanoma patients treated with immune checkpoint inhibitors (ICIs)., Methods: Eighty-five consecutive melanoma patients (M, 57; F, 28) treated with ICIs who underwent PET/CT scans before and approximately 3 months after the start of immunotherapy were retrospectively enrolled. Metabolic tumor parameters including MTV for all melanoma lesions were measured on each scan. A Cox proportional hazards model was used for univariate and multivariate analyses of metabolic parameters combined with known clinical prognostic factors associated with overall survival (OS). Kaplan-Meier curves for patients dichotomized based on median values of imaging parameters were generated., Results: The median OS time in all patients was 45 months (95% CI 24-45 months). Univariate analysis demonstrated that MTV obtained from first restaging PET/CT scans (MTVpost) was the strongest prognostic factor for OS among PET/CT parameters (P < 0.0001). The median OS in patients with high MTVpost (≥ 23.44) was 16 months (95% CI 12-32 months) as compared with more than 60 months in patients with low MTVpost (< 23.44) (P = 0.0003). A multivariate model including PET/CT parameters and known clinical prognostic factors revealed that MTVpost and the presence of central nervous system lesions were independent prognostic factors for OS (P = 0.0004, 0.0167, respectively). One pseudoprogression case (1.2%) was seen in this population and classified into the high MTVpost group., Conclusion: Whole-body metabolic tumor volume from PET scan acquired approximately 3 months following initiation of immunotherapy (MTVpost) is a strong prognostic indicator of OS in melanoma patients. Although the possibility of pseudoprogression must be considered whenever evaluating first restaging PET imaging, it only occurred in 1 patient in our cohort.

Background: Anti-PD1 immunotherapy has shown a sustainable clinical activity in patients with metastatic melanoma. However, strong predictive factors of the long-term response or risk of relapse remain to be identified., Objectives: To determine whether FDG-PET imaging could be superior to CT scan in distinguishing residual tumours versus the absence of tumour in patients with a partial response (PR) or stable disease (SD) and whether a complete metabolic response (CMR) was associated with better outcomes., Methods: Retrospective study conducted in all patients with metastatic melanoma treated with anti-PD1 immunotherapy between October 2014 and October 2017 considered to be in complete remission. The primary outcome was the occurrence of a relapse during the follow-up. CT scan and FDG-PET scan had to be performed within a maximum of 2 months of treatment discontinuation. For CT imaging, the Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 were used and included progressive disease (PD), SD, PR and complete response (CR). For FDG-PET imaging, the metabolic responses were classified as progressive metabolic disease, stable metabolic disease, residual FDG avidity (RFA) and CMR., Results: Twenty-six patients were in complete remission after collegial decision. Two patients had a SD on CT scan and a CMR on FDG-PET scan, and none of them relapsed. Ten patients had a PR on CT scan and a CMR on FDG-PET scan, and none of them relapsed. The mean treatment duration to achieve a complete remission was 7 months (3-23). A univariate analysis showed that a RFA assessed on the FDG-PET scan was significantly associated with a relapse (P = 0.00231)., Conclusions: Most patients with a PR on the CT scan and a CMR on the FDG-PET scan should be considered with a CR. Our study showed that FDG-PET imaging could play a crucial role in predicting the long-term outcome and help to decide whether treatment should be discontinued., (© 2020 European Academy of Dermatology and Venereology.)

Importance: Little evidence exists to guide the management of moderately dysplastic nevi excisionally biopsied without residual clinical pigmentation but with positive histologic margins (hereafter referred to as moderately dysplastic nevi with positive histologic margins)., Objective: To determine outcomes and risk for the development of subsequent cutaneous melanoma (CM) from moderately dysplastic nevi with positive histologic margins observed for 3 years or more., Design, Setting, and Participants: A multicenter (9 US academic dermatology sites) retrospective cohort study was conducted of patients 18 years or older with moderately dysplastic nevi with positive histologic margins and 3 years or more of follow-up data collected consecutively from January 1, 1990, to August 31, 2014. Records were reviewed for patient demographics, biopsy type, pathologic findings, and development of subsequent CM at the biopsy site or elsewhere on the body. The χ2 test, the Fisher exact test, and analysis of variance were used to assess univariate association for risk of subsequent CMs, in addition to multivariable logistic regression models. To confirm histologic grading, each site submitted 5 random representative slide cases for central dermatopathologic review. Statistical analysis was performed from October 1, 2017, to June 22, 2018., Main Outcomes and Measures: Development of CM at a biopsy site or elsewhere on the body where there were moderately dysplastic nevi with positive histologic margins., Results: A total of 467 moderately dysplastic nevi with positive histologic margins from 438 patients (193 women and 245 men; mean [SD] age, 46.7 [16.1] years) were evaluated. No cases developed into CM at biopsy sites, with a mean (SD) follow-up time of 6.9 (3.4) years. However, 100 patients (22.8%) developed a CM at a separate site. Results of multivariate analyses revealed that history of CM was significantly associated with the risk of development of subsequent CM at a separate site (odds ratio, 11.74; 95% CI, 5.71-24.15; P < .001), as were prior biopsied dysplastic nevi (odds ratio, 2.55; 95% CI, 1.23-5.28; P = .01). The results of a central dermatopathologic review revealed agreement in 35 of 40 cases (87.5%). Three of 40 cases (7.5%) were upgraded in degree of atypia; of these, 1 was interpreted as melanoma in situ. That patient remains without recurrence or evidence of CM after 5 years of follow-up., Conclusions and Relevance: This study suggests that close observation with routine skin surveillance is a reasonable management approach for moderately dysplastic nevi with positive histologic margins. However, having 2 or more biopsied dysplastic nevi (with 1 that is a moderately dysplastic nevus) appears to be associated with increased risk for subsequent CM at a separate site.

GATA2 deficiency is a recently described genetic disorder affecting hematopoietic stem cells and is associated with immunodeficiency, hematologic malignancy, and various cutaneous pathologies including cutaneous tumors. To explore the incidence and clinical course of melanoma in patients with germline GATA2 deficiencies, we conducted a retrospective chart review of 71 such patients and identified two with invasive melanoma. One melanoma was diagnosed early because it was associated with pruritus due to a graft-versus-tumor effect following bone marrow transplantation. The other one, a lentigo maligna melanoma, was locally excised but progressed to widespread metastasis and death several years later. Our observations and published studies of melanoma biology suggest an association between decreased GATA2 expression and melanoma progression. These findings suggest that GATA2 deficient patients may have an increased risk of melanoma and should be observed closely for new or changing skin lesions., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA.)

T-cell-mediated immunity has the ability to produce durable antimelanoma responses, resulting in improved survival of patients with advanced melanoma. Antigen presentation is a key determinant of T-cell responses. Gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of multiple melanoma antigens to CD4+ T cells. However, GILT expression in melanoma has not been defined. We evaluated GILT and MHC class II expression in human primary and metastatic melanomas and nevi using immunohistochemical analysis. GILT staining in melanocytes was observed in 70% of primary and 58% of metastatic melanomas versus 0% of nevi. When present, the GILT staining intensity in melanocytes was typically faint. Both GILT and MHC class II expression were increased in melanocytes of primary and metastatic melanomas compared with nevi. GILT staining in antigen-presenting cells (APCs) was detected in 100% of primary and metastatic melanomas versus 31% of nevi, and it was typically intense. GILT expression was increased in APCs of primary and metastatic melanomas compared with nevi, whereas MHC class II had equivalent high expression in APCs of all melanocytic lesions. GILT staining in keratinocytes was detected in 67% of primary melanomas versus 14% of nevi and 6% of metastatic melanomas. GILT, but not MHC class II, expression was increased in keratinocytes of primary melanomas compared with nevi and metastases. GILT expression is anticipated to result in improved presentation of melanoma antigens and more effective antimelanoma T-cell responses. GILT expression may be a biomarker of immune recognition of melanoma.

Unlabelled: Ipilimumab is a monoclonal antibody blocking the inhibitory molecule CTLA4 expressed by activated T lympocytes, used for the treatment of metastatic melanoma. Recent studies have shown its potential efficacy on brain metastases., Objectives: To assess the development of brain metastases under ipilimumab and identify clinical, histological or evolving criteria related to the appearance of these metastases. A retrospective study was conducted in 52 patients treated with 4 cycles of ipilimumab 3 mg/kg every 3 weeks for unresectable stage III or stage IV melanoma between January 2011 and July 2013 in a Department of Dermato-Oncology. As no data has been find in the literature, the results were compared to our other cohort of patients treated with vemurafenib during the same period. Ten patients (21.7 %) developed brain metastases under ipilimumab in a median time of 6.58 months after treatment initiation. The multivariate analysis showed a lower rate of brain metastases in patients with acral lentiginous melanoma and melanoma of unknown primary site. The median survival after diagnosis of brain metastases was of 2.5 months. There was no significant difference with vemurafenib-treated patients in terms of incidence rate of brain metastasis, time of development and survival after diagnosis of cerebral metastases. This was the first study focused on the development of brain metastases under treatment with ipilimumab 3 mg/kg. Although ipilimumab is used for the treatment of brain metastases, it paradoxically did not seem to reduce the risk of developing brain metastases.

The alkylating agent temozolomide (TMZ) represents an important component of current melanoma therapy, but overexpression of O6-methyl-guanine DNA methyltransferase (MGMT) in tumor cells confers resistance to TMZ and impairs therapeutic outcome. We investigated a novel perillyl alcohol (POH)-conjugated analog of TMZ, NEO212, for its ability to exert anticancer activity against MGMT-positive melanoma cells. Human melanoma cells with variable MGMT expression levels were treated with NEO212, TMZ, or perillyl alcohol in vitro and in vivo, and markers of DNA damage and apoptosis, and tumor cell growth were investigated. NEO212 displayed substantially greater anticancer activity than any of the other treatments. It reduced colony formation of MGMT-positive cells up to eight times more effectively than TMZ, and much more potently induced DNA damage and cell death. In a nude mouse tumor model, NEO212 showed significant activity against MGMT-positive melanoma, whereas TMZ, or a mix of TMZ plus POH, was ineffective. At the same time, NEO212 was well tolerated. NEO212 may have potential as a more effective therapy for advanced melanoma, and should become particularly suitable for the treatment of patients with MGMT-positive tumors., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Primary melanoma ulceration is a factor of poor prognosis at the local and regional stage. The physiopathological mechanisms which explain its prognostic impact are still little known. However, two recent studies suggest that it could be a predictive factor of good response to a non-specific immunotherapy (interferon-alpha) and to an active immunotherapy (vaccine)., Objective: The aim of this study was to determine whether ulceration could be a factor of good prognosis in the context of an adoptive immunotherapy with tumour infiltrating lymphocytes (TIL) in stage III regional lymph node metastatic melanoma (sixth American Joint Committee on Cancer staging system) and whether it was associated with an improvement in the effectiveness of this treatment compared with the control group., Methods: We have included all the patients treated in open prospective randomized TIL vs. control protocols in our unit from 1997 to 2009. Clinical data were derived retrospectively from patient files. Statistical analysis was performed using log-rank tests, Cox models and tests for interaction., Results: A total of 144 patients were included. In the group of 80 patients treated with TIL, primary melanoma ulceration remained a pejorative factor for relapse-free and overall survival in univariate and multivariate analysis. The presence of ulceration did not change the effectiveness of TIL treatment in comparison with the control group with regards to relapse-free and overall survival., Conclusion: Our study demonstrates that primary melanoma ulceration does not have any impact on the response to TIL adoptive immunotherapy and thus does not confirm its positive prognostic value suggested by two other immunotherapy approaches., (© 2011 The Authors. Journal of the European Academy of Dermatology and Venereology © 2011 European Academy of Dermatology and Venereology.)

Evidence for the in vitro lymphocyte response against autologous melanoma has been accumulating over the past 10 years, leading to the identification of numerous melanoma-associated antigens recognised by T cells. These antigens are targets for specific immunotherapy protocols. However, their expression is heterogeneous during tumour progression and may contribute to therapeutic escape mechanisms and disease progression. This study was designed to chart the importance of these escape mechanisms, and to assess the relationship between gene expression and the clinical profile (especially survival data) of patients with melanoma. We studied the expression of certain melanoma genes in tissue biopsies from 202 patients using reverse transcriptase-polymerase chain reaction (RT-PCR). The evaluated genes were Melan-A, tyrosinase, Na-17A, MAGE-1, MAGE-3 and Ny-ESO-1. We then correlated the results to the patients' survival data. 202 samples (cutaneous, nodal and visceral biopsies) were analysed by RT-PCR. No relationship was found between clinical data and gene expression. No relationship was found between survival data and gene expression, when samples of all stages were combined in the analysis. However, interactions between gene expression and disease stage were significant. When stage III samples alone were considered, MAGE-3 expression alone or in association with the expression of the other tumour-specific genes was found to be significantly associated with a higher disease-free survival (respectively, P = 0.0349; 0.007). Our results provided no evidence for a relationship between gene expression and clinical data, or between gene expression and survival data. However, with regard to certain sub-groups, such as stage III samples, tumour gene expression was significantly associated with survival.

Immunotherapy by adoptive transfer of autologous tumour-infiltrating lymphocytes (TIL) shows promising clinical results for stage III (lymph nodes metastasis) melanoma patients, but some of them remain unresponsive. Here we analysed retrospectively the impact of resistance of melanoma cells to anti-proliferative cytokines on the clinical outcome of 24 TIL-treated metastatic melanoma patients. Patient relapse-free survival correlated significantly with Oncostatin M (OSM) and/or IL-6 sensitivity of melanoma cells, but not with interferon (IFN) gamma or tumour necrosis factor (TNF) alpha sensitivity. However, OSM/IL-6 sensitivity did not correlate with other known prognostic factors. Moreover, OSM and IL-6 were produced by TIL just before their injection to patients. In immunodeficient mice, OSM reduced human melanoma xenograft tumour growth, this effect being directly through inhibition of tumour cell proliferation rather than induction of apoptosis or necrosis. Thus, OSM/IL-6 resistance of melanoma cells appears to be a new escape mechanism to TIL treatment that could be added to the existing prognostic factors for early stage melanoma patients. This mechanism of action could be also relevant in other immunotherapy protocols, and could lead to better prognosis and anti-cancer treatments.

Oncostatin M (OSM) is an interleukin-6 (IL-6) type cytokine originally described by its capacity to inhibit melanoma proliferation in vitro. Here, the mechanisms involved in resistance to growth inhibition by OSM were analysed for the first time on a large panel of metastatic melanoma cell lines. OSM resistance did not strictly correlate with IL-6, interferon-gamma or tumor necrosis factor-alpha resistance. Rather, it correlated with a specific loss of the OSM receptor-beta (OSMRbeta) subunit, in conjunction with a lower level of histone acetylation in the OSMRbeta promoter region. Treatment of various OSM-resistant melanoma cells with the histone deacetylase inhibitor Trichostatin A increased activity and histone acetylation of the OSMRbeta promoter as well as expression of OSMRbeta mRNA and protein, allowing OSM to activate the signal transducer and activator of transcription 3 (STAT3) and to inhibit proliferation. Other defects associated with OSM resistance were identified at the level of OSMRbeta transcription or protein expression, as well as downstream of or parallel to STAT3 activation. Altogether, our results suggest a role for OSM in the prevention of melanoma progression and that metastatic melanoma cells could escape this growth control by the epigenetic silencing of OSMRbeta.

Oncostatin M (OSM) is an interleukin-6 (IL-6) type cytokine originally described by its capacity to inhibit melanoma proliferation in vitro. Here, the mechanisms involved in resistance to growth inhibition by OSM were analysed for the first time on a large panel of metastatic melanoma cell lines. OSM resistance did not strictly correlate with IL-6, interferon-γ or tumor necrosis factor-α resistance. Rather, it correlated with a specific loss of the OSM receptor-β (OSMRβ) subunit, in conjunction with a lower level of histone acetylation in the OSMRβ promoter region. Treatment of various OSM-resistant melanoma cells with the histone deacetylase inhibitor Trichostatin A increased activity and histone acetylation of the OSMRβ promoter as well as expression of OSMRβ mRNA and protein, allowing OSM to activate the signal transducer and activator of transcription 3 (STAT3) and to inhibit proliferation. Other defects associated with OSM resistance were identified at the level of OSMRβ transcription or protein expression, as well as downstream of or parallel to STAT3 activation. Altogether, our results suggest a role for OSM in the prevention of melanoma progression and that metastatic melanoma cells could escape this growth control by the epigenetic silencing of OSMRβ.Oncogene (2007) 26, 881–892. doi:10.1038/sj.onc.1209844; published online 7 August 2006 [ABSTRACT FROM AUTHOR]