Mapping the Immune Landscape in Metastatic Melanoma Reveals Localized Cell-Cell Interactions That Predict Immunotherapy Response.

Unlabelled: While immune checkpoint-based immunotherapy (ICI) shows promising clinical results in patients with cancer, only a subset of patients responds favorably. Response to ICI is dictated by complex networks of cellular interactions between malignant and nonmalignant cells. Although insights into the mechanisms that modulate the pivotal antitumoral activity of cytotoxic T cells (Tcy) have recently been gained, much of what has been learned is based on single-cell analyses of dissociated tumor samples, resulting in a lack of critical information about the spatial distribution of relevant cell types.

Association of HERV-K and LINE-1 hypomethylation with reduced disease-free survival in melanoma patients.

To evaluate CpG methylation of long interspersed nuclear elements 1 (LINE-1) and human endogenous retrovirus K (HERV-K) retroelements as potential prognostic biomarkers in cutaneous melanoma. Methylation of HERV-K and LINE-1 retroelements was assessed in resected melanoma tissues from 82 patients ranging in age from 14 to 88 years. In addition, nevi from eight patients were included for comparison with nonmalignant melanocytic lesions.

The EMT Transcription Factor ZEB2 Promotes Proliferation of Primary and Metastatic Melanoma While Suppressing an Invasive, Mesenchymal-Like Phenotype.

Epithelial-to-mesenchymal transition (EMT)-inducing transcription factors (TF) are well known for their ability to induce mesenchymal states associated with increased migratory and invasive properties. Unexpectedly, nuclear expression of the EMT-TF ZEB2 in human primary melanoma has been shown to correlate with reduced invasion. We report here that ZEB2 is required for outgrowth for primary melanomas and metastases at secondary sites.

Low expression of pro-apoptotic proteins Bax, Bak and Smac indicates prolonged progression-free survival in chemotherapy-treated metastatic melanoma.

Despite the introduction of novel targeted therapies, chemotherapy still remains the primary treatment for metastatic melanoma in poorly funded healthcare environments or in case of disease relapse, with no reliable molecular markers for progression-free survival (PFS) available. As chemotherapy primarily eliminates cancer cells by apoptosis, we here evaluated if the expression of key apoptosis regulators (Bax, Bak, Bcl-2, Bcl-xL, Smac, Procaspase-9, Apaf-1, Procaspase-3 and XIAP) allows prognosticating PFS in stage III/IV melanoma patients. Following antibody validation, marker expression was determined by automated and manual scoring of immunohistochemically stained tissue microarrays (TMAs) constructed from treatment-naive metastatic melanoma biopsies.

Melanoma susceptibility variant rs869330 in the MTAP gene is associated with melanoma outcome.

The rising incidence of cutaneous melanoma (CM), an aggressive skin cancer, emphasizes the need for novel biomarkers to guide personalized care and better predict outcome. Genetic factors including germline risk variants are promising candidates for this aim. We explored the association between germline risk variants and melanoma outcome in a large genetically homogenous Belgian melanoma population, focusing on single nucleotide polymorphisms which generated the highest association with melanoma susceptibility.

Targeting PDGF-mediated recruitment of pericytes blocks vascular mimicry and tumor growth.

Aggressive tumor cells can adopt an endothelial cell-like phenotype and contribute to the formation of a tumor vasculature, independent of tumor angiogenesis. This adoptive mechanism is referred to as vascular mimicry and it is associated with poor survival in cancer patients. To what extent tumor cells capable of vascular mimicry phenocopy the angiogenic cascade is still poorly explored.

Scleroderma-like cutaneous lesions during treatment with paclitaxel and gemcitabine in a patient with pancreatic adenocarcinoma. Review of literature.

Background: Chemotherapy-induced skin sclerosis is generally not associated with other manifestations of systemic sclerosis. It is featured by skin sclerosis without visceral involvement (i.e.

Mouse Cutaneous Melanoma Induced by Mutant BRaf Arises from Expansion and Dedifferentiation of Mature Pigmented Melanocytes.

To identify the cells at the origin of melanoma, we combined single-cell lineage-tracing and transcriptomics approaches with time-lapse imaging. A mouse model that recapitulates key histopathological features of human melanomagenesis was created by inducing a BRafV600E-driven melanomagenic program in tail interfollicular melanocytes. Most targeted mature, melanin-producing melanocytes expanded clonally within the epidermis before losing their differentiated features through transcriptional reprogramming and eventually invading the dermis.

Response to targeted therapy in two patients with metastatic melanoma carrying rare BRAF exon 15 mutations: A598_T599insV and V600_K601delinsE.

Concurrent BRAF-MEK inhibition improves clinical outcomes in patients with advanced BRAF V600E/K-mutant melanoma. There is currently less evidence for the efficacy of this treatment in patients with rare BRAF non-V600E/K genotypes. We report on two patients with rare BRAF exon 15 mutations - BRAF A598_T599insV and V600_K601delinsE - obtaining clinical benefit and a radiological response to inhibitors directed against the mitogen-activated protein kinase pathway.

Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma.

Background: Cutaneous melanoma is the deadliest skin cancer, with an increasing incidence and mortality rate. Currently, staging of patients with primary melanoma is performed using histological biomarkers such as tumor thickness and ulceration. As disruption of the epigenomic landscape is recognized as a widespread feature inherent in tumor development and progression, we aimed to identify novel biomarkers providing additional clinical information over current factors using unbiased genome-wide DNA methylation analyses.

Immunohistochemical Profiling of Corneas With Fuchs Endothelial Corneal Dystrophy.

Purpose: Fuchs endothelial corneal dystrophy (FECD) is the leading indication for endothelial keratoplasty. Further insight into its pathophysiology is needed to develop alternative therapies.

Methods: Sixteen genes from a previous microarray expression experiment (FECD vs.

Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma.

Identification and functional validation of oncogenic drivers are essential steps toward advancing cancer precision medicine. Here, we have presented a comprehensive analysis of the somatic genomic landscape of the widely used BRAFV600E- and NRASQ61K-driven mouse models of melanoma. By integrating the data with publically available genomic, epigenomic, and transcriptomic information from human clinical samples, we confirmed the importance of several genes and pathways previously implicated in human melanoma, including the tumor-suppressor genes phosphatase and tensin homolog (PTEN), cyclin dependent kinase inhibitor 2A (CDKN2A), LKB1, and others.

Molecular genetic and immunotherapeutic targets in metastatic melanoma.

In recent years, melanoma treatment has radically changed with the emergence of targeted therapies and immunotherapies. Both have led to improved survival for patients with advanced or unresectable melanoma. Targeted therapies with BRAF inhibitors in the lead use the presence of activating driver mutations to inhibit tumour growth.

Identification of a novel species of papillomavirus in giraffe lesions using nanopore sequencing.

Papillomaviridae form a large family of viruses that are known to infect a variety of vertebrates, including mammals, reptiles, birds and fish. Infections usually give rise to minor skin lesions but can in some cases lead to the development of malignant neoplasia. In this study, we identified a novel species of papillomavirus (PV), isolated from warts of four giraffes (Giraffa camelopardalis).

Identification of Circulating Fibrocytes and Dendritic Derivatives in Corneal Endothelium of Patients With Fuchs' Dystrophy.

Purpose: Fuchs' endothelial corneal dystrophy (FECD) is a degenerative eye disorder affecting 4% of Americans older than 40. It is the leading indication for corneal endothelial (CE) transplantation for which there is a global donor shortage. This study aimed to gain further insight into the pathophysiology of FECD and identify targets for nonsurgical therapy.

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.

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.

Plasma cells in primary melanoma. Prognostic significance and possible role of IgA.

Melanoma is not only one of the most immunogenic cancers but also one of the most effective cancers at subverting host immunity. The role of T lymphocytes in tumor immunity has been extensively studied in melanoma, whereas less is known about the importance of B lymphocytes. The effects of plasma cells (PCs), in particular, are still obscure.

Characteristics of Skin Lesions Associated With Anti-Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease: A Cohort Study.

Background: A subgroup of patients with inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) antibodies develop skin lesions, but the lesions and their clinical course are not well-characterized.

Objective: To describe patients treated with anti-TNF antibodies who did and did not develop skin lesions.

Design: Retrospective cohort.

Novel Therapies for Metastatic Melanoma: An Update on Their Use in Older Patients.

Cutaneous melanoma is the most aggressive form of skin cancer. With age as a risk factor, melanoma is projected to become a substantial healthcare burden. The clinical course of melanoma in older patients is different from that in middle-aged and younger patients: melanomas are thicker, have higher mitotic rates and are more likely to be ulcerated.

First-in-Human Proof-of-Concept Study: Intralesional Administration of BQ788, an Endothelin Receptor B Antagonist, to Melanoma Skin Metastases.

Background: This first-in-human proof-of-concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients.

Methods: Three patients received a single intralesional BQ788 application of 3 mg. After 3-7 days, the lesions were measured and removed for analysis.