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Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumor and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC) was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. The diagnosis of melanoma can be made clinically and shall always be confirmed with dermatoscopy. If a melanoma is suspected, a histopathological examination is always required. Sequential digital dermatoscopy and full body photography can be used in high-risk patients to improve the detection of early melanoma. Where available, confocal reflectance microscopy can also improve clinical diagnosis in special cases. Melanoma shall be classified according to the 8th version of the American Joint Committee on Cancer classification. Thin melanomas up to 0.8 mm tumor thickness do not require further imaging diagnostics. From stage IB onwards, examinations with lymph node sonography are recommended, but no further imaging examinations. From stage IIC onwards whole-body examinations with computed tomography (CT) or positron emission tomography CT (PET-CT) in combination with brain magnetic resonance imaging are recommended. From stage III and higher, mutation testing is recommended, particularly for BRAF V600 mutation. It is important to provide a structured follow-up to detect relapses and secondary primary melanomas as early as possible. There is no evidence to define the frequency and extent of examinations. A stage-based follow-up scheme is proposed which, according to the experience of the guideline group, covers the optimal requirements, but further studies may be considered. This guideline is valid until the end of 2024.

Introduction Immune checkpoint inhibitors (ICIs) have become an important part of the treatment of multiple cancers, especially for advanced melanoma and non-small cell lung cancer. Some tumors are capable of escaping immunosurveillance by stimulating checkpoints on T-cells. ICIs prevent activation of these checkpoints and thereby stimulate the immune system and indirectly the anti-tumor response. However, the use of ICIs is associated with various adverse events. Ocular side effects are rare but may have a major impact on the quality of life of the patient. Methods A comprehensive literature search of the medical databases Web of Science, Embase and PubMed was performed. Articles that provided a comprehensive description of a case report containing 1) cancer patient(s) treated with (a combination of) immune checkpoint inhibitors, and 2) assessed occurrence of ocular adverse events, were included. A total of 290 case reports were included. Results Melanoma (n = 179; 61.7%) and lung cancer (n = 56; 19.3%) were the most frequent reported malignancies. The primary used ICIs were nivolumab (n = 123; 42.5%) and ipilimumab (n = 116; 40.0%). Uveitis was most the common adverse event (n = 134; 46.2%) and mainly related to melanoma. Neuro-ophthalmic disorders, including myasthenia gravis and cranial nerve disorders, were the second most common adverse events (n = 71; 24.5%), mainly related to lung cancer. Adverse events affecting the orbit and the cornea were reported in 33 (11.4%) and 30 cases (10.3%) respectively. Adverse events concerning the retina were reported in 26 cases (9.0%). Conclusion The aim of this paper is to provide an overview of all reported ocular adverse events related to the use of ICIs. The insights retrieved from this review might contribute to a better understanding of the underlying mechanisms of these ocular adverse events. Particularly, the difference between actual immune-related adverse events and paraneoplastic syndromes might be relevant. These findings might be of great value in establishing guidelines on how to manage ocular adverse events related to ICIs.

BACKGROUND: Checkpoint inhibitors have been shown to substantially improve the survival of patients with advanced melanoma. With this growing group of survivors treated with immunotherapies, assessing their health-state utilities is essential and can be used for the calculation of quality-adjusted life years and for cost-effectiveness analyses. Therefore, we evaluated the health-state utilities in long-term advanced melanoma survivors.METHODS: Health-state utilities were evaluated in a cohort of advanced melanoma survivors 24-36 months (N = 37) and 36-plus months (N = 47) post-ipilimumab monotherapy. In addition, the health-state utilities of the 24-36 months survivor group were assessed longitudinally, and utilities of the combined survival groups (N = 84) were compared with a matched control population (N = 168). The EQ-5D was used to generate health-state utility values, and quality-of-life questionnaires were used to establish correlations and influencing factors of utility scores.RESULTS: Health-state utility scores were similar between the 24-36 months'- and the 36-plus months' survival group (0.81 vs 0.86; p = .22). In survivors, lower utility scores were associated with symptoms of depression (β = - .82, p = .022) and fatigue burden (β = - .29, p = .007). Utility scores did not significantly change after 24-36 months of survival, and the utilities of survivors were comparable to the matched control population (0.84 vs 0.87; p = .07).DISCUSSION: Our results show that long-term advanced melanoma survivors treated with ipilimumab monotherapy experience relatively stable and high health-state utility scores.

Skin cancer deaths continue to rise despite the implementation of numerous preventive campaigns and programs. The aim of this systematic review was to evaluate reviews of primary and secondary skin cancer prevention strategies as reported over the past 10 years. We analyzed 63 systematic reviews and meta-analyses: 30 (46.6%) addressing primary interventions and 35 (55.6%) addressing secondary interventions. Two of the reviews covered both. The most widely reported primary prevention approaches were education programs (63.3%), followed by risk modeling to identify individuals at high risk for melanoma (17.6%), and the promotion of sunscreen use (11.8%). The most widely reported secondary prevention measures concerned imaging systems for early skin cancer detection (40%), smartphones and new technologies (22.9%), and visual diagnosis in population-based screening (17.4%). The most effective measures were primary prevention education programs to improve sun protection habits. (C) 2022 AEDV. Published by Elsevier Espana, S.L.U.

International audience; Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumor and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC) was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. The diagnosis of melanoma can be made clinically and shall always be confirmed with dermatoscopy. If a melanoma is suspected, a histopathological examination is always required. Sequential digital dermatoscopy and full body photography can be used in high-risk patients to improve the detection of early melanoma. Where available, confocal reflectance microscopy can also improve clinical diagnosis in special cases. Melanoma shall be classified according to the 8th version of the American Joint Committee on Cancer classification. Thin melanomas up to 0.8 mm tumor thickness do not require further imaging diagnostics. From stage IB onwards, examinations with lymph node sonography are recommended, but no further imaging examinations. From stage IIC onwards whole-body examinations with computed tomography (CT) or positron emission tomography CT (PET-CT) in combination with brain magnetic resonance imaging are recommended. From stage III and higher, mutation testing is recommended, particularly for BRAF V600 mutation. It is important to provide a structured follow-up to detect relapses and secondary primary melanomas as early as possible. There is no evidence to define the frequency and extent of examinations. A stage-based follow-up scheme is proposed which, according to the experience of the guideline group, covers the optimal requirements, but further studies may be considered. This guideline is valid until the end of 2024.

Introduction: The Standardized Uptake Value (SUV) in single lesions on F-18-FDG PET/CT scans and serum S-100B concentrations are inversely associated with disease-free survival in stage IV melanoma. The aim of this study was to assess the association between biomarkers (S-100B, LDH) and the PET-derived metrics SUVmean/max, metabolic active tumor volume (MATV), and total lesion glycolysis (TLG) in stage IV melanoma in order to understand what these biomarkers reflect and their possible utility for follow-up.Methods: In 52 stage IV patients the association between PET-derived metrics and the biomarkers S-100B and LDH was assessed and the impact on survival analyzed.Results: S-100B was elevated (>0.15 mu g/l) in 37 patients (71%), LDH in 11 (21%). There was a correlation between S-100B and LDH (R-2 = 0.19). S-100B was correlated to both MATV (R-2 = 0.375) and TLG (R-2 = 0.352), but LDH was not. Higher MATV and TLG levels were found in patients with elevated S-100B (p 250 U/l) (p Conclusion: In newly diagnosed stage IV melanoma patients S-100B correlates with F-18-FDG PET/CT derived MATV and TLG in contrast to LDH, is more often elevated than LDH (71% vs. 21%) and seems to be a better predictor of disease load and disease progression. However, elevated LDH is the only predictor for survival. The biomarkers, S-100B and LDH appear to describe different aspects of the extent of metastatic disease and of tumornecrosis. (C) 2020 The Authors. Published by Elsevier Ltd.

Background: Sentinel lymph node (SLN) biopsy remains crucial for melanoma staging. The European Organisation for Research and Treatment of Cancer Melanoma Group recommends performing immunohistochemical stainings for reproducible identification of melanoma metastases. S100 protein (pS100) is a commonly used melanocytic antigen because of its high sensitivity in spite of relatively low specificity. SRY-related HMG-box 10 protein (SOX10) is a transcription factor characterising neural crest-derived cells. It is uniformly expressed mostly in the nuclei of melanocytes, neural, and myoepithelial cells. Pathologists sometimes prefer SOX10 as a melanoma marker, but it has not yet been investigated on a large-scale to confirm that it is reliable and recommendable for routine SLN evaluation. Methods: Four hundred one treatment-naïve lymph node (LN) metastatic melanomas were included in high-density tissue microarrays and were assessed for the presence of SOX10 and pS100 by immunohistochemistry. The slides were digitalised, shared and evaluated by a panel of experienced melanoma pathologists. Results: The vast majority of melanomas were double-positive for pS100 and SOX10 (93.2%); a small percentage of the cases (3.9%) were double-negative melanomas. Discordance between the two markers was observed: 1.9% pS100(−)/SOX10(+) and 0.75% pS100(+)/SOX10(−). SOX10 was not expressed by immune cell types in the LN, resulting in a less controversial interpretation of the staining. Conclusions: SOX10 is as equally specific as pS100 for the detection of melanoma metastases in LNs. The interpretation of SOX10 staining is highly reproducible among different centres and different pathologists because of the absence of staining of immune cells.

BACKGROUND The use of intralesional Mycobacterium bovis BCG (intralesional live BCG) for the treatment of metastatic melanoma resulted in regression of directly injected, and occasionally of distal lesions. However, intralesional-BCG is less effective in patients with visceral metastases and did not significantly improve overall survival. METHODS We generated a novel BCG lysate and developed it into a thermosensitive PLGA-PEG-PLGA hydrogel (BCG hydrogel), which was injected adjacent to the tumor to assess its antitumor effect in syngeneic tumor models (B16F10, MC38). The effect of BCG hydrogel treatment on contralateral tumors, lung metastases, and survival was assessed to evaluate systemic long-term efficacy. Gene expression profiles of tumor-infiltrating immune cells and of tumor-draining lymph nodes from BCG hydrogel-treated mice were analyzed by single-cell RNA sequencing (scRNA-seq) and CD8+ T cell receptor (TCR) repertoire diversity was assessed by TCR-sequencing. To confirm the mechanistic findings, RNA-seq data of biopsies obtained from in-transit cutaneous metastases of patients with melanoma who had received intralesional-BCG therapy were analyzed. RESULTS Here, we show that BCG lysate exhibits enhanced antitumor efficacy compared to live mycobacteria and promotes a proinflammatory tumor microenvironment and M1 macrophage (MΦ) polarization in vivo. The underlying mechanisms of BCG lysate-mediated tumor immunity are dependent on MΦ and dendritic cells (DCs). BCG hydrogel treatment induced systemic immunity in melanoma-bearing mice with suppression of lung metastases and improved survival. Furthermore, BCG hydrogel promoted cathepsin S (CTSS) activity in MΦ and DCs, resulting in enhanced antigen processing and presentation of tumor-associated antigens. Finally, BCG hydrogel treatment was associated with increased frequencies of melanoma-reactive CD8+ T cells. In human patients with melanoma, intralesional-BCG treatment was associated with enhanced M1 MΦ, mature DC, antigen processing and presentation, as well as with increased CTSS expression which positively correlated with patient survival. CONCLUSIONS These findings provide mechanistic insights as well as rationale for the clinical translation of BCG hydrogel as cancer immunotherapy to overcome the current limitations of immunotherapies for the treatment of patients with melanoma.

Simple Summary Clear cell sarcoma (CCSA) is a rare subtype of soft tissue sarcoma characterized by EWSR1 rearrangement and subsequent MET upregulation. The European Organisation for Research and Treatment of Cancer 90101 phase II trial evaluated the MET inhibitor crizotinib in CCSA but resulted in only sporadic responses. The aim of this exploratory study was to identify the molecular alterations potentially relevant for the treatment outcome by using archival CCSA samples and trial-related clinical data. We characterized MET signaling and revealed an infrequent activation of MET, which may explain the lack of response to crizotinib in the disease cohort. Based on sequencing analyses, we discovered copy number alterations, mutations and dysregulated pathways with potentially predictive or prognostic values for patients’ outcomes. This work describes the molecular heterogeneity in CCSA and provides deep insight into the biology of this ultra-rare malignancy, which may potentially lead to better therapeutic approaches. Abstract Clear cell sarcoma (CCSA) is characterized by a chromosomal translocation leading to EWSR1 rearrangement, resulting in aberrant transcription of multiple genes, including MET. The EORTC 90101 phase II trial evaluated the MET inhibitor crizotinib in CCSA but resulted in only sporadic responses. We performed an in-depth histopathological and molecular analysis of archival CCSA samples to identify alterations potentially relevant for the treatment outcome. Immunohistochemical characterization of MET signaling was performed using a tissue microarray constructed from 32 CCSA cases. The DNA from 24 available tumor specimens was analyzed by low-coverage whole-genome sequencing and whole-exome sequencing for the detection of recurrent copy number alterations (CNAs) and mutations. A pathway enrichment analysis was performed to identify the pathways relevant for CCSA tumorigenesis. Kaplan–Meier estimates and Fisher’s exact test were used to correlate the molecular findings with the clinical features related to crizotinib treatment, aiming to assess a potential association with the outcomes. The histopathological analysis showed the absence of a MET ligand and MET activation, with the presence of MET itself in most of cases. However, the expression/activation of MET downstream molecules was frequently observed, suggesting the role of other receptors in CCSA signal transduction. Using sequencing, we detected a number of CNAs at the chromosomal arm and region levels. The most common alteration was a gain of 8q24.21, observed in 83% of the cases. The loss of chromosomes 9q and 12q24 was associated with shorter survival. Based on exome sequencing, 40 cancer-associated genes were found to be mutated in more than one sample, with SRGAP3 and KMT2D as the most common alterations (each in four cases). The mutated genes encoded proteins were mainly involved in receptor tyrosine kinase signaling, polymerase-II transcription, DNA damage repair, SUMOylation and chromatin organization. Disruption in chromatin organization was correlated with longer progression-free survival in patients receiving crizotinib. Conclusions: The infrequent activation of MET may explain the lack of response to crizotinib observed in the majority of cases in the clinical trial. Our work describes the molecular heterogeneity in CCSA and provides further insight into the biology of this ultra-rare malignancy, which may potentially lead to better therapeutic approaches for CCSA.

Objective To describe a case of complete spontaneous regression of a middle ear melanoma. Patient We present a case of a 68-year-old man with complaints of unilateral hearing loss and an ipsilateral facial nerve paresis. Radiological and histopathological examination revealed a cT4bN0M0 mucosal melanoma of the middle ear. Interventions The patient underwent a subtotal petrosectomy and postoperative radiotherapy. Main outcome measure Computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography/computed tomography with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG-PET-CT), and histopathological examination. Results After subtotal petrosectomy, histopathological examination of the resection specimen showed only fibrosis and a histiocytic and clonal T-cell infiltration, but no residual melanoma at the primary tumor site, consistent with spontaneous tumor regression. Follow-up MRI scanning 6 and 12 months after radiotherapy showed no signs of tumor recurrence. Conclusions This case describes the concept of spontaneous regression of a mucosal melanoma of the middle ear. Spontaneous tumor regression at this location has not been described before.

Contains fulltext : 238889.pdf (Publisher’s version ) (Open Access) EWSR1 belongs to the FET family of RNA-binding proteins including also Fused in Sarcoma (FUS), and TATA-box binding protein Associated Factor 15 (TAF15). As consequence of the multifunctional role of EWSR1 leading to a high frequency of transcription of the chromosomal region where the gene is located, EWSR1 is exposed to aberrations such as rearrangements. Consecutive binding to other genes leads to chimeric proteins inducing oncogenesis. The other TET family members are homologous. With the advent of widely used modern molecular techniques during the last decades, it has become obvious that EWSR1 is involved in the development of diverse benign and malignant tumors with mesenchymal, neuroectodermal, and epithelial/myoepithelial features. As oncogenic transformation mediated by EWSR1-fusion proteins leads to such diverse tumor types, there must be a selection on the multipotent stem cell level. In this review, we will focus on the wide variety of soft tissue and bone entities, including benign and malignant lesions, harboring EWSR1 rearrangement. Fusion gene analysis is the diagnostic gold standard in most of these tumors. We present clinicopathologic, immunohistochemical, and molecular features and discuss differential diagnoses.

Background: Anorectal melanoma is a rare malignancy with a dismal prognosis. The purpose of this study was to investigate whether the survival per stage is influenced by the surgical approaches (local excision or extensive resection), to assess prognostic factors of survival, and to answer the question whether the practiced surgical approaches changed over time.Methods: Dutch cancer registry organizations (IKNL and PALGA) were queried for all patients with a diagnosis of anorectal melanoma (1989-2019). Patients with disseminated disease at diagnosis were excluded. Survival outcomes were compared for the two surgical approaches stratified by stage (clinical node negative (cN0) and clinical node positive (cN+)) and date of diagnosis.Results: A total of 103 patients were included in this study. In both cN0 and cN+ patients the surgical strategy did not significantly influence survival (cN0: 21.7% 5-year survival, median 25 months for local excision versus 13.7% 5-year survival, median 17 months for extensive resection (p = 0.228), cN+: 11.1% 5-year survival for local excision, median 17 months versus 8.7% 5-year survival, median 14 months for extensive resection (p = 0.741)). Stage and date of diagnosis showed to be prognostic factors of survival. The ratio between the two surgical approaches was unchanged over three decades.Conclusions: Extensive resection does not seem to improve survival in both cN0 and cN+ anorectal melanoma patients compared to local excision. However in the past three decades no shift towards local excision has been found. cN+ stage and an older date of diagnosis are predictors for worse survival.

Supplemental Digital Content is available in the text., The molecular properties of benign melanocytic lesions are poorly understood. Only a few studies have been carried out on specific nevi subtypes, including common nevocellular nevi (NCN) or Spitz nevi (SN). Genomic alterations in melanoma-associated oncogenes are typically absent in SN. In the present study, mRNA expressions of 25 SN and 15 NCN were analyzed. Molecular profiling was performed using the RNA NanoString nCounter Gene Expression Platform (number of genes=770). Marker discovery was performed with a training set consisting of seven SN and seven NCN samples from the same patients, and validation was performed using a second set consisting of 18 SN and eight NCN samples. Using the training set, 197 differentially expressed genes were identified in SN versus NCN. Of these, 74 genes were validated in the validation set (false discovery rate q≤0.13). In addition, using random forest and least absolute shrinkage and selection operator feature selection, a molecular signature of SN versus NCN was identified including 15 top-ranked genes. The present study identified a distinct molecular expression profile in SN compared with NCN, even when lesions were obtained from the same patients. Gene set analysis showed upregulation of gene pathways with increased expression of transcripts related to immunomodulatory, inflammatory, and extracellular matrix interactions as well as angiogenesis-associated processes in SN. These findings strongly indicate that SN represent a distinct group of melanocytic neoplasms and evolve differentially and not sequentially from NCN.

[Abstract Not Available] WOS:000598746300001 2-s2.0-85097569487 PubMed: 33301211

BACKGROUND: Psychological stress is commonly cited as a risk factor for melanoma, but clinical evidence is limited. OBJECTIVES: This study aimed to evaluate the association between partner bereavement and (i) first-time melanoma diagnosis and (ii) mortality in patients with melanoma. METHODS: We conducted two cohort studies using data from the U.K. Clinical Practice Research Datalink (1997-2017) and Danish nationwide registries (1997-2016). In study 1, we compared the risk of first melanoma diagnosis in bereaved vs. matched nonbereaved people using stratified Cox regression. In study 2 we estimated hazard ratios (HRs) for death from melanoma in bereaved compared with nonbereaved individuals with melanoma using Cox regression. We estimated HRs separately for the U.K. and for Denmark, and then pooled the data to perform a random-effects meta-analysis. RESULTS: In study 1, the pooled adjusted HR for the association between partner bereavement and melanoma diagnosis was 0·88 [95% confidence interval (CI) 0·84-0·92] across the entire follow-up period. In study 2, we observed increased melanoma-specific mortality in people experiencing partner bereavement across the entire follow-up period (HR 1·17, 95% CI 1·06-1·30), with the peak occurring during the first year of follow-up (HR 1·31, 95% CI 1·07-1·60). CONCLUSIONS: We found decreased risk of melanoma diagnosis, but increased mortality associated with partner bereavement. These findings may be partly explained by delayed detection resulting from the loss of a partner who could notice skin changes. Stress may play a role in melanoma progression. Our findings indicate the need for a low threshold for skin examination in individuals whose partners have died. What is already known about this topic? Psychological stress has been proposed as a risk factor for the development and progression of cancer, including melanoma, but evidence is conflicting. Clinical evidence is limited by small sample sizes, potential recall bias associated with self-report, and heterogeneous stress definitions. What does this study add? We found a decreased risk of melanoma diagnosis, but increased mortality associated with partner bereavement. While stress might play a role in the progression of melanoma, an alternative explanation is that bereaved people no longer have a close person to help notice skin changes, leading to delayed melanoma detection. Linked Comment: Talaganis et al. Br J Dermatol 2020; 183:607-608.

BACKGROUND: Obesity is associated with metabolic abnormalities that predispose patients to increased cancer risk. Contemporary data on the long-term risk of specific cancers are sparse among patients with hospital-diagnosed overweight and obesity.OBJECTIVES: To examine the overall cancer incidence and specific site-related cancer incidences among patients with overweight and obesity, compared to the general Danish population.METHODS: For this 40-year (1977-2016), nationwide, Danish cohort study, we reviewed medical databases to identify individuals with hospital-based overweight and obesity diagnoses. We computed age- and gender-standardized incidence ratios (SIRs) for subsequent cancer compared to the general population.RESULTS: We observed 20 706 cancers among 313 321 patients diagnosed with overweight and obesity (median age 43 years; median follow-up 6.7 years, range 1-40 years) compared to the 18 480 cancers expected; thus, the SIR was 1.12 [95% confidence interval (95% CI): 1.11-1.14]. The SIR associated with overweight and obesity was increased with concomitant comorbidities, like type 2 diabetes (SIR: 1.18; 95% CI: 1.13-1.23) and alcoholism-related diseases (SIR: 1.62; 95% CI: 1.45-1.82). The SIR was 1.31 (95% CI: 1.28-1.34) for cancers previously identified as obesity-related, including pancreatic (SIR: 1.38; 95% CI; 1.27-1.49) and postmenopausal breast cancer (SIR: 1.14; 95% CI: 1.09-1.19). Obesity/overweight status also elevated the SIRs for haematological (SIR: 1.24; 95% CI: 1.18-1.29) and neurological cancers (SIR: 1.19; 95% CI: 1.11-1.27]. In contrast, SIRs were 1.01 (95% CI: 0.97-1.05) for immune-related cancers, 0.88 (95% CI: 0.82-0.95) for malignant melanoma, and 0.88 (95% CI: 0.85-0.92) for hormone-related cancers, other than postmenopausal breast cancer.CONCLUSION: In this large cohort study, overweight and obesity was associated with increased risk of several common cancers.

Purpose To evaluate the consistency of hepatic ultrasonography (US) with staging computed tomography (CT) and magnetic resonance imaging (MRI), to analyze why US was inconsistent with CT/MRI, and to compare CT/MRI. Design Reliability analysis. Methods Two hundred fifteen patients whose primary uveal melanoma was managed in the Helsinki University Hospital and who were diagnosed with hepatic metastases by US within 60 days of staging CT/MRI from January 1999 to December 2016 were included. Patients attended a real-life follow-up schedule including hepatic US, liver function tests (LFT), and a confirmatory CT/MRI. We evaluated the consistency of US with staging CT/MRI regarding the presence and number of metastases. Results The enrolled patients underwent 215 US, 167 CT, and 69 MRI examinations, and 67% of them had biopsy-confirmed metastases. Screening was regular for 98% of the patients, and 66% were asymptomatic. US was fully consistent with CT/MRI in detecting metastases in 113 (53%) patients, in 63 (29%) CT/MRI showed more metastases, and in 16 (7%) CT/MRI showed fewer metastases than US. CT/MRI was inconsistent with US in 23 (11%) patients. The sensitivity of US in detecting metastases was 96% (95% confidence interval, 92-98). US failed to suggest metastases in 10 patients. LFT were abnormal in 6 of them, and a newly detected hepatic lesion was present by US in 4. Conclusions Hepatic US is a sensitive screening modality in detecting metastases in patients with primary uveal melanoma, if combined with LFT and, in case of any newly detected lesion, a confirmatory MRI.

Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma.Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Background: In recent years there has been a plea to abandon the pelvic lymph node dissection in the treatment of patients with metastatic melanoma to the groin. A trend towards a conservative surgical treatment is already evolving in several European countries. The purpose of this study is to identify factors associated with pelvic nodal involvement, in order to improve selection of patients whom might benefit from a pelvic nodal dissection.Methods: A retrospective analysis was performed on prospectively collected data concerning patients who underwent an inguinal lymph node dissection (ILND) with pelvic lymph node dissection for metastatic melanoma at the University Medical Center Groningen. Multivariable logistic regression analysis was performed to determine factors associated with pelvic nodal involvement. Diagnostic accuracy was calculated for F-18-FDG PET + contrast enhanced CT-scan and F-18-FDG PET + low dose CT-scan.Results: Two-hundred-and-twenty-six ILND's were performed in 223 patients. The most common histologic subtype was superficial spreading melanoma (42.6%). In patients with micrometastatic disease, 15.7% had pelvic nodal involvement vs 28.2% in patients with macrometastatic disease (p: 0.030). None of the characteristics known prior to the ILND, were associated with pelvic nodal involvement. Imaging methods were unable to accurately predict pelvic nodal involvement. Negative predictive value was 78% for F-18-FDG PET + low dose CT-scan and 86% for an F-18-FDG PET + contrast enhanced CT-scan.Conclusion: There are no patient- or tumor characteristics available that can predict pelvic nodal involvement in patients with melanoma metastasis to the groin. As no imaging technique is able to predict pelvic nodal involvement it seems unjust to abandon the pelvic lymph node dissection. (C) 2018 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Sun exposure is a major environmental risk factor for skin cancers and is also an important source of vitamin D. However, while experimental evidence suggests that vitamin D may have a protective effect on skin cancer risk, epidemiologic studies investigating the influence of 25-hydroxyvitamin D (25(OH)D) level and/or vitamin D intake on skin cancer risk are conflicting. A systematic review and dose–response meta-analyses of prospective studies was conducted to clarify these associations. Relevant studies were identified by searching the PubMed database up to 30th August 2019. Random effects dose–response meta-analyses were used to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs). Overall, thirteen prospective studies were included. Circulating level of 25(OH)D was associated with higher risks of melanoma (SRR (95% CI) per 30 nmol = 1.42 (1.17–1.72)) and keratinocyte cancer (KC) (SRR (95% CI) per 30 nmol/L = 1.30 (1.13–1.49)). The SRR (95% CI) per 30 nmol/L increase in 25(OH) D level was 1.41 (1.19–1.67), and 1.57 (0.64–3.86), for basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), respectively. However, while we found that vitamin D intake (from diet, supplemental and total) was not associated with risks of melanoma and SCC, vitamin D intake was associated with slightly increased BCC risk, albeit with no heterogeneity across skin cancer type. This meta-analysis suggests positive associations between circulating 25(OH)D level and risk of melanoma and KC, however, this finding is most likely confounded by sun exposure. We found no associations between vitamin D intake skin cancers, except positive associations with BCC risk.

BACKGROUND: The development of brain metastases is common for systemic treatment failure in patients with melanoma and has been associated with a poor prognosis. Recent advances with BRAF and immune checkpoint therapies have led to improved patient survival. Herein, the authors evaluated the risk of de novo brain metastases and survival among patients with melanoma brain metastases (MBM) since the introduction of more effective therapies. METHODS: Patients with unresectable AJCC stage III/IV melanoma who received first-line systemic therapy at Moffitt Cancer Center between 2000 and 2012 were identified. Data were collected regarding patient characteristics, stage of disease, systemic therapies, MBM status/management, and overall survival (OS). The risk of de novo MBM was calculated using a generalized estimating equation model and survival comparisons were performed using Kaplan-Meier and Cox proportional analyses. RESULTS: A total of 610 patients were included, 243 of whom were diagnosed with MBM (40%). Patients with MBM were younger, with a lower frequency of regional metastasis. No significant differences were noted with regard to sex, BRAF status, or therapeutic class. The risk of de novo MBM was found to be similar among patients treated with chemotherapy, biochemotherapy, BRAF-targeted therapy, ipilimumab, and anti-programmed cell death protein 1/programmed death-ligand 1 regimens. The median OS of patients with MBM was significantly shorter when determined from the time of first regional/distant metastasis but not when determined from the time of first systemic therapy. The median OS from the time of MBM diagnosis was 7.5 months, 8.5 months, and 22.7 months, respectively, for patients diagnosed from 2000 to 2008, 2009 to 2010, and 2011 to the time of last follow-up (P5.002). CONCLUSIONS: Brain metastases remain a common source of systemic treatment failure. The OS for patients with MBM has improved significantly. Further research into MBM prevention is needed. (C) 2017 American Cancer Society.

BACKGROUND: The development of brain metastases is common for systemic treatment failure in patients with melanoma and has been associated with a poor prognosis. Recent advances with BRAF and immune checkpoint therapies have led to improved patient survival. Herein, the authors evaluated the risk of de novo brain metastases and survival among patients with melanoma brain metastases (MBM) since the introduction of more effective therapies. METHODS: Patients with unresectable AJCC stage III/IV melanoma who received first-line systemic therapy at Moffitt Cancer Center between 2000 and 2012 were identified. Data were collected regarding patient characteristics, stage of disease, systemic therapies, MBM status/management, and overall survival (OS). The risk of de novo MBM was calculated using a generalized estimating equation model and survival comparisons were performed using Kaplan-Meier and Cox proportional analyses. RESULTS: A total of 610 patients were included, 243 of whom were diagnosed with MBM (40%). Patients with MBM were younger, with a lower frequency of regional metastasis. No significant differences were noted with regard to sex, BRAF status, or therapeutic class. The risk of de novo MBM was found to be similar among patients treated with chemotherapy, biochemotherapy, BRAF-targeted therapy, ipilimumab, and anti-programmed cell death protein 1/programmed death-ligand 1 regimens. The median OS of patients with MBM was significantly shorter when determined from the time of first regional/distant metastasis but not when determined from the time of first systemic therapy. The median OS from the time of MBM diagnosis was 7.5 months, 8.5 months, and 22.7 months, respectively, for patients diagnosed from 2000 to 2008, 2009 to 2010, and 2011 to the time of last follow-up (P5.002). CONCLUSIONS: Brain metastases remain a common source of systemic treatment failure. The OS for patients with MBM has improved significantly. Further research into MBM prevention is needed. (C) 2017 American Cancer Society.

Background The optimal extent of groin completion lymph node dissection (CLND) (inguinal or ilioinguinal dissection) in patients with melanoma is controversial. The aim of this study was to evaluate whether the extent of groin CLND after a positive sentinel node biopsy (SNB) is associated with improved outcome. Methods Data from all sentinel node‐positive patients who underwent groin CLND at four tertiary melanoma referral centres were retrieved retrospectively. Baseline patient and tumour characteristics were collected for descriptive statistics, survival analyses and Cox proportional hazards regression analyses. Results In total, 255 patients were included, of whom 137 (53·7 per cent) underwent inguinal dissection and 118 (46·3 per cent) ilioinguinal dissection. The overall CLND positivity rate was 18·8 per cent; the inguinal positivity rate was 15·5 per cent and the pelvic positivity rate was 9·3 per cent. The pattern of recurrence, and 5‐year melanoma‐specific survival, disease‐free survival and distant‐metastasis free survival rates were similar for both dissection types, even for patients with a positive CLND result. Cox regression analysis showed that type of CLND was not associated with disease‐free or melanoma‐specific survival. Conclusion There was no significant difference in recurrence pattern and survival rates between patients undergoing inguinal or ilioinguinal dissection after a positive SNB, even after stratification for a positive CLND result. An inguinal dissection is a safe first approach as CLND in patients with a positive SNB., Inguinal is enough

TERT (telomerase reverse transcriptase) is the catalytic component of telomerase. TERT shows little expression in normal somatic cells but is commonly re-expressed in cancers, facilitating immortalization. Recently-discovered TERT promoter mutations create binding sites for ETS-family transcription factors to upregulate TERT. ETS1 is reported to be important for TERT upregulation in melanoma. However it is unclear when in melanoma progression TERT and ETS1 proteins are expressed. To elucidate this question, ETS1 and TERT immunohistochemistry were performed on a panel of benign (n=27) and dysplastic nevi (n=34), radial growth phase (n=29), vertical growth phase (n=25) and metastatic melanomas (n=27). Lesions were scored by percentage of positive cells. ETS1 was readily detectable in all lesions, but not in normal melanocytes. TERT was located in either the nucleolus, the nucleoplasm (non-nucleolar) or both. Non-nucleolar TERT increased in prevalence with progression, from 19% of benign nevi to 78% of metastases. It did not however correlate with cell proliferation (Ki-67 immunostaining), nor differ significantly in prevalence between primary melanomas with or without a TERT promoter mutation. These results demonstrate that ETS1 is expressed very early in melanoma progression, and interestingly only non-nucleolar TERT correlates clearly in prevalence with melanoma progression. It can be acquired at various stages and by mechanisms other than promoter mutations.

TERT (telomerase reverse transcriptase) is the catalytic component of telomerase. TERT shows little expression in normal somatic cells but is commonly re-expressed in cancers, facilitating immortalization. Recently-discovered TERT promoter mutations create binding sites for ETS-family transcription factors to upregulate TERT. ETS1 is reported to be important for TERT upregulation in melanoma. However it is unclear when in melanoma progression TERT and ETS1 proteins are expressed. To elucidate this question, ETS1 and TERT immunohistochemistry were performed on a panel of benign (n=27) and dysplastic nevi (n=34), radial growth phase (n=29), vertical growth phase (n=25) and metastatic melanomas (n=27). Lesions were scored by percentage of positive cells. ETS1 was readily detectable in all lesions, but not in normal melanocytes. TERT was located in either the nucleolus, the nucleoplasm (non-nucleolar) or both. Non-nucleolar TERT increased in prevalence with progression, from 19% of benign nevi to 78% of metastases. It did not however correlate with cell proliferation (Ki-67 immunostaining), nor differ significantly in prevalence between primary melanomas with or without a TERT promoter mutation. These results demonstrate that ETS1 is expressed very early in melanoma progression, and interestingly only non-nucleolar TERT correlates clearly in prevalence with melanoma progression. It can be acquired at various stages and by mechanisms other than promoter mutations.

BACKGROUND: Hypothetically, delay between melanoma diagnosis and SLNB could affect outcomes, either adversely by allowing growth and dissemination of metastases, or beneficially by allowing development of an anti-melanoma immune response. Available data are conflicting about the effect of SLNB delay on patient survival. Our objective was to determine whether delay between initial diagnosis and SLNB affects outcomes in patients with cutaneous melanoma.STUDY DESIGN: We performed query and analysis of a large prospectively maintained database of patients with primary cutaneous melanomas undergoing SLNB. An independent dataset from MSLT-1 (Multicenter Selective Lymphadenectomy Trial-1) was used for validation. Primary outcomes included disease-free survival and melanoma-specific survival.RESULTS: Early and delayed SLNB were defined as less than 30 and 30 or more days from initial diagnosis, respectively. There were 2,483 patients that met inclusion criteria. Positive sentinel lymph nodes were identified in 17.4% (n = 432). Among all patients, 42% had SLNB 30 or more days after diagnosis and 37% of positive sentinel lymph nodes were at 30 or more days. No differences in sex, anatomic site, or histopathologic features were identified between the 2 groups. There was no difference in melanoma-specific survival or diseasefree survival between those undergoing early or delayed SLNB. Examination of MSLT-1 trial data similarly demonstrated no difference in survival outcomes.CONCLUSIONS: This, the largest study on this subject to date, found no adverse impact on long-term clinical outcomes of patients due to delay of SLNB beyond 30 days. The MSLT-1 data confirm this result. Patients can be reassured that if the operation is performed 30 or more days after diagnosis, it will not cause harm. (C) 2017 Published by Elsevier Inc. on behalf of the American College of Surgeons.

Background. Although a well-established causative relationship exists between smoking and several epithelial cancers, the association of smoking with metastatic progression in melanoma is not well studied. We hypothesized that smokers would be at increased risk for melanoma metastasis as assessed by sentinel lymph node (SLN) biopsy.Methods. Data from the first international Multicenter Selective Lymphadenectomy Trial (MSLT-I) and the screening-phase of the second trial (MSLT-II) were analyzed to determine the association of smoking with clinicopathologic variables and SLN metastasis.Results. Current smoking was strongly associated with SLN metastasis (p = 0.004), even after adjusting for other predictors of metastasis. Among 4231 patients (1025 in MSLT-I and 3206 in MSLT-II), current or former smoking was also independently associated with ulceration (p Conclusion. The direct correlation between current smoking and SLN metastasis of primary cutaneous melanoma was independent of its correlation with tumor thickness and ulceration. Smoking cessation should be strongly encouraged among patients with or at risk for 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. Methods We performed a comprehensive DNA methylation analysis during all progression stages of melanoma using Infinium HumanMethylation450 BeadChips on a discovery cohort of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites, integrating the DNA methylome with gene expression data. We validated the discovered biomarkers in three independent validation cohorts by pyrosequencing and immunohistochemistry. Results We identified and validated biomarkers for, and pathways involved in, melanoma development (e.g., HOXA9 DNA methylation) and tumor progression (e.g., TBC1D16 DNA methylation). In addition, we determined a prognostic signature with potential clinical applicability and validated PON3 DNA methylation and OVOL1 protein expression as biomarkers with prognostic information independent of tumor thickness and ulceration. Conclusions Our data underscores the importance of epigenomic regulation in triggering metastatic dissemination through the inactivation of central cancer-related pathways. Inactivation of cell-adhesion and differentiation unleashes dissemination, and subsequent activation of inflammatory and immune system programs impairs anti-tumoral defense pathways. Moreover, we identify several markers of tumor development and progression previously unrelated to melanoma, and determined a prognostic signature with potential clinical utility. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0851-3) contains supplementary material, which is available to authorized users.

Background Inguinal lymph node dissection (ILND) for stage 3 melanoma is accompanied by high wound complication rates. During the past decades, several changes in perioperative care have been instituted to decrease the incidence of these complications. This study aimed to evaluate the effect of these different care protocols on wound complications after ILND. Methods A retrospective analysis of prospectively collected data was performed with 240 patients who underwent an ILND in the University Medical Center Groningen between 1989 and 2014. Four groups with different treatment protocols were analyzed: A (≥10 days of bed rest with a Bohler Braun splint), B (10 days of bed rest without a splint), C (5 days of bed rest), and D (1 day of bed rest). The effect of early mobilization, abolishment of the Bohler Braun splint and postural restrictions, and the introduction of prophylactic antibiotics were analyzed. Results One or more wound complications occurred in 51.2 % of the patients including wound infection (29.8 %), seroma (21.5 %), wound necrosis (13.6 %), and hematoma (5 %). In consecutive periods, respectively 44.4, 60.3, 44.9 and 55.2 % of the patients experienced wound complications. None of the instituted changes in protocols led to a decrease in wound complications. Conclusion Changes in perioperative care protocols did not affect the rate of wound complications. Perhaps a change in the surgical procedure itself can lead to the necessary reduction of wound complications after ILND.

This case series assesses whether the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual can be used to accurately estimate mortality rates of conjunctival melanoma. Key PointsQuestionCan the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual for conjunctival melanoma be used to accurately estimate metastasis and mortality rates? FindingsIn this case series of 288 patients, there was a significantly higher cumulative mortality rate among patients with cT2 and cT3 conjunctival melanoma compared with those presenting with cT1 conjunctival melanoma. MeaningHigher T-staged tumors were associated with both an earlier and greater incidence of metastasis; therefore, the results from this multicenter, international registry study support the use of the eighth edition AJCC staging system for conjunctival melanoma. ImportanceEye cancer staging systems used for standardizing patient care and research need to be validated. ObjectiveTo evaluate the accuracy of the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual in estimating metastatis and mortality rates of conjunctival melanoma. Design, Setting, and ParticipantsThis international, multicenter, registry-based case series pooled data from 10 ophthalmic oncology centers from 9 countries on 4 continents. A total of 288 patients diagnosed with conjunctival melanoma from January 1, 2001, to December 31, 2013, were studied. Data analysis was performed from July 7, 2018, to September 11, 2018. InterventionsTreatments included excision biopsy, cryotherapy, topical chemotherapy, radiation therapy, enucleation, and exenteration. Main Outcomes and MeasuresMetastasis rates and 5-year and 10-year Kaplan-Meier mortality rates according to the clinical T categories and subcategories of the eighth edition of the AJCC Cancer Staging Manual. ResultsA total of 288 eyes from 288 patients (mean [SD] age, 59.7 [16.8] years; 147 [51.0%] male) with conjunctival melanoma were studied. Clinical primary tumors (cT) were staged at presentation as cT1 in 218 patients (75.7%), cT2 in 34 (11.8%), cT3 in 15 (5.2%), and cTx in 21 (7.3%). There were no T4 tumors. Pathological T categories (pT) were pTis in 43 patients (14.9%), pT1 in 169 (58.7%), pT2 in 33 (11.5%), pT3 in 12 (4.2%), and pTx in 31 (10.8%). Metastasis at presentation was seen in 5 patients (1.7%). Metastasis during follow-up developed in 24 patients (8.5%) after a median time of 4.3 years (interquartile range, 2.9-6.0 years). Of the 288 patients, 29 died (melanoma-related mortality, 10.1%) at a median time of 5.3 years (interquartile range, 1.8-7.0 years). The cumulative rates of mortality among patients with cT1 tumors were 0% at 1 year, 2.5% (95% CI, 0.7%-7.7%) at 5 years, and 15.2% (95% CI, 8.1%-27.4%) at 10 years of follow-up; among patients with cT2 tumors, 0% at 1 year, 28.6% (95% CI, 12.9%-58.4%) at 5 years, and 43.6% (95% CI, 19.6%-77.9%) at 10 years of follow-up; and among patients with cT3 tumors, 21.1% (95% CI, 8.1%-52.7%) at 1 year of follow-up and 31.6% (95% CI, 13.5%-64.9%) at 5 years of follow-up. Patients with cT2 and cT3 tumors had a significantly higher cumulative mortality rate compared with those presenting with cT1 tumors (log-rank P

Background: Mitotic rate is a strong predictor of outcome in adult patients with primary cutaneous melanoma, but for children and adolescent patients this is unknown. Objective: We sought to assess the prognostic value of primary tumor mitotic rate in children and adolescents with primary melanoma. Methods: This was a cohort study of 156 patients who were 2 in 104 patients (67%) and correlated with increasing Breslow thickness. A positive sentinel node was found in 23 of 61 patients (38%) in whom a sentinel lymph node biopsy specimen was obtained. The median follow-up was 61 months. Five-year melanoma-specific and recurrence-free survival rates were 91% and 84%, respectively. Mitotic rate was a stronger predictor of outcome than tumor thickness and was the only factor independently associated with recurrence-free survival. Limitations: This research was conducted at a single institution and the sample size was small. Conclusion: Mitotic rate is an independent predictor of recurrence-free survival in children and adolescents with clinically localized melanoma.

This is the peer reviewed version of the following article: Støer, N.C., Botteri, E., Ghiasvand, R., Busund, M., Vangen, S., Lund, E. ... Weiderpass, E. (2019. Reproductive factors and risk of melanoma: a population-based cohort study. British Journal of Dermatology, 181(2), 282-289, which has been published in final form at https://doi.org/10.1111/bjd.17771. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Background - The association between reproductive factors and risk of cutaneous melanoma (CM) is unclear. We investigated this issue in the Norwegian Women and Cancer cohort study. Objectives - To examine the association between the reproductive factors age at menarche, menstrual cycle length, parity, age at first and last birth, menopausal status, breastfeeding duration and length of ovulatory life, and CM risk, overall and by histological subtypes and anatomical site. Methods - We followed 165 712 women aged 30–75 years at inclusion from 1991–2007 to the end of 2015. Multivariable Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Results - The mean age at cohort enrolment was 49 years. During a median follow‐up of 18 years, 1347 cases of CM were identified. No reproductive factors were clearly associated with CM risk. When stratifying by histological subtype we observed significant heterogeneity (P = 0·01) in the effect of length of ovulatory life on the risk of superficial spreading melanoma (HR 1·02, 95% CI 1·01–1·04 per year increase) and nodular melanoma (HR 0·97, 95% CI 0·94–1·01 per year increase). When stratifying by anatomical site, menopausal status (HR 0·54, 95% CI 0·31–0·92, postmenopausal vs. premenopausal) and menstrual cycle length (HR 1·07, 95% CI 1·01–1·13, per day increase) were associated with CM of the trunk, and significant heterogeneity between anatomical sites was observed for menopausal status (P = 0·04). Conclusions - In this large population‐based Norwegian cohort study, we did not find convincing evidence of an association between reproductive factors and risk of CM.

The sentinel lymph node (SLN) biopsy is a highly accurate staging procedure and the most important prognostic factor in melanoma patients. The European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group aimed to design an updated evolved SLN protocol for the histopathological workup and reporting. We herein recommend extending the distance between steps according to the short axis dimension of the lymph node and optimise both conventional sectioning and staining procedures including immunohisto-chemistry. We also provide guidance on the description of the spatial localisation of melanoma deposits in a SLN. The histopathological features to be reported include the following: presence or absence of the metastasis, the intranodal location of the metastasis (subcapsular, parenchymal, combined, extensive confluent and extensive multifocal), the number of the metastatic deposits (1, 2-5, 6-10, 11-20 and > 20), the maximum dimension of the largest metastasis (indicating its site) and the presence of extracapsular extension and of naevus cells. This updated EORTC protocol is expected to clarify and simplify the existing procedures, ensuring a reasonable workload for the laboratory and for the pathologists resulting in cost saving with no loss, and possible increase, in accuracy. (C) 2019 Elsevier Ltd. All rights reserved.

// Marjolijn D. Trietsch 1 , Maaike H.M. Oonk 2 , Lukas J.A.C. Hawinkels 3 , Rosalie Bor 3 , Jaap D.H. van Eendenburg 1 , Zina Ivanova 4 , Alexander A.W. Peters 5 , Hans W. Nijman 2 , Katja N. Gaarenstroom 5 , Tjalling Bosse 1 1 Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands 2 Department of Gynaecology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands 3 Gastroenterology-Hepatology and Molecular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands 4 Institute for Pathology and Parasitology, Bulgarian Academy of Sciences, 1040 Sofia, Bulgaria 5 Department of Gynaecology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands Correspondence to: Marjolijn D. Trietsch, e-mail: M.D.Trietsch@LUMC.nl Keywords: L1 cell adhesion molecule, L1CAM, vulvar cancer, squamous cell carcinoma, survival Received: December 31, 2015 Accepted: March 04, 2016 Published: March 25, 2016 ABSTRACT Background: Vulvar cancer treatment is mostly curative, but also has high morbidity rates. In a search for markers that can identify patients at risk of metastases, we investigated the prognostic value of L1-cell adhesion molecule (L1CAM) in large series of vulvar squamous cell carcinomas (VSCCs). L1CAM promotes cell motility and is an emerging prognostic factor for metastasis in many cancer subtypes. Results: L1CAM expression was observed at the invasive front or in spray-patterned parts of 17% of the tumours. L1CAM-positive tumours expressed vimentin more often, but L1CAM expression was not associated with TP53 or CTNNB1 mutations. Five-year survival was worse for patients with L1CAM expression (overall survival 46.1% vs 63.6%, P =.014, disease specific survival 63.8% vs 80.0%, P =.018). Multivariate analysis indicates L1CAM expression as an independent prognostic marker (HR 2.9, 95% CI 1.10–7.68). An in vitro spheroid invasion assay showed decreased invasion of L1CAM-expressing VSCC spindle cells after treatment with L1CAM-neutralising antibodies. Materials and Methods: Paraffin-embedded tumour tissue from two cohorts (N=103 and 245) of primary VSCCs were stained for L1CAM, vimentin and E-cadherin. Patients of the first cohort were tested for human papilloma virus infection and sequenced for TP53 and CTNNB1 (β-catenin) mutations. The expression of L1CAM was correlated to clinical characteristics and patient survival. Conclusion: This is the first study to show high L1CAM-expression at the infiltrating margin of VSCC’s. L1CAM-expressing VSCCs had a significantly worse prognosis compared to L1CAM-negative tumours. The highest expression was observed in spindle-shaped cells, where it might be correlated to their invasive capacity.

Background Locoregional advanced melanoma poses a complex clinical challenge that requires a multidisciplinary, patient-centered approach. Numerous agents have been studied for their suitability as intralesional therapy in the past decades, but few have successfully completed phase 3 clinical trial testing. Methods The relevant medical literature was searched for articles regarding use of intralesional therapies in metastatic melanoma. Therapies with data from phase 2 or higher studies were selected for review. This review also summarizes the mechanisms of action, adverse-event profiles, and clinical data for these agents. Results Intralesional therapies demonstrate promising effects in select patients with advanced melanoma. The optimal approach should be individually tailored and consist of a combination of intralesional therapies, regional perfusions, systemic immunotherapies, targeted therapies, and surgery, if necessary. Conclusions Due to its relatively good local response rates and tolerable adverse-event profile, intralesional therapy may be a treatment option for select patients with unresectable, locally advanced or metastatic melanoma.

Background. Patients with palpable melanoma groin metastases have a poor prognosis. There is debate whether a combined superficial and deep groin dissection (CGD) is necessary or if superficial groin dissection (SGD) alone is sufficient.Aim. The aim of this study was to analyze risk factors for deep pelvic nodal involvement in a retrospective, multicenter cohort of palpable groin melanoma metastases. This could aid in the development of an algorithm for selective surgery in the future.Methods. This study related to 209 therapeutic CGDs from four tertiary centers in The Netherlands (1992-2013), selected based on complete preoperative imaging and pathology reports. Analyzed risk factors included baseline and primary tumor characteristics, total and positive number of inguinal nodes, inguinal lymph node ratio (LNR) and positive deep pelvic nodes on imaging (computed tomography [CT] +/- positron emission tomography [PET], or PET -low-dose CT).Results. Median age was 57 years, 54 % of patients were female, and median follow-up was 21 months (interquartile range [IQR] 11-46 months). Median Breslow thickness was 2.10 mm (IQR 1.40-3.40 mm), and 26 % of all primary melanomas were ulcerated. Positive deep pelvic nodes occurred in 35 % of CGDs. Significantly fewer inguinal nodes were positive in case of negative deep pelvic nodes (median 1 [IQR 1-2] vs. 3 [IQR 1-4] for positive deep pelvic nodes; p Conclusions. Patients with negative imaging, few positive inguinal nodes, no ECE, and low LNR have a low risk of positive deep pelvic nodes and may safely undergo SGD alone.

Background. Patients with palpable melanoma groin metastases have a poor prognosis. There is debate whether a combined superficial and deep groin dissection (CGD) is necessary or if superficial groin dissection (SGD) alone is sufficient. Aim. The aim of this study was to analyze risk factors for deep pelvic nodal involvement in a retrospective, multicenter cohort of palpable groin melanoma metastases. This could aid in the development of an algorithm for selective surgery in the future. Methods. This study related to 209 therapeutic CGDs from four tertiary centers in The Netherlands (1992-2013), selected based on complete preoperative imaging and pathology reports. Analyzed risk factors included baseline and primary tumor characteristics, total and positive number of inguinal nodes, inguinal lymph node ratio (LNR) and positive deep pelvic nodes on imaging (computed tomography [CT] +/- positron emission tomography [PET], or PET -low-dose CT). Results. Median age was 57 years, 54 % of patients were female, and median follow-up was 21 months (interquartile range [IQR] 11-46 months). Median Breslow thickness was 2.10 mm (IQR 1.40-3.40 mm), and 26 % of all primary melanomas were ulcerated. Positive deep pelvic nodes occurred in 35 % of CGDs. Significantly fewer inguinal nodes were positive in case of negative deep pelvic nodes (median 1 [IQR 1-2] vs. 3 [IQR 1-4] for positive deep pelvic nodes; p

Background Metastatic melanoma patients can have durable responses to systemic therapy and even long-term survival. However, a large subgroup of patients does not benefit. Tumour metabolic alterations may well be involved in the efficacy of both targeted and immunotherapy. Knowledge on in vivo tumour glucose uptake and its heterogeneity in metastatic melanoma may aid in upfront patient selection for novel (concomitant) metabolically targeted therapies. The aim of this retrospective study was to provide insight into quantitative 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) parameters and corresponding intra- and inter-patient heterogeneity in tumour 18F-FDG uptake among metastatic melanoma patients. Consecutive, newly diagnosed stage IV melanoma patients with a baseline 18F-FDG PET/CT scan performed between May 2014 and December 2015 and scheduled to start first-line systemic treatment were included. Volume of interests (VOIs) of all visible tumour lesions were delineated using a gradient-based contour method, and standardized uptake values (SUVs), metabolically active tumour volume (MATV) and total lesion glycolysis (TLG) were determined on a per-lesion and per-patient basis. Differences in quantitative PET parameters were explored between patient categories stratified by BRAFV600 and RAS mutational status, baseline serum lactate dehydrogenase (LDH) levels and tumour programmed death-ligand 1 (PD-L1) expression. Results In 64 patients, 1143 lesions ≥ 1 ml were delineated. Median number of lesions ≥ 1 ml was 6 (range 0–168), median maximum SUVpeak 9.5 (range 0–58), median total MATV 29 ml (range 0–2212) and median total TLG 209 (range 0–16,740). Per-patient analysis revealed considerable intra- and inter-patient heterogeneity. Maximum SUVs, MATV, number of lesions and TLG per patient did not differ when stratifying between BRAFV600 or RAS mutational status or PD-L1 expression status, but were higher in the patient group with elevated LDH levels (> 250 U/l) compared to the group with normal LDH levels (P

BackgroundMalignant melanoma (MM) patients are at increasing risk of developing second primary cancers (SPCs). We assessed mortality and risk of SPCs in MM patients with siblings or parents affected with same cancer compared with that of the general population.MethodsWe used the Swedish Family-Cancer Database to assess relative risks (RRs) and causes of death in SPCs until 2015 in patients with a MM diagnosis between 1958 and 2015. We identified 35 451patients with MM among whom 3212 received a subsequent diagnosis of SPC. RRs of SPCs after MM diagnosis were calculated stratifying over concordant family history of cancer in first-degree relatives.ResultsFamilial RRs were increased for second melanoma (RR = 19.28, 95% CI = 16.71 to 22.25), squamous cell skin cancer (RR = 7.58, 95% CI = 5.57 to 10.29), leukemia (RR = 5.69, 95% CI = 2.96 to 10.94), bladder (RR = 4.15, 95% CI = 2.50 to 6.89), ovarian (RR = 3.89, 95% CI = 1.46 to 10.37), kidney cancer (RR = 3.77, 95% CI = 1.57 to 9.06), cancer of unknown primary (RR = 3.67, 95% CI = 1.65 to 8.16), nervous system (RR = 2.88, 95% CI = 1.20 to 6.93), breast (RR = 2.34, 95% CI = 1.92 to 2.84), lung (RR = 2.24, 95% CI = 1.50 to 3.35), and prostate cancer (RR = 2.22, 95% CI = 1.89 to 2.61) with statistical significance. For all cancers, familial RR was in excess (2.09, 95% CI = 2.02 to 2.16 vs 1.78, 95% CI = 1.69 to 1.87; Ptrend ConclusionsSPCs appear higher with prior family history of cancer and contribute to mortality. SPC was the most common cause of death in patients with SPC and is almost uniformly the major contributing cause of death for all cancer sites. For improved survival in MM patients, prevention and early detection of SPCs would be important.

Supplemental Digital Content is available in the text., BRAF mutational testing has become a common practice in the diagnostic process of patients with advanced melanoma. Although time-consuming, DNA sequencing techniques are the current gold standard for mutational testing. However, in certain clinical situations, a rapid test result is required. In this study, the performance of three rapid BRAF mutation tests was compared. Thirty-nine formalin-fixed paraffin-embedded melanoma tissue samples collected between 2007 and 2014 at a single center were included. These samples were analyzed by immunohistochemistry using the anti-BRAF-V600E (VE1) mouse monocolonal antibody (BRAF-VE1 IHC), a V600E-specific Droplet Digital PCR Test, and the Idylla BRAF- Mutation Test (Idylla). Results were compared with the results of conventional BRAF mutation testing, performed using high-resolution melting analysis followed by Sanger sequencing. Next-generation sequencing was performed on samples with discordant results. The Idylla test and Droplet Digital PCR Test correctly identified all mutated and wild-type samples. BRAF-VE1 IHC showed one discordant result. The Idylla test could identify BRAF-V600 mutations other than BRAF-V600E and was the fastest and least laborious test. The Idylla Mutation Test is the most suitable test for rapid BRAF testing in clinical situations on the basis of the broad coverage of treatment-responsive mutations and the fast procedure without the need to perform a DNA isolation step.

Increased density of tumor-associated lymphatic vessels correlates with poor patient survival in melanoma and other cancers, yet lymphatic drainage is essential for initiating an immune response. Here we asked whether and how lymphatic vessel density (LVD) correlates with immune cell infiltration in primary tumors and lymph nodes (LNs) from patients with cutaneous melanoma. Using immunohistochemistry and quantitative image analysis, we found significant positive correlations between LVD and CD8 + T cell infiltration as well as expression of the immunosuppressive molecules inducible nitric oxide synthase (iNOS) and 2,3-dioxygénase (IDO). Interestingly, similar associations were seen in tumor-free LNs adjacent to metastatic ones, indicating loco-regional effects of tumors. Our data suggest that lymphatic vessels play multiple roles at tumor sites and LNs, promoting both T cell infiltration and adaptive immunosuppressive mechanisms. Lymph vessel associated T cell infiltration may increase immunotherapy success rates provided that the treatment overcomes adaptive immune resistance.

The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, at least in part, responsible for its tumor-suppressive activity in prostate cancer. This evidence was supported by the enhanced prognostic potential of a signature based on the concomitant alteration of MITF and CRYAB in prostate cancer patients. In sum, our study provides proof-of-concept evidence of the potential of the bioinformatics screen of publicly available cancer patient databases as discovery platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology. The work of V. Torrano is funded by Fundacion Vasca de Innovacion e Investigacion Sanitarias, BIOEF (BIO15/CA/052), the AECC J.P. Bizkaia and the Basque Department of Health (2016111109). The work of A. Carracedo is supported by the Basque Department of Industry, Tourism and Trade (Etortek) and the Department of Education (IKERTALDE IT1106-16, also participated by A. Gomez-Munoz), the BBVA Foundation, the MINECO (SAF2016-79381-R (FEDER/EU); Severo Ochoa Excellence Accreditation SEV-2016-0644; Excellence Networks SAF2016-81975-REDT), European Training Networks Project (H2020-MSCA-ITN-308 2016 721532), the AECC IDEAS16 (IDEAS175CARR) and the European Research Council (Starting Grant 336343, PoC 754627). CIBERONC was co-funded with FEDER funds. The work of M. Graupera is supported by the MINECO (SAF2014-59950-P). The work of A. Aransay is supported by the Basque Department of Industry, Tourism and Trade (Etortek and Elkartek Programs), the Innovation Technology Department of Bizkaia County, CIBERehd Network and Spanish MINECO the Severo Ochoa Excellence Accreditation (SEV-2016-0644). R. Barrio acknowledges Spanish MINECO (BFU2014-52282-P, Consolider BFU2014-57703-REDC), the Departments of Education and Industry of the Basque Government (PI2012/42) and the Bizkaia County. J. Starkova acknowledges the Ministry of Health of Czech Republic AZV NV15-28848A. We are thankful to the Basque Biobank for Research (BIOEF) for the custody and management of human prostate specimens used in this study.

Natural killer cells (NKs) are important effectors of the innate immune system, with marked antitumor activity. Imaging NK trafficking in vivo may be relevant to following up the efficacy of new therapeutic approaches aiming at increasing tumor-infiltrating NKs (TINKs). The specific aims of present study were to efficiently target NKs using a Tc-96m-anti-CD56 and to image human NK trafficking in SCID mice bearing human cancer. Methods: The anti-CD56 monoclonal antibody (mAb) was radiolabeled with Tc-99m, and in vitro quality controls were performed to test labeling efficiency, stability, and binding affinity to CD56. In vivo biodistribution was determined by injecting 5.5 MBq (104 ng) of radiolabeled antibody in the tail vein of SCID mice, which were then sacrificed at 1, 3, 6, and 24 h after injection. Targeting experiments were performed on 2 groups of SCID mice inoculated subcutaneously with increasing numbers of human NKs in the right thigh (from 2.5 x 10(6) to 40 x 10(6)) and human granulocytes (CD56(-)) or anaplastic thyroid cancer (ARO) cells in the contralateral thigh as control. TINK trafficking imaging was achieved by injecting 5.5 MBq of Tc-99m-anti-CD56 mAb in SCID mice bearing ARO tumor xenografts in the right thigh, 24 h after being reconstituted with 10(5), 10(6), or 10(7) human NKs. Results: Anti-CD56 mAb was radiolabeled, achieving a radiochemical purity of more than 97% and a specific activity of 3,700 MBq/mg and retaining biochemical integrity and binding activity. In vivo studies revealed physiologic uptake in the liver and kidneys. Targeting experiments confirmed the specificity of labeled antibody to CD56+ cells. Human NK cells injected in CD1 nude mice accumulated in the ARO tumors within 24 h and were imaged as early as 3 h after intravenous administration of Tc-99m-anti-CD56. Conclusion: Tc-99m-anti-CD56 is a promising tool for in vivo imaging of TINK cell trafficking.

SummaryThe mechanisms by which melanoma and other cancer cells evade anti-tumor immunity remain incompletely understood. Here, we show that the growth of tumors formed by mutant BrafV600E mouse melanoma cells in an immunocompetent host requires their production of prostaglandin E2, which suppresses immunity and fuels tumor-promoting inflammation. Genetic ablation of cyclooxygenases (COX) or prostaglandin E synthases in BrafV600E mouse melanoma cells, as well as in NrasG12D melanoma or in breast or colorectal cancer cells, renders them susceptible to immune control and provokes a shift in the tumor inflammatory profile toward classic anti-cancer immune pathways. This mouse COX-dependent inflammatory signature is remarkably conserved in human cutaneous melanoma biopsies, arguing for COX activity as a driver of immune suppression across species. Pre-clinical data demonstrate that inhibition of COX synergizes with anti-PD-1 blockade in inducing eradication of tumors, implying that COX inhibitors could be useful adjuvants for immune-based therapies in cancer patients.

This study aimed to investigate the predictive value of the tumor mitotic rate per mm(2) (TMR) for sentinel lymph node (SLN) status and survival in intermediate and thick cutaneous melanoma. Patients treated for stage I and II melanoma with wide local excision and SLN biopsy between May 1995 and May 2013 were analyzed. In case of insufficient data regarding TMR, pathology slides were reanalyzed. Prognostic factors for SLN status and survival were analyzed with the emphasis on TMR, which was analyzed as a continuous variable, dichotomized (median value) and categorized by two methods. The study analyzed 453 patients with complete TMR data. The median Breslow thickness was 2.20 mm, and 31.8 % of patients had tumor-positive sentinel lymph node biopsies (SLNBs). In the univariate analysis, TMR was associated with tumor-positive SLNB. This association was not significant in the multivariate analysis. Breslow thickness, primary tumor location on trunk and legs, and younger age were associated with tumor-positive SNLB. At a median follow-up of 47 months, 119 patients (26.3 %) had recurrent disease, and 92 (20.3 %) had died of melanoma. In the univariate analysis, TMR could be established as a significant prognostic factor for disease-free and disease-specific survival, but not in the multivariate analyses. Breslow thickness, ulcerated melanoma, and tumor-positive SLNB were significant prognostic factors for survival. The study was unable to establish TMR as an independent prognostic factor associated with the presence of SLN metastasis. Regarding survival, increasing TMR showed a strong association with decreased survival in the univariate analysis, but this association was rendered nonsignificant by the importance of Breslow thickness and ulceration status in the multivariate model.

In order to define patients eligible for only a superficial groin dissection or a combined superficial and deep groin dissection, this study aimed to determine the incidence of deep lymph node metastases (LNM) in patients with melanoma metastasized to the groin, to identify patient and melanoma factors that predict deep nodal involvement, and to analyze the impact of deep nodal involvement on survival and recurrence.Patients who underwent a combined superficial (inguinal) and deep (iliac and obturator) complete (CLND) or therapeutic lymph node dissection (TLND) of the groin between 1994 and 2012 were analyzed.QueryDeep LNM were found in 8 of 62 CLND patients (13 %) and in 21 of 67 TLND patients (31 %). More than three superficial LNM was the only independent predictor for deep LNM in both CLND and TLND patients. The 5-year melanoma-specific survival (MSS) for CLND and TLND patients with deep LNM was 14.3 and 16.6 %, respectively, and was significantly worse (hazard ratio [HR] 3.39, 95 % CI 1.34-8.58, p = 0.010; and HR 2.01, 95 % CI 1.04-3.88, p = 0.039) compared with CLND and TLND patients without deep LNM (5-year MSS: 54.1 and 37.2 %, respectively). Distant recurrence was significantly associated with deep LNM in CLND patients (p = 0.032).The present study showed that LNM in the deep area of the groin are fairly common in both CLND and TLND patients and significantly affect prognosis, especially in CLND patients. The number of superficial LNM is the only factor that was found to predict a finding of deep nodal metastases.

Introduction: Intralesional therapy for metastatic melanoma has some advantages over systemic therapy. Local drug administration allows for delivery of an increased concentration of the agent and reduced systemic exposure, thereby increasing local efficacy and limiting toxicity. Moreover, since in vivo tumor nodules contain the tumor antigens, this tumor tissue may serve as an autologous vaccine to induce systemic immunity. This so-called 'bystander effect', where uninjected distant lesions exhibit a response, has been reported in select intralesional therapy trials.Areas covered: This review will give an overview of the working mechanisms, clinical evidence and side effects for available intralesional and topical therapies and summarize the most recent developments in this field.Expert opinion: The ideal treatment approach for locoregionally advanced melanoma should be multidisciplinary and tailored to the patient, taking into consideration patient-related, tumor-related factors (such as location, tumor burden, mutation status) and previous treatments received. It will likely not be a single therapy, but rather a combination of injectable treatments, regional perfusions and systemic therapies.

TERT (telomerase reverse transcriptase) is the catalytic component of telomerase. TERT shows little expression in normal somatic cells but is commonly re-expressed in cancers, facilitating immortalization. Recently-discovered TERT promoter mutations create binding sites for ETS-family transcription factors to upregulate TERT. ETS1 is reported to be important for TERT upregulation in melanoma. However it is unclear when in melanoma progression TERT and ETS1 proteins are expressed. To elucidate this question, ETS1 and TERT immunohistochemistry were performed on a panel of benign (n=27) and dysplastic nevi (n=34), radial growth phase (n=29), vertical growth phase (n=25) and metastatic melanomas (n=27). Lesions were scored by percentage of positive cells. ETS1 was readily detectable in all lesions, but not in normal melanocytes. TERT was located in either the nucleolus, the nucleoplasm (non-nucleolar) or both. Non-nucleolar TERT increased in prevalence with progression, from 19% of benign nevi to 78% of metastases. It did not however correlate with cell proliferation (Ki-67 immunostaining), nor differ significantly in prevalence between primary melanomas with or without a TERT promoter mutation. These results demonstrate that ETS1 is expressed very early in melanoma progression, and interestingly only non-nucleolar TERT correlates clearly in prevalence with melanoma progression. It can be acquired at various stages and by mechanisms other than promoter mutations.

Background The risk of melanoma in organ transplant recipients (OTR) is increased compared with the general population. Methods This retrospective study registered all cases of post-transplant melanoma in kidney, heart, lung and liver transplant recipients followed in our specialized post-transplant Dermatology clinic since 1991. The yearly prevalence of melanoma and skin carcinoma between 2000 and 2015 were computed and compared in this population. Based on another cohort of kidney transplant recipients grafted since 2005, adjusted age- and sex- standardized incidence ratio (SIR) was calculated using a renal transplantation registry. Results In our overall OTR cohort, between 1991 and 2000 five melanomas occurred in 1800 OTRs (0.28%), whereas between 1991 and 2015, 53 melanomas were diagnosed in 49 of 4510 OTR (1.09%), representing a 3.9fold increase in prevalence after 2000. Remarkably, the prevalence of non-melanoma skin cancers remained unchanged over this period. Two deaths related to melanoma were recorded with an overall follow-up of 62 months. In our cohort of 1102 renal transplant recipients, the SIR of melanoma was 4.52. Conclusion Our data suggest that, contrasting with non-melanoma skin cancer, the risk of post-transplant melanoma has considerably increased over the last decade. This article is protected by copyright. All rights reserved.

BACKGROUND: The development of brain metastases is common for systemic treatment failure in patients with melanoma and has been associated with a poor prognosis. Recent advances with BRAF and immune checkpoint therapies have led to improved patient survival. Herein, the authors evaluated the risk of de novo brain metastases and survival among patients with melanoma brain metastases (MBM) since the introduction of more effective therapies. METHODS: Patients with unresectable AJCC stage III/IV melanoma who received first-line systemic therapy at Moffitt Cancer Center between 2000 and 2012 were identified. Data were collected regarding patient characteristics, stage of disease, systemic therapies, MBM status/management, and overall survival (OS). The risk of de novo MBM was calculated using a generalized estimating equation model and survival comparisons were performed using Kaplan-Meier and Cox proportional analyses. RESULTS: A total of 610 patients were included, 243 of whom were diagnosed with MBM (40%). Patients with MBM were younger, with a lower frequency of regional metastasis. No significant differences were noted with regard to sex, BRAF status, or therapeutic class. The risk of de novo MBM was found to be similar among patients treated with chemotherapy, biochemotherapy, BRAF-targeted therapy, ipilimumab, and anti-programmed cell death protein 1/programmed death-ligand 1 regimens. The median OS of patients with MBM was significantly shorter when determined from the time of first regional/distant metastasis but not when determined from the time of first systemic therapy. The median OS from the time of MBM diagnosis was 7.5 months, 8.5 months, and 22.7 months, respectively, for patients diagnosed from 2000 to 2008, 2009 to 2010, and 2011 to the time of last follow-up (P5.002). CONCLUSIONS: Brain metastases remain a common source of systemic treatment failure. The OS for patients with MBM has improved significantly. Further research into MBM prevention is needed. (C) 2017 American Cancer Society.