Late stage melanoma is hallmarked by low NLGN4X expression leading to HIF1A accumulation.

BACKGROUND: Despite ongoing research and recent advances in therapy, metastatic melanoma remains one of the cancers with the worst prognosis. Here we studied the postsynaptic cell adhesion molecule Neuroligin 4X (NLGN4X) and investigated its role in melanoma progression. METHODS: We analysed histologic samples to assess the expression and predictive value of NLGN4X in human melanoma. The oncogenic role of NLGN4X was determined by loss or gain-of-function experiments in vitro as well as by analysis of tumorspheres, which were grafted to human skin organoids derived from pluripotent stem cells. Whole genome expression analysis and validation experiments were performed to clarify the molecular mechanism. RESULTS: We identified that suppression of NLGN4X down regulated the prefoldin member Von Hippel-Lindau binding protein 1 (VBP1). Moreover, loss of VBP1 was sufficient for accumulation of HIF1A and HIF1A signalling was further shown to be essential for the acquisition of migratory properties in melanoma. We re-established NLGN4X expression in late stage melanoma lines and observed decreased tumour growth after transplantation to human skin organoids generated from pluripotent stem cells. In line, we showed that high amounts of NLGN4X and its target VBP1 in human patient samples had a beneficial prognostic effect on patient survival. CONCLUSION: In view of these findings, we propose that decreased amounts of NLGN4X are indicative of a metastatic melanoma phenotype and that loss of NLGN4X provides a novel mechanism for HIF induction.

Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study.

BACKGROUND: Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM. METHODS: Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS). RESULTS: The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed. CONCLUSION: Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).

Real-world outcomes using PD-1 antibodies and BRAF + MEK inhibitors for adjuvant melanoma treatment from 39 skin cancer centers in Germany, Austria and Switzerland.

BACKGROUND: Programmed death-1 (PD-1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high-risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real-world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland. METHODS: Multicenter, retrospective study investigating stage III-IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear-regression machine learning model to assess the risk of early melanoma recurrence. RESULTS: In total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD-1 therapies (n = 1003). Twelve-month RFS for anti PD-1 and BRAF + MEK inhibitor-treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335-2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD-1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow-up of 17 months. Data indicates that anti PD-1 treated patients who develop immune-related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443-0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD-1 treatment (p > 0.05). In both, anti PD-1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12-month RFS and 12-month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials. CONCLUSIONS: Despite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk.

MUG Mel3 Cell Lines Reflect Heterogeneity in Melanoma and Represent a Robust Model for Melanoma in Pregnancy.

Melanomas are aggressive tumors with a high metastatic potential and an increasing incidence rate. They are known for their heterogeneity and propensity to easily develop therapy-resistance. Nowadays they are one of the most common cancers diagnosed during pregnancy. Due to the difficulty in balancing maternal needs and foetal safety, melanoma is challenging to treat. The aim of this study was to provide a potential model system for the study of melanoma in pregnancy and to illustrate melanoma heterogeneity. For this purpose, a pigmented and a non-pigmented section of a lymph node metastasis from a pregnant patient were cultured under different conditions and characterized in detail. All four culture conditions exhibited different phenotypic, genotypic as well as tumorigenic properties, and resulted in four newly established melanoma cell lines. To address treatment issues, especially in pregnant patients, the effect of synthetic human lactoferricin-derived peptides was tested successfully. These new BRAF-mutated MUG Mel3 cell lines represent a valuable model in melanoma heterogeneity and melanoma pregnancy research. Furthermore, treatment with anti-tumor peptides offers an alternative to conventionally used therapeutic options-especially during pregnancy.

Adjuvant anti-PD-1 antibody treatment in stage III/IV melanoma: real-world experience and health economic considerations.

BACKGROUND: Anti-programmed death 1 (PD-1) antibodies have evolved as a new standard of care in the adjuvant treatment of completely resected melanoma. Real-world data on treatment efficacy and safety as well as cost-effectiveness are still limited. PATIENTS AND METHODS: Treatment outcomes were retrospectively analyzed in a continuous patient cohort receiving adjuvant nivolumab (91 patients) or pembrolizumab (9 patients). Based on the obtained clinical data, a semi-Markov model was developed to evaluate cost-effectiveness. RESULTS: After a median follow-up of 11.5 months, disease recurrence was observed in 39 patients (39 %). The site of first recurrence was locoregional in 17, distant in 19, and combined locoregional and distant in three patients. Twelve-month estimates for recurrence- and distant-metastasis-free survival were 64.8 % and 77.4 %, respectively. Sixteen patients experienced grade 3 or 4 treatment-related adverse events, while 22 patients discontinued treatment due to adverse events. The base-case Markov model yielded an incremental cost-effectiveness ratio of 13,330 € per quality-adjusted life year for adjuvant anti-PD-1 antibody treatment compared to a simulated observation cohort. CONCLUSIONS: Real-world outcomes of adjuvant anti-PD-1 antibody therapy in completely resected melanoma appear comparable to clinical trial data. Moreover, our data suggests this treatment strategy to be cost-effective according to Austrian health economic standards.

Knowledge and Influence of Predatory Journals in Dermatology: A Pan-Austrian Survey.

The aim of this study was to assess the knowledge and influence of predatory journals in the field of dermatology in Austria. A total of 286 physicians (50.5% men) completed a questionnaire. The vast majority of subjects read scientific articles (n = 281, 98.3%) and took them into consideration in their clinical decision-making (n = 271, 98.5% of participants that regularly read scientific literature). Open access was known by 161 (56.3%), predatory journals by 84 (29.4%), and the Beall's list by 19 physicians (6.7%). A total of 117 participants (40.9%) had been challenged by patients with results from the scientific literature, including 9 predatory papers. Participants who knew of predatory journals had a higher level of education as well as scientific experience, and were more familiar with the open-access system (p < 0.001). These results indicate that the majority of dermatologists are not familiar with predatory journals. This is particularly the case for physicians in training and in the early stages of their career.

Function and Clinical Implications of Long Non-Coding RNAs in Melanoma.

Metastatic melanoma is the most deadly type of skin cancer. Despite the success of immunotherapy and targeted agents, the majority of patients experience disease recurrence upon treatment and die due to their disease. Long non-coding RNAs (lncRNAs) are a new subclass of non-protein coding RNAs involved in (epigenetic) regulation of cell growth, invasion, and other important cellular functions. Consequently, recent research activities focused on the discovery of these lncRNAs in a broad spectrum of human diseases, especially cancer. Additional efforts have been undertaken to dissect the underlying molecular mechanisms employed by lncRNAs. In this review, we will summarize the growing evidence of deregulated lncRNA expression in melanoma, which is linked to tumor growth and progression. Moreover, we will highlight specific molecular pathways and modes of action for some well-studied lncRNAs and discuss their potential clinical implications.

A Unifying Concept of Uveal Pigment Cell Distribution and Dissemination Based on an Animal Model: Insights into Ocular Melanogenesis.

Pigmented cells are derived from neural crest cells, which migrate along the peripheral nerve sheets into their specific final region. During their migration, cells progressively acquire pigment-producing capabilities, maturation, and the shape of melanocytes. These insights, along with specific clinical characteristics of melanocytic nevi, have led to new concepts of cutaneous, periocular, and iris nevogenesis. To further elucidate the specific ocular embryogenic melanoblast distribution and dissemination - that could explain the distinct distribution of uveal melanocytic neoplasms - we investigated the ocular pigmentation of dogs affected by a specific mutation called Merle, which results in either pigment- (wild type) or non-pigment- (mutated type) producing cells. Based on our observations, we propose a unifying concept of uveal pigment cell distribution and dissemination, which postulates melanoblast migration and maturation following the trigeminal V1 branch and, later, their entrance into the eye along the ciliary nerves and their finest iris branches. Our concept provides an explanation not only for the specific distribution of ocular melanocytic lesions, including uveal and iris nevi, but also for the different locations depending on the metastatic potential of the ocular melanoma. Though speculative, the higher metastatic potential of posterior uveal melanomas compared to iris melanomas may be related to a less differentiated stage in the maturation of migrating melanocytes in the posterior segment compared to the anterior segment of the eye. However, there is a need of further studies focusing on cell differentiation markers of melanocytes at different locations in the eye.

The Importance of a Biopsychosocial Approach in Melanoma ResearchExperiences from a Single-center Multidisciplinary Melanoma Working Group in Middle-Europe.

The biopsychosocial model represents a very important theoretical framework developed in the 21th century. According to a body mind unity theory, it postulates that research must focus not only on biomedical but also on other aspects in order to understand complex interactions occurring on different system levels. With regard to the occurrence of melanoma, both immunologic surveillance and a lack of cancerogenic factors are crucial in the suppression of tumor development. In addition, a reduction in mental stress (employing effective strategies for coping with stress) in cases of malignant disease seems to prolong life. Focusing on these theories, examples of studies that followed an interdisciplinary, biopsychosocial approach to melanoma research conducted at one center are given to emphasize the multi-dimensional and interdisciplinary aspects of the biopsychosocial model.

Association of Stress Coping Strategies with Immunological Parameters in Melanoma Patients.

In this exploratory case control study the association between stress coping strategies and lymphocyte subpopulations was calculated in 18 non-metastatic melanoma patients and 18 controls with benign skin diseases. Coping strategies were assessed using the German version of the stress-coping questionnaire (SVF 120). While in the control group patients showed significant negative correlations of lymphocyte subpopulations (CD3+, CD4+, CD8+, CD19+, CD45+ cells) with coping strategies that refer to defence, in melanoma patients significant positive correlations between lymphocyte subpopulations (CD3+, CD4+, CD19+, CD45+ cells) were found with regard to coping strategies that are characterized by diversion from stress and focusing on stress-compensating situations. The present data, in melanoma patients and controls, show contrary correlations between stress coping strategies and lymphocyte subpopulations. The interconnection between stress coping and immunologic alterations in malignant melanoma is a field deserving further multiprofessional investigation in order to provide new therapeutical approaches in the treatment and understanding of melanoma patients.

Autonomic nervous tone in vitiligo patients--a case-control study.

In this cross-sectional, exploratory case-control study the vegetative arousal in vitiligo patients compared to an age and gender matched healthy control group was assessed. Forty-eight participants (24 outpatients with generalised vitiligo and 24 healthy controls) completed a test procedure consisting of an initial period of rest (R1), a defined mental stress task (the d2 test of attention), a second period of rest (R2) followed by an individually, age adapted physical stress task (bicycle ergometry) and a final period of rest (R3). Based on a continuously recorded electrocardiogram, heart rate variability, in particular high frequency (HF) and low frequency (LF) components were determined. Within the 3 periods of rest, vitiligo patients showed a higher vegetative arousal than controls, represented by the ratio of LF/HF which mirrors the sympatho-vagal balance (R1: p = 0.027; R2: p = 0.003; R3: p = 0.029). No differences between the 2 groups were found during the mental (p = 0.187) and the physical stress task (p = 0.773). The results suggest a higher vegetative arousal in vitiligo patients.

Higher psychological and psychovegetative strain in adolescents with atypical pigment naevi.

An observational, exploratory, cross-sectional study was performed to assess whether the presence of atypical naevi (AN) in adolescents is associated with psychological and psychovegetative stress parameters. Fifty-one students of a secondary school in Graz, Austria, completed a defined test procedure consisting of an initial period of rest, a standardised mental stress task, another period rest and a questionnaire, the change-sensitive symptom list (ASS-SYM). Electrocardiogram and blood pressure were recorded continuously. The study population was divided in two groups: probands without AN (NAN, n = 33), and probands with at least one AN (n = 18). We found higher values for the AN group in all scales of ASS-SYM, reaching statistical significance in the dimensions "nervousness and mental tension" (p = 0.025), "psychophysiological dysregulation" (p = 0.020), burden of pain" (p = 0.023) and "general symptoms and problems" (p = 0.031). Regarding physiological parameters, the AN group showed higher vegetative strain reflected in heart rate and heart rate varibility during the periods of rest as well as a reduced baroreceptor sensitivity. On the basis of our results, the presence of AN in adolescents seems to be associated with a higher vegetative arousal. Additionally, participants with AN complained significantly more often about stress-associated general psychological symptoms and problems.

Psychological Stress and Immunological Modulations in Early-stage Melanoma Patients.

Mental stress may have a negative impact on the immune state of cancer patients, in whom immunologic surveillance is essential for survival. This study investigated the immunological response of 19 patients with early-stage melanoma and a matched control group undergoing the Determination Stress Test before surgery. Cytokine and chemokine levels and lymphocyte subpopulations were measured at baseline and post-stress test time-points. Following the stress test lower levels of interleukin (IL)-6 were observed in the melanoma group compared with healthy volunteers (p = 0.044). IL-10 increased significantly in the control group 30 min after the stress test (p = 0.002) in comparison with the melanoma group (p = 0.407). CCL5/Rantes decreased significantly in the melanoma group, whereas CD16/CD56+ natural killer cells increased in both groups, with a sharp decrease below baseline after stress in the melanoma group (p = 0.001). This pilot study shows an altered immunological response to stressors in melanoma patients.