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Background Basal cell carcinoma (BCC) is the most prevalent malignant tumour among Caucasians, characterised by its low metastatic potential but significant morbidity due to local tissue destruction. The COVID‐19 pandemic, declared by the WHO on 11 March 2020, led to various lockdowns and changes in patient behaviour, including reduced consultations with physicians. Objectives This study aims to assess whether surgeries for BCC decreased in Vienna, Austria, during the pandemic and to evaluate the impact of any treatment delays on tumour and surgery complexity notable so far. Methods We conducted a retrospective single‐centre observational study at Klinik Hietzing, Vienna, reviewing patients who underwent BCC surgery from March to May during the years 2017–2022. Patients were divided into pre‐COVID (2017–2019) and during‐COVID (2020–2022) groups. Data from 727 patients were analysed, including metrics such as the number of surgeries, patient demographics, comorbidities, and the distance from home to hospital. Surgery complexity was assessed using a predefined scale based on six parameters, yielding a score from 0 to 6 points. Statistical analyses, including t‐tests and ANOVA, were performed to compare differences between the groups. Results A significant decrease of 32.5% (n = 141) in BCC surgeries was observed since the pandemic (p < 0.001). The mean age of patients increased slightly from 73.9 years (median 76) pre‐COVID to 75.6 years (median 79) during‐COVID (p = 0.341). The number of comorbidities increased significantly (p = 0.042). However, there was no significant change in surgery complexity (p = 0.317), although a slight shift towards higher complexity was noted. Conclusions The COVID‐19 pandemic led to a notable reduction in BCC surgeries at our centre. Despite the delays, there was no significant increase in surgery complexity notable yet, likely due to the slow‐growing nature of BCC. Nonetheless, the increase in comorbidities and the prolonged reduction in surgical procedures highlight the need for ongoing vigilance to prevent future morbidity increases. Since the declaration of the COVID‐19 pandemic in Vienna, basal cell carcinoma surgeries decreased by 32.5%, with numbers still not reaching pre‐pandemic levels in 2022. Patients who have undergone surgery since 2020 tend to be older and present with more comorbidities. However, the complexity of surgeries has remained unchanged.

Background Conventional supervised deep‐learning approaches mostly focus on a small range of skin disease images. Recently, self‐supervised (SS) Vision Transformers have emerged, capturing complex visual patterns in hundreds of classes without any need for tedious image annotation. Objectives This study aimed to form the basis for an inexpensive and explainable AI system, targeted at the vastness of clinical skin diagnoses by comparing so‐called ‘self‐attention maps’ of an SS and a supervised ViT on 250 skin diseases—visualizations showing areas of interest for each skin disease. Methods Using a public data set containing images of 250 different skin diseases, one small ViT was pretrained S) for 300 epochs (=ViT‐SS), and two were fine‐tuned supervised from ImageNet‐weights for 300 epochs (=ViT‐300) and for 78 epochs due to heavier regularization (=ViT‐78), respectively. The models generated 250 self‐attention maps each. These maps were analyzed in a blinded manner using a ‘DermAttention’ score, and the models were primarily compared based on their ability to focus on disease‐relevant features. Results Visual analysis revealed that ViT‐SS delivered superior self‐attention‐maps. It scored a significantly higher accuracy of focusing on disease‐defining lesions (88%; confidence interval [CI] 95%: 0.840–0.920) compared to ViT‐300 (78.4%; CI 95%: 0.733–0.835; p < 0.05) and ViT‐78 (51.2%; CI 95%: 0.450–0.574; p < 0.05). It also exceeded in other subcategories of ‘DermAttention’. Conclusions SS pretraining did not translate to better diagnostic performance when compared to conventional supervision. However, it led to more accurate visual representations of varying skin disease images. These findings may pave the way for large‐scale, explainable computer‐aided skin diagnostic in an unfiltered clinical setting. Further research is needed to improve clinical outcomes using these visual tools.

Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15–25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR ₁,₂ inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR ₁,₂ in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR ₁,₂ inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR ₁,₂ inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies.

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA ( AC004540.4 ) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS . Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS . T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

Malignant melanoma is an aggressive tumor with a tendency to metastasize early and with an increasing incidence worldwide. Although in early stage, melanoma is well treatable by excision, the chances of cure and thus the survival rate decrease dramatically after metastatic spread. Conventional treatment options for advanced disease include surgical resection of metastases, chemotherapy, radiation, targeted therapy and immunotherapy. Today, targeted kinase inhibitors and immune checkpoint blockers have for the most part replaced less effective chemotherapies. Magnetic nanoparticles as novel agents for theranostic purposes have great potential in the treatment of metastatic melanoma. In the present review, we provide a brief overview of treatment options for malignant melanoma with different magnetic nanocarriers for theranostics. We also discuss current efforts of designing magnetic particles for combined, multimodal therapies (e.g., chemotherapy, immunotherapy) for malignant melanoma.

BackgroundNivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior local brain radiotherapy were excluded. We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM.MethodsPatients with MBM treated with nivolumab plus ipilimumab in 23 German Skin Cancer Centers between April 2015 and October 2018 were investigated. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS.ResultsThree hundred and eighty patients were included in this study and 31% had symptomatic MBM (60/193 with data available) at the time of start nivolumab plus ipilimumab. The median follow-up was 18 months and the 2 years and 3 years OS rates were 41% and 30%, respectively. We identified the following independently significant prognostic factors for OS: elevated serum lactate dehydrogenase and protein S100B levels, number of MBM and Eastern Cooperative Oncology Group performance status. In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (p=0.085). In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (p=0.996). Local therapy with stereotactic radiosurgery or surgery led to an improvement in OS compared with not receiving local therapy (p=0.009), regardless of the timepoint of the local therapy. Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (p=0.119).ConclusionImmunotherapy with nivolumab plus ipilimumab, particularly in combination with stereotactic radiosurgery or surgery improves OS in asymptomatic and symptomatic MBM.

BackgroundTalimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.ObjectivesThe aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.MethodsBased on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36–95 years) treated with T-VEC during the period from May 2016 to January 2020.Results88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).ConclusionThis real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.

The incidence of melanoma and nonmelanoma skin cancer has increased tremendously in recent years. Although novel treatment options have significantly improved patient outcomes, the prognosis for most patients with an advanced disease remains dismal. It is, thus, imperative to understand the molecular mechanisms involved in skin carcinogenesis in order to develop new targeted treatment strategies. Receptor tyrosine kinases (RTK) like the ERBB receptor family, including EGFR/ERBB1, ERBB2/NEU, ERBB3, and ERBB4, are important regulators of skin homeostasis and their dysregulation often results in cancer, which makes them attractive therapeutic targets. Members of the leucine‐rich repeats and immunoglobulin‐like domains protein family (LRIG1‐3) are ERBB regulators and thus potential therapeutic targets to manipulate ERBB receptors. Here, we analyzed the function of LRIG1 during chemically induced skin carcinogenesis in transgenic mice expressing LRIG1 in the skin under the control of the keratin 5 promoter (LRIG1‐TG mice). We observed a significant induction of melanocytic tumor formation in LRIG1‐TG mice and no difference in papilloma incidence between LRIG1‐TG and control mice. Our findings also revealed that LRIG1 affects ERBB signaling via decreased phosphorylation of EGFR and increased activation of the oncoprotein ERBB2 during skin carcinogenesis. The epidermal proliferation rate was significantly decreased during epidermal tumorigenesis under LRIG1 overexpression, and the apoptosis marker cleaved caspase 3 was significantly activated in the epidermis of transgenic LRIG1 mice. Additionally, we detected LRIG1 expression in human cutaneous squamous cell carcinoma and melanoma samples. Therefore, we depleted LRIG1 in human melanoma cells (A375) by CRISPR/Cas9 technology and found that this caused EGFR and ERBB3 downregulation in A375 LRIG1 knockout cells 6 h following stimulation with EGF. In conclusion, our study demonstrated that LRIG1‐TG mice develop melanocytic skin tumors during chemical skin carcinogenesis and a deletion of LRIG1 in human melanoma cells reduces EGFR and ERBB3 expression after EGF stimulation. The tyrosine kinase inhibitor leucine‐rich repeats and immunoglobulin‐like domains 1 (LRIG1) were overexpressed in the mouse skin to assess its function in this organ. While LRIG1 efficiently inactivated EGFR, epidermal LRIG1 excess showed no impact in experimentally induced skin carcinogenesis. However, transgenic animals developed remarkable melanocytic nevi induced by cleaved LRIG1, indicating a potential role for LRIG1 in melanoma.

Merkel cell carcinoma is a rare, highly aggressive skin cancer with neuroendocrine differentiation. Immune checkpoint inhibition has significantly improved treatment outcomes in metastatic disease with response rates to programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibition of up to 62%. However, primary and secondary resistance to PD-1/PD-L1 inhibition remains a so far unsolved clinical challenge since effective and safe treatment options for these patients are lacking.Fourteen patients with advanced (non-resectable stage III or stage IV, Union international contre le cancer 2017) Merkel cell carcinoma with primary resistance to the PD-L1 inhibitor avelumab receiving subsequent therapy (second or later line) with ipilimumab plus nivolumab (IPI/NIVO) were identified in the prospective multicenter skin cancer registry ADOREG. Five of these 14 patients were reported previously and were included in this analysis with additional follow-up. Overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events were analyzed.All 14 patients received avelumab as first-line treatment. Thereof, 12 patients had shown primary resistance with progressive disease in the first tumor assessment, while two patients had initially experienced a short-lived stabilization (stable disease). Six patients had at least one systemic treatment in between avelumab and IPI/NIVO. In total, 7 patients responded to IPI/NIVO (overall response rate 50%), and response was ongoing in 4 responders at last follow-up. After a median follow-up of 18.85 months, median PFS was 5.07 months (95% CI 2.43—not available (NA)), and median OS was not reached. PFS rates at 12 months and 24 months were 42.9% and 26.8 %, respectively. The OS rate at 36 months was 64.3%. Only 3 (21%) patients did not receive all 4 cycles of IPI/NIVO due to immune-related adverse events.In this multicenter evaluation, we observed high response rates, a durable benefit and promising OS rates after treatment with later-line combined IPI/NIVO. In conclusion, our patient cohort supports our prior findings with an encouraging activity of second-line or later-line IPI/NIVO in patients with anti-PD-L1-refractory Merkel cell carcinoma.