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Aim: Immune checkpoint inhibitor-induced encephalitis (ICI-iE) is a rare but life-threatening toxicity of immune checkpoint inhibitor treatment. We aim to identify the characteristics of ICI-iE and describe factors that discriminate it from herpes simplex virus (HSV)-1 encephalitis and anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis, as two alternative entities of encephalitis. Methods: In this retrospective multicentre cohort study, we collected patients with ICI-iE reported to the Side Effect Registry Immuno-Oncology from January 2015 to September 2021 and compared their clinical features and outcome with 46 consecutive patients with HSV-1 or anti-LGI1 encephalitis who were treated at a German neurological referral centre. Results: Thirty cases of ICI-iE, 25 cases of HSV-1 encephalitis and 21 cases of anti-LGI1 encephalitis were included. Clinical presentation of ICI-iE was highly variable and resembled that of HSV-1 encephalitis, while impairment of consciousness (66% vs. 5%, p = .007), confusion (83% vs. 43%; p = .02), disorientation (83% vs. 29%; p = .007) and aphasia (43% vs. 0%; p = .007) were more common in ICI-iE than in anti-LGI1 encephalitis. Antineuronal antibodies (17/18, 94%) and MRI (18/30, 60%) were mostly negative in ICI-iE, but cerebrospinal fluid (CSF) showed pleocytosis and/or elevated protein levels in almost all patients (28/29, 97%). Three patients (10%) died of ICI-iE. Early immunosuppressive treatment was associated with better outcome (r = 0.43). Conclusions: ICI-iE is a heterogeneous entity without specific clinical features. CSF analysis has the highest diagnostic value, as it reveals inflammatory changes in most patients and enables the exclusion of infection. Early treatment of ICI-iE is essential to prevent sequelae and death.

Objectives: Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30–40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes. Methods: Patients with advanced (non-resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG. Results: We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy-three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival (PFS) on ICI was 2.6 (95% CI 2.2–2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4–7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2–20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response. Conclusions: BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy. Rates of long-term benefit and survival in our study were similar to those reported for treatment-naïve patients receiving first-line MAPKi.

Background One prominent application for deep learning–based classifiers is skin cancer classification on dermoscopic images. However, classifier evaluation is often limited to holdout data which can mask common shortcomings such as susceptibility to confounding factors. To increase clinical applicability, it is necessary to thoroughly evaluate such classifiers on out-of-distribution (OOD) data. Objective The objective of the study was to establish a dermoscopic skin cancer benchmark in which classifier robustness to OOD data can be measured. Methods Using a proprietary dermoscopic image database and a set of image transformations, we create an OOD robustness benchmark and evaluate the robustness of four different convolutional neural network (CNN) architectures on it. Results The benchmark contains three data sets—Skin Archive Munich (SAM), SAM-corrupted (SAM-C) and SAM-perturbed (SAM-P)—and is publicly available for download. To maintain the benchmark's OOD status, ground truth labels are not provided and test results should be sent to us for assessment. The SAM data set contains 319 unmodified and biopsy-verified dermoscopic melanoma (n = 194) and nevus (n = 125) images. SAM-C and SAM-P contain images from SAM which were artificially modified to test a classifier against low-quality inputs and to measure its prediction stability over small image changes, respectively. All four CNNs showed susceptibility to corruptions and perturbations. Conclusions This benchmark provides three data sets which allow for OOD testing of binary skin cancer classifiers. Our classifier performance confirms the shortcomings of CNNs and provides a frame of reference. Altogether, this benchmark should facilitate a more thorough evaluation process and thereby enable the development of more robust skin cancer classifiers.

Introduction Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients. Methods In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast ( Results Median follow-up time was 30.5 (range 0.8–154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40–0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45–1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%. Conclusion Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system.

Background: Clinicians and pathologists traditionally use patient data in addition to clinical examination to support their diagnoses. Objectives: We investigated whether a combination of histologic whole slides image (WSI) analysis based on convolutional neural networks (CNNs) and commonly available patient data (age, sex and anatomical site of the lesion) in a binary melanoma/nevus classification task could increase the performance compared with CNNs alone. Methods: We used 431 WSIs from two different laboratories and analysed the performance of classifiers that used the image or patient data individually or three common fusion techniques. Furthermore, we tested a naive combination of patient data and an image classifier: for cases interpreted as ‘uncertain’ (CNN output score

Background Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. Methods This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. Results Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4–1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2–2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3–1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8–2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6–1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5–1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. Conclusions Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.

Objective The development of leptomeningeal disease (LMD) among melanoma patients is associated with short survival. Unspecific clinical symptoms and imprecise diagnostic criteria often delay diagnosis. Because melanoma patients with LMD have been excluded from most clinical trials, the efficacy of immune checkpoint blockade (ICB) and targeted therapies (TTs) has not been adequately investigated among these patients. Methods We performed a retrospective study in two tertiary-referral skin cancer centres to evaluate the clinical characteristics, diagnostics, treatments, and overall survival (OS) of melanoma patients with LMD between June 2011 and March 2019. Results In total, 52 patients were included. The median age at LMD diagnosis was 58 years. Most patients (n = 30, 58%) were men. The median time from the first diagnosis of unresectable disease to the first diagnosis of LMD was 8.5 months (range 0–91.5 months). Most patients (65%, n = 34) were BRAF V600 mutated. Sixteen patients (31%) presented with LMD only, whereas 36 patients (69%) presented with concomitant brain metastases at LMD diagnosis. Eleven patients (21%) showed no evidence of extracranial disease. Forty-four patients (85%) had clinical symptoms at LMD diagnosis. Forty-two patients (81%) had received at least one prior therapy. Forty patients (77%) received at least one treatment after LMD diagnosis, including TT (n = 17), ICB (n = 13), bevacizumab (n = 1), radiotherapy (n = 3), and intrathecal chemotherapy (n = 1); five patients received both TT and ICB. Twelve patients (23%) received no treatment because of rapid progression of LMD. The median OS for the entire cohort was 2.9 months (95% confidence interval [CI] 1.7–4.1). Among patients receiving systemic therapy, OS was 3.7 months (95% CI 2.4–4.9). Conclusions Systemic treatment with TT or ICB seems to improve OS among patients with LMD. However, despite new therapy modalities, the prognosis of LMD remains poor.

Mitogen-activated protein kinase (MAPK) pathway has an important role in normal cells and can be activated under physiological conditions. MAPK pathway activation is a fundamental step in several intracellular processes requiring a sequential phosphorylation of the different pathway components. In normal cells, when MAPK pathway activation occurs, it leads to cell growth and differentiation. In order to prevent persistent MAPK pathway activation, physiological upstream negative feedback also takes place. In cells harbouring BRAFV600 mutations, the process leading to MAPK pathway activation is different, and the negative physiological feedback does not exist thus leading to permanent MAPK pathway activation, which ultimately can lead to uncontrolled proliferation. Targeted therapy with rapidly accelerated fibrosarcoma - B (BRAF) and/or mitogen-activated extracellular signal-regulated kinase kinase (MEK) inhibitors is indicated in patients with metastatic melanoma harboring BRAFV600 mutations. However, several different resistance mechanisms to this therapy were identified. In this review, we focus on primary or intrinsic resistance mechanisms to BRAF and MEK inhibition. In this setting, although a BRAF mutation is identified, there is no response to treatment with either BRAF or MEK inhibitor.

Background Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. Methods and findings In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis. Conclusion Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.