Dual truncation of tau by caspase-2 accelerates its CHIP-mediated degradation.

Intraneuronal aggregates of the microtubule binding protein Tau are a hallmark of different neurodegenerative diseases including Alzheimer's disease (AD). In these aggregates, Tau is modified by posttranslational modifications such as phosphorylation as well as by proteolytic cleavage. Here we identify a novel Tau cleavage site at aspartate 65 (D65) that is specific for caspase-2. In addition, we show that the previously described cleavage site at D421 is also efficiently processed by caspase-2, and both sites are cleaved in human brain samples. Caspase-2-generated Tau fragments show increased aggregation potential in vitro, but do not accumulate in vivo after AAV-mediated overexpression in mouse hippocampus. Interestingly, we observe that steady-state protein levels of caspase-2 generated Tau fragments are low in our in vivo model despite strong RNA expression, suggesting efficient clearance. Consistent with this hypothesis, we find that caspase-2 cleavage significantly improves the recognition of Tau by the ubiquitin E3 ligase CHIP, leading to increased ubiquitination and faster degradation of Tau fragments. Taken together our data thus suggest that CHIP-induced ubiquitination is of particular importance for the clearance of caspase-2 generated Tau fragments in vitro and in vivo.

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.

Quality, Understandability and Reliability of YouTube Videos on Skin Cancer Screening.

In 2008, a nationwide skin cancer screening (SCS) program was implemented in Germany. However, participation rates remain low. YouTube videos on SCS might educate eligible persons to undergo SCS. Until now, no scientific evaluation of the quality of videos available for German-speaking persons eligible for SCS has been performed. Here, we identified and evaluated videos on SCS provided on YouTube. YouTube was searched in May 2022 for German terms related to SCS. Two authors evaluated the videos of the first three pages that met the predefined eligibility criteria. The quality of the videos´ information was evaluated using DISCERN and the Global Quality Scale (GQS). The understandability and actionability were assessed with the Patient Education Materials Assessment Tool (PEMAT). The reliability was assessed with the Journal of American Medical Association (JAMA) score. Subgroup differences were identified by the Kruskal-Wallis test. Overall, 38 videos were included in the evaluation. Most videos were provided by health professionals (clinics and practices). The average scores (mean (SD)) for the individual tools were as follows: DISCERN 3.1/5 points (± 0.52), GQS 3.72/5 points (± 0.7), understandability 64,27% (± 13.53%), actionability 58.22% (± 15.18%), JAMA 37.17% (± 18.94%). These results indicate a mediocre to good understandability, a mediocre quality and actionability, and a low reliability. Videos that were assessed as useful were of significantly better quality. An improvement of freely available informational videos on SCS, especially with regard to the reliability criteria, is urgently needed.

One Website to Gather them All: Usability Testing of the New German SKin Cancer INFOrmation (SKINFO) Website-A Mixed-methods Approach.

Skin cancer patients increasingly search the internet to acquire disease-related information. However, information on the internet may be misleading. Recently, SKINFO has been launched, a website exclusively created for German-speaking skin cancer patients providing information as well as additional resources of verified quality. Here, we describe the results of the first usability test of SKINFO using a mixed-methods approach. Ten adult patients with skin cancer were recruited for usability testing in the skin cancer units of the University Hospitals of Erlangen and Dresden, Germany. Testing consisted of three different scenarios where patients were asked to find specific information on the SKINFO website guided by the think-aloud method. Descriptive analysis and content analyses were performed. All patients would recommend SKINFO and appreciated its content, design, and structure. Think-aloud analysis identified the topics layout, navigation, and content and structure which would benefit from refinement. Major criticism included the navigation through the website, and the desire for more specific information addressing patients' relatives and the latest, up-to-date information. Overall, usability testing showed that the unique web-based information platform has the potential to support patients coping with skin cancer and thus strengthen informed decision-making.

Quality, Readability, and Understandability of German Booklets Addressing Melanoma Patients.

Booklets are the preferably used form among patient education materials and are often handed out during medical consultations in dermatological oncology settings. However, little is known about how beneficial they are and whether they correspond to essential quality characteristics. To assess the quality, readability, and understandability of currently freely available booklets written in German addressing melanoma patients (MP). Melanoma booklets in accordance with predefined criteria were searched and analyzed. Three reviewers independently assessed their quality and understandability by applying the DISCERN tool and PEMAT-P. The Flesch Reading Ease Score (FRES) was calculated to determine readability. Nine booklets addressing MP were analyzed. The overall median DISCERN score was 3.6 (interquartile range (IQR) 2.9-4.1), median PEMAT-P score was 91% (IQR 83-94.5), and median FRES was 43 (IQR 33.5-47.5), indicating a medium quality, a high application of understandability elements, but low readability in at least half of the booklets. Incomplete reporting on treatments and insufficient meta-information caused the main quality deficits. There is a need of content and didactic revision of German booklets for MP to raise their quality and to make them beneficial and understandable for more patients. An adaption in accordance with evidence-based criteria and an even stronger involvement of MP in assessment and development of patient education material are considered to be the best approaches.

General practitioners' perspectives on statutory skin cancer screening-A questionnaire-based cross-sectional survey in Germany.

BACKGROUND: In Germany, skin cancer screening (SCS) is available free of charge every two years to all those with statutory health insurance over the age of 35. General Practitioners (GP) can carry out the screening if they have completed an 8-hour training course. GPs play a crucial role in the implementation of SCS and act as gatekeepers between initial patient contact and referral to dermatologists. OBJECTIVE: To record how comprehensively GPs carry out SCS in terms of patient information and body examination, as well as to explore GPs opinions on the feasibility of SCS. METHODS: A cross-sectional survey was conducted. A questionnaire was sent to GPs with permission to perform SCS in two regions of Germany (Bavaria and Saxony) between August and September 2021. Data were analyzed using descriptive analysis. Subgroup analysis was performed according to regions (federal state, location of physician´s office), professional experience (experience in years, number of monthly screenings, age) and gender. Open questions were evaluated using qualitative content analysis. RESULTS: In the survey, 204 GPs responded. Genitalia (40.7%, 83/203), anal fold (62.3%, 127/204) and oral mucosa (66.7%, 136/204) were the least examined body regions during screening. Information on risks (false-positive findings: 18.6%, 38/203; false-negative findings: 13.2%, 27/203; overdiagnosis: 7.8%, 16/203) and benefits (48.0%, 98/202) were not always provided. GPs who performed screenings more frequently were more likely to provide information about the benefits of SCS (p<0.001; >10 vs. <5 screenings per month). Opinions were provided on uncertainties, knowledge requirements, structural and organizational requirements of SCS, SCS training and evaluation. The organization and remuneration of the SCS programme was seen as a barrier to implementation. GPs expressed uncertainties especially in unclear findings and in dermatoscopy. CONCLUSION: Uncertainties in the implementation of the SCS should be addressed by offering refresher courses. Good networking between GPs and dermatologists is essential to improve SCS quality.

Establishment of a high-content imaging assay for tau aggregation in hiPSC-derived neurons differentiated from two protocols to routinely evaluate compounds and genetic perturbations.

Aberrant protein aggregation is a pathological cellular hallmark of many neurodegenerative diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), where the tau protein is aggregating, forming neurofibrillary tangles (NFTs), and propagating from neuron to neuron. These processes have been linked to disease progression and a decline in cognitive function. Various therapeutic approaches aim at the prevention or reduction of tau aggregates in neurons. Human induced pluripotent stem cells (hiPSCs) are a very valuable tool in neuroscience discovery, as they offer access to potentially unlimited amounts of cell types that are affected in disease, including cortical neurons, for in vitro studies. We have generated an in vitro model for tau aggregation that uses hiPSC - derived neurons expressing an aggregation prone, fluorescently tagged version of the human tau protein after lentiviral transduction. Upon addition of tau seeds in the form of recombinant sonicated paired helical filaments (sPHFs), the neurons show robust, disease-like aggregation of the tau protein. The model was developed as a plate-based high content screening assay coupled with an image analysis algorithm to evaluate the impact of small molecules or genetic perturbations on tau. We show that the assay can be used to evaluate small molecules or screen targeted compound libraries. Using siRNA-based gene knockdown, genes of interest can be evaluated, and we could show that a targeted gene library can be screened, by screening nearly 100 deubiquitinating enzymes (DUBs) in that assay. The assay uses an imaging-based readout, a relatively short timeline, quantifies the extent of tau aggregation, and also allows the assessment of cell viability. Furthermore, it can be easily adapted to different hiPSC lines or neuronal subtypes. Taken together, this complex and highly relevant approach can be routinely applied on a weekly basis in the screening funnels of several projects and generates data with a turnaround time of approximately five weeks.

Axonal Lysosomal Assays for Characterizing the Effects of LRRK2 G2019S.

The degeneration of axon terminals before the soma, referred to as "dying back", is a feature of Parkinson's disease (PD). Axonal assays are needed to model early PD pathogenesis as well as identify protective therapeutics. We hypothesized that defects in axon lysosomal trafficking as well as injury repair might be important contributing factors to "dying back" pathology in PD. Since primary human PD neurons are inaccessible, we developed assays to quantify axonal trafficking and injury repair using induced pluripotent stem cell (iPSC)-derived neurons with LRRK2 G2019S, which is one of the most common known PD mutations, and isogenic controls. We observed a subtle axonal trafficking phenotype that was partially rescued by a LRRK2 inhibitor. Mutant LRRK2 neurons showed increased phosphorylated Rab10-positive lysosomes, and lysosomal membrane damage increased LRRK2-dependent Rab10 phosphorylation. Neurons with mutant LRRK2 showed a transient increase in lysosomes at axotomy injury sites. This was a pilot study that used two patient-derived lines to develop its methodology; we observed subtle phenotypes that might correlate with heterogeneity in LRRK2-PD patients. Further analysis using additional iPSC lines is needed. Therefore, our axonal lysosomal assays can potentially be used to characterize early PD pathogenesis and test possible therapeutics.

Baseline metastatic growth rate is an independent prognostic marker in patients with advanced BRAF V600 mutated melanoma receiving targeted therapy.

BACKGROUND: Targeted therapy (TT) of BRAF V600 mutated unresectable melanoma with inhibitors of the MAPK pathway achieves response rates of up to 76%, but most patients develop secondary resistance. Albeit TT is strikingly efficacious during the first days of treatment, even in advanced cases, long-term survival is highly unlikely, especially in patients with unfavorable baseline characteristics like elevated lactate dehydrogenase (LDH). In patients treated with anti-PD-1 immune checkpoint inhibitors, elevated baseline metastatic growth rate (MGR) was the most important prognostic factor. Here, we aimed at investigating the prognostic impact of MGR in patients with unresectable melanoma receiving TT. METHODS: Clinical records of 242 patients with at least one measurable target lesion (TL) receiving TT at seven skin cancer centers were reviewed. Baseline MGR was determined measuring the largest TL at baseline and at one earlier timepoint. RESULTS: Overall survival (OS) and progression-free survival (PFS) were significantly impaired in patients with an MGR > 3.9 mm/month (median OS: 11.4 vs. 35.5 months, P < 0.0001; median PFS: 4.8 vs. 9.2 months, P < 0.0001). Multivariable analysis of OS and PFS revealed that the prognostic impact of elevated MGR was independent of LDH, presence of brain and liver metastases, tumor burden, and line of treatment. The prognostic significance of elevated MGR was highest in patients with normal LDH. CONCLUSIONS: Baseline MGR is an important independent prognostic marker for OS and PFS in melanoma patients treated with TT. Its implementation in clinical routine is easy and could facilitate the prognostic stratification.

Second-line therapies for steroid-refractory immune-related adverse events in patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, i.e. steroid-dependent (sd) irAEs, in about 10% of cases. An evidence-based analysis of the effectiveness of second-line immunosuppressive agents with regard to irAE and tumor control is lacking. METHODS: The international web-based Side Effect Registry Immuno-Oncology (SERIO; http://serio-registry.org) is a collaborative initiative with the Paul-Ehrlich-Institute to document rare, severe, complex or therapy-refractory immunotherapy-induced side effects. The registry was queried on August 1, 2023 for cases of irAEs which were treated with second-line therapies. RESULTS: From a total of 1330 cases, 217 patients (16.3%) received 249 second-line therapies. A total of 19 different second-line therapies were employed, including TNF-alpha antagonists (46.5%), intravenous immunoglobulins (IVIG; 19.1%), mycophenolate mofetil (15.9%), and methotrexate (3.6%). Therapy choices were determined by the type of irAE. The time to onset of sr-/sd-irAEs after ICI initiation did not consistently differ from steroid-responsive irAEs. While 74.3% of sr-/sd-irAEs resolved and 13.1% had improved, 4.3% persisted, 3.9% resulted in permanent sequelae, and 4.3% in death with ongoing symptoms. Infliximab exhibited potential for earlier symptom improvement compared to mycophenolate mofetil or IVIG. Tumor response in patients with second-line treated sd-/sr-irAE was similar to patients with irAEs treated with steroids only. CONCLUSION: Several second-line therapies are effective against sr-/sd-irAEs, the second-line therapies show no clear negative impact on tumor response, and infliximab shows potential for faster improvement of symptoms. However, prospective comparative data are needed.

Raising awareness of immune-related side effects in oncological patients under palliative care: a report of two cases.

BACKGROUND: Immune checkpoint inhibitors (ICI) have emerged as a successful treatment option for diverse cancer entities. However, ICI therapy can be associated with immune-related adverse events (irAE) that can affect any organ system. These side effects can be severe, irreversible and sometimes even fatal. Due to the presentation as diverse and often unspecific clinical patterns, end-of-life care concepts may be pursued hastily suspecting disease progression in oncological patients receiving palliative care (PC). CASE DESCRIPTION: This report describes two cancer patients whose symptom burden was caused by such irAEs: One patient with metastatic cutaneous squamous cell carcinoma (SCC) presenting with disorientation and urinary incontinence, another patient with metastatic melanoma presenting with a sudden and unspecific deterioration of the overall condition. After imaging and blood sampling, an encephalitis and an immune-mediated diabetes mellitus were diagnosed. After treatment with corticosteroids and hydration alongside insulin substitution both patients experienced a complete symptom relief. CONCLUSIONS: We aim to emphasize the importance of continued collaboration between primary care givers and PC teams as well as raise awareness among PC providers of severe immune-related side effects in cancer patients receiving ICI. Especially within this patient cohort, PC teams play a crucial part in detecting possible irAEs, which resolve in the majority of cases when receiving early guideline-adapted treatment.

Adjuvant treatment and outcome of stage III melanoma patients: Results of a multicenter real-world German Dermatologic Cooperative Oncology Group (DeCOG) study.

PURPOSE: Clinical trials demonstrated significantly improved recurrence-free survival (RFS) of melanoma patients receiving adjuvant treatment. As data from controlled trials are based on selected populations, we investigated adjuvantly treated stage III melanoma patients under real-world conditions. PATIENTS AND METHODS: In a prior multicenter cohort study, stage III-IV melanoma patients were analysed for their choice of adjuvant therapy. In this follow-up study, we examined RFS, overall and melanoma-specific survival (MSS) and response to the subsequent treatment of 589 stage III patients (232 BRAF-mutated) receiving adjuvant PD-1 inhibitors (PD1; n = 479) or targeted therapy (TT; n = 110). RESULTS: The median follow-up of the total cohort was 25.7 months. The main reason for premature discontinuation of adjuvant therapy was disease progression in PD1- (28.8%, n = 138/479) and adverse events in TT-treated patients (28.2%, n = 31/110). Among BRAF-mutated patients, RFS at 24 months was 49% (95% CI 40.6-59.0%) for PD1- and 67% (95% CI 58-77%) for TT-treated patients. The risk of recurrence was higher for BRAF-mutated PD1 than TT (hazard ratio 1.99; 95% CI 1.34-2.96; hazard ratio adjusted for age, sex and tumour stage, 2.21; 95% CI 1.48-3.30). Twenty-four months MSS was 87% (95% CI 81.0-94.1) for PD1 and 92% (95% CI 86.6-97.0) for TT. Response to subsequent systemic treatment for unresectable disease was 22% for all PD1- and 16% for TT-treated patients. CONCLUSIONS: PD1-treated patients had more and earlier recurrences than TT patients. In BRAF-mutated patients, adjuvant TT might prevent early recurrences more effectively than PD1 treatment. Management of recurrence despite adjuvant treatment is challenging, with low response to current therapeutic options.

A Qualitative Needs Analysis of Skin Cancer Care from the Perspectives of Patients, Physicians, and Health Insurance Representatives-A Case Study from Eastern Saxony, Germany.

Skin cancer is one of the most common cancers worldwide and the number of patients is steadily increasing. In skin cancer care, greater interdisciplinary cooperation is required for prevention, early detection, and new complex systemic therapies. However, the implementation of innovative medical care is a major challenge, especially for rural regions with an older than average, multimorbid population, with limited mobility, that are long distances from medical facilities. Solutions are necessary to ensure comprehensive oncological care in rural regions. The aim of this study was to identify indicators to establish a regional care network for integrated skin cancer care. To capture the perspectives of different stakeholder groups, we conducted two focus groups with twenty skin cancer patients and their relatives, a workshop with eight physicians, and three semi-structured interviews with health insurance company representatives. Qualitative data were recorded, transcribed, and analyzed following Mayring's content analysis methods. We generated ten categories based on the reported optimization potentials; five categories were assigned to all three stakeholder groups: Prevention and early diagnosis, accessibility of physicians/clinics, physicians' resources, care provider's responsibilities, and information exchange. The results indicate the need for stronger integration of care in the region. They provide the basis for regional networking as, for example, the conception of treatment pathways or telemedicine with the aim to improve a comprehensive skin cancer care. Our study should raise awareness and postulate as a demand that all patients receive guideline-based therapy, regardless of where they live.

Assessment of the Quality, Understandability, and Reliability of YouTube Videos as a Source of Information on Basal Cell Carcinoma: Web-Based Analysis.

BACKGROUND: Patients with skin cancer increasingly watch online videos to acquire disease-related information. Until now, no scientific evaluation of the quality of videos available for German-speaking patients with basal cell carcinoma (BCC) has been performed. OBJECTIVE: In this study, we aimed to identify and evaluate videos about BCC provided on YouTube. METHODS: A video search on YouTube was conducted in July 2020, using German BCC-related keywords (eg, "Basalzellkarzinom," "Basaliom," "weißer hautkrebs," and "heller hautkrebs"). The first three pages (ie, 60 videos) were searched by two independent researchers for each keyword. Two authors evaluated videos that met the predefined eligibility criteria. The quality of the information of the videos was evaluated using the DISCERN tool and the Global Quality Scale (GQS). The understandability and actionability were assessed with the Patient Education Materials Assessment Tool for Audiovisual Materials (PEMAT-A/V). The reliability was assessed with the JAMA (Journal of the American Medical Association) criteria score. Subgroup differences were identified using the Kruskal-Wallis test. RESULTS: A total of 41 videos were included in the evaluation. The mean assessment scores were as follows: DISCERN, 3.3 (SD 0.80); GQS, 3.8 (SD 1.1); JAMA, 27.74% (SD 22.1%); understandability, 70.8% (SD 13.3%); and actionability, 45.9% (SD 43.7%). These values indicated that the videos were of medium to good quality and had good understandability, low actionability, and poor reliability. The quality of videos provided by health professionals was significantly higher than that of videos provided by laypersons. CONCLUSIONS: Optimization of health-related videos about BCC is desirable. In particular, adaptation to reliability criteria is necessary to support patient education and increase transparency.

Characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis: A retrospective multicentre cohort study.

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.

Dataset of a retrospective multicenter cohort study on characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis.

Over the past decade, cancer immunotherapy with immune checkpoint inhibitors (ICIs) has significantly improved the outcome of many malignancies. However, with the broad use of ICIs, neurological immune related adverse events (irAE) are increasingly recognized. ICI-induced encephalitis (ICI-iE) is a particularly severe irAE, often leading to treatment termination, long-term sequalae or death. Despite its high morbidity and mortality, data on clinical features and diagnostic criteria are limited. We aimed to define clinical, radiologic and laboratory characteristics of ICI-iE and identify factors that discriminate it from anti-leucine-rich glioma-inactivated (anti-LGI)-1 encephalitis and herpes simplex virus (HSV)-1 encephalitis - two alternative causes of encephalitis - to increase the awareness of ICI-iE and improve its diagnosis and management. To that end, we retrospectively collected 30 cases of ICI-iE that were reported to the Side Effect Registry Immuno-Oncology (SERIO) and 46 cases of anti-LGI1 encephalitis or herpes simplex virus (HSV)-1 encephalitis that presented to a large German neurological referral center (Charité Universitätsmedizin Berlin) between January 2015 and September 2021. Signs and symptoms, imaging and electroencephalogram features, laboratory findings and outcome measures were assessed using standardized case report forms as well as patients' medical records and compared between the groups. The data reported here represents the largest primary cohort of patients with ICI-iE to date and the first comparison with other types of encephalitis. As all three disorders - ICI-iE, HSV-1 encephalitis and anti-LGI1 encephalitis - are rare neurological entities, this dataset can be used as a reference in future clinical studies on ICI-induced neurotoxicity, neurological autoimmune disorders, and central nervous system infections.

Genetic characterization of advanced conjunctival melanoma and response to systemic treatment.

BACKGROUND: Conjunctival melanoma is a rare type of ocular melanoma, which is prone to local recurrence and metastasis and can lead to patient death. Novel therapeutic strategies have revolutionized cutaneous melanoma management. The efficacy of these therapies in conjunctival melanoma, however, has not been evaluated in larger patient cohorts. METHODS: In this multi-center retrospective cohort study with additional screening of the ADOREG database, data were collected from 34 patients with metastatic conjunctival melanoma who received targeted therapy (TT) (BRAF ± MEK inhibitors) or immune checkpoint inhibitors (ICI) (anti-PD-1 ± anti-CTLA4). In 15 cases, tissue was available for targeted next-generation-sequencing (611 genes) and RNA sequencing. Driver mutations, tumor mutational burden, copy number variations and inflammatory/IFNγ gene expression signatures were determined. RESULTS: Genetic characterization identified frequent BRAF (46.7%, 7/15), NRAS (26.7%, 4/15), NF1 (20%, 3/15), and TERT promoter (46.7%, 7/15) mutations. UV associated C>T and CC>TT mutations were common. Median follow-up time after start of first TT or ICI therapy was 13.2 months. In 26 patients receiving first-line ICI, estimated one-year progression-free survival (PFS) rate was 42.0%, PFS and overall survival (OS) 6.2 and 18.0 months, respectively. First-line TT was given to 8 patients, estimated one-year PFS rate was 54.7%, median PFS and OS 12.6 and 29.1 months, respectively. CONCLUSIONS: Our findings support the role of UV irradiation in conjunctival melanoma and the genetic similarity with cutaneous melanoma. Conjunctival melanoma patients with advanced disease benefit from both targeted therapies (BRAF ± MEK inhibitors) and immune checkpoint inhibitors.

Early Exanthema Upon Vemurafenib Plus Cobimetinib Is Associated With a Favorable Treatment Outcome in Metastatic Melanoma: A Retrospective Multicenter DeCOG Study.

BACKGROUND: The combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome. METHODS: This multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS). RESULTS: A total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema. CONCLUSIONS: The development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment.