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Simple Summary: The effects of immune checkpoint inhibitor (ICI) therapy on 40 melanoma patients who developed immune-related hypophysitis were examined in this study. These patients were compared to 40 matched ones who did not develop hypophysitis. The onset of hypophysitis varied depending on the type of ICI used. Symptoms commonly included fatigue, headaches, and digestive problems. Patients with hypophysitis had low T4 hormone levels regardless of ICI type. However, low T3 and TSH hormone levels were only observed in patients who developed hypophysitis from ipilimumab. A rapid drop in blood sodium levels was also noted at the time of hypophysitis diagnosis. Additionally, the number of eosinophils and lymphocytes in the blood increased consistently in hypophysitis patients. Early diagnosis of hypophysitis is important because of its potential complications. Monitoring patients for specific symptoms and blood value changes could aid in early detection, allowing for prompt intervention and management. Background: Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activities and are widely used for the treatment of advanced cancers. However, they may lead to immune-related adverse events (irAEs) and some of them, such as hypophysitis, can be life-threatening. Here, early diagnosis is critical. Methods: We retrospectively analyzed 40 melanoma patients who developed hypophysitis during ICI treatment with either ipilimumab and/or anti-PD1 therapy and compared them to 40 control patients who did not develop hypophysitis during the ICI treatment, matched for age, gender, type of immunotherapy, and stage. Clinical data and blood values such as LDH, CRP, TSH, T3, T4, and absolute immune cell counts were retrieved from the medical records. Patient characteristics, laboratory values, progression-free survival, and overall survival were compared between the two groups. Results: Patients with ir-hypophysitis had a median age of 59 years, and most of them were male. Clinically, frequent symptoms were fatigue, headache, dizziness, and gastrointestinal symptoms such as nausea or abdominal pain. The onset of ir-hypophysitis differed much between ipilimumab- (median 8 weeks) and anti-PD1 (median 40 weeks)-induced hypophysitis (p < 0.001). At baseline, besides a slightly increased CRP level (p = 0.06), no differences were observed in patients who later developed hypophysitis compared to the control. After treatment started, hypophysitis patients showed a constant and significant decline in T4 levels from the start of therapy until diagnosis (p < 0.05), independent of the ICI treatment regime. However, a decline in T3 and TSH was only noted in patients with ipilimumab-induced ir-hypophysitis. Furthermore, serum sodium levels declined rapidly at the diagnosis of hypophysitis (p < 0.001). In addition, there was a constant increase in the absolute counts of eosinophils and lymphocytes from baseline in hypophysitis patients (p < 0.05). Conclusion: Ir-hypophysitis reveals different clinical pictures and onset times depending on the ICI regime used. Whereas a drop in T4 levels was indicative of developing hypophysitis independent of the ICI regime, TSH levels only declined in patients under ipilimumab-based ICI regimes. To best monitor our patients, it is important to recognize these differences. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients suffering from metastasized melanoma can be treated with three different combinations of tablets ("targeted therapy"), with similar efficacy but different side effect profiles. When one of the combinations is not tolerated well, their physicians may switch to a different combination; however, it has not been evaluated whether the second combination is actually tolerated better. In this work, we collected data on 94 patients from six German cancer centers who received two different combinations of targeted melanoma therapy to figure out whether the second combination was tolerated better. We found that indeed many side effects did not occur again and the novel combination was overall tolerated better, which justifies switching the combination when a patient experiences severe side effects. However, new side effects may occur. We believe our results are important for oncologists to adequately counsel patients with poor tolerability of this commonly used melanoma treatment. Targeted therapy with BRAF and MEK inhibitors (BRAFi, MEKi) is one of the mainstays of melanoma treatment. When dose-limiting toxicity (DLT) is observed, an option represents the intra-class switch to a different BRAFi+MEKi combination. Currently, there is scarce evidence for this procedure. This is a multicenter, retrospective analysis from six German skin cancer centers of patients who received two different combinations of BRAFi and MEKi. In total, 94 patients were included: 38 patients (40%) were re-exposed with a different combination because of previous unacceptable toxicity, 51 (54%) were re-exposed after progression, and 5 (5%) were included for other reasons. Of the 44 patients with a DLT during their first BRAFi+MEKi combination, only five (11%) experienced the same DLT during their second combination. A new DLT was experienced by 13 patients (30%). Six patients (14%) had to discontinue the second BRAFi treatment due to its toxicity. Compound-specific adverse events were avoided in the majority of patients by switching to a different combination. Efficacy data were similar to historical cohorts of BRAFi+MEKi rechallenge, with an overall response rate of 31% for patients who had previously progressed to treatment. We conclude that switching to a different BRAFi+MEKi combination if dose-limiting toxicity occurs is a feasible and rational approach in patients with metastatic melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Merkel cell carcinoma (MCC) is a rare, malignant primary skin tumor with high rates of recurrence and stage adapted 5-year overall survival rates around 66–75% at stage I, 50–60% at stage II, 42–52% at stage III and 17–18% at stage IV. Wide local tumor excision is indicated for localized disease, usually followed by postoperative radiotherapy of the tumor bed. A positive sentinel lymph node biopsy (SLNB) is considered a poor prognostic factor, but the only randomized controlled trial on elective lymph node irradiation was in times before introduction of SLNB in MCC, hence the management of the regional lymph nodes with respect to SLNB is currently not clear. The aim of this study was to analyze the pattern of relapse of patients with MCC that underwent surgery and postoperative radiotherapy at our institution and to determine the role of elective radiotherapy to regional lymph nodes with respect to SLNB results. The aim of this study was to analyze the pattern of relapse of patients with Merkel cell carcinoma (MCC) that underwent resection of the primary tumor site and postoperative radiotherapy at the Department of Radiation Oncology of Heidelberg University and to determine the role of the elective radiotherapy of regional lymph nodes with respect to SLNB results. A total of 57 patients were included in the present retrospective analysis. A total of 33 patients had additional lymph node irradiation (LNI); 24 had postoperative radiotherapy of the tumor bed only. Median follow-up was 43 months. Recurrence rate of the total cohort was 22.8%. Most relapses (69%) occurred in the regional nodes. Cumulative infield-tumor recurrence rate was low with 5.3%. Regional recurrence was more frequent in the cohort without LNI with 85.7% versus 37.5% with LNI. These results were similar for patients with negative sentinel lymph node (SLN) only with 80% regional relapses for those without LNI versus 33% with LNI. In conclusion, our data show that regional recurrence is the most frequent site of relapse in stage I-III MCC treated with curative intended postoperative radiotherapy and that elective irradiation of the regional lymph nodes reduces the risk of regional relapse even if the SLN was negative. [ABSTRACT FROM AUTHOR]

Simple Summary: For patients with advanced basal cell carcinoma (aBCC) limited treatment options are available. In this situation, hedgehog inhibitors (HHIs) are approved as first-line treatment. Upon treatment failure or intolerance, a second-line treatment with PD1 inhibitors (PD1i) is an option. However, no third-line treatment is established. Therefore, we collected data of patients with aBCC, who received HHI reinduction following PD1i-failure. In our cohort of 12 patients, initial HHI treatment led to partial response in 8 and disease stabilization in 4 patients. Eventual HHI discontinuation was mostly due to tumor progression. Second-line PD1i resulted in a partial response in only one patient. Four out of the twelve patients responded to HHI reinduction, with the longest follow-up period being 29 months. Thus, a sequential treatment with HHI reinduction can be a feasible treatment option in a subgroup of patients with aBCC after treatment failure of first-line HHIs as well as of second-line PD1i. For patients with advanced basal cell carcinoma (aBCC) first-line treatment with hedgehog inhibitors (HHIs) and second-line treatment with PD1 inhibitors (PD1i) is available, offering combination and sequencing options. Here, we focus on the efficacy and safety of HHI reinduction after PD1i failure. Retrospective data analysis was performed with 12 patients with aBCC (locally advanced (n = 8)/metastatic (n = 4)). These patients (male:female 6:6, median age 68 years) initially received HHIs, leading to complete/partial response (66%) or stable disease (33%). Median treatment duration was 20.8 (2–64.5) months until discontinuation due to progression (n = 8), adverse events (n = 3), or patient request (n = 1). Subsequent PD1 inhibition (pembrolizumab 42%, cemiplimab 58%) yielded a partial response (8%), stable disease (33%), or progression (59%). Median treatment duration was 4.1 (0.8–16.3) months until discontinuation due to progression (n = 9), adverse events (n = 1), patient request (n = 1), or missing drug approval (n = 1). HHI reinduction resulted in complete/partial response (33%), stable disease (50%), or progression (17%). Median treatment duration was 3.6 (1–29) months. Response duration in the four responding patients was 2–29+ months. Thus, a subgroup of patients with aBCC responded to reinduction of HHI following PD1i failure. Therefore, this sequential treatment represents a feasible treatment option. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous B-cell lymphomas (CBCL) are a heterogeneous group of mature B-cells neoplasms that present in the skin without evidence of nodal or systemic involvement. Despite being indolent in nature, they tend to recur in a third of patients after treatment. As repetitive treatments may be necessary for patients with CBCL, there is a need for gentle non-invasive therapy. Rituximab is a medication that targets CD20, a receptor regularly expressed on CBCL, and thereby destroys the cancerous cells. This medication can be given as an infusion into the vein or as an injection directly into the skin tumors. In this study, we found that rituximab injections have a similar efficacy compared to infusions for patients with limited CBCL lesions. Indolent cutaneous B-cell lymphomas (CBCL) are a rare disease for which the therapeutic recommendations are based on clinical reports. Recommendations for solitary lesions include surgery or irradiation. However, the high relapse rates may require less invasive repeatable therapy. This study seeks to retrospectively assess the efficacy of intralesional rituximab (ILR) for indolent CBCL when compared with intravenous rituximab (IVR). Patients treated for indolent CBCL with ILR or IVR at the Division of DermatoOncology of the University Hospital Heidelberg were eligible for this study. Characteristics of lymphoma, treatment response, and adverse events were assessed. Twenty-one patients, 67% male at a median age of 52 (range 17–80), were included. Nineteen (90%) had only localized lymphoma (stage T1 and T2). Complete response was achieved in 92% (11/12) of ILR after a median of one cycle (three injections) and 78% (7/8) of IVR patients after a median of six cycles. Half of ILR patients and 78% of IVR patients showed relapse after a median of 15 and 23 months, respectively. Adverse reactions were usually mild and were limited to the first injection of ILR. One patient with IVR contracted a pulmonary infection. ILR may be an alternative to the intravenous administration of rituximab for localized indolent CBCL. [ABSTRACT FROM AUTHOR]

Background: The value of cerebral susceptibility-weighted imaging (SWI) in malignant melanoma (MM) patients remains controversial and the effect of melanin on SWI is not well understood.Purpose: To systematically analyze the spectrum of intracerebral findings in MM brain metastases (BM) on SWI and to determine the diagnostic value of SWI.Study Type: Retrospective.Population/subjects: In all, 100 patients with melanoma BM (69 having received radiotherapy [RT] and 31 RT-naïve) and a control group of 100 melanoma patients without BM were included. For detailed analysis of signal characteristics, 175 metastases were studied.Field Strength/sequence: Gradient echo SWI sequence at 1.5, 3.0, and 9.4 T.Assessment: Signal characteristics from melanotic and amelanotic BMs on SWI with a focus on blooming artifacts were analyzed, as well as the presence and longitudinal dynamics of isolated SWI blooming artifacts in patients with and without BM.Statistical Tests: Chi-squared and Student's t-test were used for contingency table measures and group data of signal and clinical characteristics, respectively.Results: Melanotic and amelanotic metastases did not show significant differences of SWI blooming artifacts (38% vs. 43%, P = 0.61). Most metastases without an initial SWI artifact developed a signal dropout during follow-up (80%; 65/81). Isolated SWI artifacts were detected more frequently in patients with BM (20 vs. 9, P = 0.03), of which the majority were found in patients who had received RT (17 vs. 3, P = 0.08). None of these isolated SWI blooming artifacts turned into overt metastases over time (median follow-up: 8.5 months). Similar findings persisted as remnants of successfully treated metastases (88%; 7/8).Data Conclusion: We conclude that SWI provides little additional diagnostic benefit over standard T1 -weighted imaging, as melanin content alone does not cause diagnostically relevant SWI blooming. Signal transition of SWI may rather indicate secondary phenomena like microbleeding and/or metal scavenging. Our results suggest that isolated SWI artifacts do not constitute vital tumor tissue but represent unspecific microbleedings, RT-related parenchymal changes or posttherapeutic remnants of former metastatic lesions.Level Of Evidence: 3 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2019;50:1251-1259. [ABSTRACT FROM AUTHOR]

BACKGROUND Ingrown toenails have a tendency for recurrence. Operative interventions can be successful, and several procedures are in use. OBJECTIVE Retrospective evaluation, to reveal differences in postoperative pain, time to recovery, and satisfaction with the cosmetic outcome in patients treated with a phenol (PCM) or surgical matricectomy (SM). MATERIALS & METHODS All matricectomy patients at the Dermatology Department of the Ludwigshafen City Hospital between 2004 and 2008 were interviewed over the telephone. Of 72 evaluable patients with a total of 112 ingrown nail sides, 33 were treated with PCM and 39 with SM. The patient group consisted of 40.3% women, the median age was 31. RESULTS Patients after PCM indicated two points less postoperative pain on an analogue scale from 0 to 10 ( p<.001). In the PCM group, more patients recovered from the operation in less than 1 week ( p=.007). Patient evaluation of cosmetic outcome was not different between the groups ( p=.76), but recurrence rates were significantly higher in the PCM group (31.5%, vs 6.9% in the SM group, p=.006) CONCLUSION Both matricectomies have advantages and disadvantages. We should discuss these issues with our patients to help them decide on the kind of matricectomy. The authors have indicated no significant interest with commercial supporters. [ABSTRACT FROM AUTHOR]

Simple Summary: This retrospective multicenter study examines the influence of hepatic and extrahepatic metastases on the response of immune checkpoint blockade (ICB) in patients with metastatic uveal melanoma. A better response to dual ICB was observed in the presence of extrahepatic metastases in two recently published phase II trials. Therefore, we investigated two cohorts with and without extrahepatic metastasis and have assembled a population of 178 patients treated with ICB. The survival of this large cohort of patients with advanced UM was more favorable than that reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only. Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy is the standard of care in patients harboring metastasized melanoma. However, once further tumor growth is stopped it remains unclear when immunotherapy can be safely ceased. This clinical question is increasingly raised especially in patients with a strong desire to discontinue therapy or in patients who are forced to pause treatment due to severe immune-related side effects. With our study we aim to provide data which may be helpful for clinicians and patients when treatment discontinuation is considered. Further prospective, multicenter studies are needed to further address this important clinical issue. Checkpoint inhibitors have revolutionized the treatment of patients with metastasized melanoma. However, it remains unclear when to stop treatment. We retrospectively analyzed 45 patients (median age 64 years; 58% male) with metastasized melanoma from 3 cancer centers that received checkpoint inhibitors and discontinued therapy due to either immune-related adverse events or patient decision after an (18F)2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with a low-dose CT scan (FDG-PET-CT) scan without signs for disease progression. After a median of 21 (range 1–42) months of immunotherapy an FDG-PET-CT scan was performed to evaluate disease activity. In these, 32 patients (71%) showed a complete metabolic response (CMR) and 13 were classified as non-CMR. After a median follow-up of 34 (range 1–70) months, 3/32 (9%) of CMR patients and 6/13 (46%) of non-CMR patients had progressed (p = 0.007). Progression-free survival (PFS), as estimated from the date of last drug administration, was significantly longer among CMR patients than non-CMR (log-rank: p = 0.001; hazard ratio: 0.127; 95% CI: 0.032–0.511). Two-year PFS was 94% among CMR patients and 62% among non-CMR patients. Univariable Cox regression showed that metabolic response was the only parameter which predicted PFS (p = 0.004). Multivariate analysis revealed that metabolic response predicted disease progression (p = 0.008). In conclusion, our findings suggest that patients with CMR in an FDG-PET-CT scan may have a favorable outcome even if checkpoint inhibition is discontinued. [ABSTRACT FROM AUTHOR]

Simple Summary: BRAF inhibitors (BRAFi) are standard of care for BRAF-mutated metastatic melanoma (MM). One of the most common side effects is arthralgia, for which a high incidence has been described, but whose clinical presentation and management have not yet been characterized. The aim of this retrospective study was to assess the patterns and clinical course of this drug-induced joint pain and to discuss a potential pathogenesis based on our clinical findings. In our cohort of patients treated with BRAFi between 2010 and 2018, 48 of 154 (31%) patients suffered from new-onset joint pain, which primarily affected small joints with a symmetrical pattern, as can be observed in patients affected by rheumatoid arthritis, the most frequent rheumatic and musculoskeletal disease. Most cases were sufficiently treated by non-steroidal anti-inflammatory drugs; however, some patients required dose reduction or permanent discontinuation of the BRAFi. Interestingly, we found that the occurrence of arthralgia was associated with better tumor control. Introduction: BRAF inhibitors (BRAFi), commonly used in BRAF-mutated metastatic melanoma (MM) treatment, frequently cause arthralgia. Although this is one of the most common side effects, it has not been characterized yet. Methods: We retrospectively included all patients treated with BRAFi +/− MEK inhibitors (MEKi) for MM at the National Center for Tumor Diseases (Heidelberg) between 2010 and 2018 and reviewed patient charts for the occurrence and management of arthralgia. The evaluation was supplemented by an analysis of frozen sera. Results: We included 154 patients (63% males); 31% (48/154) of them reported arthralgia with a median onset of 21 days after the start of the therapy. Arthralgia mostly affected small joints (27/36, 75%) and less frequently large joints (19/36, 53%). The most commonly affected joints were in fingers (19/36, 53%), wrists (16/36, 44%), and knees (12/36, 33%). In 67% (24/36) of the patients, arthralgia occurred with a symmetrical polyarthritis, mainly of small joints, resembling the pattern typically observed in patients affected by rheumatoid arthritis (RA), for which a role of the MAPK signaling pathway was previously described. Patients were negative for antinuclear antibodies, anti-citrullinated protein antibodies, and rheumatoid factor; arthritis was visible in 10 of 13 available PET–CT scans. The development of arthralgia was linked to better progression-free survival and overall survival. Conclusion: Arthralgia is a common side effect in patients receiving BRAFi +/− MEKi therapy and often presents a clinical pattern similar to that observed in RA patients. Its occurrence was associated with longer-lasting tumor control. [ABSTRACT FROM AUTHOR]

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. 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 (<6 months) distant progression) were analysed separately. 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%. 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. • Patients with unresectable in-transit metastases show prolonged overall survival. • Favourable disease course is more common in female patients with a primary leg tumour. • 40% received local therapy before systemic therapy for stage III unresectable disease. • ORR of PD-1 therapy was 31.4% (n = 70). [ABSTRACT FROM AUTHOR]

The interaction of gut microbiome and immune system is being studied with increasing interest. Disturbing factors, such as antibiotics may impact the immune system via gut and interfere with tumor response to immune checkpoint blockade (ICB). In this multicenter retrospective cohort study exclusively treatment-naïve patients with cutaneous or mucosal melanoma treated with first-line anti-PD-1 based ICB for advanced, non-resectable disease between 06/2013 and 09/2018 were included. Progression-free (PFS), and overall survival (OS) according to antibiotic exposure (within 60 days prior to ICB and after the start of ICB vs. no antibiotic exposure) were analyzed. To account for immortal time bias, data from patients with antibiotics during ICB were analyzed separately in the time periods before and after start of antibiotics. Among 578 patients with first-line anti-PD1 based ICB, 7% of patients received antibiotics within 60 days prior to ICB and 19% after starting ICB. Antibiotic exposure prior to ICB was associated with worse PFS (adjusted HR 1.75 [95% CI 1.22–2.52]) and OS (adjusted HR 1.64 [95% CI 1.04–2.58]) by multivariate analysis adjusting for potential confounders. The use of antibiotics after the start of ICB had no effect on either PFS (adjusted HR 1.19; 95% CI 0.89–1.60) or OS (adjusted HR 1.08; 95% CI 0.75–1.57). Antibiotic exposure within 60 days prior to ICB seems to be associated with worse PFS and OS in melanoma patients receiving first-line anti-PD1 based therapy, whereas antibiotics after the start of ICB do not appear to affect PFS or OS. • Impact of antibiotics before/during first-line ICB for melanoma on survival. • Antibiotics prior to first-line ICB for melanoma are associated with worse PFS/OS. • Antibiotics after start of ICB do not appear to affect PFS and OS. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. • Presentation of ICI-iE is variable and resembles that of HSV-1 encephalitis. • Abnormal MRI and antineuronal antibodies are less common than previously reported. • Analysis of cerebrospinal fluid has the highest diagnostic value in ICI-iE. • ICI-iE has a mortality of 10% and long-term sequelae occur in 47% of patients. • Early immunosuppressive treatment of ICI-iE is associated with full recovery. [ABSTRACT FROM AUTHOR]

MEK inhibitors (MEKi) have shown clinical efficacy for NRAS-mutated, metastasized melanoma in randomised controlled trials, yet their clinical use is currently restricted to advanced, pre-treated patients, which is a different situation compared to previous trials. Data on their efficacy in the current real-world use are scarce. In this retrospective, multi-centre study, we evaluated the clinical course of disease of patients treated with MEKi with at least one previous treatment line in five German cancer centres. Thirty-three patients were included, 19 males (58%) and 14 females (42%), with a median age of 64 years. Ninety-one percent of patients were pre-treated with immune checkpoint inhibitors, 90% of patients had elevated serum lactate dehydrogenase (LDH) levels at treatment initiation, 33% suffered from cerebral metastases and 30% had an Eastern Cooperative Oncology Group performance status of 2 or higher. The response rate was 18.2%; the disease control rate was 48.5%. Median progression-free survival was 2.8 months (95% confidence interval (CI): 1.6–3.9 months), and median overall survival was 7.1 months (95% CI: 5.8–8.3 months). In subgroup analysis, clinical efficacy was similar also in patients with high LDH levels and cerebral metastases, and there was a better outcome in males and in patients treated with trametinib vs. other MEKi, which may be based on selection bias. Overall, the clinical efficacy was similar compared to previous clinical trials in earlier treatment lines. MEKi fulfil the need for an in-between treatment to stabilise the course of disease in advanced NRAS-mutated melanoma, but expectations regarding ongoing tumour response should be tempered. • Thirty-three patients with off-label MEK inhibitor monotherapy in NRAS-mutated melanoma. • Pre-treated and highly progressed patient cohort of 5 German skin cancer centres. • The overall response rate was 18%; the disease control rate was 49%. • Overall, results are comparable to available early-line randomised controlled trials. • MEK inhibitors may provide stabilisation of disease in this challenging cohort. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Our findings support the role of UV irradiation in conjunctival melanoma. • Oncogene mutation patterns are similar to cutaneous melanoma. • In contrast to uveal melanoma, lymph node metastasis is common. • Response to immune checkpoint inhibition (ICI) is better than in uveal melanoma. • Targeted therapy (TT) should be considered in BRAF mutated conjunctival melanoma. [ABSTRACT FROM AUTHOR]

Effective treatment options are limited for patients with advanced melanoma who have progressed on immune checkpoint inhibitors (ICI) and targeted therapies (TT). Preclinical models support the combination of ICI with TT; however, clinical trials evaluating the efficacy of triplet combinations in first-line setting showed limited advantage compared to TT only. We conducted a retrospective, multicenter study, that included patients with advanced melanoma who were treated with BRAF/MEK inhibitors in combination with an anti-PD-(L)1 antibody (triplet therapy) after failure of at least one anti-PD-(L)1-based therapy and one TT in seven major melanoma centers between February 2016 and July 2022. A total of 48 patients were included, of which 32 patients, 66.7% had brain metastases, 37 patients (77.1%) had three or more metastatic organs and 21 patients (43.8%) had three or more treatment lines. The median follow-up time was 31.4 months (IQR, 22.27–40.45 months). The treatment with triplet therapy resulted in an ORR of 35.4% (n = 17) and a DCR of 47.9% (n = 23). The median DOR was 5.9 months (range, 3.39–14.27 months). Patients treated with BRAF/MEK inhibitors as the last treatment line showed a slightly lower ORR (29.6%) compared to patients who received ICI or chemotherapy last (ORR: 42.9%). Grade 3–4 treatment-related adverse events occurred in 25% of patients (n = 12), with seven patients (14.6%) requiring discontinuation of treatment with both or either drug. Triplet therapy has shown activity in heavily pretreated patients with advanced melanoma and may represent a potential treatment regimen after failure of ICI and TT. • Unmet need for advanced melanoma after failure of immune- and targeted therapy (TT) • Combination of BRAF/MEK inhibitors plus anti-PD-(L)1 as so-called triplet therapy • Triplet therapy showed efficacy after failure of anti-PD-1-based therapy and TT • Triplet therapy as a viable regimen after failure of immune- and targeted therapy [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibition (ICI) triggers immune-related adverse events (irAEs). The relevance of lipase elevation remains unclear. Skin cancer patients with newly detected serum lipase elevation (at least twofold upper normal limit) or newly diagnosed type I diabetes mellitus upon ICI therapy were retrospectively collected at 14 German skin cancer centres. We identified 68 patients with lipase elevation occurring after a median time of 19 (range 1–181) weeks on ICI, 15 (22%) thereof had symptoms consistent with pancreatitis. Forty-seven patients (73%) had other irAE, mainly colitis. Discontinuation (n = 24, 35%) or interruption (n = 26, 38%) of ICI resulted in decrease of lipase after reinduction of ICI lipase levels increased again in 12 of 24 patients. In 18 patients (27%), ICI was continued unchanged, and in 12 (67%) of them, lipase levels normalised. Twenty-two patients were identified with newly diagnosed type I diabetes mellitus related to ICI, and 12 (55%) thereof had also lipase elevation mainly shortly before or after the diagnosis of diabetes. Fourteen (64%) patients had other irAE, mainly thyroiditis. Irrespective of lipase elevation, patients frequently showed a rapid onset with ketoacidosis, decreased c-peptide, and strongly increased blood glucose levels. Increased serum lipase during ICI is often not associated with pancreatitis but with other irAE as possible cause. Therefore, it might be sufficient to regularly monitor blood glucose levels and perform further workup only in case of signs or symptoms of pancreatitis and/or exocrine pancreas insufficiency. • Lipase elevation is often associated with e.g. colitis but not pancreatitis. • Immune checkpoint inhibition diabetes occurs often with endocrine immune-related adverse event and in 50% with lipase elevation. • Lipase elevation shortly precedes the onset of type I diabetes mellitus. • Therefore, blood glucose but not lipase monitoring is recommended. [ABSTRACT FROM AUTHOR]

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. 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. Among 173 BRAF V600-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. 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. [Display omitted] • This multicentre cohort study investigated 403 melanoma patients with elevated LDH. • End-points were progression-free and overall survival (OS) in first-line therapy. • Targeted therapy (TT) achieved the highest response rates in BRAF- mutant patients. • OS appears longer for combined anti-PD-1 and anti-CTLA-4 than for TT. • OS appears longer for combined anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone. [ABSTRACT FROM AUTHOR]

With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes. Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres. In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1–128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis). Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection. • Haematological immune-related adverse events are rare and initially asymptomatic. • Anaemia, thrombocytopenia and neutropenia comprised ~1/3 of cases each. • Regular blood count and prompt management are crucial as hem-irAE can be fatal. • Management may require immunosuppression beyond corticosteroids. [ABSTRACT FROM AUTHOR]

Abstract Background Combining stereotactic radiosurgery (SRS) and active systemic therapies (STs) achieved favourable survival outcomes in patients with melanoma brain metastases (MBMs) in retrospective analyses. However, several aspects of this treatment strategy remain poorly understood. We report on the overall survival (OS) of patients with MBM treated with a combination of radiotherapy (RT) and ST as well as the impact of the v-Raf murine sarcoma viral oncogene homolog B (BRAF)-V600 mutation (BRAFmut) status, types of RT and ST and their sequence. Patients and methods Data of 208 patients treated with SRS or whole brain radiation therapy (WBRT) and either immunotherapy (IT) or targeted therapy (TT) within a 6-week interval to RT were analysed retrospectively. OS was calculated from RT to death or last follow-up. Univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic features associated with OS. Results The median follow-up was 7.3 months. 139 patients received IT, 67 received TT and 2 received IT and TT within 6 weeks to RT (WBRT 45%; SRS 55%). One-year Kaplan-Meier OS rates were 69%, 65%, 33% and 18% (P <.001) for SRS with IT, SRS with TT, WBRT with IT and WBRT with TT, respectively. Patients with a BRAFmut receiving IT combined with RT experienced higher OS rates (88%, 65%, 50% and 18%). TT following RT or started before and continued thereafter was associated with improved median OS compared with TT solely before RT (12.2 [95% confidence interval {CI} 9.3–15.1]; 9.8 [95% CI 6.9–12.6] versus 5.1 [95% CI 2.7–7.5]; P =.03). Conclusion SRS and IT achieved the highest OS rates. A BRAFmut appears to be a favourable prognostic factor for OS. For the combination of RT and TT, the sequence appears to be crucial. Combinations of WBRT and ST achieved unprecedentedly high OS rates and warrant further studies. Highlights • Two hundred eight patients with melanoma brain metastases are reported. • Patients were treated with radiotherapy (RT) and systemic therapy (ST). • Stereotactic radiosurgery and immunotherapy achieved highest overall survival (OS) rates. • For RT and targeted therapy, treatment sequencing is critical. • Whole brain RT and ST achieved unprecedentedly high OS rates. [ABSTRACT FROM AUTHOR]

Aim Programmed cell death protein 1 (PD-1) inhibitors are a common treatment strategy for metastatic melanoma and other tumour entities. Clinical trials usually exclude patients with preexisting autoimmune diseases, thus experience with PD-1 inhibitor (PD-1i) in this patient population is limited. Patients and methods Metastatic melanoma patients with preexisting autoimmune disorders or previous ipilimumab-triggered immune-related adverse events (irAE) undergoing treatment with PD-1i from seven German skin cancer centres were evaluated retrospectively with regard to flare of the preexisting autoimmunity and development of new, not preexisting irAE as well as response to PD-1i therapy. Results In total, 41 patients had either preexisting autoimmunity (n = 19, group A, including two patients with additional ipilimumab-triggered autoimmune colitis) or ipilimumab-triggered irAE (n = 22, group B). At PD-1i therapy initiation, six patients in group A and two patients in group B required immunosuppressive therapy. In group A, a flare of preexisting autoimmune disorders was seen in 42% of patients, new irAE in 16%. In group B, 4.5% of patients showed a flare of ipilimumab-triggered irAE and 23% new irAE. All flares of preexisting autoimmune disorders or irAE were managed by immunosuppressive and/or symptomatic therapy and did not require termination of PD-1i therapy. tumour responses (32% in group A and 45% in group B) were unrelated to occurrence of autoimmunity. Conclusion While preexisting autoimmunity commonly showed a flare during PD-1i therapy, a flare of ipilimumab-triggered irAE was rare. Response rates were above 30% and unrelated to irAE. PD-1i therapy can be considered in patients with autoimmune disorders depending on severity and activity of autoimmunity. [ABSTRACT FROM AUTHOR]

Abstract: BRAF-mutant melanoma can be successfully treated by BRAF kinase inhibitors (BRAFi) and MEK kinase inhibitors (MEKi). However, the administration of BRAFi followed by MEKi did not generate promising response rate (RR). The purpose of this investigation was to evaluate the time to progression (TTP) with a mitogen-activated protein kinase (MAPK) pathway upstream inhibition strategy in BRAF mutated melanoma patients. BRAF mutation positive metastatic melanoma patients were identified within the Dermatology Cooperative Oncology Group (DeCOG) network and were treated first with a MEKi and upon progression with a selective BRAFi. A total of 23 melanoma patients (six females, 17 males, aged 47–80years) were retrospectively analysed for TTP. The total median TTP was 8.9months. The median TTP for MEKi was 4.8 (1.2–23.2) and subsequent for BRAFi 4.5 (1.2–15.7) months, respectively. A higher RR for MEKi (39%, nine partial responses and 0 complete responses) than previously reported was observed. Our analysis suggests that the reversed inhibition of the MAPK pathway is feasible in BRAF mutated melanoma. The median TTP (8.9months) is close to the promising BRAF- and MEKi combination therapy (median progression-free survival (PFS) 9.4months). The total treatment duration of the MAPK inhibition when a MEKi is administered first is similar compared to the reversed sequence, but TTP shifts in favour to the MEKi. This approach is feasible with reasonable tolerability. This clinical investigation encourages further studies in prospective clinical trials to define the optimal treatment schedule for the MAPK pathway inhibition and should be accompanied by molecular monitoring using repeated biopsies. [Copyright &y& Elsevier]