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Background: Up to now, the optimal duration of immune checkpoint inhibitors (ICI) has not been evaluated in prospective studies. However, current clinical practice requires decisions to be made regarding the duration of ICI in complete responders., Material and Methods: A survey was sent to 80 DeCOG skin cancer centers to assess how decisions are made on treatment duration of ICI in melanoma after having reached complete response, and staging intervals after ICI discontinuation. All responses received by March 10, 2024 (51 centers) were included., Results: The duration of ICI after having achieved complete remission varies between centers from three to 36 months. In total, 66% of the DeCOG centers continue treatment for up to 6 months, after having achieved complete remission (CR) with ICI. In the first year after discontinuation of ICI, most centers perform staging intervals (CT/MRI) every 3 months. More than 60% of centers continue staging at least once per year even in the 4th and 5th year after discontinuation., Conclusions: There are significant differences between the centers regarding staging intervals and duration of ICI upon CR. Prospective studies are necessary to determine the optimal time point of ICI discontinuation and follow-up., (© 2025 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Background: Interferon-alpha is an important therapeutic option for the treatment of the cutaneous T-cell lymphomas (CTCL). Since the approved recombinant interferon-α-2a (IFN-α2a) has no longer been produced since January 2020, pegylated interferon-α2a (pegIFN-α2a) can be used as an alternative treatment, even though it is not approved for the treatment of CTCL. The aim of this multicentre study was to generate comprehensive data on the efficacy and tolerability of pegIFN-α2a in the treatment of CTCL., Patients and Methods: A multicenter retrospective study was conducted with 70 patients with CTCL from twelve German skin centers., Results: In total, 70 patients were included in the study, with 57.2% male and a mean age of 58.8 ± 14.9 years. Mycosis fungoides was present in 71.4% of cases and Sézary Syndrome in 28.6%. An overall response rate of 55.2% was observed with pegIFNα-2a therapy. In 50% of cases, therapy was discontinued after 63.6 ± 33.5 weeks. The most common reason for discontinuation was adverse events, which occurred in 68.6% of cases and which were classified as severe in 29.2%. Blood count changes, fatigue and liver toxicity occurred most frequently., Conclusions: Our analysis provides comprehensive data on the efficacy and tolerability of pegIFNα-2a therapy in patients with CTCL. In terms of response rates and side effect profile, pegIFNα-2a appears to be comparable to IFN-α2a therapy., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Background: Photodynamic therapy (PDT) with topical δ-Aminolevulinic acid (ALA) has efficacy in treating basal cell carcinoma (BCC) but is limited by incomplete penetration of ALA into the deeper dermis. This prospective open-label pilot trial investigated the safety and efficacy of photosensitizer jet injection for PDT (JI-PDT) for BCC treatment. It was performed with 15 patients (n = 15) with histologically confirmed, untreated, low-risk nodular BCCs at a single institution., Methods: For the intervention, JI-PDT patients (n = 11) received two sessions of jet-injected ALA with PDT separated by four to 6 weeks. To further understand treatment technique, another group of patients (n = 4) received jet-injected ALA followed by tumor excision and fluorescence microscopy (JI-E). Treatment tolerability was assessed by local skin responses (LSR) score at five distinct time intervals. Fluorescence microscopy assessed protoporphyrin IX penetration depth and biodistribution within the tumor. At the primary endpoint, tumor clearance was evaluated via visual inspection, dermoscopy and reflectance confocal microscopy. Postinjection and postillumination pain levels, and patient satisfaction, were scored on a 0-10 scale., Results: Fifteen participants with mean age of 58.3, who were 15/15 White, non-Hispanic enrolled. The median composite LSR score immediately after JI-PDT was 5 (interquartile range [IQR] = 3) which decreased to 0.5 (IQR = 1) at primary endpoint (p < 0.01). Immunofluorescence of excised BCC tumors with jet-injected ALA showed photosensitizer penetration into papillary and reticular dermis. Of the 13 JI-PDT tumors, 11 had tumor clearance confirmed, 1 recurred, and 1 was lost to follow-up. 1/11 patients experienced a serious adverse event of cellulitis. 70% of patients had local scarring at 3 months. Patients reported an average pain level of 5.6 (standard deviation [SD] = 2.3) during jet injection and 3.7 (SD = 1.8) during light illumination., Conclusions: Jet injection of ALA for PDT treatment of nodular low-risk BCC is tolerable and feasible and may represent a novel modality to improve PDT., (© 2024 Wiley Periodicals LLC.)

Purpose: Dermatologic adverse events (dAEs) occur frequently in hospitalized patients and can significantly reduce quality of life. Physicians grade dAEs using the Common Terminology Criteria of Adverse Events (CTCAE). However, they often underestimate symptom frequency and severity. The patient-reported outcomes (PRO) version of the CTCAE (PRO-CTCAE) was developed to assess symptoms from the patient's perspective. In this study, we assessed the patient-reported burden of dAEs via the PRO-CTCAE questionnaire and compared results with dAE assessment by treating oncologists and dermatologists., Methods: Patients admitted to Memorial Sloan Kettering Cancer Center from 6/1/2018 to 4/30/2019 and received a dermatology consultation were eligible. Once enrolled, participants completed a PRO-CTCAE questionnaire on 14 dermatologic symptoms. CTCAE grades assigned by oncology and dermatology were obtained from clinical notes, and kappa statistics were calculated to evaluate the level of agreement between physician and patient evaluations., Results: A total of 100 patients (mean age 59.4, 55% male) were prospectively enrolled. The most common patient-reported dAEs were rash (72%), swelling (67%), pruritus (64%), bruising (53%), and hives (37%). Oncologists and dermatologists underreported dAEs except for rash (median kappa values 0.3 [0.02-0.84] and 0.32 [0.02-0.87], respectively). Oncologists and dermatologists were concordant with each other's documented assessment of dAEs (median kappa value 0.985 [0.55-1])., Conclusion: Oncology patient-reported dAEs in a tertiary academic oncologic referral center were under-recognized by providers. PRO-CTCAE may be a useful tool to optimize inpatient dermatologic care for cancer patients by detecting and allowing management of patient-reported dAEs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The IMMUNED trial previously showed significant improvements in recurrence-free survival for adjuvant nivolumab plus ipilimumab as well as for adjuvant nivolumab alone in patients with stage IV melanoma with no evidence of disease after resection or radiotherapy. Here, we report the final analysis, including overall survival data., Methods: IMMUNED was an investigator-sponsored, double-blind, placebo-controlled, three-arm, phase 2 trial conducted in 20 academic medical centres in Germany. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Patients were randomly assigned (1:1:1) to either nivolumab plus ipilimumab (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks), nivolumab monotherapy (nivolumab 3 mg/kg every 2 weeks), or matching placebo, for up to 1 year. The primary endpoint was recurrence-free survival in the intention-to-treat population. Secondary endpoints were time-to-recurrence, overall survival, progression-free survival or recurrence-free survival 2 (in patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence), and safety endpoints. This trial is registered on ClinicalTrials.gov (NCT02523313), and is complete., Findings: Between Sept 2, 2015, and Nov 20, 2018, 175 patients were enrolled in the study, and 167 were randomly assigned to receive either nivolumab plus ipilimumab (n=56), nivolumab plus ipilimumab-matching placebo (n=59), or double placebo control (n=52). At a median follow-up of 49·2 months (IQR 34·9-58·1), 4-year recurrence-free survival was 64·2% (95% CI 49·2-75·9) in the nivolumab plus ipilimumab group, 31·4% (19·7-43·8) in the nivolumab alone group, and 15·0% (6·7-26·6) in the placebo group. The hazard ratio (HR) for recurrence for the nivolumab plus ipilimumab group versus placebo was 0·25 (97·5% CI 0·13-0·48; p<0·0001), and for the nivolumab group versus placebo was 0·60 (0·36-1·00; p=0·024). Median overall survival was not reached in any treatment group. The HR for overall survival was significantly in favour of the nivolumab plus ipilimumab group versus placebo (HR 0·41; 95% CI 0·17-0·99; p=0·040), but not for the nivolumab group versus placebo (HR 0·75; 0·36-1·56; p=0·44). 4-year overall survival was 83·8% (95% CI 68·8-91·9) in the nivolumab plus ipilimumab group, 72·6% (57·4-83·2) in the nivolumab alone group, and 63·1% (46·9-75·6) in the placebo group. The median progression-free survival or recurrence-free survival 2 of patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence was not reached (95% CI 21·2 months to not reached). Rates of grade 3-4 treatment-related adverse events remained largely unchanged compared with our previous report, occurring in 71% (95% CI 57-82) of the nivolumab plus ipilimumab group, and 29% (95% CI 17-42) of patients receiving nivolumab alone. There were no treatment-related deaths., Interpretation: Both active regimens continued to show significantly improved recurrence-free survival compared with placebo in patients with stage IV melanoma with no evidence of disease who were at high risk of recurrence. Overall survival was significantly improved for patients receiving nivolumab plus ipilimumab compared with placebo. Use of subsequent anti-PD-1-based therapy was high in patients in the placebo group after recurrence and most likely impacted the overall survival comparison of nivolumab alone versus placebo. The recurrence-free and overall survival benefit of nivolumab plus ipilimumab over placebo reinforces the change of practice already initiated for the treatment of patients with stage IV melanoma with no evidence of disease., Funding: Bristol-Myers Squibb., Competing Interests: Declaration of interests EL reports personal fees, honoraria, and other (support for attending meetings and/or travel grants) from Bristol-Myers Squibb, Medac, MSD, Novartis, Sanofi, Sun Pharma, and Pierre Fabre; EL participated on a drug safety monitoring or advisory board for Bristol-Myers Squibb, Novartis, Sanofi, and Sun Pharma. LZ reports personal fees, honoraria, and other (support for attending meetings and/or travel grants) from Bristol-Myers Squibb, MSD, Pierre Fabre, Novartis, Sanofi, and Sun Pharma; LZ participated on drug safety monitoring or advisory boards for Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi, and Sun Pharma. JCH reports personal fees, honoraria, and other (support for attending meetings and/or travel grants) from Almirall Hermal, Amgen, GSK, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma; medical writing support from Bristol-Myers Squibb outside the submitted work; and unpaid leadership or fiduciary roles for the Deutsche Krebshilfe charity and the German dermato-oncology working group. MF reports personal fees, honoraria, and other (support for attending meetings and/or travel grants), as well as participation on drug safety monitoring or advisory boards for Bristol-Myers Squibb, MSD, Novarts, Pierre Fabre, Roche, and Sanofi. TKE reports consulting fees from Bristol-Myers Squibb, Almirall Hermal, Immunocore, Novartis, Pierre Fabre, and Sanofi outside the submitted work, and an unpaid leadership or fiduciary role for DeCOG. CL reports personal fees, honoraria, and other (support for attending meetings and/or travel grants) from Almirall Hermal, Biontech, BMS, Immunocore, Kyowa Kirin, MSD, Merck Serono, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma outside the submitted work. SH reports personal fees and honoraria as well as participation on a drug safety monitoring or advisory board from/for Bristol Myers Squibb, MSD, Novartis, and Pierre Fabre, all outside the submitted work. RG reports consulting fees, personal fees, and other (support for attending meetings and/or travel grants) from Bristol-Myers Squibb, Merck Serono, Pierre Fabre, Roche, and Sun Pharma; consulting and personal fees from Almirall Hermal, Amgen, MSD, Novartis, and Sanofi; consulting fees from 4SC and Immuncore (all outside the submitted work); and participation on a drug safety monitoring or advisory board for Almirall Hermal, Amgen, Immunocore, 4SC, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma, in addition to an unpaid leadership role (ie, chair) for the German dermato-oncology working group. FM reports personal fees and honoraria as well as participation on a drug safety monitoring or advisory board from/for Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Novartis, Roche, and Sanofi. PM reports personal fees, honoraria, and other (support for attending meetings and/or travel grants) from MSD, Novartis, and Pierre Fabre; personal fees and honoraria from Almirall Hermal, Amgen, Beiersdorf, Roche, and Sanofi; and travel support from Bristol-Myers Squibb. AH reports honoraria and personal fees as well as participation on a drug safety monitoring or advisory board from/for Eisai, Merck, MSD, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi, Amgen, BMS, and MerckSerono; and additional participation on drug safety monitoring or advisory boards for Immunocore, Replimune, and Seagen. BS reports consulting fees from Almirall Hermal, Bristol-Myers Squibb, Immunocore, MSD and Sanofi; honoraria and personal fees from Bristol-Myers Squibb, Novartis, Pfizer, and Pierre Fabre; and support for attending meetings from Bristol-Myers Squibb and Pierre Fabre. CM reports grants and contracts from the German Research Fund (DFG, ME 5482/1-1) and the Society of MSK (June, 2018), as well as honoraria and personal fees from AstraZeneca, Bristol-Myers Squibb, and Recordati Rare Diseases. FK reports honoraria, consulting, and personal fees from Bristol-Myers Squibb, MSD, Novartis, and Sanofi; and honoraria from Pierre Fabre. AR reports honoraria, personal fees, and travel support from Novartis and honoraria from Bristol-Myers Squibb. MZ reports honoraria, personal fees, and travel support from Novartis; honoraria from MSD and Pierre Fabre; and participation on a data safety monitoring or advisory board for Bristol-Myers Squibb and MSD. CG reports participation on drug safety monitoring or advisory boards for Bristol-Myers Squibb, CeCeVa, MSD, NeraCare, Novartis, Philogen, and Sanofi, and has a leadership role (ie, chair) for the European Association of Dermato-Oncology (EADO). JCB reports consulting fees from Almirall Hermal, Boehringer Ingelheim, InProTher, ICON Clinical Research, Merck Serono, Pfizer, Sanofi/Regeneron, and 4SC; and honoraria from Pfizer, Recordati, and Sanofi. DS reports partial financial support from Bristol Myers Squibb for the conduct of this study and drug supply (nivolumab and ipilimumab) support; grants (or contracts) from Amgen, Array/Pfizer, Bristol-Myers Squibb, MSD, Novartis, and Roche; consulting fees from 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Haystick, Immunocore, InFlarX, Innocent, LabCorp, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, and Sun Pharma; honoraria from Bristol-Myers Squibb, MSD/Merck, Merck Serono, Novartis, Roche, Sanofi, and Sun Pharma; support for attending meetings or travel support from Bristol-Myers Squibb, MSD, Merck Serono, Novartis, Pierre Fabre, and Sanofi; participation on drug safety monitoring or advisory boards for 4SC, Amgen, Array Biopharma, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Immunocore, InFlarX, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron, and SunPharma; and leadership roles for DeCOG, German Cancer Society, Hiege-Stiftung, Deutsche Hautkrebsstiftung, Nationale Versorgungskonferenz Hautkrebs, and EuMelaReg. CW-K and LS are employees of Alcedis. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.

Opinion Statement: Modern therapy of advanced melanoma offers effective targeted therapeutic options in the form of BRAF plus MEK inhibition for patients with BRAF V600 mutations. For patients lacking these mutations, checkpoint inhibition remains the only first-line choice for treatment of metastatic disease. However, approximately half of patients do not respond to immunotherapy, requiring effective options for a second-line treatment. Advances in genetic profiling have found other possible target molecules, especially a wide array of rare non-V600 BRAF mutations which may respond to available targeted therapy.More information on the characteristics of such mutants is needed to further assess the efficacy of targeted therapies in the metastatic and adjuvant setting of advanced melanoma. Thus, it may be helpful to classify known BRAF mutations by their kinase activation status and dependence on alternative signaling pathways. While BRAF V600 mutations appear to have an overall more prominent role of kinase activity for tumor growth, non-V600 BRAF mutations show great differences in kinase activation and, hence, response to BRAF plus MEK inhibition. When BRAF-mutated melanomas rely on additional signaling molecules such as RAS for tumor growth, greater benefit may be expected from MEK inhibition than BRAF inhibition. In other cases, mutations of c-kit or NRAS may serve as important pharmacological targets in advanced melanoma. However, since benefit from currently available targeted therapies for non-V600 mutants is usually inferior regarding response and long-term outcome, checkpoint inhibitors remain the standard recommended first-line therapy for these patients.Herein, we review the current clinical data for characteristics and response to targeted therapy of melanomas lacking a V600 BRAF mutation., (© 2022. The Author(s).)

In patients with melanoma brain metastases (MBM), a combination of radiotherapy (RT) with immune checkpoint inhibitors (ICI) is routinely used. However, the best sequence of radio-immunotherapy (RIT) remains unclear. In an exploratory phase 2 trial, MBM patients received RT (stereotactic or whole-brain radiotherapy depending on the number of MBM) combined with ipilimumab (ipi) ± nivolumab (nivo) in different sequencing (Rad-ICI or ICI-Rad). Comparators arms included patients treated with ipi-free systemic treatment or without RT (in MBM-free patients). The primary endpoints were radiological and immunological responses in the peripheral blood. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Of 106 screened, 92 patients were included in the study. Multivariate analysis revealed an advantage for patients starting with RT (Rad-ICI) for overall response rate (RR: p = .007; HR: 7.88 (95%CI: 1.76-35.27)) and disease control rate (DCR: p = .036; HR: 6.26 (95%CI: 1.13-34.71)) with a trend for a better PFS (p = .162; HR: 1.64 (95%CI: 0.8-3.3)). After RT plus two cycles of ipi-based ICI in both RIT sequences, increased frequencies of activated CD4, CD8 T cells and an increase in melanoma-specific T cell responses were observed in the peripheral blood. Lasso regression analysis revealed a significant clinical benefit for patients treated with Rad-ICI sequence and immunological features, including high frequencies of memory T cells and activated CD8 T cells in the blood. This study supports increasing evidence that sequencing RT followed by ICI treatment may have better effects on the immunological responses and clinical outcomes in MBM patients., Competing Interests: TES, HS, JM, DM, KL, MFH, IH, CK, RS, and PB declare no competing interests. JCH received scientific grant support from BMS; honoraria for talks from Almirall, Amgen, BMS, GSK, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi; advisory board member for MSD, Pierre Fabre; travel grants from BMS, Immunocore, 4SC. MS received honoraria for talks from Novartis; travel grants from Merck, Abbvie, Novartis, Sanofi-Aventis, BMS, Merck Sharp & Dome, Pfizer. CM received a fellowship from the German Research Foundation (DFG) (ME 5482/1-1) 2/2020-5/2021. LK reports personal fees from Accuray Inc., and Novocure GmbH. AE received honoraria for Biotest AG, Meet the Experts, Janssen-Cilag, Klinikum Minden; consulting fees for Biotest AG, MSD, Galderma Laboratorium, Janssen-Cilag, Roche, AbbVie; advisory board member for MSD, Biotest. JD received grants from Viewray Inc, Accuray International Sari, RaySearch Laboratories AB, Vision RT Limited, Astellas Pharma GmbH, Siemens Healthcare GmbH, Solution Akademie GmbH, Egomed PLC Surrey Research Park, Quintiles GmbH, Pharmaceutical Research Associates GmbH, Boehringer Ingelheim Pharma GmbH&CoKG, PTW-Freiburg Dr. Pychlau GmbH, Nanobiotix S.A., Accuray Incorporated., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The risk of UV radiation (UVR)-induced non-melanoma skin cancer (NMSC) is dramatically increased in immunosuppressed organ transplant recipients compared to immunocompetent patients. In the skin, p53 up-regulated modulator of apoptosis (PUMA) is a central regulator of apoptosis in response to UVR damage and immune response regulation. Data on the expression of PUMA in patients with NMSC relative to immune status is limited To study differences in the expression and distribution of PUMA in cutaneous SCC and BCC by immunohistochemistry between immunocompetent patients and organ transplant recipients, and the effect of CsA-containing immunosuppressive maintenance regimens on this expression. PUMA expression in SCC (n = 34) and BCC (n = 20) was analysed comparatively by immunohistochemical staining in matched cohorts of 27 immunocompetent patients and 27 organ transplant recipients SCC and BCC showed unequivocal positive PUMA expression, however, there was no significant difference in NMSC between organ transplant recipients and immunocompetent patients. A 17% reduction in staining score for PUMA in SCC, but not in BCC, of organ transplant recipients treated with a cyclosporin (CsA)-containing regimen was noted compared to organ transplant recipients without chronic CsA intake (p = 0.0381) PUMA expression in SCC, but not BCC, is significantly reduced by CsA-containing therapy, suggesting a disturbance of apoptosis by iatrogenic immunosuppression with a divergent impact on SCC and BCC.

Background: Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced-ie, unresectable or metastatic-melanoma. This criterion, however, excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population., Methods: We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1-12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing., Findings: Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n=56), nivolumab (n=59), or placebo (n=52). As of July 2, 2019, at a median follow-up of 28·4 months (IQR 17·7-36·8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12·4 months (95% CI 5·3-33·3) in the nivolumab group and 6·4 months (3·3-9·6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0·23 (97·5% CI 0·12-0·45; p<0·0001), and for the nivolumab group versus placebo group was 0·56 (0·33-0·94; p=0·011). In the nivolumab plus ipilimumab group, recurrence-free survival at 1 year was 75% (95% CI 61·0-84·9) and at 2 years was 70% (55·1-81·0); in the nivolumab group, 1-year recurrence-free survival was 52% (38·1-63·9) and at 2 years was 42% (28·6-54·5); and in the placebo group, this rate was 32% (19·8-45·3) at 1 year and 14% (5·9-25·7) at 2 years. Treatment-related grade 3-4 adverse events were reported in 71% (95% CI 57-82) of patients in the nivolumab plus ipilimumab group and in 27% (16-40) of those in the nivolumab group. Treatment-related adverse events of any grade led to treatment discontinuation in 34 (62%) of 55 patients in the nivolumab plus ipilimumab group and seven (13%) of 56 in the nivolumab group. Three deaths from adverse events were reported but were considered unrelated to the study treatment., Interpretation: Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3-4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease., Funding: Bristol-Myers Squibb., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Objectives: Dermatoscopy may be hindered by body hair, and the development of an automated hair removal algorithm (AuHRA) might improve the diagnostic accuracy. However, the physicians' exact level of hindrance and the clinical benefit attained by AuHRA has not been assessed. The objectives of this study are to quantify the physicians' level of hindrance by body hair and the level of improvement in the visibility of underlying dermatoscopic patterns after application of AuHRA to digital images of hair-covered nevi., Patients and Methods: A cross-sectional reader study including 59 sets of dermatoscopic images of benign nevi that were presented to six dermatologists. Each set included three images of one individual nevus (unshaved/physically shaved/digitally shaved with AuHRA), which were compared to each other within each set to assess the level of improvement caused by hair removal., Results: In comparison to unshaved lesions, dermatologists attributed the highest mean level of improvement to a physical shave (+1.36, p < 0.001) followed by AuHRA's digital shave (+0.79, p < 0.001). The majority of dermatologists considered the application of AuHRA as helpful and confirmed a medical need., Conclusions: The dermatologists in our study confirmed a substantial impairment of the dermatoscopic examination by body hair. We demonstrated a clinical benefit attained by AuHRA in comparison to unshaved or physically shaved lesions., (© 2019 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Purpose of Review: Graft-versus-host disease (GVHD) is an immune mediated disorder affecting 30 - 70% of patients after allogeneic hematopoietic stem cell transplantation (alloHSCT), and is a major cause of morbidity and non-relapse mortality (NRM) [1]. Dermatologists play a critical role in acute and chronic GVHD, as skin involvement is common and often the earliest involved site of disease [2]., Recent Findings: GVHD shares clinical and histopathological features with a variety of other skin diseases, requiring thorough consideration of differential diagnoses in hematopoietic stem cell transplantation (HSCT) recipients with lesions suggestive of cutaneous GVHD. Treatment considerations for GVHD are influenced by factors such as disease classification, overall grading, organ involvement, associated symptoms, and immunological anti-tumor effect. Several treatments are available and may be indicated as monotherapy or adjuvant therapy to allow faster withdrawal or tapering of immunosuppression. While corticosteroids are often first line therapy, oral ruxolitinib has been recently approved for treatment of steroid-refractory aGHVD, and oral ibrutinib has been approved for steroid-refractory cGHVD., Summary: This article provides current clinical, diagnostic, and therapeutic considerations relevant to the hospitalist for both acute and chronic mucocutaneous GVHD. Optimal inpatient management of these diseases requires an interdisciplinary team., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

Purpose: BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K-mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited., Methods: In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed., Results: Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively ( P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma., Conclusion: Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.

Importance: Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data., Objective: To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects., Design, Setting, and Participants: We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally., Exposures: Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab)., Main Outcomes and Measures: Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects., Results: Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4)., Conclusions and Relevance: In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

Background and objectives Unmyelinated C-fibres comprise the largest group of somatic afferents and have demonstrated a crucial role not only in the perception of high-threshold mechanically, thermally or chemically induced pain, but also in non-harmful low-threshold mechanical stimuli [1,2]. The objective of our study was to characterize differential sensitivity changes of C-fibre related subclasses of high-threshold and low-threshold polymodal nociceptors and low-threshold mechanoreceptors to the local anaesthetic (LA) mepivacaine during nerve block of the purely sensory lateral femoral cutaneous nerve (LFCN) in human. We assumed a diverse response of different classes of afferents to the two different concentrations of the LA mepivacaine (Scandicaine). Methods In a double-blind randomized experimental setting, an ultrasound-guided nerve block of the LFCN was performed in 10 healthy male subjects, each with two different concentrations of mepivacaine (0.5 and 1%). Responsiveness of afferent nerve fibres to different noxious and non-noxious stimuli was tested by Quantitative Sensory Testing (QST) 30, 180, and 300 min after nerve block. Both LA concentrations of mepivacaine were compared for time course of the areas of anaesthesia for the tested sensory modalities. Results Initial extension of anaesthetic areas at 30 min did not differ between both LA concentrations. At 180 min only the anaesthetic areas to nociceptive stimuli were reduced at the site of lower mepivacaine injection (260mN: 204mm2 (18; 244; median difference and 95% confidence interval; p < 0.05), heat: 276mm2 (3; 305)). In contrast, no significant differences were found between the two concentration when non-nociceptive stimuli were used (100mN: 187mm2 (4; 240), p >0.05, brush: 159mm2 (-59; 202)). Conclusion Equal initial sizes of anaesthesia areas for all sensory modalities can be explained by supramaximal perineural LA molecule concentration in both administered mepivacaine dosages. Upon washout of the LA nociceptive function is restored faster as compared to non-nociceptive sensation and higher concentration of the LA are required to maintain the analgesia. Quantitative sensory testing is able to detect different susceptibility of low threshold mechanosensors and subtypes of nociceptive C-fibres to mepivacaine. Using painful mechanical, heat and electrical stimulation different classes of nociceptors will be activated. The analgesic areas to electrical stimulation were particularly small; one might therefore hypothesize that the proposed protocol allows to also differentiate mechano-insensitive ("silent") and mechanosensitive ("polymodal") nociceptors. Implications QST is a non-invasive method to functionally examine sensory modalities and their pharmacological modulation in humans. The method is sufficiently sensitive to differentiate the analgesic properties of mepivacaine at 0.5 and 1% and might also be adequate to different classes of nociceptors. Further development of nociceptive stimuli including supra-threshold encoding characteristics will enable to investigate peripheral analgesic effects more specifically and thus might help to design new analgesics with preferential effect on high frequency discharge of nociceptors.

A sensitive and specific radioligand receptor assay (RRA) using rat testis homogenate as the receptor source is described for measurement of luteinizing hormone (LH) in bovine blood. Interfering and non-specific substances in blood were removed by means of ion-exchange chromatography on CM-Sephadex C-50. Criteria of validation such as recovery of added LH to plasma or serum, reproducibility, and specificity gave good results. Inhibition curves obtained with bovine plasma and serum were parallel to those obtained with the bovine standard preparation. The range of the dose-response curve was between 0.5-20 ng of bovine LH. The pattern of LH concentrations in purified serum samples under different physiological conditions such as during the oestrus cycle and after administration of GnRH showed a very close correlation whether measured by means of radioimmunoassay (RIA) or receptor assay. Values of RRA-LH were consistently higher than those of RIA-LH. Thus the lower the RIA-LH levels, the more pronounced were the discrepancies between results of both assay systems. The mean ratio of RRA-LH/RIA-LH for basal levels (less than 1 ng RIA-LH/ml plasma) was 17.8 as compared to a mean ratio for higher peak values (more than 20 ng RIA-LH/ml plasma) of only 1.2.

A double-antibody radioimmunoassay for PMSG, especially for meauring PMSG in cattle blood after exogenous application, has been developed. A rabbit antiserum against PMSG and pure PMSG for radioiodination were used. There was a strong cross-reaction against equine LH and FSH, but the slight cross-reaction against bovine LH and FSH could be eliminated by adding bovine LH to each tube during the assay. Unspecific, interfering influences of equine or cow serum could be eliminated by adding a constant amount of PMSG-free serum to each tube. PMSG added to 200 microliter of serum could be recovered by this method with a mean of 90 . 5 +/- 9 . 9%. Inhibition curves obtained with pregnant mare serum or cow serum after administration of PMSG were parallel to those obtained with the PMSG standard preparation. The intra-assay coefficient of variation (CV) was 6 . 9%. The inter-assay CV was 12 . 6%. Sensitivity of the assay was 1 mi.u. PMSG/tube. Values of PMSG measured in the serum of pregnant mares by this assay were comparable with those obtained by a bioassay on the same samples. PMSG was still measurable in blood serum about 10 days after injection of 1500-3000 i.u. PMSG. After infusion of 12,000 i.u. PMSG for 3 h (2 heifers), the half-life of PMSG was found to have two components, one of 51 or 40 h and a slower one of 123 or 118 h.