Search

Background: Histopathologic regression of cutaneous melanoma is considered a favorable prognostic factor, but its significance in clinical practice remains controversial., Objective: To investigate the prognostic importance of regression in patients with primary cutaneous melanoma undergoing sentinel lymph node (SLN) biopsy and to assess its significance in patients progressing to an unresectable stage requiring systemic therapy., Methods: We retrospectively reviewed patients with newly diagnosed melanoma undergoing SLN biopsy between 2010 and 2015 and available information on histopathologic regression (n = 1179). Survival data and associations of clinical variables with SLN status were assessed., Results: Patients with regressive melanoma showed favorable relapse-free (hazard ratio [HR], 0.52; P = .00013), distant metastasis-free (HR, 0.56; P = .0020), and melanoma-specific survival (HR, 0.35; P = .00053). Regression was associated with negative SLN (odds ratio, 0.48; P = .0077). In patients who progressed to an unresectable stage, regression was associated with favorable progression-free survival under immune checkpoint inhibition (HR, 0.43; P = .031) but not under targeted therapy (HR, 1.14; P = .73) or chemotherapy (HR, 3.65; P = .0095)., Limitations: Retrospective, single-institutional design., Conclusions: Regression of cutaneous melanoma is associated with improved prognosis in patients eligible for SLN biopsy as well as in patients with unresectable disease receiving systemic therapy with immune checkpoint inhibitors., Competing Interests: Conflicts of interest Dr Wagner reports advisory board meetings for Pierre Fabre and honoraria and speaker’s fees from Novartis and Sanofi outside the submitted work. Dr Forschner reports honoraria for presentations from BMS, MSD, Novartis, Pierre Fabre; travel support and congress participation support from BMS, Pierre Fabre, Novartis; advisory board participation for MSD, BMS, Novartis, Pierre Fabre, Immunocore; and institutional funding from BMS and Stiftung Immunonkologie outside the submitted work. Dr Leiter has received consultancy fees from MSD, Novartis, and Roche; has participated in advisory board meetings for MSD, Novartis, Sun Pharma, Almirall Hermal, and Roche; has received honoraria from MSD, Novartis, Sun Pharma, Almirall Hermal, and Roche; and has received travel support from Sun Pharma and Pierre Fabre. Dr Amaral reports institutional grants from SkylineDx, institutional grants and personal fees from Novartis, institutional grants from NeraCare, personal fees from BMS, institutional grants from Sanofi, personal fees from CeCaVa, and personal fees from Pierre Fabre, all outside the submitted work. Dr Amaral serves as the current Chair of the ESMO Fellowship Development Committee and was previously the Chair of the ESMO Young Oncologists Committee. Dr Garbe reports personal fees from CeCaVa, personal fees from MSD, personal fees from NeraCare, and personal fees from Philogen, outside the submitted work. Dr Eigentler reports consultant fees from and an advisory role for Philogen, Bristol-Myers Squibb, Novartis, Roche, and Sanofi. Dr Forchhammer reports personal fees from Kyowa Kirin and Recordati Rare Diseases (speaker’s honoraria) as well as institutional grants from NeraCare, SkylineDx, and BioNTech outside the submitted work. Dr Flatz reports grants from the Swiss National Science Foundation, Swiss Cancer League, Hookipa Pharma, and Novartis Foundation outside the submitted work and an advisory role for Novartis and Bristol-Myers Squibb. Ms Knierim and Drs Luttermann, Metzler, Yazdi, Bauer, and Gassenmaier have no conflicts of interest to declare., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Melanomas of the central nervous system (CNS) based on neurocutaneous melanocytosis (NCM) are exceptionally rare in childhood and have been described only sporadically. Rapidly progressive disease may represent a major challenge for treating physicians, especially given the limited knowledge about this condition. This analysis aimed to increase knowledge about the occurrence and treatment of these malignancies., Procedure: Data on diagnosis, treatment, and outcome of patients aged 0-18 years with CNS melanoma based on NCM recorded in the German Registry for Rare Pediatric Tumors (STEP registry) were analyzed. Additionally, published case reports on this condition were analyzed., Results: In STEP, five patients with leptomeningeal melanoma based on NCM were identified, with a median age at melanoma diagnosis of 3.7 years. Various multimodal treatments were performed: (partial) resection (n = 4), irradiation (n = 2), trametinib (n = 3), different cytostatics (n = 2), and anti-GD2 immunotherapy (n = 1). All patients died between 0.3 and 0.8 years after diagnosis. Including published case reports, 27 patients were identified with a median age of 2.8 years at melanoma diagnosis (range: 0.2-16.6). Fourteen of 16 cases with reported data had a NRAS alteration (88%), particularly NRAS p.Q61K (85%). In the expanded cohort, no patient survived longer than 1 year after diagnosis despite multimodal therapy (including trametinib; n = 9), with a median survival of 0.4 years (range 0.1-0.9)., Conclusions: CNS melanomas based on NCM in childhood are aggressive malignancies without curative treatment to date. Therapeutic approaches must be individualized. Genetic tumor sequencing is essential to improve understanding of tumorigenesis and potentially identify new therapeutic targets., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

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., Competing Interests: Declaration of Competing Interest N.B.W. has participated in advisory board meetings for Novartis, Pierre Fabre, and Sanofi, and received speaker fees from Sanofi, outside the submitted work. A.Oe. has received consultant fees from MSD and Bristol-Myers Squibb; has participated in advisory board meetings for MSD and Bristol-Myers Squibb. T.A. received institutional grants from SkylineDx, Neracare, Novartis, Sanofi, and consulting fees from Novartis, Neracare, BMS, CeCaVa and Chemosat, outside the submitted work. A.F. served as a consultant to Novartis, MSD, BMS, Pierre-Fabre and Immunocore; received travel support from Novartis, BMS, Pierre-Fabre, and received speaker fees from Novartis, BMS and MSD and reports institutional research grants from BMS Stiftung Immunonkologie, outside the submitted work. U.L. has received consultancy fees from MSD, Novartis, and Roche; has participated in advisory board meetings for MSD, Novartis, and Roche; has received honoraria from MSD, Novartis, and Roche. P.T. has received honoraria and/or consultancy fees from Bristol-Myers Squibb, Curevac, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi; has received travel support from Bristol-Myers Squibb and Pierre-Fabre. J.M. has received consultancy fees from Merck/Pfizer, MSD, Amgen, Novartis, Bristol-Myers Squibb, and Pierre Fabre; has participated in advisory board meetings for Merck/Pfizer, MSD, Amgen, Novartis, Bristol-Myers Squibb, and Pierre Fabre; has received travel support from Ultrasun, L′Oreal, MSD, Bristol-Myers Squibb, and Pierre Fabre. C.L. has received consultancy fees from, has participated in advisory board meetings for, has received speaker’s fees, and/or has received travel reimbursements from Roche, Pierre Fabre, Novartis, Bristol-Myers Squibb, Merck, MSD, Biontech, Almiral Hermal, Kyowa Kirin, Sun Pharma and Sanofi. C.G. has received personal fees from CeCaVa, MSD, NeraCare and Philogen. F.M. has received speaker’s fees from, has received travel support from, and has participated in advisory board meeting for Novartis, Roche, Bristol-Myers Squibb, MSD and Pierre Fabre; has received research funding from Novartis and Roche. T.K.E. has received consultancy fees from Philogen, Bristol-Myers Squibb, Novartis, Roche, Merck, and Sanofi; has participated in advisory board meetings for CureVac, Philogen, Bristol-Myers Squibb, Novartis, Roche, and Sanofi. L.F. has received grant funding from the Swiss National Science Foundation, Swiss Cancer League, Hookipa Pharma and Novartis Foundation; has participated in advisory board meetings for Novartis and Bristol-Myers Squibb. M.M.L., K.K., L.R., M.F., N.R., R.S., C.Z., C.E., S.K., B.K., W.H., and A.C. have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: The first randomized trial of adjuvant treatment with checkpoint inhibitor in stage II melanoma reported a significant reduction in risk of tumor recurrence. This study evaluates two independent data sets to further document survival probabilities for patients with primary stage I and II melanoma., Patients and Methods: The Central Malignant Melanoma Registry (CMMR) in Germany evaluated 17,544 patients with a primary diagnosis of stage I and II melanoma from 2000 to 2015. The exploratory cohort consisted of 6,725 patients from the Center for Dermato-Oncology at the University of Tübingen, and the confirmatory cohort consisted of 10,819 patients from 11 other German centers. Survival outcomes were compared with published American Joint Committee on Cancer version 8 (AJCCv8) stage I and II survival data., Results: For the two CMMR cohorts in stage IA compared with the AJCCv8 cohort, melanoma-specific survival rates at 10 years were 95.1%-95.6% versus 98%; 89.7%-90.9% versus 94% in stage IB; 80.7%-83.1% versus 88% in stage IIA; 72.0%-79.9% versus 82% in stage IIB; and 57.6%-64.7% versus 75% in stage IIC, respectively. Recurrence rates were approximately twice as high as melanoma-specific mortality rates in stages IA-IIA., Conclusion: The melanoma-specific survival rates in the two CMMR cohorts across stages I and II are less favorable than published in AJCCv8. This has important implications for the consideration of adjuvant treatment in this population.

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.)

Immune checkpoint blockade (ICB) is standard-of-care for patients with metastatic melanoma. It may re-invigorate T cells recognizing tumors, and several tumor antigens have been identified as potential targets. However, little is known about the dynamics of tumor antigen-specific T cells in the circulation, which might provide valuable information on ICB responses in a minimally invasive manner. Here, we investigated individual signatures composed of up to 167 different melanoma-associated epitope (MAE)-specific CD8+ T cells in the blood of stage IV melanoma patients before and during anti-PD-1 treatment, using a peptide-loaded multimer-based high-throughput approach. Additionally, checkpoint receptor expression patterns on T cell subsets and frequencies of myeloid-derived suppressor cells and regulatory T cells were quantified by flow cytometry. Regression analysis using the MAE-specific CD8+ T cell populations was applied to identify those that correlated with overall survival (OS). The abundance of MAE-specific CD8+ T cell populations, as well as their dynamics under therapy, varied between patients. Those with a dominant increase of these T cell populations during PD-1 ICB had a longer OS and progression-free survival than those with decreasing or balanced signatures. Patients with a dominantly increased MAE-specific CD8+ T cell signature also exhibited an increase in TIM-3+ and LAG-3+ T cells. From these results, we created a model predicting improved/reduced OS by combining data on dynamics of the three most informative MAE-specific CD8+ T cell populations. Our results provide insights into the dynamics of circulating MAE-specific CD8+ T cell populations during ICB, and should contribute to a better understanding of biomarkers of response and anti-cancer mechanisms., Competing Interests: CG reports receiving commercial research grants from Bristol-Myers Squibb, Novartis, and Roche, and is a consultant/advisory board member for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche. BW reports receiving commercial research grants from, is a consultant/advisory board member for, and reports receiving travel reimbursement from Bristol-Myers Squibb and Merck Sharp & Dohme. FM reports receiving commercial research grants from Novartis and Roche, and has received travel support or/and speaker´s fees or/and advisor´s honoraria by Novartis, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. NW reports an advisory role for Pierre-Fabre and Sanofi, consultant’s honoraria from Novartis, and has received travel support from AbbVie and Amgen outside the submitted work. GP has received speaker´s honoraria from Novartis, Roche, Pfizer, GlaxoSmithKline and Astellas. KW-H received commercial research grants from the CatalYm GmbH and travel support from SITC (Society for Immunotherapy of Cancer). SH is the cofounder of Immumap, Tetramer-shop and PokeAcell and is the co-inventor of the patents WO2015185067 and WO2015188839 for the barcoded MHC technology which is licensed to Immudex. The data presented in this study is not directly involved in these activities. TE has received travel support or/and speaker´s fees or/and advisor´s honoraria by Sanofi, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Almiral Hermal, and Pierre Fabre. TA reports institutional grants from SkylineDx, institutional grants and personal fees from Novartis, institutional grants from NeraCare, personal fees from BMS, institutional grants from Sanofi, personal fees from CeCaVa, personal fees from Pierre Fabre, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gaißler, Meldgaard, Heeke, Babaei, Tvingsholm, Bochem, Spreuer, Amaral, Wagner, Klein, Meier, Garbe, Eigentler, Pawelec, Claassen, Weide, Hadrup and Wistuba-Hamprecht.)

Rationale and Objectives: Early tumor size reduction (TSR) has been explored as a prognostic factor for survival in patients with advanced melanoma in clinical trials. The purpose of this analysis is to validate, in a routine clinical milieu, the predictive capacity of TSR by 10% for overall survival (OS) and progression-free survival (PFS) and to compare its predictive performance with the RECIST 1.1 criteria., Materials and Methods: This retrospective study was approved by the local ethics committee. A total of 152 patients with both CT before immunotherapy initiation and at first response evaluation after immunotherapy initiation were included. Prior to statistical analysis, treatment response was trichotomized as follows: Complete response and/or partial response, stable disease and progressive disease. Furthermore, response was dichotomized regarding TSR (TSR ≥ 10% and TSR < 10%). Kaplan-Meier survival estimates, Cox regression and Harrel's concordance index (C-index) were computed for prediction of overall survival and progression-free survival., Results: Tumor size reduction by at least 10% significantly differentiated between patients with increased survival from the ones with decreased survival (median OS: TSR ≥ 10%: 2137 days vs. TSR < 10%: 263 days) (p < 0.001) (median PFS: TSR ≥ 10%: 590 days vs.  TSR < 10%: 11 days) (p < 0.001). RECIST 1.1. criteria had a slightly higher C-index for overall survival reflecting a slight superior predictive capacity (RECIST: 0.69 vs TSR: 0.64) but a similar predictive capacity regarding progression-free survival (both: 0. 63)., Conclusion: Early tumor size reduction serves as a simple-to-use metric which can be implemented on the first follow-up CT. Tumor size reduction by at least 10% can be considered an additional biomarker predictive of overall survival and progression-free survival in routine clinical care and not only in the context of clinical trials in patients with advanced melanoma undergoing immunotherapy. Nevertheless, RECIST-based criteria should remain the main tool of treatment response assessment until results of prospective studies validating the TSR method are available., (Copyright © 2021 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Anti-programmed cell death protein 1 (PD-1) antibodies are now routinely administered for metastatic melanoma and for increasing numbers of other cancers, but still only a fraction of patients respond. Better understanding of the modes of action and predictive biomarkers for clinical outcome is urgently required. Cancer rejection is mostly T cell-mediated. We previously showed that the presence of NY-ESO-1-reactive and/or Melan-A-reactive T cells in the blood correlated with prolonged overall survival (OS) of patients with melanoma with a heterogeneous treatment background. Here, we investigated whether such reactive T cells can also be informative for clinical outcomes in metastatic melanoma under PD-1 immune-checkpoint blockade (ICB)., Methods: Peripheral blood T cell stimulation by NY-ESO-1 and Melan-A overlapping peptide libraries was assessed before and during ICB in two independent cohorts of a total of 111 patients with stage IV melanoma. In certain cases, tumor-infiltrating lymphocytes could also be assessed for such responses. These were characterized using intracellular cytokine staining for interferon gamma (IFN-γ), tumor negrosis factor (TNF) and CD107a. Digital pathology analysis was performed to quantify NY-ESO-1 and Melan-A expression by tumors. Endpoints were OS and progression-free survival (PFS)., Results: The initial presence in the circulation of NY-ESO-1- or Melan-A-reactive T cells which became no longer detectable during ICB correlated with validated, prolonged PFS (HR:0.1; p>0.0001) and OS (HR:0.2; p=0.021). An evaluation of melanoma tissue from selected cases suggested a correlation between tumor-resident NY-ESO-1- and Melan-A-reactive T cells and disease control, supporting the notion of a therapy-associated sequestration of cells from the periphery to the tumor predominantly in those patients benefitting from ICB., Conclusions: Our findings suggest a PD-1 blockade-dependent infiltration of melanoma-reactive T cells from the periphery into the tumor and imply that this seminally contributes to effective treatment., Competing Interests: Competing interests: CG reports receiving commercial research grants from Bristol-Myers Squibb, Novartis, and Roche; and is a consultant/advisory board member for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche. BW reports receiving commercial research grants from, is a consultant/advisory board member for, and reports receiving travel reimbursement from Bristol-Myers Squibb and Merck Sharp & Dohme. F. Meier reports receiving commercial research grants from Novartis and Roche; and has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. LF reported grants from the Swiss National Science Foundation, Swiss Cancer League, Hookipa Pharma, and Novartis Foundation as well as an advisory role for Novartis, Sanofi, Philogen and Bristol-Myers Squibb. PT has received speaker’s honoraria from Bristol-Myers Squibb, Novartis, Merck Sharp & Dohme, Pierre-Fabre, CureVac, Roche, Kyowa Kirin, Biofrontera, consultant’s honoraria from Bristol-Myers Squibb, Merck Serono, Novartis, Sanofi, Kirin Kyowa, and Roche and travel support from Bristol-Myers Squibb and Pierre-Fabre. SF reports receiving speaker’s fees by TAKEDA Pharmaceutical. TE has received speaker’s honoraria from Bristol-Myers Squibb, Novartis, Almiral Hermal, and Roche, consultant’s honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Sanofi, Pierre Fabre and Roche. TS and HN received a research grant from Novartis. GP has received speaker’s honoraria from Novartis, Roche, GlaxoSmithKline and Astellas. MWL is a co-inventor of several patents owned by Immatics Biotechnologies, and has acted as a consultant and/or advisory board member for Boehringer Ingelheim Pharma Gmbh & Co. KG. HZ is employed by CeGaT GmbH. KW-H received commercial research grants from the CatalYm GmbH and travel support from SITC (Society for Immunotherapy of Cancer). No potential conflicts of interest were disclosed by the other authors. KW-H is the guarantor for this manuscript., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cutaneous melanoma is rare in children and, like other very rare pediatric tumors, it suffers from a shortage of knowledge and clinical expertise. The clinical management of pediatric melanoma is often challenging. Its clinical and pathological diagnosis may be difficult, and there is no standard treatment. In the absence of specific treatment guidelines, young patients are generally treated following the same principle as for adults, but concern remains about their access to clinical trials and new drugs, which have been shown to dramatically change the natural history of advanced melanoma. This paper presents the internationally recognized recommendations for the diagnosis and treatment of children and adolescents with cutaneous melanoma, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded project called PARTNER (Paediatric Rare Tumours Network - European Registry). Main recommendations for melanoma are to discuss pediatric patients in multidisciplinary teams that include both pediatric oncologists and specialists in adult melanoma; to enroll patients in prospective trials, if available; to collect data in national-international databases; and to develop an effective international collaboration between pediatric and adult melanoma groups in order to facilitate the transfer of potentially effective new agents from the adult to the pediatric setting., (© 2021 Wiley Periodicals LLC.)

Background: Checkpoint inhibitors revolutionized the treatment of metastatic melanoma patients. Although tumor burden and lactate dehydrogenase (LDH) are associated with overall survival (OS), the impact of tumor growth kinetics remains elusive and in part contradictory. The aims of this study were to develop a novel simple and rapid method that estimates pretreatment metastatic growth rate (MGR) and to investigate its prognostic impact in melanoma patients treated with antiprogrammed death receptor-1 (PD-1) antibodies., Methods: MGR was assessed in three independent cohorts of a total of 337 unselected consecutive metastasized stage IIIB-IV melanoma patients (discovery cohort: n=53, confirmation cohort: n=126, independent multicenter validation cohort: n=158). MGR was computed during the pretreatment period before initiation of therapy with anti-PD-1 antibodies nivolumab or pembrolizumab by measuring the increase of the longest diameter of the largest target lesion. Tumor doubling time served as quality control. Kaplan-Meier analysis and univariable as well as multivariable Cox regression were used to examine the prognostic impact of MGR., Results: Pretreatment MGR >3.9 mm/month was associated with impaired OS in the discovery cohort (HR 6.19, 95% CI 2.92 to 13.10, p<0.0001), in the confirmation cohort (HR 3.62, 95% CI 2.19 to 5.98, p<0.0001) and in the independent validation cohort (HR 2.57, 95% CI 1.56 to 4.25, p=0.00023). Prior lines of systemic treatment did not influence the significance of MGR. Importantly, the prognostic impact of MGR was independent of total tumor burden, diameter of the largest metastasis, number of prior lines of systemic treatment, LDH, as well as liver and brain metastasis (discovery and confirmation cohorts: both p<0.0001). Superiority of MGR compared with these variables was confirmed in the independent multicenter validation cohort (HR 2.92, 95% CI 1.62 to 5.26, p=0.00036)., Conclusions: High pretreatment MGR is an independent strong prognostic biomarker associated with unfavorable survival of melanoma patients receiving anti-PD-1 antibodies. Further investigations are warranted to assess the predictive impact of MGR in distinct systemic therapeutic regimens., Competing Interests: Competing interests: NBW reports a consulting/advisory role for Sanofi and has received travel support from AbbVie and Amgen outside the submitted work. RL has received research funding from Bristol-Myers Squibb, Pierre Fabre and Roche, honoraria and travel support from Merck Sharp & Dohme and travel support from Amgen. AO is a consultant/advisory board member for MSD and Bristol-Myers Squibb. AF has received speaker’s honoraria from Bristol-Myers Squibb, MSD, Roche, and Novartis, is advisory board member for Roche and Novartis and received travel support from Roche, Novartis, and Bristol-Myers Squibb. UL is a consultant/advisory board member for and has received honoraria from MSD, Novartis, and Roche. MG is an advisory board member of Novartis and has received grants from Novartis outside the submitted work. CB has received speaker's honoraria and consultancy fees from Amgen, Bristol-Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Regeneron, Roche, and Sanofi-Aventis outside the submitted work, and has received travel support from Bristol-Myers Squibb. ER has received honoraria from and has a consultancy or advisory role for Amgen, Bayer, Bristol-Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche and Sanofi, reports speakers' bureau for Amgen, Bristol-Myers Squibb, MSD, Merck, Novartis, Pierre Fabre and Sanofi, received research funding (at the institution) from Amgen, Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre and Roche, is a member of the research funding steering committee of Novartis, and received travel accommodations and/or expenses from Amgen, Bristol-Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche and Sanofi. JM has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol-Myers Squibb and Pierre Fabre, and has received travel support from Ultrasun, L’Oreal, Merck Sharp & Dohme, Bristol-Myers Squibb and Pierre Fabre outside of the submitted work. PT has received honoraria and/or consultancy fees from Bristol-Myers Squibb, Curevac, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi outside the submitted work, and has received travel support from Bristol-Myers Squibb and Pierre-Fabre. CL is a consultant/advisory board member for and has received advisory board fees, speaker's fees and/or travel reimbursements from Roche, Pierre Fabre, Novartis, Bristol-Myers Squibb, Merck, MSD, Biontech, Almiral Hermal, Kyowa Kirin, Sun Pharma and Sanofi. VAN has received speaker’s honoraria and consultancy fees from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche, and Takeda outside of the submitted work. CGe has received personal speaker/advisory board fees from Amgen, Beiersdorf, BMS, MSD, Novartis, Pierre Fabre, Roche, Sun Pharma and Sanofi Genzyme. FM has received travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre, and research funding from Novartis and Roche. SD has received travel support from MSD. AC has received consultancy fees from AbbVie, BMS, Almirall, Amgen, Eli Lilly, Galderma, Janssen, Kyowa Kirin, Leo, Novartis, and Sanofi. LF reports grants from the Swiss National Science Foundation, Swiss Cancer League, Hookipa Pharma and Novartis Foundation as well as an advisory role for Novartis and Bristol-Myers Squibb. CGa has received grants and personal fees from Bristol-Myers Squibb, Roche, Novartis and personal fees from Amgen, MSD and Philogen outside the submitted work. TE is a consultant/advisory board member for Philogen, Bristol-Myers Squibb, Novartis, Roche and Sanofi. No other disclosures were reported., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: As cancer cachexia (CC) is associated with cancer progression, early identification would be beneficial. The aim of this study was to establish a workflow for automated MRI-based segmentation of visceral (VAT) and subcutaneous adipose tissue (SCAT) and lean tissue water (LTW) in a B16 melanoma animal model, monitor diseases progression and transfer the protocol to human melanoma patients for therapy assessment., Methods: For in vivo monitoring of CC B16 melanoma-bearing and healthy mice underwent longitudinal three-point DIXON MRI (days 3, 12, 17 after subcutaneous tumor inoculation). In a prospective clinical study, 18 metastatic melanoma patients underwent MRI before, 2 and 12 weeks after onset of checkpoint inhibitor therapy (CIT; n = 16). We employed an in-house MATLAB script for automated whole-body segmentation for detection of VAT, SCAT and LTW., Results: B16 mice exhibited a CC phenotype and developed a reduced VAT volume compared to baseline (B16 - 249.8 µl, - 25%; controls + 85.3 µl, + 10%, p = 0.003) and to healthy controls. LTW was increased in controls compared to melanoma mice. Five melanoma patients responded to CIT, 7 progressed, and 6 displayed a mixed response. Responding patients exhibited a very limited variability in VAT and SCAT in contrast to others. Interestingly, the LTW was decreased in CIT responding patients (- 3.02% ± 2.67%; p = 0.0034) but increased in patients with progressive disease (+ 1.97% ± 2.19%) and mixed response (+ 4.59% ± 3.71%)., Conclusion: MRI-based segmentation of fat and water contents adds essential additional information for monitoring the development of CC in mice and metastatic melanoma patients during CIT or other treatment approaches.

Background: Hepatic immune-related adverse events (irAE) including elevated liver function tests (transaminases) occur in 1.4-22.3% of melanoma patients receiving immune checkpoint inhibitors (ICPI) and constitute a potentially serious toxicity that is challenging to treat. In contrast to the liver transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST), only little is known about the frequency and impact of gamma-glutamyl transferase (GGT) elevations., Methods: GGT determined prior to and during therapy of metastatic melanoma patients treated with ICPI were retrospectively assessed in two independent cohorts (PD-1: n = 218, Ipi + Nivo: n = 148). Overall survival (OS) and best objective response were analyzed according to baseline and immune-related GGT (irGGT) elevations during treatment., Results: In multivariate analysis, OS was reduced in patients with elevated baseline GGT (PD-1 group: hazard ratio [HR] 1.76, p = .0073; Ipi + Nivo group: HR 1.77, p = .032). Immune-related GGT elevation was recorded in 17% (PD-1 group) and 38.5% (Ipi + Nivo group). Of these patients, the majority (81 and 68%, respectively) had normal ALT and AST and showed no clinical signs of hepatotoxicity. Patients who experienced irGGT elevation had superior response (PD-1 group: odds ratio [OR] 3.57, p = .00072; Ipi + Nivo group: OR 1.74, p = .12) and OS (PD-1 group: HR 0.37, p = .0016; Ipi + Nivo group: HR 0.33, p = .00050)., Conclusions: The frequency of hepatic irAE is currently underestimated. The addition of the sensitive enzyme GGT to the laboratory panel before and during therapy with ICPI allows to detect two to three times more patients developing hepatic or hepatobiliary toxicity than known so far. Immune-related GGT elevations correlate with response and favorable survival. Precis for use in the Table of Contents The frequency of hepatotoxicity under immune checkpoint blockade is currently underestimated. We suggest the addition of gamma-glutamyl transferase to the laboratory panel in checkpoint inhibitor patients for the detection of hepatobiliary toxicity.

Background: Despite impressive response rates, most patients with advanced melanoma ultimately progress following therapy with B-Raf proto-oncogene (BRAF) inhibitors (BRAFi). Therefore, frequent radiologic assessments are necessary, and reliable serum biomarkers would be beneficial for disease monitoring., Objective: This study investigated the ability of lactate dehydrogenase (LDH) and S100 calcium-binding protein B (S100B) to detect response and disease progression during treatment with BRAFi., Patients and Methods: Baseline levels of LDH and S100B and repeated measurements during therapy were recorded retrospectively in 191 patients with metastatic melanoma. LDH and S100B levels were compared between distinct time points (baseline, first follow-up visit [FV], best objective response [BR], and progressive disease [PD]). The prognostic ability of the serum biomarkers in relation to disease-specific survival (DSS) was assessed with univariable and multivariable Cox regression analysis., Results: Elevated baseline LDH and S100B correlated with impaired DSS. In contrast with LDH (P = 0.12), S100B levels at FV correlated with response (P = 0.0030). Both markers significantly decreased during the first weeks of BRAFi treatment (LDH, P = 0.00034; S100B, P < 0.0001) and increased between BR and PD (LDH, P = 0.016; S100B, P < 0.0001). Patients with elevated S100B (P = 0.00062) but not with elevated LDH (P = 0.067) at the time point of radiologically confirmed PD showed significantly impaired DSS after PD. Interestingly, DSS after PD differed significantly according to S100B levels determined as early as 8 weeks (median) before PD (P = 0.0024)., Conclusions: LDH and S100B are suitable serum biomarkers during therapy with BRAFi. S100B shows stronger correlation with response and exhibits more accuracy in predicting PD. Close biomarker monitoring with S100B is recommended during treatment with BRAFi to detect PD early.

Aberrant DNA methylation is an epigenetic hallmark of melanoma, but the expression of DNA methyltransferase (Dnmt)-1 in melanocytic tumors is unknown. Dnmt1 expression was analyzed in primary melanocytes, melanoma cell lines, and 83 melanocytic tumors, and its associations with proliferation, mutational status, and response to B-Raf and mitogen-activated protein kinase kinase (MEK) inhibition were explored. Dnmt1 expression was increased incrementally from nevi [mean fluorescence intensity (MFI), 48.1; interquartile range, 41.7 to 59.6] to primary melanomas (MFI, 68.8; interquartile range, 58.4 to 77.0) and metastatic melanomas (MFI, 87.5; interquartile range, 77.1 to 114.5) (P < 0.001). Dnmt1 expression was correlated with Ki-67 expression (Spearman correlation, 0.483; P < 0.001) and was independent of BRAF mutation status (P = 0.55). In BRAF-mutant melanoma, Dnmt1 was down-regulated during response to B-Raf and MEK inhibition and was again up-regulated on drug resistance in vitro and in vivo. Degradation of Dnmt1 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid was associated with decreased cell viability in B-Raf inhibitor-sensitive and -resistant cell lines. This study demonstrates that Dnmt1 expression is correlated with proliferation in melanocytic tumors, is increased with melanoma progression, and is associated with response to B-Raf and MEK inhibition. Given its strong expression in metastatic melanoma, Dnmt1 may be a promising target for combined epigenetic and immunotherapy., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Melanoma brain metastases (MBM) are common and associated with a particularly poor prognosis; they directly cause death in 60-70% of melanoma patients. In the past, systemic treatments have shown response rates around 5%, whole brain radiation as standard of care has achieved a median overall survival of approximately three months. Recently, the combination of immune checkpoint inhibitors and combinations of MAP-kinase inhibitors both have shown very promising response rates of up to 55% and 58%, respectively, and improved survival. However, current clinical evidence is based on multi-cohort studies only, as prospectively randomized trials have been carried out rarely in MBM, independently whether investigating systemic therapy, radiotherapy or surgical techniques. Here, an interdisciplinary expert team reviewed the outcome of prospectively conducted clinical studies in MBM, identified evidence gaps and provided recommendations for the diagnosis, treatment, outcome evaluation and monitoring of MBM patients. The recommendations refer to four distinct scenarios: patients (i) with 'brain-only' disease, (ii) with oligometastatic asymptomatic intra- and extracranial disease, (iii) with multiple asymptomatic metastases, and (iv) with multiple symptomatic MBM or leptomeningeal disease. Changes in current management recommendations comprise the use of immunotherapy - preferably combined anti-CTLA-4/PD-1-immunotherapy - in asymptomatic MBM minus/plus stereotactic radiosurgery which remains the mainstay of local brain therapy being safe and effective. Adjuvant whole-brain radiotherapy provides no clinical benefit in oligometastatic MBM. Among the systemic therapies, combined MAPK-kinase inhibition provides, in BRAF V600 -mutated patients with rapidly progressing or/and symptomatic MBM, an alternative to combined immunotherapy., Competing Interests: Declaration of Competing Interest The authors declare to have following potential conflicts of interest: RG reports personal fees and non-financial support from Amgen, Bristol-Myers Squibb, Merck Serono, Novartis, Pierre Fabre, Roche and Sanofi Regeneron; personal fees from 4SC, Almirall Hermal, MSD and SUN Pharma; grants from Johnson & Johnson;, grants and personal fees form Pfizer; and grants, personal fees and non-financial support from Novartis. DV reports personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Ferring, Lilly and Roche; grants, personal fees and non-financial support from Merck. JCH reports personal fees from Bristol-Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi, SUN Pharma and grants from Bristol-Myers Squibb. DK reports personal fees from Bristol-Myers Squibb during the conduct of this project, and from Novocure. CW has nothing to disclose. DS reports personal fees and non-financial support from Amgen, Merck Serono and Roche/Genentech; personal fees from 4SC, Agenus, Array BioPharma; Immunocore, Incyte, Pierre Fabre, Nektar, Pfizer, Philogen; Sandoz, Sanofi/Regeneron and from Regeneron; non-financial support from Merck; grants, personal fees, and other from Bristol-Myers Squibb (also during the conduct of this project); grants, personal fees, non-financial support and other from Novartis. TS is an employee of Bristol-Myers Squibb GmbH & Co KGaA (Munich, Germany), and reports personal fees from Bristol Myers-Squibb. SR reports a radiosurgery study grant from Accuray Inc outside the submitted work. TP reports personal fees from Bristol-Myers Squibb (during and outside the conduct of this project), Boehringer Ingelheim, Celgene, Janssen, MSD, Novartis, Roche and Takeda. CH reports consultancy, advisory boards and/or lectures for Amgen, AstraZeneca, Bristol-Myers Squibb, Incyte, MSD, Novartis, Pierre Fabre and Roche. TKE reports personal fees from Bristol-Myers Squibb (during and outside the conduct of the project); personal fees from Leo Pharma, MSD, Novartis, Roche, Sanofi. FM reports travel support or/and speaker’s fees or/and advisor’s honoraria by Novartis, Roche, BMS, MSD and Pierre Fabre and research funding from Novartis and Roche., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background/objectives: Elevated neutrophil-to-lymphocyte ratio (NLR) in peripheral blood is associated with poor overall survival (OS) in metastatic melanoma patients receiving immunotherapy. However, the impact of peripheral blood cells in patients undergoing sentinel lymph node biopsy (SLNB) is still unclear. This study was intended to characterize the impact of peripheral blood leukocytic cells on overall survival (OS) in melanoma patients undergoing SLNB., Methods: A total of 1412 AJCC stage I-II melanoma patients scheduled for SLNB at a single institution in the period 2010-2015 with available perioperative blood tests were randomly assigned to two independent cohorts. Associations of peripheral blood leukocytes with OS were analysed using Kaplan-Meier estimator and multivariate Cox proportional hazards model., Results: NLR >4.26, absolute neutrophil count >5800/µL, relative neutrophil count >69.7% and relative lymphocyte count ≤ 17.5% were significantly associated with reduced OS in both cohorts. Absolute monocytes >810/µL, absolute eosinophils ≤200/µL, relative monocytes >6.6%, relative eosinophils ≤2.7% and relative basophils ≤0.6% were significantly associated with reduced OS in one cohort each. On multivariate analysis, a combined score including absolute levels of neutrophils, lymphocytes, monocytes and eosinophils was significantly associated with OS in both cohorts. The hazard ratio of patients with a risk score of 3-4 was 5.42 (95% confidence interval: 1.52-19.42, P = 0.0094) in cohort 1 and 9.42 (2.06-43.06, P = 0.0038) in cohort 2, respectively., Conclusions: We conclude that peripheral blood leukocytes are independently associated with OS in stage I-II melanoma patients and should be considered as prognostic markers in these patients. Eosinophils and basophils deserve more attention in future investigations., (© 2020 The Australasian College of Dermatologists.)

Purpose: Three new therapies have been approved recently for the adjuvant treatment of stage III melanoma, substantially reducing the risk of tumor recurrences. This study evaluates 3 independent data sets to clarify the survival probabilities of patients with stage III melanoma., Patients and Methods: The Central Malignant Melanoma Registry (CMMR) evaluated 1,553 patients with a primary diagnosis of stage III melanoma from 2000 to 2012. Studies from the European Organisation for Research and Treatment of Cancer (EORTC), of 573 patients in the observation arm of the 18991 study and 445 patients in the placebo arm of the 18071 study, were evaluated as reference cohorts. The survival outcomes were compared with the published American Joint Committee on Cancer version 8 (AJCCv8) stage III survival data., Results: For the CMMR stage III cohort versus the AJCCv8 cohort, the melanoma-specific survival (MSS) rates at 5 years were 67% versus 77%, and at 10 years were 56% versus 69%, respectively. For stage IIIA, the MSS rates at 5 years were 80% versus 93%, and at 10 years were 71% versus 88%; for stage IIIB, the MSS rates at 5 years were 75% versus 83%, and at 10 years were 61% versus 77%. The MSS rates of the EORTC studies either overlapped with or were lower than, the CMMR data., Conclusion: The MSS rates in the CMMR and EORTC cohorts over the entire stage III are less favorable than those published in AJCCv8. This is particularly true for substages IIIA and IIIB.

Background: Adjuvant therapies have been approved for patients with AJCC (American Joint Committee on Cancer) stage III and stage IV cutaneous melanoma (CM) after complete resection. These therapies might also be indicated for patients with high-risk stage II CM., Material and Methods: We included patients diagnosed with stage II melanoma between 2000 and 2016 and for which primary tumour tissue was available. The prognostic value of the 11-gene expression profiling score (GEPS) was evaluated as a dichotomized parameter (GEPS ≤0 vs. >0). Endpoints of the analysis were melanoma specific survival (MSS), distant metastasis-free survival (DMFS) and relapse-free survival (RFS)., Results: GEPS was determined in 245 patients ranging between -0.7 and 3.53. A total of 111 females and 134 males were included; the median follow-up was 41 months. Kaplan Meier analyses showed statistically significant survival differences between patients with high GEPS (n = 154) and low GEPS (n = 91) for MSS (p = 0.018), DMFS (p = 0.005) and RFS (p = 0.009). The 5-year and 10-year MSS was 92% in the low-GEPS and 82% and 67% in the high-GEPS group, respectively. Multivariate Cox regression analysis showed independent significance for MSS of GEPS (HR = 1.55; p = 0.006), tumor thickness (HR = 1.21; p < 0.001) and age (HR1.05; p = 0.002)., Conclusion: GEPS was validated as independent prognostic factor for MSS in stage II CM and could be used for therapeutic decisions when systemic therapies become available in stage II CM., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We aimed to identify predictive clinical and CT imaging biomarkers and assess their predictive capacity regarding overall survival (OS) and treatment response in patients with metastatic melanoma undergoing immunotherapy., Methods: The local institutional ethics committee approved this retrospective study and waived informed patient consent. 103 patients with immunotherapy for metastatic melanoma were randomly divided into training (n = 69) and validation cohort (n = 34). Baseline tumor markers (LDH, S100B), baseline CT imaging biomarkers (tumor burden, Choi density) and CT texture parameters (Entropy, Kurtosis, Skewness, uniformity, MPP, UPP) of the largest target lesion were extracted. To identify treatment response predictors, binary logistic regression analysis was performed in the training cohort and tested in the validation cohort. For OS, Cox regression and Kaplan Maier analyses were performed in the training cohort. Bivariate and multivariate models were established. Goodness of fit was assessed with Harrell's C-index. Potential predictors were tested in the validation cohort also using Cox-regression and Kaplan-Meier analyses., Results: Baseline S100B (Hazard ratio(HR) = 2.543, p0.018), tumor burden (HR = 1.657, p = 0.002) and Kurtosis (HR = 2.484, p < 0.001) were independent predictors of OS and were confirmed in the validation cohort (p < 0.048). Tumor burden and Kurtosis showed incremental predictive capacity allowing a good predictive model when combined with baseline S100B levels (C-index = 0.720). Only S100B was predictive of treatment response (OR ≤ 0.630, p ≤ 0.022). Imaging biomarkers did not predict treatment response., Conclusion: We identified easily obtainable baseline clinical (S100B) and CT predictors (tumor burden and Kurtosis) of OS in patients with metastatic melanoma undergoing immunotherapy. However, imaging predictors did not predict treatment response., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear., Methods: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression., Results: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007)., Conclusions: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.

Background: Melanoma incidence rates rise as people age, but the impact of aging on distant metastasis is unclear., Objective: To investigate how timing, pattern, and extent of distant metastasis is influenced by age., Methods: Analysis of a single-center cohort of 1457 patients of the German Central Malignant Melanoma Registry with prospectively documented follow-up. Findings were compared with those for 1682 patients from 5 different institutions. All patients presented initially with stage IA to IIC and developed distant metastasis in their further disease course., Results: The number of metastatic sites decreased with increasing age at melanoma diagnosis (P < .001). The rate of stage M1d disease decreased from 50.2% in patients aged 50 years or younger to 30.1% in patients older than 70 years, and the rate of stage M1b disease increased from 5.8% to 21.5%. The rate of lung metastases remained stable in all investigated age groups (P = .54). Distant metastases occurred earlier and were more synchronized in patients older than 70 years than in patients aged 50 years or younger. An age-dependent decrease in metastatic sites and stable rate of lung metastasis were found and confirmed by data on the multi-institutional cohort., Limitations: The study was not population based., Conclusion: Pattern, timing, and extent of distant metastasis change as people age. These findings may be considered when treating patients with melanoma of different ages., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Immunotherapy with PD-1 antibodies has greatly increased prognosis of patients with advanced melanoma. Identifying biomarkers that predict overall survival (OS) and response to immunotherapy is important., Methods: OS and best overall response according to RECIST version 1.1 were analysed, and S100B and lactate dehydrogenase (LDH) serum levels were assessed retrospectively in 152 patients treated with anti-PD-1, and in 86 patients treated with anti-PD-1 plus anti-CTLA-4 antibodies at University Hospital Tuebingen, Germany., Results: In the pembrolizumab group, patients with elevated baseline S100B or LDH exhibited significantly impaired OS compared with patients with normal S100B (1-year OS: 51.1% vs 83.1%, log-rank P < .0001) and normal LDH (1-year OS: 44.4% vs 80.8%, P = .00022), respectively. LDH increases of >25% and S100B increases of >145% compared to baseline were significantly associated with impaired OS (both P < .0001). In patients treated with ipilimumab and nivolumab, baseline S100B and increasing S100B levels of >145% as well as baseline LDH were associated with impaired OS (P < .0001, P = .00060, and P = .0050, respectively), whereas increasing LDH of >25% was not (P = .64)., Conclusions: S100B could serve as a strong baseline marker for OS in melanoma patients receiving anti-PD-1 therapy. Rising S100B levels during the first weeks of therapy could help guide treatment decisions.

Background: Ipilimumab and programmed death (PD) 1-antibodies are effective treatment options in metastatic melanoma. The safety and efficacy of ipilimumab in patients with pre-existing autoimmune disorders (AD) has only been evaluated in a selected number of patients., Methods: We performed a retrospective analysis in 14 German skin cancer centers for patients with metastatic melanoma and pre-existing AD treated with ipilimumab., Results: 41 patients with 44 pre-existing AD were treated with ipilimumab (thyroiditis n = 15, rheumatoid n = 11, dermatologic n = 10, Crohn's disease/ulcerative colitis n = 3, neurological n = 2, sarcoidosis n = 2, pancreatitis n = 1). 3 out of 41 patients had two AD, 11 patients required immunosuppressants at the time of induction of ipilimumab. 12 patients (29.2%) experienced a flare of their pre-existing AD, mainly patients with rheumatoid or dermatologic diseases. Additional immune-related adverse events (irAEs) occurred in 12 patients (29.2%). In 23 patients (56%) neither a change of their AD nor additional irAEs were observed. Objective responses were seen in five patients (one complete remission, four partial remissions, 12.1%)., Conclusion: This is the largest series of patients with pre-existing AD and treatment with ipilimumab reported. Flares of pre-existing AD were observed but manageable. Response rates and occurrence of new irAEs were comparable to previous trials. Thus, in this patient subgroup, ipilimumab can be a treatment option after a thorough discussion of pros and cons and taking severity and activity of the preexisting AD into account.

The possibility that tumescence local anaesthesia (TLA) may lead to dissemination of tumour cells in lymph nodes is presently unclear. To evaluate whether infiltration by TLA influences metastatic spread and survival probability, compared to general anaesthesia (GA), based on lymph node dissection in melanoma patients. In total, 281 patients (GA: 162; TLA: 119) with cutaneous melanoma and clinically or histologically-confirmed metastases in regional lymph nodes were included. All patients underwent complete lymph node dissection. Median follow-up was 70 months. The rate of lymph node recurrence at the dissection site was 25.3% in the GA group and 17.6% in the TLA group (p = 0.082). No significant difference was found concerning 10-year melanoma-specific survival (GA: 56.2%, TLA: 67.4%; p = 0.09), disease-free survival (GA: 72.8 %, TLA: 81.1%; p = 0.095), or lymph node-free survival (GA: 72.8%, TLA: 81.1%; p = 0.095). Distant metastases-free survival appeared to be slightly reduced in the TLA group (GA: 49.9%, TLA: 64.0%; p = 0.025). No differences were identified between the GA and TLA groups regarding prognostic outcome for overall survival or disease-free survival.

Background: Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date., Patients and Methods: Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression., Results: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p = 0.002) as independent risk factors for poor survival. Patients with elevated CRP and LDH and a REC <1.5% were at highest risk for disease progression and death (p = 0.001)., Conclusions: Blood markers predict survival in metastatic UM treated with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high REC may help identify patients with better prognosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Significant progress has been made in the treatment of metastatic melanoma during the last years. Approval of immune-checkpoint inhibitors and targeted therapies has been achieved recently. The sequencing of these therapies is an important issue. Here, we report our experience with the treatment and retreatment with PD1-inhibitors (PD1i) in eight patients. The patients (two female and seven male with a median age of 70 years, all melanoma stage IV, M1c) underwent a first treatment period with PD1i for a median of 5.5 months. Three (37.5%) patients had a stable disease as best response, two (25%) showed progression, two (25%) showed partial response, and one (12.5%) achieved complete remission. PD1i was discontinued due to disease progression in seven patients and due to side effects (pancreatitis) in one patient. Patients were subsequently treated with ipilimumab (n=2), or chemotherapy (n=4), or no other medical treatment (n=2). All eight patients were subsequently retreated with PD1i for a median of 2.5 months. One (12.5%) developed a partial response, whereas in three patients (37.5%) the disease was stabilized. PD1i have shown a high and durable response rate in the first-line treatment of metastatic melanoma. Our study suggests PD1i retreatment as a reasonable option for selected patients. Further investigations are needed to verify the value of PD1i re-exposure and to identify subgroups of patients who can benefit.

Background: Due to prolonged survival and technical advances in CT imaging, cardiac metastases in patients with malignant melanoma are observed more frequently nowadays. The aim of the present study was to assess the anatomic distribution as well as the morphologic and histologic appearance of cardiac metastases from malignant melanoma., Methods: Twenty five patients with known metastasized melanoma and with incidental finding of cardiac metastases during routine staging CT were retrospectively included in this study. CT images were assessed for the presence, localization and extent of cardiac metastases. Histological results, mutational analysis and tumor markers were reviewed., Results: Fourteen out of 25 patients presented with singular cardiac mass (56%), whereas ten patients (40%) presented with multifocal and one patient with disseminated cardiac metastases. Twelve patients presented with endocardial (48%), eight with myocardial and two with pericardial metastases. Most frequent site involved in endocardial metastases was the right atrium (67%) followed by the right ventricle (33%). There seems to be a correlation between histological subtype and location of cardiac metastasis. Median survival after diagnosis of cardiac metastases was 8 months, with no significant difference regarding the localization of metastases within the heart., Conclusion: Cardiac metastases can involve every part of the heart possibly in dependence of histological subtype. The awareness of different types of cardiac metastases and their characteristic appearance on CT images is necessary for further investigations and might contribute to targeted therapy.

Background: Combined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in numerous cancer indications, with PD-1 inhibitor nivolumab plus CTLA-4 inhibitor ipilimumab in advanced melanoma as first-ever approved therapies for combined ICB. However, gains in efficacy must be balanced against a higher frequency and severity of adverse drug reactions (ADR). Because delays in diagnosis and management might result in symptom worsening and further complications, clinicians shall be well trained to identify ADR promptly and monitor patients adequately. This paper reviews safety data assessed by the European Medicines Agency for the anti-PD-1/CTLA-4 combination and provides a literature overview on published case reports for rare ADR with suspected potential underreporting. Incidences and kinetics of immune-related ADR are described. Recommendations for the evaluation and management of ADR are convened by an interdisciplinary expert panel focusing on rare but clinically important side effects arising from combined ICB. Pooled safety data from 1551 patients with advanced melanoma, treated either with 3mg/kg ipilimumab plus 1mg/kg nivolumab (N=407), or nivolumab alone (N=787), or ipilimumab alone (N=357) demonstrate that immune-related ADR occur more frequently for the combination, with a shorter time-to-onset, and tend to be more severe. The majority of events is reversible after systemic use of glucocorticoids, notably methylprednisolone or equivalents; in certain cases of long-lasting and refractory immune toxicities, non-steroidal immunosuppressants may be used, once ICB is interrupted or terminated. Combined ICB has considerable toxicities, therefore close monitoring and high experience in diagnosis and treatment of ADR is necessary., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To assess the appearance of gastrointestinal melanoma metastases on CT and PET/CT and evaluate the diagnostic value of CT and PET/CT compared with surgery and histopathology., Methods: We retrospectively included 41 consecutive patients (aged 56.1 ± 13.5 years) with gastrointestinal melanoma metastases who underwent preoperative imaging (CT: all, PET/CT: n = 24) and metastasectomy. Two blinded radiologists assessed CT and PET/CT for gastrointestinal metastases and complications. Diagnostic accuracy and differences regarding lesion detectability and complications were assessed, using surgical findings and histopathology as standard of reference., Results: Fifty-three gastrointestinal melanoma metastases (5.0 ± 3.8 cm) were confirmed by surgery and histopathology. Lesions were located in the small bowel (81.1 %), colon (15.1 %) and stomach (3.8 %), and described as infiltrating (30.2 %), polypoid (28.3 %), cavitary (24.5 %) and exoenteric (17.0 %). Fifteen patients (37 %) had gastrointestinal complications. Higher complication rates were associated with large and polypoid lesions (p ≤ .012). Diagnostic accuracy was high for CT and PET/CT (AUC ≥ .802). For reader B (less experienced), CT yielded lower diagnostic accuracy than PET/CT (p = .044)., Conclusion: Most gastrointestinal melanoma metastases were located in the small bowel. Large and polypoid metastases were associated with higher complication rates. PET/CT was superior for detection of gastrointestinal melanoma metastases and should be considered in patients with limited disease undergoing surgery., Key Points: • Gastrointestinal melanoma metastases (GI-MM) are rare but often cause serious gastrointestinal complications. • Early detection of GI-MM is important to prevent complications and guide surgery. • PET/CT is superior to CT for detection of GI-MMs. • PET/CT should be considered for patients with limited disease before surgical resection.

Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune-related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.

Purpose: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for "brain-specific" therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases., Experimental Design and Results: Buparlisib inhibited AKT activity, decreased proliferation, and induced apoptosis in metastatic melanoma cell lines and short-term brain melanoma cells, irrespective of their BRAF and NRAS mutation status. In addition, buparlisib inhibited hyperactivated AKT and induced apoptosis in melanoma cells that were stimulated with astrocyte-conditioned medium. The growth of tumors induced by injecting human BRAF- and NRAS-mutant metastatic melanoma cells into the brain of mice was significantly inhibited by buparlisib., Conclusions: These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases. Clin Cancer Res; 22(23); 5818-28. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: In 2009, the AJCC issued a revised melanoma staging system. In addition to tumor thickness and ulceration, the mitotic rate was introduced as the third major prognostic parameter for the classification of primary cutaneous melanoma. Given that, according to the 2009 AJCC classification, the detection of one or more dermal tumor mitoses leads to an upstaging - from stage Ia to Ib - of melanomas with a tumor thickness of ≤ 1.0 mm, we set out to investigate the reproducibility of this new parameter., Methods: In order to assess interobserver reliability, 17 dermatopathologists und pathologists - all well versed in the diagnosis of cutaneous melanoma - analyzed the mitotic rate in 15 thin primary cutaneous melanomas (mean tumor thickness 0.91 mm) using identical slides. Mitotic rates were determined on H&E and phosphohistone H3 (Ser10)-stained samples. Without knowledge of their previous assessment, five of the aforementioned examiners reevaluated the samples after more than one year in order to ascertain intraobserver reliability., Results: Interobserver reliability of the mitotic rate in thin primary melanomas is disappointing and independent of whether H&E or immunohistochemically stained samples are used (kappa value: 0.088 [H&E], 0.154 [IH], respectively). Kappa values improved to 0.345 (H&E) and 0.403 (IH) when using a cutoff of 0/1 vs. 2+ mitoses. Similarly unsatisfactory, kappa values for intraobserver reliability ranged from 0.18 and 0.348, depending on the individual examiner., Discussion: Given the unsatisfactory reproducibility and large variations in assessing the mitotic rate, it remains a matter of debate whether this diagnostic parameter should play a role in therapeutic decisions., (© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Growing evidence suggests that concurrent loco-regional and systemic treatment modalities may lead to synergistic anti-tumor effects in advanced melanoma. In this retrospective multicenter study, we evaluate the use of electrochemotherapy (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with unresectable or metastatic melanoma who received the combination of ECT and immune checkpoint blockade for distant or cutaneous metastases within 4 weeks. Clinical and laboratory data were collected and analyzed with respect to safety and efficacy. A total of 33 patients from 13 centers were identified with a median follow-up time of 9 months. Twenty-eight patients received ipilimumab, while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3, nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The median duration of response was not reached in either group. The median time to disease progression was 2.5 months for the entire population with 2 months for ipilimumab and 5 months for PD-1 blockade. The median overall survival was not reached in patients with ipilimumab and 15 months in the PD-1 group. Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed. This is the first reported evaluation of ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT with concurrent ipilimumab. The local response was lower than reported for ECT only. Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate.

Purpose: To identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients., Experimental Design: Frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan-Meier and Cox regression analysis, including calibration and discrimination by C-statistics., Results: Low baseline LDH, absolute monocyte counts (AMC), Lin(-)CD14(+)HLA-DR(-/low)-MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4(+)CD25(+)FoxP3(+)-Treg frequencies were significantly associated with better survival, and were considered in a combination model. Patients (43.5%) presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2-0) was also associated with OS (P < 0.001 for all pairwise comparisons) in the main study and additionally in an independent validation cohort., Conclusions: A baseline signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12); 2908-18. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Ipilimumab is an approved immunotherapy that has shown an overall survival benefit in patients with cutaneous metastatic melanoma in two phase III trials. As results of registrational trials might not answer all questions regarding safety and efficacy of ipilimumab in patients with advanced melanoma seen in daily clinical practice, the Dermatologic Cooperative Oncology Group conducted a phase II study to assess the efficacy and safety of ipilimumab in patients with different subtypes of metastatic melanoma., Patients and Methods: We undertook a multicenter phase II study in melanoma patients irrespective of location of the primary melanoma. Here we present data on patients with pretreated metastatic cutaneous, mucosal and occult melanoma who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months., Results: 103 pretreated patients received at least one dose of ipilimumab, including 83 cutaneous, seven mucosal and 13 occult melanomas. 1-year OS rates for cutaneous, mucosal and occult melanoma were 38 %, 14 % and 27 %, respectively. Median OS was 6.8 months (95 % CI 5.3-9.9) for cutaneous, 9.6 months (95 % CI 1.6-11.1) for mucosal, and 9.9 months (lower 95 % CI 2.3, upper 95 % CI non-existent) for occult melanoma. Overall response rates for cutaneous, mucosal and occult melanoma were 16 %, 17 % and 11 %, respectively. Eleven patients had partial response (16 %) and ten patients experienced stable disease (14 %), none achieved a complete response. Treatment-related AEs were observed in 71 patients (69 %), including 20 grade 3-4 events (19 %). No new and unexpected safety findings were noted., Conclusions: Ipilimumab is a treatment option for pretreated patients with advanced cutaneous melanoma seen in daily routine. Toxicity was manageable when treated as per protocol-specific guidelines., Trial Registration: Clinical Trials.gov NCT01355120.

Background: Sentinel lymph node biopsy (SLNB) plays an important role in the prognostic classification of melanoma and is now a standard staging procedure. However, due to the complex drainage pattern and the risk of site associated morbidity, the potential survival benefit of SLNB is controversial in head and neck (H&N) melanoma., Methods: Patients with primary H&N melanoma with a tumor thickness ≥1.00 mm diagnosed in the Department of Dermatology, University of Tuebingen, Germany between 1991 and 2010 were included in this study. Regarding patterns of metastases, disease-free, and overall-survival, 259 patients with SLNB were compared retrospectively to 218 patients without SLNB., Results: The detection of micrometastasis in SLN proved to be a significant prognostic factor in H&N patients [hazard ratio (HR) 3.69, p < 0.0001]. A significant improvement of recurrence-free survival (RFS, p = 0.011), regional lymph node metastasis-free survival (LFS, p = 0.007), and distant metastasis-free survival (DMSF, p = 0.015) was observed for patients with SLNB versus non-SLNB. Furthermore, a trend towards better overall survival (OS) was found (p = 0.053) for the SLNB group., Conclusions: SLNB improved prognostic outcome in H&N melanoma in terms of disease-free and distant metastases survival, reduced subsequent regional lymph node metastases, and showed a trend towards a better OS.

Background: Prognostic factors of melanoma patients with distant metastases remain poorly established. This study aimed to compare the prognostic impact of putative serum biomarkers, namely S100B, YKL-40 or CCL17, in stage IV melanoma patients., Patients and Methods: Serum concentrations were analyzed by ELISA. Disease-specific survival of 80 patients according to S100B, YKL-40 or CCL17 and clinical factors were calculated by univariate Kaplan-Meier survival and multivariate analysis., Results: Low serum levels of S100B, high concentrations of CCL17 and female gender correlated with improved survival. A trend for favorable prognosis was observed for the M categories M1a/b versus M1c according to the AJCC classification. No correlation with survival was evident for YKL-40 serum levels and age. In multivariate analysis, S100B (HR 2.1; p = 0.005) and CCL17 (HR 1.8; p = 0.029) had independent prognostic impact. Patients with a combination of normal S100B and high CCL17 had a high chance for long-term survival, which was 43 % after 3 years., Conclusion: Serum levels of CCL17 and S100B represent independent prognostic markers for melanoma patients with distant metastases. These biomarkers were more powerful than the M category according to the AJCC classification to indicate overall survival. CCL17 represents a promising biomarker upon immune checkpoint blockade in melanoma.

Background: Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma., Methods: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF(V600) mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients., Findings: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39-0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27-41) in the pembrolizumab 2 mg/kg group, 38% (31-45) in the 10 mg/kg group, and 16% (10-22) in the chemotherapy group. Treatment-related grade 3-4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3-4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment-related grade 3-4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy., Interpretation: These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma., Funding: Merck Sharp & Dohme., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Malignant melanoma is a very rare paediatric tumour. This study was performed in order to understand clinical features and prognosis of malignant melanoma in children and adolescents., Methods: 443 patients ⩽ 18 years of age with malignant melanoma were prospectively registered with the German Central Malignant Melanoma Registry between 1983 and 2011. Cases were collected from 58 participating centres. 276 paediatric cases with a follow-up >3 months were evaluated for survival probabilities and prognostic factors by Kaplan-Meier method., Results: Age of diagnosis ranged from 3 months to 18 years (median age 16 years). The male to female ratio was 0.8 (202 male, 240 female). Most melanoma were located at the trunk (n = 195) and the lower extremity (n = 114). Patients with >3 months of follow-up (median 55 months) showed an overall survival (OS) of 94.8% in 5 years. Survival according to tumour stage was 98.5% for stage I (n = 190), 91.1% for stage II (n = 39) and 53.0% for stage III/IV tumours (n = 11). Worse outcome was seen in patients with nodular melanoma (OS 77.9%, n = 42) compared to superficial spread histotype (OS 100%, n = 138) or other histotype (OS 96.9%, n = 88) (p < 0.0001), in case of thicker tumours (Clark level IV or V, OS 87.1%, n = 84) compared to thinner tumours (Clark level I, II, III, OS 99.1%, n = 164) (p = 0.0008) and in case of ulceration (OS 65.6%, n = 17) compared to no ulceration (OS 99.2%, n = 182)., Conclusion: Patient and tumour characteristics in paediatric melanoma patients show no evident differences to adult melanoma cases. The same clinical approach as in adults should be used., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Ipilimumab is an approved anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody introducing immune responses in melanoma patients. Treatment experiences from named-patient programs support the evaluation of the efficacy and tolerability of new medicines under usual circumstances of health care practice. Here, the largest ever reported cohort treated with ipilimumab 3 mg/kg alone is described., Methods: This report retrospectively analyzes data of 198 patients who were followed up in 15 hospital centers in Germany between April 2010 and March 2013. Patients had received prior therapy for unresectable stage III or IV melanoma before receiving ipilimumab (4 doses of 3 mg/kg every 21 d). Routine staging and tumor response evaluation procedures were applied., Results: Of the patients, 119 received the planned 4-course therapy schedule; in further 79 patients, the number of doses was reduced mainly because of toxicity or fast progression. In all, 196 patients were eligible for evaluation of the efficacy of ipilimumab under routine care conditions. Median overall survival (OS) was 6.8 months [95% confidence interval, 5.6-10.3] from the start of therapy. OS differed significantly among patients who received 4 doses (n=119) and those receiving <4 doses (n=79) (14.2 vs. 2.0 mo; P<0.0001). The overall response rate (ORR) of 11% was in the same range as reported from previous clinical trials; and stable disease (SD) was observed in 11% resulting in a disease control rate (ORR+SD) of 22%. In 23 of the 79 patients with reduced dosing, dose omission was most probably caused by toxicity, whereas 56 patients had progressive disease before receiving all 4 treatment cycles. Immune-related adverse events (irAE) were reported in 30% of all treated patients, the occurrence of irAE correlated significantly with the probability of response to therapy and prolonged OS., Conclusion: In this named-patient program including heavily pretreated patients, the efficacy and tolerability of ipilimumab 3 mg/kg corresponds with findings from the confirmatory clinical trial.

Purpose: We initially observed that the presence of circulating NY-ESO-1- and/or Melan-A-specific T cells in patients with stage IV melanoma was significantly associated with prolonged survival. Here, we report the ways in which the phenotypes and functions of these T cells differentially affect survival in patients preselected for NY-ESO-1 and/or Melan-A reactivity., Experimental Design: We assayed functional antigen-reactive T cells recognizing NY-ESO-1 and/or Melan-A after in vitro stimulation using overlapping peptide pools. After restimulation, we assayed six cytokines simultaneously by intracellular cytokine staining. This allowed us to analyze the functional antigen response of both CD4(+) and CD8(+) T cells at the single-cell level., Results: We observed that NY-ESO-1 stimulated mainly CD4(+) T cells, whereas Melan-A more often stimulated CD8(+) T cells. NY-ESO-1 reactivity was not associated with an additional impact on survival, whether CD4(+) T cells, CD8(+) T cells, or both types of T cells were responding. In contrast, recognition of Melan-A by CD4(+) T cells was associated with reduced survival in our cohort of patients preselected for NY-ESO-1 and/or Melan-A reactivity (that is, in patients with exceptionally long survival). We further observed a negative effect on survival in patients with CD4(+) T cells producing IL4 and IL17 upon Melan-A stimulation. Their prognosis was comparable to patients without any Melan-A reactivity., Conclusions: The nature and prognostic impact of specific T-cell responses is different according to targeted antigen. Independent from phenotype and functional aspects, NY-ESO-1 reactivity is associated with good prognosis. In terms of Melan-A, antigen-specific CD8(+) but not CD4(+) responses are associated with prolonged survival. Clin Cancer Res; 20(16); 4390-9. ©2014 AACR., (©2014 American Association for Cancer Research.)

L19-IL2 is a recombinant protein comprising the cytokine IL2 fused to the single-chain monoclonal antibody L19. In previous studies, intralesional injection with IL2 has shown efficacy for the locoregional treatment of cutaneous/subcutaneous metastases in patients with advanced melanoma. The objectives of this study were to investigate whether (i) intralesional delivery of a targeted form of IL2 would yield similar results, with reduction of injection frequency and treatment duration; and (ii) systemic immune responses were induced by the local treatment. Patients with stage IIIB/IIIC melanoma and cutaneous/subcutaneous injectable metastases received weekly intratumoral injections of L19-IL2 at a maximum dose of 10 MIU/week for 4 consecutive weeks. Tumor response was evaluated 12 weeks after the first treatment. Twenty-four of 25 patients were evaluable for therapy-induced responses. A complete response (CR) by modified immune-related response criteria (irRC) of all treated metastases was achieved in 6 patients (25%), with long-lasting responses in most cases (5 patients for ≥24 months). Objective responses were documented in 53.9% of all index lesions [44.4% CR and 9.5% partial responses (by irRC)], and 36.5% of these remained stable, while 9.5% progressed. Toxicity was comparable with that of free IL2, and no serious adverse events were recorded. A significant temporary increase of peripheral regulatory T cells and natural killer cells, sustained increase of absolute CD4(+) lymphocytes, and decrease of myeloid-derived suppressor cells were observed upon treatment. Finally, we recorded encouraging data about the progression time to distant metastases and overall survival., (©2014 American Association for Cancer Research.)

Background: The impact of BRAF tumor mutations on the natural course of disease of melanoma patients is controversial., Patients and Methods: We analyzed the mutational status and overall survival of 215 patients receiving treatment with dacarbazine or temozolomide. All patients who started first-line treatment at our institution between 2000 and 2010 were included to prevent selection and bias due to thereafter arising therapeutic options., Results: No patient received BRAF- or MEK-inhibitors during follow-up. Survival was associated with the pattern of visceral involvement, the presence of brain metastases and the serum lactate dehydrogenase level (all p<0.001). The BRAF-V600 mutational status was not associated with survival and no differences in overall survival were detected according to age, gender or to the cytotoxic agent used for therapy. In Cox regression analysis the presence of brain metastases (hazard ratio 2.3; p<0.001) and an elevated serum LDH (hazard ratio 2.5; p<0.001) were the only factors, which independently predicted survival., Conclusions: No differences in prognosis were observed according to the BRAF mutational status in patients with distant metastasis treated with monochemotherapy.

The prognostic impact of BRAF-V600 tumor mutations in stage I/II melanoma patients has not yet been analyzed in detail. We investigated primary tumors of 437 patients diagnosed between 1989 and 2006 by Sanger sequencing. Mutations were detected in 38.7% of patients and were associated with age, histological subtype as well as mitotic rate. The mutational rate was 36.7% in patients with disease-free course and 51.7% in those with subsequent distant metastasis (p = 0.031). No difference in overall survival (p = 0.119) but a trend for worse distant-metastasis-free survival (p = 0.061) was observed in BRAF mutant compared to BRAF wild-type patients. Independent prognostic factors for overall survival were tumor thickness, mitotic rate and ulceration. An interesting significant prognostic impact was observed in patients with tumor thickness of 1 mm or less, with the mutation present in 6 of 7 patients dying from melanoma. In conclusion, no significant survival differences were found according to BRAF-V600 tumor mutations in patients with primary melanoma but an increasing impact of the mutational status was observed in the subgroup of patients with tumor thickness of 1 mm or less. A potential role of the mutational status as a prognostic factor especially in this subgroup needs to be investigated in larger studies.

The activating BRAF mutation V600E and related mutations in this codon are most important for the activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signalling pathway in melanoma. BRAF V600E mutations have been detected in ~40% of melanoma patients and BRAF V600K mutations in ~5% of melanoma patients. Activation of the MAPK pathway results in continuous stimulation of cell proliferation and inhibits programmed cell death. Vemurafenib (PLX4032) was developed as a low molecular weight molecule for the inhibition of the mutated serine threonine kinase BRAF, and it selectively binds to the ATP-binding site of BRAF-V600E kinase and inhibits its activity. The biochemical affinity of vemurafenib for mutated BRAF translates to potent inhibition of ERK phosphorylation and of cell proliferation exclusively in BRAF-mutant cell lines. In animal model experiments, it was demonstrated that vemurafenib achieved tumour regressions in cells harbouring the BRAF V600E mutation. The clinical trials with vemurafenib in unresectable metastatic melanoma in phase I, II, and III for patients harbouring BRAF V600E mutations demonstrated all unexpected high objective response rates ranging between 50 and 80%. Median progression-free survival was prolonged from two months with dacarbazine to seven months with vemurafenib, and median overall survival was respectively prolonged from 9 to 14 months. A major problem that remains is the development of resistance to vemurafenib treatment after several months in the majority of patients, and multiple resistance mechanisms have already been described. Under vemurafenib treatment, about 25% of patients developed cutaneous squamous cell carcinomas of the keratoacanthoma type with low invasive potential and without occurrence of metastasis. The overall tolerability of the drug was quite good, and a number of patients remained on treatment for long times. As other solid tumours like papillary thyroid cancer, colorectal cancer, non-small-cell lung cancer, and ovarian cancer likewise harbour BRAF mutation, vemurafenib is also tested in these entities. In future, combinations of vemurafenib with other kinase inhibitors and with immunotherapies will improve its therapeutic potential.

Introduction: The most commonly mutated oncogene identified to date in melanoma is BRAF (∼ 50%), an upstream mediator of the mitogen-activated protein kinase (MAPK) pathway. Recently, BRAF-kinase inhibitors as well as MEK-kinase inhibitors were introduced into the clinics., Areas Covered: Substantial Phase II and III clinical trials were searched in patients with advanced melanoma treated with BRAF-kinase inhibitors, MEK-kinase inhibitors and cKIT inhibitors., Expert Opinion: For patients with a BRAF, NRAS or cKIT mutation the treatment with selective, targeted drugs is considered as feasible and results in a high rate of confirmed tumor responses. In patients with BRAF mutation the progression free survival and overall survival is prolonged in patients who were treated with BRAF kinase inhibitors or MEK kinase inhibitors compared to patients receiving chemotherapy with dacarbazine. A major problem is the development of resistance to the inhibitors through multiple different mechanisms. One approach to overcome resistance is to combine BRAF and MEK inhibitors. Treatments with kinase inhibitors are more efficacious than chemotherapies, however, they compete with the newly developed immune checkpoint blockers, and may in future be preferentially applied in second- or x-line.

Vemurafenib is a highly efficient BRAF inhibitor for metastatic melanoma patients carrying the V600 mutation: progression-free survival is prolonged to ∼ 6 months and 50-80% of the patients show objective tumor responses. S100B and lactate dehydrogenase (LDH) are established tumor markers in routine melanoma follow-up. This study evaluated their potential as response and progression markers during vemurafenib treatment. A cohort of 44 patients with stage IV melanoma disease who were treated with vemurafenib was retrospectively analyzed. Staging was performed every 6-8 weeks comprising computed tomography scans and measurement of LDH and S100B levels. Response Evaluation Criteria In Solid Tumors (RECIST) criteria were used for standardized radiological response evaluations. The correlation between response or progression and LDH and S100B levels was analyzed using accuracy tests, Spearman's rank correlation ρ, and polynominal regression analyses. There was a good correlation between S100B and LDH decline and a RECIST-confirmed response, especially when S100B and/or LDH were elevated at baseline (accuracy, 81.2% for S100B and 85.7% for LDH). However, the accuracy in case of RECIST-confirmed progression and S100B/LDH levels was low - 30.3% for S100B and 32.4% for LDH. Neither Spearman's rank correlation ρ nor polynomial regression analyses showed a correlation between the clinical course and S100B/LDH levels. Measurement of S100B and LDH levels during treatment with vemurafenib indicates an initial response; however, this does not seem to be sufficient in detecting tumor progression and is thus not an alternative to monitoring with imaging examinations.