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In order to update recommendations on treatment, supportive care, education, and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European Academy of Dermatology and Venereology (EADV), and the European Organisation of Research and Treatment of Cancer (EORTC) was formed. Recommendations were based on an evidence-based literature review, guidelines, and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable), and distant metastatic cSCC. For common primary cSCC, the first-line treatment is surgical excision with postoperative margin assessment or micrographically controlled surgery. Achieving clear surgical margins is the most important treatment consideration for patients with cSCCs amenable to surgery. Regarding adjuvant radiotherapy for patients with high-risk localised cSCC with clear surgical margins, current evidence has not shown significant benefit for those with at least one high-risk factor. Radiotherapy should be considered as the primary treatment for non-surgical candidates/tumours. For cSCC with cytologically or histologically confirmed regional nodal metastasis, lymph node dissection is recommended. For patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiotherapy, anti-PD-1 agents are the first-line systemic treatment, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drugs Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC, include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiotherapy. Multidisciplinary board decisions are mandatory for all patients with advanced cSCC, considering the risks of toxicity, the age and frailty of patients, and co-morbidities, including immunosuppression. Patients should be engaged in informed, shared decision-making on management and be provided with the best supportive care to improve symptom management and quality of life. The frequency of follow-up visits and investigations for subsequent new cSCC depends on underlying risk characteristics., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Invasive cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in white populations, accounting for 20% of all cutaneous malignancies. Overall, cSCC mostly has very good prognosis after treatment, with 5-year cure rates greater than 90%. Despite the overall favourable prognosis and the proportionally rare deaths, cSCC is associated with a high total number of deaths due to its high incidence. A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European Academy of Dermatology and Venereology (EADV) and the European Organization of Research and Treatment of Cancer (EORTC), was formed to update recommendations on cSCC, based on current literature and expert consensus. Part 1 of the guidelines addresses the updates on classification, epidemiology, diagnosis, risk stratification, staging and prevention in immunocompetent as well as immunosuppressed patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Stratigos reports personal fees and/or research support from Novartis, Roche, BMS, Abbvie, Sanofi, Regeneron, Genesis Pharma, outside the submitted work. Dr. Garbe reports personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from NeraCare, grants and personal fees from BMS, personal fees from Pierre Fabre, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, outside the submitted work. Dr. Dessinioti has nothing to disclose. Dr. Lebbe reports grants and personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Novartis, personal fees from Amgen, grants and personal fees from Roche, personal fees from Avantis Medical Systems, personal fees from Pierre Fabre, personal fees from Pfizer, personal fees from Incyte, outside the submitted work. Dr. Bataille reports personal fees from Novartis, personal fees from Merck MSD, outside the submitted work. Dr. Bastholt reports personal fees for advisory board activity: BMS, Roche, Novartis, Pierre-Fabre, Astra Zeneca, InCyte, MSD/Merck, Bayer, outside the submitted work. Dr. Dréno reports grants and personal fees from BMS, personal fees from MSD, grants and personal fees from Roche, grants and personal fees from Fabre, grants and personal fees from Sanofi, outside the submitted work. Dr Dummer reports intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME outside the submitted work. Dr. Fargnoli reports personal consulting fees from Almirall, honoraria from Sanofi-Regeneron and participation in Advisory Board for Sanofi-Regeneron, outside the submitted work. Dr. Forsea reports scientific consultant/speaker fee from Novartis, Merck, outside the submitted work. Dr. Harwood reports institutional research grants and honoraria from Sanofi, Novartis, Merck, Pfizer, Galderma, MEDA, Almirall, Pellepharm, Leo Pharma, CERIES, outside the submitted work. Dr. Hauschild reports grants and personal fees from Amgen, grants and personal fees from BMS, grants and personal fees from MerckPfizer, grants and personal fees from MSD/Merck, grants and personal fees from Philogen, grants and personal fees from Pierre Fabre, grants and personal fees from Regeneron, grants and personal fees from Roche, grants and personal fees from Sanofi-Genzyme, grants and personal fees from Novartis Pharma, grants and personal fees from Eisai, personal fees from Immunocore, grants and personal fees from Replimune, personal fees from Seagen, personal fees from IO Biotech, personal fees from Dermagnostix, personal fees from Incyte, grants and personal fees from NeraCare, personal fees from Highlight Therapeutics, grants from Huya Biosciences, personal fees from Kyowa Kirin, outside the submitted work. Dr. Hoeller reports personal fees from BMS, personal fees from Novartis, grants and personal fees from Amgen, personal fees from Almirall, personal fees from Pierre Fabre, personal fees from Sanofi, personal fees from MSD, outside the submitted work. Dr. Kandolf-Sekulovic reports speakers’ honoraria for Roche, Novartis, MSD, BMS, Janssen outside the submitted work. Dr. Kaufmann reports institutional research grants (clinical trials) from: AbbVie, Amgen, Biontech, BMS, Celgene, Galderma, Janssen, Leo, Lilly, Merck, MSD, Novartis, Pierre Fabre, Pfizer, Regeneron, Roche, Wyeth. Advisory Board and Honoraria from Merz, Roche, Novartis, outside the submitted work. Dr. Kelleners-Smeets reports grants from Netherlands Organization for Health Research and Development, other from Janssen-Cilag, other from AbbVie, other from Galderma, outside the submitted work. Dr. Malvehy reports research grants from Almirall, ISDIN, Leo Pharma, Galderma, GSK, Cantabria; participation in advisory board meetings for Almirall, Sunpharma, BMS, Roche, Novartis, Pierre-Fabre, outside the submitted work. Dr. del Marmol reports personal fees from MSD, from BMS, personal fees from Sanofi, grants and personal fees from ABVIE, grants from Jansen, outside the submitted work. Dr. Moreno-Ramírez has nothing to disclose. Dr. Pellecani reports grants from university of Modena and Reggio Emilia, during the conduct of the study; grants from Novartis, grants and personal fees from Almirall, grants from Leo Pharma, from null, outside the submitted work. Dr. Peris reports honoraria for advisory board and grants from AbbVie, Almirall, Biogen Celgene, Lilly, Galderma, Leo Pharma, Novartis, Roche, Sanofi, Sun Pharma, Sandoz outside the submitted work. Dr. Saiag reports honoraria for advisory board and grants from Amgen, Bristol-Myers Squibb, MSD, Merck-Serono, Novartis, Pfizer, Roche-Genentech, Pierre Fabre, and Sanofi, outside the submitted work. Dr. Vieira has nothing to disclose. Dr. Zalaudek reports honoraria and advisory board and grants from Sanofi, Sun Pharma, Novartis, Galderma, Roche, Celgene, Almirall, Leofarma, Mylan, Difa Cooper, Cieffe Labs, La Roche Posay, Pierre Fabre. Dr. Eggermont reports over the last 5 years personal fees as a consultant advisor for Biocad, BioInvent, Bristol Myers Squibb (BMS), CatalYm, Ellipses, Glaxo Smith Kline (GSK), HalioDX, Incyte, IO Biotech, ISA Pharmaceuticals, Merck Sharpe & Dohme (MSD), Novartis, Pfizer, Polynoma, Regeneron, Sanofi, Sellas, SkylineDx. Alexander M.M. EGGERMONT: Honoraria, consultancy, SAB, IDMC, lectures for the last 2 years: Agenus, BioInvent, BioNTech, BMS, Brenus, CatalYm, Clover Pharmaceuticals, Ellipses, Galecto, GenOway, GSK, IO Biotech, IQVIA, ISA Pharmaceuticals, Merck&Co/MSD, Pierre Fabre, Pfizer, Sairopa, Sellas, SkylineDx, TigaTx, Trained Therapeutics,. Equity : IO Biotech, Sairopa, SkylineDX.Dr. Grob reports personal fees for advisory board and as speaker from Amgen, Roche, GSK, Novartis, BMS, Pierre Fabre, Merck, Sanofi, Merck, Pfizer outside the submitted work. Alexander van Akkooi: Advisory Board / Consultancy Honoraria: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, 4SC. Dr Lallas has nothing to disclose. Dr Ioannides reports support from Sanofi in a phase III clinical trial, outside the submitted work.Dr Lorigan reports honoraria (consulting/advisory/speakers' bureau) from BMS, Merck/MSD, Nektar, NeraCare, Amgen, Novartis, Oncology Education Canada, Pierre Fabre, Roche, outside the submitted work. Dr Rocken reports study grants from AB Science, Abbott, Abbvie, Alcedis, Almirall Hermal, Amgen, AnaptysBio, argenx, AstraZeneca, Bayer, Biogen idec, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, CureVac, DelArrivo, Dynavax Technologies, Eli Lilly, Galderma, Genentech, GSK, Hoffman-La Roche, Hokusai, Idera Pharmaceuticals, Ilkos Therapeutic, Immatics Biotechnologies, Incyte, Iovance Biotherapeutics, Janssen-Cilag, Johnson & Johnson, LEO Pharma, Merck, MSD Sharp & Dome, Novartis Pharmaceuticals, PellePharma, Pfizer, Philogen, Regeneron Pharmaceuticals, Sanofi-Aventis, Schering-Plough, Sun Pharma, Technische Universitat Dresden, Topaz Therapeutics, UCB, Universitatsklinikum Essen, Universitatsklinik Koln, 4SC, grants for research projects from Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Wilhelm Sander-Stiftung, consulting fees from Galderma, support for attending meetings/travel from EADV, International League of Dermatological Societies, patent PCT/EP2020/072203, stock or stock options from Bristol-Myers Squibb, CureVac, Merck, Pfizer, outside the submitted work. Dr Arenberger has nothing to disclose. Dr Tagliaferri reports honoraria from Elekta, Igea Medical, SunPharma, Sanofi, Roche, Molipharma, Nanobiotix, Novartis, outside the submitted work. Dr Leiter reports personal fees from MSD, honoraria from MSD, Novartis, Sun Pharma, Sanofi, Almiral Hermal, support for attending meetings/travel from Pierre Fabre, Sun Pharma, participation in Advisory Board for MSD, Novartis, Sun Pharma, Sanofi, Almiral Hermal, outside the submitted work. Dr Trakatelli reports travel grants from Janssen, UCB, Abbvie, honoraria from UCB, Genesis Pharma, Pierre Fabre Greece, EADV courses, travel expenses for congresses from Abbvie, Pierre Fabre Greece, Genesis Pharma, outside the submitted work., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: ImmunoCobiVem investigated whether a planned switch to atezolizumab after achieving tumour control during run-in with vemurafenib + cobimetinib improves progression-free survival (PFS) and overall survival (OS) compared to continuous targeted therapy (TT) in patients with previously untreated advanced BRAF V600 -mutated melanoma., Methods: In this multicenter phase 2 study, patients received vemurafenib plus cobimetinib. After 3months, patients without progressive disease (PD) were randomly assigned (1:1) to continue vemurafenib + cobimetinib (Arm A) or switch to atezolizumab (Arm B) until first documented PD (PD1). Primary outcome was PFS1 (time from start of run-in until PD1 or death). OS and safety were also assessed., Results: Of 185 patients enroled between November 2016 and December 2019, 135 were randomly assigned after the run-in period (Arm A, n = 69; Arm B, n = 66). Median PFS1 was significantly longer in Arm A versus Arm B (13.9 versus 5.9months; hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.37-0.84; P Stratified =0.001). Median OS was not reached in either arm (HR 1.22; 95%CI, 0.69-2.16; P Stratified =0.389); 2-year OS was higher in Arm B versus Arm A (67%; 95%CI, 53-78 versus 58%; 95%CI, 45-70). Grade 3/4 AEs occurred in 55% of patients in Arm A and 64% in Arm B; treatment-related AEs led to discontinuation of any drug in 7% and 9% of patients, respectively., Conclusion: In patients with BRAF V600 -mutated advanced melanoma who achieve tumour control with TT, early switch at 3months to atezolizumab led to rapid loss of tumour control but provided a numerical OS benefit at 2years compared with continued TT., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EL received honoraria from Novartis, Medac, Bristol Myers Squibb, Sanofi, Sun Pharma, and Pierre Fabre, reports consulting/advisory roles with Bristol Myers Squibb, Pierre Fabre, MSD, Sanofi, and Novartis; and received travel/accommodations/expenses from Pierre Fabre, Bristol Myers Squibb, Medac, and Sun Pharma. HG received honoraria from Bristol Myers Squibb, MSD Oncology, Pierre Fabre, and Sanofi/Regeneron; reports consulting/advisory roles with Bristol Myers Squibb, MSD Oncology, Amgen, Pierre Fabre, and Sanofi/Regeneron; received research funding from Bristol Myers Squibb, Roche, MSD Oncology, Amgen, Novartis, and Iovance Biotherapeutics; and received travel/accommodations/expenses from Bristol Myers Squibb, MSD, Amgen, and Pfizer. LK-S reports consulting/advisory roles with MSD Oncology, Novartis, Roche, and Bristol Myers Squibb/Medarex; was on speaker’s bureaus for MSD Oncology, Novartis, Roche, Bristol Myers Squibb, Janssen, and AbbVie; and received travel/accommodations expenses from MSD Oncology and Roche. FM reports travel support and/or speaker’s fees and/or advisor’s honoraria from Novartis, Roche, Bristol Myers Squibb, MSD, Pierre Fabre, and Sanofi and research funding from Novartis and Roche. TKE reports consulting/advisory roles with Bristol Myers Squibb/Medarex, Sanofi/Regeneron, Novartis, and Pierre Fabre, and speakers' bureaus for Almirall Hermal GmbH. MZ reports a consultant/advisory role with Bristol Myers Squibb; speakers bureaus for Bristol Myers Squibb, Novartis, MSD, and Pierre Fabre; research funding from Novartis; and travel/accommodations/expenses from Philogen. PAMT received honoraria from Almirall, Bristol Myers Squibb, Kyowa Kirin, Novartis, Pierre Fabre, Roche, Sanofi, and 4SC; reports consulting/advisory roles with Almirall, Bristol Myers Squibb, Novartis, Pierre-Fabre, Merck, Serono, Sanofi, Roche, and Kyowa Kirin; and travel/accommodations/expenses from Pierre Fabre and Bristol Myers Squibb. AHG received honoraria from Novartis, Almirall Hermal GmbH, MSD Sharp & Dohme GmbH, and Pierre Fabre Pharma GmbH; reports consulting/advisory roles with Novartis, Bristol Myers Squibb, and Pierre Fabre Pharma GmbH; and received travel/accommodations/expenses from Novartis and Pierre Fabre. RAH is an employee of Helios Kliniken. KCK reports honoraria from Bristol Myers Squibb, MSD, Novartis, and Sanofi-Aventis; reports consulting/advisory roles with Bristol Myers Squibb and MSD; received research funding from Novartis; and received travel/accommodations/expenses from Bristol Myers Squibb, MSD, Novartis, and Roche. DCZ declares no conflicts of interest. ZM received honoraria from Novartis, Janssen, La Roche-Posay, Bristol Myers Squibb/Medarex, Roche, MSD Oncology, AbbVie, Lilly, and Boehringer Ingelheim, and reports consulting/advisory roles with Lilly and Janssen. MG was on a speaker’s bureau for and received travel/accommodations/expenses from Bristol Myers Squibb. CG reports consulting/advisory roles with Bristol Myers Squibb, MSD Oncology, NeraCare GmBH, Novartis, Roche/Genentech, Sanofi, and CeCaVa; received honoraria from Bristol Myers Squibb, MSD Oncology, NeraCare GmBH, Novartis, Philogen, Roche/Genentech, Sanofi, and CeCaVa; and received research funding from Bristol Myers Squibb, NeraCare GmBH, Novartis, and Roche/Genentech. AR reports consulting/advisory roles with and received honoraria from Novartis and Bristol Myers Squibb; received research funding from Novartis, Bristol Myers Squibb, and Adtec; and received travel/accommodations/expenses from Novartis, Bristol Myers Squibb, Roche, and MSD. SU reports research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Novartis, and Roche; and travel support from Bristol Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre, outside the submitted work. RG reports honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Merck Serono, Almirall Hermal GmbH, Amgen, Sun Pharma, Pierre Fabre, Sanofi/Regeneron, and Immunocore; consulting/advisory roles with Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Almirall Hermal GmbH, 4SC, Amgen, Pierre Fabre, Merck Serono, Sun Pharma, Sanofi, and Immunocore; research funding from Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma, and Sanofi; and travel/accommodations/expenses from Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, and Sun Pharma. JJG reports consulting/advisory roles with Bristol Myers Squibb, MSD, Novartis, Roche, Amgen, Pierre Fabre, Philogen, Pfizer, Merck, and Sanofi; participates in a speaker’s bureau for Novartis and Bristol Myers Squibb; received research funding from Pierre Fabre and Bristol Myers Squibb; and received travel/accommodations/expenses from Novartis, Bristol Myers Squibb, and Pierre Fabre. FK reports consulting/advisory roles with Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Sanofi. JU is an advisory board member for and has received honoraria and travel support from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Immunocore, LEO Pharma, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi outside the submitted work. CW-K declares no conflicts of interest. SE declares no conflicts of interest. LZ; received honoraria from Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, Roche, and Pierre Fabre; reports consulting/advisory roles with Merck Sharp & Dohme, Roche, Bristol Myers Squibb, Novartis, Sanofi, Pierre Fabre, and Sun Pharma; received research funding from Novartis, and received travel/accommodations/expenses from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sun Pharma. DS received honoraria from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, Neracare, Sun Pharma, Inflarx GmbH, Ultimovacs, Sandoz, Amgen, Daiichi Sankyo Japan, LabCorp, Nektar, and Replimune; reports consulting/advisory roles with Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, and Nektar; participates in speaker’s bureaus for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi/Regeneron, and Merck KGaA; received research funding from Bristol Myers Squibb, Novartis, Roche, MSD Oncology, Array/Pfizer, and Amgen; and received travel/accommodations/expenses from Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, and Sanofi/Regeneron., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Melanoma is one of the most aggressive tumors, and in the setting of rising incidence and mortality, there is an urgent need to identify new prognostic markers. Toll-like receptors (TLRs), are aberrantly expressed in numerous cancers, including melanoma. TLR signaling provides a microenvironment that is involved in antitumor immune response, chronic inflammation, cancer cell proliferation and evasion of immune destruction. In the present study, we investigated whether single nucleotide polymorphisms (SNPs) in TLR3 and TLR4 genes are associated with clinicopathologic features, progression and survival of melanoma patients. The study was conducted on 120 melanoma patients. DNA extracted from peripheral blood was genotyped for TLR3 polymorphisms rs5743312 and rs3775291 (L412F) and TLR4 polymorphisms rs4986790 (D299G) and rs4986791 (T399I), by TaqMan Real-Time PCR Assays. Kaplan-Meier survival curves were compared by the log-rank test. TLR3 polymorphism L412F was associated with a higher mitotic index ( P  = 0.035). TLR4 D299G and T399I polymorphisms were associated with indicators of melanoma severity, nodal metastases ( P  = 0.005 and P  = 0.007, respectively) and advanced stage III ( P  = 0.005 and P  = 0.004, respectively). Cox regression analysis showed that the presence of tumor-infiltrating lymphocytes (TILs) predicted better overall survival (HR = 0.318; P  = 0.004). TLR4 T399I polymorphism was significantly associated with worse survival, P  = 0.025. The overall survival rates were significantly lower for patients carrying variant allele T of TLR4 T399I SNP (TC and TT genotypes combined) ( P  = 0.008, log-rank test), compared to wild-type genotype CC. Our findings indicate that TLR4 polymorphisms T399I (rs4986791) and D299G (rs4986790) could be potential prognostic and survival markers for melanoma patients., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Sentinel lymph node biopsy is the standard of care for nodal staging in clinically node-negative melanoma patients. Our goal was to present 10-year results of sentinel lymph node biopsy at our institution and to evaluate the clinicopathologic factors as potential predictors of sentinel lymph node and non-sentinel lymph node metastatic involvement in patients with cutaneous melanoma., Methods: We have analyzed clinicopathologic and lymphoscintigraphic characteristics in 420 patients with cutaneous melanoma who underwent sentinel lymph node biopsy between 2010 and 2019. In addition, we have examined the results of group of patients with positive sentinel lymph node biopsy undergoing complete lymph node dissection., Results: The overall detection rate of sentinel lymph node biopsies was 97.1%, of which 18.8% was metastatic. Drainage to one regional basin was seen in 345 patients (83.1%) and to multiple drainage regions in 71 patients (17%). In-transit lymph nodes were detected in 20 patients. On univariate logistic regression analysis, male gender, primary tumor thickness with nodular histology, acral location, presence of ulceration, and the number of nodes harvested were significantly associated with sentinel lymph node biopsy status ( p  < 0.05). On multivariate analysis, the Breslow thickness was the only independent predictor of sentinel lymph node biopsy status. The metastases in non-sentinel lymph node found in 26 patients with positive sentinel lymph node (35.6%) correlated on univariate, as well as on multivariate logistic regression, with tumor subtype and number of sentinel lymph node harvested., Conclusions: In addition to the well-established primary tumor thickness as a predictor of sentinel lymph node biopsy positivity, we observed acral location and nodular melanoma subtype to significantly enhance the risk of metastases in sentinel lymph node(s). Primary tumor histology and number of nodes harvested were the only statistically significant variables predicting the non-sentinel lymph node status on multivariate analysis. Lymphoscintigraphy imaging characteristics were not significantly associated with sentinel lymph node status.

Background and Objectives: The incidence of melanoma is increasing. This places significant burden on societies to provide efficient cancer care. The European Cancer Organisation recently published the essential requirements for quality melanoma care. The present study is aimed for the first time to roughly estimate the extent to which these requirements have been met in Europe., Materials and Methods: A web-based survey of experts from melanoma centres in 27 European countries was conducted from 1 February to 1 August 2019. Data on diagnostic techniques, surgical and medical treatment, organization of cancer care and education were collected and correlated with national health and economic indicators and mortality-to-incidence ratio (MIR) as a surrogate for survival. Univariate linear regression analysis was performed to evaluate the correlations. SPSS software was used. Statistical significance was set at P < 0.05., Results: The MIR was lower in countries with a high health expenditure per capita and with a higher numbers of general practitioners (GPs) and surgeons (SURG) per million inhabitants. In these countries, GPs and dermatologists (DER) were involved in melanoma detection; high percentage of DER used dermatoscopy and were involved in the follow-up of all melanoma stages; both medical oncologists (ONC) and dermato-oncologists administered systemic treatments; and patients had better access to sentinel lymph node biopsy and were treated within multidisciplinary tumour boards., Conclusion: Based on these first estimates, the greater involvement of GPs in melanoma detection; the greater involvement of highly trained DER in dermatoscopy, dermatosurgery, follow-up and the systemic treatment of melanoma; and the provision of ongoing dermato-oncology training for pathologists, SURG, DER and ONC are necessary to provide an optimal melanoma care pathway. A comprehensive analysis of the melanoma care pathway based on clinical melanoma registries will be needed to more accurately evaluate these first insights., (© 2020 European Academy of Dermatology and Venereology.)

Background: The incidence of skin cancers has been increasing steadily over the last decades. Although there have been significant breakthroughs in the management of skin cancers with the introduction of novel diagnostic tools and innovative therapies, skin cancer mortality, morbidity and costs heavily burden the society., Objective: Members of the European Association of Dermato-Oncology, European Academy of Dermatology and Venereology, International Dermoscopy Society, European Dermatology Forum, European Board of Dermatovenereology of the European Union of Medical Specialists and EORTC Cutaneous Lymphoma Task Force have joined this effort to emphasize the fundamental role that the specialist in Dermatology-Venereology has in the diagnosis and management of different types of skin cancer. We review the role of dermatologists in the prevention, diagnosis, treatment and follow-up of patients with melanoma, non-melanoma skin cancers and cutaneous lymphomas, and discuss approaches to optimize their involvement in effectively addressing the current needs and priorities of dermato-oncology., Discussion: Dermatologists play a crucial role in virtually all aspects of skin cancer management including the implementation of primary and secondary prevention, the formation of standardized pathways of care for patients, the establishment of specialized skin cancer treatment centres, the coordination of an efficient multidisciplinary team and the setting up of specific follow-up plans for patients., Conclusion: Skin cancers represent an important health issue for modern societies. The role of dermatologists is central to improving patient care and outcomes. In view of the emerging diagnostic methods and treatments for early and advanced skin cancer, and considering the increasingly diverse skills, knowledge and expertise needed for managing this heterogeneous group of diseases, dermato-oncology should be considered as a specific subspecialty of Dermatology-Venereology., (© 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

In order to update recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer was formed. Recommendations were based on evidence-based literature review, guidelines and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable) and distant metastatic cSCC. For common primary cSCC (the most frequent cSCC type), first-line treatment is surgical excision with postoperative margin assessment or microscopically controlled sugery. Safety margins containing clinical normal-appearing tissue around the tumour during surgical excision and negative margins as reported in the pathology report are necessary to minimise the risk of local recurrence and metastasis. In case of positive margins, a re-excision shall be done, for operable cases. Lymph node dissection is recommended for cSCC with cytologically or histologically confirmed regional nodal involvement. Radiotherapy should be considered as curative treatment for inoperable cSCC, or for non-surgical candidates. Anti-PD-1 antibodies are the first-line systemic treatment for patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiation, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drug Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiation therapy. Multidisciplinary board decisions are mandatory for all patients with advanced disease who require more than surgery. Patients should be engaged with informed decisions on management and be provided with best supportive care to optimise symptom management and improve quality of life. Frequency of follow-up visits and investigations for subsequent new cSCC depend on underlying risk characteristics., Competing Interests: Conflict of interest statement Dr. Stratigos reports personal fees and/or research support from Novartis, Roche, BMS, AbbVie, Sanofi, Regeneron, Genesis Pharma, outside the submitted work. Dr. Garbe reports personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from NeraCare, grants and personal fees from BMS, personal fees from Pierre Fabre, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, outside the submitted work. Dr. Dessinioti has nothing to disclose. Dr. Lebbe reports grants and personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Novartis, personal fees from Amgen, grants and personal fees from Roche, personal fees from Avantis Medical Systems, personal fees from Pierre Fabre, personal fees from Pfizer, personal fees from Incyte, outside the submitted work. Dr. Bataille reports personal fees from Novartis, personal fees from Merck MSD, outside the submitted work. Dr. Bastholt reports personal fees for advisory board activity: BMS, Roche, Novartis, Pierre Fabre, AstraZeneca, Incyte, MSD/Merck, Bayer. Dr. Dréno reports grants and personal fees from BMS, personal fees from MSD, grants and personal fees from Roche, grants and personal fees from Fabre, grants and personal fees from Sanofi, outside the submitted work. Dr. Fargnoli reports grants and personal fees from Almirall, grants and personal fees from Leo Pharma, personal fees from Janssen, grants and personal fees from Novartis, personal fees from Lilly, grants and personal fees from Sanofi, personal fees from UCB, grants and personal fees from AbbVie, personal fees from Celgene, personal fees from Pierre Fabre, grants and personal fees from Galderma, personal fees from Mylan, personal fees from Medac Pharma, personal fees from Roche, personal fees from Sun Pharma, outside the submitted work. Dr. Forsea reports scientific consultant/speaker fee from Novartis, Leo Pharma, Solartium, Pierre Fabre, outside the submitted work. Dr. Frenard has nothing to disclose. Dr. Harwood reports institutional research grants and honoraria from Sanofi, Novartis, Merck, Pfizer, Galderma, Meda, Almirall, PellePharm, Leo Pharma, Ceries. Dr. Hauschild reports honoraria and/or research grants from Almirall, BMS, Roche, Novartis, Pierre Fabre, Sun Pharma, Merck Serono, Sanofi-Aventis, Regeneron, MSD/Merck, Philogen, OncoSec outside the submitted work. Dr. Hoeller reports grants and personal fees from Amgen, personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Pierre Fabre, personal fees from Roche, personal fees from Sanofi, personal fees from Incyte, outside the submitted work. Dr. Kandolf-Sekulovic reports speakers’ honoraria for Roche, Novartis, MSD, BMS, Janssen outside the submitted work. Dr. Kaufmann reports institutional research grants (clinical trials) from AbbVie, Amgen, Biontech, BMS, Celgene, Galderma, Janssen, Leo, Lilly, Merck, MSD, Novartis, Pierre Fabre, Pfizer, Regeneron, Roche, Wyeth. Advisory board and honoraria from Merz, Roche, Novartis. Dr. Kelleners-Smeets reports grants from Netherlands Organization for Health Research and Development, other from Janssen-Cilag, other from AbbVie, other from Galderma, outside the submitted work. Dr. Malvehy reports research grants from Almirall, ISDIN, Leo Pharma, Galderma, GSK, Cantabria; participation in advisory board meetings for Almirall, Sun Pharma, BMS, Roche, Novartis, Pierre Fabre. Dr. del Marmol reports personal fees from MSD, from BMS, personal fees from Sanofi, grants and personal fees from AbbVie, grants from Janssen, outside the submitted work. Dr. Middleton reports personal fees and/or grants from Amgen, Roche, AstraZeneca, GSK, Novartis, Immunocore, BMS, Eisai and Merck. Institutional funding from Millennium, Vertex, Pfizer, Regeneron, TC Biopharm, BioLineRx, Replimune, outside the submitted work. Dr. Moreno-Ramírez has nothing to disclose. Dr. Pellecani reports grants from university of Modena and Reggio Emilia, during the conduct of the study; grants from Novartis, grants and personal fees from Almirall, grants from Leo Pharma, from null, outside the submitted work. Dr. Peris reports honoraria for advisory board and grants from AbbVie, Almirall, Biogen Celgene, Lilly, Galderma, Leo Pharma, Novartis, Roche, Sanofi, Sun Pharma, Sandoz outside the submitted work. Dr. Saiag reports honoraria for advisory board and grants from Amgen, Bristol-Myers Squibb, MSD, Merck Serono, Novartis, Pfizer, Roche-Genentech, Pierre Fabre, and Sanofi, outside the submitted work. Dr. van den Beuken-van Everdingen has nothing to disclose. Dr. Vieira has nothing to disclose. Dr. Zalaudek reports honoraria and advisory board and grants from Sanofi, Sun Pharma, Novartis, Galderma, Roche, Celgene, Almirall, Leo Pharma, Mylan, Difa Cooper, Cieffe Labs, La Roche Posay, Pierre Fabre. Dr. Eggermont reports over the last 5 years personal fees as a consultant advisor for BIOCAD, BioInvent, Bristol-Myers Squibb (BMS), CatalYm, Ellipses, GlaxoSmithKline (GSK), HalioDx, Incyte, IO Biotech, ISA Pharmaceuticals, Merck Sharpe & Dohme (MSD), Novartis, Pfizer, Polynoma, Regeneron, Sanofi, SELLAS, SkylineDx. Dr. Grob reports personal fees for advisory board and as speaker from Amgen, Roche, GSK, Novartis, BMS, Pierre Fabre, Merck, Sanofi, Merck, Pfizer outside the submitted work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Invasive cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in the white populations, accounting for 20% of all cutaneous malignancies. Factors implicated in cSCC etiopathogenesis include ultraviolet radiation exposure and chronic photoaging, age, male sex, immunosuppression, smoking and genetic factors. A collaboration of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organisation of Research and Treatment of Cancer (EORTC) was formed to update recommendations on cSCC classification, diagnosis, risk stratification, staging and prevention, based on current literature, staging systems and expert consensus. Common cSCCs are typically indolent tumors, and most have a good prognosis with 5-year cure rates of greater than 90%, and a low rate of metastases (<4%). Further risk stratification into low-risk or high-risk common primary cSCC is recommended based on proposed high-risk factors. Advanced cSCC is classified as locally advanced (lacSCC), and metastatic (mcSCC) including locoregional metastatic or distant metastatic cSCC. Current systems used for staging include the American Joint Committee on Cancer (AJCC) 8th edition, the Union for International Cancer Control (UICC) 8th edition, and Brigham and Women's Hospital (BWH) system. Physical examination for all cSCCs should include total body skin examination and clinical palpation of lymph nodes, especially of the draining basins. Radiologic imaging such as ultrasound of the regional lymph nodes, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography-computed tomography (PET-CT) scans are recommended for staging of high-risk cSCC. Sentinel lymph node biopsy is currently not recommended. Nicotinamide, oral retinoids, and topical 5-FU have been used for the chemoprevention of subsequent cSCCs in high-risk patients but are not routinely recommended. Education about sun protection measures including reducing sun exposure, use of protective clothing, regular use of sunscreens and avoidance of artificial tanning, is recommended., Competing Interests: Declaration of competing interest Dr. Stratigos reports personal fees and/or research support from Novartis, Roche, BMS, Abbvie, Sanofi, Regeneron, Genesis Pharma, outside the submitted work. Dr. Garbe reports personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from NeraCare, grants and personal fees from BMS, personal fees from Pierre Fabre, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, outside the submitted work. Dr. Dessinioti has nothing to disclose. Dr. Lebbe reports grants and personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Novartis, personal fees from Amgen, grants and personal fees from Roche, personal fees from Avantis Medical Systems, personal fees from Pierre Fabre, personal fees from Pfizer, personal fees from Incyte, outside the submitted work. Dr. Bataille reports personal fees from Novartis, personal fees from MerckMSD, outside the submitted work. Dr. Bastholt reports personal fees for advisory board activity: BMS, Roche, Novartis, Pierre-Fabre, Astra Zeneca, InCyte, MSD/Merck, Bayer. Dr. Dréno reports grants and personal fees from BMS, personal fees from MSD, grants and personal fees from Roche, grants and personal fees from Fabre, grants and personal fees from Sanofi, outside the submitted work. Dr. Fargnoli reports grants and personal fees from Almirall, grants and personal fees from Leo Pharma, personal fees from Janssen, grants and personal fees from Novartis, personal fees from Lilly, grants and personal fees from Sanofi, personal fees from UCB, grants and personal fees from Abbvie, personal fees from Celgene, personal fees from Pierre Fabre, grants and personal fees from Galderma, personal fees from Mylan, personal fees from Medac Pharma, personal fees from Roche, personal fees from Sun Pharma, outside the submitted work. Dr. Forsea reports scientific consultant/speaker fee from Novartis, Leo Pharma, Solartium, Pierre-Fabre, outside the submitted work. Dr. Frenard has nothing to disclose. Dr. Harwood reports institutional research grants and honoraria from Sanofi, Novartis, Merck, Pfizer, Galderma, MEDA, Almirall, Pellepharm, Leo Pharma, CERIES. Dr. Hauschild reports honoraria and/or research grants from: Almirall, BMS, Roche, Novartis, Pierre-Fabre, Sunpharma, MerckSerono, SanofiAventis, Regeneron, MSD/Merck, Philogen, OncoSec outside the submitted work. Dr. Hoeller reports grants and personal fees from Amgen, personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Pierre Fabre, personal fees from Roche, personal fees from Sanofi, personal fees from Incyte, outside the submitted work. Dr. Kandolf-Sekulovic reports speakers’ honoraria for Roche, Novartis, MSD, BMS, Janssen outside the submitted work. Dr. Kaufmann reports institutional research grants (clinical trials) from: AbbVie, Amgen, Biontech, BMS, Celgene, Galderma, Janssen, Leo, Lilly, Merck, MSD, Novartis, Pierre Fabre, Pfizer, Regeneron, Roche, Wyeth. Advisory Board and Honoraria from Merz, Roche, Novartis. Dr. Kelleners-Smeets reports grants from Netherlands Organization for Health Research and Development, other from Janssen-Cilag, other from AbbVie, other from Galderma, outside the submitted work. Dr. Malvehy reports research grants from Almirall, ISDIN, Leo Pharma, Galderma, GSK, Cantabria; participation in advisory board meetings for Almirall, Sunpharma, BMS, Roche, Novartis, Pierre-Fabre. Dr. del Marmol reports personal fees from MSD, from BMS, personal fees from Sanofi, grants and personal fees from ABVIE, grants from Jansen, outside the submitted work. Dr. Middleton reports personal fees and/or grants from Amgen, Roche, Astrazeneca, GSK, Novartis, Immunocore, BMS, Eisai and Merck. Institutional funding from Millennium, Vertex, Pfizer, Regeneron, TCBiopharma, BiolineRx, Replimune, outside the submitted work. Dr. Moreno-Ramírez has nothing to disclose. Dr. Pellecani reports grants from university of modena and reggio emilia, during the conduct of the study; grants from novartis, grants and personal fees from almirall, grants from leo pharma, from null, outside the submitted work. Dr. Peris reports honoraria for advisory board and grants from AbbVie, Almirall, BiogenCelgene, Lilly, Galderma, Leo Pharma, Novartis, Roche, Sanofi, Sun Pharma, Sandoz outside the submitted work. Dr. Saiag reports honoraria for advisory board and grants from Amgen, Bristol-Myers Squibb, MSD, Merck-Serono, Novartis, Pfizer, Roche-Genentech, Pierre Fabre, and Sanofi, outside the submitted work. Dr. van den Beuken-van Everdingen has nothing to disclose. Dr. Vieira has nothing to disclose. Dr. Zalaudek reports honoraria and advisory board and grants from Sanofi, Sun Pharma, Novartis, Galderma, Roche, Celgene, Almirall, Leofarma, Mylan, Difa Cooper, Cieffe Labs, La Roche Posay, Pierre Fabre. Dr. Eggermont reports over the last 5 years personal fees as a consultant advisor for Biocad, BioInvent, Bristol Myers Squibb (BMS), CatalYm, Ellipses, Glaxo Smith Kline (GSK), HalioDX, Incyte, IO Biotech, ISA Pharmaceuticals, Merck Sharpe & Dohme (MSD), Novartis, Pfizer, Polynoma, Regeneron, Sanofi, Sellas, SkylineDx. Dr. Grob reports personal fees for advisory board and as speaker from Amgen, Roche, GSK, Novartis, BMS, Pierre fabre, Merck, Sanofi, Merck, Pfizer outside the submitted work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The aberrant DNA methylation plays a critical role in a number of different malignancies, including melanoma. DNA methylation is catalyzed by DNA methyltransferases (DNMTs), involved in methylation maintenance (DNMT1) and de novo DNA methylation (DNMT3A and DNMT3B). The current study investigated the association of genetic variants in the DNMT1 and DNMT3B with the clinicopathologic features and the clinical course of melanoma patients. In the present study, DNMT1 (rs2228612, rs2228611, and rs2114724) and DNMT3B (rs406193 and rs2424932) polymorphisms were examined in 123 melanoma patients. Single nucleotide polymorphisms were assessed using TaqMan SNPs Genotyping Assays according to the manufacturer's protocols. The carriers of the variant genotype of DNMT1 rs2228612 had poorer overall survival and recurrence-free survival, (P = 0.000 and 0.000, respectively), and an increased risk for adverse outcome [hazard ratio (HR) = 6.620, 95% confidence interval (CI): 2.214-19.791, P = 0.001]. DNMT1 rs2228612 was also associated with ulceration (P = 0.045), nodal status (P = 0.030), progression (P = 0. 007), and stage of disease (P = 0.003). Univariate analysis indicated that tumor-infiltrating lymphocytes could be a marker of good prognosis in melanoma patients (HR = 0.323, 95% CI: 0.127-0.855, P = 0.025), whereas the genotype distribution of the DNMT3B rs406193 polymorphism correlated significantly with the presence of tumor-infiltrating lymphocytes (P = 0.012). The multivariate analysis showed that the DNMT1 rs2228612 polymorphism (HR = 12.126, 95% CI: 2.345-62.715, P = 0.003) is an independent predictor of poor overall survival in melanoma patients. As expected, disease progression was also found to be an independent prognostic factor in melanoma patients (HR = 37.888, 95% CI: 3.615-397.062, P = 0.002). DNMT1 rs2228612 was found to be an independent predictor of poor overall survival in melanoma patients. DNMTs polymorphisms could serve as a potential target for novel therapeutic approaches.

Background: Nodular melanoma (NM) is more likely to be fatal compared with other melanoma subtypes, an effect attributed to its greater Breslow thickness., Methods: Clinicopathological features of NM and superficial spreading melanoma (SSM) diagnosed in 17 centers in Europe (n = 15), the United States, and Australia between 2006 and 2015, were analyzed by multivariable logistic regression analysis, with emphasis on thin (T1 ≤ 1.0 mm) melanomas. Cox analysis assessed melanoma-specific survival. All statistical tests were two sided., Results: In all, 20 132 melanomas (NM: 5062, SSM: 15 070) were included. Compared with T1 SSM, T1 NM was less likely to have regression (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.29 to 0.72) or nevus remnants histologically (OR = 0.60, 95% CI = 0.42 to 0.85), and more likely to have mitoses (OR = 1.97, 95% CI = 1.33 to 2.93) and regional metastasis (OR = 1.77, 95% CI = 1.02 to 3.05). T1 NM had a higher mitotic rate than T1 SSM (adjusted geometric mean = 2.2, 95% CI = 1.9 to 2.5 vs 1.6, 95% CI = 1.5 to 1.7 per mm2, P < .001). Cox multivariable analysis showed a higher risk for melanoma-specific death for NM compared with SSM for T1 (HR = 2.10, 95% CI = 1.24 to 3.56) and T2 melanomas (HR = 1.30, 95% CI = 1.01 to 1.68), and after accounting for center heterogeneity, the difference was statistically significant only for T1 (HR = 2.20, 95% CI = 1.28 to 3.78). The NM subtype did not confer increased risk within each stratum (among localized tumors or cases with regional metastasis)., Conclusions: T1 NM (compared with T1 SSM) was associated with a constellation of aggressive characteristics that may confer a worse prognosis. Our results indicate NM is a high-risk melanoma subtype that should be considered for inclusion in future prognostic classifications of melanoma., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The Central European Cooperative Oncology Group (CECOG) and 'ESMO Open-Cancer Horizons' roundtable discussion brought together stakeholders from several European Union (EU) countries involved in drug development, drug authorisation and reimbursement or otherwise affected by delayed and unequal access to innovative anticancer drugs. The approval process of drugs is well established and access delays can be caused directly or indirectly by national or regional decision-making processes on reimbursement. The two key aspects for those involved in reimbursement decisions are first the level of evidence required to decide and second pricing, which can be challenging for some innovative oncology compounds, especially in Eastern and South-Eastern European countries. Other important factors include: available healthcare budget; the structure and sophistication of healthcare authorities and health technology assessment processes; societal context and political will. From the point of view of the pharmaceutical industry, better alignment between stakeholders in the process and adaptive pathway initiatives is desirable. Key aspects for patients are improved access to clinical trials, preapproval availability and reports on real-world evidence. Restricted access limits oncologists' daily work in Eastern and South-Eastern EU countries. The roundtable discussion suggested considering the sequencing of regulatory approval and reimbursement decisions together with more flexible contracting as a possible way forward. The panel concluded that early and regular dialogue between all stakeholders including regulators, payers, patient stakeholders and industry is required to improve the situation., Competing Interests: Competing interests: The current work of AB (for MoCA and as unpaid expert for the Austrian Federal Administrative Court) informs about payers’ attitudes/concerns regarding the reimbursement of expensive medicines. However, the opinions expressed here cannot be construed as an official position of any payer organisation. LKS received relevant financial funding for activities outside the submitted work, which are speaker’s fees from Roche, Novartis, BMS and MSD. GK received relevant financial funding outside the submitted work from MSD. AL: the views expressed in this article are the personal views of the the co-author and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties. LM is a paid employee of Fight Bladder Cancer UK, and a volunteer board member of the World Bladder Cancer Patient Coalition. Fight Bladder Cancer UK has received financial support from BMS, Janssen, MSD and F. Hoffman-La Roche AG. The World Bladder Cancer Patient Coalition has received financial support from AstraZeneca, Bayer, F. Hoffman-La Roche AG, Janssen, Ipsen, MSD and Photocure. AR is an employee of MSD International and owns shares of MSD. MSD has supported this meeting together with Boehringer Ingelheim. NW received project grants and consulting and speaking fees from a large number of pharmaceutical companies, including MSD. CZ received honoraria from Roche, Novartis, BMS, MSD, Imugene, Ariad, Pfizer, Merrimack/Shire, Merck KGaA, Fibrogen, AstraZeneca, Tesaro, Gilead, Servier, Eli Lilly and Amgen., (© Author (s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Kaposi's sarcoma (KS) is a multifocal neoplasm of lymphatic endothelium-derived cells infected with human herpesvirus 8. Four clinical subtypes are distinguished: the classic, the endemic, the epidemic subtype in HIV positive patients and the iatrogenic subtype. The diagnosis is primarily based on clinical features and confirmation by histology with immunohistochemistry. Cutaneous distribution and severity, mucosal, nodal and visceral involvement depend on the type of KS with in general indolent behaviour and chronic evolution in the classic subtype and the more severe forms in iatrogenic or epidemic subtypes. Management should aim at achieving disease control. For localised lesions, several local therapies have been developed without randomised trial comparisons. Radiotherapy, intralesional chemotherapies and electrochemotherapy have high response rates. Topical treatments-imiquimod or topical 9-cis-retinoid acid-can also be used. Systemic treatments are reserved for locally aggressive extensive and disseminated KS: the recommended first-line agents are pegylated liposomal doxorubicin (PLD) and paclitaxel. In CKS, PLD or low-dose interferon-alfa are the recommended first-line agents in younger patients. In AIDS-related KS, combination antiretroviral therapy is the first treatment option; specific systemic treatment is needed only in case of extensive disease and in the prevention and treatment of immune reconstitution inflammatory syndrome. In post-transplant KS, tapering down immunosuppressive therapy and switching to mammalian target of rapamycin (m-TOR) inhibitors are used. Follow-up schedules for patients with KS disease depend on aggressiveness of the disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi + MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p = 0.02), median market price (p = 0.001), HEPC and Mackenbach scores (p < 0.01). Price negotiations or managed entry agreements (MEAs) with national authorities were necessary for reimbursement. In conclusion, great discrepancy exists in metastatic melanoma treatment globally. Access to innovative medicines is in correlation with economic parameters as well as with healthcare system performance parameters. Patient-oriented drug development, market access and reimbursement pathways must be urgently found., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Sentinel lymph node (SLN) biopsy is a widely accepted staging procedure for cutaneous melanoma patients who are at risk of clinically occult nodal metastases. Numerous predictive factors for regional lymph node metastases have been identified; however, few have been found to be reproducibly significant. Also, the role of blue dye in identification was questioned in recent trials. Time to procedure was also found to be predictive of SLN positivity, but this was not confirmed in other studies. In our study, predictive factors for metastatic involvement of SLN were analyzed, together with the role of addition blue dye in imaging on detection rate and false-negative SLN rate. An impact of time interval to procedure on the rate of SLN positivity was also explored., Methods: Data analysis was done in 362 cutaneous melanoma patients who underwent lymphoscintigraphy and SLN biopsy at our institution from 2010 to 2016, with a median follow-up of 29 months (1-98 months). To delineate the relation of each variable (demographical, time to procedure, and clinical and pathological variables, as well as the presence of in-transit nodes, the number of draining basins, and SLN localization on scintigraphy) with positive SLN status, we used univariate logistic regression with odds ratios representing effect size., Results: Metastatic involvement SLN was found in 67 (18.8%) of 356 patients. Detection rate was similar with or without further intraoperative SLN identification with blue dye (98.8% vs 98.17%, P > 0.05). Time to procedure was not associated with higher SLN positivity rate (P > 0.05). In univariate analysis, Breslow thickness (P < 0.001), primary ulceration lesion (P = 0.001), and lymphovascular invasion (P = 0.006) were strongly correlated with SLN positivity, as well as the site of primary tumor (P = 0.024), tumor-infiltrating lymphocytes (TILs) (P = 0.021), and sex (P = 0.026). In multivariate analysis, Breslow thickness and TILs were found to be significant independent predictors of SLN status (P < 0.05)., Conclusions: Addition of blue dye did not improve SLN detection rate; time to procedure was not found to be associated with higher SLN biopsy positivity rates. Breslow thickness and TILs, as a marker of immune response to tumor, were consistently found to be significant independent predictors of SLN status.

Background: Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europe and estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF)., Materials and Methods: Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes., Results: The recommended BRAF inhibitor (BRAFi) + MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r = 0.662; p < 0.001), health expenditure per capita (r = 0.695; p < 0.001) and the Mackenbach score of health policy performance (r = 0.765; p < 0.001) with the percentage of patients treated with innovative medicines and a number of reimbursed medicines., Conclusions: Great discrepancy exists in metastatic melanoma treatment across Europe. It is crucial to increase the awareness of national and European policymakers, oncological societies, melanoma patients' associations and pharma industry., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Seventy-eight melanoma patients and 10 healthy individuals were examined. Follow-up examinations of all melanoma patients were performed regularly every three months. Myeloid-derived suppressor cells (MDSC) were defined as lineage negative (CD3(-), CD19(-), CD56(-)), HLA-DR(-/low), CD11b(+) and CD33(+). Classification of granulocytic (GrMDSC) and monocytic (MoMDSC) subsets was based on the CD15 and CD14 expression, respectively. Unlike the MoMDSC, that were present in 60% of healthy controls and 15% of melanoma patients, the GrMDSC were present in all examined participants, and the melanoma patients were found to have statistically higher frequencies compared with healthy controls. Accordingly, we kept focused on GrMDSC frequencies in relation to the melanoma stages and course of the disease. The GrMDSC values are highest in stage IV melanoma patients, with statistical significance compared with stages IA, IB, IIA and IIB. Patients with progression had statistically higher GrMDSC counts comparing with those with stable disease (P = 0.0079). Patients who had progression-free interval (PFI) < 12 months showed significantly higher GrMDSC values compared with those with PFI > 12 months (P = 0.0333). GrMDSC showed significant negative correlation with PFI intervals (P = 0.0095). The GrMDSC subset was predominant in all our patients. We confirmed that GrMDSC do accumulate early in the peripheral blood of melanoma patients and their frequencies correlate narrowly with the clinical stage and the spread of the disease. The increase in GrMDSC frequencies correlates well with a progressive disease and could be considered a potential predictive biomarker of high-risk melanoma cases that are more likely to have a shorter PFI., (© The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Sentinel lymph node biopsy (SLNB) is a widely accepted method in the management of clinically localized cutaneous melanomas. The aim of this study was to report the results on patients scheduled for preoperative lymphoscintigraphy and SLNB for staging and further treatment planning., Subjects and Methods: Two hundred and one patients (115 male and 86 female, median age 57 years, range 9-81) with cutaneous melanoma having undergone SLB at Military Medical Academy between November 2010 and October 2014, were recruited for retrospective study. Dual labeling method (Tc-99m Nanocolloid (blue dye) was used. In order to delineate the relation between patients' tumors and scintigraphic characteristics with positive SLN findings, we examined all variables by univariate logistic regression with odd ratios representing the size effect., Results: The overall identification rate of SLN was 98.5%. One or more positive SLN were seen in 47 (23.4%) of the patients. Drainage to one regional basin was noticed in 176 (88%) and multiple drainage regions, up to three, was noticed in 24 patients (12%). Transit lymph nodes were detected in 20 patients (10%). The characteristics that were assotiated significatly with sentinel lymph node metastases were Breslow thickness, nodular melanoma histological subtype and acral localization., Conclusion: Besides the well established primary tumor thickness being a predictor of SLN malignancy, we observed: acral body site location and nodular melanoma histological subtype to be significant independent factors in increasing the risk for regional metastases. Our results suport the clinical usefulness of SLNB within a multidisciplinary approach (dermatooncology, plastic/head and neck surgery, pathology, nuclear medicine), as a reliable method in staging and for treatment planning in melanoma patients.

Previous studies have reported that vitamin D receptor (VDR) gene polymorphisms are associated with the occurrence of various cancers, including melanoma. The aim of the current study was to investigate the association of VDR gene polymorphisms with melanoma risk, clinicopathological characteristics, and vitamin D levels. The study group included 117 patients (84 patients with superficial spreading melanoma and 33 patients with nodular melanoma). The control group included 122 sex-matched and age-matched healthy-blood donors of the same ethnicity. VDR gene polymorphisms FokI, EcoRV, TaqI, and ApaI were genotyped by real-time PCR. In 60 patients, the total 25-hydroxyvitamin D levels were evaluated in serum samples by direct chemiluminescence. Associations among parameters were considered to be significant if the P value was less than 0.05. Significant differences in the frequencies of VDR genotypes were observed between cases and the control group for FokI and TaqI polymorphisms (P<0.0001; P=0.005, respectively). Heterozygous Ff as well as mutant FF genotypes of the FokI polymorphism were associated with increased melanoma risk compared with the wild-type form [odds ratio (OR)=3.035, P=0.003; OR=9.276, P<0.0001, respectively]. A significantly increased melanoma risk was observed for the heterozygous Tt (OR=2.302, P=0.011) and the mutated variant tt (OR=3.697, P=0.003) of the TaqI polymorphism in comparison with the wild-type genotype. None of the polymorphisms studied was associated with clinicopathological characteristics and vitamin D serum level. Our results suggest that FokI and TaqI polymorphisms in the VDR gene may be considered as potential biomarkers for melanoma susceptibility. Low vitamin D levels in melanoma patients indicate the need for vitamin D supplementation.

Vascular thrombosis was found in different proportions of patients with Adamantiades-Behçet's disease (ABD), depending on the ethnicity of the population under study. Various thrombophilic factors, including the levels of anticardiolipin antibodies (ACA), were investigated for their role in the thrombotic process with conflicting results. The prevalence of ACA varies considerably in different studies, but their presence has not been associated with increased risk for vascular thrombosis. We present two cases with ABD, deep venous thrombosis (DVT) and elevated levels of ACA that fulfil the criteria for both ABD and antiphospholipid syndrome (APS).

Background/purpose: Contact hypersensitivity (CHS) reaction is a useful model for studying the skin immune system and inflammatory reactions in the skin. In this study, an experimental model of CHS reaction was employed to assess immunomodulatory effects of near-infrared (near-IR) low-intensity laser (LIL) irradiation, which is used as adjuvant therapy in dermatology, physical medicine, rheumatology, etc., because of its declared anti-inflammatory, biostimulative and analgesic effects., Methods: The effects of near-IR LIL irradiation (lambda=904 nm, irradiance 60 mW/cm2, fluence 3.6 J/cm2) on CHS reaction to 1-chloro-2,4-dinitrochlorobenzene (DNCB) in Albino Oxford rats were examined by irradiating experimental groups of animals before the induction phase of CHS reaction, while nonirradiated animals and animals that received vehicle instead of hapten served as controls. Ear-swelling assay, histopathological examination of H&E preparations of ear skin, computer-assisted image analysis of dermal infiltrate, ear skin organ culture with the determination of cutaneous production of tumour necrosis factor-alpha (by ELISA assay) and nitric oxide (by Griess' assay) were used for measuring the effects of LIL in the elicitation phase of CHS reaction. Cellularity, dendritic cell content, flow cytometry and proliferation assays (spontaneous and in the presence of IL-2 and concanavalin A) of the draining lymph node cells (DLNC) were performed for the assessment of LIL irradiation effects in the induction phase., Results: In the irradiated group of animals, ear swelling was significantly diminished compared to control animals (101+/-11.5% vs. 58+/-11.6%, P<0.01). This was accompanied by a highly significant decrease in the density of dermal infiltrate (22+/-0.81 vs. 14.2+/-1.75 cells per unit area, P<0.01) and a significant decrease in nitrite levels in the medium conditioned by organ-cultured ear skin (17.63+/-1.91 vs. 3.16+/-1.69 microM NaNO2; P<0.01), while TNF-alpha concentration was not changed. Cellularity and dendritic cell content in DLNC population, as well as the expression of TCR-alpha, CD4, CD8 and CD25, were not changed between irradiated and nonirradiated animals. Proliferation rates of DLNC cultured for 72 h were significantly lower in irradiated animals (17.3+/-4.1 vs. 13.9+/-0.9 x 103 c.p.m.; P<0.01). In cultures of DLNC with added rIL-2 or 0.5 microg/ml of concanavalin A, proliferation rates were also significantly decreased in irradiated animals (34.7+/-3.5 vs. 31.2+/-2. c.p.m. in IL-2-supplemented culture, P<0.01; 70.9+/-6.4 vs. 58.3+/-9.1 x 103 c.p.m. in concanavalin A-supplemented culture, P<0.01). However, this effect was overcome in the presence of the higher concentration of concanavalin A (2.5 microg/ml) (nonirradiated 38.7+/-3.1, irradiated 123.1+/-7.3 x 103 c.p.m., P<0.01)., Conclusion: LIL irradiation showed a systemic immunomodulatory effect on CHS reaction to DNCB in rats. Decreased ear swelling observed in the elicitation phase was associated with diminished proliferative responses of the DLNC in the induction phase of CHS reaction. Further experimental work is needed to examine the possible mechanisms of these effects.