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Simple Summary: The outcome of patients with advanced melanoma has profoundly improved over the last 15 years. Novel medications blocking BRAF, a protein involved in stimulating cell division, or inhibiting immune checkpoints associated with T-cell activation significantly improved overall survival. Mutations of the BRAF protein kinase cause cells to make an abnormal protein that promotes tumor growth. In patients with BRAF V600 mutations, dabrafenib and trametinib blocking BRAF V600 and MEK, respectively, have demonstrated improved efficacy in two large clinical trials (COMBI-d, COMBI-v) compared to blocking BRAF signaling with single agents. This led to the approval of dabrafenib plus trametinib for the treatment of patients with advanced melanoma. The study (COMBI-r) presented here investigated the use of dabrafenib plus trametinib in everyday clinical practice. COMBI-r confirms the data from COMBI-d and COMBI-v and provides additional data in patients with brain metastases or previous treatments who had been excluded from the pivotal trials. Combined BRAF/MEK-inhibition constitutes a relevant treatment option for BRAF-mutated advanced melanoma. The prospective, non-interventional COMBI-r study assessed the effectiveness and tolerability of the BRAF-inhibitor dabrafenib combined with the MEK-inhibitor trametinib in patients with advanced melanoma under routine clinical conditions. Progression-free survival (PFS) was the primary objective, and secondary objectives included overall survival (OS), disease control rate, duration of therapy, and the frequency and severity of adverse events. This study enrolled 472 patients at 55 German sites. The median PFS was 8.3 months (95%CI 7.1–9.3) and the median OS was 18.3 months (14.9–21.3), both tending to be longer in pre-treated patients. In the 147 patients with CNS metastases, PFS was similar in those requiring corticosteroids (probably representing symptomatic patients, 5.6 months (3.9–7.2)) compared with those not requiring corticosteroids (5.9 months (4.8–6.9)); however, OS was shorter in patients with brain metastases who received corticosteroids (7.8 (6.3–11.6)) compared to those who did not (11.9 months (9.6–19.5)). The integrated subjective assessment of tumor growth dynamics proved helpful to predict outcome: investigators' upfront categorization correlated well with time-to-event outcomes. Taken together, COMBI-r mirrored PFS outcomes from other prospective, observational studies and confirmed efficacy and safety findings from the pivotal phase III COMBI-d/-v and COMBI-mb trials. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: To describe the current management of patients diagnosed with cutaneous melanoma and melanoma in situ in Germany and assess for adherence with the existing German guideline in a first prospective population-based analysis. Methods: Prospective and longitudinal population-based study using online questionnaires. Registration by practitioners and hospitals was open for all patients diagnosed with melanoma between April and June 2008 in Germany. For data analysis, patients with melanoma stages 0–III (AJCC 2002) were included. Results: Data from 1081 patients registered by 106 different centres were available for analysis. Male patients were significantly older than female patients (61.4years versus 55.8years, p <0.0001) and presented with thicker primary tumours (1.62mm [median 0.9mm] versus 1.48mm [median 0.8mm], p =0.01). Excessive safety margin excisions were most often applied in melanoma in situ and in small centres. Insufficient excision margins (6.9%) were associated with head and neck localisation, geographical region and implementation of further staging procedures. Decision on sentinel lymph node biopsy complied with the German guideline in >85% of cases and was dependent on age and tumour localisation. Only 60% of patients received a complete lymph node dissection (CLND) after a positive SLNB, the rate of CLND was lowest in older patients. Adjuvant treatments were initiated in only 34% of patients formally qualifying for adjuvant treatment based on guideline recommendations. Approximately half of all staging procedures were done in no-risk/low-risk tumour patients. Conclusions: Management of melanoma in Germany did not show great dependency on centre size, geographical area or treating physician but rather on patient and tumour characteristics. The low rate of adjuvant treatment initiations reflects the need of treatment options in this patient group. Excessive initial staging procedures generate significant costs. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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: The growing incidence of nearly all types of skin cancer can be attributed to increased exposure to natural or artificial ultraviolet (UV) radiation. However, there is a scarcity of statistical data on risk behavior or sunscreen use, which would be important for any prevention efforts., Methods: Using the search engine Google ® , we analyzed search patterns for the terms Solarium (tanning bed), Sonnencreme (sunscreen), and Sonnenschutz (sun protection) in Germany, Austria, and Switzerland between 2004 and 2016, and compared it to search patterns worldwide. For this purpose, "normalized search volumes" (NSVs) were calculated for the various search queries. The corresponding polynomial functions were then compared with each other over the course of time., Results: Since 2001, there has been a marked worldwide decrease in the search queries for tanning bed, whereas those for sunscreen have steadily increased. In German-speaking countries, on the other hand, there have - for years - consistently been more search queries for tanning bed than for sunscreen. There is an annual periodicity of the queries, with the highest NSVs for tanning bed between March and May and those for sunscreen in the summer months around June. In Germany, the city-states of Hamburg and Berlin have particularly high NSVs for tanning bed., Conclusions: Compared to the rest of the world, German-speaking countries show a strikingly unfavorable search pattern. There is still great need for education and prevention with respect to sunscreen use and avoidance of artificial UV exposure., (© 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

A new AJCC/UICC staging classification of malignant melanoma was published in 2001 and has been in use since then. Compared to the TNM classification used for the previous 15 years, the new classification contains fundamental changes. The classification of the primary tumor is now based on newly defined classes for Breslow's tumor thickness (0 - 1.0 mm; 1.01 - 2.0 mm, 2.01 - 4.0 mm; > 4.0 mm). Histopathologically diagnosed ulceration is the second prognostic factor in primary melanoma and its presence leads to upstaging into the next higher T category. Clark level of invasion is now only relevant for tumors up to 1 mm thick; levels IV and V are also reasons for upstaging. Classification of regional lymph node metastasis distinguishes between microscopic metastasis only as detected with sentinel lymph node biopsy and clinically detectable macroscopic metastasis. Additionally, the number of metastatic nodes and the presence of satellite and in-transit metastasis are prognostic factors for classification of regional lymph node metastasis. In distant metastasis, the kind of organ involvement has a role for classification (only skin and lymph nodes vs. lung vs. other organs) and an elevated LDH value leads to upstaging. A critical analysis of data of the German Central Malignant Melanoma Registry did not confirm the strong role of histopathological ulceration of the primary tumor in all T- and N-stages. Furthermore, there is an inconsistency of the classification as stage IIC displays a significantly worse prognosis as compared to stage IIIA. In spite of these drawbacks the new staging classification should used particularly in clinical trials in order to make data internationally comparable.

Background: Recent studies revealed that incidence rates of cutaneous melanoma (CM) were leveling off predominantly among younger people and patterns suggested birth-cohort effects. The current study analyzed the development of prognostic factors and survival in incident CM over 25 years., Methods: All 45,483 patients with incident CM diagnosed between 1976 and 2000 recorded by the German Central Malignant Melanoma Registry were considered. Linear and logistic regression analyses were used to judge time trends. Trends of survival rates were tested with the multivariate Cox model., Results: Median tumor thickness decreased from 1.81 mm in 1976 to 0.53 mm in 2000 (P < 0.0001). The percentages of in situ and level II CM increased, respectively (P < 0.0001). The percentage of ulcerated CM decreased (P < 0.0001). The percentage of superficial spreading melanoma increased, whereas the percentage of nodular melanoma decreased (P < 0.0001). These time trends were all significant in the strata of gender, however, male patients presented in general with more advanced disease. Between 1976 and 2000, the average patient got older (P < 0.0001). The percentage of patients diagnosed with the primary tumor alone increased (P < 0.0001). Across the 25 years of observation, adjusted survival rates did not increase for females (P = 0.1561) but they increased for males (P < 0.0001)., Conclusions: The data demonstrated a strong trend towards prognostically more favorable CM most likely due to earlier diagnosis. Men and older people should be the focus of health promotion activities as they presented with more advanced disease., ((c) 2004 American Cancer Society)

Purpose: In 2001, the new American Joint Committee on Cancer classification of cutaneous melanoma (CM) introduced ulceration of the primary melanoma as a new key parameter being represented in respective subcategories of the tumor (T) classification. The present study was performed to validate the prognostic significance of ulceration in relation to T thickness and clinical stages of CM (stages I to III)., Patients and Methods: Patients (N = 15,158) with incident invasive primary nonmetastatic CM and follow-up data recorded between 1976 and 2000 by the German Central Malignant Melanoma Registry were investigated using survival analysis to evaluate prognostic factors such as T thickness, level of invasion, body site, histologic subtype, ulceration, regression, age, and sex., Results: Comparisons of survival probabilities according to the Kaplan-Meier method between ulcerated and nonulcerated CM were not statistically significant for subgroups with T thickness < or = 1 mm and more than 4.00 mm (P = .2601 and P = .0699, respectively) but were significant for T thickness of 1.01 to 2.00 mm and 2.01 to 4.00 mm (P < .0001 for both). This result was confirmed in the multivariate analysis. For stage III CM, the impact of ulceration on overall survival was statistically significant in the bivariate Cox model (P = .0111) but not in the multivariate Cox model (P = .0522)., Conclusion: Whereas ulceration seems to have a negative impact on the prognosis of patients with stages T2 and T3, a potential influence for patients with stages T1 and T4 could not be established. If factors of the primary CM were to be taken into consideration to judge prognosis of stage III CM, T thickness but not ulceration should be the focus.

Purpose: The increasing number of thin cutaneous melanomas (CM) with tumor thickness up to 1 mm demands a detailed analysis of prognostic factors for the classification and grading of these tumors. The aim of the present study was to identify prognostic factors in thin CM., Patients and Methods: A series of 12,728 patients with thin incident primary invasive CM and follow-up data recorded between 1976 and 2000 by the German-based Central Malignant Melanoma Registry was analyzed using the multivariate Cox proportional hazard model to evaluate prognostic factors, and classification and regression trees analysis (CART) to define prognostic groups., Results: Multivariate analysis found tumor thickness, sex, age, body site, and histopathologic subtype to be significant prognostic factors of thin CM. Ulceration and regression did not affect prognosis significantly. Prognostic classification based on the results of CART analysis resulted in three groups defined by tumor thickness, age, and sex. Ten-year survival rates of these groups varied between 91.8% and 98.1%, with improved classification as compared with subgroups by tumor thickness alone., Conclusion: Classification by tumor thickness identified prognostic subgroups with highest significance in thin CM, and the classification was improved by the introduction of age and sex. However, neither ulceration nor the level of invasion included in the new American Joint Committee on Cancer TNM system classification, revealed statistical significance as prognostic factors in thin CM.