Early switch from run-in treatment with vemurafenib plus cobimetinib to atezolizumab after 3 months leads to rapid loss of tumour control in patients with advanced BRAFV600-positive melanoma: The ImmunoCobiVem phase 2 randomised trial.

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 BRAFV600-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; PStratified=0.001). Median OS was not reached in either arm (HR 1.22; 95%CI, 0.69-2.16; PStratified=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 BRAFV600-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.

The evolving field of Dermato-oncology and the role of dermatologists: Position Paper of the EADO, EADV and Task Forces, EDF, IDS, EBDV-UEMS and EORTC Cutaneous Lymphoma Task Force.

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.

Prognostic factors in 161 patients with mucosal melanoma: a study of German Central Malignant Melanoma Registry.

BACKGROUND: Mucosal melanoma is a rare malignancy which represents approximately 1% of all melanomas. It is shown that mucosal melanomas have a different biology and less favourable prognosis than its cutaneous counterpart. OBJECTIVES: Predictive and prognostic factors of survival for mucosal melanoma have not yet been elucidated. The aim of this study was to investigate risk factors affecting the course of mucosal melanoma patients followed in our clinic. METHODS: One hundred and sixty-one patients with mucosal melanoma prospectively documented in the German Central Malignant Melanoma Registry (CMMR) were included in this study. Gender, age, localization, stage at first medical examination, tumour thickness and mutational status were documented. The American Joint Committee on Cancer (AJCC), 7th edition was used to define tumour stage. Kaplan-Meier survival curves were evaluated compared with the log-rank test. Multivariate Cox proportional hazard models were used to identify significant independent prognostic factors. RESULTS: According to the localization, patients were categorized in 44.7% oral-nasal, 28.6% genital, 20.5% anorectal and 6.2% visceral. Genital mucosal melanomas had the most favourable 5-year OS rate (58.6%) followed by visceral (58.3%) and oral-nasal (39.3%). Anorectal melanomas had the worst OS time (median: 21 ± 4.8 months) and 5-year survival rate (22.7%). Patients <60 years had a better survival than the older group (P = 0.013). Tumour stage at the time of the first medical examination was also a significant factor for survival (P = 0.001). Gender and mutational status were found to have no effect on survival. Age (<60 years vs. ≥60 years; HR = 2.1) and stage at first medical examination (Stage I vs. Stage IV; HR = 8.2) are shown to be significant independent prognostic factors on multivariate Cox regression analysis, but not localization. CONCLUSION: In this study, we observed that older age and advanced stage have significant negative effects on the survival of mucosal melanoma. Thus, the AJCC staging system is applicable for mucosal melanoma.

Late recurrence of melanoma after 10 years - Is the course of the disease different from early recurrences?

BACKGROUND: It is known that melanoma can metastasize and recur many years after the first diagnosis. Although predictive and prognostic factors for melanoma are well defined, there is still insufficient information about the factors affecting the recurrence period and the effect of the recurrence time to survival. OBJECTIVES: This study investigates the course of melanoma to show prognostic factors comparing early and late recurrence patients. The main objective is to uncover the effect of the recurrence time on the progression of the disease. METHODS: In this retrospective study, late recurrence (LR) was defined as melanoma recurrence 10 years after the first diagnosis and early recurrence (ER) was defined as recurrence within 10 years. Gender, age, localization of primary tumour, time to first metastasis, survival rates, histological subtype, stage, tumour thickness, invasion level, ulceration and regression of the primary melanoma were documented. Survival curves were evaluated using the Kaplan-Meier and compared with the log-rank test. Multivariate Cox proportional hazard models were used to identify significant independent prognostic factors for melanoma-specific survival (MSS). RESULTS: A total of 1537 melanoma patients were analysed. Early metastasis was developed in 1438 patients (93.6%), and 99 patients (6.4%) developed late metastasis. Late recurrence patients were younger (P < 0.001) and had fewer ulcerated (P = 0.005), fewer head/neck localized (P = 0.009) and thinner (P < 0.001) melanomas than ER patients. The MSS time (mean ± SD) was nearly identical for LR (31 ± 4.4 months 95% CI [22.3-39.7]) and ER (32 ± 1.9 months [28.3-35.7]). Multivariate regression analysis revealed male gender (hazard ratio [HR = 1.4, P < 0.001), truncal tumour localization (HR = 1.7, P < 0.001), tumour thickness (HR = 1.4, P < 0.045) and ulceration (HR = 1.3, P < 0.008) as significant independent prognostic factors for MSS. CONCLUSION: Although ER and LR patients are found to have different clinicopathologic features, the time of the first recurrence after diagnosis do not seem to have an effect on the survival.

Incidence and characteristics of thick second primary melanomas: a study of the German Central Malignant Melanoma Registry.

BACKGROUND: Fast-growing melanomas are thought to be responsible for the stable incidence of thick melanomas. It has been suggested that campaigns for early diagnosis are unlikely to have a major impact on prognosis as rapid vertical growth rather than diagnostic delay is the major determinant for thick melanomas. OBJECTIVE: We investigated the impact of follow-up examinations on the incidence of thick second primary melanomas (SPMs) and analysed their clinic-pathologic characteristics. METHODS: We analysed a single-centre cohort of 2253 patients of the German Central Malignant Melanoma Registry with prospectively documented follow-up examinations. RESULTS: Primary tumour and patient characteristics were well balanced between patients with and without SPMs except for age (median 61 years, interquartile range [IQR] 51-67 vs. 56 years, IQR 43-67; P = 0.005). Metachronous SPMs occurred in 107 patients (4.7% of total) were thinner than the respective first primary melanoma (FPM) (median Breslow thickness of invasive melanomas 0.40 mm, IQR 0.28-0.75 vs. 0.80 mm, IQR 0.50-2.00; P < 0.001) and less often ulcerated (0.9% vs. 15.0%; P < 0.001). Melanomas >2.00 mm occurred in 2.8% of SPMs as compared to 23.4% of FPMs (P < 0.001). Thick SPMs (>1.00 mm; 14.0%) despite close-meshed follow-up examinations were frequently associated with atypical clinical presentation and uncommon histopathologic subtypes. One-third (5/15) of thick SPMs were clinically misdiagnosed as non-melanocytic lesions, most of them as basal cell carcinomas (n = 4). CONCLUSIONS: Regular total body skin examinations enable a highly efficient detection of early-stage melanomas and reduction of thick melanomas as compared to first primary melanomas. Our data indicate that fast-growing melanomas without opportunity of early detection are rare and cannot explain the stable incidence of thick melanomas. This highlights the importance of close-meshed total body skin examinations in patient groups that are at high risk of first or multiple primary melanomas.

Time trends in incidence and mortality of cutaneous melanoma in Germany.

OBJECTIVES: To characterize incidence and mortality trends of cutaneous melanoma (CM) in Germany to extrapolate these data until 2030. METHODS: We evaluated data from the Centre for Cancer Registry Data (1999-2012) and from the Saarland Cancer Registry (1970-2012). Age-standardized (according to the European Standard Population, WHO 1976) incidence and mortality rates [age-standardized incidence rates (ASIRs) and age-standardized mortality rates (ASMRs)] and crude incidence and mortality rates [crude incidence rates (CIRs) and crude mortality rates (CMRs)] were analysed. RESULTS: In entire Germany, ASIRs increased by 55% to 19.2 and CIRs by 77% to 26.0 new cases per 100 000 from 1999 to 2012. ASMRs remained stable, whereas CMR increased by 58% to 4.1 for males and by 30% to 3.0 for females per 100 000. In the Federal State of Saarland, ASIRs increased more than four-fold to 13.1, CIRs increased six-seven fold to 18.5/100 000 from 1970 to 2012. In the same period, ASMRs increased three-fold in males and two-fold in females to 2.5 and 1.6, whereas CMRs increased 5.5-fold in males and 3.5-fold in females to 3.9 and 3.2/100 000, mainly caused by steep increases of CIRs and CMRs in age groups ≥60 years. Projected CIRs will rise to 44-46 for males and 38-40 for females in 2030. Steepest increases were extrapolated for patients ≥60 years, especially for males, but are also expected for age groups of 40-59 years. In contrast, CIRs are anticipated to stabilize for subjects <40 years. CONCLUSIONS: There is a constant increase in incidence and mortality rates for CM in Germany. As the German population is ageing and the current population has already accumulated high levels of UV exposure, a further increase in melanoma incidence is projected for the future without signs of levelling-off.

Acral lentiginous melanoma: a skin cancer with unfavourable prognostic features. A study of the German central malignant melanoma registry (CMMR) in 2050 patients.

BACKGROUND: Acral lentiginous melanoma (ALM) is one of the four major subtypes in cutaneous melanoma (CM). Although ALM has a poorer prognosis than other CM subtypes, the prognostic factors associated with ALM have only been verified in small-sized cohorts because of the low incidence of ALM worldwide. OBJECTIVES: To investigate the clinical characteristics of ALM and to evaluate their prognostic values based on a large dataset from the Central Malignant Melanoma Registry (CMMR) of the German Dermatologic Society. METHODS: The Kaplan-Meier method was used to estimate the potential influence of clinical and histological parameters on ALM disease-specific survival (DSS) curves, which were compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors for DSS. RESULTS: In total, 2050 patients with ALM were identified from 58 949 patients with CM recorded by the CMMR with follow-up data. In multivariate analyses, age (P = 0·006), ulceration (P = 0·013), tumour thickness (P < 0·001) and tumour spread (P < 0·001) turned out to be significant prognostic factors for DSS in ALM whereas sex, nevus association and level of invasion were not independent factors. CONCLUSIONS: ALM has the same prognostic factors as other subtypes of melanoma. Unfavourable prognosis probably derives from the delay in diagnosis in comparison with other melanoma subtypes.

Adjuvant treatment with pegylated interferon α-2a versus low-dose interferon α-2a in patients with high-risk melanoma: a randomized phase III DeCOG trial.

BACKGROUND: Adjuvant treatment with interferon (IFN)-α-2a improved disease-free survival (DFS) and showed a trend for improving overall survival (OS) in melanoma. This trial was designed to examine whether PEG-IFN is superior to IFN with regard to distant metastasis-free survival (DMFS), DFS and OS. PATIENTS AND METHODS: In this multicenter, open-label, prospective randomized phase III trial, patients with resected cutaneous melanoma stage IIA(T3a)-IIIB (AJCC 2002) were randomized to receive PEG-IFN (180 µg subcutaneously 1×/week; 24 months) or IFN α-2a (3MIU subcutaneously 3×/week; 24 months). Randomization was stratified for stage, number of metastatic nodes, age and previous IFN treatment. The primary end point was DMFS; secondary end points were OS, DFS, quality of life (QoL) and tolerability. RESULTS: A total of 909 patients were enrolled (451 PEG-IFN versus 458 IFN). Neither 5-year DMFS [PEG-IFN 61.0% versus IFN 67.3%; hazard ratio (HR) 1.16, P = 0.21] nor 5-year OS (PEG-IFN 73.2% versus IFN 75.2%; HR 1.05, P = 0.70) nor 5-year DFS (PEG-IFN 57.3% versus IFN 60.9%; HR 1.09, P = 0.40) showed significant differences. Subgroup analyses in patients ± ulcerated primaries and of different tumor stages did not find differences in DMFS, OS or DFS between the treatment groups. One hundred and eighteen patients (26.2%) in the PEG-IFN and 61 patients (13.3%) in the IFN population did not receive the full dosage and length of treatment due to adverse events (P < 0.001). Leukopenia and elevation of liver enzymes were more common in the PEG-IFN arm (56% versus 23.5% LCP; 19.1% versus 9.4% AST; 33.0% versus 16.5% ALT). QoL was identical for nearly all domains. CONCLUSION: PEG-IFN did not improve the outcome over IFN. A higher percentage of patients under PEG-IFN discontinued treatment due to toxicity. CLINICAL TRIALSGOV IDENTIFIER: NCT00204529.

A Case of Choroidal Melanoma Metastatic to the Breast.

A 61-year-old woman developed blurred vision in her left eye in December 2006. A clinical diagnosis of choroidal melanoma was made. The patient underwent excision of the left lens, followed by vitrectomy and stereotactic radiotherapy. She remained systemically healthy until 50 months later when, during a CT scan done for staging purposes, a newly visible lump was noted in the lower quadrant of her left breast. Core needle biopsy of the lesion in the left breast was performed, and histologic examination revealed metastasis from the choroidal melanoma. The patient underwent breast-conserving surgery of the left breast. Definitive histological examination showed clear tumor margins in the resected specimen and one sentinel lymph node without evidence of metastatic cells. Twenty-nine months after surgery, a similar nodule was detected in the upper quadrant of the left breast. Core biopsy again showed metastatic melanoma, and similar breast-conserving surgery was performed. Systemic examination, including magnetic resonance imaging of the head and computed tomography of the pelvis, abdomen, and chest, was done regularly and revealed no significant findings. Solitary breast metastases from choroidal melanoma are extremely rare. Nevertheless, clinicians should be aware of this rare form of metastasis when treating patients with suspicious breast lesions and a history of choroidal melanoma. If solitary metastasis is confirmed, then breast-conserving surgery may be recommended.

Prospective evaluation of follow-up in melanoma patients in Germany - results of a multicentre and longitudinal study.

BACKGROUND: Patient numbers requiring long-term melanoma surveillance are constantly rising. Surveillance is costly and guideline recommendations vary substantially. METHODS: In this German nationwide study, information on surveillance and treatment of patients diagnosed with melanoma and melanoma in situ (MMis) between April and June 2008 was prospectively collected over four years. Additionally, patient self-report questionnaires were evaluated to assess anxiety, depression, health-related quality of life, socio-demographic information and use of disease specific health information sources at year 4 after primary diagnosis. RESULTS: Complete data was available for 668 patients from 67 centres, of whom 96.0% were in regular melanoma surveillance. In year 3-4 of surveillance, only 55.6% of locoregionary metastases were detected during surveillance visits. Only 33.3% were self-detected by the patient even though 69.4% were documented as being clinically visible or palpable. Costs of 4year surveillance of 550 patients without tumour recurrence (stage I-IIC and MMis) accumulated to 228,155.75 €. Guideline-adherence for follow-up frequency, lymph node ultrasound, S100 serum level tests and diagnostic imaging recommendations was approximately 60% in year 3-4 of surveillance. Multivariate regression analysis showed that certain patient/tumour characteristics and regional differences were significantly associated with guideline deviations. The percentage of patients who exceeded published cut-off scores indicating clinically relevant symptoms of anxiety and depression were significantly increased. Patients frequently reported lack of psychosocial support and education but ascribed great importance to these. CONCLUSIONS: We recommend further reduction of melanoma follow-up in low-risk melanoma patients and improvement of psycho-social support and patient education for all melanoma patients.

Lack of activity of betulin-based Oleogel-S10 in the treatment of actinic keratoses: a randomized, multicentre, placebo-controlled double-blind phase II trial.

BACKGROUND: Betulinic acid and other triterpenes have shown strong antitumour activity in vitro and in vivo. A triterpene extract of birch bark formed the base of Oleogel-S10 and allowed topical application. Two previous trials have shown efficacy and tolerability in the treatment of actinic keratoses (AKs) with betulin-based Oleogel-S10. OBJECTIVES: To confirm the efficacy and tolerability/safety of Oleogel-S10 in the treatment of AKs in a multicentre placebo-controlled study. METHODS: Patients (n = 165) were treated topically for 3 months in a four-arm parallel study design, randomly allocated to A (n = 53) Oleogel-S10 once daily, B (n = 51) Oleogel-S10 twice daily, or C (n = 25) or D (n = 28) placebo (petroleum jelly) once or twice daily, respectively. Clinical efficacy in this double-blind study was assessed by the investigators. Final and baseline biopsies were evaluated by central histopathology. RESULTS: Complete clearance of the target lesions was seen in 4% of patients in group A and 7% in group B, but not in the placebo groups. A clearance rate of > 75% was seen for 15% and 18% of patients in groups A and B, respectively, and for 13% in the placebo groups. These differences were not statistically significant. Histopathologically, 43·9% of patients showed a downgrading or clearance of the marker AK with no significant differences between the groups. Treatment with Oleogel-S10 was well tolerated. The tolerability as assessed by the investigator was mostly 'very good' (78·8%), followed by 'good' (18·2%) and only 1·2% assessed it as 'intolerable'. Patient-assessed tolerability was graded mostly 'very good' (56·4%) or 'good' (34·5%). CONCLUSIONS: Treatment with Oleogel-S10 was well tolerated during a treatment period of 3 months, yet was no better than placebo in terms of efficacy in the treatment of AKs.

Serum markers lactate dehydrogenase and S100B predict independently disease outcome in melanoma patients with distant metastasis.

BACKGROUND: Established prognostic factors are of limited value to predict long-term survival and benefit from metastasectomy in advanced melanoma. This study aimed to identify prognostic factors in patients with distant metastasis. METHODS: We analysed overall survival of 855 institutional melanoma patients with distant metastasis by bivariate Kaplan-Meier survival probabilities and multivariate Cox hazard regression analysis. RESULTS: Serum lactate dehydrogenases (LDH), S100B, the interval between initial diagnosis and occurrence of distant metastasis, the site of distant metastases, and the number of involved distant sites were significant independent prognostic factors in both bivariate and multivariate analyses. Visceral metastases other than lung (hazard ratio (HR) 1.8), elevated S100B (HR 1.7) and elevated LDH (HR 1.6) had the highest negative impact on survival. Complete metastasectomy was likewise an independent prognostic factor in multivariate analysis. This treatment was associated with favourable survival for patients with normal LDH and S100B values (5-year survival, 37.2%). CONCLUSION: The serum markers LDH and S100B were both found to be prognostic factors in melanoma patients with distant metastasis. Furthermore, complete metastasectomy had an independent favourable prognostic impact in particular for the patient subgroup with normal LDH and S100B values.

Open label randomized study comparing 3 months vs. 6 months treatment of actinic keratoses with 3% diclofenac in 2.5% hyaluronic acid gel: a trial of the German Dermatologic Cooperative Oncology Group.

BACKGROUND: Actinic keratoses (AK) are carcinomata in situ with the potential to develop into invasive carcinoma. Several studies have demonstrated that 3% diclofenac in 2.5% hyaluronic acid gel (HA) is effective and well tolerated in the treatment of AK. To date there are no large randomized multicentre trials with treatment durations longer than 90 days and histopathological control of treatment outcome. OBJECTIVE: The aim of this study was to investigate whether a prolonged treatment with diclofenac in HA of 6 vs. 3 months adds to the efficacy in treatment for AK and if this will influence tolerability and quality of life (QoL). METHODS: This was a multicentre, randomized open-label study in which 418 patients with mild to moderate AKs were randomized into two treatment groups. Group A received diclofenac in HA for 3 months and group B for 6 months. Treatment efficacy was assessed by size measurement and a final biopsy of a defined marker AK. Quality of life was measured using the Dermatology Life Quality Index questionnaire. RESULTS: Clinical complete clearance was observed in 40% in group A and in 45% in group B (P = 0.38). Histopathological clearance was confirmed in 30% in group A and in 40% in group B (P = 0.16). Treatment was well tolerated and QoL was significantly improved after treatment in both treatment groups. CONCLUSION: Treatment with diclofenac in HA is effective and well tolerated during a treatment period of 3 months as well as 6 months. Prolongation of the treatment duration did not significantly affect treatment outcome.

Clinical course and prognostic factors of Merkel cell carcinoma of the skin.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine malignancy of the skin first described by Toker as 'trabecular carcinoma of the skin' in 1972. To date, the origin of the tumour cells still remains unclear. OBJECTIVES: The present study analyses prognostic factors of MCC. PATIENTS AND METHODS: The medical records of 57 patients with MCC treated between 1988 and 2006 at the Department of Dermatology in Tübingen were reviewed. RESULTS: We identified 26 (45.6%) male and 31 (54.4%) female patients with MCC; the age at diagnosis ranged from 26 to 97 years (median 71 years). Primary tumours were located mainly on the head and neck areas (27 cases, 47.4%) and upper extremities (14 cases, 24.6%); 11 tumours were found on the lower extremities (19.3%) and four lesions on the chest (7%); one patient had an unknown primary location. Forty-five (78.9%) patients were diagnosed at stage I of the disease, 11 (19.3%) at stage II, and one patient (1.8%) at stage III at initial presentation. Stage of the disease and age at initial presentation were statistically significant with regard to overall (P < 0.0001; P = 0.0327) and tumour-specific survival (P < 0.0001; P = 0.0156). Use of the Cox regression model revealed initial stage of the disease as the only significant factor in the multivariate analysis. Radiotherapy applied promptly after excision of the primary tumour extended the time to progression significantly (P = 0.0376) but did not prolong overall or tumour-specific survival. Other parameters such as sex, site of tumour, sentinel node biopsy, excision margins, skin and noncutaneous malignancies were found to be not significant. CONCLUSIONS: Currently, early recognition of the disease seems to be the only method of ensuring overall survival. However, evidence-based treatment modalities are still urgently needed.

Pathogenesis of diabetic macro- and microangiopathy.

Epidemiological investigations reveal that we must expect a rapid increase in cases of diabetes mellitus in the next few years. As a result, vascular complications in the form of macro- and microangiopathy are also expected to arise more frequently. A classical example of macroangiopathy is coronary arteriosclerosis, microangiopathy is exemplified by diabetic nephropathy. In patients suffering from diabetes, macroangiopathy manifests as atherosclerosis like in nondiabetic patients, characterized by formation of plaques that follows in stages but with an accelerated course due to the different risk factors, especially hyper- and dyslipidemia, with cumulative effects. Thus, atherosclerosis in diabetes begins earlier, is more markedly pronounced and progresses more rapidly. The pathogenetic concept is based on an endothelial lesion that occurs as a result of a diabetes-specific, endothelium-damaging parameters. In case of diabetic microangiopathy histologically characterized by a progressive glomerulosclerosis, arteriolosclerosis and interstitial fibrosis hyperglycemia, along with its consecutive and complex processes that induce matrix increase, is considered to be the primary pathogenetically relevant factor involved. Insulin resistance seems to be the major common denominator at the center of both diabetic macroangiopathy and microangiopathy.

[Cutaneous melanoma]. / Kutanes Melanom.

While the incidence of cutaneous melanoma (CM) continues to rise steadily, the mortality has stabilized. Risk factors for the development of CM are UV light exposure and individual characteristics relating to pigmentation, and especially the number of melanocytic nevi. The most important prognostic factor in CM is the vertical thickness of the primary tumor in the histological specimen. Excision of the primary tumor with adequate safety margins is the treatment of choice. In the case of a tumor 1.0 mm or more thick biopsy of the sentinel node is recommended. Interferon-alpha is currently the only adjuvant therapy shown to have significant benefit in prospective randomized trials. When distant metastases are present treatment is palliative and is aimed primarily at achieving tumor remission by operative, radiological, and pharmacological means. Dacarbazine is considered the standard drug for systemic treatment. Follow-up depends on the initial tumor parameters and the current stage of the disease.