A multicentre study of naevus-associated melanoma vs. de novo melanoma, tumour thickness and body site differences.

BACKGROUND: Whether melanoma in histological contiguity with a naevus [naevus-associated melanoma (NAM)] is distinctly different from melanoma arising de novo remains unclear. OBJECTIVES: To determine whether the characteristics of de novo melanoma differ from NAM and are not due to naevus obliteration in thicker tumours. METHODS: We conducted a multicentre retrospective study of de novo melanoma and NAM in seven referral centres in Europe, Australia and the USA between 2006 and 2015. RESULTS: In a total of 9474 localized melanomas, de novo melanoma was associated with thicker tumours and body site differences compared with NAM. In the subset of T1 melanomas (n = 5307), similar body site differences were found in multivariate analysis by body site. When compared with NAM, de novo melanoma was more likely to affect older individuals (≥ 70 years) when located on the head/neck [odds ratio (OR) 4·65, 95% confidence interval (CI) 2·55-8·46], the trunk (OR 1·82, 95% CI 1·40-2·36) or the upper extremity (OR 1·69, 95% CI 1·14-2·50), was more likely to affect female patients when located on the lower extremities (OR 1·36, 95% CI 1·03-1·80), and was more likely to be of the nodular melanoma subtype (OR 2·23, 95% CI 1·14-4·35) when located on the trunk. De novo melanoma was less likely to have regression present compared with NAM. CONCLUSIONS: Clinicopathological and body site differences between de novo melanoma and NAM support the divergent pathway model of development. These differences were also found in thin melanomas, suggesting that de novo melanomas are different from NAM and their differences are not due to the obliteration of naevus remnants in thicker tumours.

Tumor vascularization and clinicopathologic parameters as prognostic factors in merkel cell carcinoma.

PURPOSE: Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine tumor of the skin with an increasing incidence. The clinical course is variable and reliable prognostic factors are scarce. Tumor angiogenesis has been shown to have prognostic impact in different types of cancer. The aim of our study was to determine potential prognostic factors, including tumor vascularization, for clinical outcome of MCC. METHODS: The medical records of 46 patients with MCC diagnosed between 1997 and 2010 were analyzed retrospectively. Tissue samples were immune-stained for the lymphatic endothelial vessel marker podoplanin/D2-40 and the panvascular marker CD31. These immunostained sections were analyzed using computer-assisted morphometric image analyses. Aside from the parameters of tumor vascularization, clinicopathologic features were investigated, and progression-free survival (PFS) and tumor-specific survival (TSS) were assessed. Univariate and multivariate analyses were performed to determine prognostic factors. RESULTS: Male sex of the MCC patients and a high cross-sectional whole vessel area (WVA) in relation to the entire tumor area as determined on CD31-stained tumor sections were found to be negative prognostic factors for PFS in a univariate and multivariate regression analysis. Ulceration of the primary tumor was significantly associated with both impaired PFS and TSS. CONCLUSIONS: Our results indicate a high prognostic impact of tumor vascularization on the clinical outcome of MCC patients. Male sex and ulceration of the primary MCC were identified as independent unfavorable prognostic markers for the clinical outcome. As an outlook, MCC patients with increased angiogenesis might be identified and subjected to a targeted anti-angiogenic treatment.

Metastatic melanoma of unknown primary resembles the genotype of cutaneous melanomas.

BACKGROUND: Although 90% of all melanomas are of cutaneous origin, some patients present with melanoma metastases of unknown origin (MUP). Commonly, in these patients an extensive search for the primary tumor is carried out. In the past, genetic analyses have shown substantial differences in pathogenetic mutations among cutaneous, acral and mucosal melanomas. The aim of this study was to assess the mutational status of MUP in order to better characterize the putative origin of the primary tumor and to evaluate potential prognostic factors. PATIENTS AND METHODS: The medical records of 44 patients with MUP were analyzed and a survival analysis was conducted. In total, 66 paraffin samples of 44 patients were analyzed, and in 15 patients multiple metastases were tested. Mutational analysis of the BRAF, NRAS and KIT genes was carried out. RESULTS: Twenty-three patients (52.3%) had a mutation in the BRAF gene and 12 patients (23.8%) had a mutation in the NRAS gene. There were neither mutations in the KIT gene. In patients with multiple samples, there was 100% consistency regarding mutational status among the different metastases. The median overall survival (OS) was 86.4 months (39-134). The American Joint Committee on Cancer stage at first diagnosis of metastatic melanoma (stage III versus IV) was significantly associated with OS (P < 0.001), BRAF or NRAS mutation status had no significant prognostic impact on clinical outcomes. CONCLUSIONS: MUP resembles the genotype of cutaneous melanoma and not that of mucosal melanomas.

Risk evaluation in cutaneous melanoma patients undergoing lymph node dissection: impact of POSSUM.

INTRODUCTION: When lymphatic metastasis occurs, surgery is the primary treatment modality in melanoma patients. Depending on the tumour stage, patients receive a completion lymph node dissection (CLND) when a positive sentinel node is detected. Patients with clinically evident disease of the regional lymph nodes are recommended to undergo a therapeutic lymph node dissection (TLND). The aim of this study was to assess the morbidity of CLND and TLND and to evaluate the Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) for preoperative risk adjustment of postoperative morbidity. METHODS: The hospital files of 143 patients who underwent CLND and TLND for malignant melanoma were analysed. The POSSUM score was used to predict morbidity rates after surgery for the total patient group as well as separated for CLND and TLND patients. RESULTS: The overall complication rate was 28.0% and the mortality rate was 0%. The morbidity rate predicted by POSSUM was 32.9%, the mortality 8.3%. Morbidity in patients undergoing CLND was significantly higher with regard to overall wound complications compared with patients with TLND. In these subgroups, POSSUM failed to predict the rates precisely. CONCLUSIONS: The POSSUM score predicted the morbidity of the total patient group accurately but failed to predict the rates in the TLND and CLND subgroups. Patients receiving CLND showed the highest morbidity rates. Preoperative sentinel lymph node biopsy therefore has more influence on postoperative morbidity than the physiological parameters represented in the POSSUM physiological score.

[Adjuvant systemic treatment of melanoma]. / Adjuvante systemische Therapie des Melanoms.

Despite intensive clinical and research efforts during the last decades the prognosis for patients with stage IV melanoma still remains fatal. An efficient adjuvant treatment for patients with a high risk of relapse and metastases is one of the most urgent fields in clinical research. Systemic adjuvant chemotherapy was not beneficial in terms of relapse-free or overall survival improvement in several clinical trials. Treatment with IFN-α-2a and -2b treatment was the first and as yet only adjuvant therapy which has been proven to show a benefit in controlled studies and to gain approval in Germany in the indications for adjuvant therapy. Current clinical research focuses on improved treatment schedules with conventional interferon compared to pegylated interferon and on the other hand on testing new compounds, such as the CTLA4 inhibitor ipilimumab or a vaccination against the MAGE-A3 peptide.

Sorafenib and pegylated interferon-α2b in advanced metastatic melanoma: a multicenter phase II DeCOG trial.

BACKGROUND: The combination of sorafenib, a multikinase inhibitor, and pegylated interferon-α2b (Peg-IFN-α2b) could potentially lead to an improved antitumoral response. Previously, combinations of interferon and sorafenib have been used in renal cell cancer. PATIENTS AND METHODS: Patients with stage IV metastatic melanoma and no previous systemic therapies apart from adjuvant immunotherapy received Peg-IFN-α2b 3 µg/kg once per week, and sorafenib 400-mg b.i.d. for a minimum of 8 weeks. The primary study end point was disease control rate (DCR). RESULTS: Between February 2008 and February 2009, 55 patients were enrolled with a median age of 64 years (20-85). At 8 weeks, 2 patients (3.6%) had a partial response (PR) and 14 patients a stable disease (25.5%), for a DCR of 29.1% in the intention-to-treat (ITT) population. The median progression-free survival in the ITT population was 2.47 months (95% confidence interval 1.22-3.72 months). The toxicity of sorafenib and Peg-IFN-α2b combination was characterized by mainly hematological side-effects, including one treatment-related bleeding complication with a fatal outcome. Other grade 3/4 toxic effects were fatigue and flu-like symptoms. CONCLUSION: The combination of sorafenib and Peg-IFN-α2b showed modest clinical activity and some serious side-effects including fatal bleeding complications.

Malignant melanoma and Wiedemann-Beckwith syndrome in childhood.

Patients with Wiedemann-Beckwith syndrome (WBS, MIM 130650), a congenital overgrowth syndrome, have a known increased tumor risk especially for embryonic tumors. WBS belongs to the "imprinting" syndromes caused by overexpression of IGF2 and/or loss of CDKN1C on chromosome 11p15.5. A 13-year-old boy with WBS developed a spitzoid malignant melanoma (Clark level V, Breslow index 4.8 mm) on the right cheek. Genetic analyses of the patient's blood showed hypermethylation at the H19 locus on chromosome 11p. The (epi)genetic changes of the WBS locus might have played a role in the pathogenesis of melanoma development.

[Current aspects of adjuvant therapy of malignant melanoma]. / Aktuelle Aspekte der adjuvanten Therapie des malignen Melanoms.

Despite intensive clinical and research efforts during recent decades, the prognosis of patients with stage IV melanoma still remains poor. Finding effective adjuvant treatment for patients with a high risk of relapse and metastasis is one of the most urgent needs in clinical research. Systemic adjuvant chemotherapy administered in several clinical trials offered no benefit in terms of improved relapse-free or overall survival. Interferon alpha-2a and -2b treatment was the first treatment in the adjuvant setting which has shown a treatment benefit and received approval in Germany. Today clinical research focuses on improved treatment schedules with conventional interferon compared to pegylated interferon as well as on new compounds such as CTLA4 inhibitors like ipilimumab or a vaccination against the MAGE-A3 peptide.

Nail infection by Aspergillus ochraceopetaliformis.

Aspergillus ochraceopetaliformis is a rare fungal species that has not yet been identified as a proven human pathogen. Here we report a case of a toenail infection in a healthy woman caused by this fungus. Species identification was performed by scrutinizing the phenotypic and genetic characteristics of distinct isolates obtained at different times during the course of the infection. Treatment with terbinafine plus ciclopiroxolamine was effective.

Dose-intensified bi-weekly temozolomide in patients with asymptomatic brain metastases from malignant melanoma: a phase II DeCOG/ADO study.

BACKGROUND: Temozolomide has shown some efficacy in metastatic melanoma and recently received extended approval to treat brain tumours. The purpose of this study was to test a dose-intensified regimen of temozolomide in melanoma patients with brain metastases in a prospective, open-label, multicentre phase II trial. PATIENTS AND METHODS: Forty-five patients with asymptomatic brain metastases from melanoma were stratified into arm A (no prior chemotherapy; n = 21) and arm B (previous chemotherapy; n = 24). Patients received oral temozolomide either 150 mg/m(2)/day (arm A) or 125 mg/m(2)/day (arm B), days 1-7 and 15-21, every 28 days. The primary study end point was objective response, and secondary end points were overall survival and safety. RESULTS: Two patients (4.4%) achieved a partial response (PR) in brain metastases (one in each arm), one of them (2.2%) also showing a PR in extracerebral disease. An additional five patients (11.1%; two in arm A, three in arm B) showed disease stabilisation (SD) in brain and other sites. However, 82% revealed progressive disease (PD) already evident 8 weeks after therapy initiation. Median survival time from therapy onset was 3.5 months (range 0.7-8.3; arm B) and 4.3 months (range 1.6-11.8; arm A), P = 0.43. Dose modifications and prolongations of therapy cycles due to toxicity were required in 20% of patients. Grade 3/4 toxicity was observed in one patient only (2.2%). CONCLUSIONS: Oral administration of temozolomide given bi-weekly is well-tolerated in melanoma patients with cerebral involvement. However, the efficacy is limited, with lower than 5% objective responses observed in brain and extracerebral metastases.

[Modern treatment modalities in actinic keratoses of the skin]. / Moderne Behandlungsoptionen bei aktinischen Keratosen der Haut.

It has been estimated that approximately 4 million Germans are suffering from actinic keratoses, which are considered as a carcinoma in situ today. Typically, actinic keratoses appear in sun-exposed skin areas, conventionally they have been treated by curettage and cryotherapy. In the last years, new therapeutic modalities with a high efficacy and patient contentment are available. Among these, the photodynamic therapy (PDT), the anti-tumor treatment with 3 % Diclofenac in 2.5 % hyaluronic acid as well as the introduction of Imiquimod as an immune response modifier are the most important. The rate of complete clearance from actinic keratoses varies between 50 and 90 % in clinical trials. In contrast to the conventional treatment modalities, these new options promise advantages in the treatment of field and offer excellent cosmetic outcomes, too. This overview will report on the actual treatment opportunities and a careful consideration in the year 2006.