Rudolf A. Herbst

Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial

BACKGROUND Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation. METHODS In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients. FINDINGS Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20-54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9-82·1; 55 events) in the observation group and 74·9% (69·5-80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported. INTERPRETATION Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller. FUNDING German Cancer Aid.

Phase II DeCOG-Study of Ipilimumab in Pretreated and Treatment-Naïve Patients with Metastatic Uveal Melanoma

Purpose Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM. Patients and Methods We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. Results Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7–8.1), median progression-free survival 2.8 months (95% CI 2.5–2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3–4 events (36%). One drug-related death due to pancytopenia was observed. Conclusions Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines. Trial Registration ClinicalTrials.gov NCT01355120

Comparison of localized high-dose UVA1 irradiation versus topical cream psoralen-UVA for treatment of chronic vesicular dyshidrotic eczema

BACKGROUND Vesicular dyshidrotic palmoplantar eczema is a common disorder but treatment is difficult. Localized photochemotherapy (cream psoralen-UVA [PUVA]) has widely been used for therapy. Although the efficacy of cream PUVA therapy is well known, potential side effects may occur. Therefore, a more standardized safe and effective UV therapy should be carried out. OBJECTIVE This study compared the effects of localized high-dose UVA1 irradiation versus topical cream PUVA for treatment of chronic vesicular dyshidrotic eczema. METHODS On the basis of the assessment of the Dyshidrotic Area and Severity Index, the decrease of score points on the UVA1-treated side was compared with the decrease on the cream PUVA-treated side in 27 patients. In addition, analysis of serum markers was performed. RESULTS Of 27 patients, 24 showed a good response to localized UVA1 irradiation or cream PUVA. Dyshidrotic Area and Severity Index scores significantly decreased on both sides and were reduced to half of the pretreatment values. No statistically significant differences between localized UVA1 irradiation or cream PUVA could be detected. CONCLUSION This study demonstrates that localized UVA1 phototherapy is easy to perform and appears to be an effective and safe treatment for vesicular dyshidrotic eczema.

Intradermal testing in the diagnosis of allergic contact dermatitis : a reappraisal

Contact hypersensitivity may be diagnosed with patch testing or intradermal testing. Although these methods have been used earlier in parallel, patch testing has gradually become the only method in routine diagnosis of contact allergy. Recent findings in corticosteroid contact hypersensitivity have shown that patch testing is not always an optimal method, especially when poor penetrants are used. Therefore, a reappraisal of intradermal testing is presented, based on the literature. Studies employing both patch and intradermal testing are reviewed and the advantages and disadvantages of intradermal tests as compared to patch tests in contact allergy diagnostics are discussed. We find that it might be worthwile to evaluate whether contact allergy to compounds other than corticosteroids may be easier to detect with intradermal than patch test.

Identification of two distinct deletion targets at 11q23 in cutaneous malignant melanoma

Karyotypic and molecular data indicate that genetic alterations of the long arm of chromosome 11 (11q) are involved in the pathogenesis of malignant melanoma as well as of other malignancies. We have shown previously, by analysis of loss of heterozygosity (LOH), that a tumor‐suppressor gene playing an important role in malignant melanoma is likely to be located within a 51‐cM region at 11q23. Its loss appeared to be a late event in tumor progression and an indicator of a less favorable clinical outcome. To further test this hypothesis on a larger set of tumors and to refine the region(s) of common allelic loss, we analyzed 21 polymorphic microsatellite repeats on 11q. A PCR‐based assay for LOH was used to study normal and tumor tissues from 53 individuals with primary cutaneous malignant melanoma or metastatic disease. Our findings indicate that in cutaneous malignant melanoma there are at least 2 distinct regions of common allelic loss on 11q, one of them centered around marker APOC3 at 11q23.1‐q23.2 delineated by markers D11S1347 and D11S4142 and spanning approximately 5 Mb and a second 3‐Mb region around marker D11S925 at 11q23.3 delineated by markers D11S528 and D11S1345. Both regions have been described as deletion targets or as being included within larger allelic deletions detected in several other common tumor types. Thus, these 2 putative melanoma‐suppressor loci are likely to harbor tumor‐suppressor genes relevant to tumorigenesis of melanoma and a number of other common human malignancies. Int. J. Cancer80:205–209, 1999.

Guttate psoriasis triggered by perianal streptococcal dermatitis in a four-year-old boy

Perianal streptococcal dermatitis (PSD) is a superficial bacterial infection usually with group A beta-hemolytic streptococci. PSD is often misdiagnosed for long periods and patients are subjected to treatments for a variety of differential diagnoses without success. We report a 4-year-old boy with PSD who presented to our clinic with guttate psoriasis for 2 reasons: first, to make dermatologists aware of PSD and second, to emphasize the necessity to examine patients, particularly pediatric patients, with guttate psoriasis very thoroughly and swab both the pharynx and perianal and/or perigenital areas even when they are, or seem to be, asymptomatic for bacterial infections. Once PSD has been diagnosed, systemic antibiotic therapy with penicillin, erythromycin, roxithromycin, or azithromycin (probably augmented by topical mupirocin ointment) should be the treatment of choice. Therapy should be monitored by posttreatment perianal and throat swabs as well as a urine analysis to monitor for poststreptococcal glomerulonephritis.

Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macrometastatic nodes: An open-label, randomised, phase 3 European Association for Dermato-Oncology (EADO) study

AIM Both low-dose interferon (IFN) alfa-2b and pegylated interferon (Peg-IFN) alfa-2b have been shown to be superior to observation in the adjuvant treatment of melanoma without macrometastatic nodes, but have never been directly compared. Peg-IFN facilitates prolongation of treatment, which could provide additional benefit. This multicentre, open-label, randomised, phase 3 trial compared standard low-dose interferon IFN and prolonged treatment with Peg-IFN. PATIENTS AND METHODS Patients with resected melanoma ≥1.5mm thick and without clinically detectable node metastases were randomised 1:1 to treatment with IFN 3 MU subcutaneously (SC) three times weekly for 18 months or Peg-IFN 100 μg SC once weekly for 36 months. Sentinel lymph node dissection (SLND) was optional. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS) and adverse events (AEs) grade 3-4. RESULTS Of 898 patients enrolled, 896 (443 Peg-IFN, 453 IFN) were eligible for evaluation (median follow-up 4.7 years). SLND was performed in 68.2% of patients. There were no statistical differences between the two arms for the primary outcome of DFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.73-1.15) or the secondary outcomes of DMFS (HR 1.02, 95% CI 0.80-1.32) and OS (HR 1.09, 95% CI 0.82-1.45). Peg-IFN was associated with higher rates of grade 3-4 AEs (47.3% versus 25.2%; p<0.0001) and discontinuations (54.3% versus 30.4%) compared with IFN. CONCLUSION This trial did not show superiority for adjuvant Peg-IFN over conventional low-dose IFN in melanoma patients without clinically detectable nodes. ClinicalTrials.gov identifier: NCT00221702.

Diagnostics of autoimmune bullous diseases in German dermatology departments.

Background: No consistent data are available on the currently employed diagnostic tools for autoimmune bullous diseases in Germany. The aim of this survey was to describe currently performed diagnostic methods for bullous autoimmune diseases in German dermatology departments.

Drug-induced Blaschkitis

Thomas Brinkmeier, Rudolf A. Herbst, Joerg Schaller, Katrin Kuegler, Claudia Pirker, Ulrike Beiteke, Edouard Grosshans and Peter J. Frosch Department of Dermatology, Klinikum Dortmund gGmbH, Beurhausstrasse 40, DE-44137 Dortmund and University of Witten/ Herdecke, Germany, Dermatohistologic Laboratory, St Barbara-Hospital, Duisburg, Germany and Laboratoire d’Histopathologie Cutanee, Clinique Dermatologique des Hopitaux Universitaires, Strasbourg, France. E-mail: t.brinkmeier@derma.de Accepted December 4, 2003.

Survival of SLNB-positive melanoma patients with and without complete lymph node dissection: A multicenter, randomized DECOG trial.

LBA9002 Background: Complete lymph node dissection (CLND) following positive sentinel node biopsy (SLNB) was evaluated in a randomized phase III trial. METHODS 1,258 patients with cutaneous melanoma of the trunk and extremities and with positive SLNB were evaluated. Of these, 483 (39%) agreed to randomization into the clinical trial. 241 patients underwent observation only, 242 received CLND. Both groups had a subsequent 3-years follow-up. Recurrence-free (RFS), distant metastases free (DMFS) and melanoma specific (MSS) survival were analyzed as endpoints. RESULTS Patient enrolment was performedfrom January 2006 to December 2014. In the intent to treat analysis, both groups did not differ significantly in distribution of age, gender, localization, ulceration, tumor thickness (median 2,4 mm in both groups), number of positive nodes, or tumor burden in the SN. The mean follow-up time was 34 months (SD ± 22.1). No significant treatment-related difference was seen in the 5-years RFS (P = 0.72), DMFS (P= 0 .76) and MSS (P = 0.86) in the overall study population. CONCLUSIONS In this early analysis of trial results, no survival benefit was achieved by CLND in melanoma patients with positive SLNB. A subsequent analysis three years after inclusion of the last patient is planned.