The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma.

Abstract Most patients with BRAFV600-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAFV600-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a “long tail” of new mitogen-activated protein kinase (MAPK) pathway alterations (…

Differential influence of vemurafenib and dabrafenib on patient lymphocytes despite similar clinical efficacy in melanoma

Background: Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts’ immune system. Patients and methods: Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. Results: Progression-free survival (PFS) as well as overall survival (O…

The concentration of para-phenylenediamine (PPD) for routine patch testing in a standard series needs to be redefined

Patch testing in children--recommendations of the German Contact Dermatitis Research Group (DKG).

Summary Allergic contact dermatitis occurs frequently in children. Patch testing is needed to identify the responsible allergens and should be performed in children. We recommend a panel of 12 contact allergens as a standard series in children from 6–12 years. Four additional contact allergens should be tested in case of a positive history or suggestive clinical picture. For patch testing in children, the allergens should be applied for 24 hours and the readings should be performed at 48 and 72 hours. Standardized patch testing makes it possible to systematically investigate allergic contact dermatitis and identify relevant allergens in children.

CXCR3-ligand-mediated skin inflammation in cutaneous lichenoid graft-versus-host disease.

Background Lichenoid graft-versus-host disease (liGVHD) histologically shares several common features with other lichenoid dermatoses, such as cutaneous lupus erythematosus and lichen planus (LP), which collectively show a junctional infiltrate of cytotoxic lymphocytes with liquefaction of the basal layer ("interface dermatitis"). Because recent studies have shown a role for type I interferon (IFN)–associated inflammation, including lymphocyte recruitment via CXCR3 ligand interaction in cutaneous lupus erythematosus and LP, we hypothesized that similar mechanisms might also be involved in liGVHD. Methods Ten representative lesional skin biopsies taken from patients with different subsets of…

Consensus on performing skin biopsies, laboratory workup, evaluation of tissue samples and reporting of the results in patients with suspected cutaneous graft-versus-host disease

Background Histopathological diagnosis including selection of lesions, the determination of the best point of time for biopsy and workup is not trivial in cutaneous graft-versus-host disease (GvHD). Objectives To develop interdisciplinary recommendations on performing, the laboratory work up and reporting of the results of skin biopsies in patients with suspected cutaneous GvHD. Methods A working group consisting of dermatopathologists, dermatologists, transplant-physicians and transplant-pathologists prepared recommendations for performing skin biopsies, laboratory workup and evaluation of tissue samples, and reporting of the results in patients with cutaneous GvHD. After achieving a conse…

Late reactions to patch test preparations with reduced concentrations of p-phenylenediamine : a multicentre investigation of the German Contact Dermatitis Research Group

Background. p-Phenylenediamine (PPD) 1% in petrolatum has been shown in a prospective study to elicit late reactions in 1.5% of routine patch tests, which may be indicative of patch test sensitization. Objectives. To assess the frequency of late reactions to reduced PPD patch test concentrations. Methods. In 1838 patients, PPD was tested at three concentrations (0.5% pet., group I; 0.4% pet., group II; and 0.35% pet., group III). Patch tests were read on D1 (D2) to D3 (D4); additional late readings were performed on D7, D14, and D21. Patients who were not able to return for all scheduled late readings were telephoned on D7, D14, and D21, and questioned about a reaction at the patch test sit…

Antihistamine-resistant chronic spontaneous urticaria: 1-year data from the AWARE study.

BACKGROUND Previous reports indicate that patients with chronic spontaneous urticaria (CSU) are undertreated and that physicians show poor adherence to guideline recommendations. Awareness of CSU has improved in recent years, but it remains unclear if this has improved the management of these patients in clinical practice. OBJECTIVE To describe disease burden, quality of life (QoL), and treatment patterns of patients with H1 -antihistamine-refractory CSU in Germany. METHOD A World-wide Antihistamine-Refractory chronic urticaria (CU) patient Evaluation (AWARE) is a global prospective, non-interventional study of CU in the real-world setting, supported by the manufacturer of omalizumab. Patie…

Psoriasis predisposition and occupational triggering factors in the appraisal of occupational medical expertises

Summary Background Psoriasis is an immune-mediated disease with a genetic background. Local psoriatic changes can be triggered by exogenous mechanical or irritant factors. Causative occupational factors have to be distinguished from the spontaneous course of psoriasis in occupational medical evaluations. The objective of this work is to demonstrate the medico-legal grounds for a homogenous assessment. Patients and methods The presented recommendations were developed in a working group for Occupational and Environmental Dermatology (ABD) and the German contact dermatitis group (DKG) of the German Dermatologic Society (DDG) based on the German medico-legal framework. Results Causality between…