Altered density, composition and microanatomical distribution of infiltrating immune cells in cutaneous squamous cell carcinoma of organ transplant recipients.

BACKGROUND: The inflammatory tumour microenvironment is crucial for effective tumour control, and long-term immunosuppression has been identified as a major risk factor for skin carcinogenesis. In solid organ transplant recipients (OTRs) undergoing long-term pharmacological immunosuppression, an increased incidence of cutaneous squamous cell carcinoma (SCC) and more aggressive tumour growth compared with immunocompetent patients has been reported. OBJECTIVES: To determine the density and phenotype of immune cells infiltrating SCC and surrounding skin in OTRs, and to characterize the microanatomical distribution patterns in comparison with immunocompetent patients. METHODS: We analysed immune cell infiltrates within SCC and at defined regions of interest (ROIs) of tumour-surrounding skin in formalin-fixed paraffin-embedded tissue of 20 renal transplant patients and 18 carefully matched immunocompetent patients by high-resolution semiautomated microscopy on complete tissue sections stained for CD4, CD8, CD20 and CD68. RESULTS: The overall immune cell density of SCC arising in OTRs was significantly reduced compared with immunocompetent patients. Particularly CD4+ infiltrates at the directly invasive margin and tumour vicinity, intratumoral CD8+ T-cell densities and the overall density of CD20+ tumour-infiltrating B cells were significantly reduced in the tissue of OTRs. CONCLUSIONS: Immune cell infiltrates within SCC and at defined ROIs of tumour-surrounding skin in OTRs differ markedly in their composition and microanatomical distribution compared with tumours arising in immunocompetent patients. Our findings substantially broaden the understanding of how long-term systemic immunosuppression modulates the local inflammatory microenvironment in the skin and at the site of invasive SCC.

Dimethyl fumarate modulates neutrophil extracellular trap formation in a glutathione- and superoxide-dependent manner.

BACKGROUND: Neutrophil (polymorphonuclear) granulocytes (PMN) have been shown to contribute to the pathogenesis of psoriasis by releasing interleukin-17 and LL37-DNA complexes via neutrophil extracellular traps (NETs), webs of chromatin strands decorated with antimicrobial peptides, in psoriatic skin. Fumaderm® , a fumaric acid ester (FAE) formulation consisting of different FAE salts, has been successfully used to treat psoriasis for decades. Most recently, FAE treatment was reported to inhibit NET formation in murine epidermolysis bullosa acquisita. OBJECTIVES: To elucidate the effect of FAE treatment on human psoriasis and healthy donor NET formation. RESULTS: Among the compounds present in the FAE formulation, dimethyl fumarate (DMF) pretreatment of human psoriasis and healthy donor PMN resulted in a consistent inhibitory effect on NET formation in response to phorbol 12-myristate 13-acetate but not to platelet activating factor and ionomycin. This effect was l-glutathione (GSH) dependent and involved a decrease in reactive oxygen species (ROS) production, a key event in NET formation. In contrast, G-protein-coupled signalling and protein synthesis were not involved. Monomethyl fumarate (MMF) was found to slightly reduce ROS production without affecting NET formation. CONCLUSIONS: We report DMF as a potent, stimulus-specific, GSH- and ROS-dependent modulator of NET formation. Our results support the notion that modulation of NET formation contributes to the beneficial effects of FAEs in a variety of inflammatory conditions.

European Guidelines (S1) on the use of high-dose intravenous immunoglobulin in dermatology.

BACKGROUND: The treatment of severe dermatological autoimmune diseases and toxic epidermal necrolysis (TEN) with high-dose intravenous immunoglobulin (IVIg) is a well-established procedure in dermatology. As treatment with IVIg is usually considered for rare clinical entities or severe clinical cases, the use of immunoglobulin is not generally based on data from randomized controlled trials that are usually required for the practice of evidence-based medicine. Owing to the rarity of the indications for the use of IVIg, it is also unlikely that such studies will be available in the foreseeable future. Because the high costs of IVIg treatment also limit its first-line use, the first clinical guidelines on its use in dermatological conditions were established in 2008 and renewed in 2011. MATERIALS AND METHODS: The European guidelines presented here were prepared by a panel of experts nominated by the EDF and the EADV. The guidelines were developed to update the indications for treatment currently considered as effective and to summarize the evidence base for the use of IVIg in dermatological autoimmune diseases and TEN. RESULTS AND CONCLUSION: The current guidelines represent consensual expert opinions and definitions on the use of IVIg reflecting current published evidence and are intended to serve as a decision-making tool for the use of IVIg in dermatological diseases.

[Billroth and Brahms: personal encounter of medicine and music]. / Billroth und Brahms : Medizin und Musik in der persönlichen Begegnung.

Theodor Billroth and Johannes Brahms shared a decades long personal friendship. The music-loving Billroth influenced the work of the famous composer and in turn Brahms also left traces within Billroth's lifetime achievements. To shed light on the close relationship of medicine and music, this manuscript describes both Billroth's life and surgical career as they were influenced and stimulated by his close friendship to Brahms.Theodor Billroth and Johannes Brahms first met in 1865 in Zurich, Switzerland. After Billroth accepted the chair of surgery at the University of Vienna in 1867, Brahms moved to Vienna in 1869. During the following years, Billroth analyzed most of Brahms' compositions prior to publication. Similar to his effective way of teaching medical students and assistants, Billroth stimulated Brahms to publish many of his later compositions. Brahms on the other hand supported Billroth in writing his essay"Who is musical?". Furthermore, music helped Billroth to cope with the demanding working life of a surgeon.Music and surgery share both structural and emotional analogies. While both professions require meticulous techniques, personal interaction is a prerequisite for success. "Science and art scoop from the same well."

Autoantibodies in psoriasis as predictors for loss of response and anti-infliximab antibody induction.

BACKGROUND: Infliximab is successfully used to treat psoriasis and psoriatic arthritis. However, some patients lose therapeutic response after several cycles. Antibodies to infliximab (infliximab-Abs) are induced during treatment in a subgroup of patients and are thought to be associated with loss of response (LOR). Routine screening for infliximab-Abs is expensive and not regularly performed. A reliable and affordable method for identifying patients who are at risk for LOR to infliximab is desirable. OBJECTIVES: To analyse the development of antinuclear antibodies (ANA)/antidouble-stranded DNA antibodies (anti-dsDNA) over time in patients with psoriasis receiving infliximab. To analyse if there is an association between ANA titres/anti-dsDNA concentrations, infliximab-Ab status and LOR. METHODS: A retrospective data analysis of 29 patients with psoriasis receiving infliximab was carried out. ANA titres and anti-dsDNA concentrations were regularly monitored in these patients and sera were tested for infliximab-Abs by enzyme-linked immunosorbent assay. RESULTS: Median ANA titres increased from 1 : 80 [interquartile range (IQR) 0 to 1 : 320, n = 29] pretreatment, to 1 : 1280 (IQR 1 : 640 to 1 : 1920, n = 15) after infusion 10, and 1 : 1920 (IQR 1 : 1280 to 1 : 2560, n = 10) after infusion 20. Infliximab-Abs were found in 21% of patients. Infliximab-Ab-positive patients and patients with LOR had significantly higher pretreatment anti-dsDNA concentrations and higher pretreatment ANA titres than infliximab-Ab-negative and responsive patients, respectively. CONCLUSIONS: The results of this study suggest a role for autoantibodies in the identification of patients with psoriasis at higher risk of developing infliximab-Abs and of LOR under treatment with infliximab.