Successful pharmacological intervention at different levels of the complement system in an in vitro complement fixation model for bullous pemphigoid.

Bullous pemphigoid (BP) is characterized by deposition of immunoglobulins and complement along the epidermal basement membrane (BM). In humans, there is a lack of functional studies targeting the complement system (CS). This study investigates activation of all complement pathways in BP skin biopsies. Moreover, pharmacological inhibition at different levels of the CS was investigated using anti-complement compounds in a complement fixation BP assay. In this retrospective study, 21 frozen biopsies from BP patients were stained by direct immunofluorescence for C1q, MBL, ficolin-2, C4d, properdin, C3c and C5b-9. Sera from 10 patients were analysed in a complement fixation assay in the presence of C1 inhibitor, anti-factor B monoclonal antibody (mAb), anti-C3 mAb and anti-C5 mAb and compared with dexamethasone. The two readouts were the quantity of complement deposited along the BM and the release of sC5b-9 in the supernatant. Our results show classical and alternative complement pathway activation in BP skin biopsies, but could not demonstrate significant lectin pathway activation. In contrast to dexamethasone, complement deposition along the BM could be selectively inhibited by anti-C1 and anti- factor B. More downstream, selective intervention at the level of C3 and C5 could effectively reduce complement deposition along the BM and the release of sC5b-9 in the supernatant. This study shows that selective intervention in either the classical, alternative or terminal pathway prevented deposition of complement along the BM in an in vitro BP model. The results of our study greatly encourage the clinical development of complement inhibitors for the treatment of BP.

Hedgehog pathway mutations are involved in the pathogenesis of plaque-type "trichoblastoma": A report of two cases.

We present two cases of plaque-type trichoblastoma with atypical foci. A rare variant of trichoblastoma is the plaque variant, which is characterized by poor circumscription and locally infiltrative growth pattern. These lesions mostly require multiple stages of Mohs micrographic surgery. Debate still exists whether this variant should be considered as a benign entity or as "low-grade" malignant counterpart of trichoblastoma. In this report we describe two cases of plaque-type trichoblastoma with atypical foci, which harbored somatic mutations in the Hedgehog pathway, thus should be acknowledged as intermediate malignancies. In addition, extensive molecular workup of both the trichoblastic and atypical component in sequential lesions in the same patient was performed.

Trichoblastic carcinosarcoma with panfollicular differentiation (panfollicular carcinosarcoma) and CTNNB1 (beta-catenin) mutation.

We present a case of trichoblastic carcinosarcoma with panfollicular differentiation. An 80-year-old man presented with a lesion on the left ear, which had been present for several months. Histopathology revealed a well-demarcated neoplasm in the dermis composed of intimately intermingled malignant epithelial and mesenchymal cells. The epithelial component showed multilineage follicular differentiation toward all of the elements of a normal hair follicle. Molecular analysis revealed identical molecular aberrations in both epithelial and mesenchymal components including CTNNB1 and SUFU mutations. To the best of our knowledge, this is the first report of panfollicular carcinosarcoma and of the presence of a CTNNB1 mutation in trichoblastic carcinosarcoma.

Immune response and stromal changes in ductal carcinoma in situ of the breast are subtype dependent.

Ductal carcinoma in situ (DCIS) associated stromal changes and influx of immune cells might be mediators of progression to invasive breast cancer. We studied the interaction between DCIS-associated stromal changes, and immune cell distribution and composition in a well-characterized patient cohort. We included 472 patients with DCIS. The presence of stromal changes, signs of regression, and DCIS-associated immune cell position were determined on hematoxylin and eosin-stained slides. Immune cell composition was characterized by immunohistochemistry (CD4, CD8, CD20, CD68, and FOXP3). The number of intraductal immune cells was quantified per mm2. The interaction between stromal changes, signs of DCIS regression, immune cell composition and location was explored. Stromal changes and signs of DCIS regression were identified in 30 and 7% of the patients, respectively. Intraductal immune cells mainly comprised CD68+ macrophages and CD8+ T cells. Patients with stromal changes had significantly less influx of immune cells within the duct. DCIS regression was associated with an increased number of intraductal FOXP3+ T cells. The highest number of intraductal CD8+ T cells was seen in the ER+ HER2+ subtype. We suggest that DCIS-associated stromal changes prevent the interaction between immune cells and DCIS cells. However, in case of DCIS regression, we surmise a direct interaction between DCIS cells and immune cells, in particular FOXP3+ cells. Furthermore, the increased number of intraductal CD8+ T cells in the ER+ HER2+ DCIS subtype suggests a subtype-specific immune response, which is likely to play a role in the distinct biological behavior of different DCIS subtypes.

Complement Activation in Inflammatory Skin Diseases.

The complement system is a fundamental part of the innate immune system, playing a crucial role in host defense against various pathogens, such as bacteria, viruses, and fungi. Activation of complement results in production of several molecules mediating chemotaxis, opsonization, and mast cell degranulation, which can contribute to the elimination of pathogenic organisms and inflammation. Furthermore, the complement system also has regulating properties in inflammatory and immune responses. Complement activity in diseases is rather complex and may involve both aberrant expression of complement and genetic deficiencies of complement components or regulators. The skin represents an active immune organ with complex interactions between cellular components and various mediators. Complement involvement has been associated with several skin diseases, such as psoriasis, lupus erythematosus, cutaneous vasculitis, urticaria, and bullous dermatoses. Several triggers including auto-antibodies and micro-organisms can activate complement, while on the other hand complement deficiencies can contribute to impaired immune complex clearance, leading to disease. This review provides an overview of the role of complement in inflammatory skin diseases and discusses complement factors as potential new targets for therapeutic intervention.

Editor's Choice - Five Year Results of Great Saphenous Vein Treatment: A Meta-analysis.

OBJECTIVES: The most frequently used treatment options for great saphenous vein incompetence are high ligation with stripping (HL+S), endovenous thermal ablation (EVTA), mainly consisting of endovenous laser ablation (EVLA) or radiofrequency ablation, and ultrasound guided foam sclerotherapy (UGFS). The objective of this systematic review and meta-analysis was to compare the long-term efficacy of these different treatment modalities. METHODS: A systematic literature search was performed. Randomised controlled trials (RCTs) with follow-up ≥ 5 years were included. Pooled proportions of anatomical success, which was the primary outcome, rate of recurrent reflux at the saphenofemoral junction (SFJ), and mean difference in venous clinical severity score (VCSS) were compared using a z test or Student t test. Quality of life data were assessed and described. RESULTS: Three RCTs and 10 follow-up studies of RCTs were included of which 12 were pooled in the meta-analysis. In total, 611 legs were treated with EVLA, 549 with HL+S, 121 with UGFS, and 114 with HL+EVLA. UGFS had significantly lower pooled anatomical success rates than HL+S, EVLA, and EVLA with high ligation: 34% (95% CI 26-44) versus 83% (95% CI 72-90), 88% (95% CI 82-92), and 88% (95% CI 17-100) respectively; p ≤ .001. The pooled recurrent reflux rate at the SFJ was significantly lower for HL+S than UGFS (12%, 95% CI 7-20, vs. 29%, 95% CI 21-38; p ≤ .001) and EVLA (12%, 95% CI 7-20, vs. 22%, 95% CI 14-32; p = .038). VCSS scores were pooled for EVLA and HL+S, which showed similar improvements. CONCLUSION: EVLA and HL+S show higher success rates than UGFS 5 years after GSV treatment. Recurrent reflux rates at the SFJ were significantly lower in HL+S than UGFS and EVLA. VCSS scores were similar between EVLA and HL+S.