Wiebke K. Peitsch

Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma.

The majority of Merkel cell carcinomas (MCCs) are associated with the recently identified Merkel cell polyomavirus (MCV). However, as it is still unclear to which extent the presence of MCV impacts tumor characteristics or clinical outcome, we correlated the MCV status of tumor lesions obtained from 174 MCC patients including 38 MCC patients from Australia and 138 MCC patients from Germany with clinical characteristics, histomorphology, immunohistochemistry, and course of the disease. MCV DNA was present in 86% of MCCs and, in contrast to previous reports, no significant difference in MCV prevalence was present between Australian and German MCC cases. When patients were stratified according to their MCV status, only tumor localization (P=0.001), gender (P=0.024), and co-morbidity, i.e., frequency of patients with previous skin tumors (P=0.024), were significantly different factors. In contrast, year of birth and diagnosis, age at diagnosis, or histological type and features representing the oncogenic phenotype such as mitotic rate or expression of p16, p53, RB1, and Ki67 were not significantly different between MCV-positive and MCV-negative MCCs. MCV status also did not influence recurrence-free, overall, and MCC-specific survival significantly. In summary, although MCV-positive and MCV-negative MCCs may have different etiologies, these tumors have comparable clinical behaviors and prognosis.

Patient preferences for psoriasis treatments: impact of treatment experience.

Background  Patient preferences for psoriasis treatments can impact treatment satisfaction and adherence and may therefore influence clinical outcome.

Unique cell type-specific junctional complexes in vascular endothelium of human and rat liver sinusoids.

Liver sinusoidal endothelium is strategically positioned to control access of fluids, macromolecules and cells to the liver parenchyma and to serve clearance functions upstream of the hepatocytes. While clearance of macromolecular debris from the peripheral blood is performed by liver sinusoidal endothelial cells (LSECs) using a delicate endocytic receptor system featuring stabilin-1 and -2, the mannose receptor and CD32b, vascular permeability and cell trafficking are controlled by transcellular pores, i.e. the fenestrae, and by intercellular junctional complexes. In contrast to blood vascular and lymphatic endothelial cells in other organs, the junctional complexes of LSECs have not yet been consistently characterized in molecular terms. In a comprehensive analysis, we here show that LSECs express the typical proteins found in endothelial adherens junctions (AJ), i.e. VE-cadherin as well as α-, β-, p120-catenin and plakoglobin. Tight junction (TJ) transmembrane proteins typical of endothelial cells, i.e. claudin-5 and occludin, were not expressed by rat LSECs while heterogenous immunreactivity for claudin-5 was detected in human LSECs. In contrast, junctional molecules preferentially associating with TJ such as JAM-A, B and C and zonula occludens proteins ZO-1 and ZO-2 were readily detected in LSECs. Remarkably, among the JAMs JAM-C was considerably over-expressed in LSECs as compared to lung microvascular endothelial cells. In conclusion, we show here that LSECs form a special kind of mixed-type intercellular junctions characterized by co-occurrence of endothelial AJ proteins, and of ZO-1 and -2, and JAMs. The distinct molecular architecture of the intercellular junctional complexes of LSECs corroborates previous ultrastructural findings and provides the molecular basis for further analyses of the endothelial barrier function of liver sinusoids under pathologic conditions ranging from hepatic inflammation to formation of liver metastasis.

Genome-wide pooling approach identifies SPATA5 as a new susceptibility locus for alopecia areata

Alopecia areata (AA) is a common hair loss disorder, which is thought to be a tissue-specific autoimmune disease. Previous research has identified a few AA susceptibility genes, most of which are implicated in autoimmunity. To identify new genetic variants and further elucidate the genetic basis of AA, we performed a genome-wide association study using the strategy of pooled DNA genotyping (729 cases, 656 controls). The strongest association was for variants in the HLA region, which confirms the validity of the pooling strategy. The selected top 61 single-nucleotide polymorphisms (SNPs) were analyzed in an independent replication sample (454 cases, 1364 controls). Only one SNP outside of the HLA region (rs304650) showed significant association. This SNP was then analyzed in a second independent replication sample (537 cases, 657 controls). The finding was not replicated on a significant level, but showed the same tendency. A combined analysis of the two replication samples was then performed, and the SNP rs304650 showed significant association with P=3.43 × 10−4 (OR=1.24 (1.10–1.39)). This SNP maps to an intronic region of the SPATA5 (spermatogenesis-associated protein 5) gene on chromosome 4. The results therefore suggest the SPATA5 locus is a new susceptibility locus for AA.

Individualizing treatment and choice of medication in lichen planus: a step by step approach

Although lichen planus is one of the most common dermatological entities, very few reviews on its management exist in the literature. Standard therapeutic approaches include various topical treatments (including topical corticosteroids, calcineurin inhibitors, vitamin D analogs) and phototherapy modalities, as well as systemic corticosteroids and systemic retinoids. While localized skin lesions are easily managed with standard modalities, generalized forms and in particular involvement of hair follicles, nails and mucosa, as well as eyes are often challenging. This review proposes an evidence‐based and differential therapeutic regime, taking into account many new emerging systemic therapies to help clinicians optimize treatment according to the type, extent and severity of the disease. An individual therapeutic ladder has been developed for each location, starting with standard modalities and ranking alternative systemic treatments (mainly methotrexate and hydroxychloroquine, as well as cyclosporine, azathioprine and mycophenolate mofetil) according to efficacy, evidence level and side‐effect profile.

Cardiovascular and metabolic risk profile in German patients with moderate and severe psoriasis: a case control study

Patients with psoriasis have a higher risk of cardiovascular and metabolic comorbidities, attributable to lifestyle factors, but also to shared inflammatory pathways and genetic factors. To investigate the association between moderate and severe psoriasis and metabolic and cardiovascular comorbidities, 100 patients hospitalized at University Medical Centre Mannheim, Germany, for psoriasis treatment were compared to two age- and sex-matched control groups, the first comprising other hospitalized patients (HCG) and the second comprising healthy individuals from an industrial cohort study (ICG). Multivariate logistic regression analysis with stepwise inclusion of cardiovascular risk factors was performed. Patients with psoriasis had significantly increased prevalences of smoking, obesity, diabetes, insulin resistance, pro-atherogenic cholesterol profiles and myocardial infarction and significantly decreased cardioprotective adiponectin. Unexpectedly, regression models controlling for confounding factors predicted significantly decreased OR for elevated total cholesterol in psoriasis cases (vs HCG: OR=0.50, p=0.045; vs ICG: OR=0.26, p=0.006). In contrast, OR for pro-atherogenic cholesterol profiles with LDL/HDL >3 was markedly increased (OR=2.45, p=0.012 or OR=3.02, p=0.020). Moreover, participants with psoriasis had significantly increased OR for elevated CRP as compared to the ICG (5.25, p=0.001). Our findings underscore the importance of cardiovascular and metabolic risk screening for all patients with moderate and severe psoriasis, including young patients.

Matching physicians' treatment recommendations to patients' treatment preferences is associated with improvement in treatment satisfaction.

Background  Dissatisfaction with treatment is common among those with psoriasis. While incorporating patients’ preferences into the process of treatment decision‐making may improve satisfaction, this relationship has not been clearly established.

Subtypes of melanocytes and melanoma cells distinguished by their intercellular contacts: heterotypic adherens junctions, adhesive associations, and dispersed desmoglein 2 glycoproteins

In the tissue integration of melanocytes and melanoma cells, an important role is attributed to cell adhesion molecules, notably the cadherins. In cultured melanoma cells, we have previously described a more heterogeneous repertoire of cadherins than normal, including some melanoma subtypes synthesizing the desmosomal cadherin, desmoglein 2, out of the desmosomal context. Using biochemical and immunological characterization of junctional molecules, confocal laser scanning, and electron and immunoelectron microscopy, we now demonstrate homo- and heterotypic cell-cell adhesions of normal epidermal melanocytes. In human epidermis, both in situ and in cell culture, melanocytes and keratinocytes are connected by closely aligned membranes that are interspersed by small puncta adhaerentia containing heterotypic complexes of E- and P-cadherin. Moreover, melanocytes growing in culture often begin to synthesize desmoglein 2, which is dispersed over extended areas of intimate adhesive cell-cell associations. As desmoglein 2 is not found in melanocytes in situ, we hypothesize that its synthesis is correlated with cell proliferation. Indeed, in tissue microarrays, desmoglein 2 has been demonstrated in a sizable subset of nevi and primary melanomas. The biological meanings of these cell-cell adhesion molecule arrangements, the possible diagnostic and prognostic significance of these findings, and the implications of the heterogeneity types of melanomas are discussed.

Mechanisms of p53 Restriction in Merkel Cell Carcinoma Cells Are Independent of the Merkel Cell Polyoma Virus T Antigens

Merkel cell carcinoma (MCC) is a rare and very aggressive skin cancer with viral etiology. The tumor-associated Merkel cell polyoma virus (MCV) belongs to a group of viruses encoding T antigens (TAs) that can induce tumorigenesis by interfering with cellular tumor-suppressor proteins like p53. To explore possible modes of p53 inactivation in MCC p53 sequencing, expression analysis and reporter gene assays for functional analyses were performed in a set of MCC lines. In one MCV-negative and one MCV-positive cell line, p53 inactivating mutations were found. In the majority of MCC lines, however, wild-type p53 is expressed and displays some transcriptional activity, which is yet not sufficient to effectively restrict cellular survival or growth in these cell cultures. Interestingly, the MCV TAs are not responsible for this critical lack in p53 activity, as TA knockdown in MCV-positive MCC cells does not induce p53 activity. In contrast, inhibition of the ubiquitin ligase HDM-2 (human double minute 2) by Nutlin-3a leads to p53 activation and p53-dependent apoptosis or cell cycle arrest in five out of seven p53 wild-type MCC lines, highlighting p53 as a potential target for future therapies of this aggressive tumor.

Treatment Satisfaction of Patients with Psoriasis

Treatment satisfaction of patients with psoriasis largely depends on the treatment modality, but evidence on preferences for specific medications is scarce. Here we assessed treatment satisfaction of 200 participants with moderate-to-severe psoriasis from a German University hospital with a 5-point scale and the Treatment Satisfaction Questionnaire for Medication (TSQM) and determined sociodemographic and disease-related influence factors. Participants obtaining biologicals and traditional systemic medications were significantly more satisfied than those receiving phototherapy or topical agents (TSQM = 323.3, 288.0, 260.6 or 266.8; p < 0.001). The highest TSQM score was calculated for ustekinumab (350.1), followed by acitretin (338.1), adalimumab (323.0), fumaric acid esters (304.7), infliximab (300.2), etanercept (298.8), and methotrexate (272.3; p < 0.001). High disease-related quality of life impairment (β = -0.437, p < 0.001) and psoriatic arthritis (β = -0.185, p = 0.005) were associated with decreased satisfaction. Optimising satisfaction is essential to improve adherence and outcome. We show high preferences for biologicals, particularly ustekinumab, but also good satisfaction with certain traditional medications.