Management of moderate to severe psoriasis with brodalumab-Real-world evidence from the LIBERO study.

BACKGROUND: Brodalumab, a fully human monoclonal immunoglobulin IgG2 antibody that binds the human interleukin 17 receptor subunit A, is available for the treatment of moderate-to-severe plaque psoriasis in Europe since September 2017, but so far there are only a few studies on its use in real-world conditions. OBJECTIVES: To assess the management of moderate-to-severe psoriasis with brodalumab 210 mg in daily practice after 12 and 52 weeks (W). In addition, patient profiles and treatment pathways are described. METHODS: LIBERO is a prospective, multicenter, non-interventional study including adult patients with plaque psoriasis treated with brodalumab 210 mg. RESULTS: In total, 638 patients (65% male, mean age: 49.3 ± 14.4 years) from 148 sites in Germany were enrolled. The majority suffered from severe (51.1%) or very severe (13.1%) psoriasis according to physician global assessment (PGA0-5). When starting with brodalumab, 58.5% were biologic naïve and 41.5% were previously treated with another biologic, mainly adalimumab (18.5%) and secukinumab (17.9%). About 74.0% of patients met the primary endpoint of an absolute PASI ≤3 at ~W12 (n = 618, LOCF). The mean PASI was reduced significantly as of ~W2 from 17.2 (±11.7) to 9.7 (±8.8) and improved further to 3.3 (±6.3) at ~W12 (p < 0.001). At ~W52 85.5% of patients reached a PGA0/1-response (primary endpoint) and 54.1% patients were assessed as completely clear (PGA0) (both n = 399, as observed). Effectiveness of brodalumab was confirmed in relevant subgroup analysis by previous treatment regimen. Most frequently reported adverse events were nasopharyngitis (4.6%), psoriasis (4.6%) and arthralgia (4.1%), new safety signals were not detected. CONCLUSION: This representative, non-interventional study confirms the short- and long-term effectiveness and safety profile of brodalumab in the management of psoriasis in daily practice as well as in relevant treatment pathways.

Exaggerated IDO1 expression and activity in Langerhans cells from patients with atopic dermatitis upon viral stimulation: a potential predictive biomarker for high risk of Eczema herpeticum.

BACKGROUND: Atopic dermatitis (AD) is a heterogenous and highly complex disease characterized by an increased microbial colonization. For unknown reasons, a subgroup of patients with AD develops Eczema herpeticum (EH), a severe viral complication due to spreading of herpes simplex virus (HSV). Indoleamine 2,3-dioxygenase (IDO1) is a tryptophan (Trp)-catabolizing enzyme which is assumed to be instrumental in the antibacterial and antiviral defence mechanisms. METHODS: Comparative investigation of the IDO1 expression and activity in freshly isolated monocytes, plasmacytoid DC (pDC) and in vitro-generated Langerhans cells (LC) obtained from AD patients with HSV infections and EH and nonatopic controls. RESULTS: We demonstrate an increase in Trp degradation in the serum of patients during acute EH episodes. Circulating pDC from patients with history of EH display an increased IDO1 expression. An increased Trp degradation is detected in the supernatants of circulating monocytes from AD patients with acute EH. Mature LC from AD patients with history of EH and with acute EH display an increased IDO1 expression and activity, respectively. In LC from patients with history of EH, viral signals induce an exaggerated IDO1 expression and activity. CONCLUSION: IDO1 expression and activity in LC seem to be involved in the pathophysiology of EH in AD and could represent a predictive biomarker for patients with risk to develop EH and other viral complications.

Morphology of basal cell carcinoma in high definition optical coherence tomography: en-face and slice imaging mode, and comparison with histology.

BACKGROUND: Optical coherence tomography (OCT) allows real-time, in vivo examination of basal cell carcinoma (BCC). A new high definition OCT with high lateral and axial resolution in a horizontal (en-face) and vertical (slice) imaging mode offers additional information in the diagnosis of BCC and may potentially replace invasive diagnostic biopsies. OBJECTIVES: To define the characteristic morphologic features of BCC by using high definition optical coherence tomography (HD-OCT) compared to conventional histology. METHODS: A total of 22 BCCs were examined preoperatively by HD-OCT in the en-face and slice imaging mode and characteristic features were evaluated in comparison to the histopathological findings. RESULTS: The following features were found in the en-face mode of HD-OCT: lobulated nodules (20/22), peripheral rimming (17/22), epidermal disarray (21/22), dilated vessels (11/22) and variably refractile stroma (19/22). In the slice imaging mode the following characteristics were found: grey/dark oval structures (18/22), peripheral rimming (13/22), destruction of layering (22/22), dilated vessels (7/22) and peritumoural bright stroma (11/22). In the en-face mode the lobulated structure of the BCC was more distinct than in the slice mode compared to histology. CONCLUSION: HD-OCT with a horizontal and vertical imaging mode offers additional information in the diagnosis of BCC compared to conventional OCT imaging and enhances the feasibility of non-invasive diagnostics of BCC.

[10 theses of the disabled persons' organizations - why participation research with a social perspective is needed]. / 10 Thesen der Fachverbände für Menschen mit Behinderung - Warum es eine Teilhabeforschung mit sozialer Perspektive braucht.

The 5 professional associations for the disabled and the self-help organisations of disabled people state that in Germany a general concept for "participation research" is needed. This concept should address expectations and processes in developing aid services and improve self-determined participation of people with disabilities according to the human rights postulated in the UN Convention on the Rights of People with Disabilities (2006). A concept of "participation research" will go beyond the objectives and methods of i. e., disability studies - it is a focus in the context of which the social and equal participation of the disabled (especially those with multiple and/or intellectual handicaps) has to be addressed. In this context the 5 professional associations for the disabled have drafted 10 theses which are presented in the following article.

Atopic dermo-respiratory syndrome is a correlate of eczema herpeticum.

BACKGROUND: Factors favoring the emergence of eczema herpeticum (EH) in patients with atopic dermatitis (AD) remain elusive. The aim of this work was to identify changes in clinical and laboratory parameters in acute EH patients, before and after 6 weeks of treatment, as well as differences between AD patients with and without a history of EH. METHODS: A total of 235 adult subjects were included and subdivided into six groups: (i) AD patients with acute EH, (ii) AD patients with history of EH, (iii) AD without EH but with recurrent herpes simplex virus (HSV) infections, (iv) AD without EH or recurrent HSV infections and healthy non-AD controls (v) with and (vi) without recurrent HSV infections. Clinical examination of AD, assessment of atopic status and severity were performed. Total IgE, allergen-specific IgE and differential blood count were analyzed. Clinical diagnosis of acute EH was confirmed by PCR. RESULTS: More male patients with AD were affected by EH than female patients. Acute episodes of EH are characterized by lower levels of lymphocytes and higher levels of monocytes. AD patients with history of EH display higher total IgE serum levels (ADEH(+) HSV(+) vs ADEH(-) HSV(+) , P < 0.001) and higher sensitization profiles and stronger severity of AD (EASI and SCORAD; ADEH(+) HSV(+) vs ADEH(-) HSV(+) , P < 0.001). Concomitant asthma and rhinitis were identified as correlates of EH. CONCLUSION: From these data, we conclude that AD patients with EH display a distinct clinical and biological phenotype.

Management of dermatofibrosarcoma protuberans with fibrosarcomatous transformation: an evidence-based review of the literature.

Fibrosarcomatous transformation represents a rare event in dermatofibrosarcoma protuberans (DFSP) with unpredictable biological behaviour. No guidelines for the adequate treatment of patients with this rare neoplasm have been published. Herein, we present a comprehensive review of the literature comprising 157 patients with transformed DFSP focussing on surgical and adjuvant treatment modalities for this tumour. In the cohort examined, local recurrence occurred in 36% of cases and was significantly lower in patients treated by wide excision with margins ≥2 cm when compared with those treated with local excision without defined margins (P = 0.01). Consistently, negative margin status was associated with a lower recurrence rate when compared with positive or unknown margin status (P = 0.01). Distant metastases were detected in 13% of patients, which is significantly higher when compared with ordinary dermatofibrosarcoma protuberans. Systemic dissemination was preceded by local recurrence in 81% of cases, and is therefore strongly associated with tumour recurrence (P ≤ 0.001). The present data confirm that wide excision with margins ≥ 2 cm represent the gold standard in the treatment of transformed dermatofibrosarcoma protuberans, and prevents recurrence as well as metastasis. When R0-resection is not feasible, adjuvant radiation should be considered for cases with incomplete resection or unknown surgical margins. Irresectable or metastatic transformed DFSP harbouring the COL1A1-PDGFB fusion gene should be treated with imatinib in the palliative setting or as an adjunctive treatment before surgery, although responses may be short-lasting.

Regulatory requirements for clinical trial and marketing authorisation application for cell-based medicinal products.

The new era of regenerative medicine has led to rapid development of new innovative therapies especially for diseases and tissue/organ defects for which traditional therapies and medicinal products have not provided satisfactory outcome. Although the clinical use and developments of cell-based medicinal products (CBMPs) could be witnessed already for a decade, robust scientific and regulatory provisions for these products have only recently been enacted. The new Regulation for Advanced Therapies (EC) 1394/2007 together with the revised Annex I, Part IV of Directive 2001/83/EC provides the new legal framework for CBMPs. The wide variety of cell-based products and the foreseen limitations (small sample sizes, short shelf life) vs. particular risks (microbiological purity, variability, immunogenicity, tumourigenicity) associated with CBMPs have called for a flexible, case-by-case regulatory approach for these products. Consequently, a risk-based approach has been developed to allow definition of the amount of scientific data needed for a Marketing Authorisation Application (MAA) of each CBMP. The article provides further insight into the initial risk evaluation, as well as to the quality, non-clinical, and clinical requirements of CBMPs. Special somatic cell therapies designed for active immunotherapy are also addressed.

Inhibition of protein synthesis by the T cell receptor-inducible human TDAG51 gene product.

The T cell death associated gene 51 (TDAG51) was shown to be required for T cell receptor (TCR)-dependent induction of Fas/Apo1/CD95 expression in a murine T cell hybridoma. Despite the absence of a nuclear localization sequence and a nucleic acid binding domain, it was suggested to be localized in the nucleus and to function as a transcription factor regulating Fas-expression. However, we demonstrate that the human (h)TDAG51 protein is localized in the cytoplasm and the nucleoli, suggesting a role in ribosome biogenesis and/or translation regulation. Indeed, it strongly inhibited translation of a luciferase mRNA in a reticulocyte translational extract. Furthermore, cotransfection of hTDAG51 and the luciferase gene into 293T cells resulted in a strong inhibition of luciferase mRNA translation. Our findings were further strengthened by isolating in a yeast two-hybrid screen three proteins which are involved in the regulation of translation. We speculate that hTDAG51 couples TCR signaling to inhibition of protein biosynthesis in activated T lymphocytes.

Identification of the T-cell receptor alpha variable (TRAV) gene(s) in T-cell malignancies.

Due to the lack of a complete range of monoclonal antibodies (mAb) it is often impossible to rapidly identify by flow cytometry the T-cell receptor variable genes in patients suffering from T-cell malignancies. This applies especially to the alpha variable genes (TRAV), since only very few anti-TcR variable alpha mAb are available. We describe a very rapid method for inverse PCR amplification of the TcR alpha chain without prior purification of the double-stranded cDNA, provide the sequences for appropriate oligonucleotides, and describe a buffer system that dramatically enhances the amplification efficiency as compared to standard conditions.

Differentiating vector-derived mRNA from contaminating DNA templates by inverse RT-PCR.

Inverse RT-PCR was used for detecting doxycycline-induced mRNA expression after viral transduction with a retroviral vector harboring human TDAG51. After the circularization of double-stranded cDNA, induced transcripts originating from integrated vector genomes were selectively amplified, even in the presence of DNA templates. Thus, DNase treatment before amplification was unnecessary.

Variation of ACTA scanner numbers with the physical properties of the scanned material.

An experiment has been carried out in which an ACTA computerized axial-transverse tomographic scanner was used in a series of scans on a polystyrene phantom. Cavities in the phantom contained distilled water and various concentrations of acetic acid or ferric nitrate in aqueous solution. It is shown that the ACTA numbers generated for the low-Z acetic acid solution are proportional to the electron density of the solution, but that such is not the case for the higher-Z ferric nitrate, where photoelectric absorption is significant. The correlation of scanner numbers with electron density rather than with mass density is discussed and, as an illustrative example, the electron densities of whole blood and blood cells are calculated and the relative value is compared with the relative mass densities of the materials.

A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop.

Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M 'gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC.

[Advances in the pathogenesis of atopic dermatitis]. / Neues in der Pathophysiologie der atopischen Dermatitis.

The incidence of atopic dermatitis (AD) is noticeably increasing in industrialized countries. New insights into the pathogenesis of this disease are mirrored by a changed terminology suggested by the World Allergy Organization: a distinction between a so-called atopic and non-atopic dermatitis. The pathogenesis of the AD, which this article concentrates on, is highly complex. Genetic and environmental factors play a pivotal role in triggering AD. The complex pattern of cytokines and chemokines, reflecting a deviated immune response in AD patients, is a focus of research, as are the involvement of various cells and the epidermal barrier. Research concerning T cells with regulatory features as well as IgE-mediated autoreactivity will soon give insight into the defective tolerance of atopic patients and might possibly lead to new concepts in the management of the disease.

The effect of exposure to multiple lineups on face identification accuracy.

This study examines the conditions under which an intervening lineup affects identification accuracy on a subsequent lineup. One hundred and sixty adults observed a photograph of one target individual for 60 s. One week later, they viewed an intervening target-absent lineup and were asked to identify the target individual. Two days later, participants were shown one of three 6-person lineups that included a different photograph of the target face (present or absent), a foil face from the intervening lineup (present or absent), plus additional foil faces. The hit rate was higher when the foil face from the intervening lineup was absent from the test lineup and the false alarm rate was greater when the target face was absent from the test lineup. The results suggest that simply being exposed to an innocent suspect in an intervening lineup, whether that innocent suspect is identified by the witness or not, increases the probability of misidentifying the innocent suspect and decreases the probability of correctly identifying the true perpetrator in a subsequent test lineup. The implications of these findings both for police lineup procedures and for the interpretation of lineup results in the courtroom are discussed.

Analysis of the TCR Vgamma repertoire in healthy donors and HIV-1-infected individuals.

During the course of infection with HIV-1, striking alterations in the subset distribution of peripheral blood gammadelta T cells are observed. While TCR Vdelta2 expression dominates among peripheral blood gammadelta T cells in healthy adults, there is a clear preponderance of Vdelta1 cells in HIV-1-infected persons. In this study, we present the first flow cytometry (FCM) analysis of the complete TCR Vgamma gene repertoire in HIV-1-infected individuals using a panel of mAb against all expressed Vgamma genes. The quantitative analysis of TCR Vgamma transcripts after amplification of cDNA by inverse PCR suggested that Vgamma5 usage is increased in HIV-1+ donors. This was confirmed by FCM with a new anti-Vgamma5 mAb. In addition, all members of the TCR VgammaI gene family (i.e. Vgamma2, 3, 4, 5 and 8) were expressed on significantly higher percentages of gammadelta T cells in HIV+ as compared to HIV- donors, whereas VgammaII (Vgamma9) expression was drastically reduced. No preferential association of the expanded Vdelta1+ cells with a particular Vgamma gene was observed in HIV-1 + donors. These results indicate that the increase in Vgamma1+ cells during HIV-1 infection occurs independently of the Vgamma gene usage and support the hypothesis that a Vdelta1-selective ligand might be involved.

Dual TCR-expressing T lymphocytes in health and disease.

The authors briefly review recent experimental advances in elucidating the role of dual T cell receptor (TCR)-expressing lymphocytes in the development of diseases with special emphasis on autoimmunity. Moreover, they summarize present knowledge about these cells concerning their proportion among peripheral blood mononuclear cells, their functionality, and their impact on allorecognition and memory both in humans and in mice. Finally, they describe disease-associated clonal expansions of dual TCR-expressing cells in humans, most of which have been observed in peripheral T cell malignancies. Other cases occurred in inflammatory bowel disease and in HIV infection. They propose that expression of two distinct TCR on malignant T lymphocytes might be much higher than is suggested by the few cases described so far, and that their presence might impinge on therapeutic immunization strategies which make use of the TCR itself as a target.

Clonal expansion of gamma delta T cells expressing two distinct T-cell receptors.

92% of peripheral blood mononuclear cells from a patient with chronic lymphocytosis (WBC 22 x 10(9)/l) were recognized by pan-gamma delta monoclonal antibody (mAb) TCR delta 1. Further analysis with anti-V gamma/V delta mAb indicated that the expanded gamma delta T-cell population was stained by mAb specific for V gamma 2/3/4, V gamma 5 and V delta 1 but not mAb specific for V gamma 8, V gamma 9, V delta 2 or V delta 3. Cloning and sequencing of reverse transcription PCR products revealed the presence of V gamma 4, V gamma 5 and V delta 1 in-frame transcripts. All the cDNA clones obtained from each of these variable elements had identical junction regions, thus clearly demonstrating clonality. As far as we know, this is the first description of a pathological clonal expansion of gamma delta T cells with two distinct surface-expressed T-cell receptor molecules.

The role of CT scan in evaluation for laparotomy in patients with stab wounds of the abdomen.

Not every patient with a penetrating stab wound of the abdomen requires laparotomy. This report evaluates use of computerized tomographic (CT) scan in assessment of stable asymptomatic patients, with penetrating abdominal stab wounds, as an indicator of the necessity of abdominal exploration. In a prospective study, 50 patients with abdominal stab wounds were treated successfully with observation only, after admission abdominal CT scan interpretation was negative for pathology in 45 patients. In the remaining five it was of such minor nature that conservative management was justified (Series I). Twenty-eight stable asymptomatic patients with penetrating stab wounds of the abdomen comparable to the ones in Series I had CT scan on admission, and then underwent exploratory laparotomy independent of their CT scan findings (Series II). Of these 28 patients, 22 had correct CT scan findings verified by laparotomy, three were false positive for intra-abdominal injury resulting in negative explorations, and three patients had such nonspecific findings as fluid or air in the abdomen incompatible with precise organ injury identification. Our study shows that CT scan in patients with abdominal stab wounds identifies solid organ injury with great specificity and sensitivity, evaluates the retroperitoneum well, and detects peritoneal penetration by demonstrating intraperitoneal fluid or air. CT scan was unreliable in detection of bowel injury and does not demonstrate diaphragmatic injuries.

T cell receptor gamma delta repertoire in HIV-1-infected individuals.

While V gamma 9/V delta 2 cells dominate among peripheral blood gamma delta T cells in healthy adults, the majority of gamma delta T cells in most HIV-1-infected individuals express V delta 1. We asked whether these elevated levels of V delta 1 T cells were due to clonal expansion. Three-color flow cytometry with monoclonal antibodies against V gamma 2/V gamma 3/V gamma 4, V gamma 4 and V gamma 9 was used to investigate V gamma usage in 27 patients with elevated numbers of V delta 1 T cells. While the relative proportion of V gamma 9 cells among gamma delta T cells was significantly reduced in HIV-1+ individuals (10 +/- 11% vs. 80 +/- 17%, p < 0.001), the fraction of gamma delta T cells using V gamma 5 or V gamma 8 was significantly increased (54 +/- 15% vs. 7 +/- 11%, p < 0.001). In 1 patient, 76% of the V delta 1 cells expressed V gamma 2 or V gamma 3, suggesting clonality of the V delta 1 population. In line with this assumption, analysis of the V delta 1-J delta junctional regions by reverse transcription-polymerase chain reaction (RT-PCR) resulted in products of only one junctional length, as demonstrated by electrophoresis on denaturing gels, and 12 out of 16 (75%) in-frame junctional sequences were identical in this patient. In other HIV-1+ patients, RT-PCR resulted in products of several distinct sizes, also indicating a highly restricted repertoire. After sequencing the V delta 1-J delta junctional regions of 3 additional patients, we found repeated but patient-specific in-frame junctions accounting for 10-30% of the sequenced clones. However, limited V delta 1-J delta junctional diversity was also seen in healthy donors. RT-PCR products from 10 healthy individuals resulted in distinct bands on denaturing gels. In 1 of them exhibiting a single prominent band, 10 out of 17 (58%) sequenced junctions were identical. Two other healthy donors displayed 2/14 and 5/18 identical junctional sequences, respectively. Taken together, our results reveal significant alterations of V gamma usage in HIV-1+ patients, while the V delta 1 junctional repertoire is similarly restricted in HIV-1+ and HIV-1- individuals. Therefore, these data argue against an obligatory clonal expansion of V delta 1-expressing cells during HIV-1 infection.

Cell-surface expression of transrearranged Vgamma-cbeta T-cell receptor chains in healthy donors and in ataxia telangiectasia patients.

Transrearrangements between the T-cell receptor (TCR) VgammaI family and JbetaCbeta loci occur at increased frequencies in patients with ataxia telangiectasia (AT). We have used an optimized reverse transcriptase polymerase chain reaction (RT-PCR) approach to investigate the occurrence of TCRVgamma-JbetaCbeta transrearrangements involving the dominantly used Vgamma element in peripheral blood gammadelta T cells, i.e. Vgamma9. We detected in frame transcripts of Vgamma9-JbetaCbeta transrearrangements in 4/16 AT patients and in 3/13 healthy control donors. A panel of monoclonal antibodies (mAb) against all expressed TCRVgamma elements was used to monitor cell-surface expression of transrearranged TCR. A very low proportion (< 1%) of peripheral blood TCRalphabeta cells expressed Vgamma instead of Vbeta elements. For the first time, we have isolated and molecularly characterized alphabeta T cells with a Vgamma9-JbetaCbeta transrearrangement from two AT patients and we have shown that such TCR are functional. We conclude that functional TCR transrearrangements can also involve Vgamma9, the dominant Vgamma element in peripheral blood gammadelta T cells.