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I Editor i Hidradenitis suppurativa (HS) is a chronic, inflammatory disease affecting the intertriginous skin of axillary, inguinal and perianal sites.1 In these areas, patients develop painful and disabling skin lesions such as inflamed nodules, abscesses and fistula with foul-smelling secretions. Data were determined for following patient Groups: Group 1 (HS patients with drug therapy according to HS guidelines [HS drug therapy]), Group 2 (HS patients without HS drug therapy), Groups 3 (patients with suspected HS diagnosis and with HS drug therapy), Groups 4 (patients with suspected HS diagnosis and without HS drug therapy), Group 5 (potential HS patient with misdiagnosis and with HS drug therapy) and Group 6 (potential HS patient with misdiagnosis and without HS drug therapy). Importantly, the amount of mean sickness benefits was higher for HS patients than for other insured individuals (727€ vs. 311 €; average for insured patients with sickness benefit claims in SHI cohort was 311€ in 2012, calculation by the authors). [Extracted from the article]

Introduction: Dupilumab is approved for the treatment of severe type 2 (T2) asthma; however, the characteristics of patients receiving dupilumab in routine clinical practice are incompletely understood. This study describes the characteristics of patients with severe asthma before dupilumab treatment in a real-world setting., Methods: This interim analysis of an ongoing real-life study of dupilumab assessed baseline characteristics of the first patient cohort enrolled in the ProVENT study., Results: A total of 99 patients (59% females) were analyzed (17% received another biologic before dupilumab treatment and 15% were on maintenance oral corticosteroid treatment). Adult-onset asthma (>18 years) and an allergic phenotype were documented in 58% and 48% of patients, respectively. Median (interquartile range) age was 54 (40-61) years; the median number of exacerbations in the last 24 months was 1 (0-3); median fractional exhaled nitric oxide (FeNO) value was 38 (23-64) ppb; and median blood eosinophils (bEOS) count was 184 (8-505) cells/µL. According to the United Kingdom Severe Asthma Registry classification, 53% of patients had T2 intermediate asthma (bEOS ≥150 cells/µL or FeNO ≥25 ppb), 17% had T2 high asthma (bEOS ≥150 cells/µL and FeNO ≥25 ppb), and 4% had T2 low asthma (bEOS <150 cells/µL and FeNO <25 ppb). At least one GINA criterion for T2 airway inflammation was documented in 70% of patients. T2 comorbidities were observed in 64% of patients., Conclusions: This analysis suggests that patients eligible for dupilumab treatment display various clinical and biochemical characteristics rather than one clear-cut phenotype., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Objectives: The purpose of this study was to investigate the attainment of treatment goals according to the European Consensus Programme (ECP-TGs) from 2011 in patients with moderate to severe psoriasis (Pso) treated with the first conventional systemic therapy and to identify factors that might compromise the attainment of these treatment goals., Methods: In a multicenter, prospective observational study, patients with moderate to severe Pso, defined as either body surface area (BSA) >10% or psoriasis area severity index (PASI) >10 and dermatology life quality index (DLQI) >10, received a conventional systemic therapy that could be modified at each follow-up visit over the course of 18 months. All subjects signed an informed consent form, were ≥18 years of age as well as systemic therapy naïve, and had regular study visits at months 3, 6, 9, 12, and 18 after baseline. Among others and in addition to demographic and disease-related characteristics at baseline, we documented BSA, PASI, DLQI, and the physician-reported attainment of treatment goals at each follow-up visit. Factors related to a failure in achieving the ECP-TGs (i.e., either Δ PASI ≥75 or Δ PASI ≥50 and <75 with a DLQI ≤5) at month 18 were investigated by multiple logistic regression. Descriptive results are presented as the mean ± SD for interval data, and absolute as well as relative frequencies for nominal data. For this part of the analysis, data at baseline and months 6, 12, and 18 are presented., Results: A total of 133 Pso patients with a mean age and disease duration of 49.5 ± 14.4 and 15.6 ± 12.8 years, respectively, were included in the analysis; 54.1% (n = 72) were male. The mean baseline disease-related outcomes were: BSA: 21.5 ± 15.8%, PASI: 13.7 ± 7.14, and DLQI: 12.0 ± 6.11. The most common conventional systemic therapies initiated at baseline were fumaric acid esters (n = 74, 55.6%), methotrexate (n = 46, 34,6%), and ciclosporin (n = 6, 4.5%). The ECP-TGs were achieved by 58 patients (43.6%) at month 6, 86 patients (64.7%) at month 12, and 97 patients (72.9%) at month 18. An optimized reduced logistic regression model identified the presence of onycholysis/nail dystrophy at two or more digits to be associated with failing to attain the ECP-TGs (OR 10.7, 95% CI 2.5-46.7, p = 0.002)., Conclusion: Patients with onycholysis/nail dystrophy at two or more digits were identified as having a higher risk of not achieving ECP-TGs under conventional systemic therapy. The ECP-TGs from 2011 were attained by 43.6% of our patients 6 months after starting conventional systemic therapies. In the era of safe, fast, and efficacious Pso therapies, much higher treatment goals might be achieved during therapy. New treatment goals are only of use if patients and dermatologists strive to attain them., (© 2021 S. Karger AG, Basel.)

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with an adverse impact on patients' quality of life (QoL). Objectives: To quantify QoL impairment in patients in Germany suffering from HS and to identify the parameters associated with QoL impairment. Methods: A non-interventional, cross-sectional, mono-centric study with 500 HS patients. QoL data (measured using the Dermatology Life Quality Index; DLQI) and demographic, anamnestic, clinical, and blood parameters were collected. All patients were examined by dermatologists that documented the skin alterations. QoL data from 462 HS patients were available and evaluated. Results: The mean (± standard deviation) DLQI score of HS patients was 13.18 ± 7.99. Approximately 40% and 20% of HS patients declared very large and extremely large QoL impairment, respectively. The degree of QoL disturbance correlated with the severity of skin alterations, blood leucocyte count and, in particular, with anogenital localization and the presence of nodules and fistulas. Furthermore, QoL impairment was associated with specific comorbidities, such as adiposity and back pain, but not with HS family history. QoL impairment was not influenced by whether or not the patients had undergone resection surgery or antibiotic treatment but was more severe in HS patients that had undergone abscess lancing compared to patients without such treatment in the past. Limitations: It was a mono-centric study and most data were obtained from self-administered patient questionnaires. The association of QoL with type of treatment was analyzed for abscess lancing, resection surgery, and antibiotic treatment. Further therapeutic modalities recommended in the guidelines were not investigated. Conclusion: A profound impairment in QoL was present in patients with HS, and this was higher than that observed in other studied dermatoses. The degree of impairment correlated with the extent of cutaneous and some extra-cutaneous alterations. Surgical and conventional medicamentous therapies of HS were not associated with long-lasting reduction of QoL impairment. Our data support the implementation of patient-reported outcome measures for the assessment of therapy responses., Competing Interests: SS-B has received research grants, or honoraria for participation in advisory boards, clinical trials or as speaker for one or more of the following: AbbVie, Biogen IDEC, La Roche-Posay, Novartis Pharma, Parexel, and UCB Pharma. SB and JH-M were employees of AbbVie Deutschland GmbH & Co. KG at the time of publication development, may own AbbVie stock, and are currently employed at Sanofi Aventis Deutschland GmbH. KWo has received research grants, travel grants, consulting honoraria or lecturer's honoraria from AbbVie, Biogen IDEC, Celgene, Charité Research Organisation, Dr. Willmar Schwabe, Flexopharm, Janssen- Cilag, Novartis Pharma, Pfizer, Sanofi-Aventis, TFS Trial Form Support, and UCB Pharma. BF is an employee of AbbVie and may own AbbVie stock. RS has received research grants, scientific awards, or honoraria for participation in advisory boards, clinical trials or as speaker for one or more of the following: AbbVie, AMGEN, Bayer, Biogen IDEC, Boehringer Ingelheim Pharma, Celgene, Charité Research Organisation, CSL Behring, Dr. Willmar Schwabe, Flexopharm, Janssen-Cilag, La Roche-Posay Laboratoire Dermatologique, Novartis Pharma, Parexel, Pfizer, Sanofi-Aventis, TFS Trial Form Support, and UCB Pharma. The evaluation of patient data was partly supported by AbbVie Deutschland GmbH & Co. KG. AbbVie Deutschland GmbH & Co. KG contributed in writing, reviewing, and approval of the final version. No honoraria or payments were made for authorship. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schneider-Burrus, Tsaousi, Barbus, Huss-Marp, Witte, Wolk, Fritz and Sabat.)

Background: Hidradenitis suppurativa (HS) is a neglected chronic inflammatory disease with long delay in diagnosis. Besides pain, purulent discharge, and destruction of skin architecture, HS patients experience metabolic, musculoskeletal, and psychological disorders., Objectives: To determine the delay in HS diagnosis and its consequences for patients and the healthcare system., Methods: This was a prospective, multicenter, epidemiologic, non-interventional cross-sectional trial carried out in Germany and based on self-reported questionnaires and medical examinations performed by dermatologists. In total, data of 394 adult HS patients were evaluated., Results: The average duration from manifestation of first symptoms until HS diagnosis was 10.0 ± 9.6 (mean ± SD) years. During this time, HS patients consulted on average more than 3 different physicians - most frequently general practitioners, dermatologists, surgeons, gynecologists - and faced more than 3 misdiagnoses. Diagnosis delay was longer in younger and non-smoking patients. In most cases, HS was correctly diagnosed by dermatologists. The longer the delay of diagnosis, the greater the disease severity at diagnosis. Delayed HS diagnosis was also associated with an increased number of surgically treated sites, concomitant diseases, and days of work missed., Conclusion: This study demonstrates an enormous delay in the diagnosis of HS, which results in more severe disease. It also shows for the first time that a delay in diagnosis of a chronic inflammatory disease leads to a higher number of concomitant systemic disorders. In addition to the impaired health status, delayed diagnosis of HS was associated with impairment of the professional life of affected people., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Purpose: CITED4 is one member of a family of transcriptional cofactors, several of which are deregulated in a variety of tumors, including colorectal cancer (CRC). We modulated CITED4 expression, in vitro, and analyzed the associated phenotypic and gene expression changes., Methods: CITED4-overexpressing and shRNA-mediated knockdown cell lines and control cell lines were established in the CRC cell line SW480. The cells were analyzed for changes in proliferation, apoptosis/cell cycle, migration, invasion, colony formation and adhesion. mRNA expression changes were determined by microarray and pathway analysis, and several deregulated genes were validated by qRT-PCR and Western blotting. Based on results obtained from these studies, the status of the actin cytoskeleton was evaluated by phalloidin/vinculin staining., Results: Phenotypically, the CITED4-overexpressing cell line showed only moderate changes in adhesion. Microarray analysis identified several deregulated genes, including several G protein-coupled receptors. Phenotypic analysis of the CITED4 shRNA knockdown cell line demonstrated decreased cell proliferation and G2 cell cycle blockage. Microarray analysis identified many deregulated genes, and pathway analysis discovered genes linked to actin-associated adherens junctions/tight junctions (claudin-4, claudin-7, ezrin, MET, ß-catenin). Phenotypically, no morphological changes of the actin cytoskeleton were seen., Conclusions: Upregulation of CITED4 in SW480 resulted in no obvious phenotype. CITED4 shRNA-mediated knockdown led to decreased cellular proliferation and modulation of a large number of genes, including the c-MET tyrosine kinase and several actin-associated adherens junctions/tight junction genes.

Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of α-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro, as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma.

Although the prognosis of most glioblastoma patients is poor, 3%-5% patients show long-term survival of 36 months or longer after diagnosis. To study the differences in activation of biochemical pathways, we performed mRNA and protein expression analyses of primary glioblastoma tissues from 11 long-term survivors (LTS; overall survival ≥ 36 months) and 12 short-term survivors (STS; overall survival ≤ 6 months). The mRNA expression ratio of the retinoic acid transporters fatty acid-binding protein 5 (FABP5) and cellular retinoic acid-binding protein 2 (CRABP2), which regulate the differential delivery of retinoic acid to either antioncogenic retinoic acid receptors or prooncogenic nuclear receptor peroxisome proliferator-activated receptor delta, was statistically significantly higher in the tumor tissues of STS than those of LTS (median ratio in STS tumors = 3.64, 10th-90th percentile = 1.43-4.54 vs median ratio in LTS tumors = 1.42, 10th-90th percentile = -0.98 to 2.59; P < .001). High FABP5 protein expression in STS tumors was associated with highly proliferating tumor cells and activation of 3-phosphoinositide-dependent protein kinase-1 and v-akt murine thymoma viral oncogene homolog. The data suggest that retinoic acid signaling activates different targets in glioblastomas from LTS and STS. All statistical tests were two-sided.

To identify novel glioma-associated pathomechanisms and molecular markers, we performed an array-based comparative genomic hybridization analysis of 131 diffuse astrocytic gliomas, including 87 primary glioblastomas (pGBIV), 13 secondary glioblastomas (sGBIV), 19 anaplastic astrocytomas (AAIII) and 12 diffuse astrocytomas (AII). All tumors were additionally screened for IDH1 and IDH2 mutations. Expression profiling was performed for 74 tumors (42 pGBIV, 11 sGBIV, 13 AAIII, 8 AII). Unsupervised and supervised bioinformatic analyses revealed distinct genomic and expression profiles separating pGBIV from the other entities. Classifier expression signatures were strongly associated with the IDH1 gene mutation status. Within pGBIV, the rare subtype of IDH1 mutant tumors shared expression profiles with IDH1 mutant sGBIV and was associated with longer overall survival compared with IDH1 wild-type tumors. In patients with IDH1 wild-type pGBIV, PDGFRA gain or amplification as well as 19q gain were associated with patient outcome. Array-CGH analysis additionally revealed homozygous deletions of the FGFR2 gene at 10q26.13 in 2 pGBIV, with reduced FGFR2 mRNA levels being frequent in pGBIV and linked to poor outcome. In conclusion, we report that diffuse astrocytic gliomas can be separated into 2 major molecular groups with distinct genomic and mRNA profiles as well as IDH1 gene mutation status. In addition, our results suggest FGFR2 as a novel glioma-associated candidate tumor suppressor gene on the long arm of chromosome 10., (Copyright © 2010 UICC.)

Malignant gliomas are the most common primary brain tumors, and are associated with frequent resistance to therapy as well as poor prognosis. Here we demonstrate that the nuclear receptor tailless (Tlx), which in the adult is expressed exclusively in astrocyte-like B cells of the subventricular zone, acts as a key regulator of neural stem cell (NSC) expansion and brain tumor initiation from NSCs. Overexpression of Tlx antagonizes age-dependent exhaustion of NSCs in mice and leads to migration of stem/progenitor cells from their natural niche. The increase of NSCs persists with age, and leads to efficient production of newborn neurons in aged brain tissues. These cells initiate the development of glioma-like lesions and gliomas. Glioma development is accelerated upon loss of the tumor suppressor p53. Tlx-induced NSC expansion and gliomagenesis are associated with increased angiogenesis, which allows for the migration and maintenance of brain tumor stem cells in the perivascular niche. We also demonstrate that Tlx transcripts are overexpressed in human primary glioblastomas in which Tlx expression is restricted to a subpopulation of nestin-positive perivascular tumor cells. Our study clearly demonstrates how NSCs contribute to brain tumorgenesis driven by a stem cell-specific transcription factor, thus providing novel insights into the histogenesis and molecular pathogenesis of primary brain tumors.

Purpose: Glioblastoma spheroid cultures are enriched in tumor stem-like cells and therefore may be more representative of the respective primary tumors than conventional monolayer cultures. We exploited the glioma spheroid culture model to find novel tumor-relevant genes., Experimental Design: We carried out array-based comparative genomic hybridization of spheroid cultures derived from 20 glioblastomas. Microarray-based gene expression analysis was applied to determine genes with differential expression compared with normal brain tissue and to nonneoplastic brain spheroids in glioma spheroid cultures. The protein expression levels of three candidates were determined by immunohistochemistry on tissue microarrays and correlated with clinical outcome. Functional analysis of PDPN was done., Results: Genomic changes in spheroid cultures closely resembled those detected in primary tumors of the corresponding patients. In contrast, genomic changes in serum-grown monolayer cultures established from the same patients did not match well with the respective primary tumors. Microarray-based gene expression analysis of glioblastoma spheroid cultures identified a set of novel candidate genes being upregulated or downregulated relative to normal brain. Quantitative real-time PCR analyses of 8 selected candidate genes in 20 clinical glioblastoma samples validated the microarray findings. Immunohistochemistry on tissue microarrays revealed that expression of AJAP1, EMP3, and PDPN was significantly associated with overall survival of astrocytic glioma patients. Invasive capacity and RhoA activity were decreased in PDPN-silenced spheroids., Conclusion: We identified a set of novel candidate genes that likely play a role in glioblastoma pathogenesis and implicate AJAP1, EMP3, and PDPN as molecular markers associated with the clinical outcome of glioma patients.

Blue Cross and Blue Shield of Michigan assessed the intensity of inpatient laboratory use for similar patients in a sample of 30 short-term hospitals in three geographic areas. Hospital records were abstracted for 1,834 patients treated in 1980 for uncomplicated (Stage 1) admissions involving eight common diagnoses. It was found that patients treated in osteopathic teaching hospitals received significantly more laboratory tests than similar patients in allopathic teaching or nonteaching hospitals. Statistically significant differences were also found among the three geographic areas in the sample.