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BACKGROUND: Thymomas and thymic carcinomas are rare tumors of the anterior mediastinum. A WHO classification was introduced in 1999, which has been updated in 2004. Meanwhile, several retrospective studies have been carried out which have shown the prognostic significance of this classification together with Masaoka's staging system and the extent of surgery. PATIENTS AND METHODS: Between 1983 and 2000, 77 patients (37 male, 40 female) underwent resection of thymomas and thymic carcinomas in our institution. Complete resection was achieved in 57 patients. The median follow-up was 72.6 months. RESULTS: The overall 5-year survival rate was 71.4 %. The factors "histology" and "extent of resection" had the most important impact on survival. However, even among the patients with complete resection, 12 of them suffered a relapse. Among this patient group, the most important factors for disease-free survival were "tumor stage" and "histology". Patients with an incomplete resection had a 5-year survival rate of only 29 % in spite of adjuvant radiation and/or chemotherapy. Due to the high rate of relapse, the poor survival rate found in incompletely resected patients as well as the failure of classical chemotherapy regimens, especially in type B2 and type B3 thymomas and thymic carcinomas, the search for new chemotherapeutic schemes is mandatory. CONCLUSION: Our study shows that there are still encouraging therapeutic options for thymomas and thymic carinomas. Type B2, type B3 thymomas and thymic carcinomas have worse outcomes in spite of adjuvant chemo- and radiotherapies. Especially in patients with incomplete surgical resection the outcome remains poor. [ABSTRACT FROM AUTHOR]

Stress urinary incontinence is the involuntary leakage of urine during increased abdominal pressure, such as coughing, sneezing, laughing, or exercising. It can have a significant negative impact on a person's quality of life and can result in decreased physical activity and social isolation. The presented closure mechanism for a mechatronic intraurethral artificial urinary sphincter is designed to be inserted minimally invasive into the urethra. The device consists of a solid shell, which serves as a housing for the electronics and is designed to enable fixation in the urethra. During micturition, the urine flows through the system, where it is guided through an elastic silicone-tube that, on the one hand, enables closure by a squeezing mechanism and, on the other hand, prevents biofilm growth by oscillation at a frequency of 22.5 Hz. The squeezing mechanism consists of a pinch valve system actuated by a piezo motor. The system has been tested under urodynamic conditions and the results show that it is able to close the urethra effectively to restore continence. The device is able to withstand sudden loads and shows good performance in terms of biofilm prevention during first experiments with artificial urine. The results show that the mechatronic intraurethral artificial urinary sphincter has the potential to be an effective and minimally invasive alternative to current treatment options for stress urinary incontinence.Clinical Relevance- This novel concept of a mechatronic intraurethral artificial urinary sphincter presents a promising alternative treatment option for patients suffering from stress urinary incontinence. As it is designed to be inserted minimally invasive, it reduces the impact and complications associated with current treatment options. The future development and testing of the device could lead to a safe and effective option for clinicians to offer their patients with stress urinary incontinence, which can improve their quality of life, and decrease costs for society and healthcare systems.

Background: Spread through air spaces (STAS) is a recently described route of tumor invasion associated with poor prognosis in primary lung cancer. Aim of this study was to investigate the presence of STAS and to assess its prognostic significance in patients undergoing pulmonary metastasectomy (PM) for solitary metastases from colorectal cancer (CRC)., Materials and Methods: All 49 CRC patients (30 male and 19 female, median age 66 years) who underwent PM between January 2008 and December 2015 were retrospectively analyzed., Results: STAS was identified in 26.5% ( n  = 13) of resected specimens. Location of pulmonary lesions (central vs. peripheral) was assessed based on the available computed tomography imaging ( n  = 47, 96%). STAS was detected in all five patients with central metastases (100%) versus 7 of 42 (17%) with peripheral metastases ( p  = 0.0001). Locoregional recurrence occurred in STAS-positive patients ( n  = 4 of 13 vs. n  = 0 of 36), all STAS-negative patients remained recurrence-free ( p  = 0.003). Median number of alveoli with STAS involvement was four (range from 2 to 9). There was statistically positive relationship between the number of alveoli invaded with STAS and locoregional recurrence of metastases ( p  = 0.0001). The presence of STAS is not a factor affecting the 5-year overall survival rate ( p  = 0.6651)., Conclusion: We identified STAS as a frequent finding in resected CRC lung metastases and found insignificant association with outcome., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objectives: The physiological number and distribution of mast cells (MCs) in the pediatric gastrointestinal (GI) tract is not well defined and reference values of normality are missing. To define a physiological and disease defining cut-off, a systematic histological exploration of MC distribution from the esophagus to the rectum in healthy as well as in patients with gastrointestinal food allergies (GFA) was performed., Methods: Nine pediatric subjects that exhibited unremarkable histopathological evaluations or underwent endoscopy for surveillance reasons after a previous polypectomy of single colonic juvenile polyps served as reference cohort. In all of these subjects, a chronic inflammatory disease (eg, inflammatory bowel disease, celiac disease) or allergy was excluded. In addition, a group of 15 patients with gastrointestinal complaints suspected to be caused by a GFA were investigated. Immunohistochemistry was performed from all biopsies using CD117 (c-Kit) as a reliable marker to identify MCs in the lamina propria., Results: There were distinct differences of MC counts in all parts of the pediatric GI tract. The highest counts of MCs in both symptomatic patients and control cohort, were found in the duodenum, terminal ileum, cecum and ascending colon. The lowest counts were found in the esophagus. Significant disparities between GFA and healthy subjects were found in the gastric corpus (22.1 ± 4.0/ high power field [HPF] vs 32.0 ± 10.1/HPF; P = 0.034) and ascending colon (44.8 ± 10.4/HPF vs 60.4 ± 24.3/HPF; P = 0.047)., Conclusions: Mucosal MC counts in the pediatric GI tract are higher than previously reported, with a considerable overlap between healthy and GFA patients. These results provide detailed information on distribution and numbers of MCs in pediatric allergic patients while allowing estimates of physiological values in childhood for the first time. With regard to diagnostic procedures in GFA further laboratory parameters have to be integrated., Competing Interests: Conflicts of Interest: C. Ehrsam, A. Hoerning, C. Geppert, M. Raithel, R. Rieker, and A. Hartmann have no conflict of interest to declare., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA4/2 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-Jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.

Background: The outcomes of so called "salvage" resections after definitive chemoradiation vs. curative resections after neoadjuvant chemoradiation therapy (IT-resection) in patients with stage IIIA/B locally advanced non-small cell lung cancer have rarely been compared. The aim of our study was to compare perioperative results, postoperative and recurrence-free survival and to identify relevant prognostic survival factors for both therapy strategies., Patients and Methods: Between June 2008 and May 2017, 43 patients underwent pulmonary resection following induction therapy (group 1) and 14 patients underwent salvage resection after definitive chemoradiation (group 2). Retrospective analysis was performed of demographic factors, tumour stage and location, initial therapy, preoperative regression status, perioperative morbidity and mortality, postoperative and recurrence-free survival., Results: In group 2, significantly higher radiation dose was applied (p < 0.001) and the interval between chemoradiation and lung resection was significantly longer (p = 0.02). In addition, significantly higher perioperative blood loss and more frequent blood transfusions were noted (p = 0.003 and 0.005, respectively). Perioperative morbidity and mortality were statistically comparable in the two groups (p = 0.72 and 0.395, respectively). Postoperative 5 year survival in group 1 was 55%, in group 2 48% (log-rank p = 0.353). Five year recurrence-free survival in group 1 was 53%, in group 2 42% (log-rank p = 0.180). Diffuse metastasis occurred mostly in group 2, whereas in group 1 oligometastasis was more frequently noted., Conclusion: Postoperative outcome after salvage resection seems statistically comparable to results following curative resection after induction therapy. Diffuse distant metastasis is frequently noted. Careful patient selection is required., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: Systemic sclerosis (SSc) fibroblasts remain activated even in the absence of exogenous stimuli. Epigenetic alterations are thought to play a role for this endogenous activation. Trimethylation of histone H3 on lysine 27 (H3K27me3) is regulated by Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in a therapeutically targetable manner. The aim of this study was to explore H3K27me3 demethylases as potential targets for the treatment of fibrosis., Methods: JMJD3 was inactivated by small interfering RNA-mediated knockdown and by pharmacological inhibition with GSKJ4. The effects of targeted inactivation of JMJD3 were analysed in cultured fibroblasts and in the murine models of bleomycin-induced and topoisomerase-I (topoI)-induced fibrosis. H3K27me3 at the FRA2 promoter was analysed by ChIP., Results: The expression of JMJD3, but not of UTX, was increased in fibroblasts in SSc skin and in experimental fibrosis in a transforming growth factor beta (TGFβ)-dependent manner. Inactivation of JMJD3 reversed the activated fibroblast phenotype in SSc fibroblasts and prevented the activation of healthy dermal fibroblasts by TGFβ. Pharmacological inhibition of JMJD3 ameliorated bleomycin-induced and topoI-induced fibrosis in well-tolerated doses. JMJD3 regulated fibroblast activation in a FRA2-dependent manner: Inactivation of JMJD3 reduced the expression of FRA2 by inducing accumulation of H3K27me3 at the FRA2 promoter. Moreover, the antifibrotic effects of JMJD3 inhibition were reduced on knockdown of FRA2 ., Conclusion: We present first evidence for a deregulation of JMJD3 in SSc. JMJD3 modulates fibroblast activation by regulating the levels of H3K27me3 at the promoter of FRA2 . Targeted inhibition of JMJD3 limits the aberrant activation of SSc fibroblasts and exerts antifibrotic effects in two murine models., Competing Interests: Competing interests: O.D. has consulted for, or has received research funding from, 4D Science, Actelion, Active Biotech, Bayer-Schering, Biogen, Biovitrium, BMS, Boehringer, EpiPharm, Ergonex, GSK, Inventiva, Medac, Novartis, Pfizer, Roche/Genentech, Sanofi/Genzyme, Serodapharm, Sinoxa and United BioSource Corporation; JHWD has consultancy relationships and/or has received research funding from Actelion, BMS, Celgene, Bayer Pharma, Boehringer Ingelheim, JB Therapeutics, Sanofi-Aventis, Novartis, UCB, GSK, Array Biopharma, Galapagos, Inventiva and Active Biotech in the area of potential treatments of SSc and is stock owner of 4D Science., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Lung cancer is the most life-threatening cancer type worldwide. Treatment options include surgery, radio- and chemotherapy, as well as the use of immunomodulatory antibodies. Interleukin (IL)-10 is an immunosuppressive cytokine involved in tumour immune escape., Methods: Immunohistochemistry (IHC) on human lung surgery tissue as well as human tumour cell line cultures, FACS analysis, real-time PCR and experimental lung cancer., Results: Here we discovered a positive correlation between IL-10 and IL-10 receptor (IL-10R) expression in the lung with tumour diameter in patients with lung cancer (non-small cell lung cancer), the most life-threatening cancer type worldwide. IL-10 and IL-10R were found induced in cells surrounding the lung tumour cells, and IL-10R was mainly expressed on the surface of Foxp-3 + T-regulatory lymphocytes infiltrating the tumour of these patients where its expression inversely correlated with programmed cell death 1. These findings were confirmed in translational studies. In a human lung adenocarcinoma cell line, IL-10R was found induced under metabolic restrictions present during tumour growth, whereby IL-10 inhibited PDL1 and tumour cell apoptosis., Conclusions: These new findings suggest that IL-10 counteracts IFN-γ effects on PD1/PDL1 pathway, resulting in possible resistance of the tumour to anti-PD1/PDL1 immunotherapy.

Aims: Thymomas and thymic squamous cell carcinomas (TSQCCs) are rare thymic epithelial tumours. Data on angiogenesis and vascular phenotype in these tumours are limited, and no study has taken histological World Health Organization (WHO) subtypes into account. The aim of this study was to compare vascularization, pericytes coverage and expression of angiogenic growth factors in different WHO-defined subtypes of thymoma METHODS AND RESULTS: Vascular density, diameter and architecture and expression of α-smooth muscle actin (SMA), platelet-derived growth factor (PDGF) receptor-β (PDGFRβ), vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) were investigated in WHO type A, AB, B1, B2 and B3 thymomas and TSQCCs, by the use of immunostaining, quantitative morphometry, and tumour vessel isolation by trypsin digestion. Expression levels of angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), VEGF-A, PDGF-B and Hif-1α were examined by quantitative reverse transcription polymerase chain reaction. A and AB thymomas were characterized by a dense network of capillary-like vessels with tight pericyte coverage, whereas B thymomas showed a loose vascular network with increasing vascular diameters and increasing expression of SMA and PDGFRβ from B1 to B3 thymomas and TSQCCs. VEGFR1 and VEGFR2 were expressed in vessels of all analysed tumour entities, and at higher levels in epithelial cells of A and B3 thymomas and TSQCCs. mRNA of Ang-2, but not of Ang-1, was significantly up-regulated in all thymoma subtypes, with the highest levels being found in A thymomas. In TSQCCs, Ang-1 and VEGF were the predominantly up-regulated growth factors. Hif-1α was only up-regulated in B3 thymomas and TSQCCs., Conclusion: Thymomas and TSQCCs differ significantly in their vascular architecture and expression of key angiogenic growth factors. The findings could help to improve the differential diagnosis of difficult-to-classify thymic epithelial tumours, and indicate different mechanisms of tumour angiogenesis and functional differences of tumour vessels of major thymoma subtypes and TSQCCs., (© 2016 John Wiley & Sons Ltd.)

Genome-wide association studies (GWAS) associated Family with sequence similarity 13, member A (FAM13A) with non-small cell lung cancer (NSCLC) occurrence. Here, we found increased numbers of FAM13A protein expressing cells in the tumoral region of lung tissues from a cohort of patients with NSCLC. Moreover, FAM13A inversely correlated with CTLA4 but directly correlated with HIF1α levels in the control region of these patients. Consistently, FAM13A RhoGAP was found to be associated with T cell effector molecules like HIF1α and Tbet and was downregulated in immunosuppressive CD4 + CD25 + Foxp3 + CTLA4 + T cells. TGFβ, a tumor suppressor factor, as well as siRNA to FAM13A, suppressed both isoforms of FAM13A and inhibited tumor cell proliferation. RNA-Seq analysis confirmed this finding. Moreover, siRNA to FAM13A induced TGFβ levels. Finally, in experimental tumor cell migration, FAM13A was induced and TGFβ accelerated this process by inducing cell migration, HIF1α, and the FAM13A RhoGAP isoform. Furthermore, siRNA to FAM13A inhibited tumor cell proliferation and induced cell migration without affecting HIF1α. In conclusion, FAM13A is involved in tumor cell proliferation and downstream of TGFβ and HIF1α, FAM13A RhoGAP is associated with Th1 gene expression and lung tumor cell migration. These findings identify FAM13A as key regulator of NSCLC growth and progression.

The role of surgical lung resection following neo-adjuvant radio-chemotherapy (RCT) in patients with locally advanced non-small cell lung cancer (NSCLC) is yet not clearly defined. The aim of our study was to analyze the postoperative survival and to identify relevant prognostic factors. 46 patients underwent curative resections after neo-adjuvant RCT for locally advanced NSCLC (IIIA/IIIB) between February 2008 and February 2015. A retrospective data analysis regarding preoperative regression status, perioperative mortality, postoperative survival, patho-histological remission, relapse pattern and other prognostic factors was performed. A neo-adjuvant RCT with a median radiation dose of 50.4 [range, 45-60] Gy was performed in 44 (96 %) patients. Partial and/or complete regression was observed in 32 (70 %) patients. R0-resection was achieved in 44 (96 %) patients. The 30-day mortality was 4 % and the perioperative morbidity was 37 %. The overall and progression free 5-year survival rate was 47 % and respectively 45 % [in median 58 months]. The 5-year survival rate of 64 % in the "responder"-group was significantly better when compared with 24 % in the "non-responder"-group (p = 0.038). The tri-modality therapy improved the prognosis in patients with locally advanced NSCLC (stage IIIA/IIIB). The complete patho-histological remission is an important prognostic factor for better long term survival. Dividing the patients in "responder" and "non-responder" after neo-adjuvant RCT may have large therapeutically consequences in the future., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: In spite of modern therapies for non-small-cell lung cancer (NSCLC), prognosis for many patients is still poor and survival rates are low. Immunotherapy is the possibility to improve the lung immune response surrounding the tumour. However, this approach requires detailed understanding of the local immune-responses of NSCLC patients., Methods: We analysed samples from three different regions within the lungs of NSCLC patients, whereas we distinguished between patients suffering from adenocarcinoma and squamous cell carcinoma. Expression of type 1 T helper (Th1)/type 1 cytotoxic (Tc1) factors was assessed by quantitative real-time PCR, western blot analyses or immunohistochemistry. Cytotoxic cell activity of CD8(+) T cells was determined via co-culture with autologous tumour cells and apoptosis assay., Results: We found decreased levels of the transcription factor T-box expressed in T cells (T-bet or Tbx21) and of the downstream activated IFN-γ-dependent pSTAT1α isoform in the lung tumour areas of patients with NSCLC as compared with tumour-free control regions. In these patients, reduced T-bet and pSTAT1α levels were found associated with increased immunosuppressive markers like cytotoxic T lymphocyte-associated protein 4, programmed cell death 1 and with a suppression of the Th1 cell cytokine production and Tc1 cell activity., Conclusions: These findings confirm a central role of T-bet in targeted immunotherapy for patients with NSCLC.

Introduction: The 2004 version of the World Health Organization classification subdivides thymic epithelial tumors into A, AB, B1, B2, and B3 (and rare other) thymomas and thymic carcinomas (TC). Due to a morphological continuum between some thymoma subtypes and some morphological overlap between thymomas and TC, a variable proportion of cases may pose problems in classification, contributing to the poor interobserver reproducibility in some studies., Methods: To overcome this problem, hematoxylin-eosin-stained and immunohistochemically processed sections of prototypic, "borderland," and "combined" thymomas and TC (n = 72) were studied by 18 pathologists at an international consensus slide workshop supported by the International Thymic Malignancy Interest Group., Results: Consensus was achieved on refined criteria for decision making at the A/AB borderland, the distinction between B1, B2, and B3 thymomas and the separation of B3 thymomas from TCs. "Atypical type A thymoma" is tentatively proposed as a new type A thymoma variant. New reporting strategies for tumors with more than one histological pattern are proposed., Conclusion: These guidelines can set the stage for reproducibility studies and the design of a clinically meaningful grading system for thymic epithelial tumors.

Detection of activating EGFR mutations in NSCLC is the prerequisite for individualised therapy with receptor tyrosine kinase inhibitors (TKI). In contrast, mutant downstream effector KRAS is associated with TKI resistance. Accordingly, EGFR mutation status is routinely examined in NSCLC specimens, but the employed methods may have a dramatic impact on the interpretation of results and, consequently, therapeutic decisions. Specimens with low tumour cell content are at particular risk for false-negative EGFR mutation reporting by sequencing with Sanger chemistry. To improve reliability of detecting clinically relevant mutant variants of EGFR and KRAS, we took full advantage of 454 deep sequencing and developed a two-step amplification protocol for the analysis of EGFR exons 18-21 and KRAS exons 2 and 3. We systematically addressed the sensitivity, reproducibility and specificity of the developed assay. Mutations could be reliably identified down to an allele frequency of 0.2-1.5 %, as opposed to 10-20 % detection limit of Sanger sequencing. High reproducibility (0-2.1 % variant frequency) and very low background level (0.4-0.8 % frequency) further complement the reliability of this assay. Notably, re-evaluation of 16 NSCLC samples with low tumour cell content ≤40 % and EGFR wild type status according to Sanger sequencing revealed clinically relevant EGFR mutations at allele frequencies of 0.9-10 % in seven cases. In summary, this novel two-step amplification protocol with 454 deep sequencing is superior to Sanger sequencing with significantly increased sensitivity, enabling reliable analysis of EGFR and KRAS in NSCLC samples independent of the tumour cell content.

IL-6 plays a central role in supporting pathological T(H2) and T(H17) cell development and inhibiting the protective T regulatory cells in allergic asthma. T(H17) cells have been demonstrated to regulate allergic asthma in general and T-bet-deficiency-induced asthma in particular. Here we found an inverse correlation between T-bet and Il-6 mRNA expression in asthmatic children. Moreover, experimental subcutaneous immunotherapy (SIT) in T-bet((-/-)) mice inhibited IL-6, IL-21R and lung T(H17) cells in a setting of asthma. Finally, local delivery of an anti-IL-6R antibody in T-bet((-/-)) mice resulted in the resolution of this allergic trait. Noteworthy, BATF, crucial for the immunoglobulin-class-switch and T(H2),T(H17) development, was found down-regulated in the lungs of T-bet((-/-)) mice after SIT and after treatment with anti-IL-6R antibody, indicating a critical role of IL-6 in controlling BATF/IRF4 integrated functions in T(H2), T(H17) cells and B cells also in a T-bet independent fashion in allergic asthma.

Rhabdomyomas are rare benign mesenchymal tumors with skeletal muscle differentiation and a predilection for the head and neck area. A 38-year-old man presented with persistent, slowly growing, painless swelling in the left inner cheek for 2½ years. The lesion was detected during routine dental examination and was considered to represent a mucocele. The mass was removed via a transoral surgical approach, followed by a local recurrence 6 months later that was again surgically removed. The patient is alive and well 2 months after last surgery. Adult-type rhabdomyoma is a rare, occasionally recurring, benign mesenchymal tumor that should be included in the differential diagnosis of submucosal swellings in the oral cavity including the masticatory musculature. Adult-type rhabdomyoma of the cheek and masticatory area are exceptionally rare with no more than 3 cases reported to date.

The second edition of the World Health Organization (WHO) classification of thymic tumors (2004) has resumed the previous separation of thymic carcinomas (TCs) from thymomas. This "reseparation" was mainly based on new genetic data. Consequently, it is no longer recommended to label TCs as type C thymomas. TCs are very heterogeneous and comprise squamous, basaloid cell, mucoepidermoid, neuroendocrine, and many other subtypes. They resemble morphologic mimics in other organs and are labeled accordingly. However, only thymic squamous cell carcinomas (TSCCs) and lymphoepithelioma-like carcinomas are relatively common. For TSCCs, quite specific immunohistochemical markers (eg, CD5, CD70, CD117, CD205, FOXN1) and chromosomal gains and losses have been defined that help to distinguish TSCCs not only from malignant thymomas but also from pulmonary squamous cell carcinomas. Recognition of these differences is clinically important, because the prognosis of TSCC is better compared with the other TC subtypes and also compared with lung tumors. Considering the need to treat advanced TC more effectively, disparate findings in predictive molecular markers (eg, KIT mutations in TSCC, but not in thymomas) suggest that targeted treatments will have to be different in thymomas and TC. Preliminary data from single case collections and small treatment trials support this prediction., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Thymic hyperplasia is usually associated with the treatment of malignant tumours and is sometimes linked with endocrine diseases. For the first time, we report a case of thymic hyperplasia in a patient 2 years after bilateral lung transplantation. Contrast-enhanced chest CT scan was highly suspicious for a posttransplant lymphoma or thymoma. Therefore, the patient received total thymectomy. Excised specimens were sent to the Department of Pathology. Unexpectedly, the histological examination revealed hyperplastic thymic tissue without evidence for a posttransplant lymphoproliferative disorder or malignancy.

Unlabelled: The inhibition of heat shock protein 90 (Hsp90) has emerged as a promising antineoplastic strategy in diverse human malignancies. Hsp90 has been predicted to be involved in hepatocellular carcinoma (HCC) development; however, its role in hepatocarcinogenesis remains elusive. Using chemically distinctive Hsp90 inhibitors, we show that Hsp90 capacitates the aberrant expression and activity of crucial hepatocarcinogenesis-driving factors (e.g., insulin-like growth factor receptor 1, hepatocyte growth factor receptor, protein kinase B, v-raf-1 murine leukemia viral oncogene homolog 1, and cyclin-dependent kinase 4). In vitro, Hsp90 inhibition with both geldanamycin analogs (17-allylamino-17-desmethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-desmethoxygeldanamycin (17-DMAG)) and the non-quinone compound 8-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine (PU-H71) reduced the viability of various HCC cell lines, induced the simultaneous degradation of numerous hepatocarcinogenic factors, and caused substantial cell cycle arrest and apoptosis. In contrast, nontumorigenic hepatocytes were less susceptible to Hsp90 inhibition. Because conventional geldanamycin-derivate Hsp90 inhibitors induce dose-limiting liver toxicity, we tested whether novel Hsp90 inhibitors lacking the benzoquinone moiety, which has been deemed responsible for hepatotoxicity, can elicit antineoplastic activity without causing significant liver damage. In HCC xenograft mouse models, PU-H71 was retained in tumors at pharmacologically relevant concentrations while being rapidly cleared from nontumorous liver. PU-H71 showed potent and prolonged in vivo Hsp90 inhibitory activity and reduced tumor growth without causing toxicity., Conclusion: Hsp90 constitutes a promising therapeutic target in HCC. Non-quinone Hsp90 inhibitors exhibit tumor-specific accumulation and exert potent antineoplastic activity without causing significant hepatotoxicity.

Recent studies have shown that inhibition of cyclooxygenases (e.g. COX-2) exerts antitumorigenic effects on hepatocellular carcinomas (HCCs), which are to a significant extent due to the abrogation of PGE(2) synthesis. PGE(2) acts via differentially regulated prostaglandin receptors (EP(1-4)). Our study was designed to investigate the expression pattern of EP-receptors in HCCs and to evaluate the therapeutic potential of selective EP-receptor antagonists. Using tissue microarrays including a total of 14 control livers, 17 liver cirrhoses, 22 premalignant dysplastic nodules (DNs) and 162 HCCs with different histological grades, the expression of COX-2, mPGES-1 and -2 and EP(1-4)-receptors was analyzed. Western immunoblot analyses were performed to confirm the expression in HCC cell lines. The effects of EP(1-4)-receptor antagonism on cell viability and apoptosis were investigated using MTT-assays and FACS-analyses, respectively. COX-2, mPGES-1 and -2 and EP(1-4)-receptors were expressed in all HCC tissues. COX-2 expression was highest in DNs and declined with loss of HCC-differentiation. With respect to COX-2 expression, a converse expression of EP(1-3) -receptors and mPGES-1 and -2 was found in DNs compared to HCCs. Selectively antagonizing EP(1)- and EP(3)-receptors reduced the viability of HCC cells in a dose-dependent manner, which was associated with apoptosis induction. Our results suggest a differential regulation of EP-receptor subtype expression with dedifferentiation of HCCs in which a converse expression pattern for COX-2 in comparison to EP(1-3)-receptors occurs. Of clinical interest, selectively antagonizing EP(1)- and EP(3)-receptors may provide a novel systemic therapeutic approach to the treatment of HCCs., ((c) 2007 Wiley-Liss, Inc.)

Objective: The early phase following heart transplantation (HTx) is characterized by the development of right ventricular myocardial fibrosis (MF) and cardiomyocyte hypertrophy (CH). The question is if there are differences in development of MF and CH between patients with complicated versus patients with uncomplicated postoperative course., Methods: Endomyocardial biopsies were taken from 58 donor hearts before implantation and one and two weeks after HTx. According to the clinical course in the first year after HTx and the rejection grading (ISHLT), four groups were classified: (a) uneventful course, (b) transplant failure, (c) infections, and (d) rejection episodes > or = 1R. The volume densities of various tissue components and cardiomyocyte diameters were measured by stereological and morphometrical methods., Results: From implantation to the first two weeks, most groups showed a significant increase of endomysial and perimysial connective tissues. There was a significant CH recognizable, especially in the rejection group. However, nucleus surface, a hypertrophy parameter, showed no significant change during follow-up. There were no statistically significant differences in volume densities of interstitial space, capillaries, nuclei and cardiomyocytes between the collectives and points in time. Sarcomere length as marker of contraction status of cardiomyocytes remained at the same level and showed no significant differences. Demographic data showed no significant differences and will be presented., Conclusions: Patients with complicated and uncomplicated courses show different degrees of histopathological changes after HTx. The extent of hypertrophy differs especially between the collectives. Measurement of endomysial connective tissue points to later postoperative course in the recipient. These findings may reflect a pattern of remodeling specific to the transplanted heart.

Even in developed countries, tuberculosis still contributes significantly to morbidity and mortality. The most frequent causative agent is Mycobacterium tuberculosis, while infections due to other mycobacterial species are usually associated with immunocompromised patients. In the following, we describe the case of a previously healthy man who underwent laparotomy for suspected adrenal carcinoma. Peritoneal "cancerous nodules" turned out to be tuberculous granulomas. After surgery the patient developed a protracted septic shock and died 6 days after surgery. Isolation and identification of the causative agent yielded Mycobacterium microti, an uncommon species of the M. tuberculosis complex. No other pathogen could be isolated during the clinical course, which finally led to the diagnosis of Landouzy septicemia (sepsis tuberculosa acutissima).

Using comparative genomic hybridisation, DNA copy number changes were investigated in 15 cases of pigmented villonodular synovitis of the knee joint. Additionally DNA content was analysed by flow cytometry. Screening revealed numerical chromosomal imbalances in five of the examined cases. A total number of 18 gains were detected. The most frequent gains involved subregions of chromosomal arms 22q and 16p and 16q. No losses were found. One of the cases showed an aneuploid DNA-pattern, which actually proved to be the case with the most numerical chromosomal changes.