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Background: STS is a very heterogeneous family of orphan malignancies, characterized by morphological and genetic diversity. Tissue samples from individual STS patients are commonly ...used for routine diagnostic and research purposes. TMAs from multiple sarcoma tissue blocks have potential advantages over conventional tissue analysis in terms of efficiency and cost-effectiveness. We have established a comprehensive sarcoma TMA research platform. Methods: TMAs were constructed using left-over tissue from STS patients diagnosed at University Hospitals Leuven (B), Leiden University Medical Center (NL) and University Hospital Zürich (CH), and from patients with orphan sarcomas enrolled in EORTC trial 90101 “CREATE”. The clinical cases are well annotated in terms of diagnosis, treatment and follow-up. Each TMA block contains duplicate/triplicate 1.0-1.5 mm tissue cores from representative areas selected by sarcoma pathologists. The construction of TMAs was performed using TMA Grand Master (3DHistech) at University of Bern (CH) and in Leiden (NL). Results: The following subtype-specific TMAs have been created: clear cell sarcoma (CCSA, 54 cases), alveolar soft part sarcoma (ASPS, 59), inflammatory myofibroblastic tumor (IMFT, 33), alveolar rhabdomyo- (24) and leiomyosarcoma (55). For CCSA, ASPS and IMFT we have matching TMAs from clinical routine and patients entered in EORTC 90101. As a tool for broader drug- and target-screening purposes in STS we also produced a multi-sarcoma TMA combining multiple, more common subtypes on one block: angio-, dedifferentiated, pleomorphic and myxoid lipo-, leiomyo-, myxofibro-, rhabdomyo-, synovial and undifferentiated pleomorphic sarcoma, and MPNST, with 7-11 individual cases per tumor type. TMA construction is ongoing in other relevant sarcoma subtypes. Conclusions: We are currently expanding a very useful TMA platform representing the broad heterogeneity of STS, from more common to ultra-rare variants. TMAs are available for rapid, cost-effective morphological, histochemical and molecular characterization and identification of novel drug targets in collaboration with academic and commercial partners.
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Background: STS is a family of rare, heterogeneous tumors with > 70 subtypes. There is an urgent need for reliable preclinical models, especially for orphan subtypes of STS, given ...the limited treatment options. Methods: A panel of PDX models was established by s.c. implantation of fresh tumor specimens in athymic NMRI mice. Growing pieces of tumor were re-transplanted to next generations of mice. At each passage fragments were collected for histological/molecular characterization. A model was considered “established” after observing stable features for at least 2 passages. Ex-mouse tissue samples were stored, characterized by immunohistochemistry/flow cytometry and used for in vitro drug testing. Results: Between 2011-2019, 329 samples from 301 consenting patients were transplanted; 56 models are established, 16 additional models are in early passaging. Clinical information about donor and tumor (including sensitivity to standard and experimental agents) is available. The platform includes models of dedifferentiated lipo- (10 models), myxofibro- (8), leiomyo- (7), synovial (2), intimal (2), CIC-positive round cell (1), mesenchymal chondro- (1), extraskeletal osteo- (1), myxoid lipo- (1), myxoinflammatory fibroblastic (1), rhabdomyo- (2) and high-grade undifferentiated pleomorphic sarcoma (7), as well as GIST (8), MPNST (4) and epithelioid hemangioendothelioma (1). Models are well-characterized, with molecular information on copy number changes (low-coverage whole genome sequencing) and gene expression profile (RNA-Seq) available. We also constructed tissue microarrays from the xenografts which are used for target identification and model selection for preclinical studies. Xenografts are available for in vivo testing of novel agents, and results already served as a rationale for a number of prospective clinical trials. Conclusions: XenoSarc offers opportunities for studying the biology of a variety of sarcoma subtypes including ultra-rare entities and is a valuable tool for early drug screening in preparation of clinical STS trials. The platform is well maintained and continuously expanded, and available to collaborators from academia and industry.
The objective of this exploratory, open-label, single-arm, phase II clinical trial was to evaluate plitidepsin (5 mg/m2) administered as a 3-hour continuous intravenous infusion every two weeks to ...patients with locally advanced/metastatic transitional cell carcinoma of the urothelium who relapsed/progressed after first-line chemotherapy. Treatment cycles were repeated for up to 12 cycles or until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. The primary efficacy endpoint was objective response rate according to RECIST. Secondary endpoints were the rate of SD lasting ≥6 months and time-to-event variables. Toxicity was assessed using NCI-CTC v. 3.0. Twenty-one patients received 57 treatment cycles. No objective tumor responses occurred. SD lasting <6 months was observed in two of 18 evaluable patients. With a median follow-up of 4.6 months, the median PFR and the median OS were 1.4 months and 2.3 months, respectively. The most common AEs were mild to moderate nausea, fatigue, myalgia and anorexia. Anemia, lymphopenia, and increases in transaminases, alkaline phosphatase and creatinine were the most frequent laboratory abnormalities. No severe neutropenia occurred. Treatment was feasible and generally well tolerated in this patient population; however the lack of antitumor activity precludes further studies of plitidepsin in this setting.
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Background/Aims:
Platelet production is regulated by thrombopoietin (TPO), which is primarily synthesized in the liver. The TPO in patients with liver diseases could possibly be owing to impaired ...hepatic TPO production. As we reported previously, TPO serum levels are not decreased in patients with liver diseases compared with healthy controls and do not depend on the stage of cirrhosis or platelet count, but are highly elevated in patients with chronic virus hepatitis.
Methods:
To study possible mechanisms, we measured hepatic TPO mRNA levels in liver tissue samples from 31 liver cirrhosis patients by quantitative TaqMan real‐time RT–PCR and corresponding serum TPO concentrations by ELISA.
Results:
Median TPO serum levels were elevated in patients with viral hepatitis (n = 12) compared with patients with a biliary (n = 10), alcoholic (n = 6) or other (n = 3) disease etiology, while hepatic TPO mRNA levels did not differ. The TPO mRNA levels in patients with chronic liver diseases were not different from normal liver tissue sample. The TPO mRNA and TPO serum level did not correlate.
Conclusions:
We conclude that hepatic TPO gene expression appears to be maintained on a constitutive transcriptional level in patients with liver diseases and does not change dependent on disease etiology.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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