15 results on '"Tania Roskams"'
Search Results
2. DNA methylation-driven EMT is a common mechanism of resistance to various therapeutic agents in cancer
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Jeroen Dekervel, Matthias Van Haele, Sarah Cappuyns, Eric Van Cutsem, Bernard Thienpont, Jos van Pelt, Tom Venken, Diether Lambrechts, Tania Roskams, Eva Galle, Chris Verslype, and Pieter Busschaert
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Sorafenib ,Carcinoma, Hepatocellular ,Epithelial-Mesenchymal Transition ,Methyltransferase ,Biology ,Circulating Tumor DNA ,Epigenesis, Genetic ,Liquid biopsies ,Metastasis ,chemistry.chemical_compound ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Epithelial–mesenchymal transition ,Enzyme Inhibitors ,Protein Kinase Inhibitors ,Molecular Biology ,Genetics (clinical) ,Cancer ,DNA methylation ,Research ,Liver Neoplasms ,Therapy resistance ,Methylation ,medicine.disease ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Epithelial-to-mesenchymal transition ,chemistry ,Drug Resistance, Neoplasm ,Azacitidine ,Cancer research ,DNA ,Developmental Biology ,medicine.drug - Abstract
Background Overcoming therapeutic resistance is one of the major hurdles in cancer care. One mechanism contributing to therapeutic resistance is a process in which epithelial cells switch to a mesenchymal state (epithelial-to-mesenchymal transition or EMT). The precise mechanisms driving EMT-mediated therapeutic resistance have, however, not been elucidated. Results Here, we study ten cell line pairs, for which parental cell lines were made resistant to either a targeted or chemotherapy-based treatment. First, we show by miRNA-200 overexpression that treatment resistance is driven by EMT. Next, we demonstrate that DNA methylation changes occur within each cell line pair and show that exposure to 5-azacytidine or knock down of DNA methyltransferases (DNMTs), both of which globally demethylate cells, result in EMT reversal and increased therapeutic sensitivity. This suggests DNA methylation to causally underlie EMT and treatment resistance. We also observe significant overlap in methylation profiles between resistant lines, suggesting a common epigenetic mechanism to cause resistance to therapy. In line with this hypothesis, cross-resistance to other targeted and chemotherapies is observed, while importantly, this is lost upon demethylation of the cells. Finally, we clinically validate that DNA methylation changes drive EMT-mediated resistance to sorafenib in patients with advanced hepatocellular carcinoma (HCC). Specifically, we develop a capture-based protocol to interrogate DNA methylation in low amounts of circulating tumor DNA (ctDNA). By interrogating the methylation status in liquid biopsies, longitudinally collected during sorafenib treatment, we assess whether DNA methylation changes also drive EMT and therapy resistance in a clinical setting. Particularly, by monitoring methylation changes in EMT genes, we are able to predict tumor response and acquired resistance to sorafenib. Conclusions We propose methylation changes underlying EMT to constitute a common resistance mechanism to cancer therapies. This process can be reversed pharmacologically and monitored non-invasively in ctDNA to predict resistance to treatment.
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- 2020
3. The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma
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Quentin M. Anstee, Michaela Petz, Yves-Paul Vandewynckel, Frederik Nevens, Wolfgang Mikulits, Tania Roskams, Baki Topal, Jasper Wouters, Emma Scott, Olivier Govaere, Chris Verslype, and Van Vlierberghe H
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0301 basic medicine ,Cancer Research ,Receptor, Platelet-Derived Growth Factor alpha ,CANCER GENOMICS ,Autoantigens ,Proto-Oncogene Mas ,ANGIOGENESIS ,Cohort Studies ,Mice ,chemistry.chemical_compound ,Piperidines ,Medicine and Health Sciences ,RNA, Small Interfering ,rho-Associated Kinases ,Biopsy, Needle ,Liver Neoplasms ,Hep G2 Cells ,Immunohistochemistry ,3. Good health ,Ribonucleoproteins ,IRES-MEDIATED TRANSLATION ,Gene Knockdown Techniques ,Disease Progression ,Female ,Original Article ,Integrin alpha2beta1 ,Signal transduction ,Tyrosine kinase ,Signal Transduction ,Proto-oncogene tyrosine-protein kinase Src ,Crenolanib ,EXPRESSION ,Carcinoma, Hepatocellular ,Biology ,03 medical and health sciences ,Growth factor receptor ,POOR-PROGNOSIS ,LIVER-DISEASE ,Proto-Oncogenes ,Biomarkers, Tumor ,Genetics ,Animals ,Humans ,Neoplasm Invasiveness ,RECURRENCE ,Protein kinase A ,Autocrine signalling ,Molecular Biology ,Keratin-19 ,MESENCHYMAL TRANSITION ,CYTOKERATIN-19 ,Survival Analysis ,Xenograft Model Antitumor Assays ,030104 developmental biology ,chemistry ,Tumor progression ,METASTASIS ,Immunology ,Cancer research ,Benzimidazoles ,Laminin ,Follow-Up Studies - Abstract
Human hepatocellular carcinomas (HCCs) expressing the biliary/hepatic progenitor cell marker keratin 19 (K19) have been linked with a poor prognosis and exhibit an increase in platelet-derived growth factor receptor α (PDGFRα) and laminin beta 1 (LAMB1) expression. PDGFRα has been reported to induce de novo synthesis of LAMB1 protein in a Sjogren syndrome antigen B (La/SSB)-dependent manner in a murine metastasis model. However, the role of this cascade in human HCC remains unclear. This study focused on the functional role of the PDGFRα-La/SSB-LAMB1 pathway and its molecular link to K19 expression in human HCC. In surgical HCC specimens from a cohort of 136 patients, PDGFRα expression correlated with K19 expression, microvascular invasion and metastatic spread. In addition, PDGFRα expression in pre-operative needle biopsy specimens predicted poor overall survival during a 5-year follow-up period. Consecutive histological staining demonstrated that the signaling components of the PDGFRα-La/SSB-LAMB1 pathway were strongly expressed at the invasive front. K19-positive HCC cells displayed high levels of α2β1 integrin (ITG) receptor, both in vitro and in vivo. In vitro activation of PDGFRα signaling triggered the translocation of nuclear La/SSB into the cytoplasm, enhanced the protein synthesis of LAMB1 by activating its internal ribosome entry site, which in turn led to increased secretion of laminin-111. This effect was abrogated by the PDGFRα-specific inhibitor crenolanib. Importantly LAMB1 stimulated ITG-dependent focal adhesion kinase/Src proto-oncogene non-receptor tyrosine kinase signaling. It also promoted the ITG-specific downstream target Rho-associated coiled-coil containing protein kinase 2, induced K19 expression in an autocrine manner, invadopodia formation and cell invasion. Finally, we showed that the knockdown of LAMB1 or K19 in subcutaneous xenograft mouse models resulted in significant loss of cells invading the surrounding stromal tissue and reduced HepG2 colonization into lung and liver after tail vein injection. The PDGFRα-LAMB1 pathway supports tumor progression at the invasive front of human HCC through K19 expression.Oncogene advance online publication, 7 August 2017; doi:10.1038/onc.2017.260. ispartof: Oncogene vol:36 issue:47 pages:6605-6616 ispartof: location:England status: published
- Published
- 2017
4. Endoscopic resection of ampullary lesions: a single-center 8-year retrospective cohort study of 91 patients with long-term follow-up
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David Cassiman, Schalk Van der Merwe, Raymond Aerts, Mina Komuta, Tania Roskams, Chris Verslype, Wim Laleman, Baki Topal, Annelies Verreth, Werner Van Steenbergen, and Frederik Nevens
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Adenoma ,Adult ,Male ,Ampulla of Vater ,medicine.medical_specialty ,Cholangitis ,medicine.medical_treatment ,Common Bile Duct Neoplasms ,Kaplan-Meier Estimate ,Postoperative Hemorrhage ,Gastroenterology ,Endosonography ,Pancreaticoduodenectomy ,Postoperative Complications ,Internal medicine ,Carcinoma ,Humans ,Medicine ,Aged ,Retrospective Studies ,Moderate Dysplasia ,Aged, 80 and over ,Cholangiopancreatography, Endoscopic Retrograde ,business.industry ,Ampullectomy ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Surgery ,Treatment Outcome ,Adenomatous Polyposis Coli ,Pancreatitis ,Dysplasia ,Female ,Stents ,Neoplasm Grading ,Neoplasm Recurrence, Local ,business ,Carcinoma in Situ ,Follow-Up Studies - Abstract
Endoscopic ampullectomy is established as a valuable treatment for adenomas of the Vaterian papilla. Few large series are available, however, let alone any with long-term follow-up. Moreover, multiple tangible issues remain. The aim of our study was to evaluate efficacy, safety, and outcome of endoscopic ampullectomy and compare it to existing literature This is a single-center, retrospective study with a minimal follow-up of 3 years including 91 patients, including familial adenomatous polyposis (FAP) and non-FAP, who had an endoscopic ampullectomy between 2000 and 2008. Outcome parameters included ampulloma characteristics, biotical accuracy as well as safety, efficacy, recurrence rate, and survival after endoscopic ampullectomy. Endoscopic resection was successful in 71 patients (78 %). Histological review of the resected specimens revealed nonspecific changes (13.8 %), low or medium grade dysplasia (52.9 %), high grade dysplasia (21.8 %) and carcinoma (18.3 %). Bioptic accuracy was 38.3 %. Overall complications were observed in 23 patients (25.2 %): pancreatitis (15.4 %), hemorrhage (12.1 %) and cholangitis (4.9 %). Recurrence occurred in 18.3 %. Fourteen patients underwent pancreaticoduodenectomy. Survival after complete endoscopic ampullectomy was excellent for patients with low to moderate grade dysplasia and high grade dysplasia. Incomplete endoscopic resection of high grade dysplasia or invasive carcinoma was associated with unfavorable outcome when treated merely endoscopically. Endoscopic ampullectomy is obligatory for assessment of the true histological nature of an ampulloma. Endoscopic resection is a safe and efficient procedure for adenomas with low to moderate dysplasia but also for high grade dysplastic lesions, provided that a complete endoscopic resection is achieved.
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- 2013
5. Minimally invasive liver surgery for metastases from colorectal cancer: oncologic outcome and prognostic factors
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Raymond Aerts, Tania Roskams, Eric Van Cutsem, Hans Prenen, Baki Topal, Steffen Fieuws, and Joyce Tiek
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Male ,Liver surgery ,medicine.medical_specialty ,Proportional hazards model ,Colorectal cancer ,Systemic chemotherapy ,business.industry ,Liver Neoplasms ,Hepatology ,medicine.disease ,Independent predictor ,Surgery ,Internal medicine ,medicine ,Overall survival ,Hepatectomy ,Humans ,Female ,Laparoscopy ,Human medicine ,Colorectal Neoplasms ,business ,Abdominal surgery - Abstract
Background Few reports exist on long-term survival after minimally invasive liver surgery (MILS) for colorectal liver metastases (CRLM). No data are available assessing prognostic factors in the era of current modern treatment strategies. Methods Between October 2002 and December 2008, 274 consecutive patients were analyzed on an intention-to-treat basis. Open liver surgery (OLS) was performed in 193 patients for a total of 437 metastases, and MILS was performed in 81 patients for 176 metastases. Systemic chemotherapy was administered preoperatively in 173 and postoperatively in 174 patients. The impact of 23 potential prognostic factors on disease-free (DFS) and overall survival (OS) was evaluated using univariable and multivariable Cox regression models. Results Postoperative complications were observed in 54 patients after OLS and in 11 after MILS (p = 0.016). The median postoperative length of hospital stay was 9 days after OLS and 5 days after MILS (p < 0.0001). For the entire patient population, the 5 year DFS and OS rates were 29.9 and 59.5%, respectively. No differences in survival between patients treated with MILS and OLS were observed (p = 0.63). In univariable analyses, the number of liver metastases and the overall Fong’s clinical risk score (CRS) were the only two variables that predicted DFS (p ≤ 0.0035) and OS (p ≤ 0.0005). In multivariable analyses, the total CRS was the only independent predictor of both DFS (p = 0.0002) and OS (p = 0.002). Conclusion The long-term oncologic outcome of surgically treated patients with CRLM is determined by the Fong’s CRS. Although MILS does not influence long-term survival, it has a beneficial impact on the immediate postoperative clinical outcome.
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- 2012
6. Clinical diagnosis and staging of cholangiocarcinoma
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Tania Roskams, Gregory J. Gores, Mina Komuta, and Boris Blechacz
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medicine.medical_specialty ,Hepatology ,business.industry ,General surgery ,Gastroenterology ,Bile Duct Neoplasm ,Prognosis ,digestive system ,Article ,digestive system diseases ,Cholangiocarcinoma ,Biliary malignancy ,Extrahepatic Cholangiocarcinoma ,Critical appraisal ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,Biliary tract ,Clinical diagnosis ,medicine ,Humans ,Stage (cooking) ,Anatomic Location ,business ,neoplasms ,Neoplasm Staging - Abstract
Cholangiocarcinoma is the most frequent biliary malignancy. It is difficult to diagnose owing to its anatomic location, growth patterns and lack of definite diagnostic criteria. Currently, cholangiocarcinoma is classified into the following types according to its anatomic location along the biliary tree: intrahepatic, perihilar or distal extrahepatic cholangiocarcinoma. These cholangiocarcinoma types differ in their biological behavior and management. The appropriate stratification of patients with regard to the anatomic location and stage of cholangiocarcinoma is a key determinate in their management. Staging systems can guide this stratification and provide prognostic information. In addition, staging systems are essential in order to compare and contrast the outcomes of different therapeutic approaches. A number of staging systems exist for cholangiocarcinoma-several early ones have been updated, and new ones are being developed. We discuss the emerging diagnostic criteria as well as the different staging systems for cholangiocarcinoma, and provide a critical appraisal regarding these advances in biliary tract malignancies.
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- 2011
7. Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis
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Tania Roskams, Francesco Cappello, Maelle Morgan, Valerio Pazienza, Francesca Rappa, Jude A. Oben, Gianluigi Mazzoccoli, Daniela Cabibi, Chad McKee, Claire Selden, Manlio Vinciguerra, J Soeda, Barbara Sigala, A Mouralidarane, Mckee, C., Sigala, B., Soeda, J., Mouralidarane, A., Morgan, M., Mazzoccoli, G., Rappa, F., Cappello, F., Cabibi, D., Pazienza, V., Selden, C., Roskams, T., Vinciguerra, M., and Oben, J.
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medicine.medical_specialty ,Biopsy ,Gene Expression ,ADAM17 Protein ,Biology ,Amphiregulin ,Severity of Illness Index ,p38 Mitogen-Activated Protein Kinases ,digestive system ,Article ,Mice ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Growth factor receptor ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,Hepatic Stellate Cells ,medicine ,Animals ,Humans ,Protein Kinase C ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Fatty liver ,nutritional and metabolic diseases ,medicine.disease ,Fibrosis ,Actins ,digestive system diseases ,3. Good health ,Enzyme Activation ,ErbB Receptors ,ADAM Proteins ,Disease Models, Animal ,Endocrinology ,Hepatic stellate cell ,Cancer research ,030211 gastroenterology & hepatology ,Tumor necrosis factor alpha ,Collagen ,Steatohepatitis ,Signal Transduction - Abstract
Amphiregulin (AR) involvement in liver fibrogenesis and hepatic stellate cells (HSC) regulation is under study. Non-alcoholic fatty liver disease (NAFLD) and its more severe form non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular cancer (HCC). Our aim was to investigate ex vivo the effect of AR on human primary HSC (hHSC) and verify in vivo the relevance of AR in NAFLD fibrogenesis. hHSC isolated from healthy liver segments were analyzed for expression of AR and its activator, TNF-α converting enzyme (TACE). AR induction of hHSC proliferation and matrix production was estimated in the presence of antagonists. AR involvement in fibrogenesis was also assessed in a mouse model of NASH and in humans with NASH. hHSC time dependently expressed AR and TACE. AR increased hHSC proliferation through several mitogenic signaling pathways such as EGFR, PI3K and p38. AR also induced marked upregulation of hHSC fibrogenic markers and reduced hHSC death. AR expression was enhanced in the HSC of a murine model of NASH and of severe human NASH. In conclusion, AR induces hHSC fibrogenic activity via multiple mitogenic signaling pathways and is upregulated in murine and human NASH, suggesting that AR antagonists may be clinically useful anti-fibrotics in NAFLD.
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- 2015
8. Liver stem cells and their implication in hepatocellular and cholangiocarcinoma
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Tania Roskams
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Cancer Research ,Carcinoma, Hepatocellular ,Stem Cells ,Liver Neoplasms ,Cancer ,Liver Stem Cell ,Biology ,medicine.disease ,Cholangiocarcinoma ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,Liver ,Canals of Hering ,Hepatocellular carcinoma ,Genetics ,medicine ,Cancer research ,Humans ,Steatohepatitis ,Stem cell ,Progenitor cell ,Liver cancer ,Molecular Biology - Abstract
In the liver, several cell types have the longevity that is needed to be the cell of origin of a cancer: hepatocytes, cholangiocytes and progenitor cells. The latter are located in the most peripheral branches of the biliary tree, the ductules and canals of Hering. The most important risk factors for liver cancer are chronic viral hepatitis B and C and alcoholic and non-alcoholic steatohepatitis. In these and other chronic liver diseases, progenitor cell activation is seen, rendering them a target cell population for carcinogenesis. The degree of activation is positively correlated with the inflammatory activity and the stage of the disease. Recently, it has been shown that in the cirrhotic stage of most chronic liver diseases, the hepatocytes become senescent owing to telomere shortening. This makes it even more plausible that at least part of the hepatocellular carcinomas originate from a progenitor cell. Hepatocellular carcinomas expressing progenitor cell/ductular markers like cytokeratin 19 have a more aggressive clinical course. It is therefore important to recognize this entity.
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- 2006
9. Expression of neural cell adhesion molecule in human liver development and in congenital and acquired liver diseases
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Tania Roskams, David Cassiman, Valeer Desmet, and Louis Libbrecht
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Pathology ,medicine.medical_specialty ,Histology ,Intrahepatic bile ducts ,Biology ,Cytokeratin ,Biliary atresia ,medicine ,Humans ,Neural Cell Adhesion Molecules ,Molecular Biology ,Fibrous capsule of Glisson ,Bile duct ,Liver Diseases ,Infant ,Cell Biology ,medicine.disease ,Immunohistochemistry ,Ductal Plate Malformation ,Medical Laboratory Technology ,medicine.anatomical_structure ,Liver ,nervous system ,Child, Preschool ,Hepatic stellate cell ,Neural cell adhesion molecule ,Biomarkers - Abstract
In the liver, neural cell adhesion molecule (NCAM) is a marker of immature cells committed to the biliary lineage and is expressed by reactive bile ductules in human liver diseases. We investigated the possible role of NCAM in the development of intrahepatic bile ducts and aimed at determining whether immature biliary cells can contribute to the repair of damaged bile ducts in chronic liver diseases. Therefore, we performed immunohistochemistry for NCAM and bile duct cell markers cytokeratin 7 and cytokeratin 19 on frozen sections of 85 liver specimens taken from 14 fetuses, 10 donor livers, 18 patients with congenital liver diseases characterized by ductal plate malformations (DPMs), and 43 cirrhotic explant livers. Duplicated ductal plates and incorporating bile ducts during development showed a patchy immunoreactivity for NCAM, while DPMs were continuously positive for NCAM. Bile ducts showing complete or patchy immunoreactivity for NCAM were found in cirrhotic livers, with higher frequency in biliary than in posthepatitic cirrhosis. Our results suggest that NCAM may have a function in the development of the intrahepatic bile ducts and that NCAM-positive immature biliary cells can contribute to the repair of damaged bile ducts in chronic liver diseases.
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- 2001
10. Epithelioid hemangioendothelioma of the liver
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L Van Hoe, Piet K. Vanhoenacker, D'Haenens P, Tania Roskams, and K. Mermuys
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medicine.medical_specialty ,Pathology ,Radiological and Ultrasound Technology ,medicine.diagnostic_test ,business.industry ,Urology ,Gastroenterology ,Radiologic pathologic correlation ,Magnetic resonance imaging ,General Medicine ,Hepatology ,medicine.disease ,Hemangioendothelioma ,Lesion ,Internal medicine ,Biopsy ,medicine ,Radiology, Nuclear Medicine and imaging ,Radiology ,Differential diagnosis ,medicine.symptom ,business ,Epithelioid hemangioendothelioma - Abstract
Epithelioid hemangioendothelioma of the liver is a rare vascular tumor with intermediate malignant potential. On imaging studies, the lesion has a solid appearance and may mimic metastatic disease. We present a case in which the morphologic features (multifocal aspect, peripheral location, and capsular retraction) and the clinical history aided in including this entity in the differential diagnosis.
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- 2004
11. Bilateral xanthogranulomatous perinephritis without renal parenchymal involvement
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J. Verhelle, Go Verswijvel, J. Stagier, Tania Roskams, and R. H. Oyeit
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Male ,medicine.medical_specialty ,Diagnosis, Differential ,Xanthomatosis ,medicine ,Humans ,Retroperitoneal space ,Radiology, Nuclear Medicine and imaging ,Ultrasonography ,Neuroradiology ,Granuloma ,medicine.diagnostic_test ,business.industry ,Perinephritis ,Ultrasound ,Soft tissue ,Interventional radiology ,Magnetic resonance imaging ,General Medicine ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Radiology ,Differential diagnosis ,Tomography, X-Ray Computed ,business - Abstract
A case of isolated bilateral xanthogranulomatous perinephritis, which presented as a symmetrical irregular perirenal rim of soft tissue, is reported. Differential diagnosis and image features on ultrasound, computed tomography, and magnetic resonance are discussed.
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- 2000
12. Infantile Onset Panniculitis with Uveitis and Systemic Granulomatosis: immunohistochemical findings
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B. Bader Meunier, Tania Roskams, Dorothee Stichweh, Carine Wouters, Carlos D. Rose, Tammy M. Martin, Pierre Quartier, and Marilynn Punaro
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medicine.medical_specialty ,Pathology ,lcsh:Diseases of the musculoskeletal system ,Hepatosplenomegaly ,Arthritis ,Rheumatology ,Internal medicine ,Immunology and Allergy ,Medicine ,Pediatrics, Perinatology, and Child Health ,Lymph node ,Autoimmune disease ,Lung ,business.industry ,lcsh:RJ1-570 ,lcsh:Pediatrics ,medicine.disease ,medicine.anatomical_structure ,Poster Presentation ,Pediatrics, Perinatology and Child Health ,lcsh:RC925-935 ,medicine.symptom ,business ,Panniculitis ,Uveitis - Abstract
Infantile-Onset Panniculitis with Systemic Granulomatosis is a recently described clinicopathologic entity, considered part of the spectrum of pediatric granulomatous inflammatory diseases. Through the International Registry of Pediatric Granulomatous Arthritis (PGA), we now identified 5 children with this disorder, all manifesting from very young age panniculitis, fever, hepatosplenomegaly, arthritis, uveitis and acute phase response. Underlying infections, immune deficiency and autoimmune disease, were excluded. No CARD15 or CIAS1 mutations were found. Histologically, the subcutaneous nodules showed a non-vasculitic non-cytophagic lobular panniculits. Giant and epitheloid cell granulomas were found in liver (pt 1, 5), synovium (pt 2), lymph node (pt 3, 5), colon (pt 3), subcutaneous fat (pt 3), dermis and lung (pt 4). Immunohistochemical study of the granulomas revealed the presence of abundant CD68+ macrophages, numerous CD4+ T lymphocytes and few CD8+ cells. TNF stainings were only weakly positive, conversely abundant IL-6 staining was apparent, especially in the corona of lymphocytes. Despite steroid and cyclosporin treatment, the course was progressive in patient 1 with severe lung involvement and death from respiratory insufficiency at age 14. In patients 2, 3, 4 and 5, therapy with anti-TNF MoAbs allowed better disease control. Infantile onset Panniculitis with Systemic Granulomatosis may be a potentially fatal granulomatous disease in children. Although the response to anti-TNF MoAbs in four of our patients is of note, the paucity of TNF with overwhelming presence of IL-6 in situ in granulomas suggest the implication of alternative immune-inflammatory pathways. The role of the Th17 pthway is currently under investigation
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- 2008
13. Major HGF-mediated regenerative pathways are similarly affected in human and canine cirrhosis
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Tania Roskams, Brigitte Arends, Louis C. Penning, Bart Spee, Jan Rothuizen, and Ted S.G.A.M. van den Ingh
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Hepatitis ,Alcoholic liver disease ,medicine.medical_specialty ,Pathology ,Cirrhosis ,Hepatology ,Human liver ,business.industry ,Research ,Lobular dissecting hepatitis ,medicine.disease ,Gastroenterology ,Liver disease ,Internal medicine ,medicine ,business ,Acute hepatitis - Abstract
Background The availability of non-rodent animal models for human cirrhosis is limited. We investigated whether privately-owned dogs (Canis familiaris) are potential model animals for liver disease focusing on regenerative pathways. Several forms of canine hepatitis were examined: Acute Hepatitis (AH), Chronic Hepatitis (CH), Lobular Dissecting Hepatitis (LDH, a specific form of micronodulair cirrhosis), and Cirrhosis (CIRR). Canine cirrhotic samples were compared to human liver samples from cirrhotic stages of alcoholic liver disease (hALC) and chronic hepatitis C infection (hHC). Results Canine specific mRNA expression of the regenerative hepatocyte growth factor (HGF) signaling pathway and relevant down-stream pathways were measured by semi-quantitative PCR and Western blot (STAT3, PKB, ERK1/2, and p38-MAPK). In all canine groups, levels of c-MET mRNA (proto-oncogenic receptor for HGF) were significantly decreased (p < 0.05). Surprisingly, ERK1/2 and p38-MAPK were increased in CH and LDH. In the human liver samples Western blotting indicated a high homology of down-stream pathways between different etiologies (hALC and hHC). Similarly activated pathways were found in CIRR, hALC, and hHC. Conclusion In canine hepatitis and cirrhosis the major regenerative downstream pathways were activated. Signaling pathways are similarly activated in human cirrhotic liver samples, irrespective of the differences in etiology in the human samples (alcohol abuse and HCV-infection). Therefore, canine hepatitis and cirrhosis could be an important clinical model to evaluate novel interventions prior to human clinical trials.
- Published
- 2007
14. Morphological characterisation of portal myofibroblasts and hepatic stellate cells in the normal dog liver
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Jooske IJzer, Ted S.G.A.M. van den Ingh, Louis C. Penning, Tania Roskams, Jan Rothuizen, Ton Ultee, and Ronald F Molenbeek
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Pathology ,medicine.medical_specialty ,Hepatology ,biology ,Glial fibrillary acidic protein ,business.industry ,Research ,Perisinusoidal space ,Synaptophysin ,biology.protein ,Hepatic stellate cell ,Medicine ,Desmin ,Hepatic fibrosis ,business ,Myofibroblast ,Immunostaining - Abstract
Background Hepatic fibrosis is a common outcome of hepatic injury in both man and dog. Activated fibroblasts which develop myofibroblastic characteristics play an essential role in hepatic fibrogenesis, and are comprised of three subpopulations: 1) portal or septal myofibroblasts, 2) interface myofibroblasts and 3) the perisinusoidally located hepatic stellate cells (HSC). The present study was performed to investigate the immunohistochemical characteristics of canine portal myofibroblasts (MF) and HSC in the normal unaffected liver as a basis for further studies on fibrogenesis in canine liver disease. Results In the formalin-fixed and paraffin embedded normal canine liver vimentin showed staining of hepatic fibroblasts, probably including MF in portal areas and around hepatic veins; however, HSC were in general negative. Desmin proved to react with both portal MF and HSC. A unique feature of these HSC was the positive immunostaining for alpha-smooth muscle actin (α-SMA) and muscle-specific actin clone HHF35 (HHF35), also portal MF stained positive with these antibodies. Synaptophysin and glial fibrillary acidic protein (GFAP) were consistently negative in the normal canine liver. In a frozen chronic hepatitis case (with expected activated hepatic MF and HSC), HSC were negative to synaptophysin, GFAP and NCAM. Transmission electron microscopy (TEM) immunogold labelling for α-SMA and HHF35 recognized the positive cells as HSC situated in the space of Disse. Conclusion In the normal formalin-fixed and paraffin embedded canine liver hepatic portal MF and HSC can be identified by α-SMA, HHF35 and to a lesser extent desmin immunostaining. These antibodies can thus be used in further studies on hepatic fibrosis. Synaptophysin, GFAP and NCAM do not seem suitable for marking of canine HSC. The positivity of HSC for α-SMA and HHF35 in the normal canine liver may eventually reflect a more active regulation of hepatic sinusoidal flow by these HSC compared to other species.
- Published
- 2006
15. A solitary hepatic lesion: MRI-pathological correlation of an hepatic angiomyolipoma (2004:4b)
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Didier Bielen, F Ballaux, Tania Roskams, Dirk Vanbeckevoort, M Simoens, L Roex, S Allewaert, Y De Bruecker, and Raymond Aerts
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medicine.medical_specialty ,Pathology ,Angiomyolipoma ,Adenoma ,Lesion ,Humans ,Medicine ,Myocyte ,Radiology, Nuclear Medicine and imaging ,medicine.diagnostic_test ,business.industry ,Liver Neoplasms ,Echogenicity ,Magnetic resonance imaging ,General Medicine ,Anatomy ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Dynamic contrast-enhanced MRI ,Female ,Radiology ,medicine.symptom ,business ,Epithelioid cell - Abstract
A 62-year-old woman presented with a 3-month history of increasing epigastric pain. Physical examination and laboratory findings revealed no abnormalities. Upper abdominal ultrasound revealed an echogenic mass in liver segment 2, 4 cm in diameter (Fig. 1). On MRI the well-circumscribed lesion was slightly hyperintense on the T1and clearly hyperintense on the T2-weighted images. A rim surrounded the lesion, which was hypointense on the T1and isoto slightly hyperintense on the T2-weighted images (Fig. 2). There was a decrease in signal intensity all over the lesion on the out-of-phase gradient-echo images compared with the equivalent in-phase images (Fig. 3). Dynamic MRI with GdDTPA was performed and showed a heterogeneous slightly hypervascular pattern of the lesion. There was only slight enhancement of the previously described hypointense-T1 rim (Fig. 4). Left lateral segmentectomy was performed. Histological examination of the specimen revealed a tumour with a large amount of adipocytes (75%), blood vessels and smooth muscle. The muscle cells were partly of epithelioid type. Immunohistochemical examination with antibodies directed against HMB-45 and NKIC3 was positive in the epithelioid cells. The adipocytes were stained with S100, the vessels with CD34 and the smooth muscle cells with actin (and SMA). The absence of prekeratin staining (epithelial marker) in the tumour cells excluded a steatotic adenoma. A rim of atrophic hepatic tissue and dilated sinusoids (Fig. 5) surrounded the tumour. The patient's clinical condition was perfect after a follow-up period of 6 months.
- Published
- 2004
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