Karel Caca
Leipzig University
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Publication
Featured researches published by Karel Caca.
The New England Journal of Medicine | 2010
Juan Carlos García-Pagán; Karel Caca; Christophe Bureau; Wim Laleman; Beate Appenrodt; Angelo Luca; Juan G. Abraldes; Frederik Nevens; Jean Pierre Vinel; Joachim Mössner; Jaime Bosch
BACKGROUND Patients with cirrhosis in Child-Pugh class C or those in class B who have persistent bleeding at endoscopy are at high risk for treatment failure and a poor prognosis, even if they have undergone rescue treatment with a transjugular intrahepatic portosystemic shunt (TIPS). This study evaluated the earlier use of TIPS in such patients. METHODS We randomly assigned, within 24 hours after admission, a total of 63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy to treatment with a polytetrafluoroethylene-covered stent within 72 hours after randomization (early-TIPS group, 32 patients) or continuation of vasoactive-drug therapy, followed after 3 to 5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapy-EBL group, 31 patients). RESULTS During a median follow-up of 16 months, rebleeding or failure to control bleeding occurred in 14 patients in the pharmacotherapy-EBL group as compared with 1 patient in the early-TIPS group (P=0.001). The 1-year actuarial probability of remaining free of this composite end point was 50% in the pharmacotherapy-EBL group versus 97% in the early-TIPS group (P<0.001). Sixteen patients died (12 in the pharmacotherapy-EBL group and 4 in the early-TIPS group, P=0.01). The 1-year actuarial survival was 61% in the pharmacotherapy-EBL group versus 86% in the early-TIPS group (P<0.001). Seven patients in the pharmacotherapy-EBL group received TIPS as rescue therapy, but four died. The number of days in the intensive care unit and the percentage of time in the hospital during follow-up were significantly higher in the pharmacotherapy-EBL group than in the early-TIPS group. No significant differences were observed between the two treatment groups with respect to serious adverse events. CONCLUSIONS In these patients with cirrhosis who were hospitalized for acute variceal bleeding and at high risk for treatment failure, the early use of TIPS was associated with significant reductions in treatment failure and in mortality. (Current Controlled Trials number, ISRCTN58150114.)
Liver International | 2003
Peter Ferenci; Karel Caca; Georgios Loudianos; Georgina Mieli-Vergani; Stuart Tanner; Irmin Sternlieb; Michael L. Schilsky; Diane W. Cox; Frieder Berr
Wilson disease is an inherited autosomal recessive disorder of hepatic copper metabolism leading to copper accumulation in hepatocytes and in extrahepatic organs such as the brain and the cornea. Originally Wilson disease was described as a neurodegerative disorder associated with cirrhosis of the liver. Later, Wilson disease was observed in children and adolescents presenting with acute or chronic liver disease without any neurologic symptoms. While diagnosis of neurologic Wilson disease is straightforward, it may be quite difficult in non‐neurologic cases. Up to now, no single diagnostic test can exclude or confirm Wilson disease with 100% certainty. In 1993, the gene responsible for Wilson disease was cloned and localized on chromosome 13q14.3 (MIM277900) ( 1, 2 ). The Wilson disease gene ATP7B encodes a P‐type ATPase. More than 200 disease causing mutations of this gene have been described so far ( 3 ). Most of these mutations occur in single families, only a few are more frequent (like H1069Q, 3400delC and 2299insC in Caucasian ( 4–6 ) or R778L in Japanese ( 7 ), Chinese and Korean patients). Studies of phenotype‐genotype relations are hampered by the lack of standard diagnostic criteria and phenotypic classifications. To overcome this problem, a working party discussed these problems in depth at the 8th International Meeting on Wilson disease and Menkes disease in Leipzig/Germany (April 16–18, 2001) 2 . After the meeting, a preliminary draft of a consensus report was mailed to all active participants and their comments were incorporated in the final text.
American Journal of Pathology | 1999
David L. Rimm; Karel Caca; Gang Hu; Frank B. Harrison; Eric R. Fearon
Beta-Catenin has a critical role in E-cadherin-mediated cell-cell adhesion, and it also functions as a downstream signaling molecule in the wnt pathway. Mutations in the putative glycogen synthase kinase 3beta phosphorylation sites near the beta-catenin amino terminus have been found in some cancers and cancer cell lines. The mutations render beta-catenin resistant to regulation by a complex containing the glycogen synthase kinase 3beta, adenomatous polyposis coli, and axin proteins. As a result, beta-catenin accumulates in the cytosol and nucleus and activates T-cell factor/ lymphoid enhancing factor transcription factors. Previously, 6 of 27 melanoma cell lines were found to have beta-catenin exon 3 mutations affecting the N-terminal phosphorylation sites (Rubinfeld B, Robbins P, Elgamil M, Albert I, Porfiri E, Polakis P: Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997, 275:1790-1792). To assess the role of beta-catenin defects in primary melanomas, we undertook immunohistochemical and DNA sequencing studies in 65 melanoma specimens. Nuclear and/or cytoplasmic localization of beta-catenin, a potential indicator of wnt pathway activation, was seen focally within roughly one third of the tumors, though a clonal somatic mutation in beta-catenin was found in only one case (codon 45 Ser-->Pro). Our findings demonstrate that beta-catenin mutations are rare in primary melanoma, in contrast to the situation in melanoma cell lines. Nonetheless, activation of beta-catenin, as indicated by its nuclear and/or cytoplasmic localization, appears to be frequent in melanoma, and in some cases, it may reflect focal and transient activation of the wnt pathway within the tumor.
Annals of Surgery | 2006
Helmut Witzigmann; Frieder Berr; Ulrike Ringel; Karel Caca; Dirk Uhlmann; Konrad Schoppmeyer; Andrea Tannapfel; Christian Wittekind; Joachim Mössner; Johann Hauss; Marcus Wiedmann
Objective:First, to analyze the strategy for 184 patients with hilar cholangiocarcinoma seen and treated at a single interdisciplinary hepatobiliary center during a 10-year period. Second, to compare long-term outcome in patients undergoing surgical or palliative treatment, and third to evaluate the role of photodynamic therapy in this concept. Summary Background Data:Tumor resection is attainable in a minority of patients (<30%). When resection is not possible, radiotherapy and/or chemotherapy have been found to be an ineffective palliative option. Recently, photodynamic therapy (PDT) has been evaluated as a palliative and neoadjuvant modality. Methods:Treatment and outcome data of 184 patients with hilar cholangiocarcinoma were analyzed prospectively between 1994 and 2004. Sixty patients underwent resection (8 after neoadjuvant PDT); 68 had PDT in addition to stenting and 56 had stenting alone. Results:The 30-day death rate after resection was 8.3%. Major complications occurred in 52%. The overall 1-, 3-, and 5-year survival rates were 69%, 30%, and 22%, respectively. R0, R1, and R2 resection resulted in 5-year survival rates of 27%, 10%, and 0%, respectively. Multivariate analysis identified R0 resection (P < 0.01), grading (P < 0.05), and on the limit to significance venous invasion (P = 0.06) as independent prognostic factors for survival. PDT and stenting resulted in longer median survival (12 vs. 6.4 months, P < 0.01), lower serum bilirubin levels (P < 0.05), and higher Karnofsky performance status (P < 0.01) as compared with stenting alone. Median survival after PDT and stenting, but not after stenting alone, did not differ from that after both R1 and R2 resection. Conclusion:Only complete tumor resection, including hepatic resection, enables long-term survival for patients with hilar cholangiocarcinoma. Palliative PDT and subsequent stenting resulted in longer survival than stenting alone and has a similar survival time compared with incomplete R1 and R2 resection. However, these improvements in palliative treatment by PDT will not change the concept of an aggressive resectional approach.
American Journal of Pathology | 2001
Takao Hinoi; Masachika Tani; Peter C. Lucas; Karel Caca; Rodney L. Dunn; Ettore Macri; Massimo Loda; Henry D. Appelman; Kathleen R. Cho; Eric R. Fearon
Most large bowel cancers are moderately to well-differentiated adenocarcinomas comprised chiefly or entirely of glands lined by tall columnar cells. We have identified a subset of poorly differentiated colon carcinomas with a distinctive histopathological appearance that we term large cell minimally differentiated carcinomas (LCMDCs). These tumors likely include a group of poorly differentiated carcinomas previously described by others as medullary adenocarcinomas. To better understand the pathogenesis of these uncommon neoplasms, we compared molecular features of 15 LCMDCs to those present in 25 differentiated adenocarcinomas (DACs) of the colon. Tumors were examined for alterations commonly seen in typical colorectal carcinomas, including increased p53 and beta-catenin immunoreactivity, K-ras gene mutations, microsatellite instability, and loss of heterozygosity of markers on chromosomes 5q, 17p, and 18q. In addition, tumors were evaluated by immunohistochemistry for CDX2, a homeobox protein whose expression in normal adult tissues is restricted to intestinal and colonic epithelium. Markedly reduced or absent CDX2 expression was noted in 13 of 15 (87%) LCMDCs, whereas only 1 of the 25 (4%) DACs showed reduced CDX2 expression (P < 0.001). Nine of 15 (60%) LCMDCs had the high-frequency microsatellite instability phenotype, but only 2 of 25 (8%) DACs had the high-frequency microsatellite instability phenotype (P = 0.002). Our findings provide support for the hypothesis that the molecular pathogenesis of LCMDCs is distinct from that of most DACs. CDX2 alterations and DNA mismatch repair defects have particularly prominent roles in the development of LCMDCs.
Journal of Hepatology | 2012
Juan Carlos García-Pagán; Marco Di Pascoli; Karel Caca; Wim Laleman; Cristophe Bureau; Beate Appenrodt; Angelo Luca; Alexander Zipprich; Juan G. Abraldes; Frederik Nevens; Jean Pierre Vinel; Tilman Sauerbruch; Jaime Bosch
BACKGROUND & AIMS In a recent randomized international clinical trial (RCT) in high-risk cirrhotic patients with acute variceal bleeding, the early use of transjugular intrahepatic portosystemic shunt (TIPS) was associated with marked and significant reductions in both treatment failure and mortality. The aim of this study was to confirm these results in clinical practice in the same centers of the RCT study. METHODS We retrospectively reviewed patients admitted for acute variceal bleeding and high risk of treatment failure (Child C <14 or Child B plus active bleeding), treated with early-TIPS (n=45) or drugs+endoscopic therapy (ET) (n=30). RESULTS Patients treated with early-TIPS had a much lower incidence of failure to control bleeding or rebleeding than patients receiving drug+ET (3 vs. 15; p <0.001). The 1-year actuarial probability of remaining free of this composite end point was 93% vs. 53% (p <0.001). The same was observed in mortality (1-year actuarial survival was 86% vs. 70% respectively; p=0.056). Actuarial curves of failure to control bleeding+rebleeding and of survival were well within the confidence intervals of those observed in the RCT. CONCLUSIONS This study supports the early use of TIPS in patients with cirrhosis and a high-risk variceal bleeding.
Journal of Hepatology | 2001
Karel Caca; Peter Ferenci; Hans-Jürgen Kühn; Claudia Polli; Helmut Willgerodt; Bernhard Kunath; W. Hermann; Joachim Mössner; Frieder Berr
BACKGROUND/AIMS Wilson disease is caused by a large number of different mutations in the ATP7B gene. Wilson disease patients from a homogeneous ethnical background (Saxonia) were studied for distribution and phenotypes of ATP7B mutations. METHODS Eighty-two patients were analyzed. The H1069Q mutation was assayed by a polymerase chain reaction-based restriction fragment length polymorphism test. Exons 8 and 15 were sequenced in all, and the entire gene in 30, non-H1069Q-homozygotes. RESULTS Four novel and 12 known mutations were found. Thirty-two (39%) Wilson disease patients were homozygous and 39 (48%) heterozygous for the H1069Q mutation (allele frequency 63%). Together with sequence analysis of exons 8 and 15 mutations in both alleles were identified in 65% of patients. Only one patient had both mutations at other locations. In H1069Q homozygotes symptoms started later (21.3+/-7.2 years) than in H1069Q compound heterozygotes (14.6+/-5.8, P<0.001) or H1069Q negatives (10+/-4.4, P<0.001), and they had more frequently neurologic symptoms (93 vs. 47%, P<0.001) and Kayser-Fleischer rings (82 vs. 51%, P<0.001). Mutation status did not correlate with liver biopsy findings, serum ceruloplasmin levels or (64)Cu-assay results. CONCLUSIONS In spite of many known ATP7B mutations, only few occur in this homogeneous population. Limited genetic testing is useful to confirm Wilson disease in this population.
Gut | 2005
I Schiefke; A Zabel-Langhennig; S Neumann; J Feisthammel; J Moessner; Karel Caca
Introduction: Endoluminal gastroplication (EndoCinch; Bard) has been introduced as an endoscopic treatment option in gastro-oesophageal reflux disease (GORD) patients with promising short term results. However, little is known about the long term efficacy of endoscopic suturing. The aim of this study was to evaluate prospectively the long term outcome after EndoCinch. Patients and methods: A total of 70 patients treated with EndoCinch at a single referral centre were studied prospectively. All patients were interviewed using a standardised questionnaire regarding their symptoms and medication prior to and 18 months after EndoCinch. In addition, follow up included endoscopy, 24 hour pH monitoring, and oesophageal manometry. Results: The procedure was well tolerated without major short or long term complications. Eighteen months after EndoCinch, 56/70 patients (80%) were considered treatment failures as their heartburn symptoms did not improve or proton pump inhibitor medication exceeded 50% of the initial dose. Endoscopy showed all sutures in situ in 12/70 (17%) patients while no remaining sutures could be detected in 18/70 (26%). In 54 and 50 patients examined, respectively, no significant changes in 24 hour pH monitoring (median pH <4/24 hours, 9.1% v 8.5%; p = 0.82) or lower oesophageal sphincter (LOS) pressure (7.7 v 10.3 mm Hg; p = 0.051) were observed while median LOS length slightly increased (3.0 to 3.2 cm; p<0.05). Conclusion: Endoscopic gastroplication (EndoCinch) is a safe and minimally invasive endoscopic treatment for GORD with reasonable short term results. In contrast, long term outcome is disappointing, probably due to suture loss in the majority of patients. Therefore, technical improvements to ensure suture durability are mandatory before endoscopic suturing can evolve as a therapeutic option for GORD treatment.
Gastrointestinal Endoscopy | 2004
Marcus Wiedmann; Frieder Berr; Ingolf Schiefke; Helmut Witzigmann; Kay Kohlhaw; Joachim Mössner; Karel Caca
BACKGROUND Median survival of patients with non-resectable hilar cholangiocarcinoma is 3 to 6 months, even after biliary drainage. Therefore, a single-arm phase II study was conducted (July 1996 to October 1998) to investigate the effect of local photodynamic therapy; a significant improvement in survival (74%) was noted at 6 months. The present study is an analysis of the long-term follow-up for patients enrolled in that phase II study. METHODS Five-year follow-up data for the 23 patients enrolled in the original prospective study were analyzed by using Kaplan-Meier log-rank analysis. RESULTS Median survival after treatment was 11.2 months for patients without distant metastases (M0) and 9.3 months for all patients (M0+M1). The 1-year, 2-year, 3-year, and 4-year survival rates were estimated to be 47%, 21%, 11% and 5%, respectively, for patients with stage M0 cholangiocarcinoma, and 39%, 17%, 9%, and 4%, respectively, for patients with stages M0 and M1. Of the patients who died, 73.9% (n=17) were because of tumor progression; 26.1% (n=6) died as a result of cholangitis (n=4), septic shock (n=1), or appendicitis/peritonitis (n=1). For all patients, except one with diffuse liver metastases, there was improvement in cholestasis, performance, and quality of life, which was maintained for an extended period. CONCLUSIONS This 5-year follow-up study confirms that photodynamic therapy is safe and effective for non-resectable hilar cholangiocarcinoma, although it does not prevent progression of the disease.
Current Cancer Drug Targets | 2005
Marcus Wiedmann; Karel Caca
Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase (HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora kinase inhibitors, hedgehog inhibitors, and TGF-beta signalling inhibitors.