Wolfgang Sieghart

Medical University of Vienna, Wien, Vienna, Austria

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Publications (55)263.37 Total impact

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    ABSTRACT: We aimed to establish an objective point score to guide the decision for the first treatment with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC).
    Journal of hepatology. 07/2014;
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    Journal of Hepatology 03/2014; · 9.86 Impact Factor
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    ABSTRACT: Background & Aims: Non-selective β blockers (NSBBs) reduce the hepatic venous portal pressure gradient and the risk for variceal hemorrhage in patients with cirrhosis. However, development of spontaneous bacterial peritonitis (SBP) in these patients could preclude treatment with NSBBs, because of their effects on the circulatory reserve. We investigated the effects of NSBBs in patients with cirrhosis and ascites, with and without SBP. Methods We performed a retrospective analysis of data from 607 consecutive patients with cirrhosis who had their first paracentesis at the Medical University of Vienna from 2006 through 2011. Cox models were calculated to investigate the effect of NSBBs on transplant-free survival time and adjusted for Child-Pugh stage and presence of varices. Results NSBBs increased transplant-free survival in patients without SBP (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.581–0.968; P=.027) and reduced days of non-elective hospitalization (19.4 days/y for patients on NSBBs vs 23.9days/y for patients not taking NSBBs). NSBBs had only moderate effects on systemic hemodynamics at patients’ first paracentesis. However, at the first diagnosis of SBP, the proportion of hemodynamically compromised patients with systolic arterial pressure <100 mmHg was higher among those who received NSBBs (38% vs 18% of those not taking NSBBs; P=.002), as was the proportion of patients with arterial pressure <82 mmHg (64% of those taking NSBB vs NSBB 44% of those not taking NSBBs; P=.006). Among patients with SBP, NSBBs reduced transplant-free survival (HR, 1.58; 95% CI, 1.098–2.274; P=.014) and increased days of non-elective hospitalization (29.6 days/person-year in patients on NSBBs vs 23.7days/person-year in those not taking NSBBs). A higher proportion of patients on NSBBs had hepatorenal syndrome (24% vs 11% in those not taking NSBBs, P=.027) and grade C acute kidney injury (20% vs. 8% for those not taking NSBBs; P=.021). Conclusions Among patients with cirrhosis and SBP, NSBBs increase the proportion who are hemodynamically compromised, time of hospitalization, and risks for hepatorenal syndrome and acute kidney injury. They also reduce transplant-free survival. Patients with cirrhosis and SBP should not receive NSBBs.
    Gastroenterology 01/2014; · 12.82 Impact Factor
  • Hepatology 10/2013; · 12.00 Impact Factor
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    ABSTRACT: The epidemiology of biliary tract cancers (BTC) varies between geographical regions and has changed over time globally. We investigated the incidence and mortality trends of patients diagnosed with BTC over a 20-year period in Austria. Patients diagnosed with intrahepatic (iCCC)/extrahepatic cholangiocarcinoma (eCCC), ampullary carcinoma, gall bladder carcinoma (GBC), overlapping lesions or unspecified carcinomas of the biliary tract and liver were included. Data on age-adjusted incidence were obtained from the Austrian National Cancer Registry which compiles data on all newly diagnosed cancers. Data on age-adjusted mortality were obtained from the national death registry (Statistics Austria). Between 1990 and 2009, 15201 patients were diagnosed with BTC (m/f=42/58%; mean age, 73 years). The median survival of all patients with BTC was 4.8 months with a 1-/5-year survival rate of 31%/10%. In iCCC, the incidence and mortality rates increased from 1990 to 2009 in both men and women while in eCCC, the incidence and mortality rates decreased over time in both sexes. In ampullary carcinoma, the incidence slightly decreased in men and remained stable in women. The mortality rate remained stable in both sexes. In GBC, the age-adjusted incidence and mortality rates dramatically decreased in both sexes. GBC and iCCC were the most common entities amongst BTC. While incidence and mortality rates of iCCC increased in men and women over time, incidence and mortality rates of eCCC and GBC decreased in both sexes. Other carcinomas of the biliary tract i.e. ampullary carcinoma were rarely diagnosed.
    Liver international: official journal of the International Association for the Study of the Liver 09/2013; · 3.87 Impact Factor
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    ABSTRACT: Recently, we developed the ART-score (Assessment for Retreatment with TACE) to guide the decision for a second transarterial chemoembolization (TACE-2) in patients with hepatocellular carcinoma (HCC). Patients with an ART-score of 0-1.5 points gained benefit from a second TACE session, while patients with an ART-score ⩾2.5 points did not. Here, we investigated 1) the prognostic significance of the ART-score prior to the third (TACE-3) and fourth TACE (TACE-4) and 2) the feasibility of an ART-score guided retreatment strategy by sequential assessment of the ART-score in HCC patients treated with multiple TACE sessions. 109 patients diagnosed with intermediate stage HCC and treated with ⩾3 TACE sessions between 1/1999 and 12/2009 at the Medical Universities of Vienna and Innsbruck were included. The ART-score prior to each TACE session was assessed in comparison to the TACE naïve liver. The prognostic performance of the ART-score before TACE-3 and 4 was evaluated with and without stratification based on the ART-score prior to the respective last intervention. The pre-TACE-3 ART-score discriminated two groups with different prognosis and remained a valid predictor of OS independent from Child-Pugh-score (5-7 points), CRP-levels and tumor characteristics. Even in patients with an initially beneficial ART-score (0-1.5 points) before TACE-2, repeated ART-score assessment before TACE-3 identified a subgroup of patients with dismal prognosis (median OS: 27.8 vs. 10.8 months, p<0.001). Similar results were observed when the ART-score was applied before TACE-4. The sequential assessment of the ART-score identifies patients with dismal prognosis prior to each TACE session.
    Journal of Hepatology 09/2013; · 9.86 Impact Factor
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    ABSTRACT: Background Dysregulation and activation of Hedgehog (Hh) signalling may contribute to tumorigenesis, angiogenesis, and metastatic seeding in several solid tumours.
    United European Gastroenterology Journal. 08/2013; 1(4):265-275.
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    ABSTRACT: We aimed to establish an objective point score to guide the decision for retreatment with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). In all, 222 patients diagnosed with HCC and treated with multiple TACE cycles between January 1999 and December 2009 at the Departments of Gastroenterology/Hepatology of the Medical Universities of Vienna (training cohort) and Innsbruck (validation cohort) were included. We investigated the effect of the first TACE on parameters of liver function and tumor response and their impact on overall survival (OS, log rank test) and developed a point score (ART score: Assessment for Retreatment with TACE) in the training cohort (n = 107, Vienna) by using a stepwise Cox regression model. The ART score was externally validated in an independent validation cohort (n = 115, Innsbruck). The increase of aspartate aminotransferase (AST) by >25% (hazard ratio [HR] 8.4; P < 0.001), an increase of Child-Pugh score of 1 (HR 2.0) or ≥2 points (HR 4.4) (P < 0.001) from baseline, and the absence of radiologic tumor response (HR 1.7; P = 0.026) remained independent negative prognostic factors for OS and were used to create the ART score. The ART score differentiated two groups (0-1.5 points; ≥2.5 points) with distinct prognosis (median OS: 23.7 versus 6.6 months; P < 0.001) and a higher ART score was associated with major adverse events after the second TACE (P = 0.011). These results were confirmed in the external validation cohort and remained significant irrespective of Child-Pugh stage and the presence of ascites prior the second TACE. Conclusion: An ART score of ≥2.5 prior the second TACE identifies patients with a dismal prognosis who may not profit from further TACE sessions. (HEPATOLOGY 2013;57:2261–2273)
    Hepatology 06/2013; 57(6). · 12.00 Impact Factor
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    Alimentary Pharmacology & Therapeutics 11/2012; 36(10):994-5. · 4.55 Impact Factor
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    ABSTRACT: BACKGROUND: We investigated the prognostic value of C-reactive protein (CRP) in patients with hepatocellular carcinoma (HCC) not amenable to surgery. METHODS: A total of 615 patients diagnosed with HCC not amenable to surgery between 04/1999 and 12/2009 at the Departments of Gastroenterology of the Medical Universities of Vienna and Innsbruck were included. We assessed the optimal CRP cut off by regression spline analysis and tested its impact on median overall survival (OS) by the Kaplan Meier method, univariate analysis (log-rank test) and multivariate analysis (Cox proportional hazard regression model) in a training cohort (n=466, Vienna) and an independent validation cohort (n=149, Innsbruck). RESULTS: We found a sigmoid shaped association of CRP and the hazard ratio of death upon regression spline analysis and defined a CRP level <1/ò1 mg/dl as optimal cut off for further survival assessments. Elevated CRP (ò1 mg/dl) at diagnosis was associated with poor OS (CRP-elevated. vs. CRP-normal; 4 vs. 20 months; P<0.001) and remained a significant negative predictor for OS upon multivariate analysis (hazard ratio, 1.7; P<0.001), which was independent from age, Child-Pugh class, tumor characteristics, and treatment allocation. Analyses with respect to Barcelona Clinic Liver Cancer (BCLC) stage and Child-Pugh class supported the relevance of CRP (BCLC-stage C and Child-Pugh A: OS for CRP-elevated vs. CRP-normal, 6 vs. 14; P<0.001; BCLC-stage C and Child-Pugh B: (OS for CRP-elevated vs. CRP-normal, 4 vs. 15 months; P<0.001). The prognostic significance of elevated CRP was reproducible at a second CRP determination time point and confirmed in the independent validation cohort. CONCLUSION: Elevated CRP is associated with a dismal prognosis in HCC patients and may become a useful marker for patient selection in HCC management. (HEPATOLOGY 2012.).
    Hepatology 09/2012; · 12.00 Impact Factor
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    ABSTRACT: BACKGROUND: Patients coinfected with HIV and HCV are at risk for developing portal hypertension (PHT), hyperdynamic circulation and pulmonary arterial hypertension (PAH). Data on the influence of antiviral therapy with pegylated interferon-α (PEG-IFN-α) and ribavirin (RBV) are limited. METHODS: Haemodynamic parameters, including hepatic venous pressure gradient (HVPG), pulmonary arterial pressure (PAP(mean)), cardiac output (CO) and systemic vascular resistance (SysVR), were prospectively evaluated before and after PEG-IFN-α+RBV therapy in 80 HIV-HCV-coinfected patients. RESULTS: Baseline evaluation showed a mean HVPG of 4.7 mmHg, CO of 6.15 l/min and PAP(mean) of 14.8 mmHg. PHT was present in 26% of patients, hyperdynamic circulation in 5% and PAH in 4%. Patients with advanced fibrosis (METAVIR stage F3/F4; n=32) had significantly higher CO (P=0.008), lower SysVR (P=0.035), higher PAP(mean) (P=0.018) and higher pulmonary vascular resistance (P=0.022) than patients with stage F0-F2 fibrosis (n=48). Both hyperdynamic circulation and PAH were significantly associated with liver stiffness, fibrosis stage and portal pressure; a non-significant trend was found for CD4(+) T-cell counts and HIV RNA levels. No significant changes in PAP(mean), CO and SysVR were observed after PEG-IFN-α+RBV treatment, although a significant decrease in HVPG was noted in patients with HCV eradication (P=0.013). CONCLUSIONS: The overall prevalence of hyperdynamic circulation and PAH in HIV-HCV coinfection is low. Advanced fibrosis, increased liver stiffness, elevated portal pressure and probably CD4(+) T-cell count and HIV viraemia represent risk factors for hyperdynamic circulation and PAH. PHT is present in 26% of HIV-HCV-coinfected patients evaluated for antiviral therapy. Successful HCV eradication significantly decreases HVPG.
    Antiviral therapy 09/2012; · 3.07 Impact Factor
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    ABSTRACT: The combination of erlotinib with sorafenib is currently being investigated in a phase III RCT. We studied the effect of erlotinib and sorafenib on HCC in a preclinical model. The Morris Hepatoma (MH) and HepG2 cells were treated in vitro with sorafenib (1-10 μM) and erlotinib (1-5 μM) and evaluated for tumor cell viability, apoptosis, and target regulation. Antiangiogenic effects were studied by measuring VEGF levels, endothelial cell viability, apoptosis, migration, and the aortic ring assay. In vivo, MH cells were implanted into the liver of syngeneic rats and treated with vehicle, sorafenib 5-10mg/kg, erlotinib 10mg/kg, and respective combinations. In vitro, erlotinib downregulated p-ERK but showed no significant effect on tumor cell viability in MH and HEPG2 cells. Despite a similar target regulation, sorafenib significantly reduced cell viability of HCC cells by induction of apoptosis, in a dose-dependent manner (11 ± 5%; 20 ± 10%; 51 ± 5% for sorafenib 1, 5, 10 μM). No additional effect was observed upon combination with erlotinib. Of note, erlotinib treatment resulted in endothelial cell migration and vascular sprouting of aortic rings through induction of VEGF mRNA and protein levels in endothelial and tumor cells, which was blocked by sorafenib. In vivo, erlotinib had no single agent antitumor activity, raised serum-VEGF levels, and lacked a synergistic effect in combination with sorafenib. Erlotinib had no antitumor effect on HCC in vitro nor in vivo, but induced VEGF, which may reflect a resistance mechanism to erlotinib monotherapy. No improvement of sorafenib efficacy was observed upon combination with erlotinib.
    Journal of Hepatology 05/2012; 57(3):592-9. · 9.86 Impact Factor
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    ABSTRACT: To compare the efficacies of transarterial chemoembolization (TACE) and sorafenib in patients with advanced-stage hepatocellular carcinoma (HCC). The retrospective analysis of the data was approved by the institutional review board; the requirement to obtain informed consent was waived. Three hundred seventy-two patients with HCC were treated between January 1999 and December 2009. Patients with advanced HCC according to the Barcelona Clinic Liver Cancer (BCLC) staging classification (Child-Pugh class A or B, Eastern Cooperative Oncology Group performance status of 1-2, and/or macrovascular invasion or extrahepatic metastasis) were included in the study (n = 97). Thirty-four patients underwent conventional TACE with doxorubicin plus lipiodol or TACE with drug-eluting beads; 63 patients were treated with sorafenib. The median duration of sorafenib treatment was 4.6 months (95% confidence interval [CI]: 3.2, 6.0 months). The median number of TACE sessions per patient was 3 ± 2. Side effects of TACE and sorafenib were comparable to those reported in the literature. The median time to progression was similar between the two treatment groups (P = .737). The median overall survival was 9.2 months (95% CI: 6.1, 12.3 months) for patients treated with TACE and 7.4 months (95% CI: 5.6, 9.2 months) for those treated with sorafenib (P = .377). Only Child-Pugh class was associated with a better overall survival at uni- and multivariate analysis. TACE achieved a promising outcome in select patients with advanced HCC (BCLC stage C).
    Radiology 03/2012; 263(2):590-9. · 6.34 Impact Factor
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    ABSTRACT: Background: Epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) are crucial targets in cancer therapy. Combined inhibition of both targets yielded synergistic effects in vitro and in vivo in several cancer entities. However, the impact of EGFR and mTOR expression and combined inhibition in neuroendocrine lung tumors other than small-cell lung cancer remains unclear. Material and Methods: Expression and activation of EGFR/AKT/mTOR pathway constituents were investigated in typical and atypical bronchial carcinoid (AC) tumors and large-cell neuroendocrine lung carcinomas (LCNEC) by immunohistochemistry in 110 tumor samples, and correlated with clinicopathological parameters and patient survival. Cytotoxicity of mTOR inhibitor everolimus and EGFR inhibitor erlotinib alone and in combination was assessed using growth inhibition assay in NCI-H720 AC and SHP-77 LCNEC cells. Cell cycle phase distribution was determined by FACS. Apoptosis-associated activation of caspase-3/7 was measured by Caspase-Glo® assay. Activity status of EGFR and mTOR pathway components was analyzed by immunoblotting. Results: Activation of the EGFR/AKT/mTOR axis could be demonstrated in all entities and was significantly increased in higher grade tumors. Neoadjuvant chemotherapy correlated significantly with p-AKT expression and p-ERK loss. Erlotinib combined with everolimus exerted synergistic combination effects in AC and LCNEC cells by induction of apoptosis, while cell cycle phase distribution remained unaffected. These effects could be explained by synergistic downregulation of phospho-mTOR, phospho-p70S6 kinase and phospho-AKT expression by everolimus and erlotinib. Conclusions: Our study indicates that EGFR and mTOR are clinically important targets in bronchial neuroendocrine tumors, and further in vivo and clinical exploration of combined inhibition is warranted.
    Neuroendocrinology 02/2012; · 3.54 Impact Factor
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    ABSTRACT: To investigate the safety of transarterial chemoembolisation (TACE) in combination with sorafenib in patients with hepatocellular carcinoma (HCC). Patients with Child-Pugh A/B liver function, ECOG performance status 0-2 and HCC treatable with TACE received continuous sorafenib 800 mg/day, and TACE with doxorubicin (75, 50 and 25 mg/m(2) according to serum bilirubin: <1.5, 1.5-3, and >3 mg/dL) and lipiodol 2 weeks after sorafenib initiation and repeated every 4 weeks. Fifteen patients were included (Child-Pugh A/B, n = 12/3; Barcelona Clinic Liver Cancer-A/B/C, n = 1/9/5; ECOG 0/2, n = 14/1). Median time on sorafenib was 5.2 months (2.6-7.4 months); median number of TACE sessions was 3. Common adverse events were abdominal pain (n = 14), weight loss (n = 13), alopecia (n = 12), fatigue (n = 12) and hyperbilirubinaemia (n = 11). There were 32 serious adverse events (grade ≥ 3); 9/10-unscheduled hospital admissions and 4/5 deaths were considered TACE-related. The study was stopped prematurely because of safety concerns. At 6 months, 2 and 5 patients had complete or partial responses; 1 had stable disease. Median overall survival was 10.6 months (95% CI: 5.2-16 months). These findings do not support use of an intensive, high-dose doxorubicin-based TACE regimen in combination with sorafenib in this study population. • Transarterial chemoembolisation (TACE) is widely used in patients with hepatocellular carcinoma (HCC) • Various antiangiogenic and other agents have been used to augment this treatment • We tested lipiodol-TACE with bilirubin-adjusted doxorubicin dosing in combination with sorafenib • This trial was stopped prematurely because of safety reasons • Our safety results do not support the combination of sorafenib with this TACE regimen.
    European Radiology 01/2012; 22(6):1214-23. · 4.34 Impact Factor
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    ABSTRACT: Increased intrahepatic vascular resistance and hyperperfusion in the splanchnic circulation are the principal mechanisms leading to portal hypertension in cirrhosis. Several preclinical studies have demonstrated a beneficial effect of the multikinase inhibitor sorafenib on the portal hypertensive syndrome. To investigate the effect of sorafenib on hepatic venous pressure gradient (HVPG), systemic hemodynamics and intrahepatic mRNA expression of proangiogenic, profibrogenic and proinflammatory genes. Patients with liver fibrosis/cirrhosis and hepatocellular carcinoma were treated with sorafenib 400 mg b.d. HVPG measurement and transjugular liver biopsy were performed at baseline and at week 2. Changes in HVPG and intrahepatic mRNA expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), RhoA, tumour necrosis factor-alpha (TNF-α) and placental growth factor (PlGF) were evaluated. Thirteen patients (m/f = 12/1; Child-Pugh class A/B = 10/3) were included. The most common aetiology of liver disease was alcohol consumption (n = 7). Eleven patients had an elevated portal pressure, including eight patients with clinically significant portal hypertension. A significant decrease of HVPG (≥ 20% from baseline) was observed in four subjects. In HVPG responders, we observed mRNA downregulation of VEGF, PDGF, PlGF, RhoA kinase and TNF-α, while no substantial mRNA decrease was found in nonresponders in any of the five genes. In two of the four HVPG responders we observed a dramatic (43-85%) mRNA decrease of all five investigated genes. Larger controlled clinical trials are needed to demonstrate any potential beneficial effect of sorafenib on portal hypertension in patients with cirrhosis.
    Alimentary Pharmacology & Therapeutics 01/2012; 35(1):83-91. · 4.55 Impact Factor
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    Alimentary Pharmacology & Therapeutics 12/2011; 34(11-12):1348-1349. · 4.55 Impact Factor
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    ABSTRACT: Activation of the activator protein 1 (AP-1) transcription factor as well as increased serum levels of vascular endothelial growth factor (VEGF) and interleukin (IL)-8 predict poor prognosis of patients with hepatocellular carcinomas (HCCs). Moreover, HCC patients display reduced selenium levels, which may cause lipid peroxidation and oxidative stress because selenium is an essential component of antioxidative glutathione peroxidases (GPx). We hypothesized that selenium-lipid peroxide antagonism controls the above prognostic markers and tumor growth. (1) In human HCC cell lines (HCC-1.2, HCC-3, and SNU398) linoleic acid peroxide (LOOH) and other prooxidants enhanced the expression of VEGF and IL-8. LOOH up-regulated AP-1 activation. Selenium inhibited these effects. This inhibition was mediated by glutathione peroxidase 4 (GPx4), which preferentially degrades lipid peroxides. Selenium enhanced GPx4 expression and total GPx activity, while knock-down of GPx4 by small interfering RNA (siRNA) increased VEGF, and IL-8 expression. (2) These results were confirmed in a rat hepatocarcinogenesis model. Selenium treatment during tumor promotion increased hepatic GPx4 expression and reduced the expression of VEGF and of the AP-1 component c-fos as well as nodule growth. (3) In HCC patients, increased levels of LOOH-related antibodies (LOOH-Ab) were found, suggesting enhanced LOOH formation. LOOH-Ab correlated with serum VEGF and IL-8 and with AP-1 activation in HCC tissue. In contrast, selenium inversely correlated with VEGF, IL-8, and HCC size (the latter only for tumors smaller than 3 cm). Conclusion: Reduced selenium levels result in accumulation of lipid peroxides. This leads to enhanced AP-1 activation and consequently to elevated expression of VEGF and IL-8, which accelerate the growth of HCC. Selenium supplementation could be considered for investigation as a strategy for chemoprevention or additional therapy of early HCC in patients with low selenium levels.
    Hepatology 11/2011; 55(4):1112-21. · 12.00 Impact Factor
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    ABSTRACT: Transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) is one of the most frequently applied standard treatments for this disease. The role for TACE is fairly well defined within the most widely used treatment algorithm for HCC, die Barcelona Clinic Liver Cancer (BCLC) staging system and treatment algorithm. But no general treatment algorithm will go into the technical details of any procedure and several patients will not fit ideally into the patient groups predefined in BCLC or any other treatment algorithm. Furthermore, indications and contraindications sometimes are viewed differently by the various medical specialties involved in taking care of such patients. We present here the joint expert position statement of the Austrian Societies of Gastroenterology and Hepatology (ÖGGH), Interventional Radiology (ÖGIR), Hematology and Oncology (ÖGHO), and Surgical Oncology (ASSO) on the technical aspects, indications, and contraindication for the use of TACE in the management of HCC.
    Wiener klinische Wochenschrift 09/2011; 124(3-4):104-10. · 0.81 Impact Factor