Prognostic relevance of carbohydrate antigen 19-9 levels in patients with advanced biliary tract cancer.

Serum carbohydrate antigen 19-9 (CA 19-9) has been identified as biochemical marker for biliary tract cancer (BTC). The purpose of this study was to evaluate its value as a treatment response marker and its value as a prognostic parameter in patients with unresectable BTC. We analyzed 70 patients with BTC treated with chemotherapy. CA 19-9 levels before and after two treatment courses were analyzed with respect to their effect on treatment response. Patients were categorized into two subgroups according to biliary stenting: patients without endoscopic intervention or biliary drainage (non-stent subgroup) and patients with endoluminal stenting (stent subgroup). Pretreatment CA 19-9 levels were prognostic with respect to overall survival for the entire study population. Patients with CA 19-9 levels above the median of 300 units/mL had a nearly 3-fold risk for early death (hazard ratio, 2.92; 95% confidence interval, 1.51-5.64; adjusted P = 0.002) as compared with patients with CA 19-9 levels

Hepatopulmonary syndrome in patients with chronic liver disease: role of pulse oximetry.

BACKGROUND: Hepatopulmonary syndrome (HPS) is a rare complication of liver diseases of different etiologies and may indicate a poor prognosis. Therefore, a simple non-invasive screening method to detect HPS would be highly desirable. In this study pulse oximetry was evaluated to identify patients with HPS. METHODS: In 316 consecutive patients with liver cirrhosis (n = 245), chronic hepatitis (n = 69) or non-cirrhotic portal hypertension (n = 2) arterial oxygen saturation (SaO2) was determined using a pulse oximeter. In patients with SaO2 < or = 92% in supine position and/or a decrease of > or = 4% after change from supine to upright position further diagnostic procedures were performed, including contrast-enhanced echocardiography and perfusion lung scan. RESULTS: Seventeen patients (5.4%) had a pathological SaO2. Four patients (1.3%) had HPS. HPS patients had a significant lower mean SaO2 in supine (89.7%, SD 5.4 vs. 96.0%, SD 2.3; p = 0.003) and upright position (84.3%, SD 5.0 vs. 96.0%, SD 2.4; p = 0.001) and had a lower mean PaO2 (56.2 mm Hg, SD 15.2 vs. 71.2 mm Hg, SD 20.2; p = 0.02) as compared to patients without HPS. The mean deltaSaO2 (difference between supine and upright position) was 5.50 (SD 7) in HPS patients compared to non-HPS patients who showed no change (p = 0.001). There was a strong correlation between shunt volume and the SaO2 values (R = -0.94). CONCLUSION: Arterial SaO2 determination in supine and upright position is a useful non-invasive screening test for HPS and correlates well with the intrapulmonary shunt volume.

Combined TACE and PEI for palliative treatment of unresectable hepatocellular carcinoma.

AIM: To assess whether the effectiveness of a combination of transarterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) in the treatment of unresectable hepatocellular carcinoma (HCC) is superior to TACE alone a randomized controlled trial was performed. METHODS: The effect of combination therapy on long-term survival rates and duration of hospitalization was evaluated in 52 previously untreated HCCs, randomly allocated to TACE-PEI (27 pts) or TACE alone (25 pts). RESULTS: The cumulative survival rate of the TACE group was 75.8% at 6 mo, 62.9% at 12 mo, and 18.0% at 24 mo and of the TACE-PEI group 76.9%, 61.5%, and 38.7%, respectively. Comparison of overall survival in both groups showed no statistically significant difference. Regarding the patients with HCCs Okuda stage I (n = 26), the median survival of the TACE-PEI group was significantly longer (>24 mo, median not yet reached in the study period) compared to the TACE group (18.4 mo [range 11.6-21.7 mo]; P = 0.04). TACE-PEI reduced the relative risk for mortality to 0.4 (95%CI 0.15-0.96) compared to patients who received TACE alone. Median survival in patients with HCCs Okuda stage II or III was 5.0 mo in the TACE group (1.7 mo-not defined) compared to 10.4 mo in the TACE-PEI group. CONCLUSION: The combination TACE-PEI improved survival time compared to TACE alone. Our study revealed a statistically significant improved survival in HCCs Okuda stage I. Side effects were minor and the combination therapy did not prolong duration of hospitalization considerably.

Long-acting octreotide versus placebo for treatment of advanced HCC: a randomized controlled double-blind study.

UNLABELLED: Although numerous treatment modalities have been explored in patients with advanced HCC, the therapeutic options are still limited. Somatostatin has been shown to have antimitotic activity in endocrine as well as in a variety of nonendocrine tumors. Expression of somatostatin receptors is found in HCCs, but the efficacy of the somatostatin analogue octreotide remains controversial. Therefore, a randomized double-blind placebo-controlled multicenter trial was performed to assess the efficacy of long-acting octreotide for the treatment of advanced HCC. One hundred twenty untreated patients with histologically confirmed HCC were randomized to receive either long-acting octreotide (Sandostation LAR 30 mg) intramuscularly every 4 weeks or placebo. The study groups were comparable with respect to clinical characteristics. There was no difference in the cumulative survival. The median survival time was 4.7 months in the octreotide group compared with 5.3 months in the control group. Six-month survival rates were 41% for octreotide patients and 42% for control patients, respectively. The unadjusted relative risk for mortality in the octreotide group compared with patients in the control group was 1.11 (95% CI 0.76-1.63; P = 0.59). When adjusted for Okuda, CTP, and Cancer of the Liver Italian Program (CLIP) scores, the relative risk for octreotide did not change markedly and was 1.05 (95% CI 0.71-1.55; P = 0.83). The CLIP score seems to predict survival better than both Okuda and CTP score. CONCLUSION: The randomized controlled double-blind HECTOR trial showed no survival benefit for HCC patients treated with long-acting octreotide compared with placebo.

Rapid and simple detection of IFN-neutralizing antibodies in chronic hepatitis C non-responsive to IFN-alpha.

Different mechanisms have been proposed for the failure of interferon (IFN) therapy in patients with chronic hepatitis C and multiple sclerosis, for example, the presence of IFN-neutralizing antibodies. In this study, a novel assay system based on the IFN-inducible Mx-promoter was used to detect IFN-neutralizing antibodies in sera of patients with chronic hepatitis C. To monitor IFN bioactivity in IFN-treated patients, a real-time RT-PCR for MxA gene expression in PBMCs was established. Using these two methods, patients with chronic hepatitis C virus (HCV) infection receiving IFN therapy and patients with treatment induced HCV clearance were monitored. Importantly, neutralizing anti-IFN antibodies were detected in the sera of 3 of 38 chronically HCV-infected patients who failed to respond to therapy but none in sera of patients who cleared HCV after IFN therapy. Interestingly, the presence of these antibodies correlated with the lack of MxA induction in PBMCs after initiation of IFN-alpha therapy. Retrospective analysis of one patient's sera revealed that the anti-IFN-alpha antibodies had already developed after the first of four unsuccessful IFN therapies, suggesting that neutralizing antibodies may have contributed to the failure of previous IFN treatments. In summary, a novel screening assay was established that may be helpful for testing IFN non-responders for the presence of clinically relevant anti-IFN-alpha antibodies and for selecting alternative IFN preparations not neutralized by these antibodies.

Coordinated expression of cyclin D1 and LEF-1/TCF transcription factor is restricted to a subset of hepatocellular carcinoma.

BACKGROUND: While the Wnt pathway has been widely implicated in hepatocarcinogenesis, the role of cyclin D1 as a direct downstream target gene of beta-catenin-lymphoid enhancer factor-1 (LEF-1)/T-cell factor (TCF) signaling is controversely discussed. METHODS: By immunohistochemical analyses we studied the subcellular localization of LEF-1/TCF and cyclin D1 in 162 hepatocellular carcinoma (HCC). Single- and double-label imaging by brightfield and confocal laser scanning microscopy was quantitated and correlated with beta-catenin, the Ki67(+) proliferation fraction (PF), tumor size, grade, the Okuda stage and patient survival. RESULTS: The frequency of nuclear cyclin D1 expression was 28% and closely correlated with LEF-1/TCF (P<0.0001) and the Ki67(+) PF (P=0.03). Nuclear LEF-1/TCF expression was observed in 52% of all cases, but was also present in 42% of cyclin D1(-) cases. Nuclear beta-catenin was identified in 37% of all HCCs and correlated with LEF-1/TCF (P=0.04). The expression of cyclin D1, LEF-1/TCF or beta-catenin did not correlate with other clinico-pathological data. CONCLUSIONS: A large proportion of HCCs does not appear to be linked to a deregulation of cyclin D1. However, the coordinated expression of cyclin D1 and LEF-1/TCF in some cases suggests the role of cyclin D1 as a Wnt target gene in a subset of HCCs.