Background: Although colonoscopy-based screening has proven to be highly effective in detecting colorectal cancer (CRC), participation rates remain disappointing. Development of CRC is associated with a number of genetic or somatic mutations. New, non-invasive stool tests are currently being developed based on the detection of these alterations. We investigated if a non-invasive stool assay can offer sufficient sensitivity and specificity to supplement colonoscopy-based screening. Methods: We compared a combined stool assay, which incorporates fecal occult blood testing (FOBT), quantification of human DNA (hDNA) as well as detection of genetic mutations of KRAS and BRAF (Combined DNA stool assay), with commercially available FOBT and M2-PK tests in a multi-centric six-armed pre-clinical case cohort study. Seven hundred thirty-four patients were recruited prior to elective/screening colonoscopy or prior to surgery in case of a recent CRC diagnosis. According to clinical assessment and colonoscopy/histology results, the following groups were assigned: controls, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), hyper-plastic polyps, adenomas, and CRC. Finally, 566 out of 734 patients (77.1%) were screened for CRC and overall gut status via colonoscopy, FOBT, M2-PK, with combined FOBT/M2-PK and the Combined DNA stool assay as described here. Results: All sensitivities and specificities are measured against histologically confirmed results by colonoscopy. Confirmed sensitivities for detecting colorectal cancer were 68% with FOBT, 83% with M2-PK, 90% with combined FOBT and M2-PK, and 85% with the Combined DNA stool assay. Specificities were 96% with FOBT, 61% with M2-PK, 62% with combined FOBT and M2-PK, and 92% with the Combined DNA stool assay in the control group with no pathological findings during colonoscopy. Conclusions: The Combined DNA stool assay detects CRC with a significantly higher Youden Index than the other reviewed non-invasive screening options. The results also suggest that the Combined DNA stool assay represents a reliable assay for detecting colorectal cancer, sufficient to be recommended as a supplement to colonoscopy screening.

A staging system for cirrhosis has been recently proposed based on varices, ascites and bleeding (J Hepatol 2006;44: 217–31). We aimed at validating the concept of clinical stages for cirrhosis and assessing the role of hepatocellular carcinoma (hcc), encephalopathy (pse) and jaundice. A total of 1858 patients from prospective cohorts were included in the study at the seven participating centers. Survival analysis was performed by the Kaplan-Meier method by individual patient data. Predictive accuracy for 1-year mortality of Pugh score and MELD across stages was assessed by c-statistics. Etiology was from HBV 6%, HCV 35%, alcohol 41%, alcohol and HCV 11%, other 7%; mean age±sd was 56±23, male sex 62%. At diagnosis 667 patients had compensated (330 without and 337 with esophageal varices) and 1146 decompensated cirrhosis,608 with ascites, 248 portal hypertensive bleeding,and 290 ascites and bleeding. In a mean±sd follow-up of 73±79 months 996 patients died and 116 were transplanted.1- and 5-year survival was respectively 99% and 86% for compensated patients without and 96.5% and 72% with varices,85% and 78% for those with bleeding alone,74% and 46% with ascites and 70% and 33% with ascites and bleeding. While 1-year survival after hcc, pse and jaundice was respectively 55%,53% and 58%, they were the first decompensating event respectively in only 4.5%, 4.5% and 3%.Based on survival, five major clinical stages with significantly different outcomes were identified: 1 compensated, no varices, 2 compensated with varices, 3 bleeding, no ascites, 4 ascites (and/or hcc, pse, jaundice), 5 bleeding and ascites (±hcc, pse, jaundice). 1-year transition rate between stages and mortality from each stage is summarized in the figure. c-statistics for 1-year mortality for Pugh and MELD were respectively: 0.76 and 0.68 (p<0.00001). Corresponding values across stages were: 0.85 and 0.77, stage1; 0.66 and 0.48, stage2; 0.71 and 0.64 stage 3; 0.67 and 0.71, stage4; 0.73 and 0.69, stage 5.

BACKGROUND:The Model for End Stage Liver Disease (MELD) predicts mortality in end stage liver disease. Incorporation of serum sodium into the MELD may improve diagnostic accuracy in decompensated patients with ascites. However, other complications of cirrhosis are not reflected. This study investigates whether quantitative liver function tests predict survival and increase prognostic accuracy of the MELD.METHODS:604 patients with suspected cirrhosis were staged clinically and haemodynamically. Galactose-elimination-capacity, sorbitol clearance, lidocaine metabolism and indocyanin green (ICG) half life were determined. Survival was the primary end point of the study. Prognostic effects of individual parameters were calculated using Cox regression models and ROC curves.RESULTS:321 patients on standard pharmacological and endoscopic treatment (PET) and 74 patients undergoing transjugular portosystemic shunting (TIPS) were studied. Of all quantitative liver function tests, ICG half life was the most accurate in predicting survival. Upon incorporation into the MELD, it modified the score in patients with PET up to 35 points. Clinically relevant changes to the score, however, occurred in patients with a MELD score between 10 and 30, allowing an objective prognostic discrimination of individual survival based on laboratory liver function and blood flow. The MELD-ICG was validated in the second cohort of patients undergoing TIPS implantation.CONCLUSION:ICG had the highest predictive value of the examined tests. Its incorporation into the MELD adds an estimation of liver blood flow and renders the new score MELD-ICG more accurate in predicting survival in intermediate to advanced cirrhosis than the MELD and MELD-Na.

(1) Obwohl Umweltfaktoren sicherlich eine große Rolle bei der Entwicklung einer nichtalkoholischen Fettlebererkrankung spielen, sind auch genetische Faktoren von Bedeutung; so ist Übergewicht weder eine notwendige, noch eine ausreichende Bedingung für die Entwicklung einer NAFLD, und eine familiäre Häufung von NAFLD wurde ebenso beschrieben wie Unterschiede in der Prävalenz z. B. zwischen hispanischen und schwarzen Amerikanern trotz vergleichbarem BMI und vergleichbar ausgeprägter Insulinresistenz. Eine Arbeitsgruppe aus Kalifornien hat deshalb in einer Familienaggregationsstudie die Geschwister und Eltern von übergewichtigen Kindern mit histologisch gesicherter (n=33) und ohne (n=11) NAFLD bezüglich ihrer Leberverfettung (MRT) analysiert. Die Leberverfettung war als ein Leberfettgehalt von ≥5% im MRT oder eine makrovesikuläre Verfettung von ≥5% der Hepatozyten in der Histologie definiert. 17% der Geschwister und 37% der Eltern von übergewichtigen Kindern ohne NAFLD hatten eine Leberverfettung im Vergleich zu 59% der Geschwister und 78% der Eltern übergewichtiger Kinder mit NAFLD. Der Leberfettgehalt war besonders bei den Familien von Kindern mit NAFLD mit dem BMI korreliert. Nach Korrektur für Alter, Geschlecht, Rasse und BMI lag die Erblichkeit einer Leberverfettung beim Maximalwert von 1,0.

Objective. Acute hepatic fat accumulation appears to be crucial for liver regeneration after partial hepatectomy. Since fatty acids in the liver are provided by catecholamine-induced lipolysis in the adipose tissue, we investigated whether beta-adrenergic blockade of lipolysis might affect liver regeneration. Material and methods. Mice were treated with propranolol prior to partial hepatectomy. Subsequently, liver regeneration was evaluated histologically, by determination of the relative liver weight and the mitotic index at different time points after surgery. Results. Liver mass restoration was delayed by propranolol, which was associated with a lower hepatic triglyceride content. Ki-67 labelling indicated that liver regeneration was attenuated by propranolol through inhibition of mitosis. Hepatocytes were arrested in the G1 phase of the cell cycle, as shown by the expression of G1-related proteins such as proliferating cell nuclear antigen, cyclin D1 and cyclin-dependent kinase-2, and underwent apoptosis as indicated by detection of poly(adenosine diphosphate-ribose) polymerase fragments. P-adrenergic blockade of the host animal did not provide transplanted hepatocytes with a growth advantage over host cells. Conclusion. Impairment of liver regeneration by propranolol is related to the inhibition of acute hepatic fat accumulation and to a predisposition of hepatocytes to apoptosis.

Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess the efficacy of thymostimulin in a phase III trial.

BackgroundHepatocellular carcinoma (HCC) is the fifth most common global cancer. When HCC is detected early, interventions such as percutaneous ethanol injection (PEI), percutaneous acetic acid injection (PAI), and radiofrequency thermal ablation (RFTA) have curative potential and represent low invasive alternatives to surgery. The role of PEI or PAI has not been addressed in a systematic review.ObjectivesTo evaluate the beneficial and harmful effects of PEI or PAI in adults with early HCC.Search strategyA systematic search was performed in The Cochrane Hepato-Biliary Group Controlled Trials Register,the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and ISI Web of Science in May 2009. Meeting abstracts of six oncological and hepatological societies (ASCO, ESMO, ECCO, AASLD, EASL, APASL) and references of articles were handsearched. Researchers in the field were contacted.Selection criteriaRandomised trials comparing PEI or PAI with no intervention, sham intervention, other percutaneous interventions or surgery for the treatment of early HCC were considered regardless of blinding, publication status, or language. Studies comparing RFTA or combination treatments were excluded.Data collection and analysisTwo authors independently selected trials for inclusion, and extracted and analysed data. The hazard ratios for median overall survival and recurrence-free survival were calculated using the Cox regression model with Parmar's method. Type and number of adverse events were reported descriptively.Main resultsThree randomised trials with a total of 261 patients were eligible for inclusion. The risk of bias was high in all trials. Two of the trials compared PEI with PAI. Overall survival (HR 1.47; 95% confidence interval (CI) 0.68 to 3.19) and recurrence-free survival (HR 1.42; 95% CI 0.68 to 2.94) were not significantly different. Data on the duration of hospital stay were inconclusive. Data on quality of life were not available. There were only mild adverse events in both treatment modalities.The other trial compared PEI with surgery. There was no significant difference in overall survival (HR 1.57; 95% CI 0.53 to 4.61) and recurrence-free survival (HR 1.35; 95% CI 0.69 to 2.63). No serious adverse events were reported in the PEI group. Three postoperative deaths occurred in the surgery group.Authors' conclusionsPEI and PAI does not differ significantly regarding benefits and harms in patients with early HCC, but only a limited number of patients have been examined and the bias risk was high in all trials. There is also insufficient evidence to determine whether PEI or segmental liver resection is more effective, although PEI may seem safer.

e15657 Background: Hepatocellular carcinoma (HCC) is the fifth most common global cancer with high geographical variability. When HCC is detected early, percutaneous approaches such as percutaneous ethanol injection (PEI), percutaneous acetic acid injection (PAI), and radiofrequency thermal ablation (RFTA) have curative potential and represent low invasive alternatives to surgery. The role of percutaneous ethanol or acetic acid injection and other percutaneous interventions except RFTA has not been addressed in a systematic metaanalysis. The objective was to evaluate the effects of PEI and PAI for early HCC. Methods: A systematic search was performed in EMBASE, Cochrane Central, The Cochrane Hepato-Biliary Group Controlled Trials Register, Medline and Scopus as well as a handsearch of meeting abstracts. Only randomised controlled trials were included. RFTA studies were not considered. Primary endpoint was overall survival, secondary endpoints were cancer free survival, number and type of adverse events, duration of hospital stay, and quality of life. Results: 3 studies covering 261 patients were identified. Two studies compared PEI with PAI. 91 and 94 patients with one to three HCC-nodules ≤ 3cm underwent PEI and PAI, respectively. Overall survival (HR 1.47; 95% CI 0.68 to 3.19) and cancer free survival (HR 1.42; 95% CI 0.68 to 2.94) were not significantly different after treatment by PEI versus PAI. Both treatments were safe with no serious adverse events reported and modest pain being the most frequent adverse event. Data on the duration of hospital stay were inconclusive and data on quality of life not available. One study compared PEI with surgery. 38 patients were allocated to each treatment arm. There was no significant difference in survival (HR 1.57; 95% CI 0.53 to 4.61) and cancer free survival (HR 1.35; 95% CI 0.69 to 2.63). No serious adverse events were reported in the PEI group but 3 postoperative deaths occurred in the surgery arm. Conclusions: PEI and PAI are similarly effective and safe in patients with one to three small (≤ 3 cm) HCC nodules. Although the evidence is weaker, the beneficial effect of PEI is comparable to that of segmental liver resection and thus should be used preferentially due to its low morbidity and mortality. No significant financial relationships to disclose.

Budd-Chiari syndrome and membranous obstruction of the inferior vena cava frequently result in the development of mostly benign hepatic lesions. In cases of membranous obstruction of the inferior vena cava, which is prevalent mostly in the East, these lesions often progress to hepatocellular carcinoma. In contrast, malignant transformation has not yet been recognised in patients with isolated hepatic vein thrombosis. We report the case of a 37-year-old male Caucasian who presented with acute Budd-Chiari syndrome without involvement of the inferior vena cava. Despite porto-caval shunting, a hepatocellular carcinoma developed within several months. Three hepatic lesions were treated by radiofrequency thermal ablation until liver transplantation was performed. This report emphasises the possibility of malignant transformation of regenerative nodules in patients with disturbed hepatic perfusion in general. Physicians must be aware of this when assessing regenerative nodules, especially as no unambiguous predictors for the development of hepatocellular carcinoma have been identified so far.

BACKGROUND:Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma in vitro. In a phase II trial, we investigated safety and efficacy including selection criteria for best response in advanced or metastasised hepatocellular carcinoma.METHODS:44 patients (84 % male, median age 69 years) not suitable or refractory to conventional therapy received thymostimulin 75 mg subcutaneously five times per week for a median of 8.2 months until progression or complete response. 3/44 patients were secondarily accessible to local ablation or chemoembolisation. Primary endpoint was overall survival, secondary endpoint tumor response or progression-free survival. A multivariate Cox's regression model was used to identify variables affecting survival.RESULTS:Median survival was 11.5 months (95% CI 7.9-15.0) with a 1-, 2- and 3-year survival of 50%, 23% and 9%. In the univariate analysis, a low Child-Pugh-score (p = 0.01), a low score in the Okuda- and CLIP-classification (p < 0.001) or a low AFP-level (p < 0.001) were associated with better survival, but not therapy modalities other than thymostimulin (p = 0.1) or signs of an invasive HCC phenotype such as vascular invasion (p = 0.3) and metastases (p = 0.1). The only variables independently related to survival in the Cox's regression model were Okuda stage and presence of liver cirrhosis (p < 0.01) as well as response to thymostimulin (p < 0.05). Of 39/44 patients evaluable for response, two obtained complete responses (one after concomitant radiofrequency ablation), five partial responses (objective response 18%), twenty-four stable disease (tumor control rate 79%) and eight progressed. Median progression-free survival was 6.4 months (95% CI 0.8-12). Grade 1 local reactions following injection were the only side effects.CONCLUSION:Outcome in our study rather depended on liver function and intrahepatic tumor growth (presence of liver cirrhosis and Okuda stage) in addition to response to thymostimulin, while an invasive HCC phenotype had no influence in the multivariate analysis. Thymostimulin could therefore be considered a safe and promising candidate for palliative treatment in a selected target population with advanced hepatocellular carcinoma, in particular as component of a multimodal therapy concept.TRIAL REGISTRATION:Current Controlled Trials ISRCTN29319366.

Aims: Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess its efficacy in a phase III trial.

Background Capsule endoscopy (CE) sensitively detects the bleeding source in the small bowel. However, the influence of CE on long-term outcome is not well established. Methods In five tertiary hospitals, all CE investigations were retrospectively identified dating back to 3 years. Patients with intestinal bleeding and negative bidirectional endoscopy were included, and relapse of bleeding was recorded. Results A bleeding source was detected in 219 of 285 patients (76.8%); CE provided the diagnosis in 175 of 219 (79.9%) and other, repeated investigations in 44 cases (20.1%). Follow-up (mean±SD=20.7±9.4 months) in 240 patients identified rebleeding in 65 (27.1%), and readmission to a hospital in 42 (17.5%). Hospital readmission was most frequent in patients with angiectasias (31.3%, relative risk (RR)=5.0; 95% confidence interval (CI)=2.4–10.4). Other risk factors included patients being older than 60 years of age (RR=3.8; 95% CI=1.5–9.5), and anticoagulant medication (RR=3.0; 95% CI=1.5–6.0). Therapeutic measures had a mean recurrence rate of 3.7% in surgical candidates (Meckel's diverticulum, tumor), 40% in endoscopically treated and 16% in medically treated patients. In case all the detected angiectasias had been cauterized, the relapse rate was low (11.8%), but in incompletely treated patients, it was high (85.7%). Bleeding relapse was never lethal. Conclusion CE guides therapeutic measures and predicts the risk of recurrent bleeding in small intestinal bleeding. High risk of rebleeding in angiectasias is significantly reduced by the cauterization of all demonstrable lesions.

Struktur der Leitlinie ! Vorwort Die Überarbeitung der 2004 publizierten S3-Leitlinie über „Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virus-(HBV-)Infektion“ wurde vereinbart als Kooperation der Deutschen Gesellschaft für Verdauungsund Stoffwechselkrankheiten e.V. (DGVS), der Deutschen Gesellschaft für Pathologie e. V. (DGP), der Gesellschaft für Virologie (GfV), der Gesellschaft für Pädiatrische Gastroenterologie und Ernährung (GPGE) sowie des Kompetenznetz Hepatitis (Hep-Net). Hierzu wurden sieben Leitlinien-Arbeitsgruppen sowie ein Advisory Board gegründet, welches sich aus Vertretern der vier Fachgesellschaften sowie des Hep-Nets zusammensetzte (Tab. 1). Fachlich repräsentierten die Mitglieder die Disziplinen Gastroenterologie und Hepatologie, Infektiologie, Virologie, Pathologie, Chirurgie und Epidemiologie. Den Versorgungsstrukturen in Deutschland wurde durch die Beteiligung klinisch tätiger sowie niedergelassener Vertreter Rechnung getragen, die Sicht der Patienten repräsentierte die Patientenorganisation Deutsche Leberhilfe e. V.

The update of the S 3-guideline on "prophylaxis, diagnosis, and therapy of hepatitis B virus (HBV) infection" published in 2004 was agreed upon in cooperation with the German Society for Digestive and Metabolic Diseases (DGVS), the German Society for Pathology (DGP), the Society for Virology (GfV), the Society for Pediatric Gastroenterology and Nutrition (GPGE), and the Competence Network for Viral Hepatitis (Hep-Net). Seven guideline task forces and an advisory board were established. [Table 1] shows the representatives from the four societies. Members represent the disciplines gastroenterology and hepatology, infectiology, virology, pathology, surgery, and epidemiology. The structure of the German health care system was taken into account by involving doctors who work in hospitals and private practices. The patient organization Deutsche Leberhilfe e. V. represents the patients' point of view ([Table 2]).

Wait-listed (n = 226) or post-liver transplantation (n = 241) chronic hepatitis B (CHB) patients with lamivudine-resistant hepatitis B virus (HBV) were treated with adefovir dipivoxil for a median of 39 and 99 weeks, respectively. Among wait-listed patients, serum HBV DNA levels became undetectable (<1,000 copies/mL) in 59% and 65% at weeks 48 and 96, respectively. After 48 weeks, alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 77%, 76%, 60%, and 84% of wait-listed patients, respectively. Among posttransplantation patients, serum HBV DNA levels became undetectable in 40% and 65% at weeks 48 and 96, respectively. After 48 weeks, ALT, albumin, bilirubin, and prothrombin time normalized in 51%, 81%, 76%, and 56% of posttransplantation patients, respectively. Among wait-listed patients who underwent on-study liver transplantation, protection from graft reinfection over a median of 35 weeks was similar among patients who did (n = 34) or did not (n = 23) receive hepatitis B immunoglobulin (HBIg). Hepatitis B surface antigen was detected on the first measurement only in 6% and 9% of patients who did or did not receive HBIg, respectively. Serum HBV DNA was detected on consecutive visits in 6% and 0% of patients who did or did not receive HBIg, respectively. Treatment-related adverse events led to discontinuation of adefovir dipivoxil in 4% of patients. Cumulative probabilities of resistance were 0%, 2%, and 2% at weeks 48, 96, and 144, respectively. In conclusion, adefovir dipivoxil is effective and safe in wait-listed or posttransplantation CHB patients with lamivudine-resistant HBV and prevents graft reinfection with or without HBIg.