Despite complete resection, disease-free survival (DFS) of patients with cholangiocarcinoma (CCA) is less than 65 % after one year and not more than 35 % after three years. For muscle invasive gallbladder carcinoma (GBCA), prognosis is even worse, with an overall survival (OS) of only 30 % after three years. Thus, evaluation of adjuvant chemotherapy in biliary tract cancer in a large randomized trial is warranted. ACTICCA-1 is a randomized, multidisciplinary, multinational phase III investigator initiated trial. With respect to data obtained in the ABC-02 trial, we selected the combination of gemcitabine and cisplatin for 24 weeks as investigational treatment. Based on adjuvant trials in pancreatic cancer with comparable postoperative recovery time, inclusion of patients within a maximum interval of 16 weeks between surgery and start of chemotherapy was stipulated. Due to the different prognosis and treatment susceptibility of muscle invasive carcinoma, two separate cohorts (CCA and GBCA) were included to capture the potentially different treatment effects. Randomization is stratified for lymph node status for both cohorts and localization for CCA. The primary endpoint is DFS and secondary endpoints include OS, safety and tolerability of chemotherapy, quality of life, and patterns of disease recurrence. For CCA, adjuvant chemotherapy should increase DFS 24 months post-surgery from 40 to 55 % to be considered relevant. With a power of 80 % and a significance level of 5 %, 271 evaluable study patients have to be followed for 24–28 months to observe 166 events. For GBCA, chemotherapy should increase DFS 24 months post-surgery from 35 to 55 % to be of relevance; thus, 154 evaluable study patients have to be monitored for 24–28 months to observe 90 events. In both cohorts, randomization will be 1:1 with chemotherapy for 24 weeks and imaging every twelve weeks. In 2014, the study was initiated in Germany and in The Netherlands (funded by the Deutsche Krebshilfe, the Dutch Cancer Society, and supported by medac GmbH). Sites in Australia, Denmark, and the United Kingdom (funded by Cancer Research UK) are joining 2015. The study is registered with ClinicalTrials.gov ( NCT02170090 ) and the European Clinical Trials Database (2012-005078-70). Registration date is 06/18/2014.

Autochthonous hepatitis E has been observed with growing incidence in industrialized countries. Hepatitis E virus infection causes an acute hepatitis with spontaneous resolution in the majority of cases. However, in individual cases, hepatitis E may lead to life-threatening acute liver failure. In this report, we describe a case of acute liver injury caused by an autochthonous hepatitis E that resolved under steroid treatment. To our knowledge, this is the first case report describing supportive steroid monotherapy for acute liver injury due to hepatitis E. A 63-year-old Caucasian male presented with acute liver injury of unknown origin. After excluding the most prevalent causes of acute liver injury, liver histology revealed signs of immune-mediated toxic or drug-induced liver injury. Therefore, immunosuppressive treatment with prednisolone was started. After initialization of steroid treatment, polymerase chain reaction analyses of peripheral blood and liver tissue revealed an acute hepatitis E virus infection (genotype 3). Under sustained steroid treatment, acute liver injury improved and hepatitis E infection resolved. Steroid treatment might be an option to prevent progress of life-threatening liver failure and liver transplantation in patients with hepatitis E-induced acute liver injury and high-grade inflammation.

Advanced hepatocellular carcinoma (HCC) with vascular invasion and/or extrahepatic spread and preserved liver function, according to stage C of the Barcelona Clinic Liver Cancer (BCLC) classification, has a dismal prognosis. The multi-targeted tyrosine-kinase receptor inhibitor (TKI) sorafenib is the only proven active substance in systemic HCC therapy for first-line treatment. In this review, we summarize current aspects in patient selection and management of side effects, and provide an update on response evaluation during first-line sorafenib therapy. Since second-line treatment options have been improved with the successful completion of the RESORCE trial, demonstrating a survival benefit for second-line treatment with the TKI regorafenib, response monitoring during first-line therapy will be critical to deliver optimal systemic therapy in HCC. To this regard, specific side effects, in particular worsening of arterial hypertension and diarrhea, might suggest treatment response during first-line sorafenib therapy; however, clear predictive clinical markers, as well as laboratory test or serum markers, are not established. Assessment of radiologic response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) is helpful to identify patients who do not benefit from sorafenib treatment.

Hepatocarcinogenesis is a multistep process driving the progressive transformation of normal liver cells into highly malignant derivatives. Unlimited proliferation and telomere maintenance have been recognized as prerequisites for the development of liver cancer. Moreover, recent studies identified illegitimate β-catenin signaling as relevant hit in a considerable subset of patients. To further investigate the currently not well-understood malignant evolution driven by telomerase and β-catenin, we monitored cytogenetic and phenotypic alterations in untransformed telomerase-immortalized human fetal hepatocytes following forced activation of β-catenin signaling. As expected, constitutive activation of β-catenin signaling significantly enhanced proliferation with decreasing serum dependence. Previously intact contact inhibition was almost completely eliminated. Interestingly, after several passages in cell culture, immortalized clones with dominant-positive β-catenin signaling acquired additional chromosomal aberrations, in particular translocations, anchorage-independent growth capabilities, and formed tumors in athymic nude mice. In further support for the driving role of β-catenin during hepatocarcinogenesis, improved colony growth in soft agar and accelerated tumor formation was also confirmed in Huh7 cells following stable expression of the constitutively active S33Y β-catenin mutant. Telomerase inhibition showed that short-term expansion of transformed clones was not telomerase dependent. Finally, cancer pathway profiling in derived tumors revealed upregulation of characteristic genes associated with invasion and angiogenesis. In conclusion, illegitimate activation of β-catenin signaling enhances the transformation from immortalization to malignant growth in human fetal hepatocytes. Our data functionally confirm a permissive role for β-catenin signaling in the initial phase of hepatocarcinogenesis. Mol Cancer Res; 9(9); 1222–31. ©2011 AACR.

In Deutschland starben 2015 mehr als 13 000 Menschen an den Folgen einer Leberzirrhose. Die Diagnose einer fortgeschrittenen Leberschädigung kann häufig mit nicht-invasiven Methoden (z. B. mittels ultraschallbasierter Messung der Steifigkeit des Lebergewebes) bereits im noch kompensierten Stadium gestellt werden. Entscheidend ist bei Diagnosestellung eine umfassende Ursachenabklärung und konsequente Therapie der zugrundeliegenden chronischen Lebererkrankung, um einen weiteren Progress bis zur Dekompensation zu verhindern. Da insbesondere bei einer Dekompensation (angezeigt u. a. durch Ikterus, Aszites, hepatische Enzephalopathie, gastrointestinale Blutung) Morbidität und Mortalität deutlich ansteigen (z. B. steigt die 1-Jahres-Mortalität von 1 – 3,4 % auf 20 – 57 %), sind prophylaktische Maßnahmen zur Vermeidung einer Dekompensation indiziert. Diese Maßnahmen umfassen nach Risikostratifizierung einer portalen Hypertension den Einsatz von Propranolol oder Carvedilol sowie eine endoskopische Ligatur mit Gummibändern zur Primärprophylaxe einer Varizenblutung. Aufgrund des hohen Risikos für eine maligne Transformation (je nach Ätiologie der Leberzirrhose 2 – 8 % pro Jahr), ist auch eine sonografische Überwachung alle sechs Monate zur frühen Diagnose eines Leberzellkarzinoms entscheidend, um eine kurative Therapie zu ermöglichen. Diskutiert wird auch der Einsatz von Antibiotika zur Vermeidung von Infektionen, die in vielen Fällen eine akute Dekompensation auslösen. Hier ist die Datenlage noch nicht überzeugend und das Risiko einer Resistenzbildung ist zu beachten. Unbedingt sollte aber der Impfstatus überprüft und Impflücken geschlossen werden. Zur Versorgung bei kompensierter Leberzirrhose gehören auch eine ernährungsphysiologische Beratung und ggf. medikamentöse Therapien, um das Voranschreiten von Osteoporose und Muskelatrophie aufzuhalten. In diesem Aufsatz werden die einzelnen Maßnahmen zur prophylaktischen Versorgung bei kompensierter Leberzirrhose vorgestellt und vor dem Hintergrund der pathophysiologischen Grundlagen und wegweisender klinischer Studien diskutiert. Sollte es trotz dieser prophylaktischen Maßnahmen zu einer Dekompensation kommen (ca. 15 % der Patienten mit Leberzirrhose jährlich), ist die Indikation zur Lebertransplantation als definitive Therapie der Leberzirrhose zu prüfen (spätestens ab einem MELD-Index > 15). In 2015, more than 13 000 people died due to the consequences of liver cirrhosis in Germany. Frequently, relevant liver fibrosis is diagnosed by non-invasive methods (e. g., ultrasound-based measurement of liver stiffness) already in the compensated stage. Following diagnosis of liver fibrosis, a thorough investigation of the underlying chronic liver disease and effective treatment are important to prevent progression to decompensated cirrhosis. Since morbidity and mortality dramatically increase in the decompensated stage (patients may present with jaundice, ascites, hepatic encephalopathy, gastrointestinal bleeding) with an upsurge in 1-year-mortality from 1 – 3.4 % to 20 – 57 %, prophylactic measures to prevent decompensation are indicated. Based on a risk stratification, these measures include propranolol or carvedilol as non-selective betablockers, as well as endoscopic band ligations as primary prophylaxis to prevent variceal bleeding. Because of the high risk for malignant transformation (2 – 8 % per year depending on the underlying etiology), surveillance by liver ultrasound every six months is essential to detect liver cancer in an early stage and to facilitate curative therapy. Currently under debate is the administration of antibiotics to prevent bacterial infections, which commonly trigger acute decompensation. To this regard, studies are not convincing and the risk to induce drug resistance has to be observed. However, health care providers should check the vaccination status and recommend missing vaccinations. The management of compensated liver cirrhosis also includes counseling and potentially also a drug therapy to prevent osteoporosis and muscle wasting. In this review, we will discuss specific prophylactic measures in the management of compensated liver cirrhosis based on the pathophysiological background and central clinical studies. If a patient decompensates despite these prophylactic measures (approximately 15 % of patients with liver cirrhosis per year), liver transplantation has to be discussed as definitive therapy (especially in patients with MELD > 15).

Constitutive gp130 activation rapidly accelerates the transformation of human hepatocytes via an impaired oxidative stress response