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Apoptosis signaling is involved in both physiological tissue homeostasis and acute and chronic diseases. The role of regulatory apoptosis signaling molecules and their organ-specific functions are less defined. Therefore, we investigated the loss of the anti-apoptotic cellular FLICE-inhibitory protein (cFLIP) and the mechanisms of the resulting lethal organ failure in vivo using inducible knockout mice. These were generated by crossing floxed cFLIP mice to a tamoxifen inducible Rosa26-creERT2 mouse strain. Death following global loss of cFLIP resulted from liver failure, accumulation of M1-polarized macrophages and accompanying hepatic cell death and inflammation. Apoptosis was also prominent in immune cells, the kidney and intestinal epithelial cells (IECs) but not in cardiomyocytes. Cellular injury led to the release of damage-associated molecular patterns (DAMPs) and the induction of innate immune receptors including toll-like receptors (TLRs) 4 and 9, and stimulator of interferon genes (STING). Transplantation of bone marrow with intact cFLIP or depletion of macrophages prevented the phenotype of acute liver failure. Interestingly, compound deletion of cFLIP in bone marrow-derived cells and hepatocytes did not promote organ failure. Thus, cFLIP exerts a critical role in tissue homeostasis by preventing the activation of monocytic cells and innate immunity, which causes cell death and inflammation in susceptible tissues. These results encourage the development of organ-specific anti-apoptotic and anti-inflammatory therapies in acute organ failure.

The impact of erythropoiesis-stimulating agents in chemotherapy-induced anemia has been a constant topic of debate over recent years. We prospectively assessed the efficacy of epoetin beta (Epo-b) in improving hemoglobin (Hb) levels and outcome in patients within an open label, randomized clinical phase II trial with advanced or metastatic gastric/esophagogastric cancer.Previously untreated patients were randomized to receive 3-weekly cycles of capecitabine (1000 mg/m(2) bid) for 14 days plus on day 1 either irinotecan 250 mg/m(2) or cisplatin 80 mg/m(2). Epo-b (30000 IU once weekly) was initiated in patients with Hb11 g/dl and continued until Hb ≥12 g/dl was reached. If after 4 weeks the Hb increase was0.5 g/dl, Epo-b was increased to 30000 IU, twice weekly.Of 118 patients enrolled, 32 received Epo-b treatment; of these, 65 % achieved an increase in Hb levels of at least 2 g/dl, with 74 % achieving the target Hb of ≥12 g/dl. Within the study population, patients receiving Epo-b showed better overall survival (median 14.5 vs. 8.0 months, P = 0.056) as well as a significantly improved disease control rate (78 vs. 55 %, P = 0.025). Patients in the irinotecan group profited significantly (P0.05) in terms of progression-free survival and overall survival under Epo-b treatment (median 6.5 vs 4.1 months and median 15.4 vs 8.4 months, respectively).Epo-b was effective in raising Hb levels in patients with advanced esophagogastric cancer. Patients receiving Epo-b had a significantly increased response to chemotherapy and a clear trend to improved survival.

Background: The combination of sofosbuvir (SOF), ribavirin (RBV) and peg-interferon-alfa-2a (peg-IFN-alfa-2a) as well as the combination of SOF and RBV for the treatment of patients infected with hepatitis c virus (HCV) has improved rates of sustained virological response (SVR) considerably in recent trials. However, there is only limited data concerning the efficacy and safety in a “real-life” cohort. Methods: We analyzed a cohort of 119 patients with chronic HCV infection treated at four investigational sites in Germany. All patients received either a combination treatment of SOF, RBV and peg-IFN-alfa-2a or SOF and RBV. Results: The rates of SVR at 12 weeks after end of treatment (SVR 12) were as follows: Among 76 patients with genotype 1 infection the SVR 12 rate was 74 % (n = 56), among 14 patients with genotype 2 infection the SVR 12 rate was 79 % (n = 11), among 24 patients with genotype 3 infection the SVR 12 rate was 92 % (n = 22) and among 5 patients with genotype 4 infection the SVR 12 rate was 80 % (n = 4). Of all 26 patients with a relapse in our cohort, 69 % (n = 18) of these patients presented with liver cirrhosis and 58 % (n = 15) were treatment experienced. Notably, the level of HCV-RNA after 4 weeks of treatment was a significant predictor of treatment response in genotype 1 patients. Patients with HCV-RNA levels ≥ 12 IU ml-1 after 4 weeks of treatment achieved SVR 12 only in 30 % (n = 17/56, p

Die primar sklerosierende Cholangitis (PSC) ist eine idiopathische, destruierende Erkrankung der Gallengange, welche zum terminalen Leberversagen fuhren kann. Das Cholangiokarzinom (CCA) ist eine gefurchtete Komplikation der PSC. Die jahrliche Inzidenz des CCA betragt bei Patienten mit einer PSC 0,6–1,5% pro Jahr und ist besonders hoch in den ersten 2 Jahren nach Diagnose der PSC. Hierbei tragt die infauste Prognose eines fortgeschrittenen CCA entscheidend zur Gesamtmortalitat der PSC bei. Damit die Chance auf eine Erfolg versprechende Therapie des CCA gewahrt bleibt, mussen bei PSC-Patienten regelmasige Tumorvorsorgeuntersuchungen erfolgen. Bei ungenugender diagnostischer Sicherheit der einzelnen Screeningverfahren ergibt sich die beste Spezifitat und Sensitivitat aus der Kombination von endoskopischer, laborchemischer und zytologischer Diagnostik. Im Falle eines lokalisierten Befunds kann die radikale Resektion des Cholangiokarzinoms erwogen werden. Als experimentelles kuratives Therapieverfahren wird die orthotope Lebertransplantation im Anschluss an eine neoadjuvante Radiochemotherapie diskutiert. In der palliativen Situation beschranken sich die Masnahmen auf die Kontrolle der cholestatischen Komplikationen des CCA durch lokale Therapien. Die palliative Chemotherapie des CCA ist der palliativ-supportiven Therapie kaum uberlegen.