The endemic occurrence of obesity and the associated risk factors that constitute the metabolic syndrome have been predicted to lead to a dramatic increase in chronic liver disease. Non-alcoholic steatohepatitis (NASH) has become the most frequent liver disease in countries with a high prevalence of obesity. In addition, hepatic steatosis and insulin resistance have been implicated in disease progression of other liver diseases, including chronic viral hepatitis and hepatocellular carcinoma. The molecular mechanisms underlying the link between insulin signaling and hepatocellular injury are only partly understood. We have explored the role of the antiapoptotic caspase-8 homolog cellular FLICE-inhibitory protein (cFLIP) on liver cell survival in a diabetic model with hypoinsulinemic diabetes in order to delineate the role of insulin signaling on hepatocellular survival. cFLIP regulates cellular injury from apoptosis signaling pathways, and loss of cFLIP was previously shown to promote injury from activated TNF and CD95/Apo-1 receptors. In mice lacking cFLIP in hepatocytes (flip−/−), loss of insulin following streptozotocin treatment resulted in caspase- and c-Jun N-terminal kinase (JNK)-dependent liver injury after 21 days. Substitution of insulin, inhibition of JNK using the SP600125 compound in vivo or genetic deletion of the mitogen-activated protein kinase (MAPK)9 (JNK2) in all tissues abolished the injurious effect. Strikingly, the difference in injury between wild-type and cFLIP-deficient mice occurred only in vivo and was accompanied by liver-infiltrating inflammatory cells with a trend toward increased amounts of NK1.1-positive cells and secretion of proinflammatory cytokines. Transfer of bone marrow from rag-1-deficient mice that are depleted from B and T lymphocytes prevented liver injury in flip−/− mice. These findings support a direct role of insulin on cellular survival by alternating the activation of injurious MAPK, caspases and the recruitment of inflammatory cells to the liver. Thus, increasing resistance to insulin signaling pathways in hepatocytes appears to be an important factor in the initiation and progression of chronic liver disease.
HR 0.694; 95% CI 0.571, 0.842; p¼.0002). Improvements in PFS (median PFS 2.8 mo vs 1.5 mo PBO; HR 0.572; 95% CI 0.472, 0.694; p<.0001), ORR (5.4% RAM vs 0.9% PBO (p¼.0040), and disease control rate (ORR þ stable disease ¼ 56.3% RAM vs 37.2% PBO [p<.0001]) were observed. The relative dose intensity was 98.3% RAM vs 99.6% PBO. 9.5% of patients on the RAM arm vs 3.6% on PBO discontinued study treatment due to adverse events (AEs) related to study treatment. Hypertension (12.0% RAM vs 3.6% PBO) and hyponatremia (5.1% RAM vs 2.2% PBO) were the only Grade (G) !3 treatment-emergent adverse events (TEAEs) occurring in ! 5% in RAM. Conclusions: A pooled analysis of two phase 3 trials assessing ramucirumab as secondline treatment in patients with HCC following first-line sorafenib (REACH-2 and REACH) demonstrates a significant and clinically meaningful benefit with a favorable safety profile in HCC patients with baseline AFP !400 ng/mL. LBA À 002 Overall survival results from a phase III trial of trifluridine/tipiracil versus placebo in patients with metastatic gastric cancer refractory to standard therapies (TAGS)
With the advent of a minimally invasive laparoscopy technique, the advantages of diagnostic laparoscopy are being rediscovered. We report here on four patients with systemic disease of unknown origin and splenomegaly, in whom minilaparoscopy-guided splenic biopsy yielded a definitive diagnosis. Four patients with unclear systemic disease were studied using diagnostic minilaparoscopy and guided spleen biopsy, after failure of diagnostic work-up. Minilaparoscopic spleen biopsy revealed the diagnosis of a B-cell non-Hodgkin's lymphoma in two cases. In one patient, who had a history of Still's disease, the spleen biopsy showed granulocytic infiltration in the spleen typical of an acute episode of Still's disease. One patient with a known immunodeficiency syndrome (stage C III) showed multiple hypodense lesions in the spleen. Biopsy allowed a diagnosis of mycobacterial infection, with identification of Mycobacterium tuberculosis. No major complications occurred in any of the four cases; post-biopsy bleeding was observed in three of the four, but was easily managed by argon plasma coagulation or application of fibrin glue, or both. We recommend the use of spleen biopsy as a diagnostic tool in splenopathy of unknown origin if previous diagnostic methods have failed to yield a definitive diagnosis.
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