Inhibition of Akt pathway phosphorylation as a mechanism in the pathogenesis of functional intestinal obstruction in carcinomatosis peritonei

The purpose of this study was to confirm our hypothesis that the development of functional intestinal obstruction in carcinomatosis peritonei [CP] is related to cytokine-mediated inhibition of the Akt pathway and to investigate the phenomenon of relative adrenal insufficiency in CP. Human adrenocortical cells [NCI-H295R] were treated with serum derived from eight cancer patients who had intestinal obstruction and functional adrenal insufficiency. Serum from three normal healthy subjects and three who had CP but without intestinal obstruction or adrenal insufficiency were used as controls. The differential effects of serum on the treated cells were studied using Western blot analysis. Cortisol production of these treated cells was assayed with cortisol ELISA kits. Phosphorylation of Akt at Ser473 and Ser308 in cells was significantly reduced when treated with serum from patients with intestinal obstruction but not controls. Phosphorylation of PDK1 at Ser241, mTOR downstream targets like p70S6 at Thr421/Ser424 and Thr389, and lastly 4EBP-1 at Ser70 a downstream target of p70S6 was reduced by approximately 50%, 40%, and 70%, respectively. There was enhanced phosphorylation of elF4E an initiating factor in protein translation in cells treated with patient serum compared to controls. Cortisol synthesis was stimulated upon treatment with patient serum but not with control serum. Inhibition of Akt phosphorylation is a mechanism that could play a major role in the development of intestinal obstruction in carcinomatosis peritonei. The identification of the mediating cytokines will lead to the development of cogent targeted therapeutic strategies

new chemoimmunotherapy regimen [OXAFI] for advanced hepatocellular carcinoma

Chemotherapeutic treatment options for advanced unresectable and/or metastatic hepatocellular carcinoma [HCC] are limited. Currently available treatments are associated with low response rates and little evidence of improved survival, so we evaluated a new chemoimmunotherapy regimen. Seven patients with unresectable and/or metastatic HCC were treated with intravenous oxaliplatin [30mg/m[2]] and doxorubicin [20mg/m[2]] given on days 1, 8 and 15 in a 28-day cycle, a daily continuous infusion of fluorouracil [200mg/m[2]] and subcutaneous interferon alfa-2b 5 MU administered thrice weekly [OXAFI]. Treatment was administered to a maximum of six cycles. Data on the response to treatment, toxicity, surgical procedures and survival outcome was reviewed. The best response was three partial responses, three stable disease responses and one progressive disease response. Two patients underwent interval hepatic resection, and histological analysis in one patient showed a complete pathological response. Another patient underwent a liver transplant after four cycles of treatment. These three patients were alive with no evidence of disease at 23, 21 and 18 months follow-up, respectively. At a median follow-up of 14 months [range 2-23 months], one patient died 2 months after diagnosis due to progressive disease, while all six other patients were alive. Neutropenia was the predominant toxicity, but there were no episodes of febrile neutropenia, hospital admissions or deaths. There were no cases of hepatitis B virus re-activation. OXAFI shows activity in HCC and has manageable toxicity. Complete pathological remission is possible with this regimen