Downstaging disease in patients with hepatocellular carcinoma outside of Milan criteria: strategies using drug-eluting bead chemoembolization.

PURPOSE: To assess downstaging rates in patients with United Network for Organ Sharing stage T3N0M0 hepatocellular carcinoma (HCC) treated with doxorubicin-eluting bead transarterial chemoembolization to meet Milan criteria for transplantation. MATERIALS AND METHODS: A single-center retrospective review of 239 patients treated with doxorubicin-eluting bead (DEB) chemoembolization between September 2008 and December 2011 was undertaken. Baseline and follow-up computed tomography or magnetic resonance imaging was assessed for response based on the longest enhancing axial dimension of each tumor (ie, modified Response Evaluation Criteria In Solid Tumors measurements), and medical records were reviewed. Fisher exact tests and exact logistic regression were used to test the association of patient and disease characteristics with downstaging. RESULTS: After exclusions, 22 patients remained in the analysis, 17 of whom (77%) had their HCC downstaged to meet Milan criteria. Among those whose disease was downstaged, seven underwent transplantation, one remained listed for transplantation, six had disease progression beyond Milan criteria, two underwent conventional transarterial chemoembolization, and one underwent radiofrequency ablation. The seven patients who received transplants were still living, but recurrent HCC developed in two. Baseline age (P = .25), Model for End-stage Liver Disease score (P = .77), and α-fetoprotein (AFP) level (P = 1.00) were similar between patients with and without downstaged HCC. No associations were observed between the odds of downstaging and sex (P = .21), Child-Pugh class (P = .14), Child-Pugh class controlling for baseline tumor multiplicity (P = .15), Eastern Cooperative Oncology Group performance status (P = 1.00), tumor burden (P = .31), multiple tumors (P = .31), or hepatitis C virus infection (P = 1.00). Fifteen patients who did not receive transplants were alive at 1 year, with two progression-free. Baseline AFP levels differed between those who survived 1 year and those who did not (P = .02), but did not differ by progression-free survival status (P = .62). CONCLUSIONS: T3N0M0 HCC treatment with DEB chemoembolization has a high likelihood (77%) of downstaging the disease to meet Milan criteria.

Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase-beta.

Neutropenia and neutrophil dysfunction are common in many diseases, although their etiology is often unclear. Previous views held that there was a single ER enzyme, glucose-6-phosphatase-alpha (G6Pase-alpha), whose activity--limited to the liver, kidney, and intestine--was solely responsible for the final stages of gluconeogenesis and glycogenolysis, in which glucose-6-phosphate (G6P) is hydrolyzed to glucose for release to the blood. Recently, we characterized a second G6Pase activity, that of G6Pase-beta (also known as G6PC), which is also capable of hydrolyzing G6P to glucose but is ubiquitously expressed and not implicated in interprandial blood glucose homeostasis. We now report that the absence of G6Pase-beta led to neutropenia; defects in neutrophil respiratory burst, chemotaxis, and calcium flux; and increased susceptibility to bacterial infection. Consistent with this, G6Pase-beta-deficient (G6pc3-/-) mice with experimental peritonitis exhibited increased expression of the glucose-regulated proteins upregulated during ER stress in their neutrophils and bone marrow, and the G6pc3-/- neutrophils exhibited an enhanced rate of apoptosis. Our results define a molecular pathway to neutropenia and neutrophil dysfunction of previously unknown etiology, providing a potential model for the treatment of these conditions.