20 Moreover, the HCV titer did not significantly increase after B cell depletion with rituximab (Fig. 6), which is inconsistent with B cells harboring significant amounts of virus. Alternative suggestions include B cell stimulation by HCV core JAK2 inhibitor drug and E2,10, 21-23 but this also cannot explain the restricted repertoire of pathogenic B cells in HCV-related MC. Thus, we favor the hypothesis that a combination of multiple factors, including chronic antigen stimulation,23 elevated B cell growth factor expression,17 and genetic predisposition,24 trigger B cell clonal expansion. Rituximab therapy is an alternative treatment approach for MC patients who have failed antiviral therapy. All patients enrolled

in our study responded effectively to rituximab,7 as B cells were undetectable within 2 months (Fig. 6) and were recovered 6-12 months after

cessation of therapy. Prior to treatment, HCV-infected patients with MC displayed not only an increased frequency of immature Selleckchem Fulvestrant transitional B cells in the blood, but also an altered ratio of T1 to T2 immature transitional B cells. Uninfected controls generally have a 1:3 ratio of T1:T2 immature transitional B cells, but this ratio decreased to 1:5-1:6 in HCV-infected patients with MC. The altered T1:T2 ratio was not linked to apoptosis as immature B cells from HCV-infected patients with MC expressed lower levels of Bcl-2 than those of HCV-infected patients without MC and uninfected controls (data not shown). Rather, MCE it was related to cryoglobulin levels, which decreased in parallel with the in vivo proliferation rate (as measured by Ki-67 levels) of T2 immature transitional B cells (Fig. 6). In conclusion, we propose a model in which infection with HCV induces apoptosis of naïve mature B cells resulting in an increased size of the immature B cell subset. This process is accelerated in the presence of MC. Furthermore, MC promotes the proliferation of T2 immature transitional

B cells, resulting in a decreased T1/T2 ratio. Treatments that reduce cryoglobulin levels such as rituximab restore a normal T1/T2 ratio with reduced proliferation of T2 immature transitional B cells. These data provide a mechanistic explanation for the observed maintenance of normal B cell numbers and the increase in immature transitional B cells in the blood of chronic HCV patients with MC. We thank Catherine Rehm and Laura Heytons for the collection of patient samples during rituximab therapy. Additional Supporting Information may be found in the online version of this article. “
“Background and Aim:  Repeat hepatic resection for recurrent hepatocellular carcinoma (HCC) is effective in improving long-term outcome in selected patients. In the present study, we attempted to identify the prognostic factors influencing overall and recurrence-free survival after the second hepatic resection.