In order to elucidate the clinical significance of the erbB family, epidermal growth factor receptor (EGF-R), c-erbB-2, c-erbB-3 and c-erbB-4 in hepatocellular carcinoma (HCC), we investigated the expression of these proteins by means of immunohistochemistry for HCC as well as adjacent noncancerous lesions. EGF-R was expressed in 68% of the HCC examined and showed correlation with the proliferating activity, stage, intrahepatic metastasis and carcinoma differentiation. c-erbB-2 was expressed in only 21% of the cases and showed no relationships with the clinicopathological parameters. c-erbB-3 protein was observed in 84% of the HCC and 38.1% of the noncancerous lesions. Its expression in HCC was equal to or greater than noncancerous lesions in 90.5% of the cases, and was related to the stage, portal invasion, cell proliferating activity, tumour size, intrahepatic metastasis and carcinoma differentiation. c-erbB-4 protein was expressed in 61.0% of HCC and in as much as 86.1% of the noncancerous lesions. Unlike the expression of c-erbB-3, that of c-erbB-4 in HCC was less than that of the adjacent noncancerous lesions in 51.2% of the cases. No statistical significance could be established between this protein expression in HCC and clinicopathological features. EGF-R and c-erbB-3 affected disease-free survival, but were not recognized as independent prognostic factors by multivariate analysis. The present study suggests that, of the four receptors, EGF-R and c-erbB-3 play important roles in the progression of HCC. © 2001 Cancer Research Campaign www.bjcancer.com

Expression of cell-cycle modulators at the G 1 -S boundary, retinoblastoma gene product (pRb), p21, p16, p27, p53, cyclin D 1 , and cyclin E was investigated with 104 hepatocellular carcinomas (HCC), as well as 90 of their adjacent noncancerous lesions and 9 normal liver control specimens. The labeling indices (LI) of pRb, p21, p16, and p27 were higher in HCC lesions than in the adjacent noncancerous lesions and normal controls. Especially, p27 LI in noncancerous lesions was significantly higher than that in normal livers (P ‫؍‬ .011). Aberrant p53 expression and cyclin D 1 and E overexpression were observed exclusively in HCC lesions. pRb was positive in 85.6% of the HCC cases and was not related to any clinicopathological parameters. The p21 LI was generally low (average, 5.5 ؎ 9.8). Although a negative regulator, p21 LI was higher in cases with intrahepatic metastasis (P ‫؍‬ .0359). The p16 LI was significantly decreased (P ‫؍‬ .0121) in cases with advanced stage. p27 LI was significantly decreased in cases with portal invasion (P ‫؍‬ .0409), poor differentiation (P F .0001), larger size (P ‫؍‬ .0421), and intrahepatic metastasis (P ‫؍‬ .0878, borderline significance). On the other hand, aberrant p53 expression showed positive relationships with poor differentiation (P ‫؍‬ .0004) and Ki-67 LI (P ‫؍‬ .0047). Cyclin D 1 overexpression was found in 32.6% of the cases and occurred more frequently in those with high Ki-67 LI (P ‫؍‬ .0032), pRb expression (P ‫؍‬ .0202), poor differentiation (P ‫؍‬ .0612, borderline significance), and intrahepatic metastasis (P ‫؍‬ .0675, borderline significance). Cyclin E was overexpressed in 35.5% and had positive relationships with Ki-67 LI (P ‫؍‬ .0269) and stage (P ‫؍‬ .0125). In univariate analysis, cases with p27 LI F 50 (P ‫؍‬ .0004), cyclin D 1 overexpression (P ‫؍‬ .0041), and cyclin E overexpression (P ‫؍‬ .0572, borderline significance) showed poorer outcomes for disease-free survival (DFS). In multivariate analysis, p27 expression could be recognized as an independent prognostic marker for DFS. These findings suggest that in HCC: 1) p27 is active against HCC progression in early phases and, possibly, hepatocarcinogenesis as a negative regulator and can be a novel prognostic marker for DFS; and 2) cyclin D 1 predominantly works for cell-cycle progression at the G 1 -S boundary. (HEPATOLOGY 1999;30:90-99.)

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BackgroundRecently, problems associated with proton pump inhibitor (PPI) use have begun to surface. PPIs influence the gut microbiota; therefore, PPI use may increase the risk of enteric infections and cause bacterial translocation. In this study, we investigated fecal microbiota composition, fecal organic acid concentrations and pH, and gut bacteria in the blood of the same patients before and after PPI use.MethodsTwenty patients with reflux esophagitis based on endoscopic examination received 8 weeks of treatment with PPIs. To analyze fecal microbiota composition and gut bacteria in blood and organic acid concentrations, 16S and 23S rRNA-targeted quantitative RT-PCR and high-performance liquid chromatography were conducted.ResultsLactobacillus species were significantly increased at both 4 and 8 weeks after PPI treatment compared with bacterial counts before treatment (P = 0.011 and P = 0.002, respectively). Among Lactobacillus spp., counts of the L. gasseri subgroup, L. fermentum, the L. reuteri subgroup, and the L. ruminis subgroup were significantly increased at 4 and 8 weeks after treatment compared with counts before treatment. Streptococcus species were also significantly increased at 4 and 8 weeks after PPI treatment compared with counts before treatment (P < 0.01 and P < 0.001, respectively). There was no significant difference in the total organic acid concentrations before and after PPI treatment. Detection rates of bacteria in blood before and after PPI treatment were 22 and 28%, respectively, with no significant differences.ConclusionsOur quantitative RT-PCR results showed that gut dysbiosis was caused by PPI use, corroborating previous results obtained by metagenomic analysis.