Modification of the 8th American Joint Committee on Cancer staging system for gallbladder carcinoma to improve prognostic precision.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for gallbladder carcinoma (GBC) came into force since 2018. However, the prognostic precision of this staging system has not been properly assessed. This study aimed to evaluate the latest staging system and suggest modifications to improve its prognostic precision. METHODS: Data of patients with GBC was included from the Surveillance, Epidemiology and End Results (SEER) database (2004-2015) and multicenter database (2010-2017). Baseline clinicopathologic characteristics were recorded including age, sex, race, grade, T category, N category, M category and stage. The Kaplan-Meier method was used to plot survival functions. The prediction power of the AJCC 8th edition and its modified version were evaluated using the concordance index (C-index). RESULTS: A total of 2779 GBC patients were included in the SEER database and 591 were collected from multicenter database. While no significant difference in survival of patients was observed between stages IVA and IVB using the 8th AJCC staging system (p > 0.05), the prognosis of stage IIIA showed a slightly better outcome than stage IIIB (p = 0.046) in the SEER database. In the multicenter database, there was no significant difference between stage IIIA and stage IIIB (p > 0.05). Similarly, no significant difference in the survival of patients between stages IIIA and IIIB was observed when M0 patients with at least 6 lymph nodes (LNs) were analyzed (p > 0.05) for both SEER and multicenter database. On the other hand, a modified staging system was able to stratify patients from stage IIIA, stage IIIB and stage IV (p < 0.001). For the SEER database, the C-indexes of 8th AJCC staging system and that of its modified version were 0.709 and 0.742, respectively. For the multicenter database, the C-index of 8th AJCC staging system and that of our modified version were 0.635 and 0.679, respectively. CONCLUSIONS: The modified 8th staging system proposed in this study can improve the prognostic precision of the 8th AJCC staging system for GBC. We therefore suggest including these modifications in the next update of AJCC staging system for GBC.

Zinc protoporphyrin IX enhances chemotherapeutic response of hepatoma cells to cisplatin.

AIM: To investigate the effect of zinc protoporphyrin IX on the response of hepatoma cells to cisplatin and the possible mechanism involved. METHODS: Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was determined by a flow cytometric assay. Western blotting was used to measure protein expression. Heme oxygenase (HO)-1 activity was measured by determining the level of bilirubin generated in isolated microsomes. Reactive oxygen species (ROS) production was monitored by flow cytometry. Caspase-3 activity was measured with a colorimetric assay kit. Mice were inoculated with 1 × 10(7) tumor cells subcutaneously into the right flanks. All mice were sacrificed 6 wk after the first treatment and tumors were weighed and measured. RESULTS: Overexpression of HO-1 in HepG2 cell line was associated with increased chemoresistance to cis-diaminedichloroplatinum (cisplatin; CDDP) compared to other cell lines in vitro. Inhibition of HO-1 expression or activity by zinc protoporphyrin IX (ZnPP IX) markedly augmented CDDP-mediated cytotoxicity towards all liver cancer cell lines in vitro and in vivo. In contrast, induction of HO-1 with hemin increased resistance of tumor cells to CDDP-mediated cytotoxicity in vitro and in vivo. Furthermore, cells treated with ZnPP IX plus CDDP exhibited marked production of intracellular ROS and caspase-3 activity, which paralleled the incidence of cell apoptosis, whereas hemin decreased cellular ROS and caspase-3 activity induced by CDDP. CONCLUSION: ZnPP IX increases cellular sensitivity and susceptibility of liver cancer cell lines to CDDP and this may represent a mechanism of increasing ROS.