SLC7A11 and the glutathione pathway as novel prognostic markers in resectable pancreatic ductal adenocarcinoma: A metabolomics study of clinical specimens.

BACKGROUND/OBJECTIVES: Despite the poor prognosis associated with pancreatic ductal adenocarcinoma (PDAC), there remains a lack of clarity regarding the metabolic pathways and their significant impact on its phenotype. Therefore, we aimed to utilize metabolomics to capture changes in clinical PDAC tissues and elucidate the significant metabolic pathways close to its phenotypes. METHODS: This basic research was retrospectively validated using database research, immunohistochemistry, and protein analysis based on the findings obtained from metabolomics using clinical tissues collected from prospectively registered patients with PDAC. mRNA expression analysis using a database and protein analysis using archived clinical specimens was performed to validate the candidate pathways identified using metabolomics. Between-group comparisons were analyzed using paired t-tests and log-rank test, and Kaplan-Meier curves illustrated survival times. RESULTS: Patients subjected to metabolomics revealed a significant increase in glutathione disulfide levels in PDAC tissues when compared to normal pancreatic tissues. The Cancer Genome Atlas database analysis revealed significant changes in glutathione pathway-related mRNAs in PDAC compared to that in the normal pancreas. Protein analysis of previously resected specimens demonstrated a significant increase in SLC7A11 expression in PDAC tissues. The abundance ratio of SLC7A11 isoforms was associated with the post-operative prognosis in resectable PDAC. CONCLUSION: Glutathione disulfide levels were significantly increased in clinical PDAC metabolomics. Additionally, increased mRNA and protein expression in SLC7A11 was observed in PDAC. Furthermore, the SLC7A11 isoform abundance ratio may be a valuable prognostic marker in patients with resectable PDAC.

Therapeutic Outcome of Multidisciplinary Treatment in Unresectable Biliary Tract Cancer: A Multicenter Retrospective Analysis.

Background: There is little established evidence regarding treatment strategies for unresectable biliary tract cancer (BTC). This study aimed to clarify the situation of multidisciplinary treatment for unresectable BTC in the 2000s when there was no international standard first-line therapy. Methods: We retrospectively reviewed 315 consecutive patients with unresectable BTC who had been treated at seven tertiary institutions in Kanagawa Prefecture, Japan between 1999 and 2008. Results: The unresectable factors were as follows: locally advanced, 101 cases (32.1%); hematogenous metastases, 80 cases (25.4%); and peritoneal dissemination, 30 cases (9.5%). Chemotherapy or radiation therapy was administered to 218 patients (69.2%). The best supportive care was provided in 97 cases (30.8%). The most common regimen was gemcitabine monotherapy, followed by gemcitabine combination therapy and S-1 monotherapy. The 1- and 2-year survival rates of all patients were 34.6% and 12.2%, respectively. The median survival time (MST) was 8 months in all patients. The 1-year survival rate was 65%, and the MST was 12 months among the locally advanced patients, whereas patients with peritoneal dissemination had the worst outcome; the 1-year survival rate was 7%, and the MST was 5 months. Among treated 90 cases of perihilar cholangiocarcinoma, patients who received chemoradiotherapy (n = 24) had a significantly better outcome than those who received chemotherapy alone (MST: 20 vs. 11 months, P < 0.001). Conclusions: Unresectable BTC has heterogeneous treatment outcomes depending on the mode of tumor extension and location. Multidisciplinary treatment seems useful for patients with locally advanced BTC, whereas patients with metastatic disease still have a poor prognosis.