Ferroptosis-related gene glutathione peroxidase 4 promotes reprogramming of glucose metabolism via Akt-mTOR axis in intrahepatic cholangiocarcinoma.

The role of the ferroptosis-related gene glutathione peroxidase 4 (GPX4) in oncology has been extensively investigated. However, the clinical implications of GPX4 in patients with intrahepatic cholangiocarcinoma (ICC) remain unknown. This study aimed to evaluate the prognostic impact of GPX4 and its underlying molecular mechanisms in patients with ICC. Fifty-seven patients who underwent surgical resection for ICC between 2010 and 2017 were retrospectively analyzed. Based on the immunohistochemistry, patients were divided into GPX4 high (n = 15) and low (n = 42) groups, and clinical outcomes were assessed. Furthermore, the roles of GPX4 in cell proliferation, migration and gene expression were analyzed in ICC cell lines in vitro and in vivo. The results from clinical study showed that GPX4 high group showed significant associations with high SUVmax on 18F-fluorodeoxyglucose-positron emission tomography (≥8.0, P = 0.017), multiple tumors (P = 0.004), and showed glucose transporter 1 (GLUT1) high expression with a trend toward significance (P = 0.053). Overall and recurrence-free survival in the GPX4 high expression group were significantly worse than those in the GPX4 low expression group (P = 0.038 and P < 0.001, respectively). In the experimental study, inhibition of GPX4 attenuated cell proliferation and migration in ICC cell lines. Inhibition of GPX4 also decreased the expression of glucose metabolism-related genes, such as GLUT1 or HIF1α. Mechanistically, these molecular changes are regulated in Akt-mechanistic targets of rapamycin axis. In conclusion, this study suggested the pivotal value of GPX4 serving as a prognostic marker for patients with ICC. Furthermore, GPX4 can mediate glucose metabolism of ICC.

High expression of autotaxin is associated with poor recurrence-free survival in cholangiocarcinoma.

BACKGROUND AND AIM: Autotaxin (ATX) is an extracellular lysophospholipase D that catalyzes the hydrolysis of lysophosphatidylcholine into lysophosphatidic acid (LPA). Recent accumulating evidence indicates the biological roles of ATX in malignant tumors. However, the expression and clinical implications of ATX in human cholangiocarcinoma (CCA) remain elusive. METHODS: In this study, the expression of ATX in 97 human CCA tissues was evaluated by immunohistochemistry. Serum ATX levels were determined in CCA patients (n = 26) and healthy subjects (n = 8). Autotaxin expression in cell types within the tumor microenvironment was characterized by immunofluorescence staining. RESULTS: High ATX expression in CCA tissue was significantly associated with a higher frequency of lymph node metastasis (p = 0.050). High ATX expression was correlated with shorter overall survival (p = 0.032) and recurrence-free survival (RFS) (p = 0.001) than low ATX expression. In multivariate Cox analysis, high ATX expression (p = 0.019) was an independent factor for shorter RFS. Compared with low ATX expression, high ATX expression was significantly associated with higher Ki-67-positive cell counts (p < 0.001). Serum ATX levels were significantly higher in male CCA patients than in healthy male subjects (p = 0.030). In the tumor microenvironment of CCA, ATX protein was predominantly expressed in tumor cells, cancer-associated fibroblasts, plasma cells, and biliary epithelial cells. CONCLUSIONS: Our study highlights the clinical evidence and independent prognostic value of ATX in human CCA.

Preoperative diagnosis of adhesion severity between the abdominal wall and intestinal tract with novel abdominal ultrasound methodology to enhance surgical safety.

BACKGROUND: Adhesions between the abdominal wall and intestinal tract from previous surgeries can complicate reoperations; however, predicting the extent of adhesions preoperatively is difficult. This study aimed to develop a straightforward approach for predicting adhesion severity using a novel abdominal ultrasound technique that quantifies the displacement of motion vectors of two organs to enhance surgical safety. The efficacy of this methodology was assessed experimentally and clinically. METHODS: Using Aplio500T, a system we developed, we measured the displacement of the upper peritoneum and intestinal tract as a vector difference and computed the motion difference ratio. Twenty-five rats were randomized into surgery and nonsurgery groups. The motion difference ratio was assessed 7 days after laparotomy to classify adhesions. In a clinical trial, 51 patients undergoing hepatobiliary pancreatic surgery were evaluated for the motion difference ratio within 3 days preoperatively. Intraoperatively, adhesion severity was rated and compared with the motion difference ratio. A receiver operating characteristic curve was used to appraise the diagnostic value of the motion difference ratio. RESULTS: In the animal experiment, the adhesion group exhibited a significantly higher motion difference ratio than the no-adhesion group (0.006 ± 0.141 vs 0.435 ± 0.220, P < .001). In the clinical trial, the no-adhesion or no-laparotomy group had a motion difference ratio of 0.128 ± 0.074; mild-adhesion group, 0.143 ± 0.170; moderate-adhesion group, 0.326 ± 0.153; and high-adhesion group, 0.427 ± 0.152. The motion difference ratio receiver operating characteristic curve to diagnose the adhesion level (≥moderate) was 0.938, indicating its high diagnostic value (cut-off 0.204). CONCLUSION: This methodology may preoperatively predict moderate-to-high adhesions.

Completion of adjuvant S-1 chemotherapy after surgical resection for biliary tract cancer: A single center experience.

BACKGROUNDS: A recent randomized control trial (JCOG1202; ASCOT trial) demonstrated the efficacy of adjuvant S-1 chemotherapy (ASC) for biliary tract cancer (BTC) after surgical resection; however, the significance of the completion of ASC in the real-world setting remains unknown. METHODS: Data of consecutive patients who underwent surgical resection for biliary tract cancer (BTC) from 2011 to 2021 were retrospectively reviewed. Of these, patients who underwent ASC were enrolled in this study. Patients were divided into two groups according to whether ASC was completed: the completion group and the non-completion group. Clinicopathological features and survival outcomes were assessed. RESULTS: Of the 223 patients with BTC who underwent surgical resection, 75 patients who underwent ASC were included for analysis. Among them, 48 (64.0 %) completed the intended ASC course, while 27 cases (36.0 %) discontinued the treatment. The most common reason for the discontinuation was adverse event (n = 16, 59.3 %), followed by disease recurrence (n = 9, 33.3 %). Patients in the completion group showed significantly better overall survival (OS) (p < 0.001) and recurrence-free survival (RFS) (p < 0.001) compared to the non-completion group. Further, after excluding the patients in the non-completion group who discontinued ASC due to disease recurrence, the significance of ASC completion was retained for both OS and RFS. CONCLUSION: The completion of ASC was associated with improved prognosis in patients with BTC after surgical resection. The achievement of ASC should be the goal after surgical resection, while further study may be warranted regarding the resistance of ASC.