The presence of the V600E BRAF mutation was associated with worse prognosis and increased risk of recurrence. The V600E mutation was not only a stronger prognostic factor than KRAS but also was the strongest prognostic determinant in the overall cohort.

Low-intensity electrical current (or mild electrical stimulation; MES) influences signal transduction and activates phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Because insulin resistance is characterized by a marked reduction in insulin-stimulated PI3K-mediated activation of Akt, we asked whether MES could increase Akt phosphorylation and ameliorate insulin resistance. In addition, it was also previously reported that heat shock protein 72 (Hsp72) alleviates hyperglycemia. Thus, we applied MES in combination with heat shock (HS) to in vitro and in vivo models of insulin resistance. Here we show that 10-min treatment with MES at 5 V (0.1 ms pulse duration) together with HS at 42°C increased the phosphorylation of insulin signaling molecules such as insulin receptor substrate (IRS) and Akt in HepG2 cells maintained in high-glucose medium. MES (12 V)+mild HS treatment of high fat-fed mice also increased the phosphorylation of insulin receptor β subunit (IRβ) and Akt in mice liver. In high fat-fed mice and db/db mice, MES+HS treatment for 10 min applied twice a week for 12–15 weeks significantly decreased fasting blood glucose and insulin levels and improved insulin sensitivity. The treated mice showed significantly lower weight of visceral and subcutaneous fat, a markedly improved fatty liver and decreased size of adipocytes. Our findings indicated that the combination of MES and HS alleviated insulin resistance and improved fat metabolism in diabetes mouse models, in part, by enhancing the insulin signaling pathway.

IMPORTANCE Although surgery offers the best chance of a potential cure for patients with localized, resectable intrahepatic cholangiocarcinoma (ICC), prognosis of patients remains dismal largely because of a high incidence of recurrence.OBJECTIVE To predict very early recurrence (VER) (ie, recurrence within 6 months after surgery) following resection for ICC in the pre-and postoperative setting. DESIGN, SETTING, AND PARTICIPANTSPatients who underwent curative-intent resection for ICC between May 1990 and July 2016 were identified from an international multi-institutional database. The study was conducted at The Ohio State University in collaboration with all other participating institutions. The data were analyzed in December 2019. MAIN OUTCOMES AND MEASURESTwo logistic regression models were constructed to predict VER based on pre-and postoperative variables. The final models were used to develop an online calculator to predict VER and the tool was internally and externally validated. RESULTS Among 880 patients (median age, 59 years [interquartile range, 51-68 years]; 388 women [44.1%]; 428 [50.2%] white; 377 [44.3%] Asian; 27 [3.2%] black]), 196 (22.3%) developed VER.The 5-year overall survival among patients with and without VER was 8.9% vs 49.8%, respectively (P < .001). A preoperative model was able to stratify patients relative to the risk for VER: low risk (6-month recurrence-free survival [RFS], 87.7%), intermediate risk (6-month RFS, 72.3%), and high risk (6-month RFS, 49.5%) (log-rank P < .001). The postoperative model similarly identified discrete cohorts of patients based on probability for VER: low risk (6-month RFS, 90.0%), intermediate risk (6-month RFS, 73.1%), and high risk (6-month RFS, 48.5%) (log-rank, P < .001). The calibration and predictive accuracy of the pre-and postoperative models were good in the training (C index: preoperative, 0.710; postoperative, 0.722) as well as the internal (C index: preoperative, 0.715; postoperative, 0.728; bootstrapping resamples, n = 5000) and external (C index: postoperative, 0.672) validation data sets. CONCLUSION AND RELEVANCEAn easy-to-use online calculator was developed to help clinicians predict the chance of VER after curative-intent resection for ICC. The tool performed well on internal and external validation. This tool may help clinicians in the preoperative selection of patients for neoadjuvant therapy as well as during the postoperative period to inform surveillance strategies.

An externally validated "Metro-ticket" TBS model had excellent prognostic discriminatory power. TBS may be an accurate tool to account for the impact of tumor morphology on long-term survival among patients undergoing resection of CRLM.