Nrf2-mediated adenylosuccinate lyase promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma cells through ferroptosis escape.

Pancreatic cancer has one of the highest fatality rates and the poorest prognosis among all cancer types worldwide. Gemcitabine is a commonly used first-line therapeutic drug for pancreatic cancer; however, the rapid development of resistance to gemcitabine treatment has been observed in numerous patients with pancreatic cancer, and this phenomenon limits the survival benefit of gemcitabine. Adenylosuccinate lyase (ADSL) is a crucial enzyme that serves dual functions in de novo purine biosynthesis, and it has been demonstrated to be associated with clinical aggressiveness, prognosis, and worse patient survival for various cancer types. In the present study, we observed significantly lower ADSL levels in gemcitabine-resistant cells (PANC-1/GemR) than in parental PANC-1 cells, and the knockdown of ADSL significantly increased the gemcitabine resistance of parental PANC-1 cells. We further demonstrated that ADSL repressed the expression of CARD-recruited membrane-associated protein 3 (Carma3), which led to increased gemcitabine resistance, and that nuclear factor erythroid 2-related factor 2 (Nrf2) regulated ADSL expression in parental PANC-1 cells. These results indicate that ADSL is a candidate therapeutic target for pancreatic cancer involving gemcitabine resistance and suggest that the Nrf2/ADSL/Carma3 pathway has therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

Stepwise training program: A novel practice schedule for laparoscopic suturing.

Purpose: We establish stepwise training program in which laparoscopic suturing is broken down to discrete steps. The purpose is to evaluate the learning outcomes of stepwise training program. Materials and methods: Volunteer participants were enrolled from medical students and surgical trainees. Students took two courses of 2-h stepwise training, and a post-course (1st & 2nd) test was taken after each course; trainees took one course of stepwise training with a pre-course (1st) and a post-course (2nd) test. Attending surgeons took the test as control. Learning outcomes were assessed with laparoscopic suturing competency assessment tool (LS-CAT) and suturing time. Results: There were 10 students, 8 trainees and 6 surgeon controls. Suturing time and LS-CAT scores significantly improved between the 1st and 2nd test (p < 0.01). In the both tests, suturing time and LS-CAT scores of students and trainees were similar. In the 1st test, surgeons had significantly better performance in suturing time and LS-CAT score than students and trainees; in the 2nd test, the LS-CAT scores of students and trainees were similar to the surgeon controls. Conclusions: Stepwise program effectively enhances laparoscopic suturing skill for medical students and surgical trainees. Catch-up effect was demonstrated in medical students with stepwise training.

Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis.

Sorafenib, a small-molecule inhibitor targeting several tyrosine kinase pathways, is the standard treatment for advanced hepatocellular carcinoma (HCC). However, not all patients with HCC respond well to sorafenib, and 30% of patients develop resistance to sorafenib after short-term treatment. Galectin-1 modulates cell-cell and cell-matrix interactions and plays a crucial role in HCC progression. However, whether Galectin-1 regulates receptor tyrosine kinases by sensitizing HCC to sorafenib remains unclear. Herein, we established a sorafenib-resistant HCC cell line (Huh-7/SR) and determined that Galectin-1 expression was significantly higher in Huh-7/SR cells than in parent cells. Galectin-1 knockdown reduced sorafenib resistance in Huh-7/SR cells, whereas Galectin-1 overexpression in Huh-7 cells increased sorafenib resistance. Galectin-1 regulated ferroptosis by inhibiting excessive lipid peroxidation, protecting sorafenib-resistant HCC cells from sorafenib-mediated ferroptosis. Galectin-1 expression was positively correlated with poor prognostic outcomes for HCC patients. Galectin-1 overexpression promoted the phosphorylation of AXL receptor tyrosine kinase (AXL) and MET proto-oncogene, receptor tyrosine kinase (MET) signaling, which increased sorafenib resistance. MET and AXL were highly expressed in patients with HCC, and AXL expression was positively correlated with Galectin-1 expression. These findings indicate that Galectin-1 regulates sorafenib resistance in HCC cells through AXL and MET signaling. Consequently, Galectin-1 is a promising therapeutic target for reducing sorafenib resistance and sorafenib-mediated ferroptosis in patients with HCC.

Prediction of 5-Year Weight Loss and Weight Regain According to Early Weight Loss after Sleeve Gastrectomy.

BACKGROUND: Patients with morbid obesity exhibit sustained weight loss after sleeve gastrectomy (SG), but some individuals exhibit subsequent weight regain in the following years. Early weight loss was proven as a predictor of short- and mid-term weight loss and regain. However, the long-term effects of early weight loss have yet to be fully investigated. This study investigated the predictive effects of early weight loss on long-term weight loss and regain after SG. METHODS: Data of patients who underwent SG from November 2011 to July 2016 and followed through July 2021 were collected retrospectively. Weight regain was defined by weight increase more than 25% of their lost weight at the first postoperative year. Linear regression analysis and Cox proportional hazards analysis were performed to evaluate the correlations among early weight loss, weight loss, and weight regain. RESULTS: Data of 408 patients were included. The percentages of total weight loss (%TWL) at postoperative months 1, 3, 12, and 60 were 10.6%, 18.1%, 29.3%, and 26.6%, respectively. The %TWL at months 1 and 3 were significantly correlated with %TWL after 5 years (P < .01). The weight regain rate was 29.8% at 5 years. The %TWL at months 1 and 3 significantly influenced weight regain (hazard ratio: 0.87 and 0.89, P = .017 and .008). CONCLUSION: Early weight loss may be used to predict weight loss and regain 5 years after SG. Patients with poor early weight loss are recommended to receive early interventions to achieve long-term weight loss and prevent weight regain.

Morphometric and ultrasonographic determinants of difficult laryngoscopy in obese patients: A prospective observational study.

BACKGROUND: Obese people have a higher risk of difficult laryngoscopy due to their thick neck, large tongue, and redundant pharyngeal soft tissue. However, there is still no established predictive factor for difficult laryngoscopy in obese population. METHODS: We conducted a prospective assessor-blind observational study to enroll adult patients with a body mass index of 30 kg·m-2 or higher undergoing laparoscopic sleeve gastrectomy at a medical center between May 2020 and August 2021. Conventional morphometric characteristics along with ultrasonographic airway parameters were evaluated before surgery. The primary outcome was difficult laryngoscopy, defined as a Cormack and Lehane's grade III or IV during direct laryngoscopy. Logistic regression analyses were performed to evaluate the association between included factors and difficult laryngoscopy. Discrimination performance of predictive factors was assessed using area under the receiver operating characteristic curve (AUC). RESULTS: A total of 80 patients were evaluated, and 17 (21.3%) developed an event of difficult laryngoscopy. Univariate analyses identified five factors associated with difficult laryngoscopy, including age, sex, hypertension, neck circumference, and cross-sectional area of tongue base. After adjusting for these variables, neck circumference was the only independent influential factor, adjusted odds ratio: 1.227 (95% confidence interval, 1.009-1.491). Based on Youden's index, the optimal cutoff of neck circumference was 49.1 cm with AUC: 0.739 (sensitivity: 0.588, specificity: 0.889; absolute risk difference: 0.477, and number needed to treat: 3). CONCLUSION: Greater neck circumference was an independent risk factor for difficult laryngoscopy in obese patients. This finding provides a way of reducing unanticipated difficult airway in this high-risk population.

A Comparison of Oxygenation Efficacy between High-Flow Nasal Cannulas and Standard Facemasks during Elective Tracheal Intubation for Patients with Obesity: A Randomized Controlled Trial.

Obese patients are predisposed to rapid oxygen desaturation during tracheal intubation. We aimed to compare the risk of desaturation between high-flow nasal oxygenation (HFNO) and classical facemask oxygenation (FMO) during rapid sequence intubation for elective surgery in obese patients. Adults with a body mass index ≥30 kg·m−2 undergoing laparoscopic sleeve gastrectomy at a medical center were randomized into the HFNO group (n = 40) and FMO group (n = 40). In the HFNO group, patients used a high-flow nasal cannula to receive 30 to 50 L·min−1 flow of heated and humidified 100% oxygen. In the FMO group, patients received a fitting facemask with 15 L·min−1 flow of 100% oxygen. After 5-min preoxygenation, rapid sequence intubation was performed. The primary outcome was arterial desaturation during intubation, defined as a peripheral capillary oxygen saturation (SpO2) <92%. The risk of peri-intubation desaturation was significantly lower in the HFNO group compared to the FMO group; absolute risk reduction: 0.20 (95% confidence interval: 0.05−0.35, p = 0.0122); number needed to treat: 5. The lowest SpO2 during intubation was significantly increased by HFNO (median 99%, interquartile range: 97−100) compared to FMO (96, 92−100, p = 0.0150). HFNO achieved a higher partial pressure of arterial oxygen (PaO2) compared to FMO, with medians of 476 mmHg (interquartile range: 390−541) and 397 (351−456, p = 0.0010), respectively. There was no difference in patients' comfort level between groups. Compared with standard FMO, HFNO with apneic oxygenation reduced arterial desaturation during tracheal intubation and enhanced PaO2 among patients with obesity.

Inter-rater and intra-rater reliability of the current assessment model and tools for laparoscopic suturing.

BACKGROUND: Moorthy checklist (MC) and laparoscopic skill competency assessment tool (LS-CAT) are tools commonly used to evaluate the quality of laparoscopic suturing. The current assessment model is single measurement by multiple raters. Our aim is to examine the reliability of the current assessment model and tools. METHODS: With IRB approval, participants of three different backgrounds, namely medical students, trainees, and surgeons, were enrolled. The participants each accomplished a standardized laparoscopic suturing task. The performances were video-recorded and reviewed with LS-CAT and MC independently by three blinded raters. Intraclass correlation coefficients (ICC) were calculated for inter-rater and intra-rater reliability. RESULTS: 26 participants were enrolled, comprising 10 students, 10 trainees and 6 surgeons. In regard of inter-rater reliability, ICC values (95% CI) were 0.909 (0.768-0.961) and 0.868 (0.608-0.948) in LS-CAP and MC, respectively. For students, ICC values were 0.908 (0.682-0.976) and 0.815 (0.408-0.951) in LS-CAT and MC, respectively. For trainees, ICC values were 0.812 (0.426-0.947) and 0.717 (0.102-0.925), respectively. For surgeons, ICC values were 0.720 (0.064-0.955) and 0.868 (0.608-0.948), respectively. In regard of intra-rater reliability, ICC values of the mean scores from the three raters were 0.956 (0.905-0.980) and 0.925 (0.842-0.966) in LS-CAP and MC, respectively. CONCLUSION: LS-CAT and MC are both qualified assessment tools for laparoscopic suturing. LS-CAT is more reliable particularly for medical students and trainees. The current assessment model of single measurement by multiple raters provides excellent reliability.

Gastrectomy with or without omentectomy for gastric cancer: A systematic review and meta-analysis.

BACKGROUND: Omentectomy is conventionally performed in the procedure of gastrectomy for gastric cancer. However, the clinical value and importance of omentectomy remain unclear. This meta-analysis investigated the benefits and safety of gastrectomy with or without omentectomy for patients with gastric cancer. METHODS: A literature search was conducted in PubMed, Embase, and the Cochrane Library for studies comparing complete omentectomy with omentum preservation or partial omentectomy. Primary outcomes were overall survival, relapse-free survival, and incidences of recurrence and complications, whereas secondary outcomes were the total length of operation and the amount of blood loss. RESULTS: Nine studies involving 3,561 patients were included. Our meta-analysis revealed no significant differences between omentectomy and omentum preservation in terms of the 5-year overall survival (risk ratio [RR] = 0.95, 95% confidence interval [CI] = 0.89-1.01), 5-year relapse free survival (RR: 0.96, 95% CI: 0.89-1.03), incidence of recurrence in the peritoneum or other visceral organs (RR: 1.13, 95% CI: 0.80-1.60 and RR: 1.06, 95% CI: 0.78-1.45, respectively), and incidence of complications (RR: 1.15, 95% CI: 0.89-1.50). Moreover, omentum preservation significantly reduced the total length of operation (mean difference [MD] 25.70, 95% CI: 3.23-48.17) and the amount of blood loss (MD: 56.29, 95% CI: 14.02-98.56). CONCLUSION: Omentectomy may not be necessary and can be omitted during gastrectomy for gastric cancer.

Predictors of diabetes relapse after metabolic surgery in Asia.

BACKGROUND: Limited studies have focused on diabetes relapse after metabolic surgery, especially among Asians. OBJECTIVES: To identify the predictors of diabetes relapse following initial postoperative remission in Asia. SETTING: Four tertiary hospitals METHODS: We assessed 342 patients (age, 41.0 ± 10.8 yr; body mass index [BMI], 39.6 ± 7.3 kg/m2) with complete diabetes data before and 1 and 3 years after metabolic surgery. A total of 290 (84.8%) and 277 (81.0%) patients had diabetes remission at 1 and 3 years after surgery. Logistic regressions were performed to identify the independent predictors of diabetes relapse. Two published predictive models for diabetes remission were also tested for relapse. RESULTS: Of the 290 patients with 1-year diabetes remission, 29 (10%) experienced a relapse at 3 years after surgery. The area under the receiver operating characteristic curve of the ABCD score in predicting 1-year remission, 3-year remission, and 3-year relapse were .814, .793, and .795, while those of the DiaRem2 score were .823, .774, and .701, respectively. The baseline age, BMI, and insulin use were independent predictors for relapse. The most powerful predictive model for relapse was composed of preoperative insulin use, 1-year A1C, and a change in BMI between the first and third year (C-statistic: .919). CONCLUSION: The ABCD score predicted both mid-term postoperative diabetes remission and relapse in Asians. Initial older age, lower BMI, insulin use, higher 1-year A1C, and weight regain were independent predictors of relapse. Personalized strategies should be proposed for those at risk of relapse to optimize diabetes outcomes after surgery.

Efficacy of Different Procedures of Metabolic Surgery for Type 2 Diabetes in Asia: a Multinational and Multicenter Exploratory Study.

INTRODUCTION: Asian patients with diabetes exhibit different characteristics from Western patients. However, limited large-scale data are available on metabolic surgery procedures in Asia. We compared the short-term efficacies of metabolic surgery procedures for the management of Asian patients with different severities of diabetes. METHODS: We included patients undergoing metabolic surgery in five Asian institutions from January 2008 to December 2015 with at least 1-year postoperative follow-up. Outcomes of weight loss and diabetes control were determined. Diabetes remission rates in different ABCD scores and factors affecting diabetes remission were analyzed. RESULTS: A total of 1016 patients (mean BMI, 39.0 ± 7.2 kg/m2; HbA1c, 8.3% ± 1.7%) underwent metabolic surgery (197, Roux-en-Y gastric bypass [RYGB]; 171, one anastomosis gastric bypass [OAGB]; 437, sleeve gastrectomy [SG]; 130, SG with duodenal-jejunal bypass [SG-DJB]; and 81, single anastomosis duodenal-jejunal bypass with SG [SA-DJBSG]). The OAGB group exhibited significantly higher 1-year total weight loss (30.5%) and type 2 diabetes mellitus (T2DM) remission (78.4%) rates than did the other groups (p < .001). The patients with higher preoperative ABCD scores exhibited higher T2DM remission rates (81.8-100% and 9.5-46.2% in ABCD score subgroups of 9-10 and 1-2, respectively). In multivariate analysis, bypass was found to be an independent predictor of T2DM remission compared with SG (odds ratio of OAGB vs SG, 3.72; RYGB vs SG, 1.96; SG-DJB vs SG, 2.73; SA-DJBSG vs SG, 2.12). CONCLUSION: The metabolic surgeries are highly effective in T2DM treatment. However, SG may not be as effective as gastric bypass and duodenal-jejunum bypass.

Efficacy of Fibrin Sealant in Reducing Complication Risk After Bariatric Surgery: a Systematic Review and Meta-analysis.

BACKGROUND: Complications including staple-line leakage and bleeding may occur after sleeve gastrectomy and Roux-en-Y gastric bypass. In this meta-analysis, the efficacy of fibrin sealant in strengthening the staple line and reducing complication risk after bariatric surgery was evaluated. METHODS: We searched PubMed, Embase, and Cochrane Library databases for randomized controlled trials (RCTs) published up to October 2020. Pooled estimates of the outcomes were computed using a random effects model. The primary outcomes were bleeding and leakage; secondary outcomes were gastric stricture, length of hospital stay, reoperation rate, and total operation time. RESULTS: In total, 9 RCTs including 2136 patients were reviewed. Our meta-analysis revealed that compared with controls, fibrin sealants decreased incidence of bleeding significantly (risk ratio [RR] = 0.42; 95% confidence interval [CI], 0.18-0.97), but did not demonstrate significant differences in reducing the incidence of leakage (RR = 0.62; 95% CI, 0.23-1.73), gastric stricture (RR = 1.16; 95% CI, 0.46-2.91), reoperation rate (RR = 0.85; CI, 0.14-5.14), or length of hospital stay (weighted mean difference = 0.62; 95% CI, - 0.31 to 1.55). Compared with oversewing, fibrin sealant use reduced the operation time; however, their efficacies in reducing the incidence of postoperative bleeding and leakage did not differ significantly. CONCLUSIONS: Although applying fibrin sealants to the staple line in bariatric surgery may provide favorable results, but it may not reduce postoperative leakage and stricture incidence significantly. Nevertheless, the application of fibrin sealants as a method for reducing risks of complications after bariatric surgery warrant further investigation.

Validating Risk Prediction Models of Diabetes Remission After Sleeve Gastrectomy.

INTRODUCTION: Many risk prediction models of diabetes remission after bariatric and metabolic surgery have been proposed. Most models have been created using Roux-en-Y gastric bypass cohorts. However, validation of these models in sleeve gastrectomy (SG) is limited. The objective of our study is to validate the performance of risk prediction models of diabetes remission in obese patients with diabetes who underwent SG. METHOD: This retrospective cohort study included 128 patients who underwent SG with at least 1 year follow-up from Dec 2011 to Sep 2016 as the validation cohort. A literature review revealed total 11 models with 2 categories (scoring system and logistic regression), which were validated by our study dataset. Discrimination was evaluated by area under the receiver operating characteristic (AUC) while calibration by Hosmer-Lemeshow test and predicted versus observed remission ratio. RESULTS: At 1 year after surgery, 71.9% diabetes remission (HbA1c < 6.0 off medication) and 61.4% excess weight loss were observed. Individual metabolic surgery, ABCD, DiaRem, Advanced-DiaRem, DiaBetter, Ana et al., and Dixon et al. models showed excellent discrimination power (AUC > 0.8). In calibration, all models overestimated diabetes remission from 5 to 30% but did not lose their goodness of fit. CONCLUSION: This is the first comprehensive external validation of current risk prediction models of diabetes remission at 1 year after SG. Seven models showed excellent predicting power, and scoring models were recommended more because of their easy utility.

Learning curve of laparoscopic Roux-en-Y gastric bypass in an Asian low-volume bariatric unit.

BACKGROUND: Obesity has become a healthcare burden in Taiwan and the rest of Asia. Laparoscopic Roux-en-Y gastric bypass (LRYGB) provides good weight loss outcome, and improves comorbidity as well as quality of life. We present our experience of the learning curve for LRYGB in a low-volume bariatric unit. METHODS: From March 2009 to August 2011, 60 consecutive patients who underwent LRYGB were included. They were separated into two groups, with the first 30 cases in Group 1 and the remaining 30 cases in Group 2. Indicators for evaluating the learning curve for LRYGB included surgical time, rate of conversion to open surgery, surgical and total complication rates, length of hospital stay, mortality, and postoperative weight loss. RESULTS: There were no significant differences in demographic measurements between the two groups. In Group 1, the median surgical time was 120 minutes and in Group 2 it was 80 minutes (p<0.01). Two cases were converted to laparotomy in Group 1, but none in Group 2. There was no surgical mortality and the total complication rate of all patients was 16.7%. The complication rate significantly decreased from Group 1 (26.7%) to Group 2 (6.7%). Three patients needed further surgical procedures in Group 1, with no patients needing them in Group 2. There was no significant difference in hospital stay and percentage excess weight loss between the two groups. CONCLUSION: The learning curve for LRYGB has no mortality and an acceptable complication rate. The operating time and morbidity rate are the indicators for overcoming the learning curve.