Prognostic impacts of participation in prospective surgical clinical trials on surgical outcomes in gastric cancer patients.

Various prospective surgical trials have been conducted on treating patients with gastric cancer. In clinical practice, patients and surgeons may hesitate to participate in prospective surgical trials due to trial-related complications. In this study, we evaluated the effects of participation in prospective surgical trials on surgical outcomes after radical gastrectomy for gastric cancer. This study included 1689 patients who underwent curative gastrectomy for gastric cancer between 2016 and 2020. The propensity score weighting (PSW) method was used to adjust for differences in baseline clinicopathological characteristics between patients who participated and those who did not participate in prospective surgical clinical trials. Perioperative outcomes and overall survival were compared between groups. Of the 1689 patients, 309 (18.3%) participated in surgical clinical trials (SCT group). Before PSW, the SCT group had a similar operation time, intraoperative blood loss, complications, major complications, and hospital stay as the non-SCT group but had superior overall survival. After PSW, overall survival and perioperative outcomes were not significantly different between the groups. The present study suggests that participation in prospective surgical trials was not associated with surgical outcomes. Patients and surgeons may participate in prospective surgical trials without fearing adverse effects on surgical outcomes.

Deep learning using computed tomography to identify high-risk patients for acute small bowel obstruction: development and validation of a prediction model : a retrospective cohort study.

OBJECTIVE: To build a novel classifier using an optimized 3D-convolutional neural network for predicting high-grade small bowel obstruction (HGSBO). SUMMARY BACKGROUND DATA: Acute SBO is one of the most common acute abdominal diseases requiring urgent surgery. While artificial intelligence and abdominal computed tomography (CT) have been used to determine surgical treatment, differentiating normal cases, HGSBO requiring emergency surgery, and low-grade SBO (LGSBO) or paralytic ileus is difficult. METHODS: A deep learning classifier was used to predict high-risk acute SBO patients using CT images at a tertiary hospital. Images from three groups of subjects (normal, nonsurgical, and surgical) were extracted; the dataset used in the study included 578 cases from 250 normal subjects, with 209 HGSBO and 119 LGSBO patients; over 38 000 CT images were used. Data were analyzed from 1 June 2022 to 5 February 2023. The classification performance was assessed based on accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve. RESULTS: After fivefold cross-validation, the WideResNet classifier using dual-branch architecture with depth retention pooling achieved an accuracy of 72.6%, an area under receiver operating characteristic of 0.90, a sensitivity of 72.6%, a specificity of 86.3%, a positive predictive value of 74.1%, and a negative predictive value of 86.6% on all the test sets. CONCLUSIONS: These results show the satisfactory performance of the deep learning classifier in predicting HGSBO compared to the previous machine learning model. The novel 3D classifier with dual-branch architecture and depth retention pooling based on artificial intelligence algorithms could be a reliable screening and decision-support tool for high-risk patients with SBO.

Characterization of Clofazimine as a Potential Substrate of Drug Transporter.

In this study, we explored clofazimine (CFZ) as a potential substrate of uptake and efflux transporters that might be involved in CFZ disposition, using transporter gene overexpressing cell lines in vitro. The intracellular concentrations of CFZ were significantly increased in the presence of selective inhibitors of P-gp and BCRP, which include verapamil, cyclosporine-A, PSC-833, quinidine, Ko143, and daunorubicin. In a bidirectional transport assay using transwell cultures of cell lines overexpressing P-gp and BCRP, the mean efflux ratios of CFZ were found to be 4.17 ± 0.63 and 3.37 ± 1.2, respectively. The Km and maximum rate of uptake (Vmax) were estimated to be 223.3 ± 14.73 µM and 548.8 ± 87.15 pmol/min/mg protein for P-gp and 381.9 ± 25.07 µM and 5.8 ± 1.22 pmol/min/mg protein for BCRP, respectively. Among the uptake transporters screened, the CFZ uptake rate was increased 1.93 and 3.09-fold in HEK293 cell lines overexpressing OAT1 and OAT3, respectively, compared to the control cell lines, but no significant uptake was observed in cell lines overexpressing OCT1, OCT2, OATP1B1, OATP1B3, OATP2B1, or NTCP. Both OAT1- and OAT3-mediated uptake was inhibited by the selective inhibitors diclofenac, probenecid, and butanesulfonic acid. The Km and Vmax values of CFZ were estimated to be 0.63 ± 0.15 µM and 8.23 ± 1.03 pmol/min/mg protein, respectively, for OAT1 and 0.47 ± 0.1 µM and 17.81 ± 2.19 pmol/min/mg protein, respectively, for OAT3. These findings suggest that CFZ is a novel substrate of BCRP, OAT1, and OAT3 and a known substrate of P-gp in vitro.

Prevention of Gallstones After Bariatric Surgery using Ursodeoxycholic Acid: A Narrative Review of Literatures.

Obesity by itself is a factor in the development of gallstone disease, and periods of weight loss after bariatric surgery further increase the risk of gallstone formation. In patients with obesity, hypersecretion of cholesterol may increase the risk of gallstone formation, which is approximately five-fold higher than that in the general population. The incidence of gallstone formation after bariatric surgery is 10-38% and often associated with a proportional increase in the risk of developing biliary complications. Routine postoperative administration of ursodeoxycholic acid (UDCA) is recommended to prevent gallstone formation. Several randomized trials have indicated that UDCA can effectively prevent gallstones and reduce the risk of cholecystectomy after bariatric procedures. The effective daily dose of UDCA in each study ranged from 500 to 1,200 mg, and it may be considered at least during the period of rapid weight loss (first 3-6 months postoperatively) to decrease the incidence of symptomatic gallstones.

Prediction of Survival Outcomes Based on Preoperative Clinical Parameters in Gastric Cancer.

BACKGROUND: Few current preoperative risk assessment tools provide essential, optimized treatment for gastric cancer. The purpose of this study was to develop and validate a nomogram that uses preoperative data to predict survival and risk assessments. METHODS: A survival prediction model was constructed using data from a developmental cohort of 1251 patients with stage I to III gastric cancer who underwent curative resection between January 2005 and December 2008 at Ajou University Hospital, Korea. The model was internally validated for discrimination and calibrated using bootstrap resampling. To externally validate the model, data from a validation cohort of 2012 patients with stage I to III gastric cancer who underwent surgery at multiple centers in Korea between January 2001 and June 2006 were analyzed. Analyses included the model's discrimination index (C-index), calibration plots, and decision curve that predict overall survival. RESULTS: Eight independent predictors, including age, sex, clinical tumor size, macroscopic features, body mass index, histology, clinical stages, and tumor location, were considered for developing the nomogram. The discrimination index was 0.816 (adjusted C-index) in the developmental cohort and 0.781 (adjusted C-index) in the external validation cohort. Additionally, in both the developmental and validation datasets, age and tumor size were significantly correlated with each other and were independent indicators for survival (P < 0.05). CONCLUSIONS: We developed a new nomogram by using the most common and significant preoperative parameters that can help to identify high-risk patients before treatment and help clinicians to make appropriate decisions for patients with stage I to III gastric cancer.

Long-term Comparison of Robotic and Laparoscopic Gastrectomy for Gastric Cancer: A Propensity Score-weighted Analysis of 2084 Consecutive Patients.

OBJECTIVE: To compare long-term outcomes between robotic and LG approaches using propensity score weighting based on a generalized boosted method to control for selection bias. SUMMARY OF BACKGROUND DATA: Minimally invasive surgical approaches for GC are increasing, yet limited evidence exists for long-term outcomes of robotic gastrectomy (RG). METHODS: Patients (n = 2084) with GC stages I-III who underwent LG or RG between 2009 and 2017 were analyzed. Generalized boosted method was used to estimate a propensity score derived from all available preoperative characteristics. Long-term outcomes were compared using the adjusted Kaplan-Meier method and the weighted Cox proportional hazards regression model. RESULTS: After propensity score weighting, the population was balanced. Patients who underwent RG showed reduced blood loss (16 mL less, P = 0.025), sufficient lymph node harvest from the initial period, and no changes in surgical outcomes over time. With 52-month median follow-up, no difference was noted in 5-year overall survival in unweighted [91.5% in LG vs 94% in RG; hazard ratio (HR), 0.71; 95% confidence interval (CI), 0.46-1.1; P = 0.126] and weighted populations (94.2% in LG vs 93.2% in RG; HR, 0.88; 95% CI, 0.52-1.48; P = 0.636). There were no differences in 5-year recurrence-free survival (RFS), with unweighted 5-year RFS of 95.4% for LG and 95.2% for RG (HR, 0.95; 95% CI, 0.55-1.64; P = 0.845) and weighted 5-year RFS of 96.3% for LG and 95.3% for RG (HR, 1.24; 95% CI, 0.66-2.33; P = 0.498). CONCLUSIONS: After balancing covariates, RG demonstrated reliable surgical outcomes from the beginning. Long-term survival after RG and LG for GC was similar.

Prognostic value of hypocholesterolemia in patients with gastric cancer.

BACKGROUND: According to previous studies, low serum total cholesterol (TC) is associated with higher cancer incidence and mortality. However, the prognostic implications of preoperative TC in patients with gastric cancer (GC) remain to be determined. METHODS: A total of 1251 patients with GC, who underwent radical gastrectomy between 2005 and 2008, were recruited. Propensity score weighting (PSW) based on a generalized boosted method (GBM) was used to control for selection bias. RESULTS: After balancing the preoperative and operative covariates, low TC was associated with high incidence of complications (severe complication rate: 15.2% (Low TC) vs. 4.7% (Normal TC) vs 5.5% (High TC); p = 0.004). In multivariable analysis, lowering TC was associated with poor OS and RFS in weighted population. [OS: hazard ratio (HR) = 0.92; 95% CI = 0.867-0.980; P = 0.009 and RFS: HR = 0.93; 95% CI = 0.873-0.988; P = 0.02]. CONCLUSIONS: Preoperative TC is a useful predictor of postoperative survival and postoperative complications in patients with stage I-III GC and may help to identify high-risk patients for rational therapy, including nutritional support, and timely follow-up.

The Learning Curve of Linear-Shaped Gastroduodenostomy Associated with Totally Laparoscopic Distal Gastrectomy.

BACKGROUND: Linear-shaped gastroduodenostomy (LSGD) is a new method of intracorporeal reconstruction that is simpler to perform and associated with a lower rate of bile reflux than delta-shaped anastomosis. Here, we analyzed the learning curve of LSGD in totally laparoscopic distal gastrectomy. METHODS: The cumulative sum method was used to retrospectively analyze consecutive gastric cancer patients undergoing intracorporeal gastroduodenostomy after distal gastrectomy between January 2009 and May 2016. The duration of surgery, postoperative complications, hospital stay, and endoscopic findings in the postoperative period and the first, third, and fifth year were evaluated according to the two phases of the learning curve (learning period versus mastery period). RESULTS: Data from 222 patients were included in the analysis. The LSGD learning period was 29 cases. The surgical time in mastery period was significantly shorter than the learning period (124.9 ± 34.5 versus 168.2 ± 42.0 min, p < 0.001). The incidence of minor complications was significantly reduced after the learning period (p = 0.041), although there was no statistically significant difference in the rate of major complications. The long-term endoscopic findings showed that the presence of residual food decreased over the time (p = 0.022). CONCLUSIONS: LSGD can be mastered easily after a reasonable number of cases and was associated with safe and satisfactory short- and long-term outcomes before and after learning curve.

Inhibitory effects of Kampo medicines, Keishibukuryogan and Shakuyakukanzoto, on the substrate uptake activities of solute carrier organic anion transporters.

The aim of this study was to assess the effects of Keishibukuryogan (K-06) and Shakuyakukanzoto (TJ-68), commercial herbal medicines, on the substrate uptake activities of renal organic anion transporters. We performed transporter uptake and cell viability assays in Xenopus oocytes and HEK293 human kidney embryonic cells treated with K-06 or TJ-68. K-06 and TJ-68 markedly inhibited the substrate uptake activities of URAT1, OAT1, and OAT3, while they did not exhibit non-cytotoxic effects. Our findings demonstrated that K-06 and TJ-68 inhibited the substrate uptake activities of renal transporters, suggesting their mechanism of action as nephroprotective agents.

Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake Transporters In Vitro.

The substrate potentials of antituberculosis drugs on solute carrier (SLC) transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for SLC family transporter-mediated uptake, using Xenopus laevis oocytes and stably transfected HEK-293 cells in vitro The result suggested that ethambutol, isoniazid, amoxicillin, and prothionamide act as novel substrates for the SLC transporters. In addition, in the presence of representative transporter inhibitors, the uptake of the antituberculosis drugs was markedly decreased compared with the uptake in the absence of inhibitor, suggesting involvement of the corresponding transporters. A cellular uptake study was performed, and the Km values of ethambutol were found to be 526.1 ± 15.6, 212.0 ± 20.1, 336.8 ± 20.1, and 455.0 ± 28 µM for organic cation transporter 1 (OCT1), OCT2, OCTN1, and OCTN2, respectively. Similarly, the Km of prothionamide was 805.8 ± 23.4 µM for OCT1, while the Km values of isoniazid and amoxicillin for organic anion transporter 3 (OAT3) were 233.7 ± 14.1 and 161.4 ± 10.6 µM, respectively. The estimated in vivo drug-drug interaction indexes from in vitro transporter inhibition kinetics for verapamil, probenecid, and ibuprofen against ethambutol, prothionamide, isoniazid, and amoxicillin were found to show potential for clinical drug interactions. In conclusion, this is the first study that demonstrated 22 antituberculosis drug interactions with transporters. This study will be helpful for mechanistic understanding of the disposition, drug-drug interactions, and pharmacokinetics of these antituberculosis drugs.

10-Phenyltriazoyl Artemisinin is a Novel P-glycoprotein Inhibitor that Suppresses the Overexpression and Function of P-glycoprotein.

BACKGROUND: The effect of drugs on ATP-binding cassette transporters, especially permeabilityglycoprotein (P-gp), is an important consideration during new anti-cancer drug development. OBJECTIVE: In this context, the effects of a newly synthesized artemisinin derivative, 10-(4-phenyl-1H-1,2,3- triazol)-artemisinin (5a), were evaluated on P-gp expression and function. METHODS: Reverse transcript polymerase chain reaction and immunoblotting techniques were used to determine the effect of 5a on P-gp expression in LS174T cells. In addition, the ability of 5a to work as either a substrate or an inhibitor of P-gp was investigated through different methods. RESULTS: The results revealed that 5a acts as a novel P-gp inhibitor that dually suppresses the overexpression and function of P-glycoprotein. Co-treatment of LS174T cell line, human colon adenocarcinoma cell line, with 5a and paclitaxel recovered the anticancer effect of paclitaxel by controlling the acquired drug resistance pathway. The overexpression of P-gp induced by rifampin and paclitaxel in a colorectal cell line was suppressed by 5a which could be a novel inhibitory substrate inhibiting the transport of paclitaxel by P-gp. CONCLUSION: The results revealed that 5a can be classified as a type B P-gp inhibitor (with both substrate and inhibitor activities) with an additional function of suppressing P-gp overexpression. The results might be clinically useful in the development of anticancer drugs against cancers with multidrug resistance.

A Novel Roux-en-Y Reconstruction Involving the Use of Two Circular Staplers after Distal Subtotal Gastrectomy for Gastric Cancer.

PURPOSE: Although Roux-en-Y (R-Y) reconstruction after distal gastrectomy has several advantages, such as prevention of bile reflux into the remnant stomach, it is rarely used because of the technical difficulty. This prospective randomized clinical trial aimed to show the efficacy of a novel method of R-Y reconstruction involving the use of 2 circular staplers by comparing this novel method to Billroth-I (B-I) reconstruction. MATERIALS AND METHODS: A total of 118 patients were randomly allocated into the R-Y (59 patients) and B-I reconstruction (59 patients) groups. R-Y anastomosis was performed using two circular staplers and no hand sewing. The primary end-point of this clinical trial was the reflux of bile into the remnant stomach evaluated using endoscopic and histological findings at 6 months after surgery. RESULTS: No significant differences in clinicopathological findings were observed between the 2 groups. Although anastomosis time was significantly longer for the patients of the R-Y group (P<0.001), no difference was detected between the 2 groups in terms of the total surgery duration (P=0.112). Endoscopic findings showed a significant reduction of bile reflux in the remnant stomach in the R-Y group (P<0.001), and the histological findings showed that reflux gastritis was more significant in the B-I group than in the R-Y group (P=0.026). CONCLUSIONS: The results of this randomized controlled clinical trial showed that compared with B-I reconstruction, R-Y reconstruction using circular staplers is a safe and feasible procedure. This clinical trial study was registered at www.ClinicalTrials.gov (registration No. NCT01142271).

Real-time Vessel Navigation Using Indocyanine Green Fluorescence during Robotic or Laparoscopic Gastrectomy for Gastric Cancer.

PURPOSE: Identification of the infrapyloric artery (IPA) type is a key component of pylorus-preserving gastrectomy. As the indocyanine green (ICG) fluorescence technique is known to help visualize blood vessels and flow during reconstruction, we speculated that this emerging technique would be helpful in identifying the IPA type. MATERIALS AND METHODS: From August 2015 to February 2016, 20 patients who underwent robotic or laparoscopic gastrectomy were prospectively enrolled. After intravenous injection of approximately 3 mL of ICG (2.5 mg/mL), a near-infrared fluorescence apparatus was applied. The identified shape of the IPA was confirmed by examining the actual anatomy following infrapyloric dissection. RESULTS: The mean interval time between ICG injection and visualization of the artery was 22.2 seconds (range, 14-30 seconds), and the mean duration of the arterial phase was 16.1 seconds (range, 9-30 seconds). The overall positive predictive value (PPV) of ICG fluorescence in identifying the IPA type was 80% (16/20). The IPA type was incorrectly predicted in four patients, all of whom were obese with a body mass index (BMI) of more than 25 kg/m2. CONCLUSIONS: Our preliminary results indicate that intraoperative vascular imaging using the ICG fluorescence technique may be helpful for robotic or laparoscopic pylorus-preserving gastrectomy.

Billroth II with Braun Enteroenterostomy Is a Good Alternative Reconstruction to Roux-en-Y Gastrojejunostomy in Laparoscopic Distal Gastrectomy.

Background. Although Billroth II (BII) reconstruction is simpler and faster than Billroth I or Roux-en-Y (RY) reconstruction in patients undergoing totally laparoscopic distal gastrectomy (TLDG), BII reconstruction is associated with several complications, including more severe bile reflux. BII Braun anastomosis may be a better alternative to RY reconstruction. Methods. This retrospective study included 56 consecutive patients who underwent TLDG for gastric cancer, followed by BII Braun or RY reconstruction, between January 2013 and December 2015. Surgical outcomes, including length of operation, quantity of blood lost, and postoperative complications, were compared in the two groups. Results. Clinicopathological characteristics did not differ between the BII Braun and RY groups. Mean length of operation was significantly longer in the RY than the BII Braun group (157.3 min versus 134.6 min, p < 0.010), but length of hospital stay, blood loss, and complication rate did not differ between the two groups. Ileus occurred in three patients (10.0%) in the RY group. Endoscopic findings 6 months after surgery showed bile reflux in seven (28%) patients in the BII Braun group and five (17.2%) in the RY group (p = 0.343), but no significant differences in rate of gastric residue or degree of gastritis in the remnant stomach in the two groups. Conclusions. B-II Braun anastomosis is a good alternative to RY reconstruction, reducing length of operation and ileus after TLDG.

Evaluation of para-Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro.

para-Aminosalicylic acid (PAS) is a second-line antituberculosis drug that has been used to treat multidrug-resistant and extensively drug-resistant tuberculosis for more than 60 years. Renal secretion and glomerular filtration are the major pathways for the elimination of PAS. We comprehensively studied PAS transport by using cell lines that overexpressed various transporters and found that PAS acts as a novel substrate of an organic anionic polypeptide (OATP1B1), organic cationic transporters (OCT1 and OCT2), and organic anion transporters (OAT1 and OAT3) but is not a substrate of any ATP-binding cassette (ABC) transporters. Net PAS uptake was measured, and the transport affinities (Km values) for OATP1B1, OCT1, OCT2, OAT1, and OAT3 were found to be 50.0, 20.3, 28.7, 78.1, and 100.1 µM, respectively. The net uptake rates suggested that renal OAT1 and OAT3 play relatively major roles in PAS elimination. The representative inhibitors rifampin for OATP1B1, probenecid for OAT1 and OAT3, and verapamil for OCT1 and OCT2 greatly inhibited PAS uptake, suggesting that PAS is dependent on multiple transporters for uptake. We also evaluated nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), and metformin for the inhibition of PAS uptake via these transporters. Half-maximal (50%) inhibitory concentrations (IC50s) were kinetically determined and used to predict the drug-drug interactions (DDIs) affecting these transporters' activity toward PAS. We found that rifampin, probenecid, ibuprofen, naproxen, cimetidine, and quinidine each exhibited a significant potential for in vivo DDIs with PAS. In this study, PAS was found to be a novel substrate of several transporters, and drugs that inhibit these transporters can reduce PAS elimination.

Modified overlap method using knotless barbed sutures (MOBS) for intracorporeal esophagojejunostomy after totally laparoscopic gastrectomy.

BACKGROUND: Compared to end-to-side anastomosis with a circular stapler, the overlap method is favored for intracorporeal esophagojejunostomy because it facilitates handling of the stapler, even in narrow spaces, and wider anastomosis. However, it associates with technical difficulties during anastomosis, including difficult traction on the esophageal stump that necessitates stay sutures. Here, we introduce a new modified overlap method that employs knotless barbed sutures (MOBS) and report the outcomes of our case series. METHOD: All consecutive patients who underwent intracorporeal esophagojejunostomy in 2015-2016 were included. All patients underwent surgery as follows: After esophageal transection with a linear stapler, two V-loc 90 sutures (Covidien, Mansfield, MA, USA) were sutured in the center of the stapled line. The opening was made between the two threads, and the intraluminal space was identified. The jejunum was ascended toward the esophageal stump by inserting a 45-mm-long linear staple. The anastomosis was made at the space between the right and left crura. After firing the linear stapler, the entry hole was closed bidirectionally using the pre-sutured threads. RESULTS: Forty patients underwent MOBS (27 by laparoscopy; 13 by robot). Mean total operative and MOBS procedural times were 180.6 and 22.4 min, respectively. Mean hospital stay was 6.9 days. Two patients had major complications (5.0 %). There were no anastomosis-related complications. Laparoscopy and robot subgroups did not differ in mean MOBS procedural times (22.2 vs. 22.7 min, p = 0.787). CONCLUSION: MOBS is a safe and feasible method that is a good option for intracorporeal esophagojejunostomy after laparoscopic gastrectomy.