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Abstract Aim The existing predictive risk models for the surgical outcome of acute diffused peritonitis (ADP) need renovation by adding relevant variables such as ADP's definition or causative etiology to pursue outstanding data collection reflecting the real world. We aimed to revise the risk models predicting mortality and morbidities of ADP using the latest Japanese Nationwide Clinical Database (NCD) variable set. Methods Clinical dataset of ADP patients who underwent surgery, and registered in the NCD between 2016 and 2019, were used to develop a risk model for surgical outcomes. The primary outcome was perioperative mortality. Results After data cleanup, 45 379 surgical cases for ADP were derived for analysis. The perioperative and 30‐day mortality were 10.6% and 7.2%, respectively. The prediction models have been created for the mortality and 10 morbidities associated with the mortality. The top five relevant predictors for perioperative mortality were age >80, advanced cancer with multiple metastases, platelet count of

Abstract Background An elevated neutrophil‐to‐lymphocyte ratio (NLR) in peripheral blood is an independent prognostic indicator of various cancers. Aims In this study, we aimed to investigate the prognostic relevance of the intratumoral immune cell balance in gastric cancer. Methods and Results The study included 82 patients who underwent curative resection for gastric cancer. The intratumoral cluster of differentiation (CD) 15‐ and CD8‐positive cells were evaluated using immunohistochemical staining. Additionally, clinicopathological factors and prognoses were analyzed. Patients with high intratumoral CD15/CD8 ratios had significantly lower overall survival (OS) and relapse‐free survival (RFS) compared to those with low CD15/CD8 ratios (p = .0026 and p

Abstract Aim The National Clinical Database (NCD) of Japan is a nationwide data entry system for surgery, and it marked its 10th anniversary in 2020. The aim was to present the 2020 annual report of gastroenterological surgery of the NCD. Methods The data of the surgical procedures stipulated by the training curriculum for board‐certified surgeons of the Japanese Society of Gastroenterological Surgery in the NCD from 2011 to 2020 were summarized. Results In total, 5 622 845 cases, including 593 088 cases in 2020, were extracted from the NCD. The total number of gastroenterological surgeries increased gradually in these 10 years, except for the year 2020 due to the COVID‐19 pandemic. The annual number of surgeries of each organ, except the pancreas and liver, decreased by 0.4%–13.1% in 2020 compared to 2019. The surgical patients were consistently aging, with more than 20% of all gastroenterological surgeries in 2020 involving patients aged 80 years or older. The participation of board‐certified surgeons increased for each organ (75.9%–95.7% in 2020). The rates of endoscopic surgery also increased constantly. Although the incidences of postoperative complications of each organ increased by 0.7%–7.9% in these 10 years, postoperative mortality rates decreased by 0.2%–1.5%. Conclusions We present here the short‐term outcomes of each gastroenterological operative procedure in 2020. This review of the 10‐years of NCD data of gastroenterological surgery revealed a consistent increase of the number of surgeries (except for in 2020), especially endoscopic procedures, and aging of the Japanese population. The good safety of Japanese gastroenterological surgeries was also indicated.

Background/Aims Immune checkpoint blockade has recently been reported to be effective in treating microsatellite instability (MSI)-high tumors. Therefore, sufficient sampling of histological specimens is necessary in cases of unresectable pancreatic cancer (UR-PC). This multicenter study investigated the efficacy of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) using a Franseen needle for MSI evaluation in patients with UR-PC. Methods A total of 89 patients with UR-PC who underwent endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) or EUS-FNB using 22-G needles at three hospitals in Japan (2018–2021) were enrolled. Fifty-six of these patients (FNB 23 and FNA 33) were followed up or evaluated for MSI. Patient characteristics, UR-PC data, and procedural outcomes were compared between patients who underwent EUS-FNB and those who underwent EUS-FNA. Results No significant difference in terms of sufficient tissue acquisition for histology was observed between patients who underwent EUS-FNB and those who underwent EUS-FNA. MSI evaluation was possible significantly more with tissue samples obtained using EUS-FNB than with tissue samples obtained using EUS-FNA (82.6% [19/23] vs. 45.5% [15/33], respectively; p

Objectives The large-cell Niti-S stent is useful for multiple stenting in patients with malignant hilar biliary obstruction (MHBO). Recently, a novel uncovered self-expandable metallic stent (USEMS) (a Niti-S large-cell SR slim delivery system) was developed. In this study, we aimed to evaluate the efficacy of this USEMS slim delivery system in MHBO patients.Materials and methods Outcomes related to USEMS placement, the clinical course, and the period to recurrent biliary obstruction (RBO) were evaluated in MHBO patients who received multiple USEMSs with the Niti-S large-cell SR slim delivery system.Results Twenty-two MHBO patients underwent the placement of multiple USEMSs, including the novel slim-delivery stent. Six patients had a past history of upper gastrointestinal reconstruction (Billroth I: 1, Billroth II: 4, Roux-en-Y: 1). The number of USEMSs placed in each patient was 2-6. Three procedures were reinterventions. The new slim delivery system was placed as the first stent in ten patients and as an additional stent in the remaining patients. Seven patients were drained using only Niti-S large-cell SR slim delivery stents. The technical and clinical success rates were both 100%.Conclusions Placing multiple USEMSs in patients with a past history of abdominal surgery or in reintervention is difficult. Although difficult cases were included in this study, stent-in-stent placement with the novel Niti-S large-cell SR slim delivery system was useful in treating MHBO patients. In addition, this novel stent might be the first choice for MHBO patients.KEY MESSAGESEndoscopic multistenting for MHBO is challenging. In addition, reintervention or multistenting for MHBO patients with a past history of abdominal surgery becomes more difficult.The novel Niti-S large-cell SR slim delivery USEMS is useful as an additional stent because the delivery system is thin and suitable for a 0.025 guidewire. In addition, the novel stent is of the braided type and has a large mesh. Therefore, the novel stent is expected to have strong radial force and can be used as the first SEMS.The Niti-S large-cell SR slim delivery stent is long enough to be used in patients with upper gastrointestinal reconstruction. Although this study included patients with reintervention or a past history of upper gastrointestinal reconstruction, the technical success rate of multiple stenting for MHBO patients was 100%. The slim-delivery stent might overcome several difficulties of endoscopic multistenting.

Median arcuate ligament syndrome is a clinical condition in which the median arcuate ligament causes compression and narrowing of the celiac artery. It has been reported that collateral pathways, which is developed by the decrease of blood flow from the celiac artery, facilitates the formation of aneurysms. Aneurysms around the pancreas in particular require aggressive therapeutic intervention, because a rupture can be fatal. We herein report two cases of pancreaticoduodenal aneurysms associated with median arcuate ligament syndrome treated by coil embolization and median arcuate ligament incision. Case 1 required a hybrid procedure in which median arcuate ligament incision and coil embolization were performed simultaneously. In Case 2, the median arcuate ligament incision was performed about 3 months after emergency endovascular hemostasis for hemorrhagic duodenal ulcer. In both cases, there were no major postoperative complications and no recurrence of aneurysm. Median arcuate ligament incision may be effective to prevent organ ischemia and aneurysm recurrence after coil embolization of intra-abdominal aneurysms associated with median arcuate ligament syndrome.

The sequential progression from chronic liver disease to cirrhosis may be a risk factor for hepatocellular carcinoma (HCC) development. Although HCC originates from hepatitis B virus- or hepatitis C virus-associated liver cirrhosis, it has recently been reported in patients with non-alcoholic steatohepatitis (NASH) with advanced fibrosis. However, little is known about the pathophysiological mechanisms linking HCC to rheumatic disorders, including rheumatoid arthritis (RA). Herein, we describe the case of HCC with NASH complicated by RA and Sjögren’s syndrome (SS). A fifty-two-year-old patient with RA and diabetes was referred to our hospital for further examination of a liver tumor. She received methotrexate (4 mg/week) for 3 years and adalimumab (40 mg/biweekly) for 2 years. On admission, laboratory data showed mild thrombocytopenia and hypoalbuminemia, with normal hepatitis virus markers or liver enzymes. Anti-nuclear antibodies were positive with high titers (x640), and anti-SS-A/Ro (187.0 U/ml; normal range [NR]: ≤6.9 U/mL) and anti-SS-B/La (320 U/ml; NR: ≤6.9 U/mL) antibodies were also high. Abdominal ultrasonography and computed tomography revealed liver cirrhosis and a tumor in the left lobe (S4) of the liver. She was diagnosed with HCC based on imaging findings, and elevated levels of protein induced by vitamin K absence- II (PIVKA-II) were detected. She underwent laparoscopic partial hepatectomy, and histopathological examination revealed steatohepatitis HCC with background liver cirrhosis. The patient was discharged on the 8th day post-operation without any complications. At the 30 months follow-up, no significant evidence of recurrence was observed. Our case suggests that clinical screening for HCC is needed in patients with RA who are at a high risk of NASH, as they may progress to HCC even without elevated liver enzymes.

In developing a formula for manual use in clinical settings, simplicity is as important as accuracy. Whole-liver (WL) mass is often estimated using demographic and anthropometric information to calculate the standard liver volume or recommended graft volume in liver transplantation. Multiple formulas for estimating WL mass have been reported, including those with multiple independent variables. However, it is unknown whether multivariable models lead to clinically meaningful improvements in accuracy over univariable models. Our goal was to quantitatively define clinically meaningful improvements in accuracy, which justifies an additional independent variable, and to identify an estimation formula for WL graft weight that best balances accuracy and simplicity given the criterion. From the Japanese Liver Transplantation Society registry, which contains data on all liver transplant cases in Japan, 129 WL donor-graft pairs were extracted. Among the candidate models, those with the smallest cross-validation (CV) root-mean-square error (RMSE) were selected, penalizing model complexity by requiring more complex models to yield a ≥5% decrease in CV RMSE. The winning model by voting with random subsets was fitted to the entire dataset to obtain the final formula. External validity was assessed using CV. A simple univariable linear regression formula using body weight (BW) was obtained as follows: WL graft weight [g] = 14.8 × BW [kg] + 439.2. The CV RMSE (g) and coefficient of determination (R2) were 195.2 and 0.548, respectively. In summary, in the development of a simple formula for manually estimating WL weight using demographic and anthropometric variables, a clinically acceptable trade-off between accuracy and simplicity was quantitatively defined, and the best model was selected using this criterion. A univariable linear model using BW achieved a clinically optimal balance between simplicity and accuracy, while one using body surface area performed similarly.

Abstract Background We aimed to present the 2019 annual report of the gastroenterological section of the National Clinical Database (NCD). Methods We reviewed 609,589 cases recorded in 2019 and 5,029,764 cases registered from 2011 to 2019 for the 115 selected gastroenterological surgical procedures. Results The main features of gastroenterological surgery in Japan were similar to those described in the 2018 annual report, namely, that 1) operative numbers gradually increased in all procedures, except gastrectomy and hepatectomy, which decreased in these years; 2) in all eight major gastroenterological surgeries, the age distribution tended toward older patients; 3) the morbidity of esophagectomy, hepatectomy, and pancreaticoduodenectomy increased, but mortality was minimized in all procedures; 4) all eight major gastroenterological procedures have increasingly been performed under laparoscopy; and 5) board‐certified surgeons were increasingly involved. These trends in recent years were more prominent in 2019. Conclusions Thanks to the continuous cooperation and dedication of the surgeons, medical staff, and surgical clinical reviewers who registered the clinical data into the NCD, it is possible to understand the comprehensive landscape of surgery in Japan and to disclose new evidence in this field. The Japanese Society of Gastroenterological Surgery will continue to promote the value of this database and encourage the use of feedback and clinical studies using the NCD, now and in the future. Generating further approaches to surgical quality improvement are important directions for future research.

Abstract The laparoscopic living‐donor hepatectomy procedure has been developing rapidly. Although its use has increased worldwide, it is still only performed by experienced surgeons at a limited number of institutions. However, technical innovations have improved the feasibility of more widespread use of laparoscopic living‐donor hepatectomy. The advantages of laparoscopic living‐donor hepatectomy should not be overemphasized, and the fundamental principle of “living‐donor safety first” cannot be neglected. This review aims to summarize the current status of laparoscopic living‐donor hepatectomy and to emphasize that, while this procedure may soon be used as a reliable, donor‐friendly substitute for traditional open donor hepatectomy, its safety and efficacy require further substantiation first.

Abstract Background and Aim In 2015, the Japanese Society of Gastroenterological Surgery (JSGS) initiated data verification in the gastroenterological section of the National Clinical Database (NCD) and reported high accuracy of data entry. Remote audits were introduced for data validation on a trial basis in 2016 and formally accepted into use in 2017‐2018. The aim of this study was to audit the data quality of the NCD gastroenterological section for 2016‐2018 and to confirm the high accuracy of data in remote audits. Methods Each year, 45‐46 hospitals were selected for audit. Twenty cases were randomly selected in each hospital, and the accuracy of patient demographic and surgical outcome data (46 items) was compared with the corresponding medical records obtained by visiting the hospital (site‐visit audit) or by mailing data from the hospital to the JSGS office (remote audit). Results A total of 136 hospitals were included, of which 88 (64.7%) had a remote audit, and 124 936 items were evaluated with an overall data accuracy of 98.1%. There was no significant difference in terms of data accuracy between site‐visit audit and remote audit. Accuracy, sensitivity, and specificity of mortality were 99.7%, 89.7%, 100% for site‐visit audits and 99.8%, 97.3%, 100% for remote audits, respectively. Mean time spent on data verification per case of remote audits was shorter than that of site‐visit audits (10.0 minutes vs 13.7 minutes, P

Abstract Aim We evaluated the association of profiles of institutional departments with operative outcomes of eight major gastroenterological procedures. Methods We administered a 15‐item online survey to 2634 institutional departments in 2016 to investigate the association of questionnaire responses with operative mortality for the procedures. The proportions of conditions met were listed according to institutional volume and classified according to annual operative cases in 1464 departments. Group A included departments with annual performance of

Abstract Background If the depth of gallbladder malignant tumor (GBMT) invasion is deeper than the subserosa (ss), cholecystectomy is insufficient. In past reports that used endoscopic ultrasonography (EUS) to diagnose the depth of tumor invasion, it was difficult to diagnose GMBT invasion in the ss without a narrow or disrupted lateral hyperechoic layer (LHEL). Therefore, we developed a simple preoperative method to diagnose GBMTs with ss invasion. Methods Forty-nine GBMT patients who underwent both EUS and surgery were enrolled: 15 patients whose tumors invaded the mucosa (m) or muscularis propria (mp) were classified as the “shallow group”, and 34 patients whose tumors invaded the ss were classified as the “deep group”. The EUS findings were compared between the two groups. Results An irregular (narrow or thickened) LHEL was significantly more frequently observed on EUS in the deep group than in the shallow group. The diagnosis of ss invasion based on an irregular LHEL had the highest sensitivity and accuracy among the EUS imaging parameters (sensitivity 97.1% (33/34), specificity 86.7% (13/15), accuracy 93.8% (46/49)). When the deep group was limited to patients with a tumor depth of ss, the results were similar. When an irregular LHEL was used, the diagnostic accuracy of GBMTs with ss invasion was not significantly different between EUS specialists and beginners. Conclusions The observation of an irregular (thickened or narrow) LHEL observed on EUS could be a reliable and simple method of diagnosing GBMTs with ss invasion and could contribute to choosing an appropriate surgical method.

Abstract The National Clinical Database (NCD) of Japan grew rapidly, harvesting over 11 million cases of data between 2011 and 2018 from more than 5000 facilities. This is the Report of the NCD based upon gastrointestinal surgery information in 4 420 175 cases from 2011 to 2018. More than 70% of all gastrointestinal surgeries were performed at certified institutions, and the percentage of surgeries performed at certified institutions was particularly high for the esophagus (93.8% in 2018), liver (89.4%), pancreas (91.3%), and spleen (86.9%). Also, more than 70% of the surgeries were performed with the participation of the board‐certified surgeon. As the patients have been getting older, the morbidities have been increasing. However, the mortalities have been kept at a low level. The rates of endoscopic surgery have been increasing year by year, especially high in low anterior resection (67.0%) and esophagectomy (61.0%). Nationwide, this database is surely expecting to ensure the quality of board certification system and surgical outcomes in gastroenterological surgery.

Abstract The Japanese Society of Gastroenterological Surgery (JSGS) and the American College of Surgeons National Surgical Quality Improvement Program (ACS‐NSQIP) have collaboratively developed several clinical projects since 2011 using two nationwide clinical registries with the goal of achieving further improvement of surgical quality in both countries. In this review, the historical viewpoints and the collaboration between JSGS and ACS and their use of nationwide registries [National Clinical Database (NCD) and NSQIP] for research are reviewed. We have carried out a joint project, the 30‐day Mortality Risk Model Study and, currently, we are working on several joint projects such as the Morbidity‐Mortality Study, Japan‐USA Calibration Study, Geriatric Study, and Safety Culture Study as well as Auditing in JSGS/NCD with reference to the NSQIP method. These joint projects will continue to provide us with important information and data to drive improvements in surgical care in both countries. This will also help us to identify any unknown weaknesses in the health‐care systems of the USA and Japan.

Abstract Background The Japanese National Clinical Database (NCD) is a large‐scale, nationwide, web‐based data entry system that is linked to the surgical board certification system and covers almost all surgical cases carried out in Japan. Aim To evaluate outcomes according to the gastroenterological section of the NCD. Methods The 115 surgical procedures stipulated by the “Training Curriculum for Board‐Certified Surgeons in Gastroenterology” were registered from 2011 to 2017. The number of surgeries, preoperative comorbidities, and short‐term outcomes were compared between registration periods. Results In total, 3 818 414 cases have been registered. More than 70% of all surgeries were carried out at certified institutions. The annual number of cases has been increasing year after year, and the aged population has also been increasing. Although the rates of preoperative comorbidities and postoperative complications have been increasing, the postoperative mortality rate has remained relatively low; in 2017, the 30‐day mortality rate was 1.0% among those who underwent esophagectomy, 0.7% among those who underwent distal gastrectomy, 1.1% among those who underwent total gastrectomy, 1.3% among those who underwent right hemicolectomy, 0.5% among those who underwent low anterior resection, 1.3% among those who underwent hepatectomy, and 1.3% among those who underwent pancreaticoduodenectomy. The annual rate of endoscopic surgery dramatically increased over 7 years between 2011 and 2017, especially for low anterior resection (29.5%‐62.6%) and esophagectomy (31.0%‐56.1%). Conclusion This database is expected to ensure the quality of the board‐certification system and surgical outcomes in gastroenterological surgery.

Abstract Background Although annular pancreas concurrent with pancreaticobiliary maljunction has rarely been reported, some reports have pointed out a possibility that both anomalies have a common pathogenesis in pancreatic development. We herein report a case with pancreaticobiliary maljunction diagnosed long after surgical treatment for annular pancreas. Case presentation A 34-year-old female, with a surgical history of duodenal obstruction due to annular pancreas in the neonatal period, was referred to our hospital for further examination of chronic pancreatitis. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography revealed choledocholithiasis, pancreatic lithiasis, and pancreaticobiliary maljunction without biliary dilatation. Choledocholithotomy and cholecystectomy were performed, and highly elevated levels of amylase in bile from the common bile duct were found intraoperatively. Conclusion The present case highlights a possible association of pancreaticobiliary maljunction in a patient with annular pancreas.

Purpose/Aim: Although several prognostic factors for extrahepatic cholangiocarcinoma (EHC) have been reported, preoperative prognostic factors have yet to be established. We investigated the serum concentration of angiogenic, inflammatory, and nutritional parameters. Materials and Methods: Twenty-five patients with EHC were enrolled before starting treatment. Preoperative prognostic factors were identified using multivariate analyses. Results: The serum soluble intercellular adhesion molecule-1 (sICAM-1) levels were significantly higher in the patients with EHC (436.0 ± 43.2 ng/ml) than in the healthy volunteers (228.6 ± 22.0 ng/ml) (p

We describe the first case of a nonhealing duodenal ulcer with perforation after proton beam therapy (PBT) of a liver tumor that was successfully treated endoscopically using polyglycolic acid (PGA) sheets with fibrin glue. A 69-year-old man received PBT for a liver tumor. Esophagogastroduodenoscopy (EGD) 3 months after PBT revealed a duodenal ulcer. A proton pump inhibitor was administered for 7 weeks, and the ulcer healed. Six months after the EGD, recurrence of the duodenal ulcer with perforation occurred. An emergency open surgery with placement of the omental patch was performed. However, 5 days after the surgery, because the EGD revealed a perforation site in the duodenal ulcer that was not closed, the conservative treatment was continued. Twenty-eight days after the surgery, EGD revealed that the perforation size had increased. Therefore, we conducted endoscopic closure therapy using PGA sheets with fibrin glue. Eleven days after the closure procedure, the EGD showed that the perforation site was filled with granulation tissue and was closed. Forty-nine days after the procedure, EGD revealed that the ulcer had healed. This endoscopic closure treatment was effective for a nonhealing duodenal ulcer with perforation after PBT of a liver tumor.

Abstract Background Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for mucinous cystic neoplasm of the pancreas carries a potential risk of inducing peritoneal tumor cell dissemination. We investigated the diagnostic yield and safety of EUS-FNA-based cytology of cells obtained from the pancreatic invasion site of intraductal papillary-mucinous neoplasm-derived adenocarcinoma (IPMC). Methods We included 22 surgically resected IPMCs and 84 pancreatic ductal adenocarcinomas (PDACs). Among the IPMC cases, 14 did not undergo EUS-FNA before surgical resection. The diagnostic yield of EUS-FNA was compared between IPMC and PDAC. Additionally, prognosis (relapse-free and overall survival time after resection) and the rate of peritoneal dissemination were compared among IPMC with EUS-FNA, IPMC without EUS-FNA, and PDAC. A survival analysis was performed using the Kaplan-Meier method and log-rank test. Results (EUS-FNA diagnosis) There were no significant differences in the number of needle passages (PDAC 2.5 vs. IPMC 2.0 passages, P = 0.84) or puncture route (stomach/duodenum: 2/6 vs. 45/39, P = 0.29). However, the correct diagnosis rate was significantly higher in PDAC (92.9%) than in IPMC (62.5%) (P = 0.03). No procedure-related adverse events occurred. Peritoneal lavage cytology performed during the operation was negative in all cases. (Prognosis) Among IPMC with EUS-FNA, IPMC without EUS-FNA, and PDAC, there were no significant differences in relapse-free survival (21.0 vs. 22.4 vs. 12.5 months, respectively; P = 0.64) or overall survival time (35.5 vs. 53.1 vs. 35.9 months, respectively; P = 0.42), and peritoneal dissemination was detected during the observation period in 25%, 28.5%, and 21.4% cases, respectively (P = 0.82). Conclusion Even though a correct diagnosis was more difficult to obtain in IPMC than in PDAC, IPMC allows specimens to be obtained without influencing the rate of recurrence and prognosis.

Background. Tacrolimus is the key immunosuppressive drug for liver transplantation. Once-daily prolonged-release tacrolimus (TAC-PR) exhibits good drug adherence but has difficulty controlling the trough level in the early phase of liver transplantation. The aim of this study was to compare the feasibility and efficacy of immediately starting oral TAC-PR versus traditional twice-daily tacrolimus (TAC-BID) in de novo liver transplantation recipients. Methods. The study included 28 patients treated with conventional TAC-BID and 60 patients treated with TAC-PR (median follow-up 70.5 months). Short-term and long-term outcomes were compared. Results. Patient characteristics were similar except for the incidence of hepatocellular carcinoma and type of graft. Dose adjustment was more frequently required for TAC-PR than TAC-BID (73.3% vs 42.9%, P = 0.006), but trough levels of TAC during the first 3 months after liver transplantation were controlled well in both groups. The rate of acute cellular rejection and long-term renal function were similar in both groups. In both groups, renal function worsened during the first 6 months after transplantation and remained stable until the end of the follow-up period. The 1-year, 3-year, and 5-year survival rates were 96.4%, 85.7%, and 85.7% for TAC-BID and 96.7%, 94.8%, and 94.8% for TAC-PR, respectively. The overall survival curve for TAC-PR was not inferior to that of TAC-BID. Conclusions. The TAC-PR protocol was feasible and effective with strict adjustment.

Strategies to reduce the immunogenicity of pancreatic islets and to prevent the activation of proinflammatory events are essential for successful islet engraftment. Pretransplant islet culture presents an opportunity for preconditioning to improve outcomes of islet transplantation. We previously demonstrated that ex vivo mitomycin C (MMC) pretreatment and subsequent culture significantly prolonged graft survival. Fully understanding the biological process of pretreatment could result in the development of a protocol to improve the survival of islet grafts. Microarrays were employed to conduct a comprehensive analysis of genes expressed in untreated or MMC-treated rat islets that were subsequently cultured for 3 d. A bioinformatics software was used to identify biological processes that were most affected by MMC pretreatment, and validation studies, including in vivo and in vitro assay, were performed. The gene expression analysis identified significant downregulation of annotated functions associated with cellular movement and revealed significant downregulation of multiple genes encoding proinflammatory mediators with chemotactic activity. Validation studies revealed significantly decreased levels of interleukin 6 (IL-6), monocyte chemoattractant protein 3 (MCP-3), and matrix metallopeptidase 2 (MMP2) in culture supernatants of MMC-treated islets compared with controls. Moreover, we showed the suppression of leukocyte chemotactic activity of MMC-treated islets in vitro. We also showed that MMC-treated islets secreted lower levels of chemoattractants that synergistically reduced the immunogenic potential of islets. Histological and immunohistochemical analyses of the implant site revealed that infiltration of monocytes, CD3-positive T cells, and B cells was decreased in MMC-treated islets. In conclusion, the ex vivo pretreatment of islets with MMC and subsequent culture can reduce the immunogenic potential and prolong the survival of islet grafts by inducing the suppression of multiple leukocyte chemotactic factors.

Epithelial-mesenchymal transition (EMT) is involved in the characteristics of malignancy, such as invasion, metastasis, and chemoresistance. In biliary tract cancer (BTC), EMT is induced by transforming growth factor-beta 1 (TGF-β1). The EMT is reversible; therefore, it is conceivable that it could be related to some epigenetic changes. We focused on histone deacetylase (HDAC) inhibitors as regulators of TGF-β1 signaling, and investigated their effect on EMT and chemoresistance. We employed four BTC cell lines (MzChA-1, gemcitabine-resistant MzChA-1, TFK-1, and gemcitabine-resistant TFK-1) and used vorinostat as the HDAC inhibitor. The relative mRNA expression of an epithelial marker (CDH1) and mesenchymal markers (CDH2, vimentin, SNAI1) were measured by qRT-PCR to evaluate factors associated with EMT. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to evaluate the chemoresistance of each cell line. In addition, NOD/SCID mice were used to evaluate the effect of vorinostat in vivo. In the parent MzChA-1 and TFK-1 cell lines, TGF-β1 induced EMT and chemoresistance; while vorinostat inhibited the EMT and chemoresistance induced by TGF-β1. In gemcitabine-resistant cell lines that highly expressed TGF-β1, vorinostat inhibited EMT and attenuated chemoresistance. We showed that vorinostat inhibits nuclear translocation of SMAD4 which is a signaling factor of TGF-β1, and this is one of the mechanisms by which vorinostat regulates EMT. We also showed that vorinostat attenuates the binding affinity of SMAD4 to the CDH1-related transcription factors SNAI1, SNAI2, ZEB1, ZEB2, and TWIST. Furthermore, combination therapy with vorinostat and gemcitabine improved survival time in the mice xenografted with gemcitabine resistant MzChA-1 cells. In conclusion, vorinostat regulated TGF-β1-induced EMT and chemoresistance through inhibition of SMAD4 nuclear translocation.

Recent studies applying high-throughput sequencing technologies have identified several recurrently mutated genes and pathways in multiple cancer genomes. However, transcriptional consequences from these genomic alterations in cancer genome remain unclear. In this study, we performed integrated and comparative analyses of whole genomes and transcriptomes of 22 hepatitis B virus (HBV)-related hepatocellular carcinomas (HCCs) and their matched controls. Comparison of whole genome sequence (WGS) and RNA-Seq revealed much evidence that various types of genomic mutations triggered diverse transcriptional changes. Not only splice-site mutations, but also silent mutations in coding regions, deep intronic mutations and structural changes caused splicing aberrations. HBV integrations generated diverse patterns of virus-human fusion transcripts depending on affected gene, such as TERT, CDK15, FN1 and MLL4. Structural variations could drive over-expression of genes such as WNT ligands, with/without creating gene fusions. Furthermore, by taking account of genomic mutations causing transcriptional aberrations, we could improve the sensitivity of deleterious mutation detection in known cancer driver genes (TP53, AXIN1, ARID2, RPS6KA3), and identified recurrent disruptions in putative cancer driver genes such as HNF4A, CPS1, TSC1 and THRAP3 in HCCs. These findings indicate genomic alterations in cancer genome have diverse transcriptomic effects, and integrated analysis of WGS and RNA-Seq can facilitate the interpretation of a large number of genomic alterations detected in cancer genome.

Although islet transplantation can achieve insulin independence in patients with type 1 diabetes, sufficient number of islets derived from two or more donors is usually required to achieve normoglycemia. Activated neutrophils and neutrophil elastase (NE), which is released from these neutrophils, can directly cause injury in islet grafts. We hypothesized that inhibition of NE improves islet isolation and islet allograft survival. We tested our hypothesis by examining the effects of modified ET-Kyoto solution supplemented with sivelestat, a NE inhibitor (S-Kyoto solution), on islet yield and viability in islet isolation and the effect of intraperitoneally injected sivelestat on islet graft survival in a mouse allotransplant model. NE and proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 increased markedly at the end of warm digestion during islet isolation and exhibited direct cytotoxic activity against the islets causing their apoptosis. The use of S-Kyoto solution significantly improved islet yield and viability. Furthermore, treatment with sivelestat resulted in significant prolongation of islet allograft survival in recipient mice. Furthermore, serum levels of IL-6 and TNF-α at 1 and 2 weeks posttransplantation were significantly higher in islet recipients than before transplantation. Our results indicated that NE released from activated neutrophils negatively affects islet survival and that its suppression both in vitro and in vivo improved islet yield and prolonged islet graft survival. The results suggest that inhibition of NE activity could be potentially useful in islet transplantation for patients with type 1 diabetes mellitus.

Background/Aims: Immune checkpoint blockade has recently been reported to be effective in treating microsatellite instability (MSI)- high tumors. Therefore, sufficient sampling of histological specimens is necessary in cases of unresectable pancreatic cancer (UR-PC). This multicenter study investigated the efficacy of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) using a Franseen needle for MSI evaluation in patients with UR-PC. Methods: A total of 89 patients with UR-PC who underwent endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) or EUS-FNB using 22-G needles at three hospitals in Japan (2018-2021) were enrolled. Fifty-six of these patients (FNB 23 and FNA 33) were followed up or evaluated for MSI. Patient characteristics, UR-PC data, and procedural outcomes were compared between patients who underwent EUS-FNB and those who underwent EUS-FNA. Results: No significant difference in terms of sufficient tissue acquisition for histology was observed between patients who underwent EUS-FNB and those who underwent EUS-FNA. MSI evaluation was possible significantly more with tissue samples obtained using EUS-FNB than with tissue samples obtained using EUS-FNA (82.6% [19/23] vs. 45.5% [15/33], respectively; p<0.01). In the multivariate analysis, EUS-FNB was the only significant factor influencing the possibility of MSI evaluation. Conclusions: EUS-FNB using a Franseen needle is desirable for ensuring sufficient tissue acquisition for MSI evaluation. [ABSTRACT FROM AUTHOR]