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Background: The most suitable procedure for resecting small-sized gastric neoplasms remains unclear. Endoscopic mucosal resection leads to non-curative resection owing to slippage of the snare, and technically difficult endoscopic submucosal dissection (ESD) is instrumentally uneconomical. A novel, cost-effective, multifunctional snare called SOUTEN is available as a hybrid ESD (h-ESD) device developed for facilitating ESD. This study aimed to assess the acceptability of h-ESD using the SOUTEN for resecting small-sized gastric neoplasms. Methods: This was a prospective observational study conducted at our single institution between March 2019 and March 2021. Fifty-seven consecutive patients who underwent h-ESD using SOUTEN for small-sized gastric neoplasms ≤ 15 mm involving adenoma and tubular-type mucosal carcinoma without ulceration were enrolled. The primary outcome was en bloc resection rate of h-ESD. Secondary outcomes were the rates of curative resection, conversion to ESD, procedure time, rates of intra-and post-operative complications, and presence of additional knives excluding hemostatic forceps. Results: The en bloc resection rate of h-ESD was 91.2% (52/57). The curative resection rate was 94.7% (54/57) including conversion to ESD cases. The mean procedure time was 21.2 (± 16.5) minutes. One case of delayed bleeding occurred. Additional knives were applied in two cases. Conclusion: The cost-efficient h-ESD using SOUTEN can be an acceptable procedure for resecting small-sized gastric neoplasms.

Duodenal endoscopic submucosal dissection (ESD) is associated with high incidences of intraoperative complications and delayed adverse events (AEs). Delayed AEs can be reduced by closing the post-ESD defects. We developed a new method of closure after duodenal ESD, combining endoscopic ligation with O-ring closure (E-LOC) with an over-the-scope clip (OTSC) (Band OTSC; B-OTSC). Here, we conducted a single-center, retrospective, observational study to investigate the efficacy and safety of the B-OTSC method for preventing delayed AEs in patients undergoing duodenal ESD. The study included nine patients with superficial nonpapillary duodenal epithelial tumors who underwent ESD and were closed with B-OTSC from February 2021 to February 2023. There were no delayed AEs (0%), the mean (± standard deviation) closure time was 53 ± 21.6 min, the complete closure rate was 100%, and the mean hospital stay was 7.8 ± 1.8 days. The sustained closure rates at postoperative days 3 and 7 were 88.9% and 88.9%, respectively. The historical analysis indicated a significant difference in cost between B-OTSC and conventional OTSC (p < 0.01). In conclusion, B-OTSC was a safe, secure, and cost-effective method of closure after duodenal ESD, even in patients with post-ESD defects of more than half the circumference.

The risk of bleeding after gastric endoscopic submucosal dissection (ESD) in antithrombotic agent users has increased, and its management remains a problem. Second-look endoscopy (SLE) following gastric ESD in antithrombotic agent users may be effective in preventing delayed bleeding, but this requires elucidation. Therefore, this study aimed to investigate the efficacy of SLE in reducing bleeding after gastric ESD in patients receiving antithrombotic agents.This retrospective cohort study was conducted at 19 referral hospitals in Japan. A total of 1,245 patients who were receiving antithrombotic agents underwent gastric ESD between January 2013 and July 2018. The incidence of delayed bleeding was compared between SLE and non-SLE groups using propensity score matching analysis.Overall, 858 patients (SLE group, 657 patients; non-SLE group, 201 patients) were analyzed. After matching, 198 pairs were created. Delayed bleeding occurred in 10 patients (5.1%) in the SLE group and 16 patients (8.1%) in the non-SLE group [odds ratio (OR) 0.605, 95% confidence interval (CI) 0.23-1.46, p = 0.310]. In the subgroup analysis, SLE reduced the incidence of delayed bleeding in patients receiving heparin bridging therapy (6.3% and 40.0%, respectively; p = 0.004). In the SLE group, prophylactic coagulation did not significantly reduce delayed bleeding compared to the no treatment group (14.6% and 8.6%, respectively; p = 0.140).SLE was ineffective in reducing bleeding after gastric ESD in antithrombotic agent users, overall. A prospective comparative study is warranted to definitively evaluate the effectiveness of SLE in reducing bleeding in high-risk patients.

Esophagogastroduodenoscopy (EGD) is an aerosol-generating procedure. A major challenge in the COVID-19 era is how to prevent the spread of aerosols and droplets in endoscopic units. We evaluated the effectiveness of an extraoral suction device in preventing indoor aerosol diffusion and droplet exposure for examiners. The study involved 61 patients who underwent EGD at our institution from 1 February to 31 March 2022. To determine whether aerosol spread increases before or after EGD examination with an extraoral suction device located in front of the patient’s mouth, aerosols of 0.3, 0.5, 1, 3, 5, and 10 μm were measured with a handheld particle counter. The degree of contamination of the plastic gowns on the examiners was assessed using the rapid adenosine triphosphate test. The extraoral suction device significantly reduced the diffusion of large particles (3, 5, and 10 μm) after finishing the EGD examination. However, the diffusion of small particles (0.3 and 0.5 μm) was significantly increased. This extraoral suction device was effective in reducing large particle diffusion during EGD examination but was limited for minimizing small particle diffusion or droplet exposure to the examiner.

Pancreatic ductal adenocarcinoma (PDAC) is the most devastating of all cancers with an extremely poor prognosis. It has few effective and reliable therapeutic strategies. Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB). Telmisartan inhibits cancer cell proliferation, but the underlying mechanisms in PDAC, remain unknown.In the present study, we evaluated the effects of telmisartan on human PDAC cell proliferation in vitro. We assessed the effects of telmisartan on human PDAC cells using the cell lines PK-1 and PANC-1.Telmisartan inhibited the proliferation of these cells via blockade of the G0 to G1 cell cycle transition. This was accompanied by a strong decrease in cyclin D1. Telmisartan was also shown by receptor tyrosine kinase and angiogenesis arrays to reduce the phosphorylation of epidermal growth factor receptor (EGFR), and miRNA expression was markedly altered by telmisartan in PK-1 cells.In conclusion, telmisartan inhibits human PDAC cell proliferation by inducing cell cycle arrest. Furthermore, telmisartan significantly altered miRNA expression in vitro. Taken together, our study demonstrated the therapeutic potential of telmisartan and provides molecular mechanistic insights into its anti-tumor effect on PDAC cells.

Background The recently developed endoscopic full-thickness resection technique requires reliable closure. The main closure methods are the purse-string suture (PSS) technique and over-the-scope clip (OTSC) technique; however, basic data on the closure strength of each technique are lacking. This study was performed to compare the closure strengths of these two methods in an ex vivo porcine model. Methods In the traction test, a virtual 5-cm full-thickness closure line was closed by the following six methods three times each: conventional hemoclips, mucosal PSS, seromuscular PSS, mucosal OTSC, seromuscular OTSC, and surgical suture. The primary endpoint was the tension at the starting point of dehiscence, measured in Newtons (N) by an automatic traction machine. In the leak test, a 15-mm gastric full-thickness defect was closed by PSS or OTSC six times each, and the closed stomach was then pressurized in a water container. The primary endpoint was the leak pressure when air bubbles appeared. The secondary endpoints were the procedure time and presence of complete inverted closure. Results The mean tension was 2.16, 3.68, 5.15, 18.30, 19.30, and 62.40 N for conventional hemoclips, mucosal PSS, seromuscular PSS, mucosal OTSC, seromuscular OTSC, and surgical suture, respectively. Complete inverted closure was observed for seromuscular PSS, seromuscular OTSC, and surgical suture. The mean leak pressure was 13.7 and 24.8 mmHg in the PSS and OTSC group, respectively (P Conclusion The OTSC, which allows complete inverted closure, showed greater closure strength than PSS. Considering the size limitation suitable for single OTSC, a therapeutic strategy for closing the larger size is further warranted.

The management of postoperative bleeding, after gastric endoscopic submucosal dissection (ESD), has become particularly important because of the recent increase in antithrombotic use. Endoscopic shielding with polyglycolic acid (PGA) sheets has been shown to be effective. However, shrinkage and early displacement of the sheet remain challenges. This study aimed to determine the efficacy and safety of our developed method, named wafer paper and ring-mounted PGA sheet (WaRP).Twenty-four patients with antithrombotic uptake who underwent the WaRP method following gastric ESD were retrospectively examined. This involved the delivery of a PGA sheet wrapped in wafer paper with ring-thread, and its fixation on the gastric floor using hemoclips. The primary outcome was the technical success rate of the WaRP, and several secondary outcomes were evaluated.The technical success rate of WaRP was 100%. The procedure lasted a mean of 10.5 min (SD 6.7 min). The prevalence of complete retention at follow-up endoscopy was 83.3% (20/24). There were no WaRP-associated complications, but post-ESD hemorrhage occurred in two patients undergoing hemodialysis (8.3%).The WaRP method is a simple and reliable means of PGA sheet delivery and placement that reduces the incidence of post-ESD hemorrhage.

Background/Aim: Colorectal endoscopic submucosal dissection (ESD) is a difficult technique. Counter-traction may facilitate the procedure but its efficacy in non-experts remains unclear. We determined the safety and efficacy of pocket creation and ring-thread traction (PRM) for non-expert colorectal ESD. Patients and Methods: We retrospectively compared patients who underwent conventional colorectal ESD (C-group, n=50) or PRM (pocket creation, whole-circumferential cutting, ring-thread traction, submucosal dissection; PRM-group, n=48). All procedures were performed by four non-experts, each with ≤40 experiences of colorectal ESD. Results: Procedural time was significantly shorter in the PRM-group compared with the C-group (p=0.007), with less additional device usage (p

Background and Aims: Endoscopic submucosal dissection (ESD) seems to be a reasonable option for gastrointestinal subepithelial lesions (SELs) localized within the submucosa. Indications for ESD include small neuroendocrine tumors (NETs) and indeterminate SELs. However, the prospective data regarding ESD and surveillance remain unclear. This study was performed to prospectively investigate the outcomes of ESD, including organ-specific outcomes and the mid-term prognosis. Methods: This prospective multicenter study included 57 patients who underwent ESD for SELs localized within the submucosa [definite NETs (n = 42) and indeterminate SELs (n = 15)]. The efficacy and safety of ESD were evaluated in the whole cohort and in subgroups (NETs and indeterminate SELs). All patients were followed up. Results: The rates of en bloc resection, curative resection, and complications were 98.2%, 66.7%, and 7.7% for the overall population (n=57); 100%, 61.9%, and 2.4% for NETs (n=42); and 93.3%, 80.0%, and 20.0% for indeterminate SELs (n=15), respectively. The rates of curative resection for NETs were poorer in the stomach (20%, n=5) and duodenum (33%, n=3) than in the rectum (71%, n=34). Including 11 of 16 patients with NETs who underwent a conservative approach resulting in non-curative resection, no patients developed tumor recurrence during the follow-up period (median, 24.5 months; range, 1–60 months). ESD followed by surveillance demonstrated acceptable mid-term outcomes for non-curative NETs. Conclusions: ESD can be an efficient therapy for SELs localized within the submucosa. However, gastric and duodenal ESD for NETs may be limited in terms of its curative and technical aspects. Clinicians should be aware of the potential complications of ESD for indeterminate SELs.

Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared with nontumor tissue. Thus, we examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths. HCC tissue samples from 29 patients who underwent hepatectomy at our hospital in 2002–2013 were obtained. We extracted the total RNA and analyzed it by microRNA array, real-time RT-PCR, and three comparisons: 1) HBV-related HCC and adjacent nontumor tissue, 2) HCV-related HCC and adjacent nontumor tissue, and 3) non-HBV-, non-HCV-related HCC and adjacent nontumor tissue. We also performed a functional analysis of miRNAs specific for HBV-related HCC by using HBV-positive HCC cell lines. MiR-210-3p expression was significantly increased only in the HBV-related HCC tissue samples. MiR-210-3p expression was upregulated, and the levels of its target genes were reduced in the HBV-positive HCC cells. The inhibition of miR-210-3p enhanced its target gene expression in the HBV-positive HCC cells. In addition, miR-210-3p regulated the HBx expression in HBV-infected Huh7/NTCP cells. The enhanced expression of miR-210-3p was detected specifically in HBV-related HCC and regulated various target genes, including HBx in the HBV-positive HCC cells. MiR-210-3p might, thus, be a new biomarker for the risk of HBV-related HCC. NEW & NOTEWORTHY Our present study demonstrated that miR-210-3p is the only microRNA with enhanced expression in HBV-related HCC, and the enhanced expression of miR-210-3p upregulates HBx expression. Therefore, miR-210-3p might be a pivotal biomarker of HBV-related hepatocarcinogenesis, and the inhibition of miR-210-3p could prevent inducing hepatocarcinogenesis related to HBV infection.

Background We examined the efficacy of a novel endoscopic ligation technique with O-ring closure (E-LOC) to prevent bleeding after gastric endoscopic submucosal dissection (ESD) under antithrombotic therapy. Methods This single-center prospective study involved consecutive patients who were taking antithrombotic agents and underwent gastric ESD. E-LOC was performed by anchoring the nylon loop with hemoclips on both defect edges and/or the exposed muscle layer, and using O-ring band ligation around these deployed clips. The primary outcome was post-ESD bleeding rate. Secondary outcomes were complete closure rate, procedure time, sustained closure rate, and complications. Results 48 patients were finally analyzed. The post-ESD bleeding rate was 0 %, the complete closure rate was 97.9 %, and the mean closure time was 29.9 minutes. The sustained closure rate was 95.8 % at postoperative day 2–3 and 33.3 % at postoperative day 10–11. No complications occurred. Conclusion E-LOC may be an effective option for closing mucosal defects after gastric ESD under antithrombotic therapy. However, the preventive effect on post-ESD bleeding should be further investigated in high risk groups.

A man in his thirties was admitted to the hospital because of upper abdominal pain. Computed tomography showed intussusception in the ascending and transverse colon. After spontaneous discontinuation, endoscopy revealed a 25-mm 0-I tumor in the ileum. An emergency operation was performed the next day due to intussusception recurrence. The tumor was hyperplastic intestinal epithelium with dendritic smooth muscle fascicles and partly cancerous. The patient had no clinical features of Peutz-Jeghers syndrome. Therefore, the patient was diagnosed with Peutz-Jeghers type polyps based on pathological findings. This case is considered to be a rare case of intussusception in the transverse colon due to Peutz-Jeghers type polyp with canceration.

Pooled gastric residues involving blood clots and food interrupt appropriate endoscopic intervention, leading to poor outcomes in endoscopic hemostasis and lifesaving. However, procedures and devices that enable the effective removal of gastrointestinal residues remain unsatisfactory. This study aimed to evaluate the efficacy and safety of our developed suction method in ex vivo and in vivo studies. We created a hand-made device with a large suction diameter, consisting of a balloon overtube and an ultrathin endoscope for navigation. In the ex vivo study, we compared the success rate and the suctioning time for four types of simulated residue between a standard endoscope and our device. Our device had s significantly higher suction ability and a shorter procedure time than the standard endoscope. The subsequent in vivo animal study involved five beagle dogs that were administered with food jelly to mimic gastric residue. Suction was performed twice for five dogs (ten attempts). The outcome measure was the successful procedure rate, secondary outcomes were procedure-associated complications and procedure time. The procedure was successful in all attempts, without any complications. The mean procedure time was 5 min. This novel method enabled the efficient and safe removal of gastric residue, and our findings will likely lead to the development of the instrument.

White globe appearance (WGA) is defined as a microendoscopic white lesion with a globular shape underlying the gastric epithelium and is considered a marker of gastric cancer. We recently reported that endoscopically visualized white spot (WS) corresponding to WGA appeared on the nonatrophic mucosa of patients with acid-suppressing agents (A-SA) use. We evaluated patients undergoing routine esophagogastroduodenoscopy and divided the patients into an A-SA group (n = 112) and a control group (n = 158). We compared the presence of WS in both groups. We also compared WS-positive- (n = 31) and -negative (n = 43) groups within the A-SA group regarding these patients’ backgrounds and serum gastrin concentrations. Comparing the A-SA group with controls, the prevalence of WS was significantly higher (31/112 vs. 2/158, p &lt, 0.001). The number of patients with high serum gastrin concentrations was significantly higher in the WS-positive group (18/31) vs. the WS-negative group (5/43) (p &lt, 0.001). Within the A-SA group, the prevalence of WS was also significantly higher in patients taking potassium-competitive acid blockers vs. proton-pump inhibitors (21/31 vs. 10/31, p &lt, 0.001). The WS-positive group had a significantly greater percentage of patients, with a high serum gastrin level (p &lt, 0.001). WS may be associated with hypergastrinemia and potassium-competitive acid blockers.

Colon cancer is the second leading cause of cancer-related mortality worldwide, and the prognosis of advanced colon cancer has remained poor in recent years. Galectin-9 (Gal-9) is a tandem-repeat type galectin that has recently been shown to exert antiproliferative effects on various types of cancer cells. The present study aimed to assess the effects of Gal-9 on human colon and colorectal cancer cells in vitro and in vivo, as well as to evaluate the microRNAs (miRNAs/miRs) associated with the antitumor effects of Gal-9. We examined the ability of Gal-9 to inhibit cell proliferation via apoptosis, and the effects of Gal-9 on cell cycle-related molecules in various human colon and colorectal cancer cell lines. In addition, Gal-9-mediated changes in activated tyrosine kinase receptors and angiogenic molecules were assessed using protein array chips in colon and colorectal cancer cells. Moreover, miRNA array analysis was performed to examine Gal-9-induced miRNA expression profiles. We also elucidated if Gal-9 inhibited tumor growth in a murine in vivo model. We found that Gal-9 suppressed the cell proliferation of colon cancer cell lines in vitro and in vivo. Our data further revealed that Gal-9 increased caspase-cleaved keratin 18 levels in Gal-9-treated colon cancer cells. In addition, Gal-9 enhanced the phosphorylation of ALK, DDR1, and EphA10 proteins. Furthermore, the miRNA expression levels, such as miR-1246, miR-15b-5p, and miR-1237, were markedly altered by Gal-9 treatment in vitro and in vivo. In conclusion, Gal-9 suppresses the cell proliferation of human colon cancer by inducing apoptosis, and these findings suggest that Gal-9 can be a potential therapeutic target in the treatment of colon cancer.

The Over-The-Scope Clip (OTSC) can effectively treat refractory gastrointestinal diseases. However, most reports have focused on short-term effectiveness. We examined clinical outcomes of the deployed clips and long-term characteristics.Of 47 patients with OTSC treatment, 35 with follow-up periods of ≥3 months were retrospectively examined. The indications were 11 bleedings, 17 perforations, and seven fistulas. The observation period was defined as medium-term (3 to12 months) or long-term (≥12 months). The primary outcome was the clinical success rate without disease recurrence. The secondary outcomes were the complication rate, survival duration, and clip retention rate.The medium- and long-term clinical success rates were 100% during the observation period (median, 44 months; range, 3-78 months). The complication rate was 2.9% (Regardless of clip detachment, the OTSC can be effective in long-term.

The Over-the-scope clip (OTSC) has been recently introduced for multiple purposes, including refractory bleeding, perforation, fistula, and anastomotic dehiscence of the gastrointestinal tract. However, no easy access techniques for delivering OTSCs to distant sites have been described. Therefore, we have developed a simple and safe guidewire-assisted OTSC delivery (GOD) method for use on the distal intestine. This study aimed to investigate the technical feasibility and safety of the method.Between June 2018 and April 2019, all eight patients who underwent the GOD method were retrospectively examined. The primary outcome was the successful rate of OTSC delivery to the lesion without complications. The secondary outcomes were GOD procedure time, total procedure time, technical and clinical OTSC success rates, and GOD- and OTSC-associated complications.The rate of successful OTSC delivery was 100%. The median procedure time of GOD was 21 min (range 8-29). The median total procedure time was 38.5 min (range 26-41). The technical and clinical success rates of OTSC were 100% and 75% (6/8), respectively. No GOD- or OTSC-associated complications occurred.The GOD method is a feasible and safe technique for delivering OTSC toward the small and proximal large intestine.

Background Endoscopic submucosal tunnel dissection (ESTD) has recently been an effective procedure for resecting large early esophageal neoplasm. However, excessive dissection beyond the distal limit may occur because the prepared distal end often cannot be distinguished through the tunnel. This study aimed to assess the efficacy and safety of a novel crystal violet navigation (CVN) for identifying the distal end. Material and methods In the observational case series study, all 22 patients who underwent esophageal ESTD using the CVN were included. When setting the distal end, the distal incision line was dyed purple using a crystal violet solution. The rates of purple color identified via the tunnel, successful tunnel penetration without extra dissection, en bloc and curative resection, procedure time for ESTD and CVN, and procedure-associated complications were evaluated. Results The rates of purple color and successful tunnel penetration were both 100%. En bloc and curative resection were 100%, and 86%, respectively. The mean total procedure time was 103.9 ± 46.2 (mean ± SD) minutes, while the mean time for the CVN was 14.1 ± 3.44 s. No complications were observed. Conclusions The simple CVN method can be a navigation tool for identifying the distal end during the ESTD procedure.

Cholangiocarcinoma (CCA) is at an advanced stage at the time of its diagnosis, and developing a more effective treatment of CCA would be desirable. Angiotensin II type 1 (AT1) receptor blocker (ARB), telmisartan may inhibit cancer cell proliferation, but the mechanisms by which telmisartan affects various cancers remain unknown. In this study, we evaluated the effects of telmisartan on human CCA cells and to assess the expression of microRNAs (miRNAs). We studied the effects of telmisartan on CCA cells using two cell lines, HuCCT-1 and TFK-1. In our experiments, telmisartan inhibited the proliferation of HuCCT-1 and TFK-1 cells. Additionally, telmisartan induced G0/G1 cell cycle arrest via blockade of the G0 to G1 cell cycle transition. Notably, telmisartan did not induce apoptosis in HuCCT-1 cells. This blockade was accompanied by a strong decrease in cell cycle-related protein, especially G1 cyclin, cyclin D1, and its catalytic subumits, Cdk4 and Cdk6. Telmisartan reduced the phosphorylation of EGFR (p-EGFR) and TIMP-1 by using p-RTK and angiogenesis array. Furthermore, miRNA expression was markedly altered by telmisartan in HuCCT-1. Telmisartan inhibits tumor growth in CCA xenograft model in vivo. In conclusion, telmisartan was shown to inhibit human CCA cell proliferation by inducing cell cycle arrest.

Liver metastasis from gastrointestinal cancer defines a patient's prognosis. Despite medical developments, pancreatic cancer with liver metastasis confers a very poor prognosis. Galectin-9 (Gal‑9) is a tandem-repeat-type galectin that has recently been demonstrated to exert antitumor effects on various types of cancer cells by inducing apoptosis. However, the apoptotic pathway of Gal‑9 in solid tumors is unclear. The aim of the present study was to evaluate the effects of Gal‑9 on human liver metastasis from pancreatic cancer. Gal‑9 suppressed cell proliferation in metastatic liver cancer cell lines derived from pancreatic cancer (KMP2, KMP7, and KMP8) and increased the levels of caspase-cleaved keratin 18 and fluorescein isothiocyanate (FITC)-conjugated Annexin V. Furthermore, expression of apoptosis-related molecules such as caspase-7, cleaved caspase-3, cleaved PARP, cytochrome c, Smac/Diablo and HtrA2/Omi was enhanced. However, Gal‑9 did not affect expression of various cell cycle-related proteins. The microRNA (miRNA) expression profile was markedly altered by Gal‑9, and various miRNAs might contribute to tumor growth suppression. Our data reveal that Gal‑9 suppresses the growth of liver metastasis, possibly by inducing apoptosis through a mechanism involving mitochondria and changes in miRNA expression. Thus, Gal‑9 might serve as a therapeutic agent for the treatment of liver metastasis from pancreatic cancer.

Small bowel adenocarcinoma (SBAC) accounts for 3% of all gastrointestinal tract tumors and approximately 0.5% of all cancer cases. Recent studies have indicated that the use of metformin, one of the most commonly prescribed antidiabetic drugs, is associated with a better prognosis for certain malignant diseases. However, there have been no reports on the effect of metformin in SBAC. In the present study, we evaluated the effect of metformin on human SBAC cell proliferation in vitro and in vivo and identified the microRNAs (miRNAs) associated with its antitumor effects. Metformin inhibited the proliferation of HuTu80 cells in a time- and dose-dependent manner. Importantly, metformin reduced the expression of cyclin D1, cyclin E, cyclin-dependent kinase 4, and phosphorylated retinoblastoma protein, which resulted in cell cycle arrest at the G0/G1 phase. This arrest was accompanied by activation of AMPKα and inhibition of mammalian target of rapamycin and p70s6k. Additionally, metformin reduced the levels of phosphorylated epidermal growth factor receptor and ROR2 as well as markedly altered miRNA expression in HuTu80 cells. Metformin also inhibited tumor growth in vivo in a xenograft mouse model. Our data suggest that metformin might have therapeutic potential in SBAC.

Gallbladder cancer is the most common biliary tract cancer with poor prognosis and wide variation in incidence rates worldwide, being very high in some countries in Latin America and Asia. Treatment of type 2 diabetes with metformin causes a reduction in the incidence of cancer. Till date, there are no reports on the anti-tumor effects of metformin in gall bladder cancer. Therefore, this study evaluated the effects of metformin on the proliferation of human gallbladder adenocarcinoma cells in vitro and in vivo, as well as explored the microRNAs associated with the anti-tumor effects of metformin. Metformin inhibited the proliferation in gallbladder adenocarcinoma cell lines NOZ, TGBC14TKB, and TGBC24TKB, and blocked the G0 to G1 transition in the cell cycle. This was accompanied by strong reduction in the expression of G1 cyclins, especially cyclin D1 and its catalytic subunits including cyclin-dependent kinase 4, and in retinoblastoma protein phosphorylation. In addition, metformin reduced the phosphorylation of receptor tyrosine kinases, especially Tie-2, ALK, PYK, EphA4, and EphA10, as well as angiogenesis-related proteins, including RANTES, TGF-β, and TIMP-1. Moreover, metformin also markedly altered microRNA expression profile leading to an anti-tumor effect. Treatment of athymic nude mice bearing xenograft tumors with metformin inhibited tumor growth. These results suggest that metformin may be used clinically for the treatment of gallbladder adenocarcinoma.

Gastric cancer is one of the most common malignancies diagnosed worldwide. Telmisartan, an angiotensin receptor blocker (ARB), suppresses the proliferation of cancer cells and the growth of tumors through an unknown mechanism. To identify the mechanism, the present study was designed to evaluate the effects of telmisartan on gastric cancer cell lines and tumors in vitro and in vivo and the associated signaling molecules were identified. It was shown here that telmisartan suppressed the proliferation of the cultured human gastric cancer cell lines MKN74, MKN1 and MKN45 as detected in the CCK‑8 assay. In a mouse xenograft model of gastric cancer, telmisartan suppressed tumor growth by arresting the cell cycle at the G0/G1 phase through inhibition of the expression of cyclin D1, the catalytic subunit of cyclin dependent kinase 4 (CDK4), as well as the phosphorylation of the tumor suppressor retinoblastoma (pRb) protein as detected by western blotting. Notably, telmisartan did not induce apoptosis, as indicated by consistent levels of caspase‑cleaved keratin 18 in MKN74 cells. Furthermore, telmisartan inhibited the phosphorylation of epidermal growth factor receptor (EGFR) and increased the levels of the angiogenesis‑related protein tissue inhibitor of metalloproteinase‑1 (TIMP‑1). Analyses of microarrays revealed that telmisartan altered the expression of miRNAs in MKN74 cells. In conclusion, telmisartan suppressed the proliferation of human gastric cancer cells by inducing cell cycle arrest.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. The angiotensin II type 1 receptor blockers, telmisartan and candesartan, are widely used antihypertensive drugs that inhibits cancer cell proliferation; however, its underlying mechanisms in mesenchymal tumors, including GIST, remains unknown. The present study aimed to investigate the effect of telmisartan on GIST‑T1 cells and its underlying mechanism. Telmisartan and candesartan inhibited the proliferation of these cells by blocking the G0 to G1 cell cycle transition, which was accompanied by a decrease in cell cycle‑related proteins such as cyclin D1. Furthermore, telmisartan exposure significantly altered microRNA expression in vitro. In conclusion, telmisartan suppressed human GIST cell proliferation by inducing cell cycle arrest in vitro.

Esophageal squamous cell carcinoma (ESCC) is the most common primary esophageal malignancy. Telmisartan, an angiotensin II type 1 (AT1) receptor blocker (ARB) and a widely used antihypertensive, has been shown to inhibit proliferation of various cancer types. This study evaluated the effects of telmisartan on human ESCC cell proliferation in vitro and in vivo and sought to identify the microRNAs (miRNAs) involved in these antitumor effects. We examined the effects of telmisartan on three human ESCC cell lines (KYSE150, KYSE180, and KYSE850). Telmisartan inhibited proliferation of these three cell lines by inducing S-phase arrest, which was accompanied by decreased expression of cyclin A2, cyclin-dependent kinase 2, and other cell cycle-related proteins. Additionally, telmisartan reduced levels of phosphorylated ErbB3 and thrombospondin-1 in KYSE180 cells. Furthermore, expression of miRNAs was remarkably altered by telmisartan in vitro. Telmisartan also inhibited tumor growth in vivo in a xenograft mouse model. In conclusion, telmisartan inhibited cell proliferation and tumor growth in ESCC cells by inducing cell-cycle arrest.

The incidence of esophageal adenocarcinoma (EAC) is rapidly increasing in western countries. The overall mortality of this disease remains high with a 5-year survival rate of less than 20%, despite remarkable advances in the care of patients with EAC. Galectin-9 (Gal-9) is a tandem-repeat type galectin that exerts anti-proliferative effects on various cancer cell types. The aim of the present study was to evaluate the effects of Gal-9 on human EAC cells and to assess the expression of microRNAs (miRNAs) associated with the antitumor effects of Gal-9 in vitro. Gal-9 suppressed the proliferation of the EAC cell lines OE19, OE33, SK-GT4, and OACM 5.1C. Additionally, Gal-9 treatment induced apoptosis and increased the expression levels of caspase-cleaved cytokeratin 18, activated caspase-3 and activated caspase-9. However, it did not promote cell cycle arrest by reducing cell cycle-related protein levels. Furthermore, Gal-9 increased the level of the angiogenesis-related protein interleukin-8 (IL-8) and markedly altered miRNA expression. Based on these findings, Gal-9 may be of clinical use for the treatment of EAC.

Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB). This drug inhibits cancer cell proliferation, but the underlying mechanisms in various cancers, including esophageal cancer, remain unknown. The aim of the present study was to evaluate the effects of telmisartan on human esophageal cancer cell proliferation in vitro and in vivo. We assessed the effects of telmisartan on human esophageal adenocarcinoma (EAC) cells using the cell lines OE19, OE33, and SKGT-4. Telmisartan inhibited the proliferation of these three cell lines via blockade of the G0 to G1 cell cycle transition. This blockade was accompanied by a strong decrease in cyclin D1, cyclin E, and other cell cycle-related proteins. Notably, the AMP-activated protein kinase (AMPK) pathway, a fuel sensor signaling pathway, was enhanced by telmisartan. Compound C, which inhibits the two catalytic subunits of AMPK, enhanced the expression of cyclin E, leading to G0/G1 arrest in human EAC cells. In addition, telmisartan reduced the phosphorylation of epidermal growth factor receptor (p-EGFR) and ERBB2 in vitro. In our in vivo study, intraperitoneal injection of telmisartan led to a 73.2% reduction in tumor growth in mice bearing xenografts derived from OE19 cells. Furthermore, miRNA expression was significantly altered by telmisartan in vitro and in vivo. In conclusion, telmisartan suppressed human EAC cell proliferation and tumor growth by inducing cell cycle arrest via the AMPK/mTOR pathway.

Gastric cancer is the second-leading cause of cancer-related mortality worldwide, and the prognosis of advanced gastric cancer remains poor. Galectin-9 (Gal-9) is a tandem-repeat-type galectin that has recently been demonstrated to exert anti-proliferative effects on various types of cancer cells. The aim of our present study was to evaluate the effects of Gal-9 on human gastric cancer cells and the expression levels of microRNAs (miRNAs) associated with the antitumor effects of Gal-9 in vitro. In our initial experiments, Gal-9 suppressed the proliferation of gastric cancer cell lines in vitro. Our data further revealed that Gal-9 increased caspase-cleaved keratin 18 (CCK18) levels in gastric cancer cells. Additionally, Gal-9 reduced the phosphorylation of vascular endothelial growth factor receptor-3 (VEGFR-3) and insulin-like growth factor-1 receptor (IGF-1R). Furthermore, miRNA expression levels were markedly altered with Gal-9 treatment in vitro. In conclusion, Gal-9 suppressed the proliferation of human gastric cancer cells by inducing apoptosis. These findings suggest that Gal-9 could be a potential therapeutic target in the treatment of gastric cancer.

The diagnosis of diffuse-type gastric cancer, named linitis plastica (LP), is difficult because of its infiltration into the submucosa. Conventional endoscopic biopsy sampling may show false-negative results because the superficial mucosa is often normal. These macroscopic features do not often permit the distinction between benign and malignant lesions, and sampling methods have some limitations. Accordingly, a secure sampling method is required in order to increase the diagnostic yield. We have developed a submucosal tunneling technique for sampling submucosal tumors, which can visualize tumor surfaces and obtain tissue samples under direct vision. We report a rare case of indefinite gastric LP that could be diagnosed by this method. As multiple biopsies and endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) did not help us histologically diagnose the lesion, our new method of submucosal endoscopy which has advantages of visualizing tumor surfaces and obtaining tissue samples under direct vision in the submucosa was introduced. Histological examination of all acquired samples confirmed the presence of a poorly differentiated adenocarcinoma. The present case demonstrates that this method is a reasonable option for indefinite LP with features inflating into submucosa, providing an update on the contemporary concepts.

Background and study aims: Small gastrointestinal stromal tumors (GISTs) rarely have malignant potential with poor prognosis. Using conventional imaging to differentiate between small GISTs and leiomyoma, which often have similar characteristics, is difficult but essential in daily practice. Although some studies have reported on the utility of serum c-kit as a biomarker for non-small GIST and specific miRNA, clinical aspects of such testing are controversial. The aim of this study was to identify differences between small GIST and leiomyoma through the investigation of miRNA expression patterns in human cases. Patients and methods: MiRNA expression was examined in nine GIST (less than low risk, mean 18 mm in size) samples and seven leiomyoma samples acquired by a novel sampling method, submucosal tunneling biopsy (STB), which produces tumor specimens of submucosal tumor (SMT) without contamination of sufficient size to be examined under direct vision. Total RNA was extracted from these tissues and analyzed for miRNA expression patterns by microarray. Subsequently, real-time quantitative polymerase chain reaction (qPCR) were used to confirm specific miRNA overexpression, comparing GISTs with leiomyomas. Results: Microarray analysis revealed upregulation of the miR-140 family up to 20 times higher in GISTs than in leiomyomas. Real-time qPCR revealed that the expression level of miR-140-5 p in GISTs was 27.86 times higher than in leiomyomas; miR-140-3 p was 12.24 times higher as well. Conclusions: The STB method provided suitable SMT samples for miRNA analysis. MiR-140 family members may serve as specific biomarkers to distinguish GIST from leiomyoma.

Esophageal carcinoma is the eighth most common cancer worldwide and the sixth leading cause of cancer-related deaths, with one of the worst prognoses of any form of cancer. Treatment with the anti-diabetic drug metformin has been associated with reduced cancer incidence in patients with type 2 diabetes. This study therefore evaluated the effects of metformin on the proliferation, in vitro and in vivo, of human esophageal adenocarcinoma cells, as well as the microRNAs associated with the antitumor effects of metformin. Metformin inhibited the proliferation of the esophageal adenocarcinoma cell lines OE19, OE33, SK-GT4 and OACM 5.1C, blocking the G0 to G1 transition in the cell cycle. This was accompanied by strong reductions in G1 cyclins, especially cyclin D1, cyclin-dependent kinase (Cdk)4, and Cdk6, and decreases in retinoblastoma protein phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor and insulin-like growth factor and insulin-like growth factor-1 receptor, as well as angiogenesis-related proteins, such as vascular endothelial growth factor, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2. Metformin also markedly altered microRNA expression. Treatment with metformin of athymic nude mice bearing xenograft tumors reduced tumor proliferation. These findings suggest that metformin may have clinical use in the treatment of esophageal adenocarcinoma.

Background: The use of a retroflexed view exposes the entire tumor surface, which is obscured in the forward view, and contributes to complete tumor resection when combined with forward views. However, the efficacy and safety of using the retroflexed view for colorectal endoscopic submucosal dissection (ESD) are poorly understood. Methods: In this study, we assessed the efficacy and safety of the retroflexed view in colorectal ESD. From April 2009 to December 2013, 130 colorectal tumors were examined in 128 patients treated with ESD. A total of 119 patients with a mean tumor size of 27.2 mm were enrolled in the study, and these patients were assigned to undergo colorectal ESD with or without a retroflexed view. Results: The use of retroflexion was successful in 84.2% of patients. There were no perforations in the study and no complications related to the use of retroflexed views. The mean procedure time was 103.6±55.8 min in the retroflexed group, as compared with 108.0±66.5 min in the forward view group. The mean procedure time for resecting tumors >40 mm was significantly shorter in the retroflexed group relative to the forward group. Additionally, the mean dissection speed per unit area was significantly faster in the retroflexed group, as compared with the forward group. Conclusions: Retroflexed views can be used to remove lesions >40 mm and shorten procedure times. Retroflexion may also contribute to an improved en bloc resection rate.

Pancreatic cancer is the eighth‑leading cause of cancer‑associated mortality in males and the ninth‑leading cause in females worldwide. Even when diagnosed early enough to be potentially resectable, the prognosis of invasive pancreatic cancer is poor. Galectin‑9 (Gal‑9) is a tandem‑repeat type galectin that has recently been demonstrated to possess an anti‑proliferative effect on cancer cells. Therefore, the present study evaluated the effects of Gal‑9 on the proliferation of human pancreatic cancer cells and examined the microRNAs that are associated with the antitumor effects of Gal‑9. Gal‑9 suppressed the proliferation of multiple pancreatic cancer cell lines. In addition, Gal‑9 treatment increased the levels of caspase‑cleaved keratin 18 and the expression of cytochrome c in pancreatic cancer cell lines. This data suggests that Gal‑9 induces intrinsic apoptosis in pancreatic cancer cell lines through the caspase‑dependent and caspase‑independent pathways. In addition, Gal‑9 reduced the expression levels of phosphorylated epidermal growth factor receptor and numerous receptor tyrosine kinases (RTKs). In conclusion, Gal‑9 may suppress the growth of human pancreatic cancer cells in vitro. These findings suggest that Gal‑9 may be a new therapeutic agent for the treatment of pancreatic cancer.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third leading cause of cancer-related death. Telmisartan, a widely used antihypertensive drug, is an angiotensin II type 1 (AT1) receptor blocker (ARB) that might inhibit cancer cell proliferation, but the mechanisms through which telmisartan affects various cancers remain unknown. The aim of the present study was to evaluate the effects of telmisartan on human HCC and to assess the expression of microRNAs (miRNAs). We studied the effects of telmisartan on HCC cells using the HLF, HLE, HepG2, HuH-7 and PLC/PRF/5 cell lines. In our experiments, telmisartan inhibited the proliferation of HLF, HLE and HepG2 cells, which represent poorly differentiated types of HCC cells. However, HuH-7 and PLC/PRF/5 cells, which represent well-differentiated types of HCC cells, were not sensitive to telmisartan. Telmisartan induced G0/G1 cell cycle arrest of HLF cells by inhibiting the G0-to-G1 cell cycle transition. This blockade was accompanied by a marked decrease in the levels of cyclin D1, cyclin E and other cell cycle-related proteins. Notably, the activity of the AMP-activated protein kinase (AMPK) pathway was increased, and the mammalian target of rapamycin (mTOR) pathway was inhibited by telmisartan treatment. Additionally, telmisartan increased the level of caspase-cleaved cytokeratin 18 (cCK18), partially contributed to the induction of apoptosis in HLF cells and reduced the phosphorylation of ErbB3 in HLF cells. Furthermore, miRNA expression was markedly altered by telmisartan in vitro. In conclusion, telmisartan inhibits human HCC cell proliferation by inducing cell cycle arrest.

Background Comparative studies on wound surface treatments after endoscopic mucosal resection (EMR) of 10- to 20-mm colorectal polyps have not been reported. We conducted a prospective trial of postoperative hemorrhage prevention measures after EMR of such polyps. Methods Of 138 patients (397 polyps) who had undergone EMR, 62 patients (148 polyps) with 10- to 20-mm colorectal polyps were enrolled. Using the sealed envelope method, the subjects were randomly assigned to either a snare cauterization (75 polyps) or clip closure group (73 polyps). The primary assessment item was the wound surface treatment time (from immediately after polyp resection to wound surface treatment completion). The secondary assessment items were the incidence of delayed bleeding, perforation incidence 1–7 days after EMR, and difference in medical costs between the groups (University Hospital Medical Information Network: No. 000013473). Results The time required for wound surface treatment completion was 3.26 ± 1.57 min in the snare cauterization group and 12.7 ± 2.92 min in the clip closure group, thus demonstrating a significant difference (P = 0.0001). Delayed bleeding was observed in two patients in the clip group, but was not observed in the snare cauterization group (P = 0.098). The clip group required the use of 720 clips that cost \523,410, US $5,163.50, or €3,665.5. Conclusions After EMR of with 10- to 20-mm colorectal polyps, snare cauterization was superior to clip closure in terms of procedure time, and medical costs, and not inferior to clip closure in terms of the preventing effect of delayed bleeding. Electronic supplementary material The online version of this article (doi:10.1007/s00464-014-3983-y) contains supplementary material, which is available to authorized users.