Shintaro Fujihara

Antitumor effect of metformin in esophageal cancer: In vitro study

Recent studies suggest that metformin, which is a member of the biguanide family and commonly used as an oral anti-hyperglycemic agent, may reduce cancer risk and improve prognosis of numerous types of cancer. However, the mechanisms underlying the antitumor effect of metformin on esophageal cancer remain unknown. The goal of the present study was to evaluate the effects of metformin on the proliferation of human ESCC in vitro, and to study changes in the expression profile of microRNAs (miRNAs), since miRNAs have previously been associated with the antitumor effects of metformin in other human cancers. The human ESCC cell lines T.T, KYSE30 and KYSE70 were used to study the effects of metformin on human ESCC in vitro. In addition, we used miRNA array tips to explore the differences between miRNAs in KYSE30 cells with and without metformin treatment. Metformin inhibited the proliferation of T.T, KYSE30 and KYSE70 cells in vitro. Metformin blocked the cell cycle in G0/G1 in vitro. This blockade was accompanied by a strong decrease of G1 cyclins, especially cyclin D1, as well as decreases in cyclin-dependent kinase (Cdk)4, Cdk6 and phosphorylated retinoblastoma protein (Rb). In addition, the expression of miRNAs was markedly altered with the treatment of metformin in vitro. Metformin inhibited the growth of three ESCC cell lines, and this inhibition may have involved reductions in cyclin D1, Cdk4 and Cdk6.

Bloc biopsy by using submucosal endoscopy with a mucosal flap method for gastric subepithelial tumor tissue sampling (with video).

Subepithelial tumors (SETs) include widely malignant tumors such as GI stromal tumors, malignant lymphomas, carcinoid tumors, gastric cancers similar to SETs, and benign tumors such as leiomyomas, aberrant pancreas, and lipomas. Currently, minimally invasive local resection techniques such as hybrid natural orifice transluminal endoscopic surgery (NOTES), which consists of endoscopic full-thickness gastric resection, have been developed for the treatment of GI stromal tumors. 1 However, there is no consensus regarding the optimal strategy for the tissue diagnosis of SETs before determining the plans for further management such as surgical resection or observation. SET differentiation is essentially important, because different types of lesions may need different management, prognoses, and therapeutic options. EUS morphologic features alone have limited specificity for the diverse subtypes of SETs, and EUS cannot differentiate between a benign or malignant origin. Recently, several diagnostic methods have been proposed for the tissue diagnosis of SETs. EUS-guided FNA (EUS-FNA) biopsy has been introduced as an easy, safe, and valuable method for obtaining tissue samples for the accurate diagnosis of GI SETs. 2-7 In

Galectin-9 in Cancer Therapy

Galectin-9 is a tandem-repeat type galectin with two carbohydrate-recognition domains, and it was first identified as an eosinophil chemoattractant and activation factor. Subsequent studies revealed that galectin-9, similar to other galectins, modulates a variety of biological functions including cell aggregation and adhesion, as well as apoptosis of tumor cells. Galectin-9 has recently been shown to have an anti-proliferative effect on cancer cells. Recent studies have uncovered additional mechanisms by which T cell immunoglobulin mucin-3 (Tim-3), a receptor for galectin-9, negatively regulates T cell responses by promoting CD8+ T cell exhaustion and inducing expansion of myeloid-derived suppressor cells. These mechanisms are involved in tumor growth and escape from immunity. In many solid cancers, the loss of galectin-9 expression is closely associated with metastatic progression, and treatment with recombinant galectin-9 prevents metastatic spread in various preclinical cancer models. Here, we review the biology and physiological role of galectin-9, and discuss the therapeutic potential of galectin-9 in cancer as well as relevant patents.

Antidiabetic drug metformin inhibits esophageal adenocarcinoma cell proliferation in vitro and in vivo.

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.

Steroid permeation into the artificial ulcer by combined steroid gel application and balloon dilatation: Prevention of esophageal stricture

Local steroid injection therapy is effective for preventing esophageal stricture after endoscopic submucosal dissection (ESD) but is associated with the risk of puncture‐related complications, such as bleeding. We evaluated the effectiveness of the application of triamcinolone acetonide gel following permeation into a large artificial ESD ulcer by balloon dilatation compared with steroid injection.

Galectin-9 suppresses cholangiocarcinoma cell proliferation by inducing apoptosis but not cell cycle arrest

Cholangiocarcinoma is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma (HCC). Galectin-9 (Gal-9) is a tandem-repeat-type galectin that has recently been shown to exert antiproliferative effects on cancer cells. Therefore, the present study evaluated the effects of Gal-9 on the proliferation of human cholangiocarcinoma cells in vitro as well as the microRNAs (miRNAs) associated with the antitumor effects of Gal-9. Gal-9 suppressed the proliferation of cholangiocarcinoma cell lines in vitro and the growth of human cholangiocarcinoma cell xenografts in nude mice. Our data further revealed that Gal-9 increased caspase‑cleaved keratin 18 (CCK18) levels, and the expression of cytochrome c increased in Gal-9-treated cholangiocarcinoma cell lines. These data suggested that Gal-9 induced cholangiocarcinoma cell apoptosis via the intrinsic apoptosis pathway mediated by caspase-dependent or -independent pathways. In addition, Gal-9 reduced the phosphorylation of the epidermal growth factor receptor (EGFR), insulin-like growth factor and insulin-like growth factor-1 receptor (IGF-1R), hepatocyte growth factor receptor and fibroblast growth factor receptor 3 (FGFR3). These findings suggest that Gal-9 can be a candidate of therapeutic target in the treatment of cholangiocarcinoma.

The efficacy and safety of prophylactic closure for a large mucosal defect after colorectal endoscopic submucosal dissection

Endoscopic submucosal dissection (ESD) is not a common treatment for colorectal neoplasms because of its technical difficulties and has a higher incidence of complication. In particular, perforation is one of the severe complications and these patients require surgical intervention. However, whether prophylactic closure after colorectal ESD prevents perforation and other complications is not known. In the present study, we assessed the efficacy and safety of prophylactic closure for a large mucosal defect after colorectal ESD using a conventional clip and over-the-scope clip (OTSC) system. From April 2010 to December 2012, 68 patients with colorectal tumors were treated with ESD. The prohylactic closure was indicated for patients with excessive coagulation in the muscularis propria or larger resection size. The closure group reduced the peritoneal inflammatory reaction and abdominal symptoms without increasing complications. The closure group also had a significantly lower WBC count (post operative day 1), CRP (post operative day 4) and abdominal pain after colorectal ESD compared to the non-closure group. Perforation occurred in 1 case, and postoperative bleeding in 2 cases, with only 1 bleeding case needing an emergency endoscopy in the non-closure group. One perforation case needed emergency surgery because the endoscopic treatment was ineffective. Without increasing adverse effects, the prophylactic closure efficiently reduced the inflammatory reaction and abdominal symptoms of colorectal ESD in patients with large superficial colorectal neoplasms.

Metabolic syndrome, obesity, and gastrointestinal cancer.

Metabolic syndrome is a cluster of metabolic abnormalities and is defined as the presence of three or more of the following factors: increased waist circumference, elevated triglycerides, low high-density lipoprotein cholesterol, high blood pressure, and high fasting glucose. Obesity, which is accompanied by metabolic dysregulation often manifested in the metabolic syndrome, is an established risk factor for many cancers. Adipose tissue, particularly visceral fat, is an important metabolic tissue as it secretes systemic factors that alter the immunologic, metabolic, and endocrine milieu and also promotes insulin resistance. Within the growth-promoting, proinflammatory environment of the obese state, cross-talk between macrophages, adipocytes, and epithelial cells occurs via obesity-associated hormones, adipocytokines, and other mediators that may enhance cancer risk and progression. This paper synthesizes the evidence on key molecular mechanisms underlying the obesity-cancer link.

Current Innovations in Endoscopic Therapy for the Management of Colorectal Cancer: From Endoscopic Submucosal Dissection to Endoscopic Full-Thickness Resection

Endoscopic submucosal dissection (ESD) is accepted as a minimally invasive treatment for colorectal cancer. However, due to technical difficulties and an increased rate of complications, ESD is not widely used in the colorectum. In some cases, endoscopic treatment alone is insufficient for disease control, and laparoscopic surgery is required. The combination of laparoscopic surgery and endoscopic resection represents a new frontier in cancer treatment. Recent developments in advanced polypectomy and minimally invasive surgical techniques will enable surgeons and endoscopists to challenge current practice in colorectal cancer treatment. Endoscopic full-thickness resection (EFTR) of the colon offers the potential to decrease the postoperative morbidity and mortality associated with segmental colectomy while enhancing the diagnostic yield compared to current endoscopic techniques. However, closure is necessary after EFTR and natural transluminal endoscopic surgery (NOTES). Innovative methods and new devices for EFTR and suturing are being developed and may potentially change traditional paradigms to achieve minimally invasive surgery for colorectal cancer. The present paper aims to discuss the complementary role of ESD and the future development of EFTR. We focus on the possibility of achieving EFTR using the ESD method and closing devices.

Prediction of invasion depth for submucosal differentiated gastric cancer by magnifying endoscopy with narrow-band imaging

The usefulness of determining gastric cancer invasion depth by magnifying endoscopy with narrow-band imaging (NBI-ME) has not been established. The objective of our study was to retrospectively compare NBI-ME images of differentiated submucosal (SM) 1 cancer with those of SM2 to identify the indicators of invasion depth for SM2 gastric cancer. Fifteen patients with SM1 differentiated gastric cancer and 20 with SM2 removed by endoscopic submucosal resection (ESD) were included. NBI-ME images matching the invasion depth of pathological specimens were examined to define the following three findings as diagnostic indicators of SM2: non-structure, scattery vessels and multi-caliber vessels. The relationship between indicators and invasion depth and between indicator score and invasion depth was examined in 27 patients (SM1/SM2: 11/16) with depressed-type gastric cancer (D-GC) and in 8 (SM1/SM2: 4/4) with protruding-type gastric cancer (P-GC). Diagnostic accuracy for invasion depth determined by four endoscopists using regular endoscopic images was compared with that determined by the same endoscopists using NBI-ME. In D-GC, all three indicators were significantly more frequent in SM2 than in SM1 (p<0.05). All D-GC with ≥2 points were SM2, demonstrating a significant difference in score distribution between SM1 and SM2 (p<0.05). In D-GC, diagnostic accuracy by NBI-ME was higher than that by regular endoscopy by all 4 endoscopists (p<0.05). NBI-ME findings of non-structure, scattery vessels and multi-caliber vessels can possibly serve as indicators of SM2 invasion in differentiated D-GC. Scoring of the three indicators was significant.