Risk and prognostic factors of invasive gastric cancer detection during surveillance endoscopy: Multi-institutional cross-sectional study.

OBJECTIVES: Esophagogastroduodenoscopy (EGD) is important for the detection of curable gastric cancer (GC). However, there are no appropriate surveillance data during routine endoscopic inspections. This study aimed to clarify the risk factors of pT1b or deeper GC detection during surveillance endoscopy. METHODS: This was a retrospective, multicenter, cross-sectional study conducted in 15 Japanese hospitals. We retrospectively analyzed patients with GC who had previously undergone surveillance endoscopy at each institution from January 2014 to March 2020. Patients who had undergone gastrectomy, non-infection of Helicobacter pylori (Hp), and those with intervals <3 months or >10 years from a previous endoscopy were excluded. RESULTS: In total, 1085 patients with GCs detected during surveillance endoscopy were enrolled. The multivariate logistic analysis revealed that current Hp infection (odds ratio [OR] 2.18; 95% confidence interval [CI] 1.50-3.16) and a surveillance interval of >1.5 years (OR 1.96; 95% CI 1.35-2.84) were independent risk factors for pT1b or deeper GC. The 5-year disease-specific survival (5y-DSS) rate of GC was significantly lower in patients with surveillance interval of >1.5 years than in those with surveillance interval of ≤1.5 years (93.7% vs. 98.3%, P < 0.001). Similarly, the 5y-DSS rate of GC was significantly lower in patients with active Hp infection than in those without (93.7% vs. 99.4%, P < 0.001). CONCLUSION: In this study, a surveillance interval of >1.5 years and current Hp infection were independent risk factors for detecting pT1b or deeper GC. Additionally, these factors were poor prognostic factors of the detected GC during surveillance endoscopy.

Comparison of thrombocytopenia between patients with non-alcoholic fatty liver disease and those with hepatitis C virus-related chronic liver disease.

AIM: Thrombocytopenia is widely recognized as a simple surrogate marker of liver fibrosis in non-alcoholic fatty liver disease (NAFLD). Thrombocytopenia of NAFLD has not been compared with that of hepatitis C virus-related chronic liver disease (CLD-C). Here, we examined whether there is any difference in the platelet counts between patients with NAFLD and CLD-C and investigated the underlying mechanisms. METHODS: A total of 760 biopsy-confirmed NAFLD and 1171 CLD-C patients were enrolled. After stratification according to the liver fibrosis stage, platelet counts between NAFLD and CLD-C patients were compared. The platelet count, spleen size, serum albumin level, serum thrombopoietin level, and immature platelet fraction (IPF) value were also compared after covariate adjustment using propensity score (PS) matching. RESULTS: The median platelet counts (×104 /µL) of NAFLD and CLD-C patients were 20.2 and 18.7 (p = 2.4 × 10-5 ) in F1; 20.0 and 14.5 (p = 2.1 × 10-12 ) in F2; 16.9 and 12.3 (p = 8.1 × 10-10 ) in F3; and 11.1 and 8.1 (p = 0.02) in F4, respectively. In the F3 group, NAFLD patients had a significantly higher platelet count and significantly smaller spleen volume than CLD-C patients. Although the serum thrombopoietin levels were comparable between NAFLD and CLD-C patients, the IPF value of NAFLD patients was significantly higher than that of CLD-C patients. CONCLUSIONS: NAFLD patients had a significantly higher platelet count than CLD-C patients following stratification according to the liver fibrosis stage. The milder hypersplenism and higher platelet production in NAFLD than CLD-C may have contributed to this difference.

Loss of KAP3 decreases intercellular adhesion and impairs intracellular transport of laminin in signet ring cell carcinoma of the stomach.

Signet-ring cell carcinoma (SRCC) is a unique subtype of gastric cancer that is impaired for cell-cell adhesion. The pathogenesis of SRCC remains unclear. Here, we show that expression of kinesin-associated protein 3 (KAP3), a cargo adaptor subunit of the kinesin superfamily protein 3 (KIF3), a motor protein, is specifically decreased in SRCC of the stomach. CRISPR/Cas9-mediated gene knockout experiments indicated that loss of KAP3 impairs the formation of circumferential actomyosin cables by inactivating RhoA, leading to the weakening of cell-cell adhesion. Furthermore, in KAP3 knockout cells, post-Golgi transport of laminin, a key component of the basement membrane, was inhibited, resulting in impaired basement membrane formation. Together, these findings uncover a potential role for KAP3 in the pathogenesis of SRCC of the stomach.

Effects of the combined use of a scissor-type knife and traction clip on endoscopic submucosal dissection of colorectal tumors: a propensity score-matched analysis.

Background and study aims This study evaluated the technical aspects of colorectal endoscopic submucosal dissection (ESD) with the Clutch Cutter (CC) (Fujifilm Co., Tokyo, Japan), a scissor-type knife, and the S-O clip (SO) as a traction clip, and compared the safety and efficacy to ESD using a needle-type knife. Patients and methods This was a single-center retrospective study. In Study 1, we evaluated 125 ESD patients: 60 using the SO and CC (SO group) and 65 using the CC (CC group). In Study 2, we evaluated 185 ESD patients: the CC group (N = 65) and 120 using the Flush knife BT-S (Flush group) (Fujifilm Co., Tokyo, Japan). In both studies, the clinicopathological features and therapeutic outcomes were compared using a propensity score-matched analysis. Results In 36 pairs of matched patients in Study 1, the rates of en bloc resection, R0 resection, perforation, and postoperative bleeding (POB) were 97.2 %, 88.9 %, 2.8 %, and 0 %, respectively, for the SO group and 100 %, 91.7 %, 0 %, and 0 % for the CC group (not significant). The mean procedure time for the SO group among less-experienced endoscopists was significantly shorter than in the CC group (42 vs. 65 minutes, P  = 0.036). In 49 pairs of matched patients in Study 2, the rates of en bloc resection, R0 resection, perforation, and POB were 100 %, 95.8 %, 0 %, and 0 %, respectively, for the CC group and 98.0 %, 95.8 %, 0 %, and 2.0 % for the Flush group (not significant). The mean procedure time in the CC group among less-experienced endoscopists was significantly shorter than in the Flush group (52 vs. 67 minutes, P  = 0.038). Conclusions CC and the combined use of CC and SO reduced colorectal ESD procedure time among less-experienced endoscopists.

SOX2 enhances cell survival and induces resistance to apoptosis under serum starvation conditions through the AKT/GSK-3ß signaling pathway in esophageal squamous cell carcinoma.

The human SOX2 gene was recently identified as a novel major oncogene, recurrently amplified and overexpressed in esophageal squamous cell carcinoma (ESCC). However, the role and molecular mechanism of SOX2 in the carcinogenesis of ESCC remain to be elucidated. The present study investigated the effect of SOX2 on ESCC cell survival and resistance to apoptosis under serum starvation conditions. An adenoviral vector-mediated expression system and RNA interference were used to study the effect of SOX2. The present results revealed that SOX2 promoted ESCC cell survival and enhanced resistance to apoptosis under serum starvation conditions, but not in culture conditions with serum. Mechanistically, SOX2 increased the expression levels of phosphorylated AKT and glycogen synthase kinase-3ß (GSK-3ß), a downstream factor of AKT, under serum starvation conditions, leading to the promotion of ESCC cell survival. Additionally, SOX2 activated AKT through the PTEN/PI3K/phosphoinositide-dependent protein kinase 1 and mammalian target of rapamycin complex 2 signaling pathways. Therefore, SOX2 may facilitate the survival of ESCC cells under poor nutrient conditions by activating the AKT/GSK-3ß signaling pathway.

Garcin Syndrome Due to Meningeal Carcinomatosis from Gastric Cancer.

A 58-year-old woman presented to our hospital with complaints of dysphagia. Esophagogastroduodenoscopy showed an esophagogastric junction tumor with multiple duodenal intramural metastases, and computed tomography showed peritoneal metastasis. In the middle of her fourth cycle of chemotherapy, she displayed symptoms of a left-sided multi-cranial nerve palsy. She was diagnosed with Garcin syndrome caused by meningeal carcinomatosis from gastric cancer based on the results of gadolinium-enhanced brain magnetic resonance imaging and cytology of the cerebrospinal fluid. It is important not to overlook meningeal irritation symptoms or paralysis of cranial nerves and to consider the possibility of Garcin syndrome caused by meningeal carcinomatosis.

Effects of Guidelines for Gastroenterological Endoscopy in Patients Undergoing Antithrombotic Treatment on Postoperative Bleeding after Endoscopic Submucosal Dissection for Early Gastric Cancer: A Propensity Score-Matching Analysis.

BACKGROUND: Management of antithrombotic agents during endoscopic treatment changed after the publishing of -Japan Gastroenterological Endoscopy Society guidelines for gastroenterological endoscopy in antithrombotic drug users (GL-2012). OBJECTIVES: We aimed to evaluate the effect of implementing antithrombotic agent management guidelines (GL-2012) on postoperative bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) and on the prevention of thromboembolic events. METHODS: A total of 1,264 patients who underwent ESD for EGC at Kyoto Prefectural University Hospital between June 2002 and March 2017 were enrolled and divided into 2 groups: 621 patients before the publication of GL-2012 (Pre-GL group) and 643 patients after (Post-GL group). Relationships between postoperative bleeding and various clinicopathological factors in each group were investigated through propensity score-matching analysis. RESULTS: In the Pre-GL group, antihypertensive agent use (p < 0.01) and upper third of the stomach (p < 0.01) were significantly related to postoperative bleeding in univariate analysis. Antihypertensive agent use (OR 4.6, 95% CI 1.6-12.8) and upper third of the stomach (OR 4.9, 95% CI 1.8-13.4) were significantly related to postoperative bleeding in multivariate analysis. In the Post-GL group, antihypertensive agent use (p < 0.01), dual antiplatelet agents use (p < 0.01), anticoagulant agents use (p < 0.01), and heparin replacement therapy (p < 0.01) were significantly related to postoperative bleeding in univariate analysis. Antihypertensive agent use (OR 3.4, 95% CI 1.1-9.6), dual antiplatelet agents (OR 12.3, 95% CI 2.4-63.0), and heparin replacement therapy (OR 10.2, 95% CI 2.5-41.5) were significantly related to postoperative bleeding in multivariate analysis. CONCLUSIONS: The adherence to GL-2012 might reduce risk of thromboembolic events. On the other hand, dual antiplatelet agents therapy and heparin replacement therapy were the new independent risk factors for ESD postoperative bleeding in EGC after GL-2012. Especially as for heparin replacement therapy, uninterrupted warfarin or a temporary short interruption of direct oral anticoagulants without heparin replacement therapy might be recommended rather than heparin replacement therapy.

Diagnostic Ability of Magnifying Blue Light Imaging with a Light Emitting Diode Light Source for Early Gastric Cancer: A Prospective Comparative Study.

INTRODUCTION: An innovative endoscopic system using 4-color light-emitting diodes (LED) was released between 2016 and 2017 in locations that had not approved laser endoscopes for use, including the United States and Europe. OBJECTIVE: This study compared the diagnostic efficacy between magnifying blue light imaging with an LED light source (LED-BLI) and magnifying blue laser imaging with a laser light source (Laser-BLI) for early gastric cancer (EGC). METHODS: In this prospective, single-center, noninferiority study, 80 gastric lesions were evaluated between January 2017 and July 2017. The magnifying findings of gastric lesions - including the demarcation line (DL), microvascular pattern (MVP), and microsurface pattern (MSP) - were evaluated using Laser-BLI and LED-BLI according to the vessel plus surface classification system (VSCS). The primary end point was to determine whether the diagnostic accuracy of LED-BLI for EGC was noninferior to that of conventional Laser-BLI. RESULTS: Overall, we evaluated 79 gastric lesions histopathologically diagnosed as adenocarcinomas from the specimens obtained via endoscopic submucosal dissection. A DL was observed by Laser-BLI and LED-BLI in 98.7% (78/79) and 96.2% (76/79) of EGCs, respectively. The MVP observed using Laser-BLI and LED-BLI was irregular in 92.4% (73/79) and 89.9% (71/79), respectively. The MSP observed using Laser-BLI and LED-BLI was irregular in 83.5% (66/79) and 82.2% (65/79), respectively. According to the VSCS, diagnosable cancers were found in 94.9% (75/79) and 93.7% (74/79) of cases when using Laser-BLI and LED-BLI, respectively (p = 0.73; difference ratio, 1.2%; 95% CI -8.5 to 6.0%). CONCLUSIONS: LED-BLI could accurately visualize the DL, MVP, and MSP of EGCs and was not inferior to Laser-BLI. Therefore, LED-BLI can be used to diagnose EGC accurately according to the VSCS-based diagnosis criteria.

Efficacy and Feasibility of Magnifying Blue Laser Imaging without Biopsy Confirmation for the Diagnosis of the Demarcation of Gastric Tumors: A Randomized Controlled Study.

BACKGROUND: Accurate diagnosis of the demarcation line (DL) of gastric tumors is essential for curative complete resection by endoscopic submucosal dissection (ESD). It is controversial to perform only magnifying endoscopy for diagnosing the DL of gastric tumors prior to ESD. This study aimed to evaluate the diagnostic accuracy for the DL of gastric adenomas and well-differentiated adenocarcinomas using only magnifying blue laser imaging (M-BLI) compared with that using both M-BLI and biopsy confirmation. METHODS: In this prospective, single-center study, 96 well-differentiated adenocarcinomas and 32 gastric adenomas were enrolled between July 2015 and December 2016. A total of 122 lesions with a clear DL on M-BLI were randomly allocated to undergo M-BLI only (the M-BLI group) or M-BLI with biopsy confirmation (the M-BLI-BC group), performed as biopsies in 4 directions from noncancerous tissues ≈ 5 mm outside the lesion before ESD. The primary end point was to clarify the noninferiority of M-BLI without biopsy confirmation compared with that with biopsy confirmation, in terms of the diagnostic accuracy and complete resection. RESULTS: There were no significant differences in sex, median age, color, circumference, macroscopic type, biopsy-based diagnosis, and Helicobacter pylori infection between the 2 groups. The diagnostic accuracy for the DL was 100 and 95.0% and the complete resection was 100 and 100% in the M-BLI and M-BLI-BC groups, respectively. CONCLUSION: The diagnostic ability of M-BLI is excellent in diagnosing the demarcation of gastric adenoma and well-differentiated adenocarcinoma. Biopsy confirmation is not needed for these lesions with a clear DL by M-BLI.

Efficacy of Magnifying Narrow Band Imaging for Delineating Horizontal Margins of Early Gastric Cancer.

BACKGROUND/AIMS: The aim of this study was to evaluate the diagnostic accuracy of magnifying narrow-band imaging (M-NBI) with histopathological confirmation in identifying the demarcation line (DL) of early gastric cancer (EGC). METHODS: EGCs resected by endoscopic submucosal dissection after identifying the DL using M-NBI following histopathological confirmation were included. After determining the DL for the entire EGC lesion using M-NBI, at least 4 biopsies were taken from non-cancerous tissues outside the EGC lesion for histopathological confirmation. RESULTS: A total of 330 EGCs were analyzed in this study. The rate of biopsy-negative and negative horizontal margin were 96.7% (319/330) and 97.9% (323/330) in EGC respectively. Tumors larger than 20 mm showed a higher risk for showing remnant cancer cells on biopsies taken outside the DL. Risk factors for a positive horizontal resection margin were tumor size > 20 mm and moderately or poorly differentiated adenocarcinomas. CONCLUSION: The assessment of demarcation of EGC using M-NBI was excellent in well-differentiated (WD) adenocarcinoma and lesions below 20 mm in size. However, histopathological confirmation is needed to assess the demarcation of non-WD adenocarcinomas and EGC over 20 mm in size.

Efficacy of Clutch Cutter for Standardizing Endoscopic Submucosal Dissection for Early Gastric Cancer: A Propensity Score-Matched Analysis.

BACKGROUND/AIMS: The purpose of this study was to evaluate the safety and efficacy of gastric endoscopic submucosal dissection (ESD) using the Clutch Cutter (CC), a scissor-type knife, compared with those of procedures using conventional devices. METHODS: This single-center retrospective study evaluated 237 patients with early gastric cancer: 83 who underwent ESD using the CC group and 154 who underwent ESD using the insulated-tip knife 2 (IT2 group). Clinicopathological features and technical outcomes were compared between the 2 groups using a propensity score-matched analysis. RESULTS: In 61 pairs of matched patients, there was no significant difference in R0 resection, perforation, or postoperative bleeding between the CC and IT2 groups. Comparisons between the 2 groups showed similar treatment outcomes for an expert endoscopist. Nevertheless, there were significant differences between the 2 groups for nonexperts in terms of self-completion (61.7 and 24.5%, respectively, p < 0.001), mean procedure times (45 and 61 min, respectively, p = 0.002), and mean numbers of intraoperative bleeding points and bleeding points requiring hemostatic forceps (3 and 0 vs. 8 and 3, respectively, p < 0.001). CONCLUSION: Better self-completion rates and shorter procedure times were noted for gastric ESD using the CC by nonexperts than for that using IT2, probably due to hemostatic efficacy.

Oncogenic miR-96-5p inhibits apoptosis by targeting the caspase-9 gene in hepatocellular carcinoma.

The aberrant expression or alteration of microRNAs (miRNAs/miRs) contributes to the development and progression of cancer. In the present study, the functions of miR-96-5p in hepatocellular carcinoma (HCC) were investigated. It was identified that miR-96-5p expression was significantly upregulated in primary HCC tumors compared with their non-tumorous counterparts. A copy number gain was frequently observed at chromosomal region 7q32.2 in which the MIR96 locus is located, suggesting that gene amplification may be one of the mechanisms by which miR-96-5p expression is increased in HCC. Transfection of miR-96-5p mimic into HCC cells decreased the expression of CASP9, which encodes caspase-9, the essential initiator caspase in the mitochondrial apoptotic pathway, at the mRNA and protein levels. A putative binding site for miR-96-5p was identified in the CASP9 3'-untranslated region, and the results of a luciferase assay indicated that CASP9 is a potential direct target of miR-96-5p. The miR-96-5p mimic increased resistance to doxorubicin- and ultraviolet-induced apoptosis through the decrease in caspase-9 expression in HCC cells. Transfection of miR-96-5p inhibitor enhanced the cytotoxic effect of doxorubicin by increasing caspase-9 expression in the HCC cells, suggesting a synergistic effect between the miR-96-5p inhibitor and doxorubicin. In conclusion, the results of the present study suggest that miR-96-5p, which is frequently upregulated in HCC, inhibits apoptosis by targeting CASP9. Therefore, miR-96-5p may be a potential therapeutic target for HCC.

Impact of the Charlson comorbidity index and prognostic nutritional index on prognosis in patients with early gastric cancer after endoscopic submucosal dissection.

BACKGROUND AND AIM: With the aging of society, comorbidities or nutritional status are assessed prior to endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). However, it is uncertain which factors are important for predicting prognosis in EGC patients after ESD. Thus, we aimed to evaluate clinical outcomes of ESD for EGC, with respect to comorbidities or nutritional status. METHODS: We carried out a retrospective study involving 708 EGC in 585 patients who were enrolled between April 2007 and March 2012. They were classified into two groups; an elderly (≥80 years) and non-elderly (<80 years) group. Short- and long-term outcomes were evaluated between the groups. RESULTS: There were no significant differences regarding short-term outcomes. Overall survival (OS) rates in the elderly group were significantly lower than those in the non-elderly group (P = 0.001). OS rates in patients with a low (≤2) Charlson comorbidity index (CCI) were significantly higher than those in patients with a high (≥3) CCI, regardless of age. OS rates in patients with a high (≥47.7) prognostic nutritional index (PNI) were significantly higher than those in patients with a low (<47.7) PNI, regardless of age. In multivariate analysis, an Eastern Cooperative Oncology Group performance status (PS) ≥2 (hazard ratio [HR], 95% confidence interval: 3.23, 1.54-6.75), CCI ≥3 (HR 7.88, 4.50-13.80) and PNI <47.7 (HR 3.44, 2.00-5.90) were significantly associated with OS rate (P < 0.01). CONCLUSION: CCI and PNI can be prognostic indicators for non-elderly and elderly patients with EGC after ESD.

ASPP2 suppresses invasion and TGF-ß1-induced epithelial-mesenchymal transition by inhibiting Smad7 degradation mediated by E3 ubiquitin ligase ITCH in gastric cancer.

ASPP2 regulates cell polarity and cell-cell adhesion by binding to, and co-localizing with PAR3 at tight junctions. Here we show a novel role of ASPP2 in suppressing gastric cancer (GC) invasiveness. Immunoprecipitation and immunofluorescence analyses showed that ASPP2 promoted the recruitment of PAR3 to cell-cell junctions in GC cells. Diminished expression of ASPP2 and loss of junctional PAR3 localization were significantly associated with diffuse-type histology, deeper invasion depth, positive peritoneal dissemination and worse prognosis in primary GC. ASPP2 suppressed migration and invasion of GC cells in vitro and peritoneal dissemination of GC cells in vivo in a mouse model. ASPP2 suppressed epithelial-mesenchymal transition (EMT) induced by TGF-ß1-Smad2/3 signaling in GC cells through suppression of the degradation of Smad7, a negative regulator of TGF-ß1-Smad2/3 signaling, by interacting with the E3 ubiquitin ligase ITCH. In conclusion, ASPP2 suppresses invasion, peritoneal dissemination and TGF-ß1-induced EMT by inhibiting Smad7 degradation mediated by ITCH.

Loss of PAR-3 protein expression is associated with invasion, lymph node metastasis, and poor survival in esophageal squamous cell carcinoma.

Disrupted cell polarity is a feature of epithelial cancers. The partitioning defective 3 (PAR-3) protein, a key component of the PAR complex that regulates the polarization of cells, is involved in tight junction formation at epithelial cell-cell contacts. Our previous study detected a homozygous deletion of the PAR-3 gene in esophageal squamous cell carcinoma (ESCC) cell lines and frequent copy number loss of the PAR-3 gene in primary ESCC. Here, we aimed to investigate the clinicopathological relevance of altered expression of the PAR-3 protein in primary ESCC. We immunohistochemically analyzed expression of the PAR-3 protein, as well as that of other tight junction proteins, ZO-1 and claudin-1, in 74 primary ESCCs. While the PAR-3 protein was expressed in the cytoplasm of basal cells, it was localized on the plasma membrane of suprabasal cells of normal squamous epithelium of the esophagus. Of the 74 ESCC tumors, 20 (27%), 11 (15%), and 13 (18%) were negative for PAR-3, ZO-1, and claudin-1 proteins, respectively. Negative PAR-3 protein expression, but not negative ZO-1 or claudin-1 expression, was significantly associated with deeper tumor invasion (P<.01), positive lymph node metastasis (P=.03), and advanced tumor stage (P=.01). Patients with PAR-3-negative tumors showed marginally significantly shorter overall survival after surgery than those with PAR-3-positive tumors (P=.053). In conclusion, these results suggest that PAR-3 protein expression is frequently lost in primary ESCC and that loss of the PAR-3 protein is associated with aggressive clinicopathological features of ESCC.

A case report of severe ulcerative colitis with mediastinal and subcutaneous emphysema.

A 17-year-old boy developed prominent mediastinal and subcutaneous emphysema while receiving treatment with 5-aminosalicylic acid (5-ASA) and oral corticosteroids for severe ulcerative colitis. We ruled out infection and initiated oral administration of tacrolimus, after which both the underlying disease and mediastinal and subcutaneous emphysema improved. However, he continued to experience repeated bouts of ulcerative colitis, so we ultimately opted for surgical intervention. Although mediastinal and subcutaneous emphysema is rare, it is one of the known extra-intestinal complications and can be particularly concerning. In this patient, mediastinal and subcutaneous emphysema might have been caused by the vulnerability of pulmonary alveolar walls to steroid medication and the increase of pulmonary alveolar pressure with abdominal pain and breath holding. Here, we report a case of inflammatory bowel disease with mediastinal and subcutaneous emphysema, along with a review of the literature.