Endoscopic Features of Synchronous Multiple Early Gastric Cancers: Findings from a Nationwide Cohort.

INTRODUCTION: We investigated the factors associated with synchronous multiple early gastric cancers and determined their localization. METHODS: We analyzed 8,191 patients who underwent endoscopic submucosal dissection for early gastric cancers at 33 hospitals in Japan from November 2013 to October 2016. Background factors were compared between single-lesion (n = 7,221) and synchronous multi-lesion cases (n = 970) using univariate and multivariate analyses. We extracted cases with two synchronous lesions (n = 832) and evaluated their localization. RESULTS: Significant independent risk factors for synchronous multiple early gastric cancer were older age (≥75 years old) (odds ratio [OR] = 1.257), male sex (OR = 1.385), severe mucosal atrophy (OR = 1.400), tumor localization in the middle (OR = 1.362) or lower region (OR = 1.404), and submucosal invasion (OR = 1.528 [SM1], 1.488 [SM2]). Depressed macroscopic type (OR = 0.679) and pure undifferentiated histology OR = 0.334) were more common in single early gastric cancers. When one lesion was in the upper region, the other was more frequently located in the lesser curvature of the middle region. When one lesion was in the middle region, the other was more frequently located in the middle region or the lesser curvature of the lower region. When one lesion was in the lower region, the other was more frequently located in the lesser curvature of the middle region or the lower region. CONCLUSION: Factors associated with synchronous multiple early gastric cancer included older age, male sex, severe mucosal atrophy, tumor localization in the middle or lower region, and tumor submucosal invasion. Our findings provide useful information regarding specific areas that should be examined carefully when one lesion is detected.

Far-Ultraviolet Light at 222 nm Affects Membrane Integrity in Monolayered DLD1 Colon Cancer Cells.

222 nm far-ultraviolet (F-UV) light has a bactericidal effect similar to deep-ultraviolet (D-UV) light of about a 260 nm wavelength. The cytotoxic effect of 222 nm F-UV has not been fully investigated. DLD-1 cells were cultured in a monolayer and irradiated with 222 nm F-UV or 254 nm D-UV. The cytotoxicity of the two different wavelengths of UV light was compared. Changes in cell morphology after F-UV irradiation were observed by time-lapse imaging. Differences in the staining images of DNA-binding agents Syto9 and propidium iodide (PI) and the amount of cyclobutane pyrimidine dimer (CPD) were examined after UV irradiation. F-UV was cytotoxic to the monolayer culture of DLD-1 cells in a radiant energy-dependent manner. When radiant energy was set to 30 mJ/cm2, F-UV and D-UV showed comparable cytotoxicity. DLD-1 cells began to expand immediately after 222 nm F-UV light irradiation, and many cells incorporated PI; in contrast, PI uptake was at a low level after D-UV irradiation. The amount of CPD, an indicator of DNA damage, was higher in cells irradiated with D-UV than in cells irradiated with F-UV. This study proved that D-UV induced apoptosis from DNA damage, whereas F-UV affected membrane integrity in monolayer cells.

A comparison of the physical demands generated by playing different opponents in basketball friendly matches.

This study aimed to compare the physical demands of playing opponents of different skill levels in basketball. Eighteen men's college basketball players wore accelerometers to measure the relative accumulated acceleration load (AAL), estimated equivalent distance, and frequencies of sprint, jump, and exertion events during games against professional teams (Pro), teams at the same competition level (Collegiate), and teams comprising intra-team members in practice games (Scrimmage). Internal responses were calculated using the relative rating of perceived exertion (sRPE). A repeated measures analysis of variance, Bonferroni post-hoc tests, and standardized Cohen's effect sizes were calculated to compare the physical demands and internal responses across matches played against different levels of opponents. The results showed that in the game against the Pro, AAL (arbitrary units), sprint events (cases per min), and exertion events (cases per min) were significantly (p < .05) higher than those in games against the Collegiate and Scrimmage teams. As the competitive level of the opponents increased, the relative external load of the participants also increased. Conversely, internal responses measured using sRPE were lower after games against the Pro than those against the Collegiate. Internal and external loads may vary from each other depending on contextual factors.

Association between perioperative management of antiplatelet agents and risk of post-endoscopic submucosal dissection bleeding in early gastric cancer: analysis of a nationwide multicenter study.

BACKGROUND AND AIMS: Data are lacking regarding post-endoscopic submucosal dissection (ESD) bleeding in patients with early gastric cancer (EGC) who take antiplatelet agents (APAs), particularly in those taking thienopyridine and cilostazol. We aimed to clarify the association between the status of APA medication and post-ESD bleeding risk. METHODS: This study is a secondary analysis using data from a recently conducted nationwide multicenter study in Japan. We retrospectively reviewed patients treated with APAs or on no antithrombotic therapy recruited from 33 institutions who underwent ESD for EGC between November 2013 and October 2016. The primary outcome of this study was the relationship between the rate of post-ESD bleeding and the status of each APA medication. RESULTS: A total of 9736 patients were included in the analysis. Among 665 aspirin users, the continuation group was significantly associated with post-ESD bleeding (odds ratio [OR], 2.79; 95% confidence interval [CI], 1.77-4.37). Among 227 thienopyridine users, the aspirin or cilostazol replacement group was not significantly associated with post-ESD bleeding (OR, 1.85; 95% CI, .72-4.78). Among 158 cilostazol users, there was no significant association with post-ESD bleeding, irrespective of medication status. The rate of post-ESD bleeding was approximately 10% to 20% irrespective of the status of APA administration among dual-antiplatelet therapy users. No patients experienced thromboembolic events in this study. CONCLUSIONS: Replacement of thienopyridine with aspirin or cilostazol may be acceptable for minimizing both the risk of post-ESD bleeding and thromboembolism in patients with EGC. In patients on cilostazol monotherapy undergoing ESD, continuation of therapy may be acceptable.

Cooperation between artificial intelligence and endoscopists for diagnosing invasion depth of early gastric cancer.

BACKGROUND AND STUDY AIMS: The diagnostic ability of endoscopists to determine invasion depth of early gastric cancer is not favorable. We designed an artificial intelligence (AI) classifier for differentiating intramucosal and submucosal gastric cancers and examined it to establish a diagnostic method based on cooperation between AI and endoscopists. PATIENTS AND METHODS: We prepared 500 training images using cases of mainly depressed-type early gastric cancer from 250 intramucosal cancers and 250 submucosal cancers. We also prepared 200 test images each of 100 cancers from another institution. We designed an AI classifier to differentiate between intramucosal and submucosal cancers by deep learning. We examined the performance of the AI classifier and the majority vote of the endoscopists as high confidence and low confidence diagnostic probability, respectively, and cooperatively combined them to establish a diagnostic method providing high accuracy. RESULTS: Internal evaluation of the training images showed that accuracy, sensitivity, specificity, and F1 measure by the AI classifier were 77%, 76%, 78%, and 0.768, and those of the majority vote of the endoscopists were 72.6%, 53.6%, 91.6%, and 0.662, respectively. A diagnostic method based on cooperation between AI and the endoscopists showed that the respective values were 78.0%, 76.0%, 80.0%, and 0.776 for the test images. The value of F1 measure was especially higher than those by AI or the endoscopists alone. CONCLUSIONS: Cooperation between AI and endoscopists improved the diagnostic ability to determine invasion depth of early gastric cancer.

The degree of mucosal atrophy is associated with post-endoscopic submucosal dissection bleeding in early gastric cancer.

BACKGROUND AND AIM: Despite the widespread use of endoscopic submucosal dissection (ESD) for early gastric cancer, post-ESD bleeding remains a significant problem. Intragastric pH plays an important role in intragastric bleeding. Because gastric acid secretion contributes to intragastric pH, both the presence or absence of Helicobacter pylori infection and the degree of gastric mucosal atrophy may affect bleeding. The present study aimed to clarify the relationship between post-ESD bleeding and the degree of gastric mucosal atrophy based on H. pylori infection status. METHODS: We included 8170 patients who underwent ESD for early gastric cancer at 33 hospitals in Japan from November 2013 to October 2016. We analyzed the risk factors contributing to post-ESD bleeding. RESULTS: There were 3935 H. pylori-positive patients and 4235 H. pylori-negative patients. A nonsevere degree of gastric mucosal atrophy was an independent risk factor for post-ESD bleeding in H. pylori-negative patients (odds ratio: 1.51, P = 0.007), but not in H. pylori-positive patients (odds ratio: 0.91, P = 0.600). Further, in H. pylori-negative, but not H. pylori-positive, patients, the rate of post-ESD bleeding increased in a stepwise manner for patients continuing antithrombotic drug use, patients who withdrew antithrombotic drug use, and antithrombotic drug nonusers. CONCLUSIONS: Nonsevere gastric mucosal atrophy was a risk factor for post-ESD bleeding in early gastric cancer in H. pylori-negative patients but not in H. pylori-positive patients.

Bleeding following Endoscopic Submucosal Dissection for Early Gastric Cancer in Surgically Altered Stomach.

INTRODUCTION: Few studies have focused on bleeding following endoscopic submucosal dissection (ESD) in surgically altered stomach. We aimed to reveal the bleeding risk in surgically altered stomach following ESD for early gastric cancer (EGC). METHODS: We enrolled patients with ESD for EGC at 33 institutions between 2013 and 2016. In study 1, we evaluated bleeding risk following ESD in surgically altered stomach, compared with whole stomach. In study 2, we evaluated factors associated with bleeding following ESD in patients with surgically altered stomach. RESULTS: Of 11,452 patients, 445 patients had surgically altered stomach with the bleeding rate following ESD of 4.9%. In study 1, the bleeding risk in surgically altered stomach was not significant (odds ratio [OR], 1.37; 95% confidence interval [CI], 0.87-2.17) in the multivariate logistic regression analysis. No significant results were obtained when the surgically altered stomach was subdivided into various types. In study 2, the multivariate logistic regression analysis revealed that independent risk factors for bleeding following ESD were ischemic heart disease (OR, 7.52; 95% CI, 2.00-28.25) and P2Y12 receptor antagonist (OR, 4.81; 95% CI, 1.21-19.14). DISCUSSION/CONCLUSION: In this nationwide study, we found that the bleeding risk of surgically altered stomach following ESD for EGC did not significantly differ from that of whole stomach. The risk factors for ESD in patients with surgically altered stomach were ischemic heart disease and P2Y12 receptor antagonist.

Influence of hospital volume on bleeding after endoscopic submucosal dissection for early gastric cancer in Japan: a multicenter propensity score-matched analysis.

BACKGROUND: Information on whether there is a relationship between hospital volume and bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is limited. This study aimed to compare the bleeding rates after ESD for EGC according to the hospital volume. METHODS: Patients who underwent ESD for EGC at 33 institutions in Japan between November 2013 and October 2016 were included in this multicenter retrospective study. Hospital volume was categorized into three groups, based on the average annual number of ESD procedures: low- and medium-volume group (LMVG), high-volume group (HVG), and very high-volume group (VHVG). The bleeding rate after ESD for EGC was compared between the three hospital volume groups after propensity score matching. RESULTS: A total of 10,320 patients, including 2797 patients in the LMVG, 4646 patients in the HVG, and 2877 patients in the VHVG, were identified. Propensity score matching yielded 2002 patients in each hospital volume group, with an improved balance of confounding variables between the three groups. The bleeding rates in the LMVG, HVG, and VHVG were 4.3%, 3.7%, and 4.9%, respectively, and no significant difference was noted between the three groups. CONCLUSIONS: The bleeding rate after ESD for EGC did not differ between hospitals in Japan. The finding indicated that ESD for EGC is equally feasible across Japanese hospitals of different volumes regarding bleeding after ESD.

Exploring the seasonal and regional features of cat-scratch disease on the basis of anti-Bartonella henselae IgM/IgG positive rates in Japan.

OBJECTIVES: This study aimed to explore the seasonal and regional features of cat-scratch disease (CSD) based on 15-years of test results for anti-Bartonella henselae IgG and IgM by immunofluorescence assay (IFA) performed as a laboratory specialized in diagnostic testing of CSD in Japan. A literature search was performed to put our findings in perspective. METHODS: A total of 956 sera from patients suspected of CSD were submitted to our laboratory from nationwide. Seasonal changes in the monthly positive rates of IgG/IgM antibodies and regional distribution of the test specimens were analyzed. RESULTS: The monthly positive rates of anti-B. henselae IFA of IgG and IgM were both significantly high between September and January and low between March and July. The seasonal pattern observed in this study was similar to the ones reported from US and France, which were analyzed from a clinical database (monthly incidence of CSD diagnosis) or from monthly positive rates of either B. henselae PCR or anti-B. henselae IFA. However, fluctuations in the IFA monthly positive rates in this study were more pronounced than other reports. Regarding regionality, the test specimens submitted to us for IFA were prominently more from southwestern areas than from northern/middle-northern areas of Japan. The distribution coincided well with the regional distribution of CSD case reports and with a known regional prevalence of Bartonella-species bacteremia among pet cats in Japan. CONCLUSION: These epidemiological features in Japan are of relevance in the clinical diagnoses of CSD.

Antithrombotics increase bleeding after endoscopic submucosal dissection for gastric cancer: Nationwide propensity score analysis.

OBJECTIVES: Post-operative bleeding is the most common adverse event in endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). Patients taking antithrombotic agents has increased. We evaluated the influence of antithrombotic agents on delayed bleeding in ESD for EGC. METHODS: This was a post hoc analysis of nationwide, multicenter, retrospective cohort study in Japan. Altogether, 11,452 patients who underwent ESD for EGC in 33 institutions between November 2013 and October 2016 were enrolled. The primary outcome was the incidence of delayed bleeding in patients with or without antithrombotic agents. The secondary outcome was the incidence of delayed bleeding in those who took each antithrombotic agent and the cessation status of its use compared with each matched pair of patients. We used propensity matching and inverse probability of treatment weighting (IPTW) analyses. RESULTS: There were 1353 matched pairs of patients. The incidence of delayed bleeding was 2.8% and 10.7% in those without and with antithrombotic agents, respectively (odds ratio [OR] 4.15, 95% confidence interval [CI] 2.88-5.99; P < 0.001). The IPTW analysis showed similar results (OR 4.21, 95% CI 3.48-5.08; P < 0.001). Antiplatelets, anticoagulants, and their combination increased such incidence. Heparin bridging therapy had high OR (8.80), and the continuation (OR 3.46) and cessation (OR 2.95) of antithrombotic agent use had similar risk. CONCLUSIONS: Antithrombotic agents increased the incidence of delayed bleeding in patients who underwent ESD for EGC. Continuing antithrombotics may be more appropriate than heparin bridging therapy.

MC180295 Inhibited Epstein-Barr Virus-Associated Gastric Carcinoma Cell Growth by Suppressing DNA Repair and the Cell Cycle.

DNA methylation of both viral and host DNA is one of the major mechanisms involved in the development of Epstein-Barr virus-associated gastric carcinoma (EBVaGC); thus, epigenetic treatment using demethylating agents would seem to be promising. We have verified the effect of MC180295, which was discovered by screening for demethylating agents. MC180295 inhibited cell growth of the EBVaGC cell lines YCCEL1 and SNU719 in a dose-dependent manner. In a cell cycle analysis, growth arrest and apoptosis were observed in both YCCEL1 and SNU719 cells treated with MC180295. MKN28 cells infected with EBV were sensitive to MC180295 and showed more significant inhibition of cell growth compared to controls without EBV infection. Serial analysis of gene expression analysis showed the expression of genes belonging to the role of BRCA1 in DNA damage response and cell cycle control chromosomal replication to be significantly reduced after MC180295 treatment. We confirmed with quantitative PCR that the expression levels of BRCA2, FANCM, RAD51, TOP2A, and CDC45 were significantly decreased by MC180295. LMP1 and BZLF1 are EBV genes with expression that is epigenetically regulated, and MC180295 could up-regulate their expression. In conclusion, MC180295 inhibited the growth of EBVaGC cells by suppressing DNA repair and the cell cycle.

Prediction model of bleeding after endoscopic submucosal dissection for early gastric cancer: BEST-J score.

OBJECTIVE: Bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is a frequent adverse event after ESD. We aimed to develop and externally validate a clinically useful prediction model (BEST-J score: Bleeding after ESD Trend from Japan) for bleeding after ESD for EGC. DESIGN: This retrospective study enrolled patients who underwent ESD for EGC. Patients in the derivation cohort (n=8291) were recruited from 25 institutions, and patients in the external validation cohort (n=2029) were recruited from eight institutions in other areas. In the derivation cohort, weighted points were assigned to predictors of bleeding determined in the multivariate logistic regression analysis and a prediction model was established. External validation of the model was conducted to analyse discrimination and calibration. RESULTS: A prediction model comprised 10 variables (warfarin, direct oral anticoagulant, chronic kidney disease with haemodialysis, P2Y12 receptor antagonist, aspirin, cilostazol, tumour size >30 mm, lower-third in tumour location, presence of multiple tumours and interruption of each kind of antithrombotic agents). The rates of bleeding after ESD at low-risk (0 to 1 points), intermediate-risk (2 points), high-risk (3 to 4 points) and very high-risk (≥5 points) were 2.8%, 6.1%, 11.4% and 29.7%, respectively. In the external validation cohort, the model showed moderately good discrimination, with a c-statistic of 0.70 (95% CI, 0.64 to 0.76), and good calibration (calibration-in-the-large, 0.05; calibration slope, 1.01). CONCLUSIONS: In this nationwide multicentre study, we derived and externally validated a prediction model for bleeding after ESD. This model may be a good clinical decision-making support tool for ESD in patients with EGC.

Influence of anticoagulants on the risk of delayed bleeding after gastric endoscopic submucosal dissection: a multicenter retrospective study.

BACKGROUND AND AIMS: Delayed bleeding after gastric endoscopic submucosal dissection (ESD) in patients receiving anticoagulants remains an unpreventable adverse event. Although direct-acting oral anticoagulants (DOACs) have superior efficacy in preventing thromboembolism, their effects on the occurrence of delayed bleeding remain unclear. This study aimed to elucidate the clinical effect of DOACs on delayed bleeding after gastric ESD. PATIENTS AND METHODS: We retrospectively examined 728 patients who received anticoagulants and were treated for gastric neoplasms with ESD in 25 institutions across Japan. Overall, 261 patients received DOACs, including dabigatran (92), rivaroxaban (103), apixaban (45) and edoxaban (21), whereas 467 patients were treated with warfarin. RESULTS: Delayed bleeding occurred in 14% of patients taking DOACs, which was not considerably different in patients receiving warfarin (18%). Delayed bleeding rate was significantly lower in patients receiving dabigatran than in those receiving warfarin and lower than that observed for other DOACs. Multivariate analysis showed that age ≥ 65, receiving multiple antithrombotic agents, resection of multiple lesions and lesion size ≥ 30 mm were independent risk factors, and that discontinuation of anticoagulants was associated with a decreased risk of bleeding. In multivariate analysis among patients taking DOACs, dabigatran therapy was associated with a significantly lower risk of delayed bleeding. CONCLUSIONS: The effects of DOACs on delayed bleeding varied between agents, but dabigatran therapy was associated with the lowest risk of delayed bleeding. Switching oral anticoagulants to dabigatran during the perioperative period could be a reasonable option to reduce the risk of delayed bleeding after gastric ESD.

Timing of bleeding and thromboembolism associated with endoscopic submucosal dissection for gastric cancer in Japan.

BACKGROUND AND AIM: This study aimed to reveal the timing of bleeding and thromboembolism associated with endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). METHODS: We retrospectively reviewed  10,320 patients who underwent ESD for EGC during November 2013-October 2016. We evaluated overall bleeding rates and their inter-group differences. Factors associated with early/late (cut-off 5 days) bleeding and thromboembolism frequency and its association with the intake of antithrombotic agents were investigated. RESULTS: Overall, the post-ESD bleeding rate was 4.7% (489/10 320); the median time to post-ESD bleeding was 4 days. The post-ESD bleeding rates were 3.2%, 8.7%, 15.5%, and 29.9% in those not taking antithrombotic agents, those taking antiplatelet agents, those taking anticoagulants (ACs), and those taking antiplatelet agents and ACs. Warfarin (odds ratio [OR], 9.16), direct oral ACs (OR, 4.16), chronic kidney disease with hemodialysis (OR, 2.93), thienopyridine (OR, 2.25), aspirin (OR, 1.66), tumor size >30 mm (OR, 1.86), multiple tumors' resection (OR, 1.54), and tumor in the lower third of the stomach (OR, 1.40) were independent risk factors for early bleeding. The independent risk factors for late bleeding were direct oral ACs (OR, 7.42), chronic kidney disease with hemodialysis (OR, 4.99), warfarin (OR, 3.90), thienopyridine (OR, 3.09), liver cirrhosis (OR, 2.43), cilostazol (OR, 1.93), aspirin (OR, 1.92), ischemic heart disease (OR, 1.77), and male sex (OR, 1.65). There were three (0.03%) thromboembolic events (cerebral infarction = 2, transient ischemic attack = 1). CONCLUSION: We revealed the timing of bleeding and risk factors for early/late bleeding and showed the thromboembolism frequency associated with ESD for EGC.

Exumbrellar Surface of Jellyfish: A Comparative Fine Structure Study with Remarks on Surface Reflectance.

The exumbrellar surfaces of six pelagic cnidarians from three classes were ultra-structurally compared to reveal their structural diversity in relation to their gelatinous, transparent bodies. We examined two hydrozoans (Diphyes chamissonis and Colobonema sericeum), a cubozoan (Chironex yamaguchii), and three scyphozoans (Atolla vanhöffeni, Aurelia coerulea, and Mastigias papua). The exumbrellar surfaces of the mesoglea in D. chamissonis, Ch. yamaguchii, Au. coerulea, and M. papua were covered with a simple epidermis; the shapes of the epidermal cells were remarkably different among the species. The epidermal cells of Ch. yamaguchii and M. papua possessed an array of microvilli on the apical side. The array possibly reduced light reflectance and provided some other surface properties, as seen for the cuticular nipple array in tunicates, considering the length, width, and pitch of the microvilli. The reduction of light reflectance on the array of microvilli was supported by the simulation with rigorous coupled wave analysis (RCWA). Microvilli were sparse and did not form an array in metephyrae of Au. coerulea. The mesoglea matrix beneath the basal side of the epidermis was loose in all of the species. The exumbrellar side of the mesoglea was exposed only in the mesopelagic species, At. vanhöffeni and Co. sericeum, and electron-dense layer(s) covered the surface of the mesoglea. It is uncertain whether the exumbrellar epidermis is absent in these species or the epidermal cells are completely exfoliated during the sampling and handling processes. In the latter case, the electron-dense layer(s) on the mesoglea surface might originally underlie the epidermis.

Cytotoxic Effects of Water-Soluble Extracts of Coarse and Fine Atmospheric Particulate Matter on Mast Cell Lines.

Fine particulate matter (PM2.5) pollution causes serious health disorders, because PM2.5 becomes deposited in the tracheobronchial and alveoli regions. In the extrathoracic region, there are more deposits of coarse particulate matter than fine particulates. As adverse health issues caused by coarse particulates have not been well investigated, this study examined the cytotoxicity of water-soluble extracts of both fine (0.05-3 µm, PM0.05-3) and coarse (> 3 µm, PM>3) particulates collected from April 2016 to March 2019 in Fukuoka, Japan. Also evaluated were concentrations of NH4+ and SO42-, multi-components of well-known secondary generation substances. The findings revealed that PM>3 showed stronger cytotoxic effects on mast cell lines than PM0.05-3. Cytotoxic effects were observed at concentrations of over 15 mM of (NH4)2SO4 and over 30 mM of NH4Cl. In contrast, Na2SO4 caused few cytotoxic effects up to a concentration of 50 mM. The causative substances for this cytotoxicity may not have been NH4+ and SO42- because their PM>3 concentrations indicating the largest cytotoxic effects were 1 and 0.4 mM, respectively. The cytotoxicities of PM>3 and PM0.05-3 were the highest in the first half of FY2016. These cytotoxicities seem to be due to cross-border pollution, although this pollution has been declining in recent years. An increasing trend of cytotoxicity was observed in the second half of FY2018. This study showed that cytotoxicity and particulate concentrations are not always correlated. Thus, we should focus not only on the quantity of atmospheric particulate matter, but also on its quality.

Risk for lymph node metastasis in Epstein-Barr virus-associated gastric carcinoma with submucosal invasion.

OBJECTIVES: Epstein-Barr virus-associated gastric cancer (EBVGC) has been reported to be associated with a low risk for lymph node metastasis (LNM). However, the curative criteria for endoscopic submucosal dissection (ESD) for submucosal EBVGC (pT1b-EBVGC) remain unclear. Our study aimed to investigate the risk factors for LNM in pT1b-EBVGC. METHODS: This was a retrospective multicenter study at five institutes in Japan. We reviewed medical records and extracted all pT1b-EBVGC cases that met the following criteria: (i) histologically proven submucosal gastric cancer; (ii) surgical or endoscopic resection between January 2000 and December 2016; and (iii) presence of Epstein-Barr virus (EBV) in tumor cells verified by EBV-encoded small RNA in situ hybridization (EBER-ISH). The association between clinicopathological factors and LNM were assessed using multivariable logistic regression analysis. RESULTS: A total of 185 pT1b-EBVGC cases were included in the analysis. LNM was found in nine cases (4.9%). Multivariable logistic regression analysis demonstrated that lymphatic invasion (OR 9.1; 95% CI 2.1-46.1) and submucosal invasion ≥4000 µm (OR 9.2; 95% CI 1.3-110.3) were significant risk factors for LNM. When we focused on pT1b-EBVGC without lymphatic invasion and with submucosal invasion <2000 µm, the rate of LNM was 0% (0/96, 95% CI 0-3.8%). CONCLUSIONS: Our findings indicated that lymphatic invasion and submucosal invasion ≥4000 µm were significant risk factors for LNM. ESD could be an appropriate option for pT1b-EBVGC without lymphatic invasion and with submucosal invasion <2000 µm.

Rebleeding in patients with delayed bleeding after endoscopic submucosal dissection for early gastric cancer.

OBJECTIVES: Delayed bleeding is a major adverse event in endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). Some patients may experience rebleeding after successful hemostasis for delayed bleeding, yet the details of rebleeding remain unclear. We aimed to clarify the frequency and risk factors of rebleeding. METHODS: Among 11,452 patients who underwent ESD for EGC at 33 institutions in Japan between 2013 and 2016, we analyzed 489 patients showing delayed bleeding. The rate of rebleeding was investigated. Subsequently, 15 candidate variables were evaluated for their influence on the risk of rebleeding via logistic regression analysis. RESULTS: Rebleeding occurred in 11.2% (55/489) of the enrolled patients. Multivariate analysis revealed that warfarin [odds ratio (OR), 2.71; 95% confidence interval (CI), 1.26-5.84] and a resection size >40 mm (OR, 1.99; 95% CI, 1.08-3.67) were independent risk factors for rebleeding. In the analysis of the management of warfarin after index bleeding, only warfarin discontinuation (OR, 3.66; 95% CI, 1.37-9.78) was significantly associated with rebleeding in comparison with no use of warfarin. However, many rebleeding events (75.0%) occurred following the resumption of warfarin. The rebleeding rate during discontinuation status and that in taking warfarin (continuation or resumption) were 6.1% and 20.0%, respectively. CONCLUSIONS: Rebleeding was not a rare event in patients experiencing delayed bleeding after ESD for EGC. In addition to having a resection size >40 mm, warfarin usage placed patients at high risk for rebleeding, especially at the timing of its resumption following discontinuation as well as its continuation.

Estimation of salt intake from spot urine may assist the risk assessment of gastric cancer.

Daily salt intake can be estimated by measuring sodium and creatinine concentrations in spot urine. Excessive salt intake is risk factor for gastric cancer. We examined the correlation between estimated salt intake from spot urine and risk of gastric cancer. This study included gastric cancer patients who underwent treatment at our hospital and patients in whom esophagogastroduodenoscopy was performed but gastric cancer was not observed. The history of H. pylori infection was known in these patients. Spot urine was collected, and daily salt intake was estimated from urine sodium and urine creatinine. Mean estimated salt intake was significantly higher in 120 gastric cancer patients (9.18 g/day) than in 80 non-gastric cancer patients (8.22 g/day). Multivariate analysis revealed estimated salt intake and H. pylori infection to be independent risk factors for gastric cancer. Among H. pylori-infected patients, salt intake was significantly higher in gastric cancer patients (9.25 g/day) than in non-gastric cancer patients (8.01 g/day). In conclusion, salt intake estimated from spot urine was high in patients with gastric cancer, especially in H. pylori infected patients. Spot urine is a simple examination and it may be applied as a new risk assessment of gastric cancer.

EBV-associated gastric cancer evades T-cell immunity by PD-1/PD-L1 interactions.

BACKGROUND: Epstein-Barr virus (EBV) is an oncogenic human herpesvirus involved in the development of around 10% of gastric cancers. The overexpression of PD-L1 is one of the features of EBV-associated gastric cancer (EBVaGC); however, the function of PD-L1 has not been studied in EBVaGC. METHODS: We used three EBVaGC cell lines, SNU719 cells, NCC24 cells, and YCCEL1 cells, to evaluate the PD-L1 expression and function in EBVaGC. Jurkat T-lymphocytes expressing PD-1 were co-cultured with NCC24 and YCCEL1 cells and the cell cycles were analyzed. To study the regulatory mechanism for PD-L1 expression, the 3'UTR of PD-L1 was sequenced, and the effect of inhibitors of the IFN-γ signaling pathway was evaluated. RESULTS: All of the EBVaGC cell lines expressed PD-L1, and its expression was further enhanced by stimulation with IFN-γ. In Jurkat T-cells co-cultured with IFN-γ-stimulated NCC24 and YCCEL1 cells, the number of cells in the G0/G1 phase was significantly increased. This G0/G1 arrest was partially released by administration of anti-PD-L1 antibody. We found SNPs in PD-L1 3'UTR nucleotide sequences that were located at seed regions for microRNAs. Treatment of EBVaGC cell lines with JAK2-inhibitor, PI3K-inhibitor, and mTOR inhibitor reduced the level of PD-L1 expression to the same level as cells without IFN-γ stimulation. CONCLUSIONS: EBVaGC cells expressing high levels of PD-L1 suppress T-cell proliferation, and the IFN-γ signaling pathway is involved in the expression of PD-L1.