Metagenomic Identification of Microbial Signatures Predicting Pancreatic Cancer From a Multinational Study.

BACKGROUND & AIMS: To identify gut and oral metagenomic signatures that accurately predict pancreatic ductal carcinoma (PDAC) and to validate these signatures in independent cohorts. METHODS: We conducted a multinational study and performed shotgun metagenomic analysis of fecal and salivary samples collected from patients with treatment-naïve PDAC and non-PDAC controls in Japan, Spain, and Germany. Taxonomic and functional profiles of the microbiomes were characterized, and metagenomic classifiers to predict PDAC were constructed and validated in external datasets. RESULTS: Comparative metagenomics revealed dysbiosis of both the gut and oral microbiomes and identified 30 gut and 18 oral species significantly associated with PDAC in the Japanese cohort. These microbial signatures achieved high area under the curve values of 0.78 to 0.82. The prediction model trained on the Japanese gut microbiome also had high predictive ability in Spanish and German cohorts, with respective area under the curve values of 0.74 and 0.83, validating its high confidence and versatility for PDAC prediction. Significant enrichments of Streptococcus and Veillonella spp and a depletion of Faecalibacterium prausnitzii were common gut signatures for PDAC in all the 3 cohorts. Prospective follow-up data revealed that patients with certain gut and oral microbial species were at higher risk of PDAC-related mortality. Finally, 58 bacteriophages that could infect microbial species consistently enriched in patients with PDAC across the 3 countries were identified. CONCLUSIONS: Metagenomics targeting the gut and oral microbiomes can provide a powerful source of biomarkers for identifying individuals with PDAC and their prognoses. The identification of shared gut microbial signatures for PDAC in Asian and European cohorts indicates the presence of robust and global gut microbial biomarkers.

Effect of antiplatelet agent number, types, and pre-endoscopic management on post-polypectomy bleeding: validation of endoscopy guidelines.

BACKGROUND: It remains unclear whether type of antiplatelet (AP) therapy, AP combination therapy, and AP continuing or switching strategy affect the risk of post-polypectomy bleeding (PPB). In this study, we sought to elucidate this risk. METHODS: We analyzed 1050 patients who underwent colonoscopic polypectomy: 525 AP users and 525 controls matched for age, sex, comorbidities, concomitant non-steroidal anti-inflammatory drugs use, and polyp characteristics who did not receive antithrombotics. PPB risk was evaluated by AP number, type, and continuing or switching strategies during the peri-endoscopic period. RESULTS: In multivariate analysis, bleeding risk increased significantly as the number of AP agents used increased (monotherapy, adjusted odds ratio [aOR], 3.7; dual antiplatelet therapy (DAPT), 4.6; triple antiplatelet therapy (TAPT), 11.1) compared with controls. With monotherapy, significantly increased PPB risk was found for aspirin (aOR 4.3), thienopyridine (aOR 6.3), and cilostazol (aOR 5.9), but not for eicosapentaenoic acid or other APs (beraprost, limaprost, sarpogrelate, dilazep, or dipyridamole). With DAPT, significantly increased PPB risk was found for combination aspirin plus cilostazol, but not aspirin plus other APs. Bleeding rates for continuing monotherapy were 4.3% for aspirin and 0% for thienopyridine, cilostazol, and other APs, respectively. CONCLUSIONS: Analysis of this large polypectomy dataset showed that the use of low-dose aspirin, thienopyridine, or cilostazol and a combination of these is associated with increased PPB risk. Although PPB risk was high with DAPT or TAPT, PPB rate in any antiplatelet monotherapy even with a continuing strategy was low at < 5%.

Validation of the American Gastroenterological Association guidelines on management of intraductal papillary mucinous neoplasms: more than 5 years of follow-up.

OBJECTIVES: Recent guidelines suggest that imaging surveillance be conducted for 5 years for patients with at most one high-risk feature. If there were no significant changes, surveillance is stopped. We sought to validate this follow-up strategy. METHODS: In study 1, data were analysed for 392 patients with intraductal papillary mucinous neoplasms (IPMNs) and at most one high-risk feature who were periodically followed up for more than 1 year with imaging tests. In study 2, data were analysed for 159 IPMN patients without worsening high-risk features after 5 years (stop surveillance group). RESULTS: In study 1, pancreatic cancer (PC) was identified in 12 patients (27.3%) in the endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) indication group and none in the non-EUS-FNA indication group (P < 0.01). In the EUS-FNA indication group, 11 patients (25%) died, whereas 29 (8.3%) died in the non EUS-FNA indication group (P < 0.01). In study 2 (stop surveillance group), PC was identified in three patients (1.9%) at 84, 103 and 145 months. CONCLUSIONS: PC risk and mortality for IPMNs not showing significant change for 5 years is likely to be low, and the non-EUS-FNA indication can provide reasonable decisions. However, three patients without worsening high-risk features for 5 years developed PC. The stop surveillance strategy should be reconsidered. KEY POINTS: • The AGA guidelines provide reasonable clinical decisions for the EUS-FNA indication. • In stop surveillance group, PC was identified in 3 patients (1.9%). • In stop surveillance group, 2 of 3 PC patients died from PC. • Risk of pancreatic cancer in "stop surveillance" group is not negligible.

Effect of low-dose aspirin use on pancreatic cancer development and morphological changes on imaging in IPMN: A long-term cohort study.

BACKGROUND: Aspirin use may reduce the incidence of pancreatic cancer (PC), but no data are available regarding its chemopreventive effects on intraductal papillary mucinous neoplasm (IPMN). We aimed to determine whether low-dose aspirin (LDA) reduces PC development and morphological changes on imaging in IPMN patients. METHODS: A cohort of 448 IPMN patients periodically followed up with imaging tests was analyzed. We used one-to-two propensity score matching to adjust for differences between an LDA group (n = 63) and a non-LDA group (n = 385). Outcomes included increasing cyst diameter, increasing main pancreatic duct (MPD) diameter, mural nodule (MN) appearance and PC development. RESULTS: After matching, 63 LDA and 126 non-LDA patients were selected. During follow-up (median, 5.5 years), no significant differences were found in increasing cyst diameter, MN appearance, or PC development. However, there were significantly fewer cases of increasing MPD diameter in the LDA group (4.8% vs. 12.7%; p = 0.02). After adjustment for age and sex, LDA still decreased the risk of increasing MPD diameter (hazard ratio, 0.17; p = 0.02). CONCLUSION: Our results do not support a chemopreventive effect of LDA on PC development. However, LDA reduces further MPD dilation in IPMN patients.

Natural history of intraductal papillary mucinous neoplasm and non-neoplastic cyst: long-term imaging follow-up study.

BACKGROUND: To identify differences in incidence and mortality of pancreatic cancer (PC) between intraductal papillary mucinous neoplasm (IPMN) and non-neoplastic cyst. METHODS: Patients with pancreatic cyst (n = 526; 263 with IPMN and 263 with non-neoplastic cyst matched for age, sex, and diagnosis year) were periodically followed-up with imaging. Hazard ratio (HR), standardized incidence ratio (SIR), and standardized mortality ratio (SMR) for PC and PC-related mortality were estimated. RESULTS: During a mean follow-up of 57.5 months with 3,376 computed tomography scans and 1,079 magnetic resonance imaging scans, 5-year cumulative PC incidence was 4.0% for IPMN and 0% for non-neoplastic cyst, respectively (HR 5.2; P = 0.031). During a mean follow-up of 73.1 months, 5-year cumulative PC-related mortality was 2.6% for IPMN and 0% for non-neoplastic cyst, respectively (HR 4.5; P = 0.05). Compared with the general population in Japan, patients with IPMN, but not those with non-neoplastic cyst, had significantly increased risks of PC incidence (SIR 22.03) and related mortality (SMR 15.9). CONCLUSIONS: During long-term imaging follow-up, patients with IPMN developed PC over time, whereas none of the patients with non-neoplastic cyst developed it within 5 years. Compared with the general population, patients with IPMN, but not those with non-neoplastic cyst, were at risk of PC and related mortality.

Recurrence and prognosis of patients emergently hospitalized for acute esophageal variceal bleeding: A long-term cohort study.

AIM: To elucidate the rates of recurrence and mortality in acute esophageal variceal bleeding and the associated risk factors. METHODS: A cohort of 174 patients emergently hospitalized for esophageal variceal bleeding was analyzed. All patients underwent endoscopic variceal ligation within 3 h of arrival. Comorbidities, vital signs, drug use, laboratory data, etiology, endoscopic findings, transfusion requirement, and follow-up endoscopy were assessed. Cox's proportional hazards model was used to estimate hazard ratios (HR). RESULTS: Rebleeding was identified in 49 patients with a mean follow-up of 18 months. The cumulative rebleeding rate at 1 month, 1 year, and 5 years was 10.2%, 30.0%, and 51.0%, respectively. In multivariate analysis, independent risk factors for rebleeding were child-Pugh class C (HR 1.94; P = 0.027), alcoholic liver cirrhosis (HR 2.32; P = 0.01), and no follow-up endoscopy (HR 13.3; P < 0.001). During the overall mean follow-up of 22 months, 69 patients died (17 due to bleeding), and the cumulative mortality rate at 1 month, 1 year, and 5 years was 12.2%, 26.6%, and 63.0%, respectively. In multivariate analysis, independent risk factors for mortality were child-Pugh class C (HR 2.91; P < 0.001), coexistence of hepatocellular carcinoma (HR 1.92; P = 0.013), and no follow-up endoscopy (HR 23.6; P < 0.001). CONCLUSION: This study revealed more than 50% cumulative rebleeding and mortality in the 5-year period after endoscopic variceal ligation for esophageal variceal bleeding in an emergency setting. Child-Pugh C, alcoholic liver cirrhosis, and no follow-up endoscopy increased the risk of rebleeding; Child-Pugh C, coexistence of hepatocellular carcinoma, and no follow-up endoscopy increased the risk of mortality.

An experimental study to assess the best maneuver when using a reverse side-bevel histology needle for EUS-guided fine-needle biopsy.

BACKGROUND AND STUDY AIMS: Recently, ProCore™ was developed as an endoscopy ultrasound (EUS)-guided histology needle designed to address several current limitations of EUS-guided fine-needle aspiration (FNA). Nevertheless, tissue yield with the ProCore™ is not consistent. No standard technique has been established. This experimental study was conducted to ascertain the best maneuver when using the ProCore™. PATIENTS AND METHODS: We performed fine-needle aspiration and biopsy (FNAB) with a 22-gauge (G) ProCore™ using chicken tenderloin and liver. Six methods were used, with two needle movement techniques (natural speed and whipping back) and three negative pressures (no suction (NS), slow pull (SP), and 10-mL suction). RESULTS: In cases using the "natural speed" technique, a significant difference in tissue yield was found with suction pressures in both tenderloin and liver (P < 0.0001, P = 0.0079). In cases using the "whipping back" technique, for the tenderloin, no significant difference in tissue yield was found for NS vs. SP (P = 0.0596), however, a significant difference was found for SP vs. 10-mL suction (P < 0.0001) and for NS vs. 10-mL suction (P < 0.0001). For the liver, a significant difference was found among suction pressures (P = 0.0079). Comparing "natural speed" with "whipping back" using the tenderloin, no significant difference in tissue yield was found with NS and 10 mL of pressure (P = 0.1126, P = 0.0718), but a significant difference was found with SP (P = 0.0028). Regarding the liver, no significant difference was found based upon suction pressure (NS P = 0.1508; SP P = 0.0873; 10 mL P = 0.6667). CONCLUSIONS: EUS-FNAB using ProCore™ can be performed with negative pressure with any needling technique. Although ProCore™ has a reverse side-bevel, results in using it with a whipping-back technique were inconclusive.

Safety and Effectiveness of Early Colonoscopy in Management of Acute Lower Gastrointestinal Bleeding on the Basis of Propensity Score Matching Analysis.

BACKGROUND & AIMS: We investigated the safety and effectiveness of early colonoscopy (performed within 24 hours of hospital admission) for acute lower gastrointestinal bleeding (LGIB) vs elective colonoscopy (performed 24 hours after admission). METHODS: We conducted a retrospective study by using a database of endoscopies performed at the National Center for Global Health and Medicine in Tokyo, Japan from January 2009 through December 2014. We analyzed data from 538 patients emergently hospitalized for acute LGIB. We used propensity score matching to adjust for differences between patients who underwent early colonoscopy vs elective colonoscopy. Outcomes included rates of adverse events during bowel preparation and colonoscopy procedures, stigmata of recent hemorrhage, endoscopic therapy, blood transfusion requirement, 30-day rebleeding and mortality, and length of hospital stay. RESULTS: We selected 163 pairs of patients for analysis on the basis of propensity matching. We observed no significant differences between the early and elective colonoscopy groups in bowel preparation-related rates of adverse events (1.8% vs 1.2%, P = .652), colonoscopy-related rates of adverse events (none in either group), blood transfusion requirement (27.6% vs 27.6%, P = 1.000), or mortality (1.2% vs 0, P = .156). The early colonoscopy group had higher rates than the elective group for stigmata of recent hemorrhage (26.4% vs 9.2%, P < .001) and endoscopic therapy (25.8% vs 8.6%, P < .001), including clipping (17.8% vs 4.9%, P < .001), band ligation (6.1% vs 1.8%, P = .048), and rebleeding (13.5% vs 7.4%, P = .070). Patients in the early colonoscopy group stayed in the hospital for a shorter mean time (10 days) than patients in the elective colonoscopy group (13 days) (P < .001). CONCLUSIONS: Early colonoscopy for patients with acute LGIB is safe, allows for endoscopic therapy because it identifies the bleeding source, and reduces hospital stay. However, compared with elective colonoscopy, early colonoscopy does not reduce mortality and may increase the risk for rebleeding.

Development of Pancreatic Cancer, Disease-specific Mortality, and All-Cause Mortality in Patients with Nonresected IPMNs: A Long-term Cohort Study.

PURPOSE: To determine the cumulative incidence, disease-specific mortality, and all-cause mortality of pancreatic cancer (PC) in patients with intraductal papillary mucinous neoplasms (IPMNs) and to identify imaging findings that are associated with these outcomes. MATERIALS AND METHODS: This retrospective study had institutional review board approval, and the need to obtain patient consent was waived. Data from an electronic database were analyzed and supplemented by chart reviews for 285 patients with nonresected IPMNs who were periodically followed up with imaging (1273 multidetector computed tomography and 750 magnetic resonance cholangiopancreatography examinations). The Kaplan-Meier method was used to estimate the cumulative development of PC, PC mortality, and all-cause mortality (factors were compared by using the log-rank test). RESULTS: Over a median imaging follow-up period of 39 months, 12 (4.2%) of 285 patients developed PC; the cumulative 5-year PC incidence was 3.9% for branch duct (BD)-IPMNs, 45.5% for main duct (MD)-IPMNs (P < .01), 7.7% for cysts 30 mm or larger, and 5.3% for cysts smaller than 30 mm (P = .82). Over a median survival follow-up period of 47.5 months, seven (2.5%) of 285 patients died of PC and 14 (4.9%) patients died of other causes. Cumulative 5-year PC mortality was 2.1% for BD-IPMNs, 18.5% for MD-IPMNs (P < .01), 2.6% for cysts 30 mm or larger, and 2.8% for cysts smaller than 30 mm (P = .90). Cumulative 5-year all-cause mortality was 5.5% for BD-IPMNs, 18.5% for MD-IPMNs (P < .01), 12.5% for cysts 30 mm or larger, and 5.9% for cysts smaller than 30 mm (P = .89). CONCLUSION: Five-year PC development, disease-specific mortality, and all-cause mortality were approximately 4%, 2%, and 6% for BD-IPMNs and 46%, 19%, and 19% for MD-IPMNs, respectively. The presence of an MD-IPMN, but not cyst size, was significantly associated with PC development and subsequent mortality.

Usefulness of endoscopic ultrasound-guided fine-needle aspiration with a forward-viewing and curved linear-array echoendoscope for small gastrointestinal subepithelial lesions.

BACKGROUND AND STUDY AIMS: It is difficult to perform endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of small gastrointestinal (GI) subepithelial lesions (SELs) approximately 10 mm in diameter. This study was undertaken to evaluate the feasibility, safety, and diagnostic ability of EUS-FNA with a forward-viewing and curved linear-array echoendoscope (FVCLA-ES) that has a cap for small SELs. PATIENTS AND METHODS: The study enrolled 8 patients who had small upper GI SELs approximately 10 mm in diameter. To fix the SELs during FNA, a cap device was attached to the scope tip. RESULTS: The mean (standard deviation [SD]) diameter of the SELs was 10.6 mm (2.94). Even small lesions were well targeted for FNA when the FVCLA-ES with a cap device was used. The mean (SD) number of passes was 4.6 (1.59). Adequate samples were obtained from 7 patients (87.5 %) - in 6 (75 %) for cytology and in 4 (50 %) for histologic examination with immunohistochemical (IHC) staining. No complication occurred. Gastrointestinal stromal tumor (GIST) in 2 patients and leiomyoma in 2 patients were definitively diagnosed with IHC staining. CONCLUSIONS: EUS-FNA with an FVCLA-ES that has a cap device is feasible and safe. This technique is expected to contribute to histologic diagnosis, even in small SELs.

Idiopathic granulomatous gastritis diagnosed with endoscopic ultrasound-guided fine-needle aspiration: report of a case.

A 71-year-old man in whom a gastric submucosal lesion was found incidentally was referred to our hospital for detailed examination. Esophagastroduodenoscopy showed a submucosal lesion in the body of the stomach. Endoscopic ultrasound revealed a 15-mm hypoechoic round mass with calcifications arising from the muscular layer. Confusing the diagnosis, it resembled a gastrointestinal mesenchymal tumor. Subsequently, endoscopic ultrasound-guided fine-needle aspiration was conducted for definitive diagnosis. Pathologic analysis showed a granuloma. Because this patient had no prior exposure to tuberculosis or Helicobacter pylori infection and had no abnormal laboratory data, this submucosal lesion was diagnosed as idiopathic granulomatous gastritis.

Clinical effects of eosinophilic esophagitis observed using endoscopic ultrasound.

A 50-year-old woman was referred to our hospital for dysphagia and several episodes of esophageal food impaction during the prior three months. Complete blood count and basic biochemical tests were normal. No eosinophilia was found. Esophagogastroduodenoscopy (EGD) revealed the presence of concentric rings (esophageal "trachealization") and stenosis along the middle and distal esophagus. Endoscopic ultrasound (EUS) showed circumferential thickening of all layers in the same part. Cytopathologic evaluation of a specimen obtained by endoscopic biopsy of the thickened area in the distal esophagus showed eosinophilic infiltration (20 eosinophils per high-powered field). She was diagnosed as having eosinophilic esophagitis (EoE). Topical steroid therapy was started. A tendency of dysphagia for relief and improvement of characteristic EGD findings began early, but wall thickening in EUS remained. Past reports of the related literature have described that thickness of submucosa and muscularis propria remained after therapy, although significant reduction in the mucosal thickness was provided by short-term steroid therapy. One explanation for early relapse is insufficient reduction in the submucosa and muscularis propria. Consequently, our patient was given steroids until thickness on EUS improved. EUS is regarded as useful for evaluating the curative effect in patients with EoE.

Predictive findings for Helicobacter pylori-uninfected, -infected and -eradicated gastric mucosa: validation study.

AIM: To validate the usefulness of screening endoscopy findings for predicting Helicobacter pylori (H. pylori) infection status. METHODS: H. pylori infection status was determined by histology, serology, and the urea breast test in 77 consecutive patients who underwent upper endoscopy. Based on the findings, patients were categorized as H. pylori-uninfected, -infected, or -eradicated cases. Using six photos of certain sites in the stomach per case, we determined the presence or absence of the following endoscopic findings: regular arrangement of collecting venules (RAC), linear erythema, hemorrhage, fundic gland polyp (FGP), atrophic change, rugal hyperplasia, edema, spotty erythema, exudate, xanthoma, and mottled patchy erythema (MPE). The diagnostic odds ratio (DOR) and inter-observer agreement (Kappa value) for these 11 endoscopic findings used in the determination of H. pylori infection status were calculated. RESULTS: Of the 77 patients [32 men and 45 women; mean age (SD), 39.7 (13.4) years] assessed, 28 were H. pylori uninfected, 28 were infected, and 21 were eradicated. DOR values were significantly high (< 0.05) for the following H. pylori cases: uninfected cases with RAC (11.5), linear erythema (24.5), hemorrhage (4.1), and FGP (34.5); for infected cases with atrophic change (8.67), rugal hyperplasia (15.8), edema (14.2), spotty erythema (11.5), and exudate (3.52); and for eradicated cases with atrophic change (32.4) and MPE (103.0). Kappa values were excellent for FGP (0.93), good for RAC (0.63), hemorrhage (0.79), atrophic change (0.74), and MPE (0.75), moderate for linear erythema (0.51), rugal hyperplasia (0.49), edema (0.58), spotty erythema (0.47), and exudate (0.46), and poor for xanthoma (0.19). CONCLUSION: The endoscopic findings of RAC, hemorrhage, FGP, atrophic change, and MPE will be useful for predicting H. pylori infection status.