Adverse events of self-expandable metal stent placement for malignant distal biliary obstruction: a large multicenter study.

BACKGROUND AND AIMS: Endoscopic placement of self-expandable metal stents (SEMSs) for malignant distal biliary obstruction (MDBO) may be accompanied by several types of adverse events. The present study analyzed the adverse events occurring after SEMS placement for MDBO. METHODS: The present study retrospectively investigated the incidence and types of adverse events in patients who underwent SEMS placement for MDBO between April 2018 and March 2021 at 26 hospitals. Risk factors for acute pancreatitis, cholecystitis, and recurrent biliary obstruction (RBO) were evaluated by univariate and multivariate analyses. RESULTS: Of the 1425 patients implanted with SEMSs for MDBO, 228 (16.0%) and 393 (27.6%) experienced early adverse events and RBO, respectively. Pancreatic duct without tumor involvement (P = .023), intact papilla (P = .025), and SEMS placement across the papilla (P = .037) were independent risk factors for acute pancreatitis. Tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis (P < .001). Use of fully and partially covered SEMSs was an independent risk factor for food impaction and/or sludge. Use of fully covered SEMSs was an independent risk factor for stent migration. Use of uncovered SEMSs and laser-cut SEMSs was an independent risk factor for tumor ingrowth. CONCLUSIONS: Pancreatic duct without tumor involvement, intact papilla, and SEMS placement across the papilla were independent risk factors for acute pancreatitis, and tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis. The risk factors for food impaction and/or sludge, stent migration, and tumor ingrowth differed among types of SEMSs.

Clinical outcomes of the over-the-scope clip closure after duodenal endoscopic submucosal dissection: A multicenter retrospective study.

BACKGROUND AND AIM: Prophylactic closure with the over-the-scope clip (OTSC) after endoscopic submucosal dissection (ESD) of superficial non-ampullary duodenal epithelial tumors (SNADETs) has been reported to reduce postoperative adverse events (AEs). However, there are few evidences regarding AEs-associated factors and long-term outcomes of OTSCs. METHODS: From January 2011 to December 2020, 139 consecutive patients with SNADETs who underwent ESD followed by OTSC closure in five institutions were extracted in this retrospective study. The primary endpoint was the rate of postoperative AEs after prophylactic OTSC closure. The secondary endpoints were the complete closure rate, residual rate, and long-term AEs associated with residual OTSCs. RESULTS: The rate of complete closure of the mucosal defect was 97.3% (142) in 146 SNADETs, which were completely resected by ESD. Postoperative AEs, including delayed bleeding, delayed perforation, and localized peritonitis, occurred in 6.2%, 3.4%, and 2.1% of patients, respectively; however, all of the cases improved without surgical treatment. In the multivariate logistic regression analysis, the use of two or more OTSCs was a significant independent risk factor for postoperative AEs (odds ratio, 2.94; 95% confidence interval, 1.02-8.46; P = 0.046). The residual OTSC rate was 46.4% at 1 year postoperatively, and long-term AEs included duodenal erosions and ulcers associated with residual OTSCs. CONCLUSIONS: Prophylactic closure with OTSCs after duodenal ESD can provide acceptable short-and long-term outcomes for preventing postoperative AEs. However, multiple OTSCs were the independent risk factors of postoperative AEs due to the gaps between and near the OTSCs.

Comparison of 22-gauge standard and Franseen needles in EUS-guided tissue acquisition for diagnosing solid pancreatic lesions: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: This large multicenter randomized controlled trial compared the diagnostic yields of 22-gauge standard and 22-gauge Franseen needles for EUS-guided tissue acquisition (EUS-TA) of solid pancreatic lesions. METHODS: Consecutive patients with solid pancreatic lesions were prospectively randomized to EUS-TA using standard or Franseen needles. Samples obtained with the first needle pass and with second and subsequent passes were evaluated separately. The primary endpoint was the rate of accuracy for diagnosis of malignancy. Other endpoints were technical success rate, sample cellularity, adverse events, diagnostic accuracy in patient subgroups, and the diagnostic accuracy and numbers of second and subsequent needle passes. RESULTS: Of 523 patients undergoing EUS-TA, 260 were randomized to using standard 22-gauge needles and 263 to 22-gauge Franseen needles. The technical success rate in each group was 99.6%, with similar adverse event rates in the standard (1.5%) and Franseen (.8%) needle groups. First-pass EUS-TA using the Franseen needle resulted in significantly greater diagnostic accuracy (84.0% vs 71.2%, P < .001) and sensitivity (82.4% vs 66.7%, P < .001) than first-pass EUS-TA using a standard needle and also resulted in superior diagnostic accuracy in patients requiring immunostaining. Second and subsequent EUS-TA using Franseen needles showed significantly greater accuracy (94.7% vs 90.0%, P = .049) and sensitivity (94.0% vs 88.6%, P = .047) and required fewer needle passes (1.81 vs 2.03, P = .008) than using standard needles. CONCLUSIONS: EUS-TA with the Franseen needle is superior to EUS-TA with a standard needle with respect to diagnostic accuracy per pass, particularly in patients who require immunostaining, and number of passes when using macroscopic on-site evaluation. (Clinical trial registration numbers: UMIN000030634 and jRCTs052180062.).

Performance of perioperative antibiotics against post-endoscopic submucosal dissection coagulation syndrome: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: This study aimed to evaluate the efficacy of perioperative antibiotics against post-endoscopic submucosal dissection (ESD) coagulation syndrome (PECS) in patients undergoing colorectal ESD. METHODS: A prospective, multicenter, randomized controlled, parallel, superiority trial was conducted at 21 Japanese tertiary institutions. Patients with superficial colorectal lesions ≥20 mm and those undergoing ESD management for a single lesion were eligible. Patients with perforation during and after ESD were withdrawn. Before the ESD procedure, participants were randomly assigned (1:1) to either undergo conventional treatment (nonantibiotic group) or investigational treatment (antibiotic group). In the antibiotic group, 3 g of ampicillin-sulbactam was administered just before, 8 hours after, and the morning after ESD. The primary endpoint was the incidence of PECS. The onset of PECS was defined as localized abdominal pain (both spontaneous pain and tenderness) and fever (≥37.6°C) or inflammatory response (leukocytosis [≥10,000 cells/µL] or elevated C-reactive protein level [≥.5 mg/dL]). RESULTS: From February 5, 2019 to September 7, 2020, 432 patients were enrolled and assigned to the antibiotic group (n = 216) or nonantibiotic group (n = 216). After withdrawal of 52 patients, 192 in the antibiotic group and 188 in the nonantibiotic group were analyzed. PECS occurred in 9 of 192 patients (4.7%) in the antibiotic group and 14 of 188 patients (7.5%) in the nonantibiotic group, with an odds ratio of .61 (95% confidence interval, .23-1.56; P = .29). CONCLUSIONS: Perioperative use of antibiotics was not effective in reducing the incidence of PECS in patients undergoing colorectal ESD. (Clinical trial registration number: UMIN000035178.).

Signal Detection of Potential Hepatotoxic Drugs: Case-Control Study Using Both a Spontaneous Reporting System and Electronic Medical Records.

Drug-induced liver injury (DILI) is a common adverse drug event. Spontaneous reporting systems such as the Japanese Adverse Event Report Database (JADER) have been used to evaluate the association between drugs and adverse drug events. However, the association of drugs with adverse drug events may be overestimated due to reporting biases. Therefore, it is important to objectively evaluate the association using liver function test values. The aim of the present study was to predict potential hepatotoxic drugs using real-world data including electronic medical records and the JADER database. A total of 70009 (2779 with DILI and 67230 without DILI) and 438515 (10235 with DILI and 428280 without DILI) Japanese adult patients were extracted from electronic medical records and the JADER database, respectively. Drugs with ≥100 DILI patients in both of the two databases were regarded as suspected drugs for DILI. We used multivariate logistic regression to evaluate the association between the suspected drugs and increased risk of DILI. Among the suspected drugs, broad-spectrum antibiotics such as meropenem, tazobactam/piperacillin and ceftriaxone were significantly associated with an increased risk of DILI, and meropenem had a greater risk of DILI in both of the two databases. Additionally, there were significant associations of mosapride and L-carbocisteine with increased risk of DILI. In addition to well-known associations between antibiotic drugs and DILI, mosapride and L-carbocisteine were found to be new potential signals of drugs causing hepatotoxicity. This study indicates potential hepatotoxic drugs that require further causality assessment.

Continuous Anticoagulation and Cold Snare Polypectomy Versus Heparin Bridging and Hot Snare Polypectomy in Patients on Anticoagulants With Subcentimeter Polyps: A Randomized Controlled Trial.

Background: Management of anticoagulants for patients undergoing polypectomy is still controversial. Cold snare polypectomy (CSP) is reported to cause less bleeding than hot snare polypectomy (HSP). Objective: To compare outcomes between continuous administration of anticoagulants (CA) with CSP (CA+CSP) and periprocedural heparin bridging (HB) with HSP (HB+HSP) for subcentimeter colorectal polyps. Design: Multicenter, parallel, noninferiority randomized controlled trial. (University Hospital Medical Information Network Clinical Trials Registry: UMIN000019355). Setting: 30 Japanese institutions. Patients: Patients receiving anticoagulant therapy (warfarin or direct oral anticoagulants) who had at least 1 nonpedunculated subcentimeter colorectal polyp. Intervention: Patients were randomly assigned to undergo HB+HSP or CA+CSP and followed up 28 days after polypectomy. Measurements: The primary end point was incidence of polypectomy-related major bleeding (based on the incidence of poorly controlled intraprocedural bleeding or postpolypectomy bleeding requiring endoscopic hemostasis). The prespecified inferiority margin was -5% (CA+CSP vs. HB+HSP). Results: A total of 184 patients were enrolled: 90 in the HB+HSP group, 92 in the CA+CSP group, and 2 who declined to participate after enrollment. The incidence of polypectomy-related major bleeding in the HB+HSP and CA+CSP groups was 12.0% (95% CI, 5.0% to 19.1%) and 4.7% (CI, 0.2% to 9.2%), respectively. The intergroup difference for the primary end point was +7.3% (CI, -1.0% to 15.7%), with a 0.4% lower limit of 2-sided 90% CI, demonstrating the noninferiority of CA+CSP. The mean procedure time for each polyp and the hospitalization period were longer in the HB+HSP than in the CA+CSP group. Limitation: An open-label trial assessing 2 factors (anticoagulation approach and polypectomy procedure type) simultaneously. Conclusion: Patients having CA+CSP for subcentimeter colorectal polyps who were receiving oral anticoagulants did not have an increased incidence of polypectomy-related major bleeding, and procedure time and hospitalization were shorter than in those having HB+HSP. Primary Funding Source: Japanese Gastroenterological Association.

A comparison of the resection rate for cold and hot snare polypectomy for 4-9 mm colorectal polyps: a multicentre randomised controlled trial (CRESCENT study).

OBJECTIVE: To investigate the success rate of cold snare polypectomy (CSP) for complete resection of 4-9 mm colorectal adenomatous polyps compared with that of hot snare polypectomy (HSP). DESIGN: A prospective, multicentre, randomised controlled, parallel, non-inferiority trial conducted in 12 Japanese endoscopy units. Endoscopically diagnosed sessile adenomatous polyps, 4-9 mm in size, were randomly assigned to the CSP or HSP group. After complete removal of the polyp using the allocated technique, biopsy specimens from the resection margin after polypectomy were obtained. The primary endpoint was the complete resection rate, defined as no evidence of adenomatous tissue in the biopsied specimens, among all pathologically confirmed adenomatous polyps. RESULTS: A total of 796 eligible polyps were detected in 538 of 912 patients screened for eligibility between September 2015 and August 2016. The complete resection rate for CSP was 98.2% compared with 97.4% for HSP. The non-inferiority of CSP for complete resection compared with HSP was confirmed by the +0.8% (90% CI -1.0 to 2.7) complete resection rate (non-inferiority p<0.0001). Postoperative bleeding requiring endoscopic haemostasis occurred only in the HSP group (0.5%, 2 of 402 polyps). CONCLUSIONS: The complete resection rate for CSP is not inferior to that for HSP. CSP can be one of the standard techniques for 4-9 mm colorectal polyps. (Study registration: UMIN000018328).

The Clinical Features of Recurrent Endometrial Cancer in Japan: Chemotherapy Instead of Radiotherapy as Postoperative Adjuvant Treatment.

OBJECTIVE: Chemotherapy is a standard adjuvant treatment after primary surgery for endometrial cancer in Japan. We aimed to characterize the clinical features of recurrent endometrial cancer (REC) patients in Japan. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 112 REC patients who were primarily treated at 1 of 3 university hospitals in Japan from 2005 to 2012. We analyzed overall survival since the first recurrence (R-OS) in accordance with several factors. RESULTS: Median patient age was 64 years. The median follow-up period was 48 months. The distributions of cancer stage and histological subtype lacked distinctive features, and most patients had a high risk for recurrence at the time of the primary surgery. Although approximately 78% of patients received adjuvant chemotherapy, 85/112 patients (76%) experienced recurrence within 2 years after the initial treatment ended. For patients receiving adjuvant chemotherapy, regional lymph node (LN) and distant-site recurrence were more frequent (>40%) than vaginal or intra-abdominal recurrence. Median survival and 5-year R-OS were 27 months and 26.1%, respectively. The R-OS was significantly better for patients aged 65 years or older, those with negative peritoneal cytology at the time of primary surgery, those with recurrence within regional LN (eg, pelvic LN or para-aortic LN under the renal vein) and/or vagina, and those who underwent surgery and/or radiotherapy after recurrence. A multivariate analysis indicated that positive peritoneal cytology, a disease-free interval of less than 12 months, recurrent lesions in 2 or 3 areas, and treatment excluding surgery or radiotherapy were independent predictors of poor prognosis after recurrence. CONCLUSIONS: Adjuvant chemotherapy was insufficient to reduce the incidence of distant recurrence. The prognosis of patients recurred within regional LN and/or vagina was significantly better than that of patients with recurrence in other lesions because of treatment with surgery and/or radiotherapy. The disease-free interval was a significant prognostic factor for REC patients.

Comparative effect of fixed-dose combination tablets of candesartan cilexetil/amlodipine versus olmesartan medoxomil/azelnidipine on laboratory parameters in patients with hypertension: a retrospective cohort study.

We conducted a retrospective cohort study to evaluate and compare the long-term effects of two single-pill fixed-dose combinations (FDCs), candesartan/amlodipine and olmesartan/azelnidipine, on laboratory parameters in patients in routine clinical practice. We identified an equal number of new users (n = 182) of a candesartan/amlodipine (8/5 mg/day) FDC tablet (CAN/AML users) and a propensity-score matched cohort (n = 182) receiving an olmesartan/azelnidipine (20/16 mg/day) FDC tablet (OLM/AZ users). Generalized estimating equations were used to estimate and compare the effects of the drugs on serum levels of creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), uric acid, sodium, potassium, aspartate aminotransferase, and alanine aminotransferase levels up to 12 months after the start of study drug administration. There was a significant increase of serum creatinine level and a significant decrease of eGFR from the baseline period to during the exposure period in both CAN/AML and OLM/AZ users, and a significant increase of BUN level in CAN/AML users. However, there were no significant differences in the mean changes of laboratory parameters between CAN/AML and OLM/AZ users. Our findings suggested that the effects of CAN/AML and OLM/AZ on laboratory parameters, including an unfavorable effect on renal function, were similar at least during 1 year of administration.

Fully-sialylated alpha-chain of complement 4-binding protein: Diagnostic utility for ovarian clear cell carcinoma.

OBJECTIVE: While a certain fraction of endometriomas can develop de novo epithelial ovarian cancer (EOC) such as clear cell carcinoma (OCCC), there is currently no useful biomarker available for early detection of OCCC from endometriomas. The aim of this study was to describe the diagnostic utility of a novel biomarker for EOC especially for OCCC to distinguish from endometrioma. METHODS: More than 100,000 glycan structures of serum glycoproteins obtained from 134 pretreatment all stage EOC patients (including 45 OCCCs) and 159 non-cancer control women (including 36 endometriomas) were explored for a mass spectrum approach. Diagnostic accuracy of identified biomarker was compared to the one of CA-125 by comparing area under curve (AUC) and positive/negative predictive values (PPV and NPV). RESULTS: A2160, a fully-sialylated alpha-chain of complement 4-binding protein, was identified as a candidate target marker. A2160 was significantly elevated in all stages of OCCC compared to with endometriomas. Diagnostic accuracy of A2160 (cutoff 1.6U/mL) to distinguish early stage OCCC from endometrioma is significantly higher than that of CA-125 (cutoff 35IU/L): AUC for A2160 versus CA-125, 0.92 versus 0.67; PPV 95% versus 64%; and NPV 85% versus 58%. In addition, fully-sialylated glycans had a higher accuracy for diagnosing EOC as compared to partially-sialylated glycans of alpha-chain of complement 4-binding protein. CONCLUSION: Our study suggested that A2160 may be a useful biomarker to distinguish early-stage OCCC from endometrioma. This new biomarker can be potentially applied for the monitoring of endometrioma patients, making possible the early diagnosis of OCCC.

Water immersion colonoscopy facilitates straight passage of the colonoscope through the sigmoid colon without loop formation: randomized controlled trial.

BACKGROUND AND AIM: One of the major causes of pain during colonoscopy is looping of the instrument during insertion through the sigmoid colon, which causes discomfort by stretching the mesentery. There are many studies in colonoscope techniques, but they have not been assessed objectively with respect to colonoscope passage through the sigmoid colon without loop formation. The aim of the present study was to determine whether cap-fitted colonoscopy and water immersion increase the success rate of insertion through the sigmoid without loop formation. METHODS: A total of 1005 patients were randomized to standard colonoscopy, cap-fitted colonoscopy or water immersion technique. All examinations were carried out under a magnetic endoscope imaging device. Main outcome was the success rate of insertion without loop formation. RESULTS: Success rate of insertion without loop formation was 37.5%, 40.0%, and 53.8% in the standard, cap, and water groups, respectively (standard vs water P = 0.00014, cap vs water P = 0.00186). There were no significant differences among the groups regarding cecal intubation rate, cecal intubation time and number of polyps ≥5 mm per patient. CONCLUSIONS: Water immersion increases the success rate of insertion through the sigmoid colon without loop formation. This practical technique, requiring only preparation of a cap and water, is useful without compromising cecal intubation rate, cecal intubation time, or polyp detection rate.

Comparative effect of clopidogrel and aspirin versus aspirin alone on laboratory parameters: a retrospective, observational, cohort study.

BACKGROUND: Clopidogrel and aspirin are antiplatelet agents that are recommended to reduce the risk of recurrent stroke and other cardiovascular events. Combination therapy of clopidogrel and aspirin has been shown to increase the risk of hemorrhage, but the effects of the drugs on laboratory parameters have not been well studied in patients in routine clinical practice. Therefore, we evaluated and compared the effects of combination therapy with clopidogrel plus aspirin and aspirin monotherapy on laboratory parameters using a clinical database. METHODS: We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between November 2004 and April 2011, to identify cohorts of new users (n = 159) of clopidogrel (75 mg/day) plus aspirin (100 mg/day) and new users (n = 834) of aspirin alone (100 mg/day). We used a multivariable regression model and regression adjustment with the propensity score to adjust for differences in baseline covariates between settings, and compare the mean changes in serum levels of creatinine, aspartate aminotransferase, alanine aminotransferase and hematological parameters, including hemoglobin level, hematocrit, and white blood cell (WBC), red blood cell and platelet counts up to two months after the start of study drug administration. RESULTS: After adjustment, the reduction of WBC count in clopidogrel plus aspirin users was significantly greater than that in aspirin alone users. All other tests showed no statistically significant difference in the mean change from baseline to during the exposure period between clopidogrel plus aspirin users and aspirin alone users. The combination of clopidogrel and aspirin increased the risk of gastrointestinal bleeding compared with aspirin alone, with a relative risk ranging from 2.06 (95% CI, 1.02 to 4.13; p = 0.043) for the multivariate model and 2.61 (95% CI, 1.18 to 5.80; p = 0.0184) for propensity adjustment. CONCLUSION: Our findings suggested that hematological adverse effects may be greater with combination therapy of clopidogrel plus aspirin than with aspirin monotherapy.

Comparative effect of angiotensin II type I receptor blockers on serum uric acid in hypertensive patients with type 2 diabetes mellitus: a retrospective observational study.

BACKGROUND: Angiotensin II type 1 receptor blockers (ARB) are a frequently used class of antihypertensive drug. The ARB losartan is known to decrease the serum uric acid (SUA) level. However, there are very few clinical data comparing the effects of other ARBs on SUA level under the conditions of clinical practice. This study evaluated and compared the long-term effects of monotherapy with five ARBs on SUA level in Japanese hypertensive patients with type 2 diabetes mellitus (DM). METHODS: We identified hypertensive patients with type 2 DM who had been treated with monotherapy with losartan (n = 214), valsartan (n = 266), telmisartan (n = 185), candesartan (n = 458), or olmesartan (n = 192), in whom laboratory data of SUA between November 1, 2004 and July 31, 2011 were available, from the Nihon University School of Medicine's Clinical Data Warehouse (NUSM's CDW). We used a propensity-score weighting method and a multivariate regression model to adjust for differences in the background among ARB users, and compared the SUA level. The mean exposure of losartan was 264.7 days, valsartan 245.3 days, telmisartan 235.9 days, candesartan 248.9 days, and olmesartan 234.5 days. RESULTS: In losartan users, mean SUA level was significantly decreased from baseline, while it was conversely increased in users of other ARBs; valsartan, telmisartan, candesartan, and olmesartan. The mean reduction of SUA level from baseline was significantly greater in losartan users compared with that in other ARB users. Comparison of ARBs other than losartan showed no significant difference in mean change in SUA level from baseline. CONCLUSIONS: Our study showed that losartan had the most beneficial effect on SUA level among five ARBs, and that there was no significant difference in the unfavorable effects on SUA level among four ARBs other than losartan, at least during one year. These findings provide evidence of an effect of ARBs on SUA level, and support the benefit of the use of losartan in hypertensive patients with type 2 DM.