Structure-Activity Relationship Analysis of Fluoxetine for Suppression of Inflammatory Cytokine Production.

There is accumulating evidence that selective serotonin reuptake inhibitors (SSRIs), clinically used as antidepressants, have a beneficial effect on inflammatory diseases such as coronavirus disease 2019 (COVID-19). We previously compared the inhibitory effects of five U.S. Food and Drug Administration (FDA)-approved SSRIs on the production of an inflammatory cytokine, interleukin-6 (IL-6), and concluded that fluoxetine (FLX) showed the most potent anti-inflammatory activity. Here, we investigated the structure-activity relationship of FLX for anti-inflammatory activity towards J774.1 murine macrophages. FLX suppressed IL-6 production induced by the TLR3 agonist polyinosinic-polycytidylic acid (poly(I : C)) with an IC50 of 4.76 µM. A derivative of FLX containing chlorine instead of the methylamino group lacked activity, suggesting that the methylamino group is important for the anti-inflammatory activity. FLX derivatives bearing an N-propyl or N-(pyridin-3-yl)methyl group in place of the N-methyl group exhibited almost the same activity as FLX. Other derivatives showed weaker activity, and the N-phenyl and N-(4-trifluoromethyl)benzyl derivatives were inactive. The chlorine-containing derivative also lacked inhibitory activity against TLR9- or TLR4-mediated IL-6 production. These derivatives showed similar structure-activity relationships for TLR3- and TLR9-mediated inflammatory responses. However, the activities of all amino group-containing derivatives against the TLR4-mediated inflammatory response were equal to or higher than the activity of FLX. These results indicate that the substituent at the nitrogen atom in FLX strongly influences the anti-inflammatory effect.

Cost-effectiveness analysis of single colonoscopy versus single fecal test for colorectal cancer diagnosis and treatment.

BACKGROUND AND AIM: Regular endoscopy or fecal immunochemical test (FIT) is ideal for screening colorectal cancer. However, only a limited number of individuals undergo regular screening. This study aimed to compare the cost-effectiveness of a single colonoscopy with a single FIT performed for colorectal cancer screening. METHODS: A microsimulation model was constructed based on real-world observational data collected from three institutions between 2019 and 2022 that compared colonoscopy-based screening with FIT-based screening. The total costs of diagnosis and treatment of the detected lesions using the two strategies were calculated. The incremental cost-effectiveness ratio (ICER) per life year gained (LYG) of the colonoscopy-based strategy was calculated. RESULTS: Data from 11 407 patients undergoing colonoscopies and 59 176 patients undergoing FITs were used to establish a model. In the base case analysis of screening strategies, colonoscopy was more cost-effective than FIT (ICER 415 193 yen/LYG). The ICER of the colonoscopy-based strategy among 60- to 69-year-old patients was lowest at 394 200 yen/LYG, whereas that in 20- to 29-year-old patients was highest. Monte Carlo simulations showed that the colonoscopy-based strategy was more cost-effective than the FIT-based strategy (net monetary benefit [NMB]: 5 695 957 yen vs 5 348 253 yen). When the adenoma detection rate in the colonoscopy was over 30% or the positive FIT rate was lower than 8.6% in the FIT-based strategy, the NMB of the colonoscopy-based strategy exceeded that of the FIT-based strategy. CONCLUSION: In the microsimulation model, colonoscopy is recommended as a one-time screening procedure in patients aged >60 years with >30% ADR or <8.6% positive FIT rate.

An algorithm-based active cleansing protocol can reduce the bowel preparation time for screening colonoscopy: A propensity score matching study.

BACKGROUND: Methods that minimize the time for on-site bowel preparation before colonoscopy are needed. We prospectively validated that a novel algorithm-based active cleansing (ABAC) protocol could reduce the time for preparation compared with the conventional method. METHODS: This was an open-label, multicenter, prospective comparative study from April to October 2021. The study compared the bowel preparation time for colonoscopy between patients instructed with the ABAC protocol and control groups. Patients in the ABAC protocol group as well as the control group were administered 2000 mL of polyethylene glycol (PEG) within 2 hours. After the first two hours, patients in the protocol group voluntarily took 300 ml of the solution without the instruction of nursing staff depending on the number of defecations in the first 2 hours. The intervention and control groups were adjusted for background characteristics by propensity score matching (PSM). RESULTS: After adjustment by PSM, 174 patients in each of the two groups were included in the final analysis. In the intention-to-treat analysis, the preparation time was significantly shorter in the intervention group than that in the control group (126.3 ± 32.7 min vs. 144.9 ± 39.9 min, P = 0.018). The proportion of additional PEG intake was significantly higher in the intervention group (16 [9.2%] vs. 6 [3.4%], P = 0.047). The number of defecations was also higher in the intervention group than in the control group (7.8 ± 2.5 vs. 6.3 ± 2.2, P = 0.001). CONCLUSIONS: Simple active instruction protocol is effective to reduce on-site bowel preparation time and nursing staff labor for colonoscopy.

Pre-administration of super-low volume polyethylene glycol is as effective as senna laxative as bowel preparation for colonoscopy: a randomized controlled phase 2 trial.

BACKGROUND AND PURPOSE: Senna laxatives are commonly used for bowel preparation before colonoscopies in Japan. However, this laxative frequently causes complications such as abdominal pain. This study aimed to establish a novel method of bowel preparation, which involved the pre-administration of super-low volume polyethylene glycol (PEG) for three days followed by the same-day administration of low volume PEG. METHODS: This study was a prospective, multicenter, investigator-blinded, phase 2, randomized control trial. The intake of 13.9 g (120 mL) of PEG or 1 g of a senna laxative for 3 days before the examination was indicated for each group, and 2 L of PEG solution was used for preparation on the examination day. The primary endpoint was the efficacy of bowel cleansing, as assessed by the Boston bowel preparation scale. The secondary endpoints were the adenoma detection rate and occurrence of complications. RESULTS: A total of 250 patients were initially enrolled. A total of 122 patients from each group were included in the intention-to-treat analysis. In the intention-to-treat analysis, the responder rates were the same for the two groups (56.6% vs 50.8%). Additionally, the adenoma detection rate did not differ between the two groups (34.9% vs 41.8%, P = 0.3795). In contrast, adherence was higher in the PEG group (93.4% vs 82.8%, P = 0.0101), and the occurrence of complications was lower in the PEG group (1.7% vs 16.4%, P = 0.0001). CONCLUSION: The novel super-low volume PEG method for bowel preparation was as effective as the conventional method with senna laxatives.

Quality management system for screening esophagogastroduodenoscopy improves detection of Helicobacter pylori -negative interval gastric cancer.

Background and study aims Double-checking the findings of examinations is necessary for endoscopy quality control in gastric cancer screening; however, there have been no reports showing its effectiveness. We prospectively analyzed the effectiveness of a quality management system (QMS) in endoscopy for gastric cancer screening. Patients and methods QMS was defined as having images and reports checked by a second endoscopist on the same day and reporting inconsistencies to the examining endoscopist. Patients diagnosed with early gastric cancer (EGC) in the 2 years before and after the introduction of QMS were divided into two groups: the interval cancer group, which included those for whom cancer was detected within 1 year of the last endoscopy and the noninterval cancer group. Changes in detection rates were compared. Results Before the introduction of QMS, 11 interval EGC cases were diagnosed among 36,189 endoscopies, whereas after the introduction, 32 interval ECG cases were diagnosed among 38,290 endoscopies ( P  = 0.004). Fifteen noninterval EGC cases were diagnosed before the introduction, while 12 noninterval EGC cases were diagnosed after the introduction; no significant difference was observed. Subanalyses by Helicobacter pylori (HP) infection status revealed no difference in the detection rate among HP-positive EGC patients, but the detection rates among HP-eradicated and HP-naïve EGC patients were improved ( P  = 0.005 and P  = 0.011). Logistic regression analysis showed that QMS was an independent predictor for detection of HP-negative interval EGC ( P  = 0.017, OR = 4.4, 95 % CI: 2.0-9.7). Conclusions QMS improved the detection rate for HP-negative interval early gastric cancer. (UMIN000042991).

Erratum: Quality management system for screening esophagogastroduodenoscopy improves detection of Helicobacter pylori -negative interval gastric cancer.

[This corrects the article DOI: 10.1055/a-1594-1833.].

Individual feedback and monitoring of endoscopist performance improves the adenoma detection rate in screening colonoscopy: a prospective case-control study.

BACKGROUND AND PURPOSE: Previous reports have suggested that a longer withdrawal time (WT) during colonoscopy led to an improved adenoma detection rate (ADR); however, there are few controlled studies that substantiated monitoring WT as an educational method. We aimed to validate a feedback and monitoring system to improve the ADR in screening colonoscopy in a prospective case-control setting. METHODS: After collecting data in the pre-feedback period (3.5 months), the individual performance and the average ADR and WT values of the facility were provided to 6 endoscopists in the intervention group, while 3 endoscopists were isolated as the control group during the feedback period (2 weeks). The intervention group consisted of two subgroups, the Fast and Slow WT groups, according to the results from the pre-feedback period. The endoscopists in the intervention group were instructed to be aware of their own WT in each examination during the post-feedback period (4 months). The performances of all endoscopists in the post-feedback period were analyzed and compared with those in the pre-feedback period. RESULTS: Among the initial analyses, the correlation analysis and multivariate analysis revealed that WT was an independent predictor for the ADR (P = 0.0101). After providing individual performance feedback and instruction regarding real-time WT monitoring, the WT was significantly prolonged in the Fast WT group (P = 0.0346) but did not change in the Slow WT and control groups. In addition, the ADR of the Fast WT group significantly improved after the intervention (P = 0.024), whereas the ADR of the Slow WT and control groups did not change. CONCLUSION: Providing individual feedback on ADR and WT and monitoring WT helped improve the endoscopists' ADRs.

Risk of progression to eosinophilic esophagitis in patients with asymptomatic esophageal eosinophilia: A retrospective pilot study.

BACKGROUND AND AIM: As the number of patients with eosinophilic esophagitis (EoE) has increased worldwide, the likelihood of diagnosing esophageal eosinophilia (EE) in screening endoscopy has also increased. Many of these EE patients do not display any symptoms (i.e. they display asymptomatic EE: aEE), and the risk of aEE patients developing EoE has yet to be demonstrated. METHODS: A total of 62 250 cases were found in the endoscopic registries of two digestive disease centers in the context of gastric cancer screening from April 2016 to August 2018, and these were reviewed. RESULTS: Thirty-seven aEE patients (0.059%) were found in the registries, and the histories of endoscopic findings and symptoms were successfully traced for 29 of them. While 11 aEE (37.9%) patients did not show any change in endoscopic findings, 18 (62.1%) exhibited exacerbation. A comparison of the two groups showed both relative youth and diffuse disease distribution to be independent risk factors for progression (P = 0.0034 and 0.0078, respectively). Of the 18 aEE patients whose findings showed progression, 6 developed EoE (5 (17.2%) developed proton-pump inhibitor (PPI)-responsive EoE, and only 1 (3.4%) developed PPI-resistant EoE). A comparison of the non-EoE and EoE groups showed relative youth to be an independent risk factor for progression to EoE (P = 0.0146). CONCLUSIONS: While some aEE patients developed symptomatic EE, the existence among them of PPI-resistant EoE was extremely rare. Younger age and diffuse disease distribution at first detection in endoscopic findings are risk factors for progression to symptomatic EE in aEE patients.

Quality Indicators for the Detection of Helicobacter pylori-Negative Early Gastric Cancer: A Retrospective Observational Study.

BACKGROUND/AIMS: While Helicobacter pylori (HP)-negative gastric cancer is frequently reported, little is known about the predictors for detecting HP-negative early gastric cancer (EGC). We aimed to evaluate the predictors for the detection of HP-negative EGC. METHODS: We retrospectively reviewed 13,477 consecutive asymptomatic cases where upper endoscopy was performed by nine physicians from April 2017 to March 2019 and analyzed the detection rate of high-risk lesions (HRLs), including EGC, tubular adenoma, and lymphoma, according to the status of HP infection. The observation time was corrected for multiple regression analyses. RESULTS: For all physicians, the average observation time for screening HP-eradicated and -naïve patients was shorter than that for screening HP-positive patients (p<0.05). Multiple regression analyses revealed that the observation time in the three groups was an independent predictor for detecting HRLs in HP-eradicated patients (p=0.03106, 0.01263, and 0.02485, respectively), while experience of endoscopy was an independent predictor for detecting HRLs in HP-naïve patients (p=0.02638). CONCLUSION: While observation time during screening endoscopy was a quality indicator for detecting HRLs in HP-eradicated patients, experience of endoscopy was a quality indicator for detecting HRLs in HP-naïve patients.

Influence of Helicobacter pylori Infection on Endoscopic Findings of Gastric Adenocarcinoma of the Fundic Gland Type.

PURPOSE: Gastric adenocarcinoma of the fundic gland type (chief cell predominant type) (GA-FG-CCP) was first reported as a rare adenocarcinoma found in the normal fundic mucosa. Recent studies have proposed the possibility that GA-FG-CCPs were also generated in the atrophic mucosa after Helicobacter pylori (HP) eradication therapy. However, little is known on the endoscopic findings of GA-FG-CCP generated in the atrophic mucosa due to its extreme rarity. MATERIALS AND METHODS: A total of 8 patients who underwent endoscopic submucosal resection and were diagnosed with GA-FG-CCP generated in the HP-uninfected mucosa (4 cases, HP-uninfected group) or HP-eradicated atrophic mucosa (4 cases, HP-eradicated group) were retrospectively analyzed, and their endoscopic findings, including magnifying endoscopy with narrow band imaging (M-NBI), and pathological features were compared. RESULTS: While GA-FG-CCPs in the 2 groups displayed similar macroscopic appearance, M-NBI demonstrated that characteristic microvessels (tapered microvessels like withered branches) were specifically identified in the HP-eradicated group. Pathological investigation revealed that a decreasing number of fundic glands and thinned foveolar epithelium covering tumor ducts were thought to lower the thickness of the covering layer over tumor ducts in the HP-eradicated group. Moreover, dilation of vessels just under the surface of the lesions contributed to the visualization of microvessels by M-NBI. CONCLUSIONS: The change in background mucosa due to HP infection influenced the thickness of the covering layer over the tumor ducts and M-NBI finding of GA-FG-CCP.

Hammock mitral valve in an adult patient.

We describe a case of hammock mitral valve in an adult. A 38-year-old woman presented with recently acquired dyspnea. Echocardiography showed severe mitral stenosis related to a hammock mitral valve characterized by the presence of an overdeveloped papillary muscle that gives short chordae to both mitral leaflets. No other valve insufficiency was noted. At operation, we observed direct continuity accompanying several fenestrations between both leaflets and the huge abnormal muscular band just underneath the mural leaflet. Resection of the anterior leaflet and was successfully replaced with a bioprosthetic valve. Her postoperative course was unremarkable.