Influence of liver stiffness heterogeneity on staging fibrosis in patients with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Despite that hepatic fibrosis often affects the liver globally, spatial distribution can be heterogeneous. This study aimed to investigate the effect of liver stiffness (LS) heterogeneity on concordance between MR elastography (MRE)-based fibrosis staging and biopsy staging in patients with NAFLD. APPROACH AND RESULTS: We retrospectively evaluated data from 155 NAFLD patients who underwent liver biopsy and 3 Tesla MRE and undertook a retrospective validation study of 169 NAFLD patients at three hepatology centers. Heterogeneity of stiffness was assessed by measuring the range between minimum and maximum MRE-based LS measurement (LSM). Variability of LSM was defined as the stiffness range divided by the maximum stiffness value. The cohort was divided into two groups (homogenous or heterogeneous), according to whether variability was below or above the average for the training cohort. Based on histopathology and receiver operating characteristic (ROC) analysis, optimum LSM thresholds were determined for MRE-based fibrosis staging of stage 4 (4.43, kPa; AUROC, 0.89) and stage ≥3 (3.93, kPa; AUROC, 0.89). In total, 53 had LSM above the threshold for stage 4. Within this group, 30 had a biopsy stage of <4. In 86.7% of these discordant cases, variability of LSM was classified as heterogeneous. In MRE-based LSM stage ≥3, 88.9% of discordant cases were classified as heterogeneous. Results of the validation cohort were similar to those of the training cohort. CONCLUSIONS: Discordance between biopsy- and MRE-based fibrosis staging is associated with heterogeneity in LSM, as depicted with MRE.

Real-world assessment of SmartExam, a novel FibroScan computational method: A retrospective single-center cohort study.

BACKGROUND AND AIM: SmartExam is a novel computational method compatible with FibroScan that uses a software called SmartDepth and continuous controlled attenuation parameter measurements to evaluate liver fibrosis and steatosis. This retrospective study compared the diagnostic accuracy of conventional and SmartExam-equipped FibroScan for liver stiffness measurement (LSM). METHODS: The liver stiffness and the associated controlled attenuation parameters of 167 patients were measured using conventional and SmartExam-Equipped FibroScan as well as reference methods like magnetic resonance elastography (MRE) and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) measurements to assess its diagnostic performance. M or XL probes were selected based on the probe-to-liver capsule distance for all FibroScan examinations. RESULTS: The liver stiffness and controlled attenuation parameter (CAP) correlation coefficients calculated from conventional and SmartExam-equipped FibroScan were 0.97 and 0.82, respectively. Using MRE/MRI-PDFF as a reference and the DeLong test for analysis, LSM and the area under the receiver operating characteristic curve for CAP measured by conventional and SmartExam-equipped FibroScan showed no significant difference. However, the SmartExam-equipped FibroScan measurement (33.6 s) took 1.4 times longer than conventional FibroScan (23.2 s). CONCLUSIONS: SmartExam has a high diagnostic performance comparable with that of conventional FibroScan. Because the results of the conventional and SmartExam-equipped FibroScan were strongly correlated, it can be considered useful for assessing the fibrosis stage and steatosis grade of the liver in clinical practice, with less variability but little longer measurement time compared with the conventional FibroScan.

Comparison of pancreatic enzyme abnormalities and protease-activated receptor-2-positive eosinophils in the duodenum of patients with functional dyspepsia-irritable bowel syndrome overlap with functional dyspepsia alone in Asian populations.

BACKGROUND AND AIM: Some patients with functional gastrointestinal disorders exhibit pancreatic dysfunctions and pancreatic enzyme abnormalities. Thus, we aimed to clarify whether significant differences in clinical characteristics, prevalence of pancreatic enzyme abnormalities, duodenal inflammation, and protease-activated receptor 2 (PAR2) expression levels related to hypersensitivity exist between functional dyspepsia (FD) alone and FD-irritable bowel syndrome (IBS) overlap group. METHODS: Ninety-three patients based on the Rome IV criteria, FD alone (n = 44) and FD overlapped with IBS (n = 49) group were enrolled. The patients scored their own clinical symptoms after consuming high-fat meals. Serum trypsin, PLA2, lipase, p-amylase, and elastase-1 levels were measured. PAR2, eotaxin-3, and TRPV4 mRNA levels in duodenum were determined using real-time polymerase chain reaction methods. PRG2- and PAR2 in the duodenum were evaluated using immunostaining. RESULTS: FD score and global GSRS in patients with FD-IBS overlap were significantly higher than FD alone. Although the prevalence of pancreatic enzyme abnormalities in patients with FD alone was significantly (P < 0.01) higher than that in FD-IBS overlap, the ratio of aggravation of clinical symptoms following high-fat intake in patients with FD-IBS overlap was significantly higher (P = 0.007) than that in patients with FD alone. PAR2- and PRG2-double positive cells were localized in the degranulated eosinophils in the duodenum of patients with FD-IBS overlap. The number of PAR2- and PRG2-double positive cells in FD-IBS overlap was significantly (P < 0.01) higher than FD alone. CONCLUSIONS: Pancreatic enzyme abnormalities and PAR2 expression on degranulated eosinophils infiltrations in the duodenum may be associated with the pathophysiology of patients with FD-IBS overlap in Asian populations.

Comparison of clinical characteristics, eating behaviors, and clinical symptoms following fat intake in functional dyspepsia with functional dyspepsia with pancreatic enzyme abnormalities between Singapore and Japan.

BACKGROUND AND AIM: To clarify whether there were any significant differences in clinical symptoms and eating patterns between functional dyspepsia (FD) patients and FD with pancreatic enzyme abnormalities (FD-P) patients as refractory FD, we compared these factors in multicenter studies in Singapore and Japan. METHODS: One hundred ninety-eight consecutive patients presenting with FD (n = 88), FD-P patients (n = 81) based on Rome III classification and controlled group (n = 39) recruited from six institutions in Singapore and Japan. Clinical characteristics, clinical symptoms for dietary fat intake, and eating behaviors were estimated using questionnaires. Anxiety and health-related quality of life were determined by STAI-state/-trait and SF-8, respectively. RESULTS: There were no significant differences in age, sex, BMI, smoking, alcohol intake, past medical history, and history of allergy in FD and FD-P patients between Singapore and Japan. There were no significant differences in FD subtypes, gastrointestinal symptom rating scale score, severity of FD symptoms, and eating pattern in Singapore and Japan. Moreover, there were significant differences in certain eating behaviors between FD and FD-P patients in Singapore and Japan. Interestingly, epigastric pain and early satiety following fat meals in FD-P patients were significantly (P = 0.003 and P = 0.008, respectively) higher compared with those in FD patients in Japan. Physical component score in FD-P patients was significantly (P = 0.019) disturbed compared with those in FD patients in Japan. CONCLUSIONS: Epigastric pain and early satiety following fat meals in FD-P patients may be useful tools to differentiate FD-P patients from FD patients in Japan.

Effects of colorectal endoscopic submucosal dissection on postoperative abdominal symptoms: a prospective observational study.

BACKGROUND: Endoscopic submucosal dissection (ESD) is an effective procedure to resect large superficial gastrointestinal neoplasms. In gastric ESD, several studies showed the relationship between postoperative abdominal symptoms and endoscopic treatment. However, the influence of colorectal ESD on abdominal symptoms after treatment is still unknown. To the best of our knowledge, this is the first prospective multicenter study performed to investigate the impact of colorectal ESD on postoperative abdominal symptoms. This study aimed to clarify the association between change of abdominal symptoms and ESD. METHODS: This study was a prospective multicenter observational trial that enrolled 141 out of 171 patients who underwent colorectal ESD and answered the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire from March 2015 to August 2019. We evaluated abdominal symptoms in the patients using the GSRS questionnaire before ESD and a few weeks after ESD. RESULTS: Comparing the GSRS before and after ESD, overall scores changed from 1.58 ± 0.58 to 1.48 ± 0.48, and the five subscales (reflux syndrome, abdominal pain, indigestion syndrome, diarrhea syndrome, and constipation syndrome) were slightly improved. Overall scores, indigestion syndrome, and constipation syndrome were statistically significantly different before and after ESD (P < 0.05). CONCLUSIONS: In GSRS, a score of ≥ 3 is often treated as a clinically significant symptom. Therefore, our findings indicated that there was no clinically significant difference. For this reason, colorectal ESD does not affect postoperative abdominal symptoms and is considered a minimally invasive treatment. The analysis of the impact of colon ESD on gastrointestinal symptoms UMIN000016914.

Learning Curve of Endoscopic Retrograde Cholangiopancreatography Using Single-Balloon Enteroscopy.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) in patients with surgically altered anatomy is technically difficult. Extensive training is required to develop the ability to perform this procedure. AIMS: To investigate the learning curve of single-balloon-assisted enteroscopy ERCP (SBE-ERCP). METHODS: We conducted a retrospective, observational case series at a single center. We evaluated the SBE-ERCP procedures between April 2011 and February 2021. The main outcomes were the rate of reaching the target site and the success rate of the entire procedure. These parameters were additionally expressed as a learning curve. RESULTS: A total of 687 SBE-ERCP procedures were analyzed. The learning curve was analyzed in blocks of 10 cases. In this study, seven endoscopists, experts in conventional ERCP, were included. The overall SBE-ERCP procedural success rate was 92.2% (634/687 cases). Combining all data from individual endoscopists' evaluation periods, the insertion and success rates of the SBE-ERCP procedures gradually increased with increased experience performing SBE-ERCP. The insertion success rates for the number of SBE-ERCP cases (< 20, 21-30, > 30) were 82.9%, 92.9%, and 94.3%, respectively; the procedure success rates were 74.3%, 81.4%, and 92.9%, respectively. The endoscopists who had performed > 30 SBE-ERCP cases had a success rate of ≥ 90%. CONCLUSIONS: Our results suggest that performing > 30 cases is one of the targets for conventional ERCP experts to become competent in performing SBE-ERCP in patients with a surgically altered anatomy.

Comparison of the diagnostic performance of NBI, Laser-BLI and LED-BLI: a randomized controlled noninferiority trial.

BACKGROUND AND AIMS: New image-enhanced endoscopy (IEE), blue Light Imaging (LED-BLI) is launched in USA and Europe, whereas Blue Laser Imaging (Laser-BLI) is available only Asian and some countries. No studies have directly compared the diagnostic accuracy of narrow band imaging (NBI), Laser-BLI and LED-BLI for colorectal tumors. The present study aimed to compare the diagnostic accuracy of the three methods for colorectal tumor using the NBI international colorectal endoscopic (NICE) classification and the Japanese NBI Expert Team (JNET) classifications. METHODS: This was a multi-center evaluator-blinded, randomized control trial of patients who underwent endoscopic colorectal tumor resection. The patients were randomly assigned to NBI, Laser-BLI or LED-BLI. Cropped images were sent to blinded external evaluators and diagnosed according to NICE and JNET classifications. The diagnostic accuracy of each endoscopy system was compared with non-inferiority test. RESULTS: A total of 619 colonic tumors were resected from 230 patients and evaluated by external four evaluators. The diagnostic accuracy of NBI for NICE 1, NICE 2, NICE 3 was 90.6%, 90.3% and 99.5%, respectively and for JNET 1, JNET 2A, JNET 2B and JNET 3, it was 94.6%, 72.0%, 79.2% and 99.1%, respectively. In non-inferiority test, Laser-BLI and LED-BLI revealed non-inferiority to NBI in all NICE and JNET categories (p<0.001). CONCLUSIONS: Laser-BLI and LED-BLI had high diagnostic accuracy and non-inferiority of NBI, especially for hyperplastic polyp/sessile serrated lesion and low-grade dysplasia. This is first trial to compare the diagnostic accuracy with NBI, Laser-BLI and LED-BLI and useful to understand the position of each IEE. This trial was registered as UMIN000032107.

Severe acute respiratory syndrome coronavirus 2 prevalence in saliva and gastric and intestinal fluid in patients undergoing gastrointestinal endoscopy in coronavirus disease 2019 endemic areas: Prospective cross-sectional study in Japan.

OBJECTIVES: Gastrointestinal endoscopy (GIE) is useful for the early detection and treatment of many diseases; however, GIE is considered a high-risk procedure in the coronavirus disease 2019 (COVID-19) pandemic era. This study aimed to explore the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity in saliva and gastrointestinal fluids to which endoscopy medical staff are exposed. METHODS: The study was a single-center cross-sectional study. From June 1 to July 31, 2020, all patients who underwent GIE at Yokohama City University Hospital were registered. All patients provided 3 mL of saliva. For upper GIE, 10 mL of gastric fluid was collected through the endoscope. For lower GIE, 10 mL of intestinal fluid was collected through the endoscope. The primary outcome was the positive rate of SARS-CoV-2 in saliva and gastrointestinal fluids. We also analyzed serum-specific antibodies for SARS-CoV-2 and patients' background information. RESULTS: A total of 783 samples (560 upper GIE and 223 lower GIE samples) were analyzed. Polymerase chain reaction (PCR) on saliva samples did not show any positive results in either upper or lower GIE samples. However, 2.0% (16/783) of gastrointestinal fluid samples tested positive for SARS-CoV-2. No significant differences in age, sex, purpose of endoscopy, medication, or rate of antibody test positivity were found between PCR positive and PCR negative cases. CONCLUSIONS: Asymptomatic patients, even those with no detectable virus in their saliva, had SARS-CoV-2 in their gastrointestinal tract. Endoscopy medical staff should be aware of infection when performing procedures. The study was registered as UMIN000040587.

Elobixibat Effectively Relieves Chronic Constipation in Patients with Cancer Regardless of the Amount of Food Intake.

BACKGROUND: Constipation is a common, distressing complication in patients with cancer receiving palliative care. Elobixibat is a novel inhibitor of the ileal bile acid transporter that is used to treat chronic constipation by stimulating bowel function. However, its efficacy in patients with cancer has not been examined. This study investigated the drug's effectiveness in patients with cancer with chronic constipation. PATIENTS AND METHODS: This prospective-sampling, single-center, observational study included hospitalized patients with cancer diagnosed, using the Rome IV criteria, with chronic constipation. Within 2 weeks of hospitalization, each participant was administered elobixibat (5-15 mg) daily until discharge. Spontaneous bowel movements (SBMs), complete spontaneous bowel movements (CSBMs), Bristol stool form scale (BSFS) scores, and the Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL) scores were assessed before and after elobixibat administration. We also evaluated the relationship between the amount of food consumed and the SBM frequency. RESULTS: Among the 83 participants, the mean pre- and post-treatment frequencies of daily SBMs were 0.3 and 1.2 (p < .0001) and those of CSBMs were 0.1 and 0.6 (p < .0001), respectively. The mean pretreatment BSFS score was 1.6, whereas the post-treatment value was 3.5 (p < .0001); the mean PAC-QOL score (overall) improved from 1.01 to 0.74 (p = .01). There was no significant change in the daily SBM frequency between fasting and feeding states (1.2 vs. 1.3; p = .8), and there was no correlation between the amount of food intake and the SBM frequency after elobixibat administration (r = .03). Serious adverse events were not observed. CONCLUSION: This study showed that elobixibat is safe and effective for patients with cancer with chronic constipation, regardless of the food intake amount. IMPLICATIONS FOR PRACTICE: Elobixibat was effective at relieving chronic constipation in patients with various cancers. Serious adverse events were not observed, and the relief of constipation was independent of variation in food intake.

Endoscopic submucosal dissection of large pedunculated polyps with wide stalks: a retrospective multicenter study.

BACKGROUND: Endoscopic resection of large pedunculated colorectal polyps is technically difficult, especially when the polyp is large and has such a thick stalk that it is either too difficult or impossible to resect prophylactically by a conventional snare. Here, we evaluated the feasibility of ESD for large pedunculated polyps with wide stalks. METHODS: 29 patients with large pedunculated polyps that were not resectable by polypectomy or endoscopic mucosal resection were enrolled in the study. RESULTS: En bloc resection was achieved in 28/29 polyps. One suspended case was due to severe fibrosis with muscle retraction signs. The mean diameter of the 29 polyp heads was 39.7 (standard deviation 6.9) mm. Submucosal fibrosis was present in 16 polyps (9 mild; 7 severe). The stalks of severely fibrotic polyps were significantly thicker than those of polyps with no or mild fibrosis. The curative resection rate was 85.7 % without severe complications. CONCLUSIONS: ESD is feasible for the removal of large pedunculated polyps with wide stalks when conventional snare resection is difficult or impossible.

Impact of obesity in colorectal endoscopic submucosal dissection: single-center retrospective cohort study.

BACKGROUND: When performing colorectal endoscopic submucosal dissection (ESD) in obese patients, technically difficult cases are sometimes experienced because of difficulty with the insertion of the colonoscope, poor scope maneuverability, or an abundance of fat tissue in the submucosal layer. Since the association between obesity and colorectal ESD has not been investigated, we evaluated the clinical impact of obesity in patients who underwent colorectal ESD. METHODS: We retrospectively reviewed 535 patients who underwent colorectal ESD between April 2012 and February 2019. Patients were divided into three groups based on their body mass index (BMI): a control group (BMI < 25 kg/m2), an overweight group (25 kg/m2 ≤ BMI < 30 kg/m2), and an obese group (BMI ≥ 30 kg/m2), and the short-term clinical outcomes were analyzed to assess the safety and difficulty of colorectal ESD. RESULTS: No significant difference in the procedure times, en bloc resection rates, pathological diagnoses, or complications were seen among the groups. While the amount of sedative per body weight was significantly lower in the group with a higher BMI (flunitrazepam: 1.75 × 10-2 [1.27 × 10-2-2.34 × 10-2] mg/kg vs. 1.48 × 10-2 [1.08 × 10-2-2.03 × 10-2] mg/kg vs. 1.16 × 10-2 [0.98 × 10-2-1.54 × 10-2] mg/kg, P < 0.001; pethidine: 0.63 [0.55-0.72] mg/kg vs. 0.50 [0.46-0.56] mg/kg vs. 0.39 [0.32-0.45] mg/kg, P < 0.001), a reduction in percutaneous arterial oxygen saturation occurred significantly more frequently in the group with a higher BMI (123 [30.2%] vs. 43 [43.9%] vs. 10 [55.6%], P = 0.005). When the procedures were performed by trainees, the number of cases that required a procedure time of longer than 90 min was significantly larger in the group with a higher BMI (27 [10.8%] vs. 14 [21.9%] vs. 3 [25.0%], P = 0.033). CONCLUSIONS: This study showed that colorectal ESD could be performed safely and effectively in obese patients. However, ESD in obese patients requires attention, particularly to changes in respiratory conditions.

Efficacy of sedation with dexmedetomidine plus propofol during esophageal endoscopic submucosal dissection.

BACKGROUND AND AIM: During endoscopic submucosal dissection for superficial esophageal cancer, patient body movement can sometimes occur, which may cause discontinuation of the procedure. Propofol and dexmedetomidine have recently been found to be useful sedatives for endoscopic submucosal dissection. This study investigated whether sedation using propofol plus dexmedetomidine can suppress the patient's body movements during esophageal endoscopic submucosal dissection and compared this combination with sedation using propofol alone. METHODS: This was a prospective double-blind randomized controlled trial. Patients with superficial esophageal cancers who underwent esophageal endoscopic submucosal dissection at Yokohama City University Hospital were prospectively enrolled and were randomly assigned to the propofol and the propofol plus dexmedetomidine groups. The primary endpoint was the incidence of restlessness. The secondary endpoints were the satisfaction score, maintenance dose of propofol, and number of rescue propofol injections. RESULTS: Sixty-six patients (propofol group: n = 33; combination group: n = 33) were included. The combination group had a significantly lower incidence of restlessness than the propofol group (3.0% vs 27.3%, P = 0.02). In the combination group, the satisfaction scores of the endoscopists were significantly higher, the maintenance dose of propofol was significantly lower, and the number of rescue propofol injections was lower than those in the propofol group (3.0% vs 18.2%, P < 0.001). Although the incidence of bradycardia was significantly higher in the combination group (30.3% vs 3.0%, P < 0.01), no serious adverse effects occurred. CONCLUSION: The propofol plus dexmedetomidine combination provided excellent sedation that effectively suppressed the patient's body movements during esophageal endoscopic submucosal dissection.

Relationship between Stool Form and Quality of Life in Patients with Chronic Constipation: An Internet Questionnaire Survey.

INTRODUCTION: Chronic constipation (CC) is a highly prevalent functional bowel disorder with low treatment satisfaction and impaired quality of life (QOL). However, physicians tend to emphasize only "stool frequency," and relationship between "stool form" and QOL remains unclear. In this study, we aimed to investigate the actual situation of CC treatment in Japan and elucidate the relationship between stool form and QOL in patients with CC. METHODS: We conducted an online questionnaire survey in September 2018 targeting Japanese adult patients already diagnosed with CC and taking prescribed drugs. Assessments included the type of drug treatment, treatment duration, frequency of drug use, frequency of bowel movements (BMs), Bristol Stool Form Scale (BSFS), and Japanese version of the Patient Assessment of Constipation QOL (PAC-QOL) scores. Relationship between BSFS and Japanese PAC-QOL scores was analyzed, and most important factor that influences QOL was investigated. RESULTS: A total of 614 subjects were enrolled. Of these, 398 (64.8%) regularly used magnesium oxide and 162 (26.4%) used stimulant laxative, especially 81 (50.0%) used stimulant laxative "everyday." Mean score of the PAC-QOL was 1.29 ± 0.74, and the lowest score (highest QOL) of 0.94 ± 0.61 was observed in BSFS type 4. Significant difference was seen between BSFS type 4 and all the other types except type 7. Multivariate analysis revealed that normal stool form (BSFS type 4) and BMs ≥3/week are strongly related to decreases of PAC-COL score. In BSFS types 6 and 7, 36% of individuals experienced self-discontinuation of prescribed drugs and 53% self-reduced drug intake because of excessive effects. CONCLUSIONS: Stool form and frequency of BMs are relevant to QOL, especially normal stool form (BSFS type 4) is important for improving the QOL in patients with constipation. Physicians should focus on "stool form" and reconsider the prescription especially in BSFS types 6-7 patients.

Efficacy and safety of colorectal endoscopic submucosal dissection in patients with sarcopenia.

BACKGROUND: Endoscopic submucosal dissection (ESD) for early-stage colorectal cancer (CRC) has become a common and useful treatment. Although sarcopenia has been identified as an independent risk factor for complications after surgery for CRC, whether sarcopenia is also an independent risk factor for complications after colorectal ESD remains to be clarified. The aim of this study was to compare the outcomes of colorectal ESD in patients with and those without sarcopenia. METHODS: This is a retrospective cohort study. A total of 334 patients underwent colorectal ESD for 361 neoplasms at Hiratsuka City Hospital from March 2012 to October 2018. The neoplasms were divided into two groups depending on the presence or absence of sarcopenia in the patients. RESULTS: Overall, 334 patients underwent colorectal ESD for 361 neoplasms during the study period. We excluded 90 patients (90 neoplasms), and 244 patients (277 neoplasms) were included in the final analysis (134 from the sarcopenia group, 137 from the non-sarcopenia group). The en-bloc resection rate was high and was not significantly different between the sarcopenia group [126/134 (94.1%)] and the non-sarcopenia group [133/137 (97.1%)], P = 0.1778). The rate of perforation and the rate of delayed bleeding were not significantly different between the sarcopenia group and the non-sarcopenia group [6/134 (4.5%) vs. 9/137 (6.6%), P = 0.314, 4/134 (3%) vs. 6/137 (4.4%), P = 0.3885, respectively]. CONCLUSIONS: The presence of sarcopenia did not influence the rate of complications after ESD. Colorectal ESD is safe and effective even in patients with sarcopenia. Prospective multicenter studies are necessary to confirm our results.

The Role of Leaky Gut in Nonalcoholic Fatty Liver Disease: A Novel Therapeutic Target.

The liver directly accepts blood from the gut and is, therefore, exposed to intestinal bacteria. Recent studies have demonstrated a relationship between gut bacteria and nonalcoholic fatty liver disease (NAFLD). Approximately 10-20% of NAFLD patients develop nonalcoholic steatohepatitis (NASH), and endotoxins produced by Gram-negative bacilli may be involved in NAFLD pathogenesis. NAFLD hyperendotoxicemia has intestinal and hepatic factors. The intestinal factors include impaired intestinal barrier function (leaky gut syndrome) and dysbiosis due to increased abundance of ethanol-producing bacteria, which can change endogenous alcohol concentrations. The hepatic factors include hyperleptinemia, which is associated with an excessive response to endotoxins, leading to intrahepatic inflammation and fibrosis. Clinically, the relationship between gut bacteria and NAFLD has been targeted in some randomized controlled trials of probiotics and other agents, but the results have been inconsistent. A recent randomized, placebo-controlled study explored the utility of lubiprostone, a treatment for constipation, in restoring intestinal barrier function and improving the outcomes of NAFLD patients, marking a new phase in the development of novel therapies targeting the intestinal barrier. This review summarizes recent data from studies in animal models and randomized clinical trials on the role of the gut-liver axis in NAFLD pathogenesis and progression.

The efficacy of a leukotriene receptor antagonist in the treatment of human rectal aberrant crypt foci: a nonrandomized, open-label, controlled trial.

BACKGROUND: Leukotriene receptor antagonists (LTRAs) are broadly used for the management of allergic asthma and have recently been indicated to inhibit carcinogenesis and cancer cell growth. In colorectal cancer (CRC) chemoprevention studies, the occurrence of adenoma or CRC itself is generally set as the trial endpoint. Although the occurrence rate of CRC is the most confident endpoint, it is inappropriate for chemoprevention studies because CRC incidence rate is low in the general population and needed for long-term monitoring. Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and darker in methylene blue staining than normal crypts, are regarded to be a fine surrogate biomarker of CRC. Therefore, this prospective study was designed to explore the chemopreventive effect of LTRA on colonic ACF formation and the safety of the medicine in patients scheduled for a poly resection as a pilot trial leading the CRC chemoprevention trial. METHODS: This study is a nonrandomized, open-label, controlled trial in patients with colorectal ACF and polyps scheduled for a polypectomy. Participants meet the inclusion criteria will be recruited, and the number of ACF in the rectum will be counted at the baseline colonoscopic examination. Next, the participants will be assigned to the LTRA or no treatment group. Participants in the LTRA group will continue 10 mg of oral montelukast for 8 weeks, and those in the no treatment group will be observed without the administration of any additional drugs. At the end of the 8-week LTRA intervention period, a polypectomy will be conducted to evaluate the changes in the number of ACF, and cell proliferation in the normal colorectal epithelium will be analyzed. DISCUSSION: This will be the first study to investigate the effect of LTRAs on colorectal ACF formation in humans. TRIAL REGISTRATION: This trial has been registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000029926 . Registered 10 November 2017.

The efficacy of aspirin and metformin combination therapy in patients with rectal aberrant crypt foci: a double-blinded randomized controlled trial.

BACKGROUND: The incidence and mortality rates of colorectal cancer (CRC) continue to increase worldwide. Therefore, new preventive strategies are needed to lower the burden of this disease. Previous studies reported that aspirin could suppress the development of sporadic colorectal adenoma. In addition, metformin is a biguanide derivative that is long widely used for the treatment of diabetes mellitus and has recently been suggested to have a suppressive effect on carcinogenesis and cancer cell growth. Both drugs exhibit a chemopreventive effect, but their efficacy is limited. Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and stain more darkly with methylene blue than normal crypts, are more prevalent in patients with cancer and adenomas, and considered a reliable surrogate biomarker of CRC. Thus, we designed a prospective trial as a preliminary study prior to a CRC chemoprevention trial to evaluate the chemopreventive effect of aspirin combined with metformin on colorectal ACF formation in patients scheduled for polypectomy. METHODS: This study is a double-blind randomized controlled trial that will be conducted in patients with both colorectal ACF and colorectal polyps scheduled for polypectomy. Eligible patients will be recruited for the study and the number of ACF in the rectum will be counted at the baseline colonoscopy. Then, the participants will be allocated to one of the following two groups; the aspirin plus placebo group or the aspirin plus metformin group. Patients in the aspirin plus placebo group will receive oral aspirin (100 mg) and placebo for 8 weeks, and those in the aspirin plus metformin group will receive oral aspirin (100 mg) and metformin (250 mg) for 8 weeks. After 8 weeks of administration, polypectomy will be performed to evaluate changes in the number of ACF, and the cell-proliferative activity in the normal colorectal mucosa and colorectal polyps. DISCUSSION: This is the first study proposed that will explore the effect of aspirin combined with metformin on the formation of colorectal ACF in humans. TRIAL REGISTRATION: This trial has been registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000028259 . Registered 17 July 2017.

Safety and efficacy of cold snare polypectomy for pedunculated (Ip) polyps measuring less than 10 mm in diameter.

BACKGROUND: Although cold snare polypectomy (CSP) has spread rapidly, it still remains controversial whether CSP is safe for pedunculated (Ip) polyps. PURPOSE: The aim of this study was to evaluate whether CSP for Ip polyps measuring less than 10 mm in diameter might be associated with an increased rate of delayed post-polypectomy bleeding (DPPB). METHODS: A total of 1641 colorectal polyps in 634 patients were resected at Omori Red Cross Hospital between April 2018 and December 2018. The polyps were divided into two groups depending on the morphology: the Ip group (90 polyps), and the non-Ip group (1551 polyps). RESULTS: Among the 1641 polyps, there was no case of DPPB, including in the Ip group. Immediate bleeding occurred in a total of 101 (6.2%) cases. Polyp location in the rectum (OR (95% CI), 3.61 (1.843-7.092); p < 0.001), polyp diameter ≥ 6 mm (OR (95% CI), 2.65 (1.702-4.132); p < 0.001), Ip morphology (OR (95% CI), 15.66 (9.262-26.49); p < 0.001), and treatment with antithrombotic agents (OR (95% CI), 2.18 (1.358-3.501); p = 0.0012) were identified as significant risk factors for immediate bleeding. CONCLUSIONS: This is the first study conducted to examine the safety of CSP for Ip polyps measuring less than 10 mm in diameter. CSP can be performed with a high level of safety even for Ip polyps. Based on our findings, we believe that Ip polyps could be included as an indication for CSP. However, prospective, randomized studies are necessary to confirm our results.

Chemoprevention of colorectal cancer: Past, present, and future.

Chemoprevention began to be considered as a potential strategy for lowering the incidence of cancer and cancer-related deaths in the 1970s. For clinical chemoprevention trials against cancer, including colorectal cancer (CRC), well-established biomarkers are necessary for use as reliable endpoints. Difficulty in establishing validated biomarkers has delayed the start of CRC chemoprevention development. Chemoprevention trials for CRC have only recently been initiated thanks to the identification of reliable biomarkers, such as colorectal adenomas and aberrant crypt foci. Some promising agents have been developed for the prevention of CRC. The chemopreventive effect of selective cyclooxygenase 2 inhibitors has been shown, although these inhibitors are associated with cardiovascular toxicity as a crucial adverse effect. Aspirin, which is a unique agent among non-steroidal anti-inflammatory drugs (NSAIDs) showing minimal gastrointestinal toxicity and no cardiovascular risk, has prevented adenoma recurrence in some randomized controlled trials. More recently, metformin, which is a first-line oral medicine for type 2 diabetes, has been shown to be safe and to prevent adenoma recurrence. A recommendation of the United States Preventive Services Task Force published in 2016 provides a Grade B recommendation for the use of aspirin for chronic prophylaxis against diseases, including CRC, in certain select populations. However, the roles of other agents have yet to be determined, and investigations to identify novel "post-aspirin" agents are also needed. The combined use of multiple drugs, such as aspirin and metformin, is another option that may lead not only to stronger CRC prevention, but also to improvement of other obesity-related diseases.

Risk factors for incomplete polyp resection after cold snare polypectomy.

BACKGROUND: Incomplete polyp resection (IPR) is recognized as a risk factor for interval colorectal cancer (ICC), and is, therefore, an important issue in polypectomy. Cold snare polypectomy (CSP) is a procedure that does not involve electrocautery and has no burn effect. Therefore, there is the possibility that the risk of ICC associated with IPR is higher in cases undergoing CSP than in those undergoing hot polypectomy. However, little is known about the risk factors for IPR after CSP. PURPOSE: Precise identification of the risk factors can lead to prevention of IPR after CSP. Therefore, we performed this observational study for accurate identification of the risk factors for IPR after CSP. METHODS: Medical records of a total of 501 patients with 1177 colorectal polyps that were resected at Omori Red Cross Hospital between October 2017 and March 2018 were retrospectively reviewed. The lateral and deep margins of the resected polyps were evaluated to check for the resection completeness. RESULTS: Among the 1177 polyp resections, 1163 were included in the final analysis. IPR was detected in 206 (17.7%) cases. Performance of the resection by a trainee (OR (95% CI) 1.87 (1.328-2.632); P < 0.001) was identified as an independent risk factor for IPR in patients undergoing CSP. CONCLUSIONS: Performance of the polypectomy by a trainee was identified as a significant risk factor for IPR in patients undergoing CSP. Prospective, randomized studies are necessary in the future to develop effective methods for the prevention/control of IPR after CSP.