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Abstract A comprehensive endoscopic small and large intestinal untargeted step biopsy procedure was conducted to compare gene expression between the normal intestinal mucosa of healthy individuals and that of patients with colorectal tumors. From 78 participants (healthy individuals [n = 17], patients with colorectal conventional adenomas [n = 6], patients with Tis–T1 colorectal cancer [n = 41], patients with T2–4 colorectal cancer [n = 14]), biopsies of normal mucosa of the terminal ileum, right-sided colon (cecum and ascending colon), and left-sided colorectum (descending colon, sigmoid colon, and rectum) were obtained using a lower gastrointestinal endoscope. RNA was extracted from all samples, and total transcriptome sequencing was performed. Transcriptome data from 388 samples was analyzed. DNA was also extracted from tumor biopsy tissues and analyzed for whole-exome sequencing. In healthy individuals, gene expression differed significantly among the terminal ileum, right-sided colon, and left-sided colorectum, presumably linked to embryological factors. There were differences in gene expression in the normal mucosa in colorectal cancer patients, compared to healthy controls. Patients with tumors, especially T2–4 colorectal cancer, showed considerable variation in gene expression in non-tumor tissues, even in the terminal ileum distant from the tumor site. Based on endoscopic biopsies, the results imply cancer-predisposing conditions in seemingly normal tissues. The present study points to the importance of small intestine and cancer-predisposing conditions in the colon of colorectal cancer patients, with possible implications for developing novel immunotherapy and other therapeutic modalities.

Summary: Accumulating evidence demonstrates clear correlation between the gut microbiota and sporadic colorectal cancer (CRC). Despite this, there is limited understanding of the association between the gut microbiota and CRC in Lynch Syndrome (LS), a hereditary type of CRC. Here, we analyzed fecal shotgun metagenomic and targeted metabolomic of 71 Japanese LS subjects. A previously published Japanese sporadic CRC cohort, which includes non-LS controls, was utilized as a non-LS cohort (n = 437). LS subjects exhibited reduced microbial diversity and low-Faecalibacterium enterotypes compared to non-LS. Patients with LS-CRC had higher levels of Fusobacterium nucleatum and fap2. Differential fecal metabolites and functional genes suggest heightened degradation of lysine and arginine in LS-CRC. A comparison between LS and non-LS subjects prior to adenoma formation revealed distinct fecal metabolites of LS subjects. These findings suggest that the gut microbiota plays a more responsive role in CRC tumorigenesis in patients with LS than those without LS.

Abstract Background Sodium picosulfate (SP)/magnesium citrate (MC) and polyethylene glycol (PEG) plus ascorbic acid are recommended by Western guidelines as laxative solutions for bowel preparation. Clinically, SP/MC has a slower post-dose defaecation response than PEG and is perceived as less cleansing; therefore, it is not currently used for major bowel cancer screening preparation. The standard formulation for bowel preparation is PEG; however, a large dose is required, and it has a distinctive flavour that is considered unpleasant. SP/MC requires a small dose and ensures fluid intake because it is administered in another beverage. Therefore, clinical trials have shown that SP/MC is superior to PEG in terms of acceptability. We aim to compare the novel bowel cleansing method (test group) comprising SP/MC with elobixibat hydrate and the standard bowel cleansing method comprising PEG plus ascorbic acid (standard group) for patients preparing for outpatient colonoscopy. Methods This phase III, multicentre, single-blind, noninferiority, randomised, controlled, trial has not yet been completed. Patients aged 40–69 years will be included as participants. Patients with a history of abdominal or pelvic surgery, constipation, inflammatory bowel disease, or severe organ dysfunction will be excluded. The target number of research participants is 540 (standard group, 270 cases; test group, 270 cases). The primary endpoint is the degree of bowel cleansing (Boston Bowel Preparation Scale [BBPS] score ≥ 6). The secondary endpoints are patient acceptability, adverse events, polyp/adenoma detection rate, number of polyps/adenomas detected, degree of bowel cleansing according to the BBPS (BBPS score ≥ 8), degree of bowel cleansing according to the Aronchik scale, and bowel cleansing time. Discussion This trial aims to develop a “patient-first” colon cleansing regimen without the risk of inadequate bowel preparation by using both elobixibat hydrate and SP/MC. Trial registration Japan Registry of Clinical Trials (jRCT; no. s041210067; 9 September 2021; https://jrct.niph.go.jp/ ), protocol version 1.5 (May 1, 2023).

Abstract Chronic inflammation promotes development and progression of colorectal cancer (CRC). To comprehensively understand the molecular mechanisms underlying the development and progression of inflamed CRC, we perform in vivo screening and identify 142 genes that are frequently mutated in inflammation-associated colon tumors. These genes include senescence and TGFβ-activin signaling genes. We find that TNFα can induce stemness and activate senescence signaling by enhancing cell plasticity in colonic epithelial cells, which could act as a selective pressure to mutate senescence-related genes in inflammation-associated colonic tumors. Furthermore, we show the efficacy of the Cdk4/6 inhibitor in vivo for inflammation-associated colonic tumors. Finally, we functionally validate that Arhgap5 and Mecom are tumor suppressor genes, providing possible therapeutic targets for CRC. Thus, we demonstrate the importance of the inactivation of senescence pathways in CRC development and progression in an inflammatory microenvironment, which can help progress toward precision medicine.

PURPOSELimited information is available regarding the characteristics and outcomes of stage IV small bowel adenocarcinoma (SBA) in Japan. This study examined the clinical and pathological characteristics and outcomes according to the treatment strategies in patients with stage IV SBA.METHODSThis retrospective observational study used the data of patients with jejunal or ileal adenocarcinoma collected by the Small Bowel Malignant Tumor Project of the Japanese Society for Cancer of the Colon and Rectum. Descriptive statistics were expressed as the mean (standard deviation) or median (range). Survival analysis was performed using Kaplan-Meier curves and pairwise log-rank tests.RESULTSData from 128 patients were analyzed. The treatment strategies were chemotherapy alone (26 of 128, 20.3%), surgery alone (including palliative surgery; 21 of 128, 16.4%), surgery + chemotherapy (74 of 128, 57.8%), and best supportive care (7 of 128, 5.5%). The median (range) overall survival was 16 (0-125) months overall, and 11 (1-38) months, 8 (0-80) months, 18 (0-125) months, and 0 (0-1) months for the chemotherapy, surgery, surgery + chemotherapy, and best supportive care groups, respectively. Three main categories of chemotherapeutic regimen were used: a combination of fluoropyrimidine and oxaliplatin (F + Ox), fluoropyrimidine and irinotecan (F + Iri), and single-agent fluoropyrimidine. Among patients treated with chemotherapy, the median (range) OS was 16 (1-106) months overall, and 17 (1-87) months, 29 (7-39) months, and 16 (1-106) months in patients treated with fluoropyrimidine, F + Iri, and F + Ox, respectively.CONCLUSIONPatients treated with surgery, chemotherapy, or both had a better prognosis than those who received best supportive care. Among patients who received chemotherapy, survival did not differ according to the chemotherapeutic regimen.

Abstract Various complications of colorectal endoscopic submucosal dissection (ESD) have been reported, including bleeding, penetration, perforation, and coagulation syndrome. However, the occurrence of bowel obstruction after ESD is rare. We report a case of adhesive bowel obstruction after ESD for a laterally spreading tumor in the sigmoid colon. The 35‐mm tumor was successfully removed by ESD without intraoperative complications. The patient had a fever, lower abdominal pain, and a small amount of bloody stool the day after ESD. Endoscopy revealed minor bleeding from the ESD scar, which was treated by hemostatic clips. Pathological analysis showed adenocarcinoma was exposed to the vertical margin; therefore, the resection was non‐curative. At 39 days after ESD and 36 days after discharge, the patient had abdominal pain and nausea. She was readmitted with a diagnosis of adhesive bowel obstruction. Conservative treatment was ineffective; therefore, she underwent sigmoidectomy combined with partial resection of the small intestine because of small intestinal stenosis caused by inflammation. The pathological examination showed localized peritonitis around the sigmoid colon where ESD was performed. There was more fibrosis along the serous surface of the small intestine than on the sigmoid colon. We concluded that there was a micro‐perforation that could not be detected by endoscopy or physical examination. This case indicates that adhesive bowel obstruction may occur as a complication of ESD.

Background/Aims Probe-based confocal laser endomicroscopy (pCLE) requires the administration of intravenous (IV) fluorescein. This study aimed to determine the optimal dose of IV fluorescein for both upper and lower gastrointestinal (GI) tract pCLE. Methods Patients 20 to 79 years old with gastric high-grade dysplasia (HGD) or colorectal neoplasms (CRNs) were enrolled in the study. The dose de-escalation method was employed with five levels. The primary endpoint of the study was the determination of the optimal dose of IV fluorescein for pCLE of the GI tract. The reduced dose was determined based on off-line reviews by three endoscopists. An insufficient dose of fluorescein was defined as the dose of fluorescein with which the pCLE images were not deemed to be visible. If all three endoscopists determined that the tissue structure was visible, the doses were de-escalated. Results A total of 12 patients with gastric HGD and 12 patients with CRNs were enrolled in the study. Doses were de-escalated to 0.5 mg/kg of fluorescein for both non-neoplastic duodenal and colorectal mucosa. All gastric HGD or CRNs were visible with pCLE with IV fluorescein at 0.5 mg/kg. Conclusions In the present study, pCLE with IV fluorescein 0.5 mg/kg was adequate to visualize the magnified structure of both the upper and lower GI tract.

ABSTRACT Accumulating evidence indicates that the gut microbiome and metabolites are associated with colorectal cancer (CRC). However, the influence of surgery for CRC treatment on the gut microbiome and metabolites and how it relates to CRC risk in postoperative CRC patients remain partially understood. Here, we collected 170 fecal samples from 85 CRC patients pre- and approximately 1 year postsurgery and performed shotgun metagenomic sequencing and capillary electrophoresis-time of flight mass spectrometry-based metabolomics analyses to characterize alterations between pre- and postsurgery. We determined that the relative abundance of 114 species was altered postsurgery (P

Abstract Dye‐based chromoendoscopy has long been used routinely for endoscopic diagnosis of gastrointestinal tumors including colorectal tumors in Japan. In the West, on the other hand, dye‐based chromoendoscopy was not so commonly used. However, with the development of narrow band imaging (NBI), image‐enhanced endoscopy diagnosis has rapidly increased in the West. The most critical difference between Japan and the West is the histopathological evaluation of the lesions, which determines a major cause of differences in diagnostic and treatment strategies. In the West, intramucosal adenocarcinoma is not diagnosed until the cancer has invaded submucosal layer. In Japan, on the other hand, cancer is mainly diagnosed based on nuclear and structural atypia, and thus intramucosal adenocarcinoma is diagnosed in lesions that correspond to high‐grade adenoma in the West. In the West, since intramucosal carcinoma is not diagnosed by pathology, all benign adenomas are treated by piecemeal endoscopic resection, and only cancer invading the superficial submucosal layer is indicated for endoscopic submucosal dissection (ESD). Because of the risk of lymph node metastasis in the deep submucosal invasion, the European Society of Gastrointestinal Endoscopy and American Society for Gastrointestinal Endoscopy guidelines state that only superficial submucosal cancer is an indication for ESD. Unfortunately, it is impossible to selectively extract only superficial submucosal invasive cancer even with the use of magnified NBI and pit pattern observation. Therefore, we think that pathologists need to diagnose intramucosal adenocarcinoma with the potential to invade the submucosal layer based on the nuclear and structural atypia. Consequently, intramucosal adenocarcinoma and superficial submucosal cancers should be considered for en‐bloc ESD.

This systematic review aimed to assess the efficacy of the current approach to tissue traction during the endoscopic submucosal dissection (ESD) of superficial esophageal cancer, early gastric cancer, and colorectal neoplasms. We performed a systematic electronic literature search of articles published in PubMed and selected comparative studies to investigate the treatment outcomes of tractionassisted versus conventional ESD. Using the keywords, we retrieved 381 articles, including five eligible articles on the esophagus, 13 on the stomach, and 12 on the colorectum. A total of seven randomized controlled trials and 23 retrospective studies were identified. Clip line traction and submucosal tunneling were effective in reducing the procedural time during esophageal ESD. The efficacy of traction methods in gastric ESD varied in terms of the devices and strategies used depending on the lesion location and degree of submucosal fibrosis. Several prospective and retrospective studies utilized traction devices without the need to reinsert the colonoscope. When pocket creation is included, the traction devices and methods effectively shorten the procedural time during colorectal ESD. Although the efficacy is dependent on the organ and tumor locations, several traction techniques have been demonstrated to be efficacious in facilitating ESD by maintaining satisfactory traction during dissection.

Background/Aims: The accurate assessment of the depth of invasion of early gastric cancer (EGC) is critical to determine the most appropriate treatment option. However, it is difficult to distinguish shallow submucosal (SM1) invasion from deeper submucosal (SM2) invasion. We investigated the diagnostic performance of endoscopic ultrasonography (EUS) using a miniature probe for EGC with suspected SM invasion. Methods: From April 2008 to June 2018, EGCs with suspected SM invasion were analyzed retrospectively. The EGCs examined by a 20 MHz high-frequency miniature probe was included in our study. Esophago-gastric junction cancers and patients treated by chemotherapy before resection were excluded. The sensitivity and specificity for the detection of SM2 invasion by EUS were compared with those of white light imaging (WLI). Additionally, factors related to depth underestimation or overestimation were investigated using multivariate analysis. Results: A total of 278 EGCs in 259 patients were included in the final analysis. The sensitivity and specificity for SM2 or deeper by EUS were 73.7% (87/118) and 74.4% (119/160), respectively. The sensitivity and specificity by WLI were 47.5% (56/118) and 68.1% (109/160), respectively. The sensitivity of EUS was significantly superior to that of conventional endoscopy (p

Background and study aims Linked color imaging (LCI), a newly developed optical modality, enhances mucosal surface contrast. We aimed to evaluate the efficacy and feasibility of insertion-phase LCI in terms of additional benefit of colorectal polyp detection over that obtained with white light imaging (WLI). Patients and methods We consecutively enrolled eligible patients from November 2017 to June 2018. During colonoscopy, LCI or WLI was alternatively applied on scope insertion and LCI was applied on scope withdrawal. Patients were divided into two groups according to the protocolized difference of imaging modality used in the scope insertion phase (LCI and WLI groups). Group differences in clinical outcomes were evaluated. Results A total of 138 patients were enrolled in this study, with equal numbers of patients assigned to the LCI and WLI groups. Most of the lesions located in the proximal colon were detected during the withdrawal phase, without a difference in proportions between the two groups. However, in the LCI group, eight of 49 lesions (16 %) located in the sigmoid and rectosigmoid colon were only detected during the insertion phase, and no such lesions (0 %) were detected during the insertion phase in the WLI group (P = 0.045). Conclusions This study showed the efficacy and feasibility of LCI in improving colorectal polyp detection in the sigmoid colon, especially during insertion. Further studies are warranted to validate the results of our single-center study.

Background and study aims Surgery is the standard treatment for colon tumors associated with diverticulum. Use of endoscopic submucosal dissection (ESD) to treat such tumors is controversial. The aim of this study was to assess the safety and feasibility of ESD in treating superficial colorectal tumors situated near or involving diverticulum. Patients and methods Consecutive patients from two referral centers who had colorectal tumors near or involving diverticulum treated by ESD were retrospectively studied. Clinicopathological characteristics and clinical outcomes were analyzed. Results Of the 12 patients studied, six had tumors near diverticulum and six had tumors involving diverticulum. The overall en-bloc R0 resection rate, median tumor size and procedure time were 67 %, 26.5 mm (range, 15 – 80 mm) and 110 minutes (range, 50 – 220 minutes), respectively. For tumors near diverticulum group, the en-bloc R0 resection rate was 100 % and no adverse events (AEs) or residual/recurrent tumors were observed. In contrast, for intradiverticular tumors group, the en-bloc R0 resection rate was low at 33 %, and one AE (perforation) was observed. The diverticula were ≥ 6 mm in diameter in the patients with incomplete resection. However, all but one diverticulum was unrecognized before ESD. Two residual tumors were detected at the 12-month surveillance and one required surgery. Conclusions This case series indicates that ESD is safe and feasible for treating colorectal tumors near a diverticulum and might be feasible for tumors involving a diverticulum smaller than 6 mm. Selection for smaller diverticulum size may contribute to higher en-bloc R0 resection rates.

IL-33 is a pro-inflammatory cytokine with a role in colorectal cancer. Here, the authors show that circulating tumour-derived sST2, an IL-33 decoy receptor, delayed the growth and progression of colorectal cancer cells by inhibiting Th1/Th2 polarization, macrophage infiltration and angiogenesis.

Background and aim The depth of tumor invasion is currently the only reliable predictive risk factor for lymph node metastasis before endoscopic treatment for colorectal cancer. However, the most important factor to predict lymph node metastasis has been suggested to be lymphovascular invasion rather than the depth of invasion. Thus, the aim of this study was to investigate the predictive relevance of lymphovascular invasion before endoscopic treatment. Methods The data on pT1 colorectal cancers that were resected endoscopically or surgically from 2007 to 2015 were retrospectively reviewed. The cases were categorized into two groups: positive or negative for lymphovascular invasion. The following factors were evaluated by univariate and multivariate analyses: age and sex of the patients; location, size, and morphology of the lesion; and depth of invasion. Results The positive and negative groups included 229 and 457 cases, respectively. Younger age (P 65 years, OR, 1.81; 95 %CI, 1.29 – 2.53), presence of depression (OR, 1.97; CI, 1.40 – 2.77), non-LST features (OR, 1.50; CI, 1.04 – 2.15), and pT1b (OR, 3.08; CI, 1.91 – 4.97) were associated with lymphovascular invasion. Conclusion Younger age, presence of depression, T1b, and non-LST are associated with lymphovascular invasion. Therefore, careful pathological diagnosis and surveillance are necessary for lesions demonstrating any of these four factors.

Background and study aims: Five-aminolevulinic acid (5-ALA) is being increasingly used for photodynamic diagnosis and therapy of various types of tumors including brain, urologic, and other neoplasias. The use of 5-ALA to treat Barrett’s carcinomas has been documented, but its clinical effectiveness for diagnosis of gastrointestinal tumors, particularly early cancers, remains unknown. Patients and methods: The aim of our feasibility study was to evaluate the visibility of colorectal tumors using endoscopic fluorescence imaging (EFI) after oral administration of 5-ALA. The lesions identified by direct visualization and by the spectrums produced using EFI modality with 5-ALA were compared to the clinicopathologic features of resected specimens. Results: Twenty-three patients with a total of 27 known colorectal lesions were enrolled in the study. The median tumor size was 30 mm (range 10 – 75). Eleven of the lesions were flat or depressed lesions and 16 were sessile. Red fluorescence was observed in 22 out of 27 lesions. Red fluorescence was negative in 4 out of 11 flat or depressed lesions. In comparison with histopathologic findings, the rates of red fluorescence visibility were 62.5 % in low-grade intraepithelial neoplasia, 77.8 % in high-grade neoplasia, and 100 % in submucosal carcinoma. Red fluorescence visibility increased with the degree of dysplasia. There were no significant adverse events identified in this study. Conclusions: This feasibility study using EFI with 5-ALA demonstrated high visibility of superficial colorectal neoplasia. EFI with 5-ALA appears to be a novel, safe technique for improving real-time colorectal tumor imaging.