Novel endoscopic ultrasonography classification for assured vertical resection margin (≥500 µm) in colorectal endoscopic submucosal dissection.

BACKGROUND AND AIM: The risk of local recurrence might be low in pT1 colorectal carcinoma with a tumor vertical margin (VM) ≥500 µm. We investigated the relationship between endoscopic ultrasonography (EUS) findings and VM in cases with colorectal endoscopic submucosal dissection (ESD) categorized as Type 2B according to the Japan NBI Expert Team (JNET) classification. METHODS: We analyzed 179 JNET Type 2B colorectal tumors resected by ESD at Hiroshima University Hospital from January 2010 to May 2021. The distance from the tumor invasive front to the muscle layer on EUS was defined as the tumor-free distance (EUS-TFD) and classified as Type I (EUS-TFD ≥1 mm) and II (<1 mm). We investigated the relationship between EUS-TFD and VM and analyzed the predictive factors for VM ≥500 µm. RESULTS: EUS-TFD Type I was diagnosed in 133 (74.3%) lesions: VM ≥500 µm (114, 85.7%); VM <500 µm (19, 14.3%); and VM positive (VM1) (0, 0%). Type II was diagnosed in 46 (25.7%) lesions: VM ≥500 µm (14, 30.5%); VM <500 µm (22, 47.8%); and VM1 (10, 21.7%). In the EUS-TFD Type I cases, 84.5% and 87.8% were protruded and superficial types; whereas for Type II cases, these were 38.9% and 25%, respectively. EUS-TFD classification (Type I), scope operability (good), submucosal invasion depth (<2000 µm), histology at the deepest invasive portion (favorable), and degree of fibrosis (F0/F1) were significant predictors of VM ≥500 µm. CONCLUSIONS: In JNET Type 2B lesions, EUS-TFD classification is a novel diagnostic indicator to predict VM ≥500 µm in ESD preoperatively.

Development of multi-class computer-aided diagnostic systems using the NICE/JNET classifications for colorectal lesions.

BACKGROUND AND AIM: Diagnostic support using artificial intelligence may contribute to the equalization of endoscopic diagnosis of colorectal lesions. We developed computer-aided diagnosis (CADx) support system for diagnosing colorectal lesions using the NBI International Colorectal Endoscopic (NICE) classification and the Japan NBI Expert Team (JNET) classification. METHODS: Using Residual Network as the classifier and NBI images as training images, we developed a CADx based on the NICE classification (CADx-N) and a CADx based on the JNET classification (CADx-J). For validation, 480 non-magnifying and magnifying NBI images were used for the CADx-N and 320 magnifying NBI images were used for the CADx-J. The diagnostic performance of the CADx-N was evaluated using the magnification rate. RESULTS: The accuracy of the CADx-N for Types 1, 2, and 3 was 97.5%, 91.2%, and 93.8%, respectively. The diagnostic performance for each magnification level was good (no statistically significant difference). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the CADx-J were 100%, 96.3%, 82.8%, 100%, and 96.9% for Type 1; 80.3%, 93.7%, 94.1%, 79.2%, and 86.3% for Type 2A; 80.4%, 84.7%, 46.8%, 96.3%, and 84.1% for Type 2B; and 62.5%, 99.6%, 96.8%, 93.8%, and 94.1% for Type 3, respectively. CONCLUSIONS: The multi-class CADx systems had good diagnostic performance with both the NICE and JNET classifications and may aid in educating non-expert endoscopists and assist in diagnosing colorectal lesions.

Vertical tumor margin of endoscopic resection for T1 colorectal carcinoma affects the prognosis of patients undergoing additional surgery.

BACKGROUND: Vertical tumor margin-negative T1 colorectal carcinoma (CRC) is an absolute curative condition following complete endoscopic resection (ER). However, the influence on prognosis in relation to vertical tumor margin is unclear. Therefore, we evaluated the influence of the distance from vertical tumor margin to resected specimen edge (vertical margin distance) of ER for T1b (submucosal invasion depth > 1000 µm) CRC on the prognosis of patients undergoing additional surgery after ER. METHODS: In total, 215 consecutive patients with T1b CRC who underwent additional surgery after ER at Hiroshima University Hospital between February 1992 and June 2019 were enrolled. We assessed 191 patients without lymph node metastases at the additional surgery. The specimens resected by ER were classified into three groups based on the vertical margin distance: patients with a vertical margin distance of ≥ 500 µm (Group A); patients with a vertical margin distance of < 500 µm (Group B); and patients with a positive vertical tumor margin (Group C). Subsequently, we evaluated the prognosis of the patients in relation to the clinicopathological characteristics among the three groups. RESULTS: There were no significant differences in clinicopathological characteristics among the three groups. Group A had a significantly higher recurrence-free 5-year survival rate than Groups B and C (100%, 84.5%, and 81.8%, respectively). Similarly, Group A had a significantly higher disease-specific 5-year survival rate than Group C (100% vs. 95.5%). CONCLUSIONS: Complete en bloc resection with sufficient submucosal layer from the invasive front (vertical margin distance > 500 µm) by ER for T1 CRC reduces the risk of metastatic recurrence after additional surgery.

Role of tumor-associated macrophages at the invasive front in human colorectal cancer progression.

Macrophages are an essential component of antitumor activity; however, the role of tumor-associated macrophages (TAMs) in colorectal cancer (CRC) remains controversial. Here, we elucidated the role of TAMs in CRC progression, especially at the early stage. We assessed the TAM number, phenotype, and distribution in 53 patients with colorectal neoplasia, including intramucosal neoplasia, submucosal invasive colorectal cancer (SM-CRC), and advanced cancer, using double immunofluorescence for CD68 and CD163. Next, we focused on the invasive front in SM-CRC and association between TAMs and clinicopathological features including lymph node metastasis, which were evaluated in 87 SM-CRC clinical specimens. The number of M2 macrophages increased with tumor progression and dynamic changes were observed with respect to the number and phenotype of TAMs at the invasive front, especially at the stage of submucosal invasion. A high M2 macrophage count at the invasive front was correlated with lymphovascular invasion, low histological differentiation, and lymph node metastasis; a low M1 macrophage count at the invasive front was correlated with lymph node metastasis. Furthermore, receiver operating characteristic curve analysis revealed that the M2/M1 ratio was a better predictor of the risk of lymph node metastasis than the pan-, M1, or M2 macrophage counts at the invasive front. These results suggested that TAMs at the invasive front might play a role in CRC progression, especially at the early stages. Therefore, evaluating the TAM phenotype, number, and distribution may be a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential CRC therapeutic target.

Long-term prognosis after endoscopic submucosal dissection for colorectal tumors in patients aged over 80 years.

BACKGROUND: In Japan, endoscopic submucosal dissection (ESD) is standardized for large colorectal tumors. However, its validity in the elderly population is unclear. We aimed to evaluate the safety and efficacy of ESD for colorectal tumors in elderly patients aged over 80 years. METHODS: ESD was performed on 178 tumors in 165 consecutive patients aged over 80 years between December 2008 and December 2018. We retrospectively evaluated the clinicopathological characteristics and clinical outcomes of ESD. We also assessed the prognosis of 160 patients followed up for more than 12 months. RESULTS: The mean patient age was 83.7 ± 3.1 years. The number of patients with comorbidities was 100 (62.5%). Among all patients, 106 (64.2%) were categorized as class 1 or 2 according to the American Society of Anesthesiologists classification of physical status (ASA-PS), and 59 (35.8%) were classified as class 3. The mean procedure time was 97.7 ± 79.3 min. The rate of histological en bloc resection was 93.8% (167/178). Delayed bleeding in 11 cases (6.2%) and perforation in 7 cases (3.9%) were treated conservatively. The 5-year survival rate was 89.9%. No deaths from primary disease (mean follow-up time: 35.3 ± 27.5 months) were observed. Overall survival rates were significantly lower in the non-curative resection group that did not undergo additional surgery than in the curative resection group (P = 0.0152) and non-curative group that underwent additional surgery (P = 0.0259). Overall survival rates were higher for ASA-PS class 1 or 2 patients than class 3 patients (P = 0.0105). Metachronous tumors (> 5 mm) developed in 9.4% of patients. CONCLUSIONS: ESD for colorectal tumors in patients aged over 80 years is safe. Colorectal cancer-associated deaths were prevented although comorbidities pose a high risk of poor prognosis.

Effect of educational lecture on the diagnostic accuracy of Japan NBI Expert Team classification for colorectal lesions.

BACKGROUND: An educational and training program is required for generalization of Japan NBI Expert Team (JNET) classification. However, there is no detailed report on the learning curve of the diagnostic accuracy of endoscopists using JNET classification. We examined the effect of an educational lecture on beginners and less experienced endoscopists for improving their diagnostic accuracy of colorectal lesions by JNET classification. METHODS: Seven beginners with no endoscopy experience (NEE group), 7 less experienced endoscopists (LEE group), and 3 highly experienced endoscopists (HEE group) performed diagnosis using JNET classification for randomized NBI images of colorectal lesions from 180 cases (Type 1: 22 cases, Type 2A: 105 cases, Type 2B: 33 cases, and Type 3: 20 cases). Next, the NEE and LEE groups received a lecture on JNET classification, and all 3 groups repeated the diagnostic process. We compared the correct diagnosis rate and interobserver agreement before and after the lecture comprehensively and for each JNET type. RESULTS: In the HEE group, the correct diagnosis rate was more than 90% with good interobserver agreements (kappa value: 0.78-0.85). In the NEE and LEE groups, the correct diagnosis rate (NEE: 60.2 → 68.0%, P < 0.01; LEE: 66.4 → 86.7%, P < 0.01), high-confidence correct diagnosis rate (NEE: 19.6 → 37.2%, P < 0.01; LEE: 43.6 → 61.1%, P < 0.01), and interobserver agreement (kappa value, NEE: 0.32 → 0.43; LEE: 0.39 → 0.75) improved after the lecture. In the examination by each JNET type, the specificity and positive predictive value in the NEE and LEE groups generally improved after the lecture. CONCLUSION: After conducting an appropriate lecture, the diagnostic ability using JNET classification was improved in beginners or endoscopists with less experience in NBI magnifying endoscopy.

Clinical usefulness of linked color imaging for evaluation of endoscopic activity and prediction of relapse in ulcerative colitis.

PURPOSE: In the treatment of ulcerative colitis (UC), accurate evaluation of UC activity is important to achieve mucosal healing. We sought to investigate the clinical utility of linked color imaging (LCI) for the evaluation of endoscopic activity and prediction of relapse in UC patients. METHODS: We enrolled 72 consecutive UC patients in remission who underwent colonoscopy at our institution between September 2016 and October 2018. The relationship between the presence of redness in white light imaging (WLI) and LCI and histopathological inflammation (Geboes score: GS) at 238 biopsy sites was examined. We also assessed the presence or absence of planar redness in the entire rectum as ± and classified the patients into three groups according to the combination of WLI/LCI: A: WLI-/LCI-, B: WLI-/LCI+, and C: WLI+/LCI+. The relationship between WLI/LCI classification and relapse in 64 patients followed up for more than 12 months from initial colonoscopy was assessed and compared to the Mayo endoscopic subscore (MES). RESULTS: A GS of 0 or 1 accounted for 89% of WLI/LCI non-redness sites, while a GS of 2 or 3 accounted for 42% of WLI non-redness/LCI redness sites. LCI findings were significantly correlated with GS. During follow-up, 10 patients in group C and four patients in group B relapsed, but none in group A. Non-relapse rates were significantly correlated with WLI/LCI classification, but not with MES. CONCLUSION: LCI is a useful modality for accurate assessment of endoscopic activity and prediction of relapse in UC by detecting mild inflammation unrecognizable by WLI.

Clinical outcomes of endoscopic resection for rectal neuroendocrine tumors: Advantages of endoscopic submucosal resection with a ligation device compared to conventional EMR and ESD.

Objectives: There are some endoscopic resection (ER) methods for neuroendocrine tumors (NETs), however, which method is most useful remains unclear. This study aimed to compare the outcomes of different ER techniques, such as conventional endoscopic mucosal resection (cEMR), endoscopic submucosal dissection (ESD), and endoscopic submucosal resection with a ligation device (ESMR-L) for rectal NETs. Methods: We retrospectively analyzed 96 consecutive patients with 102 rectal NETs of less than 10 mm in diameter who underwent ER between January 2001 and December 2019 at Hiroshima University Hospital. We compared the clinical outcomes of each ER method (cEMR 60 lesions, ESD 21 lesions, and ESMR-L 21 lesions), divided according to the treatment periods, and evaluated the risk factors for vertical margin (VM) positivity in relation to clinicopathological and endoscopic characteristics. Results: As for the mean procedure time, ESD took significantly longer to perform than the other methods. The histological complete resection rate was 80% (48/60) for cEMR, 85.7% (18/21) for ESD, and 100% (21/21) for ESMR-L, and the VM positive rate was 20% (12/60) for cEMR, 14.3% (3/21) for ESD, and 0% (0/21) for ESMR-L, with no significant difference. However, the tumor-front-to-VM distance was significantly longer in the ESMR-L group than in the cEMR and ESD groups. cEMR and ESD were both significant risk factors for VM positivity. No perforation or local recurrence was observed in all methods. Conclusions: ESMR-L is the most useful ER method for small rectal NETs.

Efficacy of single-balloon overtube for endoscopic submucosal dissection in the proximal colon: A propensity score-matched analysis.

Objectives: A single-balloon overtube (SBO) can improve poor scope operability during colonic endoscopic submucosal dissection (ESD). We aimed to evaluate the clinical usefulness of SBO for ESD in the proximal colon and the predictive factors for cases in which SBO is useful. Methods: A total of 88 tumors located in the proximal colon resected by balloon-assisted ESD (BA-ESD) using SBO and 461 tumors resected by conventional ESD (C-ESD) between June 2015 and November 2020 were considered. Seventy-eight tumors each in the BA-ESD and C-ESD groups were matched by propensity score matching. ESD outcomes were compared between the groups, and a decision tree analysis was performed to explore the predictive factors for cases in which SBO is useful. Results: There were no significant differences between the groups in the major outcomes such as en bloc resection rate (95% vs. 99%, p = 0.17), R0 resection rate (92% vs. 96%, p = 0.30), mean dissection speed (16 mm2/min vs. 16 mm2/min, p = 0.53), and intraoperative perforation rate (5% vs. 6%, p = 0.73). Even when considering cases with poor preoperative scope operability, there were no significant differences between the groups. Comparison of tumors ≥40 mm in diameter between the groups confirmed that the intraoperative perforation rate was significantly lower in the BA-ESD group than in the C-ESD group (0% vs. 24%, p = 0.0188). Conclusion: SBO is useful for ESD of tumors ≥40 mm in diameter in the proximal colon to prevent intraoperative perforation, which usually has a long procedure time.

Risk of Bleeding after Colorectal Endoscopic Resection in Patients with Continued Warfarin Use Compared to Heparin Replacement: A Propensity Score Matching Analysis.

The Japan Gastroenterological Endoscopy Society (JGES) guidelines recommend continued warfarin treatment during gastroenterological endoscopic procedures with a high risk of bleeding as an alternative to heparin replacement in patients on warfarin therapy. However, there is insufficient evidence to support the use of warfarin in colorectal endoscopic resection (ER). The present study is aimed at verifying the risk of bleeding after ER for colorectal neoplasia (CRN) in patients with continued warfarin use. This was a single-center retrospective cohort study using clinical records. We assessed 126 consecutive patients with 159 CRNs who underwent ER (endoscopic mucosal resection, 146 cases; endoscopic submucosal dissection, 13 cases) at Hiroshima University Hospital between January 2014 and December 2019. Patients were divided into two groups: the heparin replacement group (79 patients with 79 CRNs) and the continued warfarin group (47 patients with 80 CRNs). One-to-one propensity score matching was performed to compare the bleeding rate after ER between the groups. The rate of bleeding after ER was significantly higher in the heparin replacement group than in the continued warfarin group for both before (10.1% vs. 1.3%, respectively; P = 0.0178) and after (11.9% vs. 0%, respectively; P = 0.0211) propensity score matching. None of the patients experienced thromboembolic events during the perioperative period. The risk of bleeding after colorectal ER was significantly lower in patients with continued warfarin use than in those with heparin replacement. Our data supports the recommendations of the latest JGES guidelines for patients receiving warfarin therapy.

Genomic Landscape of Early-stage Colorectal Neoplasia Developing From the Ulcerative Colitis Mucosa in the Japanese Population.

BACKGROUNDS: Colorectal neoplasias (CRN)s developing from the ulcerative colitis (UC) mucosa include both colitic and sporadic neoplasias. Although several genomic analyses of advanced colitis-associated cancer are available, such studies do not distinguish between colitic and sporadic cases, and the early-stage genomic alterations involved in the onset of colitic cancer remain unclear. To address this, we performed a genomic analysis of early-stage CRN developing from the UC mucosa (CRNUC). METHODS: We extracted DNA from 36 early-stage CRNUCs (T1 cancer, 10; dysplasia, 26) from 32 UC patients and performed targeted sequencing of 43 genes commonly associated with colitis-associated cancer and compared the results with sequencing data from the Japanese invasive colitis-associated cancer. RESULTS: The most frequently mutated gene in the CRNUC cohort was APC (mutated in 47.2% of the cases), followed by TP53 (44.4%), KRAS (27.8%), and PRKDC (27.8%). None of the TP53 mutations occurred at any of the hotspot codons. Although the TP53 mutations in The Cancer Genome Atlas of Colorectal Cancer were dispersed throughout the gene, those detected here in CRNUC cases were concentrated in the amino terminal part of the DNA-binding domain. Interestingly, the mutations in KRAS and TP53 were mutually exclusive in CRNUC, and CRNUCs with KRAS mutations had histologically serrated lesions in the gland duct. Mayo endoscopic subscore was higher in TP53-mutated CRNUCs and lower in KRAS-mutated CRNUCs. CONCLUSIONS: Our findings suggest that early-stage CRNUC can be classified into 2 groups: those developing through the carcinogenic pathway via TP53 mutations and those developing through the carcinogenic pathway via KRAS mutations.

Clinical Features and Genomic Characterization of Post-Colonoscopy Colorectal Cancer.

INTRODUCTION: Some colorectal cancers (CRCs) may be missed during colonoscopies. We aimed to determine the clinicopathological, biological, and genomic characteristics of post-colonoscopy CRCs (PCCRCs). METHODS: Of the 1,619 consecutive patients with 1,765 CRCs detected between 2008 and 2016, 63 patients with 67 PCCRCs, when colonoscopies were performed 6-60 months before diagnosis, were recruited. After excluding patients with inflammatory bowel disease, familial polyposis syndrome, CRCs that developed from diminutive adenomatous polyps, and recurrent CRCs after endoscopic resection, 32 patients with 34 PCCRCs were enrolled. The lesions' clinicopathological features, mismatch repair proteins (MMRs), and genomic alterations were investigated. RESULTS: The overall PCCRC-5y rate, rate of intramucosal (Tis) lesions, and rate of T1 or more deeply invasive cancers were 3.7% (66/1,764), 3.9% (32/820), and 3.6% (34/944), respectively. Thirty-three patients' MMRs were investigated; 7 (21%) exhibited deficient MMRs (dMMRs), comprising 4 with T2 or more deeply invasive cancers and 5 whose lesions were in the proximal colon. Twenty-three tumors' genomic mutations were investigated; PIK3CA had mutated in 5 of 6 T2 or more deeply invasive cancers, of which, 4 were located in the proximal colon. Two patients with dMMRs and BRAF mutations had poor prognoses. Sixty-one percent (17/28) of the macroscopic type 0 lesions were superficial. All superficial Tis and T1 PCCRCs were detected <24 months after the negative colonoscopies. They were distributed throughout the colon and rectum. DISCUSSION: PCCRCs may be invasive cancers in the proximal colon that exhibit dMMRs and/or PIK3CA mutations or missed early CRCs especially superficial lesions.

Clinical usefulness of the S-O clip during colorectal endoscopic submucosal dissection in difficult-to-access submucosal layer.

Background and study aims In colorectal endoscopic submucosal dissection (ESD), the S-O clip improves the accessibility to the submucosal layer of the colon. However, its safety and usefulness in difficult colorectal ESDs are unclear. Thus, in this study, we aimed to assess the effectiveness of the S-O clip in colorectal ESD in the difficult-to-access submucosal layer. Patients and methods From January 2016 to December 2016, 189 consecutive cases of colorectal ESD were performed at Hiroshima University Hospital before the S-O clip was introduced. Between January 2017 and June 2018, among 271 consecutive colorectal ESD cases, 41 cases were performed colorectal ESD using the S-O clip. We compared outcomes between the two groups (41 cases with S-O clip [use group] and 189 cases without S-O clip [non-use group]) using propensity score matching. Results Prior to propensity score matching, 41 cases with the S-O clip (use group) and 189 cases without the S-O clip (non-use group) were extracted. The degree of submucosal fibrosis was more severe and the procedure time was longer in the use group than in the non-use group. In the use and non-use groups, en bloc resection (100 % vs. 94.7 %) and complete en bloc resection (100 % vs. 92.6 %) rates were satisfactory. After propensity score matching, 33 cases in each group were extracted. As a result, complete en bloc resection rate was significantly higher in the use group than in the non-use group (100 % vs. 84.9 %). Conclusion The S-O clip is effective and can be used safely in colorectal ESD in the difficult-to-access submucosal layer.

Can surveillance colonoscopy be discontinued in an elderly population with diminutive polyps?

OBJECTIVES: Surveillance colonoscopy after endoscopic resection (ER) for adenomatous polyps reduces the incidence and mortality of colorectal cancer (CRC). However, its significance in the elderly population is uncertain. The study aimed to determine whether surveillance colonoscopy should be discontinued in the elderly population. METHODS: We enrolled 105 patients who underwent baseline colonoscopy between January 2004 and December 2009 and were subsequently followed-up over 5 years in our institution. All had diminutive colorectal polyps and were aged <80 years at baseline colonoscopy and ≥80 years at follow-up in May 2018. Patients who had undergone colectomy or who had inflammatory bowel disease, familial adenomatous polyposis, Lynch syndrome, and no diminutive polyps were excluded. The cumulative incidence of the target lesion was evaluated. Histopathological diagnoses included low-grade dysplasia (LGD), high-grade dysplasia (HGD), and carcinoma. RESULTS: The target lesion was detected in 15% (16/105) of the patients. There was no invasive carcinoma; however, two HGDs were detected. There were three lesions that had increased from previously detected diminutive lesions, all of which were LGDs. There were no target lesions detected after 84 years of age, and the cumulative incidence was 0.20. The cumulative incidence was significantly higher in the group with HGD than in the group with no target lesions at baseline colonoscopy. There was no HGD after age 79 years, and the cumulative incidence was 0.019. CONCLUSION: Surveillance colonoscopy for patients with diminutive polyps may be discontinued after age 79 years.

The utility of a novel colonoscope with retroflexion for colorectal endoscopic submucosal dissection.

Background and study aims The PCF-H290TI/L produced by Olympus is a novel colonoscope equipped with some advantageous features for endoscopic treatment. It is expected to improve the potential for retroflexion and overall endoscope operability, which can reduce the difficulty of performing colorectal ESD. The aim of this study was to evaluate the utility of the novel colonoscope in colorectal ESD. Methods Three hundred and forty-eight consecutive colorectal lesions resected via ESD between June 2014 and January 2017 at Hiroshima University Hospital were included in the retroflexion ability analysis. We compared the retroflexion potential of PCF-H290TI to that of a conventional endoscope. Two hundred and twenty-seven colorectal lesions located in the left-sided colon and resected with ESD between April 2009 and February 2018 were enrolled in the treatment outcome analysis. Treatment outcomes using PCF-H290TI compared to those of the conventional colonoscope, and outcomes of the PCF-H290TI with retroflexion compared to those of the conventional colonoscope without retroflexion were evaluated by propensity score matching. Results The retroflexion rate with the PCF-H290TI was 76 %, which was significantly higher than the 44 % rate with the conventional scope. Endoscope operability was better and dissection speed was faster when using the PCF-H290TI with retroflexion compared to the conventional colonoscope without retroflexion. There were no significant differences between the groups in en bloc resection rate and adverse events. Conclusion Compared to the conventional colonoscope, the PCF-H290TI/L made it easier to perform ESD via a retrograde approach regardless of tumor location, and thus may be useful for performing colorectal ESD.