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BackgroundThe Japanese Society of Gastroenterology (JSGE) published ‘‘Daicho Polyp Shinryo Guideline 2014′’ in Japanese and a part of this guideline was published in English as “Evidence-based clinical practice guidelines for management of colorectal polyps” in the Journal of Gastroenterology in 2015. A revised version of the Japanese-language guideline was published in 2020, and here we introduce a part of the contents of revised version.MethodsThe guideline committee discussed and drew up a series of clinical questions (CQs). Recommendation statements for the CQs were limited to items with multiple therapeutic options. Items with established conclusions that had 100% agreement with previous guidelines (background questions) and items with no (or old) evidence that are topics for future research (future research questions: FRQs) were given descriptions only. To address the CQs and FRQs, PubMed, ICHUSHI, and other sources were searched for relevant articles published in English from 1983 to October 2018 and articles published in Japanese from 1983 to November 2018. The Japan Medical Library Association was also commissioned to search for relevant materials. Manual searches were performed for questions with insufficient online references.ResultsThe professional committee created 18 CQs and statements concerning the current concept and diagnosis/treatment of various colorectal polyps, including their epidemiology, screening, pathophysiology, definition and classification, diagnosis, management, practical treatment, complications, and surveillance after treatment, and other colorectal lesions (submucosal tumors, nonneoplastic polyps, polyposis, hereditary tumors, ulcerative colitis-associated tumors/carcinomas).ConclusionsAfter evaluation by the moderators, evidence-based clinical practice guidelines for management of colorectal polyps were proposed for 2020. This report addresses the therapeutic related CQs introduced when formulating these guidelines.

Endoscopic submucosal dissection (ESD) allows en bloc resection of a lesion, irrespective of the size of the lesion. ESD has been established as a standard method for the endoscopic ablation of malignant tumors in the upper gastrointestinal (GI) tract in Japan. Although the use of ESD for colorectal lesions has been studied via clinical research, ESD is not yet established as a standard therapeutic method for colorectal lesions because colorectal carcinoma has unique pathological, organspecific characteristics that differ radically from those of the esophagus and stomach, and scope handling and control is more difficult in the colorectum than in the upper GI tract. Depending on the efficacy of endoscopic mucosal resection (EMR) and the clinicopathological characteristics of the colorectal tumor, the proposed indications for colorectal ESD are as follows: (1) lesions difficult to remove en bloc with a snare EMR, such as nongranular laterally spreading tumors (particularly the pseudodepressed type), lesions showing a type Vi pit pattern, and large lesions of the protruded type suspected to be carcinoma; (2) lesions with fibrosis due to biopsy or peristasis; (3) sporadic localized lesions in chronic inflammation such as ulcerative colitis; and (4) local residual carcinoma after EMR. Colorectal ESD is currently in the development stage, and a standard protocol will be available in the near future. We hope that colorectal tumors will be efficiently treated by a treatment method appropriately selected from among EMR, ESD, and surgical resection after precise preoperative diagnosis based on techniques such as magnifying colonoscopy.

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. We identified dynamic changes in the number and phenotype of tumor‐associated macrophages (TAMs) at the invasive front in colorectal cancer (CRC), especially at the stage of submucosal invasion. Furthermore, TAMs at the invasive front may play a role in CRC progression, especially in early stage CRC, ie, M1 macrophages at the invasive front may inhibit CRC progression, while M2 macrophages may promote CRC progression via EMT. Therefore, a marker comprising the phenotype, number, and distribution of TAMs may serve as a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential therapeutic target in CRC.

The number of deaths from colorectal cancer in Japan continues to increase. Colorectal cancer deaths exceeded 50,000 in 2016. In the 2019 edition, revision of all aspects of treatments was performed, with corrections and additions made based on knowledge acquired since the 2016 version (drug therapy) and the 2014 version (other treatments). The Japanese Society for Cancer of the Colon and Rectum guidelines 2019 for the treatment of colorectal cancer (JSCCR guidelines 2019) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment and to deepen mutual understanding between healthcare professionals and patients by making these guidelines available to the general public. These guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. Controversial issues were selected as clinical questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSCCR guidelines 2019.

BackgroundThe current status of colorectal endoscopic submucosal dissection (ESD) performed by endoscopists without colorectal ESD experience is unknown. This study evaluated the quality of colorectal ESD performed by endoscopists without colorectal ESD experience.MethodsWe retrospectively examined the outcomes of 420 consecutive patients with 427 superficial colorectal tumors (male/female, 251/169; mean age, 69 years) who underwent ESD. The procedures were performed by 31 endoscopists without colorectal ESD experience using needle knife-type devices at 13 hospitals from October 2008 to June 2017. Cases were divided into the first and second phases according to the experience of the endoscopist: the first phase included the first 20 cases and the second phase included case 21 and beyond. We also identified factors associated with en bloc resection failure.ResultsRates of colonic tumors, laterally spreading tumors of the non-granular type, poor scope operability, and severe submucosal fibrosis for the first phase were significantly lower than those for the second phase. The en bloc resection rates for the first and second phases were 93% and 96%, respectively. The factors associated with en bloc resection failure were poor scope operability (odds ratio [OR] 2.6; 95% confidence interval [CI] 1.0–6.5), severe submucosal fibrosis (OR 6.5; 95% CI 2.6–15.9), and the first 20 cases (OR 3.4; 95% CI 1.2–10.1).ConclusionInexperienced endoscopists should initially perform colorectal ESD for tumors without severe submucosal fibrosis under good scope operability for at least 20 cases.

Background We aimed to clarify the long-term outcomes of patients with T1 colorectal carcinoma (CRC) after endoscopic resection (ER) and surgical resection. Methods We examined T1 CRC patients treated during 1992–2008 and who had ≥5 years of follow-up. Patients who did not meet the curative criteria after ER according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines were defined as “non-endoscopically curable” and classified into three groups: ER alone (Group A: 121 patients), additional surgery after ER (Group B: 238 patients), and surgical resection alone (Group C: 342 patients). Long-term outcomes and predictors of recurrence were analyzed. Results Of the 882 patients with T1 CRC, 701 were non-endoscopically curable. Among these patients, recurrence and 5-year overall survival (OS) rates were 0.6 and 91.1%, respectively. In Groups A, B, and C, recurrence rates were 5.0, 5.5, and 3.8%, OS rates were 79.3, 92.4, and 91.5% ( p  < 0.01), and 5-year disease-free survival (DFS) rates were 98.1, 97.9, and 98.5%, respectively. Thirty-two patients experienced local recurrence or distant/lymph node metastasis (Group A: 6; Group B: 13; Group C: 13) and 14 patients died of primary CRC (Group A: 3; Group B: 7; Group C: 4). Age ≥65 years, protruded gross type, positive lymphatic invasion, and high budding grade were significant predictors of recurrence in non-endoscopically curable patients. Conclusions Our findings supported the JSCCR criteria for endoscopically curable T1 CRC. ER for T1 CRC did not worsen the clinical outcomes of patients who required additional surgical resection.

Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are known to play supportive roles in tumor development and progression, but their interactions in colorectal cancer (CRC) remain unclear. Here, we investigated the effects of colon-cancer-derived CAFs on TAM differentiation, migration, and tumor immunity, both in vitro and in vivo. When co-cultured with monocytes, CAFs attracted monocytes and induced their differentiation into M2 macrophages. Immunohistology of surgically resected human CRC specimens and orthotopically transplanted mouse tumors revealed a correlation between numbers of CAFs and numbers of M2 macrophages. In a mouse model of CRC orthotopic transplantation, treatment with an inhibitor of the colony-stimulating factor-1 receptor (PLX3397) depleted M2 macrophages and increased CD8-positive T cells infiltrating the tumor nest. While this treatment had a minor effect on tumor growth, combining PLX3397 with anti-PD-1 antibody significantly reduced tumor growth. RNA-seq following combination therapy showed activation of tumor immunity. In summary, CAFs are involved in the induction and mobilization of M2 macrophage differentiation in the CRC tumor immune microenvironment, and the combination of cancer immunotherapy and PLX3397 may represent a novel therapeutic option for CRC.

BackgroundEndoscopic submucosal dissection (ESD) has become a widely accepted treatment method for colorectal tumors; however, there are some persistent problems. This multi-center study aimed to characterize the risk factors for incomplete resection and perforation in standardized colorectal ESD procedures.MethodsThis study included 2423 consecutive patients who underwent ESD for 2592 colorectal tumors between August 2013 and December 2018 at 11 institutions (1 academic hospital and 10 affiliated hospitals) from the Hiroshima GI Endoscopy Research Group. We evaluated the risk factors for interruption, piecemeal resection, and perforation of standardized colorectal ESD in relation to clinicopathologic and endoscopic characteristics.ResultsThe incidences of interruption, piecemeal resection, and perforation were 0.7%, 2.9%, and 3.0%, respectively. Multivariate analysis identified the following risk factors for interruption: perforation during the procedure, deep submucosal invasion (> 1000 μm), poor scope operability, and severe submucosal fibrosis. The risk factors for piecemeal resection included poor scope operability, severe submucosal fibrosis, and procedure time (≥ 85 min). The risk factors for perforation during the procedure were severe submucosal fibrosis, poor scope operability, procedure time (≥ 85 min), and tumor size (≥ 40 mm). Independent risk factors for severe submucosal fibrosis included a history of biopsy and lesions located on the fold or flexure.ConclusionsSevere submucosal fibrosis and poor scope operability are the common risk factors for interruption, piecemeal resection, and perforation in standardized colorectal ESD.