Long-Term Outcomes of Additional Surgery After Endoscopic Resection Versus Primary Surgery for T1 Colorectal Cancer.

INTRODUCTION: There is considerable concern about whether endoscopic resection (ER) before additional surgery (AS) for T1 colorectal cancer (CRC) has oncologically potential adverse effects. Therefore, the aim of this study was to compare the long-term outcomes, including overall survival (OS), of patients treated with AS after ER vs primary surgery (PS) for T1 CRC using a propensity score-matched analysis from a large observational study. METHODS: This study investigated 6,105 patients with T1 CRC treated with either ER or surgical resection between 2009 and 2016 at 27 high-volume Japanese institutions, with those undergoing surgery alone included in the PS group and those undergoing AS after ER included in the AS group. Propensity score matching was used for long-term outcomes of mortality and recurrence analysis. RESULTS: After propensity score matching, 1,219 of 2,438 patients were identified in each group. The 5-year OS rates in the AS and PS groups were 97.1% and 96.0%, respectively (hazard ratio: 0.72, 95% confidence interval: 0.49-1.08), indicating the noninferiority of the AS group. Moreover, 32 patients (2.6%) in the AS group and 24 (2.0%) in the PS group had recurrences, with no significant difference between the 2 groups (odds ratio: 1.34, 95% confidence interval: 0.76-2.40, P = 0.344). DISCUSSION: ER before AS for T1 CRC had no adverse effect on patients' long-term outcomes, including the 5-year OS rate. ER is a viable first-line treatment option for endoscopically resectable T1 CRC.

Clinical performance of fecal calprotectin, lactoferrin, and hemoglobin for evaluating the disease activity of IBD and detecting colorectal tumors.

Background and Aim: Recently, noninvasive fecal markers have been used as indicators of intestinal inflammation in patients with inflammatory bowel disease (IBD). We conducted a clinical validation study to measure fecal calprotectin (Cp), lactoferrin (Lf), and hemoglobin (Hb) levels using an all-in-one kit in patients with IBD and colorectal tumors and aimed to clarify the utility of these fecal markers. Methods: In this study, 104 patients were analyzed, including 25 patients with ulcerative colitis (UC), 20 with Crohn's disease (CD), 48 with colorectal tumors, and 13 healthy controls (HC). Of the 48 patients with colorectal tumors, 14 had invasive cancer. We validated the utility of fecal Cp, Lf, and Hb levels by simultaneously measuring fecal markers in patients with IBD and colorectal tumors. Results: Fecal Cp and Lf had almost equivalent abilities in detecting clinical remission in patients with UC; however, fecal Cp was slightly superior to Lf. Regarding colorectal tumors, fecal Cp and Lf levels tended to be higher in patients with adenomas and colorectal cancer than in HCs. Although fecal Hb alone had the best sensitivity and specificity for detecting colorectal cancer, it had relatively low sensitivity for detecting advanced neoplasms and colorectal cancer. Conclusion: Fecal Cp and Lf can be used as almost equivalent biomarkers to assess the clinical activity in patients with UC. Fecal Hb is the most useful marker for screening colorectal cancer; however, adding fecal Cp and Lf may compensate for the low sensitivity of detecting for advanced colorectal tumors based on Hb alone.

Downregulation of SMOC1 is associated with progression of colorectal traditional serrated adenomas.

BACKGROUND: Aberrant DNA methylation is prevalent in colorectal serrated lesions. We previously reported that the CpG island of SMOC1 is frequently methylated in traditional serrated adenomas (TSAs) and colorectal cancers (CRCs) but is rarely methylated in sessile serrated lesions (SSLs). In the present study, we aimed to further characterize the expression of SMOC1 in early colorectal lesions. METHODS: SMOC1 expression was analyzed immunohistochemically in a series of colorectal tumors (n = 199) and adjacent normal colonic tissues (n = 112). RESULTS: SMOC1 was abundantly expressed in normal colon and SSLs while it was significantly downregulated in TSAs, advanced adenomas and cancers. Mean immunohistochemistry scores were as follows: normal colon, 24.2; hyperplastic polyp (HP), 18.9; SSL, 23.8; SSL with dysplasia (SSLD)/SSL with early invasive cancer (EIC), 15.8; TSA, 5.4; TSA with high grade dysplasia (HGD)/EIC, 4.7; non-advanced adenoma, 21.4; advanced adenoma, 11.9; EIC, 10.9. Higher levels SMOC1 expression correlated positively with proximal colon locations and flat tumoral morphology, reflecting its abundant expression in SSLs. Among TSAs that contained both flat and protruding components, levels of SMOC1 expression were significantly lower in the protruding components. CONCLUSION: Our results suggest that reduced expression of SMOC1 is associated with progression of TSAs and conventional adenomas and that SMOC1 expression may be a biomarker for diagnosis of serrated lesions and risk prediction in colorectal tumors.

Treatment Decision for Locally Resected T1 Colorectal Carcinoma-Verification of the Japanese Guideline Criteria for Additional Surgery Based on Long-Term Clinical Outcomes.

INTRODUCTION: To verify the value of the pathological criteria for additional treatment in locally resected pT1 colorectal carcinoma (CRC) which have been used in the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines since 2009. METHODS: We enrolled 4,667 patients with pT1 CRC treated at 27 institutions between July 2009 and December 2016 (1,257 patients with local resection alone [group A], 1,512 patients with additional surgery after local resection [group B], and 1,898 patients with surgery alone [group C]). All 5 factors of the JSCCR guidelines (submucosal resection margin, tumor histologic grade, submucosal invasion depth, lymphovascular invasion, and tumor budding) for lymph node metastasis (LNM) had been diagnosed prospectively. RESULTS: Any of the risk factors were present in 3,751 patients. The LNM incidence was 10.4% (95% confidence interval 9.4-11.5) in group B/C patients with risk factors, whereas it was 1.8% (95% confidence interval 0.4-5.3) in those without risk factors ( P < 0.01). In group A, the incidence of recurrence was 3.6% in patients with risk factors, but it was only 0.4% in patients without risk factors ( P < 0.01). The disease-free survival rate of group A patients classified as risk positive was significantly worse than those of groups B and C patients. However, the 5-year disease-free survival rate in group A patients with no risk was 99.6%. DISCUSSION: Our large-scale real-world multicenter study demonstrated the validity of the JSCCR criteria for pT1 CRC after local resection, especially regarding favorable outcomes in patients with low risk of LNM.

Association of serum superoxide dismutase activity and the incidence of colorectal cancer in a nested case-control study.

BACKGROUND: Superoxide dismutase (SOD) is an antioxidant enzyme that degrades superoxide, a major causative factor in carcinogenesis. We assessed associations between serum SOD activities and incidence of colorectal carcinoma (CRC) in a case-control study nested in the Japan Collaborative Cohort (JACC) study. METHODS: At baseline, 39,242 subjects donated serum samples. Participants diagnosed with CRC during follow-up were regarded as cases. Odds ratios (ORs) for CRC incidence associated with SOD were evaluated with conditional logistic regression models. In the current study, 176 cases and 524 controls were analyzed. RESULTS: For the overall cohort, a decreasing trend in risk of CRC with increasing SOD was observed (P for trend=0.054) and the fourth quartile of SOD level showed the lowest risk compared to the first (OR=0.52, 95% confidence interval [CI]=0.29-0.93). This was significant in men (P for trend=0.001), with the fourth quartile of SOD level showing the lowest risk compared to the first (OR, 0.23; 95%CI, 0.09-0.60). It was also exclusively observed for rectal cancer and left-sided CRC (P for trend, 0.037 and 0.020, respectively), with the fourth quartile again showing the lowest risk compared to the first (OR, 0.28 and 0.38; 95%CI, 0.09-0.84 and 0.16-0.91, respectively). Limiting subjects to those followed-up over 2 years, all trends remained unchanged. CONCLUSIONS: Our findings suggest that serum SOD activity correlates inversely with risk of CRC, particularly in men and individuals with rectal cancer/left-sided CRC.

Nomogram as a novel predictive tool for lymph node metastasis in T1 colorectal cancer treated with endoscopic resection: a nationwide, multicenter study.

BACKGROUND AND AIMS: Since 2009, the Japanese Society for Cancer of the Colon and Rectum guidelines have recommended that tumor budding and submucosal invasion depth, in addition to lymphovascular invasion and tumor grade, be included as risk factors for lymph node metastasis (LNM) in patients with T1 colorectal cancer (CRC). In this study, a novel nomogram was developed and validated by usirge-scale, real-world data, including the Japanese Society for Cancer of the Colon and Rectum risk factors, to accurately evaluate the risk of LNM in T1 CRC. METHODS: Data from 4673 patients with T1 CRC treated at 27 high-volume institutions between 2009 and 2016 were analyzed for LNM risk. To prepare a nonrandom split sample, the total cohort was divided into development and validation cohorts. Pathologic findings were extracted from the medical records of each participating institution. The discrimination ability was measured by using the concordance index, and the variability in each prediction was evaluated by using calibration curves. RESULTS: Six independent risk factors for LNM, including submucosal invasion depth and tumor budding, were identified in the development cohort and entered into a nomogram. The concordance index was .784 for the clinical calculator in the development cohort and .790 in the validation cohort. The calibration curve approached the 45-degree diagonal in the validation cohort. CONCLUSIONS: This is the first nomogram to include submucosal invasion depth and tumor budding for use in routine pathologic diagnosis based on data from a nationwide multi-institutional study. This nomogram, developed with real-world data, should improve decision-making for an appropriate treatment strategy for T1 CRC.

An older patient with active ulcerative colitis and coronavirus disease 2019 (COVID-19) pneumonia successfully treated with the combination of anti-TNFα therapy and azathioprine.

A 77-year-old patient with ulcerative colitis (UC) was transferred to our department because of worsening bloody diarrhea and abdominal pain, which was consistent with a UC flare. Two days after admission, she complained of cough and high fever. The polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was positive, and a computed tomography showed pneumonia in the left lobe, consistent with coronavirus disease 2019 (COVID-19) pneumonia. However, frequent bloody diarrhea and abdominal pain due to the UC flare persisted; therefore, an additional immunosuppressive agent needed to be considered. We initiated infliximab biosimilar (IFX-BS), and her abdominal symptoms improved. However, they deteriorated after the second IFX-BS infusion. After confirming that the patient was negative for SARS-CoV-2 by PCR, we administered a combination of azathioprine and IFX-BS. The combination treatment improved her intestinal symptoms without worsening COVID-19 pneumonia. She has remained in remission for over a year since her discharge.

Jejunal Angiodysplasia in an Elderly Patient with Aortic Stenosis: Significance of Von Willebrand Factor as an Etiologic Factor.

Heyde's syndrome is a disease in which patients with aortic stenosis (AS) bleed from angiodysplasia. An 80-year-old woman with a history of severe AS was referred to our hospital with melena and anemia. The patient underwent jejunal resection after repeated blood transfusions. A pathological examination revealed angiodysplasia, and the patient's plasma lacked high-molecular-weight von Willebrand factor (VWF) multimers, leading to the diagnosis of Heyde's syndrome. The patient underwent transcatheter aortic valve implantation (TAVI) one year after the diagnosis, and the VWF index recovered. This is a valuable case in which the pathological analysis of angiodysplasia associated with Heyde's syndrome was possible.

Red blood cell distribution width as a novel marker for predicting bleeding after endoscopic resection for early gastric cancer.

Objectives: Endoscopic resection (ER) is a minimally invasive treatment for early gastric cancer (EGC); however, there is a high occurrence of bleeding. This study aimed to clarify the significance of red blood cell distribution width (RDW) as a predictive risk factor for bleeding after ER for EGC. Methods: We conducted a retrospective study based on data for patients who underwent ER for EGC from 2019 to 2021. This study included 79 lesions in 54 patients who underwent ER for EGC. The primary outcome was the association between RDW before ER and bleeding within 28 days of treatment. Receiver operating characteristic (ROC) curves were constructed, wherein areas under the curve (AUCs) and 95% confidence intervals were calculated to compare the discriminatory power of RDW for predicting bleeding. Results: Endoscopic submucosal dissection was used as the resection method for 73 lesions, whereas endoscopic mucosal resection was used for six lesions. En bloc resection was performed in all cases. There were no cases of perforation; however, bleeding after ER occurred in five cases (9.3%). ROC curve analysis of bleeding after ER showed that the AUC was 0.843 with a good diagnostic performance. When the cut-off value of RDW was set at 14.4%, sensitivity and specificity were 80% and 85.7%, respectively. There was a bleeding rate of 36.4% (4/11) at an RDW of ≥14.4%, which was significantly higher than that of 2.3% (1/43) at an RDW of <14.4%. Conclusion: RDW can be a predictor of bleeding risk after ER for EGC.

Serum amyloid A1 recruits neutrophils to the invasive front of T1 colorectal cancers.

BACKGROUND AND AIM: The tumor microenvironment plays an essential role in the development and progression of colorectal cancer (CRC). We recently reported that crosstalk between CRC cells and tumor-associated macrophages (TAMs) via serum amyloid A1 (SAA1) promotes invasion by T1 CRCs. In the present study, we aimed to clarify the role of neutrophils in early CRCs. METHODS: Immunohistochemical analysis of CD66b, chemokine CXC motif ligand 8 (CXCL8 or interleukin-8, IL-8) and matrix metalloproteinase-9 (MMP-9) was performed using primary T1 CRCs (n = 49). The HL-60 human promyelocytic leukemia cell line and THP-1 human monocytic leukemia cell line were used to obtain neutrophil-like and macrophage-like cells, respectively. Boyden chamber assays were used to analyze cell migration and invasion, and quantitative RT-PCR was used to analyze gene expression. RESULTS: Immunohistochemical analysis revealed accumulation of neutrophils at the SAA1-positive invasive front of T1 CRCs. Experiments using HL-60 cells suggested that treatment with SAA1 induced neutrophil migration and expression of CXCL8 and MMP-9 in neutrophils and that neutrophils promote CRC cell migration and invasion. Immunohistochemistry confirmed accumulation of CXCL8- or MMP-9-positive neutrophils at the SAA1-positive invasive front of T1 CRCs. Moreover, co-culture experiments using CRC, THP-1 and HL-60 cells suggested that CRC cells activated by macrophages upregulate CXCL8 and MMP-9 in neutrophils. CONCLUSIONS: Our results suggest that interplay between macrophages and CRC cells leads to recruitment of neutrophils to the invasive front of T1 CRCs and that SAA1 secreted by CRC cells activate neutrophils to promote invasion.

Immune-related colitis and pancreatitis treated with infliximab.

Patients with various cancers benefit from immune checkpoint inhibitors. However, immune checkpoint inhibitor-induced adverse events have also been reported, such as colitis. Prednisolone is the first-line treatment for immune-related adverse events, but second-line therapy for patients refractory to steroids has not been established. Furthermore, the inflammatory cytokine expression pattern in the intestinal mucosa of patients with steroid-refractory immune-related colitis remains unclear. We present the case of a 48-year-old man diagnosed with immune-related colitis and pancreatitis induced by pembrolizumab for advanced lung cancer. First, we administered 50 mg/day of prednisolone, and the patient's abdominal symptoms improved. However, the pancreatic enzyme levels did not return to normal. Furthermore, the patient's diarrhea worsened and hematochezia appeared at a 40 mg/day prednisolone dose. A mucosal cytokine analysis identified a low interleukin-10 messenger RNA level, which has been associated with a poor response to prednisolone. Thus, we administered 5 mg/kg of infliximab; the patient's diarrhea and hematochezia immediately improved, and the pancreatic enzyme levels returned to normal. Infliximab was administered three times every 2 weeks. After, the patient's colitis and pancreatitis did not recur. To our knowledge, this is the first report demonstrating the effectiveness of infliximab for immune-related colitis and pancreatitis.

Nationwide registry for patients with neuroendocrine neoplasm of pancreas, gastrointestinal tract, lungs, bronchi, or thymus in Japan.

BACKGROUND: Neuroendocrine neoplasm (NEN) is a comparatively rare tumor that has been considered indolent. Due to these characteristics, detailed epidemiological data have not been analyzed in Japan. To elucidate the present status of NEN diagnosis and treatment in Japan, we started a registry cohort study in January 2015. METHODS: Patients pathologically diagnosed with NENs of the pancreas, gastrointestinal tract, lungs, bronchi, or thymus after January 2012 were enrolled in this registry after the date of ethics review committee approval in each hospital or institute. Follow-up was continued for enrolled patients. RESULTS: During 5 years of enrollment between January 2015 and December 2019, a total of 1526 participants from 63 departments were enrolled in this registry (mean, 305.2 participants/year), covering approximately 5.8% of the annual incidence of NENs in Japan. For pancreatic NEN, 41.9% of patients had metastasis and the dominant metastatic site was the liver, at twice the rate of lymph node metastasis in the current registry. In contrast, the frequency of lymph node metastasis from gastrointestinal (GI)-NEN was similar to that of the liver. The distribution of WHO 2019-based grades varied according to the primary site. Low-to-intermediate grade (G1-G2) was dominant for duodenal, jejunal/ileal, rectal, and pancreatic NENs, whereas high grade (G3 or NEC) was dominant for esophageal, stomach, and colon NENs. For PanNENs, G3 and NEC accounted only for 1.6% and 2.9%, respectively. CONCLUSIONS: These cohort data provide crucial information for clinical research to clarify the characteristics of NENs in Japan.

Guidelines for Colorectal Cold Polypectomy (supplement to "Guidelines for Colorectal Endoscopic Submucosal Dissection/Endoscopic Mucosal Resection").

The Japan Gastroenterological Endoscopy Society published the second edition of the "Guidelines for Colorectal Endoscopic Submucosal Dissection/Endoscopic Mucosal Resection" in 2019 to clarify the indications for colorectal endoscopic mucosal resection (EMR) and endoscopic submucosal dissection and to ensure appropriate preoperative diagnoses as well as effective and safe endoscopic treatment in front-line clinical settings. Endoscopic resection with electrocautery, including polypectomy and EMR, is indicated for colorectal polyps. Recently, the number of facilities introducing and implementing cold polypectomy without electrocautery has increased. Herein, we establish supplementary guidelines for cold polypectomy. Considering that the level of evidence for each statement is limited, these supplementary guidelines must be verified in clinical practice.

Extensive mucosal sloughing of the small intestine and colon in a patient with severe COVID-19.

Patients with coronavirus disease 2019 (COVID-19) primarily cause respiratory symptoms. However, gastrointestinal (GI) symptoms can also occur. The endoscopic characteristics of the GI tract in COVID-19 patients remain unclear. We herein report a 62-year-old male with severe COVID-19 who needed multidisciplinary treatment, including extracorporeal membrane oxygenation (ECMO). Despite the improvement in his respiratory status, GI bleeding developed. Capsule endoscopy and colonoscopy revealed extensive mucosal sloughing in the lower intestinal tract. Additionally, we performed a comprehensive analysis of the mRNA expression levels of various proinflammatory cytokines in the intestinal mucosal tissues. The results suggested a significant elevation of IL-6, which could be involved in the pathophysiology of the GI involvement in COVID-19. Further investigation with more clinical data, including endoscopic findings and molecular analyses, will contribute to a comprehensive understanding of COVID-19-associated GI injury.

Mediterranean fever gene-associated enterocolitis in an elderly Japanese woman.

An 86-year-old woman was admitted to our hospital with anemia. She had never experienced symptoms of serositis. Colonoscopy revealed colitis with erosions and a friable mucosa. First, she was diagnosed with unclassified inflammatory bowel disease (IBD-U). We suspected familial Mediterranean fever as a differential diagnosis of IBD-U, and MEFV gene analysis showed heterozygosity for Exon2 R202Q. The patient was treated with colchicine 0.5 mg. After 4 months, a follow-up colonoscopy showed remarkable improvement of the mucosal inflammation throughout the entire colon. MEFV gene-associated enterocolitis responding to colchicine may be observed in patients with IBD-U and elucidating the role of MEFV gene mutations in intestinal inflammation is a future challenge.

Snapshots of lymphatic pathways in colorectal cancer surgery using near-infrared fluorescence, in vivo and ex vivo.

INTRODUCTION: Indocyanine green (ICG) fluorescence imaging has been used for blood flow assessment in anastomoses in the field of colorectal cancer surgery. However, whether ICG fluorescence is related to the presence of cancer cells in the lymph nodes is unclear. We explored the utilization of ICG fluorescence in colorectal cancer surgery. MATERIALS AND METHODS: ICG was injected into the submucosa around the tumor before radical resection in colorectal cancer patients. Intraoperatively, near-infrared (NIR) fluorescence was used for lymphatic flow visualization. After specimen removal, harvested lymph nodes were classified as positive or negative based on the detection of fluorescence, followed by pathological examination. ICG distribution on a section of each lymph node was examined by fluorescence microscopy. RESULTS: Overall, 155 patients underwent real-time NIR fluorescence imaging-guided surgery. Altogether, 1,017 lymph nodes were retrieved from these patients. Metastatic lymph nodes were present in 36 (5.8%) of 622 fluorescence-negative lymph nodes, which was significantly higher than 11 (2.8%) of 395 fluorescence-positive lymph nodes (odds ratio: 2.15, P = 0.03). Fluorescence microscopy of metastatic lymph nodes showed that ICG fluorescence was present in the normal structural region but not in the cancerous region of the lymph nodes. Furthermore, ICG fluorescence was observed in all metastatic lymph nodes, except those with cancer cells occupying >90% of the total area. CONCLUSIONS: ICG fluorescence detected only the normal parts of the lymph node draining from the peritumoral area and not the cancer tissues. This finding is important for developing appropriate strategies for navigation surgery using NIR fluorescence.