Low Patient Weight and Long Intubation Time Are Key Factors for Pain during Colonoscopy.

Although the clinical usefulness of colonoscopy has been established, the procedure remains painful for many patients. This study was designed to clarify the factors predicting colonoscopy-related pain. We evaluated 283 consecutive patients who completed a first-ever, total colonoscopy without sedatives or analgesics. The severity of pain symptoms was evaluated by a numeric rating scale (NRS) in a questionnaire immediately after the colonoscopy. Patient backgrounds and endoscopic findings were analyzed to evaluate their association with pain. Out of 283 patients, 53 scored their pain 0-1 on the NRS while 48 scored it 6-10. We defined the colonoscopies of the former and latter patients as painless and painful, respectively, and compared the two. Multivariate analyses revealed that low body weight (OR 4.95, 95%CI 1.89-12.99) and longer intubation time (OR 3.63, 95%CI 1.46-9.03) were significant risk factors for painful colonoscopy. To identify factors contributing to the increased intubation time, we divided subjects into short- and long-intubation-time groups based on a median insertion time of 7 min. Older age (OR 2.28, 95%CI 1.31-3.98), previous abdominal surgery (OR 1.93, 95%CI 1.13-3.32) and findings of invasive cancer (OR 10.90, 95%CI 1.34-88.90) were significant factors for longer intubation time.

Endoscopic evaluation by the Kyoto classification of gastritis combined with serum anti-Helicobacter pylori antibody testing reliably risk-stratifies subjects in a population-based gastric cancer screening program.

BACKGROUND: We previously demonstrated that the Kyoto classification of gastritis was useful for judging the status of Helicobacter pylori infection in a population-based screening program, and that adding H. pylori antibody test improved its accuracy (UMIN000028629). Here, we tested whether our endoscopic diagnosis of H. pylori infection status reliably estimated gastric cancer risk in the program. METHODS: Data were collected from1345 subjects who underwent endoscopic follow-up 4 years after the end of the registration. We analyzed the association of three diagnostic methods of H. pylori infection with gastric cancer detection: (1) endoscopic diagnosis based on the Kyoto classification of gastritis; (2) serum diagnosis according to the ABC method (H. pylori antibody and pepsinogen I and II); and (3) endoscopic diagnosis together with H. pylori antibody test. RESULTS: During the follow-up, 19 cases of gastric cancer were detected. By Kaplan-Meier analysis, the detection rates of cancer were significantly higher in the past or current H. pylori infection groups than in the never-infected group with all 3 methods. By the Cox proportional hazards model, the hazard ratio for cancer detection was highest in evaluation with the combined endoscopic diagnosis and the antibody test (method 3; hazard ratio 22.6, 95% confidence interval 2.99-171) among the three methods (the endoscopic diagnosis (method 1); 11.3, 2.58-49.8, and the ABC method (method 2); 7.52, 2.49-22.7). CONCLUSIONS: Endoscopic evaluation of H. pylori status with the Kyoto classification of gastritis, especially combined with serum anti-Helicobacter pylori antibody testing, reliably risk-stratified subjects in a population-based gastric cancer screening program.

Fever and electrocoagulation syndrome after colorectal endoscopic submucosal dissection for patients with immunosuppressants and steroids.

Objectives: Transient fever and electrocoagulation syndrome after colorectal endoscopic submucosal dissection (ESD) remain a challenge. The aim of this study was to assess the risk factors of post-ESD fever and post-ESD coagulation syndrome (PECS), focusing on the involvement of immunosuppressive drugs and steroids (IM). Methods: This retrospective analysis included 510 patients who underwent colorectal ESD at Okayama University Hospital from 2015 to 2020. The incidence rate, clinical outcome, and factors associated with post-ESD fever and PECS were investigated. Results: Post-ESD fever and PECS occurred in 63 patients (12.4%) and 43 patients (8.4%), respectively. In multivariate analysis, the American Society of Anesthesiologists Physical Status ≥3, the use of immunosuppressants or prednisolone ≥5mg (IM group), and injury to muscle layer/perforation were significantly associated with post-ESD fever. In PECS, IM group, tumors located on the right side, treatment time ≥60 min, injury to the muscle layer, and multiple lesions were independent risk factors. Both post-ESD fever and PECS improved conservatively in the IM group, and no serious complication was observed. Conclusions: The use of IM was a risk factor for both post-ESD fever and PECS. However, there were no serious complications in colorectal ESD for patients taking IM.

Circulating tumor DNA dynamics analysis in a xenograft mouse model with esophageal squamous cell carcinoma.

BACKGROUND: It remains unclear which factors, such as tumor volume and tumor invasion, influence circulating tumor DNA (ctDNA), and the origin of ctDNA in liquid biopsy is always problematic. To use liquid biopsies clinically, it will be very important to address these questions. AIM: To assess the origin of ctDNA, clarify the dynamics of ctDNA levels, assess ctDNA levels by using a xenograft mouse after treatment, and to determine whether tumor volume and invasion are related to ctDNA levels. METHODS: Tumor xenotransplants were established by inoculating BALB/c-nu/nu mice with the TE11 cell line. Groups of mice were injected with xenografts at two or four sites and sacrificed at the appropriate time point after xenotransplantation for ctDNA analysis. Analysis of ctDNA was performed by droplet digital PCR, using the human telomerase reverse transcriptase (hTERT) gene. RESULTS: Mice given two-site xenografts were sacrificed for ctDNA at week 4 and week 8. No hTERT was detected at week 4, but it was detected at week 8. However, in four-site xenograft mice, hTERT was detected both at week 4 and week 6. These experiments revealed that both tumor invasion and tumor volume were associated with the detection of ctDNA. In resection experiments, hTERT was detected at resection, but had decreased by 6 h, and was no longer detected 1 and 3 d after resection. CONCLUSION: We clarified the origin and dynamics of ctDNA, showing that tumor volume is an important factor. We also found that when the tumor was completely resected, ctDNA was absent after one or more days.

Feasibility of endoscopic evaluation of Helicobacter pylori infection status by using the Kyoto classification of gastritis in the population-based gastric cancer screening program: A prospective cohort study.

BACKGROUND AND AIMS: We have started a new population-based endoscopic gastric cancer screening program in Kurashiki city with consideration of Helicobacter pylori infection status based on endoscopic features. We aimed to verify the feasibility of this attempt in a prospective case-registration study (UMIN000028629). METHODS: Data were collected from 1784 subjects without past eradication of H. pylori and who underwent endoscopic gastric cancer screening in Kurashiki Central Hospital Preventive Healthcare Plaza from September 2017 to June 2018. Endoscopic judgment of H. pylori infection status was made according to the Kyoto classification of gastritis. For comparison, a combination serum test of anti-H. pylori antibody and pepsinogen I and II, the ABC method, was used. RESULTS: The endoscopic diagnoses were nongastritis, 1215 (68.1%); active or inactive gastritis, 469 (26.3%); and undefined, 23 (1.3%). With the ABC method as a reference standard, the false-negative rate of the endoscopic judgment for H. pylori infection was 16.3% (95% confidence interval: 13.1%-20.0%). Most false-negative cases were of Group B in the ABC method, which is considered gastritis with mild mucosal atrophy. Antibody titers in this population were mostly in the weak-positive range but clinically significant elevation of the antibody suggesting current infection was observed in some cases. CONCLUSIONS: Endoscopic diagnosis of H. pylori infection status in a population-based gastric cancer screening program is mostly reliable, but false-negative results may occur, especially in patients with mild gastric atrophy. To avoid this limitation, we recommend adding H. pylori antibody test to the program.

Heterogeneous distribution of Fusobacterium nucleatum in the progression of colorectal cancer.

BACKGROUND AND AIM: Fusobacterium nucleatum (Fn) is involved in colorectal cancer (CRC) growth and is a biomarker for patient prognosis and management. However, the ecology of Fn in CRC and the distribution of intratumoral Fn are unknown. METHODS: We evaluated Fn and the status of KRAS and BRAF in 200 colorectal neoplasms (118 adenomas and 82 cancers) and 149 matched adjacent normal mucosas. The differentiation status between "surface" and "deep" areas of cancer tissue and matched normal mucosa were analyzed in 46 surgical samples; the Ki-67 index was also evaluated in these samples. RESULTS: Fusobacterium nucleatum presence in the tumor increased according to pathological stage (5.9% [adenoma] to 81.8% [stage III/IV]), while Fn presence in normal mucosa also increased (7.6% [adenoma] to 40.9% [stage III/IV]). The detection rates of Fn on the tumor surface and in deep areas were 45.7% and 32.6%, while that of normal mucosa were 26.1% and 23.9%, respectively. Stage III/IV tumors showed high Fn surface area expression (66.7%). Fn intratumoral heterogeneity (34.8%) was higher than that of KRAS (4.3%; P < 0.001) and BRAF (2.2%; P < 0.001). The Ki-67 index in Fn-positive cases was higher than that in negative cases (93.9% vs 89.0%; P = 0.01). CONCLUSIONS: Fusobacterium nucleatum was strongly present in CRC superficial areas at stage III/IV. The presence of Fn in the deep areas of adjacent normal mucosa also increased. The intratumoral heterogeneity of Fn is important in the use of Fn as a biomarker, as Fn is associated with CRC proliferative capacity.

Prediction of the prognosis of advanced hepatocellular carcinoma by TERT promoter mutations in circulating tumor DNA.

BACKGROUND ANDAIM: Human telomerase reverse transcriptase (TERT) promoter mutations were the most prevalent mutations in patients with hepatocellular carcinoma (HCC). We tried to detect the mutations with plasma circulating tumor DNA (ctDNA) in patients with advanced HCC and elucidated their clinical utility. METHODS: Circulating tumor DNA in plasma was extracted from 130 patients with advanced HCC who were treated with systemic chemotherapy (n = 86) or transcatheter arterial chemoembolization (n = 44), and TERT promoter mutations were examined with digital droplet polymerase chain reaction. The correlations between these mutations and the clinical outcome of patients were analyzed. RESULTS: Of the 130 patients examined, 71 patients (54.6%) were positive for TERT promoter mutations in ctDNA, of which 64 patients were -124bp G > A and 10 were -146bp G > A. The presence of TERT promoter mutations was correlated with large intrahepatic tumor size (P = 0.05) and high des-gamma carboxyprothrombin (P = 0.005). Overall survival of the patients with the mutations was significantly shorter than those without them (P < 0.001), and the patients with high (≥ 1%) fractional abundance of the mutant alleles showed shorter survival than those with low (< 1%) fractional abundance. Multivariate analysis revealed that TERT promoter mutation (hazard ratio [HR]: 1.94; 95% confidence interval [CI], 1.18-3.24; P < 0.01), systemic chemotherapy (HR: 2.38; 95% CI, 1.29-4.57; P < 0.01), and vascular invasion (HR: 2.16; 95% CI, 1.22-3.76; P < 0.01) were significant factors for poor overall survival. CONCLUSIONS: TERT promoter mutations in ctDNA were associated with short survival and could be a valuable biomarker for predicting the prognosis of patients with advanced HCC.

Evaluation of complete cold forceps polypectomy resection rate for 3- to 5-mm colorectal polyps.

BACKGROUND AND STUDY AIMS: The propriety of cold forceps polypectomy (CFP) using jumbo biopsy forceps for diminutive polyps remains controversial. We conducted a prospective study to evaluate the complete CFP resection rate of 3-5-mm polyps using additional endoscopic mucosal resection (EMR) specimens following CFP. PATIENTS AND METHODS: Patients with 3-5-mm protruded or flat elevated colorectal polyps diagnosed endoscopically as adenomas or serrated lesions were prospectively enrolled. CFP using jumbo biopsy forceps was used to remove the eligible polyps and repeated until the absence of residuals were confirmed via image-enhanced endoscopy or chromoendoscopy. After CFP, saline was injected at the defect, and the marginal specimen of the defect was resected using EMR to histologically evaluate the residue. The primary outcome was the complete CFP resection rate, which was defined as no residue at the EMR site. Other outcomes were the number of CFP bites and the complete resection rate by lesion size. RESULTS: Eighty patients with 120 polyps were enrolled. The mean polyp size was 4.1 ± 0.7 mm. The overall complete resection rate was 96.7% (95% confidence interval [CI], 91.7-98.7), and the rates for 3-, 4- and 5-mm polyps were 100% (95% CI, 86.7-100), 96.0% (95% CI, 86.5-98.9) and 95.5% (95% CI, 85.1-98.8), respectively. The one-bite CFP rates were 92%, 60% and 31% for the 3-, 4- and 5-mm polyps, respectively. CONCLUSIONS: The complete CFP resection rate for 3-5-mm polyps was acceptable, although the one-bite clearance rate decreased as the polyp size increased (UMIN000028841).

Liquid biopsy for patients with IBD-associated neoplasia.

BACKGROUND: It is often difficult to diagnose inflammatory bowel disease (IBD)-associated neoplasia endoscopically due to background inflammation. In addition, due to the absence of sensitive tumor biomarkers, countermeasures against IBD-associated neoplasia are crucial. The purpose of this study is to develop a new diagnostic method through the application of liquid biopsy. METHODS: Ten patients with IBD-associated cancers and high-grade dysplasia (HGD) with preserved tumor tissue and blood were included. Tumor and non-tumor tissues were analyzed for 48 cancer-related genes using next-generation sequencing. Simultaneously, circulating tumor DNA (ctDNA) was analyzed for mutations in the target genes using digital PCR. RESULTS: Out of 10 patients, seven had IBD-related cancer and three had IBD-related HGD. Two patients had carcinoma in situ; moreover, three had stageII and two had stage III. To avoid false positives, the mutation rate cutoff was set at 5% based on the control results; seven of 10 (70%) tumor tissue samples were mutation-positive. Mutation frequencies for each gene were as follows: TP53 (20.9%; R136H), TP53 (25.0%; C110W), TP53 (8.5%; H140Q), TP53 (31.1%; R150W), TP53 (12.8%; R141H), KRAS (40.0%; G12V), and PIK3CA (34.1%; R 88Q). The same mutations were detected in the blood of these seven patients. However, no mutations were detected in the blood of the remaining three patients with no tumor tissue mutations. The concordance rate between tumor tissue DNA and blood ctDNA was 100%. CONCLUSION: Blood liquid biopsy has the potential to be a new method for non-invasive diagnosis of IBD-associated neoplasia.

Blue laser imaging and linked color imaging improve the color difference value and visibility of colorectal polyps in underwater conditions.

BACKGROUND AND AIM: Underwater endoscopic mucosal resection (UEMR) has become widespread for treating colorectal polyps. However, which observational mode is best suited for determining polyp margins underwater remains unclear. To determine the best mode, we analyzed three imaging modes: white light imaging (WLI), blue laser imaging (BLI) and linked color imaging (LCI). METHODS: Images of consecutive colorectal polyps previously examined by these three modes before UEMR were analyzed according to the degree of underwater turbidity (transparent or cloudy). Color differences between the polyps and their surroundings were calculated using the Commission Internationale d'Eclairage Lab color space in which 3-D color parameters were expressed. Eight evaluators, who were blinded to the histology, scored the visibility from one (undetectable) to four (easily detectable) in both underwater conditions. The color differences and visibility scores were compared. RESULTS: Seventy-three polyps were evaluated. Sixty-one polyps (44 adenomatous, 17 serrated) were observed under transparent conditions, and 12 polyps (seven adenomatous, five serrated) were observed under cloudy conditions. Under transparent conditions, color differences for the BLI (8.5) and LCI (7.9) were significantly higher than that of WLI (5.7; P < 0.001). Visibility scores for BLI (3.6) and LCI (3.4) were also higher than that of WLI (3.1; P < 0.0001). Under cloudy conditions, visibility scores for LCI (2.9) and WLI (2.7) were significantly higher than that of BLI (2.2; P < 0.0001 and P = 0.04, respectively). CONCLUSIONS: BLI and LCI were better observational modes in transparent water; however, BLI was unsuitable for cloudy conditions.

Switching between Three Types of Mesalazine Formulation and Sulfasalazine in Patients with Active Ulcerative Colitis Who Have Already Received High-Dose Treatment with These Agents.

BACKGROUND AND AIM: Oral mesalazine and sulfasalazine (SASP) are key drugs for treating ulcerative colitis (UC). The efficacy of switching from one of the several mesalazine formulations to another is largely unknown. This study assessed the efficacy of switching among three types of mesalazine formulation and SASP for UC therapy. METHODS: UC patients receiving high-dose mesalazine/SASP who switched to other formulations due to disease activity were considered eligible. Efficacy was evaluated 2, 6, and 12 months after switching. RESULTS: A total of 106 switches in 88 UC patients were analyzed. The efficacy at 2 months after switching was observed in 23/39 (59%) cases from any mesalazine formulation to SASP, in 18/55 (33%) cases from one mesalazine to another, and in 2/12 (17%) cases from SASP to any mesalazine formulation. Nine of 43 effective cases showed inefficacy or became intolerant post-switching. Delayed efficacy more than two months after switching was observed in four cases. Steroid-free remission was achieved in 42/106 (39%) cases-within 100 days in 35 of these cases (83%). CONCLUSIONS: Switching from mesalazine to SASP was effective in more than half of cases. The efficacy of switching between mesalazine formulations was lower but may be worth attempting in clinical practice from a safety perspective.

Utility of liquid biopsy using urine in patients with pancreatic ductal adenocarcinoma.

In recent years, liquid biopsy for blood and body fluid in cancer patients has attracted attention. However, there have been few reports of liquid biopsy focusing on urine of pancreatic ductal adenocarcinoma (PDAC). In 56 patients with PDAC, DNA was extracted from urine and plasma prior to treatment, and KRAS mutations were analyzed with droplet digital PCR to examine the mutation detection rate. Our study showed that KRAS mutations were found in 27 cases (48%) in urine and 27 cases (48%) in plasma. The detection rate of urine KRAS mutations varied by renal functions. The rates were 70% (14/20) and 36% (13/36) in the creatinine clearance rate (CCr) < 70 mL/min group and in the CCr ≥ 70 mL/min group, respectively (P = .024). Whereas, no influence of the CCr was observed in the detection rates of plasma KRAS mutations. The rates were 50% (10/20) and 47% (17/36) in cases with the CCr < 70 mL/min group and the CCr ≥ 70 mL/min group, respectively. Although the sample size was small, this study clearly indicated a new possibility of less invasive urine liquid biopsy in PDAC patients.