Impact of a new dedicated sheath device for tissue sampling of biliary stricture on pathological diagnostic yield: Retrospective study.

Background and study aims Endoscopic transpapillary biliary forceps biopsy (TBFB) is a common method for obtaining specimens from biliary lesions. Its diagnostic yield is unsatisfactory; to overcome this disadvantage, a dedicated sheath has been developed. This study aimed to evaluate the outcomes of conventional TBFB and TBFB with a novel sheath device. Patients and methods Consecutive patients who underwent TBFB between January 2020 and December 2021 were retrospectively evaluated. The rate of obtaining adequate samples, failed attempts at forceps insertion into the bile duct, and sensitivity were compared between the two groups. Results Ninety-two patients who underwent 115 endoscopic retrograde cholangiopancreatographies (76 in the conventional group vs. 39 in the dedicated sheath group) were included. The rates of obtaining adequate samples, failed attempts of the forceps into the bile duct, and sensitivity were 72.4% vs. 89.7% ( P = 0.03), 28.3% vs. 0% ( P < 0.01), and 66.7% vs. 88.9% ( P = 0.02), respectively. Conclusions TBFB with the novel sheath device contributed to improved sensitivity for diagnosis of biliary stricture without insertion of forceps outside the bile duct.

Clinical outcomes and learning curve of Tip-in endoscopic mucosal resection for 15-25 mm colorectal neoplasms among non-experts.

BACKGROUND AND AIM: Tip-in endoscopic mucosal resection (EMR) has a high en bloc resection rate for large colorectal neoplasms. However, non-experts' performance in Tip-in EMR has not been investigated. We investigated whether Tip-in EMR can be achieved effectively and safely even by non-experts. METHODS: This retrospective study included consecutive patients who underwent Tip-in EMR for 15-25 mm colorectal nonpedunculated neoplasms at a Japanese tertiary cancer center between January 2014 and December 2020. Baseline characteristics, treatment outcomes, learning curve of non-experts, and risk factors of failing self-achieved en bloc resection were analyzed. RESULTS: A total of 597 lesions were analyzed (438 by experts and 159 by non-experts). The self-achieved en bloc resection (69.8% vs 88.6%, P < 0.001) and self-achieved R0 resection (58.3% vs 76.5%, P < 0.001) rates were significantly lower in non-experts with <10 cases of experience than in experts, but not in non-experts with >10 cases. Adverse event (P = 0.165) and local recurrence (P = 0.892) rates were not significantly different between experts and non-experts. Risk factors of failing self-achieved en bloc resection were non-polypoid morphology (OR 3.4, 95% CI 1.6-7.3, P = 0.001), lesions with an underlying semilunar fold (OR 3.6, 95% CI 1.6-7.3, P < 0.001), positive non-lifting sign (OR 3.1, 95% CI 1.2-8.0, P = 0.023), and non-experts with an experience of ≤10 cases (OR 3.6, 95% CI 2.1-6.3, P < 0.001). CONCLUSION: The clinical outcomes of Tip-in EMR for 15-25 mm lesions performed by non-experts were favorable.

Proportions and characteristics of interval cancer in annual fecal immunochemical test screening and postcolonoscopy colorectal cancer: Results from a Japanese multicenter prospective study using questionnaires, the C-DETECT study.

OBJECTIVES: There are several types of colorectal cancer (CRC) according to the detection methods and intervals, including interval CRC (iCRC) and postcolonoscopy CRC (PCCRC). We aimed to examine their proportions and characteristics. METHODS: We conducted a multicenter prospective study using questionnaires in Japan ("C-DETECT study"), in which differences in CRC characteristics according to detection methods and intervals were examined from consecutive adult patients. Because the annual fecal immunochemical test (FIT) was used in population-based screening, the annual FIT-iCRC was assessed. RESULTS: In total, 1241 CRC patients (1064 with invasive CRC) were included. Annual FIT-iCRC (a), 3-year PCCRC (b), and CRC detected within 1 year after a positive FIT with noncompliance to colonoscopy (c) accounted for 4.5%, 7.0%, and 3.9% of all CRCs, respectively, and for 3.9%, 5.4%, and 4.3% of invasive CRCs, respectively. The comparison among these (a, b, c) and other CRCs (d) demonstrated differences in the proportions of ≥T2 invasion ([a] 58.9%, [b] 44.8%, [c] 87.5%, [d] 73.0%), metastasis ([a] 33.9%, [b] 21.8%, [c] 54.2%, [d] 43.9%), right-sided CRC ([a] 42.9%, [b] 40.2%, [c] 18.8%, [d] 28.6%), and female sex ([a] 53.6%, [b] 49.4%, [c] 27.1%, [d] 41.6%). In metastatic CRC, (a) and (b) showed a higher proportions of BRAF mutations ([a] [b] 12.0%, [c] [d] 3.1%). CONCLUSIONS: Annual FIT-iCRC and 3-year PCCRC existed in nonnegligible proportions. They were characterized by higher proportions of right-sided tumors, female sex, and BRAF mutations. These findings suggest that annual FIT-iCRC and 3-year PCCRC may have biological features different from those of other CRCs.

Comparison of the efficacy and tolerability of elobixibat plus sodium picosulfate with magnesium citrate and split-dose 2-L polyethylene glycol with ascorbic acid for bowel preparation before outpatient colonoscopy: a study protocol for the multicentre, randomised, controlled E-PLUS trial.

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).

Efficacy of endoscopic submucosal resection with a ligation device for small rectal neuroendocrine tumor: study protocol of a multicenter open-label randomized control trial (BANDIT trial).

BACKGROUND: Endoscopic resection is widely accepted as a local treatment for rectal neuroendocrine tumors sized ≤ 10 mm. However, there is no consensus on the best method for the endoscopic resection of rectal neuroendocrine tumors. As a simplified endoscopic procedure, endoscopic submucosal resection with a ligation device (ESMR-L) indicates a histologically complete resection rate comparable to that of endoscopic submucosal dissection (ESD). We hypothesized that ESMR-L than ESD would be preferred for rectal neuroendocrine tumors. Hence, this trial aimed to verify whether ESMR-L is non-inferior to ESD in terms of histologically complete resection rate. METHODS: This is a prospective, open-label, multicenter, non-inferiority, randomized controlled trial of two parallel groups, conducted at the Shizuoka Cancer Center and 31 other institutions in Japan. Patients with a lesion endoscopically diagnosed as a rectal neuroendocrine tumor ≤ 10 mm are eligible for inclusion. A total of 266 patients will be recruited and randomized to undergo either ESD or ESMR-L. The primary endpoint is the rate of en bloc resection with histologically tumor-free margins (R0 resection). Secondary endpoints include en bloc resection rate, procedure time, adverse events, hospitalization days, total devices and agents cost, adverse event rate between groups with and without resection site closure, outcomes between expert and non-expert endoscopists, and factors associated with R0 resection failure. The sample size is determined based on the assumption that the R0 resection rate will be 95.2% in the ESD group and 95.3% in the ESMR-L group, with a non-inferiority margin of 8%. With a one-sided significance level of 0.05 and a power of 80%, 226 participants are required. Assuming a dropout rate of 15%, 266 patients will be included in this study. DISCUSSION: This is the first multicenter randomized controlled trial comparing ESD and ESMR-L for the R0 resection of rectal neuroendocrine tumors ≤ 10 mm. This will provide valuable information for standardizing endoscopic resection methods for rectal neuroendocrine tumors. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs042210124. Registered on Jan 6, 2022.

Dual recognition of multiple signals in bacterial outer membrane proteins enhances assembly and maintains membrane integrity.

Outer membrane proteins (OMPs) are essential components of the outer membrane of Gram-negative bacteria. In terms of protein targeting and assembly, the current dogma holds that a 'ß-signal' imprinted in the final ß-strand of the OMP engages the ß-barrel assembly machinery (BAM) complex to initiate membrane insertion and assembly of the OMP into the outer membrane. Here, we revealed an additional rule that signals equivalent to the ß-signal are repeated in other, internal ß-strands within bacterial OMPs, by peptidomimetic and mutational analysis. The internal signal is needed to promote the efficiency of the assembly reaction of these OMPs. BamD, an essential subunit of the BAM complex, recognizes the internal signal and the ß-signal, arranging several ß-strands and partial folding for rapid OMP assembly. The internal signal-BamD ordering system is not essential for bacterial viability but is necessary to retain the integrity of the outer membrane against antibiotics and other environmental insults.

Evaluating false-positive detection in a computer-aided detection system for colonoscopy.

BACKGROUND AND AIM: Computer-aided detection (CADe) systems can efficiently detect polyps during colonoscopy. However, false-positive (FP) activation is a major limitation of CADe. We aimed to compare the rate and causes of FP using CADe before and after an update designed to reduce FP. METHODS: We analyzed CADe-assisted colonoscopy videos recorded between July 2022 and October 2022. The number and causes of FPs and excessive time spent by the endoscopist on FP (ET) were compared pre- and post-update using 1:1 propensity score matching. RESULTS: During the study period, 191 colonoscopy videos (94 and 97 in the pre- and post-update groups, respectively) were recorded. Propensity score matching resulted in 146 videos (73 in each group). The mean number of FPs and median ET per colonoscopy were significantly lower in the post-update group than those in the pre-update group (4.2 ± 3.7 vs 18.1 ± 11.1; P < 0.001 and 0 vs 16 s; P < 0.001, respectively). Mucosal tags, bubbles, and folds had the strongest association with decreased FP post-update (pre-update vs post-update: 4.3 ± 3.6 vs 0.4 ± 0.8, 0.32 ± 0.70 vs 0.04 ± 0.20, and 8.6 ± 6.7 vs 1.6 ± 1.7, respectively). There was no significant decrease in the true positive rate (post-update vs pre-update: 95.0% vs 99.2%; P = 0.09) or the adenoma detection rate (post-update vs pre-update: 52.1% vs 49.3%; P = 0.87). CONCLUSIONS: The updated CADe can reduce FP without impairing polyp detection. A reduction in FP may help relieve the burden on endoscopists.

The Effectiveness of Screening Total Colonoscopy for Preoperative Patients with Gastric Cancer.

BACKGROUND: Colorectal cancer (CRC) is the most common cancer that coincides with gastric cancer (GC). Although the usefulness of total colonoscopy (TCS) as a CRC screening tool has been reported in preoperative patients with GC, the long-term outcome of patients with synchronous CRC (SCRC) remains unclear. This study aims to clarify the significance of preoperative screening TCS for GC in terms of survival outcomes. PATIENTS AND METHODS: We included 796 patients who underwent preoperative screening TCS for GC. The risk factors, clinicopathological features, and survival outcome of SCRC were examined. Furthermore, the cost-effectiveness was evaluated from the perspective of improving the rates of mortality caused by CRC. RESULTS: SCRC was observed in 43 patients (5.4%). Endoscopic treatment for SCRC was performed on 30 patients. In total, 15 patients underwent surgical resection, including 2 patients requiring additional surgery after endoscopic treatment. Regarding pathological stages, 25 patients had stage 0, 12 patients had stage I, 5 patients had stage II, and 1 patient had stage IIIB disease. The cumulative mortality rates were as follows: GC-related deaths, 12.6%; deaths from cancers other than CRC, 1%; deaths from other causes, 5.5%. No deaths were attributed to SCRC. Comparing the patients who did not undergo TCS, an incremental cost-effectiveness ratio analysis suggested that a screening cost of 5.86 million yen was required to prevent one CRC death. CONCLUSIONS: Curative treatment was possible in all patients with SCRC. No deaths were attributed to SCRC, suggesting that screening TCS for GC is effective.

A novel low-power pure-cut hot snare polypectomy for 10-14 mm colorectal adenomas: An ex vivo and a clinical prospective feasibility study (SHARP trial).

BACKGROUND AND AIM: Hot snare polypectomy using blend or coagulation current is widely used; however, it causes deeper tissue heat injury, leading to adverse events. We hypothesized that hot polypectomy using low-power pure cut current (PureCut, effect 1 10 W) could reduce deeper tissue heat injury. We conducted animal experiments to evaluate the deeper tissue heat injury and conducted a prospective clinical study to examine its cutting ability. METHODS: In a porcine rectum, hot polypectomy using Blend current (EndoCut, effect 3 40 W) and low-power pure cut current was performed. The deepest part of heat destruction and thickness of the non-burned submucosal layer were evaluated histologically. Based on the results, we performed low-power pure cut current hot polypectomy for 10-14 mm adenoma. The primary endpoint was complete resection defined as one-piece resection with negative for adenoma in quadrant biopsies from the defect margin. RESULTS: In experiments, all low-power pure-cut resections were limited within the submucosal layer whereas blend current resections coagulated the muscular layer in 13% (3/23). The remaining submucosal layer was thicker in low-power pure cut current than in blend current resections. In the clinical study, low-power pure-cut hot polypectomy removed all 100 enrolled polyps. For 98 pathologically neoplastic polyps, complete resection was achieved in 84 (85.7%, 95% confidence interval, 77-92%). The lower limit of the 95% confidence interval was not more than 15% below the pre-defined threshold of 86.6%. No severe adverse events occurred. CONCLUSIONS: A novel low-power pure-cut hot polypectomy may be feasible for adenoma measuring 10-14 mm. (UMIN000037678).

Atg15 is a vacuolar phospholipase that disintegrates organelle membranes.

Atg15 (autophagy-related 15) is a vacuolar phospholipase essential for the degradation of cytoplasm-to-vacuole targeting (Cvt) bodies and autophagic bodies, hereinafter referred to as intravacuolar/intralysosomal autophagic compartments (IACs), but it remains unknown if Atg15 directly disrupts IAC membranes. Here, we show that the recombinant Chaetomium thermophilum Atg15 lipase domain (CtAtg15(73-475)) possesses phospholipase activity. The activity of CtAtg15(73-475) was markedly elevated by limited digestion. We inserted the human rhinovirus 3C protease recognition sequence and found that cleavage between S159 and V160 was important to activate CtAtg15(73-475). Our molecular dynamics simulation suggested that the cleavage facilitated conformational change around the active center of CtAtg15, resulting in an exposed state. We confirmed that CtAtg15 could disintegrate S. cerevisiae IAC in vivo. Further, both mitochondria and IAC of S. cerevisiae were disintegrated by CtAtg15. This study suggests Atg15 plays a role in disrupting any organelle membranes delivered to vacuoles by autophagy.

Comprehensive Analysis of Early-onset Colorectal Cancer: A Review.

Early-onset colorectal cancer (CRC), which refers to CRC diagnosed in individuals below the age of 50 years, is a growing health concern that presents unique challenges in diagnosis, treatment, and long-term outcomes. Although approximately 70% of early-onset CRC cases are sporadic, with no apparent family history, approximately 25% have a familial component, and up to 20% may be associated with germline mutations, indicating a higher prevalence compared with the general population. Despite the progress in identifying the environmental, molecular, and genetic risk factors of early-onset CRC, the underlying causes for the global increase in its incidence remain unclear. This comprehensive review aims to provide a thorough analysis of early-onset CRC by examining the trends associated with its incidence, clinical and pathological characteristics, risk factors, molecular and genetic profiles, prognosis and screening strategies. By deepening our understanding of early-onset CRC, significant advances related to improving the outcomes and alleviating the burden of this disease on individuals, families, and healthcare systems can be achieved.

Desmin immunostaining is effective for improving interobserver variability in the depth assessment of the submucosal invasion of colorectal cancers.

Tumor depth evaluation is essential for pathological tumor staging because it affects clinical management as an independent risk factor for lymph node metastasis in colorectal cancers. However, poor interobserver variability of invasion depth has been reported. This study aimed to clarify the effectiveness of desmin immunostaining in the histological diagnosis of colorectal cancer. Overall, 63 sets of slides of colorectal cancer stained with hematoxylin and eosin (H&E) and desmin were prepared and independently reviewed by four examiners. After reviewing the desmin-stained slides, the interobserver variability of H&E slides alone was significantly improved for all examiners. For the assessment of Tis vs. T1, the sensitivity and accuracy were significantly improved for all examiners by combining H&E and desmin immunostaining. For the diagnosis of T1b vs. Tis or T1a, specificity and accuracy were significantly improved by adding desmin immunostaining. Ancillary desmin staining to assess submucosal invasion in colorectal cancers significantly improved interobserver agreement, led to efficient screening of T1 cancers, and reduced excessive T1b diagnoses. The combination of desmin immunostaining and H&E staining is highly recommended for diagnosing invasive colorectal cancer.

Local recurrence risk of esophageal squamous cell carcinoma due to intralesional damage during endoscopic submucosal dissection.

BACKGROUND AND AIM: It is unclear whether additional treatment should be considered given the recurrence risk after endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) when the vertical margin is positive or unclear (VM1/VMX) due to intralesional damage. This study aimed to elucidate the local recurrence risk of ESCC caused by intralesional damage during ESD. METHODS: Among consecutive patients with pT1a ESCCs initially treated by ESD at our institution between January 2006 and December 2018, ESCCs diagnosed as VM1/VMX were retrospectively reviewed. Exclusion criteria were piecemeal resection and any additional treatment after ESD. Intralesional damage included the following three types: a macroscopic hole inside the lesion, an incision from the lateral margin of the specimen into the lesion, and crushing injury or burn effect into the deepest area of the lesion without an obvious hole. The local recurrence rate after ESD was primarily analyzed. RESULTS: Of 1174 pT1a ESCCs initially treated using ESD, 22 lesions were histopathologically diagnosed as VM1/VMX due to intralesional damage (1.9%; 95% confidence interval [CI], 1.2-2.8%). At a median follow-up period of 60.0 (interquartile range, 15.0-84.0) months, no local recurrence was observed (0.0%; 95% CI, 0.0-13.3%) among 21 lesions finally evaluated. CONCLUSIONS: The impact of intralesional damage during ESD for ESCC on local recurrence might be negligible. Follow-up without additional treatment may be acceptable even if intralesional damage occurs and results in VM1/VMX after ESD for pT1a ESCCs.

Optimization of endoscopic ultrasound-guided tissue sample acquisition for commercially available comprehensive genome profiling.

BACKGROUND AND AIM: Optimal tumor samples are crucial for successful analysis using commercially available comprehensive genomic profiling (CACGP). However, samples acquired by endoscopic ultrasound-guided tissue acquisition (EUS-TA) are occasionally insufficient, and no consensus on the optimal number of needle passes required for CACGP exists. This study aimed to explore the optimal number of needle passes required for EUS-TA to procure an ideal sample fulfilling the prerequisite criteria of CACGPs. METHODS: Patients who underwent EUS-TA for solid masses between November 2019 and July 2021 were retrospectively studied. The correlation between the acquisition rate of an ideal sample and the number of needle passes mounted on a microscope slide was evaluated. Additionally, the factors predicting a successful analysis were investigated in patients scheduled for CACGP using EUS-TA-obtained samples during the same period. RESULTS: EUS-TAs using 22- and 19-gauge (G) needles were performed in 336 and 57 patients, respectively. There was a positive correlation between the acquisition rate and the number of passes using a 22-G needle (38.9%, 45.0%, 83.7%, and 100% for 1, 2, 3, and 4 passes, respectively), while no correlation was found with a 19-G needle (84.2%, 83.3%, and 85.0% for 1, 2, and 3 passes, respectively). The analysis success rate in patients with scheduled CACGP was significantly higher with ideal samples than with suboptimal samples (94.1% vs 55.0%, P < 0.01). CONCLUSIONS: The optimal estimated number of needle passes was 4 and 1-2 for 22- and 19-G needles, respectively.

A Japanese case of ovarian mucinous adenocarcinoma with germline double variants of MSH2 and BRCA2.

Germline double heterozygosity (GDH) is rarely reported in cases of inherited cancer syndromes, and GDH of a mismatch repair gene and BRCA has never been reported in Japan. Nonetheless, the current report demonstrates a case of ovarian mucinous adenocarcinoma with initiated Lynch syndrome (LS)-related surveillance because of a known germline MSH2 variant. Six and a half years after oophorectomy, multiple tumors developed in the patient's lungs, bones, and lymph nodes, and histology results confirmed mucinous adenocarcinoma. Systemic chemotherapy including an anti-PD-L1 antibody was effective for >1 year, but brain metastases developed. Pathology of the brain tumors showed mucinous adenocarcinoma without expression of MSH2 and MSH6, while multi-gene panel testing demonstrated not only high microsatellite instability and a high tumor mutation burden, but also germline BRCA2 variants. Further, germline testing in relatives confirmed both variants were from the paternal line, from which many LS-related cancers develop, but not BRCA-related cancer.