Background Endoscopic submucosal dissection (ESD) has been positively applied to and gradually standardized for early stomach cancer, particularly in Japan. However, because it is technically ...difficult to perform ESD of the colon, ESD is not a commonly used technique. Objective The aim of this study was to evaluate the possibility of standardizing colorectal ESD. Setting ESD was performed at the Department of Endoscopy, Hiroshima University Hospital. Design Time required for ESD, rate of complete en bloc resection, complication, and postoperative local persistence and recurrence were investigated retrospectively in 70 cases of colorectal neoplasia, wherein the lesion was more than 20 mm in diameter. Interventions All lesions were resected by ESD. Results The average (± SD) time required for ESD was 70.5 ± 45.9 minutes (range, 15-180 minutes), and the histologic rate of complete en bloc resection was 80.0% (56/70). With regard to complication, 1.4% of cases of postoperative hemorrhage (1/70) and 10.0% of cases of perforation (7/70) were observed in total. The rate of perforation was investigated with respect to the type of knife used for ESD and the period after the induction of ESD. The rate of perforation markedly decreased with the practice of the technique. Moreover, the rate of perforation was high when an insulated-tip diathermic knife was used; practicing this technique was insufficient to reduce the rate of perforation. The average duration of follow-up was 614 ± 289.5 days, and no case of local persistence and recurrence or metastasis was observed. Limitations The ESD technique depends on the level of each skill of each colonoscopist. Conclusions With regard to ESD of the colon, complication, eg, perforation, could be decreased by sufficient practice and selection of an appropriate knife. It is suggested that, in the near future, ESD will be standardized for the colon.
Conventional endoscopic resection (CER) is a widely accepted treatment for early colorectal neoplasia; however, large colorectal neoplasias remain problematic, as they necessitate piecemeal ...resection, increasing the risk of local recurrence. Endoscopic submucosal dissection (ESD) can improve the en bloc resection rate. This study aimed to evaluate local recurrence and its associated risk factors after endoscopic resection (ER) for colorectal neoplasias ≥20 mm.
A multicenter prospective study at 18 medium- and high-volume specialized institutions was conducted in Japan. Follow-up colonoscopy was performed after 12 months in cases of complete resection and after 3-6 months in cases of incomplete resection. Local recurrence was confirmed by endoscopic findings and/or pathological analysis.
Follow-up colonoscopy was performed in 1,524 of 1,845 enrolled colorectal neoplasias (mean age, 65 years; 885 men; median tumor size, 32.8 mm). The local recurrence rates were 4.3% (65/1,524), 6.8% (55/808), and 1.4% (10/716) for the entire cohort, for CER, and for ESD, respectively. The relative risks of local recurrence were 0.21 (95% confidence interval, 0.11-0.39) with ESD compared with CER, 0.32 (95% confidence interval, 0.11-0.92) with en bloc ESD compared with en bloc CER, and 0.90 (95% confidence interval, 0.39-2.12) with piecemeal ESD compared with piecemeal CER. Significant factors associated with local recurrence were piecemeal resection, laterally spreading tumors of granular type, tumor size ≥40 mm, no pre-treatment magnification, and ≤10 years of experience in CER, and piecemeal resection only in ESD.
En bloc ESD reduces the local recurrence rate for large colorectal neoplasias. Piecemeal resection is the most important risk factor for local recurrence regardless of the ER method used.
Microglia regulate synapse stability and remodeling through multiple molecular pathways. Regulated spatial distribution of microglia within nervous tissues may affect synapse dynamics. Here, we ...focused on the spatial relationship between microglia and spine synapses in the mouse neocortex and found that the distance between microglial cell bodies (MCBs) and spines is a critical parameter in spine stability. The region close to MCBs contains microglial processes with higher density and with more spine contacts. This region also shows more extensive exploration of tissue space by microglial processes. To test if the relative positions between MCBs and spines are important for spine stability, we simultaneously imaged spines and microglia in vivo and found negative correlation between spine–MCB distance and spine stability. Optical clearing methods enabled us to record the positions of all microglia in a large cortical volume and indicated their mutually exclusive distribution with similar density across cortical layers. This spatial arrangement of microglia is responsible for the repeated appearance of domains close to MCBs along dendritic arborization. The microglial position was largely independent of other cellular components. These results suggest that the spatial arrangement of microglia is critical for generating repetitive domains of synaptic instability along dendrites, which operates independently of other glial components.
Simultaneous imaging of dendritic spines and microglia in vivo revealed that a distance between microglial cell body and spine is a critical parameter in spine stability. Large‐volume optical reconstruction with a tissue‐clearing technique visualized a mutually exclusive distribution of microglia across cortical layers. Our results suggest that the spatial arrangement of microglia generates repetitive domains of instability of spines along dendrites.
Background A simple endoscopic classification to accurately predict deep submucosal invasive (SM-d) carcinoma would be clinically useful. Objective To develop and assess the validity of the NBI ...international colorectal endoscopic (NICE) classification for the characterization of SM-d carcinoma. Design The study was conducted in 4 phases: (1) evaluation of endoscopic differentiation by NBI-experienced colonoscopists; (2) extension of the NICE classification to incorporate SM-d (type 3) by using a modified Delphi method; (3) prospective validation of the individual criteria by inexperienced participants, by using high-definition still images without magnification of known histology; and (4) prospective validation of the individual criteria and overall classification by inexperienced participants after training. Setting Japanese academic unit. Main Outcome Measurements Performance characteristics of the NICE criteria (phase 3) and overall classification (phase 4) for SM-d carcinoma; sensitivity, specificity, predictive values, and accuracy. Results We expanded the NICE classification for the endoscopic diagnosis of SM-d carcinoma (type 3) and established the predictive validity of its individual components. The negative predictive values of the individual criteria for diagnosis of SM-d carcinoma were 76.2% (color), 88.5% (vessels), and 79.1% (surface pattern). When any 1 of the 3 SM-d criteria was present, the sensitivity was 94.9%, and the negative predictive value was 95.9%. The overall sensitivity and negative predictive value of a global, high-confidence prediction of SM-d carcinoma was 92%. Interobserver agreement for an overall SM-d carcinoma prediction was substantial (kappa 0.70). Limitations Single Japanese center, use of still images without prospective clinical evaluation. Conclusion The NICE classification is a valid tool for predicting SM-d carcinomas in colorectal tumors.
Background
We analyzed the influence of preceding endoscopic submucosal dissection (ESD) on the prognosis of patients with T1 colorectal carcinoma (CRC) after additional surgery using ...propensity-score matching.
Methods
1638 consecutive patients with T1 CRC were retrospectively identified between January 1998 and December 2016 at the Hiroshima GI Endoscopy Research Group. We assessed 602 patients with 602 T1 CRC who underwent additional surgery after ESD (
n
= 216) or surgery alone (
n
= 386). The enrolled patients were treated according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016, and were defined as non-endoscopically curable (non-e-curable) when they did not satisfy its curative criteria. We analyzed the pathological characteristics and the prognosis of non-e-curable patients using propensity-score matching between the additional surgery after ESD and surgery alone groups.
Results
There were no cases of recurrence and lymph node metastasis among the e-curable patients. The rate of lymph node metastasis and recurrences in the non-e-curable patients were 10.8% and 2.6%, respectively. After propensity-score matching, there were no significant differences in the 5-year overall survival rates (96.9% vs. 92.0%), 5-year disease-free survival rates (96.7% vs. 96.7%) and 5-year disease-specific survival rates (100% vs. 98.6%) after treatment of T1 CRCs between the 2 groups in non-e-curable patients.
Conclusions
Preceding ESD with histological en bloc resection for patients with T1 CRC did not affect their oncologic behavior adversely after additional surgery.
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•Series of fluspidine analogs were synthesized via original asymmetric catalysis.•Structure–ligand activity relationship study affords hybridized modified fluspidine.•Development of ...new synthetic method enables the improvement of ligand peformance.
Fluspidine is a high affinity ligand of the σ1 receptor. To further improve the ligand affinity, fluspidine analogs were systematically synthesized and screened herein. To design the modified ligand analogs, a docking simulation of the protein–ligand complex structure was examined. By using the developed synthetic strategy involving asymmetric catalytic 1,4-reduction of α,β -unsaturated carboxylic esters catalyzed by a chiral cobalt complex, 20 candidates of modified fluspidines were synthesized. The structure–activity relationships showed the development of a hybridized modified fluspidine. In addition, the inhibitory rate could be improved from 45% to 71%. This result demonstrates the importance of the development of a new synthetic method towards improving the ligand performance by providing a series of analogs.
Abstract
Objective. Colorectal endoscopic submucosal dissection (ESD) is a difficult procedure. We aimed to retrospectively assess the relationship between the outcome of ESD for colorectal tumors ...and the degree of fibrosis. Patients and methods. We examined 203 consecutive patients with colorectal tumors larger than 20 mm in diameter who had undergone ESD at our hospital from November 2002 to June 2009. During ESD, the degree of submucosal fibrosis was classified into three types (F0-2). The relationship between the degree of fibrosis and the lesion characteristics and those between the outcome of ESD and the degree of fibrosis were analyzed. Results. In the cases of granular laterally spreading tumors, the incidence of F2 fibrosis in nodular mixed-type tumors was significantly higher than that in homogenous-type tumors. An increase in the experience of the operators caused significant improvements in the rates of complete en bloc resection (p = 0.022) and perforation (p = 0.03) in the cases of lesions with F0-1 fibrosis. By contrast, operator experience did not cause any significant improvements in the rates of complete en bloc resection and perforation in the cases of lesions with F2 fibrosis. Conclusions. Experienced operators could safely perform complete en bloc resection in the cases of lesions with F0-1 fibrosis. However, in the cases of lesions with F2 fibrosis, the rate of complete en bloc resection was low and the perforation rate was high even when ESD was performed by an experienced operator.
MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression and commonly deregulated in carcinogenesis. To explore functionally crucial tumor-suppressive (TS)-miRNAs in ...hepatocellular carcinoma (HCC), we performed integrative function- and expression-based screenings of TS-miRNAs in six HCC cell lines. The screenings identified seven miRNAs, which showed growth-suppressive activities through the overexpression of each miRNA and were endogenously downregulated in HCC cell lines. Further expression analyses using a large panel of HCC cell lines and primary tumors demonstrated four miRNAs, miR-101, -195, -378 and -497, as candidate TS-miRNAs frequently silenced in HCCs. Among them, two clustered miRNAs miR-195 and miR-497 showed significant growth-suppressive activity with induction of G1 arrest. Comprehensive exploration of their targets using Argonute2-immunoprecipitation-deep-sequencing (Ago2-IP-seq) and genome-wide expression profiling after their overexpression followed by pathway analysis, revealed a significant enrichment of cell cycle regulators. Among the candidates, we successfully identified CCNE1, CDC25A, CCND3, CDK4, and BTRC as direct targets for miR-497 and miR-195. Moreover, target genes frequently upregulated in HCC in a tumor-specific manner, such as CDK6, CCNE1, CDC25A and CDK4, showed an inverse correlation in the expression of miR-195 and miR-497, and their targets. These results suggest the molecular pathway regulating cell cycle progression to be integrally altered by downregulation of miR-195 and miR-497 expression, leading to the aberrant cell proliferation in hepatocarcinogenesis.
Acute kidney injury is highly prevalent and associated with high morbidity and mortality, and there are no approved drugs for its prevention and treatment. Vagus nerve stimulation (VNS) alleviates ...inflammatory diseases including kidney disease; however, neural circuits involved in VNS-induced tissue protection remain poorly understood. The vagus nerve, a heterogeneous group of neural fibers, innervates numerous organs. VNS broadly stimulates these fibers without specificity. We used optogenetics to selectively stimulate vagus efferent or afferent fibers. Anterograde efferent fiber stimulation or anterograde (centripetal) sensory afferent fiber stimulation both conferred kidney protection from ischemia-reperfusion injury. We identified the C1 neurons-sympathetic nervous system-splenic nerve-spleen-kidney axis as the downstream pathway of vagus afferent fiber stimulation. Our study provides a map of the neural circuits important for kidney protection induced by VNS, which is critical for the safe and effective clinical application of VNS for protection from acute kidney injury.
Background and Aims: The true prevalence of Helicobacter pylori‐negative gastric cancer (HpNGC) is unknown. We attempt to clarify the prevalence and clinicopathologic features of HpNGC in Japanese.
...Methods: Helicobacter pylori infection was detected by antibody titer and microscopic observation. In addition, we confirmed the lack of endoscopic atrophy and histologic gastritis. In these cases, we added urea breath test or rapid urease test to confirm the absence of H. pylori. The mucus phenotype of gastric cancer tissue was also evaluated by immunohistochemistry.
Results: We screened 3161 gastric cancer cases from 1996 to 2010, and 21 cases were regarded as H. pylori negative. Clinically, patients with HpNGC were younger than patients with H. pylori‐positive gastric cancer (controls), and revealed a lack of male dominancy. Histologically, diffuse type was frequently found. All patients examined were pepsinogen negative. Among HpNGC cases with endoscopic resection, the depressed macroscopic appearance was dominant. The prevalence of HpNGC was calculated as 0.66% (95% confidence interval = 0.41–1.01). The mucus phenotype of HpNGC was similar to that of the controls.
Conclusion: The prevalence of HpNGC is very low and its pathological characteristics are different from common gastric cancer.
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