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).

Does the Use of Low Osmolality Contrast Medium Reduce the Frequency of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: A Comparative Study between Use of Low and High Osmolality Contrast Media.

INTRODUCTION: A few reports stating that differences in the various types of contrast media injected into the pancreatic duct are related to the onset of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) have been published, and it was indicated that iodixanol which is a nonionic iodide radiographic contrast medium with a dimeric (2 dimers) structure may reduce the incidence of PEP. The aim of this retrospective study is to evaluate the usefulness of iodaxanol for prevention PEP in comparison with megulamine amidototrizoate. METHODS: Two hundred and ninety-one patients were enrolled and divided into the 2 groups according to the contrast medium used. One hundred and fifty-five patients underwent ERCP with meglumine amidotrizoate, and 136 patients underwent ERCP with iodaxanol. The primary outcome of this study was the incidence of PEP associated with the use of each contrast medium. RESULTS: In this study, comparison of the meglumine amidotrizoate treatment and iodaxanol treatment groups showed no significant difference with respect to the incidence of PEP. In addition, there was also no difference between the groups with respect to PEP severity. CONCLUSION: Our study suggested that iodaxanol does not necessarily contribute to the prevention of PEP in comparison with meglumine amidotrizoate.

Incidence of Advanced Colorectal Neoplasia in Individuals With Untreated Diminutive Colorectal Adenomas Diagnosed by Magnifying Image-Enhanced Endoscopy.

OBJECTIVES: Because of the increasing number of detected diminutive colorectal adenomas, the "diagnose-and-do-not-resect" approach has recently attracted attention as an alternative to resection. We evaluated the cumulative incidence of advanced colorectal neoplasia (ACN) in individuals with untreated diminutive adenomas and compared this incidence in individuals without adenomas. METHODS: Data from 1,378 individuals who underwent first screening colonoscopy (CS) and at least one follow-up CS without polypectomy were analyzed. Patients with no adenomas or with only nonadvanced diminutive adenomas (<5 mm) diagnosed by magnifying image-enhanced endoscopy were scheduled to undergo a follow-up CS within 5 years after the initial CS without treatment. The participants were divided into 2 groups: those with untreated diminutive adenomas (group A) and those with no adenomas (group B). The cumulative incidence of ACN and the hazard ratio were assessed using Gray's test and the Fine and Gray model. RESULTS: During the median follow-up period of 60.9 months, 21 ACNs were detected. The 5-year cumulative incidences of ACN in group A (n = 361) and group B (n = 1,017) were 1.4% (95% confidence interval [CI]: 0.5-3.4) and 0.8% (95% CI: 0.3-1.7), respectively, without a statistically significant difference (P = 0.23). No ACNs developed from unresected adenomas. The smoking status was significantly associated with the incidence of ACN, and the hazard ratio for ACN in group A vs group B adjusted for smoking status was 1.43 (95% CI: 0.52-3.90; P = 0.48). DISCUSSION: The low 5-year cumulative incidence of ACN suggests the potential to adopt the "diagnose-and-do-not-resect" strategy as an alternative option for diminutive adenomas not requiring excessive surveillance.

Development and validation of a preoperative prognostic index independent of TNM stage in resected non-small cell lung cancer.

BACKGROUND: Previously reported prognostic tools for patients with resected non-small cell lung cancer (NSCLC) include factors found postoperatively, but not preoperatively. However, it would be important to predict patient prognosis before NSCLC resection. To suggest a novel preoperative prognostic tool, we evaluated the relationship of preoperative prognostic factors with the survival of patients with resected NSCLC. METHODS: We retrospectively reviewed the data of two independent cohorts of patients with completely resected NSCLC. To develop the prognostic index in one cohort, the overall survival (OS) was evaluated using the Cox proportional hazards model. We assessed the disease-free survival (DFS) and OS of three risk groups defined according to the prognostic index. Then, the prognostic index was validated in the other cohort. RESULTS: Seven independent risk factors for OS were selected: age ≥ 70 years, ever-smokers, vital capacity <80%, neutrophil-to-lymphocyte ratio ≥ 2.1, cytokeratin 19 fragment >normal limit, non-usual interstitial pneumonia (UIP) pattern, and UIP pattern. Three risk groups were defined: low-risk (36.9%), intermediate-risk (54.0%), and high-risk (9.1%). In the derivation cohort, the 5-year DFS rate was 77.8%, 58.8%, and 22.6% (P < 0.001), and the 5-year OS rate was 95.2%, 70.4%, and 28.9% (P < 0.001), respectively. Multivariate analyses showed that the prognostic index predicted DFS and OS, independent of pathological stage and tumor histology, in both derivation and validation cohorts. CONCLUSIONS: We developed and validated a simple preoperative prognostic index composed of seven variables, which may help clinicians predict prognosis before surgery in patients with NSCLC.

Clinical impact of endoscopic clip closure of perforations during endoscopic submucosal dissection for colorectal tumors.

BACKGROUND AND AIMS: Despite advances in endoscopic submucosal dissection (ESD), perforation can still occur. The purpose of this study is to determine the clinical course and effectiveness of endoscopic closure in addition to the clinicopathologic features related to perforation. METHODS: A total of 935 lesions in 900 consecutive patients between February 1998 and February 2013 underwent ESD for colorectal tumors at our institution. We studied the clinical course and histologic features of perforation through a matched case-control study that included 24 patients with intraprocedural perforation and 240 matched patients without perforation as a control group. Endoscopic closure by using through-the-scope endoclips was attempted in all cases of intraprocedural perforations immediately after perforation was recognized during the procedure. RESULTS: Perforation occurred in 25 cases (2.7%), including 24 intraprocedural perforation and 1 delayed perforation. All but 1 patient with intraprocedural perforation was conservatively managed by endoscopic closure. One patient with unsuccessful endoscopic closure required emergency surgery. Analysis of clinical courses revealed statistically significant differences (P < .01) between the patients with perforation and the case-controlled, nonperforation patients in total procedure time, white blood cell count, and level of serum C-reactive protein on the day after the procedure, admission period, and fasting period. Both location (P = .027) and submucosal fibrosis (P = .04) of the lesion were significantly associated with perforation. Multivariate analysis revealed that fibrosis was a significant risk factor associated with perforation (odds ratio 2.86; 95% confidence interval, 1.03-7.90). CONCLUSIONS: Endoscopic closure allows effective nonsurgical management in cases of intraprocedural perforation during ESD.

Endocuff-assisted colonoscopy increases polyp detection rate: a simulated randomized study involving an anatomic colorectal model and 32 international endoscopists.

BACKGROUND: The undetected colonic lesions behind the folds and flexures are a major factor contributing to the adenoma miss rate. OBJECTIVE: To assess the efficacy of Endocuff, a special attachment was fixed at the distal tip of a colonoscope, for the polyp detection. This soft accessory is composed of a plastic cap surrounded by flexible finger-like projections on the lateral sides of the cap that make holding of the folds during scope withdrawal easier. DESIGN: This was a simulated pilot study with one anatomic colorectal model, containing 13 polyps positioned in obvious locations and behind the folds. Thirty-two endoscopists (16 Japanese and 16 foreign visitors) with different levels of experience performed examinations on the model in a randomized order by using Endocuff-assisted colonoscopy (EAC) and standard colonoscope (SC). MAIN OUTCOME MEASUREMENTS: To assess the detection rate of polyps and the feasibility of Endocuff insertion. RESULTS: EAC detected significantly more polyps than SC with 9.9 versus 7.5 mean lesions (p = 0.03), respectively, comparing the 16 first colonoscopies in each group. Endocuff was useful independent of the level of experience of the participants. After crossover, EAC in second position allowed an additional detection of 1.8 polyps compared with SC (p = 0.001). After adjustment on experience, time of detection, and order of colonoscopy, EAC over-detected 1.2 polyps (p = 0.0037). The insertion time (p = 0.99) was identical. There was no difference in the mean time of polyp detection between EAC and SC groups (p = 0.520). LIMITATIONS: This was not a clinical study. The stiffness of the folds in the colonic model was higher than in the human large bowel. CONCLUSION: EAC was associated with a higher polyp detection rate. Even in such relatively stiff anatomic model, it was easier to spread out the colonic mucosa between the folds using this cap. This study provides an additional argument for the routine application of this easy-to-use accessory to improve polyp detection.

Association of gastric cancer risk factors with DNA methylation levels in gastric mucosa of healthy Japanese: a cross-sectional study.

Helicobacter pylori infection induces aberrant DNA methylation, and methylation levels of several specific marker genes in gastric mucosa are associated with gastric cancer risk. However, it is unclear whether gastric cancer risk factors are associated with methylation levels of marker genes in healthy individuals. We conducted a cross-sectional study of 281 Japanese cancer screenees aged 40-69 years with no history of H.pylori eradication therapy who responded to a validated food frequency questionnaire. DNA methylation levels of marker genes (miR-124a-3, EMX1 and NKX6-1) in gastric mucosa were quantified by real-time methylation-specific polymerase chain reaction. A multivariate beta regression model was used to investigate the association of pack-years of smoking and intakes of green/yellow vegetables, fruit and salt with methylation levels of marker genes. All analyses were stratified by H.pylori status. We found 2.5 to 34.1 times higher mean methylation levels among those with current H.pylori infection (n = 117) compared to those without (n = 164). After adjustment for potential confounders, we found increased levels of miR-124a-3 methylation according to pack-years of smoking and decreased levels of methylation according to green/yellow vegetable intake. We did not detect these associations among those without H.pylori infection. In conclusion, smoking habits and green/yellow vegetable intake were associated with DNA methylation levels in gastric mucosae of healthy individuals with current H.pylori infection. Our study suggests that these risk factors may modify the effect of H.pylori on methylation induction and maintenance in gastric mucosa.

Investigating endoscopic features of sessile serrated adenomas/polyps by using narrow-band imaging with optical magnification.

BACKGROUND: A sessile serrated adenoma/polyp (SSA/P) is a common type of colorectal polyp that possesses malignant potential. Although narrow-band imaging (NBI) can easily differentiate neoplastic lesions from hyperplastic polyps (HPs), SSA/Ps can be a challenge to distinguish from HPs. OBJECTIVE: To investigate specific endoscopic features of SSA/Ps by using NBI with optical magnification. DESIGN: Retrospective study. SETTING: Single high-volume referral center. PATIENTS: A total of 289 patients with histopathologically proven SSA/Ps or HPs obtained from colonoscopic polypectomy. INTERVENTION: Endoscopic images obtained by using NBI with optical magnification of 242 lesions (124 HPs, 118 SSA/Ps) removed between January 2010 and December 2012 were independently evaluated by 2 experienced endoscopists. Three external experienced endoscopists systematically validated the diagnostic accuracies by using 40 lesions (21 HPs and 19 SSA/Ps) removed between January and March 2013. MAIN OUTCOME MEASUREMENTS: Specific endoscopic features of SSA/Ps by using 5 potential characteristics: dilated and branching vessels (DBVs), irregular dark spots, a regular network pattern, a disorganized network pattern, and a dense pattern. RESULTS: Multivariate analysis demonstrated that DBV had a 2.3-fold odds ratio (95% confidence interval, 0.96-5.69) among SSA/Ps compared with HPs (sensitivity, 56%; specificity, 75%; accuracy, 65%). Interobserver and intraobserver agreement indicated almost perfect agreement for DBVs in both the evaluation and validation studies. When DBVs, proximal location, and tumor size (≥10 mm) were combined, the positive predictive value was 92% and the area under the curve was 0.783 in the receiver-operating characteristics by using the validation group. LIMITATIONS: Retrospective study. CONCLUSIONS: The current study suggests that a DBV is a potentially unique endoscopic feature of a colorectal SSA/P.

Potential perioperative advantage of colorectal endoscopic submucosal dissection versus laparoscopy-assisted colectomy.

BACKGROUND: Endoscopic submucosal dissection (ESD) has recently provided a new treatment strategy for large colorectal neoplasms, as an alternative to laparoscopy-assisted colectomy (LAC). Prospective comparative data on the perioperative course of ESD vis-à-vis LAC are scarce. METHODS: We prospectively evaluated the perioperative course of colorectal ESD in 300 patients. We evaluated en bloc and curative resection, procedure duration, postoperative parameters [white blood cell count (WBC), C-reactive protein (CRP), and hemoglobin], pain, recovery duration (time to achieve full mobilization, normal diet, and length of hospitalization), and complications. We also prospectively evaluated 190 patients undergoing LAC as a control group. RESULTS: The median size of the lesions was 30 mm for ESDs (LACs: 20 mm). The median procedure time was 90 min for ESDs (LACs: 185 min). Postoperative pyrexia was reported in 4 % of ESDs (LACs: 54 %). Only 4 % of ESDs required analgesia (LACs: 61 %). Between the preoperative period and postoperative day 1, the mean difference in WBC and CRP was +1,300/µl for ESDs (LACs: +3,100/µl), and +0.91 mg/dl for ESDs (LACs: +3.96 mg/dl), respectively. A ≥2 g/dl decrease in hemoglobin was observed in 5 % of ESDs (LACs: 30.0 %). Complications were seen in 7 % of ESDs (LACs: 15 %). The rate of delayed bleeding and perforation was 5 and 1.7 % of ESDs, respectively. Although only one of them required laparotomy for peritonitis caused by delayed perforation, others could be managed endoscopically. Additional LAC was required in 16 ESDs due to redefined risk for lymph node metastases. The median hospital stay was 5 days for ESDs (LACs: 10 days). These were consecutive patients with prospective data collection. CONCLUSIONS: Colorectal ESD is effective, minimally invasive and safe in terms of periperative clinical course. Colorectal ESD provides advantages for treatment of large adenomas and early cancers with no risk of lymph node metastasis.

Endoscopic mucosal resection for middle and large colorectal polyps with a double-loop snare.

BACKGROUND/AIMS: This study aimed to analyze the endoscopic mucosal resection (EMR) with a novel uniquely shaped, double-loop snare (Dualoop, Medico's Hirata Inc., Tokyo, Japan) for colorectal polyps. METHODS: This was a clinical trial conducted in two referral centers, Kyoto Prefectural University of Medicine and National Cancer Center Hospital in Japan. First, the firmness of various snares including 'Dualoop' was experimentally analyzed with a pressure gauge. Five hundred and eighty nine consecutive polyps that underwent EMR with 'Dualoop' were compared to 339 polyps with the standard round snare. Lesion characteristics, en bloc resection, and complications were analyzed. RESULTS: 'Dualoop' had the most firmness among the various snares. The average tumor size was 9.3 mm (5-30), and en bloc resection was achieved in 95.4%. The rate of en bloc resection for middle polyps 15-19 mm in diameter was significantly higher with the 'Dualoop' than that with the round snare (97.9 vs. 80.0%, p < 0.05). The rate of en bloc resection was 64.7% for large polyps ≥20 mm in diameter using 'Dualoop'. Higher age, larger tumor size, and superficial polyps were associated with the failure of en bloc resection. CONCLUSION: EMR with 'Dualoop' was effective for resecting both middle and large polyps en-bloc.

Short-term outcomes of colorectal endoscopic submucosal dissection performed by trainees.

BACKGROUND: Colorectal endoscopic submucosal dissection (ESD) is a relatively new therapy that has been accepted as the most effective treatment procedure for superficial colorectal neoplasms. Given the increasing acceptance and use of this procedure worldwide, the outcomes of colorectal ESD performed by trainees should be understood from a practical perspective and for developing strategies to introduce ESD to trainees. This study aimed to evaluate the clinical outcomes of ESD when conducted by less-experienced endoscopists. SUMMARY: We retrospectively reviewed the clinical outcomes of 164 patients with 164 colorectal neoplasms who underwent ESD carried out by 20 trainees performing their first colorectal ESDs between April 2005 and March 2012. For each operator, clinical data were collected between the first and 30th cases. For evaluating the technical aspects of the ESD procedure, the endoscopic characteristics of the lesions, procedure time, en bloc resection rate, R0 resection rate, invasion depth and complications were evaluated. The median procedure time was 95 min; about 75% of the lesions were resected within 120 min. Apparent perforation or electric damage in the muscularis propria was seen in 4% of lesions. In terms of factors with the potential to effect procedure time, lesion size and pathological invasion depth were significantly different between shorter and longer treatment times for granular-type laterally spreading tumors (LST). KEY MESSAGES: A granular-type LST of <40 mm is a good lesion for introducing colorectal ESD to trainees. Trainees should have a strong ability to make a depth diagnosis before starting ESD.

Colorectal endoscopic submucosal dissection: Technical advantages compared to endoscopic mucosal resection and minimally invasive surgery.

BACKGROUND AND AIM: In recent years, the effectiveness of colorectal endoscopic submucosal dissection (ESD) has been increasingly reported. Herein, we highlight the most recent developments and technical advantages of colorectal ESD compared to EMR and minimally invasive surgery. METHODS: All candidate lesions for ESD were confirmed as being intramucosal tumors by colonoscopy. Presently, the indications for colorectal ESD approved by the Japanese government's medical insurance system are early colorectal cancers with a maximum tumor size of 2-5 cm; however, many early cancers >5 cm have been treated by ESD in referral centers. RESULTS: The primary advantage of ESD compared to endoscopic mucosal resection (EMR) is a higher en-bloc resection rate for large colonic tumors that had previously been treated by surgery. ESD has several advantages compared to other therapeutic modalities, such as being a safer technique and providing better quality of life. For rectal cancer treatment, a longer procedure time is required for laparoscopic assisted colectomy, whereas trans-anal resection and trans-anal endoscopic microsurgery are more invasive than ESD with a significantly higher recurrence rate. Accordingly, ESD is the preferred choice for early colorectal cancers when there is no risk of lymph-node metastasis. CONCLUSION: ESD is an effective procedure for treating non-invasive non-polypoid colorectal tumors. These tumors may be difficult to resect en bloc by conventional EMR. The use of ESD results in a higher en-bloc resection rate and is less invasive than surgery.

Application of the fecal microRNA test to the residuum from the fecal occult blood test.

OBJECTIVE: Though the fecal occult blood test is used for colorectal cancer screening worldwide, it does not have a particularly high sensitivity for detecting colorectal cancer. Here we investigated the applicability of the fecal microRNA test to fecal samples that had been used for a previous fecal occult blood test and stored under various conditions. METHODS: Five colorectal cancer patients and five healthy volunteers were enrolled. Fecal samples were stored for 0-5 days at 4°C, room temperature or 37°C. Total RNA was extracted from the fecal occult blood test residuum and microRNA expression was analyzed by real-time reverse transcription polymerase chain reaction. RESULTS: There were no remarkable differences either in colorectal cancer patients or in controls with regard to the concentration of RNA extracted from the fecal occult blood test residuum in any of the storage groups compared with the samples prepared on day 0 (Group 0). Ribosomal RNA stored at room temperature or 37°C degraded rapidly. In contrast, the ribosomal RNA stored at 4°C remained intact for at least 5 days. The microRNAs in samples stored at 4°C and room temperature were conserved; however, the microRNAs stored at 37°C were significantly degraded compared with Group 0 (P < 0.05). In the residuum stored at 4°C up to 5 days, the relative quantification of miR-106a normalized with miR-24 in colorectal cancer patients was significantly higher than those in healthy volunteers (P < 0.05). In contrast, the quantification of normalized miR-106a was remarkably low in samples stored at room temperature and 37°C. CONCLUSIONS: Fecal microRNA of sufficient quality for reverse transcription polymerase chain reaction analysis was extracted from the fecal occult blood test residuum stored at 4°C for up to 5 days.

What is the accuracy of autofluorescence imaging in identifying non-polypoid colorectal neoplastic lesions when reviewed by trainees? A pilot study.

BACKGROUND AND AIM: Non-polypoid colorectal neoplasms are difficult to identify using conventional white light (WL) colonoscopy. The aim of the present pilot study was to compare an autofluorescence imaging (AFI) system with conventional WL colonoscopy for the identification of non-polypoid neoplasms by trainees in a colonoscopic observational situation. METHODS: We selected clear images with both AFI and WL in the same field taken by experts at the National Cancer Center Hospital, Tokyo, from December 2009 to November 2010. One hundred and eighty sets of images (137 non-polypoid neoplasms and 43 without neoplasm) were selected. The images were reviewed by two trainees without AFI experience. After attending a short educational lecture on the AFI system, the reviewers determined the presence of lesions in the randomly arranged images. The accuracy of AFI and WL for identifying non-polypoid neoplasms by trainees was assessed. RESULTS: The sensitivity and specificity for identifying non-polypoid neoplasms by trainees was not significantly different between AFI and WL. However, the specificity tended to be lower in AFI images than in WL images. CONCLUSIONS: False-positive results tended to be more frequent for the AFI images than for the WL images. Further improvements in the technology and resolution are necessary for the AFI system to be useful for the detection of colorectal neoplasms. At present, clinical application of the AFI system may require more extensive structured training to improve its accuracy in the identification of non-polypoid colorectal neoplasms.

An unusual cytological presentation of solid pseudopapillary neoplasm of the pancreas mimicking adenoid cystic carcinoma: a case report and literature review.

Endoscopic ultrasound-guided fine-needle aspiration has become the common procedure for the diagnosis of pancreatic mass, and cytological examination is usually the first approach. Solid pseudopapillary neoplasm (SPN) cytologically represents papillary structures of branching capillaries surrounded by discohesive neoplastic cells. However, it may present various degrees of tissue degeneration, causing diagnostic challenges. Here, we report a 21-year-old female who had a 2-cm-sized mass in the pancreas head. Cytological examination revealed clumps of small round/oval cells that represented microcystic configurations with mucus, mimicking adenoid cystic carcinoma or mucinous adenocarcinoma. Cercariform cells, nuclear grooves/folding, and cytoplasmic vacuoles were not observed. Histopathological examination revealed confluent small glandular structures containing acidic mucus. The tumor cells were positively stained for ß-catenin, CD10, and CD56, and negative for chromogranin A and E-cadherin, suggesting SPN, micropseudocystic variant. This variant has been scarcely described, but we should recognize it for accurate cytological triage of pancreatic tumors.

New closure technique for large mucosal defects after endoscopic submucosal dissection of colorectal tumors (with video).

BACKGROUND: Certain large colorectal tumors satisfy expanded indications for endoscopic submucosal dissection (ESD); however, the resulting large mucosal defects may contribute to complications such as delayed bleeding and perforation. Various closure devices and methods have been developed for large mucosal defects to prevent such complications. OBJECTIVE: To demonstrate the feasibility of a new and simple technique for closing large mucosal defects after colorectal ESD. DESIGN: Pilot feasibility study. SETTING: Single center. PATIENTS: Ten patients with 10 tumors half circumferential or less in size with sufficient muscle layer exposure after ESD were selected and treated by using the closure technique between July 2009 and June 2010. INTERVENTION: Small mucosal incisions were made around the mucosal defect by the same needle-knife used during ESD. These incisions provided a better grip for conventional clips, which then facilitated lifting the surrounding mucosa across the defect without slipping, thereby making it considerably easier to reduce the size of the defect and place additional clips. MAIN OUTCOME MEASUREMENTS: Patient characteristics and tumor clinicopathologic features were assessed as well as closure completion rate, closure procedure time, and closure-related complications. RESULTS: All 10 tumors were successfully treated by ESD. Mean lesion size was 26.8 mm (range 8-50 mm). All mucosal defects were completely closed by using the new closure technique, without complications. Mean closure procedure time was 15 minutes (range 8-35 minutes). LIMITATIONS: Small sample size with specifically selected patients. CONCLUSION: Large mucosal defects resulting from colorectal ESD can be completely closed with small mucosal incisions by using conventional clips.

A prospective, multicenter study of 1111 colorectal endoscopic submucosal dissections (with video).

BACKGROUND: Endoscopic submucosal dissection (ESD) is accepted as a minimally invasive treatment for early gastric cancer, although it is not widely used in the colorectum because of technical difficulty. OBJECTIVE: To examine the current status of colorectal ESDs at specialized endoscopic treatment centers. DESIGN AND SETTING: Multicenter cohort study using a prospectively completed database at 10 specialized institutions. PATIENTS AND INTERVENTIONS: From June 1998 to February 2008, 1111 colorectal tumors in 1090 patients were treated by ESD. MAIN OUTCOME MEASUREMENTS: Tumor size, macroscopic type, histology, procedure time, en bloc and curative resection rates and complications. RESULTS: Included in the 1111 tumors were 356 tubular adenomas, 519 intramucosal cancers, 112 superficial submucosal (SM) cancers, 101 SM deep cancers, 18 carcinoid tumors, 1 mucosa-associated lymphoid tissue lymphoma, and 4 serrated lesions. Macroscopic types included 956 laterally spreading tumors, 30 depressed, 62 protruded, 44 recurrent, and 19 SM tumors. The en bloc and curative resection rates were 88% and 89%, respectively. The mean procedure time ± standard deviation was 116 ± 88 minutes with a mean tumor size of 35 ± 18 mm. Perforations occurred in 54 cases (4.9%) with 4 cases of delayed perforation (0.4%) and 17 cases of postoperative bleeding (1.5%). Two immediate perforations with ineffective endoscopic clipping and 3 delayed perforations required emergency surgery. Tumor size of 50 mm or larger was an independent risk factor for complications, whereas a large number of ESDs performed at an institution decreased the risk of complications. LIMITATIONS: No long-term outcome data. CONCLUSIONS: ESD performed by experienced endoscopists is an effective alternative treatment to surgery, providing high en bloc and curative resection rates for large superficial colorectal tumors.

[Recent progress in endoscopic treatment for colorectal tumors].

BACKGROUND: Endoscopic mucosal resection (EMR) is indicated for the treatment of superficial, early-stage colorectal cancer because of its minimal invasiveness and excellent results in terms of clinical outcomes. Conventional EMR techniques currently used for the resection of laterally spreading tumors (LSTs), however, are inadequate for the en-bloc resection of flat lesions > or =20 mm because both incomplete removal and local recurrence have been observed and reported on occasion. Endoscopic submucosal dissection (ESD) is widespread as a minimally invasive treatment for early gastric cancer, however, it is not as widely used in the colorectum because of its technical difficulty and complication risk. INDICATIONS FOR COLORECTAL ESD: Based on clinicopathological analyses of LSTs, the indication for colorectal ESD is an LST non-granular type (LST-NG) >20 mm. LST granular type (LST-G) >30 mm or 40 mm are possible candidates for ESD because they have a higher submucosal (SM) invasion rate and are difficult to treat even by endoscopic piecemeal mucosal resection (EPMR). ESD PROCEDURES: ESD procedures were performed using a ball tip bipolar needle knife (B-knife) and an insulation-tip knife (IT knife) with carbon dioxide (CO2) insufflation. Glycerol and 0.4% hyaluronic acid were used as an SM injection solution in order to provide longer lasting SM elevation. CONCLUSION: ESD is an effective technique for treating colorectal IST-NGs>20 mm and LST-Gs>30 mm providing a higher en-bloc resection rate as well as being less invasive than surgery.

PD-L1 expression on tumor-infiltrating immune cells is highly associated with M2 TAM and aggressive malignant potential in patients with resected non-small cell lung cancer.

OBJECTIVES: PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) plays important roles in regulating the antitumor T cell response. However, the mechanistic and clinical significance of the effect of PD-L1 on TCs versus ICs remains unclear. On the other hand, tumor-associated macrophages (TAMs), M2 macrophages in particular, can promote tumor progression. METHODS: We evaluated PD-L1 expression on TCs and ICs using Ventana SP263 assay and the stromal M2 TAM distribution using CD163 staining in 160 consecutive patients with resected non-small cell lung cancer (NSCLC). RESULTS: PD-L1 expression on TCs and ICs was significantly higher in stromal M2 TAM-high group than in stromal M2 TAM-low group (p < 0.001 and p < 0.001, respectively). Regarding the clinical significance of PD-L1, PD-L1 expression on TCs was significantly associated with histology (p = 0.001), tumor differentiation (p < 0.001) and nodal status (p = 0.029). Furthermore, PD-L1 expression on ICs was significantly associated with histology (p < 0.001), tumor differentiation (p < 0.001), tumor status (p = 0.024), nodal status (p = 0.016), and pathologic stage (p = 0.004). The disease-free survival rate was significantly lower in patients with PD-L1-positive TC than in those with PD-L1-negative TC (p = 0.023), as well as in patients with PD-L1-positive IC than in those with PD-L1-negative IC (p < 0.001). Furthermore, the overall survival rate was significantly lower in patients with PD-L1-positive IC than in those with PD-L1-negative IC (p = 0.023). CONCLUSIONS: During tumor progression in NSCLC, the presence of M2 TAMs might affect PD-L1 expression both on TCs and ICs. In patients with NSCLC, PD-L1 expression both on TCs and ICs was associated with malignant behaviors, which was more in case of ICs.

M2 tumor-associated macrophages promote tumor progression in non-small-cell lung cancer.

Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment that can be polarized into different phenotypes, including tumor-inhibiting M1 macrophages and tumor-promoting M2 macrophages. To elucidate the biological and clinical significance of M2 TAMs in non-small-cell lung cancer (NSCLC), a comprehensive clinical assessment of the tissue distribution of M2 TAMs was performed. The tissue distribution of M2 TAMs was retrospectively analyzed using CD163 immunohistochemistry in 160 consecutive patients who underwent NSCLC resection. Tumor proliferation was evaluated via the Ki-67 proliferation index. The results revealed that the stromal density of M2 TAMs was significantly associated with the C-reactive protein (CRP) level (P=0.0250), the Ki-67 proliferation index (P=0.0090) and invasive size (P=0.0285). Furthermore, the stromal M2 TAM density was significantly associated with tumor differentiation (P=0.0018), lymph node metastasis (P=0.0347) and pathological stage (P=0.0412). The alveolar M2 TAM density was also significantly associated with the CRP level (P=0.0309), invasive size (P<0.0001), tumor differentiation (P=0.0192), tumor status (P=0.0108) and pathological stage (P=0.0110). By contrast, no association was observed between islet M2 TAM density and the aforementioned biological and clinical factors. In regards to prognosis, disease-free survival rate was significantly lower in patients with stromal M2 TAM-high tumors (P=0.0270) and in those with alveolar M2 TAM-high tumors (P=0.0283). Furthermore, the overall survival rate was also significantly lower in patients with stromal M2 TAM-high tumors (P=0.0162) and in those with alveolar M2 TAM-high tumors (P=0.0225). Therefore, during NSCLC progression, M2 TAMs may induce tumor cell aggressiveness and proliferation and increase metastatic potential, resulting in a poor prognosis in patients with NSCLC.