Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease.

OBJECTIVE: Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death. DESIGN: We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate. RESULTS: Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65). CONCLUSIONS: This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.

Incomplete Mucosal Layer Excision during Endoscopic Mucosal Resection: a potential source of recurrent adenoma.

BACKGROUND AND AIMS: Residual or recurrent adenoma detected during surveillance (RRA) is the major limitation of endoscopic mucosal resection (EMR). The pathogenesis of RRA is unknown although thermal ablation of the post-EMR defect (PED) margin reduces RRA. We aimed to identify a feature within the PED which could be associated with RRA. METHODS: Between 1/2017 and 7/2020 detailed prospective procedural data on all EMR procedures performed at a single centre were retrospectively analysed. At the completion of EMR the PED was systematically examined for features of incomplete mucosal layer excision (IME). This was defined as a demarcated area within the PED bordered by a white electrocautery ring, containing endoscopically identifiable features suggesting incomplete resection of the mucosa including lacy capillaries and/or visible fibres of the muscularis mucosae. Areas of IME were re-injected and re-excised by snare and submitted separately for blinded specialist gastrointestinal pathologist review. RESULTS: EMR was performed for 508 large non-pedunculated colorectal polyps (LNPCPs) (median size 35mm). In 10 PED (2.0%) an area of IME was identified and excised. Histopathological examination of areas of suspected IME demonstrated muscularis mucosae in 9/10 (90%), residual lamina propria in 9/10 (90.0%) and residual adenoma in 5/10 (50.0%). No RRA was detected during follow-up after re-excision of IME. CONCLUSION: We report the novel finding of IME within the PED after EMR of LNPCPs. IME may contain microscopic residual adenoma and therefore is a risk for RRA during follow-up. After completion of EMR the PED should be carefully evaluated and if IME is found it should be excised.

Histopathological effects of electrosurgical interventions in an in vivo porcine model of colonic endoscopic mucosal resection.

OBJECTIVE: Endoscopic mucosal resection (EMR) in the colon has been widely adopted, but there is limited data on the histopathological effects of the differing electrosurgical currents (ESCs) used. We used an in vivo porcine model to compare the tissue effects of ESCs for snare resection and adjuvant margin ablation techniques. DESIGN: Standardised EMR was performed by a single endoscopist in 12 pigs. Two intersecting 15 mm snare resections were performed. Resections were randomised 1:1 using either a microprocessor-controlled current (MCC) or low-power coagulating current (LPCC). The lateral margins of each defect were treated with either argon plasma coagulation (APC) or snare tip soft coagulation (STSC). Colons were surgically removed at 72 hours. Two specialist pathologists blinded to the intervention assessed the specimens. RESULTS: 88 defects were analysed (median 7 per pig, median defect size 29×17 mm). For snare ESC effects, 156 tissue sections were assessed. LPCC was comparable to MCC for deep involvement of the colon wall. For margin ablation, 172 tissue sections were assessed. APC was comparable to STSC for deep involvement of the colon wall. Islands of preserved mucosa at the coagulated margin were more likely with APC compared with STSC (16% vs 5%, p=0.010). CONCLUSION: For snare resection, MCC and LPCC did not produce significantly different tissue effects. The submucosal injectate may protect the underlying tissue, and technique may more strongly dictate the depth and extent of final injury. For margin ablation, APC was less uniform and complete compared with STSC.

Oncological outcomes after piecemeal endoscopic mucosal resection of large non-pedunculated colorectal polyps with covert submucosal invasive cancer.

OBJECTIVE: Management of covert submucosal invasive cancer (SMIC) discovered after piecemeal endoscopic mucosal resection (pEMR) of large (>20 mm) non-pedunculated colorectal polyps is challenging. The residual cancer risk is largely unknown. We sought to evaluate this in a large tertiary referral cohort. DESIGN: Cases of covert SMIC following pEMR were identified and followed. Oncological outcomes after surgery were divided based on residual intramural cancer, lymph node metastases (LNM) or both. Risk factors for residual intramural cancer and LNM were analysed based on the original pEMR histological variables. Risk parameters were analysed with respect to low and high-risk variables for residual intramural cancer and LNM. RESULTS: Among 3372 cases of large non-pedunculated colorectal polyps, 143 cases of covert SMIC (4.2%) were identified. 109 underwent surgical resection. Histological analysis of pEMR histology was available in 98 of 109 (90%) cases. 62 cases (63%) had no residual malignancy. 36 cases had residual malignancy (residual intramural cancer n=24; LNM n=5; both n=7). All cases of residual intramural cancer could be identified by a R1 histological deep margin. Cases with poor differentiation (PD) and/or lymphovascular invasion (LVI) had a high risk of LNM (12/33), with a very low risk without these criteria (<1%; 0/65). Cases at low risk for LNM with R0 deep margin have a low risk of residual intramural cancer (<1%; 0/35). CONCLUSION: The majority of cases of large non-pedunculated colorectal polyps with covert SMIC following pEMR will have no residual malignancy. The risk of residual malignancy can be ascertained from three key variables: PD, LVI and R1 deep margin.

Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?

OBJECTIVE: The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD. DESIGN: The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI) 10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069). CONCLUSIONS: Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and PNPLA3 genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds. LAY SUMMARY: NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD.

A Randomized Controlled Trial of Cold Snare Polypectomy Technique: Technique Matters More Than Snare Wire Diameter.

INTRODUCTION: Cold snare polypectomy (CSP) is safe and effective for the removal of small adenomas (≤10 mm); however, reported incomplete resection rates (IRRs) vary. The optimal CSP technique, where a wide margin of normal tissue is resected around the target lesion, and snare design have both been hypothesized to reduce the IRR after CSP. We sought to investigate the efficacy of a thin-wire versus thick-wire diameter snare on IRR, using the standardized CSP technique. METHODS: This was an international multicenter parallel design randomized trial with 17 endoscopists of varying experience (NCT02581254). Patients were randomized in a 1:1 ratio to the use of a thin-wire (0.30 mm) or thick-wire (0.47 mm) snare for CSP of small (≤10 mm) colorectal polyps. The primary end point was the IRR as determined by the histologic assessment of the defect margin after polypectomy. RESULTS: Over 52 months to January 2020, 1,393 patients were eligible. A total of 660 patients with polyps (57.4% male) were randomized to a thin-wire (n = 339) or thick-wire (n = 321) snare. The overall IRR of the cohort was 1.5%. There was no significant difference in the IRR between the thin- and thick-wire arms; relative risk-0.41, 95% CI (0.11-1.56), P = 0.21. No significant differences were observed in the rate of adverse events. DISCUSSION: In this multicenter randomized trial, CSP is safe and effective with very low rates of incomplete resection independent of the diameter of the snare wire used. This suggests that the optimal operator technique is more important than the snare design alone in minimizing residual adenoma after CSP.

Large prolapse-related lesions of the sigmoid colon.

BACKGROUND: Large prolapse-related lesions (LPRL) of the sigmoid colon have been documented histologically but may not be readily recognized endoscopically. METHODS: Colonic lesions referred for endoscopic mucosal resection (EMR) were enrolled prospectively. Endoscopic features were carefully documented prior to resection. Final diagnosis was made based on established histologic criteria, including vascular congestion, hemosiderin deposition, fibromuscular hyperplasia, and crypt distortion. RESULTS: Of 134 large ( ≥ 20 mm) sigmoid lesions, 12 (9.0 %) had histologic features consistent with mucosal prolapse. Distinct endoscopic features were: broad-based morphology; vascular pattern obscured by dusky hyperemia; blurred crypts of varying size and shape; and irregular spacing of sparse crypts. Focal histologic dysplasia was identified in 6 of 12 lesions (50.0 %). CONCLUSIONS: LPRL of the sigmoid colon exhibit a distinct endoscopic profile. Although generally non-neoplastic, dysplasia may be present, warranting consideration of EMR.

Successful treatment of CMV, EBV, and adenovirus tissue infection following HLA-mismatched allogeneic stem cell transplant using infusion of third-party T cells from multiple donors in addition to antivirals, rituximab, and surgery.

Viral infections, principally cytomegalovirus, Epstein Barr virus (EBV) and adenovirus, are a leading cause of morbidity and mortality after allogeneic stem cell transplantation. The use of systemic antivirals is limited by limited efficacy and organ toxicities. Inability to clear infection is exacerbated by transplant-related immunosuppression and prophylaxis or treatment of acute graft versus host disease. We report the first patient to clear three serious viral infections after stem cell transplant using third-party donor partially human leukocyte antigen (HLA) matched virus-specific cytotoxic T cells. The patient, a 53 year old female with transplanted for relapsed leukemia, with severe graft versus host disease received five T cell infusions from three separate donors that ultimately cleared serious systemic infections with cytomegalovirus and adenovirus, and an EBV-driven lymphoma. Systemic antivirals had resulted in failed clinical responses. Use of repeated infusions of partially HLA matched virus-specific T cells from banks containing cryopreserved cells should be strongly considered in transplant recipients with single or multiple refractory viral infections.

Correction to: Pathological assessment of endoscopic resections of the gastrointestinal tract: a comprehensive clinicopathologic review.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Pathological assessment of endoscopic resections of the gastrointestinal tract: a comprehensive clinicopathologic review.

Endoscopic resection (ER) allows optimal staging with potential cure of early-stage luminal malignancies while maintaining organ preservation. ER and surgery are non-competing but complementary therapeutic options. In addition, histological examination of ER specimens can either confirm or refine the pre-procedure diagnosis. ER is used for the treatment of Barrett's related early carcinomas and dysplasias, early-esophageal squamous cell carcinomas and dysplasias, early gastric carcinomas and dysplasia, as well as low-risk submucosal invasive carcinomas (LR-SMIC) and, large laterally spreading adenomas of the colon. For invasive lesions, histological risk factors predict risk of lymph node metastasis and residual disease at the ER site. Important pathological risk factors predictive of lymph node metastasis are depth of tumor invasion, poor differentiation, and lymphovascular invasion. Complete resection with negative margins is critical to avoid local recurrences. For non-invasive lesions, complete resection is curative. Therefore, a systematic approach for handling and assessing ER specimens is recommended to evaluate all above key prognostic features appropriately. Correct handling starts with pinning the specimen before fixation, meticulous macroscopic assessment with orientation of appropriate margins, systematic sectioning, and microscopic assessment of the entire specimen. Microscopic examination should be thorough for accurate assessment of all pathological risk factors and margin assessment. Site-specific issues such as duplication of muscularis mucosa of the esophagus, challenges of assessing ampullectomy specimens and site-specific differences of staging of early carcinomas throughout the gastrointestinal tract (GI) tract should be given special consideration. Finally, a standard, comprehensive pathology report that allows optimal staging with potential cure of early-stage malignancies or better stratification and guidance for additional treatment should be provided.

ADAPT: An Algorithm Incorporating PRO-C3 Accurately Identifies Patients With NAFLD and Advanced Fibrosis.

Given the high global prevalence of nonalcoholic fatty liver disease (NAFLD), the need for relevant noninvasive biomarkers and algorithms to accurately stage disease severity is a critical unmet medical need. Identifying those with advanced fibrosis (≥ F3) is the most crucial, as these individuals have the greatest risk of adverse, long-term, liver-related outcomes. We aimed to investigate the role of PRO-C3 (a marker of type III collagen formation) as a biomarker for advanced fibrosis in NAFLD. We measured PRO-C3 by enzyme-linked immunosorbent assay in two large independent cohorts with extensive clinical phenotyping and liver biopsy: 150 in the derivation and 281 in the validation cohort. A PRO-C3-based fibrosis algorithm that included age, presence of diabetes, PRO-C3, and platelet count (ADAPT) was developed. PRO-C3 increased with fibrosis stage (Rho 0.50; P < 0.0001) and was independently associated with advanced fibrosis (odds ratio = 1.05; 95% confidence interval [CI] 1.02-1.08; P = 0.003). ADAPT showed areas under the receiver operating characteristics curve of 0.86 (95% CI 0.79-0.91) in the derivation and 0.87 in the validation cohort (95% CI 0.83-0.91) for advanced fibrosis. This was superior to the existing fibrosis scores, aspartate aminotransferase to platelet ratio index (APRI), FIB-4, and NAFLD fibrosis score (NFS) in most comparisons. Conclusion: PRO-C3 is an independent predictor of fibrosis stage in NAFLD. A PRO-C3-based score (ADAPT) accurately identifies patients with NAFLD and advanced fibrosis and is superior to APRI, FIB-4, and NFS.

Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study.

BACKGROUND & AIMS: Little is known about the natural course of nonalcoholic fatty liver disease (NAFLD) with advanced fibrosis. We describe long-term outcomes and evaluate the effects of clinical and histologic parameters on disease progression in patients with advanced NAFLD. METHODS: We conducted a multi-national study of 458 patients with biopsy-confirmed NAFLD with bridging fibrosis (F3, n = 159) or compensated cirrhosis (222 patients with Child-Turcotte-Pugh scores of A5 and 77 patients with scores of A6), evaluated from April 1995 through November 2013 and followed until December 2016, death, or liver transplantation at hepatology centers in Spain, Australia, Hong Kong, and Cuba. Biopsies were re-evaluated and scored; demographic, clinical, laboratory, and pathology data for each patient were collected from the time of liver biopsy collection. Cox proportional and competing risk models were used to estimate rates of transplantation-free survival and major clinical events and to identify factors associated with outcomes. RESULTS: During a mean follow-up time of 5.5 years (range, 2.7-8.2 years), 37 patients died, 37 received liver transplants, 88 had initial hepatic decompensation events, 41 developed hepatocellular carcinoma, 14 had vascular events, and 30 developed nonhepatic cancers. A higher proportion of patients with F3 fibrosis survived transplantation-free for 10 years (94%; 95% confidence interval [CI], 86%-99%) than of patients with cirrhosis and Child-Turcotte-Pugh A5 (74%; 95% CI, 61%-89%) or Child-Turcotte-Pugh A6 (17%; 95% CI, 6%-29%). Patients with cirrhosis were more likely than patients with F3 fibrosis to have hepatic decompensation (44%; 95% CI, 32%-60% vs 6%, 95% CI, 2%-13%) or hepatocellular carcinoma (17%; 95% CI, 8%-31% vs 2.3%, 95% CI, 1%-12%). The cumulative incidence of vascular events was higher in patients with F3 fibrosis (7%; 95% CI, 3%-18%) than cirrhosis (2%; 95% CI, 0%-6%). The cumulative incidence of nonhepatic malignancies was higher in patients with F3 fibrosis (14%; 95% CI, 7%-23%) than cirrhosis (6%; 95% CI, 2%-15%). Death or transplantation, decompensation, and hepatocellular carcinoma were independently associated with baseline cirrhosis and mild (<33%) steatosis, whereas moderate alcohol consumption was associated with these outcomes only in patients with cirrhosis. CONCLUSIONS: Patients with NAFLD cirrhosis have predominantly liver-related events, whereas those with bridging fibrosis have predominantly nonhepatic cancers and vascular events.

Endoscopic submucosal dissection for suspected early gastric cancer: absolute versus expanded criteria in a large Western cohort (with video).

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is an effective, minimally invasive, surgery-sparing technique for the treatment of early gastric cancer (EGC). It is not well established whether EGC within the Japanese expanded criteria can be safely and effectively treated using ESD in the West. We describe the outcomes of ESD for endoscopically suspected, biopsy specimen-confirmed EGC and its adenomatous precursor lesions (pEGC) using the Vienna classification of dysplasia in a Western cohort. METHODS: Prospective data were collected on all pEGCs undergoing ESD at a single expert endoscopy center. Outcomes were compared among pEGC, satisfying the Japanese absolute and expanded criteria, those outside criteria, and those specimens that contained low-grade dysplasia (LGD) only. Specialist GI pathologists reviewed and classified all ESD specimens. Patients were followed up at 6 and 12 months. RESULTS: Over 71 months, 135 pEGCs in 121 patients (mean age, 72.0 years; 61.2% men) underwent ESD. Median pEGC size was 20 mm (interquartile range, 15-30), and 62 (45.9%) satisfied the expanded clinical criteria. Perforation occurred in 1.5% and postprocedural bleeding in 5.2%. Forty-two pEGCs (31.1%) contained LGD only. Rates of en bloc and R0 resection were 94.8% and 86.7%, respectively. One hundred seven pEGCs (79.2%) met the absolute or expanded criteria for endoscopic cure. Two pEGCs recurred during follow-up. Ten of 26 patients with pEGC (38.5%) outside criteria for cure underwent surgery after ESD with residual tumor detected in 3 specimens. Fifteen patients with outside criteria for pEGCs did not undergo surgery because of frailty or their expressed wish. Eleven of 15 patients have so far undergone first surveillance with 1 of 11 experiencing endoscopic and histologic recurrence. CONCLUSIONS: ESD is a safe and effective treatment for pEGCs in a Western context. Patients who either decline or are too frail for surgery, with outside criteria resections, may benefit from ESD for local disease control. Large Western studies of ESD for pEGCs are required to define long-term patient outcomes and surveillance guidelines, particularly where pathology shows LGD or high-grade dysplasia only. (Clinical trial registration number: NCT02306707.).

Wide-field endoscopic mucosal resection versus endoscopic submucosal dissection for laterally spreading colorectal lesions: a cost-effectiveness analysis.

OBJECTIVE: To compare the cost-effectiveness of endoscopic submucosal dissection (ESD) and wide-field endoscopic mucosal resection (WF-EMR) for removing large sessile and laterally spreading colorectal lesions (LSLs) >20 mm. DESIGN: An incremental cost-effectiveness analysis using a decision tree model was performed over an 18-month time horizon. The following strategies were compared: WF-EMR, universal ESD (U-ESD) and selective ESD (S-ESD) for lesions highly suspicious for containing submucosal invasive cancer (SMIC), with WF-EMR used for the remainder. Data from a large Western cohort and the literature were used to inform the model. Effectiveness was defined as the number of surgeries avoided per 1000 cases. Incremental costs per surgery avoided are presented. Sensitivity and scenario analyses were performed. RESULTS: 1723 lesions among 1765 patients were analysed. The prevalence of SMIC and low-risk-SMIC was 8.2% and 3.1%, respectively. Endoscopic lesion assessment for SMIC had a sensitivity and specificity of 34.9% and 98.4%, respectively. S-ESD was the least expensive strategy and was also more effective than WF-EMR by preventing 19 additional surgeries per 1000 cases. 43 ESD procedures would be required in an S-ESD strategy. U-ESD would prevent another 13 surgeries compared with S-ESD, at an incremental cost per surgery avoided of US$210 112. U-ESD was only cost-effective among higher risk rectal lesions. CONCLUSION: S-ESD is the preferred treatment strategy. However, only 43 ESDs are required per 1000 LSLs. U-ESD cannot be justified beyond high-risk rectal lesions. WF-EMR remains an effective and safe treatment option for most LSLs. TRIAL REGISTRATION NUMBER: NCT02000141.

Gastric Cancer Screening in Common Variable Immunodeficiency.

Individuals with common variable immunodeficiency (CVID) have an increased risk of gastric cancer, and gastrointestinal lymphoma, yet screening for premalignant gastric lesions is rarely offered routinely to these patients. Proposed screening protocols are not widely accepted and are based on gastric cancer risk factors that are not applicable to all CVID patients. Fifty-two CVID patients were recruited for screening gastroscopy irrespective of symptoms or blood results and were compared to 40 controls presenting for gastroscopy for other clinical indications. Overall, 34% of CVID patients had intestinal metaplasia (IM), atrophic gastritis or moderate to severe non-atrophic gastritis, which can increase the risk of gastric cancer, compared to 7.5% of controls (p < 0.01). Focal nodular lymphoid hyperplasia, a precursor lesion for gastrointestinal lymphoma, was seen in eight CVID patients (16%), one of whom was diagnosed with gastrointestinal lymphoma on the same endoscopy. High-risk gastric pathology was associated with increased time since diagnosis of CVID, smoking, Helicobacter pylori, a low-serum pepsinogen I concentration, and diarrhea, but not pepsinogen I/II ratio, iron studies, vitamin B12 levels or upper gastrointestinal symptoms. There was a lower rate of detection of IM when fewer biopsies were taken, and IM and gastric atrophy were rarely predicted by the endoscopist macroscopically, highlighting the need for standardized biopsy protocols. The prevalence of premalignant gastric lesions in patients with CVID highlights the need for routine gastric screening. We propose a novel gastric screening protocol to detect early premalignant lesions and reduce the risk of gastric cancer and gastric lymphoma in these patients.

Risk Stratification for Covert Invasive Cancer Among Patients Referred for Colonic Endoscopic Mucosal Resection: A Large Multicenter Cohort.

BACKGROUND & AIMS: Among patients with large colorectal sessile polyps or laterally spreading lesions, it is important to identify those at risk for submucosal invasive cancer (SMIC). Lesions with overt endoscopic evidence of SMIC are referred for surgery, although those without these features might still contain SMIC that is not visible on endoscopic inspection (covert SMIC). Lesions with a high covert SMIC risk might be better suited for endoscopic submucosal dissection than for endoscopic mucosal resection (EMR). We analyzed a group of patients with large colon lesions to identify factors associated with SMIC, and examined lesions without overt endoscopic high-risk signs to determine factors associated with covert SMIC. METHODS: We performed a prospective cohort study of consecutive patients referred for EMR of large sessile or flat colorectal polyps or laterally spreading lesions (≥20 mm) at academic hospitals in Australia from September 2008 through September 2016. We collected data on patient and lesion characteristics, outcomes of procedures, and histology findings. We excluded serrated lesions from the analysis of covert SMIC due to their distinct phenotype and biologic features. RESULTS: We analyzed 2277 lesions (mean size, 36.9 mm) from 2106 patients (mean age, 67.7 years; 53.2% male). SMIC was evident in 171 lesions (7.6%). Factors associated with SMIC included Kudo pit pattern V, a depressed component (0-IIc), rectosigmoid location, 0-Is or 0-IIa+Is Paris classification, non-granular surface morphology, and increasing size. After exclusion of lesions that were obviously SMIC or serrated, factors associated with covert SMIC were rectosigmoid location (odds ratio, 1.87; P = .01), combined Paris classification, surface morphology (odds ratios, 3.96-22.5), and increasing size (odds ratio, 1.16/10 mm; P = .012). CONCLUSIONS: In a prospective study of 2106 patients who underwent EMR for large sessile or flat colorectal polyps or laterally spreading lesions, we associated rectosigmoid location, combined Paris classification and surface morphology, and increasing size with increased risk for covert malignancy. Rectosigmoid 0-Is and 0-IIa+Is non-granular lesions have a high risk for malignancy, whereas proximally located 0-Is or 0-IIa granular lesions have a low risk. These findings can be used to inform decisions on which patients should undergo endoscopic submucosal dissection, EMR, or surgery. ClinicalTrials.gov, Number: NCT02000141.

A standardized imaging protocol for the endoscopic prediction of dysplasia within sessile serrated polyps (with video).

BACKGROUND AND AIMS: Dysplasia within sessile serrated polyps (SSPs) is difficult to detect and may be mistaken for an adenoma, risking incomplete resection of the background serrated tissue, and is strongly implicated in interval cancer after colonoscopy. The use of endoscopic imaging to detect dysplasia within SSPs has not been systematically studied. METHODS: Consecutively detected SSPs ≥8 mm in size were evaluated by using a standardized imaging protocol at a tertiary-care endoscopy center over 3 years. Lesions suspected as SSPs were analyzed with high-definition white light then narrow-band imaging. A demarcated area with a neoplastic pit pattern (Kudo type III/IV, NICE type II) was sought among the serrated tissue. If this was detected, the lesion was labeled dysplastic (sessile serrated polyp with dysplasia); if not, it was labeled non-dysplastic (sessile serrated polyp without dysplasia). Histopathology was reviewed by 2 blinded specialist GI pathologists. RESULTS: A total of 141 SSPs were assessed in 83 patients. Median lesion size was 15.0 mm (interquartile range 10-20), and 54.6% were in the right side of the colon. Endoscopic evidence of dysplasia was detected in 36 of 141 (25.5%) SSPs; of these, 5 of 36 (13.9%) lacked dysplasia at histopathology. Two of 105 (1.9%) endoscopically designated non-dysplastic SSPs had dysplasia at histopathology. Endoscopic imaging, therefore, had an accuracy of 95.0% (95% confidence interval [CI], 90.1%-97.6%) and a negative predictive value of 98.1% (95% CI, 92.6%-99.7%) for detection of dysplasia within SSPs. CONCLUSIONS: Dysplasia within SSPs can be detected accurately by using a simple, broadly applicable endoscopic imaging protocol that allows complete resection. Independent validation of this protocol and its dissemination to the wider endoscopic community may have a significant impact on rates of interval cancer. (Clinical trial registration number: NCT03100552.).

The clinical significance and synchronous polyp burden of large (≥ 20 mm) sessile serrated polyps in patients without serrated polyposis syndrome.

BACKGROUND: Sessile serrated polyps (SSPs) are important precursors of colorectal carcinoma and interval cancer. Large SSPs (≥ 20 mm) outside the definition of serrated polyposis syndrome (SPS) have not been studied in comparison with SPS. We aimed to describe the characteristics of patients with large SSPs in this context. METHODS: Patients with at least one SSP (≥ 20 mm) were eligible. Data from three consecutive colonoscopies were used to compare clinical and endoscopic characteristics in three patient groups: SPS, a solitary large SSP, and patients with at least two SSPs without fulfilling the criteria for SPS (oligo-SSP). Data on the diagnostic colonoscopy were collected retrospectively, whereas the remaining data was collected prospectively. RESULTS: 67/146 patients (45.9 %) had SPS, 53/146 (36.3 %) had a solitary SSP, and 26/146 (17.8 %) were categorized as oligo-SSP. Personal (16.4 %, 9.4 %, and 11.5 %, respectively) and family (17.9 %, 17.0 %, and 23.1 %, respectively) history of colorectal carcinoma did not differ significantly between groups. Polyp burden was greater in SPS compared with solitary SSP but was not different from oligo-SSP (advanced adenomas: SPS 32.8 % vs. solitary SSP 9.4 % [P = 0.002] vs. oligo-SSP 34.6 % [P = 0.87]; ≥ 10 conventional adenomas: 11.9 % vs. 0 % [P = 0.01] vs. 3.8 % [P = 0.44], respectively). Dysplasia in large SSPs was frequent in all groups (41.1 % overall). SPS was recognized by referring endoscopists in only 9.0 % of cases. CONCLUSION: Patients with oligo-SSPs have similar synchronous polyp burden and clinical characteristics as patients with SPS and may require similar surveillance. Modification of the criteria for the diagnosis of SPS to include this group seems warranted. Patients with a solitary SSP have a lower risk of synchronous polyps, including advanced adenomas. Larger studies are warranted to determine whether these patients may return to standard surveillance following complete examination and clearance of the colon.

Deep mural injury and perforation after colonic endoscopic mucosal resection: a new classification and analysis of risk factors.

OBJECTIVES: Perforation is the most serious complication associated with endoscopic mucosal resection (EMR). We propose a new classification for the appearance and integrity of the muscularis propria (MP) after EMR including various extents of deep mural injury (DMI). Risk factors for these injuries were analysed. DESIGN: Endoscopic images and histological specimens of consecutive patients undergoing EMR of colonic laterally spreading lesions ≥20 mm at a large Australian tertiary referral endoscopy unit were retrospectively analysed using our new DMI classification system. DMI was graded according to MP injury (I/II intact MP without/with fibrosis, III target sign, IV/V obvious transmural perforation without/with contamination). Histological specimens were examined for included MP and patient outcomes were recorded. All type III-V DMI signs were clipped if possible, types I and II DMI were clipped at the endoscopists' discretion. RESULTS: EMR was performed in 911 lesions (mean size 37 mm) in 802 patients (male sex 51.4%, mean age 67 years). DMI signs were identified in 83 patients (10.3%). Type III-V DMI was identified in 24 patients (3.0%); clipping was successfully performed in all patients. A clinically significant perforation occurred in two patients (0.2%). Only one of the 59 type I/II cases experienced a delayed perforation. 85.5% of patients with DMI were discharged on the same day, all without sequelae. On multivariable analysis, type III-V DMI was associated with transverse colon location (OR 3.55, p=0.028), en bloc resection (OR 3.84, p=0.005) and high-grade dysplasia or submucosal invasive cancer (OR 2.97, p 0.014). CONCLUSIONS: In this retrospective analysis, use of the new classification and management with clips appeared to be a safe approach. Advanced DMI types (III-V) occurred in 3.0% of patients and were associated with identifiable risk factors. Further prospective clinical studies should use this new classification. TRIAL REGISTRATION NUMBER: NCT01368289; results.

Endoscopic mucosal resection for large serrated lesions in comparison with adenomas: a prospective multicentre study of 2000 lesions.

OBJECTIVE: Endoscopic mucosal resection (EMR) is effective for large laterally spreading flat and sessile lesions (LSLs). Sessile serrated adenomas/polyps (SSA/Ps) are linked to the relative failure of colonoscopy to prevent proximal colorectal cancer. We aimed to examine the technical success, adverse events and recurrence following EMR for large SSA/Ps in comparison with large conventional adenomas. DESIGN: Over 74 months till August 2014, prospective multicentre data of LSLs ≥20 mm were analysed. A standardised dye-based conventional EMR technique followed by scheduled surveillance colonoscopy was used. RESULTS: From a total of 2000 lesions, 323 SSA/Ps in 246 patients and 1527 adenomas in 1425 patients were included for analysis. Technical success for EMR was superior in SSA/Ps compared with adenomas (99.1% vs 94.5%, p<0.001). Significant bleeding and perforation were similar in both cohorts. The cumulative recurrence rates for adenomas after 6, 12, 18 and 24 months were 16.1%, 20.4%, 23.4% and 28.4%, respectively. For SSA/Ps, they were 6.3% at 6 months and 7.0% from 12 months onwards (p<0.001). Following multivariable adjustment, the HR of recurrence for adenomas versus SSA/Ps was 1.7 (95% CI 0.9 to 3.0, p=0.097). Subgroup analysis by lesion size revealed an eightfold increased risk of recurrence for 20-25 mm adenomas versus SSA/Ps, but no significantly different risk between lesion types in larger lesion groups. CONCLUSION: Recurrence after EMR of 20-25 mm LSLs is significantly less frequent in SSA/Ps compared with adenomatous lesions. SSA/Ps can be more effectively removed than adenomatous LSLs with equivalent safety. Ensuring complete initial resection is imperative for avoiding recurrence. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01368289.