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.

Dysglycemia in non-functioning pancreatic neuroendocrine tumors (NF-PNET): Further insights into an under recognized entity.

Objective: Pancreatic neuroendocrine tumors (PNETs) are rare, but their incidence has risen significantly in recent years. Whereas diabetes mellitus (DM) is recognized in association with chronic pancreatitis and pancreatic cancer, it has not been well-characterized concerning non-functioning (NF)-PNETs.Study aim: to determine whether NF-PNETs are associated with DM/ Pre-DM and characterize the features of this putative association. Methods: Retrospective study to evaluate rate of Pre-DM /DM in subjects with NF-PNETs. Results: Study cohort of 129 patients with histologically confirmed NF-PNETs, ∼60% were men (M/F: 77/52). Abnormal glucose metabolism that preceded any treatment was seen in 70% of this cohort: overt DM in 34% and Pre-DM in 36% of the subjects. However, during follow-up, the overall prevalence rose to 80.6%, owing exclusively to newly diagnosed DM in subjects who received treatment.Patients with DM/Pre-DM were older (65 ± 11; 54 ± 14; p < 0.0001), the tumor was more commonly localized in the pancreatic body and tail (76.5% vs. 23.5% p = 0.03), while BMI (27 ± 6 vs. 28 ± 5 kg/m2), and tumor size (2.4 ± 2 vs. 2.9 ± 3.2 cm) were similar. The relative prevalence of DM in our cohort of NF-PNETs was 1.6 higher than that in the age and gender-adjusted general Israeli population (95 %CI: 1.197-2.212p = 0.03). Conclusions: We found a high rate of impaired glucose metabolism, either DM or Pre-DM, in a large cohort of NF-PNETs. The high prevalence of diabetes/pre-diabetes was unrelated to obesity or tumor size. This observation should increase awareness of the presence of DM on presentation or during treatment of "NF"-PNETs.

A Lymph Node Ratio Model for Prognosis of Patients with Pancreatic Neuroendocrine Tumors.

The objective of this study was to determine the prognostic value of lymph node (LN) involvement and the LN ratio (LNR) and their effect on recurrence rates and survival in patients with pancreatic neuroendocrine tumors (PNETs) undergoing surgery. This single-center retrospective study reviewed the medical records of 95 consecutive patients diagnosed with PNETs who underwent surgery at our medical center between 1997 and 2017. The retrieved information included patient demographics, pathology reports, treatments, and oncological outcomes. Results: 95 consecutive potentially suitable patients were identified. The 78 patients with PNETs who underwent surgery and for whom there was adequate data were included in the analysis. Their mean ± standard deviation age at diagnosis was 57.4 ± 13.4 years (range 20-82), and there were 50 males (64%) and 28 females (36%). 23 patients (30%) had LN metastases (N1). The 2.5- and 5-year disease-free survival (DFS) rates for the entire cohort were 79.5% and 71.8%, respectively, and their 2- and 5-year overall survival (OS) rates were 85.9% and 82.1%, respectively. The optimal value of the LNR was 0.1603, which correlated with the outcome (2-year OS p = 0.002 HR = 13.4 and 5-year DFS p = 0.016 HR = 7.2, respectively, and 5-year OS and 5-year DFS p = 0.004 HR = 9 and p = 0.001 HR = 10.6, respectively). However, the multivariate analysis failed to show that the LNR was an independent prognostic factor in PNETs. Patients with PNETs grade and stage are known key prognostic factors influencing OS and DFS. According to our results, LNR failed to be an independent prognostic factor.

Pancreatic cyst fluid glucose: a rapid on-site diagnostic test for mucinous cysts.

Background: Pancreatic cystic fluid (PCF) analysis is frequently used for cyst diagnosis with carcinoembryonic antigen (CEA) being the most accepted biomarker. Low glucose levels in PCF were previously suggested as a marker for mucinous cysts. A bed-side glucometer is a point-of care, immediate, simple, and cheap method which requires a small volume of PCF. Objectives: The aim of our study was to identify the optimal glucose cut-off level for identifying mucinous cysts, evaluate the diagnostic accuracy of glucose compared to CEA, and validate glucometry against reference laboratory biochemical analysis. Design: A single-center prospective cohort study. Methods: Consecutive patients aged 18 and older, who underwent pancreatic cyst evaluation, at the Tel Aviv Medical Center between 2016 and 2021 were analyzed. Cyst type was defined based on clinical, laboratory, and radiologic findings. Glucose was measured using laboratory biochemical analysis and two glucometers. Receiver operating characteristic analysis derived sensitivity, specificity, and accuracy were calculated and McNemar test was used to compare between methods. Results: One hundred and one PCF samples were evaluated. The areas under the receiver operating characteristics curve for identifying mucinous cysts using glucometer, glucose laboratory, and their combination were 0.88 (p < 0.001), 0.92 (p < 0.001), and 0.93 (p < 0.001), respectively. A glucose level of 87 mg/dL was identified as the optimal laboratory glucose threshold value to detect mucinous cyst with a sensitivity of 90.9%, specificity of 83.3%, and accuracy of 89.3, higher in comparison to cyst fluid CEA. Furthermore, PCF glucose levels had the strongest association with mucinous cysts. Conclusion: Our findings suggest that PCF glucose level is more accurate than CEA for the diagnosis of mucinous cysts. Glucometry glucose level assessment demonstrated an excellent correlation with laboratory glucose measurements and may become a useful diagnostic test.

Increased prevalence of colorectal neoplasia in patients with intraductal papillary mucinous neoplasms.

Background: The association between intraductal papillary mucinous neoplasms (IPMNs) and colorectal cancer (CRC) and polyps is controversial. Objectives: To compare the prevalence of CRC and colorectal polyps among patients with IPMN and matched average risk individuals. Methods: A match cross-sectional historical study comparing colonoscopy findings of 310 patients with IPMN cysts who underwent at least one colonoscopy examination from 2004 through 2019, with 310 age- and gender-matched average risk participants who underwent a screening colonoscopy. CRC and polyps were assessed in both groups. The prevalence and odds ratio were calculated. Results: CRC was diagnosed in 16 of 310 patients with IPMN (5.2%), and at least one polyp was detected in 96 patients (31%). The prevalence of CRC was greater among patients with IPMN than in matched individuals [5.2% versus 1.3%, p = 0.012, prevalence odds ratio (POR) 4, confidence interval (CI) 1.29-16.44]. The overall prevalence of polyps was not higher among patients with IPMN than in matched individuals (31% versus 26.8%, p = 0.291, POR 1.22, CI 0.85-1.76). However, the prevalence of colorectal adenomas with high-grade dysplasia was higher in patients with IPMN than in matched individuals (4.2% versus 1%, p = 0.02, POR 4.33, CI, 1.19-23.7). The prevalence of large polyps (i.e. more than 20 mm in size) was also greater in patients with IPMN than in matched individuals (6.1% versus 1.9%, p = 0.011, POR 3.6, CI, 1.29-12.40). Conclusion: Patients with IPMN have a significantly higher prevalence of CRC and advanced polyps than the average risk population. In view of our findings, we suggest that once the diagnosis of IPMN is made, special consideration of CRC should be undertaken.

Outcomes of Deep Mural Injury After Endoscopic Resection: An International Cohort of 3717 Large Non-Pedunculated Colorectal Polyps.

BACKGROUND & AIMS: Although perforation is the most feared adverse event associated with endoscopic mucosal resection (EMR), limited data exists concerning its management. Therefore, we sought to evaluate the short- and long-term outcomes of intra-procedural deep mural injury (DMI) in an international multi-center observational cohort of large (≥20 mm) non-pedunculated colorectal polyps (LNPCPs). METHODS: Consecutive patients who underwent EMR for a LNPCP ≥20 mm were evaluated. Significant DMI (S-DMI) was defined as Sydney DMI Classification type III (muscularis propria injury, target sign) or type IV/V (perforation without or with contamination, respectively). The primary outcome was successful S-DMI defect closure. Secondary outcomes included technical success (removal of all visible polypoid tissue during index EMR), surgical referral and recurrence at first surveillance colonscopy (SC1). RESULTS: Between July 2008 to May 2020, 3717 LNPCPs underwent EMR. Median lesion size was 35mm (interquartile range (IQR) 25 to 45mm). Significant DMI was identified in 101 cases (2.7%), with successful defect closure in 98 (97.0%) using a median of 4 through-the-scope clips (TTSCs; IQR 3 to 6 TTSCs). Three (3.0%) patients underwent S-DMI-related urgent surgery. Technical success was achieved in 94 (93.1%) patients, with 46 (45.5%) admitted to hospital (median duration 1 day; IQR 1 to 2 days). Comparing LNPCPs with and without S-DMI, no differences in technical success (94 (93.1%) vs 3316 (91.7%); P = .62) or SC1 recurrence (12 (20.0%) vs 363 (13.6%); P = .15) were identified. CONCLUSIONS: Significant DMI is readily managed endoscopically and does not appear to affect technical success or recurrence.

Optical Evaluation for Predicting Cancer in Large Nonpedunculated Colorectal Polyps Is Accurate for Flat Lesions.

BACKGROUND AND AIMS: The ability of optical evaluation to diagnose submucosal invasive cancer (SMIC) prior to endoscopic resection of large (≥20 mm) nonpedunculated colorectal polyps (LNPCPs) is critical to inform therapeutic decisions. Prior studies suggest that it is insufficiently accurate to detect SMIC. It is unknown whether lesion morphology influences optical evaluation performance. METHODS: LNPCPs ≥20 mm referred for endoscopic resection within a prospective, multicenter, observational cohort were evaluated. Optical evaluation was performed prior to endoscopic resection with the optical prediction of SMIC based on established features (Kudo V pit pattern, depressed morphology, rigidity/fixation, ulceration). Optical evaluation performance outcomes were calculated. Outcomes were reported by dominant morphology: nodular (Paris 0-Is/0-IIa+Is) vs flat (Paris 0-IIa/0-IIb) morphology. RESULTS: From July 2013 to July 2019, 1583 LNPCPs (median size 35 [interquartile range, 25-50] mm; 855 flat, 728 nodular) were assessed. SMIC was identified in 146 (9.2%; 95% confidence interval [CI], 7.9%-10.8%). Overall sensitivity and specificity were 67.1% (95% CI, 59.2%-74.2%) and 95.1% (95% CI, 93.9%-96.1%), respectively. The overall SMIC miss rate was 3.0% (95% CI, 2.3%-4.0%). Significant differences in sensitivity (90.9% vs 52.7%), specificity (96.3% vs 93.7%), and SMIC miss rate (0.6% vs 5.9%) between flat and nodular LNPCPs were identified (all P < .027). Multiple logistic regression identified size ≥40 mm (odds ratio [OR], 2.0; 95% CI, 1.0-3.8), rectosigmoid location (OR, 2.0; 95% CI, 1.1-3.7), and nodular morphology (OR, 7.2; 95% CI, 2.8-18.9) as predictors of missed SMIC (all P < .039). CONCLUSIONS: Optical evaluation performance is dependent on lesion morphology. In the absence of features suggestive of SMIC, flat lesions can be presumed benign and be managed accordingly.

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.

Snare-tip soft coagulation is effective and efficient as a first-line modality for treating intraprocedural bleeding during Barrett's mucosectomy.

BACKGROUND : Intraprocedural bleeding (IPB) during multiband mucosectomy (MBM) for Barrett's neoplasia can obscure the endoscopic field. Current hemostatic devices may affect procedure continuity and technical success. Snare-tip soft coagulation (STSC) as a first-line therapy for primary hemostasis has not previously been studied in this setting. METHODS: Between January 2014 and November 2019, 191 consecutive patients underwent 292 MBM procedures for Barrett's neoplasia within a prospective observational cohort in two tertiary care centers. A standard MBM technique was performed. IPB was defined as bleeding obscuring the endoscopic field that required intervention. The primary outcome was the technical success and efficacy of STSC. RESULTS: IPB occurred in 63 MBM procedures (21.6 %; 95 % confidence interval 17.3 % - 26.7 %). STSC was attempted as first-line therapy in 51 IPBs, with the remainder requiring alternate therapies because of pooling of blood. STSC achieved hemostasis in 48 cases (94.1 % by per-protocol analysis; 76.2 % by intention-to-treat analysis). No apparatus disassembly was required to perform STSC. CONCLUSIONS: STSC is a safe, effective, and efficient first-line hemostatic modality for IPB during MBM for Barrett's neoplasia.

Piecemeal cold snare polypectomy versus conventional endoscopic mucosal resection for large sessile serrated lesions: a retrospective comparison across two successive periods.

OBJECTIVE: Large (≥20 mm) sessile serrated lesions (L-SSL) are premalignant lesions that require endoscopic removal. Endoscopic mucosal resection (EMR) is the existing standard of care but carries some risk of adverse events including clinically significant post-EMR bleeding and deep mural injury (DMI). The respective risk-effectiveness ratio of piecemeal cold snare polypectomy (p-CSP) in L-SSL management is not fully known. DESIGN: Consecutive patients referred for L-SSL management were treated by p-CSP from April 2016 to January 2020 or by conventional EMR in the preceding period between July 2008 and March 2016 at four Australian tertiary centres. Surveillance colonoscopies were conducted at 6 months (SC1) and 18 months (SC2). Outcomes on technical success, adverse events and recurrence were documented prospectively and then compared retrospectively between the subsequent time periods. RESULTS: A total of 562 L-SSL in 474 patients were evaluated of which 156 L-SSL in 121 patients were treated by p-CSP and 406 L-SSL in 353 patients by EMR. Technical success was equal in both periods (100.0% (n=156) vs 99.0% (n=402)). No adverse events occurred in p-CSP, whereas delayed bleeding and DMI were encountered in 5.1% (n=18) and 3.4% (n=12) of L-SSL treated by EMR, respectively. Recurrence rates following p-CSP were similar to EMR at 4.3% (n=4) versus 4.6% (n=14) and 2.0% (n=1) versus 1.2% (n=3) for surveillance colonoscopy (SC)1 and SC2, respectively. CONCLUSIONS: In a historical comparison on the endoscopic management of L-SSL, p-CSP is technically equally efficacious to EMR but virtually eliminates the risk of delayed bleeding and perforation. p-CSP should therefore be considered as the new standard of care for L-SSL treatment.

Endoscopic mucosal resection is effective for laterally spreading lesions at the anorectal junction.

OBJECTIVE: The optimal approach for removing large laterally spreading lesions at the anorectal junction (ARJ-LSLs) is unknown. Endoscopic mucosal resection (EMR) is a definitive therapy for colorectal LSLs. It is unclear whether it is an effective modality for ARJ-LSLs. DESIGN: EMR outcomes for ARJ-LSLs (distal margin of ≤20 mm from the dentate line) in comparison with rectal LSLs (distal margin of >20 mm from the dentate line) were evaluated within a multicentre observational cohort of LSLs of ≥20 mm. Technical success was defined as the removal of all polypoid tissue during index EMR. Safety was evaluated by the frequencies of intraprocedural bleeding, delayed bleeding, deep mural injury (DMI) and delayed perforation. Long-term efficacy was evaluated by the absence of recurrence (either endoscopic or histologic) at surveillance colonoscopy (SC). RESULTS: Between July 2008 and August 2019, 100 ARJ-LSLs and 313 rectal LSLs underwent EMR. ARJ-LSL median size was 40 mm (IQR 35-60 mm). Median follow-up at SC4 was 54 months (IQR 33-83 months). Technical success was 98%. Cancer was present in three (3%). Recurrence occurred in 15.4%, 6.8%, 3.7% and 0% at SC1-SC4, respectively. Among 30 ARJ-LSLs that received margin thermal ablation, no recurrence was identified at SC1 (0.0% vs 25.0%, p=0.002). Technical success, recurrence and adverse events were not different between groups, except for DMI (ARJ-LSLs 0% vs rectal LSLs 4.5%, p=0.027). CONCLUSION: EMR is an effective technique for ARJ-LSLs and should be considered a first-line resection modality for the majority of these lesions.

Impact of en bloc resection on long-term outcomes after endoscopic mucosal resection: a matched cohort study.

BACKGROUND AND AIMS: Residual or recurrent adenoma (RRA) is the major limitation of piecemeal EMR (p-EMR) for large colonic laterally spreading lesions (LSLs) ≥20 mm. En bloc EMR (e-EMR) has been shown to achieve low rates of RRA but specific procedural and long-term outcomes are unknown. Our aim was to compare long-term outcomes of size-matched LSLs stratified by whether they were resected e-EMR or p-EMR. METHODS: Data from a prospective tertiary referral multicenter cohort of large LSLs referred for EMR over a 10-year period were analyzed. Outcomes were compared between sized-matched LSLs (20-25 mm) resected by p-EMR or e-EMR. RESULTS: Five hundred seventy LSLs met the inclusion criteria of which 259 (45.4%) were resected by e-EMR. The risk of major deep mural injury (DMI) was significantly higher in the e-EMR group (3.5% vs 1.0%, P = .05), whereas rates of other intraprocedural adverse events did not differ significantly. Five of 9 (56%) LSLs, with endoscopic features of submucosal invasion (SMI), resected by e-EMR were saved from surgery. RRA at first surveillance was lower in the e-EMR group (2.0% vs 5.7%, P = .04), but this difference was negated at subsequent surveillance. Rates of surgical referral were not significantly different between the groups at either surveillance interval. CONCLUSION: When comparing e-EMR against p-EMR for lesions ≤25 mm in size of similar morphology in a large prospective multicenter cohort, e-EMR offered no additional advantage for predicted-benign LSLs. However, it was associated with an increased risk of major DMI. Thus, en bloc resection techniques should be reserved for lesions suspicious for invasive disease. (Clinical trial registration number: NCT01368289.).

Definitive therapy of colonic angioectasia by submucosal coagulation.

Background and study aims Colonic angioectasia are the most common vascular lesions in the gastrointestinal tract and are among the most common causes for chronic or recurrent lower gastrointestinal bleeding. Endoscopic treatment involves a variety of techniques, all of which focus on destruction of the mucosal abnormality. However, recurrent bleeding after endoscopic treatment is common, with more than one treatment frequently necessary. We report a technique for definitive treatment of colonic angioectasia by targeting the feeding submucosal vessel. Patients and methods Analogous to endoscopic mucosal resection, a submucosal injection is made beneath the target lesion which is then removed by electrocautery snare resection of the mucosal lesion. The exposed feeding vessel is then destroyed by application of coagulation current. The resection defect is closed by clips. Results Six patients with a total of 14 colonic angioectasia were treated over the study period. All lesions were destroyed without adverse events. Conclusion Elevation, hot snare resection and coagulation (ESC) of the visible vessel for treating colonic angioectasia appears safe and effective. Larger prospective comparative studies are required to assess its specific role.

Hepatocyte metabolic signalling pathways and regulation of hepatitis B virus expression.

Hepatitis B virus (HBV) is a small DNA virus responsible for significant morbidity and mortality worldwide. The liver, which is the main target organ for HBV infection, provides the virus with the machinery necessary for persistent infection and propagation, a process that might ultimately lead to severe liver pathologies such as chronic hepatitis, cirrhosis and liver cancer. HBV gene expression is regulated mainly at the transcriptional level by recruitment of a whole set of cellular transcription factors (TFs) and co-activators to support transcription. Over the years, many of these TFs were identified and interestingly enough most are associated with the body's nutritional state. These include the hepatocyte nuclear factors, forkhead Box O1, Farnesoid X receptor, cyclic-AMP response element-binding (CREB), CCAAT/enhancer-binding protein (C/EBP) and glucocorticoid receptor TFs and the transcription coactivator PPARγ coactivator-1α. Consequently, HBV gene expression is linked to hepatic metabolic processes such as glucose and fat production and utilization as well as bile acids' production and secretion. Furthermore, recent evidence indicates that HBV actively interferes with some of these hepatic metabolic processes by manipulating key TFs, such as CREB and C/EBP, to meet its requirements. The discovery of the mechanisms by which HBV is controlled by the hepatic metabolic milieu may broaden our understanding of the unique regulation of HBV expression and may also explain the mechanisms by which HBV induces liver pathologies. The emerging principle of the intimate link between HBV and liver metabolism can be further exploited for host-targeted therapeutic strategies.

Isolated inferior wall ST segment depression as an early sign of acute anterior wall myocardial infarction.

BACKGROUND: Reciprocal changes may accompany ST segment elevation in the ischemic territory during acute myocardial infarction (AMI). We examined the hypothesis that isolated inferior ST segment depression on admission is an early sign of anterior wall infarction. METHODS: 49 patients admitted to the coronary care unit between January 1996 and June 2008 who presented with inferior ST segment depression in the absence of ST segment elevation. Electrocardiograms (ECGs) obtained on admission and at 24-48 h were reviewed. Culprit artery was determined based on angiographic and echocardiographic data. RESULTS: All patients had ST segment depression in the inferior leads on admission. A subgroup (55%) presented with concomitant ST segment depression in V5-V6. Follow-up ECG showed that 35% developed ST segment elevations and/or T wave inversions in anterior wall leads over 24-48 h. The left anterior descending (LAD) artery or one of its branches was the culprit in 60% of the patients. Sum of ST segment depression, V5-V6 involvement or presence of 'hyperacute' T waves did not predict LAD involvement. CONCLUSION: Isolated ST segment depression in the inferior wall leads during ACS is usually an early sign of anterior wall AMI, in which the LAD or one of its branches is the culprit artery.

Curcumin inhibits hepatitis B virus via down-regulation of the metabolic coactivator PGC-1alpha.

Hepatitis B virus (HBV) infects the liver and uses its cell host for gene expression and propagation. Therefore, targeting host factors essential for HBV gene expression is a potential anti-viral strategy. Here we show that treating HBV expressing cells with the natural phenolic compound curcumin inhibits HBV gene expression and replication. This inhibition is mediated via down-regulation of PGC-1alpha, a starvation-induced protein that initiates the gluconeogenesis cascade and that has been shown to robustly coactivate HBV transcription. We suggest curcumin as a host targeted therapy for HBV infection that may complement current virus-specific therapies.