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.
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.
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).
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.
Background & Aims Wide-field endoscopic mucosal resection (WF-EMR) of large sessile colonic polyps is a safe and cost-effective outpatient treatment. Bleeding is the main complication. Few studies ...have examined risk factors for bleeding during the procedure (intraprocedural bleeding IPB) or after it (clinically significant post-endoscopic bleeding CSPEB). We investigated factors associated with IPB and CSPEB in a large prospective study. Methods We analyzed data from WF-EMRs of sessile colorectal polyps ≥20 mm in size (mean size, 35.5 mm), which were performed on 1172 patients (mean age, 67.8 years) from June 2008–March 2013 at 7 tertiary hospitals as part of the Australian Colonic Endoscopic Resection Study. Data were collected on characteristics of patients and lesions, along with outcomes of procedures and clinical and histologic analyses. Independent predictors of IPB and CSPEB were identified by multiple logistic regression analysis. Results Of the patients studied, 133 (11.3%) had IPB. Independent predictors included increasing lesion size (odds ratio, 1.24/10 mm; P < .001), Paris endoscopic classification of 0–IIa + Is (odds ratio, 2.12; P = .004), tubulovillous or villous histology (odds ratio, 1.84; P = .007), and study institutions that performed the procedure on fewer than 75 patients (odds ratio, 3.78; P < .001). All IPB was successfully controlled endoscopically. IPB prolonged procedures and was associated with early recurrence (relative risk, 1.68; P = .011). Seventy-three patients (6.2%) had CSPEB. On multivariable analysis, CSPEB was associated with proximal colon location (odds ratio, 3.72; P < .001), use of an electrosurgical current not controlled by a microprocessor (odds ratio, 2.03; P = .038), and IPB (odds ratio, 2.16; P = .016). Lesion size and comorbidities did not predict CSPEB. Conclusions In a prospective study of patients undergoing WF-EMR of large sessile colonic polyps, IPB is associated with larger lesions, lesion histology, and Paris endoscopic classification of type 0–IIa + Is. IPB prolongs the duration of the procedure, is a marker for recurrence, and is associated with CSPEB. CSPEB occurs most frequently in the proximal colon and less when current is controlled by a microprocessor.
Wide-field endoscopic mucosal resection (WF-EMR) is an alternative to surgery for treatment of advanced colonic mucosal neoplasia up to 120 mm in size, but has been criticised for its potentially ...high recurrence rates. We aimed to quantify recurrence at 4 months (early) and 16 months (late) following successful WF-EMR and identify its risk factors and clinical significance.
Ongoing multicentre, prospective, intention-to-treat analysis of sessile or laterally spreading colonic lesions ≥20 mm in size referred for WF-EMR to seven academic endoscopy units. Surveillance colonoscopy (SC) was performed 4 months (SC1) and 16 months (SC2) after WF-EMR, with photographic documentation and biopsy of the scar.
1134 consecutive patients were enrolled when 1000 successful EMRs were achieved, of whom 799 have undergone SC1. 670 were normal. Early recurrent/residual adenoma was present in 128 (16.0%, 95% CI 13.6% to 18.7%). One case was unknown. The recurrent/residual adenoma was diminutive in 71.7% of cases. On multivariable analysis, risk factors were lesion size >40 mm, use of argon plasma coagulation and intraprocedural bleeding. Of 670 with normal SC1, 426 have undergone SC2, with late recurrence present in 17 cases (4.0%, 95% CI 2.4% to 6.2%). Overall, recurrent/residual adenoma was successfully treated endoscopically in 135 of 145 cases (93.1%, 95% CI 88.1% to 96.4%). If the initial EMR was deemed successful and did not contain submucosal invasion requiring surgery, 98.1% (95% CI 96.6% to 99.0%) were adenoma-free and had avoided surgery at 16 months following EMR.
Following colonic WF-EMR, early recurrent/residual adenoma occurs in 16%, and is usually unifocal and diminutive. Risk factors were identified. Late recurrence occurs in 4%. Overall, recurrence was managed endoscopically in 93% of cases. Recurrence is not a significant clinical problem following WF-EMR, as with strict colonoscopic surveillance, it can be managed endoscopically with high success rates.
NCT01368289.
Large laterally spreading lesions (LSL) in the colon and rectum can be safely and effectively removed by endoscopic mucosal resection (EMR). However, many patients still undergo surgery. Endoscopic ...treatment may be more cost effective. We compared the costs of endoscopic versus surgical management of large LSL.
We performed a prospective, observational, multicenter study of consecutive patients referred to 1 of 7 academic hospitals in Australia for the management of large LSL (≥ 20 mm) from January 2010 to December 2013. We collected data on numbers of patients undergoing EMR, actual endoscopic management costs (index colonoscopy, hospital stay, adverse events, and first surveillance colonoscopy), characteristics of patients and lesions, outcomes, and adverse events, and findings from follow-up examinations 14 days, 4-6 months, and 16-18 months after treatment. We compared data from patients who underwent EMR with those from a model in which all patients underwent surgery without any complications. Event-specific costs, based on Australian refined diagnosis-related group codes, were used to estimate average cost per patient.
EMR was performed on 1489 lesions (mean size, 36 mm) in 1353 patients (mean age, 67 years; 52.1% male). Total costs involved in the endoscopic management of large LSL were US $6,316,593 and total inpatient hospitalization length of stay was 1180 days. The total cost predicted for the surgical management group was US $16,601,502, with a total inpatient hospitalization length of stay of 4986 days. Endoscopic management produced a potential total cost saving of US $10,284,909; the mean cost difference per patient was US $7602 (95% confidence interval, $8458-$9220; P < .001). Inpatient hospitalization length of stay was reduced by 2.81 nights per patient (95% confidence interval, 2.69-2.94; P < .001).
In a large multicenter study, endoscopic management of large LSL by EMR was significantly more cost-effective than surgery. Endoscopic management by EMR at an appropriately experienced and resourced tertiary center should be considered the first line of therapy for most patients with this disorder. This approach is likely to deliver substantial overall health expenditure savings. ClinicalTrials.gov, Number: NCT01368289.
A gluten-free diet is the only means to manage coeliac disease, a permanent immune intolerance to gluten. We developed a therapeutic vaccine, Nexvax2, designed to treat coeliac disease. Nexvax2 is an ...adjuvant-free mix of three peptides that include immunodominant epitopes for gluten-specific CD4-positive T cells. The vaccine is intended to engage and render gluten-specific CD4-positive T cells unresponsive to further antigenic stimulation. We assessed the safety and pharmacodynamics of the vaccine in patients with coeliac disease on a gluten-free diet.
We did two randomised, double-blind, placebo-controlled, phase 1 studies at 12 community sites in Australia, New Zealand, and the USA, in HLA-DQ2·5-positive patients aged 18-70 years who had coeliac disease and were on a gluten-free diet. In the screening period for ascending dose cohorts, participants were randomly assigned (1:1) by central randomisation with a simple block method to a double-blind crossover, placebo-controlled oral gluten challenge. Participants with a negative interferon γ release assay to Nexvax2 peptides after the screening oral gluten challenge were discontinued before dosing. For the biopsy cohorts, the screening period included an endoscopy, and participants with duodenal histology who had a Marsh score of greater than 1 were discontinued before dosing. Participants were subsequently randomly assigned to either Nexvax2 or placebo in ascending dose cohorts (2:1) and in biopsy cohorts (1:1) by central randomisation with a simple block method. In the three-dose study, participants received either Nexvax2 60 μg, 90 μg, or 150 μg weekly, or placebo over 15 days; in a fourth biopsy cohort, patients received either Nexvax2 at the maximum tolerated dose (MTD) or placebo. In the 16-dose study, participants received Nexvax2 150 μg or 300 μg or placebo twice weekly over 53 days; in a third biopsy cohort, patients also received either Nexvax2 at the MTD or placebo. In the 4-week post-treatment period, ascending dose cohorts underwent a further double-blind crossover, placebo-controlled oral gluten challenge, which had a fixed sequence, and biopsy cohorts had a gastroscopy with duodenal biopsies and quantitative histology within 2 weeks without oral gluten challenge. Participants, investigators, and study staff were masked to the treatment assignment, except for the study pharmacist. The primary endpoint was the number and percentage of adverse events in the treatment period in an intention-to-treat analysis. Both trials were completed and closed before data analysis. Trials were registered with the Australian New Zealand Clinical Trials Registry, numbers ACTRN12612000355875 and ACTRN12613001331729.
Participants were enrolled from Nov 28, 2012, to Aug 14, 2014, in the three-dose study, and from Aug 3, 2012, to Sept 10, 2013, in the 16-dose study. Overall, 62 (57%) of 108 participants were randomly assigned after oral gluten challenge and 20 (71%) of 28 participants were randomly assigned after endoscopy. In the three-dose study, nine participants were randomly allocated to Nexvax2 60 μg and three to placebo (first cohort), nine were allocated to Nexvax2 90 μg and four to placebo (second cohort), eight were allocated to Nexvax2 150 μg and four to placebo (third cohort), and three were allocated to Nexvax2 150 μg and three to placebo (biopsy cohort). In the 16-dose study, eight participants were randomly allocated to Nexvax2 150 μg and four to placebo (first cohort), ten were allocated to Nexvax2 300 μg and three to placebo (second cohort), and seven were allocated to Nexvax2 150 μg and seven to placebo (biopsy cohort). The MTD for Nexvax2 was 150 μg because of transient, acute gastrointestinal adverse events with onset 2-5 h after initial doses of the vaccine, similar to those caused by gluten ingestion. In the ascending dose cohorts in the three-dose study, six (55%) of 11 placebo recipients, five (56%) of nine who received Nexvax2 60 μg, seven (78%) of nine who received Nexvax2 90 μg, and five (63%) of eight who received Nexvax2 150 μg had at least one treatment-emergent adverse event, as did all three (100%) placebo recipients and one (33%) of three Nexvax2 150 μg recipients in the biopsy cohort. In the ascending dose cohorts of the 16-dose study, five (71%) of seven placebo-treated participants, six (75%) of eight who received Nexvax2 150 μg, and all ten (100%) who received Nexvax2 300 μg had at least one treatment-emergent adverse event, as did six (86%) of seven placebo recipients and five (71%) of seven Nexvax2 150 μg recipients in the biopsy cohort. Vomiting, nausea, and headache were the only treatment-emergent adverse events that occurred in at least 5% of participants in either study. Among participants given the MTD, eight gastrointestinal treatment-emergent adverse events occurred in four (50%) of eight participants in the third cohort and none (0%) of three participants in the biopsy cohort in the three-dose study, and five events occurred in five (63%) of eight participants in the first cohort and three events in two (29%) of seven participants in the biopsy cohort of the 16-dose study. Median villous height to crypt depth ratio in distal duodenal biopsies was not significantly different between those who received the vaccine at the MTD on either schedule and those who received placebo. Of the participants who completed the post-treatment oral gluten challenge per protocol, interferon γ release assay to Nexvax2 peptides was negative (responders to treatment) in two (22%) of nine placebo-treated participants in the three-dose study versus two (33%) of six who received Nexvax2 60 μg, five (63%) of eight who received Nexvax2 90 μg, and six (100%) of six who received Nexvax2 150 μg (p=0·007); in the 16-dose study, none (0%) of five placebo-treated participants had a negative assay versus six (75%) of eight who received Nexvax2 150 μg (p=0·021).
The MTD of Nexvax2 was 150 μg for twice weekly intradermal administration over 8 weeks, which modified immune responsiveness to Nexvax2 peptides without deterioration in duodenal histology. The gastrointestinal symptoms that followed the first intradermal administration of the vaccine resembled those associated with oral gluten challenge. These findings support continued clinical development of this potential therapeutic vaccine for coeliac disease.
ImmusanT.
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.
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.
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.
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.
ClinicalTrials.gov NCT01368289.
The serrated neoplasia pathway accounts for up to 30% of all sporadic colorectal cancers (CRCs). Sessile serrated adenomas/polyps (SSA/Ps) with cytological dysplasia (SSA/P-D) are a high-risk ...serrated CRC precursor with little existing data. We aimed to describe the clinical and endoscopic predictors of SSA/P-D and high grade dysplasia (HGD) or cancer.
Prospective multicentre data of SSA/Ps ≥20 mm referred for treatment by endoscopic mucosal resection (September 2008-July 2013) were analysed. Imaging and lesion assessment was standardised. Histological findings were correlated with clinical and endoscopic findings.
268 SSA/Ps were found in 207/1546 patients (13.4%). SSA/P-D comprised 32.4% of SSA/Ps ≥20 mm. Cancer occurred in 3.9%. On multivariable analysis, SSA/P-D was associated with increasing age (OR=1.69 per decade; 95% CI (1.19 to 2.40), p0.004) and increasing lesion size (OR=1.90 per 10 mm; 95% CI (1.30 to 2.78), p0.001), an 'adenomatous' pit pattern (Kudo III, IV or V) (OR=3.98; 95% CI (1.94 to 8.15), p<0.001) and any 0-Is component within a SSA/P (OR=3.10; 95% CI (1.19 to 8.12) p0.021). Conventional type dysplasia was more likely to exhibit an adenomatous pit pattern than serrated dysplasia. HGD or cancer was present in 7.2% and on multivariable analysis, was associated with increasing age (OR=2.0 per decade; 95% CI 1.13 to 3.56) p0.017) and any Paris 0-Is component (OR=10.2; 95% CI 3.18 to 32.4, p<0.001).
Simple assessment tools allow endoscopists to predict SSA/P-D or HGD/cancer in SSA/Ps ≥20 mm. Correct prediction is limited by failure to recognise SSA/P-D which may mimic conventional adenoma. Understanding the concept of SSA/P-D and the pitfalls of SSA/P assessment may improve detection, recognition and resection and potentially reduce interval cancer.
NCT01368289.
Improved blood tests assessing the functional status of rare gluten-specific CD4+ T cells are needed to effectively monitor experimental therapies for coeliac disease (CD). Our aim was to develop a ...simple, but highly sensitive cytokine release assay (CRA) for gluten-specific CD4+ T cells that did not require patients to undergo a prior gluten challenge, and would be practical in large, multi-centre clinical trials. We developed an enhanced CRA and used it in a phase 2 clinical trial (“RESET CeD”) of Nexvax2, a peptide-based immunotherapy for CD. Two participants with treated CD were assessed in a pilot study prior to and six days after a 3-day gluten challenge. Dye-dilution proliferation in peripheral blood mononuclear cells (PBMC) was assessed, and IL-2, IFN-γ and IL-10 were measured by multiplex electrochemiluminescence immunoassay (ECL) after 24-hour gluten-peptide stimulation of whole blood or matched PBMC. Subsequently, gluten-specific CD4+ T cells in blood were assessed in a subgroup of the RESET CeD Study participants who received Nexvax2 (maintenance dose 900 μg, n = 12) or placebo (n = 9). The pilot study showed that gluten peptides induced IL-2, IFN-γ and IL-10 release from PBMCs attributable to CD4+ T cells, but the PBMC CRA was substantially less sensitive than whole blood CRA. Only modest gluten peptide-stimulated IL-2 release could be detected without prior gluten challenge using PBMC. In contrast, whole blood CRA enabled detection of IL-2 and IFN-γ before and after gluten challenge. IL-2 and IFN-γ release in whole blood required more than 6 hours incubation. Delay in whole blood incubation of more than three hours from collection substantially reduced antigen-stimulated IL-2 and IFN-γ secretion. Nexvax2, but not placebo treatment in the RESET CeD Study was associated with significant reductions in gluten peptide-stimulated whole blood IL-2 and IFN-γ release, and CD4+ T cell proliferation. We conclude that using fresh whole blood instead of PBMC substantially enhances cytokine secretion stimulated by gluten peptides, and enables assessment of rare gluten-specific CD4+ T cells without requiring CD patients to undertake a gluten challenge. Whole blood assessment coupled with ultra-sensitive cytokine detection shows promise in the monitoring of rare antigen-specific T cells in clinical studies.
Background EMR of advanced mucosal neoplasia (AMN) (ie, sessile or laterally spreading lesions of ≥20 mm) of the colon has become an increasingly popular alternative to surgical resection. However, ...data regarding safety and mortality of EMR in comparison to surgery are limited. Objective To compare actual endoscopic with predicted surgical mortality. Design Prospective, observational, multicenter cohort study. Setting Academic, high-volume, tertiary-care referral center. Patients Consecutive patients referred for EMR. Intervention EMR. Main Outcome Measurements To predict hypothetical surgical mortality, the Association of Coloproctology of Great Britain and Ireland score, composed of physiological and surgical components, was calculated for each patient. Predicted surgical mortality was then compared with actual outcomes of EMR. The results were validated by an unselected subcohort by using the Colorectal Physiologic and Operative Severity Score for Enumeration of Mortality and Morbidity. Results Among 1050 patients with AMN treated by EMR, including patients with a predicted mortality rate of greater than 5% (13.8% of cohort), no deaths occurred within 30 days after the procedure. The predicted surgical mortality rate was 3.3% with the Association of Coloproctology of Great Britain and Ireland score ( P < .0001). This suggests a significant advantage of EMR over surgery. The results were validated by using the Colorectal Physiologic and Operative Severity Score for Enumeration of Mortality and Morbidity in 390 patients predicting a surgical mortality rate of 3.2% ( P = .0003). Limitations Nonrandomized study. Conclusion In this large multicenter study of EMR for colonic AMN, the predicted surgical mortality rate was significantly higher than the actual endoscopic mortality rate. Given that endoscopic therapy is less morbid and less expensive than surgery and can be performed as an outpatient treatment, it should be considered as the first line of treatment for most patients with these lesions.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Clinically significant bleeding (CSPEB) is the most frequent adverse event following wide-field endoscopic mucosal resection (WF-EMR) of large sessile and laterally spreading colorectal lesions ...(LSL). There is limited knowledge regarding accurate prediction of CSPEB. We aimed to derive a score to predict the risk of CSPEB.
Data on patient and lesion characteristics and outcomes from WF-EMRs of LSL ≥20 mm at 8 referral hospitals were analyzed. The cohort was divided at random into equal sized training and test groups. Independent predictors of CSPEB in the training cohort were identified by multiple logistic regression analysis and used to develop a risk score. The performance of this score was assessed in the independent test cohort.
Over 80 months to June 2015, 2,128 patients with 2,424 LSL were referred for WF-EMR. Two thousand and twelve patients were eligible for analysis. There were 135 cases of CSPEB (6.7%). In the training cohort of 1,006 patients, the independent predictors of CSPEB were lesion size >30 mm (odds ratio (OR) 2.5), proximal colonic location (OR 2.3), presence of a major comorbidity (OR 1.5), and epinephrine in injection solution (OR 0.57). The derived risk score comprised lesion size >30 mm (2 points), proximal colon (2 points), presence of major comorbidity (1 point), and absence of epinephrine use (1 point). The probabilities of CSPEB for scores of 0, 1, 2, 3, 4, and ≥5 in the training cohort were 1.5, 2.0, 5.6, 7.8, 9.1, and 17.5% and were 0.9, 6.7, 4.9, 6.2, 9.0, and 15.7% in the test cohort. The probabilities of CSPEB in those with low (score 0-1), medium (score 2-4), and elevated (score 5-6) risk levels were 1.7, 7.1, and 17.5% in the training cohort and 3.4, 6.2, and 15.7% in the test cohort.
Patients at elevated risk of CSPEB can be identified using four readily available variables. This knowledge may improve the management of those undergoing WF-EMR and assist in designing studies evaluating CSPEB.
PDF
