Topically applied methylene blue dye chromoendoscopy is effective in improving detection of colorectal neoplasia. When combined with a pH- and time-dependent multimatrix structure, a per-oral ...methylene blue formulation (MB-MMX) can be delivered directly to the colorectal mucosa.
We performed a phase 3 study of 1205 patients scheduled for colorectal cancer screening or surveillance colonoscopies (50–75 years old) at 20 sites in Europe and the United States, from December 2013 through October 2016. Patients were randomly assigned to groups given 200 mg MB-MMX, placebo, or 100 mg MB-MMX (ratio of 2:2:1). The 100-mg MB-MMX group was included for masking purposes. MB-MMX and placebo tablets were administered with a 4-L polyethylene glycol–based bowel preparation. The patients then underwent colonoscopy by an experienced endoscopist with centralized double-reading. The primary endpoint was the proportion of patients with 1 adenoma or carcinoma (adenoma detection rate ADR). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for differences in detection between the 200-mg MB-MMX and placebo groups. False-positive (resection rate for non-neoplastic polyps) and adverse events were assessed as secondary endpoints.
The ADR was higher for the MB-MMX group (273 of 485 patients, 56.29%) than the placebo group (229 of 479 patients, 47.81%) (OR 1.46; 95% CI 1.09–1.96). The proportion of patients with nonpolypoid lesions was higher in the MB-MMX group (213 of 485 patients, 43.92%) than the placebo group (168 of 479 patients, 35.07%) (OR 1.66; 95% CI 1.21–2.26). The proportion of patients with adenomas ≤5 mm was higher in the MB-MMX group (180 of 485 patients, 37.11%) than the placebo group (148 of 479 patients, 30.90%) (OR 1.36; 95% CI 1.01–1.83), but there was no difference between groups in detection of polypoid or larger lesions. The false-positive rate did not differ significantly between groups (83 23.31% of 356 patients with non-neoplastic lesions in the MB-MMX vs 97 29.75% of 326 patients with non-neoplastic lesions in the placebo group). Overall, 0.7% of patients had severe adverse events but there was no significant difference between groups.
In a phase 3 trial of patients undergoing screening or surveillance colonoscopies, we found MB-MMX led to an absolute 8.5% increase in ADR, compared with placebo, without increasing the removal of non-neoplastic lesions. Clinicaltrials.gov no: NCT01694966
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Abstract
Background
Rapid access to pancreatic imaging and regular pancreatic surveillance may help identify stage I pancreatic cancer. We investigated recent trends in the stage of newly diagnosed ...pancreatic ductal adenocarcinoma (PDACs), age at diagnosis, and survival.
Methods
Trends in age-adjusted incidence of stage IA PDAC between 2004 and 2016 were determined from the National Cancer Institute’s Surveillance, Epidemiology and End Results database. All tests were two-sided.
Results
The incidence of stage IA PDAC cases diagnosed increased statistically significantly from 2004 to 2016 (annual percent change = 14.5, 95% confidence interval CI = 11.4 to 17.7; P < .001). During the study period, average age at diagnosis for stage IA and IB casesAQ3 declined by 3.5 years (95% CI = 1.2 to 5.9; P = .004) and 5.5 years (95% CI = 3.4 to 7.6; P < .001), whereas average age increased for higher-stage cases (by 0.6 to 1.4 years). Among stage IA cases, the proportion of blacks was smaller (10.2% vs 12.5%), and the proportion of other non-Caucasians was higher compared with higher-stage cases (11.9% vs 8.4%; P < .001). Stage IA cases were more likely to carry insurance (vs Medicaid or none) than higher-stage cases (cases aged younger than 65 years; odds ratio = 2.45, 95% CI = 1.96 to 3.06; P < .001). The 5-year overall survival for stage IA PDAC improved from 44.7% (95% CI = 31.4 to 63.7) in 2004 to 83.7% (95% CI = 78.6% to 89.2%) in 2012; 10-year survival improved from 36.7% (95% CI = 24.1 to 55.8) in 2004 to 49.0% (95% CI = 37.2% to 64.6%) in 2007.
Conclusions
In recent years, the proportion of patients diagnosed with stage IA PDAC has increased, their average age at diagnosis has decreased, and their overall survival has improved. These trends may be the result of improved early diagnosis and early detection.
Screening of individuals who have a high risk of pancreatic ductal adenocarcinoma (PDAC), because of genetic factors, frequently leads to identification of pancreatic lesions. We investigated the ...incidence of PDAC and risk factors for neoplastic progression in individuals at high risk for PDAC enrolled in a long-term screening study.
We analyzed data from 354 individuals at high risk for PDAC (based on genetic factors of family history), enrolled in Cancer of the Pancreas Screening cohort studies at tertiary care academic centers from 1998 through 2014 (median follow-up time, 5.6 years). All subjects were evaluated at study entry (baseline) by endoscopic ultrasonography and underwent surveillance with endoscopic ultrasonography, magnetic resonance imaging, and/or computed tomography. The primary endpoint was the cumulative incidence of PDAC, pancreatic intraepithelial neoplasia grade 3, or intraductal papillary mucinous neoplasm with high-grade dysplasia (HGD) after baseline. We performed multivariate Cox regression and Kaplan-Meier analyses.
During the follow-up period, pancreatic lesions with worrisome features (solid mass, multiple cysts, cyst size > 3 cm, thickened/enhancing walls, mural nodule, dilated main pancreatic duct > 5 mm, or abrupt change in duct caliber) or rapid cyst growth (>4 mm/year) were detected in 68 patients (19%). Overall, 24 of 354 patients (7%) had neoplastic progression (14 PDACs and 10 HGDs) over a 16-year period; the rate of progression was 1.6%/year, and 93% had detectable lesions with worrisome features before diagnosis of the PDAC or HGD. Nine of the 10 PDACs detected during routine surveillance were resectable; a significantly higher proportion of patients with resectable PDACs survived 3 years (85%) compared with the 4 subjects with symptomatic, unresectable PDACs (25%), which developed outside surveillance (log rank P < .0001). Neoplastic progression occurred at a median age of 67 years; the median time from baseline screening until PDAC diagnosis was 4.8 years (interquartile range, 1.6–6.9 years).
In a long-term (16-year) follow-up study of individuals at high-risk for PDAC, we found most PDACs detected during surveillance (9/10) to be resectable, and 85% of these patients survived for 3 years. We identified radiologic features associated with neoplastic progression.
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Background Confocal laser endomicroscopy (CLE) enables in vivo microscopic imaging of the GI tract mucosa. However, there are limited data on endoscope-based CLE (eCLE) for imaging Barrett's ...esophagus (BE). Objective To compare high-definition white-light endoscopy (HDWLE) alone with random biopsy (RB) and HDWLE + eCLE and targeted biopsy (TB) for diagnosis of BE neoplasia. Design Multicenter, randomized, controlled trial. Setting Academic medical centers. Patients Adult patients with BE undergoing routine surveillance or referred for early neoplasia. Intervention Patients were randomized to HDWLE + RB (group 1) or HDWLE + eCLE + TB (group 2). Real-time diagnoses and management plans were recorded after HDWLE in both groups and after eCLE in group 2. Blinded expert pathology diagnosis was the reference standard. Main Outcome Measurements Diagnostic yield, performance characteristics, clinical impact. Results A total of 192 patients with BE were studied. HDWLE + eCLE + TB led to a lower number of mucosal biopsies and higher diagnostic yield for neoplasia (34% vs 7%; P < .0001), compared with HDWLE + RB but with comparable accuracy. HDWLE + eCLE + TB tripled the diagnostic yield for neoplasia (22% vs 6%; P = .002) and would have obviated the need for any biopsy in 65% of patients. The addition of eCLE to HDWLE increased the sensitivity for neoplasia detection to 96% from 40% ( P < . 0001) without significant reduction in specificity. In vivo CLE changed the treatment plan in 36% of patients. Limitations Tertiary-care referral centers and expert endoscopists limit generalizability. Conclusion Real-time eCLE and TB after HDWLE can improve the diagnostic yield and accuracy for neoplasia and significantly impact in vivo decision making by altering the diagnosis and guiding therapy. (Clinical trial registration number: NCT01124214 .)
To report pancreas surveillance outcomes of high-risk individuals within the multicenter Cancer of Pancreas Screening-5 (CAPS5) study and to update outcomes of patients enrolled in prior CAPS ...studies.
Individuals recommended for pancreas surveillance were prospectively enrolled into one of eight CAPS5 study centers between 2014 and 2021. The primary end point was the stage distribution of pancreatic ductal adenocarcinoma (PDAC) detected (stage I
higher-stage). Overall survival was determined using the Kaplan-Meier method.
Of 1,461 high-risk individuals enrolled into CAPS5, 48.5% had a pathogenic variant in a PDAC-susceptibility gene. Ten patients were diagnosed with PDAC, one of whom was diagnosed with metastatic PDAC 4 years after dropping out of surveillance. Of the remaining nine, seven (77.8%) had a stage I PDAC (by surgical pathology) detected during surveillance; one had stage II, and one had stage III disease. Seven of these nine patients with PDAC were alive after a median follow-up of 2.6 years. Eight additional patients underwent surgical resection for worrisome lesions; three had high-grade and five had low-grade dysplasia in their resected specimens. In the entire CAPS cohort (CAPS1-5 studies, 1,731 patients), 26 PDAC cases have been diagnosed, 19 within surveillance, 57.9% of whom had stage I and 5.2% had stage IV disease. By contrast, six of the seven PDACs (85.7%) detected outside surveillance were stage IV. Five-year survival to date of the patients with a screen-detected PDAC is 73.3%, and median overall survival is 9.8 years, compared with 1.5 years for patients diagnosed with PDAC outside surveillance (hazard ratio 95% CI; 0.13 0.03 to 0.50,
= .003).
Most pancreatic cancers diagnosed within the CAPS high-risk cohort in the recent years have had stage I disease with long-term survival.
Endoscopic cryotherapy can eradicate neoplastic Barrett’s esophagus (BE). A new contact cryoballoon focal ablation system (CbFAS)) freezes esophageal mucosa with nitrous oxide. We studied the safety ...and efficacy of CbFAS for complete eradication of neoplastic Barrett's esophagus.
In a prospective clinical trial, consecutive BE patients with confirmed neoplasia (low-grade dysplasia LGD, high-grade dysplasia HGD, and/or intramucosal adenocarcinoma ImCA), at least 1 cm of BE, with or without prior ablation, were treated with a dose 10 seconds of spray per site. EMR was performed for nodular lesions. Treatments were repeated every 10 to 12 weeks until complete eradication, with a maximum of 5 treatments. Primary outcomes were complete eradication of all dysplasia (CE-D) and complete eradication of intestinal metaplasia (CE-IM) at 1 year (intention-to-treat analysis).
Forty-one assessable patients (22 treatment naive, 19 previously ablated) with LGD (n = 13), HGD (n = 23), or ImCA (n = 5) were treated. The median procedure time was 30 minutes. The median number of ablation procedures for CE-IM was 3 (interquartile range, 2-4). Overall 1-year CE-D and CE-IM rates were 95% and 88%, respectively. CE-D rate was significantly lower (67%) in those with ultra-long BE compared with those with <8 cm (100%, P = .02). Median pain scores were zero at day 1. Four patients (9.7%) developed mild dysphagia from stenoses requiring dilation. One patient on aspirin developed upper GI bleeding that did not require therapy.
Multifocal nitrous oxide cryotherapy using CbFAS is a promising, highly effective, and safe endoscopic treatment for primary or rescue therapy of BE-associated neoplasia and IM. (Clinical trial registration number: NCT02534233.)
Background & Aims The risk of pancreatic cancer is increased in patients with a strong family history of pancreatic cancer or a predisposing germline mutation. Screening can detect curable, ...noninvasive pancreatic neoplasms, but the optimal imaging approach is not known. We determined the baseline prevalence and characteristics of pancreatic abnormalities using 3 imaging tests to screen asymptomatic, high-risk individuals (HRIs). Methods We screened 225 asymptomatic adult HRIs at 5 academic US medical centers once, using computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasonography (EUS). We compared results in a blinded, independent fashion. Results Ninety-two of 216 HRIs (42%) were found to have at least 1 pancreatic mass (84 cystic, 3 solid) or a dilated pancreatic duct (n = 5) by any of the imaging modalities. Fifty-one of the 84 HRIs with a cyst (60.7%) had multiple lesions, typically small (mean, 0.55 cm; range, 2–39 mm), in multiple locations. The prevalence of pancreatic lesions increased with age; they were detected in 14% of subjects younger than 50 years old, 34% of subjects 50–59 years old, and 53% of subjects 60–69 years old ( P < .0001). CT, MRI, and EUS detected a pancreatic abnormality in 11%, 33.3%, and 42.6% of the HRIs, respectively. Among these abnormalities, proven or suspected neoplasms were identified in 85 HRIs (82 intraductal papillary mucinous neoplasms and 3 pancreatic endocrine tumors). Three of 5 HRIs who underwent pancreatic resection had high-grade dysplasia in less than 3 cm intraductal papillary mucinous neoplasms and in multiple intraepithelial neoplasias. Conclusions Screening of asymptomatic HRIs frequently detects small pancreatic cysts, including curable, noninvasive high-grade neoplasms. EUS and MRI detect pancreatic lesions better than CT.
Background EUS-guided fiducial placement facilitates image-guided radiation therapy (IGRT). Objective To compare 2 types of commercially available fiducials for technical success, complications, ...visibility, and migration. Design Retrospective, single-center, comparative study. Setting Tertiary-care medical center. Interventions Traditional fiducials (TFs) (5-mm length, 0.8-mm diameter) and Visicoil fiducials (VFs) (10-mm length, 0.35-mm diameter) were compared. Fiducials were placed using linear 19-gauge (for TFs) or 22-gauge (for VFs) needles. A subjective visualization scoring system (0-2; 0 = not visible, 1 = barely visible, 2 = clearly visible) was used to assess visibility on CT. Fiducial migration was calculated as a change in interfiducial distance. Main Outcome Measurements Technical success, complications, visibility, and migration of 2 types of fiducials. Results Thirty-nine patients with locally advanced pancreatic cancer underwent EUS-guided placement of 103 fiducials (77 TFs, 26 VFs). The mean number of fiducials placed per patient was 2.66 (standard deviation 0.67) for the 19-gauge needle and 2.60 (standard deviation 0.70) for the 22-gauge needle ( P = .83). No intra- or postprocedural complications were encountered. The median visibility score for TFs was significantly better than that for VFs, both when scores of 0 were and were not included (2.00, interquartile range IQR 2.00-2.00 vs 1.75, IQR 1.50-2.00, P = .009 and 2.00, IQR 2.00-2.00 vs 2.00, IQR 1.50-2.00, P < .0001, respectively). The mean migration was not significantly different between the 2 types of fiducials (0.8 mm IQR 0.4-1.6 mm for TFs vs 1.3 mm IQR 0.6-1.5 mm for VFs; P = .72). Limitations Retrospective, nonrandomized design. Conclusions Visibility was significantly better for TFs compared with VFs. The degree of fiducial migration was not significantly different for TFs and VFs. There was no significant difference in the mean number of fiducials placed, indicating a similar degree of technical difficulty for TF and VF deployment.
Our goal was to identify circulating micro RNA (miRNA) levels that could distinguish patients with low-stage pancreatic cancer from healthy and disease controls.
We measured 735 miRNAs in pancreatic ...cancer case and control sera by QRTPCR using TaqMan MicroRNA Arrays. After array analysis, we selected 18 miRNA candidates for validation in an independent set of cases and control samples.
Of the significantly elevated circulating miRNAs in patients with pancreatic cancer compared with controls, miR-1290 had the best diagnostic performance: receiver operating characteristic (ROC) analysis on miR-1290 serum level yielded curve areas (AUC) of 0.96 95% confidence interval (CI), 0.91-1.00, 0.81 (0.71-0.91), and 0.80 (0.67-0.93), for subjects with pancreatic cancer (n = 41) relative to healthy controls (n = 19), subjects with chronic pancreatitis (n = 35), and pancreatic neuroendocrine tumors (n = 18), respectively. Serum miR-1290 levels were also significantly higher than healthy controls among patients with intraductal papillary mucinous neoplasm (IPMN; n = 20; AUC = 0.76, 0.61-0.91). Serum miR-1290 levels distinguished patients with low-stage pancreatic cancer from controls better than CA19-9 levels, and like CA19-9, higher miR-1290 levels predicted poorer outcome among patients undergoing pancreaticoduodenectomy. Greater numbers of miR-1290 transcripts were detected by FISH in primary pancreatic cancer and IPMN than normal pancreatic duct cells. miR-1290 influenced in vitro pancreatic cancer cell proliferation and invasive ability. Several other circulating miRNAs distinguished sera of patients with pancreatic cancer from those of healthy controls with AUCs >0.7, including miR-24, miR-134, miR-146a, miR-378, miR-484, miR-628-3p, and miR-1825.
The detection of elevated circulating miR-1290 has the potential to improve the early detection of pancreatic cancer.
Background The detection of high-grade dysplasia and cancer in Barrett's esophagus (BE) can be challenging. Confocal laser endomicroscopy (CLE) allows in vivo visualization of mucosal histology ...during endoscopy. Objective To determine whether CLE with optical biopsy and targeted mucosal biopsy improves the diagnostic yield of endoscopically inapparent, BE-associated neoplasia compared to standard endoscopy with a 4-quadrant, random biopsy protocol. Design Prospective, double-blind, randomized, crossover study. Setting Single, tertiary-care academic center. Patients This study involved patients with BE undergoing routine surveillance or referred for treatment of nonlocalized, endoscopically inapparent, BE-associated neoplasia. Intervention All participants underwent both a confocal endomicroscopy with a targeted biopsy procedure and standard endoscopy with a 4-quadrant biopsy procedure in a randomized order. Main Outcome Measurements Increase in diagnostic yield for neoplasia, reduction in mucosal biopsy number, final pathologic diagnosis. Results CLE with targeted biopsy almost doubled the diagnostic yield for neoplasia and was equivalent to the standard protocol for the final diagnosis of neoplasia. Two thirds of patients in the surveillance group did not need any mucosal biopsies at all. Limitation Single-center study. Conclusion CLE with targeted biopsy significantly improves the diagnostic yield for endoscopically inapparent BE neoplasia compared to a standard endoscopy with a random-biopsy protocol. CLE with targeted biopsy also greatly reduces the number of biopsies needed per patient and allows some patients without neoplasia to completely forgo mucosal biopsy. (This trial was registered at www.clinicaltrials.gov , ID number NCT00487695 .)
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