Kastenberg, David

Goals: We aimed to evaluate whether direct access colonoscopy (DAC) is noninferior to office-scheduled colonoscopy (OSC) for achieving successful colonoscopy. Background: DAC may improve access to colonoscopy. We developed an algorithm assessing eligibility, risk for inadequate preparation, and need for nursing/navigator assistance. Study: This was a retrospective, single-center study of DAC and OSC patients from June 5, 2018, to July 31, 2019. Patients were 45 to 75 years old with an indication of screening or surveillance. A successful colonoscopy met 3 criteria: complete colonoscopy (cecum, anastomosis, or ileum), adequate preparation (Boston Score ≥2/segment), and performed <90 days from initial patient contact. Unsuccessful colonoscopy did not meet ≥1 criteria. Secondary end points included days to successful colonoscopy, preparation quality, polyp detection, and 10-year recall rate. Noninferiority against risk ratio value of 0.85 was tested using 1-sided alpha of 0.05. Results: A total of 1823 DAC and 828 OSC patients were eligible. DAC patients were younger, with a greater proportion of black patients and screening indications. For the outcome of successful colonoscopy, DAC was noninferior to OSC (DAC vs. OSC: 62.7% vs. 57.1%, RR 1.16, 95% LCL 1.09, P=0.001). For DAC, days to colonoscopy were fewer, and likelihood of 10-year recall after negative screening greater. Boston Score and polyp detection were similar for groups. Black patients were less likely to achieve successful colonoscopy; otherwise, groups were similar. For unsuccessful colonoscopies, proportionally more DAC patients canceled or no-showed while more OSC patients scheduled >90 days. DAC remained noninferior to OSC at 180 days. Conclusions: DAC was noninferior to OSC for achieving successful colonoscopy, comparing similarly in quality and efficiency outcomes.

Gastrointestinal (GI) bleeding is the most common GI diagnosis leading to hospitalization within the United States. Prompt diagnosis and treatment of GI bleeding is critical to improving patient outcomes and reducing high healthcare utilization and costs. Radiologic techniques including computed tomography angiography, catheter angiography, computed tomography enterography, magnetic resonance enterography, nuclear medicine red blood cell scan, and technetium-99m pertechnetate scintigraphy (Meckel scan) are frequently used to evaluate patients with GI bleeding and are complementary to GI endoscopy. However, multiple management guidelines exist which differ in the recommended utilization of these radiologic examinations. This variability can lead to confusion as to how these tests should be used in the evaluation of GI bleeding. In this document, a panel of experts from the American College of Gastroenterology and Society of Abdominal Radiology provide a review of the radiologic examinations used to evaluate for GI bleeding including nomenclature, technique, performance, advantages, and limitations. A comparison of advantages and limitations relative to endoscopic examinations is also included. Finally, consensus statements and recommendations on technical parameters and utilization of radiologic techniques for GI bleeding are provided.

Abstract Purpose: To assess whether MUC1 peptide vaccine produces an immune response and prevents subsequent colon adenoma formation. Patients and Methods: Multicenter, double-blind, placebo-controlled randomized trial in individuals age 40 to 70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0. Results: Fifty-three participants received the MUC1 vaccine and 50 placebo. Thirteen of 52 (25%) MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range, 2.9–17.3) at week 12 versus 0/50 placebo recipients (one-sided Fisher exact P &lt; 0.0001). Of 13 responders at week 12, 11 (84.6%) responded to a booster injection at week 52 with a ≥2-fold increase in MUC1 IgG measured at week 55. Recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group versus 27 of 48 (56.3%) in the MUC1 group [adjusted relative risk (aRR), 0.83; 95% confidence interval (CI), 0.60–1.14; P = 0.25]. Adenoma recurrence occurred in 3/11 (27.3%) immune responders at week 12 and week 55 (aRR, 0.41; 95% CI, 0.15–1.11; P = 0.08 compared with placebo). There was no difference in serious adverse events. Conclusions: An immune response was observed only in vaccine recipients. Adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence compared with placebo was observed in participants who had an immune response at week 12 and with the booster injection.

Objective Colon capsule endoscopy (CCE) has shown promise for colorectal neoplasia detection compared with optical colonoscopy (OC), but has not been compared with other screening tests in average risk screening patients. Design Patients 50 to 75 years of age (African Americans, 45–75 years) were randomised to CCE or CT colonography (CTC) and subsequent blinded OC. The primary endpoint was diagnostic yield of polyps ≥6 mm with CCE or CTC. Secondary endpoints included accuracy for size and histology, examination completeness, number/proportion of subjects with polyps and adenomas ≥6 mm and ≥10 mm, subject satisfaction and safety. Results From 320 enrolled subjects, data from 286 (89.4%) were evaluable. The proportion of subjects with any polyp ≥6 mm confirmed by OC was 31.6% for CCE versus 8.6% for CTC (pPr non-inferiority and superiority=0.999). The diagnostic yield of polyps ≥10 mm was 13.5% with CCE versus 6.3% with CTC (pPr non-inferiority=0.9954). The sensitivity and specificity of CCE for polyps ≥6 mm was 79.2% and 96.3% while that of CTC was 26.8% and 98.9%. The sensitivity and specificity of CCE for polyps ≥10 mm was 85.7% and 98.2% compared with 50% and 99.1% for CTC. Both tests were well tolerated/safe. Conclusion CCE was superior to CTC for detection of polyps ≥6 mm and non-inferior for identification of polyps ≥10 mm. CCE should be considered comparable or superior to CTC as a colorectal neoplasia screening test, although neither test is as effective as OC. Trial registration number ClinicalTrials.gov no: NCT02754661 .

Abstract Background: Immunoprevention via targeting antigens aberrantly expressed on colorectal cancers and adenomatous polyps offers the potential for a less invasive prevention strategy than endoscopic surveillance. Specificity of the immune response and long-term memory provide the potential for prolonged protection. Leveraging the infrastructure of the NCI-funded Cancer Prevention Network (CPN) consortium, we are conducting a double-blind randomized trial in individuals with a diagnosis of advanced colorectal adenomas within the previous year. We are evaluating MUC1 vaccine with the TLR-3 agonist polyICLC as an adjuvant, for its immunogenicity, ability to elicit immune memory and prevent recurrence of colorectal adenomas. Aims: We previously reported on the vaccine immunogenicity at week 12 (vaccine administered at 0, 2, and 10 weeks) compared to placebo. Here we report the ability of the vaccine to elicit long-term memory by measuring increase in anti-MUC1 antibody levels following a booster administered at one year. Methods: Subjects with endoscopically resected advanced adenoma (defined as ≥1cm, tubululovillous or villous histology, or with high grade dysplasia) were randomized. The primary endpoint was the response to the vaccine at week 12 assessed by monitoring anti-MUC1 IgG antibody titer ratio defined as t12/t0, where t0 was the titer pre-vaccination, and t12 was the titer at week 12. The key secondary endpoint was to assess anti-MUC1 IgG response at week 55 to a booster at week 52 in the vaccine arm compared to placebo. Results: 102 eligible subjects were randomized at 6 centers, 52 received MUC1 vaccine and 50 placebo. The mean age was 59.4±7.0 (range 40-70), 60.8% male, 88.2% white, and 18.6% Hispanic or Latino ethnicity. At 12 weeks the IgG ratio was ≥2.0 in 13/52 (25%) of individuals receiving vaccine (ratio range -0.5-17.3), vs. 0/50 in placebo group (2-sided p=.0001), and was ≥1.5 in 19/52 (36.5%) individuals receiving vaccine compared to 1/50 (2%) in placebo group (P&lt;.0001). To evaluate immune memory, 1-year booster data available for 95 patients (51-MUC1, 44-placebo) were analyzed. 10/13 (76.9%) of the week 12 vs. week 0 vaccine responders showed a response at week 52 vs. baseline and 11/13 (84.6%) at week 55 vs. week 52. Using an IgG ratio of 2 (per-protocol), the response rate was 33% for MUC1 vs. 5% for placebo (1-sided p=0.0003). Using a ratio of 1.5 yielded similar results (37% MUC1 vs. 9% Placebo (1-sided p=0.0008). The MUC1 arm had significantly higher IgG at week 52 (1-sided p=0.0294), week 55 (1-sided p=0.0048), and significantly higher week 55 to week 52 IgG ratio values (1-sided p=0.0293). Conclusions: Subjects with a recent history of advanced adenoma receiving a MUC1 vaccine compared with a placebo were significantly more likely to develop an immune response at week 12, confirming the vaccine’s immunogenicity, and to respond again at week 55 to a booster injection on week 52, confirming the vaccine’s ability to elicit immune memory. Follow-up colonoscopy to evaluate the vaccine’s potential to lower adenomatous polyp recurrence rates are in progress. Citation Format: Olivera J. Finn, Lisa Boardman, Marcia Cruz-Correa, Ajay Bansal, David Kastenberg, Chin Hurr, Sharon Kaufman, Colleen Akerley, Lynda Dzubinski, April Felt, Karrie Fursa, L.M. Rodriguez, Ellen Richmond, Asad Umar, Eva Szabo, John McKolanis, Ryan McMurray, Nathan Foster, Andres Salazar, Paul Limburg, Robert Schoen. Randomized, double-blind, placebo-controlled trial of preventative MUC1 vaccine in patients with newly diagnosed advanced adenomas: Results from one-year booster [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT236.

Abstract Background: Immunotherapy targeting tumor-associated antigens aberrantly expressed on colorectal cancers and adenomatous polyps offers the potential for a relatively non-invasive and non-toxic prevention strategy, and because of the specificity of the immune response and its long-term memory, the potential for prolonged protection. In a double-blind randomized trial in patients with a diagnosis of advanced colorectal adenomas within the previous year, we are evaluating MUC1 vaccine with the TLR-3 agonist polyICLC (Hiltonol®) as an adjuvant, for its immunogenicity and effect on colorectal adenoma recurrence at follow up colonoscopy. Aim: We report on a primary endpoint, MUC1 immunogenicity at week 12 (following vaccine or placebo administration at 0, 2, and 10 weeks), and on determinants of the immune response and vaccine toxicity. Methods: Subjects with an advanced adenoma (defined as ≥1cm, tubulovillous or villous histology, or with HGD) were randomized. Response to the vaccine was assessed by monitoring IgG anti-MUC1 antibody titer ratio; defined as t12/t0, where t0 is the initial titer measured prior to vaccination, and t12 is the titer drawn at 12 weeks. A ratio of 2.0 was used as the primary definition of a significant immune response. T Regulatory and myleoid derived suppressor cell (MDSC) levels at baseline were assessed in relation to vaccine response. Adverse events (AEs) were recorded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results: 102 subjects were randomized at 6 centers, 52 received MUC1 vaccine and 50 placebo. Subjects had a mean age of 59.4±7.0 (range 40-70) years, 60.8% were male, 88.2% were white, and 18.6% Hispanic or Latino. At 12 weeks the IgG ratio was ≥2.0 in 13/52 (25%) of patients receiving vaccine (ratio range 2.9-17.3), vs. 0/50 in placebo group (P=.0001), and was ≥1.5 in 19/52 (36.5%) of patients receiving vaccine compared to 1/50 (2%) in placebo group (P&lt;.0001). In the vaccinated group, the IgG ratio was ≥2.0 in 45% of women (9/20) vs. 12.5% of men (4/32) (P=0.009) and ≥1.5 in 55% of women (11/20) vs. 25% of men (8/32) (P=0.03). In the vaccinated group, reduced levels of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) pre-vaccination were associated with response, 0.2±0.1 among responders (n=13) vs. 0.8±1.1 among non-responders (N=39) (p=0.0006) whereas monocytic MDSC and T regulatory cells (CD4+CD25, Foxp3) were not. There were no grade 3 adverse events (AE) possibly or probably related to the vaccine. The most common AE was an injection site reaction (grade 1 or 2) which occurred in 80.8% (n=42/52) in vaccine group vs. 6.0% in the placebo group (3/50). Conclusions: Subjects with an advanced adenoma receiving MUC1 vaccine compared with a placebo are significantly more likely to develop an anti-IgG MUC1 immune response at 12 weeks. Women and subjects with lower circulating PMN-MDSC levels at baseline were more likely to respond. The vaccine was well tolerated. Follow up for the effect of the vaccine on adenomatous polyp recurrence is ongoing. Citation Format: Robert E. Schoen, Lisa A. Boardman, Marcia Cruz-Correa, Ajay Bansal, Pamela L. Beatty, David Kastenberg, Chin Hur, Lynda Dzubinski, Luz Rodriguez, Andres Salazar, John McKolanis, Drew Seisler, Nathan R. Foster, May-Yin Polley, Paul J. Limburg, Olivera J. Finn. Randomized, double-blind, placebo-controlled immunoprevention trial with MUC1 vaccine in patients with newly diagnosed advanced adenomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-305.

Abstract Guanylate cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of its luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Linaclotide is an FDA-approved oral GUCY2C agonist formulated for gastric release, inducing fluid secretion into the small bowel to treat chronic idiopathic constipation. The ability of oral linaclotide to induce a pharmacodynamic response in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of 0.87 mg of oral linaclotide daily for 7 days to healthy volunteers, after oral colon preparation with polyethylene glycol solution (MoviPrep), activates GUCY2C, resulting in accumulation of its product cyclic (c)GMP in epithelial cells of the cecum, transverse colon, and distal rectum. GUCY2C activation by oral linaclotide was associated with homeostatic signaling, including phosphorylation of vasodilator-stimulated phosphoprotein and inhibition of proliferation quantified by reduced Ki67-positive epithelial cells. In the absence of the complete oral colonoscopy preparation, linaclotide did not alter cGMP production in epithelial cells of the colorectum, demonstrating that there was an effect related to the laxative preparation. These data show that the current FDA-approved formulation of oral linaclotide developed for small-bowel delivery to treat chronic idiopathic constipation is inadequate for reliably regulating GUCY2C in the colorectum to prevent tumorigenesis. The study results highlight the importance of developing a novel GUCY2C agonist formulated for release and activity targeted to the large intestine for colorectal cancer prevention. Cancer Prev Res; 10(6); 345–54. ©2017 AACR.