Low Incidence of Aerodigestive Cancers in Patients With Negative Results From Colonoscopies, Regardless of Findings From Multitarget Stool DNA Tests.

BACKGROUND & AIMS: We aimed to compare the incidence of aerodigestive cancers in persons with negative results from colonoscopies and positive vs negative results from multitarget stool DNA tests for colorectal cancer and vs expected incidence. METHODS: We performed a retrospective cohort study of 1216 subjects with comprehensive patient records and/or cancer registry data from 3 medical centers in North America. Subjects had no neoplasia or only nonadvanced adenomas, based on screening colonoscopy, and either negative results (concordant with colonoscopy, n = 1011) or positive results (discordant colonoscopy, n = 205) from the multitarget stool DNA test. Outcomes included aerodigestive cancers in discordant vs concordant groups and comparison of observed aerodigestive cancer incidence between the groups and compared with expected incidence for the population, based on the Surveillance, Epidemiology, and End Results (SEER) data. RESULTS: Median follow-up times were comparable between subjects in the discordant (5.3 y; interquartile range, 3.5-5.8 y) and concordant (5.4 y; interquartile range, 3.7-5.8 y) groups. Aerodigestive cancers developed in 5 subjects in the discordant group vs 11 subjects in the concordant group (crude risk ratio, 2.3; 95% CI, 0.8-6.6; adjusted risk ratio, 2.2; 95% CI, 0.8-6.2; P = .151). The incidence of aerodigestive cancer was lower in the concordant group than the expected incidence based on SEER data (risk ratio, 0.4; 95% CI, 0.2-0.6; P = .0008). The incidence of aerodigestive cancer was not significantly greater in the population in the discordant group than the expected incidence based on SEER data (risk ratio, 0.8; 95% CI, 0.3-1.9; P = .599). CONCLUSIONS: In a retrospective study with a median follow-up time of 5.4 years, incident aerodigestive cancers were uncommon among subjects with negative findings from colonoscopies, regardless of discordant or concordant results from multitarget stool DNA tests. Patients with negative results from high-quality colonoscopies therefore should not undergo further testing.

Severe Diarrhea in the Setting of Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICPIs) are novel therapeutic agents targeting a variety of cancers by enhanced T cell activation. Immune-related adverse events (irAEs) commonly occur with ICPI use and can affect multiple organ systems including the gastrointestinal tract. Due to irAEs, the use of ICPIs is limited in autoimmune diseases. We present a case of microscopic colitis diagnosed after the initiation of nivolumab and a case of ipilimumab colitis and Clostridium difficile in the setting of Crohn's colitis.

Long-term Follow-up of Patients Having False-Positive Multitarget Stool DNA Tests after Negative Screening Colonoscopy: The LONG-HAUL Cohort Study.

Background: Studies of colorectal cancer screening by multitarget stool DNA (MT-sDNA) show false-positive (FP) rates of 7% to 13%. It is unclear whether FP patients are at increased long-term risk of adverse outcomes.Methods: We compared subsequent clinical events among patients with apparent FP MT-sDNA with those in patients reported as true negative (TN). This was a retrospective cohort study of participants in pre-FDA approval MT-sDNA studies having nonadvanced or negative baseline colonoscopy findings from a single referral center. Per-protocol and calibrated cutoffs defined FP and TN groups. From the time of stool collection, we measured differences between FP and TN groups in time to death, subsequent cancer diagnosis, and onset of alarm symptoms.Results: Of 1,050 eligible patients, only 6 were lost to follow-up. Median age was 65.6 years [interquartile range (IQR), 56.8-72.3]; 54% were female. Median follow-up time was 4 years (IQR, 3.5-5.3). Eight aerodigestive (lung and gastrointestinal tract) cancers occurred. FP status by calibrated, but not per-protocol, cutoffs was associated with subsequent aerodigestive cancer; however, cumulative incidence did not exceed SEER expectations from the general population. By any cutoff method, FP status was not associated with mortality or alarm symptoms.Conclusions: Although FP status was associated with long-term aerodigestive cancers, new cases were not temporally related and did not exceed incidence estimates from general population.Impact: These observations do not justify aggressive follow-up evaluation for patients with FP MT-sDNA at this time. Larger studies are needed to confirm these early findings. Cancer Epidemiol Biomarkers Prev; 26(4); 614-21. ©2016 AACR.

Celecoxib for the Prevention of Colorectal Adenomas: Results of a Suspended Randomized Controlled Trial.

BACKGROUND: Cyclooxygenase (COX)-2 inhibitors such as celecoxib were designed to preserve anti-inflammatory activity without inhibiting COX-1. Downregulation of COX-2 inhibits colorectal carcinogenesis. METHODS: The Selenium and Celecoxib Trial was a randomized, placebo-controlled trial of once-daily selenium 200 µg and celecoxib 400 mg, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of adenomas. The primary outcome was development of new adenomas. Celecoxib was suspended early because of cardiovascular toxicity in other trials. Accrual to selenium or placebo continued. Before suspension, 824 participants were randomly assigned to celecoxib or placebo, of whom 712 (86.4%) were available for analysis. All statistical tests were two-sided. RESULTS: In the placebo and celecoxib arms of 356 participants each, adenoma detection was 47.5% and 49.7% (relative risk [RR] = 1.04, 95% confidence interval [CI] = 0.90 to 1.21, P = .58), respectively, after median periods of 13.6 and 14.2 months on intervention. Among participants colonoscoped within 12 months of discontinuing intervention (n = 244), overall adenoma recurrence (RR = 0.69, 95% CI = 0.48 to 0.98, P = .04) and recurrence with advanced adenomas (RR = 0.23, 95% CI = 0.07 to 0.80, P = .02) were reduced with celecoxib. Reduction of adenoma recurrence was greatest in participants with previous advanced adenomas. Celecoxib increased risk of hypertension in participants with pre-existing cardiovascular risk factors compared with placebo (hazard ratio = 2.19, 95% CI = 1.07 to 4.50, P = .03). CONCLUSIONS: Limited-duration celecoxib prevents adenoma recurrence in patients with prior high-risk adenomas, in whom strategies to minimize cardiovascular toxicity might be feasible.

Selenium Supplementation for Prevention of Colorectal Adenomas and Risk of Associated Type 2 Diabetes.

BACKGROUND: Selenium supplementation may help to prevent colorectal cancer; as precursors of colorectal cancer, colorectal adenomas are a surrogate for colorectal cancer. Selenium supplementation may increase risk of type 2 diabetes (T2D). METHODS: The Selenium and Celecoxib (Sel/Cel) Trial was a randomized, placebo controlled trial of selenium 200 µg daily as selenized yeast and celecoxib 400 mg once daily, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of colorectal adenomas. The primary outcome was adenoma development. Celecoxib was suspended because of cardiovascular toxicity in other trials, but accrual continued to selenium and placebo. A total of 1621 participants were randomly assigned to selenium or placebo, of whom 1374 (84.8%) were available for analysis. All statistical tests were two-sided. RESULTS: In the respective placebo and selenium arms of 689 and 685 participants, adenoma detection after medians of 33.6 (range = 0.0-85.1 months) and 33.0 months (range = 0.0-82.6 months) were 42.8% and 44.1% (relative risk [RR] = 1.03, 95% confidence interval [CI] = 0.91 to 1.16, P = .68). In participants with baseline advanced adenomas, adenoma recurrence was reduced by 18% with selenium (RR = 0.82, 95% CI = 0.71 to 0.96, P = .01). In participants receiving selenium, the hazard ratio for new-onset T2D was 1.25 (95% CI = 0.74 to 2.11, P = .41), with a statistically significantly increased risk of selenium-associated T2D among older participants (RR = 2.21; 95% CI = 1.04 to 4.67, P = .03). CONCLUSIONS: Overall, selenium did not prevent colorectal adenomas and showed only modest benefit in patients with baseline advanced adenomas. With limited benefit and similar increases in T2D to other trials, selenium is not recommended for preventing colorectal adenomas in selenium-replete individuals.

Factitious Disorder in Crohn's Disease: Recurrent Pancytopenia Caused by Surreptitious Ingestion of 6-Mercaptopurine.

Factitious disorder is a rare psychiatric illness characterized by the willful and deceptive induction of illness for the purpose of assuming the sick role. It presents a substantial diagnostic challenge, as patients often go to great lengths to conceal their deception. Accordingly, its presence in the full spectrum of gastrointestinal diseases is likely underappreciated. While factitious gastrointestinal bleeding, abdominal pain and diarrhea are relatively common, factitious non-gastrointestinal symptoms in the setting of gastrointestinal illness have been infrequently reported. We present the case of a patient with Crohn's disease with recurrent pancytopenia attributed to the surreptitious ingestion of 6-mercaptopurine. In patients with possible access to immunomodulatory drugs, a high suspicion for and early identification of factitious disorder may improve patient outcomes and avoid invasive and costly diagnostic evaluations.

Gastric adenomas in familial adenomatous polyposis are common, but subtle, and have a benign course.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) are known to have an increased risk for gastric adenomas. The clinical features of gastric adenomas in FAP have not been well characterized, and there is a lack of standardized approaches to the management of these lesions. AIMS: To study the endoscopic appearance, risk factors, clinical course, and response to therapy of gastric adenomas in patients with FAP. METHODS: We retrospectively reviewed the records of 97 patients with FAP who underwent esophagogastroduodenoscopy (EGD) at Mayo Clinic (Florida, Rochester and Arizona) between 2004 and 2013. RESULTS: Nine patients (9%) had biopsy-proven gastric adenomas. Adenomas were located in the antrum (five patients), in the body and fundus in the setting of background fundic gland polyps (FGP) (three patients), and in the body not associated with FGP (one patient). Adenoma size was 3-40 mm and the number of adenomas per patient ranged from one to 20. Adenomas in the antrum were flat and subtle, whereas those in the gastric body or fundus were polypoid and difficult to differentiate from the cystic FGPs seen in patients with FAP. The performing endoscopists reported difficulty with identifying adenomas, and six patients had at least one EGD within the previous three years where gastric adenomas were not reported. Adenomas were classified as tubular in eight patients and tubulovillous in one patient. High grade dysplasia was noted in one patient. After a median follow-up of 63 months (interquartile range: 20-149 months), no patient in our entire cohort (with or without gastric adenomas) developed gastric cancer. The patients in whom gastric adenoma developed, compared to those without gastric adenoma, were more likely to be younger [36 ± 12 vs. 48 ± 15 years, p = 0.02], have concomitant chronic gastritis [22% vs. 0%, p = 0.008], and have desmoid tumors [5 (56%) vs. 19 (22%), p = 0.04]. CONCLUSIONS: Gastric adenomas are not uncommon in patients with FAP and are often difficult to identify endoscopically. Endoscopists should have a high degree of suspicion for gastric adenomas in these patients and a low threshold to biopsy. Given the benign clinical course, recommended initial management is conservative with endoscopic therapy and periodic surveillance.

Detection of colorectal serrated polyps by stool DNA testing: comparison with fecal immunochemical testing for occult blood (FIT).

OBJECTIVES: Precursors to 1/3 of colorectal cancer (CRC), serrated polyps have been under-detected by screening due to their inconspicuous, non-hemorrhagic, and proximal nature. A new multi-target stool DNA test (multi-target sDNA) shows high sensitivity for both CRC and advanced adenomas. Screen detection of serrated polyps by this approach requires further validation. We sought to assess and compare noninvasive detection of sessile serrated polyps (SSP) ≥ 1 cm by sDNA and an occult blood fecal immunochemical test (FIT). METHODS: In a blinded prospective study, a single stool sample used for both tests was collected from 456 asymptomatic adults prior to screening or surveillance colonoscopy (criterion standard). All 29 patients with SSP ≥ 1 cm were included as cases and all 232 with no neoplastic findings as controls. Buffered stool samples were processed and frozen on receipt; Exact Sciences performed sDNA in batches using optimized analytical methods. The sDNA multi-marker panel targets methylated BMP3 (mBMP3) and NDRG4, mutant KRAS, ß-actin, and hemoglobin. FIT (Polymedco OC-FIT Check) was performed in separate lab ≤ 2 days post defecation and evaluated at cutoffs of 50 (FIT-50) and 100 ng/ml (FIT-100). RESULTS: MEDIAN AGES: cases 61 (range 57-77), controls 62 (52-70), p = NS. Women comprised 59% and 51%, p = NS, respectively. SSP median size was 1.2 cm (1-3 cm), 93% were proximal, and 64% had synchronous diminutive polyps. Among multi-target sDNA markers, mBMP3 proved highly discriminant for detection of SSP ≥ 1 cm (AUC = 0.87, p<0.00001); other DNA markers provided no incremental sensitivity. Hemoglobin alone showed no discrimination (AUC = 0.50, p = NS). At matched specificities, detection of SSP ≥ 1 cm by stool mBMP3 was significantly greater than by FIT-50 (66% vs 10%, p = 0.0003) or FIT-100 (63% vs 0%, p<0.0001). CONCLUSIONS: In a screening and surveillance setting, SSP ≥ 1 cm can be detected noninvasively by stool assay of exfoliated DNA markers, especially mBMP3. FIT appears to have no value in SSP detection.

Capsule Endoscopy in Patients with Implantable Electromedical Devices is Safe.

Background and Study Aims. The presence of an implantable electromechanical cardiac device (IED) has long been considered a relative contraindication to the performance of video capsule endoscopy (CE). The primary aim of this study was to evaluate the safety of CE in patients with IEDs. A secondary purpose was to determine whether IEDs have any impact on images captured by CE. Patients and Methods. A retrospective chart review of all patients who had a capsule endoscopy at Mayo Clinic in Scottsdale, AZ, USA, or Rochester, MN, USA, (January 2002 to June 2010) was performed to identify CE studies done on patients with IEDs. One hundred and eighteen capsule studies performed in 108 patients with IEDs were identified and reviewed for demographic data, method of preparation, and study data. Results. The most common indications for CE were obscure gastrointestinal bleeding (77%), anemia (14%), abdominal pain (5%), celiac disease (2%), diarrhea (1%), and Crohn's disease (1%). Postprocedure assessments did not reveal any detectable alteration on the function of the IED. One patient with an ICD had a 25-minute loss of capsule imaging due to recorder defect. Two patients with LVADs had interference with capsule image acquisition. Conclusions. CE did not interfere with IED function, including PM, ICD, and/or LVAD and thus appears safe. Additionally, PM and ICD do not appear to interfere with image acquisition but LVAD may interfere with capsule images and require that capsule leads be positioned as far away as possible from the IED to assure reliable image acquisition.