Mark Reichelderfer

A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer

Progress toward the understanding and management of human colon cancer can be significantly advanced if appropriate experimental platforms become available. We have investigated whether a rat model carrying a knockout allele in the gatekeeper gene Adenomatous polyposis coli (Apc) recapitulates familial colon cancer of the human more closely than existing murine models. We have established a mutagen-induced nonsense allele of the rat Apc gene on an inbred F344/NTac (F344) genetic background. Carriers of this mutant allele develop multiple neoplasms with a distribution between the colon and small intestine that closely simulates that found in human familial adenomatous polyposis patients. To distinguish this phenotype from the predominantly small intestinal phenotype found in most Apc-mutant mouse strains, this strain has been designated the polyposis in the rat colon (Pirc) kindred. The Pirc rat kindred provides several unique and favorable features for the study of colon cancer. Tumor-bearing Pirc rats can live at least 17 months, carrying a significant colonic tumor burden. These tumors can be imaged both by micro computed tomography scanning and by classical endoscopy, enabling longitudinal studies of tumor genotype and phenotype as a function of response to chemopreventive and therapeutic regimes. The metacentric character of the rat karyotype, like that of the human and unlike the acrocentric mouse, has enabled us to demonstrate that the loss of the wild-type Apc allele in tumors does not involve chromosome loss. We believe that the Pirc rat kindred can address many of the current gaps in the modeling of human colon cancer.

Intestinal adenomas can develop with a stable karyotype and stable microsatellites

Loss of function of the adenomatous polyposis coli (APC)/Apc tumor suppressor gene occurs early in the etiology of intestinal cancer in mammals. In human colonic tumors, genomic instability is proposed to be associated with tumor initiation by inducing loss of APC function. We have used a mouse model of inherited intestinal cancer (ApcMin/+, Min/+) to analyze the earliest stages of tumorigenesis in this organ. We find that tumors from C57BL/6 Min/+ mice have a stable karyotype and stable microsatellites. In contrast to previous claims, we find that homozygosity for the Min allele of Apc in tumors can proceed by homologous somatic recombination. Further, our analysis of early, benign human colorectal adenomas failed to reveal any evidence for generalized chromosomal or microsatellite instability. These results cast doubt on the hypothesis that either of these forms of genomic instability is necessary for the initial development of colorectal adenomas. We contrast our analysis of autochthonous primary tumors to other studies involving xenografts or cultured cells.

Sleeping on a wedge diminishes exposure of the esophagus to refluxed acid

In a randomized crossover study, we compared the effect on gastroesophageal reflux of three sleeping positions: elevation of the head of the bed on standard eight-inch bed blocks; elevation by a foam wedge; or a flat position. Fifteen subjects with moderate to severe reflux symptoms were studied in each position on consecutive nights using continuous intraesophageal pH monitoring. We found no difference in reflux frequency among the positions. The wedge caused a statistically significant decrease in the time that distal esophageal pH was less than 4 as compared to the flat position. The wedge also decreased the longest episode experienced by the subjects. Elevation on blocks caused a similar improvement in parameters but failed in this study to achieve statistical significance. Both elevation by a wedge and on blocks showed a trend towards a decrease in clearance time as compared to the flat position. The patients did not always prefer elevation on a wedge, but for some it is a valuable alternative to elevation by bed blocks.

Evaluation of rapid colonoscopy preparation using a new gut lavage solution

The traditional colonoscopy preparation of laxatives and enemas requires 2 days to complete and is occasionally unsatisfactory. The alternative method, gut lavage with saline-based solutions, is hazardous in elderly or compromised patients because of overhydration. We studied a new, orally ingested electrolyte solution containing sodium sulfate and polyethylene glycol as preparation for elective colonoscopy in a consecutive series of 43 patients. Almost all patients achieved a good to excellent preparation. There were no changes in fluid or electrolyte balance and no complications of the procedure. Colonoscopy preparation with this technique is rapid, effective, and well tolerated and is a safe alternative to the standard approach.

Pilot study using PET/CT as a novel, noninvasive assessment of disease activity in inflammatory bowel disease.

Background: A pilot study was performed investigating the possibility that positron emission tomography (PET) activity using 18‐fluorodeoxyglucose (FDG) with nearly simultaneous computerized tomography (CT) for anatomic accuracy would identify regions of active inflammation in both ulcerative colitis (UC) and Crohns disease (CD). Methods: Prospective clinical data was collected in 12 patients experiencing an exacerbation of their inflammatory bowel disease; 7 with CD and 5 with UC. A PET/CT scan (GE Discovery LS PET/CT scanner) was performed in all patients. Twenty patients undergoing PET/CT because of solitary pulmonary nodules served as controls. We graded the small bowel and 4 colon regions (ascending, transverse, descending, and rectosigmoid) with PET activity scores assigned to each region based on the amount of FDG uptake using the liver as the reference organ. Results: In UC patients, PET activity was seen in 13 of 24 (52%) regions. There was high (23 of 24; 95.8%) correlation between PET activity and disease activity as determined by colonoscopy, disease activity indices, and radiology. In patients with CD, PET activity was seen in 19 of 32 (59.4%) regions. Again, there was a high (26 of 32; 81.3%) correlation between PET activity and clinical disease activity. Of the 20 controls, significant PET activity (Grades 2 and 3) was seen in only 2 of 100 regions (2%). Conclusions: We found that PET activity correlated well with active inflammation in both UC and CD, suggesting that this may be a noninvasive method of identifying disease activity in patients with inflammatory bowel disease.

Predictors of early recurrence of benign esophageal strictures

OBJECTIVE:In the era of liberal proton pump inhibitor (PPI) use, benign esophageal strictures remain a significant management problem, with 30–40% of patients experiencing symptomatic recurrence within 1 yr of successful dilation. We therefore sought to examine predictors of early recurrence of benign esophageal strictures after endoscopic dilation.METHODS:Predictors for stricture recurrence were examined in 87 consecutive outpatients undergoing initial dilation over a 1-yr period. Patients with symptomatic recurrence of dysphagia requiring repeat dilation within 1 yr of initial successful dilation (cases) were compared to patients who did not require redilation (controls). Predictors were assessed by univariate and multivariate analysis. Kaplan-Meier analysis of significant predictors using time to first redilation was also performed.RESULTS:Of the patients, 36 required repeat dilation within 1 yr, whereas 51 did not (median follow-up, 33 months). Of all strictures, 67 (77%) were peptic, with the remainder caused by radiation, drug-related injury, or congenital stenosis, among other causes. In multivariate analysis, nonpeptic strictures were significant predictors for early recurrence, as was a narrower stricture diameter. For peptic strictures, the persistence of heartburn after dilation and the presence of a hiatal hernia were significant predictors. Of all peptic strictures, 84% of patients were on PPIs after dilation, with no difference between cases and controls. Of all patients with persistent heartburn after dilation, 90% were on PPIs.CONCLUSIONS:The persistence of heartburn after dilation is a strong predictor for early symptomatic recurrence of benign esophageal peptic strictures, despite a high rate of PPI use. This may suggest persistent acid reflux requiring optimization of acid reduction therapy. Alternatively, combined acid and alkaline reflux may account for progressive injury despite PPI therapy. Esophageal pH studies may be invaluable in making the distinction between acid and non-acidic (alkaline) reflux. Nonpeptic strictures are also more likely to have early recurrences and are therefore more difficult to manage.

Assessment of volumetric growth rates of small colorectal polyps with CT colonography: a longitudinal study of natural history

BACKGROUND The clinical relevance and in-vivo growth rates of small (6-9 mm) colorectal polyps are not well established. We aimed to assess the behaviour of such polyps with CT colonography assessments. METHODS In this longitudinal study, we enrolled asymptomatic adults undergoing routine colorectal cancer screening with CT colonography at two medical centres in the USA. Experienced investigators (PJP, DHK, JLH) measured volumes and maximum linear sizes of polyps in vivo with CT colonography scans at baseline and surveillance follow-up. We defined progression, stability, and regression on the basis of a 20% volumetric change per year from baseline (20% or more growth classed as progression, 20% growth to -20% reduction classed as stable, and -20% or more reduction classed as regression). We compared findings with histological subgroups confirmed after colonoscopy when indicated. This study is registered with ClinicalTrials.gov, number NCT00204867. FINDINGS Between April, 2004, and June, 2012, we screened 22,006 asymptomatic adults and included 243 adults (mean age 57·4 years [SD 7·1] and median age 56 years [IQR 52-61]; 106 [37%] women), with 306 small colorectal polyps. The mean surveillance interval was 2·3 years (SD 1·4; range 1-7 years; median 2·0 years [IQR 1·1-2·3]). 68 (22%) of 306 polyps progressed, 153 (50%) were stable, and 85 (28%) regressed, including an apparent resolution in 32 (10%) polyps. We established immediate histology in 131 lesions on colonoscopy after final CT colonography. 21 (91%) of 23 proven advanced adenomas progressed, compared with 31 (37%) of 84 proven non-advanced adenomas, and 15 (8%) of 198 other lesions (p<0·0001). The odds ratio for a growing polyp at CT colonography surveillance to become an advanced adenoma was 15·6 (95% CI 7·6-31·7) compared with 6-9 mm polyps detected and removed at initial CT colonography screening (without surveillance). Mean polyp volume change was a 77% increase per year for 23 proven advanced adenomas and a 16% increase per year for 84 proven non-advanced adenomas, but a 13% decrease per year for all proven non-neoplastic or unresected polyps (p<0·0001). An absolute polyp volume of more than 180 mm(3) at surveillance CT colonography identified proven advanced neoplasia (including one delayed cancer) with a sensitivity of 92% (22 of 24 polyps), specificity of 94% (266 of 282 polyps), positive-predictive value of 58% (22 of 38 polyps), and negative-predictive value of 99% (266 of 268 polyps). Only 16 (6%) of the 6-9 mm polyps exceeded 10 mm at follow-up. INTERPRETATION Volumetric growth assessment of small colorectal polyps could be a useful biomarker for determination of clinical importance. Advanced adenomas show more rapid growth than non-advanced adenomas, whereas most other small polyps remain stable or regress. Our findings might allow for less invasive surveillance strategies, reserving polypectomy for lesions that show substantial growth. Further research is needed to provide more information regarding the ultimate fate of unresected small polyps without significant growth. FUNDING US National Institutes of Health, National Cancer Institute.

Impact of a CT Colonography Screening Program on Endoscopic Colonoscopy in Clinical Practice

OBJECTIVEThe potential effect of CT colonography (CTC) on endoscopic colonoscopy (EC) has been the topic of much speculation. The aim of this study was to evaluate the impact of a CTC screening program on colonoscopy in clinical practice.METHODSAt our institution a third-party reimbursed CTC colorectal cancer (CRC) screening program was established in 2004. The number of CTC monthly exams performed, monthly EC total and screening exams performed, EC with polypectomy performed, and the number of referrals for EC screening exams requested were prospectively examined in the first 33 months after introduction of a CTC CRC screening program.RESULTSThe mean number of overall (378.5 vs 413.1) and screening (150.7 vs 162.9) colonoscopy exams performed per month did not change significantly after screening CTC was introduced. The mean number of monthly CTC exams performed rose significantly throughout the first year of the study from 39 initially to a peak of 147.6 cases per month but decreased slightly to 114.3 monthly exams at the end of 2006. A mean 10.0 patients per month were sent for EC after a positive CTC exam. The mean number of monthly colonoscopies with polypectomy remained constant after the introduction of CTC (197.0 vs 180.2). Monthly referrals for screening EC exams initially decreased but were unchanged 3 yr after institution of a CTC screening program (255.0 vs 253.5).CONCLUSIONS(a) In our tertiary care center the initiation of a screening CTC program did not result in a decrease in the number of total colonoscopy exams, screening colonoscopy exams performed, nor requests for screening colonoscopy. (b) Only a small number of CTC exams were referred for EC with polypectomy, therefore a CTC screening program may not increase the overall number of therapeutic colonoscopies performed.

Bleeding Stomal Varices: Case Series and Systematic Review of the Literature

BACKGROUND & AIMS Bleeding stomal varices are a common problem in patients with surgical stomas and portal hypertension, and remain difficult to diagnose and manage. METHODS We identified all patients at our institution with bleeding stomal varices from 1989 to 2004. We surveyed all patients undergoing ileal pouch-anal anastomosis from 1997 to 2007 for bleeding anastomotic varices. Finally, we performed a systematic review of the literature focusing on diagnosis and treatment of bleeding stomal varices that included 74 English language studies of 234 patients. RESULTS We identified 8 patients with bleeding stomal varices. Recognition of stomal varices typically was delayed, particularly when failing to examine the ostomy without the appliance. Stomal variceal bleeding was confirmed by Doppler ultrasound or angiographic imaging. Simple local therapy usually stopped bleeding, albeit temporarily. Sclerotherapy was effective, but at the expense of unacceptable stomal damage. Decompressive therapy was required for secondary prophylaxis, including transjugular intravascular transhepatic shunts (2 patients), surgical portosystemic shunts (2 patients), and liver transplantation (1 patient). No patient with an ileal pouch-anal anastomosis developed anastomotic bleeding from varices. CONCLUSIONS Primary prevention of bleeding stomal varices requires avoidance of creating enterocutaneous stomas in patients with portal hypertension. Careful inspection of the uncovered ostomy is essential for bleeding stomal varices diagnosis. Once identified, conservative measures will stop bleeding temporarily with definitive therapy required, including transjugular intravascular transhepatic shunts, surgical shunts, or liver transplantation.

Colonoscopy in radiation colitis

Colonoscopy in 13 patients with stenosis or hemorrhage after radiation therapy is correlated with clinical and radiographic features. The authors found colonoscopy helpful in delineating the diagnosis and in guiding treatment.