Elizabeth Odstrcil

Restriction of DNA Replication to the Reductive Phase of the Metabolic Cycle Protects Genome Integrity

When prototrophic yeast cells are cultured under nutrient-limited conditions that mimic growth in the wild, rather than in the high-glucose solutions used in most laboratory studies, they exhibit a robustly periodic metabolic cycle. Over a cycle of 4 to 5 hours, yeast cells rhythmically alternate between glycolysis and respiration. The cell division cycle is tightly constrained to the reductive phase of this yeast metabolic cycle, with DNA replication taking place only during the glycolytic phase. We show that cell cycle mutants impeded in metabolic cycle–directed restriction of cell division exhibit substantial increases in spontaneous mutation rate. In addition, disruption of the gene encoding a DNA checkpoint kinase that couples the cell division cycle to the circadian cycle abolishes synchrony of the metabolic and cell cycles. Thus, circadian, metabolic, and cell division cycles may be coordinated similarly as an evolutionarily conserved means of preserving genome integrity.

Effect of a retrograde-viewing device on adenoma detection rate during colonoscopy: the TERRACE study

BACKGROUND Although colonoscopy is currently the optimal method for detecting colorectal polyps, some are missed. The Third Eye Retroscope provides an additional retrograde view that may detect polyps behind folds. OBJECTIVE To determine whether the addition of the Third Eye Retroscope to colonoscopy improves the adenoma detection rate. DESIGN Prospective, multicenter, randomized, controlled trial. SETTING Nine European and U.S. centers. PATIENTS Of 448 enrolled subjects, 395 had data for 2 procedures. INTERVENTIONS Subjects underwent same-day tandem examinations with standard colonoscopy (SC) and Third Eye colonoscopy (TEC). Subjects were randomized to SC followed by TEC or TEC followed by SC. MAIN OUTCOME MEASUREMENTS Detection rates for all polyps and adenomas with each method. RESULTS In the per-protocol population, 173 subjects underwent SC and then TEC, and TEC yielded 78 additional polyps (48.8%), including 49 adenomas (45.8%). In 176 subjects undergoing TEC and then SC, SC yielded 31 additional polyps (19.0%), including 26 adenomas (22.6%). Net additional detection rates with TEC were 29.8% for polyps and 23.2% for adenomas. The relative risk of missing with SC compared with TEC was 2.56 for polyps (P < .001) and 1.92 for adenomas (P = .029). Mean withdrawal times for SC and TEC were 7.58 and 9.52 minutes, respectively (P < .001). The median difference in withdrawal times was 1 minute (P < .001). The mean total procedure times for SC and TEC were 16.97 and 20.87 minutes, respectively (P < .001). LIMITATIONS Despite randomization and a large cohort, there was disparity in polyp prevalence between the 2 groups of subjects. CONCLUSION The Third Eye Retroscope increases adenoma detection rate by visualizing areas behind folds. ( CLINICAL TRIAL REGISTRATION NUMBER NCT01044732.).

The contribution of malabsorption to the reduction in net energy absorption after long-limb Roux-en-Y gastric bypass

BACKGROUND Roux-en-Y gastric bypass (RYGB) restricts food intake, and when the Roux limb is elongated to 150 cm, the procedure is believed to induce malabsorption. OBJECTIVE Our objective was to measure total reduction in intestinal absorption of combustible energy after RYGB and the extent to which this was due to restriction of food intake or malabsorption of ingested macronutrients. DESIGN Long-limb RYGB was performed in 9 severely obese patients. Dietary intake and intestinal absorption of fat, protein, carbohydrate, and combustible energy were measured before and at 2 intervals after bypass. By using coefficients of absorption to measure absorptive function, equations were developed to calculate the daily gram and kilocalorie quantities of ingested macronutrients that were not absorbed because of malabsorption or restricted food intake. RESULTS Coefficients of fat absorption were 92 ± 1.3% before bypass, 72 ± 5.5% 5 mo after bypass, and 68 ± 8.7% 14 mo after bypass. There were no statistically significant effects of RYGB on protein or carbohydrate absorption coefficients, although protein coefficients decreased substantially in some patients. Five months after bypass, malabsorption reduced absorption of combustible energy by 124 ± 57 kcal/d, whereas restriction of food intake reduced energy absorption by 2062 ± 271 kcal/d. Fourteen months after bypass, malabsorption reduced energy absorption by 172 ± 60 kcal/d compared with 1418 ± 171 kcal/d caused by restricted food intake. CONCLUSION On average, malabsorption accounted for ≈6% and 11% of the total reduction in combustible energy absorption at 5 and 14 mo, respectively, after this gastric bypass procedure.

Impact of experience with a retrograde-viewing device on adenoma detection rates and withdrawal times during colonoscopy: the Third Eye Retroscope study group

BACKGROUND Colonoscopy has been adopted as the preferred method to screen for colorectal neoplasia in the United States. However, lesions can be missed because of numerous factors, including location on the proximal aspect of folds or flexures, where they may be difficult to detect with the forward-viewing colonoscope. The Third Eye Retroscope (TER) is a disposable device that is passed through the instrument channel of a standard colonoscope to provide a retrograde view that complements the forward view of the colonoscope during withdrawal. OBJECTIVE To evaluate whether experience with the TER affects polyp detection rates and procedure times in experienced endoscopists who had not previously used the equipment. DESIGN, SETTING, PATIENTS This was an open-label, prospective, multicenter study at 9 U.S. sites, involving 298 patients presenting for colonoscopy, evaluating the use of the TER in combination with a standard colonoscope. INTERVENTIONS After cecal intubation, the TER was inserted through the instrument channel of the colonoscope. During withdrawal, the forward and retrograde video images were observed simultaneously on a wide-screen monitor. MAIN OUTCOME MEASUREMENTS Primary outcome measures were the number and size of adenomas and all polyps detected with the standard colonoscope and with the colonoscope combined with the TER. Secondary outcome measures were withdrawal phase time and total procedure time. Each endoscopist examined 20 subjects, divided into quartiles according to the order of their procedures, and results were compared among quartiles. RESULTS Overall, 182 polyps were detected with the colonoscope and 27 additional polyps with the TER, a 14.8% increase (P < .001). A total of 100 adenomas were detected with the colonoscope and 16 more with the TER, a 16.0% increase (P < .001). For procedures performed after each endoscopist had completed 15 procedures while using the TER, the mean additional detection rates with the TER were 17.0% for all polyps (P < .001) and 25.0% for adenomas (P < .001). For lesions 6 mm or larger, the overall additional detection rates with the TER for all polyps and for adenomas were 23.2% and 24.3%, respectively. For lesions 10 mm or larger, the overall additional detection rates with the TER for all polyps and for adenomas were 22.6% and 19.0%, respectively. The mean withdrawal times in the first and fourth quartiles were 10.6 and 9.2 minutes, respectively (P = .044). LIMITATIONS There was no randomization or separate control group. The endoscopists judged whether each lesion could have been detected with the colonscope alone by using their standard technique. CONCLUSIONS Polyp detection rates improved significantly with the TER, especially after 15 procedures, when the mean additional detection rate for adenomas was 25.0%. Additional detection rates with the TER for medium-size and large adenomas were greater than for smaller lesions. These results suggest that, compared with a colonoscope alone, a retrograde-viewing device can increase detection rates for clinically significant adenomas without detriment to procedure time or procedure complications. ( CLINICAL TRIAL REGISTRATION NUMBER NCT00969124.).

Retrograde-viewing device improves adenoma detection rate in colonoscopies for surveillance and diagnostic workup

AIM To determine which patients might benefit most from retrograde viewing during colonoscopy through subset analysis of randomized, controlled trial data. METHODS The Third Eye® Retroscope® Randomized Clinical Evaluation (TERRACE) was a randomized, controlled, multicenter trial designed to evaluate the efficacy of a retrograde-viewing auxiliary imaging device that is used during colonoscopy to provide a second video image which allows viewing of areas on the proximal aspect of haustral folds and flexures that are difficult to see with the colonoscopes forward view. We performed a post-hoc analysis of the TERRACE data to determine whether certain subsets of the patient population would gain more benefit than others from use of the device. Subjects were patients scheduled for colonoscopy for screening, surveillance or diagnostic workup, and each underwent same-day tandem examinations with standard colonoscopy (SC) and Third Eye colonoscopy (TEC), randomized to SC followed by TEC or vice versa. RESULTS Indication for colonoscopy was screening in 176/345 subjects (51.0%), surveillance after previous polypectomy in 87 (25.2%) and diagnostic workup in 82 (23.8%). In 4 subjects no indication was specified. Previously reported overall results had shown a net additional adenoma detection rate (ADR) with TEC of 23.2% compared to SC. Relative risk (RR) of missing adenomas with SC vs TEC as the initial procedure was 1.92 (P = 0.029). Post-hoc subset analysis shows additional ADRs for TEC compared to SC were 4.4% for screening, 35.7% for surveillance, 55.4% for diagnostic and 40.7% for surveillance and diagnostic combined. The RR of missing adenomas with SC vs TEC was 1.11 (P = 0.815) for screening, 3.15 (P = 0.014) for surveillance, 8.64 (P = 0.039) for diagnostic and 3.34 (P = 0.003) for surveillance and diagnostic combined. Although a multivariate Poisson regression suggested gender as a possibly significant factor, subset analysis showed that the difference between genders was not statistically significant. Age, bowel prep quality and withdrawal time did not significantly affect the RR of missing adenomas with SC vs TEC. Mean sizes of adenomas detected with TEC and SC were similar at 0.59 cm and 0.56 cm, respectively (P = NS). CONCLUSION TEC allows detection of significantly more adenomas compared to SC in patients undergoing surveillance or diagnostic workup, but not in screening patients (ClinicalTrials.gov Identifier: NCT01044732).

Olmesartan-Associated Enteropathy

Olmesartan, an angiotensin-receptor blocker frequently prescribed for hypertension, has been commercially available since 2002. In 2012, olmesartan-associated enteropathy was described, and the Food and Drug Administration now requires a black-box warning for olmesartan regarding severe diarrhea. The disorder can be life-threatening and often requires hospitalization. We present three cases that represent different aspects of this disorder, as well as some unusual features.

S1133 Effectiveness of Third Eye Retroscope in Detection of Colonic Adenomas in Elderly Patients (> 65 Years)

Background: Colonoscopy is considered to be the standard of care for the diagnosis of colorectal cancer. However, population-based studies have reported a subset of patients with cancer who do not undergo colonoscopy. The purpose of this study was to estimate the prevalence and identify the predictors of not having a colonoscopy in the period preceding colorectal cancer diagnosis. Methods: Using the population-based SEER registries, we identified patients aged >= 69 with colorectal cancer diagnosed from 1994-2005. Linked inpatient and outpatientMedicare claimswere used to identify receipt of colonoscopy prior to diagnosis. We divided this group into patients who had did not have colonoscopy within 3 years of diagnosis (Group I) and those who had 1 or more colonoscopies from 6 months prior to 30 days after diagnosis (Group II). Patient, sociodemographic and tumor factors were used to identify predictors of not having colonoscopy in univariate and multivariable logistic regression analysis. Results: We identified 79,032 patients, including 19.6% in Group I and 80.4% in Group II. Among patients in Group I, 31.6% had barium enema, 21.4% had flexible sigmoidoscopy and 57.3% underwent CT scan within 6 months prior to and 30 days after diagnosis. Independent predictors of Group I included age > 85, African American race, non-married, nursing home residence, rural residence, lower comorbidity score, diagnosis before 2000, AJCC Stage II-IV, left sided or rectal tumor site, and emergency presentation. Patients without colonoscopy were also less likely to undergo surgical resection (OR 0.55, CI 0.52-0.59). In a Cox proportional hazards model that adjusted for demographics, stage and treatment, not undergoing colonoscopy was associated with a higher risk of death (HR 1.31, CI 1.28-1.33). Conclusions: In this large, population based analysis, almost 20% of newly diagnosed colorectal cancer patients did not undergo colonoscopy at the time of diagnosis. Although these patients were more likely to be elderly with advanced disease, lack of colonoscopy appears to be an indicator of emergency presentation, less aggressive treatment and poorer prognosis.