David Limsui

Cigarette Smoking and Colorectal Cancer Risk by Molecularly Defined Subtypes

BACKGROUND Cigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer. METHODS We evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37 399 participants in a population-based cohort study (the Iowa Womens Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS Ever-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95% CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95% CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95% CI = 1.22 to 2.90), and BRAF mutation-positive tumors (RR = 1.92, 95% CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation-positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95% CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95% CI = 0.81 to 1.30), or BRAF mutation-negative subtypes (RR = 1.00, 95% CI = 0.65 to 1.27). CONCLUSIONS In this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation-positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.

Symptomatic overlap between irritable bowel syndrome and microscopic colitis

Background Microscopic colitis is diagnosed on the basis of histologic criteria, and irritable bowel syndrome (IBS) is diagnosed by symptom‐based criteria. There has been little investigation into the symptomatic overlap between these conditions. Our aim was to assess the prevalence of symptoms of irritable bowel syndrome in a population‐based cohort of patients with microscopic colitis. Methods The Rochester Epidemiology Project (REP), a medical records linkage system providing all health care data for the defined population of Olmsted County, Minnesota, was used to identify all county residents with a diagnosis of microscopic colitis between 1985 and 2001. The medical records of these individuals were reviewed to ascertain symptoms consistent with Rome, Rome II, and Manning criteria for irritable bowel syndrome. Results One hundred thirty‐one cases of microscopic colitis were identified. Median age at diagnosis was 68 years (range, 24–95); 71% were women. Sixty‐nine (53%) and 73 (56%) met Rome and Rome II criteria for irritable bowel syndrome, respectively. Fifty‐four (41%) had three or more Manning criteria. Forty‐three (33%) had previously been diagnosed with irritable bowel syndrome. Conclusions In this population‐based cohort of histologically confirmed microscopic colitis, approximately one‐half met symptom‐based criteria for the diagnosis of irritable bowel syndrome. The clinical symptom‐based criteria for irritable bowel syndrome are not specific enough to rule out the diagnosis of microscopic colitis. Therefore, patients with suspected diarrhea‐predominant irritable bowel syndrome should undergo biopsies of the colon to investigate for possible microscopic colitis if symptoms are not well controlled by antidiarrheal therapy. (Inflamm Bowel Dis 2006)

Observer variability in the histologic diagnosis of microscopic colitis

Background: Microscopic colitis is diagnosed based on histologic criteria. There has been no investigation of the reproducibility of the histologic diagnosis of microscopic colitis. Our aim was to evaluate interobserver and intraobserver variation in this diagnosis. Methods: Colonic biopsies from 90 subjects (20 lymphocytic colitis, 20 collagenous colitis, 20 inflammatory bowel disease, and 30 normal) were blindly and independently reviewed by 4 gastrointestinal pathologists. The biopsies were classified by each pathologist into 1 of 6 diagnostic categories: lymphocytic colitis, collagenous colitis, active chronic colitis, focal active colitis, normal, or other. The slides were then relabeled and blindly reinterpreted 3 months later. The degree of agreement was determined using kappa statistics (&lgr;). Results: Interobserver agreement with the 6 diagnostic categories was 69% (&kgr; = 0.76, 95% CI 0.69, 0.83) and 70% (&kgr; = 0.71, 95% CI 0.61, 0.79) for the first and second observations, respectively. Interobserver agreement with final diagnostic categories of microscopic colitis versus nonmicroscopic colitis was 91% (&kgr; = 0.90, 95% CI 0.82, 0.96) and 88% (&kgr; = 0.83, 95% CI 0.73, 0.92), respectively. Mean intraobserver agreement with the 6 diagnostic categories was 83% (&kgr; = 0.77). Mean intraobserver agreement with the final diagnostic categories of microscopic colitis versus nonmicroscopic colitis was 95% (&kgr; = 0.89). Conclusions: Both interobserver and intraobserver agreement were good in distinguishing among the 6 diagnostic categories, and excellent in distinguishing between microscopic colitis and nonmicroscopic colitis diagnoses. The histologic criteria for microscopic colitis provide for consistent and reproducible interindividual and intraindividual diagnoses in the evaluation of colonic biopsies.

Postmenopausal hormone therapy and colorectal cancer risk by molecularly defined subtypes among older women

Background Postmenopausal hormone (PMH) therapy may reduce colorectal cancer (CRC) risk, but existing data are inconclusive. Objectives To evaluate associations between PMH therapy and incident CRC, overall and by molecularly defined subtypes, in the population-based Iowa Womens Health Study of older women. Methods Exposure data were collected from Iowa Womens Health Study participants (55–69 years) at baseline (1986). Archived, paraffin-embedded tissue specimens for 553 CRC cases were collected and analysed to determine microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive) and BRAF mutation (BRAF-wildtype or BRAF-mutated) status. Multivariable Cox regression models were fit to estimate RRs and 95% CIs. Results PMH therapy (ever vs never use) was inversely associated with incident CRC overall (RR=0.82; 95% CI 0.72 to 0.93), with a significantly lower risk for MSI-L/MSS tumours (RR=0.75; 95% CI 0.60 to 0.94), and borderline significantly lower risks for CIMP-negative (RR=0.79; 95% CI 0.63 to 1.01) and BRAF-wildtype (RR=0.83; 95% CI 0.66 to 1.04) tumours. For PMH therapy >5 years, the subtype-specific risk estimates for MSI-L/MSS, CIMP-negative and BRAF-wildtype tumours were: RR=0.60, 95% CI 0.40 to 0.91; RR=0.68, 95% CI 0.45 to 1.03; and RR=0.70, 95% CI 0.47 to 1.05, respectively. PMH therapy was not significantly associated with the MSI-H, CIMP-positive or BRAF-mutated CRC subtypes. Conclusions In this prospective cohort study, PMH therapy was inversely associated with distinct molecularly defined CRC subtypes, which may be related to differential effects from oestrogen and/or progestin on heterogeneous pathways of colorectal carcinogenesis.

Cigarette Smoking and Colorectal Cancer Risk: A Burning Issue

the study include the use of strict criteria for the safety endpoint (doubling of ALT either from normal or baseline value as a sign of liver injury); therefore, even mild liver injury was likely to be detected biochemically. Because statin hepatotoxicity is thought to be dose related, the investigators also used a high therapeutic dose of pravastatin (80 mg/d). The study cohort was large and the follow-up period of 36 weeks was reasonably long enough to detect most episodes of statin-induced liver injury. Ultimately, there are some questions that remain unanswered. Patients with decompensated or severe liver diseases were excluded from the trial, so the results of this study cannot be applied to this group of patients; however, the role of therapy for dyslipidemia in this group of patients is unclear. The other point worth mentioning is that the majority of the subjects had NAFLD and the role of statins in treatment of NAFLD continues to evolve. Overall, this trial provides strong evidence that the use of statin agents among patients with chronic liver disease is safe, effective in managing dyslipidemia, and may even be beneficial in improving liver chemistries. The challenging question which faces many physicians is not can we use these drugs safely, but rather do we still need to monitor patients on statins for possible hepatotoxicity and if so, how often?

A randomized clinical trial of vitamin D3 (cholecalciferol) in ulcerative colitis patients with hypovitaminosis D3

Aim To prospectively evaluate the effects of vitamin D3 on disease activity and quality of life in ulcerative colitis (UC) patients with hypovitaminosis D. Methods The study was a prospective double-blinded, randomized trial conducted at Community Regional Medical Center, Fresno, CA from 2012–2013. Patients with UC and a serum 25(OH)D level <30 ng/ml were eligible for the study. Enrolled subjects were randomized to receive either 2,000 IU or 4,000 IU of oral vitamin D3 daily for a total of 90 days. The Short IBD Questionnaire (SIBDQ) for quality of life, the Partial Mayo Score for UC disease activity and serum lab tests were compared between the two treatment groups. Matched pair t-tests were computed to assess differences between the vitamin D levels, CRP, UC disease activity and SIBDQ scores before and after vitamin D3 therapy using SPSS version 21. Results Eight UC patients received 2,000 IU/daily and ten UC patients received 4,000 IU/daily of vitamin D3 for 90 days. Vitamin D levels increased after 90 days of oral vitamin D3 in both dose groups. However, the increase in vitamin D levels after 90 days of oral vitamin D3, in the 4,000 IU group was significantly higher 16.80 ± 9.15 (p < 0.001) compared to the 2,000 IU group of vitamin D 5.00 ± 3.12 (p = 0.008). Normal vitamin D levels (>30 ng/dl) were achieved in four out of the ten UC patients (40%) in the 4,000 IU group and in one out of the eight UC patients (12%) in the 2,000 IU group. In the group receiving 4,000 IU/day of vitamin D3 the increase in quality life scores (SIBDQ) was significant 1.0 ± 1.0 (p = 0.017) but not in the 2,000 IU vitamin D3 group 0.1 ± 1.0 (p = 0.87). In the 2,000 IU of vitamin D3 group the mean decrease in the Partial Mayo UC Score was −0.5 ± 1.5 (p = 0.38) compared to −1.3 ± 2.9 (p = 0.19) in the 4,000 IU vitamin D3 group but this was not statistically significant. CRP levels decreased after 90 days of daily vitamin D3 in both the 2,000 IU group and 4,000 IU group by −3.0 ± 9.4 (p = 0.4) and −10.8 ± 35.0 (p = 0.36) respectively. Conclusion Vitamin D3 at 4,000 IU/day is more effective than 2,000 IU/day in increasing vitamin D to sufficient levels in UC patients with hypovitaminosis D, however higher doses or treatment beyond ninety days may be required. Vitamin D3 may improve the quality of life in UC patients but clinically significant improvement is not yet established. The effect of vitamin D3 on UC disease activity is still unclear. Further larger studies are needed to investigate the effects of vitamin D in ulcerative colitis.

Role of Vitamin D in Inflammatory Bowel Disease

Vitamin D is a secosteroid hormone that possesses immunomodulatory properties and has been demonstrated to potentially influence inflammatory bowel disease (IBD) pathogenesis and activity. Epidemiologic data have associated vitamin D deficiency with an increased risk of IBD, hospitalizations, surgery, and loss of response to biologic therapy. Conversely, IBD itself can lead to vitamin D deficiency. This bidirectional relationship between vitamin D and IBD suggests the need for monitoring and repletion of vitamin D, as needed, in the IBD patient. This review discusses the role of vitamin D in IBD and provides practical guidance on vitamin D repletion.

A Man With Dysphagia, Aspiration, and Hematemesis

g m a Question: An 85-year-old Caucasian man was admitted with 3– 4 episodes of hematemesis over a period of 12 hours before presentation. He was hospitalized 2 weeks prior for melena attributed to a 1-cm duodenal ulcer seen on endoscopy at that time. Helicobacter pylori serology was negative and he was treated with high-dose proton pump inhibitors. In addition, he described a 10-year history of progressively worsening dysphagia to solids and liquids. The dysphagia was not any worse than baseline at presentation. He had 3– 4 episodes of pneumonia over the last 4 years attributed to recurrent aspiration. He was on aspirin for cardioprotection but denied use of any other nonsteroidal anti-inflammatory drugs or anticoagulants. Other medical problems included a history of paroxysmal atrial fibrillation, severe mitral regurgitation, and moderate to severe aortic regurgitation. On physical examination, his pulse was 88 beats per minute and blood pressure was 146/80 mmHg. He was uncomfortable. His abdominal examination was unremarkable. Hemoglobin was 6.8 g/dL. An urgent diagnostic and therapeutic upper endoscopy was performed as shown in the Video clip. A culprit lesion was identified and successful hemostasis was achieved. Two days later, an esophagram was done (Figure A, B). What would be the most likely cause of this patient’s dysphagia, aspiration, and hematemesis? See the GASTROENTEROLOGY web site (www. astrojournal.org) for more information on subitting your favorite image to Clinical Challenges nd Images in GI. JOHN EATON DAVID LIMSUI MADHUSUDAN GROVER Division of Gastroenterology and Hepatology Department of Internal Medicine Mayo Clinic College of Medicine Rochester, Minnesota

The Gastroenterology Fellowship Match: A Decade Later

Following a period of uncertainty and disorganization, the gastroenterology (GI) national leadership decided to reinstitute the fellowship match (the Match) under the auspices of the National Residency Matching Program (NRMP) in 2006. Although it has now been a decade since the rebirth of the Match, there have been limited data published regarding progress made. In this piece, we discuss reasons for the original collapse of the GI Match, including most notably a perceived oversupply of GI physicians and a poor job market. We discuss the negative impacts the absence of the Match had on programs and on applicants, as well as the impetus to reorganize the Match under the NRMP. We then utilize data published annually by the NRMP to demonstrate that in the decade since its rebirth, the GI Match has been remarkably successful in terms of attracting the participation of applicants and programs. We show that previous misguided concerns of an oversupply of GI physicians were not realized, and that GI fellowship positions remain highly competitive for internal medicine applicants. Finally, we discuss possible implications of recent changes in the healthcare landscape on the GI Match.

Prevalence and factors associated with gluten sensitivity in inflammatory bowel disease

Abstract Objectives: Gluten sensitivity (GS) arises with celiac disease and has also been found in non-celiac disorders, although its characteristics in inflammatory bowel disease (IBD) are unclear. This study evaluated the prevalence of GS and factors associated with GS in IBD. Methods: Adult IBD patients at a tertiary-care medical center completed a survey of their demographics, medical history, family history, social history and symptoms. Data on IBD characteristics were abstracted from the medical records. Descriptive analyses estimated the prevalence of GS. Multivariable logistic regression assessed the association between GS and patient or disease factors. Results: Of 102 IBD patients (55 Crohn’s disease [CD], 46 ulcerative colitis [UC] and 3 IBD-unclassified), GS was reported in 23.6 and 27.3% of CD and UC patients, respectively. Common symptoms included fatigue, abdominal pain, diarrhea, bloating and hematochezia. There was no difference in these symptoms when comparing patients with and without GS. When evaluating IBD-related factors, GS was associated with having had a recent flare (adjusted odds ratio [aOR] 7.4; 95% confidence interval [CI] 1.6–34.1), stenotic disease in CD (aOR 4.7; 95% CI 1.1–20.2) and dermatologic manifestations (aOR 5.5; 95% CI 1.2–24.1). Conclusion: GS was common in IBD and associated with having had a recent flare. GS may be transient for some patients, whereby dietary recommendations during and after a flare could focus on the avoidance of specific food triggers with possible reintroduction of these foods over time. This study prompts further prospective investigation into the temporal evolution of GS in IBD.