SMARCA4-Deficient Undifferentiated Esophageal Carcinoma: A Clinical Case Series and Literature Review.

PURPOSE: Undifferentiated carcinoma of the esophagus (UEC) is a rare malignancy. Deficiency in SMARCA genes, critical for chromatin regulation, has been observed in cases of UEC. Research in UEC is sparse, however, and we present a case series along with a comprehensive review of the literature. CASE SERIES: Case 1 is a 49-year-old female with abdominal pain and dysphagia and esophagogastroduodenoscopy (EGD) showing a friable mass at the gastroesophageal (GE) junction. Biopsies showed a poorly differentiated neoplasm and immunohistochemistry showed loss for SMARCA4. With metastatic disease, she agreed to undergo palliative chemotherapy and radiation, passing away at 4 months. Case 2 is an 88-year-old male with dysphagia, nausea, vomiting, and distal esophageal mass with biopsy showing a malignancy with loss of SMARCA4 expression. Due to extensive metastases, he was counseled on hospice care. Case 3 is a 53-year-old male with extensive alcohol and smoking history presenting with hematemesis, passing away shortly. Posthumous histopathology consistent with undifferentiated SMARCA4-deficient carcinoma of the esophagus. Results of the literature review indicate a predilection towards males (75.0%) and a variable age range (39-88 years). Majority (76.2%) reported with a distal esophagus location. Metastatic disease was common at initial presentation. Median survival was 2.60 months. Some were managed with chemotherapy and radiation. CONCLUSIONS: Research in SMARCA-deficient UEC is very limited. It is more common in men, age is variable, and associated with Barret's esophagus. Further research is necessary to better understand it and to establish treatment guidelines; however, it is clear that SMARCA4-deficient UEC carries a significantly poor prognosis.

Colonoscopy Utilization in Elderly Patients with Dementia: Characteristics, Complications, and Charges in a National Matched-Cohort Analysis.

BACKGROUND: It is projected that the elderly population will continue to increase. Many will develop chronic conditions such as dementia. AIMS: Our aims are to describe the utilization of colonoscopy among patients with dementia and compare outcomes in those with and without dementia. METHODS: This population-based analysis utilized the National Inpatient Sample (NIS) during 2019. Patients with dementia over the age of 60 years receiving colonoscopy were identified utilizing ICD-10 codes. Logistic regression was used for propensity score matching between the comparison groups. A Greedy one-to-one matching algorithm was utilized along with standardized mean differences to assess balance. Mcnemar test, signed rank sum, and paired t-test were used to compare the outcomes. RESULTS: Initially, 50,692 patients without dementia were compared with 4323 patients with dementia. Patients with dementia were more likely to be female, older, less likely White, had lower income, and more likely to be on Medicare. In the matched comparison (4176 in each group), complication analysis showed that patients with dementia did not have higher colonoscopy-related complications. They did have higher rates of other complications including renal/AKI (p = 0.0042), pulmonary/pneumonia (p = 0.003), cerebrovascular accidents (p = 0.0063), and sepsis (< 0.0001). Patients with dementia were also less likely to have routine discharges (< 0.0001), had longer hospital stays (< 0.0001), and higher hospital costs (< 0.0001). CONCLUSIONS: Elderly patients with dementia have similar colonoscopy-related complications as patients without dementia. However, they do have higher complications in general. The decision whether to perform colonoscopy in this patient population is multifactorial. A careful assessment of a dementia patient's history can help with this decision.

How Would You Manage This Patient With Recurrent Diverticulitis? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Acute diverticulitis, which refers to inflammation or infection, or both, of a colonic diverticulum, is a common medical condition that may occur repeatedly in some persons. It most often manifests with left-sided abdominal pain, which may be associated with low-grade fever and other gastrointestinal symptoms. Complications may include abscess, fistula formation, perforation, and bowel obstruction. The American College of Physicians recently published practice guidelines on the diagnosis and management of acute diverticulitis, the role of colonoscopy after resolution, and interventions to prevent recurrence of this condition. Among the recommendations were the use of abdominal computed tomography (CT) scanning in cases where there was diagnostic uncertainty, initial management of uncomplicated cases in the outpatient setting without antibiotics, referral for colonoscopy after an initial episode if not performed recently, and discussion of elective surgery to prevent recurrent disease in patients with complicated diverticulitis or frequent episodes of uncomplicated disease. Here, 2 gastroenterologists with expertise in acute diverticulitis debate CT scanning for diagnosis, antibiotics for treatment, colonoscopy to screen for underlying malignancy, and elective surgery to prevent recurrent disease.

Up-Front Endoscopy Maximizes Cost-Effectiveness and Cost-Satisfaction in Uninvestigated Dyspepsia.

BACKGROUND & AIMS: Practice guidelines promote a routine noninvasive, non-endoscopic initial approach to investigating dyspepsia without alarm features in young patients, yet many patients undergo prompt upper endoscopy. We aimed to assess tradeoffs among costs, patient satisfaction, and clinical outcomes to inform discrepancy between guidelines and practice. METHODS: We constructed a decision-analytic model and performed cost-effectiveness/cost-satisfaction analysis over a 1-year time horizon on patients with uninvestigated dyspepsia without alarm features referred to gastroenterology. A RAND/UCLA expert panel informed model design. Four competing diagnostic/management strategies were evaluated: prompt endoscopy, testing for Helicobacter pylori and eradicating if present (test-and-treat), testing for H pylori and performing endoscopy if present (test-and-scope), and empiric acid suppression. Outcomes were derived from systematic reviews of clinical trials. Costs were informed by prospective observational cohort studies and national commercial/federal cost databases. Health gains were represented using quality-adjusted life years. RESULTS: From the patient perspective, costs and outcomes were similar for all strategies (maximum out-of-pocket difference of $30 and <0.01 quality-adjusted life years gained/year regardless of strategy). Prompt endoscopy maximized cost-satisfaction and health system reimbursement. Test-and-scope maximized cost-effectiveness from insurer and patient perspectives. Results remained robust on multiple one-way sensitivity analyses on model inputs and across most willingness-to-pay thresholds. CONCLUSIONS: Noninvasive management strategies appear to result in inferior cost-effectiveness and patient satisfaction outcomes compared with strategies promoting up-front endoscopy. Therefore, additional studies are needed to evaluate the drivers of patient satisfaction to facilitate inclusion in value-based healthcare transformation efforts.

Systematic review and meta-analysis: efficacy of peppermint oil in irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common disorders of gut-brain interaction, with a complex pathophysiology. Antispasmodics are prescribed as first-line therapy because of their action on gut dysmotility. In this regard, peppermint oil also has antispasmodic properties. AIM: To update our previous meta-analysis to assess efficacy and safety of peppermint oil, particularly as recent studies have cast doubt on its role in the treatment of IBS METHODS: We searched the medical literature up to 2nd April 2022 to identify randomised controlled trials (RCTs) of peppermint oil in IBS. Efficacy and safety were judged using dichotomous assessments of effect on global IBS symptoms or abdominal pain, and occurrence of any adverse event or of gastro-oesophageal reflux. Data were pooled using a random effects model, with efficacy and safety reported as pooled relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: We identified 10 eligible RCTs (1030 patients). Peppermint oil was more efficacious than placebo for global IBS symptoms (RR of not improving = 0.65; 95% CI 0.43-0.98, number needed to treat [NNT] = 4; 95% CI 2.5-71), and abdominal pain (RR of abdominal pain not improving = 0.76; 95% CI 0.62-0.93, NNT = 7; 95% CI 4-24). Adverse event rates were significantly higher with peppermint oil (RR of any adverse event = 1.57; 95% CI 1.04-2.37). CONCLUSIONS: Peppermint oil was superior to placebo for the treatment of IBS, but adverse events were more frequent, and quality of evidence was very low. Adequately powered RCTs of peppermint oil as first-line treatment for IBS are needed.

Racial and Ethnic Disparities in Opioid Prescriptions in Benign and Malignant Pancreatic Disease in the United States.

OBJECTIVES: Racial-ethnic disparities in pain management are common but not known among pancreatic disease patients. We sought to evaluate racial-ethnic disparities in opioid prescriptions for pancreatitis and pancreatic cancer patients. METHODS: Data from the National Ambulatory Medical Care Survey were used to examine racial-ethnic and sex differences in opioid prescriptions for ambulatory visits by adult pancreatic disease patients. RESULTS: We identified 207 pancreatitis and 196 pancreatic cancer patient visits, representing 9.8 million visits, but weights were repealed for analysis. No sex differences in opioid prescriptions were found among pancreatitis (P = 0.78) or pancreatic cancer patient visits (P = 0.57). Opioids were prescribed at 58% of Black, 37% of White, and 19% of Hispanic pancreatitis patient visits (P = 0.05). Opioid prescriptions were less common in Hispanic versus non-Hispanic pancreatitis patients (odds ratio, 0.35; 95% confidence interval, 0.14-0.91; P = 0.03). We found no racial-ethnic differences in opioid prescriptions among pancreatic cancer patient visits. CONCLUSIONS: Racial-ethnic disparities in opioid prescriptions were observed in pancreatitis, but not pancreatic cancer patient visits, suggesting possible racial-ethnic bias in opioid prescription practices for patients with benign pancreatic disease. However, there is a lower threshold for opioid provision in the treatment of malignant, terminal disease.

Peppermint Oil Treatment for Irritable Bowel Syndrome: A Randomized Placebo-Controlled Trial.

INTRODUCTION: Peppermint oil is often used to treat irritable bowel syndrome (IBS); however, the overall quality of previous studies is low, and findings have been heterogeneous. This study aimed to compare the effects of peppermint oil vs placebo in relieving IBS symptoms. METHODS: In a 6-week, randomized, double-blind, placebo-controlled trial at a single academic center in the United States, individuals diagnosed with IBS (Rome IV criteria), with moderate to severe symptoms based on the IBS Severity Scoring System (IBS-SSS score ≥175), were randomized to enteric-coated peppermint oil 180 mg 3 times daily vs placebo in a 1:2 ratio. The primary outcome was mean change in IBS-SSS scores from baseline to 6-week endpoint. RESULTS: A modified intent-to-treat analysis revealed that there were substantial mean improvements from baseline to 6-week endpoint in the main outcome measure (IBS-SSS) for both peppermint oil (90.8, SD = 75.3) and placebo (100.3, SD = 99.6). Although the peppermint oil group reported numerically lower improvement than the placebo group, the effect size was small (d = -0.11), and the difference between the groups was not statistically significant (P = 0.97). Similarly, both groups reported substantial improvements on the secondary endpoints; but again, there were no statistically significant differences between the groups on any of the secondary measures. Sensitivity analyses using multiple imputation to replace missing data produced similar results and revealed no significant differences between peppermint oil and placebo on any outcome measure. DISCUSSION: Peppermint oil and placebo both showed clinically meaningful improvement in IBS symptoms. However, there were no significant differences between the groups. Further large, rigorous trials are needed to evaluate the role of peppermint oil for the treatment of IBS.

Obesity is associated with significantly increased risk for diarrhoea after controlling for demographic, dietary and medical factors: a cross-sectional analysis of the 2009-2010 National Health and Nutrition Examination Survey.

BACKGROUND: Obesity is associated with increased risk for various gastrointestinal and liver diseases. However, the relationship between obesity and abnormal bowel habits is poorly understood. AIM: To investigate the relationship between body mass index (BMI) and bowel habit, controlling for clinical, demographic and dietary factors, in a representative sample of the United States adult population METHODS: Data were extracted from the 2009-2010 National Health and Nutrition Examination Survey. Survey responses were included in this study if respondents completed the bowel health questionnaire (BHQ), were ≥20 years of age, and did not report history of IBD, celiac disease or colon cancer. BMI was divided into the following categories: underweight, normal weight, overweight, obese and severely obese. Stepwise logistic regression provided risk ratios of constipation and diarrhoea controlling for confounding factors (dietary, life-style, psychological and medical). RESULTS: A total of 5126 respondents completed the BHQ, had BMI data available, and met eligibility criteria. Of these, 70 (1.40%) were underweight, 1350 (26.34%) were normal weight, 1731 (33.77%) were overweight, 1097 (21.40%) were obese and 878 (17.13%) were severely obese. Up to 8.5% of obese and 11.5% of severely obese individuals had chronic diarrhoea, compared to 4.5% of normal weight individuals. Stepwise regression revealed that severe obesity was independently associated with increased risk of diarrhoea. CONCLUSION: Obesity is positively associated with chronic diarrhoea in a nationally representative US adult population after adjusting for several known confounding factors.

Safety of Endoscopy in Heritable Connective Tissue Disorders.

INTRODUCTION: Little is known about the gastrointestinal manifestations or safety of endoscopy among patients with heritable connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome (EDS). METHODS: We conducted an electronic cross-sectional survey nested within preexisting registries of patients with heritable connective tissue disorders and examined self-reported rates of endoscopic complications. RESULTS: The rate of endoscopy-related perforation was 9.4% (95% confidence interval 2.0%-25.0%) among individuals with vascular EDS, <1% in classical and hypermobility-type EDS, and zero in Marfan syndrome (P < 0.001). Spontaneous intestinal perforation was also significantly higher in the vascular EDS group. DISCUSSION: Clinicians should consider noninvasive screening methods for patients with vascular EDS.

Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis.

BACKGROUND: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess linaclotide safety in a large, pooled Phase 3 population. METHODS: In six randomized controlled trials (RCTs), patients received linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12-26 weeks; in two long-term safety (LTS) studies, patients received open-label linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Overall, 3853 patients received ≥1 dose of linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea. CONCLUSION: These pooled analyses of patients treated for ≤104 weeks confirm linaclotide's overall safety.

The Prevalence of Gastroesophageal Reflux in Patients With Excessive Central Airway Collapse.

BACKGROUND: Gastroesophageal reflux (GER) is increasingly recognized as an exacerbating or causal factor in several respiratory diseases. There is a high prevalence of GER in infants with airway malacia. However, such data are lacking in adults. METHODS: This retrospective study was conducted to determine the relationship between GER and excessive central airway collapse (ECAC). The study included consecutive patients with ECAC referred to the Complex Airway Center at Beth Israel Deaconess Medical Center who underwent esophageal pH testing for GER between July 2014 and June 2018. RESULTS: Sixty-three of 139 patients with ECAC (45.3%) had documented GER as shown by an abnormal esophageal pH test result. The mean DeMeester score was 32.2, with a symptom association probability of 39.7% of GER-positive patients. Twenty-nine of 63 patients (46%) with GER reported improvement in respiratory symptoms following maximal medical therapy or antireflux surgery without requiring further treatment for ECAC. CONCLUSIONS: GER is prevalent among patients with ECAC, and aggressive reflux treatment should be considered in these patients prior to considering invasive airway procedures or surgery.

Efficacy of Treatments for Opioid-Induced Constipation: Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Opioid-induced constipation (OIC) is a common problem in patients on chronic opioid therapy for cancer-related and non-cancer-related pain. Approved treatments for OIC are methylnaltrexone, naloxone, naloxegol, alvimopan, naldemedine, and lubiprostone. Since a meta-analysis performed in 2014, 2 new agents have been approved by the Food and Drug Administration for treatment of OIC (naloxegol and naldemedine). METHODS: We conducted a search of the medical literature following the protocol outlined in the Cochrane Handbook for systematic review. We searched MEDLINE, EMBASE, EMBASE Classic, Web of Science, and the Cochrane Central Register of Controlled Trials until March 2017 to identify randomized controlled trials of peripheral µ-opioid-receptor antagonists (methylnaltrexone, naloxone, naloxegol, alvimopan, axelopran, or naldemedine), lubiprostone, or prucalopride. Response to therapy was extracted in a dichotomous assessment as an overall response to therapy. The effect of pharmacologic therapies was pooled and reported as a relative risk (RR) of failure to respond to the treatment drug, with 95% CIs. RESULTS: We included 27 placebo-controlled trials in our meta-analysis (23 trials evaluated µ-opioid-receptor antagonists, 3 trials evaluated lubiprostone, and 1 trial evaluated prucalopride). In these trials, 5390 patients received a drug and 3491 received a placebo. Overall, µ-opioid-receptor antagonists, lubiprostone, and prucalopride were superior to placebo for the treatment of OIC, with a RR of failure to respond to therapy of 0.70 (95% CI, 0.64-0.75) and an overall number needed to treat of 5 (95% CI, 4-7). When restricted to only Food and Drug Administration-approved medications for OIC, the RR of failure to respond to therapy was 0.69 (95% CI, 0.62-0.77), with a number needed to treat of 5 (95% CI, 4-7). Sensitivity analyses and meta-regression performed to account for heterogeneity showed that treatment was more likely to be effective in study populations taking higher doses of opiates at baseline or refractory to laxatives. Study duration and prespecified primary outcome did not affect the RR of failure. Participants who received µ-opioid-receptor antagonists were significantly more likely to have diarrhea, abdominal pain, nausea, or vomiting than patients who received placebo. CONCLUSIONS: In a systematic review and meta-analysis, we found µ-opioid-receptor antagonists to be safe and effective for the treatment of OIC. Prescription-strength laxatives (prucalopride, lubiprostone) are slightly better than placebo in reducing OIC.

Low-Dose Linaclotide (72 µg) for Chronic Idiopathic Constipation: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVES: Linaclotide is a guanylate cyclase-C agonist approved in the United States, Canada, and Mexico at a once-daily 145-µg dose for the treatment of chronic idiopathic constipation (CIC); a once-daily 72-µg dose for CIC recently received FDA approval. The trial objective was to evaluate the efficacy and safety of a 72-µg linaclotide dose in CIC patients. METHODS: This double-blind, placebo-controlled trial randomized patients with CIC (Rome III criteria) to once-daily linaclotide 72 µg or 145 µg, or placebo for 12 weeks. The primary endpoint, 12-week complete spontaneous bowel movement (CSBM) overall responder, required patients to have ≥3 CSBMs and an increase of ≥1 CSBM per week from baseline in the same week for ≥9 of 12 weeks of the treatment period. Secondary endpoints included 12-week change from baseline in bowel (SBM and CSBM frequency, stool consistency, straining) and abdominal (bloating, discomfort) symptoms, monthly CSBM responders, and 12-week CSBM responders among patients who averaged >1 SBM/week at baseline. Sustained response (12-week CSBM overall responders who met weekly criteria for 3 of the 4 final weeks (weeks 9-12) of treatment) was evaluated as an additional endpoint. Adverse events (AEs) were monitored. RESULTS: The intent-to-treat population included 1,223 patients (mean age=46 years, female=77%, white=71%). The primary endpoint was met by 13.4% of linaclotide 72-µg patients vs. 4.7% of placebo patients (P<0.0001, odds ratio=3.0; statistically significant controlling for multiplicity). Sustained response was achieved by 12.4% of linaclotide 72-µg patients vs. 4.2% of placebo patients (nominal P<0.0001). Linaclotide 72-µg patients met 9-of-10 secondary endpoints vs. placebo (P<0.05; abdominal discomfort, P=0.1028). Patients treated with linaclotide 145 µg also improved CIC symptoms for the primary (12.4%) and sustained responder endpoint parameters (11.4%) and for all 10 of the secondary endpoint parameters including abdominal discomfort (P<0.05). Diarrhea, the most common AE, was mild in most instances and resulted in discontinuation of 0, 2.4%, and 3.2% of patients in the placebo, linaclotide 72-µg, and linaclotide 145-µg groups, respectively. CONCLUSIONS: Once-daily linaclotide 72 µg significantly improved CIC symptoms in both men and women with a low rate of discontinuation due to diarrhea over 12 weeks of treatment.

Chronic constipation.

Chronic constipation is a prevalent condition that severely impacts the quality of life of those affected. Several types of primary chronic constipation, which show substantial overlap, have been described, including normal-transit constipation, rectal evacuation disorders and slow-transit constipation. Diagnosis of primary chronic constipation involves a multistep process initiated by the exclusion of 'alarm' features (for example, unintentional weight loss or rectal bleeding) that might indicate organic diseases (such as polyps or tumours) and a therapeutic trial with first-line treatments such as dietary changes, lifestyle modifications and over-the-counter laxatives. If symptoms do not improve, investigations to diagnose rectal evacuation disorders and slow-transit constipation are performed, such as digital rectal examination, anorectal structure and function testing (including the balloon expulsion test, anorectal manometry or defecography) or colonic transit tests (such as the radiopaque marker test, wireless motility capsule test, scintigraphy or colonic manometry). The mainstays of treatment are diet and lifestyle interventions, pharmacological therapy and, rarely, surgery. This Primer provides an introduction to the epidemiology, pathophysiological mechanisms, diagnosis, management and quality of life associated with the commonly encountered clinical problem of chronic constipation in adults unrelated to opioid abuse.

Opioids in Gastroenterology: Treating Adverse Effects and Creating Therapeutic Benefits.

The use of opioid medications on both an acute and chronic basis is ubiquitous in the United States. As opioid receptors densely populate the gastrointestinal tract, symptoms and side effects can be expected in these patients. In the esophagus, dysmotility may result, manifesting with dysphagia and a syndrome indistinguishable from primary achalasia. In the stomach, a marked delay in gastric emptying may occur with postprandial nausea and early satiety. Postoperatively, particularly with abdominal surgery, opioid-induced ileus may ensue. In the colon, opioid-induced constipation is common. A unique syndrome termed narcotic bowel syndrome is characterized by chronic abdominal pain often accompanied by nausea and vomiting in the absence of other identifiable causes. With the recognition of the important role of opioids on gastrointestinal function, novel drugs have been developed that use this physiology. These medications include peripheral acting opioid agonists to treat opioid-induced constipation and combination agonist and antagonists used for diarrhea-predominant irritable bowel syndrome. This review summarizes the most recent data in these areas.

Pseudoachalasia Secondary to Thoracic Aortic Aneurysm.

Pseudoachalasia is known to be associated with malignancy involving the gastroesophageal junction and after esophageal operations. We present a case of pseudoachalasia secondary to an aneurysm of the descending thoracic aorta and describe successful operative management.

Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial.

BACKGROUND: Abdominal bloating is a common and bothersome symptom of chronic idiopathic constipation. The objective of this trial was to evaluate the efficacy and safety of linaclotide in patients with chronic idiopathic constipation and concomitant moderate-to-severe abdominal bloating. METHODS: This Phase 3b, randomized, double-blind, placebo-controlled clinical trial randomized patients to oral linaclotide (145 or 290 µg) or placebo once daily for 12 weeks. Eligible patients met Rome II criteria for chronic constipation upon entry with an average abdominal bloating score ≥5 (self-assessment: 0 10-point numerical rating scale) during the 14-day baseline period. Patients reported abdominal symptoms (including bloating) and bowel symptoms daily; adverse events were monitored. The primary responder endpoint required patients to have ≥3 complete spontaneous bowel movements/week with an increase of ≥1 from baseline, for ≥9 of 12 weeks. The primary endpoint compared linaclotide 145 µg vs. placebo. RESULTS: The intent-to-treat population included 483 patients (mean age=47.3 years, female=91.5%, white=67.7%). The primary endpoint was met by 15.7% of linaclotide 145 µg patients vs. 7.6% of placebo patients (P<0.05). Both linaclotide doses significantly improved abdominal bloating vs. placebo (P<0.05 for all secondary endpoints, controlling for multiplicity). Approximately one-third of linaclotide patients (each group) had ≥50% mean decrease from baseline in abdominal bloating vs. 18% of placebo patients (P<0.01). Diarrhea was reported in 6% and 17% of linaclotide 145 and 290 µg patients, respectively, and 2% of placebo patients. AEs resulted in premature discontinuation of 5% and 9% of linaclotide 145 µg and 290 µg patients, respectively, and 6% of placebo patients. CONCLUSIONS: Once-daily linaclotide (145 and 290 µg) significantly improved bowel and abdominal symptoms in chronic idiopathic constipation patients with moderate-to-severe baseline abdominal bloating; in particular, linaclotide significantly improved abdominal bloating compared to placebo, an important finding given the lack of agents available to treat abdominal bloating in chronic idiopathic constipation patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01642914.

Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects.

Diarrhea-predominant irritable bowel syndrome (IBS) is diagnosed through clinical criteria after excluding "organic" conditions, and can be precipitated by acute gastroenteritis. Cytolethal distending toxin B (CdtB) is produced by bacteria that cause acute gastroenteritis, and a post-infectious animal model demonstrates that host antibodies to CdtB cross-react with vinculin in the host gut, producing an IBS-like phenotype. Therefore, we assessed circulating anti-CdtB and anti-vinculin antibodies as biomarkers for D-IBS in human subjects. Subjects with D-IBS based on Rome criteria (n=2375) were recruited from a large-scale multicenter clinical trial for D-IBS (TARGET 3). Subjects with inflammatory bowel disease (IBD) (n=142), subjects with celiac disease (n=121), and healthy controls (n=43) were obtained for comparison. Subjects with IBD and celiac disease were recruited based on the presence of intestinal complaints and histologic confirmation of chronic inflammatory changes in the colon or small intestine. Subjects with celiac disease were also required to have an elevated tTG and biopsy. All subjects were aged between 18 and 65 years. Plasma levels of anti-CdtB and anti-vinculin antibodies were determined by ELISA, and compared between groups. Anti-CdtB titers were significantly higher in D-IBS subjects compared to IBD, healthy controls and celiac disease (P<0.001). Anti-vinculin titers were also significantly higher in IBS (P<0.001) compared to the other groups. The area-under-the-receiver operating curves (AUCs) were 0.81 and 0.62 for diagnosis of D-IBS against IBD for anti-CdtB and anti-vinculin, respectively. Both tests were less specific in differentiating IBS from celiac disease. Optimization demonstrated that for anti-CdtB (optical density≥2.80) the specificity, sensitivity and likelihood ratio were 91.6%, 43.7 and 5.2, respectively, and for anti-vinculin (OD≥1.68) were 83.8%, 32.6 and 2.0, respectively. These results confirm that anti-CdtB and anti-vinculin antibodies are elevated in D-IBS compared to non-IBS subjects. These biomarkers may be especially helpful in distinguishing D-IBS from IBD in the workup of chronic diarrhea.

Motility disorders of the colon and rectum.

PURPOSE OF REVIEW: Symptoms associated with disorders of the motility of colon and rectum are common problems in clinical practice. Advances in this field continue to expand our understanding of these disorders and provide new and different treatments with promising results. RECENT FINDINGS: This article reviews new advances in the past year on the measurement and diagnosis of colonic transit. Recently published data question the importance of dietary fiber in the prevention of colonic diverticulosis and diverticulitis, and support the efficacy of a number of different therapies aimed at improving colonic motility and visceral sensation in constipation and reversing the effects of opioid induced constipation with peripherally acting opioid antagonists. SUMMARY: The articles referenced in this review help inform the reader on new developments in the diagnosis and management of patients with colonic and rectal motility disorders.