A Clinicopathological Appraisal of Duodenal Neuroendocrine Tumors at a Racially Diverse Safety Net Hospital.

INTRODUCTION: Significant knowledge gaps exist regarding clinicopathological profiling as well as treatment, surveillance, and survival of duodenal neuroendocrine tumors (dNETs). METHODS: We clinicopathologically characterized and identified racial differences among patients with dNETs at a large safety net hospital. Tumor grades were updated based on the World Health Organization 2019 NET classification, and overall survival was determined. RESULTS: We identified 17 dNETs and found no differences in clinicopathologic characteristics across racial groups. Pathological diagnosis was upgraded in 35% of dNETs, and age >65 years significantly shortened overall survival. DISCUSSION: Larger-scale studies are needed to determine the significance of these findings.

Esophageal adenocarcinoma heterogeneity in clinicopathology and prognosis: A single center longitudinal study of 146 cases over a 20-year period.

Recent genomic studies suggest that esophageal adenocarcinoma (EAC) is not homogeneous and can be divided into true (tEAC) and probable (pEAC) groups. We compared clinicopathologic and prognostic features between the two groups of EAC. Based on endoscopic, radiologic, surgical, and pathologic reports, tumors with epicenters beyond 2 cm of the gastroesophageal junction (GEJ) were assigned to the tEAC group (N = 63), while epicenters within 2 cm of, but not crossing the GEJ, were allocated to the pEAC group (N = 83). All 146 consecutive patients were male (age: median 70 years, range: 51-88) and White-predominant (98.6 %). There was no significant difference in gastroesophageal reflux disease, obesity, comorbidity, and the prevalence of Barrett's esophagus, and cases diagnosed during endoscopic surveillance. However, compared to the pEAC group, the tEAC group had significantly more cases with hiatal hernia (P = 0.003); their tumors were significantly smaller in size (P = 0.007), more frequently with tubular/papillary adenocarcinoma (P = 0.001), had fewer cases with poorly cohesive carcinoma (P = 0.018), and demonstrated better prognosis in stage I disease (P = 0.012); 5-year overall survival (34.9 months) was significantly longer (versus 16.8 months in pEACs) (P = 0.043). Compared to the patients without resection, the patients treated with endoscopic or surgical resection showed significantly better outcomes, irrespective of stages. We concluded that EACs were heterogeneous with two distinct tEAC and pEAC groups in clinicopathology and prognosis; resection remained the better option for improved outcomes. CONDENSED ABSTRACT: Esophageal adenocarcinoma can be divided into true or probable groups with distinct clinicopathology and better prognosis in the former than in the latter. we showed that resection remained the better option for improved outcomes.

Activation of Bombesin Receptor Subtype-3 Promotes Antigen-Presenting Action in Human Bronchial Epithelial Cells.

BACKGROUND: Bombesin receptor subtype-3 (BRS-3) is a member of the bombesin-like peptide receptor family. Our previous studies demonstrated that activation of the human BRS-3 plays a protective role in oxidation-injured human bronchial epithelial cells (HBEC). The present study was designed to determine the role of BRS-3 activation in the antigen-presenting action of HBEC and the corresponding proliferation and differentiation of T cells. MATERIALS AND METHODS: In vivo, an asthma animal model was established and the expression and distribution of BRS-3 were analyzed by immunocytochemistry. In vitro, 2 kinds of B7 costimulatory molecules, i.e., B7H1 and B7DC, on HBEC were analyzed by flow cytometry. The antigen uptake by HBEC was examined by confocal microscopy and flow cytometry. The antigen-presenting-action-induced proliferation of T cells was determined by MTT assays. IFN-γ and IL-4 levels were measured by ELISA. All studies were performed in the absence or presence of the synthetic peptide P3513. RESULTS: BRS-3 expression was induced in asthma animal models and mainly distributed in bronchial epithelial cells. HBEC express the costimulatory molecules B7H1 and B7DC. BRS-3 activation increased B7H1 expression but decreased B7DC expression on HBEC. BRS-3 activation also increased the antigen uptake by HBEC and the subsequent T cell proliferation. In addition, BRS-3 activation promoted the releases of IFN-γ, but not IL-4, in the supernatant of cocultured HBEC and T cells. CONCLUSION: These data suggest that HBEC can present antigen to T cells and BRS-3 activation promotes the process of antigen presentation and subsequent T cell proliferation and Th1 differentiation.

Incident severe thrombocytopenia in veterans treated with pegylated interferon plus ribavirin for chronic hepatitis C infection.

PURPOSE: We sought to determine the incidence and risks for severe thrombocytopenia (platelets < 50,000/µL) in United States Veteran patients treated with pegylated interferon (PEG-IFN) plus ribavirin for hepatitis C virus-positive (HCV) chronic liver disease (CLD). METHODS: Using a retrospective, observational cohort study design to analyze databases from the New England Veterans Healthcare System, we identified 979 patients diagnosed with HCV-positive CLD treated solely with PEG-IFN plus ribavirin. The cohort was stratified by pre-treatment platelet counts of 50,000-100,000/µL (N = 90), >100,000-150,000/µL (N = 162), and >150,000µL (N = 727). The cumulative incidence of severe thrombocytopenia and major bleeding events were determined for each baseline platelet group for 48 weeks following treatment initiation. Multivariable Cox regression was used to identify risk factors for incident severe thrombocytopenia. RESULTS: Overall, severe thrombocytopenia occurred in 6.1% (N = 60), but in 41.1% of patients with pre-treatment platelet counts 50, 000-100,000/µL compared with 11.7% (p < 0.001) and 0.55% (p < 0.001) in the two higher pre-treatment platelet groups. Most episodes occurred within the first 12 weeks of treatment. Median nadir count for these 60 patients was 35,000/µL (inter-quartile range 28,000, 44,000). Baseline platelet counts of 50,000-100,000/µL [adjusted hazard ratio (HR) = 3.81; 95%CI = 2.07-7.00] and hemoglobin <10 g/dL (adjusted HR = 3.39; 95%CI = 1.45-7.960) associated with severe thrombocytopenia. Major bleeding events during the 48-week observation period were rare (N = 5, 0.51%). CONCLUSIONS: The incidence of severe thrombocytopenia in a large, observational cohort of veteran patients with HCV CLD treated with PEG-IFN plus ribavirin was 6.1%. Low pre-treatment platelet counts and hemoglobin levels associated with early, incident severe thrombocytopenia.

Potassium-competitive acid blockers and acid-related disorders.

PURPOSE OF REVIEW: Potassium-competitive acid blockers (PCABs) represent a new class of compounds for the treatment of acid-related disorders. Recent FDA approval of the PCAB vonoprazan for erosive esophagitis has started an important new approach to acid-related disorders. RECENT FINDINGS: Compared to conventional proton pump inhibitors (PPIs), PCABs provide more rapid, potent, and sustained suppression of gastric acid with faster and more durable symptom relief. Studies have demonstrated the efficacy of PCABs for erosive esophagitis, nonerosive reflux disease, and peptic ulcer disease including H. pylori. However, the PCAB vonoprazan was only approved in the US as part of combination therapy for eradication of H. pylori. Clinical trials have now demonstrated noninferiority of vonoprazan to lansoprazole for treatment of erosive esophagitis, particularly noting superiority of vonoprazan in patients with severe esophagitis resulting in FDA approval of vonoprazan for treatment of erosive esophagitis. Emerging data suggests a possible utility of vonoprazan for PPI-resistant gastroesophageal reflux disease (GERD) and on-demand therapy for nonerosive reflux disease. Vonoprazan is generally well tolerated but long-term safety data is not well established. SUMMARY: The PCAB vonoprazan is a newly FDA approved treatment option for erosive esophagitis. Its possible role in PPI-resistant GERD and nonerosive reflux disease warrants further investigation.

Prognostic factors in clinicopathology of oesophagogastric adenocarcinoma: a single-centre longitudinal study of 347 cases over a 20-year period.

Oesophagogastric adenocarcinoma (EGA) includes oesophageal (EA), gastro-oesophageal junctional (GEJA), and gastric (GA) adenocarcinomas. The prognostic values of clinicopathological factors in these tumours remain obscure, especially for GEJA that has been inconsistently classified and staged. We studied the prognosis of EGA patients among the three geographic groups in 347 consecutive patients with a median age of 70 years (range 47-94). All patients were male, and 97.1% were white. Based on tumour epicentre location, EGAs were sub-grouped into EA (over 2 cm above the GEJ; n=3, 18.1%), GEJA (within 2 cm above and 3 cm below the GEJ; n=231, 66.6%), and GA (over 3 cm below the GEJ; n=53, 15.3%). We found that the median overall survival (OS) was the longest in EA (62.9 months), compared to GEJA (33.4), and GA (38.1) (p<0.001). Significant risk factors for OS included tumour location (p=0.018), size (p<0.001), differentiation (p<0.001), adenocarcinoma subtype (p<0.001), and TNM stage (p<0.001). Independent risk factors for OS comprised low-grade papillary adenocarcinoma [odds ratio (OR) 0.449, 95% confidence interval (CI) 0.214-0.944, p<0.05), mixed adenocarcinoma (OR 1.531, 95% CI 1.056-2.218, p<0.05), adenosquamous carcinoma (OR 2.206, 95% CI 1.087-4.475, p<0.05), N stage (OR 1.505, 95% CI 1.043-2.171, p<0.05), and M stage (OR 10.036, 95% CI 2.519-39.993, p=0.001)]. EGA was further divided into low-risk (common well-moderately differentiated tubular and low-grade papillary adenocarcinomas) and high-risk (uncommon adenocarcinoma subtypes, adenosquamous carcinoma) subgroups. In this grouping, the median OS was significantly longer in the low-risk (83 months) than in the high-risk (10 months) subgroups (p<0.001). In conclusion, the prognosis of EGA patients was significantly better in EA than in GEJA or GA and could be stratified into low and high-risk subgroups with significantly different outcomes.

Thrombocytopenia and bleeding in veterans with non-hepatitis C-related chronic liver disease.

BACKGROUND: Thrombocytopenia in chronic liver disease (CLD) typically reflects disease severity and may indicate an increased risk for bleeding. AIMS: To describe the longitudinal course of thrombocytopenia and risks for bleeding in veteran patients with non-hepatitis C-related CLD. METHODS: We identified 2,349 patients with non-hepatitis C-related CLD from databases of the New England Veterans Healthcare System between 1999 and 2008. The cohort was stratified by baseline platelet counts of <50,000, 50-100,000, > 100,000-150,000, and >150,000/µl. Primary outcomes were the incidence and hazard rates for bleeding episodes requiring hospitalization and incident severe thrombocytopenia (<50,000/µl). RESULTS: Over a median follow-up of 3.3 years (IQR 1.2, 6.3), incident major bleeds, predominantly gastrointestinal, occurred in 254 patients (10.8 % of the cohort) and in 19.9 % of those with baseline platelets <50,000/µl. Incident severe thrombocytopenia occurred in 315 patients (13.4 % of cohort) and in 40.7 % of those with baseline platelet counts between 50,000 and 100,000/µl. Baseline platelet counts between 50,000 and 100,000/µl independently predicted bleeding [adjusted HR 2.89 (1.76, 4.73) p < 0.001] as did esophageal varices, hemoglobin ≤ 9.9 g %, and INR 1.4-2.0. Incident severe thrombocytopenia and minimum platelet counts <25,000/µl each associated with bleeding episodes, but the average of minimum platelet counts recorded for those who bled was 76,000/µl. CONCLUSIONS: Among veteran patients with non-hepatitis C-related CLD, baseline platelet counts of 50,000 to 100,000/µl increased subsequent risks for both incident severe thrombocytopenia and major bleeding events. Whereas associations between severe thrombocytopenia and bleeding most likely reflect CLD severity, liver-related coagulopathies, and co-morbid bleeding risks, interventions to enhance platelet production may be beneficial for such patients.

Biomarkers in gastroenteropancreatic neuroendocrine neoplasms.

PURPOSE OF REVIEW: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) represent a heterogenous group of rare tumors emanating from neuroendocrine cells that are clinically silent for prolonged periods of time without detection. Traditional biomarkers lack sufficiently high enough specificity and sensitivity for these tumors and their secreted products. New molecules are sought to improve accuracy of detection and monitoring of GEP-NENs. The purpose of this review is to highlight recent advances in the discovery of novel biomarkers and their potential characteristics and utility as markers of GEP-NENs. RECENT FINDINGS: Several recent GEP-NEN investigations regarding NETest demonstrate superior sensitivity and specificity in diagnosis and disease monitoring as compared with chromogranin A. Among several tissue-based emergent candidate molecules as biomarkers for GEP-NEN INSM1 has demonstrated consistently excellent characteristics when compared with traditional markers including chromogranin A, synaptophysin, and CD56. SUMMARY: For the diagnosis and clinical monitoring of NEN, there still exists a considerable need for better biomarkers. Novel technology has resulted in a promising liquid biopsy for the detection and monitoring of GEP-NENs. The search for improved tissue biomarkers has resulted in identification of one potential candidate whereas several others remain in the investigatory phase.

Patients with esophageal adenocarcinoma showed better prognosis than those with adenocarcinoma of the gastroesophageal junction.

OBJECTIVES: We followed The Cancer Genome Atlas (TCGA) grouping criteria and conducted a clinicopathological cohort study in a unique patient population to gain insight into the pathobiology of esophageal adenocarcinoma (EAC) and adenocarcinoma of the gastroesophageal junction (AGEJ). METHODS: We studied and statistically compared the clinicopathological and prognostic features of both cancers in 303 consecutive patients treated at the Veterans Affairs Boston Healthcare System over a 20-year period using uniform criteria and standardized routines. RESULTS: Over 99% of patients were white men with a mean age of 69.1 years and an average body mass index (BMI) of 28.0 kg/m2 . No significant differences were detected in age, gender, ethnicity, BMI, and history of tobacco abuse between the two groups. Compared to AGEJ patients, a significantly higher proportion of EAC patients had gastroesophageal reflux disease, long-segment Barrett's esophagus, common adenocarcinoma type, smaller tumor size, better differentiation, more stages I or II but fewer stages III or IV diseases, scarcer lymph node invasion, fewer distant metastases, and better overall, disease-free, and relapse-free survival. The 5-year overall survival rate was significantly higher in EAC patients than in AGEJ patients (41.3% vs 17.2%, P < 0.001). This improved survival among EAC patients remained significant after censoring all cases detected during endoscopic surveillance, suggesting different pathogenesis mechanisms between EAC and AGEJ. CONCLUSIONS: EAC patients showed significantly better outcomes than AGEJ patients. Our results require validation in other patient populations.

Appetite-modifying effects of bombesin receptor subtype-3 agonists.

Studies on bombesin-like peptides (BLP) and their respective mammalian receptors (Bn-r) have demonstrated a significant biological impact on a broad array of physiological and pathophysiological conditions. Pharmacological experiments in vitro and in vivo as well as utilization of genetic rodent models of the gastrin-releasing peptide receptor (GRP-R/BB2-receptor), neuromedin B receptor (NMB-R/BB1-receptor), and the bombesin receptor subtype-3 (BRS-3/BB3-receptor) further delineated their role in health and disease. All three mammalian bombesin receptors have been shown to possess some role in the regulation of energy balance and appetite and satiety. Compelling experimental evidence has accumulated indicating that the orphan BRS-3 is an important regulator of body weight, energy expenditure, and glucose homeostasis. BRS-3 possesses no high affinity to the endogenous bombesin-like peptides (BLP) bombesin, GRP, and NMB, and its endogenous ligand remains unknown. Recently, the synthesis of novel, selective high-affinity BRS-3 agonists and antagonists has been accomplished and has demonstrated that BRS-3 regulates energy balance independent of other established pathways. Accordingly, the availability of new BRS-3 selective agonists and antagonists will facilitate further elucidation of its role in energy homeostasis and provides a potential approach for the pharmacological treatment of obesity.

Irritable bowel syndrome and diet.

PURPOSE OF REVIEW: Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder (FGID) characterized by chronic abdominal pain and altered bowel habits. The diagnosis of IBS is based on the presence of defined clinical Rome IV criteria in the absence of alarm features. The majority of patients with IBS report of food triggers eliciting typical IBS symptoms and trying to modify their dietary intake. RECENT FINDINGS: FGID including IBS are defined as disorders of the gut-brain interaction. A large proportion of individuals with IBS link their symptoms to dietary factors, and recent clinical studies have shown benefits of a diet low in FODMAPs (Fermentable Oligo-, Di-, and Monosaccharides and Polyols) on IBS symptoms and quality of life. Dietary interventions mediate directly changes of luminal gut contents affecting chemosensing-enteroendocrine cells in the modulation of the gut brain microbiome axis in IBS patients. Long-term assessment of clinical outcomes in patients on a low FODMAP diet is needed. Professional guidelines have incorporated the suggestion to offer IBS patients a diet low in FODMAPs. SUMMARY: The FGIDs, including IBS, are defined as gut-brain disorders. Low FODMAP diet has been shown in clinical trials to reduce IBS symptoms but long-term efficacy and nutritional side-effects remain uncertain.

Targeted pharmacotherapy of irritable bowel syndrome.

PURPOSE OF REVIEW: Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal (GI) disorder with negative impact on quality of life and it represents a substantial economic burden on healthcare cost. The medical management of IBS is symptom directed. This review provides an update related to clinical trial data for novel treatment modalities in IBS targeting the gut epithelium secretagogue receptors and channels. RECENT FINDINGS: The new Rome IV criteria define functional gastrointestinal disorders (FGID) as disorders of the gut-brain interaction. Pharmacological treatment modalities for IBS target gastrointestinal receptors and ion channels, peripheral opioid receptor, gut serotonin receptors, and the gut microbiome. New targeted pharmacotherapies have shown efficacy and safety in the treatment of patients with IBS. SUMMARY: Diagnostic criteria for FGID, including IBS, have been revised in Rome IV and are defined as gut-brain disorders. Newly approved pharmacotherapy options with proven efficacy and acceptable side-effect profiles are available for the symptom-based management of IBS.

Irritable bowel syndrome and gut microbiota.

PURPOSE OF REVIEW: To provide an overview of recent studies exploring the gut microbiota in pathogenesis and treatment of irritable bowel syndrome (IBS). RECENT FINDINGS: Primary bacterial gut disturbances have been linked to the development and severity of IBS. Dysbiosis, or alteration in the normal intestinal flora, modulates intestinal permeability, inflammation, gut motility and likely quality of life. These biomechanical changes are associated with enteric and central nervous system processing as well. When compared to healthy controls, IBS patients display poor quality of life measures and are at increased risk of depression and anxiety. The severity of psychological and gastrointestinal symptoms in IBS has been linked with a distinct intestinal microbiota signature. Efforts to modulate intestinal dysbiosis in IBS have shown little improvement in large systematic reviews. The low FODMAP diet reduces bacteria, such as Bifidobacterum and Actinobacteria. Although rifaximin improves symptoms, it may only stimulate a transient effect on the gut microbiota. Fecal microbiota transplant does not provide prolonged symptom relief in IBS. SUMMARY: This review elucidates recent advances in IBS and the gut microbiota. Microbiota changes are one underlying factor in perpetuating global IBS symptoms. The opportunity to exploit this disturbance through treatment modalities requires further investigation.

Transcription factor YY1 expression in human gastrointestinal cancer cells.

Over-expression of the multifunctional zinc-finger transcription factor Yin Yang 1 (YY1) has been associated with cellular proliferation and resistance to apoptotic stimuli. In this study, we report that YY1 was uniformly highly over-expressed in a wide range of human cancer cell lines and in human colon cancer tissue samples. The examination of YY1-specific mRNA expression demonstrated at least six mRNA isoforms ubiquitously expressed in normal human adult and fetal tissues. Substantial over-expression of two specific mRNA isoforms of 7.5 and 2.9 kb size, respectively, was detected in gastrointestinal and other cancer cells in vitro, whereby mRNA stability differed significantly between various cell lines. YY1 protein expression levels were similar in different colon cancer cell lines. Using FISH analysis of several colorectal cancer cell lines, the human YY1 locus was expectedly identified on chromosome 14q32 and no evidence of gene amplification and chromosomal translocation was observed. However, varying degree of aneuploidy was noted in vitro. YY1 immunoreactivity in human colon tumor samples was found more intense in poorly differentiated tumors than in moderately and well differentiated colon cancers and lower expression levels tended to be associated with shorter survival. In conclusion, YY1 was over-expressed in colon cancer in the absence of gene amplification and chromosomal translocation. YY1 mRNA and protein stability are important regulatory mechanisms of YY1 expression in colon cancer.

PPARalpha and AP-2alpha regulate bombesin receptor subtype 3 expression in ozone-stressed bronchial epithelial cells.

Previously, we found that bombesin receptor subtype 3 (BRS-3) significantly increased in an ozone-stressed airway hyperresponsiveness animal model and resulted in induced wound repair and protection from acute lung injury. In the present study, we determined molecular mechanisms of BRS-3 regulation in human BECs (bronchial epithelial cells) in response to ozone stress. Ten oligonucleotide probes corresponding to various regions of the BRS-3 promoter were used in EMSA (electrophoretic mobilityshift assays). Four were found to have an enhanced mobility shift with extracts from ozone-stressed cells. On the basis of the assay of mutated probes binding with extracts and antibody supershift, they were verified as MTF-1 (metal-regulatory-element-binding transcription factor-1), PPARalpha (peroxisome-proliferator-activated receptor alpha), AP-2alpha (activator protein 2alpha) and HSF-1 (heat-shock factor 1). Next, ChIP (chromatin immunoprecipitation) assay, site-directed mutagenesis technology and antisense oligonucleotide technology were used to observe these transcription factors associated with the BRS-3 promoter. Only AP-2alpha and PPARalpha increased ozone-inducible DNA binding on the BRS-3 promoter and BRS-3 expression. The time courses of AP-2alpha and PPARalpha activation, followed by BRS-3 expression, were also examined. It was shown that ozone-inducible BRS-3 expression and AP-2alpha- and PPARalpha-binding activity correlated over a 48 h period. The translocation of PPARalpha was observed by immunofluorescence assay, which showed that PPARalpha nuclear translocation increased after ozone exposure. Our data suggest that AP-2alpha and PPARalpha may be especially involved in this ozone-inducible up-regulation mechanism of BRS-3 expression.

Updates on the biology of serotonin and tryptophan hydroxylase.

PURPOSE OF REVIEW: To summarize the most recent findings relevant to the biology of serotonin (5-hydroxytryptamine; 5-HT) and the enzyme tryptophan hydroxylase (TPH) in human gastrointestinal disease. RECENT FINDINGS: Serotonin is synthesized in the central nervous system (CNS) and the gastrointestinal tract where it is secreted from enteroendocrine cells. Its biosynthesis is regulated by two isoforms of the enzyme TPH of which TPH1 is localized predominantly in gastrointestinal enteroendocrine cells. Serotonin activates the peristaltic reflexes, regulates gastrointestinal motility, and has a role in intestinal inflammation. Inhibition of TPH with novel molecules represents a new pharmacological tool in the successful management of carcinoid syndrome in patients with gastrointestinal neuroendocrine tumors (GI-NETs). Certain 5-HT receptor subtype agonists and antagonists are useful in the treatment of functional gastrointestinal disorders. SUMMARY: The gastrointestinal tract is the largest storage organ for serotonin where its biosynthesis is regulated by TPH1. It has several important functions in gastrointestinal motility, secretion, and inflammation. Furthermore, TPH represents a target for inhibitory pharmacological therapy of serotonin access states such as the carcinoid syndrome.

New treatment options for irritable bowel syndrome with predominant diarrhea.

PURPOSE OF REVIEW: Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder with negative impact on quality of life and it represents a substantial economic burden on healthcare cost. The medical management of IBS remains largely symptomatic. This review provides an update related to the most recently published diagnostic Rome IV criteria for IBS and clinical trial data for novel treatment modalities in IBS targeting the peripheral opioid receptors of the enteric nervous system and the gut microbiota. RECENT FINDINGS: The new Rome IV criteria define functional gastrointestinal disorders as disorders of the gut-brain interaction. In addition to previously introduced pharmacological treatment modalities for IBS with constipation (IBS-C) with synthetic peptides and small molecules targeting gastrointestinal receptors and ion channels, the newly Food and Drug Administration-approved mixed peripheral opioid receptor agonist/antagonist eluxadoline and the nonabsorbable antibiotic rifaximin demonstrate efficacy and safety in the treatment of IBS with predominant diarrhea (IBS-D). SUMMARY: Diagnostic criteria for functional gastrointestinal disorders, including IBS, have been revised in Rome IV and are defined as gut-brain disorders. The mixed peripheral opioid receptor agonist/antagonist eluxadoline and the antibiotic rifaximin have been recently Food and Drug Administration approved for the treatment of diarrhea-predominant IBS (IBS-D) with proven efficacy and acceptable side-effect profiles.

Opioid-induced constipation in chronic noncancer pain.

PURPOSE OF REVIEW: Opioid-based management of noncancer pain has become much more prevalent over the last 2 decades and is responsible for a wide range of side-effects, particularly affecting the intestinal tract causing opioid-induced constipation (OIC). This review will consider results of recent clinical trials that have provided evidence of new pharmacological management options for the treatment of OIC. RECENT FINDINGS: Supportive use of conventional agents, such as stool softeners, osmotic laxatives, and stimulating laxatives in OIC has limited efficacy. The peripheral µ-opioid receptor antagonist (PAMORA) methylnaltrexone (MNTX) was first FDA approved for OIC in patients with advanced illness and later also for OIC in noncancer pain patients; clinical trial results indicated MNTX did not reverse opioid analgesia and did not trigger central opioid withdrawal. Another PAMORA, the orally available naloxegol, has also gained recent FDA approval for the treatment of OIC in adults with chronic, noncancer pain. Lubiprostone, a bicyclical fatty acid acting via activation of intestinal chloride channel-2 (ClC-2), was also approved for OIC treatment in patients with noncancer pain. SUMMARY: PAMORA MNTX and naloxegol and the intestinal chloride channel-2 (ClC-2) activator lubiprostone represent additional possible therapeutic options for the management of OIC in patients with chronic noncancer pain.