Mesenchymal Stem/Stromal Cell Therapy Is More Cost-Effective Than Fecal Diversion for Treatment of Perianal Crohn's Disease Fistulas.

Crohn's disease (CD) is an inflammatory bowel disease with increasing incidence and prevalence worldwide. Perianal fistulas are seen in up to 26% of CD patients and are often refractory to medical therapy. Current treatments for CD perianal fistulas (pCD) include antibiotics, biologics, and for refractory cases, fecal diversion (FD) with ileostomy or colostomy. Mesenchymal stem/stromal cell therapy (MSCs) is a new modality that have shown efficacy in treating pCD. MSCs locally injected into pCD can lead to healing, and a phase III clinical trial (ADMIRE-CD) showed 66% clinical response, leading to approval of MSCs (Alofisel, Takeda) in the European Union. It is unclear if MSCs would be more cost-effective than the current standard of FD. We therefore developed a decision tree model to determine the cost-effectiveness of MSCs compared to FD for pCD. Our study showed that both autologous and allogeneic MSCs are more cost-effective than FD in an academic medical center and even in a worst-case scenario with 100% chance of all complications for MSCs treatment and 0% chance of complications for FD, both allogeneic and autologous MSCs are still cost saving compared to FD.

Efficacy and Safety of Mesenchymal Stem/Stromal Cell Therapy for Inflammatory Bowel Diseases: An Up-to-Date Systematic Review.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gut that can lead to severe gastrointestinal symptoms, malnutrition, and complications such as fistulas and cancer. Mesenchymal stem/stromal cells (MSCs) are being investigated as a novel therapy for IBD and have been demonstrated to be safe and effective for perianal fistulizing Crohn's disease (PFCD). This systematic review aims to present the most recent studies on the safety and efficacy of MSC therapy in IBD. A detailed search strategy of clinical trials on MSCs and IBD was performed on PubMed, with 32 studies selected for inclusion in this review. The newest studies on local MSC injection for PFCD continue to support long-term efficacy while maintaining a favorable safety profile. The evidence for systemic MSC infusion in luminal IBD remains mixed due to marked methodological heterogeneity and unclear safety profiles. Although further studies are needed to better establish the role of this novel treatment modality, MSCs are proving to be a very exciting addition to the limited therapies available for IBD.

Breath Test Gas Patterns in Inflammatory Bowel Disease with Concomitant Irritable Bowel Syndrome-Like Symptoms: A Controlled Large-Scale Database Linkage Analysis.

INTRODUCTION: Breath testing (BT) has gained interest for diagnosing small intestinal bacterial overgrowth (SIBO) in IBD patients with irritable bowel syndrome (IBS) overlap. We aim to characterize the rate of SIBO and BT gas patterns in IBD patients with IBS-like symptoms compared to non-IBD patients. METHODS: A database of 14,847 consecutive lactulose BTs was developed from patients with IBS-like symptoms between November 2005 and October 2013. BTs were classified as normal, H2 predominant, CH4 predominant, and flatline based on criteria established from the literature. BT data linkage with electronic health records and chart review identified IBD patients along with disease phenotype, location, severity, and antibiotic response. Poisson loglinear model evaluated differences in gas patterns between the two groups. RESULTS: After excluding patients with repeat breath tests, we identified 486 IBD and 10,505 non-IBD patients with at least one BT. Positive BT was present in 57% (n = 264) of IBD patients. Crohn's disease (odds ratio (OR) 0.21, [95% confidence interval (CI) 0.11-0.38]) and ulcerative colitis (OR 0.39, [95% CI 0.22-0.70]) patients were less likely to produce excess CH4. IBD patients were more likely to have flatline BT (OR 1.82, [95% CI 1.20-2.77]). In IBD patients with SIBO, 57% improved symptomatically with antibiotics. CONCLUSION: In a cohort of IBD patients with IBS-like symptoms, a high rate of patients had positive BT and symptomatic improvement with antibiotics. In IBD, methanogenesis is suppressed and flatline BT is more frequent, suggesting excess hydrogenotrophic bacteria. These findings suggest methanogenic and hydrogenotrophic microorganisms as potential targets for microbiome-driven biomarkers and therapies.

Comparing the Real-World Effectiveness of Competing Colonoscopy Preparations: Results of a Prospective Trial.

OBJECTIVES: National societies provide little guidance regarding which colonoscopy bowel preps are best tolerated and most effective; this reflects a lack of comparative effectiveness studies that directly evaluate the available preps in a "real-world" setting. To address this gap, we conducted a prospective, commercially unfunded comparative effectiveness study of currently available bowel preps and measured their impact on bowel cleansing. METHODS: We included patients aged ≥18 years, who presented for an outpatient colonoscopy at a large medical center serving more than 70 academic and community-based endoscopists who are free to prescribe the bowel prep of their choice. The primary outcome was bowel cleansing quality as measured by the Boston Bowel Preparation Scale. We performed regression models with random effects on the outcomes to adjust for confounding. RESULTS: Approximately 4,339 colonoscopies were performed by 75 endoscopists. Magnesium citrate, MiraLAX with Gatorade, MoviPrep, OsmoPrep, Prepopik/Clenpiq, and Suprep all had significantly higher prep tolerability compared with GoLYTELY (all P < 0.05). For bowel cleansing, Suprep (7.28 ± 1.66; P < 0.001), MoviPrep (7.11 ± 1.62; P = 0.004), and MiraLAX with Gatorade (7.09 ± 1.64; P < 0.001) had higher total Boston Bowel Preparation Scale scores compared with GoLYTELY (6.67 ± 1.87); there were no significant differences among the remaining preps. Split-prep dosing was associated with better cleansing; however, men, opioid and tricyclic antidepressent users, and patients with diabetes and cirrhosis had worse cleansing (all P < 0.05). CONCLUSIONS: In this prospective, real-world comparative effectiveness study of available bowel preps, we found that MiraLAX with Gatorade, MoviPrep, and Suprep were prospectively associated with superior tolerability and bowel cleansing.

Correction: Validation of near infrared fluorescence (NIRF) probes in vivo with dual laser NIRF endoscope.

[This corrects the article DOI: 10.1371/journal.pone.0206568.].

Electronic patient agenda forms: comparing agreement between the reason for specialty consultation reported by referring providers and patients.

OBJECTIVE: Little is known about the agreement between referring providers' reason for specialty evaluation and patients' understanding of why they are referred for consultation. Here, we compared the reason for consult (RFC) documented by referring providers during usual care vs. the perceived RFC independently reported by patients through an e-portal just prior to the specialist visit. METHODS: We performed an observational study among patients referred for gastrointestinal (GI) evaluation. Patients referred to the specialty clinic submitted their self-reported RFC using an online patient agenda form prior to their visit. Therefore, each participant had a referring provider- and patient-documented RFC. Blinded physicians reviewed the RFCs in random order using a priori coding criteria. We then compared whether the provider and patient RFC pairs were concordant (i.e., ≥1 clinical topic[s] in the RFCs matched). RESULTS: Sixty patients completed the e-portal prior to their visit, leading to 60 provider-patient RFC pairs. The RFC pairs were concordant in only 52% of cases. CONCLUSIONS: There is poor agreement between referring providers' reason for GI referral and patients' understanding of why they are visiting the clinic. Future research examining whether electronic patient agenda forms impact diagnostic and management precision, patient satisfaction, and healthcare utilization is warranted.

Validation of near infrared fluorescence (NIRF) probes in vivo with dual laser NIRF endoscope.

PURPOSE: The development of NIRF cathepsin activity probes offered the ability to visualize tumor associated tumor reaction and act as a surrogate marker to delineate the dysplastic lesions. One major type is a NIRF substrate of cathepsins (SBP), which is involved in catalytic way to produce high levels of fluorescence emission. The other major type (ABP) reacts with active cathepsins in stoichiometric manner since they bind covalently with their active center. Little is known about the sensitivity and the specificity of the NIRF probes to detect autochthonous developed dysplastic lesions. Dual laser NIRF endoscope provides a good tool to determine the efficiency of various NIRF probes in vivo in the same lesions. EXPERIMENTAL DESIGN: In the current study, we validated both types of NIRF probes by using the dual laser NIRF endoscope to detect lesions colon cancer mouse model (TS4Cre/cAPC +/lox). RESULTS: The dual laser NIRF endoscope is emitting equal power with both lasers. It can detect with the same efficiency in 680 mode, as well as, 750 mode when NIFR probes of the same scaffold in vivo. When SBP and ABP were used, our results showed both probes are efficient enough to detect large polyps but small dysplastic lesions could not efficiently imaged with the ABP. CONCLUSIONS: The dual laser NIRF endoscope is a powerful tool to validate probes. The probes that react catalytically with the active center of cathepsins are more efficient than the ones that react stoichiometrically in detecting small lesions.

TLR4 activates the ß-catenin pathway to cause intestinal neoplasia.

Colonic bacteria have been implicated in the development of colon cancer. We have previously demonstrated that toll-like receptor 4 (TLR4), the receptor for bacterial lipopolysaccharide (LPS), is over-expressed in humans with colitis-associated cancer. Genetic epidemiologic data support a role for TLR4 in sporadic colorectal cancer (CRC) as well, with over-expression favoring more aggressive disease. The goal of our study was to determine whether TLR4 played a role as a tumor promoter in sporadic colon cancer. Using immunofluorescence directed to TLR4, we found that a third of sporadic human colorectal cancers over-express this marker. To mechanistically investigate this observation, we used a mouse model that over-expresses TLR4 in the intestinal epithelium (villin-TLR4 mice). We found that these transgenic mice had increased epithelial proliferation as measured by BrdU labeling, longer colonic crypts and an expansion of Lgr5+ crypt cells at baseline. In addition, villin-TLR4 mice developed spontaneous duodenal dysplasia with age, a feature that is not seen in any wild-type (WT) mice. To model human sporadic CRC, we administered the genotoxic agent azoxymethane (AOM) to villin-TLR4 and WT mice. We found that villin-TLR4 mice showed an increased number of colonic tumors compared to WT mice as well as increased ß-catenin activation in non-dysplastic areas. Biochemical studies in colonic epithelial cell lines revealed that TLR4 activates ß-catenin in a PI3K-dependent manner, increasing phosphorylation of ß-catenin(Ser552), a phenomenon associated with activation of the canonical Wnt pathway. Our results suggest that TLR4 can trigger a neoplastic program through activation of the Wnt/ß-catenin pathway. Our studies highlight a previously unexplored link between innate immune signaling and activation of oncogenic pathways, which may be targeted to prevent or treat CRC.