Standard of Care Versus Octreotide in Angiodysplasia-Related Bleeding (the OCEAN Study): A Multicenter Randomized Controlled Trial.

BACKGROUND & AIMS: Gastrointestinal angiodysplasias are vascular anomalies that may result in transfusion-dependent anemia despite endoscopic therapy. An individual patient data meta-analysis of cohort studies suggests that octreotide decreases rebleeding rates, but component studies possessed a high risk of bias. We investigated the efficacy of octreotide in reducing the transfusion requirements of patients with angiodysplasia-related anemia in a clinical trial setting. METHODS: The study was designed as a multicenter, open-label, randomized controlled trial. Patients with angiodysplasia bleeding were required to have had at least 4 red blood cell (RBC) units or parental iron infusions, or both, in the year preceding randomization. Patients were allocated (1:1) to 40-mg octreotide long-acting release intramuscular every 28 days or standard of care, including endoscopic therapy. The treatment duration was 1 year. The primary outcome was the mean difference in the number of transfusion units (RBC + parental iron) between the octreotide and standard of care groups. Patients who received at least 1 octreotide injection or followed standard of care for at least 1 month were included in the intention-to-treat analyses. Analyses of covariance were used to adjust for baseline transfusion requirements and incomplete follow-up. RESULTS: We enrolled 62 patients (mean age, 72 years; 32 men) from 17 Dutch hospitals in the octreotide (n = 31) and standard of care (n = 31) groups. Patients required a mean number of 20.3 (standard deviation, 15.6) transfusion units and 2.4 (standard deviation, 2.0) endoscopic procedures in the year before enrollment. The total number of transfusions was lower with octreotide (11.0; 95% confidence interval [CI], 5.5-16.5) compared with standard of care (21.2; 95% CI, 15.7-26.7). Octreotide reduced the mean number of transfusion units by 10.2 (95% CI, 2.4-18.1; P = .012). Octreotide reduced the annual volume of endoscopic procedures by 0.9 (95% CI, 0.3-1.5). CONCLUSIONS: Octreotide effectively reduces transfusion requirements and the need for endoscopic therapy in patients with angiodysplasia-related anemia. CLINICALTRIALS: gov, NCT02384122.

Research progress of colon-targeted oral hydrogel system based on natural polysaccharides.

The quality of life is significantly impacted by colon-related diseases. There have been a lot of interest in the oral colon-specific drug delivery system (OCDDS) as a potential carrier to decrease systemic side effects and protect drugs from degradation in the upper gastrointestinal tract (GIT). Hydrogels are effective oral colon-targeted drug delivery carriers due to their high biodegradability, substantial drug loading, and great biocompatibility. Natural polysaccharides give the hydrogel system unique structure and function to effectively respond to the complex environment of the GIT and deliver drugs to the colon. In this paper, the physiological factors of colonic drug delivery and the pathological characteristics of common colonic diseases are summarized, and the latest advances in the design, preparation and characterization of natural polysaccharide hydrogels are reviewed, which are expected to provide new references for colon-targeted oral hydrogel systems using natural polysaccharides as raw materials.

Therapeutic targeting of the oncogenic Wnt signaling pathway for treating colorectal cancer and other colonic disorders.

The canonical Wnt pathway is one of the key cellular signaling cascades that regulates, via the transcriptional co-activator ß-catenin, numerous embryogenic developmental processes, as well as tissue homeostasis. It is therefore not surprising that misregulation of the Wnt/ß-catenin pathway has been implicated in carcinogenesis. Aberrant Wnt signaling has been reported in a variety of malignancies, and its role in both hereditary and sporadic colorectal cancer (CRC), has been the subject of intensive study. Interestingly, the vast majority of colorectal tumors harbor mutations in the tumor suppressor gene adenomatous polyposis coli (APC). The Wnt pathway is complex, and despite decades of research, the mechanisms that underlie its functions are not completely known. Thus, although the Wnt cascade is an attractive target for therapeutic intervention against CRC, one of the malignancies with the highest morbidity and mortality rates, achieving efficacy and safety is yet extremely challenging. Here, we review the current knowledge of the Wnt different epistatic signaling components and the mechanism/s by which the signal is transduced in both health and disease, focusing on CRC. We address some of the important questions in the field and describe various therapeutic strategies designed to combat unregulated Wnt signaling, the development of targeted therapy approaches and the emerging challenges that are associated with these advanced methods.

Therapeutic Opportunities for Intestinal Angioectasia- Targeting PPARγ and Oxidative Stress.

Recurrent and acute bleeding from intestinal tract angioectasia (AEC) presents a major challenge for clinical intervention. Current treatments are empiric, with frequent poor clinical outcomes. Improvements in understanding the pathophysiology of these lesions will help guide treatment. Using data from the US Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS), we analyzed 12 million patient reports to identify drugs inversely correlated with gastrointestinal bleeding and potentially limiting AEC severity. FAERS analysis revealed that drugs used in patients with diabetes and those targeting PPARγ-related mechanisms were associated with decreased AEC phenotypes (P < 0.0001). Electronic health records (EHRs) at University of Cincinnati Hospital were analyzed to validate FAERS analysis. EHR data showed a 5.6% decrease in risk of AEC and associated phenotypes in patients on PPARγ agonists. Murine knockout models of AEC phenotypes were used to construct a gene-regulatory network of candidate drug targets and pathways, which revealed that wound healing, vasculature development and regulation of oxidative stress were impacted in AEC pathophysiology. Human colonic tissue was examined for expression differences across key pathway proteins, PPARγ, HIF1α, VEGF, and TGFß1. In vitro analysis of human AEC tissues showed lower expression of PPARγ and TGFß1 compared with controls (0.55 ± 0.07 and 0.49 ± 0.05). National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) RNA-Seq data was analyzed to substantiate human tissue findings. This integrative discovery approach showing altered expression of key genes involved in oxidative stress and injury repair mechanisms presents novel insight into AEC etiology, which will improve targeted mechanistic studies and more optimal medical therapy for AEC.

A Case of Kawasaki Disease with Intussusception.

Kawasaki disease (KD) is a systemic vasculitis of unknown cause and is associated with various digestive disorders, although only a few cases of intussusception associated with KD have been reported. We describe a case of intussusception followed by KD in a 3-year-old boy. The patient was admitted to our hospital for evaluation of severe abdominal pain. Because the target sign was seen on ultrasonography, intussusception was diagnosed and hydrostatic reduction was performed. On the second day after admission, he developed a high fever (38°C) and an irregular rash over his whole body. On the fourth day after admission, the high fever continued, and bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, strawberry tongue, indurated edema of the dorsa of the hands and feet, and diffuse erythema of the palms and soles appeared, and KD was ultimately diagnosed. He was treated with intravenous immunoglobulin 2 g/kg, aspirin 30 mg/kg/day, and prednisolone 2 mg/kg/day. The high fever and other clinical symptoms resolved immediately after the start of treatment. There was no relapse of KD symptoms after initial treatment, and periungual desquamation was observed on the 10th day after admission. He was discharged on the 15th day, without abnormalities such as coronary dilatation, 3 months after the onset of KD symptoms. Patients with intussusception and KD were older (≥3 years vs <3 years) than those with intussusception alone. In addition, the site of intussusception in KD was mainly colonic rather than ileocolic. If intussusception precedes development of the characteristic clinical symptoms of KD, diagnosis of KD may be delayed. KD should be considered in children older than 3 years with intussusception at a colonic site.

Early Combined Immunosuppression May Be More Effective for Reducing Complications in Isolated Colonic- vs Ileal-Dominant Crohn Disease.

BACKGROUND: We assessed whether differential efficacy of early combined immunosuppression (ECI) in comparison with conventional management (CM) is present in patients with Crohn disease (CD) according to disease location. METHODS: In this posthoc analysis of the Randomized Evaluation of an Algorithm for Crohn's Treatment trial, the effect of ECI vs CM modified by disease location (isolated-colonic vs ileal-dominant) in terms of time to first complication (hospitalization, surgery, or disease-related complications-presence of a new abscess, fistula, or stricture; serious worsening of disease activity; extraintestinal manifestations) was analyzed using a marginal Cox proportional hazard model to account for cluster randomization. Factors adjusted included practice size, country, and other covariates selected in a backward logistic regression analysis with the first composition as outcome and P < 0.10. RESULTS: Of the 1969 patients with CD, 435 had isolated colonic CD (ECI n = 257, CM n = 178) and 1534 had ileal CD (ECI n = 817, CM n = 717). Over 24 months there was a significant differential impact for ECI vs CM for reducing the risk of a CD-related complication between patients with colonic CD and ileal CD (colonic CD hazard ratio [HR] = 0.51; 95% CI, 0.30-0.85 vs ileal CD HR = 0.79; 95% CI, 0.57-1.10; P = 0.033). No difference was identified between ECI vs CM for reducing the risk of surgery (colonic HR = 0.52 vs ileal HR = 0.74; P = 0.468) or hospitalization (colonic HR = 0.77 vs ileal HR = 0.83; P = 0.806). CONCLUSIONS: In this posthoc analysis of the Randomized Evaluation of an Algorithm for Crohn's Treatment trial, symptom-based ECI was associated with greater efficacy for reducing the risk of CD-related complications in patients with colonic disease location relative to ileal disease location.

Oral delivery of self-assembling bioactive peptides to target gastrointestinal tract disease.

Peptides are known for their diverse bioactivities including antioxidant, antimicrobial, and anticancer activity, all three of which are potentially useful in treating colon-associated diseases. Beside their capability to stimulate positive health effects once released in the body, peptides are able to form useful nanostructures such as hydrogels. Combining peptide bioactivity and peptide gel-forming potentials can create interesting systems that can be used for oral delivery. This combination, acting as a two-in-one system, has the potential to avoid the need for delicate entrapment of a drug or natural bioactive compound. We here review the context and research progress, to date, in this area.

Effects of Sphingolipid Fractions from Golden Oyster Mushroom (Pleurotus citrinopileatus) on Apoptosis Induced by Inflammatory Stress in an Intestinal Tract in vitro Model.

Previously, we reported that the polar lipid fraction from the golden oyster mushroom, Pleurotus citrinopileatus, suppresses colon injuries which result from apoptosis induced by inflammatory stresses in vivo and in vitro (Yamashita et al., J. Oleo Sci., 69, 751-757 (2020)). Here, we investigated the use of lipid classes in mushroom polar lipid fraction in alleviating colon injury using differentiated Caco-2 cells as an intestinal tract model. The mushroom polar lipid fraction was separated into four fractions using silica thin layer chromatography. Each mushroom polar lipid fraction suppressed lipopolysaccharide (LPS)-induced decreases in the viability of intestinal cells, and the effects of sphingolipid fractions were significantly stronger than those of fraction that did not contain sphingolipids. Addition of sphingolipid fractions suppressed the expression of apoptosis-related proteins (e.g., death receptors and caspases) in the LPS-treated cells. Mushroom polar lipids, especially sphingolipids suppress intestinal apoptosis induced by inflammatory stress, and highly polar sphingolipids may exert stronger suppressive effects.

Hodkgin lymphoma concomitant of tuberculosis, a therapeutic challenge for multidisciplinary management.

Hodgkin lymphoma (HL) is a disease characterized by a high curability rate, and the treatment benefit-risk balance must be carefully addressed to achieve complete disease control with low risk of long-term toxicities. Most patients are treated with a combination of chemotherapy and radiotherapy, after disease staging and response to treatment evaluated by FDG PET/CT. We report the case of a 28-year-old patient concomitantly diagnosed of a Hodgkin lymphoma and active tuberculosis. Initial staging was difficult due to pulmonary and abdominal tuberculosis localization that induced FDG PET/CT hypermetabolism. Anti-tuberculosis treatment was first started, allowing secondary an early accurate Hodgkin lymphoma staging by FDG PET/CT. The patient was then treated by chemotherapy and radiotherapy. Helical TomoTherapy® was used with involved site (IS) irradiation volume was performed to decrease the high doses to organs-at-risk (OAR), especially lungs in this context of tuberculosis.

The Effect of Carbazochrome Sodium Sulfonate in Patients with Colonic Diverticular Bleeding: Propensity Score Matching Analyses Using a Nationwide Inpatient Database.

Objective Carbazochrome sodium sulfonate (CSS) has been routinely used to treat bleeding; however, no study has examined the effect of CSS for gastrointestinal bleeding. Therefore, we aimed to investigate the effect of CSS for colonic diverticular bleeding. Methods We performed a nationwide observational study using the Japanese Diagnosis Procedure Combination inpatient database. We identified patients who were admitted for diverticular bleeding from July 2010 to March 2018. Patients who received CSS on the day of admission were defined as the CSS group, and those not receiving CSS were defined as the control group. The primary outcome was in-hospital mortality. Secondary outcomes were length of stay, total costs, and blood transfusion within 7 days of admission. Propensity score matching analyses were performed to compare outcomes between the two groups. Results A total of 59,965 patients met our eligibility criteria. Of these, 14,437 (24%) patients received CSS on the day of admission. One-to-one propensity score matching created 14,379 matched pairs. There was no significant difference in the in-hospital mortality between the CSS and control groups (0.6% vs. 0.5%, respectively; odds ratio: 0.96; 95% confidence interval: 0.72-1.29). The length of stay was longer in the CSS group than in the control group (11.4 vs. 11.0 days, respectively; difference: 0.44; 95% confidence interval: 0.14-0.73). There were no significant differences in the total costs or the proportion of patients receiving blood transfusion between the groups. Conclusions CSS may not reduce in-hospital mortality, length of stay, total costs, or the need for blood transfusion in patients with colonic diverticular bleeding.

Advances in colon-targeted nano-drug delivery systems: challenges and solutions.

Nano-drug delivery systems (NDDS) for colon-targeted drug delivery are an active area of research on local diseases affecting the colon, such as ulcerative colitis, Crohn's disease, colon cancer, and for the delivery of peptide or protein drugs and vaccinations. In particular, targeted nano-drug delivery to the colon is advantageous for colon-specific diseases because nanoparticles can accumulate in diseased parts, improve the efficacies of therapeutics, and enable localized treatments, which reduces systemic toxicity. However, there are many hurdles, such as burst drug release, enzyme and acidic degradation of drug and carrier in the stomach, pH variations, mucus entrapment, and systemic uptake in the upper small intestine, which could challenge and compromise the successful delivery of NDDS to the colon. With advancements in NDDS, it may be possible to overcome these challenges leading to efficient drug delivery for colon-specific disorders. This review describes a few of the potential colon-specific drug delivery areas and the challenges faced by colon-targeted orally administered delivery systems, and provides an updated summary of recent advances in the development of orally administered NDDS for colon targeting, and the future advances in this research.

Slug and Snail have differential effects in directing colonic epithelial wound healing and partially mediate the restitutive effects of butyrate.

Restitution of wounds in colonic epithelium is essential in the maintenance of health. Microbial products, such as the short-chain fatty acid butyrate, can have positive effects on wound healing. We used an in vitro model of T84 colonic epithelial cells to determine if the Snail genes Slug (SNAI2) and Snail (SNAI1), implemented in keratinocyte monolayer healing, are involved in butyrate-enhanced colonic epithelial wound healing. Using shRNA-mediated Slug/Snail knockdown, we found that knockdown of Slug (Slug-KD), but not Snail (Snail-KD), impairs wound healing in scratch assays with and without butyrate. Slug and Snail had differential effects on T84 monolayer barrier integrity, measured by transepithelial resistance, as Snail-KD impaired the barrier (with or without butyrate), whereas Slug-KD enhanced the barrier, again with or without butyrate. Targeted transcriptional analysis demonstrated differential expression of several tight junction genes, as well as focal adhesion genes. This included altered regulation of Annexin A2 and ITGB1 in Slug-KD, which was reflected in confocal microscopy, showing increased accumulation of B1-integrin protein in Slug-KD cells, which was previously shown to impair wound healing. Transcriptional analysis also indicated altered expression of genes associated with epithelial terminal differentiation, such that Slug-KD cells skewed toward overexpression of secretory cell pathway-associated genes. This included trefoil factors TFF1 and TFF3, which were expressed at lower than control levels in Snail-KD cells. Since TFFs can enhance the barrier in epithelial cells, this points to a potential mechanism of differential modulation by Snail genes. Although Snail genes are crucial in epithelial wound restitution, butyrate responses are mediated by other pathways as well.NEW & NOTEWORTHY Although butyrate can promote colonic mucosal healing, not all of its downstream pathways are understood. We show that the Snail genes Snail and Slug are mediators of butyrate responses. Furthermore, these genes, and Slug in particular, are necessary for efficient restitution of wounds and barriers in T84 epithelial cells even in the absence of butyrate. These effects are achieved in part through effects on regulation of ß1 integrin and cellular differentiation state.

Walnut phenolic extract inhibits nuclear factor kappaB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice.

PURPOSE: Walnuts (Juglans regia) are known to have anti-cancer and immunomodulatory effects. However, little information is available on the effects of walnut phenolic extract (WPE) on intestinal inflammation and colitis-associated colon cancer. METHODS: COLO205 cells were pretreated with WPE and then stimulated with tumor necrosis factor (TNF)-α. In the acute colitis model, wild type mice (C57BL/6) were administered 4% dextran sulfate sodium (DSS) for 5 days. In the chronic colitis model, interleukin (IL)-10-/- mice were administered with either the vehicle or WPE (20 mg/kg) by oral gavage daily for 2 weeks. In an inflammation-associated tumor model, wild type mice were administered a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption. RESULTS: WPE significantly inhibited IL-8 and IL-1α expression in COLO205 cells. WPE attenuated both the TNF-α-induced IκB phosphorylation/degradation and NF-κB DNA binding activity. The administration of oral WPE significantly reduced the severity of colitis in both acute and chronic colitis models, including the IL-10-/- mice. In immunohistochemical staining, WPE attenuated NF-κB signaling in the colons of both colitis models. Finally, WPE also significantly reduced tumor development in a murine model of colitis-associated colon cancer (CAC). CONCLUSIONS: WPE ameliorates acute and chronic colitis and CAC in mice, suggesting that WPE may have potentials for the treatment of inflammatory bowel disease.

Budesonide MMX Is Effective in Patients Having Persistent Symptoms and Raised Fecal Calprotectin Following Treatments for Diverticular Disease.

BACKGROUND AND AIM: Although rifaximin and mesalazine seem to be effective in treating the majority of people suffering from diverticular disease (DD), some patients still experience symptoms following those treatments. The aim of this study was to assess the efficacy of budesonide MMXTM in managing symptoms and raised fecal calprotectin (FC) in patients with endoscopic diagnosis of DD and not responding to standard treatments. METHODS: We performed a post-hoc analysis of the patients enrolled in the DICA prospective study. All patients were at the first diagnosis of DD, scored according to DICA classification. We assessed abdominal pain, meteorism, constipation and diarrhea (scored from 0 to 10) and FC expression at baseline and after six months. Patients were treated with budesonide MMXTM for 4 weeks (9 mg/day for 2 weeks, followed by 9 mg every other day for further 2 weeks), followed by mesalazine 2.4 grams/day for further 5 months. RESULTS: We studied 24 patients (18 females and 6 males, median age 64, inter quartile range (IQR): 57.5- 73.5), previously treated with mesalazine and/or rifaximin (equally subdivided between DICA 2 and DICA 3). At 6-month follow-up, a significant reduction of all symptoms assessed was observed (abdominal pain and meteorism: p<0.001; constipation: p=0.007; diarrhea: p=0.009). Median (IQR) FC level was 244.5 (171.5- 322.0) µg/g at baseline and 51.0 (IQR: 35.5-61.5) µg/g (p< 0.001) after 6 months. No side effects were recorded. CONCLUSIONS: Treatment with budesonide MMXTM seems to be effective in obtaining symptoms' control and dropping of FC in patients with DD and not responding to standard treatments.