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Malakoplakia is a rare granulomatous inflammation that has mainly been reported in the urinary bladder of dogs. Only one case of canine colonic malakoplakia has been reported to date; however, successful treatment of this disease has not been reported. Here, we report a case of colonic malakoplakia in a 5-month-old spayed female French Bulldog. The dog was referred to a veterinarian because of chronic diarrhea and mucinous blood feces; empirical treatment did not improve its condition. Histologically, numerous macrophages containing periodic acid-Schiff-positive granules infiltrated the lamina propria of the large intestine. Furthermore, targetoid basophilic inclusion bodies (Michaelis-Gutmann bodies) were observed. Complete clinical remission was achieved after 8 months of enrofloxacin treatment and favorable progress after 2 months of medication.

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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 TGFβ1. In vitro analysis of human AEC tissues showed lower expression of PPARγ and TGFβ1 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., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

The canonical Wnt pathway is one of the key cellular signaling cascades that regulates, via the transcriptional co-activator β-catenin, numerous embryogenic developmental processes, as well as tissue homeostasis. It is therefore not surprising that misregulation of the Wnt/β-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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

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.

Competing Interests: Competing interests: None declared.

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.

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.

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., (Copyright © 2020 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

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.

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.

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 β1 integrin and cellular differentiation state.

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.

An 84-year-old woman presented with acute worsening of diarrhoea for a few weeks, with a background of chronic diarrhoea over the past 12 months accompanied by weight loss. Computed tomography during this admission revealed air in the biliary tree and resolution of gallstones in keeping with a cholecystocolonic fistula. Owing to her comorbidities, surgical management was deemed not to be the best option. She was trialled on octreotide, a somatostatin analogue, which effectively resolved her symptoms. This case presents an effective and novel method of managing cholecystocolonic fistulas conservatively in a patient where medical therapy is the ceiling of care.

Three-dimensional printing has become a feasible manufacturing technique for pharmaceutical products providing cheap and accurate freeform systems with a great potential for personalized-dose drugs. Fused Deposition Modeling (FDM) highlights among other 3D technologies due to its low cost and easy to operate but, until now, it has the drawbacks of the low drug loaded and the impossibility to print thermosensitive drugs. So, intermediate processes such as hot melt extrusion are frequently associated with FDM. Here, pharmaceutical dosage forms have been manufactured for the first time with a 3D printer combining two different printing technologies: FDM and injection volume filling (IVF), performing customized extruded scaffolds in which a liquid or semisolid system can be injected at room temperature. A model drug and a pH-sensitive polymer were successfully incorporated during the construction of the extruded backbone of the systems, called printfills (printed systems filled with a liquid or semisolid). SEM microphotographs of printfills show the sealing of the structure in the perimeter and the homogeneity of the colonic film formed in the upper side. Thus, the addition of the pH-sensitive polymer does not need an additional process in a fluidized bed or coating pan. Results from drug release studies performed at different pH confirm the ability of printfills for colon-specific drug delivery. Therefore, IVF technology complements FDM, solving its main limitations providing an easy, automatized and versatile technology to manufacture tailored drug delivery platforms, avoiding other intermediate processes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Although glucocorticosteroids (GS) and mesalazine are effective and widely employed to treat moderate-to-severe ulcerative colitis (UC), information regarding the factors responsible for response to such therapy is still scarce. One of these factors is thought to be an increased number of mucosal eosinophils. The aim of our study was to determine whether the presence of hypereosinophilia in colonic mucosa of UC patients might influence the short-term response to l treatment with GS and mesasalazine., Methods: Clinical, endoscopic, and pathologic data from patients with a recent diagnosis of moderate UC, who had not undergone treatment, were obtained, and the short-term outcome after 1 month of conventional first-line treatment (mesalazine plus GS) was evaluated., Results: There were 53 patients with a median age of 37 years (95% CI 30-47).Overall, at the end of treatment period 16 (30%) patients responded, whereas a response was not observed in the other 37 (70%) patients. Interestingly, all patients of this latter group had colonic mucosal hypereosinophilia. No significant differences were found between the two groups concerning sex and age at diagnosis, but hypereosinophilia was inversely correlated with the duration of the disease (p = 0.054), and significantly correlated to the localization of UC (p = 0.0023). In addition, The Mayo score was significantly higher in patients with hypereosinophilia (median 8; 95% CI 8-9;) when compared to patients without hypereosinophilia (median 7; 95% CI 7-7, p < 0.0001) including the Mayo endoscopic subscore (median 3; 95% CI 2-3 vs median 2; 95% CI 2-2, respectively; p = 0.007)., Conclusions: The presence of colonic mucosal hypereosinophilia may be useful to predict the short-term outcome to conventional first-line therapy in treatment-naïve UC patients. It remains to be seen whether this might be important in modifying the first-line therapy in this subgroup of patients.

Current treatments for intestinal diseases including inflammatory bowel diseases, irritable bowel syndrome, and colonic bacterial infections are typically small molecule oral dosage forms designed for systemic delivery. The intestinal permeability hurdle to achieve systemic delivery from oral formulations of macromolecules is challenging, but this drawback can be advantageous if an intestinal region is associated with the disease. There are some promising formulation approaches to release peptides, proteins, antibodies, antisense oligonucleotides, RNA, and probiotics in the colon to enable local delivery and efficacy. We briefly review colonic physiology in relation to the main colon-associated diseases (inflammatory bowel disease, irritable bowel syndrome, infection, and colorectal cancer), along with the impact of colon physiology on dosage form design of macromolecules. We then assess formulation strategies designed to achieve colonic delivery of small molecules and concluded that they can also be applied some extent to macromolecules. We describe examples of formulation strategies in preclinical research aimed at colonic delivery of macromolecules to achieve high local concentration in the lumen, epithelial-, or sub-epithelial tissue, depending on the target, but with the benefit of reduced systemic exposure and toxicity. Finally, the industrial challenges in developing macromolecule formulations for colon-associated diseases are presented, along with a framework for selecting appropriate delivery technologies., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Introduction: This study aimed to investigate the effects of melatonin on the healing of colon anastomosis following chemotherapy., Methods: 32 rats were randomised into four groups: (a) control group, which underwent sigmoid colon transection and primary anastomosis; (b) melatonin group, which received melatonin daily following anastomosis; (c) 5-fluorouracil (5-FU) group, which received 5-FU for five days prior to anastomosis; and (d) 5-FU+melatonin group, which received 5-FU for five days prior to anastomosis and melatonin daily following anastomosis. The rats were sacrificed on Postoperative Day 7 and anastomotic bursting pressures were measured. The anastomotic segment was extracted for hydroxyproline, luminol and lucigenin measurement and histopathological examination. Blood samples were obtained from the vena cava for measurement of tumour necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) plasma levels., Results: Compared to the 5-FU group, bursting pressures of anastomosis and hydroxyproline levels were significantly higher, while luminol and lucigenin levels were significantly lower, in the control and 5-FU+melatonin groups. In addition, TNF-α and IL-1β plasma levels were significantly lower in the control and 5-FU+melatonin groups than in the 5-FU group. Histopathological examination showed a significant decrease in inflammation and necrosis formation in the melatonin group when compared to the control group. The positive effect of melatonin was also seen in the rats that received 5-FU., Conclusion: Our study results showed that the adverse effects of chemotherapy on the mechanical, biochemical and histopathological parameters of anastomosis healing were attenuated through melatonin treatment., (Copyright: © Singapore Medical Association.)

Corticotropin-releasing hormone (CRH) mediates stress responses in the brain-gut axis. Administration of CRH modulates brain activation, for example by controlling the autonomic nervous system in response to colorectal distention. Here, we investigated the relationship between sympathoadrenal and hypothalamic-pituitary-adrenal (HPA) responses to colorectal distention in patients with irritable bowel syndrome (IBS). We enrolled 32 patients with IBS (16 women and 16 men) and 32 healthy subjects (16 women and 16 men), and randomly divided them between CRH and saline injection groups. The patients randomly underwent no (0 mmHg), mild (20 mmHg), or strong (40 mmHg) colorectal distension. CRH (2 μg/kg) or saline was then administered via injection, and the distention protocol was repeated. The heart rate (HR) and HR variability (HRV; calculated as the low [LF] to high frequency [HF] peak ratio, LF/HF) were analyzed using electrocardiography. Plasma noradrenaline, adrenaline, adrenocorticotropic hormone (ACTH), and cortisol levels were measured at the time of each distention. Plasma adrenaline levels were shown to be associated with plasma ACTH levels in HCs injected with CRH during distention using structural equation modeling analysis. Patients with IBS injected with placebo during distention displayed a closer association between these two parameters than those injected with CRH. Generalized estimating equation analysis revealed a significant distention × group × drug interaction for HF power. Moreover, there was a strong correlation between adrenaline and HRV upon CRH injection in controls, but not patients with IBS. The relationship between HPA-sympathoadrenal responses and CRH levels during colorectal distention differs between patients with IBS and controls. Modulation of adrenal gland activity in response to ACTH stimulation may contribute to the brain-gut pathophysiology characteristic of IBS., Competing Interests: The authors have declared that no competing interests exist.

Changes in the methionine metabolism can cause a state called hyperhomocysteinemia, inducing oxidative stress in the gut. The production of free radicals is important in the colon damage caused by methionine. This study aimed at evaluating the effect of the use of L-cysteine and N-acetyl-L-cysteine on the colon morphometry of young rats treated with methionine. A total number of 32 male rats were distributed in a randomized experimental design in 4 groups: control group treated with saline; methionine group; cysteine + methionine group, and N-acetyl-L-cysteine + methionine group. After 21 days of treatment, rats were sacrificed and the colon samples were taken for histological and biochemical analysis. Methionine load increased depth of crypts, the lamina muscularis mucosae thickness, the mucosal height, and the number of cells in lamina propria (p < 0.01). Combination of methionine with L-cysteine (C group) and with N-acetyl-L-cysteine (N group) reversed methionine effects. Methionine treatment increased the GPx activity and MDA concentration, while L-cysteine and N-acetyl-L-cysteine increased the catalase activity compared to methionine group. It was concluded that the use of L-cysteine and N-acetyl-L-cysteine was beneficial to decrease intestinal mucosal height and oxidative damage when methionine was used in combination with them.

Study Question: What is the degree of patient satisfaction in women with symptomatic colorectal endometriosis who choose medical or surgical treatment after a shared decision-making (SDM) process?, Summary Answer: The degree of satisfaction with treatment was high both in women who chose medical treatment with a low-dose oral contraceptive (OCP) or a progestin, and in those who chose to undergo surgical resection of bowel endometriosis., What Is Known Already: Hormonal therapies and surgery for colorectal endometriosis have been investigated in non-comparative studies with inconsistent results., Study Design, Size, Duration: Parallel cohort study conducted on 87 women referring to our centre with an indication to surgery for colorectal endometriosis. A standardised SDM process was adopted, allowing women to choose their preferred treatment. Median follow-up was 40 [18-60] months in the medical therapy group and 45 [30-67] in the surgery group., Participants/materials, Setting, Methods: Patients with endometriosis infiltrating the proximal rectum, the rectosigmoid junction, and the sigmoid, not causing severe sub-occlusive symptoms were enroled. A total of 50 patients chose treatment with an OCP (n = 12) or a progestin (n = 38), whereas 37 women confirmed their previous indication to surgery. Patient satisfaction was graded according to a 5-category scale. Variations in bowel and pain symptoms were measured by means of a 0-10 numeric rating scale. Constipation was assessed with the Knowles-Eccersley-Scott Symptom Questionnaire (KESS), health-related quality of life with the Short Form-12 questionnaire (SF-12), psychological status with the Hospital Anxiety and Depression scale (HADS) and sexual functioning with the Female Sexual Function Index (FSFI)., Main Results and the Role of Chance: Six women in the medical therapy group requested surgery because of drug inefficacy (n = 3) or intolerance (n = 3). Seven major complications were observed in the surgery group (19%). At 12-month follow-up, 39 (78%) women in the medical therapy group were satisfied with their treatment, compared with 28 (76%) in the surgery group (adjusted odds ratio (OR), 1.37; 95% confidence interval (CI), 0.45-4.15; intention-to-treat analysis). Corresponding figures at final follow-up assessment were 72% in the former group and 65% in the latter one (adjusted OR, 1.74; 95% CI, 0.62-4.85). The 60-month cumulative proportion of dissatisfaction-free participants was 71% in the medical therapy group compared with 61% in the surgery group (P = 0.61); the Hazard incidence rate ratio was 1.21 (95% CI, 0.57-2.62). Intestinal complaints were ameliorated by both treatments. Significant between-group differences in favour of medical treatment were observed at 12-month follow-up in diarrhoea, dysmenorrhoea, non-menstrual pelvic pain and SF-12 physical component scores. The total HADS score improved significantly in both groups, whereas the total FSFI score improved only in women who chose medical therapy., Limitations Reasons for Caution: As treatments were not randomly assigned, selection bias and confounding are likely. The small sample size exposes to the risk of type II errors., Wider Implications of the Findings: When adequately informed and empowered through a SDM process, most patients with non-occlusive colorectal endometriosis who had already received a surgical indication, preferred medical therapy. The possibility of choosing the preferred treatment may allow maximisation of the potential effect of the interventions., Study Funding/competing Interest(s): This study was financed by Italian fiscal contribution '5 × 1000'-Ministero dell'Istruzione, dell'Università e della Ricerca-devolved to Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy. P.V., M.P.F., R.R., D.D., A.R., P.M., O.D.G. and M.C. declare that they have no conflicts of interest. E.S. received grants from Ferring and Serono., (© The Author(s) 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Background: Langerhans cell histiocytosis is a rare systemic disease characterized by the abnormal overproduction of histiocytes that tend to infiltrate single or multiple organ systems leading to significant tissue damage. It mainly affects - by order of decreasing frequency - the bone, the skin, the lymph nodes, the liver, and lungs. Gastrointestinal tract involvement is extremely rare in adults., Case Presentation: We describe the case of a 32-year-old Middle Eastern man with Langerhans cell histiocytosis involving his lungs and the colorectoanal part of his gastrointestinal tract, with complete resolution of gastrointestinal tract lesions following a non-standardized chemotherapy regimen., Conclusions: Gastrointestinal tract lesions are a rare manifestation of Langerhans cell histiocytosis, especially when associated with extraintestinal involvement, such as the lungs. Chemotherapy protocols have not been well established for the treatment of the disease. The clinical impact of the effective chemotherapy regimen used to treat this uncommon presentation of Langerhans cell histiocytosis will be viewed in this case report.

Purpose: Colonic obstruction causes loss of collagen and impairment of anastomotic integrity by matrix metalloproteinases (MMPs). Unexpectedly, pharmacological MMP inhibition increased anastomotic leakage (AL) in obstructed colon possibly due to the non-selective nature of these compounds and the experimental model applied. We therefore studied the effects of selective MMP inhibition on the healing of anastomoses in colon obstructed by a novel laparoscopic technique., Methods: Left colon was obstructed in 38 male Sprague-Dawley rats (226-284 g). After 12 h, stenoses were resected and end-to-end anastomoses constructed. Baseline breaking strength was determined in 6 animals on day 0. The remaining 32 rats were randomized to daily treatment with the selective MMP-8, MMP-9, and MMP-12 inhibitor AZD3342 (n = 16) or vehicle (n = 16). On day 3, anastomoses were evaluated for AL and breaking strength. Isolated anastomotic wound tissue was analyzed on total collagen and pepsin-insoluble and pepsin-soluble collagen by hydroxyproline. The soluble collagens were further differentiated into native, measured by Sircol, and fragmented forms., Results: Baseline breaking strength was maintained with AZD3342 but decreased by 25% (P = 0.023) in the vehicle group. The anastomotic breaking strength of AZD3342-treated rats was 44% higher (P = 0.008) than the vehicle-treated rats. Furthermore, the AL rate was reduced (P = 0.037) with AZD3342 compared with vehicle treatment. AZD3342 treatment influenced neither the total or insoluble collagen concentrations nor the degree of fragmentation of the soluble collagen triple helices., Conclusion: Selective MMP inhibition increased anastomotic breaking strength and reduced AL after resection of colonic obstruction.

Aim: To investigate management of patients who develop ipilimumab-mediated enterocolitis, including association of endoscopic findings with steroid-refractory symptoms and utility of infliximab as second-line therapy., Methods: We retrospectively reviewed all patients at our center with metastatic melanoma who were treated with ipilimumab between March 2011 and May 2014. All patients received a standard regimen of intravenous ipilimumab 3 mg/kg every 3 wk for four doses or until therapy was stopped due to toxicity or disease progression. Basic demographic and clinical data were collected on all patients. For patients who developed grade 2 or worse diarrhea (increase of 4 bowel movements per day), additional data were collected regarding details of gastrointestinal symptoms, endoscopic findings and treatment course. Descriptive statistics were used., Results: A total of 114 patients were treated with ipilimumab during the study period and all were included. Sixteen patients (14%) developed ≥ grade 2 diarrhea. All patients were treated with high-dose corticosteroids (1-2 mg/kg prednisone daily or equivalent). Nine of 16 patients (56%) had ongoing diarrhea despite high-dose steroids. Steroid-refractory patients received one dose of intravenous infliximab at 5 mg/kg, and all but one had brisk resolution of diarrhea. Fourteen of the patients underwent either colonoscopy or sigmoidoscopy with variable endoscopic findings, ranging from mild erythema to colonic ulcers. Among 8 patients with ulcers demonstrated by sigmoidoscopy or colonoscopy, 7 patients (88%) developed steroid-refractory symptoms requiring infliximab. With a median follow-up of 264 d, no major adverse events associated with prednisone or infliximab were reported., Conclusion: In patients with ipilimumab-mediated enterocolitis, the presence of colonic ulcers on endoscopy was associated with a steroid-refractory course., Competing Interests: Conflict-of-interest statement: Jain A and Lazarev MG have no declarations. Lipson EJ has served as a consultant for Bristol-Myers Squibb, EMD, Serono, Merck and Novartis; He has received research funding from Genentech and AstraZeneca. Sharfman WH has served as a consultant for Merck, Genentech, and Castle Biosciences, and he has received research funding from Bristol-Myers Squibb, Glaxo Smith Kline, and Novartis. Brant SR has served as an advisory board member for Asana Medical Inc., and he has received research funding from Johnson and Johnson.

Objective: To evaluate the mucosal healing in the terminal ileum, colon and small bowel in patients receiving infliximab treatment for small bowel Crohn's disease (SBCD)., Methods: The clinical data of 18 patients with SBCD treated with infliximab were analyzed for laboratory findings (routine blood tests, C-reative protein, and albumin), Crohn's disease activity index (CDAI), Lewis score (LS), Crohn's disease simplified endoscopic score (SES-CD) and adverse effects before and after 30 weeks of infliximab treatment., Results: SES-CD, LS, CDAI and CRP were all decreased significantly, but the body mass index and albumin were significantly increased in the 18 patients after 30 weeks of IFX treatment. Sixteen (88.9%) of the patients were in clinical remission, 10 (58.8%) showed terminal ileum and colonic mucosal healing, 4 (22.2%) showed small bowel mucosal healing, and 3 (17.6%) were in deep remission. The 4 patients with small bowel mucosal healing all showed terminal ileum and colon mucosal healing, and 6 patients with terminal ileum and colon mucosal healing did not show small bowel mucosal healing., Conclusion: Infliximab treatment can effectively reduce inflammatory activity, induce and maintain clinical remission of SBCD and achieve mucosal healing; small bowel mucosal healing occurs later than terminal ileum and colonic mucosal healing, indicating the importance of small bowel mucosal healing in efficacy analysis of the treatment.

Background: Targeting drug delivery is an attractive research area, as it enables localized treatment, improves the efficacy of therapeutics and reduces systemic toxicity. Colon targeting delivery is particularly beneficial to the treatment of colon diseases, such as inflammatory bowel disease and colon cancer, due to the improved local drug concentrations. The traditional strategies for colon targeting delivery include time-dependent and pH-dependent technologies, etc. In recent years, nanotechnology has emerged as a novel and efficient tool for targeting drug delivery. After oral administration, nano-based formulations are able to protect drug from the harsh gastrointestinal environment and selectively increase the drug concentration at the disease site. Various orally administered drug-loaded nano-systems for colon targeting delivery have been well documented and shown great potentials in colon disease therapy., Objective: In this work, we aim to provide a comprehensive understanding of the recent progress in the area of colon targeting delivery in combination with introduction of the pathophysiological changes of diseased colon sites and the obstacles for drug delivery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

A 24-year-old woman was transferred to our hospital under suspicion of an exacerbation of her known ulcerative colitis. Colonoscopy revealed an edematous swelling and multifocal discharge of pus throughout the descending colon, concurrent with active ulcerative colitis findings in the rectum and sigmoid colon. Computed tomography showed a thickened wall and multifocal abscesses within the wall of the descending colon. Two weeks after starting antimicrobial therapy, she was discharged home. This is the first case report of multifocal colonic wall abscesses. In order not to increase the risk of serious infection associated with anti-TNF-α therapy, proper qualification and strict monitoring are essential.

Introduction: It has become increasingly clear that dietary habits may affect the risk/progression of chronic diseases with a pathogenic inflammatory component, such as colorectal cancer. Considerable attention has been directed toward the ability of nutritional agents to target key molecular pathways involved in these inflammatory-related diseases., Areas Covered: ω-3 Polyunsaturated fatty acids (PUFA) and their oxidative metabolites have attracted considerable interest as possible anti-inflammatory and anti-cancer agents, especially in areas such as the large bowel, where the influence of orally introduced substances is high and tumors show deranged PUFA patterns. On this basis, we have analyzed pre-clinical findings that have recently revealed new insight into the molecular pathways targeted by ω-3 PUFA., Expert Opinion: The findings analyzed herein demonstrate that ω-3 PUFA may exert beneficial effects by targeting the epigenetic regulation of gene expression and altering M2 macrophage polarization during the inflammatory response. These mechanisms need to be better explored in the large bowel, and further studies could better clarify their role and the potential of dietary interventions with ω-3 PUFA in the large bowel. The epigenomic mechanism is discussed in view of the potential of ω-3 PUFA to enhance the efficacy of other agents used in the therapy of colorectal cancer.

Prucalopride is a new prokinetic agent, recently available in Europe for the treatment of functional constipation in adults in whom treatment with laxatives failed to provide adequate relief. However, due to its intrinsic properties (highly selective agonist activity and high affinity for 5-HT4 receptors, neuroprotection), this drug has shown the potential to be used in other pathologic conditions, in and outside of the gastrointestinal tract. We performed a systematic review of the evidence supporting these possible alternative uses of prucalopride. Further studies in this area are, however, mandatory.

Background - Crohn's disease is a clinically heterogeneous condition. Our aim was to identify the phenotype evolution of Crohn's disease over time according to the Montreal Classification and to precise predictive factors of the need for immunosuppressant treatment or surgery. Methods - We included Crohn's disease patients who were followed up for at least 5 years. We excluded patients who were lost to follow up before five. Patients were classified according to the Montreal classification for phenotype at diagnosis and five years later. The evolution of phenotype over time and the need for surgery, immunosuppressive or immunomodulatory drugs were evaluated. Results - One hundred twenty consecutive patients were recruited: 70 males and 50 females. At diagnosis, 68% of patients belong to A2 as determined by the Montreal classification. Disease was most often localized in the colon. The disease location in Crohn's disease remains relatively stable over time, with 93.4% of patients showing no change in disease location. Crohn's disease phenotype changed during follow up, with an increase in stricturing and penetrating phenotypes from 6% to 11% after 5 years. The only predictive factor of phenotype change was the small bowel involvement (OR=3.7 [1.2-7.6]). During follow-up, 82% of patients have presented a severe disease as attested by the use of immunosuppressive drugs or surgery. The factors associated with the disease severity were: small bowel involvement (L1), the stricturing (B2) and penetrating (B3) phenotypes and perineal lesions (OR=17.3 [8.4-19.7]; 12 [7.6-17.2]; 3[1.7-8.3] and 2.8 [2.2-5.1] respectively), without association with age, sex or smoking habits. Conclusion - Crohn's disease evolves over time: inflammatory diseases progress to more aggressive stricturing and penetrating phenotypes. The ileal location, the stricturing and penetrating forms and perineal lesions were predictive of surgery and immunosuppressant or immunomodulatory treatment.

Background: Malignant bowel obstruction is a highly symptomatic, often recurrent, and sometimes refractory condition in patients with intra-abdominal tumor burden. Gastro-intestinal symptoms and function may improve with anti-inflammatory, anti-secretory, and prokinetic/anti-nausea combination medical therapy., Objective: To describe the effect of octreotide, metoclopramide, and dexamethasone in combination on symptom burden and bowel function in patients with malignant bowel obstruction and dysfunction., Design: A retrospective case series of patients with malignant bowel obstruction (MBO) and malignant bowel dysfunction (MBD) treated by a palliative care consultation service with octreotide, metoclopramide, and dexamethasone. Outcomes measures were nausea, pain, and time to resumption of oral intake., Results: 12 cases with MBO, 11 had moderate/severe nausea on presentation. 100% of these had improvement in nausea by treatment day #1. 100% of patients with moderate/severe pain improved to tolerable level by treatment day #1. The median time to resumption of oral intake was 2 days (range 1-6 days) in the 8 cases with evaluable data. Of 7 cases with MBD, 6 had For patients with malignant bowel dysfunction, of those with moderate/severe nausea. 5 of 6 had subjective improvement by day#1. Moderate/severe pain improved to tolerable levels in 5/6 by day #1. Of the 4 cases with evaluable data on resumption of PO intake, time to resume PO ranged from 1-4 days., Conclusion: Combination medical therapy may provide rapid improvement in symptoms associated with malignant bowel obstruction and dysfunction., (© The Author(s) 2015.)