Validation of rapid fecal calprotectin assay using particle enhanced turbidimetric immunoassay for inflammatory bowel disease.

Fecal calprotectin (FC) is a promising biomarker for diagnosis and treatment of inflammatory bowel disease, ulcerative colitis (UC), and Crohn's disease. An enzyme immunoassay (EIA) is widely used for FC detection, though the considerable lag time, up to several days, causes clinical management delay. This study was performed to examine the new rapid kit fCAL-turbo, which is based on a particle-enhanced turbidimetric immunoassay (15 min), by comparing FC values with other EIAs (EliA, PhiCal, Bühlmann) and endoscopic scores. Using 94 samples, fCAL-turbo showed strong significant positive correlations with the other kits (Spearman's r = 0.9178-0.9886). Of 74 UC patients, 69 underwent an endoscopy and fCAL-turbo reflected endoscopic activity with a moderate correlation with Mayo endoscopic subscore (MES) (r = 0.6945, others r = 0.6682-0.7013). Receiver operating characteristic analyses based on MES 0 versus 1-3 showed a similar efficacy as compared to the other kits (cut-off and area under the curve: 89.70 µg/g and 0.8592, respectively, others 62.35-138.4 µg/g and 0.8280-0.8611, respectively). Furthermore, multiple regression analysis confirmed that fCAL-turbo results significantly contributed to prediction of MES 0 with a higher t-value as compared to the other biomarkers. fCAL-turbo showed strong correlations with the other kits and also demonstrated excellent performance for predicting endoscopic remission of UC.

Clinicopathologic differences of gastric neoplasms between Helicobacter pylori-infected and -naïve patients: a multicenter retrospective analysis.

BACKGROUND: The incidence of gastric neoplasms in Helicobacter pylori (Hp)-naïve patients has recently increased due to a remarkable decrease in the Hp-infected population in Japan. We investigated the clinicopathologic differences between Hp-infected gastric neoplasms (HpIGNs) and Hp-naïve gastric neoplasms (HpNGNs) that have not been fully elucidated so far. METHODS: This retrospective multicenter study investigated 966 consecutive patients with 1131 gastric dysplasia or cancers who underwent endoscopic or surgical treatment for the recent decade. Clinicopathologic features were compared between HpIGN and HpNGN cases. RESULTS: One thousand and sixty-eight HpIGNs in 916 patients included 877 differentiated types and 191 undifferentiated types. Sixty-three HpNGNs in 50 patients included 57 differentiated types (35 foveolar types, 15 intestinal types, 6 fundic-gland types, and 1 other differentiated type) and 6 undifferentiated types. HpNGNs occurred in younger (59.5 vs. 71.8 years, p < 0.05) and female patients (40.0% vs. 26.5%, p < 0.05), were found more frequently in the proximal compartment (p < 0.05), and had smaller size (median 4.0 vs. 20.0 mm, p < 0.05). Histologically, HpNGNs and HpIGNs both primarily consisted of differentiated type (90.5% vs. 82.1%, p = 0.089) and HpNGNs showed lower prevalence of invasive cancer (11.1% vs. 37.6%, p < 0.05) and lymphovascular invasion (1.6% vs. 31.6%, p < 0.05). Nearly all HpNGNs (62/63, 98.4%) were diagnosed in early pathological stage, while 16.1% (172/1068) of HpIGNs were diagnosed in advanced stage (p < 0.05). CONCLUSIONS: HpNGNs is recently on the increase but shows lower malignant nature regardless of histologic type than HpIGN. Endoscopic gastric cancer screening will be reviewed via cost effectiveness for Hp-naïve individuals in future.

Gastric Metastasis from Salivary Duct Carcinoma Mimicking Scirrhous Gastric Cancer.

A 59-year-old man underwent submandibular gland excision for salivary duct carcinoma (SDC). One year later, esophagogastroduodenoscopy indicated gastric diffuse mucosal thickening with luminal contraction, mimicking scirrhous gastric carcinoma. Biopsy specimens showed dense proliferation of neoplastic cells expressing androgen receptor and human epidermal growth factor 2, indicating SDC. Gastric diffuse infiltrative metastasis is generally characteristic of gastric metastasis from invasive ductal carcinoma, which shows histologic features similar to SDC. This is the first known report of gastric diffusely infiltrating metastasis in an SDC patient. Rapidly progressing, diffuse gastric wall thickening should also be considered indicative of salivary tumor-associated gastric metastasis.

Endoscopic differential diagnosis between foveolar-type gastric adenoma and gastric hyperplastic polyps in Helicobacter pylori-naïve patients.

BACKGROUND: Foveolar-type gastric adenoma (FGA) occurs in Helicobacter pylori (Hp)-naïve individuals and morphologically mimics Hp-naïve gastric hyperplastic polyp (HpN-GHP). FGA is often difficult to distinguish from HpN-GHP even by biopsy, due to its low-grade histologic atypia. We conducted a retrospective study to create an endoscopic diagnostic index. METHODS: We analyzed 51 FGAs in 41 patients and 36 HpN-GHPs in 24 patients. All lesions were photographed by white-light endoscopy (WLE) and narrow-band imaging with magnification endoscopy (NBIME). Three experts and three non-experts reviewed the WLE and WLE+NBIME images to assess six items for lesion diagnosis. We analyzed correlations between the diagnostic items and histologic features and compared the diagnostic accuracy between modalities. We created a composite diagnostic index and calculated its accuracy and consistency. RESULTS: FGAs more frequently showed the following features vs. HpN-GHPs: bright-red color (94.1% vs. 44.4%), peripheral hyperplasia (58.8% vs. 8.3%), papillary/gyrus-like microstructure (96.1% vs. 33.3%), visible capillaries (70.6% vs. 38.9%), and demarcation line (98.0% vs. 41.7%) (P < 0.05). White-zone thickening was seen only in HpN-GHPs (52.8%). Diagnostic accuracy (mean, WLE vs. WLE+NBIME) was 90.8 ± 1.1% vs. 93.5 ± 2.4% (P = 0.15) for experts and 88.5 ± 3.0% vs. 86.6 ± 3.5% (P = 0.51) for non-experts. When satisfying the four criteria (bright-red color, papillary/gyrus-like microstructure, demarcation line, and absent white-zone thickening), sensitivity and specificity for FGA were 90.2% and 94.4%, respectively, with a kappa value of ≥ 0.6 for interobserver diagnostic agreement. CONCLUSIONS: Composite diagnostic index contributes to the reproducible, accurate, preoperative differential diagnosis of FGA and HpN-GHP.

Trajectory analyses to identify persistently low responders to COVID-19 vaccination in patients with inflammatory bowel disease: a prospective multicentre controlled study, J-COMBAT.

BACKGROUND: The degree of immune response to COVID-19 vaccination in inflammatory bowel disease (IBD) patients based on actual changes in anti-SARS-CoV-2 antibody titres over time is unknown. METHODS: Data were prospectively acquired at four predetermined time points before and after two vaccine doses in a multicentre observational controlled study. The primary outcome was humoral immune response and vaccination safety in IBD patients. We performed trajectory analysis to identify the degree of immune response and associated factors in IBD patients compared with controls. RESULTS: Overall, 645 IBD patients and 199 control participants were analysed. At 3 months after the second vaccination, the seronegative proportions were 20.3% (combination of anti-tumour necrosis factor [TNF]α and thiopurine) and 70.0% (triple combination including steroids), despite that 80.0% receiving the triple combination therapy were seropositive at 4 weeks after the second vaccination. Trajectory analyses indicated three degrees of change in immune response over time in IBD patients: high (57.7%), medium (35.6%), and persistently low (6.7%). In the control group, there was only one degree, which corresponded with IBD high responders. Older age, combined anti-TNFα and thiopurine (odds ratio [OR], 37.68; 95% confidence interval [CI], 5.64-251.54), steroids (OR, 21.47; 95%CI, 5.47-84.26), and tofacitinib (OR, 10.66; 95%CI, 1.49-76.31) were factors associated with persistently low response. Allergy history (OR, 0.17; 95%CI, 0.04-0.68) was a negatively associated factor. Adverse reactions after the second vaccination were significantly fewer in IBD than controls (31.0% vs 59.8%; p < 0.001). CONCLUSIONS: Most IBD patients showed a sufficient immune response to COVID-19 vaccination regardless of clinical factors. Assessment of changes over time is essential to optimize COVID-19 vaccination, especially in persistently low responders.

Low Fecal Calprotectin Predicts Histological Healing in Patients with Ulcerative Colitis with Endoscopic Remission and Leads to Prolonged Clinical Remission.

BACKGROUND: Consensus regarding the cutoff value of fecal calprotectin (FC) for predicting histological healing (HH) in ulcerative colitis (UC) is lacking. This study aimed to determine an optimal FC cutoff value for predicting HH in patients with UC with clinical and endoscopic remission. Furthermore, FC's predictability for prolonged clinical remission (CR) was investigated. METHODS: Patients with UC in clinical and endoscopic remission, defined as a partial Mayo score (PMS) ≤ 2 points and a Mayo endoscopic subscore 0-1, were prospectively enrolled. Biopsy samples were evaluated by Geboes score (GS), with HH defined as a GS < 2.0. Patients were followed for 2 years or until relapse, defined as a PMS > 2 or medication escalation. RESULTS: Seventy-six patients with UC were included. The median FC value in patients with HH (n = 40) was 56.2 µg/g, significantly lower than that in those with histological activity (118.1 µg/g; P < .01). The area under the curve (AUC) in a receiver operating characteristic (ROC) curve analysis to predict HH for FC was 0.71 (95% confidence interval [CI], 0.59-0.83), with an optimal cutoff value of 82.7 µg/g (73% sensitivity; 64% specificity; P < .01). Of 74 patients observed for 2 years, 54 (73%) had prolonged CR. In the ROC curve analysis, the AUC to predict prolonged CR for FC was 0.79 (95% CI, 0.68-0.90), equivalent to that for HH (0.73; 95% CI, 0.64-0.86; P = .40). The optimal FC cutoff value to predict prolonged CR was 84.6 µg/g (72% sensitivity; 85% specificity; P < .01). CONCLUSIONS: Fecal calprotectin < 82 µg/g predicts HH in patients with UC with clinical and endoscopic remission. Low FC leads to prolonged CR, equivalent to HH.

Fecal calprotectin (FC) levels < 82 µg/g predict histological healing in ulcerative colitis patients with clinical and endoscopic remission. Low FC leads to prolonged clinical remission for up to 2 years in those with clinical and endoscopic remission, equivalent to histological healing.

Long-lasting renal dysfunction following tacrolimus induction therapy in ulcerative colitis patients.

Although tacrolimus (TAC) has remarkable effects in ulcerative colitis (UC) patients when given as remission induction therapy, some can develop renal dysfunction during TAC administration, resulting in withdrawal, though related details remain poorly understood. This study was conducted to determine the impact of oral TAC on renal function for remission induction therapy in UC patients. Fifty-five patients (10 elderly, 45 non-elderly) with UC and treated with oral TAC at our hospital were retrospectively evaluated. Renal function was assessed using estimated glomerular filtration rate (eGFR). Although a high clinical response to TAC was seen in both elderly and non-elderly, a decline in eGFR was noted in nearly all patients regardless of age, with a maximum change of -34.4% from the baseline value at week 11. Furthermore, eGFR decline recovered quickly after TAC discontinuation, though did not return to the baseline at two years following cessation. The rate of eGFR change at week 12 was significantly associated with patient age (ß = -0.3242, p = 0.0103) and peak serum trough level during TAC treatment (ß = 0.3563, p = 0.0051). Furthermore, the rate of decline in eGFR was significantly greater during treatment with TAC in the elderly as compared to non-elderly, with a large difference in eGFR decline rate between those groups also noted at two years after withdrawal of treatment. Careful attention to renal function when administering oral TAC for UC is important and changes in eGFR should be monitored closely in elderly patients even after treatment cessation.

The Simultaneous Onset of Pancreatitis and Colitis as Immune-related Adverse Events in a Patient Receiving Nivolumab Treatment for Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs), which have anti-tumor effects, are currently approved for treatment of several kinds of advanced malignancies. However, with their increasing use, a variety of immune-related adverse events (irAEs) in administered patients have been reported. We herein report a rare case of the simultaneous onset of acute pancreatitis and colitis as irAEs during nivolumab treatment given to a patient with renal cell carcinoma, who then shown marked improvement with corticosteroid therapy.

Enteric Microbiota-Mediated Serotonergic Signaling in Pathogenesis of Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a chronic functional disorder that affects the gastrointestinal tract. Details regarding the pathogenesis of IBS remain largely unknown, though the dysfunction of the brain-gut-microbiome (BGM) axis is a major etiological factor, in which neurotransmitters serve as a key communication tool between enteric microbiota and the brain. One of the most important neurotransmitters in the pathology of IBS is serotonin (5-HT), as it influences gastrointestinal motility, pain sensation, mucosal inflammation, immune responses, and brain activity, all of which shape IBS features. Genome-wide association studies discovered susceptible genes for IBS in serotonergic signaling pathways. In clinical practice, treatment strategies targeting 5-HT were effective for a certain portion of IBS cases. The synthesis of 5-HT in intestinal enterochromaffin cells and host serotonergic signaling is regulated by enteric resident microbiota. Dysbiosis can trigger IBS development, potentially through aberrant 5-HT signaling in the BGM axis; thus, the manipulation of the gut microbiota may be an alternative treatment strategy. However, precise information regarding the mechanisms underlying the microbiota-mediated intestinal serotonergic pathway related to the pathogenesis of IBS remains unclear. The present review summarizes current knowledge and recent progress in understanding microbiome-serotonin interaction in IBS cases.

Juvenile social defeat stress exposure favors in later onset of irritable bowel syndrome-like symptoms in male mice.

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder. Traumatic stress during adolescence increases the risk of IBS in adults. The aim of this study was to characterize the juvenile social defeat stress (SDS)-associated IBS model in mice. Juvenile mice were exposed to an aggressor mouse for 10 min once daily for 10 consecutive days. Behavioral tests, visceral sensitivity, immune responses, and fecal bacteria in the colon were evaluated in 5 weeks after SDS exposure. Social avoidance, anxiety- and depression-like behavior, and visceral hypersensitivity were observed. Juvenile SDS exposure significantly increased the number of 5-HT-containing cells and calcitonin gene-related peptide-positive neurons in the colon. The gut microbiota was largely similar between the control and juvenile SDS groups. The alterations in fecal pellet output, bead expulsion time, plasma corticosterone concentration, and colonic 5-HT content in response to restraint stress were exacerbated in the juvenile SDS group compared with the control group. The combination of juvenile SDS and restraint stress increased the noradrenaline metabolite 3-Methoxy-4-hydroxyphenylglycol (MHPG) content and MHPG/noradrenaline ratio in the amygdala when compared with restraint stress in control mice. These results suggest that juvenile SDS exposure results in later onset of IBS-like symptoms.

Primary Extragastrointestinal Stromal Tumor of Greater Omentum with Intraperitoneal Bleeding.

Gastrointestinal stromal tumors (GISTs) develop in the digestive tract, mainly in the stomach, small intestine, colon, or esophagus. However, primary tumors with the same pathologic features as GISTs have been reported to occur outside of the digestive tract and are called extragastrointestinal stromal tumor (EGIST). We herein report a rare case of EGIST arising from the greater omentum in a patient with abdominal pain caused by intraperitoneal bleeding from the tumor.

Detection and Quantification of Transforming Growth Factor-ß1 Produced by Murine B Cells: Pros and Cons of Different Techniques.

Transforming growth factor (TGF)-ß1 is one of the regulatory cytokines produced by B cells and has a pivotal role in intestinal homeostasis. TGF-ß1 can determine the fate of naive T cells, such as differentiation, proliferation, and apoptosis, which are relevant to the pathogenesis of autoimmunity, infection, inflammation, allergy, and cancer. Here, we describe detailed methods for detection and quantification of TGF-ß1 secreted by B cells using ELISA, flow cytometry, and real-time PCR.

Differential gene expression analysis of dasatinib-induced colitis in a patient with chronic myeloid leukemia followed for 3 years: a case report.

BACKGROUND: Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) developed for treatment of patients with chronic myeloid leukemia (CML). The drug has been shown to act as a potent multikinase inhibitor by blocking not only the BCR-ABL1 gene sequence but also the SRC kinase family, though unexpected adverse events such as pleural effusion have recently been reported in patients undergoing treatment with dasatinib. Hemorrhagic colitis is a unique gastrointestinal adverse events associated with dasatinib and its pathogenesis remains poorly understood. CASE PRESENTATION: We report here a case of dasatinib-induced asymptomatic colitis in a patient with CML, who showed no exacerbation in careful observations and maintained deep molecular response (DMR) during a 3-year period. In addition, we performed transcriptome analysis of inflamed colonic mucosa specimens to clarify the possible mechanism of colitis that develops in association with dasatinib administration. Our results demonstrated that differential gene expression, especially lymphocyte-associated genes and chemokines, is substantially involved in inflammation of colonic mucosa in affected patients. CONCLUSION: Dasatinib induces immune-mediated colitis following lymphocyte infiltration.

Intermittent Purpura Development Associated with Leukocytoclastic Vasculitis Induced by Infliximab for Crohn's Disease.

Anti-tumor necrosis factor (TNF) α agents, widely used for the treatment of Crohn's disease (CD), can sometimes induce skin-associated adverse events, which mainly include psoriasis-like eruptions, eczema, and cutaneous infections. In contrast, purpura caused by vasculitis is rarely seen. We herein report a unique case of leukocytoclastic vasculitis induced by infliximab administered for CD in which intermittent purpura development was noted. Fluorescent immunostaining showed no immunoglobulin A deposition on the vessel walls. No purpura was initially seen after starting infliximab, but it appeared approximately 10 months later; however, administration did not have to be discontinued, and the condition was later resolved. The present findings provide important details regarding vasculitis induced by anti-tumor necrosis factor-α agent administration.

Molecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is one of the most prevalent functional gastrointestinal disorders, and accumulating evidence gained in both preclinical and clinical studies indicate the involvement of enteric microbiota in its pathogenesis. Gut resident microbiota appear to influence brain activity through the enteric nervous system, while their composition and function are affected by the central nervous system. Based on these results, the term "brain-gut-microbiome axis" has been proposed and enteric microbiota have become a potential therapeutic target in IBS cases. However, details regarding the microbe-related pathophysiology of IBS remain elusive. This review summarizes the existing knowledge of molecular mechanisms in the pathogenesis of IBS as well as recent progress related to microbiome-derived neurotransmitters, compounds, metabolites, neuroendocrine factors, and enzymes.

Comorbid irritable bowel syndrome symptoms and headache have greater association with anxiety than depression: Annual health check-up survey results.

High rates of co-existing irritable bowel syndrome (IBS) and headache have been reported in western countries. We investigated that comorbidity in individuals in Japan, along with anxiety and depression in subjects with and without IBS symptoms and/or headache.This cross-sectional study was performed from April 2012 to January 2013 at the Matsue Seikyo General Hospital Health Check Center. Questionnaires concerning symptoms related to IBS (Rome III) and headache, as well as anxiety/depression score were sent to individuals scheduled to undergo an annual health check-up, then returned during the visit and analyzed in a blinded manner.A total of 2885 individuals returned completed questionnaires and were enrolled, of whom 218 (7.6%) met the IBS criteria. The rates of co-existing headache in subjects with and without IBS symptoms were 44.0% (96/218) and 22.9% (611/2667), respectively, indicating a significantly higher rate of co-existing headache in subjects with as compared to without IBS (odds ratio [OR] 2.65, P < .001). Furthermore, the percentage of subjects with anxiety along with comorbid IBS symptoms and headache was significantly greater as compared to those with IBS (OR 3.01, P = .001) or headache (OR 2.41, P < .001) alone. Unlike anxiety, the percentage of subjects with depression was not significantly different among the IBS/non-headache, non-IBS/headache, and IBS/headache groups.Subjects with IBS symptoms had a higher rate of co-existing headache as compared to those without IBS. Furthermore, those with comorbid IBS symptoms and headache had a greater association with anxiety than with depression, as compared to those with only IBS or headache.

Prevalence of functional dyspepsia-like symptoms in ulcerative colitis patients in clinical remission and overlap with irritable bowel syndrome-like symptoms.

Objective: Quiescent ulcerative colitis (UC) patients often have irritable bowel syndrome (IBS)-like symptoms and we recently showed that the prevalence of IBS-like symptoms in UC patients in clinical remission was significantly higher as compared to healthy control subjects. However, the prevalence of functional dyspepsia (FD)-like symptoms in quiescent UC patients remains unknown. The purpose of this study was to evaluate the prevalence of FD-like symptoms and the overlap with IBS-like symptoms in such patients.Materials and Methods: We reanalyzed the records of UC patients in remission using the subject cohort from our previous study. Clinical remission was defined as a clinical activity index (CAI) value ≤4 for at least 6 months. Diagnoses of FD- and IBS-like symptoms were evaluated by questionnaire according to the Rome III criteria.Results: One hundred seventy-two UC patients in clinical remission and 330 healthy control subjects were analyzed. Of the 172 patients, 9 (5.2%) met the criteria of FD, which was comparable with the controls (22/330, 6.7%). The prevalence rate of FD-like symptoms in UC patients with IBS-like symptoms (7/46, 15.2%) was lower as compared to that of the control subjects (6/16, 37.5%). On the other hand, a high percentage of the UC patients with FD-like symptoms also had IBS-like symptoms (7/9, 77.8%).Conclusions: Although the prevalence of FD-like symptoms in quiescent UC patients with IBS-like symptoms was low, UC patients with FD-like symptoms frequently had IBS-like symptoms.

Ten-year follow-up study of linear immunoglobulin A dermatosis complicated with ulcerative colitis.

Linear immunoglobulin A dermatosis (LAD) is rarely complicated in patients with ulcerative colitis (UC), though the long-term prognosis in those with concurrent LAD and UC is not fully understood. Here, we report findings obtained in follow-up examinations performed over a 10-year period of a UC patient initially complicated with LAD. We treated an 18-year-old male for relapse of UC with deteriorating blisters diagnosed as LAD. Following successful induction therapy for both UC and LAD with oral prednisolone, the patient was followed for 10 years. Skin condition remained good at each examination, even with second and third relapses of UC. Our findings in this case indicate that LAD is rarely complicated with UC, while it has no association with colitis disease activity. Furthermore, adequate treatment following an initial diagnosis of LAD is important for management of affected UC patients.

Manipulating resident microbiota to enhance regulatory immune function to treat inflammatory bowel diseases.

Altered intestinal microbial composition (dysbiosis) and metabolic products activate aggressive mucosal immune responses that mediate inflammatory bowel diseases (IBD). This dysbiosis impairs the function of regulatory immune cells, which normally promote mucosal homeostasis. Normalizing and maintaining regulatory immune cell function by correcting dysbiosis provides a promising approach to treat IBD patients. However, existing microbe-targeted therapies, including antibiotics, prebiotics, probiotics, and fecal microbial transplantation, provide variable outcomes that are not optimal for current clinical application. This review discusses recent progress in understanding the dysbiosis of IBD and the basis for therapeutic restoration of homeostatic immune function by manipulating an individual patient's microbiota composition and function. We believe that identifying more precise therapeutic targets and developing appropriate rapid diagnostic tools will guide more effective and safer microbe-based induction and maintenance treatments for IBD patients that can be applied in a personalized manner.

Eosinophilic Granulomatosis with Polyangiitis Initially Diagnosed as Eosinophilic Gastroenteritis.

We herein report two cases of eosinophilic granulomatosis with polyangiitis (EGPA) initially diagnosed as eosinophilic gastroenteritis (EGE) based solely on endoscopic biopsy results. One year after the EGE diagnosis, one patient presented with multiple purpura, and skin biopsy findings resulted in a change of the diagnosis to EGPA. In another patient, multiple skin and colonic ulcerations emerged eight years after the diagnosis of EGE, at which time histological examinations of endoscopic biopsy specimens revealed vasculitis, and the diagnosis was changed to EGPA. Physicians should be aware of the possible existence of EGPA in cases diagnosed as EGE.