Significance of Conducting 2 Types of Fecal Tests in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: We compared the diagnostic accuracy of the fecal calprotectin (FCP) test vs the fecal immunochemical blood test (FIT) in determining the endoscopic severity and predicting outcomes of patients with ulcerative colitis (UC). METHODS: We performed a nationwide study of 879 patients with UC, enrolled at medical centers across Japan, from March 2015 to March 2017. We collected data on fecal biomarkers, endoscopic severities, and other clinical indices from Cohort 1 (n = 427) and assessed the diagnostic accuracy of FCP measurement and FIT results in determining clinical severity, based on Mayo score, and endoscopic remission, based on Mayo endoscopic sub-score (MES) or UC endoscopic index of severity. We also followed 452 patients in clinical remission from UC (Cohort 2) for 12 months and evaluated the associations of FCP levels and FIT results with clinical recurrence. RESULTS: The levels of FCP and FIT each correlated with the MES and UC endoscopic index of severity. There were no significant differences in the areas under the curve of FCP vs FIT in distinguishing patients with MES≤1 from those with MES≥2 (P = .394) or in distinguishing patients with MES=0 from those with MES≥1 (P = .178). Among 405 patients in clinical remission at baseline, 38 (9.4%) had UC recurrences within 3 months and 90 (22.2%) had recurrences within 12 months. FCP≥146 mg/kg (hazard ratio [HR], 4.83; 95% confidence interval [CI], 2.80-8.33) and FIT≥77 ng/mL (HR, 2.92; 95% CI, 1.76-4.83) were independently associated with clinical recurrence within 12 months. UC recurred within 12 months in 69% of patients with levels of FCP≥146 mg/kg and FIT ≥77 ng/mL; this value was significantly higher than the rate of recurrence in patients with levels of FCP≥146 mg/kg and FIT <77 ng/mL (31.5%, P < .001) or patients with levels of FCP<146 mg/kg and FIT ≥77 ng/mL (30.0%, P < .001). CONCLUSION: In a nationwide study of patients with UC in Japan, we found that the level of FCP and FIT could each identify patients with endoscopic markers of disease severity (MES≥2). The combination of FCP and FIT results can identify patients in remission who are at risk for disease recurrence. Clinical Trials Registry no: UMIN000017650 (http://www.umin.ac.jp/ctr/).

Short- and Long-Term Outcomes of Infliximab Treatment for Steroid-Refractory Ulcerative Colitis and Related Prognostic Factors: A Single-Center Retrospective Study.

BACKGROUND/AIMS: The aim of this study was to analyze the short- and long-term outcomes of infliximab (IFX) treatment to cure steroid-refractory ulcerative colitis (UC) and related prognostic factors. METHODS: Retrospective data were collected from 125 patients with steroid-refractory UC who received IFX treatment at our center from July 2005 to November 2013. The Lichtiger clinical activity index score was calculated at baseline, 2 weeks, 6 weeks, and 1 year, and the cumulative non-colectomy rate following IFX administration was estimated. Remission rate prognostic factors and the cumulative colectomy rate prognostic factors were evaluated using multivariate logistic regression analysis and multivariate Cox regression analysis, respectively. RESULTS: Remission rates at 2 weeks, 6 weeks, and 1 year were 46, 58, and 45%, respectively. The 1-, 3-, and 5-year cumulative non-colectomy rates were 80, 78, and 75%, respectively. Previous treatment with calcineurin inhibitors was a significant prognostic factor for lower remission and cumulative non-colectomy rates, whereas concomitant immunomodulators was a significant prognostic factor for the higher remission rate. Gender (female) was a prognostic factor for higher remission rate at 1 year and higher cumulative non-colectomy rate. CONCLUSIONS: This study revealed good short- and long-term outcomes of IFX treatment in patients with steroid-refractory UC. Previous treatment with calcineurin inhibitors was a prognostic factor for poor outcomes of IFX treatment, whereas concomitant immunomodulators and gender (female) were prognostic factors for good outcomes.

A case of Takayasu's arteritis detected in a patient with Crohn's disease following infliximab treatment.

A 19-year-old male with diarrhea, abdominal pain, fever, and elevated C-reactive protein (CRP) levels was admitted to our hospital. Endoscopic examination and small intestinal contrast radiography revealed multiple longitudinal ulcers in the large intestine and ileum. A specimen biopsied from one of these ulcers revealed non-caseating epithelioid cell granuloma. He also had a draining anal fistula. Plain chest computed tomography (CT) and abdominal contrast-enhanced CT did not reveal any vascular abnormality. A diagnosis of Crohn's disease was made, and infliximab was administered. Following infliximab administration, the diarrhea and abdominal pain disappeared, longitudinal ulcers in the large intestine healed (as evidenced by endoscopic examination), and his anal lesion improved. However, fever and elevated CRP levels persisted. With the concomitant use of prednisolone, the fever and elevation of CRP levels eventually improved, and the patient was discharged. Both, however, recurred as the patient was weaned off prednisolone treatment; consequently, he was re-hospitalized. Contrast-enhanced CT upon re-admission revealed stenoses of the right renal artery, left common carotid artery, and left subclavian artery. In addition to Crohn's disease, the patient was diagnosed with co-existing Takayasu's arteritis.

Mesenchymal stem cells cancel azoxymethane-induced tumor initiation.

The role of mesenchymal stem cells (MSCs) in tumorigenesis remains controversial. Therefore, our goal was to determine whether exogenous MSCs possess intrinsic antineoplastic or proneoplastic properties in azoxymethane (AOM)-induced carcinogenesis. Three in vivo models were studied: an AOM/dextran sulfate sodium colitis-associated carcinoma model, an aberrant crypt foci model, and a model to assess the acute apoptotic response of a genotoxic carcinogen (AARGC). We also performed in vitro coculture experiments. As a result, we found that MSCs partially canceled AOM-induced tumor initiation but not tumor promotion. Moreover, MSCs inhibited the AARGC in colonic epithelial cells because of the removal of O(6)-methylguanine (O(6) MeG) adducts through O(6) MeG-DNA methyltransferase activation. Furthermore, MSCs broadly affected the cell-cycle machinery, potentially leading to G1 arrest in vivo. Coculture of IEC-6 rat intestinal cells with MSCs not only arrested the cell cycle at the G1 phase, but also induced apoptosis. The anti-carcinogenetic properties of MSCs in vitro required transforming growth factor (TGF)-ß signaling because such properties were completely abrogated by absorption of TGF-ß under indirect coculture conditions. MSCs inhibited AOM-induced tumor initiation by preventing the initiating cells from sustaining DNA insults and subsequently inducing G1 arrest in the initiated cells that escaped from the AARGC. Furthermore, tumor initiation perturbed by MSCs might potentially dysregulate WNT and TGF-ß-Smad signaling pathways in subsequent tumorigenesis. Obtaining a better understanding of MSC functions in colon carcinogenesis is essential before commencing the broader clinical application of promising MSC-based therapies for cancer-prone patients with inflammatory bowel disease.

Effectiveness and Persistency of Ustekinumab Treatment for Ulcerative Colitis: A Phoenix retrospective Cohort Study.

Background: Real-world data regarding ustekinumab (UST) for ulcerative colitis (UC) particularly in biologics-naïve patients is currently limited. This study aimed to elucidate the real-world effectiveness and safety of UST for UC. Methods: Overall, 150 patients with UC treated with UST from March 2020 to January 2023 were enrolled across 7 referral hospitals. To assess the clinical efficacy and persistence of UST, retrospective analyses were conducted from weeks 8 to 56. Predictive factors concerning the response and persistence of UST were examined through univariate and multivariate analyses. Results: Of the 150 patients, 125 received UST for remission induction, including 36% biologics-naïve. The response and remission rates were 72.8% and 56.0% at week 8 and 73.2% and 63.4% at week 56, respectively. Biologics-naïve patients represented higher response and remission rates at week 8 (84.4% and 73.3%) than those with biologics exposure (66.2% and 46.2%). Patients with prior antitumor necrosis factor (anti-TNF) and vedolizumab (VDZ) exposure had relatively lower response and remission rates (34.5% and 24.1%, respectively). The 1-year cumulative persistence rate was 84.0%. Multivariate analysis revealed that the chronic continuous type and prior anti-TNF and VDZ exposure were negative predictive factors for week 8 responsiveness. Clinical response at week 8 was a predictor of 1-year persistence. Adverse event incidence remained notably low at 6.4%. Conclusions: This study highlights the safety and effectiveness of UST as an induction and maintenance therapy for UC. Chronic continuous type and previous anti-TNF and VDZ exposure negatively contributed to short-term effectiveness, whereas short-term effectiveness provided good persistency.

Serum leucine-rich alpha-2 glycoprotein levels for predicting active ultrasonographic findings in intestinal lesions of patients with Crohn's disease in clinical remission.

This study aimed to investigate the cutoff value of leucine-rich alpha-2 glycoprotein (LRG) in predicting active intestinal ultrasonography (IUS) findings in patients with Crohn's disease (CD) in clinical remission. Data were retrospectively collected from patients with CD evaluated using LRG and undergoing IUS from September 2020 to August 2022. Patients with a Harvey-Bradshaw Index of ≤4 were included and those who underwent intestinal resection were excluded. Bowel wall thickness and stratification and blood flow signal using superb microvascular imaging (SMI) were used to assess ultrasonography findings. SMI signals were categorized into 4 grades following the Limberg score. Receiver operating characteristic curves were constructed and the area under the curve was calculated to determine the LRG cutoff values for predicting active IUS findings and were compared with those of C-reactive protein. This study included 213 patients. The LRG cutoff values to predict active bowel wall thickness, loss of bowel wall stratification, and SMI of ≥1, ≥2, and 3 were 14.6 µg/mL, 14.6 µg/mL, 14.6 µg/mL, 14.6 µg/mL, and 16.9 µg/mL, respectively, with significantly higher areas under the curve in SMI of ≥1 and 3 than in C-reactive protein. The best LRG cutoff value for predicting active IUS findings was 14.6 µg/mL in patients with CD in clinical remission, suggesting that LRG is better than C-reactive protein for detecting active IUS findings in CD.

Predicting a rapid response to adalimumab treatment and favorable short-term outcomes through the high platelet count in patients with ulcerative colitis: A multicenter retrospective cohort study.

This study aimed to investigate the short-term effectiveness of adalimumab therapy in patients with ulcerative colitis (UC), especially its rapid response.This retrospective, multicenter, cohort study involved 7 institutes in Japan, compiling data from patients with UC who had received at least 1 induction dose of 160 mg of adalimumab between June 2013 and May 2017. Patients should have a Lichtiger clinical activity index score of ≥5 at the initial adalimumab administration. Remission was defined as clinical activity index score of ≤4, whereas response was defined as a reduction of ≥50% from the baseline value. Rapid responders are defined as patients who achieved response at 2 weeks.A total of 91 patients were included in this study: 37.4% and 45.1% achieved clinical response at 2 and 8 weeks, respectively, whereas clinical remission rates 12 weeks were 45.1%. Among the rapid responders, 82.4% achieved clinical remission at 12 weeks. Multivariate logistic regression analysis identified a higher platelet count as an independent prognostic factor for a higher rate of rapid response. Receiver operating characteristic curve showed that a platelet counts cutoff value of ≥312 × 10/L was associated with a rapid response.Approximately 40% of patients with UC showed a rapid response to adalimumab therapy after 2 weeks. Up to 80% of the rapid responders also achieved remission at 12 weeks. A higher platelet count was identified as an independent prognostic factor for a higher rapid response rate.

Highly Bioavailable Curcumin Derivative Ameliorates Crohn's Disease Symptoms: A Randomized, Double-Blind, Multicenter Study.

BACKGROUND & AIMS: The new curcumin derivative Theracurmin® has a 27-fold higher absorption rate than natural curcumin powder. Theracurmin® is an inhibitor of nuclear factor-κB, which mediates the expression of inflammatory cytokines. The effect of Theracurmin® on inflammatory bowel disease in humans has not been explored; therefore, we investigated the efficacy and safety of Theracurmin® in patients with Crohn's disease. METHODS: In this randomized, double-blinded study performed at 5 independent medical centers in Japan, Theracurmin® (360 mg/day, n = 20) or placebo (n = 10) was administered to patients with active mild-to-moderate Crohn's disease for 12 weeks. The agent's efficacy was assessed by evaluating clinical and endoscopic remission, healing of anal lesions, and blood levels of inflammatory markers. RESULTS: In the Theracurmin® group, a significant reduction in clinical disease activity was observed in week 12 relative to that in week 0 (p = 0.005). On intention-to-treat analysis, clinical remission rates were 35%, 40%, and 40% at weeks 4, 8, and 12, respectively, which were significantly higher than those in the placebo group (all 0%; p = 0.033, p = 0.020, and p = 0.020, respectively). Furthermore, reduction in endoscopic Crohn's disease severity (p = 0.032) was observed at week 12 in the Theracurmin® group. The endoscopic remission rates were 15% and 0% in the Theracurmin® and placebo groups, respectively. Significant healing of anal lesions (p = 0.017) was observed at week 8 in the Theracurmin® group. No serious adverse events were observed in either group throughout the study. CONCLUSIONS: Theracurmin® shows significant clinical and endoscopic efficacy together with a favorable safety profile in patients with active mild-to-moderate Crohn's disease. CLINICAL TRIAL UMIN REGISTRATION ID: UMIN000015770.

[A case of Giant GIST of the stomach successfully treated with imatinib mesylate neoadjuvant therapy and followed postoperatively].

Since the advent of imatinib mesylate (IM), its clinical efficacy against gastrointestinal stromal tumor (GIST) has been widely acknowledged, and therapeutic strategies for this disease have undergone great changes. We recently experienced a case of giant GIST of the stomach that was successfully treated with IM neoadjuvant therapy prior to surgical resection, but liver metastasis recurred 1 year and 7 months after the operation. The patient was a 65-year-old male who presented at our department with the chief complaints of dizziness, malaise, and fever in April 2002. An abdominal CT revealed a mass with a maximum diameter of 17 cm, as well as a cystic septate mass, 12 cm in diameter, with a thick capsule in the left lobe of the liver. The patient was diagnosed with GIST of the stomach and liver metastasis. Since radical operation was considered difficult at that point, IM (400 mg/day) was started on May 9. The result of treatment was determined to be PR, and radical operation was considered feasible. On March 18, 2003, total gastrectomy and left hepatic lobectomy/S 6 partial lobectomy were performed in the surgery department of our hospital. The postoperative course was favorable and oral administration of IM was resumed soon after the operation. However, the drug was discontinued for financial reasons and a decreased white blood cell count (grade 3) 2 months after the operation. Recurrence in the liver and abdominal wall was found in October 2004, and oral administration of IM was resumed again. Currently, treatment with IM is ongoing. Case reports on the efficacy of IM neoadjuvant therapy are occasionally found in the literature, but there are few reports on its long-term prognosis. We report this case with a discussion of future therapeutic options.

Contextual niche signals towards colorectal tumor progression by mesenchymal stem cell in the mouse xenograft model.

BACKGROUND: The role of mesenchymal stem/stromal cells (MSCs) in tumorigenesis remains controversial. This study aimed to determine whether heterotypic interactions between MSCs and colon cancer cells can supply contextual signals towards tumor progression. METHODS: Xenografts consisting of co-implanted human colorectal cancer cells with rat MSCs in immunodeficient mice were evaluated by tumor progression, angiogenic profiles, and MSC fate. Furthermore, we investigated how MSCs function as a cancer cell niche by co-culture experiments in vitro. RESULTS: Tumor growth progressed in two ways, either independent of or dependent on MSCs. Such cell line-specific dependency could not be explained by host immune competency. COLO 320 xenograft angiogenesis was MSC-dependent, but less dependent on vascular endothelial growth factor (VEGF), whereas HT-29 angiogenesis was not MSC-dependent, but was VEGF-dependent. MSCs and COLO 320 cells established a functional positive feedback loop that triggered formation of a cancer cell niche, leading to AKT activation. Subsequently, MSCs differentiated into pericytes that enhanced angiogenesis as a perivascular niche. In contrast, the MSC niche conferred an anti-proliferative property to HT-29 cells, through mesenchymal-epithelial transition resulting in p38 activation. CONCLUSIONS: In conclusion, MSCs demonstrate pleiotropic capabilities as a cancer cell or perivascular niche to modulate colorectal cancer cell fate in a cell line-dependent manner in a xenogeneic context.

Conditioned mesenchymal stem cells produce pleiotropic gut trophic factors.

BACKGROUND: Although mounting evidence implicates mesenchymal stem cells (MSCs) in intestinal tissue repair, controversy remains regarding the engraftment, proliferation, and differentiation for repopulating MSCs in recipient tissues. Therefore, we investigated the paracrine and/or endocrine role of MSCs in experimental colitis. METHODS: We analyzed the therapeutic effects of MSC-conditioned medium (MSC-CM) on dextran sulfate sodium (DSS)- or 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. We investigated the effects of MSC-CM on the epithelial cell viability, mobility, cell cycle, and cytokine production in ex vivo lamina propria/mesenteric lymphocytes, a macrophage cell line, and the mixed lymphocyte reaction. An optimal regimen against colitis was explored. The contents of MSC-CM were analyzed using a WNT signaling pathway polymerase chain reaction array, an inflammatory cytokines antibody array, and liquid chromatography-tandem mass spectrometry analysis. RESULTS: Independent of the systemic administration route, MSC-CM concentrates were effective for the inductive phase of TNBS-induced colitis and for the recovery phase of DSS-induced colitis. Hypoxia appeared to be one of the optimal preconditioning factors assessed by cell motility and viability through activating the PI3K-Akt pathway in rat small intestine epithelial cells, IEC-6. Thus, Hypoxia had profound effects on the contents of MSC-CM, which comprised pleiotropic gut trophic factors involved in each wound healing process, including the anti-inflammatory, proliferative, and tissue remodeling phases. CONCLUSIONS: Identification and optimization of potential gut trophic factors in MSC-CM is urgently needed to form the basis for new drug discovery and for optimizing cell-based therapies for inflammatory bowel disease.