Efficacy and safety of filgotinib for ulcerative colitis: A real-world multicenter retrospective study in Japan.

BACKGROUND AND AIMS: While filgotinib, an oral Janus kinase (JAK) 1 preferential inhibitor, is approved for moderately to severely active ulcerative colitis (UC), real-world studies assessing its short- and long-term efficacy and safety are limited. METHODS: This is a multicenter, retrospective study of UC patients who started filgotinib between March 2022 and September 2023. The primary outcome was clinical remission, defined as a partial Mayo score ≤1 with a rectal bleeding score of 0, or Simple Clinical Colitis Activity Index (SCCAI) ≤2 with a blood-in-stool score of 0. Secondary outcomes included clinical response, corticosteroid-free remission, and endoscopic improvement. Outcomes were assessed at 10, 26, and 58 weeks based on patients with available follow-up. Adverse events were evaluated. RESULTS: We identified 238 UC patients and 54% had prior exposure to biologics/JAK inhibitors. The median baseline partial Mayo score and SCCAI were 5 (IQR 3-6) and 4 (IQR 2-7). Clinical remission rates based on per-protocol analysis at 10, 26, and 58 weeks were 47% (70/149), 55.8% (48/86), and 64.6% (31/48), respectively. At a median follow-up of 28 weeks (IQR 10-54) with a discontinuation rate of 39%, the rates of clinical remission, clinical response, corticosteroid-free remission, and endoscopic improvement were 39.9% (81/203), 54.7% (111/203), and 36.5% (74/203), and 43.5% (10/23), respectively. These rates were comparable between biologic/JAK inhibitor-naïve and -experienced patients. While three patients (1.3%) developed herpes zoster infection, no cases of thrombosis or death were reported. CONCLUSIONS: Real-world data demonstrate favourable clinical and safety outcomes of filgotinib for UC.

Utility of Combined Use of Transabdominal Ultrasonography and Fecal Immunochemical Test Examinations in Ulcerative Colitis.

This study examined the utility of the combined use of transabdominal ultrasonography (TUS) and fecal immunochemical testing (FIT) to detect mucosal inflammation, vis-a-vis the Mayo endoscopic subscore (MES), in ulcerative colitis (UC). Sixty-three UC patients who underwent TUS and FIT were retrospectively enrolled. For TUS, the colon was divided into five segments, and the bowel wall thickness was measured and evaluated. The accuracy of FIT (> 100 ng/ml) in detecting mucosal inflammation (MES>0) was 0.93, whereas that of TUS (BWT>2 mm) in each segment was 0.84-0.97. The combined use of TUS and FIT may be helpful in noninvasive treatment strategies.

Simultaneous analysis of shape and internal structure of a curved Hibiscus cannabinus pulvinus: X-ray microtomography and semi-automated quantification.

In the Malvaceae family, dynamic solar tracking by leaves is actuated by the deformation of the pulvinus, a thickened region at the leaf blade-petiole junction. While the internal structure is believed to play a crucial role in this process, experimental verification has been challenging due to technical limitations. To address this gap, we developed a semi-automated workflow, which integrates data analysis and image processing to simultaneously analyze the shape and internal structure of a Malvaceae pulvinus using X-ray microtomography. Firstly, we found that kenaf (Hibiscus cannabinus L.), a Malvaceae species with curved pulvini, exhibited solar-tracking leaf movement and selected it as a model system. We employed diffusible iodine-based contrast-enhanced computed tomography to visualize the internal structure of the kenaf pulvinus. Analysis of the pulvini's shape revealed variations in pulvinus morphology, yet plausible prediction of the centerline was accomplished using polar polynomial regression. Upon slicing the pulvini perpendicular to the centerline, we observed distinct gray value gradients along the proximo-distal and adaxial-abaxial axes, challenging threshold-based tissue segmentation. This workflow successfully generated three modified 3D images and derived quantitative parameters. Using these quantitative parameters, we conducted network analysis and found the linkage between the size-normalized cortex cross-sectional area and curvature. Polynomial least absolute shrinkage and selection operator (LASSO) regression revealed the relationship between the size-normalized cortex cross-sectional area and curvature commonly in all three tested samples. This workflow enables simultaneous analysis of the shape and internal structure, significantly improving the reproducibility of Malvaceae leaf pulvinus characterization.

Low Patient Weight and Long Intubation Time Are Key Factors for Pain during Colonoscopy.

Although the clinical usefulness of colonoscopy has been established, the procedure remains painful for many patients. This study was designed to clarify the factors predicting colonoscopy-related pain. We evaluated 283 consecutive patients who completed a first-ever, total colonoscopy without sedatives or analgesics. The severity of pain symptoms was evaluated by a numeric rating scale (NRS) in a questionnaire immediately after the colonoscopy. Patient backgrounds and endoscopic findings were analyzed to evaluate their association with pain. Out of 283 patients, 53 scored their pain 0-1 on the NRS while 48 scored it 6-10. We defined the colonoscopies of the former and latter patients as painless and painful, respectively, and compared the two. Multivariate analyses revealed that low body weight (OR 4.95, 95%CI 1.89-12.99) and longer intubation time (OR 3.63, 95%CI 1.46-9.03) were significant risk factors for painful colonoscopy. To identify factors contributing to the increased intubation time, we divided subjects into short- and long-intubation-time groups based on a median insertion time of 7 min. Older age (OR 2.28, 95%CI 1.31-3.98), previous abdominal surgery (OR 1.93, 95%CI 1.13-3.32) and findings of invasive cancer (OR 10.90, 95%CI 1.34-88.90) were significant factors for longer intubation time.

Pulvinar slits: Cellulose-deficient and de-methyl-esterified pectin-rich structures in a legume motor cell.

The cortical motor cells (CMCs) in a legume pulvinus execute the reversible deformation in leaf movement that is driven by changes in turgor pressure. In contrast to the underlying osmotic regulation property, the cell wall structure of CMCs that contributes to the movement has yet to be characterized in detail. Here, we report that the cell wall of CMCs has circumferential slits with low levels of cellulose deposition, which are widely conserved among legume species. This structure is unique and distinct from that of any other primary cell walls reported so far; thus, we named them "pulvinar slits." Notably, we predominantly detected de-methyl-esterified homogalacturonan inside pulvinar slits, with a low deposition of highly methyl-esterified homogalacturonan, as with cellulose. In addition, Fourier transform infrared spectroscopy analysis indicated that the cell wall composition of pulvini is different from that of other axial organs, such as petioles or stems. Moreover, monosaccharide analysis showed that pulvini are pectin-rich organs like developing stems and that the amount of galacturonic acid in pulvini is greater than in developing stems. Computer modeling suggested that pulvinar slits facilitate anisotropic extension in the direction perpendicular to the slits in the presence of turgor pressure. When tissue slices of CMCs were transferred to different extracellular osmotic conditions, pulvinar slits altered their opening width, indicating their deformability. In this study, we thus characterized a distinctive cell wall structure of CMCs, adding to our knowledge of repetitive and reversible organ deformation as well as the structural diversity and function of the plant cell wall.

Usefulness of Intestinal Ultrasound to Detect Small Intestinal Stenosis in Patients With Crohn's Disease.

OBJECTIVES: Double balloon enteroscopy (DBE) with retrograde contrast is useful as a monitoring tool for small intestinal lesions in Crohn's disease (CD), but these are burdensome for patients. Intestinal ultrasound (IUS) can be used with ease in daily clinical practice, but there is less evidence regarding the accuracy of detection of small intestinal stenosis in CD. This study aimed to examine the diagnostic power of IUS for small intestinal stenosis in patients with CD. METHODS: The findings of DBE and IUS in 86 patients with CD with small intestinal lesions were evaluated. Using DBE as the reference standard, we examined the detection rate of IUS for small intestinal stenosis. We evaluated three parameters: luminal narrowing, prestenotic dilation, and to-and-fro movement for determining stenosis using IUS. In addition, we compared the characteristics between the stenosis-detectable and stenosis-undetectable groups by IUS. RESULTS: Of the 86 patients, 30 had small intestinal stenosis. In IUS findings, when lesions that met two or more of the three parameters were judged as stenosis, the detection rate was 70.0% for sensitivity, 98.2% for specificity, and 88.4% for accuracy. Moreover, there were patients with a younger age at diagnosis (P < 0.05) and more ileocolonic disease location (P < 0.05) in the stenosis-detectable group by IUS. The stenoses detected by IUS were significantly longer than those undetected by IUS (14.1 mm versus 5.2 mm, P < 0.05). CONCLUSIONS: IUS delivered reliable results for clinically important small intestinal stenosis of CD with high diagnostic accuracy.

Mechanics of Reversible Deformation during Leaf Movement and Regulation of Pulvinus Development in Legumes.

Plant cell deformation is a mechanical process that is driven by differences in the osmotic pressure inside and outside of the cell and is influenced by cell wall properties. Legume leaf movements result from reversible deformation of pulvinar motor cells. Reversible cell deformation is an elastic process distinct from the irreversible cell growth of developing organs. Here, we begin with a review of the basic mathematics of cell volume changes, cell wall function, and the mechanics of bending deformation at a macro scale. Next, we summarize the findings of recent molecular genetic studies of pulvinar development. We then review the mechanisms of the adaxial/abaxial patterning because pulvinar bending deformation depends on the differences in mechanical properties and physiological responses of motor cells on the adaxial versus abaxial sides of the pulvinus. Intriguingly, pulvini simultaneously encompass morphological symmetry and functional asymmetry along the adaxial/abaxial axis. This review provides an introduction to leaf movement and reversible deformation from the perspective of mechanics and molecular genetics.

The Colon Wall Thickness Measured Using Transabdominal Ultrasonography Is Useful for Detecting Mucosal Inflammation in Ulcerative Colitis.

Objective Transabdominal ultrasonography (TUS) is a non-invasive procedure that is reportedly useful for managing ulcerative colitis (UC) and assessing bowel wall thickness (BWT), the most common measure of mucosal inflammation. However, the exact range of BWT that reflects disease activity remains undetermined. The present study clarified the BWT due to disease activity by comparing the use of TUS in each segment of the colon versus using colonoscopy (CS) and determined the usefulness of TUS in patients with UC. Methods We divided the colon into five segments and measured the BWT using TUS. The results were then compared to the Mayo endoscopic subscore (MES) classification to determine the accuracy of BWT measurement. Patients Eighty patients with UC who underwent TUS within 14 days of CS were retrospectively registered. Results We evaluated a total of 268 images depicting each segment among 80 patients with UC. The BWT was positively correlated with endoscopic activity (0.69, p<0.0001). In each segment, the relationship between a BWT>2 mm and an MES>0 had the highest sensitivity, specificity, and accuracy (0.85-1.00, 0.67-0.92, and 0.81-0.97, respectively). Conclusion This study concluded that TUS was a useful method of detecting an MES>0, which indicates the presence of inflammation and its location among UC patients. MES>0 was found to be highly accurate when a BWT>2 mm was considered positive. This non-invasive method may help control disease activity in patients with UC.

Diagnostic Utility of the PD-L1 Immunostaining in Biopsy Specimens of Patients with Biliary Tract Neoplasms.

BACKGROUND: Anti-programmed death 1/programmed death ligand 1 (PD1/PD-L1) antibodies have been successfully used as treatment agents for several solid tumors; however, it is difficult to predict their effectiveness. We evaluated whether biopsy specimens could predict the positive status of PD-L1 in surgically resected tissue. METHODS: Among 91 patients who underwent tissue sampling with endoscopic or liver biopsy before surgery for biliary tract neoplasms in an academic center, 45 (49%) patients were selected for retrospective analysis because the quality and quantity of their biopsy specimens were adequate for histologic evaluation. We performed immunohistochemical staining to investigate the PD-L1 expression in both resected and biopsy specimens. The percentage of the positively stained cells was calculated for subsequent use in the correlation investigation. RESULTS: The biopsy methods were endoscopic retrograde cholangiopancreatography (ERCP) in 28 cases, percutaneous liver biopsy in 10 cases, and endoscopic ultrasound fine-needle aspiration in 7 cases. Among the 45 patients, when patients with > 10% positive tumor cells in surgically resected tissues were regarded as truly positive PD-L1, the positive and negative concordance rates between surgically resected tissues and biopsy samples were 56% (5/9) and 100% (36/36), respectively. With regard to the use of preoperative biopsy as a diagnostic tool, all (5/5) PD-L1-positive patients had a positive resected specimen. The accuracy of each biopsy method was as follows: ERCP, 89% (25/28); fine-needle aspiration, 86% (6/7); and liver biopsy, 100% (10/10). CONCLUSIONS: Biopsy samples could be a surrogate material for the assessment of the PD-L1 expression with substantial positive and high negative concordance rates.

Metformin ameliorates chronic colitis in a mouse model by regulating interferon-γ-producing lamina propria CD4+ T cells through AMPK activation.

Metformin, a commonly prescribed drug for type 2 diabetes mellitus, has been shown to activate AMP-activated protein kinase (AMPK). Notably, AMPK activation has recently been observed to be associated with anti-inflammatory responses. Metformin is also reported to elicit anti-inflammatory responses in CD4+ T cells, resulting in improvement in experimental chronic inflammatory diseases, such as systemic lupus erythematosus. To investigate the effect of metformin on inflammatory bowel disease (IBD), we developed a T cell-transfer model of chronic colitis in which SCID mice were injected with CD4+ CD45RBhigh T cells to induce colitis. We examined the effects of metformin via in vitro and in vivo experiments on lamina propria (LP) CD4+ T cells. We observed that metformin suppresses the frequency of interferon (IFN) -γ-producing LP CD4+ T cells in vitro, which were regulated by AMPK activation, a process possibly induced by the inhibition of oxidative phosphorylation. Furthermore, we examined the effects of metformin on an in vivo IBD model. Metformin-treated mice showed AMPK activation in LP CD4+ T cells and ameliorated colitis. Our study demonstrates that metformin-induced AMPK activation in mucosal CD4+ T cells contributes to the improvement of IBD by suppressing IFN-γ production. Moreover, our results indicate that AMPK may be a target molecule for the regulation of mucosal immunity and inflammation. Thus, AMPK-activating drugs such as metformin may be potential therapeutic agents for the treatment of IBD.

Leucine-rich alpha-2 glycoprotein as a marker of mucosal healing in inflammatory bowel disease.

Leucine-rich alpha-2 glycoprotein (LRG) may be a novel serum biomarker for patients with inflammatory bowel disease. The association of LRG with the endoscopic activity and predictability of mucosal healing (MH) was determined and compared with those of C-reactive protein (CRP) and fecal markers (fecal immunochemical test [FIT] and fecal calprotectin [Fcal]) in 166 ulcerative colitis (UC) and 56 Crohn's disease (CD) patients. In UC, LRG was correlated with the endoscopic activity and could predict MH, but the performance was not superior to that of fecal markers (areas under the curve [AUCs] for predicting MH: LRG: 0.61, CRP: 0.59, FIT: 0.75, and Fcal: 0.72). In CD, the performance of LRG was equivalent to that of CRP and Fcal (AUCs for predicting MH: LRG: 0.82, CRP: 0.82, FIT: 0.70, and Fcal: 0.88). LRG was able to discriminate patients with MH from those with endoscopic activity among UC and CD patients with normal CRP levels. LRG was associated with endoscopic activity and could predict MH in both UC and CD patients. It may be particularly useful in CD.

Multicenter survey on mesalamine intolerance in patients with ulcerative colitis.

BACKGROUND AND AIM: Although oral mesalamine is the first-choice drug for treating mild-to-moderate ulcerative colitis (UC), some patients show symptoms of intolerance, including exacerbation of diarrhea and abdominal pain. The present study clarified the current state and clinical courses of patients with mesalamine intolerance. METHODS: Patients who were diagnosed with UC and administered oral mesalamine at eight hospitals in Japan with a follow-up period exceeding 1 year were analyzed. RESULTS: Sixty-seven (11%) of 633 patients showed intolerance to at least one formulation of oral mesalamine. The frequency of mesalamine intolerance has increased in recent years, rising from 5.3% in 2007-2010 to 9.1% in 2011-2013 and 16.2% in 2014-2016. The most common complications were the exacerbation of diarrhea (n = 29), a fever (n = 25), and abdominal pain (n = 22). Readministration of mesalamine/sulfasalazine was attempted in 43 patients, mostly with other types of formulation of mesalamine, and more than half of these patients proved to be tolerant. The risk factors for mesalamine intolerance were female gender (odds ratio [OR] = 1.83; 95% confidence interval [CI], 1.08-3.12), age < 60 years old (OR = 2.82; CI, 1.19-8.33), and pancolitis (OR = 2.09; 95% CI, 1.23-3.60). There were no significant differences in the use of anti-tumor necrosis factor-α agents, colectomy, or steroid-free remission at the last visit between patients with and without mesalamine intolerance. CONCLUSIONS: Mesalamine intolerance is not rare, and its frequency has been increasing recently. The prognosis of patients with mesalamine intolerance did not differ significantly from that of those without intolerance.

Evaluation of complete cold forceps polypectomy resection rate for 3- to 5-mm colorectal polyps.

BACKGROUND AND STUDY AIMS: The propriety of cold forceps polypectomy (CFP) using jumbo biopsy forceps for diminutive polyps remains controversial. We conducted a prospective study to evaluate the complete CFP resection rate of 3-5-mm polyps using additional endoscopic mucosal resection (EMR) specimens following CFP. PATIENTS AND METHODS: Patients with 3-5-mm protruded or flat elevated colorectal polyps diagnosed endoscopically as adenomas or serrated lesions were prospectively enrolled. CFP using jumbo biopsy forceps was used to remove the eligible polyps and repeated until the absence of residuals were confirmed via image-enhanced endoscopy or chromoendoscopy. After CFP, saline was injected at the defect, and the marginal specimen of the defect was resected using EMR to histologically evaluate the residue. The primary outcome was the complete CFP resection rate, which was defined as no residue at the EMR site. Other outcomes were the number of CFP bites and the complete resection rate by lesion size. RESULTS: Eighty patients with 120 polyps were enrolled. The mean polyp size was 4.1 ± 0.7 mm. The overall complete resection rate was 96.7% (95% confidence interval [CI], 91.7-98.7), and the rates for 3-, 4- and 5-mm polyps were 100% (95% CI, 86.7-100), 96.0% (95% CI, 86.5-98.9) and 95.5% (95% CI, 85.1-98.8), respectively. The one-bite CFP rates were 92%, 60% and 31% for the 3-, 4- and 5-mm polyps, respectively. CONCLUSIONS: The complete CFP resection rate for 3-5-mm polyps was acceptable, although the one-bite clearance rate decreased as the polyp size increased (UMIN000028841).

Transabdominal ultrasound sonography findings in peritonitis due to the spread of Crohn's disease to the penetration.

In the presence of the clinical signs of peritonitis, transabdominal ultrasound sonography by experienced technicians or physicians could be a fast and reliable imaging tool for confirmation of disease status.

Liquid biopsy for patients with IBD-associated neoplasia.

BACKGROUND: It is often difficult to diagnose inflammatory bowel disease (IBD)-associated neoplasia endoscopically due to background inflammation. In addition, due to the absence of sensitive tumor biomarkers, countermeasures against IBD-associated neoplasia are crucial. The purpose of this study is to develop a new diagnostic method through the application of liquid biopsy. METHODS: Ten patients with IBD-associated cancers and high-grade dysplasia (HGD) with preserved tumor tissue and blood were included. Tumor and non-tumor tissues were analyzed for 48 cancer-related genes using next-generation sequencing. Simultaneously, circulating tumor DNA (ctDNA) was analyzed for mutations in the target genes using digital PCR. RESULTS: Out of 10 patients, seven had IBD-related cancer and three had IBD-related HGD. Two patients had carcinoma in situ; moreover, three had stageII and two had stage III. To avoid false positives, the mutation rate cutoff was set at 5% based on the control results; seven of 10 (70%) tumor tissue samples were mutation-positive. Mutation frequencies for each gene were as follows: TP53 (20.9%; R136H), TP53 (25.0%; C110W), TP53 (8.5%; H140Q), TP53 (31.1%; R150W), TP53 (12.8%; R141H), KRAS (40.0%; G12V), and PIK3CA (34.1%; R 88Q). The same mutations were detected in the blood of these seven patients. However, no mutations were detected in the blood of the remaining three patients with no tumor tissue mutations. The concordance rate between tumor tissue DNA and blood ctDNA was 100%. CONCLUSION: Blood liquid biopsy has the potential to be a new method for non-invasive diagnosis of IBD-associated neoplasia.

Factors Predicting a Favorable Disease Course Without Anti-TNF Therapy in Crohn's Disease Patients.

Determining factors that predict a favorable disease course without anti-tumor necrosis factor (TNF) agents would help establish a more cost-effective strategy for Crohn's disease (CD). A retrospective chart review was performed for CD patients with disease durations > 10 years who had not received anti-TNF agents as first-line therapy. Patients were divided into 2 groups: those who received neither anti-TNF agents nor bowel resection (G1), and those who had received an anti-TNF agent and/or bowel resection (G2). The patient backgrounds, therapies and clinical courses were compared between the groups. A total of 62 CD patients met the inclusion criteria (males: 71%; median duration of follow-up: 19 years). Six patients were included in G1; they were significantly less likely to have upper gastrointestinal lesions than G2 (p=0.007). A multivariate analysis revealed that the significant factors for avoidance of bowel resection without anti-TNF treatment were non-stricturing and non-penetrating behaviors, and absence of upper gastrointestinal lesions at the diagnosis (hazard ratios 0.41 and 0.52; p=0.004 and 0.04, respectively). In consideration of the long treatment course of CD, patients with non-stricturing and non-penetrating behaviors and no upper gastrointestinal lesions should not be treated with anti-TNF agents as first-line therapy.

Multiple Deep-seated Dentofacial Abscesses Caused by Multidrug-resistant Viridans Group Streptococci.

Odontogenic infections, generally caused by dental caries and periodontal disease, can result in fatal illness. We herein report a 71-year-old Japanese woman with type 2 diabetes and hemodialysis who suffered from multiple dentofacial abscesses mainly caused by multidrug-resistant Streptococcus oralis. She complained of pain and swelling of her face, with an extraoral fistula from the left cheek. Following 3 surgical debridement procedures and partial mandibulectomy, in addition to 12 weeks of antimicrobial therapy, the multiple dentofacial abscesses were ameliorated. A combination of surgical and antimicrobial treatments following an early diagnosis is essential for reducing further complications.

Observer agreement for the diagnosis of intestinal acute graft-vs.-host disease based on the presence of villous atrophy in the terminal ileum.

Intestinal graft-vs.-host disease (GVHD) is a serious complication of allo-hematopoietic stem cell transplantation (allo-HSCT). Villous atrophy in the terminal ileum is considered a useful diagnostic indicator for GVHD. However, the inter- and intra-observer agreement regarding the ileocolonoscopic findings indicative of acute intestinal GVHD, i.e., villous atrophy in the terminal ileum, are currently insufficient in multiple institutions. Thus, the present study aimed to investigate the incidence of villous atrophy in the terminal ileum to diagnose acute intestinal GVHD and determine the inter- and intra-observer agreement regarding this result for experienced endoscopists from multiple institutions. Consecutive patients who underwent allo-HSCT were referred to our institution between May 2008 and September 2015. A total of 54 patients underwent total ileocolonoscopy after allo-HSCT due to suspected intestinal acute GVHD. Subsequently, three observers from different institutions evaluated the cases for the presence of villous atrophy in the terminal ileum. In this study, the pathology results were a gold standard to evaluate the predictive value of ileocolonoscopy detection. Definitive pathological and non-pathological GVHD was diagnosed in 22 and 32 cases, respectively. The results of examining whether villous atrophy could predict GVHD were as follows. For three observers (A, B and C), the sensitivity of villous atrophy in the terminal ileum was 86.4, 77.3 and 79.2%, respectively, whereas the specificity was 62.5, 62.5 and 86.7%, respectively. The positive predictive value (PPV) and negative predictive value (NPV) of villous atrophy for GVHD were as follows: The PPV of appearance was 61.3, 58.6 and 82.6%, respectively, whereas the NPV was 87.0, 80.0 and 83.9%, respectively. Kappa coefficients for the inter-observer reliability were 0.85, 0.63 and 0.63 for observers A and B, A and C, and B and C, respectively. The intra-observer kappa coefficient was 0.88 for observer A, 0.73 for observer B and 0.75 for observer C. A substantial observer agreement was achieved for the analysis of villous atrophy in the terminal ileum and the agreement for the predictive histological diagnosis was also excellent. Based on the results of the present study, identification of villous atrophy in the terminal ileum was a clinically effective diagnostic parameter, even if different endoscopists were involved in the diagnosis at multiple institutions. The present study was registered as a trial with the University Hospital Medical Information Network (UMIN; registration no. UMIN000025390).