Real-World Data on the Effectiveness and Safety of Filgotinib for Ulcerative Colitis in Japanese Patients: A Single-Center Experience.

Introduction Filgotinib is a JAK-1 selective inhibitor approved for ulcerative colitis (UC) treatment in Japan. Its effectiveness has been confirmed but remains unknown in actual clinical practice. Therefore, we aimed to evaluate the effectiveness and safety of filgotinib and identify suitable patients in the Japanese population. Methods We retrospectively reviewed the background, clinical course, and laboratory data of patients treated with filgotinib 200 mg for UC between May 2022 and December 2023. Results The median observation period for the 25 patients was 232 days (interquartile ranges (IQR) 102-405). The median age of the patients was 43 years (IQR 29-55), disease duration was nine years (IQR 2-12), and 36% (9/25) of patients were biologic or small molecule naïve. The median patient-reported outcome (PRO2) and partial Mayo (pMayo) scores at agent initiation were 3 (IQR 1-4) and 4.5 (IQR 3-6), respectively. The PRO2 and pMayo scores improved significantly two weeks after treatment initiation (p < 0.05). Clinical remission rates at 24 weeks after treatment initiation were 60% (15/25) for PRO2 ≤ 1 and 52% (13/25) for pMayo ≤ 1. The Mayo endoscopic subscore significantly improved after filgotinib initiation (p=0.04), and the endoscopic remission rate was 47% (8/17). At 24 weeks, patients in clinical remission, compared to those not in remission, had significantly lower baseline PRO2 and pMayo scores and longer disease duration (p=0.03, p=0.03, and p=0.04, respectively). The filgotinib persistence rate was 68% (17/25), with no discontinuation because of adverse events. Patients who continued treatment had significantly lower PRO2, pMayo scores, and blood neutrophil counts at initiation than those who discontinued (p=0.02, p=0.03, and p=0.02, respectively). Conclusion Filgotinib appears to be effective and safe in Japanese patients with UC. Effectiveness and persistence were high in patients whose PRO2 and pMayo scores were low at the time of treatment initiation.

Red dichromatic imaging and linked color imaging as reliable image-enhanced endoscopic procedures for detecting the distal end of the palisade vessels in the columnar metaplastic mucosa of the gastroesophageal junction zone.

BACKGROUND: There is a consensus that identifying the distal end of the palisade vessels (DEPV) is important for diagnosing gastroesophageal junction (GEJ). However, optimum observation methods have not been established. This study investigated the use of effective image-enhanced endoscopy (IEE) for DEPV detection. METHODS: One hundred endoscopic images in 20 cases of columnar metaplastic mucosa of the GEJ recorded with white-light imaging (Olympus-WLI and Fujifilm-WLI) and IEEs (narrow-band imaging; RDI1/2/3, red dichromatic imaging; texture and color enhancement imaging 1/2; blue-laser imaging; and LCI, linked color imaging) from two manufacturers were extracted and evaluated by 10 evaluators. Up to 24 radial straight lines from the center of the lumen were placed on the image, and the evaluators placed markings according to confidence level (high, low, and not detectable) at the DEPV locations. The detectability and reproducibility at the rate of the confidence level and coefficient of variance of markings among the evaluator were analyzed. RESULTS: In total, 15,180 markings were obtained. In terms of detectability, RDI1 (49.4%), RDI2 (53.0%), RDI3 (54.1%), TXI2 (49.7%), and LCI (34.6%) had a significantly higher rate of high confidence among the IEEs in each manufacturer. By contrast, Olympus-WLI (40.6%), Fujifilm-WLI (17.6%), narrow-band imaging (15.9%), and blue laser imaging (9.8%) presented with a significantly lower rates of high confidence. Regarding reproducibility, RDI3 and LCI had the lowest coefficient of variance for each manufacturer. CONCLUSIONS: RDI and LCI could be reliable modalities for detecting DEPVs in the columnar metaplastic mucosa of the GEJ zone.

Pancreatico-renal fistula associated with pancreatic cysts caused by type 1 autoimmune pancreatitis.

To our best knowledge, the formation of a pancreatico-renal fistula and the presence of pancreatic fluid collection in the renal subcapsular space have not been reported as autoimmune pancreatitis (AIP) complications. We describe a case of a pancreatico-renal fistula associated with type 1 AIP. The patient presented with abdominal and back pain accompanied by pancreatic cystic lesions during an untreated course of AIP. The diagnosis of pancreatico-renal fistula was based on the presence of a left renal subcapsular fluid collection containing pancreatic amylase, disappearance of pancreatic cysts, and a defect in the partial anterior renal fascia observed on imaging studies. Treatment with steroids and percutaneous drainage resulted in improvement. Pancreatic pseudocysts can affect other organs owing to their digestive action. Similar symptoms may occur in patients with AIP.

An effective endoscopic hand-suturing method for fistula closure after endoscopic transgastric drainage for walled-off necrosis.

Video 1How to use an endoscopic hand-suturing device (video version).

Hetero-oligomerization of TDP-43 carboxy-terminal fragments with cellular proteins contributes to proteotoxicity.

Carboxy terminal fragments (CTFs) of TDP-43 contain an intrinsically disordered region (IDR) and form cytoplasmic condensates containing amyloid fibrils. Such condensates are toxic and associated with pathogenicity in amyotrophic lateral sclerosis. However, the molecular details of how the domain of TDP-43 CTFs leads to condensation and cytotoxicity remain elusive. Here, we show that truncated RNA/DNA-recognition motif (RRM) at the N-terminus of TDP-43 CTFs leads to the structural transition of the IDR, whereas the IDR itself of TDP-43 CTFs is difficult to assemble even if they are proximate intermolecularly. Hetero-oligomers of TDP-43 CTFs that have recruited other proteins are more toxic than homo-oligomers, implicating loss-of-function of the endogenous proteins by such oligomers is associated with cytotoxicity. Furthermore, such toxicity of TDP-43 CTFs was cell-nonautonomously affected in the nematodes. Therefore, misfolding and oligomeric characteristics of the truncated RRM at the N-terminus of TDP-43 CTFs define their condensation properties and toxicity.

Stress Granule Dysfunction via Chromophore-Associated Light Inactivation.

Stress granules (SGs) are cytoplasmic condensates composed of various proteins and RNAs that protect translation-associated machinery from harmful conditions during stress. However, the method of spatiotemporal inactivation of condensates such as SGs in live cells to study cellular phenotypes is still in the process of being demonstrated. Here, we show that the inactivation of SGs by chromophore-associated light inactivation (CALI) using a genetically encoded red fluorescence protein (SuperNova-Red) as a photosensitizer leads to differences in cell viability during recovery from hyperosmotic stress. CALI delayed the disassembly kinetics of SGs during recovery from hyperosmotic stress. Consequently, CALI could inactivate the SGs, and the cellular fate due to SGs could be analyzed. Furthermore, CALI is an effective spatiotemporal knockdown method for intracellular condensates/aggregates and would contribute to the elucidation of importance of such condensates/aggregates.

Association between colonic adenoma size and proliferative zone in the crypt.

BACKGROUND: We previously reported unusual adenomas with proliferative zones confined to the lower two-thirds of the crypt. The proliferative zones of colorectal adenomas have three patterns: 'lower,' 'superficial' and 'entire'. This study aimed to clarify the characteristics of each adenoma pattern. METHODS: We investigated 2925 consecutive patients who underwent colonoscopy at our institute. All polyps that were removed were histologically examined using hematoxylin and eosin staining. The location of the proliferative zone was assessed for adenomas. Data were compared using Dunn's and Kruskal-Wallis tests. RESULTS: Colorectal adenomas with 'lower' proliferative zone often appeared similar to hyperplastic polyps (42.8%), and the frequency was significantly higher than that of adenomas with 'superficial' and 'entire' proliferative zones (p < 0.001). The mean sizes of adenomas were 2.4, 3.0 and 3.9 mm for 'lower,' 'superficial' and 'entire' proliferative zones, respectively. A significant gradual increase was observed. Regarding morphology, the proportion of type 0-I in adenomas with an 'entire' proliferative zone was significantly higher than that in adenomas with 'superficial' proliferative zone (p < 0.001). CONCLUSION: While colorectal adenomas develop and increase in size, the proliferative zone appears to shift upward and become scattered.

Clinicopathological characteristics of Lynch-like syndrome.

BACKGROUND: Lynch-like syndrome (LLS) has recently been proposed as a third type of microsatellite instability (MSI) tumor after Lynch syndrome (LS) and sporadic MSI colorectal cancer (CRC) without either a germline variant of mismatch repair (MMR) genes or hypermethylation of the MLH1 gene. The present study aimed to clarify and compare the clinicopathological characteristics of LLS with those of the other MSI CRC subtypes. METHODS: In total, 2634 consecutive patients with CRC who underwent surgical resection and subsequently received universal tumor screening (UTS), including MSI analysis were enrolled between January 2008 and November 2019. Genetic testing was performed in patients suspected of having Lynch syndrome. RESULTS: UTS of the cohort found 146 patients with MSI CRC (5.5%). Of these, excluding sporadic MSI CRC, 30 (1.1%) had a diagnosis of LS, and 19 (0.7%) had no germline pathogenic variants of the MMR gene. The CRC type in the latter group was identified as LLS. LLS occurred significantly more often in young patients, was left-sided, involved a KRAS variant and BRAF wild-type, and had a higher concordance rate with the Revised Bethesda Guidelines than sporadic MSI CRC. No significant differences were observed in terms of the clinicopathological factors between LLS and LS-associated MSI CRC; however, LLS had a lower frequency of LS-related neoplasms compared with LS. CONCLUSIONS: Distinguishing clinically between LS and LLS was challenging, but the incidence of neoplasms was higher in LS than in LLS, suggesting the need for different screening and surveillance methods for the two subtypes.

A Novel Hemostatic Peptide Solution for Common Acute Gastrointestinal Bleeding Diseases: First Case Series Study on the Treatment Results of Endoscopic Hemostasis by Nonexpert Endoscopists.

INTRODUCTION: We investigated the hemostatic effect and safety of a hemostatic peptide solution for the treatment of gastrointestinal bleeding requiring emergency endoscopy. METHODS: We retrospectively examined the patient backgrounds, hemostatic results, and procedural safety in patients who were treated with a hemostatic peptide solution for hemostasis during emergency endoscopies for gastrointestinal bleeding. All hemostatic procedures were performed by nonexpert physicians with less than 10 years of endoscopic experience. All of the cases were treated at a single institution over the months from January 2022 to January 2023. RESULTS: Twenty-six consecutive patients (17 males and 9 females) with a median age of 74 (45-95) years were included. Their conditions requiring emergency endoscopy were melena in 8 patients, hematochezia in 2, hematemesis in 8, anemia in 6, and bleeding during esophagogastroduodenoscopy in 2. The sites of bleeding were the esophagus in 3 patients, the stomach in 17, the duodenum in 3, the small intestine in 2, and the colon in 1. Hemostasis was obtained with another hemostasis device used in conjunction with the hemostatic peptide solution in 13 cases and with the hemostatic peptide solution alone in 13 cases. The hemostasis success rate was 100%, with no complications. Rebleeding occurred within 1 week in 4 cases. CONCLUSION: Hemostasis with the hemostatic peptide solution was safe and provided a temporary high hemostatic effect in emergency gastrointestinal endoscopy.

Changes in oral microflora following 0.3% cetylpyridinium chloride-containing mouth spray intervention in adult volunteers after professional oral care: Randomized clinical study.

OBJECTIVES: This study explored the changes in bacterial flora composition and total bacterial count in the saliva and tongue coating, along with the change in the tongue coating index (TCI) following an intervention with 0.3% cetylpyridinium chloride (CPC) mouth spray after professional oral care. MATERIALS AND METHODS: Fifty-two adult volunteers aged 30-60 years were equally divided into CPC spray (n = 26) and control (n = 26) groups. All subjects underwent scaling and polishing. The CPC spray group was administered four puffs of CPC spray to the tongue dorsum four times a day for 3 weeks. The control group performed only routine daily oral care (brushing) and did not use any other spray. Bacteriological evaluation of saliva and tongue coating was performed using 16S ribosomal RNA gene sequencing and quantitative polymerase chain reaction. The tongue coating was evaluated to calculate the TCI. A per-protocol analysis was conducted for 44 subjects (CPC spray group, n = 23; control group, n = 21). RESULTS: At 1 and 3 weeks after CPC spray use, the flora of the saliva and tongue coating changed; the genus Haemophilus was dominant in the CPC spray group, whereas the genus Saccharibacteria was dominant in the control group. The sampling time differed among individual participants, which may have affected the bacterial counts. There was no significant intragroup change in TCI in either group. CONCLUSIONS: CPC spray affected the bacterial flora in the saliva and tongue coating, particularly with respect to an increase in the abundance of Haemophilus. However, CPC spray did not change the TCI. These results suggest that it may be optimal to combine CPC spray with a physical cleaning method such as using a tongue brush or scraper. Clinical Trial Registration: University Hospital Medical Information Network UMIN000041140.

Multiple ulcerative colitis-associated aseptic abscesses successfully treated with infliximab: a case report.

Aseptic abscesses are rare extraintestinal manifestations of inflammatory bowel disease. Herein, we present the case of a 69-year-old female patient with ulcerative colitis in whom multiple aseptic abscesses were successfully treated with infliximab. Aseptic abscesses associated with ulcerative colitis are difficult to differentiate from infectious abscesses. In the present case, we reached a diagnosis of aseptic abscesses associated with ulcerative colitis as antibiotics were ineffective and repeated Gram stains and cultures of blood and abscess were negative. Aseptic abscesses are commonly found in the spleen, lymph nodes, liver, and skin; however, in the present case, the periosteum was the major site. Prednisolone is often effective for aseptic abscesses; however, the present patient was initially treated with a combination of 40 mg/day of prednisolone and granulocyte and monocyte adsorption apheresis, with inadequate effect. Infliximab was administered as the patient was steroid-resistant, with strong effect. Subsequently, infliximab treatment has been continued, with no recurrence after 2 years. However, as there have been reports of cases of recurrence even after remission with treatment, careful follow-up in the future is therefore necessary.

Simple drainage versus drainage with minocycline infusion for symptomatic hepatic cysts.

Percutaneous treatment of symptomatic hepatic cysts includes simple drainage and drainage with sclerosing agents. We compared the efficacy of simple drainage with that of drainage with minocycline infusion for treating symptomatic hepatic cysts. We retrospectively evaluated 11 patients who underwent percutaneous drainage of symptomatic hepatic cysts. In seven cases, minocycline infusion was added at the discretion of the clinician. Cyst volume was evaluated before drainage, immediately after drainage, and after long-term follow-up. Cyst volume was calculated before treatment by multiplying the orthogonal diameters using the ellipsoid formula. Relapse was defined as the regrowth of the cyst with symptoms. Cyst volume immediately after drainage and after long-term follow-up was significantly less than that before treatment for the drainage with minocycline infusion group (p<0.05) but not for the simple drainage group. The relapse rates were 25% (1/4) for the simple drainage group and 0% for the drainage with minocycline infusion group. Drainage with minocycline infusion could be a promising option for treating symptomatic hepatic cysts, although simple drainage was not reliable.

Efficacy and Safety of a Novel Hemostatic Peptide Solution During Endoscopic Submucosal Dissection: A Multicenter Randomized Controlled Trial.

INTRODUCTION: To compare the effectiveness of the novel hemostatic peptide, TDM-621, with that of conventional hemostatic methods in treating intraoperative blood oozing during endoscopic submucosal dissection (ESD). METHODS: This multicenter, open-label, randomized controlled trial involved 227 patients with gastric and rectal epithelial tumors in whom ESD was indicated. Patients in whom the source of blood oozing was difficult to identify with waterjet washing during the procedure and required hemostasis with hemostatic forceps were randomly assigned to the TDM-621 and control groups. The TDM-621 group (in which hemostasis was achieved with TDM-621, followed by coagulation hemostasis with hemostatic forceps, as needed) was compared with the control group (in which hemostasis was achieved with hemostatic forceps). The primary end point was the mean number of coagulations with hemostatic forceps, determined by a blinded independent review committee. The secondary end points were the rate of achievement of hemostasis with only TDM-621, the dosage of TDM-621, and adverse events in the TDM-621 group. RESULTS: The mean number of coagulations with hemostatic forceps was significantly reduced in the TDM-621 group (1.0 ± 1.4) compared with that in the control group (4.9 ± 5.2) ( P < 0.001). The rate of hemostasis achievement with only TDM-621 was 62.2%; the mean dosage of TDM-621 was 1.75 ± 2.14 mL. The rates of grade ≥3 adverse events were 6.2% and 5.0% in the TDM-621 and control groups, respectively. DISCUSSION: TDM-621 is a useful, easily operable hemostatic peptide for treatment of blood oozing during gastric and rectal ESD, with no serious safety concerns.

Dual functions of discoidinolysin, a cholesterol-dependent cytolysin with N-terminal discoidin domain produced from Streptococcus mitis strain Nm-76.

Background: Some strains of Streptococcus mitis exhibit ß-hemolysis due to the ß-hemolytic activity of cholesterol-dependent cytolysin (CDC). Recently, a gene encoding an atypical lectinolysin-related CDC was found in S. mitis strain Nm-76. However, the product of this gene remains uncharacterized. We aimed to characterize this atypical CDC and its molecular functions and contribution to the pathogenicity of S. mitis strain Nm-76. Methods: Phylogenetic analysis of the CDC gene was conducted based on the web-deposited information. The molecular characteristics of CDC were investigated using a gene-deletion mutant strain and recombinant proteins expressed in Escherichia coli. Results: The gene encoding CDC found in Nm-76 and its homolog are distributed among many S. mitis strains. This CDC is phylogenetically different from other previously characterized CDCs, such as S. mitis-derived human platelet aggregation factor (Sm-hPAF)/lectinolysin and mitilysin. Because this CDC possesses an additional N-terminal domain, including a discoidin motif, it was termed discoidinolysin (DLY). In addition to the preferential lysis of human cells, DLY displayed N-terminal domain-dependent facilitation of human erythrocyte aggregation and intercellular associations between human cells. Conclusion: DLY functions as a hemolysin/cytolysin and erythrocyte aggregation/intercellular association molecule. This dual-function DLY could be an additional virulence factor in S. mitis.

Endoscopic hand suturing for mucosal defect closure after gastric endoscopic submucosal dissection may reduce the risk of postoperative bleeding in patients receiving antithrombotic therapy.

OBJECTIVES: Endoscopic hand suturing (EHS) is expected to decrease the risk of post-endoscopic submucosal dissection (ESD) bleeding by closing mucosal defects. We investigated the efficacy of EHS after gastric ESD in patients with antithrombotic agents. METHODS: In this prospective single-arm trial, patients taking antithrombotic agents for cardiovascular disease, arrhythmia, cerebrovascular disease and/or peripheral arterial disease and having <3-cm gastric neoplasms were recruited. The mucosal defects after ESD were closed by EHS in which the needle was delivered through an overtube, and the mucosal rim of the defect was continuously sutured in a linear fashion by manipulating the needle grasped with the needle holder, followed by cutting the remnant suture and retrieval of the needle. The primary endpoint was the incidence of postoperative bleeding within 4 weeks after ESD. RESULTS: Twenty-two lesions in 20 patients (continuing antiplatelet agents in 11, anticoagulant agents in eight, both in one) underwent ESD followed by EHS. All defects (median size, 30 mm; range, 12-51 mm) were completely closed by EHS and remained closed on postoperative day 3. The median number of stitches was six (range, 4-8) and median suturing time was 36 (range, 24-60) min. There were no adverse events during/after EHS or postoperative bleeding. CONCLUSIONS: Postoperative bleeding was not observed in patients taking antithrombotic agents without perioperative cessation. EHS appears to be useful for prevention of post-gastric ESD bleeding in high-risk patients. (Clinical registration number: UMIN000024184).

Evaluation of the visibility of bleeding points using red dichromatic imaging in endoscopic hemostasis for acute GI bleeding (with video).

BACKGROUND AND AIMS: We aimed to clarify whether red dichromatic imaging (RDI), a new type of image-enhanced endoscopy, improves the visibility of bleeding points in acute GI bleeding (AGIB) compared with white-light imaging (WLI). METHODS: Images and videos of bleeding points acquired with WLI and RDI during endoscopic hemostasis for AGIB were retrospectively compared. In images, the color difference between bleeding points and surrounding blood was analyzed. In videos, 4 expert and 4 trainee endoscopists evaluated the visibility on a scale of 1 (undetectable) to 4 (easily detectable). Furthermore, the correlation between the color difference and visibility score was evaluated. RESULTS: We analyzed 64 lesions. The color difference was significantly higher in RDI (13.11 ± 4.02) than in WLI (7.38 ± 3.68, P < .001). The mean visibility score for all endoscopists was significantly higher in RDI (3.12 ± .51) compared with WLI (2.72 ± .50, P < .001); this was also observed in experts (3.18 ± .51 vs 2.79 ± .54, P < .001) and trainees (3.05 ± .54 vs 2.64 ± .47, P < .001). The color difference and visibility score were moderately correlated for all endoscopists (γ = .56, P < .001) and for experts (γ = .53, P < .001) and trainees (γ = .57, P < .001). CONCLUSIONS: RDI improves the visibility of bleeding points in AGIB compared with WLI. RDI can help endoscopists at all levels of experience to recognize bleeding points by enhancing the color contrast relative to surrounding blood.

Clinical usefulness of red dichromatic imaging in hemostatic treatment during endoscopic submucosal dissection: First report from a multicenter, open-label, randomized controlled trial.

OBJECTIVES: To verify the efficacy and safety of red dichromatic imaging (RDI) in hemostatic procedures during endoscopic submucosal dissection (ESD). METHODS: This is a multicenter randomized controlled trial of 404 patients who underwent ESD of the esophagus, stomach, colorectum. Patients who received hemostatic treatments by RDI during ESD were defined as the RDI group (n = 204), and those who received hemostatic treatments by white light imaging (WLI) were defined as the WLI group (n = 200). The primary endpoint was a shortening of the hemostasis time. The secondary endpoints were a reduction of the psychological stress experienced by the endoscopist during the hemostatic treatment, a shortened treatment time, and a non-inferior perforation rate, in RDI versus WLI. RESULTS: The mean hemostasis time in RDI (n = 860) was not significantly shorter than that in WLI (n = 1049) (62.3 ± 108.1 vs. 56.2 ± 74.6 s; P = 0.921). The median hemostasis time was significantly longer in RDI than in WLI (36.0 [18.0-71.0] vs. 28.0 [14.0-66.0] s; P = 0.001) in a sensitivity analysis. The psychological stress was significantly lower in RDI than in WLI (1.71 ± 0.935 vs. 2.03 ± 1.038; P < 0.001). There was no significant difference in the ESD treatment time between RDI (n = 161) and WLI (n = 168) (58.0 [35.0-86.0] vs. 60.0 [38.0-88.5] min; P = 0.855). Four perforations were observed, but none of them took place during the hemostatic treatment. CONCLUSIONS: Hemostatic treatment using RDI does not shorten the hemostasis time. RDI, however, is safe to use for hemostatic procedures and reduces the psychological stress experienced by endoscopists when they perform hemostatic treatment during ESD. UMIN000025134.

Pseudomelanosis Duodeni Appearing after Oral Iron Therapy.

Pseudomelanosis duodeni is a rare condition characterized by the endoscopic appearance of diffuse dark pigmentation of the duodenal mucosa. It is typically seen in older women and has been reported to be associated with hypertension, chronic renal disease, diabetes mellitus, gastrointestinal hemorrhage, and the use of medications such as oral iron, furosemide, thiazide, hydralazine, and propranolol. We present a case of pseudomelanosis duodeni appearing after 2 years of oral iron therapy in an 85-year-old woman. Although oral iron supplementation seemed the strongest possible etiology, our patient had multiple comorbidities and was on other medications that have been described as associations. The majority of individuals taking oral iron or under these clinical conditions do not develop this entity; some other factors in patients may be responsible for its occurrence.