Efficacy and Safety of Upadacitinib Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis as Induction for Intractable Ulcerative Colitis.

Monotherapy with a selective Janus kinase (JAK) inhibitor or intensive granulocyte and monocyte adsorptive apheresis (GMA) has been limited to patients with intractable ulcerative colitis (UC). No previous reports have described the efficacy including histopathological evaluations and the safety of combination therapy with upadacitinib (UPA) plus intensive GMA (two sessions per week) for intractable UC showing resistance to conventional agents and adalimumab. This retrospective study evaluated the 10-week clinical and histopathological efficacy of induction combination therapy with UPA plus intensive GMA in patients with intractable UC. Among eight patients (moderate UC, n = 1; severe UC, n = 7) who received combination therapy with UPA plus intensive GMA, 50.0% had achieved clinical remission by 10 weeks. Percentages of patients with histological-endoscopic mucosal improvement and mucosal healing at 10 weeks were 62.5% and 12.5%, respectively. After excluding one patient who discontinued treatment by week 10 because of intolerance for UPA, mean full Mayo score, endoscopic subscore and C-reactive protein concentration at baseline were 11.43 ± 0.37, 3 ± 0 and 1.29 ± 0.70 mg/dL, respectively. Corresponding values at 10 weeks were 2.28 ± 0.77 (P < 0.03), 1.14 ± 0.34 (P < 0.03) and 0.03 ± 0.008 mg/dL (P < 0.05), respectively. Adverse events of herpes zoster, temporary increase in creatinine phosphokinase and anemia were observed in one patient each. One patient discontinued combination therapy at week 4 because of temporary taste abnormality due to UPA. Combination comprising UPA plus intensive GMA appears likely to achieve satisfactory induction of clinical remission and histopathological improvement for patients with intractable UC for whom conventional agents and anti-tumor necrosis factor-α antibody have failed.

Late-onset Rupture of the Intrahepatic Pseudoaneurysm Developed by Endoscopic Ultrasonography-guided Hepaticogastrostomy: A Case Report and Literature Review.

Endoscopic ultrasonography-guided hepaticogastrostomy (EUS-HGS) has emerged as an alternative drainage technique for patients with malignant biliary obstruction. However, few reports have discussed the occurrence of late-onset rupture of hepatic artery pseudoaneurysms following EUS-HGS. A recently available drill dilator equipped with a long screw segment was used in the dilation step of EUS-HGS. We highlight the potential concern that this long screw segment may increase the risk of damage to the hepatic artery, leading to late-onset life-threatening rupture of a pseudoaneurysm.

Impact of a Time-Related Benchmark on the Adenoma Detection Rate in Surveillance Colonoscopy: A STROBE Statement-Oriented Cross-Sectional Cohort Study.

BACKGROUND/AIMS: Colorectal adenomas are precursor lesions of globally increasing colorectal cancer. Hence, a high adenoma detection rate in colonoscopy is pivotal. We investigated the clinical impact of stratified colonoscopy observation time combined with observation time/intubation time ratio on the detection of colorectal adenomas. MATERIALS AND METHODS: We conducted a single-center retrospective study including 369 consecutive patients who underwent colonoscopy following fecal immunochemical tests between May 2021 and April 2022. The primary outcome measure was the impact of the stratified observation time and observation time/ intubation time ratio (category 1: <6.0 minutes and <1.0, category 2: <6.0 minutes and ≥1.0, category 3: ≥6.0 minutes and <1.0, and category 4: ≥6.0 minutes and ≥1.0) on adenoma detection rate. RESULTS: Cecum intubation was obtained in 367 patients (99.5%). Adenomas were detected in 226 patients (61.2%). From the univariate analysis, age ≥53 years, habitual alcohol intake, colonoscopy attachment (+), and observation time with observation time/intubation time ratio categories 3 and 4 were determined as significant factors for adenoma detection rate. From the logistic regression analysis, age ≥ 53 years (odds ratio: 4.86, 95% CI: 2.25-10.52), habitual alcohol intake (odds ratio: 2.26, 95% CI: 1.33-3.82), category 3 (odds ratio: 3.66, 95% CI: 1.81-7.45), and category 4 (odds ratio: 5.60, 95% CI: 2.92-10.73) were significant factors for adenoma detection rate. CONCLUSION: We propose the observation time with observation time/intubation time ratio combined benchmark (with categories' thresholds based on observation time >6 minutes and scope withdrawal time exceeding intubation time [observation time/intubation time ratio > 1]) as a novel colonoscopy quality indicator. These findings represent an important educational message for endoscopists.

A novel concept of passive loop-forming wire-guided biliary cannulation using an ultra-deep angled tip guidewire (with video).

Background and study aims Wire-guided biliary cannulation (WGBC) is a standard technique during endoscopic retrograde cholangiopancreatography-related interventions. However, no dedicated guidewire is available. We investigated a novel "passive loop-forming WGBC" concept using a 0.035-inch ultra-deep angled tip guidewire. Patients and methods This single-arm, single-center, retrospective study included consecutive 111 patients who underwent passive loop-forming WGBC as the first biliary intervention between October 2021 and December 2022. Results WGBCs were completed within 5 minutes and overall were performed at a median papillary negotiation time of 81 seconds (interquartile range [IQR], 39-170) and 114 seconds (IQR, 49-303) in 83 (74.8%) and 106 (95.5%) cases, respectively. Logistic regression analysis identified age ≥ 80 years (odds ratio [OR]: 3.56, 95% confidence interval [CI]: 1.12-11.31) and unintentional pancreatic guidewire insertion (OR: 17.67, 95% CI: 5.75-54.31) as significant risk factors for failed WGBC within 5 minutes. Among the 106 obtained cannulations, the guidewire leading part formed a small-looped tip and wide-looped body in 83 (78.3%) and 23 (21.7%) cases, respectively. Adverse events included post-procedure pancreatitis (2/111 [1.8%]) and guidewire penetration (3/111 [2.7%]). Conclusions Passive loop-forming WGBC using an ultra-deep angled tip guidewire is a feasible procedure.

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.

Reovirus combined with a STING agonist enhances anti-tumor immunity in a mouse model of colorectal cancer.

Reovirus, a naturally occurring oncolytic virus, initiates the lysis of tumor cells while simultaneously releasing tumor antigens or proapoptotic cytokines in the tumor microenvironment to augment anticancer immunity. However, reovirus has developed a strategy to evade antiviral immunity via its inhibitory effect on interferon production, which negatively affects the induction of antitumor immune responses. The mammalian adaptor protein Stimulator of Interferon Genes (STING) was identified as a key regulator that orchestrates immune responses by sensing cytosolic DNA derived from pathogens or tumors, resulting in the production of type I interferon. Recent studies reported the role of STING in innate immune responses to RNA viruses leading to the restriction of RNA virus replication. In the current study, we found that reovirus had a reciprocal reaction with a STING agonist regarding type I interferon responses in vitro; however, we found that the combination of reovirus and STING agonist enhanced anti-tumor immunity by enhancing cytotoxic T cell trafficking into tumors, leading to significant tumor regression and survival benefit in a syngeneic colorectal cancer model. Our data indicate the combination of reovirus and a STING agonist to enhance inflammation in the tumor microenvironment might be a strategy to improve oncolytic reovirus immunotherapy.

A Rare Case of New-Onset Crohn's Disease in a Patient With Chronic Palmoplantar Pustulosis.

A 44-year-old woman who had been diagnosed with palmoplantar pustulosis (PPP) at 34 years old was diagnosed with moderate Crohn's disease (CD) based on endoscopic, radiological, and pathological findings. As treatment with corticosteroids, ultraviolet, and cyclosporin had achieved partial response, PPP had been refractory in a chronic continuous state. Oral prednisolone was initially started to treat CD, but clinical remission was not achieved. Intravenous ustekinumab was subsequently started at 260 mg for clinical remission of CD. Eight weeks after starting ustekinumab, clinical remission and mucosal healing were achieved and PPP manifestations on the palms and soles were markedly improved. Ustekinumab appears to offer an effective therapeutic option for patients with PPP but has yet to be approved for this induction in Japan. CD is a rare gastrointestinal involvement in PPP patients that requires attention.

Induction Therapy With a Combination of Weekly Adalimumab Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis in Patients With Ulcerative Colitis and Failure of Conventional Agents, Biologics and Janus Kinase Inhibitor.

Every-week (ew) adalimumab (ADA) maintenance following induction therapy with a standard induction regimen has recently been approved for use in Japan. The efficacy and safety of combination therapy with ew-ADA maintenance following standard induction regimen plus intensive granulocyte and monocyte adsorptive apheresis (GMA) (two sessions/week) for the treatment of refractory ulcerative colitis (UC) displaying failure of conventional, biologics and Janus kinase inhibitor have not been evaluated previously. The present retrospective study evaluated the 10-week efficacy of this combination therapy among refractory UC patients. Six patients were given initial ADA combination therapy (ADA at 160 mg in week 0, ADA 80 mg in week 2, and 40 mg in week 4, followed by ew-ADA at 40 mg/week) plus intensive GMA. One patient (16.6%) achieved clinical remission and two patients (33.3%) achieved endoscopic improvement by week 10. After excluding two patients who discontinued treatment, mean full Mayo score (P = 0.14), endoscopic subscore (P = 0.18) and C-reactive protein level (P = 0.27) at 10 weeks were numerically decreased compared with baseline in the remaining four cases, although the differences were not significant. Use of ew-ADA maintenance following standard induction regimen plus intensive GMA appears unlikely to achieve satisfactory induction of clinical remission in UC patients for whom conventional agents, biologics and Janus kinase inhibitors have failed.

A Transanal Endoscopic Ultrasound-guided Fine-needle Aspiration Biopsy for an Intrapelvic Tumor Diagnosed as Recurrence of a Smooth Muscle Tumor of Uncertain Malignant Potential Following Uterine Morcellation.

A transoral endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) is a well-established tissue-sampling method. However, performing a transanal EUS-FNAB remains challenging. Uterine morcellation has emerged as a minimally invasive approach for benign tumor treatment. However, uterine myomas are heterogeneous and include malignant and indeterminate malignant cells. We herein report a rare case of intrapelvic tumor diagnosed by a transanal EUS-FNAB as a recurrence of smooth muscle tumors of uncertain malignant potential following uterine morcellation. Physicians should be aware that a previous uterine myoma resected under morcellation has the possibility of intra-abdominal recurrence. A transanal EUS-FNAB is a practical option for making a pathological diagnosis.

Potential Risk of Misjudgment in the Decision-making Process Based on the 2018 Tokyo Guidelines in Older Patients with Acute Cholecystitis.

Objective The 2018 Tokyo Guidelines (TG18) were published to facilitate the decision-making processes (DMP), including the diagnosis and operation of acute cholecystitis (AC). However, only a few guidelines consider older adults. This study evaluated the DMP based on the TG18, focusing on older patients with AC. Methods This was a single-armed, single-center retrospective study. The primary outcome measure was the "undiagnosable" AC rate, and the secondary outcome measure was the degree of concordance of "unfit for surgery" decisions. Patients Two hundred and nine patients with AC. Results Sixty (28.7%) of 209 patients with AC were "undiagnosable" on admission based on the TG18 criteria. The numbers and rate of "undiagnosable" AC in patients ≤59, 60-79, and ≥80 years old were 4 (10.0%), 20 (24.4%), and 36 (41.4%), respectively (p<0.001). The multiple logistic regression analysis following the univariate analysis revealed that age >73 years old was the most significant risk factor for undiagnosable AC [p=0.006, odds ratio (OR): 3.06, 95% confidence interval (CI): 1.38-6.81]. Female sex (p=0.033, OR: 2.09, 95% CI: 1.06-4.09) and severe AC (p=0.049, OR: 2.97, 95% CI: 1.01-8.76) were also significant risk factors for undiagnosable AC. The number of cases unfit for surgery based on the Charlson Comorbidity Index and American Society of Anesthesiologists physical status was 90 (43.1%) and 75 (35.9%), respectively. The κ value between these 2 indicators revealed a minimal concordance of 0.33 (95% CI: 0.20-0.47). Conclusion The DMP based on the TG18 potentially harbors a misjudgment risk, especially in older patients with AC (UMIN000047715).

Upadacitinib Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis for Ulcerative Colitis Achieved Ulcer Healing for Pyoderma Gangrenosum.

A 44-year-old woman who had been diagnosed with ulcerative colitis (UC) at 22 years old was diagnosed with severe flare-up of UC based on endoscopic findings associated with new-onset active pyoderma gangrenosum (PG) on both lower legs after she decided to discontinue UC treatment. Systemic treatment with intravenous prednisolone at 30 mg/day had achieved insufficient response to UC and PG, resulting in a diagnosis of corticosteroid-refractory UC and PG. Combination therapy with upadacitinib at 45 mg/day plus intensive granulocyte and monocyte adsorptive apheresis (GMA) was started to achieve clinical remission of UC. Ten weeks after starting this combination therapy, clinical improvement of UC was achieved with PG ulcer healing on both lower legs. A combination of upadacitinib plus intensive GMA may offer an effective therapeutic option for patients with active PG in addition to UC but has yet to be approved for induction or maintenance treatment of PG worldwide. PG is a dermatological involvement in UC patients that requires attention.

Acute Promyelocytic Leukemia in a Patient With Chronic Continuous Type of Crohn's Disease.

Chronic inflammation can induce leukemogenic mutations in hematopoietic stem cells (HSCs). We report a case of acute promyelocytic leukemia (APL) in a patient with chronic continuous type of Crohn's disease. The patient had been diagnosed with Crohn's disease at the age of 28 years and had received conventional treatments with biologics, but not azathioprine. At the age of 51, he was diagnosed with APL with ider(17). Long-term exposure to chronic continuous inflammation from Crohn's disease might be a factor inducing genomic instability in HSCs, which lead to the subsequent development of APL. APL is a rare hematological manifestation that required attention in Crohn's disease patients.

Higher vs Standard Adalimumab Induction and Maintenance Dosing Regimens for Treatment of Ulcerative Colitis: SERENE UC Trial Results.

BACKGROUND & AIMS: SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction and maintenance dose regimens in patients with ulcerative colitis. METHODS: This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18-75 years, full Mayo score 6-12, centrally read endoscopy subscore 2-3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens. RESULTS: In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069). In the integrated (main + Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (nominal P = .045). Safety profiles were comparable between dosing regimens. CONCLUSION: Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. CLINICALTRIALS: gov, Number: NCT002209456.

Relationship between gene mutations and clinicopathological features in nonampullary duodenal epithelial tumors.

BACKGROUND: Molecular features of nonampullary duodenal epithelial tumors (NADETs) remain unclear. AIM: The aim of this study is to determine the association between the genetic features and clinicopathological findings of NADETs. METHODS: In total, 75 NADETs were enrolled in this study, and was performed targeted DNA sequencing of the GNAS, KRAS, TP53, and APC genes. Histological grade was classified as category 3 or category 4/5 according to the Vienna classification, and the immunophenotype was categorized as the gastric phenotype (G type), gastrointestinal phenotype (GI type), or the intestinal phenotype (I type). RESULTS: The prevalence of GNAS and KRAS mutations was significantly higher in the G type than in the GI/I type (GNAS, P = 0.027; KRAS, P = 0.005). In contrast, the frequency of TP53 mutations was significantly higher in the GI/I type than in the G type (P = 0.049). Notably, APC mutations, excluding c.4479 G>A which was synonymous mutation, were more frequently identified in category 4/5 tumors than in category 3 tumors (50% vs. 24.5%; P = 0.039). CONCLUSION: G-type NADETs harbored frequent GNAS and KRAS mutations, whereas TP53 mutations are common in NADETs with intestinal features. APC mutations were significantly associated with high-grade neoplasia and invasive carcinoma.

Combination Therapy With Ustekinumab Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis in Patients With Refractory Ulcerative Colitis.

There are currently no reports on the efficacy and safety of combination therapy with ustekinumab (UST) plus intensive granulocyte and monocyte adsorptive apheresis (GMA) for the treatment of refractory ulcerative colitis (UC). We retrospectively evaluated the 10-week effectiveness of combination therapy with UST plus intensive GMA on refractory UC patients including two corticosteroid (CS)-dependent patients, two CS-refractory patients and one patient with loss of response to tacrolimus. Four patients were administered initial combination therapy of UST (6 mg/kg UST followed by subcutaneous injections of 90 mg UST every 8 weeks) plus intensive GMA. Of the four patients who received this combination therapy, two (50%) achieved clinical remission at 10 weeks. The rate of patients achieving endoscopic improvement (endoscopy subscore ≤ 1) at 10 weeks was 50%. In all cases, CSs were discontinued within 10 weeks. No adverse events were observed. Combination therapy with UST plus intensive GMA is helpful to reduce clinical disease activities in refractory UC patients and appears well tolerated.

5-aminolaevulinic acid (5-ALA) accumulates in GIST-T1 cells and photodynamic diagnosis using 5-ALA identifies gastrointestinal stromal tumors (GISTs) in xenograft tumor models.

Gastrointestinal stromal tumor (GIST) diagnosis using conventional gastrointestinal endoscopy is difficult because such malignancies cannot be distinguished from other types of submucosal tumors. Photodynamic diagnosis (PDD) is based on the preferential uptake of photosensitizers by tumor tissues and its detection by fluorescence emission upon laser excitation. In this study, we investigated whether PDD using 5-aminolevulinic acid (5-ALA), a standard photosensitizer used worldwide, could be used for GIST diagnosis. 5-ALA is metabolized to endogenous fluorescent protoporphyrin IX (PpIX). We examined the accumulation of PpIX in GIST-T1 cells using flow cytometry and immunofluorescent staining. Furthermore, we established GIST-T1 xenograft mouse models and examined PpIX accumulation in the resultant tumors. PpIX accumulated in GIST-T1 cells and was localized mainly to lysosomes. PpIX accumulation was also observed in murine xenograft tumors. Moreover, tumor and normal tissues could be distinctly identified by relative PpIX fluorescence. Thus, our results demonstrated that PDD with 5-ALA has substantial clinical potential for GIST diagnosis.