Pretreatment serum monocyte chemoattractant protein-1 as a predictor of long-term outcome by ustekinumab in patients with Crohn's disease.

BACKGROUND AND AIMS: Ustekinumab has been proven to be effective for treatment of patients with Crohn's disease; however, 30-40% of patients have been reported to lose clinical response within 2 years. We aimed to evaluate the efficacy of ustekinumab and identify predictors of short-term and long-term efficacy in Crohn's disease. METHODS: Patients with Crohn's disease receiving their first ustekinumab infusion in our hospital between June 2017 and September 2020 were prospectively enrolled. Concentrations of serum cytokines and chemokines were measured using a multiplex bead array assay. RESULTS: Fifty-nine Crohn's disease patients were enrolled in this study. Among 34 clinically active patients, 38.2% achieved a clinical response at week 8. None of the assayed factors were associated with short-term clinical response. Cumulative persistence rates of ustekinumab were 77.6% at 1 year and 58.9% at 2 years. Univariate Cox regression analysis revealed that Harvey-Bradshaw Index scores at baseline, concomitant immunomodulator treatment, and concentrations of interferon gamma-induced protein-10, monocyte chemoattractant protein-1 (MCP-1), and interleukin (IL)-1RA, IL-4, IL-6, and IL-8 were significantly associated with loss of efficacy. Multivariate Cox regression analysis found that biologic naïve status (hazard ratio [HR]: 0.1191, 95% confidence interval [CI]: 0.02458-0.5774) and MCP-1 concentrations (HR: 1.038, 95% CI: 1.015-1.062) were significantly and associated with loss of sustained efficacy for ustekinumab treatment. CONCLUSIONS: Our findings suggest that pretreatment serum MCP-1 analysis, combined with a history of biologic use, could be a novel biomarker for predicting the long-term efficacy of ustekinumab in patients with Crohn's disease.

Required Elements in tRNA for Methylation by the Eukaryotic tRNA (Guanine-N2-) Methyltransferase (Trm11-Trm112 Complex).

The Saccharomyces cerevisiae Trm11 and Trm112 complex (Trm11-Trm112) methylates the 2-amino group of guanosine at position 10 in tRNA and forms N2-methylguanosine. To determine the elements required in tRNA for methylation by Trm11-Trm112, we prepared 60 tRNA transcript variants and tested them for methylation by Trm11-Trm112. The results show that the precursor tRNA is not a substrate for Trm11-Trm112. Furthermore, the CCA terminus is essential for methylation by Trm11-Trm112, and Trm11-Trm112 also only methylates tRNAs with a regular-size variable region. In addition, the G10-C25 base pair is required for methylation by Trm11-Trm112. The data also demonstrated that Trm11-Trm112 recognizes the anticodon-loop and that U38 in tRNAAla acts negatively in terms of methylation. Likewise, the U32-A38 base pair in tRNACys negatively affects methylation. The only exception in our in vitro study was tRNAValAAC1. Our experiments showed that the tRNAValAAC1 transcript was slowly methylated by Trm11-Trm112. However, position 10 in this tRNA was reported to be unmodified G. We purified tRNAValAAC1 from wild-type and trm11 gene deletion strains and confirmed that a portion of tRNAValAAC1 is methylated by Trm11-Trm112 in S. cerevisiae. Thus, our study explains the m2G10 modification pattern of all S. cerevisiae class I tRNAs and elucidates the Trm11-Trm112 binding sites.

[Current real-world treatments for Japanese patients with eosinophilic esophagitis].

A total of 306 patients with eosinophilic esophagitis (EoE) were analyzed at our department. Proton pump inhibitors or potassium-competitive acid blockers were used as the first-line treatment in 286 (93.5%) patients. Fifty-five (18.0%) patients received topical steroid swallowing therapy. During 17.7-month mean follow-up, 46.4% of the patients were followed-up with no medications, 37.3% of the patients received maintenance or on-demand therapy using acid-suppressive drugs, and 9.8% of the patients received maintenance therapy with steroid swallowing. The majority of patients with EoE were treated using a therapeutic strategy similar to that used for gastroesophageal reflux disease. However, some patients were refractory to the treatment. Current real-world treatment strategies for Japanese patients with EoE are clarified.

[Diagnostic value of a simple scoring system for the diagnosis and treatment of non-emergency small bowel obstruction].

In order to improve the diagnostic accuracy and treatment strategy for small bowel obstruction, we developed a non-emergency small bowel obstruction scoring system (0-4). We performed a retrospective analysis on 94 patients diagnosed with mechanical small bowel obstruction at our hospital. Anterior adhesion, small bowel feces sign, scoring system, and the usefulness of small bowel feces subtypes were examined. When the non-emergency small bowel obstruction scores 3-4, 99% were non-emergency obstructions, with the exclusion of strangulated small bowel obstruction. On the contrary, when the non-emergency small bowel obstruction scores 0-1, 47.5% were strangulated small bowel obstruction. As the effectiveness of withholding food and fluids (NPO) or short tube is high (about 70%) when small bowel feces are dry, placing a long tube may not be needed.

Serum interleukin-6 level is associated with response to infliximab in ulcerative colitis.

OBJECTIVES: Infliximab is effective in patients with ulcerative colitis (UC); however, one-third of patients do not respond and require additional therapies such as other biologic agents. Therefore, the aim of this study was to analyze the association between pro-inflammatory molecules and clinical efficacy to elucidate possible mechanisms for the non-response to infliximab to aid in treatment selection. MATERIALS AND METHOD: Patients with moderate-to-severe active UC receiving infliximab in our hospital between 2010 and 2016 for whom pre-treatment serum samples were available were retrospectively evaluated. We analyzed the association between serum interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) and the clinical efficacy of infliximab. The primary endpoint was clinical response at the end of the induction period. RESULTS: Forty-one patients were included in this study. After induction therapy, 27 patients (65.9%) showed a clinical response. Serum IL-6 levels were significantly lower in responders than in non-responders (p = .012), whereas no significant differences were noted in other factors including sMAdCAM-1 and TNF-α. Multivariate analysis identified that serum IL-6 level (odds ratio = 0.72; 95% confidence interval, 0.54-0.96; p = .027) was independently associated with response to infliximab. CONCLUSIONS: Serum IL-6 level is associated with response to infliximab in UC. Elevated concentrations of IL-6 may provide insight to the mechanism of non-response to infliximab.

[A retrospective study of the clinical characteristics and treatment of 93 adult patients with eosinophilic gastroenteritis].

We performed a retrospective analysis on three patients diagnosed with EGE (eosinophilic gastroenteritis) at our hospital and 90 cases obtained from a case database. The cases' genders, ages, peripheral eosinophils, ascites, endoscopic findings, biopsy findings, diagnostic scores, and rates of glucocorticoid use were evaluated. The gender ratio was 40 males to 53 females, and the median age was 50. 78.5% of cases had peripheral eosinophilia. The prevalence of allergic diseases was 31.2%, and the incidence of ascites was 34.4%. 83.9% of endoscopic findings were positive, and 92.5% of biopsies were positive. The total rate of glucocorticoid use was 77.4%. When both score <5 and age <33 conditions were met, the rate of glucocorticoid use was approximately 30%, meaning it was possible to avoid glucocorticoid use.

Self-assembling DNA hydrogel-based delivery of immunoinhibitory nucleic acids to immune cells.

Immunoinhibitory oligodeoxynucleotides (INH-ODNs) are promising inhibitors of Toll-like receptor 9 (TLR9) activation. To efficiently deliver INH-ODNs to TLR9-positive cells, we designed a Takumi-shaped DNA (Takumi) consisting of two partially complementary ODNs as the main component of a DNA hydrogel. Polyacrylamide gel electrophoresis showed that Takumi-containing INH-ODNs (iTakumi) and iTakumi-based DNA hydrogel (iTakumiGel) were successfully generated. Their activity was examined in murine macrophage-like RAW264.7 cells and DC2.4 dendritic cells by measuring tumor necrosis factor-α and interleukin-6 release after the addition of a TLR9 ligand (CpG ODN). Cytokine release was efficiently inhibited by the iTakumiGel. Flow cytometry analysis and confocal microscopy showed that cellular uptake of INH-ODN was greatly increased by the iTakumiGel. These results indicate that a Takumi-based DNA hydrogel is useful for the delivery of INH-ODNs to immune cells to inhibit TLR9-mediated hyperinduction of proinflammatory cytokines. From the Clinical Editor: Toll-like receptor 9 activation has been reported to be associated with many autoimmune diseases. DNA inhibition using oligodeoxynucleotides is one of the potential treatments. In this article, the authors described hydrogel-based platform for the delivery of the inhibitory oligodeoxynucleotides for enhanced efficacy. The positive findings could indicate a way for the future.

Tuberculosis risk in patients with Crohn's disease on biologics: a retrospective analysis of the Japanese Medical Claims Database.

Background/Aims: Treatment using tumor necrosis factor-α (TNF-α) inhibitors is one of the risk factors for active tuberculosis (TB) in patients with Crohn's disease (CD). Biologics, such as ustekinumab (UST) and vedolizumab (VDZ), are less likely to cause opportunistic infections. However, large-scale studies for active TB and biologics other than TNF-α inhibitors are limited. We aimed to investigate the association between biologics and active TB utilizing a Japanese medical claims database. Methods: We analyzed retrospectively the association of the risk of active TB development with treatment using TNF-α inhibitors and other biologics (UST and VDZ) in patients with CD using the Japanese Medical Data Vision (MDV) database between April 2008 and June 2022. The durations of each biologic and biologic-free treatment were calculated for each patient. Univariate and multivariate analyses were performed using the Cox proportional hazards model, with the utilization of biologics considered as time-dependent covariates. Results: We included 28,811 patients with CD in MDV database. Finally, 17,169 patients were analyzed. In total, 7,064 patients were categorized as biologic-naïve, while 10,105 were classified as biologic-experienced. Seventeen patients developed active TB, including 7 on infliximab, 5 on adalimumab, and 5 on no biologics. None of the patients treated with UST and VDZ developed active TB. Multivariate analysis suggested that TNF-α inhibitors were the risk factors for active TB (hazard ratio, 3.66; P= 0.020). Conclusions: TNF-α inhibitors, but not UST or VDZ, are risk factors for active TB in Japanese patients with CD.

[Tumor lysis syndrome after transarterial embolization for hepatocellular carcinoma].

A man in his 70's was admitted to our hospital for treatment of a huge hepatocellular carcinoma (HCC) by transcatheter hepatic arterial embolization (TAE). After treatment, anuria occurred, and laboratory examinations revealed a diagnosis of tumor lysis syndrome (TLS). He underwent conservative therapy including hemodialysis, resulting in complete remission of TLS. On the other hand, poor hepatic functional reserve was seen temporarily. After conservative therapy, biochemical markers returned dramatically. TLS is a group of metabolic complications in cancer therapy. It may occur in highly sensitive tumors, resulting from a rapid release of cytoplasmic degradation products of malignant cells. Generally it is rare in the treatment of solid tumors. In the case of TAE for huge HCC, we should keep the possibility of TLS in mind.

Efficacy of Upadacitinib as a Second-line JAK Inhibitor in Ulcerative Colitis: A Case Series.

Upadacitinib, a recently approved Janus kinase (JAK) inhibitor specific for JAK1, may be a promising candidate in patients with ulcerative colitis (UC) who present no response or intolerance to first-line JAK inhibitors. We assessed the therapeutic impact of upadacitinib on six UC patients who demonstrated an inadequate response or intolerance to tofacitinib or filgotinib. After 2 months of treatment, 5 patients (83.3%) achieved clinical remission, and all patients experienced decreased levels of CRP. One patient had coronavirus disease 2019 pneumonia and showed a mild increase in transaminase levels. This case series highlights the potential utility of a rotation strategy among JAK inhibitors.

The gap between development and manufacturing in gene therapy: Strategic options for overcoming traps.

Gene therapy has been one of the most promising therapeutic approaches in recent years. This study analyzed a research and development (R&D) system for adeno-associated virus (AAV)-based gene therapies, and confirmed that there was a gap between the development and manufacturing capabilities. Although a start-up company that has no academic or manufacturing facilities can begin the clinical development process, it cannot successfully continue development activities without forming alliances and capital investment or, at a certain stage, without appropriate manufacturing and marketing strategies. We reviewed a series of case studies to categorize the acquisition patterns of pharmaceutical companies that are engaged in AAV gene therapy. These results provide insights into the R&D structures for AAV gene therapies from a technological management perspective.

The impact of COVID-19 on Japanese patients with eosinophilic gastrointestinal disorders during the vaccination era.

Background: Eosinophilic gastrointestinal disorders (EGIDs) are chronic allergic diseases categorized as eosinophilic esophagitis (EoE) and non-EoE EGIDs. Few studies regarding the association between EGIDs and coronavirus disease 2019 (COVID-19) have been reported. Although most Japanese individuals received the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine, the incidence of COVID-19 remained high in 2022. This study examines the incidence of COVID-19 in patients with EGIDs during the vaccination era. Methods: Patients with EGIDs who visited our department between October and December 2022 were enrolled in the study. The incidence and severity of COVID-19 prior to October 1, 2022 were determined. Patients who reported having COVID-19 also reported their hospitalization history, intensive care unit admissions, and EGID flares. The number of SARS-CoV-2 vaccinations received and treatment for EGIDs were obtained from the patients' medical records. Results: Of 111 patients with EGIDs (65 with EoE and 46 with non-EoE EGIDs) included in this study, 31 (28%) patients reported having COVID-19, including 14 (22%) with EoE and 17 (37%) with non-EoE EGIDs. Fifty-nine (84%) patients received two or more vaccinations, and 11 (16%) patients received no vaccinations. COVID-19 was mild in all but one patient who had moderate symptoms. COVID-19 was not associated with EGID flares. EGID treatments and an unvaccinated status were not associated with an increased risk of COVID-19. Conclusion: COVID-19 was mild in patients with EGIDs and not associated with EGIDs flares during the vaccination era. There was a relatively high incidence of COVID-19 among patients with non-EoE EGIDs.

Impact of the COVID-19 Pandemic on the Lifestyle and Psychosocial Behavior of Patients with Inflammatory Bowel Diseases: A Narrative Review.

The coronavirus disease (COVID-19) pandemic has had a considerable impact on the global healthcare system and potentially the clinical course of patients with inflammatory bowel disease (IBD). Although IBD is a chronic disease, its therapy (except steroid therapy) does not increase the risk of contracting or aggravating COVID-19. However, the clinical course of patients is significantly influenced by environmental factors. Social restrictions due to the pandemic or the fear of contracting the virus have influenced lifestyle and psychosocial behaviors that may worsen the clinical course of patients with IBD. This narrative literature review summarizes the current evidence on the impact of the COVID-19 pandemic on the lifestyle and psychosocial behaviors of patients with IBD. The COVID-19 pandemic negatively affected the lifestyle and psychosocial behaviors of patients with IBD. Furthermore, patients with IBD failed to maintain medication adherence, thus affecting the clinical course of their condition.

Neutrophil-to-lymphocyte ratio may predict clinical relapse in ulcerative colitis patients with mucosal healing.

Endoscopic mucosal healing (MH) is an important treatment goal for patients with ulcerative colitis (UC). The neutrophil-to-lymphocyte ratio (NLR) reflects systemic inflammation and has been reported to be a useful predictive marker for UC. This study aimed to evaluate the clinical utility of the NLR for predicting clinical relapse in UC patients with MH. We retrospectively enrolled patients with UC who underwent colonoscopy at the Osaka City University Hospital between January 2010 and December 2010, whose Mayo Endoscopic Subscore was 0 or 1. The correlation between the incidence of relapse and demographic factors, including the NLR, was analyzed. We included 129 patients in the present study. The median NLR at the time of endoscopy was 1.98, and differences in the high NLR group and the low NLR group were compared. During a median follow-up period of 46.4 months, 58 patients (45.0%) experienced relapse. The cumulative relapse-free rate was significantly higher in the low NLR group than in the high NLR group (P = 0.03, log-rank test). Multivariate analysis identified high NLR as an independent prognostic factor for clinical relapse (hazard ratio, 1.74; 95% confidence interval, 1.02-2.98; P = 0.04). NLR is a novel and useful predictor of clinical relapse in UC patients with MH, and it can potentially be a strong indicator to determine the appropriate treatment strategy and decision-making in clinical practice.

[A case of bleeding giant gastrointestinal stromal tumor of the stomach who achieved partial response by chemotherapy].

A 80-year-old female was referred to our hospital for hematomesis. An abdominal CT revealed a heterogeneous giant tumor of about 11 cm, rich in vascularity, extending from the gastric fundus, beyond the upper side of the spleen, to the left thoracic diaphragm. Gastroscopy showed a 5 cm submucosal tumor with a visible vessel at the gastric fundus. After biopsy was performed, she was diagnosed with a c-kit-positive gastrointestinal stromal tumor (GIST)of the stomach. Following endoscopic hemostasis for gastric bleeding, imatinib mesilate was administered. The tumor reduced markedly, and vascularity in the tumor was diminished, the visible vessels of the tumor disappeared. For curative resection, total gastrectomy with a distal pancreato -splenectomy and a left diaphgram resection is necessary, but surgery was high-risk for this patient because she was advanced in age. She is now achieving a good partial response without surgery.

Effect of the Coronavirus Disease 2019 Lockdown on Lifestyle Factors in Japanese Patients with Inflammatory Bowel Disease.

Objective To examine the effect of the coronavirus disease 2019 (COVID-19) lockdown on lifestyle factors and psychological stress in patients with inflammatory bowel disease (IBD). Methods A retrospective study was conducted on patients with IBD in Japan 2 months after the initiation of the first state of emergency (June 16 to August 21, 2020). A self-reported questionnaire was used to collect data, and lifestyle factors and psychological stress levels before and after the state of emergency were compared. Patients Patients with IBD who were followed up regularly at Osaka City University Hospital from June 16 to August 21, 2020, were included and were classified into elderly (≥65 years old) and non-elderly groups (<65 years old). Results The study sample comprised 451 responders (241, ulcerative colitis; 210, Crohn's disease; 0, COVID-19). The sleep duration increased, whereas the exercise, working, and walking durations decreased during the COVID-19 lockdown. The proportion of patients with psychological stress due to COVID-19, those with an inability to exercise, and those staying indoors increased significantly during COVID-19 lockdown. Lifestyle factors changed more markedly in non-elderly patients, those who were more stressed due to COVID-19, those with the inability to exercise, and those staying indoors during COVID-19 lockdown. Among elderly patients, no significant changes were identified in stress-causing factors. Conclusion The COVID-19 lockdown affected lifestyle factors and psychological stress in patients with IBD, particularly non-elderly patients. These findings may be helpful in suggesting favorable lifestyle changes for patients with IBD.

Pyogenic Spondylitis Caused by Staphylococcus schleiferi in a Patient with Crohn's Disease.

Staphylococcus schleiferi has rarely been reported to cause pyogenic spondylitis. A 42-year-old man had been treated for Crohn's disease with immunosuppressive agents and home parenteral nutrition via a central vein (CV) port. The patient was admitted to our hospital, presenting with neck pain and a fever. A neurological examination showed slight weakness in his left-hand muscles, and he was diagnosed with pyogenic spondylitis of C6 and C7 vertebral bodies due to catheter-related blood stream infection caused by S. schleiferi. An early diagnosis by magnetic resonance imaging, CV port removal and antibiotic therapy targeting S. schleiferi improved his symptoms.

Lustrous White Erosions Surrounded by an Erythematous Mucosa: A Novel Endoscopic Finding of Gastric Lesions in Patients with Wilson Disease.

Wilson disease is an inherited copper metabolism disorder. We herein report a novel endoscopic finding in three men with Wilson disease. These patients underwent upper endoscopy due to gastrointestinal symptoms or during follow-up. In each case, endoscopy revealed lustrous white erosions surrounded by an erythematous mucosa in the greater curvature of the gastric body. A biopsy of the lesions showed orcein-positive tissue, indicating copper deposition, in the interstitial stroma and fundic glands of the mucosa. All patients had been receiving treatment with zinc acetate. These endoscopic findings might have been related to the cytotoxicity of the accumulated copper and zinc acetate.

[A case of peritoneal serous papillary carcinoma].

A 65-year-old female was admitted to our hospital with abdominal distension. Abdominal CT and MRI revealed massive ascites and an omental cake, but the ovaries were of normal size. After an omentum biopsy was performed during open abdominal surgery, she was diagnosed as peritoneal serous papillary adenocarcinoma. After 6 courses of chemotherapy with paclitaxel and carboplatin, the massive ascites totally disappeared, and a second look operation could be performed. She is still alive with no sign of recurrence.

The Impact of Human Herpesviruses in Clinical Practice of Inflammatory Bowel Disease in the Era of COVID-19.

Human herpesviruses (HHVs): herpes simplex virus (HSV) types 1 (HSV-1) and 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6, HHV-7, and HHV-8, are known to be part of a family of DNA viruses that cause several diseases in humans. In clinical practice of inflammatory bowel disease (IBD), the complication of CMV enterocolitis, which is caused by CMV reactivation under disruption of intestinal barrier function, inflammation, or strong immunosuppressive therapy, is well known to affect the prognosis of disease. However, the relationship between other HHVs and IBD remains unclear. In the transplantation field, reactivation of other viruses, such as HHV-6, could cause colitis under immunosuppressed condition. Recent research revealed that combined infection of some HHVs could be a risk factor for colectomy in patients with ulcerative colitis. This suggests that it would be important to clarify HHV behavior in the treatment for patients with IBD, especially in those under immunosuppressive therapies. Looking at the relationship with recently emerged novel coronaviruses (SARS-CoV-2), there are reports describe that SARS-CoV-2 might induce reactivation of HSV-1, EBV, VZV (herpes zoster), and HHV-6/7. If SARS-CoV-2 infection becomes common, vigilance against HHV reactivation may become more crucial. In this review, we discuss the impact of HHVs in clinical practice of inflammatory bowel diseases, especially during the SARS-CoV-2 pandemic.