Inhibitory Effect of Pyra-Metho-Carnil on the Differentiation and Maturation of Macrophages in Normal and Cancer Microenvironments.

BACKGROUND/AIM: In a previous study, we have demonstrated heightened Pyra-Metho-Carnil (PMC) efficacy in nude mice with intact innate immunity that lack T and B cells. This has prompted hypothesizing that PMC may target macrophages that promote cancer growth. In this study, we conducted co-culture experiments with macrophages derived from THP-1 human monocyte cell lines and spheroids representing normal and cancer microenvironments. We then performed RNA sequencing and flow cytometry analysis to elucidate the mechanisms by which PMC affects macrophage differentiation and maturation. MATERIALS AND METHODS: THP-1 cells were differentiated by phorbol 12-myristate 13-acetate (PMA) and matured by PMA and lipopolysaccharide (LPS) either with or without PMC. Co-cultures were performed using stimulated THP-1 cells and HKe3-wild-type KRAS or HKe3-mutant (mt) KRAS spheroids. We then performed RNA-seq analysis of THP-1 cells stimulated by PMA (either with or without PMC) and flow cytometry analysis of mice peripheral blood obtained after PMC administration. RESULTS: THP-1 cells matured by PMA and LPS specifically increased the area of HKe3-mtKRAS cancer spheroids and the addition of PMC to THP-1 cells was found to inhibit cancer spheroid growth. RNA-seq data suggested that PMC treatment of THP-1 cells stimulated with PMA suppressed cell motility regulatory functions via down-regulation of the NF[Formula: see text]B pathway. Furthermore, flow cytometry results showed that PMC treatment suppressed monocyte maturation in B6 mice. CONCLUSION: The high level of in vivo tumor suppression caused by PMC may be due to inhibition of the differentiation and maturation of tumor-associated macrophages via the NF[Formula: see text]B signaling pathway.

Radial force and wire structure determine the onset of covered self-expandable metal stent migration in endoscopic ultrasound-guided hepaticogastrostomy: Measurement of sliding-resistance force using a porcine model.

BACKGROUND: Self-expandable metal stent (SEMS) migration after endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is a severe complication. The migration risk could be related to the surface friction of SEMS, assumed to be affected by the wire structure and mechanical properties, including radial force (RF); however, their relevance remains unclear. This experimental study aimed to assess the mechanical properties of SEMS involved in the onset of stent migration by measuring the sliding-resistance force (SF) as the SEMS moves through the stomach wall. METHODS: The SF of seven types of 8-mm diameter SEMS (four braided and three laser-cut types) and porcine stomach wall was measured with a universal testing machine. The SF of each SEMS was measured three times, and the average maximum SF (SFmax) was used for analysis. The correlation between SFmax and RF of each SEMS was evaluated. RESULTS: SFmax and RF showed a very strong positive correlation (r = 0.92). Compared to the regression line predictions in the scatter plots of SFmax and RF, the SFmax of laser-cut and braided type SEMSs had positive and negative residuals, respectively. CONCLUSIONS: Selecting a laser-cut type SEMS with a higher RF may more effectively prevent the onset of stent migration against the stomach wall in EUS-HGS.

Tranilast Inhibits TRPV2 and Suppresses Fibrosis Progression and Weight Gain in a NASH Model Mouse.

BACKGROUND/AIM: This study aimed to investigate the role of transient receptor potential vanilloid 2 (TRPV2) in a mouse model with non-alcoholic steatohepatitis (NASH) and to examine the effects of tranilast on TRPV2 and fibrosis-related cytokines. MATERIALS AND METHODS: C57BL/6N mice were fed a Gubra-Amylin NASH (GAN) diet for 20 weeks to induce NASH. The tranilast groups received oral administration of tranilast at doses of 300, 400 and 500 mg/kg/day, five days per week for 20 weeks, in addition to the GAN diet. The effects of tranilast were assessed based on the dosage of food intake, changes in body weight, liver weight, blood biochemical parameters, histopathological examination, and expression of TRPV2 and inflammatory cytokines. RESULTS: Hepatic expression of TRPV2 was observed in the GAN-fed NASH mouse model. The tranilast groups showed significantly suppressed increases in body and liver weights. The development of intrahepatic fat deposition and liver fibrosis, assessed histopathologically, was inhibited. Tranilast administration improved the expression of TRPV2 and inflammatory cytokines in the liver. Additionally, blood tests indicated a reduction in elevated liver enzyme levels. CONCLUSION: In GAN diet NASH models, TRPV2 was up-regulated in the liver and tranilast inhibited TRPV2 and suppressed fibrosis. Therefore, it might prevent the incidence of hepatocellular carcinoma associated with NASH.

Efficacy and safety of mirikizumab as induction and maintenance therapy for Japanese patients with moderately to severely active ulcerative colitis: a subgroup analysis of the global phase 3 LUCENT-1 and LUCENT-2 studies.

BACKGROUND/AIMS: Mirikizumab is a p19-directed anti-interleukin-23 antibody with potential efficacy against ulcerative colitis (UC). We evaluated the efficacy and safety of mirikizumab in a Japanese subpopulation with moderately to severely active UC from the LUCENT-1 and LUCENT-2 studies. METHODS: LUCENT-1 and LUCENT-2 were phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab therapy in adults with moderately to severely active UC. LUCENT-1 was a 12-week induction trial where patients were randomized 3:1 to receive intravenous mirikizumab 300 mg or placebo every 4 weeks (Q4W). Patients achieving a clinical response with mirikizumab following the induction study were re-randomized 2:1 to double-blind treatment with either mirikizumab 200 mg or placebo subcutaneously Q4W during the 40-week maintenance study. The primary outcomes were clinical remission at week 12 of LUCENT-1 and week 40 of LUCENT-2. RESULTS: A total of 137 patients enrolled in Japan were randomized to mirikizumab (n = 102) or placebo (n = 35). Compared with placebo, patients who received mirikizumab showed numerically higher clinical remission at week 12 of induction (32.4% [n = 33] vs. 2.9% [n = 1]) and at week 40 of maintenance (48.9% [n = 23] vs. 28.0% [n = 7]). A greater number of patients achieved key secondary endpoints in the mirikizumab group compared with placebo. The frequency of treatment-emergent adverse events was similar across mirikizumab and placebo groups. Efficacy and safety results observed in the Japanese subpopulation were generally consistent with those in the overall population. CONCLUSIONS: Mirikizumab induction and maintenance treatments were effective in Japanese patients with moderately to severely active UC. No new safety concerns were identified.

Structural factors influencing the clinical performance of 0.025-inch guidewires for pancreatobiliary endoscopy: An experimental study.

Background and study aims To develop a pancreatobiliary endoscopic guidewire with good clinical performance, an understanding of its structure is necessary. This study aimed to investigate the structural factors influencing the clinical performance of pancreatobiliary endoscopic guidewires. Methods Eight types of 0.025-inch guidewires were evaluated. The following structural properties were measured: tip length, tip deflection height, tip weight (TW), ratio of tip core weight to TW, shaft coating type (flat or uneven), outer diameter, and core wire diameter (CWD). Four performance tests were conducted to evaluate shaft stiffness as bending force (BF), shaft lubricity as friction force (FF), torque response as torque response rate (TRR), and seeking ability as total insertion success (TIS) in a technical test using a 3D bile duct model. The correlation coefficients of each variable were analyzed. Results The BF and CWDs were strongly correlated, as well as the FF and CWDs and BF. Among the guidewires with similar CWDs, the guidewires with uneven coating had significantly lower FF than those with flat coating. The TRR was strongly correlated with the CWDs; furthermore, guidewires with lower FF had better TRR. TIS was strongly correlated with the TRR, TWs, and ratio of the tip core weight to TW. Conclusions CWD affects shaft stiffness; CWD and coating type affect shaft lubricity and torque response. Because TRR and TW are correlated with seeking ability, an appropriate combination of core wire thickness, TW, and coating design is required to develop a guidewire with good seeking ability.

Two cases of severe oral mucositis caused by atezolizumab plus bevacizumab combination therapy for hepatocellular carcinoma.

Atezolizumab is an immune checkpoint inhibitor specific for the programmed death-1 (PD-1) receptor. In this case report, we describe two cases of oral mucositis that developed following the initiation of a systemic chemotherapy regimen comprising atezolizumab and bevacizumab for recurrent hepatocellular carcinoma. After 2 or 3 cycles of treatment, each patient presented with mucosal ulcers in the mouth, oral pain, difficulty in speech and oral intake, and both were admitted to our hospital for management. Following rule out of other conditions such as pharyngeal ulcers, herpetic mucositis, denture or oral trauma, or necrotizing mucositis, both patients were diagnosed with oral mucositis as a severe immune-related adverse event. Oral candidiasis was observed in both cases and should be considered a risk factor for the development of oral mucositis. Chemotherapy was discontinued and treatment with prednisolone was started, along with supportive care. The oral mucositis improved, and prednisolone was gradually reduced; however, in one patient, discontinuation of chemotherapy led to a recurrence of hepatocellular carcinoma. The other patient was lost to follow-up. In patients with risk factors, attention must be paid to the development of oral mucositis during immune checkpoint inhibitor treatment.

[Embolic stroke due to ascending aortic thrombus in a patient with treatment-resistant ulcerative colitis].

The patient was a 49-year-old man presenting with recurrent melena due to progressive ulcerative colitis. One day, he developed left lower facial weakness and dysarthria, and the next day, he was transferred to our hospital because of muscle weakness in his left upper and lower extremities. On admission, neurological findings revealed left hemiplegia, including left facial palsy, dysarthria, and left hemispatial neglect. Brain MRI with diffusion-weighted image showed a fresh infarction in the right anterior and middle cerebral artery territory. Contrast-enhanced CT showed thrombus in the ascending aorta in addition to occlusion of the right internal carotid artery, suggesting the diagnosis of cerebral infarction with an embolic source in the aortic lesion. The intra-aortic thrombus disappeared after 48th day of antithrombotic therapy. Laboratory findings revealed elevated blood viscosity, proteinase-3-anti-neutrophil cytoplasmic antibody (PR3-ANCA), and ß2GP1-IgG antibodies, suggesting that the cause of the aortic thrombus may be due to elevated blood viscosity and autoantibodies, as well as highly active ulcerative colitis.

Nationwide multicenter study on adverse events associated with a patency capsule: Additional survey of appropriate use of patency capsule study.

BACKGROUND AND AIM: The PillCam patency capsule (PC) without a radio frequency identification tag was released to preclude retention of the small bowel capsule endoscope (CE) in Japan in 2012. We conducted a multicenter study to determine tag-less PC-related adverse events (AEs). METHODS: We first conducted a retrospective survey using a standardized data collection sheet for the clinical characteristics of PC-related AEs among 1096 patients collected in a prospective survey conducted between January 2013 and May 2014 (Cohort 1). Next, we retrospectively investigated additional AEs that occurred before and after Cohort 1 within the period June 2012 and December 2014 among 1482 patients (Cohort 2). RESULTS: Of the 2578 patients who underwent PC examinations from both cohorts, 74 AEs occurred among 61 patients (2.37%). The main AEs were residual parylene coating in 25 events (0.97%), PC-induced small bowel obstruction, suspicious of impaction, in 23 events (0.89%), and CE retention even after patency confirmation in 10 events (0.39%). Residual parylene coating was significantly associated with Crohn's disease (P < 0.01). Small bowel obstruction was significantly associated with physicians with less than 1 year of experience handling the PC and previous history of postprandial abdominal pain (P < 0.01 and P < 0.03, respectively). CE retention was ascribed to erroneous judgment of PC localization in all cases. CONCLUSIONS: This large-scale multicenter study provides evidence supporting the safety and efficiency of a PC to preclude CE retention. Accurate PC localization in patients without excretion and confirmation of previous history of postprandial abdominal pain before PC examinations is warranted (UMIN000010513).

Partial splenic embolization improved stomal varices in patient with decompensated liver cirrhosis: a case report.

A 63-year-old man with decompensated liver cirrhosis was admitted for treatment of stomal hemorrhage. Eighteen months earlier, he was diagnosed with rectal and sigmoid colon cancer with multiple lymph node metastases, and he underwent colostomy surgery and postoperative chemotherapy. Sixteen months after the surgery, his stoma began to bleed repeatedly, and he required frequent blood transfusions. A contrast-enhanced computed tomography revealed ectopic varices around the stoma. We considered surgical or endoscopic treatment; however, these approaches would have been technically difficult in this patient. The patient was treated with partial splenic embolization to improve thrombocytopenia and portal hypertension. After two-stage partial splenic embolization, the platelet counts increased, and the concentration of the liver fibrosis marker, Mac-2 binding protein, decreased. In addition, blood flow in the stomal varices decreased, with no recurrence of bleeding. This is a case of recurrent hemorrhage from stomal varices that was successfully treated with partial splenic embolization in a patient with liver cirrhosis. There are no guidelines for hemorrhage from ectopic varices. PSE may present potential utility as a treatment for ectopic variceal bleeding, such as stomal varices.

Prospective clinical trial of EUS-guided choledochoduodenostomy without fistula dilation for malignant distal biliary obstruction.

Background and Objectives: During EUS-guided choledochoduodenostomy (EUS-CDS), fistula dilation before stent insertion is associated with adverse events (AEs), such as bile leakage and peritonitis. We hypothesized that EUS-CDS without fistula dilation using a novel self-expandable metal stent (SEMS) with a thin delivery system could overcome this problem, and we conducted this study to evaluate its feasibility and safety. Methods: This was an open-label, single-arm, phase II study at a single institution. We planned EUS-CDS without fistula dilation using a fully covered SEMS with a 5.9-Fr delivery system for unresectable malignant distal biliary obstruction. The primary outcome was overall technical success. Secondary outcomes were technical success without fistula dilation, procedure time, functional success, time to recurrent biliary obstruction, and AEs. The planned sample size was 25 patients. Results: In total, 24 patients were included in this study. In 21 patients, EUS-CDS was performed as primary drainage. The overall technical success rate was 100% (24 of 24 patients). The technical success rate without fistula dilation was 96% (23 of 24). The median procedure time was 16 min (range, 10-66 min). The functional success rate was 96% (23 of 24). The median time to recurrent biliary obstruction was 148 days (95% confidence interval, 29-266 days). There were no procedure-related AEs. Furthermore, computed tomography immediately after the procedure showed no leakage of contrast medium into the abdominal cavity in any patient. Conclusions: EUS-guided choledochoduodenostomy without fistula dilation using a fully covered SEMS with a 5.9-Fr delivery system is feasible with a high probability and can be achieved quickly while effectively preventing bile leakage and peritonitis.

Disappearance of Hepatocellular Adenoma in a Patient with Cornelia de Lange Syndrome after Treatment with Transcatheter Arterial Embolization.

Cornelia de Lange syndrome (CdLS) is a congenital disorder occasionally associated with congenital portosystemic shunt (CPSSs). We herein report a patient with CdLS and CPSS who developed hepatocellular adenomas (HCAs). The patient presented to our hospital for the further investigation of newly diagnosed liver tumors. Imaging findings and pathological examination results indicated that the liver tumors were inflammatory HCAs that subsequently shrank following transcatheter arterial embolization (TAE). Patients with CdLS and CPSS are at risk of developing HCAs, and TAE may be an effective management strategy for HCA in these patients.

Long-term outcome and eligibility of radiofrequency ablation for hepatocellular carcinoma over 3.0 cm in diameter.

Percutaneous radiofrequency ablation (RFA) is effective for the treatment of small hepatocellular carcinoma (HCC) with a diameter ≤ 3.0 cm. The present study aimed to elucidate the prognostic factors and clarify the indication of treatment for RFA outcomes in patients with HCC with a diameter > 3.0 cm. Among 2188 patients with HCC who underwent RFA, 100 patients with HCC with a diameter > 3.0 cm were enrolled in this study between August, 2000 and August, 2021. We analyzed local therapeutic efficacy, long-term outcomes, and prognostic factors in patients with HCC with a diameter > 3.0 cm. Among all patients, 77 patients achieved complete ablation in one session. There were no treatment-related deaths or major complications. Local tumor recurrence occurred in 48% (n = 48) of the patients, and distant tumor recurrence occurred in 82% (n = 82) of the patients during the study period. The survival rates at 1-, 3-, 5-, 10-, and 15- years were 93.0%, 66.0%, 40.0%, 15.5%, and 10.2%, respectively. Cox proportional hazards regression analysis confirmed that distant tumor recurrence, Child-Pugh class B, and pre-ablation des-γ-carboxy prothrombin (DCP) levels ≥ 200 mAU/mL were independent unfavorable prognostic factors with a hazard ratio of 3.34 (95% CI, 1.57-7.11; P = 0.002), 2.43 (95% CI, 1.35-4.37; P = 0.003), and 1.83 (95% CI, 1.14-2.93; P = 0.012), respectively. In conclusion, patients with HCC with a diameter > 3.0 cm with Child-Pugh class A and DCP levels < 200 mAU/mL might be eligible for RFA treatment.

Malnutrition and inflammation status in nonobese patients with inflammatory bowel disease are associated with nonalcoholic fatty liver disease: a retrospective study.

BACKGROUND/AIMS: The frequency and details of nonalcoholic fatty liver disease (NAFLD) complications in patients with inflammatory bowel disease (IBD) remain unclear. This study aimed to clarify characteristics of NAFLD in patients with IBD. METHODS: We retrospectively identified and enrolled patients with IBD diagnosed with or without NAFLD by undergoing abdominal computed tomography (CT) at our institution between 2005 and 2020. The primary endpoint was the complication rate of NAFLD in patients with IBD. Secondary endpoints were the clinical characteristics of nonobese patients with IBD and comorbid NAFLD and their association with nutritional and inflammatory parameters. RESULTS: Twenty-one (21.9%) of 96 eligible patients with IBD also had NAFLD. In nonobese patients (defined as patients with a body mass index <25 kg/m2), C-reactive protein (CRP; P<0.001) and alanine aminotransferase (P=0.018) levels were higher and the albumin level (P=0.005) and prognostic nutritional index (PNI; P=0.002) values were lower in patients with NAFLD than in those without NAFLD. The PNI value was positively correlated (P<0.001) and the CRP level was negatively correlated (P=0.001) with the hepatosplenic ratio. However, in the NAFLD combined group, PNI (P<0.05) and CRP values (P<0.001) were improved over time after CT imaging by continuing IBD treatment. CONCLUSIONS: Worsening nutritional and inflammatory status in IBD patients is associated with complications of NAFLD. Diagnosis of NAFLD in IBD patients using CT imaging might be useful not only for early detection of NAFLD but also in assessing the need for therapeutic intervention for IBD.

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.

Preoperatively diagnosed intraductal oncocytic papillary neoplasm of the pancreas with prominent invasion: a case report.

Previously considered as one of the less-invasive subtypes of intraductal papillary mucinous neoplasm, intraductal oncocytic papillary neoplasm (IOPN) has recently been acknowledged as a new entity of pancreatic tumor. We herein present a case of preoperatively diagnosable IOPN invasion in the stomach and colon. A 78-year-old woman was referred to our hospital for evaluation of anorexia and gastroesophageal reflux. Upper gastrointestinal endoscopy revealed a gastric subepithelial lesion with ulcerated mucosa that required hemostasis. Computed tomography revealed a 96-mm-diameter solid tumor with a well-defined border and centrally positioned necrotic area, extending from the stomach to the transverse colon and pancreatic tail. Because it was suspected to be a pancreatic solid tumor with direct stomach invasion, endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) was performed, which led to a preoperative diagnosis of IOPN. Moreover, laparoscopic pancreatosplenectomy, proximal gastrectomy, and transverse colectomy were performed. Analysis of the surgical specimen revealed that the tumor was IOPN and had invaded the stomach and transverse colon. Lymph node metastasis was also confirmed. These findings indicate that IOPN can manifest as an invasive tumor, and EUS-FNB may be equally helpful for assessing the invaded area of a cystic lesion as it is for a solid lesion.