Clinical Characteristics of Cryopyrin-Associated Periodic Syndrome and Long-Term Real-World Efficacy and Tolerability of Canakinumab in Japan: Results of a Nationwide Survey.

OBJECTIVE: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. METHODS: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. RESULTS: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. CONCLUSION: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.

Strongyloidiasis presenting during treatment of low-dose glucocorticoid plus rituximab for anti-signal recognition particle antibody-positive polymyositis: A case report.

Strongyloidiasis, an intestinal parasitic infection caused by Strongyloides stercoralis, rarely occurs in Japan. When treated with immunosuppressive drugs, two potentially lethal conditions, hyperinfection and dissemination, may develop in asymptomatic carriers of this parasite. We report the development of strongyloidiasis during treatment of polymyositis with glucocorticoids plus rituximab (RTX). A 44-year-old woman had been diagnosed with anti-signal recognition particle antibody-positive polymyositis with interstitial pneumonia 6 years previously, for which she had recently been receiving prednisolone at 5 mg/day and RTX at 375 mg/m2 twice every 3 months. Her condition appeared to be well controlled. She was admitted to our hospital with a 1-month history of chronic diarrhoea and epigastric pain. Standard microscopic examination of a sample of faeces revealed the presence of S. stercoralis; however, serologic testing for parasites was negative. Treatment with ivermectin alleviated her inflammatory diarrhoea and eradicated the faecal parasites. We believe that our patient had an exacerbation of S. stercoralis infection (hyperinfection syndrome) that was exacerbated by low-dose glucocorticoids plus RTX. Strongyloidiasis should be considered in immunocompromised individuals with unexplained diarrhoea, even in non-endemic areas.

Nation-wide cohort study of remission induction therapy using rituximab in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis: Effectiveness and safety in the first 6 months.

OBJECTIVES: The aim of this article is to evaluate the effectiveness and safety of rituximab (RTX) for microscopic polyangiitis and granulomatosis with polyangiitis in Japan. METHODS: In this prospective observational study, all patients with microscopic polyangiitis and granulomatosis with polyangiitis administered RTX were enrolled at each institution. During the observation period of 2 years, data up to 6 months were analysed. Cox proportional hazards analysis was used to assess the factors associated with an outcome. RESULTS: Of the 75 patients who received RTX for remission induction therapy, 53 achieved remission by the sixth month and 50 were in remission at the sixth month. During therapy, 38 serious adverse events were observed in 24 patients, 21 serious infections in 16 patients, and 9 patients died. No factors were associated with remission; however, there was a significant difference between patients with and without remission in serious adverse events (22.6% vs. 54.5%), serious infections (11.3% vs. 45.4%), and death (1.9% vs. 36.4%). The hazard ratio (95% confidence interval) for serious infection was 3.49 (1.29-9.74) for patients aged ≥ 75 years and 3.53 (1.31-9.53) for pulmonary complications. Four patients maintained remission for 6 months. CONCLUSIONS: The effectiveness and safety of RTX for microscopic polyangiitis and granulomatosis with polyangiitis for up to 6 months was demonstrated.

Inhibition of pancreatic cancer-cell growth and metastasis in vivo by a pyrazole compound characterized as a cell-migration inhibitor by an in vitro chemotaxis assay.

Pancreatic cancer is recalcitrant to treatment as it is highly metastatic and rapidly progressive. While observing the behavior of human pancreatic BxPC-3 cells using an optical assay device called TAXIScan, we found that several synthetic pyrazole and pyrimidine derivatives inhibited cell migration. One such compound, 14-100, inhibited metastasis of fluorescence-labeled BxPC-3 cells, which were transplanted into the pancreas of nude mice as a subcutaneously grown cancer fragment. Surprisingly, despite its low cytotoxicity, the compound also showed an inhibitory effect on cancer cell proliferation in vivo, suggesting that the compound alters cancer cell characteristics needed to grow in situ. Single-cell RNA-sequencing revealed changes in gene expression associated with metastasis, angiogenesis, inflammation, and epithelial-mesenchymal transition. These data suggest that the compound 14-100 could be a good drug candidate against pancreatic cancer.

Endoscopic bilateral revision after metal stent deployment for hepatic hilar obstruction using molting technique (with videos).

Background: After multiple uncovered self-expandable metal stent (UCSEMS) deployments, endoscopic revision becomes complex and potentially challenging. A novel stent delivery system with a dilation function has recently been developed in Japan. This study evaluated the technical feasibility of this device for patients with unresectable malignant hilar biliary obstruction (MHO) after multiple UCSEMS deployments. Method: Participants comprised consecutive patients with unresectable MHO who had undergone multiple UCSEMS deployments and required endoscopic revision for the right or left hepatic bile ducts, as decided by cholangiography under endoscopic retrograde cholangiopancreatography (ERCP) guidance. Results: A total of 14 patients requiring endoscopic revision of right and left hepatic bile ducts were enrolled in this study. Among these 14 patients, guidewire insertion through the mesh of previously placed stents failed in 2 patients. As a result, these two patients underwent only unilateral UCSEMS deployment. Because clinical success was not obtained, transmural placement of the UCSEMS under Endoscopic Ultrasound (EUS) guidance to the segment of the liver not being drained was performed in those patients. The molting technique was attempted in 12 patients, proving successful in all patients. The technical success rate was therefore 92.8% (12/14). Mean procedure time was 23.2 min. Conclusion: This novel stent delivery system with a dilation function may be useful in endoscopic revision techniques for bilateral UCSEMS deployment.

Axial Spondyloarthritis in Japan.

PURPOSE OF REVIEW: The differences in the epidemiology and management of patients with axial spondyloarthritis (axSpA) among regions and countries largely depend on the positivity of human leukocyte antigen (HLA)-B27 and the health care system. This review article focused on axSpA in Japan, where the prevalence of HLA-B27 is extremely low (0.3%) and the universal health insurance system typically provides a 70% or more copayment by the government. RECENT FINDINGS: A nationwide survey was conducted in Japan in 2018, which estimated that there were 3200 patients (95% confidence interval [CI]: 2400-3900) with ankylosing spondylitis (AS), a term interchangeable with radiographic axSpA (r-axSpA), and 800 patients (95% CI: 530-1100) had non-radiographic (nr)-axSpA. These data indicate a prevalence of 2.6/100,000 or 0.0026% for AS and 0.6/100,000 or 0.0006% for nr-axSpA. Patients with AS, but not those with nr-axSpA, are designated as suffering from intractable diseases in Japan; thus, their medical expenses are reduced by grant under the Act on Medical Care for Patients with Intractable Diseases. As of February 2022, infliximab, adalimumab, secukinumab, ixekizumab, and brodalumab have been approved for AS, and secukinumab, ixekizumab, and brodalumab have been approved for nr-axSpA. An algorithm for nr-axSpA in Japan has been developed for the proper diagnosis and use of these therapeutic agents. A low prevalence of axSpA, especially that of nr-axSpA, was found in Japan. Early referral and the resultant diagnosis and appropriate treatment of these patients by rheumatologists are crucial issues in Japan, as in other countries.

Partially covered self-expandable metal stent with antimigratory single flange plays important role during EUS-guided hepaticogastrostomy.

Background and study aims Stent migration into the abdominal cavity, which can occur due to stent shortening or stomach mobility, is a critical adverse event (AE) in EUS-HGS. To prevent this AE due to stent shortening, a novel, partially covered self-expandable metal stent with an antimigratory single flange has recently become available in Japan. The present study evaluated the clinical feasibility and safety of EUS-HGS using this novel stent. Patients and methods We measured stent length in the abdominal cavity and the luminal portion after EUS-HGS using computed tomography (CT) performed 1 day after EUS-HGS (early phase). To evaluate stent shortening and the influence of stomach mobility, we also measured stent length at the same sites on CT performed at least 7 days after EUS-HGS (late phase). Results Thirty-one patients successfully underwent EUS-HGS using this stent. According to CT in the early phase, stent length in the abdominal cavity was 7.13 ±â€Š2.11 mm and the length of the luminal portion was 53.3 ±â€Š6.27 mm. Conversely, according to CT in the late phase, stent length in the abdominal cavity was 8.55 ±â€Š2.36 mm and the length of the luminal portion was 50.0 ±â€Š8.36 mm. Stent shortening in the luminal portion was significantly greater in the late phase than in the early phase ( P  = 0.04). Conclusions CT showed that stent migration can occur even with successful stent deployment, due to various factors such as stent shortening. The antimigratory single flange may be helpful to prevent stent migration, but further prospective comparative studies are needed to confirm our results.

Impacts of SNPs on adverse events and trough concentration of imatinib in patients with gastrointestinal stromal tumors.

Although imatinib has dramatically improved the outcomes of patients with gastrointestinal stromal tumor (GIST), marked inter-individual differences in its efficacy and toxicity have been observed. Extensive pharmacogenetic studies in Caucasian and Asian populations have demonstrated that several genetic polymorphisms are involved in these differences; however, no studies have focused on Japanese patients with GIST. This study aimed to evaluate the impacts of genetic polymorphisms of drug metabolizing enzymes and transporters on the incidence of adverse events and trough plasma concentrations (Ctroughs) of imatinib in Japanese patients with GIST. Of 35 candidate SNPs genotyped from 65 patients, ABCG2 421C>A was significantly associated with increased incidence rates of grade 2 or higher rash. When relationships between the genotypes and Ctroughs were examined in a subgroup of 38 patients from whom plasma was available, 5 SNPs were associated with significant trends toward increased or decreased dose-adjusted Ctroughs. Of them, SLCO1B3 334T>G and SLCO1A2 -1032G>A made significant contributions to the individual variability of Ctrough by multivariate regression analysis. Genetic variations in ABCG2, SLCO1B3, and SLCO1A2 may play important roles in the safety and pharmacokinetics of imatinib in Japanese patients with GIST, although a replication study is necessary for validation.

Republication: A Prospective Observational Study of Adoptive Immunotherapy for Cancer Using Zoledronate-Activated Killer (ZAK) Cells - An Analysis for Patients With Incurable Pancreatic Cancer.

BACKGROUND/AIM: Adoptive immunotherapy (AIT) using autologous zoledronate-activated killer (ZAK) cells has been performed for developing a novel modality of cancer treatment. In this study, data series from incurable pancreatic cancer were analyzed. PATIENTS AND METHODS: Patients were treated with AIT using intravenous administration of ZAK cells every 3 to 4 weeks in combination with standard chemotherapy and possible clinical benefits were examined. RESULTS: Seventy-five patients were treated. A median overall survival (OS) time of 6.7 months was achieved for all patients and 13.1 months for those treated 5 times or more, that increased to 14.6 and 18.3 months, respectively, when the previous treatment period of chemotherapy alone was included in the analysis. The disease control rate was 58.5 %. Multivariate regression analysis showed a significant positive correlation between the survival and baseline value of lymphocyte percentage in white blood cell counts (p=0.031). CONCLUSION: The data suggest that AIT using ZAK cells in combination with chemotherapy is safe and feasible and may be effective in prolonging survival for patients with incurable pancreatic cancer. The lymphocyte percentage at baseline may be a good biomarker for predicting the survival benefit of ZAK cell AIT.

Erratum: Adoptive immunotherapy for gastric cancer using zoledronate-activated killer cells: A prospective observational study.

[This corrects the article DOI: 10.3892/mco.2020.2125.].

A nationwide questionnaire survey on the prevalence of ankylosing spondylitis and non-radiographic axial spondyloarthritis in Japan.

OBJECTIVE: This nationwide study aimed to reveal the prevalence of ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-ax SpA), and the positivity rate of human leukocyte antigen (HLA) among such patients in Japan. METHODS: The first survey was conducted in 2221 randomly selected facilities (26.3%) in September 2018, where the patients with AS/nr-ax SpA were taken care of from January to December 2017. We estimated the total number of these patients using response and extraction rates. A second survey was conducted in 117 facilities (49.8%) to assess for HLA-B27 positivity rate and clinical features. RESULTS: The estimated total numbers of the patients with AS and nr-ax SpA were 3200 (95% confidence interval [CI]: 2400-3900) and 800 (530-1100), suggesting that the prevalence values of AS and nr-ax SpA in general population were 2.6/100,000 (0.0026%) and 0.6/100,000 (0.0006%), respectively. Although 55.5% (76/137) of patients with AS were HLA-B27-positive, those whose age of onset was estimated to be over 50 years tended to undergo less HLA-B27 testing. CONCLUSION: This study revealed the lower prevalence of AS/nr-ax SpA in Japan, compared to those in other countries. Further studies are required to reveal the association of HLA-B27 with the clinical features.