Kazuichi Okazaki

Background and Aims The role of 5-aminosalicylates (5-ASA) in maintaining remission in patients with ulcerative colitis (UC) receiving advanced therapy remains controversial. This study evaluated the safety and feasibility of 5-ASA discontinuation and dose reduction in patients with UC who achieved remission with advanced therapies. Methods This multicenter retrospective cohort study included patients with UC who achieved steroid-free clinical remission with advanced therapies at three centers (2010–2025). Patients were categorized into continuation or discontinuation groups based on 5-ASA status after achieving remission. The primary outcome was time to clinical relapse. Dose reduction versus dose maintenance was also evaluated among patients who continued 5-ASA. Results 170 treatment episodes were analyzed: 153 in the continuation group and 17 in the discontinuation group. The relapse rate was 17.6% (3/17) in the discontinuation group and 18.3% (28/153) in the continuation group, with no significant difference in relapse-free survival (log-rank P = 0.597). Among continuers, 21 underwent dose reduction and 132 maintained their dose; dose reduction did not increase relapse risk (log-rank P = 0.273). Cox regression analysis showed 5-ASA discontinuation was not associated with increased relapse risk (HR: 0.719, 95% CI: 0.218–2.378, P = 0.589), with only prior advanced therapy exposure significantly predicting relapse. Conclusion This is the first real-world study evaluating 5-ASA discontinuation in patients with UC achieving remission with advanced therapies. Discontinuation or dose reduction of 5-ASA might not be associated with increased relapse risk in carefully selected patients. Although limited sample size restricts definitive conclusions, these findings suggest reducing medication burden may be feasible in selected patients.

Immune responses in humanized mice are generally inefficient without co-transplantation of human thymus or HLA transgenes. Previously, we generated humanized mice via the intra-bone marrow injection of CD133+ cord blood cells into irradiated adult immunodeficient mice (IBMI-huNSG mice), which could mount functional immune responses against HTLV-1, although the underlying mechanisms were still unknown. Here, we investigated thymocyte development in IBMI-huNSG mice, focusing on the roles of human and mouse MHC restriction. IBMI-huNSG mice had normal developmental profiles but aberrant thymic structures. Surprisingly, the thymic medulla-like regions expanded after immunization due to enhanced thymocyte expansion in association with the increase in HLA-DR+ cells, including CD205⁺ dendritic cells (DCs). The organ culture of thymus from immunized IBMI-huNSG mice with a neutralizing antibody to HLA-DR showed the HLA-DR-dependent expansion of CD4 single positive thymocytes. Mature peripheral T-cells exhibited alloreactive proliferation when co-cultured with human peripheral blood mononuclear cells. Live imaging of the thymus from immunized IBMI-huNSG mice revealed dynamic adhesive contacts of human-derived thymocytes and DCs accompanied by Rap1 activation. These findings demonstrate that an increase in HLA-DR+ cells by immunization promotes HLA-restricted thymocyte expansion in humanized mice, offering a unique opportunity to generate humanized mice with ease.

The mechanisms underlying the transition from colitis-associated inflammation to carcinogenesis and the cell origin of cancer formation are still unclear. The azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model reproduces human colitis-associated colorectal cancer. To elucidate the mechanisms of cancer development and dynamics of the linker threonine-phosphorylated Smad2/3 (pSmad2/3L-Thr)-positive cells, we explored the early stages of colitis-associated colorectal cancer in AOM/DSS mice. The AOM/DSS mice were sacrificed at 4 to 6 weeks following AOM administration. To analyze the initial lesions, immunofluorescence staining for the following markers was performed: β-catenin, Ki67, CDK4, Sox9, Bmi1, cyclin D1, and pSmad2/3L-Thr. Micro-neoplastic lesions were flat and unrecognizable, and the uni-cryptal ones were either open to the surfaces or hidden within the mucosae. These neoplastic cells overexpressed β-catenin, Sox9, Ki67, and Cyclin D1 and had large basophilic nuclei in the immature atypical cells. In both the lesions, pSmad2/3L-Thr-positive cells were scattered and showed immunohistochemical co-localization with β-catenin, CDK4, and Bmi1 but never with Ki67. More β-catenin-positive neoplastic cells of both lesions were detected at the top compared to the base or center of the mucosae. We confirmed initial lesions in the colitis-associated colorectal cancer model mice and observed results that suggest that pSmad2/3L-Thr is a biomarker for tissue stem cells and cancer stem cells.

Objectives: Endoscopic ultrasound‐guided tissue acquisition (EUS‐TA) plays a crucial role in the diagnosis of pancreatic tumors. The present study aimed to investigate the current status of needle tract seeding (NTS) after EUS‐TA of pancreatic tumors based on a nationwide survey in Japan.Methods: Patients who underwent surgical resection of primary pancreatic tumors after EUS‐TA performed between April 2010 and March 2018 were surveyed. The incidence rates of NTS were determined, and compared in patients with pancreatic ductal adenocarcinomas (PDACs) and other tumors, and in patients who underwent transgastric and transduodenal EUS‐TA of PDACs. The detailed features and prognosis of patients with NTS were also assessed.Results: A total of 12,109 patients underwent surgical resection of primary pancreatic tumors after EUS‐TA. The overall incidence rate of NTS was 0.330%, and the NTS rate was significantly higher in patients with PDAC than in those with other tumors (0.409% vs. 0.071%, P = 0.004). NTS was observed in 0.857% of patients who underwent transgastric EUS‐TA, but in none of those who underwent transduodenal EUS‐TA. Of the patients with NTS of PDACs, the median time from EUS‐TA to occurrence of NTS and median patient survival were 19.3 and 44.7 months, respectively, with 97.4% of NTS located in the gastric wall and 65.8% of NTS resected. The patient survival was significantly longer in patients who underwent NTS resection than in those without NTS resection (P = 0.037).Conclusions: Needle tract seeding appeared only after transgastric not after transduodenal EUS‐TA. Careful follow‐up provides an opportunity to remove localized NTS lesions by gastrectomy.

IgG4 related-disease (IgG4-RD) is a fibroinflammatory disorder recognized as a novel clinical entity with either synchronous or metachronous multi-organ involvement. Autoimmune pancreatitis (AIP) is classified into two types: type 1 AIP as a pancreatic manifestation of IgG4-RD, and type 2 AIP with granulocytic epithelial lesion and occasional association with ulcerative colitis. Although the pathogenic mechanism still remains unclear, possible multi-pathogenic factors such as genetic factors, disease specific or related antigens, and abnormal innate or adaptive immunity may be involved in the development of IgG4-RD. Many immunocytes including M2 macrophages, plasmablasts, B cells and T-cells (Th2-CD4+T, follicular helper T cells and CD4+SLAMF7+cytotoxic T cells) play important roles in the pathogenesis . Conventional induction and maintenance therapies with glucocorticoid or rituximab are recommended in all symptomatic patients with active IgG4-RD. In those at risk for irreversible damage in any organs, this should be done urgently, regardless of symptoms. As no randomized clinical trials other than glucocorticoid maintenance therapy for type 1 AIP have been performed, the comprehensive management for IgG4-RD has not been established yet. Targeted treatment approaches against the plasmablast to B cell lineage and the CD4+SLAMF7+cytotoxic T cell seem to be promising for the future-directed treatment.

In response to the latest knowledge and the amendment of the Japanese diagnostic criteria for autoimmune pancreatitis (AIP) in 2018, the Japanese consensus guidelines for managing AIP in 2013 were required to be revised. Three committees [the professional committee for developing clinical questions (CQs) and statements by Japanese specialists; the expert panelist committee for rating statements by the modified Delphi method; and the evaluating committee of moderators] were organized. Twenty specialists in AIP extracted the specific clinical statements from a total of 5218 articles (1963–2019) from a search in PubMed and the Cochrane Library. The professional committee made 14, 9, 5, and 11 CQs and statements for the current concept and diagnosis, extra-pancreatic lesions, differential diagnosis, and treatment, respectively. The expert panelists regarded the statements as valid after a two-round modified Delphi approach with individually rating these clinical statements, in which a clinical statement receiving a median score greater than 7 on a 9-point scale from the panel was regarded as valid. After evaluation by the moderators, the amendment of the Japanese consensus guidelines for AIP has been proposed in 2020.

Background Stimulation of Toll-like receptor 3 (TLR3) induces autoimmune-mediated pancreatitis in susceptible mice, whereas stimulation of TLR4 causes nonautoimmune-mediated pancreatitis. However, the effects of TLR2 stimulation on the pancreas are unknown. Aims We investigated the role of TLR2 stimulation on pancreatic damage by repeatedly stimulating mice with TLR2 ligands. Methods Wild-type (WT) and interleukin 10-deficient (IL-10-knockout (KO)) mice were administered zymosan and lipoteichoic acid (LTA) intraperitoneally at various doses twice weekly for 4 weeks. Syngeneic T-cell-deficient mice, B-cell-deficient mice, recombination activating gene 2-deficient (RAG2–KO) mice and RAG2–KO mice that had been reconstituted with CD4⁺ or CD8⁺ T cells isolated from WT mice were treated with zymosan similarly. Mice were killed, the severity of pancreatitis was graded histologically, and serum cytokine levels were measured. Results Repeated administration of zymosan induced pancreatitis dose dependently in both WT and IL-10–KO mice. Administration of LTA induced pancreatitis only in IL-10–KO mice. Adoptive transfer of splenocytes obtained from IL-10–KO mice with pancreatitis did not cause pancreatitis in recipient RAG2–KO mice. Pancreatitis was scarcely observed in RAG2–KO mice and was attenuated in T-cell-deficient and B-cell-deficient mice compared with WT mice. A single administration of zymosan significantly increased the serum level of monocyte chemoattractant protein 1 (MCP-1) in WT mice. Conclusions Repeated stimulation of TLR2 and dectin-1 induced nonautoimmune-mediated pancreatitis in mice. Participation of acquired immunity seems to play an important role in the pathogenesis of pancreatitis in association with the increase in serum MCP-1 level.