Inotuzumab ozogamicin (IO), an anti-CD22 antibody conjugated with calicheamicin, is highly effective against relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, acquired resistance limits the long-term efficacy of IO. To elucidate the underlying mechanisms of IO resistance and explore strategies to overcome it, six IO-resistant B-ALL sublines were newly established. Although CD22 expression was preserved in all resistant sublines, more than 80-fold increases in 50% inhibitory concentration (IC50) were observed, accompanied by acquired resistance to IO-induced apoptosis. Microarray analysis revealed upregulation of ABCB1, which was further confirmed by overexpression of the encoded protein, the drug efflux pump P-glycoprotein (P-gp). P-gp inhibition restored IO sensitivity by inhibiting calicheamicin efflux, a key resistance mechanism. Concurrently, poly (ADP-ribose) polymerase (PARP) inhibition of DNA damage repair enhanced IO cytotoxicity. Notably, in the triplet combination of IO with P-gp and PARP inhibitors, PARP inhibition of the repair of DNA damage caused by calicheamicin accumulation following P-gp inhibition markedly enhanced the antitumor effects of IO. This approach may offer a novel and effective therapeutic strategy for IO-resistant B-ALL.
Immune checkpoint inhibitors, such as nivolumab, have become pivotal in the treatment of advanced gastric cancer, particularly when combined with chemotherapy. While immune-related adverse events (irAEs) are commonly viewed as complications, their occurrence has been increasingly associated with favorable treatment responses. We report the case of a 59-year-old man diagnosed with advanced gastric cancer with liver and multiple lymph node metastases. The patient received chemotherapy, including nivolumab, but developed multiple grade 3 irAEs during treatment, including hypophysitis with secondary adrenal insufficiency, type 1 diabetes mellitus, and late-onset colitis. Despite these toxicities, imaging and endoscopy showed complete disappearance of the primary tumor and metastatic lesions, and a complete response was achieved per the Response Evaluation Criteria in Solid Tumors. Nivolumab monotherapy was continued for maintenance until gastrointestinal symptoms recurred due to irAE-associated colitis, which was successfully treated with corticosteroids. No tumor relapse was observed during this period. This case highlights that multi-organ irAEs are predictive of a favorable treatment response and that appropriate treatment of irAEs may result in excellent treatment outcomes in advanced gastric cancer.
This is the official English summary of the Japanese 2025 guide. The first edition of the guide for the diagnosis and management of connective tissue disease (CTD) associated with interstitial lung disease (ILD) was published in 2020 as a joint initiative by the Japanese Respiratory Society and the Japanese College of Rheumatology. This updated edition reflects major advances over the past five years, incorporating the latest international guidelines, consensus statements, and considerations unique to the Japanese healthcare reimbursement system. The guide is structured to facilitate timely clinical decision-making by highlighting key diagnostic and therapeutic milestones. The newly added content includes a conceptual framework for understanding ILD in CTD, practical clinical flowcharts, screening strategies, and risk factors, an overview of acute exacerbations, and a comprehensive approach to rehabilitation. Notably, treatment algorithms for ILD associated with polymyositis/dermatomyositis and systemic sclerosis have been revised to align with the most recent evidence and disease-specific recommendations, thereby enhancing their relevance to real-world practice. In addition, a provisional algorithm was proposed for the management of rheumatoid arthritis-associated ILD. The updated guide aims to standardize the multidisciplinary management of CTD-associated ILD and offers future perspectives to guide research and improve patient outcomes.
Acute fatty liver of pregnancy (AFLP) is a rare pregnancy-related liver disorder that can rapidly progress to multiorgan failure, including disseminated intravascular coagulation (DIC) and renal dysfunction. It is potentially fatal if not promptly recognized and treated; however, the diagnostic role of imaging modalities remains poorly defined. We report a case of a 29-year-old primigravida who presented with progressive jaundice, liver dysfunction, coagulopathy, and renal impairment at 33 weeks of gestation. Abdominal computed tomography (CT) demonstrated decreased hepatic attenuation, with a CT value of 23.0 Hounsfield units, suggestive of fatty deposition. Based on fulfillment of 7 of the 14 Swansea criteria and the presence of fetal distress, an emergency cesarean section was performed. On postoperative day 18, the controlled attenuation parameter (CAP) obtained by vibration-controlled transient elastography indicated a steatosis grade of S0, with a CAP value of 196 dB/m, whereas ultrasound-guided liver biopsy revealed microvesicular steatosis on histological examination, confirmed by adipophilin immunostaining. Electron microscopy further demonstrated numerous microvesicular lipid droplets and dilatation of the rough endoplasmic reticulum, leading to a definitive diagnosis of AFLP. This case suggests that CAP may underestimate hepatic fat accumulation when steatosis is predominantly microvesicular, as in AFLP, and that detailed pathological and ultrastructural evaluation may be valuable for diagnostic confirmation and improved understanding of disease pathophysiology.
Background Clinical remission has emerged as an ambitious therapeutic goal in severe asthma, shifting emphasis from symptomatic relief to long-term disease modification. Tezepelumab, a monoclonal antibody targeting thymic stromal lymphopoietin, has demonstrated broad-spectrum anti-inflammatory activity. However, prospective data assessing clinical remission with tezepelumab, especially in biologic-experienced patients, remain limited. Objective The Tezepelumab-induced Clinical Remission in Severe Asthma (TERESA) study is a multicenter, prospective, single-arm, investigator-initiated phase 4 study evaluating clinical remission at week 52 in patients with uncontrolled severe asthma receiving tezepelumab every 4 weeks. Methods Clinical remission was defined as the absence of asthma exacerbations, discontinuation of maintenance oral corticosteroids, an Asthma Control Questionnaire 6 score of ≤1.5, and stabilized lung function. Secondary end points included complete remission (clinical remission plus type 2 biomarker negativity). Results Among 107 patients enrolled (including 50 biologic-experienced patients), 34.6% (95% confidence interval, 26.2, 44.0) obtained clinical remission at week 52. Complete remission was observed in 9.3%. Biologic-naive patients demonstrated higher remission rates than biologic-experienced patients (47.4% vs 20.0%, respectively). Multivariable logistic regression identified absence of previous biologic receipt (adjusted odds ratio, 3.61; 95% confidence interval, 1.29, 10.15) and baseline blood eosinophil count ≥ 300 cells/μL (adjusted odds ratio, 5.10; 95% confidence interval, 1.23, 21.18) as independent predictors of clinical remission. Conclusion In this single-arm study with 1 year’s follow-up, tezepelumab resulted in clinical remission in approximately one third of patients with severe asthma, with a favorable safety profile. Higher baseline eosinophil count and biologic-naive status were key predictors of remission, underscoring tezepelumab’s potential to obtain comprehensive disease control in appropriately selected patients. Clinical trial registration Japan Registry of Clinical Trials (jRCTs071230026).
