PURPOSE:Many patients with various cancer types have received immune checkpoint inhibitors (ICI) worldwide since their approval, and novel unexpected complications from their long-term use are apparent. We identified some cases of B-cell lymphoma occurring during PD-1 blockade therapy as such unexpected complications. In this study, we aimed to evaluate the incidence of hematologic malignancies in patients with lung cancer receiving PD-1 blockade therapy and to elucidate the mechanisms underlying the progression of these malignancies. EXPERIMENTAL DESIGN:We performed IHC staining on the clinical samples from patients with B-cell lymphoma that developed during PD-1 blockade therapy and analyzed large-scale real-world datasets. We further investigated the underlying mechanisms through in vitro and in vivo experiments. RESULTS:A higher incidence of B-cell malignancies has been observed in patients with lung cancer treated with PD-1 blockade therapies based on large-scale real-world data analyses (n = 15,670). The identified lymphomas had a large amount of CD4+ T follicular helper (TFH) cell infiltration. In addition, PD-1 blockade activated PD-1+ TFH cells, which promoted lymphoma proliferation via the IL4/IL4R, IL21/IL21R, and CD40L/CD40 axes. Notably, the lymphomas exhibited high expression of IL4R, IL21R, and CD40. CONCLUSIONS:Our findings highlight the need for careful monitoring and consideration of the potential B-cell malignancy complications in clinical settings in which ICIs are used.

Cumulative incidence of leukemia (left) and multiple myeloma (right) with immune checkpoint inhibitors

Background:In the field of team-based care, pharmacists are vital for optimizing medication therapy. However, many medical professionals lack the opportunity to learn how to propose prescription changes with precision. Objective:This study aimed to address this knowledge gap by developing and assessing a new educational program for pharmacy students focused on prescription support and interprofessional collaboration. Methods:We recruited 191 fifth-year pharmaceutical students during the 2022-2024 academic years. The program featured a 7-day intensive curriculum that included learning how to assist with prescriptions, analyzing clinical data, and engaging in role-playing exercises. A web-based questionnaire and a paper test were used to evaluate students' awareness and knowledge both before and after the program. Statistical analyses were performed to verify the significance of changes; we utilized the Wilcoxon signed-rank test for the ordinal data derived from the specific behavioral objectives and 2-tailed paired t tests for the interval data from the knowledge tests. The magnitude of change was quantified using r for Wilcoxon tests and Cohen dz for 2-tailed t tests, with 95% CI calculated to ensure the stability and reliability of the observed results. Results:Analysis of the primary outcome specific behavioral objectives revealed statistically significant effects across all items (Wilcoxon signed-rank test; P<.001). Effect sizes (r=0.505-0.835) ranged from moderate to large, with particularly large effects observed in identifying contents issue (r=0.835, 95% CI 0.126-0.330; P<.001). Knowledge test scores showed significant improvement in the following 3 subjects: pharmacology (r=-0.504, 95% CI -0.215 to 0.127; P<.001), organic chemistry (r=0.254, 95% CI -0.148 to -0.193; P=.004), and communication (r=0.221, 95% CI -0.151 to -0.190; P=.01). No significant changes were observed in pathology or pharmacokinetics. Conclusions:This program provides strong evidence that practical, hands-on learning with hospital pharmacists helps improve pharmacy students' professional skills and optimize pharmaceutical therapies in interprofessional care. By teaching pharmacists to effectively propose prescription changes, the program equips them to become integral members of interprofessional care, ultimately leading to optimized pharmaceutical care for patients.

This study aimed to evaluate the global trends in systemic sclerosis (SSc)-related mortality by age, sex, and geographic region. SSc is a multisystem autoimmune disease characterized by tissue fibrosis, vascular dysfunction, and multi-organ involvement, which is associated with a high mortality risk. Using the World Health Organization Mortality Database, we examined trends in SSc-related crude mortality rates (SSc-CRs) and age-standardized mortality rates (SSc-ASMR) per 1,000,000 population from 2001 to 2023. Locally weighted regression was applied to visualize long-term patterns, and Joinpoint regression was used to assess the national trends from 2010 to 2023. Across 74 countries, 85,291 SSc-related deaths were reported, with 79.41

Summary of staining antibodies in flow cytometry analyses

Immune checkpoint inhibitor (ICI)–induced cardiac immune-related adverse events (cardiac irAEs) are rare yet serious complications. Clinical assessment tools to identify at-risk patients would allow for more effective prevention strategies, thus improving clinical outcomes. We constructed various machine learning (ML) models to predict these events among patients receiving ICI therapy. A cohort of patients receiving ICI therapy from 2010 to 2023 was identified from the TriNetX database. Cardiac irAEs were defined as the occurrence of relevant diagnosis codes within 90 days of ICI initiation, with corresponding hospital visits. We created ML models to predict these events, including elastic net logistic regression and multiple tree-based approaches (gradient boosted trees and random forest). We evaluated model performance with different performance measures and utilized assigned risk scores to stratify risk of cardiac irAEs into low, medium, and high-risk tiers. We identified 61,117 patients receiving ICI therapy, with nearly 2

Immunohistochemistry for CD40, IL-4R, and IL-21R in FL and DLBCL

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. Tetrabenazine (TBZ), a vesicular monoamine transporter 2 inhibitor, is commonly used to manage chorea; however, it may exhibit fluctuating plasma levels and elicit frequent adverse events. In this study, we aimed to clarify the effects of TBZ deuteration on its safety profile. We compared the safety profiles of TBZ and deutetrabenazine (DTBZ) in real-world clinical practice using disproportionality analysis and the large-scale pharmacovigilance database, VigiBase-the WHO's global database of adverse drug reactions. Adverse event signals were assessed using the information component (IC). Seriousness was classified according to clinical outcome, and time to onset (TTO) was analyzed for selected events. TBZ showed signals for disorientation, dystonia, and sleep disorders (IC025 > 0), whereas DTBZ did not. Serious adverse events were reported in 54.7% of TBZ cases and 37.9% of DTBZ cases. The TTO of sleep disorder was also evaluated; however, the number of cases with available TTO information was limited. DTBZ showed fewer adverse event signals and a lower proportion of serious adverse events than TBZ. These findings suggest potential differences in the safety profiles of the two drugs, which may influence tolerability in the treatment of HD.

Patient selection flowchart in the MDV database

No head-to-head studies have directly compared differences in adverse events (AEs) associated with carfilzomib, elotuzumab, and ixazomib plus lenalidomide and dexamethasone therapies (KRd, EloRd, and IxaRd, respectively) in patients with multiple myeloma. Here, we comprehensively compare the AE profiles of KRd, EloRd, and IxaRd using data from the World Health Organization global pharmacovigilance database, VigiBase. AE reports related to KRd, EloRd, and IxaRd up to December 2024 were extracted from VigiBase. Disproportionality analyses were performed using reporting odds ratios (RORs) with 95% confidence intervals (CIs) for both the system organ class (SOC) and preferred term (PT) levels. Overall, 3950, 1210, and 3948 reports were extracted for KRd, EloRd, and IxaRd, respectively. KRd showed significant disproportionality signals in four SOCs, including Blood and lymphatic system (ROR [95% CI]: 1.74 [1.44-2.10] vs EloRd and 1.60 [1.42-1.81] vs IxaRd) and Cardiac (1.71 [1.32-2.22] and 2.14 [1.79-2.56]) disorders. Representative PTs included neutropenia and cardiac failure. IxaRd exhibited the broadest AE profile, with significant signals in seven SOCs, notably Gastrointestinal (2.47 [2.18-2.80] vs KRd and 3.05 [2.46-3.77] vs EloRd) and Nervous system (1.52 [1.33-1.74] and 2.82 [2.19-3.62]) disorders. Representative PTs encompassed nausea and peripheral neuropathy. In contrast, EloRd exhibited no SOC with significant signals in comparison with both the other therapies. Distinct AEs were identified with KRd and IxaRd, while EloRd exhibited a relatively narrower AE profile. These findings highlight the importance of considering therapy-specific toxicities when selecting appropriate treatments for patients with multiple myeloma.

Subgroup analyses of lymphoma risk by demographic and treatment factors in the MDV dataset

Incidence rate of lymphoma in Japan

Gating strategy for B cells in flow cytometry analysis

ICD-10 codes for diagnoses of lung cancer and hematological events

Immune checkpoint inhibitors (ICIs), essential in cancer therapy, can cause severe immune-related adverse events (irAEs), including myocarditis with a high fatality rate. Currently, the pathogenesis, biomarkers, and risk factors of ICI-induced myocarditis (ICIM) are not fully understood. This exploratory study aimed to develop machine learning-based models to predict the onset of ICIM within 3 months of starting ICI therapy, using a large health insurance database. The models were constructed using the Light Gradient Boosting Machine (LightGBM) and Random Forest algorithms, incorporating clinical variables such as comorbidities and prior medication classifications. In this study, a strategy combining undersampling and bagging was used to minimize the impact of highly imbalanced datasets. The Random Forest model demonstrated superior performance compared with the LightGBM model, and the SHapley Additive exPlanations (SHAP) analysis for the Random Forest model revealed that the concurrent use of ICIs was the most important variable for predictions. Although predictive performance remains limited (AUROC ≈ 0.63), this exploratory framework demonstrates the feasibility of developing data-driven risk prediction models for ICIM. Future studies with expanded datasets and integration of laboratory parameters are warranted to improve predictive accuracy and potential clinical applicability.

Importance:Head and neck cancer (HNC) accounts for nearly 1 million new cases and approximately half a million deaths annually worldwide, representing a substantial global health burden. Despite an overall decline in mortality in many regions, patterns vary across anatomical subsites and countries. Objective:To evaluate international and national mortality trends in HNC and its major anatomical subsites from 2001 to 2023. Design, Setting, and Participants:This observational epidemiologic study analyzed population-based mortality data from the World Health Organization (WHO) Mortality Database for 73 countries between 2001 and 2023. Data collection was conducted in May 2025, and the data were analyzed between May and October 2025. Eligible countries had medium- to high-quality vital registration data. Age-standardized mortality rates (ASRs) were calculated using the new WHO World Standard Population. Country-specific trends from 2010 to 2023 were assessed using joinpoint regression among countries with at least 7 years of available data. Main Outcomes and Measures:ASRs and average annual percentage change in HNC mortality overall and by anatomical subsite using population-based analysis. Results:From 2001 to 2023, 2 000 066 HNC-related deaths (450 657 females; 1 549 409 males) were recorded. Internationally, ASRs decreased by 38.9%, with greater reductions among male individuals than among female individuals. Substantial divergence was observed across subsites: laryngeal cancer mortality decreased markedly (-50.1%), whereas increasing trends in oropharyngeal cancer mortality were observed in many countries in recent years, particularly in high-income countries such as the UK (average annual percentage change, 4.30%) and the US (average annual percentage change, 3.26%). Conclusions and Relevance:Results of this study suggest that, although overall HNC-related ASRs have declined internationally, marked variation across subsites and countries persists. The contrasting trends between laryngeal and oropharyngeal cancers underscore the need for subtype-specific prevention strategies and continued global surveillance.