Citations

Abstract The benefit of rituximab maintenance after first-line (1L) bendamustine-rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010 and 2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient and disease characteristics. In the landmark analysis, rituximab maintenance was associated with improved event-free survival (EFS; median, 49.9 vs 29.7 months; P< .001) as well as overall survival (OS; median, 109.5 vs 74.2 months; P< .001). The EFS and OS benefits were observed across most of the subgroups. EFS and OS differences were statistically significant in those who achieved a complete response to 1L BR (n = 590; median EFS, 62.7 vs 31.1 months [P< .001]; median OS, 136.1 vs 75.3 months [P< .001]), but the analysis among those who achieved a partial response to 1L BR was limited by the small sample size. These results provide additional evidence for the survival benefit of rituximab maintenance after BR in MCL and support its use in clinical trial design and routine practice.

Abstract Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e−4). At disease progression, multiple myeloma cells upregulated cancer–testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune–tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression. Significance: Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune–tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.

Abstract Introduction Erectile Dysfunction (ED) is becoming increasingly recognized as a potential marker of chronic medical conditions. Recent research has examined the association between ED and Parkinson’s disease. In fact, recent findings indicate that men with ED have upwards of a fourfold higher risk of developing Parkinson’s disease compared to those without a diagnosis of ED. Objective Our research investigates associations between self-reported ED severity and neurobiological factors, including measures of cognitive function and neuroimaging of dopaminergic integrity. Methods We performed a retrospective analysis of 93 male research participants with ED extracted from an observational cohort study of aging and Parkinson’s disease biomarkers. Though some patients experienced some age-related mild cognitive changes, all participants were classified as clinically neurologically healthy. Patients received cognitive testing through the Montreal Cognitive Assessment (MoCA), with scores ranging from 0-30. Neuroimaging of the bilateral caudate and putamen, components of the striatum implicated in Parkinson’s disease pathology and dopaminergic binding, was measured through dopamine transporter SPECT imaging (DaTScan) binding ratios. ED was self-reported using questions 22-23 on the Scales for Outcomes in Parkinson’s Disease – Autonomic Dysfunction (SCOPA-AUT). Question 22 stated “In the past month, have you been impotent (unable to have or maintain an erection?)” and question 23 stated “In the past month, how often have you been unable to ejaculate?”. SCOPA-AUT scores ranged from 0 (sometimes) to 3 (often) and were averaged across both questions. Patients taking dopaminergic Parkinson’s disease medications or PDE5 inhibitors at baseline were excluded due to potential confounding. Due to violations of normality assumption, numerical associations utilized an age-adjusted partial spearman correlation coefficient. Descriptive statistics are displayed as median (IQR). Results Of the 93 selected participants, one individual was excluded due to incomplete neuroimaging DaTScan data. Therefore, 92 patients were included in our analysis. The median age of participants was 67.3 years (61.4 – 73.0) and the median MoCA score was 27.2 (26.0, 28.7) which represents minimal cognitive impairment. Age-adjusted spearmen correlation coefficient showed no association between MoCA measured cognitive performance and ED severity (r = -0.116, p = 0.275). Age-adjusted associations of striatal DaTScan showed a significant, mild relationship between ED severity and both right caudate dopamine binding ratios (r = 0.236, p=0.0242) and left putamen dopamine binding ratios (r = 0.262, p = 0.0121). However, associations between ED severity and both left caudate (r = 0.150, p = 0.155) and right putamen (r = 0.143, p = 0.176) dopamine binding ratios did not reach statistical significance. Conclusions Although no association was observed between ED severity and cognitive function, greater ED severity was significantly associated with increased striatal dopaminergic binding. This positive, age-adjusted association may reflect a compensatory dopaminergic response similar to that seen in the early stages of Parkinson’s disease. Overall, our findings suggest that ED could serve as a potential marker of central dopaminergic and autonomic alterations, even in the absence of clinically evident neurological disease. Disclosure No

Abstract Introduction Sperm cryopreservation is becoming increasingly accessible and cost-effective. One of the most common indications for cryopreservation remains prior to gonadotoxic therapies and surgeries. However, it may be used by patients undergoing vasectomy as an alternative to potential future more invasive procedures including reversal or sperm retrieval. Objective To characterize demographic and individual factors associated with the utilization of cryopreservation prior to vasectomy. Methods We conducted a retrospective review of all patients from January 2023 to May 2025 at a single academic medical center who underwent a vasectomy. All 186 patients who completed the pre-vasectomy questionnaire were included in our analysis. At the time of vasectomy consultation, patients were informed of the procedure’s permanent nature and, per guidelines, were educated on future fertility options, including vasectomy reversal and sperm retrieval for use with in vitro fertilization. All patients were also separately offered sperm cryopreservation. Demographic and questionnaire data was collected and analyzed. Pre-vasectomy questionnaire information included age, relationship information, familial information, and reason for vasectomy, among other factors. Numerical variables were described as medians with interquartile range and categorical variables were described in counts. Due to violation of the normality assumption, Fisher’s Exact test was used for categorical variables and the Kruskal-Wallis rank sum test was used for numerical variables. Results 186 patients completed the pre-vasectomy questionnaire and were used in our analysis. Of these individuals, 5.4% (n=10) utilized cryopreservation at the time of vasectomy. Individuals utilizing cryopreservation had a median age 5 years younger than those who did not utilize the same service (p = 0.046). Moreover, 40.0% (n=4) of individuals in the cryopreservation group had children compared to 83.5% (n=147) in the no cryopreservation group (p=0.004). Current relationship length was significantly longer for individuals who did not utilize cryopreservation, with a median reported relationship length of 11 years as compared to a median length of 5 years for individuals utilizing cryopreservation (p=0.025). The shorter relationship length is likely related to an additional finding that the percentage of individuals who utilized cryopreservation were married approximately 30% less often than individuals who did not use the same service (p=0.039). Conclusions While only a small proportion of patients undergoing vasectomy choose to pursue cryopreservation despite counselling at their visit, significant differences in demographic and individual characteristics were observed for those who did. These individuals tended to be younger, married at lower rates, without children, and in shorter relationships. With improved access to reproductive services, further work is needed to understand decision choices for men offered sperm cryopreservation prior to permanent sterilization. Disclosure No

Delirium is a serious neuropsychiatric condition marked by acute confusion and cognitive decline, commonly affecting postoperative and critically ill patients. It is especially prevalent in older adults and those requiring intensive care, including patients undergoing major surgery or receiving mechanical ventilation. For anesthesiologists, delirium is a critical and often underrecognized postoperative complication with complex perioperative contributors. Intensive care unit patients with delirium face increased mortality, cognitive impairment, and persistent symptoms beyond discharge. Despite its clinical significance, the pathophysiology of delirium remains poorly understood, with no standardized classification or targeted therapy. In light of emerging evidence connecting blood–brain barrier (BBB) permeability to the onset of delirium, we found that BBB dysfunction may represent a key mechanism underlying its pathophysiology. Through a thorough examination of predisposing and precipitating factors that impair both BBB integrity and cognitive function, we identified many points of connection between BBB dysfunction and delirium specifically. We include here a summary of our diagnostic approach with the aim of improving therapeutic strategies based on preserving BBB function to prevent or mitigate delirium.

Adoptive cell therapy (ACT) has shown remarkable success in the treatment of some malignancies, particularly leukemia. However, there are multiple factors that limit the durability of ACT in solid tumors, including dose-limiting toxicities, the immunosuppressive tumor microenvironment, and T-cell exhaustion. As the manufacture and preparation of adoptive T-cell therapies allows time and adequate conditions for ex vivo T-cell engineering, forward genetic screens can identify novel genetic targets that could improve their effectiveness. CRISPR is a commonly used functional genomics tool that has been successfully used to both enhance our understanding of mechanisms of resistance and to discover potential genetic edits to improve ACT. A complementary approach, Sleeping Beauty transposon mutagenesis provides additional opportunities to identify novel genetic edits without being constrained by the annotated human genome. Here, we summarize forward genetic screens and their tools to uncover strategies to enhance ACT. Complementary approaches can be combined and improved on to identify translatable genetic editing strategies through studies that accurately recapitulate disease-specific challenges.

ABSTRACT Background Older adults are at high risk for severe injuries and death from falls. Physical therapist (PT) and occupational therapist (OT) evaluations have been introduced into Emergency Department (ED) care to assist with fall risk evaluation and fall prevention care. An evaluation of current evidence was undertaken to inform the Geriatric ED Guidelines 2.0. Methods Systematic review of physical and/or occupational therapy evaluation for fall prevention in the ED. The intervention was evaluation by a rehabilitation therapist (PT, OT, or both) for fall prevention, fall assessment, or mitigation of fall risk factors. Studies that did not perform the evaluation during the ED or ED Observation Unit visit were excluded, such as referrals for home consultation. The published literature was searched using strategies created by a medical librarian and was implemented in Embase and PubMed in March 2025. Covidence was used for article collation and review. Risk of bias was assessed using the Cochrane Risk of Bias v2 and the Ottawa–Newcastle scale. Results The search resulted in 387 articles with 52 duplicates, for 335 unique citations. Ten articles on 6 datasets were included (4 abstracts and 6 published manuscripts). One article was at high risk of bias as very few intervention patients received therapist evaluation. The remaining 5 datasets had varied co‐interventions in addition to PT and/or OT evaluations. PT or OT evaluation in the ED was associated with reduced ED revisits at 1, 2, and 6 months. Evaluations in the ED were not associated with increased hospital admission rates or ED length of stay. A meta‐analysis was infeasible due to varied outcome timeframes. Conclusions PT and/or OT evaluations for fall prevention were associated with reduced subsequent ED revisits for older adults. However, the impact of co‐interventions and heterogeneity limits strong conclusions.

ABSTRACT Radiology education is critical for medical students' anatomical competence and clinical readiness. However, it remains insufficiently integrated in medical curricula as residency program directors describe interns' basic image interpretation as unsatisfactory. This review aims to assess the efficacy of ultrasound, CT, MRI, and X‐ray in facilitating the learning of anatomy among medical students. Following PRISMA guidelines, 983 articles were screened, and 52 studies published between 2000 and 2025 met the inclusion criteria by comparing radiology‐integrated anatomy education with traditional methods such as cadaver and atlas use. Data extraction covered study design, radiology modalities, and effect sizes. Both integrated and traditional methods consisted of medical student cohorts assessed on objective knowledge and skills with recorded quantitative outcomes. Included studies showed knowledge gains on multiple choice assessments (pooled Cohen's d = 0.99, 95% CI: 0.34–1.65) but with high heterogeneity among studies ( I 2 = 99.5%). Controlled designs were used in 21% of studies. Other investigations (68% of studies) used attitudinal surveys that revealed strong student preference for radiology‐integrated learning. Of the modalities present, ultrasound was predominant (85% of studies), with other modalities (CT: 15%; MRI/X‐ray: < 5%) substantially underrepresented despite clinical relevance. Radiology integration was shown to enhance anatomy education and clinical preparedness. The incorporation of radiology, specifically ultrasound, into anatomical education leads to a significant and substantial improvement in student learning outcomes. Future investigations can standardize assessments, expand multimodal research, and address global curricular disparities.

Abstract Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced-intensity regimens were associated with lower T-cell and myeloid donor chimerism, particularly when non–busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hot spot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS, or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS after HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This trial was registered at www.clinicaltrials.gov as NCT02064933.

Abstract Pyroptosis is a form of programmed cell death characterized by the cleavage of the gasdermin (GSDM) family proteins that form pores in the plasma membrane, cell rupture, and the release of proinflammatory cytokines. In this study, we performed immunohistochemistry for cleaved gasdermin D (GSDMD), gasdermin E (GSDME) N-terminus, and gasdermin C (GSDMC) in 2 different cohorts of diffuse large B-cell lymphoma (DLBCL) and analyzed the impact of GSDM expression on prognosis and immunity. The results showed frequent cleaved GSDMD (N-terminal) expression. Only cytoplasmic GSDMD N-terminal expression correlated with significantly better patient survival in the 2 cohorts. In contrast, GSDME was mainly expressed in the vascular endothelium, and correlated with significantly adverse prognostic effect. Correlating with the multiplex fluorescent immunohistochemistry results, we found that cytoplasmic GSDMD N-terminal expression was associated with increased CD38+ (activated) M1 macrophages in both cohorts, cognate interactions between live DLBCL cells and activated M1 macrophages (and T cells), and lower PD-1/PD-L1 expression in the analyzed cases. In contrast, T-cell pyroptosis, lymphoma cell-resistance to cell death, and phagocytosis by M2 macrophages were observed in tissues with predominantly nuclear GSDMD N-terminal expression. Bulk gene expression profiling and deconvolution analysis revealed associations of cytoplasmic GSDMD N-terminal expression with downregulation of “Don’t eat me”–signaling genes, upregulation of many RNA genes, decreased frequency of “inflammatory” lymphoma microenvironment subtype, increased frequencies of prognostically favorable cell states and ecotypes, and decreased frequency of T-cell exhaustion state. In summary, this study showed distinct cellular and subcellular patterns of 3 GSDM proteins and their associated immune response phenotypes and prognostic effects, with implications for novel therapeutic strategies for B-cell lymphoma.