Citations

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Background The Woven EndoBridge (WEB) device is a prevalent treatment for intracranial aneurysms. While many studies have assessed the obliteration rate post-WEB embolization, few have focused on long-term outcomes in partially thrombosed aneurysms. Objective To assess whether partially thrombosed aneurysms are at higher risk of recurrence or retreatment following WEB embolization compared with non-thrombosed aneurysms. Methods We evaluated data from 22 academic institutions, focusing on previously untreated cerebral aneurysms treated with the WEB device. Logistic regression was utilized to analyze factors predicting long-term aneurysm obliteration and retreatment necessity. Results Among 1303 patients, 26 presented with a partially thrombosed aneurysm. In the partially thrombosed group, the mean aneurysm maximal diameter was 10.7±4 mm with a neck ratio of 1.99±1.19 mm, larger than in the control group where the mean aneurysm maximal diameter was 6.81±2.37 mm with a neck ratio of 1.64±0.51 mm (P<0.001 for both maximal diameter and neck ratio). At the final follow-up, partially thrombosed aneurysms treated by the WEB device had a 38.5% retreatment rate, compared with 7.0% for non-thrombosed aneurysms (P<0.001). Among partially thrombosed aneurysms, the Raymond-Roy type IIIa/b occlusion rate was higher (38.5% vs 9.9%, P<0.001). On multivariate analysis, partially thrombosed aneurysms compared with non-thrombosed aneurysms had an increased rate of retreatment (OR 3.64, 95% CI 1.28 to 10.1). Conclusion Partially thrombosed aneurysms are associated with a poorer occlusion rate and a higher rate of retreatment following WEB embolization. For partially thrombosed aneurysms, the WEB device appears suboptimal as a first-line treatment, and therefore alternative techniques should be prioritized.

Abstract INTRODUCTION Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. DISCUSSION In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations. Highlights Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

Abstract Despite the advent of novel targeted therapies with high overall response rates, chronic lymphocytic leukemia (CLL) is still largely incurable due to the development of resistance. The bone marrow microenvironment (BMME) plays an important role in the survival and drug resistance in CLL. BM stromal cells (BMSCs) are considered a key component of BMME. Our long-term goal is to gain further insights of BMSCs-CLL crosstalk influencing both survival and drug resistance in CLL. To understand the global biologic changes that occur in leukemic CLL cells when in contact with BMSCs, we assessed RNA-seq in paired CLL cells isolated from untreated blood and BM and in untreated patients’ CLL cells cultured alone or with BMSCs. CLL cells from blood/BM and cultured alone/with BMSCs were also examined by Immunoprecipitation (IP), Western blot (WB), untargeted metabolomics (LCMS+GCMS), and preclinical drug sensitivity assays. We detected only 13 upregulated genes that overlap between CLL cells from BM and cocultured with BMSCs (p&lt0.05, fold change &gt1.5). When we analyzed the expression of these 13 genes in CLL cells from a cohort of 162 untreated patients by RNA-seq, we found associations between 4 genes (PNP, C16orf54, MOB3A, CDK2AP2) and clinical outcomes including overall survival (OS), progression free survival (PFS), and time to first treatment (TTFT) [multivariable Cox proportional hazards models, p&lt0.05]. Of the 4 genes, purine nucleoside phosphorylase (PNP), an enzyme in the purine pathway, had the most significant association with OS, PFS, and TTFT. Metabolomic profiling indicated an increased level of purine pathway metabolites adenosine, adenine, inosine, and hypoxanthine in cocultured CLL cells. WB analysis showed variable baseline PNP protein expression with 2 cohorts: low /no (L) and high (H) PNP using CLL blood cells. An induction in PNP protein levels were noticed in CLL cells expressing only LPNP when cocultured. Given the association of HPNP with adverse clinical outcomes, we tested for L vs. HPNP cohorts drug sensitivity to known BTK inhibitors(is) or Bcl2is. Treatment of CLL cells from untreated patients with Bcl2is venetoclax, S55746, and LP-118 (Bcl2-Bclxli, Newave) showed increased sensitivity to the Bcl2/Bclxlis in HPNP but not in LPNP cells. In addition, BTKis showed no difference in drug sensitivity associated with CLL PNP levels. To explain this discrepancy, WB and IP analyses were conducted in L vs. HPNP leukemic cells for apoptotic profiles, where we found increased phosphorylated-Bcl2(S70) and an increased association of Bcl2 with Bax in LPNP-expressing CLL cells compared to HPNP. These findings support increased resistance to apoptosis afforded by inhibiting Bcl2 for LPNP vs. HPNP-expressing CLL cells. Our future goals are to continue to understand the prognostic significance of the 4 genes with adverse clinical outcomes and to investigate how best to exploit the peculiar, enhanced sensitivity to Bcl2/Bclxlis found in the HPNP CLL cells. Citation Format: Sutapa Sinha, Weiguo Han, Zhiquan Wang, Brianna M. Finke, Heather C. Darby, Kari G. Rabe, Susan L. Slager, Chantal E. McCabe, Daniel R. O'Brien, Sameer A. Parikh, Esteban Braggio, Yi Chen, Fenlai Tan, Stephen P. Anthony, Yu Chen, Bing Dai, Yue Shen, Neil E. Kay. CLL drug resistance- A multifaceted mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4423.

Abstract Introduction: With over 80, 000 new cases of non-Hodgkin's lymphoma (NHL) diagnosed annually, modifiable risk factors remain unclear. Circadian disruption, linked to cancers like breast and prostate, affects immune cells (e.g., natural killer cells and T-helper cells) by altering their trafficking and proliferation. Some studies (PMID: 30566672, 27611440) suggest long sleep may increase overall NHL risk, including a Mendelian randomization (MR) study (PMID: 32895918). However, no research has examined the causal relationship between sleep traits, including long sleep, and NHL risk, by subtypes. We hypothesize that sleep traits are causally associated with NHL subtypes in European populations, testing this using MR with data from the International Lymphoma Epidemiology Consortium (InterLymph). Methods: We conducted two-sample MR using genome-wide association studies (GWAS) summary data for sleep traits and NHL subtypes. Only independent, genome-wide significant (p &lt; 5×10-8) Single Nucleotide Polymorphisms (SNPs) were selected as valid instruments, sourced from the UK Biobank. Sleep traits included chronotype (153 SNPs), insomnia (48 SNPs), sleep duration (78 SNPs), excessive daytime sleepiness (37 SNPs), short sleep (27 SNPs), and long sleep (8 SNPs). NHL subtype data were from InterLymph: follicular lymphoma (6, 508 cases / 64, 183 controls), mantle cell lymphoma (1, 169 cases / 61, 603 controls), Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL: 1, 697 cases / 59, 333 controls), and chronic lymphocytic leukemia (8, 522 cases / 67, 653 controls). The primary analysis used inverse-variance weighted (IVW) random-effects, with MR-Egger for pleiotropy adjustment. Results: Using the IVW method, we did not identify any statistically significant causal association between sleep traits and the risk of NHL subtypes, but did yield several intriguing trends. Long sleep (sleep duration &gt;= 9 h per night) showed a marginally increased NHL risk [Odds ratio (OR) range: 1.51 - 247.9] across each subtype. Short sleep (sleep duration &lt; 7 h per night) showed a similar trend [OR range: 1.25 - 1.81], except for WM/LPL, where we noticed a negative trend. The confidence limit for long sleep was imprecise due to the small number of variants. We did not notice any significant directional horizontal pleiotropy or weak instrument bias. Conclusions: We found no conclusive evidence of a relationship between sleep traits and four NHL subtypes. However, we see suggestive trends of long and short sleep associated with higher risk of some NHL subtypes. These findings align with the previous studies, which showed long sleep was associated with higher risk of NHL overall. Future directions include expanding our analysis to additional NHL subtypes, generating polygenic risk scores, and conducting stratified analyses. Citation Format: Pankhil Shah, Brittany Crawford, Anwar Merchant, Brenda Birmann, Angelica Macauda, Michelle A. Hildebrandt, Aaron Norman, Neil E. Caporaso, Meredith Yeager, Michael Dean, Immaculata De Vivo, Lynn Goldin, Nicola J. Camp, Rosalie Griffin, Delphine Casabonne, Federico Canzian, Pelin Unal, Elad Ziv, Catherine R. Marinac, Alexandra Nieters, Stephen J. Chanock, Mitchell J. Machiela, Michael Conry, Charlie Zhong, Hanla A. Park, Simon Cheah, Jonathan N. Hofmann, Elizabeth E. Brown, Celine Vachon, Susan Slager, Sonja Berndt, Sophia S. Wang, Vijai Joseph, James McKay, Henrik Hjalgrim, Lara Sucheston-Campbell, Karl Smith-Byrne, Alyssa Clay-Gilmour. Association between sleep traits and risk of non-Hodgkin's lymphoma subtypes: a mendelian randomization study in the International Lymphoma Epidemiology (InterLymph) Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7415.

Abstract Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia among adults in the US. Despite significant improvement of current novel agent treatments, CLL remains incurable with many eventually experiencing disease relapse. Therefore, it remains of high interest to expand therapeutic options. Transcriptional chemical inducers of proximity (TCIPs) are a new class of anticancer drugs designed and developed by Stanford teams. These agents recruit cancer drivers or transcription factors to activate proapoptotic genes' expression and kill cancer cells. Current TCIPs are produced by covalently linking small molecules that bind B-cell lymphoma 6 (BCL6) to those that bind to transcriptional activators, such as bromodomain-containing protein 4 (BRD4) (BRD4-BCL6, TCIP1) or cyclin-dependent kinases 9 (CDK9) (CDK9-BCL6, TCIP2). In collaboration with the Stanford teams, we have initiated TCIPs cytotoxicity assessment in primary leukemic cells from untreated CLL patients and found heterogeneous but evident drug responsiveness with a panel of TCIPs. Our current work has shown that TCIP2 demonstrated remarkable killing ability of CLL B cells with IC50 of 9nM in 72-hours (h), while the IC50 of TCIP1 was 560nM. TCIPs showed time and dose-dependent drug-associated killing in primary CLL B cells over a 24-72h interval using a flow cytometry-based apoptosis assay. After 24, 48, and 72h exposure of CLL B cells to TCIPs, the IC50 was 1054, 820 and 555nM for TCIP1, and 9, 8, and 9nM for TCIP2, respectively. TCIP2 is designed and produced by covalently linking BI-3812 (BCL6 inhibitor) as a BCL6 binder and SNS-032 (CDK9 inhibitor) as a CDK9 binder with a rigid linker. Comparing TCIP2 to its negative controls (TCIP compounds with only one active binder, either BCL6 or CDK9), TCIP2 exhibited significant cytotoxicity in primary CLL B cells. TCIP2 also showed a significant increase in potency, compared to SNS-032 and BI-3812 alone at 72h. Normal human peripheral blood mononuclear cells (PBMCs) were 6-fold less sensitive to TCIP2 compared to CLL PBMCs with high percentage of CLL B cells. Immunoblotting data showed induction of BCL6 protein level after 20nM TCIP1 treatment in CLL B cells. In samples from relapsed/refractory (RR) CLL patients, TCIPs maintained good cytotoxicity with IC50 of 1805nM for TCIP1 and 84nM for TCIP2 in 24h using a cell viability assay. Our study indicates that TCIPs targeting BCL6 and BRD4/CDK9 have a strong capacity to induce high levels of cell death in primary CLL B cells. This notable killing effect may be due to its unique gain-of-function drug mechanism where BCL6 is induced. This is the first study of TCIPs ability to target CLL B cells from both untreated and RR patients. Further studies to more fully evaluate the preclinical activity of TCIPs and investigate the molecular mechanism(s) for TCIP mediated killing of leukemic B cells will help to define the potential role of TCIPs as a novel therapeutic approach in CLL. Citation Format: Weiguo Han, Aisharya Bhattacharya, Basel Karim, Wenzhi Ji, Roman C. Sarott, Meredith Nix, Sai Gourisankar, Andrey Krokhotin, Sutapa Sinha, Zhiquan Wang, Tait D. Shanafelt, Sameer A. Parikh, Nathanael S. Gray, Gerald R. Crabtree, Neil E. Kay. Rewiring cancer drivers to induce apoptosis in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5633.

Non-ST-segment elevation myocardial infarction (NSTEMI) can be managed by ischemia guide strategies or early invasive strategies. Here, we present the findings of an updated contemporary analysis regarding the use of intracoronary imaging (ICI)-guided PCI versus angiography-guided PCI and in-hospital mortality in patients with NSTEMI in the United States using the NIS database from 2016 to 2021. ICI use increased by nearly threefold between 2016 and 2021, without a significant difference in in-hospital mortality, though interestingly, mortality rates compared with angiography guidance were similar and relatively low. In this study, the use of ICI was associated with lower adjusted odds of in-hospital mortality, cardiogenic shock, and cardiac arrest, but with a longer length of stay and cost of hospitalization.

ImportanceSpecialized ophthalmology terminology limits comprehension for nonophthalmology clinicians and professionals, hindering interdisciplinary communication and patient care. The clinical implementation of large language models (LLMs) into practice has to date been relatively unexplored.ObjectiveTo evaluate LLM–generated plain language summaries (PLSs) integrated into standard ophthalmology notes (SONs) in improving diagnostic understanding, satisfaction, and clarity.Design, Setting, and ParticipantsRandomized quality improvement study conducted from February 1, 2024, to May 31, 2024, including data from inpatient and outpatient encounters in a single tertiary academic center. Participants were nonophthalmology clinicians and professionals and ophthalmologists. The single inclusion criterion was any encounter note generated by an ophthalmologist during the study dates. Exclusion criteria were (1) lack of established nonophthalmology clinicians and professionals for outpatient encounters and (2) procedure-only patient encounters.InterventionAddition of LLM-generated plain language summaries to ophthalmology notes.Main Outcomes and MeasuresThe primary outcome was survey responses from nonophthalmology clinicians and professionals assessing understanding, satisfaction, and clarity of ophthalmology notes. Secondary outcomes were survey responses from ophthalmologists evaluating PLS in terms of clinical workflow and accuracy, objective measures of semantic quality, and safety analysis.ResultsA total of 362 (85%) nonophthalmology clinicians and professionals (33.0% response rate) preferred the PLS to SON. Demographic data on age, race and ethnicity, and sex were not collected. Nonophthalmology clinicians and professionals reported enhanced diagnostic understanding (percentage point increase, 9.0; 95% CI, 0.3-18.2; P = .01), increased note detail satisfaction (percentage point increase, 21.5; 95% CI, 11.4-31.5; P &amp;lt; .001), and improved explanation clarity (percentage point increase, 23.0; 95% CI, 12.0-33.1; P &amp;lt; .001) for notes containing a PLS. The addition of a PLS was associated with reduced comprehension gaps between clinicians who were comfortable and uncomfortable with ophthalmology terminology (from 26.1% [95% CI, 13.7%-38.6%; P &amp;lt; .001] to 14.4% [95% CI, 4.3%-24.6%; P &amp;gt; .06]). PLS semantic analysis found high meaning preservation (bidirectional encoder representations from transformers score mean F1 score: 0.85) with greater readability than SONs (Flesch Reading Ease: 51.8 vs 43.6; Flesch-Kincaid Grade Level: 10.7 vs 11.9). Ophthalmologists (n = 489; 84% response rate) reported high PLS accuracy (90% [320 of 355] a great deal) with minimal review time burden (94.9% [464 of 489] ≤1 minute). PLS error rate on ophthalmologist review was 26% (126 of 489). A total of 83.9% (104 of 126) of errors were deemed low risk for harm and none had a risk of severe harm or death.Conclusions and RelevanceIn this study, use of LLM-generated PLSs was associated with enhanced comprehension and satisfaction among nonophthalmology clinicians and professionals, which might aid interdisciplinary communication. Careful implementation and safety monitoring are recommended for clinical integration given the persistence of errors despite physician review.

ABSTRACTObjectiveThe primary objective of this study is to review the evidence for aspirin use to prevent the growth of vestibular schwannomas (VS) and to propose a prospective trial to determine the progression‐free survival of VS patients after up to 42 months of treatment with aspirin. Secondary study objectives are to determine the effect of aspirin on VS growth, hearing function, serum biomarker levels, and the quality of life, as well as to determine the tolerability of aspirin treatment and whether serum biomarker and salicylate levels predict the response to aspirin.Study DesignLiterature review.SettingSix academic and private medical centers.MethodsReview of recent English literature regarding prophylactic aspirin use for VS.ResultsThe retrospective reviews on the utility of aspirin to prevent VS growth are inconclusive. Eighty‐four patients have been enrolled in a prospective double‐blinded, placebo‐controlled trial thus far to determine the effect of aspirin on VS.ConclusionsCompletion of a robust study design is necessary. The current aspirin dose has been well tolerated, with minimal adverse events to date.Level of EvidenceReview of retrospective studies: Level 4; Proposed randomized, placebo‐controlled, double‐blinded clinical trial: Level 2.