Citations

Abstract Purpose: Polatuzumab vedotin (polatuzumab) was approved for up-front treatment of diffuse large B-cell lymphoma in combination with chemoimmunotherapy (Pola-R-CHP) based on the POLARIX trial. However, when stratified by cell of origin (COO), polatuzumab seems to have greater efficacy in activated B-cell than germinal center B-cell (GCB) subtype disease. Most studies of polatuzumab used RNA expression to assess COO, whereas in routine clinical practice, the immunohistochemistry-based Hans algorithm is used. Experimental Design: To assess the impact of COO by immunohistochemistry on polatuzumab efficacy, we conducted a multicenter real-world study of adults with large B-cell lymphoma (LBCL) receiving polatuzumab from 2015 to 2024, split by receipt of polatuzumab in first-line versus relapsed/refractory settings. The primary endpoint was overall response rate (ORR) to polatuzumab-based treatment in GCB versus non-GCB relapsed/refractory LBCL. Results: Of 740 patients, 305 received polatuzumab in the first-line setting and 435 in the relapsed/refractory setting. In the relapsed/refractory cohort, the ORR in non-GCB versus GCB LBCL was 59.7% versus 36.3% [OR, 2.6; 95% confidence interval (CI), 1.77–3.84; P < 0.0001], with a complete response rate of 35.7% versus 17.7% (OR, 2.6; 95% CI, 1.66–4.02; P < 0.0001). Progression-free survival was longer for patients with non-GCB versus GCB COO (HR, 0.64; 95% CI, 0.5–0.83; P = 0.0006). In the first-line cohort, ORR, complete response rate, and progression-free survival were similar in non-GCB versus GCB LBCL, as hypothesized based on outcomes in the Pola-R-CHP arm of POLARIX, suggesting that the addition of polatuzumab overcomes the adverse risk of non-GCB COO in patients receiving R-CHOP. Conclusions: Based on these data, COO classification by the Hans algorithm is a strong predictor of polatuzumab efficacy in LBCL, informing real-world treatment decisions.

Background: Tremor in multiple sclerosis (MS) is often refractory to medications. Deep brain stimulation (DBS) may help, but possible side effects and disease exacerbation limit its use. Objectives: Evaluate outcomes of DBS for MS-associated tremor. Methods: Retrospective review of 18 patients with MS-associated tremor who underwent DBS, analyzing Expanded Disability Status Scale (EDSS) and Fahn–Tolosa–Marin (FTM) tremor scores. Results: Median age at surgery was 49.5 years (range, 28–75), with postoperative follow-up 2.5 years (range, 0–22). No relapses (0/18) or new lesions (0/8) occurred postoperatively. All had ventral intermediate nucleus leads; other targets were not used in programming. EDSS remained stable (median 6 to 6.25; p = 0.2). FTM scores improved (median 14.5 to 10, p = 0.008). Patients with EDSS 3.5–6 had variable outcomes ( p = 0.02). Conclusions: DBS is a potential treatment for severe MS tremor and did not provoke relapse. Targeting VIM alone may optimize tremor control and maintain magnetic resonance imaging (MRI) access.

ABSTRACT As artificial intelligence (AI) continues to rapidly reshape health care, there is a critical need for clear frameworks for clinicians to ensure ethical, equitable, and effective integration and use of AI in patient care. Key integrations of AI include enhancing health communications, patient engagement, clinicians' training, pharmaceutical advertising, clinical decision‐making, and automation of clinical operations and workflow. However, there are growing concerns related to regulatory gaps, the spread of misinformation, security threats, patient and data privacy leaks, and widening health disparities gaps. These concerns are exacerbated by limited institutional infrastructure and limited AI literacy of clinicians and patients. Recent policy developments reflect efforts to guide responsible AI development and use. While progress has been made, the lack of standardized human oversight remains a critical gap, particularly as policies may not fully consider the challenges and complexities at institutional, societal, technical, and individual levels. Thus, herein, the Drug Information Practice and Research Network (DI PRN) of the American College of Clinical Pharmacy (ACCP) : (1) explores current and emerging multifaceted challenges, a call to action, and opportunities of AI integration in health care including examination of the regulatory, ethical, operational, and health equity implications; and (2) provides practical recommendations for responsible use of AI through DI PRN‐developed example case‐based approaches and best practices infographics to enhance AI literacy for diverse learners including clinicians, trainees, and patients. This DI PRN opinion paper highlights the importance of proactive governance frameworks and equips and empowers diverse learners with practical AI literacy tools to confidently engage with AI technologies in patient care.

Abstract Introduction Obesity, defined as an elevated Body Mass Index (BMI) >30, is a prevalent public health concern with far-reaching implications for various medical procedures and outcomes. In the context of inflatable penile prosthesis placement (IPP), where patient well-being and surgical success are of paramount importance, the impact of obesity on postoperative and intraoperative complications warrants thorough investigation. Objective Our study aimed to investigate the impact of BMI on both postoperative and intraoperative complications in an international, multi-institutional cohort of patients who underwent IPP placement. Methods We performed a retrospective chart review of 4398 cases. These cases were divided into two distinct groups based on BMI: less than 30 (n = 2260) and greater than or equal to 30 (n = 2138). The study assessed various surgical factors as well as complications, including overall complications, corporal scarring, incontinence, intraoperative complications, proximal perforation, distal perforation, proximal crossover, distal crossover, and urethral injury. Results Our analysis revealed that there were no statistically significant differences in intraoperative or postoperative complications between the two BMI categories. Notably, proximal corporal measurement was significantly higher for >30 BMI group (9.55 +/−2.18) compared to <30 BMI group (9.14 +/−2.19), (p = < 0.001). The incidence rates for overall complications (30.2% vs. 28.7%; p = 0.164), corporal scarring (18.2% vs. 16.7%; p = 0.36), incontinence (3.53% vs. 3.13%; p = 0.076), intraoperative complications (1.94% vs. 1.68%; p = 0.253), and specific complications all exhibited no significant differences. Similarly, post-operative complications, including both non- infectious (6.99% vs. 6.22%; p = 0.215) and infectious (2.61% vs. 1.87%; p = 0.165) complications, did not significantly vary between BMI categories. Conclusions Our findings indicate that BMI does not exert a statistically significant influence on postoperative and intraoperative complications in the context of high-volume prosthetic urology. In the absence of any other differences between patients of differing BMIs, surgeons may need to be mindful of pump tubing length concerns in obese patients. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast, Clarus Therapeutics, Antares Pharma, Acerus.

Abstract INTRODUCTION Preclinical Alzheimer's disease (AD) can be described relative to biomarker positivity onset time. METHODS We estimated time from amyloid positivity (A+) using sampled iterative local approximation (SILA) in a longitudinal autosomal dominant AD (ADAD) sample ( N = 379) with amyloid positron emission tomography. We compared (1) predicted age at A+ to imputed age, (2) estimated age at A+ to estimated age at symptom onset, and (3) variance in cognitive performance explained. RESULTS Mean error between imputed and SILA‐estimated age at A+ ( N = 26) was 1.15 years. Age at A+ explained 39% of estimated years to symptom onset (EYO) variance. Time from A+ explained 19% of cognitive composite variance and 14% of Clinical Dementia Rating Sum of Boxes CDR‐SB variance; EYO explained 43% and 57%, respectively. DISCUSSION SILA estimates A+ age in ADAD with reasonably good accuracy. SILA‐estimated time from A+ describes the start of pathology, but the time from A+ onset to symptoms is variable in ADAD and better described by EYO. Highlights Amyloid chronicity predicts a 14‐year preclinical AD phase in ADAD. SILA accurately estimates age at A+ (MAE < 2 years). EYO outperforms chronicity in predicting symptom onset. APP mutation carriers show atypical amyloid accumulation. Chronicity models help reveal AD heterogeneity in preclinical stages.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Background: Patients performing self-triage for chest pain need to pick an algorithm which includes questions pertinent to chest pain to triage accurately. Objective: Our study reviews patient self-triage choices and outcomes for patients who completed an online self-triage encounter before being triaged by a nurse for chest pain. Methods: Patients who underwent telephone nurse triage for chest pain, and also had an online self-triage encounter within the prior 24 hours were reviewed for the frequency with which they chose “chest pain” as their symptom to triage for during self-triage, whether they reported chest pain during the self-triage encounter (if asked as part of the algorithm for their chosen self-triage symptom) and whether the patient had any follow up evaluation within 1 week. Results: There were 70 self-triage and nurse triage dyads during the study period where triage nurses chose “chest pain” as the primary symptom to be triaged for during the telephone triage encounter. Of these, only 5 (7.1%) patients chose the “chest pain” self-triage option during online self-triage. During the self-triage encounter, 50 (71%) reported chest pain, 10 (14%) denied chest pain and 10 chose to self-triage their symptoms with an algorithm that did not include a question on whether chest pain was present. Of the 70 total dyads 59 (84%) had a follow up emergency department (40 patients) or office visit (19 patients) documented. Conclusion: Most patients chosen to be triaged for chest pain by triage nurses did not choose the online self-triage algorithm for chest pain even though the majority did report chest pain during their self-triage encounter (when asked). This is concerning from a safety perspective as a non-chest pain self-triage option chosen by the patient may not always ask about the presence or absence of chest pain and thus could increase the risk of being triaged inaccurately. Implications for improvement of self-triage could include diagrams for patients to choose the symptom area.

Abstract Failure to repair radiation (RT)-induced DNA damage results in cell lethality, and combined treatment with DNA repair inhibitors can markedly enhance tumor control achieved with radiation. These inhibitors also can potentiate acute RT toxicities by suppressing DNA repair. Capitalizing on this normal tissue radiosensitizing effect, we determined effective radiosensitizing dosing regimens in mice for the ATM inhibitor WSD0628 and the DNAPK inhibitor WNC0901 in mice. Drugs were administered via oral gavage prior to each RT dose, and RT was delivered using an anterior/posterior 225 kVp beam. In an initial iteration of this model, various combinations of WSD0628 and RT were administered to cohorts of mice (n=5/group) and body weight was followed for 2 weeks. The resulting data were modeled to define the total dose of radiation estimated to cause 50% of mice to lose &gt;20% body weight (D50). There was an inverse relationship between the WSD0628 and D50 doses: 0 mg/kg WSD0628/24.0 Gy (95% confidence interval (CI) 24.5–24.7); 0.25 mg/kg/19.2 Gy (95% CI 16.7–21.8); 1 mg/kg/13.7 Gy (95% CI 13.2–14.2); 2.5 mg/kg/11.0 Gy (95% CI 10.5–11.5); 5 mg/kg/11.3 Gy (95% CI 6.7–15.9) and 7.5 mg/kg/7.8 Gy (95% CI 7.8–7.9). Histological review of tongues from animals treated with 15 Gy RT (5Gy x 3) + 7.5 mg/kg WSD0628 demonstrated epithelial denudation and acute inflammation consistent with oral mucositis, while these features were not seen with the same dose as RT alone. Similar WSD0628 doses were evaluated in combination with 8 Gy supratentorial RT (via lateral beams) in orthotopic GBM43 PDX tumors. By treatment arm, the median time to a moribund state was: sham (29 days (d)), RT (39d), 1 mg/kg (42d), 2.5 mg/kg (49d), 5 mg/kg (65d), and 10 mg/kg (123d, overall p&lt;0.0001). A second mucositis model was used for evaluation of WNC0901. Cohorts of 5 mice/group were treated with a set dose of RT (4Gy x 3) to the oral cavity alone and in combination with various doses of WNC0901, and the fraction of mice with &gt;20% weight loss within 2 weeks was determined. The results of this study are as follows: placebo (0 of 5 mice with &gt;20% weight loss); 15 mg/kg (3 of 5 mice); 25, 50, or 100 mg/kg (5 of 5 mice). Based on these data, we defined 25 mg/kg WNC0901 as the minimally effective dose and predicted that 50 mg/kg would provide robust radiosensitization. Consistent with this prediction, co-treatment of B16 melanoma flank tumor xenografts with RT (8Gy x 1) and WNC0901 (50 mg/kg) more than doubled the median tumor control duration (median 42 [range 24-45] days; time from implantation for tumor to exceed 1500 mm3) as compared to RT alone (24 [13-30] days) or sham treatment (17 [13-17] days; overall p&lt;0.0001). This study describes how a radiation-induced oral mucositis model can be used to identify effective radiosensitizing regimens faster and with fewer resources than relying on tumor control studies alone. Citation Format: Danielle Burgenske, Darwin Garcia, Jiayan Le, Wenjuan Zhang, Sneha Rathi, Katrina K. Bakken, Lauren L. Ott, Zeng Hu, Brett L. Carlson, Ann Mladek, Jessica L. Abraham, Paul A. Decker, Matthew L . Kosel, Jeanette E. Eckel-Passow, William F. Elmquist, Wei Zhong, Jann N. Sarkaria. Radiation-induced oral mucositis to rapidly determine effective radiosensitizing dosing regimens for ATM and DNAPK inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B090.

The COVID-19 pandemic caused unprecedented disruption of social networks and negatively impacted social determinants of health (SDoH, e.g., economic stability, mental health, health care access) among African Americans. The FAITH! (Fostering African-American Improvement in Total Health!) Program, an academic-community partnership with African American churches, pivoted to pandemic-related impacts on health behaviors of African Americans. This exploratory, cross-sectional study examined associations between multilevel factors influencing difficulty maintaining a healthy lifestyle during the early pandemic phase, including mental/emotional health and COVID-19 hardships (e.g., job/food/housing insecurity, paying utilities). An online survey was distributed via FAITH!-affiliated churches and social media. Logistic regression (odds ratios [ORs], adjusted for age/gender) and associated 95% confidence intervals [CIs]) examined associations between difficulty maintaining a healthy lifestyle and multilevel factors. Greater than half of respondents reported difficulty maintaining a healthy lifestyle (N = 169, 54% [91/169]). Adjusted odds of having difficulty maintaining a healthy lifestyle were greater for those reporting mental/emotional health issues (high-stress OR 4.0; 95% CI [1.9,8.9], p < .001); occasional symptoms of depression (OR 3.7; 95% CI [01.9,7.7]; p < .001); anger (OR 2.5; 95% CI [1.2,5.4]; p = .044), and anxiety (OR 2.8; 95% CI [1.4,6.0]; p = .008)). COVID-19 hardships of job insecurity (OR 1.4.; 95% CI [0.7, 2,8]; p = .015), difficulty paying rent (OR 4.4; 95% CI [2.1,9.9]; p < .001) or difficulty paying for food/utilities (OR 5.4; 95% CI [2.6,11.7]; p < .001) were associated with difficulty maintaining a healthy lifestyle. Our study revealed the negative impact of mental/emotional health and COVID-19 hardships on maintaining a healthy lifestyle among African Americans. This could inform SDoH-focused lifestyle interventions during future public health crises.

Stereotactic radiosurgery was associated with a higher obliteration rate compared with embolization in patients with eloquent brain arteriovenous malformations, whereas there was no evidence of a difference in functional outcomes or complications after adjustment.