Citations

Abstract Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma involving the brain, cerebrospinal fluid, or retina/vitreous without systemic involvement. Induction with high-dose methotrexate (HD-MTX) followed by consolidation with autologous stem cell transplant (auto-SCT) has become the standard treatment paradigm for most patients. However, limited data are available regarding the efficacy of a maintenance approach with HD-MTX. Herein, we retrospectively reviewed the characteristics and outcomes of 148 patients diagnosed with PCNSL between October 2010 and June 2022, who underwent HD-MTX–based induction therapy followed by either auto-SCT consolidation (n = 70) or HD-MTX maintenance therapy (n = 37). At a median follow-up time of 4.5 years, the progression-free survival (PFS) was 8.3 years and the overall survival (OS) was not reached. Compared to patients who underwent auto-SCT, patients who received maintenance HD-MTX had a higher median age at diagnosis of 72 vs 62 years and a trend toward higher proportion of patients being Eastern Cooperative Oncology Group 2 or higher (41% vs 29%). At 5-years postinduction treatment initiation, the PFS rates in the auto-SCT cohort and HD-MTX maintenance cohort were 74.6% and 72.6%, respectively, and the OS rates were 76.0% and 82.4%, respectively. Overall, there was no significant difference in PFS or OS based on postinduction management strategy. Our data suggest that maintenance HD-MTX may be a reasonable, time-limited treatment strategy for patients with PCNSL responding to initial induction therapy.

ImportanceAcute pulmonary embolism (PE) is a major cause of morbidity and mortality in patients with cancer in the US and worldwide.ObjectivesTo assess the trends in PE-related mortality from 2011 to 2020 among US patients with cancer across age, sex, ethnic and racial groups, urbanicity, and regionality.Design, Setting, and ParticipantsThis cohort study used the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research data system to determine national trends in age-adjusted mortality rates (AAMRs) due to acute PE among US patients with cancer aged 15 years or older from January 2011 to December 2020. Concomitant trends in cancer mortality and incidence that may have contributed to PE-related mortality were obtained from US Cancer Statistics. Data were analyzed from September to November 2024.ExposurePE-related mortality.Main Outcomes and MeasuresThe primary outcome was PE-related deaths among individuals with cancer. AAMRs and cancer incidence were assessed using joinpoint regression modeling, expressed as an average annual percentage change (AAPC) with relative 95% CIs.ResultsFrom 2011 to 2020, a total of 27 280 194 individuals aged 15 years or older (13 897 519 male [50.9%]; 13 382 675 female [49.1%]) died in the US. The AAMR for PE-related mortality in patients with cancer increased during this time period (AAPC, 2.5%; 95% CI, 1.4% to 3.6%; P = .001), without differences between sexes (P for parallelism = .38). The AAMR increased among those aged 15 to 64 years (AAPC, 3.2%; 95% CI, 1.9% to 4.6%; P = .001), non-Hispanic and non-Latinx White individuals (AAPC, 2.7%; 95% CI, 1.52% to 3.94%; P = .001), non-Hispanic and non-Latinx Black or African American individuals (AAPC, 2.2%; 95% CI, 0.7% to 3.7%; P = .001), Hispanic and Latinx individuals (AAPC, 2.6%; 95% CI, 0.7% to 4.5%; P = .006), and among individuals residing in the Southern US (AAPC, 3.7%; 95% CI, 1.3% to 6.2%; P = .003). During the same period, age-adjusted cancer incidence and cancer-related mortality decreased while the absolute number of new cancer diagnoses and cancer-related deaths increased.Conclusions and RelevanceThis cohort study found that despite decreases in cancer-related mortality rates, age-adjusted PE-related mortality in US patients with cancer increased over the last decade; concerning trends included rising PE-related mortality in younger individuals aged 15 to 64 years, particular ethnic and racial groups, and the Southern region of the US. Recognition of such patterns may inform further research into thromboprophylaxis and treatment of PE as a complication of cancer and cancer-directed therapy.

Background and Objectives: Hearing loss is relatively common in older individuals, and individuals with frontotemporal lobar degeneration (FTLD) are no exception; this can exacerbate communication difficulties stemming from speech-language impairments. The co-occurrence of these symptoms can contribute to increased frustration and isolation for patients and their communication partners. The objective of this study was to evaluate the feasibility of self-administered hearing testing. Ultimately, this could be administered remotely, which would increase access to assessment and inform management for this population. Method: Seventeen patients with underlying FTLD, clinically presenting with progressive apraxia of speech with and without agrammatic aphasia, independently completed the Home Hearing Test supervised while in office. Results: Three patients self-reported hearing loss, but results for 100% recommended formal evaluation. Eleven patients demonstrated good test accuracy. Six patients had “poor” or not computable accuracy; among them, five had evidence of cognitive impairment and/or behavioral changes, and one had known severe hearing loss, although differences between those with good and poor test accuracy were not significant. Patients with poor test accuracy had more difficulty with limb praxis. Conclusions: Most participants independently completed the test, though some had reduced test accuracy that may have been associated with cognitive impairment and/or limb apraxia. This study supports the need for hearing screenings in all patients with progressive apraxia of speech and aphasia and highlights both the feasibility and caution required in implementing self-administered testing protocols. Further work should evaluate the feasibility of in-home hearing screenings in a broader range of FTLD phenotypes and directly compare sensitivity and specificity of hearing loss detection with in-clinic administration. Supplemental Material: https://doi.org/10.23641/asha.28306613

Background: Early surgical intervention in nerve palsies with a high probability of nerve integrity and natural recovery risks unnecessary surgery. Understanding the variables influencing surgeons to offer surgery might provide insight into variations in surgeon beliefs and guide treatment recommendations. Methods: Sixty-nine surgeons of the Science of Variation Group participated in a survey consisting of 6 traumatic and 3 nontraumatic nerve palsy scenarios. Participants were asked what their preferred treatment was and how likely they were to offer surgery on a scale from 0 to 10. Participants were randomized to choose for themselves (n = 31) or for a patient of their age and sex (n = 38). Results: There was no difference in the overall likelihood of offering surgery or in the types of treatment offered to patients compared with oneself. Surgery was least recommended for idiopathic palsies and most for ulnar (β = 0.91; 95% CI, 0.10 to 1.7; P = 0.027) or radial (β = 0.92; 95% CI, 0.12 to 1.7; P = 0.025) nerve palsy following closed distal radius or humerus fractures. Longer symptom duration increased the likelihood of offering surgery. Conclusions: Surgeons were moderately likely to recommend surgery for nerve palsies, with no variation in opinions regardless of whether they were deciding for themselves or for patients. For specific nerve palsies with a documented benign natural history, this likely represents overtreatment. Future studies can assess whether balancing awareness of a benign natural history with the pressure to act and the sense that recovery is “taking too long” might limit the offer of unnecessary surgery.

Abstract Rationale Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. The extent of medication nonadherence in PAH is uncertain and may be linked to adverse outcomes. There has been a lack of multicenter, registry-based studies assessing medication nonadherence and patient-centered outcomes in PAH. Objectives To determine the prevalence of self-reported nonadherence in Pulmonary Hypertension Association Registry (PHAR) participants with PAH or chronic thromboembolic pulmonary hypertension and the relationship of nonadherence with several patient-centered outcomes (mortality, hospitalization rates, emergency department visits, and health-related quality of life). Methods Self-reported PAH medication nonadherence was captured at PHAR enrollment and during follow-up visits. Predictors of nonadherence were modeled using generalized estimating equations assuming a binary distribution. Outcomes associated with nonadherence were modeled using generalized estimating equations with a Poisson distribution. Results A total of 1,543 patients were included, of whom 1,092 (70.8%) were female and 1,340 (86.8%) had PAH. The overall rate of any self-reported nonadherence was 6.1% (95% confidence interval [CI], 5.3–6.9). Predictors of nonadherence included self-reported male sex at birth (odds ratio [OR], 1.4; 95% CI, 1.0–1.9; P = 0.02), poverty (OR, 1.6; 95% CI, 1.2–2.3; P = 0.01), not being married or partnered (OR, 1.5; 95% CI, 1.1–1.9; P = 0.01), having Medicaid or no health insurance (OR, 2.1; 95% CI, 1.5–2.9; P < 0.001), and having completed high school but not having a college degree (OR, 1.7; 95% CI, 1.1–2.9; P < 0.001). PHAR participants who reported any nonadherence had 50.0% more emergency department visits (P < 0.001), 13.3% more hospital admissions (P = 0.03), and 61.9% more days hospitalized (P = 0.01). No relationship was observed between nonadherence and the type or number of PAH therapies or all-cause mortality. Participants reporting nonadherence had worse mean Short Form-12 scores (P < 0.001) and worse emPHasis-10 scores (P = 0.02). Conclusions The rate of self-reported nonadherence in PHAR registrants was low but was associated with male sex and several social determinants of health. Although the complexity or type of PAH regimen did not appear to influence nonadherence, nonadherence was associated with numerous adverse patient-centered outcomes, including greater healthcare use and worse health-related quality of life. Because of limitations in the structure of the gathered data, relationships between exposure and outcomes were not temporally definitive; these observations warrant additional prospective studies.

261 Background: Clinicians use next-generation sequencing (NGS) to tailor targeted treatments for PCa patients. However, the results are often available in unstructured formats and are saturated with technical jargon, making them inaccessible for patients. Therefore, we aimed to assess the efficacy of LLMs to accurately extract genomic characteristics from unstructured reports and generate patient-friendly summaries for ease of variant interpretation in PCa patients. Methods: This retrospective study included patients with PCa who underwent NGS from 2023-2024. The GPT4 model was utilized using structured zero-shot prompts to extract genomic characteristics from unstructured reports in a non-decomposed manner. Prompt development was conducted iteratively using a 2% random sample of the dataset. Genomic characteristics ascertained by LLM were assessed against held out vendor-curated test dataset for evaluation. Performance was assessed using weighted evaluation metrics (precision, recall, and F1-score). Additionally, the extracted variables were organized using rule-based criterion and presented as a separate prompt to GPT4 to generate summaries for interpretation at the level of each biologically relevant variant. Mean Flesch-Kincaid scores and Vocd-D statistic with standard deviations were computed to assess readability and lexical diversity of LLM-generated variant interpretation summaries. Results: A total of 331 patients (370 NGS reports) were included in the study. Evaluation on the held-out test dataset (Table) showed that the weighted average precision ranged from 80% for extracting tumor mutational burden to 100% for extracting the CtDNA fraction from unstructured reports. The weighted average recall ranged from 85% for extracting CtDNA tumor fraction to 99% for ascertaining variant/alteration. The weighted average F1-scores varied from 0.83 for extracting tumor mutational burden to 1.0 for extracting specimen site from NGS reports. The mean Flesch-Kincaid score was 8.29 ± 1 indicating average/standard readability ease. The mean Vocd-D statistic was 7.55 ± 1 indicating focused summaries, however, with limited lexical diversity. Conclusions: This study suggests that large language models can effectively extract genomic characteristics from unstructured reports and can potentially improve genomic literacy among prostate cancer patients by providing easy-to-interpret variant summaries. However, targeted prompting may be required to increase lexical diversity for improved engagement. Performance across different genomic characteristics. Category Precision Recall F1-Score Altered gene 0.86 0.97 0.89 Variant/alteration type 0.98 0.99 0.98 Variant allele fraction 0.96 0.96 0.96 Test name/type 1 0.99 1 Specimen site 1 0.99 1 Tumor mutational burden 0.8 0.93 0.83 CtDNA tumor fraction 1 0.85 0.92 MSI status 0.99 0.97 0.98

247 Background: Approximately 10% to 15% of men with metastatic castration-resistant prostate cancer (mCRPC) harbor germline mutations. Circulating tumor-derived DNA (ctDNA) as non-invasive approach to characterizing somatic alterations. In this study, we report longitudinal ctDNA assessments in mCRPC patients who have undergone germline testing. Methods: A total of 238 patients, who had undergone both germline testing and ctDNA assessment from Tulane Cancer Center were included in this study. Germline testing was conducted using a multi-gene cancer panel from Invitae, covering 50-86 genes, while somatic alterations in ctDNA were tested through Guardant 360, including 70-83 genes. Somatic alterations with <0.1%, synonymous, and variants of unknown significance were excluded from analyses. Statistical analyses were performed using Pearson Chi-Square Test or Fisher Exact Test. Results: From 2015-2024, 17.2% (41/238) had pathogenic or likely-pathogenic (P/LP) germline mutations. The most common pathogenic germline mutations were in BRCA2 (17.1%; 7/41), BRCA1 (9.8%; 4/41), and CHEK2 (9.8%; 4/41). In ctDNA, germline positive patients were more likely to have frameshift mutations (OR= 1.75, 95% C.I. [1.09, 2.81], p=0.02) and less likely to have copy number amplifications (OR= 0.58, 95% C.I. [0.36, 0.93], p= 0.03) compared to germline negative patients. Among mCRPC patients with germline HRR P/LP mutations, frameshift alterations were significantly more frequent (OR=5.03, 95% CI [2.03, 13.23], p-value=0.0008). mCRPC patients with germline P/LP mutations were more likely to have somatic mutations in BRCA2 (OR=2.85; 95% CI: [1.62, 4.93]; p=0.0002) and GATA3 (OR=3.37, 95% CI: [1.26, 8.51]; p=0.016) detected ctDNA and less likely to have EGFR alterations (mutations and/or amplifications) (OR=0.46; 95%CI: [0.25, 0.80]; p=0.0094). BRCA2 somatic mutations are also more likely to be detected in patients with germline P/LP mutations in HRR genes (OR=0.11, 95% CI [0.03, 0.33], p=0.00004). Conclusions: mCRPC patients with pathogenic germline mutations are more likely to have frameshift and less likely to have copy number amplifications compared to germline negative mCRPC patients. Frameshift mutations are more likely to be detected in patients with germline P/LP in HRR genes. Patients with germline P/LP mutations are more likely to have somatic mutations BRCA2 and GATA3 and less likely to have mutations and/or amplifications in EGFR.

245 Background: Circulating tumor DNA (ctDNA) can be used as a prognostic biomarker in mCRPC patients, with changes in ctDNA providing insight into patient survival. In this study, we evaluate the ctDNA landscape of patients with mCRPC prior to their death. Methods: A retrospective clinical data review, 2015-2024, was conducted at Tulane Cancer Center to identify mCRPC patients who underwent ctDNA testing prior to death. All ctDNA data were obtained through a multi-gene cancer panel via the Guardant 360 assay (70-83 genes). Lethal mCRPC was defined as patients who underwent ctDNA testing ≤3 months prior to death. A matched control group (CTRL) was defined as mCRPC patients with ctDNA collection ≥2 years prior to death or most recent follow-up. Statistical analyses were performed using Pearson Chi-Square Test or Fisher Exact Test whenever appropriate. Furthermore, survival analysis was conducted using the Kaplan-Meier method. Results: There were 70 patients in lethal mCRPC group and 157 patients in CTRL group. Compared to the CTRL group, in lethal mCRPC, somatic mutations and/or amplifications in BRAF(OR=2.1549, 95% C.I. [1.1136,4.1523], p=0.0298), CCND2 (OR=3.7925, 95% C.I.[1.1937,13.3380], p=0.03326), MYC (OR=2.6332, 95%C.I. [1.4158, 4.9120], p=0.0029), PDGFRA (OR=2.5235, 95% C.I. [1.1438, 5.5793], p=0.0291), and PIK3CA (OR=2.0328, 95% C.I. [1.1098, 3.7166], p=0.02846) were significantly more frequent. Additionally, lethal mCRPC patients were more likely to have missense (OR=4.3194, 95% C.I. [1.443456,19.3338], p=0.01687) and nonsense (OR=1.9364, 95% C.I. [1.06091,3.5250], p=0.04112) mutations at the end-of-life. Patients with a higher allelic fraction (≥0.6%) of TP53 alterations had a shorter median survival (p-value= 0.034). Conclusions: ctDNA mutations and/or amplifications in BRAF, CCND2, MYC, PDGFRA, and PIK3CA were more frequently detected in lethal mCRPC compared to matched CTRLs. Additionally, mCRPC patients with a lethal phenotype were more likely to have missense and nonsense mutations compared to the CTRL group. CtDNA assessment of copy number alterations was limited to amplifications only; additionally, with this assay, distinguishing between gene level and large scale chromosomal amplification is not assessable. Though this study is limited to a single-institution with retrospective analyses of clinical testing, understanding the somatic landscape of lethal mCRPC is critical for development of new biomarkers, strategies and ultimately druggable targets.

TPS303 Background: The treatment of advanced prostate cancer (PC) is challenging, with undesirable side effects that impact patient quality of life. Radioimmunotherapy (RIT) can localize therapy to specific tumor cells in multiple organs to reduce or eliminate damage to normal tissue. The cell surface glycoprotein prostate-specific membrane antigen (PSMA) is an ideal therapeutic target as it is highly expressed by malignant prostate cells. There is a strong rationale for further investigation of the 177 Lu-labeled, chelator-conjugated antibody, 1 77 Lu-rosopatamab, as a potential first-line RIT candidate for the treatment of PC. Methods: This multinational, multicenter, prospective, randomized, open label phase 3 study will have 2 parts: a dosimetry and safety lead-in (n=30) and a randomized treatment expansion (n=490). In Part 1, patients will be divided into 3 groups (n=10 each) to receive 2 single intravenous (IV) injections of 76 millicuries (mCi) each, 14 days apart, of 177 Lu-rosopatamab with best standard of care (SoC) combinations with abiraterone, enzalutamide, or docetaxel to fully characterize biodistribution and safety profiles of 177 Lu-DOTA-rosopatamab + SoC combinations. SoC received will be determined prior to treatment with 177 Lu-rosopatamab. In Part 2, patients will be enrolled in a 2:1 ratio to receive either the best SoC or 2 single IV injections of 76 mCi each (equivalent to a 45 mCi/m 2 dose in a standard 1.7m 2 individual) of 177 Lu-rosopatamab, given 14 days apart, plus best SoC. SoC will be determined prior to randomization, and a change in planned SoC will not be permitted. Eligible patients must have PSMA-expressing metastatic castration-resistant PC (mCRPC) that have progressed despite prior therapy with either enzalutamide or abiraterone plus prednisone, and 1 line of prior taxane therapy or have refused or are ineligible for taxanes. Patients must have adequate organ function including at least 150x10 9 /L platelets, hemoglobin 10 g/dL, and have PSMA-positive disease on 68 Ga-PSMA-11 PET/CT imaging as confirmed by a central reader. Key exclusion criteria include small cell histology, increased risk of hemorrhage or bleeding, known brain or hepatic metastases, or history of stroke, seizure, or treatment with radioisotopes within 6 months prior to randomization. The primary endpoint is radiographic progression-free survival. Key secondary endpoint is OS. Additional secondary endpoints include 5-year overall survival, tumor objective response rate, time to symptomatic skeletal event, and health-related quality of life. Clinical trial information: NCT04876651 .