Citations

410 Background: Inflammasomes are multiprotein complexes that regulate inflammation-associated signaling pathways. Although inflammation plays a crucial role in cancer cell proliferation, the specific role of inflammasomes in prostate cancer (PCa) remains underexplored. This study aims to elucidate the expression of inflammasome-related genes in PCa and assess their association with clinical outcomes. Methods: De-identified transcriptome data from a cohort of 52,266 radical prostatectomy (RP) samples tested (2016-2024) with the Decipher prostate genomic classifier (Veracyte, San Diego, CA) were retrieved from the GRID registry (NCT02609269). Expression analysis focused on 33 genes involved in inflammatory pathways. Outcomes analysis was conducted on a retrospective cohort of 855 patients treated with RP (META855), using Cox regression analysis, adjusting for baseline pathological characteristics. Results: Analysis of baseline gene expression in the GRID RP cohort revealed that most genes exhibit low baseline expression, whereas HSP90AB1, APP, TXN, and TXNIP demonstrate strong expression signals. Higher expression of most genes was associated with higher rate of Gleason grade group 4 or 5 in the GRID RP cohort. On survival analysis of the META855 cohort, higher expression (top 25%) of AIM2 and HSP90AB1 were associated with worse metastasis-free survival (p<0.05 for both). Conversely, both high and low expression levels of NLRP3 were associated with better metastasis-free survival outcomes following RP compared to average expression (p<0.05). On multivariable Cox regression analysis, adjusting for grade group, seminal vesicle involvement, lymph node involvement, and margin status, higher expression of AIM1 (HR 1.75) and HSP90AB1 (HR 1.60) were significantly associated with shorter time to metastasis following RP (p<0.05 for both). Conclusions: There is a molecular heterogeneity within pro-inflammatory genes among patients with PCa.Our findings showed thathigher expression of HSP90AB1 is linked to poorer oncological outcomes, whereas both high and low expression levels of NLRP3 are associated with better outcomes following RP.Further refinement is required to build a robust signature, along with external validation of these findings in other cohorts.

425 Background: Prostate cancer (PC) ranks among the most prevalent cancers in men, with incidence rising due to factors like aging populations and enhanced screening techniques. Effective data extraction from clinical records is crucial for advancing research and improving patient care; however, traditional manual methods can be time-consuming and susceptible to mistakes. This study seeks to evaluate RadOnc-GPT against human annotation for extracting essential clinical information from prostate cancer clinical records. Methods: RadOnc-GPT is a retrieval augmented generation (RAG)-based chatbot with access to a variety of patient data including treatment details, radiology reports, and clinical notes. RadOnc-GPT uses Open AI’s gpt-4o model. Patients who received curative intent radiotherapy as initial treatment for PC in our institution between 2014 and 2023 were randomly selected for evaluation. Relevant Clinical factors were extracted by a human expert annotator on our on-site RedCap database. The extraction of the same variables was performed using RadOnc-GPT. A comparison between the ground truth (human annotation) and RadOnc-GPT, to evaluate the performance of the AI system, was carried out including accuracy, recall and F1 score. Results: A total of 382 PC patients were included in the cohort for data extraction. The clinical variables extracted were the treatment intent, NCCN risk category, T and N stage, Gleason score, radiation volume, and Androgen Deprivation therapy (ADT) use. The overall performance of RadOnc-GPT was excellent, with the highest accuracy achieved for treatment intent (99.7%), Gleason score (98.4%), and Treatment Volume (90.1-99.5%). Conclusions: RadOnc-GPT performed excellent at extracting relevant clinical details from the electronic medical record and radiation oncology information systems with dramatic reduction in time and cost compared with manual review. LLMs could be highly useful for large-scale data extraction in PC research, offering a promising solution for automating the accurate data extraction process. Correct (n) Total (n) Accuracy Recall F1 score RT with curative intent 381 382 99.7 99.9 99.9 Prostate Cancer Risk Category 345 382 90.3 90.4 95.1 Primary tumor staging (T) at diagnosis 368 382 96.3 96.3 97.9 Regional nodal status (N) at diagnosis 352 382 92.1 92.2 95.9 Gleason Score Primary Secondary Total 376372376 382382382 98.497.498.4 98.597.498.5 99.298.799.2 Treated Areas Prostate Pelvic Nodes Para-Aortic Nodes Distant Site 380344378372 382382382382 99.590.19997.4 99.490.199.197.4 99.79599.598.7 ADT Use with RT 365 382 95.5 95.7 97.8

424 Background: Advances in prostate cancer (PC) care have led to a 98% 10-year survival rate. Prostate Specific Antigen (PSA) is the primary method of follow-up after definitive radiotherapy (RT), with benign PSA ‘bounce’ occurring in up to 30% of patients, causing uncertainty and anxiety. Distinguishing between PSA bounce and biochemical recurrence (BCR) remains challenging. The Phoenix Criteria is the standard definition of BCR since 2006, defined as PSA nadir + 2 ng/dl, but does not consider patient specific information. Our study aims to explore factors associated with bounce and BCR and develop a predictive tool to differentiate between these two events. Methods: PC patients who received RT at our institution between 2006 and 2022 were identified, including only patients with a PSA increase during follow-up. Exclusion criteria included palliative RT, prostatectomy, or insufficient follow-up information. Patients’ clinical data was collected, and PSA increase was classified as bounce or BCR. Variables were compared using Kruskal Wallis or Chi-square. Multivariate logistic regression was performed in the subset of patients with absolute PSA value >2 (n= 581). Results: Of 1783 patients reviewed due to PSA rise after treatment, 694 met the inclusion criteria. There were 213 (30.7%) with PSA bounce and 481 (69.3%) with recurrence. Prior to meeting the Phoenix Criteria, 20 (4.2%) had biopsy-proven recurrence and 18 (3.7%) imaging-proven recurrence. The median delta PSA was 0.8 ng/mL for bounce vs 5 ng/mL for recurrence (p<0.001). The median time from treatment to event was 14.4 months for bounce vs 45.3 months for BCR (p<0.001). Recurrence was significantly associated (p<0.001) with older age at diagnosis, N1 stage, higher risk category, Gleason score, and higher baseline PSA. In the subgroup of patients without ADT, recurrence was associated with a lower median first PSA post-RT (1.9 vs. 2.4, p=0.046) and a lower median nadir before event (0.6 vs. 1.8, p<0.001). Multivariate logistic regression achieved an accuracy of 0.94, with a sensitivity of 0.83, specificity of 0.98, and an area under the curve (AUC) of 0.97. Conclusions: Our results highlight significant differences in clinical factors between bounce and recurrence in post-RT patients. The multivariate logistic regression differentiated the events with 94% accuracy for patients with a rising PSA value >2 subgroup. We highlight the possible improvement that could be accomplished by personalizing a PSA threshold for recurrence versus the Phoenix definition. This tool offers patients and providers a highly specific tool to differentiate between PSA recurrence and bounce, and may reduce stress and unnecessary testing, or help diagnosis recurrence faster. Next steps include prospective validation of the model to assess the impact on clinical practice costs, patient experience, and cancer outcomes.

Key Points Patient-centered care in an interdisciplinary CKD clinic addresses complex needs and supports comprehensive CKD management. Implementation of an interdisciplinary CKD clinic reduced hospital admissions by 26%, emergency department visits by 30%, and increased nephrology consultations. Comprehensive care models with integrated registries enhance tailored interventions, leading to improved CKD management outcomes. Background CKD is a significant public health issue globally. Its progressive nature calls for innovative care models to mitigate disease progression and enhance patient outcomes. An interdisciplinary clinic model may offer comprehensive care tailored to the needs of patients with CKD. The aim of this study was to evaluate the effect of an interdisciplinary CKD clinic on disease progression, health care utilization, and social determinants of health (SDOH). Methods We conducted a retrospective cohort study at the Mayo Clinic in Rochester, Minnesota. The study included 534 patients enrolled in the CKD clinic between March 5, 2021, and May 31, 2022, excluding those who opted out of research. The intervention involved a clinical registry and an interdisciplinary team delivering evidence-based care pathways, patient education, shared decision making, and care coordination. The primary outcomes assessed were CKD progression and health care utilization, while secondary outcomes examined the effect of SDOH. Results At entry, the median age was 73 (interquartile range, 64–79) years, with 60% at stage 4 or lower. Clinic implementation correlated with a 26% decrease in hospital admissions (incidence rate ratio [IRR], 0.74; 95% confidence interval [CI], 0.60 to 0.91; P = 0.004) and a 30% reduction in emergency visits (IRR, 0.70; 95% CI, 0.57 to 0.87; P = 0.001). Nephrology consultations increased by 46% (IRR, 1.46; 95% CI, 1.34 to 1.60; P < 0.001), reflecting enhanced specialized care. Lower exercise frequency and unemployment were linked to increased CKD progression and health care usage. Conclusions An interdisciplinary CKD clinic supported by a registry can potentially reduce health care utilization among patients with CKD, with SDOH playing a critical role in disease management.

Abstract Purpose: Tumor-infiltrating lymphocytes are associated with a decreased risk of recurrence in human papillomavirus–associated oropharyngeal squamous cell carcinoma. The composition and spatial distribution of tumor-infiltrating lymphocytes and tumor-infiltrating immune cells are not well characterized. Experimental Design: Formalin-fixed, paraffin-embedded primary and lymph node (LN) tumor tissues from 10 progressors (cases) and 10 matched nonprogressors (controls) were interrogated by imaging mass cytometry. Immune, stromal, and tumor cells were quantified from selected regions of interest using machine learning. Nearest neighbors, cell–cell interactions, and niche analyses were performed. Results: In primary regions of interest, immune cell, lymphocyte, T cell, CD8+ T cell, and innate cell prevalence was significantly greater in controls. High prevalence of immune cells, lymphocytes, innate cells, and CD4+ T cells in primary tissues was significantly associated with increased time to event (TTE). Although primary and LN prevalence of T cells, CD4+ T cells, CD8+ T cells, macrophages, and tumor cells were significantly correlated, differences in LNs were neither significant nor associated with TTE. Average distances between T cells and the nearest B cells and between lymphocytes and the nearest tumor cells were decreased in control primary tissues. Interactions between B and T cells were less organized in primary tissues from cases. A niche predominantly comprising lymphocytes was associated with longer TTE. Conclusions: In human papillomavirus–associated oropharyngeal squamous cell carcinoma, immune cell subset prevalence in primary tumors differs with outcome and is associated with TTE. Interactions between B cells and both T-cell subsets are associated with longer TTE, underscoring the importance of active intratumoral immune responses in outcomes.

121 Background: In the Phase 3 VISION trial, treatment with the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) + protocol-permitted standard of care (SoC) significantly improved median radiographic progression-free survival (rPFS; 8.7 vs 3.4 months [mo]) and overall survival (OS; 15.3 vs 11.3 mo) in patients with metastatic castration-resistant prostate cancer (mCRPC) vs SoC alone. However, it is unclear how the addition of androgen receptor pathway inhibitors (ARPIs) affected 177 Lu-PSMA-617 treatment outcomes. Here we compared the efficacy and safety of 177 Lu-PSMA-617 in patients treated with vs without concomitant ARPIs. Methods: In VISION, adult patients with PSMA-positive mCRPC previously treated with ≥1 prior ARPI and 1–2 taxane chemotherapy regimens were randomized 2:1 to receive 177 Lu-PSMA-617 (7.4 GBq Q6W, 4–6 cycles) + SoC (which included ARPIs) vs SoC alone. In this secondary analysis, we assessed baseline characteristics, OS, rPFS, prostate-specific antigen (PSA) response rate, duration of PSA response, PSA-PFS, and safety among patients in the intervention arm who were treated with vs without concomitant ARPIs. Results: In total, 289 patients were treated with concomitant ARPIs and 262 patients were not (N=551). Imbalances between the groups were observed in some baseline characteristics: patients treated with concomitant ARPIs were younger, had lower ECOG performance scores, lower mean PSA and lactate dehydrogenase levels, and fewer prior taxane chemotherapy regimens. Baseline mean standardized [ 68 Ga]Ga-PSMA-11 uptake values and mean hemoglobin levels were well-balanced. A statistically significant difference in median OS was observed in patients treated with concomitant ARPIs vs those without (17.8 vs 12.4 mo; HR, 0.72; 95% CI, 0.58–0.89; nominal P=0.001). No statistically significant between-group differences were observed for rPFS, PSA response rate, duration of PSA response or PSA-PFS. The proportion of adverse events reported was similar in patients with or without concurrent ARPI, except for the number of adverse events leading to interruption of best supportive care/SoC, which was higher in patients treated with concurrent ARPIs. Conclusions: OS was significantly different in patients treated with concomitant ARPIs vs those without, while other efficacy endpoints were not. No new safety signals were observed for 177 Lu-PSMA-617 with concomitant ARPI. These findings may be confounded by varied exposure to ARPIs, or differing patient characteristics; patients who received concomitant ARPIs may represent a more favorable treatment population than those who did not. These findings should be considered as hypothesis-generating, and a multivariate analysis has been planned to ascertain the influence of these potential biases. Clinical trial information: NCT03511664 .

Cardiac amyloidosis is an underdiagnosed cause of infiltrative cardiomyopathy, leading to heart failure across the spectrum of ejection fractions. Although there are approved disease-modulating therapies for the transthyretin subtype (transthyretin amyloid cardiomyopathy [ATTR-CM]), the role of heart failure medications remains uncertain and challenging in clinical practice. Their effects on clinical outcomes, such as mortality and hospitalization, are unknown for ATTR-CM. This review aims to explore the use of these medications in ATTR-CM, considering the disease’s stage and patient-specific issues, such as fluid homeostasis, autonomic dysfunction, conduction disorders, low and fixed stroke volumes, and decreased functional capacity. As our understanding of this condition deepens, it is important to reassess the impact of contemporary heart failure medication in ATTR-CM. Finally, the relevance of guideline recommendations for heart failure drugs based on left ventricular ejection fraction should be reconsidered in the context of ATTR-CM.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR &amp;lt;1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR &amp;lt;1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; &amp;lt;1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683