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Associations of heatwaves and their characteristics with ischaemic stroke hospital admissions

Clinical utility of measuring steady-state plasma level of lenvatinib in advanced renal cell carcinoma.

486 Background: As a multitarget tyrosine kinase inhibitor, lenvatinib (LEN) efficacy and toxicity are dose-dependent, and dose adjustment is common for toxicity. A therapeutic level of LEN has not been defined in renal cell carcinoma (RCC), leading to uncertainty whether the patient is on an effective dose. LEN is also widely used in combination with immune checkpoint inhibitor (ICI), adding complexity due to overlapping toxicity. In this investigator-initiated study, we aimed to assess: A) inter- and intra-patient variability in LEN steady-state plasma level (C ss ) after dose adjustment for target toxicity; and B) associations between C ss and health-related quality of life (HRQoL) outcomes and treatment-related toxicity (trAE). Methods: Patients on LEN for advanced RCC underwent C ss assessment – first when LEN dose was stable after adjusting for target of CTCAE grade 1 to 2 toxicities for at least 6 weeks prior; and another 6 weeks or more later to assess for intra-patient variation. HRQoL and trAE data were collected at the time of phlebotomy. Additional C ss samples were taken when patients required dose interruption due to significant trAE, as determined by the treating clinician. Bivariate linear regression model was used to analyse association between C ss and HRQoL (EORTC-QLQ-C30 Summary Score and QL2 domain), plus C ss and CTCAE Composite Score (CTCAE grade multiplied by number of days the event was present during preceding 30 days). Results: Between Apr 2023 – Jun 2024, 47 plasma samples from 19 RCC patients were collected and analysed. Patients were predominantly male (95%; 18/19) with clear cell subtype (74%; 14/19). At time of first sample collection: 13/19 (68%) patients have been on their LEN dose for more than 6 months (median time on dose 348 days), and 14/19 (79%) patients were on combination systemic therapy (10 with ICI; 1 with belzutifan; 3 with ICI+belzutifan). The median daily LEN dose was 14 mg (range 8-20). Median C ss was 17.9 µg/L (interquartile range, IQR, 14.3-23.0). The median intra-patient variation was low at 1.09% (IQR -11.9 to 11.9%). Moderate correlation was observed between C ss and QLQ-C30 Summary Score reflecting overall symptom burden (b= -0.713, R 2 =0.387, p<0.0001). Similar correlation was also observed between C ss and QLQ-C30 QL2 domain reflecting global health status (b= -1.20, R 2 =0.456, p<0.0001). There was little correlation between C ss and CTCAE Composite Score (b= 2.06, R 2 =0.105, p=0.030). Conclusions: LEN C ss after dose adjustment for a target toxicity showed minimal intra-patient variation. Our study indicates that after dose adjustment, LEN C ss correlates with patient-reported symptom burden and global health status. Future prospective studies to evaluate recommended therapeutic range, and integration of therapeutic drug monitoring in real-world clinical settings may ensure patients are receiving an effective dose.

COBRA: Assessment of the efficacy of ⁶⁴ Cu-SAR-bisPSMA using histopathology as reference standard in patients with biochemical recurrence of prostate cancer following definitive therapy.

44 Background: Accurate staging of recurrent prostate cancer (PC) is essential to inform the best treatment strategy. Prostate-specific membrane antigen (PSMA) is used as an imaging target in PC. 64 Cu-SAR-bisPSMA may offer several advantages over the currently approved PSMA positron emission tomography (PET) agents due to its bivalent structure (SAR-bisPSMA) and longer half-life of 64 Cu (12.7h vs. <2h for 18 F and 68 Ga). 64 Cu-SAR-bisPSMA has demonstrated higher tumor uptake (2-3x), prolonged retention and detection of additional PC lesions compared to approved PSMA agents. Methods: This was a Phase 1/2 study assessing the safety and efficacy of 64 Cu-SAR-bisPSMA (200 MBq) in PC patients with biochemical recurrence (BCR) and negative or equivocal standard of care (SOC) imaging (NCT05249127). PET/computed tomography (CT) imaging was performed on Day 0 and Day 1 (1-4h and 24±6h post-dose, respectively) and interpreted by 3 blinded central readers. PET/CT results were assessed against a Reference Standard (histopathology, SOC imaging, prostate-specific antigen response). Efficacy endpoints included detection rate (DR) and correct detection rate (CDR). The number of lesions detected, their size and the intended change in PC treatment due to the 64 Cu-SAR-bisPSMA results were recorded. Results: Fifty-two patients were enrolled (50 had 64 Cu-SAR-bisPSMA PET results). The DR range across readers on Day 0 was 44–58% (95% confidence interval [CI]: 30–71.8), increasing on Day 1 to 58–80% (95% CI: 43.2–90). The CDR as assessed against the Reference Standard on Day 0 was 19.0–26.2% (95% CI: 8.6; 42.0), increasing to 26.2–33.3% (95% CI: 13.9; 49.5) on Day 1. CDR was considerably higher when using the gold standard of histopathology as the Reference Standard (44.4–55.6% and 55.6–77.8% for Day 0 and Day 1, respectively; N=9). This highlights the limitations of using less sensitive methods (e.g. current SOC imaging) to verify the 64 Cu-SAR-bisPSMA PET findings. More lesions were identified on Day 1 than on Day 0 (82–153 vs. 53–80). The 64 Cu-SAR-bisPSMA imaging led to clinicians changing their intended treatment plans in 24/50 (48%) of participants. Conclusions: This study showed that 64 Cu-SAR-bisPSMA is effective in detecting PC lesions. 64 Cu-SAR-bisPSMA identified lesions in up to 80% of participants with BCR of PC and negative or equivocal SOC scan. Histopathology confirmed the presence of PC in lesions identified by 64 Cu-SAR-bisPSMA in up to 78% of cases in which biopsies were performed. More lesions and patients with a positive scan were identified on next-day imaging. PET results led to clinicians changing the intended treatment plan in approximately half of the patients. These findings have important clinical implications as the identification of lesions in BCR patients can inform different treatment pathways. Clinical trial information: NCT05249127 .

Gene expression signatures in biopsy cores as predictors of coexisting higher-grade disease in Gleason group 1 prostate cancer: Results from the Miami MAST prospective clinical trial.

239 Background: Despite several improvements in Active Surveillance (AS), pathologic reclassification remains frequent. Therefore, we examined if gene expression signatures in biopsy cores with Gleason Group (GG) 1 cancer can predict coexisting higher-grade disease elsewhere in the prostate among participants of the Miami Active Surveillance Trial (MAST). Methods: MAST enrolled 205 men with low and favorable intermediate-risk prostate cancer undergoing AS. Participants underwent an MRI and confirmatory biopsy at enrollment, and annually thereafter for three years. Positive cores underwent expression profiling with the whole-transcriptome Decipher genomic classifier (DGC). Derived Genomic Prostate Score (dGPS) and Cell Cycle Progression (dCCP) signatures were obtained. The primary objective was to compare signature scores in GG1 cores from prostates with (positive) vs. without (negative) coexisting GG2+ cancer elsewhere. The three signatures were also compared for coexisting GG3+ cancer elsewhere, and a sub-analysis using only the highest-volume GG1 core from each biopsy session was performed. Results: There was no significant difference between groups in DGC or dCCP scores regarding the primary objective, whereas median (IQR) dGPS was 0.14 (0.08–0.24) in positive vs. 0.10 (0.07–0.16) in negative groups (p=0.018). For coexisting GG3+ elsewhere, DGC or dCCP scores again did not differ, while dGPS was 0.24 (0.19–0.29) vs. 0.10 (0.07–0.16) in positive and negative groups, respectively (p=0.005). In a sub-analysis using only the highest volume GG1 core from each biopsy, as is the usual standard of care when using genomic testing on biopsy tissue, there was no significant difference in score between the groups for any of the signatures. Conclusions: Neither Decipher GC, dCCP, nor dGPS signatures showed clinically significant differences between GG1 cores with vs. without coexisting higher-grade cancer elsewhere when using the highest volume GG1 core for genomic testing. Our findings suggest that prostate cancer foci are heterogeneous and genomically independent. Clinical trial information: NCT02242773 .

Inferring ECOG performance status (PS) using large language models in patients with advanced prostate cancer.

136 Background: The ECOG performance status (PS) is a critical measure for evaluating functional capacity and determining clinical trial eligibility in patients with advanced prostate cancer. We aim to assess the capability of large language models (LLMs) to accurately infer ECOG PS from unstructured oncology notes. Methods: This retrospective study included patients with metastatic castration-resistant prostate cancer (mCRPC) receiving Lutetium-177–PSMA-617 ( 177 Lu) at the Mayo Clinic (2022-2023). Baseline ECOG PS scores were manually curated by a trained clinician from clinical notes recorded within four weeks prior to 177 Lu initiation. Structured zero-shot prompts were then used to prompt GPT-4 to infer ECOG PS scores from unstructured oncology notes. Total dataset was randomly sampled to prompt development (20%) and held-out test set (80%). Three experimental setups were employed to assess model performance: (i) utilizing unmasked clinical notes, (ii) clinical notes with only numerical ECOG PS scores masked while retaining narrative descriptive/assessment by oncologist of ECOG score, and (iii) clinical notes with both numerical scores and narrative ECOG descriptors masked. Final performance was assessed using evaluation metrics (precision, recall, F1 score) on the held-out test set. Results: A total of 240 patients (n: 50 prompt development; n: 190 test set) were included in the analysis. The median age was 70 (IQR: 66-76); a majority of patients were White (n: 229; 95%) and non-Hispanic (n: 233; 97%). The most prevalent ECOG PS score was 0 (n: 140; 58%), followed by 1 (n: 88; 37%), and 2 (n: 12; 5%). The performance was numerically higher when using unmasked notes (weighted average precision: 0.89; recall: 0.89; F1: 0.89), compared to using notes with masked scores only (weighted average precision: 0.76; recall: 0.79; F1: 0.75) and notes with both scores and narrative masked (weighted average precision: 0.57; recall: 0.53; F1: 0.48). Metrics by each ECOG PS score is outlined (Table). Conclusions: Large language models demonstrate significant potential in precisely extracting ECOG performance status from unstructured oncology notes, offering valuable support for treatment decision-making and clinical trial enrollment. However, model performance declines as reliance on implicit reporting within clinical notes increases. Future efforts focusing on prediction of ECOG using a series of notes over time will be the next step. ECOG Unmasked oncology notes ECOG Score masked only ECOG Score + ECOG narrative marked Precision Recall F1 Score Precision Recall F1 Score Precision Recall F1 Score 0 0.89 0.92 0.91 0.75 0.93 0.83 0.59 0.74 0.66 1 0.88 0.86 0.87 0.76 0.74 0.75 0.19 0.47 0.27 2 1.00 0.82 0.90 0.78 0.33 0.47 0.78 0.16 0.26

Energy level alignment of confined hole states in InAs1−x−ySbxPy asymmetric double quantum dots for single-photon energy up- and downconversion

We present a combined experimental and theoretical study of uncapped In(As, Sb, P) graded composition laterally coupled asymmetric double quantum dots (DQDs), suited for application in nanodiodes or single-photon nano-optical up- and downconverters in the mid-infrared spectral range. We provide details on the growth process using liquid-phase epitaxy and characterization using atomic-force microscopy and scanning electron microscopy (SEM). We find that most DQDs exhibit asymmetry such that the two quantum dots (QDs) of each pair have different dimensions, giving rise to correspondingly different quantum confinement of hole states localized in each QD. Based on these data, we have performed systematic simulations using an eight-band k·p model to identify the relationship between QD dimensions and the energy difference between corresponding confined hole states in the two QDs. Finally, we have determined the strength of an applied electric field required to energetically align the hole ground states of two QDs of different dimensions in order to facilitate hole tunneling to the next QD for further recombination and single-photon emission with a different wavelength.

An integrated workflow combining machine learning and wavelet transform for automated characterization of heterogeneous groundwater systems

Abstract Groundwater aquifers are complex systems that require accurate lithological and hydrogeological characterization for effective development and management. Traditional methods, such as core analysis and pumping tests provide precise results but are expensive, time-consuming, and impractical for large-scale investigations. Geophysical well logging data offers an efficient and continuous alternative, though manual interpretation of well logs can be challenging and may result in ambiguous outcomes. This research introduces an automated approach using machine learning and signal processing techniques to enhance the aquifer characterization, focusing on the Quaternary system in the Debrecen area, Eastern Hungary. The proposed methodology is initiated with the imputation of missing deep resistivity logs from spontaneous potential, natural gamma ray, and medium resistivity logs utilizing a gated recurrent unit (GRU) neural network. This preprocessing step significantly improved the data quality for subsequent analyses. Self-organizing maps (SOMs) are then applied to the preprocessed well logs to map the distribution of the lithological units across the groundwater system. Considering the mathematical and geological aspects, the SOMs delineated three primary lithological units: shale, shaly sand, and sand and gravel which aligned closely with drilling data. Continuous wavelet transform analysis further refined the mapping of lithological and hydrostratigraphical boundaries. The integrated methods effectively mapped the subsurface aquifer generating a 3D lithological model that simplifies the aquifer into four major hydrostratigraphical zones. The delineated lithology aligned closely with the deterministically estimated shale volume and permeability, revealing higher permeability and lower shale volume in the sandy and gravelly layers. This model provides a robust foundation for groundwater flow and contaminant transport modeling and can be extended to other regions for improved aquifer management and development.

Evaluating the role of cancer-associated fibroblasts in T cell–mediated proinflammatory reprogramming of tumor associated macrophages in the prostate cancer tumor microenvironment.

248 Background: Tumor-associated macrophages (TAMs) have been implicated as a critical mediator of T cell exclusion and inhibition within the prostate TME. However, using a microscale cell culture platform, known as Stacks, we have previously demonstrated that while prostate tumor cells induce an immunosuppressive phenotype in TAMs, activated T cells can reprogram these macrophages towards a proinflammatory phenotype that augments tumor-directed T cell responses. To investigate how other cell populations within the TME impact T cell mediated macrophage reprogramming, we expanded our models to include cancer-associated fibroblasts (CAFs), which have been previously shown to have immunosuppressive effects that regulate macrophage function in the TME. Methods: Primary T cells and autologous monocyte-derived macrophages (MDMs) were derived from the peripheral blood samples of patients receiving care at the University of Wisconsin Carbone Cancer Center and with William S Middleton Memorial Veterans Hospital in Madison, WI. MDMs were cultured with prostate tumor (22Rv1) and CAF (hPrCSC-44) cells in mono-, co-, and tri-culture models for 72h in the Stacks microfluidic cell culture platform. Activated autologous T cells were then added to each condition for an additional 24h of culture. Models were analyzed for T cell migration and surface marker expression by confocal microscopy, secreted cytokine and chemokine profiles by protein bead array, and gene expression by qRT-PCR. Results: We found that MDM-mediated augmentation of CD4 + and CD8+ T cell migration within the prostate TME models was abrogated in the presence of CAFs. Analysis of gene expression further demonstrated that the presence of CAFs in our quad culture models resulted in a decrease in expression of T cell recruitment chemokines by the MDMs, including CCL2, CCL5, CXCL9, CXCL10, and CXCL11, compared to MDM tri-culture with tumor cells and T cells. MDMs also expressed higher levels of IL-10 mRNA, a potent immune suppressive factor, when CAFs were present in the TME. Conclusions: Using microscale cell culture technologies, we provide the first direct evidence that CAFs inhibit T cell mediated proinflammatory reprogramming of MDMs in the prostate TME. Furthermore, we demonstrate that this inhibition of MDM reprogramming is associated with a decrease in tumor-directed T cell migration compared to MDM, tumor cell, and T cell tri-cultures. This data suggests that CAFs, through their effects on MDMs/TAMs, may be playing a vital role in the inhibition of tumor-directed T cell responses. The pathways that are mediating this effect therefore represent valuable therapeutic targets to augment immunotherapeutic efficacy in prostate cancer treatment.

GLP1R expression in prostate cancer patients and effects of GLP1R agonism on prostate cancer cells.

182 Background: As a disease of aging, metabolic co-morbidities are managed concurrently with prostate cancer. Recent FDA approvals have launched widespread use of GLP1 receptor agonist semaglutide for Type II Diabetes Mellitus and obesity. Mechanistically, semaglutide primarily activates GLP1 receptors in the pancreas. However, GLP1R is also expressed in advanced prostate cancer tissues where GLP1 agonism could affect signaling and disease progression. Understanding the effects of semaglutide treatment in prostate cancer is critical to gain a complete picture of the systemic effects this drug and potentially expose additional contexts where semaglutide can be therapeutically valuable in this disease space. Methods: RNA-sequencing data was accessed from dbGaP (consolidated, n=664) and Gene Expression Omnibus (GSE204057, n=55) to assess GLP1R expression in prostate cancer patients. Bioinformatics analyses were utilized to identify signaling pathways associated with GLP1R expression. Proliferation, metabolism, and signaling after GLP1R agonism with semaglutide were assessed in vitro in prostate cancer cell line models using incucyte, Seahorse, and a kinase proteome profiler array. Results: We identified GLP1R expression in advanced prostate cancer samples including 145/310 (46.8%) of metastases, 59/115 (51.3%) of castration-resistant prostate cancer (CRPC), and 9/15 (60%) of neuroendocrine prostate cancer (NEPC), where it was associated with Notch and Hedgehog Signaling. Semaglutide treatment in pre-clinical prostate cancer models resulted in decreased cell proliferation, decreased glycolytic function, and decreased activation of kinase-mediated signaling. This overall suppression of signaling downstream of GLP1R is consistent with Gai-coupled GPCR signaling, which was confirmed using a cAMP assay. Interestingly, in a trans-differentiation model there was a significant negative correlation between GLP1R and AR expression. Further, proliferation of prostate cancer cells was significantly decreased with combination treatment of enzalutamide with semaglutide compared to either treatment alone. Conclusions: GLP1R was expressed in advanced prostate cancer patients and treatment with semaglutide suppressed growth, metabolism, and signaling. This is clinically significant due to concurrent treatment for metabolic co-morbidities in men with prostate cancer. Our preliminary data shows that co-targeting AR and GLP1R decreased cell growth, suggesting GLP1R agonism may be therapeutically useful in combination with androgen receptor antagonists in advanced prostate cancer.

Results from the prior treatment cohort of a phase I/II study of nivolumab and axitinib in patients with advanced renal cell carcinoma.

548 Background: Combination tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (IO) are an established standard of care for patients with metastatic renal cell carcinoma (mRCC). We report updated analysis of a multi-center, investigator-initiated (IIT), phase I/II study of axitinib (axi) with nivolumab (nivo) in the previously treated patient cohort. Methods: The study investigated the combination of axi/nivo in an initial dose finding phase I portion and a phase II portion including 2 parallel arms: treatment naïve mRCC patients and mRCC patients previously treated with TKIs or IO/IO combination (NCT03172754). We are presenting final results from the previously treated cohort. Included patients had pathology with any clear cell component, ECOG performance status of 0-1, no known or symptomatic brain metastases, and no history of autoimmune disease. The recommended phase 2 dose of axi was 5 mg BID and patients were treated for up to 2 years then could stop one or both therapies. The primary endpoint of the phase II portion was objective response rate (ORR) per investigator assessment. Results: Twenty-six patients were accrued to the previously treated arm, all evaluable for efficacy and toxicity. The median age was 62 yrs (range: 42-81), 80.8% were male and 88.5% were white. Twenty pts had 1 prior line of therapy (18 TKI alone), 6 pts had 2 or more prior lines of Tx. Two pts had prior nivo with ipilimumab. Median follow-up was 47.2 months. The ORR was 30.8% (all PRs) and 57.7% achieved stable disease. The primary PD rate was 11.5%. Median OS was 48.4 months and median PFS was 13.0 months. Six pts (23.1%) completed two years of Tx on trial and elected to stop one or both drugs (2 elected to stay on axi alone). Five pts remain progression-free and have received no subsequent therapy with a median progression-free interval of 23.2 months. None had received prior IO. Adverse event (AE) data was similar to published data for IO/TKI combinations. There was one Gr4 TRAE of elevated lipase and 12 pts (46%) experienced a Gr3 TRAE. One pt (4%) discontinued the study due to TRAEs. Conclusions: Final results from the previously treated cohort of this IIT of axi/nivo for pts with mRCC demonstrated an ORR of 30.8% and a DCR of 88.5% with no unexpected AEs. Though there were no CRs, disease control rate and median OS were encouraging in this previously treated population. This is the only reported IO/TKI trial that allowed for stopping of all Tx at 2 years, with 6 pts (23.1%) meeting this milestone, 5 of whom (19% of all pts) remain progression-free for a median period close to 2 years. Clinical trial information: NCT03172754 .

The prognostic role of circulating tumor DNA (ctDNA) clearance as a biomarker in localized and metastatic renal cell carcinoma (RCC): A single-center experience.

570 Background: The use of ctDNA-based molecular residual disease detection represents a promising prognostic biomarker in multiple solid tumors, yet limited data exist in RCC. This study aims to prospectively assess the utility of longitudinal ctDNA monitoring in localized and metastatic RCC. Methods: We conducted a retrospective analysis on the use of longitudinal ctDNA testing in a single academic center for patients with RCC from 2022 - 2024. We used a clinically validated, personalized, tumor-informed, multiple PCR-NGS assay (Signatera, Natera, Inc.) to detect and quantify ctDNA. A total of 229 plasma samples from 69 patients were analyzed. Clinical data were collected on pathologic subtype, tumor stage and grade including the presence of sarcomatoid/rhabdoid features and type of treatment. ctDNA dynamics were categorized as follows : clearance, decrease, or increase in ctDNA levels. Treating physicians were not blinded to ctDNA results, no treatment decisions were made based on ctDNA dynamics. Results: A total of 69 patients (mean age=62, 23% female) with RCC were included in the analysis, (median: 3 samples/patient), with 33 (48%) having localized RCC and 36 (52%) having metastatic RCC (mRCC). Clear cell RCC was the predominant subtype, present in 61 (88%) patients. Among 33 patients with localized disease, 8 (24%) patients were on surveillance, and 25 (76%) patients received adjuvant pembrolizumab. Among 36 patients with mRCC, 32 (89%) patients were on systemic therapy and 4 (11%) patients were on surveillance. Among those with localized RCC, 1 (3%) patient was ctDNA positive 12 months after nephrectomy and, subsequently developed metastatic disease 1 month from ctDNA detection. Thirty-two (97%) patients with localized RCC and ctDNA negative results remained relapse-free with a median follow-up of 9 months. Among patients with mRCC, 22 (61%) patients were ctDNA positive, 12 (55%) achieved ctDNA clearance (10 after systemic therapy and 2 spontaneously on surveillance). Of these, 10 (83%) remained progression-free at a median follow-up of 11.5 months, while 2 had rise in ctDNA levels after clearance, correlating with disease progression. At median follow-up of 15 months (range 2 to 70 months), all 4 patients with radiographic progression had rising ctDNA levels (median lead time 4 weeks). One patient had rising ctDNA without evidence of radiographic progression. Conclusions: Our findings highlight the potential of ctDNA detection and dynamics as a valuable prognostic biomarker for patients with both localized and metastatic RCC. These results support further prospective studies to establish the clinical utility of ctDNA clearance as a predictive marker in metastatic RCC.

Fiber-tip photothermal transducer with gold-coated multi-beam interferometric cavity for high sensitivity gas detection

The power-boosted laser transmitted via a fiber tip sinusoidally excites the target trace molecules, generating a photothermal (PT) effect. The Gaussian-distributed plane wave heats the medium adjacent to the Fresnel reflection surface. Meanwhile, a continuous probe light traverses the heating field, and the periodic temperature change then modulates the phase of the probe light. A multi-beam interferometer formed by aligning the Fresnel reflection surface to a gold-coated high-reflection surface possesses high resolution and sensitivity, significantly enhancing the detection performance. A well-established theoretical model of instantaneous PT transduction and optical phase modulation is employed to obtain the optimized interferometric configuration. To validate the effective interferometric phase transformation within the cavity, a comparison is made between the simple silicon cavity and the gold-coated cavity. The limitation of detection of such extrinsic fiber-tip PT sensors indicates one magnitude lower as compared to the conventional PT interferometric gas sensor with such robust and compact sensing designs. This work lays a solid foundation for future research on gas laser phase modulators and nonlinear laser–matter interactions.

Identification and validation of diagnostic biomarkers for temporal lobe epilepsy related to ferroptosis and potential therapeutic targets

Evaluation of time to metastasis (TTM) from prostatectomy and survival in patients (pts) with metachronous metastatic hormone-sensitive prostate cancer (mHSPC) receiving androgen deprivation therapy (ADT) intensification: A real-world study.

100 Background: Metachronous mHSPC is associated with improved outcomes compared to synchronous (de novo) mHSPC. However, there are limited data on the effect of TTM after radical prostatectomy in patients with metachronous mHSPC treated with systemic therapies. Our objective was to explore the association of TTM after prostatectomy with survival outcomes in a real-world population. Methods: In this IRB-approved retrospective study, eligibility criteria were: pts with metachronous mHSPC who underwent radical prostatectomy and were treated with ADT plus androgen receptor pathway inhibitor (ARPI). Metachronous disease was defined as the absence of metastatic disease within 90 days of initial prostate cancer diagnosis. TTM was defined from the time of prostatectomy to the time of initial metastatic diagnosis and was analyzed as a continuous variable, then categorized. Progression-free survival (PFS) was defined from the start of therapy for mHSPC to disease progression or death from any cause. Overall survival (OS) was defined from treatment initiation for mHSPC to death from any reason or censored at the last follow-up. Multivariable analyses for PFS and OS were performed using a Cox proportional hazards model, adjusting for disease volume (per CHAARTED criteria), Gleason score, log-transformed PSA, and age. Results: Overall, 186 pts with metachronous mHSPC who previously underwent prostatectomy were eligible and included. Pts with a Gleason score of ≥ 8 comprised 44% of the cohort and those with age ≥ 65 comprised 68% of the cohort. A high volume of disease was present in 34% of the pts. Overall, median TTM was 46 months. On univariate analysis, a longer TTM was not associated with improved PFS (HR 1.0, 95% CI 1.0-1.1, P=0.3) or OS (HR 1.0, 95% CI 1.0-1.1, P=0.8), and results were consistent on multivariate analysis. No PFS or OS benefit was observed in pts achieving a TTM ≥1, 2, 3, and 4 years respectively, versus those who do not (Table). Conclusions: A prolonged TTM is not associated with survival outcomes after onset of metachronous mHSPC in pts treated with ADT + ARPI. OS and PFS in the mHSPC setting appear to be independent of timing of metastatic disease post prostatectomy in this pt population. Univariate Multivariate HR (P-value) PFS OS PFS OS TTM Continuous 1.0 (0.3) 1.0 (0.8) 1.0 (0.5) 1.0 (0.4) TTM <1 vs ≥1 0.9 (0.7) 0.8 (0.6) 0.7 (0.5) 0.7(0.5) TTM <2 vs ≥2 0.9 (0.8) 0.9(0.7) 0.6 (0.3) 0.6 (0.3) TTM <3 vs ≥3 0.9 (0.5) 0.8 (0.6) 0.6 (0.2) 0.6 (0.2) TTM <4 vs ≥4 0.9 (0.7) 1.1 (0.7) 0.9 (0.7) 0.9 (0.7)

Utilizing ChatGPT for assessing disease volume in patients (pts) with metastatic prostate cancer (mPC).

42 Background: Artificial intelligence (AI) has transformed many aspects of healthcare, particularly in medical imaging analysis. In mPC, accurate identification of bone metastases is crucial in guiding pt management. This proof-of-concept study explores the application of ChatGPT-4o, a multimodal, generative pre-trained transformer (large language model) with emerging image recognition capabilities, in diagnosing bone metastases from bone scans and determining disease volume in pts with mPC. Methods: In this IRB-approved, retrospective study, pts with newly diagnosed mPC and bone-predominant disease were randomly selected. Those who had previously received bone-protecting agents, chemotherapy, hormone therapy, or radiation therapy prior to the bone scan were excluded. Using CHAARTED criteria, high-volume versus low-volume bone disease was classified based on radiologist reports. The bone scan images were then uploaded to ChatGPT, which was instructed to act as a radiologist and asked to classify the disease volume. ChatGPT's classifications were compared to the radiologists’ findings by using Cohen’s Kappa test. Confusion’s matrix was used to represent the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of ChatGPT. Results: A total of 110 pts were selected, with a median age of 67 years (range: 44 to 89). The majority were Caucasian (98.2%). The median Gleason score was 9, and 77.3% of pts had de novo metastatic disease. The median PSA value at diagnosis was 35.2 ng/ml (range: 1-5843). High-volume disease was present in 52% of pts. ChatGPT's overall concordance with radiologists was 74% (Cohen's Kappa = 0.65). For high-volume disease, ChatGPT demonstrated a high sensitivity of 92.3% (48/52). However, it misclassified 45.8% of low-volume cases as high-volume (specificity: 54.2%). The PPV and NPV of ChatGPT were 68.6% and 86.7%, respectively. Interestingly, ChatGPT’s accuracy was significantly higher when each case was analyzed individually (77.7%) compared to when cases were grouped in a single conversation (43.5%, p<0.001). Conclusions: This hypothesis-driven research demonstrated that ChatGPT-4o has the potential to read medical images independently and apply existing knowledge, such as the CHAARTED criteria, to assist in content generation. However, its reliability remains a significant challenge for broader use in healthcare. Notably, it exhibited "information fatigue," where accuracy significantly declined when similar or repetitive information accumulated within a single conversation.

Assessing genomic instability (GI) by shallow whole-genome sequencing (sWGS) to predict PARP inhibitor (PARPi) response in metastatic castration-resistant prostate cancer (mCRPC).

194 Background: The heterogeneous efficacy of PARPi in patients with mCRPC and homologous recombination deficiency (HRd)-associated genetic alterations has emphasized the need for a more accurate selection of responding patients. sWGS offers a cost-effective method to identify HRd through GI analysis. However, the correlation between GI from sWGS and specific genotypes, along with its predictive value for PARPi response, remains unreported. Methods: A total of 289 samples from 267 patients were analyzed for GI by sWGS. Of these, 121 were newly sequenced with a mean depth of 2.05x and 168 were in silico down-sampled to 2x. Eighty-four percent of the samples were collected in the CRPC setting. Copy number analysis was performed using iChorCNA with a 50 Kb window size, and multiple genome-wide copy number plots were generated per sample with varying tumor content and ploidy. Two researchers independently selected the optimal plot, with discordant cases reviewed by a third, to quantify large-scale transitions and telomeric allelic imbalances per sample, which together constituted an adjusted GI score (aGIS). Results: The median aGIS of all samples was 21 (interquartile range [IQR] 16 – 30). Samples with HRd-associated genetic alterations (43%) had a higher median aGIS (26) than to those without (19, P < 0.0001). Deleterious aberrations in PALB2 resulted in the highest aGIS, followed by BRCA2 and ATM . The aGIS for genotypes with >3 samples are detailed (Table). Out of the 267 patients, 71 received PARPi. Their median aGIS was 27 (IQR: 19–37). The 33 patients with ≥50% PSA decline had a higher aGIS than the 37 without (aGIS 35 vs 22, P = 0.0001). In 60 patients with radiologic assessment, 22 had a partial response, 27 stable disease, and 11 progressive disease. The median aGIS for these groups were 32 (IQR: 25.5–49), 26 (IQR: 17.5–35), and 21 (IQR: 16.5–26.5), respectively, with a significant difference between partial and progressive disease (P = 0.0053). The Cox proportional hazards model did not show a significant effect of aGIS on progression-free survival (P = 0.144). Still, patients with the highest 25% aGIS had a median progression-free survival of 11 months, compared to 4 months for the lowest 25%, and 8 months for the remaining. Conclusions: The quantity of large-scale transitions and telomeric allelic imbalances, from sWGS, correlates with HRd-associated genetic alterations. In PARPi-treated patients, this aGIS is significantly associated with biochemical and radiologic response, even after selection by genotyping. These findings support the development of an sWGS-adjusted GI score for predicting PARPi response in mCRPC. Aberration in: N Median aGIS (IQR) PALB2 4 30.5 (15 – 44.75) BRCA2 50 29 (22 – 38.75) ATM 37 28 (20 – 34) BARD1 4 26.5 (15.5 – 34.5) RAD51B 5 26 (25 – 26) CDK12 20 18.5 (10.75 – 20.25) CHEK2 5 16 (12 – 17)

Real-world treatment patterns in patients diagnosed with metastatic castration-resistant prostate cancer in the US, 2018-2023.

74 Background: The treatment landscape in patients with metastatic castration-resistant prostate cancer (mCRPC) has evolved in recent years. This real-world study evaluates treatment patterns among a large contemporary cohort of patients with mCRPC in the US. Methods: This retrospective cohort study included patients with a confirmed mCRPC diagnosis from 1/1/2018 to 12/31/2023 in the US nationwide Flatiron Health electronic health record-derived deidentified database. Treatment patterns were evaluated by disease setting (metastatic hormone-sensitive prostate cancer [mHSPC], nonmetastatic castration-resistant prostate cancer [nmCRPC], mCRPC) and by use of androgen receptor pathway inhibitors (ARPI; abiraterone, enzalutamide, apalutamide, darolutamide) before mCRPC diagnosis. Patients were considered ARPI-experienced if they received at least 1 line of therapy (LOT) containing an ARPI before progressing to mCRPC. Patients were considered ARPI-naive otherwise. Results: Of 6301 patients with mCRPC (mean age, 75 years), 4915 (78%) received ≥1 LOT in the mCRPC setting. Among those with ≥1 LOT, 48% received second-line (2L) therapy. The most common first-line (1L) and 2L therapies in mCRPC were ARPI (1L, 75%; 2L, 55%) and chemotherapy (1L,16%; 2L, 33%). Most patients (4491, 71%) were ARPI-naive before mCRPC diagnosis. Among the 1810 (29%) patients who were ARPI-experienced before their mCRPC diagnosis, the median treatment duration with ARPI was 23 months. Use of ARPI in the mHSPC setting increased from 11% to 39% in patients diagnosed with mCRPC in 2018 and 2022, respectively. Similarly, in the nmCRPC setting, this figure rose from 20% to 39%. Consecutive use of ARPI in the mCRPC setting, with variations based on the year of mCRPC diagnosis, was observed in 54% to 65% of ARPI-naive patients and 31% to 48% of ARPI-experienced patients who received 1L ARPI and any 2L therapy. Use of chemotherapy increased from 13% to 19% in 1L and 29% to 40% in 2L in the mCRPC setting but decreased from 11% to 7% in mHSPC setting. Conclusions: In this community practice-based study, ARPI was the most common 1L and 2L therapy, followed by chemotherapy, in patients diagnosed with mCRPC from 2018 to 2023. Although ARPI use before mCRPC diagnosis has increased, more than two-thirds of patients overall remain ARPI-naive at mCRPC diagnosis. Despite not being recommended by guidelines, consecutive use of ARPI in the mCRPC setting was common in patients regardless of ARPI use before mCRPC diagnosis.

Anticathode effect on multimodal azimuthal oscillations in electron beam generated E×B plasma

Electron beam (e-beam) generated plasmas with applied crossed electric and magnetic (E×B) fields are promising for low-damage (gentle) material processing. However, these plasmas can be subject to the formation of plasma non-uniformities propagating in the E×B direction. These rotating plasma structures (or “spokes”) enhance the transport of charged species across the magnetic field, which can harm the gentle processing capability of the plasma. In this work, we investigate the role of electrostatically active boundaries on the spoke formation by incorporating a variable bias conducting boundary (known as an anticathode) placed on the axially opposite side of the cathode. Our findings indicate azimuthal mode suppression occurs when the anticathode is electron collecting. Furthermore, we show selective azimuthal mode suppression by biasing the anticathode to an intermediate potential between the cathode and anode potentials. These findings suggest a link between the axial electron confinement in the e-beam generated plasma and azimuthally propagating plasma structure formation.

Male reproductive phenotype alterations in heterozygous β-globin gene knockout thalassemia (BKO) mice as a model for β-thalassemia patients

Impact of tumor burden on treatment patterns and outcomes in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) treated with avelumab first-line maintenance (1LM).

764 Background: With the evolving treatment (tx) landscape in la/mUC, patient (pt) clinical characteristics are increasingly important when selecting systemic anticancer tx. This study describes pt characteristics, tx patterns, and clinical outcomes by tumor burden in pts with la/mUC treated with avelumab 1LM following 1L platinum-based chemotherapy (PBC) with no progressive disease (PD). Methods: In this noninterventional retrospective study, pts with la/mUC were identified using Flatiron Health’s electronic health record database. Inclusion criteria were pts aged ≥18 years diagnosed with la/mUC between Jan 1, 2019, and Jul 31, 2023, treated with 1L PBC with no PD, followed by avelumab 1LM on/after Jul 1, 2020. Pt characteristics at 1LM initiation, tx patterns, and real-world overall response rate (rwORR) were reported using descriptive statistics. Real-world overall survival (rwOS), progression-free survival (rwPFS), time to next tx (TTNT), and time to tx discontinuation (TTD) were assessed using Kaplan-Meier methods. Subgroup analyses by disease burden were conducted reported: visceral (bone and other visceral) vs nonvisceral metastases (bone only) and lymph node only (includes distant lymph node) vs distant metastases. Results: Of 290 pts included, 156 (53.8%) were still receiving avelumab 1LM at data cutoff (Jul 31, 2023). Median age was 71 years; most pts were male (75.9%), White (70.7%), and had ECOG performance status 0/1 (78.3%). Median follow-up from 1LM initiation was 8.7 months. Among 266 pts with metastases, these were visceral in 142 (53.4%), nonvisceral in 124 (46.6%), distant in 183 (68.8%) and lymph node only in 83 (31.2%). 1L PBC was cisplatin-based in 52.4% and carboplatin-based in 47.6%. Median rwPFS and rwOS from avelumab 1LM initiation were 5.0 (95% CI, 3.9-5.8) and 22.0 (95% CI, 18.2-24.8) months, respectively. In pts with tumor assessment during avelumab 1LM (n=236), rwORR was 34.7%. Outcomes by disease burden are shown in the table. Conclusions: These results provide insights into clinical outcomes by tumor burden in pts with la/mUC treated with avelumab 1LM. Pts with nonvisceral and/or lymph node-only metastases had more favorable outcomes, consistent with the JAVELIN Bladder 100 trial. Outcome from 1LM start, median (95% CI), months Pts with metastases (n=266) Nonvisceral (n=124) Visceral (n=142) rwPFS 5.6 (4.1-7.8) 3.6 (3.1-5.0) rwOS 23.8 (15.4-NE) 19.1 (12.5-23.8) TTNT 6.6 (6.6-9.8) 6.0 (4.3-7.4) TTD 5.3 (4.2-10.1) 4.4 (3.5-5.7) Lymph node only (n=83) Distant (n=183) rwPFS 8.7 (5.0-NE) 3.6 (3.1-4.6) rwOS 24.3 (20.7-NE) 16.5 (12.5-22.6) TTNT 8.1 (6.2-23.8) 5.2 (4.3-6.7) TTD 10.1 (4.9-NE) 4.2 (3.3-5.5) NE, not estimable.