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Author Correction: Exploring online public survey lifestyle datasets with statistical analysis, machine learning and semantic ontology

Impact of physicians’ awareness of prostate-specific antigen doubling time (PSADT) on treatment (Tx) decisions in high-risk (HR) biochemically recurrent (BCR) prostate cancer (PC).

354 Background: PSADT is one of the strongest predictors of outcomes in patients (pts) with BCR PC and a criterion for HR BCR definition. As such, it is crucial to determine whether physicians are aware of pts’ PSADT and how this influences Tx in routine practice. We compared Tx patterns in pts with HR BCR whose PSADT was known (kPSADT) or unknown (uPSADT) by the physician. Methods: This physician-abstracted chart review used data of pts with HR BCR from the Cardinal Health Oncology Provider Extended Network (2018–2020) in the US. HR BCR definition: PSADT ≤9 months (mo) with PSA at or above the threshold per the EMBARK trial. Follow-up was from the index date (date on which HR BCR definition was met) until disease progression, last follow-up, or death through 2022. Physicians reported PSADT in case report forms (CRFs) using doubling time from labs, clinical judgement, or an online calculator (kPSADT). If not provided in the CRF, PSADT was calculated retrospectively based on PSA values up to the index date that the physician had entered in the CRF (uPSADT). We analyzed time to treatment after index via the Kaplan–Meier method. Results: Among 284 pts with HR BCR, median time from initial PC diagnosis to the end of follow-up was 39.1 mo; most pts had kPSADT). There were differences between in age, time from localized PC diagnosis to BCR, Gleason score, and PSA at initial diagnosis and at BCR (Table). A higher proportion of pts with uPSADT had a fast PSADT (≤3 mo) (61% vs 20%, P < 0.001). A higher proportion of pts with kPSADT (64%) vs uPSADT (17%) received Tx within 60 days after index, with a shorter median time to Tx (1.0 vs 6.7 mo; HR: 3.4, 95% CI: 2.6–4.4, P < 0.0001). Conclusions: Most physicians did not know their pts’ PSADT. Even though pts with HR BCR PC who had kPSADT were older and had slower PSADT, they were over three times more likely to receive Tx vs pts with uPSADT. The results suggest that many pts with HR BCR PC may be missed in clinical practice, which limits these pts’ opportunity to receive guideline-concordant Tx to delay progression. Characteristics of index kPSADTn = 104 uPSADTn = 180 P value Age (years), mean (SD) 70.0 (7.6) 65.6 (7.0) <0.001 Primary definitive PC Tx, n (%) Radiotherapy 28 (27) 51 (28) Prostatectomy 76 (73) 129 (72) Time from localized PC diagnosis to BCR ≤2 years, n (%) 97 (93) 143 (79) 0.002 Gleason score ≥8, n (%) 76 (73) 81 (45) <0.001 PSA before initial localized PC diagnosis (ng/mL), median (IQR) 9.0 (6.7) 7.9 (8.6) 0.019 PSA at BCR (ng/mL), median (IQR) 3.4 (9.0) 2.6 (2.8) <0.001

Trends in cardiovascular mortality in older adults with malignant neoplasms of male genital organs in the United States from 1999 to 2020.

29 Background: The American Cancer Society estimated that 1.9 million new cancer cases were identified in 2021, comprising 260,210 newly diagnosed male genital neoplasm cases. Prostate cancer is considered the second leading cause of cancer-related mortality among men in the United States (US). Cardiovascular events are commonly observed in patients receiving androgen deprivation therapy or platinum-based chemotherapy, fundamental treatments for malignant male reproductive organ tumors. Therefore, the objective of our study is to evaluate the temporal and regional trends of cardiovascular mortality in men 55 years or older with malignant neoplasms of the male genital organs in the US from 1999 to 2020. Methods: We used the death certificate data from the Centers for Disease Control and Prevention’s Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database to determine crude mortality rates (CMRs) and age-adjusted mortality rates (AAMRs) per 100,000 individuals. Joinpoint regression calculated the annual percent change (APC) and average annual percent change (AAPC) in AAMR. Results: A total of 109,970 cardiovascular-related deaths occurred in older adults with neoplasms of male genital organs in the US from 1999-2020, with an overall AAMR of 18.55. A gradually decreasing trend in mortality was observed until 2003 (APC -4.43, 95% CI = -5.33 to -3.16), followed by a sharp decline until 2013 (APC -6.89, 95% CI = -7.36 to -6.62), and another gradual decline till 2018 (APC -3.12, 95% CI = -4.21 to -1.99). However, from 2018 to 2020, a drastic increase was observed (APC 6.03, 95% CI = 3.41 to 7.96). Individuals older than 85 showed the highest mortality (130.17), followed by those aged 75 to 84 (31.79). Among racial groups, the highest AAMR was seen in Non-Hispanic (NH) Black or African Americans (33.87), followed by NH Whites (18.14), NH American Indians or Alaskan Natives (13.26), Hispanics (11.50), and NH Asians or Pacific Islanders (7.98). Among census regions, the highest and lowest mortality were observed in the Western region (20.04) and Southern region (16.34), respectively. While urban areas reported a significantly higher number of deaths (88,263) compared to rural areas, the AAMR was higher in rural areas (20.20) than in urban areas (18.16). Conclusions: An overall decreasing trend of cardiovascular mortality was observed among older adults with malignant neoplasms of male genital organs from 1999 to 2020 in the US; however, the sharp rise from 2018 to 2020 is important to consider. There were notable disparities in mortality among NH Blacks or African Americans, males over 85, and residents of rural and Western regions. The results of our study highlight the necessity of providing cardiovascular treatment to cancer patients at earlier stages, particularly in vulnerable subgroups, necessitating close collaboration between oncologists and cardiologists.

Combined analysis of circulating tumor cells and PSMA imaging metrics to predict efficacy of ¹⁷⁷ Lu-PSMA-617 in metastatic prostate cancer.

215 Background: Radioligand therapy targeting prostate-specific membrane antigen (PSMA), such as 177 Lu-PSMA-617, has demonstrated clinical efficacy in PSMA-PET-positive metastatic castration-resistant prostate cancer (mCRPC). However, not all PSMA-positive mCRPC patients benefit from this therapy, highlighting the need for novel biomarkers to predict treatment response. We aimed to evaluate whether molecular analysis of circulating tumor cells (CTCs) could provide predictive biomarkers of 177 Lu-PSMA-617 therapy. Methods: In this single-institution biomarker study, male patients with PSMA-PET-positive mCRPC scheduled to begin treatment with 177 Lu-PSMA-617 were enrolled. Informed consent was obtained (DF-HCC 13-416). CTCs were isolated from blood samples collected prior to the initiation of 177 Lu-PSMA-617 therapy using a microfluidic device (CTC-iChip). Half of the CTCs from each patient were immunostained with antibodies against cytokeratin, EpCAM, and PSMA and counterstained with CD45 to exclude leukocytes. The stained CTCs were imaged using a Vectra Polaris multispectral microscope. The fluorescence intensity of PSMA in each CTC was categorized into four levels (3+, 2+, 1+, 0). The remaining CTCs were analyzed using droplet digital polymerase chain reaction (ddPCR) to profile the expression of prostate-specific genes, the androgen receptor splice variant AR-V7 , and neuroendocrine genes. CTC analyses and pre-treatment PSMA-PET imaging metrics were compared with clinical outcomes. Radiographic progression-free survival (rPFS) was evaluated using Kaplan-Meier analysis and log-rank tests. Results: Blood samples from 24 enrolled patients were analyzed, with a median follow-up of 7.5 months. Median age was 71.5 years (range 53-83). Median CTC count was 5.9 cells/7.5mL blood. Patients with high CTC count (>5.85 cells/7.5 mL) and presence of PSMA-negative CTCs had worse rPFS compared to others, although the difference was not statistically significant (median 86 vs. 393 days, log-rank p = 0.0840). Patients who were AR-V7 -positive before treatment had significantly shorter rPFS compared to AR-V7 -negative patients (median 67 vs. 393 days, log-rank p = 0.0031). Additionally, DLL3 -positive patients had significantly shorter rPFS than DLL3 -negative patients (median 109 days vs. 402 days, log-rank p = 0.0348). Using machine learning, a predictive model was developed incorporating the following factors: mean SUV, CHGA , ARV7 , STEAP2 , DLL3 , AGR2 , and E2F1 . This model demonstrated a high predictive accuracy for treatment outcomes (Low-risk group: median survival 447 days vs. High-risk group: 109 days, log-rank p = 0.0002). Conclusions: The molecular analysis of CTCs in combination with PSMA PET imaging metrics may be useful for predicting the therapeutic efficacy of ¹⁷⁷Lu-PSMA-617 treatment, and warrants validation in additional cohorts.

Assessing HIV transmission knowledge and rapid test history among the general population in Iran

Assessment of cardiovascular (CV) toxicity by providers in advanced prostate cancer (PCa) patients (pts) on novel hormonal therapy (NHT).

125 Background: Addition of NHT, including Abiraterone, Enzalutamide, Apalutamide, and Darolutamide, to androgen deprivation therapy in patients with advanced PCa demonstrated improved survival in large randomized controlled trials. However, NHTs are associated with development of metabolic syndrome and CV toxicity. Treatment related adverse events (TRAEs) may include hypertension (HTN), hyperglycemia, atrial fibrillation, myocardial infarction (MI), congestive heart failure (CHF), and stroke. As such, monitoring for these toxicities by treating providers is essential. Cardio-oncology is an emerging field that addresses CV needs of cancer pts and fosters collaboration between oncologists and cardiologists. Methods: This is a retrospective analysis of 92 pts with advanced PCa, who initiated an NHT in 2022 at the University of California Irvine. Medical records were analyzed for various metrics relating to CV risk assessment performed by treating providers. Results: Pts of 11 different providers, including medical and urologic oncology, were examined. Characteristics of the study population at NHT start are described (Table). Within specific study population subgroups outlined, corresponding provider interventions within 3 months of NHT start are also listed. Conclusions: In this dataset of pts with pre-existing features of metabolic syndrome and CV risk factors at NHT start, only a minority had screening for hyperglycemia, hyperlipidemia, and cardiac dysfunction as well as had counseling about appropriate nutrition or referred to cardiology. Provider education about NHT-related TRAEs and emphasis on early screening for CV toxicity is key. Characteristics of the study population and corresponding provider interventions. Pt characteristic at NHT start % of pts Had lipid panel checked (%) Had hemoglobin A1C checked (%) Seen by cardiology before NHT start (%) Referred to cardiology post NHT start (%) Had documented counseling about nutrition (%) Had echocardiogram (%) Body mass index (BMI) 25.0 - 29.9 50.0 26.1 32.6 23.9 6.5 10.9 23.9 BMI ≥30 21.7 40.0 40.0 35.0 0.0 10.0 30.0 Former or active smoker 41.3 42.1 42.1 23.7 5.3 5.3 34.2 Hx of HTN 69.6 29.7 42.2 29.7 3.1 7.8 23.4 On ≥2 blood pressure (BP) agents 29.3 48.1 55.6 40.7 3.7 3.7 40.7 Hx of hyperlipidemia 64.1 30.5 35.6 28.8 1.7 8.5 25.4 On a statin 51.1 31.9 34.0 29.8 2.1 8.5 27.7 Hx of MI 20.7 36.8 36.8 52.6 0.0 5.3 31.6 Hx of CHF 9.8 44.4 77.8 55.6 11.1 0.0 55.6 Hx of arrhythmia 20.7 42.1 57.9 57.9 0.0 0.0 31.6 Hx of stroke 8.7 25.0 62.5 37.5 0.0 0.0 25.0 Hx of diabetes mellitus (DM) 34.8 34.4 50.0 37.5 3.1 9.4 31.3 On a non-insulin DM agent 38.0 28.6 37.1 28.6 2.9 14.3 25.7 On insulin for DM 14.1 23.1 61.5 23.1 0.0 7.7 15.4

Clinical outcomes for radiographic node-positive prostate cancer following definitive radiotherapy.

352 Background: The incidence of regional lymph node metastases at diagnosis is approximately 15%. Androgen deprivation therapy (ADT) with radiotherapy (RT) remains a standard treatment option, but long-term effects and outcomes are understudied. Methods: Data was retrospectively collected from 304 subjects with radiographic node-positive prostate cancer treated with RT from 2014-2024. Covariates include use of androgen receptor signaling inhibitors (ARSI), use of brachytherapy boost to primary disease in prostate, pre-RT PSA, and Gleason Score (GS). Endpoints included biochemical progression (bPFS), distant metastases free survival (DMFS) and overall survival (OS). Kaplan-Meier method, log rank test, univariate (UVA) and multivariate regression analyses (MVA) were used for time to event endpoints. Results: Patient features are summarized in table. 48% of patients had ECOG 0. On MVA, GS 9-10 was significantly associated with worse OS (HR 2.26, 95%CI 1.15 – 4.43, p=0.02), DMFS (HR 2.37, 95%CI 1.32 – 4.24, p<0.01) and bPFS (HR 2.10, 95%CI 1.23 – 3.59, p<0.01). Worse performance status was associated with significantly worse OS (HR 3.14, 95%CI 1.35 – 7.29, p<0.01), DMFS (HR 2.03, 95%CI 0.95 – 4.35, p=0.07) and bPFS (HR 2.01, 95%CI 0.99 – 4.07, p=0.05). Radiation boost dose to involved lymph nodes was significantly associated with OS (p=0.03) and DMFS (p=0.03) but not bPFS. There were no other statistically significant associations on MVA. There was no significant association on UVA between pre-radiation maximum PSA and OS, DMFS, or bPFS. Conclusions: In this cohort of patients treated with ADT and definitive RT, 5-year DMFS was 67%. Gleason score and age were the strongest prognostic features. There was no significant association, but there was numerically higher survival seen with use of ARSI or brachytherapy boost. Future work includes characterizing patterns of care and failure to help optimize management. Characteristics and univariable regression results for OS, DMFS, and bPFS using age and pre-RT PSA as continuous variables. N (%) 5yr OS HR (95%CI) p-value 5yr DMFS HR (95%CI) p-value 5yr bPFS HR (95%CI) p-value Age (continuous) Median age (IQR) 69 (64 – 75) 74% 1.04 (1.00 – 1.09) p=0.07 67% 1.02 (0.99 – 1.06) p=0.2 65% 1.02 (0.99 – 1.05) p=0.3 Gleason 8 156 (54%) 83% 74% 71% 9-10 135 (46%) 69% 2.05 (1.06 – 3.95) p=0.03 62% 2.17 (1.25 – 3.77) p<0.01 60% 2.06 (1.22 – 3.49) p<0.01 Brachytherapy Use Yes 86 (28%) 80% 0.60 (0.27 – 1.35) p=0.2 79% 0.62 (0.31 – 1.22) p=0.2 79% 0.61 (0.32 – 1.16) p=0.13 ARSI Use Yes 182 (60%) 78% 0.91 (0.50 – 1.64) p=0.7 67% 0.90 (0.54 – 1.50) p=0.7 67% 0.79 (0.48 – 1.29) p=0.3 Volume Nodal Boost – Below median Median (IQR) 16.1 cc (7.3 – 33.9) 76% 0.99 (0.54 – 1.80) p>0.9 72% 0.93 (0.55 – 1.56) p=0.8 68% 1.05 (0.64 – 1.73) p=0.8 Volume of radiographically involved lymph nodes assessed as binary variable.

Paraneoplastic and symptomatic score for prediction of overall and cancer-specific survival in patients with renal cell carcinoma.

527 Background: Patients presenting with symptomatic renal cell carcinoma (RCC) tend to have more aggressive disease and poorer prognosis. Paraneoplastic syndromes (PNS), manifesting as atypical symptoms or abnormal laboratory values, are similarly associated with worse outcomes. However, the impact of symptoms and PNS on prognosis remains unclear. The aim of this study is to develop a Paraneoplastic and Symptomatic Score (PNSS) to better predict prognosis by considering clinical presentation and the presence of PNS at diagnosis. Methods: Prospectively collected data from 5743 T1-T4, N0/1, M0/1 RCC patients treated with surgery across four centers (UC San Diego, IRCCS San Raffaele, Emory University, Tokyo Medical and Dental University) were retrospectively analyzed. The PNSS was developed using preoperative variables: hematuria, flank pain, fever, nausea/vomiting/appetite loss, anemia (<11.5 g/dL for women and <12.5 g/dL for men), hypoalbuminemia (<3.5 g/dL), hypercalcemia (>10.5 mg/dL), elevated De Ritis ratio (AST/ALT>1.25), elevated C-reactive protein (>5 mg/dL), polycythemia (hematocrit >47% for women, >53% for men) and leukocytosis (WBC>11x10^9/L). Patients were stratified into four categories: Low PNSS=0; Favorable-intermediate=1-2; Unfavorable-intermediate=1-2 + Anemia; High PNSS ≥3. Multivariable Cox regression analyses (MVA) tested the association of PNSS categories with overall (OS) and cancer-specific survival (CSS). Kaplan-Meier analysis (KMA) was used to show survival differences among groups. Receiver operating characteristic (ROC) curves and area under the curve (AUC) were used to assess the score's predictive validity for OS and CSS. Results: Of the 5743 patients, 48% (n=2770) were classified as Low PNSS, 29% (n=1656) as Favorable-intermediate, 17% (n=982) as Unfavorable-intermediate and 6% (n=335) as High PNSS. At MVA, increasing PNSS was significantly associated with worse OS and CSS (all p<0.05). High PNSS patients had the highest hazard ratios (HR) for OS [HR=6.5; 95% Confidence Interval (95CI)=4.4-9.5; p<0.05) and CSS (HR=9.6; 95CI=5.4-16.8; p<0.05). KMA showed a clear separation of survival curves across PNSS categories (log-rank p<0.001). Five-year OS rates were 92% (95CI=91-94) for Low, 84% (82-86) for Favorable-intermediate, 68% (65-72) for Unfavorable-intermediate and 47% (42-54) for High, while 5-year CSS rates were 96% (95-97), 91% (89-93), 79% (76-82) and 60% (53-67), respectively. ROC AUCs were 0.70 for OS and 0.71 for CSS, indicating strong predictive accuracy. Conclusions: Increasing PNSS scores were significantly associated with worse oncological outcomes. The PNSS represents a comprehensive tool for predicting overall and cancer-specific survival in RCC patients. Including PNSS in preoperative assessments aids in identifying patients at higher risk and guiding clinical decision-making.

Natural color composition induces oddball P3 asymmetry associated with processing fluency

Prospective COTRIMS (Cologne trial of retroperitoneal lymphadectomy in metastatic seminoma) trial: Final results.

618 Background: Radiation or chemotherapy represent the standard treatment in clinical stage IIA/B seminoma. Despite high cure rates both modalities are associated with significant long-term toxicities. The COTRIMS trial evaluated the oncological and functional efficacy of primary retroperitoneal lymphadenectomy (RPLND) without adjuvant chemotherapy in CS IIA/B seminomas. Methods: 34 patients with CS IIA/B pure semimomas were prospectively recruited. Exclusion criteria were adjuvant chemotherapy following orchiectomy, CS IIC, previous retroperitoneal surgery or radiation, positive tumor markers. All patients underwent nerve sparing RPLND with a unilateral template; no adjuvant chemotherapy was delivered. Follow-up was done according to EAU guidelines. In 22 patients miR371 was evaluated preoperatively and correlated with pathohistology of lymph nodes. The primary endpoint of the study was a relapse-free rate of < 20% at 3 years. Results: Median age is 34.2 (21-54) years, mean and median follow-up is 41.5 (4-73) and 33.4 (13-56) months. 22 and 12 pts had CS IIA and CS IIB, resp. Mean OR-time, blood loss and hospitalisation were 131 (105-195) min, < 150ml and 4 (3-9) days. 4 (11.7%) pts experienced Clavien Dindo 3a complication. Antegrade ejaculation was preserved in 88%. A mean of 19 (7-57) lymph nodes were dissected. Mean number of positive lymph nodes was 1.4 (1-2), mean diameter was 2.3 (0.8-4.1) cm. Seminoma was present in 85%, non-malignancy and nonseminoma were found in 8.9% and 5.9%. miR371 was positive in 17/18 pts with metastases und negative in 3/3 with benign lesions. 4 (11.7%) pts relapsed after 4, 6, 9 and 12 months and all were salvaged by chemotherapy. Conclusions: RPLND results in high cure rates associated with low frequency of surgery – related complication even after a follow-up of about 3 years. Nearly 90% of patients can be managed without systemic chemotherapy. RPLNSD should be included in the treatment options for CS IIA/B seminomas. miR371 appears to be a valid biomarker to predict presence of lymph node metastases. Clinical trial information: DRKS00025384 .

Safety evaluation of stereotactic body radiation therapy (SBRT) during lutetium-177-PSMA-617 (177Lu-PSMA-617) treatment for patients with metastatic prostate cancer.

129 Background: Few studies have explored the use of focal therapies to address select sites of resistant disease in men receiving 177-Lu-PSMA-617 for metastatic castrate resistant prostate cancer (mCRPC). Our institutional practice is to offer SBRT for patients with up to 5 sites of oligoprogression or non-responding lesions while undergoing 177Lu-PSMA-617 (every 6 weeks for 6 cycles total). This is determined by PSMA or choline PET imaging during the course of 177Lu-PSMA-617. Herein, we evaluated the safety of adding target SBRT during treatment with 177Lu-PSMA-617. Methods: This retrospective single institution analysis was conducted via systematic chart review to evaluate for adverse events during or after treatment. Grading of treatment-related adverse events was conducted using Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5). Results: Thirty-one patients receiving 177Lu-PSMA-617 with 51 sites of oligoprogressive or non-responding metastatic disease were treated with SBRT. The median number of sites treated was 1 (range 1-4). Most patients received SBRT immediately after cycle 6 (32%) or after cycle 3 or 4 (42%). Bone was the most commonly treated site of disease (90%) with the majority (54%) of bone sites being spine or sacrum, followed by lymph nodes (10%). Ultimately, 84% of patients completed all 6 cycles of 177Lu-PSMA-617 (range 4-6). The median follow-up time was 19.1 months (IQR 15.5-22.4) after 177Lu-PSMA-617 therapy start. A total of 2 patients experienced a pathologic fracture within the SBRT treatment field that could possibly be related to radiotherapy. One patient experienced a grade 2 neuropathy which may have been related to radiation therapy. Other potential adverse events are listed (Table). Conclusions: Our data demonstrates a low rate of significant toxicity with the use SBRT during treatment with 177Lu-PSMA-617. Further study is indicated to determine the oncologic efficacy and potential late side effects of this treatment strategy. Adverse events. Event All Grades Grade > 3 Any Adverse Event 104 2 Anemia 29 (94%) 0 Low Platelets 11 (35.5%) 1 (3.2%) Any Pathologic Fracture 7 (22.5%) 1 (3.2%) Possible SBRT-related Pathologic Fracture 2 (6.5%) 1 (3.2%) Bone Pain Flare 3 (9.6%) 0 Neuropathy 1 (3.2%) 0

A single-institution experience of pneumonitis in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors.

475 Background: Immunotherapy (IO) has dramatically changed the treatment landscape for patients with metastatic renal cell carcinoma (mRCC). The expanded use of IO in mRCC has led to an increased risk of immune-related adverse events (irAEs) in this population. Pneumonitis is an uncommon but potentially fatal irAE. Data describing the incidence of pneumonitis among mRCC patients treated with IO are sparse and the clinical experience of these patients is not widely described. Methods: We retrospectively identified patients with mRCC who received IO therapy at the University of Virginia and investigated the incidence of pneumonitis in this population. Clinical, radiologic, and pathologic features of pneumonitis were collected and analyzed by a multidisciplinary team of medical oncologists, pulmonologists, and radiologists. Images were reviewed by two independent radiologists. Associations among pneumonitis incidence, therapy received, and patient characteristics were examined using univariate regression models with p-values adjusted using the Benjamini-Hochberg algorithm, as well as associations between clinical and radiologic features of pneumonitis and outcomes. Results: Data were available for 146 patients with mRCC who received IO as first- (n=117) or second- (n=29) line treatment. The overall incidence of pneumonitis in our cohort was 8.9%. Pneumonitis occurred in 9.4% of patients who received IO as first line therapy and 6.9% of second line. Incidence was 10.8% among those treated with IO/IO, 10% with IO/TKI, and 4.7% with IO monotherapy. Fifty-four percent of patients who developed pneumonitis had received prior chest radiation vs 11% who did not develop pneumonitis (p-adj: 0.014). Eight of the 13 pneumonitis cases (61.5%) were grade 1 to 2, and 85% improved/resolved with drug holding and/or steroid administration. Five patients were rechallenged with IO and two experienced recurrent pneumonitis; both cases were grade 2 and resolved with oral steroids. Two patients worsened clinically after initial pneumonitis diagnosis and died during management; cause of death was attributable to pneumonitis in one patient and multifactorial in the other. Radiologic and pathologic features of pneumonitis were diverse and not significantly associated with severity or clinical outcome. Conclusions: Our study describes the variable clinical, radiologic, and pathologic characteristics of IO-associated pneumonitis in a single institution mRCC population. Our analysis suggests that incidence of pneumonitis in our mRCC population may be associated with prior receipt of chest radiation. Most cases of pneumonitis in our study were mild and successfully managed, however two patients had worsening symptoms despite escalating treatment and did not survive. Broader investigation of the incidence, causes, and clinical experience of pneumonitis in mRCC is needed.

Publisher Correction: Nasal carriage of MRSA among clinically affiliated undergraduate students at the College of Health and Medical Sciences, Haramaya University, Ethiopia

A phase 1b, open-label, multicenter study of xaluritamig in patients with biochemical recurrence of prostate cancer after definitive therapy.

TPS435 Background: Biochemical recurrence (BCR) develops in 20%–50% of patients with prostate cancer (PCa) after initial definitive treatment and is associated with an increased risk of distant metastasis and mortality (1). Despite significant advances, the most effective treatments for BCR often involve long-term toxicities, and most patients progress to metastatic disease (2). Thus, there is an unmet need for therapies with durable and deep responses without the long-term side effects and impaired health related quality of life associated with prolonged androgen deprivation therapy (ADT). In different tumor entities bispecific T-cell engagers (BITEs) may have better efficacy and safety in earlier stages of the disease (3). Xaluritamig, a BITE, simultaneously engages the six-transmembrane epithelial antigen of the prostate 1 (STEAP1) expressed on PCa cells and the CD3 complex on T cells, leading to T-cell mediated lysis of the STEAP1 expressing PCa cells. In an ongoing trial (NCT04221542), xaluritamig has demonstrated encouraging responses in patients with metastatic castration-resistant PCa. In the current study, safety, tolerability, and preliminary efficacy of xaluritamig are evaluated in patients with high-risk BCR. Methods: This Phase 1b, open-label, multicenter study aims to enroll approximately 40 patients diagnosed with high-risk BCR following definitive therapy. Eligibility criteria include histologically or cytologically confirmed prostate adenocarcinoma with BCR (defined as screening prostate specific antigen [PSA] ≥1 ng/mL after radical prostatectomy [RP], or ≥2 ng/mL after radiotherapy [XRT]); initial treatment with definitive therapy (either RP or XRT, or both); PSA doubling time of ≤12 months; and no evidence of metastasis in conventional imaging (PSMA-PET only positive imaging is allowed). The study includes a 28-day screening period, a six-cycle treatment period (each cycle lasting 28 days), a safety follow-up visit (30 days post-treatment), and a long-term follow-up period (up to 36 months). Xaluritamig will be administered as a short-term intravenous infusion over six cycles as monotherapy without ADT. Primary outcomes evaluate safety and tolerability through treatment-emergent and treatment-related adverse events. Secondary outcomes assess PSA response rates, time to progression, time to additional therapies, metastasis-free survival, treatment completion, and pharmacokinetics of xaluritamig. Statistical analysis for safety will include all enrolled patients receiving at least one dose of xaluritamig. Enrollment began in September 2024 and is ongoing. 1. Shore ND et al. Prostate Cancer Prostatic Dis. 2024 Jun;27(2):192-201. 2. Nguyen PL et al. Eur Urol. 2015;67(5):825-836. 3. Litzow MR et al. N Engl J Med. 2024;391(4):320-333. Clinical trial information: NCT06555796 .

Finding the Right Partner: Triplet Therapy for First-Line Advanced Biliary Tract Cancers

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice.

Absence of prostate cancer events after 3 years of tailored screening in high-risk individuals with germline pathogenic variants in DNA repair genes.

337 Background: The increasing focus on patient-centered care and the development of precision medicine emphasize the need for alternative screening pathways for high-risk individuals. Family history is a significant risk factor for prostate cancer (PCa), and identifying patients with a genetic predisposition is crucial. The discovery of germline pathogenic variants (PVs) in DNA repair genes (DRGs) underscores the importance of a dedicated screening approach. This study aimed to evaluate the effectiveness and compliance of a tailored screening protocol in that population, incorporating the Prostate Health Index (PHI) and multiparametric MRI (mpMRI). Methods: This prospective study, based on a novel concept of a dedicated screening protocol and funded by AIRC (project IG 2020 ID 25027), was conducted at a tertiary hospital in collaboration with department of Oncology, Urology, Pathology, Radiology, and Medical Genetics. The study included men aged 35-69 with documented PVs in DRGs who consented to participate in the screening protocol. Probands were recruited in two categories: Male relatives of women with PVs in DRGs who were affected by breast or ovarian cancer; Male relatives of men with PVs in DRGs diagnosed with high-grade PCa (ISUP >2). Participants underwent annual PSA testing, PHI assessments, digital rectal examinations (DRE), and mpMRI based on individual risk stratification (PHI<20, 20<PHI<40, PHI>40). Results: Between 2021 and 2024, 102 patients were enrolled, with a median age of 52 years (IQR 46-61). Of these, 100 were from the women’s cohort, and 2 were from the men’s cohort. The median PSA level was 0.9 ng/mL (IQR 0.5-1.7), and the median PHI was 17 (IQR 12.0-23.2). The distribution of pathogenic variants (PVs) included BRCA2 (56.1%), BRCA1 (18.6%), ATM (4.92%), PMS2 (2.94%), and other less frequent PVs. Screening compliance was high, with 95% of patients completing the T1 visit, 86% completing the T2 visit, and 100% completing the T3 visit. Among patients with PHI >20 and <40, 81.5% underwent mpMRI. Only one patient had a positive mpMRI result and underwent a biopsy, which was negative for PCa. An additional three patients underwent biopsy due to clinical suspicion, with all resulting negative. Of those with PHI >40, 66.7% underwent mpMRI and, as per protocol, a biopsy, which also resulted negative for PCa. Interestingly, at T2, 33.3% of patients with PSA >3 had a PHI <20, thereby avoiding the need for mpMRI. Despite no cases of PCa being detected after three years of follow-up, two patients were diagnosed with bladder cancer (BC). Conclusions: This study demonstrated, so far, a low effectiveness in diagnosing prostate cancer (PCa), with no cases identified, in contrast to the results of the referral IMPACT study. However, compliance with the screening protocol was high, and the two cases of bladder cancer (BC) raise new perspectives on the role of PVs in DRGs and their relationship with urological neoplasms. Enrollment in the study is ongoing, and further follow-up may provide additional insights.

Multi-scale differences in landscape connectivity evaluation and protection strategies: a case study of Chongqing, China

Initial report of a randomized trial of post-prostatectomy prostate cancer radiotherapy using either fluciclovine ( ¹⁸ F) or PSMA ( ⁶⁸ Ga) PET/CT for target dose-escalation.

326 Background: Fluciclovine PET-guided prostate cancer (PCa) radiotherapy (XRT) improves failure-free survival (FFS) over conventional imaging (CI) alone in post-prostatectomy (RRP) recurrence (EMPIRE-1, PMID: 33971152). In this randomized trial we explored dose-escalation (DE) to sites of PET uptake (not done in EMPIRE-1) using either fluciclovine or 68 GaPSMA PET/CT-guided XRT and compared cancer control to the fluciclovine PET arm of EMPIRE-1 2Y failure free survival (FFS) of 79.6%. Methods: From 2019-2023, 140 pts w/ PCa with detectable PSA post-RRP & negative CI were stratified by: (a) PSA (<1.0 v ≥ 1.0 ng/mL), (b) adverse path [+ECE, +SV, +margin, +node] (0 v any) & (c) ADT (Y v N) & randomized to XRT directed by fluciclovine (Arm 1) v 68 GaPSMA (Arm 2). In both Arms, XRT decisions were PET determined: (A) extrapelvic (EP) uptake (no XRT); (B) pelvic uptake (XRT to pelvis + prostate bed [PB]); (C) PB only uptake (XRT to PB); & (D) no uptake (XRT to PB). Pelvic dose: 45.0-50.4/1.8 Gy (with optional DE {to PET uptake} up to 56 Gy); PB dose: 64.8-70.2 Gy (with optional DE up to 76 Gy). Failure was defined as in EMPIRE-1. Primary endpoint, declared a priori, was 2Y FFS comparing entire cohort [Arms (1+2)] to the 79.6% 2Y FFS of the fluciclovine PET arm of EMPIRE-1 using Z-test. KM curves for Arms 1 & 2 were compared using log-rank test. Univariate (UV) & multivariable (MV) analyses were performed by Cox proportional hazards model on demographic, disease, & treatment factors. Provider-reported [acute & late, GI & GU] toxicities were compared using χ 2 test. Results: 140 pts were enrolled (Arm 1: 70; Arm 2: 70). Arms were balanced on age, race, PSA, GG, ECE, SV, margin, node, & ADT use. 5 pts in Arm 1 and 1 pt in Arm 2 withdrew before PET. For pts completing XRT (Arm 1: 59; Arm 2: 60), median FU was 2.00 years. For primary endpoint, 2Y FFS for Arm (1+2) 87.4 v 79.6% target from EMPIRE-1 (p=0.018). There were no significant differences in 2Y FFS between Arm 1 v Arm 2 (88.2% v 86.9%, p=0.604). PET uptake in Arms 1 v 2 were: EP: 5 v 8; pelvic+/-PB: 10 v 10; PB only: 47 v 24; none: 3 v 27. Typical PB DE (n=74) was 74 Gy & pelvis DE (n= 16) was 55 Gy. For Arm 1 v Arm 2, covariates reaching p <0.10 on UV analysis were: +SV (p=0.010), +margin (p=0.039), PB uptake (p=0.068), & PB boost (p=0.085), and on MV analyses were: +SV (p=0.004), ADT (p=0.067), +margin (p=0.069), & PB boost (p=0.096). Toxicity was similar & low in both Arms 1 & 2. Conclusions: Although fluciclovine had higher diagnostic yield in the PB & 68 GaPSMA had higher yield for EP disease, both radiotracers had similar yield in the pelvic LN, & both radiotracers had similar impact on FFS in this setting. Integrating either fluciclovine or 68 GaPSMA into post-RRP XRT planning for DE to sites of PET uptake in PB or pelvis resulted in improved FFS over a prior trial in which no DE was performed; other factors may also have contributed to this observed difference. Clinical trial information: NCT03762759 .

Targeting highly aggressive ductal prostate tumours with poly ADP ribose polymerase inhibitor (PARPi) and androgen receptor signaling inhibitor (ARSi) combination therapy.

420 Background: Prostatic ductal adenocarcinoma (DAC) is an aggressive prostate cancer variant, prone to early metastasis at low PSA levels and showing poor response to androgen blockade despite androgen receptor expression. Although DACs do not have any efficacious therapies, DACs frequently harbour DNA damage repair (DDR) mutations. We investigate the efficacy of combined PARP inhibitor (PARPi) and androgen signalling inhibitor (ARSi) therapy in DDR-proficient DAC tumours. Methods: To model DAC, organoids were developed in Matrigel from patient-derived xenografts (PDXs) originating from DDR-proficient radical prostatectomy (287R, 275R) and BRCA2 heterozygous mutant metastatic (201.1) tumours, retaining key histologic and genomic features. These organoids were exposed to different PARP inhibitors (Talazoparib, Saruparib) and androgen signalling inhibitors (Enzalutamide, Apalutamide, Darolutamide) for up to 11 days. Cell viability and growth responses were assessed using PrestoBlue and CellTiter-Glo assays and automated imaging analysis. SynergyFinder software calculated synergy scores for each treatment combination. Results were further validated in vivo using DDR-proficient 287R PDXs. Mechanistic insights were explored through RNA sequencing of 20 DAC and ten acinar radical prostatectomy samples, and four matched DAC and acinar PDXs, with γH2AX immunohistochemistry to examine DNA damage response. Results: Overall, PARPi/ARSi combination treatment significantly reduced organoid viability compared to PARPi alone or ARSi in DDR-proficient and heterozygous BRCA2 -mutant DAC tumours. The levels of synergy were comparable regardless of which PARPi and ARSi agents were combined. In vivo results using DDR-proficient PDX 287R confirmed the efficacy of PARPi + ARSi combination by reducing tumour volume by 58% compared to control ( p =0.0198) and by 40% versus PARPi alone ( p = 0.0326). Mechanistically, RNA sequencing demonstrated upregulation of multiple DDR pathways in DACs compared to acinar prostate tumours, regardless of the DDR status. After treatment with PARPi + ARSI combination, there was an increase in γH2AX compared to the control in the DDR-proficient PDX 287R (mean 1.42 vs 0.5, p=0.0056), suggesting enhanced DNA damage may contribute to the efficacy of the combination treatment. Conclusions: Our results show that PARPi increases the efficacy of ARSi in DAC. This is notable given the poor response of DAC to AR-directed treatments and provides the rationale for a pre-planned phase 1/2 study.

<i>HSD3B1</i> and overall survival (OS) in high-risk non-metastatic (M0) and metastatic (M1) prostate cancer starting androgen deprivation therapy (ADT) in the enzalutamide (ENZ) and abiraterone acetate plus prednisolone (AAP) STAMPEDE phase 3 trial.

234 Background: The HSD3B1 gene encodes for the 3βHSD1 enzyme which regulates the rate-limiting step in potent androgen synthesis from non-gonadal precursors. The missense-encoding adrenal-permissive form of HSD3B1 generates a hyperactive 3βHSD1 enzyme compared to the adrenal-restrictive form. We aimed to test associations with OS for HSD3B1 genotyped patients randomized 1:1 to ADT vs. ADT+ENZ+AAP in the STAMPEDE platform protocol. Methods: HSD3B1 genotype was performed in germline DNA using a validated melting assay. We included patients who donated saliva or white blood cells for translational studies and were not planned for “triplet therapy with” docetaxel. Association between HSD3B1 gene and overall survival was estimated using Cox survival models adjusted for randomised group, age at randomization, WHO performance status, regular aspirin or NSAID use, planned radiotherapy and metastatic disease status. Predictive effect was estimated with the addition of an interaction term. We pre-specified M1 low volume as of primary interest given prior associations in the CHAARTED trial. Results: Germline HSD3B1 genotype was obtained for 259 men in the ADT arm and 335 men in the ADT+ENZ+AAP arm (594 total). 319 (54%) men were adrenal-permissive and 275 were adrenal-restrictive. Adrenal-permissive HSD3B1 was associated with shorter OS (HR, 1.32 [1.04-1.67, p=0.025]), which by pre-specified sub-group analysis was most strongly prognostic in low volume (N=185, HR 1.70 [1.12-2.59], p=0.012) versus M0 (N=248, HR 1.21 [0.74-1.96], p=0.442) or M1 high volume (N=161, HR 1.14 [0.78-1.67] p=0.490) Although, there was no evidence of an interaction between treatment arm and genotype (p=0.800, 0.231 and 0.480 for M0, M1 LV and M1 HV, respectively), the treatment effect in the M1 LV restrictive group was 0.37 [0.19, 0.71] versus 0.7 [0.41, 1.21] in the permissive group. Conclusions: Adrenal-permissive HSD3B1 inheritance is associated with increased risk of death in men starting long-term ADT ± ENZ+AAP in STAMPEDE. This result is consistent with prior analyses of the CHAARTED trial and prostatectomy cohorts. This effect is most notable in M1 LV and not overcome by addition of ENZ+AAP to ADT.