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Abstract Introduction Down-sized inflatable penile prosthesis (IPP) cylinders are used in challenging penile fibrosis scenarios, such as after priapism or prior implant infection. Their role in primary penile prosthesis surgery, however, is not well studied. Objective This study aims to identify factors associated with the use of down-sized cylinders in men undergoing primary IPP placement. Methods We conducted a multicenter, retrospective study on men undergoing primary IPP surgery, categorizing them into a down-sized cylinder group (AMS 700 CXR and Coloplast NB) and a standard cylinder group (AMS 700 CX, AMS 700 LGX, and Coloplast Titan). We collected demographic, intraoperative, and postoperative variables and performed a multivariable analysis. Results 4,389 men were included in the study with a mean age of 62.3±10.3 years. Overall, 1,485 (34%) men had diabetes, and 2,131 (49%) had hypertension. Down-sized cylinders were placed in 406 men (174 CXRs, 232 NBs), while standard cylinders were placed in 3,983. Multivariable analysis indicated that down-sized cylinders were more commonly used in men with diabetes (OR 2.6 [1.9, 3.7], p<0.001) and less frequently in men with hypertension (OR 0.5 [0.4, 0.7], p<0.001). A history of priapism did not significantly impact the use of down-sized cylinders (p≥0.152). Sequential dilation was performed more often with the use of down-sized cylinders (OR 4.0 [2.8, 5.7], p<0.001). Down-sized cylinders were associated with an increased rate of non-infectious complications (OR 1.9 [1.3, 2.9], p<0.001), however, there was no significant association with implant infection (OR 2.1 [0.9, 4.6], p=0.07). Non-infectious complications occurred in 44 (25%) men with down-sized cylinders. In the down-sized group, hematomas occurred in 10 (2.5%) men and wound-related complications occurred in 7 (1.7%) men (Table 1). Cylinder-related complications occurred in 7 (1.7%) men with down-sized cylinders. Device-related malfunctions were seen in 8 (2%) men. Conclusions This study demonstrates that down-sized cylinders are more frequently used in men with diabetes and surgeons should be prepared to place down-sized cylinders in these men. Prosthetic urologists are also more likely to use down-sized cylinders in men requiring sequential dilation likely due to fibrosis or more challenging dilations. Down-sized cylinders are associated with a low overall complication rate. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Intuitive Surgical, Fidelis, Urofill, Boston Scientific, Coloplast, Cynosure, Antares Pharma, Clarus Pharmaceuticals, Acerus Pharma; Endo Pharma.

TPS3184 Background: Replication stress (RS) creates cancer cell vulnerability to which the critical DNA damage response kinase, ATR (Ataxia-Telangiectasia and Rad3-related) responds. ATR senses the stress, halts the cell cycle, and promotes DNA repair to allow proliferation. Alnodesertib is an ATR inhibitor developed to prevent cancer cells from successfully repairing RS and proliferating further. In earlier stages of alnodesertib development, preclinical and translational research demonstrated that tumor cells experience three combined biological insults: irinotecan-induced RS, endogenous RS via ataxia-telangiectasia mutated (ATM) loss, and RS rescue prevention by ATR inhibition. Data from the dose escalation and initial dose expansion cohorts of this trial in a tumor agnostic population showed encouraging results in ATM-negative cancers (confirmed Overall Response Rate of 50% in 20 patients with ATM negative cancers and responses across 8 cancer types including complete responses, Ulahannan et al, AACR 2025). Tumor-specific dose expansion cohorts are now enrolling, including colorectal cancer (CRC) and pancreas ductal adenocarcinoma (PDAC). Methods: Two tumor-specific cohorts are now open, each enrolling approximately 50 patients (pts): ATM-negative CRC and ATM-negative PDAC. Pts will receive the recommended dose of alnodesertib 200mg orally on days 1-3 and 8-10 combined with low-dose irinotecan 60mg/m 2 IV on days 1 and 8, of each 21-day cycle. Tumor tissue is prescreened by immunohistochemistry for ATM protein loss (H score 0) for enrollment eligibility. Pts with CRC must have received a maximum of 2 prior chemotherapies excluding prior trifluridine/tipiracil, fruquintinib, or regorafenib, and pts with PDAC must have received a maximum of 1 prior chemotherapy for advanced disease. Prior targeted agents are allowed and do not count as prior lines of therapy. Key objectives include safety, tolerability, and preliminary efficacy. Clinical trial information: NCT04657068 .

TPS1147 Background: Due to dramatic improvements in neoadjuvant and adjuvant HER2-directed therapy (tx), most patients (pts) with early HER2+ breast cancer are cured. As a result, over half of pts newly diagnosed with HER2+ metastatic breast cancer (MBC) now present with de novo stage IV disease. Anti-HER2 tx has also significantly extended survival for pts with HER2+ MBC, with a subgroup of exceptional responders alive many years (yrs) after diagnosis. However, the paradigm for HER2+ MBC remains non-curative, and pts receive tx indefinitely with significant toxicities and costs. The SAPPHO study is investigating whether an intensification approach of sequential, non-cross resistant anti-HER2 tx followed by tx discontinuation is associated with long-term disease control in pts with HER2+ MBC. Methods: SAPPHO is an open-label, phase II, single-arm trial testing a sequential regimen of non-cross resistant, HER2-targeted tx with curative intent in pts with de novo HER2+ MBC. Eligible pts must have biopsy-proven, de novo MBC with high HER2 expression (3+ by immunohistochemistry). Pts with brain metastases are eligible upon receipt of local tx. Treatment consists of an induction regimen (trastuzumab-pertuzumab-taxane [THP] x 4 cycles, followed by trastuzumab deruxtecan [TDXd] x 6 cycles, followed by trastuzumab emtansine [TDM1]-tucatinib x 4 cycles), followed by a maintenance regimen (HP-tucatinib for 1 yr). Given results from DESTINY-Breast09, the sequence of TDXd-P x 6 cycles followed by THP x 4 followed by TDM1-tucatinib x 4 can be chosen as alternative induction tx per investigator and patient choice. Pts who remain progression-free after completing maintenance will stop all anti-HER2 tx. Endocrine tx will be continued for pts with hormone receptor+/HER2+ tumors. Tumor specimens from breast and a metastatic site are collected at baseline and the end of induction. Serial plasma samples for ctDNA analysis are collected at baseline, during treatment, and during follow-up. The primary endpoint is the probability of being progression-free and off anti-HER2 tx 4 yrs from the start of induction. With a sample size of 72 pts, the study is designed to have 91% power to reject the null hypothesis that the probability of being off anti-HER2 tx and progression-free is less than 24%, with an alternative hypothesis of 40%. Key secondary endpoints are overall survival, overall response rate by modified RECIST 1.1 after induction, and safety. Correlative endpoints include the relationship between ctDNA dynamics and outcomes. Patient-reported outcomes will be analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, distress about cancer progression, perception of benefit and risk of progression. SAPPHO began enrollment in Q3 2024, and the study is open at 4 US sites within the Translational Breast Cancer Research Consortium (NCT05721248). Clinical trial information: NCT05721248 .

7029 Background: Mosun, a CD20xCD3 T-cell engaging bispecific antibody, is approved for relapsed/refractory follicular lymphoma after ≥2 prior lines of therapy. We report an interim analysis and PROs with Mosun SC in elderly/unfit patients with previously untreated DLBCL. Methods: MorningSun (NCT05207670) is a Phase 2, basket study of Mosun SC in patients with B-cell non-Hodgkin lymphoma. In the DLBCL cohort, eligible patients (aged ≥80 years, or 65–79 years and ineligible for chemoimmunotherapy) received outpatient Mosun SC: Day (D) 1 (5 mg), D8 (45 mg) and D15 (45 mg) of Cycle (C) 1, then 45 mg on D1 for up to 17 21-day cycles. Primary endpoint was progression-free survival (PFS) rate at 24 months. Other endpoints included overall survival (OS), objective response rate (ORR), complete response (CR) rate, change from baseline (CfB) in lymphoma symptoms as assessed by the Functional Assessment of Cancer Therapy-Lymphoma subscale (FACT-Lym LYMS; higher scores indicate improvement, a ≥3-point increase is considered clinically meaningful) and safety. Results: Forty-nine patients were enrolled, primarily from community sites (n=34). Median age was 83 years (range: 71–101). International Prognostic Index was 3–5 in 53.1% patients and 18.4% of patients had bulky disease. As of February 10, 2025, the median duration of follow-up was 12.5 months (range: 1.4–30.8). PFS and OS rates at 12 months were 71.3% (95% confidence interval [CI]: 54.8–82.7) and 74.7% (95% CI: 58.5–85.4), respectively. ORR was 73.5% and CR rate was 59.2%. Completion rates for FACT-Lym LYMS were ≥95% at baseline and remained ≥87% at each subsequent timepoint. Patients reported improvement in health-related quality of life (HRQoL) over time, demonstrated by increased mean CfB (standard deviation [SD]) in FACT-Lym LYMS scores: C4D1, 5.1 (9.8); C9D1, 5.6 (11.8); C17D1, 9.8 (11.4). Clinically meaningful improvements in lymphoma symptoms were observed in 53.1% (95% CI: 38.3–67.5) of patients. The most common any-grade adverse event (AE) was injection site reaction (53.1%; all Grade [Gr] 1/2). Gr 3/4 AEs were reported in 65.3% of patients and 8.2% experienced a Gr 5 AE (no Gr 5 AEs were Mosun related, per investigator assessment). Serious AEs occurred in 42.9% of patients. Infection AEs occurred in 49.0% of patients (Gr 1: 4.1%; Gr 2: 28.6%; Gr 3: 16.3%) and resolved in 91.7%. Cytokine release syndrome occurred in 12.2% of patients (Gr 1: 10.2%; Gr 2: 2.0%; all resolved). Updated data with around one additional year of follow-up will be presented. Conclusions: Mosun SC showed promising efficacy with manageable safety in elderly/unfit patients with previously untreated DLBCL in an outpatient setting. Clinically meaningful improvements in lymphoma symptoms suggest that Mosun SC improves aspects of HRQoL in this population. Clinical trial information: NCT05207670 .

5054 Background: Rucaparib significantly improved radiographic progression-free survival (rPFS) versus physician’s choice of docetaxel or an androgen-receptor pathway inhibitor (ARPI) (abiraterone or enzalutamide) in men with BRCA mutations who were chemotherapy-naïve in the mCRPC setting and had received one prior ARPI in the phase 3 TRITON3 trial (NCT02975934). This post-hoc analysis evaluated whether the timing of prior ARPI therapy impacted the efficacy of rucaparib. Methods: Patients were randomized 2:1 to rucaparib (600 mg BID) or physician’s choice of docetaxel or ARPI, after progression on 1 prior second-generation ARPI in any setting. The primary endpoint was rPFS. Outcomes were analyzed according to whether patients received the prior ARPI in the metastatic castration sensitive (mCSPC) or castration resistant (mCRPC) setting. Data cutoff was August 25, 2022. Results: Of the 302 BRCA1/2 patients, 68 received prior ARPI in the mCSPC setting (42 rucaparib; 26 physician’s choice) and 234 in the mCRPC setting (159 rucaparib; 75 physician’s choice). Baseline characteristics were generally similar. Prior treatments in the mCSPC and mCRPC groups, respectively, included abiraterone (73.5% vs 53.0%), enzalutamide (29.4% vs 48.3%), and docetaxel (17.6% vs 24.8%). Median rPFS favored rucaparib over physician’s choice in both groups (mCSPC: 13.6 vs 8.2 months; HR 0.60 [95% CI, 0.32–1.15]; mCRPC: 11.2 vs 5.8 months; HR 0.43 [95% CI, 0.30–0.61]). Median OS was similar between treatments in both settings (mCSPC: 23.2 vs 21.7 months; HR 0.81 [95% CI, 0.47–1.41]; mCRPC: 23.2 vs 21.0 months; HR 0.91 [95% CI, 0.66–1.25]). Treatment-related adverse events occurred at comparable rates (89.6% vs 86.1%). Conclusions: Rucaparib demonstrated efficacy in patients with BRCA-mutated mCRPC, regardless of whether prior ARPI was administered in the mCSPC or mCRPC setting. Clinical trial information: NCT02975934 .

1056 Background: Resistance to HER2-directed therapies remains a major challenge in HER2-positiveMBC. In preclinical models, HER2+ tumors overexpress poly (ADP-ribose) polymerase (PARP), and PARP inhibition induces apoptosis through NF-κB suppression even in the absence of pathogenic mutations in BRCA 1/2 . We evaluated the safety, efficacy, and translational correlates of niraparib combined with trastuzumab in patients (pts) with refractory HER2+ MBC. Methods: This open-label Phase 1b/2 trial (NCT03368729) enrolled pts with HER2+ MBC (IHC 3+ and/or FISH amplified), measurable disease, LVEF ≥50%, and progression on ≥1 prior HER2-targeted therapy; stable CNS disease was allowed. Pts with germline BRCA1/2 mutations or prior PARP inhibitor exposure were excluded. Niraparib 300 mg orally was administered on Days 1–21 of a 21-day cycle with trastuzumab 6 mg/kg IV every 3 weeks (loading dose 8 mg/kg on cycle 1). The Phase 2 portion used a Gehan/Simon two-stage design with early stopping for futility (P0=24%); ≥1 response among the first 20 patients triggered expansion to 40 patients. ORR was assessed by RECIST v1.1, meeting the primary endpoint and allowing response rate estimation with <7% standard error and a two-sided 95% exact CI width of 0.28. Gene expression profiling of paired tumor tissue and peripheral blood mononuclear cells (PBMCs) was performed using the NanoString nCounter Tumor Signaling 360 panel at pretreatment compared to cycle 2. Results: Forty-six pts were enrolled (9/2019–2/2025); 41 were evaluable for response. Pts were heavily pretreated (median 3 prior regimens), including trastuzumab deruxtecan in 22 pts; 33% had brain metastases. Treatment-related adverse events were predominantly grade 1–2 and manageable. Clinical benefit rate (CBR) was 44% (18/41) including 1 complete response, 2 partial responses, and 15 stable disease. Eleven patients achieved disease control ≥ 6 months; 1 patient remained on treatment at data cutoff. Tumor profiling revealed enrichment of a B-cell–driven tertiary lymphoid structure signature with reduced hypoxia signaling in responders. Matched PBMC analyses demonstrated coordinated downregulation of interferon signaling, DNA damage response, metabolic activation, angiogenesis, and resistance pathways in clinical responders, whereas non-responders retained signatures of chronic stress and immune exhaustion. Conclusions: Niraparib plus trastuzumab demonstrated a favorable safety profile and durable clinical benefit in heavily pretreated HER2+ MBC. Integrated tumor and blood-based analyses identify immune-organized tumor microenvironments and systemic immune normalization as key correlates of prolonged response, supporting further investigation of PARP inhibition strategies. Clinical trial information: NCT03368729 .

Expert consensus recommendations from 21 academic centers were established for appropriate radiography utilization at 12 potentially low-yield anatomic sites through a multidisciplinary process endorsed by six major American medical societies.

Abstract INTRODUCTION Research into cognitive dispersion – a cognitive process score measuring the intra‐individual variability (IIV) across a single testing session – suggests utility in neurodegenerative populations. Given widespread deficits observed in sporadic early‐onset Alzheimer's disease (EOAD), however, it is unclear if examining cognitive dispersion shows benefit in this condition. METHODS A total of 309 participants (188 amyloid‐positive EOAD, 43 amyloid‐negative early‐onset dementia [EOnonAD], 78 cognitively normal [CN]) completed neuropsychological testing twice over 12 months. Dispersion‐related differences among groups were assessed, as was cognitive dispersion's capacity to predict domain‐specific cognitive trajectories, and its convergence with imaging biomarkers. RESULTS EOAD participants displayed higher cognitive dispersion than EOnonAD participants, and associations with EOAD‐specific biomarkers. Additionally, cognitive dispersion was associated with 12‐month reliable change across several cognitive domains. DISCUSSION These preliminary results examine cognitive dispersion in sporadic EOAD. When used with baseline cognitive performance, cognitive dispersion measures may enrich future clinical trials in EOAD by enhancing treatment monitoring over time.

Abstract Rationale Acute cellular rejection (ACR) within first-year post-lung transplantation has important implications for prognosis. Calcineurin inhibitors (CNI), including tacrolimus or cyclosporine, along with cell cycle inhibitors (CCI) and steroids, remain the standard immunosuppression regimen post-transplant. Although tacrolimus is used as the primary CNI, target therapeutic levels vary across recipients due to adverse effects and tolerability, sometimes requiring switching over to Cyclosporine. We hypothesized that ACR within the first year is associated with switching CNI from Tacrolimus to Cyclosporine. Methods We performed a cross-sectional study of 255 adult lung transplant recipients between June 2019 to November 2024 at Mayo Clinic, Florida. Demographics, induction regimens, CNI type and their levels (average low and high levels) were compared between the 2 groups. The institutional maintenance immunosuppression regimen is Tacrolimus, Mycophenolate Mofetil (MMF) and prednisone, but could be switched to Cyclosporine if the previous regimen is not tolerated. The primary outcome was ACR &lt;1 year diagnosed based on biopsy and/or clinical criteria. Comparisons between groups were performed using Chi-Square test for categorical variables and t-test or Wilcoxon Rank sum test for continuous variables. Multivariable regression analysis was performed with ACR &lt;1 year as the outcome to adjust for the confounders. Results Our cohort included 255 lung transplant recipients with median age of 63 years, 61% Male, 84% Caucasians, 88% bilateral lung transplant (Further details elucidated in Table 1). A total of 173 (67%) out of 255 patients had ACR &lt;1 year. The group with ACR &lt; 1 year had higher proportion of Interstitial Lung Disease (ILD) (81% vs 68%, p = 0.044), use of Basiliximab for induction (70% vs 55%, p = 0.018), and cyclosporine instead of tacrolimus (23% vs 11%, p = 0.027). Group with ACR &lt;1 year also had higher Antibody Mediated Rejection (AMR) &lt; 1year (15% vs 6.1%, p = 0.041) and higher CLAD (BOS 0p-3: 43% vs 25.6%, p = 0.033) compared to the group without ACR &lt; 1 year (Table 1.1). Multivariate regression analysis showed ILD (adjusted odds ratio, aOR 2.84, 95% CI 1.31 - 6.27, p = 0.008) and use of cyclosporine (aOR 2.55, 95% CI 1.07 - 6.78, p = 0.034) as independent predictors of ACR &lt; 1 year (Table 2). Conclusions The presence of ACR &lt; 1 year was associated with the use of Cyclosporine over Tacrolimus as a maintenance regimen. Also, ACR &lt; 1year was associated with higher AMR and CLAD. Further prospective studies are needed to study this long-term given its significant prognostic implications. This abstract is funded by: Not Applicable

Abstract Rationale Respiratory disease is a major cause of mortality in Down syndrome (DS; trisomy 21, T21). DS is considered a progeroid syndrome, with elevated cellular senescence (SEN) and oxidative stress. Because SEN shapes organogenesis, its dysregulation may impair lung morphogenesis. We previously found SEN/SASP (senescence-associated secretory phenotype) abnormalities in prenatal human T21 lungs. Here, we test whether these alterations persist and change after birth. Methods We analyzed human lung single-nuclear RNA (snRNA-seq) datasets (prenatal and postnatal) to quantify epithelial and mesenchymal SEN/SASP signatures. Sex- and age-matched T21 and non-T21 prenatal and postnatal lungs were studied; fibroblasts were isolated as prenatal human lung fibroblasts (HFLF) and postnatal human lung fibroblasts (HLF). SEN/SASP were measured by RT-qPCR and immunofluorescence (IF) in tissue and HFLF/HLF. HFLF/HLF were assayed for SA-β-gal, oxidative stress (CellROX/MitoSOX), and Ca²+ dynamics (Fura-2 AM). 48h treatments with tunicamycin (1µM, SEN inducer), 4-phenylbutyrate (4-PBA, 2 mM, ER Stress inhibitor), or pyrroloquinoline quinone (PQQ, 20 μM, antioxidant) were performed on T21 and non-T21 HFLF/HLF. Conditioned media (CM) were collected after 48h from untreated cultures and then applied to cells of the opposite genotype for 24, 48, and 72h. Results Overall SEN profile was similar in epithelium and mesenchyme across ages, but pathway signatures differed. Epithelium shows an inflammatory SASP, while mesenchyme shows a less-inflammatory, remodeling/growth-factor SASP. These lineage patterns were more evident postnatally. Whole-tissue IF showed increased γ-H2AX and p21 in T21 vs non-T21 both prenatally and postnatally (p &lt; 0.05). At baseline, T21 HFLF/HLF had higher CDKN1A, CDKN2A, TP53, CDKN2B, and SERPINE1 (p &lt; 0.05; n = 5-6), with increased γ-H2AX/p21 IF (p &lt; 0.01; n = 6), SA-β-gal (p &lt; 0.05; n = 5-6), and ER/mitochondrial stress (p &lt; 0.05; n = 5-6). Fura-2 AM showed greater Ca²+ release in T21 HFLF/HLF at baseline and after acetylcholine (10 μM, p &lt; 0.01; n = 5). Mitochondrial-morphology genes (FIS1, DNM1L, MFN1) were elevated in T21 HFLF/HLF (p &lt; 0.05; n = 6). In T21 HFLF, 4-PBA and PQQ each reduced SA-β-gal (p &lt; 0.01; n = 6). In postnatal HLF, PQQ had the stronger effect (p &lt; 0.05; n = 5). T21 CM induced progressively greater SEN/SASP over 24/48/72h in non-T21 cells (p &lt; 0.05; n = 5-6), while non-T21 CM partially rescued T21-HLF phenotypes at 24h only (p &lt; 0.05; n = 5-6). Conclusion These data indicate that lung senescence in T21 initiates in utero and intensifies after birth and reflects lineage-specific pathways. ER-stress-related mechanisms are more prominent prenatally, while mitochondrial/redox mechanisms are predominant postnatally. This evidence suggests age and lineage-dependent drivers of senescence that may help explain DS lung disease and highlight potential new mechanistic targets. This abstract is funded by: NIH/NHLBI