Browse Articles

Pathogenic germline variant prevalence and genetic testing outcomes in patients with urothelial carcinoma.

741 Background: Urothelial carcinoma (UC) is rarely attributed to hereditary causes, but recent studies suggest inherited factors may play a larger role. Current guidelines recommend considering genetic evaluation in patients with bladder cancer diagnosed at <50 years old or a personal or family history of Lynch Syndrome-associated cancers. However, the full pathogenic germline variant landscape and optimal genetic evaluation criteria in UC remain poorly understood. In this study, we report the genetic testing outcomes and clinicopathologic characteristics of patients with UC who underwent genetic evaluation. Methods: A retrospective analysis of all patients with UC who underwent genetic evaluation and testing at the University of Michigan Cancer Genetics Clinic between 2002 and 2024 was performed. Patients who did not have a UC diagnosis code or did not undergo germline testing were excluded. Genetic testing outcomes, variant prevalence and characterization, and associated clinicopathologic features were recorded. Fisher’s Exact test was used to compare clinicopathologic factors between individuals found to have a pathogenic or likely pathogenic variant (PV/LPV) vs. those with negative or uninformative testing. Results: Among 151 patients referred to cancer genetics, 129 underwent genetic testing. Median age at diagnosis was 59 (IQR: 48-68). Most patients (58%) had non-muscle invasive disease at initial diagnosis; 26% had muscle invasive disease, 9% had metastatic disease, and 7% were unknown. Pure urothelial histology was most frequent (71%). A majority (83%) had primary tumor location in the bladder. The most common reasons for referral to genetic counseling were personal history of multiple cancers (58%), diagnosis at perceived younger age (19%), and suspicion for a hereditary syndrome based on syndromic features (9%). Among all tested patients, 35 (27%) had a confirmed PV/LPV; 18 (14%) had a variant of unknown significance (VUS) only. Most frequent PV/LPV genes were MSH2 (n=8, 6%), BRCA2 (n=5, 4%), CHEK2 (n=4, 3%), APC (n=4, 3%), and MUTYH (n=4, 3%). There were no statistically significant differences in testing outcomes based on age of diagnosis (<65 vs >65, p=0.83; <55 vs >55, p=0.16; <45 vs >45, p=0.61), primary tumor location, stage at initial diagnosis, personal history of other cancers, or first-degree family history of urothelial cancer. Oncoprint visualization will be presented. Conclusions: Among patients with UC referred to cancer genetics who had genetic testing, 27% had a confirmed PV/LPV, although this cohort was a selected population. Age threshold and traditional clinicopathologic features were not associated with genetic testing results. These findings may suggest a broader use of genetic evaluation in UC. Future studies should determine the optimal genetic evaluation criteria in UC given the impact on cascade testing and potential therapeutic implications.

Late onset of apalutamide-related skin toxicity in Black men with advanced prostate cancer: A diverse real-world analysis.

23 Background: Apalutamide (APA)- related skin toxicity is a common adverse reaction of varying incidence by ethnicity 1 . We have limited data on APA-related skin toxicity in Black men due to under-representation in clinical trials 2 . This real-world analysis evaluates APA-related skin toxicity and its differential impact across Black and White men in an ethnically diverse population at two high-volume cancer centers in London, United Kingdom. Methods: We investigated 120 prostate cancer patients treated with APA between 2021 and 2023. Skin toxicity incidence and grading, time to onset and drug discontinuation rates were examined. Adverse event causality was attributed by treating physicians and graded by the Common Terminology Criteria for Adverse Events v5.0 based on body surface area involvement. The cumulative incidence of APA-related skin toxicity and APA discontinuation rates were estimated by Gray’s method. Results: 111 patients were included in our analysis, represented by 35 (31.5%) Black and 76 White men (68.4%). 18 men (16.2%) had pre-existing autoimmune or skin disease. 108 men (97%) commenced APA at 240 mg. At 24-month follow up, APA-related skin toxicity of any grade and Grade 3, were seen in 23 (23%) and 12 men (12%) respectively. There was no significant difference in skin toxicity incidence or severity between Black and White men (Table). The median time to skin toxicity was 179 and 84 days in Black and White men respectively, with late onset (>6 months) events more commonly seen in Black men. APA discontinuation rate due to skin or other Grade 3 toxicity was similar (24-month, 11.4% in Black vs 9.2% in White men). Based on multivariable competing risk analysis, skin or autoimmune disease, or eosinophil count at baseline had no significant impact on incidence or severity of skin toxicity. Conclusions: Late onset of APA-related skin toxicity is seen more commonly in Black men, thus requires clinical vigilance and monitoring. There is no significant ethnicity disparity in incidence or severity for APA-related skin toxicity. No significant risk factors for incidence and severe skin toxicity were identified. Cumulative incidence of APA-related skin toxicity at 6 and 24 months. Skin Toxicity Ethnicity 6-months 24-months p-value Any grade 0.851 White 14% 21% Black 11% 25% Grade 3 0.954 White 9.2% 11% Black 2.9% 13%

Effects of integrating palliative care on the uptake of advance care planning among elderly patients with advanced genitourinary cancers.

49 Background: Integrating palliative care (PC) into oncology has been demonstrated to significantly enhance the quality of life for these patients and facilitating patient decision-making, particularly concerning advance care planning (ACP). ACP is a structured process that ensures patients' values and preferences regarding the end-of-life care are respected, and frequently results in the completion of advance directives (AD). This study aims to evaluate the impact of PC on the uptake of ACP among patients with advanced GU cancers. Methods: A retrospective analysis was conducted using a claims database from Ramathibodi Hospital, encompassing elderly cancer patients who had a medical claim for death between Jan1, 2016, and Dec31, 2021 included 1,013 patients, with 532 males, and a mean age of 72.37 years (60.5-99). Among these, 215 patients (21.2%) received integrated palliative care (PC). 102 patients with GU malignancies, including 44 with TCC, 36 with prostate cancer, 22 with RCC. Of these, 22 patients (21.6%) were treated with PC. The primary outcomes measured were the completion rates of ACP and AD. Secondary outcomes included the utilization of treatments in the 6 months preceding death. Comparative analyzes were performed between the PC and UC groups to assess the impact of PC on these outcomes. Results: Regarding ACP, 78.9% of patients in the UC group engaged in ACP, with a median time of 4.5 days (range: 0-324 days) before death. In contrast, 100% of patients in the PC group engaged in ACP, with a median time of 259.7 days (range: 0-2,077 days) before death. 46.5% of patients in the PC group completed AD, whereas no patients in the UC group completed AD. Patients receiving palliative chemotherapy within 30 days before death were significantly lower in the PC group, with an odds ratio of 3.30 (P < 0.001). In the 6 months preceding death, the PC group exhibited significantly lower ER visits (P = 0.011), inpatient admissions (P < 0.001), and total hospital visits (P = 0.002) compared to the UC group. Conclusions: Integrating palliative care into the oncology treatment framework significantly improves the uptake of ACP among patients with advanced GU cancers. This comprehensive approach not only reduces the utilization of aggressive treatments near the end of life, but also enhances the alignment of medical care with patients' values and preferences. Clinical trial information: COA. MURA2023/258 .

Peculiar spin Hall magnetoresistance in polycrystalline WTe2/Ni80Fe20 heterostructures

Charge–spin interconversion is a key issue in spintronics. It gives rise to a series of new phenomena, such as spin Hall magnetoresistance (SMR). In the present work, we report the peculiar SMR behaviors in heterostructures composed of polycrystalline WTe2 nanoplate and Ni80Fe20(Py) film. We observe a negative SMR, which is contrary to the positive SMR usually measured in heavy metal/ferromagnet bilayers. We further observe a transition from negative to positive SMR with increasing thickness of the WTe2 layer, as well as SMR sign reversal with increasing temperature in heterostructures with thicker WTe2. The peculiar SMR behaviors in polycrystalline WTe2/Py heterostructures are attributed to the interface-induced spin current and its competition with the spin Hall-induced spin current. The findings in this work offer a fundamental input for the future exploitation of heterostructures based on two-dimensional transition metal dichalcogenides.

Adult ADHD predicts intimate partner violence perpetration and victimization irrespective of gender and age

Abstract Understanding the determinants of intimate partner violence (IPV) from perpetrator and victim perspectives has become a major objective of behavioral science. Empirical evidence suggests that adults at risk for Attention-Deficit/Hyperactivity Disorder (ADHD), compared to the general population, tend to have more conflictual partnerships, and the presence of ADHD increases the risk of aggressive behavior. Possible influences of gender have not been sufficiently investigated yet. Using data from an anonymous online survey, this study examined the relationship between ADHD and IPV in 316 male and female individuals with (n = 131) and without (n = 185) ADHD. Multiple linear regression analyses showed that adults at risk for ADHD had more frequently become both victims and perpetrators of IPV compared to the healthy control group. ADHD achieved significant incremental variance over gender and age. Thus, the presence of ADHD seems to be an important risk factor for IPV irrespective of gender and age. Accordingly, research and treatment approaches focusing on ADHD must not neglect the risk of IPV among patients but should offer specific psychological support.

Bone metastases and use of bone protective agents (BPA) for metastatic renal cell carcinoma (mRCC): A contemporary national real-world analysis.

490 Background: Bone Metastases (BM) occur in approximately 30% of mRCC patients (pts) with evidence suggesting that they portend a worse prognosis. Systemic therapies such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICI) are felt to be active in these pts, with radiation therapy (RT) often employed for BM-directed treatment. The evidence for and use of BPAs, such as bisphosphonates and denosumab, is limited in the current ICI era. We investigated the outcomes of mRCC pts with BM and use of BPA in a contemporary real-world cohort. Methods: We analyzed data collected from the prospectively maintained, multi-institutional Canadian Kidney Cancer Information System (CKCis). Patients with clear cell mRCC treated between January 2011-June 2023 were included. Outcomes were compared between BM+ and BM- pts using Cox proportional hazards models. Kaplan-Meier estimates were used to assess time to treatment failure (TTF) and overall survival (OS) adjusted by IMDC criteria. Results: Of 2,307 patients with clear cell mRCC, 893 (39%) had BM+, of whom 691 (77%) underwent RT, and 139 (16%) received a BPA. Median follow-up was longer for BM- patients (34.6 vs 29.1 mos). Significant differences were noted in Karnofsky performance status (> 80%: 84% vs 78%), IMDC risk group (intermediate/poor: 76% versus 82%) use of RT (35% vs 78%), and use of BPAs (2% vs 16%) between BM- vs BM+ pts (all p < 0.05). In our cohort, first-line treatment in BM+ pts was monotherapy TKI (67%), doublet ICI (20%), and combination TKI+ICI (13%). Median TTF was similar in BM- vs BM+ pts: 9.6 vs 8.6 mos (HR 0.92; 95% CI 0.91-1.02). However, median OS was higher in BM- vs BM+ pts: 57.6 vs 35.8 mos (HR 0.67; 0.58-0.76; p<0.0001); this was consistent irrespective of type of systemic therapy. In BM+ pts, those who did not receive BPAs had a lower TTF (7.9 vs 13.4 mos) and OS (34.0 vs 46.0 mos); however, these were not statistically different when adjusted by IMDC criteria (TTF HR 1.2; 0.95-1.51 and OS HR 1.12; 0.85-1.46). There was no significant difference in TTF (HR 0.89; 0.72-1.10) or OS (HR 0.94; 0.73-1.22) in BM+ pts selected to receive RT. Conclusions: BM remain a poor prognostic factor in mRCC in this contemporary cohort of patients. While BPA use was limited, we observed no improvement in TTF or OS in BM+ pts with their use. These data warrant further investigation of BPA in mRCC including assessment of SREs and potential complications.

Nectin-4 and Trop-2 expression as potential therapeutic target in collecting duct carcinoma: Preliminary results from the CICERONE trial (NCT05372302).

587 Background: Collecting Duct Carcinoma (CDC) represents 1% of all renal cell carcinomas (RCC) and is characterized by aggressive clinical behavior and a particularly dismal prognosis. Cabozantinib and platinum-based chemotherapy are active therapeutic options, but survival remains poor with no novel agents approved for the treatment of metastatic disease. Antibody-Drug Conjugate (ADC) targeting Nectin-4 and TROP-2 are dramatically changing the therapeutic landscape of Urothelial Carcinoma (UC). Given the biological and clinical similarities between CDC and UC, we evaluated Nectin-4 and TROP-2 expression in CDC. Methods: CDC tissue samples were collected from patients enrolled in the CICERONE study (NCT05372302), a multicentric trial that aims to define the transcriptomic profile of CDC with the goal of changing the paradigm of CDC management by using biology-driven treatments. Nectin-4 and TROP-2 are surface proteins involved in cell adhesion and proliferation. Their expression was assessed by immunohistochemistry (IHC) using a validated assay with a Nectin-4 antibody (clone M22-321b41.1) and a TROP-2 antibody (Ab227689 by Abcam).Staining area was quantified as a percentage (0–100%) and considered positive if >10% of the tumor surface was stained. Staining intensity was dichotomized into positive and weakly positive, based on a clear distinction from the negative control. Results: 59 tissue samples from patients with diagnosis of CDC were considered eligible after centralized histological review. Fresh or archival tumor tissue was collected from either primary lesion or metastatic sites biopsies at baseline before the start of systemic therapy. Preliminary results demonstrated that Nectin-4 was expressed in 24 out of 59 samples (41%), while TROP-2 positivity was observed in 58/59 cases (98%). Conclusions: CDC appears to be a unique kidney tumor, which lies between UC and RCC clinically and biologically. Here we report for the first time the expression of two potential therapeutic targets in metastatic CDC, Nectin-4 and TROP-2, confirming the similarities between CDC and UC.Based on this encouraging data, along with the interesting results from EV-302 trial, we hypothesize that pembrolizumab in combination with Antibody-Drug Conjugate (ADC) could be active in mCDC and this combo will be assessed in the phase II RePRINT trial (NCT06302569). Clinical trial information: NCT05372302 .

Exploring the efficacy of belzutifan in the treatment of renal cell carcinoma associated with von Hippel-Lindau disease: A comparative analysis with external control arm.

469 Background: Randomized controlled trials are the gold standard for demonstrating treatment efficacy but are not feasible in certain disease settings. In such cases, external control arm (ECA) analysis can be an effective way to interpret experimental treatment results. Our aim, based on a natural history study (NHS), was to develop an ECA for a Phase 2 single-arm trial (LITESPARK [LS]-004) for belzutifan in 61 patients with VHL disease-associated RCC. With a median follow-up of 37.8 months in LS-004, the objective response rate (ORR) for VHL RCC patients was 64% (95%CI: 50.6, 75.8) and the median time to surgery (TTS) was not reached. Methods: The ECA was developed using NHS data for VHL RCC patients undergoing active surveillance at the US National Cancer Institute with up to 5 years of follow-up. Key LS-004 eligibility criteria (e.g., no prior systemic therapy or metastasis) were applied. Propensity score (PS) weighting was used to balance baseline characteristics (age, sex, number and size of RCC, prior surgery and time from prior surgery, VHL mutation status) between LS-004 and ECA, with balance evaluated using standardized mean difference (SMD). PS adjusted point estimates and 95% CI for ORR, assessed by independent blinded committee review using RECIST 1.1, and TTS were estimated. For the ECA, the ORR was evaluated among patients with ≥3 serial scans to allow the opportunity for a confirmed response. Results: The ECA included 244 patients with 178 patients in the ORR analysis. Prognostic factors were well balanced between the ECA and LS-004 with a SMD<0.1 for all covariates. The PS adjusted ORR (95% CI) for LS-004 and the ECA was 63.9% (51.9, 76.0) and 1.5% (0.0, 3.3), respectively. Median (95% CI) TTS was 44.4 (35.7, 51.1) months in the ECA, and not yet reached in LS-004. Conclusions: The magnitude of the treatment effect with belzutifan is large compared with the ECA. Although residual confounding is still possible, including effects of unmeasured confounders, observing such a large effect is unlikely due to chance. The results support the demonstrated antitumor activity and efficacy of belzutifan in the treatment of VHL RCC.

Surgical variables and risk factors associated with urinary leak following partial nephrectomy: Insights from a high-risk population.

604 Background: Urinary leak (UL) is a common complication following partial nephrectomy (PN). This study aims to identify the risk factors and surgical variables associated with the development of UL following PN in a cohort that includes a significant number of patients with hereditary renal cancer syndromes, multiple tumors, and a history of prior PNs. Methods: A retrospective chart review was conducted to identify patients who underwent PN at our institution from January 2006 to December 2023. Clinical, demographic, and surgical characteristics were recorded and analyzed. Statistical analysis was performed with SPSS v.29.0. Results: A total of 1173 PNs were analyzed, of which 89 (7.6%) had a UL. Patients had a median age at time of surgery of 50 [Interquartile range (IQR): 38 - 59] years, and 3 [IQR: 1 - 6] tumors removed per procedure. The robotic approach was utilized in 61.6% of cases, and the most common diagnosis was von Hippel-Lindau disease (47.4%). The frequency of UL was 5.1% for first-time PN, 10.4% for second, and 19.6% for third. Multivariable-adjusted analysis demonstrated an increased risk of UL with 3 rd PN (OR 2.379; p = 0.013), higher intraoperative estimated blood loss (per 100mL: OR 1.016; p = 0.006) and a decreased risk with robotic approach (OR 0.376; p < 0.001). (Table) Overall, 98.9% of UL cases (88 patients) were successfully managed with conservative management (post-op drain and foley), ureteral stent placement, percutaneous drain, or nephrostomy tube. Conclusions: In this cohort, UL is associated with the complexity of the surgery (repeat PN and higher EBL). A robotic approach had a lower risk of UL, while all but one UL were effectively managed non-operatively. Future research should investigate intraoperative and postoperative strategies to minimize this complication. Multivariable-adjusted logistic regression analysis evaluating the association between clinical variables and urinary leak after partial nephrectomy.* OR 95% CI p-value Partial nephrectomy count 1 1 2 1.693 0.973 - 2.944 0.062 3 2.379 1.200 - 4.714 0.013 ≥ 4 1.121 0.326 - 3.848 0.856 Surgical approach Open 1 Laparoscopic 0.324 0.042 - 2.517 0.281 Robotic 0.376 0.225 - 0.631 < 0.001 EBL (per 100 mL) 1.016 1.004 - 1.028 0.006 CI: Confidence interval, EBL: Estimated blood loss, OR: Odds ratio. *Analysis conducted using variables listed as well as age, gender, kidney laterality, race, ethnicity, presence of solitary kidney, surgical technique, total number of tumors removed, and size of largest tumor removed.

Evolution of point defects in Bi2Te3-based materials and performance of thermoelectric modules subjected to <i> <b>γ</b> </i>-irradiation

Bismuth telluride (Bi2Te3), renowned for its exceptional thermoelectric (TE) properties near room temperature, is used in extreme environments such as deep space exploration, leading to extensive attention on the radiation-induced defects to Bi2Te3. However, the evolution of point defects during gamma (γ)-irradiation is still poorly understood. In this paper, we report the evolution of point defects in Bi2Te3 materials subjected to varying doses of γ-irradiation and their impact on TE performance. Precisely, Bi0.5Sb1.5Te3 and Bi2Te2.7Se0.3 materials, along with TE modules, were fabricated and subsequently subjected to γ-irradiation. The segregation of Te elements in Bi2Te3 was observed under low irradiation dose, attributing to the formation of interstitial atom–vacancy pair of Te induced by γ-irradiation. In addition, the formation of point defects has a positive relation with the irradiation dose. The positron annihilation (PA) measurements revealed that the number of vacancies in Bi2Te3 diminished with increasing irradiation dose. The accompanying changes in carrier concentration (nH) and mobility (μH) suggest that γ-ray drives Bi atoms to occupy Te vacancies, forming antisite defects. The TE performance of Bi2Te3 was subsequently evaluated, and the findings revealed a strong correlation with the evolution of point defects. This study provides insights into the damage mechanisms and property alterations of Bi2Te3 materials under γ-irradiation.

Identifying modifiable factors that influence walking in patients undergoing surgery for neurogenic claudication: a prospective longitudinal study

Racial disparities in renal cell carcinoma histology and outcomes: Insights from the French Kidney Cancer Research Network (UroCCR-191).

442 Background: In the U.S., racial disparities in renal cell carcinoma (RCC) are documented for common histologies, highlighting differences in incidence and outcomes between Black and non-Black patients. Such disparities are underexplored in European populations, especially across a broader histology spectrum within a universal healthcare system. We aim to investigate racial disparities in RCC histologies and their outcomes among Black and non-Black patients in France. Methods: We conducted a retrospective cohort study utilizing the UroCCR database, spanning from March 1957 to May 2024. This multicenter study, referred as UroCCR-191, involved 30 tertiary centers in France, analyzing 9,404 patients (338 Black and 9,066 non-Black) with confirmed histology. Patients with unknown racial background or unidentified/multiple histologies were excluded. Histological distribution, demographics, clinical presentations, tumor features, and outcomes were compared. Results: Clear cell RCC (ccRCC) was more prevalent among non-Black patients (68.8% vs 47.6%; odds ratio [OR]: 2.4, p &lt; 0.001). Non-clear cell histologies were more common in Black patients, including papillary RCC (23.1% vs 11.8%, p &lt; 0.001), the rare clear cell papillary renal cell tumor (1.5% vs 0.5%, p = 0.044), and other rare molecularly-defined histologies such as translocation RCC (2.1% vs 0.6%, p = 0.005), FH-deficient RCC (0.6% vs 0.1%, p = 0.067) and renal medullary carcinoma (0.3% vs 0, p = 0.001); all with OR ≥2 and a false discovery rate &lt;0.15. Black patients were younger at diagnosis, with earlier-stage tumors and higher rates of partial nephrectomy. No significant differences were observed in cancer-specific survival; however, Black patients showed better distant recurrence-free survival (hazard ratio [HR]: 0.55, p = 0.020). Race was not an independent prognostic factor when accounting for other clinical variables (Table). Conclusions: Black patients in France exhibit higher incidences of non-clear cell RCC and are diagnosed at earlier stages compared to non-Black patients. The absence of race as an independent prognostic factor, unlike U.S. data, highlights the potential influence of healthcare systems in modulating racial disparities. This underscores the need for tailored RCC management that considers racial backgrounds to refine diagnosis and outcomes. Hazard ratios using multivariate Cox regression for predictors of distant recurrence-free survival. Variable Reference group Comparison group HR 95% CI p -value Race non-Black Black 0.96 0.51-1.79 0.889 Age (years) ≤63 &gt;63 1.25 1.07-1.47 0.005 Sex Female Male 1.29 1.09-1.53 0.004 Nephrectomy type Partial Radical 2.98 2.46-3.61 &lt;0.001 T stage T1 + T2 T3 + T4 2.36 1.96-2.85 &lt;0.001 N stage N0 N1 + N2 2.84 2.25-3.58 &lt;0.001 Fuhrman grade 1 + 2 3 + 4 2.39 1.97-2.91 &lt;0.001 Histology ccRCC non-ccRCC 0.81 0.65-1.01 0.062

CUPID ( ⁶⁴ Cu-TLX592 phase I PK, biodistribution and dosimetry): A proof-of-concept study of TLX592-targeted alpha therapy in prostate cancer.

177 Background: Antibody-based PSMA-targeting therapies have potential to overcome limitations of small molecule approaches such as undesirable off-target side effects. TLX592 utilizes RADmAb technology engineered to optimize clearance rates while retaining advantages of antibody-based approaches including high target selectivity &amp; rapid internalization. 225 Ac is a high energy emitter with a short path length. 225 Ac-PSMA-RADmAb is a "next generation" targeted alpha therapy for patients with prostate cancer (PC) who progress after 177 Lu-based therapy. We report preliminary results from an open-label, first-in-human mass dose escalation study of TLX592 in patients with advanced PC. To demonstrate proof-of-targeting, copper-64 ( 64 Cu), detectable by PET, was used as a surrogate for 225 Ac. Methods: 11 patients with PC confirmed with PSMA imaging as either oligometastatic (≤5 metastatic lesions; Groups 1-3, dose escalation) or higher tumor burden (≥10 metastatic lesions; Group 4) were assigned to the following: 1) 300 MBq, 2mg 64 Cu-TLX592 (n=3); 2) 300 MBq, 2mg 64 Cu-TLX592+8mg unlabeled TLX592 (10mg mass dose; n=3); 3) 300 MBq, 2mg 64 Cu-TLX592+18mg unlabeled TLX592 (20mg mass dose; n=2); or 4) 300 MBq, 2mg 64 Cu-TLX592+18mg unlabeled TLX592 (20mg mass dose, based on dose escalation results; n=3). PET/CT scans were performed 1h±5, 4±0.5h, &amp; 20±4h after infusion for Groups 1-3 &amp; 4h±0.5h, 20±3h &amp; 48±4h after infusion for Group 4. Blood samples were collected before each imaging period, &amp; vital signs were collected before infusion, after infusion, 1h after infusion, &amp; prior to each imaging period. The primary endpoint was tumor-to-healthy tissue SUV &amp; residence times. Secondary endpoints included safety assessments &amp; absorbed radiation doses. Results: TLX592 blood clearance was more rapid than TLX591 (T ½ =19.86+1.96, T ½ =33.65+11.04h, resp.) with similar organ uptake. TLX592 circulating levels increased with mass dose. Whole-body effective dose (mean±SD mSv/MBq) was 0.043±0.007 &amp; 0.042±0.002 in Groups 3 &amp; 4, resp. Residence times for Groups 3 &amp; 4 are shown (Table). At 20h, TLX592 uptake in bone lesions in Group 4 correlated with 68 Ga-PSMA-11 uptake (r=.756, P =.003). No serious adverse events were observed. Conclusions: Preliminary results demonstrate successful proof-of-concept of RADmAb technology, intended for use with therapeutic alpha-emitting radionuclides. Rapid antibody clearance has potential to minimize radiation exposure &amp; augment the safety &amp; tolerability profile of antibody-based therapies. Clinical trial information: NCT04726033 . Residence times (mean±SD) MBq.hr.MBq -1 . Source Organ Group 3 Group 4 Kidneys 0.305±0.059 0.370±0.064 Liver 5.440±1.188 5.443±0.771 Lungs 0.890±0.139 1.227±0.184 Salivary glands 0.005±0.001 0.006±0.003 Bone/red marrow 0.576±0.424 0.513±0.218 Spleen 0.444±0.104 0.470±0.201 Remainder of body 7.615±0.049 9.990±0.448

Impact of the 2012 and 2018 USPSTF statements on prostate cancer screening and metastatic rates in Kaiser Permanente Northern California.

359 Background: To assess how the United States Preventive Services Task Force (USPSTF) Prostate Cancer Screening Statements of 2012 (Grade D - “recommends against”) and 2018 (Grade C - “selectively offering...based on professional judgment and patient preferences”) influenced race-specific rates of PSA screening and metastatic cancer at presentation among screen-eligible men in Kaiser Permanente Northern California. Methods: This is a retrospective study from 2006 to 2022, in screen-eligible (ages 50-69), Kaiser Permanente Northern California members. We compared the race-specific rates of PSA screening and metastatic cancer at presentation before and after the changes in the USPSTF Statements. Results: In 2006 there were 324,950 screen-eligible men (11% Black, 17% Asian, 73% White). In 2022 there were 434,705 screen-eligible men (11% Black, 27% Asian, 63% White). Race-specific, annual screening and metastatic rates are shown (Table). Following the 2012 USPSTF statement, all races experienced similar declines in screening and an increase in metastatic rates which was greatest among Black men. Following the 2018 statement, all races experienced similar increases in screening (with the exception of the time around the pandemic in 2020); yet as of 2022, the rate of metastatic cancer has continued to increase. Conclusions: The 2012 USPSTF Statement (Grade D) was associated with a decline in screening and an increase in metastatic rates among all races, yet was greatest among Black men, a high-risk group. Following the 2018 USPSTF Statement (Grade C), screening rates have increased yet metastatic rates continue to rise and remains greatest among Black men. Biennial race-specific screening and metastatic rates. 2006 2008 2010 2012 2014 2016 2018 2020 2022 Screening Rates(per 100,000 person-yrs) Asian 477 511 512 453 406 370 380 262 432 Black 441 452 468 398 364 328 338 255 381 White 438 461 455 398 354 315 329 242 384 Metastatic Rates(per 100,000 person-yrs) Asian 0.06 0.22 0.08 0.06 0.12 0.20 0.25 0.16 0.34 Black 0.44 0.34 0.33 0.31 0.66 0.76 0.85 0.72 1.18 White 0.26 0.23 0.19 0.17 0.30 0.31 0.42 0.48 0.73

Characterizing the activity of inflammasome genes and their association with oncological outcomes in prostate cancer.

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

The effect of transcranial random noise stimulation (tRNS) over bilateral parietal cortex in visual cross-modal conflicts

Second-line platinum-based chemotherapy (PBT) in patients with metastatic urothelial carcinoma (mUC) treated with first-line pembrolizumab plus enfortumab vedotin (P/EV): A single-center, retrospective study.

785 Background: Although the efficacy of PBT as first-line therapy for mUC has been known for more than 30 years, the recent integration of P/EV as a preferred first-line option prevented the use of evidence-based regimen. Since the available second-line regimens depend on what was given as first-line, we evaluate the efficacy and tolerability of second-line PBT in mUC patients treated with first-line P/EV. Methods: We retrospectively reviewed the medical records of 37 patients with mUC who were treated with first-line P/EV, mostly in clinical trials, between Jan 2022 and Jan 2024 at Samsung Medical Center (Seoul, Korea). Patients with mUC whose disease progressed during or after first-line treatment with P/EV received PBT involving gemcitabine plus either cisplatin or carboplatin (determined on the basis of cisplatin-eligibility). Primary endpoints included safety and response rates. Results: Among a total of 37 first-line P/EV patients, 10 received second-line PBT: gemcitabine plus cisplatin (n = 8) and plus carboplatin (n = 2). The median age was 68 years (range, 48 to 82 years) and the median interval from the last dose of P/EV was 50 days (range, 15 to 89 days). A total of 33 PBT cycles were given (median, 2; range 1 to 6). One patient achieved a complete response and 3 had a stable disease. Although peripheral neuropathy and gastrointestinal toxicities were the most frequently encountered adverse events, safety profile was generally manageable. Median progression-free and overall survivals were 3.4 months (95% CI, 2.3 to 4.5) and 8.0 months (95% CI, 6.1 to 19.9), respectively. Conclusions: Second-line PBT for mUC patients treated with first-line P/EV does not appear highly active but the observation of responders merits further studies in those with medically-fit, platinum-eligible patients.

Time to real-world progression (TTrwP) among patients (pts) with relapsed/refractory (R/R) testicular germ cell tumors (GCT) undergoing palliative chemotherapy (CT) in the United States (US).

628 Background: Pts with R/R testicular GCT are considered to be incurable, having experienced progressive disease (PD) after salvage conventional-dose CT (CDCT) and/or high-dose CT (HDCT). Therapeutic options are limited to palliative CT, with an estimated real-world (rw) overall survival of 8 months from initiation of their first palliative CT regimen. Understanding TTrwP may help further inform clinical care. Methods: The Komodo Research Database (KRD; 01/2016-03/2023) was used to identify adult males in the US with testicular GCT who received palliative CT after salvage CT. TTrwP was estimated using Kaplan-Meier analysis and defined as time from index date (initiation of first palliative CT regimen) to first rw proxy of PD, which included 1) radiation after the first cycle of palliative CT, 2) treatment addition/switch, 3) treatment discontinuation prior to death, 4) hospice admission, or 5) death. Treatments received pre-/post index were described. Results: Among 248 pts receiving palliative CT, 97 (39.1%) had sufficient data to confirm prior salvage CT and, of those, 80 (82.5%) had ≥12 months of potential follow-up for outcome assessment. Median age was 33.0 years and most pts had commercial (51.3%) or Medicaid (42.5%) coverage. Before index, 49 (61.3%) pts were exposed to HDCT with or without CDCT (+/- CDCT) and 31 (38.8%) pts to CDCT only. Index regimens included gemcitabine-oxaliplatin (47.5%), oral etoposide (13.8%), gemcitabine-paclitaxel (13.8%), and gemcitabine-oxaliplatin-paclitaxel (7.5%). Median (95% confidence interval) TTrwP was 3.8 (2.6-4.7) months overall, 3.5 (2.3-4.7) months after prior HDCT +/- CDCT, and 4.0 (1.7-6.6) months after CDCT only. First PD events included radiation (32.5%), treatment discontinuation (31.3%), and treatment addition/switch (22.5%), occurring at a median of 2.8, 2.1, and 4.7 months from index, respectively. Death was observed for 91.3% of pts and occurred at a median of 2.4 months from PD event, including 3 (3.8%) pts with death as their PD event (Table). Conclusions: This study is the first to use rw proxies for PD in claims data to estimate TTrwP in pts with R/R testicular GCT. With no curable treatment options remaining, the short TTrwP highlights the poor outcomes in this patient population and need for novel therapies to improve clinical outcomes. RW PD events observed in pts with R/R GCT (N=80). First PD event N (%) Time to event (months), median [IQR] Death, N (%) Time from PD event to death (months), median [IQR] Radiation 26 (32.5%) 2.8 [1.4 - 4.6] 26 (100.0%) 3.0 [1.9 - 6.3] Treatment discontinuation 25 (31.3%) 2.1 [1.0 - 3.9] 25 (100.0%) 1.8 [1.3 - 3.1] Treatment addition/switch 18 (22.5%) 4.7 [3.0 - 6.1] 16 (88.9%) 3.8 [3.2 - 6.1] Hospice 3 (3.8%) 9.9 [0.5 - 17.1] 3 (100.0%) 0.3 [0.3 - 3.0] Death 3 (3.8%) 30.4 [3.8 - 32.0] 3 (100.0%) 0.0 [0.0 - 0.0] No PD 5 (6.3%) – 0 (0.0%) –

Results of a cross-sectional survey to explore determinants of health-promoting activities among Hispanic/Latino (H/L) patients (pts) with prostate cancer (PCa) on androgen deprivation therapy (ADT).

321 Background: H/L pts with PCa are at an increased risk of developing ADT-related side effects. Diet and exercise can improve PCa-related outcomes, including reducing ADT-related toxicities. However, little is known about individual perspectives on factors impacting engagement in health-promoting behaviors among H/L men with PCa. Methods: We developed a survey to examine sociodemographic characteristics, exercise/dietary habits, motivation for change, and barriers to participate in lifestyle interventions. We surveyed pts with PCa who self-identified as H/L ethnicity, treated at UCSD, and who were either previously or currently on ADT at the time of the survey. Questionnaires were administered in Spanish or English, either in person or by telephone, using interpreter services based on pt preference. Results: Between April and August 2024, 61 pts (median age 66 years) completed the survey with an 88% response rate. Most pts were of Mexican descent (85%), born outside the U.S. (72%), had public health insurance (51%), resided in disadvantaged neighborhoods (54%) based on the Area Deprivation Index, from H/L ethnic enclaves (64%), and were primarily Spanish speakers (51%), with 36% reporting no English proficiency. About half (49%) reported household financial distress, yet 92% felt supported by their community or family during PCa diagnosis. At the time of the survey, 85% of pts were on ADT, 68% had distant metastasis, and 69% had undergone local therapy. Most had a BMI ≥ 30 kg/m2 (52%), diabetes (51%), and 66% had a history of coronary artery disease or a high-risk atherosclerotic cardiovascular disease score of ≥ 20%. Most pts (51%) reported limited dietary monitoring and 71% reported less than 50 min/week of moderate-intensity exercise, with 41% not engaging in any moderate exercise. However, most expressed motivation to initiate lifestyle changes (91% exercise; 83% diet) and 82% showed interest in joining a community lifestyle intervention program. Pts identified participation incentives including family involvement (73%), other H/L participants (77%), Spanish-speaking staff (86% among Spanish speakers), and a driving distance of less than 5 miles. Conclusions: We report that H/L pts with PCa on ADT have substantial cardiometabolic risk factors. While engagement in health-promoting activities was limited, patients expressed motivation to improve health-promoting practices, with actionable incentives to enhance participation, underscoring the need for tailored intervention to mitigate ADT toxicity in this pt population. These findings will inform the design of an interventional study that examines the impact of a combined group exercise and nutrition counseling intervention on physical fitness and cardiovascular health among H/L men with PCa on ADT.

Utility of extended interval dosing of denosumab in patients with metastatic prostate cancer.

68 Background: Bone modifying agents, such as zoledronic acid and denosumab, are commonly used in patients (pts) with metastatic solid tumors to reduce the incidence of skeletal-related events (SREs). The FDA-approved administration schedule for both agents is every 4 weeks, however less frequent administration (i.e. every 12 weeks) is commonly observed in practice due to patient convenience. The efficacy and safety of these extended interval regimens is well-established for zoledronic acid, however there is little evidence available supporting this practice with denosumab. Methods: Pts with metastatic prostate cancer were evaluated for development of SREs during treatment with extended intervals of denosumab. 103 pts evaluated and treated at Indiana University Health between September 2019 and September 2024 were included in this analysis. A historical control group of pts receiving every 4-week dosing was used as comparison (1). SREs were defined as pathologic fracture, spinal cord compression, operation, or radiation to bone. Extended interval dosing is defined as an administration schedule &gt;4 weeks apart on a consistent basis. Results: Median age at starting bone preserving agent was 70.6 years (range, 49.5-90). 24 pts (23.3%) had metastatic castration-sensitive prostate cancer and 79 pts (76.7%) had metastatic castration-resistant prostate cancer (mCRPC) at time of last follow-up. Incidence of SREs in all patients receiving extended interval denosumab was 23.3%. The incidence of SREs in patients with mCRPC receiving extended interval dosing was 26.6%. This compares favorably to historical data with incidence of SRE in the every 4 weeks dosing group at 35.9% (p=0.10). Median time to development of SRE was not estimable when all patients in the denosumab extended interval group were included in analysis. Median time to SRE in the mCRPC extended interval dosing group was 42.8 months and 20.7 months in the historical every 4-week dosing group (p&lt;0.01). SREs identified for all patients receiving extended dosing interval denosumab were pathologic fracture (3, 2.9%), spinal cord compression (1, 1.0%), surgery (2, 1.9%), and radiation to bone (22, 21.4%). Conclusions: Our findings suggest that extended interval dosing of denosumab in patients with metastatic prostate cancer is not associated with an increased risk of development of SREs and may offer convenience for pts. Larger prospective studies are needed to validate these findings. 1. Fizazi K, Carducci M, Smith M, et al. Lancet 2011; 377: 813–822.