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Yeast-derived volatiles orchestrate an insect-yeast mutualism with oriental armyworm moths

Lenvatinib plus tislelizumab as first-line therapy for advanced fumarate hydratase-deficient renal cell carcinoma: A single-center, single-arm, phase II study.

443 Background: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and aggressive subtype of RCC with dismal prognosis. Although bevacizumab plus erlotinib (Beva/Erlo) showed promising anti-tumor activity, treatment option was limited. Date from our retrospective study showed comparable response rates between tyrosine kinase inhibitors plus immune checkpoint inhibitors (TKI/ICI) and Beva/Erlo, while the TKI/ICI group had better overall survival. Here, we reported the preliminary result of an investigator-initiated phase II study evaluating lenvatinib plus tislelizumab for advanced FH-RCC in the first-line setting. Methods: Eligible patients were aged 18-80 years old, diagnosed with pathologically confirmed, unresectable advanced or metastatic FH-RCC, had measurable disease defined by RECIST 1.1 and no history of systemic therapy. A definitive diagnosis of FH-RCC was confirmed when germline or somatic FH mutations were detected via DNA sequencing. All eligible patients received concurrent therapy with lenvatinib 20 mg P.O. daily and tislelizumab 200 mg intravenously every 3 weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was objective response rate (ORR). Secondary end points included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year and 2-year overall survival (OS) rate, and safety. Results: From September 2023 to October 2024, 17 patients were enrolled (male: 14, female: 3). The median age was 37 (24-61). FH germline alteration was identified in 12 patients, while the remaining 5 patients were considered carrying somatic biallelic FH mutations. Thirteen patients had a history of nephrectomy. The most common site of recurrence or metastasis was retroperitoneal space (14/17, 82.1%), followed by bone metastasis (9/17, 52.9%). The median follow up was 7.0 (1.0-12.0) months. Fifteen patients were available for efficacy assessment at data cutoff，fourteen of them had an objective response (ORR 93.3%), and the complete response rate was 20.0% (3/15). The median time to response was 6 weeks. One PFS and OS event occurred. Median PFS and OS were not reached, while 6-month PFS and OS rate were 93.3% and 100% respectively. All grades and ≥G3 AE occurred in 16 (94.1%) and 4 patients (23.5%) respectively. Treatment discontinuation or dosage reduction occurred 8 patients (47.1%). Conclusions: Lenvatinib plus tislelizumab combination showed encouraging anti-tumor efficacy and acceptable toxicity profile. The potential of TKI/ICI/ combination to be recommended as the first-line therapy in advanced FH-RCC patient needs further evaluation. Clinical trial information: NCT05877820 .

The role of cytoreductive radical prostatectomy in the management of patients with metastatic hormone-sensitive prostate cancer.

157 Background: Cytoreductive radical prostatectomy (cRP) has emerged as an alternative treatment option to radiation therapy in men with low risk metastatic hormone sensitive prostate cancer (mHSPC). It was the purpose of our analysis to evaluate if different combinations of androgen deprivation therapy have an impact on pathohistological findings and oncological outcome in men undergoing cRP. Methods: We performed a retrospective analysis of 104 patients who underwent cRP and pelvic lymph node dissection for low volume mHSPC. Prior to cRP, all patients underwent at least 6 months of neoadjuvant systemic therapy with ADT (n=15, 14.4%), ADT + Abi (n=26, 25%), ADT+Apalutamide (n=37, 35.6%), ADT+enzalutamide (n=10, 9.6%), ADT+docetaxel (n=18, 17.3%). We analyzed pathohistology of the cRP and lymphadenectomy specimens and we assessed cancer specific survival (CSS), progression-free survival (PFS), metastatic PFS and overall survival (OS). In addition, surgery related complications and continence were assessed. Results: Mean age was 63 (45-76) years. Median follow-up was 62.1 (2-186) months. Median initial PSA and median PSA at time of surgery was 110 (25-465) ng/ml and 1.25 (<0.01-5.6) ng/ml, resp. Pathohistology of the total group revealed pT0 in 5 (4.8%) pts and pT2a-c, pT3a/b in 16(15.4%) and 83 (79.8%), resp. Pathohistology depending on the type of ADT is given in table 1. pN+ was observed in 45 (43.2%) patients with 1-19 positive lymph nodes and positive surgical margins were identified in 36 (34.6%). Local recurrence was observed in 2 (1.9%) pts. We observed Clavien-Dindo grade III-IV complications in 16 (15.4%) patients. With regard to continence, no, mild (1-2 pads/day) or severe incontinence was observed in 67.7%, 18.2%, and 14.1%, resp. Median OS was 84 months, median clinical progression free survival was 72 months. Conclusions: Based on our data, 75% of patients demonstrate viable and significant prostate cancer despite optimal PSA response to combined neoadjuvant ADT making this a strong argument for local surgical treatment in well selected patients with mHSPC. ADT/apalutamide and ADT/docetaxel are associated with the lowest risk of lymph node metastases making this the preferrable combination. Analysis of CSS, OS and PFS are under way to assess if those findings translate into superior oncological outcome. Surgery related side effects are low if cRP is performed in experienced hands. cRP should be discussed as one option of local treatment in multidisciplinary tumor boards. Pathology dependent on type of ADT. n pT0n (%) pT2a/bn (%) pT2cn (%) pT3a/bn (%) pN+n (%) R1n (%) ADT 15 1 (0.7) 0 2 (13.3) 12 (75) 9 (60) 5 (33.3) ADT + Abi/Pred 26 1 (0.4) 1 (0.4) 3 (11.5) 21 (80.8) 13 (50) 11 (42.3) ADT + Apalutamide 37 2 (0.5) 2 (0.5) 5 (13.5) 27 (73) 7 (19) 7 (19) ADT + enzalutamide 8 0 1 (0.12) 0 7 (87) 6 (75) 3 (37.5) ADT + docetaxel 18 1 (0.5) 1 (0.5) 1 (0.5) 15 (83.3) 7 (38.9) 9 (50)

Metastatic renal cell carcinoma (mRCC) primary refractory patients to first-line IO-TKI and IO-IO combinations (Meet-URO 33 analysis).

499 Background: Immune-combinations have become the cornerstone of the mRCC treatment scenario, but direct comparisons between the different first-line therapeutic strategies are lacking and few real-world data are available in this setting. In this context, little evidence is available on those patients with disease progression as best response (primary refractory), who have very poor prognosis and lower possibility to receive further therapies compared to the overall population. Methods: The Meet-URO 33 study is an Italian retrospective/prospective registry of the first-line setting of mRCC patients from January 2021 (Trial registration: CESC IOV 2023-78, PMID: 38914928) with the aim to answer as many clinical questions as possible. This analysis focused on assessing the baseline clinical characteristics and the survival outcomes of mRCC primary refractory patients to first-line immune-combinations. Results: Among 892 patients enrolled from 40 Italian centres, 166 (13%) primary refractory patients were assessed: 37 (31.9%) received IO-IO combination, 68 (58.6%) received IO-TKI combinations and 11 (9.5%) received TKI. After a mFUP of 6.9 months (mo), mPFS was 2.8 mo and mOS 8.2 mo, with no differences in terms of IO-TKI vs IO-IO combinations (HR for PFS = 0.75, p=0.17; HR for OS = 1.06, p=0.81). According to baseline clinical characteristics, compared to other patients, primary refractory patients have a worse IMDC score (favorable-risk: 7.1% vs 23.8%, poor-risk: 36.3% vs 18.6%, p<0.001), Meet-URO score (group 1: 7.5% vs 19.5%, group 5: 12.9% vs 6.4%, p<0.001) and performance status (ECOG PS 2-4: 19.8% vs 7.9, p<0.001); a higher use of steroids pre-first line therapy (11.2% vs 6.2%, p=0.046); a lower percentage of nephrectomy (50% vs 65.3%, p=0.001), clear cell histology (75% vs 83%, p=0.037) and sarcomatoid features (51.7% vs 58.3%, p=0.066); a higher percentage of lung (69% vs 56.1%, p=0.09), lymph node (55.2% vs 43.4%, p=0.018) and bone metastases (38.8% vs 27.8%, p=0.016); a lower percentage of pancreatic metastases (4.3% vs 9.3%, p=0.076). Primary refractory patients received a higher percentage of IO-IO combination (31.9% vs 19.3%) and a lower percentage of TKI (9.% vs 20.6%) compared to the other patients (p<0.001). Conclusions: These preliminary analyses of the ongoing Meet-URO 33 study show distinct baseline clinical characteristics of primary refractory mRCC patients to current first-line immune-combinations. No survival differences were recorded according to the type of immune-combination (IO-TKI vs IO-IO). A longer follow-up and further enrolment are needed to examine in depth the different performance of immune-combinations in primary refractory mRCC patients.

Impact of site of metastatic involvement on IMDC classification in metastatic renal cell carcinoma patients treated with immunotherapy.

483 Background: The IMDC risk classification is indispensable for managing metastatic renal cell carcinoma (mRCC) patients (pts). However, it was not developed for pts treated with immunotherapy (ICI) and lacks certain clinically relevant prognostic factors. We aim to explore whether the site of metastatic (SM) involvement can improve prognostic accuracy, as organotropism may be dictated by the underlying tumor's biology. Methods: This multicenter retrospective study analyzed ICI-treated mRCC pts from 2015 to 2023. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier and multivariate Cox regression analyses. We developed a new score, IMDC-SM, by incorporating SM independently associated with OS into the IMDC classification. Model fitness was assessed using the AIC and BIC. Results: 525 pts were enrolled (73% male, 87% clear cell RCC, 10% with sarcomatoid dedifferentiation), including 191 (36.4%) pts treated in first line (1L). Among pts in 1L and ≥2L, 25% and 18%, 56% and 60%, and 25% and 22% were classified as favorable risk (FR), intermediate risk (IR), and poor risk (PR) by IMDC, respectively. In 1L cohort, most pts were treated with ICI + ICI (56%) and ICI + tirosine kinase inhibitors (38%). 70% of pts had lung involvement, 50% nodal, 29% bone, 20% adrenal, 17% liver, 16% tumoral thrombosis, 9% pleural, 9% peritoneal carcinomatosis, and 7% pancreatic involvement. Pleural, bone, and adrenal metastases were independently associated with worse OS in the multivariate analysis after adjusting for IMDC classification, age, sarcomatoid or rhabdoid dedifferentiation and histology. These SM were incorporated into the IMDC, adding 1 point for each SM present, to create the IMDC-SM score. Using the IMDC-SM, in 1L setting, 16 pts (8%) were reclassified from FR to IR and 28 pts (15%) from IR to PR Results of mOS and mPFS in 1L using both scores are shown in the table. IMDC-SM demonstrated better performance than the original IMDC classification for both in OS (Table). Within PR pts, those with ≥5 points had the worst mOS and mPFS (7 and 5.8m) than the remaining PR pts (24 and 14m). When applying the SM-IMDC in ≥2L pts 31 (9%) were reclassified from FR to IR, 66 pts (20%) from IR to PR and 1pt (0,2%) risk changed from FR to PR. The IMDC-SM classification also shows a superior prognostic value (Table). Conclusions: Combining site of metastasis information with the IMDC classification into a single scoring system significantly improves prognostic accuracy in ICI-treated mRCC pts, in both 1L and 2L. A validation cohort is necessary to determine a prediction model’s reproducibility. Group Risk Score 1L 2L N mOS (m) mPFS (m) N mOS (m) mPFS (m) FR IMDCIMDC-SM 4731 NANA NANA 5927 3748 1015 IR IMDCIMDC-SM 9684 4254 1318 198164 2026 88 PR IMDCIMDC-SM 4876 1521 1212 76142 58 33 OS-AIC IMDCIMDC-SM 691.5686.2 2404.72397.5 OS-BIC IMDCIMDC-SM 696.2690.9 2411.72404.5

Polymerization of proanthocyanidins under the catalysis of miR397a-regulated laccases in Salvia miltiorrhiza and Populus trichocarpa

Regional and racial disparities in testicular cancer-related mortality among HIV/AIDS adults in the United States and Texas: A 21-year retrospective study (1999-2020).

624 Background: Men with HIV/AIDS have a significantly higher risk of developing germ cell tumors (GCT), with a notable increase in the incidence of testicular cancer (TC). We aim to study the annual trends and sociodemographic factors in testicular cancer-related mortality in individuals with HIV/AIDS in the United States and its state of Texas from 1999 to 2020 to analyze public health initiatives and to identify areas requiring targeted intervention and prevention strategies. Methods: Mortality trends in TC among HIV/AIDS adults aged ≥25 years were analyzed using CDC WONDER database, identifying through ICD-10 codes C62.9 “Testicular neoplasms” and B20 “HIV/AIDS”. Crude and age-adjusted mortality rates (AAMRs) per 100,000 people were extracted. Annual percent changes (APCs) in AAMRs, with 95% confidence intervals, were determined using joint point regression analysis across various demographic (sex, race/ethnicity, age) and geographic (state, urban-rural, regional) subgroups. Results: Between 1999 and 2020, 89721 documented deaths were attributed to TC due to HIV. The overall AAMR for TC-related mortality in HIV/AIDS adults increased in the US from an adjusted rate (AR) 0.8 in 1999 to (2.9) in 2004 (APC: 4.17%; 95% CI: -2.76% to 38.8%), then it decreased to 1.5 in 2020 (APC: -5.01%; 95% CI: -15.5% to -3.94%). In Texas, AAMR for TC in immunocompromised adults increased from AR 1.5 in 1999 to 3.5 in 2001 (APC: 42.3%; 95% CI: 10.5% to 74.8%), after which it decreased to 1.9 in 2020 (APC: -0.03%; 95% CI: -1.47% to 1.89%). The AAMR in U.S. men increased from 1.4 in 1999 to 4.1 in 2001 (APC: 27.6%; 95%CI: -1.34% to 59.1%) and then decreased to 2.4 in 2020 (APC: -3.99%; 95% CI: -6.09% to -3.27%). The non-Hispanic (NH) Black or African American (AA) (4.9) population has the greatest AAMR, followed by the NH American Indian or Alaska Native (1.9) and the Hispanic or Latino population with AAMR (1.7). The lower-risk population was NH White with AAMR (0.9) and NH Asian or Pacific Islander (0.4). AAMR also varied by region (South: 1.9; Northeast: 1.5; West: 1.3; Midwest: 1) and metropolitan areas had higher AAMR (large central metropolitan: 2.3; large fringe areas: 1.4) than non-metropolitan areas (small metro: 1.1; micropolitan: 1.1; non-core areas: 1.2). The states in the upper 90th percentile of AAMRs were New York, Maryland, South Carolina, Georgia, Florida, Mississippi, Louisiana, and New Jersey exhibited an approximately two-fold increase in AAMRs, compared to states falling in the lower 10th percentile i.e Idaho, Wyoming, Utah, Wisconsin, Minnesota and North Dakota. Conclusions: Mortality rates from testicular cancer among HIV/AIDS adults have declined in the United States and Texas over the past two decades. However, NH Black or AA, NH American Indian or Alaska Native, Hispanic or Latino men are at more risk than NH White and NH Asian or Pacific Islander.

Radiographic progression without PSA progression in advanced prostate cancer patients.

213 Background: Androgen Receptor Pathway Inhibitors (ARPIs) are frequently combined with Androgen Deprivation Therapy (ADT) to treat prostate cancer patients (pts) with castration sensitive (CSPC) or castration resistant (CRPC) disease. We sought to characterize pts who experienced radiographic progression without PSA progression (R-PD) while under treatment with ADT with or without an ARPI. Methods: We undertook a retrospective analysis of two phase 3 trials testing apalutamide (Apa) + ADT vs Placebo (Pbo) + ADT: TITAN (NCT02489318) in pts with metastatic CSPC (mCSPC) and SPARTAN (NCT01946204) in pts with non-metastatic CRPC (nmCRPC). We compared pts with R-PD with pts who experienced PSA progression before or concurrently with radiographic progression (PSA-PD). Kaplan-Meier and Cox proportional-hazard models were used to estimate time-to-event and hazard ratios. Results: The distribution of types of progression, and location of R-PD by study is shown in the table. Pts with R-PD had shorter overall survival (OS) compared with PSA-PD pts in both studies (median OS R-PD vs PSA-PD: 22.9 m vs 37.4 m in TITAN; 49.8 m vs 53.7 m in SPARTAN). Compared with Pbo, Apa delayed the time to R-PD in both studies (HR 0.51, 95% CI: 0.36 to 0.73 in TITAN; HR 0.17, 95% CI: 0.1 to 0.28 in SPARTAN). No pre-treatment variables predictive of R-PD vs PSA-PD were identified; transcriptional profile analysis is ongoing. Conclusions: Radiographic progression in the absence of PSA progression is not uncommon amongst patients with advanced prostate cancer, and carries a poor prognosis. The addition of Apa prolongs the median time to R-PD. Our findings underscore the importance of monitoring these pts with imaging, independent of PSA dynamics. The impaired survival of R-PD pts warrants evaluation of new therapeutic approaches for these pts. OVERALL TITAN (mCSPC; n=1052) SPARTAN (nmCRPC; n=1207) % pts with R-PD 12.4% 10.4% % pts with PSA-PD 41.2% 45.4% Sites of progression in R-PD pts (% of randomized pts) Bone only 6.3% 1% Non-bone 6% 8.8% Both 0.1% 0%

Effects of emerin dysregulation on the very-small-nuclear phenotype and neuronal differentiation and its association with a clinically aggressive subtype of prostate cancer.

207 Background: Circulating tumor cells (CTCs) with a very-small-nuclear (vsn) phenotype (i.e., vsnCTCs) in prostate cancer (PCa) represent a distinct subset of CTCs characterized by nuclei smaller than 8.5 μm. Our previous studies established a link between vsnCTCs and the presence of visceral metastasis. Emerging evidence suggests that the reduction of emerin (EMD), a nuclear envelope protein, contributes to PCa metastasis and is associated with nuclear shape instability. This study aims to validate vsnCTCs as a biomarker in metastatic castration-resistant prostate cancer (mCRPC) and investigate the correlation between EMD expression and the vsnCTC phenotype. Methods: CTCs were isolated from 93 mCRPC patients using the NanoVelcro CTC assay and categorized as either vsnCTC-positive (vsnCTC+) or vsnCTC-negative (vsnCTC-). We compared overall survival (OS) and progression-free survival (PFS) between these two groups. In vitro experiments were conducted using PCa cell lines (C4-2B, 22Rv1, and DU145) with EMD knockdown via siRNA or shRNA to study its impact on cellular phenotypes. Additionally, we measured EMD expression and nuclear size in abiraterone- and enzalutamide-resistant (Abi-R/Enza-R) C4-2B cells. Results: vsnCTC+ patients had significantly worse OS and PFS compared to vsnCTC- patients. Multivariate analysis revealed that vsnCTC+ status was independently associated with poorer OS and PFS. EMD expression was markedly reduced in CTCs from vsnCTC+ patients compared to vsnCTC- patients, with a significant positive correlation between EMD expression and CTC nuclear size. EMD knockdown in PCa cells resulted in smaller nuclei, enhanced invasion, and the upregulation of genes associated with neuronal de-differentiation (e.g., SOX2, CHGA, MYCN, and AURKA). Additionally, C4-2B Abi-R/Enza-R cells had significantly smaller nuclei and lower EMD expression, consistent with our clinical observation of the vsnCTCs association with ARSI resistance. These resistant cells also demonstrated elevated expression of neuronal de-differentiation genes. Conclusions: The presence of vsnCTCs represents a novel hallmark of an aggressive subtype of mCRPC, closely linked to EMD dysregulation and neuroendocrine differentiation. These findings highlight the potential of vsnCTCs and associated biological changes as a predictive biomarker. Our findings underscore the importance of EMD in the progression and therapeutic resistance of advanced PCa.

Quality of Treatment Selection for Medicare Beneficiaries With Cancer

PURPOSE The Medicare part D Low-Income Subsidy (LIS) improves access to oral cancer drugs, but provides no assistance for clinician-administered/part B drugs. This analysis assessed the association between LIS participation and receipt of optimal cancer treatment. METHODS We investigated initial systemic therapy using SEER-Medicare data (2015-2017) and National Comprehensive Cancer Network (NCCN) Evidence Blocks (EB) as the standard for treatment recommendations. We included cancer clinical scenarios wherein (1) ≥one treatment was optimal (higher efficacy and safety scores) versus other treatments; (2) identifiable in SEER-Medicare (eg, not defined by clinical data unavailable in registry data or claims); and (3) both EB and ASCO Value Framework agreed regarding optimal treatment. We fit logistic regression models to assess the association between receipt of systemic therapy ( v no therapy) and patient and provider characteristics. Contingent on receipt of treatment, we modeled the likelihood of receiving a treatment ranked (by EB scores) within the highest or lowest quartile for that cancer type. RESULTS Nine thousand two hundred and ninety patients were included across 11 clinical scenarios. Fifty-seven percent (5,336) of patients received any systemic therapy and 43% (3,954) received no systemic therapy. Compared with non-LIS participants, LIS participants were less likely to receive any systemic therapy versus no systemic therapy (odds ratio, 0.64 [95% CI, 0.57 to 0.72]). Contingent on receiving systemic therapy, LIS participants received treatment ranked within the worst quartile 24.8% of the time, compared with 21.9% of non-LIS patients (adjusted prevalence difference, 4.3% [95% CI, 0.5 to 8.2]). CONCLUSION LIS participants were less likely to receive systemic therapy at all and were more likely to receive treatments that receive low NCCN EB scores.

Intercellular bridges are essential for transposon repression and meiosis in the male germline

Low-dose abiraterone in metastatic castration-resistant prostate cancer.

164 Background: Abiraterone acetate (AA) is a selective and irreversible inhibitor of CYP17 approved for locally advanced and metastatic prostate cancer. The standard dose is 1000 mg orally while fasting. However, AA has a significant food effect, with serum levels increasing 5-7 times with a low-fat meal. Data suggest that a lower dose (250 mg with food, AALD) provides similar oncological outcomes to the standard dose, with a 75% cost reduction. In Brazil, 80% of patients are treated through the national public healthcare system, which does not afford AA in its label dose. Hospital de Base incorporated AALD since March 2021.Herein we present the data of patients with metastatic castration resistant prostate cancer treated with AALD. Methods: We retrospectively reviewed patients with mCRPC who received AALD at any treatment line, regardless of prior chemotherapy, from March 2021 to May 2023. The primary endpoint was PSA response rate (defined as a decrease of ≥ 50% in PSA concentration after 12 weeks of treatment). Secondary endpoints included time to treatment failure (TTF), overall survival (OS), and PSA response rate ≥ 50% at nadir. Data were summarized in medians, means and proportions. Chi-square was used for associations. Survival was calculated through Kaplan-Meier method. Cox-proportional hazards was used to compare groups. A p < 0.05 was considered statistically significant. Results: Ninety-six patients were included. The median age was 75 years (IQR 12.5), and most had an ECOG scoreof 1 (52.1%). Sixty-three patients (65.6%) received AALD in first-line, 26 (27.1%) in second-line, and 7 (7.3%) in third-line or beyond. The median PSA level before AALD was 20.9 (IQR 98.7). Twenty-seven patients (28.1%) had received docetaxel in mCRPC. After a median follow-up of 24.4 months, 53 patients (60.2%) had a ≥ 50% PSA response at 12 weeks, and 65 (69.9%) achieved a reduction of ≥ 50% at nadir. Patients treated with AALD pre-docetaxel had a higher PSA response at 12 weeks (68.3% vs. 40%, p = 0.015) and at nadir (76.1% vs. 53.8%, p = 0.036). First-line AALD was associated with better PSA responses. The median TTF was 7.9 months (5.5 – 10.3), and the median OS was 20.6 months (14.1 – 26). Achieving a ≥ 50% PSA response at 12 weeks was associated with improved TTF (13.6 vs. 4.6 months, HR = 0.37, p < 0.001) and OS (28.9 vs. 12.2 months, HR = 0.44, p = 0.004). Conclusions: AALD showed meaningful efficacy and survival outcomes. We advocate for AALD, particularly in settings where the standard dose is not affordable.

The Man Van phase 2 results: Mobile targeted case finding for prostate cancer.

317 Background: Early intervention is potentially lifesaving in prostate cancer and is a major limitation of cancer outcomes with ethnicity and deprivation being determinants of inequalities that impact outcomes. The Man Van is designed to address health inequalities and barriers to accessing healthcare that affect prostate cancer with novel community-based targeting of high-risk groups using a mobile clinical unit. These inequalities are particularly relevant for men from ethnic minorities and lower socio-economic groups. Methods: A bespoke nurse-led mobile clinical unit was moved to community-based locations in areas of high deprivation indices in London (UK) with targeted invitations to high-risk men. Men were offered prostate-specific antigen (PSA) tests and a general health check including: blood pressure, body mass index and an HbA1c test for diabetes. Results: Between January 2023 and January 2024, 3379 men attended a Man Van clinic (non-attendance rate 15.1%). The median age of attendees was 59 years (range 39-97). 36.4% of attendees were non-White including 16.7% of men who were Black. The median IMD rank was within the 6 th lowest decile. 310 men were referred for prostate cancer investigations, 262 had prostate MRI scans. 139 (53.1%) of MRIs were PIRADS 1/2, 35 (13.4%) PIRADS 3, 85 (32.4%) were PIRADS 4/5. 3 (1.1%) scans could not be scored. 127 patients underwent a prostate biopsy (48.5% of men having an MRI scan), with 94 prostate cancers diagnosed (74.0% of biopsies). 81 (86.2%) of these were cancers with clinically significant disease, being grade group 2 (i.e. Gleason 7) or higher (all with >5% pattern 4 Gleason scores). The overall diagnostic rate of clinically significant disease was 2.8%. No prostate cancers were metastatic at presentation, with only one being T4. Of the men diagnosed with prostate cancer (N=94), 25 (26.6%) were managed with active surveillance, 2 (2.1%) were managed with cryotherapy, 2 (2.1%) were managed with low dose-rate brachytherapy, 39 (41.5%) underwent robotic prostatectomy and 26 (27.7%) underwent radiotherapy. 59 patients were referred on two week wait pathways for haematuria (visible or persistent non-visible). One bladder cancer (TCC) was diagnosed (G3pT1bN0M1). 43 patients (2%) were diagnosed with diabetes, 207 patients (11%) with pre-diabetes. Conclusions: The Man Van initiative is a novel method of linking primary and secondary care for a range of health checks, including PSA. With a streamlined and more efficient service we have maintained high uptakes for health checks a willingness to engage with health improvement measures from deprived and ethnic minority groups. As well as comparatively high levels of prostate cancers diagnosed at early stages, high levels of other health conditions were found; improving the economic value of the service. Clinical trial information: NCT06357416 .

Prevention, diagnosis, and management of penile cancer in the LGBTQ+ community: A systematic review and meta-analysis.

2 Background: Penile cancer is a rare but significant malignancy with unique prevention, diagnosis, and treatment challenges within the LGBTQ+ community. This systematic review and meta-analysis aims to evaluate the existing evidence on penile cancer for LGBTQ+ individuals, addressing disparities and unique needs to improve clinical outcomes. Methods: Following PRISMA 2020 guidelines, a systematic search was conducted across PubMed, Embase, Scopus, and clinical trial registries up to September 2024. Studies were included if they involved penile cancer prevention, screening, or treatment in LGBTQ+ populations, with no restrictions on study design or language. Data extraction focused on epidemiological patterns, risk factors (e.g., HPV infection), screening practices, diagnostic approaches, treatment modalities, and outcomes. The risk of bias was assessed using the Newcastle-Ottawa Scale for cohort studies and the Cochrane risk-of-bias tool for randomized controlled trials. The meta-analysis used a random-effects model to pool prevention and treatment outcomes data. Results: Of the 872 studies screened, 18 met the inclusion criteria, encompassing 1,232 LGBTQ+ patients. High-risk populations included men who have sex with men (MSM) and transgender women with elevated rates of HPV-associated penile cancer. HPV vaccination was underutilized in these populations despite its potential to prevent penile cancer. Early diagnosis was often delayed due to stigma, lack of awareness, and healthcare access barriers. Treatment outcomes varied, with higher rates of post-surgical complications and psychological distress reported. Meta-analysis revealed that HPV vaccination reduced the risk of penile cancer by 60% (pooled relative risk: 0.40, 95% CI: 0.25-0.64), while early surgical intervention improved 5-year survival rates by 45% (HR: 0.55, 95% CI: 0.32-0.79). Conclusions: Penile cancer prevention and management in LGBTQ+ populations require tailored strategies, including increased HPV vaccination coverage, early screening, and culturally competent healthcare. Addressing barriers related to stigma and healthcare access could significantly improve outcomes. Further research is needed to optimize treatment protocols and incorporate LGBTQ+-specific considerations in penile cancer care. Summary of meta-analysis results. Outcome Measure Number of Studies Pooled Effect Estimate 95% Confidence Interval (CI) Heterogeneity (I²) % HPV Vaccination Effectiveness 8 Relative Risk (RR): 0.40 0.25–0.64 42 Barriers to Early Diagnosis 5 Odds Ratio (OR): 2.25 (higher risk) 1.45–3.51 38 Post-Surgical Complication Rate 4 Risk Ratio (RR): 1.30 (higher rate) 1.12–1.50 27 Psychological Distress Post-Treatment 3 Standard Mean Difference (SMD): 0.75 0.50–1.00 60 5-Year Survival Improvement with Early Surgery 6 Hazard Ratio (HR): 0.55 0.32–0.79 49

EV-302: Updated analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC).

664 Background: EV-302 /KEYNOTE-A39 (NCT04223856) demonstrated significant progression-free survival (PFS) and overall survival (OS) benefit with first-line (1L) EV+P vs chemo in patients (pts) with la/mUC. EV+P is the standard of care (SOC) in global treatment guidelines for pts with untreated la/mUC. We present 12 mo of additional follow-up for EV-302 (>2 y of median follow-up) and an exploratory analysis of pts with confirmed complete response (cCR). Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive EV (1.25 mg/kg; Days 1 and 8; IV) and P (200 mg; Day 1; IV) or gemcitabine with cisplatin or carboplatin every 3 wks. Dual primary endpoints were PFS by blinded independent central review (BICR) and OS. Select secondary endpoints were confirmed objective response rate (cORR), duration of response (DOR), and safety. An exploratory analysis evaluated treatment outcomes and safety in pts with cCR. Results: 886 pts were randomized to receive EV+P (n=442) or chemo (n=444). At data cutoff (Aug 8, 2024), median follow-up was 29.1 mo (95% CI, 28.5-29.9). PFS by BICR (HR, 0.48 [95% CI, 0.41-0.57]) and OS (HR, 0.51 [95% CI, 0.43-0.61]) were improved in the EV+P vs chemo arms (Table). OS benefit was seen irrespective of cisplatin eligibility or presence of liver metastases (mets). In the response-evaluable set, cORR was 67.5% for EV+P and 44.2% for chemo. Median DOR was 23.3 mo (95% CI, 17.8-not estimable [NE]) for EV+P and 7.0 mo (95% CI, 6.2-9.0) for chemo. 30.4% of pts in the EV+P arm and 14.5% in the chemo arm achieved cCR. Median duration of cCR was not reached for EV+P and 15.2 mo (95% CI, 10.3-NE) for chemo. Grade ≥3 treatment-related (TR) adverse events (AEs) in the EV+P vs chemo arms occurred in 57.3% vs 69.5% of pts in the safety analysis set (Table) and 61.7% vs 71.9% of pts in the cCR subgroup, respectively. TR deaths occurred in 1.1% vs 0.9% of pts in the safety analysis set in the EV+P vs chemo arms, respectively; none occurred in the cCR subgroup. Conclusions: EV+P continues to demonstrate superior efficacy vs chemo in a broad population, consistent with the primary analysis. Results confirm durable EV+P efficacy with no new safety signals, reinforcing EV+P as SOC for the 1L treatment of pts with la/mUC. Clinical trial information: NCT04223856 . Key efficacy and safety outcomes. EV+P Chemo EV+P vs chemo Efficacy (intent to treat set) n mo n mo HR (95% CI) Median PFS 442 12.5 (95% CI, 10.4-16.6) 444 6.3 (95% CI, 6.2-6.5) 0.48 (0.41-0.57) Median OS 442 33.8 (95% CI, 26.1-39.3) 444 15.9 (95% CI, 13.6-18.3) 0.51 (0.43-0.61) Cisplatin eligible 244 36.7 234 18.7 0.54 (0.42-0.70) Cisplatin ineligible 198 25.6 210 12.7 0.50 (0.39-0.64) Liver mets present 100 19.1 99 10.1 0.56 (0.40-0.78) Liver mets absent 342 39.3 345 18.3 0.50 (0.40-0.62) Safety (safety analysis set) n n Grade ≥3 TRAE 440 252 (57.3%) 433 301 (69.5%) –

ER-mitochondria contacts mediate lipid radical transfer via RMDN3/PTPIP51 phosphorylation to reduce mitochondrial oxidative stress

Impact of loss of PRLHR on aneuploidy and initiation of bladder cancer.

854 Background: The question still remains for the presence of yet unknown genetic modifiers in the initiation and/or progression of bladder cancer (BC). It remains challenging to identify the key factors, the mechanism and potential target behind. A genome-wide CRISPR library colony formation assay was performed using UROtsa cells, an immortalized ureter epithelium cell line, in order to identify novel genes that promote the transformation of normal urothelial cells. As one of the top candidate genes, the Prolactin Releasing Hormone Receptor (PRLHR) was identified. To date, only a few studies addressed the impact and the correlation of PRLHR in cancer and reports in the context of BC are missing altogether. Methods: We assessed the gene and protein expressions via public database, qPCR and Western blot analyses in a set of nontumour cell strains (Y235T, UROtsa) and a set of BC cell lines (RT4, T24). Following the shRNA knockdown in the PRLHR-proficient cells(Y235T) and the ectopic PRLHR expression in the cell lines with low/absent PRLHR expression(T24), we performed functional experiments, such as soft agar colony formation assay, MTT, invadopodia and gelatine degradation assays. We determined the invasion and migration abilities of these genetically modified cells by using the and wound-healing, Boyden chamber and porcine bladder ex vivo organ culture invasion assay. Metaphase spread assay and Immunofluorescence was performed in modified Y235T cells for chromosome counting and microscopy observation (centrsomes, chromosomal misalignments and lagging chromosomes). Results: The available in silico expression data and expression analyses in BC cell lines and matched normal/tumour patient samples revealed the repression of PRLHR early in BC tumorigenesis. Soft agar experiments confirmed that ectopic PRLHR impairs colony formation of T24 cells, providing indirect evidence that the CRISPR-Cas9 mediated deficiency of PRLHR promoted UROtsa cells transformation in the screening assay. Functional experiments using the MTT and the wound healing assays showed that ectopic PRLHR improved the viability and migration abilities of BC cells. The Boyden chamber assay and the porcine bladder organ culture model revealed that PRLHR impairs BC cell invasion, likely by the inhibition of the AKT/PKB pathway. Moreover, we observed an abnormal number of centrosomes, an increasing number of lagging chromosomes in the anaphase and telophase of the PRLHR-knockdown cells during mitosis. Conclusions: The screening procedure identified PRHLR as a new candidate tumour suppressor factor, and that loss/down-regulation of this protein contributes to the progression of bladder cancer. Downregulation of PRLHR leads to aneuploidy and genome instability in urothelial cells. PRLHR might serve as a novel biomarker or potential target for BC.

Global and regional burden of kidney cancer: Analysis and future predictions based on GBD data from 1990 to 2021.

521 Background: Kidney cancer, as a common urological malignancy with poor prognosis, shows significant variations in incidence and mortality rates in different countries and regions worldwide. This study aims to investigate the global burden and trends of kidney cancer from 1990 to 2021, and to analyze its associations with various factors. Methods: First, data on the number of kidney cancer cases and age-standardized rates (ASR) of incidence, prevalence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2021 were collected and analyzed globally. Subgroup analyses based on sex, country, region, and sociodemographic index (SDI) were then performed to examine the current status and time trends from 1990 to 2021 of kidney cancer in the total population and various subgroups. In addition, the age-period-cohort (APC) and Bayesian age-period-cohort analysis (BAPC) models were used to track dynamic changes in disease burden and predict future trends of the above indicators. Finally, risk factors and trend changes related to kidney cancer mortality within SDI subgroups were analyzed. Results: Globally, the incidence of kidney cancer increased sharply from 1.6×10 5 in 1990 to 3.9×10 5 in 2021. The ASRs for all measures of kidney cancer burden were higher for men than for women. China has the highest number of cases, deaths and DALYs in 2021, followed by the United States. The country of Cabo Verde and the region of Western Europe have the fastest growing ASRs for both incidence and mortality. 49 countries or regions, mainly in Western Europe and North America, have a decreasing trend in ASR for mortality over the period. Overall, the burden of kidney cancer increased with higher SDIs, with countries with middle and low-middle SDIs having the fastest growing burden of kidney cancer, such as North Africa and the Middle East. The APC and BAPC models predicted a steady decline in the ASRs of incidence, prevalence, mortality and DALYs for kidney cancer over the next 20 years, although the APC model predicted a continued steady increase in the absolute numbers of these indicators. In addition, high BMI and smoking were identified as the major risk factors contributing to kidney cancer deaths. High body mass index was particularly pronounced in countries with low SDIs. Conclusions: From 1990 to 2021, the incidence of kidney cancer has declined from historical peaks in developed countries, but remains on an upward trend in developing countries and represents a significant health threat. Revealing some previously unreported findings, the formulation of appropriate policies to reduce population exposure to risk factors associated with kidney cancer could be beneficial in the context of global aging trends.

PORTOS gene signature as a predictor of risk of adverse events after dose-escalated vs. lower-dose prostate radiation therapy in NRG/RTOG 0126.

375 Background: Dose-escalated radiation therapy is standard treatment for patients with prostate cancer. Dose-escalation improves cancer control but also increases the risk of treatment adverse effects. We hypothesized RNA-based tumor gene expression recapitulates normal tissue gene expression and therefore could identify patients at increased risk of adverse events after dose-escalated radiation. We specifically evaluated the 24-gene PORTOS score which characterizes response to DNA damage and radiation. Methods: PORTOS scores were calculated from biopsy samples obtained from 215 patients treated on the NRG/RTOG 0126 clinical trial that randomized patients with intermediate-risk prostate cancer between 70.2 Gy and 79.2 Gy delivered in 1.8 Gy fractions. In this trial, adverse events were categorized using RTOG criteria. Fine-Gray multivariable analysis of continuous and categorical PORTOS (tertiles) were used to calculate subdistribution hazard ratios (sHR), treating death without events as a competing risk, adjusting for age. Results: Median age was 70 years [IQR 65-74]. Fifty percent received 70.2 Gy (n=107), 50% received 79.2 Gy (n=108) and median follow up was 12.8 years. Patient and treatment characteristics were well balanced across treatment arms (all p>0.05) and across PORTOS groups (all p>0.05). Forty-five percent (n=97) of patients experienced grade 2 or higher adverse events after treatment. In patients receiving standard dose 70.2 Gy radiation, PORTOS was not associated with grade 2 or higher adverse events. However, in patients receiving dose-escalated 79.2 Gy radiation, higher PORTOS score was associated with a higher rate of grade 2 or higher adverse events (sHR = 1.12 [95% CI 1.03-1.22], p=0.01). There was a statistically significant interaction between continuous PORTOS scores and treatment arm for grade 2 or higher adverse events (p=0.01). Regarding treatment arm effects by PORTOS tertile, we observed that for patients with higher tertile PORTOS scores, dose-escalated radiation is more likely to cause grade 2 or higher adverse events compared to lower-dose radiation (sHR = 2.15 [1.04 - 4.44], p = 0.04; five-year cumulative incidence adverse events of 61% after 79.2 Gy vs. 36% after 70.2 Gy). In contrast, risk of grade 2 or higher adverse events was similar after treatment with dose-escalated vs. lower-dose radiation for patients with lower (p=0.41) or mid-tertile (p=0.78) PORTOS scores. Conclusions: HigherPORTOS scores were associated with an increased risk of adverse events after administration of dose-escalated radiation compared to standard-dose radiation. PORTOS is the first radiation sensitivity biomarker to be validated for toxicity with data from a phase III randomized trial and could be used to help personalize radiation therapy dose for patients to limit risk of treatment toxicity.

Impact of adherence to a remote exercise program on health-related quality of life in prostate cancer patients undergoing treatment: A prospective study in Brazil.

130 Background: Patients with metastatic prostate cancer (mPCa) undergoing treatment often experience declines in health-related quality of life (HRQoL) and increased symptom burden. Exercise interventions are known to mitigate these effects, but adherence to such programs remains a challenge. This study aimed to assess the impact of adherence to a remote, home-based exercise program on HRQoL and symptom burden among patients with mPCa in a joint cancer practice in Brazil. Methods: This prospective study recruited patients with mPCa undergoing active treatment for both hormone sensitive and hormone resistant disease. Patients were assessed at baseline (T1) and after 12 weeks (T2) using the Functional Assessment of Cancer Therapy-General (FACT-G; scale: 0-108) and the Edmonton Symptom Assessment System (ESAS; scale: 0-90). Eligible participants received weekly exercise guidance through WhatsApp and performed prescribed exercise regimens (3 to 5 hours per week of combined resistance and aerobic training), with proper techniques demonstrated using the Vedius platform. Adherence was categorized as moderate to high (MH) ≥6 weeks of exercise, or low (L) ≤5 weeks. The primary outcomes included changes in HRQoL and symptom burden. Results: A total of 35 patients were recruited. The median age of participants was 74 years (range 58-91), with a majority being white (65.7%), married (82.9%), highly educated (88.6%), and retired (85.7%). All patients were receiving ADT plus abiraterone (34.3%), or docetaxel (25.7%), or enzalutamide (22.8%), or chemotherapy + abiraterone (14.3%). At 12 weeks, patients with moderate to high adherence demonstrated significant improvements in HRQoL (MH Mean T2 =94.9, L Mean T2 =88.7, P=0.01), particularly in physical (MH Mean T2 =25.1, Mean T2 =23.6, P=0.03), functional (MH Mean T2 =22.8, L Mean T2 =20.7, P=0.03), and emotional (MH Mean T2 =22.2, L Mean T2 =20.28, P=0.03) well-being domains, compared to those with low adherence. Additionally, those with higher adherence reported a lower symptom burden (MH Mean T2 =9.1 vs L Mean T2 =14.7, P=01). Conclusions: This study demonstrates that adherence to a remote exercise program significantly improves HRQoL and reduces symptom burden in patients with prostate cancer undergoing treatment. These findings underscore the importance of promoting exercise adherence through accessible platforms, such as WhatsApp, to enhance patient outcomes in mPCa.