BACKGROUND:About 30% of men with localised prostate cancer undergoing radiotherapy with curative intent have disease recurrence associated with progression-related symptoms and substantial toxicity of salvage therapies. Previous studies with aglatimagene besadenovec (CAN-2409, hereafter referred to as aglatimagene) showed synergy with radiation and immune-mediated cytotoxicity in patients with prostate cancer. We aimed to assess whether addition of aglatimagene plus prodrug (valacyclovir) to standard-of-care external beam radiation therapy (EBRT) could improve disease-free survival in this population. METHODS:We conducted a phase 3, randomised, double-blind, placebo-controlled trial at 51 medical centres (26 community and 25 institutional or military) across the USA and Puerto Rico in patients with intermediate or high-risk prostate cancer. Patients aged at least 18 years who were planning to undergo EBRT and with an Eastern Cooperative Oncology Group score of 0-2 were eligible. Patients were randomly assigned (2:1) via central block-randomisation to receive either three courses of intraprostatic aglatimagene (5 × 1011 viral particles) plus valacyclovir or placebo plus valacyclovir, with randomisation stratified by risk category and androgen deprivation therapy (ADT) use. Patients received standard-of-care EBRT (78 Gy in 2 Gy fractions) or hypofractionated EBRT (60 Gy in 3 Gy fractions or 70 Gy in 2·5 Gy fractions) with optional ADT. The primary endpoint was disease-free survival, defined as time-from-randomisation to prostate cancer recurrence or death in the intent-to-treat population (all randomly assigned patients). Safety was assessed in all individuals who received at least one injection. The trial is registered at ClinicalTrials.gov, NCT01436968, and long-term follow-up is ongoing. FINDINGS:Between Feb 21, 2012, and Sept 9, 2021, 745 men (591 [79%] White, 121 [16%] Black) were randomly assigned to receive aglatimagene plus valacyclovir (n=496) or placebo plus valacyclovir (n=249). After a median follow-up of 50·3 months (IQR 35·2-63·3), median disease-free survival was not reached (95% CI 121·78 to not reached) in the aglatimagene plus valacyclovir group versus 86·1 (IQR 29·7-143·0) months in the placebo plus valacyclovir group (hazard ratio 0·70, 95% CI 0·52-0·94; p=0·016). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 40 (8%) of 479 patients in the aglatimagene group and 17 (7%)of 232 patients in the placebo group. The most common TEAE of grade 3 or worse was acute kidney injury in both the aglatimagene group (nine [2%] of 479 patients) and the placebo group (four [2%] of 232 patients). Serious adverse events occurred in 28 (6%) of 479 patients in the aglatimagene group and 17 (7%) of 232 in the placebo group. Treatment-related serious adverse events occurred in eight (2%) patients in the aglatimagene group (four acute kidney injury, two pyrexia, and one each influenza-like symptoms and urinary retention) and five (2%) in the placebo group (four acute kidney injury, and one each increased creatinine levels and skin rash; one patient reported two serious adverse events). No treatment-related deaths were reported. INTERPRETATION:Aglatimagene plus valacyclovir was associated with longer disease-free survival than placebo plus valacyclovir when added to standard of radiotherapy for the treatment of localised prostate cancer, offering a meaningful benefit without increasing clinically significant toxicity. FUNDING:Candel Therapeutics and US National Institutes of Health.
Addressing prostate cancer, particularly in its aggressive forms, poses challenges that call for innovative treatment modalities. Our research focuses on developing a nanotechnological solution to enhance targeted cancer therapy. We have synthesized advanced nanocapsules embedded with indocyanine green (ICG) and conjugated with the Anti-hPSMAEC domain to improve specificity towards prostate cancer cells. These nanocapsules are engineered to perform dual-mode phototherapy through photothermal and photodynamic mechanisms. In vitro experiments demonstrated the nanocapsules effectively target and induce apoptosis in prostate cancer cells upon exposure to near-infrared light. Furthermore, in vivo assessments in murine models revealed excellent tumor localization and a substantial reduction in tumor volume with minimal impact on healthy tissues. This innovative approach underscores the potential of nanotechnology to transform the therapeutic landscape of prostate cancer by achieving precise targeting and reducing systemic side effects. Such nanocapsule systems’ continued development and refinement may substantially improve clinical outcomes and provide promising therapeutic strategies for treating complex cancers. APCI nanoparticles for sensitive tumor imaging andenhanced PTT in vivo PDT. (A) Schematic design of APCI for targeted cancer cell delivery; (B) visualization and therapy of orthotopic and metastatic prostate cancer.
e17041 Background: Treating mCRPC remains challenging, with limited options for prolonging overall survival (OS). Sipuleucel-T, an autologous prostate-specific antigen (PSA)-targeting cellular immunotherapy (therapeutic vaccine), was FDA-approved in April 2010. We examined the outcomes of treatment for mCRPC since 2010 in SoNaR for Prostate Cancer, the deidentified PPS Analytics/Specialty Networks Uro-oncology electronic medical record (EMR) database that encompasses 90 United States (US) community urology practices with over 3,200 providers. Methods: This multicenter, retrospective study analyzed OS in 2 cohorts of men aged ≥18 years who were diagnosed with mCRPC between January 1, 2010 and May 31, 2024 and treated (Cohort 1) or not treated (Cohort 2) with sipuleucel-T in community urology settings. For the preliminary covariates of race, US region, and age and Gleason group scores at diagnosis, patient characteristics were summarized descriptively, Kaplan-Meier (KM) methods and log-rank tests compared OS, and Cox proportional hazards estimated hazard ratios (HRs). Results: Of a total 11,265 men, 46.9% received sipuleucel-T (Cohort 1). Data from the the sipuleucel-T-treated cohort are described in text; all patients are described in the table. Mean age was 73.4 years, 14% were Black, and 46% were in the Southern US region (Table). At PC diagnosis, the mean Gleason score was 7.3, categorizing 53% as high-risk. At mCRPC diagnosis, the mean PSA level was 49.1 ng/mL (median 6.3 ng/mL). Median OS was 44 months (Table). Among the 4,494 patients of cohort 1 with known status, 28% were still alive 5 years after treatment; their median OS was 97 months. Conclusions: Despite their high-risk disease, patients who received sipuleucel-T had a 44-month median OS, with 28% being alive at 5 years later. This highlights the potential therapeutic benefit of integrating sipuleucel-T into real-world treatment for mCRPC. Further analysis is needed, leveraging the rich nature of this dataset. Supported by Dendreon Pharmaceuticals, LLC. Patient characteristics and outcomes. Overall (n=11,265) Cohort 1Sipuleucel-T (n=5,281) Cohort 2No Sipuleucel-T(n=5,984) P -value, Cohort 1 vs 2 Median age, years 76 74 78 <0.001 Race, % (White/Black/Other) 67/15/19 69/14/17 65/15/21 <0.001 US region, % (Midwest/Northeast/South/West) 25/16/45/14 25/16/46/13 26/16/44/14 0.124 PSA at mCRPC diagnosis (mean/median) 81.1/8.0 49.1/6.3 110.0/10.3 <0.001 Gleason score at PC diagnosis, mean 7.3 7.3 7.2 0.064 Alive at 5 years, % 20% 28% 12% <0.001 KM OS (median, 95% CI), months 33 (32, 34) 44 (43, 46) 24 (24, 25) HR (95%CI), Cohort 1 vs 2 1.7 (1.6-1.8)<0.001 CI, confidence interval.
Urethral cuff erosion is a well described complication of artificial urinary sphincter (AUS) with reported rates of 2 to 18 percent. Current guidelines recommend prompt removal of the device upon erosion diagnosis. This study examines the short- and long-term outcomes of delayed versus immediate removal of non-infected AUS erosions. We reviewed our prospectively maintained AUS QI database from 2011 to 2024 and identified patients who underwent AUS removal for confirmed erosions via cystoscopy. Patients with suspected device infection, defined by SIRS criteria or symptoms like fevers >101.5F, erythema, or scrotal swelling, were excluded. Patients were divided into two groups: immediate removal (IR) within 24 hours and delayed removal (DR) beyond 24 hours from diagnosis. The DR pathway included device deactivation, broad-spectrum antibiotics, and outpatient removal within a week. Outcomes were compared using Pearson’s Chi-squared test. Among the 1104 implanted AUS devices, 110 patients had erosions. 90 met inclusion criteria (42 IR, 48 DR). Baseline clinical characteristics were not statistically different. Common risk factors included prior erosion (30% IR vs 25% DR), prior radiation (74% IR vs 69% DR), and posterior urethral stenosis (30% IR vs 20% DR). The mean device age at erosion was 23.75 months (1-108) for IR and 30 months (2-106) for the DR group. The mean time to AUS removal was 4 hours (7-24) in the IR and 5 days (1-23) in the DR group. Complications included persistent extravasation of contrast during retrograde urethrogram (30% IR, 33% DR, OR 1.12, CI 95% 0.46-2.71) and urethral stricture formation (IR 33%, 24% DR, OR 0.67 CI 95% 0.27-1.67) (Table 1). Urethrocutaneous fistulas were seen in two IR and one DR patient. One patient per group developed pubic osteomyelitis. At median follow of 357 (162,3081) days, there was no significant difference in overall complications between IR vs DR (OR 2.82, CI 95% 0.47-1.16, p-value= 0.09). Contrary to the classic belief of the need for immediate removal of non-infected AUS erosions, delayed management has similar outcomes to immediate AUS removal. These findings are important for patient counseling and clinical decision making in the AUS patient. Yes, this is sponsored by industry/sponsor: Boston Scientific Corporation Clarification: Industry funding only - investigator initiated and executed study
Background: Mesenchymal stem cells (MSCs) have been identified to have a unique migratory pattern toward tumor sites across diverse cancer types, playing a crucial role in cancer progression, treatment resistance, and immunosuppression. This study aims to formulate a prognostic model focused on MSC-associated markers to efficiently predict the clinical outcomes and responses to therapy in individuals with bladder cancer (BC). Methods: Clinical and transcriptome profiling data were extracted from The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) and GSE31684 databases. Systematic quantification of MSC prevalences and stromal indices was undertaken, culminating in the discernment of genes correlated with stromal MSCs following a thorough application of weighted gene coexpression network analysis techniques. Subsequently, an exhaustive risk signature pertinent to MSC was formulated by amalgamating methods from univariate and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression models. Drugs targeting genes associated with MSCs were screened using molecular docking. Results: The prognostic model for MSC incorporated five critical genes: ZNF165, matrix remodeling-associated 7 (MXRA7), CEMIP, ADP-ribosylation factor-like 4C (ARL4C), and cerebral endothelial cell adhesion molecule (CERCAM). In the case of BC patients, stratification was performed into discrete risk categories, utilizing the median MSC risk score as a criterion. It was striking that those classified within the high-MSC-risk bracket demonstrated correlations with unfavorable prognostic implications. Enhanced responsiveness to immunotherapy in low-MSC-risk patients was delineated compared to their high-MSC-risk counterparts. A heightened receptivity was noted toward particular chemotherapy drugs, encompassing gemcitabine, vincristine, paclitaxel, gefitinib, and sorafenib, within this high-risk group. Conversely, a superior reaction to cisplatin was distinctly evident among those marked by low MSC scores. The results of molecular docking demonstrated that kaempferol exhibited favorable docking with ZNF165, quercetin exhibited favorable docking with MXRA7, mairin exhibited favorable docking with CEMIP, and limonin diosphenol exhibited favorable docking with ARL4C. Conclusions: The five-gene MSC prognostic model demonstrates substantial efficacy in prognosticating clinical outcomes and gauging responsiveness to chemotherapy and immunotherapy regimens. The genes ZNF165, MXRA7, CEMIP, ARL4C, and CERCAM are underscored as promising candidates warranting further exploration for anti-MSC therapeutic strategies, thereby offering novel insights for personalized treatment approaches in BC.
