Browse Articles

Impact of PSMA-PET and conventional imaging on contemporary management in patients with biochemical recurrence after radical prostatectomy.

43 Background: Prostate-specific membrane antigen (PSMA) PET imaging is recommended for patients with biochemical recurrence (BCR) after radical prostatectomy (RP). This study describes the early clinical impact of PSMA-PET compared to conventional imaging (CT, MRI, or bone scintigraphy) in a contemporaneous period. Methods: This retrospective study includes patients with BCR after RP (defined as PSA≥0.2 after undetectable PSA post-operatively) who underwent PSMA-PET or conventional imaging (CI) between 2010-2023. The primary outcome was positive detection rate. The secondary outcomes were rates of salvage treatment (XRT±ADT) and second BCR. Cox proportional hazards modeling was used to predict risk of salvage treatment and second BCR. Results: 217 post-RP patients were included. Of the 146 patients who underwent PSMA-PET and the 71 who underwent CI, 77 (52.7%) and 7 (9.9%) patients had positive imaging findings at a median PSA value of 0.23 (IQR 0.21-0.33) and 0.25 (IQR 0.25-0.44), respectively (p=0.36). 48 patients received both imaging modalities; 4 had positive results in both PSMA-PET and CI, while 26 were positive for PSMA-PET only, and 2 were positive on CI only. Patients underwent salvage therapy at lower median PSA values in the PSMA-PET group (0.40 vs 0.51, p<0.01). On unadjusted survival analysis, there were no differences in salvage therapy rates or second BCR rates between PSMA-PET or CI groups. On multivariable Cox proportional hazards modeling, year of PSA recurrence (HR 0.89, 95% CI 0.84-0.95), BMI (HR 1.45, 95% CI 1.02-2.07), ≥GG3 (HR 1.77 95% CI 1.3-2.4), and undetectable PSA≥6 months after RP (HR 0.50 95% CI 0.34-0.72) were associated with salvage treatment, but imaging modality was not. High genomic risk scores (Decipher>0.60) may be associated with second BCR (HR 2.03 95% CI 0.99-4.18, p=0.05) while other variables were not. Conclusions: PSMA-PET usage increased over the period of this study with higher sensitivity at lower median PSA at BCR. Imaging modality did not predict rates of salvage therapy or second BCR, while other clinical risk factors such as adverse pathology and high genomic risk score did. Analysis with a historical cohort is pending.

Epigenomic profiling of circulating chromatin for early detection and monitoring of neuroendocrine prostate cancer.

253 Background: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that can arise after androgen blockade. Early detection of NEPC has prognostic and therapeutic implications but remains challenging. Neuroendocrine (NE) transformation is spatially heterogeneous, with co-existing NE and adenocarcinoma (AD) components across a patient's disease burden, leading to underdiagnosis using tumor biopsy. Moreover, treatment response assessment with cross-sectional imaging cannot distinguish changes in co-existing NE and AD components. To address these challenges, we developed a non-invasive approach to monitor NE transformation in patients with prostate AD (PRAD) through profiling of circulating chromatin. Methods: Plasma samples were collected longitudinally from patients initially diagnosed with PRAD who later developed NEPC at the Dana-Farber Cancer Institute. Chromatin immunoprecipitation and sequencing on cell-free DNA (cfChIP-seq) was performed for H3K27ac, a histone modification enriched at active promoters and enhancers. To separately quantify circulating chromatin derived from NE and AD components in a given patient, we measured H3K27ac at NE-specific enhancers (NE-score) and androgen receptor binding sites (AD-score), respectively. Whole genome sequencing was performed to estimate the cfDNA tumor fraction (TF) using ichorCNA. To evaluate cfChIP-seq for monitoring NEPC treatment response, we calculated changes in NE-score and TF for each pair of consecutive plasma draws after NE transformation. We then compared these changes during intervals of disease progression, stability, or response using the Kruskal-Wallis test. Results: This study included 32 plasma samples from 5 patients, with 14 pre-NE and 18 post-NE diagnosis, collected between December 2016 and April 2022. The NE-score was significantly elevated in post-NE compared to pre-NE samples (Wilcoxon sum rank p<0.01). NE-scores between consecutive draws increased at times of disease progression, changed minimally with disease stability, and decreased during response (median change: 16 vs. 2.0 vs. -32%, resp.; p=0.035). Importantly, changes in TF, which reflects an aggregate of AD and NE-derived tumor DNA, were less pronounced (11 vs. -0.5 vs. -13%, resp.; p=0.3). The AD-score was positively correlated with PSA levels (R=0.59; p<0.001). In 2 patients with plasma collected within 3 months prior to NE transformation, NE scores increased prior to pathologic diagnosis of NEPC. Another case revealed an increase in AD-score and PSA accompanied by a decrease in NE-score when a patient stopped ADT and started platinum-based chemotherapy for NEPC. Conclusions: Epigenomic profiling of circulating chromatin may enable early detection of NEPC and monitoring of NE and AD components in metastatic prostate cancer.

SUBDUE-3: Sub-urothelial durvalumab-sirconium to investigate local and systemic distribution of durvalumab when injected in the sub-urothelium.

TPS903 Background: Sub-urothelial injection of durvalumab presents a novel therapeutic approach for bladder cancer. SUBDUE-1, a first-in-human Phase Ib dose escalation study presented at ASCO 2022, demonstrated the safety and tolerability of sub-urothelial durvalumab in patients with bladder cancer scheduled for radical cystectomy, with no treatment-related adverse events and preliminary evidence of immunomodulation in the tumour microenvironment 1 . SUBDUE-3 will use radiolabelled 89 Zirconium-durvalumab ( 89 Zr-durvalumab) to define local and systemic biodistribution following sub-urothelial injection. Methods: SUBDUE-3 is an open-label, non-randomized Phase 0 trial sponsored by ANZUP (ANZUP 2402, ACTRN 12624001245583p). Ethics approval has been obtained for this study which is currently recruiting patients diagnosed with either high-risk non-muscle-invasive bladder cancer (HR-NMIBC) or muscle-invasive bladder cancer (MIBC), scheduled for radical cystectomy. 25mL of sub-urothelial 89 Zr-durvalumab will be injected in 1mL aliquots throughout the bladder using a 5Fr Bonee needle via 22Fr rigid cystoscope at a GA cystoscopy performed 2 weeks pre-cystectomy. After injection, PET imaging will be performed at several time points over 7 days. At each imaging time point, blood samples will be collected to evaluate the systemic bioavailability of 89 Zr-durvalumab using a gamma counter. Additionally, the urinary radiation dose will be measured during the first imaging session. Quality control measures will assess dissociation of 89 Zr from durvalumab. Dosimetric analyses will determine the distribution and radiation dose of 89 Zr-durvalumab both within the bladder and systemically, providing critical insights for future therapeutic strategies in bladder cancer treatment. Primary endpoint: visual and semi-quantitative assessment of 89 Zr-durvalumab distribution within the bladder wall and systemic organs (liver, kidney, lung, bone marrow) via PET imaging. Secondary endpoints: bladder and other organ tracer biodistribution; comparison of dosimetry data with cohorts receiving systemic 89 Zr-durvalumab; safety; feasibility. The trial has a one-year recruitment strategy aiming to recruit up to 3 patients and is expected to finish recruiting in 2025. References: 1. Hayne D. Et al. The SUB-urothelial DUrvalumab InjEction-1 (SUBDUE-1) trial: first-in-human trial in patients with bladder cancer. BJU Int. 2024 Aug;134(2):283-290. doi: 10.1111/bju.16325. Epub 2024 Mar 12. PMID: 38469652. Clinical trial information: ACTRN 12624001245583p.

Regorafenib plus sintilimab as a salvage treatment for microsatellite stable metastatic colorectal cancer: a single-arm, open-label, phase II clinical trial

Mapping of regions with low tuberculosis notification and estimation of diagnostic gaps in Cameroon, evidence from OpenStreetMap and WorldPop data

Adherence to clinical surveillance guidelines in von Hippel-Lindau (vHL) disease: Evaluating the impact of a coordinated care centre implementation in Canada.

460 Background: VHL is a rare hereditary cancer syndrome, predisposing to the development of multiorgan tumour growth, including bilateral and recurrent clear cell renal cell carcinoma. While guidelines for the screening and management of these patients exist, adherence to guidelines is variable. The development of coordinated clinical care centres with multidisciplinary expertise in rare diseases has been demonstrated to improve outcomes. Methods: In this study, we reviewed adherence to surveillance guidelines prior to and after development of a Canadian provincial vHL clinic at our institution, British Columbia (BC) Cancer. Care in this clinic is provided both in-person and through telehealth. We sought to evaluate whether patient geographic distance from the clinic impacted time to being seen for consultation, and whether there was a change in management plan after being seen in the clinic. Results: Between June 2022, and April 2024, 57 patients were seen in the vHL clinic (median age 34, 58% female, and 42% male). Of these, 13 lived within 50km from the clinic, 7 within 50-100km, 8 within 100-500km, and 29 lived more than 500km away. We found significant improvement in adherence to nearly all surveillance guidelines after the development of the vHL Clinic (table). 10.5% of patients had never had germline confirmation of vHL and were referred for expedited testing after being seen. We did not find any difference in time from referral to consultation based on patient geographic proximity to the clinic, F(3,53)=1.10, p =0.35 nor the modality of initial consultation (t(55)=1.07, p =0.29; in person vs telehealth). Finally, after initial consultation, 87% of patients had a change in their management plans, most commonly involving referral for further subspecialty evaluation (n=41) or initiation of pharmaceutical treatment (n=24). Conclusions: Our results add to existing evidence that coordinated care centres with multidisciplinary expertise in vHL are feasible in the Canadian public healthcare system and can result in improvements in quality of care. Our clinic model has a robust multidisciplinary care team that utilizes technology to reach patients for equitable access to care. Future work will evaluate potential cost savings to the healthcare system with this model, as well as patient satisfaction with their care pre and post participation in the vHL clinic. Adherence to clinical screening guidelines for patients with vHL before and after consultation with the BC cancer provincial vHL clinic. Screening Guideline Parameter Pre connection with vHL clinic Post connection with vHL clinic Central nervous system imaging 51.8% 100%* Abdomen/Pelvis imaging 44.6% 100%* Metanephrines 8.9% 64.3%* Ophthalmologic 75.0% 85.7% Audiology 21.4% 85.7%* *Statistically significant difference ( p <0.05).

Who undergoes cytoreductive nephrectomy now? An analysis of perioperative risk characteristics in contemporary patients.

493 Background: Cytoreductive nephrectomy (CN) has traditionally been the first step in managing metastatic renal cell carcinoma (mRCC). However, the role of routine upfront cytoreductive nephrectomy in mRCC was questioned by the 2018 publications of CARMENA and SURTIME. That same year, Checkmate 214 highlighted the superior effectiveness of immune checkpoint inhibition as first-line systemic therapy in mRCC compared to sunitinib. IMDC risk assessment is widely used in mRCC decision-making. Data from the ACS-NSQIP, a validated method for assessing surgical risk, is commonly used to predict perioperative mortality and morbidity. We sought to understand how the risk characteristics of patients undergoing CN have changed since the reporting of CARMENA, SURTIME, and Checkmate 214 in 2018. Methods: This study used ACS-NSQIP data sets from 2015-2022. It included patients undergoing nephrectomy for mRCC with disseminated cancer, excluding those from 2018. Baseline characteristics and perioperative outcomes were compared using chi-square tests, t-tests, or logistic regression as appropriate. Data was available to approximate 3 of the 6 IMDC criteria (anemia, thrombocytosis, and performance status). Results: Of 82268 nephrectomies performed from 2015-2022, 2191 CN were appropriate for inclusion. The proportion of CN as a share of all nephrectomies in NSQIP has decreased since 2018 (Table, p<0.05). Similarly, the proportion of patients undergoing CN with at least 1, 2, or 3 IMDC criteria has also dropped (Table, p<0.05). The median NSQIP-predicted mortality and morbidity have significantly declined (Table, p<0.05). Assessment of 18 baseline characteristics revealed that no single factor could fully account for the observed risk differences. Since 2018, the median length of stay has reduced from 4 to 3 days, and the proportion of outpatient surgeries has risen from 2.6% to 6% (p<0.05). Despite variations in baseline risk, no significant differences were observed in mortality, major complications, operative characteristics, or readmission rates. Conclusions: Since 2018, patients undergoing CN have had lower IMDC and NSQIP risk profiles, and the overall number of CN procedures has declined. These shifts should be taken into account when interpreting historical data on CN. Further research is needed to assess whether this more selective approach to CN has resulted in improved outcomes since 2018. Characteristics of patients undergoing CN (all p<0.05). Characteristic Pre-2018 (n=1165) Post-2018 (n=1026) Cytoreductive nephrectomy / total nephrectomies in NSQIP during period 1165/32071 = 3.6% 1026/50197 = 2.0% Minimum IMDC Criteria* 0 50.0% 54.5% 1 39.1% 37.7% 2 10.2% 7.8% 3 0.7% 0% Predicted Mortality Median 1.5% 1.2% 90 th percentile 5.6% 4.8% Predicted Morbidity Median 10.3% 9.9% 90 th percentile 14.0% 12.3% *Only anemia, thrombocytosis, and performance status could be assessed.

Intravesical gemcitabine and docetaxel combined with intravenous tislelizumab as a durable strategy for high-risk non–muscle-invasive bladder cancer.

703 Background: For decades, intravesical Bacillus Calmette-Guérin (BCG) has been the standard treatment for high-risk non-muscle-invasive bladder cancer (HR NMIBC). However, its poor tolerability and limited availability underscore the urgent need for more effective therapies. Intravesical sequential gemcitabine and docetaxel (GemDoce) has demonstrated efficacy in HR NMIBC, and immune checkpoint inhibitors (ICIs) have shown effectiveness as second-line therapy for patients with BCG-unresponsive NMIBC. Nevertheless, the combination of immunotherapy with intravesical GemDoce has not yet been reported. Methods: We retrospectively analyzed HR NMIBC patients, who received intravesical GemDoce combined with intravenous tislelizumab at Fujian Medical University Union Hospital from February 2023 to August 2024. Induction GemDoce was administered weekly for 6 weeks, then monthly maintenance. Tislelizumab started during the second GemDoce treatment and continued every 4 weeks. Inclusion required at least 6 weekly GemDoce after complete transurethral resection of bladder tumor (TURBT). Data including patient clinicopathologic features, treatment history, adverse events (AEs), and oncologic outcomes were retrospectively reviewed and analyzed. Results: 30 patients included in study, with a median number of 16 (range:6-22) GemDoce treatments and 12 (range:2-18) tislelizumab cycles. Median age was 70 (range:49-80) years. All patients had papillary disease with or without CIS, including 11 (36.7%) with HGTa and 19 (63.3%) with HGT1. CIS with HGTa was present in 2 (6.7%) patients. 5 (16.7%) patients were BCG-naïve HR NMIBC, while 25 (83.3%) patients were recurrent HR NMIBC. Most patients were male (90%, 27/30), and 56.7% (17/30) had a smoking history. Treatment was well tolerated with no discontinuations or dose reductions. In total, 12 (40%) patients reported AEs following treatment, all of which were grade 1-2. Median follow-up of 11.5 (range:2-18) months, no patients had recurrence, underwent RC, or died. Conclusions: These results suggest that intravesical GemDoce with intravenous tislelizumab is an effective and tolerable treatment option for patients with HR NMIBC. Further prospective study is warranted.

RAD-SG: Adaptive radiation therapy with concurrent sacituzumab govitecan (SG) for bladder preservation in patients (pts) with muscle invasive bladder cancer (MIBC).

TPS896 Background: Concurrent chemoradiotherapy (CRT) is a recommended treatment option for pts with MIBC interested in bladder-preservation and/or not candidates for radical cystectomy (RC). Systemic radio-sensitizing chemotherapy may have off target side effects and exploring novel agents with radiation is an unmet need. SG is an antibody drug conjugate (ADC) and has shown efficacy in metastatic urothelial cancer (UC). RAD-SG is a single-arm phase 1 trial investigating the concurrent administration of SG with adaptive radiotherapy (RT) in pts with MIBC. Methods: Eligibility criteria include pts with localized MIBC (T2-T4aN0M0), ECOG PS Score of 0-2, normal organ and marrow function including creatinine clearance ≥ 30 mL/min, must undergo a TURBT within ≤ 60 days prior to treatment. Variant subtypes are allowed. Pts must not have had UC or any histological variant at any site outside of bladder within 24 months except Ta/T1/Carcinoma in situ (CIS) of the upper urinary tract including renal, pelvis, and ureter if underwent complete nephroureterectomy. Other exclusion criteria include bilateral hydronephrosis and prior pelvic / local RT for MIBC or any other cancer type. SG targets TROP-2, a surface protein expressed in UC, it will be given IV at 7.5 mg/kg every 21days starting prior to RT and 2 subsequent cycles with concurrent adaptive RT over a period of 6 weeks (64 Gy). The primary endpoint is safety, tolerability, and feasibility of trimodality therapy with concurrent SG and adaptive image-guided radiation therapy for patients with localized MIBC. The secondary endpoints are bladder intact event-free survival (BI-EFS) with concurrent SG and RT for MIBC and compare historical controls with other concurrent CRT regimens. BI-EFS is defined as the time from treatment to the first documented occurrence of residual/recurrent MIBC, nodal or distant metastases on imaging, RC, or death from any cause. Correlative objectives include 1) elucidation of the genetic and microenvironmental mechanisms that drive efficacy and resistance to combined ADC plus RT and 2) characterization of tumor clonal dynamics, immune repertoire editing, and imaging changes following treatment with SG plus RT. The study will accrue 20 pts at Cleveland Clinic Foundation and enrollment is ongoing. (NCT05833867). Clinical trial information: NCT05833867 .

Global potential of sustainable single-cell protein based on variable renewable electricity

Abstract The environmental impacts of the food system exceed several planetary boundaries, with protein production being a major contributor. Single-Cell Protein (SCP) is a protein-rich microbial biomass that offers a sustainable alternative when derived from renewable energy and sustainable feedstocks. We evaluate the global potential for SCP production utilising electrolytic hydrogen and oxygen, atmospheric carbon dioxide and nitrogen, and hourly-optimised hybrid PV-wind power plants at a 0.45° × 0.45° spatial resolution. We outline a roadmap for industrial-scale production, commencing in 2028, targeting an annual capacity of 30 million tonnes of protein by 2050. Here we show that the cost of renewable electricity-based protein (e-protein) could decline at optimal sites from 5.5–6.1 € kg−1 in 2028 to 4.0–4.5 € kg−1 by 2030, and further to 2.1–2.3 € kg−1 by 2050. Consequently, e-protein production can mostly decouple protein supply from water and arable land constraints, substantially mitigating the environmental impacts of food production.

Exploration of phosphoproteomic association during epimorphic regeneration

Individualized neoantigen vaccine with nivolumab plus cabozantinib for translocation renal cell carcinoma: Single patient investigational new drug.

537 Background: Translocation renal cell carcinoma (tRCC) is a rare renal cell carcinoma subtype found in about 1-4% of adult patients with RCC and 40% of pediatric RCC cases. Management of advanced tRCC has been guided by clear cell RCC therapy and retrospective reviews which include tRCC cohorts. Novel therapeutic strategies are needed to improve outcomes. This study assessed an individualized neoantigen vaccine with nivolumab plus cabozantinib in a patient with metastatic TFE3-tRCC. Methods: Patient was consented (IRB# 20-011945) for a single-patient investigational new drug (IND#27755). In-house neoantigen prediction bioinformatics pipeline (REAL-neo v2.0) was performed to identify and prioritize neoantigen candidates. Patient underwent lymphodepletion with cyclophosphamide followed by vaccine administration on days 1, 4, 8, 11, 20, 40, week 12, and week 20. Patient was also treated with concurrent nivolumab 480 mg every 4 weeks and cabozantinib 40 mg daily. Objective response rate (ORR) and progression-free survival (PFS) were measured. Results: Patient was diagnosed with TFE3-tRCC and underwent nephrectomy prior to developing metastatic disease. He was treated with multiple liver surgeries, ablations, and radiation therapy without systemic therapy. This controlled his disease for 7 years before he required systemic therapy with ipilimumab plus nivolumab. After 4 cycles, imaging showed progression and was started on cabozantinib which controlled his disease for 1 year. Patient was consented for the neoantigen vaccine. Cycle 1 was administered in April 2022. Three liver lesions and 1 periportal lymph node were monitored. After 4 months of therapy, imaging showed partial response with 34% decrease in sum of target lesions. In June 2023, partial response was ongoing with a 57.4% decrease. A 2 nd vaccine series was administered in June 2023 and had stable disease until progression in June 2024 when patient held his cabozantinib for at least 4 weeks. Neoantigen combination therapy achieved a progression-free survival of 26 months and was well tolerated without significant vaccine-related adverse events. Conclusions: Individualized neoantigen vaccine plus nivolumab and cabozantinib achieved a durable partial response with prolonged progression-free survival. A randomized clinical trial is warranted to further evaluate the efficacy of this combination therapy.

Impact of adding immunotherapy to chemotherapy for metastatic neuroendocrine bladder cancer in the National Cancer Database.

748 Background: Metastatic neuroendocrine bladder cancer is a rare and aggressive malignancy characterized by poor prognosis and limited effective treatment options. Standard chemotherapy has shown limited success, necessitating novel therapies. We hypothesized that adding immunotherapy to chemotherapy would improve overall survival (OS) in these patients. Methods: We conducted a retrospective cohort study of 1,410 patients diagnosed with metastatic neuroendocrine bladder cancer between 2004 and 2020 using the National Cancer Database (NCDB). Treatment groups included no treatment, chemotherapy alone, and combined immunochemotherapy. Survival outcomes were analyzed using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards regression models, adjusting for age, tumor size, Charlson-Deyo comorbidity score, and residential area. Results: Median OS was 1.8 months (95% CI: 1.6-2.0) for patients receiving no treatment (n=460), 9.6 months (95% CI: 8.9-10.1) for chemotherapy alone (n=860), and 11.7 months (95% CI: 9.6-14.8) for combined immunochemotherapy (n=90) (P < 0.001 for immunochemotherapy vs. both other groups). Further analysis revealed that first-line immunotherapy initiated within 30 days of chemotherapy (n=21) significantly improved OS (median 11.6 months; 95% CI: 6.8–16.1; P=0.0374) compared to chemotherapy alone. Notably, immunotherapy initiated after 30 days (n=69, median OS 12.4 months; 95% CI: 9.0–14.8; P=0.0264), whether as first-line or second-line therapy, also showed superior efficacy to chemotherapy alone. These findings suggest that if first-line immunotherapy is not administered, subsequent immunotherapy should still be considered. Multivariable Cox regression analysis showed that immunochemotherapy compared to chemotherapy alone was associated with a lower hazard for death (HR = 0.80; 95% CI: 0.66-0.97; P = 0.0242), while patients receiving no treatment had an increased risk of death (HR = 3.50; 95% CI: 3.00-3.90; P < 0.0001). Additional factors associated with increased mortality included older age, larger tumor size, and higher Charlson-Deyo score. Conclusions: Adding immunotherapy to chemotherapy significantly improved OS in metastatic neuroendocrine bladder cancer. First-line immunochemotherapy showed substantial benefits, but late initiation also improved outcomes. These findings support incorporating immunotherapy into first-line protocols and consider it for subsequent lines. Prospective clinical trials are needed to optimize immunotherapeutic strategies for this aggressive malignancy.

Determining an immunohistochemical profile to predict response to intravesical bacillus Calmette–Guérin (BCG) in patients with high-grade non-muscle invasive bladder cancer.

847 Background: Intravesical Bacillus Calmette–Guérin (BCG) remains the gold standard for the management of high-grade non-muscle invasive bladder cancer (NMIBC). However, up to 70% of patients fail BCG therapy. We aimed to define potential mechanisms for BCG resistance and develop an immunohistochemical (IHC) panel to help identify patients likely to respond to intravesical BCG. Methods: Patients with NMIBC undergoing induction intravesical BCG at a tertiary institution were identified. Twelve BCG-responders and 13 non-responders were matched for patient and tumour factors. RNA sequencing was performed with hierarchical clustering and Gene Set Enrichment Analysis to identify response resistance mechanisms. Immune cell subsets were measured using pre and post-BCG therapy for CD4, CD8, T-Bet, GATA-3 and PD-1 antibodies. GATA-3 and T-Bet stains were used as surrogates for Th-2 and Th-1 cells, respectively. T-tests were used to assess differences. An integrated IHC panel using CD4, CD8, T-Bet, GATA and PD1 was developed and correlated with BCG response using Receiver Operator Characteristic (ROC) curves. Results: On hierarchical clustering, BCG-responders and non-responders had distinct gene expression profiles pre- and post-BCG. Prior to exposure to BCG, non-responders had enrichment for a pro-inflammatory gene signature with a higher CD4:CD8 ratio (2.94 vs 1.71, p=0.0003) and a higher Th-2/Th-1 (GATA/T-Bet) ratio (5.95 vs 2.97, p=0.0026) compared to BCG-responders, on IHC. However, on exposure to BCG, non-responders had no changes to the CD4:CD8 or Th-2/Th-1 ratios but had a 78% increase in the PD-1 expression (MD 20.83/5hpf, p=0.016) with BCG, indicating T cell exhaustion. In contrast, upon exposure to BCG, responders had an increase in the Th-2/Th-1 ratio (mean difference 0.9323, p=0.0228) with enrichment of the natural killer cell pathway compared to non-responders (p<0.05). The area under the ROC curve using the integrated IHC panel to predict BCG response was 0.864 (95% CI: 0.663 to 1.000). Conclusions: BCG non-responders had a pro-inflammatory TME, which showed marked T cell exhaustion on exposure to BCG. In contrast, responders had a baseline TME with low CD4:CD8 and low Th-2/Th-1 ratios at baseline, which allowed activation of both humoral and adaptive responses to BCG. These immune changes can be utilised as an IHC panel to predict response to BCG therapy.

Evaluating the impact of single vs. combination therapy on survival outcomes in mHSPC patients stratified by BMI.

187 Background: Metastatic hormone sensitive prostate cancer (mHSPC) is a heterogenous disease with a variety of treatment options. De novo mHSPC can be treated with androgen deprivation therapy (ADT) monotherapy or combinations including docetaxel or androgen receptor pathway inhibitors. Body mass index (BMI) is known to be associated with survival, but there is little data to show the effectiveness of treatment intensity (single or combination therapy) based on BMI. Methods: Patients treated for mHSPC within the Veterans Health Affairs from 2017-2023 were included. BMI was assessed using height and weight at diagnosis and treatment intensity was determined by treatments within 4 months of start of ADT. Additional baseline characteristics for each group included age, prostate specific antigen (PSA), and Charlson Comorbidity Index (CCI). Survival was estimated using the Kaplan-Meier method and Cox proportion hazard modeling was used to account for known covariates. Results: There were 4184 veterans identified with 33.5% BMI <25, 35% BMI 25-30, and 31.5% with BMI >30. The BMI 25-30 group had longer survival compared to BMI of <25 (37.3 vs. 30.7 months, HR 0.78 95% CI 0.71-0.86) and the BMI >30 had longer survival compared to BMI 25-30 (42.5 vs. 37.3 months, HR 0.87 95% CI 0.79-0.96). In patients with BMI of <25 combination therapy was associated with longer survival (HR 0.73 (0.63-0.83)) and in patients with BMI of 25-30, combination therapy was also associated with longer survival 0.76 (0.67-0.88). However, in patients with BMI >30, there was no difference in overall survival based on combination or monotherapy (HR 0.97 (0.83-1.13)). In a multivariable model including age, PSA, CCI, and treatment intensity, BMI >30 and BMI 25-30 was associated with decreased risk of death compared to BMI <25, aHR 0.80 (95% CI 0.72-0.89) and aHR 0.89 (95% CI 0.81-0.98) respectively. Conclusions: In patients with mHSPC, higher BMI is associated with longer survival compared to lower BMI. In all patients, combination therapy was associated with longer survival, however, there was no difference in survival with combination therapy compared to monotherapy in patients with BMI >30. Future studies could investigate the reason why combination therapy is only associated with benefit in patients with BMI <30. BMI (kg/m 2 ) <25 n=1403 25-30 n=1465 >30 n=1316 P value (ANOVA) Age (mean years) 76.2 74.4 71.8 p<0.001 PSA (median ng/mL) 177 91.6 61.25 p<0.001 Overall Survival (median months) 30.7 37.3 42.5 p<0.001 ADT monotherapy 26.9 (n=736) 33.1 (n=683) 42.5 (n=582) Combination therapy 36.3 (n=667) 41.5 (n=782) 42.6 (n=734) HR (95% CI) 0.73 (0.63-0.83) 0.76 (0.67-0.88) 0.97 (0.83-1.13)

Structural, molecular and developmental evidence for cell-type diversity in cnidarian mechanosensory neurons

Experimental study on adiabatic pre-cooling systems for air cooled condensers in hot and humid climates

Clinical outcomes of invasive primary urethral cancer: A real world multi-institutional study.

654 Background: Primary urethral cancer (PUC) is a rare and highly aggressive malignancy with a spectrum of various histologies without an established treatment approach. Due to the lack of prospective studies in patients with PUC, the clinical outcomes with different treatment modalities are unknown. We aimed to investigate the clinical outcomes based on various treatment approaches and histology. Methods: Our retrospective study included patients from 10 international cancer centers in the United States, Europe, and Asia. Eligibility criteria included patients diagnosed with invasive PUC based on the TNM stage (T2-T4, N0-N2). We defined disease free survival (DFS) as time from date of cancer diagnosis to recurrence or death, whichever came first. We utilized Kaplan-Meier survival analysis to study the DFS rate. Results: We identified 82 patients diagnosed with PUC, of which 60% were men and 40% were women. The common histologies were urothelial carcinoma (40%), squamous carcinoma (32%), adenocarcinoma (12%). Patients had stage II (30%), III disease (26%) and IV disease (44%). In this cohort 51% underwent surgery only (S), 19% received neoadjuvant chemotherapy f/w surgery (NCT), 11% received concurrent chemoradiation f/w by surgery (CRT), 2% received radiation f/w surgery. In our cohort 43% patients had recurrence of disease. In our study cohort, the DFS rate was 54 % after a median follow up of 15.5 months. The 2-year DFS rates were 64.2% for urothelial carcinoma, 45.7% for adenocarcinoma, and 40.0% for squamous cell carcinoma. Based on treatment, 2-year DFS rates were 68% for NCT, 58.3% for CRT, and 46% for S respectively. Median DFS rate was 41 months in patients with lymph node metastasis (LMN) vs 30 months in patients without LMN. Among 14 patients who underwent genomic testing, the most common gene alterations were seen in PIK3CA (35%), PTEN (21%), ERBB-2 (14%) and CDKN2A/B (28%). Conclusions: The management of PUC is complex given the variable histologies. Clinical outcomes appear suboptimal with high rates of recurrence in patients with invasive PUC regardless of histology, treatment, and sex. While our study is limited by its retrospective design, sample size and limited follow up, data suggest that multimodal therapy incorporating chemotherapy with or without radiation may offer better outcomes in invasive PUC. Future large scale prospective studies are needed to optimize treatment approaches in patients with PUC. 2-year DFS based on histology, treatment approach and stage. Survival rate (%) [95%CI] DFS (Histology)  Urothelial 64 [43 - 79]  Adenocarcinoma 45 [14 - 72]  Squamous 40 [17 - 61] DFS (Treatment)  S 46 [29 - 62]  NCT 68 [35 - 86]  CRT 58 [18 - 84] DFS (Gender)  Male 51 [34 - 66]  Female 51 [31 - 67] DFS (AJCC stage)  II 62 [39 - 79]  III 50 [29 - 70]  IV 50 [25 - 67]

Phase III randomized trial of stereotactic ablative radiotherapy (SAbR) for oligometastatic advanced renal carcinoma (EA8211-SOAR).

TPS615 Background: The optimal frontline management strategy for oligometastatic renal cell carcinoma (omRCC) is uncertain. Systemic therapy (ST) is the standard, but Stereotactic Ablative Radiation (SAbR) offers an alternative, and may potentially reduce ST-associated toxicity. However, concerns remain about occult micro-metastases progression with SAbR. Retrospective studies suggest focal therapies may improve outcomes in select patients, but prospective data is limited. This ECOG-ACRIN phase 3 randomized trial compares SAbR with ST in omRCC, assessing whether SAbR followed by delayed ST can offer non-inferior OS with lower toxicity compared to upfront ST. The co-primary endpoints are OS and grade ≥3 toxicity. Hypothesis: For omRCC patients with 2-5 measurable metastases, SAbR followed by delayed ST will result in non-inferior OS compared to immediate while reducing grade ≥3 toxicity. Methods: This phase 3 trial will enroll patients with oligometastatic RCC with 2-5 extracranial metastases amenable to SAbR and an ECOG performance status of 0-2, categorized as favorable or intermediate risk according to modified IMDC criteria. Patients must have their primary tumor treated by surgery or radiation before enrollment. Exclusions include brain metastases, sarcomatoid histology, prior systemic therapy for metastatic disease (adjuvant therapy is allowed), and poor-risk IMDC classification. Participants will be stratified by number of metastases, histology, IMDC risk, prior adjuvant therapy, and time since primary site treatment. Patients will be randomized to either upfront ST or SAbR with delayed ST. Statistical Design: The trial has 85% power to establish non-inferiority of SAbR with respect to OS, assuming a null hazard ratio of 1.24 and an alternative of 0.85. If non-inferior OS is shown, the study will test whether SAbR reduces grade ≥3 toxicity. Secondary endpoints include progression-free survival (PFS) and quality of life, measured by NFKSI-19 and EQ-5D-5L scales. Exploratory endpoints will assess cost-effectiveness and circulating tumor DNA (ctDNA) as a biomarker. The study opened in September 2023. Research sponsor: U.S. National Institutes of Health. Clinical trial information: NCT05863351 .

A prospective trial of a structured exercise program to lessen fatigue in patients with advanced prostate cancer (aPC) undergoing androgen deprivation therapy (ADT).

120 Background: Cancer-related fatigue, one of the most significant issues affecting quality of life (QOL), is reported by up to 75% of men with advanced prostate cancer (aPC) on ADT. Exercise may serve as a tool to improve fatigue in cancer patients. We examined the effect of a structured exercise program on fatigue in men with aPC. Methods: This prospective trial enrolled participants with aPC treated with an ADT-based regimen on a 12 week exercise program at a single institution. Patients with at least 4/10 tiredness, self-reported sedentary lifestyle (<90 min/week exercise), no evidence of disease progression, and no chemotherapy within 3 months were eligible. Participants underwent peak aerobic capacity, muscular strength and endurance testing before and after 12 weeks of structured, guided exercise through the institution’s hospital-based exercise oncology program called Personal Optimism With Exercise Recovery (POWER). Participants completed symptom questionnaires including the 7-item PROMIS fatigue at baseline and after 6 and 12 weeks. Participants had 45-60 min supervised sessions weekly, either in person or virtually, and were instructed to work up to 150 min of moderate activity and 2 resistance training sessions weekly. The primary endpoint was change in fatigue; a 4 point reduction in T score is a clinically important difference. The key secondary endpoint was change in relative peak aerobic capacity (ml/kg/min). Mean and 95% Gaussian confidence intervals are reported. Results: 119 participants with aPC, 92% of whom had metastatic disease, enrolled between 2018 and 2022. Nine withdrew from the study and 10 were lost to follow-up. Data were incomplete for 28 participants primarily due to inadequate follow-up during COVID. Of the 119 enrolled participants, 96% were white, 83% were married, 52% had at least a college degree, and 25% were currently employed. Mean age was 70.3 years and mean BMI was 30.5 kg/m 2 . 29 participants (24%) were receiving treatment with ADT alone, and the rest were receiving a combination of ADT and targeted therapy. The primary endpoint was evaluable in 72 participants. There was a clinically significant reduction in fatigue of 5.1 points (95%CI 3.6-6.7) between baseline (56.7 [95%CI 55.1-58.0]) and 12 weeks (51.4 [95%CI 49.8-53.1]). Of those who completed both aerobic fitness assessments (n=76), there was a 3.1 ml/kg/min (95%CI 2.1-4.0) improvement in relative peak aerobic capacity from a mean 27.5 [95%CI 25.8-29.2] at baseline to a mean 30.6 [95%CI 28.8-32.3] at 12 weeks. Conclusions: Completion of a 12 week supervised exercise regimen led to a clinically significant improvement in fatigue and peak aerobic exercise capacity. These findings support routinely recommending exercise for and examining symptom management in patients with metastatic cancer to improve QOL. Clinical trial information: NCT03421782 .