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Impact of the eastern Tibetan Plateau on the ecological sensitivity of the West Qinling Mountains

Body composition and immunotherapy outcomes in patients with advanced urothelial carcinoma.

762 Background: Abnormalities in body composition, including sarcopenia and myosteatosis, have been identified as prognostic factors in patients (pts) receiving cytotoxic chemotherapy. However, data regarding the impact of these factors in patients undergoing immune checkpoint inhibitors (ICI) therapy, particularly in those with advanced urothelial carcinoma (aUC), remain limited. This study aimed to evaluate the prognostic significance of body compositions obtained from abdomen-pelvis computed tomography (APCT) in pts with aUC. Methods: This retrospective study included pts with aUC who received ICI (atezolizumab or pembrolizumab) between Jan 2019 and Dec 2022 at Asan Medical Center, Seoul, Korea. Body composition was evaluated using selected axial images at the L3 lumbar vertebrae level from APCT, through an artificial intelligence-driven imaging analysis platform. T-score ≤-2 (-2 SD from the mean reference value in Korean population) was used as cutoff points for sarcopenia and myosteatosis. Visceral obesity (VO) was defined as visceral fat area ≥ 100cm 2 and subcutaneous obesity (SFO) as subcutaneous fat area / height 2 ≥ 50cm 2 /m 2 in males and 42cm 2 /m 2 in females. The associations between body composition parameters with overall survival (OS) and progression-free survival (PFS) were analyzed. Results: A total of 212 pts were included. Median age was 68 (range, 31-86) and 53 pts (25%) were females. ICIs were primarily administered as second-line treatment following failure to platinum-based treatment (N=207, 98%), with 5 pts (2%) receiving ICI as first-line treatment in a metastatic setting. Atezolizumab was given to 174 pts (82%) and pembrolizumab to 38 pts (18%). The prevalence of sarcopenia prior to treatment was 22% (45/212), while myosteatosis was observed in 52% of pts (110/212). VO and SFO were present in 62% and 43% of pts, respectively, with 37% classified as overweight (body mass index (BMI) ≥25kg/m 2 ). Myosteatosis at baseline was associated with an increased risk of mortality (HR 1.58, 95% CI: 1.11–2.23), while sarcopenia, VO, SFO, and BMI did not show significant associations with OS. PFS was not affected by any body composition parameters. Multivariate Cox regression analysis demonstrated that liver metastasis (HR 2.78, 95% CI: 1.94–4.00), hemoglobin (HR 0.52, 95% CI 0.35-0.77), and myosteatosis (HR 1.57, 95% CI 1.12-2.19) were independently associated with OS after adjusting for age and sex. Conclusions: In pts with aUC treated with ICI, myosteatosis showed poorer OS, while sarcopenia, VO, SFO, and BMI did not demonstrate a significant impact. Myosteatosis was significantly associated with OS after adjusting for other clinical factors, which suggests a possibility of a novel prognostic marker in pts with aUC receiving ICI.

Assessing molecular heterogeneity of prostate cancer biopsy sampling: Insights from the MAST trial.

240 Background: Prostate cancer is heterogeneous and multi-focal, and biopsy sampling often undersamples the tumor or samples different tumor foci. Such heterogeneity can lead to inaccurate molecular classifications of tumor biology on tissue-based prognostic tests. Consequently, this impacts treatment decision making and management in localized prostate cancer. Herein, we evaluate the degree of variability in transcriptomic profiles when assessing genomic profiles from MRI-guided versus template biopsy using the Decipher GRID platform. Methods: A total of 205 men enrolled in the Miami MRI selection for Active Surveillance versus Treatment (MAST) trial (NCT02242773), from which 408 biopsy samples from 159 patients with successful genomic profiling were used in this study. Across the whole time-course, all biopsy cores with successful gene expression profiling were categorized by mpMRI-targeted (149 samples) or template (259 samples) sampling. Three main prognostic signatures (Decipher genomic classifier DGC, derived cell cycle progression CCP, and derived Genomic Prostate score GPS) were used to assess the variation in genomic risk between MRI targeted and template cores and among different PI-RADS lesions. Similar analysis was performed in a selected cohort with Gleason grade 1 disease only to exclude the impact of grade on genomic risk assessment. Results: Using the main genomic signatures in unpaired analysis (comparing all targeted and template biopsies), targeted lesions had higher scores as compared to the random biopsies, except for Decipher score (p=0.105). However, in the paired analysis (only including targets and templates from the same patient), we saw no difference between the groups in all three of the signatures. In the subset of patients with GG1, there was no difference between random and targeted biopsies in paired analysis. Among MRI targeted biopsy cores, PI-RADS level was correlated to Decipher and CCP scores with higher PI-RADS levels resulting in higher genomic scores (p=0.007 and 0.002, respectively). However, when restricting to a subgroup of patients with only GG1 cancer, there was no longer an association between PIRADS and genomic score. Higher concordance of DGC scores between visible and non-visible lesions were observed in the low-risk group. Conclusions: mpMRI sampling showed higher genomic scores compared to template sampling. While we see an association between higher PI-RADS scores and higher genomic scores, this relationship appeared to be driven by grade. Among the subgroup of men with GG1 cores, we found no association between PI-RADS and genomic scores. These findings need further validation in a larger cohort to truly understand the impact of MRI targeting on genomic risk assessment among AS patients. Clinical trial information: NCT02242773 .

Belzutifan monotherapy in Chinese patients (pts) with von Hippel-Lindau (VHL) disease–associated tumors: Results of LITESPARK-015 study.

534 Background: Pts with VHL disease are at risk of developing malignant tumors such as renal cell carcinoma (RCC) due to VHL gene inactivation, leading to activation of hypoxia-inducible factors (HIFs). In the phase 2 LITESPARK-004 study, HIF-2α inhibitor belzutifan (MK-6482) demonstrated antitumor activity and a manageable safety profile in pts with VHL disease–associated tumors; however, the study did not include pts from Asia. We present results for pts from mainland China with VHL disease–associated localized tumors enrolled in cohort B1 of the phase 2, open-label, single-arm LITESPARK-015 study (NCT04924075). Methods: Eligible pts were aged ≥18 yrs with localized VHL disease–associated tumors diagnosed by local germline testing and/or clinically (per family history and ≥1 VHL-related tumor, ≥2 retinal/central nervous system [CNS]-hemangioblastomas [HBs], or 1 retinal/CNS-HB and ≥1 VHL-related visceral tumor [except renal/epididymal cysts]), and with ≥1 measurable pheochromocytoma/paraganglioma (PPGL), pancreatic neuroendocrine tumor (pNET), or RCC per RECIST v1.1 by blinded independent central review (BICR) not requiring immediate surgery. Pts received belzutifan 120 mg orally QD until PD or unacceptable toxicity. A primary endpoint for cohort B1 was ORR per RECIST v1.1 by BICR in VHL disease–associated RCC in patients from China. Secondary endpoints included disease control rate (DCR), time to response (TTR), duration of response (DOR), PFS (BICR), OS, and safety. Results: 23 pts from China enrolled and treated in cohort B1 had ≥1 primary tumor: RCC, n=18; CNS-HB (solid component), n=7; CNS-HB (solid + cystic components), n=10; pNET, n=12; and PPGL, n=4. Median study follow-up was 14.9 (range, 12.0–17.1) months at data cutoff (May 23, 2024). ORR in pts with RCC was 83% (95% CI, 59%–96%); 15 pts achieved PR. All 4 pts with PPGL had SD. Additional data are shown in the Table. No PFS or OS events had occurred. All-cause AEs occurred in all 23 pts (100%), most commonly (incidence ≥20%) anemia, ALT increased, AST increased, asthenia, URI, and GGT increased. Grade 3 AEs occurred in 9 pts (39%; no grade 4–5), serious AEs in 3 pts (13%). AEs that led to treatment discontinuation occurred in 1 pt (treatment-related tumor hemorrhage of kidney). Conclusions: Belzutifan showed a favorable benefit/risk profile for VHL disease–associated localized tumors in pts from China, with a clinically meaningful response rate, durable responses, and manageable safety profile. Clinical trial information: NCT04924075 . RCCN = 18 a CNS-HB (Solid)N = 7 a CNS-HB (Solid + Cystic)N = 10 a pNETN = 12 a ORR (95% CI), % 83(59–96) 100(59–100) 60(26–88) 67(35–90) DCR (95% CI), % 100(82–100) 100(59–100) 100(69–100) 100(74–100) TTR, median (range), mo 5.6(2.7–11.1) 2.8(2.6–3.0) 2.9(2.6–5.6) 5.6(2.5–8.4) DOR, median (range), mo NR(2.7+ to 11.1+) NR(8.1+ to 14.1+) NR(5.6+ to 14.1+) NR(2.8+ to 11.3+) a Pts may have had ≥1 primary tumor type.

Sensitive tissue-based detection of AR-V7 and other androgen receptor alterations using combined DNA/RNA comprehensive genomic profiling.

195 Background: Mechanisms of resistance to agents targeting the androgen receptor (AR) axis in prostate cancer (PC) include AR amplification (AMP), ligand-binding domain mutations (MUT), and splice variants (AR-Vs), such as AR-V7, which has been associated with resistance to the AR signaling inhibitors (ARSi) abiraterone and enzalutamide in castration resistant PC (CRPC). Clinically employed AR-V7 assays involve detection in circulating tumor cells (CTCs) based on either nuclear protein immunofluorescent staining or RNA expression. We sought to define the AR landscape of PC using DNA and RNA comprehensive genomic profiling (CGP) of tissue biopsies (TBx). Methods: We queried an institutional database (Foundation Medicine, Inc.) of CGP results. DNA and RNA co-extracted from formalin fixed paraffin embedded (FFPE) tumor TBx were profiled, respectively, using FoundationOne CDx (F1CDx) and FoundationOne RNA (F1RNA). AR-V7 positivity was defined by the presence of ≥10 unambiguous supporting reads in RNA. In DNA, AMP was defined as an amplification ratio of the modeled gene copy number to sample ploidy of ≥3. Results: 94% (51/54) of PC FFPE samples underwent successful F1CDx + F1RNA, while 3 of 54 had inadequate RNA. The most commonly altered genes were AR (51.9%), PTEN (37.0%), ERG (25.9%), TP53 (24.1%) and SPOP (13.0%). AR alterations were more prevalent in metastatic/non-primary tumor versus primary prostate biopsy sites (70.6% [12/17] vs 43.2% [16/37]). Notably, 6 AR-V7+ prostate tumors were confirmed as hormone naive. 82.1% (23/28) of AR -altered samples harbored AR-V7 with no other detected AR alteration, while 4 samples with AR-V7 harbored additional AR DNA alterations (3 w/ AMP, 1 w/ MUT), all of which were from secondary TBx sites. Conclusions: We describe the prevalence of AR alterations in PC TBx using F1CDx, which captures AR AMP and MUT in DNA, and F1RNA, which detects AR-V7 in RNA. The high prevalence of AR-V7 in secondary TBx sites in our cohort (>70%) reflects known increased expression associated with successive lines of anti-androgen/AR therapy. However, a high prevalence of AR-V7 was also detected in primary prostate biopsies (>40% compared to a reported <1% in CTCs), including in 6 hormone naive patients, suggesting sensitivity to detect low-level abundance even in hormone sensitive PC (HSPC). While detection of AR-V7 in CTCs suggests a patient may benefit from taxane chemotherapy over an ARSi in the setting of CRPC, the clinical significance in HSPC is not well understood. Clinical validation is required to determine the utility of AR-V7 detection in TBx using F1RNA in both the CRPC and HSPC settings. A combination DNA/RNA CGP strategy reporting on the spectrum of AR resistance alterations (AMP, MUT, AR-V7), along with non- AR genomic features, has the potential to enable informed use of ARSi and other agents at key decision nodes in PC patient care.

High-power femtosecond mid-IR source with tunable center frequency and chirp

We present an experimental implementation of a chirped mid-infrared (mid-IR) high-power laser source with variable center frequency between 4 and 30 THz and continuously tunable frequency sweep of up to 20% within one pulse, with a pulse duration of 2 ps. The peak electric field obtained at 4 THz is 1.5 MV/cm. We generate the mid-IR light using a difference-frequency generation process with two phase-locked, chirped IR pulses. The obtained mid-IR electric field waveform is characterized using electro-optic sampling. We compare our experimental results with the predictions of numerical simulations. The results indicate the potential for efficient driving of vibrational modes into a strongly anharmonic regime, in cases where using Fourier-transform-limited pulses to achieve similar vibrational amplitudes would lead to dielectric breakdown.

Anion gap predicting 90-Day mortality and guiding furosemide use in ARDS

Clinical significance of urotensin 2 plasma level in patients diagnosed with prostate cancer.

249 Background: Urotensin-II is a small somatostatin-like cyclic peptide characterized by its potent vasoconstrictor activity. Urotensin-II (UT-II) and its receptor (UTR) have been shown to play a role in the formation of different epithelial cancers. To date, many studies have been reported in prostate cancer that provide genetic contributions with diagnostic, prognostic and therapeutic potential for carcinogenesis. However, the role of urotensin-II in prostate carcinogenesis has not yet been elucidated. There are several limitations to using PSA as a biomarker in prostate cancer follow-up. More accurate and specific biomarkers are needed to improve diagnosis and monitoring of prostate cancer. Our study aimed to reveal the clinical importance of plasma UT-2 level in metastatic prostate cancer patients and to investigate its correlation and prognostic importance with clinical parameters such as PSA level and pathological parameters such as Gleason Score. Methods: Patients who applied to İzmir Katip Celebi University Atatürk Training and Research Hospital Medical Oncology Polyclinic in 2023 were included in our study. The demographic information of the patients was scanned from the oncology file system and recorded. Measurements of plasma ÜT-2 level were made by a biochemistry specialist at İzmir Katip Celebi University Atatürk Training and Research Hospital Biochemistry Laboratory. For the ELISA method, Urotensin 2 ELISA (Elabscience lot no: E-EL-2047) kit was used in the Biotek (ELx800, USA) semi-automatic ELISA device. Results: A total of 147 patients, 100 metastatic and 47 control groups, were included in our study. No statistically significant difference was observed between the groups in terms of additional diseases that may be related to UT-2 level: Diabetes Mellitus, hypertension, peripheral artery disease, coronary artery disease, chronic renal failure and smoking characteristics (p>0.05). When the PT-2 level was compared between the de-novo and non-de-novo metastasis groups and the control groups, both metastasis groups had a higher average than the control groups (p = 0.004). The cut-off value for UT-2 was determined as 1.269 ng/mL. UT-2 sensitivity, specificity, positive predictive value and negative predictive value were found to be 81%, 53%, 79% and 57%, respectively. Conclusions: Today, studies are continuing rapidly to increase the efficiency of PSA and to find new tumor markers. In our study, UT-2 levels in metastatic prostate cancer patients were found to be statistically higher than other groups. This is the first study in the literature to study the UT-2 plasma level in prostate cancer, and UT-2 may be an important biomarker in predicting prognosis in prostate cancer.

Association between combination of VI-RADS based on T2WI and morphological features and pathological outcome and prognosis in bladder cancer.

690 Background: VI-RADS is widely used to identify muscle-invasive bladder cancer (MIBC). However, it is not known whether structural category (SC; VI-RADS based on T2-weighted images) alone is useful in diagnosing clinicopathological features and prognosis of bladder cancer. This study investigates the diagnostic performance of SC in the detection of MIBC. We also measured tumour contact length (TCL), difference in signal intensity ratio (dSIR) and coefficient of variation (CV) within the tumour on T2WI. We evaluated whether these factors could improve the diagnostic performance of SC for MIBC and explored the correlation between these morphological features and clinicopathological characteristics and prognosis. Methods: Between August 2018 and July 2023, we performed 587 transurethral resections of bladder tumours. This study includes 236 patients who underwent preoperative MRI. We first evaluated the diagnostic performance of VI-RADS and SC for MIBC. TCL, dSIR and CV were measured on T2WI. The dSIR was defined as the difference between the signal intensity (SI) of the tumour and that of the underlying muscle layer, divided by the SI of the normal muscle layer. The CV was calculated as the standard deviation of the SI within the tumour divided by the mean SI. All patients were divided into high and low SC groups and the relationship between MIBC and TCL, dSIR and CV was examined. Cut-off values for the diagnosis of MIBC and overall survival (OS) were calculated based on ROC curves for the most correlated factors in each group, which were added to the SC score to evaluate the diagnostic value. We also examined the correlation between each factor and pathological findings. Results: The diagnostic performance of VI-RADS with a cut-off score of 4 was an AUC of 0.888. Meanwhile, the diagnostic performance of SC with a cut-off score of 4 was AUC of 0.885. The association between MIBC and each factor was compared in the SC≥4 and SC≤3 groups. In the SC≥4, multivariate analysis showed significant differences in dSIR (p<0.001). In the SC≤3, multivariate analysis showed TCL is significantly longer in MIBC (p<0.001). The diagnostic performance was an AUC of 0.912 for suspected MIBC with SC≥4 and dSIR<1.03 and SC≤3 and TCL≥36mm. In pathological features, TCL is significantly longer in high-grade (p=0.018), necrosis(p<0.001), variant(p=0.002), lymph node metastasis (p<0.001) and organ metastasis (p<0.035). Univariate COX analysis showed that SC≥4 was risk factors for OS (HR = 2.15, P = 0.031). In the SC≥4, patients with TCL≥40 mm had worse OS (HR = 3.06, P < 0.015). In the SC≤3, patients with TCL≥31 mm had worse OS (HR = 10.59, P < 0.001). Conclusions: The present study showed that SC combined with dSIR and TCL has good diagnostic performance for MIBC. We also found that TCL correlates with high-grade tumor, necrosis, and variant histology. The combination of SC and TCL effectively predicts OS in bladder cancer.

The CABOLD study: A real life prospective cohort evaluating the combination of cabozantinib and nivolumab among older patients with renal-cell carcinoma.

TPS607 Background: In the era of combination therapy, and due to age-related physiological changes, management of older patients with Clear-cell renal cell carcinoma (ccRCC) is a challenge. The combination of cabozantinib and nivolumab is one of the recommended treatments in untreated metastatic or locally advanced ccRCC. However, data regarding the use of this treatment among 70 years old or more (70+) patients are scarce. The CABOLD study seeks to address these gaps by assessing the real-life use of this combination in older patients. Methods: The CABOLD study is a prospective, multicentric, single-arm cohort trial conducted across 10 centers in France. It aims to enroll 50 patients aged 70 years and above with advanced or metastatic ccRCC, who are treatment-naïve in this setting. Eligible participants must have a Performance Status (PS) of 0 to 2. Patients will receive standard-of-care treatment consisting of cabozantinib at 40 mg daily and nivolumab on a 28-day cycle (240 mg on Days 1 and 15 for the first two cycles, followed by 480 mg on Day 1 for subsequent cycles). The starting dose of cabozantinib may be reduced to 20 mg daily at the investigator’s discretion. Patients will benefit of a multi-modal follow-up including medical oncologists, geriatricians and trained nurses to monitor safety closely. Abbreviated geriatric assessment, using G-CODE, will be performed at inclusion, under treatment, and during follow-up, along with quality of life (QoL) evaluation. Optional pharmacological monitoring for cabozantinib will be conducted to assess potential associations with clinical outcomes. Patients will be followed for 12 months in the study, followed by a long-term follow-up after one year. Primary objective is to describe real-life treatment patterns of nivolumab-cabozantinib, including dose modifications and interruptions due to toxicity. Main secondary objectives include efficacy, survival, tolerance, QoL. Enrollment for the study has not yet begun at the time of submission. The CABOLD study is designed to provide insights into the real-world use of cabozantinib and nivolumab in 70+ patients with metastatic ccRCC. By incorporating geriatric assessments and pharmacological monitoring, the trial aims to improve our understanding of treatment tolerability, efficacy, and quality of life in this vulnerable population, potentially guiding tailored therapeutic strategies for older adults with RCC.

Metastasis-directed treatment (MDT) for patients (pts) with non-clear cell renal cell carcinoma (nccRCC): Results from a matched 15-year retrospective cohort.

497 Background: nccRCC represents a diverse group of diseases with variable clinicopathological features. We aimed to evaluate the impact of MDT on clinical outcomes of pts with nccRCC. Methods: We reviewed our institutional database (São Paulo State Cancer Institute, University of São Paulo) to identify pts with ICD-C64 (kidney cancer) with nccRCC. Electronic medical records were reviewed to register the clinical and pathological features. Histological subtypes were classified as per the 2022 World Health Organization classification. MDT was considered as any focal treatment (surgery or radiation) given with non-palliative intent. Overall survival (OS) was calculated as the time from diagnosis of metastatic disease until death or last follow-up. Survival probabilities were estimated using the Kaplan-Meier method and compared via the log-rank test. To correct for imbalances between MDT recipients and non-recipients, we applied a propensity score matching based on the International Metastatic RCC Database Consortium (IMDC) classification, ECOG-PS, subtype, number of affected organs, and presence of sarcomatoid features in the primary tumor. Results: From September 2009 to January 2024, we identified 2,867 pts with kidney cancer. From 620 pts diagnosed with nccRCC, 143 (23.1%) had metastatic disease. Of these, MDT was administered to 39 pts. Clinicopathological features of pts treated with MDT vs. non-treated with MDT were described in the table. Most common MDT was surgery (n=30), followed by radiosurgery (n=9). MDT was associated with improved OS (HR 0.24, 95% CI 0.14-0.40, median 8.0 vs. 58.6 months), confirmed after propensity score matching (HR 0.31, 95% CI 0.17-0.56, median 17.5 vs. 58.6 months). In the matched cohorts, MDT was associated with increased OS in chromophobe (HR 0.33; 95% CI 0.08-1.29, median 23.3 vs. 69.3 months), papillary (HR 0.29; 95% CI 0.12-0.70, median 16.7 vs. 47.7 months), and unclassified subtypes (HR 0.16; 95% CI 0.04-0.66, median 3.1 vs. 18.9 months). Conclusions: This retrospective analysis suggests that a subset of pts with nccRCC may benefit from MDT, regardless of histological subtype. Clinicopathological features of pts treated with MDT vs. non-treated with MDT. Variable Overall Population (%) MDT (%) Non-MDT (%) Age (median) 57 53.8 57.3 T StageT1- T2T3-T4 25 (17)90 (62) 11 (28)22 (56) 14 (13)68 (64) IMDCFavorableIntermediatePoor 29 (20)64 (44)49 (34) 13 (33)19 (49)6 (15) 16 (15)45 (42)43 (40) ECOG0 – 1≥2 93 (64)42 (29) 32 (82)4 (10) 61 (57)38 (36) SubtypePapillary Chromophobe Collecting DuctAngiomyolipoma MIT Translocation Unclassified Others Medullary carcinoma 72 (49) 20 (13) 4 (3) 1 (1) 12 (8) 25 (17) 7 (5) 5 (3) 19 (48)9 (23)001 (3)8 (21)2 (5)0 53 (50)11 (10)4 (4)1 (1)11 (10)17 (16)5 (5)5 (5) MetastasisLungLiverCNSBone 59 (40)15 (10) 48 (33) 76 (52) 14 (36)13 (33)6 (15)13 (33) 62 (58)35 (33)9 (8)46 (43)

Exploring the potential of 2D PtTe2-based memristors for neuromorphic computing

Neuromimetic devices have emerged as transformative technologies with the potential to redefine traditional computing paradigms and enable advanced artificial neural systems. Among various innovative materials, two-dimensional (2D) materials have garnered attention as frontrunners for next-generation device fabrication. In this work, we report the fabrication and comprehensive characterization of a memristor based on 2D PtTe2. The device demonstrates exceptional performance metrics, including a high OFF/ON ratio, low switching voltage, and long data retention time. Leveraging density functional theory calculations, we unravel the underlying conduction mechanism, revealing the pivotal role of Ag conductive filaments in resistive switching behavior. Furthermore, the neuromorphic capabilities of the PtTe2 memristor were evaluated through its emulation of key brain-inspired synaptic functionalities, such as long-term depression/enhancement, paired-pulse facilitation, and spike-timing-dependent plasticity. By modulating its electrical conductance, we implemented a convolutional neural network for MNIST handwritten digit recognition, achieving a remarkable accuracy of 97.49%. To further illustrate its adaptive learning capabilities, we demonstrated a Pavlov's dog experiment using the device. This study establishes 2D PtTe2 as a promising material for neuromorphic applications and represents a critical step forward in bridging the gap between advanced materials and next-generation computing architectures. These findings lay a robust foundation for future exploration of PtTe2 in the field of neuromorphic engineering.

Lightweight mechanical equipment fault diagnosis framework based on GCGAN-MDSCNN-ICA model

Assessment of <i>PARP1</i> mRNA expression as prognostic of aggressive pathology and adverse outcomes, and as predictor of response to PARP inhibition in castration-sensitive prostate cancer.

202 Background: While several PARP inhibitors are approved in combination with hormonal therapies for metastatic castrate resistant prostate cancer (CRPC), their use in castrate sensitive prostate cancer (CSPC) is understudied. We previously reported that olaparib monotherapy (without ADT) shows significant clinical activity in BRCA2 -altered patients with biochemically recurrent (BCR) prostate cancer. Here, we explored prognostic and predictive PARP-related mRNA biomarkers derived from primary prostate tumors. Methods: We characterized the expression of 16 PARP transcripts using a cohort of 52,266 radical prostatectomy (RP) specimens (2016-2024) undergoing Decipher prostate genomic classifier testing (Veracyte Inc). Transcriptome-wide mRNA expression data as well as baseline clinical/pathologic factors were retrieved from the Decipher GRID database (NCT02609269). Associations between high PARP expression (top 25%), baseline factors, and gene signatures were examined using logistic regression. We assessed the association between PARP expression and distant metastases in 3 retrospective cohorts (n= 545, 855, and 325). Finally, we evaluated PARP expression in our prior phase II trial (NCT03047135, n=39) of olaparib monotherapy in the setting of BCR following RP. Results: Higher mRNA levels of PARP1 , 2 , 8 and 14 showed strong associations (all P &lt;0.001) with known adverse prognostic factors such as very-high Decipher score (&gt;0.85), high Gleason grade (GG5) and non-organ confined disease (EPE, SVI and LNI), while higher PARP6 and 7 expression were associated with more favorable disease characteristics. High PARP1 expression was positively correlated with DNA-repair deficiency (r=0.77) and tumor immune microenvironment (r=0.62) signatures. In 3 independent retrospective cohorts of intermediate-high risk PCa patients, higher PARP1 expression was strongly associated with development of distant metastases after RP (HR 1.70, 1.81, and 1.67 respectively; all P &lt;0.05). Finally, in our phase II trial of patients with BCR who received olaparib monotherapy, PARP1 (but not PARP2 ) expression from RP was 1.5-fold higher in samples with BRCA2 mutations (median 0.416 vs 0.276, P =0.01) and was associated with overall improved PSA progression-free survival (continuous variable, HR 0.55, P =0.01) and longer time to next systemic treatment (continuous variable, HR 0.66, P =0.02). Conclusions: High PARP1 mRNA expression, measured at RP, is associated with aggressive disease biology and greater risk of metastasis. However, high PARP1 (but not PARP2 ) levels are associated with improved response to PARP inhibition in the setting of BCR prostate cancer. Future trials testing PARP (including PARP1-selective) inhibitors in the CSPC space should consider measuring PARP1 mRNA levels in addition to BRCA1/2 mutation status. Clinical trial information: NCT02609269 , NCT03047135 .

Phase II study of oral APL-1202 plus tislelizumab or tislelizumab alone as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC).

793 Background: Interim results of the randomized phase II trial of neoadjuvant tislelizumab +/- oral APL-1202 (nitroxoline) revealed promising pathological complete response (pCR) rates and met prespecified thresholds for study expansion (ASCO GU 2024). Here, we report the final primary endpoint analysis of this trial. Methods: Patients with cT2-T4aN0M0 urothelial cancer of the bladder based on local assessment, planned for radical cystectomy (RC), and ineligible for or refusing cisplatin-based chemotherapy were eligible. Patients were randomly assigned to APL-1202 plus tislelizumab (A+T) or tislelizumab (T), stratified by PD-L1 expression. Neoadjuvant tislelizumab was administered q3weeks for 3 cycles and APL1202 was administered orally tid. The primary endpoint was centrally assessed (pCR, pT0N0) rate and secondary endpoints included central pathologic response (PaR, &lt; ypT2N0) rate and safety. Results: A total of 103 patients were enrolled; 28 patients declined RC after neoadjuvant treatment (A+T=16, T=12). Consequently, 75 patients remained in the efficacy analysis set (EAS); RC was completed after A+T in 42/43 patients and after T in 31/32 patients. The pCR and PaR results in the EAS are presented in the table. On retrospective central pathology review of baseline TURBT specimens, a large subset of patients were determined to be ineligible due to &lt;cT2 disease (33/75). There was a numerically higher pCR rate in an exploratory analysis of this retrospectively defined ‘protocol eligible’ subset (A+T: 9/22, T: 4/20). Treatment related adverse events (TRAEs) occurred in 35 (59%) on the A+T arm and 19 (44%) on the T arm. TRAEs (94%) were predominantly ≤ CTCAE grade 2. Conclusions: Neoadjuvant A+T in cisplatin-ineligible patients prior to RC was safe. Evaluation of the efficacy in MIBC is complicated by the large subset of patients enrolled retrospectively determined to have &lt;cT2 disease but pCR rates were similar between groups in the EAS. A signal of higher activity of A+T may be present in PD-L1 “low” tumors supporting further exploration of the immunomodulatory effects of A+T. Evaluation of efficacy is further complicated by a large subset of patients declining RC after neoadjuvant treatment underlining the need for novel bladder-sparing approaches. Clinical trial information: NCT04813107 . pCR rate, pT0N0 PaR rate, &lt; ypT2N0 EAS (n=75) n(%) A+T (n=43) T (n=32) A+T (n=43) T (n=32) All evaluable patients 12 (33)* 7 (26)* 19 (44) 13 (41) PD-L1 h igh 5/18 (28) 4/16 (25) 7/18 (39) 8/16 (50) PD-L1 l ow 7/25 (28) 3/16 (19) 12/25 (48) 5/16 (31) *pCR rate is calculated using UMVUE method when the final sample size of Simon's two-stage is changed.

Outcomes of high-risk prostate-specific antigen level during active surveillance with targeted and systematic prostate biopsy.

343 Background: National Comprehensive Cancer Network (NCCN) recommendations for very low to intermediate-risk prostate cancer (PCa) include active surveillance (AS). Patients who develop a prostate-specific antigen (PSA) level over 20 ng/mL during AS, however, are re-classified as NCCN high-risk and are recommended to undergo definitive management. In the past decade, the diagnostic accuracy for PCa has significantly improved with a combined approach to prostate biopsies (magnetic resonance imaging and ultrasound fusion targeting + systematic). This study aims to describe the outcomes of patients who continued AS following a PSA of 20 ng/mL or higher. Methods: Patient information and clinical data were obtained from a prospectively maintained database at the National Cancer Institute (NCT02594202). Patients on AS with a minimum of one subsequent combined biopsy (fusion + systematic) following a PSA of 20 ng/mL or higher were identified. Descriptive statistics were obtained using GraphPad Prism 10.1 (Boston, Massachusetts USA). Results: A total of 20 patients were identified, of whom 15 (67.7%) subsequently underwent definitive management. Patients had a median age of 72.0 [IQR 71-74.8] years, with a median of 13 [IQR 10-12] years on AS. In the continued AS cohort, the most recent PSA was below 20 ng/mL in two patients with a median of 22.9 ng/mL [IQR 15.2 -23.6], while repeat biopsy showed benign tissue or grade group (GG) 1 disease. In those who underwent definitive management, the last PSA on AS was a median of 23.2 ng/mL [IQR 21.9-32.8], with all patients having GG 2 or higher disease. Twelve patients underwent surgery and three external beam radiotherapy with long-term androgen deprivation therapy, within a median time of 2 mos [IQR 2.0 - 2.5 mos] after their last biopsy. For those who underwent surgery, 4 (33.3%) had GG upstaging, 2 (16.7%) had GG downstaging, while 6 (50.0%) had no change in overall GG on final pathology. The first post-operative PSA was undetectable in all but one patient. Conclusions: A PSA greater than 20 ng/mL is a high-risk feature that continues to have clinical significance during AS in the contemporary era of combined prostate biopsies. In our small cohort, one quarter of the patients remain on AS, while three-quarters of the patients underwent definitive management. GG upgrading occurred in one third of patients and therefore continued AS in these patients should be approached with caution and limited to those with benign findings or GG 1 disease on follow-up combined biopsy.

Determining optimal patient selection for high-intensity focused ultrasound (HIFU) for prostate cancer: Results from a single-institution cohort.

362 Background: High-intensity focused ultrasound (HIFU) uses magnetic resonance imaging (MRI) and transrectal ultrasound to target areas affected by prostate cancer (PCa). HIFU has moderate PCa control outcomes with little impact on sexual or urinary side effects, but there is concern for disease recurrence and need for salvage treatment. Here we share institutional biopsy-proven recurrence and treatment failure outcomes following HIFU and identify clinicodemographic factors associated with adverse outcomes. Methods: All men who underwent robotic HIFU (Focal One) in 2021-2023 at the University of California, San Francisco and underwent 1-year post-procedure MRI-fusion biopsy were included. The primary outcome was treatment failure, defined as salvage treatment or metastases. Secondary outcomes were in-field recurrence, defined as Gleason Grade 2 (≥GG2) in the same region of HIFU treatment, overall recurrence, defined as ≥GG2 diagnosed anywhere in the prostate, and change in urinary and sexual function by International Prostate Symptom Score (IPSS) and Sexual Health Inventory for Men (SHIM) scores, respectively. Cox Proportional Hazards regression models and multivariable logistic regression and were used to estimate associations between clinical characteristics and outcome events. Results: Of 133 men who underwent HIFU, 110 had post-HIFU biopsy follow-up at median (IQR) of 12.5 (12-14) months. 18 (16%) had treatment failure, and median (IQR) time from recurrence to salvage treatment for 16 men was 3.5 (2-5) months. Cox proportional hazard regression showed pre-HIFU PSA to be associated with the risk of treatment failure (HR 1.14; 95% CI 1.05-1.24; p&lt;0.01). Additional modeling comparing clinically relevant PSA groupings (&lt;6, 6-10, and &gt;10) revealed a significant association between treatment failure and PSA &gt;10 (HR 5.35; 95% CI 1.54-18.57; p&lt;0.01), but not PSA 6-10 (HR 1.94; 95% CI 0.53-7.06). In-field and overall recurrence on 1-year biopsy was 42% and 50%, respectively. On logistic regression analysis, pre-HIFU Gleason Grade of 3 or greater (≥GG3) was associated with a higher likelihood of in-field recurrence (OR, 3.11; 95% CI, 1.13-8.56), and both ≥GG3 (OR 3.07; 95% CI 1.04-9.10, p=0.04) and higher PSA (OR 1.20; 95% CI 1.05-1.37; p&lt;0.01) were associated with a higher likelihood of overall recurrence. No significant differences were found for IPSS and SHIM scoring groups before and after HIFU. Conclusions: Treatment failure rate was 16%, and in-field and overall recurrence rates on biopsy one year after HIFU were 42% and 50%, respectively. Higher pre-HIFU PSA was associated with treatment failure and overall recurrence on biopsy, and ≥GG3 was associated with in-field and overall recurrence on biopsy. These findings emphasize the importance of careful patient selection for HIFU, which has potential for modest cancer control with minimal side effects in the appropriate PCa patient.

Inductive effect of charge transfer in ferroelectrics and plasmonic Ag heterojunctions for enhanced CO2 photoreduction

Converting carbon dioxide into fuel and chemicals by utilizing solar energy represents a cutting-edge approach to carbon recovery and energy renewal. The transfer behavior of photogenerated electrons and built-in electric field of photocatalysts greatly affect the efficiency of the photoreduction reaction. Herein, the heterostructures composed of bismuth sodium titanate (BNT) ferroelectrics and silver nanoparticles (Ag NPs) are constructed to promote the photocatalytic CO2 performance. The large spontaneous polarization of BNT optimizes the transfer dynamics of photoinduced electrons and holes and causes energy band bending with strong intrinsic electric field. With the aid of Ag NPs, the BNT@xAg heterojunctions exhibit intensified light absorption due to the phenomenon of localized surface plasmon resonance (LSPR), which extends the visible light absorption spectrum and strengthens charge transfer. The modified catalysts demonstrate improved charge separation capacity and notably prolonged electron lifetime up to 40.95 ns. The synergistic effect of LSPR and intrinsic polarization significantly boosts the photocatalytic efficiency together with ultrahigh CO product selectivity, which is outstanding among the ferroelectric and other representative photocatalysts. This study elucidates the photocatalytic enhancement mechanism of plasmonic Ag decorated BNT and offers an alternative route for the design of efficient catalysts.

Standalone ultrasound-based highly visualized volumetric spine imaging for surgical navigation

Gut microbiota as a biomarker for the efficacy of pembrolizumab in patients with advanced urothelial carcinoma treated in a prospective multicenter study.

825 Background: Pembrolizumab (Pb) is a treatment (trt) for advanced urothelial carcinoma (aUC). In this study, we analyzed the fecal metaproteome of aUC patients (pts) to investigate the differences in the taxonomic and functional composition of the gut microbiome in responders (R) vs non-responders (NR) to pembrolizumab monotherapy as second-line trt. Methods: We designed a prospective multicenter study in France. Stool samples were collected before and nine weeks after the start of Pb, with a maximum follow-up of 36 weeks. Trt efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors v1.1. Proteins were extracted from each sample and analyzed using high-resolution tandem mass spectrometry combined with liquid reverse phase chromatography. Raw data were interpreted without a priori assumptions. The R package Metacoder was used to analyze taxonomic diversity, while the mixOmics package was used to perform partial least squares discriminant analysis (sPLSDA) to reveal microbiota changes between R and NR pts. A Benjamini-Hochberg (BH)-corrected Wilcoxon test identified microbial functions with different frequencies in R and NR pts. A multivariate logistic regression analysis with Bonferroni correction was conducted to create a response-prediction classifier based on clinical variables and identified relevant microbial genera. The significance threshold was set at 5%. Results: From 2019 to 2022, 53 samples were taken from 34 different pts. Of these, 3 (8.8%) pts with complete response, 5 (14.7%) with partial response and 2 (5.9%) with stable disease were classified as R. Four (11.8%) deceased pts before response evaluation were excluded from the analysis. NR corresponded to disease progression in 20 pts (58.8%). No dysbiosis was detected. There were no statistically significant differences in alpha diversity over time or between R and NR. Beta diversity index showed microbiome stability at individual level during follow-up. sPLSDA at the genus level pooling all samples (before and after trt) showed a distinctive separation between R and NR (p ≤ 0.05). Of the genera contributing most to this separation, 4 genera were identified using logistic regression: Anaerostipes, Sutterella, Escherichia, Evtepia (adj. p ≤ 0.05). Functional composition analysis identified 31 signaling pathways that differ between R and NR. These signaling pathways were clustered highlighting 7 functions that differed between R and NR when modulated by Pb. Host function analysis identified the “response to external biotic stimuli” signaling pathway significantly associated to R (BH adj p-value ≤0.05). Conclusions: The composition of the gut microbiome and metabolic functions differed between R and NR pts with aUC under Pb. The genera Anaerostipes , Sutterella, Escherichia and Evtepia could be biomarkers for the efficacy of pembrolizumab. Clinical trial information: NCT03584659 .