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Patient perceptions about their treatment for muscle-invasive bladder cancer (MIBC) over the last decade.

765 Background: The Bladder Cancer Advocacy Network (BCAN) is a national patient advocacy organization that has promoted awareness about the signs, symptoms, diagnosis, treatment and need for a multidisciplinary approach to the care of patients with MIBC. To better understand the impact of these efforts, and patients’ perceptions of their care, we surveyed bladder cancer patients initially in 2013 and again in 2023 through the BCAN website. Methods: We developed a 32-question survey with input from physicians, nurses, patients and caregivers. The survey was posted on the BCAN website 06/13-10/14 (Cohort A) and again from 06/23-04/24 (Cohort B). Questions focused on time from initial symptoms to diagnosis and treatment; proportion seeing a medical oncologist (MO) or radiation oncologist (RO); and treatments offered/received. Results: Overall, 337 (243 and 94) patients completed the survey. Respondents were self-selected and most were from the US/Canada, male, white, and had at least an undergraduate education. Median age was 61 (cohort A; range 31-93) and 63 (cohort B; range 38-87), respectively, at the time of diagnosis. The most common presenting symptom was hematuria (88% vs 78%, p=0.05). Overall, 35% vs 30% (p=0.56) waited > 3 months to seek medical attention; in 38% and 43% it took > 3 months to obtain a pathologic diagnosis (p=0.76). Men were more likely than women to be diagnosed within 1-2 months of seeking medical attention: Cohort A (68% vs 47% p=0.03) and Cohort B (70% vs 37%, p=0.03). In both cohorts, prior to surgery, approximately 50% saw a medical oncologist and were offered neoadjuvant chemotherapy; however, less than 10% saw a radiation oncologist and were offered bladder sparing approaches. Most patients reported having all the necessary information, knowing the right questions to ask, and were satisfied with their choices. A higher proportion in Cohort A vs Cohort B felt they had enough time to make their decisions (77% vs 67%, p=0.004). Conclusions: Despite nearly two decades of advocacy, there are ongoing areas of unmet need in MIBC. These include reducing time to definitive diagnosis and treatment, especially in women, and increasing multidisciplinary assessments prior to definitive surgery. Respondents were self-selected, had access to the BCAN website, and were highly educated, potentially limiting the generalizability of these results.

ZnO/Cu2S PN-junctions with built-in electric field for enhanced CO2 electroreduction

A full stack strategy, including facilitating the capture of CO2 molecules on catalysts, regulating intermediates, and releasing products, is highly needed to break the bottleneck for CO2 electroreduction to CO. The electric field is expected to promote capture of CO2, reduce energy barriers of reaction, and efficiently release CO, boosting the overall CO2 reduction reaction (CO2RR) activities. In this work, ZnO/Cu2S PN-junctions with a built-in electric field were fabricated. Kelvin probe force microscopy measurements confirmed that the presence of the built-in electric field facilitates the adsorption of more CO2 molecules onto the catalyst surface. Furthermore, theoretical calculations and electrochemical testing demonstrated that the built-in electric field lowers the reaction energy barrier and effectively modulates the reaction intermediates, contributing to enhanced catalytic performance. This work provides a full stack strategy to improve CO2RR performance and thinking for gas-fed catalytic reactions.

Cross-cultural adaptation and multicentric validation of the Italian version of the Simplified Evaluation of CONsciousness Disorders (SECONDs)

Introduction The Coma Recovery Scale-Revised (CRS-R) is the recommended tool to assess consciousness in patients with prolonged Disorders of Consciousness (pDoC). However, the time needed to administer it may limit its use. A shorter tool has been validated: the Simplified Evaluation of CONsciousness Disorders (SECONDs). This multicentre study aimed to develop and validate a cross-cultural adaptation of the SECONDs into Italian. Methods An interdisciplinary expert team, from both Fondazione Don Carlo Gnocchi and Istituto Neurologico Carlo Besta, led the translation processes. Independent certified translators were also involved in a blinded modality. Patients diagnosed with Unresponsive Wakefulness Syndrome (UWS) or Minimally Conscious State (MCS) admitted to 3 Italian rehabilitation units were enrolled. The CRS-R and SECONDs were administered in 5 sessions over two weeks by 3 blinded examiners at each center (3 times, with 2 sessions conducted by the same examiner). Weighted Fleiss’ kappa and Spearman correlation coefficients were used to assess intrarater and interrater reliability and concurrent validity. Results Sixty adults with pDoC were assessed: 23 women; median age: 64 years; 14 trauma, median post-onset time: 2 months. Intrarater and interrater reliability showed almost perfect agreement (kappa coefficients 0.968 and 0.935, respectively; p<0.001). The comparison of CRS-R vs. SECONDs on the same day or the best out of 5 SECONDs/CRS-R led to a substantial to almost perfect agreement both for the total score of the CRS-R and the SECONDs’ Additional Index (ρ = 0.772–1.000; p<0.001) and for the consciousness diagnosis (k = 0.784–0.935; p<0.001). The disagreement rate between the overall best diagnosis of the SECONDs and the best CRS-R diagnosis was 6.7%. Conclusion The Italian version of the SECONDs has been cross-culturally adapted to serve as a shorter assessment tool for the diagnosis of pDoC. Our study shows its excellent reliability and concurrent validity when compared to the CRS-R.

Circuit implementation and analysis of a quantum-walk based search complement algorithm

Association between molecular changes and perioperative immunotherapy in patients with advanced clear cell renal cell carcinoma undergoing cytoreductive nephrectomy.

573 Background: Immunotherapy (IO) combinations are standard first-line treatments for advanced clear cell renal cell carcinoma (ccRCC). However, identifying patients who will respond to IO remains a challenge, complicating treatment selection. Previous studies on biomarkers for IO response or resistance often used unmatched biopsies, limiting insights into therapy-induced changes due to patient heterogeneity. This study aims to evaluate transcriptomic changes in matched pre- and post-IO patient samples to detect treatment-induced gene and pathway alterations. Methods: A retrospective analysis was performed on patients with advanced ccRCC receiving IO-based therapies who underwent cytoreductive nephrectomy (Nx) at UT Southwestern/Simmons Comprehensive Cancer Center (SCCC). Patient-level data were extracted from an IRB-approved registry, and samples were collected from the SCCC biorepository. The primary endpoint was to identify IO-induced transcriptomic changes using paired pre- and post-treatment tissue sections. Regions of interest (ROIs) were selected based on pan-cytokeratin (PanCK) expression using the GeoMx Digital Spatial Profiler (DSP, NanoString). Whole-transcriptome analysis was performed, and data were analyzed using a two-sample t-test. Results: We identified 58 patients with advanced ccRCC who received perioperative IO regimens and deferred Nx. Of these, 7 patients had paired pre- and post-treatment samples sequenced (3 received ipilimumab/nivolumab, 3 nivolumab, and 1 pembrolizumab/axitinib). Individual analysis of each matched pair revealed an average of 92 DE genes (log fold-change >1.3, p<0.01). Gene set enrichment analysis (GSEA) showed differential enrichment in pathways such as immune response (interleukin signaling, JAK/STAT signaling, innate immune system activation), translational machinery, MHC-mediated tumor antigen presentation, axon guidance, and cell death pathways. Notably, a key post-IO downregulated pathway was GPCR signaling, which is implicated in tumor growth and metastasis. Taken in aggregate, bulk analysis revealed only 9 differentially expressed (DE) genes in PanCK+ tumor regions, and GSEA did not identify commonly enriched pathways. Conclusions: While bulk analysis detected few changes, individual pair analysis highlighted significant transcriptomic shifts in RCC tumors post-IO. These RCC tumors upregulated gene expression in several immune pathways, including interleukin, JAK/STAT, and innate immune pathways. This study underscores the importance of matched samples to capture patient-specific changes after IO combinations.

Outcomes for ¹⁷⁷ Lu-PSMA-617 with and without concurrent use of ARPIs in patients with mCRPC.

112 Background: We now have more than a decade of experience using Androgen Receptor Pathway Inhibitors (ARPIs) across various disease states of prostate cancer, and the safety of their combination with Lutetium-177–PSMA-617 has been demonstrated in VISION and other large randomized clinical trials. However, real-world data on treatment patterns and outcomes involving combination therapies with 177 Lu-PSMA-617 remain limited. Methods: For this analysis, we utilized the Mayo Clinic Rochester radiopharmaceutical database, a prospectively maintained retrospective database containing all patients who received 177 Lu-PSMA-617 at our institution. We focused on patients who started treatment from March 2022 to March 2023. Patients receiving an ARPI (abiraterone acetate, enzalutamide, apalutamide, or darolutamide) during the course of 177 Lu-PSMA-617 treatment were identified, inclusive of patients who continued using an ARPI prescribed as a prior line of treatment and those who started (i.e., switched) to a new ARPI. Baseline clinicopathologic and imaging characteristics were abstracted and compared using the Mann-Whitney U and Chi-square tests. Best PSA response during treatment was reported as a percent decline from baseline. Survival was calculated from the date of the first cycle of 177 Lu-PSMA-617. PSA50 response and overall survival (OS) outcomes for the two groups (concurrent use of ARPI vs. 177 Lu-PSMA-617 alone) were compared using the Chi-square test and Kaplan-Meier method, respectively. A multivariate Cox regression analysis was performed, including established prognostic factors. Results: An ARPI was prescribed to 106 of the 256 patients (41.4%) starting 177 Lu-PSMA-617 in the interval of March 2022 to March 2023. With regards to baseline characteristics, those receiving an ARPI concurrently with 177 Lu-PSMA-617 had a lower PSA (3.4 vs 29.7 ng/mL, p < 0.001) and a lower frequency of bone (77.4% vs. 87.4%, p = 0.035) and visceral metastases (18.9 vs 34%, p = 0.008) at start of treatment. Median follow-up for the overall cohort (IQR) was 19.1 months (8.7 – 23.6). Patients receiving an ARPI plus 177 Lu-PSMA-617, as compared to 177 Lu-PSMA-617 alone, were more likely to complete all 6 planned doses of treatment (63.2% vs. 48.7%, p < 0.001), though the PSA50 response rate was similar (49.1% vs 47.3%, p = 0.786). Median OS [95% CI] for the overall cohort was 21.3 [16.7 – 25.9] months and significantly longer for those receiving ARPI with 177 Lu-PSMA-617 (NR [NE – NE]) as compared to 177 Lu-PSMA-617 alone (15.3 mo [11.6 – 19.1], p < 0.001). However, on multivariate analysis including known prognostic variables, use of ARPI was not independently associated with improved survival (HR = 1.03 [CI: 0.68 to 1.55], p = 0.891). Conclusions: Patients receiving an ARPI with 177 Lu-PSMA-617 were more likely to complete all 6 cycles of treatment, but no clear differences in survival were observed on multivariate analysis.

Use and clinical outcomes of androgen receptor inhibitors (ARIs) for non-metastatic castration resistant prostate cancer (nmCRPC) at labeled doses in Japan.

170 Background: The androgen receptor inhibitors (ARIs) darolutamide (DAR), enzalutamide (ENZ), and apalutamide (APA) are recommended for treatment of nmCRPC in Japan. However, not all patients (pts) start ARI treatment at the label dose. This study provides real-world variations in nmCRPC treatment dosing in Japan and their impact on pt outcomes. Methods: Retrospective observational cohort study using administrative health claims data from >480 acute care hospitals in Japan’s Medical Data Vision (MDV) database. Pts who started an ARI for the first time from 2/2020–4/2023 were classified into 3 cohorts based on the ARI (DAR, ENZ, or APA) prescribed for nmCRPC. This study describes the starting dose, treatment discontinuation and duration, and time to progression to metastatic castration-resistant prostate cancer (mCRPC) among pts who initiated treatment with ARIs at the label dose or lower (<100% label dose). Results: A total of 2746 pts with nmCRPC were treated with ARIs (DAR n=418; ENZ n=1898; APA n=430). Of these, the proportion of pts initiating treatment at the label dose was DAR 78%, ENZ 58%, and APA 62%. Of the pts who continued treatment at 6 months, the proportions receiving the label dose were DAR 76%, ENZ 57%, and APA 45%. Pts who initiated an ARI at the label dose tended to be younger and treated at cancer-specialist hospitals (Table). Among pts who initiated an ARI at the label dose, the DAR cohort had numerically lower discontinuation rates (49% vs ENZ [63%] and APA [74%]), and the probability of progression was lower for the DAR cohort vs ENZ and APA (Table). Among pts who initiated an ARI at a low dose, all 3 cohorts had similar discontinuation and progression rates. Conclusions: A higher proportion of Japanese pts receiving DAR were treated at the label dose during the study period and were more likely to stay on treatment. Within each dose subgroup, pts receiving DAR progressed more slowly to mCRPC than those receiving ENZ or APA. Clinical trial information: N/A. Label dose Low dose (<100% label dose) DAR (n=324) ENZ (n=1097) APA (n=266) DAR (n=94) ENZ (n=796) APA (n=164) Age, median (Q1, Q3), years 80 (75–85) 79 (73–84) 78 (72–83) 84 (78–88) 84 (79–88) 79 (74–84) Charlson Comorbidity Index score ≥1, n (%) 124 (38) 471 (43) 111 (42) 33 (35) 397 (50) 95 (58) Designated cancer hospitals, n (%) 262 (81) 789 (72) 206 (77) 76 (81) 529 (67) 116 (71) Follow-up, arithmetic median (Q1, Q3), months 19 (11–25) 21 (13–31) 27 (17–34) 17 (10–26) 21 (12–31) 21 (12–30) Median (95% CI) time to discontinuation, months 17.6 (13.3−24.8) 11.6 (10.4−13.4) 5.0 (3.9−7.1) 12.8 (7.2−20.2) 12.9 (11.8−14.3) 10.8 (7.6−14.0) KM probability of mCRPC progression at 12 months (95% CI)* 0.16 (0.12−0.21) 0.27 (0.24−0.29) 0.29 (0.24−0.35) 0.18 (0.11−0.28) 0.22 (0.19−0.25) 0.24 (0.18−0.32) *Median time to mCRPC progression was not reached during the study period.

Evaluation of systemic therapy and surgical consolidation in patients with node positive upper tract urothelial carcinoma.

816 Background: The recommended treatment for high-grade upper tract urothelial carcinoma (UTUC) includes radical nephroureterectomy with regional lymph node dissection for clinically organ-confined disease. The timing of peri-operative systemic therapy is multifactorial, with extrapolation of data from muscle-invasive bladder cancer in the neoadjuvant setting, and level 1 data for UTUC in the adjuvant setting. The timing of peri-operative systemic therapy and need for surgical consolidation in the clinically node positive setting is even more unclear. The goal of this study is to compare survival in cN+ patients managed with neoadjuvant, adjuvant, and systemic therapy alone approaches. Methods: Patients with cT0-4 N1-3 M0 UTUC who received chemotherapy with or without nephroureterectomy (NU) between 2018 and 2021 in the National Cancer Database (NCDB) were included. Patients were stratified into three treatment groups: chemotherapy only (CO), neoadjuvant chemotherapy followed by nephroureterectomy (NAC-NU), and nephroureterectomy followed by adjuvant chemotherapy (NU-AC). OS was analyzed using Kaplan-Meier analysis and log rank tests. Cox proportional hazard models were employed to adjust for potential confounders. Results: A total of 1193 patients were included (CO, NAC-NU, and NU-AC treatment groups consisted of 495, 287, and 411 patients, respectively). Patients in the CO group were older (P<0.001), more commonly males (P<0.001) compared with NAC-NU and NU-AC cohorts. There was no significant difference in Charlson comorbidity index between the three groups. The pathologic complete response rate (ypT0N0) in the NAC-NU was 6.5%. Patients managed with NAC-NU exhibited the most favorable OS compared to NU-AC and CO (P<0.0001), with 3-year OS 65.4% (95% CI 58.4%-73.3%), 53.5% (47.9%-59.6%), and 20.8% (15.7%-27.6%) in these groups, respectively. On multivariate analysis controlling for age, sex, and clinical stage using NAC-NU as a referent, NU-AC and CO exhibited inferior OS (HR 1.48, 95% CI 1.06-2.06, P=0.021 and HR 2.92, 2.14-4.00, P<0.001, respectively). Conclusions: The use of neoadjuvant chemotherapy followed by nephroureterectomy provides optimal survival outcomes in patients with cN+ high-grade UTUC. These data suggest that, when feasible, surgical consolidation is an important treatment component in patients with cN+ disease, likely owing to low rates of pathologic complete response. Estimated overall survival at 1- and 3-year endpoints. Treatment Sample Size 1 Year Survival (95% CI) 3 Year Survival (95% CI) Chemo Alone 348 57.6% (52.5% - 63.2%) 20.8% (15.7% - 27.6%) Chemo before Surgery 202 80.8% (75.4% - 86.6%) 65.4% (58.4% - 73.3%) Surgery before Chemo 329 72.8% (68.1% - 77.8%) 53.5% (47.9% - 59.6

Designing the weak Fermi pinning and p-type Ohmic contacts to monolayer halide perovskite Cs3Bi2I9

The contact between two-dimensional (2D) perovskite and metal electrodes is often plagued by strong Fermi-level pinning (FLP) effects, which limit the electronic performance of devices. By utilizing van der Waals design strategies, the contact performance between Cs3Bi2I9 and 1T/H-XA2 (X = V, Nb, Ta; A = S, Se) was investigated. P-type Schottky contacts are obtained in all 1T/H-XA2 contacts to Cs3Bi2I9, and the contacts can be engineered from Schottky to Ohmic contacts via external electric fields. Furthermore, a large pinning factor to suppress the FLP effects was observed to approach the Schottky–Mott limit, and the origin is elucidated. In addition, the transport properties of various 2D metals contacts to Cs3Bi2I9 were calculated and screened out. Finally, Curie temperature (Tc) of magnetic systems were calculated using the Monte Carlo method, and the Tc of 1H-VS2/Cs3Bi2I9 significantly enhances largely to surpass room temperature, thereby expanding the application field of spintronic devices. This study provides potential guidance for the design of efficient 2D Cs3Bi2I9-based nanodevices as well as high-temperature spintronic devices.

Breastfeeding self-efficacy status and associated factors among postpartum mothers at Hadiya Zone public hospitals, Southern Ethiopia

Background Breastfeeding is a crucial health-promoting behavior that has several positive effects on the health of both mothers and newborns. Breastfeeding self-efficacy (BFSE) status is an important factor that is positively related to breastfeeding, as it influences a woman’s decision to breastfeed or not. Therefore, the objective of this study is to assess the BFSE status and its associated factors among postpartum mothers at public hospitals in the Hadiya Zone. Method A cross-sectional study design was conducted from August 1–30, 2022, at public hospitals in the Hadiya Zone, southern Ethiopia. Data were collected from 416 participants using a pretested, structured questionnaire. Study participants were selected using a systematic random sampling technique from four public hospitals. The data were entered into Epi Data version 3.1 and analyzed using the SPSS version 24. Bivariable analysis was conducted initially, and variables with p values ≤ 0.25 were entered into multivariable logistic regression. Statistical significance was declared at a p value ≤ 0.05. Results The results of this study showed that 48% had a high level of BFSE. On multivariable logistic regression analysis, the variables age ≥ 35 years old [AOR = 3.596; 95% CI (1.564, 8.26)], age 20 to 34 [AOR = 2.352; 95% CI (1.2275, 4.506)], spontaneous vaginal delivery [AOR = 2.755; 95% CI (1.636, 5.566)], breastfeeding experience [AOR =1.845; 95% CI (1.028, 3.3)], more than secondary educational status [AOR = 6.856; 95% CI (2.670–17.603)], and intended pregnancy [AOR = 4.156; 95% CI (2.239, 7.714)] were significantly associated with high breastfeeding self-efficacy status. Conclusion The study findings suggest that mothers attending postpartum care at Hadiya Zone Hospital have a low status of breastfeeding self-efficacy. Therefore, efforts should be made to enhance mothers’ breastfeeding self-efficacy status before they are discharged from the hospital.

An automatic control system based on machine vision and deep learning for car windscreen clean

Understanding metastatic squamous cell carcinoma patients receiving pelvic exenteration vs radical cystectomy: A nationwide context.

681 Background: Squamous Cell Carcinoma (SCC) is a rare subtype of bladder cancers, consisting of 2-5% of all bladder cancers. SCC is associated with chronic bladder inflammation often due to catheters, kidney stones, and bladder outlet obstruction. While gold standard treatment for SCC is radical cystectomy (RC), many patients receive more extensive surgery such as pelvic exenteration (PE). PE involves removing all organs from a person’s pelvic cavity whereas RC involves removing the bladder and nearby tissue. This study will examine the characteristics of metastatic SCC patients receiving PE vs RC to better understand why some patients may not receive RC. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with bladder squamous cell carcinoma from 2004 to 2020 using the histology codes 8050, 8070-8076, 8084 and NCDB analytic stage code IV as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, and Cox Proportional Hazards tests were performed. Data was analyzed using SPSS version 27 and statistical significance was set at α = 0.05. Results: Of the 561 patients in the sample, 211 (37.6%) received PE and 350 (62.4%) received RC. Patients receiving PE survived 32.8 months and patients receiving RC survived 35.8 months (p>0.05). Patients receiving PE were more likely to receive adjuvant radiation or chemoradiation, have no residual tumor or microscopic residual tumor after surgery, receive care from an academic facility, and to have lymph vascular invasion (p<0.05). These patients were also more likely to present at a younger age (62.86 vs 65.37 years) yet interestingly were more likely to have fewer regional lymph nodes positive (9.27 vs 14.90) (p<0.05). There were no significant differences between income level, race, the number of comorbid conditions (Charlson-Deyo Score), insurance status, tumor size, or time to surgery (p>0.05) between the two groups. Conclusions: 37.6% of patients in this sample received PE over RC, the gold standard. PE patients had disease that more greatly invaded the lymphatics and had better surgical margins, yet PE offered no significant survival benefit. More research is needed to better understand why some patients receive more extensive surgical intervention.

Efficacy, Toxicity, and Cosmesis of Partial Breast Irradiation: Honing in on Dose and Patient Selection

Survival outcomes of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) receiving lutetium-177-PSMA-617 (Lu) based on line of therapy.

82 Background: Lu is a prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical that delivers beta radiation to PSMA-positive cells. It is approved for pts with mCRPC who had prior progression on an androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy. However, there are limited real-world data on the efficacy of Lu based on the line of therapy. Herein, we aimed to assess the survival outcomes of pts with mCRPC receiving Lu in a real-world setting. Methods: This retrospective study utilized the nationwide Flatiron Health electronic health record (EHR) derived de-identified database. Eligibility: pts diagnosed with mCRPC who received Lu for the first time. Survival was calculated from the date pts received their first treatment with Lu. Time to next treatment (TTNT) and overall survival (OS) were summarized using Kaplan Meier survival estimates and its 95% confidence intervals (CI). Results: Of the overall cohort of 24,105 pts with metastatic prostate cancer in the dataset, 303 diagnosed between 1/1/2013 and 7/11/2023 received treatment with Lu. The median age of these pts was 75 years (IQR 69 – 80). The majority were White non-Hispanic (69%), treated in a community practice (82%), covered by a commercial health plan (86%), and received Lu in the third line or later (91.4%). For pts treated with Lu, the median TTNT was 8.5 months (95% CI, 7.3 – 9.8), and the median OS was 12 months (95% CI, 11 – 15). Median TTNT and OS by line of therapy are summarized (Table). Conclusions: Lu retains clinical activity in pts with mCRPC regardless of line of therapy. These data may aid with patient counseling, prognostication, and selection of therapy in the clinic. Median TTNT and OS by line of therapy in pts with mCRPC receiving Lu. Line of therapy Number of pts, n (%) Median TTNT (mo) (95% CI) Median OS (mo) (95% CI) 2 26 (8.6) 8.5 (5.6, -) 12 (8.5, -) 3 77 (25.4) 8.0 (6.4, 11) 17 (8.9, -) 4 82 (27) 8.2 (6, 10) 10 (7.2, 22) 5 64 (21) 9.8 (6, 13) 13 (11, -) 6 28 (9.2) 9 (5.7, -) 13 (12, -) 7 17 (5.6) 10 (7.3, -) 10 (7.3, -) 8 6 (2) 7 (3.7, -) (3.7, -) 9 2 (0.7) 7.3 (3, -) 10 (8.6, -) 14 1 (0.3) 8.6 (-, -) 14 (-, -)

Additivity and the efficacy of immune checkpoint blockade-based combination regimens in urothelial cancer.

779 Background: Immune checkpoint blockade (ICB)-based combination regimens have transformed the treatment landscape of advanced solid tumors including urothelial cancer. Understanding whether such combinations are synergistic, additive, or less than additive is crucial for (a) refining combination therapy in urothelial cancer, (b) dissecting the role of concurrent versus sequential treatment, and (c) identifying which cytotoxic agents combine most favorably with ICB. Here we analyzed phase III trials in advanced urothelial cancer to determine if the efficacy of combination therapies were predictable by additivity or exhibited non-additive effects. Methods: We analyzed progression-free survival (PFS) from phase III trials of ICB-containing regimens for advanced urothelial cancer (Table). PFS distributions of constituent drugs were used to calculate the predicted PFS of combination therapy under the null hypothesis of additive PFS times (Hwangbo et al, Nature Cancer, 2023). For KEYNOTE-361 and IMvigor130, which allowed investigator’s choice of cisplatin or carboplatin, separate predictions were made for cisplatin- and carboplatin-treated cohorts. The Cox Proportional Hazards model tested whether observed PFS significantly differed from additivity. Results: PFS of combination therapies in EV-302, CheckMate901, and DANUBE were statistically indistinguishable from additivity (Table). Trials using choice of cisplatin or carboplatin (KEYNOTE-361, IMvigor130) showed that ICB with cisplatin produced additive PFS, but ICB with carboplatin was significantly antagonistic (inferior to additive PFS; P = 0.00004). Conclusions: Recently approved regimens enfortumab vedotin + pembrolizumab, and nivolumab + gemcitabine-cisplatin, were as effective as predicted by additivity, demonstrating that combining individually effective agents without synergy can make effective regimens. In advanced urothelial cancer, PD-1 or PD-L1 inhibitors are antagonistic with carboplatin, but confer additive PFS benefits with cisplatin. Modeling the PFS of combination regimens from single agent data could have predicted the success of most contemporary phase III trials in advanced urothelial cancer. Trial Combination Predicted HR for PFS (95% CI) Observed HR for PFS (95% CI) P value EV-302 Enfortumab vedotin + Pembrolizumab 0.49 (0.44 - 0.55) 0.45 (0.38 - 0.54) 0.93 CheckMate901 Nivolumab + Gemcitabine-Cisplatin 0.69 (0.60 - 0.79) 0.72 (0.59 - 0.88) 0.78 DANUBE Durvalumab + Tremelimumab 0.87 (0.78 - 0.98) 0.88 (0.75 - 1.03) 0.92 KEYNOTE-361 Pembrolizumab + Chemotherapy 0.67 (0.59 - 0.77) 0.78 (0.65 - 0.93) 0.02 IMvigor130 Atezolizumab + Chemotherapy 0.61 (0.55 - 0.68) 0.82 (0.70 - 0.96) 0.0006 Pooled ICB + Gemcitabine-Cisplatin 0.65 (0.56 - 0.74) 0.71 (0.58 - 0.86) 0.78 Pooled ICB + Gemcitabine-Carboplatin 0.63 (0.57 - 0.70) 0.84 (0.73 - 0.97) 0.00004

Erratum: “Epitaxial (AlxGa1−x−yIny)2O3 alloys lattice matched to monoclinic Ga2O3 substrates” [Appl. Phys. Lett. <b>125</b> , 172106 (2024)]

Assessment of potential dominant factors for brownfield landscape regeneration: A case study in Xi’an, China

Rapid global urbanization has made brownfield reuse a vital issue for sustainable urban development. However, the regeneration of brownfield landscapes is a complex and lengthy process that requires a combination of factors to be considered. Their landscape regeneration must be planned and prioritized to utilize brownfield sites and achieve positive social benefits. Therefore, an urgent need must be established to establish an assessment framework and system for various types of brownfield landscape regeneration dominant factors to find different brownfield landscape regeneration dominant factors. This research developed an assessment model using the Analytic Hierarchy Process (AHP), covering five brownfield types: industrial, mining, military, transportation, and landfill in Xi’an, China. The potential assessment factors in three levels were analyzed for weighting to explore the dominant factors for the potential regeneration of brownfield landscapes in Xi’an. The results showed that, firstly, among the five first-level assessment factors, the physicality factor was the most important. Secondly, among the 16 second-level factors, the spatial and physical features of the visual landscape were the most critical. Finally, among the 40 three-level factors, spatial features were the primary factor. Therefore, the purpose of this research is to provide a specific assessment system and data analysis methods and ideas for the dominant factors of urban brownfield landscape regeneration in China and other regions based on the assessment framework with strong adaptability proposed by the AHP method, which can be flexibly adapted in the different areas and countries, to realize the sustainable development of cities in various regions.

Antiviral defence arsenal across members of the Bacillus cereus group

Abstract Bacteria co-evolve with bacteriophages to overcome each other’s defence arsenal. Bacillus cereus group gathers bacteria of medical and agricultural importance, including foodborne pathogens. So far, few studies have portrayed a complete defence arsenal of microorganisms, and the role of antiviral systems in the Bacillus cereus group has been overlooked. Here, we investigate the repertoire of defence systems in 6354 B. cereus group’s genomic assemblies, using bioinformatics tools DefenseFinder and PADLOC. Our analyses provide an overview of the diversity and abundance of defence systems in this group, with 83,738 systems distributed by 2 to 33 within each assembly. Comparing PADLOC and DefenseFinder predictions showed that the most prevalent strategy is Restriction-Modification, but many abortive infection systems also intervene in the group’s defence, such as Septu, Gabija and Lamassu. Most defences were encoded on both plasmids and the chromosome, though some tend to have a preferential genomic location. We also studied the defence systems associations within the genomic assemblies. Overall, our results establish a baseline picturing the rich and complex antiviral arsenal encoded by B. cereus group’s species and provide clues for studying co-existing strategies displayed by these bacteria to subvert phages and other MGEs invasions.

Evaluating associations between genomic classifier and digital pathology–based multi-modal AI biomarkers in oligometastatic castration-sensitive prostate cancer.

231 Background: Prostate cancer is a heterogeneous disease ranging from indolent localized to metastatic castration-resistance. Efforts to generate prognostic and predictive biomarkers to understand disease trajectory beyond clinical variables alone include the Decipher Prostate Genomic Classifier (GC) and Artera Multimodal AI (MMAI). Both are validated prognostic biomarkers within localized prostate cancer and are currently being evaluated in the metastatic setting. It is unknown if these biomarkers are reporting on similar biology through different means (gene expression vs digital pathology) or if they are complementary and provide orthogonal insights. Herein, we aim to correlate GC and MMAI scores in patients with metastatic prostate cancer. Methods: We conducted a retrospective review of patients with oligometastatic castration-sensitive prostate cancer (omCSPC) with available transcriptome and digital H&amp;E images from prostate biopsy tissue. GC scores were calculated from RNA sequencing data using the same coefficients but scores were re-scaled to a reference cohort from GRID registry while missing features were imputed as 0. Following digitization of H&amp;E slides, an AI-detected, 128 image feature vector (IFV) was generated per patient which was subsequently combined with Gleason score, PSA, and T stage for final MMAI scoring (Artera, Inc). The primary endpoint was to assess correlations between these biomarkers as continuous variables with linear regression. Given the MMAI score is composed of both AI-detected digital pathology features and clinical features, we evaluated any associations between the GC and AI-detected image features. Uniform Manifold Approximation and Projection (UMAP) was performed on the 128 IFV to generate digital pathology clusters which were then associated with GC both as a continuous and categorical variable using ANOVA and chi-square test, respectively. Results: 85 patients (Metachronous n=74; Synchronous n=11) were included in the analysis. The median GC and MMAI scores were 0.60 and 0.52, respectively. Linear regression identified a very weak positive association between scores (R 2 =0.08, 95%CI 0.00-0.20). UMAP identified 4 digital pathology clusters. No cluster was found to be enriched with higher GC scores with median scores of 0.64, 0.67, 0.58, and 0.5 for clusters 1-4 respectively (p=0.138). Additionally, no cluster was enriched with either low (GC &lt;.45, p=0.87), intermediate (GC ≥ 0.45-&lt;0.6, p=0.73), or high (GC≥0.6, p=0.12) GC risk groups. Conclusions: We demonstrate for the first time that Decipher GC and Artera MMAI scores do not strongly correlate in a population of patients with omCSPC. This suggests these biomarkers may be complementary, identifying independently prognostic disease biology. Further work validating these findings is warranted.

Can magnetic resonance imaging safely replace a confirmatory biopsy in patients on active surveillance for prostate cancer?

331 Background: Active surveillance (AS) is recognized as the preferred management for patients with low-risk prostate cancer, and many with favorable intermediate risk tumors as well. AS has been increasing in utilization both within the Veterans Affairs (VA) Healthcare System and nationally in the U.S. However, the limited data evaluating the quality of AS protocols suggests wide variability. One area of controversy is whether magnetic resonance imaging (MRI) can replace prostate biopsy to guide decisions about whether to remain on AS. We aimed to quantify the performance characteristics of MRI as a potential replacement for biopsy in a large, diverse, national VA cohort. Methods: The study cohort consists of veterans diagnosed with Gleason grade group (GG) 1 or 2 prostate cancer at their diagnostic biopsy undergoing AS. The cohort is further limited to patients that underwent at least one post-diagnosis (confirmatory) biopsy and had at least one MRI with an assigned Prostate Imaging-Reporting and Data System (PI-RADS) score completed within 180 days prior to their confirmatory biopsy (CBx) and/or any subsequent surveillance biopsy (SBx). MRI was evaluated as negative (PI-RADS v2.1 score of 1-2) or positive (PI-RADS score of 3-5) in its ability to predict GG≥2 prostate cancer on post-diagnosis biopsy, vs. either negative or GG1. We focused on the negative predictive value (NPV), given the key clinical question whether MRI can safely replace biopsy, and stratified results by PSAD (&lt; 0.15 ng/mL and &gt;= 0.15 ng/mL) and GG groups (GG1 vs GG2) at diagnosis. Results: We identified 1,662 cases with eligible confirmatory biopsies and 796 cases with eligible surveillance biopsies among 2,188 patients. Biopsies were from patients with a median age of 67 with 80% having GG1 cancer at their diagnostic biopsy and the remaining 20% at GG2. The negative predictive value (NPV) was 74% for all confirmatory biopsies and 75% for subsequent surveillance biopsies. Performance was worse in some contexts: for example, among patients with GG2 at diagnosis, NPV was only 38% at the confirmatory biopsy and 60% at subsequent surveillance biopsies. On the other hand, for those with PSAD less than 0.15 ng/mL, NPV at the surveillance biopsy was 82% (Table). Conclusions: Negative MRI—as defined by PI-RADS 1-2—does not consistently rule out the presence of GG≥2 prostate cancer and therefore cannot safely replace confirmatory biopsy. In some contexts (e.g., subsequent surveillance biopsy for patients with low PSAD) MRI may be an adequate surrogate. Group Type of Biopsy Count NPV PPV Sensitivity Specificity Overall CBx 1,662 0.74 0.53 0.96 0.13 Overall SBx 796 0.75 0.52 0.97 0.10 GG1 CBx 1,317 0.79 0.49 0.96 0.14 GG1 SBx 672 0.77 0.48 0.96 0.10 GG2 CBx 345 0.38 0.69 0.96 0.06 GG2 SBx 124 0.60 0.72 0.98 0.08 Low PSAD CBx 755 0.78 0.60 0.98 0.10 Low PSAD SBx 382 0.60 0.61 0.96 0.08 High PSAD CBx 693 0.75 0.43 0.93 0.15 High PSAD SBx 309 0.82 0.42 0.96 0.12