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Comparative assessment of pre- and post-COVID-19 pandemic nephrectomy outcomes for renal cell carcinoma: Analysis of the ACS-NSQIP registry.

466 Background: The COVID-19 pandemic placed significant strain on healthcare systems in the U.S. Public health directives aimed at mitigating the spread of new COVID-19 cases, such as regional stay-at-home orders, resulted in the cancellation or significant delay of many surgical cases. This study aimed to examine the impact of COVID-19 on surgical outcomes after elective nephrectomy in patients with renal cell carcinoma (RCC). Methods: The ACS NSQIP database for 2019 through 2021 was queried for adult patients with RCC undergoing partial nephrectomy (CPT codes 50240, 50543) or radical nephrectomy (CPT codes 50220, 50225, 50230, 50545, 50546). Patients were stratified into pre-pandemic (2019 Q1-Q4, 2020 Q1) and post-pandemic (2020 Q2-Q4, 2021 Q1-Q4) cohorts. Outcomes included total operation time, length of total hospital stay, unplanned reoperation, hospital readmission, prolonged stay in the hospital, urologic-specific complications (superficial incisional SSI, deep incisional SSI, organ/space SSI, wound disruption, acute renal failure, urinary tract infections), systemic complications (pneumonia, unplanned intubation, on ventilator for greater than 48 hours, stroke/CVA, cardiac arrest requiring CPR, myocardial infarction, bleeding transfusion, DVT/thrombophlebitis, sepsis, sepsis shock), and 30-day mortality. Results: A total of 19,102 patients met inclusion criteria, with 8,321 patients in the pre-pandemic cohort and 10,781 in the post-pandemic cohort. On univariate analysis, the post-pandemic cohort had longer operative times ( p <0.001), shorter length of total hospital stay (p<0.001), and a higher proportion of outpatient procedures ( p <0.001). The post-pandemic cohort also had a higher proportion of patients with an ASA Physical Status Classification of III or above ( p =0.003), diabetes mellitus ( p = 0.006), or CHF in the 30 days prior to surgery ( p <0.001). Multivariate analysis of 30-day complications and adverse outcomes revealed no significant difference between the two cohorts, except that patients who underwent partial nephrectomy in the pre-pandemic cohort experienced septic shock significantly more often than patients in the post-pandemic cohort (OR=4.19, 95% CI: 1.17-15.00, p =0.028). Conclusions: While the onset of the COVID-19 pandemic was associated with longer operative times, shorter hospital stays, and a higher proportion of outpatient procedures, there is no evidence that the pandemic worsened 30-day surgical outcomes after nephrectomy in patients with RCC. Multivariate adjusted analysis of 30-day complications and adverse events associated with radical and partial nephrectomy (reference group set as the post-pandemic cohort). Radical Nephrectomy Partial Nephrectomy OR [95% CI] P Value OR [95% CI] P Value Any complication 0.93[0.82-1.04] 0.201 1.01[0.88-1.17] 0.894 Death 0.97[0.58-1.67] 0.898 0.68[0.27-1.72] 0.420 Hospital readmission 0.86[0.71-1.04] 0.115 0.93[0.77-1.13] 0.480 Unplanned reoperation 0.83[0.61-1.13] 0.230 0.96[0.71-1.30] 0.773 Still in hospital > 30 days 1.07[0.45-2.54] 0.881 2.21[0.45-10.97] 0.332

Impact of the COVID-19 pandemic on outcomes of acute ischemic stroke patients treated with endovascular therapy: A multicenter Canadian study

Objective The novel coronavirus disease 2019 (COVID-19) pandemic led to the implementation of wide-ranging institutional infection control protocols. The purpose of this study is to determine the effect of the pandemic on outcomes of large vessel occlusion (LVO) acute ischemic stroke (AIS) patients treated with endovascular therapy (EVT). Materials and methods Data were obtained from prospectively collected quality improvement stroke databases at six Canadian comprehensive stroke centres from March 11, 2020 to March 11, 2021. This patient cohort was compared to pre-pandemic patients consecutively treated with EVT from March 11, 2019 to March 10, 2020. The primary outcome is a 90-day modified Rankin Score (mRS). The secondary outcomes are angiographic time metrics. Results A total of 1329 EVT patients (pre-pandemic n = 666) were included. The initial NIHSS was statistically significantly lower in the pandemic cohort. Other baseline patient characteristics were comparable between the two periods. Median (interquartile range, IQR) time from last seen normal (LSN) to emergency department (ED) (172 (68–316) vs 210 (97–382) min; p = 0.0001), LSN to puncture (235 (160–378) vs 280 (184–475); p < 0.0001), computed tomography (CT) to angiographic table (68 (44–108) vs 84 (57–125) min; p = 0.002), ED to angiographic table (65 (37–96) vs 80 (50–112) min; p = 0.001), CT to recanalization (117 (84–156) vs 130 (89–173) min; p = 0.038) and LSN to recanalization (279 (198–453) vs 327 (219–561) min; p = 0.002) were longer in the pandemic period as compared to the pre-pandemic. There were no significant differences in median time from angiographic table to arterial puncture (13 (8–19) vs 12 (9–16) min; p = 0.70) or arterial puncture to first pass (21 (14–31) vs 20 (14–30) min; p = 0.50). Patients were more likely to have favourable outcomes (mRS at 90 days score of ≤ 2) post-EVT pre-pandemic than pandemic (53% vs 44%; p = 0.02). Furthermore, analysis of the time interval from “LSN to arterial puncture” in relation to functional outcomes showed that the percentage of unfavorable outcomes increased among patients who underwent EVT within 240 minutes. Specifically, the rate of unfavorable outcomes rose from 32.9% to 42.9% (p = 0.37 for intervals under 150 minutes) and from 41.6% to 52.3% (p = 0.15 for intervals between 151 and 240 minutes) when comparing pre-pandemic to pandemic periods. However, the detrimental effect associated with the pandemic was diminished in patients who received EVT beyond 240 mins (p = 1.0). Conclusion In this multicenter study involving six Canadian stroke centers, patients exhibited a higher probability of unfavorable long-term functional outcomes following EVT during the pandemic period compared to those in the pre-pandemic cohort, particularly during the first year of the pandemic.

Improved image reconstruction from brain activity through automatic image captioning

ProstACT GLOBAL: A phase 3 study of ¹⁷⁷ Lu-rosopatamab (TLX591) with and without the best standard of care for patients with PSMA expressing metastatic castration-resistant prostate cancer progressing despite prior treatment with a novel androgen axis drug.

TPS303 Background: The treatment of advanced prostate cancer (PC) is challenging, with undesirable side effects that impact patient quality of life. Radioimmunotherapy (RIT) can localize therapy to specific tumor cells in multiple organs to reduce or eliminate damage to normal tissue. The cell surface glycoprotein prostate-specific membrane antigen (PSMA) is an ideal therapeutic target as it is highly expressed by malignant prostate cells. There is a strong rationale for further investigation of the 177 Lu-labeled, chelator-conjugated antibody, 1 77 Lu-rosopatamab, as a potential first-line RIT candidate for the treatment of PC. Methods: This multinational, multicenter, prospective, randomized, open label phase 3 study will have 2 parts: a dosimetry and safety lead-in (n=30) and a randomized treatment expansion (n=490). In Part 1, patients will be divided into 3 groups (n=10 each) to receive 2 single intravenous (IV) injections of 76 millicuries (mCi) each, 14 days apart, of 177 Lu-rosopatamab with best standard of care (SoC) combinations with abiraterone, enzalutamide, or docetaxel to fully characterize biodistribution and safety profiles of 177 Lu-DOTA-rosopatamab + SoC combinations. SoC received will be determined prior to treatment with 177 Lu-rosopatamab. In Part 2, patients will be enrolled in a 2:1 ratio to receive either the best SoC or 2 single IV injections of 76 mCi each (equivalent to a 45 mCi/m 2 dose in a standard 1.7m 2 individual) of 177 Lu-rosopatamab, given 14 days apart, plus best SoC. SoC will be determined prior to randomization, and a change in planned SoC will not be permitted. Eligible patients must have PSMA-expressing metastatic castration-resistant PC (mCRPC) that have progressed despite prior therapy with either enzalutamide or abiraterone plus prednisone, and 1 line of prior taxane therapy or have refused or are ineligible for taxanes. Patients must have adequate organ function including at least 150x10 9 /L platelets, hemoglobin 10 g/dL, and have PSMA-positive disease on 68 Ga-PSMA-11 PET/CT imaging as confirmed by a central reader. Key exclusion criteria include small cell histology, increased risk of hemorrhage or bleeding, known brain or hepatic metastases, or history of stroke, seizure, or treatment with radioisotopes within 6 months prior to randomization. The primary endpoint is radiographic progression-free survival. Key secondary endpoint is OS. Additional secondary endpoints include 5-year overall survival, tumor objective response rate, time to symptomatic skeletal event, and health-related quality of life. Clinical trial information: NCT04876651 .

An online clustering algorithm predicting model for prostate cancer based on PHI-related variables and PI-RADS in different PSA populations.

328 Background: Prostate cancer is the most common male malignancy. Current diagnostic methods using single TPSA and PHI lack specificity. Some researches have created nomograms for predicting risk, but these are not easily visualized. Our study aims to find the best negative predictive value (NPV) for PHI, then build a clustering model to display prostate cancer risk categories, particularly useful for patients with PSA>20 and be actually applied in clinical work. Methods: We collected 708 patients in the training cohort and 143 in the validation cohort, divided into three groups based on their PSA levels. Next, we determined optimal and customized PHI cut-off values, calculated NPV and PPV, and selected logistic regression as the best method among several machine-learning algorithms. Subsequently, the significant variables were identified, and then a clustering algorithm was constructed. Finally, the model was validated and made available online for further clinical application. Results: The Optimal PHI cut-off lower limits for PSA>4, PSA4-20, PSA>20 subgroups were 23.85, 24.35, and 40.75, with upper limits of 142.9, 143, and 135.6, respectively. The clustering model of the optimal cohort for PSA>4 and PSA 4-20 sub-groups showed a superior Silhouette coefficients of 0.433 and 0.526 than that of the customized PHI cohort (0.432, 0.452). The PSA>20 subgroup owned the highest Silhouette coefficient of 0.572. The validation cohort showed AUC values of 0.761, 0.823, 0.833 for these 3 sub-groups, with accuracy rates of 88.81%, 90.38%, and 82.05%. Conclusions: In conclusion, our clustering model effectively categorizes patients into distinct risk groups with clear visualization and has demonstrated stability and reliability in the validation cohort, potentially aiding in early diagnosis of prostate cancer in clinical practice.

Efficacy and safety of nivolumab plus ipilimumab (Nivo/Ipi) in patients with metastatic variant histology renal cell carcinoma.

558 Background: Nivo/ipi is a standard of care first-line (1L) therapy for patients with metastatic clear-cell renal cell carcinoma (ccRCC) but its role in patients with metastatic variant histology RCC (vhRCC) has not been fully defined. Methods: We report a single-institution experience with nivo/ipi to treat 55 patients with metastatic vhRCC between Nov. 2017 and Feb. 2024 at MD Anderson Cancer Center. Tumor response was measured by blinded radiologists using RECIST v1.1. Descriptive statistics and the Kaplan-Meier method were used. Results: Twenty-five (45.5%) patients had papillary histology (pRCC), 12 (21.8%) patients had chromophobe (chRCC), and 18 (32.7%) patients had unclassified RCC (uRCC) (Table). Fifty-two (94.5%) patients received nivo/ipi in 1L. Sarcomatoid features (SF) were found in 20 (36.4%) cases. Overall response rate (ORR) was 48% (12/25) for pRCC, 25% (3/12) for chRCC, 27.8% (5/18) for uRCC, and 55% (11/20) across histologies with SF. Median progression-free survival (PFS) was 10.6 mo [95% CI: 2.8 – 22.8] in pRCC, 3.6 mo [95% CI: 0.9 – NE] in chRCC, and 3 mo [95% CI: 2.1 – 7] in uRCC. Six-month PFS milestone was 56% [95% CI: 36.3 – 75.7], 41.7% [95% CI: 21.7 – 56.1], and 47.2% [95% CI: 35.3– 59.1] in pRCC, chRCC and uRCC, respectively. Median overall survival (OS) was 36.7 mo [95% CI: 11.5 – 54.8] in pRCC, 25.7 mo [95% CI: 0.9 – NE] in chRCC, and 11.1 mo [95% CI: 6.5 – NE] in uRCC. Grade 3/4 immune-mediated adverse events (IMAEs) were noted in 17 (30.9%), including colitis (n=6), pneumonitis (n=3), hepatitis (n=3), nephritis (n=2), thyroiditis (n=1), pancreatitis (n=1), and thrombocytopenia (n=1). Targeted DNA sequencing in 26 patients identified the most frequent alterations, TP53 (42%), PTEN (23%) and TERT (23%), and distinct molecular profiles of pRCC and chRCC, with TERT mutations enriched in pRCC and TP53 mutations more common in chRCC. Conclusions: Nivo/ipi produced favorable outcomes in pRCC. Despite ORR of 25% and 27.8%, respectively, patients with chRCC and uRCC had short PFS, with inferior OS in patients with uRCC. IMAEs with nivo/ipi were consistent with published reports. Outcome pRCC(n=25) chRCC(n=12) uRCC(n=18) Total(n=55) Best Overall Response, n (%) CR 1 (4%) 0 (0%) 1 (5.6%) 2 (3.6%) PR 11 (44%) 3 (25%) 4 (22.2%) 18 (32.7%) SD 4 (16%) 3 (25%) 3 (16.7%) 10 (18.2%) PD* 6 (24%) 4 (33.3%) 8 (44.4%) 18 (32.7%) NE 3 (12%) 2 (16.7%) 2 (11.1%) 7 (12.7%) ORR in pts with SF, n (%) 4/6 (66.7%) 3/8 (37.5%) 4/6 (66.7%) 11/20 (55%) Median OS, mo [95% CI] 36.7 [11.5 – 54.8] 25.7 [0.9 – NE] 11.1 [6.5 – NE] 19.4 [11.5 – 36.7] 12-month PFS milestone (%) [95% CI] 31% [11.4 – 54.7] 25% [0.5 – 49.5] 16.7% [0 – 33.9%] 25% [13.1 – 36.9] Median follow-up, mo [95% CI] 35.1 [12.3 – 72.6] 51.4 [21.2 – 58.8] 33.5 [24.4 – 42.9] 35.1 [30.8 – 52.3] Median duration of response, mo [95% CI] 20.1 [8.3 - NE] 8 [8 – NE] 8.5 [2.9 – NE] 8.5 [8 – NE] Median time on treatment, mo [IQR] 2.9 [0.4 – 10.9] 2.6 [0.9 – 10.2] 2.1 [1.2 – 5.4] 2.1 [0.7 – 10.3]

Why are individuals tracing travel trends? A case study of City Walk in Malaysia

Studying the emerging travel trends of City Walk is a beneficial activity for young groups. However, there is a lack of research and understanding regarding the motivation and mechanism behind these trends, both in theory and practice. The aim of this study was to investigate the motivation of persons who follow the travel trend of City Walk and evaluate how behavioral intentions are formed by exploring the link between motivation and behavioral intention using the self-determination theory, and social influence theory. Social influence, variety seeking, and self-identification were extrinsic and intrinsic motivations of behavioral intention. A quantitative purposive survey approach was employed, wherein 315 young individuals aged 18 to 40 were recruited to respond. The findings derived from the partial least squares structural equation modeling demonstrate that extrinsic incentives related to social influence, variety seeking, and health care have a considerable impact on behavioral intention, and to some extent influence self-identification. Self-identification has a mediating role in the relationship between health care and behavioral intention. By examining both theoretical and practical aspects, it seeks to provide useful theoretical insights and practical contributions to advance research and industry in the field of rural tourism.

Developing a nomogram for risk prediction of the low T3 syndrome

A liquid biopsy-based proteomic assay to identify circulating tumor cell (CTC) –derived druggable targets in cancer patients.

258 Background: Cancers are often thought of as a disease of a specific tissue; however, the drugs designed to fight them are tissue agnostic. These drugs function by typically targeting mutant or amplified proteins such as kinases, transcription factors, or other cell surface proteins. An ever-growing body of research shows that many well characterized protein targets are commonly found across many cancer types and can serve as potential targets for pan-cancer therapies. Despite this, enrollment criteria for clinical trials often do not include any test to measure the presence of a particular protein drug target, and almost universally do not attempt to quantify the target. As a result, patient-specific protein profiles should be utilized to not only minimize patient harm but to categorize patients so that drug trials can be more intentional in identifying only the patients most likely to benefit from a selected drug. To that end, we developed a liquid biopsy-based proteomic assay to measure multiple proteins of interest simultaneously from enriched circulating tumor cells (CTCs) in blood and to detect druggable protein targets. Methods: CTCs were isolated using Astrin Bioscience’s proprietary enrichment system yielding matched CTC and white blood cell (WBC) fractions. Samples were then processed in parallel following a custom developed protein aggregation capture protocol followed by trypsin digestion to yield peptide samples for bottom-up targeted peptide analysis by mass spectrometry on a FAIMS equipped Exploris 480 instrument. Results: We prospectively enrolled 20 heavily-pretreated metastatic castration resistant prostate cancer (mCRPC) patients from whom matched CTC and WBC profiles were analyzed. The median age of these patients was 74 years, 80% had Gleason GG4-5, 30% had visceral metastases, median number of prior systemic therapies was 5, and median PSA level was 135 ng/mL. The mean CTC count was 10.4 cells/mL with a median of 4.9 CTCs/mL. After CTC enrichment, we observed vastly diverse intra- and inter-patient proteomic profiles. Highly relevant proteins to mCRPC were identified and quantified from CTCs in 100% of patients for androgen receptor (AR) and B7 homolog 3 (B7-H3), 57% of patients for trophoblast cell surface antigen-2 (TROP2), 43% of patients for prostate specific membrane antigen (PSMA), 28% of patients for programmed cell death antigen 1 (PD-L1), and 14% of patients for neuroendocrine markers chromogranin A (CHGA) and delta like ligand 3 (DLL3). Conclusions: The clear differences seen between the CTC and WBC fractions, combined with expected proteins observed in the CTC fraction, supports the successful isolation of CTCs. Together, this demonstrates a first of its kind assay able to probe multiple highly relevant proteins from CTCs that could be crucial to help minimize patient harm and better design precision therapeutics.

Innovative diagnostic approaches: Serum protein markers in renal cell carcinoma.

560 Background: In the era of precision medicine, we pursue less invasive, more powerful methods for screening, response prediction, and recurrence detection. While liquid biopsy has proven useful in other malignancies, similar diagnostic and prognostic tools for renal cell carcinoma (RCC) remain to be elucidated. We therefore aimed to investigate serum protein expression in patients before their RCC diagnosis vs. non-cancer controls to identify protein-cancer associations likely to have a role in cancer development and progression. Methods: Utilizing UK Biobank, we analyzed proteomic data in patients previously diagnosed with RCC (n=2245) vs. patients without RCC at time of serum collection who were later diagnosed (n=1225) vs. a cohort of non-cancer controls (n=44386). We estimated hazard ratios (HRs) and 95% confidence intervals (CI) using Cox proportional regression models. We investigated protein and RCC cancer-risk associations to examine the effects of reverse causality and conducted analyses to generate area under the curve (AUC) values to evaluate diagnostic performance of biomarkers. Results: We identified associations between elevated levels of tafa5, klk11, klk8, csdn, and clmp proteins and undiagnosed RCC. Highly expressed proteins in each cohort showed increased HR for cancer association (95% CI), with tafa5 exhibiting the highest HR in the treated group HR 9.7 (95%CI 6.3-12.0;p<0.00). Receiver operating characteristic curve demonstrated strong predictive capabilities: igfbp4 (AUC 0.9127;SN 0.8056;SP 0.8606), tafa5 (AUC 0.9134;SN 0.7500;SP 0.8996), tgfbr2 (AUC 0.9057;SN 0.6667;SP 0.9083), scarb2 (AUC 0.8968;SN 0.7500;SP 0.9197), nectin4 (AUC 0.9269;SN 0.7222;SP 0.9299) in the treated group. These findings indicate that specific proteomic biomarkers may have a significant association with RCC diagnosis, with high AUC values supporting their potential utility in RCC diagnosis and prognosis. Prospective validation in clinical settings is warranted. Conclusions: Our study highlights distinct protein elevations between patients presenting with RCC vs. those who were later diagnosed. Although further studies are warranted, the favorable HR, AUC, SN, and SP values for several proteins identified here underscore their potential as biomarkers for RCC diagnosis and prognosis.

Surveillance with plasma ctDNA in non-muscle invasive bladder cancer.

864 Background: Non-muscle invasive bladder cancer (NMIBC), constitutes 70% of all bladder cancer. Routine surveillance methods for detecting patients at risk of progression to muscle-invasive or metastatic disease are invasive and may delay intervention. Circulating tumor DNA (ctDNA) analysis presents a non-invasive alternative for monitoring minimal residual disease, potentially allowing for earlier detection of disease progression or recurrence. This study evaluates the role of plasma ctDNA in the early detection and monitoring of high-risk NMIBC. Methods: Eleven high-risk NMIBC patients were enrolled in this study. All patients underwent standard transurethral resection of bladder tumors (TURBT) before enrollment. Blood samples were collected prior to initiation of intravesical therapy and then every three months for two years (from January 12, 2022, to February 1, 2024). Plasma ctDNA was analyzed using Natera's Signatera, employing multiplex PCR and next-generation sequencing to detect tumor-specific mutations. Individual mutation profiles were established via whole-exome sequencing of tumor and matched normal tissue. Detection of ctDNA was compared with results from routine cystoscopy, urine cytology, and upper-tract imaging. Disease outcomes of interest included relapse, progression to muscle-invasive disease, and metastasis. Results: Of the eleven high-risk patients, one patient developed diffuse bilateral upper tract high-grade recurrence followed by metastatic disease that was preceded by positive ctDNA. Another patient was noted to have muscle-invasive disease again following the detection of ctDNA and subsequently underwent radical cystectomy. This patient eventually developed metastasis six months later. One patient elected to withdraw from the study. In our study, 20% of patients with high-grade papillary NMIBC had detectable ctDNA nine months post-diagnosis. Notably, both patients with positive ctDNA had normal findings on routine surveillance. However, they eventually progressed to stage IV urothelial carcinoma. In contrast, ctDNA was undetectable in the remaining eight patients, all of whom remained recurrent free to-date. These findings suggest ctDNA may serve as an early predictor of relapse and progression, with a number needed to test of 5 to prevent one delayed identification of disease progression. Conclusions: Plasma ctDNA analysis shows promise as a non-invasive tool for identifying NMIBC patients at risk of disease progression. Early ctDNA detection may enable more personalized treatment approaches, improving patient outcomes. Larger studies are warranted to confirm these findings and support the integration of ctDNA into standard NMIBC surveillance protocols.

Validity of heart rate measurements in wrist-based monitors across skin tones during exercise

Purpose To evaluate the accuracy of a wrist-based heart rate (HR) monitor at different exercise intensities across different skin tones. Methods Using a cross-sectional design, we compared HR measures from the wrist-based photoplethysmography Fitbit Charge 5 to the Polar H10 chest strap at rest and during the YMCA Protocol using a recumbent cycle ergometer. Participant were grouped into three skin tone categories: light (Fitzpatrick Scale Skin Types 1+2), medium (Types 3+4), and darker skin tone (Types 5+6). HR measures using the Polar chest strap during the exercise test were categorized as <40%, 40–60%, or >60% HR reserve (HRR). Absolute error in beats per minute (bpm) between the two devices was calculated for each measure. A linear mixed effects model was used to assess interaction effects between skin tone and exercise intensity, with participants as the random effect. Bland-Altman plots were used for visual analyses. Results Twenty-five participants [mean (SD): 25.8 (1.9) years old; 64% female] were included with 495 observations of simultaneous Fitbit and Polar HR recordings collected during exercise. During exercise, we observed a statistically significant interaction effect between skin tone and exercise intensity. Compared with light skin tone at <40% HRR, mean error was greater for medium skin tone at >60% HRR [mean error (95%CI): 11.8 (5.6–17.9) bpm, p<0.001] and darker skin tone at 40–60% HRR [7.6 (1.7–13.5) bpm, p = 0.011] and >60% HRR [11.7 (5.3–18.0) bpm, p<0.001]. Conclusion HR measurement error using a wrist-based device was greater with increasing exercise intensity for people with darker skin tones.

White-box methodologies for achieving robust correlations in hydrogen storage with metal-organic frameworks

Decipher genomic classifier (DGC) of early prostate cancer (EPC), and underlying transcriptomic profile (TP): American (Am) versus non-American (NA).

414 Background: Data on DGC in EPC, come predominantly from US patients (pts), revealing significant reclassification of NCCN risk Despite its global use, data among NA is scant. We aimed to analyze DGC results and TP among NA versus (vs) Am with EPC. Methods: From the DGC database (Decipher Biosciences Inc), we identified and analyzed the results (risk and TP) of Israeli (Is) vs matched Am pts with EPC. Matching was according to common NCCN clinicopathologic features (T and N stage, Gleason grade, number of adverse pathologic features). Results: Among Is pts, 692 (median age, ma, 69) had a biopsy (bx) DGC, and 115 (ma 67) a post prostatectomy (PP) DGC. Their median DGC in bx was 0.47, and PP 0.78. DGC risk was 45% low, 24% intermediate, 31% high, in bx, and 13% low, 16% intermediate, 71% high, PP. Bx DGC led to reclassification of risk in 33% of pts with clinical NCCN low-favorable intermediate risk, and 48% of pts with clinical NCCN unfavorable intermediate-high risk. Among matched Am, 103,108 (ma 68) had a bx DGC, and 40,906 (ma 65) a PP DGC. Am median DGC was 0.43 in bx, and 0.65 PP. Am DGC risk was 52% low, 20% intermediate, 28% high, in bx, and 28% low, 17% intermediate, 55% high, PP. While NCCN risk grouping was similar between Is vs matched Am (p=1.0), median DGC risk was significantly higher among Is (p<0.001), and the distribution of DGC risk groups significantly different (p=0.004 for bx, p<0.001 PP). A correlative TP analysis revealed greater overall differences of Isi vs matched Am. Significant (p<0.001) differences in bx DGC, included AR status (intact vs deficient), prostate subtype classifier (PSC, luminal differentiated, luminal proliferating, basal immune, basal neuroendocrine), PAM50 (Luminal A, Luminal B, Basal), RSI (1), Cell cycle progression (2), activated CD8, T regulatory cells, angiogenesis (Uhlik), Myeloid derived suppressor cells, Interferon response alpha hallmark, and immune 190. Significant (p<0.001) differences in PP DGC, included AR activity, p53 mutation, PSC, PAM50, SC/NE (adenocarcinoma, neuroendocrine carcinoma (3), RSI, activated CD4 and CD8, T regulatory cells, angiogenesis (Uhlik), tertiary lymphoid structure, PDL2 signature, Myeloid derived suppressor cells, and Interferon response alpha hallmark. Conclusions: In early prostate cancer, as previously reported among American pts, DGC may be an important tool for accurate patients risk assessment, leading to NCCN risk reclassification in a significant proportion, Furthermore, the present study preliminary results suggest that geographic variation DGC may exist, and correlate with differences in transcriptomic profile. 1. Torres-Roca 2009. 2. Cuzick 2011. 3. Beltran 2016.

Do tissue-based biomarkers in metastatic clear cell renal cell carcinoma perform better when derived from a metastatic site?

569 Background: Gene expression and mutation analyses in metastatic clear cell renal cell carcinoma (ccRCCs) have attempted to identify tumors that differentially respond to tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) – broadly an angiogenic and an immunogenic clade. However, ccRCC is genomically heterogeneous and sequencing a single-region of a primary tumor does not necessarily represent the metastatic clone. We re-analyzed the biomarker results of the Phase III IMmotion151 trial, stratifying patients into primary-derived and metastasis-derived sequencing, to assess if metastasis-derived sequencing performed better in differentiating response to therapy. Methods: We replicated the IMmotion151 biomarker analyses on transcriptomic clusters and mutations on all patients and then stratified to 198 patients with metastasis-derived and 625 patients with primary-derived sequencing. We assessed progression-free survival (PFS) with Cox proportional hazards while controlling for IMDC risk group for atezolizumab and bevacizumab (atezo + bev) versus sunitinib based on previously-described angiogenic groupings: Cluster 1 (Angiogenic/Stromal), Cluster 2 (Angiogenic), and PBRM1 mutant tumors; and immunogenic groupings: Cluster 4 (T-effector/Proliferative), Cluster 5 (Proliferative), PBRM1 wild-type and CDKN2A -loss tumors. Results: PFS favored Sunitinib in angiogenic Cluster 2 and Clusters 1+2 when sequencing was derived from the metastatic site (HR 3.39, p=0.011; HR 2.91, p=0.005) but not the primary (HR 1.04 p=0.82; HR 1.02, p=0.88) (Table). A similar trend was observed for other angiogenic groups (Cluster 1 & PBRM1 mutant), but did not reach significance. PFS favoring atezo + bev for immunogenic groupings remained significant when derived from the primary. Conclusions: Angiogenic signatures distinctly favored sunitinib in advanced ccRCC when sequencing was derived from the metastasis but not the primary tumor. Immunogenic signatures favored atezo + bev even when derived from the primary site. A prevalent angiogenic signature throughout the primary tumor, that is now always present in the metastatic clone, may explain these results. Cox proportional hazards results for Atezo + Bev versus Sunitinib corrected for IMDC risk-group. HR >1 favors Sunitinib, HR <1 favors Atezo + Bev. Marker All patientsN= 823 for RNA-seqN= 715 patients for mutations Metastasis-Derived Sequencing OnlyN= 198 for RNA-seqN= 152 patients for mutations Primary Derived Sequencing OnlyN= 625 for RNA-seqN= 563 patients for mutations DFS- HR P- value DFS- HR P- value DFS- HR P- value Markers Favoring Angiogenic Response / Sunitinib Cluster 1- Angio/Stromal(n=98) 1.21 0.48 3.10 0.14 1.02 0.95 Cluster 2- Angio(n=245) 1.22 0.25 3.33 0.024 1.04 0.82 Cluster 1 + 2(n=343) 1.20 0.22 2.66 0.011 1.02 0.88 PBRM1 mutant(n=333) 1.05 0.73 1.72 0.13 0.86 0.33

The comparison of clinical utility between pan-cancer panel and PCa-specific panel for mCRPC.

47 Background: To compare the diagnostic efficiency of pathogenic variants and the value for clinical decision making between a pan-cancer panel and a prostate cancer (PCa)-specific panel among patients with metastatic castration-resistant PCa (mCRPC). Methods: 637 mCRPC patients underwent panel-based targeted gene sequencing (Cohort A), among which, 327 patients underwent genomic profiling with a PCa-specific panel of 50 genes and 310 patients with a pan-cancer panel of 672 genes. Furthermore, 56 patients in Cohort A received both panel-based targeted gene sequencing approaches at the same time (Cohort B). The comparisons of the diagnostic efficiencies of pathogenic variants and clinical actionable variants (CAVs) were analyzed by proportion test. Results: The diagnostic efficiency of pathogenic variants was significantly higher in pan-cancer panel group than in PCa-specific panel group either in cohort A or cohort B (p<0.0001). In cohort A, 504 of 970 genomic variants were defined as pathogenic variants among which 304 were classified as CAVs in PCa-specific panel group. In pan-cancer panel group, 1457 of 4205 genomic variants were defined as pathogenic variants among which only 304 were classified as CAVs. In cohort B, 96 of 182 genomic variants were defined as pathogenic variants among which 56 were classified as CAVs in PCa-specific panel group. In pan-cancer panel group, 260 of 788 genomic variants were defined as pathogenic variants among which only 59 were classified as CAVs. The detection rate of CAVs between the two groups was no difference either in cohort A or cohort B (p>0.05). Conclusions: The pan-cancer panel had increased detection yield of pathogenic variants and provided a rich source of data, which was helpful for genetic researches. However, the PCa-specific panel proved to be as powerful as the pan-cancer panel in the detection of CAVs for tailored treatments, which might be better in guiding clinical decision making in a cost-effectiveness and time-saving way. Thus, the NGS panels available in different sizes might be chosen depending on basic research or clinical objectives.

Navigating Industry 4.0: Leveraging additive technologies for competitive advantage in Colombian aerospace and manufacturing industries

Industry 4.0 initiatives aim to improve competitive advantage. Additive technologies are a technological innovation and have great potential in a developing country like Colombia, The study analyzes how additive technologies, strategies, and process innovation interact to generate positive results, measured by the achievement of operational effectiveness in the aerospace sector and the manufacturing industry in general. Furthermore, the study explores the integration of additive technologies within the framework of Industry 4.0, focusing on the Colombian aerospace and manufacturing sectors. It investigates how these technologies, strategies, and process innovation contribute to operational effectiveness. Data were collected using a Likert-style questionnaire, developed based on established models of innovation framework and operational effectiveness model994 responses were obtained, of which 945 were deemed usable (423 from manufacturing and 522 from aerospace sectors). The analysis involved confirmatory factor analysis (CFA) and structural equation modeling (SEM) using SPSS and AMOS software, ensuring robustness through indicators like Cronbach’s Alpha and fit indices. The study compared findings across the two sectors to highlight differences in how additive technologies influence organizational outcomes. Initial results reveal that while additive technologies significantly enhance process innovation across sectors, their direct impact on operational effectiveness is evident only in the aerospace industry. The findings underscore that the aerospace sector benefits from additive technologies due to their need for complex, high-quality, and small-batch production, emphasizing their role in fostering precision and customization. However, the lack of impact in the manufacturing context is attributed to limited strategic alignment and inadequate implementation practices. Moreover, the results indicate that process innovation is a critical mediator, facilitating the translation of technological advancements into improved operational outcomes. Despite moderate correlations between strategies and operational effectiveness in manufacturing, aerospace organizations exhibit more substantial strategic alignment due to stringent performance demands. These findings highlight the importance of fostering a culture of innovation, adapting organizational strategies, and addressing structural challenges to maximize the benefits of additive technologies. The study contributes to understanding the differential adoption of Industry 4.0 technologies in developing economies, with implications for enhancing competitiveness and sustainability in global markets.

m7G gene expression and disease risk model construction in patients with herpes zoster

Carcinoma of prostate sequencing of tumor and clinical endpoints (CAPSTONE): Clinical implications of recurrent genomic alterations in lethal prostate cancer.

220 Background: Prostate cancer (PC) is genetically heterogeneous, and genomic alterations may impact prognosis and therapy response. We created CAPSTONE, a database of lethal PC that integrates comprehensive genomic sequencing with deep clinical phenotyping to explore the clinical implications of castrate resistant prostate cancer (CRPC) evolution. Methods: PC patients underwent tissue collection (4/05-7/21) for tumor RNA-sequencing and tumor/normal whole exome sequencing (HUM00046018, HUM00048105, HUM00067928, SU2C). Sequencing was processed using Turnkey Precision Oncology. We analyzed somatic and germline mutations, gene fusions, copy number alterations, and chromosomal instability (CIN) along with transcriptomic signatures and pathways. We collected clinical data (05/21-01/22) including overall survival from time of castrate resistant prostate cancer (OScrpc) and from time of biopsy (OSb). Patients were split into discovery and validation cohorts. We used cox proportional hazard models to evaluate OS. Results: Data was available for 454 men (n=192, n=262). Median follow up from CRPC was 32.1 (IQR: 14.7-50.1) and 33.3 (IQR: 20.9-55.6) months respectively. Median age at CRPC was 66 (IQR: 60-73) and 67 (IQR: 62-72) years. Of the 1,581 recurrently altered genes (>2%), 72 had a significant (p<0.01) univariate association with OS in the discovery cohort. From these, 3 (RB1, TP53, CDKN1B) were significantly associated with OS in the validation cohort (T1). Subgroup analysis revealed AR mutations but not amplifications were associated with improved OS (T1). AR amplifications were enriched in samples with TP53 alterations (p<1.0e-3, p<1.0e-3) and high CIN (p<1.0e-3, p=8.7e-3). Finally, using discovery data, we generated a gene signature associated with OS independent of TP53, RB1, and CDKN1B and validated this signature in the validation cohort (T1). Conclusions: RB1, TP53, and CDKN1B were recurrently altered genes independently associated with worse OS in CRPC. Further, we identified a gene signature associated with poor OS in CRPC independent of these alterations. Association with OSb in CRPC. Discovery Validation (n=192) (n=262) Univariate HR (95% CI) [p] Multivariate HR (95% CI) [p] Univariate HR (95% CI) [p] Multivariate HR (95% CI) [p] OSb RB1 2.74 (1.69-4.43) [4.3e-5] 2.5 (1.47-4.24) [0.00067] 2.37 (1.53-3.68) [0.00012] 2.33 (1.49-3.63) [2e-04] TP53 2.23 (1.57-3.11) [5.9e-6] 2.55 (1.78-3.66) [3.8e-07] 1.52 (1.14-2.03) [0.0046] 1.48 (1.1-1.98) [0.0094] CDKN1B 3.39 (1.42-8.13) [0.0061] 3.46 (1.47-8.15) [0.0046] 2.47 (1.32-4.6) [0.0045] 2.86 (1.51-5.42) [0.0013] Gene signature 2.08 (1.72-2.5) [1.5e-14] 1.88 (1.56-2.28) [5e-11] 1.36 (1.17-1.57) [4.3e-05] 1.32 (1.13-1.53) [0.00035] AR amplification 1.03 (0.74-1.44) [0.86] - 1.15 (0.86-1.54) [0.34] - AR mutation 0.55 (0.3-1) [0.049] - 0.64 (0.4-1.02) [0.063] -

JCCG ALL-B12: Evaluation of Intensified Therapies With Vincristine/Dexamethasone Pulses and Asparaginase and Augmented High-Dose Methotrexate for Pediatric B-ALL

PURPOSE The JCCG ALL-B12 clinical trial aimed to evaluate the effectiveness of unvalidated treatment phases for pediatric ALL and develop a safety-focused treatment framework. PATIENTS AND METHODS Patients age 1-19 years with newly diagnosed B-ALL were enrolled in this study. These patients were stratified into standard-risk (SR), intermediate-risk (IR), and high-risk (HR) groups. Randomized comparisons assessed the effectiveness of vincristine (VCR)/dexamethasone pulses in the SR group, evaluated the effects of L-asparaginase (ASP) intensification in the IR group, and compared standard consolidation including block-type treatment with experimental consolidation with high-dose methotrexate (HD-MTX) intensified with VCR and ASP in the HR group. RESULTS Of 1,936 patients enrolled, 1,804 were eligible for the experimental treatment. The overall 5-year event-free survival and overall survival rates were 85.2% (95% CI, 83.5 to 86.8) and 94.3% (95% CI, 93.1 to 95.3), respectively. The cumulative incidence of relapse and postremission nonrelapse mortality was 13.2% (95% CI, 11.6 to 14.8) and 0.6% (95% CI, 0.3 to 1.0), respectively. Random assignment in the SR group showed no significant benefit from pulse therapy. In the IR group, ASP intensification had limited effects. In the HR group, standard block therapy and HD-MTX yielded equivalent outcomes. CONCLUSION The ALL-B12 trial achieved favorable outcomes in a nationwide cohort by stratifying treatment on the basis of risk and balancing treatment intensity. This study not only demonstrated that existing standard of care can be further refined but also indicated that improvement in outcomes with intensified chemotherapy has reached a plateau.