bluuebunny/crossref_metadata_2025_split huggingface dataset:
A systematic review: Are the findings of indirect treatment comparisons (ITCs) in metastatic hormone-sensitive prostate cancer (mHSPC) consistent?
Authors: Shore Neal D. , Morgans Alicia K. , Paracha Noman , Hodgkinson Sarah , Eichinger Christian , Millar Craig , Chen Stephanie , Boegemann Martin 
Published: January 2024

324 Background: Multiple treatment options exist for mHSPC, including androgen receptor-axis-targeted (ARAT) therapies with or without docetaxel (DOC). Many ITCs have been published that compare efficacy and safety of treatment alternatives in mHSPC that have not been directly compared in head-to-head clinical trials. We assessed the methodology and findings of previously published ITCs, focusing on outcomes related to triple therapy with darolutamide (DARO) + androgen deprivation therapy (ADT) + DOC from the ARASENS clinical trial. Methods: We performed systematic literature review searches in MEDLINE, Embase and Cochrane databases to identify ITCs published from 1946 to May 2023 (PROSPERO, CRD42023429478). We focused on reporting ITCs that included ARASENS trial data and treatment versus treatment comparisons. Results: We included 12 ITCs across 17 publications. There was variation across the ITCs in the number of trials included (range: 2–10), and the statistical method used (frequentist or Bayesian network meta-analyses, random or fixed effects). Furthermore, reporting of treatment effect modifiers, network inconsistency/heterogeneity, and subgroup analysis was inconsistent across studies. Despite methodological differences, ITCs were consistent in showing a significant benefit in overall survival (OS) with DARO triple therapy compared with ADT (4 ITCs), and with DOC+ADT (7 ITCs; in line with ARASENS trial results). DARO triple therapy demonstrated a numerical benefit in OS compared with doublet (ARAT+ADT) and with other triple therapies (abiraterone acetate+prednisone [AAP] or enzalutamide [ENZ]+DOC+ADT) (Table 1). DARO triple therapy was consistently ranked highest, above other ARAT double and triple therapies, on OS across 9 ITCs. The risk of grade ≥3 adverse events (AEs) were numerically greater with DARO triplet therapy compared with ARAT doublets (6 ITCs). Available ITC evidence comparing AEs across triple therapies showed numerically fewer AEs for DARO compared with AAP (2 ITCs). Conclusions: Despite variability in their methodology, ITCs were consistent in showing OS benefit and highest ranking with DARO triple therapy, above the other ARAT therapies, and in reporting fewer AEs for DARO compared with AAP. As the number of mHSPC publications grows, so too does the need for standardizing ITC methodology to ensure robustness of findings and to optimize treatment decision-making. [Table: see text]
Real-world homologous recombination repair mutation (HRRm) testing patterns in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib in the United States.
Authors: George Daniel J. , Kariburyo-Yay Furaha , Aggarwal Himani , Tepsick Jon G. , Yu Rebekah , Li Weiyan , McLaurin Kimmie K. , Orji Chinelo , Lal Lincy S. , Ghate Sameer R. 
Published: January 2024

332 Background: Olaparib is one of the first targeted therapies for patients (pts) with mCRPC. This study focused on assessing treatment patterns and results of genetic testing for HRRm in mCRPC pts treated with olaparib monotherapy. Methods: This retrospective study used data abstracted from electronic medical records in the ConcertAI Oncology Dataset with PC diagnosis between 1990 and 2023. Pts with confirmed mCRPC diagnosis, age ≥21 years, treated with olaparib monotherapy after exposure to abiraterone or enzalutamide, and with positive HRRm status were included. HRRm was defined as a mutation in at least 1 of 14 genes of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L) regardless of test type. Pt demographic and clinical characteristics, patterns of individual HRRm, testing type, and timing of biomarker testing were summarized. The index date was the start date of the earliest olaparib monotherapy treatment. Results: A total of 192 mCRPC olaparib treated pts with at least one HRRm were identified. The median age was 73 years at index date. More than half of pts (56.3%) had an ECOG score of 0 or 1, and 51.0% of pts had a Gleason Score of ≥8 at index. Most pts (87.0%) had bone metastasis at index, and 20.3% had 3 or more sites of distant metastasis. Nearly one-third of pts (31.7%) had documentation of opioid use at index. Over half of the pts (56.2%) had any BRCA mutation ( BRCA2 33.3%, BRCA1 4.7%, co-occurring HRRm 18.2%) and 43.8% had non- BRCA mutation ( ATM 20.8%, CDK12 4.2%, co-occurring HRRm 11.5%, other non- BRCA 7.3%) Over 40% of pts had somatic only testing (40.6%), while 15.1% had germline only testing, 27.6% of the pts had both germline and somatic testing, and 16.7% had other testing. Most pts were tested on or after mCRPC diagnosis (142 pts; 74.0%) and the median time from mCRPC diagnosis to the first biomarker test was 16.9 (IQR 23.3) months. Conclusions: This real-world analysis highlights the need for earlier HRRm testing in pts with mCRPC to allow for optimal timing of novel treatment options that have shown efficacy in a biomarker-selected population. Most pts in this study were tested and diagnosed with HRRm many months after mCRPC diagnosis, at which point they had high levels of bone metastasis, multiple sites of distant metastases, and opioid use at the initiation of olaparib treatment. HRR testing in pts before or at the time of mCRPC would allow for olaparib therapy earlier in the disease course. [Table: see text]
Exploring the utility of prostate-derived extracellular vesicles as a urine biomarker for clinically significant prostate cancer.
Authors: Deol Ekamjit Singh , Britton Cameron J , Andrews Jack R. , Horjeti Edlira , Kim Yohan J , Joshi Vidhu B. , Ahmed Mohamed E. , Karnes R. Jeffrey , Lucien Fabrice 
Published: January 2024

334 Background: Prostate cancer (PCa) screening has relied on prostate-specific antigen (PSA) levels to screen patients for biopsy. However, the limited specificity of serum PSA leads to high rates of negative biopsies and detection of clinically insignificant cancers. Tumor-derived extracellular vesicles, microscopic particles released by tumor cells and ubiquitously found in all bodily fluids, have emerged as novel biomarkers for a diverse set of malignancies. This study explored the utility of urine prostate-specific extracellular vesicles (ProsEVs) identified by unique surface protein markers with novel flow cytometry-based techniques as biomarkers for PCa screening. Methods: This prospective study recruited at a tertiary care center between Oct 2019 and Mar 2022. Patients with PSA≥2 ng/ml underwent prebiopsy mpMRI followed by transperineal prostate biopsy (PI-RADS 1-2) or combined MRI-guided biopsy (PI-RADS ≥ 3). Patients with metastatic PCa or prior systemic therapy were excluded. Urine samples were collected at MRI using Colli-Pee. ProsEVs were labeled using monoclonal antibodies for PSMA and STEAP1 and ProsEV concentrations were determined using nanoscale flow cytometry. EV densities were calculated by normalizing EV counts to prostate volume. Multivariable logistic regression models were constructed and model performance was compared used ROC curve analysis. Results: This study had a total of 179 patients prospectively recruited, 95 were diagnosed with Gleason score (GS) ≥ 7 prostate cancer (csPCa), while the remaining had GS <7 or benign disease. Analysis of urinary ProsEV densities revealed a significant dose-response relationship between benign, GS <7 PCa and GS ≥ 7 PCa groups and ProsEV densities (p=0.01 for PSMA, and <0.001 for STEAP1). The log sum of the PSMA and STEAP1 EV densities exhibited the strongest correlation with other ProsEV variables and was selected for model development. ROC curve analysis showed that the final model including Log Sum ProsEVs, PSA, and PI-RADS outperformed one including PSA and PI-RADS (0.733 vs 0.651, p=0.02). Specificity for detecting csPCa at a sensitivity of 90% was 39.5% in the final model compared to 37% for PSA and PI-RADS (Table). Conclusions: This study highlights the potential of urine ProsEVs as novel biomarkers for improving screening specificity for csPCa detection. Future works should explore analysis of intra-ProsEV content to further improve specificity and advance liquid biopsy techniques. [Table: see text]
Comparison of pathologist and deep learning–based prostate cancer grading for prediction of metastatic outcomes in primary prostate cancer.
Authors: DePaula Oliveira Lia , Lu Jiayun , Erak Eric , Mendes Adrianna , Bonthu Saikiran , Joshi Uttara , Kondragunta Chaith , Joshu Corinne E , Singhal Nitin , De Marzo Angelo M , Lotan Tamara L. 
Published: January 2024

345 Background: Gleason grading is the most potent prognostic variable in primary prostate cancer, however inter-observer variability remains a major issue, particularly where subspecialty-trained pathologists are not available. Artificial intelligence algorithms for prostate cancer grading may improve health care equity by ensuring widespread access to standardized, high quality grading, however most algorithms have not been tested for performance with respect to oncologic outcomes. Here, we compared deep learning-based and pathologist-based Gleason grading for prediction of metastatic outcome in three large radical prostatectomy cohorts. Methods: Three previously published radical prostatectomy cohorts from Johns Hopkins were utilized for this study. The Natural History Cohort (n=318, PMID: 26058959) and Case-Cohort (n=231, PMID: 36006048) both utilized a case-cohort design on the outcome of metastasis, while the Race Cohort (n=335, PMID: 30851334) was designed for a grade-matched comparison of self-identified White and Black patients. For each cohort, a single representative H&E-stained slide from the dominant tumor nodule was scanned and Gleason Grade Group (GG) assessed by a modified deep learning-based grading algorithm (PMID: 35233002), or by a subspecialty-trained pathologist. Harrell’s C-indices based on unadjusted Cox models for time to metastasis were compared for the pathologist- and deep learning-assigned GG in each cohort. Results: The C-index for deep learning-assigned GG in the Natural History Cohort was 0.757 (95% confidence interval [CI]: 0.703-0.811) compared to 0.748 (95% CI: 0.692-0.804) for the pathologist-assigned GG. The C-index for deep learning-assigned GG in the Case-Cohort was 0.848 (95% CI: 0.727-0.969) compared to 0.843 (95% CI: 0.722-0.964) for the pathologist-assigned GG. The C-index for deep learning-assigned GG in the Race Cohort was 0.754 (95% CI: 0.697-0.810) compared to 0.780 (95% CI: 0.717-0.844) for the pathologist-assigned GG. In a combined analysis of all three cohorts, the C-index for the deep learning-assigned GG was 0.765 (95% CI: 0.725-0.805) compared to 0.772 (95% CI: 0.730-0.814) for the pathologist-assigned grade group. In the combined cohorts, the historical pathologist-assigned GG for the entire case had a C-index of 0.796 (95% CI: 0.757-0.836). Conclusions: Deep learning and subspecialty-trained pathologist grading were highly comparable for association with metastatic outcome across three large radical prostatectomy cohorts.
PSMA PET imaging for evaluation of recurrent or persistent prostate cancer after primary prostate radiation.
Authors: Bennett Richard , Li Eric , Ho Austin Y. , Aguiar Jonathan , Mahenthiran Ashorne Krithiesh , Kumar Sai , Suk-ouichai Chalairat , Neill Clayton , Patel Hiten Dilip , Schaeffer Edward M. , Savas Hatice , Ross Ashley 
Published: January 2024

35 Background: PSMA PET is increasingly utilized for the evaluation of disease stage at biochemical recurrence. Here we evaluate the association of clinico-pathologic features with PSMA findings in biochemically recurrent patients after primary prostate radiation therapy (RT). Methods: We queried the Northwestern Medical System Electronic Data Warehouse between July 2021 and March 2023 to identify 122 men treated with primary RT for presumptive localized prostate cancer who subsequently underwent Gallium-68 or F-18 piflufolastat (DCFPyL) PSMA PET/CT for staging. Patient characteristics, including demographic, clinical, pathological, and imaging variables were obtained. PSMA positivity for suspicious nodal or metastatic disease was determined based on radiology interpretation, with equivocal or likely benign lesions considered as negative findings. Patients with incomplete clinical history (n=3) were excluded. Clinical variables were compared using a Wilcoxon rank-sum and Fisher’s exact tests. Regression analysis was performed to determine variables associated with PSMA positivity in biochemically recurrent patients. Statistical significance was determined if the p-value was less than 0.05. Results: Among the 119 men staged with PET PSMA after RT, median PSA was 3.18 (IQR 1.35, 5.55 ng/mL). 78% (93/119) were found to have suspicious PSMA positive disease. 39% had PSMA positivity in the prostate only (46/119), 6.7% had pelvic nodal disease (8/119), and 33% had extrapelvic disease (39/119). On univariable regression analysis, PSA at the time of PSMA was the only factor associated with PSMA positivity (OR 1.32 per 1 point increase, 95% CI 1.10, 1.67, p=0.01; Table). Higher PSAs at the time of scan were additionally associated with distant recurrence (73.3% of men with distant recurrence if scanned at PSA >10ng/mL versus 31.9% if scanned at PSA <4ng/mL p=0.029). 20% (9/46) of men with PSMA positivity within the prostate were biopsied identifying 78% (7/9) positivity, of which 67% (4/6) receiving treatment selected management with salvage treatments. Conclusions: Patients with prostate cancer initially treated with RT showed significant rates of PSMA positive disease even when scanned at low PSAs (including many below the nadir+2ng/mL definition). Evaluation at low PSAs favors the identification of localized disease only which can be cured by salvage therapy if confirmed by biopsy (i.e. prostatectomy, cryoablation, HIFU). [Table: see text]
Belzutifan versus everolimus in participants (pts) with previously treated advanced renal cell carcinoma (RCC): Patient-reported outcomes (PROs) in the phase 3 LITESPARK-005 study.
Authors: Powles Thomas , Albiges Laurence , Jalkanen Katriina Johanna , De Velasco Guillermo , Burotto Mauricio , Ghatalia Pooja , Suárez Cristina , Lam Elaine T. , Iacovelli Roberto , Gumus Mahmut , Verzoni Elena , Kollmannsberger Christian K. , Stadler Walter Michael , Venugopal Balaji , Shinde Reshma , Saretsky Todd L. , He Li , Vickery Donna , Choueiri Toni K. , Rini Brian I. 
Published: January 2024

361 Background: In the randomized, open-label, phase 3 LITESPARK-005 (NCT04195750) study, belzutifan treatment showed superior PFS (primary endpoint; HR 0.75 [95% CI 0.63–0.90]; P<.001) and ORR (key secondary endpoint; estimated percentage-point difference 18.4 [95% CI 14.0–23.2]; P<.00001) vs everolimus in pts with advanced/metastatic clear cell RCC that progressed after prior immune checkpoint and anti-angiogenic therapies. We present PRO findings for belzutifan vs everolimus in LITESPARK-005. Methods: PROs were evaluated by FKSI-DRS and EORTC QLQ-C30 questionnaires in all randomized pts with ≥1 dose study treatment and ≥1 completed PROs assessment, administered electronically on d 1 of wk 1, 3, 5, and 9, Q4W thereafter, at treatment discontinuation, and d 30 after last dose. Time to deterioration (TTD) and least square (LS) mean change from baseline as measured by FKSI-DRS and QLQ-C30 global health status/quality of life (GHS/QoL) and physical functioning (PF) scales were prespecified as secondary endpoints. PROs were not formally statistically tested and 95% CI and P-values were nominal and descriptive. Results: As of June 13, 2023 (data cutoff date at second prespecified interim analysis), median (range) follow-up was 25.7 mo (16.8–39.1). Median (range) duration of treatment was 7.6 mo (0.1–35.8) with belzutifan vs 3.9 mo (0.0–33.2) with everolimus; 84 (22.6%) vs 18 (5.0%) pts remained on treatment. 366 of 374 pts randomized to belzutifan and 354 of 372 pts randomized to everolimus were included in the PRO analysis population. Completion rates for FKSI-DRS and QLQ-C30 were >90% at baseline and >55% at wk 17 (~4 mo) in each arm. Meaningfully longer TTD in FKSI-DRS and QLQ-C30 GHS/QoL scores were observed for belzutifan vs everolimus (Table). LS mean changes in FKSI-DRS and QLQ-C30 GHS/QoL scores suggested stability from baseline to wk 17 with belzutifan vs worsening with everolimus, and a potential greater worsening in PF scores with everolimus vs belzutifan. Conclusions: Belzutifan was associated with prolonged TTD in FKSI-DRS and EORTC QLQ-C30. Score changes from baseline to wk 17 also favored belzutifan over everolimus. Overall, PRO results indicate better disease-specific symptoms and quality of life among pts treated with belzutifan compared with everolimus. Clinical trial information: NCT04195750 .[Table: see text]
Assessing tobacco-related mortality trends in genitourinary cancers: A 1990-2019 analysis.
Authors: Jani Chinmay , Kareff Samuel A. , Salazar Ana S. , Sharma Janaki Neela 
Published: January 2024

368 Background: Tobacco consumption is a well-established risk factor for genitourinary cancers like urothelial and renal cell. This study aims to examine mortality trends associated with tobacco use in these cancer types, both globally and within the U.S., over the period of 1990 to 2019. Methods: Data from the Global Burden of Disease database, based on the International Classification of Diseases versions 10 and 9, were utilized to extract mortality statistics for bladder cancer (BC) and kidney cancer (KC). Age-standardized death rates (ASDRs) for the overall population, as well as Tobacco Attributable Mortality (TAM) were collected by sex and year. TAM was calculated by applying population attributable fraction to cause-specific deaths and disability-adjusted life years by year, location, age group and sex. The database also provided Annual Percentage Change (APC) data. Trends were analyzed using Joinpoint regression. Results: Smoking rates as well as mortality due to tobacco consumption have steadily decreased for both cancers in both sexes globally as well as in the U.S. during the study period. Globally, ASDRs exhibited a decreasing trend for BC and KC, and for both sexes, excluding an increase in ASDR for KC in males (+0.2). In the U.S. ASDR decreased for KC but not for BC in males (Table 1). BC demonstrated the highest proportion of tobacco-induced mortality among the three cancer types, with a nearly 50% contribution globally among males in 1990 that reduced to 39% in 2019. Overall, the tobacco-induced ASDR for kidney cancer in males remained relatively constant globally. Despite reductions over three decades, BC still exhibited a high proportion of mortality attributed to tobacco, particularly among males (39% globally; 31% in the U.S.). In 2019, the U.S. continued to experience higher tobacco-induced mortality rates among females for both KC (17.1 vs. 8.8%) and BC (26.9 vs. 14.3%) compared to the global average. Conclusions: Despite the multiple advances in cancer treatment in the last decades, TAM remains minimally unchanged. While there has been a general reduction in smoking rates overall, a substantial burden persists for tobacco-related malignancies—particularly for BC and KC. These findings underscore the need for heightened awareness and more robust tobacco control policies both globally and within the U.S. [Table: see text]
Germline pathogenic variants in universal screening of genitourinary malignancies: A multisite single institution prospective study.
Authors: Choudry Mouneeb , Durant Adri , Edmonds Victoria , Warren Christoper , Kunze Katie , Golafshar Michael A. , Nielsen Sarah M. , Heald Brandie , Andrews Jack R. , Samadder N. Jewel , Tyson Mark 
Published: January 2024

376 Background: Germline genetic testing (GGT) is becoming increasingly important in the management of genitourinary (GU) malignancies as novel targeted drug therapies emerge. Selection for genetic studies and testing has historically been highly selective and based on pathologic characteristics, family history, and age of diagnosis. The aim of our study was to investigate the prevalence of pathogenic variants (PGVs) in inherited cancer susceptibility genes utilizing a universal testing approach and to characterize the rate of PGVs that would have been missed based on current NCCN guidelines. Methods: A multisite single-institutional prospective study (INTERCEPT) offered GGT to all patients with new or active diagnoses of GU malignancies (bladder, prostate, and renal cancers) from April 1, 2018 to March 31, 2020 at Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester. Participants were offered GGT with a panel of >80 genes through Invitae Corp. Demographic, tumor characteristics and genetic results were evaluated. PGVs were classified as high-, intermediate-, or low- penetrance variants based on published literature. Respective NCCN GU GGT guidelines were used to determine if the PGVs discovered using our universal testing approach would have been missed with guideline-directed GGT. Results: A total of 3095 pan-cancer patients were enrolled in the study; 601 of which had a GU malignancy including: prostate cancer (358 patients), renal cancer (137), and bladder cancer (106). The mean age of enrollment was 66.8 years (SD 9.1), 89% were male, and 85.9% of patients were Non-Hispanic white. PGVs were identified in 82 of all GU patients (13.6%) and variants of undetermined significance (VUS) in 289 (48.1%) patients. PGV prevalence breakdown by cancer type was: 13.7% of prostate, 13.1% renal, and 14.2% bladder cancer patients. The proportion of high penetrance PGVs varied by malignancy type. Of all patients, 326 (54.2%) had advanced (stage III/IV) disease and 377 (64.4%) of these were metastatic upon initial evaluation. The majority of all PGVs identified were incremental, defined as PGVs that would not have been identified based on guideline-concordant GGT: 100% (15/15 patients) with bladder, 77.8% (14/18) with renal, and 57.1% (28/49) with prostate cancer. Conclusions: Universal GGT for prostate, renal and bladder cancer revealed that over 1 in 10 patients harbored potentially actionable PGVs, most of which would not have been identified with guidelines-based GGT. Utilization of GGT can impact our understanding of GU cancer pathogenesis, aid in familial cascade testing, and influence treatment decisions.