bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep learning (DL) algorithms to predict prostate cancer progression on low/intermediate-risk needle core biopsies.
Authors: Ding Chien-Kuang Cornelia , Vidotto Thiago , Erak Eric , De Paula Oliveira Lia , Bonthu Saikiran , Kondragunta Chaith , Joshi Uttara , Singhal Nitin , De Marzo Angelo M , Lotan Tamara L. 
Published: January 2024

335 Background: Gleason Grade Group (GG) remains the standard of care to guide disease management in prostate cancer. Deep Learning (DL) algorithms assessing GG on whole slide images (WSI) have been largely validated by comparison to pathologist-determined GG. However, few studies have assessed DL grading of needle biopsies for predicting relevant clinical end-points. Methods: WSI of biopsies from two previously published cohorts (PMID 30279579, 27693448) were analyzed by a modified DL system for Gleason grading (PMID 35233002). In the Active Surveillance (AS) cohort (case-control design), all patients (n=137) had an initial biopsy with GG1 disease. Cases (63/137) had grade reclassification to GG2+ on repeat biopsies, or GG3+ or non-organ-confined disease by radical prostatectomy (RP), while the controls (74/137) continued on AS for >8 years without grade reclassification. For the Grade Group 2 (GG2) cohort, all patients (n=285) had GG2 disease on biopsy followed by RP, and progression was defined as biochemical recurrence (38/285). One representative H&E slide containing up to two biopsy cores from the diagnostic or confirmatory biopsy in both cohorts was graded by the DL system, and evaluated by 2-3 blinded uropathologists to provide consensus Gleason grading. Results: The agreement of GG between uropathologists and the modified DL system (κquad) was 0.32 for the AS cohort and 0.37 for the GG2 cohort. In the AS cohort, upgrading of the initial GG1 biopsy to GG2+ by the uropathologists occurred in 10% of cases compared to 7% of controls (p = 0.78). Upgrading by the DL system to GG2+ occurred in 33% of cases compared to 8% of controls (p=0.0005). In the GG2 cohort, biochemical recurrent after RP was not significantly associated with upgrading of the original biopsy to GG3+ by the uropathologists (HR= 0.55; 95% CI: 0.21-14.88; p=0.58) but significantly associated with upgrading by the DL system (HR=4.47; 95% CI: 1.32-15.09; p=0.01) in multivariable models including pre-operative PSA, clinical stage and fraction cores involved by tumor. Conclusions: In low or intermediate risk needle biopsies (GG1 and GG2), the agreement of grading between uropathologists and modified DL system is lower than that seen in analyses on a broader range of grade groups (PMID 35233002). Nevertheless, the DL system grading outperformed uropathologist consensus in predicting progression in patients with low/intermediate grade prostate cancer receiving active surveillance or radical prostatectomy.
DNA methyl-transferases (DNMTs) as potential therapeutic vulnerability in prostate cancer.
Authors: Koul Hari K. , Vatanmakanian Mousa , Lima Ellen Nogueira , Chaturvedi Lakshmi S , Koul Sweaty K 
Published: January 2024

339 Background: Prostate cancer (PCa) presents a significant health challenge in men, with a substantial number of deaths attributed to resistance to current Androgen Receptor inhibitors, and emergence of CRPC-adeno, CRPC-NEPC and CRPC-DNPC phenotypes. There is an urgent and unmet need for developing new targets for CRPC especially CRPC-NEPC and CRPC-DNPC. Because cellular plasticity plays a central role in transition to NEPC and DNPC, molecular targets that are critical for prostate cancer cellular plasticity could serve as actionable targets in therapy resistance in prostate cancer. In this study we explored potential role of DNA methyl-transferases in prostate cancer therapy resistance. Methods: We analyzed publicly available clinical datasets to investigate expression of DNMTs (DNMT1, DNMT3a, and DNMT3b), and the association between expression of DNMTs, and prostate cancer progression, neuroendocrine features and overall survival. We evaluated effects of DNMT inhibitor [5-aza-2′-deoxycytidine (5AdC)] in short term experiments PCa cell lines to measure cell viability. We performed epigenetic reprograming by culturing PCa cells in sublethal doses of 5AdC over long term and measured cell migration and invasion. Results: Expression of DNMTs (DNMT1, 3a and 3b) is increased during prostate cancer progression, and there is a positive correlation between DNMT (DNMT1, DNMT3a, and DNMT3b) expression and tumor progression (increasing Gleason score) and NEPC score, and a negative correlation between DNMT expression and patient survival. DNMT1, DNMT3a and DNMT3b are expressed in androgen dependent as well as CRPC cell lines. All PCa cell lines were sensitive to DNMT inhibition (5AdC treatment). 5AdC was as effective as enzalutamide in limiting cell growth and proliferation in enzalutamide sensitive LNCaP cells, and sensitized these cells to enzalutamide. Moreover, 5AdC treatment also halted growth and proliferation of CRPC cell lines (PC3 and DU145) and epigenetic reprograming of these cells with 5AdC decreased cell migration and invasion. Conclusions: These results indicate DNMT expression is associated with prostate cancer progression. These studies suggest DMNT activity as a potential therapeutic vulnerability that can be exploited for limiting cellular plasticity, tumor progression, and therapy resistance in prostate cancer. Because DNMT inhibitors are currently approved for other malignancies, addition of these inhibitors to current treatment regiments could be readily explored in PCa.
Prevalence of variant of unknown significance (VUS) in men with prostate cancer who serve as a benchmark for enhanced screening and for personalized therapy.
Authors: Fasulo Vittorio , Lazzeri Massimo , Casale Paolo , Saita Alberto , Hurle Rodolfo , Paciotti Marco , Finocchiaro Alessio , Aljoulani Muhannad , Cavalli Pietro , Soldà Giulia , De Simone Ilaria , Colombo Piergiuseppe , Cieri Miriam , Maura Federica , Lughezzani Giovanni , Asselta Rosanna , Buffi Nicolò Maria 
Published: January 2024

342 Background: Pathogenic variants (PVs) in DNA repair genes (DRG), such as in BRCA1, BRCA2, ATM, CHEK2, etc., have implications for prostate cancer (PCa) family genetic counselling, testing and risk stratification in men. However, understanding how to counsel patients with variants of unknown significance (VUS) is an unmet clinical need. On the other hand, there is the necessity to cautiously interpret VUS findings and to bolster VUS evaluations with additional evidence for pathogenicity. In this study, we aim to investigate the prevalence of germline VUS in men with PCa and their association with outcomes after robot-assisted radical prostatectomy (RARP). Methods: This is a nested cohort case study from an ongoing PCa screening, set to identify and screen men in the Italian population with a genetic predisposition (AIRC - Fondazione AIRC per la Ricerca sul Cancro project IG 2020 ID 25027). Cases for the current analysis were selected by “Adam's rib strategy” searching for germline DRG variant in men with a diagnosis of high-risk PCa who were scheduled for RARP. After informed consent was signed, a blood sample was obtained. A previously validated multigene panel test was used to assess the presence of germline variants. PVs and VUS were classified according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology consensus criteria and International Agency for Research on Cancer guidelines. The primary endpoint was to describe the prevalence of VUS and the secondary to correlate VUS with pathological outcomes after RARP. Results: A total of 118 men with diagnosis of PCa who underwent RP were enrolled. The mean age at diagnosis of PCa was 65.9 (±6.42) years; pathological grade was ISUP 1-2 in 58.0% patients and 3-5 in 42.0%. Of the 76 men evaluated, 18 (23.7%) had a VUS and 1 (1.32%) a pathogenic germline variant in BRCA1 and PALB2. Among those with VUS younger men at diagnosis were more likely to carry a VUS than older at diagnosis mean (age 64 ± 6.41 vs. 66 ± 7.20 years). Additionally, 33.3% vs 16.2 % were carrier of VUS and N+ and required adjuvant androgen deprivation therapy. No difference between ISUP at final pathology and positive margin rate were found. Conclusions: Our findings showed a high prevalence of VUS germline mutations in PCa patients undergoing RARP. These mutations seem to be associated with worse pathological outcomes. Limitations includes short follow-up and absence of non-Caucasian patients.
Differences between whole body magnetic resonance imaging (WB-MRI) and chest/abdomen/pelvis computed tomography (CT)/bone scan (CT/B) in patients staged as having metastatic hormone-sensitive prostate cancer (mHSPC): A retrospective comparative study within a single trust in the UK.
Authors: Hassan Mona , Anpalakhan Shobana , Maniam Akash , Ghose Aruni , Lokman Utku , Olejnik Tomasz , Banna Giuseppe Luigi 
Published: January 2024

37 Background: Diagnostic imaging for metastases detection in HSPC varies across different countries with increasing use of WB-MRI and PSMA-PET. However, CT/B has still been the most used modality in the real world and recent registration clinical trials in this disease setting. Methods: We performed a cross-sectional retrospective descriptive study comparing WB-MRI with CT/B used as baseline staging modalities in patients diagnosed with mHSPC between February 2017 and August 2023 in two hospitals belonging to the same NHS trust in the UK routinely using one of the two. The study aimed at the detection of differences between the two modalities in the identification of metastatic sites and CHAARTED volume/LATITUDE risk, and the relative impact on patients’ received therapies and outcomes. Results: Of 213 patients diagnosed with mHSPC, 121 had baseline WB-MRI, 86 CT/B and 7 choline or PSMA PET. Compared to CT/B, patients staged by WB-MRI were diagnosed with significantly higher bone-only (47 vs 24%, p=0.002) and lower lymph-node only disease (11 vs 27%, p=0.005); higher high-volume (49 vs 21%, p<0.001) and -risk disease (48 vs 17%, p<0.001); higher de-novo metastatic disease (91 vs 66%, p<0.001); had previously received less radical surgery (2 vs 13%, p=0.003) or radiotherapy (7 vs 24%, p<0.001); received more frequently ADT plus Docetaxel (65 vs 44%, p=0.005). Treatment and outcome results in the overall cohorts’ populations and according to disease volume/risk will be presented. Conclusions: In a homogenous cohort of patients, we found a relevant discrepancy between the use of WB-MRI and CT/B in the identification of high-volume/risk and de-novo disease in mHSPC related to a higher detection rate of bone-only disease by the WB-MRI. This may prompt clinicians to offer different systemic therapies according to the disease burden and could also have a role in avoiding overtreatments for the under-staged disease.
Real world evidence from a retrospective multi-center analysis on first-line therapy for metastatic renal cell carcinoma with non-clear cell and/or sarcomatoid histologies.
Authors: Paffenholz Pia , Zschaebitz Stefanie , Casuscelli Jozefina , Rinderknecht Emily , Mattigk Angelika , Gür Melis , Ivanyi Philipp , Hilser Thomas , Darr Christopher , Mandal Subhajit , Schlack Katrin , Seidl Daniel , Handke Analena , Klee Melanie , Nestler Tim , Rehlinghaus Marc , Hijazi Sameh , Heidenreich Axel , Grünwald Viktor , Schostak Martin ,   GUARDIAN
Published: January 2024

392 Background: Papillary (pRCC), chromophob (chRCC) and predominantly sarcomatoid renal cell carcinoma (sRCC) as well as RCC with sarcomatoid features are rare cancers. We evaluated real-world treatment outcomes of 1st line treatment in these cohorts in Germany. Methods: We retrospectively analyzed patients with non-clear cell RCC treated at 17 German tertiary cancer centres. Adverse events (AE) were reported according to CTCAE 5.0, objective response rate (ORR) according to RECIST 1.1. Progression free survival (PFS) and overall survival (OS) were calculated from start of treatment to progression or death, respectively and determined by KM plots. Results: We included 189 patients with a median age of 63 years (IQR 54-72). Of these, 49% were pRCC, 12% chRCC, 12% sRCC. 17% of all RCC had a sarcomatoid features. 87% had an ECOG PS of 0/1. IMDC risk was favorable/intermediate/poor in 15/54/31%. 74% received prior nephrectomy. Lymphatic (63%) and pulmonary (51%) metastases were the most common metastatic sites. 72% patients received first-line IO-combinations (IO-IO: 36%, TKI-IO: 64%) and 28% patients TKI-monotherapy, predominantly sunitinib. AE of all grades occurred in 86% and 72% during IO-based therapy or TKI monotherapy, and CTCAE grade ≥ 3 in 46% or 36%, of which led to discontinuation of treatment in 42% or 29% of patients, respectively. ORR and survival outcomes with median follow-up of 17 months (IQR 9-30) are described in the table. Conclusions: IO-combinations are frequently applied in pRCC, chRCC and sRCC. Our data suggests that first-line IO-combinations yields higher ORR compared to single agent TKI in sRCC, but not in chRCC. However, the retrospective nature and small sample size are major limitations of our analysis. Additional analyses to tailor treatment strategies in patients with metastatic nccRCC or sRCC is warranted. [Table: see text]
Real-world metastatic renal cell carcinoma (mRCC) treatment trends in Mexico: A public vs private sector analysis.
Authors: González Espinoza Iván Romarico , Garcia Montes Lizbett Vanessa , Hernandez Flores Osvaldo , Remolina Bonilla Yuly Andrea , Sanchez-Trujillo Luis Arturo , Rios Mercado Maria del Socorro Isabel , Jaimes Diana 
Published: January 2024

397 Background: Metastatic renal cell carcinoma (mRCC) treatment avenues have expanded, yet Mexico’s fragmented healthcare system could impact real-world setting, scarce information is available, and little is known regarding this issue. This study aims to characterize the treatment patterns for mRCC in Mexico’s public and private healthcare sectors. Methods: De-identified patient data collected from 180 oncologists (03/2022 to 02/2023) using Evidera LiveTracker were assessed. Data from adult mRCC patients outside clinical study protocols were included. Patients were categorized by healthcare sectors, and line of treatment (L). A descriptive analysis was conducted. Results: Of 651 patients, 182 (28.0%) were favorable risk-stratified, 332 (51.0%) intermediate, and 137 (20.0%) high-risk. Treatment in 1L involved 542 (83.3%), 96 (14.7%) in 2L and 13 (2.0%) ≥3L. Sectors were evenly split: 327 (50.2%) public and 324 (49.8%) private. Among patients in 1L, 60.7% underwent TKI monotherapy (72.8% public vs 48.1% private) mainly with sunitinib (49.8%) and pazopanib (20.9%). Immunotherapy (IO) combination IO+IO was indicated in 26.2% (17.0% public vs 35.7% private), and IO+TKI in 7.9% (5.4% public vs 10.5% private). similar disparities trends were observed in 2L, where TKI monotherapy increased to 70.8% (84.5% public vs 58.8% private), whereas 21.9% (13.3% public vs 29.4% private) and 4.2% (2.2% public vs 5.9% private) received IO monotherapy and IO+TKI, respectively (Table). Conclusions: Despite clinical practice guidelines favoring the use of IO for mRCC 1L treatment, many Mexican patients receive currently TKI monotherapy, particularly in public healthcare, and this is consistent in subsequent lines of treatment. Potential access barriers warrant further exploration. [Table: see text]
Optimal timing of delayed cytoreductive nephrectomy in metastatic renal cell carcinoma during the immunotherapy era.
Authors: Selene Insija Ilyas , Lei Feitong , Huang Bin , Dhahri Amina , Heckman Patrick , Bardhan Roshmita , Jose Jemin , Myint Zin 
Published: January 2024

403 Background: The CARMENA study found no survival benefit from cytoreductive nephrectomy (CN) in poor-risk metastatic renal cell cancer (mRCC) patients treated with first line Sunitinib. Although retrospective studies have reported survival benefits with CN following immunotherapy (IO)-based therapy, the timing remains unclear. We aimed to investigate the ideal timing of CN following IO using the National Cancer Database. Methods: 783 patients with de novo mRCC were diagnosed between 2016 and 2020 who received upfront systemic therapy and underwent CN, 343 patients met our criteria. Patients were categorized into four groups based on the timing of nephrectomy: CN ≤3 months (Group A), 4 to 6 months (Group B), 7 to 9 months (Group C) and ≥ 10 months (Group D) following the initiation of IO-based therapy. Descriptive analysis was performed to examine the demographic and clinical characteristics. Follow up time was measured from the date of surgery to reduce bias. Kaplan-Meier plots were used to analyze survival curves, and a multivariable cox regression analysis was performed to explore associations between timing and survival. Results: 343 patients who received upfront IO -based therapy were divided into four groups: 104 (30%) in A, 114 (33%) in B, 74 (22%) in C and 51 (15%) in D. 71%were male, white (90%), age 40 – 64 (62%), comorbidity index 0 (70%), clear cell histology (69%), sarcomatoid (14%). 54% were treated in academia, 57% had bone metastasis, 50% had lung, 11% had liver, and 7% had brain metastases. 66% received only IO, and 34% received IO + TKI. No significant association between CN timing and survival observed in multivariate cox regression model. (HR 0.87, 95% CI: 0.5- 1.7, p = 0.84). Compared to group A, the HR were 0.96 (95% CI, 0.73 to 1.27; p=0.78), 0.77 (95% CI, 0.53 to 1.13; p=0.19), and 0.66 (95% CI, 0.37 to 1.20; p=0.17) respectively for groups B, C and D. Conclusions: Our study did not find significant survival improvement with an optimal timing of CN following IO-based therapy, while HRs were reduced after 6 months of delay, though insignificant. This could be due to the small sample size or other confounders.
Impact of renal function eligibility criteria in clinical trials and real-world survival outcomes among patients with metastatic renal cell carcinoma.
Authors: Miron Benjamin , Wang Xiaoliang , Hasler Jill S. , Royce Trevor Joseph , Geynisman Daniel M. 
Published: January 2024

407 Background: Registration trials in metastatic renal cell carcinoma (mRCC) establishing the efficacy of first-line (1L) combination regimens employed strict renal function eligibility criteria (NCT02853331, NCT02811861, NCT03141177, NCT02231749); however, pharmacokinetics and safety of immune checkpoint inhibitors and anti-vascular endothelial growth factor therapies have been shown to be similar regardless of baseline renal function. Therefore, we aim to evaluate the impact of renal function eligibility criteria used in previous trials on real world outcomes. Methods: Data from the US nationwide Flatiron Health electronic health record-derived de-identified database included adult patients (pts) with mRCC who received any 1L systemic treatment on or after 4/16/2018 (first FDA combination regimen approval), had hemoglobin level ≥9 g/dL and ECOG performance status (ECOG) 0-1 at 1L. Renal function eligibility criteria at 1L (-60 days to +7 days) include serum creatinine (≤1.5 vs >1.5 x ULN), eGFR (≥30 vs <30 ml/min/1.73m2) and calculated CrCl (≥40 vs <40 ml/min) based on registration trial protocols. Outcomes include real world progression free survival (rwPFS), time to next treatment (rwTTNT), and overall survival (rwOS) from 1L. Inverse probability of treatment weighted (IPTW) Kaplan Meier methods and Cox proportional hazard models with multiple imputation were applied. Results: Of 2038 pts in this cohort, 1390 (68.2%) met all criteria for renal function (included), 140 (6.9%) met at least one criteria (relaxed), 46 (2.3%) met none (excluded), and 462 (22.7%) had unknown renal function. Compared to included pts, excluded pts were more likely to be older (median age: 74 vs 66), female (35% vs 27%), have recurrent disease (61% vs 53%), less likely to have ECOG 0 (24% vs 40%) and favorable IMDC risk (9% vs 14%). Excluded pts are also more likely to be Non-Latinx Black (13% vs 6%) and have lowest SES quintile (22% vs 15%) compared to included pts. Although, after weighting included pts had higher median rwPFS of 9.3 (95% CI 8.4 - 10.1) vs 6.9 (95% CI 3.7 - 9.9), rwTTNT 12.0 (95% CI 11.0 - 13.1) vs 9.1 (95% CI 5.5 - 16.4) and rwOS 38.5 mo (95% CI 35.9 - 44.5) vs 19.3 mo (95% CI 16.6 - 41.8) compared to relaxed/excluded pts, none of the hazard ratios (HRs) were statistically significant after multiple imputation (Table). Conclusions: In this real world study, we found that although only 68.2% of patients met all renal function eligibility criteria, survival outcomes were not different across pts groups. This suggests that mRCC patients with reduced renal function may benefit similarly to 1L treatment and should not be excluded from clinical trials. [Table: see text]
Health-related quality of life (HrQoL) of first-line treatments in metastatic renal cell carcinoma (mRCC): A network meta-analysis.
Authors: Abidoye Oluseyi , Naqvi Syed Arsalan Ahmed , Faisal Kunwer Sufyan , Imran Manal , Khakwani Kaneez Zahra Rubab , Raina Ammad , Tripathi Nikita , Abdul-Muhsin Haidar , Costello Brian Addis , Singh Parminder , Bryce Alan Haruo , Riaz Irbaz Bin 
Published: January 2024

412 Background: Previously we have reported comparative effectiveness data regarding survival of first line (1L) treatment options in mRCC. However, it is not known how the life-prolonging frontline combinations compare to patient-reported outcomes. Methods: Electronic databases including MEDLINE and EMBASE were searched from each database’s inception through July 1st 2023. Phase III randomized controlled trials (RCTs) assessing 1L immune-checkpoint inhibitor (ICI) combination therapies for mRCC and reporting HrQoL were included. Small sample size adjusted standardized mean differences (SMD; Hedges’ g) with 95% confidence intervals (CI) were computed for global, physical, functional, and emotional QoL. Positive SMD indicated an improvement. A network meta-analysis was conducted to assess the comparative HrQoL across different treatment options. P-scores were computed to assess relative treatment rankings. Results: Of 5770 citations identified, five trials (nine references) were included in this analysis. Patient-reported outcomes have not been reported in the JAVELIN Renal 101 or COSMIC-313 trials yet. Global QoL was significantly improved with cabozantinib-nivolumab (CaboNivo) as compared to Nivo-ipilimumab (SMD 2.74, 95% CI 2.54; 2.93), lenvatinib-pembrolizumab (LenPem; 2.79, 2.53; 3.06), sunitinib (2.87, 2.72; 3.03), Pem-axitinib (PemAxi; 3.09, 2.89; 3.30) and atezolizumab-bevacizumab (AteBev; 3.24, 3.04; 3.45). Global QoL improvement was also observed with NivoIpi compared to sunitinib (0.14, 0.02; 0.25), PemAxi (0.36, 0.18; 0.54) and AteBev (0.51, 0.33; 0.68). Physical QoL improvement were consistent with CaboNivo. Likewise, LenPem significantly improved QoL compared to sunitinib (0.26, 0.04; 0.47), PemAxi (0.38, 0.13; 0.64) and NivoIpi (0.51, 0.27; 0.76). Significant functional QoL benefits were only observed with CaboNivo (0.32, 0.17; 0.48) and NivoIpi (0.19, 0.08; 0.31) compared to sunitinib. No significant mixed treatment comparisons were observed for emotional QoL, however, currently available data suggests that LenPem (rank 1) may potentially improve QoL (Table). Conclusions: CaboNivo and NivoIpi as 1L therapy may offer an improved overall HrQoL compared to other contemporary treatment options in mRCC. [Table: see text]