bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world evidence analysis of early-stage prostate cancer using natural language processing.
Authors: Juárez Álvaro , Carles Joan , Conde-Moreno Antonio José , Maroto-Rey Pablo , Puente Javier , Muñoz Del Toro Jacobo , Calderon Jose M , Lopez Maria , Valdivieso Juan , Casadevall David , Taberna Miren , Alcaraz Antonio 
Published: June 2023

e17007 Background: Real-world evidence (RWE) on the epidemiology and management of localized/locally advanced prostate cancer (LPC) is lacking. Here we used EHRead, a natural language processing framework based on SNOMED CT terminology, to extract clinical information from electronic health records (EHRs) to perform a comprehensive description of a real-world cohort of LPC patients. Here we present a follow-up of the project already communicated at ESMO 2020. Methods: This is an observational, multicenter, retrospective study based on the secondary analysis of free-text and structured clinical information found in EHRs from all observed adult patients with LPC between January 2014 and December 2018 in 12 Spanish hospitals. A total of 375 variables were extracted using EHRead to assess patient clinical characteristics, treatment patterns and journey across different prostate cancer stages. Event-free survival (EFS) was analyzed in incident LPC patients with presence of Gleason or PSA and follow-up greater than 0 days. A multivariable Cox-proportional hazards model was applied to obtain adjusted hazard ratios (aHR). Results: We observed 19788 patients with LPC during a median of 3.5 (interquartile range 1.4-7.4) years of follow-up. 52% of patients had low- (LR), 21% intermediate- (IR) and 27% high-risk (HR) disease. 3938 (18%) patients transitioned to other disease stages, leading to castration-resistant prostate cancer (mCRPC) in 4%, 7%, 16% of patients with LR, IR, and HR LPC, respectively. 7884 (42%) patients received radiotherapy (RT), 7021 (38%) prostatectomy (PT), 6061 (31%) androgen deprivation therapy (ADT), and 1034 (6%) active surveillance. Local recurrence was observed in 3% and distant metastasis in 11% (57% bone, 37% visceral). Distant metastases were observed in 7%, 12% and 21% of HR, IR and LR; 8% vs. 9% of PT vs. RT; and 16% vs 6% of ADT vs. no ADT, respectively. EFS was assessed in 7465 (38%) patients, with a 4-year EFS rate of 18%. Median EFS was 22, 13, and 8 months for LR, IR, HR; 23 vs. 12 months for PT vs. RT; and 8 vs. 21 months for ADT vs. no ADT, respectively. A multivariable cox proportional hazards model is presented in the following Table. Conclusions: During the study period, 11% of all LPC patients developed metastatic disease, with only 18% remaining event-free at 4 years. Transition to mCRPC was 4- and 2-fold higher in HR vs. IR and LR disease, respectively. Disease risk, treatment with RT and/or addition of ADT were independently associated with shorter EFS. Our findings suggest that, despite adjuvant treatment, LPC local extension and histopathological characteristics at diagnosis remain critical determinants of patient prognosis. A more detailed analysis in patients with available Gleason and PSA is underway. [Table: see text]
Circulating ether lipids in prostate cancer.
Authors: Horvath Lisa , Lin Hui-Ming , Huynh Kevin , Meikle Thomas , Joshua Anthony M. , Azad Arun , Tan Winston , Butler Lisa , Meikle Peter 
Published: June 2023

e17009 Background: Decreased circulating levels of ether lipids (glycerophospholipids with an ether-linked fatty alcohol, e.g. plasmalogens) have been observed in obesity, diabetes and cardiovascular disease. In vitro and in vivo studies suggest that ether lipids are anti-inflammatory and protective against obesity. A recent landmark study revealed that ether lipids can kill cancer cells through ferroptosis. However, the role of ether lipids in prostate cancer has not been thoroughly investigated despite the known association of dysregulated lipid metabolism with poorer clinical outcomes. The aim of this study was to assess the relationship between the circulating profiles of ether lipids and clinical outcomes in localised and metastatic prostate cancer. Methods: The profiles of ~150 ether lipids (8 lipid classes) in plasma lipidomic data from localised prostate cancer (389 men in Australia) and metastatic castration-resistant prostate cancer (mCRPC)(2 cohorts –147 men in USA, 128 men in Australia) were analysed for associations with disease progression or overall survival (OS). Open-access genomic data of mCRPC tumours (108 men, CbioPortal) were analysed for aberrations in genes associated with ether lipid metabolism in relation to clinical outcome. Results: Previously in these study cohorts, we had identified men with poorer prognosis based on their plasma lipidome and our validated sphingolipid signature. These men with poorer prognosis have lower plasma levels of ether lipids than those with better prognosis (t-test p < 0.05, localised disease – 110 ether lipids, mCRPC – 54 ether lipids). Decreased plasma levels of up to 46 ether lipid species were associated with higher rates of clinical relapse in localised disease (hazard ratio (HR) range 0.37-0.73, p-value range 0.006-0.049), shorter radiological progression-free survival in mCRPC (HR range 0.35-0.73, p-value range 0.00009-0.049), and shorter OS in mCRPC (HR range 0.33-0.79, p-value range 0.000004-0.0497). Chromosomal loss of tumour GNPAT, an essential gene in ether lipid synthesis, was associated with shorter OS in mCRPC (HR = 1.36, 95% CI 1.02-1.81, p = 0.03). Conclusions: Lower circulating levels of ether lipids were associated with worse prognosis in localised and metastatic prostate cancer, suggesting that these lipids are protective against disease progression. Further research is required to understand the role of ether lipids in disease progression, and to determine if modulation of ether lipid levels through supplementation is beneficial.
The clinical value of homologous recombination deficiency score in prostate cancer.
Authors: Wang Yan , Qu Min , Dong Zhenyang , Hao Qing , Lin Guomin , Song Jinyi , Gao Xu 
Published: June 2023

e17011 Background: Aberrations in homologous recombination repair (HRR) genes serve as biomarkers for guiding the treatment decision of PARP inhibitors in prostate cancer (PCa). Homologous recombination deficiency (HRD) score which directly shows the consequence of the loss of HRR function (genomic scars) may be a more reliable biomarker for identifying patients who are sensitive to PARP inhibitors. Methods: This study involved 50 patients with PCa, including mHSPC (n = 37), mCRPC (n = 11), and locally advanced PCa (n = 2). Tumor tissue specimens were collected for targeted next-generation sequencing for 406 cancer-related genes and HRD detection. HRD score was calculated based on over 50,000 single-nucleotide polymorphisms (SNP) distributed across the human genome, incorporating three SNP-based assays: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transition. All the experiments were performed in OrigiMed, a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Results: The median HRD score was 34.5 (ranged from 14 to 64). With the median value as cutoff, the mutation rates of HRR were 32% (8/25) and 12% (3/25) in the high and low HRD score groups, respectively. BRCA2 mutations (P = 0.011), AR mutations (P = 0.032), RB1 mutations (P = 0.035) and altered HRR pathway (P = 0.017) were associated with high HRD scores. The mutation frequencies of AR and TP53 were significantly higher in mCRPC compared to mHSPC ( AR: 45.5% [5/11] vs 2.7% [1/37], P < 0.001; TP53: 63.6% [7/11] vs 24.3% [9/37], P = 0.027). A total of 9 patients carried HRR germline mutations (5 BRCA2, 1 BRIP1, 1 RAD50, 1 RAD51D, and 1 ATM). It was found that patients with BRCA2 germline mutations had a higher HRD score (median = 37) than those with other germline mutations ( BRIP1: 25, RAD50: 19, RAD51D: 35, ATM: 36). In the 6 patients who received HRD-related treatments (including cisplatin based chemotherapy or olaparib), 1 of the 2 patients with low HRD score had PSA progression after 251 days (the other one was lost to follow up), while no PSA progression was observed in the 4 patients with high HRD score with a median follow-up of 107 days (range: 40-274 days). A mCRPC case with high HRD score (37) and HRR wild-type who received second line docetaxel+cisplatin even achieved undetectable PSA. Another mHSPC patient with a high HRD score (37) and a BRCA2 germline mutation also had no detectable PSA after first-line docetaxel+cisplatin therapy. Conclusions: To our knowledge, this is the first study in China reporting the association of HRD score and platinum-based treatments in PCa. Our results supported the possibility that HRD score could be predictive for the efficacy of platinum-based chemotherapy.
X-linked inhibitor of apoptosis protein (XIAP) expression level analyzed by immunohistochemistry (IHC) as it relates to clinical and pathologic characteristics in prostate cancer.
Authors: Beckerman Jennifer Kate , Valburg Claire , Subrahmanyam Ramesh , Nava Victor , Zara Rozalen Alexandra , Diao Guoqing , Liu Shanshan , Antonio Martha , Jain Maneesh Rajiv 
Published: June 2023

e17012 Background: XIAP acts in both the extrinsic and intrinsic apoptotic pathways as an inhibitor of cell death, protecting cells from a range of triggers. Regulation due to apoptosis resistance may represent a targetable factor for therapeutic intervention in prostate cancer. This study focuses on XIAP as a biomarker and its expression in correlation with disease aggression. Methods: Expression levels of XIAP was analyzed by immunohistochemistry (IHC), graded 1 through 3 according to signal intensity, in radical prostatectomy samples from 90 patients with prostate cancer with a range of phenotypes including: indolent (A), locally advanced (B), progressive to metastatic (C) and de novo metastatic (D). Prognostic data was collected and Fisher’s exact statistical analysis was performed. Secondary analyses included a Fisher’s exact test with a pairwise comparison between individual disease grades and Gleason scores. Results: Higher XIAP protein expression levels on IHC correlated with disease grade and with total Gleason score (p = 0.0008 and p = 0.0002 respectively) by Fisher’s exact test analysis, indicating more aggressive disease phenotypes. Secondary results looked at a pairwise Fisher’s exact analysis comparing XIAP expression levels among disease grades (A-D) and Gleason scores. XIAP expression only significantly differed between those with grade A and D as well as between individuals with grades B and D (measured by Bonferroni-adjusted p-value of 0.003 and 0.018 respectively). Statistical significance was also achieved in XIAP expression levels when comparing among Gleason scores 6 and 8 (p = 0.025), 6 and 9 (p = 0.0125), as well as 7 and 9 (p = 0.030). Conclusions: This study demonstrates a correlation between XIAP expression levels by IHC and aggressiveness of disease, demonstrating clinical significance of XIAP as a prostate cancer biomarker. [Table: see text]
Total and anatomically contextualized quantitative 18F-DCFPyL PET at biochemical recurrence to predict subsequent biochemical progression free survival in patients with prostate cancer.
Authors: Song Hong , Sjöstrand Karl , Duan Heying , Ferri Valentina , Mari Aparici Carina , Davidzon Guido , Franc Benjamin Lewis , Moradi Farshad , Anand Aseem , Iagaru Andrei 
Published: June 2023

e17015 Background: PSMA PET has been widely adopted in restaging of prostate cancer at biochemical recurrence. We assess the clinical utility of quantitative parameters on 18F-DCFPyL PET/CT at biochemical recurrence and their association with the subsequent biochemical progression free survival (bPFS). Methods: This is a retrospective image analysis and longitudinal follow up of a prospective study evaluating 18F-DCFPyL PET in prostate cancer patients with biochemical recurrence after primary definitive treatment at Stanford Hospital. The 18F-DCFPyL PET images were quantitatively analyzed automatically by the aPROMISE application, a semi-automated analysis and structured reporting of PSMA PET/CT. aPROMISE uses deep learning to segment detailed anatomical information from the CT images and uses this information in combination with the PET image to detect and quantify candidates for prostate cancer lesions. The reader works in tandem with the software to vet the final list of lesions, from which the quantitative assessments and final report is created automatically. Based on the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria. SUVmean, PSMA positive total tumor volume (PSMAttv) and aPSMA scores, a quantitative score for tumor burden measuring the interaction of tumor volume and uptake stratified by local tumors (aPSMA-miT), regional lymph nodes (aPSMA-miN) and distant metastases (aPSMA-miMa for extrapelvic metastases, miMb for bone metastases and miMc for other organ metastases) were obtained based on the miTNM classification. The association of these quantitative parameters with the subsequent bPFS was evaluated. Results: 134 patients (age 70.1 ± 7.6, range 51 -91 years; PSA 13.9 ± 98.5, range 0.12 – 1126 ng/mL) were included in the quantitative image analysis. aPROMISE detected nodal and/or bone metastases in 94 of 134 patients (70%) and only 12 of 134 patients (9%) had visceral disease. With median follow up of 37 months, 66 of 134 patients (49%) have progressed again biochemically after treatment. The bPSF was 25.8 ± 15.1 months. Quantitative analysis of 18F-DCFPyL PET found that the subsequent bPFS is significantly associated with aPSMA-miMb ( P < 0.001), PSMAttv ( P < 0.001), aPSMA-miN ( P < 0.01), aPSMA-miMa ( P < 0.05) but not with SUVmean or aPSMA-miMc. Conclusions: Total and anatomically contextualized quantitative image analysis of 18F-DCFPyL PET/CT at biochemical recurrence may be useful in predicting the subsequent bPFS. Studies in larger patient cohort is necessary to validate these findings. Given many patients were treated based on lesions found on 18F-DCFPyL PET/CT, clinical implication of this findings remains to be elucidated.
Analysis of androgen receptor dynamics through immunofluorescent staining of circulating tumor cells in castration-resistant prostate cancer.
Authors: Barnett Ethan , Gupta Santosh , Erazo Tatiana , Lam Ernest , Carbone Emily , Zanone Michelle , Nystrom Lucy , Gajar Ria N , Wenstrup Rick , Scher Howard I. 
Published: June 2023

e17021 Background: Prostate adenocarcinomas are initially dependent on the androgen receptor (AR) for growth and proliferation. Androgen synthesis inhibitors and AR antagonists are the most commonly used first line treatments in metastatic prostate cancer, but these agents are not curative and virtually all tumors progress to a castration resistant state often associated with AR amplification (ARamp) and overexpression. Small molecule AR degraders designed to overcome ARamp/overexpression and other AR alterations associated with resistance are now in clinical development. In parallel, it is important to identify and validate biomarkers that predict sensitivity and inform treatment selection. Methods: CTC samples collected at progression from 114 men with metastatic castration resistant prostate cancer were stained for CK, DAPI, CD45, and AR. AR cRatio (ratio between a cell’s immunofluorescent [IF] intensity and the median IF intensity across all cells) was quantified for each CTC. Low-pass whole genome sequencing (lpWGS) was performed on candidate CK-positive (CK+) CTCs to generate copy number profiles. Cohen’s kappa was used to evaluate the relationship between AR copy number and IF at the single cell level. Dynamics in high AR expressing (ARhigh) CTCs were analyzed separately in a longitudinal cohort of patients (n = 18) from whom CTCs were collected at baseline, early on-treatment (4-12 weeks), and at progression on their 1st AR signaling inhibitor (1L-ARSI). Results: lpWGS was performed on 726 CK+ CTCs, of which 23% (170) were ARamp and 27% (195) were ARhigh (AR cRatio ≥ 3). Fifty-six percent (96/170) of CTCs with ARamp were ARhigh. Overall, a fair agreement was observed between AR copy number and IF (76.1% agreement; k = 0.37, 95%CI = 0.29 – 0.44). At baseline prior to 1L-ARSI, the median CK+ CTC burden was 7.9 CTC/mL (IQR: 1.3 – 10.5). One or more ARhigh CTC was detected in 28% (5/18) of patients, but no patient had more than 0.7 ARhigh CTCs per mL of blood. ARhigh CTCs were not observed in early on-treatment samples. At progression, the median CTC burden was 2.3 CTC/mL (IQR: 0.9 – 9.45) and, despite lower CTC burden, the emergence of a substantial (≥1 CTC/mL) ARhigh CTC subpopulation was observed in 17% (3/18) of patients. In samples with ≥1 detected CTC, the mean AR cRatio was 1.106 and 1.777 at baseline and progression, respectively. Conclusions: AR protein can be measured in CTCs with IF staining and is supported by the agreement with data from lpWGS. ARhigh CTC subpopulations can be detected at baseline for 1L-ARSI, but these cells were all cleared from circulation after 4-12 weeks of therapy. In a subset of patients at progression, resistance appears at least partially attributable to selection for ARhigh CTC subclones. [Table: see text]
Awareness of testicular cancer and testicular self-examination in young adults, and the efficacy of education-based media.
Authors: Walt Aaron M. , Levy Micah , Chin Chih Peng , Liaw Bobby Chi-Hung , Palese Michael 
Published: June 2023

e17022 Background: The prevalence of testicular cancer in adolescents and young adults creates a unique opportunity for education through social media. We investigated this populations’ baseline knowledge of testicular cancer (TC) and testicular self-examination (TSE) and identified the efficacy of various forms of media in educating young individuals. Methods: A survey was designed to assess participants’ baseline knowledge of TC and TSE. Participants were randomly shown one of three forms of educational media created by the Testicular Cancer Society and the National Cancer Institute. These were an infographic, a short (60 second) and a long (6 minute) video. Participants were then asked to correctly identify facts regarding TC and TSE. Baseline knowledge was analyzed by age (< 24 vs. > 25), and post-media knowledge was analyzed to determine the efficacy of each media form. Results: Responses from 328 participants were analyzed, with a mean age of 24.3 years, 40.9% male, 72.0% white, and 70.7% graduated college or a graduate program. Only 30.7% of participants reported being educated about TC, 25.9% correctly identified the 15-35 age group as having the highest prevalence of TC, and 26.3% correctly identified the TC survival rate as being 75-100%. The > 25-year-old group were significantly more likely to have heard of TSE (p < 0.001), performed a TSE if male (p = 0.043), encouraged males to perform TSE if female (p < 0.001) and correctly identify TC survival rate (p = 0.006) and treatability (p = 0.007). Long video viewers were significantly less likely to watch it in its entirety compared to infographic and short video viewers, and they were less likely to report an understanding of TSE compared to infographic viewers. Short video viewers were less likely to have properly identified the TC survival rate compared to both infographic (P < 0.001) and long video viewers (p = 0.001). Conclusions: Overall there is poor awareness and education regarding TC and TSE, with adolescents performing significantly worse than young adults. The infographic performed the best overall in completion and education about TC and TSE, with the short video performing similarly well, and the long video performing the worst. This suggests that easily dispersed and viewable forms of media may be the most effective tool for educating young people.[Table: see text]
Germline thrombophilia gene alterations and thrombosis rates among patients with advanced germ cell tumors treated with chemotherapy.
Authors: Brown Landon Carter , Robinson Myra M. , McCormack Michael Joseph , Steuerwald Nury , Symanowski James Thomas , Bose Rupali , Neelands Brittany , Akinyelu Tobi , Livasy Chad , Li Wencheng , Haynes Nathanael C. , Grigg Claud , Raghavan Derek , Clark Peter E , Patel Jai Narendra , Burgess Earle F 
Published: June 2023

e17023 Background: Men with advanced germ cell tumors (GCT) treated with cisplatin-based chemotherapy are at high risk of venous thromboembolism (VTE). Validated predictors of VTE would allow development of targeted prophylactic anticoagulation strategies in this population. We hypothesized that a high genomic risk score from a previously identified panel of germline single nucleotide polymorphisms (SNPs) in thrombophilia genes would be associated with an increased risk of VTE within 6 months of chemotherapy initiation for GCT. Methods: Men with stage IIA or higher GCT who received 3-4 cycles of cisplatin-based chemotherapy were identified at two centers with available tissue for germline sequencing. High genomic risk was defined as having 4 or more risk alleles from an established 5 SNP germline panel composed of ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914). Univariable and multivariable logistic regression were used to evaluate the impact of genomic risk on VTE incidence within six months of chemotherapy initiation. Results: 123 patients were identified with 72% having non-seminoma histology and 28% categorized as IGCCCG intermediate or poor risk. The VTE rate was 26% (32/123), and the incidence of high genomic risk was 21% (26/123). Men with high genomic risk did not have a significantly higher VTE rate (31%, 8/26) than men with low genomic risk (25%, 24/97), unadjusted OR 1.4 (95% CI 0.5 – 3.5, p = 0.54). A multivariable model identified Khorana score, N3 status and elevated LDH as predictors for VTE (Table). The association between high genomic risk and VTE strengthened when adjusting for clinical variables, but remained non-significant, adjusted OR 2.1 (95% CI 0.7 – 6.5, p = 0.18). The optimal threshold to define high genomic risk in this cohort was 3 or more risk alleles, adjusted OR 2.5 (95% CI 0.9 – 6.8, p = 0.08). ABO (non-O blood type) was the only individual SNP significantly associated with VTE (p < 0.01). Conclusions: In this multi-institutional cohort, a previously established germline thrombophilia panel was not clearly associated with increased VTE risk among patients with GCT receiving chemotherapy. Khorana score, elevated LDH, clinical nodal stage, and non-O blood type were the strongest predictors of VTE. Exploratory analysis of the association between VTE risk and 76 additional SNPs is ongoing. Prospective studies of prophylactic anticoagulation are warranted in high-risk patients with advanced GCT undergoing chemotherapy.[Table: see text]