bluuebunny/crossref_metadata_2025_split huggingface dataset:
High doses of chemotherapy and autologous hematopoietic stem cell transplantation in patients with relapsed/refractory testicular germ cell tumors: Multicenter real-world experience in Argentina.
Authors: Losco Federico , Angel Martin , Sade Juan Pablo , Vitriu Adriana Verónica , Soulé Tomás , Ayala Luis , Gelo Olivia , Sierra Jeremías , Berro Mariano , Castro Martín , Palmer Silvina , Burgos Ruben , Cruset Soledad , Ferini Gonzalo Ariel , Perez Mariel , Wernicke Priscila , Pelayes Tortosa Sofia , Duarte Patricio , Yantorno Sebastián , Foncuberta María Cecilia 
Published: January 2024

508 Background: Germ cell tumors (GCTs) are the most common type of cancer in adolescent and young adult males. Most of them are curable with multimodal treatment: platinum-based chemotherapy (CT) + surgery. Patients who fail first-line treatment usually receive salvage CT with response rates between 30 and 50%. High-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDCT) is an effective treatment in this context. Methods: We conducted a multicenter retrospective analysis of patients ≥ 15 years old with relapsed/refractory GCTs who received HDCT in 13 centers of the Argentine Group of Bone Marrow Transplantation and Cellular Therapy (GATMO-TC) from 2010 to 2022. Results: 114 patients were included, with a median age of 32 years (range: 15-58). Most had non-seminoma histology (66%); The primary tumor site was testis (65%), retroperitoneum (17%), and mediastinum (9%). Forty percent (n:46) had an unfavorable prognosis according to the IGCCCG score. Eighty-two % received ≥ 2 lines of CT before HDCT, 27% being platinum-refractory disease (PRD), and 45% received 2 consecutive courses of HDCT (tandem). All patients received a carboplatin-etoposide-based conditioning regimen. The median engraftment time was 12 days (d) (r8;25) for neutrophils and 15 d (r6;58) for platelets. Bacteremia (25%) and Hepatotoxicity (14.9%) were the most frequent G3-4 adverse events. With a median follow-up of 12.6 months (r1-138), 100 pts were evaluable for survival. 12- and 24-months OS was 67%- 64%; and PFS 56%; - 54% respectively. PRD patients had worse OS and PFS. Eighteen patients remained alive and without relapsing beyond 5 years of follow-up. Conclusions: This real-world multicentric study demonstrates that some patients with refractory/relapsed metastatic GCT are curable by HDCT, being an effective and safe feasible treatment with response rates similar to those described in the literature. The superiority of the tandem approach could not be demonstrated due to the heterogeneity of the sample.[Table: see text]
Primary retroperitoneal germ-cell tumours (pR-GCT): Evaluation of treatment outcomes of an international retrospective collaboration (PRIMERE study).
Authors: Giannatempo Patrizia , Sebastiano Nazzani , Taglialatela Ida , Valentina Bernasconi , Mego Michal , Bimbatti Davide , Secondino Simona , Claps Melanie , Biasoni Davide , Catanzaro Mario , Zimatore Matteo , Torelli Tullio , Stagni Silvia , Macchi Alberto , Tesone Antonio , Pedrazzoli Paolo , Basso Umberto , Procopio Giuseppe , Nicolai Nicola 
Published: January 2024

510 Background: pR-GCT corresponds to the clinical case of retroperitoneal ascertained GCT without radiological evidence of primary testicular tumor and accounts for up to 40% of extragonadal GCTs. An occult primary testicular tumor is often missed at diagnosis. Treatment modalities and outcomes have not been specifically addressed, preventing robust recommendations. We performed an international call to assess prognosis of treatment outcomes of these patients. Methods: Clinical, pathological and treatment data pts with pR-GCT between 04/1988 and 01/2022 were retrospectively collected across 4 referral centers. Kaplan Meier methods, univariable and multivariable Cox regression models (MCRMs) were used. Results: Ninety-nine patients (median age 37 yrs - IQR: 29-45) were collected. Ninety-three (94%) had histological diagnosis by biopsy or primary retroperitoneal lymph-node dissection (RPLND): 60 (62.5%) had non-seminomatous pR-GCTs (pR-NSGCTs) and 33 (34.4%) had seminomatous pR-GCTs (pR-SGCTs). IGCCCG prognostic allocation was possible in 91 pts: 34 (35.8%) were good, 23 (24.2%) intermediate and 34 (35.8%) poor risk, respectively. All pts underwent cisplatin-based chemotherapy, usually BEP regimen (94.9%). After chemotherapy, 25 (25.3%) pts underwent orchiectomy: viable tumor was present in 8 (32%), burn-out lesions in 6 (24%) and no lesion in 11 (44%) cases. After a median follow-up of 45 mos (IQR:15-90), the 5-years OS was 58%, being 85% in case of pR-SGCT and 46% in case of pR-NSGCT. According to IGCCCG classification 5-years OS was 83.3% for good, 57% for intermediate and 42% for poor risk patients, respectively. No difference in term of OS (60% vs 56%, p-value 0.81) was observed between patient who had or not radical orchiectomy. At MCRMs only IGCCCG poor risk category (HR 3.2, CI: 1.18-8.84, p-value 0.02) was independent predictors of a worse OS. Conclusions: Eventually, a significant proportion of pts with a pR-GCT had a misclassified primary testicular tumor. 5 yrs-OS according to IGCCCG classification is worse than expected. The role of a surgical exploration of the suspected primary tumor remains controversial and the existence of a real category of p-GCT cannot be excluded.
Pre-orchiectomy serum miRNA-371a-3p and 372-3p levels in men with clinically localized testicular masses.
Authors: Baky Fady , Matulewicz Richard , Knezevic Andrea , Ye Fei , Williams Brandon , Bromberg Maria , Benfante Nicole , Valentino Alisa , Kantor Rachel , So Rachel , Hossain Jahwa , Sheinfeld Joel , Funt Samuel A , Feldman Darren R. 
Published: January 2024

519 Background: MicroRNA (miRNA) are short noncoding RNAs involved in regulation of gene expression and have shown promise as novel biomarkers in the diagnosis and management of testicular germ cell tumors (GCT). We report the accuracy of our combined miRNA assay in men with Clinical Stage I (CSI) GCTs. We also sought to explore the relationship between miRNA levels and patient and oncologic variables to better understand how these factors may influence miRNA results. Methods: We retrospectively identified patients at Memorial Sloan Kettering (MSK) with a newly identified testicular mass concerning for GCT who were planned for radical or partial orchiectomy and had pre-orchiectomy MSK miRNA Assay (miRNA-371a-3p and miRNA-372-3p, collectively MMA) drawn. All patients had clinically localized disease based on initial staging imaging and normalized traditional serum tumor markers (STM) post-orchiectomy. Specific miRNA levels were determined using stem-loop RT-qPCR (quantitative reverse transcription PCR), as described previously. Patient and disease factors were abstracted from the medical record. Outcomes of interest were sensitivity, specificity, PPV and NPV of MMA, and area under the receiver operating characteristic curve (AUC) of miRNA-371a-3p and 372-3p levels, calculated relative to detection of viable GCT at orchiectomy. We explored the relationship between pre-orchiectomy miRNA-371a-3p and 372-3p levels and various patient and pathologic factors using Spearman correlation and Wilcoxon rank-sum test. Results: Forty-eight patients were included in this study, 39 of whom had viable GCT at orchiectomy and 9 with no cancer or non-GCTs. Thirty-seven patients with GCT had positive pre-orchiectomy MMA results (sensitivity 94.9%, 95% CI: 88-100), while 1 of 9 patients (Leydig cell tumor) without viable GCT had a positive MMA result (specificity 88.9%, 95% CI: 68.4-100). MMA PPV was 97.4% (95% CI: 92.3-100) and NPV was 80% (95% CI: 55.2-100). AUC of miRNA-371a-3p and miRNA-372-3p was 96% (95% CI: 91.0-100) and 92% (95% CI: 84.2-99.9), respectively. Pre-orchiectomy miRNA-371a-3p and miRNA-372-3p levels were positively correlated with tumor size (Spearman coefficient ρ=0.64, 0.63, respectively; p<0.001), and with serum HCG (ρ=0.55, 0.56; p<0.001) and LDH (ρ=0.46, 0.46; p<0.001), but not AFP (ρ=0.19, 0.17; p=0.20, 0.24). Pre-orchiectomy MMA was not associated with other tested pathologic or patient characteristics including age, BMI, renal function, liver function and andrology labs. Conclusions: miRNA 371a-3p and 372-3p are highly sensitive and specific for presence of viable GCT in patients with clinically localized disease. Tumor size was the only studied pathologic factor or patient characteristic correlated with MMA levels.
Unraveling the testicular seminoma tumor microenvironment by single-cell RNA-sequencing.
Authors: Giannikou Krinio , Lafin John T. , Sfakianos John P. , Horowitz Amir , Hopkins Benjamin , Yu Haocheng , Amatruda James F. , Bagrodia Aditya 
Published: January 2024

522 Background: Seminomas is a malignant germ cell tumor (GCT) affecting male adults and is characterized by low somatic mutation burden, histological homogeneity, and high survival rate. It is currently unknown what drives tumorigenesis of this curable testicular cancer. Tumor/immune microenvironment (TME) has a vital role in cancer survival and progression with implications in cell death resistance and immune escape. Herein, we aimed to unravel the transcriptomic TME landscape of seminomas and better understand seminoma pathogenesis. Methods: We performed single cell RNA-sequencing (scRNA-seq; 10X-Illumina platform) on surgically resected pure seminomas from four patients. A total of ~24,000 single cells were analyzed using Seurat/Bioconductor R packages and standard means for data visualization. Key findings were validated by in situ hybridization RNA analysis (RNAscope) on histological sections from these samples. Results: T-cells and Natural-Killer cell populations were mostly predominantly enriched in this seminoma cohort, where tumor cells consisted of a distinct subpopulation with limited presence (1%). Other distinct cell populations were also identified for additional immune cell types e.g., B-cells, macrophages/monocytes, endothelial and smooth muscle cells. ScRNA-seq revealed a unique set of signature marker genes (e.g., POU5F1, KHDC3L, DPPA5, NANOS3) highly expressed in seminoma cells which are associated with pivotal cellular processes e.g., developmental pluripotency and germ cell development. Notably, this gene set was also highly differentially expressed (DE) in The Cancer Genome Atlas (TGCA) seminomas (n=73) compared to TCGA non-seminomas (n=38) (FDR<0.01). Amongst top marker genes, KHDC3L, also higher expressed in seminomas compared to normal testis, was validated by RNA-scope. KHDC3L demonstrated the strongest positive correlation with DPPA5 (Spearman/Pearson; R2=0.8, p<0.0001), top #3 ranked DE gene as well as with other top 20 DE genes identified by scRNA-seq. Remarkably, similar strong correlations among other top DE genes were also found in the testicular TGCA cohort. Top DE genes including master transcription factors (e.g., POU5F1, NANOG, SOX4) are involved in the same protein pathway/networks likely suggesting synergic effect/involvement in the same regulatory circuitry. Gene Set Enrichment (GSEA) analyses demonstrated enrichment in immune signatures and pivotal pathways e.g., Wnt/beta catenin signaling and MYC targets. Conclusions: Our analyses revealed novel marker genes and immune signatures, uniquely expressed in seminomas which consist of a homogeneous cell population across all 4 tumors analyzed, clearly distinct from other cell types identified.
Financial toxicity from PARP inhibitors in castrate-resistant prostate cancer.
Authors: Benjamin David Joseph , Lester-Coll Nataniel Hernan , Rezazadeh Arash 
Published: January 2024

54 Background: Approximately 5-10% of men with prostate cancer (PC) are eligible for treatment with PARP inhibitors. As an estimated 120,000 men living in the US have metastatic PC, between 6,000-12,000 men may be eligible for treatment with PARP inhibitors. Recently, several PARP inhibitors have been approved as single or combination therapies in the first-line castrate-resistant (CR) setting and later-line setting including: olaparib, olaparib plus abiraterone (AAP), and talazoparib plus enzalutamide. It is unclear if these newly approved therapies may be cost prohibitive for patients and/or health care systems. Methods: Using average sale price data from UpToDate for PARP inhibitors and novel hormone therapies (NHTs), we calculated the total cost of treatment for each single or combination therapy regimen. We used phase II/III clinical trial data to determine the median duration of treatment for each regimen. Results: The three approved PARP inhibitors have total costs in descending order as follows: AAP plus olaparib ($689,813.77), talazoparib plus enzalutamide ($388,390.46), and olaparib ($202,845.22). In comparison, in the PROfound trial, the cost of AAP alone was $192,140.37 and in the TALAPRO-2 trial, the cost of enzalutamide alone was $ 253,780.80. The difference in estimated cost between olaparib plus AAP versus talazoparib plus enzalutamide per patient is $37,970.29. Conclusions: Despite several new approved therapies in BRCA mutated and HRR mutated mPC, the total costs for PARP inhibitors remain prohibitive for health care institutions. The estimated difference between two newly approved PARP plus NHT regimens could translate in a difference of $455,643,480 in healthcare system costs if all eligible U.S. men received treatment with olaparib plus AAP over talazoparib plus enzalutamide. [Table: see text]
Demographic and prognostic factors in papillary transitional cell carcinoma: An analysis of the National Cancer Database.
Authors: Vinayak Sankalp , Samuel Maya , Han Emily , Silberstein Peter T. , Hsia Beau , Hu Robert 
Published: January 2024

541 Background: Transitional cell carcinomas account for the majority of bladder cancers, with the papillary subtype comprising most of these cases. The role of race in bladder cancers has been investigated in the past, but there have been no studies that collectively investigated the role of different demographic factors in survival and mortality in papillary transitional cell carcinoma (PTCC). This study analyzes the effects of demographic factors on overall mortality (OM) in patients with PTCC. Methods: A retrospective cohort analysis was conducted using National Cancer Database data from 2004-2019, including 12,300 patients with histologically confirmed PTCC (ICD-O-3=8130). Sex, race (Black, White, and Other), insurance status, and median household income quartile (based on 2016-2020 American Community Survey data) were examined. Kaplan-Meier curves were used to calculate 2, 5, and 10 year survival (2-5-10 YS). Multivariable Cox regression was used to calculate hazard ratios (HR) to identify independent prognostic factors. Statistical significance was set at α=0.05. Results: Females had higher 2-5-10 YS and decreased OM compared to males (HR=0.85, P<.001). White patient survival was higher at 2 years compared to Black patients, but Black patient survival was higher at 5 and 10 years. There was no significant difference in OM between Black and White patients (HR=1.07, P=0.260). Patients of other races had higher 2-5-10 YS and decreased OM compared to White (HR=0.85, P=0.023) and Black patients (HR=0.80, P=0.011). Patients on Medicaid had lower 2-5-10 YS and increased OM compared to patients on private insurance (HR=1.19, P=0.036). Patients on Medicaid had higher 2-5-10 YS than patients on Medicare, but no significant difference in OM (HR=0.87, P=0.091). Patients on private insurance (HR=0.70, P<.001) and Medicare (HR=0.73, P=0.003) had decreased OM compared to uninsured patients. Patients in the fourth income quartile had decreased OM compared to patients in the first (HR=0.82, P<.001), second (HR=0.87, P<.001), and third quartiles (HR=0.90, P=0.003). Conclusions: Male sex, uninsured status, and lower income were associated with increased OM. Black patients and White patients had increased OM compared to patients of other races. Future research should investigate the reasons for these disparities and how to minimize them. [Table: see text]
Disparities in the incidence of next-generation sequencing (NGS) among patients (pts) with advanced or metastatic prostate cancer (mPC) and urothelial carcinoma (mUC).
Authors: Jo Yeonjung , Tripathi Nishita , Roy Soumyajit , Mathew Thomas Vinay , Galarza Fortuna Gliceida , Hage Chehade Chadi , Gebrael Georges , Narang Arshit , Campbell Patrick , Gupta Sumati , Maughan Benjamin L. , Agarwal Neeraj , Swami Umang 
Published: January 2024

542 Background: Based on availability of approved agents targeting tumor somatic mutations, current guidelines recommend NGS for Pts with mPC and mUC. However, large cohort studies in mPC and mUC evaluating disparities in NGS testing have not been reported. Herein, we investigated the effect of social determinant of health (SDOH) on disparities in NGS testing in a large real-world dataset of pts with mPC and mUC. Methods: Pts data were extracted from the nationwide Flatiron Electronic Health Record (EHR)-derived de-identified database. Inclusion: new diagnosis of advanced or metastatic (adv/met) PCa and UCa between March 2015 to December 2022 and receipt of cancer therapy (to include only treatment eligible pts). Disparities in incidence of NGS testing after adv/met diagnosis by SES, R/E, region, and insurance were assessed using Fine and Grey’s (FG) modified stratified Cox proportional hazard (PH) model. FG model considered death as a competing risk. Stratification was done by year of adv/met diagnosis (accounting heterogeneity) and R/E (an effect modifier for SES, region, and insurance), assuming different baseline hazards in each stratum. All analysis done using R v.4.2.3. Results: Analytic cohorts comprised 11,936 pts with mPC and 6,490 pts with mUC. Hazard ratios (HR) and 95% confidence intervals (CI) from FG Cox PH models are reported in the table. For both cancer types, pts were more likely to get NGS testing when they were White, non-Hispanic (compared to Black, non-Hispanic), had higher SES, and had commercial insurance. Conclusions: Our data suggest an association between incidence of NGS testing and several SDOH in mPC and mUC. Further studies are needed to elucidate the reasons for these disparities and ways to mitigate them. [Table: see text]
Development of a novel RNA-based fibroblast growth factor receptor response signature (FGFR-PRS) for use in patients with urothelial cancer (UC).
Authors: Pappan Kirk L. , Mayhew Gregory , Davison James M. , Shibata Yoichiro , Eisner Joel Robert , Beebe Kirk , Milburn Michael Vance 
Published: January 2024

548 Background: Interest in FGFR-targeted (FGFRi) therapies for UC or pan-tumor use is growing (ongoing clinical studies include erdafitinib (NCT05316155; NCT04172675; NCT03390504; NCT04083976), LOXO-435 (NCT05614739), and pemigatinib (NCT03914794) following accelerated approval of erdafitinib in locally advanced/metastatic (m) post-chemotherapy UC patients with FGFR2/3 (i.e., DNA mutations and fusions) alterations (ALT). However, ALT status may not fully capture all who may show clinical benefit as responses are observed in both ALT (+) and (-) patients. Improved test strategies are needed to identify patients most likely to respond to FGFRi. FGFR-PRS is an RNA-based signature developed to capture the biology of FGFR-active tumors independent ALT status and is intended to be used as a diagnostic (Dx) to identify a broader patient population likely to respond to FGFRi. Methods: Known oncogenic FGFR3 ALTs (S249C, R248C, FGFR3c-Y373C, FGFR3c-G370C, FGFR3:TACC3 and FGFR3:BAIAP2L1) were used as training labels for nearest centroid classifier development as described in Dabney et al, 2005 ( https://doi.org/10.1093/bioinformatics/bti681 ) using 2/3 of data from the TCGA BLCA dataset, predominantly comprised of muscle-invasive bladder cancer patients and a few mUC patients, for training. The resulting 80-gene signature was applied to the remaining 1/3 of TCGA and a separate BACI mUC dataset (Rose et al, 2021; https://doi.org/10.1038/s41416-021-01488-6) as test sets. In vitro drug sensitivity was evaluated using data from the Genomics of Drug Sensitivity in Cancer database (GDSC; https://www.cancerrxgene.org/ ). Differential gene expression (DGE) results were analyzed using WebGestalt 2019 (https://www.webgestalt.org/). Results: Thirteen and 18% of the TCGA and BACI UC cohorts were ALT (+), whereas 49% and 48% were FGFR-PRS (+) independent of ALT status. About half of the patients in either cohort were ALT (-)/ FGFR-PRS (-) and only 1% were ALT (+)/FGFR-PRS (-). FGFR 1-3 selective drugs had strong inverse correlations between FGFR-PRS score and IC50 across 18 GDSC bladder cancer cell lines. FGFR-PRS (+) samples had enhanced co-expression of FGFR3, FOXA1, and SHH and selected multiple differentiation ontologies. Conclusions: FGFR-PRS (+) captured most ALT (+) tumors and an additional 2X more with similar FGFR pathway activation. FGFR-PRS (+) tumors were associated with gene enrichments for ontologies linked to FGFR3 signaling. The correlation of FGFR-PRS score with in vitro FGFRi activity provided initial utility of the signature, which is undergoing clinical evaluation in the ALAMANCE retrospective study of UC patients treated with FGFRi or other standard-of-care therapies. Analytical validation is ongoing to support FGFR-PRS for use as a clinical trial assay and eventual Dx.
Economic burden of radical cystectomy and trimodal therapy for bladder cancer in the United States: Real-world study.
Authors: Williams Stephen B. , Yapici Halit O. , Singhal Puneet K. , Weimer Ian , Pathan Farah , Lodaya Kunal , Li Haojie 
Published: January 2024

555 Background: Bladder cancer (BC) is exponentially deadly once it invades muscle, with the highest per patient treatment costs among cancers. Radical cystectomy (RC) and trimodal therapy (TMT) are recommended treatment options for muscle-invasive BC. This study describes patient/treatment characteristics and short- and long-term costs/healthcare utilization (HCU) associated with RC and TMT. Methods: Patients with BC undergoing RC or TMT were identified using Optum claims data (October 2015-April 2023). Incident cases were captured, and individuals diagnosed with a prior BC, secondary bladder neoplasm, and non-bladder malignancies were excluded. Costs and HCU (e.g., inpatient, outpatient, emergency, pharmacy) were evaluated up to 5 years of follow-up. Results: Median [IQR] ages of the RC (N=839) and TMT (N=484) cohorts were 71 [66-76] and 75 [69-81] years, and NCI comorbidity index was 0.50±0.43 and 0.52±0.45, respectively. Median follow-up durations were 30 [19,47] and 32 [20,48] months for RC and TMT patients, respectively. Median cost and HCU per patient in the RC cohort were $70,671 [$55,878-$106,812] with 26 [16-39] visits in 3 months, $103,579 [$71,12-$158,489] with 56 [39-86] visits in 12 months and increased to $211,671 [$138,597-$346,389] with 163 [119-218] visits in 60 months. For TMT, median cost and HCU per patient were $34,612 [$16,705-$64,263] with 19 [12-33] visits in 3 months, $116,259 [$65,300-$188,622] with 72 [46-94] visits in 12 months, and increased to $274,462 [$186,337-$421,534] with 186 [144-238] visits in 60 months (N=72). Outpatient care was the highest cost contributor for both cohorts across all time periods, except the first 3 months for RC, where inpatient care was predominant. Approximately 25% (N= 211) of patients received neoadjuvant chemotherapy before RC. For patients receiving TMT, median radiotherapy fractions delivered was 36 [18-43], and 8.1% underwent salvage RC. Conclusions: The burden of RC or TMT-treated BC patients remains high, suggesting key targets for cost containment to optimize value-based care. However, our costs are lower compared to previous literature, possibly due to 3rd party payer (i.e., closed networks), treatment advancements, and patient selection. Future research should evaluate the cost and HCU implications of guideline-recommended treatments i.e., neoadjuvant chemotherapy followed by RC vs. TMT with advised chemotherapy type/duration for both. [Table: see text]