bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutrophil extracellular traps in relation to efficacy of systemic therapy for metastatic renal cell carcinoma.
Authors: Xie Rui-Yang , Shang Bing-Qing , Shi Hongzhe , Bi Xin-Gang , Song Yan , Qu Wang , Bai Hongsong , Wu Jie , Cui Honglei , Du Gan , Guo Lei , Zheng Shan , Ying Jianming , Li Changling , Ma Jianhui , Zhou Ai-Ping , Zhang Shudong , Shou Jianzhong 
Published: January 2024

441 Background: The efficacy of systemic therapy regimens, such as immune checkpoint inhibitors and tyrosine kinase inhibitors (IO-TKI) and targeted therapy, for metastatic clear cell renal cell carcinoma (ccRCC) remains unpredictable due to the lack of effective biomarkers. This study investigates the predictive value of neutrophil extracellular traps (NETs) in determining the efficacy of metastatic ccRCC. Methods: In this retrospective study, patients with metastatic ccRCC who received targeted drugs and IO-TKI were included. Immunofluorescence staining was utilized to quantify the levels of tissue NETs through cell counts of H3Cit(+) and MPO(+) cells. The correlation between NETs and clinicopathological features was analyzed, and the predictive value of NETs for drug efficacy and prognosis was assessed using Cox proportional hazard analysis. Results: A total of 183 patients with metastatic ccRCC were enrolled, including 150 patients who received TKIs and 33 patients who received IO-TKI. H3Cit and MPO were predominantly expressed in the nucleus and cytoplasm, respectively. The levels of NETs in tumor tissue were significantly higher than in para-tumor tissue (p<0.001). Increased levels of NETs in tumor tissue were associated with tumor N stage (p=0.02) and neutrophil-to-lymphocyte ratio (NLR) (p=0.02). In terms of predicting drug efficacy, a correlation between NETs levels and progression-free survival (PFS) was observed in the TKI with metachronous metastasis group (HR 1.73 [95% CI 1.02-2.91], log-rank p=0.037), while no correlation was observed in the targeted agent with synchronous metastasis group and IO-TKI group. Regarding overall survival (OS), activated NETs levels were associated with poor OS (HR 1.87 [95% CI 1.24-2.81], log-rank p=0.003). Cox analysis revealed that IMDC score (HR 1.462 [95% CI 1.030-2.075], p=0.033) and tumor tissue NETs level (HR 1.733 [95% CI 1.165-2.579], p=0.007) were independent prognostic risk factors for OS in patients with metastatic ccRCC. Conclusions: The active NETs level in tumor tissue can serve as a predictor of drug efficacy in patients with metastatic ccRCC who received targeted agents with metachronous metastasis. However, no significant correlation was observed in the IO-TKI group, and further investigation is required. Elevated levels of NETs in tumor tissue were also associated with poor prognosis in OS prediction.
Multi-omic characterization of acquired resistance to immune checkpoint inhibitors in patients with metastatic renal cell carcinoma.
Authors: Saad Eddy , Labaki Chris , Miron Benjamin , Park Jihye , Bakouny Ziad , Nassar Amin , Saliby Renee Maria , Semaan Karl , Eid Marc , Meli Kevin , Nabil Laimon Yasmin , Geynisman Daniel M. , Kokate Rutika , Braun David A. , Signoretti Sabina , McGregor Bradley Alexander , Plimack Elizabeth R. , Choueiri Toni K. , Van Allen Eliezer Mendel , Zibelman Matthew R. 
Published: January 2024

459 Background: While immune checkpoint inhibitors (ICI) have improved outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC), acquired resistance (ARX) is commonly encountered. We aimed to characterize the genomic and transcriptomic correlates underlying ARX in ICI-treated mRCC patients. Methods: We identified pts with mRCC at Dana-Farber Cancer Institute and Fox Chase Cancer Center, treated with ICI-based regimens who had an initial response to therapy followed by disease progression. Tissue samples from the primary tumors or metastases were collected before ICI treatment and after ARX from a treatment-emergent escape lesion. Whole exome sequencing (WES) and bulk RNA-sequencing (RNA-seq) were performed. Somatic mutations were called using the Cancer Genome Analysis pipeline. Differential gene expression analysis (DGE) was run using DESeq2, followed by gene set enrichment analysis (GSEA). Immune cell fractions were estimated using CIBERSORTx. Cell fraction and tertiary lymphoid structures (TLS) scores were compared between post and pre-ARX samples using the Wilcoxon test. Results: A total of 41 samples (n=23 pre-ARX and n=18 post-ARX) were collected from 14 unique patients. After quality control, WES and RNA-seq data were available for 27 samples (14 pre-ARX and 13 post-ARX) and 9 samples (3 pre-ARX and 6 post-ARX), respectively. No discernable enrichment of gene mutations was detected in the post-ARX setting compared to the pre-ARX. DGE identified 61 downregulated immunoglobulin genes in the post-ARX setting. GSEA revealed significant depletion of pathways associated with B-cell and T-cell function in post-ARX samples (all adjusted p<0.05). Similarly, a trend towards decreased naïve B cell and CD8+ T cell fractions was observed in the post-ARX setting (p=0.17 for both). Three previously reported TLS-associated expression signatures were depleted in the post-ARX samples compared to pre-ARX (p=0.015, p=0.065 and p=0.065, respectively). Immunohistochemistry assessment of 3 samples from one pt using ant-CD3 and CD20 antibodies confirmed the presence of TLS in the pre-ARX sample and their absence in two different post-ARX samples. Conclusions: In our cohort of pts with mRCC, no gene mutations were implicated as drivers of ARX. However, ARX was associated with downregulation of B-cell signaling and humoral mediated immunity, as well as absence of TLS. Ongoing efforts are in progress to include more samples.
Identification of a novel prognostic gene signature in a clear cell renal cell carcinoma (ccRCC) population using an integrated multi-study single-cell RNAseq dataset.
Authors: García-Esteve Samuel , Jiménez Natalia , Aversa Caterina , Ferrer-Mileo Laura , Garcia de Herreros Marta , Fernandez-Mañas Laia , González-Aguado Laura , Rubio-Pérez Carlota , Cobo-Diego Inés , Mazariegos Manuel , Prat Aleix , Mellado-González Begoña , Reig-Torras Òscar 
Published: January 2024

465 Background: Clear cell renal cell carcinoma (ccRCC) is a highly heterogeneous disease with varying prognoses and treatment responses. Understanding the underlying molecular determinants of this diversity is key to tailoring effective treatment strategies for each patient (pt). Here, we leveraged single–cell RNA sequencing (scRNA–seq) data to assess intra–tumoral diversity and its impact on pt prognosis. Methods: scRNA–seq raw data from five published studies were processed with Seurat’s standard workflow and integrated to remove biases using Harmony. We then re–analyzed the malignant cell cluster, defined by CA9, NDUFA4L2, and IGFBP3 expression, at a higher resolution. The resulting tumor cell sub–clusters were subjected to differentially expressed gene (DEG) and gene ontology (GO) enrichment analyses. A signature based on all DEGs with a fold change > 1.25 was applied on TCGA–KIRC cohort using single–sample gene set enrichment analysis and then correlated with relapse–free survival (RFS) and overall survival (OS) by Kaplan–Meier and multivariate Cox analyses. Results: We integrated scRNA–seq data from 50 samples from 44 pt’s (40% T3–4, mean age 75, 10% females). A total of 288K cells were classified into 19 clusters. The tumor cluster was re–analyzed and three biologically distinct tumor cell sub–clusters (labeled MC1, MC2, and MC3) were identified, each with unique molecular markers. GO analysis showed enrichment in genes associated with iron sequestration, oxidative phosphorylation, and apoptotic signaling, respectively. In the KIRC cohort, a 23–DEG signature from MC2 strongly correlated with RFS (HR 0.49; 95% CI 0.35−0.67 p < 0.001; 5-RFS: 74% vs. 54%) and OS (HR 0.44; 95% CI 0.33−0.60 p < 0.001; 5-OS: 75% vs. 51%) and was independent of other clinical variables in the multivariate analysis (Table 1). Moreover, this signature identified a subset of T1–T2 tumors (47.8%) with low risk of relapse (HR 0.38; 95% CI 0.19−0.78, p = 0.008; 5-RFS: 92% vs. 80%) and longer OS (HR 0.35; 95% CI 0.20−0.62 p < 0.001; 5-RFS: 90% vs. 68%). Conclusions: We have identified three distinct tumor cell sub–populations in an integrated scRNA–seq database, each characterized by unique transcriptomic profiles. A gene expression signature based on the MC2 sub–cluster was prognostic in the TCGA dataset and may help in identifying patients with a higher risk of relapse and candidates to adjuvant therapy.[Table: see text]
The distribution of mutations across tumor size in ccRCC and their prognostic importance in small masses.
Authors: Monda Steven , Gulati Shuchi , May Allison , Dall'era Marc 
Published: January 2024

479 Background: Substantial efforts have been made to delineate mutational pathways to progression in ccRCC and the prognostic importance of key mutations, yet the distribution of these mutations across tumor size remains unknown. We hypothesized that VHL and PBRM, as more truncal mutations, would be roughly equally prevalent across tumor sizes, while mutations associated with aggressive disease - SETD2, BAP1, and CDKN2a copy-number loss - would be predominantly observed in larger tumors. We further hypothesized that SETD2, BAP1, and CDKN2a copy-number loss mutations, when present in smaller (≤7 cm) ccRCC tumors, would portend worse prognosis. Methods: We assessed a combined cohort of 333 ccRCC tumors from TCGA-KIRC and TRACERx Renal for the distribution of mutations across tumor size. Logistic regression was used to model the presence of each mutation against tumor size. We assessed a subset of 194 tumors ≤7cm for associations of key mutations with clinical outcomes while controlling for size. In small masses, logistic regression was used to model the presence of metastatic disease and invasive disease, and Cox proportional hazards was used to model overall survival, against SETD2, BAP1, CDKN2a copy-number loss, and tumor size. Results: On logistic regression an increase in one centimeter of tumor size was associated with SETD2, BAP1, and CDKN2a loss at odds ratios of 1.16, 1.11, 1.19 (p<0.05); whereas no significant association was observed between tumor size and both VHL and PBRM1 (p=0.18, p=0.65). Among 194 tumors ≤7 cm, SETD2 and CDKN2a loss were associated with metastatic disease at odds ratios of 3.86 and 3.84 (p<0.05); CDKN2a loss was associated with worse overall survival at hazard ratio 2.19 (p<0.05), all while controlling for tumor size. Conclusions: SETD2 mutations, BAP1 mutations, and CDKN2a copy-number loss are rare in small ccRCC and are increasingly common in larger tumors, whereas VHL and PBRM1 are fairly evenly distributed across tumor sizes. In tumors≤7 cm, SETD2 mutation and CDKN2a loss were associated with metastatic disease and CDKN2a loss was associated with worse overall survival. SETD2 mutations and CDKN2a loss may help risk stratify ccRCC in biopsied and resected tumors. [Table: see text]
Genomic profiling in bladder cancer across a spectrum of measured socioeconomic inequality: A retrospective review utilizing next generation sequencing.
Authors: Barker Kenneth , Ruzdija Denis , Bertolo Aaron , Paster Irasema Concepcion , Guillen-Rodriguez Jose , Estrada-Mendizabal Ricardo J. , Chipollini Juan , Recio-Boiles Alejandro 
Published: January 2024

545 Background: Socioeconomic inequality (SI) is a known risk factor for worse prognosis in bladder cancer. The mechanism behind this is likely due to a complex interplay between many factors including access to care, diet and exercise disparities, and frequency of tobacco/alcohol use. There remains a scarcity of studies looking at the impact of socioeconomic inequality on tumor biology in bladder cancer, yet genomic profiling to look for biomarkers with therapeutic targetability is becoming increasingly common through testing modalities such as next-generation sequencing (NGS). This study aimed to further understanding of the effect of SI on the genomic alterations with therapeutic implications seen in bladder cancer. Methods: This was a retrospective analysis of 108 patients (75 male and 33 female) ranging from 18-92 years old with bladder cancer presenting to the University of Arizona Cancer Center from 2016-2023. Of these 108 patients, 97 had NGS data available. Each actionable pathogenic mutation, tissue mutational burden (TMB), and combined positive score (CPS) for PDL1 expression was recorded for each patient. TMB score of >10 and/or CPS of >10 were considered as actionable mutations for immunotherapy. The Area Deprivation Index was used to measure SI levels of each patient’s neighborhood based on a national scale from 1-100 with 100 being most disadvantaged and 1 being the least. These patients were then split into three tertiles: 1-33, 34-67, and 68-100 to compare the frequency of genomic alternations using chi-squared for contingency tables and kruskal-wallis rank test for multiple samples. Results: Of the 97 patients with NGS, 18 were in tertile 1, 47 in tertile 2, and 34 in tertile 3. TMB-High>10 was significantly different between tertiles with the following frequencies of TMB >10: tertile 3 8/34 (23.5%), tertile 2 21/47 (44.6%), and tertile 1 10/18 (55.5%), (p=<0.05). The mean mutational burden in tertile 1, 2, and 3 was 11.3, 10.17, and 8.22 respectively (p=0.147). There was no correlation of SI with the selected frequent mutations KDM, ARID1A, TERT, TP53, PIK3CA, TP53, and TERT (p>0.05). Conclusions: Higher TMB in bladder cancer has been associated with a more favorable prognosis and predictive response to immunotherapy. Our results show patients from neighborhoods of higher SI have a significantly lower frequency of TMB score >10, and this could offer partial explanation for the worse prognosis seen with higher SI levels. Our relatively small sample size limits the power of our study. Further investigation through larger scale studies of the genomic alterations seen between SI levels have important implications in understanding both why and how to better address the worse outcomes seen in bladder cancers in patients with greater SI levels.
The association between social vulnerability and clinical trials awareness and participation: A HINTS-SEER analysis.
Authors: Sekar Rishi , Herrel Lindsey A. , Stensland Kristian 
Published: January 2024

546 Background: Clinical trials are integral to science and can ensure access to standard of care treatments, providing benefits to individual participants and society. Unfortunately, fewer than 5% of eligible cancer patients participate in clinical trials, and large facets of the population remain starkly underrepresented, excluding them from these benefits and potentially compromising the generalizability of biomedical knowledge. Adverse social determinants of health (SDOH), or social vulnerability, may affect awareness and the decision to participate in a clinical trial, especially in underrepresented or historically excluded populations. In this study, we evaluate the association between population-level SDOH and clinical trials awareness and participation. Methods: We performed a cross-sectional analysis of the 2021 Health Information National Trends – Surveillance, Epidemiology, and End Results (HINTS-SEER), a nationally representative survey of 1,234 cancer survivors. The primary outcomes of interest included awareness of clinical trials “as a possible treatment option for your cancer” and “participation in a clinical trial for treatment of your cancer”. The primary exposure was the Centers for Disease Control and Prevention Social Vulnerability Index (CDC SVI), which was linked to each survey respondent by ZIP code of residence. Survey weighted multivariable logistic regression analyses were performed to evaluate the association between SVI quintile and clinical trial awareness and participation, adjusting for age, sex, race/ethnicity, and education level. Results: This survey weighted analysis represents a population of over 400,000 patients. Only 15.1% of patients were aware of clinical trials, with the most socially vulnerable patients having lower rates of awareness compared to the least socially vulnerable patients (8.5% vs. 17.9%). Similarly, only 7.7% of patients participated in a clinical trial, with the most socially vulnerable patients having lower rates of participation compared to the least socially vulnerable patients (3.0% vs. 10.1%). On multivariable analysis, the most socially vulnerable patients had significantly lower odds of clinical trials awareness (OR 0.43, CI 0.20 – 0.94) and clinical trials participation (OR 0.15, CI 0.03 – 0.73) compared to the least socially vulnerable patients, adjusting for age, sex, race/ethnicity, and education level. Conclusions: In this analysis of HINTS-SEER, a contemporary and novel survey of cancer survivors, rates of clinical trial awareness and participation remain concerningly low. Notably, adverse SDOH has a strong influence, with the most vulnerable patients being far less likely to be aware of or participate in a clinical trial. With the goal of achieving equitable cancer care, identifying and alleviating barriers to clinical trial participation, especially those rooted in SDOH, is critical.
Role of geriatric assessment and oncological multidimensional prognostic index (Onco-MPI) in a real-world cohort of elderly patients with advanced urothelial carcinoma.
Authors: Bimbatti Davide , Cavasin Nicolò , Bergo Eleonora , De Toni Chiara , Lai Eleonora , Erbetta Elisa , Jubran Salim , Pierantoni Francesco , Ruffini Camilla , Brunello Antonella , Basso Umberto , Maruzzo Marco 
Published: January 2024

563 Background: At least 75% of bladder cancer (BC) are diagnosed in adults aged ≥65 years, with a median of 72 years. Older adults have poor outcomes but are also an heterogeneous population in which the functional status often does not reflect the chronological age. ASCO and SIOG recommend the use of geriatric assessment (GA) to guide management of these patients (pts) but very few data are present to date. Methods: We investigated the role of GA and an oncological version of MPI in pts ≥70 years old affected by advanced/metastatic urothelial carcinoma. Data were retrieved from a prospectively maintained database from 2010 to 2022. Comprehensive GA (CGA) is a multidimensional tool used to classify pts as fit, vulnerable and frail according to Balducci’s criteria. Onco-MPI was calculated by a validated algorithm derived from different GA domains and tumour characteristics. We also collected characteristics of pts, tumors and treatment regimens. Correlation between GA and treatments used and oncological outcomes were analysed. Results: Complete data and follow up were available for 181 patients. Pts characteristics are reported in Table 1. According to Onco-MPI all the pts but 7 were at high risk. The mFU was 46.2 months, while mOS was 8.2 months. Balducci’s CGA and Bellmunt groups had a concordance of 58%, p<0.01. Strong correlations between these scores and type of treatment received were found (pts fit or 0 score received more often a platinum-based treatment without reduction dose while frail or 2-3 score received more often treatment with a reduced dose or no treatment at all, p<0.01). The two scores have a strong prognostic value (18.5 vs 10.8 vs 3.8 months, p<0.01; 21.9 vs 8.5 vs 4.1 months, p<0.01, respectively for CGA and Bellmunt subgroups). At univariate analysis also timing of mets, number of sites, type of treatment and dose were good prognostic variables. All these variables retained their prognostic value at a multivariate analysis incorporating each of the two scores separately. Conclusions: CGA has a great prognostic value in older adults with metastatic urothelial cancer. This tool could help in decision making and patients stratification but validation in prospective cohort is needed. Onco-MPI could also be useful but new cut offs must be set in this specific population.[Table: see text]
Real-world survival of men with metastatic castration-sensitive prostate cancer (mCSPC) initiated on apalutamide (APA) or enzalutamide (ENZ) in an oncology database: ROME Study.
Authors: Bilen Mehmet Asim , Du Shawn , Khilfeh Ibrahim , Rossi Carmine , Korsiak Jill , Rahman Alvi , Lefebvre Patrick , Pilon Dominic , Shore Neal D. 
Published: January 2024

57 Background: Androgen receptor signaling inhibitors (ARSIs), including APA and ENZ, have demonstrated progression-free and overall survival benefits for men with mCSPC in the clinical trial setting, but data evaluating real-world treatment effectiveness remains limited. The aim of this study was to describe real-world survival among men with mCSPC who initiated APA or ENZ in the United States (US). Methods: In this retrospective longitudinal cohort study, clinical data from the Flatiron Metastatic Prostate Cancer (PC) Core Registry Electronic DataMart (1/1/2013–05/31/2023) were used. Patients with chart-confirmed metastasis and without castration resistance were classified into two treatment cohorts based on earliest initiation of APA or ENZ on/after 12/16/2019 (index date). Patients had ≥12 months of clinical data pre-index and were followed from the index date until the earliest of 24 months post-index, end of clinical activity, or end of data availability. Patients’ date of death was obtained from electronic medical records, Social Security Death Index, or other confirmed sources. Using an intention-to-treat approach, Kaplan-Meier analysis was used to describe the proportion of patients surviving by 24 months post-index. An unadjusted Cox proportional hazards model was used to describe crude differences in survival rates between patients initiating APA and ENZ. Results: There were 234 APA (mean age: 73.2 years; 59.8% White, 13.7% Black) and 527 ENZ (mean age: 73.9 years; 55.2% White, 13.1% Black) patients included in this study (Table). APA median time on-treatment was 10.9 months over a median observation period of 13.3 months, while ENZ median time on-treatment was 11.1 months over a median 14.8 months observation period. By 24 months, a higher proportion of patients in the APA cohort survived than in the ENZ cohort (85.4% vs 73.9%; unadjusted hazard ratio=0.59, 95% confidence interval: 0.39, 0.95; p=0.030; Table). Conclusions: In this real-world analysis of patients with mCSPC, more patients treated with APA survived by 24 months following treatment initiation as compared to treatment with ENZ. While the current study reports unadjusted analyses, future studies adjusting for potential confounding variables should be conducted to confirm these findings in order to inform clinicians on treatment selection for patients with mCSPC. [Table: see text]