bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival outcomes of metastatic renal cell carcinoma (RCC) patients with pancreatic metastases (PM): Pooled analysis from a large clinical trials database.
Authors: Shaya Justin , Lin Xun , Cabal Angelo , Panian Justine , Weise Nicole , McKay Rana R. 
Published: May 2020

e17072 Background: Pancreatic metastases are a rare site of metastasis for RCC. It has been suggested that patients with metastases to the pancreas have a more indolent disease course, however long term survival outcomes with systemic therapy are not well defined. Methods: We conducted a pooled analysis of metastatic RCC patients treated in phase II/III clinical trials. The primary objective was to evaluate overall survival in patients with PM compared to those without PM. Secondary objectives included progression-free survival (PFS) and objective response rate. Outcome measures were evaluated in the overall cohort and stratified by line and type of therapy and IMDC risk group. Statistical analyses were performed using Cox regression and Kaplan-Meier analysis. Results: We identified 4736 patients treated with either vascular endothelial growth factor (VEGF) targeted (n=3511), mammalian target of rapamycin (mTOR) targeted (n=665), or cytokine therapy (n=560), of which 5.0% (n=235) had PM at initiation of therapy. Median OS (mOS) in patients with PM was significantly prolonged compared to those without PM (Table). In a multivariate Cox regression model, this improvement in mOS remained statistically significant when adjusting for concurrent metastases to the lung, bone, or liver, line and type of therapy, and IMDC risk group. In further subgroup analysis, among patients with PM, superior mOS was noted in patients with favorable or intermediate IMDC risk, treatment naive patients, and treatment with VEGF inhibitors or cytokine therapy (Table). For the overall cohort, PFS was 10.9 vs 6.9 months for patients with and without PM (HR 0.72, 95% CI: 0.60, 0.86). Objective responses were higher in patients with PM vs those without PM (37% vs 24%, p<0.01). Conclusions: The presence of PM in advanced RCC is an independent positive predictor for survival. This effect is pronounced in patients treated with VEGF inhibitors and IMDC favorable and intermediate risk disease. Unraveling the molecular determinates of pancreatic tropism in RCC will be important for personalizing therapy for patients. [Table: see text]
The role of cytoreductive nephrectomy in metastatic renal cell carcinoma.
Authors: Alnimer Yanal Mufeed , Qasrawi Ayman , Katato Khalil 
Published: May 2020

e17080 Background: The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (MRCC) is unclear. Two randomized clinical trials (RCT) in the cytokine era demonstrated a survival benefit of CN in MRCC. However, the efficacy of this approach is unknown after the introduction of tyrosine kinase inhibitor (TKI) therapy and immunotherapy (IC) in the frontline setting of MRCC. Methods: We studied the the impact of CN in MRCC on overall survival (OS) using the Surveillance, Epidemiology, and End Results (SEER)-18 registries. The R software was used for statistical analysis. Results: A total of 5488 patients with MRCC between 2010-2016 were identified. The median age was 62 years, 70% were males and 55% underwent partial or total nephrectomy. After a median follow-up time of 36 months, median OS was 12 months. Histology was clear cell (CC) in 79% the cases and 21% were non-clear cell (NCC). On univariate Cox regression, patients with CC histology who underwent CN had a 0.35 [95% confidence interval (CI), 0.33-0.38] lower risk of death compared to those who did not. After adjustment for age, gender, number of sites involved by metastasis (bone, liver, lung and/or brain), grade and administration of chemotherapy, patients who got CN had a 0.33 (CI, 0.29-0.36) lower risk of death compared to those who did not. The following factors were associated with higher risk of death in multivariable Cox proportional hazard ratio (HR) model: number of metastatic sites, HR = 1.50 (CI, 1.43-1.58); grade III vs. II, HR = 1.39 (CI, 1.22-1.59); grade IV vs. II, HR = 2.08 (CI, 1.80-2.39); female gender, HR = 1.16 (CI, 1.07-1.26), those who didn’t receive chemotherapy (or unknown status) with a HR of 1.39 (CI, 1.28-1.50) and increasing age with a hazard ratio of 1.009 (CI 1.005-1.013) for each year increase. With NCC, the following factors were associated with higher mortality: number of metastatic sites, HR = 1.34(CI, 1.24-1.46), older age, HR = 1.01(CI, 1.003-1.014) for each year increase, grade III vs. II,HR = 1.97(CI,1.41-2.77);IV vs. II,HR = 1.98 (CI, 1.41-2.77); and those who didn’t receive chemotherapy with HR = 1.52 (CI, 1.32-1.74). On the other hand, those who had CN had lower mortality, HR = 0.46 (CI, 0.38-0.55). Conclusions: In this large cohort, there was a survival benefit of CN in MRCC. However, our study is limited by the lack of treatment details and possible selection bias for the patients who got CN. TARIBO is an ongoing RCT that aims to identify the benefit from CN in MRCC in the TKI and IC era. Until the trial is concluded, CN should be considered for eligible patients with MRCC, regardless of histology.
The change of serum C-reactive protein levels during molecular-targeted treatments could predict the response to anti-PD-1 treatment in metastatic renal cell carcinoma patients.
Authors: Takamatsu Kimiharu , Mizuno Ryuichi , Hayakawa Nozomi , Tanaka Nobuyuki , Kosaka Takeo , Kikuchi Eiji , Oya Mototsugu 
Published: May 2020

e17085 Background: Immuno-oncology (IO) checkpoint inhibitors, such as programmed death-1/programmed death-ligand1 (PD-1/PD-L1) inhibitors have been standard of care in the metastatic renal cell carcinoma (mRCC) systemic treatment. However, predictive biomarkers for IO checkpoint inhibitors which is clinically usable have been still unclear. The aim of this study was to evaluate the clinical significance of the change of serum C-reactive protein (CRP) levels during molecular-targeted treatments (VEGFR-TKI and mTOR-I) prior to nivolumab as the predictive marker for the response of nivolumab in patients with refractory mRCC. Methods: A total of 73 mRCC patients (favorable 25(34%), Intermediate 38(52%) and poor 10(14%) risk group by IMDC criteria) treated with nivolumab were retrospectively reviewed. We evaluated the serum CRP levels before and after molecular-targeted treatments. The elevation of serum CRP during molecular-targeted therapies before nivolumab induction was defined as the CRP-elevation group. The clinical impact of CRP-elevation as well as other clinical and pathological prognostic factors on progression-free survival (PFS) and overall survival (OS) from nivolumab were assessed. Results: The median follow-up period after nivolumab initiation was 13.2 months (range 3.0-60.8). Forty-nine patients (67%) were categorized into the CRP-elevation group. A clear impact of the CRP-elevation on the response of nivolumab was observed: the median PFS of the CRP-elevation group was 11.9 months, and that of the CRP-non elevation was not-reached (p = 0.038). On multivariate analysis, the CRP-elevation before nivolumab was the independent prognostic factor to predict PFS in nivolumab treatment (HR: 2.68, 95% CI: 1.01-7.11, p = 0.047). CRP-elevation group had a tendency of shorter OS than CRP-non elevation group (p = 0.071). Conclusions: The change of serum CRP levels during molecular-targeted therapies could be the predictive factor for the efficacy of nivolumab in mRCC patients.
Trends in the use of administrative databases in urologic oncology: 2000-2019.
Authors: Leopold Zev , Dave Priya , Menon Adarsh , Patel Hiren V. , Srivastava Arnav , Jang Thomas L , Singer Eric A. 
Published: May 2020

e17111 Background: Administrative databases (AD) provide investigators with nationally representative study populations to answer research questions using large sample sizes. Their use has significantly grown over the past 20 years, particularly in urologic oncology. We aimed to quantify the trends and incidence of AD use in published manuscripts in urologic oncology. We examined six commonly used databases: National Cancer Database (NCDB), Surveillance, Epidemiology and End Results Database (SEER), SEER-Medicare (SEER-M), Nationwide Inpatient Sample, National Surgical Quality Improvement Program, and Premier Healthcare Database. Methods: A literature review powered by PubMed and DistillerSR from 2000 to 2019 aggregated manuscripts that used the aforementioned databases to study a genitourinary malignancy. Included publications were categorized by database used, corresponding author department affiliation, organ, journal, year, and contribution - defined as temporal treatment trends, outcomes and survival, comparative effectiveness research, and cost-effectiveness. Results: There were 2265 publications across 307 journals that met the inclusion criteria. Between 2000 and 2019 the compound annual growth rate of these publications was 18.7%. SEER contributed most heavily over the study period, with a 14.6% growth rate. NCDB use grew 75.6% annually starting in 2012. Prostate cancer comprised the majority of publications (51.3%), followed by kidney (23.1%) and bladder (22.5%) cancer. Journals publishing these manuscripts had a median impact factor of 2.78 (range 0.36 - 223.68) in 2018. Urologists published 52.5% of AD manuscripts over the study period, with epidemiologists and radiation oncologists publishing 18.2% and 10.6%, respectively. Conclusions: Our results show substantial growth in the use of ADs for the study of genitourinary oncology. The increased use is likely multi-factorial and may be driven by increasing competition to secure funding, ability to answer questions previously limited by sample size, and improved quality of databases. Given the broad use of ADs, investigators and specialty societies should advocate for continued improvement in the data captured by them.
Integrated-omics of MRI-visible and -invisible prostate cancer identifies molecular correlations with clinical outcome.
Authors: Kim Eric , Miheecheva Natalia , Ramachandran Akshaya , Lyu Yang , Galkin Ilia , Svekolkin Viktor , Postovalova Ekaterina , Bagaev Alexander , Nomie Krystle , Ogloblina Anna , Frenkel Felix , Ataullakhanov Ravshan , Hsieh James J , Pachynski Russell Kent 
Published: May 2020

e17506 Background: The inclusion of multiparametric MRI (mpMRI) to prostate cancer (PCa) diagnostics has increased the detection rate and has improved the prediction rate of clinically significant PCa. Yet, mpMRI has a false negative rate of 12.6%, missing 6-13% of clinically significant PCa. The mechanisms underlying MRI visibility are poorly understood; therefore, to probe the molecular and cellular underpinnings of PCa MRI visibility, we profiled tissue from Gleason score and clinically matched patients with MRI-visible and MRI-invisible PCa who underwent radical prostatectomy. Methods: MRI-invisible (n = 7) and MRI-visible (n = 8) PCa tumors were evaluated with multiplex immunofluorescence (MxIF; 14 markers) and were subjected to gene expression profiling using the HTG EdgeSeq Oncology Biomarker Panel (2,549 genes). Gene expression analysis was also performed using The Cancer Genome Atlas (TCGA), including normal prostate (n = 52) and PCa (n = 387) tissue. Analyses were performed using the BostonGene automated pipeline. Results: MpMRI-visible PCa tumors (62.5%) displayed compact epithelial tumor architecture compared with mpMRI-invisible PCa tumors (28.5%). mpMRI-visible PCa had higher malignant cell density (p = 0.04) and increased neighboring malignant cells (p = 0.07), correlating with MRI-visible PCa complex tumor architecture (r = 0.49 for neighboring malignant cells vs tumor cell density). Tumor stromal organization differences were determined by measuring Wasserstein distances between distributions, and mpMRI-invisible PCa stroma appeared more similar to normal tissue. The visible group exhibited lower expression of stroma-enriched genes such as filamin C (FLNC) (FDR < 0.1) and cellular adhesion-related genes (FDR < 0.4), with gene expression signatures markedly different compared to normal prostate tissue. Higher malignant cell density, neighboring malignant cells, and Wasserstein distances, and low FLNC expression – all mpMRI visibility characteristics – were associated with patient relapse (p = 0.02). Low stroma signature expression in the TCGA cohort correlated with inferior PCa PFS (p = 0.005). Conclusions: This is the first integrated multi-omics analysis of clinically matched mpMRI-visible and -invisible PCa. mpMRI-invisible tumors exhibited molecular, cellular, and structural characteristics more akin to normal prostate tissue, which may render them undetectable by imaging. A stroma-associated gene signature, a mpMRI-invisible tumor feature, correlated with better PCa clinical outcomes.
A genomic blood test (NETest) identifies neuroendocrine transformation of prostate cancer.
Authors: Rahbar Kambiz , Kidd Mark S. , Drozdov Ignat A. , Malczewska Anna , Bodei Lisa , Rajwa Pawel , Boegemann Martin , Bernemann Christof , Kitz Alexandra , Modlin Irvin Mark 
Published: May 2020

e17511 Background: Neuroendocrine-like differentiation (NELD) and an aggressive phenotype are key features of castration-resistant prostate cancer (CRPC). Current blood-based biomarkers cannot detect these treatment-refractory variants. Our aim was to evaluate the NETest, a blood-based 51-marker gene neuroendocrine detection tool, as a CRPC-diagnostic versus prostate cancer (PCA). Methods: In silico evaluation: NETest gene identification in the TCGA-PRAD ( n= 500 PCA) and CRPC RNAseq datasets (cBIOPortal: dbGap-phs000909.v.p1, tissue samples: n= 47, including 15 CRPC). Blood gene expression: PCA: n= 50, CRPC: n= 40, hormone-sensitive PCA: n= 75 and benign prostatic hyperplasia (BPH: n= 41). NETest assay: Normalized gene expression, algorithmically assessed and scored: 0-100. Cut-off 20. PSA: ECLIA diagnostic assay: cut-off 4ng/L, > 10ng/ml = actionable value. Statistics: ANOVA, AUROC analyses and sensitivity/specificity metrics. Data is mean±SEM. Results: RNAseq: Two (4%) of the 51 NETest genes were identified in TCGA-PCA. In contrast, all 51 NETest genes (100%) were identified in CRPC tumors. Thirty-three (65%) were detected as upregulated (1.09-1425-fold vs. normal tissue). Blood-PCR: 49/51 (96%) NETest genes detected in CRPC blood. NELD-gene expression was significantly upregulated ( > 2-fold, p< 0.01) in CRPC vs. PCA ( TPH1, PNMA2, SSTR etc). NETest scores were elevated in CRPC (79±2.8) (ANOVA, p< 0.0001) vs. PCA (22±2) and BPH (23±3). The AUC differentiating CRPC from PCA was 0.93 ( p< 0.0001). NETest was elevated in 94% of CRPC vs. 13% PCA and 15% BPH (both p< 0.001). The diagnostic sensitivities and specificities were 94% and 87%, respectively. PSA: PSA was elevated in CRPC (220±372ng/ml). This was different to PCA (14±20ng/ml, p< 0.0001) and BPH (10.3±5.7ng/ml, p< 0.003). The AUC for CRPC vs. PCA/BPH was 0.70 ( p= 0.10). PSA > 10ng/ml occurred in 70% of CRPC, 60% of PCA ( p= NS) and 39% of BPH ( p< 0.05). The AUC for NETest (0.93) was significantly better than PSA (z-statistic: 4.63, p< 0.0001). Conclusions: The NETest is a liquid biopsy that detects neuroendocrine neoplasia genes in the blood and accurately identifies NELD in castration-resistant prostate cancer. We anticipate that the NETest could be used to provide real-time information relevant to the evolving neuroendocrine status of a PCA during therapy.
Effect of PSA on equal treatment of high-risk patients.
Authors: Ferenczi Basil , Frankel Jason , Jung Nathan , Porter Christopher , Flores John Paul 
Published: May 2020

e17514 Background: National Comprehensive Cancer Network (NCCN) guidelines recommend definitive treatment for high risk prostate cancer (HRPCa). This study aims to assess treatment trends for men with HRPCa, focusing on men deemed high risk on the basis of an elevated PSA alone with otherwise low risk features. Our hypothesis is that this group is treated differently than other patients with high risk disease. Methods: The National Cancer Database (NCDB) prostate cancer (PCa) participant use file was queried for high risk patients ages 18-75 with biopsy proven PCa from 2010-2016. The NCDB represents approximately 55% of men treated for PCa in the United States. Patients were divided into two groups: the study group with PSA > 20 and otherwise low risk features, and a comparison group comprised of high-risk patients due to cT stage ≥T3a or Gleason Grade Group ≥4. Patients with nodal or metastatic disease were excluded. Rates of treatment by modality were compared over the years studied. Survival was modeled using Kaplan Meier analysis. Results: 91,565 patients met eligibility criteria with 12,156 in the study group and 79,409 in the comparison group (Table). In the study group, a significantly higher number of patients underwent surveillance (10.2%) versus the comparison group (0.3%)(p < 0.001). Furthermore, there was an upward trend in use of surveillance in the study group, with a surveillance rate of 18.9% in 2016. Amongst patients receiving radiation, only 26.1% received androgen deprivation therapy (ADT) in the study group versus 82.8% in the comparison group. Despite these findings, survival analysis demonstrated significantly higher 5-year overall survival in the study group (95.1%) vs the comparison group (87.8%) (HR = 0.41, p < 0.001). Conclusions: Men categorized as HRPCa by PSA alone with otherwise low risk features are treated less aggressively than other high-risk patients with significantly higher rates of surveillance and radiation without ADT. However, these men appear to have better survival outcomes than other high-risk patients at 5-year follow-up. [Table: see text]
Insights into Chinese prostate cancer germline gene mutation profile: HOXB13 G84E mutation is unsuitable for genetic testing.
Authors: Dong Baijun , Yang Bin , Li Yonghong , Chen Wei , Li Jing , Xu Zhenzhou , Wu Kaijie , Zhang Fengbo , Zhu Shimiao , Yi Lu , Hua Lixin , PAN Hao , Ma Hong , Sun Zhongquan , Cheng Huihua , Zhang Zhenting , Li Mingzhao , Chen Zhiwen , Wang Fangqin , Xue Wei 
Published: May 2020

e17515 Background: Philadelphia Prostate Cancer Consensus Conference 2017 developed an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA. However, the consensus was mainly based on data from Caucasian populations. Genetic differences in the PC molecular landscape between Asian and Caucasian men have been established. Whether Caucasian-based genetic information can be used to guide clinical practice in Chinese population needs further evidence. Methods: 1123 patients with confirmed prostate cancer admitted from March 2018 to August 2019 from 18 Chinese centers were included in this retrospective study. We sequenced the association of 50 gene with prostate cancer risk, clinical treatment implications and predisposition, focusing on DNA repair gene and genetic susceptibility genes pathogenic mutations in Philadelphia Prostate Cancer Consensus Conference. Only protein-truncating alterations (nonsense/stop-gains, frameshift insertions and deletions, and donor and acceptor splice-site mutations) were coded as pathogenic or likely pathogenic protein-truncating alterations. Results: Among all cases, DNA repair gene pathogenic mutations were found in 133 men (11.84%), including BRCA2 (62 [5.5%]), ATM (15 [1.3%]), PALB2 (11 [0.97%]), GEN1 (7 [0.62%]), BRCA1 (6 [0.53%]), MLH3 (4 [0.35%]), MUTYH (4 [0.35%]), PMS1 (4 [0.35%]), RAD50 (4 [0.35%]), ATR (3 [0.27%]), CHEK2 (3 [0.27%]), FANCD2 (3 [0.27%]) etc. Similar germline DRG mutation frequencies were observed between our cohort and Caucasian men. Noticeably, G84E mutation in HOXB13, a rare but recurrent missense mutation associated with a significantly increased risk of hereditary prostate cancer was not found in our cohort of patients. Furthermore, the frequency of HSD3B1 (1245C) allele in the Chinese patients is much lower than that in the Caucasian populations (11.7% vs 63%). Conclusions: Our study retrospectively analyzed germline mutation profile of prostate cancer in Chinese population. The frequency of HSD3B1 (1245C) allele varies across ethnic populations in spite of the similar DNA repair gene mutations rates. Considering the gene list should be tested based on clinical/familial scenarios from the Philadelphia Prostate Cancer Consensus Conference, a prevalence of certain mutations, G84E mutation in HOXB13 was unnecessary for genetic testing in Chinese population.
Evaluating the clinical, environmental, genetic, and genomic profile of men with early-onset aggressive prostate cancer (PCa).
Authors: Zarzour Ahmad , Morgans Alicia K. , Palmbos Philip , Jovanovic Borko , Tomlins Scott A. , VanderWeele David James , Yang Ximing J , Schaeffer Edward M. , Sharifi Roohollah , Meeks Joshua J , Abdulkadir Sarki , Hussain Maha H. A. 
Published: May 2020

e17517 Background: Although PCa incidence has stabilized/decreased in most age groups, the incidence of metastatic disease has increased among men 50-69 years-old. The incidence of fatal PCa has decreased for most age groups, it has remained unchanged in men under 55 years-old. Studies have described genetic abnormalities in aggressive localized or end-stage PCa, but early-onset cases are not included or are under-represented. The primary objective of this study is to characterize the clinical, environmental, genetic and genomic features of high-risk advanced PCa. Methods: Study cohort includes men with PCa ≤ 60 years old with N1 or M1 stage at diagnosis or who develop metastases in 5-years after local therapy. Clinical (race, family history (Hx), environmental exposure), laboratory,/pathology, cell-free DNA germline analysis were collected. Primary/metastatic tumor tissue tested via the Tempus-Xe platform (DNA sequencing, whole transcriptome expression profiling, copy number analysis, comprehensive fusion gene analysis and calculation of tumor mutational burden). We report interim analysis. Results: Study completed accrual with 30 pts. Median age 55 years (41-60), 87% are white, 13% are black, 77% had a family Hx of malignancy in 1-6 family members, including 40% with family hx of PCa. Only 33% had Hx of smoking. Median Gleason score 9. Only 27% had nodal disease, and 73% had metastatic disease at diagnosis. Molecular data are available in 25 pts. Most common germline mutations: BRCA2 (12%), ATM (12%), RB1 (8%), MSH3 (8%) and MYBPC3 (8%). Most common somatic mutations:TP53 (40%), TMPRSS2-ERG fusion (32%), MUC4 (16%), PTEN (12%), C2CD4D (12%), SPOP (12%), OBSCN (12%), MXRA5 (12%), and MYO15A (12%). Microsatellite stability status was available in 15 pts and all were stable. Tumor mutational burden was low in all pts, ranging between 0.7 to 2.7 mutations/megabase. Conclusions: Our preliminary data suggest high rates of germline mutations in early onset lethal PCa. This aggressive subset of disease requires further studying to better characterize the underlying clinical/genomic factors driving this disease.