bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating ensembles of tumor-associated cells in genitourinary cancers.
Authors: Srinivasan Ajay , Akolkar Dadasaheb B. , Fulmali Pradip , Fulmali Pooja , Srivastava Navin , Patil Darshana , Patil Revati , Apurwa Sachin , Patil Sanket , Patel Shoeb , Datta Vineet , Sims Cynthe , Datar Rajan 
Published: February 2020

718 Background: Detection of genitourinary cancers is based on histopathological analysis of tumor tissue obtained by invasive biopsies following manifestation of clinical or radiological symptoms. There is presently no non-invasive blood-based test with high specificity and sensitivity for detection of genitourinary cancers. Considering that unprovoked thromboembolism is a significant risk in multiple cancers, we hypothesized that tumor derived circulating emboli in peripheral blood could comprise cancer cells and would serve as a reliable biomarker for detection of genitourinary cancers. These Circulating Ensembles of Tumor Associated Cells (C-ETACs) are defined as clusters of 3 or more cells of tumorigenic origin (EpCAM+, CK+ and CD45±). Methods: We obtained 15ml of blood from 8828 individuals, including 103 cases of Renal cancer, 79 cases of bladder cancer, 153 cases of prostate cancers as well as from 8493 asymptomatic individuals with age related elevated risk and were negative in various screening investigations (CEA, AFP, CA19-9, CA125, PSA, LDCT, Mammography, PAP Smear). PBMC were isolated by centrifugation. C-ETACs were enriched, harvested and characterized by immunofluorescence staining for EpCAM, CK, CD45 as well as organ specific markers for renal, bladder and prostate cancers. Results: C-ETACs were detected in 87 (84.5%) of 103 renal cancers, 71 (89.9%) of 79 bladder cancers and 138 (90.2%) of 153 prostate cancers respectively irrespective of extent (stage / metastatic status) of disease and prior treatments. Overall sensitivity among 335 cancer patients was 88.4%. Among the 8493 asymptomatic individuals, C-ETACs were detected in 255 individuals (97% specificity). Conclusions: C-ETACs were ubiquitously detected in cancers of Kidney, Bladder and Prostate regardless of stage and treatment status, and pose significant latent risk of metastasis/recurrence. The relative undetectability of C-ETACs in the asymptomatic cohort indicates causative connection with malignancies and are hence suitable for screening for these cancers.
Targeting metabolic dysregulation of T cells in kidney cancer.
Authors: Beckermann Katy , Young Kirsten , Hongo Rachel , Ye Xiang , Contreras Diana , Barone Sierra , Roe Caroline E. , Smith Christof C. , Vincent Benjamin Garrett , Irish Jonathan M. , Rathmell Wendy Kimryn , Rathmell Jeffrey C. 
Published: February 2020

722 Background: Cancer cells can inhibit effector T cells through both immunomodulatory receptors and alteration of the tumor microenvironment. Rather than efficient use of aerobic glycolysis by activated effector T cells, Renal Cell Carcinoma (RCC) infiltrating T cells (TIL) fail to increase glucose metabolism, and instead display increased reactive oxygen species (ROS) and mitochondrial dysfunction. CD8 RCC TIL also have notable differences in mitochondrial morphology compared to healthy control CD8 T cells and were punctate and dispersed rather than fused in networks. Here we test if RCC TIL can be re-activated and identify metabolic requirements for inflammatory TIL function. Methods: De-identified samples from tumor or adjacent normal tissue donations from patients with RCC were collected under an approved IRB protocol and processed into single cell suspensions of tumor and associated cells by mechanical dissociation to test TIL activation and metabolic requirements upon in vitro re-stimulation. Results: RNA-seq data suggested that CD8 from TIL rely on distinct metabolic pathways compared to control. While control T cells increased effector cytokine production and glycolysis with antigen receptor alone and further augmented this pathway with co-stimulation, single cell RNAseq showed that CD8 RCC TIL required co-stimulation for this transition. Co-stimulation can promote T cell glycolysis and we found antigen receptor stimulation with CD28-mediated co-stimulation increased function of CD8 RCC TIL as indicated by increased surface markers of activation and IFNγproduction. This was accompanied by rescue of metabolic markers, including increased mitochondrial mass and markers of electron transport. Improved functional capacity was dependent upon glycolysis because inhibition with 2-deoxyglucose limited CD8 RCC TIL activation following CD28 co-stimulation. Conclusions: Bypassing metabolic defects restore markers of TIL activation and effector function.These datademonstrate that CD8 RCC TIL can be functionally restored but that this requires the ability to increase glucose metabolism. These findings may allow for combined therapies to improve response rates of checkpoint inhibition in this disease.
Prognostic value of risk stratification using blood biochemical parameters in Japanese patients with metastatic renal cell carcinoma treated by nivolumab.
Authors: Yamamoto Yoshiaki , Matsuyama Hideyasu , Matsumoto Hiroaki , Sakano Shigeru , Fujii Nakanori , Oba Kazuo , Yamamoto Mitsutaka , Kamiryo Yoriaki , Hiragino Takeshi , Nagao Kazuhiro , Takai Kimio , Aoki Akihiko , Yoshihiro Satoru , Tsukamoto Manabu , Akao Jumpei , Kitahara Seiji , Misumi Taku , Komatsu Hirotaka , Oka Shintaro , Suga Akinobu 
Published: February 2020

724 Background: Nivolumab is a standard treatment for previously treated advanced renal-cell carcinoma (RCC). However, nivolumab is effective in only a limited number of patients; therefore, we evaluated the prognostic value of several biomarkers, including inflammation-based prognostic scores and changes in these scores following nivolumab treatment in Japanese patients with metastatic RCC. Methods: We retrospectively reviewed the medical records of 65 patients with previously treated metastatic RCC and who received nivolumab. MSKCC and IMDC risk, inflammation-based prognostic scores, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and Glasgow prognostic score before and 6 weeks after the treatment were recorded. Categorical variables influencing disease-specific and overall survival were compared using Cox proportional-hazards regression models. Results: Univariate analysis showed that MSKCC risk score ( P = 0.0052), lactate dehydrogenase (LDH) ( P = 0.0266), LMR ( P = 0.0113), and PLR ( P = 0.0017) had a significant effect on disease-specific survival. Multivariate analyses showed that PLR and LDH were found to be independent prognostic factors for disease-specific survival ( P = 0.0008, RR = 7.95, 95% CI, 2.16–51.64 and P = 0.0123, RR = 3.92, 95% CI, 1.37–10.80, respectively). The combination of PLR and LDH was the most significant prognostic biomarker in metastatic RCC for disease-specific ( P < 0.0001) and overall ( P < 0.0001) survival. Changes in LMR and PLR in response to nivolumab were significant prognostic factors for disease-specific survival ( P < 0.0001 and P = 0.0477, respectively). Conclusions: The combination of PLR and LDH may be a potential biomarker for estimating disease-specific and overall survival in Japanese patients with metastatic RCC treated by nivolumab. If changes of inflammation-based prognostic scores in response to nivolumab treatment might be improved, nivolumab treatment should be continued.
Longitudinal multiplex cytokine analysis for patients (pts) with metastatic renal cell carcinoma (mRCC) treated with ipilimumab/nivolumab (I+N).
Authors: Zhang Tian , Wu Yuan , Agarwal Anika , Starr Mark D. , Reyes-Martinez Marco , Anand Monika , Runyambo Daniella , Harrison Michael Roger , Armstrong Andrew J. , George Daniel J. , Nixon Andrew B. 
Published: February 2020

731 Background: I+N is an established treatment for mRCC, where circulating protein biomarkers are prognostic. In a longitudinal correlative study, we characterized circulating proteins in mRCC pts treated with standard of care I+N. Methods: mRCC pts treated with I+N were prospectively enrolled at Duke Cancer Institute (NCT02978118), contributing EDTA plasma at baseline, week(wk)-4, wk-12, and disease progression. Best overall responses were characterized as disease control (DC; stable disease, partial & complete responses) versus progressive disease (PD). Plasma was batch analyzed using a 46-plex MesoScale Discovery ELISA assay (IFN-g, interleukins [IL]-1b, 2, 4, 5, 6, 7, 8, 10, 12, IL-12-IL-23p40, 13, 15, 16, 17A, 21, 22, 27, 31, MIP-3a, Eotaxin, Eotaxin-3, IP-10, MCP-1&4, MDC, MIP-1a & 1b, TARC, TNF-a & b, GM-CSF, CRP, ICAM-1, SAA, VCAM-1, FGFb, FLT-1, PlGF, Tie-2, VEGF, VEGF-, and VEGF-D). Mean and standard deviations of cytokine concentrations are reported, along with a Wilcoxon rank sum test between PD and DC groups; unadjusted p-values are nominal. Results: We enrolled 25 pts with mRCC (15 DC and 10 PD). Baseline IL-7, IL-8, IL-12-IL-23p40, ICAM-1, TNF-a, VEGF-C, and VEGF-D were lower in PD pts than DC pts (Table). MIP-1b was significantly lower for PD than DC pts at baseline (Table) and wk-4 change (PD 0.30 +/- 1.82, DC 0.83 +/- 6.49, p = 0.056). Although baseline IFN-g did not differ between groups, wk-4 IFN-g significantly increased in DC and decreased in PD pts (DC 3.5 +/- 7.1; PD -1.33 +/- 5.47, p = 0.056). Conclusions: In this pilot exploratory analysis, a subset of ILs are higher at baseline in DC than PD pts. A wk-4 increase in circulating IFN-g is associated with DC vs PD and could be linked to increased early inflammation and response to I+N. Larger prospective studies are needed to validate these findings.[Table: see text]
Novel risk scoring system for metastatic renal cell carcinoma (mRCC) patients (pts) treated with cabozantinib (C).
Authors: Kline Meredith R , Martini Dylan J. , Liu Yuan , Shabto Julie M. , Carthon Bradley Curtis , Hitron Elise , Russler Greta , Caulfield Sarah , Yantorni Lauren Beth , Harris Wayne , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim 
Published: February 2020

734 Background: Cabozantinib (C) is an effective treatment for metastatic renal cell carcinoma (mRCC) patients (pts). The international mRCC database consortium (IMDC) criteria is the gold standard for mRCC risk stratification. We created a risk scoring system for mRCC pts treated with C. Methods: We performed a retrospective review of 87 mRCC pts treated with C at Winship Cancer Institute from 2015-19. Overall survival (OS) and progression free survival (PFS) were defined as months from C initiation. The baseline characteristics and inflammation biomarkers included were monocyte, neutrophil, and platelet-to-lymphocyte ratios (MLR, NLR, and PLR respectively), RCC histology, body mass index (BMI), metastatic sites (mets), and Eastern Cooperative Oncology Group performance status (ECOG PS). Upon variable selection in multivariable analysis (MVA), elevated baseline MLR (≥0.71), presence of sarcomatoid histology, ECOG PS > 1, and absence of bone metastases were assigned 1 point. A three-level risk scoring system was created: low (score = 0-1), intermediate (score = 2), and high risk (score = 3-4). The Kaplan-Meier method, Cox proportional hazard model, and Uno’s C-statistics were used to examine performance. Results: The majority of pts were males (71%) with clear-cell RCC (75%). Most pts (67%) received 1+ prior line of therapy. High and intermediate risk pts had significantly shorter OS and PFS compared to low risk pts (Table). The C-statistics for our risk scoring system were higher than IMDC in predicting OS (0.7 vs. 0.62) and PFS (0.65 vs 0.57). Conclusions: Pts treated with C may benefit from risk scoring using RCC histology, ECOG PS, mets, and MLR. These results are hypothesis-generating and should be validated in a larger study.[Table: see text]
Genomic alterations and tumor mutational features of Chinese Xp11.2 translocation renal cell carcinoma patients.
Authors: Qu Yuan-Yuan , Zhang Hailiang , Xu Wenhao , Wang Hongkai , Tian Xi , Cao Dalong , Qu Yueting , Shi Guohai , Ye Dingwei 
Published: February 2020

736 Background: Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) is a rare subtype of RCC which occurs predominantly in children and adolescents. Xp11.2 RCC is characterized by the gene fusions of transcription factor E3 (TFE3). Since there is a high false-positive and false-negative rate of immunohistochemistry (IHC) for TFE3 and an uncertainty of TFE3 fusion partners by fluorescence in situ hybridization (FISH), a genetic approach, such as DNA sequencing, is necessary for auxiliary diagnosis. Methods: Thirty Chinese Xp11.2 RCC patients with positive TEF3 fusion diagnosed by FISH were involved in this analysis. Formalin-fixed, paraffin-embedded (FFPE) samples were collected for a next-generation sequencing (NGS)-based 576 gene panel assay. Genomic alterations including single base substitution, copy number variations, gene fusions, and rearrangements were assessed. Tumor mutational burden (TMB) and microsatellite instability (MSI) status were also analyzed by an NGS algorithm. Results: The 30 patients in the Xp11.2 RCC cohort included 13 males and 17 females, and had a median age of 30 years. TFE3 fusions of these patients were confirmed by both FISH and NGS. Out of the 30 Xp11.2 RCC patients, 2 patients (6.7%) showed negative TFE3 IHC expression and 4 patients (13.3%) showed equivocal TFE3 IHC expression. ASPL (9/30), PRCC (5/30), PSF (5/30), and NONO (3/30) were the most common partners of TFE3 fusion in this cohort. Moreover, we identified uncommon or novel partner genes by NGS, including ZNF627 (1/30), PTPN12 (1/30), PBM10 (1/30), PARP14 (1/30), MED15 (2/30), MATR3 (1/30), LUC7L3 (1/30), KHSRP (1/30), and EWSR1 (1/30). Based on the NGS results, several actionable genomic alterations including CDKN2A, BRCA2, and ATM were found in this study. All samples were identified as microsatellite stable (MSS). The median TMB of the entire cohort was 1.35 muts/Mb (range, 0-9.2 muts/Mb). Conclusions: In summary, we identified the partner genes of TFE3 fusion in 30 Chinese Xp11.2 RCC patients by NGS. Ten uncommon or novel partner genes (33.3%) of TFE3 were identified in this study. Overall, our results provide evidence for diagnosis and therapeutic strategies for Xp11.2 RCC patients.
Screening and identification of novel promoter signatures in clear cell renal cell carcinoma metastasis.
Authors: Qu Yuan-Yuan , Tian Xi , Xu Wenhao , Anwaier Aihemutaijiang , Ye Dingwei , Zhang Hailiang 
Published: February 2020

737 Background: Clear cell renal cell carcinoma (ccRCC) patient usually face aggressive progression when metastasis occurs. Therefore, in-depth investigation is needed to elucidate underlying mechanisms behind the metastasis of ccRCC to promote therapeutic benefits.This study aims to explore and investigate prognostic gene expression profiles based on multi-cohorts. Methods: Three microarray datasets were obtained from the Gene Expression Omnibus (GEO) database to screen and identify differentially expressed genes (DEGs) according to normalization annotation information. A total of 112 DEGs with functional enrichment were identified as candidate prognostic biomarkers. A protein–protein interaction network (PPI) of DEGs was developed, and the modules were analyzed using STRING and Cytoscape. Results: LASSO Cox regression suggested 31 significant involved genes, and 10 hub genes were identified as independent oncogenes in ccRCC patients. Distinct integrated scores of the hub genes mRNA expression showed statistical significance in predicting disease-free survival (DFS; p<0.001) and overall survival (OS; p<0.001) in TCGA and real-world cohorts. Meanwhile, ROC curves were constructed to validate specificity and sensitivity of the Cox regression penal to predict prognosis. The AUC index for the integrated genes scores was 0.758 for OS and 0.772 for DFS. Conclusions: In conclusion,the present study identifies DEGs and hub genes that may be involved in earlier recurrence and poor prognosis of ccRCC. The expression levels of ADAMTS9, C1S, DPYSL3, H2AFX, MINA, PLOD2, RUNX1, SLC19A1, TPX2 and TRIB3 are of high prognostic value, and may help us understand better the underlying carcinogenesis or progression of ccRCC.
The spinal distribution of metastatic renal cell carcinoma: Support for locoregional rather than arterial hematogenous mode of early bony dissemination.
Authors: Attalla Kyrollis , Duzgol Cihan , McLaughlin Lily , Flynn Jessica , Ostrovnaya Irina , DiNatale Renzo G. , Silagy Andrew W. , Coleman Jonathan , Lee Chung-Han , Carlo Maria Isabel , Voss Martin H , Russo Paul , Bilsky Mark , Hakimi A. Ari , Moss Nelson 
Published: February 2020

742 Background: To investigate the distribution of spinal metastasis in metastatic renal cell carcinoma (mRCC) and to explore relationships between biological and clinical factors and patterns of spinal spread. Methods: An institutional database was queried to identify patients with mRCC and spinal metastatic involvement from June 2005 – November 2018. A blinded radiologist examined all cross-sectional imaging involving the spine and scored each level for absence or presence of disease. Clinical and biologic features including primary tumor size and degree of spinal and non-bony metastatic involvement (including regional lymph node and distant deposits) were collected. Spinal distributions were evaluated by the Kolmogorov Smirnov test and compared across radiographic and clinical parameters. Results: One-hundred patients with 685 spinal levels involved by mRCC were evaluated. A nonuniform spatial distribution was observed across the cohort; a preponderance of thoracolumbar involvement was noted with the mode at L3 (p<0.001). No difference in metastatic distribution was observed in right versus left-sided tumors. Tumors <4cm compared to >7cm, patients who had distant spread versus bone-only disease, and patients with increasing number of spine levels involved (1 versus >5 levels) had a significantly different distribution (p<0.001 for all comparisons). Smaller tumor size, distant spread, and greater number of involved levels appeared to have a more uniform distribution of spinal metastasis. Conclusions: These data support a dominant locoregional as opposed to arterial hematogenous mechanism for the early dissemination of mRCC to the spine. This is concordant with the theory of the valveless Batson plexus acting as a conduit for such spread, as the kidneys are compartmentally distinct from, but reside just anterior to the spine at L1-L3. Characterizations of the biologic molecular features contributing to osseous tropism and aggressive tumor biology (as seen in the subset of patients with uniform spread, such as outlier patients with small tumors), have implications for surveillance and are an area of active investigation.
Predicting toxicity-related docetaxel discontinuation and survival in metastatic castration-resistant prostate cancer (mCRPC) using open phase III trial data.
Authors: Parikh Anish B. , Martini Alberto , Sfakianos John , Galsky Matt D. , Oh William K. , Tsao Che-Kai 
Published: February 2020

75 Background: Docetaxel (D) is widely used in mCRPC, however its optimal use remains unclear in the current treatment (tx) landscape. Biomarkers to predict D toxicity may help inform tx selection. Methods: Through Project Data Sphere, we pooled patient (pt) data from the control arms of three frontline mCRPC trials: ASCENT2, VENICE, and MAINSAIL. Tx in each control arm consisted of D 75mg/m2 every 21 days + prednisone 5mg twice/day. The primary outcome was occurrence of toxicity-related D discontinuation (TRDD). Reasons for D discontinuation were recorded and demographic/clinical data were considered in a competing risks regression (CRR) to develop a model to predict TRDD. Cumulative incidence (CI) of TRDD was estimated after accounting for the occurrence of competing events (death or progression). This model was used to build a risk calculator to predict TRDD, the output of which was used in a classification and regression tree (CART) to identify 3 risk groups. Overall survival (OS) for the pooled cohort and for each risk group was assessed via the Kaplan-Meier (KM) method. Results: 1568/1600 pts had complete data and were studied. 41.4% died from any cause during the trials; median follow-up for survivors was 12.1 months (mos). Median OS for the entire cohort was 21 mos. CRR yielded the following significant factors that were included in the predictive model and risk calculator: age, ECOG performance status, AST, bilirubin, use of analgesics, and diagnoses of diabetes and chronic kidney disease. Pooled CI of TRDD was 19% after accounting for competing events (death, 474 pts; progression, 59 pts) within 12 mos of starting tx. CART analysis defined the risk groups as low (model-derived TRDD risk ≤24%), intermediate (25-64%), and high (≥65%). In each risk group, probability of TRDD during tx was 14%, 58%, and 79%, and median OS was 24 mos, 20 mos, and 13 mos, respectively (p<0.001). Conclusions: Tx selection in mCRPC remains a challenge. Our model can help clinicians balance D toxicity and efficacy in order to make better-informed decisions.
Urological malignancy incidence rates over time by county rurality.
Authors: Gadzinski Adam John , Gore John L. , Odisho Anobel Y. , Porten Sima P. , Carroll Peter , Cooperberg Matthew R. 
Published: February 2020

750 Background: Approximately 20% of the U.S. population resides in non-metropolitan (rural) areas. We aimed to evaluate urological cancer incidence among populations residing in metropolitan (metro) and rural counties, categorized by adjacency to a metro area. Methods: Using data from CDC’s National Program of Cancer Registries and NCI’s Surveillance, Epidemiology, and End Results Program, we compared incidence rates of prostate (PCa), kidney (KCa), and bladder (BCa) cancers diagnosed during 2007–2011 and 2012–2016 among adults age ≥ 20 years residing in metro and rural counties, as designated by rural-urban continuum codes. Rural counties were divided into those adjacent to a metro area (Rural-A) and those not adjacent to a metro area (Rural-NA). For the time period studied, these data cover approximately 97% of the US population. Rates were age-adjusted to the 2000 U.S. standard population. Results: We identified 1,980,168 PCa, 541,225 KCa, and 688,562 BCa cases newly diagnosed during 2007–2016. Patients from rural-A counties comprised 11% of all cases, rural-NA counties 6%, and metro counties 83%. Table shows the age-adjusted incidence per 100,000 with 95% confidence intervals. Overall, PCa and BCa incidence decreased over time; KCa incidence increased. PCa exhibited higher incidence rates in metro areas; KCa and BCa had higher incidence rates in rural counties (Table). Conclusions: Rural counties have higher BCa and KCa incidence relative to metro counties, but lower PCa incidence. Changes in PCa screening practices may have contributed to decreases in PCa incidence. Further investigation is needed to understand how rurality influences KCa and BCa epidemiology. Disclaimer: The findings and conclusion of this report are those of the authors and do not represent the official position of the CDC.[Table: see text]