bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nomogram to estimate the activity of second-line therapy for advanced urothelial carcinoma (UC).
Authors: Sonpavde Guru , Pond Gregory Russell , Agarwal Neeraj , Choueiri Toni K. , Qu Angela Q. , Fougeray Ronan , Salhi Yacine , Vaughn David J. , James Nicholas David , Niegisch Guenter , Albers Peter , Galsky Matt D. , Wong Yu-Ning , Stadler Walter Michael , O'Donnell Peter H. , Vogelzang Nicholas J. , Sridhar Srikala S. , Ko Yoo-Joung , Sternberg Cora N. , Bellmunt Joaquim 
Published: March 2020

4524 Background: Prognostic factors may impact on endpoints used in phase II trials of second-line therapy for advanced UC. We aimed to study the impact of prognostic factors (liver metastasis [LM], anemia [Hb<10 g/dl], ECOG-performance status [PS] ≥1, time from prior chemotherapy [TFPC]) on PFS6 and RR. Methods: Twelve phase II trials evaluating second-line chemotherapy and/or biologics (n=748) in patients with progressive disease were pooled. PFS was defined as tumor progression or death from any cause. PFS6 was defined from the date of registration and calculated using the Kaplan-Meier method. RR was defined using RECIST 1.0. A nomogram predicting PFS6 was constructed using the RMS package in R (www.r-project.org). Results: Data regarding progression, Hb, LM, PS and TFPC were available from 570 patients. The mean age was 65.1 years, 45.3% had ECOG-PS ≥1, 30.2% had LM, 14.6% had anemia and TFPC was <6 months (mo) in 60.2%. The overall median PFS was 2.7 mo, PFS6 was 22.2% (95% CI: 18.8-25.9) and RR was 17.5% (95% CI: 14.5%-20.9%). For every unit increase in risk group, the hazard of progression increased by 41% and the odds of response decreased by 48% (Table). A nomogram was constructed to predict PFS6 on an individual patient level. Conclusions: PFS6 and RR vary as a function of prognostic factors in patients receiving second-line therapy for advanced UC. A nomogram incorporating prognostic factors might facilitate the evaluation of activity across phase II trials enrolling heterogeneous populations and can help to select and stratify patients for phase III evaluation of suitable agents. [Table: see text]
Development of a genomic-clinical classifier for predicting progression after radical cystectomy in patients with muscle invasive bladder cancer.
Authors: Mitra Anirban Pradip , Erho Nicholas , Lam Lucia L.C. , Vergara Ismael A. , Sierocinski Thomas , Zimmermann Benedikt , Haddad Zaid , Ghadessi Mercedeh , Crisan Anamaria , Triche Timothy J. , Daneshmand Siamak , Buerki Christine , Davicioni Elai , Black Peter C. 
Published: March 2020

4542 Background: The mainstay of muscle-invasive bladder cancer treatment is surgical resection with/without multi-agent chemotherapy. Management decisions are based on a small number of clinical and pathologic parameters with poor prognostic and predictive power. There is an urgent need for enhanced biomarkers to guide therapy of this lethal disease. Here we have developed a genomic signature of bladder cancer progression using whole transcriptome profiling technology. Methods: 251 FFPE bladder cancer specimens were obtained from patients undergoing radical cystectomy at the University of Southern California (1998-2004). All patients had pT2-T4a,N0 urothelial carcinoma in the absence of pre-operative chemotherapy. Median follow-up was 5 years. RNA expression levels were measured with 1.4 million feature oligonucleotide microarrays. Patients were divided into a training set (2/3 of cohort) to develop a genomic classifier for risk of progression (defined as any type of bladder cancer recurrence), and a validation set (1/3 of cohort). In parallel, multivariable analysis was used to develop a clinical classifier using typical clinical and pathologic variables. Finally, a genomic-clinical classifier was built combining the genomic classifier with clinical variables using logistic regression. The receiver-operator characteristic (ROC) area under the curve (AUC) metric was used to evaluate each classifier in the validation set. Results: The genomic classifier consisted of 89 features corresponding to 80 genes that were combined in a k-nearest neighbor model (KNN89). KNN89 showed an AUC of 0.77 in ROC analysis on the validation set. The best clinical classifier showed an AUC of 0.72. The genomic-clinical classifier demonstrated an AUC of 0.81. Multivariable analysis incorporating all clinical parameters and KNN89 further revealed that KNN89 was the only significant predictor of bladder cancer progression (p=0.0077). Conclusions: We have developed a combined genomic-clinical classifier that shows improved performance over clinical models alone for prediction of progression after radical cystectomy. External validation of this classifier is ongoing.
VHL-mutant renal cell carcinomas contain cancer cells with mesenchymal phenotypes.
Authors: Gedye Craig , Sirskyj Danylo , Lobo Nazleen Carol , Evans Andrew , Fleshner Neil Eric , Robinette Michael , Zlotta Alexandre , Hamilton Robert , Kulkarni Girish S. , Finelli Antonio , Gallie Brenda L. , Jewett Michael A. S. , Ailles Laurie 
Published: March 2020

4568 Background: To study “cancer stem cells” it is imperative to account for all stromal cell populations within the tumour. The existence of “cancer stem cells” in clear cell renal cell carcinoma (ccRCC) has not been examined in ex vivo patient samples. Methods: We established a multiplex flow cytometry (FC) antibody panel in ccRCC, which reliably identified stromal lineages including CD45+ immune, CD31+/CD144+ endothelial and fibroblast-marker-positive subpopulations, thus allowing isolation of "lineage-negative" tumor cells. To verify the identity of tumour-derived populations as either cancer cells or normal stromal cells, we took advantage of the fact that mutations in VHL occur early during ccRCC tumorigenesis and are found in two-thirds of patients. Results: We sequenced 18 patient tumor samples, 12 of which had VHL exome mutations. Targeted re-sequencing of FC sorted subpopulations from these patients’ samples revealed that while CD45+ immune cells and CD31+/CD144+ endothelial cells were genetically normal, a population of VHL-mutant fibroblast-marker positive cells was consistently identified in every patient’s tumour. Immunohistochemistry showed that fibroblast marker-positive VHL-mutant cells do not have the large “clear cell” morphology typical of the majority of the cancer cells in these tumours. When purified and cultured, these fibroblast marker-positive VHL-mutant cells proliferate extensively under mesenchymal culture conditions, but displayed different morphologies to lineage-negative VHL-mutant tumor cells. Functional characterization of these FC sorted cell subpopulations is ongoing, including proliferation, migration, invasion, differentiation and treatment resistance. Conclusions: The phenotype and preliminary functional characterization of these VHL-mutant fibroblast-marker positive cells suggests a mesenchymal differentiation program in ccRCC, with implications for the ontogeny, biology and clinical management of VHL-mutant renal cancer.
Pazopanib (P) and bevacizumab (B) in patients with metastatic renal cell carcinoma (mRCC) or other advanced refractory tumors: Phase I combination study final analysis.
Authors: Negrier Sylvie , Imbs Diane Charlotte , Pérol David , Bahleda Ratislav , Hollebecque Antoine , Boyle Helen Jane , Ferlay Celine , Metzger Severine , Blanc Ellen , Soria Jean-Charles , Escudier Bernard J. , Chatelut Etienne 
Published: March 2020

4574 Background: Since previous experiments of B with VEGFR tyrosine kinase inhibitors showed overlapping and limiting toxicities, a dose-finding study was designed to explore the safety and feasibility of the combination of a recent VEGFR inhibitor P with B in mRCC treatment-naive patients (pts) or in pts with other advanced refractory solid tumors. Methods: This double center trial was conducted with 3+3+3 escalation doses of P + B. The maximum tolerated dose (MTD) was the highest dosage not expected to cause a dose limiting toxicity (DLT) in more than 2/3, 3/6 or finally 3/9 pts, during the first 8 weeks of treatment. After preliminary DLT results, an approved by IDSMB extension cohort was enrolled and treated at MTD level.The effect of B on steady-state pharmacokinetic (PK) of P was also investigated by comparing PK at day 1 (D1) and D15 (day of B infusion). Results: 25 pts were enrolled with mRCC (n=7) or other advanced refractory solid tumors (n=18). Median age is 62 (41-79), 14 pts are male. At DL2 (n=10) 3 nephrectomized and 2 non-nephrectomized pts experienced DLT, as presented in the Table. In the 6-non-nephrectomized-pt extension cohort at DL1, 3 additional DLT were observed. Mean P AUC at D1 was higher than previously described in phase I P monotherapy (Clin Cancer Res 2009;15:4220). Mean P AUC at steady-state (D15) at both P dose levels was also significantly higher, though without being influenced by B infusion. Conclusions: The MTD of the P + B combination is respectively 400 mg/d and 7.5mg/kg (DL1) in all patients. Final PK analysis showed that there is no influence of B on P PK and that P AUC is higher than previously reported. Clinical trial information: NCT01202032. [Table: see text]
Impact of cytoreductive nephrectomy on disease-specific survival (DSS) in the cytokine and targeted therapy eras: Age- and TNM-stage matched analysis of SEER data.
Authors: Nelson Rebecca A. , Vogelzang Nicholas J. , Pal Sumanta Kumar 
Published: March 2020

4579 Background: The role of cytoreductive nephrectomy (CN) for patients with mRCC was well-defined in the cytokine era. However, its role is controversial in the era of targeted therapies. Methods: The Survival, Epidemiology, and End Results (SEER) Database was queried to compare the relative benefit of CN in the cytokine era (defined as 1992-2004) as compared to the targeted therapy era (defined as 2005-2009). Patients with mRCC and clear cell, papillary or chromophobe histology were identified, and divided into cohorts with and without CN. Within each category, patients diagnosed during the cytokine era were matched by age and TNM stage to patients diagnosed during the targeted therapy era. Associations between clinicopathologic characteristics and DSS were explored through univariate and multivariate analyses. Results: Amongst matched pts who had received CN (n=2,218), no significant differences in age, gender, race, histology (clear cell v non-clear cell), T-stage, or N-stage were observed. Median DSS was superior in those patients diagnosed during the targeted therapy era as compared to the cytokine era (22 mos v 17 mos, P<0.0001). On multivariate analysis including the aforementioned clinicopathologic variables and DSS, diagnosis during the targeted therapy era was an independent predictor of improved survival amongst patients who had received CN (HR 0.78, 95%CI 0.70-0.87; P<0.0001). Amongst matched pts who had not received CN (n=4,214), there were no differences in clinicopathologic characteristics. Median DSS was similar in patients diagnosed during the targeted therapy era as compared to the cytokine era within this group (4 mos for each; P=NS). Conclusions: Patients who received CN during the targeted therapy era had a superior DSS as compared to patients who received the procedure during the cytokine era. In contrast, patients who had not received CN had a similar DSS across both time periods. While prospective trials mature (i.e., CARMENA and EORTC 30073), these data support the continued use of CN in the context of targeted agents.
Novel stratification of the recurrence risk following surgical extirpation of clear cell renal cell carcinoma using tissue biomarkers in the mammalian target of rapamycin pathway.
Authors: Krabbe Laura-Maria , Darwish Oussama M , Raj Ganesh , Youssef Ramy F. , Kapur Payal , Bagrodia Aditya , Belsante Michael , Lotan Yair , Margulis Vitaly 
Published: March 2020

4581 Background: Aberrant activation of the mammalian target of rapamycin (mTOR) pathway promotes invasiveness and metastatic potential in a variety of malignancies. The aim of the present study was to evaluate the association of altered expression of mTOR pathway components with recurrence outcome in non-metastatic clear cell renal cell carcinoma (ccRCC) patients. Methods: Immunohistochemistry for phos-S6, phos-mTOR, mTOR, phos-AKT, HIF-1α, RAPTOR, PTEN, PI3K, and phos-4EBP1 was performed on tissue microarrays of patients treated for non-metastatic kidney cancer between 1997-2010. Patients were defined as having a low (<) or high risk (≥) of nomogram predicted recurrence (2001 MSKCC RCC post-op) using an 8% cutoff. The relationship between individual marker expression, as well as combined marker score (low, intermediate and high defined as ≤ 3, 4-5, >5 altered biomarkers; respectively) with the actual and predicted relapse rates was assessed. Results: The study included 419 non- metastatic ccRCC patients (pT1-T2 79.5%, pT3-T4 20.5%, Fuhrman nuclear grade 1-2 in 69%, 3-4 in 31%). 219 and 200 patients had low (<8%) and high (≥8%) nomogram-predicted 5-year risk of recurrence respectively. With a median follow-up of 2.2 years, recurrences were detected in 5 (2.3%) of the predicted low risk and 30 (15%) of the predicted high risk patients. mTOR pathway biomarker profiles were not predictive for patients at low predicted risk of recurrences. For patients at high predicted risk of recurrence, low, intermediate and high combined marker scores were found in 84 (42%), 79 (39.5%), and 37 (18.5%), respectively. The actual rates of recurrence were noted for 8.3% of low, 13.9% of intermediate and 32.4% of high combined marker score in a statistically significant distribution (p=0.027). Conclusions: The cumulative number of aberrantly expressed mTOR biomarkers correlates with a higher rate of recurrence. The combined marker score may help further stratify patients with high nomogram predicted risk of recurrence. Our data supports prospective evaluation of these biomarkers to augment current clinico-pathologic predictors of outcomes in ccRCC.
An exploratory analysis of bone scan lesion area (BSLA), circulating tumor cell (CTC) change, pain reduction, and overall survival (OS) in patients (pts) with castration-resistant prostate cancer (CRPC) treated with cabozantinib (cabo): Updated results of a phase II nonrandomized expansion (NRE) cohort.
Authors: Scher Howard I. , Smith Matthew R. , Sweeney Christopher , Corn Paul Gettys , Logothetis Christopher , Vogelzang Nicholas J. , Smith David C. , Hussain Maha , George Daniel J. , De Bono Johann Sebastian , Higano Celestia S. , Small Eric Jay , Goldin Jonathan , Brown Matthew S. , Aftab Dana T. , Noursalehi Mojtaba , Weitzman Aaron , Basch Ethan M. 
Published: March 2020

5026 Background: The results of 144 pts with metastatic CRPC treated in a phase II NRE cohort with daily cabo 100 mg and 40 mg starting doses have been previously reported. Substantial rates of bone scan improvement, reductions in CTC counts and pain relief were observed. To better understand the implication of these effects, the association with OS was explored. Methods: Relevant baseline variables (LDH, BSLA, visceral disease, pain, hemoglobin, CTCs) and post-treatment changes at week 6: ≥30% reduction in BSLA using computer-aided assessment, CTC conversion (>5 vs. 4 or less/7.5 ml of blood), and pain intensity (7 day averaged worst pain score; BPI scale; using an IVR system) were associated with OS in 144 CRPC pts with bone metastasis who progressed within 6 months of docetaxel (D) treatment (≥225 mg/m2) in either bone or soft tissue. Median OS was compared between responders and non-responders for each of the above outcomes categories using a Cox proportional hazard model. The findings were examined further after adjusting for significant baseline covariates selected from a stepwise Cox regression model. Results: See Table. Conclusions: Recognizing the limitations of associating response with survival, this retrospective analysis of decreases in BSLA, CTC conversions and reductions in pain intensity support further study in ongoing phase III trials. Clinical trial information: NCT00940225. [Table: see text]
Genomic heterogeneity of circulating tumor cells in castration-resistant prostate cancer (CRPC) revealed by single-cell sequencing.
Authors: Welsh Allison , Danila Daniel Costin , Anand Aseem , Kendall Jude , Sawyers Charles L. , Fleisher Martin , Wigler Michael , Hicks James B , Scher Howard I. 
Published: March 2020

5030 Background: Circulating tumor cells (CTC) provide an opportunity to sample multiple metastatic tumor sites through a single blood draw – a ”fluid biopsy.” NextGen DNA sequencing provides the means to obtain detailed genetic information from captured cells prior to and during treatment. Here we demonstrate the use of DNA sequencing to interrogate genome-wide copy number variations (CNV) at the single-cell level in CTC isolated from pts with CRPC. Methods: Pre- and post-treatment blood samples were obtained from pts treated at MSKCC. EpCAM+ events were collected singly and in groups by cytometric flow sorting and were subjected to DNA amplification and Illumina NextGeneration sequencing. Parallel samples were assayed using the Veridex CellSearch method to ensure the presence of malignant cells. Results: Samples with up to 50 EpCAM+ events analyzed in bulk displayed CNV patterns expected from published CRPC data. Subsequent single cell analyses showed that the method could reliably detect common genomic markers in CRPC, including AR amplification, PTEN and RB1 loss, and the TMPRSS-ERG fusion. Individual genomic CNV profiles obtained from 125 single cells isolated from 15 patients were then analyzed. Using unsupervised clustering, cells from each pt showed a closely related lineage structure, consistent with an evolution from a common ancestor. The degree of genomic heterogeneity within CTC from an individual pt was highly variable, with R2 correlation coefficients ranging from >0.92 (nearly homogeneous) to <0.75 (mixed populations). Two pts harbored separate subpopulations with both amplified AR and non-amplified AR cells and another displayed mixtures of genetic markers that changed over the course of treatment. Conclusions: The observed variation in complexity of CTC populations in CRPC pts underscores the importance of being able to sample and analyze multiple cells from an individual pt on multiple occasions and with real time analytics. Doing so is essential to understand and identify mechanisms of resistance so that they can be targeted effectively. Supported by STARR Cancer Consortium, NCI SPORE in Prostate Cancer; Department of Defense; Prostate Cancer Foundation.
Prostate-specific mRNA detection in whole blood as an analytically validated prognostic biomarker for patients with castration-resistant prostate cancer (CRPC).
Authors: Anand Aseem , Danila Daniel Costin , Heller Glenn , Herkal Amrita , Patel Chintan , Khanin Raya , Schultz Nikolaus , Lilja Hans , Fleisher Martin , Scher Howard I. 
Published: March 2020

5032 Background: Detection of prostate-specific transcripts in blood has been associated with survival, but validated assays are lacking. We analytically validated a qPCR-based assay in CLIA environment to detect prostate cancer enhanced transcripts in whole blood and determine its prognostic significance relative to circulating tumor cell (CTC) enumeration. Methods: Blood was collected from patients with progressive CRPC in PAXgene tubes for total RNA extraction. Five genes overexpressed in prostate tissue, KLK3, KLK2, HOXB13, GRHL2, and FOXA1, were analyzed by RT-qPCR. Each qPCR-reaction was performed in 6 replicates and detection thresholds for each gene were chosen by receiver operator curve analysis. Detection rates were compared to enumeration using CellSearch in an independent data set of 97 CRPC patients and survival associations explored by concordance probability estimate (CPE). Results: Two or more genes were detected by qPCR in 53% (51 of 97, 95% CI 43-63%) of patients, and unfavorable CTC counts (≥5cells) were seen in 46% (45 of 97, 95% CI 36–56%). Transcripts were detectable in 21% (11 of 52, 95% CI 8–35%) of patients with favorable CTC counts (≤4). Similar to CTC enumeration, transcript detection predicted overall survival in a proportional hazards model. The predictive accuracy of qPCR detection in combination with CTC enumeration had a CPE of 0.752 (SE=0.038). Conclusions: This validated RT-qPCR assay detects prostate-specific mRNA in whole blood in more patients than CellSearch, is prognostic for survival, and may assess patient risk in conjunction with CTC enumeration. Its clinical utility will be prospectively explored. Supported by NCI SPORE in Prostate Cancer (P50 CA92629); the Department of Defense Prostate Cancer Research Program; Prostate Cancer Foundation; Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Experimental Therapeutics Center; DoD Prostate Cancer Research Program Physician Research Award W81XWH-09-1-0307.
Validation of a genomic classifier that predicts metastatic disease progression in men with biochemical recurrence post radical prostatectomy.
Authors: Ross Ashley E. , Ghadessi Mercedeh , Davicioni Elai , Crisan Anamaria , Buerki Christine , Erho Nicholas , Mitra Anirban Pradip , Thompson Darby J. S. , Triche Timothy J. , Feng Felix Yi-Chung , Schaeffer Edward M. 
Published: March 2020

5033 Background: Almost 50,000 men per year will present with biochemical recurrence (BCR) following local treatment for prostate cancer. These men with rising PSAs as the lone indicator of recurrence present a management dilemma due to their varied outcomes with only a proportion developing subsequent metastatic disease. Thus, there is a clear need to improve patient risk stratification in this context. Here, we evaluate Decipher, a genomic classifier (GC) in men with BCR following radical prostatectomy (RP) for its ability to predict metastasis. Methods: The 22-marker GC was validated in a prospectively designed case-cohort study of 1,010 clinically high-risk RP patients. 219 patients, including 85 who developed BCR at least 6 months post-RP were subjected to microarray analysis and GC scores were generated. Survival ROC curves, weighted Cox proportional hazards, and decision curves were used to compare the performance of the GC to Gleason score (GS), PSA doubling time (PSAdT) and time to BCR (ttBCR). Results: GC scores significantly stratified these men into those who would or would not develop metastasis after BCR (8% versus 40% of patients developed metastasis at 3 years following BCR depending on GC score category, p<0.001). The AUC for GC was 0.82 (95% CI, 0.76-0.86), compared to that of GS 0.64 (0.58-0.70), PSAdT 0.69 (0.61-0.77) and ttBCR 0.52 (0.46-0.59). In decision curve analysis, the GC had the highest overall ‘net benefit’ and in multivariable modeling with clinicopathologic variables, only GC (p=0.006) and GS (p=0.046) scores were significant predictors of metastasis. Conclusions: When compared to clinicopathologic variables, the GC better predicted metastatic progression among men with BCR following RP. While confirmatory studies in additional patient populations are required, these results suggest that use of the GC can allow for better selection of men requiring additional treatment at the time of BCR.