bluuebunny/crossref_metadata_2025_split huggingface dataset:
Meta-analysis of randomized control trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors.
Authors: Richards Christopher J. , Je Youjin , Schutz Fabio A. B. , Choueiri Toni K. 
Published: February 2017

349 Background: Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have become the cornerstone in the treatment of several malignancies. These drugs have also been associated with an increase in the risk of potentially life-threatening adverse events, such as arterial thrombotic events, bleeding, congestive heart failure, and others. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in patients with cancer treated with VEGFR TKIs. Methods: MEDLINE and PubMed databases were searched for articles published from January 1966 to February 2011. Eligible studies were limited to trials of US Food and Drug Administration– approved VEGFR TKIs (pazopanib, sunitinib, and sorafenib) that reported on patients with cancer with any primary tumor type, randomized design, and adequate safety profile. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% CIs by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: In all, 4,679 patients from 10 randomized controlled trials (RCTs) were included, with 2,856 from sorafenib, 1,388 from sunitinib, and 435 from pazopanib trials. The incidence of FAEs related to VEGFR TKIs was 1.5% (95% CI, 0.8% to 2.4%) with an RR of 2.23 (95% CI, 1.12 to 4.44; P .023) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between different VEGFR TKIs or tumor types. No evidence of publication bias was observed. Conclusions: In a meta-analysis of RCTs, the use of VEGFR TKIs was associated with an increased risk of FAEs compared with control patients.
Conditional survival (CS) for patients with metastatic renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy (TT): Results from the International mRCC Database Consortium.
Authors: Choueiri Toni K. , Xie Wanling , Harshman Lauren Christine , Bjarnason Georg A. , Knox Jennifer J. , MacKenzie Mary J. , Wood Lori , Vaishampayan Ulka N. , Tan Min-Han , Rha Sun Young , Donskov Frede , Agarwal Neeraj , Kollmannsberger Christian K. , North Scott A. , Rini Brian I. , Heng Daniel Yick Chin 
Published: February 2017

358 Background: Survival estimates for patients with mRCC are traditionally reported from the time of TT initiation. These survival projections, however, may not be applicable to patients who have already survived a period of time after initiating therapy. CS accounts for elapsed time since starting therapy, providing more relevant prognostic information. Methods: Data on 1673 patients treated with first-line VEGF TT between 4/7/2003 and 10/12/2010 was analyzed. Median follow up for patients still alive is 20.1 months. Conditioned survival was calculated on the set of patients alive or on TT at 3 months and using 3 months increments for up to 18 months. Results: The 2-year CS probability tends to slightly improve from 44 to 51% when conditioned on having already survived 0 to18 months since initiation of TT, respectively. The Heng et al (JCO 2009) risk criteria (defined at therapy initiation) retains prognostic ability over time independent of previous survival time or previous time on TT up to 18 months (p<0.0001 for all comparisons). In the subgroup analysis stratified by Heng risk groups, 2-year CS minimally changes over time in the favorable (FAV) and in the intermediate (INT) groups, but in the poor risk group, the 2-year CS improves from 11% initially to 33% after 18 months. When conditioned on time on TT, 2-year CS improves from 44% to 68% overall, from 74% to 90% in the FAV risk group, 49% to 57% in the INT risk group and 11% to 73% in the poor-risk group. Conclusions: Conditional survival may be a more relevant measure of prognosis for those who have already survived or have been on TT for a period of time. The largest improvement was seen in patients in the poor risk group. [Table: see text]
Cytoreductive nephrectomy in the United States: Patterns of care and patient characteristics.
Authors: Tsao Che-Kai , Moshier Erin , Small Alexander C. , Sonpavde Guru , Godbold James , Oh William K. , Galsky Matt D. 
Published: February 2017

366 Background: Two randomized trials published in 2001 established cytoreductive nephrectomy (CyNx) for patients (pts) with metastatic renal carcinoma (mRCC) as a treatment standard in the cytokine era (Flanigan, J Urol, 2004). However, first-line systemic therapy for mRCC changed in 2005 with FDA approval of VEGFR tyrosine kinase inhibitor (TKIs). We evaluated the patterns of use of CyNx in the pre- and post-TKI era and characteristics of pts undergoing CyNx. Methods: The National Cancer Database was queried for pts diagnosed with mRCC between 2000 and 2008. Pts who underwent CyNx were identified and were further categorized by pre- versus post-TKI era (2000–2006 vs. 2006–2008), race, insurance status, and hospital. For these subcategories, prevalence ratios (PR) were generated using the proportion of pts with mRCC undergoing CyNx versus those not undergoing CyNx. Results: Of the 47,417 patients (pts) with mRCC diagnosed between 2000 and 2008, 25,616 pts (54%) did not undergo CyNx. The prevalence of cytoreductive nephrectomy increased 3% each year from 2000 to 2006 (p<0.0001), then decreased 3% each year from 2006 to 2008 (p=0.0048), with a significant difference between the pre- and post-2006 PR (0.97 versus 1.025; p<0.0001). Blacks (PR 1.17) and Hispanics (PR 1.05) were significantly more likely than Caucasian to not undergo CyNx (p<0.008). Pts with Medicaid (PR 1.25), Medicare (PR 1.40), and no insurance (PR 1.42) were significantly more likely than pts with private insurance to not undergo CyNx (p<0.0001). Pts diagnosed at community hospitals (PR 1.29) were significantly more likely than pts at teaching hospitals to not undergo CyNx (p <0.0001). Conclusions: The use of CyNx has declined in the post-TKI era. In addition, racial and socioeconomic disparities exist in the use of CyNx. The results of pending randomized trials evaluating the role of CyNx in the post-TKI era are awaited to optimize use of this modality.
Results of a high-throughput screen to identify compounds that modulate VHL proteostasis.
Authors: Ding Zhiyong , German Peter , Bai Shanshan , Gao Meng , Sobieski Mary M. , Stephan Clifford C. , Mills Gordon B. , Jonasch Eric 
Published: February 2017

369 Background: Mutated von Hippel Lindau (VHL) protein causes disease in sporadic renal cell carcinoma (RCC), and in the eponymous hereditary VHL disease. We developed and tested a cell-based screening tool to identify compounds that stabilize or upregulate full-length, point mutated VHL, and potentially reverse the disease phenotype. Methods: The 786-0 cell line was infected with full-length W117A mutated VHL linked to a C-terminal Venus fluorescent protein. This VHL-W117A-Venus line was used to screen the Prestwick drug library and was tested against the known proteasome inhibitors MG132 and bortezomib. Western blot validation and evaluation of downstream functional readouts, including HIF and GLUT1 levels, were performed. Results: The proteasome inhibitors bortezomib and MG132, and the Prestwick compounds 8-azaguanine, thiostrepton and thioguanosine were found to reliably upregulate VHL-W117A-Venus in 786-0 cells. Thiostrepton has also been recognized as having proteasome inhibitory effects. 8-azaguanine was found to downregulate HIF2α levels, and was augmented by the presence of VHL W117A. VHL p30 band intensities varied as a function of compound used, suggesting alternate post-translational processing. In addition, nuclear-cytoplasmic localization of pVHL varied amongst the different compounds, additionally suggesting unique effects of each of the agents on VHL homeostasis. Conclusions: We have successfully identified compounds that stabilize mutated VHL, including several proteasome inhibitors. It is possible that proteasome inhibition will have a specific clinical effect on patients with point-mutated pVHL. Further work is currently underway to further test this hypothesis in animal xenograft studies using cell lines containing various mutated VHL isoforms, and clinical trials using next-generation proteasome inhibitors are being explored.
CpG-island methylation of GATA-family members GATA3 and GATA5 in renal cell carcinoma and association with clinicopathological parameters and progression-free survival.
Authors: Peters Inga , Gebauer Kai , Atschekzei Faranaz , Hennenlotter Joerg , Kramer Mario W. , Traenkenschuh Wolfgang , Merseburger Axel S. , Kuczyk Markus , Serth Juergen 
Published: February 2017

370 Background: Transcriptional inactivation and CGI methylation of GATA3 and −5 has been reported to be involved in mammary carcinoma, pancreatic cancer, colorectal and gastric carcinogenesis. A recent study demonstrated that a loss of GATA-3 expression due to partially methylation silencing in several renal cell carcinoma (RCC) patients. We quantitatively investigated GATA3 and −5 CGI methylation in RCC and analyzed its association with clinical characteristics as well as progression free survival of patients. Methods: Methylation data were obtained from a quantitative methylation-specific polymerase chain reaction assay (QMSP) for both genes. We investigated 108 RCC and 77 paired tissue samples as well as six RCC cell lines. Statistical analyses were carried out using the paired t-test for matched tumor (TU) and adjacent normal (adN) samples, logistic regression for comparisons of independent samples and cox regression for survival analysis. Results: In paired samples we found a significant higher methylation in TU compared to adN for GATA3 (P=0.007) and for GATA5 (P=3.6*10−9) for all RCCs. GATA5 showed also strong correlations between methylation and status of metastasis (P=0.05) and advanced (pT≥3 and/or N+, M+) tumor samples compared to localized (pT≤2, N0, M0) tumors (P=4.7*10−9). A decreased progression free survival in cox proportional hazard model analysis could be demonstrated for patients with a high GATA5 methylation (P=0.0006, HR=6.5) and a trend could also be seen for GATA3 methylated patients (P=0.06). Conclusions: GATA3 and −5 were identified to demonstrate tumor-specific CGI hypermethylation in renal cell cancer patients. The association of GATA5 CGI methylation with metastasis, advanced disease and progression free survival of patients indicates that epigenetic alterations of both genes are involved in renal cell carcinogenesis. GATA5 methylation could serve as a biomarker for tumor progression. Further prospective and functional investigations are necessary to clarify whether CGI methylation of GATA family members can provide independent information for future clinical management of patients with RCC.
Long-term survival in patients with metastatic renal cell carcinoma (mRCC) in the era of new targeted therapies: Five-year follow-up in a single Spanish medical institution (Genito-Urinary Tumor Unit, University Hospital 12 de Octubre).
Authors: de Velasco Oria G , Sepulveda J , Villacampa F , Ghanem I , Castellano Daniel E. 
Published: February 2017

376 Background: Recently, new targeted therapies have proved the efficacy in patients with mRCC in terms of progression-free survival (PFS) and overall survival (OS). There is also growing evidence that successive targeted treatments has achieved objective responses and sustained time to progression. Here, we report data from our insitution analysing the OS benefit of continuing targeted therapy after disease progression. Methods: We identified 58 metastatic clear cell RCC patients who started targeted therapy between September 2005 and December 2008. The data were collected from our clinical trials registry. The patients were evaluated for differences in baseline characteristics and known prognostic factors (PFs) in metastatic RCC. We assessed overall survival for all patients. Results: We identified 58 pts, 24 are still alive (43%). Median age was 56 (range 31–78). ECOG PS 0/1/2: 33/24/1. 46% (27) had diagnosis to treatment intervals < 1 year. Sites of metastatic disease included: lung 46%(26), bone 32%(19), hepatic 29%(17) and retroperitoneal 24%(14). Nephrectomy was pesented in 90% of all pts. The number of metastases location was: 1/2/3: 32%/11%/7%. The drugs administered are listed in table. Median number of treatments: 3 (range 1–7). The median overall survival (OS) was 44 months and the 3- year OS was 60.4%. Pts by MSKCC risk-group were: favourable prognostic (FP) 19%, intermediate prognostic (IP) 63%, poor prognostic (PP) 18%. The overall survival for FP group was not reached, and 3-year OS was 81%; for IP group the median survival time was 44 months and 3-year OS was 59%; and for PP group the median survival time was 25 months. Conclusions: The survival for patients with mRCC who receive multiple lines of targeted therapy has increased to close to 4 years. These results indicate a clear shift in the evolution of mRCC but lack a great deal about what the best sequence. Final analysis of the best sequence of treatment will be presented at the meeting. [Table: see text]
External validation of the Glasgow prognostic score (mGPS) for renal cancer.
Authors: Master Viraj A. , Johnson Timothy V. , Kucuk Omer , Canter Daniel , Pattaras John , Ogan Ken , Cross Brian , Nieh Peter T , Harris Wayne 
Published: February 2017

378 Background: Inflammation has been termed the 7th hallmark of cancer (Hanahan and Weinberg Cell 2011). Measurement of systemic inflammatory responses in malignancy is possible using a selective combination of two commonly available, cost-effective serum assays. The combination of these two serum markers, C-reactive protein (CRP) and albumin, is termed the modified Glasgow prognostic score (mGPS), and is strongly correlated with outcome in a variety of cancers, including mRCC. Recently, mGPS has been shown to be predictive of outcome in localized RCC (ASCO GU 2010 #390). We sought to externally validate these results. Methods: Nephrectomized patients with clinically localized (T1-T4N0M0) clear cell RCC with negative surgical margins were followed for a mean of 25 months (range: 1-81 months). Relapse and survival was identified through routine follow-up. Patients were categorized by mGPS score as Low Risk (mGPS = 0 points), Intermediate Risk (mGPS = 1 point), and High Risk (mGPS = 2 points). One point was assigned to patients for an elevated CRP (>10 mg/L) and hypoalbuminemia (<3.5 mg/dL). Patients with normal CRP and hypoalbuminemia were assigned 0 points. Kaplan-Meier and multivariate Cox regression analyses examined relapse-free survival (RFS) and overall survival (OS) across patient and disease characteristics. Results: Of 248 patients, 17.9% relapsed and 18.6% died. Of Low, Intermediate, and High Risk patients, 7.2%, 7.7%, and 45.5%, respectively relapsed and 5.2%, 15.4%, and 39.4%, respectively died during the study. In multivariate analysis including stage and grade, mGPS was significantly associated with RFS and OS. Compared to Low-Risk patients, High-Risk patients experienced a 3-fold (OR: 2.906, 95% CI: 1.055-8.001) increased risk of relapse and 4-fold (HR: 3.722, 95% CI: 1.046-13.245) increased risk of mortality. AUC is 0.813, which compares very favorably to existing prognostic algorithms. Conclusions: In this external validation cohort of US patients, mGPS continues to be a predictor of relapse and overall mortality following nephrectomy for localized RCC. Clinicians may consider using mGPS as an adjunct to identify high-risk patients for possible enrollment into clinical trials, or for patient counseling.
The role of tumor vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) polymorphisms in the prediction of clinical outcome for patients with advanced renal cell carcinoma receiving first-line sunitinib.
Authors: Bianconi Maristella , Scartozzi Mario , Faloppi Luca , Giampieri Riccardo , Maccaroni Elena , Bittoni Alessandro , Del Prete Michela , Loretelli Cristian , Belvederesi Laura , Conti Alessandro , Minardi Daniele , Burattini Luciano , Montironi Rodolfo , Cascinu Stefano 
Published: February 2017

380 Background: Metastatic renal cell carcinoma (mRCC) still represents a medical challenge in cancer therapy. In recent years the introduction of new targeted therapies has radically changed the approach to the disease and patients outcome. Currently the therapeutic strongholds are TKIs directed against the VEGF family. The aim of our study is to evaluate the potential predictive and prognostic role of VEGF and VEGFR polymorphisms, in determining the clinical outcome of mRCC patients receiving first-line sunitinib. Methods: 41 histologic samples (biopsies and surgical specimens) of mRCC patients were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients progression free survival (PFS) and overall survival (OS) were analyzed for first line treatment. Results: VEGF AIV rs833061 C>T polymorphism was statistically significant in PFS (17 months for C vs 4 months for T; P = 0.0029) and OS (35.93 months for C vs 11 months for T; P = 0.0267). VEGF AV rs699947 A>C was statistically significant for PFS (17 months for A vs 3.97 months for C; P = 0.0023) and OS (35.93 months for A vs 10.98 for C; P = 0.0272). VEGF AVI rs2010963 G>C was significant in PFS (16.98 months for G vs 4.65 for G/C vs 2.73 for C; P = 0.0188). VEGR3 III rs6877011 C>G was significant in PFS (8.22 months for C vs 2.22 for C/G; P = 0.0361) and OS (35.93 months for C vs 12.08 for C/G; P = 0.0183). Conclusions: In our analysis patients with C polymorphism of rc833061 , A polymorphism rs699947 and G polymorphism of rs2010963 seem to have a better PFS and OS in first line. These polymorphisms of the VEGF-A gene are probably connected with a better control of the neoangiogenesis process during TKIs therapy, maybe leading to vasculature normalization. Patients with C polymorphism of rs6877011 seem equally to have a favourable impact in first line therapy. VEGFR-3 role is still matter of debate but seems to be involved in vessels sprouting and architecture.
Can we predict malignancy in Bosniak III renal lesions identified on multiphasic CT scan?
Authors: Klink Joseph C. , Goenka Ajit H. , Remer Erick M. , Smith Andrew D. , Obuchowski Nancy A. , Campbell Steven C. 
Published: February 2017

381 Background: To identify independent predictors of malignancy in Bosniak III (BIII) renal lesions and to build a prediction model based only on readily identifiable clinical and imaging variables. Methods: In this IRB-approved retrospective study, radiology and hospital information systems were interrogated for BIII lesions in CT reports from January 1, 1994 to August 31, 2009. Patients with histopathology available were included. The following variables were recorded: age, gender, body mass index (BMI), race, symptoms at presentation, smoking history and history of renal cell carcinoma (RCC), presence of a co-existent BIII or BIV lesion. Univariate analyses were first performed using logistic regression analysis with generalized estimating equations and an exchangeable working correlation matrix to test each variable. Factors with univariate p-values <0.20 were considered in the multiple-variable analysis. The main effects of the factors were first evaluated. For the main effects with p-values <0.10, two-way interactions were assessed. Interactions with p-values <0.05 were included in the final model along with their main effects. The c-index was used to test accuracy of the models. Final model was chosen based on its parsimony and accuracy. Results: Mean patient age was 58 years (range 27–80). There were 51 females and 50 males. Of the 107 BIII lesions in 101 patients (6 patients had two lesions each), 59 (55%) were malignant and 48 (45%) were benign. The strongest predictors of malignancy were race (p=0.04), history of RCC (p=0.03), co-existing III (p=0.03) or IV lesion (p=0.10) and BMI (p=0.10). In multiple-variable analysis, a history of RCC was the strongest independent predictor of malignancy (OR 12.7, 95% CI 1.8– 91, p=0.01) followed by BMI (OR 1.1, 95% CI 0.99–1.20, p=0.08). No other main effects or interactions had p-values <0.10. The model with these two predictors had an accuracy of 0.68. At >90% probability of malignancy, the model has a 77% sensitivity and 61% positive predictive value. Conclusions: Clinical and imaging variables provide significant ability to predict malignancy for BIII renal lesions. A model encompassing history of RCC and BMI appears promising but merits refinement on an independent dataset.
Long-term durable oncologic outcomes after radiofrequency ablation for T1 renal cell carcinoma.
Authors: Psutka Sarah P. , McGovern Francis J. , Mueller Peter , McDougal W. Scott , Gervais Debra , Feldman Adam S. 
Published: February 2017

384 Background: Long-term oncologic outcomes for radiofrequency ablation (RFA) of renal cell carcinoma (RCC) are limited. The objective of this study was to assess the long-term oncological efficacy of RFA for treatment of renal cell carcinoma. Methods: Between 1998 and 2008, 311 biopsy-proven RCC were treated with RFA in 274 patients. Exclusion criteria included history of prior RCC or known metastatic RCC at time of RFA (n=92). 26 patients were lost to follow-up prior to their 6-month imaging study. We retrospectively reviewed the long-term oncologic outcomes for 193 patients. Mean follow-up was 4.6 yrs (range 1–12, SD 2.3). Results: Median age was 71 years (IQR: 63 –79 years). Median Charlson Score was 5.46 (IQR: 5–6). Median size of tumor treated was 3 cm (IQR: 2–3.9 cm, range 1–7.1cm) and 64 of these tumors (33%) were endophytic. Tumor breakdown by stage was T1a: n=153 (79%), T1b: n=37 (19%), and T2: n=3 (2%). Initial treatment success rate was 89%. There were 6 local recurrences (3%) in 4 patients with T1b disease and 2 patients with T2 disease with an average time-to-recurrence of 2.9 years (SD 0.7). 95% of patients with T1a RCC were disease free at last follow-up, in comparison to 81% of those with T1b and 33% of those with T2 disease (p=0.008). At last follow-up 178 (92%) patients were disease-free. 16 (8.2%) developed metastatic disease and 4 patients (2%) died of RCC. Mean disease-free survival was 4.3 years (SD 2.4). Conclusions: In patients who are poor surgical candidates, RFA results in durable local control and a low risk of disease recurrence in T1 RCC. Higher stage, however, correlates with a decreased disease free survival and alternate treatments should be considered when counseling these patients.