bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes, complications, and costs of care of Bosniak IIF, III, and IV cystic renal lesions/malignancies: Data from the largest multi-institutional study to date.
Authors: Smith Andrew D. , Allen Brian , Sanyal Rupan , Zhang Haowei , Carson Daniel , Zhang Xu 
Published: February 2017

344 Background: To evaluate outcomes, complications and costs associated with management of Bosniak IIF, III, and IV cystic renal lesions/malignancies. Methods: An IRB-approved HIPAA-compliant multi-institutional retrospective data registry of prospectively classified Bosniak IIF (N=143), III (N=114), and IV (N=29) cystic renal lesions diagnosed in adults between January 2000 and October 2011 at UMMC, UAB, or WFUBMC was performed. Included patients were managed by surgical excision (N=86), ablation (N=19), or imaging-surveillance >1yr (N=181). De-identified coded data was entered into a web-based REDCap database containing 168 fields/patient. Complication severity was assessed using the Clavien classification system. Inpatient/outpatient technical/professional charges from 6 months prior to 6 months after surgery or ablation were gathered. Results: Patient level malignancy on surgical pathology was 38% (3/8) for BIIF, 40% (26/65) for BIII, and 89% (17/19) for BIV lesions. No metastatic BIIF lesions (0/143). One metastatic BIII lesion (1/114) developed after thermal ablation in a patient with a prior history of papillary RCC. One metastatic BIV (1/29) at the time of initial diagnosis (necrotic papillary RCC). Moderate/severe complications in 19%(16/86) of surgical and 5%(1/19) of ablative patients (p = 0.299). 0%(0/181) complications in patients managed by imaging surveillance >1yr. 0%(0/286) deaths for any management strategy. Median charges of $51,902 for partial nephrectomy (N=50), $42,411 for complete nephrectomy (N=36), and $22,442 for ablation (N=19) were significantly different (p < 0.001). Median charges in surgical patients with moderate/severe complications was $80,393 (N=16), significantly higher than $45,024 (N=70) for no/mild complications (p = 0.002). Conclusions: No deaths from Bosniak IIF or III lesions, irrespective of management approach. Imaging surveillance appears to be a safe primary management strategy for Bosniak III lesions. Moderate/severe complications occurred in 19% of surgery and 5% of ablation patients and nearly doubled the charges for surgery.
Overall survival results from a phase III study of tivozanib hydrochloride versus sorafenib in patients with renal cell carcinoma.
Authors: Motzer Robert John , Eisen Timothy , Hutson Thomas E. , Szczylik Cezary , Krygowski Mizue , Strahs Andrew Louis , Esteves Brooke , Krivoshik Andrew P. , Berkenblit Anna , Nosov Dmitry 
Published: February 2017

350 Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor targeting all three vascular endothelial growth factor receptors, with a long half-life. Tivozanib has shown tolerability and superior progression-free survival and overall response rate versus sorafenib in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma. Final overall survival (OS) data (August 27, 2012) from TIVO-1 and its open-label, multicenter extension study are reported. Methods: A total of 517 patients were randomized 1:1 to tivozanib 1.5 mg/d (3 weeks on, 1 week off) or sorafenib 400 mg/d (twice a day, continuously) (J Clin Oncol2012;30[suppl]:Abstract 4501). In the extension study, patients who progressed (PD) on sorafenib based on investigator assessment were eligible to receive tivozanib, and patients with PD on tivozanib received subsequent treatment according to regional standards of care. Final OS analysis was planned to be conducted after all patients had died or were lost to follow-up, or when all patients in follow-up had been on study for at least 2 years, whichever occurred first. OS was compared using the stratified log-rank test. OS distribution was estimated using the Kaplan-Meier method. Hazard ratio (HR) was estimated using the Cox proportional hazard regression model. Results: At the time of final OS analysis (2 years after last patient was enrolled), 219 deaths had occurred (tivozanib, n=118 [45.4%]; sorafenib, n=101 [39.3%]) (stratified HR=1.245; 95% confidence interval [CI] 0.954–1.624; p=0.105), trending in favor of the sorafenib arm. Median OS (95% CI) was 28.8 months (22.5–NA) for tivozanib and 29.3 months (29.3–NA) for sorafenib. Of the 257 patients on sorafenib, 155 (60.3%) had started next-line tivozanib at the time of the analysis. Conclusions: There was no significant difference in OS between the two treatment arms. The high rate of utilization of second-line tivozanib in patients following PD on sorafenib may have affected the OS outcome. Clinical trial information: NCT01030783.
Relationship between biomarkers and everolimus efficacy in the phase III RECORD-1 trial of patients with metastatic renal cell carcinoma (mRCC).
Authors: Oudard Stephane , Escudier Bernard J. , Thompson John A. , Grünwald Viktor , Masini Cristina , Bracarda Sergio , Panneerselvam Ashok , Gogov Sven , Chen David , Motzer Robert John 
Published: February 2017

352 Background: Compared with placebo, everolimus provided significant improvement in median PFS in the RECORD-1 study of VEGFr-TKI-refractory mRCC. To investigate the role of angiogenesis pathway molecules as potential biomarkers of everolimus efficacy in RECORD-1, plasma levels of sVEGFR-2, VEGF-A, and bFGF were estimated. Methods: In addition to best supportive care, patients received everolimus 10 mg/day (n = 277) or placebo (n = 139). Placebo patients who progressed were offered everolimus. Predose blood samples were collected on day 1 of the first four 28-day treatment cycles. Plasma levels of sVEGFR-2, VEGF-A, and bFGF were assessed by ELISA. Effect of treatment over time on each biomarker was assessed by a mixed effects model. Hazard ratios (HR) for prognostic effects were obtained using log baseline biomarker values as continuous variables in a stratified Cox proportional hazards model. Results: Plasma levels of sVEGFR-2, VEGF-A, and bFGF were available for 45%, 45%, and 39% of everolimus patients and 50%, 50%, and 45% of placebo patients. Patients with biomarker data had baseline characteristics similar to those of the overall population. Mean baseline levels (pg/mL) of sVEGFR-2, VEGF-A, and bFGF were similar for everolimus (8945, 245, and 8, respectively) and placebo (8985, 253, and 13, respectively). Everolimus significantly improved median PFS over placebo irrespective of baseline levels of the analyzed biomarkers (p < 0.001), indicating they are not predictive of everolimus efficacy. Prolonged PFS in the biomarker population was associated with lower VEGF-A baseline level (HR, 1.27; 95% CI, 1.03-1.57; p = 0.028), suggesting VEGF-A may be prognostic for mRCC. Compared with placebo, everolimus significantly reduced bFGF (p = 0.0095) and sVEGFR-2 (p< 0.001) levels over the time course of the study; no effect on VEGF-A levels was observed. Conclusions: Everolimus significantly improved PFS compared with placebo, regardless of baseline biomarker levels. Lower VEGF-A levels may be a potential prognostic factor for longer PFS. Everolimus treatment significantly downregulated plasma levels of bFGF and sVEGFR-2 from baseline. Clinical trial information: NCT00410124.
Relationship of hypoxia signature with variant subgroup of clear cell renal cell carcinoma (ccRCC) and its association with clinical activity on tivozanib hydrochloride.
Authors: Robinson Murray Owen , Feng Bin , Nicoletti Richard , Berkenblit Anna , Strahs Andrew Louis , Esteves Brooke , Eisen Timothy , Motzer Robert John 
Published: February 2017

361 Background: TIVO-1, a randomized Phase III trial in first-line targeted therapy for patients (pts) with ccRCC, demonstrated significant improvement in progression-free survival (PFS) in pts receiving tivozanib hydrochloride (T) vs. sorafenib (S) (11.9 vs. 9.1 months [12.7 vs. 9.1 in treatment-naïve pts]). To further characterize molecular ccRCC subtypes and assess relationships between subtypes and vascular endothelial growth factor tyrosine kinase inhibitor activity, we characterized available molecularly annotated datasets from TIVO-1. Methods: Tumor subtypes were established using hierarchical clustering and evaluated in two microarray ccRCC datasets using gene set enrichment analysis with 51 signatures representing a set of molecular phenotypes. A 9-gene signature comprising genes associated with hypoxia-inducible factor (HIF) transcription was quantified by RT-PCR on all available (69/517) formalin-fixed, paraffin-embedded material from patients using a predefined classifier score and cutoff. Results: Hierachical clustering generated 3 distinct tumor classes. Molecular clusters defining HIF gene expression (low), endothelial cell content (low), extracellular matrix (low), proliferation (high) epithelial cell phenotype (high), and metabolism (high) were differentially expressed in cluster 3 tumors, which represented approximately 15% of the populations. Based on predefined analysis, the hypoxia signature was significantly associated with better PFS on T using a previously established classifier (Table). The hypoxia signature was not significantly associated with PFS on S. There was no significant correlation to single largest diameter for either agent. Conclusions: A novel molecular subtype of ccRCC is characterized by a distinct molecular profile and can be classified by a low hypoxia signature. This hypoxia gene signature may help identify T responders. This signature is seen in subsets of other solid tumors supporting the broad exploration of this candidate T response biomarker. Clinical trial information: NCT01030783. [Table: see text]
Outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with pazopanib after progression on other targeted therapies (TT): Updated results.
Authors: Matrana Marc Ryan , Duran Cihan , Shetty Aditya , Xiao Lianchun , Atkinson Bradley J. , Corn Paul G. , Charnsangavej Chusilp , Jonasch Eric , Tannir Nizar M. 
Published: February 2017

367 Background: Pazopanib is an multi-tyrosine kinase inhibitor shown to prolong progression-free survival (PFS) compared to placebo in treatment-naive and cytokine-refractory mRCC. Outcomes and safety on its use after TT are limited. Methods: We retrospectively reviewed records of consecutive pts with mRCC who were treated with pazopanib between November 2009-November 2011 after having progressive disease (PD) with other TT. Radiographic response was assessed by a blinded radiologist using RECIST v1.1 criteria. PFS and overall survival (OS) were estimated by the Kaplan-Meier method. Hazard ratios (HR) were estimated by fitting univariable and multivariable Cox proportional hazards models to evaluate the association of PFS with patient co-variates. Results: 112 pts (median age 63 years, 67% male, 83% clear cell) met inclusion criteria. Median number of previous TT was 2 (range 1-5). 85 events (PD or death) occurred. 14 pts (12.5%) had a partial response. Median PFS was 5.7 months (95% CI: 4.3-8.9 months). PFS was significantly associated with male gender (HR=0.55; 95% CI: 0.34-0.87; p=0.011), clear-cell histology (HR=0.42; 95% CI: 0.24-0.74; p=0.0031), number of metastatic sites (HR= 1.26; 95% CI: 1.05-1.52; p=0.0123), pancreatic metastases (HR=0.40; 95% CI: 0.18-0.85;p=0.0185), Karnofsky PS< 80 (HR=2.07; 95% CI: 1.22-3.48; p=0.0062), and elevated LDH (HR=1.63; 95% CI: 1.03-2.573; p=0.035). Median OS was 16.9 months (95% CI: 10.3–21.9). 26% of pts were still receiving pazopanib at the time of analysis. 51% discontinued pazopanib due to PD and 12% died of PD on treatment. 11% discontinued pazopanib due to adverse events (AEs). There were no treatment related deaths. Common AEs included fatigue (43%), increase LFTs (34%), diarrhea (28%), nausea/vomiting (14%), anorexia (14%), hypertension exacerbation (12%), and hypothyroidism (11%). 89% of AEs were grade 1/2. Conclusions: Pazopanib demonstrated meaningful clinical activity in heavily pretreated pts with mRCC following PD with other TT. AEs were mild/moderate and manageable.
Using presurgical sunitinib to select patients with newly diagnosed metastatic clear cell renal cell carcinoma for cytoreductive nephrectomy: A phase II study.
Authors: Jonasch Eric , Wood Christopher G. , Corn Paul G. , Sharma Padmanee , Pagliaro Lance C. , Aparicio Ana , Do Kim-Anh , Wang Xuemei , Marcott Valerie D. , Matin Surena F. , Tannir Nizar M. 
Published: February 2017

371^ Background: Timing of cytoreductive nephrectomy (CN) is still a matter of debate in mRCC. This study was designed to test the hypothesis that lead-in treatment with sunitinib (Su) selects patients (pts) most likely to benefit from nephrectomy, and can aid in assessing determinants of response and resistance. Methods: Pts with biopsy proven, newly diagnosed clear cell mRCC with measurable disease, performance status of 0/1, and resectable primary tumor were eligible. Pts received one cycle of sunitinib 50mg PO QD on a 28 day on/14 day off cycle, were restaged, and if stable/responding underwent nephrectomy between day 7 and 21 of second cycle of Su. If disease remained stable on postop scans, pts continued Su. Mutations in a 200 gene cancer gene panel as well as copy number variation were used to correlate molecular changes with clinical outcome. Results: 50 pts were enrolled: 36 (72%) were male and 38 (76%) Caucasian, Median age 61 years (range: 43–84). 44 had intermediate MSKCC score and 6 were poor risk. 45 pts (90%) were evaluable. No drug-related perioperative complications were noted. A total of 9 (18%) pts did not have nephrectomy: 6 because of progression, 2 because of drug related toxicity, and one who required emergency surgery during the first cycle for bowel obstruction. Median primary tumor shrinkage after 1 cycle was 4 percent (range -18 to +11%). 4 (8%) pts were found to have nonclear cell pathology at nephrectomy (2 sarcomatoid, 1 papillary, 1 unclassified). Among the 45 evaluable pts, the median PFS was 8.7 months (95% CI: 5.8 – 37.3 months). 24 (53%) pts came off for progressive disease, and five (11%) pts came off for toxicity. With a median follow-up time of 27.3 months, median OS was 32.2 months (95% CI: 17.2 – Not estimable). To date, 20 (40%) pts have died. Copy number and genomic data analysis are underway, and will be presented and correlated with clinical outcome. Conclusions: Pretreatment with Su safely triaged mRCC pts into nephrectomy versus nonnephrectomy groups, with acceptable efficacy and OS. Ongoing studies will define molecular characteristics defining subgroups most likely to benefit from Su. Clinical trial information: NCT00715442.
Significance of zoledronic acid on survival in patients with bone metastases from renal cell carcinoma.
Authors: Yasuda Yosuke , Fujii Yasuhisa , Yuasa Takeshi , Kitsukawa Shinichi , Urakami Shinji , Yamamoto Shinya , Yonese Junji , Takahashi Shunji , Fukui Iwao 
Published: February 2017

374 Background: It remains unclear whether zoledronic acid (ZOL) improves overall survival (OS) for renal cell carcinoma (RCC) patients with bone metastases. We retrospectively investigated the clinical benefit of ZOL for OS in RCC patients with bone metastases. Methods: Between 1978 and 2010, 77 patients who had RCC metastatic to bone were treated in our hospital. Of them, 36 were treated with ZOL and their OS was significantly better than that of the other 41 patients (1- and 3-year survival, 84% and 73% vs. 49% and 27%, respectively, p < 0.001). OS rates were clearly discriminated according to MSKCC model stratification: 3-year survival rates in the favorable, intermediate and poor risk groups were 83% (n = 12), 49% (n = 45), and 19% (n = 20), respectively (p=0.0033). To match characteristics in our retrospective study, we selected 45 patients conforming to MSKCC intermediate risk group criterion. In this cohort, 23 patients received ZOL (ZOL-treated group) whereas the other 22 did not (non-ZOL-treated group). The primary endpoint was OS and the secondary endpoint was the skeletal-related event (SRE) rate defined as the total number of SREs divided by the total years on study. Results: For the cohort of 45 patients, the median OS from diagnosis of bone metastases was 27.2 months. Multivariate analysis showed that low serum calcium (hazard ratio [HR]: 2.58, 95% confidence interval [CI]: 1.31 to 4.69; p = 0.0083) and ZOL treatment (HR: 1.89, 95% CI: 1.27 to 2.96; p = 0.0013) were independent factors predicting longer survival. The ZOL-treated group had significantly longer OS (1-year survival: 80.8%) than the non-ZOL-treated group (1-year survival: 59.1%, p = 0.0034). A difference in OS between the two groups still was present (p = 0.012) when the duration of molecular-targeted therapy was excluded from the OS period. Patients in the ZOL-treated group experienced a lower SRE rate (0.87/year) than patients in the non-ZOL-treated group (1.82/year, p = 0.0453). In particular, none of the patients in the ZOL-treated group developed spinal compression whereas 6 (28%) in the non-ZOL-treated group did (p = 0.0479). Conclusions: The current study indicates that ZOL not only reduces SREs but possibly improves OS in these patients.
Multiplexed tissue protein assay to predict patient response to targeted therapy in advanced renal cell carcinoma.
Authors: Vaishampayan Ulka N. , Sethi Seema , Chen Wei , Derrien-Colemyn Alexandrine , Gillespie John Williams , Dickow Brenda , Smith Daryn W. , Rait Vladimir , Tunon Peter 
Published: February 2017

382 Background: Although a number of prognostic biomarkers have been explored in advanced renal cancer, to date none have been useful in therapeutic outcome prediction. Methods: Following regulatory approval, formalin-fixed paraffin embedded pre-therapy (sunitinib and/or mTOR inhibitors) tissue samples and clinical data on kidney cancer patients (pts) were obtained. The samples were analyzed using layered immunohistochemistry which allows analysis of multiple biomarkers using a single tissue section. Two panels of 9 protein biomarkers each were used to probe tissue sections for proteins along the mTOR and/or the VEGFR/PDGFR signaling pathways. Biomarker expression in regions of cancer were scored and levels correlated with the patient’s clinical outcome status. Results: Tissue samples of 30 pts treated with sunitinib were analyzed and scored in a blinded fashion using 4 biomarkers. If the sum of the scores assigned to VEGFA, VEGF2 and HIF2alpha was above 19, pt was predicted to be a responder. If initial score < 19 and the sum of VEGFR2 and VEGFB was 2 or more, the pt was predicted to have an objective response (OR)/stable disease (SD). If score < 2 the pt was predicted to have no benefit from sunitinib. 14 of 15 OR/SD pts and 11 of 15 with progressive disease (PD) were accurately predicted. 35 cases treated with mTOR inhibitor were analyzed. 6 biomarkers in the mTOR pathway were used to create a composite score. 11/14 OR/SD pts (sensitivity 79%) and 18/21 PD pts (specificity 86%) were accurately predicted using a score cutoff of 10. Median time to treatment failure (TTF) was 2 months in the PD pts, as compared to 11 months in the OR/SD group. A subgroup analysis of patients followed for 18 months or less showed linear correlation between the biomarkers and the TTF (Spearman correlation coefficient 0.43 with p value 0.04). Statistical modeling, results of ongoing validation testing, and score correlation with TTF will be presented. Conclusions: These results indicate that an assay based on multiplexed protein analysis of tumor tissue is capable of providing clinically applicable information, to help guide therapy. Funding source: Supported in part by NCI BRIDGE Grant 5R44CA123994-06 and by 20/20 gene systems.
Increase in blood pressure with sorafenib exposure in renal cell carcinoma versus other solid tumors.
Authors: Shah Amishi , Motiwala Shweta , O'Dwyer Peter J. , Flaherty Keith T. , Keefe Stephen Michael 
Published: February 2017

384 Background: Tyrosine kinase inhibitors (TKIs) such as sorafenib are widely used in the treatment of solid tumor malignancies. Incident hypertension with angiogenesis inhibitors has been well-documented in the population of patients with renal cell carcinoma (RCC) where incident hypertension on treatment is associated with improved clinical outcome. Little has been reported about increases in blood pressure with TKIs in other solid tumor malignancies. Methods: We performed a retrospective cohort study examining changes in blood pressure with sorafenib among the 101 patients treated at the University of Pennsylvania on a randomized discontinuation trial examining sorafenib in patients with advanced solid tumor malignancies. Solid tumor diagnoses were established on the basis of tumor histology. Treatment of patients on study with sorafenib was initiated at 400 mg BID. Patients were treated for at least 12 weeks and were evaluated at least every three weeks in the clinic. Blood pressure was recorded at each visit. Sorafenib exposure was recorded by patients in a pill diary. The primary endpoint for this study was a maximal change in blood pressure defined as the difference between baseline blood pressure and highest subsequent recorded systolic and diastolic blood pressures on treatment. Results: 72% of RCC patients developed an increase in systolic blood pressure (SBP) of at least 20 mmHg as compared to 32% of non-RCC patients. The mean increase in SBP on study for RCC patients was 30 mmHg versus 19 mmHg in non-mRCC patients. RCC patients in the top quartile of increased SBP showed a mean increase of 54 mmHg as compared to 35 mmHg for non-mRCC patients. A chi-squared test of proportions and t-tests were used to compare rates and means, respectively. Each of the aforementioned differences were found to be statistically significant with p-values <0.003. These relationships also held true for diastolic blood pressure. There was no difference in SBP between groups in terms of age or sorafenib exposure. Conclusions: In these patients treated with sorafenib the proportion of patients with increased blood pressure and the mean amplitude of change in blood pressure both were significantly greater in the RCC population than in the non-RCC group.