bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between clinical response and toxicities with drug exposure in an alternative dosing regimen of sunitinib.
Authors: Kanesvaran Ravindran , Teo Yi Ling , Chue Xiu Ping , Chau Noan-Minh , Tan Min-Han , Wee Hwee Lin , Ho Han Kiat , Chan Alexandre 
Published: February 2017

439 Background: An alternative dosing (AD) regimen of 37.5mg daily in repeated 4-weeks on, 2-weeks off cycle has been proposed to ameliorate frequent dose modifications due to toxicities as observed with the approved dosing regimen of sunitinib for metastatic renal cell carcinoma (mRCC). This study aims to determine the effect of drug exposure (sunitinib and active metabolite, SU12662) on clinical response and toxicities in patients receiving this AD regimen. Methods: All mRCC patients initiating AD sunitinib were invited to participate in this study. In week 4 of each cycle, toxicities were assessed and plasma steady-state levels (Cmax) were quantified using high-performance liquid chromatography. Clinical response was assessed after 2 treatment cycles; and was used with drug exposure and toxicities data for dose adjustments. Results: 36 patients with a mean age of 59.1 ± 10.1 years were recruited. Majority were males (81%) and Chinese (86%). Among the 24 and 16 analyzable cases for cycle 1 and 2, median total Cmax were 0.088 and 0.094 µg/ml respectively. Sixteen patients completed 2 treatment cycles; 7 (44%) partial response, 5 (31%) stable disease and 4 (25%) progressive disease. A dose increment to 50mg daily was performed for a patient with disease progression. Common grade 2 and above toxicities were hypertension, hand foot syndrome (HFS) and mucositis. Higher drug exposures were observed among patients who achieved clinical response and among those who experienced at least grade 2 toxicities. Conclusions: Drug exposure could likely be associated with clinical response and toxicities in this AD regimen. [Table: see text]
Heterogeneity of intermediate prognosis patients (pts) with metastatic renal cell cancer (mRCC) treated with sunitinib.
Authors: Sella Avishay , Michaelson M. Dror , Matczak Ewa M. , Simantov Ronit , Lechuga Mariajose , Lin Xun , Figlin Robert A. 
Published: February 2017

446 Background: The Memorial Sloan Kettering Cancer Center risk model (MSKCC) stratifies pts with mRCC into 3 prognostic groups based on 5 risk factors. The Intermediate Prognosis (INTMP) risk group is characterized by the presence of 1 or 2 factors, equivalent to 15 possible distinct entities. This heterogeneity suggests that the efficacy of tyrosine kinase inhibitors may be less predictable in the INTMP than in the other groups. Methods: We identified 548 patients with INTMP mRCC from a pooled analysis of patients treated with sunitinib in 6 prospective phase II and III clinical trials. Statistical analysis was performed using Cox regression and Kaplan-Meier methods and Pearson chi-square tests. Results: Most INTMP pts were male (69%), with clear cell carcinoma (93%), good ECOG performance status (PS) (60.5% PS 0; 38% PS 1; 1.5% PS 2) and median age 60. There were 325 pts (56%) with 1risk factor, and the most common were <1 year from diagnosis (38%); low hemoglobin (Hg) (29%), or both (16%). Objective response rate (RR) was 35.4%, progression free survival (PFS) was 8.4 months (m) and overall survival (OS) was 20.5 m. The 325 (59.3%) pts with one risk factor fared better than the 223 (40.7%) patients with two: PFS 10.7 vs 6.5 m, HR 0.684(95% CI 0.563-0.832, p<0.001); OS 26.3 vs 14.1 m, HR 0.522 (95% CI 0.420-0.648, p<0.001). RR was similar (38.5% vs 30.9%, p=0.071). Sunitinib was more effective in pts with PS 0: PFS 9.7 vs 7.8 m, HR 0.797 (95% CI 0.654-0.972, p=0.0242); OS 24.7 vs 14.0 m, HR 0.529 (95% CI 0.426-0.657, p<0.001), RR 38.9% vs 30.1%, (p=0.036). The most common grade 3/4 adverse events (AE) were fatigue (17%), hypertension (10%), hand foot skin reaction (9%), and nausea (4%). Overall, 17% of patients discontinued due to AE, and the overall pattern of AEs did not vary among the subgroups. Conclusions: MSKCC INTMP is a heterogeneous group comprised mostly of pts with low Hg and/or < 1 year from diagnosis. PFS and OS are superior in pts with 1 vs. 2 risk factors, and PS is also an important factor in the INTMP group. Sunitinib is active and well-tolerated in INTMP pts. Clinical trial information: NCT00077974, NCT00083889, NCT00137423, NCT00267748, NCT00338884, NCT00054886.
Discrimination between Von Hippel-Lindau gene and hypoxia-regulated alterations in the metabolism and protein expression in renal cell carcinoma using ome-based strategies.
Authors: Seliger Barbara , Leisz Sandra , Schulz Kristin , Erb Susanne , Wang Ena , Marincola Francesco , Stehle Franziska 
Published: February 2017

447 Background: The objective of this project is to dissect the von Hippel-Lindau- and hypoxia-regulated alterations in human renal cell carcinoma to define both novel prognostic markers as well as therapeutic targets. Methods: For this, the VHL-negative RCC cell line 786-O next to recently established gain of function VHL transfectants thereof were used as a model system and subsequently cultured under normoxic or hypoxic conditions. Whereas direct effects on the altered energy metabolism were determined by lactate, pyruvate and pH measurements. the resulting effects at the gene/protein expression profiles were determined by comparative cDNA micro array analysis/ 2DE-based proteome analyses, respectively. Some of the differentially expressed genes/proteins were verified by qPCR and/or Western blot analysis in a panel of RCC cell lines. Results: By employing the VHL-/VHL+RCC model system VHL-dependent, HIF-dependent as well as VHL/HIF-independent alterations in the gene and protein expression pattern were found. Some of the differentially expressed genes/proteins were either associated with the loss of VHL function, the hypoxic conditions or both. The genes/proteins defined as differentially expressed under these conditions are mainly involved in the cellular metabolism and predominantly localized in the cytoplasm or mitochondrion. The verification of the differentially expressed genes/proteins by qPCR and Western blot analysis revealed a heterogeneous expression in RCC cells and lesions. One such gene/protein is represented by the glutamine gamma glutamyl transferase (TGM2). Its expression was associated with the loss of VHL and induction of hypoxia. Furthermore, TGM2 might be an important marker for both VHL-independent and/or hypoxia-induced responses. Conclusions: The data demonstrate that VHL functionality and/or hypoxia induce distinct effects on the metabolic switch of RCC.
Sterotactic body radiosurgery for primary small renal tumors: A retrospective analysis.
Authors: Kaplan Irving D. , Wagner Andrew , Mahadevan Anand , Dagoglu Rabia N 
Published: February 2017

475 Background: Small renal tumors are being diagnosed with increased frequency with the increasing use of axial imaging. Partial or total nephrectomy is the "gold standard" for management. Often patients are not candidates or refuse surgery. Stereotactic Radiotherapy (SBRT) is used to treat brain metastases from RCC. This study is aimed to evaluate the efficacy and toxicity of SBRT in the treatment of renal tumor. Methods: From June 2009 to December 2012, 21 patients with 22 lesions treated with 48Gy in 3 fractions were retrospectively evaluated. 21 patients had RCC and 1 had lymphoma. All patients had tracking during respiration. The Cyberknife system was used. All patients were with ondansetron and /or prochlorperazine to prevent nausea. Follow-up abdominal CT scans or MRI’s were used to evaluate efficacy. Blood Creatinine and urea values were used to track renal function. Clinical records were also evaluated for hypertension. Results: The median Follow up was 21 months (3-48 months). The median age was 82 (56-95). 4 patients had baseline chronic renal failure and 13 patients had baseline hypertension. 12 lesions (54.5%) were left sided and 10 lesions (45.5%) were right sided. 9 lesions (42.9%) were located at upper pole, 6 (28.5%) at lower pole, 5 (23.8%) at middle pole and 1 (4.8%) at renal pelvis. Median maximal tumor size was 3.8cm (1.9-7.7) and median treatment volume was 46cc (7.7-237cc). Five patients developed acute grade 1 fatigue and one patient developed pain which was attributed to inflammation and resolved. One patient developed worsening renal function and 1 patient developed hypertension. There were two local failures at 13 and 21 months. Two patients underwent surgery because one had progressive disease and one as a result of patient choice. 1y and 2y overall survival were both 95%. 1 y and 2 y local control rates were 92 and 84% respectively. Conclusions: This is the largest experience to report on the use of SBRT to treat small renal tumors. SBRT with a dose of 48Gy in 3 fractions of 16 Gy for small renal tumors seems to be an effective and a safe treatment with minimal acute toxicities. In addition tumors in locations not amenable to ablation (renal pelvis) can be safely treated with SBRT.
Results from a phase 2 trial of bortezomib (B) and sorafenib (S) in unresectable or metastatic renal cell cancer.
Authors: Lauer Richard C. , Rabinowitz Ian , Novak Terry , Edelman Martin J. 
Published: February 2017

495 Background: B is a small molecule proteasome inhibitor that affects multiple signaling pathways. S is an orally active multikinase inhibitor with known activity in renal cell cancer. In vitro data has shown that S and B interact synergistically in a number of neoplastic cell lines to cause apoptosis. A phase 1 trial of S and B demonstrated no unexpected toxicities. We now report the results of this phase 2 efficacy trial. Methods: Eligibility included cytologically confirmed clear cell cancer with no prior chemotherapy, PS 0-1, Cr < 1.5 mg/dl, normal LFTs. Regimen: S 200 mg PO BID and B 1mg/m2 IV days 1,4,8, & 11 every 21 days. Patients were treated until disease progression or unacceptable toxicity. The primary objective of the study was to achieve a PFS of 70 weeks. Results: Seventeen patients were enrolled between April of 2011 and January of 2013. Median age was 62y (range 44-75). Four of 17 patients had known brain metastasis on entry to the trial. Median number of cycles = 4 (range 1-45+). Response: CR/PR/SD/PD =0/1/12/4 (RR: 6%, 95% CI = 0%, 29%) Median progression free survival was 13.7 weeks; median overall survival was 110 weeks Toxicity: See table. Only 1 pts. treatment was stopped due to an AE of pancreatitis. There were no toxic deaths. The study was halted for futility. Conclusions: 1.The combination of S and B was well tolerated. 2. The RR of 6% and PFS of 13.7 weeks is not superior to S as a single agent. 3. The combination of SB is not recommended for further development. Clinical trial information: NCT 01100242.
Epidemiology and outcome of sarcomatoid renal cell cancer compared to clear cell renal cancer: A Surveillance, Epidemiology, and End Results (SEER) database review.
Authors: Kanaan Mohammed Nawaf , Singh Parminder , Ahmann Frederick R. , Agarwal Amit Balkrishna 
Published: February 2017

504 Background: Sarcomatoid renal cell carcinoma (SRCCa) is a rare type of RCCa. Few case series in literature indicated its dismal prognosis. We studied the epidemiology and survival outcome of SRCCa compared to clear RCCa (CRCCa) by reviewing the SEER database. Methods: SEER database (8.1.2) was reviewed for patients (pts) with histologically confirmed SRCCa and CRCCa between 2004 -2007. Variables included were: age, race, gender, laterality, surgery of primary RCCa and AJCC stage. Primary outcome was 3 year Disease Specific Survival (DSS). Data was analyzed using Chi square, Kaplan Meier and Cox proportional hazard model. Results: A total of 7,653 pts with CRCCa and 540 with SRCCa were included between 2004 and 2007. Mean age in SRCCa was 61 compared to 62 yrs in CRCCa. White to black race ratio was 7.5:1 in both types. Left primary was 54% in SRCCa and 51% in CRCCa. Male to female ratio was 1.9:1 in SRCCa and 1.7:1 in CRCCa (Table). The main stage at presentation was stage IV (63%) in SRCCa and stage I (53%) in CRCCa. Surgery rate was higher in SRCCa in stage II and IV, same between two groups in stage II and higher in CRCCa in stage I. When we analyzed the effect of RCCa type on DSS for each stage separately, SRCCa had worse 3-year DSS in stage I, II, III and IV independent of age, sex, race, gender and surgery. The Hazard Ratio was 4.97 for stage I, 11.37 for stage II, 3.91 for stage III and 1.58 for stage IV (p <0.001). Conclusions: SRCCa have no statistical significant difference in age, race, gender and laterality compared to CRCCa. When compared stage to stage, SRCCa have worse outcome than RCCa even after adjusting for potential confounders including age, race, gender and surgery. The effect appears to be less prominent in higher stages than in lower stages of the disease. [Table: see text]
Validation of imaging biomarker in a multicentric study to predict PFS in mRCC treated with TKI.
Authors: Lassau Nathalie , Koscielny Serge , Taieb Sophie , Lacroix Joelle , Aziza Richard , Joly Florence , Chevreau Christine , Negrier Sylvie , Gravis Gwenaelle , Escudier Bernard J. 
Published: February 2017

526 Background: Tyrosine kinase inhibitors including sunitinib are the most effective treatments of metastatic renal cell carcinoma (mRCC). A multi-centric study of 539 patients (different tumors treated anti-angiogenic treatments) evaluating dynamic contrast-enhanced ultrasound (DCE-US), showed that a decrease of AUC (Area under the curve) correlated to the blood volume at one month is predictive of response. Our first objective was to validate the correlation between this parameter and the PFS in a sub-group of mRCC treated with Sunitinib The second objective was to study the variability of AUC. Methods: Each Patient had CT-scan every 2 months in order to evaluate the Response assessment using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).DCE-US were performed at baseline and at D30. At each examination, we quantified 7 DCE-US parameters after bolus injection of contrast agent and mathematical modelization of raw linear data recorded during 3 minutes. We also estimated the variation between baseline and D30. The main endpoint was progression free survival assessed according to RECIST. We first selected the best parameters. We studied the trend between the parameter value and freedom from progression. After, the best cut-points were searched through a grid search. The best single cut-point was that with the lowest P-value for progression free survival. We performed this analysis in the sub-group of patients with mRCC treated with sunitinib. Morever, we studied the variability of AUC in 30 other patients treated with TKI . We performed in this group 2 DCE-US the same day before and after lunch. Results: A total of 81 mRCC patients treated with sunitinib were selected. All had DCE-US at baseline and one month. The median of follow-up was 18 months. For DCE-US, the decrease of 90 % of AUC at D 30 was correlated to the PFS (p =0.03). The difference of PFS between the groups defined by this cut-point was 4 months (bad responders) and 14 months (good responders). The results of variability are on-going. Conclusions: The decrease of more than 90% of AUC with DCE-US at one month is a potential predictive biomarker of response in mRCC patients treated with sunitinib. The results of variability of this parameter will be also presented. Clinical trial information: no. 912346.
Prognosis of patients with metastatic renal cell carcinoma and pancreatic metastases.
Authors: Kalra Sarathi , Atkinson Bradley J. , Matrana Marc Ryan , Matin Surena F. , Wood Christopher G. , Karam Jose A. , Tamboli Pheroze , Sircar Kanishka , Rao Priya , Corn Paul Gettys , Tannir Nizar M. , Jonasch Eric 
Published: February 2017

527 Background: Pancreatic metastases are seen in a relatively small percentage of patients with renal cell carcinoma (mRCC). The prognostic impact of pancreatic metastases in patients receiving treatment for mRCC has not been extensively studied, and drivers of pancreatic metastases are not known. Methods: Retrospective review of mRCC patients in an outpatient clinic was done from January 2006 to November 2011. Patient characteristics including demographics, laboratory data, and outcomes were analyzed. Comparison of baseline characteristics was done using chi2and t-test and overall survival (OS) was estimated using Kaplan-Meier methods. Predictors of OS were analyzed using Cox regression. Results: A total of 228 patients were reviewed of which 44 (19.3%) had metastases to the pancreas and 184 (81.7%) had metastasis to sites other than the pancreas. The distribution of baseline characteristics and other factors was equal in both cohorts. 4 patients had isolated metastases to the pancreas, however, the majority of patients (68%) with pancreatic metastases had at least three different organ sites of metastases, as compared to 29% in patients without pancreatic metastases (p<0.01). Distribution of organ sites of metastases was similar (p>0.05), excluding pancreas. Median OS was 39 months (95% confidence interval [CI], 24-57) for patients with pancreatic metastases, compared to 26 months (95% CI, 21-31) for patients without pancreatic metastases (p-value <0.01). Conclusions: Despite a higher number of affected organ sites in the pancreatic metastasis cohort, mRCC behavior in this cohort appears to be more indolent, as demonstrated by a higher median OS. These findings suggest that host or tumor features associated with pancreatic metastases induce a less aggressive tumor phenotype. [Table: see text]
Changes of pulmonary function test and development of non-infectious pneumonitis in patients with metastatic renal cell carcinoma treated with everolimus.
Authors: Park Kwon-Oh , Lee Jae-Lyun , Ahn Jin-Hee , Jeong In Gab , Song Cheryn , Hong Bum-Sik , Hong Jun Hyuk , Ahn Hanjong 
Published: February 2017

530 Background: The aim of this study was to evaluate the changes of pulmonary function test (PFT) during everolimus treatment and to assess whether the change of PFT is associated with the development of non-infectious pneumonitis in patients with metastatic renal cell carcinoma. In addition, we tried to determine whether everolimus-associated pneumonitis could affect the efficacy of everolimus. Methods: Patients with mRCC who had received everolimus (10 mg dose once daily) after failure to VEGF-TKI treatment and underwent baseline PFT with regular PFT follow up were included in this study. The diffusing capacity divided by the alveolar volume (DLCO/VA) was used among various parameters of PFT. Repeated-measures ANOVA was used to describe changes of DLCO/VA. A Cox proportional hazard model with pneumonitis onset as a time-dependent covariate used to assess the prognostic role of pneumonitis. Results: This study included 36 patients. Nine patients (30%) developed everolimus-associated pneumonitis (pneumonitis group) and 27 were included in non-pneumonitis group. Five patients (14%) among pnemonitis group were symptomatic. The baseline DLCO/VA of patients was 90.0%. It decreased to 80.2%, 76.4%, 76.0%, and 72.1% after everolimus treatment of 6, 12, 18, and 24 weeks, respectively. DLCO/VA declined significantly as the treatment duration becomes longer (p < 0.001). There was no significant difference in change of DLCO/VA between patients with pneumonitis and those without pneumonitis (p =0.435). On time-variant Cox analysis, the decrease of DLCO/VA was not correlated with the efficacy of everolimus in terms of progression free survival (PFS, HR=1.0, p=0.94) and overall survival (OS, HR=0.98, p=0.18), while development of pneumonitis was associated with poor PFS (HR=4.60, p=0.005). Conclusions: Although the eveolimus treatment decreased DLCO/VA, the decline of DLCO/VA was not associated with the development of pneumonitis. Changes in DLCO/VA were not related with efficacy of everolimus, while the development of pneumonitis was a prognostic factor for PFS.
Liver metastases as predictors of outcome in renal cell carcinoma (RCC) patients (pts) treated with first-line sunitinib (SU) and sorafenib (SO).
Authors: Grassi Paolo , Verzoni Elena , Porcu Luca , Testa Isabella , Iacovelli Roberto , Garanzini Enrico , Salvioni Roberto , De Braud Filippo G. , Procopio Giuseppe 
Published: February 2017

536 Background: The predictive role of metastatic sites in RCC pts treated with tyrosine kinase inhibitors (TKIs) is unclear. Aim of this study was to investigate whether first line SU and SO was associated to metastatic sites in terms of progression-free survival (PFS) and overall survival (OS). Methods: A retrospective cohort of consecutive metastatic RCC (mRCC) pts treated with TKIs at Istituto Nazionale Tumori of Milan was analyzed. All pts received at least one targeted therapy including: SO, SU, bevacizumab plus interferon-alfa, pazopanib or temsirolimus. The product limit method was used to estimate survival functions and Cox regression to estimate hazard ratios (HRs) and to test statistical interaction between sub-groups identified by different metastatic sites. Results: 358 mRCC pts receiving first line TKIs between January 2005 and October 2012 were evaluated. Overall 206 pts (58%) received SO while 103 pts (29%) SU. Median duration of treatment for SU and SO groups was 16 (95%CI 12.0-20.1) and 9 months (mo) respectively (95%CI 7.0-12.0). After a median follow-up of 56.1 mo (range: 1.0-93.2) median OS for SO group was 19.9 mo (95%CI 16.0-25.1) while OS for SU group was not yet defined. Noteworthy 142 pts (69%) treated with SO received SU at disease progression (PD) while 36 pts (35%) received SO at SU failure. A statistically significant interaction between first line treatment and metastatic sites was found for the liver site in terms of PFS and OS (PFS p=0.034; OS p=0.004). SU was associated with a 18% [95%CI (-37%)- 123%] higher risk of PD as compared to SO in pts with liver mets while pts without liver mets showed a 46% [95%CI (-61%)-(-24%)] decreased risk of PD as compared to SO. SU was associated with a 40% [95%CI (-32%)-187%] higher risk of death as compared to SO in pts with liver mets while pts without liver mets showed a 62% [95%CI (-76%)-(-40%)] decreased risk of death as compared to SO. The predictive role of liver mets was confirmed introducing the Motzer score (PFS p=0.084; OS p=0.009). Conclusions: mRCC pts with liver mets treated with first line SO showed a better outcome as compared to SU while pts without liver mets treated with first line SO showed a worse outcome as compared to SU.