bluuebunny/crossref_metadata_2025_split huggingface dataset:
Archexin, a novel AKT-1–specific inhibitor for the treatment of metastatic renal cancer: Preliminary phase I data.
Authors: Tagawa Scott T. , Chatta Gurkamal S. , Mazhari Reza , Benaim Ely 
Published: February 2017

550 Background: Archexin (RX-0201) is a 20-mer oligonucleotide that is complementary to AKT-1 messenger ribonucleic acid (mRNA). The specificity of Archexin's effect on AKT-1 mRNA levels was examined in human renal cell carcinoma (von Hippel-Lindau protein-deficient renal cell carcinoma cell line) UMRC2 cells and resulted in decreased AKT-1 mRNA levels. Methods: The current study is a proof of concept phase Ib/2, multicenter, open label 2-stage study for subjects who progressed on at least 1 VEGF-targeted therapy. Stage 1 is an open-label, dose-escalation phase Ib study of Archexin administered in combination with everolimus. Archexin is administered by a 24 hour continuous intravenous infusion for 14 days followed by 7 days of rest. It is hypothesized that 250 mg/m2/day or a lower dose of Archexin will be identified as safe and well-tolerated when administered in combination with 10 mg of everolimus. The dose of Archexin identified in Stage 1 will be studied further in Stage 2 which is the randomized, open-label, 2-arm study of Archexin in combination with 10 mg of everolimus versus 10 mg of everolimus alone. Plasma concentrations were measured using a validated LC-MS/MS assay, and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. Results: Five subjects with metastatic clear cell renal carcinoma received 125 mg/m2/day (n = 3) or 200 mg/m2/day (n = 2) of Archexin with 10 mg of everolimus administered daily. Two subjects have had stable disease for 160 and 257 days. The most frequently reported treatment related adverse events for the combination were thrombocytopenia, vomiting and fatigue; no dose limiting toxicities have been reported currently. At all dose levels post-infusion, Archexin plasma concentrations increased rapidly and quickly reached a virtual plateau. Upon cessation of infusion on Day 14, plasma concentrations declined rapidly. Conclusions: At the dose levels tested, Archexin, in combination with everolimus, appears to be well tolerated in patients with metastatic renal cancer. Dose escalation/modification is ongoing to determine the recommended phase II dose of Archexin to be studied further in Stage 2 (randomized) when combined with everolimus. Clinical trial information: NCT02089334.
Patient-derived AVATAR mouse models to predict prognosis in advanced renal cell carcinoma.
Authors: Suarez Cristina , Martinez Mar , Trilla Enrique , Jimenez-Valerio Gabriela , de Torres Ines , Morales Rafael , Jimenez Jose , Lorente David , Vivancos Ana , Nuciforo Paolo , Morote Juan , Carles Joan , Casanovas Oriol 
Published: February 2017

551 Background: Anti-angiogenic (AA) drugs are the cornerstone of first-line (FL) treatment in renal cell carcinoma (RCC). While several mechanisms of resistance to AA have been described, second line (SL) therapies are disappointing with short PFS reported. A recent strategy makes use of individual patient-derived tumor models in animals for drug testing simultaneously with that patient’s FL and SL treatments (AVATARs). The predictive value of each specific AVATAR for that same original patient will be key in order to predict SL treatment response in the clinic trying to help in decision making in this setting. Methods: We generated a unique panel of patient-derived mouse models of RCC based on the orthotopic implantation of primary renal tumor biopsies or metastasis directly obtained from patients. Sunitinib FL treatment followed by different SL treatments are evaluated in each mouse model. Response to treatments in these models and molecular profiling in search of predictive factors of response/resistance will be performed. Results: In this subset of 12 advanced RCC patients, tumor take rate in mice to develop AVATARs was 75% at 5 months after implantation. Previous data demonstrated a positive association of grafting capacity with tumor stage and Fuhrman grade (p < 0.0001). AVATAR models faithfully reproduced each patient’s histological characteristics and metastatic capacity. Time to tumor growth in AVATAR models significantly correlated to clinical outcome in each patient (spearman correlation, p < 0.0001). These advanced AVATAR models are treated FL with AA drugs and, at the moment of emergence of resistance to therapy, treatment is switched to known and experimental SL treatments in different animal cohorts. Updated results on AVATAR treatment and prediction of patient’s responses will be presented. Conclusions: Thorough characterization of these AVATAR models together with their response to AA treatments we will be able to predict response/resistance to new SL treatments for our RCC patients as a personalized cancer therapy approach.
The impact of weight change during treatment with targeted therapy in patients with metastatic renal cell carcinoma (mRCC).
Authors: Albiges Laurence , McKay Rana R. , Lin Xun , de Velasco Guillermo , Simantov Ronit , Choueiri Toni K. 
Published: February 2017

557 Background: A growing body of evidence suggests a relationship between baseline body mass index and outcomes in patients (pts) with mRCC. However, the role of weight loss (WL) during treatment in pts with mRCC is poorly characterized. The aim of this study was to investigate the impact of weight change in mRCC pts treated with targeted agents. Methods: We conducted an analysis of mRCC pts treated on phase II-III clinical trials sponsored by Pfizer from 2003-2013. Weight change was defined as WL (≥ 5% weight reduction from baseline), stable weight (SW) or weight gain (WG, ≥2 % weight increase). We assessed the impact of weight change on overall survival (OS) (primary endpoint), progression-free survival (PFS) and overall response rate (ORR) at week (wk) 12. Statistical analyses were performed using Cox regression and Kaplan-Meier method. Multivariate analysis was adjusted for known prognostic factors for mRCC, including IMDC criteria. Results: Among 3,311 pts, 1,916 (58 %) had SW, 936 (28 %) had WL and 459 (14%) had WG at wk 12. Overall, pts with WL demonstrated both reduced OS and PFS compared to SW (median OS: 18.68 vs. 26.94 vs. 23.03 months in WL, SW and WG respectively; median PFS: 7.17 vs. 10.12 vs. 9.93 months in WL, SW and WG), and were consistent when considering 2 other time points (table). WL at wk 12 was associated with worse ORR (23.4 vs. 32.1 vs. 35.9% in WL, SW, WG; adjusted odd ratio 0.715, 95% CI 0.590-0.867, p=0.03). Discontinuation rate due to adverse events was similar between groups. Conclusions: We demonstrated that WL during therapy for mRCC is strongly associated with worse clinical outcomes. This observation remains valid for WL at 6, 12 and 24 weeks. Weight change may be an early prognostic factor and guide physician in clinical management. Measures to avoid WL during therapy may lead to better outcomes from targeted therapy. [Table: see text]
PD-1 expression on classical monocytes (CM) as an independent predictor of cancer specific survival in clear cell renal carcinoma (ccRCC).
Authors: Haseebuddin Mohammed , Macfarlane Alexander , Ruth Karen , Uzzo Robert G. , Plimack Elizabeth R. , Jillab Mowafaq , Dulaimi Essel , Al-Saleem Tahseen I. , Campbell Kerry 
Published: February 2017

562 Background: We have previously shown that PD-1 expression in peripheral blood lymphocytes is elevated in RCC patients at diagnosis and decreases subsequent to surgery. We theorize that classical monocyte (CM) inhibition through PD-1 interferes with antigen presentation necessary to stimulate adaptive immune responses, and, thus, preop CM PD-1 expression is prognostic of poor outcomes. Methods: Blood samples were obtained from RCC patients (n = 90) preop and age-matched healthy donors (n = 25). Flow cytometric (FC) data were quantified as mean fluorescence intensity (MFI) or % of cells that express a biomarker. Patients were excluded if they had comorbid CLL, had prior surgeries for RCC, had non-ccRCC histology, or if the FC data was missing. We have defined elevated CM PD-1 expression at the third quartile level of CM PD-1 expression (784 MFI) in the healthy donors. CM PD-1 level was correlated with patient clinico-pathologic data using non-parametric tests. Cancer specific survival (CSS) curves were estimated with Kaplan-Meier methods and a multivariate analysis was performed. Results: The average age of the ccRCC cohort (n = 68) was 60 (range 25-88) years. 35 patients were Fuhrman Grade III/IV high-grade (HG) histology. With median follow-up of 41 months, 10 patients died with ccRCC. No patients with low-grade disease died. Median CM (%) was lower in those who died of disease compare to censored (64% vs 52%, p = 0.029). Patients with CM PD-1 expression > 784 MFI had lower survival compared to patients with CM PD-1 < 784 MFI (p = 0.02). Among HG patients, CSS at 24 months for CM PD-1 MFI > 784 was 62.1% (95% CI 34.2-81.0) vs 93.3% (95% CI 61.3-99.0) for CM PD-1 MFI < 784. On multivariable analysis, controlling for stage related covariates, CM PD-1 MFI > 784 is associated with inferior CSS (hazard ratio = 5.1 [95% CI: 1.1-24.4], p = 0.04) among HG disease patients. Conclusions: In patients with ccRCC, an elevated preoperative CM PD-1 MFI level was associated with lower survival independent of pathological T stage and localized disease status. Preoperative CM PD-1 MFI may be an important biomarker to stratify patients at risk for poor outcome who may benefit from immunotherapy.
Isolation and analysis of circulating tumor cell samples from both spiked analytical sources and patients with renal cell cancer and prostate cancer.
Authors: Amato Robert J. , Rosenblatt Kevin P , Dehghani Mehdi , Souza Glauco R , Brobey Reynolds , Ionescu-Zanetti Cristian , Jensen Jeff , Tseng Hubert 
Published: February 2017

584 Background: Tumor genotyping using fluid samples such as blood can potentially allow tracking of dynamic changes in mutational profiles over time and allow better access than biopsies. We present a method to detect somatic mutations from a blood draw, where circulating tumor cell (CTC) enrichment above 10% of total cell numbers allows the use of standard gene panels typically used to analyze tissue-based biopsies. Methods: Analytical samples were obtained from 9 prostate cancer (PC) patients and 6 renal cell cancer (RCC) patients, followed by CTC enrichment using the IsoFlux System. Cells were lysed and DNA amplified by whole genome amplification (WGA) using the NGS Kit (Fluxion Biosciences) and quantified via qPCR. Samples were enumerated to determine CTC load, with CTCs defined as CK+, CD45- nucleated cells (DAPI+). Next-generation sequencing was performed using 3 targeted cancer panels on the Ion torrent PGM platform: the Ion ampliseq cancer hotspot panel (50 genes; 6 PC samples), the Oncomine (143 genes; 3 PC samples), and a 29-gene panel of actionable mutations in RCC (6 samples). Data was analyzed using a customized variant calling/filtering pipeline based on standard alignment and variant calling tools. Variant filtering and functional interpretation was performed using VarSeq. All data was analyzed in a blinded manner. Results: Our method was able to isolate CTCs from all patient samples. Whole genome amplified DNA concentration was at a range of 25-164 ng/µL (median, 69) in PC and 29-180 ng/µL (median, 69) in RCC. CTCs were recovered in 2.9-33.7% (median, 10.5%) of PC samples and 1.9-33% (median, 14.5%) of RCC samples After WGA, we found 1 variant/sample using hotpot, 12/sample using Oncomine, and 3/sample using the RCC panel. Conclusions: Our assay consistently detected somatic variants from blood draw using standard gene panels in both PC and RCC. Obtaining repeat tumor biopsies from patients during treatment and/or at time of progression is both challenging and impractical from a clinical perspective. Our assay provides molecular characterization using standard blood draws and will be prospectively validated in clinical trials.
Impact of precise quantitative assessment of visceral obesity on outcomes of patients with metastatic renal cell carcinoma treated with systemic therapy.
Authors: Mizuno Ryuichi , Miyajima Akira , Hayakawa Nozomi , Kikuchi Eiji , Mikami Shuji , Jinzaki Masahiro , Oya Mototsugu 
Published: February 2017

597 Background: With its excellent resolution of adipose tissue, CT presents precise quantitative assessment of visceral obesity. We assessed the impact of visceral obesity on progression free and overall survival in patients treated with systemic therapy for metastatic renal cell carcinoma. Methods: This retrospective cohort study included 114 patients treated with systemic therapy for metastatic renal cell carcinoma between 2007 and 2015 at Keio university hospital in Japan. The visceral fat area was measured at the level of umbilicus using CT. A visceral fat area ≥100cm2 was used as the definition of visceral obesity. Progression free and overall survival was compared according to visceral obesity. Results: In the whole cohort, the median progression free survival in first line treatment was 12.0 month. The median overall survival was 42.5 month. According to Memorial Sloan-Kettering Cancer Center classification, 31 patients were favorable risk, 61 were intermediate risk, and 22 were poor risk; median overall survival for these groups were 76.9, 40.8, and 23.7 months, respectively (P<0.0001). Visceral obesity correlated with improved progression free (P=0.0095) and overall survival (P=0.0002). On multivariate analysis, visceral obesity (HR 0.64, P=0.0393) and Memorial Sloan-Kettering Cancer Center classification (P=0.0037) were independent indices to predict progression free survival in first line treatment. In addition, visceral obesity (HR 0.42, P=0.0016) and Memorial Sloan-Kettering Cancer Center classification (P=0.0006) independently predicted overall survival. Conclusions: The precision of CT imaging for measuring visceral fat tissue provides useful clinical venue to predict prognosis for metastatic renal cell carcinoma. Visceral obesity may be a useful and independent indicator for a better prognosis in patients treated with systemic therapy for metastatic renal cell carcinoma.
Multi-institutional evaluation of multiparametric MRI and fusion-guided prostate biopsy in a biopsy-naive population.
Authors: Kadakia Meet , George Arvin Koruthu , Siddiqui Minhaj , Rais-Bahrami Soroush , Rastinehad Ardeshir , Vourganti Srinivas , Fascelli Michele , Kongnyuy Michael , Muthigi Akhil , Sidana Abhinav , Frye Thomas P , Kilchevsky Amichai , Nix Jeffrey , Yarlagadda Vidhush K. , Su Daniel , Merino Maria J , Wood Bradford J. , Choyke Peter L. , Turkbey Ismail B. , Pinto Peter A. 
Published: February 2017

60 Background: Multiparametric MRI (mpMRI) and fusion biopsy (FB) has proven beneficial in men with a prior negative systematic biopsy (SB) or diagnosis of prostate cancer (CaP). The aim of the study was to evaluate mpMRI and FB in a biopsy-naive population. Methods: A multi-institutional review was performed on patients with no prior biopsy history who underwent mpMRI followed by concurrent FB and SB. Imaging protocol was standardized across institutions. Gleason score (GS) distribution/risk classifications were recorded. Univariate analysis was performed to compare FB versus SB. Results: A total of 361 biopsy-naive men were identified from 4 institutions. GS distribution/risk classification for FB and SB are presented in the table. Overall cancer detection rate (CDR) was 65.4%. In biopsy-naive men, FB detected a greater absolute number of high grade disease with 13% more high risk CaP than SB (78 vs 69). Additionally, FB detected 21% fewer cases of GS 6 CaP (57 vs 69). The CDR for FB alone was 57.3% with only 3 intermediate-risk and 1 high-risk patient not identified. The addition of SB to FB resulted in diagnosing 25 added cases of low-risk disease for each high risk CaP detected. The CDR of SB alone was 59.6%, however, 2 intermediate- and 4 high-risk CaP were missed. The addition of FB to SB alone resulted in only 4 added cases of low-risk CaP for each high-risk CaP detected. Conclusions: In biopsy-naive men, mpMRI and fusion biopsy detects a greater number of patients with high-risk disease while decreasing the detection of low-risk CaP. Additional studies with greater power will be required to validate the potential benefit of mpMRI and FB in patients with no prior biopsy history. [Table: see text]
Metastasis-associated mutations in clear cell renal cell carcinoma.
Authors: Gowrishankar Banumathy , Janakiraman Manickam , Lee Chung-Han , Thodima Venkata Jaganmohan , Molina Ana M. , Patel Premal H , Gold Theresa Margaret , Motzer Robert J. , Chaganti Raju S.K. , Kamalakaran Sitharthan , Houldsworth Jane 
Published: February 2017

600 Background: Over 30% of patients with clear cell renal cell carcinoma (ccRCC) exhibit metastasis at the time of diagnosis and exhibit poor outcome. About 20-50% of patients with localized disease eventually develop metastasis after nephrectomy. The goal of the current study was to identify target gene mutations associated with ccRCC metastasis. Methods: In this IRB approved study, genomic DNA from 128 ccRCC resected specimens (128 unique patients) were profiled using a custom targeted next-generation sequencing (NGS) panel comprising 70 frequently mutated genes and prognostic SNPs in renal cancer. The specimen cohort consisted of 78 primary (29 stage I-III, 30 stage IV, 19 unknown) and 50 metastatic (10 lung, 9 bone, 25 other sites, 6 unknown) lesions. Following hybrid capture, sequencing was performed (MiSeq, Illumina) and variants identified using CLCbio (Qiagen). Chi-square test was used to test for significance. Results: The median specimen had 4 non-synonymous mutations (123/128 samples had at least one mutation). 66 genes showed a non-synonymous mutation in at least one specimen. There was no significant difference between total mutation count between primary and metastatic specimens (Mann-Whitney test). TSC1 mutation was significantly enriched in metastatic (8/50) compared with primary lesions (3/78). No TSC1 mutation was found in the 29 localized (stage I-III) primary lesions. Interestingly, TSC1 maps to 9q34 and our prior copy number studies indicated that loss of 9q is also enriched in metastatic lesions. Of the 11 specimens bearing TSC1 mutation in this cohort, 5 also had loss of 9q. In 44 specimens with known sites of resection, SETD2 and TSC1 mutations were not found in metastases to the lung but found in 30-40% of lesions at other sites, KDM5C and TSC1 mutations were not found in metastases to the bone while 25-30% of lesions at other sites exhibited these mutations. Due to the limited sample size, significance could not be determined for these associations. Conclusions: Preliminary results of this study implicated TSC1 in the metastasis of ccRCC. Since TSC1 mutation is known to confer sensitivity to mTOR inhibitors, our initial finding of absence of TSC1 mutation in lung and bone sites of metastasis may have therapeutic implications.
Effect of concomitant proton pump inhibitor (PPI) on effectiveness of tyrosine kinase inhibitor (TKI) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Au Trang H. , Bailey Erin B. , Patel Shiven B. , Tantravahi Srinivas Kiran , Agarwal Neeraj , Stenehjem David D. 
Published: February 2017

608 Background: PPIs may reduce TKI bioavailability resulting in reduced efficacy, shortened time on TKI treatment, and disease progression. Axitinib, sorafenib, and pazopanib exhibit pH-dependent solubility. Esomeprazole reduced the AUC and Cmax of pazopanib by 40%, but there was no significant interaction for sorafenib with omeprazole or axitinib with rabeprazole. In real world practice, the effect of PPIs as a class on the efficacy of TKIs as a class in mRCC has not been reported. Methods: This observational cohort study evaluated adult patients treated with a TKI for mRCC. Time on TKI treatment was defined as TKI initiation date to date of discontinuation, change in therapy, lost to follow-up, or death. We performed a treatment line analysis. Time on TKI treatment was compared between patients with and without concurrent PPI (Kaplan-Meier, log-rank). Results: Analysis included 128 treatment lines, including 49 TKI with PPI and 79 TKI with no PPI treatment lines. TKIs included sunitinib, pazopanib, sorafenib, and axitinib. PPIs included omeprazole, lansoprazole, esomeprazole, pantoprazole, and rabeprazole. The three most common TKI/PPI combinations involved omeprazole with sunitinib (26), pazopanib (13), and axitinib (3). No difference in time on TKI treatment with PPI (median 8.7 months) and with no PPI (median 7.0 months, p = 0.41) was observed. In pazopanib treatment lines, no difference in time on treatment was observed in those treated with omeprazole or esomeprazole (n = 14, median 4.8 months) compared to those without PPI (n = 18, median 1.7 months, p = 0.22). Conclusions: Among the TKI/PPI combinations evaluated, there was no difference in time to TKI discontinuation with or without concurrent PPI. This suggests that concurrent PPI does not affect time to discontinuation of TKI. Study limitations include the small sample size, limited number of TKI/PPI combinations, and retrospective study design. A larger study is needed to validate these findings.
Axitinib in advanced renal cell carcinoma: Outcomes following pazopanib or sunitinib.
Authors: Laskey Jennifer , Venugopal Balaji , Thomson Nicola , O'Donoghue Roisin , Jones Robert J. 
Published: February 2017

609 Background: Axitinib is licensed in Europe for the treatment of adult patients with advanced renal cell carcinoma after failure of sunitinib, but not pazopanib. Efficacy is based on the AXIS trial which reported a progression free survival (PFS) of 4.8 months and an overall survival (OS) of 15.2 months in patients who had received prior sunitinib. Despite widespread use of pazopanib in the first line setting there is no randomised trial evidence to support the use of axitinib after pazopanib. The Beatson Cancer Centre (BCC) renal cancer clinic provides all systemic therapy for a population of 2.8 million. Within BCC axitinib is used post sunitinib or pazopanib. We performed an analysis of patient outcomes in patients who commenced axitinib in WOS between November 2013 and November 2014. Methods: Data were collected prospectively from the electronic clinical records. Duration of treatment was used as a surrogate for progression free survival (PFS). Data were analysed in April 2015 which served as the censor date for those still alive. Results: 46 patients were included. At the time of analysis 38 patients had stopped axitinib and 30 patients had died. 22 patients (48%) had received prior pazopanib and 21 (46%) prior sunitinib. For the patients who received axitinib in the 2nd line setting (n = 38) median duration of treatment was 4.8 months (95% CI 0.55 – 9.12). Median duration post sunitinib and pazopanib was 4.8 months (95% CI 0 – 9.7) and 5.3 months (95% CI 2.2- 8.4). Median OS was 9.2 months (95% CI 6.44 – 12.05) overall and 9.44 months (95% CI 5.36 – 13.5) and 8.36 months (95% CI 1.7 – 11.6) post sunitinib and pazopanib respectively. Conclusions: PFS appears to be comparable to reported trial data irrespective of first line treatment indicating similar efficacy and tolerability in real life. We found no evidence of a significant difference in OS regardless of first line treatment which supports the current practice of using axitinib post sunitinib or pazopanib. The inferior OS compared to AXIS trial could be multifactorial and requires further investigation.