bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dovitinib in first-line renal cell carcinoma: An investigation into tumour gene status and correlation with efficacy: A phase II clinical trial.
Authors: Broom Reuben James , Duffey Steven , Fraser-Browne Carol , Wilson Georgia , Thompson Kerin , Hanning Fritha , Mitchell Nicola Jane , Zwi Jonathan , McKeage Mark James , Dranitsaris George , Oei Paul , Fong Peter C.C. 
Published: February 2017

443 Background: Dovitinib is an anti-VEGFR tyrosine kinase inhibitor, differentiated by its inhibition of FGFR-1,-2,-3 and PDGFRβ. We evaluated its activity as 1st-line therapy in patients with metastatic clear-cell renal cell carcinoma (mCCRCC) in correlation with status of genes relevant to its mechanism of action. Methods: 31 treatment-naïve patients with mCCRCC were enrolled in this single-arm, single-site, phase II study (ACTRN12612000140853) and received dovitinib at 500mg 5 days on/2 days off until progression. Patients were offered an optional post-treatment biopsy to elucidate resistance mechanisms. The primary endpoint was progression free survival (PFS) using RECIST 1.1. Secondary endpoints include response rate (RR) and efficacy by FGFR gene status (FISH and DNA sequence using Sequenom OncoCarta panel). Results: Accrual occurred over 15 months from March 2012. Median patient age was 64 years and 72% were male. ECOG performance status was 0 in 45% and 1 in 55%. Heng prognostic group was favorable-risk in 38%, intermediate-risk in 52% and poor-risk in 10%. 38% of patients had bone metastases. Four patients stopped treatment due to toxicity and 1 patient withdrew (investigator decision). Median PFS was 6.2 months (inter quartile range: 3.3 to 8.2). Of 28 evaluable patients, best response was; PR (29%), SD (53%) and PD (18%). All-cause grade 3/4 adverse events (AE’s) occurring in ≥5% of patients were; fatigue (16%), abdominal pain (13%), pancreatitis (10%), gout (7%), diarrhea (7%), bone pain (7%), hypercalcaemia (7%), elevated lipase (7%) and pulmonary embolism (7%). No Grade 5 AE’s occurred. Pre-treatment tumor tissue is available for analysis from primary and metastatic sites from 93% and 54% of patients respectively. To date, 6 patients have donated post-progression tumor tissue. Gene status (FISH) for FGFR-1,-2,-3, PDGFβ and PDGFRβ is available for 20 primary and 17 metastatic specimens. Conclusions: Dovitinib has activity when administered in the 1st-line setting of mCCRCC with a tolerable safety profile at this dosing schedule. Correlation of this activity to relevant gene status in tumor samples from study patients will be presented. Clinical trial information: ACTRN12612000140853.
Impact on clinical prognosis using DNA methylation of the SLC16A3 promoter and expression of the human lactate transporter MCT4 in renal cancer.
Authors: Bedke Jens , Fisel Pascale , Winter Stefan , Kruck Stephan , Scharpf Marcus , Nies Anne , Fend Falko , Stenzl Arnulf , Schaeffeler Elke , Schwab Matthias 
Published: February 2017

452 Background: The monocarboxylate transporter 4 (MCT4) is a metabolic target in tumor biology because it mediates lactate transport across membranes resulting in antiapoptotic effects. Cell experiments support the importance of MCT4 in clear cell renal cell carcinoma (ccRCC). In this study, we assessed the prognostic potential of MCT4 expression in ccRCC and its epigenetic regulation by DNA methylation as novel predictive marker for patient outcome using independent ccRCC cohorts. Methods: MCT4 protein expression was quantified in 207 ccRCC and corresponding nontumor tissues. Data of an independent ccRCC cohort from The Cancer Genome Atlas (TCGA) were analyzed on MCT4 mRNA (n = 482) and DNA methylation (n = 283) level. The findings on MCT4 expression and DNA methylation in the SLC16A3 promoter were validated in a third cohort (n = 64). Promoter activity assays were conducted in four RCC cell lines. Results: MCT4 protein expression was upregulated (p < 0.0001) in ccRCC and showed significant association with cancer-related death. Upregulation of MCT4 mRNA expression (p < 0.00001) was confirmed in the TCGA cohort. Single CpG sites correlated inversely with mRNA expression and were associated with overall survival in Kaplan-Meier analyses [HR = 0.39; 95% confidence interval (CI), 0.24-0.64; P[log-rank] = 1.23e(-04)]. Promoter activity studies confirmed MCT4 regulation by DNA methylation. The significant correlation between MCT4 protein and gene expression or DNA methylation at single CpG sites was validated in a third cohort. Again, higher methylation at individual CpG sites was associated with prolonged survival [HR = 0.05; 95% CI, 0.01-0.40; P[log-rank] = 6.91e(-05)]. Conclusions: This study identified SLC16A3 promoter DNA methylation as a novel epigenetic mechanism for MCT4 regulation in ccRCC. First evidence of a biological rationale for prognosis and clinical outcome is supported by this specific SLC16A3 promoter DNA methylation.
Src pathway activation in RCC and the correlation with grade and survival and the development of a rational new target in RCC.
Authors: Lee Chung-Han , Voss Martin Henner , Mano Roy , Motzer Robert John , Hsieh James 
Published: February 2017

453 Background: Loss of the VHL tumor suppressor in clear cell renal cell carcinoma (ccRCC) leads to the accumulation of Hypoxia Inducible Factor (HIF) and aberrant transcription of downstream targets such as VEGF. Inhibition of VEGF is the underlying therapeutic principle of several approved targeted agents; however, other HIF transcriptional targets remain to be explored. Increased expression of the HIF transcriptional target CUB domain-containing protein 1 (CDCP1) is associated with poor survival in ccRCC. CDCP1 is a substrate and binding partner for Src-family tyrosine kinases (SFKs) and dictates substrate specificity. Crosstalk between the SFK signaling cascade and the HIF pathway may result in feed forward signal amplification. Upregulation of Src signaling increases HIF-dependent transcription by both VHL-dependent and -independent mechanisms. Reciprocally, HIF accumulation can activate Src through PDGFRα, focal adhesion kinase, and CDCP1. Methods: Data from The Cancer Genome Atlas (TCGA) was used to assess mRNA expression and protein phosphorylation as well as clinical parameters and outcome in patients with ccRCC. Correlations were analyzed via Mann-Whitney U-test. Survival data was obtained using the TCGA portal, and analyzed by logrank test. To investigate the therapeutic potential of Src inhibition, the IC50 of Dasatinib in primary tumors derived cell lines were determined by an AlamarBlue Assay. Results: Increased Src and CDCP1 mRNA expression and decreased phosphorylation on the Src inhibitory site Y527 correlated with increased Fuhrman grade. Decreased phosphorylation on the inhibitory site Y527 correlated with worse median overall survival (78.4 vs. 19.7 months, p< 0.00001). Similarly, increased Src and CDCP1 mRNA expression correlated with worse overall survival (78.4 vs. 26.9 months, p < 0.00001, 78.4 vs. 37.2 months, p = 0.005). In vitro inhibition of Src with Dasatinib induces growth inhibition of primary cell lines with sarcomatoid or rhabdoid features, histomorphologic criteria associated with higher grade disease and worse prognosis. Conclusions: The Src pathway might be biologically relevant for ccRCC, and Src inhibition may have therapeutic potential.
Conditional survival (CS) of metastatic renal cell carcinoma (mRCC) patients treated with high dose interleukin-2 (HD IL-2).
Authors: Parikh Kinjal , Stenehjem David D. , Sendilnathan Arun , Crispin Hilda , Van Atta Joan , Batten Julia Anne , Sageser Daniel , Grossmann Kenneth F. , Wang Junfeng , Samlowski Wolfram E. , Tantravahi Srinivas Kiran , Agarwal Neeraj 
Published: February 2017

460 Background: CS is a clinically useful prediction measure that adjusts prognosis of patients on the basis of survival since treatment initiation or therapy duration. CS was recently reported in mRCC patients treated with VEGF targeted therapy in patients stratified by Heng’s criteria. CS has not been reported in mRCC in the context of treatment with HD IL-2. Methods: Patients with histologically confirmed clear cell mRCC treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000 to 2012 were evaluated. Performance status and prognostic risk groups were included. Two-year CS was defined as the probability of surviving an additional 2 years from initiation of HD IL-2 to 18 months after the start of HD IL-2 at 3-month intervals estimated by Kaplan-Meier methodology. Results: A total of 85 patients were included with a median age of 56 years (range 32-76 years) and 79% (n = 67) were male. The median overall survival from HD IL-2 administration was 817 days. Stratification by Heng’s criteria at therapyinitiation resulted in survival estimates for the favorable (n = 13; 15%), intermediate (n = 56; 66%) and poor (n = 16; 19%) prognostic groups of 1616 (p = 0.1993 vs intermediate), 817 (p = 0.0041 vs poor), and 365 (p < 0.0001 vs favorable) days, respectively. Two-year overall CS increased from 56.2% at therapy initiation to 89.5% at 18 months (Table). Two-year CS stratified by Heng’s favorable, intermediate, and poor prognostic risk groups is presented in the Table. Conclusions: CS is a relevant prediction measure in the context of mRCC treated with HD IL-2.A longer survival interval from HD IL-2 treatment was associated with an increased survival probability. CS in this cohort was especially relevant in adjusting prognosis for patients with Heng’s intermediate risk. [Table: see text]
Long-term responders to everolimus: A subgroup analysis of the sector study.
Authors: Barthelemy Philippe , Escudier Bernard , Joly Florence , Geoffrois Lionnel , Laguerre Brigitte , Houede Nadine , Gross-Goupil Marine , Yann-Alexandre Vano , Lucidarme Olivier , Bidault François , Kelkouli Nadia , Oudard Stephane 
Published: February 2017

462 Background: Everolimus is considered as a standard of care for the second line treatment of metastatic renal cell carcinoma (mRCC). Currently no clinical or biological predictive factors are available to help physicians to choose the best second line option between everolimus or TKI. Whether correlation exists between response to first line and response to second line remains debatable. Methods: We performed a subgroup analysis of the SECTOR study, a retrospective survey of patients (pts) receiving everolimus after TKI in 26 french centers to analyse long responders to everolimus. Long-term response to everolimus was defined as progression-free >9 months. Recorded variables included: patients characteristics of first line TKI (duration, response), duration of everolimus, efficacy and toxicity as well as overall survival. Results: 164 patients in 26 french cancer centres were included in the SECTOR study between october 2008 and october 2012. All patients received everolimus as second line treatment. Median age was 64.6 y.o, main histological subtype was clear-cell carcinoma (92.3%). Among the whole study cohort, we identified 30 patients (21%) as long-term responders (ranging from 9 to 33 months). Analysis of this patient population is ongoing and will be presented at the meeting. Correlation between long response and prognostic factors, as well as response to first TKI will be determined. Conclusions: Everolimus achieves long-term response in more than 20% of mRCC treated in second line. Prolonged treatment was relatively well tolerated without any unexpected late toxicity. Further investigations, especially biological studies, are warranted to identify predictive factors which will help physicians to identify long-term responder and choose the best second line option for mRCC patients.
A study of real-time CLIA-enabled whole genome tumor sequencing: Results for testicular cancer and sarcomatoid RCC.
Authors: Bryce Alan Haruo , Borad Mitesh J. , Condjella Rachel M. , Egan Jan B. , Champion Mia D. , Hunt Katherine S , McWilliams Robert R. , McCullough Ann E. , Kurdoglu Ahmet , Aldrich Jessica , Izatt Tyler , Nasser Sara , Christoforides Alexis , Phillips Lori , Liang Winnie S. , Barrett Michael T. , Craig David W. , Carpten John D. , Stewart A. Keith 
Published: February 2017

463 Background: The genomic assessment of cancer has been revolutionized by next-generation sequencing and is increasingly being applied in the clinic to guide therapeutic decision-making. Time to reporting of results, specimen quantity, and analyte quality have constrained initial clinical applications to gene panels and whole exome based strategies. Methods: Patients underwent surgical resection, excisional or core biopsies, or bone marrow biopsy. Samples were analyzed by whole genome or exome sequencing and RNA sequencing, bioinformatics analysis, and therapeutic target prioritization by a multi-disciplinary Clinical Genomics Board. All prioritized targets were CLIA validated using Sanger sequencing, RT-qPCR, FISH, or IHC as appropriate. Treatment was delivered using off-label FDA approved drugs, clinical trials, or single patient INDs. Results: We have enrolled 40 patients with advanced, treatment-refractory cancers of whom sequencing data is available on 33. The initial 6 patients were evaluated in a non-CLIA pilot phase and 27 in the CLIA enabled phase. Upon availability of the initial report, identified targets of putative therapeutic relevance were then prioritized by the CGB in 22/27 patients (81%) for subsequent CLIA validation. Eleven patients have been treated with genomically selected therapy with partial response in 3/10 assessed patients. A testicular cancer patient had aberrations in two testes specific genes, a copy number gain in TSSK6 and a novel gene fusion between thyroid hormone receptor associated protein 3 (THRAP3) and Tektin 2 (TEKT2). Additionally, a case of papillary renal cell carcinoma had an amplification of YAP1 and a previously unreported P287T mutation in CCND1, suggesting potential benefit with a CDK4/6 inhibitor. Treatment is ongoing and results will be reported. Conclusions: Integrated whole genome analysis in a CLIA setting is feasible. Integration of SNV, copy number and transcriptional data may allow for selection of putative driver genes to enhance targeted therapy decisions. Barriers for future broader implementation include the need for reduced time from biopsy to report and availability of therapies.
Impact of altered Wnt1/ß-catenin expression on clinicopathology and prognosis in renal cell carcinoma.
Authors: Kruck Stephan , Eyrich Christian , Scharpf Marcus , Fend Falko , Stenzl Arnulf , Bedke Jens 
Published: February 2017

465 Background: Members of the Wnt/ß-catenin signaling pathway are abnormally expressed in renal cell carcinoma (RCC). This study analyzed the role of Wnt1/ß-catenin alterations in clear cell RCC (ccRCC) with regard to clinicopathology, overall survival (OS) and cancer specific survival (CSS) to prove the options of a Wnt targeted therapy. Methods: Corresponding ccRCCs and benign renal tissue were analyzed in 278 patients for Wnt1 and ß-catenin by immunohistochemistry in tissue microarrays. Expression scores including intensity and percentage of stained cells were compared between normal kidney and ccRCCs. Data was categorized according to the mean expressions core and correlated to tumor and patients’ characteristics and analyzed for OS and CSS according to the Kaplan-Meier and log-rank test. To identify prognostics value of wnt1 and ß-catenin, univariable and multivariable Cox proportional hazard regression models were used. Results: High Wnt1 tumor expression was associated with increased tumor diameter (p=0.01), stage (p=0.004) and vascular invasion (p=0.02). Positive membranous ß-catenin was associated with advanced stage (p=0.003), vascular invasion (p=0.01) and tumor necrosis (p=0.004). Increased tumor diameter (p=0.01), stage (p=0.003), node involvement (0.04), grade (p=0.001), vascular invasion (p=0.002), and sarcomatoid differentiation (p=0.01) were found in patients with high cytoplasmic ß-catenin. Furthermore, this patient subgroup showed reduced OS (p=0.03) and CSS (p=0.009). Conclusions: Significant clinicopathological associations underline the oncogenic potential of Wnt1/ß-catenin pathway parameters. Whereas, cytoplasmic ß-catenin was identified as the most valuable parameter with regard to clinico-prognostic implications for future targeted therapies.
In vitro and in vivo effects of the mTOR inhibitors everolimus (EVE) and temsirolimus (TEM).
Authors: Chen David , O'Reilly Michael Terence , McSheehy Paul M.J. 
Published: February 2017

466 Background: Two mTOR inhibitors are approved for treating mRCC: EVE following the failure of VEGF-targeted therapy and TEM as first-line therapy in poor-risk patients. Both agents exert their clinical effect by binding to FKBP-12, which then interacts with mTOR to inhibit its kinase activity. We compared the activity of EVE and TEM in in vitro and in vivo models. Methods: EVE and TEM binding to mTOR was assessed using time-resolved fluorescence resonance energy transfer. Inhibition of cell proliferation in A549, NCI-H460, and MCF7 human tumor cell lines was assessed by methylene blue protein staining. Phosphorylation of the downstream mTOR target pS6 was assessed via immunohistochemistry in A549 cells. Antitumor activity of EVE (oral) and TEM (intraperitoneal) at doses between 0.1 and 2.5 mg/kg once daily was assessed in vivo in A549, KB-31, KB-8511, and HCT-116 human tumor xenograft models. Results: The binding efficiency of TEM for mTOR was reduced 10-fold compared with that of EVE (EC50, 56 nM vs 6 nM; p < 0.01). EVE demonstrated 6- to 7-fold greater inhibition of cell proliferation than TEM (IC50, 1.0 nM vs 6.5 nM in A549 [p < 0.001], 0.7 nM vs 4.7 nM in NCI-H460 [p < 0.01], and 19.4 nM vs 150 nM in MCF7 [p < 0.001]). Complete inhibition of pS6 phosphorylation in A549 cells at 24 hours was achieved with 6.7 nM EVE, but required 20 nM TEM. In all xenograft models, EVE and TEM showed a dose-response relationship over the range of 0.1-2.5 mg/kg/day. EVE was significantly more potent than TEM in the A549 model (EC50, 0.11 mg/kg vs 0.51 mg/kg; p = 0.002); no appreciable differences between EVE and TEM were observed in the KB-31, KB-8511, and HCT-116 xenograft models. However, correcting for drug exposure suggests increased potency of EVE over TEM. Conclusions: Compared with TEM, EVE had a higher affinity for the molecular target of FKBP-12. This was consistent with more potent antitumor activity in vitro and in vivo. Whether these data would translate into a better therapeutic index for EVE is unknown. However, the results suggest that these mTOR inhibitors may not be clinically interchangeable.
PD-L1 expression in primary clear cell renal cell carcinomas (ccRCCs) and their metastases.
Authors: Callea Marcella , Genega Elizabeth M , Gupta Mamta , Fay André P , Song Jiaxi , Carvo Ingrid , Bhatt Rupal Satish , McDermott David F. , Atkins Michael B. , Choueiri Toni K. , Freeman Gordon J , Signoretti Sabina 
Published: February 2017

467 Background: Clinical trials evaluating anti-PD-1 and anti-PD-L1 antibodies (Abs) in ccRCC have shown promising efficacy in a subset of patients. Preliminary studies have demonstrated that tumor PD-L1 expression increases the likelihood of benefit with anti-PD-1 Ab, but fails to identify all responders. One potential explanation for these results is that predictive biomarkers are usually evaluated in the primary tumors, which are more readily available; however, biomarker expression in nephrectomy samples may not accurately reflect expression in the metastases that are being targeted by therapy. In this study, we compared PD-L1 expression in a series of ccRCCs and their metastases. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue blocks from 34 primary ccRCCs and corresponding metastases were retrieved. Multiple areas of the primary tumors, including areas of predominant and highest Fuhrman nuclear grade (FNG), were selected for analysis. Slides were immunostained with a mouse monoclonal anti-PD-L1 antibody (405.9A11). The assay was validated using FFPE cell line controls known to be positive or negative for PD-L1 expression by flow cytometry. The presence of tumor cells with membranous staining was assessed. A case was considered positive when any tumor cell positivity was detected. Results: Positive membranous PD-L1 expression in tumor cells was observed in 10/34 (29%) primary ccRCCs. In 3 of these 10 cases (30%), the metastases were negative. In 2 cases the primary tumor was negative but the metastases were positive. In twenty-two cases, both the primary tumor and the corresponding metastasis were negative. The pattern of PD-L1 staining was highly heterogeneous in the primary tumors and was restricted to areas of highest FNG. The staining was more homogeneous in the metastases. PD-L1 expression by the tumor infiltrating immune cells is currently being evaluated. Conclusions: Discordant expression of PD-L1 between the primary tumor and the corresponding metastases was detected in 5/34 (15%) cases, suggesting that accurate assessment of predictive biomarkers for PD-1 blockade in ccRCC might require analysis of metastatic lesions. Analysis of a larger patient cohort is ongoing to confirm these findings.
Correlation of distinctive angiogenetic profiles with clinical outcome for different treatment sequences in mRCC.
Authors: Bianconi Maristella , Scartozzi Mario , Faloppi Luca , Loretelli Cristian , Zizzi Antonio , Giampieri Riccardo , Bittoni Alessandro , Del Prete Michela , Burattini Luciano , Montironi Rodolfo , Cascinu Stefano 
Published: February 2017

474 Background: Renal cell carcinoma treatment has radically changed in recent years, revolutioning patients’ outcome. Treatment strategies comprises TKIs, mainly directed against the angiogenic pathway, and mTOR inhibitors. Patients’ response to these treatments is widely variable and the optimal sequence is still matter of debate. In our previous report VEGF and VEGFR polymorphisms showed a predictive and prognostic role in the first-line treatment with sunitinib or pazopanib. The aim of our study was to evaluate the potential predictive and prognostic role of VEGF and VEGFR polymorphisms in defining a tailored sequence for RCC patients. Methods: 97 formalin-fixed paraffin-embedded tissue blocks from mRCC patients were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients were divided into two groups of sequences TKI-mTOR and TKI-TKI. SNPs results were correlated with progression free survival (PFS) and overall survival (OS). Results: 68 patients received second line treatment, either TKI or mTOR inhibitor. Patients expressing a TT polymorphism of VEGF A rs833061 had a better PFS compared to CC+CT polymorphism patients if receiving a mTOR inhibitor; while patients receiving a TKI had a better PFS if with a CC+CT polymorphism instead of a TT polymorphism of the same SNP (p<0,0001). OS analysis showed a similar correlation between polymorphism and treatment (p=0,0002). Conclusions: Our findings suggest that angiogenetic profile according to VEGF A rs833061 polymorphism may have a relevant role in selecting the most appropriate treatment sequence in mRCC patients. This selection tool would allow clinicians to improve efficacy and avoid unnecessary toxicity thus resulting in a better patients’ outcome and global quality of life.