bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response to systemic therapy in non-clear cell renal cell carcinomas: A systematic review and meta-analysis.
Authors: Vera-Badillo Francisco Emilio , Templeton Arnoud , Ocana Alberto , deGouveia Paulo , Aneja Priya , Knox Jennifer J. , Tannock Ian , Duran Ignacio , Escudier Bernard J. , Amir Eitan 
Published: February 2017

425 Background: Clinical data supporting the efficacy of systemic therapy in non-clear cell renal cell carcinoma (non-ccRCC) are limited and based on retrospective analyses, expanded access programs and single arm phase II trials. Therefore the optimal treatment for this subgroup remains uncertain. Methods: A systematic review of electronic databases was conducted to identify publications evaluating the outcomes of patients with non-ccRCC (excluding those with sarcomatoid tumors) treated with different systemic approaches (immunotherapy, chemotherapy, targeted agents, small molecules). The primary endpoint was response rate and secondary endpoints were median progression free (PFS) and overall survival (OS). Where possible, data were pooled in a meta-analysis using the Mantel-Haenszel random-effect modeling. For studies comprising of unselected patients, outcomes of those with non-ccRCC were compared with clear cell renal cell carcinoma (ccRCC). Results: Forty-nine studies comprising 7,799 patients were included: 471 patients were enrolled on studies conducted exclusively in non-ccRCC and 7,328 patients on studies of unselected renal cell carcinoma. Among these, 903 (12%) had non-ccRCC and 6,425 (88%) had ccRCC. For non-ccRCC, overall response rate, median PFS and median OS were 9%, 7.9 and 13.4 months, respectively. By comparison, the overall response rate for ccRCC was 15% (Risk Ratio for response [RR] 0.67, 95% CI 0.52-0.86, p=0.002). This association was independent of type of treatment administered. Among the different novel agents (bevacizumab, lenalidomide, linefanib, sorafenib, sunitinib, pazopanib, everolimus and temsirolimus), sunitinib was significantly less efficacious in non-ccRCC than ccRCC (RR 0.56, 95% CI 0.42-0.72), but there was no significant difference in response rates for sorafenib (RR 0.64, 95% CI 0.31-1.35) or other agents (RR 1.10, 95% CI 0.50-2.44), However, confidence intervals were wide. Results of further analyses will be presented at the meeting. Conclusions: Patients with non-ccRCC have lower response rates than those with ccRCC, but the absolute difference between them is modest. Further study of targeted therapy in non-ccRCC is warranted.
Circulating biomarkers and outcomes in a single-arm phase II trial of first-line sunitinib alternating with everolimus for advanced renal cell carcinoma (aRCC): EVERSUN ANZUP trial 0901.
Authors: Yip Sonia , Pavlakis Nick , Harvie Rozelle , Martin Andrew , Jovanovic Lidija , Hudson Amanda , Thompson Jennifer F. , Nelson Colleen , Long Anne , Steer Christopher , Harrison Michelle L. , Kannourakis George , Goldstein David , Kichenadasse Ganessan , Lowenthal Raymond M. , Stockler Martin R. , Davis Ian D. ,   ANZUP Cancer Trials Group
Published: February 2017

428 Background: We sought biomarkers at baseline associated with clinically important outcomes in this trial of alternating sunitinib and everolimus. Methods: Baseline blood was tested for circulating tumor cells (CTCs) using CellSearch CTC system (Veridex). Baseline serum was tested for protein biomarkers: bFGF, CAIX; e-selectin; HIF1; IL8; NGAL; PDGF; PLGF; vCAM; VEGF-A, C and D; VEGFR1-3; by multiplex immunoassays (Bio-Plex system BioRad) or ELISA (R&D Systems DuoSets). Biomarker levels were dichotomised according to median or limit of detectability. Outcomes were progression free, overall survival (PFS, OS), objective tumour response (OTR) and toxicity (cycle 1 grade 3-5 AEs). Regression models were used for hazard ratios (HR), odds ratios (OR), p-values (p) in univariable analysis, adjusted for established prognostic factors in multivariable analysis. Results: Patient (n=55) characteristics were mean age 61 yrs: male 71%; MSKCC good risk 16%, intermediate risk 84%. There were 47 progression events and 30 deaths after a median follow-up of 20 mos. CTCs were detected in 5/31 (16%). Univariable analysis showed associations between OTR and low levels of bFGF (6 v 0, p 0.009); shorter OS and high levels of both NGAL (HR 2.5, p 0.02) and IL8 (HR 2.3, p 0.04); toxicity with detectable levels of CAIX (OR 4.7, p 0.03); none was associated with PFS. Adjusting for MSKCC prognostic score, age, gender and presence of liver or bone metastases: shorter PFS was associated with high bFGF (HR 2.0, p 0.03), low vCAM1 (HR 0.50, p 0.04), undetectable HIF1 (HR 0.33, p 0.01), shorter OS was associated with high NGAL (HR 2.5, p 0.03) and undetectable HIF1 (HR 0.35, p 0.04). Toxicity was associated with detectable CAIX (OR 5.8, p 0.04). None were statistically significant after adjusting for multi-comparisons. Conclusions: This exploratory study did not find strong statistical evidence for the prognostic value of these circulating baseline biomarkers. Prognostic value of changes from baseline during therapy remains an important area of study. EVERSUN is an ANZUP Cancer Trials Group Ltd trial coordinated by NHMRC Clinical Trials Centre (ACTRN12609000643279).
Integrated analysis of metastatic disease in clear cell renal cell carcinoma: A collaborative TCGA analysis.
Authors: Hakimi A. Ari , Jacobsen Anders , Mano Roy , Gonen Mithat , Voss Martin Henner , Reuter Victor E. , Rathmell Kimryn , Maranchie Jodi Kathleen , Appleman Leonard Joseph , Tamboli Pheroze , Signoretti Sabina , Choueiri Toni K. , Russo Paul , Motzer Robert John , Hsieh James ,   Clinical TCGA ccRCC Consortium
Published: February 2017

432 Background: We sought to identify molecular and genetic features that were associated with metastatic disease at presentation in a cohort of patients derived from the Cancer Genome Atlas (TCGA) ccRCC dataset though our collaborative Clinical TCGA (cTCGA) consortium. Methods: Three hundred forty two patients comprising the cTCGA dataset were further evaluated for additional clinical information including the presence and timing of metastatic disease. Patients with clinical stage I or II disease were excluded. Clinical, molecular and genetic data were obtained and evaluated for their association with metastatic disease at presentation. Using somatic mutations (Exome-seq), DNA copy number (aCGH), mRNA expression (RNA-seq), and miRNA expression (miRNA-seq) data, we inferred molecular and genetic features associated with metastasis. We used random forest and elastic-net statistical learning methods to infer sparse feature combinations associated with metastatic disease at presentation. Results: The study cohort consisted of 147 patients, 81 (55%) of which had metastatic disease at presentation. Median follow was 26 months (Interquartile Range 10, 60) from the time of RCC diagnosis No significant difference in patient gender and age as well as tumor necrosis was found between patients with or without metastatic disease. However, patients with metastatic disease had larger tumors (median diameter 9.2cm vs. 6.8cm, p<0.001), and a higher percent of Fuhrman nuclear grade 3 or 4 disease (85% vs. 71%, p=0.04). Using both statistical learning methods we found that lower expression levels of GARNL3, C1orf172, NEK6 and SLC12A7 and higher expression levels of CEBPD, PITX2 and COMMD5 were associated with metastatic disease at presentation. Conclusions: When evaluating for various clinical, molecular and genetic features, alterations in specific gene expression are associated with metastatic disease in ccRCC patients. External validation in additional data sets is currently underway and further functional studies are required to better understand the therapeutic potential of these genes.
ADAPT: An ongoing international phase III randomized trial of autologous dendritic cell immunotherapy (AGS-003) plus standard treatment in advanced renal cell carcinoma (RCC).
Authors: Figlin Robert A. , Wood Christopher G. ,   ADAPT Study Group
Published: February 2017

449^ Background: AGS-003 is an autologous immunotherapy designed to induce an immune response to a patient’s own tumor. Sunitinib is a receptor tyrosine kinase inhibitor that has emerged as the standard of care in treatment-naïve RCC patients. The antitumor activity of sunitinib, together with its ability to reverse the immune suppression seen in RCC patients provided the rationale to combine sunitinib treatment with AGS-003 immunotherapy. In a single arm phase 2 study, AGS-003 in combination with sunitinib was safe and yielded a median overall survival (OS) of over 30 months in synchronous mRCC patients with one (DxTx<1yr) or more RCC risk factors. Methods: The study is seeking to enroll adults with synchronous mRCC with a time from diagnosis to treatment of < 1yr (DxTx<1yr) who are good candidates for surgery and standard targeted therapy (initiating with, but not limited to sunitinib), clear cell histology, 1-4 Heng RCC risk factors, KPS ≥ 70%, life expectancy of at least 6 months and adequate end organ function. Exclusion criteria include prior systemic RCC treatment, brain metastases, or requirement for chronic immunosuppressive therapy. While therapy initiates with sunitinib for all subjects, changes to other TKIs or mTOR inhibitors is permitted for early progression or toxicity. Results: Currently 94 sites have been initiated with more than 120 patients consented for tumor collection and 35 randomized to treatment as of September 2013. To date, nearly 50% of patients consented for tumor collection have been excluded from participation in the treatment phase of the ADAPT study due to non-clear cell histology, cardiac history, thromboembolic disorders and other criteria making them unsuitable candidates to initiate standard TKI therapy. Conclusions: Patients with newly diagnosed, synchronous mRCC present with poor prognosis and other features which may prohibit the safe or effective initiation and administration of TKIs. Exclusion criteria have recently been amended to optimize enrollment. Further details regarding study progress, baseline patient characteristics, eligibility disposition and updated figures will be presented. Clinical trial information: NCT01582672.
Outcomes of patients (pts) with metastatic non-clear-cell renal cell carcinoma (nccRCC) treated with pazopanib.
Authors: Matrana Marc Ryan , Baiomy Ali , Elsayes Khaled M. , Shetty Aditya , Teegavarapu Purnima Sravanti , Xiao Lianchun , Jonasch Eric , Tannir Nizar M. 
Published: February 2017

456 Background: Pazopanib prolongs progression-free survival (PFS) in treatment-naive and cytokine-refractory metastatic clear-cell RCC. Outcomes and safety data with pazopanib in metastatic nccRCC are limited. Methods: We retrospectively reviewed records of metastatic nccRCC pts who received pazopanib in the frontline and salvage settings (11/2009-11/2011). Response was assessed by a blinded radiologist (RECIST v1.1). PFS and overall survival (OS) were estimated by Kaplan-Meier methods. Log rank tests and univariate Cox models were used to evaluate the associations of OS and PFS with pt characteristics. Results: 29 pts were identified (frontline, 9; salvage after PD with other targeted therapies, 20). Seven (24%) had papillary, 4 (14%) chromophobe, 5 (17%) unclassified, and 13 (45%) other subtypes. PFS, OS, and objective response rates (ORR) are shown in the table. Improved OS was associated with prior nephrectomy in frontline pts, and in salvage pts with younger age, non-white race, absence of bone metastases, normal platelet count, higher albumin level, KPS>80, and MSKCC good-risk disease. There were no significant associations between frontline pt characteristics and PFS, but improved PFS was associated with normal platelet count, KPS>80, lower LDH, and higher albumin level in the salvage setting. Common adverse events (AEs): fatigue (31%), elevated transaminases (24%), diarrhea (21%), nausea/vomiting (17%), anorexia (17%), hypothyroidism (7%), and hypertension exacerbation (7%); 83% of AEs were grade 1/2. Six (21%) discontinued therapy due to AEs. There were no treatment-related deaths. Conclusions: Pazopanib demonstrated efficacy in pts with metastatic nccRCC. Toxicity was mild/moderate and manageable. [Table: see text]
Neutrophil to lymphocyte ratio (NLR) and its effect on the prognostic value of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model for patients treated with targeted therapy (TT).
Authors: Templeton Arnoud J. , Heng Daniel Yick Chin , Choueiri Toni K. , McDermott David F. , Fay André P , Srinivas Sandy , Harshman Lauren Christine , Beuselinck Benoit , Smoragiewicz Martin , Kim Jenny J. , Knox Jennifer J. 
Published: February 2017

470 Background: The neutrophil to lymphocyte ratio (NLR) is a marker of host inflammation and appears to have prognostic value in many solid tumors. We have found in a pilot RCC study that a NLR > 2.5 was predictive of a lower likelihood of response to TT on a multivariable analysis. Here we aim to explore the added value of the NLR to improve the prognostic value of the established IMDC criteria (Heng et al JCO 2009). Methods: We included patients from 7 consortium sites where NLR data was available for patients treated with TT and compared NLR cutoff <= 2.5 vs. >2.5 (i.e. low vs. high NLR) and adjusted using proportional hazards regression for the known poor prognostic criteria (listed in Table). Results: Data from 859 patients were included. NLR values were: Mean 4.98, Median 3.51, Mode 2.5, 95%CI 1.42 – 14.0. Using Cutoff <=2.5 vs. >2.5 Median overall survival (OS) is 30.4 months (95%CI 24.9-37.0, n= 237) vs. 15.7 months (95%CI 13.0-17.2, n=622); log-rank p value <0.0001. If we adjust for all six IMDC poor prognosis criteria in a proportional hazards regression model: HR of death for high NLR is 1.506 (1.177-1.928) p=0.0011, demonstrating NLR is still an independent predictor of poor OS even after using IMDC criteria. Conclusions: The NLR is a simple clinical value and is independently associated with poor overall survival even after adjustment for IMDC factors, including neutrophilia. The updated data set will be presented. [Table: see text]
Preclinical activity of the heat shock protein 90 inhibitor ganetespib in clear cell renal cell carcinoma.
Authors: Parasramka Mansi , Proia David A. , Joseph Richard Wayne 
Published: February 2017

478 Background: Resistance invariably develops in all patients with metastatic ccRCC treated with mTOR inhibitors. Previously we demonstrated that dual inhibition of Hsp90 and the mTOR pathway in lung cancer models leads to synergistic reductions in tumor growth. Herein, we tested the efficacy of ganetespib as a single agent and in combination with mTOR inhibition using in vitro and in vivoccRCC models. Methods: For the in vitro work we utilized the following seven ccRCC cell lines: Caki-1, Caki-2, A-498, A-704, 769-P, 786-O, ACHN. For the in vivo work we used A498 xenografts. In vitro, we determined the single agent EC50 of everolimus and ganetespib at 72 hours by assessing percent viability of A498 cells compared to vehicle using the MTS assay. We then performed combinations of ganetespib and everolimus at EC20, EC30, and EC50 in A498 cells. Translating these studies in vivo, we compared the combinatorial activity of ganetespib and temsirolimus to monotherapy in mice bearing A498 tumor xenografts. Results: As a single agent, all ccRCC cell lines tested were sensitive to ganetespib at nanomolar concentration (EC50 15 – 75 nm) and to everolimus at micromolar concentrations (EC50 4 – 54 mm). In vitro, the combination of ganetespib and everolimus also decreased cell viability in an additive fashion. In vivo, ganetespib and temsirolimus demonstrated comparable single agent activity at sub-MTD doses (T/C = 63 and 60, respectively). Combining ganetespib with temsirolimus improved tumor growth suppression by ~30% (T/C = 43). Conclusions: Given the broad in vitro sensitivity of ccRCC cell lines to single agent ganetespib as well as the in vivo activity of the combination of ganetespib and temsirolimus, we believe ganetespib warrants further study in ccRCC. Updated results will be presented at the conference including the in vivo activity of the combination of ganetespib and antivascular endothelial growth factor agents.
Circulating tumor cell kinetics in mRCC patients treated with sunitinib.
Authors: Mittal Kriti , Williams Anthony , Rawal Siddarth , Alva Venur Vyshak , Lu Bo , Torres-Munoz Jorge , Borden Ernest C. , Ao Zheng , OMalley Martin , Wood Laura S. , Zheng Siyang , Datar Ram H , Tai Yu-Chong , Cote Richard J. , Rini Brian I. 
Published: February 2017

481 Background: Detection of circulating tumor cells (CTCs) in renal cell carcinoma (RCC) is limited by inconsistent expression of epithelial cell adhesion molecule. We have previously detected CTCs using microfilter devices that exploit size differences between larger epithelial tumor and smaller non-tumor blood cells. Methods: Treatment naive pts with clear cell metastatic RCC (mRCC) were enrolled on a prospective phase II trial of intermittent sunitinib. Peripheral blood samples were collected at baseline, day 28 of cycles 1, 2, 4, and after the 8-week off-treatment period. Peripheral blood was diluted 1:1 with PBS and 1% formalin. Cells were captured with microfilters, stained with pan cytokeratin (CK) and CD45, conjugated with Alexa Fluor (AF) 594 and AF 488. Microfilters were cover-slipped with a DAPI containing medium for nuclear visualization. CTCs were identified as large CK+/CD45- events. Results: Pt characteristics (n=17) included 13 male/4 female; median age 65 years; median performance status KPS 90%; 100% prior nephrectomy. By Heng criteria, 4 pts were favorable, 12 intermediate and 1 poor risk. Site of metastases included lungs (59%), bone (41%) and lymph nodes (35%). Baseline CTCs (35 total samples collected) were detectable in at least one sample in 9 patients (53%), with a median CTC count of 6 (range, 1-31/ml); overall median CTC count was 1 CTC/ml including undetectable patients at baseline. Intrapatient variability was observed with the maximum intrapatient range of 4 to 58 CTCs/ml. After cycle 1 of sunitinib, median CTCs increased to 23 cells/ml (range, 0-94). Median CTCs after cycle 2 was 2 cells/ml (range, 0-322) and cycle 4 was 4.5 cells/ml (range, 0-500). After the 8 week off-treatment period, a median of 3.5 CTCs/ml (range, 0-242) were detected. In 6 patients with undetectable CTCs at baseline, CTCs were detected during the first 2 cycles of treatment, and in 4 of these patients, they declined or became undetectable by the last sampling period. Conclusions: A high rate of CTC detection is demonstrated using micro-filters in mRCC. CTC levels tend to increase during the first few weeks of treatment with sunitinib, and then decline with continued sunitinib and after sunitinib is held.
The regulation of clear cell renal cancer cells proliferation and tyrosine kinase inhibitors responsiveness by tumor micro-environmental factors.
Authors: Czarnecka Anna Malgorzata , Solarek Wojciech , Matak Damian , Khan Mohammed Imran , Kornakiewicz Anna , Szymanski Lukasz , Czarnecka Karolina , Lewicki Slawomir , Zdanowski Robert , Szczylik Cezary 
Published: February 2017

488 Background: Tumor microenvironment is a complex network of multiple cell types, paracrine and endocrine signaling molecules, ECM and physical factors, which orchestrate the fate of tumor progression. In the field of ccRCC little attention has been paid to non-immunologic factors in tumor niche. Objectives of this study include the analysis of hypoxia, triiodothyronine (T3), insulin, insulin-like growth factor-1 and -2 impact on ccRCC cells. The effect of above mentioned tumor niche factors on TKI activity on ccRCC cells was to be quantified. The study was initiated as ccRCC cells are known to harbor disrupted hypoxia response and TRbeta (TRβ) - T3 receptor - functions as a tumor suppressor with tissue hypothyroidism involved in maintaining a proliferative advantage, whereas hypothyroidisms was defined as biomarker of sunitinib treatment efficacy. Moreover obesity and diabetes (DM2) are considered risk factors for ccRCC and high IGF-I expression is associated with poor long-term patient survival. This research aims to find molecular background for clinically relevant observations. Methods: ccRCC cells from primary and metastatic tumors (ATCC, MSK collections) along with cancer progenitor cells (CD133+) were cultured in normoxic or hypoxic conditions; in defined media supplemented with T3, IN, IGF, TRβ inhibitor and TKIs (sunitinib, axitinib). Cell proliferation was evaluated using AlamarBlue and MTT. Colony formation potential was evaluated. TRβ gene expression was measured with RealTime-RT PCR and sequenced under standard protocol. Normal kidney proximal tube cells were used as negative control. Results: ccRCC TKI responsiveness is limited by hypoxia, at the same time tumor cell proliferation may be promoted by T3, IN and IGF. Colony formation potential of ccRCC cells under TKI treatment in hypoxic conditions is downregulated. Conclusions: Multiple micro-environmental factors modify the proliferation and/or differentiation of ccRCC cell populations. Understanding the complex molecular feedback loops between cancer cells and the surrounding microenvironment should aid the identification of novel targets for improving TKIs clinical management.
Sunitinib versus sorafenib as first-line therapy for patients with metastatic renal cell carcinoma with favorable or intermediate MSKCC risk factors: A multicenter randomized trial, CROSS-J-RCC.
Authors: Tomita Yoshihiko , Naito Sei , Sassa Naoto , Takahashi Atsushi , Kondo Tsunenori , Koie Takuya , Obara Wataru , Kobayashi Yasuyuki , Teishima Jun , Takahashi Masayuki , Matsuyama Hideyasu , Ueda Takeshi , Yamaguchi Kenya , Kishida Ken , Shiroki Ryoichi , Saika Takashi , Nobuo Shinohara , Oya Mototsugu , Kanayama Hiro-Omi 
Published: February 2017

502 Background: Sorafenib (SO), an earlier introduced kinase inhibitor, and sunitinib (SU), a standard first-line treatment drug for metastatic renal cell carcinoma (mRCC), were associated with progression-free survival (PFS) of 5.7 and 11 months (M) in independent clinical trials, respectively. We compared PFS of first-line SU and SO in a multicenter, randomized, open-label, phase III trial. Methods: Patients with untreated, measurable (by RECIST v1.1) clear-cell mRCC stratified according to MSKCC risk criteria, nephrectomy, and institution were randomized in 1:1 to receive SU (50 mg qd 4 wks on-2 wks off) or SO (400 mg bid). The calculated sample size was 59/group for α = 0.05, β = 0.10, and a censoring rate of 15%. Results: Of 124 enrolled patients, from Feb. 2010 to Jul. 2012, from 39 institutions, 120 were evaluable (SU, 57 and SO, 63). Patient baseline characteristics in the SU vs SO groups were as follows: favorable risk, 21% vs 22%; presence of stable brain metastasis, 8.8% vs 1.6% and with nephrectomy, 88% vs 89%. Median PFS (mPFS) was 8.7 and 7.0 M in the SU and SO groups, respectively (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.42–1.08; p= 0.095). mPFS was 31.2 and 6.2 M (HR 0.27, 95%CI 0.08–0.90; p = 0.023) in the favorable risk group, 11.9 and 6.5 M (HR 0.31, 95%CI 0.14–0.69; p = 0.035) in patients with T1 or T2 primary tumors, and 11.6 and 7.0 M (HR 0.41, 95%CI 0.36–0.98; p = 0.038) in those without brain metastasis, in the SU and SO groups, respectively. Objective response rates for SU group was 35.3%; SO was 27.8% (p = 0.407). Overall survival was not reached. The most common adverse events (all grade, all cause) were hand-foot syndrome (SU vs SO, 71% vs 86%), hypothyroidism (70% vs 33%), fatigue (57% vs 40%), hypertension (55% vs 44%) and diarrhea (23% vs 38%). Conclusions: The primary endpoint was not achieved, but SU tended to be associated with longer mPFS in all cases. In patients with favorable risk, T1 or T2 primary tumors or in those without brain metastasis, significantly longer mPFS were noticed. Brain metastasis was associated with poorer prognosis even if it was stable at baseline. Clinical trial number: NCT01481870. Clinical trial information: 01481870.