bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic significance of indeterminate lung nodules in renal cell carcinoma.
Authors: Xu Rena , Horick Nora , McGovern Francis J. , Dahl Douglas M. , Feldman Adam S. , Blute Michael L. , Olumi Aria F. , Michaelson M. Dror 
Published: February 2017

377 Background: Many patients with newly diagnosed renal cell carcinoma (RCC) are found to have indeterminate lung nodules at the time of diagnosis. Current guidelines are vague about the necessity and frequency of additional chest imaging. We sought to determine whether the presence of indeterminate lung nodules at the time of diagnosis affects long-term survival for patients with early stage RCC. Methods: A retrospective review was performed of all patients at our institution who underwent nephrectomy for stage I-III RCC between 2001 and 2006 and had baseline chest imaging available for review. Presence of indeterminate lung nodule(s) on preoperative chest imaging was determined, along with tumor stage, grade, and histology; patient age, gender, body mass index, and smoking status; and Charlson comorbidity score. The time from diagnosis to last documented follow-up, and to first detected metastasis and/or death if applicable, was determined. Univariate and multivariate analyses were performed. The primary outcome of interest was disease-free survival; the secondary outcome was overall survival. The study follow-up period extended to July 2012. Results: In a multivariate analysis of 240 patients, disease-free survival was significantly associated with the presence of indeterminate lung nodules (HR 1.900, 95% CI: [1.042, 3.463]; p = 0.036). The number and size of the nodules did not add statistical significance. Disease-free survival was also associated with tumor stage (stage II: HR 5.611, p < 0.001; stage III: HR 2.488, p = 0.0129) and grade (HR 2.433 for grade 3 or 4, p = 0.005). Overall survival was only associated with Charlson comorbidity score (HR 1.294, p < 0.0001) and primary tumor size (HR 1.287, p < 0.0001). Conclusions: The presence of indeterminate lung nodules at the time of diagnosis of RCC had a negative impact on disease-specific survival. Tumor stage and grade were also significant prognostic factors. These findings underscore the importance of baseline chest imaging as well as vigilant surveillance of patients in whom lung nodules are identified.
Contrasting the vascular response to sunitinib as measured by DCE-CT, DCE-MRI, and DCE-US.
Authors: Hudson John M. , Williams Ross , Bailey Colleen , Kiss Alex , Milot Laurent M. , Atri Mostafa , Stanisz Greg J. , Burns Peter N. , Bjarnason Georg A. 
Published: February 2017

378 Background: Medical imaging (DCE-MRI, DCE-CT, DCE-US) provides localized information about the integrity and hemodynamics of the tumor microvasculature. Methods: 34 treatment (Rx) naive pts with mRCC and an abdominal tumor suitable for imaging received Sunitinib 50 mg on a 4wk-on/2wk-off schedule. DCE-US, DCE-CT, and DCE-MRI were done at baseline, during the first course of Rx and after 2wks off Rx. Imaging parameters obtained included vessel permeability (Ktrans), extracellular volume fraction (ve) and Ktrans/ve=Kep (by DCE-MRI), permeability surface product (PS, by DCE-CT), blood volume (BV, by DCE-CT and DCE-US), and blood flow (by DCE-US). We also developed a morphology parameter (MP) that relates the flow kinetics of an intravascular microbubble contrast agent to tumor vascular morphology using DCE-US. Results: A range of imaging parameters that predicted for progression free survival (PFS) were identified in responding pts (N = 26). Baseline imaging parameters correlated with PFS: Ktrans by DCE-MR (r = 0.53, p = 0.01, N = 24), BV by DCE-CT (r = 0.48, p = 0.02, N = 25) and disorganized vessel morphology (large MP) by DCE-US (Spearman r = 0.-0.45, p = 0.02, N = 24). Changes from baseline imaging parameters correlated with PFS: BV by DCE-US at 2 wks (r = -0.46, p = 0.02, N = 24), Kep by DCE-MR at 2 wks (r = -0.45, p = 0.03, N = 24) and MP at 1wk (r = 0.67, p = 0.02, N = 12). There was a correlation between imaging methods: BV measured by DCE-CT correlated with BV by DCE-US (r = 0.46, p = 0.03, N = 23) and Kep by DCE-MR (r = 0.59, p = 0.003, N = 22); Permeability measured by DCE-MR (Ktrans) and DCE-CT (PS) correlated at 2wks (r = 0.56, p = 0.01, N = 21). Conclusions: This is the first study to contrast DCE-US, DCE-CT, and DCE-MRI imaging in pts receiving antiangiogenic therapy. Baseline parameters for all three methods can predict for PFS. Changes from baseline in DCE-US and DCE-MRI parameters also predict for PFS. There is a correlation between imaging methods in parameters that measure BV and permeability. A novel DCE-US parameter was developed (MP) that quantifies the degree of tumor vascular disorganization. Baseline values in MP and changes during Rx correlate with PFS. Clinical trial information: OCT1205, SU Timing RCC.
Effect of VEGF and VEGFR polymorphisms on clinical outcome and response in patients with advanced renal cell carcinoma receiving first-line treatment.
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

388 Background: For the last few years, sunitinib has been considered the standard treatment for first-line metastatic renal cell carcinoma, but in 2010 a new drug pazopanib had been approved for treatment in this setting. Recent data from the COMPARZ and PISCES study seem to suggest a non-inferiority of pazopanib confronted with sunitinib in PFS and OS and a patients’ preference for pazopanib if we consider quality of life parameters. The aim of our study is to investigate whether polymorphisms of VEGF and VEGFR can influence PFS and OS when patients are treated either with sunitinib or pazopanib as first-line treatment. Methods: 97 histologic samples of mRCC patients were tested for VEGF-A, VEGF-C, and VEGFR-1, 2, 3 single nucleotide polymorphisms (SNPs). Patients’ progression free survival (PFS) and overall survival (OS) were analyzed for first-line treatment. Results: In patients treated with sunitinib VEGF-A rs833061 resulted significant in PFS (CC+CT vs TT, p < 0.0001) and OS (p < 0.0001). VEGF-A rs699947 was significant for PFS (AA+AC vs. CC) p = 0.0001) and OS (p < 0.0001). VEGF-A rs2010963 was significant in PFS (CC vs. CG vs. GG, p = 0.0001) and in OS (p = 0.0045). VEGR3 rs6877011 was significant in PFS (CC vs. CG, p = 0.0075) and OS (p = 0.0001). At multivariate analysis rs833061, rs2010963, and rs68877011 were significant in PFS. rs833061 and rs68877011 were independent factors in OS. In the pazopanib treated groups of patients VEGF-A rs833061 resulted significant in PFS (TT+CT vs. CC p = 0.027) Conclusions: In our analysis patients with CC or CT polymorphism of rc833061 had a favourable PFS and OS if treated with sunitinib instead patients treated with pazopanib seems to have benefit if CT+TT polymorphism, A polymorphism rs699947 and G polymorphism of rs2010963 seem to have a better PFS and OS in first line with sunitinib. Patients with C polymorphism of rs6877011 and G polymorphism of rs307822 seem equally to have a favourable impact in first-line therapy with sunitinib. Our data seem to suggest that biology could have a role in the choice of first-line treatment for mRCC patients. Further data will be presented at the Symposium.
Association of a 2-weeks-on and 1-week-off schedule of sunitinib with decreased toxicity in metastatic renal cell carcinoma.
Authors: Najjar Yana George , Elson Paul , Wood Laura S. , Garcia Jorge A. , Dreicer Robert , Rini Brian I. 
Published: February 2017

406 Background: Treatment of metastatic renal cell carcinoma (mRCC) with sunitinib can be associated with toxicity leading to dose reduction. Maintaining adequate sunitinib dosing and avoiding dose interruptions that lower drug levels are essential for optimizing clinical efficacy. Standard sunitinib schedule is 4 weeks of treatment and 2 weeks of rest (schedule 4/2). Empirically in clinical practice, several metastatic RCC patients at The Cleveland Clinic (CCF) have been changed from a 4/2 schedule to a 2 weeks on /1 week off (2/1) schedule after experiencing toxicity in an attempt to maintain daily dose but reduce toxicity. Methods: The medical records of mRCC patients who were changed to a 2/1 schedule of sunitinib at CCF were retrospectively reviewed. Patient toxicity on each schedule was recorded during routine clinic visits and graded according to the Common Toxicity Criteria, version 4.0. Results: 21 patients were identified: 71% male, 78% clear cell histology, and 29% prior systemic therapy. All but one had prior nephrectomy. 95% of patients on the 4/2 schedule had grade 3 or 4 toxicity which led to the schedule change to 2/1. No grade 4 toxicities were observed on the 2/1 schedule, and 33% of patients experienced grade 3 toxicity (p = 0.0001 for comparison of worst grade toxicity on 4/2 versus 2/1). Two of the most common toxicities, fatigue and hand-foot syndrome (HFS), were significantly less frequent on the 2/1 schedule than on the 4/2 schedule (fatigue 52% all grade/33% grade 3 on 4/2 versus 33%/14% on 2/1; HFS 33%/29% on 4/2 versus 14%/0% on 2/1; p =.04 for both). Median overall treatment duration on the 4/2 schedule was 13.5 months (range 1.1-60.6 months) and median overall treatment duration on the 2/1 schedule was 24.4 months (range 1.3 to 67.6+ months). Conclusions: Treatment with sunitinib on a 2/1 schedule is associated with significantly decreased toxicity in patients who initially experience grade 3 or greater toxicity on the 4/2 schedule and can extend treatment duration considerably. Prospective clinical trials are required to define the optimal schedule of sunitinib to balance efficacy and toxicity.
Relative quantification of protein expression in metastatic renal cell carcinoma using iTRAQ LC-MS/MS analysis reveals galectin-1 as a potential prognostic marker and therapeutic target.
Authors: White Nicole M.A. , Masui Olena , DeSouza Leroi , Krakovska Olga , Matta Ajay , Bjarnason Georg A. , Siu K.W. Michael , Yousef George M. 
Published: February 2017

412 Background: Metastatic renal cell carcinoma (RCC) is one of the most treatment-resistant cancers. Identification of proteins involved in tumor progression will help gain a better understanding of the disease and will form the basis for the identification of novel therapeutic targets. Methods: Using six fresh-frozen primary and six unmatched metastatic RCC tumors, we used iTRAQ labeling and LC-MS/MS analysis to identify proteins differentially expressed in metastatic versus primary RCC. We verified protein expression by western blot and immunohistochemical analyses and the measured the effect of dysregulated protein expression on biological processes with RCC cell line models. Results: After analysis, we identified 29 proteins differentially expressed in metastatic versus primary RCC. We verified expressions of profilin-1, 14-3-3 zeta/delta, and galectin-1 (Gal-1) on two independent tissue sets by western blot (10 primary and 10 metastatic RCC tissues) and immunohistochemistry (22 primary and 23 metastatic tissues). Overexpression of Gal-1 in CAKI-1 cells lead to decreased actin, increased vimentin expression, and increased cellular migration. Additionally, when Gal-1 was decreased via siRNA, cells showed decreased cellular migration. Protein array analysis showed expression of cell motility-related proteins HSP27, JNK, and RSK, were altered after siRNA transfection. We also showed that Gal-1 expression was increased in response to HIF-1alpha. Furthermore, we analyzed the expression of Gal-1 mRNA in 404 RCC patients using the Cancer Genome Anatomy Project, and found that patients who had higher Gal-1 expression in the primary RCC had significantly decreased overall survival (41 vs. 78 months; p < 0.01). Conclusions: Gal-1 is increased in metastatic RCC and can effect cell migration by targeting proteins involved in cell motility. This may be a downstream effect of HIF-1α dysregulation. Decreased Gal-1 significantly decreased cellular migration suggesting Gal-1 may serve as a potential therapeutic target. Additionally, we showed that increased Gal-1 expression was associated with decreased overall survival.
Prognostic impact of baseline serum C-reactive protein in metastatic renal cell carcinoma treated with sunitinib.
Authors: Yann-Alexandre Vano , Beuselinck Benoit , Wolter Pascal , Teghom Corine , Philip Debruyne , Karadimou Alexandra , Lerut Evelyne , Robert Paridaens , Schöffski Patrick , Oudard Stephane 
Published: February 2017

425 Background: The aim of our study was to determine whether baseline serum C-reactive protein (CRP) level could predict outcome of patients with metastatic renal cell carcinoma (mRCC) receiving sunitinib in first-line setting. Methods: We reviewed the charts of 187 consecutive patients in three hospitals in Belgium and France who started sunitinib as first targeted treatment between 2005 and 2012. Data were collected from each individual patient file on known prognostic factors for mRCC and anatomical location of metastatic sites, response rate, progression free survival (PFS), and overall survival (OS). Results: 187 eligible patients were identified by retrospective chart review. Median PFS was 26 months in the group with baseline CRP within normal limits (≤5 mg/l) versus 8 months in the group with elevated baseline CRP (>5 mg/l) (p < 0.0001). Median OS was 50 versus 12 months respectively (p < 0.0001). In the group with normal baseline CRP, 69% of patients experienced a partial response (PR) compared to 31% of patients in the group with elevated baseline CRP (p < 0.0001). On multivariate analysis, taking into account baseline neutrophil count, platelet count, ECOG PS, serum lactate dehydrogenase (LDH) activity, hemoglobin levels, corrected serum calcium levels, interval between initial diagnosis of RCC and start of systemic therapy </≥12 months, presence/absence of liver metastases or bone metastases and prior nephrectomy, baseline serum CRP-level was found to be an independent variable associated with poor PFS (p = 0.01) and OS (p < 0.0001). Conclusions: Baseline serum CRP level is an independent parameter correlated with ORR, PFS and OS in mRCC patients treated with sunitinib in first-line. [Table: see text]
Prostate-specific mRNA detection in whole blood as an analytically validated prognostic biomarker for patients with castration-resistant prostate cancer (CRPC).
Authors: Danila Daniel Costin , Anand Aseem , Heller Glenn , Wan Mingliang , Herkal Amrita , Patel Chintan , Khanin Raya , Schultz Nikolaus , Lilja Hans , Fleisher Martin , Scher Howard I. 
Published: February 2017

45 Background: To estimate the association between molecular biomarkers and outcomes, robust assays are needed before qualification in prospective trials. Although tumor specific transcripts detected in blood by PCR have been associated with outcome, an analytically validated PCR platform enabling detection of CTC-associated transcripts in clinical settings remains to be identified. Here we explore detecting a panel of prostate specific transcripts in conjunction with conventional markers in CRPC. Methods: Blood was collected from 97 patients with progressive CRPC in PAXgene tubes (2.5 ml) for total RNA extraction. Five genes expressed in prostate but not in nucleated blood cells were analyzed by primer-specific RT-PCR. Fluidigm Dynamic Array platform was analytically validated for KLK3, KLK2, HOXB13, GHRL2 and FOXA1 assays. Each PCR-reaction was run in 6 replicates, detection thresholds for each gene were chosen by ROC analysis of an independent set of 56 CRPC patients versus 51 healthy volunteers, and results were reported as transcripts present or absent. CellSearch reported CTC number/7.5 ml of blood drawn into CellSave tube. Results: Prostate specific transcripts for KLK3, KLK2, HOXB13, GHRL2 and FOXA1were detected in 50 (52%), 39 (40%), 53 (55%), 28 (29%) and 47 (48%) of patients, respectively.Two or more genes were detected in 53/97 patients (55%, 95% CI 45-65%) of patients with progressive CRPC studied with a median survival time of 17 months (95% CI: 13.8, 23.5). 40/45 CRPC-patients with ≥5 CTC and 13/52 CRPC patients with <5 CTC had transcripts present in blood. CTC and the gene panel had a substantial level of agreement, kappa of 0.631 (95% CI: 0.479, 0.783). Transcript detection predicted overall survival in proportional hazards models that included LDH dichotomized at 250. The predictive accuracy (CPE) of PCR detection + LDH was 0.759 (SE 0.035), comparable to CTC-enumeration + LDH (0.771, SE 0.033). Conclusions: Detecting prostate specific mRNA in whole blood using validated RT-PCR assays, applicable to larger CRPC cohorts, provides prognostic value. The clinical utility in monitoring treatment will be prospectively explored.
Postoperative modified Glasgow prognostic score as an independent predictor of overall survival in clinically localized clear cell renal cell carcinoma.
Authors: Herrel Lindsey Allison , Tai Caroline Gar-Ling , Westby Ruth , Ogan Ken , Canter Daniel , Pattaras John , Nieh Peter , Master Viraj A. 
Published: February 2017

456 Background: Renal cell carcinoma (RCC) demonstrates heterogeneous behavior. Approximately 30% to 40% of patients with clinically localized RCC will later metastasize. Current tools are imperfect for predicting who will have distant spread of disease. The utility of the modified Glasgow Prognostic Score (mGPS) calculated from C-reactive protein (CRP) and albumin levels, has been well-studied as a pre-operative predictive tool in patients with various solid organ malignancies, including clear cell renal cell carcinoma. This score has not been used in the post-operative setting, and we hypothesized that mGPS can be a powerful tool to predicting overall survival. Methods: Patients undergoing nephrectomy for clinically localized RCC from 2005 to 2010 were studied. Inclusion criteria required clear cell histology and no nodal or metastatic disease at the time of surgery. Additionally, only patients with post-operative C-reactive protein and albumin recorded were included in the analyses. Demographic and clinico-pathological variables were analyzed as categorical variables with the exception of age and tumor size, which were analyzed as continuous variables. Patients were assigned an mGPS score of 0, 1, or 2 based on post-operative data (0 = CRP ≤ 10 mg/l, 1 = CRP>10 mg/l and 2 = CRP>10 mg/l and albumin<3.5 g/dL). Survival analyses utilized Kaplan-Meier and multivariate Cox regression models. Results: Study criteria were met in 142 patients. Mean age was 59 years and 61% were men. No patients had T4 disease while 25% had T3, 9% had T2, and 66% had T1 disease. A post-operative mGPS of 0, 1, and 2 was assigned to 69%, 13% and 18% of the study population, respectively. Multivariate analysis identified post-operative high mGPS (mGPS = 2) as an independent predictor of overall survival (HR 5.591; CI 95% 1.508, 20.734; p = 0.010). Conclusions: In patients with clinically localized clear cell renal cell carcinoma, post-operative mGPS score is an independent predictor of overall survival. Accordingly, mGPS may be a useful tool to monitor disease progression in this patient population.
Renal cell carcinoma: A prognostic target for spectral pathology.
Authors: Hughes Caryn S. , Brown Mick D. , Gardner Peter , Shanks Johnathan H. , Clarke Noel W. , Jimenez-Hernandez Melody 
Published: February 2017

459 Background: In contrast to standard pathology, where stained cells and tissues are examined visually under a microscope, spectral pathology is the study of changes in cellular composition of unstained tissue using molecular fingerprint techniques, such as infrared and Raman spectroscopy. Hyperspectral images are collected which provide not only spatial information but also data of high dimensionality, probing the global biochemistry of the biological specimen in the mid-infrared range. Methods: 9 paraffin-embedded, formalin-fixed clear cell renal carcinoma tissue sections (8μm thick) of different grade, stage and with respective matched pairs, were floated onto infrared-transmitting substrates. After dewaxing, Fourier transform infrared imaging spectroscopy was performed on a Varian 670-IR spectrometer coupled with a Varian 620-IR imaging microscope (Agilent Technologies, CA) equipped with a 128×128 pixel Mercury-Cadmium-Telluride focal planar array detector. A hyperspectral image is obtained whereby each pixel records an infrared spectrum at a pixel resolution of ~5.5x5.5μm. Mosaic images were captured of full tissue specimens (one imaging tile equates to a tissue sampling area of ~700×700μm). Results: We have been able to detect the phenotype of ccRCC and observed a diminishing glycogen-rich signal during tumour progression towards high grade tissue. The spectral characteristics of ccRCC have been correlated with H and E, PAS, and CA-IX staining. Conclusions: Cancer metabolism can be tracked by lipid and glycogen infrared bands that carry a unique spectral signature, depending on tumour aggressiveness. The future focus is to generate a prognostic model for small renal masses.
Effect of novel growth hormone-releasing hormone antagonists on growth of experimental renal cell carcinomas.
Authors: Rick Ferenc , Szalontay Luca , Abi-Chaker Andrew , Block Norman L. , Halmos Gabor , Schally Andrew V. 
Published: February 2017

469 Background: Although targeted therapy has improved the clinical outcome for patients with metastatic renal cell carcinoma (RCC), a complete response is rare and therapy has adverse effects. Early antagonists of growth hormone-releasing hormone (GHRH) were shown to inhibit experimental RCC cell line, Caki-1, in vitro and in vivo. Herein, we investigate the effects of novel and highly potent antagonists of GHRH of MIA class on the growth of three RCC cell lines. Methods: The expression of GHRH receptor in all three cell lines was evaluated by ligand competition studies. The influence of GHRH antagonists MIA-602, MIA-604, MIA-606, and MIA-690 on cell viability was assessed by MTS assay in ACHN, A498, and 786-0 human RCC cells. GHRH antagonists were given at dose of 5µg daily in these three nude-mice xenograft models. Cell cycle parameters were analyzed by laser flow cytometry. Results: Ligand competition studies revealed specific, high affinity binding sites for GHRH receptor in all three RCC cell lines. GHRH antagonists inhibited the proliferation of all three RCC cells in a dose dependent manner. GHRH antagonists caused significant inhibition of tumor growth of ACHN, A498, and 786-0 RCCs ranged from 53-75% after 35 days of treatment (p<0.001). Treatment of ACHN cells with MIA-690 (10µM) led to a significant increase in number of cells with subG1DNA content, suggesting apoptosis. Conclusions: The effectiveness of the novel GHRH antagonists in inhibiting growth of experimental RCC models in vitro and in vivo was demonstrated. The inhibitory effect of GHRH antagonists is mainly due to direct inhibitory effects exerted through GHRH receptors. Biochemical and histological evaluation is needed to explore the mechanisms of action of GHRH antagonists in RCC.