bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic polymorphisms and sunitinib outcome in metastatic renal-cell carcinoma: A prospective observational study and validation.
Authors: Farfán Carlos A. , Castellano Daniel E. , Rodriguez-Antona Cristina , Benitez Julio , De Velasco Guillermo , Villacampa Felipe , de la Rosa Federico , Andres Eva , Sepúlveda Juan Manuel 
Published: February 2017

403 Background: Sunitinib (SU) is an oral small-molecule, multi-targeted receptor tyrosine kinase inhibitor, which is approved as first-line treatment for metastatic renal cell carcinoma (RCC). In a previous study, using a commercially available DNA microarray genotyping system, we identified a group of single nucleotide polymorphisms (SNPs) associated with survival and toxicity in RCC patients, treated with SU. In this study, we validated our previous data using an independent series (García-Donas J, et al. Lancet Oncol 2011). Methods: 27 metastatic RCC treatment-naive patients, recruited prospectively from January 2010 to May 2011. All the patients received SU standard treatment. A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes involved in the pharmacokinetic and pharmacodynamic pathways of drugs, were analyzed using Drug inCode pharmacogenetic service. For validation we performed genotyping in 83 samples using the KASPar SNP genotyping system. Results: In patients with CYP1A2*1F and CYP2C19 *2 and *4 polymorphisms, no statistically significant associations were observed, among drug metabolizing genes and toxicity or survival. Catechol-O-methyltransferase(COMT) is involved in the inactivation of several substances suchs as cathecolamines and estrogens and Val(158)Met polymorphism which were associated with PFS and OS, it was observed in our initial study. Met/Met and Val/Met carriers had statistical significant difference in PFS and OS (p = 0.0001 and p = 0.0001, respectively) compared to Val/Val carriers. In the validation series, we were able to confirm the effect on PFS (p = 0.0102). Conclusions: Our preliminary analysis suggested that CYP1A2*1F and CYP2C19*2 and *4polymorphism may be associated with SU toxicity in RCC patients, but findings were not validated in an independent series. However, we could confirm an association between COMT VAl(158)Met polymorphisms and PFS. To our knowledge this is the first study to report COMT polymorphism to be associated with RCC survival.
Prognostic role of cell cycle–related biomarkers in clear cell renal cell carcinoma.
Authors: Gayed Bishoy A. , Youssef Ramy F. , Bagrodia Aditya , Kapur Payal , Sagalowsky Arthur I. , Lotan Yair , Margulis Vitaly 
Published: February 2017

404 Background: Cell cycle regulatory molecules are implicated in various stages of carcinogenesis. In this study we systematically evaluate the impact of aberrant expression of cell cycle regulators on oncological outcomes in clear cell renal carcinoma (ccRCC). Methods: After obtaining IRB approval, immunohistochemistry for Cyclin D, Cyclin E, p16, p21, p27, p53, p57, and Ki-67 was performed on tissue microarray constructs of patients treated with radical or partial nephrectomy for ccRCC between 1997-2010. Comprehensive clinical and pathologic data elements were collected. A prognostic marker score (MS) was defined as favorable if ≤4 biomarkers were altered; unfavorable if >4 biomarkers were altered. The relationship between MS and aggressive pathological features and oncological outcomes was evaluated. Results: The study included 452 patients, 277 males (61%). Median age was of 57 years (range, 17-85) and median follow up of 20 months (range, 0-150). The tumors demonstrated extrarenal extension (pT3-T4) in 120 (27%) patients and advanced grade (G 3/4) in 169 (37%). Regional nodal involvement and systemic metastases at the time of nephrectomy was present in 22 (5%) and 51(11%) patients, respectively. Unfavorable MS was found in 80 (18%) patients and was associated with distant and nodal metastasis, advanced T stage, advanced grade, tumor necrosis, sarcomatoid differentiation, lymphovascular invasion, fat invasion, adrenal involvement, and presence of venous thrombus (p < .05). A statistically significant correlation between unfavorable MS and disease recurrence (HR 6.5 and p = 0.01) and a correlation approaching significance with cancer specific mortality (HR 3.4 and p = 0.06) was demonstrated in Kaplan Meier survival analysis. In a multivariate Cox regression analysis, unfavorable MS was an independent predictor of disease recurrence (HR 2.268, CI 1.00-5.12 p = 0.049). Conclusions: The cumulative number of aberrantly expressed cell cycle biomarkers correlates with aggressive pathological features and inferior oncologic outcomes. Our findings support prospective pathway-based exploration of biomarkers to augment current clinico-pathologic predictors of oncologic outcomes in ccRCC.
Validation of the pretreatment neutrophil-lymphocyte ratio as prognostic factor regarding cancer-specific, metastasis-free, and overall survival in a European cohort of patients with renal cell carcinoma.
Authors: Hutterer Georg C. , Pichler Martin , Stoeckigt Caroline , Chromecki Thomas F. , Stojakovic Tatjana , Golbeck Silvia , Gerger Armin , Pummer Karl , Zigeuner Richard 
Published: February 2017

410 Background: The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammation response and data from previous studies report controversial results about its independent prognostic role in non-metastatic renal cell carcinoma (RCC). Thus, we decided to evaluate the prognostic significance of NLR in a large cohort of RCC patients. Methods: Data from 843 consecutive non-metastatic RCC patients, operated with radical nephrectomy or nephron sparing surgery between 2000 and 2010 at a single tertiary academic center, were evaluated retrospectively. Pre-treatment NLR was calculated one day before surgical intervention. Patients were categorized according to a NLR cut-off value of 3.2. Cancer-specific–, metastasis-free–, as well as overall survival were assessed using the Kaplan-Meier method. To evaluate NLR’s independent prognostic significance, a multivariate Cox regression model was performed for all three endpoints. Results: An increased NLR was associated with several well established prognostic factors including tumor size, tumor grade, and histologic tumor necrosis (all p<0.05). Although an increased NLR was statistically significantly associated with poor outcome for all clinical endpoints (p<0.001), multivariate analysis identified an increased NLR as an independent prognostic factor for overall (HR=1.58, 95% CI=1.12-2.20, p=0.008), but not for cancer-specific (HR=1.55, 95% CI=0.89-2.70, p=0.116), nor for metastasis-free survival (HR=1.37, 95% CI=0.88-2.14, p=0.160). Conclusions: Risk prediction for cancer-related endpoints using NLR does not seem to add independent prognostic information to other well established prognostic factors in patients with non-metastatic RCC. Regarding patients’ overall survival, an increased NLR represented an independent risk factor, which might reflect a higher risk for cardiovascular, infectious, as well as for gastrointestinal morbidities and mortalities.
Retrospective analysis of sorafenib as first- or second-line targeted therapy in patients with mRCC: Three-year Italian experience.
Authors: Procopio Giuseppe , Derosa Lisa , Gernone Angela , Morelli Franco , Sava Teodoro , Zagonel Vittorina , De Giorgi Ugo , Ferrari Vittorio D. , Masini Cristina , Gasparro Donatello , Felici Alessandra , Berardi Rossana , Calvani Nicola , Lo Re Giovanni , Lipari Helga , Brizzi Maria Pia , Sisani Michele , Porta Camillo , Galligioni Enzo , Contu Antonio Silverio ,   RESET Study Group
Published: February 2017

415 Background: The Retrospective analysis of Sorafenib (So) as the first- or second- target therapy (RESET) study in metastatic renal cell carcinoma (mRCC) patients assessed the use and safety of sorafenib under daily-life treatment conditions in a community-based patient population in Italian centers. Methods: RESET was a retrospective, observational, non-interventional field study in mRCC patients. Treatment decisions were determined by each physician according to local prescribing guidelines and clinical practice. Patients for whom a decision to treat with sorafenib single agent as first- or second- target therapy (TT) for mRCC has been made, were eligible for inclusion. Patients that started So treatment between January 1, 2008 and December 31, 2010 were included. Data collection started retrospectively in 2012, in order to have a period of observation of at least 1 year up to 31st Dec 2011. Endpoints included safety, overall survival (OS), progression-free survival (PFS), response rate (RR), and treatment duration. Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, prior therapy, number of metastases, and line of TT with So. Results: From February to Jululy 2012, 358 pts from 37 Italian centers were enrolled. The most common ≥ grade 3 drug-related adverse events were hand-foot skin reaction (6.3%), rash (2.3%), hypertension, fatigue, and diarrhea (1.7% each). In the overall population, median OS was 17.2 months (mos) (95% CI 15.5 – 19.6 mos) and median PFS was 5.9 mos (95% CI 5.0-6.8 mos). Median duration of treatment with So was 5.09 mos. Complete response was observed in 3 (0.8%) pts, partial response in 53(15.0%) pts and stable disease in 139(39.4%) pts. In pts receiving So as first- or second- TT, median OS was 19.9 mos (95% CI 15.4-25.3 mos) and 16.6 mos (95% CI 13.1-18.4 mos) respectively, and median PFS was 6.6 mos (95% CI 4.9-9.3 mos) and 5.3 mos (95% CI 4.4-6.2 mos) respectively. Conclusions: The efficacy and safety of So under routine clinical practice conditions in the setting of community-based practice in Italy were similar to that reported in prospective clinical trials. The efficacy of So was observed in the subgroup of pts receiving So as either the first or second TT for mRCC.
Induction of immunogenicity after irradiation of renal carcinoma cell lines.
Authors: Janda Gregory , Habiby Mohammad , Hoffmeyer Jan , Romano Michelle , Warren Graham Walter , Schwaab Thomas 
Published: February 2017

417 Background: Cellular vaccine therapy in RCC has shown disappointing clinical and immunologic results. Poor immunogenicity of tumor associated antigens (TAAs) and their restricted expression may account for a lack of antigen-specific T cell responses. Irradiation induces TAA expression and enhances the immunogenicity of tumor cells. We investigated the influence of irradiation on the immunogenicity of RCC tumor cells. Methods: Six (ACHN, 786-0, 769-P, Caki-1, A-498, A-704) commercially available RCC cell lines were cultured and subsequently exposed to 0, 12, or 16 Gy of ionizing radiation. Alive cells and supernatant were isolated at 2, 24, and 48 hours after irradiation. The TAA expression (CA9, 5T4, MUC-1, NY-ESO-1, HSP-70) was assessed using flow cytometry. Expression relative to control (ERC) was calculated. Cytokine analysis was performed using a 9-plex Luminex human cytokine assay and reported as the mean concentration of all cell lines. Results: CA9, 5T4, and NY-ESO-1 demonstrated a marked increase in expression in 4 of 6 cell lines while MUC-1 and HSP-70 had increased expression in all cell lines after irradiation. The range and mean ERC across all six cell lines at 48 hours after irradiation with 16 Gy are shown in the table. Il-2, Il-6, IFN-gamma and Il-4 increased in irradiated cells with peak concentrations vs. control of: 0.55 vs. 0.47, 1631 vs. 1358, 10.06 vs. 7.61, 1.07 vs. 0.77 pg/ml, respectively. Conclusions: Irradiation of RCC cell lines increased TAA expression in the majority of cell lines. Immunomodulatory cytokines were induced with radiation. These data suggest that RCC tumor irradiation may provide a novel means to increase the immunogenicity and subsequent efficacy of RCC-targeted immunotherapy. [Table: see text]
Relationship of aberrant glycosylation of n-glycan on immunoglobulins with survival of patients with renal cell carcinoma.
Authors: Hatakeyama Shingo , Amano Maho , Koie Takuya , Tobisawa Yuki , Yoneyama Tohru , Mori Kazuyuki , Tsuchiya Norihiko , Habuchi Tomonori , Nishimura Shin-Ichiro , Ohyama Chikara 
Published: February 2017

438 Background: Biomarkers for early detection and prediction of patient survival for renal cell carcinoma (RCC) have not yet been established. We have developed a novel glycoblotting method that allows high-throughput, comprehensive, and quantitative glycan analysis of whole human serum. We examined the relationship between serum N-glycan profiling and survival of the patient with RCC. Furthermore, we attempted to identify carrier protein to which the responsible N-glycan attached. Methods: We performed a comprehensive N-glycan structural analysis of sera from 64 patients with RCC using the glycoblotting methods and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). The intensity of the N-glycans was then analyzed with the help of the logistic regression analysis and a receiver operating characteristic curve to select N-glycans which associated with patient survival in RCC. The candidate N-glycans which had statistically significant relationship in overall survival were evaluated their independency using Cox-regression model to elucidate its superiority comparing to other conventional biomarkers of RCC. Then, we recovered the responsible N-glycan together with its carrier protein by sialobloting method to identify the carrier protein. Results: We identified 56 kinds of N-glycans in sera from RCC patients. The intensity of peak 19 was significantly higher, and the intensity of peak 49 was significantly lower in the patients who survived longer. Multivariate analysis revealed that peaks 19 and 49 were independent predictors of overall survival as well as conventional risk factors. Protein analysis for the carrier protein revealed that the aberrant N-glycan was harbored by IgA1 or IgG4. Conclusions: Aberrant glycosylation of N-glycan on IgA1 or IgG4 may serve as novel biomarkers for RCC. Further validation study is warranted.
A comparison of outcomes regarding robotic versus open partial nephrectomy.
Authors: Hamilton Zachary Adam , Le Margaret , Saad Kahlil , Duchene David , Holzbeierlein Jeffrey M. , Mirza Moben 
Published: February 2017

441 Background: The latest SEER Cancer Statistics estimated that 60,920 new cases of kidney cancer were diagnosed in 2011 in the United States. The standard of care for small renal masses has transitioned from radical to partial nephrectomy with strong data to support excellent oncologic outcomes, long-term preservation of renal function, and better overall survival. The literature shows that laparoscopic approaches are favorable when compared to open techniques, but outcomes in robotic surgery are still gaining data. The objective of this study is to perform a review of outcomes comparing open versus robotic partial nephrectomy. Our hypothesis is that surgical outcomes and length of stay will favor robotic surgery. Methods: We performed a retrospective review of partial nephrectomies from 2009 to 2012 for solitary masses suspected as carcinoma at the Kansas University Medical Center. Estimated blood loss, age, length of stay, intraoperative transfusion, and margin status were recorded. When available, nephrometry scores were calculated based on preoperative imaging. Results: A total of 78 open partial nephrectomies and 63 robotic partial nephrectomies were analyzed. In the open cohort, the surgical blood loss was higher compared to the robotic cohort (328ml vs. 222ml, p=0.03). Nephrometry scores and mean mass size were higher in the open cohort (7.3 vs. 5.9, p<0.01 and 3.2cm vs. 2.7cm, p=0.01, respectively). The mean length of stay was 2.8 days for the robotic cohort and 4.3 days for the open cohort. No significant difference was noted in age or BMI. Of note, there were five intraoperative blood transfusions in the open group and none in the robotic group. Four margins were positive in the robotic cohort and one in the open cohort. Nephrometry score and mass size did not correlate with blood loss. Conclusions: For partial nephrectomy blood loss is significantly lower with robotic techniques as compared to open surgery. This relationship is not affected by mass size or nephrometry score. Positive margins rate is higher in robotic surgery, while blood transfusion rate is lower in robotic surgery. Length of stay is decreased with robotic surgery. Robotic partial nephrectomy seems to afford the advantage of decreased blood loss and decreased length of stay.
Sunitinib-associated hypothyroidism in patients with metastatic renal cell carcinoma.
Authors: Jagdev Satinder , Hayward Kate , Sim Sheryl 
Published: February 2017

443 Background: Sunitinib (sun) treatment for patients (pts) with metastatic renal cancer (mRCC) can often lead to fatigue. The incidence of sun-induced hypothyroidism (HT) in the phase III pivotal study of pts with mRCC was 14% for all grades and 2% for grades 3-4. Subsequent retrospective and prospective studies described incidences of between 30–85%. Elevated TSH alone may be seen in up to 85% of mRCC pts treated with sun. Symptoms of HT, eg: fatigue, constipation, cold intolerance, hair thinning, and dry skin have been reported in the majority of sun-treated pts. Methods: We reviewed of all cases of mRCC pts initiating sun treatment between January 2008 and December 2009 using the electronic record system Patient Pathway Manager. Pts with underlying HT, abnormal TFTs at baseline or those on sun for less than two cycles were excluded. TFTs were performed at baseline and then day 1 of every two cycles. Response was assessed every 2-3 cycles. The aims of the study were to Identify rate of sun-induced HT in St James’s Institute of Oncology and determine whether there is a correlation between HT and disease response. Results: 84 pts were included (median age 62 years). 90% had good or intermediate prognosis disease by Memorial Sloane-Kettering Cancer Centre (MSKCC) criteria. 52 pts had TSH <6mU/L and 32 had TSH of >6mU/L. Progression-free survival was significantly longer in those pts with TSH of >6mU/L (29.6 months) compared to those with TSH <6mU/L (11.3 months). Conclusions: Sun-induced HT occurred in approximately 30% of pts and predicted for improved progression-free survival. Further studies are needed to characterise this and updated data will be presented.
Association of CTCAE v4 grading of hypertension with toxicity in patients with renal cancer receiving vascular endothelial growth factor (VEGF)-targeting agents.
Authors: Akhtar Naveed Hassan , Karpenko Irene , Singh Beerinder , Beltran Himisha , Nanus David M. , Tagawa Scott T. 
Published: February 2017

447 Background: The NCI Common Terminology Criteria for Adverse Events (CTCAE) system underwent a change to version 4 in May 2009. In addition to system re-organization, several AE categories underwent changes in grading, including hypertension (HTN). As many anti-neoplastic agents, particularly those targeting VEGF are associated with HTN, changing in the grading system may result in changes to maximum tolerated or recommended phase II doses (MTD or RP2D) in dose-escalation studies using classic trial schemas (such as 3+3 design). Methods: We reviewed individual patient data of a phase I/II trial of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC). The phase I portion of the study was conducted to define the dose-limiting toxicity and RP2D of the combination (Am J Clin Oncol, 2011). The phase II portion further assessed efficacy as defined by objective response rate. Initial grading of AE’s during this study used CTCAE v3. Individual patient data was reviewed and HTN AE’s were re-graded using CTCAE v4 criteria for up to 12 cycles of therapy on study. Results: Of 28 pts enrolled, 23 (82.1%) had complete source documents available for the complete evaluation of HTN. The table compares each individual’s highest CTCAE v3 versus v4 grading of HTN on study. All pts had HTN AE’s using CTCAE v4. Only 1 pt maintained grading using both versions (Gr 3), with 22 (95.7%) changing grades. Two (8.7%) moved from Gr 0 to Gr 1, fourteen 60.9(%) from Gr 0 to Gr 2, four (17.4%) from Gr 1 to Gr 2, one from Gr 1 to Gr 3, and two (8.7%) from Gr 2 to Gr 3. Conclusions: Re-classification of grading in this study demonstrates that only 4.3% maintained stable grading of HTN across systems, with 65.2% increasing by 2 grades. The change in AE reporting criteria has the potential significantly impact results of clinical trials. This may be particularly important with VEGF-targeted agents, with emerging data pointing towards HTN as a pharmacodynamic marker in pts with RCC, and may affect dosing of other drugs with blood pressure effects, including CYP17 inhibitors for prostate cancer. Clinical trial information: NCT00121251. [Table: see text]
Molecular expression profiling and pathway analysis of formalin-fixed paraffin-embedded primary renal tumor specimens.
Authors: Antón Aparicio Luis M. , Medina Villaamil Vanessa , Aparicio Gallego Guadalupe , Santamarina Cainzos Isabel , Quindós Varela Maria , Valladares Ayerbes Manuel 
Published: February 2017

448 Background: Many studies have demonstrated genetic and environmental factors lead to renal cell carcinoma (RCC) occurring during a protracted period of tumorigenesis. It seemed suitable identify and characterize potential molecular markers which might provide rapid and effective possibilities for early detection of RCC. The purpose from this analysis was to derive predictive models which could predict more accurately than any one factor alone. Methods: We assessed using quantitative real-time PCR (qPCR) with SYBR Green the profile of 32 predictive markers involved in the cascade of events leading to the formation and progression of this disease to evaluate their involvement in oncogenesis. RNA of quality was obtained in 90% of samples (N=80, 52/80 clear RCC, 6/80 papillary RCC and 14/80 chromophobe RCC) to carry out the study of gene expression. GenEx software was used for qPCR data processing and analysis. The potential correlation between mRNA expression and the pathological features of the study subjects was assessed by Pearson Chi-squared. Linear rather than logistic regression models were used (SPSS statistics 21.0 software). Additionally, a knowledgebases of biological pathways, Reactome and Snow (Babelomics), were used to superimpose our quantitative expression data. Results: The best gene predictors related to different pathological variables (histological type, tumor size, Fuhrman grade, number of involved nodes, renal pelvis invasion, lymphatic vessels invasion, and rupture of the renal capsule): Hif1-α (p < 0.001), Hif1-β (p = 0.035), DLL1 (p = 0 .012), DLL3 (p< 0.001), c-Kit (p = 0.002), PDGFR-β (p =0.002), PDGFR-α (p = 0.026), Bax-β (p = 0.005), Survivin (p = 0.028), Notch1 (p = 0.006), Notch2 (p = 0.007), Notch3 (p = 0.016), Notch4 (p = 0.005), EGFR (p = 0.029), Glut3 (p = 0.026), Glut5 (p = 0.036), FH (p = 0.018), CA9 (p = 0.030), and VHL-1(p = 0.015). Conclusions: Our data suggested that altered expression of certain members involved in the main pathways which feed RCC and their downstream targets analyzed together could improve the diagnostic accuracy for renal cancer by combining determinations of mRNA markers.