EAU guidelines on renal cell carcinoma: the 2010 update. Key Steps in Conducting Systematic Reviews for Underpinning Clinical Practice Guidelines: Methodology of the European Association of Urology. Methods for Development of the European Commission Initiative on Breast Cancer Guidelines Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study Large prospective investigation of meat intake, related mutagens, and risk of renal cell carcinoma. Intake of fiber and fiber-rich plant foods is associated with a lower risk of renal cell carcinoma in a large US cohort. Blood pressure and risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition. Clear Cell Renal Cell Carcinoma: Machine Learning-Based Quantitative Computed Tomography Texture Analysis for Prediction of Fuhrman Nuclear Grade Updated activity and safety results of a phase II randomized discontinuation trial (RDT) of AV-951, a potent and selective VEGFR1, 2, and 3 kinase inhibitor, in patients with renal cell carcinoma (RCC). Body size and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). Systemic Therapy for Non-Clear Cell Renal Cell Carcinoma. Reporting standards for percutaneous thermal ablation of renal cell carcinoma. Cytokine induced killer cell-based immunotherapies in patients with different stages of renal cell carcinoma. Polymorphisms of DNA repair genes are associated with renal cell carcinoma. Efficacy and toxicity of the angiogenesis inhibitor SU5416 as a single agent in patients with advanced renal cell carcinoma, melanoma, and soft tissue sarcoma. Association of abnormal preoperative laboratory values with survival after radical nephrectomy for clinically confined clear cell renal cell carcinoma. Dietary fiber, glycemic index, glycemic load and renal cell carcinoma risk. A preoperative prognostic model for patients treated with nephrectomy for renal cell carcinoma. A phase III, randomized, controlled study to compare tivozanib with sorafenib in patients (pts) with advanced renal cell carcinoma (RCC). A prospective comparison of laparoscopic and robotic radical nephrectomy for T1-2N0M0 renal cell carcinoma Circulating 25-Hydroxyvitamin D3 and Survival after Diagnosis with Kidney Cancer Effect of temsirolimus versus interferon-α on outcome of patients with advanced renal cell carcinoma of different tumor histologies
CONTEXT AND OBJECTIVES The European Association of Urology Guideline Group for renal cell carcinoma ( RCC ) has prepared these guidelines to help clinicians assess the current evidence -based management of RCC and to incorporate the present recommendations into daily clinical practice . EVIDENCE ACQUISITION The recommendations provided in the current up date d guidelines are based on a thorough review of available RCC guidelines and review articles combined with a systematic literature search using Medline and the Cochrane Central Register of Controlled Trials . EVIDENCE SYNTHESIS A number of recent prospect i ve r and omised studies concerning RCC are now available with a high level of evidence , whereas earlier publications were based on retrospective analyses , including some larger multicentre validation studies , meta-analyses , and well- design ed controlled studies . CONCLUSIONS These guidelines contain information for the treatment of an individual patient according to a current st and ardised general approach . Up date d recommendations concerning diagnosis , treatment , and follow-up can improve the clinical h and ling of patients with RCC CONTEXT The findings of systematic review s ( SRs ) and meta-analyses ( MAs ) are used for clinical decision making . The European Association of Urology has committed increasing re sources into the development of high quality clinical guidelines based on such SRs and MAs . OBJECTIVE In this paper , we have summarised the process of conducting SRs for underpinning clinical practice guidelines under the auspices of the European Association of Urology Guidelines Office . EVIDENCE ACQUISITION The process involves explicit methods and the findings should be reproducible . When conducting a SR , the essential first step is to formulate a clear and answerable research question . An extensive literature search lays the foundation for evidence synthesis . Data are extracted independently by two review ers and any disagreements are resolved by discussion or arbitration by a third review er . EVIDENCE SYNTHESIS In SRs , data for particular outcomes in individual r and omised controlled trials may be combined statistically in a meta- analysis to increase power when the studies are similar enough . Biases in studies included in a SR/MA can lead to either an over estimation or an under estimation of true intervention effect size , result ing in heterogeneity in outcome between studies . A number of different tools are available such as Cochrane Risk of Bias assessment tool for r and omised controlled trials . In circumstances where there is too much heterogeneity , or when a review has included nonr and omised comparative studies , it is more appropriate to conduct a narrative synthesis . The GRADE tool for assessing quality of evidence strives to be a structured and transparent system , which can be applied to all evidence , regardless of quality . A SR not only identifies , evaluates , and summarises the best available evidence , but also the gaps to be targeted by future studies . CONCLUSIONS SRs and MAs are integral in developing sound clinical practice guidelines and recommendations . PATIENT SUMMARY Clinical practice guidelines should be evidence based , and systematic review s and meta-analyses are essential in their production . We have discussed the key steps of conducting systematic review s and meta-analyses in this paper In December 2003 , the European Council identified best practice as key for ensuring development of high- quality cancer-screening programs . To support national policies on cancer control , the European Union institutions progressed several initiatives on cancer . The European Commission ( EC ) Initiative on Breast Cancer ( ECIBC ) is the most recent of these projects and the most implementation driven . Within this initiative , the European Guidelines for Breast Cancer Screening and Diagnosis ( in short , European Breast Guidelines ) are being developed ( http://ecibc.jrc.ec.europa.eu/ ) . Guidelines are approaches to generally improve prevention , diagnosis , treatment , and follow-up of diseases , overcoming inappropriate variations by providing recommendations for best care . The new era of guidelines promises recommendations that are based on the best available evidence summarized in systematic review s while providing the necessary flexibility needed to individualize decisions . The best methods for development of practice guidelines have experienced intense elaboration and attention during the past decades ( 17 ) . The impetus for this attention has been the change from expert- or consensus-based to evidence -based health care recommendations . Although this change in terminology should express the shift from un systematic development of guidelines to systematic and trustworthy recommendations , it is often misunderstood and misconstrued as meaning that experts are now meaningless in the process or as if consensus through discussion is a matter of the past . Neither is correct . Experts from various disciplines and consensus as a result of deliberation remain a mainstay of health care guideline development ( 810 ) . These experts are responsible for prioritization of questions that should be addressed in guidelines ; judgments that result from interpretation of evidence , including the rating of the certainty of the available evidence ; and decisions about how the judgments on the different criteria bear on recommendations . What has changed over time in guideline development are the rules , the structure and explicitness of the process , and the guideline product . Indeed , review s of guideline development methodology and how guidelines can be improved have led to more structured and documented processes that allow a reduction of bias and provide balanced views of appropriately composed guideline panels ( 2 , 5 , 6 ) . Core components for trustworthy guideline development ( 13 , 5 , 7 , 11 ) include that guidelines be developed by a knowledgeable , multidisciplinary panel of experts and representatives from key affected groups ; be based on a systematic review of the existing evidence ; consider important patient subgroups and patient preferences as appropriate ; be based on an explicit and transparent process that minimizes distortions , biases , and conflicts of interest ( 12 ) ; provide a clear explanation of the logical relationships between alternative care options and health outcomes and provide ratings of both the quality of evidence and the strength of the recommendations ( 1316 ) ; and be reconsidered and revised as appropriate when important new evidence warrants modifications . In addition , greater transparency in linking the considered research evidence and the recommendations , as well as the requirement of making structured expert judgments , represents a shift in the guideline development paradigm ( 5 , 11 , 1719 ) . At the same time , developing guidelines for a large number of member states and those that aim to adapt the guidelines poses challenges , such as the feasibility of implementing strategies that may exist in some member countries but not others ( for example , organized population -based screening in Italy but not Greece ) . Addressing these challenges requires considerations that extend beyond strictly clinical efforts in guideline development and mastering the many factors that influence recommendations and their implementation . This article describes the rationale , methods , and processes the ECIBC has adopted to develop the European Breast Guidelines in the context of evolving international st and ards . It also describes an innovative approach to presenting , disseminating , and accelerating implementation of recommendations . Guideline Methodology and Development To adhere to the core requirements for guideline development , the EC has taken several steps . First , it selected , via an open call ( https://ecibc.jrc.ec.europa.eu/ guidelines -team ) , a panel with broad representation of expertise , knowledge , and background , which includes patients , health care professionals , epidemiologists , guideline method ologists , and others ( Appendix ) . These individuals voluntarily participate in the ECIBC and compose the guidelines development group ( GDG ) . Second , it ensured that all recommendations were supported by systematic review s of the evidence conducted by independent scientists from Cochrane Iberoamricathe systematic review team (SRT)following st and ard Cochrane Collaboration methods ( 20 , 21 ) . Third , because this is a women-centered initiative , we included women advocates in the GDG as full voting guideline group members . We separately considered important subgroups of women during recommendation development ( for example , different age groups ) , and we specifically focused on evidence that supports best ways of communicating this information to women to inform their decisions . Fourth , we applied EC conflict of interest rules ( http://ecibc.jrc.ec.europa.eu/rules ) , which are consistent with international recommendations , and used GRADE ( Grading of Recommendations Assessment , Development and Evaluation ) Evidence to Decision ( EtD ) frameworks to minimize the influence of competing interests on the recommendations ( 12 , 17 , 18 ) . These EtD frameworks help guideline panels use evidence in a structured , transparent way to inform decisions with a series of criteria , such as anticipated harms and benefits of the options considered , the certainty of the evidence for those effects , and the costs and feasibility of the options , to help them reach their decision . Fifth , using the GRADE approach to guideline development and its EtD frameworks , we focused our questions and recommendations on outcomes that matter to women and provided a rating of the certainty or quality of evidence and the strength of recommendations that is widely accepted as the reference st and ard ( Figures 1 and 2 ) . Sixth , our evidence review s are up to date when the recommendations are formulated , and we engage in international stakeholder feedback to ensure that recommendations remain timely and relevant to public health and clinical practice . The ECIBC is committed to review ing and updating the recommendations as required when new evidence becomes available . The general process is explained in Figure 3 and is based on the Guidelines International NetworkMcMaster Guideline Development Checklist ( https://hei grade .mcmaster.ca/ guideline -development/using-checklist ) ( 5 ) . Figure 1 . According to GRADE , certainty , quality , strength of evidence , or confidence in the estimate of effect is determined on the basis of a systematic review of the evidence for each outcome ( based on the domains risk of bias , indirectness , imprecision , inconsistency , and publication bias that lower certainty and , usually only for nonr and omized studies , large effects , doseresponse relations and opposing plausible residual confounding that may increase the certainty ) . For recommendations , the overall certainty is determined across outcomes based on the lowest certainty outcome among those critical for decision making for the specific context . The guidelines development group applies the GRADE Evidence -to-Decision frameworks to make recommendations that are made available on the European Commission Web site . ( Reproduced from reference 15 , with permission from Schnemann HJ . ) . GRADE = Grading of Recommendations Assessment , Development and Evaluation . Figure 2 . GRADE EtD frameworks . The GRADE EtD frameworks as available in the GRADE pro software ( www . grade pro.org ) . They help with structuring the entire guideline process into 4 sections and support the conduct of guideline group meetings , presentation , and implementation . They clarify the perspective that is taken by the guideline panel or decision maker and the type of question that is asked in the question section . The section on assessment includes the criteria if the problem is a priority , the balance of health benefits and harms , values and preferences related to the outcomes , cost , re sources and cost-effectiveness , equity , acceptability , and feasibility . Conclusions provide the decision or recommendation with a justification and implementation , as well as research considerations . The presentation function supports the conduct of guideline group meetings and facilitates the output of EtD frameworks to other implementation tools , such as Web sites , h and -held apps , and interactive decision aids . EtD = Evidence to Decision ; GRADE = Grading of Recommendations Assessment , Development and Evaluation ; HTA = health technology assessment ; PICO = population , intervention , comparators , and outcomes . Figure 3 . Approach to guideline development used by the European Commission Initiative on Breast Cancer . The European Commission JRC has oversight of the organization , budgeting , planning , and training . The JRC also manages conflicts of interest , documents all aspects of the work , and manages the membership and group processes . The guideline development group and JRC formulate the questions and work with the systematic review team on identifying and assessing the evidence . The guidelines development group is responsible for developing the recommendations . The JRC is responsible for most other aspects as described in the figure under dissemination , implementation , and updating . JRC = Joint Research Centre ; PICO = population , intervention , comparator , and outcomes . ( Reproduced with adaptation to the JRC process from BACKGROUND The European Advanced Renal Cell Carcinoma Sorafenib ( EU-ARCCS ) exp and ed-access study provided sorafenib to advanced renal cell carcinoma ( RCC ) patients in whom previous systemic therapy had failed . The study assessed the safety and use of sorafenib for the treatment of advanced RCC in a large community-based patient population across 11 countries in Europe . PATIENTS AND METHODS EU-ARCCS was a single-arm , open-label trial of  sorafenib in advanced RCC patients . End points included safety , time to progression , progression-free survival ( PFS ) , and disease control rate ( DCR ) . Subgroup analyses included age , Eastern Cooperative Oncology Group performance status , histology , prior therapy , and number and sites of metastases . RESULTS About 1159 advanced RCC patients were enrolled . Most patients ( 94 % ) experienced drug-related adverse events ( AEs ) of any grade , with the most common grade ≥3 AEs including h and -foot skin reaction ( 13 % ) , diarrhea ( 7 % ) , fatigue ( 7 % ) , hypertension ( 6 % ) , and rash/desquamation ( 5 % ) . The incidence of AEs in the subgroups was similar to that in the overall population . Median PFS was 6.6 months ; DCR at ≥8 and ≥12 weeks was 85 % and 78 % , respectively . CONCLUSIONS The sorafenib safety profile in European community-based practice setting s was similar to that reported in clinical trials . The heterogeneous advanced RCC patient population in EU-ARCCS permitted assessment of sorafenib in important sub population s of advanced RCC patients Background Several obesity-related factors have been associated with renal cell carcinoma ( RCC ) , but it is unclear which individual factors directly influence risk . We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian r and omization ( MR ) framework . This methodology limits bias due to confounding and is not affected by reverse causation . Methods and findings Genetic markers associated with obesity measures , blood pressure , lipids , type 2 diabetes , insulin , and glucose were initially identified as instrumental variables , and their association with RCC risk was subsequently evaluated in a genome-wide association study ( GWAS ) of 10,784 RCC patients and 20,406 control participants in a 2- sample MR framework . The effect on RCC risk was estimated by calculating odds ratios ( ORSD ) for a st and ard deviation ( SD ) increment in each risk factor . The MR analysis indicated that higher body mass index increases the risk of RCC ( ORSD : 1.56 , 95 % confidence interval [ CI ] 1.44–1.70 ) , with comparable results for waist-to-hip ratio ( ORSD : 1.63 , 95 % CI 1.40–1.90 ) and body fat percentage ( ORSD : 1.66 , 95 % CI 1.44–1.90 ) . This analysis further indicated that higher fasting insulin ( ORSD : 1.82 , 95 % CI 1.30–2.55 ) and diastolic blood pressure ( DBP ; ORSD : 1.28 , 95 % CI 1.11–1.47 ) , but not systolic blood pressure ( ORSD : 0.98 , 95 % CI 0.84–1.14 ) , increase the risk for RCC . No association with RCC risk was seen for lipids , overall type 2 diabetes , or fasting glucose . Conclusions This study provides novel evidence for an etiological role of insulin in RCC , as well as confirmatory evidence that obesity and DBP influence RCC risk BACKGROUND The evidence for meat intake and renal cell carcinoma ( RCC ) risk is inconsistent . Mutagens related to meat cooking and processing , and variation by RCC subtype may be important to consider . OBJECTIVE In a large US cohort , we prospect ively investigated intake of meat and meat-related compounds in relation to risk of RCC , as well as clear cell and papillary RCC histologic subtypes . DESIGN Study participants ( 492,186 ) completed a detailed dietary assessment linked to a data base of heme iron , heterocyclic amines ( HCA ) , polycyclic aromatic hydrocarbons ( PAHs ) , nitrate , and nitrite concentrations in cooked and processed meats . Over 9 ( mean ) y of follow-up , we identified 1814 cases of RCC ( 498 clear cell and 115 papillary adenocarcinomas ) .  HRs and 95 % CIs were estimated within quintiles by using multivariable Cox proportional hazards regression . RESULTS Red meat intake [ 62.7 g ( quintile 5 ) compared with 9.8 g ( quintile 1 ) per 1000 kcal ( median ) ] was associated with a tendency toward an increased risk of RCC [ HR : 1.19 ; 95 % CI : 1.01 , 1.40 ; P-trend = 0.06 ] and a 2-fold increased risk of papillary RCC [ P-trend = 0.002 ] . Intakes of benzo(a)pyrene ( BaP ) , a marker of PAHs , and 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine ( PhIP ) , an HCA , were associated with a significant 20 - 30 % elevated risk of RCC and a 2-fold increased risk of papillary RCC . No associations were observed for the clear cell subtype . CONCLUSIONS Red meat intake may increase the risk of RCC through mechanisms related to the cooking compounds BaP and PhIP . Our findings for RCC appeared to be driven by strong associations with the rarer papillary histologic variant . This study is registered at clinical trials.gov as NCT00340015 BACKGROUND Plant-based and fiber-rich diets high in vegetables , fruit , and whole grains are recommended to prevent cancer and chronic conditions associated with renal cell carcinoma ( RCC ) , such as obesity , hypertension , and diabetes . Diet may play a role in the etiology of RCC directly and /or indirectly . OBJECTIVE In a large prospect i ve cohort of US men and women , we comprehensively investigated dietary intake and food sources of fiber in relation to RCC risk . DESIGN Participants of the NIH-AARP Diet and Health Study ( n = 491,841 ) completed a self-administered question naire of demographics , diet , lifestyle , and medical history . Over 9 ( mean ) years of follow-up we identified 1816 incident cases of RCC .  HRs and 95 % CIs were estimated within quintiles by using multivariable Cox proportional hazards regression . RESULTS Total dietary fiber intake was associated with a significant 15 - 20 % lower risk of RCC in the 2 highest quintiles compared with the lowest ( P-trend = 0.005 ) . Intakes of legumes , whole grains , and cruciferous vegetables were also associated with a 16 - 18 % reduced risk of RCC . Conversely , refined grain intake was positively associated with RCC risk in a comparison of quintile 5 with quintile 1 ( HR : 1.19 ; 95 % CI : 1.02 , 1.39 ; P-trend = 0.04 ) . The inverse association between fiber intake and RCC was consistent among participants who never smoked , had a body mass index [ BMI ( in kg/m(2 ) ) ] < 30 , and did not report a history of diabetes or hypertension . CONCLUSIONS Intake of fiber and fiber-rich plant foods was associated with a significantly lower risk of RCC in this large US cohort . This trial was registered at clinical trials.gov as NCT00340015 Elevated blood pressure has been implicated as a risk factor for renal cell carcinoma ( RCC ) , but prospect i ve studies were confined to men and did not consider the effect of antihypertensive medication . The authors examined the relation among blood pressure , antihypertensive medication , and RCC in the European Prospect i ve Investigation into Cancer and Nutrition ( EPIC ) .  Blood pressure  was measured in 296,638 women and men , recruited in eight European countries during 1992 - 1998 , 254,935 of whom provided information on antihypertensive medication .  During a mean follow-up of 6.2 years , 250 cases of RCC were identified . Blood pressure was independently associated with risk of RCC . The relative risks for the highest versus the lowest category of systolic ( > /=160 mmHg vs. < 120 mmHg ) and diastolic ( > /=100 mmHg vs. < 80 mmHg ) blood pressures were 2.48 ( 95 % confidence interval : 1.53 , 4.02 ) and 2.34 ( 95 % confidence interval : 1.54 , 3.55 ) . Risk estimates did not significantly differ according to sex or use of antihypertensive medication . Individuals taking antihypertensive drugs were not at a significantly increased risk unless blood pressure was poorly controlled . These results support the hypothesis that hypertension , rather than its medications , increases the risk of RCC in both sexes , while effective blood pressure control may lower the risk Objective To evaluate the performance of quantitative computed tomography ( CT ) texture analysis using different machine learning ( ML ) classifiers for discriminating low and high nuclear grade clear cell renal cell carcinomas ( cc-RCCs ) . Material s and methods This retrospective study included 53 patients with pathologically proven 54 cc-RCCs ( 31 low- grade [ grade 1 or 2 ] ; 23 high- grade [ grade 3 or 4 ] ) . In one patient , two synchronous cc-RCCs were included in the analysis . Mean age was 57.5 years . Thirty-four ( 64.1 % ) patients were male and 19 were female ( 35.9 % ) .  Mean tumour size based on the maximum diameter was 57.4 mm ( range , 16–145 mm ) . Forty patients underwent radical nephrectomy and 13 underwent partial nephrectomy .  Following pre-processing steps , two-dimensional CT texture features were extracted using portal-phase contrast-enhanced CT . Reproducibility of texture features was assessed with the intra-class correlation coefficient ( ICC ) . Nested cross-validation with a wrapper-based algorithm was used in feature selection and model optimisation . The ML classifiers were support vector machine ( SVM ) , multilayer perceptron ( MLP , a sort of neural network ) , naïve Bayes , k-nearest neighbours , and r and om forest . The performance of the classifiers was compared by certain metrics . Results Among 279 texture features , 241 features with an ICC equal to or higher than 0.80 ( excellent reproducibility ) were included in the further feature selection process . The best model was created using SVM . The selected subset of features for SVM included five co-occurrence matrix ( ICC range , 0.885–0.998 ) , three run-length matrix ( ICC range , 0.889–0.992 ) , one gradient ( ICC = 0.998 ) , and four Haar wavelet features ( ICC range , 0.941–0.997 ) . The overall accuracy , sensitivity ( for detecting high- grade cc-RCCs ) , specificity ( for detecting high- grade cc-RCCs ) , and overall area under the curve of the best model were 85.1 % , 91.3 % , 80.6 % , and 0.860 , respectively . Conclusions The ML-based CT texture analysis can be a useful and promising non-invasive method for prediction of low and high Fuhrman nuclear grade cc-RCCs . Key Points• Based on the percutaneous biopsy literature , ML-based CT texture analysis has a comparable predictive performance with percutaneous biopsy.• Highest predictive performance was obtained with use of the SVM.• SVM correctly classified 85.1 % of cc-RCCs in terms of nuclear grade , with an AUC of 0.860 5032 Background : AV-951 is a potent inhibitor of VEGFR-1 , 2 & 3 kinases ( IC50 0.21 , 0.16 and 0.24 nM respectively ) , and inhibits cKit and PDGFR at 10-times higher concentrations ( IC50 1.63 and 1.72 nM respectively ) . In a phase II RDT of AV-951 ( 1.5 mg/day ; 3 wks on , 1 wk off ) in RCC , preliminary ORR at wk 16 was 28 % ( ASCO GU . 2008 ; abstract # 283 ) . METHODS Pts with locally advanced or metastatic RCC ( any histology ) and no prior VEGF-targeted therapy received AV-951 for 16 wks , after which further treatment was assigned based on response . Pts with ≥ 25 % tumor shrinkage continued treatment with AV-951 , while pts with < 25 % change from baseline were r and omly assigned to receive AV-951 or placebo for 12 wks ( double-blinded ) . The primary end points were ( 1 ) objective response rate ( ORR ) at 16 wks , ( 2 ) percentage of r and omly assigned pts remaining progression free at 12 wks following r and omization , ( 3 ) safety profile . RESULTS 272 pts were enrolled : 70 % male , 93 % white , median age 56 yrs . 53 % pts were treatement naïve , 72 % had undergone nephrectomy and 83 % had RCC with clear cell component . With a median duration of treatment of 5 mo ( range 0 - 12 mo ) , the investigator assessed ORR ( CR+PR ) is 27.2 % ( 30 % in clear cell RCC ) , SD 60.5 % and Disease Control Rate ( CR/PR + SD ) 88 % . 118 ( 43 % ) pts were r and omized to AV-951 or placebo . The most common treatment-related AEs ( all grade s ) were hypertension ( HTN , 42 % ) and dysphonia ( 16 % ) . Guidelines for management of HTN were provided to investigators , and 52 % pts received anti-hypertensives . Minimal ( all grade s ) diarrhea ( 9 % ) , fatigue ( 8 % ) , stomatitis ( 3 % ) and h and -foot syndrome ( 2 % ) were observed . Laboratory abnormalities ( all grade s ) were notable for minimal neutropenia ( 8 % ) and elevations of AST ( 21 % ) and ALT ( 21 % ) . AEs led to dose reduction in 4 % and treatment discontinuation in 5.5 % of pts . CONCLUSIONS Interim results of this phase II study demonstrate that AV-951 is active in RCC . The AE profile of AV-951 is consistent with that of a selective VEGFR inhibitor , with minimal off-target toxicities . Up date d results of ORR ( including independent radiology assessment ) , safety , percentage of r and omly assigned pts remaining progression free at 12 wks , and overall PFS will be presented . [ Table : see text ] Previous studies suggest that obesity is related to increased risk of renal cell carcinoma ( RCC ) ; however , only a few studies report on measures of central vs. peripheral adiposity . We examined the association between anthropometric measures , including waist and hip circumference  and  RCC risk among 348,550 men and women free of cancer at baseline from 8 countries of the European Prospect i ve Investigation into Cancer and Nutrition ( EPIC ) . During 6.0 years of follow-up we identified 287 incident cases of RCC . Relative risks were calculated using Cox regression , stratified by age and study center and adjusted for smoking status , education , alcohol consumption , physical activity , menopausal status , and hormone replacement therapy use . Among women , an increased risk of RCC was conferred by body weight ( relative risk [ RR ] in highest vs. lowest quintile = 2.13 ; 95 % confidence interval [ CI ] = 1.16 - 3.90 ; p-trend = 0.003 ) , body mass index ( BMI ) ( RR = 2.25 ; 95 % CI = 1.14 - 4.44 ; p-trend = 0.009 ) , and waist ( RR = 1.67 ; 95 % CI = 0.94 - 2.98 ; p-trend = 0.003 ) and hip circumference ( RR = 2.30 ; 95 % CI = 1.22 - 4.34 ; p-trend = 0.01 ) ; however , waist and hip circumference were no longer significant after controlling for body weight . Among men , hip circumference ( RR = 0.44 ; 95 % CI = 0.20 - 0.98 ; p-trend = 0.03 ) was related significantly to decreased RCC risk only after accounting for body weight . Height was not related significantly to RCC risk . Our findings suggest that obesity is related to increased risk of RCC irrespective of fat distribution among women , whereas low hip circumference is related to increased RCC risk among men . Our data give further credence to public health efforts aim ing to reduce the prevalence of obesity to prevent RCC , in addition to other chronic diseases Treatment options for metastatic clear cell renal cell carcinoma ( ccRCC ) have evolved markedly over the past decade , with multiple targeted therapies approved for the disease . In contrast , little improvement has been made in the management of metastatic non-clear cell RCC ( nccRCC ) . Non-clear cell disease is an umbrella term that encompasses multiple biologically distinct entities , including but not limited to papillary , chromophobe , and sarcomatoid RCC . To date , prospect i ve studies have largely explored treatments for ccRCC ( e.g. , VEGF- and mTOR-directed therapies ) in trials that aggregate non-clear cell histologies . However , the studies do not acknowledge the varying biology of each non-clear cell subtype . Emerging studies in nccRCC should examine individual histologies and apply biologically relevant therapies . An example of this is SWOG 1500 , a r and omized phase II study that will compare a  VEGF-inhibitor  to one of three  MET-directed therapies  in patients with metastatic papillary RCC . Until the biologic diversity of nccRCC is appreciated , outcomes are likely to remain dismal WITH the increasing incidence of renal cell carcinoma ( RCC ) in the United States and the increasing proportion of patients with tumors detected at an early stage ( 1–5 ) , nephron-sparing approaches are becoming more popular . These alternatives to radical nephrectomy include partial nephrectomy , wedge resection , and , more recently , in situ thermal ablation . Five-year survival rates after partial nephrectomy are equivalent to those after radical nephrectomy ( 6–8 ) , supporting the rationale of in situ tumor destruction to further reduce morbidity and invasiveness . In situ thermal destruction of RCC uses techniques that destroy tumor tissue through heating ( eg , radiofrequency [ RF ] ablation , microwave ablation , laser interstitial therapy , high-intensity focused ultrasound [ US ] ) or freezing ( eg , cryotherapy ) . Each of these techniques relies on controlled energy delivery to minimize collateral damage to normal renal parenchyma and other surrounding structures . In the United States , RF ablation and cryoablation are currently the most widely used techniques for in situ RCC destruction . Thermal ablation of RCC may be performed percutaneously , laparoscopically , or through open surgery . Our current underst and ing of the role of percutaneous thermal ablation in the management of primary RCC is limited by a paucity of prospect i ve studies ( 9,10 ) . Given the relative newness of this technology , most series to date report short-term or midterm outcomes , with no reports extending to 5 years of survival outcomes . No r and omized trials have been performed to date comparing thermal ablation against a gold st and ard ( ie , partial nephrectomy ) or against other thermal ablation techniques . The optimal size range of RCC amenable to thermal ablation has not been clearly defined and is closely related to anatomic factors that influence the ability to deposit sufficient thermal dose to coagulate tissue , including proximity to major vessels and the urinary collecting system , which can act as a heat sink . The kidney has approximately four times the blood flow of the liver , so convective heat loss during thermal ablation is potentially significant ( 11 ) . The role of percutaneous thermal ablation compared with laparoscopic or open thermal ablation also remains a topic of controversy . The combination of thermal ablation with other imageguided therapies ( eg , transcatheter embolization ) and adjuvant therapies such as chemotherapy and antiangiogenic agents for larger RCCs in patients who are poor operative c and i date s is another potential use of this technique . Although most recent reports of percutaneous RCC ablation have involved RF ablation , other ablation technologies are now available with percutaneous applicators ( eg , cryoablation , microwave , laser interstitial therapy ) , and reporting st and ards should be uniform for all forms of energy-based ablation . This document provides recommended reporting st and ards for physicians performing percutaneous thermal ablation of primary RCC and will serve as a template in the design of clinical trials to further evaluate this technology . From the Section of Vascular and Interventional Radiology , Department of Radiology ( T.W.I.C. ) , New York University School of Medicine , New York , New York ; Department of Radiology ( S.F.M. ) , University of Western Ontario , Peterborough Regional Health Center , Peterborough , Ontario , Canada ; Department of Radiology , Gastrointestinal/Genitourinary Division ( D.A.G. ) , Massachusetts General Hospital ; Department of Radiology ( S.N.G. ) , Beth Israel Deaconess Medical Center , Boston ; Department of Radiology ( C.J.G. ) , Lahey Clinic Medical Center , Burlington ; Department of Radiology ( D.A.P. ) , University of Massachusetts Memorial Health Care , Worcester , Massachusetts ; Department of Radiology ( T.B.K. ) , University of California San Diego Medical Center , San Diego , California ; Department of Radiology ( D.S. ) , The Reading Hospital and Medical Center , Reading , Pennsylvania ; and Department of Radiology ( J.F.C. ) , University of Colorado Health Sciences Center , Denver , Colorado . Received June 19 , 2006 ; revision requested June 19 ; final revision received June 29 ; and accepted July 3 . Address correspondence to T.W.I.C. , c/o Tricia McClenny , Society of Interventional Radiology , 3975 Fair Ridge Dr , Suite 400 North , Fairfax , VA 22033 ; E-mail : Cytokine induced killer ( CIK ) cell-based treatments have shown antitumor activity against renal cell carcinoma ( RCC ) in vitro and in vivo . But the therapeutic options and benefits of various CIK cells were unknown for different stages of RCC . In this r and om clinical trial , the 3-year disease free survival ( DFS ) of operable RCC patients treated with autologous tumor lysate-pulsed dendritic cells co-cultured with cytokine induced killer ( Ag-DC-CIK ) was 96.7 % compared with 57.7 % in the control group . Ag-DC-CIK immunotherapy decreased the risk of post-operative disease progression and relapse ( P = 0.0418 ) . In inoperable RCC patients treated with CIK  , the 3-year overall survival ( OS ) and progression-free survival ( PFS ) were significantly longer than the control group ( P = 0.0116 and P = 0.0212 ) . The CD4(+)/CD8(+ ) T cell ratio in peripheral blood increased after the last cell infusion in the CIK treatment group , and especially further increased in the Ag-DC-CIK treatment group ( P = 0.002 ) . No severe toxicity was observed after infusion of CIK cells . Therefore , tumor antigen-sensitized Ag-DC-CIK cells might be more efficient and personalized for the patients with tumor resection , and CIK cells could improve the prognosis for those inoperable patients . According to the stages of RCC patients , different CIK cell-based immunotherapies would help to achieve more beneficial effects DNA repair gene alterations have been shown to cause a reduction in DNA repair capacity and may influence an individual 's susceptibility to carcinogenesis . Single nucleotide polymorphisms ( SNPs ) of DNA repair genes have been shown to cause a reduction in repair activity . We hypothesized that SNPs of DNA repair genes may be a risk factor for renal cell carcinoma ( RCC ) . To test this hypothesis , DNA sample s from 112 cases of renal cell cancer and healthy controls ( n=180 ) were analyzed by PCR-RFLP to determine the genotypic frequency of six different polymorphic loci on five DNA repair genes ( XRCC1 , XPC , ERCC1 , XRCC3 , and XRCC7 ) . The chi(2 ) test was applied to compare the genotype frequency between patients and controls . We found that the frequency of 399Gln variant at XRCC1 Arg399Gln was significantly higher in RCC cases than in controls ( OR=2.83 , 95%CI=1.24 - 6.49 , P=0.01 ) . The frequency of T-A haplotype of XRCC1 194 Trp and XRCC1 399Gln was significantly higher in RCC than controls . No differences in genotypes were observed at the other sites . This is the first report on SNPs of DNA repair genes in renal cell carcinoma that suggests XRCC1 399Gln polymorphism may be a risk factor for RCC . Our present data suggest that the XRCC1 399Gln allele may be linked to susceptibility for RCC INTRODUCTION Vascular endothelial growth factor ( VEGF ) is a key regulator in angiogenesis . Pre clinical and clinical data support the role of VEGF and angiogenesis in renal cell carcinoma ( RCC ) , melanoma ( M ) , and soft tissue sarcoma ( STS ) . The tyrosine kinase inhibitor SU5416 is a potent inhibitor of the VEGF receptors 1 and 2 . EXPERIMENTAL DESIGN We investigated 145 mg/m(2 ) SU5416 twice weekly in patients with advanced or metastatic RCC , M , and STS . The primary objectives were efficacy and safety . Disease assessment s were performed after 4 and 8 weeks of treatment and every 2 months thereafter . Documented stable disease ( SD ) lasting for > or =3 months was considered an antitumor response . RESULTS A group of 29 patients was entered in the RCC trial , 20 patients in the M trial , and 31 patients in the STS trial .  Response was observed in 6 ( 1 minor response and 5 SDs ) of 24 evaluable patients ( 25 % ) in the RCC group , 6 ( 1 minor response and 5 SDs ) of 26 patients ( 23 % ) in the STS group , and none of the patients in the M group . Progression-free survival ranged from 7 to 252 days ( median 59 days ) in the RCC group , from 7 to 260 days ( median 60 days ) in the STS group , and from 14 to 139 days ( median 41 days ) in the M group . Toxicities observed were those reported previously for SU5416 . CONCLUSION SU5416 single agent is well tolerated . The antitumor response was low in patients with RCC and STS , whereas no responses were seen in patients with OBJECTIVES To determine whether preoperative laboratory values are independently associated with death from clinical ly confined clear cell renal cell carcinoma ( RCC ) after radical nephrectomy . METHODS We identified 1707 patients with clinical ly confined ( pNx/pN0 , pM0 ) , unilateral , sporadic clear cell RCC treated with radical nephrectomy between 1970 and 2002 . Associations of abnormal preoperative laboratory values including hypercalcemia , anemia , elevated erythrocyte sedimentation rate ( ESR ) , and elevated alkaline phosphatase with death from RCC were evaluated using Cox proportional hazards regression models , both univariately and multivariately by adjusting for known prognostic features of the 2002 primary tumor classification , tumor size , nuclear grade , and coagulative tumor necrosis . RESULTS At last follow-up , 1009 patients had died , including 425 who  died  from RCC at a median of 3.0 years after surgery ( range , 0 to 26 years ) . Even after adjusting for known prognostic features , 9 % of patients with preoperative hypercalcemia exhibited significantly increased likelihood of dying from RCC compared with patients with normal or lower levels of serum calcium ( relative ration [ RR ] 1.64 ; P = 0.002 ) . Similarly , preoperative anemia ( 35 % of patients ; RR 1.27 ; P = 0.026 ) and elevated ESR ( 44 % of patients ; RR 1.66 ; P = 0.003 ) portended an increased risk of death from RCC even after multivariate adjustment . CONCLUSIONS Abnormal preoperative laboratory values including hypercalcemia , anemia , and elevated ESR are independently associated with increased risk of cancer-specific death from clinical ly confined clear cell RCC . Consideration of these variables in future models may improve prognostic accuracy . We believe these factors should be routinely assessed and included in prospect i ve studies of outcome in RCC patients Several epidemiological studies have investigated the potential association between dietary fiber , glycemic index ( GI ) or glycemic load ( GL ) , and renal cell carcinoma ( RCC ) risk with inconsistent results . The aim of this study was to systematic ally evaluate this issue with a meta- analysis approach . A comprehensive literature search up to March 2018 was performed in PubMed and Web of Science data bases . Summary relative risks ( RRs ) and 95 % confidence intervals ( CIs ) were estimated with a r and om-effects model . Twelve studies were finally included in this study ( eight for fiber analysis , five for GI and five for GL ) . A significant positive association was observed between GI and the risk of RCC ( summary RR 1.16 , 95 % CI 1.02 - 1.32 ) , and no significant heterogeneity was detected among studies ( I2 = 22.8 % , P = 0.262 ) . A significant inverse association was found between fiber intake and the risk of RCC ( summary RR 0.82 , 95 % CI 0.72 - 0.92 ) , and no significant heterogeneity was observed across studies ( I2 = 27.6 % , P = 0.218 ) . GL was not significantly associated with RCC risk ( summary RR 1.14 , 95 % CI 0.81 - 1.60 ) , and significant heterogeneity was found across studies ( I2 = 78.6 % , P < 0.001 ) . In conclusion , this systematic review and meta- analysis suggests that dietary GI and fiber may be associated with the risk of RCC . Further large prospect i ve cohort studies are still warranted to confirm our preliminary findings BACKGROUND Currently two pretreatment prognostic models with limited accuracy ( 65 - 67 % ) can be used to predict survival in patients with localized renal cell carcinoma ( RCC ) . OBJECTIVE We set out to develop a more accurate pretreatment model for predicting RCC-specific mortality after nephrectomy for all stages of RCC . DESIGN , SETTING , AND PARTICIPANTS The data originated from a series of prospect ively recorded contemporary cases of patients treated with radical or partial nephrectomy between 1984 and 2006 . Model development was performed using data from 2474 patients from five centers and external validation was performed using data from 1972 patients from seven centers . MEASUREMENTS The probability of RCC-specific mortality was modeled using Cox regression . The significance of the predictors was confirmed using competing risks analyses , which account for mortality from other causes . RESULTS AND LIMITATIONS Median follow-up in patients who did not die of RCC-specific causes was 4.2 yr and 3.5 yr in the development and validation cohorts , respectively . The freedom from cancer-specific mortality rates in the nomogram development cohort were 75.4 % at 5 yr after nephrectomy and 68.3 % at 10 yr after nephrectomy . All variables except gender achieved independent predictor status . In the external validation cohort the nomogram predictions were 88.1 % accurate at 1 yr , 86.8 % accurate at 2 yr , 86.8 % accurate at 5 yr , and 84.2 % accurate at 10 yr . CONCLUSIONS Our model substantially exceeds the accuracy of the existing pretreatment models . Consequently , the proposed nomogram-based predictions may be used as benchmark data for pretreatment decision making in patients with various stages of RCC 310 Background : Drugs that block vascular endothelial growth factor ( VEGF ) pathway signaling , such as the tyrosine kinase inhibitor sorafenib , have become st and ard treatment for pts with RCC .  Tivozanib ( AV-951 ) is a potent , selective small-molecule pan-VEGF receptor ( VEGFR ) inhibitor , with activity against the VEGFR-1 , -2 , and -3 kinases at subnanomolar concentrations . Preliminary results from a phase II r and omized discontinuation trial of tivozanib ( 1.5 mg/d ; 3 wks on , 1 wk off ) in pts with RCC demonstrated an objective response rate ( ORR ) of 27 % and a median progression-free survival ( PFS ) of 11.8 mo by independent radiology review , with a favorable safety profile . Patients with clear cell RCC who had undergone nephrectomy had an ORR of 32 % and median PFS of 14.8 mo ( Bhargava , et al. ASCO 2010 . Abstract 4599 ) . Based on this antitumor activity a phase III , r and omized , controlled , global , multicenter trial is currently in progress to compare tivozanib with sorafenib in pts with advanced RCC . METHODS Approximately 500 adults with clear cell RCC who have undergone nephrectomy and received ≤ 1 prior systemic treatment ( no prior VEGF-targeted therapy ) were r and omized 1:1 to treatment with tivozanib or sorafenib . Pts are receiving 1.5 mg/d tivozanib orally in 4-week cycles ( 3 wks on , 1 wk off ) or continuous 400 mg sorafenib orally twice daily . The primary endpoint will be PFS by independent radiology review ; secondary endpoints will include overall survival , ORR , and duration of response . Safety is being monitored through adverse event reporting and laboratory analyses ; toxicities are grade d using the NCI Common Terminology Criteria for Adverse Events , version 3.0 . The effect of therapy on health-related quality of life will be compared between arms using kidney cancer-specific ( FKSI-DRS ) , oncology ( FACT-G ) , and general ( EQ-5D ) assessment s. Pharmacokinetics and biomarker analyses will be performed . RESULTS Pending . CONCLUSIONS Enrollment completed in August 2010 . An ongoing extension study will allow access to tivozanib for pts who demonstrate progressive disease on sorafenib , as well as long-term treatment with tivozanib or sorafenib for pts who demonstrate clinical benefit . [ Table : see text ] Objectives We prospect ively evaluated the safety , feasibility , and efficiency of robotic radical nephrectomy ( RRN ) for localized renal tumors ( T1 - 2N0M0 ) and compared this with laparoscopic radical nephrectomy ( LRN ) . Material s and methods Between October 2006 to August 2007 , a prospect i ve data analysis of 15 cases of renal cell carcinoma ( RCC ) stage T1 - 2N0M0 , undergoing RRN was done . These patients were compared with a contemporary cohort of 15 patients of RCC with clinical stage T1 - 2N0M0 , undergoing LRN .  To keep comparison robust , all cases were performed by a single surgeon . Demographic , intra-operative , post-operative outcomes , pathological characteristics and follow-up data of the two groups were recorded and analyzed statistically . Results Patients in group A ( RRN ) experienced significantly ( P = 0.001 ) long operating time than group B ( LRN ) . However , mean estimated blood loss , intra-operative and post-operative complications , blood transfusion rate , analgesic requirement , hospital stay and convalescence were comparable in two groups ( P < 0.05 ) . There was one conversion to open surgery in group A , and none in group B. The mean follow-up was comparable in two groups ( 8.3 and 9.1 months , respectively , in group A and B , P = 0.09 ) . There were no local , port-site or distal recurrences in either group . Conclusions Robotic radical nephrectomy is a safe , feasible and effective for performing radical nephrectomy for localized RCC . Both groups ( RRN and LRN ) had comparable intra-operative , peri-operative , post-operative and oncological outcomes except for longer operating time with increased cost for RRN . In this comparative study , there were no outst and ing benefits of RRN observed over LRN for localized RCC Prospect i ve cohort studies have provided some evidence that circulating vitamin D is associated with risk of , and survival from , renal cell carcinoma ( RCC ) , but it is unclear whether concentrations of vitamin D at the time of diagnosis of RCC are associated with prognosis . We conducted a case – cohort study of 630 RCC cases , including 203 deaths , from a multicenter case – control study in Eastern Europe .  Vitamin D was assessed as 25-hydroxyvitamin D3 [ 25(OH)D3 ] , and we used weighted Cox models to estimate hazard ratios ( HR ) and 95 % confidence intervals ( CI ) by categories of season-adjusted 25(OH)D3 . Higher concentrations of 25(OH)D3 were associated with lower risk of death after adjusting for stage , age , sex , and country ( HR highest vs. lowest category 0.57 ; 95 % CI , 0.34–0.97 ) . The inverse associations of 25(OH)D3 with death were most notable among those who died from non-RCC causes and those diagnosed with early-stage disease . In summary , 25(OH)D3 concentration at diagnosis of RCC was inversely associated with all-cause mortality rates , but not specifically with RCC outcome . Cancer Epidemiol Biomarkers Prev ; 24(8 ) ; 1277–81 . © 2015 AACR Purpose Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma ( ARCC ) trial were conducted to assess the influence of tumor histology on outcome of patients treated with temsirolimus ( Torisel ™ ) or interferon-α ( IFN ) .  Patients and methods Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN ( 3 million units [ MU ] subcutaneously three times weekly , escalating to 18 MU ) or temsirolimus ( 25 mg intravenously weekly ) . Results Approximately 80 % of patients had clear cell and 20 % of patients had other histologies , the majority of which were papillary . Patients with clear cell and other RCC histologies , treated with temsirolimus , demonstrated comparable median overall and progression-free survival . In contrast , patients with other RCC histologies , treated with IFN , demonstrated shorter median overall and progression-free survival than patients with clear cell RCC . Hazard ratios for death for treatment with temsirolimus versus IFN were less than 1 for patients regardless of tumor histology . For patients treated with temsirolimus , 59 % with clear cell and 68 % with other RCC histologies experienced tumor reductions . For patients treated with IFN , 35 % with clear cell and 14 % with other RCC histologies had tumor reductions . However , temsirolimus did not appear to improve the objective response rate compared to IFN . Temsirolimus result ed in a superior clinical benefit rate compared with IFN , regardless of tumor histology . Conclusion Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can , therefore , be used for the treatment of all types of RCC
The 2014 guideline has been up date d by a multidisciplinary panel using the highest method ological st and ards , and provides the best and most reliable contemporary evidence base for RCC management .
CONTEXT The European Association of Urology Guideline Panel for Renal Cell Carcinoma ( RCC ) has prepared evidence -based guidelines and recommendations for RCC management .
OBJECTIVES To provide an up date of the 2010 RCC guideline based on a st and ardised methodology that is robust , transparent , reproducible , and reliable .