Nephron Sparing Treatment (NEST) for Small Renal Masses: A Feasibility Cohort-embedded Randomised Controlled Trial Comparing Percutaneous Cryoablation and Robot-assisted Partial Nephrectomy.

There is a paucity of high-level evidence on small renal mass (SRM) management, as previous classical randomised controlled trials (RCTs) failed to meet accrual targets. Our objective was to assess the feasibility of recruitment to a cohort-embedded RCT comparing cryoablation (CRA) to robotic partial nephrectomy (RPN). A total of 200 participants were recruited to the cohort, of whom 50 were enrolled in the RCT. In the CRA intervention arm, 84% consented (95% confidence interval [CI] 64-95%) and 76% (95% CI 55-91%) received CRA; 100% (95% CI 86-100%) of the control arm underwent RPN. The retention rate was 90% (95% CI 79-96%) at 6 mo. In the RPN group 2/25 (8%) were converted intra-operative to radical nephrectomy. Postoperative complications (Clavien-Dindo grade 1-2) occurred in 12% of the CRA group and 29% of the RPN group. The median length of hospital stay was shorter for CRA (1 vs 2 d; p = 0.019). At 6 mo, the mean change in renal function was -5.0 ml/min/1.73 m2 after CRA and -5.8 ml/min/1.73 m2 after RPN. This study demonstrates the feasibility of a cohort-embedded RCT comparing CRA and RPN. These data can be used to inform multicentre trials on SRM management. PATIENT SUMMARY: We assessed whether patients with a small kidney tumour would consent to a trial comparing two different treatments: cryoablation (passing small needles through the skin to freeze the kidney tumour) and surgery to remove part of the kidney. We found that most patients agreed and a full trial would therefore be feasible.

Growth and renal function dynamics of renal oncocytomas in patients on active surveillance.

OBJECTIVES: To study the natural history of renal oncocytomas and address indications for intervention by determining how growth is associated with renal function over time, the reasons for surgery and ablation, and disease-specific survival. PATIENTS AND METHODS: The study was conducted in a retrospective cohort of consecutive patients with renal oncocytoma on active surveillance reviewed at the Specialist Centre for Kidney Cancer at the Royal Free London NHS Foundation Trust (2012 to 2019). Comparison between groups was performed using Mann-Whitney U-tests and chi-squared tests. A mixed-effects model with a random intercept for patient was used to study the longitudinal association between tumour size and estimated glomerular filtration rate (eGFR). RESULTS: Longitudinal data from 98 patients with 101 lesions were analysed. Most patients were men (68.3%) and the median (interquartile range [IQR]) age was 69 (13) years. The median (IQR) follow-up was 29 (26) months. Most lesions were small renal masses, and 24% measured over 4 cm. Over half (64.4%) grew at a median (IQR) rate of 2 (4) mm per year. No association was observed between tumour size and eGFR over time (P = 0.871). Nine lesions (8.9%) were subsequently treated. Two deaths were reported, neither were related to the diagnosis of renal oncocytoma. CONCLUSION: Natural history data from the largest active surveillance cohort of renal oncocytomas to date show that renal function does not seem to be negatively impacted by growing oncocytomas, and confirms clinical outcomes are excellent after a median follow-up of over 2 years. Active surveillance should be considered the 'gold standard' management of renal oncocytomas up to 7cm.

Protocol for a feasibility study of a cohort embedded randomised controlled trial comparing NEphron Sparing Treatment (NEST) for small renal masses.

INTRODUCTION: Small renal masses (SRMs; ≤4 cm) account for two-thirds of new diagnoses of kidney cancer, the majority of which are incidental findings. The natural history of the SRM seems largely indolent. There is an increasing concern regarding surgical overtreatment and the associated health burden in terms of morbidity and economy. Observational data support the safety and efficacy of percutaneous cryoablation but there is an unmet need for high-quality evidence on non-surgical management options and a head-to-head comparison with standard of care is lacking. Historical interventional trial recruitment difficulties demand novel study conduct approaches. We aim to assess if a novel trial design, the cohort embedded randomised controlled trial (RCT), will enable carrying out such a comparison. METHODS AND ANALYSIS: Single-centre prospective cohort study of adults diagnosed with SRM (n=200) with an open label embedded interventional RCT comparing nephron sparing interventions. Cohort participants will be managed at patient and clinicians' discretion and agree with longitudinal clinical data and biological sample collection, with invitation for trial interventions and participation in comparator control groups. Cohort participants with biopsy-proven renal cell carcinoma eligible for both percutaneous cryoablation and partial nephrectomy will be randomly selected (1:1) and invited to consider percutaneous cryoablation (n=25). The comparator group will be robotic partial nephrectomy (n=25). The primary outcome of this feasibility study is participant recruitment. Qualitative research techniques will assess barriers and recruitment improvement opportunities. Secondary outcomes are participant trial retention, health-related quality of life, treatment complications, blood transfusion rate, intensive care unit admission and renal replacement requirement rates, length of hospital stay, time to return to pre-treatment activities, number of work days lost, and health technologies costs. ETHICS AND DISSEMINATION: Ethical approval has been granted (UK HRA REC 19/EM/0004). Study outputs will be presented and published. TRIAL REGISTRATION: ISRCTN18156881; Pre-results.

Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma.

BACKGROUND: Cytoreductive nephrectomy has been the standard of care in metastatic renal-cell carcinoma for 20 years, supported by randomized trials and large, retrospective studies. However, the efficacy of targeted therapies has challenged this standard. We assessed the role of nephrectomy in patients with metastatic renal-cell carcinoma who were receiving targeted therapies. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with confirmed metastatic clear-cell renal-cell carcinoma at presentation who were suitable candidates for nephrectomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model. Patients received sunitinib at a dose of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. The primary end point was overall survival. RESULTS: A total of 450 patients were enrolled from September 2009 to September 2017. At this planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy-sunitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confidence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy-sunitinib group. No significant differences in response rate or progression-free survival were observed. Adverse events were as anticipated in each group. CONCLUSIONS: Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor-risk disease. (Funded by Assistance Publique-Hôpitaux de Paris and others; CARMENA ClinicalTrials.gov number, NCT00930033 .).

Centralising specialist cancer surgery services in England: survey of factors that matter to patients and carers and health professionals.

BACKGROUND: The centralisation of specialist cancer surgical services across London Cancer and Greater Manchester Cancer, England, may significantly change how patients experience care. These centres are changing specialist surgical pathways for several cancers including prostate, bladder, kidney, and oesophago-gastric cancers, increasing the specialisation of centres and providing surgery in fewer hospitals. While there are potential benefits related to centralising services, changes of this kind are often controversial. The aim of this study was to identify factors related to the centralisation of specialist surgical services that are important to patients, carers and health care professionals. METHODS: This was a questionnaire-based study involving a convenience sample of patient and public involvement (PPI) and cancer health care professional (HCP) sub-groups in London and Greater Manchester (n = 186). Participants were asked to identify which of a list of factors potentially influenced by the centralisation of specialist cancer surgery were important to them and to rank these in order of importance. We ranked and shortlisted the most important factors. RESULTS: We obtained 52 responses (28% response rate). The factors across both groups rated most important were: highly trained staff; likelihood and severity of complications; waiting time for cancer surgery; and access to staff members from various disciplines with specialised skills in cancer. These factors were also ranked as being important separately by the PPI and HCP sub-groups. There was considerable heterogeneity in the relative ordering of factors within sub-groups and overall. CONCLUSIONS: This study examines and ranks factors important to patients and carers, and health care professionals in order to inform the implementation of centralisation of specialist cancer surgical services. The most important factors were similar in the two stakeholder sub-groups. Planners should consider the impact of reorganising services on these factors, and disseminate this information to patients, the public and health care professionals when deciding whether or not and how to centralise specialist cancer surgical services.

Contemporary surgical management of renal oncocytoma: a nation's outcome.

OBJECTIVE: To report on the contemporary UK experience of surgical management of renal oncocytomas. PATIENTS AND METHODS: Descriptive analysis of practice and postoperative outcomes of patients with a final histological diagnosis of oncocytoma included in The British Association of Urological Surgeons (BAUS) nephrectomy registry from 01/01/2013 to 31/12/2016. Short-term outcomes were assessed over a follow-up of 60 days. RESULTS: Over 4 years, 32 130 renal surgical cases were recorded in the UK, of which 1202 were oncocytomas (3.7%). Most patients were male (756; 62.9%), the median (interquartile range [IQR]) age was 66.8 (13) years. The median (IQR; range) lesion size was 4.1 (3; 1-25) cm, 43.5% were ≤4 cm and 30.3% were 4-7 cm lesions. In all, 35 patients (2.9%) had preoperative renal tumour biopsy. Most patients had minimally invasive surgery, either radical nephrectomy (683 patients; 56.8%), partial nephrectomy (483; 40.2%) or other procedures (36; 3%). One in five patients (243 patients; 20.2%) had in-hospital complications: 48 were Clavien-Dindo classification grade ≥III (4% of the total cohort), including three deaths. Two additional deaths occurred within 60 days of surgery. The analysis is limited by the study's observational nature, not capturing lesions on surveillance or ablated after biopsy, possible underreporting, short follow-up, and lack of central histology review. CONCLUSION: We report on the largest surgical series of renal oncocytomas. In the UK, the complication rate associated with surgical removal of a renal oncocytoma was not negligible. Centralisation of specialist services and increased utilisation of biopsy may inform management, reduce overtreatment, and change patient outcomes for this benign tumour.

Surveillance versus ablation for incidentally diagnosed small renal tumours: the SURAB feasibility RCT.

BACKGROUND: There is uncertainty around the appropriate management of small renal tumours. Treatments include partial nephrectomy, ablation and active surveillance. OBJECTIVES: To explore the feasibility of a randomised trial of ablation versus active surveillance. DESIGN: Two-stage feasibility study: stage 1 - clinician survey and co-design work; and stage 2 - randomised feasibility study with qualitative and economic components. METHODS: Stage 1 - survey of radiologists and urologists, and development of patient information materials. Stage 2 - patients identified across eight UK centres with small renal tumours (< 4 cm) were randomised (1 : 1 ratio) to ablation or active surveillance in an unblinded manner. Randomisation was carried out by a central computer system. The primary objective was to determine willingness to participate and to randomise a target of 60 patients. The qualitative and economic data were collected separately. RESULTS: The trial was conducted across eight centres, with a site-specific period of recruitment ranging from 3 to 11 months. Of the 154 patients screened, 36 were eligible and were provided with study details. Seven agreed to be randomised and one patient was found ineligible following biopsy results. Six patients (17% of those eligible) were randomised: three patients received ablation and no serious adverse events were recorded. The 3- and 6-month data were collected for four (67%) and three (50%) out of the six patients, respectively. The qualitative substudy identified factors directly impacting on the recruitment of this trial. These included patient and clinician preferences, organisational factors (variation in clinical pathway) and standard treatment not included. The health economic questionnaire was designed and piloted; however, the sample size of recruited patients was insufficient to draw a conclusion on the feasibility of the health economics. CONCLUSIONS: The trial did not meet the criteria for progression and the recruitment rate was lower than hypothesised, demonstrating that a full trial is presently not possible. The qualitative study identified factors that led to variation in recruitment across the sites. Implementation of organisational and operational measures can increase recruitment in any future trial. There was insufficient information to conduct a full economic analysis. TRIAL REGISTRATION: Current Controlled Trials ISRCTN31161700. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 81. See the NIHR Journals Library website for further project information.

Cascade Fumarate Hydratase mutation screening allows early detection of kidney tumour: a case report.

BACKGROUND: Fumarate hydratase (FH) deficiency is a rare autosomal recessive disorder which results in a major defect in cellular metabolism. It presents in infancy with progressive encephalopathy, hypotonia, seizures and failure to thrive and is often fatal in childhood. It is caused by mutations in the FH gene (1q42.1) that result in deficiency of the citric acid cycle enzyme fumarate hydratase, resulting in accumulation of fumaric acid. Heterozygous germline mutations in the FH gene predispose to an aggressive autosomal dominant inherited early-onset kidney cancer syndrome: hereditary leiomyomatosis and renal cell cancer (HLRCC). CASE PRESENTATION: Cascade FH mutation screening enabled the early diagnosis of a renal tumour in an asymptomatic parent of a child with fumarate hydratase deficiency, resulting in timely and possibly life-saving treatment. CONCLUSION: While the theoretical risk of kidney cancer in parents of children with recessive fumarate hydratase deficiency is well recognized, to our knowledge this is the first report of a kidney tumour being detected in a parent by screening performed for this indication. This underscores the importance of offering lifelong kidney surveillance to such parents and other heterozygous relatives of children born with fumarate hydratase deficiency.

Cytoreductive Nephrectomy in the Tyrosine Kinase Inhibitor Era: A Question That May Never Be Answered.

Despite great interest, two randomised controlled trials (RCTs) of cytoreductive nephrectomy in the tyrosine kinase inhibitor setting in metastatic renal cell carcinoma have either closed early (SURTIME) or are recruiting very slowly (CARMENA) after 7 yr. Challenges in RCT delivery in uro-oncologic surgery are many. Multiple steps are needed to ensure strong recruitment to trials addressing important urologic cancer questions. Feasibility/pilot studies are key stepping stones towards successful delivery of surgical RCTs.

Reorganising specialist cancer surgery for the twenty-first century: a mixed methods evaluation (RESPECT-21).

BACKGROUND: There are longstanding recommendations to centralise specialist healthcare services, citing the potential to reduce variations in care and improve patient outcomes. Current activity to centralise specialist cancer surgical services in two areas of England provides an opportunity to study the planning, implementation and outcomes of such changes. London Cancer and Manchester Cancer are centralising specialist surgical pathways for prostate, bladder, renal, and oesophago-gastric cancers, so that these services are provided in fewer hospitals. The centralisations in London were implemented between November 2015 and April 2016, while implementation in Manchester is anticipated in 2017. METHODS/DESIGN: This mixed methods evaluation will analyse stakeholder preferences for centralisations; it will use qualitative methods to analyse planning, implementation and sustainability of the centralisations ('how and why?'); and it will use a controlled before and after design to study the impact of centralisation on clinical processes, clinical outcomes, cost-effectiveness and patient experience ('what works and at what cost?'). The study will use a framework developed in previous research on major system change in acute stroke services. A discrete choice experiment will examine patient, public and professional preferences for centralisations of this kind. Qualitative methods will include documentary analysis, stakeholder interviews and non-participant observations of meetings. Quantitative methods will include analysis of local and national data on clinical processes, outcomes, costs and National Cancer Patient Experience Survey data. Finally, we will hold a workshop for those involved in centralisations of specialist services in other settings to discuss how these lessons might apply more widely. DISCUSSION: This multi-site study will address gaps in the evidence on stakeholder preferences for centralisations of specialist cancer surgery and the processes, impact and cost-effectiveness of changes of this kind. With increasing drives to centralise specialist services, lessons from this study will be of value to those who commission, organise and manage cancer services, as well as services for other conditions and in other settings. The study will face challenges in terms of recruitment, the retrospective analysis of some of the changes, the distinction between primary and secondary outcome measures, and obtaining information on the resources spent on the reconfiguration.

Safety and Efficacy of Pazopanib Therapy Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer.

IMPORTANCE: The role of cytoreductive nephrectomy in patients with metastatic renal cancer in the era of targeted therapy is uncertain. OBJECTIVE: To establish the safety and efficacy of upfront pazopanib therapy prior to cytoreductive nephrectomy in previously untreated patients with metastatic clear cell renal cancer. DESIGN, SETTING, AND PARTICIPANTS: Single-arm phase 2 study of 104 previously untreated patients with metastatic clear cell renal cancer recruited between June 2008 and October 2012 at cancer treatment centers with access to nephrectomy services. The minimum follow-up was 30 months. INTERVENTIONS: Patients received 12 to 14 weeks of preoperative pazopanib therapy prior to planned cytoreductive nephrectomy and continued pazopanib therapy after surgery. Treatment was stopped at disease progression. MAIN OUTCOMES AND MEASURES: The primary end point was clinical benefit (using Response Evaluation Criteria in Solid Tumors, version 1.1) prior to surgery (at 12-14 weeks). Secondary end points included surgical complications, progression-free survival (PFS), overall survival (OS), and biomarker analysis. RESULTS: Of 104 patients recruited, 100 patients were assessable for clinical benefit prior to planned nephrectomy; 80 of 104 (76.9%) were men; median [interquartile range] age, 64 [56-71] years). Overall, 84 of 100 (84% [95% CI, 75%-91%]) gained clinical benefit before planned nephrectomy. The median reduction in the size of the primary tumor was 14.4% (interquartile range, 1.4%-21.1%). No patients were unable to undergo surgery as a result of local progression of disease. Nephrectomy was performed in 63 (61%) of patients; 14 (22%) reported surgical complications. The 2 most common reasons for not undergoing surgery were progression of disease (n = 13) and patient choice (n = 9). There was 1 postoperative surgical death. The median PFS and OS for the whole cohort were 7.1 (95% CI, 6.0-9.2) and 22.7 (95% CI, 14.3-not estimable) months, respectively. Patients with MSKCC poor-risk disease or progressive disease prior to surgery had a poor outcome (median OS, 5.7 [95% CI, 2.6-10.8] and 3.9 [95% CI, 0.5-9.1] months, respectively). Surgical complications were observed in 14 (22%) of the nephrectomies. Biomarker analysis from sequential tissue samples revealed a decrease in CD8 expression (20.00 vs 13.75; P = .05) and significant reduction in expression of von Hippel-Lindau tumor suppressor (100 vs 40; P < .001) and C-MET (300 vs 100; P < .001) and increased programmed cell death ligand 1 expression (0 vs 1.5; P < .001) in the immune component. No on-treatment biomarker correlated with response. CONCLUSIONS AND RELEVANCE: Nephrectomy after upfront pazopanib therapy could be performed safely and was associated with good outcomes in patients with intermediate-risk metastatic clear cell renal cancer.

Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients.

BACKGROUND: 8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50%. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). METHODS: SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing. RESULTS: High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y(419)) and FAK (Y(861)) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein. CONCLUSIONS: Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism.

Prostate Cancer Unit Initiative in Europe: A position paper by the European School of Oncology.

The Prostate Cancer Programme of the European School of Oncology developed the concept of specialised interdisciplinary and multiprofessional prostate cancer care to be formalized in Prostate Cancer Units (PCU). After the publication in 2011 of the collaborative article "The Requirements of a Specialist Prostate Cancer Unit: A Discussion Paper from the European School of Oncology", in 2012 the PCU Initiative in Europe was launched. A multiprofessional Task Force of internationally recognized opinion leaders, among whom representatives of scientific societies, and patient advocates gathered to set standards for quality comprehensive prostate cancer care and designate care pathways in PCUs. The result was a consensus on 40 mandatory and recommended standards and items, covering several macro-areas, from general requirements to personnel to organization and case management. This position paper describes the relevant, feasible and applicable core criteria for defining PCUs in most European countries delivered by PCU Initiative in Europe Task Force.

Translational research will fail without surgical leadership: SCOTRRCC a successful surgeon-led Nationwide translational research infrastructure in renal cancer.

BACKGROUND: High quality human biosamples with associated high quality clinical data are essential for successful translational research. Despite this, the traditional approach is for the surgeon to act as a technician in the tissue collection act. Biomarker research presents multiple challenges and the field is littered with failures. Tissue quality, poor clinical information, small sample numbers and lack of validation cohorts are just a few reasons for failure. It is clear that the surgeon involved in tissue acquisition must be fully engaged in the process of biosampling for a specific condition, as this will negate many of the issues for translational research failure due to an inadequate bioresource. APPROACH: In this Matter for Debate paper, the Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC) is discussed as an example of a urological surgery lead bioresource which has resulted in a National collection of renal cancer tissue and blood (from over 900 patients to date), negating all of the traditional issues with biobanks because of close enagagement and acknowledgement of urologists and uropathologists from seven centres around Scotland. SCOTRRCC has leveraged renal cancer research in Scotland resulting in several high impact publications and providing a springboard for future research in this disease in Scotland and beyond. CONCLUSIONS: The SCOTRRCC model presented here can be transferred to other surgical disciplines for success in translational research.

Sunitinib Treatment Exacerbates Intratumoral Heterogeneity in Metastatic Renal Cancer.

PURPOSE: The aim of this study was to investigate the effect of VEGF-targeted therapy (sunitinib) on molecular intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mccRCC). EXPERIMENTAL DESIGN: Multiple tumor samples (n = 187 samples) were taken from the primary renal tumors of patients with mccRCC who were sunitinib treated (n = 23, SuMR clinical trial) or untreated (n = 23, SCOTRRCC study). ITH of pathologic grade, DNA (aCGH), mRNA (Illumina Beadarray) and candidate proteins (reverse phase protein array) were evaluated using unsupervised and supervised analyses (driver mutations, hypoxia, and stromal-related genes). ITH was analyzed using intratumoral protein variance distributions and distribution of individual patient aCGH and gene-expression clustering. RESULTS: Tumor grade heterogeneity was greater in treated compared with untreated tumors (P = 0.002). In unsupervised analysis, sunitinib therapy was not associated with increased ITH in DNA or mRNA. However, there was an increase in ITH for the driver mutation gene signature (DNA and mRNA) as well as increasing variability of protein expression with treatment (P < 0.05). Despite this variability, significant chromosomal and transcript changes to key targets of sunitinib, such as VHL, PBRM1, and CAIX, occurred in the treated samples. CONCLUSIONS: These findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes/proteins in mccRCC. The results, based on primary tumor analysis, do not support the hypothesis that resistant clones are selected and predominate following targeted therapy.

Carbonic anhydrase 9 expression increases with vascular endothelial growth factor-targeted therapy and is predictive of outcome in metastatic clear cell renal cancer.

BACKGROUND: There is a lack of biomarkers to predict outcome with targeted therapy in metastatic clear cell renal cancer (mccRCC). This may be because dynamic molecular changes occur with therapy. OBJECTIVE: To explore if dynamic, targeted-therapy-driven molecular changes correlate with mccRCC outcome. DESIGN, SETTING, AND PARTICIPANTS: Multiple frozen samples from primary tumours were taken from sunitinib-naïve (n=22) and sunitinib-treated mccRCC patients (n=23) for protein analysis. A cohort (n=86) of paired, untreated and sunitinib/pazopanib-treated mccRCC samples was used for validation. Array comparative genomic hybridisation (CGH) analysis and RNA interference (RNAi) was used to support the findings. INTERVENTION: Three cycles of sunitinib 50mg (4 wk on, 2 wk off). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Reverse phase protein arrays (training set) and immunofluorescence automated quantitative analysis (validation set) assessed protein expression. RESULTS AND LIMITATIONS: Differential expression between sunitinib-naïve and treated samples was seen in 30 of 55 proteins (p<0.05 for each). The proteins B-cell CLL/lymphoma 2 (BCL2), mutL homolog 1 (MLH1), carbonic anhydrase 9 (CA9), and mechanistic target of rapamycin (mTOR) (serine/threonine kinase) had both increased intratumoural variance and significant differential expression with therapy. The validation cohort confirmed increased CA9 expression with therapy. Multivariate analysis showed high CA9 expression after treatment was associated with longer survival (hazard ratio: 0.48; 95% confidence interval, 0.26-0.87; p=0.02). Array CGH profiles revealed sunitinib was associated with significant CA9 region loss. RNAi CA9 silencing in two cell lines inhibited the antiproliferative effects of sunitinib. Shortcomings of the study include selection of a specific protein for analysis, and the specific time points at which the treated tissue was analysed. CONCLUSIONS: CA9 levels increase with targeted therapy in mccRCC. Lower CA9 levels are associated with a poor prognosis and possible resistance, as indicated by the validation cohort. PATIENT SUMMARY: Drug treatment of advanced kidney cancer alters molecular markers of treatment resistance. Measuring carbonic anhydrase 9 levels may be helpful in determining which patients benefit from therapy.

Reclassification of the Fuhrman grading system in renal cell carcinoma-does it make a difference?

PURPOSE: The aim of this study was to determine whether reclassifying the Fuhrman grading system provides further prognostic information. MATERIALS AND METHODS: We studied the pathological features and cancer specific survival of 237 patients with clear cell cancer undergoing surgery between 1997-2007 in a single centre. The original Fuhrman grading system was investigated as well as various simplified models utilising the original Fuhrman grade. RESULTS: The median follow up was 69 months. On univariate analysis, the conventional Fuhrman grading system as well various simplified models were predicative of cancer specific survival. On multivariate analysis, only the three tiered modified model in which grades 1 and 2 were combined whilst grades 3 and 4 were kept separate was an independent predictor of cancer specific survival (p=0.001, HR 2.17, 95% CI 1.37-3.43). Furthermore this simplified model demonstrated a stronger relationship to recurrence than the conventional 4 tiered Fuhrman grading system. CONCLUSIONS: A modified, three-tiered Fuhrman grading system has been demonstrated to be an independent predictor of cancer specific survival.

Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is a histopathologically and molecularly heterogeneous disease with the chromophobe subtype (chRCC) accounting for approximately 5% of all cases. The median overall survival of advanced RCC has improved significantly since the advent of tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors. However, high-quality evidence for the use of new generation tyrosine kinase inhibitors in patients with advanced chRCC is lacking. Few published case reports have highlighted the use of temsirolimus in chRCC. CASE PRESENTATION: Here, we report the case of a 36-year-old Caucasian woman with metastatic chRCC with predominantly skeletal metastases who was refractory to sunitinib who demonstrated a durable clinical response to temsirolimus lasting 20 months. We review the available evidence pertaining to the use of new generation molecularly targeted agents, in particular mTOR inhibitors in chRCC and discuss their emerging role in the management of this disease which would aid the oncologists faced with the challenge of treating this rare type of RCC. CONCLUSION: Conducting randomised clinical trials in this rarer sub-group of patients would be challenging and our case report and the evidence reviewed would guide the physicians to make informed decision regarding the management of these patients.

The epidemiology and risk factors for renal cancer.

BACKGROUND: Renal cancer is a frequently occurring malignancy with over 270,000 new cases diagnosed and it being responsible for 110,000 deaths annually on a global basis. Incidence rates have gradually increased whilst mortality rates are starting to plateau. OBJECTIVE: To review epidemiology and risk factors for renal cancer. METHODS: The current data is based on a thorough review of available original and review articles on epidemiology and risk factors for renal cancer with a systemic literature search utilising Medline. RESULTS: The prevalence of associated risk factors such as genetic susceptibility, smoking, hypertension and obesity are changing and could account for the changes in incidence whilst the role of diet and occupational exposure to carcinogens requires further investigation. CONCLUSION: Despite the evidence of various associated risk factors, further work is required from well designed studies to gain a greater understanding of the etiology of renal cancer.