Publications by authors named "Grant D Stewart"

154 Publications

Early detection of kidney cancer using urinary proteins: a truly non-invasive strategy.

BJU Int 2021 Sep 27. Epub 2021 Sep 27.

Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Hill's Road, Cambridge, CB2 0QQ, UK.

Objectives: To review urinary protein biomarkers as potential non-invasive, easily obtainable, early diagnostic tools in renal cell carcinoma (RCC).

Methods: A PubMed database search was performed up to the year 2020 to identify primary studies reporting potential urinary protein biomarkers for RCC. Separate searches were conducted to identify studies describing appropriate methods of developing cancer screening programmes and detection of cancer biomarkers.

Results: Several urinary protein biomarkers are under validation for RCC diagnostics, e.g., Aquaporin-1, Perilipin-2, Carbonic Anhydrase-9, Raf-Kinase Inhibitory Protein, Nuclear Matrix Protein-22, 14-3-3 Protein β/α and Neutrophil Gelatinase-Associated Lipocalin. However, none has yet been validated or approved for clinical use due to low sensitivity or specificity, inconsistencies in appropriate study design, or lack of external validation.

Conclusions: Evaluation of biomarkers' feasibility, sample preparation and storage, biomarker validation, and the application of novel technologies may provide a solution that maximises the potential for a truly non-invasive biomarker in early RCC diagnostics.
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http://dx.doi.org/10.1111/bju.15601DOI Listing
September 2021

Dynamic biomarker and imaging changes from a phase II study of pre- and post-surgical sunitinib.

BJU Int 2021 Sep 22. Epub 2021 Sep 22.

Cambridge University Hospitals NHS Foundation Trust, Department of Oncology, Box 193, Hills Road, Cambridge, CB2 0QQ, UK.

Objective: To explore translational biological and imaging biomarkers for Sunitinib treatment prior to and after debulking nephrectomy.

Methods: Treatment-naïve patients with metastatic renal cell carcinoma (mRCC) received 50mg OD Sunitinib for 12 days pre-surgically, then post-surgery on 4 week-on, 2 week-off, repeating 6 week cycles until disease progression in a single arm phase II trial. Structural and dynamic contrast-enhanced MR imaging (DCE-MRI) and research blood sampling were performed at baseline and after 12 days. CT Imaging was performed at baseline and post-surgery then every 2 cycles. The primary endpoint was objective response rate (RECIST) excluding the resected kidney. Secondary endpoints included changes in DCE-MRI of the tumour following pre-surgery Sunitinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Translational and imaging endpoints were exploratory.

Results: 14 patients received pre-surgery Sunitinib, 71% (10/14) took the planned 12 doses. All underwent nephrectomy, and 13 recommenced Sunitinib post-operatively. 58.3% (7/12) of patients achieved partial or complete response (PR or CR) (95% CI: 27.7 - 84.8%). Median OS was 33.7months and median PFS was 15.7months. Amongst those achieving PR or CR, median response duration was 8.7months. No unexpected surgical complications, Sunitinib-related toxicities, or surgical delays occurred. Within the translational endpoints, pre-surgical Sunitinib significantly increased necrosis, and reduced CD31, Ki67, circulating VEGF-C, and Ktrans (measured using DCE-MRI) (all p<0.05). There was a trend for improved OS in patients with high baseline plasma VEGF-C expression (p=0.02). Reduction in radiological tumour volume after pre-surgical Sunitinib correlated with high percentage of solid tumour components at baseline (Spearman's coefficient ρ=0.69, p=0.02). Conversely, percentage tumour volume reduction correlated with lower baseline percentage necrosis (coefficient=-0.51, p=0.03).

Conclusion: Neoadjuvant studies such as NeoSun can safely and effectively explore translational biological and imaging endpoints.
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http://dx.doi.org/10.1111/bju.15600DOI Listing
September 2021

RAMPART: A phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse.

Contemp Clin Trials 2021 09 16;108:106482. Epub 2021 Sep 16.

MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, 2nd Floor 90 High Holborn, London WC1V 6LJ, UK.

Background: 20-60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting.

Methods/design: RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3-11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART).

Trial Registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39, CTA #: 20363/0380/001-0001, MREC #: 17/LO/1875, ClinicalTrials.gov Identifier: NCT03288532, RAMPART grant number: MC_UU_12023/25, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0.
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http://dx.doi.org/10.1016/j.cct.2021.106482DOI Listing
September 2021

RAMPART: A model for a regulatory-ready academic-led phase III trial in the adjuvant renal cell carcinoma setting.

Contemp Clin Trials 2021 09 16;108:106481. Epub 2021 Sep 16.

MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, 2nd Floor 90 High Holborn, London WC1V 6LJ.

The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve outcomes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations. Trial Registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39. CTA #: 20363/0380/001-0001. MREC #: 17/LO/1875. ClinicalTrials.gov Identifier: NCT03288532 RAMPART grant number: MC_UU_12023/25. . RAMPART Protocol version 5.0.
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http://dx.doi.org/10.1016/j.cct.2021.106481DOI Listing
September 2021

Validation and public health modelling of risk prediction models for kidney cancer using the UK Biobank.

BJU Int 2021 Sep 19. Epub 2021 Sep 19.

Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Objectives: To externally validate risk models for the detection of kidney cancer, as early detection of kidney cancer improves survival and stratifying the population using risk models could enable an individually tailored screening programme.

Methods: We validated the performance of 30 existing phenotypic models predicting the risk of kidney cancer in the UK Biobank cohort (n = 450 687). We compared the discrimination and calibration of models for men, women, and a mixed-sex cohort. Population level data were used to estimate model performance in a screening scenario for a range of risk thresholds (6-year risk: 0.1-1.0%).

Results: In all, 10 models had reasonable discrimination (area under the receiver-operating characteristic curve >0.60), although some had poor calibration. Modelling demonstrated similar performance of the best models over a range of thresholds. The models showed an improvement in ability to identify cases compared to age- and sex-based screening. All the models performed less well in women than men.

Conclusions: The present study is the first comprehensive external validation of risk models for kidney cancer. The best-performing models are better at identifying individuals at high risk of kidney cancer than age and sex alone; however, the benefits are relatively small. Feasibility studies are required to determine applicability to a screening programme.
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http://dx.doi.org/10.1111/bju.15598DOI Listing
September 2021

Single cell derived mRNA signals across human kidney tumors.

Nat Commun 2021 06 23;12(1):3896. Epub 2021 Jun 23.

Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Tumor cells may share some patterns of gene expression with their cell of origin, providing clues into the differentiation state and origin of cancer. Here, we study the differentiation state and cellular origin of 1300 childhood and adult kidney tumors. Using single cell mRNA reference maps of normal tissues, we quantify reference "cellular signals" in each tumor. Quantifying global differentiation, we find that childhood tumors exhibit fetal cellular signals, replacing the presumption of "fetalness" with a quantitative measure of immaturity. By contrast, in adult cancers our assessment refutes the suggestion of dedifferentiation towards a fetal state in most cases. We find an intimate connection between developmental mesenchymal populations and childhood renal tumors. We demonstrate the diagnostic potential of our approach with a case study of a cryptic renal tumor. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer.
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http://dx.doi.org/10.1038/s41467-021-23949-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222373PMC
June 2021

Reproducibility of CT-based radiomic features against image resampling and perturbations for tumour and healthy kidney in renal cancer patients.

Sci Rep 2021 06 2;11(1):11542. Epub 2021 Jun 2.

Advanced Research Center on Electronic Systems (ARCES), University of Bologna, 40125, Bologna, Italy.

Computed Tomography (CT) is widely used in oncology for morphological evaluation and diagnosis, commonly through visual assessments, often exploiting semi-automatic tools as well. Well-established automatic methods for quantitative imaging offer the opportunity to enrich the radiologist interpretation with a large number of radiomic features, which need to be highly reproducible to be used reliably in clinical practice. This study investigates feature reproducibility against noise, varying resolutions and segmentations (achieved by perturbing the regions of interest), in a CT dataset with heterogeneous voxel size of 98 renal cell carcinomas (RCCs) and 93 contralateral normal kidneys (CK). In particular, first order (FO) and second order texture features based on both 2D and 3D grey level co-occurrence matrices (GLCMs) were considered. Moreover, this study carries out a comparative analysis of three of the most commonly used interpolation methods, which need to be selected before any resampling procedure. Results showed that the Lanczos interpolation is the most effective at preserving original information in resampling, where the median slice resolution coupled with the native slice spacing allows the best reproducibility, with 94.6% and 87.7% of features, in RCC and CK, respectively. GLCMs show their maximum reproducibility when used at short distances.
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http://dx.doi.org/10.1038/s41598-021-90985-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172898PMC
June 2021

Leibovich score is the optimal clinico-pathological system associated with recurrence of non-metastatic clear cell renal cell carcinoma.

Urol Oncol 2021 07 20;39(7):438.e11-438.e21. Epub 2021 May 20.

Urology Department, Western General Hospital, NHS Lothian, Edinburgh; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh.

Purpose: To determine the optimal post-operative risk stratification system associated with survival following surgery for clear cell renal cell carcinoma (ccRCC): tumour grade, tumour stage, Leibovich 2003, Leibovich 2018, Kattan, Stage, size, grade and necrosis (SSIGN) or UCLA Integrated Staging System (UISS) scores.

Methods: 542 patients with non-metastatic ccRCC who underwent nephrectomy 2008-2018 were reviewed. Primary outcome was recurrence-free survival (RFS), with secondary outcomes cancer-specific survival (CSS) and overall survival (OS).

Results: All systems were significantly associated with RFS, CSS and OS by Kaplan-Meier and unadjusted Cox-regression. ROC analysis identified that Leibovich 2003, Leibovich 2018A or B and SSIGN were optimally association with 5year RFS (AUC (Area under curve) 0.87, 0.86, 0.86 and 0.86), but Leibovich 2003 or 2018A offered additional information on adjusted regression analysis (HR 1.24, P = 0.02; HR 1.17, P = 0.04). ROC analysis identified that Leibovich 2018B, Leibovich 2003, SSIGN and UISS were equally associated with 5 year OS (AUC 0.76, 0.74, 0.73 and 0.72). UISS added additional explanation of the variance in OS on adjusted regression analysis (HR 1.96, P = 0.002). A novel combination of Leibovich 2003 score and Eastern Co-operative Oncology Group (ECOG) performance status improved 5 year OS association compared to the Leibovich 2003 alone (AUC 0.78, P = 0.001), without affecting association with 5year RFS (AUC 0.87, P = 0.75).

Conclusions: All systems were robust tools associated with RFS, CSS and OS in ccRCC. In our cohort, the Leibovich 2003 and Leibovich 2018A scores may be better associated with RFS compared to other strategies. The UISS, Leibovich 2018B or Leibovich 2003 combined with ECOG performance status may stratify OS better than other modalities.
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http://dx.doi.org/10.1016/j.urolonc.2021.04.007DOI Listing
July 2021

Reasons for intending to accept or decline kidney cancer screening: thematic analysis of free text from an online survey.

BMJ Open 2021 05 18;11(5):e044961. Epub 2021 May 18.

The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, Cambridgeshire, UK

Objectives: Kidney cancer has been identified as a disease for which screening might provide significant benefit for patients. The aim of this study was to understand in detail the facilitators and barriers towards uptake of a future kidney cancer screening programme, and to compare these across four proposed screening modalities.

Design: An online survey including free-text responses.

Setting: UK PARTICIPANTS: 668 adults PRIMARY AND SECONDARY OUTCOME MEASURES: The survey assessed participants' self-reported intention to take-up kidney cancer screening with four different test methods (urine test, blood test, ultrasound scan and low-dose CT). We conducted thematic analysis of 2559 free-text comments made within the survey using an inductive approach.

Results: We identified five overarching themes that influenced screening intention: 'personal health beliefs', 'practicalities', 'opinions of the test', 'attitudes towards screening' and 'cancer apprehension'. Overall, participants considered the tests presented as simple to complete and the benefits of early detection to outweigh any drawbacks to screening. Dominant facilitators and barriers varied with patterns of intention to take up screening across the four tests. Most intended to take up screening by all four tests, and for these participants, screening was seen as a positive health behaviour. A significant minority were driven by practicalities and the risks of the tests offered. A smaller proportion intended to reject all forms of screening offered, often due to fear or worry about results and unnecessary medical intervention or a general negative view of screening.

Conclusions: Most individuals would accept kidney cancer screening by any of the four test options presented because of strong positive attitudes towards screening in general and the perceived simplicity of the tests. Providing information about the rationale for screening in general and the potential benefits of early detection will be important to optimise uptake among uncertain individuals.
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http://dx.doi.org/10.1136/bmjopen-2020-044961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137225PMC
May 2021

Pattern, timing and predictors of recurrence after surgical resection of chromophobe renal cell carcinoma.

World J Urol 2021 Oct 13;39(10):3823-3831. Epub 2021 Apr 13.

Division of Surgery and Interventional Science, University College London, London, UK.

Purpose: Currently there are no specific guidelines for the post-operative follow-up of chromophobe renal cell carcinoma (chRCC). We aimed to evaluate the pattern, location and timing of recurrence after surgery for non-metastatic chRCC and establish predictors of recurrence and cancer-specific death.

Methods: Retrospective analysis of consecutive surgically treated non-metastatic chRCC cases from the Royal Free London NHS Foundation Trust (UK, 2015-2019) and the international collaborative database RECUR (15 institutes, 2006-2011). Kaplan-Meier curves were plotted. The association between variables of interest and outcomes were analysed using univariate and multivariate Cox proportional hazards regression models with shared frailty for data source.

Results: 295 patients were identified. Median follow-up was 58 months. The five and ten-year recurrence-free survival rates were 94.3% and 89.2%. Seventeen patients (5.7%) developed recurrent disease, 13 (76.5%) with distant metastases. 54% of metastatic disease diagnoses involved a single organ, most commonly the bone. Early recurrence (< 24 months) was observed in 8 cases, all staged ≥ pT2b. 30 deaths occurred, of which 11 were attributed to chRCC. Sarcomatoid differentiation was rare (n = 4) but associated with recurrence and cancer-specific death on univariate analysis. On multivariate analysis, UICC/AJCC T-stage ≥ pT2b, presence of coagulative necrosis, and positive surgical margins were predictors of recurrence and cancer-specific death.

Conclusion: Recurrence and death after surgically resected chRCC are rare. For completely excised lesions ≤ pT2a without coagulative necrosis or sarcomatoid features, prognosis is excellent. These patients should be reassured and follow-up intensity curtailed.
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http://dx.doi.org/10.1007/s00345-021-03683-9DOI Listing
October 2021

Should patients with low-risk renal cell carcinoma be followed differently after nephron-sparing surgery vs radical nephrectomy?

BJU Int 2021 Sep 26;128(3):386-394. Epub 2021 Apr 26.

UCL Division of Surgical and Interventional Science, Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, UK.

Objective: To investigate whether pT1 renal cell carcinoma (RCC) should be followed differently after partial (PN) or radical nephrectomy (RN) based on a retrospective analysis of a multicentre database (RECUR).

Subjects: A retrospective study was conducted in 3380 patients treated for nonmetastatic RCC between January 2006 and December 2011 across 15 centres from 10 countries, as part of the RECUR database project. For patients with pT1 clear-cell RCC, patterns of recurrence were compared between RN and PN according to recurrence site. Univariate and multivariate models were used to evaluate the association between surgical approach and recurrence-free survival (RFS) and cancer-specific mortality (CSM).

Results: From the database 1995 patients were identified as low-risk patients (pT1, pN0, pNx), of whom 1055 (52.9%) underwent PN. On multivariate analysis, features associated with worse RFS included tumour size (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.14-1.39; P < 0.001), nuclear grade (HR 2.31, 95% CI 1.73-3.08; P < 0.001), tumour necrosis (HR 1.5, 95% CI 1.03-2.3; P = 0.037), vascular invasion (HR 2.4, 95% CI 1.3-4.4; P = 0.005) and positive surgical margins (HR 4.4, 95% CI 2.3-8.5; P < 0.001). Kaplan-Meier analysis of CSM revealed that the survival of patients with recurrence after PN was significantly better than those with recurrence after RN (P = 0.02). While the above-mentioned risk factors were associated with prognosis, type of surgery alone was not an independent prognostic variable for RFS nor CSM. Limitations include the retrospective nature of the study.

Conclusion: Our results showed that follow-up protocols should not rely solely on stage and type of primary surgery. An optimized regimen should also include validated risk factors rather than type of surgery alone to select the best imaging method and to avoid unnecessary imaging. A follow-up of more than 3 years should be considered in patients with pT1 tumours after RN. A novel follow-up strategy is proposed.
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http://dx.doi.org/10.1111/bju.15415DOI Listing
September 2021

Outcome after resection of occult and non-occult lymph node metastases at the time of nephrectomy.

World J Urol 2021 Sep 25;39(9):3377-3383. Epub 2021 Feb 25.

Department of Urology, Renal Cancer Unit, Royal Free Hospital, London, UK.

Purpose: There is sparse evidence on outcomes of resected occult LN metastases at the time of nephrectomy (synchronous disease). We sought to analyse a large international cohort of patients and to identify clinico-pathological predictors of long-term survival.

Materials And Methods: We collected data of consecutive patients who underwent nephrectomy and LND for T cN0-1pN1 and cM0-1 RCC at 7 referral centres between 1988 and 2019. Patients were stratified into four clinico-pathological groups: (1) cN0cM0-pN1, (2) cN1cM0-pN1(limited, 1-3 positive nodes), (3) cN1cM0-pN1(extensive, > 3 positive nodes), and (4) cM1-pN1. Overall survival (OS) was estimated using the Kaplan-Meier method, and associations with all-cause mortality (ACM) were evaluated using Cox models with multiple imputations.

Results: Of the 4370 patients with LND, 292 patients with pN1 disease were analysed. Median follow-up was 62 months, during which 171 patients died. Median OS was 21 months (95% CI 17-30 months) and the 5-year OS rate was 24% (95% CI 18-31%). Patients with cN0cM0-pN1 disease had a median OS of 57 months and a 5-year OS rate of 43%. 5-year OS (median OS) decreased to 29% (33 months) in cN1cM0-pN1(limited) and to 23% (23 months) in cN1cM0-pN1(extensive) patients. Those with cM1-pN1 disease had the worst prognosis, with a 5-year OS rate of 13% (9 months). On multivariable analysis, age (p = 0.034), tumour size (p = 0.02), grade (p = 0.02) and clinico-pathological group (p < 0.05) were significant predictors of ACM.

Conclusion: Depending on clinico-pathological group, grade and tumour size, 5-year survival of patients with LN metastases varies from 13 to 43%. Patients with resected occult lymph node involvement (cN0/pN1 cM0) have the best prognosis with a considerable chance of long-term survival.
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http://dx.doi.org/10.1007/s00345-021-03633-5DOI Listing
September 2021

Prevalence, Disease-free, and Overall Survival of Contemporary Patients With Renal Cell Carcinoma Eligible for Adjuvant Checkpoint Inhibitor Trials.

Clin Genitourin Cancer 2021 04 7;19(2):e92-e99. Epub 2021 Jan 7.

Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, UCL Division of Surgical and Interventional Science, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address:

Introduction: Designing adjuvant trials is challenging because of uncertainties of prevalence and outcome of high-risk renal cell cancer (RCC) despite use of validated risk scores. Our objective is to investigate how differences in eligibility criteria may impact on potential study results in RCC adjuvant trials.

Patients And Methods: RECUR is a multicenter European database capturing patient and tumor characteristics, recurrence patterns, and survival of those curatively treated for non-metastatic RCC from 2006 to 2011 without any adjuvant therapy. We used RECUR to evaluate prevalence, disease-free survival (DFS), and overall survival (OS) according to eligibility criteria of immunotherapy-based adjuvant trials IMMotion 010 (NCT03024996), Checkmate 914 (NCT03138512), Keynote-564 (NCT03142334), RAMPART (NCT03288532), and PROSPER (NCT03055013).

Results: Of 3024 relevant patients in RECUR, 408 (13.5%), 725 (24%), 609 (20.1%), 1363 (45.1%), and 1071 (35.4%) met eligibility criteria for IMMotion-010, CheckMate-914, Keynote-564, RAMPART, and PROSPER, respectively. The median and 5-year DFS Kaplan-Meier estimates in RECUR corresponding to each trial eligibility criteria were: not reached and 69.6% for RAMPART; not reached and 64.5% for PROSPER; 109.3 months (95% confidence interval [CI], 83.9-134.6 months) and 57% for CheckMate-914; 75.8 months (95% CI, 52.7-98.8 months) and 54.3% for Keynote-564; and 43.6 months (95% CI, 30.8-56.4 months) and 45% for IMMotion-010. Our analysis may be limited by the retrospective design.

Conclusions: RECUR provides estimated DFS and OS benchmarks for placebo arms of adjuvant checkpoint inhibitor studies and hence likely time to trial reporting. Well-documented contemporary registries rather than past risk models should be used to design future adjuvant trials.
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http://dx.doi.org/10.1016/j.clgc.2020.12.005DOI Listing
April 2021

Novel Liquid Biomarkers and Innovative Imaging for Kidney Cancer Diagnosis: What Can Be Implemented in Our Practice Today? A Systematic Review of the Literature.

Eur Urol Oncol 2021 Feb 3;4(1):22-41. Epub 2021 Jan 3.

European Association of Urology (EAU) Young Academic Urologists (YAU) Renal Cancer Working Group; Department of Urology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Division of Experimental Oncology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Context: The epidemiological signature of renal cell carcinoma (RCC) during the past decades is explained by overdetection and overtreatment of indolent cancers; furthermore, a non-negligible proportion of patients undergoing surgery for suspected RCC harbour benign renal tumours. As the gold standard for RCC diagnosis remains histopathological analysis of surgical or biopsy specimens, implementation of noninvasive diagnostic strategies to discriminate between benign and malignant renal masses is an urgent unmet need.

Objective: To systematically review novel liquid biomarkers and imaging modalities for RCC diagnosis.

Evidence Acquisition: A systematic review of the recent English-language literature was conducted according to the European Association of Urology guidelines and the PRISMA statement recommendations (PROSPERO ID: CRD42020190773) using the MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov databases. Risk-of-bias assessment was performed according to the QUADAS 2 tool.

Evidence Synthesis: Overall, 15 studies (six on biomarkers and nine on imaging) and eight clinical trials were included. None of the biomarkers or imaging modalities has been validated or shown to have a distinct clinical value for RCC. Specific combinations of urinary cell-free and exosomal miRNAs, urinary miR-15a, and specific panels of urinary metabolites assessed by metabolomics appear promising. In addition, machine/deep learning algorithms and radiomics applied to cross-sectional images may have potential to improve RCC diagnosis. Most studies are limited by the retrospective design, size, and lack of external validation.

Conclusions: Liquid biomarkers or imaging modalities are not ready for integration in the clinic and further well-designed studies must validate preliminary findings and explore utility in clinical decision-making.

Patient Summary: We provide a comprehensive overview of the currently available biomarkers (measured in blood or urine) and novel imaging tests (other than conventional imaging) to discriminate kidney cancer from benign renal masses in a noninvasive fashion. None of the biomarkers or imaging modalities studied was validated or added clinical value; therefore, none of them can be implemented in the clinic. However, these approaches appear to be promising for improving the diagnosis of kidney cancer in the future.
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http://dx.doi.org/10.1016/j.euo.2020.12.011DOI Listing
February 2021

Computerized Image Analysis of Tumor Cell Nuclear Morphology Can Improve Patient Selection for Clinical Trials in Localized Clear Cell Renal Cell Carcinoma.

J Pathol Inform 2020 6;11:35. Epub 2020 Nov 6.

School of Medicine, University of St Andrews and Lothian NHS University Hospitals, St Andrews, Scotland.

Background: Clinicopathological scores are used to predict the likelihood of recurrence-free survival for patients with clear cell renal cell carcinoma (ccRCC) after surgery. These are fallible, particularly in the middle range. This inevitably means that a significant proportion of ccRCC patients who will not develop recurrent disease enroll into clinical trials. As an exemplar of using digital pathology, we sought to improve the predictive power of "recurrence free" designation in localized ccRCC patients, by precise measurement of ccRCC nuclear morphological features using computational image analysis, thereby replacing manual nuclear grade assessment.

Materials And Methods: TNM 8 UICC pathological stage pT1-pT3 ccRCC cases were recruited in Scotland and in Singapore. A Leibovich score (LS) was calculated. Definiens Tissue studio® (Definiens GmbH, Munich) image analysis platform was used to measure tumor nuclear morphological features in digitized hematoxylin and eosin (H&E) images.

Results: Replacing human-defined nuclear grade with computer-defined mean perimeter generated a modified Leibovich algorithm, improved overall specificity 0.86 from 0.76 in the training cohort. The greatest increase in specificity was seen in LS 5 and 6, which went from 0 to 0.57 and 0.40, respectively. The modified Leibovich algorithm increased the specificity from 0.84 to 0.94 in the validation cohort.

Conclusions: CcRCC nuclear mean perimeter, measured by computational image analysis, together with tumor stage and size, node status and necrosis improved the accuracy of predicting recurrence-free in the localized ccRCC patients. This finding was validated in an ethnically different Singaporean cohort, despite the different H and E staining protocol and scanner used. This may be a useful patient selection tool for recruitment to multicenter studies, preventing some patients from receiving unnecessary additional treatment while reducing the number of patients required to achieve adequate power within neoadjuvant and adjuvant clinical studies.
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http://dx.doi.org/10.4103/jpi.jpi_13_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737492PMC
November 2020

A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case-control study.

PLoS Med 2020 12 10;17(12):e1003489. Epub 2020 Dec 10.

Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with around 9% of patients surviving >5 years. Asymptomatic in its initial stages, PDAC is mostly diagnosed late, when already a locally advanced or metastatic disease, as there are no useful biomarkers for detection in its early stages, when surgery can be curative. We have previously described a promising biomarker panel (LYVE1, REG1A, and TFF1) for earlier detection of PDAC in urine. Here, we aimed to establish the accuracy of an improved panel, including REG1B instead of REG1A, and an algorithm for data interpretation, the PancRISK score, in additional retrospectively collected urine specimens. We also assessed the complementarity of this panel with CA19-9 and explored the daily variation and stability of the biomarkers and their performance in common urinary tract cancers.

Methods And Findings: Clinical specimens were obtained from multiple centres: Barts Pancreas Tissue Bank, University College London, University of Liverpool, Spanish National Cancer Research Center, Cambridge University Hospital, and University of Belgrade. The biomarker panel was assayed on 590 urine specimens: 183 control samples, 208 benign hepatobiliary disease samples (of which 119 were chronic pancreatitis), and 199 PDAC samples (102 stage I-II and 97 stage III-IV); 50.7% were from female individuals. PDAC samples were collected from patients before treatment. The samples were assayed using commercially available ELISAs. Statistical analyses were performed using non-parametric Kruskal-Wallis tests adjusted for multiple comparisons, and multiple logistic regression. Training and validation datasets for controls and PDAC samples were obtained after random division of the whole available dataset in a 1:1 ratio. The substitution of REG1A with REG1B enhanced the performance of the panel to detect resectable PDAC. In a comparison of controls and PDAC stage I-II samples, the areas under the receiver operating characteristic curve (AUCs) increased from 0.900 (95% CI 0.843-0.957) and 0.926 (95% CI 0.843-1.000) in the training (50% of the dataset) and validation sets, respectively, to 0.936 in both the training (95% CI 0.903-0.969) and the validation (95% CI 0.888-0.984) datasets for the new panel including REG1B. This improved panel showed both sensitivity (SN) and specificity (SP) to be >85%. Plasma CA19-9 enhanced the performance of this panel in discriminating PDAC I-II patients from controls, with AUC = 0.992 (95% CI 0.983-1.000), SN = 0.963 (95% CI 0.913-1.000), and SP = 0.967 (95% CI 0.924-1.000). We demonstrate that the biomarkers do not show significant daily variation, and that they are stable for up to 5 days at room temperature. The main limitation of our study is the low number of stage I-IIA PDAC samples (n = 27) and lack of samples from individuals with hereditary predisposition to PDAC, for which specimens collected from control individuals were used as a proxy.

Conclusions: We have successfully validated our urinary biomarker panel, which was improved by substituting REG1A with REG1B. At a pre-selected cutoff of >80% SN and SP for the affiliated PancRISK score, we demonstrate a clinically applicable risk stratification tool with a binary output for risk of developing PDAC ('elevated' or 'normal'). PancRISK provides a step towards precision surveillance for PDAC patients, which we will test in a prospective clinical study, UroPanc.
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http://dx.doi.org/10.1371/journal.pmed.1003489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758047PMC
December 2020

Acceptability and potential impact on uptake of using different risk stratification approaches to determine eligibility for screening: A population-based survey.

Health Expect 2021 04 2;24(2):341-351. Epub 2020 Dec 2.

Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK.

Background: Using risk stratification approaches to determine eligibility has the potential to improve efficiency of screening.

Objectives: To compare the public acceptability and potential impact on uptake of using different approaches to determine eligibility for screening.

Design: An online population-based survey of 668 adults in the UK aged 45-79 including a series of scenarios in the context of a potential kidney cancer screening programme in which eligibility was determined by age, sex, age and sex combined, a simple risk score (age, sex, body mass index, smoking status), a complex risk score additionally incorporating family history and lifestyle, or a genetic risk score.

Outcome Measures: We used multi-level ordinal logistic regression to compare acceptability and potential uptake within individuals and multivariable ordinal logistic regression differences between individuals.

Results: Using sex, age and sex, or the simple risk score were less acceptable than age (P < .0001). All approaches were less acceptable to women than men. Over 70% were comfortable waiting until they were older if the complex risk score or genetics indicated a low risk. If told they were high risk, 85% would be more likely to take up screening. Being told they were low risk had no overall influence on uptake.

Conclusions: Varying the starting age of screening based on estimated risk from models incorporating phenotypic or genetic risk factors would be acceptable to most individuals and may increase uptake.

Patient Or Public Contribution: Two members of the public contributed to the development of the survey and have commented on this paper.
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http://dx.doi.org/10.1111/hex.13175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077132PMC
April 2021

Public attitudes towards screening for kidney cancer: an online survey.

BMC Urol 2020 Oct 28;20(1):170. Epub 2020 Oct 28.

The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB2 0SR, UK.

Background: Kidney cancer is often asymptomatic, leading to proposals for a screening programme. The views of the public towards introducing a new screening programme for kidney cancer are unknown. The aim of this study was to explore attitudes towards kidney cancer screening and factors influencing intention to attend a future screening programme.

Methods: We conducted an online population-based survey of 1021 adults aged 45-77 years. The main outcome measure was intention to attend four possible screening tests (urine, blood, ultrasound scan, low-dose CT) as well as extended low-dose CT scans within lung cancer screening programmes. We used multivariable regression to examine the association between intention and each screening test.

Results: Most participants stated that they would be 'very likely' or 'likely' to undergo each of the screening tests [urine test: n = 961 (94.1%); blood test: n = 922 (90.3%); ultrasound: n = 914 (89.5%); low-dose CT: n = 804 (78.8%); lung CT: n = 962 (95.2%)]. Greater intention to attend was associated with higher general cancer worry and less perceived burden/inconvenience about the screening tests. Less worry about the screening test was also associated with higher intention to attend, but only in those with low general cancer worry (cancer worry scale ≤ 5). Compared with intention to take up screening with a urine test, participants were half as likely to report that they intended to undergo blood [OR 0.56 (0.43-0.73)] or ultrasound [OR 0.50 (0.38-0.67)] testing, and half as likely again to report that they intended to take part in a screening programme featuring a low dose CT scan for kidney cancer screening alone [OR 0.19 (0.14-0.27)].

Conclusion: Participants in this study expressed high levels of intention to accept an invitation to screening for kidney cancer, both within a kidney cancer specific screening programme and in conjunction with lung cancer screening. The choice of screening test is likely to influence uptake. Together these findings support on-going research into kidney cancer screening tests and the potential for combining kidney cancer screening with existing or new screening programmes.
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http://dx.doi.org/10.1186/s12894-020-00724-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592501PMC
October 2020

The Impact of Histological Subtype on the Incidence, Timing, and Patterns of Recurrence in Patients with Renal Cell Carcinoma After Surgery-Results from RECUR Consortium.

Eur Urol Oncol 2021 Jun 24;4(3):473-482. Epub 2020 Oct 24.

Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, UCL Division of Surgical and Interventional Science, London, UK; Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: Current follow-up strategies for patients with renal cell carcinoma (RCC) after curative surgery rely mainly on risk models and the treatment delivered, regardless of the histological subtype.

Objective: To determine the impact of RCC histological subtype on recurrence and to examine the incidence, pattern, and timing of recurrences to improve follow-up recommendations.

Design, Setting, And Participants: This study included consecutive patients treated surgically with curative intention (ie, radical and partial nephrectomy) for nonmetastatic RCC (cT1-4, M0) between January 2006 and December 2011 across 15 centres from 10 countries, as part of the euRopEan association of urology renal cell carcinoma guidelines panel Collaborative multicenter consortium for the studies of follow-Up and recurrence patterns in Radically treated renal cell carcinoma patients (RECUR) database project.

Outcome Measurements And Statistical Analysis: The impact of histological subtype (ie, clear cell RCC [ccRCC], papillary RCC [pRCC], and chromophobe RCC [chRCC]) on recurrence-free survival (RFS) was assessed via univariate and multivariate analyses, adjusting for potential interactions with important variables (stage, grade, risk score, etc.) Patterns of recurrence for all histological subtypes were compared according to recurrence site and risk criteria.

Results And Limitations: Of the 3331 patients, 62.2% underwent radical nephrectomy and 37.8% partial nephrectomy. A total of 2565 patients (77.0%) had ccRCC, 535 (16.1%) had pRCC, and 231 (6.9%) had chRCC. The median postoperative follow-up period was 61.7 (interquartile range: 47-83) mo. Patients with ccRCC had significantly poorer 5-yr RFS than patients with pRCC and chRCC (78% vs 86% vs 91%, p = 0.001). The most common sites of recurrence for ccRCC were the lung and bone. Intermediate-/high-risk pRCC patients had an increased rate of lymphatic recurrence, both mediastinal and retroperitoneal, while recurrence in chRCC was rare (8.2%), associated with higher stage and positive margins, and predominantly in the liver and bone. Limitations include the retrospective nature of the study.

Conclusions: The main histological subtypes of RCC exhibit a distinct pattern and dynamics of recurrence. Results suggest that intermediate- to high-risk pRCC may benefit from cross-sectional abdominal imaging every 6 mo until 2 yr after surgery, while routine imaging might be abandoned for chRCC except for abdominal computed tomography in patients with advanced tumour stage or positive margins.

Patient Summary: In this analysis of a large database from 15 countries around Europe, we found that the main histological subtypes of renal cell carcinoma have a distinct pattern and dynamics of recurrence. Patients should be followed differently according to subtype and risk score.
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http://dx.doi.org/10.1016/j.euo.2020.09.005DOI Listing
June 2021

Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial.

J Clin Oncol 2020 12 14;38(34):4064-4075. Epub 2020 Oct 14.

Medical Research Council Clinical Trials Unit at University College London (UCL), Institute of Clinical Trials and Methodology, London, United Kingdom.

Purpose: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence.

Patients And Methods: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo.

Results: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib.

Conclusion: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.
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http://dx.doi.org/10.1200/JCO.20.01800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768344PMC
December 2020

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

J Clin Oncol 2021 01 6;39(1):66-78. Epub 2020 Oct 6.

University of Cambridge, Cambridge, United Kingdom.

Purpose: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway.

Patients And Methods: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation).

Results: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76).

Conclusion: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks.
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http://dx.doi.org/10.1200/JCO.20.01933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189635PMC
January 2021

How achievable are COVID-19 clinical trial recruitment targets? A UK observational cohort study and trials registry analysis.

BMJ Open 2020 10 5;10(10):e044566. Epub 2020 Oct 5.

Department of Medicine, University of Cambridge, Cambridge, UK

Objectives: To analyse enrolment to interventional trials during the first wave of the COVID-19 pandemic in England and describe the barriers to successful recruitment in the circumstance of a further wave or future pandemics.

Design: We analysed registered interventional COVID-19 trial data and concurrently did a prospective observational study of hospitalised patients with COVID-19 who were being assessed for eligibility to one of the RECOVERY, C19-ACS or SIMPLE trials.

Setting: Interventional COVID-19 trial data were analysed from the clinicaltrials.gov and International Standard Randomized Controlled Trial Number databases on 12 July 2020. The patient cohort was taken from five centres in a respiratory National Institute for Health Research network. Population and modelling data were taken from published reports from the UK government and Medical Research Council Biostatistics Unit.

Participants: 2082 consecutive admitted patients with laboratory-confirmed SARS-CoV-2 infection from 27 March 2020 were included.

Main Outcome Measures: Proportions enrolled, and reasons for exclusion from the aforementioned trials. Comparisons of trial recruitment targets with estimated feasible recruitment numbers.

Results: Analysis of trial registration data for COVID-19 treatment studies enrolling in England showed that by 12 July 2020, 29 142 participants were needed. In the observational study, 430 (20.7%) proceeded to randomisation. 82 (3.9%) declined participation, 699 (33.6%) were excluded on clinical grounds, 363 (17.4%) were medically fit for discharge and 153 (7.3%) were receiving palliative care. With 111 037 people hospitalised with COVID-19 in England by 12 July 2020, we determine that 22 985 people were potentially suitable for trial enrolment. We estimate a UK hospitalisation rate of 2.38%, and that another 1.25 million infections would be required to meet recruitment targets of ongoing trials.

Conclusions: Feasible recruitment rates, study design and proliferation of trials can limit the number, and size, that will successfully complete recruitment. We consider that fewer, more appropriately designed trials, prioritising cooperation between centres would maximise productivity in a further wave.
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http://dx.doi.org/10.1136/bmjopen-2020-044566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536634PMC
October 2020

Development of a DNA Methylation-Based Diagnostic Signature to Distinguish Benign Oncocytoma From Renal Cell Carcinoma.

JCO Precis Oncol 2020 28;4. Epub 2020 Sep 28.

Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA.

Purpose: A challenge in the diagnosis of renal cell carcinoma (RCC) is to distinguish chromophobe RCC (chRCC) from benign renal oncocytoma, because these tumor types are histologically and morphologically similar, yet they require different clinical management. Molecular biomarkers could provide a way of distinguishing oncocytoma from chRCC, which could prevent unnecessary treatment of oncocytoma. Such biomarkers could also be applied to preoperative biopsy specimens such as needle core biopsy specimens, to avoid unnecessary surgery of oncocytoma.

Methods: We profiled DNA methylation in fresh-frozen oncocytoma and chRCC tumors and adjacent normal tissue and used machine learning to identify a signature of differentially methylated cytosine-phosphate-guanine sites (CpGs) that robustly distinguish oncocytoma from chRCC.

Results: Unsupervised clustering of Stanford and preexisting RCC data from The Cancer Genome Atlas (TCGA) revealed that of all RCC subtypes, oncocytoma is most similar to chRCC. Unexpectedly, however, oncocytoma features more extensive, overall abnormal methylation than does chRCC. We identified 79 CpGs with large methylation differences between oncocytoma and chRCC. A diagnostic model trained on 30 CpGs could distinguish oncocytoma from chRCC in 10-fold cross-validation (area under the receiver operating curve [AUC], 0.96 (95% CI, 0.88 to 1.00)) and could distinguish TCGA chRCCs from an independent set of oncocytomas from a previous study (AUC, 0.87). This signature also separated oncocytoma from other RCC subtypes and normal tissue, revealing it as a standalone diagnostic biomarker for oncocytoma.

Conclusion: This CpG signature could be developed as a clinical biomarker to support differential diagnosis of oncocytoma and chRCC in surgical samples. With improved biopsy techniques, this signature could be applied to preoperative biopsy specimens.
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http://dx.doi.org/10.1200/PO.20.00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529536PMC
September 2020

Current evidence on screening for renal cancer.

Nat Rev Urol 2020 Nov 28;17(11):637-642. Epub 2020 Aug 28.

Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK.

Renal cell carcinoma (RCC) incidence is increasing worldwide. A high proportion of individuals are asymptomatic at diagnosis, but RCC has a high mortality rate. These facts suggest that RCC meets some of the criteria for screening, and a new analysis shows that screening for RCC could potentially be cost-effective. Targeted screening of high-risk individuals is likely to be the most cost-effective strategy to maximize the benefits and reduce the harms of screening. However, the size of the benefit of earlier initiation of treatment and the overall cost-effectiveness of screening remains uncertain. The optimal screening modality and target population is also unclear, and uncertainties exist regarding the specification and implementation of a screening programme. Before moving to a fully powered trial of screening, future work should focus on the following: developing and validating accurate risk prediction models; developing non-invasive methods of early RCC detection; establishing the feasibility, public acceptability and potential uptake of screening; establishing the prevalence of RCC and stage distribution of RCC detected by screening; and evaluating the potential harms of screening, including the impact on quality of life, overdiagnosis and over-treatment.
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http://dx.doi.org/10.1038/s41585-020-0363-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610655PMC
November 2020

Three-Dimensional Printed Molds for Image-Guided Surgical Biopsies: An Open Source Computational Platform.

JCO Clin Cancer Inform 2020 08;4:736-748

Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.

Purpose: Spatial heterogeneity of tumors is a major challenge in precision oncology. The relationship between molecular and imaging heterogeneity is still poorly understood because it relies on the accurate coregistration of medical images and tissue biopsies. Tumor molds can guide the localization of biopsies, but their creation is time consuming, technologically challenging, and difficult to interface with routine clinical practice. These hurdles have so far hindered the progress in the area of multiscale integration of tumor heterogeneity data.

Methods: We have developed an open-source computational framework to automatically produce patient-specific 3-dimensional-printed molds that can be used in the clinical setting. Our approach achieves accurate coregistration of sampling location between tissue and imaging, and integrates seamlessly with clinical, imaging, and pathology workflows.

Results: We applied our framework to patients with renal cancer undergoing radical nephrectomy. We created personalized molds for 6 patients, obtaining Dice similarity coefficients between imaging and tissue sections ranging from 0.86 to 0.96 for tumor regions and between 0.70 and 0.76 for healthy kidneys. The framework required minimal manual intervention, producing the final mold design in just minutes, while automatically taking into account clinical considerations such as a preference for specific cutting planes.

Conclusion: Our work provides a robust and automated interface between imaging and tissue samples, enabling the development of clinical studies to probe tumor heterogeneity on multiple spatial scales.
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http://dx.doi.org/10.1200/CCI.20.00026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469624PMC
August 2020

Risk Prediction Models for Kidney Cancer: A Systematic Review.

Eur Urol Focus 2020 Jul 14. Epub 2020 Jul 14.

The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Context: Early detection of kidney cancer improves survival; however, low prevalence means that population-wide screening may be inefficient. Stratification of the population into risk categories could allow for the introduction of a screening programme tailored to individuals.

Objective: This review will identify and compare published models that predict the risk of developing kidney cancer in the general population.

Evidence Acquisition: A search identified primary research reporting or validating models predicting the risk of kidney cancer in Medline and EMBASE. After screening identified studies for inclusion, we extracted data onto a standardised form. The risk models were classified using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines and evaluated using the PROBAST assessment tool.

Evidence Synthesis: The search identified 15 281 articles. Sixty-two satisfied the inclusion criteria; performance measures were provided for 11 models. Some models predicted the risk of prevalent undiagnosed disease and others future incident disease. Six of the models had been validated, two using external populations. The most commonly included risk factors were age, smoking status, and body mass index. Most of the models had acceptable-to-good discrimination (area under the receiver-operating curve >0.7) in development and validation. Many models also had high specificity; however, several had low sensitivity. The highest performance was seen for the models using only biomarkers to detect kidney cancer; however, these were developed and validated in small case-control studies.

Conclusions: We identified a small number of risk models that could be used to stratify the population according to the risk of kidney cancer. Most exhibit reasonable discrimination, but a few have been validated externally in population-based studies.

Patient Summary: In this review, we looked at mathematical models predicting the likelihood of an individual developing kidney cancer. We found several suitable models, using a range of risk factors (such as age and smoking) to predict the risk for individuals. Most of the models identified require further testing in the general population to confirm their usefulness.
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http://dx.doi.org/10.1016/j.euf.2020.06.024DOI Listing
July 2020

Improving patient-clinician communication following nephrectomy in renal cell carcinoma: Development, content validation and pilot testing of a conversation aid tool.

Patient Educ Couns 2021 01 30;104(1):99-108. Epub 2020 Jun 30.

Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Objectives: This study developed, and established the content validity, of a conversation aid tool (CAT) for use in clinical practice with renal cell carcinoma (RCC) patients who receive a curative nephrectomy and are at high-risk of recurrence. The CAT was pilot tested in a sample of RCC patients to establish whether the CAT increases knowledge of RCC, treatment options (such as adjuvant therapy), and care options.

Methods: A cross-sectional, mixed methods design was used involving initial, exploratory interviews with RCC patients, RCC specialists and a steering group. Further content validation interviews were conducted with RCC patients and specialists. A web-based survey was conducted with RCC patients (N = 60), to compare the CAT versus a standard of care (SOC) consultation comparator tool on patient knowledge.

Results: Findings from exploratory interviews were used to develop the CAT. Content validation interviews demonstrated that the CAT was well understood and relevant to RCC patients. The web-based survey demonstrated that viewing the CAT significantly improved participants knowledge of RCC, and care options, when compared to the SOC.

Conclusion: The findings highlight that the CAT is a relevant, comprehensive and well-understood tool for use in the post-nephrectomy consultation.

Practice Implications: Use of the CAT may increase patient knowledge of RCC and care options.
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http://dx.doi.org/10.1016/j.pec.2020.06.029DOI Listing
January 2021

ctDNA monitoring using patient-specific sequencing and integration of variant reads.

Sci Transl Med 2020 06;12(548)

Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.

Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >10 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to parts per million. This resulted in median area under the curve (AUC) values of 0.98 in advanced cancers and 0.80 in early-stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that INVAR may be applied without requiring personalized sequencing panels so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.
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http://dx.doi.org/10.1126/scitranslmed.aaz8084DOI Listing
June 2020

Challenges of early renal cancer detection: symptom patterns and incidental diagnosis rate in a multicentre prospective UK cohort of patients presenting with suspected renal cancer.

BMJ Open 2020 05 11;10(5):e035938. Epub 2020 May 11.

Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.

Objectives: To describe the frequency and nature of symptoms in patients presenting with suspected renal cell carcinoma (RCC) and examine their reliability in achieving early diagnosis.

Design: Multicentre prospective observational cohort study.

Setting And Participants: Eleven UK centres recruiting patients presenting with suspected newly diagnosed RCC. Symptoms reported by patients were recorded and reviewed. Comprehensive clinico-pathological and outcome data were also collected.

Outcomes: Type and frequency of reported symptoms, incidental diagnosis rate, metastasis-free survival and cancer-specific survival.

Results: Of 706 patients recruited between 2011 and 2014, 608 patients with a confirmed RCC formed the primary study population. The majority (60%) of patients were diagnosed incidentally. 87% of patients with stage Ia and 36% with stage III or IV disease presented incidentally. Visible haematuria was reported in 23% of patients and was commonly associated with advanced disease (49% had stage III or IV disease). Symptomatic presentation was associated with poorer outcomes, likely reflecting the presence of higher stage disease. Symptom patterns among the 54 patients subsequently found to have a benign renal mass were similar to those with a confirmed RCC.

Conclusions: Raising public awareness of RCC-related symptoms as a strategy to improve early detection rates is limited by the fact that related symptoms are relatively uncommon and often associated with advanced disease. Greater attention must be paid to the feasibility of screening strategies and the identification of circulating diagnostic biomarkers.
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http://dx.doi.org/10.1136/bmjopen-2019-035938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223292PMC
May 2020

The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro.

Biology (Basel) 2020 Apr 7;9(4). Epub 2020 Apr 7.

Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.

Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; < 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death ( < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib.
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http://dx.doi.org/10.3390/biology9040074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236799PMC
April 2020
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