Fast and High-Resolution T2 Mapping Based on Echo Merging Plus k-t Undersampling with Reduced Refocusing Flip Angles (TEMPURA) as Methods for Human Renal MRI.

PURPOSE: To develop a highly accelerated multi-echo spin-echo method, TEMPURA, for reducing the acquisition time and/or increasing spatial resolution for kidney T2 mapping. METHODS: TEMPURA merges several adjacent echoes into one k-space by either combining independent echoes or sharing one echo between k-spaces. The combined k-space is reconstructed based on compressed sensing theory. Reduced flip angles are used for the refocusing pulses, and the extended phase graph algorithm is used to correct the effects of indirect echoes. Two sequences were developed: a fast breath-hold sequence; and a high-resolution sequence. The performance was evaluated prospectively on a phantom, 16 healthy subjects, and two patients with different types of renal tumors. RESULTS: The fast TEMPURA method reduced the acquisition time from 3-5 min to one breath-hold (18 s). Phantom measurements showed that fast TEMPURA had a mean absolute percentage error (MAPE) of 8.2%, which was comparable to a standardized respiratory-triggered sequence (7.4%), but much lower than a sequence accelerated by purely k-t undersampling (21.8%). High-resolution TEMPURA reduced the in-plane voxel size from 3 × 3 to 1 × 1 mm2, resulting in improved visualization of the detailed anatomical structure. In vivo T2 measurements demonstrated good agreement (fast: MAPE = 1.3%-2.5%; high-resolution: MAPE = 2.8%-3.3%) and high correlation coefficients (fast: R = 0.85-0.98; high-resolution: 0.82-0.96) with the standardized method, outperforming k-t undersampling alone (MAPE = 3.3-4.5%, R = 0.57-0.59). CONCLUSION: TEMPURA provides fast and high-resolution renal T2 measurements. It has the potential to improve clinical throughput and delineate intratumoral heterogeneity and tissue habitats at unprecedented spatial resolution.

Risk-stratified screening for the early detection of kidney cancer.

Earlier detection and screening for kidney cancer has been identified as a key research priority, however the low prevalence of the disease in unselected populations limits the cost-effectiveness of screening. Risk-stratified screening for kidney cancer may improve early detection by targeting high-risk individuals whilst limiting harms in low-risk individuals, potentially increasing the cost-effectiveness of screening. A number of models have been identified which estimate kidney cancer risk based on both phenotypic and genetic data, and while several of the former have been shown to identify individuals at high-risk of developing kidney cancer with reasonable accuracy, current evidence does not support including a genetic component. Combined screening for lung cancer and kidney cancer has been proposed, as the two malignancies share some common risk factors. A modelling study estimated that using lung cancer risk models (currently used for risk-stratified lung cancer screening) could capture 25% of patients with kidney cancer, which is only slightly lower than using the best performing kidney cancer-specific risk models based on phenotypic data (27%-33%). Additionally, risk-stratified screening for kidney cancer has been shown to be acceptable to the public. The following review summarises existing evidence regarding risk-stratified screening for kidney cancer, highlighting the risks and benefits, as well as exploring the management of potential harms and further research needs.

Short-term psychosocial outcomes of adding a non-contrast abdominal computed tomography (CT) scan to the thoracic CT within lung cancer screening.

OBJECTIVES: To evaluate psychological, social, and financial outcomes amongst individuals undergoing a non-contrast abdominal computed tomography (CT) scan to screen for kidney cancer and other abdominal malignancies alongside the thoracic CT within lung cancer screening. SUBJECTS AND METHODS: The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding a non-contrast abdominal CT scan to the thoracic CT within lung cancer screening. A total of 500 participants within the YKST, comprising all who had an abnormal CT scan and a random sample of one-third of those with a normal scan between 14/03/2022 and 24/08/2022 were sent a questionnaire at 3 and 6 months. Outcomes included the Psychological Consequences Questionnaire (PCQ), the short-form of the Spielberger State-Trait Anxiety Inventory, and the EuroQoL five Dimensions five Levels scale (EQ-5D-5L). Data were analysed using regression adjusting for participant age, sex, socioeconomic status, education, baseline quality of life (EQ-5D-5L), and ethnicity. RESULTS: A total of 380 (76%) participants returned questionnaires at 3 months and 328 (66%) at 6 months. There was no difference in any outcomes between participants with a normal scan and those with abnormal scans requiring no further action. Individuals requiring initial further investigations or referral had higher scores on the negative PCQ than those with normal scans at 3 months (standardised mean difference 0.28 sd, 95% confidence interval 0.01-0.54; P = 0.044). The difference was greater in those with anxiety or depression at baseline. No differences were seen at 6 months. CONCLUSION: Screening for kidney cancer and other abdominal malignancies using abdominal CT alongside the thoracic CT within lung cancer screening is unlikely to cause significant lasting psychosocial or financial harm to participants with incidental findings.

Lithographically defined encoded magnetic heterostructures for the targeted screening of kidney cancer.

Renal cell carcinoma (RCC) is the 7th commonest cancer in the UK and the most lethal urological malignancy; 50% of all RCC patients will die from the condition. However, if identified early enough, small RCCs are usually cured by surgery or percutaneous procedures, with 95% 10 year survival. This study describes a newly developed non-invasive urine-based assay for the early detection of RCC. Our approach uses encoded magnetically controllable heterostructures as a substrate for immunoassays. These heterostructures have molecular recognition abilities and embedded patterned codes for a rapid identification of RCC biomarkers. The magnetic heterostructures developed for this study have a magnetic configuration designed for a remote multi axial control of their orientation by external magnetic fields, this control facilitates the code readout when the heterostructures are in liquid. Furthermore, the optical encoding of each set of heterostructures provides a multiplexed analyte capture platform, as different sets of heterostructures, specific to different biomarkers can be mixed together in a patient sample. Our results show a precise magnetic control of the heterostructures with an efficient code readout during liquid immunoassays. The use of functionalised magnetic heterostructures as a substrate for immunoassay is validated for urine specimen spiked with recombinant RCC biomarkers. Initial results of the newly proposed screening method on urine samples from RCC patients, and controls with no renal disorders are presented in this study. Comprehensive optimisation cycles are in progress to validate the robustness of this technology as a novel, non-invasive screening method for RCC.

Diagnosis, treatment, and survival from kidney cancer: real-world National Health Service England data between 2013 and 2019.

OBJECTIVES: To report the NHS Digital (NHSD) data for patients diagnosed with kidney cancer (KC) in England. We explore the incidence, route to diagnosis (RTD), treatment, and survival patterns from 2013 to 2019. MATERIALS AND METHODS: Data was extracted from the Cancer Data NHSD portal for International Classification of Diseases, 10th edition coded KC; this included Cancer Registry data, Hospital Episode Statistics, and cancer waiting times data. RESULTS: Registrations included 66 696 individuals with KC. Incidence of new KC diagnoses increased (8998 in 2013, to 10 232 in 2019), but the age-standardised rates were stable (18.7-19.4/100 000 population). Almost half of patients (30 340 [45.5%]) were aged 0-70 years and the cohort were most frequently diagnosed with Stage 1-2 KC (n = 26 297 [39.4%]). Most patients were diagnosed through non-urgent general practitioner referrals (n = 16 814 [30.4%]), followed by 2-week-wait (n = 15 472 [28.0%]) and emergency routes (n = 11 796 [21.3%]), with older patients (aged ≥70 years), Stage 4 KCs, and patients with non-specified renal cell carcinoma being significantly more likely to present through the emergency route (all P < 0.001). Invasive treatment (surgery or ablation), radiotherapy, or systemic anti-cancer therapy use varied with disease stage, patient factors, and treatment network (Cancer Alliance). Survival outcomes differed by Stage, histological subtype, and social deprivation class (P < 0.001). Age-standardised mortality rates did not change over the study duration, although immunotherapy usage is likely not captured in this study timeline. CONCLUSION: The NHSD resource provides useful insight about the incidence, diagnostic pathways, treatment, and survival of patients with KC in England and a useful benchmark for the upcoming commissioned National Kidney Cancer Audit. The RTD data may be limited by incidental diagnoses, which could confound the high proportion of 'emergency' diagnoses. Importantly, survival outcomes remained relatively unchanged.

Estimating the Effectiveness of Kidney Cancer Screening Within Lung Cancer Screening Programmes: A Validation in UK Biobank.

In the absence of population-based screening, addition of screening for kidney cancer to lung cancer screening could provide an efficient and low-resource means to improve early detection. In this study, we used the UK Biobank cohort (n = 442 865) to determine the performance of the Yorkshire Lung Cancer Screening Trial (YLST) eligibility criteria for selecting individuals for kidney cancer screening. We measured the performance of two models widely used to determine eligibility for lung cancer screening (PLCO[m2012] and the Liverpool-Lung-Project-v2) and the performance of the combined YLST criteria. We found that the lung cancer models have discrimination (area under the receiver operating curve) between 0.60 and 0.68 for kidney cancer. In the UK, one in four cases (25%) of kidney cancer cases is expected to occur in those eligible for lung cancer screening, and one case of kidney cancer detected for every 200 people invited to lung cancer screening. These results suggest that adding kidney cancer screening to lung cancer screening would be an effective strategy to improve early detection rates of kidney cancer. However, most kidney cancers would not be picked up by this approach. This analysis does not address other important considerations about kidney cancer screening, such as overdiagnosis. PATIENT SUMMARY: It has been proposed that adding-on kidney cancer screening to lung cancer screening (both carried out by a computed tomography scan of the chest/abdomen) would be an easy and low-cost way of detecting cases of kidney cancer earlier, when these can be treated more easily. Lung cancer screening is usually targeted at people who are at a high risk (eg, older smokers); therefore, here we look at whether the same group of people are also at a high risk of kidney cancer. Our analysis shows that one in four people later diagnosed with kidney cancer are also at a high risk of lung cancer; hence, a combined screening programme could detect up to a quarter of kidney cancers.

Patient experience of follow-up after surgery for kidney cancer: a focus group study.

OBJECTIVE: To explore patient experience of follow-up care after kidney cancer surgery and to develop recommendations for best practice. METHODS: We conducted two focus groups, including 14 participants with experience of kidney cancer follow-up after surgery, to elicit patient views on current follow-up care. Thematic analysis was used to identify unifying themes to describe the patient experience of follow-up, and the results were then used to develop a set of recommendations for best practice. RESULTS: We identified six themes (feelings of abandonment; uncertainty about the plan; anxiety about appointments; variation in care; a need for information; and a need for emotional support) that described current patient experience and areas in which current care could be improved. In particular, while most of the participants felt that their physical needs had been met, many had struggled with unmet emotional needs and a lack of information and resources. This was especially noted in the period immediately following surgery, when feelings of abandonment were common, and around follow-up scans and routine appointments, which were a source of anxiety. Our participants also described concerns about the lack of consistency between different hospitals and centres around the United Kingdom, with differences in the content and quality of follow-up care. Based on the results, we developed a list of recommendations to address some of the challenges described through relatively minor changes to the care pathway. CONCLUSIONS: We identified gaps and variability in current follow-up care after kidney cancer surgery, and have developed a set of recommendations that, if implemented, would improve the follow-up care experience for these patients.

Public Preferences for Determining Eligibility for Screening in Risk-Stratified Cancer Screening Programs: A Discrete Choice Experiment.

BACKGROUND: Risk stratification has been proposed to improve the efficiency of population-level cancer screening. We aimed to describe and quantify the relative importance of different attributes of potential screening programs among the public, focusing on stratifying eligibility. METHODS: We conducted a discrete choice experiment in which respondents selected between 2 hypothetical screening programs in a series of 9 questions. We presented the risk factors used to determine eligibility (age, sex, or lifestyle or genetic risk scores) and anticipated outcomes based on eligibility criteria with different sensitivity and specificity levels. We performed conditional logit regression models and used the results to estimate preferences for different approaches. We also analyzed free-text comments on respondents' views on the programs. RESULTS: A total of 1,172 respondents completed the survey. Sensitivity was the most important attribute (7 and 11 times more important than specificity and risk factors, respectively). Eligibility criteria based on age and sex or genetics were preferred over age alone and lifestyle risk scores. Phenotypic and polygenic risk prediction models would be more acceptable than screening everyone aged 55 to 70 y if they had high discrimination (area under the receiver-operating characteristic curve ≥0.75 and 0.80, respectively). LIMITATIONS: Although our sample was representative with respect to age, sex, and ethnicity, it may not be representative of the UK population regarding other important characteristics. Also, some respondents may have not understood all the information provided to inform decision making. CONCLUSIONS: The public prioritized lives saved from cancer over reductions in numbers screened or experiencing unnecessary follow-up. Incorporating personal-level risk factors into screening eligibility criteria is acceptable to the public if it increases sensitivity; therefore, maximizing sensitivity in model development and communication could increase uptake. HIGHLIGHTS: The public prioritized lives saved when considering changing from age-based eligibility criteria to risk-stratified cancer screening over reductions in numbers of people being screened or experiencing unnecessary follow-up.The risk stratification strategy used to do this was the least important component, although age plus sex or genetics were relatively preferable to using age alone and lifestyle risk scores.Communication strategies that emphasize improvements in the numbers of cancers detected or not missed across the population are more likely to be salient than reductions in unnecessary investigations or follow-up among some groups.Future research should focus on developing implementation strategies that maximize gains in sensitivity within the context of resource constraints and how to present attributes relating to specificity to facilitate understanding and informed decision making.

Diagnostic Performance of Biomarkers for Bladder Cancer Detection Suitable for Community and Primary Care Settings: A Systematic Review and Meta-Analysis.

Evidence on the use of biomarkers to detect bladder cancer in the general population is scarce. This study aimed to systematically review evidence on the diagnostic performance of biomarkers which might be suitable for use in community and primary care settings [PROSPERO Registration: CRD42021258754]. Database searches on MEDLINE and EMBASE from January 2000 to May 2022 resulted in 4914 unique citations, 44 of which met inclusion criteria. Included studies reported on 112 biomarkers and combinations. Heterogeneity of designs, populations and outcomes allowed for the meta-analysis of three biomarkers identified in at least five studies (NMP-22, UroVysion, uCyt+). These three biomarkers showed similar discriminative ability (adjusted AUC estimates ranging from 0.650 to 0.707), although for NMP-22 and UroVysion there was significant unexplained heterogeneity between included studies. Narrative synthesis revealed the potential of these biomarkers for use in the general population based on their reported clinical utility, including effects on clinicians, patients, and the healthcare system. Finally, we identified some promising novel biomarkers and biomarker combinations (N < 3 studies for each biomarker/combination) with negative predictive values of ≥90%. These biomarkers have potential for use as a triage tool in community and primary care settings for reducing unnecessary specialist referrals. Despite promising emerging evidence, further validation studies in the general population are required at different stages within the diagnostic pathway.

Local Treatment of Recurrent Renal Cell Carcinoma May Have a Significant Survival Effect Across All Risk-of-recurrence Groups.

Background: Retrospective comparative studies suggest a survival benefit after complete local treatment of recurrence (LTR) in renal cell carcinoma (RCC), which may be largely due to an indication bias. Objective: To determine the role of LTR in a homogeneous population characterised by limited and potentially resectable recurrence. Design setting and participants: RECUR is a protocol-based multicentre European registry capturing patient and tumour characteristics, risk of recurrence (RoR), recurrence patterns, and survival of those curatively treated for nonmetastatic RCC from 2006 to 2011. Per-protocol resectable disease (RD) recurrence was defined as (1) solitary metastases, (2) oligometastases, or (3) renal fossa or renal recurrence after radical or partial nephrectomy, respectively. Intervention: Local treatment of recurrence. Outcome measurements and statistical analysis: Overall survival (OS) and cancer-specific survival was compared in the RD population that underwent LTR versus no LTR. We constructed a multivariate model to predict risk factors for overall mortality and analysed the effect of LTR across RoR groups. Results and limitations: Of 3039 patients with localised RCC treated with curative intent, 505 presented with recurrence, including 176 with RD. Of these patients, 97 underwent LTR and 79 no LTR. Patients in the LTR group were younger (64.3 [40-80] vs 69.2 [45-87] yr; p = 0.001). The median OS was 70.3 mo (95% confidence interval [CI] 58-82.6) versus 27.4 mo (95% CI 23.6-31.15) in the LTR versus no-LTR group (p < 0.001). After a multivariate analysis, having LTR (hazard ratio [HR] 0.37 [95% CI 0.2-0.6]), having low- versus high-risk RoR (HR 0.42 [95% CI [0.20-0.83]), and not having extra-abdominal/thoracic metastasis (HR 1.96 [95% CI 1.02-3.77]) were prognostic factors of longer OS. The LTR effect on survival was consistent across risk groups. OS HR for high, intermediate, and low risks were 0.36 (0.2-0.64), 0.27 (0.11-0.65), and 0.26 (0.08-0.8), respectively. Limitations include retrospective design. Conclusions: This is the first study assessing the effectiveness of LTR in RCC in a comparable population with RD. This study supports the role of LTR across all RoR groups. Patient summary: We assessed the effectiveness of local treatment of resectable recurrent renal cell carcinoma after surgical treatment of the primary kidney tumour. Local treatment of recurrence was associated with longer survival across groups with a risk of recurrence.

Assessment of association between lower ureteric excision technique and oncological outcomes for upper urinary tract urothelial carcinoma: retrospective analysis from the Scottish Renal Cancer Consortium.

PURPOSE: Nephroureterectomy(NU) remains the gold-standard surgical option for the management of upper urinary tract urothelial carcinoma(UTUC). Controversy exists regarding the optimal excision technique of the lower ureter. We sought to compare post-UTUC bladder tumour recurrence across the Scottish Renal Cancer Consortium(SRCC). METHODS: Patients who underwent NU for UTUC across the SRCC 2012-2019 were identified. The impact of lower-end surgical technique along with T-stage, N-stage, tumour location and focality, positive surgical margin, pre-NU ureteroscopy, upper-end technique and adjuvant mitomycin C administration were assessed by Kaplan-Meier and Cox-regression. The primary outcome was intra-vesical recurrence-free survival (B-RFS). RESULTS: In 402 patients, the median follow-up was 29 months. The lower ureter was managed by open transvesical excision in 90 individuals, transurethral and laparoscopic dissection in 76, laparoscopic or open extra-vesical excision in 31 and 42 respectively, and transurethral dissection and pluck in 163. 114(28.4%) patients had a bladder recurrence during follow-up. There was no difference in B-RFS between lower-end techniques by Kaplan-Meier (p = 0.94). When all factors were taken into account by adjusted Cox-regression, preceding ureteroscopy (HR 2.65, p = 0.001), lower ureteric tumour location (HR 2.16, p = 0.02), previous bladder cancer (HR 1.75, p = 0.01) and male gender (HR 1.61, p = 0.03) were associated with B-RFS. CONCLUSION: These data suggest in appropriately selected patients, lower ureteric management technique does not affect B-RFS. Along with lower ureteric tumour location, male gender and previous bladder cancer, preceding ureteroscopy was associated with a higher recurrence rate following NU, and the indication for this should be carefully considered.

Protocol for a MULTI-centre feasibility study to assess the use of 99mTc-sestaMIBI SPECT/CT in the diagnosis of kidney tumours (MULTI-MIBI study).

INTRODUCTION: The incidence of renal tumours is increasing and anatomic imaging cannot reliably distinguish benign tumours from renal cell carcinoma. Up to 30% of renal tumours are benign, with oncocytomas the most common type. Biopsy has not been routinely adopted in many centres due to concerns surrounding non-diagnostic rate, bleeding and tumour seeding. As a result, benign masses are often unnecessarily surgically resected. 99mTc-sestamibi SPECT/CT has shown high diagnostic accuracy for benign renal oncocytomas and other oncocytic renal neoplasms of low malignant potential in single-centre studies. The primary aim of MULTI-MIBI is to assess feasibility of a multicentre study of 99mTc-sestamibi SPECT/CT against a reference standard of histopathology from surgical resection or biopsy. Secondary aims of the study include obtaining estimates of 99mTc-sestamibi SPECT/CT sensitivity and specificity and to inform the design and conduct of a future definitive trial. METHODS AND ANALYSIS: A feasibility prospective multicentre study of participants with indeterminate, clinical T1 renal tumours to undergo 99mTc-sestamibi SPECT/CT (index test) compared with histopathology from biopsy or surgical resection (reference test). Interpretation of the index and reference tests will be blinded to the results of the other. Recruitment rate as well as estimates of sensitivity, specificity, positive and negative predictive value will be reported. Semistructured interviews with patients and clinicians will provide qualitative data to inform onward trial design and delivery. Training materials for 99mTc-sestamibi SPECT/CT interpretation will be developed, assessed and optimised. Early health economic modelling using a decision analytic approach for different diagnostic strategies will be performed to understand the potential cost-effectiveness of 99mTc-sestamibi SPECT/CT. ETHICS AND DISSEMINATION: Ethical approval has been granted (UK HRA REC 20/YH/0279) protocol V.5.0 dated 21/6/2022. Study outputs will be presented and published nationally and internationally. TRIAL REGISTRATION NUMBER: ISRCTN12572202.

Impact of COVID-19 on the management and outcomes of ureteric stones in the UK: a multicentre retrospective study.

OBJECTIVES: To determine if management of ureteric stones in the UK changed during the coronavirus disease 2019 (COVID-19) pandemic and whether this affected patient outcomes. PATIENTS AND METHODS: We conducted a multicentre retrospective study of adults with computed tomography-confirmed ureteric stone disease at 39 UK hospitals during a pre-pandemic period (23/3/2019-22/6/2019) and a period during the pandemic (the 3-month period after the first severe acute respiratory syndrome coronavirus-2 case at individual sites). The primary outcome was success of primary treatment modality, defined as no further treatment required for the index ureteric stone. Our study protocol was published prior to data collection. RESULTS: A total of 3735 patients were included (pre-pandemic 1956 patients; pandemic 1779 patients). Stone size was similar between groups (P > 0.05). During the pandemic, patients had lower hospital admission rates (pre-pandemic 54.0% vs pandemic 46.5%, P < 0.001), shorter mean length of stay (4.1 vs 3.3 days, P = 0.02), and higher rates of use of medical expulsive therapy (17.4% vs 25.4%, P < 0.001). In patients who received interventional management (pre-pandemic 787 vs pandemic 685), rates of extracorporeal shockwave lithotripsy (22.7% vs 34.1%, P < 0.001) and nephrostomy were higher (7.1% vs 10.5%, P = 0.03); and rates of ureteroscopy (57.2% vs 47.5%, P < 0.001), stent insertion (68.4% vs 54.6%, P < 0.001), and general anaesthetic (92.2% vs 76.2%, P < 0.001) were lower. There was no difference in success of primary treatment modality between patient cohorts (pre-pandemic 73.8% vs pandemic 76.1%, P = 0.11), nor when patients were stratified by treatment modality or stone size. Rates of operative complications, 30-day mortality, and re-admission and renal function at 6 months did not differ between the data collection periods. CONCLUSIONS: During the COVID-19 pandemic, there were lower admission rates and fewer invasive procedures performed. Despite this, there were no differences in treatment success or outcomes. Our findings indicate that clinicians can safely adopt management strategies developed during the pandemic to treat more patients conservatively and in the community.

Artificial intelligence for early detection of renal cancer in computed tomography: A review.

Renal cancer is responsible for over 100,000 yearly deaths and is principally discovered in computed tomography (CT) scans of the abdomen. CT screening would likely increase the rate of early renal cancer detection, and improve general survival rates, but it is expected to have a prohibitively high financial cost. Given recent advances in artificial intelligence (AI), it may be possible to reduce the cost of CT analysis and enable CT screening by automating the radiological tasks that constitute the early renal cancer detection pipeline. This review seeks to facilitate further interdisciplinary research in early renal cancer detection by summarising our current knowledge across AI, radiology, and oncology and suggesting useful directions for future novel work. Initially, this review discusses existing approaches in automated renal cancer diagnosis, and methods across broader AI research, to summarise the existing state of AI cancer analysis. Then, this review matches these methods to the unique constraints of early renal cancer detection and proposes promising directions for future research that may enable AI-based early renal cancer detection via CT screening. The primary targets of this review are clinicians with an interest in AI and data scientists with an interest in the early detection of cancer.

Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression.

Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we integrate multimodal analyses of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) grown in physiological media to identify key stage-specific metabolic vulnerabilities. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism sustains the de novo biosynthesis of aspartate and arginine enabling tumor cells with the flexibility of partitioning the nitrogen of the amino acids depending on their needs. Importantly, we identify the epigenetic reactivation of argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, as a crucial event for metastatic renal cancer cells to acquire the capability to generate arginine, invade in vitro and metastasize in vivo. Overall, our study uncovers a mechanism of metabolic flexibility occurring during ccRCC progression, paving the way for the development of novel stage-specific therapies.