This systematic review aims to assess whether studies that followed the 2016 and updated 2024 European Association of Urology (EAU) Renal Cell Carcinoma (RCC) guidelines for CT during follow-up after tumor ablation (TA) yield different oncological outcomes compared to studies that performed more frequent imaging. A literature search of relevant search engines was performed up to June 6th, 2025. Studies that reported follow-up schedules of patients after TA for cT1 RCC were included. Studies utilizing more CT scans than recommended by the 2016 and 2024 EAU guidelines were compared with those adhering to the guidelines. Data on recurrences and survival were analyzed. Thirty-seven studies met the inclusion criteria, involving patients with cT1 RCC treated with TA. The mean 5-year overall survival rate was 82.9

BACKGROUND AND OBJECTIVE:To determine whether the existing European Organisation for Research and Treatment of Cancer (EORTC) QLQ-NMIBC24 and QLQ-BLM30 modules remain fit for purpose and to assess health-related quality of life (HRQoL) issues relevant for patients with metastatic bladder cancer (mBC). METHODS:Following the EORTC Quality of Life Group (QLG) guidelines, phase 1 included an expert meeting, five systematic reviews, and interviews with 14 healthcare professionals (HCPs) and 48 bladder cancer (BC) patients across six countries. HRQoL issues were identified through the literature and rated by HCPs and patients for relevance and importance. Decision rules guided selection for phase 2. In phase 2, selected issues were translated into items using the EORTC Item Library and expert consensus. KEY FINDINGS AND LIMITATIONS:A total of 443 articles and 62 interviews yielded 150 unique HRQoL issues; 40 issues and two branching questions were retained for the provisional module. Seventeen new items were added beyond the existing EORTC BC modules, while 11 existing items were excluded. Issues specific to mBC and newer treatments, such as immunotherapy, were identified. Limitations include potential selection bias due to purposive sampling and small sample sizes per treatment subgroup. CONCLUSIONS AND CLINICAL IMPLICATIONS:This phase 1-2 study supports the need to update the existing EORTC BC modules and incorporate additional items relevant to all disease stages, including mBC. A single, flexible module with branching logic may improve clinical applicability across patient subgroups. The provisional module will undergo international pretesting and psychometric evaluation in phase 3.

Renal cell carcinoma (RCC) with inferior vena cava (IVC) tumour thrombus is an uncommon but highly complex presentation associated with substantial surgical morbidity and poor natural history. This review summarises contemporary evidence on diagnostic evaluation, multidisciplinary management and operative strategies, with novel contributions on evolving minimally invasive and robotic surgical approaches, the emerging role of neoadjuvant immune checkpoint inhibition as a thrombus downstaging strategy and the inclusion of stereotactic ablative radiotherapy (SABR) in the multidisciplinary treatment pathway. A narrative review of the literature was performed, incorporating large institutional series, registry data, systematic reviews, and recent prospective and retrospective clinical studies. Evidence relating to imaging, perioperative optimisation, surgical techniques by thrombus level, decision making for cardiopulmonary bypass, neoadjuvant therapies and SABR was utilised. Radical nephrectomy with IVC thrombectomy remains the standard treatment and confers a significant survival benefit compared with non-operative management, despite perioperative mortality rates of 2–10

4512 Background: Adjuvant pembrolizumab (pembro) is standard of care in renal cell carcinoma (RCC). We explored whether patients retrospectively regret their decision to receive adjuvant pembro and hypothesised that this is related to long-term toxicity that is not adequately captured by CTCAE criteria. To address this we developed a patient-informed tool, co-designed with patients, focusing specifically on long-term toxicity. Methods: Patients with RCC who received adjuvant pembro across three tertiary cancer centres in London between June 2022-Dec 2024 were invited to participate. Eligible patients completed the validated Ottawa Decision Regret Scale (DRS) and a complementary questionnaire exploring factors influencing regret including toxicity and disease recurrence. CTCAE-graded immune-related adverse events (irAEs) were collected and correlated with decision regret (DR). In parallel, patients categorised irAEs as life-changing, significant or non-significant and these were correlated with DR. DRS > 25 was defined as moderate-high regret. Appropriate ethical approval was obtained. Results: 104 patients were included post adjuvant pembro (88% pT3N0, 4% pT3N1 and 8% M1 NED). Median follow up was 30 months. 14% patients have relapsed. CTCAE ≥G3 irAEs occurred in 18%. 28% and 11% reported toxicity as significant (S) or life changing (LC) respectively. Patient reported S and LC toxicity did not correlate with ≥G3 CTCAE ( p = 0.11), with 33% CTCAE G1-2 events reported as significant. Mean DR score was 14.9 (95% CI 8.5-21.3) with 13% expressing regret. 1/14 patients who had disease recurrence expressed regret (mean DRS = 10.3 [1.4-19.3]). Patients that reported LC & S toxicity expressed more regret (26.9 LC v 26.1 S v 2.1 NS, p = 0.0021). There was no difference in regret between patients that sustained CTCAE G1-2 versus G3-4 irAE (14.9 vs 15.1, p = 0.23). DR was highest with permanent endocrine (n = 24) or musculoskeletal (n = 22) irAEs (endo: DRS 28.8 v 9.5, p = 0.003; MSK: DRS 25.1 v 12.8, p = 0.042). Lower baseline expectations of toxicity correlated with greater DR ( p = 0.002). Conclusions: DR after adjuvant pembro is driven by long-term, low-grade toxicity rather than disease recurrence. Novel patient-informed tools that capture life-changing or permanent toxicities outperform CTCAE in identifying patients at risk of regret. Improved baseline education on long-term risks may reduce decision regret and improve shared decision-making.

[This corrects the article DOI: 10.1016/j.euros.2025.12.004.].

Recurrence after nephrectomy in high-risk localized renal cell carcinoma is common, but the genomic and transcriptomic differences between primary and recurrent tumors are not well understood. In the IMmotion010 trial, patients were randomized to receive adjuvant atezolizumab versus placebo. Tumor tissue was collected at pre-treatment baseline (n = 754) and subsequently at the time of recurrence (n = 80). We performed matched transcriptomic (n = 80) and genomic (n = 52) analyses on primary versus recurrent samples. Using previously described transcriptomic classifications, resected primary tumors had a higher proportion of angiogenic and small nucleolar RNA transcriptomic signatures and lower proportion of T-effector/proliferative and stromal/proliferative signatures compared with published metastatic cohorts. Sites of recurrence exhibited upregulation of signatures related to cell proliferation, fatty acid synthesis, and stromal biology, including matrix and fibroblasts. Comparing treatment arms, tumors that recurred in placebo-treated patients demonstrated increased B cell and macrophage signatures, while tumors that recurred despite adjuvant atezolizumab showed downregulation of major histocompatibility complex (MHC)-I. Although requiring further clinical validation, the latter finding may substantiate scientifically a potential rationale for transitioning to vascular endothelial growth factor (VEGF)-inhibition after adjuvant checkpoint inhibition.

BACKGROUND AND PURPOSE:Patients with renal cell carcinoma (RCC) in a solitary kidney have limited treatment options. Stereotactic MRI-guided adaptive radiotherapy (SMART) offers a non-invasive alternative that preserves healthy kidney tissue. This study evaluated the clinical outcomes of SMART in patients with renal tumors in a solitary kidney. Oncological outcomes, renal function preservation, and treatment-related toxicity were assessed. MATERIALS AND METHODS:All consecutive patients with RCC in a solitary kidney treated with SMART between 2018 and 2024 in a single center were analyzed. Local control was defined as any response or stable disease using RECIST criteria. Kaplan-Meier analysis was used for survival outcomes and paired t-tests assessed renal function changes. RESULTS:Thirty-two patients with a median age of 70 years were included. Most patients had WHO status 0-1 (93.8%) and had prior nephrectomy for RCC (78.1%). Median tumor size was 4.2 cm, and median pre-treatment eGFR was 45.8 ml/min. Seven patients were treated for multiple lesions, in simultaneous or separate sessions. Most patients were treated in a single (22.8%) or five (74.3%) fractions. After a median follow-up of 21.3 months, the local control rates at 1 and 2 years were 96.2% and 90.1%, respectively. Mean eGFR change was -6.6 ml/min, none required dialysis. No grade ≥ 3 toxicity was observed. The overall survival rate at 2 years was 80.9%. CONCLUSION:SMART provides high local control with minimal impact on renal function, offering a non-invasive, kidney-sparing treatment option that also enables repeated treatments within the solitary kidney.

4532 Background: KC negatively impacts the emotional well-being of patients, and patient support services are a critical component of care to improve emotional health and patient outcomes. Since 2018, the IKCC and its network have conducted a biennial GPS to assess patient/caregiver experiences on KC burden, diagnosis, and management, determine unmet needs and country variances, and identify opportunities to close gaps. We present global data from the 2025 GPS on emotional well-being and use of patient support resources. Methods: An IKCC steering committee of patient advocates, medical experts and the Picker Institute (UK) designed the 2025 GPS targeting KC patients and caregivers. It was cognitively tested, translated into 16 languages, and hosted online and on paper. Data were independently analyzed using cross-tabulations. Results: Between Sept 24 and Nov 15, 2024, 2677 responses were received from patients (n=2049) and caregivers (n=628) from 46 countries. Globally, 85% of respondents were impacted emotionally due to KC, with impacts observed across all disease stages. The most common were disease-related anxiety (50%), fear of recurrence (49%), sadness/depression (36%), and fear of dying (35%). Respondents aged 80+ and 66–80 years reported fewer emotional concerns than younger respondents. Globally, only 40%–66% of respondents discussed emotional concerns with a healthcare provider (HCP). Respondents from India and Mexico were more likely to discuss concerns with an HCP, while those from the Republic of Korea were least likely to discuss concerns. Many conversations with HCPs were considered unhelpful; notably, 33% indicated discussions about difficulties navigating the healthcare system were unhelpful. Globally, 50% of respondents accessed a patient support group, either in person or online. Respondents from Japan (19%), Türkiye (24%), France (25%), and Italy (27%) were least likely to access a patient support group, while those from India (90%) and the Republic of Korea (88%) were most likely to access a group. Overall, 47% said support groups were helpful. Patient organization websites (28%) and online support groups (27%) were considered most helpful, with variations observed across countries. Respondents indicated a desire for more counselling and/or psychological support, in-person support, peer-to-peer support, and online support. Conclusions: Most respondents experienced an impact on their emotional well-being due to KC; however, many did not discuss their emotional concerns with an HCP or access a patient support group either in person or online. Improved communication is needed between patients/caregivers and HCPs to address emotional concerns. HCPs can improve patient well-being through referrals to counselling/psychological support, and patient organizations in their country.

4540 Background: Estimating risk of renal cell cancer (RCC) relapse based only on pre-surgical data is key to future neoadjuvant trial design. The EA PROSPER phase 3 study accrued pts with clinical stage ≥T2 or T any N+ RCC of any histology for nephrectomy. Pts were randomized to presurgical nivolumab (nivo) followed by primary tumor resection and 9 cycles of adjuvant nivo, or surgery alone followed by observation. We used PROSPER data to assess how baseline data informs risk. We reviewed cT to pT stage transitions, associated cT stages with outcome, and asked if size in addition to cT stage increases predictive accuracy. Methods: Pts with clear cell (cc) RCC were included. cT to pT concordance was assessed by TNM 8 th edition. DFS analysis (time from surgery to recurrence, second primary, or any cause death) was performed; pts with no event were censored at date of last assessment. DFS analysis compared cT groups (cT1/cT2 vs cT3/cT4) in the overall eligible study population and within each study arm. A subset DFS analysis by tumor size among cT2a (> 7-8cm vs >8-10cm) and cT3a (< 7cm vs 7-8cm vs > 8cm) was explored. Cox proportional hazards models were used, and log-rank test was reported to represent global p-value of each model. Wald test p-value was reported for individual group comparison (in assessing more than two groups). Two-sided p-values are reported, all p-values were considered significant at 0.05. Results: Of 819 pts randomized, 732 ccRCC pts (382 surgery only, 350 nivo + surgery) had data available. DFS was significantly different between cT1/cT2 vs. cT3/cT4 group, favoring cT1/cT2 among all pts (HR [cT1/cT2 as reference]=1.56, two-sided log-rank p < 0.001) and in each of the treatment arms separately (nivo + surgery arm HR=1.48, two-sided log-rank=0.04 ; surgery only arm HR=1.63, two-sided log-rank p=0.007). About half of cT1/T2 pts were upstaged to pT3/4, whereas <10% of cT3a were downstaged to pT1b. Higher grade cT1/T2 were more likely to upstage (p-value < 0.001).119 pts with cT2a and 233 pts with cT3a had tumor size data available. There was no significant DFS difference between tumor size groups in the cT2a subset. In cT3a patients, DFS analysis by tumor size showed a trend of increasing risk for 7-8cm and > 8cm groups when compared to < 7cm group, with a statistically significant difference comparing > 8cm vs < 7cm (HR=3.33, two-sided Wald p < 0.001) signifying worse outcome for pts if tumor size > 8cm. Conclusions: In ccRCC pts, baseline cT assessment is associated with DFS outcome. High grade cT1/2 pts risk pathological upstaging to pT3. cT3+ identifies high risk pts, with <10% being downstaged. Pts with cT3a > 8cm have a worse prognosis than patients with < 7cm tumors. These findings should be accounted for in eligibility criteria and risk assessment models for neoadjuvant trials, and explored in other international datasets.

LBA4511 Background: RAMPART is evaluating one year of immune checkpoint inhibitor therapy versus active monitoring in patients with renal cell carcinoma (RCC) at intermediate or high risk of recurrence following nephrectomy according to the Leibovich Score (LS) or following complete resection of limited metastatic disease (M1NED). The trial has already shown that durvalumab and tremelimumab improves disease free survival (DFS), largely driven by effect in the higher risk population (LS high and M1NED). Methods: We recruited participants (pts) from 80 sites and randomised them in a 3:2:2 ratio between: Arm A, active monitoring; Arm B, 1 year (13 cycles) of durvalumab (1500mg); or Arm C, 1 year (13 cycles) of durvalumab (1500mg) plus tremelimumab (75mg, cycles 1 and 2 only). Based on the results of the KEYNOTE-564 trial, pembrolizumab became a treatment option for many of the patients who would be eligible for RAMPART, and recruitment was stopped earlier than planned. We revised the RAMPART design without knowledge of the accumulating trial results. In the modified design there is 80% power to detect a hazard ratio (HR) for the primary outcome of DFS of 0.60 for arm B vs. A, and of 0.55 for arm C vs. A. The overall familywise type I error rate remains strongly controlled at 2.5% (1-sided) across all primary analyses. The analysis plan includes a pre-specified, pre-powered analysis by risk of relapse. Results: Between October 2018 and June 2023, we randomised 790 pts (340, 225, and 225 to arms A, B, and C) from the UK (70%), France (21%), Australia (5%) and Spain (4%). Baseline characteristics were balanced across arms. Median age (range) was 60 (22, 83) years, 72% were male, 84% clear cell histology. Treatment with durvalumab (Arm B) was associated with a 26% relative reduction in the hazard of disease recurrence or death; conventional statistical significance was not reached (DFS HR = 0.74; 95% CI 0.53–1.04; 1p=0.041). DFS at 3 years was 78% with Arm B vs 72% Arm A. In the pre-specified DFS analysis by risk of recurrence, no evidence of a treatment-by-subgroup interaction was observed. This contrasts with the results of Arm C vs Arm A. Table 1 summarises results of the two RAMPART primary analyses. Exposure to treatment, safety, quality of life, overall survival and efficacy in non-clear cell subtypes will be presented. Conclusion: In RAMPART, durvalumab plus tremelimumab was associated with a statistically significant improvement in DFS, which was not observed with durvalumab monotherapy. Clinical trial information: NCT03288532 . Primary analysis results. Arm C vs A Arm B vs A All pts N=565; HR=0.65, 95%CI 0.45-0.93 N=565; HR=0.74, 95 CI 0.53–1.04 Higher Risk N=311; HR=0.52, 95%CI 0.34-0.80 N=312, HR=0.77, 95%CI 0.53–1.12 Intermediate Risk N=254, HR= 1.19, 95% CI 0.61-2.32 N=253, HR= 0.64, 95%CI 0.30–1.34 Test for Interaction HR=0.43, 95%CI 0.19-0.95 HR=1.20, 95%CI 0.52-2.74

Abstract Background Clinical trials are essential for advancing cancer care, yet patient participation remains suboptimal worldwide. While structural and clinician-reported barriers are well described, patient perspectives across diverse geographic and socioeconomic settings are less understood. The International Kidney Cancer Coalition (IKCC) conducts a biennial Global Patient Survey (GPS) to assess patient and caregiver experiences with kidney cancer, including clinical trials, to identify unmet needs and inform global advocacy. Methods The 2025 IKCC GPS was developed by a steering committee comprising patient advocates, medical experts, and the Picker Institute. The target population was kidney cancer patients, with responses provided directly by patients or caregivers reporting on their behalf. The survey was cognitively tested, translated into 16 languages, and distributed globally via online and paper formats. Data were analyzed using descriptive statistics and cross-tabulations. Results A total of 2,677 respondents (patients, n = 2,049; caregivers, n = 628) from 46 countries participated, including 551 from low- and middle-income countries (LMICs) and 2,126 from high-income countries (HICs). Respondents were predominantly male (54%), aged 46–80 years (80%), with clear cell histology (62%); 19% presented with stage IV disease, and 52% were diagnosed within the past four years. Globally, 64% reported willingness to participate in a clinical trial if offered; willingness was significantly higher in HICs than LMICs (69% vs. 46%, p < 0.001). Only 30% reported being asked to participate, with HIC respondents asked more often than those in LMICs (30% vs. 23%, p < 0.001). Among those asked, 83% agreed and 63% ultimately enrolled — rates comparable between HICs and LMICs. The leading drivers of participation were physician recommendation (64%), perceived access to better treatments (53%), and desire to contribute to KC research (48%). Overall trial satisfaction was 77%, with no significant difference between HICs and LMICs. Qualitative feedback (n = 333) identified perceived clinical benefit as the dominant satisfaction driver (63%), followed by close monitoring and specialized care (45–54%), access to new treatments (50%), psychological reassurance (29%), and altruism (18%). Dissatisfaction was most commonly attributed to treatment-related factors, including toxicity (58%) and lack of efficacy or limited duration of benefit (46%). System-level issues were also prominent: communication gaps — such as insufficient explanation of side effects and lack of feedback on trial results — were reported by 34%; operational challenges, including enrollment delays and lack of coordination by 28%; and logistical burdens such as travel and frequent visits by 25%. Additionally, 22% described emotional distress related to uncertainty or unmet expectations, and 18% perceived limited patient-centeredness, including rigid protocols or insufficient individualized care. Conclusions While willingness to participate in clinical trials is high, opportunities remain critically limited — fewer than one in three patients were offered participation, with even lower rates in LMICs. When offered, acceptance and enrollment rates are substantial. Although overall satisfaction is high, patient experience is meaningfully undermined by toxicity, limited efficacy, and systemic care delivery challenges. These findings highlight the urgent need to integrate routine clinical trial discussions into standard oncology care, expand equitable global access, and prioritize patient-centered trial design and delivery.

Abstract Background Combination immune checkpoint inhibitor (ICI) approaches are now standard of care for advanced clear cell renal cell carcinoma (ccRCC), yet validated biomarkers to guide selection of optimal combination regimens remain lacking. A key rationale for combined PD-1/CTLA-4 inhibition is the subset of patients achieving durable responses. The tumour immune microenvironment (TiME) is increasingly recognised as a key determinant of this benefit, yet its cellular composition, functional state and spatial organisation, and how these evolve under dual ICI therapy, remain undefined. Methods Tumour specimens from 30 metastatic ccRCC patients across two independent cohorts (TRACERx Renal and the Netherlands Cancer Institute; NKI) were subject to longitudinal multi-modal profiling, all of whom underwent deferred cytoreductive nephrectomy following treatment with combined CTLA-4 (Ipilimumab) and PD-1 (Nivolumab) inhibition. Patients were classified as durable responders (DR; no documented progression event; median follow-up 40.8 months) or as having acquired resistance (AR; initial CR/PR/SD > 6 months prior to progression). Where available, matched pre-treatment biopsy material and multi-regional post-treatment surgical specimens underwent multi-modal spatial profiling (n = 116 tumour regions), co-registering high-plex protein imaging (66-plex antibody panel; Akoya PhenoCycler), with spatial transcriptomics (RNA in situ platform targeting 480 kidney tumour-specific genes; 10x Genomics Xenium) on the same tissue sections, enabling simultaneous protein and transcriptomic characterisation of the TiME at single-cell resolution. In a subset (n = 8; n = 28 tumour regions), single-cell RNA sequencing with paired TCR and BCR sequencing was performed to resolve treatment-induced clonotypic and phenotypic dynamics within T and B cell compartments. Results Dual ICI therapy induced consistent immune remodelling across the cohort irrespective of response, characterised by increases in B cells and CD8+ T cells and a reduction in monocytes/macrophages. At baseline, durable response was associated with increased pericyte coverage of tumour vasculature, whilst acquired resistance patients exhibited decreased pericyte coverage alongside elevated CD39 expression on tumour endothelial cells, implicating dysfunctional, immunosuppressive vasculature as an early determinant of resistance. Post-treatment, durable responders demonstrated enrichment of CCR7+ dendritic cell (DC) niches containing CD4+ T cells, CD8+ T cells and B cells across tumour and stromal compartments, alongside monocytes/macrophages and NK cells within tumour regions. By contrast, acquired resistance CCR7+ DC niches lacked specific immune cell enrichment, displayed dysregulated transcriptional programmes. Acquired resistance was further characterised by enrichment of TREM2+ immunosuppressive macrophages and peri-vascular spatial interactions between macrophages and CD4+ T cells, defining an immunosuppressive niche. scRNA-seq with paired TCR sequencing identified novel and shared memory/resident T-cell clonotypes enriched in durable responders, whilst clonally expanded IgG2 plasma cells were orthogonally validated by BCR sequencing and spatial profiling as a hallmark of durable response. Conclusions Using an integrated multi-omic spatial framework combining high-plex proteomics, single-cell and spatial transcriptomics, we provide a comprehensive characterisation of TiME remodelling under dual ICI therapy in ccRCC. Durable response is preceded at baseline by a normalised vascular phenotype and is subsequently characterised post-treatment by the presence of coordinated CCR7+ DC niches, clonally expanded IgG2 plasma cells, and the emergence of memory/ resident T-cell clonotypes. Conversely, acquired resistance is characterised by an immune exclusion programme, defined by dysfunctional vasculature, TREM2+ macrophage enrichment, impaired DC niche organisation and peri-vascular immunosuppressive niches. By identifying spatially resolved cellular niches underpinning differential responses to combination ICI approaches, this work provides insights into biomarkers of durable response, whilst providing a framework for rational combination strategies to overcome resistance.

Background: Prognostic classification of patients with metastatic clear cell renal cell carcinoma (mccRCC) is instrumental for clinical trials and treatment decision. Hence, performance of prognostic models is crucial. This study aimed to develop and externally validate the new prognostic CPI2 (Clinical Prognostic Index in the Checkpoint Inhibitor era) model using clinical trial data, and and to externally validate the International Metastatic RCC Database Consortium (IMDC) model. Methods: Individual patient data from the clinical trials CheckMate-214 (1,096 patients) and CheckMate-9ER (651 patients) were used for development and external validation of the CPI2 model, respectively. Using a Cox proportional hazards model, predictors were selected using Akaike Information Criterion-based backwards selection. Bootstrapping was used to estimate coefficients and a shrinkage factor to correct for optimism. Calibration plots and Uno’s C-index for discriminative accuracy were calculated for the CPI2 model and IMDC model in both trial populations. Findings: A prognostic model with age, Karnofsky performance status, prior nephrectomy, metastatic locations, and seven laboratory parameters was selected based on CheckMate-214 data. Calibration showed adequate agreement between predicted and observed mortality risks. Classification into three prognostic groups provided discriminative accuracy at 36 months of 0.72 (95% CI 0.69-0.75) in CheckMate-214 and 0.72 (0.68-0.76) in CheckMate-9ER, which was 0.65 (0.62-0.68) and 0.61 (0.57-0.65) for the IMDC classification, respectively. PD-L1 expression did not improve prognostic accuracy. CPI2 favorable, intermediate and poor patients formed 43%, 33% and 24% of CheckMate-214 and 39%, 30% and 30% of CheckMate-9ER populations, respectively. Interpretation: The CPI2 model, using fourteen readily available clinical parameters, demonstrated substantial improvement in discriminative accuracy compared to the IMDC model. This classification should be further validated in other trial and observational populations and be used to (re)analyse heterogeneity of treatment effects of immune checkpoint inhibitor-based combination regimens of trials shaping the current and future treatment landscape.

To understand the perspectives and experiences of patients and healthcare professionals regarding the trial design, recruitment and randomisation process to a novel cohort-embedded RCT design for Nephron Sparing Treatment (NEST) for small renal masses. Participants were adult patients with a small renal mass (< 4 cm) randomised to receive either percutaneous cryotherapy (CRO) or robot-assisted partial nephrectomy (PRN), and clinicians involved in a trial comparing the two treatments. Semi-structured interviews followed a phenomenological approach and were transcribed verbatim and analysed using thematic analysis. Interviews were conducted with 37 patients and 10 clinicians. Wanting to ‘give back’ influenced participants’ decisions to take part in the trial. Most patients expressed that they had a positive and informed experience of the trial. Patients who accepted randomisation to cryotherapy (experimental intervention) were influenced by information provided regarding a potentially shorter recovery timeframe, length of hospitalisation, and lower risk of complication. Those who were randomised to receive partial nephrectomy (standard of care intervention) stated that they felt less anxious receiving ‘non-experimental’ treatment and felt safer in the knowledge that the tumour was removed. Clinicians expressed that the trial presented an opportunity to work collegially in identifying the best treatment for patients presenting with SRMs, though highlighted that limited consultation time was a challenge to recruitment. Findings support the potential feasibility of a future multicentre trial comparing percutaneous cryoablation to robot-assisted partial nephrectomy in the treatment of small renal masses. The study’s design, process and intervention were accepted by most, though not all, participants. ISRCTN18156881

SUMMARY Clear cell renal cell carcinoma (ccRCC) progresses along two predominant evolutionary trajectories, defined by PBRM1 (∼40%) or BAP1 (∼15%) mutations on a VHL -inactivated background. They have distinct patterns of evolutionary tempo and mode, and vastly different clinical outcomes, yet the underlying genotype-specific molecular phenotypic programmes are unknown. We established a patient-derived preclinical model biobank that captures the genetic diversity of ccRCC. Through integrative analyses of preclinical models and tumour bulk and single cell profiling, we identified transcriptional and epigenetic changes specific to PBRM1 - and BAP1 -driven ccRCC. Modelling PBRM1 loss in vitro demonstrates that it reinforces renal lineage identity and maintains progenitor-like cell state. In contrast, BAP1 loss drives inflammatory signalling and chromosomal instability. These insights reconcile the distinct evolutionary modes (branched versus punctuated), tempo (slow versus fast) and clinical outcomes associated with PBRM1 and BAP1 mutations, respectively, establishing a framework for patient stratification and genotype-directed therapeutic development.

Abstract Background Localised renal cell carcinoma is treated with radical nephrectomy (RN) or partial nephrectomy (PN). Nephron-sparing PN increases preservation of renal function, reducing incidence of end stage renal failure and associated cardiovascular events. In patients with exophytic T1a (≤ 4 cm) tumours and normal contralateral kidney, PN is standard of care. In patients with T1b (> 4–7 cm) or endophytic T1a tumours and normal contralateral kidney, the benefits of PN over RN are less clear as there are increased surgical complications and more tissue may be excised reducing the preservation of renal function. There are no high-quality studies to address if PN is superior to RN in these more complex cases. Methods PARTIAL is a pragmatic randomised controlled parallel group unblinded superiority trial with embedded internal pilot and economic and process evaluation. A total of 420 participants will be recruited in UK NHS centres with expertise in minimally invasive nephrectomy techniques. Eligible consenting adults with a single T1 renal cell carcinoma, normal contralateral kidney and equipoise within the multidisciplinary team confirming suitability to receive both interventions by minimally invasive approaches are randomised 1:1 to PN or RN. Patients with metastatic disease, existing chronic kidney disease, solitary functioning kidney, congenital renal abnormality, inherited kidney cancer syndrome, who lack capacity to consent or are pregnant or breast feeding are excluded. Primary outcomes are gains in preservation of renal function at 2 years and surgical complications over the peri-operative period. Secondary outcomes are quality of life and recovery, cost and cost-effectiveness, rates of positive surgical margin, recurrence and cardiovascular events, overall survival, progression to chronic kidney disease and end stage renal failure, operative conversion and patient acceptability. Participants are followed up for 2 years with outcomes collected from medical records and participant questionnaires. Discussion PARTIAL will determine if gains from PN are superior to RN and offset the potential harms and costs in complex T1 renal tumours suitable for either approach. If PN is not found to provide clinically significant gains and excess complications are confirmed, then a practice-changing case for RN as standard of care could be made. Trial registration ISRCTN 11293415. Registered prospectively on 19 January 2023.

BACKGROUND:Inconsistent, varied, and selective outcome reporting is problematic in localized renal cell cancer (RCC) research. Core outcome sets (COSs) offer a solution by defining a standardized minimum set of outcomes that should be measured and reported in all trials in a specific area of health or health care. OBJECTIVE:We aimed to develop a COS for localized RCC (L-RCC). DESIGN, SETTING AND PARTICIPANTS:COS development was conducted over three phases. Phase 1 identified potentially relevant outcomes via a systematic review and patient interviews. In Phase 2, Phase 1 outcomes were entered into a 2-round online Delphi study, whereby patients, health care professionals (HCPs), and researchers scored each outcome's importance. In Phase 3, a series of meetings were conducted to reach a consensus on defining outcomes and selecting appropriate measurements. RESULTS AND LIMITATIONS:Phase 1 identified 200 outcomes. The outcome list was deduplicated and refined before the Delphi study. Round one of the Delphi was completed by 168 participants, of whom 140 completed Round 2. The consensus meeting series was attended by 20 participants (HCPs, researchers, and patients). The L-RCC-COS consists of 21 agreed-upon outcomes, of which 10 apply to all treatments and 11 are intervention-specific. Consensus meeting participants were exclusively based in Europe; future validation work should determine if the L-RCC-COS outcomes are conceptually transferable to other languages and cultures. CONCLUSIONS:There is a broad agreement from HCPs, researchers, and patients on which outcomes are important and how they should be defined in L-RCC. We developed the L-RCC-COS suitable for effectiveness trials, observational studies, and routine practice. Use of the L-RCC-COS to standardize outcome reporting in clinical trials and real-world evidence data collection will enable more precise and powerful evidence syntheses and reduce research waste.