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Approximately one-third of advanced renal cell carcinoma (RCC) patients develop osteolytic bone metastases, leading to skeletal complications. In this review, we first provide a comprehensive perspective of seminal studies on bone metastasis of RCC describing the main molecular modulators and growth factor signaling pathways most important for the RCC-stimulated osteoclast-mediated bone destruction. We next focus on newer developments revealing with in-depth details, the bidirectional interplay between renal cancer cells and the immune and stromal microenvironment that can through epigenetic reprogramming, profoundly affect the behaviors of transformed cells. Understanding their mechanistic interactions is of paramount importance for advancing both fundamental and translational research. These new investigations into the landscape of RCC-bone metastasis offer novel insights and identify potential avenues for future therapeutic interventions., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: Immuno-oncology (IO) therapies have become integral to renal cell carcinoma (RCC) management, RCC remains a complex malignancy with diverse clinical behaviors and a heterogeneous tumor microenvironment, highlighting the need for predictive biomarkers to optimize therapy., Areas Covered: This review synthesizes recent findings from clinical trials, translational studies, and molecular analyses to provide an updated perspective on biomarker research for IO therapies in RCC. A literature search was conducted using PubMed, Embase, and Web of Science for articles published between January 2010 and November 2024., Expert Opinion: IO combination therapies have demonstrated significant improvements in progressionfree survival and overall survival compared with sunitinib. However, treatment outcomes vary according to the IMDC risk groups, metastatic sites, and histological subtypes, such as sarcomatoid differentiation. Advances in molecular biology have elucidated the roles of genetic alterations and immune phenotypes in modulating IO efficacy. Emerging biomarkers, including tertiary lymphoid structures, human endogenous retroviruses, and the gut microbiome, show promise but require further validation. Addressing challenges such as intratumoral heterogeneity and dynamic immune responses will be key to identifying actionable biomarkers. Continued integration of clinical and molecular insights is essential for improving patient selection and outcomes in RCC treated with IO therapies.

Background and Objective: In oncology, patient-reported outcome measures (PROMs) capturing health-related quality of life (HRQOL) play an increasing role in clinical trials, drug approval, and policy making. This scoping review aimed to identify and elaborate on HRQOL-focussed PROMs used in renal cell cancer (RCC) clinical trials., Methods: MEDLINE, Web of Science, PsychINFO, Academic Search Elite, CINAHL, Embase, and the Cochrane Library were searched systematically for original peer-reviewed articles on clinical trials including RCC patients and using PROMs, published between 1950 and 2023. Prespecified trial characteristics and information on the PROMs used were extracted. Frequencies and proportions of categorical data, and ranges and medians of continuous variables were calculated., Key Findings and Limitations: Of the 48 unique studies included, the majority followed a randomised controlled design (34, 71%) and evaluated systemic treatments (38, 79%). The trials used 27 different PROMs (max = 6, median = 2), of which only 4 (15%) were developed specifically for kidney cancer patients. Of the trials, 46% did not use any RCC-specific PROM. European Quality of Life-5 Dimensions (EQ-5D), European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30), Functional Assessment of Cancer Therapy Kidney Symptom Index (FKSI) -15/19-item version, FKSI-Disease Related Symptoms, and Functional Assessment of Cancer Therapy-General (FACT-G) were the most frequently used questionnaires, with pain, ability to work, fatigue, worry, and sleep quality being the most commonly assessed issues., Conclusions and Clinical Implications: A variety of PROMs are used in RCC patients, hindering interpretability across trials. The PROMs used differ in terms of both the domains assessed and how the issues are translated into questionnaire items. Though RCC-specific PROMs exist, these have flaws in terms of relevance to patients. To answer predefined relevant HRQOL research questions, revised RCC-specific PROMs and standardisation of their integration into clinical trials are warranted., Patient Summary: Researchers are more and more interested in the health-related quality of life of kidney cancer patients and use questionnaires to measure it. This review shows that there are many different health-related quality of life questionnaires that are used in different combinations in clinical trials for kidney cancer patients. This makes it very difficult to compare these study results and draw reliable conclusions for the actual clinical treatment. It was even found that some of the questionnaires used do not capture things that patients actually consider important (eg, emotional issues such as dealing with thoughts about cancer and depression). Therefore, more work needs to be done to develop questionnaires that ask what is really important to kidney cancer patients' health-related quality of life. If these questionnaires are used in a consistent way in clinical trials, the results can be better compared. This will help treat kidney cancer patients in the best possible way., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Renal cell carcinoma and upper tract urothelial cancer are increasing in incidence. Rates of local recurrence and complications vary with the treatment modality, but the imaging appearance of recurrence and complications is similar no matter the method of local treatment. The use of contrast-enhanced, multiphase imaging is recommended to best evaluate the treatment bed for recurrence and complications. In this article, we cover the most common current local treatments for these cancers along with the patterns of recurrence and complications., Competing Interests: Disclosures The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Clinical trials enable renal cell carcinoma (RCC) patients to receive promising investigational agents, yet access may be limited. Telemedicine (TM) is an increasingly utilized platform that can expand access, but perspectives on its use in clinical trial care are unknown., Patients and Methods: A prospective study was conducted between Jan 2023 - Oct 2023 at Memorial Sloan Kettering Cancer Center. RCC patients enrolled on therapeutic clinical trials who had prior TM visits were eligible. Surveys in English were distributed to patients, treating clinical trial nurses (CTNs), and oncology providers engaged in clinical trials., Results: 39 patients, 7 CTNs, and 15 oncology providers were included in our analysis. Regarding clinical trial care, 26 patients (67%) preferred in-person, 4 (11%) preferred TM, and 9 (22%) had no preference. However, 25 patients (64%) reported TM provided an equal quality of care, and 38 (97%) reported a positive or neutral experience. Conversely, 7 CTNs (100%) and 11 providers (73%) preferred in-person care while 4 (27%) indicated no preference. Most, including 6 CTNs (86%) and 13 providers (87%), reported that TM quality of care was inferior. However, most, including 7 CTNs (100%) and 14 providers (93%), reported a positive experience with TM., Conclusions: In this study, one third of RCC participants preferred TM or had no preference, and a majority felt TM delivered equal quality of care. Providers, however, preferred in-person visits and reported inferior quality of care with TM. These findings warrant further evaluation of safety and feasibility to optimize TM integration for clinical trial care delivery., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Renal cell carcinoma (RCC) is a malignant tumor with highly heterogeneous and complex molecular mechanisms. Through systematic analysis of TCGA, COSMIC and other databases, 24 mutated genes closely related to RCC were screened, including VHL, PBRM1, BAP1 and SETD2, which play key roles in signaling pathway transduction, chromatin remodeling and DNA repair. The PI3K/AKT/mTOR signaling pathway is particularly important in the pathogenesis of RCC. Mutations in genes such as PIK3CA, MTOR and PTEN are closely associated with metabolic abnormalities and tumor cell proliferation. Clinically, mTOR inhibitors and VEGF-targeted drugs have shown significant efficacy in personalized therapy. Abnormal regulation of metabolic reprogramming, especially glycolysis and glutamine metabolic pathways, provides tumor cells with continuous energy supply and survival advantages, and GLS1 inhibitors have shown promising results in preclinical studies. This paper also explores the potential of immune checkpoint inhibitors in combination with other targeted drugs, as well as the promising application of nanotechnology in drug delivery and targeted therapy. In addition, unique molecular mechanisms are revealed and individualized therapeutic strategies are explored for specific subtypes such as TFE3, TFEB rearrangement type and SDHB mutant type. The review summarizes the common gene mutations in RCC and their molecular mechanisms, emphasizes their important roles in tumor diagnosis, treatment and prognosis, and looks forward to the application prospects of multi-pathway targeted therapy, metabolic targeted therapy, immunotherapy and nanotechnology in RCC treatment, providing theoretical support and clinical guidance for individualized treatment and new drug development., Competing Interests: Conflict of interest The authors declare that there were no commercial or financial relationships during this study that could be considered conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Context: Frailty, a geriatric syndrome characterized by decreased resilience and physiological reserve, impacts the prognosis and management of older adults significantly, particularly in the context of surgical and oncological care., Objective: To provide an overview of frailty assessment in the management of older patients with a renal mass/renal cell carcinoma (RCC), focusing on its implications for diagnostic workup, treatment decisions, and clinical outcomes., Evidence Acquisition: A narrative review of the literature was conducted, focusing on frailty definitions, assessment tools, and their application in geriatric oncology, applied to the field of RCC. Relevant studies addressing the prognostic value of frailty, its impact on treatment outcomes, and potential interventions were summarized., Evidence Synthesis: Frailty is a poor prognostic factor and can influence decision-making in the management of both localized and metastatic RCC. Screening tools such as the Geriatric Screening Tool 8 (G8) and the Mini-COG test can aid clinicians to select older patients (ie, aged ≥65 yr) for a further comprehensive geriatric assessment (CGA) performed by dedicated geriatricians. The CGA provides insights to risk stratify patients and guide subsequent treatment pathways. As such, the involvement of geriatricians in multidisciplinary tumor boards emerges as an essential priority to address the complex needs of frail patients and optimize clinical outcomes. Herein, we propose a dedicated care pathway as a first key step to implement frailty assessment in clinical practice and research for RCC., Conclusions: Frailty has emerged as a crucial factor influencing the management and outcomes of older patients with RCC. Involvement of geriatricians in diagnostic and therapeutic pathways represents a pragmatic approach to screen and assess frailty, fostering individualized treatment decisions according to holistic patient risk stratification., Patient Summary: Frailty, a decline in resilience and physiological reserve, influences treatment decisions and outcomes in elderly patients with renal cell carcinoma, guiding personalized care. In this review, we focused on pragmatic strategies to screen patients with a renal mass suspected for renal cell carcinoma, who are older than 65 yr, for frailty and on personalized management algorithms integrating geriatric input beyond patient- and tumor-related factors., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Polybromo 1 (PBRM1) inactivating mutations are associated with clinical benefit from immune checkpoint inhibitor treatments in clear cell renal cell carcinoma (ccRCC). However, whether targeting PBRM1 has the potential to enhance immunotherapy efficacy in patients with wild-type PBRM1 and the upstream pathways that regulate PBRM1 protein stability remain unclear. Here, it is demonstrated that PBRM1 knockdown induced M1 macrophage polarization and infiltration, which enhanced the efficacy of anti-PD-1 immunotherapy in RCC. Meanwhile, CDC20 catalyzes K27 ubiquitination of PBRM1 and promotes its degradation via p62-mediated selective autophagy. A bicyclic peptide (PB1-p62) is designed and constructed to target PBRM1 and p62, thereby promoting the degradation of PBRM1. As a result, the efficacy of anti-PD-1 immunotherapy is enhanced, leading to improved overall survival rates in syngeneic mouse tumor models. Overall, this finding suggest the clinical application of PB1-p62 and provide a novel approach for enhancing the effectiveness of immunotherapy in RCC patients with wild-type PBRM1., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Purpose: Evaluation of the prognostic significance of four different scoring systems in a real-world cohort of patients with metastatic urothelial carcinoma (mUC) or renal cell carcinoma (mRCC) undergoing immunotherapy (IO)., Methods: For 120 patients with mUC (n = 67) and mRCC (n = 53) who received IO between July 2016 and December 2020 at the tertiary Urological University Medical Centre Mannheim, the following scores were recorded at pre-treatment baseline: modified Glasgow prognostic score (mGPS), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-eosinophil ratio (NER). Overall survival (time between the beginning of IO until the patients' death or last contact) was determined for every patient., Results: Kaplan-Meier analyses revealed that high baseline mGPS, SII (> 979) and NLR (> 3) were associated with poor overall survival (OS) (p < 0.05). Cox proportional hazards regression analyses showed that baseline mGPS and NLR had a significant independent prognostic influence on OS (p < 0.05), of which mGPS had a greater significance (p < 0.001, mGPS Score 2 vs. Score 0: HR 4.1, 95% CI 1.9-8.8). Although a high baseline NER (63.9) was associated with poor OS, it did not reach statistical significance. Baseline NER was also not identified as a significant score in the regression analyses., Conclusion: mGPS, SII and NLR are scoring systems that are easy to record in routine clinical practice. As they provide good prediction of OS in patients with mUC and mRCC under IO, they may allow identification of patients at high-risk and monitor them more cautiously in addition to imaging., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Treatment beyond progression (TBP) is common in patients treated with immune-checkpoint inhibitors (ICI), however, there is no biomarker to select patients that are more likely to derive benefit from TBP. Here, we investigated the potential of the modified Glasgow Prognostic Score (mGPS) as a predictive biomarker to select patients for TBP., Methods: We performed a post-hoc analysis of the immunotherapy arms in the randomized phase 3 trials IMmotion151 (renal cell carcinoma), OAK (non-small cell lung cancer) and IMvigor211 (urothelial cancer). The main outcome was post-progression overall survival (PPOS) after the first investigator-assessed disease progression (PD), in mGPS risk groups. The mGPS classifies patients into three risk groups based on C-reactive protein (CRP) and albumin., Results: We found a strong prognostic value for the mGPS when assessed at the time of PD (PD-mGPS) in all three trials. High-risk PD-mGPS was associated with significantly shorter PPOS compared to low-risk PD-mGPS (HR for death 18.3 (95 % CI 6.71-50.0, p < 0.001)) for RCC, UC: HR 4.16 (95 % CI 2.58-6.69, p < 0.001) and NSCLC HR 2.53 (95 % CI 1.70-3.77, p < 0.001). Importantly, patients within all three trials only derived benefit from ICI-TBP compared to switch to further-line treatment in the PD-mGPS low-risk group (RCC: HR 0.18 (95 % CI 0.06-0.55, p = 0.002); UC: HR 0.59 (95 % CI 0.34-1.00, p = 0.052); NSCLC: 0.62 (0.41-0.92, p = 0.018) compared to PD-mGPS intermediate/ high risk)., Conclusions: These findings suggest that the mGPS measured at the time of radiologic PD can identify patients with a better prognosis who may benefit from continued atezolizumab therapy, aiding in the selection for TBP in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with metastatic renal cell carcinoma (mRCC) experience emotional distress and limited supportive care access. This study assesses a mindfulness app's feasibility, acceptability, and preliminary efficacy in improving emotional symptoms, trait mindfulness, and overall quality of life for patients with mRCC on immunotherapy., Methods: This multinational study recruited patients with mRCC undergoing immunotherapy from Brazil and the United States. Participants were required to engage in mindfulness app-based activities for 20-30 min daily, at least 4 days per week, over a 4-week period. Assessments were conducted at weeks 0, 2, 4, and 12 to evaluate emotional symptoms (PROMIS-Anxiety and Depression, Fear of Cancer Recurrence-7), fatigue (Brief Fatigue Inventory), trait mindfulness (Mindfulness Attention Awareness Scale), and quality of life (Functional Assessment of Chronic Illness Therapy-General). Self-reported data were used to assess adherence. Linear mixed-effects models were used to evaluate changes over time for the measured outcomes., Results: Among 50 patients with mRCC, the feasibility of this intervention was demonstrated; 96% of patients were assessed at week 4, with high adherence rates reported by 75% of patients. Participants expressed positive feedback on the smartphone-based approach. Significant improvements were observed in emotional symptoms, fatigue, and quality of life scores from baseline to post-intervention (P = .001 for each), suggesting the positive impact of this intervention., Conclusion: Our findings provide encouraging evidence for the feasibility and acceptability of a mindfulness app-based intervention among patients with mRCC. This intervention may offer a viable and accessible means of providing psychosocial support to patients with mRCC., (© The Author(s) 2025. Published by Oxford University Press.)

Background: Siglec-E is an immune checkpoint inhibitory molecule. Expression of Siglec-E on the immune cells has been shown to promote tumor regression. This study aimed to develop an adenovirus (Ad) vaccine targeting Siglec-E and carbonic anhydrase IX (CAIX) (Ad-Siglec-E/CAIX) and to evaluate its potential antitumor effects in several preclinical renal cancer models., Methods: Ad vaccines encoding Siglec-E or CAIX were developed and evaluated for their therapeutic potential in mouse subcutaneous, lung metastatic, and orthotopic tumor models. The expression of Ad-Siglec-E/CAIX was confirmed via PCR and flow cytometry. Immune responses induced by Ad-Siglec-E/CAIX were assessed in vitro and in vivo using flow cytometry, immunohistochemistry, ELISA, histological analysis, cell proliferation, enzyme-linked immunosorbent spot, cytotoxic T lymphocytes (CTL) killing, and cell depletion assays., Results: Ad-Siglec-E/CAIX vaccine induced the increase of tumor-infiltrated immune cells, and significantly suppressed the subcutaneous tumor growth of renal carcinoma. Immunization with Ad-Siglec-E/CAIX promoted the induction and maturation of CD11c + dendritic cells and their subsets, which in turn enhanced tumor-specific CD8 + T cell immune responses, as evidenced by increased CD8 + T cell proliferation and CTL activity. Importantly, the deletion of CD8 + T cells in vivo abolished the antitumor effect of the Ad-Siglec-E/CAIX vaccine, highlighting the essential role of functional CD8 + T cell responses. The potent therapeutic efficacy of the Ad-Siglec-E/CAIX vaccine was also observed in lung metastasis and orthotopic tumor models through tumor-specific CD8 + T cell immune responses., Conclusions: Our results indicate that targeting Siglec-E enhances the therapeutic efficacy of Ad-CAIX against renal carcinoma, providing a promising therapeutic option for solid tumors., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Sex differences in the outcomes of advanced renal cell carcinoma (RCC) treated with immune checkpoint inhibitors (ICIs) and the profiles of tumor-infiltrating immune cells (TIICs) remain unclear. We retrospectively evaluated data from 563 patients with RCC receiving systemic therapy, including first-line dual ICI combinations (i.e., immunotherapy [IO]-IO), combinations of ICIs with tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI), TKI monotherapy, and subsequent nivolumab monotherapy. Survival and tumor response were compared between the sexes in each treatment group, and TIIC profiles were compared using 116 RCC tumor samples analyzed by flow cytometry. Progression-free survival (PFS) was shorter in female than in male patients in the IO-IO (p = 0.0227) and nivolumab monotherapy (p = 0.0478) groups. Furthermore, sex remained an independent factor for shorter PFS after adjusting for covariates in the IO-IO (p = 0.0340) and nivolumab monotherapy (p = 0.0322) groups. In contrast, PFS was not significantly different between sexes in the IO-TKI or TKI monotherapy groups (p > 0.05). Overall survival and objective response rates were not significantly different between the sexes in any of the treatment groups (p > 0.05). Some TIIC populations, including that of CD8 + T cells (p = 0.0096), decreased to a greater extent in female than in male patients in the advanced-stage population. In conclusion, the effectiveness of ICIs on PFS was lower in female patients than in male patients, potentially because of the different profiles of the immune microenvironment, particularly the decreased number of CD8 + T cells in females., Competing Interests: Declarations. Conflicts of interest: Toshio Takagi received honorariums from Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd., Merck KGaA, and Takeda Pharmaceutical Co., Ltd. Tsunenori Kondo received honoraria from Pfizer, Novartis, Bristol-Myers Squibb, and Ono Pharmaceutical Co., Ltd., (© 2024. The Author(s).)

Purpose of Review: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for metastatic renal cell carcinoma (mRCC), significantly improving overall survival and achieving durable responses. This review is timely due to the increasing number of ICI-based regimens now considered standard care for RCC. There is an urgent need to identify reliable biomarkers that can predict therapeutic responses and resistance, a key challenge in current research., Recent Findings: While tumor-specific factors such as pathological characteristics, genomic mutations, and transcriptional profiles have been extensively studied, no definitive predictive biomarker has yet emerged. Additionally, advanced technologies are being explored to address tumor heterogeneity. Recent research has focused on novel areas such as the microbiome, radiomics, and spatial transcriptomics, which show promise as potential biomarkers., Summary: The translation of these emerging biomarker findings into clinical practice is essential to improving personalized treatment strategies for RCC. Until reliable biomarkers are clinically available, clinical factors may play a pivotal role in guiding individualized treatment decisions to optimize patient outcomes., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

In patients with renal masses, when intervention is warranted, partial nephrectomy is preferred when feasible, especially for T1 renal masses. Thermal ablation, however, has become an accepted alternative treatment of small renal neoplasms with excellent oncologic outcomes. The National Comprehensive Cancer Network guidelines include thermal ablation as a treatment strategy for managing T1a and select T1b masses. Other potential locoregional treatments for malignant and benign renal masses are emerging. Stereotactic body radiation therapy (SBRT) is gaining traction in the management of select localized renal masses and can be considered in patients who are not surgical candidates. Imaging findings after SBRT differ from those after thermal ablation. As this technique becomes more widely used, the temporal evolution of post-SBRT changes needs to be understood to correctly identify local tumor progression. Renal artery embolization is accepted as safe and effective for patients with renal angiomyolipoma. It can also be used in the management of renal cell carcinoma as an adjunct to definitive treatment or for palliation in advanced disease. With the growing acceptance of local-regional treatment of renal masses and the corresponding number of related patients undergoing surveillance and postablation imaging, the diagnostic radiologist will have greater responsibility in the appropriate interpretation of follow-up imaging to accurately assess normal postprocedural findings and define oncologic outcomes. Such interpretations should be based on understanding of the procedure and related imaging findings, both acutely and in the years after treatment. Procedural complications and recurrent tumor are identifiable based on deviations from the expected course. © RSNA, 2024 Supplemental material is available for this article.

Background: The present study aimed to investigate the prognostic and predictive roles of Hb/RDW ratio in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI)., Materials and Methods: We performed a sub-analysis of a multicenter retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations., Results: Three hundred and twenty-nine patients were enrolled, 244 males and 85 females. Median age was 65.5 years. The prognostic impact of the Hb/RDW ratio on PFS and OS was observed in the whole population examined. Hb/RDW ratio had a correlation with neutrophil-to-lymphocyte ratio (NLR), a blood inflammatory parameter., Conclusion: Hb/RDW ratio is a new inflammatory prognostic factor, easy to use in daily clinical practice.

Background/aim: Clear cell renal cell carcinoma (ccRCC) represents the most common type of renal cancer. When resectable, nephrectomy is the only radical treatment for ccRCC, however metastasis is already present at 30% of the patient population. Although great progress has been made in the field of targeted therapy with the emergence of immune checkpoint inhibitors (ICIs) the cure of metastatic ccRCC (mccRCC) remains far from achieved. Additionally, the need of biomarkers capable of predicting their therapeutic efficacy with the aim to ameliorate patient treatment and management is crucial. This study aimed to investigate potential changes in the expression of 3 cuproptosis-related lncRNAs, FOXD2-AS1, MINCR, LINC02154, in the blood of mccRCC patients that receive ICI-based treatments and whether these changes could be used to distinguish patients with clinical benefit (CB) from patients with progressive disease (PD)., Materials and Methods: Peripheral blood from 31 mccRCC patients was obtained, prior to administration of ICI-immunotherapy. Using the RECIST criteria patients were subdivided into CB and PD groups. The fold change of FOXD2-AS1, MINCR, LINC02154 was evaluated using qRT-PCR., Results: The tested lncRNAs showed an increase in peripheral blood with the most notable up-regulation in FOXD2-AS1 and LINC02154 (fold change of 3.7 and 3.8 respectively), followed by MINCR, (fold change of 2.6) in the PD patient group., Conclusion: Cuproptosis-related lncRNAs FOXD2-AS1, MINCR, LINC02154 show promise for the prediction of patient response (CB vs. PD) in ICI-based therapeutic schemes in patients with mccRCC., (Copyright © 2025, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Interferon-induced protein 35 (IFI35), an immunomodulator, is highly expressed in tumor cells, yet its role in enhancing tumor vaccine efficacy remains unclear. In this study, an adenovirus (Ad) vaccine encoding dual targets, IFI35 and carbonic anhydrase IX (CAIX), was developed for renal carcinoma treatment. Co-immunization with Ad-IFI35/CAIX effectively inhibited tumor growth in a subcutaneous model and significantly increased the infiltration of CD8 + T cells and dendritic cells (DCs). Furthermore, Ad-IFI35/CAIX administration induced strong cytotoxic T lymphocyte (CTL) responses and expanded multifunctional CD8 + T cell populations. Depletion of CD8 + T cells abolished the vaccine's tumor regression effects, confirming that its therapeutic effect relies on CD8 + T cell-mediated immunity. In addition, Ad-IFI35/CAIX treatment enhanced the induction of memory CTL responses, effectively suppressing the growth of tumors implanted contralaterally. The Ad-IFI35/CAIX vaccine also elicited a strong CD8 + T cell-mediated immunity against tumor metastasis and growth in lung metastasis and orthotopic renal carcinoma models. These results indicate that the Ad vaccine dual targeting IFI35 and CAIX is a potential strategy for renal carcinoma treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

CD70 is an emerging target for anticancer therapies. It is an ideal antigen target given its limited expression in normal physiologic tissues and propensity to be aberrantly expressed in a variety of malignancies, thus limiting off-target toxicities. It is also heavily involved in immune homeostasis, and disruption of this pathway can help overcome tumor-related immune cell exhaustion. Recent phase I/II trials using cellular therapies targeting CD70, such as chimeric antigen receptor-T cells, have shown promising effectiveness and safety in treating relapsed or refractory renal cell carcinoma. Noncellular therapies targeting CD70, such as antibody-drug conjugates, monoclonal antibodies, radionuclides, and cytokines, are currently under investigation, with early data showing encouraging results as well. Efforts are already underway to further improve and optimize CD70-based therapies.

Purpose of Review: Renal cell carcinoma (RCC) is resistant to chemotherapy. Adjuvant interferon and tyrosine kinase inhibitors were ineffective. Immune checkpoint inhibitors (ICIs), however, have shed new hope in this setting. In the current review, updated evidence of adjuvant therapy in RCC is summarized., Recent Findings: KEYNOTE-564 demonstrated survival benefits of adjuvant Pembrolizumab in RCC. EAU guidelines now recommend adjuvant pembrolizumab to ccRCC patients at an increased risk of recurrence, as defined in the study. At a median follow-up of 24 months, the disease-free survival (DFS) was significantly longer for the Pembrolizumab group than placebo group [DFS 77.3 vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval (95% CI), 0.53-0.87; P  = 0.002]. From its updated analysis, at median follow up of 57.2 months, overall survival (OS) benefit of Pembrolizumab was demonstrated (hazard ratio for death, 0.62; 95% CI, 0.44-0.87; P  = 0.005). A number of other adjuvant ICI trials have though been negative., Summary: Pembrolizumab is currently the only adjuvant therapy for RCC showing survival benefits, amid a number of negative trials on adjuvant immunotherapy. Currently, there is no role for adjuvant tyrosine-kinase inhibitors and radiotherapy for RCC. Meanwhile, a multidisciplinary approach and shared decision-making should be adopted., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Clinical guidelines have recently advised combination therapy involving immunotherapy (IO) and tyrosine kinase inhibitors (TKI) as the first-line therapy approach for advanced renal cell carcinoma (RCC). Nevertheless, there is currently no available biomarker that can effectively distinguish the progression-free survival (PFS). RNA-sequencing and immunohistochemistry were conducted on our cohort of metastatic RCC patients, namely ZS-MRCC, who received combination therapy consisting of IO and TKI. We further applied RNA-sequencing, immunohistochemistry, and flow cytometry to examine the immune cell infiltration and functionality inside the tumor microenvironment of high-risk localized RCC samples. SPP1 expression was significantly higher in non-responders to IO-TKI therapy. Elevated levels of SPP1 were associated with poor PFS in both the ZS-MRCC cohort (HR = 2.73, p  = .018) and validated in the JAVELIN Renal 101 cohort (HR = 1.61, p  = .004). By multivariate Cox analysis, SPP1 was identified as a significant independent prognosticator. Furthermore, there existed a negative correlation between elevated levels of SPP1 and the presence of GZMB + CD8 + T cells (Spearman's ρ= -0.48, p  < .001). Conversely, SPP1 expression is associated with T cell exhaustion markers. A significant increase in the abundance of Tregs was observed in tumors with high levels of SPP1. Additionally, a machine-learning-based model was constructed to predict the benefit of IO-TKI treatment. High SPP1 is associated with therapeutic resistance and unfavorable PFS in IO-TKI therapy. SPP1 expression have also been observed to be indicative of malfunction and exhaustion in T cells. Increased SPP1 expression has the potential to serve as a potential biomarker for treatment selection of metastatic RCC.

Studies conducted in the last few years have suggested a connection between clinical outcomes and the time of immune checkpoint inhibitors (ICIs) infusion. However, few data are available regarding the differences between early and late time-of-day (ToD) administration in metastatic renal cell carcinoma (mRCC) patients receiving immunotherapy and immune-based combinations. In this meta-analysis, we aimed to fully investigate the influence of timing of administration on the efficacy of mRCC immunotherapy, by comparing early ToD versus late ToD dosing in this setting. The present systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Overall Survival (OS) was measured as Hazard Ratios (HRs) and 95% confidence intervals (CIs). Our search resulted in the identification of 1429 potentially relevant reports, which were subsequently restricted to four following independent evaluation of three authors. The pooled HR for OS in RCC patients receiving early ToD versus late ToD dosing was 0.62 (95% Confidence Interval, 0.50-0.72; p < 0.001). According to our findings, a statistically significant improvement in terms of OS for mRCC patients receiving early ToD administration compared with late ToD dosing was observed, with a reduction of death by 38%. Well-designed, randomized clinical and translational trials are required to clarify this issue and to establish recommendations for personalized treatments according to ToD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

To analyze hotspots and trends in renal cell carcinoma (RCC)-macrophage research using bibliometric analysis, although numerous studies on macrophages in RCC have been recently reported, understanding the progressive trends in this field remains challenging. Publications focused on macrophages in RCC were extracted from the Web of Science Core Collection. VOSviewer, Citespace, and Bibliometrics online platforms were used to visualize hot topics and global trends in RCC-macrophage research. In total, 778 papers were collected. China produced the most articles; however, the United States accounted for the largest number of citations. Oncology journals published the most articles, and these were cited most frequently. Based on keyword analysis, "prognosis," "immunotherapy," "tumor microenvironment," and "immune infiltration" represented the primary research hotspots. In summary, RCC-macrophage studies have emerged as a key research focus; particularly, incorporating multiomics data and applying artificial intelligence for predictive modeling have demonstrated significant potential. Our study suggests that the resistance mechanism of immune checkpoint inhibitors and the interaction between macrophages and immune checkpoint inhibitors will be pivotal areas for future research., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Renal cell carcinoma (RCC) is the most common type of kidney cancer arising from renal tubular epithelial cells and is characterized by a high aggressive behavior and invasiveness that lead to poor prognosis and high mortality rate. Diagnosis of RCC is generally incidental and occurs when the stage is advanced and the disease is already metastatic. The management of RCC is further complicated by an intrinsic resistance of this malignancy to chemotherapy and radiotherapy, which aggravates the prognosis. For these reasons, there is intense research focused on identifying novel biomarkers which may be useful for a better prognostic assessment, as well as molecular markers which could be utilized for targeted therapy. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that has been identified as a key modulator of oxidative stress response, and its overexpression is considered a negative prognostic feature in several types of cancers including RCC, since it is involved in various key cancer-promoting functions such as proliferation, anabolic metabolism and resistance to chemotherapy. Given the key role of Nrf2 in promoting tumor progression, this enzyme could be a promising biomarker for a more accurate prediction of RCC course and it can also represent a valuable therapeutic target. In this review, we provide a comprehensive literature analysis of studies that have explored the role of Nrf2 in RCC, underlining the possible implications for targeted therapy.

Background: Chimeric antigen receptor (CAR) T cells have demonstrated remarkable breakthroughs in treating hematologic malignancies, yet their efficacy in solid tumors is limited by the immunosuppressive microenvironment. Sympathetic nerves significantly contribute to this immunosuppressive milieu in solid tumors. However, the impact of tumor sympathetic denervation on enhancing CAR T-cell antitumor efficacy remains unclear., Methods: We screened for sympathetic gene sets in various types of cancers and investigated the association of sympathetic nerves with immunosuppression in renal clear cell carcinoma. Using antibodies to block the nerve growth factor (NGF) pathway, we explored sympathetic nerve distribution in tumor tissues and tumor progression. Additionally, we engineered CAR T cells to secrete NGF single chain fragment variable (scFv) to achieve tumor immunosympathectomy and assessed their antitumor efficacy. Bulk RNA sequencing and single-cell RNA sequencing analyses were conducted to evaluate changes in immune cell phenotypes within the tumor microenvironment., Results: Blocking the NGF pathway with antibodies effectively reduced sympathetic nerve distribution in tumor tissues and delayed tumor progression. CAR T cells engineered to secrete NGF scFv achieved a similar tumor immunosympathectomy and exhibited enhanced tumor suppression. RNA sequencing analyses revealed that this augmented effect was primarily due to the inhibition of the terminal exhaustion phenotype in tumor-infiltrating CD8 T cells and the prevention of macrophage polarization from M1 to M2. This approach maintained a stronger antitumor immune state at the tumor site. Additionally, splenic T cells also exhibited a more potent immune effector phenotype following the infusion of NGF scFv-secreting CAR T cells., Conclusions: Our results suggest that immunosympathectomy is a novel approach to weaken tumor microenvironment immunosuppression and synergistically enhance CAR T-cell efficacy against solid tumors., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Clear cell renal cell carcinoma (ccRCC) represents a prevalent malignancy of the urinary system. Despite the integration of immune checkpoint inhibitors (ICIs) into the treatment paradigm for advanced RCC, resistance to immunotherapy has emerged as a pivotal determinant impacting the clinical outlook of ccRCC. Accumulating evidence underscores the pivotal role of immune evasion-related genes and pathways in enabling tumor escape from host immune surveillance, consequently influencing patients' responsiveness to immunotherapy. Nonetheless, the clinical relevance of immune evasion-related genes in ccRCC patients undergoing immunotherapy remains inadequately understood. In this study, we aggregated RNA sequencing and clinical data from ccRCC patients across three cohorts: the Cancer Genome Atlas (TCGA), CheckMate cohorts, and the JAVELIN Renal 101 trial. Leveraging a curated immune evasion-related gene set from Lawson et al., we employed the LASSO algorithm and Cox regression analysis to identify eight genes (LPAR6, RGS5, NFYC, PCDH17, CENPW, CNOT8, FOXO3, SNRPB) significantly associated with immune therapy prognosis (HR, 3.57; 95 % CI, 2.38-5.35; P<0.001). A predictive algorithm developed utilizing these genes exhibited notable accuracy in forecasting patients' progression-free survival in the training set (AUC, 0.835). Furthermore, stratification of patients by risk score revealed discernible differences in immunotherapy response and tumor microenvironment. In summary, we present a prognostic model intricately linked with immune status and treatment response. For ccRCC patients undergoing immunotherapy, this approach holds promise in aiding clinical decision-making by providing more precise and tailored treatment recommendations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Vaccines targeting immune checkpoints represent a promising immunotherapeutic approach for solid tumors. However, the therapeutic efficacy of dual targeting immune checkpoints is still unclear in renal carcinoma., Methods: An adenovirus (Ad) vaccine targeting B7H1 and B7H3 was developed and evaluated for its therapeutic efficacy in subcutaneous, lung metastasis or orthotopic renal carcinoma mouse and humanized models using flow cytometry, Enzyme-linked immunosorbent spot (ELISPOT), cytotoxic T lymphocyte (CTL) killing, cell deletion, hematoxylin and eosin (HE) staining, and immunohistochemistry (IHC) assays., Results: The Ad-B7H1/B7H3 immunization effectively inhibited tumor growth and increased the induction and percentages of CD8 + T cells in subcutaneous tumor models. The vaccine enhanced the induction and maturation of CD11c + or CD8 + CD11c + cells, promoting tumor-specific CD8 + T cell immune responses. This was evidenced by increased proliferation of CD8 + T cells and enhanced CTL killing activity. Deletion of CD8 + T cells in vivo abolished the anti-tumor effect of the Ad-B7H1/B7H3 vaccine, highlighting the pivotal role of functional CD8 + T cell immune responses. Moreover, significant therapeutic efficacy of the Ad-B7H1/B7H3 vaccine was observed in lung metastasis, orthotopic, and humanized tumor models through multifunctional CD8 + T cell immune responses., Conclusions: The Ad vaccine targeting dual immune checkpoints B7H1 and B7H3 exerts a potent therapeutic effect for renal carcinoma and holds promise for solid tumor treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To evaluate the postoperative complications and prognosis of renal cell carcinoma (RCC) in a solitary kidney after irreversible electroporation (IRE)., Materials and Methods: A total of 8 patients with 9 RCCs in a solitary kidney treated with computed tomography (CT)-guided IRE from February 2017 to September 2020 were retrospectively analyzed. Follow-up included contrast-enhanced CT or magnetic resonance imaging examinations at 1 day, 1 week, 1 month, 3 months, 6 months, 12 months, and each year after IRE and the evaluation of the incidence of postoperative complications, renal function changes, local tumor recurrence, and metastasis., Results: Technical success was achieved in all 8 patients treated with IRE. No serious complications were observed. Recurrence or metastasis occurred in two patients. The renal function and hemoglobin values of the 8 patients before treatment and at the last follow-up showed no significant difference., Conclusion: IRE is a relatively effective, safe, and feasible treatment for RCCs in a solitary kidney, which improved the effective survival and quality of life of these patients., (Copyright © 2025 Journal of Cancer Research and Therapeutics.)

B7-H3 is a type I transmembrane protein that belongs to the B7 immune checkpoint protein family, is aberrantly expressed in cancer cells, but rarely expressed in normal tissues, making it an attractive target for cancer therapy. Here, we found B7-H3 is highly expressed in the renal cell carcinoma (RCC) tumor tissues and RCC cell lines, but is undetectable in normal renal tissues. Therefore, we engineered second-generation CAR-T cells targeting B7-H3, incorporating either CD28 or 4-1BB co-stimulatory domains. Both CAR-T cell variants demonstrated potent antitumor activity against RCC tumors in vitro and in metastatic and orthotopic RCC mouse models. Furthermore, the B7-H3 CAR-T cells exhibited remarkable proliferation and robust cytokine release when co-cultured with RCC cancer cells. These findings demonstrated that targeting B7-H3 by CAR-T cells potentially offering a new treatment option for RCC patients., Competing Interests: Declaration of Competing Interest GD and HD filed a patent for the CAR targeting B7-H3, the patent number is US10519214, and title is METHODS AND COMPOSITIONS FOR CHIMERIC ANTIGEN RECEPTOR TARGETING CANCER CELLS. No potential conflicts of interest were disclosed by the other authors., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The detection of solid renal masses has increased over time due to incidental findings during imaging studies conducted for unrelated medical conditions. Approximately 20% of lesions measuring less than 4 cm are benign and 80% are malignant. Clear cell renal cell carcinoma (ccRCC) is the most frequent among renal carcinomas, responsible for 65-80% of cases. The increased detection of renal masses facilitates early diagnosis and treatment. However, it also leads to more invasive interventions, which result in higher morbidity and costs. Currently, only histological analysis can offer an accurate diagnosis. Surgical nephron loss significantly elevates morbidity and mortality rates. Active surveillance represents a conservative management approach for patients diagnosed with a solid renal mass that is endorsed by both American Urological Association and the European Society for Medical Oncology. However, active surveillance is used in a minority of patients and varies across institutions. The lack of clinical studies using a standardized approach to incidentally detected small renal masses precludes the widespread use of active surveillance. Hence, there is an urgent need for better patient selection, distinguishing those who require surgery from those suitable for active surveillance. The clear cell likelihood score (ccLS) represents a novel MRI tool for assessing the probability of a renal mass being a ccRCC. In this study, we present a comprehensive review of renal masses and their evaluation using the ccLS to facilitate shared decision between urologists and patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The effectiveness of the clinical outcome of CN (Cytoreductive Nephrectomy) in cases of mccRCC (Metastatic Clear Cell Renal cell Carcinoma) is still uncertain despite two trials, SURTIME and CARMENA. These trials, conducted with Sunitinib as the standard treatment, did not provide evidence supporting the use of CN., Methods: We queried the NCDB for stage IV mccRCC patients between the years of 2004 to 2020, who received (immunotherapy) IO with or without nephrectomy. Overall survival (OS) was calculated among three groups of IO alone, IO followed by CN (IOCN), CN followed by IO (CNIO). Cox models compared OS by treatment group after adjusting for sociodemographic, health, and facility variables., Results: From 1,549,101 renal cancer cases, 7983 clear and nonclear cell renal cell carcinoma cases were identified. After adjusting for sociodemographic and health covariates, patients who received IO followed by CN or CN followed by IO had a respective 64% (adjusted Hazard Ratio [aHR] = 0.36, 95% CI = 0.30-0.43, P = .006] and 47% (aHR = 0.53, 95% CI = 0.49-0.56, P = .001) mortality risk reduction respectively compared to patients who received IO alone. Compared to White adults, individuals who identified as Black exhibited 17% higher risk mortality (aHR = 1.17, 95% CI = 1.06-1.30, P = .002). Patients who received CN prior to IO had a 59% associated mortality risk compared to patients who received IO followed by CN who had a lower risk, 35.7% (P < .001)., Conclusions: Patients receiving CN regardless of sequence with IO did better than IO alone in this national registry-based adjusted analysis for mccRCC. Presently available data indicates that the combination of CN and IO holds promise for enhancing clinical results in patients with mRCC., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sunitinib is a first-line treatment for renal cell carcinoma (RCC), but suffers from drug resistance, causing therapy failure. Therefore, nano-scale delivery systems should be introduced for targeted delivery. Metal-organic frameworks (MOFs) are attractive drug carriers that not only enable multidrug combination therapies but also exert photodynamic effects by incorporating photosensitizers as components. Here, a Zr-based porphyrinic nanoscale MOF, PCN-224, was prepared as the carrier for the co-delivery of sunitinib and the siRNA against vascular endothelial growth factor receptor-2 (VEGFR-2). Drug-loaded PCN-224 is coated with hyaluronic acid (HA) to prevent drug molecular leakage and to exert tumor-targeting effects (CD44 in tumor cells). Photodynamic therapy was conducted under 660 nm laser (50 mW·cm -2 , 10 min) irradiation. Compared with St/siVEGFR-2@PCN-224@HA without the HA coating, St/siVEGFR-2@PCN-224@HA significantly suppressed cell viability and promoted cell apoptosis. Laser irradiation further increased the anti-cancer effect of St/siVEGFR-2@PCN-224@HA by generating cytotoxic ROS. H&E staining of major organs revealed no signs of damage, indicating the biosafety of St/siVEGFR-2@PCN-224@HA. The prepared St/siVEGFR-2@PCN-224@HA system enables triple inhibition of tumor growth via a combination of targeted therapy and genetic and photodynamic therapy to enhance the therapeutic effects on RCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: This project aims to shed light on how various treatment approaches affect RCC patients' chances of survival and create a prediction model for them., Methods: Data from the Surveillance, Epidemiology, and End Results database were used in this investigation. OS and RCSS after radiation, chemotherapy, and surgery were investigated using the Kaplan-Meier approach. Fourteen factors, including gender, age, race, and others, were subjected to univariate and multivariate COX analyses. Predicting RCSS at three, five, or ten years is the main goal. Predicting OS at three, five, or ten years is the secondary endpoint. Cox analyses, both univariate and multivariate, were used to identify prognostic factors. Furthermore, a nomogram was developed to precisely forecast patient survival rates at 3-, 5-, and 10-year intervals. DCA, calibration curves, and ROC were used to assess the nomogram's efficacy., Results: Kaplan-Meier analysis revealed that PN was associated with better survival compared to RN for tumors ≤10 cm. Cox analysis identified 10 independent prognostic factors. These variables included gender, age, race, histological type, histological grade, AJCC stage, N stage, T stage, M stage, and surgical type. Based on these variables, a nomogram for OS and RCSS prediction was created., Conclusion: PN is advised over RN for RCC patients whose tumors are less than 10 cm in diameter since it offers more advantages. The combined nomogram model, which is based on clinicopathological characteristics, therapy data, and demographic variables, may be used to predict the survival of RCC patients and perform prognostic and survival analysis with accuracy.

Background: Bilateral synchronous renal masses (BSRMs) are a rare finding, and the optimal treatment strategy remains undetermined. This study depicts the management of BSRM at eight European high-volume centers., Methods: This is a retrospective analysis of prospective institutional databases collecting all patients presenting with clinical T1-2 N0 M0 BSRMs between 1993 and 2020 at 8 tertiary referral high-volume centers for renal cancer treatment in Europe. The treatment options included active surveillance (AS), tumor ablation (TA) and surgery (partial and radical nephrectomy)., Results: Overall, 134 patients were analyzed. Renal mass biopsy prior treatment was performed in 8% of cases. 15%, 4%, and 81% of patients underwent AS, a combination of surgery and TA, and bilateral (one-stage or two-stage) surgery. Among patients undergoing bilateral surgery (N.=109), a staged approach was chosen in 78% (N.=85) of cases treating the lower complexity tumor first in 51/85 (60%) cases and in 34/85 (40%) treating the higher complexity tumor first. Concordance of the histological analysis was found in 77% of patients with 10% of bilateral benign masses., Conclusions: Even if considering only referral centers, a high heterogeneity for decision-making in the treatment of BSRM should be expected. Advances in genetic diagnosis, the implementation of novel imaging technologies, and the strengthening role of alternative treatment, may lead to a standardized decision-making process in the setting of BSRMs.

Patients with brain metastases (BrM) from renal cell carcinoma and their outcomes are not well characterized owing to frequent exclusion of this population from clinical trials. We analyzed data for patients with or without BrM using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). A total of 389/4799 patients (8.1%) had BrM on initiation of systemic therapy. First-line immuno-oncology (IO)-based combination therapy was associated with longer median overall survival (OS; 32.7 mo, 95% confidence interval [CI] 22.3-not reached) versus tyrosine kinase inhibitor monotherapy (20.6 mo, 95% CI 15.7-24.5; p = 0.019), as were intensive focal therapies with stereotactic radiotherapy or neurosurgery (31.4 mo, 95% CI 22.3-37.5) versus whole-brain radiotherapy alone or no focal therapy (16.5 mo, 95% CI 10.2-21.1; p = 0.028). On multivariable analysis, IO-based regimens (HR 0.49, 95% CI 0.25-0.97; p = 0.040) and stereotactic radiotherapy or neurosurgery (HR 0.48, 95% CI 0.29-0.78; p = 0.003) were independently associated with longer OS, as was IMDC favorable or intermediate risk (HR 0.40, 95% CI 0.24-0.66; p < 0.001). Intensive systemic and focal therapies were associated with better prognosis in this population. Further studies should explore the clinical effectiveness of multimodal strategies. PATIENT SUMMARY: In a large group of patients with advanced kidney cancer, we found that 8.1% had brain metastases when starting systemic therapy. Patients with brain metastases had significantly poorer prognosis than those without brain metastases. Receipt of combination immunotherapy, stereotactic radiotherapy, or neurosurgery was associated with longer overall survival., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Birt-Hogg-Dubé syndrome (BHD syndrome) is an autosomal dominant multisystem disorder with variable expression due to pathogenic constitutional variants in the FLCN gene. Patients with BHD syndrome are predisposed to benign cutaneous fibrofolliculomas/trichodischomas, pulmonary cysts with an associated risk of spontaneous pneumothorax, and renal cell carcinoma. A requirement for updated International consensus recommendations for the diagnosis and management of BHD syndrome was identified. Based on a comprehensive literature review and expert consensus within the fields of respiratory medicine, urology, radiology, dermatology, clinical oncology and clinical genetics, updated recommendations for diagnosis, surveillance and management in BHD syndrome were developed. With the widespread availability of FLCN genetic testing, clinical scenarios in which a diagnosis should be considered and criteria for genetic testing were defined. Following a clinical and/or molecular diagnosis of BHD syndrome, a multidisciplinary approach to disease management is required. Regular renal cancer surveillance is recommended in adulthood and life-long, but the evidence base for additional tumour surveillance is limited and further research warranted. Recommendations for the treatment of cutaneous, pulmonary and renal manifestations are provided. Awareness of BHD syndrome needs to be raised and better knowledge of the clinical settings in which the diagnosis should be considered should enable earlier diagnosis. Further details, including areas for future research topics are available at: https://www.genturis.eu/l=eng/Guidelines-and-pathways/Clinical-practice-guidelines.html ., Competing Interests: Competing interests: All members of the ERN GENTURIS BHD Guideline Group, including the Core Working Group, have provided disclosure statements on all relationships that they have that might be perceived to be a potential source of a conflict of interest. Core Working Group patient representatives KN and JH were employed by the Myrovlytis Trust. MGM reports receipt of honoraria or consultation fees from Ipsen. CMC reports receipt of research funding from Boehringer Ingelheim, honoraria or consultation fees from Savara Inc, Theravance, AI Therapeutics, Roche, Aerogen as well as grants from Health Research Board, LAM Foundation and Enterprise Ireland. NR reports participation in a company sponsored speaker’s bureau from Takeda UK. MTAW reports receipt of honoraria or consultation fees from Microsoft. All participants of the ERN GENTURIS BHD syndrome Delphi survey have provided disclosure statements on all relationships that they have that might be perceived to be a potential source of competing interests. Patrick Benusiglio reports receipt of honoraria or consultation fees from AstraZeneca, Bristol Myers Squibb and Merck Sharp & Dohme. Raphael Borie reports receipt of grants/research support from Roche and Boehringer Ingelheim, as well as receipt of honoraria or consultation fees from Roche, Boehringer Ingelheim and Sanofi. Jesper Rømhild Davidsen reports receipt of honoraria or consultation fees from Boehringer Ingelheim. Arndt Hartmann reports receipt of grants/research support from AstraZeneca, Biocartis, Biontech, Cepheid, Gilead, Illumina, Janssen, Nanostring, Novartis, Owkin, Qiagen, QUIP GmbH, Roche and Sanofi, as well as receipt of honoraria or consultation fees from Abbvie, AstraZeneca, Biocartis, Biontech, BMS, Boehringer Ingelheim, Cepheid, Diaceutics, Gilead, Illumina, Ipsen, Janssen, Lilly, MSD, Nanostring, Novartis, Qiagen, QUIP GmbH, Roche, Sanofi and 3DHistotech. Arjan C. Houweling reports receipt of a research grant from the Myrovlytis Trust. Stefan J. Marciniak reports receipt of grants/research support from the Myrovlytis Trust, Asthma+Lung UK, Alpha 1 Foundation, the Medical Research Council (MRC) UK, and the Engineering and Physical Sciences Research Council (EPSRC). Maria Molina-Molina reports receipt of grants/research support from Boehringer Ingelheim and Roche, as well as receipt of honoraria or consultation fees from Ferrer, Chiesi, Boehringer Ingelheim, Roche and Esteve-Teijin. Charles Van Praet reports receipt of honoraria or consultation fees from Astellas, IPSEN and Baxter. Robin de Putter reports receipt of honoraria or consultation fees from AstraZeneca. Lore van Riel reports receipt of a research grant from the Myrovlytis Trust. Jacobo Sellarés Torres reports receipt of grants/research support from Roche and Boehringer Ingelheim, receipt of honoraria or consultation fees from Boehringer Ingelheim, as well as participation in a speaker’s bureau sponsored by Boehringer Ingelheim. Grant D. Stewart reports receipt of grants/research support from AstraZeneca and Pfizer, receipt of honoraria or consultation fees from Pfizer, Merck, EUSA Pharma and Eisai, as well as participation in a speaker’s bureau sponsored by Eisai., (© 2024. The Author(s).)

Immune checkpoint blockers (ICBs) therapy stands as the first-line treatment option for advanced renal cell carcinoma (RCC). However, its effectiveness is hindered by the immunosuppressive tumor microenvironment (TME). Sonodynamic therapy (SDT) generates tumor cell fragments that can prime the host's antitumor immunity. Nevertheless, the hypoxic microenvironment and upregulated autophagy following SDT often lead to cancer cell resistance. In response to these challenges, a hypoxia-responsive polymer (Poly(4,4'-azobisbenzenemethanol-PMDA)-mPEG 5k , P-APm) encapsulating both a HIF-2α inhibitor (belzutifan) and the ultrasonic sensitize (Chlorin e6, Ce6) is designed, to create the nanoparticle APm/Ce6/HIF. APm/Ce6/HIF combined with ultrasound (US) significantly suppresses tumor growth and activates antitumor immunity in vivo. Moreover, this treatment effectively transforms the immunosuppressive microenvironment from "immune-cold" to "immune-hot", thereby enhancing the response to ICBs therapy. The findings indicate that APm/Ce6/HIF offers a synergistic approach combining targeted therapy with immunotherapy, providing new possibilities for treating RCC., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Purpose of Review: This review addresses the evolving role of metastasis-directed therapy (MDT) in the management of oligometastatic and oligoprogressive renal cell carcinoma (RCC). With advances in both surgical techniques and stereotactic ablative radiotherapy (SABR), it is timely to explore how MDT can improve patient outcomes in these distinct disease states. The review highlights the potential of MDT to delay systemic therapy and improve quality of life while noting the lack of randomized clinical trial data guiding its use., Recent Findings: Recent literature emphasizes the outcomes of MDT, including metastasectomy and SABR, in managing oligometastatic and oligoprogressive RCC. Key studies suggest that MDT may prolong progression-free survival and delay systemic therapy. SABR has demonstrated high local control rates and manageable toxicity, offering a less invasive alternative to surgery. Despite these findings, there remains uncertainty about MDT's long-term impact on overall survival due to the absence of prospective randomized trials., Summary: MDT holds promise in treating RCC by offering symptom relief, improving quality of life, and potentially delaying systemic therapy. However, the long-term benefits, particularly regarding survival outcomes, remain unclear. Further research, including prospective trials, is needed to better define the role of MDT in clinical practice, particularly in the absence of clear guidelines for patient selection., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Despite demonstrating promising outcomes in treating hematologic malignancies, the efficacy of chimeric antigen receptor-modified T (CAR-T) cell therapy remains limited when applied to solid tumors due to tumor immune microenvironment (TIME). Strategies to augment CAR-T cell efficacy against solid tumors have been investigated by ameliorating TIME to a certain extent. In this study, Cabozantinib was utilized in combination with CAR-T cells targeting carbonic anhydrase IX (CAIX) for the treatment of renal cancer. Our findings indicate that combination therapy with CAIX-CAR-T and Cabozantinib demonstrated synergistic efficacy against an orthotopic xenograft tumor model and a subcutaneous tumor model of renal cell carcinoma in mice. Mechanistically, it was observed that CAR-T cells combined with Cabozantinib led to an increase in the infiltration of tumor-infiltrating T cells, while reducing tumor-associated macrophages and M2 polarization. Additionally, Cabozantinib blocked the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis by decreasing the expression of PD-L1 in tumor cells and PD-1 in T cells. Furthermore, Cabozantinib promoted CAR-T cell effector function and reduced T cell exhaustion. This combination therapy represents a novel approach to enhancing CAR-T cell efficacy against solid tumors and holds significant promise for advancing CAR-T cell therapy in clinical settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/objectives: Our aim was to compare the complication rates of different embolization materials (absolute ethanol and gelatin sponges) used for combined transarterial embolization (TAE) and to investigate the impact of tumor size on operative time and cryoneedle use during percutaneous cryoablation (PCA)., Methods: We treated 27 patients (9 women and 18 men; mean age, 74 years) with 28 early-stage (T1a) renal cell carcinoma (RCC) lesions using combined TAE and PCA between September 2018 and January 2021. During TAE, 15 lesions in 14 patients were embolized using mixed absolute ethanol and iodized oil. The remaining 13 lesions (in 13 patients) were embolized using a gelatin sponge followed by iodized oil. The PCA was performed within 3 to 21 days of the TAE. We compared complications between the TAE subgroups (i.e., absolute ethanol and gelatin sponge) and assessed potential correlations between tumor size and the operative time of the PCA., Results: All patients were successfully treated by combined TAE-PCA. Local control was achieved for all patients (monitoring period, 1-48 months; median, 28 months). Although the effect of TAE did not differ between subgroups, a significantly higher number of patients in the absolute ethanol group experienced intraprocedural pain than in the gelatin sponge group ( p < 0.05). The operative time of the PCA was significantly correlated with the size of the RCC lesion ( p < 0.01). The number of cryoneedles used for the PCA was also correlated with the size of the RCC lesion ( p < 0.0001)., Conclusions: For TAE prior to PCA for early-stage RCC, gelatin sponges can replace absolute ethanol to reduce intraprocedural pain. Tumor size correlates with operative time and the number of cryoneedles needed for PCA, which suggests the total medical cost for PCA therefore varies based on the tumor's size.

The tumour immunological microenvironment is involved in the development of clear cell renal cell carcinoma (ccRCC). Nevertheless, the role of the immunological microenvironment in ccRCC has not been thoroughly investigated. In this study, we combined six ccRCC cohorts into a large cohort and quantified the expression matrix into 53 immunological terms using the ssGSEA algorithm. Five immune terms related to prognosis were screened through 1000 iterations of L1-penalised (lasso) estimation and Cox regression analysis for immune-related risk score (IRS) calculation. The IRS showed satisfactory prognosis prediction efficacy in ccRCC. We then compared the clinical and genomic characteristics of two IRS subgroups. Patients with low IRS showed a high level of tumour mutational burden (TMB) and a low level of copy number variation (CNV), indicating that low IRS group patients have a higher probability of responding to immunotherapy. We employed TIDE and subclass mapping analyses to corroborate our results, and the findings demonstrated that patients with a low IRS had a significantly greater percentage of immunotherapy response. According to the Genomics of Drug Sensitivity in Cancer (GDSC), patients with a high IRS had a decreased IC50 for sunitinib, which is the first-line treatment for ccRCC patients. As a result, the immune characteristics of the microenvironment of ccRCC tumours have been explored, and a signature has been constructed. Analysis demonstrated that our signature could effectively predict prognosis and immunotherapy response rate., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Introduction: Systemic treatment options for renal cell carcinoma (RCC) have expanded considerably in recent years, and both tyrosine kinase inhibitors and immune checkpoint inhibitors, alone or in combination, have entered the clinical arena. Adoptive cell immunotherapies have recently revolutionized the treatment of cancer and hold the promise to further advance the treatment of RCC., Areas Covered: In this review, we summarize the latest preclinical and clinical development in the field of adoptive cell immunotherapy for the treatment of RCC, focusing on lymphokine-activated killer (LAK) cells, cytokine-induced killer (CIK) cells, tumor-infiltrating T cells (TILs), TCR-engineered T cells, chimeric antigen receptor (CAR) T cells, and dendritic cell vaccination strategies. Perspectives on emerging cellular products including CAR NK cells, CAR macrophages, as well as γδ T cells are also included., Expert Opinion: So far, areas of greater therapeutic success of adoptive cell therapies include the adjuvant administration of CIK cells and the transfer of anti-CD70 CAR T cells in patients with metastatic RCC. Bench to bedside and back research will be needed to overcome current limitations of adoptive cell therapies in RCC, primarily aiming at improving the safety of immune cell products, optimizing their antitumor activity and generating off-the-shelf products ready for clinical use.

Herein, a ccRCC targeting nanodrug is designed to enhance chemodynamic therapy (CDT) as well as activate cuproptosis and tumor immunotherapy via ccRCC cell membrane modifying CuO@Gd 2 O 3 yolk-like particles (CGYL) loaded with lactate oxidase (LOx) (mCGYL-LOx). Benefiting from the homologous targeting effect of Renca cell membranes, the mCGYS-LOx can be effectively internalized by Renca cells, open the "gate", and then release LOx and copper (Cu) ions. LOx can catalyze excessive lactate in Renca cells into H 2 O 2 , following that the produced H 2 O 2 is further converted by Cu ions to the highly toxic ·OH, contributing to tumor CDT. Meanwhile, the excessive Cu ions effectively trigger tumor cuproptosis. These synergistic effects induce the release of damage associated molecular patterns (DAMPs) and activate immunogenic cell death (ICD), leading to DC maturation and infiltration of immune effector cells. Moreover, LOx-mediated lactate consumption downregulates the expression of PD-L1, crippling tumor immune escape. In addition, the mCGYL-LOx improves T 1 -weighted MRI signal, allowing for accurate diagnosis of ccRCC. This study demonstrates that the mCGYL-LOx has great potential for improving therapy of ccRCC via the synergistic actions of CDT and cuproptosis as well as immunotherapy., (© 2024 Wiley‐VCH GmbH.)

Autologous therapeutic tumor-infiltrating lymphocyte (TIL) therapy is a promising strategy to enhance antitumor immunity. Optimization of ex vivo TIL expansion could expand current immunotherapy options. Previous attempts to generate TIL in renal cell carcinoma (RCC) have been technically challenging. We applied a second-generation manufacturing process, currently used to generate the melanoma TIL product lifileucel, in RCC. Resected primary and metastatic RCC samples were processed using the Gen 2 manufacturing process comprising of pre-Rapid Expansion Protocol (pre-REP) and REP steps. We assessed REP TILs for viability and performed phenotypic and functional characterization. We correlated the tumor immune microenvironment (TIME) with successful TIL expansion. Eight of 11 RCC samples underwent successful REP. Three failed cases demonstrated low CD8/FoxP3 ratio and high expression of PD-1 within FoxP3 cells. Expression of exhaustion markers differed between the TIME and expanded TILs; the latter had a TIM3-high/PD-1-low phenotype but retained functional capacity comparable to lifileucel. The Gen 2 manufacturing process used for lifileucel successfully expanded functional TILs from RCC samples, enabling further study in a clinical trial. TIME features such as low CD8/FoxP3 ratio and high PD-1 expression within FoxP3 cells warrant study as potential biomarkers of successful TIL expansion., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Immunotherapy (IO) drugs have been increasingly utilized in locally advanced or metastatic clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma of the bladder (UC). Multiple trials have demonstrated clear survival benefit, however, there are often barriers to access for these advanced therapies which has been demonstrated in other non-urologic malignancies. The goal of this study was to assess socioeconomic and demographic factors associated with the receipt of IO for advanced ccRCC and UC., Materials and Methods: We queried the National Cancer Database (NCDB) for patients with stage IV ccRCC and UC. The study period was 2015 to 2020 for ccRCC (FDA approval date of IO) and 2017 to 2020 for UC (FDA approval date of broadened indication for IO, initial limited approval in 2016). The primary outcome of interest was receipt of IO therapy using multivariable logistic regression, adjusting for relevant socioeconomic and demographic variables., Results: We identified 15,926 patients with stage IV ccRCC and 10,380 patients with stage IV UC of which 5,419 (34.0%) and 2,231 (21.5%) received IO therapy, respectively. IO utilization increased with each successive year. In both malignancies, treatment at a non-academic facility, education level, income, and insurance were independently associated with IO utilization. For ccRCC, black (OR = 0.77, 95% CI, 0.64-0.93, P = 0.009) and Hispanic race (OR = 0.73, 95% CI, 0.61-0.86, P = 0.006) were each associated with decreased IO utilization but there were no independent associations between race and receipt of IO in patients with UC., Conclusions: In the era of FDA-approved IO therapy for advanced ccRCC and UC, this national cohort analysis suggests that IO utilization is increasing over time, but significant disparities exist based on income, education, and insurance status in both malignancies. Additionally, patients treated at non-academic facilities were less likely to receive IO therapy for these specific genitourinary malignancies. In ccRCC, additional disparities were seen black and Hispanic races which each were associated with lower odds of IO receipt. Identifying strategies to mitigate these differences and provide equitable access to IO therapy is of imperative need., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Over the past decade, the realm of immunotherapy-based combination therapy has witnessed rapid growth for renal cell carcinoma (RCC), however, success has been constrained thus far. This limitation primarily stems from the absence of biomarkers essential for identifying patients likely to derive benefits from such treatments., Methods: In this study, the immunotherapy-based combination associated score (IBCS) was established using single-sample gene set enrichment analysis (ssGSEA) based on the genes identified in the key modules extracted by weighted correlation network analysis (WGCNA) in the IMmotion151 dataset, a randomized, global phase III trial., Results: High IBCS patients showed better responses to immunotherapy-based combinations and had longer progression-free survival (PFS). Further transcriptomic analysis revealed that IBCS was negatively correlated to TIDE score, identifying a subset of RCC patients characterized by enrichment of T-effector and moderate cell-cycle/angiogenesis gene expression. Our analysis of hub genes unveiled a novel molecule that could potentially serve as a target antigen in RCC. Validation through multiplex immunofluorescence assays on tissue microarrays (TMAs) containing 180 samples confirmed the pivotal role of this hub gene in immunoregulation. Furthermore, we developed an independent risk score model, which is significant for prognostic evaluation and patient stratification. Notably, we devised a forecasting nomogram using this risk score model, surpassing the IMDC score (a widely accepted risk score for predicting survival in patients undergoing VEGF-targeted therapy) in prognostic accuracy for patients treated with immunotherapy-based combinations., Conclusion: This study has collectively developed an immunotherapy-based combination associated score, pinpointed effective biomarkers for prognostic and responsiveness of kidney cancer patients to immunotherapy-based combinations, and delved into their potential biological mechanisms, offering promising targets for further exploration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Patients with metastatic renal cell carcinoma (mRCC) face complex treatment decisions and frequently turn to the Internet for treatment information. The content of patient educational websites about mRCC treatment has not been evaluated. This study evaluated the accuracy, readability, and quality of websites about the treatment of mRCC., Methods: A total of 2,700 Internet queries were performed. Across 3 Internet search engines, 25 links of 36 permutations of mRCC keywords and their synonyms were screened for eligibility. Eligible websites were English-language websites containing information about mRCC treatments. Sponsored, social media, provider-facing, and news websites were excluded. Accuracy of eligible websites was evaluated in 2 domains: (1) Completeness by calculating the percentage of mRCC facts included in websites using an investigator-created checklist based on the NCI's RCC Treatment (PDQ®)-patient version, and (2) Correctness by identifying incorrect statements that were inconsistent with guidelines. Websites containing ≥60% of checklist items had a "passing" completeness score. Incorrect statements were tallied and qualitatively categorized. Readability was evaluated using the Fry and SMOG formulae, which calculate reading grade levels. Quality was evaluated using validated instruments that appraise health information quality: QUEST (scored 0-28), which focuses on online information, and DISCERN (scored 16-80), which focuses on treatment choices., Results: Thirty-nine websites were analyzed. Mean completeness score was 30% (range 0%-69%); only 2 (5%) websites had a passing score. Twelve (31%) websites had ≥1 incorrect statement, such as listing homeopathy or hormone therapy as mRCC treatment options, or including outdated statements. Mean readability levels were 11th and 12th grades for the Fry and SMOG methods, respectively. No website had a reading level lower than 9th grade. Mean QUEST score was 19 (range 9-28); authorship, complementarity, and currency items had the lowest scores. Mean DISCERN score was 56 (range 42-76), with 7 (18%) websites rated "excellent", 22 (56%) rated "good", and 10 (26%) rated fair., Conclusions: Many websites about mRCC treatment have incomplete, inaccurate, and unreadable information. Quality is highly variable. Efforts to improve accuracy, readability, and quality are needed to ensure that patients with mRCC can make well-informed treatment decisions and avoid harm from misinformation., Competing Interests: Declaration of competing interest The authors have no competing financial interests to report in relation to the work described., (Published by Elsevier Inc.)

Increasing evidence highlights the important role of ubiquitination in cancer. The objective of our study is to establish a reliable marker for predicting clinical outcomes and treatment responses in patients with clear cell renal cell carcinoma (ccRCC) using genes related to ubiquitination (URGs). The URGs subtypes were identified using consensus clustering based on TCGA-KIRC, and a signature containing the prognostic differentially expressed genes of the subtypes was determined using LASSO and Cox regression analysis. To demonstrate the strength of the signature, verification analyses were performed on both E-MTAB-1980 and TCGA-KIRC test datasets. We developed a nomogram to enhance the effectiveness of our predictive tool. Risk genes expression was determined through RT-qPCR. Six genes were combined to create the URGs signature, which had a highly correlated with patient prognosis in patients with ccRCC. A nomogram was developed based on the URGs signature and clinicopathological characteristics. We found that the predictive power was substantially greater than the other individual predictors. Moreover, the study on the immune microenvironment revealed significant variations in the levels of immune cells and the expression of immune checkpoint genes among the groups categorized as high-risk and low-risk. Furthermore, it was found that immunotherapy yielded better outcomes in cohorts with low risk. The URGs signature might serve as a novel and powerful prognosis biomarker and offer a momentous reference for individualized treatment for patients in ccRCC., (© 2024. The Author(s).)

Background: von Hippel-Lindau ( VHL ) harbors the highest mutational frequency in clear cell renal cell carcinoma (ccRCC). Although VHL mutational subtypes exert diverse impacts on the functionality of the VHL protein, the clinical significance of VHL mutational heterogeneity remains largely obscure., Methods: This study included a total of 1331 patients with ccRCC from localized data sets, including our localized Zhongshan Hospital (ZSHS) cohort (n=1270) and Zhongshan immune checkpoint blockade cohort (n=61), as well as 525 patients with ccRCC from two publicly available data sets with matched clinical annotation and multidimensional data. According to the putative biological effect, we subclassified VHL mutation into VHL Trunc and VHL Miss . The association of VHL status with clinical outcomes, genomic, oncogenic and immunologic characteristics was further depicted., Results: VHL Miss ccRCC was associated with reduced survival in the localized ZSHS and The Cancer Genome Atlas cohorts. Clinical benefit from immunotherapy was observed in VHL Miss patients in all immunotherapy cohorts. VHL Miss ccRCC exhibited hyper-activated cell cycle and nuclear factor kappa B (NF-κB) instead of canonical hypoxia inducible factor pathways, which might contribute to its proliferative morphology. Meanwhile, VHL Miss ccRCC featured an inflamed microenvironment with enriched tertiary lymphoid structures., Conclusions: VHL Miss mutations delineate an aggressive ccRCC subtype with distinct clinical outcomes, likely attributed to its specific oncogenic, morphologic and immunologic features., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Patient engagement and shared decision-making (SDM) between patients and clinicians is the foundation of patient-centered care. It aims to reach a treatment option that fits the patient's preference and is guideline-concordant. We sought to evaluate the possible causes and outcomes of patient's non-guideline-concordant care choices. Using a retrospective analysis of the medical records of patients who underwent cryoablation for small renal masses between January 2010 and January 2023. Inclusion criteria were patients with renal tumor(s) who underwent cryoablation which was not recommended by the multidisciplinary team (MDT). We present three patients with unilateral clear cell renal cell carcinoma. Based on imaging and other findings, the oncology MDT recommended partial/radical nephrectomy. Upon consultation, each refused surgery and preferred cryoablation. Respecting their choice, cryoablation was undertaken. The patients had treatment failure and developed recurrences that could have possibly been avoided with guideline-concordant care. Shared decision-making in healthcare involves several aspects: patient/family; uncertainty of available evidence of various treatments; MDT meetings; and treatment team. For patients to select 'wise' treatment preferences i.e. guideline-concordant care, multi-layered complex intellectual and cognitive processes are required, where experience may play a role. Healthcare professionals require guidance and training on appropriate SDM in clinical settings, and awareness of tools to solicit patient choice to guideline-concordant care whilst observing patient autonomy. Patients and treatment teams need the capacity, knowledge, and skills to reach a 'wise' guideline-concordant care treatment preference jointly. Patients' unwise preference could lead to suboptimal outcomes, in the case of our patients, tumor recurrence., Competing Interests: The authors declare no competing interests., (Copyright: Khalid Al Rumaihi et al.)