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Turpin R, Peltonen K, Rannikko JH, Liu R, Kumari AN, Nicorici D, Lee MH, Mutka M, Kovanen PE, Niinikoski L, Meretoja T, Mattson J, Järvinen P, Lahdensuo K, Järvinen R, Tornberg S, Mirtti T, Boström P, Koskivuo I, Thotakura A, Pouwels J, Hollmén M, Mustjoki S, Klefström J. Patient-derived tumor explant models of tumor immune microenvironment reveal distinct and reproducible immunotherapy responses. Oncoimmunology 2025; 14:2466305. [PMID: 39960413 PMCID: PMC11834457 DOI: 10.1080/2162402x.2025.2466305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 02/04/2025] [Accepted: 02/07/2025] [Indexed: 02/20/2025] Open
Abstract
Tumor-resident immune cells play a crucial role in eliciting anti-tumor immunity and immunomodulatory drug responses, yet these functions have been difficult to study without tractable models of the tumor immune microenvironment (TIME). Patient-derived ex vivo models contain authentic resident immune cells and therefore, could provide new mechanistic insights into how the TIME responds to tumor or immune cell-directed therapies. Here, we assessed the reproducibility and robustness of immunomodulatory drug responses across two different ex vivo models of breast cancer TIME and one of renal cell carcinoma. These independently developed TIME models were treated with a panel of clinically relevant immunomodulators, revealing remarkably similar changes in gene expression and cytokine profiles among the three models in response to T cell activation and STING-agonism, while still preserving individual patient-specific response patterns. Moreover, we found two common core signatures of adaptive or innate immune responses present across all three models and both types of cancer, potentially serving as benchmarks for drug-induced immune activation in ex vivo models of the TIME. The robust reproducibility of immunomodulatory drug responses observed across diverse ex vivo models of the TIME underscores the significance of human patient-derived models in elucidating the complexities of anti-tumor immunity and therapeutic interventions.
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Affiliation(s)
- Rita Turpin
- Cancer Cell Circuitry Laboratory, Translational Cancer Medicine, Medical Faculty, University of Helsinki, Helsinki, Finland
- MediCity Research Laboratory and InFLAMES Flagship, University of Turku, Turku, Finland
| | - Karita Peltonen
- Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
| | - Jenna H. Rannikko
- MediCity Research Laboratory and InFLAMES Flagship, University of Turku, Turku, Finland
| | - Ruixian Liu
- Cancer Cell Circuitry Laboratory, Translational Cancer Medicine, Medical Faculty, University of Helsinki, Helsinki, Finland
| | - Anita N. Kumari
- Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Daniel Nicorici
- Cancer Cell Circuitry Laboratory, Translational Cancer Medicine, Medical Faculty, University of Helsinki, Helsinki, Finland
| | - Moon Hee Lee
- Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Minna Mutka
- Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
| | - Panu E. Kovanen
- Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
| | - Laura Niinikoski
- Division of Breast Surgery, Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Tuomo Meretoja
- Division of Breast Surgery, Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Johanna Mattson
- Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Petrus Järvinen
- Abdominal Center, Urology, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Kanerva Lahdensuo
- Abdominal Center, Urology, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Riikka Järvinen
- Abdominal Center, Urology, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Sara Tornberg
- Abdominal Center, Urology, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Tuomas Mirtti
- Department of Pathology, Helsinki University Hospital and Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland
| | - Pia Boström
- Department of Pathology, Turku University Hospital, Turku, Finland
| | - Ilkka Koskivuo
- Department of Digestive Surgery and Urology, Turku University Hospital and University of Turku, Turku, Finland
| | - Anil Thotakura
- Immuno-Oncology, Oncology Research, Orion Corporation, Turku, Finland
| | - Jeroen Pouwels
- Cancer Cell Circuitry Laboratory, Translational Cancer Medicine, Medical Faculty, University of Helsinki, Helsinki, Finland
| | - Maija Hollmén
- MediCity Research Laboratory and InFLAMES Flagship, University of Turku, Turku, Finland
| | - Satu Mustjoki
- Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
| | - Juha Klefström
- Cancer Cell Circuitry Laboratory, Translational Cancer Medicine, Medical Faculty, University of Helsinki, Helsinki, Finland
- Finnish Cancer Institute, Helsinki, Finland
- FICAN South, Helsinki University Hospital, Helsinki, Finland
- Department of Cell & Tissue Biology, University of California, San Francisco, USA
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Weng B, Braaten M, Lehn J, Morrissey R, Asghar MS, Silberstein P, Abdul Jabbar AB, Mathews A, Tauseef A, Mirza M. Survival and treatment of stage IV renal cell carcinoma in academic vs non-academic medical centers. World J Nephrol 2025; 14:103923. [DOI: 10.5527/wjn.v14.i2.103923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/22/2025] [Accepted: 02/08/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND Renal cell carcinoma (RCC) is treated with surgical resection as the gold standard, as it is notoriously resistant to systemic therapy. Advancements with targeted therapies contribute to declining mortality, but metastatic RCC (mRCC) survival remains poor. One possible factor is treatment at academic centers, which employ advanced providers and novel therapies. This study compared outcomes of mRCC in patients treated at academic/research facilities compared to those treated at non-academic centers.
AIM To compare survival outcomes of mRCC and their various etiologies between academic and non-academic centers.
METHODS The National Cancer Database was used to identify mRCC patients including all histology subtypes and stage IV disease. Descriptive statistics and Kaplan-Meier curves measured survival outcomes for user file facility types sorted into a binary academic/research and non-academic research variable. Multivariate logistic regression and Cox proportional hazard testing generated odds ratio and hazard ratio. Data was analyzed using Statistical Package for the Social Sciences version 29.0 using a significance level of P < 0.05.
RESULTS Overall, academic facility patients experienced greater 5-year and 10-year overall survival than non-academic facility patients. Treatment at non-academic facilities was associated with increased odds of death that persisted even after controlling for age, tumor size, sex, and distance traveled to treatment center. In comparison, non-academic facility patients also experienced greater risk of hazard.
CONCLUSION Patients with mRCC treated at academic/research facilities experienced increased survival compared to patients treated at non-academic facilities, were more likely to be younger, carry private insurance, and come from a large metropolitan area. They also were significantly more likely to receive surgery and adjuvant immunotherapy.
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Affiliation(s)
- Bob Weng
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Marco Braaten
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Jenna Lehn
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Reid Morrissey
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Muhammad Sohaib Asghar
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, United States
| | - Peter Silberstein
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Ali Bin Abdul Jabbar
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Abraham Mathews
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Abubakar Tauseef
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Mohsin Mirza
- Department of Internal Medicine, Creighton University School of Medicine, Omaha, NE 68178, United States
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3
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Rojas PA, Carracedo D, Moscatiello P, González L, Gimbernat H, Santiago M, Toledo M, Pereira N, Sánchez-Encinas M. Do patients with intermediate-risk renal carcinoma who receive adjuvant pembrolizumab really benefit in recurrence-free survival? Analysis of a cohort of nephrectomies over 10 years. World J Urol 2025; 43:307. [PMID: 40377723 DOI: 10.1007/s00345-025-05599-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 03/24/2025] [Indexed: 05/18/2025] Open
Abstract
PURPOSE Pembrolizumab has shown benefits as adjuvant therapy in the Keynote-564 trial, improving disease-free survival (DFS) across broad patient subgroups. However, it remains unclear if all patients, including those potentially cured by surgery alone, derive real benefits or are unnecessarily exposed to adverse effects and costs. This study aimed to evaluate DFS in Keynote-564-like patients who underwent nephrectomy without adjuvant pembrolizumab. METHODS We included nephrectomy patients meeting Keynote-564 criteria. Clinical and pathological features were analyzed, and Cox regression was used to identify predictors. DFS and overall survival (OS) were assessed. RESULTS Forty-three patients met Keynote-564 criteria (100% intermediate risk). Among them, 12 patients (28%) experienced recurrence. Significant differences between recurrent (Re+) and non-recurrent (Re-) patients were observed in ECOG ≥ 1 frequency (25% vs. 0%; p < 0.05), tumour size (9.4 vs. 6.9 cm; p = 0.02), and renal pelvis invasion (50% vs. 19%; p = 0.04). Cox regression identified ECOG ≥ 1 as a predictor of recurrence (HR = 17.97, 95% CI 1.76-187.16; p = 0.016). After a median follow-up of 59.5 months, 2-year DFS and OS were 86% and 93%, respectively. Treating only relapsed patients with pembrolizumab would have saved €1,254,167. CONCLUSION Our recurrence rate was lower than Keynote-564, whereby no strong predictors of recurrence were identified. Although ECOG ≥ 1 was statistically significant, its clinical utility remains limited. Further research is needed to determine if adjuvant pembrolizumab provides a true benefit in intermediate-risk patients.
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Affiliation(s)
- Pablo A Rojas
- Servicio de Urología, Hospital Universitario Rey Juan Carlos, Móstoles, Madrid, 28933, España
- Servicio de Urología, Complejo Asistencial Doctor Sótero del Río, Santiago, Chile
| | - David Carracedo
- Servicio de Urología, Hospital Universitario Rey Juan Carlos, Móstoles, Madrid, 28933, España.
- Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, 28040, España.
| | - Pietro Moscatiello
- Servicio de Urología, Hospital Universitario Rey Juan Carlos, Móstoles, Madrid, 28933, España
| | - Laura González
- Servicio de Urología, Hospital Universitario Rey Juan Carlos, Móstoles, Madrid, 28933, España
| | - Helena Gimbernat
- Servicio de Urología, Hospital Universitario Rey Juan Carlos, Móstoles, Madrid, 28933, España
| | - Marta Santiago
- Servicio de Urología, Hospital Universitario Rey Juan Carlos, Móstoles, Madrid, 28933, España
| | - Miguel Toledo
- Servicio de Urología, Hospital Universitario Rey Juan Carlos, Móstoles, Madrid, 28933, España
| | - Nathalie Pereira
- Servicio de Urología, Hospital Universitario Rey Juan Carlos, Móstoles, Madrid, 28933, España
| | - Miguel Sánchez-Encinas
- Servicio de Urología, Hospital Universitario Rey Juan Carlos, Móstoles, Madrid, 28933, España
- Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, 28040, España
- Facultad Ciencias de la Salud, Universidad Rey Juan Carlos, Móstoles, Madrid, 28933, España
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Castillo LZ. Combined Therapies in Renal Cell Carcinoma: The Challenge of Overcoming Resistance. JCO Oncol Pract 2025:OP2500255. [PMID: 40354594 DOI: 10.1200/op-25-00255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 04/09/2025] [Accepted: 04/11/2025] [Indexed: 05/14/2025] Open
Affiliation(s)
- Liliana Z Castillo
- Universidad de Carabobo, Valencia, Venezuela
- Department of Oncology, Dr Miguel Pérez Carreño Oncology Institute, Valencia, Venezuela
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Shin D, Lim B, Song C, You D, Jeong IG, Hong JH, Ahn H, Hong B, Jeong CW, Han JH, Suh J. Comparative analysis of oncologic outcomes in surgically treated patients with renal cell carcinoma and renal vein thrombosis by pathologic subtypes. Sci Rep 2025; 15:15946. [PMID: 40335555 PMCID: PMC12059190 DOI: 10.1038/s41598-025-00452-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 04/28/2025] [Indexed: 05/09/2025] Open
Abstract
This study compares recurrence-free survival (RFS) and overall survival (OS) in patients with non-clear cell (nccRCC) and clear cell renal cell carcinoma (ccRCC) undergoing surgical nephrectomy with thrombectomy (SNTx) for RCC with venous thrombus. Data from patients who underwent SNTx at two tertiary centers (June 1990-December 2022) were retrospectively reviewed. Patients were grouped as ccRCC or nccRCC and stratified by metastasis status at surgery. Primary endpoints were RFS and OS for metastasis-naive RCC and OS for the entire cohort, including both metastasis-naive and metastatic RCC. Kaplan-Meier analysis with log-rank tests and adjusted multivariable Cox proportional hazards models were performed, with TN adjustments for the metastasis-naive group and TNM adjustments for the entire population. Among 604 patients, 504 (83.5%) were ccRCC. In nccRCC, 44 (44.0%) were papillary, 17 (17.0%) were chromophobe, and 39 (39.0%) were rare subtypes, most commonly TFE3 rearranged RCC, followed by the RCC not otherwise specified subtype (according to the 2022 World Health Organization Classification of RCC). Median OS was 85.8 months for ccRCC, 37.7 for papillary, 90.2 for chromophobe, and 16.9 for rare subtypes. Rare RCC histology was significantly associated with worse RFS (HR 1.63, p = 0.038) and OS (HR 1.82, p = 0.039) in metastasis-naive RCC. For the entire cohort including metastatic diseases, rare subtypes had worse OS (HR 2.20, p < 0.001), while other nccRCC subtypes did not differ significantly from ccRCC in OS. In patients with RCC with venous thrombosis, rare nccRCC subtypes exhibited poorer survival outcomes, even after adjustment for TN(M) stage.
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Affiliation(s)
- Dongrul Shin
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Bumjin Lim
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Cheryn Song
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Dalsan You
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - In Gab Jeong
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Jun Hyuk Hong
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Hanjong Ahn
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Bumsik Hong
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea
| | - Chang Wook Jeong
- Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jang Hee Han
- Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Jungyo Suh
- Department of Urology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Republic of Korea.
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Han L, Huang B, Li L, Xu B, Yang Y, Zhao L, Wang Z, Zhang C, Gao Q. Utility of the neutrophil-to-lymphocyte ratio and the ratio of neutrophil-to-lymphocyte ratio after and before adverse events for differential diagnosis of immune-related adverse events and bacterial infections in cancer patients treated with PD-(L)1 inhibitors. J Leukoc Biol 2025; 117:qiaf029. [PMID: 40083232 DOI: 10.1093/jleuko/qiaf029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 12/25/2024] [Accepted: 03/13/2025] [Indexed: 03/16/2025] Open
Abstract
Differential diagnosis of immune-related adverse events (irAEs) or bacterial infections is sometimes very difficult in cancer patients undergoing treatment with PD-(L)1 inhibitors. This study aimed to assess the effectiveness of the neutrophil-to-lymphocyte ratio (NLR) in distinguishing between irAEs and bacterial infections in cancer patients receiving PD-(L)1 inhibitors. We conducted a retrospective analysis of cancer patients who received at least 1 dose of PD-(L)1 inhibitors at Affiliated Cancer Hospital of Zhengzhou University from 2018 to 2023. We compared the changes in peripheral blood cell counts before and after the occurrence of adverse events, as well as the ratios of the NLR that were closest after the occurrence of adverse events (post-NLR) to the NLR that were closest before the occurrence of adverse events (pre-NLR). Among the 4173 patients who were administered PD-(L)1 inhibitors, 217 individuals experienced a total of 249 irAEs, while 256 patients were diagnosed with 257 bacterial infections. The post-NLR increased significantly compared with pre-NLR in patients with bacterial infection (P < 0.001), while the post-NLR had smaller increase compared with pre-NLR in patients sufffering irAEs (P < 0.001). Notably, the NLR was significantly higher in patients with bacterial infection compared with those with irAEs (P < 0.001). Furthermore, the post-NLR/pre-NLR ratio was higher in the bacterial infection group than in the irAEs group (P < 0.001). The NLR along with the post-NLR/pre-NLR ratio could serve as valuable diagnostic indicators for irAEs and bacterial infections in cancer patients undergoing treatment with PD-(L)1 inhibitors.
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Affiliation(s)
- Lu Han
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Beibei Huang
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Linlin Li
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Benling Xu
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Yonghao Yang
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Lingdi Zhao
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Zibing Wang
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Chaoji Zhang
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Quanli Gao
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
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Pinto-Marín Á, Trilla-Fuertes L, Miranda Poma J, Vasudev NS, García-Fernández E, López-Vacas R, Miranda N, Wilson M, López-Camacho E, Pertejo A, Dittmann A, Kunz L, Brown J, Pedroche-Just Y, Zapater-Moros A, de Velasco G, Castellano D, González-Peramato P, Espinosa E, Banks RE, Fresno Vara JÁ, Gámez-Pozo A. A prognostic microRNA-based signature for localized clear cell renal cell carcinoma: the Bio-miR study. Br J Cancer 2025:10.1038/s41416-025-03008-2. [PMID: 40335662 DOI: 10.1038/s41416-025-03008-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 03/18/2025] [Accepted: 03/28/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Two thirds of renal cell carcinoma (RCC) patients have localized disease at diagnosis. A significant proportion of these patients will relapse. There is a need for prognostic biomarkers to improve risk-stratification and specific treatments for patients that relapse. The objective of this study is to determine the clinical utility of microRNA signatures as prognostic biomarkers in localized clear cell RCC (ccRCC) and propose new therapeutic targets in patients with a high-risk of relapse. PATIENTS AND METHODS The microRNA profiles from a discovery cohort of 71 T1-T2 ccRCC patients (n = 88) were analyzed using microarrays. MicroRNAs prognostic value was established, and a microRNAs signature predicting relapse for T1b-T3 disease was defined. Independent validation was carried out by qPCR in cohorts from UK (n = 75) and Spain (n = 180), and the TCGA cohort (n = 175). In the Spanish validation cohort, proteomics experiments were done. Proteins were extracted from FFPE tissue and analyzed using by data-independent acquisition mass spectrometry. Additionally, ccRCC TCGA RNA-seq data was also analyzed. Both protein and RNA-seq data was analyzed using Significance Analysis of Micorarrays (SAM) and probabilistic graphical models, which allow the identification of relevant biological processes between low and high-risk tumors. RESULTS A 9-microRNAs signature, Bio-miR, classified patients into low- and high-risk with disease-free survival (DFS) at 5 years of 87.12 vs. 54.17% respectively (p = 0.0086, HR = 3.58, 95%CI: 1.37-8.3). Results were confirmed in the validation cohorts with 5-year DFS rates of 94% vs. 62% in the UK cohort (HR = 7.14, p = 0.001), 82.9% vs. 58.7% in the Spanish cohort (HR = 2.46, p = 0.0013), and 5-year overall survival rates of 72.7% vs. 44.5% in the TCGA cohort (HR = 2.43, p = 0.0012). Among low-risk patients according to adjuvant immunotherapy clinical trial criteria, Bio-miR identified a high-risk group. Maybe those patients ought to be considered to receive adjuvant therapy. Proteins overexpressed in the high-risk group were mainly related to focal adhesion, serine and inositol metabolism, and angiogenesis. Probabilistic graphical models defined eight functional nodes related to specific biological processes. Differences between low- and high-risk tumors were detected in complement activation and translation functional nodes. In ccRCC TCGA cohort, 676 genes were differentially expressed between low and high-risk patients, mainly related to complement activation, adhesion, and chemokine and cytokine cascades. In this case, probabilistic graphical models defined ten functional nodes. Calcium binding, membrane, adhesion, extracellular matrix, blood microparticle, inflammatory response and immune response had higher functional node activity, and metabolism node, containing genes related to retinol and xenobiotic and CYP450 metabolism, had lower activity in the high-risk group. CONCLUSIONS Bio-miR dichotomizes ccRCC patients with non-metastatic disease into those with low- and high-risk of relapse. This has implications for treatment and follow-up, identifying patients most likely to benefit from adjuvant treatment in clinical trials, preventing unnecessary exposure to side-effects, and providing health economics benefits. Additionally, promising therapeutic targets, as angiogenesis, immune response, metabolism, or complement activation, were found deregulated in high-risk ccRCC patients defined by Bio-miR. These findings may be useful to select patients for tailored, molecularly-driven clinical trials. Identifying which patients with kidney cancer are most at risk of their cancer coming back after surgery is critical, so that they can be prioritized for early treatment. We have identified a combination of biomarkers present in the cancer tissue (called BiomiR) which can help to do this.
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Affiliation(s)
- Álvaro Pinto-Marín
- Medical Oncology Service, Hospital Universitario La Paz, IDIPAZ, Madrid, Spain.
| | | | - Jesús Miranda Poma
- Medical Oncology Service, Hospital Universitario La Paz, IDIPAZ, Madrid, Spain
| | - Naveen S Vasudev
- Leeds Institute of Medical Research at St James's, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK
| | | | - Rocío López-Vacas
- Molecular Oncology Lab, Hospital Universitario La Paz, IDIPAZ, Madrid, Spain
| | - Natalia Miranda
- Urology Service, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Michelle Wilson
- Leeds Institute of Medical Research at St James's, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK
| | | | - Ana Pertejo
- Medical Oncology Service, Hospital Universitario La Paz, IDIPAZ, Madrid, Spain
| | - Antje Dittmann
- Proteomics Group, Functional Genomics Center Zurich, Zurich, Switzerland
| | - Laura Kunz
- Proteomics Group, Functional Genomics Center Zurich, Zurich, Switzerland
| | - Joanne Brown
- Leeds Institute of Medical Research at St James's, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK
| | | | | | | | - Daniel Castellano
- Medical Oncology Service, Hospital Universitario 12 de Octubre, Madrid, Spain
| | | | - Enrique Espinosa
- Medical Oncology Service, Hospital Universitario La Paz, IDIPAZ, Madrid, Spain
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain
| | - Rosamonde E Banks
- Leeds Institute of Medical Research at St James's, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK
| | - Juan Ángel Fresno Vara
- Molecular Oncology Lab, Hospital Universitario La Paz, IDIPAZ, Madrid, Spain
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain
| | - Angelo Gámez-Pozo
- Molecular Oncology Lab, Hospital Universitario La Paz, IDIPAZ, Madrid, Spain.
- Biomedica Molecular Medicine SL, Madrid, Spain.
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8
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Cavallo K, Brody F. Clot Between a Rock and a Hard Place: Renal Cell Carcinoma with IVC Tumor Thrombus. J Laparoendosc Adv Surg Tech A 2025. [PMID: 40323726 DOI: 10.1089/lap.2024.0352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2025] Open
Abstract
Renal cell carcinoma (RCC) is the most common renal cancer and constitutes a significant burden of disease. Tumor thrombus is present in approximately 10% of cases at initial diagnosis and impacts the morbidity and mortality of the disease. The primary treatment for RCC involves resection of the tumor. The presence of tumor thrombus, therefore, is not only important for prognosis but also for operative planning. Operative approach, including vascular control and caval closure are important consideration when resecting RCC with inferior vena cava (IVC) tumor thrombus and varies based on the patient presentation, extent of the tumor, and the surgeon's experience. This article presents a patient with RCC with IVC thrombus who ultimately underwent surgical resection with general surgery, vascular surgery, and urology to showcase the multidisciplinary care, surgical considerations, and current management and treatment strategies for RCC with tumor thrombus.
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Affiliation(s)
- Kathryn Cavallo
- Department of Surgery, George Washington University Hospital, Washington, District of Columbia, USA
| | - Fredrick Brody
- Department of Surgery, Washington DC VA Medical Center, Washington, District of Columbia, USA
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9
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Bi Y, Wei H, Ma Q, Wang R, Jin J, Qu K, Liu Y, Zhai Z, Zhu L, Wang J. The fragility index of randomized controlled trials in advanced/metastatic renal cell cancer. Urol Oncol 2025; 43:333.e9-333.e15. [PMID: 40155257 DOI: 10.1016/j.urolonc.2025.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 02/06/2025] [Accepted: 03/02/2025] [Indexed: 04/01/2025]
Abstract
PURPOSE The fragility index (FI) has been applied as a supplement to the noncomprehensive P-values to assess the robustness of randomized controlled trials (RCTs). The objective of this study is to evaluate the statistical robustness of RCTs of advanced/metastatic renal cell cancer (a/mRCC) using the FI. MATERIALS AND METHODS RCTs related to a/mRCC published in the 4 highest-impact general medical journals and the 25 highest-impact urological journals between January 1, 2000, and December 31, 2023, were identified from PubMed database. The FI was calculated by using Fisher's exact test. Spearman's correlation analysis was conducted to assess potential correlates regarding FI. RESULTS 16 eligible RCTs were screened with a median total sample size of 654.5 (IQR, 461-847) and a median patients lost to follow-up of 14 (IQR, 3-23). The median FI was 12.5 (IQR, 8.5-27), suggesting that a switch in outcomes in only 13 patients would have reversed the significance of the trials. The number of patients lost to follow-up exceeded or equaled to the FI in 7 (44%) RCTs. P-values were negatively associated with the FI, while the number of patients lost to follow-up and patients enrolled were not statistically significant. CONCLUSION Not all RCTs associated with a/mRCC are as statistically robust as previously considered and should therefore be construed carefully. We suggest that additional reporting of FI in urological RCTs as a supplement to the P-value to assist readers in concluding reliably by considering the fragility of the outcomes.
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Affiliation(s)
- Yingwei Bi
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Haotian Wei
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300202, China
| | - Qifeng Ma
- College of Basic Medicine, Dalian Medical University, Dalian 116041, China
| | - Rui Wang
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Jiacheng Jin
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Kexin Qu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Yuxin Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Ziwei Zhai
- College of Basic Medicine, Dalian Medical University, Dalian 116041, China
| | - Liang Zhu
- College of Basic Medicine, Dalian Medical University, Dalian 116041, China; College of Basic Medicine, Dalian University of Technology, Dalian 116081, China.
| | - Jianbo Wang
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
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10
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Alonso-Gordoa T, Anguera G, Domínguez-Esteban M, Reig Ò, Martínez-Barros H, Molina-Cerrillo J, Cruz P, Maroto P. Expert consensus on patterns of progression in kidney cancer after adjuvant immunotherapy and subsequent treatment strategies. Cancer Treat Rev 2025; 136:102925. [PMID: 40186886 DOI: 10.1016/j.ctrv.2025.102925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 04/07/2025]
Abstract
Immunotherapy has changed the management of localized clear cell renal cell carcinoma (ccRCC) since the approval of adjuvant pembrolizumab, which demonstrated significant improvements in disease-free survival (DFS) and overall survival (OS) in patients at intermediate and high risk of recurrence. This new approach impacts rescue strategies in patients who relapse after local treatment and during or after adjuvant pembrolizumab. Nevertheless, there is currently no robust scientific evidence on therapeutic decision-making in this clinical situation, representing an area for further debate and research. In this article, a group of experts from the Genitourinary Alliance for Research and Development (GUARD) have reviewed the available scientific evidence to establish the basis for therapeutic decision-making in patients with ccRCC who progress after adjuvant treatment with immunotherapy. Despite the lack of randomized clinical trials in this setting, this group of experts recommends classifying patients according to relapse volume (oligometastatic vs. polymetastatic), time to relapse and certain molecular characteristics. Rescue treatments beyond relapse should be individualized and might include locoregional treatments such as surgery or radiotherapy as well as antiangiogenic therapies in patients defined as resistant to immunotherapy.
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Affiliation(s)
| | - Georgia Anguera
- Medical- Oncology Department, Santa Creu i Sant Pau Hospital, Barcelona, Spain.
| | | | - Òscar Reig
- Laboratory of Translational Genomics and Targeted Therapies in Solid Tumours, Fundació de Recerca Clínic Barcelona - Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Medicine Department, Barcelona University, Medical Oncology Department, Clínic Hospital, Barcelona, Spain.
| | | | | | - Patricia Cruz
- Medical Oncology Department, Ciudad Real General University Hospital, Ciudad Real, Spain.
| | - Pablo Maroto
- Medical Oncology Department, Santa Creu i Sant Pau Hospital, Barcelona, Spain.
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11
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Henriksson T, Mitchell K, El Naili R, Hajiran A. The intersection of histologies: navigating the complexity of a renal collision tumor. THE CANADIAN JOURNAL OF UROLOGY 2025; 32:95-99. [PMID: 40331258 DOI: 10.32604/cju.2025.065002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 12/31/2024] [Indexed: 05/08/2025]
Abstract
Renal cell carcinoma is a heterogeneous group of renal tumors characterized by several histological subtypes. Herein, we discuss an unusual case of a 55-year-old male who presented as a consultation to our urology clinic with an incidentally found renal mass. After shared decision making patient proceeded with a Robotic Assisted Laparoscopy (RAL) left sided partial nephrectomy. Final pathology confirmed the presence of high nuclear grade mixed clear cell and papillary renal cell carcinoma (RCC) of the left kidney (pT3aN0M0). This case elucidates a very rare incidence of a patient seen to have a collision tumor, and furthermore demonstrates guideline-based treatment.
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Affiliation(s)
| | - Katharina Mitchell
- Department of Urology, West Virginia University, Morgantown, WV 26505, USA
| | - Reima El Naili
- Department of Pathology, West Virginia University, Morgantown, WV 26505, USA
| | - Ali Hajiran
- Department of Urology, West Virginia University, Morgantown, WV 26505, USA
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12
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Ellmann S, von Rohr F, Komina S, Bayerl N, Amann K, Polifka I, Hartmann A, Sikic D, Wullich B, Uder M, Bäuerle T. Tumor grade-titude: XGBoost radiomics paves the way for RCC classification. Eur J Radiol 2025; 188:112146. [PMID: 40334367 DOI: 10.1016/j.ejrad.2025.112146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 04/21/2025] [Accepted: 04/28/2025] [Indexed: 05/09/2025]
Abstract
This study aimed to develop and evaluate a non-invasive XGBoost-based machine learning model using radiomic features extracted from pre-treatment CT images to differentiate grade 4 renal cell carcinoma (RCC) from lower-grade tumours. A total of 102 RCC patients who underwent contrast-enhanced CT scans were included in the analysis. Radiomic features were extracted, and a two-step feature selection methodology was applied to identify the most relevant features for classification. The XGBoost model demonstrated high performance in both training (AUC = 0.87) and testing (AUC = 0.92) sets, with no significant difference between the two (p = 0.521). The model also exhibited high sensitivity, specificity, positive predictive value, and negative predictive value. The selected radiomic features captured both the distribution of intensity values and spatial relationships, which may provide valuable insights for personalized treatment decision-making. Our findings suggest that the XGBoost model has the potential to be integrated into clinical workflows to facilitate personalized adjuvant immunotherapy decision-making, ultimately improving patient outcomes. Further research is needed to validate the model in larger, multicentre cohorts and explore the potential of combining radiomic features with other clinical and molecular data.
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Affiliation(s)
- Stephan Ellmann
- Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; Radiologisch-Nuklearmedizinisches Zentrum (RNZ), Martin-Richter-Straße 43, 90489 Nürnberg, Germany.
| | - Felicitas von Rohr
- Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Selim Komina
- Institute of Pathology, Faculty of Medicine, Ss Cyril and Methodius University ul. 50 Divizija bb 1000 Skopje, North Macedonia
| | - Nadine Bayerl
- Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Kerstin Amann
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; BZKF: Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Iris Polifka
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; Humanpathologie Dr. Weiß MVZ GmbH, Am Weichselgarten 30a, 91058 Erlangen-Tennenlohe, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen - EMD, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; BZKF: Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Danijel Sikic
- Clinic of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; BZKF: Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Bernd Wullich
- Clinic of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Comprehensive Cancer Center Erlangen - EMD, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; BZKF: Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Michael Uder
- Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen - EMD, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; BZKF: Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Tobias Bäuerle
- Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; University Medical Center of Johannes Gutenberg-University Mainz, Department of Diagnostic and Interventional Radiology, Langenbeckstr. 1, 55131 Mainz, Germany
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13
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Buck L, von Knobloch HC, Kohler J, Yalcin F, Stuhlmann-Laeisz CM, Rodler S, Jarczyk J, Nuhn P. [First diagnosis of renal cell carcinoma via a testicular metastasis]. UROLOGIE (HEIDELBERG, GERMANY) 2025:10.1007/s00120-025-02584-8. [PMID: 40272474 DOI: 10.1007/s00120-025-02584-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/21/2025] [Indexed: 04/25/2025]
Abstract
This case report describes a rare case of testicular metastasis from renal cell carcinoma, which led to first diagnosis of the primary. The patient presented with a progressive painless swelling of the left testicle. After initial suspicion of a testicular tumor, inguinal excision of the testis was performed, which confirmed the presence of a clear cell carcinoma. Further investigations revealed evidence of a primary carcinoma on the left-lower pole of the kidney, which was removed by partial nephrectomy. Histopathologically, clear cell renal cell carcinoma was confirmed. Treatment was supplemented by adjuvant immunotherapy with pembrolizumab. Postoperative follow-up has shown no evidence of recurrence to date.
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Affiliation(s)
- Leonhard Buck
- Klinik für Urologie, Universitätsklinikum Schleswig-Holstein - Campus Kiel, Kiel, Deutschland.
| | | | - Jakob Kohler
- Klinik für Urologie, Universitätsklinikum Schleswig-Holstein - Campus Kiel, Kiel, Deutschland
| | - Fatih Yalcin
- Institut für Pathologie, Universitätsklinikum Schleswig-Holstein - Campus Kiel, Kiel, Deutschland
| | | | - Severin Rodler
- Klinik für Urologie, Universitätsklinikum Schleswig-Holstein - Campus Kiel, Kiel, Deutschland
| | - Jonas Jarczyk
- Klinik für Urologie, Universitätsklinikum Schleswig-Holstein - Campus Kiel, Kiel, Deutschland
| | - Philipp Nuhn
- Klinik für Urologie, Universitätsklinikum Schleswig-Holstein - Campus Kiel, Kiel, Deutschland
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14
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Oki R, Takemura K, Urasaki T, Fujiwara R, Numao N, Yonese J, Miura Y, Yuasa T. Prevailing challenges in personalized treatment for metastatic renal cell carcinoma: a narrative review. Expert Rev Anticancer Ther 2025:1-13. [PMID: 40210604 DOI: 10.1080/14737140.2025.2491647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 04/05/2025] [Accepted: 04/07/2025] [Indexed: 04/12/2025]
Abstract
INTRODUCTION The management of metastatic renal cell carcinoma (mRCC) has advanced with recent therapies, yet optimizing treatment remains challenging due to disease heterogeneity and the growing number of options. Integrating systemic and local treatments requires a multidisciplinary approach to improve outcomes. AREA COVERED This review summarizes recent developments in treatment for mRCC. Upfront immuno-oncology (IO)-based combinations have improved survival, though concerns about overtreatment and toxicity persist. While the role of cytoreductive nephrectomy (CN) has declined to some extent, it may still benefit well-selected patients. Metastasis-directed therapies, including metastasectomy and stereotactic radiotherapy, provide prognostic value, particularly for oligometastatic lesions or brain metastases. Comprehensive genomic profiling (CGP) holds promise for personalized treatment but is currently limited by the lack of actionable mutations and predictive biomarkers. EXPERT OPINION A personalized, multimodal approach is essential for optimizing mRCC management. Careful patient selection is key to balancing the benefits of treatment with the risks of toxicity. While CN and metastasis-directed therapies remain useful in select cases, advancing individualized care requires the development of validated biomarkers and broader application of CGP.
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Affiliation(s)
- Ryosuke Oki
- Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kosuke Takemura
- Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tetsuya Urasaki
- Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Ryo Fujiwara
- Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Noboru Numao
- Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Junji Yonese
- Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuji Miura
- Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takeshi Yuasa
- Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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15
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Ornstein MC. From Challenges to Cures: Improving Outcomes in Patients With Renal Cell Carcinoma. JCO Oncol Pract 2025:OP2500219. [PMID: 40203218 DOI: 10.1200/op-25-00219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 03/12/2025] [Indexed: 04/11/2025] Open
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16
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Arai Y, Miyai K, Hamamoto K, Furukawa Y, Asano T, Kobayashi H, Shinchi M, Tsujita Y, Kuroda K, Horiguchi A, Tsuda H, Ito K. Impact of tumor-infiltrating immune cells expressing PD-1 and those expressing PD-L1 on recurrence and prognosis in pathological T1b clear cell renal cell carcinoma. Jpn J Clin Oncol 2025:hyaf054. [PMID: 40183516 DOI: 10.1093/jjco/hyaf054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 03/21/2025] [Indexed: 04/05/2025] Open
Abstract
BACKGROUND The numbers of tumor-infiltrating immune cells (TIICs) expressing programmed death (PD)-1 or PD-ligand 1 (PD-L1) reportedly predict prognosis and resistance to targeted drugs in clear cell renal cell carcinoma (ccRCC). The impact of local tumor microenvironment based on immunosuppressive TIICs on recurrence and prognosis has not been fully investigated in localized ccRCC. METHODS A total of 105 patients with pT1b ccRCC were included. Immunostaining for PD-1 and PD-L1 were performed. PD-1-positive TIICs and PD-L1-positive TIICs were counted in the tumor periphery (TP) and the tumor nest (TN). RESULTS Patients with elevated PD-1-positive TIIC scores and those with elevated PD-L1-positive TIIC scores had significantly lower recurrence-free survival (RFS) rates than their counterparts (3-year RFS rates; patients with high vs. low PD-1-positive TIIC score of TN = 73.9% vs. 95.0%, those with high vs. low PD-1-positive TIIC score of TP = 73.8% vs. 93.8%, those with high vs. low PD-L1-positive TIIC score of TN = 70.9% vs. 93.0%, and those with high vs. low PD-L1-positive TIIC score of TP = 80.3% vs. 92.6%). Univariate analysis showed that high PD-1-positive scores, high PD-L1-positive scores, high PD-L1-positive tumor cell score, high-grade tumor, tumor necrosis, and lymphovascular invasion were significantly associated with RFS. Multivariate analysis revealed that tumor necrosis [hazard ratio (HR) = 2.841, P = .0269] and PD-1-positive TIIC score of TN (HR = 6.135, P = .0023) were independent risk factors for RFS. Risk stratification using the two factors efficiently predicts recurrence (3-year RFS rates: 96.4% with 0 factor, 83.8% with 1 factor, and 61.4% with 2 factors). CONCLUSION PD-1-positive TIIC score of TN and tumor necrosis may efficiently predict recurrence in pT1b ccRCC.
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Affiliation(s)
- Yuichi Arai
- Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Kosuke Miyai
- Department of Basic Pathology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
- Department of Laboratory Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Koetsu Hamamoto
- Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Yoshiyuki Furukawa
- Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Takako Asano
- Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Hiroaki Kobayashi
- Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Masayuki Shinchi
- Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Yujiro Tsujita
- Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Kenji Kuroda
- Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Akio Horiguchi
- Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Hitoshi Tsuda
- Department of Basic Pathology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Keiichi Ito
- Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
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17
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Ziogas DC, Theocharopoulos C, Aravantinou K, Boukouris AE, Stefanou D, Anastasopoulou A, Lialios PP, Lyrarakis G, Gogas H. Clinical benefit of immune checkpoint inhibitors in elderly cancer patients: Current evidence from immunosenescence pathophysiology to clinical trial results. Crit Rev Oncol Hematol 2025; 208:104635. [PMID: 39889861 DOI: 10.1016/j.critrevonc.2025.104635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 02/03/2025] Open
Abstract
The age-related decline in immunity appears to be associated not only with cancer development but also with differential responses to immune checkpoint inhibitors (ICIs). Despite their increasing utility across various malignancies and therapeutic settings, limited data -derived primarily from subgroup analyses of randomized controlled trials (RCTs), pooled meta-analyses, and retrospective studies- are available on the effects of aging on their efficacy and toxicity. Immunosenescence, characterized by the progressive decline of the function of the immune system, and inflammaging, a state of persistent low-grade sterile inflammation, may influence ICI outcomes. Additionally, the incidence, severity, and subtypes of immune-related adverse events (irAEs) may differ between older and younger individuals due to loss of immunotolerance. In the current review, starting from a a comprehensive discussion of the pathophysiology of immunosenescence, we proceed to critically review age-related retrospective and randomized evidence supporting FDA-approved ICIs. We highlight similarities or differences across age groups and the clinical benefit of ICIs in elderly versus younger cancer patients. The optimal integration of ICIs in geriatric oncology necessitates greater inclusion of this patient demographic in RCTs along with real-world data in order to acquire robust data which will guide evidence-based treatment decisions for this population.
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Affiliation(s)
- Dimitrios C Ziogas
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Charalampos Theocharopoulos
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Katerina Aravantinou
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Aristeidis E Boukouris
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Dimitra Stefanou
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Amalia Anastasopoulou
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Panagiotis-Petros Lialios
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - George Lyrarakis
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Helen Gogas
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
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18
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Bedke J, Ghanem YA, Albiges L, Bonn S, Campi R, Capitanio U, Dabestani S, Hora M, Klatte T, Kuusk T, Lund L, Marconi L, Palumbo C, Pignot G, Powles T, Tran M, Volpe A, Bex A. Updated European Association of Urology Guidelines on the Use of Adjuvant Immune Checkpoint Inhibitors and Subsequent Therapy for Renal Cell Carcinoma. Eur Urol 2025; 87:491-496. [PMID: 39904712 DOI: 10.1016/j.eururo.2025.01.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 01/09/2025] [Accepted: 01/19/2025] [Indexed: 02/06/2025]
Abstract
The KEYNOTE-564 trial showed that adjuvant immune checkpoint inhibitor (ICI) therapy with pembrolizumab, a PD-1 antibody, significantly improved disease-free survival (DFS) and overall (OS) survival in localised clear-cell renal cell carcinoma (RCC) with a high risk of relapse. The TiNivo and CONTACT-03 trials have reported results for subsequent therapy after progression on ICI therapy in the metastatic setting. The European Association of Urology (EAU) RCC guidelines panel reassessed the new trial results to update recommendations for adjuvant therapy and post-adjuvant therapy. Adjuvant pembrolizumab significantly improved OS (hazard ratio 0.62, 95% confidence interval 0.44-0.87; p = 0.005). Recent trials of subsequent ICI after recurrence on ICI in the metastatic setting do not support ICI monotherapy or combination therapy in patients with recurrence on or after adjuvant ICI therapy. There are no prospective trial results for treatment after adjuvant pembrolizumab failure. On the basis of the recent results, the EAU RCC guidelines panel has updated the recommendation for adjuvant therapy and now issues a strong recommendation for adjuvant pembrolizumab. ICI monotherapy or combination therapy is not recommended in patients with recurrence during or shortly after adjuvant pembrolizumab. PATIENT SUMMARY: Treatment with an immunotherapy drug called pembrolizumab after surgery in patients with intermediate-risk or high-risk kidney cancer delays the time to recurrence of cancer and prolongs survival. Therefore, pembrolizumab after surgery is strongly recommended for these patients. However, a significant proportion of patients have life-changing or serious side effects and these must be discussed.
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Affiliation(s)
- Jens Bedke
- Department of Urology and Transplantation Surgery and Eva Mayr-Stihl Cancer Center Klinikum Stuttgart Stuttgart Germany
| | - Yasmin Abu Ghanem
- Department of Urology Chaim Sheba Medical Center Tel-Hashomer Ramat-Gan Israel
| | - Laurence Albiges
- Department of Cancer Medicine Gustave Roussy Université Paris-Saclay Villejuif France
| | - Stephanie Bonn
- Clinical Epidemiology Division Department of Medicine Solna Karolinska Institutet Stockholm Sweden
| | - Riccardo Campi
- Unit of Urological Robotic Surgery and Renal Transplantation University of Florence Careggi Hospital Florence Italy; Department of Experimental and Clinical Medicine University of Florence Florence Italy; European Association of Urology Young Academic Urologists Renal Cancer Working Group Arnhem The Netherlands
| | - Umberto Capitanio
- Department of Urology San Raffaele Scientific Institute Milan Italy; Division of Experimental Oncology/Unit of Urology Urological Research Institute IRCCS San Raffaele Hospital Milan Italy
| | - Saeed Dabestani
- Department of Translational Medicine Division of Urological Cancers Lund University Malmö Sweden
| | - Milan Hora
- Department of Urology University Hospital Pilsen and Faculty of Medicine in Pilsen Charles University Pilsen Czechia
| | - Tobias Klatte
- Department of Urology Charité-Universitätsmedizin Berlin Berlin Germany
| | - Teele Kuusk
- Department of Urology Addenbrookes Hospital Cambridge UK
| | - Lars Lund
- Karolinska University Hospital Stockholm Sweden; Division of Cardiology Department of Medicine Karolinska Institutet Stockholm Sweden
| | - Lorenzo Marconi
- Department of Urology Coimbra University Hospital Coimbra Portugal
| | - Carlotta Palumbo
- Department of Translational Medicine University of Eastern Piedmont Maggiore Della Carità Hospital Novara Italy
| | | | - Thomas Powles
- Royal Free London NHS Trust and Barts Cancer Institute Queen Mary University of London London UK
| | - Maxine Tran
- Division of Surgery and Interventional Sciences University College London London UK; Specialist Centre for Kidney Cancer Royal Free Hospital London UK
| | - Alessandro Volpe
- Department of Urology University of Eastern Piedmont Maggiore della Carità Hospital Novara Italy
| | - Axel Bex
- Division of Surgery and Interventional Sciences University College London London UK; Specialist Centre for Kidney Cancer Royal Free Hospital London UK; The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands.
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19
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Mjaess G, Diamand R, Roumeguère T. The Fallacy of Categorization in Urology: A Call for Continuous Thinking in the Era of Artificial Intelligence. Eur Urol Oncol 2025; 8:239-241. [PMID: 39732567 DOI: 10.1016/j.euo.2024.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 12/17/2024] [Indexed: 12/30/2024]
Abstract
Categorization of patients according to their characteristics may simplify decision-making, but it fails to account for the continuous nature of risk and individual variability. Artificial intelligence has the ability to handle more complex continuous data for more precise, individualized recommendations, but several challenges must be overcome to unlock this potential.
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Affiliation(s)
- Georges Mjaess
- Department of Urology, Jules Bordet Institute and Erasme Hospital, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Romain Diamand
- Department of Urology, Jules Bordet Institute and Erasme Hospital, Hôpital Universitaire de Bruxelles, Brussels, Belgium
| | - Thierry Roumeguère
- Department of Urology, Jules Bordet Institute and Erasme Hospital, Hôpital Universitaire de Bruxelles, Brussels, Belgium.
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20
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Marandino L, Campi R, Amparore D, Tippu Z, Albiges L, Capitanio U, Giles RH, Gillessen S, Kutikov A, Larkin J, Motzer RJ, Pierorazio PM, Powles T, Roupret M, Stewart GD, Turajlic S, Bex A. Neoadjuvant and Adjuvant Immune-based Approach for Renal Cell Carcinoma: Pros, Cons, and Future Directions. Eur Urol Oncol 2025; 8:494-509. [PMID: 39327187 DOI: 10.1016/j.euo.2024.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/22/2024] [Accepted: 09/07/2024] [Indexed: 09/28/2024]
Abstract
CONTEXT Immune-oncology strategies are revolutionising the perioperative treatment in several tumour types. The perioperative setting of renal cell carcinoma (RCC) is an evolving field, and the advent of immunotherapy is producing significant advances. OBJECTIVE To critically review the potential pros and cons of adjuvant and neoadjuvant immune-based therapeutic strategies in RCC, and to provide insights for future research in this field. EVIDENCE ACQUISITION We performed a collaborative narrative review of the existing literature. EVIDENCE SYNTHESIS Adjuvant immunotherapy with pembrolizumab is a new standard of care for patients at a higher risk of recurrence after nephrectomy, demonstrating a disease-free survival and overall survival benefit in the phase 3 KEYNOTE-564 trial. Current data do not support neoadjuvant therapy use outside clinical trials. While both adjuvant and neoadjuvant immune-based approaches are driven by robust biological rationale, neoadjuvant immunotherapy may enable a stronger and more durable antitumour immune response. If neoadjuvant single-agent immune checkpoint inhibitors demonstrated limited activity on the primary tumour, immune-based combinations may show increased activity. Overtreatment and a risk of relevant toxicity for patients who are cured by surgery alone are common concerns for both neoadjuvant and adjuvant strategies. Biomarkers helping patient selection and treatment deintensification are lacking in RCC. No results from randomised trials comparing neoadjuvant or perioperative immune-based therapy with adjuvant immunotherapy are available. CONCLUSIONS Adjuvant immunotherapy is a new standard of care in RCC. Both neoadjuvant and adjuvant immunotherapy strategies have potential advantages and disadvantages. Optimising perioperative treatment strategies is nuanced, with the role of neoadjuvant immune-based therapies yet to be defined. Given strong biological rationale for a pre/perioperative approach, there is a need for prospective clinical trials to determine clinical efficacy. Research investigating biomarkers aiding patient selection and treatment deintensification strategies is needed. PATIENT SUMMARY Immunotherapy is transforming the treatment of kidney cancer. In this review, we looked at the studies investigating immunotherapy strategies before and/or after surgery for patients with kidney cancer to assess potential pros and cons. We concluded that both neoadjuvant and adjuvant immunotherapy strategies may have potential advantages and disadvantages. While immunotherapy administered after surgery is already a standard of care, immunotherapy before surgery should be better investigated in future studies. Future trials should also focus on the selection of patients in order to spare toxicity for patients who will be cured by surgery alone.
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Affiliation(s)
- Laura Marandino
- Skin and Renal Units, The Royal Marsden NHS Foundation Trust, London, UK; European Association of Urology (EAU) Young Academic Urologists (YAU) Renal Cancer Working Group, Arnhem, The Netherlands.
| | - Riccardo Campi
- European Association of Urology (EAU) Young Academic Urologists (YAU) Renal Cancer Working Group, Arnhem, The Netherlands; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Unit of Urological Robotic Surgery and Renal Transplantation, Careggi Hospital, Florence, Italy.
| | - Daniele Amparore
- European Association of Urology (EAU) Young Academic Urologists (YAU) Renal Cancer Working Group, Arnhem, The Netherlands; Division of Urology, Department of Oncology, School of Medicine, San Luigi Hospital, University of Turin, Orbassano, Italy
| | - Zayd Tippu
- Skin and Renal Units, The Royal Marsden NHS Foundation Trust, London, UK; Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK; Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK
| | - Laurence Albiges
- Department of Medical Oncology, Gustave Roussy, Villejuif, France
| | - Umberto Capitanio
- IRCCS San Raffaele Scientific Institute, Urological Research Institute (URI), Milan, Italy; University Vita-Salute San Raffaele, Milan, Italy
| | - Rachel H Giles
- VHL Europa, Vlaardingen, The Netherlands; International Kidney Cancer Coalition, Duivendrecht, The Netherlands
| | - Silke Gillessen
- Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
| | - Alexander Kutikov
- Department of Urology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - James Larkin
- Skin and Renal Units, The Royal Marsden NHS Foundation Trust, London, UK
| | | | | | - Thomas Powles
- Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, London, UK; Royal Free National Health Service Trust, London, UK
| | - Morgan Roupret
- GRC 5 Predictive Onco-Uro, Department of Urology, AP-HP, Pitié Salpétrière Hospital, Sorbonne University, Paris, France
| | - Grant D Stewart
- Department of Surgery, University of Cambridge, Cambridge, UK; CRUK Cambridge Centre, Cambridge, UK
| | - Samra Turajlic
- Skin and Renal Units, The Royal Marsden NHS Foundation Trust, London, UK; Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK; Melanoma and Kidney Cancer Team, The Institute of Cancer Research, London, UK
| | - Axel Bex
- The Royal Free London NHS Foundation Trust, London, UK; UCL Division of Surgery and Interventional Science, University College London, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
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21
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Schmidinger M, Huebner-Resch I. Adjuvant personalized cancer vaccine: is this the end of metastatic kidney cancer. Nat Rev Urol 2025:10.1038/s41585-025-01018-6. [PMID: 40148578 DOI: 10.1038/s41585-025-01018-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Affiliation(s)
- Manuela Schmidinger
- Department of Urology, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria.
| | - Irene Huebner-Resch
- Department of Urology, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
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22
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Furukawa J, Tomida R, Daizumoto K, Sasaki Y, Fukawa T. Advances in Adjuvant Therapy for Renal Cell Carcinoma: Perspectives on Risk Stratification and Treatment Outcomes. Int J Urol 2025. [PMID: 40123286 DOI: 10.1111/iju.70050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 02/06/2025] [Accepted: 03/13/2025] [Indexed: 03/25/2025]
Abstract
Radical surgery is effective for localized renal cell carcinoma (RCC). However, recurrence occurs in up to 40% of patients, underscoring the need for adjuvant therapy to improve the prognosis. Historically, adjuvant treatments, including tyrosine kinase inhibitors, have shown limited success, failing to improve overall survival. The introduction of the immune checkpoint inhibitor pembrolizumab, as demonstrated in the KEYNOTE-564 trial, has revolutionized the field by showing significant overall survival benefits and prompting updates to RCC treatment guidelines. Accurate risk assessment is critical for identifying high-risk patients most likely to benefit from adjuvant therapy. Established risk models, such as the UCLA Integrated Staging System and the Leibovich score, incorporate clinical and pathological factors to stratify recurrence risk. Recent enhancements in these models have improved predictive accuracy, enabling better optimization of inclusion criteria for clinical trials targeting high-risk recurrence and the development of individualized surveillance protocols to refine patient selection for adjuvant treatment. This review examines the evolution of risk stratification models and adjuvant therapy for RCC, highlighting the potential of innovative biomarkers, such as liquid biopsies, to further enhance patient selection and optimize treatment outcomes. Ongoing clinical trials investigating new combinations of immune checkpoint inhibitors hold promise, and integrating accurate risk assessment with advanced immunotherapy will be key to improving postoperative survival rates for patients with RCC.
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Affiliation(s)
- Junya Furukawa
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Ryotaro Tomida
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Kei Daizumoto
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Yutaro Sasaki
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Tomoya Fukawa
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
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23
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Hannan R, Mollica V, Palumbo C, Erdem S. Stereotactic Radiation for Primary Renal Cell Carcinoma: Is It Ready for Prime Time? Eur Urol Oncol 2025:S2588-9311(25)00051-3. [PMID: 40089404 DOI: 10.1016/j.euo.2025.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 02/27/2025] [Indexed: 03/17/2025]
Affiliation(s)
- Raquibul Hannan
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Veronica Mollica
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Carlotta Palumbo
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy; Urology Unit, Maggiore della Carità Hospital, Novara, Italy
| | - Selcuk Erdem
- Division of Urologic Oncology, Department of Urology, Faculty of Medicine, Istanbul University, Istanbul, Turkey.
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24
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Bex A, Ghanem YA, Albiges L, Bonn S, Campi R, Capitanio U, Dabestani S, Hora M, Klatte T, Kuusk T, Lund L, Marconi L, Palumbo C, Pignot G, Powles T, Schouten N, Tran M, Volpe A, Bedke J. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2025 Update. Eur Urol 2025:S0302-2838(25)00139-3. [PMID: 40118739 DOI: 10.1016/j.eururo.2025.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 02/25/2025] [Indexed: 03/23/2025]
Abstract
BACKGROUND AND OBJECTIVE The European Association of Urology (EAU) renal cell carcinoma (RCC) guideline panel has updated their evidence-based guidelines and recommendations for the management of RCC. Here we present a summary of the 2025 RCC guidelines updated with standardised methodology to provide reproducible evidence for the management of RCC. METHODS For the 2025 update, a literature search was performed covering the period from May 1, 2023 to May 1, 2024 using the Medline, EMBASE, and Cochrane Libraries. The data search focused on meta-analyses, systematic reviews, randomised controlled trials (RCTs), and retrospective or controlled comparator-arm studies. Evidence was synthesised as outlined for all EAU guidelines. KEY FINDINGS AND LIMITATIONS Clinical practise recommendations were updated in all chapters of the RCC guidelines on the basis of a structured literature search. The studies included were predominantly retrospective with matched or unmatched cohorts based on single- or multi-institutional data. Several prospective studies and RCTs provided data that resulted in recommendations based on higher levels of evidence. Specifically, updates include new recommendations on stereotactic body radiotherapy for localised RCC, adjuvant therapy, systemic therapy for clear-cell RCC in later lines, other subtypes, and a new chapter on hereditary RCC. CONCLUSIONS AND CLINICAL IMPLICATIONS The 2025 RCC guidelines have been updated by a multidisciplinary panel of experts using methodological standards to provide a contemporary evidence base for the management of RCC.
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Affiliation(s)
- Axel Bex
- Royal Free London NHS Foundation Trust, London, UK; Division of Surgery and Interventional Science, University College London, London, UK; Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
| | - Yasmin Abu Ghanem
- Department of Urology, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
| | - Laurence Albiges
- Department of Cancer Medicine, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Stephanie Bonn
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Riccardo Campi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; Unit of Urology and Renal Transplantation, Careggi Hospital, Florence, Italy
| | - Umberto Capitanio
- Department of Urology, San Raffaele Scientific Institute, Milan, Italy; Division of Experimental Oncology/Unit of Urology, Urological Research Institute, IRCCS San Raffaele Hospital, Milan, Italy
| | - Saeed Dabestani
- Department of Translational Medicine, Division of Urological Cancers, Lund University, Malmö, Sweden
| | - Milan Hora
- Department of Urology, University Hospital Pilsen and Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
| | - Tobias Klatte
- Department of Urology, Helios Hospital, Bad Saarow, Germany; Faculty of Health Sciences Brandenburg, Brandenburg Medical School Theodor Fontane, Brandenburg, Germany
| | - Teele Kuusk
- Homerton University Hospital London to now Addenbrooke's Hospital, Cambridge, UK
| | - Lars Lund
- Department of Urology, Odense University Hospital and Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Lorenzo Marconi
- Department of Urology, Coimbra University Hospital, Coimbra, Portugal
| | - Carlotta Palumbo
- Division of Urology, Department of Translational Medicine, University of Eastern Piedmont, Maggiore Della Carità Hospital, Novara, Italy
| | - Geraldine Pignot
- Department of Surgical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Thomas Powles
- Royal Free NHS Trust and Barts Cancer Institute, Queen Mary University of London, London, UK
| | | | - Maxine Tran
- Division of Surgery and Interventional Sciences, University College London, London, UK; Specialist Centre for Kidney Cancer, Royal Free Hospital, London, UK
| | - Alessandro Volpe
- Department of Urology, University of Eastern Piedmont, Maggiore della Carità Hospital, Novara, Italy
| | - Jens Bedke
- Department of Urology and Transplantation Surgery and Eva Mayr-Stihl Cancer Center, Klinikum Stuttgart, Stuttgart, Germany
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25
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Cui B, Luo H, He B, Liu X, Lv D, Zhang X, Su K, Zheng S, Lu J, Wang C, Yang Y, Zhao Z, Liu X, Wang X, Zhao Y, Nie X, Jiang Y, Zhang Z, Liu C, Chen X, Cai A, Lv Z, Liu Z, An F, Zhang Y, Yan Q, Kelley KW, Xu G, Xu L, Liu Q, Peng F. Gut dysbiosis conveys psychological stress to activate LRP5/β-catenin pathway promoting cancer stemness. Signal Transduct Target Ther 2025; 10:79. [PMID: 40038255 PMCID: PMC11880501 DOI: 10.1038/s41392-025-02159-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 01/02/2025] [Accepted: 01/23/2025] [Indexed: 03/06/2025] Open
Abstract
Psychological stress causes gut microbial dysbiosis and cancer progression, yet how gut microbiota determines psychological stress-induced tumor development remains unclear. Here we showed that psychological stress promotes breast tumor growth and cancer stemness, an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice. Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota, especially Akkermansia muciniphila (A. muciniphila), and decreases short-chain fatty acid butyrate. Supplement of active A. muciniphila, butyrate or a butyrate-producing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model. Mechanistically, RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway, dampening breast cancer stemness. Moreover, butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36, which further accelerates LRP5 mRNA decay by binding adenine uridine-rich (AU-rich) elements of LRP5 transcript. Clinically, fecal A. muciniphila and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression, poor prognosis and negative mood in breast cancer patients. Altogether, our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness, and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.
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Affiliation(s)
- Bai Cui
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Huandong Luo
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Bin He
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Xinyu Liu
- Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian, China
| | - Dekang Lv
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Xiaoyu Zhang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Keyu Su
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Sijia Zheng
- Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian, China
| | - Jinxin Lu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Cenxin Wang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Yuqing Yang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Zhuoran Zhao
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Xianxian Liu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Xu Wang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Yingrui Zhao
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Xiaoshan Nie
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Yuanyuan Jiang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Ziyu Zhang
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Congcong Liu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Xinyi Chen
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Anqi Cai
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Zhumeng Lv
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Zhihang Liu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Fan An
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Yunkun Zhang
- Department of Pathology, The Second Hospital of Dalian Medical University, Dalian, China
| | - Qiulong Yan
- Department of Microbiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Keith W Kelley
- Department of Pathology, College of Medicine and Department of Animal Sciences, College of ACES, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Guowang Xu
- Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian, China
| | - Lingzhi Xu
- Department of Oncology, the Second Affiliated Hospital, Dalian Medical University, Dalian, China.
| | - Quentin Liu
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
| | - Fei Peng
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
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Durbin SM, Zubiri L, Perlman K, Wu CY, Lim T, Grealish K, Hathaway N, LoPiccolo J, Wang M, Falade A, Molina G, Jacoby TV, Shah N, Mooradian MJ, Reynolds KL. Late-Onset Immune-Related Adverse Events After Immune Checkpoint Inhibitor Therapy. JAMA Netw Open 2025; 8:e252668. [PMID: 40146104 PMCID: PMC11950896 DOI: 10.1001/jamanetworkopen.2025.2668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 01/19/2025] [Indexed: 03/28/2025] Open
Abstract
Importance The use of immune checkpoint inhibitors (ICIs) is increasing. Little is known about the frequency of late-onset immune-related adverse events (irAEs) and the patient-specific risk factors associated with their development. Objectives To assess the incidence of persistent or de novo late-onset irAEs requiring hospitalization and identify patient factors associated with risk of late-onset irAEs. Design, Setting, and Participants This retrospective observational cohort study conducted from January 2011 to October 2022 included patients who received ICIs and were hospitalized with irAEs at an academic medical center. Exclusion criteria included ICI therapy outside of the hospital system and no irAE diagnosis during admission. Data were analyzed from November 15, 2022, to January 8, 2025. Exposure Late-onset irAEs. Main Outcomes and Measures The main study outcomes were (1) incidence of irAE hospitalization at 0 to 6 months (early), more than 6 to 12 months (intermediate), and more than 12 months (late) after ICI initiation and (2) patient factors associated with risk of late-onset irAEs. Results Among the 795 patients hospitalized with irAEs, the median age was 67.3 years (IQR, 58.3-74.8 years); 476 (59.9%) were male. Most patients (n = 517 [65.0%]) received anti-programmed death ligand 1 (PD-L1) and anti-programmed cell death 1 monotherapy, with the most common indications being melanoma (n = 335 [42.1%]) and lung cancer (n = 167 [21.0%]). The median time from start of ICI therapy to hospital admission was 2.7 months (IQR, 1.2-6.1 months), with 14.7% of patients (n = 117 of 795) presenting 6 to 12 months after initial ICI exposure and 10.8% of patients (86 of 795) presenting more than 12 months after initial exposure. The irAEs most likely to present late included those involving the kidney (10 of 32 [31.3%]) and hematologic (5 of 23 [21.7%]) organ systems. In univariate analysis, ICI type was significantly associated with the timing of hospital admission for irAEs; of the 517 patients receiving anti-PD-L1-based therapy, 13.5% (n = 70) presented late compared with 5.4% (9 of 167) receiving dual therapy with anti-cytotoxic T-lymphocyte-associated protein 4 (P < .001). Patients receiving perioperative ICI therapy were significantly more likely to be admitted at the intermediate interval (16 of 68 [23.5%]) compared with those with metastatic disease (87 of 678 [12.8%]) (P = .03). Timing of irAE was also significantly associated with active ICI exposure; among the patients presenting late, 7.4% (48 of 651) had received ICI therapy within the last 60 days compared with 26.4% (38 of 144) who had not had recent ICI exposure (P < .001). Conclusions and Relevance The findings of this retrospective observational cohort study suggest that late irAEs are possible, with a subset of patients presenting years after the start of ICI therapy. Clinicians must remain vigilant for irAEs regardless of elapsed time from ICI therapy, especially as patients live longer and ICIs become more widely used. Future investigations are needed to better understand the risk factors for late-onset irAEs and the distinct immunologic pathways that underlie such events.
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Affiliation(s)
- Sienna M. Durbin
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Leyre Zubiri
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Katherine Perlman
- Department of Dermatology, Massachusetts General Hospital & Harvard Medical School, Boston
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Chia-Yun Wu
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
- Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Tristan Lim
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Kelley Grealish
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Nora Hathaway
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Jaclyn LoPiccolo
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
- Dana Farber Cancer Institute, Boston, Massachusetts
| | - Mike Wang
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Ayo Falade
- Department of Oncology, Mayo Clinic, Rochester, Minnesota
- Department of Internal Medicine, Mass General Brigham Salem Hospital, Salem, Massachusetts
| | - Gabriel Molina
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Ted Victor Jacoby
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Nishi Shah
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Meghan J. Mooradian
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Kerry L. Reynolds
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
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27
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Calhoun SR, Vass C, Myers K, Imai K, Bussberg C, Bhattacharya R, Pinto CA, Poulos C. Patient preferences for adjuvant therapy in renal cell carcinoma: a discrete-choice experiment. Future Oncol 2025; 21:843-851. [PMID: 39935407 PMCID: PMC11921160 DOI: 10.1080/14796694.2025.2463276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 02/03/2025] [Indexed: 02/13/2025] Open
Abstract
INTRODUCTION To quantify patients' preferences for adjuvant renal cell carcinoma (RCC) treatments. PATIENTS AND METHODS Preferences were elicited using a discrete-choice experiment requiring RCC patients to choose between 2 hypothetical treatments. Data were analyzed using random-parameters logit and latent-class models. RESULTS Patients (n = 250) preferred treatments that increase disease-free and overall survival (OS), are taken less frequently, require no concomitant medication, have a shorter duration, and have lower side-effect risks. The analyses also highlighted their willingness to make tradeoffs between these benefits and risks. Patients were generally tolerant of increases in the risks of treatment-related severe diarrhea, dizziness, and fatigue and were willing to accept increases in these risks in exchange for improvements in overall or disease-free survival. Latent-class analysis identified 3 classes: class 1 (37.5%) and class 2 (26.9%) preferred not to opt out of treatment and prioritized increased OS and disease-free survival, respectively; class 3 (35.5%) preferred to opt out and prioritized mode, duration, and risks. CONCLUSIONS Heterogeneity suggests patient-physician discussions are important when considering RCC treatments.
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Affiliation(s)
| | | | - Kelley Myers
- RTI Health Solutions, Research Triangle Park, NC, USA
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Shapiro DD, Msaouel P. Challenges and Considerations in Modern Adjuvant Therapy Trials in Renal Cell Carcinoma: A Call to Power. Eur Urol 2025; 87:278-280. [PMID: 39472204 DOI: 10.1016/j.eururo.2024.10.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 09/22/2024] [Accepted: 10/18/2024] [Indexed: 02/21/2025]
Abstract
Identification of effective adjuvant therapies for renal cell carcinoma remains challenging despite the development of immune checkpoint inhibitors. Enhancement of the design of trials of adjuvant therapy by focusing on populations with the highest risk and increasing the sample size is essential for reliable assessments of therapeutic efficacy.
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Affiliation(s)
- Daniel D Shapiro
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Division of Urology, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
| | - Pavlos Msaouel
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Suzuki S, Yamamoto Y, Kato T, Hatano K, Matsui T, Hashimoto K, Miyamura T, Nagashima Y, Nonomura N, Kawashima A. Postmortem genetic diagnosis of hereditary leiomyomatosis and renal cell carcinoma syndrome: Identification through normal kidney tissues after surgical removal. IJU Case Rep 2025; 8:109-113. [PMID: 40034895 PMCID: PMC11872217 DOI: 10.1002/iju5.12820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/26/2024] [Indexed: 03/05/2025] Open
Abstract
Introduction Hereditary leiomyomatosis and renal cell cancer is an autosomal dominant disorder caused by germline mutations in the FH gene and is associated with poor prognosis of aggressive renal cancer. Case presentation A 33-year-old man presented with asymptomatic gross hematuria and was diagnosed with a right renal tumor, cT3aN1M0. He underwent open radical nephrectomy, and pathological examination revealed papillary renal cell carcinoma. Despite aggressive treatment, the disease progressed rapidly, and discussions regarding genetic testing could not take place during his lifetime, although circulating-tumor DNA showed mutation of FH gene. After death, his wife requested postmortem genetic testing. Genetic analysis using DNA extracted from normal kidney tissues in surgical specimens (blood sample absence) confirmed the FH mutation, and hereditary leiomyomatosis and renal cell cancer was diagnosed posthumously. Conclusion This highlights the utility of postmortem genetic testing of surgical specimens to diagnose hereditary leiomyomatosis and renal cell cancer and provide genetic counseling to families, despite limitations during the patient's life.
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Affiliation(s)
- Shodai Suzuki
- Department of UrologyOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Yoshiyuki Yamamoto
- Department of UrologyOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Taigo Kato
- Department of UrologyOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Koji Hatano
- Department of UrologyOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Takahiro Matsui
- Department of PathologyOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Kae Hashimoto
- Department of Genetic CounselingOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Takako Miyamura
- Department of PediatricsOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Yoji Nagashima
- Department of Surgical PathologyTokyo Women's Medical University HospitalTokyoJapan
| | - Norio Nonomura
- Department of UrologyOsaka University Graduate School of MedicineSuitaOsakaJapan
| | - Atsunari Kawashima
- Department of UrologyOsaka University Graduate School of MedicineSuitaOsakaJapan
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30
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Braun DA, Moranzoni G, Chea V, McGregor BA, Blass E, Tu CR, Vanasse AP, Forman C, Forman J, Afeyan AB, Schindler NR, Liu Y, Li S, Southard J, Chang SL, Hirsch MS, LeBoeuf NR, Olive O, Mehndiratta A, Greenslade H, Shetty K, Klaeger S, Sarkizova S, Pedersen CB, Mossanen M, Carulli I, Tarren A, Duke-Cohan J, Howard AA, Iorgulescu JB, Shim B, Simon JM, Signoretti S, Aster JC, Elagina L, Carr SA, Leshchiner I, Getz G, Gabriel S, Hacohen N, Olsen LR, Oliveira G, Neuberg DS, Livak KJ, Shukla SA, Fritsch EF, Wu CJ, Keskin DB, Ott PA, Choueiri TK. A neoantigen vaccine generates antitumour immunity in renal cell carcinoma. Nature 2025; 639:474-482. [PMID: 39910301 PMCID: PMC11903305 DOI: 10.1038/s41586-024-08507-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 12/10/2024] [Indexed: 02/07/2025]
Abstract
Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens1-6. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient's tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden. Here we conducted a phase I trial (ClinicalTrials.gov identifier NCT02950766) to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV) with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 months after surgery, none of the 9 participants enrolled in the study had a recurrence of RCC. No dose-limiting toxicities were observed. All patients generated T cell immune responses against the PCV antigens, including to RCC driver mutations in VHL, PBRM1, BAP1, KDM5C and PIK3CA. Following vaccination, there was a durable expansion of peripheral T cell clones. Moreover, T cell reactivity against autologous tumours was detected in seven out of nine patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations and can induce antitumour immunity. These observations, in conjunction with the absence of recurrence in all nine vaccinated patients, highlights the promise of PCVs as effective adjuvant therapy in RCC.
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Affiliation(s)
- David A Braun
- Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
- Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
| | - Giorgia Moranzoni
- Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Vipheaviny Chea
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Bradley A McGregor
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Eryn Blass
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Chloe R Tu
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Allison P Vanasse
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Cleo Forman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Juliet Forman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Alexander B Afeyan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Nicholas R Schindler
- Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Yiwen Liu
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Shuqiang Li
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jackson Southard
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Steven L Chang
- Harvard Medical School, Boston, MA, USA
- Department of Urology, Brigham and Women's Hospital, Boston, MA, USA
| | - Michelle S Hirsch
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Nicole R LeBoeuf
- Harvard Medical School, Boston, MA, USA
- Center for Cutaneous Oncology, Dana-Farber Brigham and Women's Cancer Center, Boston, MA, USA
- Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA
| | - Oriol Olive
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ambica Mehndiratta
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Haley Greenslade
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Keerthi Shetty
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Susan Klaeger
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | | | - Christina B Pedersen
- Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
- Center for Genomic Medicine, Rigshospitalet-Copenhagen University Hospital, Copenhagen, Denmark
| | - Matthew Mossanen
- Harvard Medical School, Boston, MA, USA
- Department of Urology, Brigham and Women's Hospital, Boston, MA, USA
| | - Isabel Carulli
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Anna Tarren
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Joseph Duke-Cohan
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Alexis A Howard
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
| | - J Bryan Iorgulescu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Molecular Diagnostics Laboratory, Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bohoon Shim
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jeremy M Simon
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - Sabina Signoretti
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jon C Aster
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | | | - Steven A Carr
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Ignaty Leshchiner
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, USA
| | - Gad Getz
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | | | - Nir Hacohen
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Lars R Olsen
- Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Giacomo Oliveira
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Donna S Neuberg
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Kenneth J Livak
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sachet A Shukla
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Edward F Fritsch
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Catherine J Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Derin B Keskin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Computer Science, Metropolitan College, Boston University, Boston, MA, USA
| | - Patrick A Ott
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Toni K Choueiri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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Bilen MA, Vo BT, Liu Y, Greenwald R, Davarpanah AH, McGuire D, Shiradkar R, Li L, Midya A, Nazha B, Brown JT, Williams S, Session W, Russler G, Caulfield S, Joshi SS, Narayan VM, Filson CP, Ogan K, Kucuk O, Carthon BC, Del Balzo L, Cohen A, Boyanton A, Prokhnevska N, Cardenas MA, Sobierajska E, Jansen CS, Patil DH, Nicaise E, Osunkoya AO, Kissick HT, Master VA. Neoadjuvant cabozantinib for locally advanced nonmetastatic clear cell renal cell carcinoma: a phase 2 trial. NATURE CANCER 2025; 6:432-444. [PMID: 40016487 DOI: 10.1038/s43018-025-00922-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 01/29/2025] [Indexed: 03/01/2025]
Abstract
Cabozantinib is an oral multikinase inhibitor approved for treatment in metastatic renal cell carcinoma (RCC). We conducted a phase 2, nonrandomized, single-arm clinical trial (NCT04022343) of cabozantinib treatment for 12 weeks in 17 patients with locally advanced, biopsy-proven, nonmetastatic clear cell RCC before surgical resection. The primary end point was the objective response rate (complete and partial responses) at week 12 and secondary end points included safety, tolerability, clinical and surgical outcomes, and quality of life. Six patients (35%) experienced a partial response and 11 patients (65%) had stable disease. The most common adverse events were diarrhea (n = 12, 70.6%), anorexia, fatigue and hypertension (n = 10, 58.8%), nausea and palmar-plantar erythrodysesthesia syndrome (n = 9, 52.9%). No treatment grade 4 or 5 adverse events related to cabozantinib or surgery occurred. The 1-year disease-free survival and overall survival were 82.4% (95% CI 54.7-93.9%) and 94.1% (95% CI 65-99.1%), respectively. Cabozantinib treatment activated CD8+ T cells in the blood, depleted myeloid populations and induced immune niches for TCF1+ stem-like CD8+ T cells. Cabozantinib was clinically active and safe in the neoadjuvant setting in patients with locally advanced nonmetastatic clear cell RCC.
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Affiliation(s)
- Mehmet A Bilen
- Winship Cancer Institute of Emory University, Atlanta, GA, USA.
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
| | - BaoHan T Vo
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Yuan Liu
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Rachel Greenwald
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Amir H Davarpanah
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Donald McGuire
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
- Emory Vaccine Center, Emory University, Atlanta, GA, USA
| | - Rakesh Shiradkar
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Liping Li
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Adhishek Midya
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Bassel Nazha
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - Jacqueline T Brown
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - Sierra Williams
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Wilena Session
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Greta Russler
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Sarah Caulfield
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Pharmaceutical Services, Emory University School of Medicine, Atlanta, GA, USA
| | - Shreyas S Joshi
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Vikram M Narayan
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | | | - Kenneth Ogan
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Omer Kucuk
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - Bradley Curtis Carthon
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - Luke Del Balzo
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Athena Cohen
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Adriana Boyanton
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | | | | | - Ewelina Sobierajska
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Caroline S Jansen
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Dattatraya H Patil
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Edouard Nicaise
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Adeboye O Osunkoya
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
- Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA
| | - Haydn T Kissick
- Winship Cancer Institute of Emory University, Atlanta, GA, USA.
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.
- Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
- Emory Vaccine Center, Emory University, Atlanta, GA, USA.
| | - Viraj A Master
- Winship Cancer Institute of Emory University, Atlanta, GA, USA.
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA.
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Zhang D, Shen C, Zhang W, Chen H, Zhao J. Efficacy and safety of PD-1/PD-L1 inhibitors alone or in combination in the treatment of metastatic or advanced renal cell carcinoma: a network meta-analysis. Front Immunol 2025; 16:1524497. [PMID: 40070839 PMCID: PMC11893867 DOI: 10.3389/fimmu.2025.1524497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 01/20/2025] [Indexed: 03/14/2025] Open
Abstract
Background This study systematically reviews the efficacy and safety of the single or combined use of programmed factor 1 (PD-1)/programmed factor 1 ligand (PD-L1) inhibitors for treating metastatic or advanced renal cell carcinoma (RCC). Methods Relevant articles were collected for meta-analysis through searches on PubMed, Web of Science, Embase, Cochrane Library, and Clinical Trials, as well as for relevant randomized controlled experiments. Results Based on eleven studies, the effectiveness of the experimental group was found to be significantly better than the control in terms of overall survival (OS) [R=0.74, 95%CI: 0.69~0.80, P<0.00001], progression-free survival (PFS) [HR=0.68, 95%CI: 0.57~0.81, P<0.0001], objective response rate (ORR) [RR=1.71, 95%CI: 1.39~2.12, P<0.00001], complete response rate (CR) [RR=2.99 95%CI: 2.34~3.83, P<0.0001], partial response rate (PR) [RR=1.56, 95%CI: 1.20~2.01, P=0.001], and disease control rate (DCR) [RR=1.13, 95%CI: 1.06~1.20, P<0.0001]. No statistical significance was observed between the experimental and control groups in overall adverse reactions (AEs) [RR=1.01, 95%CI: 0.98~1.04, P=0.598], the incidence of stage I~II adverse reactions [RR=1.02, 95%CI: 0.88~1.17, P=0.818], or stage III~V adverse reactions [RR=0.98, 95%CI: 0.81~1.18, P=0.817]. Regarding subgroup analysis, the incidence of dysphonia, rash, hypothyroidism, arthralgia, and pruritus in the experimental group was significantly higher than in the control. Compared with the control group, the incidence of diarrhea, nausea, indigestion, and fatigue in the experimental group was not statistically significant. Conclusion A good efficacy was found in treating metastatic or advanced RCC using PD-1/PD-L1 inhibitors alone or in combination, which significantly improved and enhanced OS, PFS, ORR, CR, PR, and DCR in patients with RCC. The incidence of adverse reactions in patients was not increased, and adverse reactions were controllable. These findings indicate that the single or combined use of PD-1/PD-L1 inhibitors shows good efficacy and safety in the treatment of metastatic or advanced RCC.
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Affiliation(s)
- Dongli Zhang
- Hebei University of Engineering School of Medicine, Handan, Hebei, China
| | - Chong Shen
- Hebei University of Engineering School of Medicine, Handan, Hebei, China
| | - Weichuan Zhang
- Second Department of Urology and Surgery, Affiliated Hospital of Hebei Engineering University, Handan, China
| | - Haibin Chen
- Second Department of Urology and Surgery, Affiliated Hospital of Hebei Engineering University, Handan, China
| | - Jianjun Zhao
- Second Department of Urology and Surgery, Affiliated Hospital of Hebei Engineering University, Handan, China
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Najem EJ, Shaikh MJS, Shinagare AB, Krajewski KM. Navigating advanced renal cell carcinoma in the era of artificial intelligence. Cancer Imaging 2025; 25:16. [PMID: 39966980 PMCID: PMC11837394 DOI: 10.1186/s40644-025-00835-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 02/05/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Research has helped to better understand renal cell carcinoma and enhance management of patients with locally advanced and metastatic disease. More recently, artificial intelligence has emerged as a powerful tool in cancer research, particularly in oncologic imaging. BODY: Despite promising results of artificial intelligence in renal cell carcinoma research, most investigations have focused on localized disease, while relatively fewer studies have targeted advanced and metastatic disease. This paper summarizes major artificial intelligence advances focusing mostly on their potential clinical value from initial staging and identification of high-risk features to predicting response to treatment in advanced renal cell carcinoma, while addressing major limitations in the development of some models and highlighting new avenues for future research. CONCLUSION Artificial intelligence-enabled models have a great potential in improving clinical practice in the diagnosis and management of advanced renal cell carcinoma, particularly when developed from both clinicopathologic and radiologic data.
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Affiliation(s)
- Elie J Najem
- Department of Imaging, Dana-Farber Cancer Institute, Boston, MA, USA.
| | - Mohd Javed S Shaikh
- Department of Imaging, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA
| | - Atul B Shinagare
- Department of Imaging, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA
| | - Katherine M Krajewski
- Department of Imaging, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA
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Peláez I, Lázaro-Quintela M, Pérez-Fentes D, Esteban-González E, Gallardo E, Álvarez-Fernández C, Álvarez Rodríguez P, Anido-Herranz U, Azpitarte Raposeiras C, Castro-Iglesias ÁM, Fernández Calvo O, Fernández Núñez N, Folgar-Torres A, García Lorenzo C, González-Del-Alba A, Méndez-Vidal MJ, Molina Díaz A, Gómez IR, Vázquez-Estévez S. Clinical advances and practice updates in genitourinary cancers: a 2024 review from the multidisciplinary Spanish 'Cambados annual meeting'. Clin Transl Oncol 2025:10.1007/s12094-025-03850-z. [PMID: 39961959 DOI: 10.1007/s12094-025-03850-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 01/08/2025] [Indexed: 03/28/2025]
Abstract
Prostate, bladder and kidney neoplasms are among the most prevalent genitourinary (GU) cancers worldwide. Significant therapeutic advancements in recent years have substantially improved patient outcomes. In response to this rapid progress, the Santiago de Compostela Health Research Institute (IDIS) has organized the annual 'Cambados Consensus Forum on Genitourinary Tumors' (Pontevedra, Spain) since 2018. This 2-day multidisciplinary meeting gathers Spanish medical oncologists, radiation oncologists, urologists, and hospital pharmacists to present and discuss the latest evidence in the field, merging from international congresses or journal publications. This review provides an overview of the most recent evidence regarding therapeutic advances in prostate cancer, renal cell carcinoma, and bladder cancer presented at the 2024 meeting (October), with a special focus on practice-changing innovations.
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Affiliation(s)
- Ignacio Peláez
- Medical Oncology Service, Hospital Universitario de Cabueñes, Gijón, Asturias, Spain
| | - Martín Lázaro-Quintela
- Medical Oncology Department, Complexo Hospitalario Universitario de Vigo, Pontevedra, Spain
| | - Daniel Pérez-Fentes
- Urology Department, Complexo Hospitalario Universitario de Santiago de Compostela, A Coruña, Spain
| | | | - Enrique Gallardo
- Department of Oncology, Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain
| | | | | | - Urbano Anido-Herranz
- Medical Oncology Department, Complexo Hospitalario Universitario de Santiago de Compostela, A Coruña, Spain
| | | | | | - Ovidio Fernández Calvo
- Medical Oncology Department, Complejo Hospitalario Universitario Ourense, Ourense, Spain
| | | | - Alicia Folgar-Torres
- Radiation Oncology Department, Hospital Universitario Lucus Augusti, Lugo, Spain
| | - Carme García Lorenzo
- Medical Oncology Department, Complexo Hospitalario Universitario Ferrol, A Coruña, Spain
| | | | - María José Méndez-Vidal
- Medical Oncology Department, Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Aurea Molina Díaz
- Medical Oncology Department, Complexo Hospitalario Universitario A Coruña, A Coruña, Spain
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Wu X, Lazris D, Wong R, Tykodi SS. Belzutifan for the treatment of renal cell carcinoma. Ther Adv Med Oncol 2025; 17:17588359251317846. [PMID: 39926260 PMCID: PMC11806488 DOI: 10.1177/17588359251317846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/17/2025] [Indexed: 02/11/2025] Open
Abstract
Belzutifan received its first FDA approval in 2021 for treating clinical manifestations of von Hippel-Lindau (VHL) disease including renal cell carcinoma (RCC) followed by approval in 2023 for treating advanced sporadic RCC that has progressed through multiple lines of treatment. It is the first FDA-approved drug to target hypoxia-inducible factor 2 alpha (HIF-2α). By inhibiting the HIF-2α transcription factor, belzutifan prevents HIF-2α from dimerizing with HIF-1β, thereby preventing the transcription of downstream oncogenes. Most clear cell renal cell carcinoma (ccRCC) tumors are associated with VHL deletion or inactivation resulting in HIF-2α overexpression that represents a key contributor to tumorigenesis, thereby making belzutifan a uniquely optimal drug for targeting ccRCC. Belzutifan has demonstrated activity in clinical trials as a front- and later-line therapy, and in combination with tyrosine kinase inhibitors. It has been largely well tolerated, although anemia represents a common on-target side effect and, along with hypoxia, requires monitoring during treatment. Ongoing phase III trials are investigating belzutifan in combination regimens in the relapsed/refractory, front-line, and adjuvant settings. Future studies will focus on identifying predictive biomarkers and resistance pathways.
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Affiliation(s)
- Xiancheng Wu
- Department of Medicine, Division of Hematology and Oncology, University of Washington/Fred Hutchinson Cancer Center, 1100 Fairview Avenue N – M1-B208, Seattle, WA 98109-1024, USA
- Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - David Lazris
- Department of Medicine, Division of Internal Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Risa Wong
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Scott S. Tykodi
- Department of Medicine, Division of Hematology and Oncology, University of Washington, Seattle, WA, USA
- Fred Hutchinson Cancer Center, Seattle, WA, USA
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Bischoff ME, Shamsaei B, Yang J, Secic D, Vemuri B, Reisz JA, D’Alessandro A, Bartolacci C, Adamczak R, Schmidt L, Wang J, Martines A, Venkat J, Tcheuyap VT, Biesiada J, Behrmann CA, Vest KE, Brugarolas J, Scaglioni PP, Plas DR, Patra KC, Gulati S, Landero Figueroa JA, Meller J, Cunningham JT, Czyzyk-Krzeska MF. Copper Drives Remodeling of Metabolic State and Progression of Clear Cell Renal Cell Carcinoma. Cancer Discov 2025; 15:401-426. [PMID: 39476412 PMCID: PMC11803400 DOI: 10.1158/2159-8290.cd-24-0187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 09/23/2024] [Accepted: 10/30/2024] [Indexed: 11/02/2024]
Abstract
SIGNIFICANCE The work establishes a requirement for glucose-dependent coordination between energy production and redox homeostasis, which is fundamental for the survival of cancer cells that accumulate Cu and contributes to tumor growth.
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Affiliation(s)
- Megan E. Bischoff
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Behrouz Shamsaei
- Department of Biostatistics, Health Informatics and Data Sciences, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Division of Biostatistics and Bioinformatics, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Juechen Yang
- Department of Biostatistics, Health Informatics and Data Sciences, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Division of Biostatistics and Bioinformatics, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Dina Secic
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Bhargav Vemuri
- Department of Biostatistics, Health Informatics and Data Sciences, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Julie A. Reisz
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado
| | - Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado
| | - Caterina Bartolacci
- Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Rafal Adamczak
- Institute of Engineering and Technology, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University, Torun, Poland
| | - Lucas Schmidt
- Trace Elements Group, Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jiang Wang
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Amelia Martines
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Jahnavi Venkat
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Vanina Toffessi Tcheuyap
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jacek Biesiada
- Division of Biostatistics and Bioinformatics, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Catherine A. Behrmann
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Katherine E. Vest
- Department of Molecular and Cellular Biosciences, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - James Brugarolas
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Pier Paolo Scaglioni
- Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - David R. Plas
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Krushna C. Patra
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Shuchi Gulati
- Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Division of Oncology and Hematology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, California
| | - Julio A. Landero Figueroa
- Trace Elements Group, Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jarek Meller
- Department of Biostatistics, Health Informatics and Data Sciences, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Division of Biostatistics and Bioinformatics, Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Institute of Engineering and Technology, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University, Torun, Poland
- Department of Computer Science, University of Cincinnati College of Engineering and Applied Sciences, Cincinnati, Ohio
| | - John T. Cunningham
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Maria F. Czyzyk-Krzeska
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Department of Veterans Affairs, Veteran Affairs Medical Center, Cincinnati, Ohio
- Department of Pharmacology and System Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio
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Jian Y, Yang K, Li J, Tang L, Zeng G, Sun X, Yu X, Al-Danakh A, Chen Q, Yang D, Wang S. Comprehensive analysis of α2,3-sialyltransferases as prognostic biomarkers and immunotherapy targets in kidney renal clear cell carcinoma. Cancer Cell Int 2025; 25:36. [PMID: 39920744 PMCID: PMC11806589 DOI: 10.1186/s12935-025-03640-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 01/07/2025] [Indexed: 02/09/2025] Open
Abstract
Kidney renal clear cell carcinoma (KIRC), a therapy-resistant aggressive kidney cancer, exhibits resistance to immune checkpoint inhibitors. Altered sialylation is involved in tumor development, affecting immune microenvironment dynamics. In the study, through systematic bioinformatics analysis and experimental verification, we demonstrated that ST3Gal5 expression was elevated in tumor tissues of KIRC patients, correlating with poor prognosis, and ST3Gal1 was downregulated and associated with a better prognosis. Immunohistochemistry analysis confirmed the expression patterns of ST3Gal1 and ST3Gal5 in 30 KIRC patients. Furthermore, KIRC patients were stratified into two clusters based on ST3Gal1 and ST3Gal5 levels using consensus clustering to investigate their roles in KIRC tumorigenesis, immune characteristics and treatment sensitivity. KIRC patients in Cluster 2, characterized by increased ST3Gal5 and downregulated ST3Gal1 expression, exhibited increased expression of immune checkpoints, immune cell infiltration, immune escape scores, and worse prognosis. Knockdown of ST3Gal5 in KIRC cell lines (786-O and 769-P) resulted in reduced tumor proliferation, migration, and invasion in vivo and in vitro. Together, the dysregulation of sialyltransferases (ST3Gal1 and ST3Gal5) in KIRC influences tumorigenesis and immune responses. These findings underscore the potential of ST3Gal1 and ST3Gal5 as prognostic factors and immunotherapy targets for KIRC.
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Affiliation(s)
- Yuli Jian
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, 116011, China
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Kangkang Yang
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Jinjing Li
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Ling Tang
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Guang Zeng
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Xiaoxin Sun
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Xiao Yu
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Abdullah Al-Danakh
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, 116011, China
| | - Qiwei Chen
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, 116011, China.
| | - Deyong Yang
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, 116011, China.
| | - Shujing Wang
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
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A personalized cancer vaccine to prevent the return of high-risk kidney cancer. Nature 2025:10.1038/d41586-025-00308-8. [PMID: 39910358 DOI: 10.1038/d41586-025-00308-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2025]
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Khene ZE, Bhanvadia R, Tachibana I, Sharma P, Trevino I, Graber W, Bertail T, Fleury R, Acosta O, De Crevoisier R, Bensalah K, Lotan Y, Margulis V. Impact of contrast enhancement phase on CT-based radiomics analysis for predicting post-surgical recurrence in renal cell carcinoma. Jpn J Radiol 2025:10.1007/s11604-025-01740-6. [PMID: 39907976 DOI: 10.1007/s11604-025-01740-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 01/09/2025] [Indexed: 02/06/2025]
Abstract
PURPOSE To investigate the effect of CT enhancement phase on radiomics features for predicting post-surgical recurrence of clear cell renal cell carcinoma (ccRCC). METHODS This retrospective study included 144 patients who underwent radical or partial nephrectomy for ccRCC. Preoperative multiphase abdominal CT scans (non-contrast, corticomedullary, and nephrographic phases) were obtained for each patient. Automated segmentation of renal masses was performed using the nnU-Net framework. Radiomics signatures (RS) were developed for each phase using ensembles of machine learning-based models (Random Survival Forests [RSF], Survival Support Vector Machines [S-SVM], and Extreme Gradient Boosting [XGBoost]) with and without feature selection. Feature selection was performed using Affinity Propagation Clustering. The primary endpoint was disease-free survival, assessed by concordance index (C-index). RESULTS The study included 144 patients. Radical and partial nephrectomies were performed in 81% and 19% of patients, respectively, with 81% of tumors classified as high grade. Disease recurrence occurred in 74 patients (51%). A total of 1,316 radiomics features were extracted per phase per patient. Without feature selection, C-index values for RSF, S-SVM, XGBoost, and Penalized Cox models ranged from 0.43 to 0.61 across phases. With Affinity Propagation feature selection, C-index values improved to 0.51-0.74, with the corticomedullary phase achieving the highest performance (C-index up to 0.74). CONCLUSIONS The results of our study indicate that radiomics analysis of corticomedullary phase contrast-enhanced CT images may provide valuable predictive insight into recurrence risk for non-metastatic ccRCC following surgical resection. However, the lack of external validation is a limitation, and further studies are needed to confirm these findings in independent cohorts.
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Affiliation(s)
- Zine-Eddine Khene
- Department of Urology, University of Texas Southwestern Medical Center, 2001 Inwood Rd, WCB3, Floor 4, Dallas, TX, 75390, USA.
- Department of Urology, University of Rennes, Rennes, France.
- Image and Signal Processing Laboratory, Inserm U1099, University of Rennes, Rennes, France.
| | - Raj Bhanvadia
- Department of Urology, University of Texas Southwestern Medical Center, 2001 Inwood Rd, WCB3, Floor 4, Dallas, TX, 75390, USA
| | - Isamu Tachibana
- Department of Urology, University of Texas Southwestern Medical Center, 2001 Inwood Rd, WCB3, Floor 4, Dallas, TX, 75390, USA
| | - Prajwal Sharma
- Department of Urology, University of Texas Southwestern Medical Center, 2001 Inwood Rd, WCB3, Floor 4, Dallas, TX, 75390, USA
| | - Ivan Trevino
- Department of Urology, University of Texas Southwestern Medical Center, 2001 Inwood Rd, WCB3, Floor 4, Dallas, TX, 75390, USA
| | - William Graber
- Department of Urology, University of Texas Southwestern Medical Center, 2001 Inwood Rd, WCB3, Floor 4, Dallas, TX, 75390, USA
| | | | - Raphael Fleury
- Department of Urology, University of Rennes, Rennes, France
| | - Oscar Acosta
- Image and Signal Processing Laboratory, Inserm U1099, University of Rennes, Rennes, France
| | - Renaud De Crevoisier
- Image and Signal Processing Laboratory, Inserm U1099, University of Rennes, Rennes, France
- Department of Radiation Oncology, CLCC Eugene Marquis, Rennes, France
| | - Karim Bensalah
- Department of Urology, University of Rennes, Rennes, France
| | - Yair Lotan
- Department of Urology, University of Texas Southwestern Medical Center, 2001 Inwood Rd, WCB3, Floor 4, Dallas, TX, 75390, USA
| | - Vitaly Margulis
- Department of Urology, University of Texas Southwestern Medical Center, 2001 Inwood Rd, WCB3, Floor 4, Dallas, TX, 75390, USA
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Sugiyama K, Gordon A, Popat S, Okines A, Larkin J, Chau I. Is pathological response an adequate surrogate marker for survival in neoadjuvant therapy with immune checkpoint inhibitors? ESMO Open 2025; 10:104122. [PMID: 39874902 PMCID: PMC11808614 DOI: 10.1016/j.esmoop.2024.104122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 12/17/2024] [Accepted: 12/18/2024] [Indexed: 01/30/2025] Open
Abstract
Pathological response (PR) is an oncological outcome measure that indicates the therapeutic response to neoadjuvant therapy. In clinical trials involving neoadjuvant or perioperative interventions, overall survival and disease/event-free survival are typically the primary outcome measures. Although some evidence suggests that pathological complete response (pCR) can serve as a surrogate marker for the primary endpoint in prospective trials, it remains uncertain whether pCR is a true surrogate marker for patients with cancer undergoing curative resection across all solid tumours. Here, we review the role of PR as a surrogate marker and its associated methodological issues in the era of perioperative immune checkpoint inhibitors.
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Affiliation(s)
- K Sugiyama
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, UK; Department of Medical Oncology, NHO Nagoya Medical Center, Nagoya, Aichi, Japan
| | - A Gordon
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, UK
| | - S Popat
- Lung Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, UK
| | - A Okines
- Breast Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, UK
| | - J Larkin
- Skin Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, UK
| | - I Chau
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, UK.
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Monda SM, Carney BW, May AM, Gulati S, Salami SS, Chandrasekar T, Keller ET, Huebner NA, Palapattu GS, Dall'Era MA. Differences in mutations across tumour sizes in clear-cell renal cell carcinoma. BJU Int 2025; 135:269-278. [PMID: 39263870 PMCID: PMC11745994 DOI: 10.1111/bju.16527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
OBJECTIVE To assess the distribution of key mutations across tumour sizes in clear-cell renal cell carcinoma (ccRCC), and secondarily to examine the prognostic impact of aggressive mutations in smaller ccRCCs. PATIENT AND METHODS The distribution of mutations (VHL, PBRM1, SETD2, BAP1 and CDKN2A loss) across tumour sizes was assessed in 1039 ccRCCs treated with nephrectomy in cohorts obtained from the Tracking Cancer Evolution (TRACERx), The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) projects. Logistic regression was used to model the presence of each mutation against size. In our secondary analysis, we assessed a subset of ccRCCs ≤7 cm for associations of key aggressive mutations (SETD2, BAP1, and CDKN2A loss) with metastasis, invasive disease and overall survival, while controlling for size. A subset of localised tumours ≤7 cm was also used to assess associations with recurrence after nephrectomy. RESULTS On logistic regression, each 1-cm increase in tumour size was associated with aggressive mutations, SETD2, BAP1, and CDKN2A loss, at odds ratios (ORs) of 1.09, 1.10 and 1.19 (P < 0.001), whereas no significant association was observed between tumour size and PBRM1 (OR 1.02; P = 0.23). VHL was mildly negatively associated with a 1-cm increase in size (OR 0.95; P = 0.01). Among tumours ≤7 cm, SETD2 and CDKN2A loss were associated with metastatic disease at ORs of 3.86 and 3.84 (P < 0.05) while controlling for tumour size. CDKN2A loss was associated with worse overall survival, with a hazard ratio (HR) of 2.19 (P = 0.03). Among localised tumours ≤7 cm, SETD2 was associated with worse recurrence-free survival (HR 2.00; P = 0.03). CONCLUSION Large and small ccRCCs are genomically different. Aggressive mutations, namely, SETD2, BAP1, and CDKN2A loss, are rarely observed in small ccRCCs and are observed more frequently in larger tumours. However, when present in tumours ≤7 cm, SETD2 mutations and CDKN2A loss were still independently associated with invasive disease, metastasis, worse survival, and recurrence after resection, after controlling for size.
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Affiliation(s)
- Steven M. Monda
- Department of Urologic SurgeryUC DavisSacramentoCAUSA
- Department of RadiologyUC DavisSacramentoCAUSA
| | | | - Allison M. May
- Department of UrologyUniversity of MichiganAnn ArborMIUSA
| | - Shuchi Gulati
- Division of Hematology and OncologyUC DavisSacramentoCAUSA
| | | | | | - Evan T. Keller
- Department of UrologyUniversity of MichiganAnn ArborMIUSA
| | - Nicolai A. Huebner
- Department of Urologic SurgeryUC DavisSacramentoCAUSA
- Department of UrologyMedical University of ViennaViennaAustria
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Strati A, Adamopoulos C, Kotsantis I, Psyrri A, Lianidou E, Papavassiliou AG. Targeting the PD-1/PD-L1 Signaling Pathway for Cancer Therapy: Focus on Biomarkers. Int J Mol Sci 2025; 26:1235. [PMID: 39941003 PMCID: PMC11818137 DOI: 10.3390/ijms26031235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 01/26/2025] [Accepted: 01/29/2025] [Indexed: 02/16/2025] Open
Abstract
The PD1/PD-L1 axis plays an important immunosuppressive role during the T-cell-mediated immune response, which is essential for the physiological homeostasis of the immune system. The biology of the immunological microenvironment is extremely complex and crucial for the development of treatment strategies for immunotherapy. Characterization of the immunological, genomic or transcriptomic landscape of cancer patients could allow discrimination between responders and non-responders to anti-PD-1/PD-L1 therapy. Immune checkpoint inhibitor (ICI) therapy has shown remarkable efficacy in a variety of malignancies in landmark trials and has fundamentally changed cancer therapy. Current research focuses on strategies to maximize patient selection for therapy, clarify mechanisms of resistance, improve existing biomarkers, including PD-L1 expression and tumor mutational burden (TMB), and discover new biomarkers. In this review, we focus on the function of the PD-1/PD-L1 signaling pathway and discuss the immunological, genomic, epigenetic and transcriptomic landscape in cancer patients receiving anti-PD-1/PD-L1 therapy. Finally, we provide an overview of the clinical trials testing the efficacy of antibodies against PD-1/PD-L1.
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Affiliation(s)
- Areti Strati
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece;
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.A.); (A.G.P.)
| | - Christos Adamopoulos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.A.); (A.G.P.)
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ioannis Kotsantis
- Department of Medical Oncology, Second Department of Internal Medicine, Attikon University General Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Amanda Psyrri
- Department of Medical Oncology, Second Department of Internal Medicine, Attikon University General Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Evi Lianidou
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece;
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.A.); (A.G.P.)
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Miller JW, Johnson JS, Guske C, Mannam G, Hatoum F, Nassar M, Potez M, Fazili A, Spiess PE, Chahoud J. Immune-Based and Novel Therapies in Variant Histology Renal Cell Carcinomas. Cancers (Basel) 2025; 17:326. [PMID: 39858107 PMCID: PMC11763753 DOI: 10.3390/cancers17020326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/13/2025] [Accepted: 01/18/2025] [Indexed: 01/27/2025] Open
Abstract
Renal cell carcinoma (RCC) is a heterogeneous disease that represents the most common type of kidney cancer. The classification of RCC is primarily based on distinct morphological and molecular characteristics, with two broad categories: clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC). Clear cell RCC is the predominant subtype, representing about 70-80% of all RCC cases, while non-clear cell subtypes collectively make up the remaining 20-30%. Non-clear cell RCC encompasses many histopathological variants, each with unique biological and clinical characteristics. Additionally, any RCC subtype can undergo sarcomatoid dedifferentiation, which is associated with poor prognosis and rapid disease progression. Recent advances in molecular profiling have also led to the identification of molecularly defined variants, further highlighting the complexity of this disease. While immunotherapy has shown efficacy in some RCC variants and subpopulations, significant gaps remain in the treatment of rare subtypes. This review explores the outcomes of immunotherapy across RCC subtypes, including rare variants, and highlights opportunities for improving care through novel therapies, biomarker-driven approaches, and inclusive clinical trial designs.
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Affiliation(s)
- Justin W. Miller
- USF Health Morsani College of Medicine, Tampa, FL 33602, USA; (J.W.M.)
| | - Jeffrey S. Johnson
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Christopher Guske
- USF Health Morsani College of Medicine, Tampa, FL 33602, USA; (J.W.M.)
| | - Gowtam Mannam
- USF Health Morsani College of Medicine, Tampa, FL 33602, USA; (J.W.M.)
| | - Firas Hatoum
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | | | - Marine Potez
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Adnan Fazili
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Philippe E. Spiess
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Jad Chahoud
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
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Qin Q, Tachibana I, Margulis V, Cadeddu JA, Zhang T. A Review of Neoadjuvant Therapy for Localized and Locally Advanced Renal Cell Carcinoma. Cancers (Basel) 2025; 17:312. [PMID: 39858094 PMCID: PMC11763366 DOI: 10.3390/cancers17020312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/02/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
The introduction of vascular endothelial growth factor receptor-tyrosine kinases (VEGFR-TKIs) and immune checkpoint inhibitors (IOs) have drastically altered the treatment landscape for kidney cancer, with doublet combination immunotherapy (IO/IO or IO/VEGFR-TKI) now set as the standard front-line treatment for advanced renal cell carcinoma (RCC). However, the roles of VEGFR-TKIs and IOs in the neoadjuvant setting for locoregional/locally advanced RCC remain undefined, where the goals may be primary tumor downsizing/downstaging and potentially eradicating micrometastatic disease. This review will examine VEGFR-TKI monotherapy, IO monotherapy, and VEGFR-TKI/IO combination regimens in a preoperative setting with a focus on the efficacy, toxicity, surgical, and long-term implications.
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Affiliation(s)
- Qian Qin
- Division of Hematology and Medical Oncology, Department of Internal Medicine, University of Texas Southwestern, Dallas, TX 75235, USA;
| | - Isamu Tachibana
- Department of Urology, University of Texas Southwestern, Dallas, TX 75235, USA; (I.T.); (V.M.); (J.A.C.)
| | - Vitaly Margulis
- Department of Urology, University of Texas Southwestern, Dallas, TX 75235, USA; (I.T.); (V.M.); (J.A.C.)
| | - Jeffrey A. Cadeddu
- Department of Urology, University of Texas Southwestern, Dallas, TX 75235, USA; (I.T.); (V.M.); (J.A.C.)
| | - Tian Zhang
- Division of Hematology and Medical Oncology, Department of Internal Medicine, University of Texas Southwestern, Dallas, TX 75235, USA;
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Motzer RJ, Bex A, Russo P, Tomita Y, Cutuli HJ, Rojas C, Gross-Goupil M, Schinzari G, Melichar B, Barthélémy P, Ruiz Garcia A, Sosman J, Grimm MO, Goh JC, Suarez C, Kollmannsberger CK, Nair SG, Shuch BM, Huang J, Simsek B, Spiridigliozzi J, Lee CW, van Kooten Losio M, Grünwald V. Adjuvant Nivolumab for Localized Renal Cell Carcinoma at High Risk of Recurrence After Nephrectomy: Part B of the Randomized, Placebo-Controlled, Phase III CheckMate 914 Trial. J Clin Oncol 2025; 43:189-200. [PMID: 39303200 PMCID: PMC11709003 DOI: 10.1200/jco.24.00773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/13/2024] [Accepted: 07/18/2024] [Indexed: 09/22/2024] Open
Abstract
PURPOSE CheckMate 914 is a two-part, randomized phase III trial evaluating adjuvant nivolumab plus ipilimumab (part A) or adjuvant nivolumab monotherapy (part B) versus placebo in mutually exclusive populations of patients with localized renal cell carcinoma (RCC) at high risk of postnephrectomy recurrence. Part A showed no disease-free survival (DFS) benefit for adjuvant nivolumab plus ipilimumab versus placebo. We report results from part B. METHODS Patients were randomly assigned (2:1:1) to nivolumab (240 mg once every 2 weeks for up to 12 doses), placebo, or nivolumab (240 mg once every 2 weeks for up to 12 doses) plus ipilimumab (1 mg/kg once every 6 weeks for up to four doses). The planned treatment duration was 24 weeks (approximately 5.5 months). The primary end point was DFS per blinded independent central review (BICR) for nivolumab versus placebo; safety was a secondary end point. RESULTS Overall, 825 patients were randomly assigned to nivolumab (n = 411), placebo (n = 208), or nivolumab plus ipilimumab (n = 206). With a median follow-up of 27.0 months (range, 18.0-42.4), the primary end point of improved DFS per BICR with nivolumab versus placebo was not met (hazard ratio [HR], 0.87 [95% CI, 0.62 to 1.21]; P = .40); the median DFS was not reached in either arm, and 18-month DFS rates were 78.4% versus 75.4%. The HR for DFS per investigator was 0.80 (95% CI, 0.58 to 1.12; P = .19). Grade 3-4 all-cause adverse events (AEs) occurred in 17.2%, 15.0%, and 28.9% of patients with nivolumab, placebo, and nivolumab plus ipilimumab, respectively. Any-grade treatment-related AEs led to discontinuation in 9.6%, 1.0%, and 28.4%, respectively. CONCLUSION Part B of CheckMate 914 did not meet the primary end point of improved DFS for nivolumab versus placebo in patients with localized RCC at high risk of postnephrectomy recurrence.
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Affiliation(s)
- Robert J. Motzer
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Axel Bex
- Netherlands Cancer Institute, Amsterdam, the Netherlands
- University College London, London, United Kingdom
| | - Paul Russo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Yoshihiko Tomita
- Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | | | | | | | - Giovanni Schinzari
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Bohuslav Melichar
- Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic
| | | | | | | | | | | | - Cristina Suarez
- Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
| | | | | | | | - Jian Huang
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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Moinard-Butot F, Thouvenin J, Bigot P, Martinez-Chanza N, Gaillard V, Cazzato RL, Boissier R, Margue G, Boudier P, Maillet D, Gross-Goupil M, Bernhard JC, Barthélémy P. Efficacy of immune checkpoint inhibitors in renal cell carcinoma venous tumour thrombus shrinkage (UroCCR 128). World J Urol 2025; 43:66. [PMID: 39792158 PMCID: PMC11723841 DOI: 10.1007/s00345-024-05428-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 12/26/2024] [Indexed: 01/12/2025] Open
Abstract
PURPOSE Surgery remains the cornerstone of localized renal cell carcinoma (RCC) care. Pembrolizumab has recently been recommended as a standard of care for RCC patients who are at high risk of recurrence. Data regarding the efficacy of ICIs either alone or in combination with ICIs or VEGF TKIs for VTT shrinkage are scarce. METHODS In the framework of the French kidney cancer research network UroCCR (NCT03293563), we performed a retrospective multicentric European study to evaluate VTT shrinkage in patients treated with ICIs with metastatic or locally advanced renal cell carcinoma (RCC). The primary endpoint was the objective response rate (ORR) of patients with VTT to ICI-based therapy. Radiological assessment was performed by a treating physician according to the RECISTv1.1 criteria. RESULTS We included 44 patients. The median age was 69 years (range 37-88). All patients was intermediate or poor IMDC risk group. Twenty-three patients were treated with anti-PD-1 in combination with anti-CTLA-4 therapy, 13 patients with ICI monotherapy, and 8 patients with ICIs in combination with antiangiogenic TKI. At baseline, the median VTT diameter was 22 mm (range 7-93). After a median duration of treatment of 5.8 months (range 1.8-39.1), the ORR was 38% (n = 17), including 4 complete responses (CRs) and 13 partial responses (PRs). Ten patients had stable disease (SD), and 17 had progressive disease (PD) as the best response of the VTT. CONCLUSION These data highlight the potential efficacy of ICIs to shrink the VTT even if they seem to have little impact on the extent of VTT.
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Affiliation(s)
- Fabien Moinard-Butot
- Medical Oncology Department, Institut de Cancérologie Strasbourg Europe, Strasbourg, France
| | - Jonathan Thouvenin
- Medical Oncology Department, Hospices Civils de Lyon, Pierre-Bénite, France
| | - Pierre Bigot
- Department of Urology, Angers University Hospital, Angers, France
- Kidney Cancer Group of the French Association of Urology Cancer Committee, Paris, France
| | | | - Victor Gaillard
- Urology Department, Nouvel Hôpital Civil, Strasbourg, France
| | | | - Romain Boissier
- Department of Urology and Renal Transplantation, La Conception University Hospital, APHM, Marseille, France
- Kidney Cancer Group of the French Association of Urology Cancer Committee, Paris, France
| | - Gaëlle Margue
- Department of Urology, Bordeaux University Hospital, Bordeaux, France
- Kidney Cancer Group of the French Association of Urology Cancer Committee, Paris, France
| | - Philippe Boudier
- Medical Oncology Department, Institut de Cancérologie Strasbourg Europe, Strasbourg, France
| | - Denis Maillet
- Medical Oncology Department, Hospices Civils de Lyon, Pierre-Bénite, France
| | | | - Jean-Christophe Bernhard
- Department of Urology, Bordeaux University Hospital, Bordeaux, France
- Kidney Cancer Group of the French Association of Urology Cancer Committee, Paris, France
| | - Philippe Barthélémy
- Medical Oncology Department, Institut de Cancérologie Strasbourg Europe, Strasbourg, France.
- Kidney Cancer Group of the French Association of Urology Cancer Committee, Paris, France.
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Wang LL, Puri D, Saitta C, Liu F, Afari JA, Meagher MF, Hakimi K, Nguyen MV, Shah A, Ghassemzadeh S, Murphy JD, Javier-Desloges J, McKay RR, Derweesh IH. Trends and Outcomes in Sarcomatoid Renal Cell Carcinoma: Analysis of the National Cancer Data Base. EUR UROL SUPPL 2025; 71:96-105. [PMID: 39758852 PMCID: PMC11699467 DOI: 10.1016/j.euros.2024.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2024] [Indexed: 01/07/2025] Open
Abstract
Background and objective Our aim was to determine the clinical characteristics, temporal trends, and survival outcomes for sarcomatoid-dedifferentiated renal cell carcinoma (sRCC), as sRCC has historically had poor prognosis and a contemporary cohort has not been well characterized in a population-based study. Methods Data for 302 630 RCC cases from 2010 to 2019 were extracted from the National Cancer Data Base, of which 4.1% (12 329) were sRCC. Trend analyses were conducted using the Cochran-Armitage test. Multivariable analyses were used to assess factors associated with sRCC diagnosis and clinicopathologic characteristics associated with all-cause mortality (ACM). Overall survival (OS) was computed via Kaplan-Meier analysis. Key findings and limitations sRCC incidence increased from 3.9% in 2010 to 4.1% in 2019 (p = 0.020). The incidence of stage I sRCC increased from 14.5% in 2010 to 19.2% in 2019 (p < 0.001). sRCC diagnosis was associated with male sex, tumor size, cN1 status, and collecting duct histology. Worse ACM in localized sRCC was associated with age, tumor size, cN1 stage, collecting duct histology, and positive surgical margins; and was inversely associated with partial nephrectomy (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.49-0.76; p < 0.001). Worse ACM in metastatic sRCC was associated with age, tumor size, cN1, collecting duct histology, positive surgical margins, and no surgery at the primary site (HR 1.66, 95% CI 1.20-2.30; p = 0.006). The 5-yr OS rates for stage I, stage II, stage III, and stage IV sRCC were 74%, 63%, 42%, and 16%, respectively (p < 0.001). Conclusions and clinical implications The proportion of sRCC cases overall and of stage I sRCC cases increased from 2010 to 2019, supporting the hypothesis of stage migration and the potential for early sarcomatoid dedifferentiation. Further studies on the causal mechanisms underpinning better survival after partial nephrectomy in localized disease and after cytoreductive surgery in metastatic disease are warranted. Patient summary We analyzed trends and outcomes for a type of aggressive kidney cancer (sarcomatoid renal cell carcinoma, sRCC) using records from the National Cancer Data Base. We found that the percentage of sRCC cases among all kidney cancers increased from 2010 to 2019. Factors such as tumor size and patient age were linked to worse survival. Surgery to remove the cancer was linked to better survival.
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Affiliation(s)
- Luke L. Wang
- Department of Urology, University of California-San Diego School of Medicine, La Jolla, CA, USA
| | - Dhruv Puri
- Department of Urology, University of California-San Diego School of Medicine, La Jolla, CA, USA
| | - Cesare Saitta
- IRCCS Humanitas Clinical and Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Franklin Liu
- Department of Medicine, University of Arizona College of Medicine, Tuscon, AZ, USA
| | - Jonathan A. Afari
- Department of Urology, University of California-San Diego School of Medicine, La Jolla, CA, USA
| | - Margaret F. Meagher
- Department of Urology, University of California-San Diego School of Medicine, La Jolla, CA, USA
| | - Kevin Hakimi
- Department of Urology, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Mimi V. Nguyen
- Department of Urology, Mayo Clinic Arizona, Phoenix, AZ, USA
| | - Aastha Shah
- Department of Urology, University of California-San Diego School of Medicine, La Jolla, CA, USA
| | - Saeed Ghassemzadeh
- Department of Urology, University of California-San Diego School of Medicine, La Jolla, CA, USA
| | - James D. Murphy
- Department of Therapeutic Radiology, University of California-San Diego School of Medicine, La Jolla, CA, USA
- Moores UCSD Cancer Center, University of California-San Diego School of Medicine, La Jolla, CA, USA
| | - Juan Javier-Desloges
- Department of Urology, University of California-San Diego School of Medicine, La Jolla, CA, USA
| | - Rana R. McKay
- Moores UCSD Cancer Center, University of California-San Diego School of Medicine, La Jolla, CA, USA
- Department of Medicine, University of California-San Diego School of Medicine, La Jolla, CA, USA
| | - Ithaar H. Derweesh
- Department of Urology, University of California-San Diego School of Medicine, La Jolla, CA, USA
- Moores UCSD Cancer Center, University of California-San Diego School of Medicine, La Jolla, CA, USA
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Maffezzoli M, Signori A, Campobasso D, Giudice GC, Simoni N, Filippo MD, Silini EM, Buti S. External Validation of the GRade, Age, Nodes and Tumor (GRANT) Score for Patients with Surgically Treated Papillary Renal Cell Carcinoma. Technol Cancer Res Treat 2025; 24:15330338251329848. [PMID: 40129395 PMCID: PMC11938862 DOI: 10.1177/15330338251329848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 02/28/2025] [Accepted: 02/28/2025] [Indexed: 03/26/2025] Open
Abstract
IntroductionStratifying the risk of recurrence for surgically treated papillary renal cell carcinoma (pRCC) could be challenging. Prognostic models are crucial for patient counselling and individualized surveillance. The GRANT score is one of the models suggested by guidelines to predict prognosis of surgically treated pRCC. This study aims to externally validate the GRANT score using a three-risk group stratification in a large cohort of pRCC patients.Materials and MethodsThe present analysis utilized retrospective data from pRCC patients who underwent radical or partial nephrectomy. The GRANT score parameters included tumor grade, age, pathological T-stage, and N-stage. Patients were stratified into three risk groups (0-1 vs 2 vs 3-4 risk factors). Cancer-specific survival (CSS) was assessed using the Kaplan-Meier method, and differences between groups were evaluated using the log-rank test. Harrell's c-index was used to measure model accuracy, and restricted mean survival time (RMST) was calculated for up to 120 months.ResultsA total of 1942 patients were included. The median follow-up was 64.6 months. At 60 months, CSS was 93.2% (95%CI 91.7%-94.6%) for group 1, 60.8% (95%CI 54.0%-78.6%) for group 2, and 26% (95%CI 15.7%-42.9%) for group 3, with significant differences between each group (p < 0.001). The median CSS was not reached for group 1 (95%CI NR-NR), 86.0 months in group 2 (95%CI 65-NR), and 22.8 months in group 3 (95%CI 16.4-48.0). The c-index for CSS was 0.732. The RMST at 120 months was 113.3 months for group 1, 75.9 months for group 2, and 56.6 months for group 3, with a statistically significant difference (p < 0.001).ConclusionThe GRANT score effectively stratified surgically treated pRCC patients into three risk groups, demonstrating good prognostic accuracy. This validation supports the GRANT score's utility as a reliable and easy-to-use prognostic tool.
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Affiliation(s)
| | - Alessio Signori
- Section of biostatistics, Department of Health Sciences (DISSAL), University of Genova, Genova, Italy
| | | | | | - Nicola Simoni
- Radiotherapy Unit, University Hospital of Parma, Parma, Italy
| | - Massimo De Filippo
- Department of Medicine and Surgery, Section of Radiology, University of Parma, Parma, Italy
| | | | - Sebastiano Buti
- Medicine and Surgery Department, University of Parma, Parma, Italy
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
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49
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Zang PD, Angeles A, Pal SK. CD70: An Emerging Anticancer Target in Renal Cell Carcinoma and Beyond. Annu Rev Med 2025; 76:257-266. [PMID: 39570653 DOI: 10.1146/annurev-med-070623-045906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2024]
Abstract
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.
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Affiliation(s)
- Peter D Zang
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA;
| | | | - Sumanta K Pal
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA;
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50
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Greene J, Wang Z, Harris BHL, Dodwell D, Lord SR. The Impact of Body Mass Index (BMI) on Clinical Outcomes for Patients Receiving Systemic Anti-Cancer Therapies for Advanced Clear Cell Renal Carcinoma. Cancer Control 2025; 32:10732748251317681. [PMID: 40098278 PMCID: PMC11915284 DOI: 10.1177/10732748251317681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 01/03/2025] [Accepted: 01/07/2025] [Indexed: 03/19/2025] Open
Abstract
IntroductionObesity is a risk factor for the development of renal cell carcinoma (RCC), however observational studies have suggested patients with RCC receiving systemic anti-cancer therapy (SACT) and BMI ≥25 kg/m2 may have a better prognosis than patients with a normal or low BMI, a phenomenon often referred to as the obesity paradox.MethodsThe impact of BMI on survival outcomes in patients with advanced clear cell RCC receiving SACT within the National Health Service (NHS) in England between 2010 and 2018 was investigated. A retrospective analysis was performed using the SACT dataset from NHS-England.ResultsA total of 1034 patients were included. The majority of patients commenced treatment with oral SACT, pazopanib (53.3%) and sunitinib (43.7%). Median overall survival for patients with BMI ≤25 kg/m2 was 12.6 months (95% CI; 10.1-14.4) and 17.9 months (15.4-20.0) for patients with BMI ≥25 kg/m2 (P < .001). The association between BMI and improved survival was greatest in the first year of commencing SACT with the adjusted mortality rate of 68.9% for patients with BMI less than 25 kg/m2 compared to 48.6% for patients with BMI greater than 25 kg/m2 (rate ratio .77, .63 to .93).ConclusionA high BMI compared to a normal or low BMI was associated with improved survival in patients with metastatic RCC who were predominantly treated with oral SACT. Improved survival in obese patients with advanced RCC may be associated with improved response to systemic targeted therapies.
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Affiliation(s)
- John Greene
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Computational Biology and Integrative Genomics Lab, Department of Oncology, University of Oxford, Oxford, UK
| | - Zhe Wang
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Benjamin H. L. Harris
- Computational Biology and Integrative Genomics Lab, Department of Oncology, University of Oxford, Oxford, UK
| | - David Dodwell
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Computational Biology and Integrative Genomics Lab, Department of Oncology, University of Oxford, Oxford, UK
| | - Simon R. Lord
- Computational Biology and Integrative Genomics Lab, Department of Oncology, University of Oxford, Oxford, UK
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