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1
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Bou-Nehme Sawaya G, Tanguay S, Wood LA, Kollmannsberger C, Basappa NS, Bansal R, Soulières D, Finelli A, Heng DYC, Castonguay V, Canil C, Winquist E, Graham J, Bjarnason GA, Bhindi B, Lalani AK, Pouliot F, Breau RH, Saleh R, Dragomir A. Optimal Timing of Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma Patients Considering Sarcomatoid Status: A Real-World Study. Clin Genitourin Cancer 2025; 23:102342. [PMID: 40288275 DOI: 10.1016/j.clgc.2025.102342] [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: 10/21/2024] [Revised: 03/29/2025] [Accepted: 03/31/2025] [Indexed: 04/29/2025]
Abstract
OBJECTIVE To compare the outcomes of metastatic renal cell carcinoma (mRCC) patients, with or without sarcomatoid features, who underwent cytoreductive nephrectomy (CN) before or after systemic therapies (ST). METHODS Synchronous metastatic RCC patients of IMDC intermediate- and high-risk diagnosed between January 2011 to December 2022, treated with CN before or after ST, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system (CKCis). Patients were classified by treatment sequence received: (1) CN after ST (2) CN before ST. Inverse probability of treatment weighting using propensity scores was used to balance for covariates. Cox proportional hazards models were used to assess the impact of initial treatment received on overall survival (OS). RESULTS Of 709 eligible patients, 105 were treated with CN after ST and 604 with CN before ST. 75% were male, and the majority (70%) received targeted therapies (TT) used alone. In nonsarcomatoid patients (80 CN after ST and 454 CN before ST), treatment with CN after ST was associated with an improvement in OS, that was not statistically significant, compared to CN before ST (median of 60 vs. 48 months, HR 0.84, 95% CI 0.64-1.11). In sarcomatoid patients (25 CN after ST and 150 CN before ST), CN after ST was also not associated with better survival (median of 24 vs. 36 months, HR 1.10, 95% CI 0.70-1.73). CONCLUSION In conclusion, this study demonstrated that, no matter the sarcomatoid status, there is no statistical difference between receiving CN after ST or CN before ST. The timing of CN could potentially be linked more so to clinical assessments than the knowledge of sarcomatoid status.
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Affiliation(s)
- Ghady Bou-Nehme Sawaya
- Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montréal, Quebec, Canada
| | - Simon Tanguay
- McGill University Health Centre, Montréal, Quebec, Canada
| | - Lori A Wood
- Queen Elizabeth II Health Sciences Center, Dalhousie University, Halifax, Nova Scotia, Canada
| | | | | | - Rahul Bansal
- Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada
| | - Denis Soulières
- Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
| | - Antonio Finelli
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | | | - Vincent Castonguay
- Centre Hospitalier Universitaire de Québec, Université Laval, Québec, Quebec, Canada
| | - Christina Canil
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Eric Winquist
- Department of Oncology, Western University and London Health Sciences Centre, London, Ontario, Canada
| | | | | | | | - Aly-Khan Lalani
- Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada
| | - Frédéric Pouliot
- Centre Hospitalier Universitaire de Québec, Université Laval, Québec, Quebec, Canada
| | - Rodney H Breau
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Ramy Saleh
- McGill University Health Centre, Montréal, Quebec, Canada
| | - Alice Dragomir
- Université de Montréal, Faculté de Pharmacie, Montréal, Quebec, Canada.
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2
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McManus HD, Long JB, Westvold SJ, Leapman MS, Hurwitz ME, Mitchell AP, Pollack CE, Gross CP, Dinan MA. Off-Label Use of First-Line Immunotherapy for Metastatic Renal Cell Carcinoma. Clin Genitourin Cancer 2025; 23:102330. [PMID: 40186898 DOI: 10.1016/j.clgc.2025.102330] [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: 01/16/2025] [Revised: 03/10/2025] [Accepted: 03/11/2025] [Indexed: 04/07/2025]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICI) were approved by the Food and Drug Administration (FDA) for patients with metastatic renal cell carcinoma (mRCC) in the second- line setting in 2015 and the first-line (1L) in 2018. Little is known about 1 L ICI use in the off-label (before FDA indication-specific approval) and postapproval settings. PATIENTS AND METHODS We retrospectively analyzed off-label and post-FDA-approval 1 L ICI receipt in a cohort of Medicare beneficiaries ≥66 years old diagnosed with mRCC from 2015 to 2019. Off-label and postapproval 1 L ICI were defined as before or on/after 4/16/2018 (1L ipilimumab/nivolumab approval). Associations between demographic characteristics and 1 L ICI receipt in the off-label and postapproval periods were examined using multivariable logistic regression. RESULTS We identified 23,469 patients, of which 368 (2.4%) off-label and 1,663 (21%) postapproval received 1 L ICI. In the off-label period, patients with co-morbid conditions were more likely to receive 1 L ICI compared to patients with no co-morbidities (3+ conditions, OR = 2.00; 95% CL, 1.31-3.05). In the postapproval period, older patients were less likely to receive 1 L ICI (81+ vs. 66-70, OR = 0.60; 95% CL, 0.52-0.69), and patients who were frail were less likely to receive 1 L ICI (OR = 0.77; 95% CL, 0.69-0.87). There were not significant differences in 1 L ICI receipt based on race/ethnicity. CONCLUSION Older patients and patients with more comorbidities were more likely to receive 1 L ICI off-label, but these differences did not persist after FDA approval. After 1 L ipilimumab/nivolumab approval, patients receiving 1 L ICI were more likely younger, healthy, and receiving dual-ICI regimens.
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Affiliation(s)
- Hannah D McManus
- Department of Medicine, Duke University School of Medicine, Durham, NC.
| | - Jessica B Long
- Yale Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, CT; Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Sarah J Westvold
- Yale Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, CT; Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Michael S Leapman
- Yale Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, CT; Department of Urology, Yale School of Medicine, New Haven, CT; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT
| | - Michael E Hurwitz
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Aaron P Mitchell
- Health Outcomes Research Group, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Craig Evan Pollack
- Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD and Johns Hopkins School of Nursing, Baltimore, MD
| | - Cary P Gross
- Yale Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, CT; Department of Internal Medicine, Yale School of Medicine, New Haven, CT; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT
| | - Michaela A Dinan
- Yale Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, CT; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT
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Sugai A, Miyai K, Ito K, Matsukuma S, Sato K. Kidney Injury Molecule-1 Expression in Pathological T1b Clear Cell Renal Cell Carcinoma: A Putative Biomarker of High Immune-Inflamed Status and Recurrence. Pathol Int 2025. [PMID: 40365941 DOI: 10.1111/pin.70024] [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: 03/27/2025] [Revised: 04/25/2025] [Accepted: 05/06/2025] [Indexed: 05/15/2025]
Abstract
Kidney injury molecule-1 (KIM-1) is a potential prognostic marker of advanced-stage clear cell renal cell carcinoma (ccRCC) and is associated with tumor immunogenicity. Little is known about its role in early-stage ccRCC, especially in pathological T1b (pT1b) disease, which shows a higher recurrence rate than pT1a disease. Resected specimens from 112 pT1b ccRCC cases were reviewed and immunohistochemically analyzed for KIM-1 expression. High membranous KIM-1 expression was defined as H score ≥ 140, based on the immunoreactive intensity and area, and cytoplasmic expression in ≥ 10% of cancer cells was considered as high cytoplasmic KIM-1 expression. KIM-1 expression status was compared with clinicopathological variables, including tumor-associated immune cell (TAIC) status. Among the 112 cases, high membranous and cytoplasmic KIM-1 expression was observed in 30 (27%) and 38 (34%) cases, respectively. High membranous KIM-1 expression was significantly associated with a higher nuclear grade, tumor necrosis, hot TAIC status, and shorter recurrence-free survival (RFS) and cancer-specific survival, whereas high cytoplasmic expression was only related to a higher nuclear grade. Multivariate Cox regression analysis revealed that high membranous KIM-1 expression and tumor necrosis were independent predictors of shorter RFS. Our results indicate that membranous KIM-1 expression could be a biomarker for predicting postnephrectomy recurrence in pT1b ccRCC.
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Affiliation(s)
- Ayuna Sugai
- Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan
| | - Kosuke Miyai
- Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan
- Department of Laboratory Medicine, National Defense Medical College Hospital, National Defense Medical College, Tokorozawa, Japan
| | - Keiichi Ito
- Department of Urology, National Defense Medical College, Tokorozawa, Japan
| | - Susumu Matsukuma
- Department of Laboratory Medicine, National Defense Medical College Hospital, National Defense Medical College, Tokorozawa, Japan
| | - Kimiya Sato
- Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan
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Wang Z, Feng C, Chen G, Cai Q. Astragaloside IV regulates macrophage polarization via the TLR4/NF-κB/STAT3 pathway to inhibit the malignant phenotype of renal clear cell carcinoma. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04219-3. [PMID: 40343452 DOI: 10.1007/s00210-025-04219-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 04/23/2025] [Indexed: 05/11/2025]
Abstract
Clear cell renal cell carcinoma (ccRCC) is a common and aggressive type of kidney cancer. This study aimed to investigate the effect of astragaloside IV (AS-IV) on ccRCC. A variety of cell experimental techniques were used, inducing macrophage polarization, and detecting relevant indicators by flow cytometry, qRT-PCR, immunofluorescence, MTT, wound healing, Transwell, and western blot. A nude mouse xenograft tumor model was constructed for in vivo studies, and siRNA interference technology was used to explore the signaling pathway. The results demonstrated successful macrophage polarization, with AS-IV inhibiting M2 macrophage polarization and promoting the transition from M0 to M1 polarization. Additionally, AS-IV suppressed ccRCC cell proliferation, migration, and invasion, while reversing the malignant effects of M2 macrophages. The study further revealed that AS-IV inhibited M2 polarization through the TLR4/NF-κB/STAT3 signaling pathway. In vivo experiments showed that AS-IV inhibited the growth of ccRCC tumors. This study revealed that AS-IV influences macrophage polarization by regulating the TLR4/NF-κB/STAT3 signaling pathway, thereby inhibiting the malignant phenotype of ccRCC. This finding provides new insights and potential therapeutic strategies for the treatment of ccRCC.
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Affiliation(s)
- Zhanshi Wang
- Department of Urology, Tongde Hospital of Zhejiang Province, No. 234 Gucui Road, Xihu District, Hangzhou City, Zhejiang Province, 330012, China
| | - Chao Feng
- Department of Urology, Tongde Hospital of Zhejiang Province, No. 234 Gucui Road, Xihu District, Hangzhou City, Zhejiang Province, 330012, China
| | - Guodong Chen
- Department of Urology, Tongde Hospital of Zhejiang Province, No. 234 Gucui Road, Xihu District, Hangzhou City, Zhejiang Province, 330012, China
| | - Qi Cai
- Department of Urology, Tongde Hospital of Zhejiang Province, No. 234 Gucui Road, Xihu District, Hangzhou City, Zhejiang Province, 330012, China.
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5
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Jones GD, Murthy S. Pulmonary Metastasectomy in Renal Cell Carcinoma. Thorac Surg Clin 2025; 35:175-187. [PMID: 40246407 DOI: 10.1016/j.thorsurg.2024.12.001] [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: 04/19/2025]
Abstract
Recent advances in immunotherapy and targeted therapy have resulted in survival rates as high as 90% at 1 year in metastatic renal cell carcinoma patients; however, sustained response and ultimate cure is rarely achieved with systemic therapy alone (complete response rates remain <5%), and progression of disease at distant sites is common. Pulmonary metastasectomy is recommended as a component of multimodal management in patients with favorable-risk or intermediate-risk classification and can be associated with excellent survival if complete resection is obtained.
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Affiliation(s)
- Gregory D Jones
- Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44118, USA. https://twitter.com/GregoryJonesMD
| | - Sudish Murthy
- Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44118, USA; Center of Major Airway Disease, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44118, USA.
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6
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Ito N, Ueda K, Ohnishi S, Suekane H, Hiroshige T, Watanabe K, Chikui K, Uemura K, Nishihara K, Nakiri M, Suekane S, Igawa T. Analysis of Early Progression in Advanced Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab. CANCER DIAGNOSIS & PROGNOSIS 2025; 5:344-352. [PMID: 40322204 PMCID: PMC12046654 DOI: 10.21873/cdp.10446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 03/17/2025] [Accepted: 03/18/2025] [Indexed: 05/08/2025]
Abstract
Background/Aim In the CheckMate 214 trial, approximately 40% of patients with advanced renal cell carcinoma (aRCC) treated with nivolumab plus ipilimumab (NIVO + IPI) achieved long-term survival and a durable response to treatment. However, about 20% of patients experienced early disease progression (EDP). This retrospective study aimed to identify predictive factors for EDP among patients with aRCC treated with NIVO + IPI. Patients and Methods We retrospectively analyzed clinical information from patients with aRCC, 19 patients in the EDP group and 40 patients in the control disease group, all of whom were treated with NIVO + IPI at Kurume University Hospital between September 2018 and February 2024. Results The EDP group exhibited significantly worse progression-free survival and overall survival compared to the control disease group. Multivariate analyses revealed that a performance states (PS) ≥2 (p=0.0312) and the presence of bone metastases (p=0.0374) were independent predictors of EDP. Conclusion Treatment with NIVO + IPI in patients with aRCC who have a poor PS or bone metastases may be linked to a high risk of EDP.
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Affiliation(s)
- Naoki Ito
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
| | - Kosuke Ueda
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
| | - Satoshi Ohnishi
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
| | - Hiroki Suekane
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
| | - Tasuku Hiroshige
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
| | - Kouta Watanabe
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
| | - Katsuaki Chikui
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
| | - Keiichiro Uemura
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
| | - Kiyoaki Nishihara
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
| | - Makoto Nakiri
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
| | - Shigetaka Suekane
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
| | - Tsukasa Igawa
- Department of Urology, Kurume University School of Medicine, Kurume, Japan
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7
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Vento J, Zhang T, Kapur P, Hammers H, Brugarolas J, Qin Q. Systemic Treatment of Locally Advanced or Metastatic Non-Clear Cell Renal Cell Carcinoma. Cancers (Basel) 2025; 17:1527. [PMID: 40361453 PMCID: PMC12071997 DOI: 10.3390/cancers17091527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/24/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
Non-clear cell renal cell carcinoma (nccRCC) represents a heterogenous group of malignancies with varying degrees of clinical aggressiveness and response to different systemic therapies. As the characterization of subtypes of nccRCC continues to evolve, it is important to understand the evidence around systemic treatments used in advanced or metastatic stages of specific subtypes. Here, we review the literature on systemic therapies in nccRCC, with a focus on prospective trials that included patients with papillary renal cell carcinoma (RCC), chromophobe RCC, RCC not further classified/unclassified RCC, translocation RCC, collecting duct RCC, and renal medullary carcinoma. We also review emerging treatments for other molecularly defined subtypes of this disease.
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Affiliation(s)
- Joseph Vento
- Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern, Dallas, TX 75235, USA
| | - Tian Zhang
- Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern, Dallas, TX 75235, USA
| | - Payal Kapur
- Department of Pathology, University of Texas Southwestern, Dallas, TX 75235, USA
| | - Hans Hammers
- Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern, Dallas, TX 75235, USA
| | - James Brugarolas
- Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern, Dallas, TX 75235, USA
| | - Qian Qin
- Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern, Dallas, TX 75235, USA
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Chen YW, McKay RR. Mitigating the Risk of Skeletal Events in Metastatic Renal Cell Carcinoma. Eur Urol Focus 2025:S2405-4569(25)00085-9. [PMID: 40280849 DOI: 10.1016/j.euf.2025.04.007] [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: 02/03/2025] [Accepted: 04/04/2025] [Indexed: 04/29/2025]
Abstract
Bone metastases affect approximately one-third of patients with metastatic renal cell carcinoma (mRCC) and contribute to substantial skeletal complications and shorter survival. Management of these metastases requires a multidisciplinary approach combining systemic therapies, localized treatments, and supportive care. Immune checkpoint inhibitor (ICI)-based combinations, especially doublets comprising an ICI and a VEGF-targeted tyrosine kinase inhibitor, have shown significant efficacy in mRCC with bone involvement. Bone-modifying agents such as zoledronic acid and denosumab help in mitigating symptomatic skeletal-related events and enhance bone integrity, although the unique bone pathology of RCC may limit their effectiveness. Local therapies, such as surgery and stereotactic body radiotherapy, play a pivotal role in providing symptom relief and controlling localized disease, particularly in oligometastatic cases. A personalized, patient-centered strategy is essential in minimizing systemic therapy disruptions, addressing skeletal morbidity, and improving clinical outcomes. PATIENT SUMMARY: Bone metastases in patients with kidney cancer can cause severe complications such as pain, fractures, and other serious issues, reducing quality of life and survival. Treatment involves a combination of therapies, including medications, targeted radiation, surgery, and immunotherapy, tailored to each patient to manage symptoms and improve outcomes.
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Affiliation(s)
- Yu-Wei Chen
- Division of Hematology-Oncology, University of California-San Diego School of Medicine, La Jolla, CA, USA.
| | - Rana R McKay
- Division of Hematology-Oncology, University of California-San Diego School of Medicine, La Jolla, CA, USA; Moores Cancer Center, University of California-San Diego, La Jolla, CA, USA
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9
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Huang R, Kee L, Gont A, Meens J, Ferens FG, Irwin MS, Ailles L, Yuzwa SA, Robinson CM, Ohh M. Comparative single-cell transcriptomic profiling of patient-derived renal carcinoma cells in cellular and animal models of kidney cancer. FEBS Open Bio 2025. [PMID: 40241258 DOI: 10.1002/2211-5463.70022] [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: 09/05/2024] [Revised: 02/26/2025] [Accepted: 03/06/2025] [Indexed: 04/18/2025] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer that often displays resistance to conventional cancer therapies, including chemotherapy and radiation therapy. Targeted treatments, including immunotherapies and small molecular inhibitors, have been associated with improved outcomes. However, variations in the patient response and the development of resistance suggest that more models that better recapitulate the pathogenesis and metastatic mechanisms of ccRCC are required to improve our understanding and disease management. Here, we examined the transcriptional landscapes of in vitro cell culture as well as in vivo orthotopic and metastatic NOD/SCID-γ mouse models of ccRCC using a single patient-derived RCC243 cell line to allow unambiguous comparison between models. In our mouse model assays, RCC243 cells formed metastatic tumors, and all tumors retained clear cell morphology irrespective of model type. Notably, gene expression profiles differed markedly between the RCC243 tumor models-cell culture, orthotopic tumors, and metastatic tumors-suggesting an impact of the experimental model system and whether the tumor was orthotopic or metastatic. Furthermore, we found conserved prognostic markers between RCC243 tumor models and human ccRCC patient datasets, and genes upregulated in metastatic RCC243 were associated with worse patient outcomes.
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Affiliation(s)
- Richard Huang
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada
| | - Lynn Kee
- Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
| | - Alexander Gont
- Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
| | - Jalna Meens
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Fraser G Ferens
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada
| | - Meredith S Irwin
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada
- Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Canada
- Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada
| | - Laurie Ailles
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Canada
| | - Scott A Yuzwa
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada
| | - Claire M Robinson
- School of Medicine, Health Sciences Centre, University College Dublin, Dublin 4, Ireland
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
| | - Michael Ohh
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada
- Department of Biochemistry, University of Toronto, Canada
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10
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Zhang J, Liu G, Wang W. PRSS53 is a potential novel biomarker related to prognosis and immunity in clear cell renal cell carcinoma. Discov Oncol 2025; 16:362. [PMID: 40111561 PMCID: PMC11925835 DOI: 10.1007/s12672-025-02114-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 03/10/2025] [Indexed: 03/22/2025] Open
Abstract
OBJECTIVE To analyze the expression levels, clinical significance, Immune infiltration and prognostic value of PRSS53 (Protease Serine 53) in clear cell renal cell carcinoma (ccRCC) using bioinformatics methods. METHODS Data on PRSS53 in ccRCC were extracted from databases and platforms, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), The Gene Expression Omnibus (GEO), Xiantao Academic Tool, Human Protein Atlas (HPA) and so on. We analyzed the relationship between PRSS53 expression and the clinical and pathological characteristics, diagnosis, immune infiltration and prognosis in ccRCC patients. Additionally, immunohistochemical analysis was performed on 9 pairs of ccRCC patient samples. RESULTS PRSS53 was significantly upregulated in ccRCC and was closely associated with the TNM stage and histological grade of ccRCC. Receiver operating characteristic (ROC) curve analysis demonstrated the excellent diagnostic performance of PRSS53 in ccRCC (AUC = 0.928). Patients with high PRSS53 expression exhibited lower overall survival (OS) and disease-specific survival (DSS). Gene set enrichment analysis (GSEA) revealed that PRSS53 is involved in cellular functions such as anchored component of membrane, basement membrane and RNA-binding involved in post-transcriptional gene silencing. Single-sample GSEA (ssGSEA) indicated a positive correlation between PRSS53 expression and T helper cells infiltration levels, and a negative correlation with T gamma delta (Tgd) cell infiltration. PRSS53 was predominantly expressed in renal proximal tubules. The immunohistochemical results and HPA database showed that PRSS53 protein expression was significantly lower in clinical ccRCC tissues compared to normal tissues. CONCLUSION PRSS53 is a new prognostic biomarker and potential therapeutic target for ccRCC.
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Affiliation(s)
- Jiajun Zhang
- The Yancheng Clinical College of Xuzhou Medical University, Yancheng, 224006, China
| | - Guocheng Liu
- The Yancheng Clinical College of Xuzhou Medical University, Yancheng, 224006, China
| | - Wei Wang
- The Yancheng Clinical College of Xuzhou Medical University, Yancheng, 224006, China.
- Department of Urology, Yancheng No.1 People's Hospital, Yancheng, 224006, China.
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11
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Xia H, He T, Li X, Zhao K, Zhang Z, Zhu G, Yang H, Yan X, Wang Q, Li Z, Jiang Z, Wang K, Yin X. Study on the mechanism of BGN in progression and metastasis of ccRCC. BMC Med Genomics 2025; 18:55. [PMID: 40108593 PMCID: PMC11924620 DOI: 10.1186/s12920-025-02124-5] [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: 03/24/2024] [Accepted: 03/12/2025] [Indexed: 03/22/2025] Open
Abstract
PURPOSE To investigate the role of Biglycan(BGN) in the progression and metastasis of clear cell renal cell carcinoma(ccRCC). METHODS Based on multiple public databases, we investigated the expression level of BGN in ccRCC, its clinical significance, and its association with immune cells. Real-time fluorescence quantitative polymerase chain reaction(PCR) was employed to validate BGN expression in tumor and adjacent normal tissues from ten patients. We utilized RNA sequencing results for further analysis, including differential gene analysis, GO-KEGG analysis, and GSEA analysis, to identify the signaling pathways through which BGN exerts its effects. BGN knockdown cells(786-0 and Caki-1) were generated through lentiviral transfection to examine the impact of BGN on ccRCC. Cell proliferation, migration, and invasion were assessed using CCK8, colony formation, wound healing, Transwell migration, and invasion assays, respectively. RESULTS Our findings from database analysis and PCR revealed a significant upregulation of BGN expression in kidney cancer tissues compared to normal tissues. Further analysis demonstrated a correlation between high BGN expression and ccRCC progression and immune infiltration. In vitro experiments confirmed that BGN silencing effectively inhibited cell proliferation, migration, and invasion of ccRCC. Mechanistically, these effects may be mediated through the MAPK signaling pathway. CONCLUSION BGN potentially plays a pivotal role in the progression and metastasis of ccRCC, possibly acting through the MAPK signaling pathway. Therefore, BGN holds promise as a potential therapeutic target for ccRCC.
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Affiliation(s)
- Hanqing Xia
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong, China
| | - Tianzhen He
- Institute of Special Environmental Medicine, Nantong University, Nantong, China
| | - Xueyu Li
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong, China
| | - Kai Zhao
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong, China
| | - Zongliang Zhang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong, China
| | - Guanqun Zhu
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong, China
| | - Han Yang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong, China
| | - Xuechuan Yan
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong, China
| | - Qinglei Wang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong, China
| | - Zhaofeng Li
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong, China
| | - Zaiqing Jiang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong, China
| | - Ke Wang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong, China
| | - Xinbao Yin
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, Shangdong, China.
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Dong Z, Huang Y, Xia W, Liao Y, Yang CG. A patenting perspective of fat mass and obesity associated protein (FTO) inhibitors: 2017-present. Expert Opin Ther Pat 2025:1-10. [PMID: 40052926 DOI: 10.1080/13543776.2025.2477482] [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: 09/04/2024] [Accepted: 03/06/2025] [Indexed: 03/14/2025]
Abstract
INTRODUCTION The fat mass and obesity-associated protein (FTO) catalytically demethylates RNA N6-methyl adenosine (m6A) modification, dynamically regulates gene expression in eukaryotes. Interestingly, FTO is highly expressed and functions as an oncogenic factor in a wide range of cancers. Therefore, using small-molecule inhibitors to target FTO has been established as a promising therapeutic strategy for combating cancers. AREAS COVERED Patent literature claiming novel chemical entities as FTO inhibitors disclosed from 2017 to present is available in Espacenet, including dozens of patent documents. EXPERT OPINION The pivotal influence of FTO demethylase in a particular epigenetic layer of regulation of gene expression renders it promising for FTO to be a therapeutical target for many diseases, including malignant cancers. Several institutions were prompted and have patented chemical frameworks as FTO inhibitors. Remarkedly, the FTO inhibitor CS1 (Bisantrene) has advanced to clinical trials for treating acute myeloid leukemia (AML). The successful advancement of CS1 into clinical trials would continuingly stimulate researches on RNA epigenetic enzymes targeted first-in-class anticancer drug discovery.
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Affiliation(s)
- Ze Dong
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Yue Huang
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Wenyang Xia
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Yonggang Liao
- Rname Pharmaceutical Technology (Shanghai) Co., LTD., Shanghai, China
| | - Cai-Guang Yang
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, China
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13
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Zhao B, Fu S, Shi Y, Yang J, Bi C, Yang L, Yang Y, Li X, Shi Z, Duan Y, Luo Z, Zhang G, Wang J. Development and validation of prognostic and diagnostic models utilizing immune checkpoint-related genes in public datasets for clear cell renal cell carcinoma. Front Genet 2025; 16:1521663. [PMID: 40104395 PMCID: PMC11913831 DOI: 10.3389/fgene.2025.1521663] [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: 11/02/2024] [Accepted: 02/17/2025] [Indexed: 03/20/2025] Open
Abstract
Background Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma, and immune checkpoint regulator-based immunotherapy has emerged as an effective treatment for advanced stages of the disease. However, the expression patterns, prognostic significance, and diagnostic value of immune checkpoint-related genes (ICRGs) in ccRCC remain underexplored. This study utilized large-scale ccRCC datasets from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the International Cancer Genome Consortium (ICGC) to analyze ICRGs and develop a prognostic and diagnostic model, which was validated using quantitative PCR in clinical samples from ccRCC patients. Methods RNA-seq data and clinical information were retrieved from TCGA, ICGC, and GEO databases. Differentially expressed genes (DEGs) were identified, and immune checkpoint-related genes (DICRGs) were selected by intersecting DEGs with ICRGs, followed by validation in independent datasets. Univariate and multivariate Cox regression analyses were used to develop the prognostic model. Protein expression of key genes was validated through immunohistochemistry (IHC) using data from the Human Protein Atlas (HPA). qRT-PCR confirmed gene expression levels in ccRCC and normal kidney tissues. Diagnostic models were constructed using machine learning, and functional enrichment and immune infiltration analyses were performed. Results Fourteen DICRGs were identified, with four (EGFR, TRIB3, ZAP70, and CD4) showing prognostic significance in Cox analyses. IHC revealed high expression of these genes in ccRCC tissues, and qRT-PCR confirmed increased expression of EGFR, TRIB3, and CD4, while ZAP70 expression showed no significant change. A prognostic risk score was developed based on gene expression levels. Functional analysis identified enriched pathways related to organic anion transport and metabolism, while immune infiltration analysis revealed associations between ZAP70, CD4, and risk scores. Conclusion This study establishes a prognostic model for ccRCC based on four ICRGs, providing valuable insights into the molecular mechanisms underlying prognosis and diagnosis in ccRCC.
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Affiliation(s)
- Bin Zhao
- Department of Urology, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Shi Fu
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yuanlong Shi
- Department of Urology, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Jinye Yang
- Department of Urology, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Chengwei Bi
- Department of Urology, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Libo Yang
- Department of Urology, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yong Yang
- Department of Urology, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Xin Li
- Department of Urology, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Zhiyu Shi
- Department of Urology, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yuanpeng Duan
- Department of Urology, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Zongyan Luo
- Department of Urology, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Guoying Zhang
- Department of Urology, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Jiansong Wang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
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14
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Eom KY, Mann B, Halpern MT. Integrated care among patients with kidney or urinary bladder cancer: An NCI patterns-of-care analysis. Urol Oncol 2025; 43:191.e13-191.e27. [PMID: 39658477 PMCID: PMC11875945 DOI: 10.1016/j.urolonc.2024.11.012] [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: 04/15/2024] [Revised: 10/11/2024] [Accepted: 11/07/2024] [Indexed: 12/12/2024]
Abstract
INTRODUCTION Cancer patients often have complex medical needs from diagnosis to survivorship/end-of-life care. Integrated care, including care coordination, multidisciplinary rounds, and supportive care services, is crucial for high-quality cancer care. Yet, factors influencing integrated care receipt are not well understood. This study describes patterns of integrated care among individuals diagnosed with kidney or urinary bladder cancer and examines patient- and hospital-level factors associated with these services. METHODS Analyzing 2019 National Cancer Institute Patterns-of-Care data, we assessed integrated care service receipt among stage I to IV kidney and stage 0a to IVb urinary bladder cancer patients aged ≥ 20 years using a stratified Surveillance, Epidemiology, and End Results registry sample. Integrated care services within 12 months postdiagnosis were identified by medical record abstraction. Multivariable logistic regression analyses identified patient, clinical, and hospital-level factors significantly associated with receipt of integrated care. RESULTS Significant variations in receiving integrated care were observed based on insurance status; uninsured patients less likely to receive these services. Racial/ethnic differences were also noted, as non-Hispanic white patients had higher likelihoods of receiving integrated care. Stage IV kidney cancer patients were 2.63 times [1.44-4.79] more likely to receive integrated care than stage I patients. Treatment characteristics and hospital-level factors appeared to have minimal impact on receiving these services. CONCLUSION The lower likelihood of receiving integrated care among patients with no insurance and among certain racial/ethnic groups underscores gaps in equitable access to patient-centered cancer care. Future research should include patient perspectives to enhance understanding of unmet needs and influencing factors related to integrated care services.
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Affiliation(s)
- Kirsten Y Eom
- Healthcare Delivery Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, Rockville, MD.
| | - Bhupinder Mann
- Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, National Cancer Institute, NIH, Rockville, MD
| | - Michael T Halpern
- Department of Health Policy and Health Services Administration, University of Texas School of Public Health San Antonio, San Antonio, TX
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15
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Zhong B, Du J, Liu F, Sun S. The Role of Yes-Associated Protein in Inflammatory Diseases and Cancer. MedComm (Beijing) 2025; 6:e70128. [PMID: 40066231 PMCID: PMC11892025 DOI: 10.1002/mco2.70128] [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: 04/17/2024] [Revised: 02/02/2025] [Accepted: 02/11/2025] [Indexed: 03/17/2025] Open
Abstract
Yes-associated protein (YAP) plays a central role in the Hippo pathway, primarily governing cell proliferation, differentiation, and apoptosis. Its significance extends to tumorigenesis and inflammatory conditions, impacting disease initiation and progression. Given the increasing relevance of YAP in inflammatory disorders and cancer, this study aims to elucidate its pathological regulatory functions in these contexts. Specifically, we aim to investigate the involvement and molecular mechanisms of YAP in various inflammatory diseases and cancers. We particularly focus on how YAP activation, whether through Hippo-dependent or independent pathways, triggers the release of inflammation and inflammatory mediators in respiratory, cardiovascular, and digestive inflammatory conditions. In cancer, YAP not only promotes tumor cell proliferation and differentiation but also modulates the tumor immune microenvironment, thereby fostering tumor metastasis and progression. Additionally, we provide an overview of current YAP-targeted therapies. By emphasizing YAP's role in inflammatory diseases and cancer, this study aims to enhance our understanding of the protein's pivotal involvement in disease processes, elucidate the intricate pathological mechanisms of related diseases, and contribute to future drug development strategies targeting YAP.
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Affiliation(s)
- Bing Zhong
- Department of Otolaryngology‐Head and Neck SurgeryWest China HospitalSichuan UniversityChengduSichuanChina
| | - Jintao Du
- Department of Otolaryngology‐Head and Neck SurgeryWest China HospitalSichuan UniversityChengduSichuanChina
| | - Feng Liu
- Department of Otolaryngology‐Head and Neck SurgeryWest China HospitalSichuan UniversityChengduSichuanChina
| | - Silu Sun
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesChinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and ManagementWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
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16
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Berg SA, La Rosa S, Zhang T, Pierorazio PM, Albiges L, Beckermann KE, Campbell MT, Carlo MI, Coleman K, George DJ, Geynisman DM, Johnson R, Jonasch E, Maranchie JK, McGregor BA, Shapiro DD, Singer EA, Shuch BM, Stadler WM, Tannir NM, Zakharia Y, Vaishampayan UN, Thall PF, Msaouel P. Impact of postprogression therapies on overall survival: Recommendations from the 2023 kidney cancer association think tank meeting. Urol Oncol 2025; 43:135-146. [PMID: 39500687 DOI: 10.1016/j.urolonc.2024.10.022] [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: 07/30/2024] [Revised: 10/14/2024] [Accepted: 10/17/2024] [Indexed: 03/03/2025]
Abstract
Modern advances in systemic and localized therapies for patients with renal cell carcinoma (RCC) have significantly improved patients' outcomes. If disease progression occurs after initial treatment, clinicians often have multiple options for a first salvage therapy. Because salvage and initial treatments both may affect overall survival time, and they may interact in unanticipated ways, there is a growing need to determine sequences of initial therapy and first salvage therapy that maximize overall survival while maintaining quality of life. The complexity of this problem grows if a second salvage therapy must be chosen for patients with treatment-resistant disease or a second progression occurs following first salvage. On November 9, 2023, a think tank was convened during the International Kidney Cancer Symposium (IKCS) North America to discuss challenges in accounting for postprogression therapies when estimating overall survival (OS) time based on randomized controlled trial (RCT) data. The present manuscript summarizes the topics discussed, with the aim to encourage adoption of statistical methods that account for salvage therapy effects to obtain scientifically valid OS estimation. We highlight limitations of traditional methods for estimating OS that account for initial treatments while ignoring salvage therapy effects and discuss advantages of applying more sophisticated statistical methods for estimation and trial design. These include identifying multistage treatment strategies, correcting for confounding due to salvage therapy effects, and conducting Sequentially Multiple Assignment Randomized Trials (SMARTs) to obtain unbiased comparisons between multistage strategies. We emphasize the critical role of patient input in trial design, and the potential for information technology (IT) advances to support complex trial designs and real-time data analyses. By addressing these challenges, future RCTs can better inform clinical decision-making and improve patient outcomes in RCC.
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Affiliation(s)
- Stephanie A Berg
- Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
| | | | - Tian Zhang
- Division of Hematology and Oncology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Phillip M Pierorazio
- Division of Urology, Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | | | - Kathryn E Beckermann
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Matthew T Campbell
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Maria I Carlo
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Katie Coleman
- Chromophobe and Oncocytic Tumor Alliance, Austin TX, USA
| | - Daniel J George
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC, USA
| | - Daniel M Geynisman
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | | | - Eric Jonasch
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jodi K Maranchie
- Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Bradley A McGregor
- Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Daniel D Shapiro
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Eric A Singer
- Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Brian M Shuch
- Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Walter M Stadler
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Nizar M Tannir
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yousef Zakharia
- Division of Hematology Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | | | - Peter F Thall
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Pavlos Msaouel
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
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17
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Dason S, Wang SJ, Franceschelli D, Singer EA. Metastasis-directed therapy in oligometastatic and oligoprogressive renal cell carcinoma. Curr Opin Urol 2025; 35:194-204. [PMID: 39744755 DOI: 10.1097/mou.0000000000001254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
PURPOSE OF REVIEW This review addresses the evolving role of metastasis-directed therapy (MDT) in the management of oligometastatic and oligoprogressive renal cell carcinoma (RCC). With advances in both surgical techniques and stereotactic ablative radiotherapy (SABR), it is timely to explore how MDT can improve patient outcomes in these distinct disease states. The review highlights the potential of MDT to delay systemic therapy and improve quality of life while noting the lack of randomized clinical trial data guiding its use. RECENT FINDINGS Recent literature emphasizes the outcomes of MDT, including metastasectomy and SABR, in managing oligometastatic and oligoprogressive RCC. Key studies suggest that MDT may prolong progression-free survival and delay systemic therapy. SABR has demonstrated high local control rates and manageable toxicity, offering a less invasive alternative to surgery. Despite these findings, there remains uncertainty about MDT's long-term impact on overall survival due to the absence of prospective randomized trials. SUMMARY MDT holds promise in treating RCC by offering symptom relief, improving quality of life, and potentially delaying systemic therapy. However, the long-term benefits, particularly regarding survival outcomes, remain unclear. Further research, including prospective trials, is needed to better define the role of MDT in clinical practice, particularly in the absence of clear guidelines for patient selection.
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Affiliation(s)
- Shawn Dason
- Division of Urologic Oncology
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Shang-Jui Wang
- Division of Urologic Oncology
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Dominic Franceschelli
- Division of Urologic Oncology
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Eric A Singer
- Division of Urologic Oncology
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
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18
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Albiges L, Gross-Goupil M, Barthélémy P, Bamias A, Bedke J, Bex A, Fontes-Sousa M, Grünwald V, Melichar B, Pickering L, Porta C, Procopio G, Rottey S, Schmidinger M, Suárez C, Velasco G, Escudier B. Towards a Consensus on the Management of Metastatic Renal Cell Carcinoma: Insights from a European Delphi Study. Eur Urol Oncol 2025:S2588-9311(25)00028-8. [PMID: 39924391 DOI: 10.1016/j.euo.2025.01.007] [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: 10/11/2024] [Revised: 12/19/2024] [Accepted: 01/09/2025] [Indexed: 02/11/2025]
Abstract
BACKGROUND AND OBJECTIVE Management of metastatic renal cell carcinoma (mRCC) remains complex despite clinical guidelines. The aim of this Delphi study was to achieve consensus among RCC experts on the definition, diagnosis, and first-line treatments for mRCC. METHODS Between May 2023 and April 2024, 14 experts from ten European countries completed two Delphi rounds of a 51-item questionnaire covering four topics: (1) oligometastatic RCC; (2) first-line treatment for metastatic clear-cell RCC; (3) treatment duration for metastatic clear-cell RCC; and (4) treatment of non-clear-cell RCC. Agreement was scored as absent/poor (<50%), fair (50-74%), or consensus (≥75%). KEY FINDINGS AND LIMITATIONS Consensus was reached for 12 of 51 items (24%) in the first round and 25 of 49 items (51%) by the study end. Notably, 79% of experts defined oligometastatic RCC as five or fewer metastases and agreed that it typically does not require immediate systemic treatment. All experts (100%) emphasized the importance of clinical performance status in guiding treatment for metastatic clear-cell RCC, with 86% agreeing on additional factors such as International Society of Urological Pathology grade and sarcomatoid features. Nivolumab plus cabozantinib was favored for patients with brain or bone metastases (93% and 86% agreement, respectively), while there was fair agreement on pembrolizumab plus lenvatinib for patients with liver metastases. In addition, 71% supported stopping immune checkpoint inhibitors after 2 yr, while 86% agreed on the undefined duration of tyrosine kinase inhibitor therapy. CONCLUSIONS AND CLINICAL IMPLICATIONS This Delphi study offers insights into mRCC management, and highlights the importance of multidisciplinary discussions for this challenging disease.
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Affiliation(s)
- Laurence Albiges
- Department of Oncology Institute Gustave Roussy Villejuif France
| | - Marine Gross-Goupil
- Department of Medical Oncology University Hospital of Bordeaux Bordeaux France
| | - Philippe Barthélémy
- Department of Medical Oncology Institut de Cancérologie Strasbourg Europe Strasbourg France
| | | | - Jens Bedke
- Department of Urology and Transplantation Surgery Eva Mayr-Stihl Cancer Center Stuttgart Klinikum Stuttgart Stuttgart Germany
| | - Axel Bex
- Department of Urology Netherlands Cancer Institute Amsterdam The Netherlands; University College London Division of Surgery and Interventional Science London UK
| | - Mário Fontes-Sousa
- Department of Medical Oncology Hospital CUF Tejo Lisbon Portugal; Department of Medical Oncology Hospital S. Francisco Xavier Lisbon Portugal
| | - Viktor Grünwald
- Clinic for Medical Oncology and Clinic for Urology University Hospital Essen Essen Germany
| | - Bohuslav Melichar
- Department of Oncology Faculty of Medicine and Dentistry Palacký University Olomouc Czechia
| | | | - Camillo Porta
- Interdisciplinary Department of Medicine A. Moro University of Bari Bari Italy; Division of Medical Oncology Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari Bari Italy
| | - Giuseppe Procopio
- Department of Medical Oncology Fondazione IRCCS Istituto Nazionale Tumori Milan Italy
| | - Sylvie Rottey
- Department of Medical Oncology University Hospital Ghent Ghent Belgium
| | - Manuela Schmidinger
- Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria
| | - Cristina Suárez
- Medical Oncology Vall d'Hebron Institute of Oncology Hospital Universitari Vall d'Hebron Barcelona Spain
| | - Guillermo Velasco
- Department of Medical Oncology University Hospital 12 de Octubre Instituto de Investigación Madrid Spain
| | - Bernard Escudier
- Department of Oncology Institute Gustave Roussy Villejuif France.
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Yang Z, Cai J, Li J, Liu X, Liu W, Cui K, Bai Z, Dong Y, Peng D, Duan Q, Shahzad A, Zhang Q. The Mechanism of TRIM21 Inhibiting the Invasion and Migration of ccRCC by Stabilizing ASS1. Mol Carcinog 2025; 64:260-278. [PMID: 39513657 DOI: 10.1002/mc.23840] [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: 08/30/2024] [Revised: 10/13/2024] [Accepted: 10/22/2024] [Indexed: 11/15/2024]
Abstract
Clear cell renal cell carcinoma (ccRCC) is characterized by its aggressive invasion and metastasis, presenting significant clinical challenges. Gaining insights into the molecular mechanisms underlying its progression is crucial for the development of effective therapeutic strategies. Addressing a critical knowledge gap in understanding ccRCC tumorigenesis, this study aims to elucidate the expression patterns of TRIM21 in ccRCC, unravel its impact on ccRCC patient prognosis, and investigate the regulatory role of TRIM21 in ASS1 expression and urea cycle dysregulation within the context of ccRCC. The results demonstrate that TRIM21 is downregulated in ccRCC, and low expression of TRIM21 predicts an unfavorable prognosis for ccRCC patients. Furthermore, the upregulation of TRIM21 can inhibit the migration and invasion of ccRCC cells by regulating the ubiquitination modification of ASS1. This not only expands the functional role of TRIM21 in ccRCC tumorigenesis but also demonstrates its ability to reverse urea cycle dysregulation through stabilizing ASS1 expression. Specifically, abnormal downregulation of TRIM21 in ccRCC reduces K63 ubiquitination modification of ASS1, leading to decreased stability of the ASS1 protein, aggravated urea cycle dysregulation, and facilitated migration and invasion of ccRCC cells. Additionally, reduction in ASS1 reverses the depressed migration and invasion caused by overexpression of TRIM21 in ccRCC cells. In summary, our findings contribute to a deeper understanding of the functional role played by TRIM21 in ccRCC progression, pinpoint a unique and novel regulatory mechanism involving ectopic downregulation-mediated ASS1 ubiquitination modification and urea cycle dysfunction during ccRCC progression, and provide fresh insights for further investigation into the pathogenesis and metabolic reprogramming associated with ccRCC.
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Affiliation(s)
- Zhe Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
- Departments of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Jihao Cai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Jingjing Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Xiangjie Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Wenjing Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Kun Cui
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Ziyuan Bai
- Departments of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yurong Dong
- Departments of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Dongmei Peng
- Departments of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Qiuxin Duan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Asif Shahzad
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Qiao Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
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20
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Kulasegaran T, Oliveira N, Gedye C, Sengupta S. Adjuvant immunotherapy for high-risk renal cell carcinoma-now or never? BJU Int 2025; 135:235-236. [PMID: 39513301 DOI: 10.1111/bju.16584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2024]
Affiliation(s)
- Tivya Kulasegaran
- Mater Hospital Brisbane, Mater Misericordiae Ltd., South Brisbane, Queensland, Australia
- School of Clinical Medicine, Mater Clinical Unit, The University of Queensland, Brisbane, Queensland, Australia
| | - Niara Oliveira
- Mater Hospital Brisbane, Mater Misericordiae Ltd., South Brisbane, Queensland, Australia
- School of Clinical Medicine, Mater Clinical Unit, The University of Queensland, Brisbane, Queensland, Australia
| | - Craig Gedye
- Icon Cancer Centre Adelaide, Kurralta Park, South Australia, Australia
| | - Shomik Sengupta
- Department of Urology, Eastern Health, Box Hill, Victoria, Australia
- Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia
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21
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Dason S, Goradia R, Heh V, Sood A, Lee M, Son Y, Yang Y, Wang SJ, Hasanov E, Posid T, Singer EA. Impact of Preoperative Systemic Therapy on Cytoreductive Nephrectomy Outcomes in the National Surgical Quality Improvement Program (NSQIP). Clin Genitourin Cancer 2025; 23:102258. [PMID: 39615117 PMCID: PMC11757078 DOI: 10.1016/j.clgc.2024.102258] [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: 09/17/2024] [Revised: 10/20/2024] [Accepted: 10/26/2024] [Indexed: 12/14/2024]
Abstract
INTRODUCTION Management of metastatic renal cell carcinoma (mRCC) is highly individualized and often involves cytoreductive nephrectomy (CN) and systemic therapy (ST). The optimal sequencing of CN and ST is uncertain. A difference in perioperative outcomes based on sequence of CN and ST could influence decisionmaking. We analyzed the National Surgical Quality Improvement Program (NSQIP) database to assess whether preoperative systemic therapy adversely impacted perioperative outcomes in patients receiving deferred CN. METHODS This analysis was conducted using the American College of Surgeons NSQIP Participant Use Data File for years 2019 and 2020. Groups were stratified by their receipt of preoperative systemic therapy within 90 days before CN. The primary outcome of our study was overall major complication rate. Secondary outcomes included overall complication rate, length of stay, operative time, discharge to home, adjunctive procedures, conversion from minimally-invasive to open surgery and infectious complications. Multivariate logistic regression was used to assess the role of preoperative systemic therapy and other predictors on the primary and secondary outcome(s). RESULTS The study cohort comprised of 752 patients (586 upfront vs. 166 deferred) undergoing cytoreductive nephrectomy from 2019-2021. There were no significant differences in major complication rate (8% upfront vs. 5% deferred, P = .188) or overall complication rate (33% upfront vs. 39% deferred, P = .152). On multivariate analysis, bleeding diathesis, adjunctive procedures, and higher ASA class were predictive of major complications. Patients receiving preoperative ST were more likely to be on steroids (23% vs. 7%, p.
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Affiliation(s)
- Shawn Dason
- Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH.
| | - Rajvi Goradia
- Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Victor Heh
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Akshay Sood
- Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Matthew Lee
- Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Young Son
- Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Yuanquan Yang
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Shang-Jui Wang
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Elshad Hasanov
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Tasha Posid
- Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Eric A Singer
- Division of Urologic Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
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22
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Barragan-Carrillo R, Saad E, Saliby RM, Sun M, Albiges L, Bex A, Heng D, Mejean A, Motzer RJ, Plimack ER, Powles T, Rini BI, Zhang T, Choueiri TK. First and Second-line Treatments in Metastatic Renal Cell Carcinoma. Eur Urol 2025; 87:143-154. [PMID: 39505582 DOI: 10.1016/j.eururo.2024.10.019] [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: 05/08/2024] [Revised: 07/18/2024] [Accepted: 10/14/2024] [Indexed: 11/08/2024]
Abstract
BACKGROUND AND OBJECTIVE The treatment landscape for metastatic renal cell carcinoma (mRCC) has evolved significantly in recent years, leading to improved outcomes. The aim of this review is to provide clinicians with a practical guide for selecting first- and second-line treatments on the basis of current evidence. METHODS We critically evaluated systemic treatment strategies for mRCC. A comprehensive literature search was conducted in PubMed and Embase, alongside manual searches of guidelines and conference proceedings up to October 2024. A narrative review was performed to reach a consensus, with voting used to resolve differing opinions among authors. KEY FINDINGS AND LIMITATIONS First-line treatment options include immune checkpoint inhibitor (ICI)-based combinations or tyrosine kinase inhibitors (TKIs). Four combination regimens have been approved internationally. Owing to the lack of head-to-head trials and standardized biomarkers, treatment decisions rely on factors such as International Metastatic RCC Database Consortium (IMDC) risk score, functional status, safety profiles, sarcomatoid features, use of immunosuppressive drugs, and need for immediate response. Despite advances, many patients will experience disease progression on ICI-based therapy, necessitating further treatment. The need for standardized second-line approaches remains unmet. TKIs, alone or with everolimus, show promising efficacy, while HIF2a inhibitors offer newer options with a favorable toxicity profile. Rechallenge with ICIs after early progression is not recommended. CONCLUSIONS AND CLINICAL IMPLICATIONS For optimal mRCC treatment selection, clinicians must carefully balance efficacy, toxicity, and patient preferences, especially when transitioning between first- and second-line therapies, to provide individualized care.
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Affiliation(s)
| | - Eddy Saad
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Renee-Maria Saliby
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Maxine Sun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Axel Bex
- Specialist Centre for Kidney Cancer, Royal Free NHS Foundation Trust, University College London Division of Surgery and Interventional Science, London, UK
| | - Daniel Heng
- Department of Oncology, Tom Baker Cancer Centre, Calgary, Canada
| | - Arnaud Mejean
- Department of Urology, Hôpital Européen Georges Pompidou, Paris, France
| | - Robert J Motzer
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Elizabeth R Plimack
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Thomas Powles
- Barts Health NHS Trust and the Royal Free NHS Foundation Trust, Barts Cancer Institute, London, UK; Queen Mary University of London, London, UK
| | - Brian I Rini
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Tian Zhang
- Division of Hematology and Oncology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Toni K Choueiri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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23
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Liu Y, Yan Z, Liu C, Yang R, Zheng Q, Jian J, Wang M, Wang L, Weng X, Chen Z, Liu X. Integrated RNA sequencing analysis and machine learning identifies a metabolism-related prognostic signature in clear cell renal cell carcinoma. Sci Rep 2025; 15:1691. [PMID: 39799252 PMCID: PMC11724983 DOI: 10.1038/s41598-025-85618-7] [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: 10/15/2024] [Accepted: 01/06/2025] [Indexed: 01/15/2025] Open
Abstract
The connection between metabolic reprogramming and tumor progression has been demonstrated in an increasing number of researches. However, further research is required to identify how metabolic reprogramming affects interpatient heterogeneity and prognosis in clear cell renal cell carcinoma (ccRCC). In this work, single-cell RNA sequencing (scRNA-seq) based deconvolution was utilized to create a malignant cell hierarchy with metabolic differences and to investigate the relationship between metabolic biomarkers and prognosis. Simultaneously, we created a machine learning-based approach for creating metabolism-related prognostic signature (MRPS). Gamma-glutamyltransferase 6 (GGT6) was further explored for deep biological insights through in vitro experiments. Compared to 51 published signatures and conventional clinical features, MRPS showed substantially higher accuracy. Meanwhile, high MRPS-risk samples demonstrated an immunosuppressive phenotype with more infiltrations of regulatory T cell (Treg) and tumour-associated macrophage (TAM). Following the administration of immune checkpoint inhibitors (ICIs), MRPS showed consistent and strong performance and was an independent risk factor for overall survival. GGT6, an essential metabolic indicator and component of MRPS, has been proven to support proliferation and invasion in ccRCC. MRPS has the potential to be a highly effective tool in improving the clinical results of patients with ccRCC.
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MESH Headings
- Humans
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/metabolism
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/mortality
- Carcinoma, Renal Cell/drug therapy
- Kidney Neoplasms/genetics
- Kidney Neoplasms/metabolism
- Kidney Neoplasms/pathology
- Kidney Neoplasms/mortality
- Kidney Neoplasms/drug therapy
- Machine Learning
- Prognosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Sequence Analysis, RNA/methods
- Male
- Female
- Gene Expression Regulation, Neoplastic
- Middle Aged
- Single-Cell Analysis
- gamma-Glutamyltransferase/metabolism
- gamma-Glutamyltransferase/genetics
- Cell Line, Tumor
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Affiliation(s)
- Yunxun Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Zhiwei Yan
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Cheng Liu
- Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Rui Yang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Qingyuan Zheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Jun Jian
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Minghui Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Lei Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Xiaodong Weng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Zhiyuan Chen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Xiuheng Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
- Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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24
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Matsumoto J. [Precision Medicine for Patients with Renal Cell Carcinoma Based on Drug-metabolizing Enzyme Expression Levels]. YAKUGAKU ZASSHI 2025; 145:7-14. [PMID: 39756928 DOI: 10.1248/yakushi.24-00166] [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: 01/07/2025]
Abstract
Notable advances have recently been achieved in drug therapies for renal cell carcinoma (RCC). Several tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have been approved for metastatic RCC (mRCC). The current first-line treatment for mRCC involves combination therapies using TKIs and ICIs. However, there is no consensus on which TKI+ICI therapy is best or how to select the appropriate therapy for individual patients with RCC. The kidney expresses various metabolic enzymes, including CYP and uridine diphosphate glucose (UDP)-glucuronosyltransferase (UGT). Although information on CYP and UGT expression in the kidney is limited compared to our understanding of liver expression, the main CYP and UGT subtypes expressed at high levels in the kidney are estimated to be CYP2B6, CYP3A5, CYP4A11, CYP4F2, UGT1A6, UGT1A9, and UGT2B7. In RCC, the expression profiles and levels of these enzymes are somewhat altered compared with normal kidney. The main known subtypes of CYP and UGT in RCC are CYP1B1, CYP3A5, CYP4A11, UGT1A6, UGT1A9, UGT1A10, and UGT2B7. High CYP expression has been reported in several cancers, possibly conferring resistance to anti-cancer drugs including TKIs, due to extensive drug metabolism. Additionally, CYP and UGT expression levels may possibly affect cancer prognosis by metabolizing endogenous substrates, regardless of their role in anti-cancer drug metabolism. In this review, I discuss CYP and UGT expression level profiles in RCC based on previously published papers, including ours, and examine possible relationships between these enzyme expression profiles and treatment outcomes for patients with RCC.
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Affiliation(s)
- Jun Matsumoto
- Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
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25
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Matei E, Ciurea S, Herlea V, Dumitrascu T, Vasilescu C. Surgery for an Uncommon Pathology: Pancreatic Metastases from Renal Cell Carcinoma-Indications, Type of Pancreatectomy, and Outcomes in a Single-Center Experience. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:2074. [PMID: 39768953 PMCID: PMC11678890 DOI: 10.3390/medicina60122074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 11/25/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025]
Abstract
Background and Objectives: The role of surgery in pancreatic metastases of renal cell carcinoma (PM_RCC) is highly controversial, particularly in the context of modern systemic therapies and the conflicting results of studies published so far. This study aims to explore a single surgical center experience (including mainly pancreatic resections) regarding the indications, the type of pancreatectomies, and early and long-term outcomes for PM_RCC. Materials and Methods: The data of all patients with surgery for PM_RCC (from 1 January 2002 to 31 December 2023) were retrospectively assessed, and potential predictors of survival were explored. Results: 20 patients underwent surgery for PM_RCC (pancreatectomies-95%). Metachronous PM_RCC was 90%, with a median interval between the initial nephrectomy and PM_RCC occurrence of 104 months. For elective pancreatectomies, the overall and severe morbidity and mortality rates were 24%, 12%, and 0%, respectively; 32% of patients underwent non-standardized pancreatic resections. The median survival of patients with negative resection margins was 128 months after pancreatectomies, with an 82% 5-year survival rate. Left kidney RCC and the body/tail PM_RCC were favorable prognostic factors for the overall survival after pancreatectomies for PM_RCC. Body/tail, asymptomatic PM_RCC, and an interval after initial nephrectomy > 2 were favorable prognostic factors for the overall survival after initial nephrectomy for RCC. Conclusions: Pancreatectomies for PM_RCC can achieve long-term survival whenever complete resection is feasible, with acceptable complication rates. Patients with left kidney RCC, body/tail, and asymptomatic PM_RCC and an interval of more than 2 years after nephrectomy exhibit the best survival rates.
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Affiliation(s)
- Emil Matei
- Department of General Surgery, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, Fundeni Street No. 258, 022328 Bucharest, Romania; (E.M.); (S.C.); (C.V.)
| | - Silviu Ciurea
- Department of General Surgery, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, Fundeni Street No. 258, 022328 Bucharest, Romania; (E.M.); (S.C.); (C.V.)
| | - Vlad Herlea
- Department of Pathology, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, Fundeni Street No. 258, 022328 Bucharest, Romania;
| | - Traian Dumitrascu
- Department of General Surgery, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, Fundeni Street No. 258, 022328 Bucharest, Romania; (E.M.); (S.C.); (C.V.)
| | - Catalin Vasilescu
- Department of General Surgery, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, Fundeni Street No. 258, 022328 Bucharest, Romania; (E.M.); (S.C.); (C.V.)
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26
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Taniguchi T, Iinuma K, Kawada K, Ishida T, Takagi K, Tomioka M, Kawase M, Kawase K, Nakane K, Tobisawa Y, Koie T. Real-World Oncological Outcomes of Nivolumab Plus Ipilimumab in Advanced or Metastatic Renal Cell Carcinoma: A Multicenter, Retrospective Cohort Study in Japan. Curr Oncol 2024; 31:7914-7923. [PMID: 39727706 DOI: 10.3390/curroncol31120583] [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: 11/15/2024] [Revised: 12/04/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024] Open
Abstract
A combination of nivolumab and ipilimumab (NIVO + IPI) is the only approved combination of two immune checkpoint inhibitors for metastatic or advanced renal cell carcinoma (mRCC). Inadequate evidence of treatment with NIVO + IPI has been reported in Japanese cohorts. We evaluated the clinical efficacy of NIVO + IPI treatment. Patients with mRCC who received NIVO + IPI at nine Japanese facilities between August 2018 and March 2023 were enrolled in this study. The primary endpoint in this study was the assessment of oncological outcomes in patients with mRCC who received NIVO + IPI. Eighty-four patients with mRCC were enrolled. The median follow-up period was 18.3 months, and median progression-free and overall survival were 13.3 and 50.9 months, respectively. The objective response rate was 47.6%, and the disease control rate was 78.6%. To our knowledge, this is the largest study that evaluates Japanese patients with mRCC receiving NIVO + IPI treatment. In this study, the real-world oncological outcomes after NIVO + IPI treatment were comparable to those in the CheckMate 214 study.
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Affiliation(s)
- Tomoki Taniguchi
- Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
- Department of Urology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki 503-8502, Japan
| | - Koji Iinuma
- Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Kei Kawada
- Department of Urology, Gifu Prefectural General Medical Center, 4-6-1 Noisiki, Gifu 500-8717, Japan
| | - Takashi Ishida
- Department of Urology, Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu 500-8513, Japan
| | - Kimiaki Takagi
- Department of Urology, Daiyukai Hospital, 1-9-9 Sakura, Ichinomiya 491-8551, Japan
| | - Masayuki Tomioka
- Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Makoto Kawase
- Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Kota Kawase
- Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Keita Nakane
- Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Yuki Tobisawa
- Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Takuya Koie
- Department of Urology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
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27
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Lou K, Wang J, He H, Wang Y, Mi Y, Li W, Chen L, Zhang Y, Mao Y, Lin J, Fu H, Yu C. Value of [ 68Ga]Ga-NYM046 PET/CT, in Comparison with 18F-FDG PET/CT, for Diagnosis of Clear Cell Renal Cell Carcinoma. J Nucl Med 2024; 65:1884-1890. [PMID: 39542699 PMCID: PMC11619588 DOI: 10.2967/jnumed.124.267527] [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: 01/31/2024] [Accepted: 10/23/2024] [Indexed: 11/17/2024] Open
Abstract
This study aimed to investigate the diagnostic efficacy of [68Ga]Ga-NYM046 PET/CT in animal models and patients with clear cell renal cell carcinoma (ccRCC) and to compare its performance with that of 18F-FDG PET/CT. Methods: The in vivo biodistribution of [68Ga]Ga-NYM046 was evaluated in mice bearing OS-RC-2 xenografts. Twelve patients with ccRCC were included in the study; all completed paired [68Ga]Ga-NYM046 PET/CT and 18F-FDG PET/CT. The diagnostic efficacies of these 2 PET tracers were compared. Moreover, the positive rate of carbonic anhydrase IX in the pathologic tissue sections was compared with the SUVmax obtained by PET/CT. Results: The tumor accumulation of [68Ga]Ga-NYM046 at 1 h after injection in OS-RC-2 xenograft tumor models was 7.21 ± 2.39 injected dose per gram of tissue. Apart from tumors, the kidney and stomach showed high-uptake distributions. In total, 9 primary tumors, 96 involved lymph nodes, and 147 distant metastases in 12 patients were evaluated using [68Ga]Ga-NYM046 and 18F-FDG PET/CT. Compared with 18F-FDG PET/CT, [68Ga]Ga-NYM046 PET/CT detected more primary tumors (9 vs. 1), involved lymph nodes (95 vs. 92), and distant metastases (137 vs. 127). In quantitative analysis, the primary tumors' SUVmax (median, 13.5 vs. 2.4; z = -2.668, P = 0.008) was significantly higher in [68Ga]Ga-NYM046 PET/CT. Conversely, the involved lymph nodes' SUVmax (median, 5.9 vs. 7.6; z = -3.236, P = 0.001) was higher in 18F-FDG PET/CT. No significant differences were found for distant metastases (median SUVmax, 5.0 vs. 5.0; z = -0.381, P = 0.703). Higher [68Ga]Ga-NYM046 uptake in primary tumors corresponded to higher expression of carbonic anhydrase IX, with an R 2 value of 0.8274. Conclusion: [68Ga]Ga-NYM046 PET/CT offers a viable strategy for detecting primary tumors, involved lymph nodes, and distant metastases in patients with ccRCC.
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Affiliation(s)
- Kequan Lou
- Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Jialiang Wang
- Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Huihui He
- Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yanjuan Wang
- Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yuanyuan Mi
- Department of Urological Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Wenjin Li
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Liping Chen
- Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yu Zhang
- Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Yong Mao
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China; and
| | - Jianguo Lin
- Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, China
| | - Haitian Fu
- Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China;
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Chunjing Yu
- Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China;
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
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28
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Agarwal N, Brugarolas J, Ghatalia P, George S, Haanen JB, Gurney H, Ravilla R, Van der Veldt A, Beuselinck B, Pokataev I, Suelmann BBM, Tuthill MH, Vaena D, Zagouri F, Wu J, Perini RF, Liu Y, Merchan J, Atkins MB. Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma. Ann Oncol 2024; 35:1148-1156. [PMID: 39233312 DOI: 10.1016/j.annonc.2024.08.2338] [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: 05/30/2024] [Revised: 07/29/2024] [Accepted: 08/19/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND Belzutifan is a first-in-class hypoxia-inducible factor subunit 2α (HIF-2α) inhibitor approved at a dose of 120 mg once daily for certain adults with VHL disease and adults with advanced renal cell carcinoma (RCC) following therapy with a programmed cell death protein 1 (PD-1) [or programmed death ligand 1 (PD-L1)] inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. However, whether the belzutifan dose could be optimized is unclear. PATIENTS AND METHODS The phase II LITESPARK-013 study (NCT04489771) enrolled patients with advanced clear cell RCC whose disease progressed after one to three prior systemic therapies, including an anti-PD-(L)1 regimen. Patients were randomly assigned 1 : 1 to receive belzutifan 120 or 200 mg once daily. The primary endpoint was the objective response rate (ORR) per RECIST version 1.1. The secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS Overall, 154 patients were enrolled (120 mg: n = 76; 200 mg: n = 78). The median follow-up was 20.1 months (range 14.8-28.4). The ORR was 23.7% versus 23.1% for the 120 mg and 200 mg groups, respectively [P = 0.5312; -0.5%, 95% confidence interval (CI) -14.0% to 12.9%]. The median DOR was not reached for the 120 mg arm and was 16.1 months (2.1+ to 23.5+) for the 200 mg arm. No between-group differences were observed for PFS [hazard ratio (HR) 0.94, 95% CI 0.63-1.40] or OS (medians not reached; HR 1.11, 95% CI 0.65-1.90). Grade 3 or 4 treatment-related adverse events were observed in 35 patients (46.1%) in the 120 mg group and 36 patients (46.2%) in the 200 mg group. CONCLUSIONS The efficacy of belzutifan was similar between the 120 mg dose and the 200 mg dose for previously treated clear cell RCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg once daily as the preferred dose for belzutifan.
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Affiliation(s)
- N Agarwal
- Director, Genitourinary Oncology Program, Huntsman Cancer Institute, University of Utah (NCI-CCC), Salt Lake City.
| | - J Brugarolas
- Director, Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas; Department of Internal Medicine, Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas
| | - P Ghatalia
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia
| | - S George
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, USA
| | - J B Haanen
- Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - H Gurney
- Director of Medical Oncology and Clinical Trials, MQ Health, Macquarie University, Sydney, Australia
| | - R Ravilla
- Department of Medical Oncology, New York Oncology Hematology, Albany, USA
| | - A Van der Veldt
- Department of Radiology & Nuclear Medicine, Medical Oncology, Erasmus MC, Rotterdam, Netherlands
| | - B Beuselinck
- Department of General Medical Oncology, University Hospital Leuven, KU Leuven, Leuven, Belgium
| | - I Pokataev
- S. S. Yudin City Clinical Hospital, Department of Health of Moscow, Moscow, Russia
| | - B B M Suelmann
- Department of Medical Oncology, Universitair Medisch Centrum Utrecht, Utrecht, Netherlands
| | - M H Tuthill
- Department of Oncology and Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - D Vaena
- Department of Medical Oncology/Hematology, West Cancer Center and Research Institute, Germantown, USA
| | - F Zagouri
- Clinical Therapeutics, Alexandra Regional General Hospital Athens, Athens, Greece
| | - J Wu
- Merck & Co., Inc., Rahway
| | | | - Y Liu
- Merck & Co., Inc., Rahway
| | - J Merchan
- Department of Medicine, Medical Oncology Division, University of Miami - Sylvester Comprehensive Center Cancer, Miami
| | - M B Atkins
- Department of Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, USA
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Wu Q, Shao H, Zhai W, Huang G, Liu J, Calais J, Wei W. Molecular imaging of renal cell carcinomas: ready for prime time. Nat Rev Urol 2024:10.1038/s41585-024-00962-z. [PMID: 39543358 DOI: 10.1038/s41585-024-00962-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2024] [Indexed: 11/17/2024]
Abstract
The clinical diagnosis of renal cell carcinoma (RCC) is constantly evolving. Diagnostic imaging of RCC relying on enhanced computed tomography (CT) and magnetic resonance imaging (MRI) is commonly used for renal mass characterization and assessment of tumour thrombosis, whereas pathology is the gold standard for establishing diagnosis. However, molecular imaging is rapidly improving the clinical management of RCC, particularly clear-cell RCC. Molecular imaging aids in the non-invasive visualization and characterization of specific biomarkers such as carbonic anhydrase IX and CD70 within the tumours, which help to assess tumour heterogeneity and status. Target-specific molecular imaging of RCCs will substantially improve the diagnostic landscape of RCC and will further facilitate clinical decision-making regarding initial staging and re-staging, monitoring of recurrence and metastasis, patient stratification and selection, and the prediction and evaluation of treatment responses.
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Affiliation(s)
- Qianyun Wu
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hongda Shao
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Zhai
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Gang Huang
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianjun Liu
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Jeremie Calais
- Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.
| | - Weijun Wei
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Zhu X, Al-danakh A, Jian Y, Safi M, Luo S, Chen Q, Wang S, Yang D. High RRM2 Correlates with Mitochondrial and Immune Responses in the Eosinophilic Subtype of Clear Cell Renal Cell Carcinoma. J Inflamm Res 2024; 17:8117-8133. [PMID: 39507262 PMCID: PMC11539861 DOI: 10.2147/jir.s478993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/24/2024] [Indexed: 11/08/2024] Open
Abstract
Background Clear cell renal cell carcinoma (ccRCC), the predominant subtype of RCC, is distinguished by unique biological characteristics and heterogeneity, including eosinophilic and clear subtypes. Notwithstanding progress in therapy, immune checkpoint inhibitors (ICIs), and tyrosine kinase inhibitors (TKIs), the prognosis for individuals with metastatic ccRCC remains poor, presumably owing to metabolic alterations leading to mitochondrial dysfunction, which affects treatment response variability. Methods We analyzed histological and immunohistochemical data from a cohort at Dalian Medical University's First Affiliated Hospital alongside RNA-sequencing transcriptome data from the TCGA database. Histologically, eosinophilic and clear ccRCC subtypes were evaluated using Kaplan-Meier and Cox proportional hazards models for survival analysis and prognosis. Differential gene expression (DEG) analysis and Gene Set Enrichment Analysis were performed to explore transcriptomic differences and relevant pathways. Results The study discovered substantial histological and molecular differences between the eosinophilic and clear cell subtypes of ccRCC. The eosinophilic subtype linked with frequent high-grade tumors (69.05% eosinophil vs 35.35% clear) and a poorer prognosis (HR=2.659, 95% CI:1.437-4.919, P=0.002). DEG analysis revealed distinct expression patterns among subtypes and identified a risk score signature that remained significant even after adjusting for clinical variables (HR=3.967, 95% CI: 1.665-9.449, P=0.002), showing less favorable survival in the high-risk group (P < 0.0001). RRM2 emerged as the most prognostic gene from this risk score, particularly in the eosinophilic subtype, alongside other clinical variables. By IHC, RRM2 shows high IHC score in eosinophilic compared to clear subtype (P=0.019). In addition, highly expressed RRM2 correlates with poor outcomes and is linked to mitochondrial genes, immunological pathways, and ICIs treatment. Conclusion These findings show significant differences in prognosis between subtypes. RRM2 was the most prognostic gene from the discovered novel risk score signature associated with subtypes. Future research is essential to validate these insights and their therapeutic implications for ccRCC management.
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Affiliation(s)
- Xinqing Zhu
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China
| | - Abdullah Al-danakh
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China
| | - Yuli Jian
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, LiaoningPeople’s Republic of China
| | - Mohammed Safi
- Thoracic/Head and Neck Medical Oncology Department, MD Anderson Cancer Center, Houston, TX, USA
| | - Sijie Luo
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China
| | - Qiwei Chen
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China
| | - Shujing Wang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, LiaoningPeople’s Republic of China
| | - Deyong Yang
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China
- Department of Surgery, Healinghands Clinic, Dalian, Liaoning, People’s Republic of China
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Ishihara H, Nemoto Y, Mizoguchi S, Nishimura K, Ikeda T, Fukuda H, Yoshida K, Shimmura H, Hashimoto Y, Iizuka J, Kondo T, Takagi T. Changes in outcome of patients with advanced non-clear cell renal cell carcinoma from the tyrosine kinase inhibitor era to the immuno-oncology era. Int J Clin Oncol 2024; 29:1730-1739. [PMID: 39143429 DOI: 10.1007/s10147-024-02606-z] [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: 05/18/2024] [Accepted: 08/04/2024] [Indexed: 08/16/2024]
Abstract
BACKGROUND The therapeutic benefit of immuno-oncology (IO) therapy for patients with advanced non-clear-cell renal cell carcinoma (nccRCC) remains unclear. PATIENTS AND METHODS We reviewed clinical data from 93 patients with advanced nccRCC who received first-line systemic therapy including IO combination therapy and tyrosine kinase inhibitor (TKI) monotherapy at our affiliated institutions. Patients were divided based on the period when the treatment was implemented as the standard of care into the IO and TKI eras. Survival and tumor response outcomes were compared between the IO and TKI eras. RESULTS Of the 93 patients, 50 (54%) and 43 (46%) were categorized as IO era and TKI era groups, respectively. Progression-free survival (PFS) and overall survival (OS) were significantly longer in the IO era than in the TKI era (median PFS: 8.97 vs. 4.96 months, p = 0.0152; median OS: 38.4 vs. 13.5 months, p = 0.0001). After the adjustment using other covariates, the treatment era was an independent factor for PFS (hazard ratio: 0.59, p = 0.0235) and OS (hazard ratio: 0.27, p < 0.0001). Objective response and disease control rates was not significantly different between the treatment eras (26% vs. 16.3%, p = 0.268; 62% vs. 62.8%, p = 0.594). CONCLUSION The implementation of IO therapy was significantly associated with longer survival in the nccRCC population. Further studies are needed to establish a more effective treatment strategy in this population using multiple regimens of IO combination therapy.
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Affiliation(s)
- Hiroki Ishihara
- Department of Urology, Saiseikai Kawaguchi General Hospital, 5-11-5 Nishikawaguchi, Kawaguchi, Saitama, Japan.
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan.
| | - Yuki Nemoto
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
- Department of Urology, Jyoban Hospital, Uenodai 57, Joban Kamiyunagayamachi, Iwaki, Fukushima, Japan
| | - Shinsuke Mizoguchi
- Department of Urology, Saiseikai Kazo Hospital, 1680 Kamitakayanagi, Kazo, Saitama, Japan
| | - Koichi Nishimura
- Department of Urology, Tokyo Women's Medical University Adachi Medical Center, 4-33-1 Kouhoku, Adachi-ku, Tokyo, Japan
| | - Takashi Ikeda
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Hironori Fukuda
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Kazuhiko Yoshida
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Hiroaki Shimmura
- Department of Urology, Jyoban Hospital, Uenodai 57, Joban Kamiyunagayamachi, Iwaki, Fukushima, Japan
| | - Yasunobu Hashimoto
- Department of Urology, Saiseikai Kawaguchi General Hospital, 5-11-5 Nishikawaguchi, Kawaguchi, Saitama, Japan
| | - Junpei Iizuka
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Tsunenori Kondo
- Department of Urology, Tokyo Women's Medical University Adachi Medical Center, 4-33-1 Kouhoku, Adachi-ku, Tokyo, Japan
| | - Toshio Takagi
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
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Zhang Y, Wang T, Mutailipu D, Li Y, Liang S, Yi Q, Zhu R, Ma J. ZBP1 as a prognostic biomarker correlated with cell proliferation in clear cell renal cell carcinoma. Heliyon 2024; 10:e39267. [PMID: 39469683 PMCID: PMC11513510 DOI: 10.1016/j.heliyon.2024.e39267] [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: 05/19/2024] [Revised: 10/02/2024] [Accepted: 10/10/2024] [Indexed: 10/30/2024] Open
Abstract
Background Z-DNA-binding protein 1 (ZBP1) is a critical Z-DNA- and Z-RNA-binding protein. However, its diagnostic and prognostic significance, as well as its functions in clear cell renal cell carcinoma (ccRCC), are not well understood. Materials and methods Paired and unpaired differential expression analyses of ZBP1 were performed in pan-cancer cells. Receiver operating characteristic (ROC) curves and survival analyses were used to evaluate the clinical significance of ZBP1. Functional enrichment and immune infiltration analyses were used to explore the mechanisms underlying ZBP1 expression. Western blotting, qRT-PCR, CCK-8, and colony formation assays were used to investigate the potential function of ZBP1 in ccRCC cells. Molecular docking was utilized to identify drugs targeting ZBP1. Results ZBP1 was highly expressed in ccRCC, demonstrating significant diagnostic and prognostic value. ZBP1 mRNA expression correlated with TNM stage, pathologic stage, and histologic grade. Functional enrichment analyses indicated that ZBP1 is involved in multiple immune processes. Moreover, ZBP1 mRNA expression was positively correlated with the infiltrating levels of T cells and cytotoxic cells, and negatively correlated with the infiltrating levels of mast cells and Th17 cells in ccRCC. Biological experiments confirmed that ZBP1 promotes ccRCC cell proliferation. Molecular docking studies identified rucaparib as a potential drug targeting ZBP1. Conclusion Our research findings suggest that targeting ZBP1 could represent a novel therapeutic approach to inhibit the progression of ccRCC.
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Affiliation(s)
- Yuqing Zhang
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Tao Wang
- Department of Urology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Taicang, China
| | - Daniyaerjiang Mutailipu
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Yang Li
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Shengjie Liang
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Qingtong Yi
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Rujian Zhu
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
| | - Junjie Ma
- Department of Urology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Taicang, China
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Wei GH, Wei XY, Fan LY, Zhou WZ, Sun M, Zhu CD. Comprehensive assessment of the association between tumor-infiltrating immune cells and the prognosis of renal cell carcinoma. World J Clin Oncol 2024; 15:1280-1292. [DOI: 10.5306/wjco.v15.i10.1280] [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: 07/04/2024] [Revised: 08/07/2024] [Accepted: 08/13/2024] [Indexed: 09/29/2024] Open
Abstract
BACKGROUND According to current statistics, renal cancer accounts for 3% of all cancers worldwide. Renal cell carcinoma (RCC) is the most common solid lesion in the kidney and accounts for approximately 90% of all renal malignancies. Increasing evidence has shown an association between immune infiltration in RCC and clinical outcomes. To discover possible targets for the immune system, we investigated the link between tumor-infiltrating immune cells (TIICs) and the prognosis of RCC.
AIM To investigate the effects of 22 TIICs on the prognosis of RCC patients and identify potential therapeutic targets for RCC immunotherapy.
METHODS The CIBERSORT algorithm partitioned the 22 TIICs from the Cancer Genome Atlas cohort into proportions. Cox regression analysis was employed to evaluate the impact of 22 TIICs on the probability of developing RCC. A predictive model for immunological risk was developed by analyzing the statistical relationship between the subpopulations of TIICs and survival outcomes. Furthermore, multivariate Cox regression analysis was used to investigate independent factors for the prognostic prediction of RCC. A value of P < 0.05 was regarded as statistically significant.
RESULTS Compared to normal tissues, RCC tissues exhibited a distinct infiltration of immune cells. An immune risk score model was established and univariate Cox regression analysis revealed a significant association between four immune cell types and the survival risk connected to RCC. High-risk individuals were correlated to poorer outcomes according to the Kaplan-Meier survival curve (P = 1E−05). The immunological risk score model was demonstrated to be a dependable predictor of survival risk (area under the curve = 0.747) via the receiver operating characteristic curve. According to multivariate Cox regression analysis, the immune risk score model independently predicted RCC patients' prognosis (hazard ratio = 1.550, 95%CI: 1.342–1.791; P < 0.001). Finally, we established a nomogram that accurately and comprehensively forecast the survival of patients with RCC.
CONCLUSION TIICs play various roles in RCC prognosis. The immunological risk score is an independent predictor of poor survival in kidney cancer cases.
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Affiliation(s)
- Guo-Hao Wei
- Department of Oncology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Xi-Yi Wei
- The State Key Laboratory of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210003, Jiangsu Province, China
| | - Ling-Yao Fan
- Department of Oncology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Wen-Zheng Zhou
- Department of Oncology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Ming Sun
- Department of Oncology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Chuan-Dong Zhu
- Department of Oncology, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
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Yang Y, Gan X, Zhang W, Zhu B, Huangfu Z, Shi X, Wang L. Research progress of the Hippo signaling pathway in renal cell carcinoma. Asian J Urol 2024; 11:511-520. [PMID: 39534002 PMCID: PMC11551326 DOI: 10.1016/j.ajur.2024.02.005] [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: 08/23/2023] [Accepted: 01/15/2024] [Indexed: 11/16/2024] Open
Abstract
Objective This review aimed to summarize the role of the Hippo signaling pathway in renal cell carcinoma (RCC), a urologic malignancy with subtle initial symptoms and high mortality rates due to metastatic RCC. The Hippo signaling pathway, which regulates tissue and organ sizes, plays a crucial role in RCC progression and metastasis. Understanding the involvement of the Hippo signaling pathway in RCC provides valuable insights for the development of targeted therapies and improved patient outcomes. Methods In this review, we explored the impact of the Hippo signaling pathway on RCC. Through an analysis of existing literature, we examined its role in RCC progression and metastasis. Additionally, we discussed potential therapeutic strategies targeting the Hippo pathway for inhibiting RCC cell growth and invasion. We also highlighted the importance of investigating interactions between the Hippo pathway and other signaling pathways such as Wnt, transforming growth factor-beta, and PI3K/AKT, which may uncover additional therapeutic targets. Results The Hippo signaling pathway has shown promise as a target for inhibiting RCC cell growth and invasion. Studies have demonstrated its dysregulation in RCC, with altered expression of key components such as yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ). Targeting the Hippo pathway has been associated with suppressed tumor growth and metastasis in preclinical models of RCC. Furthermore, investigating crosstalk between the Hippo pathway and other signaling pathways has revealed potential synergistic effects that could be exploited for therapeutic interventions. Conclusion Understanding the role of the Hippo signaling pathway in RCC is of paramount importance. Elucidating its functions and molecular interactions contributes to RCC diagnosis, treatment, and the discovery of novel mechanisms. This knowledge informs the development of innovative therapeutic strategies and opens new avenues for research in RCC. Further investigations are warranted to fully comprehend the complex interplay between the Hippo pathway and other signaling pathways, ultimately leading to improved outcomes for RCC patients.
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Affiliation(s)
- Yiren Yang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Xinxin Gan
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
- School of Materials Science and Engineering, University of Shanghai for Science and Technology, China
| | - Wei Zhang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Baohua Zhu
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Zhao Huangfu
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Xiaolei Shi
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Linhui Wang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
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Qiu J, Fu Y, Liu T, Wang J, Liu Y, Zhang Z, Ye Z, Cao Z, Su D, Luo W, Tao J, Weng G, Ye L, Zhang F, Liang Z, Zhang T. Single-cell RNA-seq reveals heterogeneity in metastatic renal cell carcinoma and effect of anti-angiogenesis therapy in the pancreas metastatic lesion. Cancer Lett 2024; 601:217193. [PMID: 39159881 DOI: 10.1016/j.canlet.2024.217193] [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: 06/10/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 08/21/2024]
Abstract
Metastatic clear cell renal cell carcinoma has heterogenous tumor microenvironment (TME). Among the metastatic lesions, pancreas metastasis is rare and controversy in treatment approaches. Here, extensive primary and metastatic lesion samples were included by single-cell RNA-seq to decipher the distinct metastasis TME. The hypoxic and inflammatory TME of pancreas metastasis was decoded in this study, and the activation of PAX8-myc signaling, and metabolic reprogramming were observed. The active components including endothelial cells, fibroblasts and T cells were profiled. Meanwhile, we also evaluated the effect of anti-angiogenesis treatment in the pancreas metastasis patient. The potential mechanisms of pancreatic tropism, instability of genome, and the response of immunotherapy were also discussed in this work. Taken together, our findings suggest a clue to the heterogeneity in metastasis TME and provide evidence for the treatment of pancreas metastasis in renal cell carcinoma patients.
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Affiliation(s)
- Jiangdong Qiu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Yifan Fu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Tao Liu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Jun Wang
- Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Yueze Liu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Zeyu Zhang
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Ziwen Ye
- Department of Urology, The Fist Affiliated Hospital of Harbin Medical University, Harbin, China.
| | - Zhe Cao
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Dan Su
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Wenhao Luo
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Jinxin Tao
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Guihu Weng
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Liyuan Ye
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Feifan Zhang
- Department of Computer Science, University College London, UK.
| | - Zhiyong Liang
- Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Taiping Zhang
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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Pant S, Cho BC, Kyriakopoulos CE, Spira A, Tannir N, Werner TL, Yan X, Neuteboom S, Chao R, Goel S. Targeting multiple receptor tyrosine kinases with sitravatinib: A Phase 1b study in advanced renal cell carcinoma and castrate-resistant prostate cancer. Invest New Drugs 2024; 42:547-558. [PMID: 39168901 PMCID: PMC11625060 DOI: 10.1007/s10637-024-01465-9] [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: 05/22/2024] [Accepted: 08/12/2024] [Indexed: 08/23/2024]
Abstract
Sitravatinib (MGCD516) is an oral inhibitor of several closely related oncogenic tyrosine kinase receptors that include VEGFR-2 (vascular endothelial growth factor receptor-2), AXL, and MET (mesenchymal-epithelial transition). The safety and antitumor activity of sitravatinib are reported in patients from two histologic cohorts (anti-angiogenesis-refractory clear cell renal cell carcinoma [RCC] and castrate-resistant prostate cancer [CRPC] with bone metastases) who participated in a Phase 1/1b study. The patients were enrolled using a 3-stage design that was based on observed objective responses. Objective response rate (ORR) was the primary endpoint. Duration of response, progression-free survival (PFS), overall survival (OS), and safety were also assessed. Overall, 48 patients (RCC n = 38, CRPC n = 10) received ≥ 1 dose of sitravatinib. Both cohorts were heavily pretreated (median number of prior systemic therapies: RCC cohort 3, CRPC cohort 6). In the RCC cohort, ORR was 25.9%, P = 0.015 (null hypothesis [ORR ≤ 10%] was rejected). Responses were durable (median duration 13.2 months). Median PFS was 9.5 months and median OS was 30.0 months. No objective responses were seen in the CRPC cohort; median PFS and OS were 5.8 months and 10.1 months, respectively. Across both cohorts, diarrhea (72.9%), fatigue (54.2%), and hypertension (52.1%) were the most frequent all-cause treatment-emergent adverse events (TEAEs). Diarrhea and vomiting (both, 6.3%) were the most frequent serious TEAEs considered related to study treatment. Sitravatinib demonstrated an acceptable safety profile and promising clinical activity in patients with clear cell RCC refractory to prior angiogenesis inhibitor therapy. Strong indicators for clinical activity were not seen in patients with CRPC and bone metastases. Clinical trial registration:ClinicalTrials.gov NCT02219711.
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Affiliation(s)
- Shubham Pant
- University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Byoung Chul Cho
- Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | | | | | - Nizar Tannir
- University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Theresa L Werner
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | | | | | | | - Sanjay Goel
- Montefiore Medical Center, Bronx, NY, USA.
- Rutgers Cancer Institute, New Brunswick, NJ, USA.
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Villafuerte CJQ, Swaminath A. Stereotactic Body Radiotherapy for Renal Cell Carcinoma-A Review of Use in the Primary, Cytoreductive and Oligometastatic Settings. Cancers (Basel) 2024; 16:3334. [PMID: 39409955 PMCID: PMC11475850 DOI: 10.3390/cancers16193334] [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: 08/19/2024] [Revised: 09/17/2024] [Accepted: 09/17/2024] [Indexed: 10/20/2024] Open
Abstract
Renal cell carcinoma (RCC) has been increasing in incidence by around 1.5% per year for several years. However, the mortality rate has been decreasing by 1.6% per year, and this can be attributed to stage migration and improvements in treatment. One treatment modality that has emerged in recent years is stereotactic body radiotherapy (SBRT), which is an advanced radiotherapy technique that allows the delivery of high-dose radiation to the tumor while minimizing doses to the organs at risk. SBRT has developed a role in the treatment of early-stage, oligometastatic and oligoprogressive RCC. In localized disease, phase II trials and meta-analyses have shown that SBRT provides a very high probability of long-term local control with a low risk of severe late toxicity. In oligometastatic (OMD) RCC, the same level of evidence has similarly shown good local control and minimal toxicity. SBRT could also delay the necessity to start or switch systemic treatments. Medical societies have started to incorporate SBRT in their guidelines in the treatment of localized disease and OMD. A possible future role of SBRT involves cytoreduction. It is theorized that SBRT can lower tumor burden and enhance immune-related response, but it cannot be recommended until the results of the phase II trials are published.
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Affiliation(s)
| | - Anand Swaminath
- Department of Oncology, Division of Radiation Oncology, Juravinski Cancer Centre, McMaster University, Hamilton, ON L8V 5C2, Canada
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Khene ZE, Tachibana I, Bertail T, Fleury R, Bhanvadia R, Kapur P, Rajaram S, Guo J, Christie A, Pedrosa I, Lotan Y, Margulis V. Clinical application of radiomics for the prediction of treatment outcome and survival in patients with renal cell carcinoma: a systematic review. World J Urol 2024; 42:541. [PMID: 39325194 DOI: 10.1007/s00345-024-05247-z] [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: 05/17/2024] [Accepted: 08/27/2024] [Indexed: 09/27/2024] Open
Abstract
PURPOSE The management of renal cell carcinoma (RCC) relies on clinical and histopathological features for treatment decisions. Recently, radiomics, which involves the extraction and analysis of quantitative imaging features, has shown promise in improving RCC management. This review evaluates the current application and limitations of radiomics for predicting treatment and oncological outcomes in RCC. METHODS A systematic search was conducted in Medline, EMBASE, and Web of Science databases or studies that used radiomics to predict response to treatment and survival outcomes in patients with RCC. The study quality was assessed using the Radiomics Quality Score (RQS) tools. RESULTS The systematic review identified a total of 27 studies, examining 6,119 patients. The most used imaging modality was contrast-enhanced abdominal CT. The reviewed studies extracted between 19 and 3376 radiomics features, including Histogram, Texture, Filter, or transformation method. Radiomics-based risk stratification models provided valuable insights into treatment response and oncological outcomes. All developed signatures demonstrated at least modest accuracy (AUC range: 0.55-0.99). The studies included in this analysis reported heterogeneous results regarding radiomics methods. The range of Radiomics Quality Score (RQS) was from - 5 to 20, with a mean RQS total of 9.15 ± 7.95. CONCLUSION Radiomics has emerged as a promising tool in the management of RCC. It offers the potential for improved risk stratification and response assessment. However, future trials must demonstrate the generalizability of findings to prospective cohorts before progressing towards clinical translation.
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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
| | - Isamu Tachibana
- Department of Urology, University of Texas Southwestern Medical Center, 2001 Inwood Rd, WCB3, Floor 4, Dallas, TX, 75390, USA
| | - Theophile Bertail
- Department of Urology, University of Rennes, Rennes, France
- Radiation Oncology Department, CLCC Eugene Marquis, Rennes, France
| | - Raphael Fleury
- Department of Urology, 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
| | - Payal Kapur
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Satwik Rajaram
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Junyu Guo
- Department of Radiology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Alana Christie
- Simmons Comprehensive Cancer Center Biostatistics, University of Texas, Southwestern Medical Center, Dallas, TX, USA
| | - Ivan Pedrosa
- Department of Radiology, UT Southwestern Medical Center, Dallas, TX, USA
| | - 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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Xiong B, Liu W, Liu Y, Chen T, Lin A, Song J, Qu L, Luo P, Jiang A, Wang L. A Multi-Omics Prognostic Model Capturing Tumor Stemness and the Immune Microenvironment in Clear Cell Renal Cell Carcinoma. Biomedicines 2024; 12:2171. [PMID: 39457484 PMCID: PMC11504857 DOI: 10.3390/biomedicines12102171] [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: 08/06/2024] [Revised: 09/11/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Cancer stem-like cells (CSCs), a distinct subset recognized for their stem cell-like abilities, are intimately linked to the resistance to radiotherapy, metastatic behaviors, and self-renewal capacities in tumors. Despite their relevance, the definitive traits and importance of CSCs in the realm of oncology are still not fully comprehended, particularly in the context of clear cell renal cell carcinoma (ccRCC). A comprehensive understanding of these CSCs' properties in relation to stemness, and their impact on the efficacy of treatment and resistance to medication, is of paramount importance. Methods: In a meticulous research effort, we have identified new molecular categories designated as CRCS1 and CRCS2 through the application of an unsupervised clustering algorithm. The analysis of these subtypes included a comprehensive examination of the tumor immune environment, patterns of metabolic activity, progression of the disease, and its response to immunotherapy. In addition, we have delved into understanding these subtypes' distinctive clinical presentations, the landscape of their genomic alterations, and the likelihood of their response to various pharmacological interventions. Proceeding from these insights, prognostic models were developed that could potentially forecast the outcomes for patients with ccRCC, as well as inform strategies for the surveillance of recurrence after treatment and the handling of drug-resistant scenarios. Results: Compared with CRCS1, CRCS2 patients had a lower clinical stage/grading and a better prognosis. The CRCS2 subtype was in a hypoxic state and was characterized by suppression and exclusion of immune function, which was sensitive to gefitinib, erlotinib, and saracatinib. The constructed prognostic risk model performed well in both training and validation cohorts, helping to identify patients who may benefit from specific treatments or who are at risk of recurrence and drug resistance. A novel therapeutic target, SAA2, regulating neutrophil and fibroblast infiltration, and, thus promoting ccRCC progression, was identified. Conclusions: Our findings highlight the key role of CSCs in shaping the ccRCC tumor microenvironment, crucial for therapy research and clinical guidance. Recognizing tumor stemness helps to predict treatment efficacy, recurrence, and drug resistance, informing treatment strategies and enhancing ccRCC patient outcomes.
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Affiliation(s)
- Beibei Xiong
- Department of Oncology, The First People’s Hospital of Shuangliu District, Chengdu 610200, China;
| | - Wenqiang Liu
- Department of Urology, Changhai Hospital, Navel Medical University (Second Military Medical University), Shanghai 200433, China; (W.L.); (Y.L.); (T.C.); (J.S.)
| | - Ying Liu
- Department of Urology, Changhai Hospital, Navel Medical University (Second Military Medical University), Shanghai 200433, China; (W.L.); (Y.L.); (T.C.); (J.S.)
| | - Tong Chen
- Department of Urology, Changhai Hospital, Navel Medical University (Second Military Medical University), Shanghai 200433, China; (W.L.); (Y.L.); (T.C.); (J.S.)
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; (A.L.); (P.L.)
| | - Jiaao Song
- Department of Urology, Changhai Hospital, Navel Medical University (Second Military Medical University), Shanghai 200433, China; (W.L.); (Y.L.); (T.C.); (J.S.)
| | - Le Qu
- Department of Urology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China;
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; (A.L.); (P.L.)
| | - Aimin Jiang
- Department of Urology, Changhai Hospital, Navel Medical University (Second Military Medical University), Shanghai 200433, China; (W.L.); (Y.L.); (T.C.); (J.S.)
| | - Linhui Wang
- Department of Urology, Changhai Hospital, Navel Medical University (Second Military Medical University), Shanghai 200433, China; (W.L.); (Y.L.); (T.C.); (J.S.)
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Derks SHAE, van der Meer EL, Joosse A, de Jonge MJA, Slagter C, Schouten JW, Hoop EOD, Smits M, van den Bent MJ, Jongen JLM, van der Veldt AAM. The development of brain metastases in patients with different therapeutic strategies for metastatic renal cell cancer. Int J Cancer 2024; 155:1045-1052. [PMID: 38703351 DOI: 10.1002/ijc.34984] [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: 01/09/2024] [Revised: 02/27/2024] [Accepted: 04/09/2024] [Indexed: 05/06/2024]
Abstract
A diagnosis of brain metastasis (BM) significantly affects quality of life in patients with metastatic renal cell cancer (mRCC). Although systemic treatments have shown efficacy in mRCC, active surveillance (AS) is still commonly used in clinical practice. In this single-center cohort study, we assessed the impact of different initial treatment strategies for metastatic RCC (mRCC) on the development of BM. All consecutive patients diagnosed with mRCC between 2011 and 2022 were included at the Erasmus MC Cancer Institute, the Netherlands, and a subgroup of patients with BM was selected. In total, 381 patients with mRCC (ECM, BM, or both) were identified. Forty-six patients had BM of whom 39 had metachronous BM (diagnosed ≥1 month after ECM). Twenty-five (64.1%) of these 39 patients with metachronous BM had received prior systemic treatment for ECM and 14 (35.9%) patients were treatment naive at BM diagnosis. The median BM-free survival since ECM diagnosis was significantly longer (p = .02) in previously treated patients (29.0 [IQR 12.6-57.0] months) compared to treatment naive patients (6.8 [IQR 1.0-7.0] months). In conclusion, patients with mRCC who received systemic treatment for ECM prior to BM diagnosis had a longer BM-free survival as compared to treatment naïve patients. These results emphasize the need for careful evaluation of treatment strategies, and especially AS, for patients with mRCC.
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Affiliation(s)
- Sophie H A E Derks
- Department of Neuro-Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Edgar L van der Meer
- Department of Neuro-Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Arjen Joosse
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Maja J A de Jonge
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Cleo Slagter
- Department of Radiotherapy, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Joost W Schouten
- Department of Neurosurgery, Erasmus MC, Rotterdam, The Netherlands
| | - Esther Oomen-de Hoop
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Marion Smits
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Martin J van den Bent
- Department of Neuro-Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Joost L M Jongen
- Department of Neuro-Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Astrid A M van der Veldt
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
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Anderson AC, Ho J, Hall ET, Hannan R, Liao JJ, Louie AV, Ma TM, Psutka SP, Rengan R, Siva S, Swaminath A, Tachiki L, Tang C, Teh BS, Tsai J, Tykodi SS, Weg E, Zaorsky NG, Lo SS. Focal therapy for oligometastatic and oligoprogressive renal cell carcinoma: a narrative review. Future Oncol 2024; 20:2573-2588. [PMID: 39258792 PMCID: PMC11534104 DOI: 10.1080/14796694.2024.2389769] [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: 05/22/2024] [Accepted: 08/05/2024] [Indexed: 09/12/2024] Open
Abstract
Metastatic renal cell carcinoma (RCC) can present with oligometastatic disease and/or develop oligoprogression following systemic therapy. Cytoreductive and focal metastasis-directed therapy options include resection, stereotactic ablative radiation and thermal ablation. Aggressive focal therapy may allow delay in initiation of or modification to systemic therapy and improve clinical outcomes. In this narrative review we synthesize current practice guidelines and prospective data on focal therapy management options and highlight future research. Patient selection and the choice of focal treatment techniques are controversial due to limited and heterogeneous data and patients may benefit from multidisciplinary evaluation. Prospective comparative trials with clearly defined inclusion criteria and relevant end points are needed to clarify the risks and benefits of different approaches.
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Affiliation(s)
- August C Anderson
- University of Washington, Department of Radiation Oncology, Seattle, WA 98195, USA
- Fred Hutchinson Cancer Center, Radiation Oncology Division, Seattle, WA 98195, USA
| | - Joel Ho
- Pfizer Inc., Bothell, WA 98011, USA
| | - Evan T Hall
- University of Washington, Division of Hematology & Oncology, Seattle, WA 98195,USA
- Fred Hutchinson Cancer Center, Clinical Research Division, Seattle, WA 98195, USA
| | - Raquibul Hannan
- The University of Texas Southwestern Medical Center, Radiation Oncology, Dallas, TX 75235, USA
- Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Kidney Cancer Program, Dallas, TX75235, USA
| | - Jay J Liao
- University of Washington, Department of Radiation Oncology, Seattle, WA 98195, USA
- Fred Hutchinson Cancer Center, Radiation Oncology Division, Seattle, WA 98195, USA
| | - Alexander V Louie
- Sunnybrook Health Sciences Centre, Department of Radiation Oncology, Toronto, ON, M4N 3M5, Canada
| | - Ting Martin Ma
- University of Washington, Department of Radiation Oncology, Seattle, WA 98195, USA
- Fred Hutchinson Cancer Center, Radiation Oncology Division, Seattle, WA 98195, USA
| | - Sarah P Psutka
- Fred Hutchinson Cancer Center, Clinical Research Division, Seattle, WA 98195, USA
- University of Washington, Department of Urology, Seattle, WA 98195, USA
| | - Ramesh Rengan
- University of Washington, Department of Radiation Oncology, Seattle, WA 98195, USA
- Fred Hutchinson Cancer Center, Radiation Oncology Division, Seattle, WA 98195, USA
| | - Shankar Siva
- Peter MacCallum Cancer Centre, Division of Radiation Oncology & Cancer Imaging, Melbourne, VIC, 3052, Australia
- The University of Melbourne, Sir Peter MacCallum Department of Oncology, Melbourne, VIC, 3052, Australia
| | - Anand Swaminath
- Juravinski Cancer Centre, Radiation Therapy, Hamilton, ON, L8V 5C2, Canada
- McMaster University, Division of Radiation Oncology, Hamilton, ON,L8S 4L8,Canada
| | - Lisa Tachiki
- University of Washington, Division of Hematology & Oncology, Seattle, WA 98195,USA
- Fred Hutchinson Cancer Center, Clinical Research Division, Seattle, WA 98195, USA
| | - Chad Tang
- The University of Texas MD Anderson Cancer Center, Genitourinary Radiation Oncology, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center, Investigational Cancer Therapeutics, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center, Translational Molecular Pathology, Houston, TX 77030, USA
| | - Bin Sing Teh
- Houston Methodist Hospital, Radiation Oncology, Houston, TX 77030, USA
| | - Joseph Tsai
- University of Washington, Department of Radiation Oncology, Seattle, WA 98195, USA
- Fred Hutchinson Cancer Center, Radiation Oncology Division, Seattle, WA 98195, USA
| | - Scott S Tykodi
- University of Washington, Division of Hematology & Oncology, Seattle, WA 98195,USA
- Fred Hutchinson Cancer Center, Clinical Research Division, Seattle, WA 98195, USA
| | - Emily Weg
- University of Washington, Department of Radiation Oncology, Seattle, WA 98195, USA
- Fred Hutchinson Cancer Center, Radiation Oncology Division, Seattle, WA 98195, USA
| | - Nicholas G Zaorsky
- University Hospitals Seidman Cancer Center, Case Western Reserve University, Department of Radiation Oncology, Cleveland, OH 44106, USA
| | - Simon S Lo
- University of Washington, Department of Radiation Oncology, Seattle, WA 98195, USA
- Fred Hutchinson Cancer Center, Radiation Oncology Division, Seattle, WA 98195, USA
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Yang L, Wei Q, Chen X, Yang Y, Huang Q, Wang B, Ma X. Identification of HDAC10 as a candidate oncogene in clear cell renal carcinoma that facilitates tumor proliferation and metastasis. Diagn Pathol 2024; 19:120. [PMID: 39237939 PMCID: PMC11378624 DOI: 10.1186/s13000-024-01493-2] [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: 02/06/2024] [Accepted: 05/06/2024] [Indexed: 09/07/2024] Open
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) remains one of the most lethal urological malignancies even though a great number of improvements in diagnosis and management have achieved over the past few decades. Accumulated evidence revealed that histone deacetylases (HDACs) play vital role in cell proliferation, differentiation and apoptosis. Nevertheless, the biological functions of histone deacetylation modification related genes in ccRCC remains poorly understood. METHOD Bulk transcriptomic data and clinical information of ccRCC patients were obtained from the TCGA database and collected from the Chinese PLA General Hospital. A total of 36 histone deacetylation genes were selected and studied in our research. Univariate cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression, random forest (RF) analysis, and protein-protein interaction (PPI) network analysis were applied to identify key genes affecting the prognosis of ccRCC. The 'oncoPredict' algorithm was utilized for drug-sensitive analysis. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to explore the potential biological function. The ssGSEA algorithm was used for tumor immune microenvironment analysis. The expression levels of HDAC10 were validated by RT-PCR and immunohistochemistry (IHC). 5-ethynyl-2'-deoxyuridine (EdU assay), CCK-8 assay, cell transwell migration and invasion assay and colony formation assay were performed to detect the proliferation and invasion ability of ccRCC cells. A nomogram incorporating HDAC10 and clinicopathological characteristics was established to predict the prognosis of ccRCC patients. RESULT Two machine learning algorithms and PPI analysis identified four histone deacetylation genes that have a significant association with the prognosis of ccRCC, with HDAC10 being the key gene among them. HDAC10 is highly expressed in ccRCC and its high expression is associated with poor prognosis for ccRCC patients. Pathway enrichment and the experiments of EdU staining, CCK-8 assay, cell transwell migration and invasion assay and colony formation assay demonstrated that HDAC10 mediated the proliferation and metastasis of ccRCC cells and involved in reshaping the tumor microenvironment (TME) of ccRCC. A clinically reliable prognostic predictive model was established by incorporating HDAC10 and other clinicopathological characteristics ( https://nomogramhdac10.shinyapps.io/HDAC10_Nomogram/ ). CONCLUSION Our study found the increased expression of HDAC10 was closely associated with poor prognosis of ccRCC patients. HDAC10 showed a pro-tumorigenic effect on ccRCC and promote the proliferation and metastasis of ccRCC, which may provide new light on targeted therapy for ccRCC.
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Affiliation(s)
- Luojia Yang
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Qin Wei
- The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200125, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200125, China
| | - Xinran Chen
- Medical School of Chinese PLA, Beijing, 100853, China
- Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yang Yang
- Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Qingbo Huang
- Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Baojun Wang
- Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Xin Ma
- Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
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Forman R, Long JB, Westvold SJ, Agnish K, Mcmanus HD, Leapman MS, Hurwitz ME, Spees LP, Wheeler SB, Gross CP, Dinan MA. Cost trends of metastatic renal cell carcinoma therapy: the impact of oral anticancer agents and immunotherapy. JNCI Cancer Spectr 2024; 8:pkae067. [PMID: 39133171 PMCID: PMC11376369 DOI: 10.1093/jncics/pkae067] [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: 02/09/2024] [Revised: 07/02/2024] [Accepted: 07/30/2024] [Indexed: 08/13/2024] Open
Abstract
BACKGROUND Immunotherapy (IO) and oral anticancer agents (OAA) have improved outcomes for metastatic renal cell carcinoma (mRCC), but there is a need to understand real-world costs from the perspective of payers and patients. METHODS We used retrospective fee-for-service Medicare 100% claims data to study patients diagnosed with mRCC in 2015-2019. We identified initial treatment type and costs (the year after diagnosis) and analyzed differences in monthly and 12-month costs over time and between OAA, IO, and combination groups and the association between Out-Of-Pocket (OOP) costs and adherence. RESULTS We identified 15 407 patients with mRCC (61% male; 85% non-Hispanic White). A total of 6196 received OAA, IO, or combination OAA/IO as initial treatment. OAA use decreased (from 31% to 11%) with a simultaneous rise in patients receiving IO (3% to 26%) or combination IO/OAA therapy (1% to 11%). Medicare payments for all patients with mRCC increased by 41%, from $60 320 (95% confidence interval = 58 260 to 62 380) in 2015 to $85 130 (95% confidence interval = 82 630 to 87 630) in 2019. Payments increased in patients who received OAA, IO, or combination OAA/IO but were stable in those with other/no treatment. Initial higher OOP responsibility ($200-$1000) was associated with 13% decrease in percent days covered in patients receiving OAA in the first 90 days of treatment, compared with those whose OOP responsibility was less than $200. CONCLUSION From 2015 to 2019, costs for Medicare patients with mRCC rose substantially due to more patients receiving IO or IO/OAA combined therapy and increases in costs among those receiving those therapies. Increased OOP costs was associated with decreased adherence.
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Affiliation(s)
- Rebecca Forman
- Section of Medical Oncology, Internal Medicine Department, Yale School of Medicine, New Haven, CT, USA
| | - Jessica B Long
- Yale Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, New Haven, CT, USA
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Sarah J Westvold
- Yale Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, New Haven, CT, USA
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | | | - Hannah D Mcmanus
- Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Michael S Leapman
- Yale Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, New Haven, CT, USA
- Department of Urology, Yale School of Medicine, New Haven, CT, USA
| | - Michael E Hurwitz
- Section of Medical Oncology, Internal Medicine Department, Yale School of Medicine, New Haven, CT, USA
| | - Lisa P Spees
- Department of Health Policy and Management, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Health Policy and Management, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Stephanie B Wheeler
- Department of Health Policy and Management, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Health Policy and Management, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Cary P Gross
- Yale Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, New Haven, CT, USA
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Michaela A Dinan
- Yale Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, New Haven, CT, USA
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
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Ezaki A, Yano H, Pan C, Fujiwara Y, Anami T, Ibe Y, Motoshima T, Yatsuda J, Esumi S, Miura Y, Kamba T, Komohara Y. Potential protumor function of CD74 in clear cell renal cell carcinoma. Hum Cell 2024; 37:1535-1543. [PMID: 39080216 DOI: 10.1007/s13577-024-01110-w] [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: 03/12/2024] [Accepted: 07/22/2024] [Indexed: 08/23/2024]
Abstract
CD74 is a transmembrane protein that functions as a specialized chaperone of HLA class II and CD74 in tumor cells was suggested to be involved in cell proliferation in several kinds of malignant tumors. CD74 is also known to be expressed in macrophages, therefore, we investigated the CD74 expression in clear cell renal cell carcinoma (ccRCC). Immunohistochemistry of CD74 indicated that CD74 was expressed not only in cancer cells but also macrophages. CD74 was detected in surface membrane and cytoplasm of cancer cells in 92 of 94 cases (98%) and of 87 of 94 cases (93%). CD74 was expressed both in cancer cells and TAMs in 86 of 94 cases (91%). In vitro studies using cancer cell lines and monocyte-derived macrophages stimulated by anti-CD74 antibodies showed that CD74 signal accelerated cancer cell proliferation and macrophage activation. However, macrophage activation via CD74 signal did not influence macrophage-mediated cancer cell growth. RNA-sequence of macrophages stimulated by anti-CD74 antibodies indicated that CD74 signal was associated to inflammatory responses in macrophages. In conclusion, we examined the expression and functional significance of CD74 in ccRCC using tissue specimens and cell culture studies. The function of CD74 was suggested to be different in cancer cells and in macrophages, and further studies are necessary to clarify the functional significance of CD74 in ccRCC.
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MESH Headings
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/metabolism
- Humans
- Kidney Neoplasms/pathology
- Kidney Neoplasms/genetics
- Kidney Neoplasms/metabolism
- Antigens, Differentiation, B-Lymphocyte/metabolism
- Antigens, Differentiation, B-Lymphocyte/genetics
- Antigens, Differentiation, B-Lymphocyte/physiology
- Cell Proliferation/genetics
- Histocompatibility Antigens Class II/metabolism
- Macrophages/metabolism
- Macrophages/immunology
- Cell Line, Tumor
- Macrophage Activation/genetics
- Gene Expression/genetics
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Affiliation(s)
- Ayano Ezaki
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Hiromu Yano
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Cheng Pan
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Yukio Fujiwara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Toshiki Anami
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuki Ibe
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takanobu Motoshima
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Junji Yatsuda
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shigeyuki Esumi
- Department of Anatomy and Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuji Miura
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan
- Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan
| | - Tomomi Kamba
- Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto Chuo-Ku, Kumamoto, 860-8556, Japan.
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan.
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Ishihara H, Nishimura K, Ikeda T, Fukuda H, Yoshida K, Iizuka J, Kondo T, Takagi T. Impact of body composition on outcomes of immune checkpoint inhibitor combination therapy in patients with previously untreated advanced renal cell carcinoma. Urol Oncol 2024; 42:291.e27-291.e37. [PMID: 38653590 DOI: 10.1016/j.urolonc.2024.04.008] [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: 02/20/2024] [Revised: 03/22/2024] [Accepted: 04/02/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Data on the association between body composition and outcomes in patients with advanced renal cell carcinoma (RCC) treated with immune checkpoint inhibitor (ICI) combination therapy are limited. METHODS We retrospectively evaluated the clinical and radiographic data of 159 patients with advanced RCC, including 84 receiving ICI dual combination therapy (immunotherapy [IO]-IO group) and 75 receiving combinations of ICIs with tyrosine kinase inhibitors (TKIs) (IO-TKI group). Pretreatment computed tomography images were used to calculate body composition, including skeletal muscle mass and fat tissue area. Sarcopenia was defined based on skeletal muscle and psoas muscle indexes. The total fat index, subcutaneous fat index (SFI), and visceral fat index were also calculated. RESULTS In the IO-IO treatment group, there was no significant association between body composition and survival or tumor response (P > 0.05). In the IO-TKI treatment group, the high SFI was associated with longer progression-free survival (hazard ratio, 2.70; P = 0.0091) and overall survival (hazard ratio, 26.0; P = 0.0246) than the low SFI, which remained significant after adjusting for covariates. Furthermore, in the high-SFI population, patients treated with IO-TKI therapy had longer progression-free survival (P = 0.0019) and overall survival (P = 0.0287) than those treated with IO-IO therapy, while there was no significant survival difference between the 2 treatment groups in the low-SFI population (P > 0.05). CONCLUSION The SFI can be potentially utilized as an effective predictive and prognostic biomarker for first-line ICI combination therapy for advanced RCC.
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Affiliation(s)
- Hiroki Ishihara
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan.
| | - Koichi Nishimura
- Department of Urology, Tokyo Women's Medical University Adachi Medical Center, 4-33-1 Kouhoku, Adachi-ku, Tokyo, Japan
| | - Takashi Ikeda
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Hironori Fukuda
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Kazuhiko Yoshida
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Junpei Iizuka
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
| | - Tsunenori Kondo
- Department of Urology, Tokyo Women's Medical University Adachi Medical Center, 4-33-1 Kouhoku, Adachi-ku, Tokyo, Japan
| | - Toshio Takagi
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
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46
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Guo Z, Cai C, Zhou K, Song L, Wang X, Chen D, Weng G, Huang S. SHC1 serves as a prognostic and immunological biomarker in clear cell renal cell carcinoma: a comprehensive bioinformatics and experimental analysis. Sci Rep 2024; 14:20150. [PMID: 39209911 PMCID: PMC11362144 DOI: 10.1038/s41598-024-70897-3] [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: 02/08/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024] Open
Abstract
SHC1 plays a crucial regulatory role in various tumors, but its significance in predicting prognosis and immune response in clear cell renal cell carcinoma (ccRCC) is yet to be determined. In this study, we conducted a bioinformatics analysis of SHC1 expression, prognosis, and immunological functions in ccRCC using multiple databases. The association between SHC1 and immune infiltration, immune escape, and immunotherapy in ccRCC was systematically established. In addition, we validated our results by western blot of tumor and adjacent-tumor samples from nine ccRCC patients, as well as three renal carcinoma cell lines compared to a normal renal cell line. Our analysis revealed that the mRNA expression level of SHC1 in ccRCC tissues is significantly higher than that in normal tissues. Consistently, western blot experiment showed ccRCC tissues and cell lines exhibit higher protein levels that normal tissues and cell lines. Importantly, patients with low expression of SHC1 demonstrated a higher survival rate, indicating that SHC1 could serve as an independent prognostic factor for predicting survival in ccRCC. Additionally, high expression of SHC1 was associated with increased severe immune cell infiltration, enhanced immune escape, and higher immunotherapy scores. Hence, SHC1 emerges as a novel and easily detectable biomarker for predicting clinical outcomes, immune escape, and immunotherapy response in patients with ccRCC.
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MESH Headings
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/immunology
- Carcinoma, Renal Cell/metabolism
- Carcinoma, Renal Cell/pathology
- Humans
- Kidney Neoplasms/genetics
- Kidney Neoplasms/immunology
- Kidney Neoplasms/pathology
- Kidney Neoplasms/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Src Homology 2 Domain-Containing, Transforming Protein 1/metabolism
- Src Homology 2 Domain-Containing, Transforming Protein 1/genetics
- Computational Biology/methods
- Prognosis
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic
- Female
- Male
- Middle Aged
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Affiliation(s)
- Zhuangyu Guo
- Laboratory of Renal Carcinoma, Ningbo Urology and Nephrology Hospital, Urology and Nephrology Institute of Ningbo University, No.998 North Qianhe Road, Yinzhou District, Ningbo, 315100, Zhejiang, China
| | - Congbo Cai
- Laboratory of Renal Carcinoma, Ningbo Urology and Nephrology Hospital, Urology and Nephrology Institute of Ningbo University, No.998 North Qianhe Road, Yinzhou District, Ningbo, 315100, Zhejiang, China
| | - Kena Zhou
- School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Lingmin Song
- Laboratory of Renal Carcinoma, Ningbo Urology and Nephrology Hospital, Urology and Nephrology Institute of Ningbo University, No.998 North Qianhe Road, Yinzhou District, Ningbo, 315100, Zhejiang, China
| | - Xue Wang
- Laboratory of Renal Carcinoma, Ningbo Urology and Nephrology Hospital, Urology and Nephrology Institute of Ningbo University, No.998 North Qianhe Road, Yinzhou District, Ningbo, 315100, Zhejiang, China
| | - Dongying Chen
- Department of Community Work, Ningbo Yinzhou No.3 Hospital, Ningbo, 315100, China
| | - Guobin Weng
- Laboratory of Renal Carcinoma, Ningbo Urology and Nephrology Hospital, Urology and Nephrology Institute of Ningbo University, No.998 North Qianhe Road, Yinzhou District, Ningbo, 315100, Zhejiang, China.
| | - Shuaishuai Huang
- Laboratory of Renal Carcinoma, Ningbo Urology and Nephrology Hospital, Urology and Nephrology Institute of Ningbo University, No.998 North Qianhe Road, Yinzhou District, Ningbo, 315100, Zhejiang, China.
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Chen TY, Chang YC, Yu CY, Sung WW. Targeting the Adenosine A2A Receptor as a Novel Therapeutic Approach for Renal Cell Carcinoma: Mechanisms and Clinical Trial Review. Pharmaceutics 2024; 16:1127. [PMID: 39339165 PMCID: PMC11434806 DOI: 10.3390/pharmaceutics16091127] [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: 07/10/2024] [Revised: 08/14/2024] [Accepted: 08/23/2024] [Indexed: 09/30/2024] Open
Abstract
Renal cell carcinoma (RCC) accounts for nearly 2% of cancers diagnosed worldwide. For metastatic RCC, targeted therapy is one of the most common treatment methods. It can include approaches that target vascular endothelial growth factor (VEGFR) or rely on immune checkpoint inhibitors or mTOR inhibitors. Adenosine A2A receptor (A2AR) is a type of widely distributed G-protein-coupled receptor (GPCR). Recently, an increasing number of studies suggest that the activation of A2AR can downregulate anti-tumor immune responses and prevent tumor growth. Currently, the data on A2AR antagonists in RCC treatment are still limited. Therefore, in this article, we further investigate the clinical trials investigating A2AR drugs in RCC. We also describe the epidemiology and current treatment of RCC, along with the physiological role of A2AR, and the types of A2AR drugs that are associated with tumor treatment.
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Affiliation(s)
- Ting-Yu Chen
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (T.-Y.C.); (Y.-C.C.); (C.-Y.Y.)
| | - Ya-Chuan Chang
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (T.-Y.C.); (Y.-C.C.); (C.-Y.Y.)
- Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Chia-Ying Yu
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (T.-Y.C.); (Y.-C.C.); (C.-Y.Y.)
- Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Wen-Wei Sung
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (T.-Y.C.); (Y.-C.C.); (C.-Y.Y.)
- Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
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48
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Tejura A, Fernandes R, Hubay S, Ernst MS, Valdes M, Batra A. Contemporary Management of Renal Cell Carcinoma: A Review for General Practitioners in Oncology. Curr Oncol 2024; 31:4795-4817. [PMID: 39195342 PMCID: PMC11352690 DOI: 10.3390/curroncol31080359] [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: 07/10/2024] [Revised: 08/12/2024] [Accepted: 08/19/2024] [Indexed: 08/29/2024] Open
Abstract
Renal cell carcinoma accounts for a significant proportion of cancer diagnoses in Canadians. Over the past several years, the management of renal cell cancers has undergone rapid changes in all prognostic risk categories, resulting in improved oncologic outcomes. Novel strategies for metastatic disease make use of the synergy between checkpoints and angiogenesis inhibition. Moreover, combination checkpoint inhibition has demonstrated durable efficacy in some patients. Adjuvant immunotherapy has recently shown a survival benefit for the first time in select cases. Significant efforts are underway to explore new compounds or combinations for later-line diseases, such as inhibitors of hypoxia-inducible factors and radiolabeled biomolecules targeting tumor antigens within the neoplastic microenvironment for precise payload delivery. In this manuscript, we provide a comprehensive review of the available data addressing key therapeutic areas pertaining to systemic therapy for metastatic and localized disease, review the most relevant prognostic tools, describe local therapies and management of CNS disease, and discuss practice-changing trials currently underway. Finally, we focus on some of the practical aspects for general practitioners in oncology caring for patients with renal cell carcinoma.
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Affiliation(s)
- Anish Tejura
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada; (A.T.); (R.F.)
- Verspeeten Family Cancer Centre, Victoria Hospital, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Ricardo Fernandes
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada; (A.T.); (R.F.)
- Verspeeten Family Cancer Centre, Victoria Hospital, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Stacey Hubay
- Department of Oncology, Grand River Regional Cancer Centre, 835 King St. W., Kitchener, ON N2G 1G3, Canada; (S.H.); (M.S.E.); (M.V.)
| | - Matthew Scott Ernst
- Department of Oncology, Grand River Regional Cancer Centre, 835 King St. W., Kitchener, ON N2G 1G3, Canada; (S.H.); (M.S.E.); (M.V.)
| | - Mario Valdes
- Department of Oncology, Grand River Regional Cancer Centre, 835 King St. W., Kitchener, ON N2G 1G3, Canada; (S.H.); (M.S.E.); (M.V.)
| | - Anupam Batra
- Department of Oncology, Grand River Regional Cancer Centre, 835 King St. W., Kitchener, ON N2G 1G3, Canada; (S.H.); (M.S.E.); (M.V.)
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Nakayama T, Takeshita H, Kagawa M, Washino S, Shirotake S, Miura Y, Hyodo Y, Izumi K, Inoue M, Matsuoka Y, Miyagawa T, Oyama M, Saito K, Kawakami S. Prognostic significance of inflammatory markers in patients with advanced renal cell carcinoma receiving nivolumab plus ipilimumab. Int J Clin Oncol 2024:10.1007/s10147-024-02593-1. [PMID: 39046676 DOI: 10.1007/s10147-024-02593-1] [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: 04/15/2024] [Accepted: 07/17/2024] [Indexed: 07/25/2024]
Abstract
BACKGROUND A useful biomarker for the efficacy of immune checkpoint inhibitors (ICIs) in advanced renal cell carcinoma (RCC) has not yet been established. This study aims to investigate whether inflammatory markers are associated with the efficacy of nivolumab plus ipilimumab therapy before and during treatment. METHODS Data from patients with advanced clear cell RCC who received a combination treatment of nivolumab plus ipilimumab were retrospectively analyzed. The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) levels were assessed at baseline and 3, 6, and 9 weeks after treatment initiation. The correlation between these inflammatory markers and the patient's prognosis was investigated. RESULTS Eighty-four patients were identified. The multivariate analysis identified NLR at week 3, CRP at week 6, and NLR and CRP at week 9 as the consistent predictor associated with poor overall survival (OS) at each time point. The survival analysis and receiver operating characteristic (ROC) curve analysis revealed that an NLR of ≥ 2.4 at week 3, CRP of ≥ 1.4 mg/dL at week 6, and NLR of ≥ 4.8 and CRP of ≥ 1.0 mg/dL at week 9 were associated with worse OS (hazard ratios (HR) = 5.70, P = 0.008, HR = 3.23, P = 0.004, HR = 7.38, P < 0.001 and HR = 3.55, P = 0.002). CONCLUSIONS Both NLR and CRP were considered useful biomarkers for understanding the prognosis during nivolumab plus ipilimumab therapy. Furthermore, an NLR of ≥ 4.8 and CRP of ≥ 1.0 mg/dL at week 9 are helpful in reconsidering treatment continuation.
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Affiliation(s)
- Takayuki Nakayama
- Department of Urology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan
- Musashinno Study Group, Saitama, Japan
| | - Hideki Takeshita
- Department of Urology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan.
- Musashinno Study Group, Saitama, Japan.
| | - Makoto Kagawa
- Department of Urology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan
- Musashinno Study Group, Saitama, Japan
| | - Satoshi Washino
- Department of Urology, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
- Musashinno Study Group, Saitama, Japan
| | - Suguru Shirotake
- Department of Uro-Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan
- Musashinno Study Group, Saitama, Japan
| | - Yuji Miura
- Department of Medical Oncology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
- Musashinno Study Group, Saitama, Japan
| | - Yoji Hyodo
- Department of Urology, Dokkyo Medical University Saitama Medical Center, 2-1-50, Minami-Koshigaya, Koshigaya, Saitama, 343-8555, Japan
- Musashinno Study Group, Saitama, Japan
| | - Keita Izumi
- Department of Urology, Dokkyo Medical University Saitama Medical Center, 2-1-50, Minami-Koshigaya, Koshigaya, Saitama, 343-8555, Japan
- Musashinno Study Group, Saitama, Japan
| | - Masaharu Inoue
- Department of Urology, Saitama Cancer Center, 780 Komuro, Ina-machi, Kita-Adachi-gun, Saitama, 362-0806, Japan
- Musashinno Study Group, Saitama, Japan
| | - Yoh Matsuoka
- Department of Urology, Saitama Cancer Center, 780 Komuro, Ina-machi, Kita-Adachi-gun, Saitama, 362-0806, Japan
| | - Tomoaki Miyagawa
- Department of Urology, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan
| | - Masafumi Oyama
- Department of Uro-Oncology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Kazutaka Saito
- Department of Urology, Dokkyo Medical University Saitama Medical Center, 2-1-50, Minami-Koshigaya, Koshigaya, Saitama, 343-8555, Japan
| | - Satoru Kawakami
- Department of Urology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan
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50
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Chen W, Li S, Huang D, Su Y, Wang J, Liang Z. Identification of prognostic RNA editing profiles for clear cell renal carcinoma. Front Med (Lausanne) 2024; 11:1390803. [PMID: 39091293 PMCID: PMC11291244 DOI: 10.3389/fmed.2024.1390803] [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: 02/24/2024] [Accepted: 07/04/2024] [Indexed: 08/04/2024] Open
Abstract
Objective Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer and currently lacks effective biomarkers. This research aims to analyze and identify RNA editing profile associated with ccRCC prognosis through bioinformatics and in vitro experiments. Methods Transcriptome data and clinical information for ccRCC were retrieved from the TCGA database, and RNA editing files were obtained from the Synapse database. Prognostic models were screened, developed, and assessed using consistency index analysis and independent prognostic analysis, etc. Internal validation models were also constructed for further evaluation. Differential genes were investigated using GO, KEGG, and GSEA enrichment analyses. Furthermore, qPCR was performed to determine gene expression in human renal tubular epithelial cells HK-2 and ccRCC cells A-498, 786-O, and Caki-2. Results An RNA editing-based risk score, that effectively distinguishes between high and low-risk populations, has been identified. It includes CHD3| chr17:7815229, MYO19| chr17:34853704, OIP5-AS1| chr15:41590962, MRI1| chr19:13883962, GBP4| chr1:89649327, APOL1| chr22:36662830, FCF1| chr14:75203040 edited sites or genes and could serve as an independent prognostic factor for ccRCC patients. qPCR results showed significant up-regulation of CHD3, MYO19, MRI1, APOL1, and FCF1 in A-498, 786-O, and Caki-2 cells, while the expression of OIP5-AS1 and GBP4 was significantly down-regulated. Conclusion RNA editing site-based prognostic models are valuable in differentiating between high and low-risk populations. The seven identified RNA editing sites may be utilized as potential biomarkers for ccRCC.
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Affiliation(s)
- Weihong Chen
- Department of Anxi County Hospital, Quanzhou, China
| | - Shaobin Li
- Department of Anxi County Hospital, Quanzhou, China
| | | | - Yuchao Su
- Department of Anxi County Hospital, Quanzhou, China
| | - Jing Wang
- Xilin Gol League Central Hospital, Xilin Hot, China
| | - Zhiru Liang
- Xilin Gol League Central Hospital, Xilin Hot, China
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