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

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

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

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

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

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

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

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

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

Background: Even though cytoreductive nephrectomy (CN) was once the standard of care for patients with advanced renal cell carcinoma (RCC), its role in treatment has not been well analyzed or defined in the era of immunotherapy (IO)., Materials and Methods: This study analyzed pathological outcomes in patients with advanced or metastatic RCC who received IO prior to CN. This was a multi-institutional, retrospective study of patients with advanced or metastatic RCC. Patients were required to receive IO monotherapy or combination therapy prior to radical or partial CN. The primary endpoint assessed surgical pathologic outcomes, including American Joint Committee on Cancer (AJCC) staging and frequency of downstaging, at the time of surgery. Pathologic outcomes were correlated to clinical variables using a Wald-chi squared test from Cox regression in a multi-variable analysis. Secondary outcomes included objective response rate (ORR) defined by response evaluation criteria in solid tumors (RECIST) version 1.1 and progression-free survival (PFS), which were estimated using the Kaplan-Meier method with reported 95% CIs., Results: Fifty-two patients from 9 sites were included. Most patients were male (65%), 81% had clear cell histology, 11% had sarcomatoid differentiation. Overall, 44% of patients experienced pathologic downstaging, and 13% had a complete pathologic response. The ORR immediately prior to nephrectomy was stable disease in 29% of patients, partial response in 63%, progressive disease in 4%, and 4% unknown. Median follow-up for the entire cohort was 25.3 months and median PFS was 3.5 years (95% CI, 2.1-4.9)., Conclusions: IO-based interventions prior to CN in patients with advanced or metastatic RCC demonstrates efficacy, with a small fraction of patients showing a complete response. Additional prospective studies are warranted to investigate the role of CN in the modern IO-era., (© The Author(s) 2023. Published by Oxford University Press.)

In this study we evaluated outcomes of patients with metastatic renal cell carcinoma who received immunotherapy before surgery. We found that receiving immunotherapy combinations before surgery can offer patients benefits in reducing tumor size and improving disease control., Background: Immunotherapy (IO) has improved outcomes for patients with metastatic renal cell carcinoma (mRCC). However, the timing of surgical intervention for cytoreductive nephrectomy (CN) is still controversial for this group of patients., Patients and Methods: We identified patients with mRCC receiving IO-based therapies and undergoing CN. Patients were divided into 2 cohorts: those who underwent upfront CN and those who underwent deferred CN. Pathologic and radiographic features along with clinical outcomes were systematically collected. Comparisons were performed using Chi-square test, paired t-Test or Mann-Whitney-U test. Progression Free survival (PFS) and Overall Survival (OS) were estimated using the Kaplan-Meier method., Results: Fifty-one patients with mRCC were included, with a median follow-up of 21 months. 38 (74.5%) patients received IO-based therapies prior to CN, while 13 (25.5%) patients underwent up-front CN. IO-based therapies reduced median tumor size from pretreatment 10 cm to 8.6 cm post-treatment when given prior to CN. IO-TKI had a trend toward higher tumor shrinkage (-2.3 vs -1.2 cm). Pathologic T downstaging occurred in 42% (n=16) of patients, 11% (n=4) of whom had pT0 disease. Thrombus downstaging occurred in 13% (n=6) of patients, all with either partial response (PR) or complete response (CR) in metastases. PFS (HR=0.7, 95% CI 0.29-1.98, p=0.58) and OS (HR 0.4, 95% CI 0.13-1.57, p=0.21) were not statistically significant between 2 cohorts., Conclusions: IO-based therapies, particularly IO-TKIs, resulted in pathologic necrosis and reductions in tumor size prior to deferred CN. PFS and OS were similar for patients who received either upfront IO-based therapy or after CN., Competing Interests: Disclosure James Brugarolas: Advisory board/consultant: Eisai, Johnson and Johnson, Exelixis, Telix. ayal Kapur: Advisory board/consultant: ClearNano. Hans Hammers: Advisory board/consultant-ARMO Biosciences, Inc., Bayer AG, Bristol-Myers Squibb, Corvus Pharmaceuticals, Exelixis, Inc., Eli Lilly and Company, Merck & Co., Inc.,Pfizer, Inc., Novartis International AG, and Surface Oncology, Inc.; PI/research funding-Bristol-Myers Squibb and Merck & Co., Inc., ararvive,Surface Oncology,NGM Biopharmaceutical. Qian Qin: Advisory board/consultant – Exelixis. Solomon Woldu: Advisory Role/consultant: Urogen pharma. Yair Lotan: Advisory role/Consultant: Nanorobotics, Photocure, Astra Zeneca, Merck, Fergene, Abbvie, Nucleix, Ambu, Seattle Genetics, Hitachi, Ferring Research, verity pharmaceutics, virtuoso surgical, Stimit, Urogen, Vessi medical, CAPs medical, Xcures, BMS, Nonagen, Aura Biosciences, Inc., Convergent Genomics, Pacific Edge, Pfizer, Phinomics Inc, CG oncology, Uroviu, On target lab, Promis Diagnostics, Valar labs, Uroessentials. Jeffrey Cadeddu: Advisory Role/consultant: DeepQure, Distalmotion, Ownership: Levita Mganetics, EtiraRx, Onconanno. Tian Zhang: PI/research funding – Research support (to UTSW) from CPRIT, Merck, Janssen, Astra Zeneca, Pfizer, Astellas, Eli Lilly, Tempus, ALX Oncology, Janux Therapeutics, Exelixis, FBD Biologics, Guardant, OncoC4; Consulting/advisory relationships: Merck, Exelixis, Sanofi-Aventis, Janssen, Astra Zeneca, Pfizer, Amgen, BMS, Seagen, Eisai, Aveo, Eli Lilly, Bayer, Gilead, Novartis, EMD Serono, Aravive, MJH Associates, Vaniam, Aptitude Health, Peerview, eChinaHealth., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Immune checkpoint inhibitor (ICI)-based combinations have revolutionized the management of first-line metastatic renal cell carcinoma (mRCC) by improving patient survival. Large phase 3 randomized trials assessing ICI-based combinations have reported complete response (CR) rates of 10% to 18% in the first-line setting. However, there is a scarcity of data about the effect of treatment of residual disease regarding CR rates improvement., Materials and Methods: We included retrospectively all consecutive mRCC patients treated in first-line setting at the Institut de Cancérologie Strasbourg Europe with an ICI-based combination involving ICI or TKI, either alone or with added local treatment of residual disease. Patients were characterized according to IMDC risk. Radiologic response was defined according to RECIST v1.1., Results: We enrolled 80 mRCC patients treated with ICI-based combinations between May 2015 and May 2022. The median age was 63 years. Regarding IMDC risk, there were 12 favourable (15%), 50 intermediate (63%), and 18 poor-risk (22%) patients. Forty-seven patients (59%) received ICI + ICI, 24 (30%) received ICI + TKI, and 9 (11%) received another ICI-based therapy. In total, 8 achieved CR (10%), 36 patients (45%) achieved partial response, 23 (29%) achieved stable disease and 12 achieved progressive disease (15%) as the best response with systemic therapy alone. By adding local treatment of residual disease, 11 additional patients (14%) achieved radiological NED. Residual disease resected sites included kidney (n = 6), lymph nodes (n = 5), lung metastases (n = 2) and liver metastases (n = 1)., Conclusions: The resection of residual disease after first-line ICI-based therapy is associated with improved CR rate (CR + NED) in patients with mRCC. These results need to be validated in prospective trial., Patient Summary: In recent years, the advent of immunotherapy has radically changed the management of patients with metastatic kidney cancer. Approximately 10% to 18% of these patients using immune checkpoint inhibitor (ICI)-based combinations no longer have detectable disease on CT scans (complete response). There are currently few data on the use of treatment of residual disease to increase the number of patients in complete response. In this retrospective study, the complete response rate with ICI-based treatment was 10%. When local treatment was added, the number of patients with a complete response increased to 24%. This strategy could increase the number of patients with a prolonged complete response in the future., Competing Interests: Disclosures Fabien Moinard-Butot certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: F. Moinard-Butot has served in advisory roles for BMS. T. Tricard has received travel and accommodation expenses from Janssen. RL. Cazzato has received travel and accommodation expenses from Medtronic, Ipsen and QUANTUM SURGICAL. L. Pierard has received travel and accommodation expenses from Ipsen, Johnson & Johnson, Pfizer, Eli lilly and company, MUNDI PHARMA. V. Lindner reports speaker services for AstraZeneca, Ipsen; and has received travel and accommodation expenses from Ipsen, MSD and Pfizer. S. Martin has served in advisory roles for BMS. M. Burgy has served in advisory roles for Lilly; reports speaker services for BMS and MSD; has received travel and accommodation expenses from Pfizer, Ipsen and MUNDIPHARMA. G. Malouf has served in advisory roles for BMS, MSD and Ipsen; has received travel and accommodation expenses from MSD, Ipsen and BMS. H. Lang reports speaker services for Johnson & Johnson, Astellas pharma. P. Barthélémy has served in advisory roles for Amgen, Astellas, Bayer, BMS, Ipsen, Janssen Cilag, Merck, MSD, Novartis, Gilead Sciences and Pfizer and reports speaker services for AstraZeneca and Seagen. M. Oriel, V. Gaillard, P. Werle, C. Schuster, C. Roy, A. Anthony, C. Bigot, P. Boudier and A. Fritsch have any conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

C-C chemokine ligand 5 (CCL5) plays a crucial role in the advancement of human cancer. Nevertheless, little is known about the multi-omics characterisation of CCL5 and its significance for the immune microenvironment and prognosis of tumor patients. The basal expression levels of the CCL5 gene in normal human tissues, aberrant expression in disease, genomic alterations, prognostic roles, pathway enrichment, immune microenvironment, association with immune checkpoints, drug sensitivity, and the ability to predict patients' immunotherapeutic response to immune checkpoint inhibitors (ICIs) and small molecule drugs were all thoroughly analyzed using data gathered from 33 cancers. Lastly, we were able to validate CCL5's involvement in renal clear cell carcinoma by experimental means. We discovered that CCL5 has distinct expression patterns and a diagnostic biomarker significance in cancer. Furthermore, we discovered that CCL5 is essential for both the tumor microenvironment and pan-cancer. TMB and MSI are two frequent immunological checkpoints that are significantly correlated with CCL5, and patients who express high levels of CCL5 have stronger immunotherapeutic response and a better prognosis after immunotherapy. Eventually, molecular docking was used to find small molecule inhibitors that can specifically target CCL5. Ultimately, it was shown that CCL5 knockdown impeded renal clear cell carcinoma cells' ability to proliferate and invade. Our findings demonstrate the significant potential of CCL5 as an immunotherapeutic response biomarker and prognostic indicator, which may pave the way for more studies on the mechanism of tumor infiltration and CCL5's potential therapeutic applications in cancer., (© 2024. The Author(s).)

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Immunotherapy has emerged as a promising approach for cancer treatment, with oncolytic adenoviruses showing power as immunotherapeutic agents. In this study, we investigated the immunotherapeutic potential of an adenovirus construct expressing CXCL9, CXCL10, or IL-15 in clear cell renal cell carcinoma (ccRCC) tumor models. Our results demonstrated robust cytokine secretion upon viral treatment, suggesting effective transgene expression. Subsequent analysis using resistance-based transwell migration and microfluidic chip assays demonstrated increased T-cell migration in response to chemokine secretion by infected cells in both 2D and 3D cell models. Flow cytometry analysis revealed CXCR3 receptor expression across T-cell subsets, with the highest percentage found on CD8+ T-cells, underscoring their key role in immune cell migration. Alongside T-cells, we also detected NK-cells in the tumors of immunocompromised mice treated with cytokine-encoding adenoviruses. Furthermore, we identified potential immunogenic antigens that may enhance the efficacy and specificity of our armed oncolytic adenoviruses in ccRCC. Overall, our findings using ccRCC cell line, in vivo humanized mice, physiologically relevant PDCs in 2D and patient-derived organoids (PDOs) in 3D suggest that chemokine-armed adenoviruses hold promise for enhancing T-cell migration and improving immunotherapy outcomes in ccRCC. Our study contributes to the development of more effective ccRCC treatment strategies by elucidating immune cell infiltration and activation mechanisms within the tumor microenvironment (TME) and highlights the usefulness of PDOs for predicting clinical relevance and validating novel immunotherapeutic approaches. Overall, our research offers insights into the rational design and optimization of viral-based immunotherapies for ccRCC., Competing Interests: Oncolytic viruses encoding for cytokines CXCL9, CXCL10 and IL-15 have been licensed to Ximbio/CancerTools.org for commercialization to other academic or commercial researchers. V.S. is currently employed by AstraZeneca. V.C is a co-founder and shareholder at VALO Therapeutics. Other authors report there are no competing interests to declare., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Importance: Renal cell carcinoma (RCC) is a common malignancy, with an estimated 434 840 incident cases worldwide in 2022. In the US, it is the sixth most common cancer among males and ninth among females., Observations: Clear cell RCC is the most common histologic subtype (75%-80% of cases) and is characterized by inactivation of the von Hippel Lindau (VHL) tumor suppressor gene. Many patients (37%-61%) are diagnosed with RCC incidentally on an abdominal imaging study such as ultrasound or computed tomographic scan, and 70% of patients have stage I RCC at diagnosis. Although its incidence has increased approximately 1% per year from 2015 through 2019, the mortality rate of RCC has declined about 2% per year in the US from 2016 through 2020. Patients with a solid renal mass or complex cystic renal mass should be referred to urology. Treatment options for RCC confined to the kidney include surgical resection with partial or radical nephrectomy, ablative techniques (eg, cryoablation, radiofrequency ablation, radiation), or active surveillance for some patients (especially those with renal masses <2 cm). For patients with renal masses less than 4 cm in size (48% of patients), partial nephrectomy can result in a 5-year cancer-specific survival of more than 94%. For advanced or metastatic RCC, combinations of immune checkpoint inhibitors or the combination of immune checkpoint inhibitors with tyrosine kinase inhibitors are associated with tumor response of 42% to 71%, with a median overall survival of 46 to 56 months., Conclusions and Relevance: RCC is a common malignancy that is often diagnosed incidentally on an abdominal imaging study. Seventy percent of patients are diagnosed with stage I RCC and 11% of patients with stage IV. First-line treatments for early-stage RCC are partial or radical nephrectomy, which can result in 5-year cancer-specific survival of more than 94%, ablative techniques, or active surveillance. New treatment options for patients with metastatic RCC include immune checkpoint inhibitors and tyrosine kinase inhibitors.

Background: The population diagnosed with renal cell carcinoma, especially in Asia, represents 36.6% of global cases, with the incidence rate of renal cell carcinoma in Korea steadily increasing annually. However, treatment options for renal cell carcinoma are diverse, depending on clinical stage and histologic characteristics. Hence, this study aims to develop a machine learning based clinical decision-support system that recommends personalized treatment tailored to the individual health condition of each patient., Results: We reviewed the real-world medical data of 1,867 participants diagnosed with renal cell carcinoma between November 2008 and June 2021 at the Pusan National University Yangsan Hospital in South Korea. Data were manually divided into a follow-up group where the patients did not undergo surgery or chemotherapy (Surveillance), a group where the patients underwent surgery (Surgery), and a group where the patients received chemotherapy before or after surgery (Chemotherapy). Feature selection was conducted to identify the significant clinical factors influencing renal cell carcinoma treatment decisions from 2,058 features. These features included subsets of 20, 50, 75, 100, and 150, as well as the complete set and an additional 50 expert-selected features. We applied representative machine learning algorithms, namely Decision Tree, Random Forest, and Gradient Boosting Machine (GBM). We analyzed the performance of three applied machine learning algorithms, among which the GBM algorithm achieved an accuracy score of 95% (95% CI, 92-98%) for the 100 and 150 feature sets. The GBM algorithm using 100 and 150 features achieved better performance than the algorithm using features selected by clinical experts (93%, 95% CI 89-97%)., Conclusions: We developed a preliminary personalized treatment decision-support system (TDSS) called "RCC-Supporter" by applying machine learning (ML) algorithms to determine personalized treatment for the various clinical situations of RCC patients. Our results demonstrate the feasibility of using machine learning-based clinical decision support systems for treatment decisions in real clinical settings., (© 2024. The Author(s).)

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., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: We discovered a novel human endogenous retrovirus (CT-RCC HERV-E) that was selectively expressed in most clear cell renal cell carcinomas (ccRCC) and served as a source of antigens for T cell-mediated killing. Here, we described the cloning of a novel T cell receptor (TCR) targeting a CT-RCC HERV-E-derived antigen specific to ccRCC and characterized antitumor activity of HERV-E TCR-transduced T cells (HERV-E T cells)., Methods: We isolated a CD8 + T cell clone from a patient with immune-mediated regression of ccRCC post-allogeneic stem cell transplant that recognized the CT-RCC-1 HERV-E-derived peptide in an HLA-A11-restricted manner. We used 5'Rapid Amplification of cDNA Ends (RACE) to clone the full length HERV-E TCR and generated retrovirus encoding this TCR for transduction of T cells. We characterized HERV-E T cells for phenotype and function in vitro and in a murine xenograft model. Lastly, we implemented a good manufacturing practice-compliant method for scalable production of HERV-E T cells., Results: The HLA-A11-restricted HERV-E-reactive TCR exhibited a CD8-dependent phenotype and demonstrated specific recognition of the CT-RCC-1 peptide. CD8 + T cells modified to express HERV-E TCR displayed potent antitumor activity against HLA-A11 + ccRCC cells expressing CT-RCC HERV-E compared with unmodified T cells. Killing by HERV-E T cells was lost when cocultured against HERV-E knockout ccRCC cells. HERV-E T cells induced regression of established ccRCC tumors in a murine model and improved survival of tumor-bearing mice. Large-scale production of HERV-E T cells under good manufacturing practice conditions generated from healthy donors retained specific antigen recognition and cytotoxicity against ccRCC., Conclusions: This is the first report showing that human ccRCC cells can be selectively recognized and killed by TCR-engineered T cells targeting a HERV-derived antigen. These preclinical findings provided the foundation for evaluating HERV-E TCR-transduced T cell infusions in patients with metastatic ccRCC in a clinical trial (NCT03354390)., Competing Interests: Competing interests: The authors (EC, MIN and RWC) declare a filed patent WO2018006054A1, licensed by T-Cure BioScience, represented by GZ and GP., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Lipid droplets (LD) in renal clear cell carcinoma (ccRCC)play a crucial role in lipid metabolism and immune response modulation. The purpose of this study was to create a LD-related signature to predict prognosis and guide the immunotherapy and targeted therapy in ccRCC patients., Methods: We conducted a comprehensive analysis using transcriptional profiles and clinical data obtained from The Cancer Genome Atlas (TCGA). LD-related genes were identified from existing literature and the GeneCards database, and differentially expressed genes were determined. Sequentially, we conducted Cox regression analysis and Lasso regression analysis, to establish a prognostic risk model. The performance of the risk model was evaluated using Kaplan-Meier (KM) analysis and time-dependent receiver operating characteristic (ROC) analysis. Additionally, gene set enrichment analysis (GSEA), ESTIMATE, CIBERSORT, and immunophenoscore (IPS) algorithm were used to assess the tumor microenvironment (TME) and treatment response., Results: We constructed a risk signature with four LD-related genes in the TCGA dataset, which could be an independent prognostic factor in ccRCC patients. Then, patients were classified into two risk groups and exhibited notable differences in overall survival (OS), progression-free survival (PFS), and TME characteristics. Furthermore, we developed a comprehensive nomogram based on clinical features, which demonstrated good prognostic predictive value. According to the results of GSEA analysis, immune-related pathways were found to be significantly enriched in the high-risk group. Additionally, the high-risk group displayed high levels of immune cell infiltration, TMB and IPS scores, indicating better efficacy of immune checkpoint inhibitors (ICIs). Finally, high-risk demonstrated reduced IC50 values compared to the low-risk counterpart for specific targeted and chemotherapeutic drugs, suggesting that the patients receiving these targeted drugs in high-risk group had better treatment outcomes., Conclusions: Our findings suggested that the LD-related gene signature could potentially predict the prognosis of ccRCC patients. Additionally, it showed promise for predicting responses to immunotherapy and targeted therapy in ccRCC patients. These insights might potentially have guided the clinical management of these patients, but further validation and broader data analysis are needed to confirm these preliminary observations., (© 2024. The Author(s).)

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., (© The Author(s) 2024. Published by Oxford University Press.)

The therapy of the clear cell renal cell carcinoma (ccRCC) is crucial for the human healthcare due to its easy metastasis and recurrence, as well as resistance to radiotherapy and chemotherapy. In this work, we propose the synthesis of MoS 2 @red phosphorus (MoS 2 @RP) heterojunction to induce synergistic photodynamic and photothermal therapy (PDT/PTT) of ccRCC. The MoS 2 @RP heterojunction exhibits enhanced spectra absorption in the NIR range and produce local heat-increasing under the NIR laser irradiation compared with pure MoS 2 and RP. The high photocatalytic activity of the MoS 2 @RP heterojunction contributes to effective transferring of the photo-excited electrons from the RP to MoS 2 , which promotes the production of various types of radical oxygen species (ROS) to kill the ccRCC cells. After the NIR irradiation, the MoS 2 @RP can effectively induce the apoptosis in the ccRCC cells through localized hyperthermia and the generation of ROS, while exhibiting low cytotoxicity towards normal kidney cells. In comparison to MoS 2 , the MoS 2 @RP heterojunction shows an approximate increase of 22 % in the lethality rate of the ccRCC cells and no significant change in toxicity towards normal cells. Furthermore, the PDT/PTT treatment using the MoS 2 @RP heterojunction effectively eradicates a substantial number of deep-tissue ccRCC cells in vivo without causing significant damage to major organs. This study presents promising effect of the MoS 2 @RP heterojunction-based photo-responsive therapy for effective ccRCC treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

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

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

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

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

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

Background: Approximately 15 000 people receive a diagnosis of renal cell carcinoma (RCC) in Germany each year; in 20-30% of cases, metastatic RCC (mRCC) is already present at the time of diagnosis. This disease in the metastatic stage is still mainly treated palliatively, yet the multimodal therapeutic landscape has changed markedly over the past 15 years, with the approval of many new treatments for patients with mRCC., Methods: This review is based on prospective studies retrieved by a selective search in PubMed and the ASCO and ESMO databases and on the German and European oncological and urological guidelines for RCC., Results: Drugs are the mainstay of treatment. mRCC can be treated with a combination of two immune checkpoint inhibitors (CPIs), a CPI and a tyrosine-kinase inhibitor (TKI) (evidence level IA), or a TKI as monotherapy (evidence level IIC-IC). With prognosis-based sequential drug treatment, a mean progressionfree survival of 12 to 24 months and an overall survival of approximately 50 months can be achieved from the time of initiation of first-line therapy. Aside from pharmacotherapy, the multidisciplinary tumor board should evaluate the indications for local treatments such as cytoreductive nephrectomy, metastasectomy, and radiotherapy, depending on the individual prognostic constellation and the patient's present condition., Conclusion: Optimal individualized decisions require a high level of expertise and the collabo - ration of a multidisciplinary tumor board. Older prognostic parameters currently play a leading role in decision-making, while predictive parameters and molecular markers are not yet adequately validated.

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.

Renal cell carcinoma (RCC) is one of the most common tumors that afflicts the urinary system, accounting for 90-95% of kidney cancer cases. Although its incidence has increased over the past decades, its pathogenesis is still unclear. Tumor-associated macrophages (TAMs) are the most prominent immune cells in the tumor microenvironment (TME), comprising more than 50% of the tumor volume. By interacting with cancer cells, TAMs can be polarized into two distinct phenotypes, M1-type and M2-type TAMs. In the TME, M2-type TAMs, which are known to promote tumorigenesis, are more abundant than M1-type TAMs, which are known to suppress tumor growth. This ratio of M1 to M2 TAMs can create an immunosuppressive environment that contributes to tumor cell progression and survival. This review focused on the role of TAMs in RCC, including their polarization, impacts on tumor proliferation, angiogenesis, invasion, migration, drug resistance, and immunosuppression. In addition, we discussed the potential of targeting TAMs for clinical therapy in RCC. A deeper understanding of the molecular biology of TAMs is essential for exploring innovative therapeutic strategies for the treatment of RCC., (© 2024. The Author(s).)

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant syndrome caused by a germline mutation in the fumarate hydratase (FH) gene that manifests with cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. In this study, we described a case of aggressive HLRCC in a 33-year-old female who exhibited a novel heterozygous germline insertion mutation in exon 8 of the FH gene (c.1126 C > T; p.Q376*). The patient underwent laparoscopic resection of the right kidney, but metastases appeared within 3 months after surgery. Histological staining of the resected tumor revealed high expression levels of programmed cell death-ligand 1 (PD-L1). Therefore, the patient was treated with immunotherapy. The patient achieved a partial response to immunotherapy, and the treatment of metastatic lesions has continued to improve. A thorough literature review pinpointed 76 historical cases of HLRCC-RCC that had undergone immunotherapy. From this pool, 46 patients were selected for this study to scrutinize the association between mutations in the FH gene and the effectiveness of immunotherapy. Our results indicate that immunotherapy could significantly improve the overall survival (OS) of patients with HLRCC-RCC. However, no influence of different mutations in the FH germline gene on the therapeutic efficacy of immunotherapy was observed. Therefore, our study suggested that immunotherapy was an effective therapeutic option for patients with HLRCC regardless of the type of FH germline mutation., (© 2024. The Author(s).)

Background: Clear cell renal carcinoma is a common urological malignancy with poor prognosis and treatment outcomes. lncRNAs are important in metabolic reprogramming and the tumor immune microenvironment, but their role in clear cell renal carcinoma is unclear., Methods: Renal clear cell carcinoma sample data from The Cancer Genome Atlas was used to establish a new risk profile by glycolysis-associated lncRNAs via machine learning. Risk profile-associated column-line plots were constructed to provide a quantitative tool for clinical practice. Patients with renal clear cell carcinoma were divided into high- and low-risk groups. Clinical features, tumor immune microenvironments, and immunotherapy responses were systematically analyzed. We experimentally confirmed the role of LINC01138 and LINC01605 in renal clear cell carcinoma., Results: The risk profile, consisting of LUCAT1, LINC01138, LINC01605, and HOTAIR, reliably predicted survival in patients with renal clear cell carcinoma and was validated in multiple external datasets. The high-risk group presented higher levels of immune cell infiltration and better immunotherapy responses than the low-risk group. LINC01138 and LINC01605 knockdown inhibited the proliferation of renal clear cell carcinoma., Conclusions: The identified risk profiles can accurately assess the prognosis of patients with clear cell renal carcinoma and identify patient populations that would benefit from immunotherapy, providing valuable insights and therapeutic targets for the clinical management of clear cell renal carcinoma.

Objectives: To identify the cooperation of authors, countries, institutions and explore the hot spots regarding research of renal cell carcinoma with venous tumor thrombus. Methods: Relevant articles were obtained from the Web of Science Core database (WoSC) from 1999 to 2024. CiteSpace was used to perform the analysis and visualization of scientific productivity and emerging trends. Network maps were generated to evaluate the collaborations between different authors, countries, institutions, and keywords. Results: A total of 2180 related articles were identified. We observed an increased enthusiasm in related fields during the past two decades. The USA dominated the field in all countries, and the University of Miami was the core institution. Ciancio G might have a significant influence with more publications and co-citations. Current research hotspots in this field mainly included thrombectomy, tyrosine kinase inhibitors, immune checkpoint inhibitors, vena cava inferior, and microvascular invasion. Thrombectomy complications, thrombectomy survival outcome, and preoperative neoadjuvant immunotherapy represented the frontiers of research in this field, undergoing an explosive phase. Conclusion: This is the first bibliometric study that comprehensively visualize the research trends and status of RCC with VTT. We hope that this work will provide new ideas for advancing the scientific research and clinical application., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: To examine associations between ablative therapy (AT) and partial nephrectomy (PN) and the occurrence of local recurrence (LR), distant metastatic recurrence (DMR) and all-cause mortality in a nation-wide real-world population-based cohort of patients with nonmetastatic renal cell carcinoma (nmRCC)., Methods: Data on 2751 AT- or PN-treated nmRCC tumours diagnosed during 2005-2018, representing 2701 unique patients, were obtained from the National Swedish Kidney Cancer Register. Time to LR/DMR or death with/without LR/DMR was analysed using Cox regression models., Results: During a mean of 4.8 years follow-up, LR was observed for 111 (4.0%) tumours, DMR for 108 (3.9%) tumours, and death without LR/DMR for 206 (7.5%) tumours. AT-treated tumours had a 4.31 times higher risk of LR (P < 0.001) and a 1.91 times higher risk of DMR (P = 0.018) than PN-treated, with no significant differences in risk of death without LR/DMR. During a mean of 3.2 and 2.5 years of follow-up after LR/DMR, respectively, 24 (21.6%) of the LR cases and 56 (51.9%) of the DMR cases died, compared to 7.5% in patients without LR/DMR. There were no significant differences between AT- and PN-treated regarding risks of early death after occurrence of LR or DMR., Conclusion: AT treatment of patients with nmRCC implied significantly higher risks of LR and DMR compared with PN treatment. To minimize the risks of LR and DMR, these results suggest that PN is preferred over AT as primary treatment, supporting the EAU guidelines to recommended AT mainly to frail and/or comorbid patients., (© 2024. The Author(s).)

The landscape of the management of renal cell carcinoma has evolved substantially in the last decade, leading to improved survival in localised and advanced disease. We review the epidemiology, pathology, and diagnosis of renal cell carcinoma and discuss the evidence for current management strategies from localised to metastatic disease. Developments in adjuvant therapies are discussed, including use of pembrolizumab-the first therapy to achieve overall survival benefit in the adjuvant setting. The treatment of advanced disease, including landmark trials that have established immune checkpoint inhibition as a standard of care, are also reviewed. We also discuss the current controversies that exist surrounding the management of metastatic renal cell carcinoma, including the use of risk assessment models for disease stratification and treatment selection for frontline therapy. Management of non-clear cell renal cell carcinoma subtypes is also reviewed. Future directions of research, including a discussion of ongoing clinical trials and the need for reliable biomarkers to guide treatment in kidney cancer, are also highlighted., Competing Interests: Declaration of interests No funding or payment has been directed towards this review or the authors' decision to submit for publication. MY has received honoria from Eisai. BS has received reimbursement for travel expenses from Genentech, Merck Sharp & Dohme (MSD), Pfizer, and Bristol-Myers Squibb (BMS); has received research funding from Roche, Genentech, Merck Sharp & Dohme, Pfizer, and Bristol-Myers Squibb; and has received honoraria from Merck, Roche, Pfizer, Ellipses, Ipsen, and Janssen. TP declares grants from or contracts with AstraZeneca, BMS, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seagen, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; TP reports payment or honoraria for lectures, presentations, or speakers' bureaus from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, MSD, Novartis, Pfizer, Seagen, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, and Mash Up; and reports travel support from Roche, Pfizer, MSD, AstraZeneca, and Ipsen. CS declares research funding from AB Science, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim España, BMS, Clovis Oncology, Exelixis, Genentech, GlaxoSmithKline, F Hoffmann-La Roche, Novartis, Pfizer, and Sanofi-Aventis; speakers' bureau fees from Astellas Pharma, BMS, F Hoffmann-La Roche, Ipsen, and Pfizer; participation on a data safety monitoring board or advisory board for Astellas Pharma, Bayer, BMS, Eusa Pharma, F Hoffmann-La Roche, Ipsen, MSD, Novartis, Pfizer, and Sanofi-Aventis. AB has received company speaker honoraria from Pfizer; and has participated in trials for Pfizer Europe; has participated in advisory boards for BMS, GlaxoSmithKline, and Novartis; is a consultant for Pfizer and Novartis; and has received grants and research support from Pfizer. All other authors declare no competing interests., (Crown Copyright © 2024 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: Durable complete response rates for metastatic renal cell carcinoma (mRCC) and metastatic bladder cancer (mBC) are low despite new therapy. Palliative care focuses on life extension and quality of life (QoL), not cure. This study aims to investigate patients' perceptions of treatment outcomes in mRCC and mBC and to assess the influence of QoL and optimism levels on these perceptions., Methods: From March 15, 2023, to January 15, 2024, a multicenter, cross-sectional online survey was carried out, targeting patients diagnosed with mRCC and mBC. The survey comprised structured questions aimed at evaluating perceptions concerning disease cure, symptom improvement, daily activity performance, and life extension due to treatment. Additionally, to evaluate optimism and QoL, the European Organization for Research and Treatment of Cancer 30.3 QoL questionnaire and life orientation test were implemented. Study on patients' perceptions of treatment outcomes in metastatic kidney and bladder cancer shows high optimism, inaccurate cure beliefs., Results: In total, 169 patients participated in the survey; the majority of the patients stated their general health status as good (72.2%) and excellent (13.6%). Patients who rated their overall health status as good-excellent had a higher median general QoL and optimism score compared with those who rated it as fair-poor. In all, 85.2% of patients considered the possibility of a cure very likely or likely. Most participants believed treatment could provide symptom relief (30.2% very likely, 49.1% likely), enhanced ability to perform daily activities (28.4% very likely, 55.6% likely), and life extension (32.5% very likely, 53.3% likely). Patients responding very likely and likely to these questions regarding treatment outcomes had higher QoL and optimism scores than those responding a little likely and not possible., Conclusion: The majority of patients with mRCC and mBC held inaccurate beliefs about treatment outcomes. Better QoL and optimism were associated with increased inaccuracy.

Introduction: Renal cell carcinoma is as the most prevalent form of kidney cancer, with the clear cell subtype comprising approximately 75% of cases. The identification of predictive and prognostic biomarkers has emerged as a crucial area of research within the field. Despite advancements in treatment, metastatic renal cell carcinoma presents formidable challenges, with survival rates heavily dependent upon the optimal choice of treatment., Materials and Methods: This review summarizes the current literature regarding the prognostic and predictive value of biomarkers in patients with renal cell carcinoma. We conducted a comprehensive literature search to identify studies that reference biomarkers of interest in this domain. We selected studies based on their relevance, publication date, and the quality of the research. Data from these selected papers were compiled and analyzed to provide an overview of the current understanding and advancements in the field. The findings were then synthesized into a concise discussion highlighting the state of biomarker research in renal cell carcinoma today., Results and Conclusions: While various nucleic acid and protein biomarkers have shown promise in other malignancies, their application in renal cell carcinoma remains limited by the lack of validated predictors. This review aims to highlight the pressing need for robust predictive and prognostic biomarkers in renal cell carcinoma to guide clinicians in tailoring optimal therapeutic strategies. The discussion encompasses the limitations of existing markers and underscores the significance of the most recent advancements within the field. Despite these strides, the clinical application of renal cell carcinoma biomarkers requires further study and validation.

Kidney cysts and tumors often are identified during imaging for unrelated issues. Kidney cysts can be attributable to heritable polycystic kidney diseases. These cysts are rare in children. In adults, they affect approximately 50% of individuals older than 50 years. Kidney cysts are categorized on imaging using the Bosniak Classification of Cystic Renal Masses, which determines the likelihood that cysts are malignant or benign. Asymptomatic Bosniak class I and II cysts require no further evaluation or follow-up; however, symptomatic large simple cysts might require treatment. Bosniak class III and IV cysts might be malignant and require excision. Kidney tumors also occur in children and adults. In children, the most common is Wilms tumor, but after age 10 years renal cell carcinoma (RCC) is more common. In adults, kidney tumors may be malignant or benign. RCC accounts for 85% of kidney tumors in adults, often with metastatic disease. In patients with kidney tumors, biopsy typically is avoided to prevent spread of malignant cells. Tumors that appear suspicious for cancer on imaging are managed directly, which can include total or partial nephrectomy, ablation therapy, and adjuvant therapies, along with chemotherapy and radiotherapy depending on tumor stage. For some patients, evaluation may involve consideration of genetic testing for hereditary cancer syndromes. Patients with these syndromes should undergo periodic screening for RCC., (Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.)

Introduction: Systemic and local therapies for patients with metastatic renal cell carcinoma (mRCC) are often challenging despite the evolution of multimodal cancer therapies in the last decade. In this review, we will focus on recent multidisciplinary approaches for patients with mRCC., Areas Covered: Systemic therapies for patients with mRCC have been garnering attention particularly after the approval of immuno-oncology (IO) agents, including anti-programmed death 1/programmed death-ligand 1. IO combinations have significantly prolonged overall survival in patients with mRCC in the first-line setting. Regarding local therapies, cytoreductive nephrectomy (CN) has become less common in the post-Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques (CARMENA) trial era, even though CN may still benefit selected patients with mRCC. In addition, metastasis-directed local therapies, namely metastasectomy or stereotactic radiotherapy, particularly for oligo-metastatic lesions or brain metastases, may have a prognostic impact. Several ablative techniques are also evolving while maintaining high local control rates with acceptable safety., Expert Opinion: Multimodal cancer therapies are essential for conquering complex cases of mRCC. Modern systemic therapies including IO-based combination therapy as well as local therapies including CN, metastasectomy, stereotactic radiotherapy, and ablative techniques appear to improve oncologic outcomes of patients with mRCC, although appropriate patient selection is indispensable.

Introduction: Renal cell carcinoma (RCC) has been associated with an increased risk for acute ischemic stroke (AIS). As individuals with cancer who experience AIS tend to face higher mortality rates compared to AIS patients without cancer, recognizing the implications of RCC in AIS is crucial for identifying high-risk patients for major complications and directing management strategies., Objective: To examine risk factors, interventions, and outcomes for patients with AIS stratified by their RCC diagnosis., Methods: The National Inpatient Sample (NIS) database was queried for the period 2010-2019 using International Classification of Disease 10th Edition (ICD-10) codes for acute ischemic stroke and renal malignancies. We assessed demographic information, comorbidities, and clinical interventions between patients presenting with AIS, with and without renal malignancies. A logistic regression model was employed to further examine mortality outcomes., Results: Among 1,609,817 patients identified with AIS, 2,068 (0.12%) had a concomitant diagnosis of RCC. AIS patients with RCC were older (72.09 yrs. vs. 70.9 yrs., p < 0.01), more often white (72.05% vs. 68.16%, p < 0.01), and had similar stroke severity scores. RCC patients received less tissue plasminogen activator (tPA; 4.98% vs. 6.2%, p = 0.02) but underwent endovascular mechanical thrombectomy (MT) at similar rates. RCC patients had more complications (p < 0.01) as well as longer hospital stays (8.19 days vs. 5.98 days, p < 0.01), and higher rates of mortality (11.27% vs. 5.63%, p < 0.01), when compared to their non-RCC counterparts. Propensity score-adjusted analysis largely confirmed these findings, with RCC being positively associated with in-hospital mortality (OR: 1.373, p < 0.01) and longer stays (OR: 2.591, p < 0.01)., Conclusion: In addition to describing the demographics and clinical course of AIS patients diagnosed with RCC, our study underscores the substantial impact of RCC on AIS outcomes. Despite experiencing strokes of similar severity, AIS patients diagnosed with RCC are at a heightened risk of complications, including thromboembolic events and infections, leading to elevated in-hospital mortality rates and prolonged hospital stays., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

In this article, we report the breakthrough acquisitions for renal cell carcinoma (RCC) management presented at the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium. The results from Keynote 564 showed an impressive overall survival (OS) advantage for pembrolizumab, in patients at higher risk of relapse after surgery and confirmed the benefit in terms of disease-free survival (DFS). Until now, pembrolizumab is the only immune checkpoint inhibitor (ICI) to prove a survival advantage. On the contrary, the results from CheckMate 914 trial showed the lack of benefit of adjuvant nivolumab. In the metastatic setting, the longer-term follow-up data of the CheckMate 9ER and CheckMate 214 trials reassessed the undoubtable role of ICI-based combination in first-line treatment, with a clear survival advantage in the subgroup of patients at intermediate/poor IMDC prognosis. No OS advantage was seen in favorable IMDC risk group patients. This 2024 ASCO Genitourinary Cancer Symposium laid the foundations for further knowledge development necessary for an increasingly personalized therapy for RCC patients.

Renal cell carcinoma (RCC) is a hot tumor infiltrated by large numbers of CD8 + T cells and is highly sensitive to immunotherapy. However, tumor-associated macrophages (TAMs), mainly M2 macrophages, tend to undermine the efficacy of immunotherapy and promote the progression of RCC. Here, macrophage-derived nanosponges are fabricated by M2 macrophage membrane-coated poly（lactic-co-glycolic acid）（PLGA）, which could chemotaxis to the CXC and CC chemokine subfamily-enriched RCC microenvironment via corresponding membrane chemokine receptors. Subsequently, the nanosponges act like cytokine decoys to adsorb and neutralize broad-spectrum immunosuppressive cytokines such as colony stimulating factor-1(CSF-1), transforming growth factor-β（TGF-β）, and Lnterleukin-10（IL-10）, thereby reversing the polarization of M2-TAMs toward the pro-inflammatory M1 phenotype, and enhancing the anti-tumor effect of CD8 + T cells. To further enhance the polarization reprogramming efficiency of TAMs, DSPE-PEG-M2pep is conjugated on the surface of macrophage-derived nanosponges for specific recognition of M2-TAMs, and the toll like receptors 7/8（TLR7/8） agonist, R848, is encapsulated in these nanosponges to induce M1 polarization, which result in significant efficacy against RCC. In addition, these nanosponges exhibit undetectable biotoxicity, making them suitable for clinical applications. In summary, a promising and facile strategy is provided for immunomodulatory therapies, which are expected to be used in the treatment of tumors, autoimmune diseases, and inflammatory diseases., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Introduction: We aimed to evaluate the effect of transcatheter arterial embolization (TAE) with iodized oil (Lipiodol) on temperature change during cryoablation (CA) for renal cell carcinoma (RCC)., Material and Methods: We retrospectively reviewed patients receiving CA for RCC from February 2020 to July 2021, including those who received Lipiodol TAE prior to CA (TAE group) and those who underwent only CA with comparable clinical and tumor characteristics (non-TAE group). Clinical data and tumor characteristics of both groups were recorded. The temperature readings of each cryoprobe at every 15 s and 'time to -100 °C' were compared between the groups., Results: A total of 17 patients with 18 RCCs were recruited (seven in the TAE group and 11 in the non-TAE group). The 'time to -100 °C' was significantly longer in the TAE group than in the non-TAE group (64.5 ± 24.3 s vs. 48.8 ± 9.7 s, p  = 0.018). Positive correlation between 'time to -100 °C' and tumor maximal diameter, RENAL nephrometry and PADUA score were observed in the non-TAE group, while no corresponding correlation was found in the TAE group., Conclusions: Pre-embolization with iodized oil influences the temporal temperature changes during cryoablation by disrupting the positive correlation between the time to reach the target temperature and tumor characteristics.

In the last decade, the standard treatment for advanced renal cell carcinoma (RCC) has evolved, mainly driven by the development and approval of immune checkpoint inhibitors (ICIs). Currently, ICI monotherapy and ICI-based combinations with tyrosine kinase inhibitors and targeted therapies against mammalian target of rapamycin or vascular endothelial growth factor have become new standard treatments for first-line and subsequent-line therapies. ICIs play an important role as an adjuvant postoperative therapy, and this field is the subject of active research. Furthermore, ongoing randomized controlled trials are investigating the clinical value of more intense treatments by combining multiple effective treatments for RCC. Additionally, novel biomarkers for prognosis have been investigated. This study reviews the current evidence on immunotherapy as a treatment for RCC patients, randomized controlled trials, and ongoing studies including RCC patients and recent findings, and discusses future perspectives., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Competing Interests: DB receives consultancy fees, honoraria for presentations, participation on data safety and monitoring boards or advisory boards, and support for travel accommodation from Bristol Myers Squibb and MSD, and grants paid to their institution from Bristol Myers Squibb. KB receives consultancy fees, honoraria for presentations, and participation on data safety and monitoring board or advisory boards from Bristol Myers Squibb and MSD, and support for travel accommodation from MSD.

Purpose: To evaluate the incidence of postoperative complications after cytoreductive nephrectomy (CN) following first-line treatment for metastatic renal cell carcinoma (mRCC), and to compare it with postoperative complications of upfront CN., Methods: For this population-based retrospective study, the PearlDiver Mariner database (PearlDiver Technologies, Colorado Springs, CO), a database of insurance billing records was analyzed. Using relevant ICD-9/10 and CPT codes, patients diagnosed with mRCC between 2011 and 2021, who received first-line systemic molecular therapy (SMT), either tyrosine kinase inhibitors (TKI) or immune-checkpoint inhibitors (ICI), were identified. The selected population was stratified into two cohorts according to the timing of CN (deferred: after SMT vs. upfront: before SMT). Propensity-score matching (PSM) was performed as per baseline patients' characteristics to control for potential confounders between the two cohorts. The primary outcome was to compare 30-day postoperative complications rate between patients undergoing upfront vs. deferred CN., Results: After PSM, 162 patients who received upfront CN were compared with 162 patients who underwent deferred CN. The overall rate of 30-day postoperative complications was statistically significantly higher in patients undergoing deferred CN (33.9%), compared to patients treated with upfront CN (21%, p < 0.01). In addition, the rate of both medical (26.5% vs. 14.2%, p < 0.01) and surgical (14.8 vs. 7.4%, p = 0.03) complication rate was statistically significantly higher in deferred vs. upfront CN. Multivariable logistic regression analysis revealed that none of the treatment regimens significantly predicted the occurrence of postoperative complications., Conclusion: Patients undergoing deferred CN experience a higher rates of overall, medical, and surgical 30-day postoperative complications compared to those receiving upfront surgery. Findings from this study should be interpreted within the limitations of this type of analysis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)