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Introduction: Cabozantinib monotherapy is an option for treatment of advanced renal cell carcinoma (RCC). However, cabozantinib dose modification and discontinuation due to symptomatic adverse events (AEs) remains a challenge. The use of patient-reported outcomes (PROs) may help manage symptomatic AEs, which is reported to lead to improved quality of life (QOL), avoidance of drug discontinuation and better survival. This study aims to investigate the clinical benefits of PROs in patients with RCC receiving cabozantinib and the most appropriate medium for PRO monitoring (electronic [e]-PRO or paper-PRO)., Methods and Analysis: This study is being conducted at about 35 sites in Japan. Patients aged ≥18 years with unresectable or metastatic RCC initiating treatment with cabozantinib monotherapy are eligible and will be randomised to: (1) e-PRO monitoring, (2) paper-PRO monitoring or (3) usual care without PRO monitoring. Recruitment began in December 2021 (target sample size, 105). Patients start treatment with cabozantinib 60 mg once daily, and in the PRO groups, will record daily medication intake, weight, temperature, blood pressure and AEs. Endpoints include the proportion of patients with a ≥5-point deterioration on the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-19; primary endpoint), progression-free survival, QOL, dose adjustments, relative dose intensity, treatment-emergent AEs and frequency of interventions for AEs outside of the scheduled visits. Patient and physician opinions of the PRO monitoring systems and patient compliance with e-PRO/paper-PRO input are also being measured., Ethics and Dissemination: The study is being conducted in compliance with the Declaration of Helsinki, the International Council for Harmonisation guidelines for Good Clinical Practice and the Clinical Trials Act. Written informed consent is being obtained from all patients, and the protocol has been approved by the Hokkaido University Hospital Certified Review Board (approval number, CRB021-005). The results will be presented at conferences and submitted to a peer-reviewed journal., Trial Registration Number: jRCTs011210055., Competing Interests: Competing interests: TOsak, RT and SI are employees of Takeda. TOsaw and YN have no conflicts of interest to declare. YF has received honoraria from Astellas Pharma, AstraZeneca, Bayer, Janssen, Kissei, Merck, MSD, Myriad, Nippon Shinyaku, Ono, Pfizer, Sanofi and Takeda; has undertaken consulting or advisory services for Astellas Pharma, AstraZeneca, Eisai and Merck; and has received research funding from Astellas Pharma, Ono and Takeda. GK has received honoraria from Bristol Myers Squibb Japan, Ono Yakuhin and Chugai Pharma; has undertaken consulting or advisory services for Eisai; and has been a speaker for Bristol Myers Squibb Japan, Ono Yakuhin, MSD, Chugai Pharma, Bayer Yakuhin, Janssen, Merck Biopharma, Sanofi and Takeda. HK has received honoraria from Astellas Pharma, AstraZeneca/Daiichi Sankyo, MSD, Bayer Yakuhin, Takeda, Merck/Pfizer, Sanofi, Janssen, Bristol Myers Squibb Japan, Nippon Kayaku, Nippon Shinyaku and Chugai Pharma; has undertaken consulting or advisory services for Astellas Pharma, AstraZeneca/Daiichi Sankyo, MSD, Janssen, Pfizer, Takeda, Chugai Pharma, Eisai and Kissei Pharmaceutical; and has received research funding from Takeda, Bayer Yakuhin, Sanofi, Astellas Pharma, MSD and AstraZeneca/Daiichi Sankyo. NS has been a speaker for Pfizer, Ono, Takeda, MSD and AstraZeneca; and has received research funding from Ono, Takeda and Astellas Pharma., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.

Renal cell carcinoma (RCC) has poor survival prognosis because it is asymptomatic at an early, more curative stage. Recently, urine perilipin-2 (PLIN-2) was demonstrated to be a sensitive and specific biomarker for the noninvasive, early detection of RCC and an indispensable indicator to distinguish cancer from a benign renal mass. However, current Western blot or ELISA PLIN-2 assays are complicated, expensive, time-consuming or insensitive, making them unsuitable for routine analysis in clinical settings. Here we developed a plasmonic biosensor based on the high refractive index sensitivity of gold nanorattles for the rapid detection of PLIN-2 in patient urine. The paper-based plasmonic assay is highly sensitive and has a dynamic range of 50 pg/ml to 5 μg/ml PLIN-2. The assay is not compromised by variations in urine pH or high concentrations of interfering proteins such as albumin and hemoglobin, making it an excellent candidate for routine clinical applications. The urine PLIN-2 assay readily distinguished patients with pathologically proven clear cell carcinomas of various size, stage and grade (55.9 [39.5, 75.8] ng/ml, median [1st and 3rd quartile]) from age-matched controls (0.3 [0.3, 0.5] ng/ml), patients with bladder cancer (0.5 [0.4, 0.6] ng/ml) and patients with diabetic nephropathy (0.6 [0.4, 0.7] ng/ml). Urine PLIN-2 concentrations were roughly proportional to tumor size (Pearson coefficient 0.59). Thus, this cost-effective and label-free method represents a novel approach to conduct a non-invasive population screen or rapid differential diagnosis of imaged renal masses, significantly facilitating the early detection and diagnosis of RCC., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Tyrosine kinase inhibitors still play a very important role in the treatment of metastatic renal cell carcinoma despite a continuously changing scenario, in which immunotherapy and several combination-based approaches are also available. In this light, patient-reported outcomes and health-related quality of life are important factors in the selection of the best first-line treatment. This Review focuses on the existing evidence on patient-reported outcomes and health-related quality of life with several tyrosine kinase inhibitors (pazopanib, sunitinib, cabozantinib and tivozanib) used as first-line treatment for metastatic renal cell carcinoma.

Treatments currently recommended for metastatic renal cell cancer (mRCC) have not been evaluated specifically in elderly patients. Here we consider what may be learned by analysing according to age the efficacy and toxicity data from key phase III trials of the targeted agents sorafenib (Nexavar), sunitinib (Sutent), temsirolimus (Torisel), and bevacizumab (Avastin), and from a study of expanded access to sunitinib and sorafenib. This paper represents the first systematic review of the role of targeted agents specifically in the elderly population. Retrospective subgroup analyses of clinical trial data cannot be considered definitive. However, they suggest in general that the progression-free and overall survival benefits seen in mRCC patients aged 65 years and over are similar to those in the younger age group. The frequency of major toxicities in elderly patients treated with targeted agents is no greater than in younger patients, although such toxicities may have greater impact on the quality of life. That said, no meaningful data are available for patients over 85 years. To confirm and extend these conclusions, prospective studies should be undertaken in the elderly to determine whether recommendations made for the wider mRCC population apply equally to this group of patients in whom comorbidities, comedication and the greater impact of low-grade toxicity may influence the efficacy and tolerability of treatment. Such studies are increasingly needed, given the growing number of elderly people and their rising life expectancy. Meanwhile, when considering the most appropriate drug to use in a particular patient, the toxicity profiles of the individual targeted agents--and any implications for specific comorbid conditions--should be taken into account.

A physician's alert prompted us to investigate workers' cancer risk at a paperboard printing manufacturer. We conducted a retrospective cohort mortality study of all 2,050 persons who had worked at the facility for more than 1 day, calculated standardized incidence ratios (SIRs) for bladder and renal cell cancer, and conducted a nested case-control study for renal cell cancer. Standardized mortality ratios (SMRs) from all causes [SMR = 1.0, 95% confidence interval (CI) = 0.9-1.2] and all cancers (SMR = 0.6, 95% CI = 0.3-1.0) were not greater than expected. One bladder cancer and one renal cell cancer were included in the mortality analysis. Six incident renal cell cancers were observed, however, compared with less than two renal cell cancers expected (SIR = 3.7, 95% CI = 1.4-8.1). Based on a nested case-control analysis, the risk of renal cell cancer was associated with overall length of employment but was not limited to any single department or work process. Although pigments containing congeners of dichlorobenzidine and o-toluidine had been used at the plant, environmental sampling could not confirm any current exposure. Several limitations and a potential selection bias limit the inferences that can be drawn.

Introduction: Clear cell renal cell carcinoma (ccRCC) is the most lethal subtype of renal cell carcinoma with a high invasive potential. Radiomics has attracted much attention in predicting the preoperative T-staging and nuclear grade of ccRCC., Objective: The objective was to evaluate the efficacy of dual-energy computed tomography (DECT) radiomics in predicting ccRCC grade and T-stage while optimizing the models., Methods: 200 ccRCC patients underwent preoperative DECT scanning and were randomized into training and validation cohorts. Radiomics models based on 70 KeV, 100 KeV, 150 KeV, iodine-based material decomposition images (IMDI), virtual noncontrasted images (VNC), mixed energy images (MEI) and MEI + IMDI were established for grading and T-staging. Receiver operating characteristic analysis and decision curve analysis (DCA) were performed. The area under the curve (AUC) values were compared using Delong test., Results: For grading, the AUC values of these models ranged from 0.64 to 0.97 during training and from 0.54 to 0.72 during validation. In the validation cohort, the performance of MEI + IMDI model was optimal, with an AUC of 0.72, sensitivity of 0.71, and specificity of 0.70. The AUC value for the 70 KeV model was higher than those for the 100 KeV, 150 KeV, and MEI models. For T-staging, these models achieved AUC values of 0.83 to 1.00 in training and 0.59 to 0.82 in validation. The validation cohort demonstrated AUCs of 0.82 and 0.70, sensitivities of 0.71 and 0.71, and specificities of 0.80 and 0.60 for the MEI + IMDI and IMDI models, respectively. In terms of grading and T-staging, the MEI + IMDI model had the highest AUC in validation, with IMDI coming in second. There were statistically significant differences between the MEI + IMDI model and the 70 KeV, 100 KeV, 150 KeV, MEI, and VNC models in terms of grading (P < .05) and staging (P ≤ .001). DCA showed that both MEI + IDMI and IDMI models outperformed other models in predicting grade and stage of ccRCC., Conclusions: DECT radiomics models were helpful in grading and T-staging of ccRCC. The combined model of MEI + IMDI achieved favorable results., Competing Interests: The authors have no conflicts of interest to disclose, (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: To analyze the top 100 most-cited articles on renal cell carcinoma (RCC) using bibliometric methods based on the Web of Science core collection database and to explore the research status, hotspots, and emerging trends in RCC., Methods: The literature on RCC was searched in the Web of Science core collection database using a specific search strategy, and the types of literature were limited to articles and reviews, with no restrictions to language and publication date. The top 100 articles with the highest number of citations were extracted after the manual screening. The publication year, the number of citations, authors, country, institution, journal, and keywords of these articles were collected and analyzed. Descriptive statistics and visual analysis were performed using Microsoft Excel, VOSviewer, CiteSpace, R, and SPSS., Results: The number of citations of the top 100 articles varied from 541 to 4530, with a median citation count of 807.5, and the citation rates ranged from 13.8 to 448.4 citations per year. Motzer RJ (n = 22), Escudier B (n = 13), Rini BI (n = 13), and Hutson TE (n = 11) were major contributors to this research area, with Motzer RJ publishing 16 articles as the first author. The US (n = 73), France (n = 5), Canada (n = 4), and Sweden (n = 4) were the leading countries for RCC studies. MEMORIAL SLOAN KETTERING CANCER CENTER (n = 22) was the institution with the highest number of publications. These 100 articles were derived from 24 journals, and the New England Journal of Medicine had the largest number of articles published (n = 18, impact factor = 91.245). The keyword co-occurrence network analysis showed that research hotspots in this field included molecular mechanisms of RCC development and progression, surgical treatment, targeted drug-related clinical trials, and immunotherapy., Conclusion: We analyzed the top 100 articles with the highest number of citations in the field of RCC and identified the influential authors, countries, institutions, and journals in this field. This study also presented the current research status, hotspots, and future trends in RCC., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: We aimed to assess the relative importance of attributes and the willingness to pay for pharmacological therapies among patients with renal cell carcinoma in China., Methods: Patients with renal cell carcinoma completed a D-efficient-designed, discrete-choice experiment online survey that presented a series of ten trade-off questions and one examining scenario. Based on the literature review and consultations with patients with renal cell carcinoma and clinicians, each question included a pair of hypothetical renal cell carcinoma medication profiles characterized by seven attributes including progression-free survival, objective response rate, medication regimen, fatigue, gastrointestinal reaction, hand-foot syndrome, and monthly out-of-pocket costs. Relative importance and willingness to pay were calculated using coefficients estimated by mixed logit regression in the main analysis. Subgroup analyses were conducted considering the heterogeneity of the participants, based on sex, education level, and income level, using conditional logit regression., Results: The analysis incorporated responses from 182 Chinese respondents. Except for the medication regimen, all attributes were statistically significant. Progression-free survival was the most important attribute, followed by objective response rate, monthly out-of-pocket costs, fatigue, gastrointestinal reaction, and hand-foot syndrome. Patients were willing to pay ￥2010.51 ($298.30), ￥494.93 ($73.43) for 1 unit improvement of progression-free survival, and objective response rate, and￥7558.93 ($1121.50), ￥6927.24 ($1027.78) to avoid experiencing fatigue and gastrointestinal reaction, respectively. Differences in preferences and willingness to pay were found according to patients' gender, income, and education level., Conclusions: In China, patients with renal cell carcinoma preferred medications with better efficacy (objective response rate and progression-free survival) and lower out-of-pocket costs. Heterogeneity can be found in preferences and willingness to pay based on patients' gender, income, and education levels., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Advances in cancer therapy have significantly improved overall patient survival; however, AKI remains a common complication in patients with cancer, occurring in anywhere from 11% to 22% of patients, depending on patient-related or cancer-specific factors. Critically ill patients with cancer as well as patients with certain malignancies ( e.g., leukemias, lymphomas, multiple myeloma, and renal cell carcinoma) are at highest risk of developing AKI. AKI may be a consequence of the underlying malignancy itself or from the wide array of therapies used to treat it. Cancer-associated AKI can affect virtually every compartment of the nephron and can present as subclinical AKI or as overt acute tubular injury, tubulointerstitial nephritis, or thrombotic microangiopathy, among others. AKI can have major repercussions for patients with cancer, potentially jeopardizing further eligibility for therapy and leading to greater morbidity and mortality. This review highlights the epidemiology of AKI in critically ill patients with cancer, risk factors for AKI, and common pathologies associated with certain cancer therapies, as well as the management of AKI in different clinical scenarios. It highlights gaps in our knowledge of AKI in patients with cancer, including the lack of validated biomarkers, as well as evidence-based therapies to prevent AKI and its deleterious consequences., (Copyright © 2022 by the American Society of Nephrology.)

Introduction: Oral targeted therapies (OTTs) are widely used for cancer management. However, there is no consensus on OTT dose adaptation in older patients with cancer., Methods: This noninterventional, retrospective study was a real-life assessment of dose adaptation for six OTTs (afatinib, everolimus, palbociclib, pazopanib, sorafenib and sunitinib), at baseline and during treatment, and the reasons for the changes, in ≥70-year-old patients treated between February 2016 and August 2019. Data were compared with univariate models fitted with all variables., Results: Among the 986 patients treated with OTT, the group of ≥70-year-old patients (n = 122) received afatinib (15.6%), everolimus (14.8%), palbociclib (50.8%), pazopanib (9.8%), sorafenib (5.8%) or sunitinib (3.2%). At baseline, the prescribed OTT dose was adapted (reduction) in 29% of ≥70-year-old patients (35/122). These 35 patients were significantly older (mean age 80 vs 74 years, P < .001), and more frequently had a performance status score ≥2 (P < .01) than the other patients (n = 87). In the standard dose group, higher toxicity grades (P = .18) and subsequent dose reduction (41% of patients, 36/87) tended to be more frequent compared with the baseline adapted dose group (26%, 9/35, P = .1). At the study end, 53% of patients in the whole cohort (65/122) were taking a lower dose than the recommended one., Conclusion: At OTT initiation, dose was adapted in 29% of older adults with cancer, rarely after a formal oncogeriatric evaluation (6.5% of all patients). In the absence of recommendations, clinical studies are needed to evaluate the efficacy and safety of baseline OTT dose reduction in older adults with cancer., (© 2022 British Pharmacological Society.)

Background: Clear cell renal cell carcinoma (ccRCC) remains a deadly disease with a poor prognosis. Here, we identified the ETS homologous factor (EHF) and its target Filamin-B (FLNB) as molecules related to immune evasion in ccRCC. We also explored the upstream modifier that manipulates EHF in ccRCC., Design: Cell proliferation and apoptosis assay, wound healing assay, and Transwell assay were designed to analyze the effects of EHF or FLNB knockdown on the biological activity of ccRCC cells. The growth of differently treated ccRCC cells was assessed by orthotopic tumors. ccRCC cells with different treatments were co-cultured with macrophages, and the role of the lysine-specific demethylase 5B (KDM5B)/EHF/FLNB axis on macrophage polarization or ccRCC progression was characterized by detecting the expression of M2 macrophage markers in the co-culture system or tumor tissues of tumor-bearing mice., Results: The expression of EHF and FLNB was higher, while KDM5B was lower in HK2 cells than in ccRCC cells. EHF overexpression inhibited the biological behavior of ccRCC cells and tumor growth in mice. EHF activated FLNB transcription. Knockdown of FLNB supported the biological activity of ccRCC cells and tumor growth and reversed M2 macrophage polarization in tumor tissues of mice in the presence of EHF. KDM5B inhibited EHF expression by H3K4me3 demethylation, and EHF knockdown potentiated M2 macrophage polarization and tumor growth in vivo repressed by KDM5B knockdown., Conclusions: KDM5B inhibited the expression of EHF by repressing H3K4me3 modification and the transcription of FLNB by EHF to promote immune evasion and progression of ccRCC., 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.)

Renal cell carcinoma (RCC) represents a significant portion of genitourinary cancers, marked by challenging prognosis and high metastasis rates. Immunotherapy has been applied in managing advanced renal cell carcinoma, but the therapeutic outcomes are unsatisfactory. In this study, we order to construct a Janus kinase/signal transduction and activator transcriptional (JAK/STAT)-related signature linked to kidney patient outcomes for better predicting the efficacy to immune checkpoint inhibitors (ICIs) and to provide guidance for effective combination therapy. We screened 25 differentially expressed genes (DEGs) that exhibited high expression in RCC samples and were enriched in the JAK-STAT signaling pathway. Among these genes, 11 key genes were identified and correlated with the expectation of Kidney Clear Cell Carcinoma (KIRC) patients and all these genes was significantly elevated in RCC tumor tissues and cancer cells compared to para-cancer tissues and normal renal cells. Utilizing these 11 genes, we divided RCC patients into high-risk and low-risk groups. We found a clear correlation between the clinicopathologic factors of KIRC patients and the JAK-STAT-related risk score. And the IHC results shown that the JAK3 and STAT4 expression of tumor was significantly higher than normal tissue in RCC patients, the level of JAK3 and STAT4 was positively related to the T stage of RCC patients. In addition, high-risk patients had a poorer prognosis and greater protumor immune cell infiltration, and benefitted less from immunotherapy than did low-risk patients. Furthermore, the JAK-STAT-related risk score can predict disease-free survival (DFS) in RCC patients according to the nomogram, which constructed in combination with other clinical features such as age, TNM-staging and stage. Our study demonstrated the JAK-STAT signaling pathway's important regulatory function in RCC tumor immunity. This insight not only enhances our ability to accurately predict the survival rate of RCC patients, but also underscores a potential therapeutic alternative for RCC, involving the combined targeting of the JAK-STAT pathway and immune checkpoints., 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.)

Background: The incidence of renal cell carcinoma (RCC) is already in the top ten of all types of cancers, with more than 4 %. Epigallocatechin gallate (EGCG), a polyphenolic compound extracted from green tea, has been shown to be effective in the treatment of various tumors. However, limited studies have demonstrated the effect of EGCG on RCC and its underlying molecular mechanisms., Methods: After exposure to gradient concentration (0,5,10,20,40,60,80,100 μM) of EGCG, the cell viability of RCC cells was determined by MTT assay. The migration and invasion abilities of RCC cells were investigated by wound healing and transwell assays. The expression levels of proteins involved in the epithelial-mesenchymal transition (EMT) and autophagy were explored by Western blotting assays. The formation of autophagosome was detected by electron microscope and LC3 puncta assays. Nude mouse xenograft model was used as the model system in vivo., Results: In the present study, EGCG significantly inhibited the migration, invasion and EMT of RCC cells in a concentrated manner. Further exploration of its mechanism indicated that autophagy is involved in EGCG-mediated metastasis inhibition and EMT inhibition of RCC cells. In addition, EGCG could significantly up-regulate the transcription factor EB (TFEB) and promotes its nuclear localization. The incorporation of TFEB into the nucleus enhanced the transcriptional levels of molecules associated with autophagy. TFEB knockdown inhibited EGCG-mediated autophagy activation, metastasis and EMT inhibition in RCC cells., Conclusions: In conclusion, these findings demonstrate for the first time that EGCG inhibits migration, invasion, and EMT of RCC by activating TFEB-mediated autophagy. Therefore, the combination of EGCG and TFFB activators or EMT inhibitors is expected to be a promising therapeutic strategy for RCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Rationale and Objectives: This study aimed to develop a diagnostic model based on clinical and CT features for identifying clear cell renal cell carcinoma (ccRCC) in small renal masses (SRMs)., Material and Methods: This retrospective multi-centre study enroled patients with pathologically confirmed SRMs. Data from three centres were used as training set (n = 229), with data from one centre serving as an independent test set (n = 81). Univariate and multivariate logistic regression analyses were utilised to screen independent risk factors for ccRCC and build the classification and regression tree (CART) diagnostic model. The area under the curve (AUC) was used to evaluate the performance of the model. To demonstrate the clinical utility of the model, three radiologists were asked to diagnose the SRMs in the test set based on professional experience and re-evaluated with the aid of the CART model., Results: There were 310 SRMs in 309 patients and 71% (220/310) were ccRCC. In the testing cohort, the AUC of the CART model was 0.90 (95% CI: 0.81, 0.97). For the radiologists' assessment, the AUC of the three radiologists based on the clinical experience were 0.78 (95% CI:0.66,0.89), 0.65 (95% CI:0.53,0.76), and 0.68 (95% CI:0.57,0.79). With the CART model support, the AUC of the three radiologists were 0.93 (95% CI:0.86,0.97), 0.87 (95% CI:0.78,0.95) and 0.87 (95% CI:0.78,0.95). Interobserver agreement was improved with the CART model aids (0.323 vs 0.654, P < 0.001)., Conclusion: The CART model can identify ccRCC with better diagnostic efficacy than that of experienced radiologists and improve diagnostic performance, potentially reducing the number of unnecessary biopsies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

The efficacy of conventional chemotherapies in treating clear cell renal cell carcinoma (ccRCC) is often limited due to its high molecular diversity, generally low response rates to standard treatments, and prevalent drug resistance. Recent advancements in the molecular understanding of ccRCC, alongside the discovery of novel therapeutic agents targeting specific proteins, have significantly altered the treatment landscape for ccRCC. Here, we synthesized 27 new compounds that are derivatives of TG-101209 to modulate BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B). BUB1B has been recently identified as a drug target for the development of effective ccRCC treatment based on global transcriptomics profiling of ccRCC tumours and gene co-expression network analysis. We characterized the molecular structures of these 27 compounds by 1 H and 13 C NMR and Mass spectrometry. We evaluated the effect of these 27 compounds by analysing the modulation of the BUB1B expression. Our primary objective was to design and assess the efficacy of these new compounds in reducing the viability of Caki-1 cells, a ccRCC cell line. We performed the computational docking studies by the Schrödinger Maestro software and demonstrated that three of these compounds (13a, 5i, and 5j) effectively downregulated BUB1B expression and eventually triggered necrosis and apoptosis in the Caki-1 cell line based on the structure-activity relationship (SAR) analysis. The IC50 values for compounds 13a, 5i, and 5j were calculated as 2.047 µM, 10.046 µM, and 6.985 µM, respectively, indicating their potent inhibitory effects on cell viability. Our study suggests that these compounds targeting BUB1B could offer a more effective and promising approach for ccRCC treatment compared to the conventionally used tyrosine kinase inhibitors. Our study underscores the potential of leveraging targeted therapies against specific molecular pathways in ccRCC may open new avenues for the development of effective treatment strategies against ccRCC., 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., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: Radiogenomics of clear cell renal cell carcinoma (ccRCC) has been developed thanks to the availability of genomic data, both gene expressions and gene mutations, obtained through the sequencing of ccRCC genome. These data are collected in the Cancer Genome Atlas (TCGA) Research Network-work. Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12) gene belongs to the family of genes coding for multidomain and multifunctional type I transmembrane proteins ADAMs. These proteins are fundamental for regulating cell adhesion and mediating proteolysis of a series of cell surface receptors and signal molecules extracellular domains. Recently, a correlation was detected between ADAM12 expression in ccRCC and tumor aggressiveness in terms of cell proliferation, migration, invasion, tumor progression, metastases, and poor prognosis, suggesting ADAM12 as a prognostic marker and therapeutic target in ccRCC. The computed tomography (CT) imaging phenotype of ADAM12 expression in ccRCC has never been studied. The aim of this study is to investigate the CT imaging phenotype of ADAM12 expression in ccRCC patients., Materials and Methods: In this retrospective study, we enrolled 202 ccRCC patients divided into two groups: ccRCC patients with ADAM12 expression (n = 35) and ccRCC patients without ADAM12 expression (n = 167). Different imaging features were evaluated on CT scan at first diagnosis. The statistical significance threshold was set at p < 0.05., Results: A statistically significant correlation was found with larger primary tumor size (p = 0.020), ill-defined tumor margins (p = 0.044), tumor necrosis (p = 0.011), and collecting system invasion (p = 0.014)., Conclusion: This study demonstrates CT imaging features associated to ADAM12 expression in ccRCC. These results could help delve into ADAM12 gene status through CT approach and to further investigate towards the development of targeted therapies in ccRCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: To establish a computed tomography (CT)-based radiomics model to predict Fork head box M1(FOXM1) expression levels and develop a combined model for prognostic prediction in patients with clear cell renal cell carcinoma (ccRCC)., Materials and Methods: A total of 529 patients were utilized to assess the prognostic significance of FOXM1 expression and were subsequently categorized into low and high FOXM1 expression groups. 184 patients with CT images were randomly divided into training and validation cohorts. Radiomics signature (Rad-score) for predicting FOXM1 expression level was developed in the training cohort. The predictive performance was evaluated using receiver operating characteristic (ROC) curves. A clinical model based on clinical factors and a combined model incorporating clinical factors and Rad-score were developed to predict ccRCC prognosis using Cox regression analyses. The concordance index(C-index) was employed to assess and compare the predictive capabilities of the Rad-score, TNM stage, clinical model, and combined model. The likelihood ratio test was used to compare the models' performance., Results: The Rad-score demonstrated high predictive accuracy for high FOXM1 expression with areas under the ROC curves of 0.713 and 0.711 in the training and validation cohorts. In the training cohort, the C-indexes for the Rad-score, TNM Stage, clinical model, and combined model were 0.657, 0.711, 0.737, and 0.741, respectively. Correspondingly, in the validation cohort, the C-indexes were 0.670, 0.712, 0.736, and 0.745. The combined model had the highest C-index, significantly outperforming the other models., Conclusion: The Rad-score accurately predicts FOXM1 expression levels and is an independent prognostic factor for ccRCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Abnormal alternative splicing (AS) caused by dysregulated expression of splicing factors plays a crucial role in tumorigenesis and progression. The serine/arginine-rich (SR) RNA-binding protein family is a major class of splicing factors regulating AS. However, their roles and mechanisms in renal cell carcinoma (RCC) development and progression are not fully understood. Here, we found that SR splicing factor 3 (SRSF3) was an important splicing factor affecting RCC progression. SRSF3 was downregulated in RCC tissues and its low level was associated with decreased overall survival time of RCC patients. SRSF3 overexpression suppressed RCC cell malignancy. Mechanistically, the binding of SRSF3 to SP4 exon 3 led to the inclusion of SP4 exon 3 and the increase of long SP4 isoform (L-SP4) level in RCC cells. L-SP4, but not S-SP4 overexpression suppressed RCC cell malignancy. Meanwhile, L-SP4 participated in SRSF3-mediated anti-proliferation by transcriptionally promoting SMAD4 expression. Taken together, our findings provide new insights into the anticancer mechanism of SRSF3, suggesting that SRSF3 may serve as a novel potential therapeutic target for RCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rationale and Objectives: To describe imaging and pathology features of newly defined papillary renal cell carcinoma (pRCC) based on the WHO 2022 update., Materials and Methods: This retrospective study included 87 patients with 93 pathologically proven papillary renal cell carcinomas who underwent pre-treatment renal mass protocol CT or MRI. Baseline and post-treatment follow-up imaging was evaluated by two radiologists systematically based on established lexicon., Results: At pathology, 63 (68%) were grade 1-2, 29 (31%) were grade 3-4, and 1 (%) was unreported. At surgical pathology, 84 (90%) were localized (≤pT2b), 5 (5%) were pT3a, and none were ≥pT3b; 4 (4%) had unknown pT stage (core biopsies). 33 (35%) had necrosis and 39 (41%) had hemorrhage. None had sarcomatoid or rhabdoid differentiation. At imaging, 73 (83%) were solid and 16 (17%) were cystic. Of 16 cystic masses, four were Bosniak class IIF (three were heterogeneously T1 hyperintense) and 12 were class IV. All were well-circumscribed. 92 (99%) were hypovascular. Median follow-up for 74 patients was 30 months (IQR 12-56). One untreated patient had non-regional nodal metastasis at presentation, and one patient had metastasis to lymph nodes and bones after surgery, but the patient had unresected renal masses elsewhere without pathology. Otherwise, no recurrence or metastases were detected., Conclusion: Most pRCCs present as a hypovascular, circumscribed, solid renal mass. A few pRCCs present as the newly defined Bosniak class IIF subtype. Our results can form the basis of a non-invasive, likelihood score to identify this relatively indolent pathology in the era of virtual biopsy and active surveillance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

The TFE3 fusion gene, byproduct of Xp11.2 translocation, is the diagnostic marker for translocation renal cell carcinoma (tRCC). Absence of any clinically recognized therapy for tRCC, pressing a need to create novel and efficient therapeutic approaches. Previous studies shown that stabilization of the G-quadruplex structure in oncogenes suppresses their expression machinery. To combat the oncogenesis caused by fusion genes, our objective is to locate and stabilize the G-quadruplex structure within the PRCC-TFE3 fusion gene. Using the Quadruplex-forming G Rich Sequences (QGRS) mapper and the Non-B DNA motif search tool (nBMST) online server, we found putative G-quadruplex forming sequences (PQS) in the PRCC-TFE3 fusion gene. Circular dichroism demonstrating a parallel G-quadruplex in the targeted sequence. Fluorescence and UV-vis spectroscopy results suggest that pyridostatin binds to this newly discovered G-quadruplex. The PCR stop assay, as well as transcriptional or translational inhibition using real time PCR and Dual luciferase assay, revealed that stable G-quadruplex formation affects biological processes. Confocal microscopy of HEK293T cells transfected with the fusion transcript confirmed G-quadruplexes formation in cell. This investigation may shed light on G-quadruplex's functions in fusion genes and may help in the development of therapies specifically targeted against fusion oncogenes, which would enhance the capability of current tRCC therapy approach., 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.)

Recently, mounting evidence has highlighted the essential function of the C-terminal binding protein-1 divergent transcript (CTBP1-DT) in malignancies. However, its role in kidney renal clear cell carcinoma (KIRC) remains largely unknown. Our study aimed to identify the potential function of CTBP1-DT in KIRC. RT-qPCR, Kaplan-Meier survival analysis, Cox regression analysis, and nomogram analysis were utilized to determine the expression and effects of CTBP1-DT on survival. The subcellular localization of CTBP1-DT was determined using RNA fluorescence in situ hybridization (FISH). To investigate the functions of CTBP1-DT in regulating KIRC cell proliferation, migration, invasion, lipid synthesis, and apoptosis, we conducted CCK8, EdU, Transwell, and Oil Red O staining and cell apoptosis staining assays. The relationships between CTBP1-DT and the tumor microenvironment were investigated with multiple bioinformatics analysis algorithms and databases, including CYBERSORT, TIMER2, Spearman correlation test, tumor mutation burden (TMB), microsatellite instability (MSI), and immunophenoscore (IPS). According to our results, CTBP1-DT is a lncRNA located in the nucleus that is significantly upregulated in KIRC and is correlated with better clinical outcomes. Downregulating CTBP1-DT inhibited cell viability, migration, invasion, and lipid synthesis but triggered cell apoptosis. Additionally, we explored the potential effect of CTBP1-DT in regulating immune cell infiltration in KIRC and other malignancies. Furthermore, CTBP1-DT could be used to predict the effectiveness of targeted drugs and immune checkpoint inhibitors. In conclusion, we identified CTBP1-DT as a potential immunological biomarker and discovered the potential role of CTBP1-DT in regulating lipid synthesis and apoptosis resistance., 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.)

Objectives: Adherent perinephric fat (APF) poses significant challenges to surgical procedures. This study aimed to evaluate the usefulness of machine learning algorithms combined with MRI-based radiomics features for predicting the presence of APF., Materials and Methods: Patients with renal cell carcinoma who underwent surgery between April 2019 and February 2022 at Chonnam National University Hwasun Hospital were retrospectively screened, and 119 patients included. Twenty-one and seventeen patients were set aside for the internal and external test sets, respectively. Pre-operative T1-weighted MRI acquired at 60 s following a contrast injection (T1w-60) were collected. For each T1w-60 data, two regions of interest (ROIs) were manually drawn: the perinephric fat tissue and an aorta segment on the same level as the targeted kidney. Preprocessing steps included resizing voxels, N4 Bias Correction filtering, and aorta-based normalization. For each patient, 851 radiomics features were extracted from the ROI of perinephric fat tissue. Gender and BMI were added as clinical factors. Least Absolute Shrinkage and Selection Operator was adopted for feature selection. We trained and evaluated five models using a 4-fold cross validation. The final model was chosen based on the highest mean AUC across four folds. The performance of the final model was evaluated on the internal and external test sets., Results: A total of 15 features were selected in the final set. The final model achieved the accuracy, sensitivity, specificity, and AUC of 81% (95% confidence interval, 61.9-95.2%), 72.7% (42.9-100%), 90% (66.7-100%), and 0.855 (0.615-1.0), respectively on the internal test set, and 88.2% (70.6-100%), 100% (100-100%), 80% (50%-100%), 0.971 (0.871-1.0), respectively on the external test set., Conclusions: Our study demonstrated the feasibility of machine learning algorithms trained with MRI-based radiomics features for APF prediction. Further studies with a multi-center approach are necessary to validate our findings., 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 cyclin-dependent kinase inhibitor 3 (CDKN3) gene, is over expressed in renal cell carcinoma (RCC). However, the cell biology functions of RCC are not well understood. The present study aimed to verify the ability of CDKN3 to promote the proliferation and migration of RCC through in vitro experiments. Subsequently, the clinical prognostic effects were analyzed using The Cancer Genome Atlas (TCGA; https://www.cancer.gov/) and Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/). The chelators, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), an analogue of the anti-tumor agent, were screened through bioinformatics analysis. The expression of CDKN3 is positively correlated with the IC 50 of Dp44mT. In two RCC cell lines, 786-0 and Caki-1, we conducted small interfering RNA (siRNA) knockdown of CDKN3 and overexpression of CDKN3 by transfection plasmid. Subsequently, we administered Dp44mT to examine the resulting alterations in cell proliferation, migration, and apoptosis, thereby elucidating the role of CDKN3 and Dp44mT in these processes. The results of the experiment revealed a positive association between CDKN3 expression and the proliferation of RCC cell lines. Down-regulating CDKN3 significantly increased the apoptosis rate and inhibited cell migration in 786-0 and Caki-1 cells. Furthermore, bioinformatics analysis revealed a high expression of CDKN3 in RCC and a negative association between CDKN3 expression and survival. Gene set enrichment analysis (GSEA) revealed a significant association between high CDKN3 expression and the cell cycle pathway. Furthermore, we identified Dp44mT as a drug highly correlated with CDKN3 through the database. Subsequent addition of Dp44mT resulted in similar findings to those observed upon CDKN3 knockdown. Our findings have important implications for the diagnosis and treatment of CDKN3 in RCC. Additionally, Dp44mT is likely to be a promising candidate for future clinical applications., 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.)

The main objective of this paper is to analyze the prognostic and immunological value of CDC45 in kidney renal clear cell carcinoma (KIRC) using single-cell and bulk RNA-sequencing approaches. The expression of CDC45 in KIRC was evaluated by the HPA database, the TCGA-KIRC dataset and verified by PCR analysis and single-cell RNA-sequencing. The ability of CDC45 to independently predict prognosis in KIRC was confirmed by univariate/multivariate regression analysis. Gene set enrichment analysis (GSEA) was employed to explore CDC45-related pathways in KIRC. In addition, Relationships between CDC45 and immunity were also examined. Elevated CDC45 expression in KIRC was demonstrated at mRNA and protein levels. The results of the correlation analysis showed that as CDC45 expression increased, so did the histological grade, clinical stage, and TNM stage of the patients (p < 0.05). Univariate/multivariate regression analysis suggested CDC45 as an independent prognostic factor for KIRC. Seven pathways related to CDC45 were screened through GSEA. Meanwhile, we found that CDC45 was correlated with tumor mutational burden (TMB) and microsatellite instability (MSI) but not tumor neoantigen burden (TNB). Regarding immunity, CDC45 exhibited correlations with the tumor microenvironment, immune cell infiltration, and immune checkpoints. Besides, low CDC45 expression was shown to be associated with a better response to immunotherapy. Single-cell RNA-sequencing revealed that CDC45 was differently expressed in T cells (p < 0.05). CDC45 showed potential as a prognostic biomarker and therapeutic target for KIRC. Meanwhile, the CDC45 low expression group was more sensitive to immunotherapy., (© 2023. The Author(s).)