[Chinese expert consensus on the systemic treatment of advanced clear cell renal cell carcinoma (2024 edition)].

Renal cell carcinoma (RCC) accounts for approximately 2% to 3% of malignant tumors in adults, with a male-to-female ratio of approximately 1.5∶1 worldwide. It can occur in all age groups, with a peak incidence in the 60-70 age range, and the median age is approximately 64 years. The current causes of kidney cancer are still unclear, but smoking, obesity, hypertension, and some genetic factors are considered risk factors for kidney cancer development. Conducive to the gradual popularization of physical examination and screening, more and more patients with kidney cancer are being detected and treated in the early stages. However, nearly 30% of patients still have locally advanced or metastatic kidney cancer at the time of initial diagnosis. Traditional chemotherapy drugs are generally ineffective for advanced RCC, and currently, advanced RCC is mainly treated with anti-vascular and immunotherapy. At present, first-line treatment is mostly stratified based on clinical characteristics such as International mRCC Database Consortium (IMDC) prognosis risk, and there are multiple options available, including anti vascular therapy, anti-vascular combined immunotherapy, and dual immunotherapy. Subsequently, first-line treatment often selects drugs based on the composition, effectiveness, and safety of first-line treatment plans. In recent years, research has found that the molecular typing and metastasis characteristics of RCC also affect the prognosis of patients, leading to many controversies in the treatment of advanced RCC. This consensus is guided by the controversial clinical issues in the management of advanced RCC. After discussion and voting by multidisciplinary clinical experts, a consensus of 10 clinical issues has been reached. At the same time, experts recommend domestic clinical and research institutions to lead or participate in more large-scale clinical trials, providing more basis for clinical decision-making and the selection of the best beneficiaries.

PRMT1 inhibition perturbs RNA metabolism and induces DNA damage in clear cell renal cell carcinoma.

In addition to the ubiquitous loss of the VHL gene in clear cell renal cell carcinoma (ccRCC), co-deletions of chromatin-regulating genes are common drivers of tumorigenesis, suggesting potential vulnerability to epigenetic manipulation. A library of chemical probes targeting a spectrum of epigenetic regulators is screened using a panel of ccRCC models. MS023, a type I protein arginine methyltransferase (PRMT) inhibitor, is identified as an antitumorigenic agent. Individual knockdowns indicate PRMT1 as the specific critical dependency for cancer growth. Further analyses demonstrate impairments to cell cycle and DNA damage repair pathways upon MS023 treatment or PRMT1 knockdown. PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development.

Sunitinib in Patients with Metastatic Renal Cell Carcinoma with Favorable Risk: Be Aware of PD-L1 Expression.

The treatment landscape for metastatic renal cell carcinoma (RCC) has advanced significantly with first-line immunotargeted therapy combinations. However, no statistically significant differences were observed in the cohort of patients with favorable risk and some oncologists continue to use sunitinib in these patients. PD-L1 expression has emerged as a negative prognostic factor in RCC, particularly in sunitinib-treated patients, where higher PD-L1 levels are linked to worse outcomes. This article discusses the potential risks associated with the use of sunitinib in PD-L1-positive patients.

Temporary treatment cessation compared with continuation of tyrosine kinase inhibitors for adults with renal cancer: the STAR non-inferiority RCT.

Background: There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. Trial design: A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma. Methods: Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals. Interventions: At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death. Objective: To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years. Co-primary outcomes: For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire. Results: Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years. Limitations: The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison. Future work: Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma. Conclusions: Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible. Trial registration: This trial is registered as ISRCTN06473203. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.

Treatment breaks in cancer are of significant interest to patients and health professionals. Renal cell carcinoma is the most common type of kidney cancer. Sunitinib and pazopanib are both targeted treatments. They were commonly used to treat advanced kidney cancer but often cause side effects, sometimes requiring use of a reduced dose or even stopping treatment. The STAR trial was designed to see whether planned treatment breaks made patients with advanced kidney cancer being treated with sunitinib and pazopanib feel better, without substantially affecting how well the treatment worked. After 24 weeks of treatment, patients took sunitinib and pazopanib either as they normally would or in the alternative way with planned treatment breaks. Treating patients in this way was continued until drug-related side effects stopped treatment, patients' disease worsened while taking treatment or the patient died. The trial compared how well the different treatment strategies worked in terms of how long patients lived and their quality of life over that time. This trial is the largest United Kingdom trial in advanced renal cell carcinoma. Patients took part from 60 United Kingdom centres between 2012 and 2017. It was funded by the National Institute for Health and Care Research Health Technology Assessment Programme and run by the Leeds Clinical Trials Research Unit. In total, 920 patients took part. Four hundred and sixty-one patients were allocated to continue treatment and 459 were allocated to start at least one treatment break. Treatment breaks lasted on average 87 days. The length of time patients lived in both arms of the trial appeared similar, but this cannot be concluded due to insufficient information. Being allocated to have treatment breaks rather than continuing treatment did not negatively impact a patient's quality of life. Additionally, allocating patients to have treatment breaks was shown to have significant cost savings compared to just continuing treatment. Importantly planned treatment breaks were shown to be feasible.

RCC-Supporter: supporting renal cell carcinoma treatment decision-making using machine learning.

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.

Lenvatinib plus pembrolizumab for untreated advanced renal cell carcinoma: a systematic review and cost-effectiveness analysis.

Background: Renal cell carcinoma is the most common type of kidney cancer, comprising approximately 85% of all renal malignancies. Patients with advanced renal cell carcinoma are the focus of this National Institute for Health and Care Excellence multiple technology appraisal. A patient's risk of disease progression depends on a number of prognostic risk factors; patients are categorised as having intermediate/poor risk or favourable risk of disease progression. Objectives: The objectives of this multiple technology appraisal were to appraise the clinical effectiveness and cost-effectiveness of lenvatinib plus pembrolizumab versus relevant comparators listed in the final scope issued by the National Institute for Health and Care Excellence: sunitinib, pazopanib, tivozanib, cabozantinib and nivolumab plus ipilimumab. Methods: The assessment group carried out clinical and economic systematic reviews and assessed the clinical and cost-effectiveness evidence submitted by Eisai, Hatfield, Hertfordshire, UK (the manufacturer of lenvatinib) and Merck Sharp & Dohme, Whitehouse Station, NJ, USA (the manufacturer of pembrolizumab). The assessment group carried out fixed-effects network meta-analyses using a Bayesian framework to generate evidence for clinical effectiveness. As convergence issues occurred due to sparse data, random-effects network meta-analysis results were unusable. The assessment group did not develop a de novo economic model, but instead modified the partitioned survival model provided by Merck Sharp & Dohme. Results: The assessment group clinical systematic review identified one relevant randomised controlled trial (CLEAR trial). The CLEAR trial is a good-quality, phase III, multicentre, open-label trial that provided evidence for the efficacy and safety of lenvatinib plus pembrolizumab compared with sunitinib. The assessment group progression-free survival network meta-analysis results for all three risk groups should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons owing to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. The assessment group overall survival network meta-analysis results for the intermediate-/poor-risk subgroup suggested that there was a numerical, but not statistically significant, improvement in the overall survival for patients treated with lenvatinib plus pembrolizumab compared with patients treated with cabozantinib or nivolumab plus ipilimumab. Because of within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption, the assessment group overall survival network meta-analysis results for the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons. Only one cost-effectiveness study was included in the assessment group review of cost-effectiveness evidence. The study was limited to the all-risk population, undertaken from the perspective of the US healthcare system and included comparators that are not recommended by the National Institute for Health and Care Excellence for patients with untreated advanced renal cell carcinoma. Therefore, the extent to which resource use and results are generalisable to the NHS is unclear. The assessment group cost-effectiveness results from the modified partitioned survival model focused on the intermediate-/poor-risk and favourable-risk subgroups. The assessment group cost-effectiveness results, generated using list prices for all drugs, showed that, for all comparisons in the favourable-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated fewer benefits than all other treatments available to NHS patients. For the intermediate-/poor-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated more benefits than treatment with cabozantinib and nivolumab plus ipilimumab. Conclusions: Good-quality clinical effectiveness evidence for the comparison of lenvatinib plus pembrolizumab with sunitinib is available from the CLEAR trial. For most of the assessment group Bayesian hazard ratio network meta-analysis comparisons, it is difficult to reach conclusions due to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. However, the data (clinical effectiveness and cost-effectiveness) used to populate the economic model are relevant to NHS clinical practice and can be used to inform National Institute for Health and Care Excellence decision-making. The assessment group cost-effectiveness results, generated using list prices for all drugs, show that lenvatinib plus pembrolizumab is less cost-effective than all other treatment options. Study registration: This study is registered as PROSPERO CRD4202128587. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR134985) and is published in full in Health Technology Assessment; Vol. 28, No. 49. See the NIHR Funding and Awards website for further award information.

Renal cell carcinoma is the most common type of kidney cancer. Several drug treatment options are available for NHS patients with advanced or metastatic disease, and the choice of treatment varies depending on a patient's risk of disease progression. A new drug combination, lenvatinib plus pembrolizumab, may soon become available to treat NHS patients. This review explored whether treatment with lenvatinib plus pembrolizumab offered value for money to the NHS. We reviewed the effectiveness of treatment with lenvatinib plus pembrolizumab versus other NHS treatment options. We also estimated the costs and benefits of treatment with lenvatinib plus pembrolizumab versus current NHS treatments for patients with higher and lower risks of disease progression. Compared with current NHS treatments, treatment with lenvatinib plus pembrolizumab may increase the time that people with a higher risk of disease progression (i.e. worsening disease) were alive. However, for patients with a lower risk of disease progression, the available evidence is limited and only shows that treatment with lenvatinib plus pembrolizumab may prolong the time that patients have a stable level of disease. For all patients, compared to all current NHS treatments, treatment with lenvatinib plus pembrolizumab is very expensive. Compared with current NHS treatments for untreated renal cell carcinoma, using published prices (which do not include any discounts that are offered to the NHS), treatment with lenvatinib plus pembrolizumab may not provide good value for money to the NHS.

New staging criteria predicting m-tor inhibitors treatment effect of renal angiomyolipoma in tuberous sclerosis complex patients.

BACKGROUND: We aimed to launched new staging criteria to predict mTOR inhibitors treatment effect of renal angiomyolipomas (r-AMLs) in TSC patients. METHODS: 40 TSC patients with 69 r-AMLs were divided into two groups based on the efficacy of 6-month mTOR inhibitor treatment. Epidemiological data, therapeutic response, and predictive factors of enrolled patients were collected and analyzed. Age, sex, maximum diameter, maximum cross-sectional area (CSAmax), unenhanced mean CT value, enhanced mean CT value, and added value of enhanced CT of largest r-AML at baseline were assessed as potential influencing factors. Receiver operating characteristic (ROC) curve analysis and the area under the ROC curve (AUC) was used to estimate prediction power. RESULTS: After 6 months of mTOR inhibitor treatment, the tumor reduction rates in the two groups were 55.87% and 16.44% (P < 0.001). At the start of treatment, the maximum diameters, CSAmax, added value of enhanced CT of the target lesion in two groups were 7.70 ± 0.73 cm vs. 13.18 ± 1.23 cm(P = 0.028), 57.40 ± 10.76cm2 vs. 167.29 ± 33.09cm2 (P = 0.015), and 62.32 ± 5.03HU vs. 33.06 ± 3.13HU (P = 0.009), respectively. AUCs of CSAmax, added value of enhanced CT, and combination of both were 0.8024, 0.7672, and 0.8116, respectively (P < 0.001). Cut-off values of CSAmax combined with the added value of enhanced CT were 40cm2 and 46HU. AUCs of maximum diameters, combination of maximum diameters and added value of enhanced CT were 0.7600 and 0.8100, respectively (P < 0.001), with cut-off values of 6.6 cm and 46 HU. CONCLUSION: New staging criteria, based on CSAmax and added value of enhanced CT, can predict the treatment efficiency of m-TOR inhibitors for r-AMLs in TSC patients. A simplified version based on maximum diameter and added value of enhanced CT of lesion has also been proposed.

In Silico Exploration of AHR-HIF Pathway Interplay: Implications for Therapeutic Targeting in ccRCC.

The oxygen-sensing pathway is a crucial regulatory circuit that defines cellular conditions and is extensively exploited in cancer development. Pathogenic mutations in the von Hippel-Lindau (VHL) tumour suppressor impair its role as a master regulator of hypoxia-inducible factors (HIFs), leading to constitutive HIF activation and uncontrolled angiogenesis, increasing the risk of developing clear cell renal cell carcinoma (ccRCC). HIF hyperactivation can sequester HIF-1ß, preventing the aryl hydrocarbon receptor (AHR) from correctly activating gene expression in response to endogenous and exogenous ligands such as TCDD (dioxins). In this study, we used protein-protein interaction networks and gene expression profiling to characterize the impact of VHL loss on AHR activity. Our findings reveal specific expression patterns of AHR interactors following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in ccRCC. We identified several AHR interactors significantly associated with poor survival rates in ccRCC patients. Notably, the upregulation of the androgen receptor (AR) and retinoblastoma-associated protein (RB1) by TCDD, coupled with their respective downregulation in ccRCC and association with poor survival rates, suggests novel therapeutic targets. The strategic activation of the AHR via selective AHR modulators (SAhRMs) could stimulate its anticancer activity, specifically targeting RB1 and AR to reduce cell cycle progression and metastasis formation in ccRCC. Our study provides comprehensive insights into the complex interplay between the AHR and HIF pathways in ccRCC pathogenesis, offering novel strategies for targeted therapeutic interventions.

Comprehensive analysis of the potential biological significance of CCL5 in pan-cancer prognosis and immunotherapy.

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.

The efficacy of second-line tyrosine kinase inhibitor for patients with metastatic non-clear cell renal cell carcinoma following first-line immune-oncology combination therapy.

PURPOSE: Metastatic non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous disease with a poor prognosis and is treated with immunotherapy (IO)-based combinations according to the clear cell renal cell carcinoma. Tyrosine-kinase inhibitors (TKIs), such as cabozantinib and axitinib, are commonly used as the 2nd line therapy after 1st line IO combination therapy, but their efficacy as 2nd line TKI therapy for nccRCC is unknown. In this study, we performed a retrospective multicenter analysis of nccRCC patients who were previously treated with IO combination therapy and received 2nd line TKIs. METHODS: Among 254 patients enrolled in the Japanese multicenter retrospective study, 52 patients with nccRCC histology who received second-line TKIs were included in this study. Progression-free survival and overall survival (OS) from 2nd line TKIs were analyzed by log-rank test and Cox-proportional hazard model. Objective response rate (ORR) of 2nd line TKIs were analyzed. RESULTS: The 1-year PFS and OS rates were 25.0% (95% CI = 13.1-36.8) and 63.8% (95% CI, 48.0-75.9), respectively. No patients had a complete response, 11 had a partial response, and 18 had stable disease. ORR was 21.1%. IMDC poor risk and sunitinib as the 2nd line therapy were significantly associated with poor PFS. CONCLUSION: The 2nd-line TKI was effective for a small group of nccRCC patients previously treated with IO combination therapy, although this study was retrospectively analyzed with a small number of cases.

Turning the tide: pembrolizumab's triumph in adjuvant RCC therapy.

In recent years, kidney cancer has shown an increased worldwide incidence of more than 400 000 novel cases annually. Although more than half of patients are diagnosed at a localised stage, this disease presents a high-risk of relapse after surgery. Thus, there is a need for adjuvant therapy post-resection to reduce cancer recurrence and prolong disease-free and overall survival. Thorough investigation of adjuvant drugs for renal cell carcinoma (RCC) has shown little promise in the last fifty years, with no recorded overall survival benefits. This was the case until pembrolizumab, an immune checkpoint inhibitor, was introduced into the adjuvant RCC space through the KEYNOTE-564 trial. The adjuvant administration of this novel anti-PD-1 drug demonstrated a significant overall survival benefit which has led to an update in the current treatment guidelines of RCC. This substantial change in the standard of care also caused an investigation of possible treatment combinations and an adoption of innovative predictive biomarkers. In this review, we will present the evolution of past adjuvant ICI trials for the treatment of RCC, the implications of pembrolizumab's overall survival benefits and a discussion of future directions concerning new RCC drug trials and liquid biopsy-based biomarkers.

Letter to the editor regarding the paper by A. Boileve et al.: Safety of direct oral anticoagulants in patients with advanced solid tumors receiving anti­VEGF agents: a retrospective study.

Concomitant direct oral anticoagulants (DOACs) and tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (anti-VEGF TKI) have been associated with a higher risk of bleeding. Nevertheless, concomitant administration seems frequent in clinical practice in patients with cancer-associated thrombosis and appears to be safe according to the retrospective study by Boileve A. et al. But the risk of an additional pharmacokinetic interaction between anti-VEGF TKI and DOACs must be considered, in case of P-glycoprotein (P-gp) inhibition by the TKI. We describe a case report with a major bleeding event in a renal metastatic cancer patient treated with cabozantinib and rivaroxaban. This case highlights the difficult therapeutic decision in a complex patient with cancer-associated thrombosis, who refused the anticoagulant subcutaneous route. Accumulation of bleeding risk factors (genito-urinary tumor localization) was additive to several pharmacodynamic interactions (acetylsalicylic acid, venlafaxine) and a potential pharmacokinetic interaction between cabozantinib and rivaroxaban. Indeed, cabozantinib-related P-glycoprotein inhibition could have led to a supratherapeutic level of rivaroxaban, contributing partly to the bleeding event. Before combining an anti-VEGF TKI and DOACs, a multidisciplinary pretherapeutic assessment seems crucial to evaluate the patient's bleeding risk factors, pharmacodynamic interactions, and the risk of pharmacokinetic interactions mediated by P-gp.

Can Cytoreductive Nephrectomy Improve Outcomes of Nivolumab Treatment in Patients with Metastatic Clear-Cell Renal Carcinoma?

Background: This study aimed to investigate the effect of cytoreductive nephrectomy (CN) on the survival outcomes of nivolumab used as a subsequent therapy after the failure of at least one anti-vascular endothelial growth factor (VEGF) agent in patients with metastatic clear-cell renal-cell carcinoma (ccRCC). Methods: We included 106 de novo metastatic ccRCC patients who received nivolumab after progression on at least one anti-VEGF agent. Multivariate Cox regression analysis was performed to investigate the factors affecting survival in patients receiving nivolumab. Results: Of the 106 de novo metastatic ccRCC patients, 83 (78.3%) underwent CN. There were no statistical differences between the two groups in terms of age, gender, Eastern Cooperative Oncology Group (ECOG) score, tumor size, International Metastatic RCC Database Consortium (IMDC) risk group, number of previous treatment lines, first-line anti-VEGF therapy, or metastasis sites (p = 0.137, p = 0.608, p = 0.100, p = 0.376, p = 0.185, p = 0.776, p = 0.350, and p = 0.608, respectively). The patients who received nivolumab with CN had a longer time to treatment discontinuation (TTD) [14.5 months, 95% confidence interval (CI): 8.6-20.3] than did those without CN 6.7 months (95% CI: 3.9-9.5) (p = 0.001). The median overall survival (OS) was 22.7 months (95% CI: 16.1-29.4). The patients with CN had a median OS of 22.9 months (95% CI: 16.3-29.4), while those without CN had a median OS of 8.1 months (95% CI: 5.6-10.5) (p = 0.104). In the multivariate analysis, CN [hazard ratio (HR): 0.521; 95% CI: 0.297-0.916; p = 0.024] and the IMDC risk score (p = 0.011) were statistically significant factors affecting TTD; however, the IMDC risk score (p = 0.006) was the only significant factor for overall survival. Conclusions: Our study showed that the TTD of nivolumab was longer in metastatic ccRCC patients who underwent cytoreductive nephrectomy.

HECTD2 as a target for veratric acid in the regulation of ferroptosis in renal cell carcinoma.

Function of HECTD2 in renal cell carcinoma malignant progression is undefined. Molecular mechanism behind anti-cancer effects of veratric acid (VA) from traditional Chinese medicine (TCM) is underexplored. The Cancer Genome Atlas was leveraged to study HECTD2 expression in renal cell carcinoma and its relationship with histological grading. Kaplan-Meier survival analysis was performed. HECTD2 expression was detected in cancer cells and tissues via qRT-PCR and immunohistochemistry. GPX4 and SLC7A11 expression in tumor samples with high or low HECTD2 expression was examined by immunohistochemistry, cell viability by CCK8, cell proliferation by colony formation assay, lipid ROS and mitochondrial superoxide levels by flow cytometry, Fe2+ and MDA content by assay kits, and GPX4 and SLC7A11 proteins by western blot. SeeSAR software screened TCM small molecule compounds with highest affinity to HECTD2, confirmed with cellular thermal shift assay. VA IC50 was measured by CCK8. Xenograft model was developed and treated with VA. Tumor size and weight were monitored, with immunohistochemistry to detect HECTD2 expression in tumors and assess ferroptosis-related markers. HECTD2 was overexpressed in tumor tissues and cells, which positively correlated with histological grading. HECTD2 depletion inhibited cell vitality and proliferation, raised intracellular lipid ROS, mitochondrial superoxide, Fe2+, and MDA. HECTD2 was a target with highest VA affinity. In vitro and vivo experiments concurred that VA treatment hindered malignancy of renal cell carcinoma and enhanced its susceptibility to ferroptosis. HECTD2 supports ferroptosis resistance in renal cell carcinoma, but VA, through its targeting of HECTD2, initiates ferroptosis, showcasing its anti-cancer efficacy.

pH-Responsive Block Copolymer Micelles of Temsirolimus: Preparation, Characterization and Antitumor Activity Evaluation.

Purpose: Renal cell carcinoma (RCC) is the most common and lethal type of urogenital cancer, with one-third of new cases presenting as metastatic RCC (mRCC), which, being the seventh most common cancer in men and the ninth in women, poses a significant challenge. For patients with poor prognosis, temsirolimus (TEM) has been approved for first-line therapy, possessing pharmacodynamic activities that block cancer cell growth and inhibit proliferation-associated proteins. However, TEM suffers from poor water solubility, low bioavailability, and systemic side effects. This study aims to develop a novel drug formulation for the treatment of RCC. Methods: In this study, amphiphilic block copolymer (poly(ethylene glycol) monomethyl ether-poly(beta-amino ester)) (mPEG-PBAE) was utilized as a drug delivery vehicle and TEM-loaded micelles were prepared by thin-film hydration method by loading TEM inside the nanoparticles. Then, the molecular weight of mPEG-PBAE was controlled to make it realize hydrophobic-hydrophilic transition in the corresponding pH range thereby constructing pH-responsive TEM-loaded micelles. Characterization of pH-responsive TEM-loaded nanomicelles particle size, potential and micromorphology while its determination of drug-loading properties, in vitro release properties. Finally, pharmacodynamics and hepatorenal toxicity were further evaluated. Results: TEM loading in mPEG-PBAE increased the solubility of TEM in water from 2.6 µg/mL to more than 5 mg/mL. The pH-responsive TEM-loaded nanomicelles were in the form of spheres or spheroidal shapes with an average particle size of 43.83 nm and a Zeta potential of 1.79 mV. The entrapment efficiency (EE) of pH-responsive TEM nanomicelles with 12.5% drug loading reached 95.27%. Under the environment of pH 6.7, the TEM was released rapidly within 12 h, and the release rate could reach 73.12% with significant pH-dependent characteristics. In vitro experiments showed that mPEG-PBAE preparation of TEM-loaded micelles had non-hemolytic properties and had significant inhibitory effects on cancer cells. In vivo experiments demonstrated that pH-responsive TEM-loaded micelles had excellent antitumor effects with significantly reduced liver and kidney toxicity. Conclusion: In conclusion, we successfully prepared pH-responsive TEM-loaded micelles. The results showed that pH-responsive TEM-loaded micelles can achieve passive tumor targeting of TEM, and take advantage of the acidic conditions in tumor tissues to achieve rapid drug release.

Screening of differential gene expression patterns through survival analysis for diagnosis, prognosis and therapies of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer. Although there is increasing evidence linking ccRCC to genetic alterations, the exact molecular mechanism behind this relationship is not yet completely known to the researchers. Though drug therapies are the best choice after the metastasis, unfortunately, the majority of the patients progressively develop resistance against the therapeutic drugs after receiving it for almost 2 years. In this case, multi-targeted different variants of therapeutic drugs are essential for effective treatment against ccRCC. To understand molecular mechanisms of ccRCC development and progression, and explore multi-targeted different variants of therapeutic drugs, it is essential to identify ccRCC-causing key genes (KGs). In order to obtain ccRCC-causing KGs, at first, we detected 133 common differentially expressed genes (cDEGs) between ccRCC and control samples based on nine (9) microarray gene-expression datasets with NCBI accession IDs GSE16441, GSE53757, GSE66270, GSE66272, GSE16449, GSE76351, GSE66271, GSE71963, and GSE36895. Then, we filtered these cDEGs through survival analysis with the independent TCGA and GTEx database and obtained 54 scDEGs having significant prognostic power. Next, we used protein-protein interaction (PPI) network analysis with the reduced set of 54 scDEGs to identify ccRCC-causing top-ranked eight KGs (PLG, ENO2, ALDOB, UMOD, ALDH6A1, SLC12A3, SLC12A1, SERPINA5). The pan-cancer analysis with KGs based on TCGA database showed the significant association with different subtypes of kidney cancers including ccRCC. The gene regulatory network (GRN) analysis revealed some crucial transcriptional and post-transcriptional regulators of KGs. The scDEGs-set enrichment analysis significantly identified some crucial ccRCC-causing molecular functions, biological processes, cellular components, and pathways that are linked to the KGs. The results of DNA methylation study indicated the hypomethylation and hyper-methylation of KGs, which may lead the development of ccRCC. The immune infiltrating cell types (CD8+ T and CD4+ T cell, B cell, neutrophil, dendritic cell and macrophage) analysis with KGs indicated their significant association in ccRCC, where KGs are positively correlated with CD4+ T cells, but negatively correlated with the majority of other immune cells, which is supported by the literature review also. Then we detected 10 repurposable drug molecules (Irinotecan, Imatinib, Telaglenastat, Olaparib, RG-4733, Sorafenib, Sitravatinib, Cabozantinib, Abemaciclib, and Dovitinib.) by molecular docking with KGs-mediated receptor proteins. Their ADME/T analysis and cross-validation with the independent receptors, also supported their potent against ccRCC. Therefore, these outputs might be useful inputs/resources to the wet-lab researchers and clinicians for considering an effective treatment strategy against ccRCC.

Adjuvant therapy in renal cell carcinoma: Tyrosine kinase inhibitor versus immune checkpoint inhibitor.

BACKGROUND: To date, no meta-analysis has been conducted to compare the effectiveness and safety of adjuvant tyrosine kinase inhibitors (TKIs) and adjuvant immunotherapies (IMTs) in renal cell carcinoma (RCC) patients using reconstructed individual patient data (IPD). This study aims to fill that gap by assessing the efficacy and safety profiles of these treatments in such patients. METHODS: This study employed a systematic approach for identifying relevant literature from the PubMed and EMBASE databases. We included articles published in English from the inception of these databases until November 11, 2023, focusing specifically on appropriate phase III randomized controlled trials (RCTs). To reconstruct survival curves, we utilized a semiautomated tool, WebPlotDigitizer, in conjunction with a novel shiny application integrated with R software. For adverse events (AEs), the summary measures were incidences, expressed as a 95% confidence interval (CI), calculated using a random-effects model with a logit transformation. RESULTS: The analysis included 8 RCTs with a total of 9119 patients. Compared to adjuvant TKIs, adjuvant IMTs showed a similar disease-free survival (DFS) (hazard ratio [HR] 1.03, 95% CI [0.98-1.09], P = .281). However, the overall survival (OS) rates between the 2 groups couldn't be directly compared due to unmatched control groups in the IMT and TKI studies. Against placebo, adjuvant IMTs demonstrated superior DFS (HR 0.82, 95% CI [0.71-0.94], P = .004) but comparable OS (HR 0.79, 95% CI [0.59-1.06], P = .120). Against placebo, adjuvant TKIs showed superior DFS (HR 0.85, 95% CI [0.79-0.92], P < .0001) and marginally better OS (HR 0.89, 95% CI [0.80-0.996], P = .042). Regarding severe AEs and discontinuation rates due to AEs, adjuvant IMTs had a significantly lower incidence of severe AEs (25% [320/1282] vs 59% [2192/3716], odds ratio [OR] 0.23, 95% CI [0.20-0.27], P < .0001) and a markedly better discontinuation rate (39% [499/1282] vs 52% [2068/4018], OR 0.60, 95% CI [0.53-0.68], P < .0001) compared to TKIs. CONCLUSION: This paper presents a thorough analysis of DFS, OS, and treatment-related AEs across various groups in RCC patients, offering a valuable resource for clinicians in everyday practice. Our findings indicate that while adjuvant IMTs and adjuvant TKIs demonstrate similar DFS, IMTs are notably superior in terms of safety and compliance.

Effect of isavuconazole on the pharmacokinetics of sunitinib and its mechanism.

BACKGROUND: Sunitinib, a newly developed multi-targeted tyrosine kinase inhibitor (TKI), has become a common therapeutic option for managing advanced renal cell carcinoma (RCC). Examining the mechanism underlying the interaction between sunitinib and isavuconazole was the aim of this effort. METHODS: The concentrations of sunitinib and its primary metabolite, N-desethyl sunitinib, were analyzed and quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Our study evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models. For the in vivo study, two groups (n = 5) of Sprague-Dawley (SD) rats were randomly allocated to receive sunitinib either with or without co-administration of isavuconazole. Additionally, the effects of isavuconazole on the metabolic stability of sunitinib and N-desethyl sunitinib were studied in RLM in vitro. RESULTS: Our findings demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC50 (half maximal inhibitory concentration) value of 1.33 µM. Meanwhile, in HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC50 of 5.30 µM. In vivo studies showed that the presence of isavuconazole significantly increased the pharmacokinetic characteristics of sunitinib, with the AUC(0→t), AUC(0→∞), and Tmax rising to approximately 211.38%, 203.92%, and 288.89%, respectively, in contrast to the control group (5 mg/kg sunitinib alone). The pharmacokinetic characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib. CONCLUSIONS: Isavuconazole had a major impact on sunitinib metabolism, providing fundamental information for the precise therapeutic administration of sunitinib.

Pathological Response and Outcomes in Patients With Metastatic Renal Cell Carcinoma (mRCC) Receiving Immunotherapy-Based Therapies and Undergoing Deferred Cytoreductive Nephrectomy (CN).

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.