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Scientific Reports Mar 2024To provide evidence for optimization of multi-kinase inhibitors (MKIs) use in the clinic, we use the public database to describe and evaluate electrolyte disorders (EDs)... (Observational Study)
Observational Study
To provide evidence for optimization of multi-kinase inhibitors (MKIs) use in the clinic, we use the public database to describe and evaluate electrolyte disorders (EDs) related to various MKIs treated for renal cell carcinoma. We analyzed spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS) in an observational and retrospective manner. Selecting electrolyte disorders' adverse events to multikinase inhibitors (axitinib, cabozantinib, lenvatinib, pazopanib, sunitinib, and sorafenib). We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms to analyze suspected adverse reactions of electrolyte disorders induced by MKIs (which were treated for renal cell carcinoma) between January 2004 and December 2022. As of December 2022, 2772 MKIs (which were treated for renal cell carcinoma) ICSRs were related to electrolyte disorders AEs. In general, there were more AEs cases in males, except lenvatinib and 71.8% of the cases were submitted from North America. ICSRs in this study, the age group most frequently affected by electrolyte disorders AEs was individuals aged 45-64 years for axitinib, cabozantinib, pazopanib, and sunitinib, whereas electrolyte disorders AEs were more common in older patients (65-74 years) for sorafenib and lenvatinib. For all EDs documented in ICSRs (excluding missing data), the most common adverse outcome was hospitalization(1429/2674, 53.4%), and the most serious outcome was death/life-threat(281/2674, 10.5%). The prevalence of mortality was highest for sunitinib-related EDs (145/616, 23.5%), excluding missing data (n = 68), followed by cabozantinib-related EDs (20/237, 8.4%), excluding missing data (n = 1). The distribution of time-to-onset of Each drug-related ICSRs was not all the same, and the difference was statistically significant (P = 0.001). With the criteria of ROR, the six MKIs were all significantly associated with electrolyte disorders AEs, the strongest association was the association between cabozantinib and hypermagnesaemia. MKIs have been reported to have significant electrolyte disorders AEs. Patients and physicians need to recognize and monitor these potentially fatal adverse events.
Topics: Aged; Humans; Male; Anilides; Axitinib; Bayes Theorem; Carcinoma, Renal Cell; Electrolytes; Indazoles; Kidney Neoplasms; Pharmacovigilance; Phenylurea Compounds; Pyridines; Pyrimidines; Quinolines; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; United States; United States Food and Drug Administration; Female; Middle Aged
PubMed: 38454105
DOI: 10.1038/s41598-024-56335-4 -
IJU Case Reports Mar 2024Patients with translocation renal cell carcinoma (tRCC) have a poor prognosis without standardized treatment.
INTRODUCTION
Patients with translocation renal cell carcinoma (tRCC) have a poor prognosis without standardized treatment.
CASE PRESENTATION
The first case was of a 72-year-old woman who underwent robot-assisted partial nephrectomy for a left renal tumor and was pathologically diagnosed with tRCC. Recurrence was observed in the left retroperitoneal soft tissue. After treatment with avelumab-axitinib, continued progression-free survival was confirmed at the 90-week follow-up. The second case was of a 41-year-old woman referred to our hospital and presented with translocation renal cell carcinoma metastasis to a para-aortic lymph node. After treatment with avelumab-axitinib, continued progression-free survival was confirmed at the 43-week follow-up.
CONCLUSION
The outcomes of these cases indicate that avelumab-axitinib therapy has a long-term antitumor effect in some patients with tRCC.
PubMed: 38440705
DOI: 10.1002/iju5.12685 -
IJU Case Reports Mar 2024Combination therapies of immune checkpoint and tyrosine kinase inhibitors for end-stage kidney disease and patients on hemodialysis need careful consideration as few...
INTRODUCTION
Combination therapies of immune checkpoint and tyrosine kinase inhibitors for end-stage kidney disease and patients on hemodialysis need careful consideration as few case reports provide suitable management decisions.
CASE PRESENTATION
A 70-year-old man who had undergone hemodialysis for 6 years due to nephrosclerosis. Avelumab plus axitinib combination therapy was performed for repeated lung metastasis, and a complete response was achieved without major side effects.
CONCLUSION
A complete response was achieved after Ave plus Axi combination therapy for clear cell renal cell carcinoma in a patient undergoing dialysis. This suggests that Ave plus Axi combination therapy may be safe and effective for dialysis patients.
PubMed: 38440696
DOI: 10.1002/iju5.12689 -
Translational Cancer Research Jan 2024Epigenetic alterations driven by chromatin regulators (CRs) are well-recognized cancer hallmarks. Growing evidence suggests that the imbalance of CRs may lead to the...
BACKGROUND
Epigenetic alterations driven by chromatin regulators (CRs) are well-recognized cancer hallmarks. Growing evidence suggests that the imbalance of CRs may lead to the occurrence of various diseases including tumors. However, the role and prognostic value of CRs in clear cell renal cell carcinoma (ccRCC) remain undefined.
METHODS
Consensus clustering analysis was used to identify different subtypes. Univariate and multivariate Cox regression analysis were performed to identify prognosis-related CRs and constructed a risk model. Transcriptome sequencing was used to verify gene expression levels. Kaplan-Meier survival analysis was used to compare overall survival (OS) between high- and low-risk groups. The area under the curve (AUC) value of the receiver operating characteristic (ROC) curve was used to evaluate the performance of the model. The ESTIMATE algorithm and single-sample gene set enrichment analysis (ssGSEA) were executed to evaluate the immune characteristics of samples. Correlation analysis was used to assess the relationship between risk score and immune checkpoint genes, the relationship between expression levels of CRs and immune cell infiltration and drug therapeutic response. Finally, we also compared differences in drug sensitivity between low- and high-risk groups.
RESULTS
We identified three CRs-related subtypes with different characteristics. A prognostic model was built with four CRs and can precisely predict the OS of patients in different risk groups. The model has good stability and applicability and was further verified in the internal and external dataset. The transcriptomic levels of the four CRs were also validated, and the risk score was an independent prognostic factor for ccRCC. Obvious differences in the immune microenvironment and the expression levels of immune checkpoints were observed in low- and high-risk group. Higher immune activity and immune cell infiltration were found in the high-risk group. Besides, the expression levels of CRs were associated with drug therapeutic response. Patients with high-risk score may be more sensitive to gemcitabine, vinblastine, paclitaxel, axitinib, sunitinib, and temsirolimus.
CONCLUSIONS
CRs were strongly associated with the occurrence and development of ccRCC. Targeting CRs may become a new therapeutic strategy for ccRCC. Besides, CRs-related gene signature can predict the prognosis and therapeutic significance of ccRCC, which provides an important reference for clinical decision-making.
PubMed: 38410230
DOI: 10.21037/tcr-23-1383 -
Frontiers in Immunology 2024Although immune checkpoint inhibitors (ICIs) show a significant overall survival advantage over standard advanced renal cell carcinoma (aRCC) therapies, tumor response... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although immune checkpoint inhibitors (ICIs) show a significant overall survival advantage over standard advanced renal cell carcinoma (aRCC) therapies, tumor response to these agents remains poor. Some studies have shown that combination therapy including an ICI appears to be the best treatment; however, the overall benefit in terms of efficacy and toxicity still needs to be assessed. Thus, we performed a network meta-analysis to evaluate the differences in the efficacy of several combinations that include an ICI to provide a basis for clinical treatment selection.
METHODS
We conducted a thorough search of PubMed, EMBASE, and the Cochrane Library for articles from January 2010 to June 2023. R 4.4.2 and STATA 16.0 were used to analyze data; hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CI) were used to assess the results.
RESULTS
An indirect comparison showed that nivolumab plus cabozantinib and pembrolizumab plus lenvatinib were the most effective treatments for progression-free survival (PFS), with no significant differences between the two interventions (HR, 1.31; 95% CI, 0.96-1.78; P=0.08); rank probability showed that pembrolizumab plus lenvatinib had a 57.1% chance of being the preferred treatment. In the absence of indirect comparisons between pembrolizumab plus axitinib, nivolumab plus ipilimumab, avelumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, pembrolizumab plus axitinib (40.2%) was the best treatment option for overall survival (OS). Compared to pembrolizumab plus lenvatinib, nivolumab plus ipilimumab (OR, 0.07; 95% CI, 0.01-0.65; P=0.02) and pembrolizumab plus axitinib (OR, 0.05; 95% CI, 0.00-0.78; P<0.001) had a lower incidence of overall adverse events (AEs).
CONCLUSION
Pembrolizumab plus lenvatinib and pembrolizumab plus axitinib resulted in the highest PFS and OS rates, respectively. Pembrolizumab plus axitinib may be the best option when AEs are a concern.
SYSTEMATIC REVIEW REGISTRATION
https://inplasy.com/, identifier INPLASY202410078.
Topics: Humans; Carcinoma, Renal Cell; Axitinib; Nivolumab; Immune Checkpoint Inhibitors; Ipilimumab; Network Meta-Analysis; Kidney Neoplasms; Anilides; Phenylurea Compounds; Pyridines; Quinolines
PubMed: 38390328
DOI: 10.3389/fimmu.2024.1255577 -
Cancer Discovery Mar 2024The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with...
UNLABELLED
The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and an abundance of innate immune subsets in the A+Ax arm. Treatment with A+Ax led to greater T-cell repertoire modulation and less change in T-cell numbers versus sunitinib. In the A+Ax arm, patients with tumors harboring mutations in ≥2 of 10 previously identified PFS-associated genes (double mutants) had distinct circulating and tumor-infiltrating immunologic profiles versus those with wild-type or single-mutant tumors, suggesting a role for non-T-cell-mediated and non-natural killer cell-mediated mechanisms in double-mutant tumors. We provide evidence for different immunomodulatory mechanisms based on treatment (A+Ax vs. sunitinib) and tumor molecular subtypes.
SIGNIFICANCE
Our findings provide novel insights into the different immunomodulatory mechanisms governing responses in patients treated with avelumab (PD-L1 inhibitor) + axitinib or sunitinib (both VEGF inhibitors), highlighting the contribution of tumor biology to the complexity of the roles and interactions of infiltrating immune cells in response to these treatment regimens. This article is featured in Selected Articles from This Issue, p. 384.
Topics: Humans; Carcinoma, Renal Cell; Sunitinib; Axitinib; Biomarkers; Kidney Neoplasms
PubMed: 38385846
DOI: 10.1158/2159-8290.CD-23-0680 -
Frontiers in Oncology 2024Chromophobe renal cell carcinoma (ChRCC) is a rare pathological type of renal cell carcinoma (RCC). Related systematic studies involving large numbers of patients are...
Chromophobe renal cell carcinoma (ChRCC) is a rare pathological type of renal cell carcinoma (RCC). Related systematic studies involving large numbers of patients are lacking, and more importantly, there is currently no international consensus on post-line treatment guidelines for ChRCC. The rapid development of systemic treatment with molecular targeted therapies and immune checkpoint inhibitors has brought effective approaches for patients with clear cell renal cell carcinoma (ccRCC), while progress in the treatment of ChRCC is still limited. In this case report, the patient was initially diagnosed at the early stage; 4 years post-surgery, she developed lung metastases and the disease progressed once again after being treated with sunitinib monotherapy for 3 years. However, after combining the immunotherapy sintilimab with the targeted therapy axitinib as second-line treatment, imageological examination showed lesions in the lungs that gradually decreased, and the bone metastases remained stable. To date, the patient has been continuously treated for over 2 years and is still undergoing regular treatment and follow-up. This case is the first to report the long-term survival of metastatic disease by using this treatment regimen and to propose a potential therapeutic option for patients with metastatic ChRCC. Since only one case was observed in this report, further study is needed.
PubMed: 38371628
DOI: 10.3389/fonc.2024.1325999 -
Pharmacological Research Mar 2024The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides their well-known involvement in physiological... (Review)
Review
The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides their well-known involvement in physiological angiogenesis/lymphangiogenesis and in diseases associated to pathological vessel formation, play multifaceted functions in the central nervous system (CNS). In addition to shaping brain development, by controlling cerebral vasculogenesis and regulating neurogenesis as well as astrocyte differentiation, the VEGFs/VEGFRs axis exerts essential functions in the adult brain both in physiological and pathological contexts. In this article, after describing the physiological VEGFs/VEGFRs functions in the CNS, we focus on the VEGFs/VEGFRs involvement in neurodegenerative diseases by reviewing the current literature on the rather complex VEGFs/VEGFRs contribution to the pathogenic mechanisms of Alzheimer's (AD) and Parkinson's (PD) diseases. Thereafter, based on the outcome of VEGFs/VEGFRs targeting in animal models of AD and PD, we discuss the factual relevance of pharmacological VEGFs/VEGFRs modulation as a novel and potential disease-modifying approach for these neurodegenerative pathologies. Specific VEGFRs targeting, aimed at selective VEGFR-1 inhibition, while preserving VEGFR-2 signal transduction, appears as a promising strategy to hit the molecular mechanisms underlying AD pathology. Moreover, therapeutic VEGFs-based approaches can be proposed for PD treatment, with the aim of fine-tuning their brain levels to amplify neurotrophic/neuroprotective effects while limiting an excessive impact on vascular permeability.
Topics: Animals; Parkinson Disease; Alzheimer Disease; Vascular Endothelial Growth Factor Receptor-1; Central Nervous System; Brain
PubMed: 38336311
DOI: 10.1016/j.phrs.2024.107101 -
Cancer Biology & Therapy Dec 2024Axitinib is an oral multi-target tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). Because of the severe adverse events (AEs) associated...
OBJECTIVE
Axitinib is an oral multi-target tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). Because of the severe adverse events (AEs) associated with axitinib, patients often need dose reductions or discontinue its use, highlighting the need for effective biomarkers to assess efficacy and/or AEs. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in the pharmacodynamic action of axitinib and clinical prognosis and AEs in metastatic RCC (mRCC) patients.
METHODS
This study included 80 mRCC patients treated with first-, second-, or third-line axitinib (5 mg orally twice daily). Clinical parameters and genetic polymorphisms were examined in 75 cases (53 males and 22 females). We assessed three SNPs in each of three candidate genes namely, angiotensin-converting enzyme (ACE), nitric oxide synthase 3 (NOS3), and angiotensin II receptor type 1 (AT1R), all of which are involved in axitinib effects on vascular endothelial function.
RESULTS
Axitinib-treated patients carrying the ACE deletion allele suffered more frequently from hand-foot syndrome and a deterioration in kidney function (p = .045 and = 0.005, respectively) whereas those carrying the NOS3 G allele suffered more frequently from proteinuria and multiple AEs (p = .025 and = 0.036, respectively).
CONCLUSIONS
Our study found that the ACE deletion allele and the NOS3 G allele are associated with increased AEs.
Topics: Humans; Male; Female; Axitinib; Carcinoma, Renal Cell; Kidney Neoplasms; Indazoles; Polymorphism, Single Nucleotide; Antineoplastic Agents
PubMed: 38327067
DOI: 10.1080/15384047.2024.2312602 -
Journal of Veterinary Science Jan 2024Axitinib, a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor (VEGFR) tyrosine kinase 1,2 and 3, is used in chemotherapy because it...
BACKGROUND
Axitinib, a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor (VEGFR) tyrosine kinase 1,2 and 3, is used in chemotherapy because it inhibits tumor angiogenesis by blocking the VEGF/VEGFR pathway. In veterinary medicine, attempts have been made to apply tyrosine kinase inhibitors with anti-angiogenic effects to tumor patients, but there are no studies on axitinib in canine mammary gland tumors (MGTs).
OBJECTIVES
This study aimed to confirm the antitumor activity of axitinib in canine mammary gland cell lines.
METHODS
We treated canine MGT cell lines (CIPp and CIPm) with axitinib and conducted CCK, wound healing, apoptosis, and cell cycle assays. Additionally, we evaluated the expression levels of angiogenesis-associated factors, including , , , and , using quantitative real-time polymerase chain reaction. Furthermore, we collected canine peripheral blood mononuclear cells (PBMCs), activated them with concanavalin A (ConA) and lipopolysaccharide (LPS), and then treated them with axitinib to investigate changes in viability.
RESULTS
When axitinib was administered to CIPp and CIPm, cell viability significantly decreased at 24, 48, and 72 h ( < 0.001), and migration was markedly reduced (6 h, < 0.05; 12 h, < 0.005). The apoptosis rate significantly increased ( < 0.01), and the G2/M phase ratio showed a significant increase ( < 0.001). Additionally, there was no significant change in the viability of canine PBMCs treated with LPS and ConA.
CONCLUSION
In this study, we confirmed the antitumor activity of axitinib against canine MGT cell lines. Accordingly, we suggest that axitinib can be applied as a new treatment for patients with canine MGTs.
Topics: Animals; Dogs; Humans; Axitinib; Vascular Endothelial Growth Factor A; Leukocytes, Mononuclear; Lipopolysaccharides; Mammary Glands, Human; Indazoles; Cell Line, Tumor
PubMed: 38311316
DOI: 10.4142/jvs.23191