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Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs.
Fogli, S, Porta, C, Del Re, M, Crucitta, S, Gianfilippo, G, Danesi, R, Rini, BI, Schmidinger, M
Cancer treatment reviews. 2020;:101966
Abstract
Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in various tumors, particularly in patients affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) comprise a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with metastatic RCC (mRCC). In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of mRCC, highlighting the relevant differences; moreover we aim to define the main pharmacologic characteristics of these drug.
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Systemic Treatment of Bone Disease in Metastatic Urinary Malignancies.
Patel, SH, Panian, J, Bree, K, Derweesh, I, Millard, F, Randall, J, Mckay, R
European urology focus. 2020;(1):17-25
Abstract
CONTEXT Bone metastasis is a common site of metastatic disease in patients with genitourinary malignancies. Given that the presence of bone metastasis decreases survival and has a negative impact on quality of life impact, it is critical to optimize management of this patient population. OBJECTIVE To systematically review literature on the systemic treatment of bone metastasis in prostate cancer, renal cell carcinoma, urothelial carcinoma, and germ cell tumors. EVIDENCE ACQUISITION We performed a nonsystematic critical review of PubMed/Medline, clinicaltrials.gov, and the Cochrane Library from January 2001 to February 2019. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials, and selected based on reporting skeletal related events and symptomatic skeletal events for patients with urologic malignancies. EVIDENCE SYNTHESIS Skeletal metastases occur frequently in genitourinary malignancies, at rates around 80% for patients with metastatic prostate cancer and 30% for patients with metastatic renal cell and urothelial carcinoma, and are uncommon in patients with germ cell tumors. Skeletal related events and symptomatic skeletal events can occur in these patients. Optimization of bone health involves dietary and lifestyle modifications, and use of osteoclast-targeted agents in select individuals. Additionally, disease-modifying agents, such as radiopharmaceutical, immunotherapy, and cMET inhibitors, which have activity in the bone, have improved outcomes for patients, including skeletal-related events and symptomatic skeletal events. CONCLUSIONS While the presence of bone metastases is associated with increased mortality and worse outcomes in patients with genitourinary malignancies, strategies have been developed to improve quality of life and survival for patients with skeletal metastases. Future studies investigating novel therapeutic options and bone supporting agents are warranted to target this patient population. PATIENT SUMMARY In this report, we reviewed the current literature and recent clinical trials involving treatment of bone metastases in urinary cancers. The use of bone-targeting agents can improve outcomes for patients, and additional lifestyle modification can optimize bone health in this population.
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Reprogramming of Metabolism in Kidney Cancer.
Wettersten, HI
Seminars in nephrology. 2020;(1):2-13
Abstract
Metabolic reprogramming is one of the major steps that tumor cells take during cancer progression. This process allows the cells to survive in a nutrient- and oxygen-deprived environment, to become stress tolerant, and to metastasize to different sites. Recent studies have shown that reprogramming happens in stromal cells and involves the cross-talk of the cancer cell/tumor microenvironment. There are similarities between the metabolic reprogramming that occurs in both noncancerous kidney diseases and renal cell carcinoma (RCC), suggesting that such reprogramming is a means by which renal epithelial cells survive injury and repair the tissue, and that RCC cells hijack this system. This article reviews reprogramming of major metabolism pathways in RCC, highlighting similarities and differences from kidney diseases and potential therapeutic strategies against it.
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Renal Toxicity of Systemic Therapy for Renal Cell Carcinoma.
Jaimes, EA
Seminars in nephrology. 2020;(1):49-58
Abstract
The incidence of kidney cancer has been increasing steadily and, until recently, there was a substantial lack of effective therapies for a cancer that is now among the 10 most common cancers in men and women. During the past 10 years, novel therapies have been developed including antiangiogenic drugs targeting vascular endothelial growth factor and its receptors, immune checkpoint inhibitors, and mammalian target of rapamycin inhibitors that have resulted in a significant improvement in clinical outcomes in a traditionally difficult-to-treat cancer. These new drugs, however, also have important side effects and toxicities that often have an impact on the treatment of these patients. The use of anti-angiogenic drugs often results in the development of hypertension and, less frequently, varying degrees of proteinuria including nephrotic range proteinuria. A variety of agents are used for the treatment of hypertension and proteinuria including blockers of the renin angiotensin system and calcium channel blockers, but there are no randomized clinical trials comparing different therapeutic agents in these patients. Immune checkpoint inhibitors have become one of the cornerstones of therapy in kidney cancer, but their use is linked to a variety of side effects that affect almost every organ and resemble autoimmune diseases. In the kidney, these drugs can induce acute interstitial nephritis in close to 5% of patients with varying degrees of severity that in some cases require discontinuation of treatment and systemic treatment with corticosteroids. Although mammalian target of rapamycin inhibitors now also are part of the therapeutic armamentarium available for these patients, all clinical trials have been performed in patients with normal renal function and therefore their effects in patients with abnormal renal function are not known.
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Efficacy of povidone-iodine against accidental tumor incision during nephron-sparing surgery: experimental study in patients with renal cell carcinoma.
Li, G, Zhi, C, Zhu, D, Liu, Z, Niu, Y
The Journal of international medical research. 2019;(10):4993-5002
Abstract
PURPOSE Accidental tumor incision (ATI) can occur during nephron-sparing surgery (NSS) and correlates with recurrence and metastasis. This study investigated risk factors of intraoperative ATI in renal cell carcinoma (RCC) patients after NSS and the efficacy of povidone-iodine for ATI. METHODS A retrospective analysis was performed on 150 consecutive stage I (pT1N0M0) RCC patients who underwent NSS at The Second Hospital of Tianjin Medical University between May 2010 and October 2015 for the causes of ATI. Furthermore, in vitro experiments investigated whether tumor cells remained on the surface of scissors and the effect of treatment with povidone-iodine on the number of remaining 786-O cells. RESULTS Among the 150 cases, 15 showed ATI, of which three suffered local recurrence during a median follow-up of 56 months. Pseudocapsules, satellite nodules, and renal cystic tumors were observed in ATI cases. In vitro experiments showed that tumor cells remained on the surface of scissors after ATI during NSS and that 0.5% povidone-iodine effectively killed tumor cells in 30 minutes. CONCLUSIONS The probability of ATI is high in patients with complex-type RCC during NSS. ATI potentially increases the chance of metastasis and local recurrence, and 0.5% povidone-iodine kills tumor cells more effectively than distilled water.
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Loss of SETD2 Induces a Metabolic Switch in Renal Cell Carcinoma Cell Lines toward Enhanced Oxidative Phosphorylation.
Liu, J, Hanavan, PD, Kras, K, Ruiz, YW, Castle, EP, Lake, DF, Chen, X, O'Brien, D, Luo, H, Robertson, KD, et al
Journal of proteome research. 2019;(1):331-340
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Abstract
SETD2, a histone H3 lysine trimethyltransferase, is frequently inactivated and associated with recurrence of clear cell renal cell carcinoma (ccRCC). However, the impact of SETD2 loss on metabolic alterations in ccRCC is still unclear. In this study, SETD2 null isogenic 38E/38F clones derived from 786-O cells were generated by zinc finger nucleases, and subsequent metabolic, genomic, and cellular phenotypic changes were analyzed by targeted metabolomics, RNA sequencing, and biological methods, respectively. Our results showed that compared with parental 786-O cells, 38E/38F cells had elevated levels of MTT/Alamar blue levels, ATP, glycolytic/mitochondrial respiratory capacity, citrate synthase (CS) activity, and TCA metabolites such as aspartate, malate, succinate, fumarate, and α-ketoglutarate. The 38E/38F cells also utilized alternative sources beyond pyruvate to generate acetyl-CoA for the TCA cycle. Moreover, 38E/38F cells showed disturbed gene networks mainly related to mitochondrial metabolism and the oxidation of fatty acids and glucose, which was associated with increased PGC1α, mitochondrial mass, and cellular size/complexity. Our results indicate that SETD2 deficiency induces a metabolic switch toward enhanced oxidative phosphorylation in ccRCC, which can be related to PGC1α-mediated metabolic networks. Therefore, this current study lays the foundation for the further development of a global metabolic analysis of cancer cells in individual patients, which ultimately will have significant potential for the discovery of novel therapeutics and precision medicine in SETD2-inactivated ccRCC.
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Association of Methylenetetrahydrofolate Reductase, Vitamin D Receptor, and Interleukin-16 Gene Polymorphisms With Renal Cell Carcinoma Risk.
Zhou, T, Li, H, Xie, WJ, Zhong, Z, Zhong, H, Lin, ZJ
Technology in cancer research & treatment. 2019;:1533033819859413
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Abstract
In this meta-analysis, we investigated the association of methylenetetrahydrofolate reductase, vitamin D receptor, and interleukin-16 gene polymorphisms with the risk of renal cell carcinoma. We searched the PubMed and Cochrane Library databases up to July 1, 2017, and included 12 eligible case-control studies in our analysis. The vitamin D receptor ApaI A allele, ApaI AA and aa genotypes, BsmI B allele, and Fok1 FF genotype were all associated with the risk of renal cell carcinoma in Asian populations. However, methylenetetrahydrofolate reductase (rs1801133 and rs1801131), vitamin D receptor (TaqI and Fok1), and interleukin-16 (rs4778889 and rs11556218) gene polymorphisms were not associated with the risk of renal cell carcinoma. Our study indicates that the vitamin D receptor ApaI A allele, ApaI AA and aa genotypes, BsmI B allele, and Fok1 FF genotype are associated with renal cell carcinoma risk.
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Systematic review of modifiable risk factors for kidney cancer.
Al-Bayati, O, Hasan, A, Pruthi, D, Kaushik, D, Liss, MA
Urologic oncology. 2019;(6):359-371
Abstract
To perform a systematic review of modifiable risk factors associated with the incidence of renal cell cancer (RCC). A systematic search of the literature was conducted using PubMed, Cochrane, and Web of Science databases from January 1996 until August 2017. We also extracted articles from the reference lists of identified studies and reviews. We targeted modifiable risk factors for RCC to include exercise, smoking, alcohol, diet, obesity, hypertension, and diabetes. We utilized predefined inclusion criteria and the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. We identified a total of 464 relevant articles and excluded 209 via title and 130 after abstract review. We thoroughly reviewed a total of 125 manuscripts. Seven supplementary tables describe (a) case controls and (b) prospective cohort studies. We summarize the tables in figures to visualize the overall impact of these studies association (beneficial, harmful, or null) with RCC. Total physical activity if beneficial (10/12 studies), smoking is harmful (13/14 studies), alcohol was protective (i.e., beneficial, 13/16 studies), diet was indeterminate (13 beneficial, 13 harmful, and 9 nulls), obesity and hypertension were overwhelmingly harmful (36/36 studies and 17/18, respectively), and diabetes was detrimental (23/27 studies). Modifiable risk factors play an essential role in the development of RCC, and we should develop targeted RCC prevention strategies in at-risk individuals.
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Is Axitinib Still a Valid Option for mRCC in the Second-Line Setting? Prognostic Factor Analyses From the AXIS Trial.
Bracarda, S, Bamias, A, Casper, J, Negrier, S, Sella, A, Staehler, M, Tarazi, J, Felici, A, Rosbrook, B, Jardinaud-Lopez, M, et al
Clinical genitourinary cancer. 2019;(3):e689-e703
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Abstract
BACKGROUND Axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting. PATIENTS AND METHODS AXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors. RESULTS Of 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter < 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments. CONCLUSION In patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.
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Decreased expression of SLC16A12 mRNA predicts poor prognosis of patients with clear cell renal cell carcinoma.
Mei, J, Hu, K, Peng, X, Wang, H, Liu, C
Medicine. 2019;(30):e16624
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Abstract
Solute carrier family 16, member 12 (SLC16A12) is a highly -expressed protein in the kidney and has been reported to participate in the transport of creatine. However, the clinical values of SLC16A12 in clear cell renal cell carcinoma (ccRCC) have not been explored.SLC16A12 RNA-seq data and clinical information were downloaded from the Cancer Genome Atlas (TCGA) database. We compared its expression in ccRCC and paracancerous tissues, then the result was further validated with our cohort. The impact on the clinical significance of SLC16A12 in ccRCC was also assessed.Compared with paracancerous tissue, SLC16A12 was significantly downregulated in the tumor tissues both in mRNA and protein level. In TCGA cohort, SLC16A12 mRNA expression was associated with several clinicopathological parameters, including T stages (P < .001), M stages (P = .009), TNM stages (P < .001), and differentiated grades (P = .001). Kaplan-Meier analysis showed that the overall survival of patients with low expression of SLC16A12 mRNA was significantly worse than that of patients with high expression (P < .001). Furthermore, both univariate (HR = 0.371, 95%CI: 0.269-0.513, P < .001) and multivariate (HR = 0.485, 95%CI: 0.297-0.793, P = .004) Cox regression analyses suggested that low expression of SLC16A12 mRNA was an independent prognostic factor for patients with ccRCC.Overall, we uncovered that decreased expression of SLC16A12 is a poor prognostic factor for patients with ccRCC. SLC16A12 might be a potential biomarker and therapeutic target in ccRCC.