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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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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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Diagnostic Accuracy of Dual-Energy CT for Evaluation of Renal Masses: Systematic Review and Meta-Analysis.
Salameh, JP, McInnes, MDF, McGrath, TA, Salameh, G, Schieda, N
AJR. American journal of roentgenology. 2019;(4):W100-W105
Abstract
OBJECTIVE The purpose of this study is to determine the diagnostic accuracy of dual-energy CT (DECT) using quantitative iodine concentration in patients with renal masses using histopathologic analysis or follow-up imaging as the reference standard. The secondary objective is to compare the accuracy of DECT (using iodine concentration) to that of conventional CT (using Hounsfield unit measurements). MATERIALS AND METHODS We searched the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases for studies evaluating the accuracy of DECT for renal mass characterization (1947-2018). To be included, studies had to evaluate quantitative iodine concentrations in human patients with indeterminate renal masses. Risk of bias and applicability were assessed using quality assessment of diagnostic accuracy studies-2. A bivariate random-effects model was used to determine pooled sensitivity and specificity. Variability was assessed by subgroup analyses (DECT technique and risk of bias) and metaregression using test type and threshold applied as covariates. RESULTS Of 201 studies identified, five were included (367 patients). Pooled sensitivity and specificity for DECT were 96.6% (95% CI, 85.9-99.3%) and 95.1% (95% CI, 90.7-97.5%), respectively. Metaregression evaluating the influence of the test type (DECT vs conventional CT) did not identify differences in accuracy (p = 0.06). No differences in accuracy based on risk of bias or DECT technique were identified. Limitations include the small number of studies, most of which were at risk of bias. CONCLUSION DECT with iodine quantification shows sensitivity and specificity greater than 95% for evaluation of renal masses and may be an alternative to conventional CT for assessment of renal masses. Larger scale trials are needed to corroborate our findings.
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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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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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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.
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Folic Acid Reduces Mucositis in Metastatic Renal Cell Carcinoma Patients: A Retrospective Study.
Fristrup, N, Donskov, F
Clinical genitourinary cancer. 2019;(4):254-259
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BACKGROUND Mucositis is often experienced in metastatic renal cell carcinoma (mRCC) patients treated with targeted therapies. This might impair daily quality of life and lead to dose reduction, discontinuation, or treatment shift. We assessed the effect of folic acid to reduce mucositis. PATIENTS AND METHODS Patients treated with systemic therapy for mRCC who developed Grade ≥2 mucositis according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) received oral folic acid to reduce mucositis. The medical charts were retrospectively reviewed. RESULTS A total of 77 patients had Grade ≥2 mucositis during therapy with sunitinib (n = 29), pazopanib (n = 24), everolimus (n = 10), axitinib (n = 4), temsirolimus (n = 3), interleukin-2/interferon-α (n = 3), cabozantinib (n = 2), bevacizumab (n = 1), and nivolumab (n = 1). Given in doses of 1 to 5 mg daily, folic acid significantly reduced mucositis, mean CTCAE grade 0.88 (95% confidence interval [CI], 0.74-1.03) versus 2.38 (95% CI, 2.26-2.54; P < .0001). Stratified according to treatment, folic acid significantly reduced mucositis grade for sunitinib (0.97 [95% CI, 0.75-1.18] vs. 2.45 [95% CI, 2.23-2.67], P < .0001), pazopanib (0.96 [95% CI, 0.67-1.25] vs. 2.20 [2.03-2.38], P < .0001), everolimus (0.60 [95% CI, 0.10-1.10] vs. 2.60 [95% CI, 2.23-2.97], P < .0001), and other treatments (0.79 [95% CI, 0.38-1.19] vs. 2.36 [95% CI, 2.07-2.64], P < .0001). Of the 77 patients, 8 (10%) patients received dose reduction. Overall progression-free survival was 14 months and overall survival was 31 months. CONCLUSION Folic acid reduced mucositis in mRCC patients receiving systemic therapy. This finding needs prospective validation. A double-blind, placebo-controlled prospective evaluation of folic acid is ongoing (NCT03581773).
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High fat mass associates with occurrence of targeted therapy-induced left ventricular ejection fraction reduction in patients with renal cell carcinoma.
Kazemi-Bajestani, SMR, Becher, H, Venner, P, North, S, Baracos, V
Clinical nutrition (Edinburgh, Scotland). 2018;(3):1070-1072
Abstract
BACKGROUND & AIMS Recent research suggests that variations of skeletal muscle (SM) and fat predict the severity of chemotherapy-induced toxicities in patients with renal cell carcinoma (RCC). Cardio-toxicity has not been evaluated in this context. METHODS In this study we considered 47 RCC patients who participated in randomized clinical trials of sorafenib or sunitinib (i.e., targeted therapy). To capture cardio-toxicity, multi gated acquisition (MUGA) scan-defined left ventricular ejection fraction (LVEF) tests (at least 3 tests over 1 year of treatment) were abstracted. Computed tomography (CT) cross-sectional images were analyzed before start of targeted therapy and at 1 year to define SM and fat at baseline and changes over time concurrent with MUGA-defined LVEF measurement. RESULTS MUGA-defined cardio-toxicity (usually fall in LVEF >10% to an absolute LVEF<55%) occurred in 8/47 (17%) patients over 1 year of targeted therapy (all were male). Percentage of patients with high fat mass (baseline CT-defined total adipose tissue/indexed by height2 greater than the gender-specific median value) was higher among patients with cardio-toxicity versus patients without cardio-toxicity [7 (87.5%) versus 16 (41.0%); p = 0.02]. The percentage of SM loss in patients with cardio-toxicity was higher than the patients without cardio-toxicity [median of loss (%) -7 versus 0 respectively; p = 0.04]. CONCLUSION Cardio-toxicity in RCC patients might be associated with high fat mass. This finding is distinct from prior observations that low body weight and sarcopenia associated with non-cardiac toxicities of targeted therapies. Concurrence of SM loss over time and development of cardio-toxicity is reported for the first time.
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Autophagic cell death associated to Sorafenib in renal cell carcinoma is mediated through Akt inhibition in an ERK1/2 independent fashion.
Serrano-Oviedo, L, Ortega-Muelas, M, García-Cano, J, Valero, ML, Cimas, FJ, Pascual-Serra, R, Fernandez-Aroca, DM, Roche, O, Ruiz-Hidalgo, MJ, Belandia, B, et al
PloS one. 2018;(7):e0200878
Abstract
OBJECTIVES To fully clarify the role of Mitogen Activated Protein Kinase in the therapeutic response to Sorafenib in Renal Cell Carcinoma as well as the cell death mechanism associated to this kinase inhibitor, we have evaluated the implication of several Mitogen Activated Protein Kinases in Renal Cell Carcinoma-derived cell lines. MATERIALS AND METHODS An experimental model of Renal Cell Carcinoma-derived cell lines (ACHN and 786-O cells) was evaluated in terms of viability by MTT assay, induction of apoptosis by caspase 3/7 activity, autophagy induction by LC3 lipidation, and p62 degradation and kinase activity using phospho-targeted antibodies. Knock down of ATG5 and ERK5 was performed using lentiviral vector coding specific shRNA. RESULTS Our data discard Extracellular Regulated Kinase 1/2 and 5 as well as p38 Mitogen Activated Protein Kinase pathways as mediators of Sorafenib toxic effect but instead indicate that the inhibitory effect is exerted through the PI3K/Akt signalling pathway. Furthermore, we demonstrate that inhibition of Akt mediates cell death associated to Sorafenib without caspase activation, and this is consistent with the induction of autophagy, as indicated by the use of pharmacological and genetic approaches. CONCLUSION The present report demonstrates that Sorafenib exerts its toxic effect through the induction of autophagy in an Akt-dependent fashion without the implication of Mitogen Activated Protein Kinase. Therefore, our data discard the use of inhibitors of the RAF-MEK-ERK1/2 signalling pathway in RCC and support the use of pro-autophagic compounds, opening new therapeutic opportunities for Renal Cell Carcinoma.
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Efficacy of tivozanib treatment after sorafenib in patients with advanced renal cell carcinoma: crossover of a phase 3 study.
Molina, AM, Hutson, TE, Nosov, D, Tomczak, P, Lipatov, O, Sternberg, CN, Motzer, R, Eisen, T
European journal of cancer (Oxford, England : 1990). 2018;:87-94
Abstract
BACKGROUND Tivozanib is a selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 tyrosine kinases. This open-label, crossover clinical study (AV-951-09-902) provided access to tivozanib for patients who progressed on sorafenib in TIVO-1, comparing tivozanib with sorafenib in patients with advanced renal cell carcinoma (RCC). METHODS Patients enrolled in this single-arm, phase 2 crossover study were previously randomised to sorafenib on TIVO-1, progressed and then crossed over to tivozanib. Patients received tivozanib (1.5 mg/day orally; 3 weeks on/1 week off) within 4 weeks after their last sorafenib dose. FINDINGS Crossover patients were exposed to tivozanib for a median of eight cycles. From the start of tivozanib treatment, median progression-free survival was 11.0 months (95% confidence interval [CI]: 7.3-12.7) and median overall survival was 21.6 months (95% CI: 17.0-27.6). Best overall response was partial response in 29 (18%) patients and stable disease in 83 (52%) patients, with a median duration of response of 15.2 and 12.7 months, respectively. About 77% of patients experienced adverse events, most frequently hypertension (26%), followed by diarrhoea (14%) and fatigue (13%); 53% of patients had treatment-related adverse events, including 24% grade ≥3. About 9% and 16% of patients had dose reductions and dose interruptions due to adverse events, respectively. A total of 30% of patients had serious adverse events, and 4% had treatment-related serious adverse events. INTERPRETATION This crossover study of patients with advanced RCC demonstrated potent tivozanib anti-tumour activity. Safety and tolerability profiles were acceptable and consistent with the established adverse event profile of tivozanib.