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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.
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Relationship between Vitamin D receptor gene polymorphism and renal cell carcinoma susceptibility.
Lin, ZJ, Zhang, XL, Yang, ZS, She, XY, Xie, Y, Xie, WJ
Journal of cancer research and therapeutics. 2018;(4):820-825
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Abstract
AIM OF STUDY Results on the association of Vitamin D receptor (VDR) gene polymorphism with renal cell carcinoma (RCC) susceptibility from the present reports are still debating. This meta-analysis was conducted to assess the association of VDR ApaI (rs7975232), BsmI (rs1544410), TaqI (rs731236), and Fok1 (rs2228570) gene polymorphisms with RCC risk. MATERIALS AND METHODS The association studies were recruited from PubMed on May 1, 2016, and eligible reports were extracted and data were synthesized using meta-analysis method. RESULT Six investigations were included into this meta-analysis for the relationship between VDR gene polymorphism and RCC susceptibility. In this meta-analysis, the ApaI A allele, AA genotype, aa genotype, and Fok1 FF genotype were associated with RCC susceptibility in Asians. However, VDR BsmI and TaqI gene polymorphisms were not associated with the RCC risk in Asians, Caucasians, and overall populations. Furthermore, Fok1 gene polymorphism was not associated with the RCC risk in Caucasians and overall populations. CONCLUSION ApaI gene polymorphism and Fok1 FF genotype were associated with RCC susceptibility in Asians.
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Genome-wide association study identifies multiple risk loci for renal cell carcinoma.
Scelo, G, Purdue, MP, Brown, KM, Johansson, M, Wang, Z, Eckel-Passow, JE, Ye, Y, Hofmann, JN, Choi, J, Foll, M, et al
Nature communications. 2017;:15724
Abstract
Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10-10), 3p22.1 (rs67311347, P=2.5 × 10-8), 3q26.2 (rs10936602, P=8.8 × 10-9), 8p21.3 (rs2241261, P=5.8 × 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10-8), 11q22.3 (rs74911261, P=2.1 × 10-10) and 14q24.2 (rs4903064, P=2.2 × 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
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Therapy of Treatment-Related Hypertension in Metastatic Renal-Cell Cancer Patients Receiving Sunitinib.
Ivanyi, P, Beutel, G, Drewes, N, Pirr, J, Kielstein, JT, Morgan, M, Ganser, A, Grünwald, V
Clinical genitourinary cancer. 2017;(2):280-290.e3
Abstract
INTRODUCTION Treatment-related hypertension (tHTN) is frequent during sunitinib treatment. However, data on risk factors and treatment of tHTN remain scarce. PATIENTS AND METHODS Patients with metastatic renal-cell carcinoma treated with sunitinib from June 2004 to December 2011 were included. Medical records were retrospectively analyzed for tHTN risk factors and antihypertensive treatments (AHT). Descriptive statistics, Cox regression, and competitive risk models were applied. RESULTS A total of 51 (70.8%) of 72 patients developed tHTN after a median sunitinib treatment of 28 days. Mean blood pressure increased from 130/75 (range, 90 to 190/58 to 101) mm Hg on day 1 to 140/80 (range, 90 to 190/60 to 120, P < .001) mm Hg on day 28. Standard dose of sunitinib, age > 50 years, and prehypertension were identified as independent risk factors for tHTN. Thirty-eight patients (72.5%) in the tHTN subgroup received modification of AHT. Calcium channel blockers (CCB) were identified as the best at controlling tHTN compared to other drugs (P = .045). The combination of AHT was more potent than a dose increase of a single-drug AHT, and early AHT intervention was more efficacious than delayed start of therapy. CONCLUSION Patients at risk for tHTN require more rigorous blood pressure measurement. CCB seemed to be most potent and efficient, and an early combination of different classes of AHT was more efficacious than full-dose, single-agent AHT.
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Patterns of Care and Clinical Outcomes in Patients With Metastatic Renal Cell Carcinoma-Results From a Tertiary Cancer Center in India.
Ramaswamy, A, Joshi, A, Noronha, V, Patil, VM, Kothari, R, Sahu, A, Kannan, RA, Sable, N, Popat, P, Menon, S, et al
Clinical genitourinary cancer. 2017;(3):e345-e355
Abstract
INTRODUCTION The current treatment of metastatic renal cell carcinoma (mRCC) revolves around targeted agents, which have resulted in a median overall survival of 22 to 26 months in registration trials. However, the outcomes in a non-trial, real-world Indian population have not yet been evaluated. MATERIALS AND METHODS The present study was a part of a prospective Clinical Trials Registry-India-registered study, the Kidney Cancer Registry, a prospectively maintained kidney cancer registry. The data of patients with a diagnosis of mRCC from February 2007 to August 2015 who were potential candidates for systemic therapy were extracted from the database and analyzed for treatment patterns and outcomes. RESULTS The data from 212 patients were eligible for analysis. Of these 212 patients, 204 (96.2%) received first-line systemic treatment with sunitinib (40.6%), sorafenib (37.7%), pazopanib (2.8%), temsirolimus (2.8%), or everolimus (1.9%). The risk status of 91% of the patients could be stratified using the Heng criteria into favorable (18.9%), intermediate (43.9%), and poor risk (28.3%) categories. The response rate, clinical benefit rate, median progression-free survival, and median overall survival with first-line targeted therapy were 22.5%, 60.7%, 7.09 months, and 12.87 months, respectively. The common adverse events seen included skin rash (31.7%), hypertension (29.4%), grade 3 hand-foot syndrome (27.4%), mucositis (26.4%), dyslipidemia (20%), and hyperglycemia (17.6%). Patients receiving second-line therapy (22.6%) had superior overall survival to patients who had not (16.46 vs. 10.67 months; P = .032). CONCLUSION The present registry-based study is the first, to the best of our knowledge, of its type from India and showed that the overall outcomes in this real-world cohort appear comparable to non-trial data worldwide. An increased incidence of metabolic adverse events that require monitoring during treatment was also found.
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Systemic therapy in metastatic renal cell carcinoma.
Bedke, J, Gauler, T, Grünwald, V, Hegele, A, Herrmann, E, Hinz, S, Janssen, J, Schmitz, S, Schostak, M, Tesch, H, et al
World journal of urology. 2017;(2):179-188
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PURPOSE Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC). METHODS A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing. RESULTS Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited. CONCLUSIONS Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI-TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.
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Data-Independent Acquisition-Based Quantitative Proteomic Analysis Reveals Potential Biomarkers of Kidney Cancer.
Song, Y, Zhong, L, Zhou, J, Lu, M, Xing, T, Ma, L, Shen, J
Proteomics. Clinical applications. 2017;(11-12)
Abstract
PURPOSE Renal cell carcinoma (RCC) is a malignant and metastatic cancer with 95% mortality, and clear cell RCC (ccRCC) is the most observed among the five major subtypes of RCC. Specific biomarkers that can distinguish cancer tissues from adjacent normal tissues should be developed to diagnose this disease in early stages and conduct a reliable prognostic evaluation. EXPERIMENTAL DESIGN Data-independent acquisition (DIA) strategy has been widely employed in proteomic analysis because of various advantages, including enhanced protein coverage and reliable data acquisition. In this study, a DIA workflow is constructed on a quadrupole-Orbitrap LC-MS platform to reveal dysregulated proteins between ccRCC and adjacent normal tissues. RESULTS More than 4000 proteins are identified, 436 of these proteins are dysregulated in ccRCC tissues. Bioinformatic analysis reveals that multiple pathways and Gene Ontology items are strongly associated with ccRCC. The expression levels of L-lactate dehydrogenase A chain, annexin A4, nicotinamide N-methyltransferase, and perilipin-2 examined through RT-qPCR, Western blot, and immunohistochemistry confirm the validity of the proteomic analysis results. CONCLUSIONS AND CLINICAL RELEVANCE The proposed DIA workflow yields optimum time efficiency and data reliability and provides a good choice for proteomic analysis in biological and clinical studies, and these dysregulated proteins might be potential biomarkers for ccRCC diagnosis.
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Primary hypothyroidism and isolated ACTH deficiency induced by nivolumab therapy: Case report and review.
Zeng, MF, Chen, LL, Ye, HY, Gong, W, Zhou, LN, Li, YM, Zhao, XL
Medicine. 2017;(44):e8426
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RATIONALE Nivolumab is a monoclonal IgG antibody blocking programmed death receptor-1 (PD1), leading to restoration of the natural T-cell-mediated immune response against the cancer cells. However, it also causes plenty of autoimmune-related adverse events, which often involves endocrine system. PATIENT CONCERNS A 54-year-old male with renal clear cell carcinoma was treated with nivolumab intravenously. Routine monitoring showed elevated thyroid-stimulating hormone and low free thyroxine after the 6th administration of nivolumab. After the 12th administration, he developed general fatigue, recurrent hypoglycemia, and relative hypotension. Laboratory tests showed low sodium, low morning cortisol without correspondence increase of corticotrophin (ACTH). Other pituitary hormones were normal. MRI showed no space-occupying lesions, but heterogeneous enhancement of the pituitary gland. DIAGNOSES Primary hypothyroidism and isolated ACTH deficiency. The etiologies were assumed to be nivolumab induced autoimmune lymphocytic thyroiditis and hypophysitis, respectively. INTERVENTIONS Hormone replacements with levothyroxine and acetate cortisone were given orally. Nivolumab was adjusted to lower dose and longer interval. OUTCOMES The patient felt good after adequate replacement. Nivolumab was returned to routine dose and interval six months later. And the metastasis was not obviously progressed during this time. LESSONS The present report provides the first detailed presentation of combined hypothyroidism and isolated ACTH deficiency induced by nivolumab. Adrenal deficiency often develops insidiously. We suggest routine monitoring of fasting blood-glucose, blood pressure and serum sodium as well as thyroid function during nivolumab and other cancer immunotherapies. When unexpected fatigue, hypoglycemia, hypotension or hyponatremia appeared, adrenal deficiency should be taken into consideration.