Retrospective study assessing the association of single nucleotide polymorphisms in VEGFR3 and on-target toxicity in patients with advanced renal-cell carcinoma (RCC) treated with sunitinib.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 537-537
Author(s):  
Jf. Rodriguez-Moreno ◽  
Emilio Esteban ◽  
Luis Javier Leandro-García ◽  
Daniel E. Castellano ◽  
Aranzazu Gonzalez del Alba ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Nucleotide Polymorphisms ◽  
Secondary Effects ◽  
Single Nucleotide ◽  
Genetic Changes ◽  
First Line Therapy ◽  
Study Results ◽  
Antiangiogenic Drugs ◽  
Grade Ii

537 Background: Sunitinib is a tyrosine kinase inhibitor approved as first line therapy of RCC. Some Adverse Events (AEs) of sunitinib are due to its inhibition of VEGFR and could be considered as “on-target” toxicity. They are a class-effects and have been observed even with the most selective antiangiogenic drugs. We aimed to correlate such secondary effects with germline SNPs in VEGFR3. Methods: In order to define “on target ” toxicity we considered any AEs ≥ Grade II (CTCAE 4.0) recorded in more than 10% of the patients included the pivotal studies of axitinib and tivozanib (the most selective tyrosin kinase inhibitors targeting VEGF(R). We assessed associations between polymorphisms in VEGFR3 and on-target toxicity for patients with advanced RCC treated with sunitinib prospectively included in the SUTRENT Study. Results: Polymorphisms in VEGFR3 are associated with less on-target toxicity. Probably these genetic changes confer a reduced susceptibility to the action of sunitinib. This could explain, at least partially, the worse outcome showed in this population. Conclusions: Polymorphisms in VEGFR3 are associated with less on-target toxicity. Probably these genetic changes confer a reduced susceptibility to the action of sunitinib. This could explain, at least partially, the worse outcome showed in this population.

Surgery of locally advanced and metastatic kidney cancer after tyrosine kinase inhibitors therapy: single institute experience

2018 ◽  
Vol 104 (5) ◽  
pp. 388-393
Author(s):  
Alberto De Gobbi ◽  
Davide Biasoni ◽  
Mario Catanzaro ◽  
Nicola Nicolai ◽  
Luigi Piva ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Target Therapy ◽  
Tnm Classification ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Metastatic Tumor ◽  
Grade Ii

Purpose: Renal cell carcinoma (RCC) is the most common tumor of the kidney. Considering the TNM classification of 2009, locally advanced and metastatic diseases are included in the groups stage III and IV. The surgical treatment of these tumors could be divided into 3 categories: (1) curative (nephrectomy and/or metastasectomy), (2) cytoreductive, and (3) palliative. Targeted agents showed impressive antitumor efficacy and prolongation of progression-free survival. The integration between target therapy and surgery in patients with locally advanced or metastatic RCC has sometimes facilitated surgery. We aimed to evaluate patients’ response to tyrosine kinase inhibitor (TKI) therapy and the feasibility of surgery after that and to observe complications related to surgery. Methods: From February 2007 to September 2014 in the Istituto Tumori of Milan, IRCCS, we selected patients with locally advanced or metastatic diseases, treated with target therapy before surgery (which comprised nephrectomy or partial nephrectomy, cytoreductive surgery, and metastasectomy) and cryoablation. Results: We selected 33 patients who underwent surgery after TKI therapy. As for response to TKIs, 20 patients (60%) had stable disease, 9 patients (28%) had a partial response, and 4 patients (12%) had progressive disease. A total of 17 patients (51%) presented complications directly or indirectly related to surgery and most of those were classified as grade II Clavien-Dindo score. Conclusions: The association between TKI and surgery seems to have no contraindications. Our dataset provides an example of how surgery after TKI is possible in locally advanced metastatic tumor and does not have an excessive rate of postoperative complications.

Role of pharmacogenetic studies in early clinical development: Phase I studies with lapatinib

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3029-3029 ◽  
Author(s):  
T. Z. Zaks ◽  
A. Akkari ◽  
L. Briley ◽  
M. Mosteler ◽  
A. G. Stead ◽  
...  
Keyword(s):  
Phase I ◽  
Healthy Volunteers ◽  
Kinase Inhibitor ◽  
Clinical Development ◽  
Pharmacokinetic Data ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Phase I Studies ◽  
Clinical Drug Development

3029 Background: Rash and diarrhea are a class effect of ERBB1 inhibitors. These events are relatively mild with Lapatinib (a dual ERBB1/ERBB2 kinase inhibitor). Finding a genetic basis for patients who may be predisposed to these adverse events, from the outset of clinical development, may improve the understanding of the mechanisms of these side effects and may have implications for use and dosing. Methods: DNA was isolated from peripheral blood of 107 Caucasian subjects from eight monotherapy phase I studies including 73 healthy volunteers and 34 cancer patients, 100 of whom had associated pharmacokinetic data. 284 single nucleotide polymorphisms (SNPs) from five candidate genes of transporters (ABCB1, ABCG2) and enzymes (CYP 3A4 and 3A5, and 2C19) for which lapatinib is a substrate were genotyped and examined for associations with pharmacokinetic variables (dose-normalized AUC, Cmax, and Tmax) as well as rash (15 cases) and diarrhea (18 cases). Results: Skin rash and diarrhea in this phase I cohort were only mild, (i.e. grade I or II). Statistically significant associations were observed between 34 SNPs in CYP2C19, rash (22 SNPs) and diarrhea (6 SNPs), and between 15 SNPs in ABCB1 and Tmax. Notably, 3/3 subjects (2 healthy volunteers, one patient) homozygous for the CYP2C19*2 allele experienced both mild rash and diarrhea. Extensive linkage disequilibrium was observed among these associated SNPs. Conclusions: Our results suggest that it is possible to determine pharmacogenetic associations with side effect phenotypes during the earliest phase of clinical drug development. These results are currently being validated on a larger cohort of patients from phase II lapatinib clinical trials. [Table: see text]

scholarly journals The Genetic Changes of Hepatoblastoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Huitong Chen ◽  
Qian Guan ◽  
Huiqin Guo ◽  
Lei Miao ◽  
Zhenjian Zhuo
Keyword(s):  
Nucleotide Polymorphisms ◽  
Genetic Syndromes ◽  
Disease Treatment ◽  
Single Nucleotide ◽  
Genetic Changes ◽  
Future Studies ◽  
The Past ◽  
Malignant Liver ◽  
Genetic Events ◽  
Made In

Hepatoblastoma is the most common malignant liver cancer in childhood. The etiology of hepatoblastoma remains obscure. Hepatoblastoma is closely related to genetic syndromes, hinting that hepatoblastoma is a genetic predisposition disease. However, no precise exposures or genetic events are reported to hepatoblastoma occurrence. During the past decade, significant advances have been made in the understanding of etiology leading to hepatoblastoma, and several important genetic events that appear to be important for the development and progression of this tumor have been identified. Advances in our understanding of the genetic changes that underlie hepatoblastoma may translate into better patient outcomes. Single nucleotide polymorphisms (SNPs) have been generally applied in the research of etiology’s exploration, disease treatment, and prognosis assessment. Here, we reviewed and discussed the molecular epidemiology, especially SNPs progresses in hepatoblastoma, to provide references for future studies and promote the study of hepatoblastoma’s etiology.

Influence of Genetic Polymorphisms in CYP2C8 and ABCB1 on the Mobilization Ability and Toxicity of Paclitaxel,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4050-4050
Author(s):  
María L. Lozano ◽  
Elkin A. Niño ◽  
Ana Isabel Anton ◽  
Jose Padilla ◽  
Jose Rivera ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Marrow Transplant ◽  
Hematological Toxicity ◽  
Nucleotide Polymorphisms ◽  
Allelic Discrimination ◽  
Single Nucleotide ◽  
First Line Therapy ◽  
Cd34 Cells ◽  
Polymerase Chain

Abstract Abstract 4050 Introduction. We and others have described the efficacy of paclitaxel-based chemotherapy in mobilizing large amounts of hematopoietic progenitors (HP) both in patients with solid tumors,(Bone Marrow Transplant 2000;25:231–5), and with hematological malignancies (Haematologica 2008; 93:161–3). Like most drugs, the taxanes are not controlled by the actions of one gene, but believed to be dependent on several polymorphic proteins. Single nucleotide polymorphisms (SNPs) in the ABCB1 gene, which encodes the transport protein P-glycoprotein, or in in metabolic enzymes, such as CYP2C8, have been suggested to influence the pharmacokinetics and clinical response to paclitaxel. Aim. To retrospectively evaluate the effects of five known allelic variants in the CYP2C8, and ABCB1genes on the mobilization ability and toxicity of the anticancer agent paclitaxel. Patients and Methods. 107 patients with hematological malignancies (43 lymphoma, 41 myeloma, 23 acute leukemia) received paclitaxel 170 mg/m2 i.v. by continuous infusion for 24 hours (day 1) followed by 8 mg/kg s.c G-CSF daily until the last apheresis. 77% received this treatment after failure of mobilization with G-CSF, and the rest as first line therapy because of risk factors for failure to achieve successful mobilization. The genetic variants (ABCB1 rs1045642 A >G, ABCB1 rs2032582 C>A, ABCB1 rs2032582 C>T, CYP2C8 rs10509681 C>T, and CYP2C8 rs11572080 A>G), were genotyped by allelic discrimination polymerase chain reaction (PCR) assays using TaqMan®Genotyping Assays (Applied Biosystems). The effect of genotypes on mobilization efficacy and on maximal hematological toxicity (according to the NCI version 3) was retrospectively assessed. Results. Allelic frequencies for rs1045642 A>G, rs2032582 C>A, rs2032582 C>T, rs10509681 C>T, and rs11572080 A>G variants, were 0.46, 0.40, 0.8, 0.13, and 0.13, respectively. Successful mobilization (>2 106/kg CD34+ cells) was achieved in 57% of patients. No reproducible significant associations between genotype and outcome (evaluated as number of CD34+ cells/kg in the first and total apheresis, number of collections performed, and on the mobilization success [p>0.05]), nor on myeloid or platelet toxicity (p>0.05) were found for any of the SNPs analyzed. Discussion. This study on a well-defined patient population suggests that the presently evaluated variant alleles in CYP2C8 and ABCB1 genes do not explain the substantial interindividual variability in the outcome or hematological toxicity of the mobilization schedule using paclitaxel and G-CSF. Funding. This study was supported in part by a research grants 04515/GERM/06; RECAVA RD06/0014/0039, and FIS 10/02594. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Peripheral Interleukin-1β Levels are Elevated in Chronic Tension-Type Headache Patients

2013 ◽  
Vol 18 (6) ◽  
pp. 301-306 ◽  
Author(s):  
Chris Della Vedova ◽  
Stuart Cathcart ◽  
Alan Dohnalek ◽  
Vanessa Lee ◽  
Mark R Hutchinson ◽  
...  
Keyword(s):  
Empirical Studies ◽  
Tension Type Headache ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genetic Changes ◽  
Chronic Tension Type Headache ◽  
Immune Mediators ◽  
Cytokine Levels ◽  
Healthy Control ◽  
Type Headache

BACKGROUND: Tension-type headache is the most common form of headache and its chronic form, chronic tension-type headache (CTTH), is one of the most difficult to treat. The etiology of CTTH is not well understood, but is believed to be multifactorial and to vary among individuals. In the present study, the authors sought to identify common mechanisms of CTTH pathology. Empirical studies have implicated various immunomodulatory cytokines as mediators of chronic pain disorders, including CTTH.OBJECTIVES: To determine the role of peripheral cytokines and genetic factors in the development of CTTH.METHODS: A panel of cytokines hypothesized to play a role in the pathogenesis of CTTH was measured using cytometric bead arrays and ELISAs in 56 individuals with CTTH and 42 healthy control participants between 18 and 65 years of age.RESULTS: Levels of interleukin (IL)-1β were significantly elevated in participants diagnosed with CTTH relative to healthy controls, while IL-18 levels were found to be significantly elevated in men with CTTH. Because the levels of these immune mediators were increased in the apparent absence of injury or infection, the authors sought to determine whether genetic changes were responsible for fluctuations in cytokine levels. Polymerase chain reaction and restriction fragment length polymorphism analyses were used to determine individual genotypes at key single nucleotide polymorphism positions in theIL-1Bgene. No association was observed between CTTH and single nucleotide polymorphisms in the IL-1β gene.CONCLUSIONS: These findings suggest that increases in key proinflammatory cytokine levels are associated with CTTH and the pathology of the disorder involves sterile neurovascular inflammation.

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