RESUMO
OBJECTIVE: Chemoprevention trials have shown that celecoxib reduces adenoma recurrence but can cause cardiovascular toxicity. In this pilot study, we evaluated associations between genetic variation in several candidate pathways (e.g. prostaglandin synthesis) and adenoma recurrence and cardiovascular and gastrointestinal toxicities. METHODS: Genotyping analysis was carried out on 117 Israeli colorectal adenoma patients who participated in the Prevention of Colorectal Sporadic Adenomatous Polyps trial. Reassessment followed after 3 years on celecoxib and after 2 years from termination of treatment with celecoxib. Efficacy (absence of colorectal adenomas) was measured by colonoscopy at years 1, 3, and 5. Toxicities were assessed by investigators during celecoxib treatment and by self-report post-treatment. A linkage disequilibrium-based selection algorithm (r2≥0.90, MAF≥4%) identified 255 tagSNPs in 25 analyzed candidate genes. Genotyping was performed by using Illumina GoldenGate technology. RESULTS: Multiple genetic variants were associated with adenoma recurrence and toxicity. Genetic variability in COX1, COX2, and ALOX12/15 genes played a role in adenoma recurrence, particularly among patients on placebo. More gene variants (especially variants in PGES, CRP, SRC, and GPX3) were associated with increased risk for cardiovascular toxicity and symptoms, compared with gastrointestinal toxicity and symptoms. The increased risk for cardiovascular toxicity/symptoms associated with the SRC gene variants (rs6017996, rs6018256, rs6018257) ranged from 6.61 (95% confidence interval 1.66-26.36, P<0.01) to 10.71 (95% confidence interval 1.96-58.60, P<0.01). CONCLUSION: Genetic polymorphisms in multiple inflammation-related genes appear to interact with celecoxib on adenoma recurrence and its attendant toxicity, particularly cardiovascular toxicity/symptoms. Larger studies validating these pharmacogenetic relationships are needed.
Assuntos
Adenoma/tratamento farmacológico , Doenças Cardiovasculares/induzido quimicamente , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Gastroenteropatias/induzido quimicamente , Polimorfismo de Nucleotídeo Único , Pirazóis/efeitos adversos , Sulfonamidas/efeitos adversos , Adenoma/genética , Pólipos Adenomatosos/tratamento farmacológico , Pólipos Adenomatosos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/genética , Celecoxib , Neoplasias Colorretais/genética , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Feminino , Gastroenteropatias/genética , Variação Genética , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/genética , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/prevenção & controle , Farmacogenética , Projetos Piloto , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêuticoRESUMO
Vitamin D and folate are associated with decreased colorectal cancer risk and their association with colorectal cancer prognosis is under investigation. We assessed the levels of plasma 25-hydroxyvitamin D3 (25(OH)D3), folate and vitamin B12 in an international pilot study in order to determine variability of these biomarkers based on geographical location. Plasma 25(OH)D3, folate and vitamin B12 concentrations were measured in 149 invasive, newly diagnosed colorectal cancer cases from Heidelberg (Germany), Seattle (WA, USA), and Tampa (FL, USA) and in ninety-one age- and sex-matched controls. Their associations with potential predictors were assessed using multivariate linear regression analyses. Plasma 25(OH)D3, folate and vitamin B12 concentrations differed by location. Other predictors were season for 25(OH)D3 and tumour stage (vitamin B12). Season-corrected average 25(OH)D3 concentrations were higher in Heidelberg (31·7 ng/ml; range 11·0-83·0 ng/ml) than in Seattle (23·3 ng/ml; range 4·0-80·0 ng/ml) and Tampa (21·1 ng/ml; range 4·6-51·6 ng/ml). In Heidelberg, a strong seasonal variation was observed. Folate (11·1 ng/ml) and vitamin B12 (395 pg/ml) concentrations in Heidelberg were lower than those in Seattle (25·3 ng/ml and 740 pg/ml, respectively) and Tampa (23·8 ng/ml and 522 pg/ml, respectively). Differences in plasma 25(OH)D3 and folate concentrations between Heidelberg and the US sites were observed, probably reflecting variation in outdoor activities and sun-avoidance behaviour during summer as well as in folic acid fortification and supplement use. Intra-site differences at each study location were greater than between-location variability, suggesting that individual health behaviours play a significant role. Nevertheless, the intra-site differences we observed may be due to chance because of the limited sample size. Our pilot study illustrates the value of an international cohort in studying colorectal cancer prognosis to discern geographical differences in a broad range of exposures.
RESUMO
The infrapopulation size, or crowding, is an important measure in parasitology because of its impact on many facets of parasite biology. However, crowding values are difficult to handle statistically because of dependencies. Therefore, a bootstrap procedure was proposed in order to compare crowding between 2 groups or samples of hosts. Here, we propose Lepage's location-scale test based on intensities as an alternative to test whether there is a difference in mean crowding. Simulation results indicate that Lepage's test is superior to the bootstrap, even when sample sizes are large as needed for the bootstrap procedure. Lepage's test, however, can also be applied with moderate or small sample sizes.
