Search

Background. Docetaxel is a highly effective treatment of a wide range of malignancies but is often associated with peripheral neuropathy. The genetic variability of genes involved in the transportation or metabolism of docetaxel may be responsible for the variation in docetaxel-induced peripheral neuropathy (DIPN). The main purpose of this study was to investigate the impact of genetic variants in GSTP1 and ABCB1 on DIPN.Material and methods. DNA was extracted from whole blood from 150 patients with early-stage breast cancer who had received adjuvant docetaxel from February 2011 to May 2012. Two polymorphisms in GSTP1 and three in ABCB1 were selected for the primary analysis, and a host of other candidate genes was explored and compared between 75 patients with clinician-reported DIPN grade ≥ 2 and 75 patients without DIPN.Results. Patients with the genetic variants GSTP1 rs1138272 C/T or T/T (114Ala/114Val or 114Val/114Val) genotype had an adjusted odds ratio of 3.82; 95% confidence interval 1.34–11.09 of developing DIPN. This result was confirmed in both analysis of cumulated docetaxel dose and haplotype analysis. None of the explorative genes investigated were significantly correlated with DIPN. Patients with a BMI ≥ 30 were five-fold more likely to have DIPN than patients with BMI < 25.Conclusion. We found that GSTP1 Ala114Val polymorphism is associated with occurrence of DIPN. This supports the theory that oxidative stress is involved in DIPN pathophysiology. If confirmed, this may be helpful in the risk assessment of DIPN and perhaps help to achieve better management of neurotoxicity.

BACKGROUND: Dysfibrinogenemia is a rare group of qualitative fibrinogen disorders caused by structural abnormalities in the fibrinogen molecule. The laboratory diagnosis of dysfibrinogenemia is controversial. Fibrinogen Paris V, clinically termed Dusart Syndrome, is a dysfibrinogenemia caused by a single base substitution in the gene coding for the Aα-chain of the fibrinogen molecule.OBJECTIVES: To diagnose the first Scandinavian family with Fibrinogen Paris V affecting several family members; the proband, a seven-year-old boy with cerebral vein thrombosis.METHODS: The diagnosis was established following the ISTH guideline for laboratory testing supplemented with fibrin structure analysis and fibrinogen gene analysis.RESULTS: Prolonged thrombin time and reduced ratio between the functional and the protein concentration of fibrinogen were observed in four family members who also were characterized by significantly reduced fibrin polymerization (p < 0.001), reduced fibrin fibre diameter (p < 0.001), reduced fibrin mass-length ratio (p < 0.001) and significantly reduced t-PA-induced fibrinolysis of the fibrin clots (p < 0.001) when compared to controls. Fibrinogen gene analysis demonstrated that five of the family members carried the Fibrinogen Paris V mutation. All laboratory tests were normal in the family members carrying the wild type of the fibrinogen gene. Four of the affected patients had suffered from thrombotic episodes. A noticeable feature in the present family was the presence of both venous and arterial thrombosis.CONCLUSIONS: Excellent concordance was observed between the screening and confirmatory tests, fibrin structure analysis and fibrinogen gene analysis. Fibrin structure analysis should be considered in the laboratory algorithm for diagnosis of dysfibrinogenemia.