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Responsabile Roberta Rolla
Settore di ricerca Patologia Clinica
Personale docente Giorgio Bellomo  Oscar Alabiso 
Personale non-docente Patrizia Pergolini  Alessandro Lupi  Matteo Vidali  Marica Prando  Chiara Saggia         
Obiettivi della ricerca 1) SIDE EFFECTS ASSOCIATED WITH ULTRARAPID CYTOCHROME P450 2D6 GENOTYPE AMONG WOMEN WITH EARLY STAGE BREAST CANCER TREATED WITH TAMOXIFEN
Risultati ottenuti 1) Background: The side effects of tamoxifen, a drug widely used for the treatment and the prevention of recurrence in patients with estrogen receptor positive breast cancers (ER+), have been reported in clinical trials, but to date no information is available on their possible association with an increased enzymatic activity of CYP2D6 (ultra-metabolizers, UMs).
The aim of this study was therefore to evaluate the association between the presence of multiple functional CYP2D6 alleles and the occurrence of side effects.
Methods: 61 women with ER+ breast cancer receiving tamoxifen monotherapy have been investigated in order to assess the relationships between CYP2D6 UM phenotype and side effects. Genotyping of 16 CYP2D6 polymorphisms was performed using a new DNA microarray technology.
Results: A highly significant difference (41.2 % of difference, 95 % CI 6-61%, Fisher`s exact test, p = 0.030) between numbers of Ultrarapid Metabolizers patients (UM; high activity) with two or more adverse drug reactions to tamoxifen (7/9; 77.8 %), compared to number of Extensive Metabolizers (EM; normal activity), Intermediate Metabolizers (IM; reduced activity) and Poor Metabolizers (PM; no activity) with at least two side effects (19/52, 36.5 %) was detected.
Similar difference was also observed comparing the two groups (UM vs EM-IM-PM) for the number of side effects (median and inter quartile range, IQR: AM / EM / IM 1, IQR 0-2 vs. ULTRA 2, IQR 2-4; Mann-Whitney p = 0.005).
Conclusions: Our results suggest a new association between CYP2D6 gene duplication and side effects to tamoxifen, indicating a possible role of CYP2D6 in their occurrence. 
Obiettivi della ricerca 2) ROLE OF THE LABORATORY IN MONITORING PATIENTS RECEIVING DUAL ANTIPLATELET THERAPY
Risultati ottenuti 2) Background: The increasing demand for therapeutic monitoring in patients receiving antiplatelet therapy has been paralleled by the development of instruments and tests whose clinical usefulness is still under debate. We devised a laboratory approach to detect patients with antiplatelet resistance at risk to develop thrombotic events.
Methods: One hundred and eighty patients, under aspirin and clopidogrel after angioplasty and stent implantation, were studied by PFA100 with collagen/epinephrine (CoEPI, cutoff 165s) cartridge and by Multiplate using arachidonic acid (ASPItest, pos < 862AUC), ADP(ADPtest, pos < 417AUC), and collagen (COLtest, pos < 607AUC).
Results: Only 67 of 173 patients with ASPI < 862 displayed a prolonged CoEPI and up to 65 patients had normal CoEPI despite ASPI < 300. Patients with ASPI < 300 had significantly lower COL than patients with ASPI > 300. One hundred and thirty-eight
patients displaying ADP < 417 had significantly lower COL than those with ADP > 417. Association between COL and ADP remained after ASPI stratification: in patients with suboptimal (ASPI 300-892) or maximal (ASPI < 300) response to aspirin, having ADP < 417 (clopidogrel responsive) increased COL positivity, respectively, from 9.5 to 58.8% and from 47.6 to 82.7%.
Conclusion: A combination of specific tests may be useful in identifying higher-risk patients with poor compliance or drug resistance who potentially may benefit from therapy change. 
Obiettivi della ricerca 3) HEMOLYSIS IS A MAJOR CAUSE OF VARIABILITY IN INSULIN MEASUREMENT DURING ORAL GLUCOSE TOLERANCE TEST IN CHILDREN
Risultati ottenuti 3) Background: The oral glucose tolerance test (OGTT) is widely employed to evaluate insulin resistance in children with growth hormone deficiency. Due to the difficulty in blood sampling, hemolysis is a frequent pre-analytic interference. The present study was performed to characterize the effects of hemolysis on insulin assay, in order to assess the need to generate automatic hemolysis report and/or to rejected hemolyzed samples.
Methods: Insulin plasma levels were measured using Siemens ADVIA Centaur in samples obtained from children with suspected GH deficiency at risk for insulin resistance during (OGTT).
Results: The presence of hemolysis (with a concentration of free hemoglobin above 75 mg/dL ) promotes a dose- and time-dependent decrease in immunoreactive insulin at any time-point evaluated during OGTT. As a consequence, the variability of insulin is particularly high (often exceeding 100 % of the mean value) as compared to that of glucose. This variability is markedly reduced after removal of the hemolyzed samples.
Conclusions: When the hemolysis is not taken into account a misinterpretation of insulin secretion pattern can occur. It is then compelling to: (i) analyze blood samples immediately after sampling, (ii) reject samples with a concentration of free hemoglobin equal or above 125 mg/dL and (iii) always report the possible interference.
 
Obiettivi della ricerca 4) PLASMA FIBRINOGEN LEVELS AND RESTENOSIS AFTER PRIMARY PERCUTANEOUS CORONARY INTERVENTION
Risultati ottenuti 4) Background:Plasma fibrinogen levels influence restenosis following elective percutaneous coronary intervention (PCI) for stable angina. It is unknown whether the same is true in the setting of primary PCI. The aim of the study was therefore to assess whether fibrinogen levels were associated to 6-month in-stent restenosis (ISR) in STEMI patients undergoing successful primary PCI.
Methods: From January 2003 to October 2004, 267 patients were admitted to our Institution for STEMI and treated by primary PCI. Of these, 171 patients met the inclusion criteria and were enrolled in our study. Fibrinogen levels were assessed at admission, 12 h, 24 h, 48 h, 72 h following PCI and at discharge. Six-month angiographic follow-up was 100% complete.
Results: Subjects with 6-month ISR showed higher fibrinogen levels than patients without ISR. Patients in the upper fibrinogen tertile showed a higher 6-month incidence of symptoms and/or inducible myocardial ischemia (27.1% vs. 7.1%, P = 0.006) and a larger late lumen loss (1.3 ± 0.8 vs. 1.0 ± 0.9 mm, P = 0.049). Logistic regression analysis demonstrated a significant and independent association between fibrinogen levels and ISR.
Conclusions: Our study suggests that increased plasma fibrinogen levels are related to ISR in STEMI patients undergoing primary PCI. Larger studies are warranted to assess the prognostic value of fibrinogen over harder end-points.

 
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Pubblicazioni
Side effects associated with ultrarapid cytochrome P450 2D6 genotype among women with early stage breast cancer treated with tamoxifen.
Hemolysis is a major cause of variability in insulin measurement during oral glucose tolerance test in children.
Role of the laboratory in monitoring patients receiving dual antiplatelet therapy.
Plasma fibrinogen levels and restenosis after primary percutaneous coronary intervention.
Short-term effects of aspirin and clopidogrel on mean platelet volume among patients with acute coronary syndromes. A single-center prospective study.
Accidental digitoxin intoxication: an interplay between laboratory and clinical medicine.
Recognizing purple bag syndrome at first look.
Levosimendan protection against kidney ischemia/reperfusion injuries in anesthetized pigs.
Analysis of electrical and mechanical left atrial properties in patients with persistent atrial fibrillation.
Association of haplotype combination of serotonin transporter gene polymorphisms with monthly headache days in MOH patients.
Uric acid does not affect the prevalence and extent of coronary artery disease. Results from a prospective study.