scholarly journals Gender effects on cytidine analogue metabolism and myelodysplastic syndrome treatment outcomes

2012 ◽  
Author(s):  
Kenneth Chan ◽  
Jaroslaw Maciejewski ◽  
Yonghua Ling ◽  
Tomas Radivoyevitch ◽  
Kory Engelke ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Treatment Outcomes ◽  
Gender Effects ◽  
Cytidine Analogue

Gender Is A Major Determinant of Cytidine Analogue Metabolism and May Contribute to Differences in Treatment Outcomes

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1434-1434
Author(s):  
Reda Z Mahfouz ◽  
Ania Jankowska ◽  
Quteba Ebrahem ◽  
Zhenbo Hu ◽  
Kenneth K. Chan ◽  
...  
Keyword(s):  
Gender Differences ◽  
Bone Marrow ◽  
Overall Survival ◽  
Enzyme Activity ◽  
Treatment Outcomes ◽  
Interindividual Variability ◽  
T Test ◽  
Treatment Groups ◽  
Time Points ◽  
Cytidine Analogue

Abstract Abstract 1434 Cytidine analogues are mainstays in hematologic malignancy therapy. One documented limitation of therapy is interindividual variability in cytidine analogue pharmacokinetics that compromises predictability, safety and efficacy. Causes of interindividual variability include single nucleotide polymorphisms (SNPs) in cytidine metabolizing enzymes, particularly cytidine deaminase (CDA): the CDA SNP A79C (rs2072671) is present in >70% of Caucasians and decreases CDA enzyme activity. Gender is another known genetic determinant of cytidine analogue clinical activity, although the pathway is unknown (Dimopoulou et al, Ann Oncol 2004). With high dose cytarabine therapy, CDA may be saturated, dampening the clinical impact of CDA SNPs. However, the recently approved cytidine analogues 5-azacytidine and decitabine are used as single agents at relatively low doses, and interindividual variability could have greater clinical significance, since drug levels may be close to minimum thresholds required for efficacy. To evaluate this possibility, the impact of A79C and gender on treatment outcomes was examined in a cohort of patients with myelodysplastic syndrome (MDS, n=127) and acute myeloid leukemia (AML, n=74) classified by WHO criteria, initiated on treatment between 1/2002 and 12/2007, with IRB approved tissue-banked bone marrow samples available for analysis for the A79C SNP by sequencing and SNP array, and with verifiable follow-up and survival annotation. Other variables analyzed were those known to have major prognostic importance in patients with MDS and AML (bone marrow myeloblast percentage, karyotype, age). Patients were analyzed in three treatment groups: (i) did not receive cytidine analogues (n=35), (ii) treated with cytarabine (n=76), (iii) treated with 5-azacytidine or decitabine (n=90). In all three treatment groups, heterozygosity or homozygosity for A79C was not associated with significant differences in overall survival (OS). Similarly, there was no significant difference in overall survival in females versus males who were treated with cytarabine or who did not receive cytidine analogues. However, in the 5-azacytidine/decitabine treatment group, females had significantly longer overall survival than males (median 1033 v 563 days, Log Rank p=0.014). In multivariate analysis incorporating age, karyotype, bone marrow blast percentage and A79C, only age, gender and karyotype were significantly (Cox Proportional Hazards p<0.01) associated with survival, with the hazard ratio for female gender 0.356 (95%CI 0.165–0.766). An important caveat is that MDS in females has a less aggressive natural history (Nosslinger et al, Ann Oncol 2010), therefore, it is possible that gender differences in cytidine analogue metabolism do not underlie the difference in overall survival. Nonetheless, in AML myeloblasts (GSE15434) and normal liver tissue (measured by microarray), CDA mRNA expression in females was significantly lower than in males (Wilcoxon test p=0.005 and p=0.025 respectively). To measure functional CDA activity, uridine conversion from cytidine by plasma was measured by uHPLC (Dionex). As expected, there was a significant 2-fold decrease in mean enzyme activity in individuals homozygous for the A79C variant (CC, n=32) compared to individuals homozygous for the ancestral allele (AA, n=32, t-test p=0.02). However, the decrease in mean enzyme activity in females (n=48) compared to males (n=48) was even greater (3-fold, t-test p<0.001). In an analysis of decitabine pharmacokinetics after administration of oral decitabine 1 mg/kg to female (n=18) and male (n=18) adult mice, plasma levels of decitabine measured by LCMSMS were consistently higher in females at all time-points (1.169-4.375 fold at the different time points, paired t-test p=0.001). In conclusion, decreased cytidine analogue conversion to uridine counterparts in females, most likely from differences in CDA expression, could be relevant to gender differences in treatment outcomes with 5-azacytidine or decitabine. Disclosures: No relevant conflicts of interest to declare.

Does daclizumab induction in the hepatitis C transplant recipient influence treatment outcomes

2001 ◽  
Vol 120 (5) ◽  
pp. A561-A562
Author(s):  
T HEFFRON ◽  
G SMALLWOOD ◽  
M DEVERA ◽  
L DAVIS ◽  
E MARTINEZ ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Transplant Recipient ◽  
Treatment Outcomes

Evaluating research in developmental disabilities: a conceptual framework for reviewing treatment outcomes

1999 ◽  
Vol 41 (1) ◽  
pp. 55-59 ◽  
Author(s):  
Charlene Butler ◽  
Henry Chambers ◽  
Murray Goldstein ◽  
Susan Harris ◽  
Judy Leach ◽  
...  
Keyword(s):  
Developmental Disabilities ◽  
Conceptual Framework ◽  
Treatment Outcomes

Wechsler Memory Scale, Rivermead Behavioral Memory Test, and Everyday Memory Questionnaire in Healthy Adults and Alzheimer Patients

2002 ◽  
Vol 18 (1) ◽  
pp. 63-77 ◽  
Author(s):  
Anastasia Efklides ◽  
Efterpi Yiultsi ◽  
Theopisti Kangellidou ◽  
Fotini Kounti ◽  
Fotini Dina ◽  
...  
Keyword(s):  
Spatial Memory ◽  
Semantic Memory ◽  
Memory Test ◽  
Healthy Adults ◽  
Gender Effects ◽  
Everyday Memory ◽  
Wechsler Memory Scale ◽  
Everyday Memory Questionnaire ◽  
Behavioral Memory ◽  
Memory Questionnaire

Summary: The Wechsler Memory Scale (WMS) is a laboratory-based memory test that has been criticized for its lack of ecological validity and for not testing long-term memory. A more recent memory test, which aims at testing everyday memory, is the Rivermead Behavioral Memory Test (RBMT); it tests prospective memory and other forms of memory not tapped by WMS. However, even this test does not capture all aspects of everyday memory problems often reported by adults. These problems are the object of the Everyday Memory Questionnaire (EMQ). This study aimed at identifying the relationships between these three memory tests. The differential effect of Alzheimer's disease (AD) on the above relationships was also studied. The sample consisted of 233 healthy adults (20 to 75+ years of age) and 39 AD patients (50 to 75 years of age). Confirmatory factor analysis revealed the following latent factors: Verbal Memory, Visual Reconstruction, Orientation, Message (action embedded in spatial context), Visual Recognition, Spatial Memory, New Learning/Association Forming, Prospective/Episodic Memory, and Metamemory. These first-order factors were further explained by two second-order factors: Semantic Memory and Coordination of Semantic and Visuo-Spatial Memory. This basic structure was preserved in the sample of AD patients, although AD patients performed less well on the WMS and the RBMT. Some interesting findings regarding semantic memory, face recognition, and metamemory in AD patients are also reported. Age, education, but no gender effects on memory performance were also detected.

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