Accuracy and precision of the Axis-Shield Afinion hemoglobin A1c measurement device.

BACKGROUND: The Afinion HbA1c (Axis-Shield) is a newer point-of-care device for measurement of hemoglobin A1c (A1C) using a boronate affinity method unlike the more commonly used DCA immunoassay method (Siemens Medical Solutions Diagnostics). The Afinion's accuracy and precision, when compared with high-performance liquid chromatography (HPLC) and DCA methods, have not been established in pediatric practice settings. METHODS: Capillary blood was collected from 700 subjects with diabetes mellitus at seven Pediatric Diabetes Consortium sites. Each subject's A1C was measured locally using Afinion and DCA devices, and by a central laboratory (University of Minnesota) using a Tosoh HPLC method. In addition, repeated measurements on six whole blood samples provided by the National Glycohemoglobin Standardization Program (NGSP) were taken at three clinical centers using the Afinion and DCA methods and centrally using the Tosoh HPLC method to assess the precision of each device. RESULTS: The coefficient of variation for measurements of whole blood samples for precision analysis was 2% for Afinion, 3% for DCA, and 1% for HPLC. In the patient samples measured at the seven clinic sites, the Afinion generated higher A1C results than the HPLC (mean difference = +0.15; p < 0.001), while the DCA produced lower values (mean difference = -0.19; p < 0.001). The absolute differences with HPLC were similar for the Afinion and DCA (median 0.2%) with a slight advantage for the Afinion when compared with DCA (p < 0.001 by rank test). The DCA tended to read lower than HPLC, particularly at high A1C levels (p < 0.001), while the Afinion's accuracy did not vary by A1C. CONCLUSIONS: When compared to the central laboratory HPLC method, the differences between the results of the Afinion and DCA devices are clinically insignificant, and the Afinion and DCA have similar accuracy and precision when used in pediatric practice settings.

Diet-induced obesity accelerates acute lymphoblastic leukemia progression in two murine models.

Obesity is associated with an increased incidence of many cancers, including leukemia, although it is unknown whether leukemia incidence is increased directly by obesity or rather by associated genetic, lifestyle, health, or socioeconomic factors. We developed animal models of obesity and leukemia to test whether obesity could directly accelerate acute lymphoblastic leukemia (ALL) using BCR/ABL transgenic and AKR/J mice weaned onto a high-fat diet. Mice were observed until development of progressive ALL. Although obese and control BCR/ABL mice had similar median survival, older obese mice had accelerated ALL onset, implying a time-dependent effect of obesity on ALL. Obese AKR mice developed ALL significantly earlier than controls. The effect of obesity was not explained by WBC count, thymus/spleen weight, or ALL phenotype. However, obese AKR mice had higher leptin, insulin, and interleukin-6 levels than controls, and these obesity-related hormones all have potential roles in leukemia pathogenesis. In conclusion, obesity directly accelerates presentation of ALL, likely by increasing the risk of an early event in leukemogenesis. This is the first study to show that obesity can directly accelerate the progression of ALL. Thus, the observed associations between obesity and leukemia incidence are likely to be directly related to biological effects of obesity.

Diet-induced obesity alters vincristine pharmacokinetics in blood and tissues of mice.

Obesity is associated with poorer outcome from many cancers, including leukemia. One possible contributor to this could be suboptimal chemotherapy dosing in obese patients. We have previously found that vincristine (VCR) is less effective in obese compared to non-obese mice with leukemia, despite weight-based dosing. In the present study, we administered (3)H-VCR to obese and control mice to determine whether obesity would cause suboptimal VCR exposure. Blood VCR concentrations were fitted with a three-compartment model using pharmacokinetic analysis (two-stage PK) in three subsets of VCR concentrations vs. time method. Tissue and blood VCR concentrations were also analyzed using non-compartmental modeling. Blood VCR concentrations showed a triexponential decay and tended to be slightly higher in the obese mice at all time-points. However, the t(1/2,beta) and t(1/2,gamma) were shorter in the obese mice (9.7 min vs. 44.5 min and 60.3h vs. 85.6h, respectively), resulting in a lower AUC(0-infinity) (13,099 ng/m Lh vs. 15,384 ng/mL h). Had the dose of VCR been "capped", as is done in clinical practice, the AUC(0-infinity) would have been 36% lower in the obese mice than the controls. Tissue disposition of VCR revealed a biexponential decay from spleen, liver, and adipose. Interestingly, VCR slowly accumulated in the bone marrow of control mice, but had a slow decay from the marrow in the obese mice. Thus, obesity alters VCR PK, causing a lower overall exposure in circulation and bone marrow. Given the high prevalence of obesity, additional PK studies should be performed in obese subjects to optimize chemotherapy dosing regimens.

Adipocytes impair leukemia treatment in mice.

Obesity is associated with increased cancer incidence and mortality. We have previously found that obesity in children is associated with a 50% increased recurrence of acute lymphoblastic leukemia (ALL) in high-risk patients. We have therefore developed novel in vivo and in vitro preclinical models to study the mechanism(s) of this association. Obesity increased relapse after monotherapy with vincristine (P = 0.03) in obese mice injected with syngeneic ALL cells. This occurred although the drug was dosed proportionally to body weight, equalizing blood and tissue drug levels. In coculture, 3T3-L1 adipocytes significantly impaired the antileukemia efficacy of vincristine, as well as three other chemotherapies (P < 0.05). Interestingly, this protection was independent of cell-cell contact, and it extended to human leukemia cell lines as well. Adipocytes prevented chemotherapy-induced apoptosis, and this was associated with increased expression of the two prosurvival signals Bcl-2 and Pim-2. These findings highlight the role of the adipocyte in fostering leukemia chemotherapy resistance, and may help explain the increased leukemia relapse rate in obese children and adults. Given the growing prevalence of obesity worldwide, these effects are likely to have increasing importance to cancer treatment.