Relationship Between Hypoglycemia Awareness Status on Clarke/Gold Methods and Counterregulatory Response to Hypoglycemia.

Context: Impaired awareness of hypoglycemia (IAH) is characterized by the diminished ability to perceive symptoms of hypoglycemia. Gold and Clark questionnaires are commonly used to identify patients with IAH. The relationship between IAH status on questionnaires and a person's symptom and epinephrine responses to hypoglycemia are not well understood. Objective: We aimed to examine the relationship between hypoglycemia awareness status on Clarke and Gold questionnaires with both hormonal and symptomatic responses to experimental hypoglycemia. Methods: In this university medical center study, we examined data from 78 subjects with type 1 diabetes (T1D) who completed both questionnaires and underwent a hyperinsulinemic hypoglycemic clamp (target glucose 50 mg/dL). Results: Clarke and Gold scores were highly correlated with one another (r = 0.82) and each had a moderate negative relationship with epinephrine (Clarke: r = -0.51, Gold: r = -0.50) and total symptom response (Clarke: r = -0.59, Gold: r = -0.57). However, 32% of the subjects were classified inconsistently by Clark vs Gold. A clustering analysis was done to examine how disagreement between the 2 questionnaires on IAH classification relates to epinephrine and symptoms responses during hypoglycemia. Subjects who had partial loss of symptoms or of epinephrine response were more likely to be classified inconsistently. Conclusion: Our results show that IAH classification may be discordant between Clark and Gold questionnaires and that hypoglycemia awareness status on Clarke and Gold questionnaires poorly predicts hormonal and symptomatic responses to hypoglycemia in subjects with T1D and moderate blunting of symptoms or epinephrine.

CYP51A1 polymorphism and voriconazole-associated hepatotoxicity in children undergoing hematopoietic cell transplant.

Fungal CYP51A (14α-sterol demethylase) is the target of an azole antifungal, voriconazole (VCZ), which also partially inhibits human CYP51A1. Hepatotoxicity is a common adverse effect of azoles, which is reported to be caused by altered gene expressions secondary to cholesterol synthesis inhibition by azoles. This is a post-hoc analysis of a previously conducted phase 1 dose-finding study of prophylactic VCZ in 56 pediatric hematopoietic cell transplant recipients. We explored an association between variants in human CYP51A1 (rs2282976 and rs6465348) and VCZ-induced hepatotoxicity. Genotype A/G or G/G in rs6465348 showed lower odds of hepatotoxicity after adjusting for VCZ area-under-the-curve (OR: 0.10, 95% CI: 0.01 - 0.79, vs. A/A).

Impact of Obesity on Voriconazole Pharmacokinetics among Pediatric Hematopoietic Cell Transplant Recipients.

Voriconazole (VCZ) is an antifungal agent with wide inter- and intrapatient pharmacokinetic (PK) variability and narrow therapeutic index. Although obesity was associated with higher VCZ trough concentrations in adults, the impact of obesity had yet to be studied in children. We characterized the PK of VCZ in obese patients by accounting for age and CYP2C19 phenotype. We conducted intensive PK studies of VCZ and VCZ N-oxide metabolite in 44 hematopoietic stem cell transplantation (HSCT) recipients aged 2 to 21 years who received prophylactic intravenous VCZ every 12 hours (q12h). Blood samples were collected at 5 and 30 minutes; at 1, 3, 6, and 9 hours after infusion completion; and immediately before the next infusion start. We estimated PK parameters with noncompartmental analysis and evaluated for an association with obesity by multiple linear regression analysis. The 44 participants included 9 (20%) with obesity. CYP2C19 metabolism phenotypes were identified as normal in 22 (50%), poor/intermediate in 13 (30%), and rapid/ultrarapid in 9 patients (21%). Obesity status significantly affects the VCZ minimum concentration of drug in serum (Cmin) (higher by 1.4 mg/liter; 95% confidence interval [CI], 0.0 to 2.8; P = 0.047) and VCZ metabolism ratio (VCZRATIO) (higher by 0.4; 95% CI, 0.0 to 0.7; P = 0.03), while no association was observed with VCZ area under the curve (AUC) (P = 0.09) after adjusting for clinical factors. A younger age and a CYP2C19 phenotype were associated with lower VCZ AUC. Obesity was associated with decreased metabolism of VCZ to its inactive N-oxide metabolite and, concurrently, increased VCZ Cmin, which is deemed clinically meaningful. Future research should aim to further characterize its effects and determine a proper dosing regimen for the obese.

The Role of Dual-Phase FDG PET/CT in the Diagnosis and Follow-Up of Brain Tumors.

OBJECTIVE. FDG PET/CT of brain tumors is limited by background activity. Dual-phase FDG PET/CT can eliminate this limitation and allow discernment of viable tumors. Our aim was to assess the diagnostic capability of dual-phase FDG PET/CT qualitatively and quantitatively and to determine cutoff values for dual-phase FDG PET/CT in brain tumor imaging. MATERIALS AND METHODS. Retrospectively, 51 malignant brain tumors were evaluated with dual-phase FDG PET/CT in 32 patients. Acquisitions were performed 30 minutes (time 1) and 3 hours (time 2) after administration of 10 mCi (370 MBq) FDG and 6 hours of fasting. Two observers independently and qualitatively evaluated lesions. A weighted Cohen kappa was used to calculate interrater reliability and accuracy. Quantitatively, maximum standardized uptake value (SUVmax) was measured in the lesions, contralateral white matter (CWM), contralateral caudate nucleus head, and ipsilateral cerebellar cortex (CC). Lesion-to-CWM SUVmax, lesion-to-contralateral caudate nucleus head SUVmax, and lesion-to-ipsilateral CC SUVmax ratios at time 1 and time 2 were calculated. ROC analysis was used to determine optimum cutoff values, and AUC ratios were compared among quantitative parameters. Lesion outcome was determined by pathologic results (available in 15 lesions), lesion stability on serial MRI examinations (representing nonviable tumor), or decreased tumor size on serial MRI examinations after new treatment (representing viable tumor). RESULTS. Thirty-seven viable and 14 nonviable lesions were evaluated. Qualitatively, the diagnostic accuracy (first observer: κ = 0.45 to κ = 0.59; second observer: κ = 0.41 to κ = 0.66) and interrater reliability (at time 1: κ = 0.51; at time 2: κ = 0.83) improved with delayed imaging. AUC and ROC analysis showed comparably high sensitivity, specificity, and accuracy profiles for early and delayed dual-phase FDG PET/CT. Some of the proposed cutoff values were as follows: lesion SUVmax at time 1, 7.20 (sensitivity, 89.2%; specificity, 85.7%); lesion SUVmax at time 2, 7.80 (sensitivity, 97.3%; specificity, 71.4%); lesion-to-CWM SUVmax at time 1, 2.05 (sensitivity, 78.4%; specificity, 92.9%); and lesion-to-CWM SUVmax at time 2, 2.36 (sensitivity, 81.1%; specificity, 85.7%). CONCLUSION. Dual-phase FDG PET/CT improves lesion detection and diagnostic accuracy in malignant brain tumors.