Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients.

BACKGROUND: This study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic myeloid leukemia (CML). PATIENTS AND METHODS: In total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy. RESULTS: The CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR. CONCLUSIONS: The results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.

Transfusion-associated iron overload as a predictive factor for poor stem cell mobilization in patients with haematological malignancies.

Transfusion-associated iron overload is often observed in patients with haematological malignancies. We analysed the effect of iron overload, indicated by high serum ferritin level, on the mobilization of CD34(+) peripheral blood stem cells (PBSCs). We evaluated the association between the serum ferritin level prior to PBSC collection and the number of CD34(+) cells collected through leukapheresis in 51 patients with various haematological malignancies. Patients with serum ferritin level over 1000 ng mL(-1) were defined as high-ferritin group. Comparing the good (> or =1 x 10(6) per kg CD34(+) cells) and poor (<1 x 10(6) per kg CD34(+) cells) mobilizing groups, there was no difference in disease status, previous chemotherapies and white blood cell count at the first day of apheresis. However, there was a significant difference in the median units of red blood cell transfused between the good and poor mobilizer (2 vs. 8 units; P = 0.012). Serum ferritin level was notably higher in the poor mobilizer (1670 +/- 1320 ng mL(-1)) compared with the good mobilizer (965 +/- 705 ng mL(-1), P = 0.035). The cumulative number of CD34(+) cells per kg collected during the whole procedure was significantly lower in the high-ferritin group (5.5 +/- 4.7 x 10(6) per kg vs. 13.1 +/- 9.1 x 10(6) per kg, P = 0.01). Multivariate analysis revealed that serum ferritin level remained as an independent predictive factor for poor PBSC mobilization. Our study indicated that transfusion-associated iron overload is a predictive factor for poor PBSC mobilization. Iron chelation therapy prior to apheresis may be required to collect sufficient numbers of PBSCs in the iron overload patients.

Bulk-Fill Composites: Effectiveness of Cure With Poly- and Monowave Curing Lights and Modes.

This study compared the effectiveness of cure of bulk-fill composites using polywave light-emitting diode (LED; with various curing modes), monowave LED, and conventional halogen curing lights. The bulk-fill composites evaluated were Tetric N-Ceram bulk-fill (TNC), which contained a novel germanium photoinitiator (Ivocerin), and Smart Dentin Replacement (SDR). The composites were placed into black polyvinyl molds with cylindrical recesses of 4-mm height and 3-mm diameter and photopolymerized as follows: Bluephase N Polywave High (NH), 1200 mW/cm2 (10 seconds); Bluephase N Polywave Low (NL), 650 mW/cm2 (18.5 seconds); Bluephase N Polywave soft-start (NS), 0-650 mW/cm2 (5 seconds) → 1200 mW/cm2 (10 seconds); Bluephase N Monowave (NM), 800 mW/cm2 (15 seconds); QHL75 (QH), 550 mW/cm2 (21.8 seconds). Total energy output was fixed at 12,000 mJ/cm2 for all lights/modes, with the exception of NS. The cured specimens were stored in a light-proof container at 37°C for 24 hours, and hardness (Knoop Hardness Number) of the top and bottom surfaces of the specimens was determined using a Knoop microhardness tester (n=6). Hardness data and bottom-to-top hardness ratios were subjected to statistical analysis using one-way analysis of variance/Scheffe's post hoc test at a significance level of 0.05. Hardness ratios ranged from 38.43% ± 5.19% to 49.25% ± 6.38% for TNC and 50.67% ± 1.54% to 67.62% ± 6.96% for SDR. For both bulk-fill composites, the highest hardness ratios were obtained with NM and lowest hardness ratios with NL. While no significant difference in hardness ratios was observed between curing lights/modes for TNC, the hardness ratio obtained with NM was significantly higher than the hardness ratio obtained for NL for SDR.

The clonal origins of leukemic progression of myelodysplasia.

The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.

Single monosomy as a relatively better survival factor in acute myeloid leukemia patients with monosomal karyotype.

Monosomal karyotype (MK) defined by either ⩾2 autosomal monosomies or single monosomy with at least one additional structural chromosomal abnormality is associated with a dismal prognosis in patients with acute myeloid leukemia (AML). It was detected in 174 of 3041 AML patients in South Korean Registry. A total of 119 patients who had received induction therapy were finally analyzed to evaluate the predictive factors for a positive prognosis. On multivariate analysis, single monosomy, the absence of abn(17p), ⩾10% of cells with normal metaphase and the achievement of a complete remission (CR) after induction therapy were significant factors for more favorable outcomes. Especially, single monosomy remained as a significantly independent prognostic factor for superior survival in both patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in CR and who did not. Allo-HSCT in CR improved overall survival significantly only in patients with a single monosomy. Our results suggest that MK-AML may be biologically different according to the karyotypic subtype and that allo-HSCT in CR should be strongly recommended to patients with a single monosomy. For other patients, more prudent treatment strategies should be examined. Furthermore, the biological mechanism by which a single monosomy influences survival should be investigated.

Helical computerized tomography arteriography for evaluation of live renal donors undergoing laparoscopic nephrectomy.

PURPOSE: Traditionally, live renal donors are evaluated with excretory urography and renal arteriography. Helical computerized tomography (CT) arteriography offers a less invasive alternative for demonstrating necessary anatomical information before laparoscopic allograft harvest. We evaluate the accuracy of helical CT arteriography in depicting renal vascular anatomy with an emphasis on the detection of arterial and venous anomalies. MATERIALS AND METHODS: Imaging studies were done on 175 patients according to a standard CT arteriography protocol with early arterial phase scanning (14 to 20-second delay), and 1 mm. axial and 3-dimensional maximum intensity projection reconstructions. Renal vascular anatomy was mapped with attention to aberrant arterial and venous anatomy. Intraoperative findings were correlated at laparoscopic donor nephrectomy. RESULTS: There was overall agreement between CT arteriography and laparoscopic findings in 163 cases (93%). Supernumerary renal arteries were identified in 40 cases (23%). Sensitivity, specificity and accuracy of CT arteriography for arterial anatomy were 91, 98 and 96%, respectively. Cases with less than 2 mm. accessory arteries or early branching single vessels simulating dual arteries were misdiagnosed. Venous anomalies occurred in 11 patients (6.3%). Sensitivity, specificity and accuracy of CT arteriography for venous anatomy were 65, 100, and 97%, respectively. Misdiagnoses included early venous bifurcations and supernumerary tributary veins, which were poorly opacified. CONCLUSIONS: Helical CT is highly accurate and specific for the demonstration of renal arterial anatomy. Poor opacification resulted in a lower sensitivity for venous anatomy. Overall, helical CT provides essential anatomical information, and is an alternative to standard urography and arteriography.