Correlation between imatinib trough concentration and efficacy in Chinese chronic myelocytic leukemia patients.

BACKGROUND: Trough imatinib plasma concentration, intracellular drug levels and expression of drug transporters can be indicative of clinical responses in chronic myelocytic leukemia (CML) patients receiving imatinib. We aimed to determine plasma imatinib concentration, intracellular imatinib concentration, human organic cation transporter 1 (hOCT1) and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) mRNA expression in bone marrow cells of CML patients in order to evaluate the potential usefulness of these measures as markers of imatinib efficacy and understand their clinical relationships. METHODS: Eighty-four CML patients receiving imatinib treatment were included in this study. Imatinib trough concentration was determined by high-performance liquid chromatography-tandem mass spectrometry. Real-time quantitative PCR with a TaqMan probe was used to assess hOCT1 and ABCB1 mRNA expression in bone marrow cells. All patients were divided into the major molecular response (MMR), complete cytogenetic response (CCyR), partial cytogenetic response (PCyR) or drug-resistant groups according to their response. RESULTS: The plasma imatinib trough concentration was significantly higher in the MMR group than in the PCyR (p = 0.002) or drug-resistant groups (p = 0.011). The plasma imatinib trough concentration was also significantly higher in the CCyR group than in the PCyR group (p = 0.027). There were no significant differences between the CCyR and MMR groups with regard to the plasma imatinib trough concentration (p = 0.136). The intracellular imatinib concentration in bone marrow cells was significantly higher in the CCyR group compared to the drug-resistant or PCyR groups (p = 0.013). The hOCT1 mRNA expression in bone marrow cells was significantly higher in the CCyR group than in the drug-resistant or PCyR groups (p = 0.036). The ABCB1 mRNA expression in bone marrow cells was significantly higher in the drug-resistant group than in the CCyR or PCyR groups (p = 0.013). Plasma imatinib trough concentration was positively correlated with α(1)-acid glycoprotein (r = 0.443, p < 0.001) or dose (r = 0.422, p < 0.001). CONCLUSIONS: Clinical responses in CML patients are correlated with both the plasma trough concentrations and intracellular levels of imatinib.

[Effects of hOCT1 and ABCB1 gene on the efficacy of imatinib mesylate in chronic myelocytic leukemia].

OBJECTIVE: To detect the expression of hOCT1 and ABCB1 in marrow cells and examine the efficacy of imatinib mesylate (IM) in patients with chronic myelocytic leukemia (CML). METHODS: hOCT1 and ABCB1 gene in 90 samples with chronic phase CML diagnosed at our hospital from January 2008 and June 2011 were detected by taqman probe real-time reverse transcription-PCR (RT-PCR). The samples were divided into 3 groups: drug-resistant group (n = 17), partial cytological remission (PCyR) group (n = 11) and complete cytogenetic remission (CCR) group (n = 62) according to IM efficacy and 3 - 6, 7 - 12, 13 - 24, 25 - 48, > 48 months five groups (n = 21, 8, 15, 29, 17) according to IM treatment course. The relationship was explored between two genes and different disease states, course of treatment and time from first CCR. RESULTS: The hOCT1 gene mRNA expression of CCR group (-3.77 ± 0.55) was higher than drug-resistant group (-4.12 ± 0.47) and PCyR group (-4.24 ± 0.35) (P = 0.047, 0.019). The ABCB1 gene mRNA expression of drug-resistant group (-2.93 ± 0.49) was higher than CCR group (-3.02 ± 0.56) and PCyR group (-3.51 ± 0.45) (P = 0.045, 0.021). The hOCT1 and ABCB1 mRNA expressions showed no significant difference between five groups divided by IM treatment course (P = 0.270, 0.367). The median follow-up time was 30 (3 - 117) months. In same IM treatment course patients, the CCR rates in hOCT1 and ABCB1 low-expression groups were higher than that in high-expression groups separately (P = 0.006, 0.049). CONCLUSIONS: The expression levels of hOCT1 and ABCB1 vary in different disease states of patients on IM. And these two genes may influence the time from first CCR. But there is no significant relationship with course of the treatment.

[Serum α1-acid glycoprotein, imatinib concentration and efficacy in chronic myeloid leukemia patients].

OBJECTIVE: To explore the relationship between serum α1-acid glycoprotein (AGP), disease progression, imatinib plasma trough concentration and efficacy in the patients with chronic myeloid leukemia (CML). METHODS: A total of 112 CML patients were recruited from August 2008 to February 2010 in our hospital. There were 72 males and 40 females with a median age of 39 years old (range: 6 - 76 years old). Among them, 102 patients were in chronic phase, 4 in accelerated phase and 6 in blastic phase. Ninety-nine patients were treated with imatinib while 13 patients received hydroxyurea. Twenty healthy blood donors were designated as the control group. The serum AGP levels of all patients were detected by immuno-turbidimetric assay. And the concentrations of AGP and imatinib were detected in 12 patients before and after 3 months of imatinib therapy respectively. For 84 CML patients, their plasma trough concentrations of imatinib were detected by high performance liquid chromatography-tandem mass spectrometry simultaneously. All patients were divided into 5 groups by efficacy to evaluate the significance of serum AGP and its relationship with imatinib concentration. RESULTS: Serum AGP of no response (NR) group [(1.18 ± 0.26) g/L] was significant higher than that of complete cytogenetic response (CCR), complete hematologic response (CHR) and control group [(0.60 ± 0.21), (0.71 ± 0.17), (0.52 ± 0.15) g/L, all P < 0.05]. Serum AGP of accelerated/blastic phase group [(1.28 ± 0.50) g/L] was significant higher than CCR or control group (P < 0.05). Serum AGP of CHR group was higher than that of control group (P < 0.05). No significant difference existed between CCR, CHR or control group (P > 0.05). There were no significant differences between NR, relapse or accelerated/blastic phase group (P > 0.05). The serum AGP of 12 patients on a 3-month therapy of imatinib were lower than that of patients at pre-treatment [(0.54 ± 0.17) g/L vs (0.83 ± 0.31) g/L, P < 0.01]. The plasma trough concentration of imatinib was (1307 ± 586) µg/L (range: 109 - 3400 µg/L) in 84 patients. And it was positively correlated with the serum level of AGP (r = 0.443, P < 0.01). CONCLUSION: The serum level of AGP can reflect the in vivo loads of leukemic cells for CML patients. There is a positive correlation between the serum level of AGP and the plasma trough concentration of imatinib. Serum AGP can be used as a monitoring index of efficacy for CML patients.

[A forensic pathological study of eighty-two cases of adrenal hemorrhage].

OBJECTIVE: To analyze the relationship between adrenal hemorrhage and the cause of death, age and gender. METHODS: Eighty-two cases of adrenal hemorrhage were statistically analyzed. RESULTS: Adrenal hemorrhage occurred mostly in cases of sudden death, infection, trauma and asphyxia. Male had more chance than female to have adrenal hemorrhage. Adrenal hemorrhage caused by sudden death, trauma and poisoning was more frequently seen in young adults, whereas adrenal hemorrhage in children as well as in fetus and newborns was often caused by infection as well as sudden death and asphyxia respectively. Adrenal hemorrhage caused by sudden death and asphyxia was mainly located in medulla, while the infection usually induced hemorrhage in cortex. Adrenal hemorrhage caused by trauma showed an equal opportunity in either the cortex or medulla. CONCLUSION: Our data indicate that adrenal hemorrhage might provide some clues in searching for the cause of death.

Association between the concentration of imatinib in bone marrow mononuclear cells, mutation status of ABCB1 and therapeutic response in patients with chronic myelogenous leukemia.

Low concentrations of imatinib (IM) in bone marrow cells have been linked with poor prognosis in patients with chronic myeloid leukemia (CML), which may be caused by the emergence of ATP-binding cassette transporter B1 (ABCB1) mutations. The aim of present study was to investigate how clinical outcomes vary among patients with different single nucleotide polymorphisms (SNPs) of ABCB1. A total of 48 adult patients with CML and higher than median ABCB1 mRNA levels were selected for testing of ABCB1 SNPs. In 28 of the 48 patients, the IM concentration and expression levels of human organic cation transporter 1 (hOCT1) and ABCB1 in bone marrow mononuclear cells (BMMCs) were also tested. Correlations between treatment outcomes and IM concentration or the SNP status of ABCB1 were analyzed. Patients were classified by therapeutic response as major molecular response (MMR) (n=11), complete cytogenetic response (CCyR) (n=19) and non-CCyR (n=18) groups. It was found that the concentration of IM in BMMCs of the CCyR group was significant higher than that of the resistant groups (P=0.013). In addition, the IM concentration was positively correlated with the expression of hOCT1 mRNA (R=0.456, P=0.033), but negatively correlated with the expression of ABCB1 mRNA (R=-0.491, P=0.015). Furthermore, the mRNA expression level of ABCB1 was not associated with therapeutic response, but SNPs of the ABCB1 gene were associated with the response to IM. In conclusion, the concentration of IM in BMMCs may be regulated by the ABCB1 gene, and SNPs of the ABCB1 gene predict the therapeutic response to IM in patients with CML.

[Early diagnosis of the tumors in orbital apex and optic nerve].

OBJECTIVE: To obtain clues for early diagnosis of the tumors in orbital apex and optic nerve. METHODS: Twenty-two cases (22 eyes) of orbital tumors without proptosis were collected, and their clinical manifestations, especially main or first symptoms, the course of their diagnosis and treatment as well as the data of ultrasonography-B, CT and MRI were analyzed. RESULTS: Among 22 cases of the orbital tumors, there were 6 cases of cavernous hemangioma, 6 cases of the tumors from paransal sinuses or nasopharyngeal cavity, 4 cases of neurilemmoma and optic nerve sheath meningioma, neurofibroma, and 1 case of optic nerve glioma. There were 17 cases with visual impairment as the first presenting symptom and 3 cases with visual impairment associated with diplopia which was misdiagnosed as optic neuritis or optic atrophy. Finally, all cases were diagnosed accurately by CT or MRI. The vast majority of that originated from the orbital apex or optic nerve sheath, and the biggest diameter of the tumors was smaller than 1.5 cm. CONCLUSIONS: The early symptoms of the tumors in orbital apex and optic nerve tumors were visual impairment without proptosis. It is important that these patients were examined early by CT and MRI.

[Study on imatinib trough concentration, efficacy and their relation in chronic myelocytic leukemia].

OBJECTIVE: To determine plasma imatinib concentration, intracellular imatinib concentration, and hOCT1 and ABCB1 mRNA expression in bone marrow cells of CML patients to further evaluate the potential usefulness of these measures as markers of imatinib efficacy and their clinical relationships. METHODS: Eighty CML patients in chronic phase receiving imatinib were enrolled in this study, including 56 males and 24 females with a median age of 39.5 (6 - 76) years. Imatinib was administered at a median dose of 400 (200 - 800) mg/d orally per day with a median course of 24 (3 - 90) months. The intracellular imatinib concentrations in bone marrow cells of 28 patients were simultaneously determined. Real-time quantitative PCR with a taqman probe was used to assess hOCT1 and ABCB1 mRNA expression on bone marrow cells of 36 patients. Imatinib trough concentration was determined by high-performance liquid chromatography-tandem mass spectrometry with a detectability of 2 - 10 000 µg/L. Serum α1-acid glycoprotein (AGP) was measured by immune turbidimetry on a BNProspec protein analyzer (Dade Behring, USA). All patients were divided into MMR, CCyR, PCyR or drug-resistant groups according to response. RESULTS: Plasma imatinib trough concentration of 80 patients was (1274.1 ± 559.1) (109.0 - 3400.0) µg/L. The plasma imatinib trough concentration of 59 (73.8%) patients with a dose of 400 mg/d was (1252.0 ± 569.5) (109 - 3400) µg/L, including 37 (62.7%) patients with concentrations of more than 1000 µg/L and 9 (15.2%) patients more than 800 µg/L. Plasma imatinib trough concentration in the MMR group \[(1531.9 ± 634.1) µg/L\] was significant higher than in the PCyR \[(812.8 ± 480.3) µg/L\] or drug-resistant group \[(875.2 ± 243.1) µg/L\] (P < 0.05). Plasma imatinib trough concentration in the CCyR group \[(1288.4 ± 498.2) µg/L\] was significant higher than in the PCyR group (P = 0.027). There was no significant difference between CCyR and MMR groups with regard to plasma imatinib trough concentration (P = 0.136). The intracellular imatinib concentration in bone marrow cells in the CCyR group \[12.6 (2.4 - 90.4) µg/L\] was significantly higher than drug-resistant \[6.6 (2.6 - 111.0) µg/L\] or PCyR \[2.7 (2.4 - 4.7) µg/L\] groups (P = 0.013). The hOCT1 mRNA expression on bone marrow cells in the CCyR group \[25.9(0.7 - 123.9) × 10(-5)\] was significantly higher than in drug-resistant \[7.8 (2.5 - 33.5) × 10(-5)\] or PCyR \[4.2 (1.4 - 11.9) × 10(-5)\] groups (P = 0.036). The ABCB1 mRNA expression on bone marrow cells in drug-resistant group \[136.7 (15.0 - 1604.9) × 10(-5)\] was significantly higher than in CCyR \[129.1 (12.9 - 783.3) × 10(-5)\] or PCyR \[34.4 (2.2 -108.2) × 10(-5)\] groups (P = 0.013). Plasma imatinib trough concentration was positively correlated with AGP (r = 0.446, P = 0.000) or dose (r = 0.346, P = 0.002). There were no significant correlations between plasma imatinib trough concentration and height, weight or body surface area (P > 0.05). There were no significant differences among different courses with regard to plasma imatinib trough concentration (P > 0.05). CONCLUSION: Clinical responses in CML patients were correlated with plasma and intracellular imatinib trough concentrations. Imatinib concentration was regulated by AGP and the activities of hOCT1 and ABCB1.