Measurement of thiopurine metabolites is helpful to monitor adverse effects and assess compliance in patients on thiopurine treatment. The purpose of this study was to develop and validate an analytical method for measurement of thiopurine metabolites, thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine nucleotide (6-MMPN), in RBCs. We developed and validated a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the quantification of 6-TGN and 6-MMPN and evaluated the stability of the thiopurine metabolites in RBC and whole blood states without any preprocessing at various storage conditions. The linear range was 0.1–10 µmol/L and 0.5–100 µmol/L for 6-TGN and 6-MMPN, respectively. The mean extraction recovery at the two concentrations was 71.0% and 75.0% for 6-TGN, and 102.2% and 96.4% for 6-MMPN. Thiopurine metabolites in preprocessed RBC samples were stable at 25℃ and 4℃ after storage for 4 hours and at −70℃ for up to 6 months. However, 6-TGN decreased by 30% compared with the initial concentration when stored at −20℃ for 180 days. In whole blood states, 6-TGN decreased by about 20% at four days after storage at 4℃. We validated a reliable LC-MS/MS method and recommend that the patient's whole blood sample be preprocessed as soon as possible.
Compliance ; Humans ; Mass Spectrometry ; Methods* ; Nucleotides ; Thioguanine

PURPOSE: We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated. RESULTS: A total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate-activity group 24.4 vs. normalactivity group 31.1, p < 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p < 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate-activity group 92 days vs. normal-activity group 59 days, p < 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group. CONCLUSION: NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels.
6-Mercaptopurine ; Blood Cell Count ; Child* ; Humans ; Leukemia ; Leukopenia ; Precursor Cell Lymphoblastic Leukemia-Lymphoma* ; Thioguanine

BACKGROUND: Thiopurine S-methyltransferase (TPMT) is an important enzyme in the metabolism of thiopurines including azathioprine (AZA), 6-mercaptopurine, and 6-thioguanine. TPMT genotyping is widely used for screening of AZA-related toxicity during routine clinical practice in Korea. However, the data of TPMT genotypes and its AZA-related toxicity have not been studied in the field of dermatology. OBJECTIVE: The aim of this study was to evaluate the genetic basis of TPMT polymorphism in Korean dermatologic patients and subsequently to investigate the relationship between mutant TPMT and adverse responses to AZA treatment. METHODS: This study was retrospective, single-center study. One hundred forty-nine Korean dermatologic patients who underwent TPMT screening test were included. Each patient's medical records, the result of TPMT screening test, dose and treatment period of AZA, and side effects, were reviewed. Laboratory tests were assessed at each visit in order to monitor adverse drug reactions. Leukopenia grading was used in accordance with the common terminology criteria for adverse events (CTCAE) ver. 4.03. RESULTS: Behçet's disease was the leading disorder among the patients. The frequency of TPMT mutation was 4.0% (6/149) among the participants in this study. Four of the six patients with genetic alterations were treated with a low-dose AZA regimen, but no AZA-related adverse events were observed. CONCLUSION: Our results suggest that 1) TPMT polymorphisms in Korean dermatologic patients are similar to those previously reported in Asian patients with the most common mutant allele being TPMT*3C and 2) AZA can be used in the patients with these polymorphisms under a careful dosing regimen.
6-Mercaptopurine ; Alleles ; Asian Continental Ancestry Group ; Azathioprine ; Behcet Syndrome ; Dermatology ; Drug-Related Side Effects and Adverse Reactions ; Genotype ; Humans ; Korea ; Leukopenia ; Mass Screening ; Medical Records ; Metabolism ; Retrospective Studies ; Thioguanine

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children. Despite good remission rate has achieved nowadays, the patients still face a substantial risk of relapse. It has long been recognized that thiopurines are critical components in the treatment for prevention of recurrence in childhood ALL, the 6-mercaptopurine (6-MP) has usually been used in daily long-term maintenance therapy, and 6-thioguanine (6-TG) limited to the reinforcement of therapy. However, there is no optimal regimen for 6-TG or 6-MP. The related research advances on the clinical effectiveness of the two thiopurines are reviewed.
Child ; Humans ; Mercaptopurine ; therapeutic use ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; Thioguanine ; therapeutic use

Antimetabolites, Antineoplastic ; adverse effects ; Child ; Female ; Hepatic Veno-Occlusive Disease ; chemically induced ; Humans ; Male ; Thioguanine ; adverse effects

A polymer gel dosimeter was fabricated. A 3-dimensional dosimetry experiment was performed in the small field of the photon of the cyberknife. The dosimeter was installed in a head and neck phantom. It was manufactured from the acrylic and it was used in dosimetry. By using the head and neck CT protocol of the CyberKnife system, CT images of the head and neck phantom were obtained and delivered to the treatment planning system. The irradiation to the dosimeter in the treatment planning was performed, and then, the image was obtained by using 3.0T magnetic resonance imaging (MRI) after 24 hours. The dose distribution of the phantom was analyzed by using MATLAB. The results of this measurement were compared to the results of calculation in the treatment planning. In the isodose curve on the axial direction, the dose distribution coincided with the high dose area, 0.76mm difference on 80%, rather than the low dose area, 1.29 mm difference on 40%. In this research, the fact that the polymer gel dosimeter and MRI can be applied for analyzing a small field in a 3 dimensional dosimetry was confirmed. Moreover, the feasibility of using these for the therapeutic radiation quality control was also confirmed.
Antineoplastic Combined Chemotherapy Protocols ; Cytarabine ; Head ; Magnetic Resonance Imaging ; Neck ; Polymers ; Quality Control ; Thioguanine

Hepatic sinusoidal obstruction syndrome (hSOS) can be developed as a common complication after hematopoietic stem cell transplantation (HSCT), and rarely after 6-thioguanine-based chemotherapy without HSCT. A four-year-old boy with heterozygotic polymorphism for thiopurine methyltransferase (TPMT) developed hSOS after he received chemotherapy with cytarabine, cyclophosphamide, intrathecal methotrexate and 6-thioguanine (6-TG) as reconsolidation chemotherapy of acute lymphoblastic leukemia (ALL). He was treated with defibrotide, N-acetylcysteine, urusodeoxycholic acid, glutathione, and supportive care. He recovered completely in nine days without long-term complication, and completed chemotherapy with 6-mercaptopurine without severe complication. We report a case of hSOS developed in an ALL patient with TPMT heterozygote after 6-TG based reconsolidation chemotherapy.
6-Mercaptopurine ; Acetylcysteine ; Child ; Cyclophosphamide ; Cytarabine ; Glutathione ; Hematopoietic Stem Cell Transplantation ; Hepatic Veno-Occlusive Disease ; Heterozygote ; Humans ; Methotrexate ; Methyltransferases ; Polydeoxyribonucleotides ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Thioguanine

OBJECTIVETo improve the treatment of drug related childhood hepatic veno-occlusive disease (HVOD), clinical characteristics of 6 children with hematologic neoplasm from 2 hospitals of China Children's Leukemia Group (CCLG) treated with 6-thioguanine (6-TG) complicated with HVOD were analyzed.

METHODAll the drug related HVOD patients were treated with CCLG acute lymphoblastic leukemia (ALL)-2008 protocol. They were from Children's Hospital of Fudan University and Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College from April 2008 to April 2009. The diagnosis was made according to the modified Seattle criteria and Baltimore criteria, including 2 or 3 of the following clinical features: hepatomegaly and upper right abdominal pain, jaundice (bilirubin ≥ 35 µmol/L), ascites or confirmed by pathology. The 6 HVOD patients' clinical manifestations, laboratory finding, imageologic and pathologic data were collected and analyzed.

RESULTOf the 6 patients, 2 were males and 4 females. Mean age of the 6 patients was 3.89 years (range from 3 years 1 month to 4 years 11 months). The original disease was acute lymphoblastic leukemia. HVOD occurred during chemotherapy protocols of CAM (CTX + Ara-C + 6-TG) or maintenance period (MTX + 6-TG). Most of 6 HVOD patients presented with pain in liver area, hepatomegaly on imaging, elevated aminotransferase and bilirubin (often ≥ 35 µmol/L), hydroperitonia was common, one with pleural fluid, illegible hepatic veins. All the patients recovered after being treated with hepatoprotective, jaundice-relieving and supportive therapeutics, some patients were treated with low molecular weight heparin. The prognoses were good.

CONCLUSIONHVOD was a serious complication of chemotherapy with 6-TG. Hepatoprotective and jaundice-relieving and low molecular weight heparin could improve the prognosis.

Antineoplastic Agents ; therapeutic use ; Child, Preschool ; Female ; Hepatic Veno-Occlusive Disease ; drug therapy ; Humans ; Leukemia ; therapy ; Male ; Thioguanine ; therapeutic use

The purpose of this study provides measurements of radiation dose from MDCT of head, chest, abdomen and pelvic examinations. A series of dose quantities that are measured of patient weight to compare the dose received during MDCT examinations. Data collected included: weight together with CT dose descriptors, volume CT dose index (CTDIvol) and dose length product (DLP). The effective dose was also estimated and served as collective dose estimation data. Data from 1,774 adult patients attending for a CT examination of the head (n=520) or chest (n=531) or abdomen (n=724) was obtained from spiral CT units using a same CT protocol. Mean values of CTDIvol was a range of 48.6 mGy for head and 6.9, 10.5 mGy for chest, abdomen examinations, respectively. And mean values of DLP was range of 1,604 mGy.cm for head, 250 mGy.cm for chest, 575 mGy.cm for abdomen examinations, respectively. Mean effective dose values for head, chest, abdominal CT were 3.6, 4.2, and 8.6 mSv, respectively. The degree of CTDIvol and DLP was a positive correlation with weight. And there was a positive correlation for weight versus CTDIvol (r2=0.62), DLP (r2=0.694) in chest. And head was also positive correlation with weight versus CTDIvol (r2=0.691), DLP (r2=0.741). We conclude that CTDIvol and DLP is an important determinant of weight within the CT examinations. The results for this study suggest that CT protocol should be tailored according to patient weight.
Abdomen ; Adult ; Antineoplastic Combined Chemotherapy Protocols ; Cone-Beam Computed Tomography ; Cytarabine ; Gynecological Examination ; Head ; Humans ; Subject Headings ; Thioguanine ; Thorax ; Tomography, Spiral Computed

We investigated the outcome of idarubicin plus N4-behenoyl-1-beta-D-arabinofuranosyl cytosine (BHAC)-based chemotherapy (BHAC group, n=149) compared to idarubicin plus cytarabine-based chemotherapy (cytarabine group, n=191) for childhood acute myeloid leukemia (AML). Between January 1996 and December 2005, 340 children with AML from 5 university hospitals in Korea received the BHAC-based or cytarabine-based chemotherapy, with or without hematopoietic stem cell transplantation. After induction therapy, 264 (77.6%) of 340 children achieved a complete remission (CR) and 43 (12%) achieved a partial remission (PR). The CR rate in the BHAC group was higher than in the cytarabine group (85.2% vs. 71.7%, P=0.004). However, the overall response rate (CR+PR) was not different between the two groups (93.3% vs. 87.9%, P=0.139). The 5-yr estimates of overall survival (OS) of children in the two groups were similar (54.9% for the BHAC group vs. 52.4% for the cytarabine group, P=0.281). Although the results were analyzed according to the treatment type and cytogenetic risk, the OS showed no significant difference between the BHAC group and the cytarabine group. In the present study, the clinical outcomes of the BHAC-based chemotherapy, consisting of BHAC, idarubicin, and 6-TG, are comparable to that of the cytarabine-based chemotherapy for childhood AML.
Adolescent ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Child ; Child, Preschool ; Combined Modality Therapy ; Cytarabine/*analogs & derivatives/*therapeutic use ; Cytogenetics ; Female ; Hematopoietic Stem Cell Transplantation ; Humans ; Idarubicin/*therapeutic use ; Infant ; Infant, Newborn ; Leukemia, Myeloid, Acute/*drug therapy/mortality ; Male ; Republic of Korea ; Retrospective Studies ; Survival Analysis ; Thioguanine/*therapeutic use ; Young Adult