Partição de Comprimidos Antineoplásicos Utilizados no Tratamento de Leucemias Agudas em Crianças e Adolescentes / Splitting of Antineoplastic Tablets Used in Acute Leukemias Treatment in Children and Adolescents / Partición de Comprimidos Antineoplásicos Empleados en el Tratamiento de Leucemias Agudas en Niños y Adolescentes

Introdução: A manipulação de antineoplásicos para ajuste de dose, como partição de comprimidos, é comum no tratamento de leucemias agudas de crianças e adolescentes. Objetivo: Identificar a frequência e descrever a prática da partição domiciliar de comprimidos antineoplásicos utilizados no tratamento oral de crianças e adolescentes com leucemias agudas na fase de manutenção. Método: Trata-se de um estudo transversal descritivo, realizado em um hospital pertencente à rede de saúde pública do Distrito Federal com assistência especializada em pediatria. Foram incluídos no estudo crianças e adolescentes entre 1 e 18 anos, diagnosticados com leucemias agudas e em fase de manutenção do tratamento no período de estudo. Foi aplicado um questionário semiestruturado ao responsável principal pela administração dos medicamentos quimioterápicos via oral, podendo ser o cuidador ou a própria criança/adolescente. Foram coletadas variáveis sociodemográficas dos pacientes e cuidadores e variáveis sobre a prática de partição de medicamentos antineoplásicos no domicílio. Resultados: Todos os 48 entrevistados no período do estudo relataram ter partido comprimidos antineoplásicos ao longo do tratamento de leucemias agudas, sendo estes mercaptopurina (n=45 [93,75%]) e tioguanina (n=3 [6,25%]). Conclusão: A partição de comprimidos antineoplásicos foi uma prática unânime em virtude da necessidade referida de ajuste de dose individual para o tratamento de leucemias agudas de crianças e adolescentes, considerando a indisponibilidade de formulações adequadas. Os resultados reforçam a necessidade de a partição ser uniformizada e realizada de maneira a minimizar os riscos e a garantir a segurança para as crianças e adolescentes e seus cuidadores.

Introduction: Antineoplastic drug manipulation for dose adjustment, such as tablet splitting, is standard in acute leukemia treatment for children and adolescents. Objective: To identify the frequency and describe the practice of household splitting of antineoplastic tablet for oral treatment of children and adolescents with acute leukemias in the maintenance phase. Method: Cross-sectional descriptive study performed in a public health system hospital from Distrito Federal (Brazil) with specialized pediatric assistance. Children and teenagers between 1 and 18 years old, diagnosed with acute leukemia and in treatment maintenance phase during the study period were included. A semi-structured questionnaire was applied to the main responsible for administering oral chemotherapy drugs, which could be the caregiver or the child/adolescent themselves. Sociodemographic variables of patients and caregivers and variables on the practice of splitting antineoplastic drugs at home were collected. Results: All 48 interviewees in the study period reported having split antineoplastic tablets during the treatment for acute leukemias, such as mercaptopurine (n = 45 [93.75%]) and thioguanine (n = 3 [6.25%]). Conclusion: The splitting of antineoplastic tablets was a unanimous practice due to the reported need to adjust the individual dose for acute leukemia treatment in children and adolescents, considering the unavailability of adequate formulations. The results reinforce the need for splitting to be standardized and performed in a way that minimizes risks and ensures safety for patients and their caregivers

Introducción: La manipulación de fármacos antineoplásicos para el ajuste de dosis, como las particiones de comprimidos, es frecuente en el tratamiento de las leucemias agudas en niños y jóvenes. Objetivo: Identificar la frecuencia y describir la práctica de la división domiciliaria de medicamentos antineoplásicos utilizados en el tratamiento oral de niños y adolescentes con leucemias agudas en la fase de mantenimiento. Método: Se trata de un estudio transversal descriptivo realizado en un hospital de la red de salud pública del Distrito Federal (Brasil) con asistencia especializada en pediatría. El estudio incluyó a niños y jóvenes de entre 1 y 18 años de edad diagnosticados con leucemia aguda y en fase de mantenimiento del tratamiento en el período del estudio. Se aplicó un cuestionario semiestructurado a la persona principal responsable de la administración de fármacos quimioterapéuticos por vía oral, que puede ser el cuidador o el propio niño/joven. Fueron colectadas variables sociodemográficas de los pacientes y cuidadores y variables sobre la práctica de la división de los medicamentos antineoplásicos en domicílios. Resultados: Los 48 entrevistados en el período de estudio informaron haber roto las pastillas antineoplásicas durante el tratamiento de la leucemia aguda, siendo éstas mercaptopurina (n=45 [93,75%]) y tioguanina (n=3 [6,25%]). Conclusión: La partición de comprimidos antineoplásicos fue una práctica unánime debido a la necesidad mencionada de ajustar la dosis individual para el tratamiento de las leucemias agudas de niños y adolescentes, considerando la falta de formulaciones apropiadas. Los resultados refuerzan la necesidad de estandarizar y realizar la partición para minimizar los riesgos y garantizar la seguridad de los niños, jóvenes y sus cuidadores.

NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia / Journal of the Korean Cancer Association, 대한암학회지

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.

Evaluation of Stability of Thiopurine Metabolites Using a Validated LC-MS/MS Method

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.

Thiopurine S-Methyltransferase Polymorphisms in Korean Dermatologic Patients

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.

Progress of Research on 6-Thioguanine versus 6-Mercaptopurine in childhood ALL / 中国实验血液学杂志

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.

6-Thioguanine-Induced Hepatic Sinusoidal Obstruction Syndrome in a Leukemic Child with TPMT Heterozygote / 임상소아혈액종양

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-Thioguanine-Induced Hepatic Sinusoidal Obstruction Syndrome in a Leukemic Child with TPMT Heterozygote / 임상소아혈액종양

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.

3-Dimensional Dosimetry of Small Field Photon Beam / 의학물리

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.

Improving the outcomes of elderly patients with acute myeloid leukemia in a Brazilian University Hospital

OBJECTIVE: To evaluate the outcomes of acute myeloid leukemia patients who were older than 60 years of age at the time of diagnosis following the implementation of a treatment algorithm based on age, performance status, and cytogenetic results. METHODS: We retrospectively compared the results of 31 elderly acute myeloid leukemia patients (median age of 74 years) who were treated according to the new algorithm. RESULTS: Fifteen patients with a good performance status and no unfavorable karyotypes were treated with either intensive cytotoxic chemotherapy (<70 years, nine cases) or adapted etoposide, 6-thioguanine and idarubicine (>70 years, six cases); 16 cases with a poor performance status or unfavorable cytogenetics received supportive care only. Six patients achieved a complete remission and two achieved a partial remission after chemotherapy. There were three toxic deaths during induction, two in the adapted etoposide, 6-thioguanine and idarubicine group and one in the intensive cytotoxic chemotherapy group. The overall median survival time was 2.96 months, 1.3 months in the supportive care group, and 4.6 months in the treatment group. CONCLUSIONS: Our results illustrate the importance of treatment guidelines adapted to local resources in an attempt to improve the survival of elderly acute myeloid leukemia patients in developing countries.

Clinical characteristics of hepatic veno-occlusive disease in 6 children with hematologic neoplasm treated with 6-thioguanine / 中华儿科杂志

<p><b>OBJECTIVE</b>To 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.</p><p><b>METHOD</b>All 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.</p><p><b>RESULT</b>Of 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.</p><p><b>CONCLUSION</b>HVOD was a serious complication of chemotherapy with 6-TG. Hepatoprotective and jaundice-relieving and low molecular weight heparin could improve the prognosis.</p>

Idarubicin Plus Behenoyl Cytarabine and 6-thioguanine Compares Favorably with Idarubicin Plus Cytarabine-based Regimen for Children with Previously Untreated Acute Myeloid Leukemia: 10-Year Retrospective, Multicenter Study in Korea

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.

Estimate of Radiation Doses in MDCT Using Patient Weight / 의학물리

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.

Monitoração terapêutica da azatioprina: uma revisão: [revisão] / Therapeutic drug monitoring of azathioprine: a review: [review]

Os nucleotídeos de tioguanina (6-TGN), metabólitos ativos da azatioprina (AZA) e da 6-mercaptopurina (6-MP), atuam como antagonistas das purinas, inibindo as sínteses de DNA, RNA e a protéica, e induzindo à citotoxicidade/imunossupressão. A enzima geneticamente determinada, tiopurina metiltransferase (TPMT), está envolvida no metabolismo desses agentes e, hipoteticamente, determina a resposta clínica às tiopurinas. A baixa atividade dessa enzima diminui a metilação das tiopurinas, resultando em potencial sobredose, enquanto altos níveis de TPMT levam à superprodução do metabólito tóxico 6-metilmercaptopurina (6-MMP) e à não-efetividade terapêutica da AZA e da 6-MP. Várias mutações no gene da TPMT têm sido identificadas e correlacionadas com fenótipos de baixa atividade. Neste artigo, também se discute a monitoração terapêutica desses fármacos por meio da medida dos níveis de 6-TGN intra-eritrocitários, os quais se correlacionam com imunossupressão e mielotoxicidade. Já a 6-MMP está diretamente relacionada com hepatotoxicidade. Esses ensaios estão associados ao uso de doses adequadas dessa droga, resultando num melhor controle da doença e menor uso de corticosteróides.

Thioguanine nucleotides (6-TGN), active metabolites of azathioprine (AZA) and 6-mercaptopurine (6-MP), act as purine antagonists, inhibiting DNA, RNA, and protein synthesis and inducing cytotoxicity and immunosuppression. The genetically determined thiopurine methyltransferase enzyme (TPMT) is involved in the metabolism of these agents and, theoretically, determines the clinical response to thiopurines. Low activity of this enzyme decreases the methylation of thiopurines, what results in potential overdosing, whereas high TPMT status leads to overproduction of toxic metabolite 6-methilmercaptopurine (6-MMP) and ineffectiveness of AZA and 6-MP. Several mutations in the TPMT gene have been identified and correlated with low activity phenotypes. In this study, we also discuss the therapeutic monitoring of these drugs by means of red blood cell 6-TGN levels, which correlate with immunosuppression and mielotoxicity. 6-MMP is directly connected with hepatotoxicity. These metabolites assays are associated with the use of appropriate doses of this drug, what results in a better control of the disease and a decreased use of corticosteroids.

Pancreatitis Induced by 6-mercaptopurine and 6-thioguanine in Childhood Acute Lymphoblastic Leukemia / 대한혈액학회지

Although pancreatitis is known as a common complication during the treatment of acute lymphoblastic leukemia, acute pancreatitis that's induced by 6-mercaptopurine or 6-thioguanine is very uncommon. We experienced the case of an 11-year-old boy with consecutive acute pancreatitis, and this was induced by 6-mercaptopurine and 6-thioguanine during maintenance chemotherapy of childhood acute lymphoblastic leukemia. We report here on this along with a review of the pertinent literature.

Response of lymphocytes to radiation in untreated breast cancer patients as detected with three different genetic assays / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To detect the response of lymphocytes to radiation in untreated breast cancer patients with three different genetic assays.</p><p><b>METHODS</b>Blood samples were collected from 25 untreated patients and 25 controls. Each blood sample was divided into two parts: one was irradiated by 3-Gy X-ray (irradiated sample), the other was not irradiated (non-irradiated sample). The radiosensitivity of lymphocytes was assessed by comet assay, cytokinesis-block micronucleus (CBMN) assay and 6-TG-resistant cells scored (TG) assay.</p><p><b>RESULTS</b>The baseline values of micronucleated cell frequency (MCF) and micronucleus frequency (MNF) in the patients were significantly higher than those in the controls (P < 0.01), and 3-Gy X-ray induced genetic damage to lymphocytes in the patients increased significantly as compared with that in the controls as detected with the three genetic assays (P < 0.01). The proportion of radiosensitive cases in the patient group was 48% for the mean tail length (MTL), 40% for the mean tail moment (MTM), 40% for MCF, 44% for MNF, and 48% for mutation frequencies of the hprt gene (Mfs-hprt), respectively, whereas the proportion of radiosensitive cases in the control group was only 8% for all the parameters.</p><p><b>CONCLUSION</b>The difference in the lymphocyte radiosensitivity between the breast cancer patients and the controls is significant. Moreover, there are wide individual variations in lymphocyte radiosensitivity of patients with breast cancer. In some cases, the radiosensitivity of the same patient may be different as detected with the different assays. It is suggested that multiple assays should be used to assess the radiosensitivity of patients with breast cancer before therapy.</p>

An improved HPLC method for the quantitation of 6-mercaptopurine and its metabolites in red blood cells

A procedure is described for the rapid determination of the intra-erythrocyte concentration of 6-mercaptopurine (6-MP) and its metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). Erythrocytes (8 x 10(8) cells) in 350 æl Hanks solution containing 7.5 mg dithiothreitol were treated with 50 æl 70 percent perchloric acid. The precipitate was removed by centrifugation (13,000 g) and the supernatant hydrolyzed at 100§C for 45 min. After cooling, 100 æl was analyzed directly by HPLC using a Radialpack Resolve C18 column eluted with methanol-water (7.5:92.5, v/v) containing 100 mM triethylamine. 6-TG, 6-MP and the hydrolysis product of 6-MMP, 4-amino-5-(methylthio)carbonyl imidazole, were monitored at 342, 322 and 303 nm using a Shimadzu SPD-M10A diode array UV detector. The analytes eluted at 5.3, 6.0 and 10.2 min, respectively. The calibration curves were linear (rý > 0.998), and the analytical recoveries were 73.2 percent for 6-TG, 119.1 percent for 6-MP and 97.4 percent for 6-MMP. The intra- and inter-assay variations were highest for 6-MP (9.6 and 14.3 percent, respectively). The lowest detectable concentrations were 3, 3 and 25 pmol/8 x 10(8) erythrocytes for 6-TG, 6-MP and 6-MMP, respectively. The quantification limits (coefficients of variation <15 percent) were 8, 10 and 70 pmol/8 x 10(8) erythrocytes for 6-TG, 6-MP and 6-MMP, respectively. The method was applied to the analysis of 183 samples from 36 children under chemotherapy for acute lymphoblastic leukemia. The concentrations of the metabolites in the red cells of the patients ranged from 0 to 1934 pmol/8 x 10(8) erythrocytes for 6-TGN, and from 0 to 105.8 and 0 to 45.9 nmol/8 x 10(8) erythrocytes for 6-MP and 6-MMP, respectively. The procedure gave results that were in agreement with those obtained with other methods designed to detect cases of non-compliance with treatment, including patient interviews and medical evaluation, among others, demonstrating its applicability to monitoring the treatment of leukemic children.

A Case of Bronchiolitis Obliterans Organizing Pneumonia Developed after Treatment of Acute Myelogenous Leukemia (M2) with Chloroma and Retinopathy / 대한소아혈액종양학회지

Chloroma, a tumor consisted of primitive myeloid cells and located in extramedullary tissues, usually develops during or preceding the course of systemic leukemia, particularly acute myelogenous leukemia (FAB M2) with translocation between chromosomes 8 and 21. Leukemic retinopathy which observed rarely in children than adults, generally related to thrombocytopenia and anemia in leukemic patients. Bronchiolitis obliterans organizing pneumonia (BOOP) is unusual clinicopathologic syndrome in association with a variety of causes or conditions, and histologically defined by the presentation of granulation tissue plugs consisting of fibroblasts and collagen within the lumen of the distal air space. We experienced a 12-year old girl who presented with weakness and ocular pain. She was diagnosed with acute myeloid leukemia with chloroma and retinopathy, and treated with chemotherapy (daunomycin, ara-C, thioguanine, etoposide. mitoxantrone, cyclosporin). Five weeks after the chemotherapy, she developed coughing and persistent fever, and diagnosed with BOOP, which resolved completely after prednisolone therapy.

Chromosomal rearrangement in Down syndrome with acute myeloid leukemia.

The incidence of acute leukemia in children with Down syndrome (DS) is high as compared to general population. Recent findings have demonstrated that DS children with acute myeloid leukemia (AML) have the highest event free survival rates with high dose cytosine arabinoside (Ara-C). We present 3 year-old DS female child with AML-M5, whose chromosomal analysis revealed constitutional t(21;21) alongwith del(5)(q31q33) and a unique translocation t(16;20)(q13;q12). After chemotherapy, child achieved complete clinical remission. Karyotype analysis of remission marrow showed disappearance of abnormal clone of der(20) t(16;20)(q13;q12), del(5q) indicating cytogenetic remission too. This case alongwith supportive literature indicate that pediatric DS-AML is a distinct biologic sub-group differs from that of non-DS-AML with respect to chemosensitivity.

A Case of Acute Leukemia Remitted by Adding Cyclosporin-A Previously Failed with Induction Therapy

Clinical chemotherapy refractoriness is characterized by resistance to multiple drugs. Multidrug resistance(MDR) is caused by over-reactivity of a unidirectional drug efflux pump, transmembrane glycoprotein(P-glycoprotein), which is encoded by the MDR1 gene. P-glycoprotein leads to increased drug efflux and decreased intracellular drug concentration. Clinical trials that attempt to reverse or modulate MDR have been done. Cyclosporin-A and verapamil are the most extensively studied agents and several trials of cyclosporin-A as a MDR modulator have been reported. We report a case of an 8-year-old girl with acute mixed type leukemia who failed to respond 3 times to remission-induction therapy. It led us to conclude she had multidrug resistance. We tried a fourth induction chemotherapy including cytarabine, idarubicin and 6-thioguanine to which cyclosporin-A was added. Then, she showed signs of severe bone marrow depression and fulminant perianal cellulitis. But she recovered and successfully achieved complete remission. The addition of cyclosporine could be useful in achieving complete remission for cases of acute leukemia that resist to usual chemotherapy. Futher observation including more cases will be needed to assess long-term survival and efficacy of adding cyclosporine.