Outcome of medulloblastoma in children treated with reduced-dose radiation therapy plus adjuvant chemotherapy.

Medulloblastoma is the most common malignant brain tumor in children. Post-surgical craniospinal irradiation (CSI; 30-36 Gy) plus local boost radiation therapy (RT; 54-56 Gy) is a standard treatment for children with medulloblastoma who are over 3 years old, resulting in a 5-year overall survival (OS) rate of 46% to 65% in average-risk patients and 50% in high-risk patients. The addition of chemotherapy has the benefit of reducing complications from radiation and improving the OS rate. Using this approach, the estimated 5-year OS rates for patients with average- and high-risk medulloblastomas treated with different protocols are 65% to 85% and 16% to 70%, respectively. In this study, we determined the outcome of patients with average- and high-risk medulloblastomas treated with reduced dosage CSI and chemotherapy with an oral etoposide-based regimen. The study included 49 patients, with a mean age of 7.7 ± 3.4 years. Twenty-six patients (53%) were classified as average-risk and 23 patients (47%) as high-risk. In the average-risk group, the 5-year progression free survival (PFS) rate was 62.9% ± 10% and the 5-year OS rate was 70.4% ± 9.5%. In the high-risk group the 5-year PFS rate was 48.9% ± 13% and the 5-year OS rate was 49.7% ± 13%. In the average-risk group, patients who received CSI of either 24 Gy (n=20) or 36 Gy (n=9) showed no difference in their 5-year PFS and OS rates. We found that patients who were ≤ 10 years old and patients who were female had a significantly better 5-year PFS rate.

Persistent hyperinsulinemic hypoglycemia of infancy associated with congenital neuroblastoma: a case report.

The authors report a rare case of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) with congenital neuroblastoma without feature(s) of Beckwith-Wiedemann syndrome. A term newborn with a birth weight of 3,900 g developed hypoglycemia one hour after birth and required up to 20 mg/kg/min of intravenous glucose infusion to maintain euglycemia. Investigations during the critical period revealed an inappropriately high insulin level. An abdominal CT scan revealed a normal pancreas, right suprarenal mass, and liver nodules. A condition of stage 4S neuroblastoma was suspected and supported by an increased ratio of urine vanillylmandelic acid to creatinine. The bone marrow smear was normal. She underwent near total pancreatectomy at the age of 2 months. The suprarenal mass and liver nodules were not found during the operation or during repeated abdominal CT scans at 3 month of age. Spontaneous regression of neuroblastoma was suspected. The pathology of the pancreas was compatible with PHHI.

Late effects in survivors of childhood acute lymphoblastic leukemia: a study from Thai Pediatric Oncology Group.

Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk of long-term late effects. Therefore, systematic screenings of the late complications are essential. The objective of this study was to determine the prevalence of late effects of Thai children and adolescents after completion of ALL therapy. We performed a cross-sectional study for evaluation of the late effects in ALL survivors who came for follow-up at 10 pediatric oncology centers in Thailand. We evaluated the treatment-related late complications of children and adolescents who had finished ALL treatment for at least 2 years. Demographic data, treatment modalities, and late effects were recorded and analyzed. There were 258 survivors with a median age of 12.2 years (range 3.6-23.3 years). The median follow-up time was 7.2 years (range 2-17.5 years). Forty-seven percent (122 cases) suffered from at least one late effect. Overweight/obesity was the most common late effect. Radiation of central nervous system was a significant risk factor for overweight/obesity (OR 1.97, 95% CI 1.02-3.81) and educational problems (OR 4.3, 95% CI 1.32-14.02). Our data have demonstrated a significant prevalence of late effects after childhood ALL therapy. A long-term follow-up program for survivors of childhood cancer is therefore needed in our country.

Inhibitory effect of curcumin on MDR1 gene expression in patient leukemic cells.

When patients with cancers are treated with chemotherapeutic agents a long time, some of the cancer cells develop the multidrug resistance (MDR) phenotype. MDR cancer cells are characterized by the overexpression of multidrug resistance1(MDR1) gene which encodes P-glycoprotein (Pgp), a surface protein of tumor cells that functions to produce an excessive efflux and thereby an insufficient intracellular concentration of chemotherapeutic agents. A variety of studies have sought potent MDR modulators to decrease MDR1 gene expression in cancer cells. Our previous study has shown that curcumin exhibits characteristics of a MDR modulator in KB-V1 multidrug-resistant cells. The aim of this study was to further investigate the effect of curcumin on MDR1 gene expression in patient leukemic cells. The leukemic cells were collected from 78 childhood leukemia patients admitted at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand, in the period from July 2003 to February 2005. There were 61 cases of acute lymphoblastic leukemia (ALL), 14 cases of acute myeloblastic leukemia (AML), and 3 cases of chronic myelocytic leukemia (CML). There were 47 males and 31 females ranging from 1 to 15 years old. Bone marrows were collected. The leukemic cells were separated and cultured in the presence or absence of 10 microM curcumin for 48 hours. MDR1 mRNA levels were determined by RT-PCR. It was found that curcumin reduced MDR1 gene expression in the cells from 33 patients (42%). Curcumin affected the MDR1 gene expression in 5 of 11 relapsed cases (45%), 10 of 26 cases of drug maintenance (38%), 7 of 18 cases of completed treatment (39%), and 11 of 23 cases of new patients (48%). The expression levels of MDR1 gene in leukemic patient cells as compared to that of KB-V1 cells were classified as low level (1-20%) in 5 of 20 cases (25%), medium level (21-60%) in 14 of 32 cases (44%), and high level (61-100%) in 14 of 20 cases (70%). In summary, curcumin decreased MDR1 mRNA level in patient leukemic cells, especially in high level of MDR1 gene groups. Thus, curcumin treatment may provide a lead for clinical treatment of leukemia patients in the future.

Curcumin inhibits WT1 gene expression in human leukemic K562 cells.

AIM: Wilms' tumor1 (WT1) gene is highly expressed in leukemic blast cells of myeloid and lymphoid origin. Thus, WT1 mRNA and protein serve as promising tumor markers for the detection of leukemia and monitoring of disease progression. The purpose of this study was to investigate the modulating effects of curcumin on WT1 gene expression in the human leukemic cell line K562. METHODS: The cytotoxicity of curcumin on the K562 cell line was evaluated by using 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. The K562 cell line was treated with a non-cytotoxic dose of curcumin (5, 10, or 15 micromol/L) for 13 d. The expression levels of WT1 protein and WT1 mRNA were assessed by Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR), respectively. RESULTS: Curcumin had a cytotoxic effect on K562 leukemic cells with an inhibitory concentration at 50% (IC50) of approximately 20 microg/mL (54.3 micromol/L). Non-cytotoxic doses of curcumin, at concentrations of 5, 10, and 15 micromol/L for 2 d, decreased the level of WT1 protein and WT1 mRNA in the K562 cell line in a dose-dependent manner. Similarly, curcumin at a concentration of 10 micromol/L significantly decreased the level of WT1 protein and mRNA in a time-dependent manner. CONCLUSION: The inhibitory effects of curcumin are associated with a decrease in the levels of both WT1 protein and WT1 mRNA. The current study provides a molecular basis for future clinical trials in leukemic patients. Thus, curcumin could be a promising chemotherapeutic agent for human leukemia.

Inhibitory effect of curcumin on WT1 gene expression in patient leukemic cells.

Leukemias are common worldwide. Wilms' tumor1 (WT1) protein is highly expressed in leukemic blast cells of myeloid and lymphoid origin. Thus, WT1 mRNA serves as a tumor marker for leukemias detection and monitoring disease progression. Curcumin is well known for its anti-cancer property. The objective of this study was to investigate the effect of curcumin on WT1 gene expression in patient leukemic cells. The leukemic cells were collected from 70 childhood leukemia patients admitted at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand, in the period July 2003 to February 2005. There were 58 cases of acute lymphoblastic leukemia (ALL), 10 cases of acute myeloblastic leukemia (AML), and 2 cases of chronic myelocytic leukemia (CML). There were 41 males and 29 females ranging from 1 to 15 years old. Leukemic cells were cultured in the presence or absence of 10 mM curcumin for 48 h. WT1 mRNA levels were determined by RT-PCR. The result showed that curcumin reduced WT1 gene expression in the cells from 35 patients (50%). It affected the WT1 gene expression in 4 of 8 relapsed cases (50%), 12 of 24 cases of drug maintenance (50%), 7 of 16 cases of completed treatment (44%), and 12 of 22 cases of new patients (54%). The basal expression levels of WT1 gene in leukemic patient cells as compared to that of K562 cells were classified as low level (1-20%) in 6 of 20 cases (30%), medium level (21-60%) in 12 of 21 cases (57%), and high level (61-100%) in 17 of 23 cases (74%). In summary, curcumin decreased WT1 mRNA in patient leukemic cells. Thus, curcumin treatment may provide a lead for clinical treatment in leukemic patients in the future.

Hospital-based epidemiologic survey of malignancies in children infected with human immunodeficiency virus in Thailand.

To determine the incidence and spectrum of malignancies in human immunodeficiency virus-infected children, we surveyed 48 hospitals in Thailand between 1996 and 2000. There were 23 children (14 boys and 9 girls; average age at diagnosis of malignancy, 4.2 years), and the incidence rate was 0.6 per 1000 person-years. The most common malignancy was lymphoma (87.0%). The prognosis was poor.

Molecular and clinical features of Hb H disease in northern Thailand.

Clinical assessment, hematological studies and molecular analyses were performed in 102 pediatric patients with Hb H disease in northern Thailand. A total of six mutations of the alpha-globin gene, which produced five genotypes, were detected. All patients had an alpha(0)-thalassemia (thal) deletion on one chromosome 16. All but one of these were of the South East Asian type (--SEA); one patient had the THAI deletion (--THAI). The deletional alpha(+)-thal mutations comprised 3.7 kb (-alpha(3.70) and 4.2 kb (-alpha(4.2)) deletions which were found in 34 (33.3%) and 10 (9.8%) alleles, respectively. The nondeletional alpha(+)-thal mutations comprised 55 (53.9%) alleles of Hb Constant Spring (CS) (alpha142, TAA --> CAA) and three (2.9%) alleles of Hb Pakse (alpha142, TAA --> TAT). Six patients with Hb H-CS disease also carried Hb E (AEBart's CS disease). The clinical features were diverse and the nondeletional genotypes were associated with more severe clinical and hematological features, including younger age at presentation, larger size of liver and spleen, lower hemoglobin (Hb) level, and higher transfusion requirements. The high proportion of nondeletional Hb H disease observed in this study was inconsistent with the previously reported gene frequencies of alpha-thal in the region, suggesting that many deletional Hb H patients with milder symptoms may have escaped recognition.

Hemoglobin E levels in double heterozygotes of hemoglobin E and SEA-type alpha-thalassemia.

Coinheritance of alpha-thalassemia and hemoglobin E (Hb E) is prevalent in Thailand, where the gene frequencies of thalassemia and hemoglobinopathies are high. Hb E carriers with, concomitant inheritance of alpha-thalassemia 1 are known to have a lower level of Hb E. In this study, we reviewed the Hb E levels in Hb E carriers, who either had or did not have Southeast Asian (SEA)-type alpha-thalassemia, in order to seek a Hb E level that may be used as a predictor for concomitant alpha-thalassemia carrier status. The Hb E levels as measured by microcolumn chromatography in 844 Hb E carriers detected during a prenatal screening program for severe thalassemia at Chiang Mai University Hospital were reviewed. Hb E levels ranged from 12.3-35.0% (23.3 +/- 3.1%) in 751 Hb E carriers without SEA-type alpha-thalassemia and from 11.6-32.0% (17.0 +/- 3.7%) in 93 concomitant Hb E and SEA-type alpha-thalassemia carriers. The difference was significant (p < 0.01). However, the absence of SEA-type alpha-thalassemia could not be predicted by the higher Hb E level alone, as 3% of double heterozygotes demonstrated a level of more than 25%. Our study confirms a lower Hb E level in double heterozygotes with Hb E and SEA-type alpha-thalassemia. Nevertheless, the difference does not provide sufficient discriminatory power for the reliable exclusion of alpha-thalassemia status.

The use of recombinant activated factor VII for controlling life-threatening bleeding in Dengue Shock Syndrome.

To report the use of recombinant activated factor VII (rFVIIa) in controlling life-threatening bleeding episodes in patients with grades III and IV Dengue Hemorrhagic Fever (DHF), also known as Dengue Shock Syndrome. Fifteen patients (seven boys, eight girls), whose median age was 8 years, were enrolled in the study. They were divided into two groups. Group 1 included nine patients, mainly grade III, waiting for platelet concentrate, and group 2 included six patients, mainly grade IV, who had already received platelet concentrate with unresponsiveness. A single dose or repeated doses of 100 microg/kg rFVIIa was/were given at intervals of 4 h according to the bleeding symptoms. The median times from the onset of bleeding to rFVIIa initiation were 6.5 and 29.8 h in groups 1 and 2, respectively. Each patient received one to three doses. An effective response was found in eight patients (53.3%), including six patients in group 1 and two patients in group 2. They had complete cessation of bleeding without recurrence for 48 h. An ineffective response was found in seven patients (46.7%) including three patients in group 1 and four patients in group 2 for which the bleeding recurred (n = 2), temporarily slowed down (n = 3), continued (n = 1) or occurred at a new site (n = 1). These included three patients in profound shock 24-48 h before referral to comprehensive treatment centers, two patients receiving ibuprofen before hospitalization, one patient with extensive volume overloading, and one patient requiring surgical intervention to ligate the torn intercostal artery and vein. The platelet concentrate was promptly transfused to stop bleeding in patients with ineffective responses. The results revealed that the earlier initiation of rFVIIa in the mainly grade III DHF in group 1 yielded a higher effective response (66.7%) than the delayed initiation in the mainly grade IV DHF in group 2 (33.3%). Moreover, patients previously receiving ibuprofen or volume expander of low molecular weight dextran or urea-linked gelatin tended to have lower effective responses (28.6%) than patients without associated medication (75.0%). Ultimately, three of six patients with grade IV DHF died, while all nine patients with grade III DHF survived. Thus, the case-fatality rate in this study was 20%. No clinical evidence of thromboembolic complications was observed. rFVIIa seems to be effective in restoring hemostasis in a limited series of patients with Dengue Shock Syndrome exhibiting life-threatening bleeding episodes. Further study is warranted.

Hematological and molecular characterization of beta-thalassemia/Hb Tak compound heterozygote.

We report a case of beta-thalassemia/Hb Tak compound heterozygote. The 7 year-old Thai boy presented with plethora since birth. Hemoglobin electrophoresis showed a major band between Hb A2 and Hb F and absent Hb A. DNA sequencing study demonstrated an AC insertion at the terminal codon of the beta-globin gene. The clinical feature of polycythemia reflected a high oxygen affinity of Hb Tak.

Psychosocial problems in children with thalassemia and their siblings.

Beta-thalassemia is a chronic illness causing serious symptoms to children and a burden to families. The purpose of this study was to evaluate psychosocial problems in children with thalassemia and their siblings by using a semi-structured interview and the Pediatric Symptom Checklist (PSC). The study sample included 82 children with thalassemia, 20 siblings, and 50 control children without a chronic illness. With children and families demographically controlled, psychosocial problems were significantly more common in children with thalassemia than in those without chronic illness, 28.05 per cent vs 4 per cent (p=0.001), but there was no difference between siblings and the controls, 5 per cent vs 4 per cent (p=0.64). The mean PSC score in children with thalassemia was higher than that in the sibling and control group (18.34 vs 10.95 and 10.28, respectively; p<0.001). These findings suggest an increased risk of psychosocial problems in children with thalassemia that psychosocial intervention may be required to prevent major psychiatric disorders.