Tai-Tsung Chang

Long-term results of Taiwan Pediatric Oncology Group studies 1997 and 2002 for childhood acute lymphoblastic leukemia

The long-term outcome of 1390 children with acute lymphoblastic leukemia (ALL), treated in two successive clinical trials (Taiwan Pediatric Oncology Group (TPOG)-ALL-97 and TPOG-ALL-2002) between 1997 and 2007, is reported. The event-free survival improved significantly (P=0.0004) over this period, 69.3±1.9% in 1997–2001 to 77.4±1.7% in 2002–2007. A randomized trial in TPOG-97 testing L-asparaginase versus epidoxorubicin in combination with vincristine and prednisolone for remission induction in standard-risk (SR; low-risk) patients yielded similar outcomes. Another randomized trial, in TPOG-2002, showed that for SR patients, two reinduction courses did not improve long-term outcome over one course. Decreasing use of prophylactic cranial irradiation in the period 1997–2008 was not associated with increased rates of CNS relapse, prompting complete omission of prophylactic cranial irradiation from TPOG protocols, beginning in 2009. Decreased use of etoposide and cranial irradiation likely contributed to the low incidence of second cancers. High-risk B-lineage ALL, T-cell, CD10 negativity, t(9;22), infant, and higher leukocyte count were consistently adverse factors, whereas hyperdiploidy >50 was a consistently favorable factor. Higher leukocyte count and t(9;22) retained prognostic significance in both TPOG-97 and TPOG-2002 by multivariate analysis. Although long-term outcome in TPOG clinical trials is comparable with results being reported worldwide, the persistent strength of certain prognostic variables and the lower frequencies of favorable outcome predictors, such as ETV6-RUNX1 and hyperdiploidy >50, in Taiwanese children warrant renewed effort to cure a higher proportion of patients while preserving their quality of life.

Unexpected mortality from the use of E. coli L-asparaginase during remission induction therapy for childhood acute lymphoblastic leukemia: A report from the Taiwan Pediatric Oncology Group

The relative efficacy and toxicity of E. coli L-asparaginase and epidoxorubicin used in remission induction therapy for childhood acute lymphoblastic leukemia (ALL) were assessed in a randomized trial conducted in Taiwan. All patients had standard-risk ALL, defined as a leukocyte count <10 × 109/l and were aged between 1 and 2 or 7 and 10 years, or a leukocyte count <50 × 109/l and were aged between 2 and 7 years, without evidence of a T cell or mature B cell immunophenotype, central nervous system leukemia or expression of two or more myeloid-associated antigens. Ninety-three patients were randomized to receive E. coli L-asparaginase at 10 000 IU/m2 thrice weekly for nine doses and 108 to receive epidoxorubicin at 20 mg/m2 weekly for two doses during remission induction with daily prednisolone, weekly vincristine and, on day 22, a dose of etoposide plus cytarabine. Patients treated with L-asparaginase had a significantly higher rate of fatal infection with or without hemorrhage than did those who received epidoxorubicin during remission induction (six of 93 vs none of 108, P = 0.009), resulting in a lower rate of complete remission in the former group (93.6 vs 99.1%, P = 0.05). In addition, patients treated with L-asparaginase had a higher frequency of hyperglycemia and hypoalbuminemia. The overall rate of event-free survival was lower in patients treated with L-asparaginase than in other patients (P = 0.06); estimated 3-year rates were 72% (95% confidence interval, 55–89%) and 87.2% (78–96%), respectively. We conclude that L-asparaginase (Leunase) given at 10 000 IU/m2 for nine doses was poorly tolerated and resulted in excessive toxicity, both through its effects as a single agent and possibly through potentiation of etoposide.

Improved efficacy and tolerability of oral deferasirox by twice-daily dosing for patients with transfusion-dependent β-thalassemia†

Deferasirox is an oral iron‐chelating agent taken once‐daily by patients with transfusion‐dependent iron overload. However, some patients are unresponsive or unable to tolerate once‐daily deferasirox. The current study evaluated whether twice‐daily deferasirox treatment showed increased efficacy or tolerability in unresponsive or intolerant patients.

Lipid peroxidation and antioxidative status in β-thalassemia major patients with or without hepatitis C virus infection

Abstract Background: Information pertaining to the lipid peroxidation and antioxidative status of patients with β-thalassemic major, with or without hepatitis C virus infection, has been scanty. Methods: We report here the results of our efforts in the evaluation of lipid peroxidative status, antioxidants, and vitamin A, E and C levels in the sera of a group of patients (n=42) with transfusion-dependent β-thalassemic major with or without HCV infection. Results: Firstly, plasma thiobarbituric acid reactive substance, a lipid peroxidation product, in these patients was found to be increased significantly when compared to the disease-free controls (p<0.05). Conversely, levels of plasma vitamins A, E and C were all shown to be drastically reduced as compared to the disease-free controls (p<0.01). In parallel with these data, we also found that HCV infection did play some role in aggravating the depletion of plasma vitamin E and C levels in the β-thalassemic patients. In contrast, HCV infection did not seem to alter the levels of reduced glutathione (GSH) as well as antioxidant enzyme activities including superoxide dismutase and GSH peroxidase. Conclusions: Taken together, our data indicate that excessive lipid peroxidation and a profound depletion of plasma vitamin A, E and C levels exist in patients with β-thalassemic major. These data suggest that antioxidant supplementation to the patients for the purpose of alleviating the oxidative stress may be warranted. Clin Chem Lab Med 2006;44:1226–33.

Thrombocytosis in Children at One Medical Center of Southern Taiwan

Thrombocytosis in children is common, but usually without symptoms. The causes of thrombocytosis in children are considered to be mostly due to infection, trauma, surgery, blood disease, prematurity, renal disease and chronic inflammation. To evaluate the incidence and etiology of thrombocytosis of the hospitalized patients, patients who were admitted to the Pediatric Department of Kaohsiung Medical College Hospital (KMCH) from October 1996 to November 1997 were studied. There were 2910 cases studied and 220 cases (127 male and 93 female) had thrombocytosis (> or = 500 x 10(9)/L) with a rate of 7.6%. The causes of thrombocytosis are infections (49.5%), Kawasaki disease (6.4%), postsplenectomy (7.8%), blood diseases (3.7%), malignancies (3.2%), renal disorders (3.2%), prematurity (3.2%), tissue damage (4.5%), chronic inflammation (1.8%), recovery from marrow suppression (1.3%), immunologic disturbances (2.2%), essential thrombocythemia (0.5%), and miscellaneous factors (3.7%). Thrombocytosis associated with multiple, simultaneous causative factors was found in 9.0% of these cases. Thrombocytosis secondary to infectious diseases or Kawasaki disease was significantly more common in children under 2 years old. The most commonly associated infectious disease was respiratory tract infection (61.1%). There were 29 children (13.2%) presenting a platelet count of more than 800,000/mm3. However, no thrombotic complications were seen in any of the children. By far, the major cause of thrombocytosis in our cases was reactive in character. Most of the thrombocytosis cases were due to infections, inflammatory diseases, or Kawasaki disease.

Immune tolerance induction therapy for patients with hemophilia A and FVIII inhibitors particularly using low-dose regimens†

Inhibitory antibodies against infused clotting factor VIII concentrates (FVIII) developed in 20–30% of patients with hemophilia A. Bypass therapy may control the bleeds in patients with FVIII inhibitors, however, immune tolerance induction (ITI) therapy is the only proven modality for eradicating FVIII inhibitors. Since the cost of high‐dose (200 IU/kg) ITI is extremely expansive, we conducted this study to identify whether low‐dose ITI can be an alternative strategy besides high‐dose ITI or bypass therapy.

Ganglioneuroma of Posterior Mediastinum in a 6-year-old Girl: Imaging for Pediatric Intrathoracic Incidentaloma

Intrathoracic tumor is a rare entity in the pediatric population and neurogenic tumors account for 40‐50% of childhood intrathoracic tumors. They can cause severe symptoms, such as respiratory distress, neurological dysfunction and metabolic disturbances. Posterior mediastinal ganglioneuroma (GN) usually occurs in children and can be found accidentally. Precise preoperative diagnosis is very difficult and has a great influence on surgical intervention. Here, we report a 6‐year‐old girl with a posterior mediastinal GN that was found incidentally on chest radiography. Computed tomography and magnetic resonance imaging demonstrated a right paraspinal tumor with punctuate calcification and intraspinal extension. 18F‐fluorodeoxyglucose positron emission tomography revealed low‐grade fluorodeoxyglucose avidity of this tumor. Computed tomography and magnetic resonance imaging can characterize GN and positron emission tomography is helpful for differentiating benign or malignant lesions.

Efficient detection of factor IX mutations by denaturing high-performance liquid chromatography in Taiwanese hemophilia B patients, and the identification of two novel mutations

Hemophilia B (HB) is an X‐linked recessive disorder characterized by mutations in the clotting factor IX (FIX) gene that result in FIX deficiency. Previous studies have shown a wide variation of FIX gene mutations in HB. Although the quality of life in HB has greatly improved mainly because of prophylactic replacement therapy with FIX concentrates, there exists a significant burden on affected families and the medical care system. Accurate detection of FIX gene mutations is critical for genetic counseling and disease prevention in HB. In this study, we used denaturing high‐performance liquid chromatography (DHPLC), which has proved to be a highly informative and practical means of detecting mutations, for the molecular diagnosis of our patients with HB. Ten Taiwanese families affected by HB were enrolled. We used the DHPLC technique followed by direct sequencing of suspected segments to detect FIX gene mutations. In all, 11 FIX gene mutations (8 point mutations, 2 small deletions/insertions, and 1 large deletion), including two novel mutations (exon6 c.687–695, del 9 mer and c.460–461, ins T) were found. According to the HB pedigrees, 25% and 75% of our patients were defined as familial and sporadic HB cases, respectively. We show that DHPLC is a highly sensitive and cost‐effective method for FIX gene analysis and can be used as a convenient system for disease prevention.

TEL/AML1 fusion gene in childhood acute lymphoblastic leukemia in southern Taiwan.

Chromosomal abnormalities are found in 80–90% of childhood cases of acute lymphoblastic leukemia (ALL). Leukemia‐specific chromosome aberrations not only have prognostic value, but also provide important clues for further investigation into leukogenesis, leukemic cell transformation, and proliferation. This study used reverse transcriptase–polymerase chain reaction techniques to detect transcripts of the leukemia‐specific chromosome fusion gene, TEL/AML1, and to monitor the expression levels of the TEL‐AML1 fusion transcript in ALL patients at sequential intervals during their treatment course. Twenty‐five ALL patients were enrolled, including 20 who were newly diagnosed and five in relapse. The incidence of the TEL/AML1 fusion gene in this study was 32%. The clinical features of our eight TEL/AML1‐positive ALL cases were similar to those in other studies. Blotting analysis of the levels of the TEL‐AML1 fusion transcript was used to detect minimal residual disease. Reduced levels of TEL/AML1 expression were found in four of the six patients whose bone marrow or peripheral blood samples were obtained after treatment. Further investigation with a larger sample size is warranted.

Successful Large-volume Leukapheresis for Hematopoietic Stem Cell Collection in a Very-low- weight Brain Tumor Infant with Coagulopathy

Peripheral apheresis has become a safe procedure to collect hematopoietic stem cells, even in pediatric patients and donors. However, the apheresis procedure for small and sick children is more complicated due to difficult venous access, relatively large extracorporeal volume, toxicity of citrate, and unstable hemostasis. We report a small and sick child with refractory medulloblastoma, impaired liver function, and coagulopathy after several major cycles of cisplatin-based chemotherapy. She successfully received large-volume leukapheresis for hematopoietic stem cell collection, although the patient experienced severe coagulopathy during the procedures. Health care providers should be alert to this potential risk.