Chih Cheng Hsiao

IKZF1 deletions predict a poor prognosis in children with B‐cell progenitor acute lymphoblastic leukemia: A multicenter analysis in Taiwan

Despite current risk‐directed therapy, approximately 15–20% of pediatric patients with acute lymphoblastic leukemia (ALL) have relapses. Recent genome‐wide analyses have identified that an alteration of IKZF1 is associated with very poor outcomes in B‐cell progenitor ALL. In this study, we determined the prognostic significance of IKZF1 deletions in patients with childhood ALL. This study analyzed 242 pediatric B‐cell progenitor ALL patients in Taiwan. We developed a simple yet sensitive multiplex quantitative PCR coupled with capillary electrophoresis to accurately determine the allele dose of IKZF1, and high resolution melting was used for mutation screening for all coding exons of IKZF1. Twenty‐six (10.7%) pediatric B‐cell progenitor ALL patients were found to harbor these deletions. Most of the deletions were broader deletions that encompassed exon 3 to exon 6, consistent with previous reports. Genomic sequencing of IKZF1 was carried out in all cases and no point mutations were identified. Patients with IKZF1 deletions had inferior event‐free survival (P < 0.001), and overall survival (P = 0.0016). The association between IKZF1 deletions and event‐free survival was independent of age, leukocyte count at presentation, and cytogenetic subtype by multivariate Cox analysis (P = 0.003, hazard ratio = 2.45). This study indicates that detection of IKZF1 deletions upon diagnosis of B‐cell progenitor ALL may help to identify patients at risk of treatment failure. IKZF1 deletions could be incorporated as a new high‐risk prognostic factor in future treatment protocols. To the best of our knowledge, this is the first study to examine the poor prognosis of IKZF1 deletions in an Asian population. (Cancer Sci 2011; 102: 1874–1881)

Differential expression of delta-like gene and protein in neuroblastoma, ganglioneuroblastoma and ganglioneuroma

Neuroblastoma is an extremely malignant solid tumor in children, characterized by spontaneous differentiation and regression. An epidermal growth factor-like homeotic protein, delta-like (dlk), has been involved in differentiation of neuroblastoma cell lines, but is unknown in in vivo expression of neuroblastoma. By using in situ hybridization and immunohistochemistry, dlk mRNA and protein expression were studied in formalin-fixed archival tissues from 10 patients with neuroblastoma, five with ganglioneuroblastoma, and five with ganglioneuroma. Three adrenal tissues from children died of diseases other than adrenal tumors and one from an adult with pheochromocytoma were severed as normal and disease controls. The results showed strong immunoreactive dlk staining in endothelial cells in neuroblastoma, ganglioneuroblastoma and ganglioneuroma. Dlk was detectable in mature neuromatous stroma and gangliocytes of ganglioneuroma, but not in neuroblasts of neuroblastoma and ganglioneuroblastoma, neither in gangliocytes of ganglioneuroblastoma. In contrast, dlk mRNA expression was mainly observed in the gangliocytes, but was less intense in the neuroblasts and neuromatous stroma cells. Endothelial cells were essentially devoid of dlk mRNA expression. The findings indicated that there is differential expression of dlk gene and protein among neuroblastoma, ganglioneuroblastoma and ganglioneuroma. The stronger expression of dlk in gangliocytes in ganglioneuroma, in contrast to weaker or no expression in gangliocytes in ganglioneuroblastoma and neuroblasts in neuroblastoma, suggests upregulation of dlk during differentiation of neuroblastoma into more benign form. Furthermore, higher dlk protein expression in the tumor endothelium than in the endothelium of normal adrenal gland implies that dlk may regulate the endothelial function in neuroblastic tumors.

Deferiprone or deferoxamine vs. combination therapy in patients with β-thalassemia major: A case study in Taiwan

Deferiprone (L1) has been recommended as an effective oral chelation therapy for patients with β-thalassemia major (TM). From 1999 to 2004, 114 patients with TM from five treatment centers were enrolled in this program: iron (Fe) was chelated with L1 in 57 patients, deferoxamine (DFO) in 26, and combined L1/DFO therapy in 31. We found that serum ferritin (SF) was significantly lower in nine patients receiving L1 for more than 5 years (p = 0.04), 22 patients receiving L1 for 1–2 years (p < 0.01) and 31 receiving the combined therapy (p = 0.01), yet significantly higher in those receiving DFO only (p < 0.01). One patient showed transient neutropenia; arthropathy in one patient and gastrointestinal upset in two were noted, with no significant change in alanine aminotransferase (ALT) level. Of 17 patients who were submitted to a liver biopsy, 15 showed no significant change in hepatic fibrosis scores after therapy with L1. None of the 88 patients, including 31 who received the combined therapy, have abandoned oral L1 treatment due to adverse effects. Results of this study proved that L1 or combined therapy with L1 and DFO is effective in reducing SF; incidence of adverse events was low in patients with TM.

Evaluating the acceptability and efficacy of a psycho-educational intervention for coping and symptom management by children with cancer: a randomized controlled study.

AIMS To evaluate the acceptability and efficacy of a psycho-educational intervention designed to improve effective coping and reduce symptom severity in children with cancer. BACKGROUND Cancer treatments increase survival rates and also cause physical and psychological effects on children with cancer. A psycho-educational intervention is used to assist children and adolescents with these effects and its efficacy has been described in several studies. DESIGN A randomized controlled trial. METHODS Participants being treated were recruited and randomly assigned to two groups from September 2011-February 2013 in Taiwan. The intervention group received a psycho-educational intervention in addition to standard care, while the control group received only standard care. Each participant was assessed using a paediatric cancer coping scale and perceived symptom severity was evaluated at three time points (baseline, 1 month and 3 months). A repeated-measures analysis of variance was used to estimate the effects of intervention. Qualitative findings were analysed using content analysis. RESULTS No significant difference in coping scores was found between groups, but the experimental group reported significantly lower scores in gastrointestinal problems and pain. Most symptoms decreased significantly over time in both groups, except for gastrointestinal problems. The scores in pain, bone marrow suppression and body image showed significant interaction effects between groups on changes over time. Qualitative results reported that participants evaluated the intervention positively, especially about receipt of psychological support and learnt coping skills. CONCLUSIONS The psycho-educational intervention administered was acceptable for children with cancer and was found to reduce gastrointestinal problems and pain.

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T-cell acute lymphoblastic leukemia.

The absence of biallelic TCRγ deletion (ABD) is a characteristic of early thymocyte precursors before V(D)J recombination. The ABD was reported to predict early treatment failure in T‐cell acute lymphoblastic leukemia (ALL). This study aimed to investigate its prognostic value in Taiwanese patients with T‐cell ALL.

Update on Thalassemia Treatment in Taiwan, Including Bone Marrow Transplantation, Chelation Therapy, and Cardiomyopathy Treatment Effects

Over the past few decades, Taiwan has seen striking improvements in the life expectancy of its 400 registered β-thalassemia major (β-TM) patients due mainly to adequate transfusion regimens and effective iron chelation therapy. Since 1995, Taiwanese citizens have enjoyed universal health care through National Health Insurance (NIH), receiving comprehensive treatment at minimal cost. In 1984, a national program for thalassemia prevention, control, and hematopoietic stem cell transplantation (HSCT) was initiated. Recent data show 1- and 2-year event-free survival rates of 85 and 78%, respectively. Chelation agents like deferoxamine (DFO), deferiprone (L1) and deferasirox (DFRA) are available in Taiwan, and therapy is tailored to individuals based on drug availability and tissue distribution of iron load. Intensive chelation regimens combining L1 and DFO are recommended in patients with cardiac complications, while DFRA has been found to be effective in reducing serum ferritin, with acceptable side effects. Here, we report advances in thalassemia treatment in Taiwan and suggest treatment guidelines.

Childhood Langerhans cell histiocytosis increased during El Niño 1997-98: A report from the Taiwan Pediatric Oncology Group

From 1995-1999, a nation-wide study of Langerhans cell histiocytosis (LCH) in children less than 15 years old was conducted by the Taiwan Pediatric Oncology Group. The demographic and clinical data of 55 cases were analyzed. Thirty-two cases presented from the beginning of 1997 to the end of 1998, when the most severe El Niño in the century occurred. The incidence was higher than expected during this El Niño period (32 cases versus 22 cases, p = 0.003). During 1997-98, most LCH was diagnosed in summer (n = 15), autumn (n = 8), and winter (n = 8) but rarely in spring (n = 1); coincidentally, rainfall was least in winter but peaked in summer. During 1997-98, the most significant increase occurred in the polyostotic LCH subcategory (p = 0.017), with younger ages at diagnosis (p = 0.039). The incidence of LCH cytopenia, fever, and diseases of the skin, liver, spleen or other organs did not differ significantly. Local treatment modality, disseminated diseases and diagnosis during the El Niño of 1997-98 were independent risk factors predicting the recurrence or progression of LCH. Our findings suggest that particular infections or other environmental factors associated with El Niño might be related to the etiology of childhood LCH.

Multiplex reverse transcription-polymerase chain reaction as diagnostic molecular screening of 4 common fusion chimeric genes in Taiwanese children with acute lymphoblastic leukemia

Background The classification of B-lineage acute lymphoblastic leukemia (ALL) by specific chromosomal translocations has prognostic implications for risk-directed therapy. Reverse transcription-polymerase chain reaction (RT-PCR) assay is a useful tool for detecting fusion transcripts from common chromosomal translocations of ALL cells. Methods Multiplex RT-PCR and nested-PCR assays were used to detect ALL-type BCR-ABL1 transcripts of the t(9;22), TCF-PBX1 transcripts of t(1;19), the MLL-AF4 transcripts of t(4;11), and 2 variants of ETV6-RUNX1 of the cryptic t(12;21) in 148 leukemic samples upon diagnosis. The patients received risk-directed protocols of the Taiwan Pediatric Oncology Group-ALL-2002 that consisted of multiple chemotherapeutic agents of different intensities. Event-free survival (EFS) and overall survival (OS) rates were analyzed for genetic abnormalities detected by multiplex PCR and conventional cytogenetic analysis by the Kaplan-Meier method, and compared with the Mantel-Haenszel test. The Cox proportional hazards model was implemented to identify independent prognostic factors for EFS and OS. Results In this cohort of Taiwanese children, the relative frequencies of the 4 translocations of B-lineage ALL were 8% with ALL-type t(9;22)/BCR-ABL1, 4% with (1;19)/TCF-PBX1, 2% with t(4;11)/MLL-AF4, and 17.6% with t(12;21)/ETV6-RUNX1. Patients with t(12;21)/ETV6-RUNX1 fusion, hyperdiploidy, and t(1;19)/TCF-PBX1 fusion had the most favorable outcomes, whereas those with the t(9;22)/BCR-ABL1 fusion or t(4;11) and other MLL gene rearrangement had poor prognosis (P<0.001 for EFS and OS). BCR-ABL1, MLL gene rearrangement, and very high-risk group were independent prognostic factors after Cox regression analysis. Conclusions The biological factors of leukemia cells are associated with treatment outcomes in childhood ALL. Multiplex RT-PCR assay is an efficient and sensitive diagnostic tool that may improve the ability to accurately and rapidly risk-stratify children with ALL.

Treatment for childhood acute lymphoblastic leukemia in Taiwan: Taiwan Pediatric Oncology Group ALL-2002 study emphasizing optimal reinduction therapy and central nervous system preventive therapy without cranial radiation

Reinduction therapy has improved the outcomes in children with acute lymphoblastic leukemia (ALL). We sought to determine the optimal course(s) of reinduction therapy for standard‐risk (SR, or “low‐risk” in other groups) patients. Also, we evaluated outcomes using triple intrathecal therapy without cranial radiation (CrRT) for central nervous system (CNS) preventive therapy.

Outcomes Following Discontinuation of E. coli l-Asparaginase Upon Severe Allergic Reactions in Children With Acute Lymphoblastic Leukemia

Discontinuation of E. coli l‐asparaginase in patients with acute lymphoblastic leukemia (ALL) is unavoidable upon severe allergic reaction. We sought to examine outcomes following E. coli l‐asparaginase discontinuation due to severe allergic reactions.