Chao Neng Cheng

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)

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.

Hypoalbuminaemia is an independent predictor for hemophagocytic lymphohistiocytosis in childhood Epstein-Barr virus-associated infectious mononucleosis.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal condition in children with Epstein–Barr virus (EBV)‐associated infectious mononucleosis (IM). This study aimed to identify commonly available clinical and laboratory predictors that might help clinicians decide to perform the bone marrow and immunological tests for HLH in paediatric EBV‐associated IM.

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.

Successful matched-unrelated bone marrow transplantation in a patient with beta-thalassemia major.

The authors describe a 5-year-old boy with beta-thalassemia major who received bone marrow transplantation (BMT) from a human leukocyte antigen (HLA)-matched unrelated donor. The conditioning regimen consisted of 16 mg/kg busulfan and 200 mg/kg cyclophosphamide. The transplantation was complicated with grade II graft-versus-host disease, although prophylaxis with cyclosporine and short-term methotrexate was carried out. Cytomegalovirus disease occurred at 2 months after transplantation but was controlled successfully. The child remains disease-free and in good clinical condition 53 months after BMT. The authors suggest that BMT from an HLA-matched unrelated donor could be considered as an alternative treatment in patients with beta-thalassemia major when no HLA-matched donor is available.

Pediatric acute lymphoblastic leukemia with t(1;19)/TCF3-PBX1 in Taiwan

In childhood acute lymphoblastic leukemia (ALL), t(1;19)(q23;p13.3) with TCF3‐PBX1 fusion is one of the most frequent translocations. Historically, it has been associated with poor prognosis. Intensive treatment, however, has improved its outcome. We determined the outcome of children with this genotype treated with contemporary intensive chemotherapy in Taiwan.

Identification of fungal pathogens from clinical specimens using multi-locus PCR coupled with electrospray ionization mass spectrometry.

Polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) was successfully used to identify a variety of fungi, including mixed fungal species, from 10 of 12 clinical specimens (10 culture-negative) of biopsy tissues or body fluids from patients with fungal infections. The application of PCR/ESI-MS for identifying fungal pathogens is discussed.

Clinico-pathological features of intussusception in children beyond five years old.

BACKGROUND The pathoetiology and outcomes of intussusception in older children are different from those in young children. This study aims to investigate the characteristics and outcomes of intussusception in children older than 5 years in a tertiary referring hospital. METHODS A retrospective review of patients aged older than five years having received a postoperative or roentgenographic diagnosis of intussusception between 1988 and 2005 was conducted. The clinical presentations, diagnostic and treatment methods, and outcomes of all cases were reviewed. RESULTS A total of 12 cases were recorded. They were eight males and four females, with a median age of 7.6 years (range 5.0-11.1 years). Four (33.3%) children had symptoms lasting more than one week before a prompt diagnosis was made. The most commonly encountered symptom was abdominal pain (100%), followed by nausea/vomiting (75.0%). Recurrent intussusception occurred in 33% of cases. Abdominal sonogram identified intussusceptum in all patients when this procedure was performed. Six patients were treated operatively. Lead lesions including two malignant lymphomas, one Meckel diverticulum, and one colon polyp were found in 4 cases. Three of the four lead points were diagnosed and treated by colonoscopy preoperatively. Complications after operations were adhesive ileus (33.3%) and recurrent intussusception (16.7%). All patients remained well, including those who had lead points identified after prompt treatments. CONCLUSIONS Intussusception in older children presents a higher frequency of persistent symptoms, lead points, and recurrence. Pediatricians need to be aware of the etiology and treatment options for intussusception in older children.

A novel pathogenic mutation on Interleukin-7 receptor leading to severe combined immunodeficiency identified with newborn screening and whole exome sequencing

BACKGROUND Patients with severe combined immunodeficiency (SCID), which is caused by genetic defects in immune-related genes involved in the development or activation of the adaptive immune system, often died in infancy due to severe infections before definite molecular diagnosis could be made. Although recent improvement in early diagnosis has been achieved by newborn screening, the genetic basis of many of the patients is still unknown. METHODS Here we performed whole exome sequencing (WES) to investigate the underlying genetic causes of SCID in a proband identified with newborn screening. Inheritance of the mutation was confirmed with targeted sequencing of the parents. Homozygosity mapping from the WES was used to investigate the consanguinity of the parents. Immunoblotting was used to confirm the loss of expression of the mutant protein. RESULTS A novel homozygous frameshift mutation of IL7R was identified through WES. Both parents are carriers for this 1-bp deletion. HLA typing and exome-wide homozygous stretch mapping suggested that the parents are consanguineous. Immunoblotting showed no expression of IL7Rα isoform in the whole blood sample of the proband. The proband received peripheral blood stem cell transplantation and her general condition became stable. Our results suggest that IL7R is essential for T cell development but dispensable for the development of certain human NK cells B cells and suggest that WES can be a useful tool for precise genetic diagnosis of SCID following newborn screening in the index patient without the need to screen other members of the whole family.