Jen-Yin Hou

Cooperating gene mutations in childhood acute myeloid leukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2, and DNMT3A

Gene mutations involving epigenetic regulators recently have been described in adult acute myeloid leukemia (AML). Similar studies are limited in children. We analyzed gene mutations and cooperation in pediatric AML with special reference on mutated epigenetic regulators. Nineteen gene mutations, including 8 class I genes, 4 class II genes, WT1 and TP53 (class III), and 5 epigenetic regulator genes (class IV), were analyzed in 206 children with de novo AML. Mutational analysis was performed with polymerase chain reaction-based assay followed by direct sequencing. One hundred seventeen of 206 patients (56.8%) had at least one mutation: 51% class I, 13% class II, 6.8% class III, and 5.6% class IV. FLT3-internal tandem duplication was most frequent, and 29% of patients had more than one gene mutation. Two patients carried ASXL1 mutations, both with t(8;21), 2 had DNMT3A mutations, 2 had IDH1 mutations, 1 had IDH2 mutation, and 3 had TET2 mutations. Both patients with IDH1 mutations had AML-M0 subtype and MLL-partial tandem duplication. Cooperating mutations with mutated epigenetic regulators were observed in 8 of 10 patients. We conclude that mutated epigenetic regulators were much less than those in adult AML but with frequent cooperating mutations. ASXL1, TET2, and IDH1 mutations were associated with specific genetic subtypes.

Severe infections in children with acute leukemia undergoing intensive chemotherapy can successfully be prevented by ciprofloxacin, voriconazole, or micafungin prophylaxis.

The purpose of the current study was to prevent bloodstream infection and invasive fungal infection (IFI) by administering prophylactic antibiotic and antifungal agents during intensive chemotherapy in patients being treated for acute leukemia.

Triple Intrathecal Therapy Alone With Omission of Cranial Radiation in Children With Acute Lymphoblastic Leukemia

PURPOSE To eliminate the toxicities and sequelae of cranial irradiation (CrRT) and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, a prospective study of a modified CNS-directed therapy was conducted in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Since June 1999, children with newly diagnosed ALL have been treated with triple intrathecal therapy (TIT) alone without CrRT. The first TIT was delayed until the disappearance of blasts from peripheral blood (PB) for up to 10 days of multidrug induction, and CrRT was omitted in all patients. If PB blasts persisted on treatment day 10 (d10), the TIT was then performed. RESULTS Of a total of 156 patients, 152 were eligible. Seventeen patients did not have PB blasts at diagnosis. Three fourths of the remaining patients achieved complete clearance of PB blasts by d10. Only hyperleukocytosis at diagnosis showed a significantly lower clearance rate. Six standard-risk patients were upgraded to high risk because of detectable PB blasts on d10. TLPs were encountered in four patients (2.6%), but none were contaminated with lymphoblasts. Neither CNS-2 (less than 5 WBCs/μL with blasts in a nontraumatic sample) nor CNS-3 (≥5 WBCs/μL with blasts in a nontraumatic sample or the presence of cranial nerve palsy) was present. The 5-year event-free survival and overall survival rates±SE were 84.2%±3.0% and 90.6%±2.4%, respectively. No isolated CNS relapse occurred, but two patients experienced combined CNS relapses. The 7-year cumulative risk of any CNS relapse was 1.4%±1.0%. CONCLUSION Delaying first TIT until circulating blasts have cleared may improve CNS control in children with newly diagnosed ALL and preclude the need for CrRT.

Comparison of Feature Selection Methods for Cross-Laboratory Microarray Analysis

The amount of gene expression data of microarray has grown exponentially. To apply them for extensive studies, integrated analysis of cross-laboratory (cross-lab) data becomes a trend, and thus, choosing an appropriate feature selection method is an essential issue. This paper focuses on feature selection for Affymetrix (Affy) microarray studies across different labs. We investigate four feature selection methods: t-test, significance analysis of microarrays (SAM), rank products (RP), and random forest (RF). The four methods are applied to acute lymphoblastic leukemia, acute myeloid leukemia, breast cancer, and lung cancer Affy data which consist of three cross-lab data sets each. We utilize a rank-based normalization method to reduce the bias from cross-lab data sets. Training on one data set or two combined data sets to test the remaining data set(s) are both considered. Balanced accuracy is used for prediction evaluation. This study provides comprehensive comparisons of the four feature selection methods in cross-lab microarray analysis. Results show that SAM has the best classification performance. RF also gets high classification accuracy, but it is not as stable as SAM. The most naive method is t-test, but its performance is the worst among the four methods. In this study, we further discuss the influence from the number of training samples, the number of selected genes, and the issue of unbalanced data sets.

Minimally early morbidity in children with acute myeloid leukemia and hyperleukocytosis treated with prompt chemotherapy without leukapheresis

BACKGROUND/PURPOSE Patients with acute myeloid leukemia (AML) and hyperleukocytosis, defined as an initial white blood cell (WBC) count of ≥ 100 × 10(9)/L, are often treated with leukapheresis. In this study, we have reported our experience of treating AML without leukapheresis. METHODS From November 1, 1995, to May 31, 2012, there were 74 children (≤18 years old) with de novo AML other than acute promyelocytic leukemia. Seventeen patients had an initial WBC count ≥ 100 × 10(9)/L. Prompt chemotherapy was started within hours whereas leukapheresis was not performed. RESULTS The median age of the 17 patients with hyperleukocytosis was 7.4 years (range: 0-16 years), and the median initial WBC count was 177 × 10(9)/L (range: 117-635 × 10(9)/L). The median time between admission and initiation of chemotherapy was 4.5 hours (range: 2-72 hours) in patients with hyperleukocytosis, whereas it was 13 hours (range: 2-120 hours) in those without hyperleukocytosis. Seven patients (7/17, 41%) had one or more early complications before or during the first 2 weeks of chemotherapy. Fifteen of the 16 patients who received prompt chemotherapy achieved complete remission (93.8%), comparable with those without hyperleukocytosis (98.2%; p = 0.33). CONCLUSION Children with AML and hyperleukocytosis, treated with prompt chemotherapy without leukapheresis, had minimal early morbidities.

Mutational status of NRAS, KRAS, and PTPN11 genes is associated with genetic/cytogenetic features in children with B-precursor acute lymphoblastic leukemia

We aimed to investigate the frequencies and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B‐precursor acute lymphoblastic leukemia (ALL), the largest cohort in Asians.

Henoch-Schönlein Purpura and Elevated Hepatitis C Virus Antibody in a Girl With Nasopharyngeal Diffuse Large B-Cell Lymphoma

Henoch-Schönlein purpura (HSP) or hepatitis C virus (HCV) infection was reported in association with malignancies. However, HSP and HCV infection rarely present in pediatric patients with non-Hodgkins lymphoma. We describe an 8-year-old girl with Stage-IV diffuse large B-cell lymphoma who presented with HSP and elevated HCV antibody titer at diagnosis and at relapse. After treatment, purpura disappeared and HCV antibody titer returned to normal range. There was no recurrence of HSP or elevated HCV antibody during a follow-up of 2 years.

Primary diaphragmatic yolk sac tumor and review of the literature.

Primary yolk sac tumor of the diaphragm in children is very rare, and diagnosis of a diaphragmatic tumor poses challenges to clinical physicians. Here, we report a primary diaphragmatic yolk sac tumor in a 9-month-old girl, together with a review of 4 earlier reported cases in the English literature. Carboplatin-containing regimen successfully decreased the tumor size and a total resection of the tumor was made subsequently. The patient was disease-free 8 months after the completion of treatment.

Clinical and biological relevance of genetic alterations in pediatric T-cell acute lymphoblastic leukemia in Taiwan

The leukemogenesis of T‐cell acute lymphoblastic leukemia (T‐ALL) involves multistep processes of genetic alterations. We aimed to determine the genetic alterations including common fusion transcripts, overexpression of T‐cell transcription factor oncogenes, and deletion or mutation of targeted genes in pediatric T‐ALL in Taiwan as well as their impact on outcomes in those treated with the Taiwan Pediatric Oncology Group‐ALL‐2002 protocol.

Treatment of childhood acute lymphoblastic leukemia with delayed first intrathecal therapy and omission of prophylactic cranial irradiation: Results of the TPOG-ALL-2002 study: Treatment Outcomes of Childhood ALL

To eliminate cranial irradiation (CrRT)–related sequelae and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, the Taiwan Pediatric Oncology Group (TPOG) introduced a modified central nervous system (CNS)–directed regimen characterized by delayed triple intrathecal therapy (TIT) and the omission of CrRT for all children with newly diagnosed acute lymphoblastic leukemia (ALL).