Ting-Chi Yeh

Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples

c-KIT mutations have been described in core-binding factor (CBF) acute myeloid leukemia (AML) at diagnosis. The role of c-KIT mutations in the relapse of CBF–AML is not clear. The role of CSF1R mutation in the pathogenesis of AML remains to be determined. We analyzed receptor tyrosine kinases (RTKs) and Ras mutations on 154 children with AML. Also, we examined the paired diagnosis and relapse samples in CBF–AML. CBF–AML accounted for 27% (41/154). c-KIT mutations were detected in 41.5% of CBF–AML at diagnosis (6 in exon 8, 10 in exon 17 and 1 in both exons 8 and 17) , FLT3–TKD 2.7%, N-Ras mutations 7.3% and K-Ras mutations 4.9%. FLT3–LM and CSF1R mutations were not found in CBF–AML. The mutations of RTKs and Ras were mutually exclusive except for one patient who had both c-KIT and N-Ras mutations. Eight of the 41 CBF–AML patients relapsed; four patients retained the identical c-KIT mutation patterns as those at diagnosis, the remaining four without c-KIT mutations at diagnosis did not acquire c-KIT mutations at relapse. Our study showed that 54% of childhood CBF–AML had RTKs and/or Ras mutations; c-KIT but not CSF1R mutations play a role in the leukemogenesis of childhood CBF–AML.

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.

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.

Recombinant Urate Oxidase (Rasburicase) for the Prevention and Treatment of Tumor Lysis Syndrome in Patients with Hematologic Malignancies

In this multicenter, nonrandomized, open-label clinical trial conducted from July 2003 to July 2004, recombinant urate oxidase (rasburicase) was administered to patients at risk for tumor lysis syndrome before or during the initiation of chemotherapy. Forty-five patients were enrolled, including 18 children (10 with acute lymphoblastic leukemia, 6 with high-grade lymphoma, and 2 with acute myeloid leukemia) and 27 adults (8 with acute lymphoblastic leukemia, 4 with high-grade lymphoma, 9 with multiple myeloma, and 6 with acute myeloid leukemia). The age ranged from 3 to 98 years, with a median age of 7 years in children and 59.3 years in adults. There were 14 males and 4 females in the pediatric group and 18 males and 9 females in the adult group. Rasburicase 0.2 mg/kg was administered intravenously once a day for 2–6 days, for a median of 3 days in children and of 4 days in adults. After 3 days of treatment, the median uric acid levels in the 18 children decreased from 10.5 mg/dl (range 8–18.6) to 0.5 mg/dl (range 0.0–1.7). Similarly, in the 27 adults, the median levels decreased from 10.8 mg/dl (range 8–24.4) to 0.5 mg/dl (range 0.0–1.6). No significant changes were observed in serum potassium, calcium, and phosphorus concentrations. None of the patients required dialysis for acute renal failure. Rasburicase was very well tolerated, with only 1 adult having grade 1 vomiting. We conclude that rasburicase is safe and highly effective for preventing the complications of tumor lysis syndrome in patients with hematologic malignancies.

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.

Frequencies of ETV6–RUNX1 fusion and hyperdiploidy in pediatric acute lymphoblastic leukemia are lower in far east than west†

Both ETV6–RUNX1 (TEL–AML1) fusion and hyperdiploidy (>50 chromosomes) in transformed lymphoblasts are favorable genetic features in childhood acute lymphoblastic leukemia (ALL).

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.

Triple intrathecal therapy without cranial irradiation for central nervous system preventive therapy in childhood acute lymphoblastic leukemia

To evaluate the treatment results of central nervous system preventive therapy (CNSP) with triple intrathecal therapy (TIT) alone in children with acute lymphoblastic leukemia (ALL).

Percutaneous endoscopic gastrostomy in children: 15 cases experience

For long-term tube feeding in children, percutaneous endoscopic gastrostomy (PEG) has the advantages of a short surgical time, early feeding following surgery, and lower rate of complications. From July 2000 to September 2002, we enrolled fifteen children (mean age: 8.2 years old) who underwent PEG placement for long-term nutritional support. Their underlying diseases included mucopolysaccharidosis (MPS) type II severe form, mitochondrial disease, Ehlers-Danlos syndrome associated with Robin sequence, spinal muscular atrophy (SMA) type II, nesidioblastosis, neurofibromatosis and other neurological disorders. We assessed the complications and outcome in these patients after PEG placement. There were no difficulties in PEG tube-feeding after procedure. One patient had a wound infection at the insertion site which required parenteral antibiotic therapy. Symptomatic gastroesophageal reflux (GER) occurred in two patients and was controlled with medication. One patient developed a gastrocutaneous fistula, requiring surgical removal of the PEG tube. One patient underwent laparoscopic gastrojejunostomy and Nissen fundoplication for persistent vomiting. Two patients with mitochondrial disease expired. The other eleven devices have continued to function on follow-up. Placement of a PEG is a simple, feasible procedure for children with swallowing difficulty who require long-term nutritional support. Although complications may sometimes occur, in our experience many can be managed conservatively.

Characteristics of Primary Osteomyelitis Among Children in a Medical Center in Taipei, 1984-2002

BACKGROUND AND PURPOSE The presentation and sequelae of osteomyelitis are variable. This study evaluated the clinical manifestations and outcome of osteomyelitis in children in different age groups, and in different periods before and after the implementation of National Health Insurance (NHI). METHODS The records of pediatric patients with osteomyelitis treated at a medical center in Taipei from 1984 to 2002 were reviewed. Clinical features, pathogens, laboratory and imaging findings, treatment, and outcome were analyzed. The patients were stratified into 3 groups based on age: infants (< or = 3 months of age), young children (between 4 months and 5 years), and older children and adolescents (> 5 years). Based on the date of implementation of the NHI program, the study period was divided into 2 stages: prior to implementation, from January 1984 to February 1995; and after implementation, from March 1995 to December 2002. RESULTS The records of 209 patients were reviewed, including 45 infants, 77 young children, and 87 older children. The most common presenting findings were local tenderness (79%), local swelling (72%), and fever (57%). The lower limbs were the most commonly involved sites (65%). Staphylococcus aureus (34%), Mycobacterium tuberculosis (10%), Salmonella species (7%), and Pseudomonas aeruginosa (6%) were the most frequently isolated pathogens. At the time of diagnosis, abnormalities were found on radiographs in 83% of patients and on radionuclide bone scans in 86%. Surgical intervention with local debridement and curettage was performed in 102 patients (49%). Sixty five patients (31%) developed complications, including specific bony sequelae in 26 (12%). Sepsis and septic arthritis were more common in infants (p < 0.01). A history of trauma, protracted course of osteomyelitis, and surgical intervention were more common in older children and adolescents (p < 0.01). After the implementation of NHI, a larger proportion of patients had negative cultures (p < 0.01), and the mean duration of antibiotic therapy was shorter (p = 0.01). CONCLUSIONS The clinical characteristics of osteomyelitis associated with sepsis or septic arthritis, chronic changes, and the need for surgery may differ depending on the age of the child. S. aureus, M. tuberculosis, and salmonellae were the most common pathogens in this Taiwanese series. Implementation of NHI in the more recent decade of the study period was associated with a shorter duration of intravenous antibiotic administration.