Hsi Che Liu

Auditory and visual toxicity during deferoxamine therapy in transfusion-dependent patients

Deferoxamine is a chelating agent that has extended the life expectancy of patients with thalassemia. In the 1980s, many investigators reported otologic and visual toxicity caused by deferoxamine. In July 1999 and 2 years later, the authors performed audiologic and ophthalmologic assessments in 30 transfusion-dependent patients receiving deferoxamine therapy (40-50 mg/kg per dose, subcutaneously for 8-10 hours, 4-7 days per week). In 1999, six patients (20%) had deferoxamine-related hearing impairment (>25 dB), all at high frequencies. Because the authors believed the benefits of chelation therapy outweighed the risk of ototoxicity, the dose of deferoxamine was not reduced. Two years later, the hearing impairment had not progressed in any of the patients. There was no association between ototoxicity and ferritin level. No patients had abnormalities of visual acuity or funduscopy in either 1999 or 2001. Based on this experience, deferoxamine at doses lower than 50 mg/kg/d was safe for the eyes and slightly toxic to the ears. The ototoxicity probably relates to individual susceptibility. Regular monitoring of auditory function and close follow-up of abnormal findings are recommended. According to this limited experience, reducing the dose or withdrawing deferoxamine might not be necessary if the hearing loss is stable in the face of ferritin levels above 2,000 ng/mL. Because of the relatively small patient numbers, more data are needed to confirm these conclusions.

High-dose cytarabine-containing chemotherapy with or without granulocyte colony-stimulating factor for children with acute leukemia.

We sought to determine the role of granulocyte colony‐stimulating factor (G‐CSF) as an adjunct therapy in high‐dose cytarabine‐containing chemotherapy (HD C/T) for children with acute leukemia. Seventeen patients, aged 9 months to 18 years old, 8 ALL and 9 AML, were treated with cytarabine (Ara‐C) 1 g/m2 q12h for 8 doses with mitoxantrone, idarubicin, VP‐16, or asparaginase. A total of 71 courses of HD C/T was given. G‐CSF was not used in 14 courses (Group A). Prophylactic G‐CSF was given in 57 courses (Group B) as 200 μg/m2/d SC started one day after the completion of HD C/T and continued until the neutrophil recovery was maintained. The incidences of sepsis per course in Group A and Group B were 35.7% (5/14) and 40.4% (23/57), respectively. While 2 patients in Group A died of sepsis or pneumonia, none in Group B died. The mortality and delay in chemotherapy were fewer in Group B (P = 0.037 and 0.0006, respectively, Fisher exact test). There was a shorter average number of days of neutrophil <500/cumm, antibiotic usage, fever, and hospital stay in Group B (11, 8, 5, 17 days in Group B vs. 21, 17, 10, 37 days in Group A; P = 0.0001, log‐rank test; 0.0006, 0.0023, 0.0001, Wilcoxon rank sum test, respectively). The incidence of neutropenic fever was lower in Group B, but the difference did not reach statistical significance (P = 0.06, Fisher exact test). We conclude that G‐CSF as an adjunct therapy in HD C/T is effective in reducing mortality, days of neutropenia, antibiotic usage, fever, hospital stay, and frequency of delay in chemotherapy. The efficacy of this treatment approach requires further testing in a randomized, controlled trial. Am. J. Hematol. 58:20–23, 1998.

The stage I yolk sac tumor of testis in children younger than 2 years, chemotherapy or not?

Yolk sac tumor is the most frequent germ cell tumor of testis in children. For stage I yolk sac tumor of testis in children younger than 2 years, high inguinal orchiectomy alone has been the standard treatment, with a cure rate of at least 75%. Here, we compare the treatment results of receiving chemotherapy or no chemotherapy after orchiectomy, to analyze the role of chemotherapy. From February 1987 to January 1997, 22 children younger than 2 years, with stage I yolk sac tumor of testis, were included in the study. All patients had high inguinal orchiectomy without retroperitoneal lymphadenectomy. Initial diagnostic imaging studies included computed tomographic scan of abdomen, chest radiography, and long bone survey. Clinical stage I was defined as a tumor completely resected with no evidence of local regional lymph node involvement or distant metastases. Serum alpha-fetoprotein (AFP) was assessed at diagnosis. After orchiectomy, diagnosis, and staging, patients were stratified into two treatment groups, with or without chemotherapy, according to the decision of the parents. Ten children received chemotherapy consisting of cisplatin, vinblastine, and bleomycin (PVB, modified Einhorn regimen) for 12 weeks. The remaining 12 patients were followed up according to a wait and see policy. Determination of AFP was performed monthly during the first postoperative year, every other month during the second year, every 3 months during the third year, every 6 months during the fourth year, and yearly until the fifth postoperative year at least. The duration of follow-up ranged from 3 months to 119 months (median, 53 months). The Kaplan-Meier plot estimated an overall survival rate of 91.6% at 7 years after diagnosis. Among the 12 patients without chemotherapy, 2 children had relapses at 4 and 6 months after diagnosis, respectively. One was cured with PVB chemotherapy. The other patient died with refractory lung metastasis, in spite of intensive multimodality salvage therapy. The Kaplan-Meier plot showed a survival rate of 80% at 7 years and a relapse-free survival rate of 81.8% at 5 years after diagnosis. All children receiving chemotherapy were alive and free from relapse. There was no significant treatment-related toxicity. Our results may suggest that PVB chemotherapy after orchiectomy is an affective and safe regimen for stage I yolk sac tumor of testis in children younger than 2 years. Instead of four courses of PVB as used here, two or three courses could be enough. To elucidate the necessity for chemotherapy and to determine the number of courses of PVB needed (if chemotherapy is given), a randomized study of more cases is warranted.

Long-term Treatment Results of Hepatoblastoma at a Single Institution in Taiwan

From 1990 to 2004, there were 23 consecutive patients with hepatoblastoma treated at Mackay Memorial Hospital in Taipei, Taiwan. There were 7 patients of stage I, 3 of stage II, 13 of stage III, and none had stage IV disease. Two siblings had congenital hepatoblastoma and both survived. Two patients were prematurity. Beckwith-Wiedemann syndrome, isosexual precocity, chronic B hepatitis presented in 1 patient each. In addition to surgery, we used cisplatin 90u2009mg/m2/d on day 1 and epirubicin 25u2009mg/m2/d for days 1 to 3 as first-line chemotherapy. Each course was repeated every 3 weeks. Epirubicin was chosen because of its lower cardiotoxicity. Carboplatin/etoposide and vincristine/cyclophosphamide/5-fluorouracil were the second-line chemotherapy for considering cumulative toxicity of first-line chemotherapy. If initial total excision was feasible, postoperative chemotherapy of 4 to 6 courses were given. Three patients died of progressive disease, infection, and relapse 1 each. The median duration of follow-up for 20 survived patients was 94 months. The 5-year event-free and overall survival rates were 73.9%±9.2% (SE) and 87%±7.0%, respectively. Tumor recurred in 5 patients. The commonest toxicity was febrile neutropenia. There was no cardiotoxicity event. In conclusion, with sequential combination of surgery and chemotherapy, the treatment results for hepatoblastoma were satisfactory as compared with other groups.

OVERALL AND EVENT-FREE SURVIVALS FOR ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN AT A SINGLE INSTITUTION IN TAIWAN

The results of treatment for childhood acute lymphoblastic leukemia (ALL) have improved dramatically over the past three decades. The authors present the long-term outcome of patients ( n = 151) with ALL enrolled in 4 consecutive clinical trials conducted from 1982 to 1993 at Mackay Memorial Hospital. During this period, the backbone of the treatment remained relatively unchanged, including a 3- to 4-drug remission induction, central nervous system(CNS)-directed therapy, and cyclic pulses of vincristine and dexamethasone during maintenance therapy. More intensive therapy, consisting of reintensification and addition of more drugs during maintenance, was reserved for high-risk and very-high-risk paitents. The overall survival and event-free survival ( - 1 SE) were 70 - 4.1% and 64 - 4.3%, respectively, with follow-up ranging from 7.6 to 18.7 years (median 12.2 year). The isolated CNS relapse rate was 4.3%. The dropout rate significantaly decreased from 35% in 1982-1984 to 0% in 1991-1993. Although the patient population is small, the overall results for childhood ALL at the authors hospital are encouraging as compared to earlier reports in Taiwan.

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.

Interferon-α for alarming hemangiomas in infants: Experience of a single institution

Background:u2002 Hemangioma is the most common tumor in infancy. ‘Alarming hemangiomas’ refer to the lesions that potentially impair vital structures or cause life‐endangering complications, and which warrant vigorous treatment. Interferon‐α has been used for alarming hemangiomas at Mackay Memorial Hospital, Taipei, Taiwan, since 1994.

The development of a novel protocol for the treatment of de novo childhood acute myeloid leukemia in a single institution in Taiwan

From November 1, 1995 to July 31, 2004, 49 children with de novo acute myeloid leukemia (AML) were treated at our institution. One patient who was treated by a different protocol was excluded. In total, 48 patients with de novo AML were enrolled in this study. Forty-two patients with AML other than acute promyelocytic leukemia (non-APL) were treated consecutively with 2 novel protocols: Mackay Memorial Hospital (MMH)-AML-96, designed as a pilot phase, and Taiwan Pediatric Oncology Group (TPOG)-AML-97A, on the basis of MMH-AML-96 with minor modifications. Six patients with APL were treated consecutively with 2 protocols, TPOG-APL-97 and APL-2001. As of July 31, 2006, the remission rates were 79%, 92%, and 98% after 1, 2, and 3 courses of induction therapy, respectively. The 5-year overall survival was 64%±6.9% (SE), and the 5-year event-free survival was 60%±7.1%; for non-APL AML, the rates were 62%±7.5% and 59%±7.6%; for APL, 83±15.2 and 67±19.3%. Among the factors analyzed, a complete remission achieved after 1 course of induction therapy, lactate dehydrogenase <500u2009IU/L at diagnosis, patients without invasive fungal infection during chemotherapy, and male sex were associated with a favorable outcome.

The relationship of N-myc amplification and apoptosis in neuroblastoma

About 30% of neuroblastomas exhibit N-myc amplification. Neuroblastomas with Nmyc amplification tend to have a stroma-poor undifferentiated histopathologic phenotype and a high mitosis-karyorrhexis index (MKI). Karyorrhectic or pyknotic cells in neuroblastomas are closely related to apoptosis. Using fluorescence in situ hybridization (FISH) technique on formal in-fixed paraffin-embedded tissue, we conducted a retrospective study on 42 cases of neuroblastomas to investigate the relationship between N-myc amplification and apoptosis. The identification of apoptotic cells was based on morphology and terminal deoxynucleotidyl transferase-mediated uridine 5-triphosphate (UTP)-biotin nick end labeling (TUNEL) method. Eleven (26%) of 42 tumors demonstrated N-myc amplification. After exclusion of nine tumors from patients who had prior chemotherapy, 3 3 tumors were available for thorough investigation. Based on the morphology of apoptotic cells, seven of the eight neuroblastomas with N-myc amplification had high apoptotic cell counts (more than 200 per 5,000 tumor cells), whereas only three of the 25 tumors without N-myc amplification revealed high apoptotic cells. Our results suggest that N-myc amplification can be readily detected in routinely processed tissue sections by FISH technique. Its presence has prognostic value and tends to be associated with a high number of apoptotic cells in neuroblastomas.