Der Cherng Liang

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.

Complete surgical resection plus chemotherapy prolongs survival in children with stage 4 neuroblastoma

The factors that affect survival in patients with stage 4 neuroblastoma vary. Several prospective and retrospective studies have provided conflicting conclusions regarding the benefit of combining aggressive chemotherapy with complete surgical resection. We analyzed our experience to evaluate the effect of complete surgical resection of the primary tumor on survival when disseminated disease has been controlled by chemotherapy. We retrospectively reviewed the medical records of 44 consecutive children with neuroblastoma treated between 1990 and 2000. Twenty-six children with stage 4 disease were enrolled. Most were treated with surgical resection combined with chemotherapy. The survival rate was compared based on the timing (primary versus delayed until chemotherapy had been given) and results of surgery (complete tumor resection, microscopic residual disease, and gross residual disease). The mean survival (52.8xa0months) of children with delayed complete surgical resection (CSR) was statistically superior to that of those with microscopic residual (20.8xa0months, p=0.0111) or gross residual tumor (12.2xa0months, p=0.0141). In the CSR group, 1-, 2-, 3-, and 5-year survival rates were 88%, 77%, 77%, and 65%, respectively, vs. 80%, 40%, 20%, and 0% in the microscopic residual group. In conclusion, complete resection of the primary tumor with no residual disease was associated with improved survival in children with advanced neuroblastoma whose metastatic disease had been controlled by chemotherapy.

Epstein-Barr virus-associated acute renal failure: diagnosis, treatment, and follow-up

We retrospectively reviewed our experience of Epstein-Barr virus (EBV)-associated acute renal failure. Of 165 previously healthy children hospitalized with serologically proven primary EBV infection, 8 had acute renal failure, of whom 5 (group A) did not have virus-associated hemophagocytic syndrome (VAHS), while 3 (group B) did have VAHS. All had complications in four or more organ systems. Two patients in group A had renal biopsies showing acute tubulointerstitial nephritis, and the clinical and laboratory findings in the other 3 group A patients were consistent with acute tubulointerstitial nephritis. Acyclovir was used in 1 patient, but she died of hepatic failure and pulmonary hemorrhage. The other 4 spontaneously recovered renal function after supportive care, including hemodialysis in 1 patient. Our experience does not support the routine use of corticosteroids or antiviral agents in these patients. Children in group B had a relatively normal urinalysis. Renal biopsies were not performed, but their presentations were compatible with acute tubular necrosis. We conclude that EBV should be considered as a possible etiological agent in all children presenting with acute renal failure of unknown cause. The diagnosis depends on a high index of suspicion and careful serological evaluation in atypical cases.

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.

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.

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.

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.