Toshiji Shitara

Six Months of Maintenance Chemotherapy After Intensified Treatment for Acute Lymphoblastic Leukemia of Childhood

PURPOSE We postulated that intensification of chemotherapy immediately after remission induction might reduce the leukemic cell burden sufficiently to allow an abbreviated period of antimetabolite therapy. PATIENTS AND METHODS Three hundred forty-seven children (ages 1 to 15 years) with previously untreated acute lymphoblastic leukemia (ALL) were enrolled onto the Tokyo L92-13 study, which excluded patients with mature B-cell ALL and patients less than 1 year old. One hundred twenty-four patients were classified as standard risk, 122 as high risk, and 101 as extremely high risk, according to age, peripheral-blood leukocyte count, selected genetic abnormalities, and immunophenotype. All subjects received four drugs for remission induction, followed by a risk-directed multidrug intensification phase and therapy for presymptomatic leukemia in the CNS. Maintenance chemotherapy with oral mercaptopurine and methotrexate was administered for 6 months, with all treatment stopped by 1 year after diagnosis. RESULTS The mean (+/- SD) event-free survival (EFS) and overall survival rates for all patients were 59.5% +/- 3.4% and 81.5% +/- 2.2%, respectively, at 5. 5 years after diagnosis. EFS rates by risk category were similar (60. 2% +/- 6.0% for standard risk, 57.7% +/- 5.6% for high risk, and 62. 5% +/- 5.7% for extremely high risk), whereas overall survival rates differed significantly (91.2% +/- 2.7%, 80.0% +/- 4.1%, and 72.1% +/- 4.5%, respectively, P <.0001 by the log-rank test). There were 107 relapses. Eighty-five (79.4%) of these 107 patients achieved second complete remissions, with subsequent EFS rates of 61.5% +/- 7. 9% (standard risk), 42.6% +/- 8.1% (high risk), and 9.6% +/- 6.4% (extremely high risk). Of the five risk factors analyzed, only the response to prednisolone monotherapy among extremely high-risk patients proved important. CONCLUSION Early treatment intensification did not compensate for a truncated phase of maintenance chemotherapy in children with standard- or high-risk ALL. However, 6 months of antimetabolite treatment seemed adequate for extremely high-risk patients who were good responders to prednisolone and received intensified chemotherapy that included high-dose cytarabine early in the clinical course.

IRINOTECAN FOR CHILDREN WITH RELAPSED SOLID TUMORS

Irinotecan is expected to become a new drug for childhood solid tumors. Sixteen children with relapsed solid tumors received irinotecan 180 mg/m2/day for 3 consecutive days, repeated once after 25 days off. Their original tumors were neuroblastoma in 7, rhabdomyosarcoma in 3, nephroblastoma and undifferentiated sarcoma in 2 each, and primitive neuroectodermal tumor and leiomyosarcoma in 1 each. The average age at trials was 6 years. Partial response was achieved in 5 (31.3%) (neuro-blastoma, rhabdomyosarcoma, nephroblastoma, undifferentiated sarcoma, and leiomyosarcoma), and decrease in tumor marker in the other 2. Irinotecan appears promising, and could become included in the first-line treatment.

Current treatment and future directions in neuroblastoma

Objective : The International Neuroblastoma Staging System (INSS) and Pathology Classification (INPC) were applied to analyze the results of treatment of 644 patients with neuroblastoma treated in Japan during the years from 1995 to 1999, and it was found that the pathology classification (INPC) showed the strongest relevance to prognosis compared to other factors such as stage,MYNC amplification, DNA ploidy and 1p-deletion. Current results of treatment for advanced neuroblastoma are still not satisfactory, so innovative therapeutic methods have been sought during the past 10 years.Methods : Prospects for irinotecan and recombinant human endostatin (rhEndostatin) were studied experimentally and clinically.Results. Irinotecan is a water-soluble derivative of camptothecin, which is isolated from a Chinese tree,Camptotheca acuminata; Its effectiveness against neuroblastoma was confirmed byin vivo preclinical studies, and phase I clinical trials in Japan concluded the maximum tolerated dose of this agent is 160–180 mg/m2/day for 3 consecutive days, repeated after 25 days off. Phase II trials with this dose began, and we could obtain some encouraging results with the clinical use of irinotecan. rhEndostatin has been studied inin vivo experimental models. The action of rhEndostatin was quite different from those of other cytotoxic chemotherapeutic agents, and continuous administration of this substance showed a more marked anti-effect than its intermittent use.Conclusion : Irinotecan appears to be promising when it is given to the patients neuroblastoma, whereas rhEndostatin needs to have more preclinical studies before it is used in patients.

Histologic survey of neuroblastomas after intensive induction chemotherapy

Histology after intensive induction chemotherapy is expected to become a beacon indicating when and how extensively radical surgery and lymph node dissection should be performed in advanced neuroblastoma. A thorough histologic review of surgical specimens was undertaken.

Invasive Aspergillosis in Leukemic Children

Two cases of invasive aspergillosis are reported. Case 1, a 3-year-old boy with leukemic transformation of myelodysplastic syndrome, had an aspergillus infection in the hand, resulting in necrosis of the thumb. Case 2, an 18-year-old girl with acute megakaryoblastic leukemia, had an aspergillus skin infection on the wrist, accompanied by swelling and discoloration of the arm. In Case 2, angiography revealed a hypovascular lesion and vascular irregularity, suggesting that vessels were involved. Intraarterial infusion of urokinase and amphotericin B led to improvement of these symptoms in this patient. The combination of urokinase and an antifungal drug should be considered for intractable aspergillus infections involving the extremities.

Cystic duplication of the cecum lined by dermal type squamous epithelium

This is a case report of a cystic duplication of the cecum in a 6-month-old female infant, which was lined by both columnar and squamous epithelium. This squamous epithelium did not resemble esophageal epithelium but dermal epithelium. The so-called split notochord theory can explain the possibility of the coexistence of ectoderm and entoderm components. However, the present case had no vertebral abnormalities.

A case of congenital leukemia with monosomy 7

SummaryA case of congenital leukemia with monosomy 7 is reported. Immunological study of the blast cells using monoclonal antibodies was suggestive of both myelomegakaryocytic and T-lymphoblastic leukemia. Chromosomal analysis of the bone marrow cells showed monosomy 7. Chemotherapy was initiated with a combination of adriamycin, cytosine arabinoside, 6-mercaptopurine, and prednisolone. The patient obtained complete remission, which has been maintained for 4 years and 1 month. He receives no chemotherapy now. Our case shows that monosomy 7 in congenital leukemia is rare, but the presence of monosomy 7 in congenital leukemia does not necessarily indicate a poor prognosis.

Erythroleukemia in a child associated with monosomy 7

A case of erythroleukemia (EL) associated with monosomy 7 is reported. The EL was diagnosed 20 months after the initial diagnosis of monosomy 7 was made. An immunologic study of the blast cells using a monoclonal antibody was positive for glycophorin A, which suggested that they were of erythroid origin; this was confirmed by electron microscopy. Chemotherapy was started with low dose cytarabine. However, the patient had severe bone marrow suppression and died of pneumonia. Our case shows that monosomy 7 is an abnormality of the pluripotential stem cells, including erythroid cells, that resulted in a true erythroid neoplasm.

Proinflammatory Cytokinemia Associated with Transient Myeloproliferative Disorder in Down Syndrome

A transient myeloproliferative disorder (TMD) occurs in 10% of the infants with Down syndrome. While most cases resolve within a few months, in 20% of them TMDs are life-threatening or fatal. We encountered 4 patients with TMD, including 1 patient who died of liver failure and disseminated intravascular coagulation. Suspecting involvement of proinflammatory cytokines, we serially assayed them in patients’ sera. Cytokines were significantly more abundant in patients than in controls. Interleukins 1 and 2, tumor necrosis factor alpha, interferon gamma, and granulocyte-macrophage colony-stimulating factor were greatly increased, especially in the infant who died. Sustained cytokinemia is likely to participate in TMD pathophysiology, and very high serum concentrations might predict a poor outcome.