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The prognosis of mediastinal neuroblastoma has been reported to be better than for other neuroblastomas. The reason for this is however not clear. Furthermore, a comparison between mediastinal neuroblastoma and the other neuroblastomas has been rarely reported so far. In this study, the characteristics of mediastinal neuroblastoma (84 cases) are investigated and compared with those of other neuroblastomas (440 cases). Regarding clinical factors, the age distribution and the rate of cases detected at mass screening were similar in both groups. According to Evan's staging system, the rates of early stage (I, II) were 62% in the mediastinal neuroblastoma and 38% in the other neuroblastomas (p

Since 1985, a nationwide program of mass screening for neuroblastoma has been available for 6-month-old infants throughout Japan. From 1985 to 1993, the authors studied 285 patients with neuroblastoma among their regional population of 15 million. There was an increase in the total number of patients per year in comparison to the previous 6-year period (1979 to 1984). However, no significant difference was noted in the number of patients older than 1 year or in the incidence of advanced-stage (stages III and IV) unscreened cases. The majority of neuroblastomas in the screened group showed favorable biological factors, even in the advanced stages. However, there was a small group with histologically and/ or biologically unfavorable factors; five of 115 had amplified N- myc oncogene, four of 74 showed unfavorable Shimada histological findings, and three of 33 had an unfavorable DNA ploidy pattern. One case from this group with unfavorable factors died of the tumor. 3) Thirty-eight cases were negative at the time of mass screening, but later presented with neuroblastoma. Most of them were diagnosed between 1 and 3 years of age, and 30 of the 38 cases (78.9%) were advanced stage with unfavorable prognostic factors. Thus, the authors conclude that mass screening at 6 months can detect a selected population of infants with neuroblastoma; some of the tumors may represent subclinical masses destined for spontaneous regression. However, some tumors with unfavorable factors have been detected by mass screening before progression and/ or dissemination. Infants in this group are considered to benefit most from early diagnosis and treatment.

A total of 125 children, who were diagnosed as having high-risk acute lymphoblastic leukemia (ALL), were treated with two consecutive protocols designated as AL851 (1985-1988) and ALHR88 (1988-1990). All patients received induction therapy consisting of vincristine (VCR), prednisolone (PSL), daunorubicin (DNR), and I-asparaginase (I-Asp). In the ALHR88 protocol, the patients whose blasts in the bone marrow (BM) were ≥25% on day 14 of induction therapy and who were classified into T-cell type received additional cytosine arabinoside (AraC). After consolidation with intermediate-dose methotrexate (MTX), reinduction therapy including VCR, dexamethasone, and adriamycin followed by high-dose AraC was done for all patients. Intrathecal MTX and 24Gy of cranial irradiation were used to prevent central nervous system leukemia. A maintenance therapy consisting of 6-mercaptopurine, cyclophosphamide, MTX, DNR, VCR, and AraC was administered for 3 years after achieving a complete remission (CR). CR was achieved in 51/55 (92.7%) for AL851 and 68/70 (97.1%) for ALHR88. The 5-year event-free survival rates were 49.1 ± 6.7% in AL851 and 62.5 ± 6.1% in ALHR88. The factors related to a poor prognosis were a high initial leukocyte count of greater than 50x10 9 /L (P < 0.001), an L2 morphology of leukemic cells by FAB classification (P = 0.009), the chromosomal abnormality (P = 0.004) and high residual leukemic cells in BM (≥25%) on day 14 of induction therapy (P < 0.001). Taking these factors into consideration, more intensive protocols were started in 1990 for the patients with high-risk ALL.

We evaluated the efficacy and toxicity of aclarubicin for acute non-lymphocytic leukemia (ANLL) refractory to daunorubicin in childhood. Twenty-four patients were treated with aclarubicin and prednisolone with or without 6-mercaptopurine and behenoyl-cytosine arabinoside daily for 5 to 14 days. Of 21 evaluable patients, 14 (67%) responded: 12 obtained complete remission and 2 partial remission. The median time to reach complete remission was 37 days (range, 16 to 60 days), and the median duration of complete remission was 5.5 months (range, 2 to 41 months). The cumulative dose of anthracycline administered before the study was not considered significant for the response. The only major complication was severe bone marrow suppression; infectious episodes occurred in 14 patients (58%) and three died of sepsis and/or bleeding. The observed non-hematologic toxicities included hematuria, an elevation of serum amylase, nausea/vomiting, and angitis. In addition, one patient showed abnormal cardiac function. Aclarubicin is therefore considered a highly active drug for remission reinduction of previously treated children suffering from ANLL with an acceptable toxicity.

Neuroblastoma is a common childhood malignant tumor having a very poor prognosis because of its very invasive characteristics. However, the central nervous system (CNS) is usually not affected, with the exception of the disseminating stage. A case with a mediastinal neuroblastoma having a solitary relapse in the CNS after completing therapy is reported here. A lumbar puncture revealed neuroblastoma cell clumps in the cerebrospinal fluid (CSF). This is a rare condition referred to as “meningeal neuroblastoma,” and aggressive therapy, including the intrathecal administration of nimustine (ACNU), was effective in removing the clump from the CSF.

We studied the growth of 89 patients who were long-term survivors of childhood leukemia and lymphoma. Eight patients with CNS relapse had a greater decrease in height standard deviation score (SDS) after the relapse than 81 patients without CNS relapse (p less than 0.0001). Two patients who received cranial irradiation when they were younger than 2 years of age demonstrated a marked decrease in height SDS more than 3.0 SD. Five patients appeared to have a decline in height SDS before their CNS relapse. There were no apparent changes in the weight of patients with or without CNS relapse. In endocrine studies, all eight patients with CNS relapse failed to show the normal growth hormone (GH) response to arginine, GH-releasing factor, and glucagon-propranolol tests, while spontaneous GH secretion during sleep was normal. Magnetic resonance imaging (MRI) revealed small pituitary glands in seven patients with CNS relapse. These findings suggest that in leukemia and lymphoma patients with CNS relapse, GH secretion is impaired at the hypothalamic level, resulting in a secondary atrophy of the pituitary gland. The MRI together with selected endocrinologic tests may help to clarify the mechanism of growth impairment in such patients. A decline in height SDS in each patient may be a useful marker for predicting a CNS relapse in a child with leukemia or lymphoma.

The clinical and histological findings of a 10-year-old girl with virus-associated haemophagocytic syndrome are presented. The serum levels of Epstein-Barr viral antigens were elevated. Epstein-Barr virus (EBV) genome was detected by polymerase chain reaction in bone marrow and lymph node specimens. Histologically, haemophagocytic histiocytes were present in bone marrow, and areas of non-suppurative necrosis were present in lymph nodes, where silver grain deposition of the EBV genome was demonstrated by in situ hybridization.

Inhibin is a glycoprotein hormone produced mainly by ovarian granulosa cells. Recently measurement of serum inhibin levels was made possible by radioimmunoassay. We describe a patient with a juvenile granulosa cell tumor, a distinctive and rare form of granulosa cell tumor. This patient's serum inhibin level was extremely high preoperatively and returned to normal after the tumor was resected. This case suggests that serum inhibin level may be a useful marker of granulosa cell tumors.

A total of 62 patients with standard-risk acute lymphoblastic leukemia received three-drug induction consisting of vincristine, prednisolone, and L-asparaginase (l-Asp) followed by consolidation therapy with intermediate-dose methotrexate (MTX), intrathecal MTX, and 18 Gy of cranial irradiation. Maintenance therapy consisting of 6 drugs including daunorubicin (DNR, 450 mg/m2 in total) was continued for 3 years. Patients were randomized and half of them received weekly l-Asp during maintenance therapy as a late intensification. Complete remission (CR) was achieved in 61/62 (98.4%), and 11 of 61 patients relapsed. At 10 years, the event-free survival (EFS) was 80.6 +/- 5.0% and overall survival was 88.7 +/- 4.0%; median follow-up time was 9.3 years. The 10-year EFS of patients with additional l-Asp (84.8 +/- 6.2%) was superior to that without l-Asp (75.9 +/- 7.9%), although it was not statistically significant. No patients who received a full dose of DNR and maintained CR developed heart failure, although the shortening fraction decreased from 41.0% at diagnosis to 35.2% (median). The protocol AL841 provided good long-term disease control without severe late cardiac dysfunction.

Background/Purpose: A statistical analysis of the mass screening for neuroblastoma in Japan based on a population study rarely has been reported. This study aims to evaluate retrospectively the effectiveness of mass screening at 6 months of age using the available population data. Methods: The data on the neuroblastoma cases registered by the Committee for Pediatric Solid Malignant Tumors in the Kyushu area were analyzed based on both screened and unscreened populations in the Kyushu area. Results: From 1988 to 1992, the cumulative incidence of neuroblastoma in children less than 5 years of age was 82 in 484,599 for screened children, and 11 in 92,966 for unscreened children, respectively. Fourteen of the 82 screened patients had negative findings at 6 months of age (MS-negative cases). No significant difference was observed in the cumulative mortality rates from neuroblastoma in children younger than 5 years of age between the screened children and the unscreened children. Six of seven patients who died among the screened children were MS-negative cases with stage III or IV disease. In addition, no significant difference was found in the cumulative mortality rates from the neuroblastoma cases in patients less than 5 years of age between the children screened from 1988 to 1992 (7 of 484,599) and all children from 1980 to 1984 (14 of 668,084). Conclusions: These findings suggests that the majority of the patients detected by mass screening had a favorable prognosis, and, mass screening in Japan for children less than 6 months of age was not observed to reduced the incidence and mortality from neuroblastoma. Therefore, mass screening at 6 months of age was not found to improve substantially the prognosis of patients with unfavorable neuroblastoma identified over 1 year of age, which is the primary purpose of such mass screening for neuroblastoma.

Choriocarcinoma is a rare disease in pediatric neoplasms. The prognosis of the disease is extremely poor once when patients relapse or become refractory to cisplatin (CDDP). A 17-year-old male who had retroperitoneal pure choriocarcinoma of advanced stage was treated with CDDP-based intensive chemotherapy. In spite of the initial good response to CDDP-based intensive chemotherapy, the tumor metastasized to multiple areas of the brain during chemotherapy. Since the brain in this case was thought to be a sanctuary, after radiotherapy to the whole cranium, the patient was treated with high-dose chemotherapy consisting of etoposide, carboplatin, and ranimustine (MCNU), which can penetrate the blood-brain barrier, followed by autologous bone marrow transplantation (ABMT). Twenty-four months after ABMT, the patient had no sign of disease recurrence. MCNU-containing high-dose chemotherapy with ABMT appears to be quite effective in cases that present with relapsing multiple brain metastases during CDDP-based chemotherapy.

Herpes zoster (HZ) has been often observed after bone marrow transplantation (BMT) in childhood. The occurrence of HZ was reviewed in children who received BMT. The clinical features of HZ were reviewed in 44 children who underwent BMT at Kyushu Cancer Center. Among the 35 recipients with a history of varicella before BMT, several factors associated with BMT and the lymphocyte subsets were compared between the patients who developed HZ (HZ + group) and those who did not (HZ- group). Twenty-two recipients (50%) developed HZ; in two-thirds of these cases (15/22: 68%), HZ occurred between 80 and 120 days after BMT (median 101 days). The recipients treated with busulfan had a higher occurrence of HZ than those treated without it. The patients with Grade II-IV acute graft-versus-host disease (GVHD) developed HZ more frequently. In the HZ + group, the absolute number of lymphocytes, CD3+, CD4+ or CD8+ cells at 3 months was significantly lower than that observed at 12 months after BMT and the CD4/CD8 ratio was significantly lower at 1 month than after 3 months of BMT. In conclusion, recipients were susceptible to HZ at around 100 days after BMT. The development of HZ may be associated with unbalanced T lymphocytes at that time.

Infants with neuroblastoma are known to have a better prognosis than older children. In Japan in 1985, mass screening for neuroblastoma in infants aged 6 months was introduced. With this policy, there has been an increase in the number of patients seen with neuroblastoma between 6 and 11 months of age. In a previous report the authors described the management and prognosis of infants with disease detected by mass screening, but there is still little information regarding the strategies of management for infants with neuroblastoma aged less than 6 months. The authors analyzed the data regarding 27 patients aged less than 6 months registered in their region (population 15 million) from 1985 to 1992, and compared it with that of the previous 8-year period. In the younger age group, there was a significantly higher rate of advanced disease stages (III and IV). In spite of the variation in treatment related to the choice of individual institutions, infants with stages I, II, and III disease had a good outcome, suggesting that aggressive chemotherapy is not necessary unless poor prognostic factors are present. One patient with stage IV disease died of disseminated disease and one with stage IVs and 22 copies of N-myc oncogene also died of tumor relapse in spite of aggressive chemotherapy. It is therefore concluded that the prognosis in infants with stage IV and IVs neuroblastoma under the age of 6 months is not as good as had previously been believed, and that such patients, therefore, require special consideration.

Since 1985, a nationwide program of mass screening (MS) for neuroblastoma has been underway for 6-month-old infants throughout Japan. As a result, the number of patients with stage I or II disease has obviously increased, and this has resulted in overall improvement of the prognosis for neuroblastoma. Some cases detected by MS were already in an advanced stage and have also had a good prognosis. In such cases, no definitive treatment protocol has been developed. Therefore, the authors investigated (1) the clinical and biological features of the advanced neuroblastoma cases detected by MS and (2) the best way to deal with such cases. The authors analyzed 94 cases of advanced-stage neuroblastoma registered in the Kyushu area (population, 15 million) between 1985 and 1990. Eighteen cases (16 stage III, 2 stage IV) were found by MS, and the others (23 stage III, 53 stage IV) were diagosed clinically. The following results were obtained: (1) No N- myc amplifications were observed in cases detected by MS, whereas 16 of the 45 examined patients in the non-MS group had high amplifications of N- myc . (2) With regard to Shimada's classification, DNA content, and S-100 protein positivity, most of the advanced tumors found by MS showed characteristics indicating a good prognosis. (3) The 5-year survival rate for the non-MS group is less than 25%, whereas all of the patients whose tumors were detected by MS are alive, even after undergoing mild chemotherapy. Thus, the authors conclude that the cases of advanced neuroblastoma detected by MS are a unique population that possess characteristics that generally indicate a good prognosis, and therefore aggressive chemotherapy might be unnecessary in such cases.

Summary. We report a child with acute promyelocytic leukaemia (APL) who was treated with etoposide (VP16) for Langerhans cell histiocytosis (LCH). A 3-year-old Japanese girl was diagnosed as having LCH. She was treated with combination chemotherapy using VP16 and prednisolone. 56 months after beginning the chemotherapy she developed APL. Her bone marrow was occupied with atypical promyelocytes including giant granules and multiple Auer bodies. A cytogenetic analysis of the leukaemic cells showed 46, XX,11–,14q +, t(15,17). The cumulative dose of the administered VP16 was 12120 mg/m2, which suggested that VP16 may be responsible for the development of APL. The risk of developing secondary leukaemia after the administration of VP16 should therefore be considered when managing patients with LCH.

Ten children with Langerhans cell histiocytosis (LCH) were treated with etoposide. For five patients, this was the initial diagnosis. The other five had failed to respond to previous therapies. Etoposide (100 mg/m2) was given intravenously twice a week for 4 weeks, followed by maintenance therapy every 2 to 4 weeks for 2 years. All 10 patients responded to etoposide, and 6 of them (60%) have been in complete remission for 3 to 36 months without any side effects. One patient relapsed with diabetes insipidus, one with a soft tissue mass, and two others developed multiple bone lesions. Chemotherapy with etoposide appears to be effective and safe for the treatment of children with systemic LCH.

We examined 52 children with advanced neuroblastoma who were diagnosed and treated during the past 7 years, and investigated the correlation between the degree of lymph node (LN) metastasis and the prognosis of neuroblastoma. In 8 of the 52 patients, distant LN metastasis was confirmed both radiographically and histologically. The urinary homovanillic acid (HVA) level was markedly elevated in these patients, and it was higher than that in patients with regional LN metastasis (p less than .05). The urinary vanillylmandelic acid (VMA) level and the VMA/HVA ratio were not significantly different between patients with regional and distant LN metastasis. None of the four examined patients with distant LN metastasis showed N-myc amplification of neuroblastoma tumors. An analysis of the survival rate in each patient group classified according to the degree of LN metastasis showed that the prognosis of the patients without LN metastasis or with distant LN metastasis tended to be better than that of patients with regional LN metastasis. Our results indicate that patients with distant LN metastasis may belong to a subclass with different biological features and a better prognosis than those of other groups.

Thirty-six (17.8%) of 202 children with acute lymphoblastic leukemia (ALL) and 2 (3.7%) of 54 children with acute nonlymphoblastic leukemia (ANLL) had a platelet count over 150 x 10(9)/l at diagnosis. Children with ALL and a platelet count over 150 x 10(9)/l were analysed in detail. The ALL patients without thrombocytopenia tended to be male predominant and had less frequent bleeding manifestations (p less than 0.01). These patients without thrombocytopenia had also significantly less marked leukocytosis (p less than 0.01), less severe anemia (p less than 0.05) and lower percentages of bone marrow blasts (p less than 0.05) than those with thrombocytopenia. In addition, ALL patients without thrombocytopenia had a significantly higher probability of continuous complete remission than those with thrombocytopenia (p less than 0.01).

Ten children with myelodysplastic syndrome underwent an allogeneic bone marrow transplantation (BMT) with an intensified conditioning regimen. The median age of the patients was 8 years (range 2-10), and included 6 males and 4 females. The subtype of the disease was refractory anemia (RA) in 4, RA with excess blasts (RAEB) in 4, RAEB in transformation (RAEB-T) in 1, and juvenile chronic myelogenous leukemia (JCML) in 1. All patients were conditioned with high-dose cytosine arabinoside (12000 mg/m2), cyclophosphamide (120 mg/kg) and either total body irradiation (10-13.2 Gy) or busulfan (16 mg/kg or 560 mg/m2). Cyclosporine A and/or methotrexate were used for the prophylaxis of graft-versus-host disease (GVHD). Engraftment was prompt in all but one patient. Severe acute GVHD (grade 3) (n = 1), interstitial pneumonitis (n = 1) and veno-occlusive disease of the liver (n = 1) occurred. The disease relapsed in one patient with RAEB-T. Seven of the 10 patients were alive and disease free 2-74 months after BMT. The disease-free survival rate at 4 years was 69 +/- 15%. All surviving patients were in the full performance status. The examined children with MDS tolerated this intensified conditioning regimen well.

Combined chemotherapeutic regimens of (1) cyclophosphamide (40 mg/kg x two days), (2) cisplatinum (20 mg/m2 x five days) plus VM-26 (100 mg/m2), and (3) Adriamycin (60 mg/m2) plus DTIC (250 mg/m2 x five days) were prescribed for 42 Japanese children greater than 1 year of age with stage III or IV neuroblastoma. The protocol was separated into three forms (A, B, and C) from the combination pattern of three such high-dose courses. The cumulative survival rates for those with stages III and IV 48 months after initiation of therapy were 76.2% and 20.1%, respectively, and the overall rate was 36.7%. The tumor disappeared during the course of treatment in 25 of 42 children (59.5%). The 48-month survival rate was superior in patients greater than 5 years of age than younger patients (P less than .01). Even in patients with a tumor originating in the suprarenal region, the 48-month survival rate was 30.5%. Among 12 patients in whom the N-myc oncogene was measured, one of five with one to ten copies of amplification died, whereas all seven with greater than ten copies died or had a recurrence. Thus, the present chemotherapeutic regimens, in particular alternate administration of each high-dose course, considerably improved the survival of patients with stage III neuroblastoma. More aggressive protocols are needed for those with stage IV neuroblastoma who are greater than 1 year of age, particularly in those with an amplified N-myc oncogene.

Thirty-four children with acute lymphoblastic leukemia (ALL) and 45 normal children as controls were tested for natural killer (NK) cell activity in vitro using the K-562 cell line as target cell. In the group of patients off all chemotherapy, the levels of NK cell activity were found to be comparable to normal controls. The levels of activity in the intermittent chemotherapy group were higher than or the same as those of normal controls. Low levels of NK cell activity were observed, shortly after intermittent chemotherapy. Patients who had more than two remissions had levels of NK cell activity comparable to normal controls. In contrast, low levels of NK cell activity were found in patients shortly before relapse, but returned to normal levels after achieving complete remission. Significant differences in the clinical stages between relapse and remission were found by paired t-test analysis (0.02 < p < 0.05).

Two novel acute lymphoblastic leukemia (ALL) cell lines, HOON and HYON, have been established from patients with non-T, non-B ALL. The cell lines have been characterized and shown to express phenotypic markers on non-T, non-B ALL. By indirect immunofluorescence and flow cytometry they express Ia and common ALL (CALLA) antigens and are reactive with monoclonal antibodies BA-1, BA-2 and OKT-9. However, the cells do not express detectable amounts of B1 antigen or of cytoplasmic mu chain, which are markers of pre-B cells. Quantitation of Ia and CALLA antigens on HOON and HYON cell lines using a cellular radioimmunoassay revealed that both cells bind high levels of anti-Ia antibodies, 110 X 10(4) molecules per cell, and low levels of anti-CALLA antibodies, 7 X 10(4) molecules per cell. Although both HOON and HYON carry equivalent amounts of Ia on their surface, only the former is a good stimulator of the one-way mixed lymphocyte reaction.

Superoxide (O2-) generation of leukemic cells was investigated in 28 children with acute leukemia. Leukemic cells of seven with acute myelomonocytic leukemia and one with acute monocytic leukemia produced various amounts of O2- (0.13-0.87 nmol/min/10(6) cells) when stimulated with wheat germ agglutinin (WGA) and phorbol myristate acetate (PMA). Other types of leukemia cells exhibited no such functions. Leukemic cells of two patients diagnosed as unusual cases of acute lymphoblastic leukemia generated significant amounts of O2- when stimulated with WGA and PMA. Both patients went into complete remission while on acute nonlymphoblastic leukemia treatment. Thus O2- generating activity can serve as a functional marker of leukemic cells in myelomonocytic lineage.

The objective of this study was to analyze the configuration of the lymphocytes in Wiskott-Aldrich syndrome (WAS) by studying the surface antigens from nine cases using dual-color immunofluorescence analysis. All the patients showed the increase of non-MHC-restricted cytotoxic cells, namely CD3+WT31−δTCS1+ (γδ-T cell receptor (TCR)-bearing cells) and/or CD16+ natural killer cells. The γδ-TCR+ cells of WAS, however, were unique since they did not express CD5, which is present on ordinary γδ-TCR+ cells. A reduced number of CD4+ cells and an increased percentage of CD11b+Leu7+ cells within a CD8+ subset were observed in all cases. With regard to B cell subpopulations, most cases showed reduced FcϵR2-bearing B cells, despite an elevated serum IgE.

Daunomycin is a new antibiotic in the anthracycline group obtained from Streptomyces peucetius. It consists of a pigmented aglycone (daunomycinone) in glycoside linkage with an amino sugar (daunosamine). Differences in the biological effects of daunomycin, which reacts with DNA, and actinomycin D which complexes with DNA in a different manner to inhibit RNA production, are discussed. The toxic effects of daunomycin are a severe local reaction if the drug extravasates, bone marrow depression resulting in leucopenia, anemia, thrombocytopenia and bleeding, fever, oral ulcers and alopecia. In patients receiving maintenance doses of daunomycin the development of tachypnea, tachycardia pulmonary insufficiency, heart failure and hypotension possibly is associated with daunomycin but the evidence is unclear. Sixty per cent of children with leukemia obtained brief complete or partial hematological remissions from a single course of daunomycin. The remission could be prolonged by maintenance therapy. Daunomycin is temporarily effective in some cases of neuroblastoma, reticulum cell sarcoma and rhabdomyosarcoma.

Clinical and biological significance of increased urinary excretion of dopamine in Japanese children with neuroblastoma was investigated. There was an increase in dopamine excretion in 19 of 29 patients (66%) and 15 of 19 in stages III and IV (79%). When the ratio of noradrenaline and dopamine was divided into two at the value of 3.5 x 10(-2), the disease-free survival rate was four of 16 (25%) in the low ratio group and nine of 19 (69%) in the high ratio group. In five patients, the urinary analysis revealed that only the level of dopamine was elevated before initiation of the therapy. The common features of these patients were as follows: (1) the age at diagnosis was 1 to 4 years; (2) all originated from the suprarenal region; (3) stages were advanced III or IV; and (4) the prognosis was poor. N-myc oncogene of the primary tumor was evident in three, and all were amplified to 32, 37, and 112 copies. These observations suggested that the immaturity of catecholamine metabolism may correlate to the poor prognosis and that "dopaminergic neuroblastoma" may be a clinical subentity of poor prognostic neuroblastoma.