Takeo Takeda

Treatment results of advanced neuroblastoma with the First Japanese Study Group protocol

PURPOSE To elucidate the efficacy of intensive induction and consolidation chemotherapy regimens (Study Group of Japan for Advanced Neuroblastoma [JANB] 85) for patients with advanced neuroblastoma aged 1 year or older. PATIENT AND METHODS One hundred fifty-seven patients with newly diagnosed advanced neuroblastoma were entered into this study between January 1985 and December 1990. Eligible patients were 12 months old or older with stage III or IV disease. The patients first received six cyclic courses of intensive induction chemotherapy (designated regimen A1) consisting of cyclophosphamide (1,200 mg/m2), vincristine (1.5 mg/m2), tetrahydro-pyranyl Adriamycin (pirarubicin; 40 mg/m2), and cisplatin (90 mg/m2). The patients were further treated with three different consolidation protocols: 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosour ea, dacarbazine, and bone marrow transplantation. RESULTS Overall survival rates for patients with stage III disease without reference to the consolidation protocols were 80.8%, 76.9%, and 66.3% at 2, 5, and 10 years, respectively. The overall survival rates for patients with stage IV disease were 58.8%, 34.4%, and 28.9% at 2, 5, and 10 years, respectively. There were no statistically significant differences between the three consolidation treatment groups. Patients who did not achieve complete remission (CR) with induction chemotherapy and surgery all died, suggesting that CR is essential for the cure of advanced neuroblastoma. The overall 5-year survival rate of the 24 patients with N-myc amplified stage III and IV disease was 33.3%, and the longest survival time of a relapse-free patient was 103 months. CONCLUSION The intensive induction chemotherapy regimen used in this study may be of significant value in increasing the CR rate and survival for patients with N-myc amplified and nonamplified advanced neuroblastoma.

Mass screening for neuroblastoma and mortality in birth cohorts

Mortality resulting from neuroblastoma in birth cohorts in both Sapporo City and the whole of Japan was investigated to evaluate the effects of a high‐performance liquid chromatography (HPLC) mass screening program, targeting on 6 month‐old infants. In Sapporo City, the non‐HPLC screened cohort showed no reduction in mortality at 4 years of age compared with the pre‐screening cohort. However, the HPLC screened cohort showed a reduction of 69% in mortality compared with the pre‐screening cohort. On a nation‐wide scale, there was a significant decline in mortality for the non‐HPLC screened cohort compared with the pre‐screening cohort; for the HPLC screened cohort for 1989‐1991, there was also a reduction in mortality for children younger than 2 years of age. The incidence of neuroblastoma at 1‐4 years of age in the HPLC cohort in Sapporo City was about half that in the pre‐screening cohort, along with and probably because of an increasing incidence among infants in the same cohort. Our findings suggest that HPLC screening may detect some poor‐prognosis neuroblastoma cases at early stages, thus providing for more favorable therapy. Int. J. Cancer 71:552‐555, 1997.

Mass screening of neuroblastoma in Sapporo City, Japan.

In Sapporo City a mass screening program for neuroblastoma aiming at 6-month-old infants has been performed since April 1981. By March 1990, 136,001 infants were screened; 26 true-positive cases of neuroblastoma and six false-negative cases were detected. The sensitivity of the mass screening method was about 80% throughout the 9 years. During the 9-year period, a total of nine children with neuroblastoma who were not screened were also identified. Clinical stage, age at diagnosis, and survival rate for the 32 patients who were screened (26 true positives and six false negatives) were much more favorable than those for the nine patients who were not screened. A remarkable decrease in the incidence of cases of neuroblastoma with advanced clinical stages over 1 year of age, especially among children 1-4 years of age, was noted after the start of the mass screening. The mortality from this tumor in children up to 4 years of age significantly decreased after the start of the urinary screening program. Rescreening at 14 months of age was begun in April, 1991 in Sapporo City. Performing two screening examinations decreases the probability of overlooking a patient. Thus, it is expected that tumors missed on the first screening would be detected by the second screening.

Mass screening for neuroblastoma targeting children age 14 months in sapporo city

In Sapporo City a mass screening program for neuroblastoma targeting children age 6 months (6‐MS) was initially introduced in 1981. Since April 1991, an additional program has been implemented, aimed at children age 14 months (14‐MS).

Epidemiology of childhood leukemia in Hokkaido, Japan

The population‐based epidemiological indices (crude incidence, survival rate, mortality, etc.) of childhood leukemia (0–14 years of age) from 1969 to 1993 in Hokkaido Prefecture, Japan, were calculated, using data obtained from the Registry of Childhood Malignancies in Hokkaido Prefecture. A total of 1,084 cases of leukemia were diagnosed in the 1969–93 period. The annual incidence of all types of leukemia from 1984 to 1993 was about 4 per 100,000 children aged 0–14 years, with the incidence of ANLL decreasing slightly and that of ALL increasing. The ratio of ALL/ANLL could similarly be seen to be increasing in all age groups. Out of a cohort of 100,000 live births, about 65 children developed leukemia by 14 years of age, and in this longitudinal observation the ratio of ALL/ANLL was increasing. The incidence of ALL and ANLL and the ratio of ALL/ANLL in Japanese children are approaching those of Caucasians. Approximately 80% of the ALL cases were of the LI type (FAB classification), and about 65% of these could be immunologically classified as “common” ALL. The 5‐year survival rate of T‐ and B‐cell ALL cases was 50% or less, while that of “common” ALL cases was about 80%.

Mass-screening of neuroblastoma using urine from infants by high-performance liquid chromatographic method: results of first (6th month) and second (14th month) screening

To detect neuroblastoma in early stages, mass-screening of this tumor was carried out by HPLC method using the urine of six-month-old infants. Screening began in April, 1981, and a total of 42 cases were detected by December, 1994. The incidence of detection was about 1:5,000 babies tested. All of these patients have survived without relapses except one, who died of surgical complications. Nevertheless, tumors developed at later stages in 14 cases from the group which resulted negative at the 6-month screening. To determine whether such tumors could be detected by a second check, a 14-month screening was carried out, beginning in April, 1991. By December, 1994, 3 patients with neuroblastoma were found among 41,809 babies tested, and were subsequently treated. While one of these three patients was not screened at 6 months, the other two had shown approximate cut-off values in urinary VMA as well as HVA at their 6-month screening. Therefore, if the tumors had already existed at the 6-month screening, and had grown gradually until the second check at 14 months, at least some of these tumors were of the late-onset variety and could have been detected at an earlier stage.

The addition of dopamine determination to the measurement of acidic catecholamine metabolites in urine screening for neuroblastoma

Abstract Introduction: Urinary dopamine (DA) is well-known as a useful marker in the detection and follow-up of neuroblastomas, especially advanced cases. We have established a new method based on the simultaneous measurement of urinary DA and acidic catecholamine metabolites using high performance liquid chromatography (HPLC). The method described here has been applied in a regular neuroblastoma screening at age 6 months and in a second pilot screening at age 14 moths in Sapporo. Methods: Urine samples were taken from either dried specimens on filter paper or acidified 24-h urine specimens collected at a hospital. The analytical column used was an Inertsil ODS-2. N-octanesulfonate salt as an ion-pair reagent was added in the mobile phase. A coulometric detector with dual electrodes was utilized so that dopamine and other acidic catecholamine metabolites could be monitored on each electrode separately. Results: DA, vanillylmandelic acid (VMA) and homovanillic acid (HVA) were eluted at 9.9, 3.5 and 13.5 min, respectively. Samples were injected into the column every 15.5 min. Urinary DA was detectable between the range of 1.5 ng/ml and 5 μg/ml. Of 41809 infants who tested negative or did not participate in the first neuroblastoma screening and who received screening at age 14 months, we detected two neuroblastoma cases. Urinary DA levels were within normal limits in both. Conclusion: Measurement of urinary DA in addition to VMA and HVA was described. The method could be useful to reduce the likelihood of missing a patient who may develop neuroblastoma, even advanced or dopaminergic cases, though a pilot study using this assay could not prove the possibility yet.

Mass screening and occurrence of neuroblastoma in Sapporo City

Abstract In Sapporo City from April 1981 to March 1986, 73,226 infants were screened for neuroblastoma and 24,636 were not screened. By March 1992, out of the screened group 15 true-positive cases and five false-negative cases were found. The 20 cases in this group give an incidence of 27: 100,000. Out of the unscreened group five patients were found during the same period, giving an incidence in this group of 20:100,000. Since the incidence in the screened. group was by 1.34-times higher than that in the unscreened group, it is possible that about 30% of the true-positive cases are those whose tumors regress spontaneously. However, since the incidences of cases 1–4 years of age and of cases with advanced stages in this same age group as well as the total mortality in the screened group were lower in the screened group than in the unscreened group, it is certain that the mass screening makes a contribution to early detection of this disease. Calculation from data of false-negative cases and unscreened cases showed that about half of the cases with poor prognosis might be caught by the mass screening. Calculation from the mortality data also showed that the mass screening might reduce deaths from neuroblastoma by about half.

Quality of life of patients detected in mass screening for neuroblastoma

Abstract Introduction: Most of the children identified with neuroblastoma in mass screening for neuroblastoma are cured, but little is known about their quality of life. We investigated quality of life characteristics in these children as compared with those who had false positive results from this screening. Methods: A questionnaire was sent to every family of a child with neuroblastoma identified by mass screening and treated in Sapporo National Hospital and to every family of a child found to be false positive in this screening. Quality of life features investigated included growth, development, vaccinations and problems of daily life. Results: In the children who had neuroblastoma there was delay in the onset of walking, low coverage rates of DPT and polio vaccinations, and greater likelihood of contracting infectious diseases at kindergarten. However, they had little disadvantage in leading their daily lives. In fact, they had accelerated onset of speaking a word of significant meaning. Surgical operations and chemotherapy had virtually no effect in growth, and side effects by chemotherapy were slight. There was no restriction upon their physical exercise at kindergarten. Conclusions: Mass screening for neuroblastoma does not have an adverse effect on the daily life of children found to have neuroblastoma.

Hepatitis C virus infection and chronic liver diseases after treatment of malignant disease in children: A multicenter study from the Children's Cancer and Leukemia Study Group of Japan

BackgroundWe studied the prevalence of chronic liver diseases, including hepatitis C virus (HCV) and hepatitis B virus (HBV) infection, as late effects of therapeutic regimens against childhood malignancies in Japan.MethodsPatients were long-time survivors of acute lymphoblastic leukemia (ALL), acute non-lymphoblastic leukemia (ANLL), non-Hodgkins lymphoma (NHL), neuroblastoma, and osteosarcoma, who had been treated and completed the Childrens Cancer and Leukemia Study Group (CCLSG) protocols for more than 6 months at CCLSG participating institutions. The study was initially done in 1993, and as a follow-up study using a retrospective questionnaire in 1997.ResultsThe overall prevalence of HCV infection in the 1993 study was 8.1% of 443 children. Among those long-term survivors in the 1993 study, 36 (8.1%) children (24 with ALL, 6 with ANLL, 2 with NHL, and 4 others) showed liver dysfunction. The details of the HCV-positive long-term survivors were 26 (13.3%) with ALL, 4 (12.9%) with ANLL, 1 (2%) with NHL, and 5 (3%) with others. The overall prevalence of HCV infection in the 1997 study at the same institutions was 0.6%. Only a slight reduction (5.6%) of HCV antibody positivity was noted in the 1997 follow-up study, while marked reduction (77.2%) of chronic liver disorders was noted during the same follow-up period in 623 children.ConclusionsThe high frequency of HCV hepatitis among ALL children is thought to be related to frequent blood transfusions. The 1997 study is the lowest reported prevalence of HCV hepatitis among children with leukemia and malignant diseases.