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3 children with malignant tumors in one kidney were treated with radiation in doses of 30 (3 weeks), 35 (6 weeks), and 33 Gy (8 weeks). The clinical and histological findings of radiation-induced nephritis from 2 children are demonstrated. In the third case radiation was performed because of adrenocortical carcinoma. 10,5 years after radiation the child developed a renal cell carcinoma.

Unlabelled: It was the aim of the cooperative therapy study HD-82 for children with Hodgkin's disease to reduce chemo- and radiotherapy and to investigate of a strategy for selective splenectomy previously developed in the Hodgkin study HD-78. Between December 1981 and December 1984 207 patients (131 boys and 76 girls) below 16 years of age were enrolled in this study. In 174 out of 207 patients (84.1%) the criteria for selective splenectomy were applied i.e. the spleen was only removed when the splenic surface was nodular or when the lymphnodes at the splenic hilus and/or the pancreatic tail were enlarged. 69 out of 174 patients (39.7%) had a splenectomy. 50 of the removed 69 spleens (72%) showed histological evidence of Hodgkin's disease. These results were comparable to the 36% and 73% predicted from the retrospective analysis in the HD-78 study. According to the stage of Hodgkin's disease three different treatment groups with 2, 4 and 6 cycles of OPPA/COPP were formed (stage I/IIA, IIB/IIIA and IIIB/IV). Radiation therapy was given as involved field irradiation with a total dose of 35, 30 and 25 Gy depending on the extent of the chemotherapy. 203 patients were treated according to the protocol. Until the 30th of November 1985 3 patients died from intercurrent disease during a follow-up period of 11 to 47 months (median 29 months). 5 patients relapsed. The probability for disease-free survival after 3 1/2 years is 96% for the total group and 99%, 96% and 87% for the three treatment groups including 100, 53 and 50 patients in each group respectively., Conclusions: 1. The OPPA/COPP chemotherapy eliminates reliably occult microfoci. 2. The radiation doses in combination with the chemotherapy are sufficient to prevent local recurrences. 3. The decisional model for selective splenectomy has proved to be extremely valuable prospectively.

BMT has gained its place in the treatment of childhood leukaemia. Nevertheless, there are still many questions open. In acute lymphoblastic leukaemia children should normally be grafted in 2nd remission (CR). Some high risk cases, however, should probably be grafted in 1st CR. It is not clear whether children with late relapses benefit more from BMT than from renewed chemotherapy. Children with a relapse during maintenance therapy, however, have a better survival rate with BMT. In acute nonlymphoblastic leukaemia certain high risk patients should be grafted in 1st CR but it has still to be shown that BMT is superior to chemotherapy in such cases. It is not clear whether children with a relapse following intensive chemotherapy (such as the BFM-protocols) will benefit from BMT at all. In chronic myelocytic leukaemia, BMT in chronic phase should be performed. Thus, for the first time cure has become possible for this disease. Waiting for acceleration or even the occurrence of a blast crisis decreases the chance of survival after BMT dramatically. Since complications of BMT such as graft-versus-host reaction or severe infections are less frequent in children, relapses remain the main problem after BMT in childhood leukaemia.

The initial findings and the course of 20 children and adolescents with adult CML from 10 children hospitals were analyzed retrospectively. The Philadelphia chromosome was found in 18 patients. Initial findings, the course and the prognosis were similar to those published from adult patients. 7 of the 11 children who received chemotherapy alone are still alive with a median survival time of 26 months (range: 14 to 68 months). One patient survived the third blast crisis. For 9 children with a bone marrow transplantation during the chronic phase (median time before transplantation 30 months) the follow-up of 7 months is still too short. 4 of these patients died following graft versus host reaction, 5 show no signs of a renewed occurrence of CML so far. Since CML is rare in children, there is little large scale experience. Hence, there is an urgent need for the prospective and cooperative study of these patients.

71 patients with resectable osterosarcoma received chemotherapy for one year including high-dose methotrexate (18 x 200 mg/kg), adriamycin (5 x [2 x 45] mg/m2) and cyclophosphamide (6 x 1200 mg/m2). During the initial 15 weeks adriamycin was used preferentially and cytostatic agents were applied in a higher frequency than later on. 41/71 patients are continuously free of disease with a median follow up of 39 (24-54) months. The latest appearance of pulmonary metastases was observed at 28 months so far. 18/27 (67%) patients with extension of tumor lesion beyond 1/3 long bones length by x-ray examination relapsed in contrast to 12/43 (28%) patients with smaller lesions. 1 patient died from adriamycin induced cardiomyopathy. Generally therapy was well tolerated. An average of 70-80% of planned drug dosages could be realized without measurable influence of individual differences on outcome.

In therapy study ALL-BFM 83 a total of 630 patients with acute lymphoblastic leukemia (ALL) have prospectively been evaluated for initial response on therapy with corticosteroids. It was the aim to qualify the in vivo cytoreduction as a new predictor for therapy failure. All patients were exposed for 7 days to prednisone before combination chemotherapy at day 8 has been started. At day 0 one additional dose of Methotrexate was given intrathecally. Therapy for all patients with non-B-ALL has been stratified according to initial tumor burden (risk factor) providing four therapy branches: standard risk low (SR-L), standard risk high (SR-H), medium risk (MR), high risk (HR). After a median duration of study of 21 months, event-free survival (EFS) is for all 630 patients 73%, 81% for SR-L, 76% for SR-H, 69% for MR, and 35% for HR patients (date of evaluation Jan. 1, 1987). In this prospective study, a small subgroup of patients (n = 48; 7.6% of total group) is characterized by greater than 1000 leukemic blasts/mm3 peripheral blood at day 8 after exposure to prednisone. In this subgroup the EFS is only 43% in contrast to 76% in the complementary group of 582 patients with less than 1000 leukemic blasts/mm3 peripheral blood at day 8. Patients of that risk group are derived from therapy branches SR-H, M and HR, the latter contributing relatively most patients. In this negatively selected group all patients with an initial high white blood count, CNS disease at diagnosis, immune subtypes as prae-T-ALL (n = 6), T-ALL (n = 18), null-ALL (n = 5), and males clearly dominate. Of 48 patients with greater than 1000 blasts/mm3 at day 8 4 subsequently failed to enter remission and 8 were qualified as lateresponders. 18 patients relapsed, most of them earlier compared to those of the complementary group. The initial in vivo response on corticosteroid therapy is considered a supplementary prognostic predictor for early failure. It will be utilized in trial ALL/NHL-BFM 86 to qualify patients at the highest risk for relapse. This group of patients is supplemented in addition by non- and lateresponders and children with acute undifferentiated leukemia (AUL). The in vivo corticosteroid test is simple, generates early and reliable results and can be obtained almost always. Thus it may be recommended for use in a multicenter trial.

Two further cases with myeloproliferative disorders (a child with smoldering leukemia and a young male with acute nonlymphocytic leukemia of FAB type M2) and a translocation t(6;9)(p23;q34) are described. Special attention is paid to environmental factors and the early age of onset of patients within the group of leukemias with this specific translocation. In one of our cases a secondary chromosomal anomaly has arisen, which is comparable with another case from the literature.

22 children with metastatic neuroblastoma received myeloablative chemoradiotherapy followed by bone marrow transplantation (BMT). The duration of preceding chemotherapy was 4-30 months and included treatment of recurrences in 10 children. At BMT 12 patients were in CR, 9 in PR and one had tumor progression. 10/15 of autologous bone marrows were purged using immunomagnetic bead method of Kemshead and 2/15 using 4 hydroperoxycyclophosphamide. Myeloablative therapy consisted of melphalan and total body irradiation (TBI) in 13 patients (three each supplemented by vincristine or adriamycin/etoposide), in one child of melphalan and mIBG and in 3 children of melphalan alone. 3 children received double autograft and 2 cyclophosphamide (and TBI). 10 patients survived 0-32 months from BMT and 5-48 months from diagnosis, respectively. 12 patients died including 7/12 of tumor progression and 5/12 of toxicity (venoocclusive disease, gut toxicity, septicemia, pneumonia). We conclude that at this point BMT after conventional high dose chemotherapy may provide the only real chance of survival for a significant number of children with metastatic neuroblastoma.

Neuroblastoma is the third most frequent malignant tumor in childhood. One-third of the patients over one year of age at the time of diagnosis suffer from the disseminated form (stage IV). Despite highly aggressive chemotherapy survival rates are poor. One hundred and eighty-seven patients with neuroblastoma stage IV have been treated according to the German protocol NB 85. The probability of disease free survival is only 15% after 70 months. Treatment strategy in our protocol includes autologous and allogeneic bone marrow transplantation (BMT) for patients with stage IV (and greater than 1 year old). Twenty-two patients were grafted (7 allogeneic and 15 autologous). The conditioning regimen consisted mainly of high-dose melphalan (180 mg/m2) and total body irradiation (TBI) (3.4 Gy). Survival rates are discussed in the context of the chemotherapy protocol. Our own experience with autologous BMT is poor, despite of different purging methods. For this reason we decided to focus on allogeneic BMT. We have grafted five patients within the last 3 years. Three of them are alive and well, on died from veno-occlusive disease 70 days after BMT, and the remaining patient, grafted from a syngeneic donor, died from relapsing tumor. The main problem in neuroblastoma stage IV is resistance to chemotherapy. Intensification of the conditioning regimen or double autografting leads to a rate of toxic deaths close to 20% (Zucker, EBMT 1987) which is not tolerable. New improvements in the conditioning regimen have to be found to increase the effect of BMT.

From 1970 to 1977, two nonrandomized groups of children with acute lymphoblastic leukemia (ALL) were treated with two different induction regimens. A total of 168 patients (group DAL) received induction therapy closely adapted to St. Jude protocol VII. A total of 119 patients (group BFM) were treated with the West Berlin induction protocol. Evaluable for analysis were 138 patients of group DAL and 113 patients of group BFM. Thirty children had thymic involvement (Thy+), 15 in each group. In children without thymic involvement (Thy+), the median initial white blood count (WBC) was 8400/mm3 in group DAL and 8000/mm3 in group BFM. In contrast, the initial WBC was 42,000/mm3 and 79,200/mm3 in the corresponding group with thymic involvement (Thy+). The probability of continuous complete remission (CCR) at 9 years is 0.41 +/- 0.05 for patients without thymic involvement and 0.09 +/- 0.09 for patients with thymic involvement in group DAL, and 0.65 +/- 0.05 for those without thymic involvement and 0.52 +/- 0.13 for those who had thymic involvement in group BFM. After adjustment for initial WBC (regression analysis) the presence of thymic involvement was still a predictor of poor outcome in group DAL (p less than 0.001), whereas it was not a predictor of poor response in group BFM. In view of comparable patient composition in both treatment groups, the favorable prognosis in BFM patients has to be related to the mode of induction therapy.

From 1974 to 1978, 21 children with rhabdomyosarcoma were treated in a combined interdisciplinary protocol. All children received a polychemotherapy for 18 months. Radiotherapy and surgery were used according to the stage and localization of the tumor. The overall two-year survival rate is 86 +/- 9%, the tumor free survival rate is 78 +/- 11%. 7 patients have no evidence of disease after the end of treatment.

Between December, 1978, and October, 1982, 151 children with acute myelogenous leukemia from 30 pediatric clinics entered the cooperative study. The treatment consisted of a 10-week intensive induction therapy and a subsequent maintenance therapy, which is terminated for children in complete continuous remission after 2 years. The induction treatment during the first 4 weeks consisted of a combination of prednisone, 6-thioguanine (TG), vincristine, adriamycin (ADR) and cytosine-arabinoside (ARA-C). In the following 4 weeks i.v. cyclophosphamide, i.th. methotrexate and prophylactic cranial irradiation were administered in addition to TG, ARA-C and ADR. 119 of the 151 patients (79%) achieved complete remission. 13 children (9%) died of early hemorrhages, 2 of them before onset of therapy. 5 patients died initially of other complications, another 6 after remission has been achieved. 13 children did not respond or responded poorly to the induction therapy. So far, 40 relapses occurred, mainly in the bone marrow. In 6 relapses the central nervous system was involved. The probability for a continuous complete remission for the total group is 0.41 +/- 0.05 (life table analysis) and for the total group 0.56 +/- 0.06 after 45 months. The corresponding probability for survival after 46 months are 0.43 +/- 0.06 for the remission group. The risk for occurrence of early fatal hemorrhages was higher in children with acute monocytic leukemia than in the other morphological subtypes. An initial leukocyte count of more than 100,000/microliters was found significantly more often in patients who did not achieve remission (early deaths and nonresponders) than in children of the remission group. So far, no factors could be identified which influence the risk for relapse. The present results of the study allow the conclusion, that with the applied treatment strategy it is possible to achieve not only in a high portion of children with AML remission but also to improve the chances for long-time remission and perhaps cure.