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In 154 splenectomized children and adolescents with histologically proven Hodgkin's disease in the therapy study DAL-HD-78, the incidence of splenic involvement was 39%. In single-parameter analyses 6 of 16 examined pre- and intraoperative findings showed significant correlation to splenic involvement: B-symptoms, palpable splenic enlargement, mediastinal/lung hilus involvement, nodular changes of splenic surface, enlarged lymph nodes at splenic hilus/pancreatic tail, or enlargement of other upper-abdominal lymph nodes. The results of multivariant analyses (Cox regression model) of these six parameters showed that the two most significant intraoperative parameters--changes of splenic surface and enlargement of lymph nodes at splenic hilus/pancreatic tail-gave almost all of the information which can be obtained about splenic involvement. With these two parameters, an intraoperative decisional strategy for selective splenectomy has been developed which allows the omission of splenectomy in about two thirds of children with Hodgkin's disease while still obtaining detailed information about infradiaphragmatic spread of disease. Since minor splenic involvement remains undetected in about 10% of the nonsplenectomized patients (i.e., 6% of all patients), this method should be used only in combination with chemotherapy.

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One hundred fifty-one children with acute myelogenous leukemia (AML) entered the cooperative study BFM-78 between December 1978 and October 1982. The initial therapy consisted of an intensive induction and consolidation regimen over eight weeks with seven different drugs and cranial irradiation. It was followed by maintenance with thioguanine and cytosine arabinoside for two years and additional Adriamycin during the first year. One hundred nineteen (79%) patients achieved a complete remission. Thirteen (9%) children died of early hemorrhages. After a median follow-up time of 36 (12 to 57) months, 47 relapses have occurred, with CNS involvement in seven cases. The life table analysis revealed a probability for overall survival after almost five years of 45% (SD, 4%), for event-free survival 41% (SD, 4%), and for the event-free interval 52% (SD, 5%). Up to now, no relapse was seen after 2 1/2 years. Risk factor analysis showed that early fatal hemorrhages occurred predominantly in children with M5 FAB type and with initial leukocytosis. An initial high WBC count and liver enlargement were unfavorable parameters for achieving remission. No factors could be identified concerning the risk for relapse. These data indicate that the applied treatment strategy is successful in inducing complete remissions in about three fourths of children with AML and also in enhancing considerably the chances for long-term remission.

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In two consecutive therapy studies, the BFM multicenter study group treated 55 children with B-NHL from 1975 until 1981 and another 55 children with B-NHL and 22 with B-ALL since 1981. In the 1975/81 study, a therapeutic regimen which produced excellent results in non-B-NHL and -ALL, emerged to be much less effective in disseminated B-NHL. With this regimen the probability of continuous complete remission (CCR) in advanced disease was 34% only after 7 years. Since 1981, a new therapeutic regimen of higher specificity for B-neoplasias improved the probability of CCR at the present time to 100% in localised B-NHL, to 63% in disseminated B-NHL and even in B-ALL to 49%.

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Several studies have reported a decline in intelligence and cognitive functions in survivors of childhood acute lymphoblastic leukemia (ALL). Other investigators, however, have found no intellectual impairment in these children. Fifty-one long-term survivors of ALL, having been treated according to the protocols of the BFM Study Group from 1970 to 1979, were assessed retrospectively using neurophysical methods. The results were compared with those obtained from 30 patients with other malignancies, who had received neither radiation therapy to the central nervous system (CRT) nor any methotrexate during chemotherapy. Additionally, neurological examinations and cranial computed tomography (CCT) were performed. neuropsychological examinations included verbal functions, intelligence (performance), psychomotor speed, motor skills and sensory integration. The results of verbal tests and the IQs, tested by nonspeed-related measures, were within normal limits in both groups. About one-third of all patients showed mild disturbances of psychomotor speed and motor skills. Children with leukemia had lower scores than those with solid tumors for nearly all tasks, but only tests for sensory integration revealed significant differences between former ALL patients and tumor patients. Furthermore, the following results were obtained related to different therapeutic modalities: The higher total radiation doses had been during CRT (maximum 24 GY), the more neuropsychological functions were impaired, particularly motor accuracy and sensory integration. These disturbances improved with the length of survival. Widening of subarachnoidal space was found in 33% of the CCT obtained. There was no correlation between the intellectual functions of the survivors and the CCT abnormalities. Neurological findings mainly consisted of slight fine motor disturbances.(ABSTRACT TRUNCATED AT 250 WORDS)

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Lymphomatous cell samples from 86 patients with B-cell neoplasia (34 chronic lymphocytic leukaemia, 8 hairy-cell leukaemia, 5 prolymphocytic leukaemia, 20 immunocytic lymphoma, 9 centrocytic lymphoma, 3 centroblastic/centrocytic lymphoma, 3 lymphoblastic lymphoma, 1 plasma cell leukaemia and 3 plasmacytoma) were studied using the monoclonal antibody Leu 1, detecting a p69,71 antigen complex present on nearly all thymocytes, most (greater than 85%) peripheral T-lymphocytes as well as some malignant B-cells. Furthermore, we compared the reactivity of Leu 1-positive B-cells with those exhibiting conventional surface markers such as mouse-erythrocyte-receptor, FcIgG-receptor, C3b- or C3d-receptor and surface immunoglobulins of the various heavy- and light-chain types. Our results demonstrate a correlation between the expression of p69,71 antigen complex and distinct phenotypes revealed by conventional markers and underline the value of Leu 1 monoclonal antibody in the differential diagnosis of human B-cell neoplasia.

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Abnormal widening of cortical sulci as seen in posttherapeutic cranial computed tomography (CCT) of 64 children in complete continuous remission (CCR) of acute lymphoblastic leucemia (ALL)/non Hodgkin's lymphoma (NHL) was related to patient data and neurological complications during the application of West Berlin treatment protocol. Age and neurological/neurodevelopmental findings of the patients at diagnosis of their disease positively and significantly correlated with CCT abnormalities. Abnormal pre- and intratherapeutic electroencephalographic (EEG) recordings, the development of a severe polyneuropathy syndrome and/or a considerable loss of weight during treatment were frequently associated with an abnormal widening of cortical sulci. Occurrence of transient early encephalopathy syndrome, development of radiation induced blood brain barrier disturbance and somnolence syndrome were not correlated with these CCT changes. Possible explanations of these abnormalities are discussed.

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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.

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From 1970 to 1979, two subsequent BFM studies were performed with different modalities of systemic chemotherapy and preventive central nervous system (CNS) therapy. Eighteen out of 275 children experienced isolated CNS relapses within 2 years after diagnosis. The present analysis should clarify the following questions: 1. Could the risk for CNS relapse be assessed by initial diagnostic findings? 2. Is the CNS relapse rate influenced by more intensive systemic chemotherapy? 3. Is the CNS relapse rate altered by different doses of radiation therapy? The risk for relapse was assessed using a risk index (RI) based on findings at diagnosis. All patients were treated with an 8 weeks induction and consolidation chemotherapy protocol. In part, children with increased risk for relapse (RI greater than = 3) received an additional 6 weeks reinduction protocol within the first six months after diagnosis. Preventive treatment to the CNS consisted of radiotherapy at doses of less than = 18 Gy or 24 Gy and intrathecal methotrexate given during the consolidation phase. The results are as follows: 1. The RI proved to be predictive also for the risk of CNS relapse. However, CNS relapse rates were not substantially higher in children with RI greater than = 3 when they had been exposed to radiation doses of 24 Gy instead of less than = 18 Gy. 2. Intensive systemic reinduction therapy did not influence the CNS relapse rate in children with RI greater than = 3. 3. Three percent of children with RI less than = 2 experienced CNS relapses, irrespectively of lower or higher radiation doses. In patients with RI greater than = 3, however, irradiation at doses of less than = 18 Gy instead of 24 Gy led to a 3-4 fold higher incidence of CNS relapses, irrespectively of chemotherapy. We conclude that radiation doses of less than = 18 Gy are capable of preventing CNS relapses effectively in children with RI less than = 2. The exposure of patients with RI greater tha = 3 to doses of 24 Gy is justified.

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The principle of giving intensive polychemotherapy in the time between operation and irradiation was applied in a cooperative phase-2-study in children with medulloblastoma of the posterior fossa. A first evaluation of 33 of 47 registered patients was attempted after the study existing now for 1 year and 10 months. In the majority of patients the chemotherapy protocol could be fully realized without any deductions. Side effects including two therapy related fatalities were analysed. In all patients irradiation was not delayed and could be started about 11 weeks after operation and could be carried through without any major draw-backs. Analysis of survival can only be preliminary due to the short duration of the study, but patients' survival is compatible with other reported studies. The therapeutic principle presented here shall be compared in a randomized and extended fashion with a conventional therapeutic approach.

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58 children were admitted to a prospective randomized leukemia induction and CNS-prophylaxis three different protocols were followed for maintenance. A (n = 20): 6-MP (50 mg/m2) p.o. daily + MTX (20-30 mg/m2) p.o. weekly; B (n = 20): 6-MP (50 mg/m2) p.o. daily + MTX (75-150 mg/m2) i.v. every two weeks; C (n = 18): 6-MP (50 mg/m2) p.o. daily + alternating 8-week-courses of four biweekly i.v. injections of MTX (75-150 mg/m2) and four biweekly i.v. injections of Cyclo (600 mg/m2). After all patients have been followed for at least 48 months, the rates of continuous complete remission are 42% in protocol A, 63% in protocol B, and 29% in protocol C. No encephalopathies have been observed with regimen B.

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A retrospective statistical analysis of the acute lymphoblastic leukemia study BFM 70/76 revealed the prognosis being strongly dependent on the initial leukemia cell count/mm3 in the peripheral blood, and the enlargement of liver and spleen below the costal margin. Based on postmortem examinations reported in the literature a method was developed to estimate the tumor mass in these three compartments in an order of magnitude. The estimated blast cell mass related to the patient's body weight proved to be highly significant (p much less than 0.001). Simplification of the method led to the definition of a "risk factor" allowing the separation of patients into 3 groups with a distinctly different risk for relapse. In the current study BFM 81 the risk factor is used to stratify patients with respect to the individually needed therapeutic intensity.

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