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We examined the frequency and kind of cancer in families with a child having a neoplasm at the Universitätskinderklinik Homburg/Saar, at the Universitätskinderklinik Freiburg and at the Institut für Medizinische Statistik und Dokumentation der Johannes Gutenberg-Universität Mainz. The following could be shown: 1. There is no difference in the distribution of various kinds of cancer in children, whether they have relatives with cancer or not. 2. It is necessary to examine the family history repeatedly to obtain an accurate documentation of familial cancer. 3. Cancer in familial members did occur in a third of all families on an average. 4. Independently of the diagnosis of the child, in most families only one additional family member did have cancer. 5. The majority of relatives with cancer are grandparents. 6. Cancer of the lung and of the breast are the most frequent kinds of neoplasms occurring in family members. 7. Comparing the most frequent kinds of neoplasms in family members in this study with the distribution of cancer in adults, it is obviously, that there is a higher percentage of leukemia and brain tumors in relatives of children with cancer than is expected. 8. Typical tumor constellations can be found in affected families like breast cancer and soft tissue sarcomas.

The increasing importance of radiotherapy in tumor of childhood demands the investigation and consideration of the psychological aspects of this afflicting therapy. In this paper the results obtained by questioning and observing 28 children of different ages, their parents, attendants and employees of several radiological departments are discussed. As the children's fantasies and the resulting anxieties and reactions are depending on the respective intellectual and emotional developmental stage detailed proposals concerning the preparation and performance of radiation in toddlers, school children and adolescents are presented.

Rabbit splenic capsular strips contract in response to angiotensin II and simultaneously release prostaglandins E and F into the bath fluid. Contractions, though not sustained, and prostaglandin release are dependent on the concentrations of angiotensin II. Addition of indometacin to the bath fluid inhibits prostaglandin release and potentiates the angiotensin II-induced contractions. Similarly, 5,8,11,14-eicosatetraynoic acid, another blocker of prostaglandin synthesis, potentiates contractions elicited by angiotensin II. Exogenous prostaglandin E1 (300 ng/ml) tends to decrease angiotensin II-induced contractions, while prostaglandin E2 (300 ng/ml) as well as prostaglandin F2alpha (300 ng/ml) significantly increase the contractions produced by angiotensin II. The prostaglandin endoperoxide analogues (15S)-hydroxy-9alpha,11alpha-(epoxymethano)prosta-5Z,13 E-dienoic acid and (15S)-hydroxy-11alpha,9alpha-(epoxymethano)-prosta-5Z,13 E-dienoic acid in concentrations of 300 ng/ml are either without effect or weak smooth muscle stimulants of their own, but do not influence the effect of angiotensin II. By the simultaneous use of sensitive and specific radioimmunoassays for prostaglandins E1 and E2 the prostaglandin E-like substance released by the rabbit splenic capsular strips was found to resemble serologically much more the dienoic prostaglandin E2 than prostaglandin E1. The potentation of the effect of angiotensin II by indometacin and 5,8,11,14-eicosatetraynoic acid might be caused by inhibition of synthesis of prostaglandins or related compounds in the splenic tissue. However, an undefined sensitizing effect of indometacin and 5,8,11,14-eicosatetraynoic acid, not related to their effect on prostaglandin synthetase, on the smooth muscle preparation cannot be excluded.

An intensive 7-day combination chemotherapy protocol was designed to reinduce children with early bone marrow relapse of acute lymphoblastic leukemia (less than 6 months after the end of or during preceding treatment). This aggressive approach seemed to be justified for a group of patients who were at the highest risk for ultimate treatment failure. In all, 38 children were enrolled for study. The ratio of male (median age, 10 years) to female (median age, 13 years) subjects was 27:11. Thirty patients were treated for their first relapse and eight for their second or subsequent relapse. Isolated bone marrow involvement was present in 24 cases. All patients had received heavy pretreatment including anthracyclines with cumulative doses of between 120 and 240 mg/m2. 22 of these patients, achieved complete remission, ten did not respond to therapy, and six died from the toxicity of the protocol. Cardiac failure was the cause of death in one child (after additional radiotherapy for a mediastinal mass). No further clinical manifestation of cardiomyopathy could be observed. The other five patients died from hemorrhages or infectious complications. The main side effects were fever, gastrointestinal problems, stomatitis, and severe bone marrow aplasia lasting for about 2 weeks with nadirs of platelets and white blood count around days 10-14. The remission rate of 60% was acceptable, though not satisfactory. Only four children survived disease-free for 13+, 14+, 20+, and 22+ months after diagnosis of relapse.

Rabbit splenic capsular strips release prostaglandins E and F when contracted by noradrenaline or methoxamine. Contractions and prostaglandin release are dose-dependent. Cocaine increases significantly the effect of noradrenaline, but not that of methoxamine, on contraction of the strips and release of prostaglandin E. Release of prostaglandin F was increased by the addition of cocaine not only when noradrenaline was used as an agonist but also at two of three dose levels of methoxamine. When indometacin is added to the bath fluid, it inhibits prostaglandin release and at the same time potentiates the contractile effects of noradrenaline and methoxamine on the rabbit splenic capsular strips. The prostaglandin-synthetase blocker 5,8,11,14-eicosatetraynoic acid also potentiates the contractions induced by noradrenaline and methoxamine. Both the effects on prostaglandin synthesis and on contraction exerted by indometacin can be reversed, when indometacin is washed out. Exogenous prostaglandins E1, E2 and F2alpha in concentrations up to 150 ng/ml do not influence contractions of the strips induced by either noradrenaline or methoxamine. At higher concentrations prostaglandin E1 decreases, but prostaglandins E2 and F2alpha increase the contractions induced by both agonists. The potentiation of the effects of noradrenaline and methoxamine on rabbit splenic strips by indometacin and 5,8,11,14-eicosatetraynoic acid cannot be explained by inhibition of uptake1 or uptake2, release of endogenous noradrenaline or inhibition of metabolism of the agonists. It is suggested that the potentiation is caused by inhibition of synthesis of endogenous prostaglandins, although an undefined sensitizing effect of indometacin and 5,8,11,14-eicosatetraynoic acid cannot be completely exclused.

Two children aged 3 and 11 years are described in whom a combined autoimmune neutro-and thrombocytopenia developed in association with pronounced cell-membrane bound IgG. These latter antibodies were detected by the unlabelled immunoperoxidase (PAP) method. Prednisone therapy proved to be beneficial.

During l-Asparaginase (l-Asp) treatment the development of specific antibodies of IgG isotype is frequently observed. In most instances elevated IgG antibodies to l-Asp activate the complement system and induce allergic reactions following l-Asp infusion. However, in some cases no adverse reactions and no activation of complement are noticed, despite the presence of elevated anti-l-Asp levels. We studied the development of specific IgG antibodies to l-Asp in different subclasses in 12 children who had produced high levels of specific IgG. Results showed that all patients had elevated levels of IgG1. In 5 cases we were able to demonstrate the development of specific IgG3 antibodies and in 1 case of IgG4 antibody. Patients with high levels of IgG3 (above 100 AU) had the highest risk for subsequent anaphylaxis. Thus, subclass-specific determination of antibodies to l-Asparaginase might improve the estimation of the risk of anaphylaxis prior to 1-Asp infusions.

Among twelve patients with homozygous alpha1-antitrypsin deficiency (Pi-type Z), five cases of infantile liver disease were diagnosed. The course of the disease was extremely variable; only one patient died of liver cirrhosis at the age of fourteen. In four cases the clinical, biochemical and histological (2 cases) findings became normal over a follow-up period of one to fifteen years. The results of these observations demonstrate that in alpha1-antitrypsin deficiency even when associated with proven liver disease the prognosis need not be unfavorable.

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.

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.

A cervical lymph node enlarged since 3 weeks was to be removed in a 12-year-old boy, whose only complaint was slight fatigue. Routine screening revealed hypercalcemia of 7.3-8.1 mval/l. This rose to 9.2 mval/l despite furosemide-induced high fluid turnover and prednisone while diagnostic evaluation proceeded. Serum phosphate was low consistently. Malignancy, vitamin D-intoxication, immobilisation and familial conditions could be ruled out as causes. Highly elevated serum-parathormone levels inspite of hypercalcemia, and ultrasonography of the neck were the most helpful evidence of a parathyroid adenoma. Calcitonin was effective in lowering serum-calcium to 6-7 mval/l preoperatively.

2 boys aged 4 and 6 1/2 years and a 1 1/2-year-old girl in whom persistent EBV-infections developed are described. Serological investigations showed a markedly increased IgG-antibody titer against the virus-capsid antigen (VCA-IgG). Furthermore there was a persistence of anti-early-antigen-antibodies (anti-EA-antibodies) resp. VCA-IgA indicating a chronic infection. The observation period was 1 to 4 years. Cellular immunity in these children was depressed. They show the typical clinical symptoms of infectious mononucleosis; additionally they often suffer from other infectious diseases.

The analysis of the results of two German Pediatric Oncology (GPO) cooperative, neoadjuvant chemotherapy trials after a followup of 7 (COSS-80) and 5 years (COSS-82) allows several conclusions concerning both systemic and local treatment of patients suffering from osteosarcoma. A metastasis free survival rate (MFS) of 59% was reached in the reduced study group of the first study, COSS-80. In addition to size of the primary tumor, the extent of chemotherapy induced devitalisation was very closely related to the probability of survival without systemic recurrence. Following this observation, it was the aim of the next study, COSS-82, to improve the MFS of patients with poorly responding tumors by altering their postoperative chemotherapy regimen. However, this "salvage" approach failed. Moreover, an effort to reduce treatment related toxicity by sparing some patients from the side effects of two particularly toxic drugs, adriamycin (ADR) and cisplatinum (CDDP), by only giving these postoperatively and only after insufficient tumor response to preoperative therapy, failed (MFS of the study arm of COSS-82 45% at 5 years vs. 68% for the control arm with primary use of ADR and CDDP, p less than 0.05). The value of an effective primary chemotherapy is further enhanced by the observation, that en bloc resection of tumors which were poor responders to preoperative therapy was associated with an increased risk of distant metastases when compared with amputation and rotation plasty, while this was not the case for good responders. In conclusion, both systemic tumor control and optimal local therapy require that all effects drugs are to be used as early as possible in the primary treatment of osteosarcoma, in order to enforce maximum tumor cell destruction and hence an optimistic outlook for the individual patient.

In a cooperative adjuvant chemotherapy study of osteosarcoma (COSS-80), 192 patients were registered from December 1979 to March 1982. Forty-one patients have been excluded from study because of their nonadjuvant situation, therapy-limiting clinical conditions, or inadequate diagnosis. One hundred and fifty-one patients have been randomized to receive either the drug combination bleomycin + cyclophosphamide + dactinomycin (BCD) or cisplatinum (CPL) within a course of sequential multidrug chemotherapy including adriamycin (ADR) and high dose methotrexate (HDMTX). After exclusion of 51 patients with some deviation in history and/or management 100 selected patients were randomized once more to receive in addition or not fibroblast interferon after preoperative chemotherapy and surgical removal of the primary tumor. Patients were stratified for age and sex and for site and extension of tumor as well in both randomizations. Median follow up is now 12 (1-16) months. The expected 2-year disease free survival (DFS) rate of the total doubly randomized group is 78% and of the single randomized group 76%. No difference could be discerned between recombined groups receiving BCD vs CPL or interferon vs no interferon. The effect of preoperative chemotherapy on the tumor was evaluated clinically and by histopathologic grading; 66/85 (78%) patients were judged clinically as responders with pathohistologic verification of this finding in 71% of these cases. No adverse effect arose from delaying definite surgery for preoperative chemotherapy, but initial application of chemotherapy as well as planning, preparing, and performing of the surgical procedure have been facilitated. The majority of patients received some kind of limb-salvage treatment without local recurrences so far. A statistically insignificant but intriguing tendency for a slightly higher incidence of pulmonary metastases after resection as opposed to amputation could be detected. Similar to observations in the previous study COSS-77.

5 patients 10 to 20 months old with severe normochromic, normocytic anemia and reticulocytopenia are reported. All patients recovered within 10 days to 5 weeks. No steroid therapy was given. Failure to recognize the clinical entity leads to unnecessary diagnostic and therapeutic procedures including the transfusion of blood.

A boy aged 15 years is described in whom a combined autoimmune neutro- and thrombocytopenia developed since the age of 11. Cell-membrane bound IgG antibodies were detected on neutrophils and platelets. A therapy with prednisone and/or immunoglobulins showed only a transient normalization of the peripheral blood values. In the course of this disease a lymph node adenopathy occurred showing histologically follicle hyperplasia with multiple plasma cells and relative atrophy of the paracortical T-cell region.

A 3-year-old child presented with vague abdominal pain, fever, leucocytosis and elevation of alkaline phosphatase. Ultrasonography revealed a space occupying process within the extrahepatic bile ducts surrounded by fluid. Various densities (between 15-25 Hounsfield units) were measured in this intrabiliary tumor by computed tomography.

23 out of 151 patients of the childhood AML study BFM-78 were less than two years of age at the time of diagnosis, 10 of them being less than one year old. The incidence of M5-subtype was high in infants with 12/23 (52%) compared with 20/128 (16%) in those 2 to 17 years of age. The percentage of boys was 44% in the young children compared with 56% in the older ones. Initial skin infiltrations were seen in five infants with monoblastic subtypes (M4, M5) and in only three patients more than two years of age. The incidence of liver and spleen enlargement greater than or equal to 5 cm below the costal margin was significantly higher in young children. Due to infectious complications frequent therapy-free intervals and/or reduced drug dosages were necessary in the 8-week induction treatment regimen. The prophylactic cranial irradiation with 12 Gy in the first year of life and 15 Gy in the second year has so far not caused any long-term sequelae. The results were similar to those in older children: 18/23 (78%) of the infants achieved complete remission compared with 101/128 (79%) of those 2 to 17 years old. With a follow-up period of 16 to 49 months the probability of continuous complete remission (disease-free interval) was 52% in children under the age of 2 and 54% in those more than 2 years of age. We conclude that with the improved prognosis an intensive chemotherapy is justified in infants with acute myelogenous leukemia.

99 children with non-Hodgkin's lymphoma entered the prospective, multicenter BFM study 81/83. They were treated with a four-fold stratified therapy according to clinical stage and origin of the lymphoma from B- or non-B-lymphocytes. In the BFM study 75/81, these criteria had been proven to be most relevant for prognosis. Therapy of non-B-NHL was very similar to the therapeutic concept as applied in acute lymphoblastic leukemias by the BFM group. For the NHL of B-type, a new therapeutic regimen was developed. Cytostatic drugs applied in this group were: medium dose methotrexate, cyclophosphamide in a fractionated manner of application, adriamycin, cytarabine, VM 26 and prednisone. The probability of disease-free survival was 80% after nearly 3 years for all patients. In non-B-NHL it was 89% in localized, and 79% in disseminated disease. All patients with localized B-NHL are surviving without relapse, while the probability of disease-free survival in patients with disseminated B-NHL was 67%. Thus, the therapy result in the latter group was doubled as compared to the result of the BFM study 75/81.

The GPO Cooperative Ewing's Sarcoma Study (CESS 81 with 10 months four-drug combination chemotherapy (vincristine, actinomycin D, cyclophosphamide, and adriamycin = VACA) and local control with surgery and/or radiation, following week 18, resulted in a Kaplan-Meier estimated disease-free survival of 51% after 6 1/2 years (51/93 patients disease-free). Tumor volume and histological response to primary chemotherapy were identified as most significant prognostic factors. As a consequence, the CESS 86 regimen was stratified according to risk of relapse. Standard risk patients (extremity tumors less than 100 ml tumor volume) were continued on VACA chemotherapy. In high risk patients (extremity tumors greater than 100 ml tumor volume, central tumors), cyclophosphamide in conventional dose (1200 mg/m2/course) was replaced by high doses of ifosfamide (6 g/m2/course) with mesna uroprotection (VAIA). Local control was obtained following week 9. Patients with radiation were randomised for conventional fractionation or accelerated split-course hyperfractionation. The study was piloted from February to December 1985: 27/37 patients were disease-free on October 1, 1987. The ongoing trial was started on January 1, 1986. On October 1, 1987. 63/66 patients were disease-free. In patients with large primaries, according to Kaplan-Meier life-table analysis, the disease-free survival was significantly better in patients receiving VAIA chemotherapy, compared to the previous VACA regimen. The toxicity of both combination chemotherapy regimens was comparable.

Increasing concentrations of angiotensin I and different perfusion rates were used to study the conversion of angiotensin I in guinea-pig and rat lungs. Even the highest concentration used (32.0 muM), which is a thousand times higher than that which occurs in vivo, was unable to saturate the converting system indicating the enormous capacity of this system. SQ 20881 proved to be a reversible inhibitor of the converting system. Its effect on the angiotensin I conversion was greater in guinea-pig lungs than in rat lungs (ID50 was 40.0 nM in guinea-pig lung and above 360.0 nM in rat lungs at a substrate concentration of 38.6 nM).

In therapy study ALL-BFM 81 633 previously untreated patients with acute lymphoblastic leukemia (ALL) less than 18 years of age have been recruited from April 1, 1981 to September 30, 1983 and treated in 37 institutions throughout West-Germany and Austria. Here only therapy results of 611 patients with non-B-ALL are presented. Patients with ALL of B-type are described elsewhere. In this fourth consecutive trial of the BFM study group three major questions have been asked: 1. Is it possible to assess the individual risk for relapse more accurately by the use of a risk factor rather than by the risk score which was the discriminator in studies ALL-BFM 76 and ALL-BFM 79? Does this risk factor discriminate more precisely patients at the highest risk for relapse? Offers more intensive risk-adapted therapy to this patient group a better chance for disease-free survival? 2. In patients at a standard risk for relapse with a risk factor below 1.2--approximately 60% of patients with non-B-ALL--can radiotherapy for prevention of CNS disease effectively be replaced by chemotherapy (intermediate dose Methotrexate)? 3. It is possible to reduce duration of maintenance therapy by 6 months to a total duration of 18 months with no unfavorable effect? To assess the radiation problem in standard risk patients and to evaluate the importance of duration of maintenance therapy two randomisations have been utilized. After a median duration of study ALL-BFM 81 of 4 1/2 years and 3 1/4 years after the study had been closed (date of evaluation January 1, 87) the answers are as follows: 1. For the majority of patients risk-adapted therapy had a curative effect. The probability for event-free survival (EFS) in standard risk patients in slightly above 70%, in medium risk patients 67%. In high-risk patients risk-adapted therapy did not improve prognosis, the EFS being still in the order of 50%. A good assessment of the individual risk for relapse is possible by the newly introduced risk factor. This principle is superior to the risk score used in former studies ALL-BFM 76 and ALL-BFM 79 because a low risk group (risk factor below 0.8) could be identified including approximately 25% of all patients with non-B ALL. Selection, quality, and timing of therapy elements remain the decisive prognostic factors, however. 2. Standard risk patients with a risk factor below 0.8 can effectively be protected for CNS relapse by treatment with intermediate dose Methotrexate.(ABSTRACT TRUNCATED AT 400 WORDS)