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The trial ALL-BFM 95 for treatment of childhood acute lymphoblastic leukemia was designed to reduce acute and long-term toxicity in selected patient groups with favorable prognosis and to improve outcome in poor-risk groups by treatment intensification. These aims were pursued through a stratification strategy using white blood cell count, age, immunophenotype, treatment response, and unfavorable genetic aberrations providing an excellent discrimination of risk groups. Estimated 6-year event-free survival (6y-pEFS) for all 2169 patients was 79.6% (+/- 0.9%). The large standard-risk (SR) group (35% of patients) achieved an excellent 6y-EFS of 89.5% (+/- 1.1%) despite significant reduction of anthracyclines. In the medium-risk (MR) group (53% of patients), 6y-pEFS was 79.7% (+/- 1.2%); no improvement was accomplished by the randomized use of additional intermediate-dose cytarabine after consolidation. Omission of preventive cranial irradiation in non-T-ALL MR patients was possible without significant reduction of EFS, although the incidence of central nervous system relapses increased. In the high-risk (HR) group (12% of patients), intensification of consolidation/reinduction treatment led to considerable improvement over the previous ALL-BFM trials yielding a 6y-pEFS of 49.2% (+/- 3.2%). Compared without previous trial ALL-BFM 90, consistently favorable results in non-HR patients were achieved with significant treatment reduction in the majority of these patients.

Neurofibromatosis type 1 (NF 1) is a neuroectodermal tumor in which abdominal manifestations occur in about 25% of cases in addition to the typical cutaneous lesions. A child with a severe form of an abdominal manifestation of NF 1 was treated in the Hanover Medical School by tumorresection. Pre-operative diagnosis using CT, angiography and ultrasound showed an enormous abdominal tumor constricting the mesenteric vessels. The tumor and the affected portion of the small intestine (150 cms) were removed surgically. No tumor recurrence was observed nine months after operation. Surgical removal is the only currently available therapy for treating tumors of this size.

A 9-year-old body with X-linked agammaglobulinemia developed chronic enteroviral meningoencephalitis (CEMA) caused by echovirus type 6. Intravenous treatment with selected immunoglobulin charges containing high titers against echovirus type 6 or combination with beta-interferon did not result in improvement. After implantation of a Rickham reservoir and periodical administration of intraventricular and intravenous immunoglobulin the virus recurred rapidly each time treatment was stopped. After 20 months of treatment the patient received a combined therapy with beta-interferon and selected immunoglobulin. Both drugs were given by lumbar puncture, intravenously and via Rickham reservoir. Subsequently echovirus type 6 could not be isolated in culture or PCR. Cerebrospinal fluid pleocytosis disappeared. The remission is lasting for more than three years. Intrathecal and intraventricular beta-interferon therapy for CEMA is being reported for the first time. Facing the unfavourable prognosis of the disease this mode of treatment is a new therapeutic approach following failure of other therapies.

Even in patients with normal renal function, high-dose methotrexate therapy (HDMTX) may be followed by extremely prolonged MTX elimination through alkaline diuresis is performed correctly. By inquiry in Germany, Austria and Switzerland for HDMTX infusions with MTX plasma concentration 42 h after start of exposure (MTX-42) higher than 5 mumol/l (microM), we analyzed data from 21 patients in whom impairment of renal methotrexate elimination had received 5 g/m2.24h, 3 had received 12 g/m2.4h. They presented with MTX-48 serum level between 1.7 and 1404 microM. There was no recognizable causative factor. As early signs for impaired elimination, we identified enhanced vomiting during MTX infusion in 8/21, elevated steady-state-MTX in 11/15, and a rise of serum creatinine greater than 50% in 14/16 patients in whom respective data were available. Creatinine rose to a maximum of 1.0-4.9 mg/dl within 1-4 days in 19/21 patients (accompanied by diuresis problems in only 5 patients) and normalized within 3-17 days in all but two patients. Creatinine maximum correlated weakly with MTX-48 (r = 0.34) and with extrarenal toxicity. 8 patients had normal (WHO 0-II degree), 8 other had intensified (III-IV degrees) but not critical extrarenal MTX toxicity with calcium folinate (CF) doses of 0.2-1.6 mg/kg.microM MTX q 6 h started 28-54 h after beginning of MTX exposure. 5 patients had unusual toxicity. 2 patients suffered from severe but reversible encephalopathies with CF doses of 0.05 and 1 mg/kg.microM MTX q 6 h started after 51 and 36 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aim of the Study: The pathogenesis of fifth day fits in newborns has not yet been explained. From 1989-1991 we observed an epidemic occurrence of 21 cases in 1917 hospitalized newborn children. After finding rotavirus in the faeces of several cases we suspected a coincidence., Methods: We tested the faeces of 19 fifth day fitters as well as 30 healthy newborns (4.-6. day of life) for rotavirus infection. The results of all clinically indicated rotavirus examinations in neonates of 4 to 6 days of age from 1989-1991 were analysed. In 6 rotavirus positive fifth day fitters we performed an immunologic and electron microscopic examination of cerebrospinal fluid., Results: 18 of 19 examined children with fifth day fits (95%) had rotavirus in the faeces. Within the healthy control group we found 12 of 30 (40%, Chi-square 12.46, p < 0.001) and in the group of sick neonates without convulsions 98 of 202 (48.5%, Chi-square 12.44, p < 0.001). This shows a statistically significant coincidence of rotavirus positive faeces with fifth day fits. Rotavirus was not present in cerebrospinal fluid., Conclusions: We suggest a causal relation between fifth day fits and rotavirus infections. Pathogenetic details remain unclear.

From 1984 to 1989, 47 children with relapsed, refractory, and/or metastasized neuroblastoma were treated with 131I-metaiodobenzylguanidine (mIBG) in several different treatment combinations. At initial diagnosis, 36 children had Evans stage IV and 11 stage III disease. In 16 of the 47 children, tumor recurred after complete remission prior to mIBG treatment, 26 of 47 progressed from residual or nonresponding tumor, and in 5 of 47 tumor progression during chemotherapy was observed. Altogether the children were treated with a total of 112 courses (range 1-6) with a mean dosage of 8.9 +/- 6.7 mCi/kg body weight/treatment course. Total dose was 283.2 +/- 203.7 mCi for stage III and 388.9 +/- 218.6 mCi for stage IV. Nine of 47 children reached a complete or a very good partial remission (CR and VGPR) from mIBG treatment alone, 13 of 47 achieved partial remission (PR). In an early analysis, 10 patients treated with mIBG in the neuroblastoma trial NB 85 of the German Society of Pediatric Oncology showed no significant difference in survival time compared with 30 conventionally treated children. However, the recent therapy series has been done with higher doses of mIBG, and during improved therapeutic scanning many more bone lesions could be detected than during earlier diagnostic scanning. We conclude that mIBG treatment has not yet fulfilled the expectations for it but still seems for certain indications to be a promising tool to treat neuroblastoma in the future. Moreover, the frontier of neuroblastoma detection is still advancing.

The selective uptake and accumulation of 131J-Metaiodobenzylguanidine in neuroblastoma cells in vivo may be utilized for targeted irradiation. The experience with 32 neuroblastoma patients refractory to conventional high dose chemotherapy is reported. At diagnosis 8 patients had Evans stage III and 22 stage IV. 11/32 experienced recurrences after complete tumor disappearance and before mIBG treatment, 16/32 progressed from residual or nonresponding tumor and in 3/32 insufficient tumor regression by chemotherapy was observed. 2 children received one mIBG course each with no evidence of disease. Mean applied activity was 128 mCi per course (35-300 mCi), 360 mCi per patient (80-1033 mCi) and 19.2 mCi/kg per patient (3.2-37.9 mCi/kg), respectively. A total of 84 courses was given (mean 2.6 per patient). Pain relief was noticed in 14/14 patients with bone pain. Complete or very good partial remission was achieved in 5/32, partial remission in 11/32 and stable disease in 6/32 patients. In 8 children progression occurred and 2 patients were not evoluable. 20 children died, 12 are still alive (6 patients with initial stage IV, 6 with stage III disease). Main side effect was transient thrombocytopenia, which became more severe with increasing number of courses. We conclude that mIBG treatment is effective in some patients with refractory neuroblastoma and may be utilized in the future as front line therapy for patients achieving only incomplete regressions after high dose chemotherapy.

In a prospectively randomized study we investigated the influence of vitamin E on the development of bronchopulmonary dysplasia (BPD) in neonates with artificial ventilation. Out of 78 neonates two randomized groups of each 39 were formed; one was treated, the other served as control group. We evaluated the cases of those children who remained on respiratory therapy for more than 3 days and who survived 14 days or longer, 19 in each group. The vitamin E treated infants received 20 mg/kg vitamin E i.m. daily during artificial ventilation, but not longer than 14 days. A total of 5 infants (13%) developed BPD, 3 in the vitamin E group, 2 in the control group. All patients with BPD died after 1/2-4 months. After 3 months 17 treated and 16 untreated infants survived. X-rays of the lungs were normal in 12 and 13 respectively. These results do not suggest a beneficial effect of vitamin E in respirator-treated newborn infants.

A newborn is presented with hyperexcitability, drowsiness and later-on with frequent vomiting and muscular hypotonia. Examination of the urine by gas chromatography-mass spectrometry lead to the diagnosis of propionic acidemia which was confirmed enzymatically in fibroblasts. Two unusual features were encountered in this case: There were severe bouts of hyperglycemia with blood glucose values up to 396 and 747 mg/100 ml; furthermore x-ray studies and autopsy revealed a hypertrophic pyloric stenosis.

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.

Two newborn infants with hyperleukocytosis and blast cells in the peripheral blood are compared. Case 1 represents a connatal leukemia, which could be characterized as monocytic by the naphthol-ASesterase reaction, which was inhibited by NaF. The child died after a few hours. Case 2 must be diagnosed as "pseudoleukemia" in mongolism. The blast cells were classified as lymphoblastic on the basis of a strong granular beta-glucuronidase reaction. The patient achieved spontaneous remission.

5 patients with ALL under protocol Freiburg 71 suffered bone marrow relapse. They received a conservative reinduction treatment with vincristine-prednisone +/- daunorubicin, followed in one case by L-asparaginase. Complete remission was achieved in 4, partial remission in 1. The duration of complete remissions was 1 to 11+ months.

The authors report on an infant with myeloproliferative syndrome of the myelomonocytic type. The findings fulfilled the criteria for juvenile chronic myeloid leukemia except that there was no increase of fetal hemoglobulin and no depression of erythrocyte carbonic anhydrase I. In one half of the bone marrow cells a Ph1-chromosome was found. During the course of the disease the Ph1-positive clone was successively replaced by cell lines with different chromosomal aberrations. The relationship between the cytogenetic mosaicism and the clinical and laboratory findings is discussed.

In 56 children with acute lymphoblastic leukemia (ALL) T and B lymphocytes and immunoglobulins (IgG, IgM, and IgA) were studied before, during, and after therapy. At the time of diagnosis T lymphocytes were normal, the number of B lymphocytes was increased, and immunoglobulins usually were normal. Only two of 30 children had abnormally low immunoglobulin levels. Under therapy a progressive lymphopenia was observed. B cells were depressed most extensively. IgG and IgA levels showed a nadir during early treatment, i.e. after remission induction for IgG and 4-8 months after diagnosis for IgA. IgM was markedly elevated after meningosis prophylaxis. After cessation of therapy lymphocytes increased with an intense rebound of B cells. The recovery was not fully completed after one year free of therapy.

Lymphoblasts from ten patients with ALL or stage IV malignant lymphoma were studied cytochemically and investigated for rosette-forming capacity with sheep red blood cells (SRBC) as a T cell surface marker. SRBC binding capacity and acid phosphatase or beta-glucuronidase were tested simultaneously in single lymphocytes isolated from normal blood donors. Our results suggest that the presence of acid phosphatase (and beta-glucuronidase) represents a functional state of lymphocytes or lymphoblasts qualitatively independent of T cell differentiation, but quantitatively more pronounced in T cells than in B lymphocytes or non-T lymphoblasts.

A newborn baby was born with scrotal hematoma and a diagnosis of testicular torsion was made. This diagnosis proved false, when the hematoma was resorbed after a few days and other hematomas developed instead (abdomen, elbow, foot, scalp). A total of nine hemorrhagic episodes were observed, most of them occurring on the scalp. All lesions were sharply delineated, started with red to purple discoloration and then turned to bluish-black indicating gangrene. Histology revealed extensive bleeding into the corium, fibrin thrombi within the capillaries, and complement and IgG in the small arterial walls. Each bleeding was associated with hypofibrinogenemia and thrombocytopenia. A diagnosis of hereditary protein C deficiency was made. Blood levels were consistent with heterozygosity of both the parents and homozygosity of the child. Bleedings were controlled by Cohn fraction I and heparin. It was impossible, however, to prevent further hemorrhage by continuous i.v. heparin. In addition aprotinin, epsilon-aminocaproic acid, AT III, and prednisone were ineffective. Continuous remission finally could be sustained with oral phenprocoumon.

In 1978 353 premature and mature newborns were admitted to our neonatal and intensive care unit. 34 children developed bacterial infections. B-streptococci were the offending organisms in 6 cases, pneumococci in 1 case, 5 of these 7 infections were of the early-onset type, 2 of the late-onset type. The early-onset type disease manifests itself by respiratory distress and shock. It is transmitted vertically from mother to child before or during birth. 3 of our 5 affected children died. The late-onset type disease occurs after 5-10 days, is transmitted as horizontal, mostly nosocomial infection, and presents as sepsis with meningitis or - as in one of our cases - with osteomyelitis. In addition to the 7 sick infants 8 of the 353 admitted newborns were colonized without signs of disease. Early diagnosis, therapy, and prophylaxis of these infections present still unsolved problems.

For B-All, we treated a five-year-old boy with a combination chemotherapy course including intermediate-dose methotrexate (MTX) with citrovorum factor rescue (CF) two days after a mild sunburn. The insolation inflammation vanished completely, but was reactivated after three days much more severely than the original sunburn, and healed slowly over three weeks. The reactivation phenomenon has previously been described in man and in the guinea pig. It differs substantially from "radiation recall" caused by other cytostatic drugs, as sunburn is not enhanced by MTX applied simultaneously with insolation and is not reactivated if MTX is given more than a week later. Previously irradiated skin regions are spared from the reactivation. Although the phenomenon is not prevented by CF, it can probably be understood as enhanced MTX toxicity to the hyperproliferating basal cell layer of skin after insolation damage. MTX should therefore not be applied for one week after sunburn.

In ALL the first complete remission would be terminated by CNS-relapse in two thirds of the patients if they received a modern chemotherapeutic treatment without meningosis-prophylaxis. The incidence of meningosis is reduced to 10% by prophylactic irradiation of the cranium (60Co, 2400 rd) and intrathecal methotrexate shortly after hematological remission has been achieved. Non-Hodgkin's lymphomas may be complicated by CNS disease, especially if the risk of spread to the bone marrow is high. Therefore, meningosis-prophylaxis should be included into treatment programs for malignant lymphomas of the lymphocytic poorly differentiated type beyond stage I, especially if the mediastinum is involved. CNS-prophylaxis cannot be recommended for patients with malignant lymphomas in pathological stage I. For the rest of the patients with malignant lymphomas guidelines cannot be given at the present time, because sufficient empirical data are lacking.

A 19-year-old patient with congenital Blackfan-Diamond anaemia has been maintained on a regular red cell transfusion schedule since he was two months old. From the age of four he has received desferrioxamine injections at regular intervals with different dose levels. In spite of the treatment with the chelating agent secondary siderosis developed with typical endocrinological abnormalities and cardiac arrhythmias. Increasing the dose of desferrioxamine to 16 g/24 h resulted in an iron excretion of 184 mg/24 h. Such an intensification of treatment finally produced a negative iron balance and the cardiac arrhythmias disappeared. Desferrioxamine therapy should be done under controlled circumstances only, an iron balance is mandatory, and the dose should be adjusted to the results of the balance.

Reye's syndrome is characterized by severe encephalopathy and fatty infiltration of the liver. Probably this is a polyetiological syndrome. In most cases the disease is preceded by influenza B or varicella infection. As known to date, damage to mitochondria is the essential feature. Therapy is symptomatic. A review is given of the clinical symptoms and of the many unsolved problems of pathogenesis.

An algorithmic approach to the diagnosis of anemias is presented. It starts with history, physical examination, and a basic laboratory program including erythrocyte morphology. On the basis of the reticulocyte count and MCH-value anemias are divided into hypo- and hyperregenerative as well as micro-, normo-, or macrocytic forms. Within these groups it is easy to diagnose common anemias by only a few laboratory tests. Rare forms of anemia will be recognized as such and diagnosed by special investigations.

I-131-metaiodobenzylguanidine was used for treatment of neuroblastoma stage IV in three children after surgery and or chemotherapy had failed to be effective. In two of the children with multilocular lesions, after an impressive improvement of clinical symptoms tumor progression was observed. Because in about 25% of children with relapsing neuroblastoma complete remission may be achieved by combining surgery, chemotherapy, and I-131-MIBG treatment, this therapeutic modality should be included in the therapeutic strategy of stage III and IV neuroblastoma.

42 patients with ALL were treated according to the following protocol: induction with vincristine + prednisone (+/- L-asparaginase), CNS-prophylaxis with cranial irradiation (2400 rads) and intrathecal methotrexate, maintenance for 3 years with 6-MP 50 mg/m2/d p.o. + MTX 75-150 mg/m2/2 wk i.v. X 4, alternating in a cyclic fashion with 6-MP 50 mg/m2/d p.o. + cyclophophshamide 600 mg/m2/2 wk i.v. X 4. The observation time is 24-67 (median 49) months. The actuarial complete remission curve shows 40% continuous complete remissions at 36 months and 30% at 60 months.--The frequency and temporal distribution of typical infectious complications are presented. The incidence of varicella was comparable to that in a southgerman normal control group (5,7% per year). During treatment there were two zoster manifestations per one varicella case, the incidence of zoster being 1 case per 106 patient-months, viz 11,4% per year.