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The etiology of congenital dyserythropoietic anemia (CDA) type II is unknown. The diagnosis is based on morphologic and immunologic criteria. We present three girls with well documented CDA II who were followed for 5-8 years. The anemia was mild, progressive body iron overload was found. In none of the girls splenectomy was indicated. Morphologic features of ++erythrocytes and bone marrow erythroid cells were studied by means of light and electron microscopy. Up to 45% of erythrocytes showed invaginations with endocytic cisterns and shape abnormalities (echinocytes, anisocytosis, microcytosis). Typical abnormalities of the external surface of RBC membrane: invaginations, depressions, pits and plaques were shown in the scanning electron microscopic studies. Our studies indicate that the morphological features of erythrocyte in our patients may be consequence of the biochemical changes in the membranes and may contribute to the shortened life span of erythrocytes in patients with CDA II.

Skeletal lesions in Hodgkin's disease can be due to different underlying causes. Reports on bone changes in Hodgkin's disease are reviewed and compared with two of our patients. The first patient, a fourteen year old girl with Hodgkin's disease, staged IV B, had skeletal involvement at the time of diagnosis. The other patient developed, three and a half years after the onset of the disease, bone lesions which might have been thought to be a manifestation of Hodgkin's disease. But by bacteriologic and histologic studies salmonella osteomyelitis could be proven.

86 patients with Wilms' tumor were treated in Heidelberg between 1951 and 1980. Using the histopathologic grading according to Hardwick and Stowens the sarcomatous tumor type has an unfavorable prognosis. All the patients in stage III to V developed metastases. In contrast to other types of Wilms' tumor these sarcomatous tumors do metastasize to bones, not primarily to the lung. Boys up to 5 years are mostly affected by the tumor. These were "cold" lesions in bone scan using different radionuclides on skeletal osteolytic metastases, which is limiting the application of scans to detect bone metastases in Wilms' tumor. A more aggressive chemotherapy should be given to improve prognosis of the sarcomatous type of Wilms' tumor.

Glucocorticoid receptors (GR) have been reported to predict clinical responsiveness to glucocorticoid therapy and to possess prognostic significance in leukemia. A raised level in terminal deoxynucleotidyl transferase (TdT) also seems to suggest clinical responsiveness to prednisone and vincristine therapy. We have investigated these two biochemical markers in the leukemic blasts in 23 patients with acute myeloid leukemia (AML) and in 19 patients with acute lymphoblastic leukemia (ALL) and have compared the binding data with clinical glucocorticoid sensitivity, with response to chemotherapy, with survival and with TdT. In 25 of these patients we have also investigated the in vitro glucocorticoid sensitivity by measuring dexamethasone inhibition of radiolabelled uridine and thymidine incorporation into the leukemic blasts. In patients with AML, GR levels were mostly high but did not correlate with the in vitro sensitivity, response to chemotherapy or survival. On the other hand, in the 19 patients with ALL there seemed to be a correlation between GR and in vitro sensitivity and between GR and clinical responsiveness to glucocorticoid therapy. Furthermore, patients with low levels of either TdT or GR seemed to be associated with poor prognosis. TdT activity and GR, however, did not associate with one another. TdT is a useful marker for the identification of lymphoblasts but, by itself, is not connected with glucocorticoid sensitivity. Gr, when applied to ALL, could supplement TdT determination by predicting response to therapy.

Bone tumours and tumour-like lesions occurring in newborns and infants are described presenting 5 own cases and a literature review. Age specific features in diagnosis, therapy and prognosis are discussed. Due to the rarity of these diseases a centralized registry at a national level is recommended.

The blood-CSF barrier inhibits permeation of most chemotherapeutic agents into the central nervous system (CNS). The influence of systemic chemotherapy and prohylactic CNS irradiation on the permeability of the blood-CSF barrier was studied in 49 children treated for acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma. To study the permeability of the blood-CSF barrier under treatment according to BFM-ALL protocols, nephelometric determinations of albumin, immunoglobulin G (IgG), and alpha-2-macroglobulin in serum and CSF and total protein in CSF were performed at several time intervals during chemotherapy and prophylactic cranial irradiation. During systemic induction chemotherapy, no significant changes of blood-CSF barrier could be observed. In contrast, in the course of prophylactic CNS irradiation and intrathecal methotrexate application, a significant elevation of albumin, alpha-2-macroglobulin and total protein in CSF, and a significant decrease of blood:CSF ratios for albumin and alpha-2-macroglobulin were observed. IgG did not change significantly. After prophylactic CNS treatment and during maintenance chemotherapy protein concentrations and blood:CSF ratios gradually returned to normal range. This normalization was accelerated by cortisone treatment during the reinduction period.

14 year old patient suffering from a renal cell carcinoma was treated by surgery and irradiation. 1 1/1 years after diagnosis he developed multiple metastases in the brain, skin, bones, and in regional lymph nodes. Cyclophosphamid and vincristin did not reduce the metastases. The literature is reviewed with regard to symptoms, diagnostic procedures, therapy, and prognosis of hypernephrome in childhood.

Binding of interleukin-2 (IL-2) to high affinity receptors on activated normal T cells was shown to be the essential step in induction of proliferation of such cells. The finding of abundant IL-2 receptors on malignant T cells in adult T cell leukemia suggested a deregulation of the IL-2/IL-2 receptor system and was assumed to account for aberrant growth in malignant disorders of T cells. In this study we use malignant T cells from nine patients with the clinical diagnosis of T-ALL or T-NHL and did not detect IL-2 dependent growth under conditions in which normal T cells responded to IL-2. IL-2 receptors comparable in numbers to activated T cells were found on T-ALL/T-NHL cells stimulated with PHA and PMA. However, binding studies using radiolabeled IL-2 indicated that the receptors present on malignant T cells were not able to bind to IL-2 with high affinity. Therefore, if IL-2 is involved in the proliferation of malignant T cells, its mechanism of growth regulation may be different from the one for normal T cells. Alternatively, IL-2 may not play a role in the regulation of growth of malignant T cells in vitro.

Plasma concentration of arginine-vasopressin (AVP) was measured in 145 healthy subjects aged one day to 18 years of age. AVP decreased with age immediately after birth. Above one year of age values of children did not significantly differ from those in adults. AVP significantly correlated with plasma and urine osmolality after water deprivation during 16 h. Plasma AVP rose during exercise and fell after volume expansion. Nausea and vomiting are potent nonosmotic determinants of AVP release in children. Nonosmotic factors of AVP release should be controlled when sampling blood for measuring AVP in children for diagnostic and investigational purposes.

Over a period of 6 years 88 children with acute lymphocytic leukemia and malignant non-Hodgkin lymphoma were treated according to the West-Berlin protocol. In 72 children skeletal surveys were performed initially and these showed leukemic bone changes in 31 patients. Follow-up was obtained in 70 patients for up to 8 years after diagnosis: 20 of these patients died and of these 8 showed initial skeletal involvement. In 17 children relapses occurred and 10 of them had bone lesions at first presentation. There was no significant correlation between the extent of the skeletal involvement and the survival time as calculated by life table analysis.

The mechanism responsible for the toxic late effects of cranial irradiation, followed by the administration of systemic methotrexate (MTX) on brain tissue, is still under discussion. We studied the influence of X-irradiation on dihydrofolate reductase (E.C. 1.5.1.3) activity (DHFR), the enzyme inhibited by MTX. New Zealand white rabbits, 6-9 weeks old, underwent 24 Gy fractionated or 20 Gy single-dose brain irradiation using a 60Co source. Before, immediately following, and 1, 2, 4, 12 weeks after irradiation, DHFR was measured in brain and liver tissue by a photometric assay. DHFR in brain tissue was 11.9 +/- 2.9 mU/g wet weight (ww) X h and in liver tissue 121.8 +/- 24.2 mU/g ww X h. Fractionated brain irradiation with 2 Gy per day produced no significant changes in brain DHFR. Single-dose cranial irradiation significantly decreased brain DFHR (7.3 +/- 0.6 mU/g ww X h). Suppression of the developmental increase of DHFR by X-irradiation in young rabbits could be excluded by determining the unchanged brain-to-liver ratios of DHFR in the animals with fractionated brain irradiation.

Local relapses in mediastinal non-Hodgkin's lymphomas in childhood are rare. Of the 15 children treated in our hospital during the last 11 years, 2 had early local or pleural relapses. At presentation both had extensive pleural effusions, and after completion of induction therapy still some fluid in the pleural space was present. A local irradiation was not performed initially. Be review of the literature for risks and benefit of local irradiation in mediastinal non-Hodgkin's lymphoma, local irradiation in children receiving aggressive chemotherapy should only be considered in few patients; preferentially in those, with incomplete disappearance of the mediastinal tumor or, as we may conclude from our patients, incomplete disappearance of pleural effusion.

A 2-year-old girl was admitted with clitoromegaly, mediastinal tumour and enlarged kidneys. A seventh cranial nerve palsy was associated with an increased cell count in cerebrospinal fluid. The diagnosis of a lymphoblastic lymphoma was confirmed by a cervical lymph-node biopsy. Six years after diagnosis and treatment according to the BFM protocol the girl remains in first complete remission.

An increasing number of children with acute leukemia show cerebral complications. 10 out of 78 children treated in our hospital for acute lymphoblastic leukemia or non-Hodgkin's lymphoma who underwent remission induction therapy or were in continuous complete remission developed central nervous system complications. During intensive initial therapy, intracerebral hemorrhages (2) and metabolic disturbances with concomitant cerebral convulsions (3) were seen. Unusual central-nervous infections occured in each treatment period (3). Cerebral degenerations could be observed only during the maintenance therapy (2). Cerebral convulsions were the leading symptom in 7 children. With intensive control of the coagulation system and the metabolic parameters central nervous system complications in the treatment of acute lymphoblastic leukemia should be reduced significantly.

To test the possibility that autoimmunity could be related to increased levels of anti-bovine antibodies and/or circulating immune complexes in selective IgA deficiency, we studied the sera of 30 consecutive patients for the quantitative level of antibody to bovine milk, the presence of antigen--antibody complexes and 10 selected autoantibodies. Higher titres of anti-milk antibody and circulating immune complexes were to be correlated with positive serological tests of autoimmunity in these patients, and rheumatoid arthritis (three cases) and neurological disease (four cases) were found in individuals who had both milk precipitins and circulating immune complexes. We suggest that the chronic excessive permeability of the gastrointestinal tract in selective IgA deficiency may permit the excessive absorption of many food proteins, leading to the formation of antigen--antibody complexes and autoimmunity.

477 patients with soft tissue sarcomas, including 87 children (18.2%) were treated at the Surgical Center of the University of Heidelberg between 1950 and 1980. 22.8% of the patients with solid tumors (excluding brain tumors) in childhood were soft tissue sarcomas. In the pediatric age group there were 30% rhabdomyosarcoma and 20% angioblastic sarcoma. Since introduction of combined tumor therapy (surgery, radiation, and chemotherapy) the survival rate increased impressively from (29% to 58%).

Thirty mature and peripubertal male rabbits were examined for endocrine function and tissue methotrexate (MTX) concentration after single (57.5 mg/kgBW, group 1) and repeated (6 mg/kgBW, once a week for 14 weeks, group 2) MTX doses. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and androstenedione plasma levels were measured by radioimmunoassay (RIA). We found elevated plasma FSH levels in both groups. Elevated plasma androstenedione level and reduced plasma testosterone level in group 2 suggest an enzymatic defect in the gonadal steroid synthesis. Unchanged LH plasma level, when compared to controls, is thought to be the result of a combined effect of MTX on the gonadal steroids and gonadotropin synthesis.

The authors report on their experiences with metaiodine-benzylguanidine (MIBG) scintiscanning in a total of 36 patients. 7 of these patients had a benign pheochromocytoma, 4 a malignant one; neuroblastoma was seen in 10 patients. Scintiscan diagnosis was supplemented by measurements of irradiation exposure and attainable tumour dose. It was also shown that it is possible to mark neuroblastoma cells in cultures. The results of these studies are discussed and compared with those of other working groups. If the physiological pattern of distribution is taken into consideration, and if the proper imaging technique is adopted, MIBG scintiscan is a sensitive and highly specific method in diagnosing pheochromocytomas and neuroblastomas.

Hepatoblastoma was diagnosed in a 12 month old boy presenting with hepatomegaly and isosexual precocious puberty. Preoperative levels of both alpha-1-fetoprotein (AFP) and human chorionic gonadotropin (HCG) were highly elevated. The tumor was removed by hepatic trisegmentectomy. Tumor tissue contained high concentrations of AFP and HCG. On combination chemotherapy with cyclophosphamide (CYC), vincristine (VCR), adriamycin (ADR) and 5-fluorouracil (5-FU) HCG dropped over a period of 9 months to normal values. In contrast, AFP was undetectable following surgery. One year after initiation of therapy there is no clinical or radiological evidence of recurrence of the malignancy but the observation period is too short to draw any conclusions on the effect of therapy and the final outcome.

Thirteen children with acute lymphoblastic leukemia (ALL) were investigated before and during cytotoxic therapy. EEG findings were correlated with the clinical course and the therapy protocol and compared with normal data obtained from 295 healthy children. Frequency analysis of the background activity of the EEG revealed an initial slowing of the background activity prior to therapy and further slowing each time a combination of vincristine (VCR), daunorubicin (DAU) or adriblastine (ADR), prednisone (PRED), and L-asparaginase (L-ASP) was administered. The slowing of the background activity correlated only with the administration of these drugs. DAU, ADR, and PRED are not known to influence the EEG; therefore, VCR and L-ASP remain the primary candidates responsible for the central nervous system alteration.

The presence of circulating immune complexes (ICS) in freshly drawn sera of 67 children with neuroblastoma was studied by the Raji cell radioimmunoassay of Theofilopoulos et al. (J. Clin. Invest. 57: 169--182), with particular emphasis on the correlation of levels of ICS with stage of disease and changes attributable to treatment. There was a close correlation between amount of complexes and stage of disease and treatment. Levels of ICS increased as the stage of the disease advanced, and were significantly higher (P less than 0.005) in stage IV than in all other stages combined. When patients with stage IV disease were subdivided into "before," "during," and "after" treatment groups, there was a significant decrease in ICS levels as treatment progressed. Studies of complement and complement components did not give such a clear relationship. A significant decrease of hemolytic C1 values was found in patients with "active disease" compared to normal age-matched controls. Some high C3 levels, determined immunochemically, were associated with low hemolytic levels of C3, which were attributed to C3 cleavage detected by immunoelectrophoresis. Based on our survival data, ICS, which were significantly different in 20 patients now decreased when compared to those of other patients, are very valuable in the prognosis of neuroblastoma.

Meta-iodine-benzylguanidine (MIBG) scanning provides, for the first time, specific radiological means for diagnosis, treatment follow-up and post-treatment care of patients with neuroblastoma. Of 10 such patients studied by MIBG scanning, 7 had histologically confirmed neuroblastoma. In 6 of them there was markedly increased activity in the primary tumor, in 3 metastases were demonstrated. In at least one patient the intensity of increased activity suggested the possibility of selective therapeutic administration.

Serum levels of circulating immune complexes (CIC) assayed by the Raji cell radioimmunoassay, total haemolytic complement (TCH50), Clq and C3 were correlated with clinical stage, histological type, age, sex and treatment of eighty-six children with Hodgkin's disease over a period of 4 years. Most significant findings were the changes of levels of CIC, TCH50, Clq and C3 during disease activity and following treatment. Significant perturbations were also seen in association with relapse. Levels of C and CIC were significantly elevated (P less than 0.001) at the time of diagnosis prior to splenectomy and/or any treatment. In the group before treatment, 81 percent of CIC levels were above 16 micrograms/ml with a maximum value of 1120 micrograms/ml. During treatment 33 percent were still above normal with a maximum of 320 micrograms/ml. Within 1 year after cessation of treatment, 37 percent also remained above normal levels with a maximum of 240 micrograms/ml. At relapse prior to treatment, 63 percent were again elevated with a maximum of 1280 micrograms/ml. The most significant difference on TCH50 levels relates to treatment periods. Sera of patients with active disease who are previously untreated show elevation of TCH50 levels (P less than 0.001) (average 127 CH50 mu/ml. During and after treatment eht TCH50 levels drop to 96 and 102 CH50 mu/ml, as compared to normal control of 100 CH50 mu/ml. In sera of patients at the first, second or third relapse, the combined TCH50 levels are significantly different from controls and across treatment periods (P less than 0.005).

Seven children and adolescents with sclerotic and periosteal alterations of the clavicle are reported, two of them in detail. Malignancies and bacterial inflammatory processes, which were first suspected, could be excluded. Clinical and radiographic features as well as differential diagnosis are discussed, as is the pertinent literature. The etiology of this uncommon bone lesion, which is described under different names, could not be clarified.

Skeletal involvement in childhood nonosseous tumors can be due to primary involvement, arrosion or metastasis, secondary due to therapy induced alterations or osteomyelitis following diminished immunity. The occurence of bone changes differs widely from those in adults. Neuroblastoma, rhabdomyosarcoma and malignant lymphoma are discussed in detail. Rare tumors are listed for synopsis. As diagnostic screening method skeletal scintigraphy is recommended, whereas in localized disease X-rays should be performed. Beside roentgenmorphology-particularly in primary disease-localisation, frequency and age dependency may give essential diagnostic hints. Prognosis depends on primary tumor.

We have previously shown that a selective absence of serum and secretory immunoglobulin A (IgA) may lead to the development of circulating immune complexes which appear to contain bovine milk antigens. We report here that high levels of circulating immune complexes were found in the serum of a child who was treated for severe combined immunodeficiency by bone marrow transplantation but in whom the IgA-producing cells subsequently failed. As increasing amounts of complexes appeared over a two year period, the child had a parallel progression of an apparent chronic graft versus host disease including a Sjögrens syndrome and scleroderma. Very large amounts of complexes were eventually formed but the level fell 77 per cent after milk was excluded from the diet. Chemical studies on the complexes showed that the majority of complexes did contain bovine milk proteins, and fluorescence antibody staining of skin biopsy samples showed the presence of dense deposits of bovine casein in the dermis. The relationship between bovine protein-antigen antibody complexes and the chronic graft reaction remains uncertain.

During the past 17 years at the Department für Pediatric Surgery, University of Heidelberg, 38 children aged 1.6 to 14 years were adrenalectomized (unilateral 3.3, bilateral 5). Individual diagnoses were: neuroblastoma 23; pheochromocytoma 5; adrenocortical carcinoma 8; adrenocortical adenoma 4; bilateral nodular hyperplasia 2 cases. Patients with histologically benign lesions are alive and without recurrence more than 5 years after surgery, except one patient who developed Nelson's tumor after bilateral adrenalectomy for Cushing's disease. Of the patients with malignant adrenal tumors 21 died within 18 months after therapy was started, a 7 years old girl with an adrenal carcinoma died after a period of 3.6 years of combined treatment. In most cases of adrenocortical tumors virilization was the prominent feature.

Over the past 10 years 18 patients have been operated upon (sometimes repeatedly) because of pulmonary metastases. The primary tumour with pulmonary secondaries was usually an osteosarcoma or a Wilm's tumour. The indication for surgery and the result of treatment are discussed. The pre-operative diagnosis is helped considerably by ventilatory and perfusion isotope studies.

Brain damage following cranial radiation therapy can be crippling or even life-threatening and has been studied in both patients and animals. An additional toxic effect of chemotherapy has been found in children, who died following brain irradiation and systemic chemotherapy for the treatment of acute lymphoblastic leukemia. To study the interaction of radiation and drugs on brain tissue, we treated rabbits with brain irradiation and/or i.v. methotrexate. For a period of up to 3 months following radiation therapy, brain morphology was compared in seven treatment groups. Weekly doses of methotrexate administered i.v. produced no brain damage. Histological examination showed myelin swelling and beading 14 weeks after fractionated brain irradiation with 24 Gy. Combination of brain irradiation and methotrexate produced additional hypertrophy of microglia and pyknosis of adventitial cells. In none of these groups, even after doses of 48 Gy brain irradiation, was calcification or brain necrosis observed during the first 14 weeks following irradiation.

Studies on glutamate uptake, with special reference to perfusion, were carried out in 35 rats, each bearing one of five different tumor transplants; also in 15 rats after bone fracture, and in three rabbits. Single-pass extraction of N-13 glutamate was 85-93% in the VX2 tumor of the rabbit and in muscle. Bone fracture in rats caused a threefold increase of tracer uptake 2 days after the event. In tumor transplants, the tumor-to-muscle uptake ratio reached a maximum immediately following injection of the tracer. Comparing N-13 glutamate uptake with the retention of 1-121 microspheres, identical tumor-to-muscle ratios were found for three out of five tumor lines. Comparing the uptake with that of C-11 butanol (ten rats), a close correlation was observed throughout the range of tumor lines. The results suggested that glutamate uptake by malignant tumors is related to blood flow. In nine patients with malignant or benign lesions tumor-to-muscle uptake of N-13 glutamate and TI-201 showed a linear correlation close to identity.

Serum ferritin (SF) was determined by an immunoradiometric assay in a heterologous antibody system in 184 children of different ages with and without hematologic or biochemical signs of disturbed iron metabolism. SF levels as determined by this assay were higher than with a homologous antibody system, allowing a reliable discrimination of iron deficiency and overload. In normal children SF increased with age. In latent iron deficiency all SF values were below the normal range, if patients with signs of infections, elevated serum transaminases or parenteral iron therapy were excluded. In anemia of chronic renal failure there was a wider range of values than in controls, especially in children on intermittent hemodialysis. Highest SF values were obtained in polytransfused children with thalassemia. Significant correlations were observed between SF on one hand and Hb, MCV, MCH and serum transferrin saturation on the other hand, except in children with chronic renal failure on conservative treatment. Under hemodialysis there was a significant relation to the number of blood transfusions given.

Isolated mandibular metastasis in Wilms' tumour resulted in cold lesion on a bone scan.

Twelve children with their first relapse of acute lymphoblastic leukemia who had the same initial therapy were treated on an out-patient basis. After 28 days all entered second remission. Medium remission duration was 11 months. At the end of the study seven patients were in continuous complete remission. Of the twelve children seven suffered bone marrow, two meningeal, two testicular relapses and one a combined bone marrow and meningeal relapse. Side effects were compatible with an out-patient treatment.

Synaptophysin, an Mr 38,000 integral membrane glycoprotein of neurotransmitter vesicles, has been identified in diverse primary neuroendocrine (NE) tumors of both neural and epithelial origin (Wiedenmann and co-workers, Proc Natl Acad Sci USA 1986; 83: 3500-3504). In the present study, metastases of several types of NE tumors, including medullary thyroid carcinoma, gastrinoma, insulinoma, small (oat) cell carcinoma of the lung, gastrointestinal carcinoid, and neuroblastoma, were examined for the presence of synaptophysin by immunocytochemistry, with the use of tissue sections as well as centrifuged cell suspensions and by immunoblotting of tumor proteins. The results show that expression of synaptophysin can be maintained during formation of metastases. Therefore, the authors propose that synaptophysin antibodies be used for the positive identification of metastatic NE tumors, notably in differential diagnosis. The possible implications of these findings for tumor diagnosis are discussed.

Methotrexate (MTX) has the potential of eradicating small infiltrations of leukemic cells in the gonads. We examined the morphological changes in rabbit testes after a single dose (57.5 mg/kgBW) or repeated low doses (6 mg/kgBW once a week for 14 weeks) of MTX IV. Fertility rate and spermatogenic activity were evaluated using the tubular fertility index (TFI). Testicular MTX concentrations (measured by RIA) were in the same range in both groups. Only after repeated MTX application were reduction of TFI and signs of germinal cell line degeneration found. When given repetitively, MTX therapy may modify the fertility and tubular morphology. Long-term follow-up will show how these changes affect future fertility.