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Die Verfahrensanweisung zur Radioiodtherapie (RIT) und zur 131I-Ganzkorperszintigraphie beim differenzierten Schilddrusenkarzinom im Kindes- und Jugendalter reiht sich thematisch neben die entsprechenden Verfahrensanweisungen (Version 3), die fur erwachsene Patienten verfasst sind, und konkretisiert die interdisziplinare Leitlinie der Deutschen Krebsgesellschaft um die nuklearmedizinischen Aspekte. Besonderheiten im Kindes- und Jugendalter sind die hohere Aggressivitat des papillaren Schilddrusenkarzinoms, die Haufigkeit eines organuberschreitenden Tumorwachstums und einer disseminierten pulmonalen Metastasierung sowie die hohe lokale Rezidivrate. Die TNM-Klassifikation wird aufgrund der geringen Ausdehnung der normalen kindlichen Schilddruse der Risikostratifikation nicht gerecht. Grundsatzlich besteht auch bei Kindern die Empfehlung zur Radioiodtherapie, wobei die 131I-Aktivitat gewichtsabhangig appliziert wird. Bei kleinen papillaren Schilddrusenkarzinomen (≤1 cm) ist die Indikation zu einer ablativen Radioiodtherapie eher groszugig zu stellen. Nach Hormonentzug wird die TSH-Stimulation bereits nach zwei Wochen (Kinder) bzw. drei Wochen (Jugendliche) erreicht. Antiemetika werden groszugig verordnet. Die Indikation zur CT des Thorax und zur Lungenfunktionsuntersuchung ist bei Metastasenverdacht groszugig zu stellen. Auf die diagnostische 131I-Ganzkorperszintigraphie drei bis sechs Monate nach ablativer Radioiodtherapie sollte wegen der Haufigkeit einer lymphogenen Metastasierung nicht verzichtet werden. Nachsorgeintervalle sind eher kurzer zu wahlen, um eine unzureichende Compliance bei Kindern fruhzeitig zu erfassen und um die Hormondosis gewichtsbezogen anzupassen. Der hohere Normbereich von fT3 fur Kinder ist zu beachten. Es liegt keine ausreichende Evidenz vor, ob und wann eine nicht-suppressive Einstellung der Schilddrusenfunktion sinnvoll ist. Daher ist die TSHSuppression grundsatzlich anzustreben.

Hodgkin's disease (HD) is commonly associated with latent Epstein-Barr virus (EBV) infection. The aim of our study was a detailed molecular analysis of the EBV status in the peripheral blood of paediatric patients with HD. Blood samples from HD patients were examined before (n=28) and after treatment (n=12). The control group consisted of 20 healthy children and 10 immunosuppressed children with primary EBV infection. EBV load in plasma and peripheral blood mononuclear cells (PBMC) were determined by real time quantitative polymerase chain reaction (RQ-PCR) as recently described. Before treatment, EBV DNA was detected in the plasma of 13/24 EBV-seropositive HD patients, whereas in plasma of healthy controls no EBV DNA was detectable (P0.001). After treatment, no EBV genomes were found in the plasma of 6 HD patients in stable and complete remission. In contrast, 2/5 HD patients with relapse of disease were positive for EBV DNA in the plasma. In PBMCs, no differences were found in EBV load measured in HD patients before or after treatment and healthy controls. A high EBV load was found in both the plasma and PBMCs of all immunosuppressed patients with primary EBV infection. Thus, EBV DNA detection in the plasma of paediatric HD patients might be of value for non-invasive diagnostic, prognostic and follow-up tests for HD.

To the Editors: In a recent article published in the European Respiratory Journal , Bont et al. 1 presented data on systemic cytokine responses in hospitalized ventilated and nonventilated infants with respiratory syncytial virus (RSV) bronchiolitis. Their main findings were a lower production of interferon-γ (IFN-γ) and elevated plasma levels of interleukin (IL)-8 in ventilated patients. They concluded from their data that a depressed lymphocyte function and elevated IL-8 plasma levels are markers of severe RSV bronchiolitis in infants requiring ventilation. However, the median age in ventilated patients was significantly lower than in nonventilated patients (1 versus 4 months). Furthermore, eight out of 14 ventilated patients were prematurely born. From that point of view it is difficult to compare these different groups because IFN-γ response is age-related and increases after 2 months of age 2. Performing a recently developed technique …

Cellular drug resistance is one of the main causes of the frequent ultimate failure of chemotherapy in childhood acute myeloid leukemia (AML). We here summarize the results of a literature review on in vitro drug resistance in childhood AML, focusing on studies using so-called cell culture assays. We also briefly describe some results of an ongoing collaborative study between the Research Laboratory of Pediatric Oncology in Amsterdam (University Hospital Vrije Universiteit) and the German BFM-AML Group. In general, the literature and our preliminary data on in vitro cellular drug resistance in AML are promising in terms of clinical relevance. Cell biological features and clinical response to chemotherapy are related to in vitro drug resistance. However, a large study including multivariate analysis is required to more firmly establish the clinical value of cellular drug resistance testing in childhood AML, and the collaborative study will therefore be continued. Possible applications of cell culture assays include risk-group stratification, rational improvements of current treatment protocols for subgroups of patients based on specific drug resistance profiles, individualised tailored therapy, the study of cross-resistance patterns between drugs, the study of possibilities to modulate or circumvent drug resistance, the study of drug interactions, selection of patients for clinical phase II studies and drug screening.

Excellent treatment results have been obtained for children with Hodgkin's disease (HD). Children with immunodeficiencies who present with HD do not have such a favourable prognosis.A systematic literature search using MEDLINE and a search for immunodeficiencies in the database of the trials DAL HD78-HD90 and GPOH HD95 (n = 2263) were carried out. Age, sex, type of immunodeficiency, disease stage, treatment and outcome of all HD cases with known immunodeficiency were recorded.28 published cases and 13 children in the DAL/GPOH trials were identified. 19/28 and 6/13 patients have immunodeficiencies with increased DNA breakage (24/25 ataxia teleangiectasia, 1/25 Nijmegen breakage syndrome) who present largely with stage III - IV HD. Among the published cases with increased DNA breakage there is only one child who is surviving 16 months after diagnosis, while there are 6/9 survivors in the group of immunodeficiencies without increased DNA breakage. Similarly, only 1/6 children survives in the group of children reported to the DAL/GPOH trials suffering from HD and immunodeficiency with increased DNA breakage, while the outcome in children suffering from immunodeficiency without increased DNA breakage is much better with 5/7 survivors.The literature review and data analysis of the DAL/GPOH studies show that treatment outcome is almost invariably fatal in children with HD and immunodeficiency with increased DNA breakage. Thus we propose to treat children with or without increased DNA breakage differently to improve the outcome of Hodgkin's disease in the subgroup of children with immunodeficiency.

Early diagnosis of Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) is required to detect a stage of disease that is more likely to respond to treatment. Elevated levels of EBV DNA were found in peripheral blood of patients at the onset of PTLD.To compare plasma and peripheral blood mononuclear cells (PBMCs) as material for real-time quantitative polymerase chain reaction (RQ-PCR) measurement of Epstein-Barr viral load, we used two sets of primers and probes specific for the BAM HI-K or BAM HI-W region of the EBV genome.Patients with PTLD had a median viral load of 19,200 EBV genomes/microg DNA (n=9) or 3,225 EBV genomes/100 microl plasma (n=5), being significantly higher compared with immunosuppressed patients with primary (n=9) or reactivated (n=20) EBV infection or immunosuppressed patients without serological signs of active EBV infection (n=67) (P0.001). Hence, a value of greater than 5,000 EBV genomes/microg PBMC DNA was considered as a diagnostic parameter for PTLD with a sensitivity and specificity of 1.00 or 0.89, respectively. When plasma was analyzed, however, a value of greater than 1,000 EBV genomes/100 microl plasma had both a sensitivity and specificity of 1.00 for the diagnosis of PTLD. During remission of PTLD, viral load was more effectively cleared in plasma compared with PBMCs. In plasma of nonimmunosuppressed individuals, even a qualitative detection of EBV-related sequences was sensitive and specific for the diagnosis of primary EBV infection, whereas for analysis of PBMC DNA a quantitative parameter had to be considered to differentiate healthy individuals (100 EBV genomes/microg PBMC DNA) from patients with primary EBV infection (100 EBV genomes/microg PBMC DNA).Although both PBMCs and plasma were useful as material for EBV-specific RQ-PCR in immunosuppressed patients and nonimmunosuppressed individuals, the specificity of analysis seemed to be higher if plasma was taken for analysis.

An 11 year old girl presented with hypertension and tachycardia. Excess urinary catecholamine excretion suggested phaeochromocytoma but imaging studies failed to demonstrate a tumour. Other symptoms included insomnia and weight loss, and she was found to have a raised concentration of mercury in blood and urine. Mercury intoxication should be considered in the differential diagnosis of hypertension with tachycardia even in patients presenting without the skin lesions typical of mercury intoxication and without a history of exposure.

A novel Hodgkin disease (HD)-derived cell line, designated HKB-1, was established from pulmonary HD of nodular sclerosing subtype of a 14-year-old-girl.Immunophenotypically, HKB-1 cells are of B cell in phenotype, being also positive for markers CD15, CD25 and CD30. Transformation of the cell line by Epstein-Barr virus (EBV) was excluded by failure to detect EBV antigens and EBV DNA in cultured cells. Chromosome studies of HKB-1 showed a pseudodiploid karyotype with complex clonal structural aberrations. The detection of a monoclonal immunoglobulin heavy chain (IgH) gene rearrangement confirmed the derivation of the HKB-1 from the B cell lineage and its monoclonality. HKB-1 produced high amounts of interleukin (IL)-6 as detected in culture supernatant whereas no secretion of IL-1 beta, IL-2, IL-4, IL-10, IL-12 or interferon (IFN)-gamma was detected.Our studies indicate that this cell line is of tumor origin.

Malignant histiocytic disorders, other than leukemias, are extremely rare in childhood. Despite unresolved nosologic and terminologic difficulties, they should be classified according to the lineage of the aberrant cells in a given tumor. There are no common and typical clinical presentations, nor are there established treatment modalities available. For the disseminated forms, aggressive systemic treatment modalities--similar if not identical to those used for large cell anaplastic lymphomas--appear to be the best treatment option. For the localized forms, which are primarily dendritic cell sarcomas, a more localized and individualized therapy is appropriate.

Pathologists and pediatric hematologist/ oncologists of the World Health Organization's Committee on Histiocytic/Reticulum Cell Proliferations and the Reclassification Working Group of the Histiocyte Society present a classification of the histiocytic disorders that primarily affect children. Nosology, based on the lineage of lesional cells and biological behavior, is related to the ontogeny of histiocytes (macrophages and dendritic cells of the immune system). Dendritic cell-related disorders of varied biological behavior are dominated by Langerhans cell histiocytosis, but separate secondary proliferations of dendritic cells must be differentiated. Juvenile xanthogranuloma represents a disorder of dermal dendrocytes, another dendritic cell of skin. The hemophagocytic syndromes are the most common of the macrophage-related disorders of varied biological behavior. Guidelines for distinguishing the exceedingly rare malignant diseases of histiocytes from large cell lymphomas through the use of a battery of special studies are provided.

From January 1986 until August 1995 230 adult patients received an allogeneic or autologous transplantation of bone marrow or hematopoietic blood stem cells. The conditioning and myeloablative treatment regimens were chosen according to the underlying disease and type of transplant.The observation period comprises 1 to 115 months after transplantation. After allogeneic transplantation from HLA-identical family donors, the probabilities of disease-free survival were for acute myeloid leukemia in first complete remission (CR) (n = 35) 77%, for acute lymphoid leukemia in 1st CR (n = 7) 72% and in 2nd CR (n = 10) 40%, in first chronic phase of chronic myeloid leukemia (n = 34) 50% and in severe aplastic anemia (n = 7) 100%. Following myeloablative therapy and autologous transplantation the probabilities of disease-free survival were 47% in relapsed Hodgkin's disease (n = 22) and 42% for relapsed high-grade non-Hodgkin's lymphoma (n = 12). Eight of 10 patients with acute myeloid and 7 of 8 with acute lymphoid leukemia suffered a leukemic relapse after autologous bone marrow transplantation. Three of 8 patients with relapsed testicular cancer survived relapse-free. Treatment failures were due to more advanced acute graft versus host disease after allogeneic transplantation and caused by relapse after autologous transplantation. Current protocols evaluate the allogeneic transplantation of enriched CD34+ blood stem cells. In chronic myeloid leukemia the autologous transplantation of blood stem cells after myeloablative therapy is being studied.

The purpose of this study was to evaluate the pharmacokinetics, biological interactions, and toxicities of ifosfamide and carboplatin combined with 41.8 degrees C whole-body hyperthermia (WBH) for 1 h in a pilot clinical study. Nineteen patients with refractory sarcoma or malignant teratoma were treated. To obtain baseline pharmacokinetic data for ifosfamide, the first chemotherapy course was given without WBH in six patients. This enabled comparison of systemic toxicity and pharmacokinetics of the drug combination with and without WBH (+/- WBH). All other patients received three thermochemotherapy treatments every 3 weeks. Ifosfamide was escalated from 5 to 10 g/m2 with a fixed carboplatin dose of 480 mg/m2. WBH was induced by extracorporally heated blood (in a hemodialysis apparatus) with general anesthesia. The drugs were given at target temperature. A total of 49 thermochemotherapy treatments was administered. The use of the hemodialysis device resulted in an approximate one-third reduction of blood concentrations of 4-hydroxyifosfamide, one activated intermediate metabolite of ifosfamide and carboplatin, but in an increase of chloroacetaldehyde, the other main ifosfamide metabolite. The WBC counts and the platelet nadirs (up to WBH grade 4) were not significantly different +/- WBH. Of 19 evaluable patients, 7 partial remissions, 8 disease stabilizations (average duration, 3 months), and 4 patients with progressive disease were observed. There was no WBH-related mortality. Toxicities observed included mild (anasarca, diarrhea, pressure sores, and perioral herpes simplex) and severe (reversible neuropathy, cardiopulmonary distress, and severe renal dysfunction). No hepatic or central nervous system toxicity occurred. Nephropathy was the dose-limiting toxicity. In conclusion, ifosfamide and carboplatin can be administered with extracorporally induced WBH with acceptable toxicity. Results obtained are consistent with continued evaluation of this combined modality approach.

Non-Hodgkin's lymphomas (NHL) are classified as low or high grade malignant lymphomas of either B or T cell origin. Cells of low grade malignant NHL (LG-NHL) of B cell type represent either follicular or postfollicular, cells of LG-NHL of T cell type postthymic maturation stages in the lymphoid differentiation pathway. LG-NHL often fail to undergo long-term complete remission or cure in adults, no matter what type of conventional therapy is applied. In three pediatric therapy studies frequency and probability of continuous complete remission (pCCR) were studied for LG-NHL and peripheral pleomorphic T-cell lymphomas (PTCL). Of 432 evaluated patients only six children (1.4%) were qualified as LG-NHL. LG-NHL of T cell type were diagnosed in three children (one T-zone lymphoma, two PTCL of small cell type), LG-NHL of B cell type in another three cases. Two children presented with nodular type of centroblastic/centrocytic lymphoma (CB/CC), one with lymphoplasmocytoid type of immunocytoma (IC). In addition to the two patients with low grade malignant PTCL, there have been also four children with high grade malignant PTCL. The analysis showed that there was not significant difference for event free survival of children with LG-NHL and HG-NHL, respectively (pCCR: 0.63 and 0.82, p = 0.29). In contrast, when comparing high and low grade PTCL versus all other types of childhood NHL (non-PTCL), a significant difference seems to exist (pCCR for PTCL: 0.44, for non-PTCL: 0.83; p = 0.02). However, for further concisive conclusions more patients are needed for evaluation.

In the period immediately following bone marrow transplantation, most patients contract infections which contribute significantly to morbidity and mortality. These infections during the granulocytopenic phase following pretreatment for BMT are more severe than during the granulocytopenia caused by conventional cytotoxic treatment. The higher doses of cytostatic drugs damage the defense mechanisms of the mechanical barriers such as skin and mucous membranes. The mucositis in the mouth and the entire gastrointestinal tract caused by cytostatic drugs and radiation can be superinfected by colonizing microflora, producing an initial focus for severe septic infections during granulocytopenia.

In the granulocytopenic period immediately following bone marrow trapsplantation, most patients contract infections which contribute considerably to morbidity and mortality.

Erythropoietin (EPO) stimulates bone marrow erythropoietic progenitor cells in vitro and in vivo [1, 3]. Recombinant human EPO (rhEPO) has been used successfully to treat anemia due to renal failure [2]. It also stimulates erythropoiesis under normal conditions without EPO deficiency. EPO might be effective in accelerating regeneration of erythropoiesis after bone marrow transplantation (BMT) and thus shorten the period of red blood cell support. In an attempt to evaluate this possibility, in comparison with historical data, we administered rhEPO intravenously after allogeneic and autologous BMT.

Cells belonging to the mononuclear phagocytic system may give rise to a wide variety of proliferative disorders. These neoplastic or reactive diseases of monocytes, histiocytes and macrophages are still poorly understood, both from a biological, clinical and pathological point of view. In 1984 a new type of non-Hodgkin's lymphomas has been described, which recently was termed large cell anaplastic lymphoma (LCAL). Since both "true" malignant histiocytosis (MH) and LCAL display some clinico-pathological similarities, we reevaluated eleven children with the primary diagnosis of MH, who entered the multicentric therapy study DAL-HX 83. On the basis of the typical morphology LCAL and not MH has been diagnosed in all cases. The Ki-1 (CD 30) positive tumor cells of LCAL can display different phenotypes, either T-lymphoid, B-lymphoid, histiocytic or neither of them (O-phenotype). Therefore we investigated the lineage specificity of tumor cells in 15 paediatric patients with LCAL. Tumor cells of histiocytic origin could be demonstrated in only one of them. In 7 patients the neoplastic cells were of T cell and in the remaining 7 cases of non T/non B cell (O) phenotypes, confirming the extreme rarity of MH in children. It is our opinion that MH and LCAL seem to be different diseases not only nosologically but also clinico-pathologically. In the multicentric therapy studies NHL-BFM 81 and NHL-BFM 83 the frequency of LCAL in childhood is compared to all other subentities at 3%.

Summary Out of 54 open renal biopsies performed on children, 17 were selected and studied not only bylight microscopy but also by electron microscopy. Statistical-mathematical analysis of basement membrane thickness-measurements was carried out. It is concluded that electron microscopic investigation of the renal biopsy material is required in selected cases involving diagnostic or therapeutic problems. In nephrotic syndrome it may help above all to separate minimal changes from early forms of glomerular lesion of the focal sclerosing type. Electron microscopy can also be useful in any of the mono- and oligosymptomatic renal diseases. In those cases only electron microscopy makes it possible to provide exact morphological diagnosis which is necessary to the proper therapy.

Summary Interendothelial and subendothelial monocytes/macrophages are extremely rare in normal rabbit aortas compared with humans and swine, as has been shown by the present study and previous investigations of surface preparations. Light microscopy was used to study the development of immune complex-induced hematogenic macrophage infiltrations in 26 rabbits from the 4th to the 28th day after the last antigen administration. Of particular interest was the intensity, localization and duration of the hematogenic cell infiltrates with a view to establishing the role of immunological stimuli for subendothelial monocyte and lymphocyte accumulation. It was found that immune complex-induced hematogenic macrophage infiltrates are very short-lived and disappear after 20–28 days following immune complex deposition. They concentrate in the ostium regions of the thoracic and abdominal aorta and are subject to flow dynamics similar to those of cholesterol-induced sudanophile lipid deposition. Subendothelial macrophage infiltrates increase the permeability of the aorta for low-molecular but not for macromolecular plasma particles, do not affect the endothelial silver line picture and do not lead to lipid accumulation.

Hodgkin's disease (HD) with its characteristic cell, the Sternberg-Reed (SR) cell, presents many contradictions. The controversial theories and results are most prominent concerning the problem of the origin of the SR cell. Among the cells composing the structure of a normal lymph node, there is so far almost no cell which has not been suspected as being the normal counterpart of SR cells. Summarising the most relevant opinions, we wish to try to solve some conflicting evidence concerning the origin of the SR cells. In attempting this some other pecularities of the disease may also be explained. Some, from the historical point of view interesting but no longer relevant theories (e.g. haemohistioblast, megakaryocyte, adventitial or reticular cell, endothelial cell) will not be mentioned [53].