Systemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial.

BACKGROUND: Adrenocortical cancer (ACC) in childhood is a rare disease with poor prognosis. Complete surgical resection, systemic chemotherapy, and mitotane therapy are important curative treatment options for patients with advanced-stage tumors. Since 1997, pediatric ACC patients in Germany have been treated according to the non-randomized, single arm study GPOH-MET-97. PATIENTS AND METHODS: Data regarding disease course, treatment, and survival rates of 60 patients (age 0.24-17.8 years) with ACC treated according to the GPOH-MET-97 protocol were collected and analyzed to determine outcome, with a focus on examining the effectiveness of mitotane therapy. RESULTS: Among all patients, event-free survival and overall survival were found to be 43.3% and 64.8%, respectively. Chemotherapy with VCR, IFO, ADR, CARBO, and VP16 had been provided to 34 patients (56.6%) in different settings (neoadjuvant, adjuvant, and salvage) and mitotane therapy to 32 patients (53.3%). Duration of mitotane treatment longer than 6 months and mitotane levels greater than 14 mg/l were found to be associated with significantly better survival. Local relapse was found to be associated with a worse prognosis compared to distant metastasis only. CONCLUSIONS: Systemic chemotherapy and mitotane therapy are important therapeutic options in the treatment of advanced pediatric ACC patients. Neoadjuvant therapy should be considered for patients with primarily incomplete resectable or inoperable tumors, and tumor spillage is an indication for adjuvant chemo- and mitotane therapy. All pediatric ACC patients should be treated in pediatric oncological centers according to a consistent protocol in a highly interdisciplinary setting.

[Procedure guideline for radioiodine therapy and 131iodine whole-body scintigraphy in paediatric patients with differentiated thyroid cancer]. / Verfahrensanweisung zur Radioiodtherapie und 131I-Ganzkörperszintigraphie bei differenzierten Schilddrüsenkarzinomen im Kindes- und Jugendalter.

The procedure guideline for radioiodine ((131)I) therapy and (131)I whole-body scintigraphy of differentiated thyroid cancer in paediatric patients is the counterpart to the procedure guidelines (version 3) for adult patients and specify the interdisciplinary guideline for thyroid cancer of the Deutsche Krebsgesellschaft concerning the nuclear medicine part. Characteristics of thyroid cancer in children are the higher aggressiveness of papillary thyroid cancer, the higher frequency of extrathyroidal extension and of disseminated pulmonary metastases as well as the high risk of local recurrences. Radioiodine therapy is generally recommended in children, the (131)I activity depends on the children's body weight. Radioiodine ablation in children with small papillary cancer (< or =1 cm) should be considered. TSH stimulation is reached two weeks (children) or three weeks (adolescents) after withdrawal of thyroid hormones. Anti-emetic drugs are highly recommended. CT of the chest and examination of pulmonary function are clearly indicated if there is any suspicion on metastases. 3-6 months after (131)I ablation, the (131)I whole-body scintigraphy is highly recommended as lymph node metastases are frequently detected in paediatric patients. Follow-up care should be arranged in shorter intervals than in adults to test the compliance and to adapt dosage of thyroid hormones to the children's body weight. Reference values of fT3 are higher in children than in adults. Evidence is insufficient to describe in which constellation the TSH may be kept within the low normal level. Therefore, TSH suppression is generally recommended.

Ifosfamide and carboplatin combined with 41.8 degrees C whole-body hyperthermia in patients with refractory sarcoma and malignant teratoma.

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.

Successful treatment strategy for Ki-1 anaplastic large-cell lymphoma of childhood: a prospective analysis of 62 patients enrolled in three consecutive Berlin-Frankfurt-Munster group studies.

PURPOSE: To prove prospectively the efficacy of a short-pulse chemotherapy for treatment of Ki-1 anaplastic large-cell lymphoma (ALCL) of childhood. PATIENTS AND METHODS: From October 1983 to December 1992, 62 patients (median age, 9.7 years) with newly diagnosed Ki-1 ALCL were enrolled onto Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Munster (NHL-BFM) studies 83, 86, and 90. The most frequent immunophenotype was T cell. Ki-1 ALCL differed from other subsets of NHL of childhood by the more frequent involvement of bone, soft tissue, and skin, and by the lack of bone marrow (BM) disease. A 5-day prephase course (prednisone/cyclophosphamide) was followed by two different 5-day courses of chemotherapy: course A consisted of dexamethasone, methotrexate (MTX) 0.5 g/m2 (24-hour infusion), intrathecal chemotherapy, ifosfamide, cytarabine (Ara-C), and etoposide (VP-16); course B consisted of cyclophosphamide and doxorubicin instead of ifosfamide, and Ara-C/VP-16, respectively. Treatment was stratified into three branches. Branch 1 (stage I and stage II resected) received three courses; branch 2 (stage II not resected, stage III), six courses; and branch 3 (stage IV), six intensified courses containing MTX 5 g/m2, and Ara-C 2 g/m2. Local radiotherapy was not performed. RESULTS: Four patients failed to enter remission, and one died of infection. Seven patients relapsed within 9 months after diagnosis; two patients had isolated local relapses, but BM and CNS were never involved. Fifty patients have been in first continuous complete remission (CR) for 0.6 to 9.7 years (median, 2.5), and 56 are alive. The probabilities for survival and event-free survival (EFS) at 9 years are 83% +/- 7% (SE) and 81% +/- 5%. Skin involvement was the only negative prognostic parameter. CONCLUSION: Short-pulse chemotherapy over 2 to 5 months without local therapy modalities is effective in the treatment of Ki-1 ALCL.

Detection of Epstein-Barr virus DNA in peripheral blood of paediatric patients with Hodgkin's disease by real-time polymerase chain reaction.

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 (P<0.001). 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.

Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction.

BACKGROUND: 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. METHODS: 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. RESULTS: 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) (P<0.001). 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). CONCLUSION: 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.

Malignant histiocytic disorders in children. Clinical and therapeutic approaches with a nosologic discussion.

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.

Antiphospholipid antibodies in children without and in adults with and without thrombophilia.

Antiphospholipid antibodies (APAs) are considered risk factors in patients with thromboembolic diseases. Although the incidence of such acquired coagulation disturbances in adults are well described, only few data exist for children. Therefore, in a first step to collect new data we analyzed the presence of different APAs in 202 consecutive children and compared them with two groups of adults. The children screened for APA were exclusively those who did not have any thromboembolic complications or a tendency for thrombophilia due to other underlying diseases such as systemic lupus or malignancy in their past or present medical history. Consecutive blood samples were evaluated from routine laboratory specimens. The two groups of adults comprised 200 patients after deep vein thrombosis and 200 patients without thromboembolic events that served as controls. Four lupus anticoagulant (LA) screening tests were determined: the dilute Russell's viper venom test; a lupus anticoagulant-sensitive activated partial thromboplastin time reagent; a second lupus-sensitive activated partial thromboplastin time; and the Kaolin clotting time. Furthermore, three different antiphospholipid antibodies ELISA assays against cardiolipin (ACA), beta2-glycoprotein I, and phosphatidyl-serine, were determined. The children had a much higher prevalence for LA than did the adults. On the other hand, their values for ACA were significantly lower than in adults with a history of thromboembolism. Findings in children were similar to the normal adult group. This has to be taken into account when evaluating children with thromboembolic diseases.

Epidemiology and therapy of thyroid cancer in childhood and adolescence.

Thyroid cancer is a rare disease in childhood and adolescence. However, it represents the most frequent cancer type in this age group. Thyroid cancer amounts about 0.5%-1.5% of all malignancies in children and adolescents. In Germany 10-30 cases could be expected in a year. The most common histologic type for this age group is the differentiated thyroid cancer (DTC), i.e. the papillary and follicular subtypes (90%). In 10% of patients medullary thyroid cancer (MTC) will be diagnosed. DTC occur more often in girls than in boys (female/male-ratio 2:1), with a median age of about 12-13 years (yrs). An important aetiological factor of DTC is a former exposition to different kinds of radiation. In childhood and adolescence MTC mostly appears in patients suffering from the syndrome MEN-2, whereas the sporadic form is rare. As in DTC, more girls than boys can be diagnosed for MTC (female/male-ratio 2-3:1), with a median age about 10 yrs. The anaplastic/undifferentiated subtype occurs extremely rare. For all types of thyroid cancer the most important therapeutic approach is the surgical intervention. In most cases of DTC an optimal disease control could be achieved by radioiodine therapy. Prognosis of DTC in children and adolescents is favourable. However, therapeutic strategies and modalities reported in the literature are very different. In contrast, prognosis of MTC is rather poor, that of the anaplastic type is infaust. No other effective therapy option than surgery is available. To evaluate the therapeutic efficacy of a combined modality therapy by both radiotherapy and cytostatic drugs in children and adolescents with poor prognosis types of thyroid cancer, an interdisciplinary multicenter therapy study will now be started in Germany.

[10 years transplantation of bone marrow and hematopoietic stem cells in adults at the Hannover Medical School]. / Zehn Jahre Transplantation von Knochenmark und hämatopoetischen Stammzellen bei Erwachsenen an der Medizinischen Hochschule Hannover.

PATIENTS AND METHODS: 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. RESULTS: 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.

[Isolation of immune complexes from the vascular wall in experimental immunovasculitis]. / Immunkomplexek érfali kimutatása kísérletes immunvasculitisben.

In experimental immunvasculitis immunocomplexes of the vessel wall have been detected by indirect immunofluorescence method. In the aortic intima linear deposition, in the small arteries and arterioles segmental fluorescence was observed in all layers of the vessel wall. In some regions a marked positive perivascular reaction was also revealed. Immuncomplexes of the vessel wall may play a part in the preservation and prolongation of the alterations of the vessel wall.

The 1-hour D-xylose test in the diagnosis of villous atrophy.

The results obtained in 40 cases of intestinal mucosal biopsy and parallel 1-hour D-xylose test are presented. Of 40 patients, 15 had subtotal villous atrophy, while in 25 the villous structure was intact. Among the 15 patients with villous atrophy 10 gave D-xylose values of less than 20 mg per dl. In the control group all D-xylose values were above 20 mg per dl.

Failure to thrive in a 14-month-old boy with lymphopenia and eosinophilia.

We describe the case of a 14-month-old boy with delayed-onset SCID due to ADA-deficiency which was masqueraded only by failure to thrive. Remarkably, the child had no serious infections and an adequate immune response. However, absolute lymphopenia, eosinophilia and absent thymus on chest x-ray were indicative for immunodeficiency.

Mercury intoxication presenting with hypertension and tachycardia.

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.