[Endoplasmic granulocyte function in hypoparathyroidism and other disorders of calcium metabolism].
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Adolescent↗
Biomedical subjects
W Havers
Publications and source records attributed to W Havers.
[Problems in the treatment of chylothorax in congenital abnormalities of the lymphatic vessels].
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Chylothorax↗
[Congenital leucosis with unusual involvement of the brain(author's transl)].
A case of congenital paraleucoblast-leucosis is reported. The diagnosis rested on pronounced infiltrations of the skin and leucemic signs in blood and bone marrow. The child died on the 20th day after developing signs of bleeding and cerebral involvement. At necropsy leucotic infiltration was found in may organs, mainly in pancreas, skin and bone marrow. The most prominent findings and cause of death were diffuse hemorrhagic foci with a high proportion of leucemic cells in the brain and cerebellum.
Acute Disease↗
[Inborn neuroblastoma of both suprarenal glands (author's transl)].
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Adrenal Gland Neoplasms↗
[Accidental optalidone poisoning in childhood].
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Aminopyrine↗
[Exomphalos-macroglossia-gigantism syndrome (Wiedemann-Beckwith syndrome) in three siblings].
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Abnormalities, Multiple↗
[Diagnosis and genetics of congenital dyserythropoietic anemias (CDA)].
The congenital dyserythropoietic anemias (CDA) are hereditary diseases characterized by a lifelong, mostly moderate anemia. CDA can be diagnosed already in early childhood. However, diagnosis is complicated due to poor knowledge of morphological criteria and the large number of differential diagnoses that have to be excluded. CDA type I is characterized by macrocytic anemia with megaloblastic changes in erythropoiesis and chromatin bridges between isolated erythroblasts. Type II shows a normocytic anemia with a positive acidified serum test and increased agglutination with anti-i. Erythroblasts can present with 2 or more nuclei. CDA type III presents with a macrocytic anemia and erythroblasts with up to 12 nuclei, the so called gigantoblasts. Some patients lack the typical morphological abnormalities of type I-III (variants or type IV). Besides light microscopic abnormalities, CDA type-specific changes in electron microscopy are described. The clinical picture of the patients vary between the different forms: signs of hemolysis and ineffective erythropoiesis such as icterus, splenomegaly and gall stones can be present. Most important is the tendency of a part of patients to have an increased iron absorption and iron storage. Patients with and without transfusion dependency are described. Supportive care such as iron chelation can be necessary in some patients. The CDA are inherited in an autosomal recessive manner; in type III an additional autosomal dominant variant exists. Recently, the determination of gene loci for type I, II and III was enabled by linkage analysis on different regions of chromosome 15 and 22. It is considered that CDA I and II are genetically heterogenic. Until now no gene has been identified in either type of CDA. In CDA type II, a glycosylation defect of erythrocyte membrane proteins is present. An international group plans to do further research. Therefore, identification and registration of patients in a registry is necessary. Patients' data and material would enable gene characterization. The results would allow an extended classification according to genotype and prediction of the course of the disease. Additionally, information on the regulation and control of normal and abnormal erythropoiesis could be obtained.
Anemia, Dyserythropoietic, Congenital↗
Microarray-analysis: a new approach to study the molecular mechanisms of thermo-chemotherapy.
BACKGROUND: Experimental studies for the treatment of relapsed neuroblastoma include the use of hyperthermia in combination with chemotherapeutic drugs. Cytotoxic effects of alkylants and platinum compounds on tumor cells can be enhanced by hyperthermia in various in vitro models. However, the underlying molecular mechanisms are still largely unknown. METHOD: In this study, we used microarray-analysis as a new biological approach to gain insight into the pharmacogenomics and possible target genes of thermochemotherapy. As a model, LAN 1 neuroblastoma cells were treated for 1 h with low doses of cisplatin alone, with simultaneous heating to 42 degrees C or with hyperthermia alone. Gene expression was analyzed at five time points 0 to 24 h after treatment using U95Av2 oligonucleotide arrays (Affymetrix Inc). Significant changes of gene expression levels were calculated by similarity metrices and Pearson correlation. RESULTS: Only a few genes (n = 23) demonstrated altered expression following treatment of LAN 1 cells with cisplatin alone. Hyperthermia alone resulted in significant expression changes of 136 genes in comparison to untreated control cells. Combination therapy of cisplatin and hyperthermia resulted in expression changes of 251 genes, interestingly including 131 genes with unchanged expression under treatment with either cisplatin or hyperthermia alone. Significant changes of expression levels could be annotated to genes involved in heat shock response, protein degradation and apoptosis. These results are now being validated on mRNA- and protein levels by RT-PCR and Western Blot analysis. CONCLUSION: Microarray-Analysis is a suitable new approach for the identification of target genes, which might play an important role for the synergistic effect of hyperthermia and chemotherapy in tumor cells.
Antineoplastic Agents↗
Proteomics: techniques and applications in cancer research.
Proteomics can be defined as functional analysis of the full set of proteins by high-throughput technologies in a given system. The workflow of proteomics is a multi-step process comprising sample preparation, separation, quantification and identification of proteins. Due to the high complexity of different protein species and the wide dynamic range of protein amount within a cell system it is necessary to apply appropriate analysis methods. One approach is to separate proteins first by two-dimensional gel electrophoresis (2-DE) according to charge and molecular weight. Proteins are then fragmented and analyzed using matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS). Identification of proteins can be achieved by comparing the mass/charge-ratios of these peptides to respective databases. Proteome analysis with respect to the identification of disease-associated patterns of molecules in different tissues is in the early stages, because standardisation of these techniques often remains to be established. However, proteome analyses is a promising tool to obtain holistic insights into the physiological status of a cell or cellular system. Compared to RNA-based studies some advantages are obvious: (1) post-translational modifications, e. g. phosphorylation, contributing to the activity status can be detected at the protein level only, (2) RNA-levels do not necessarily coincide with protein levels for a particular gene, (3) feedback-mechanisms within regulatory pathways can control protein activity without measurable changes in mRNA content.
Algorithms↗
[Non-testicular germ cell tumors: analysis of the therapy study MAKEI 83/86 anc changes in the protocol for the follow-up study].
205 patients with germ cell tumors were entered into the GPO Cooperative Study MAKEI 83/86 and classified as follows: 97 teratomas, 66 yolk sac tumors, 22 dysgerminomas, 17 embryonal carcinomas and three choriocarcinomas; 20% of all tumors were classified as mixed histology. Predominant primary sites were the ovaries (91 pts), the saccrococcygeal region (74 pts), the mediastinum (12 pts), the peritoneal cavity (10 pts) and other sites (18 pts). The treatment of teratomas was primarily surgery. Localised dysgerminomas received radiotherapy following surgery, in advanced stages (III, IV) four courses of chemotherapy vinblastine 3 mg/m2/day (days 1 + 2), bleomycin 15 mg/m2/day (days 1-3) and cisplatinum 20 mg/m2/day (days 4-8) (VBC) were applied. The other fully malignant tumors received four courses of VBC chemotherapy, in extragonadal primary tumors and advanced stages of all sites additional four courses of VP16 100 mg/m2/day (days 1-3), ifosfamide 1500 mg/m2/day (days 1-5) and cisplatin 20 mg/m2/day (days 1-5) (VPIC) were administered. To avoid mutilating surgery in advanced disease, four courses of VBC chemotherapy were administered prior to resection. The relapse-free survival according to Kaplan-Meier for protocol patients with teratomas is 0.97 +/- 0.01, for dysgerminomas 0.73 +/- 0.09 and for other fully malignant histologic entities 0.81 +/- 0.02 with a median period of observation of 31 months. The toxicity mainly consisted of myelosuppression during VPIC chemotherapy in 39 of 62 pts resulting in twelve incidents of sepsis with lethal outcome in two pts. Impaired renal function was reported in 14 pts, the incidence of neuropathy, ototoxicity and pulmonary toxicity was negligible. For the follow-up study a reduction in chemotherapy seems justified in patients with favourable prognosis. The substitution of VP16 for vinblastine may result in reduced toxicity.
Adolescent↗
Growth in children with adrenocortical tumors.
Longitudinal growth was assessed in 10 children aged 0.8 to 11.8 years with adrenocortical tumors. All children had signs of androgen excess. In addition, 5 children had glucocorticoid excess, 1 child had estrogen excess. Multiple height recordings, expressed as height standard deviation score for chronological age, were available in 7 children. 5 patients in whom the tumor was successfully removed had postoperatively decreasing height standard deviation scores. 2 patients in whom tumor disease and hormone overproduction were not effectively controlled continued to show increased growth. When simultaneously present in one patient, the growth-promoting effects of androgen excess appear to override the growth-blocking properties of endogenous glucocorticoid excess. The importance of longitudinally recorded growth data for early diagnosis of an adrenocortical tumor is limited to those few children in whom hormone excess is given enough time to act on the skeleton before other tumor-related symptoms appear.
Adrenal Cortex Hormones↗
[Treatment of acute lymphoblastic leukemia in childhood and adolescence: results of the multicenter therapy study ALL-BFM 81].
In therapy study ALL-BFM 81 633 previously untreated patients with acute lymphoblastic leukemia (ALL) less than 18 years of age have been recruited from April 1, 1981 to September 30, 1983 and treated in 37 institutions throughout West-Germany and Austria. Here only therapy results of 611 patients with non-B-ALL are presented. Patients with ALL of B-type are described elsewhere. In this fourth consecutive trial of the BFM study group three major questions have been asked: 1. Is it possible to assess the individual risk for relapse more accurately by the use of a risk factor rather than by the risk score which was the discriminator in studies ALL-BFM 76 and ALL-BFM 79? Does this risk factor discriminate more precisely patients at the highest risk for relapse? Offers more intensive risk-adapted therapy to this patient group a better chance for disease-free survival? 2. In patients at a standard risk for relapse with a risk factor below 1.2--approximately 60% of patients with non-B-ALL--can radiotherapy for prevention of CNS disease effectively be replaced by chemotherapy (intermediate dose Methotrexate)? 3. It is possible to reduce duration of maintenance therapy by 6 months to a total duration of 18 months with no unfavorable effect? To assess the radiation problem in standard risk patients and to evaluate the importance of duration of maintenance therapy two randomisations have been utilized. After a median duration of study ALL-BFM 81 of 4 1/2 years and 3 1/4 years after the study had been closed (date of evaluation January 1, 87) the answers are as follows: 1. For the majority of patients risk-adapted therapy had a curative effect. The probability for event-free survival (EFS) in standard risk patients in slightly above 70%, in medium risk patients 67%. In high-risk patients risk-adapted therapy did not improve prognosis, the EFS being still in the order of 50%. A good assessment of the individual risk for relapse is possible by the newly introduced risk factor. This principle is superior to the risk score used in former studies ALL-BFM 76 and ALL-BFM 79 because a low risk group (risk factor below 0.8) could be identified including approximately 25% of all patients with non-B ALL. Selection, quality, and timing of therapy elements remain the decisive prognostic factors, however. 2. Standard risk patients with a risk factor below 0.8 can effectively be protected for CNS relapse by treatment with intermediate dose Methotrexate.(ABSTRACT TRUNCATED AT 400 WORDS)
Adolescent↗
[Value of ophthalmoscopy and histology for the prognosis of patients with retinoblastoma].
The predictive value of prognostic factors is of utmost importance for the treatment of patients with retinoblastoma. Functional results, that may be expected following sight saving therapy, can be deducted from ophthalmoscopic findings. Large tumors, tumors located centrally, the presence of extensive retinal detachment or diffuse vitreous seeding are poor prognostic signs. Histopathologic findings of the enucleated eye harbouring retinoblastoma correlate well with the incidence of metastatic disease. Patients in which the tumor has invaded the choroid, optic nerve or sclera have a high risk of developing metastases.
Child↗
[Results of treatment of primary metastatic Ewing sarcoma. A retrospective analysis of 48 patients].
The clinical presentation of the disease and the results of treatment in 48 patients with metastases at diagnosis of Ewing's sarcoma, entered into the Cooperative Ewing's Sarcoma Studies (CESS) 1981 and 1986 of the German Society of Pediatric Oncology (GPO), were analysed. The period of observation ranged from 1 to 82 months, the median relapse-free time was 26 months. There was a male predominance of 35 to 13, which was even more pronounced in patients older than 15 years. The predominant localization of the primary tumor was the pelvic region, followed by the extremities, the chest wall, and the spine. The most common site of primary metastases were the lungs, followed by bone and bone marrow. Nine patients presented with combined metastases. The disease-free survival according to Kaplan-Meier life-table analysis was 18% after 7 years. Best results were obtained in patients with pulmonary metastases only, who underwent surgical resection of the primary tumor and received radiation to the lungs. Without bone marrow transplantation the prognosis of patients with bone metastases was extremely poor.
Adolescent↗
[Neurologic and psychosocial disorders in children with brain tumors].
We studied 15 tumor-free patients, that had already finished treatment at the university-hospital Essen. Beside from a neurological check-up our complete assessment included the following tests: CMM (Columbia Mental Maturity Scale), BM and CM (Raven Test), PPVT (Peabody Picture Vocabulary Test), BA (Following Directions), KP (Dotting), d2, HAWIK-Test (Mathematical part), LOS (Lincoln Oseretzky Motor Development Scale) and GFT (Göttinger Formreproduktionstest). A half structured interview of parents was performed, too. All, but two patients, had neurological disorders of different degrees. All these 13 patients had signs of ataxia. For the intelligence- and development-tests (CMM, BA, BM, CM and PPVT) the results for all patients were better than the 50th percentile, for the KP and LOS-test worse (40-47%). A diminished ability for concentration and slowness shows the d2-reached only a rate of 22 percent. The results of the HAWIK-test shows a test-age-equivalent, which is 3,4 years above the actual age. From the results of the GFT you can conclude, that these disorders are caused by brain damage. Parents mentioned during the interviews abnormalities in behaviour, interaction-problems between siblings and inadequate emotional reactions. For all these reasons we want to point out, that for an overall assessment of these patients and there families a well-planed therapeutical procedure including rehabilitive measures is necessary for diminishing the described disturbances as far as possible.
Adaptation, Psychological↗
[Chronic liver disease after treatment of malignancies in children].
Chemotherapy, which has greatly improved the prognosis of children with malignant diseases, is potentially hepatotoxic. Furthermore, there is a risk for viral hepatitis acquired by blood products. In this study we looked for hepatotoxicity and for chronic viral hepatitis during and after chemotherapy in 50 unselected children with malignant diseases. 29 children had been treated for leukemia or lymphoma, 19 for solid tumors, 2 for histiocytosis. All patients had been treated before 1991 and had received blood products not screened for hepatitis C-antibodies. In 18 girls and 32 boys aged 12.3 years (range 6.7-24.5 years) hepatitis B- and hepatitis C-serology and liver function tests were measured during a routine check-up 3.6 years (range 0.5-11.8 years) after the last chemotherapy. Liver function tests during chemotherapy were reviewed retrospectively. During chemotherapy 86% of children showed increased ALT and AST levels, 10% had levels above 500 U/l. At follow up 16 children (32%) had pathological liver function tests, especially slightly increased AST and ALT, 13 of these 16 patients had chronic hepatitis C. In contrast only 2 of 34 patients with normal liver function tests had a viral hepatitis (p = 0.001). Patients with elevation of AST and ALT above 100 U/l during chemotherapy had significantly more often a viral hepatitis than those with normal or slightly elevated aminotransferases. Our study shows that hepatocellular damage is a frequent complication following chemotherapy. However this progresses to chronic liver disease very rarely unless the patient acquired a viral hepatitis. The prevalence of chronic hepatitis C was very high in our patients. As screening of blood products for hepatitis C-antibodies is routinely performed since 1991 this problem is likely to have decreased.
Adolescent↗
Cellular drug resistance in acute myeloid leukemia: literature review and preliminary analysis of an ongoing collaborative study.
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.
Acute Disease↗
Prevention of CNS recurrence in childhood ALL: results with reduced radiotherapy combined with CNS-directed chemotherapy in four consecutive ALL-BFM trials.
BACKGROUND: The introduction of cranial radiotherapy (CRT) has provided efficient control of overt or subclinical meningeosis in acute lymphoblastic leukemia (ALL). Especially due to the long-term toxicity of CRT, reduction or elimination of radiotherapy appeared mandatory after cure rates of more than 70% had been achieved in ALL. The Berlin-Frankfurt-Münster (BFM) Study Group initiated several attempts in certain ALL subgroups to omit or reduce CRT while using more CNS-directed chemotherapy but without extended intrathecal treatment during maintenance therapy. This analysis summarizes the essential results that are in particular relevant because irradiation of the central nervous system (CNS) has been further reduced in the most recent trial ALL-BFM 95. PATIENTS AND METHODS: More than 4000 patients enrolled between 1981 and 1995 in one of the last four ALL-BFM trials have been analyzed to demonstrate the efficiency of intensive systemic and intrathecal chemotherapy with or without reduced CRT in the prevention of CNS relapses. RESULTS: In trial ALL-BFM81, it was shown that only in low-risk (LR) patients preventive radiotherapy can be replaced safely by intermediate dose (0.5 g/m2) methotrexate (MHD-MTX). In intermediate risk (IR) patients this attempt failed: IR pts had 8 times more CNS relapses if treated by MHD-MTX without CRT. In the subsequent trial ALL-BFM 83, all pts received MHD-MTX. IR pts were randomly treated with 12 or 18 Gy of preventive CRT which did not result in a significantly different outcome. The results from the subsequent trial ALL-BFM 86, using a more intensive consolidation with high-dose methotrexate (HD-MTX), demonstrated that the elimination of CRT in low-risk ALL, the reduced CRT of 12 Gy for IR, 18 Gy for medium (MR), and the reduced CRT with 18 Gy for high risk (HR) ALL, respectively, was justified: the incidence of relapses with CNS involvement was reduced to less than 5% (Reiter et al. 1994, Blood 84: 3122). When even less intensive preventive CRT (12 Gy for all medium and high risk patients) was used in trial ALL-BFM 90, the rate of CNS-related relapses was again below 5%. HR patients now treated with more CNS-directed chemotherapy had the lowest rate of CNS-related relapses observed so far in the BFM trials, even though CRT was also reduced to 12 Gy. Patients with T-cell ALL were shown to be protected from CNS recurrence by the combination of CRT (12 Gy) and HD-MTX more effectively than by HD-MTX in consolidation and TIT therapy during maintenance, especially if they presented with high WBC as shown in a joint AIEOP/BFM analysis (Conter et al. 1997, JCO 15: 2786). Patients with overt meningeosis which are characterized by a high leukemic cell load at diagnosis had a rate of recurrences that was comparable to that of patients with high WBC but no CNS disease. CONCLUSION: Low-risk ALL patients can be efficiently prevented from CNS relapse by intensive systemic and intrathecal chemotherapy without CRT. Patients with intermediate or medium risk ALL, including T-cell ALL, did not suffer from more CNS or systemic relapses when CRT was reduced to only 12 Gy. Patients with inadequate response to therapy are at particularly high risk for relapse with CNS involvement. Therefore, more CNS-directed systemic and intrathecal chemotherapy was applied in trial ALL-BFM 90, combined with only 12 Gy cranial irradiation, and improved the control of CNS recurrence. It seems likely that larger subsets of B-precursor ALL can be protected from CNS-related relapse by intensive chemotherapy without extended IT treatment and without CRT. This is being investigated in the ongoing trial ALL-BFM 95.
Adolescent↗