DRR drives brain cancer invasion by regulating cytoskeletal-focal adhesion dynamics.

Malignant glioma invasion is a primary cause of brain cancer treatment failure, yet the molecular mechanisms underlying its regulation remain elusive. We developed a novel functional-screening strategy and identified downregulated in renal cell carcinoma (DRR) as a regulator of invasion. We show that DRR drives invasion in vitro and in vivo. We found that while DRR is not expressed in normal glial cells, it is highly expressed in the invasive component of gliomas. Exploring underlying mechanisms, we show that DRR associates with and organizes the actin and microtubular cytoskeletons and that these associations are essential for focal adhesion (FA) disassembly and cell invasion. These findings identify DRR as a new cytoskeletal crosslinker that regulates FA dynamics and cell movement.

Treatment of paediatric pontine glioma with oral trophosphamide and etoposide.

To evaluate the overall survival of paediatric patients with pontine gliomas treated with oral trophosphamide and etoposide. Patients between 3 and 17 years of age with either typical diffuse pontine glioma on MRI or histologically proven anaplastic astrocytoma/glioblastoma multiforme located in the pons, were eligible. Treatment consisted of oral trophosphamide 100 mg x m(-2) x day(-1) combined with oral etoposide at 25 mg x m(-2) x day(-1) starting simultaneously with conventional radiation. Twenty patients were enrolled (median age 6 years, male : female=9 : 11). Surgical procedures included: no surgery: five, open biopsy: three, stereotactic biopsy: six, partial resection: three, and sub-total resection: three. Histological diagnoses included pilocytic astrocytoma: one, astrocytoma with no other specification: three, anaplastic astrocytoma: three, glioblastoma multiforme: eight, no histology: five. The most frequent side effects were haematologic and gastrointestinal. There was no toxic death. The response to combined treatment in 12 evaluable patients was: complete response: 0, partial response: three, stable disease: four, and progressive disease: five. All tumours progressed locally and all patients died. The overall median survival was 8 months. The overall survival rates at 1 and 4 years were: 0.4 and 0.05 respectively. This was not different from a control group of patients documented in the same population. Oral trophosphamide in combination with etoposide did not improve survival of pontine glioma patients. The treatment was well tolerated and should be evaluated for more chemoresponsive paediatric malignancies.

Oral trofosfamide and etoposide in pediatric patients with glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme in childhood is rare, and the prognosis for patients with the disease is poor. The Pediatric Oncology Society of the Germanic language group (GPOH) enrolls patients in a series of pilot trials, the first of which is reported here (HIT-GBM-A). METHODS: Twenty-two patients with glioblastoma multiforme, World Health Organization Grade 4, between the ages of 3-15 years (45% male) were enrolled during the period 1995-1997. There were 13 supratentorial tumors, 8 brainstem tumors, and 1 cerebellar tumor. The patients underwent the following procedures: stereotactic biopsy (n = 3 patients), open biopsy (n = 1 patient), partial resection (n = 6 patients), subtotal resection (n = 4 patients), and macroscopic total resection (n = 8 patients). Adjuvant treatment consisted of oral chemotherapy with trofosfamide, 100 mg/m(2), and etoposide, 25 mg/m(2), daily or for 21-day cycles interrupted by 1-week rests. Standard fractionated radiation (54 grays) was started concurrently with the first cycle. RESULTS: The chemotherapy was well tolerated, with no treatment-related deaths and only minor side effects. The responses in 12 evaluable patients after two cycles were as follows: 1 complete response, 1 partial response, 3 patients with stable disease, and 7 patients with progressive disease. The median overall survival was 12 months. The 1-year, 2-year, and 4-year overall survival rates were 52%, 26%, and 22%, respectively, and the event free survival rates were 26%, 22%, and 4%, respectively. None of the four surviving patients (3.2 years, 3.4 years, 4.0 years, and 4.2 years after diagnosis) is event free. Two patients are alive after tumor progression: One patient was diagnosed with a medulloblastoma, and one patient was diagnosed with an osteosarcoma as second malignancies. A control group extracted from the Surveillance, Epidemiology, and End Results data had lower survival rates: the difference between the groups was not statistically significant (P = 0.26). CONCLUSIONS: This chemotherapy will not be used in a randomized trial of patients with glioblastoma; however, it may be evaluated for patients with tumors that have more chemoresponsive histologies.

Hypoleptinaemia in patients with anorexia nervosa and in elite gymnasts with anorexia athletica.

Leptin, the product of the ob-gene, is specifically released by adipocytes. In addition to its metabolic function it seems to affect the feedback-mechanisms of the hypothalamic-pituitary-gonadal-axis. We studied 13 female juvenile elite gymnasts with anorexia athletica (AA) and 9 female patients with anorexia nervosa (AN) regarding the relation between leptin, fat stores, and the reproductive hormone levels. Leptin levels in females with anorexia nervosa (Tanner stage B4 [median]; mean age: 17.8 +/- 1.7 years) were low (2.9 +/- 2.7 microg/L), and were related to body mass index (BMI) (r = 0.71; p = 0.03) and percentage body fat mass (r = 0.78; p = 0.01). Leptin levels of the elite gymnasts were even more decreased (1.2 +/- 0.8 microg/L) caused by the low amount of fat stores. Leptin correlated with BMI (r= 0.77; p = 0.004) and the percentage body fat mass (r = 0.6; p = 0.04). In elite gymnasts leptin levels correlated with CA showing an age-dependent increase (r= 0.59; p = 0.04). Oestradiol was secreted at a low level in both groups (AN: 25.6 +/- 17.4 microg/L; AA: 24.4 +/- 13.5 microg/L). A delay in menarche and a retarded bone maturation occurred in AA. Our results clearly show that leptin levels are low in restrained eaters. Leptin levels represent the fat stores in the body and play a permissive role for female pubertal development. There is evidence that the mechanisms leading to a dysregulation of the reproductive-axis in patients with AN are comparable with those leading to delayed puberty in juvenile elite gymnasts with AA. This implies that AN and AA are overlapping groups and AA can lead to the development of AN.

Chemosensitivity of glioma cells in vitro: a meta analysis.

PURPOSE: The disappointing results of chemotherapy in glioblastoma might be caused by the choices of agents, which mostly include nitrosurea. We compared the in vitro efficacy of chemotherapeutic agents, developing a method to summarize published data. METHOD: Between 1966 and 1995 chemotherapy in glioma cells was reported in 1643 articles. Efficacy was mostly described by the drug concentration that killed 50% of the cells (LC50). It was measured with various cell-culture techniques, of which a colorimetric test [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltrazolium bromide] was mostly used. We calculated factors from these data to transform results to LC50 values as if the colorimetric test was used in all of them. This allowed data from all publications to be summarized in a new type of meta analysis. RESULTS: The most important agents and the average LC50 values (mg/l) were actinomycin-D 0.042, vincristine 0.075, mitoxantrone 0.12, vinblastine 0.21, doxorubicin 0.29, diaziquone 0.76, cisplatin 1.1, methotrexate 1.1, cytasine arabinoside 1.59, 5-flurouracil 2.33, bleomycin 18.6, carboplatin 29.8, carmustine 37.0, nimustine 48.9, and lomustine 76.7. The most resistant cell was SNB56, followed with increasing sensitivity by SF128 and A172, and primary cultures P497, SF210, U87MG, SF126, 9L, P540, U251MG, HU62, C6. The complete list of original data is available upon request. CONCLUSION: The efficacy of nitrosourea in vitro is low.

Using the Vista 350 telephone to communicate the results of home monitoring of diabetes mellitus to a central database and to provide feedback.

PURPOSE: Self-monitoring of blood glucose has become routine practice in the management of diabetes mellitus. When all the data is complete, however, the amount of information to be taken into account when making therapeutic decisions becomes overwhelming not only for the patient but for the healthcare provider. Computers excel at processing large amounts of information quickly and impassively, which makes them potentially helpful for collating and communicating the data in a manner that facilitates decision-making by patient and healthcare provider. This should in turn improve control and help prevent acute and chronic complications. METHOD: Using the Vista 350 telephone, we have developed a system that enables patients with diabetes to record home monitoring data to a central database and receive feedback summaries. A small trial was conducted to determine if the Vista 350 telephone is an acceptable and feasible method to communicate the results of home monitoring of diabetes mellitus to a central database and receive feedback summaries. A total of 35 volunteers with insulin-requiring diabetes mellitus in the London area were randomly allocated to either use the Vista 350 phone for 6 months, or to a control group that continued to use traditional methods for recording home monitoring data. RESULTS: 33 of the 35 patients enrolled completed the trial. All 16 patients who began using the phone continued to do so for 6 months confirming the feasibility of the system. Questionnaires completed at 3 and 6 months confirmed the Vista 350 telephone system to be acceptable to the subjects. The results will enable some minor modifications to be made to the telephone system before a larger definitive trial, designed to determine the effect on diabetes control, is conducted later this year.

Monitoring tumor activity in low grade glioma of childhood.

Chemotherapeutic or radiotherapeutic regimens are being increasingly used in low grade glioma of childhood. These protocols require methods to monitor tumor activity. We report our experience in eleven patients. The tumors were localized in the optic pathway (3), cerebral cortex (4) and thalamus/hypothalamus (4). Histological diagnoses included low grade astrocytoma (6), gliofibroma (1) and ganglioglioma (2). Two children with neurofibromatosis type 1 (NF-1) and typical optical tumors were not biopsied. 13 episodes of progression were noted including 3 altered diagnoses. This was evident from clinical symptoms in 11/13 episodes, computed tomography (CT) or magnetic resonance imaging (MRI) in 10/13 situations, iodine-123-alpha-methyltyrosine (123I-IMT) single-photon emission computed tomography (SPECT) in 10/10 situations, fluorine-18 fluorodesoxyglucose (18F-FDG) positron emission tomography (PET) in 0/3 and thallium-201 (201Tl) SPECT in 1/1. Seven responses to chemotherapy were recorded. Clinical symptoms indicated this in 7/7 situations, MRI in 5/7, 123I-IMT SPECT in 1/2 and 201Tl SPECT in 1/1. These data suggest that 123I-IMT SPECT is a valuable addition to low grade glioma diagnostic and stress the need for a prospective study.

[Nutritional behavior of female and male high performance gymnasts]. / Ernährungsverhalten bei weiblichen und männlichen Hochleistungsturnern.

Elite gymnasts pass through their whole physical and intellectual development with intensive physical training. In this period malnutrition can lead to delayed pubertal development with insufficient growth spurt and an increased incidence of stress fractures or osteoporoses. Different aspects about nutrition like body composition, objective and subjective eating-behaviour and sex-specific differences will be evaluated in our study. We examined 22 elite female gymnasts (age: median = 13.5 [12.0-16.1] years) und 19 elite male gymnasts (age: median = 12.3 [10.1-14.8] years). The following anthropometric measurements were carried out: weight, length, body mass index, upper arm circumference, arm muscle area, triceps skinfold, arm fat area. Eating diaries were compared with the recommendations of the German Federation of Nutrition and subjective eating behaviour was evaluated by questionnaires. Measurement of body composition showed an increase of musclemass at the cost of fatmass. The girls were smaller and leaner than the boys. Caloric intake in both groups was insufficient. Moreover the girls showed a tendency towards pathologic eating behaviour.

Favorable outcome of giant cell glioblastoma in a child. Report of an 11-year survival period.

Giant cell glioblastomas are defined as glioblastomas with a marked predominance of bizarre, multinucleated giant cells. They represent about 5% of all glioblastomas and can occur at any site of the central nervous system, but the temporal and frontal lobes are the sites of predilection. Overall, giant cell glioblastomas show a prolonged survival period compared with common glioblastoma multiforme, and survival periods of 7 and 9 years have been reported in adults. Here we report on a child aged 11 years at diagnosis, who has so far survived for 11 years since operation and adjunctive radio- and chemotherapy.

[Assessment of independence in daily life in pediatric oncology by FMH-questionnaire]. / Quantifizierung von Krankheitsfolgen in der pädiatrischen Onkologie--klinische Erfahrungen mit der Fertigkeitenskala Münster/Heidelberg.

Therapy-related late effects are important for therapeutic decisions in pediatric oncology. We quantified the degree of impairment of independence in daily life in children with cancer. The German questionnaire "Fertigkeitenskala Münster/Heidelberg (FMH)" is a standardized tool for measurement of motoric and verbal functioning. A point-score leads to an age-related percentile ranking similar to typical percentiles in pediatrics. We used the FMH in 215 cancer patients (mean age 10.3 years, range 0.5-23.5 years, 56.3% male). Diagnoses were leukaemia (n = 91), bone tumors (n = 33), nephro- and neuroblastoma (n = 21), brain tumors (n = 18), lymphoma (n = 23), rhabdomyosarcoma (n = 11) and others (n = 18). The average time to answer the questionnaire was 4.5 min. Patients with brain and bone tumors showed significant lower percentile scores compared to patients with other diagnoses (p < 0.05). The FMH-scores increased with time since diagnosis (n = 215). This trend was confirmed in a longitudinal study over one year (n = 29). Quantitative assessment of independence and functioning in patients with cancer--especially in multicenter-studies--is possible. Because of therapy-related late effects this seems to be of special importance in brain and bone tumor patients.

Dexamethasone inhibits glioma-induced formation of capillary like structures in vitro and angiogenesis in vivo.

Dexamethasone is used frequently in brain tumor therapy of patients. In animal models it is known to inhibit the angiogenesis of solid tumors. We addressed the question, if this is also true in brain tumors. C6 malignant glioma and 9L gliosarcoma cells were implanted into rat-brains. Dexamethasone 3 mg/kg/d intraperitoneal increased the survival compared to saline treated controls. The tumors size and the vascular density were smaller in the dexamethasone groups in both models. In vitro dexamethasone inhibited the growth of the C6 cells but not of 9L cells. Thus the growth inhibition of brain tumors in vivo appeared to be mediated partly by direct growth inhibition of tumor cells in C6 cells but additionally by antiangiogenesis in both tumor models. Several in vitro models were used to address the mechanisms of antiangiogenesis. There was no effect of dexamethasone on the proliferation of central nervous endothelial cells and no effect on the formation of capillary like structures on matrigel. Dexamethasone inhibited, however, the formation of capillary like structures in a coculture model with glioma cells in vitro. Surprisingly, progesterone had the same effect in this model. The in vitro effect was mediated via glucocorticoid receptors since receptor antagonists could inhibit it. The primary target appeared to be the tumor cell because only this cell had the complete set of receptors. These data show, that antiangiogenic therapeutic effects are possible by influencing primarily the tumor cell. This way of targeting might be of value for future developments of new strategies.

Diabetes insipidus due to hypophysitis.

Central diabetes insipidus is a chronic disorder which in most patients occurs secondary to tumor, infection, trauma or other lesions. In about 20-30% of patients etiology is unclear, however a destructive autoimmune process in the hypophysis may play a role. We report the case of an 18-year-old girl with central diabetes insipidus. Vasopressin levels were typically decreased. Examinations performed 1.5 years after manifestation showed no pathologic changes on MRI and no additional endocrine disorder. MRI was repeated 1.5 years later whereon a thickening of the pituitary stalk as a typical sign of hypophysitis was apparent. No other reasons could be found for the vasopressin deficiency. The finding of hypophysitis in our patient 3 years after disease manifestation suggests that the characteristic MRI changes may take as long as 3 years to become apparent.

Multiple drug-resistant C6 glioma cells cross-resistant to irradiation.

Although many advances in antineoplastic therapy have taken place, a clinical breakthrough in the therapy of malignant gliomas is still required. One of the reasons for this is the poor response to cytotoxic drugs and irradiation. We established a subline of the rat glioma cell line C6, named C6,5 x 10(-7) Dox, by exposure to increasing doses of doxorubicin for 5 months. C6,5 x 10(-7) Dox cells expressed high levels of P-glycoprotein (Pgp), known to function as an energy-dependent efflux pump for lipophilic drugs causing the multidrug resistance phenotype. Pgp, which normally has a molecular weight of 170 to 180 kd, appears in C6,5 x 10(-7) Dox cells as two bands with a molecular weight of 140 and 120 kd in western blots. In addition to the typical cross-resistance to doxorubicin, daunorubicin, vincristine and etoposide, we observed a significant resistance of the C6,5 x 10(-7) Dox cell line to irradiation, which cannot be explained by Pgp-expression.

Effects of antibiotics on metabolism of peptidoglycan, protein, and lipids in Bifidobacterium bifidum subsp. pennsylvanicus.

The formation of cell envelope components of Bifidobacterium bifidum subsp. pennsylvanicus was studied by measuring the incorporation of [(3)H]glycine, (14)C-labeled fatty acids, and N-benzoyl-[(14)C]glucosamine into the membrane protein, membrane lipids, and cell wall peptidoglycan, respectively. Inhibition of peptidoglycan synthesis by antibiotics (penicillin G, vancomycin, d-cycloserine, and bacitracin) and by the omission of glucosamine-containing growth factors caused a marked decrease in glycine incorporation into cellular as well as membrane protein, which was accompanied by a considerable enhancement of fatty acid incorporation. The uncoupling of protein and lipid synthesis led to the release of marked amounts of lipids from the cell under these conditions. Arrestment of protein synthesis by antibiotics (chloramphenicol, tetracycline, and actinomycin D) decreased peptidoglycan and lipid synthesis only partially, but did not lead to lipid release. Mg(2+) deficiency of the medium caused about 60% inhibition of growth and lipid synthesis, but protein synthesis and especially peptidoglycan synthesis were much less inhibited. Staphylococcin 1580 arrested the growth and also the synthesis of protein and peptidoglycan. However, the synthesis and turnover of lipids were considerably increased and a release of large amounts of lipids was observed. Peptidoglycan and cellular protein did not show any turnover either during normal growth or after the inhibition of cell wall and protein synthesis.

Studies on various aspects of the indirect haemagglutination test for malaria.

This paper gives the results of studies on various technical aspects of the indirect haemagglutination (IHA) test for malaria, on the similarity of the results obtained in the IHA test and in the indirect fluorescent antibody test, on the use of various plasmodial extracts as sensitizing antigens in the IHA test, and on the influence of heterophile antibodies on the titres obtained in the IHA test. Some longitudinal observations on induced malaria infections of man and monkey showed that the infection can induce the production of heterophile antibodies: their appearance, however, remains unpredictable. In some infections agglutinins against host erythrocyte components are also produced. Absorption of sera with tanned sheep cells sensitized with noninfected host red blood cell antigens is advocated as a control on the IHA titre for specific agglutinins.