miR-200a-mediated suppression of non-muscle heavy chain IIb inhibits meningioma cell migration and tumor growth in vivo.

miR-200a has been implicated in the pathogenesis of meningiomas, one of the most common central nervous system tumors in humans. To identify how miR-200a contributes to meningioma pathogenesis at the molecular level, we used a comparative protein profiling approach using Gel-nanoLC-MS/MS and identified approximately 130 dysregulated proteins in miR-200a-overexpressing meningioma cells. Following the bioinformatic analysis to identify potential genes targeted by miR-200a, we focused on the non-muscle heavy chain IIb (NMHCIIb), and showed that miR-200a directly targeted NMHCIIb. Considering the key roles of NMHCIIb in cell division and cell migration, we aimed to identify whether miR-200a regulated these processes through NMHCIIb. We found that NMHCIIb overexpression partially rescued miR-200a-mediated inhibition of cell migration, as well as cell growth in vitro and in vivo. Moreover, siRNA-mediated silencing of NMHCIIb expression resulted in a similar migration phenotype in these cells and inhibited meningioma tumor growth in mice. Taken together, these results suggest that NMHCIIb might serve as a novel therapeutic target in meningiomas.

Relative survival of patients with non-malignant central nervous system tumours: a descriptive study by the Austrian Brain Tumour Registry.

BACKGROUND: Unlike malignant primary central nervous system (CNS) tumours outcome data on non-malignant CNS tumours are scarce. For patients diagnosed from 1996 to 2002 5-year relative survival of only 85.0% has been reported. We investigated this rate in a contemporary patient cohort to update information on survival. METHODS: We followed a cohort of 3983 cases within the Austrian Brain Tumour Registry. All patients were newly diagnosed from 2005 to 2010 with a histologically confirmed non-malignant CNS tumour. Vital status, cause of death, and population life tables were obtained by 31 December 2011 to calculate relative survival. RESULTS: Overall 5-year relative survival was 96.1% (95% CI 95.1-97.1%), being significantly lower in tumours of borderline (90.2%, 87.2-92.7%) than benign behaviour (97.4%, 96.3-98.3%). Benign tumour survival ranged from 86.8 for neurofibroma to 99.7% for Schwannoma; for borderline tumours survival rates varied from 83.2 for haemangiopericytoma to 98.4% for myxopapillary ependymoma. Cause of death was directly attributed to the CNS tumour in 39.6%, followed by other cancer (20.4%) and cardiovascular disease (15.8%). CONCLUSION: The overall excess mortality in patients with non-malignant CNS tumours is 5.5%, indicating a significant improvement in survival over the last decade. Still, the remaining adverse impact on survival underpins the importance of systematic registration of these tumours.

RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference.

Heterozygous germline mutations in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 cause hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, a dominantly inherited cancer susceptibility syndrome. Recent reports provide evidence for a novel recessively inherited cancer syndrome with constitutive MMR deficiency due to biallelic germline mutations in one of the MMR genes. MMR-deficiency (MMR-D) syndrome is characterized by childhood brain tumors, hematological and/or gastrointestinal malignancies, and signs of neurofibromatosis type 1 (NF1). We established an RNA-based mutation detection assay for the four MMR genes, since 1) a number of splicing defects may escape detection by the analysis of genomic DNA, and 2) DNA-based mutation detection in the PMS2 gene is severely hampered by the presence of multiple highly similar pseudogenes, including PMS2CL. Using this assay, which is based on direct cDNA sequencing of RT-PCR products, we investigated two families with children suspected to suffer from MMR-D syndrome. We identified a homozygous complex MSH6 splicing alteration in the index patients of the first family and a novel homozygous PMS2 mutation (c.182delA) in the index patient of the second family. Furthermore, we demonstrate, by the analysis of a PMS2/PMS2CL "hybrid" allele carrier, that RNA-based PMS2 testing effectively avoids the caveats of genomic DNA amplification approaches; i.e., pseudogene coamplification as well as allelic dropout, and will, thus, allow more sensitive mutation analysis in MMR deficiency and in HNPCC patients with PMS2 defects.

Malignant predominantly minigemistocytic glioma in two infants: a distinctive glioma variant?

We report unusual distinctive histopathological features in malignant supratentorial tumours of two infants (patient 1: congenital, patient 2: 30 months). Both patients had paraventricularly located well-delineated tumours. Gross total resection could be performed and postoperative chemotherapy was administered. At the last follow-up, 18 (patient 1) and 10 months (patient 2) postoperatively, both patients were in continuous complete remission. Histologically, both tumours were characterized by high cellular density and monomorphic appearance. Tumour cells were small to medium-sized and the majority of cells showed a distinctive minigemistocytic shape. A small fraction of cells lacked a distinct cytoplasm. Mitotic figures were abundant, tumour necrosis and hypertrophic vascular proliferations were absent. Immunohistochemically, the tumour cells expressed glial (GFAP, S100) and focally neuronal (NFP) proteins. Comparative genomic hybridization showed few, dissimilar chromosomal aberrations in the two tumours. Although sharp demarcation and monomorphic architecture of both tumours are reminiscent of a primitive neuroectodermal tumour, cytological and immunohistochemical glial differentiation refer to a glial tumour origin. To our knowledge the histopathological features of the described tumours do not correspond unequivocally to any established glioma variant and could represent a distinctive new glioma subtype.

Histopathological prognostic factors in medulloblastoma: high expression of survivin is related to unfavourable outcome.

Standard postoperative treatment of medulloblastoma consists of craniospinal irradiation and chemotherapy. Currently, only clinical factors are used for therapy stratification. To optimise treatment and patient outcome, biological prognostic markers are needed. In the present study we tested the prognostic influence of four histopathological parameters considered in recent publications as prognostic factors in medulloblastoma. We analysed a series of 82 Austrian medulloblastoma patients who were treated according to the consecutive HIT protocols for medulloblastoma conducted by the German Society of Paediatric Haematology and Oncology. Histological subtype and immunohistochemical expression of erbB-2, TRKC, and survivin were determined on paraffin embedded tumour tissue and correlated with patient outcome. Statistical analysis showed a significant correlation of high expression levels of survivin with decreased survival. None of the other investigated histopathological factors correlated significantly with patient outcome. Our data indicate that high survivin expression is related to unfavourable clinical outcome in medulloblastoma patients.

Nectin-like molecule 1 is a high abundance protein in cerebellar neurons.

Nectins and Nectin-like molecules belong to the Ca-independent immunoglobulin superfamily of cell adhesion molecules and are mandatory for various cellular functions such as morphogenesis, differentiation and proliferation. Among them, Nectin-like molecule 1 (Necl-1) is unique for its exclusive expression in the brain where it is localized at the contact sites among axon terminals and glia cell processes, cooperatively forming synapses. We hereby aimed to unambiguously characterize Necl-1 at the protein level in rat brain. Rat cerebellar neurons were lysed, proteins extracted and run on two-dimensional gel electrophoresis with subsequent in-gel digestion and mass spectrometrical (MS/MS) analysis of protein spots. One spot at pI 5.96 with an observed molecular weight of 26 kDa was identified as Nectin-like molecule 1. MS/MS analyses of three matching peptides warranted unambiguous identification for the first time. Additionally, we verified the result by immunoblotting and detected two bands at about 48 kDa and 60 kDa. The proposed roles of Necl-1 in cerebellar morphogenesis as well as plasticity of synapses challenge further research on its function in more detail and we hereby provide a fair analytical tool for the unequivocal determination of Necl-1, independent of antibody availability and specificity.

Aberrant cytosolic acyl-CoA thioester hydrolase in hippocampus of patients with mesial temporal lobe epilepsy.

A series of enzyme alterations has been shown to be associated with several forms of epilepsy, in mesial temporal lobe epilepsy (MTLE), however, information is limited. It was therefore the aim of the study to determine brain enzyme protein expression using a proteomic screening approach. Hippocampi of controls and patients with drug-resistant MTLE were used for evaluation of protein expression. We applied two-dimensional electrophoresis (2-DE) with mass spectrometrical identification and immunoblotting. 2-DE revealed a remarkably decreased spot identified as cytosolic acyl-CoA thioester hydrolase (BACH; EC 3.1.2.2) in patients with MTLE. Western blotting showed absence of bands at 37 kDa in MTLEs using an antibody against mouse BACH and at 140 kDa in MTLEs using anti-rat BACH. This study demonstrates that BACHs were deranged in hippocampus of MTLE patients. This finding may well contribute to the understanding of the still elusive pathomechanisms involved in MTLE.

Expression of proteasomal proteins in ten different tumor cell lines.

Controlled intracellular protein degradation is crucial for the maintenance of normal cell functions. An evolving concept claims that alterations in the exact timely degradation of proteins involved in growth control, apoptosis, signaling and differentiation contribute to carcinogenesis. This tightly regulated process is facilitated by the ubiquitin-26S proteasome system, a multi-enzyme complex, and inhibitors of this pathway have already been developed as potential anticancer agents. In order to generate proteasomal protein expression patterns of tumor cells and to provide an analytical tool we applied two-dimensional electrophoresis (2-DE) followed by mass spectrometry (MALDI-TOF-TOF with LIFT technology) in ten individual tumor cell lines (Saos-2; SK-N-SH; HCT-116; Caov3; A-549; HL60; A-673; A-375; MCF-7; HeLa) widely used in tumor research. A series of 39 proteasomal/proteolytic proteins was unambiguously identified by this proteomic approach, comprising proteins of the 20S core complex, the 19S regulatory complex, the 11S regulator, components of the ubiquitin pathway and proteases. Construction of individual protein maps by 2-DE and mass spectrometry provides an analytical tool and reference base for studying the pivotal importance of the proteasome and other proteolytic enzymes in tumor cells, independent of antibody availability and specificity. This preliminary database enables for designing studies in this area of research and reveals proteins that can be used as targets for new therapeutic strategies.

Immunity against vaccine-preventable potentially neurotropic diseases in children treated for malignant brain tumours with HIT-91 chemo- and radiotherapy.

Following surgery, chemotherapy and/or irradiation, patients with malignant brain tumours are at risk of neurotropic diseases, although these are partly vaccine-preventable. In a retrospective, controlled, observational study, the impact of the German-Austrian chemo- and radiotherapy protocol (HIT-91) on antibody concentrations against vaccine-preventable diseases and on vaccination behaviour was analysed. A significant level of seronegativity for measles- and mumps-IgG, and a reduced protection induced by inactivated vaccines was observed after HIT-91 therapy. Failure of seroconversion following measles and mumps live vaccinations was assessed in the HIT-91-treated group and in a group with benign brain tumours (BBT). Analysis of cellular immunological parameters revealed significant aberrations in the HIT-91-treated group 36 months after completion of HIT-91 therapy. A retrospective analysis of the patient's vaccination history revealed an incorrect risk perception concerning the choice of vaccinations. We therefore recommend clinical vaccination with serosurveillance in patients who have undergone treatment for brain tumours.

DNA topoisomerase IIalpha expression in optic pathway gliomas of childhood.

DNA topoisomerase IIalpha (Topo IIalpha) is linked to tumour cell growth and chemoresistance. We examined immunohistochemically Topo IIalpha expression levels in a series of 36 consecutive paediatric optic pathway glioma (OPG) patients. Topo IIalpha labelling index (LI) ranged from 0.0 to 11.6 and was significantly associated with patient age, with higher levels of Topo IIalpha in children < or = 3 years (P=0.031). Topo IIalpha expression did not correlate with patient survival. Topo IIalpha LI was not significantly increased in specimens of repeat surgery. Topo IIalpha LI closely correlated with MIB-1 LI (R=0.781, P<0.001). We conclude that Topo IIalpha expression correlates with tumour cell proliferation in paediatric OPGs. Assessment of cell proliferation, however, does not assist in refining prognostic predictions. Enhanced Topo IIalpha expression in children < or = 3.0 years suggests that Topo IIalpha-interfering anticancer compounds for adjuvant treatment of OPGs may be of particular benefit to young children.

Prolonged second response to cisplatin, etoposide, and ifosfamide in a child with a recurrent brainstem glioblastoma.

The prognosis for patients with malignant brainstem tumors is poor. The authors report on a 6-year-old girl with a biopsy proven pontine glioblastoma, who, after initial chemo-radiotherapy and tumor progression, experienced a prolonged second response to a salvage therapy consisting of cisplatin, etoposide, and ifosfamide. The patient recovered from her life-threatening condition with almost complete resolution of all neurologic deficits paralleled by a dramatic shrinkage of the tumor documented by magnetic resonance imaging.

Intracranial hemorrhage from an aneurysm encased in a pilocytic astrocytoma--case report and review of the literature.

The authors present an unusual complication of a recurrent chiasmal/hypothalamic pilocytic astrocytoma. From his second year of life onwards, the patient was repeatedly operated on and also underwent external radiation therapy (54 Gy total dose) 1 month after the first subtotal tumor resection. Nine years after irradiation, the patient was referred to our center with a sudden onset of severe headache, vomiting and neck stiffness. Computed tomography, magnetic resonance imaging, and cerebral angiography demonstrated an intratumoral, intraventricular, and subarachnoidal hemorrhage from an anterior communicating artery aneurysm encased in the pilocytic astrocytoma. The aneurysm was clipped and the patient recovered nicely from the hemorrhage. Three years later, the patient suddenly died of cardiac failure. Autopsy disclosed vessel wall changes compatible with radiation-induced vasculopathy. In light of this finding, the importance of radiation therapy and intracranial neoplasms for aneurysm formation is discussed.

Vascular endothelial growth factor (VEGF) is elevated in brain tumor cysts and correlates with tumor progression.

Vascular endothelial growth factor (VEGF), a key regulatory protein in neoangiogenesis, is strongly expressed in a variety of primary brain tumors, particularly malignant gliomas. In previous studies, high levels of VEGF were also reported in tumor cysts of glioblastomas. Using an ELISA method we measured the concentration of VEGF in matched samples of aspiration fluid from tumor cysts and serum. Samples were collected from 14 patients with primary brain tumors of various histology (six glioblastomas, one protoplasmatic astrocytoma, two pilocytic astrocytomas, one ependymoma, one meningioma, and three craniopharyngiomas) and two patients with solitary cystic brain metastases from adenocarcinomas of the lung. Aspiration fluids of tumor cysts from all patients revealed high VEGF levels ranging between 882 and 1,263,000 pg/ml, which were 2 to more than 2,000 times higher than the corresponding serum levels. Maximum VEGF levels were detectable in cyst fluids from recurrent glioblastoma. Serum VEGF levels ranged between 125 and 716 pg/ml and did not differ from serum levels in 145 healthy volunteers. In a single patient with metastatic lung cancer the concentration of VEGF in serum and cyst fluid was determined during disease progression. During 60 days of follow-up VEGF concentrations in the cyst fluid collected by puncture of an Ommaya reservoir increased 650-fold, while serum levels remained rather constant. These findings indicate that immunoreactive VEGF is produced at the tumor site and abundantly released into the cyst fluid of primary and metastatic brain tumors. Interestingly, this abundant local release is not reflected in serum VEGF levels, even in the case of very high VEGF concentrations in tumor cysts. Thus, VEGF may be biologically relevant for the formation of tumor cysts in brain tumors and correlates with local disease progression.

Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91.

PURPOSE: The German Society of Pediatric Hematology and Oncology (GPOH) conducted a randomized, prospective, multicenter trial (HIT '91) in order to improve the survival of children with medulloblastoma by using postoperative neoadjuvant chemotherapy before radiation therapy as opposed to maintenance chemotherapy after immediate postoperative radiotherapy. METHODS AND MATERIALS: Between 1991 and 1997, 158 patients were enrolled and 137 patients randomized. Seventy-two patients were allocated to receive neoadjuvant chemotherapy before radiotherapy (arm I, investigational). Chemotherapy consisted of ifosfamide, etoposide, intravenous high-dose methotrexate, cisplatin, and cytarabine given in two cycles. In arm II (standard arm), 65 patients were assigned to receive immediate postoperative radiotherapy, with concomitant vincristine followed by 8 cycles of maintenance chemotherapy consisting of cisplatin, CCNU, and vincristine ("Philadelphia protocol"). All patients received radiotherapy to the craniospinal axis (35.2 Gy total dose, 1.6 Gy fractionated dose / 5 times per week followed by a boost to posterior fossa with 20 Gy, 2.0 Gy fractionated dose). RESULTS: During chemotherapy Grade III/IV infections were predominant in arm I (40%). Peripheral neuropathy and ototoxicity were prevailing in arm II (37% and 34%, respectively). Dose modification was necessary in particular in arm II (63%). During radiotherapy acute toxicity was mild in the majority of patients and equally distributed in both arms. Myelosuppression led to a mean prolongation of treatment time of 11.5 days in arm I and 7.5 days in arm II, and interruptions in 35% of patients in arm I. Quality control of radiotherapy revealed correct treatment in more than 88% for dose prescription, more than 88% for coverage of target volume, and 98% for field matching. At a median follow-up of 30 months (range 1.4-62 months), the Kaplan-Meier estimates for relapse-free survival at 3 years for all randomized patients were 0.70+/-0.08; for patients with residual disease: 0.72+/-0.06; without residual disease: 0.68+/-0.09; M0: 0.72+/-0.04; M1: 0.65+/-0.12; and M2/3: 0.30+/-0.15. For all randomized patients without M2/3 disease: 0.65+/-0.05 (arm I) and 0.78+/-0.06 (arm II) (p < 0.03); patients between 3 and 5.9 years: 0.60+/-0.13 and 0.64+/-0.14, respectively, but patients between 6 and 18 years: 0.62+/-0.09 and 0.84+/-0.08, respectively (p < 0.03). In a univariate analysis the only negative prognostic factors were M2/3 disease (p < 0.002) and an age of less than 8 years (p < 0.03). CONCLUSIONS: Maintenance chemotherapy would seem to be more effective in low-risk medulloblastoma, especially in patients older than 6 years of age. Neoadjuvant chemotherapy was accompanied by increased myelotoxicity of the subsequent radiotherapy, causing a higher rate of interruptions and an extended overall treatment time. Delayed and/or protracted radiotherapy may therefore have a negative impact on outcome. M2/3 disease was associated with a poor survival in both arms, suggesting the need for a more intensive treatment. Young age and M2/3 stage were negative prognostic factors in medulloblastoma, but residual or M1 disease was not, suggesting a new stratification system for risk subgroups. High quality of radiotherapy may be a major contributing factor for the overall outcome.

Combined postoperative irradiation and chemotherapy for anaplastic ependymomas in childhood: results of the German prospective trials HIT 88/89 and HIT 91.

PURPOSE: To evaluate the outcome in children with anaplastic ependymomas after surgery, irradiation, and chemotherapy; and to identify prognostic factors for survival. METHODS AND MATERIALS: Fifty-five children (n = 27 girls, 28 boys; median age at diagnosis, 6.2 years) with newly diagnosed anaplastic ependymomas were treated in the multicenter, prospective trials HIT 88/89 and HIT 91. Macroscopic complete resection was achieved in 28 patients; 27 patients underwent incomplete resection. All patients received chemotherapy before (n = 40) or after irradiation (n = 15). The irradiation volume encompassed either the neuraxis followed by a boost to the primary tumor site (n = 40) or the tumor region only (n = 13). No radiotherapy was administered in two patients. RESULTS: Median follow-up was 38 months. The overall survival rate at 3 years after surgery was 75.6%. Disease progression occurred in 25 children with local progression occurring in 20. The median time to disease progression was 45 months. The only significant prognostic factor was the extent of resection (estimated progression-free survival [EPFS] after 3 years was 83.3% after complete resection and 38.5% after incomplete resection) and the presence of metastases at the time of diagnosis (0% vs. 65.8% 3-year EPFS in localized tumors). Age, sex, tumor site, mode of chemotherapy, and irradiation volume did not influence survival. CONCLUSIONS: Treatment centers should be meticulous about surgery and diagnostic workup. Because the primary tumor region is the predominant site of failure it is important to intensify local treatment. Dose escalation by hyperfractionation or stereotactic radiotherapy might be a promising approach in macroscopically residual disease. The role of adjuvant chemotherapy requires further study.

Proliferative activity as measured by MIB-1 labeling index and long-term outcome of visual pathway astrocytomas in children.

Although most visual pathway tumors are low-grade gliomas their biologic behavior is highly unpredictable. In order to determine whether assessment of proliferative activity can assist in predicting tumor behavior, we studied the MIB-1 labeling indices (MIB-1 LIs) in surgical specimens and monitored tumor growth in 31 consecutive children operated on between 1978 and 1997. The MIB-1 LIs at diagnosis varied from 0-10.6% (mean +/- SD, 3.27 +/- 2.49%). Tumor progression occurred in 19 patients leading to death in seven, three of whom had neurofibromatosis type 1 (NF1). No association between MIB-1 LI at initial diagnosis and both progression free and overall survival was apparent. However, the MIB-1 LIs increased to 15.2% and 18% in two patients with NF1 who developed highly malignant gliomas 6 and 6.5 years after irradiation. In the remaining patients the MIB-1 LIs did not change significantly over time in a total of 17 repeat surgeries. Three patients with LIs of 6.8%, 10.6% and 8.8% are stable after 6, 4.5 and 3.5 years with partial resection, biopsy and subtotal resection, respectively, and no further therapy in the first two and chemotherapy in the latter. Three patients (10%) with LIs of 6.4%, 4.8% and 2.2% either presented with or developed leptomeningeal spread during follow-up. While MIB-1 LI does not appear to assist in clinical decision making patient numbers were too small to find out whether response to chemotherapy varies with proliferative potential.

Hyaluronidase additional to standard chemotherapy improves outcome for children with malignant brain tumors.

Ex vivo experiments with vital brain tumor samples show that hyaluronidase enhances the permeation of carboplatin into tumor tissue with a matrix rich in hyaluronic acid. We achieved long-lasting second remissions for children with relapsed malignant brain tumors treated with carboplatin, etoposide and this enzyme. Thereafter, we initiated a pilot study where we added hyaluronidase to the first line standard therapy to prevent the deadly relapses right from the beginning. All 19 patients with malignant brain tumors admitted to our pediatric neurooncological center from 1992 to 1994 were included in the study. Kaplan-Meier estimation of event-free survival and overall survival after 3 years follow-up indicates a significantly better outcome for the hyaluronidase-treated group. The children receiving supportive hyaluronidase suffered significantly less relapses (P = 0.034) and had a significantly better chance for survival (P = 0.045) compared to the historical control of 21 children treated with the same standard regimen but without supportive hyaluronidase (product limit analysis and the log-rank test, P < 0.05). Children aged >3 years receiving hyaluronidase together with primary treatment seemed to gain the most benefit.

Intrathecal mafosfamide therapy for pediatric brain tumors with meningeal dissemination.

The treatment of childhood brain tumors with cerebrospinal fluid (CSF) dissemination is limited by the relative inaccessibility of the CSF to drugs administered systemically and the paucity of available agents for intrathecal therapy. Mafosfamide is a cyclophosphamide derivative, which does not require hepatic activation and thus can be utilized for regional therapy. Between May 1994 and December 1996, 16 patients 2 to 19 (median 12) years old with various disseminated brain tumors were treated with intraventricular mafosfamide via an indwelling subcutaneous reservoir. The patients received mafosfamide at a dose of 20 mg once or twice weekly until remission was achieved, followed by weekly administrations as consolidation therapy, and every 3 to 4 weeks thereafter for maintenance therapy. Except for transient headaches, nausea and vomiting during and immediately after mafosfamide administration no toxicities were observed. Nine of the 16 patients were evaluable for response by CSF cytology. Eight had complete responses and one patient did not respond. In addition to mafosfamide all patients received systemic chemotherapy as well. However, 4 of the 8 responding patients had developed CSF dissemination under concurrent systemic therapy and cleared their CSF only after administration of intrathecal mafosfamide. At a median follow-up of 21 months, 7 patients are in complete and 4 in partial remission, 2 have stable disease and 3 died of tumor progression. We conclude that mafosfamide at a dose of 20 mg can be safely administered into the CSF and may produce responses and prolong remission of the leptomeningeal disease.

Reversible occlusion shunt for intraventricular chemotherapy in shunt-dependent brain tumor patients.

Intraventricular chemotherapy is increasingly used in the treatment of pediatric brain tumors with leptomeningeal seeding. However, some patients are shunt dependent after surgery, probably due to adhesions in the area of surgery. To avoid drug diversion in these patients we connected the reservoir to a reversible occlusion device. Over a 2-year period a shunt value with an on-off device was inserted into the shunt assembly of eight children with various brain tumors with a poor prognosis undergoing intraventricular chemotherapy. All eight patients had tumor cells in the ventricular cerebrospinal fluid (CSF) and/or metastases by magnetic resonance imaging. The number of intraventricular drug applications ranged from 10 to 51. No shunt malfunctions or shunt-related infections occurred. The temporary closure of the shunt after drug delivery was well tolerated. In all six children with tumor cells in the ventricular CSF a negative cytology was achieved over a 3- to 8-week period.