National Cancer Institute®
Last Modified: March 1, 2002
UI - 11840333
AU - Shou J; Ali-Osman F; Multani AS; Pathak S; Fedi P; Srivenugopal KS
TI - Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA.
SO - Oncogene 2002 Jan 31;21(6):878-89
AD - Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Road, Houston, TX 77030, USA.
The human Dkk-1 (hDkk-1) gene, a transcriptional target of the p53 tumor suppressor, encodes a powerful inhibitor of the Wnt signaling pathway and regulates the spatial patterning/morphogenesis of the mammalian central nervous system. We investigated the p53-related functions of the hDkk-1 gene by studying its response to DNA damage and its modulation of apoptosis in human glioma cells. Various chemotherapeutic and other agents that induce DNA adducts and compromise its integrity (1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, H(2)O(2) and UV rays) enhanced the expression of hDkk-1 significantly. The damage-induced increase in hDkk-1 mRNA levels occurred in many human tumor cell lines, irrespective of their p53 gene status. The human glioblastoma cell line, U87MG, which had undetectable hDkk-1 expression, was engineered to express moderate levels of the hDkk protein by stable transfection. The engineered cells did not show any morphological changes, but underwent marked apoptosis after ceramide treatment. Further, the DNA cross-linking drugs BCNU and cisplatin, but not the microtubule poison vincristine, induced significant cell death in U87MG/hDkk cells, and this was accompanied by altered Bcl-2/Bax expression and a reduction in the amount of telomere DNA as visualized by fluorescence in situ hybridization. These results show that hDkk-1 is a pro-apoptotic gene and suggest that it may play important roles in linking the oncogenic Wnt and p53 tumor suppressor pathways.
UI - 11840337
AU - Konduri SD; Osman FA; Rao CN; Srinivas H; Yanamandra N; Tasiou A; Dinh
TI - DH; Olivero WC; Gujrati M; Foster DC; Kisiel W; Kouraklis G; Rao JS Minimal and inducible regulation of tissue factor pathway inhibitor-2 in human gliomas.
SO - Oncogene 2002 Jan 31;21(6):921-8
AD - Division of Cancer Biology, Department of Biomedical and Therapeutic Sciences, University of Illinois School of Medicine, One Illini Drive, Peoria, IL 61656, USA.
Tissue factor pathway inhibitor-2 (TFPI-2), a serine protease inhibitor abundant in the extra cellular matrix, is highly expressed in non-invasive cells but undetectable levels in highly invasive human glioma cells. The mechanisms responsible for its transcriptional regulation are not well elucidated. In this study, we made several deletion constructs from a 3.6 kb genomic fragment from Hs683 cells containing the 5'-flanking region of the TFPI-2 gene, transiently transfected with these constructs into non-invasive (Hs683) and highly invasive (SNB19) human glioma cells, and assessed their expression by using a luciferase reporter gene. Three constructs showed high promoter activity (pTF5, -670 to +1; pTF6, -312 to +1; pTF2, -1511 to +1). Another construct, pTF8 (-81 to +1), showed no activity. PTF9, a variant of pTF5 in which a further 231 bp fragment (-312 to -81) was deleted, from the [-670 to +1] pTF5 region, also showed no promoter activity. Hence, (-312 to -81) this region is essential for the transcription of TFPI-2 in glioma cells. Sequencing of this promoter region revealed that it has a high G+C content, contains potential SP1 and AP1 binding motifs, and lacks canonical TATA and CAAT boxes immediately upstream of the major transcriptional initiation site, although CAAT boxes were found about -3000 bp upstream of the transcription start site. We also found a strong repressor in the region between -927 to -1181, upstream of the major transcriptional initiation site, followed by positive elements or enhancers between -1511 to -1181. These positive elements masked the silencer effect. Finally TFPI-2 was induced in Hs683 cells transfected with the pTF6 construct (-312 to +1) and stimulated with phorbol-12-myristate-13-acetate (PMA). We conclude that the -312 to +1 region is critical for the minimal and inducible regulation of TFPI-2 in non-invasive (Hs683) and highly invasive (SNB19) human glioma cell lines.
UI - 11858377
AU - Yaris N; Akyuz C; Coskun T; Kutluk T; Buyukpamukcu M
TI - Nutritional status of children with cancer and its effects on survival.
SO - Turk J Pediatr 2002 Jan-Mar;44(1):35-9
AD - Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
In the present study we aimed to determine the nutritional status of our patients and to assess its relationship with survival. The nutritional status of 47 patients with cancer was evaluated at diagnosis, three months after initiation of the treatment and at the end of therapy. Weight for height, height for age, and weight for age of children were expressed as percent of standard. Values for each nutritional index were converted into standard deviation (Z) scores. Three-year overall survival (OS) and event-free survival (EFS) rates of patients were determined according to their nutritional status. The overall prevalence of malnutrition at diagnosis was 29.8%. Three months later the malnutrition ratio reached 38.3% and then decreased again to 18.5% at the end of the therapy. Although the prevalence of malnutrition at the third month of treatment was significantly higher from the prevalence at diagnosis (p: 0.001) and at the end of the therapy (p: 0.009), the mean Z scores of the nutritional indexes before and during the treatment were not significantly different. The survival rates of malnourished patients were not different from those of well nourished patients. In conclusion, malnutrition is one of the main problems in children with cancer; hovewer, nutritional status has no effect on survival.
UI - 11778821
AU - Sano K
TI - Intracranial dysembryogenetic tumors: pathogenesis and their order of malignancy.
SO - Neurosurg Rev 2001 Dec;24(4):162-7; discussion 168-70
AD - Department of Neurosurgery, Teikyo University School of Medicine, Tokyo, Japan. email@example.com
Dysembryogenetic tumors can be classified into three main categories: (1) tumors derived from embryonal cell rests in situ such as craniopharyngioma, Rathke's cleft cyst, chordoma, etc., (2) tumors derived from embryonal cells straying into the tissue ("verirrte Keime") such as so-called germ cell tumors, epidermoid, dermoid, lipoma, hamartoma, etc., and (3) included twin (fetus-in-fetu) tumors. The pathogenesis of the second one may be that the embryonic cells of various stages of embryogenesis are misplaced in the bilaminar embryonic disc at the time of the primitive streak formation, becoming involved in the stream of lateral mesoderm and carried to the neural plate area to become incorrectly enfolded into the brain at the time of neural tube formation. The third category of tumor may be related to sequestration of cells of the blastocyst before differential blocking of the genome has occurred. The author propounds the following hypothesis: intracranial dysembryogenetic tumors composed of cells resembling the cells that appear in the earlier stages of embryogenesis are more malignant than those composed of cells resembling those appearing in the later stages of embryogenesis.
UI - 11778828
AU - Csokay A; Nagy L; Novoth B
TI - Avoidance of vascular compression in decompressive surgery for brain edema caused by trauma and tumor ablation.
SO - Neurosurg Rev 2001 Dec;24(4):209-13
AD - Department of Neurosurgery, National Institute of Traumatology, Budapest, Hungary. firstname.lastname@example.org
BACKGROUND: In case of severe brain swelling especially caused by trauma or other operative manipulation (tumor ablation), decompressive craniectomy with durotomy has not resulted in significant chances of recovery. Decompressive craniectomy has been defined only as an option within guidelines. METHOD: A new operative technique was developed to improve the efficacy of decompressive surgery. With an increase in intracranial pressure (ICP) threatening with brainstem herniation, wide bilateral craniectomy was carried out, followed by dura opening and subsequent formation of a vascular tunnel in a simple way--using hemostatic sponge cushions--around the main cortical veins at the entering points of the herniated area. The maintenance of vessel patency prevents the herniated brain segment from venous congestion, i.e., from further swelling and necrosis. RESULTS: Twenty operations with traumatic brain edema were performed using this vascular tunnel method. All patients were exposed to surgery in the state of coma. One operation was performed after tumor removal. The results were promising in comparison with the well-known surgical or conservative treatment. DISCUSSION: Applying very strict selection criteria (Glasgow coma scale < 6, signs of severe edema on CT, or intracranial pressure permanently > or = 30 mmHg) in this small series of patients with severe brain injury, good results were achieved using the new operative technique. In case of postoperative edema after tumor ablation, it also showed promising results.
UI - 11857005
AU - Swanson KR; Alvord EC Jr; Murray JD
TI - Virtual brain tumours (gliomas) enhance the reality of medical imaging and highlight inadequacies of current therapy.
SO - Br J Cancer 2002 Jan 7;86(1):14-8
AD - Department of Applied Mathematics, Box 352420, University of Washington, Seattle, Washington WA 98195, USA. email@example.com
Gliomas are brain tumours that differ from most other cancers by their diffuse invasion of the surrounding normal tissue and their notorious recurrence following all forms of therapy. We have developed a mathematical model to quantify the spatio-temporal growth and invasion of gliomas in three dimensions throughout a virtual human brain. The model quantifies the extent of tumorous invasion of individual gliomas in three-dimensions to a degree beyond the limits of present medical imaging, including even microscopy, and makes clear why current therapies based on existing imaging techniques are inadequate and cannot be otherwise without other methods for detecting tumour cells in the brain. The model's estimate of the extent of tumourous invasion beyond that defined by standard medical imaging can be useful in more accurately planning therapy regimes as well as predicting sites of potential recurrence without waiting for reemergence on follow-up imaging.
UI - 11857311
AU - Perret AG; Duthel R; Fotso MJ; Brunon J; Mosnier JF
TI - Stromelysin-3 is expressed by aggressive meningiomas.
SO - Cancer 2002 Feb 1;94(3):765-72
AD - Department of Pathology, Hopital de Bellevue, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France.
BACKGROUND: Stromelysin-3 (ST3) that belongs to the metalloproteinase family is proposed to play a role in tumor invasion. The purpose of this work was to study the variation of ST3 expression in meningiomas. METHODS: Twenty atypical meningiomas were retrieved from the Pathology Department's files at Hopital de Bellevue, Saint-Etienne, France. They were compared with 20 benign meningiomas randomly selected from the same file. The tumors were classified using standard histologic criteria. Frozen sections of the tumors were immunostained for ST3 and MIB-1 to evaluate the proliferative activity of tumor cells. RESULTS: The study included 5 fibrous meningiomas, 10 transitional meningiomas, 20 syncitial meningiomas, 2 secretory meningiomas, 2 microcystic meningiomas, and 1 angiomatous meningioma. Stromelysin-3 was expressed within the stromal and neoplastic cells of only 1 benign meningioma and 13 atypical meningiomas. The MIB-1 proliferation index was significantly higher in the meningiomas expressing ST3 (Student t test: P < 0.001). The invasion of bone, muscle, and brain by meningiomas as well the recurrence were statistically correlated with their ST3 expression (Kruskal-Wallis nonparametric correlation test, P = 0.001 and P = 0.008, respectively). CONCLUSIONS: Stromelysin-3 might play an important role in the invasiveness of meningiomas. Therefore, considering, ST3 in association with evaluation of the MIB-1 proliferating index may be an useful tool to assess the behavior of meningiomas. Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10270
UI - 11850836
AU - Vortmeyer AO; Huang SC; Pack SD; Koch CA; Lubensky IA; Oldfield EH;
TI - Zhuang Z Somatic point mutation of the wild-type allele detected in tumors of patients with VHL germline deletion.
SO - Oncogene 2002 Feb 14;21(8):1167-70
AD - Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Building 10, Room 5D37, Bethesda, MD 20892, USA.
The majority of patients with Von Hippel-Lindau (VHL) disease are affected by a VHL germline mutation involving one copy of the VHL gene. Loss of heterozygosity of the second VHL allele can be consistently demonstrated in tumor tissue from these patients, suggesting that allelic deletion is a very early or even initiating event for tumorigenesis. Approximately 20% of VHL disease patients, however, exhibit germline deletion of one entire copy or at least a substantial part of the VHL gene. To investigate the nature of the "second genetic hit" in this patient population, we analysed two renal cell carcinomas and one CNS hemangioblastoma from three unrelated patients for genetic changes of the second copy of the VHL gene. All three tumors showed retention of one VHL allele by FISH. Single-strand conformation polymorphism and mutation analysis of microdissected tumor DNA revealed somatic point mutations of the wild-type VHL copies in each of the three tumors. The results indicate that the "two hit model" is equally applicable to patients with VHL germline mutation and VHL germline deletion. In contrast to tumors from patients with VHL germline mutation, however, point mutations of the wild-type allele can be detected in tumors from patients with VHL germline deletion.
UI - 11054516
AU - Do V; Gebski V; Barton MB
TI - The effect of waiting for radiotherapy for grade III/IV gliomas.
SO - Radiother Oncol 2000 Nov;57(2):131-6
AD - Division of Radiation Oncology, Westmead Hospital, Westmead, NSW 2145, Australia.
AIM: To determine the effect of waiting time for radiotherapy on the overall survival of patients with high-grade gliomas. METHODS: We examined records of patients with grade III/IV gliomas who were referred to radiotherapy after surgery or biopsy - ECOG <3, any age, radical intent or palliative intent with dose >50 Gy, no interstitial or radiosurgery boost. Waiting time was defined in two ways, time from biopsy to radiotherapy and time from presentation to radiotherapy department to start of radiotherapy. RESULTS: There were 182 patients in the study having a median survival of 8.5 months, with a median follow up of 10.5 months. The group comprised of 63 (35%) grade III and 119 (65%) grade IV gliomas. Median times and ranges from biopsy and presentation to treatment were 26 days (4-78 days) and 15 days (1-62 days), respectively. The median dose was 60 Gy in a median of 30 fractions over a median of 46 days. Tumour progression before and during radiotherapy occurred in seven patients (4%) and 19 patients (11%), respectively. One hundred and seventy-nine patients died of disease. The seven patients whose tumour progressed before radiotherapy were excluded from the analysis of prognostic variables. In a multivariate analysis the variables that were significantly associated with worse survival were older age, reduced dose and prolonged waiting time from presentation. The risk of death increased by 2% for each day of waiting for radiotherapy. CONCLUSION: The study showed longer waiting time from presentation at radiotherapy department to treatment to be a significant predictor of overall survival for patients with high-grade glioma.
UI - 11603814
AU - Przkora R; Meyer-Puttlitz B; Schmitt O; Berthold F; Nothen M; Krauss J;
TI - Tonn JC; von Deimling A; Wiestler OD; Pietsch T Analysis of the TSC2 gene in human medulloblastoma.
SO - Acta Neuropathol (Berl) 2001 Oct;102(4):380-4
AD - Department of Neuropathology, University of Bonn Medical Center, Germany.
Medulloblastoma (MB) represents the most frequent malignant brain tumor of childhood. Recent studies have shown that deregulation of developmental control genes may play an important role in its pathogenesis. Tuberous sclerosis is associated with hamartomas and cortical tubers, consisting of both glial and neuronal cellular components. MBs can also show markers of these lineages, raising the question of the potential involvement of TSC genes in these malignant tumors. Here we investigated tuberous sclerosis 2 (TSC2), one of the two genes responsible for tuberous sclerosis, in sporadic MBs. We analyzed MBs for allelic losses at the TSC2 locus and for the frequency of a polymorphism first described in gangliogliomas. Sixty-eight MBs were examined for this polymorphism located in intron 4, 3 base pairs 5' to the first coding nucleotide of exon 5. The distribution of the alleles was significantly different in MBs as compared to 208 control samples, (P=0.0017, Chi-square test). In MBs the frequency of the rare allele (A2) was 0.184 (18.4%), whereas in the control group it occurred in a frequency of 8.7%. Microsatellite analysis of the TSC2 region in 50 tumors did not identify allelic losses. TSC2 mRNA transcript was detectable via reverse transcription-PCR in all tumors as well as in normal cerebellum. Northern blot analysis of an MB cell line homozygous for the rare allele of the polymorphism and two other cell lines homozygous for the frequent allele revealed normal splicing patterns and normal expression levels of the TSC2 transcript. These findings may indicate that the presence of the rare TSC2 allele is associated with a predisposition for the development of MBs.
UI - 11760795
AU - Erdem E; Zimmerman RA; Haselgrove JC; Bilaniuk LT; Hunter JV
TI - Diffusion-weighted imaging and fluid attenuated inversion recovery imaging in the evaluation of primitive neuroectodermal tumors.
SO - Neuroradiology 2001 Nov;43(11):927-33
AD - Department of Radiology, The Children's Hospital of Philadelphia, PA 19104, USA.
The aim of our study was to determine whether fluid-attenuated inversion recovery (FLAIR) imaging and diffusion-weighted imaging (DWI) would be helpful in characterizing primitive neuroectodermal tumors (PNET) from other pediatric brain tumors. We expected that the compact cellular nature and the relatively small extracellular space of this tumor would affect the signal intensity on both pulse sequences relative to the more sparsely cellular glial tumors that have larger extracellular spaces. Eighteen pediatric patients with PNET were examined on a 1.5 T MRI with routine imaging plus FLAIR and compared with 28 patients with nonPNET. DWI was also performed in 7 PNET and 18 non-PNET. Seventyeight percent of PNET were isointense to gray matter on FLAIR while 82% of non-PNET were hyperintense and only one was isointense (3%). Diffusion was abnormally restricted in all 7 PNET examined (100%) but was restricted in non-PNET in only 1 out of 18 (6%) patients who had DWI. The differences in the histologic architecture between PNET and non-PNET are reflected in both FLAIR imaging and in DWI.
UI - 11760804
AU - Brunereau L; Leveque C; Bertrand P; Tranquart E; Cordoliani Y; Rouleau
TI - P; Labauge P Familial form of cerebral cavernous malformations: evaluation of gradient-spin-echo (GRASE) imaging in lesion detection and characterization at 1.5 T.
SO - Neuroradiology 2001 Nov;43(11):973-9
AD - Service de Radiologie Adultes Bretonneau, CHRU Tours, France. firstname.lastname@example.org
The purpose of this study was to evaluate the turbo gradient-spin-echo sequence (GRASE) in the MR assessment of the familial form of cerebral cavernous malformations (CCM). Twenty-one patients (15 male, six female) aged from 21 to 68 years (mean = 42.2 years) were prospectively examined with cerebral MR imaging, including T2-weighted turbo gradient-spin-echo (TGSE), turbo spin-echo (TSE) and gradient-echo (GRE) sequences. All sequences were performed in the same plane, the same matrix and the same field of view and were analyzed for signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), susceptibility effects, number of CCM, size of CCM and signal of CCM. It was found that SNR and CNR in the TGSE sequence were significantly inferior to those in both TSE and GRE sequences. TGSE and TSE sequences were significantly less prone to susceptibility effects than the GRE sequence. The sensitivity of TGSE and TSE sequences in detecting CCM was significantly lower than that of the GRE sequence. TGSE and TSE sequences provided comparable information about CCM size and signal. It was concluded that GRASE imaging was less sensitive than the GRE sequence in the detection of CCM and provided information similar to that yielded by the TSE sequence in the characterization of lesions, but with a higher number of artifacts. GRASE imaging cannot therefore replace TSE or GRE sequences in the MR evaluation of the familial form of CCM.
UI - 11826027
AU - Shinar Y; Ben-Zeev B; Brand N; Lahat H; Gross-Zur V; MacGregor D; Bahan
TI - T; Kastner DL; Pras E A common ancestral haplotype in carrier chromosomes from different ethnic backgrounds in vacuolating megalencephalic leucoencephalopathy with subcortical cysts.
SO - J Med Genet 2002 Jan;39(1):54-7
UI - 11830784
AU - Eisner W; Steude U; Burtscher J; Bise K
TI - Surgery of lesions in the motor strip combining a stereotactically-guided mini-craniotomy with electrophysiological mapping of the motor cortex.
SO - Minim Invasive Neurosurg 2001 Dec;44(4):230-3
AD - Department of Neurosurgery, Leopold Franzens University, Innsbruck, Austria. email@example.com
The removal of space-occupying lesions in the sensori-motor cortex carries a considerable risk of postoperative palsy. Therefore subcortical lesions located in the sensori-motor strip are often considered to be inoperable. Treatment options are stereotactic biopsy and radiosurgery beside radiological control examinations without surgery or surgery with a higher risk of postoperative deficits. The following article focusses on a combined approach involving a stereotactically guided and electrophysiologically controlled surgery. The instruments used (stereotactical system and electric stimulator) are available in almost every neurosurgical department in the Western and Eastern world and had been the first navigation systems in the human brain.
UI - 11788993
AU - Hanash SM; Bobek MP; Rickman DS; Williams T; Rouillard JM; Kuick R;
TI - Puravs E Integrating cancer genomics and proteomics in the post-genome era.
SO - Proteomics 2002 Jan;2(1):69-75
AD - University of Michigan Medical Center, Ann Arbor, MI 48109-0656, USA. firstname.lastname@example.org
The dawn of the post-genome era is leading to extraordinary opportunities in biomedicine. Our group has embarked on a major effort to integrate genomics, transcriptomics and proteomics for the profiling of tumor tissues, an approach we refer to as operomics. Our major goals are the molecular classification of tumors and the identification of markers for the early detection of cancer. Molecular analyses of tumors rely on microdissected tissues, which are simultaneously investigated for genomic, transcriptomic and proteomic changes. Genomic alterations in tumor cells being investigated include deletions, amplifications and methylation changes across the entire genome as well as point mutations in specific genes. Expression analysis at the RNA level is being undertaken using oligonucleotide and cDNA based microarrays. An important aspect of our approach is the large-scale identification and quantitative analysis of tumor proteins in whole cell lysates as well as in protein compartments. Protein separation strategies include two-dimensional polyacrylamide gel electrophoresis and liquid chromatography. Specific protein subsets, of interest include membrane proteins, secreted proteins and antigenic proteins as sources of biomarkers for early detection of cancer. Our current approach is illustrated with findings stemming from our studies of human gliomas.
UI - 11721860
AU - Pitzalis S; Di Russo F
TI - Spatial anisotropy of saccadic latency in normal subjects and brain-damaged patients.
SO - Cortex 2001 Sep;37(4):475-92
AD - Department of Psychology, University of Rome La Sapienza, Italy.
In the present study, reaction time of oblique and orthogonal saccades was investigated in normal subjects and in two groups of patients with right (RBD) and left (LBD) vascular cerebral lesions and no signs of spatial neglect. Clear altitudinal effects were present in each group of subjects: saccadic latencies were longer in the lower than in the upper part of the visual field for both orthogonal and oblique saccades. Asymmetry along the horizontal meridian was present only in case of right hemisphere damage. This supports the view that a lesion in the right hemisphere causes a greater deficit of visual-spatial processing than a left hemisphere lesion. A cerebral lesion in the right and/or left hemisphere produces a general slowing in the saccadic latency and a general reduction in the accuracy of saccades with respect to normal subjects performance. Further, it seems that making saccades in oblique direction reduces the general saccade efficiency.
UI - 11807556
AU - Pomeroy SL; Tamayo P; Gaasenbeek M; Sturla LM; Angelo M; McLaughlin ME;
TI - Kim JY; Goumnerova LC; Black PM; Lau C; Allen JC; Zagzag D; Olson JM; Curran T; Wetmore C; Biegel JA; Poggio T; Mukherjee S; Rifkin R; Califano A; Stolovitzky G; Louis DN; Mesirov JP; Lander ES; Golub TR Prediction of central nervous system embryonal tumour outcome based on gene expression.
SO - Nature 2002 Jan 24;415(6870):436-42
AD - Division of Neuroscience, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. email@example.com
Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis.
UI - 11857353
AU - Castino R; Pace D; Demoz M; Gargiulo M; Ariatta C; Raiteri E; Isidoro C
TI - Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas.
SO - Int J Cancer 2002 Feb 20;97(6):775-9
AD - Dipartimento di Scienze Mediche, Laboratorio di Patologia Molecolare, Universita A. Avogadro, Novara, Italy.
Neuroblastoma is the most common type of cancer in infants. In children this tumor is particularly aggressive; despite various new therapeutic approaches, it is associated with poor prognosis. Given the importance of endosomal-lysosomal proteolysis in cellular metabolism, we hypothesized that inhibition of lysosomal protease would impact negatively on neuroblastoma cell survival. Treatment with E-64 or CA074Me (2 specific inhibitors of cathepsin B) or with pepstatin A (a specific inhibitor of cathepsin D) was cytotoxic for 2 neuroblastoma cell lines having different degrees of malignancy. Cell death was associated with condensation and fragmentation of chromatin and externalization of plasma membrane phosphatidylserine, 2 hallmarks of apoptosis. Concomitant inhibition of the caspase cascade protected neuroblastoma cells from cathepsin inhibitor-induced cytotoxicity. These data indicate that prolonged inhibition of the lysosomal proteolytic pathway is incompatible with cell survival, leading to apoptosis of neuroblastoma cells, and that the cathepsin-mediated and caspase-mediated proteolytic systems are connected and cooperate in the regulation of such an event. Since modern antitumor chemotherapy is aimed at restoring the normal rate of apoptosis in neoplastic tissues, the demonstration that endosomal-lysosomal cathepsins are involved in this process may constitute a basis for novel strategies that include cathepsin inhibitors in the therapeutic regimen. Copyright 2001 Wiley-Liss, Inc.
UI - 11857361
AU - Paunu N; Pukkala E; Laippala P; Sankila R; Isola J; Miettinen H; Simola
TI - KO; Helen P; Helin H; Haapasalo H Cancer incidence in families with multiple glioma patients.
SO - Int J Cancer 2002 Feb 20;97(6):819-22
AD - Department of Pathology, Tampere University Hospital, Tampere, Finland.
Twenty-four Finnish families with 2 or more glioma patients were identified through questionnaires sent to 369 consecutive glioma patients receiving surgery at Tampere University Hospital during 1983-94. To explore whether unusual cancer susceptibility is involved, the cancer risk of 2,664 family members was estimated using population-based data from the Finnish Cancer Registry. Among the total cohort of relatives, 88 cancers were observed during 1953-97. The overall cancer risk among 12 families with juvenile onset gliomas was significantly decreased (standardized incidence ratio [SIR] 0.6, 95% confidence interval [CI]: 0.4-0.9). Among 12 families with adult onset gliomas, the overall cancer risk was equal to that of the reference population (SIR 1.1, 95% CI: 0.8-1.4) whereas the risk of skin melanoma (SIR 4.0, 95% CI: 1.5-8.8) and meningioma (SIR 5.5, 95% CI: 1.1-16) were significantly increased. Several other tumors, including those associated with neurofibromatosis 1 and 2, tuberous sclerosis and Li-Fraumeni and Turcot syndromes were surveyed, but no elevated risks were observed. In conclusion, the presence of meningiomas and skin melanomas in glioma families may indicate a novel association as a cancer susceptibility trait. Copyright 2001 Wiley-Liss, Inc.
UI - 11784893
AU - Pereira RA; Koifman S
TI - [Association between dietary factors and brain tumors in adults: a review]
SO - Cad Saude Publica 2001 Nov-Dec;17(6):1313-34
AD - Instituto de Nutricao Josue de Castro, Centro de Ciencias da Saude, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-590, Brasil. firstname.lastname@example.org
This paper reviews the scientific literature published from 1986 to 1999 assessing the relationship between dietary factors and brain tumors in adults. The work aimed to describe the estimated associations and to discuss methodological aspects that might influence the results. The studies generally appear to show a moderate association between dietary factors and brain tumors. There is evidence that N-nitroso compounds enhance the risk of developing such tumors and that consumption of fruits and vegetables can inhibit them. Use of proxies in most of the studies may have introduced bias, thereby contributing to some inconsistent observations. Epidemiological research on diet and brain tumors should consider other components of food besides N-nitroso compounds. It is important to carefully assess exposure periods and to prevent bias related to control selection and recall.
UI - 11678426
AU - Izumoto S; Ohnishi T; Kanemura H; Arita N; Maruno M; Moriuchi T; Suzuki
TI - S; Yoshimine T PTEN mutations in malignant gliomas and their relation with meningeal gliomatosis.
SO - J Neurooncol 2001 May;53(1):21-6
AD - Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Japan. email@example.com
A putative tumor suppressor, the PTEN gene at chromosome 10q23. was identified and found to be mutated in many different human tumors. PTEN was recently found to be also involved in focal cell adhesion and cell migration. To identify the role of PTEN gene in malignant gliomas. we used PCR-SSCP and direct sequencing methods to examine 44 malignant gliomas comprising 29 cases without and 15 cases with meningeal gliomatosis. In malignant gliomas without meningeal gliomatosis, 2/29 (7%) of the cases showed alteration of the PTEN gene. In contrast, 5/15 (33%) of malignant gliomas with meningeal gliomatosis cases showed this alteration. These findings indicate that PTEN gene mutation contributes not only to the neoplastic evolution in gliomas but also to the meningeal dissemination of glioma cells.
UI - 11678428
AU - Korones DN; Butterfield R; Meyers SP; Constine LS
TI - The role of surveillance magnetic resonance imaging (MRI) scanning in detecting recurrent brain tumors in asymptomatic children.
SO - J Neurooncol 2001 May;53(1):33-8
AD - Department of Pediatrics, University of Rochester School of Medicine and Dentistry, New York, USA. firstname.lastname@example.org
BACKGROUND: There is controversy regarding the utility of routine surveillance scanning for asymptomatic children with brain tumors. Although the role of CT or magnetic resonance imaging (MRI) scanning in this setting has been examined in several studies, none have focused on children followed exclusively by MRI. The purpose of this study was to determine how often recurrent brain tumors are detected by routine MRI surveillance in asymptomatic children. METHODS: The medical records of all children with brain tumors treated at Children's Hospital at Strong from 1990-1999 were reviewed. Recurrence was defined as an increase in size of the tumor on MRI scan. Astrocytomas and gangliogliomas were classified as low-grade tumors; high-grade astrocytomas, medulloblastomas, and ependymomas were classified as high-grade tumors. RESULTS: Of the 112 evaluable children with brain tumors during this time period, 46 (41%) suffered an MRI-documented recurrence. Of these 46 patients, 13 (28%) had low-grade tumors and 33 (72%) had high-grade tumors. Twenty-seven of the 46 recurrences (59%) occurred in asymptomatic children. Ten of the 13 children (77%) with recurrent low-grade tumors were asymptomatic compared to 17 of 33 children (52%) with recurrent high-grade tumors (p = 0.18). The median survival from time of recurrence for the symptomatic children was seven months, while the median survival from time of recurrence for the asymptomatic children has not yet been reached (p = 0.025). When the analysis was confined to children with high-grade tumors, there was no difference in median survival from the time of recurrence for symptomatic versus asymptomatic children (5 mo. versus 7 mo.) (p = 0.25). The frequency of detection of recurrences by surveillance scanning in asymptomatic children was 4.2% (one recurrence detected per 24 surveillence MRI scans). CONCLUSION: The majority of recurrent brain tumors are detected by MRI surveillence in asymptomatic children. However, asymptomatic recurrences were detected in only a small proportion of surveillance scans and had no impact on survival in children with high-grade tumors.
UI - 11678430
AU - Diete S; Treuheit T; Dietzmann K; Schmidt U; Wallesch CW
TI - Sex differences in length of survival with malignant astrocytoma, but not with glioblastoma.
SO - J Neurooncol 2001 May;53(1):47-9
AD - Department of Neurology, Otto-von-Guericke-University, Magdeburg, Germany.
In a retrospective analysis based on a malignant glioma databank, we describe effects of age, sex and diagnosis upon survival in patients with malignant cerebral glioma with a pre-treatment Karnofsky-index of 60 or more. All patients had been treated with 55-60Gy radiotherapy and nitrosurea-based adjuvant chemotherapy. We found an age-dependent sex effect upon survival in grade III astrocytoma patients, but not with glioblastoma.
UI - 11786566
AU - Samnick S; Bader JB; Hellwig D; Moringlane JR; Alexander C; Romeike BF;
TI - Feiden W; Kirsch CM Clinical value of iodine-123-alpha-methyl-L-tyrosine single-photon emission tomography in the differential diagnosis of recurrent brain tumor in patients pretreated for glioma at follow-up.
SO - J Clin Oncol 2002 Jan 15;20(2):396-404
AD - Department of Nuclear Medicine, Saarland University Medical Center, Homburg/Saar, Germany. email@example.com
PURPOSE: To assess the clinical potential of iodine-123-alpha-methyl-L-tyrosine (IMT) and single-photon emission tomography (SPET) in the differential diagnosis of recurrences in patients pretreated for gliomas at follow-up. PATIENTS AND METHODS: Seventy-eight patients were examined after primary therapy over 36 months. Histopathologic diagnoses of all patients was known at first treatment; magnetic resonance and/or computed tomography examination was performed in addition to IMT-SPET. Cerebral SPET images were acquired 20 minutes after intravenous application of 190 +/- 10 MBq of IMT. SPET images were classified as positive or negative for recurrent tumor visually and by calculating the ratios between tracer accumulation in the lesion and the unaffected contralateral regions of reference using region of interest. Final diagnoses were based on prospective clinicopathologic findings obtained independently of IMT-SPET. RESULTS: IMT-SPET detected all high-grade recurrent gliomas (grade 4; sensitivity, 100%). A difference could be demonstrated in grade 2 and 3 recurrences (sensitivity, 84% and 92%, respectively). Moreover, benign posttherapeutic lesions (postoperative scars, radiation necrosis) were correctly diagnosed as negative for tumor recurrence. In general, IMT uptake in grade 2 (1.45 +/- 0.24) was significantly lower than that in grades 3 (1.70 +/- 0.41) and 4 (1.88 +/- 0.32). However, it was difficult to evaluate tumor grade only from the IMT accumulation in individual cases. CONCLUSION: IMT-SPET seems highly useful for detecting and delineating recurrent gliomas and differentiating between benign posttherapeutic lesions and malignant tumor tissue. It may be a valuable clinical tool to diagnose recurrences in patients pretreated for gliomas at follow-up. However, it showed limitations in determining histologic tumor grade.
UI - 11844831
AU - Chakravarti A; Noll E; Black PM; Finkelstein DF; Finkelstein DM; Dyson
TI - NJ; Loeffler JS Quantitatively determined survivin expression levels are of prognostic value in human gliomas.
SO - J Clin Oncol 2002 Feb 15;20(4):1063-8
AD - Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA. firstname.lastname@example.org
PURPOSE: Survivin is a novel antiapoptotic gene that has been recently cloned and characterized. Its expression has been found to be of prognostic significance in several tumor types. This is the first study on the prognostic significance of survivin expression in human gliomas. MATERIALS AND METHODS: We used quantitative Western blot analysis with densitometry to determine survivin protein expression levels in 92 glioma cases for which frozen tissue was available for analysis. Survivin positivity and expression levels were correlated with histopathologic features of the tumors, apoptosis (as measured by cleaved, or activated, caspase 3 levels), and clinical outcome. RESULTS: Survivin expression has clear prognostic value in human gliomas. Patients with detectable survivin expression had significantly shorter overall survival times (P <.0001) compared with those without detectable expression when all glioma patients were considered. Although glioblastoma multiforme (GBM) patients had significantly higher rates of survivin positivity and higher levels of survivin expression (P <.0001) than their non-GBM counterparts, the prognostic value of survivin expression seemed to be independent of histology alone. Survivin-positive GBM patients had significantly shorter overall survival times compared with survivin-negative GBM patients (P <.0001). Likewise, survivin-positive non-GBM patients had shorter survival times compared with survivin-negative non-GBM patients (P =.029). Furthermore, increasing levels of survivin expression significantly correlated with reduced survival times when all glioma patients were considered, and markedly so for GBM patients (P <.0001). Increasing survivin levels significantly correlated with reduced expression of cleaved caspase 3, indicating its association with antiapoptotic activity. CONCLUSION: Survivin positivity and protein expression levels, as determined quantitatively, are of significant prognostic value in human gliomas and seem to be associated with reduced apoptotic capacity of these tumors.
UI - 11878577
AU - Stavrou T; Bromley C M; Nicholson H S; Byrne J; Packer R J; Goldstein A
TI - M; Reaman G H Prognostic factors and secondary malignancies in childhood medulloblastoma.
SO - J Pediatr Hematol Oncol 2001 Oct;23(7):431-6
AD - Department of Hematology-Oncology, Children's National Medical Center, Washington, DC, USA.
PURPOSE: Little is known of the outcome of long-term survivors of childhood medulloblastoma, one of the most common pediatric malignancies. To determine the potential for secondary malignancies, a retrospective outcome evaluation in 88 consecutive cases of childhood medulloblastoma was performed. PATIENTS AND METHODS: The records of all patients with childhood medulloblastoma diagnosed at Children's National Medical Center in Washington, DC from 1969 through 1997 were reviewed. RESULTS: The median follow-up time was 92 months (range 6-257 months). Overall survival was 59% at 5 years and 52% at 10 years. Univariate analysis showed that age at diagnosis, extent of surgical resection, presence of metastatic disease (M stage), ventriculoperitoneal shunt placement within 30 days from diagnosis, posterior fossa radiation therapy dose, and adjuvant chemotherapy significantly affected survival. Although based on small numbers, the risk of second neoplasms was significantly increased in this cohort. Multiple basal cell carcinomas developed in the areas of radiation therapy in two patients; these patients also had nevoid basal cell carcinoma syndrome (NBCCS) diagnosed. One other patient died of glioblastoma multiforme 8 years after treatment of medulloblastoma. A meningioma developed in another patient 10 years after radiation therapy. CONCLUSION: As survival of medulloblastoma patients improves, increased surveillance regarding secondary malignancies is required, especially because radiation-induced tumors may occur many years after treatment. These two cases of NBCCS also illustrate the importance of considering the concomitant diagnosis of NBCCS in young patients with medulloblastoma. In those patients, alternative therapy should be considered to minimize radiation therapy-related sequelae.
UI - 11826360
AU - Wyatt-Ashmead J; Kleinschmidt-DeMasters B; Mierau GW; Malkin D; Orsini
TI - E; McGavran L; Foreman NK Choroid plexus carcinomas and rhabdoid tumors: phenotypic and genotypic overlap.
SO - Pediatr Dev Pathol 2001 Nov-Dec;4(6):545-9
AD - Pathology Department, The Children's Hospital, 1056 East 19th Avenue B120, Denver, CO 80218, USA.
Five of six poorly differentiated choroid plexus carcinomas identified at our institution contained cells displaying a rhabdoid phenotype. Immunoperoxidase stains showed focal positivity for cytokeratin, epithelial membrane antigen, glial fibrillary acidic protein, S100, and vimentin. The MIB-1 proliferative index ranged from 7.0% to 27.1%. All six tumors were p53 positive. Only the one child with Li-Fraumeni syndrome had a p53 germline mutation. Electron microscopy verified choroid plexus differentiation and the co-existence of rhabdoid cells. Of the five studied, four had deletions of chromosome 22 [three with monosomy 22 and one with del(22)(q12)]. Thus, there was a phenotypic and genotypic overlap between choroid plexus carcinomas and rhabdoid tumors.