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Back To Vidyya Abstracts October 2000:

The Diagnosis, Histopathology And Pathogenesis Of Brain Tumors

The abstracts below are those that have been added to the CANCERLIT database for October, 2000 regarding the diagnosis, histopathology and pathogenesis of brain tumors. Every effort has been made to ensure the search strategy used produces the most accurate results.

Does (99m)Tc-Sestamibi in high-grade malignant brain tumors reflect blood-brain barrier damage only?

Unique Identifier: 20336942

Author: Staudenherz A; Fazeny B; Marosi C; Nasel C; Hoffmann M; Puig S; Killer M; Leitha T

Source: Neuroimage 2000 Jul;12(1):109-11

Address: Department of Nuclear Medicine, University Hospital of Vienna-AKH, Waehringer-Guertel 18-20, A-1090, Vienna, Austria.

    (99m)Tc-Sestamibi (MIBI) has been successfully applied in recurrent glioblastoma. The aim of this study was to evaluate the incremental diagnostic information of MIBI as a tumor-avid radiopharmaceutical compared with (99m)Tc-pertechnetate ((99m)Tc) as sole indicator of the integrity of the blood-brain barrier. Twenty-five patients with confirmed recurrent brain tumors were included. MIBI SPET was performed 10 min after injection of 555 MBq MIBI intravenously with a triple-headed gamma camera equipped with LE-UHR-PAR collimators over 360 degrees (3 degrees /step) and stored in a 128(2) matrix. Identical acquisition parameters were used for (99m)Tc SPET, which was acquired 3 h after injection of 740 MBq (99m)Tc. Normalized tumor uptake (NU) was calculated from attenuation-corrected transaxial slices. In addition, tumor/plexus, tumor/nasopharynx, and tumor/parotid gland ratios were assessed in both studies. No statistically significant differences were detected for the mean NU of tumor tissue with MIBI (0.26 +/- 0.10) and (99m)Tc (0.39 +/- 0. 33) and for the tumor/nasopharynx and tumor/parotid gland ratios; only the tumor/plexus ratio was significantly higher for (99m)Tc than for MIBI (p < 0.05). In conclusion, our data indicate that MIBI scintigraphy in brain tumors at 10 min postinjection reveals no additional visual information over that provided by the conventional (99m)Tc-pertechnetate brain scan, and in addition, tracer retention reflects primarily blood-brain barrier damage. Copyright 2000 Academic Press.

Identification of PATCHED mutations in medulloblastomas by direct sequencing.

Unique Identifier: 20334946

Author: Dong J; Gailani MR; Pomeroy SL; Reardon D; Bale AE

Source: Hum Mutat 2000 Jul;16(1):89-90

Address: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA.

    Medulloblastoma is the most common malignant embryonic tumors of the central nervous system. The nevoid basal cell carcinoma syndrome (NBCCS), which is caused by mutations of PTCH gene on chromosome 9q22, accounts for about 2% of all medulloblastomas. Previous studies of PTCH in sporadic medulloblastomas using single strand conformational polymorphism (SSCP) detected mutations in about 10% of the tumors. In this study, we directly sequenced the PTCH gene in 20 sporadic medulloblastoma DNA samples. A nonsense mutation (Q694X) and a splice site alteration (2875+1G>A) were identified in two of the samples. The mutations are predicted to result in a truncated PTCH protein and aberrant splicing, respectively. In both cases, only the mutant alleles were identified, indicating that the mutations were associated with loss of the wild-type PTCH allele in the tumor cells. Several novel variants, including 1653T>C, 1672C>T, and 2292C>T, were also found in these tumor samples. One of the two mutations detected in this study had been missed by SSCP, suggesting that the true rate of PTCH mutations in sporadic medulloblastomas may be underestimated by SSCP screening. Nevertheless, the frequency of mutations in this study did not differ from previous reports. Copyright Wiley-Liss, Inc.

Common brain tumours in children: diagnosis and treatment.

Unique Identifier: 20391178

Author: Bouffet E

Source: Paediatr Drugs 2000 Jan-Feb;2(1):57-66

Address: Children's Department, Royal Marsden Hospital NHS Trust, Sutton, England.

    Dramatic advances have been made in the diagnosis of childhood brain tumours thanks to the development of modern imaging techniques. Advances in the management of these tumours have, however, been slow because of the limitations of an aggressive surgical approach and the risks associated with radiotherapy on the growing, and still immature, brain. The role of chemotherapy remains ill-defined in many patients with brain tumours and large variations in practice exist between groups and institutions. This article provides an overview of the most common paediatric brain tumours, mainly gliomas, medulloblastomas, ependymomas, germ-cell tumours and craniopharyngiomas. Considerations regarding the management of brain tumours in very young children are also examined. The long term outcome for children with brain tumours is discussed, stressing the need to focus on quality of life for survivors.

Intracranial neoplasms in Ibadan, Nigeria.

Unique Identifier: 20401126

Author: Olasode BJ; Shokunbi MT; Aghadiuno PU

Source: East Afr Med J 2000 Jan;77(1):4-8

Address: Department of Pathology, University College Hospital, Ibadan, Nigeria.

    OBJECTIVE: To determine the pattern of histopathological variants of intracranial neoplasms, relative distribution of the variants in the age groups and also to determine the gender differences that exist in these tumours. DESIGN: Case control study. SETTING: Department of Pathology, University College Hospital, Ibadan, Nigeria. PATIENTS: Two hundred and ten histologically confirmed cases of intracranial neoplasms seen during eleven-year period (1980 to 1990) were analysed. INTERVENTIONS: Slides of tumours stained with haematoxylin and eosin, reticulin and phosphotungstic acid haematoxylin. RESULTS: Two hundred and ten intracronial neoplasms comprising 172 primary and 48 secondary neoplasms were seen. One hundred and thirty five neoplasms occurred in adults and 75 in children. There was no gender difference, the ratio being 1:1. Gliomas accounted for the largest group of tumours followed by metastases to the brain. Of the gliomas, astrocytoma was the commonest. Craniopharyngiomas were found to be common in children. Germ cell tumours were found to be uncommon. CONCLUSION: Gliomas are the commonest group of intracranial neoplasms in both adults and children. This is followed by metastatic tumours. Tumours of the sella turcica are predominantly found in children. Involvement of the brain in disseminated Burkitt's lymphomas is predominantly found in Africans as the Burkitt's tumour is uncommon in non Africans.

Cytogenetic analysis of gemistocytic cells in gliomas.

Unique Identifier: 20406590

Author: Kros JM; Waarsenburg N; Hayes DP; Hop WC; van Dekken H

Source: J Neuropathol Exp Neurol 2000 Aug;59(8):679-86

Address: Department of Pathology, University Hospital Rotterdam-Dijkzigt, The Netherlands.

    Gemistocytes are glial cells characterized by voluminous, eosinophilic cytoplasm and a peripherally positioned, often flattened nucleus. Gemistocytes, usually present in anoxic-ischemic brains, are regularly encountered in glial neoplasms. The presence of gemistocytes in gliomas has been associated with an unfavorable clinical course, notwithstanding the low proliferative potential of these cells. It is not known whether gemistocytes residing in gliomas are dormant tumor cells, or alternatively, represent interspersed reactive glial cells. Whereas gemistocytic astrocytomas have been subject to various genetic investigations, no genomic analysis comparing individual cells in gliomas has been reported so far. In the present study, 3 astrocytomas, 3 oligodendrogliomas, and 3 mixed oligoastrocytomas, all harboring gemistocytic cells, were genetically analyzed by DNA in situ hybridization to paraffin-embedded, formalin-fixed tissue samples with optimal preservation of cellular morphology. To this end, probes for the centromeric regions of chromosome 7 and 10, known to show copy number aberrations in gliomas, were used. In addition, probes for centromeric regions of chromosomes 1 and 17 were used for the ploidy status of the tumors. The spot counts for the various chromosomes were statistically compared. Gains of chromosome 7 were found in 1 anaplastic astrocytoma, 1 anaplastic oligodendroglioma, and 1 anaplastic oligoastrocytoma. Loss of chromosome 10 was seen in 2 anaplastic astrocytomas, in 1 anaplastic oligodendroglioma, and in 1 anaplastic oligoastrocytoma. In 3 cases, significant differences in spot distributions between gemistocytes and non-gemistocytes were found, but the other cases showed no difference in spot distribution. It is concluded that, although many gemistocytic cells in gliomas may be considered reactive cells, in a subset of tumors, part of the gemistocytic cells should be considered neoplastic.

Efficacy of neuroradiological imaging, neurological examination, and symptom status in follow-up assessment of patients with high-grade gliomas.

Unique Identifier: 20383829

Author: Galanis E; Buckner JC; Novotny P; Morton RF; McGinnis WL; Dinapoli R; Schomberg P; O'Fallon JR

Source: J Neurosurg 2000 Aug;93(2):201-7

Address: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.

    OBJECT: It is standard practice for the oncological follow-up of patients with brain tumors (especially in the setting of clinical trials) to include neurological examination and neuroradiological studies such as computerized tomography (CT) or magnetic resonance (MR) imaging in addition to evaluation of the patients' symptomatology and performance score. The validity of this practice and its impact on the welfare of patients with high-grade gliomas has not been adequately assessed. The purpose of this study is to provide such an assessment. METHODS: The authors studied 231 similarly treated patients who were participating in three prospective North Central Cancer Treatment Group or Mayo Clinic trials who developed progressive disease during follow up. According to the protocol, the symptom status, performance score, results of neurological examination, and CT or MR status were recorded prospectively in each patient at each evaluation (every 6-8 weeks). At progression, 177 (77%) of 231 patients experienced worsening of their baseline symptoms or they developed new ones. In the remaining 54 asymptomatic patients (23%), neuroradiological imaging revealed the progression. Asymptomatic progression was more likely to be detected on MR imaging compared with CT studies (p < 0.01). In no asymptomatic patient was progression detected on neurological examination alone. The median survival time after tumor recurrence was 13.3 weeks in symptomatic patients compared with 41.7 weeks in the asymptomatic group (p < 0.0001). Asymptomatic patients were more aggressively treated, with surgery (p < 0.0001) and second-line chemotherapy (p < 0.0002). Multivariate analysis of survival time following first progression by using both classification and regression trees and Cox models showed that treatment at recurrence was the most important prognostic variable. CONCLUSIONS: Symptoms are the most frequent indicators of progression in patients with high-grade gliomas (77%). All asymptomatic progressions were detected on neuroradiological studies; MR imaging was more likely than CT scanning to reveal asymptomatic recurrences. Survival after disease progression was significantly longer in asymptomatic patients and could be related both to treatment following progression and to other favorable prognostic factors such as performance score.

Wild-type p53-dependent etoposide-induced apoptosis mediated by caspase-3 activation in human glioma cells.

Unique Identifier: 20383841

Author: Yin D; Tamaki N; Kokunai T

Source: J Neurosurg 2000 Aug;93(2):289-97

Address: Department of Neurosurgery, Kobe University School of Medicine, Japan.

    OBJECT: In an attempt to understand the roles of several apoptosis-related genes in human glioma cells, the authors investigated the relationship of wild-type p53, interleukin-1beta-converting enzyme (ICE), caspase-3 (CPP32), bax, and bcl-2 to the apoptotic response of three glioma cell lines after treatment with etoposide. METHODS: A human glioma cell line (U-87MG) that expresses wild-type p53, one that expresses mutant p53 (T-98G), and a T-98G derivative (T-98G/p53) that was transfected with a wild-type p53 expression vector (pCDM8-p53/neo) were used. Cell growth inhibition in response to etoposide was quantified using a modified methylthiazol tetrazolium colorimetric assay. Induction of apoptosis was evaluated using Hoechst 33258 staining and a DNA fragmentation assay. To study the expression of the apoptosis-related proteins and messenger RNAs in the three glioma cell lines, Western blotting and polymerase chain reaction were performed. A caspase assay and Western blot analysis were used to assess CPP32 and ICE protease activity. A CPP32 inhibition assay was used to determine whether a specific CPP32 inhibitor, DEVD-CHO, affects the apoptosis induced by etoposide in malignant glioma cells. Etoposide significantly inhibited the growth of U-87MG and T-98G/p53 cells in a dose-dependent manner compared with the growth of the T-98G cells. Treatment with low concentrations of etoposide resulted in the increased expression of wild-type p53; it also initiated CPP32 activity and induced apoptosis in the U-87MG cells. Apoptosis was not induced in T-98G cells at low concentrations of etoposide, although it was induced at high concentrations. Furthermore, low concentrations of etoposide also induced apoptosis in the T-98G/p53 cells by enhancing the expression of transfected wild-type p53, decreasing the expression of bcl-2, and activating CPP32 activity. However, etoposide did not alter the expression of bax and did not initiate ICE activity in these three glioma cell lines. Etoposide-induced apoptosis can be suppressed by the CPP32 inhibitor DEVD-CHO. CONCLUSIONS: These findings indicate that wild-type p53, CPP32, and bcl-2 may mediate apoptosis induced by etoposide. Forced expression of wild-type p53 increases etoposide cytotoxicity in human glioma cells by inducing apoptosis and may have important therapeutic implications.

Gene amplification in PNETs/medulloblastomas: mapping of a novel amplified gene within the MYCN amplicon.

Unique Identifier: 20341809

Author: Fruhwald MC; O'Dorisio MS; Rush LJ; Reiter JL; Smiraglia DJ; Wenger G; Costello JF; White PS; Krahe R; Brodeur GM; Plass C

Source: J Med Genet 2000 Jul;37(7):501-9

Address: Division of Pediatric Hematology and Oncology, The Ohio State University and the Comprehensive Cancer Center, Columbus 43210, USA.

    OBJECTIVES: The pathological entity of primitive neuroectodermal tumour/medulloblastoma (PNET/MB) comprises a very heterogeneous group of neoplasms on a clinical as well as on a molecular level. We evaluated the importance of DNA amplification in medulloblastomas and other primitive neuroectodermal tumours (PNETs) of the CNS. METHOD: Restriction landmark genomic scanning (RLGS), a method that allows the detection of low level amplification, was used. RLGS provides direct access to DNA sequences circumventing positional cloning efforts. Furthermore, we analysed several samples by CGH. DESIGN: Twenty primary medulloblastomas, five supratentorial PNETs, and five medulloblastoma cell lines were studied. RESULTS: Although our analysis confirms that gene amplification is generally a rare event in childhood PNET/MB, we found a total of 17 DNA fragments that were amplified in seven different tumours. Cloning and sequencing of several of these fragments confirmed the previous finding of MYC amplification in the cell line D341 Med and identified novel DNA sequences amplified in PNET/MB. We describe for the first time amplification of the novel gene, NAG, in a subset of PNET/MB. Despite genomic amplification, NAG was not overexpressed in the tumours studied. We have determined that NAG maps less than 50 kb 5' of DDX1 and approximately 400 kb telomeric of MYCN on chromosome 2p24. CONCLUSION: We found a similar but slightly higher frequency of amplification than previously reported. We present several DNA fragments that may belong to the CpG islands of novel genes amplified in a small subset of PNET/MB. As an example we describe for the first time the amplification of NAG in the MYCN amplicon in PNET/MB.

14-3-3 testing in diagnosing Creutzfeldt-Jakob disease: a prospective study in 112 patients.

Unique Identifier: 20411661

Author: Lemstra AW; van Meegen MT; Vreyling JP; Meijerink PH; Jansen GH; Bulk S; Baas F; van Gool WA

Source: Neurology 2000 Aug 22;55(4):514-6

Address: Department of Neurology, Academic Medical Center, University of Amsterdam, The Netherlands.

    OBJECTIVE: To study the sensitivity and specificity of 14-3-3 testing in a prospective series of patients suspected of having Creutzfeldt-Jakob disease (CJD). BACKGROUND: The 14-3-3 protein immunoassay on CSF has favorable test characteristics as a premortem diagnostic tool in CJD. However, the 14-3-3 protein is a normal cellular protein expressed in various tissues, and its presence in CSF reflects extensive destruction of brain tissue as in CJD, but also in ischemic stroke and meningoencephalitis. METHODS: 14-3-3 was tested in the CSF of a prospective series of 110 consecutive patients suspected of having CJD. RESULTS: The sensitivity was 97% and the specificity was 87% in this series. False-positive results were mainly caused by stroke and meningoencephalitis. CONCLUSION: The 14-3-3 protein is a highly sensitive and specific marker for CJD when used in the appropriate clinical context.

Surgical pathologic findings of extratemporal-based intractable epilepsy. A study of 133 consecutive cases [editorial]

Unique Identifier: 20382602

Author: Vinters HV

Source: Arch Pathol Lab Med 2000 Aug;124(8):1111-2

    No abstract available.

The identification of novel therapeutic targets for the treatment of malignant brain tumors.

Unique Identifier: 20341001

Author: Kroes RA; Jastrow A; McLone MG; Yamamoto H; Colley P; Kersey DS; Yong VW; Mkrdichian E; Cerullo L; Leestma J; Moskal JR

Source: Cancer Lett 2000 Aug 11;156(2):191-8

Address: The Chicago Institute of Neurosurgery and Neuroresearch, 2515 N. Clark St., Suite 800, Chicago, IL, 60614, USA.

    A two-step strategy was developed consisting of differential display reverse transcriptase polymerase chain reaction (DDRT-PCR) with cultured normal human fetal astrocytes and U-373MG glioma cells followed by reverse Northern analysis of normal brain and primary tumor tissues. hu-dek, alpha-NAC, ribosomal proteins L7a and L35a, and five novel genes were identified. Since none of these genes has been previously shown to be associated with malignant brain tumor formation, this approach may be useful to identify novel targets for the diagnosis and treatment of brain tumors.

Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors.

Unique Identifier: 20397457

Author: Trask TW; Trask RP; Aguilar-Cordova E; Shine HD; Wyde PR; Goodman JC; Hamilton WJ; Rojas-Martinez A; Chen SH; Woo SL; Grossman RG

Source: Mol Ther 2000 Feb;1(2):195-203

Address: Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA.

    Between December 1996 and September 1998, 13 patients with advanced recurrent malignant brain tumors (9 with glioblastoma multiforme, 1 with gliosarcoma, and 3 with anaplastic astrocytoma) were treated with a single intratumoral injection of 2 x 10(9), 2 x 10(10), 2 x 10(11), or 2 x 10(12) vector particles (VP) of a replication-defective adenoviral vector bearing the herpes simplex virus thymidine kinase gene driven by the Rous sarcoma virus promoter (Adv.RSVtk), followed by ganciclovir (GCV) treatment. The VP to infectious unit ratio was 20:1. Our primary objective was to determine the safety of this treatment. Injection of Adv.RSVtk in doses <==2 x 10(11) VP, followed by GCV, was safely tolerated. Patients treated with the highest dose, 2 x 10(12) VP, exhibited central nervous system toxicity with confusion, hyponatremia, and seizures. One patient is living and stable 29.2 months after treatment. Two patients survived >25 months before succumbing to tumor progression. Ten patients died within 10 months of treatment, 9 from tumor progression and 1 with sepsis and endocarditis. Neuropathologic examination of postmortem tissue demonstrated cavitation at the injection site, intratumoral foci of coagulative necrosis, and variable infiltration of the residual tumor with macrophages and lymphocytes.

Three-dimensional magnetic resonance spectroscopic imaging of brain and prostate cancer.

Unique Identifier: 20386195

Author: Kurhanewicz J; Vigneron DB; Nelson SJ

Source: Neoplasia 2000 Jan-Apr;2(1-2):166-89

Address: Magnetic Resonance Science Center, Department of Radiology, University of California, San Francisco 94143-1290, USA.

    Clinical applications of magnetic resonance spectroscopic imaging (MRSI) for the study of brain and prostate cancer have expanded significantly over the past 10 years. Proton MRSI studies of the brain and prostate have demonstrated the feasibility of noninvasively assessing human cancers based on metabolite levels before and after therapy in a clinically reasonable amount of time. MRSI provides a unique biochemical "window" to study cellular metabolism noninvasively. MRSI studies have demonstrated dramatic spectral differences between normal brain tissue (low choline and high N-acetyl aspartate, NAA) and prostate (low choline and high citrate) compared to brain (low NAA, high choline) and prostate (low citrate, high choline) tumors. The presence of edema and necrosis in both the prostate and brain was reflected by a reduction of the intensity of all resonances due to reduced cell density. MRSI was able to discriminate necrosis (absence of all metabolites, except lipids and lactate) from viable normal tissue and cancer following therapy. The results of current MRSI studies also provide evidence that the magnitude of metabolic changes in regions of cancer before therapy as well as the magnitude and time course of metabolic changes after therapy can improve our understanding of cancer aggressiveness and mechanisms of therapeutic response. Clinically, combined MRI/MRSI has already demonstrated the potential for improved diagnosis, staging and treatment planning of brain and prostate cancer. Additionally, studies are under way to determine the accuracy of anatomic and metabolic parameters in providing an objective quantitative basis for assessing disease progression and response to therapy.

Brain tumor demarcation using optical spectroscopy; an in vitro study.

Unique Identifier: 20394699

Author: Lin WC; Toms SA; Motamedi M; Jansen ED; Mahadevan-Jansen A

Source: J Biomed Opt 2000 Apr;5(2):214-20

Address: Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, USA.

    Optical spectroscopy for brain tumor demarcation was investigated in this study. Fluorescence and diffuse reflectance spectra were measured from normal and tumorous human brain tissues in vitro. A fluorescence peak was consistently observed around 460 nm (+/- 10 nm) emission from both normal and tumorous brain tissues using 337 nm excitation. Intensity of this fluorescence peak (F460) from normal brain tissues was greater than that from primary brain tumorous tissues. In addition, diffuse reflectance (Rd) between 650 and 800 nm from white matter was significantly stronger than that from primary and secondary brain tumors. A good separation between gray matter and brain tumors was found using the ratio of F460 and Rd at 460 nm (Rd460). Two empirical discrimination algorithms based on F460, Rd625, and F460/Rd460 were developed. These algorithms yielded an average sensitivity and specificity of 96% and 93%, respectively.

Role of 17p13.3 chromosomal region in determining p53 protein immunopositivity in human astrocytic tumors.

Unique Identifier: 20299863

Author: Sarkar C; Rathore A; Chattopadhyaya P; Mahapatra AK; Sinha S

Source: Pathology 2000 May;32(2):84-8

Address: Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.

    Immunohistochemistry of p53 protein is being increasingly performed as a clinical service as well as in research for prediction of tumor behavior. Although early reports suggested that p53 immunopositivity was associated with p53 gene alterations, recent evidence indicates that this is not always true. Earlier, we had demonstrated the significant association of loss of heterozygosity (LOH) of the chromosomal region 17p13.3 with higher grades of human astrocytic tumors. This was independent of the heterozygosity status of p53. LOH of p53 was taken as an indicator of p53 gene alteration, which was substantiated by sequencing a subset of the tumors. In the present study, we report that p53 immunopositivity in 40 of the same set of tumors (five could not be evaluated because of paucity of tissue) was significantly associated with LOH of 17p13.3 region (Fisher's exact two-tailed, P = 0.012; odds ratio, 12) but not with LOH of p53 (Fisher's exact two-tailed, P = 0.324; odds ratio, 2.24). This indicates that the gene(s) on the 17p13.3 region of the human chromosome may be influencing the p53 immunopositivity status of glial tumors and possibly other tumors in general. This has great implications in interpreting p53 immunohistochemistry results of biopsies of various tumor types as due to p53 mutations alone. The study thus points to a new molecular correlate for p53 immuno-positivity in tumors.

Sporadic p53 mutations and absence of ras mutations in glioblastomas.

Unique Identifier: 20383549

Author: Gomori E; Doczi T; Pajor L; Matolcsy A

Source: Acta Neurochir (Wien) 1999;141(6):593-9

Address: Department of Pathology, University Medical School, Pecs, Hungary.

    As concerns human adult brain neoplasms, the biological behaviour of glioblastoma, a high-grade neuro-ectodermal tumour, is among the most disadvantageous. Glioblastoma may develop either as a primary tumour without clinical and histological evidence of a prior precursor lesion, or as the final stage of malignant transformation of a low-grade or anaplastic astrocytoma. There are conflicting reports in connection with the association of the p53 tumour suppressor gene mutation with the clinical and histological progression of gliomas. Previous studies likewise led to contradictory results concerning the significance of ras oncogenes in different histological malignancies, and especially in neuro-epithelial tumours. The possible roles of p53 and ras gene alterations in the development of "primary" and "transformed" glioblastomas were studied in this work. Eighteen tumours were investigated by means of immunohistochemistry and polymerase chain reaction-assisted-single strand conformation polymorphism (PCR-SSCP) sequence analysis in a search for molecular genetic differences between primary and transformed glioblastomas. An increased incidence of p53-immunopositive cells was observed in both types of glioblastomas but there was no significant difference between the transformed tumours and the primary form. All samples were screened for point mutation in codons 12 and 61 of the H-, K-, and N-ras oncogenes and exons 5-8 of the p53 gene. No aberrant band or mutation was found in the H-, K- and N-ras oncogenes. Aberrant bands were seen in only 2 (11%) of the 18 tumours in the SSCP analyses of exons 6 and 8. Sequence analysis of the 2 abnormal cases revealed G --> C transmission in the second nucleotide of codon 280 on exon 8, which resulted in a change in the encoded amino acid from arginine to threonine (case 15). A ttagtct --> ttggtct transmission on intron 5 (case 8) was also found. No genetic difference could be identified between the primary and the transformed glioblastoma forms as concerns their p53 and ras oncogenes. There are two possible explanations for these findings: (a) The p53 and ras gene mutations were not primary events in the morphological transformations. Alterations in these genes may therefore take place at an early stage in glioma progression. (b) The different genetic changes may accumulate during glioblastoma development. These specific genetic events may additionally play a role in multistep tumourigenesis.

Bibliography. Current world literature. Brain and nervous system.

Unique Identifier: 20297897

Author: Anonymous

Source: Curr Opin Oncol 2000 May;12(3):B79-92

    No abstract available.

Magnetic resonance spectroscopy of brain tumors.

Unique Identifier: 20297886

Author: Lee PL; Gonzalez RG

Source: Curr Opin Oncol 2000 May;12(3):199-204

Address: NMR Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown 02129, USA.

    Magnetic resonance spectroscopy provides metabolic information about brain tumors beyond what can be obtained from anatomic images. In contrast to other metabolism-based imaging techniques such as single photon emission computed tomography and positron-emission tomography, magnetic resonance spectroscopy yields multiparametric data, does not require radio-labeled tracers or ionizing radiation, and can be performed in conjunction with other magnetic resonance imaging studies. Magnetic resonance spectral patterns have been shown to be distinct for different tumor types and grades. Response to radiation therapy is also reflected by magnetic resonance spectral patterns. Although there are quantitative issues still to be addressed, correlation of in vivo spectral patterns with ex vivo spectral patterns obtained from actual biopsy samples indicates that magnetic resonance spectroscopy is a fundamentally valid tool for monitoring disease progression and therapeutic response in patients with brain tumors.

Gains and losses of DNA sequences in childhood brain tumors analyzed by comparative genomic hybridization.

Unique Identifier: 20416151

Author: Shlomit R; Ayala AG; Michal D; Ninett A; Frida S; Boleslaw G; Gad B; Gideon R; Shlomi C

Source: Cancer Genet Cytogenet 2000 Aug;121(1):67-72

Address: Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Israel.

    Primary central nervous system neoplasms are the most common solid tumors in children. Genetic changes underlying childhood brain-tumor development and progression are incompletely characterized. To get an overview of the genetic events leading to the development of brain tumors and to identify chromosomal regions that may contain genes important in brain-tumor progression, we employed a comparative genomic hybridization technique. Twenty-four pediatric primary brain tumors were analyzed in this study. DNA copy number changes were observed in most of the samples (79%), and almost all chromosomes were involved. The total number of genetic aberrations (copy-number gains and losses per tumor) was significantly higher in the cerebellar primitive neuroectodermal tumor subgroup than in the gliomas. The high-grade tumors had more DNA changes than did the low-grade tumors. The most often gained chromosomes were: 6q (45%), 4q (34.5%), and chromosome 1 (24% of the cases). The minimal common regions involved in DNA gains were narrowed down to 6q14-16 and 4q26-28. Losses of a specific chromosome (partly or as a whole) occurred on average in 7% of the cases. Chromosomal regions that were most often lost included chromosome 1 (17%), chromosome 16 (17%), and chromosome 2 (14%). These findings suggest that genes localized to these minimal common chromosomal regions play a role in the tumorogenesis of childhood brain tumors. Our results indicate: (1) a great degree of genomic imbalance in these tumors; (2) that a high number of aberrations correlate with aggressive tumor biology; (3) and that nonrandom genetic changes may be associated with particular tumor types.

Central neurocytomas are genetically distinct from oligodendrogliomas and neuroblastomas.

Unique Identifier: 20389654

Author: Tong CY; Ng HK; Pang JC; Hu J; Hui AB; Poon WS

Source: Histopathology 2000 Aug;37(2):160-5

Address: Department of Anatomical & Cellular Pathology and Neurosurgical Unit, Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.

    AIMS: Central neurocytoma is a rare central nervous system tumour typically found in the lateral ventricles and at the septum pellucidum. Histologically, it resembles oligodendrogliomas and yet ultrastructurally, it shows neuronal differentiation. Its molecular oncogenesis is not known. The aim of this study was to examine whether major genetic events found in oligodendrogliomas and neuronal tumours, namely allelic deletions of chromosomes 1p and 19q and N-myc amplification, can be found in central neurocytomas. As there was one report describing gain of chromosome 7 in central neurocytomas, we also examined epidermal growth factor receptor (EGFR) amplification, as the EGFR gene is located at chromosome 7p. METHODS AND RESULTS: Nine central neurocytomas and matched blood samples were examined for loss of heterozygosity (LOH) of 1p and 19q13.2-13.4 with 23 finely mapped microsatellite markers. N-myc amplification was studied by fluorescence in-situ hybridization using paraffin-embedded sections. EGFR amplification was tested for by differential PCR. Six of nine (67%) tumours showed LOH at one or more loci at 1p and 5/9 (56%) of cases showed LOH at 19q. However, common regions of deletion cannot be identified. The majority of informative markers are retained at 1p (84%) and 19q (86%). Only one tumour showed amplification of N-myc and none of the cases showed amplification of EGFR. CONCLUSION: Central neurocytomas are genetically distinct from oligodendrogliomas, and chromosomes 1p and 19q probably do not play an important role in their pathogenesis. N-myc and EGFR amplification are rare.

A sequence-ready BAC clone contig of human chromosome 10p15 spanning the loss of heterozygosity region in glioma.

Unique Identifier: 20396131

Author: Harada K; Nishizaki T; Maekawa K; Kubota H; Harada K; Suzuki M; Ohno T; Sasaki K; Soeda E

Source: Genomics 2000 Aug 1;67(3):268-72

Address: Department of Pathology, Department of Neurosurgery, Yamaguchi University School of Medicine, Japan.

    Deletion of chromosome 10 is one of the most common chromosomal alterations in glioma. At 10p15, the telomeric region of the short arm of chromosome 10, loss of heterozygosity (LOH) has been frequently observed by microsatellite analysis, suggesting the presence of a tumor suppressor gene. We examined LOH in 34 gliomas on chromosome 10, and frequent LOH on 10p was detected on 10p15, in agreement with deletion mapping studies on chromosome 10. We then constructed a bacterial artificial chromosome (BAC) clone contig covering the critical region, which spanned the interval between D10S249 and D10S533 on 10p15. The map contained 68 BAC clones connected by 74 sequenced tag sites (STSs) and covered approximately 2.7 Mb, with one gap. A total of 74 STSs, including 6 microsatellite markers, 29 expressed sequenced tags (ESTs), and 39 BAC end STSs, were physically arranged. Twenty-eight ESTs were mapped in the interval between D10S249 and D10S559 (approximately 1200 kb), and another EST was mapped in the interval between D10S559 and D10S533 (approximately 1300 kb). This sequence-ready BAC clone contig map will be a basic resource for high-quality sequencing and positional cloning of the putative tumor suppressor gene at 10p15 in glioma. Copyright 2000 Academic Press.

Molecular cytogenetic analysis of medulloblastomas and supratentorial primitive neuroectodermal tumors by using conventional banding, comparative genomic hybridization, and spectral karyotyping.

Unique Identifier: 20424359

Author: Bayani J; Zielenska M; Marrano P; Kwan Ng Y; Taylor MD; Jay V; Rutka JT; Squire JA

Source: J Neurosurg 2000 Sep;93(3):437-48

Address: University Health Network, Hospital for Sick Children, and Department of Laboratory Medicine and Pathobiology and Medical Biophysics, Faculty of Medicine, University of Toronto, Ontario, Canada.

    OBJECT: Medulloblastomas and related primitive neuroectodermal tumors (PNETs) of the central nervous system are malignant, invasive embryonal tumors with predominantly neuronal differentiation that comprise 20% of pediatric brain tumors. Cytogenetic analysis has shown that alterations in chromosome 17, particularly the loss of 17p and the formation of isochromosome 17q, as well as the gain of chromosome 7 are the most common changes among this group of tumors. Comparative genomic hybridization (CGH) studies have largely confirmed these cytogenetic findings and have also identified novel regions of gain, loss, and amplification. The advent of more sophisticated multicolored fluorescence in situ hybridization (FISH) procedures such as spectral karyotyping (SKY) now permits complete recognition of all aberrations including extremely complex rearrangements. The authors report a retrospective analysis of 19 medulloblastoma and five PNET cases studied using combinations of classic banding analysis, FISH, CGH, and SKY to examine comprehensively the chromosomal aberrations present in this tumor group and to attempt to identify common structural rearrangement(s). METHODS: The CGH data demonstrate gains of chromosomes 17q and 7 in 60% of the tumors studied, which confirms data reported in the current literature. However, the authors have also combined the results of all three molecular cytogenetic assays (Giemsa banding, CGH, and SKY) to reveal the frequency of chromosomal rearrangement (gained, lost, or involved in structural rearrangement). CONCLUSIONS: The combined results indicate that chromosomes 7 and 17 are the most frequently rearranged chromosomes (10.1% and 8.9%, respectively, in all rearrangements detected). Furthermore, chromosomes 3 (7.8%), 14 (7%), 10 (6.7%), and 22 (6.5%) were also found to be frequently rearranged, followed by chromosomes 6 (6.5%), 13 (6.2%), and 18 (6.2%). Eight (33%) of 24 tumors exhibited high-level gains or gene amplification. Amplification of MYCN was identified in four tumors, whereas amplification of MYCC was identified in one tumor. One tumor exhibited a high-level gain of chromosome 9p. Additionally, desmoplastic medulloblastomas and large-cell medulloblastomas exhibited higher karyotype heterogeneity, amplification, and aneusomy than classic medulloblastomas.

Quantitative 201Tl SPET imaging in the follow-up of treatment for brain tumour: a sensitive tool for the early identification of response to chemotherapy?

Unique Identifier: 20280834

Author: Kallen K; Geijer B; Malmstrom P; Andersson AM; Holtas S; Ryding E; Rosen I

Source: Nucl Med Commun 2000 Mar;21(3):259-67

Address: Department of Neurology, University Hospital, Lund, Sweden.

    The aim of this study was to establish if repeated quantitative 201Tl SPET scanning during follow-up of astrocytoma therapy can provide information that is relevant for clinical management. Sixteen consecutive patients, with histopathologically verified highly malignant astrocytoma, were followed during PCV chemotherapy. Imaging with 201Tl SPET and CT was performed repeatedly over 8-16 weeks until treatment discontinuation, with a maximum follow-up of 74 weeks. Tumour uptake volume (TUV), a measure of metabolically active tumour tissue, was calculated from the SPET images. The reliability of early identification of treatment failure, defined as > 25% tumour volume increase, following one course (week 8) and three courses (week 24) of chemotherapy, was calculated for the two imaging methods. 201Tl SPET positive patients (> 25% tumour volume increase) were compared with 201Tl SPET negative patients in terms of time to treatment discontinuation (TTD) and survival time (ST). The patients were followed with a total of 59 SPET examinations, and treatment was continued for a median 27 weeks (range 16-78 weeks). The comparative reliability of SPET and CT showed the highest sensitivity and accuracy for SPET in the early identification of astrocytoma treatment failure at the week 24 assessment. Patients with positive 201Tl SPET after three courses of chemotherapy had a significantly reduced TTD (P = 0.040) but not significantly reduced ST. Of the ten patients who received concomitant radiation and chemotherapy, five had a small (0-10 ml) TUV at the week 24 assessment. Patients with a TUV > 10 ml at this assessment had a shorter TTD (P = 0.016) and a reduced ST (P = 0.024) compared to patients with a TUV < 10 ml. In conclusion, the assessment of progressive disease by quantitative 201Tl SPET appears to provide information on treatment response, earlier and with a higher reliability than CT. Repeated 201Tl SPET scanning during follow-up of astrocytoma treatment is an alternative tool for the early identification of treatment failure.

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation.

Unique Identifier: 20420817

Author: Leung SY; Yuen ST; Chan TL; Chan AS; Ho JW; Kwan K; Fan YW; Hung KN; Chung LP; Wyllie AH

Source: Oncogene 2000 Aug 17;19(35):4079-83

Address: Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong.

    We have previously reported high-frequency microsatellite instability (MSI-H) and germ-line mismatch repair gene mutation in patients with unusually young onset of high-grade glioma. Some of these patients developed metachronous MSI-H colorectal cancer and conformed to the diagnosis of Turcot's syndrome. Frameshift mutation of TGFbetaRII was present in all the colorectal carcinomas but not in brain tumours. We further characterized the genetic pathways of tumour evolution in these metachronous gliomas and colorectal carcinomas. All MSI-H glioblastomas had inactivation of both alleles of the p53 gene and showed over-expression of the p53 protein while none of the colorectal carcinomas had p53 mutation or protein over-expression. Flow cytometry and comparative genomic hybridization revealed that all glioblastomas were chromosomal unstable with aneuploid DNA content, and with a variable number of chromosomal arm aberrations. In contrast, the colorectal carcinomas had diploid or near-diploid DNA content with few chromosomal arm aberrations. The pattern of chromosomal aberrations in the two organs was different. Loss of 9p was consistently observed in all glioblastomas but not in colorectal carcinomas. Epidermal growth factor receptor amplification was absent in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its effects differ greatly in the two organs. Following loss of mismatch repair function, p53 inactivation and chromosomal instability are not necessary for development of colorectal carcinoma, but are required for genesis of glioblastoma. Oncogene (2000) 19, 4079 - 4083.

Distinguishing recurrent tumor and radiation necrosis with positron emission tomography versus stereotactic biopsy.

Unique Identifier: 20312951

Author: Thompson TP; Lunsford LD; Kondziolka D

Source: Stereotact Funct Neurosurg 1999;73(1-4):9-14

Address: University of Pittsburgh School of Medicine and The Center for Image Guided Neurosurgery, PA 15213, USA.

    With the recent approval of reimbursement for positron emission tomography (PET), it has become important to clarify the utility of this diagnostic study. We evaluated the utility of PET to distinguish radiation necrosis from recurrent tumor in a retrospective review of patients with primary glial neoplasms. Fifteen patients had preoperative contrast-enhanced MRI and PET images followed by stereotactic biopsy or craniotomy and histological confirmation. The sensitivity of PET was 43% (6/14) and the specificity was 100% (1/1). We examined the sensitivity of PET as a function of volumetric contrast enhancement on MRI. Eighty percent of true-positive PET studies occurred with volume enhancement greater than 10 cm(3). Seventy-five percent of false negatives occurred with volume enhancement less than 6 cm(3). Given the clinical significance of distinguishing tumor progression from radiation necrosis, we believe that PET is insufficient to resolve radiation necrosis versus tumor progression. Copyright 2000 S. Karger AG, Basel

Spontaneous apoptosis and retinoic acid receptor incidence in neuroblastomas and peripheral neuroectodermal tumors.

Unique Identifier: 20303649

Author: Farid P; Babosa M; Hauser P; Schuler D; Szende B

Source: Pediatr Hematol Oncol 2000 Jun;17(4):315-21

Address: 1st Department of Pathology, Joint Research Organization of the Hungarian Academy of Sciences, Budapest, Hungary.

    Twelve cases of neuroblastoma (NB) (7 boys and 5 girls) and 4 cases of primitive peripheral neuroectodermal tumor (PNET) (3 boys and 1 girl) were investigated for the presence of apoptosis and retinoic acid receptor (RAR) by immunhistochemical method. The apoptotic index in NB was zero or 1% in 8 children and relatively low (2-4.8%) in the other 4 cases, while it was higher (4.1-10.5%) in PNET. The RAR index determined by immunoperoxidase reaction in NB was zero or 3% in 5 cases and 9-34% in 7 children. RAR index in PNET was 16-68% in all the 4 cases. Good correlation (r = .47 according to Pearson-Bravis) was found between the number of RAR and spontaneous apoptosis. These results suggest that the RAR index in untreated NB and PNET shows great individual variation since its determination is necessary for the evaluation of the efficacy of retinoic acid treatment.

Double-shot magnetic resonance imaging of cerebral lesions: fast spin-echo versus echo planar sequences.

Unique Identifier: 20375311

Author: Wolansky LJ; Sheth MP; Axen R; Prasad V

Source: J Neuroimaging 2000 Jul;10(3):131-7

Address: Department of Radiology, New Jersey Medical School/University of Medicine and Dentistry of New Jersey, Newark 07103, USA.

    The authors compared two new rapid MRI techniques: double-shot echo-planar imaging (DS-EPI) versus double-shot fast spin-echo (DS-FSE) in the evaluation of cerebral lesions. The authors examined 35 patients with 37 lesions, which were hyperintense on long TR images. Patients were scanned with both DS-EPI and DS-FSE with a time of repetition (TR) of 10,000 milliseconds and an echo time (TE) of 80 milliseconds. Conspicuity was determined from region of interest measurements to calculate contrast to noise ratio (C/N). Visual comparisons between DS-EPI and DS-FSE, and between DS-EPI and T2-weighted conventional spin-echo (CSE) were also performed to evaluate the sequences' ability to depict hemorrhage. The mean C/N for both sequences was comparable: 36.7 for DS-FSE and 35.6 for DS-EPI, with no statistically significant difference (p = 0.77). With regards to depicting blood products, DS-EPI proved far more effective than DS-FSE and comparable to CSE. Also, DS-EPI proved to be more time-efficient, requiring 1.67 seconds per section, while DS-FSE required 3.33 seconds per section. Whereas DS-FSE and DS-EPI are comparable in their ability to depict hyperintense cerebral pathology, DS-EPI is more time-efficient, and therefore appears preferable. Because of the high magnetic susceptibility of DS-EPI, geometric distortion degrades visualization of lesions in the posterior fossa or near the sinuses. On the other hand, the high magnetic susceptibility results in high conspicuity of blood products.

MRI findings in 32 consecutive lipomas using conventional and advanced sequences [letter]

Unique Identifier: 20375324

Author: Truwit C

Source: J Neuroimaging 2000 Jul;10(3):190-1

    No abstract available.

Benign central neurocytoma.

Unique Identifier: 20419772

Author: Ashkan K; Casey AT; D'Arrigo C; Harkness WF; Thomas DG

Source: Cancer 2000 Sep 1;89(5):1111-20

Address: Departments of Neurological Surgery and Neuropathology, National Hospital for Neurology and Neurosurgery, London, England.

    BACKGROUND: "Central neurocytoma" is classically considered as an intraventricular benign tumor, largely based on data from small retrospective series. The authors present prospective data on 12 patients with tumors diagnosed as central neurocytoma, to highlight the diverse nature of this tumor and challenge the classic notion. METHODS: Between 1991 and 1997, 12 patients had tumors diagnosed prospectively as "central neurocytoma". Clinical, radiologic, and histologic data were collected, and Karnofsky performance score was evaluated for each patient. Proliferation marker studies were performed using Ki-67 labeling index. RESULTS: In two patients, the tumors were located in atypical locations, namely, the parietal lobe and the spine. Aggressive behavior characterized by clinical and radiologic evidence of tumor progression was noted in two additional patients. In both these cases, unusually high proliferation rates of 5.3% and 11.2% were noted. Total excision of the tumor, when possible, was the treatment of choice. Postoperative radiotherapy to the residual tumor may be of benefit in patients with clinically aggressive tumors, or those with high proliferation rates. CONCLUSIONS: Given the findings of this study, it is suggested that the traditional concept of central neurocytoma as a benign intraventricular tumor warrants reconsideration.

Sequential scintigraphic strategy for the differentiation of brain tumours.

Unique Identifier: 20310858

Author: Matheja P; Rickert C; Weckesser M; Palkovic S; Lottgen J; Riemann B; Kopka K; Kuwert T; Wassmann H; Paulus W; Schober O

Source: Eur J Nucl Med 2000 May;27(5):550-8

Address: Department of Nuclear Medicine, University of Munster, Germany.

    Both thallium-201 and iodine-123 alpha-methyltyrosine (123I-IMT) have been shown to be useful in the diagnostic evaluation of brain tumours. The aim of this study was to investigate the respective contributions of 201Tl and 123I-IMT single-photon emission tomography (SPET) in the non-invasive evaluation of intracerebral tumours. We analysed 65 patients with the following brain tumours: 8 non-neoplastic lesions, 4 meningiomas, 12 low-grade gliomas, 28 high-grade gliomas, 11 metastases and 2 high-grade lymphomas. 201Tl SPET and 123I-IMT SPET were performed [start of 201Tl SPET: 15 min p.i. (early) and 180 min p.i. (delayed); start of 123I-IMT SPET: 15 min p.i.]. The intensity of uptake was quantified as the ratio between tracer accumulation in the tumour and in the contralateral hemisphere. None of the non-neoplastic lesions or low-grade gliomas expressed marked 201Tl uptake. All malignant tumours except one small metastasis and all meningiomas except one small, cystic and degenerated lesion showed significant 201Tl accumulation [Tl(15')>2.0]; 123I-IMT uptake was either absent or intermediate in non-malignant lesions except in two low-grade gliomas; the highest levels were observed in high-grade gliomas followed by metastases and lymphomas (mean IMT: 2.7 vs. 2.1 vs. 1.8), with metastases showing a high variability in 123I-IMT uptake (range: 0.8-3.6). Using 201Tl to distinguish non-neoplastic lesions from malignant tumours and meningiomas, 63 of 65 patients were characterised correctly. In the latter group, high-grade gliomas were correctly identified in 27 of 28 cases by their amino acid uptake. It is concluded that the combination of 201Tl and 123I-IMT surpasses the accuracy of each single test in the differentiation of space-occupying lesions of the brain. Based on these preliminary results, a sequential strategy is proposed involving an initial 201Tl SPET study and an additional 123I-IMT SPET study in the event of positive 201Tl uptake.

[MRI technique for brain tumors in adults]

Unique Identifier: 20351484

Author: Cosnard G; Duprez T; Grandin C

Source: J Neuroradiol 2000 Mar;27(1):31-8

Address: Departement d'imagerie medicale, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain avenue Hippocrate 10 B-1200 Bruxelles.

    No abstract available.

[MR diffusion and perfusion imaging in clinical practice]

Unique Identifier: 20351485

Author: Le Bars E; Gondry-Jouet C; Deramond H; Le Gars D; Idy-Peretti I

Source: J Neuroradiol 2000 Mar;27(1):39-51

Address: Unite de Recherche en Imagerie Medicale.

    MR functional imaging, due to the improvement in ultra-speed imaging technology such as echo-planar imaging, has become a very powerful technique since the beginning of the nineties. This imaging technique is divided into diffusion imaging, perfusion imaging and cerebral activation. Diffusion imaging probes the mobility of water molecules characterized by a diffusion coefficient called the apparent diffusion coefficient (ADC) for biological tissues. Perfusion imaging gives hemodynamic information due to the regional cerebral blood volume by the use of contrast agents such as chelates of gadolinium carrying strong magnetic susceptibility. Both imaging techniques can provide information in a wide nosological range : cerebral ischemia, in the acute phase and in case of intracranial tumors, contributing to tumoral grading, localizing the site of biopsy, and assessing response to therapy (after radiotherapy for example). Nevertheless, a wide range of domains remains incompletely studied, for example cerebral white matter diseases and neurodegenerative diseases. For clinical applications, a precise knowledge of the potentials of both techniques and their limitations is needed. Limitations result from the large number of often patient-related parameters, imaging technique (perfusion) and data analysis. Powerful software has been developed in the workstation environment. Thus this imaging technique requires up-to-date equipment and close collaboration between clinical and research teams for optimal efficiency.

Grading of diffusely infiltrating astrocytomas by quantitative histopathology, cell proliferation and image cytometric DNA analysis. Comparison of 133 tumours in the context of the WHO 1979 and WHO 1993 grading schemes.

Unique Identifier: 20392234

Author: Sallinen PK; Sallinen SL; Helen PT; Rantala IS; Rautiainen E; Helin HJ; Kalimo H; Haapasalo HK

Source: Neuropathol Appl Neurobiol 2000 Aug;26(4):319-31

Address: Department of Pathology, Tampere University Hospital and the University of Tampere, Tampere, Finland.

    The aim of the study was to evaluate the applicability of quantitative histopathology as an aid for grading diffusely infiltrating astrocytomas. Primary astrocytomas were analysed for parameters (mean nuclear size, mitosis count, area fraction of endothelial cells and tumour necrosis, area fraction of nuclei, and Ki-67 (MIB-1) labelling index), which are closely related to the World Health Organization (WHO) 1979 and WHO 1993 grading criteria. All estimates correlated with the WHO histopathological grade and patient outcome. According to the receiver-operating characteristics curve, the presence of tumour necrosis and mitosis count (cut-off at 3 mitoses/mm2 of neoplastic tissue) showed the best sensitivity and specificity in separating patients with different survival. The multivariate survival analyses confirmed this result. A decision-tree model was constructed based on these two variables: twig I with less than 3 mitoses/mm2, twig II with equal or more than 3 mitoses/mm2 but no necrosis, and twig III with tumour necrosis. This model was found to be more strongly associated with survival than the WHO 1979 or WHO 1993 grading schemes. Low-malignancy astrocytomas (WHO grade II or twig I tumours) could be further divided into two prognostic categories by the image cytometric DNA analysis. The results put an emphasis on astrocytoma grading on mitosis counts (grade II vs. III) and tumour necrosis (grade III vs. IV). To standardize the sampling for mitosis counting, it is suggested that a parallel Ki-67 immunostaining be used for the identification of the most proliferative areas.

Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas.

Unique Identifier: 20392239

Author: Gutmann DH; Donahoe J; Brown T; James CD; Perry A

Source: Neuropathol Appl Neurobiol 2000 Aug;26(4):361-7

Address: Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.

    The critical role of the neurofibromatosis 1 (NF1) gene as a tumour suppressor has been clearly demonstrated for malignancies arising in NF1 patients. However, little is known about the more common benign tumours, such as the pilocytic astrocytoma. Most NF1-associated astrocytomas are benign and clinically non-progressive, though aggressive tumours are occasionally encountered. In this study, eight pilocytic astrocytomas from six individuals affected with NF1 were analysed for NF1 expression. All eight tumours demonstrated loss of neurofibromin expression by immunohistochemistry, which was confirmed in one case using Western blot analysis. Microsatellite analysis showed loss of a single NF1 allele (LOH) in two of four NF1-associated tumours. These results demonstrate that, in contrast to sporadic astrocytomas, loss of NF1 expression is an important primary genetic event in the pathogenesis of NF1-associated pilocytic astrocytomas.

Vascular endothelial growth factor expression in oligodendrogliomas: a correlative study with Sainte-Anne malignancy grade, growth fraction and patient survival.

Unique Identifier: 20392241

Author: Varlet P; Guillamo JS; Nataf F; Koziak M; Beuvon F; Daumas-Duport C

Source: Neuropathol Appl Neurobiol 2000 Aug;26(4):379-89

Address: Department of Pathology-Neurooncology, Hopital Sainte-Anne, Paris, France.

    Microangiogenesis is a delayed but crucial event in the malignant progression of oligodendrogliomas. Accord-ingly, in the new Sainte-Anne grading system of oligodendrogliomas, endothelial hyperplasia and contrast enhancement, both being indicators of microangiogenesis, are key criteria for the distinction of grade A from grade B tumours. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor: a strong correlation between VEGF expression, Sainte-Anne malignancy grade and patient outcome might thus be expected. In order to assess this hypothesis, VEGF immunostaining was performed in a series of 34 oligodendrogliomas that included 11 grade B and 23 grade A, of which nine became grade B during the study period (mean clinical and imaging follow-up: 41 months). VEGF expression correlated strongly with Sainte-Anne tumour grade (P < 0.001), and inversely with patient survival (P < 0.001) and recurrence-free survival (P = 0.002). One hundred per cent of grade B but only 17% of grade A were VEGF-positive. By contrast, the MIB-1 labelling index did not correlate with VEGF expression, total survival or recurrence-free survival. In accordance with the grading system, this study showed that, in oligodendrogliomas, VEGF expression and microangiogenesis are progression-related phenomena that confer on these tumours a growth advantage by presumably reducing hypoxia-induced apoptotic cell death. These findings might have important implications in the future for the indication and timing of anti-angiogenic therapies.

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