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In a phase II trial we treated more than 100 patients with malignant brain tumors with 2-mg/kg Photofrin iv. and intraoperative cavitary PDT. We concluded that PDT was safe in patients with newly diagnosed or recurrent supratentorial malignant gliomas. Regression analysis showed that pathology, performance grade and light dose were significantly related to survival time. We identified a prolongation of survival in selected patients when an adequate light dose was used. The surgical mortality rate was less than 3%. We have initiated two randomized prospective trials - the first, to determine if the addition of PDT to standard therapy [surgery, radiation and/or chemotherapy] prolongs the survival of patients with newly diagnosed malignant astrocytic tumors; and the second, to determine whether high light dose PDT [120 J/cm2] is superior to low light dose PDT [40 J/cm2] in patients with recurrent malignant astrocytic tumors. In the first 20 months of these clinical studies, 90 patients have been recruited. There were 52 in the recurrent study and 37 in the newly diagnosed study. 64% of the tumors were glioblastoma and 23% malignant astrocytoma or malignant mixed glioma. In the trial of newly diagnosed tumors 17 were randomized to surgery with a mean age of 58 ! 2.9 [sem] and 20 to surgery plus PDT with a mean age of 54 ! 2.5. In recurrent glioma trial 26 were randomized to low light dose PDT [mean age 48.1 ! 2.7] and 26 to high light dose [age 52 ! 2.7]. An update of our phase 2 data and a description of brain tumor PDT techniques is presented below. The clinical studies are supported in part by grant CA 43892 awarded by DHHS/NIH/NCI.

A decade ago, neuro-oncologists began asking important questions about the optimal management of patients with low-grade gliomas of the cerebral hemispheres.1 Should all patients be exposed to the risks of surgery, simply for diagnosis? Does radiotherapy prolong tumor control and patient survival? Is early radiotherapy preferable to delayed treatment? Will better tumor control by radiation be negated by cognitive impairment or other toxicities? Is high-dose radiotherapy more effective than lower dose treatment? Is there a role for chemotherapy in the treatment of low-grade glioma? In this issue of Neurology , Olson et al.2 address many of these important questions as they pertain to patients with oligodendrogliomas and oligoastrocytomas, two subtypes of hemispheric low-grade glioma with similar clinical features and molecular origins. Their analysis shows that patients with oligodendrogliomas and oligoastrocytomas have remarkably favorable prognoses. The median progression-free survival time in this series was 5 years, and the median overall survival time was 16.3 years. These good outcomes, among the best “on-record,” attest to the slow growth of oligodendrogliomas and mixed gliomas and to earlier diagnosis in the era of modern neuroimaging. Since the introduction of CT and …

Background: Low-grade oligodendrogliomas and mixed gliomas can be indolent and remain unchanged for years. Optimal timing and effectiveness of initial treatment is uncertain and therapy can be associated with toxicity. Methods: Retrospective review of patients diagnosed between 1979 and 1997 with low-grade oligodendroglioma or mixed glioma. Time to progression, survival, prognostic factors, and treatment toxicities were evaluated. Results: A total of 106 patients (77 oligodendroglioma, 29 mixed glioma) were identified; median age was 36.7 years. Initial presenting symptoms were seizures in 76 (72%) and headache in 11 (10%); tumor was diagnosed as an incidental finding in five patients. Tumor progression was diagnosed in 72 patients (68%). Overall median time to progression (MTTP) was 5.0 years (range 0.5 to 14.2). Median overall survival (OS) was 16.7 years. No prognostic factors reached statistical significance. MTTP and OS were not significantly affected by treatment. Of 62 patients who received radiation therapy, 9 (15%) developed radiation necrosis and 13 developed radiation therapy–related cognitive changes, requiring ventriculoperitoneal shunting in six. Significant myelosuppression was seen in 35 of 76 (46%) patients treated with chemotherapy. Conclusions: Low-grade oligodendroglioma and mixed glioma have a long median overall survival. There were no apparent differences in either immediate versus deferred treatment or choice of initial therapy on disease-free or overall survival. Chemotherapy was associated with significant acute toxicity in almost one half of patients; radiation therapy produced late neurotoxicity in one third, justifying deferred treatment until clinically necessary.

Photodynamic therapy [PDT] is a local treatment for malignant tumors. In a phase 2 trial in patients with supratentorial gliomas treated with 2 mg/kg Photofrin i.v. and intraoperative cavitary PDT, we were able to conclude that PDT was safe in patients with either newly diagnosed or recurrent supratentorial malignant gliomas. There appears to be prolongation of survival in selected patients when an adequate light dose is used. The surgical mortality rate was less than 3%. We have initiated two randomized prospective trials - the first to determine if the addition of PDT to standard therapy [surgery, radiation and/or chemotherapy] prolongs the survival of patients with newly diagnosed malignant astrocytic tumors; and the second, to determine whether high light dose PDT [120 J/cm 2 ] is superior to low light dose PDT [40 J/cm 2 ] in patients with recurrent malignant astrocytic tumors. In the first 12 month 60 patients [36 males and 24 females] have been recruited to these phase III trials. There were 37 in the recurrent study and 23 in the newly diagnosed study. 64% of the tumors were glioblastoma and 23% malignant astrocytoma or malignant mixed glioma. In the trial of newly diagnosed tumors 12 were randomized to surgery with a mean age of 63.2 ± 4.0 [sem] and 11 to surgery plus PDT with a mean age of 53.4 ± 3.1. In recurrent glioma trial 19 were randomized to low light dose PDT [mean age 48.1 ± 2.5] and 18 to high light dose [age 46.4 ± 2.9]. An interim analysis will be undertaken at the time of 25 deaths in each of the studies. A multispectral digital camera has been developed for the purpose of fluorescence detection; we have used the device in PDT brain tumor cases. This investigation is supported in part by grant CA 43892 awarded by DHHS/NIH/NCI.

An in vivo bromodeoxyuridine (BrdU) labeling index (LI) was estimated in 43 cases of astrocytic tumors and mixed gliomas by one hour intra-operative intravenous infusion at a dose of 200 mg/m2 and correlated with (a) histological grading using a computer aided malignancy classifier TESTAST-268; and (b) histological typing using WHO classification. The lowest BrdU LI was seen in pilocytic and gemistocytic astrocytomas followed by astrocytomas, anaplastic astrocytomas and glioblastoma multiforme in that order. Mixed oligoastrocytomas followed the pattern of their astrocytic counterparts. Tumors of similar histological type showed different BrdU LI values especially amongst astrocytomas and glioblastomas. A statistically significant difference in the BrdU LI was also noted between the higher TESTAST grades of astrocytomas (T III and IV) versus the lower TESTAST grades (T II). Unlike earlier reports in literature, in the present study the category of BrdU LI of1 contained no case of anaplastic astrocytoma or glioblastoma multiforme (TESTAST grades III and IV). Likewise, the category of BrdU LI5 contained only anaplastic astrocytoma and glioblastoma multiforme (TESTAST grades III and IV). Maximum spread of cases was seen in the BrdU LI category of 1-5, not only in terms of histological types but also TESTAST grades. Thus there appeared to be a positive trend of increasing BrdU LI values both with histological types and increasing TESTAST grades. Further, an interesting observation was that by using a combination of TESTAST grades and BrdU LI, the histologically homogenous glioblastoma group could be further subdivided into 4 categories which showed a trend towards prognostic correlation. Thus, this study though preliminary with number of cases being small in some groups, highlights the possible usefulness of combined histological typing, TESTAST grading and in vivo BrdU LI for prognostication of gliomas especially glioblastoma multiforme.

18 cases oí' low-graded rnixed gliornas were studied using the two lectins Concanavalin A (Con A) and Peanut lectin (PNA). Con A stained cytoplasm and processes of turnoral astrocytes, whereas PNA stained cell membranes of tumoral oligodendrocytes. Con A and PNA are reliable markers for astrocyte and oligodendrocyte areas of mixed gliornas, respectively. A part of cells were overlappingly positive for both lectins. They expressed an oligosaccharide pattern of both gliorna types and represented a third, interrnediate cell type of rnixed gliomas. The existence of interrnediate cells close to astrocytic and oligodendroglial cell types in mixed gliomas could result frorn transformation processes of neoplastic glial cells or frorn the malignant transformation of a common glial precursor cell.

Objective Tenascin-C (TN) is an extracellular matrix glycoprotein with a characteristic six-armed structure. The aim of this study was to determine whether the concentration of TN in the cyst fluid of brain tumors can be used as a marker for angiogenesis and glioma grade. Methods We investigated the expression of TN in the cyst wall and cyst fluid of human brain tumors by immunohistochemistry, immunoprecipitation, and immunoblotting. The tumors included 12 astrocytomas (5 glioblastoma multiforme tumors, 1 anaplastic astrocytoma, 1 low-grade astrocytoma, 4 juvenile pilocytic astrocytomas, and 1 mixed glioma), 2 dysembryoplastic neuroepithelial tumors, 3 craniopharyngiomas, 2 ependymomas, 2 metastatic carcinomas, 3 arachnoid cysts, 1 glial ependymal cyst, and 1 inflammatory cyst. Results We detected no expression of TN in the cyst fluids of the ependymomas, craniopharyngiomas, and nonpilocytic low-grade astrocytoma. By contrast, TN was detected in the cyst fluids of all the other tumors. Results of quantitative immunoblotting using a PhosphorImager unit (Molecular Dynamics, Sunnyvale, CA) revealed that, on average, a 5-fold higher signal was observed in the glioblastoma multiforme tumors as compared with the anaplastic astrocytoma, and a 10-fold higher signal as compared with the mixed glioma, juvenile pilocytic astrocytomas, and dysembryoplastic neuroepithelial tumors. Results of TN immunohistochemistry in the astrocytomas correlated with glioma grade, with stronger staining of the hyperplastic vessels and tumor cells being observed in higher grade gliomas. No TN immunoreactivity was detected in the walls of the ependymomas, arachnoid cysts, and glial ependymal cyst that lack hyperplastic vessels, and minimal TN immunoreactivity was observed in the perivascular gliotic rim of the craniopharyngiomas. No TN was detected in the cyst fluid of these cystic processes. Conclusion The presence of TN in and around the hyperplastic vessels and tumor cells present in the cyst walls of astrocytomas and its deposition in the intratumoral cyst fluid in which angiogenic factors have been detected further suggests a role for TN as an angiogenic modulator. These preliminary results suggest that immunodetection of TN in the tumor cyst fluid may indicate tumor type and grade.

The oligoastrocytoma, as a mixed glioma, represents a nosologic dilemma with respect to precisely defining the oligodendroglial and astroglial phenotypes that constitute the neoplastic cell lineages of these tumors. In this study, cell image analysis with Feulgen-stained nuclei was used to distinguish between oligodendroglial and astrocytic phenotypes in oligodendrogliomas and astrocytomas and then applied to mixed oligoastrocytomas. Quantitative features with respect to chromatin pattern (30 variables) and DNA ploidy (8 variables) were evaluated on Feulgen-stained nuclei in a series of 71 gliomas using computer-assisted microscopy. These included 32 oligodendrogliomas (OLG group: 24 grade II and 8 grade III tumors according to the WHO classification), 32 astrocytomas (AST group: 13 grade II and 19 grade III tumors), and 7 oligoastrocytomas (OLGAST group). Initially, image analysis with multivariate statistical analyses (Discriminant Analysis) could identify each glial tumor group. Highly significant statistical differences were obtained distinguishing the morphonuclear features of oligodendrogliomas from those of astrocytomas, regardless of their histological grade. When compared with the 7 mixed oligoastrocytomas under study, 5 exhibited DNA ploidy and chromatin pattern characteristics similar to grade II oligodendrogliomas, I to grade III oligodendrogliomas, and I to grade II astrocytomas. Using multifactorial statistical analyses (Discriminant Analysis combined with Principal Component Analysis). It was possible to quantify the proportion of "typical" glial cell phenotypes that compose grade II and III oligodendrogliomas and grade II and III astrocytomas in each mixed glioma. Cytometric image analysis may be an important adjunct to routine histopathology for the reproducible identification of neoplasms containing a mixture of oligodendroglial and astrocytic phenotypes.

A 49-year-old female presented with a 2-year history of occipitalgia, a 3-month history of dysesthesia, and dull sensation of the left upper extremity. T1-weighted magnetic resonance (MR) imaging revealed a low-intensity mass without gadolinium-diethylenetriaminepenta-acetic acid enhancement extending from the cisterna magna to the spinal canal. T2-weighted MR imaging revealed a high-intensity mass. Neuroradiological findings were inadequate to establish the mass as intra-axial or extra-axial. Operative findings discovered an intra-axial mass which was totally removed. Histological examination found the mass was an oligoastrocytoma. Cerebellar glioma developing exophytically is very rare. Adequate surgical removal is possible and likely to be curative if total.

Only a few cases reported in the literature fulfil the currently established criteria for accepting the traumatic origin of some intracranial tumors. A case of post-traumatic glioma is presented. Several years after sustaining a commotive left parietal trauma, our patient developed symptoms of intracranial tumor. Neuroimaging (CT and MRI) showed a large neoplasia in the left temporo-parietal-occipital region, and stereotactic biopsy revealed a mixed glioma in continuity with the scar resulting from the trauma.

To determine the clinical correlation of histological grading systems of astrocytic tumors, we examined Kernohan’s grading system (the 1979 WHO [World Health Organization] grading system), Burger’s grading system (the 1993 WHO grading system), and Daumas-Duport’s grading system. Each grading system was applied to our cases, and its clinical correlation was evaluated by Kaplan-Meier’s survival curve. Subjects of the study, who were all adult (>15 years old), had astrocytic tumors that excluded mixed glioma, gliosarcoma, and pleomorphic xanthoastrocytoma. Thirty-eight of 157 intracranial astrocytic tumors, all located in the cerebral hemisphere, were selected. Our results indicated that the Daumas-Duport grading system and that of Burger were simple and easy to use, and showed good clinical correlation. Kernohan’s grading system, however, had poor clinical correlation.

Mixed oligoastrocytoma was categorized into mixed glioma by the Would Health Organization (WHO) classification, and its clinical behavior has not been well investigated. The therapy and histology of mixed oligoastrocytoma were previously investigated in studies on oligodendroglioma, but there have been few reports on radiotherapy and chemotherapy for mixed oligoastrocytoma. We diagnosed mixed oligoastrocytoma in 20 patients by immunohistochemical examination, assessed the proliferative ability of mixed oligoastrocytoma in these cases using MIB-1, a monoclonal antibody for proliferation marker Ki67. We also investigated the prognosis of these patients. The 20 patients with mixed oligoastrocytoma included 11 men and 9 women ranging from 1 to 54 years in age (mean age, 39 years). Of the 20 patients, 7 received radiotherapy only, 1 received chemotherapy only, 8 received both radiotherapy and chemotherapy, and 4 received neither treatment. Currently, 12 have survived for 1–13 years; 6 patients had recurrence with death ensuing in 2 of the 6. Malignant transformation was documented histologically in 5 of the 6 patients with recurrence. The 20 patients were divided into a recurrence group and a nonrecurrence group; Furthermore, mixed oligoastrocytoma was classified into type A, in which the lesion had oligodendroglial components and astrocytic components that were relatively separate, and type B, a lesion in which oligodendroglial components and astrocytic components were present in a diffused and composite form.

Standardized postembedding immunoelectron microscopy was performed to demonstrate glial fibrillary acidic protein (GFAP) and vimentin in individual intermediate filaments to determine the diagnostic value of demonstrating ultrastructural and immunophenotypic characteristics of intermediate filaments in routine brain biopsy specimens. Dual expression of GFAP and vimentin was observed in the astroblastoma and astrocytes of Alexander's disease. The antigen availability for vimentin, however, was too low to allow reliable assessment of the GFAP:vimentin ratio in individual intermediate filaments and/or filament bundles. In meningioma, only vimentin positive intermediate filaments were found. GFAP positive intermediate filaments were present in all other specimens except the oligodendroglial components of the mixed glioma, which were devoid of intermediate filaments. GFAP positivity in the filamentous periphery and electron-dense core of Rosenthal fibers was demonstrated. Technical and tissue processing factors had a significant effect on particle density values obtained for individual specimens. Although the number, distribution, and density of glial intermediate filaments varies in different astroglial entities, correlation of particle density values determined by immunoelectron microscopy with relative GFAP concentrations in different lesions requires utmost caution. Nevertheless, application of the postembedding approach to routinely fixed biopsy specimens indicated an association of different entities with the exclusive presence of GFAP and/or vimentin in individual intermediate filaments, thus emphasizing the diagnostic value of intermediate filament typing for pathological characterization.

Neoplastic transformation occurs in all glial cell types of the human nervous system, producing a wide variety of clinico-pathological entities and morphological variants. Astrocytomas are most common and span an unusually wide spectrum, ranging from the slowly growing juvenile pilocytic astrocytoma to the highly malignant glioblastoma multiforme. Diffusely infiltrating astrocytomas of the cerebral hemispheres show an inherent tendency for progression towards a more malignant phenotype. This change is morphologically categorized in histologic grading schemes (e.g., WHO Grade II to IV) and is associated with the sequential acquisition of genetic alterations, including mutations in the p53 and homozygous deletions of the p16 tumour suppressor genes. Loss of heterozygosity on chromosomes 10 and 19q as well as amplification of the EGF receptor are largely restricted to malignant gliomas and thus considered late events in astrocytoma progression. Gliomas often show phenotypic expression of different glial cell lineages (e.g., oligoastrocytoma). Recent studies suggest that the occurrence of mixed gliomas is not indicative of a polyclonal origin but rather reflects altered gene expression, leading to a change in the balance of growth factors influencing glioma differentiation.

Recent studies have suggested that the triphenylethylene antiestrogen tamoxifen inhibits the proliferation in vitro of a substantial percentage of cell lines derived from adult high-grade gliomas, potentially acting through inhibition of the second messenger protein kinase C. These findings have formed the impetus for clinical trials of this agent in adults with malignant gliomas. However, it has previously remained uncertain whether tamoxifen has a similar inhibitory effect on the proliferation of pediatric high-grade gliomas, and whether low-grade gliomas, which constitute the majority of glial neoplasms in children, are also inhibited by this agent. To address these issues, the present study examined the effect of tamoxifen on proliferation and viability in a series of low-passage cell lines derived both from low-grade and high-grade pediatric gliomas. This agent was tested in three malignant gliomas, two pilocytic astrocytomas, two non-pilocytic low-grade astrocytomas, 1 mixed glioma, and 1 oligodendroglioma. Tamoxifen produced a dose-dependent inhibition of proliferation in two of the three malignant glioma cell lines and in each of the low-grade glioma cell lines with a 50% effective dose of approximately 3 µg/ml (5.4 µM), which is comparable to the IC50 for inhibition of PKC activity by this agent. No significant cytotoxicity was encountered at this concentration. However, complete elimination of proliferation was achieved with a dose of 10 µg/ml (17.8 µM), which produced a direct cytotoxic effect. We conclude that tamoxifen inhibits proliferation of cell lines derived from both low-grade and high-grade pediatric glial tumors in vitro at concentrations that may be achievable clinically with high-dose oral therapy. Accordingly, clinical trials using this agent have been initiated for children with high-grade glial tumors that have progressed after standard therapy to determine the safety and efficacy of tamoxifen for these patients.

We are studying the p53 gene profile in primary glial tumors by seeking alterations in the hybridization pattern of the tumor DNA probed with a p53 gene probe. This report documents a rearranged p53 gene with loss of the normal allele in a low-grade mixed glioma which has not recurred during 4-year follow-up. The tumor had a low 5-bromodeoxyuridine (BrdU)-labeling index and low AgNOR count. The p53 protein was not detected on immunochemical staining. To our knowledge, this is the first report of an altered p53 gene in a low-grade nonrecurrent glial tumor and highlights the presence of further checks and balances on the control of cell proliferation and other malignancy-associated phenotypes, even in an already-established tumor.

We reviewed the clinical course of 17 children who underwent surgical resection of an intra-axial cervicomedullary tumor between 1980 and 1992. The clinical symptoms, which reflected medullary dysfunction in nine children and cervical cord deficits in eight, were present for a mean of 2.1 years before diagnosis (range, 2 months to 7.5 years), and for at least 1 year in 80% of the patients. Neurodiagnostic imaging (MRI in 14, CT in 3) showed the tumor epicenter in the medulla in 11 and in the upper cervical cord in six. Surgery was performed for newly diagnosed tumor in 11 children, and for progressive disease in six who had received prior radiotherapy. The surgical resection was gross total in two and partial (60 to 95%) in fifteen. Fifteen patients had low-grade glial tumors (10 astrocytomas, four gangliogliomas, and one mixed glioma), and two had anaplastic gangliogliomas. Four-year progression-free and total survival rates after surgery for patients who had surgery as initial therapy were 70 and 100%; for those who had surgery at the time of progression, these were 41 and 62%. Postsurgical neurologic complications occurred in five children. Four of these children had received prior radiotherapy. Two of them already had severe preoperative deficits and three had moderate deficits that worsened after surgery. Twelve patients with mild deficits were unchanged or improved postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

✓ The authors report a series of 31 children under 17 years of age with primary spinal cord tumors who underwent radiation treatment following decompression laminectomy with or without tumor resection between 1959 and 1990. The tumors consisted of 15 astrocytomas, 11 ependymomas, one mixed glioma, one ganglioglioma, and three of unknown histology. Ten- and 20-year survival rates and 10- and 20-year relapse-free survival rates for the 28 patients with known histology were 80% and 53%, and 73% and 67%, respectively. Eleven patients (35%) had no resection, 14 (45%) had a partial resection, and six (19%) had a grossly complete resection. Eight patients (26%) are dead: five due to recurrent tumor, two due to a second malignant tumor, and one due to intercurrent disease. Primary tumor relapse or progression occurred in nine patients (29%), four of whom were salvaged. A second malignant tumor developed in four patients (13%), two of whom died. Local control of the tumor was finally achieved in 26 cases (84%), despite either grossly incomplete or no resection in 25 of these cases (81%). These statistics suggest that radiation treatment without resection may achieve long-term control in children with astrocytoma or ependymoma of the spinal cord.

Background: The central nervous system tumors are a rare neoplasm with little knowledge with Human Leukocyte Antigen (HLA) involvement. Primary brain tumors are cancers that originate in brain classified according to their appearance under a microscope as low grade (grade I and II) with diffuse astrocytomas, pliocytic astrocytomas, oligodendrogliomas, gangliogliomas, and mixed gliomas as common subtypes and high grade (grade III and IV). Materials and Methods: HLA associations in common glioma are reported from other parts of the world. The normal cancer treatment is surgery, followed by radiotherapy, and chemotherapy; nowadays immunotherapy is advised. HLA distribution in a Glioma patient was done based on serology and molecular techniques. The immune response gene studies have implicated the HLA allele association in most of the common diseases from India. Considerable variations are noted in HLA association with cancers; hence, we have summarized the HLA involvement in Glioma with respect to the literature. Results: HLA A*030101, A*310102, B*350101, B*4406, Cw*040101, Cw*070101, DRB1*070101, and DRB1*1001. Conclusion: Ethnic diversity and HLA polymorphism precipitate differential immune response genes involved in variable disease manifestations. Therefore, caste-specific HLA allelic specificity needs to be identified, which may help in early identification of the associated HLA allele and establishing clinical practices among glioma patients.

Histopathological features that suggest the diagnosis of ganglioglioma require, in most cases, confirmation by special stains to distinguish these tumors from other gliomas. For this purpose, immunostaining for synaptophysin, which has previously been shown to selectively label the cell surface of neoplastic ganglion cells, was used to retrospectively examine glioma tumor specimens. Sixty-three cases of ganglioglioma were identified. The files of the Division of Neuropathology of New York University Medical Center contained 45 tumors that had been diagnosed as ganglioglioma, of which 42 were verified by synaptophysin; three cases were reclassified, two as astrocytomas and one as a gangliocytic paraganglioma. Thus, a tumor identified as ganglioglioma based on other criteria was likely to be a ganglioglioma. The other 21 cases of gangliogliomas were originally diagnosed as astrocytoma or mixed glioma, but were shown by synaptophysin staining to be gangliogliomas. In some cases the ultimate diagnosis was obtained after radical surgery provided relatively abundant amounts of tissue, thereby limiting sampling errors, in contrast to the biopsies from which the original diagnoses were made. Histopathological review of these cases demonstrated that four features represent important clues to the correct diagnosis: 1) clusters of large cells potentially representing neurons (without such cells the tumor cannot be classified as a ganglioglioma); 2) no perineuronal clustering of the glial cells around the alleged neoplastic neurons; 3) fibrosis (desmoplasia); and 4) calcification. Binucleate neurons, previously suggested to be common in gangliogliomas, were not frequently found in this series, and lymphocytic infiltrates, while common, are so often found in other tumors that they gave no specific hint that any single neoplasm was a ganglioglioma. The glial elements were astrocytic in all cases, except that one tumor also had oligodendroglial and ependymal patterns. Four tumors also had small mature neurons, as seen in neurocytomas. Cells from one tumor were successfully grown in short-term tissue culture; the culture contained large dividing neurons with synaptophysin immunoreactivity as well as smaller dividing cells, demonstrating that the neuronal cells are a proliferating element in gangliogliomas.

We evaluated the treatment outcome of 17 patients with anaplastic oligodendroglioma and 17 patients with anaplastic mixed oligodendroglioma-astrocytoma. In the anaplastic oligodendroglioma group, eight patients were treated at the time of the initial admission with radiotherapy and adjuvant chemotherapy, and nine patients were treated at the time of recurrence with salvage chemotherapy. Three patients for whom adjuvant chemotherapy was not successful were also treated with chemotherapy at the time of recurrence. In the initial group, one patient had complete response, three had partial responses, and 4 had stable disease (response and stable disease, 100%), but all except one progressed within 10 months. Of the 12 patients who received chemotherapy during recurrence, there was 1 complete response, 2 partial responses, and 6 stable disease (response and stable disease, 75%), with long response duration and long survival (15-132+ mo). In the anaplastic mixed oligodendroglioma-astrocytoma group, 12 patients were treated at the time of the initial admission and 6 patients treated at the time of recurrence. The initial treatment resulted in two complete responses, three partial responses, and seven stable disease (response and stable disease, 100%), with most responses lasting longer than 12 months. The treatment of the patients with recurrent disease resulted in one partial response and five stable disease (response and stable disease, 100%), with a median time to progression of 6 months. These results suggest that aggressive treatment is beneficial for recurrent anaplastic oligodendrogliomas and mixed gliomas as well as initial mixed gliomas but may offer only minimal advantage over conventional radiotherapy for the initial treatment of anaplastic oligodendrogliomas.

Classification of the glial subset of neuroepithelial tumours is based on the predominant cell type. Admixture of other neoplastic cells occurs quite frequently and should not, unless substantial, lead to an excessive diagnosis of mixed gliomas.

Long-term survival after the diagnosis of malignant glioma is uncommon but not rare. To define better the population of patients who have extended survival with this disease, we reviewed the records of 22 of our patients who survived more than 4 years after the biopsy-proven diagnosis of anaplastic astrocytoma, malignant mixed glioma, or glioblastoma multiforme. Surprisingly, 21 of the 22 patients are still alive and being actively followed by the authors. The long-term survivors were typically young and with minimal or no functional impairment at the time of diagnosis. Survivals ranged from 4.2 to 15.8 years. The quality of survival was generally good, with the surviving patients having a mean Karnofsky Performance Score of 76. Three-quarters of the patients had no enhancement or mass effect on their most recent computed tomography scans. A review of the available literature, together with our own series, suggests that death from recurrent disease is unusual in glioma patients who survive more than 4 or 5 years.

Primary malignant neoplasms of the brain and spinal cord occurred in 20/718 male (2.8%) and in 13/717 female (1.8%) Crl:CD®Br strain Sprague-Dawley rats. Of 33 neoplasms, 30 were found in brain while 3 were in the spinal cord. In males and females, the most common brain neoplasm was astrocytoma (13 males, 9 females). Other neoplasms, granular cell tumor (1 male), mixed glioma (2 males, 1 female), reticulosis (1 male, 2 females), and oligodendroglioma (2 males), were especially uncommon. Spinal cord neoplasms included 2 schwannomas (1 male, 1 female) and an astrocytoma (1 male). The overall brain neoplasm incidence was similar for males (2.8%) compared to data compiled for this strain, and there was a 2-fold increase for females (1.8% vs 0.9%) compared to available incidence data.

Of 100 children with supratentorial gliomas (excluding gliomas of the anterior visual pathways) treated at the Children's Hospital of Pittsburgh from 1980 to 1990, 34 had malignant gliomas. Follow-up was adequate in 33 of these patients, and an antemortem diagnosis of dissemination of the malignant glioma via the cerebrospinal fluid (CSF) was made in 11. Of these 11, 8 were boys and 3 were girls; they ranged in age from 17 months to 16 years at the time of diagnosis of the primary glioma. The distribution of histological types was as follows: glioblastoma multiforme, 4; malignant oligodendroglioma, 3; anaplastic astrocytoma, 2; malignant mixed glioma, 1; and malignant ependymoma, 1. The interval between diagnosis and CSF dissemination ranged from 1 week to 59 months (median, 8 months). Survival after dissemination ranged from 3 weeks to 11 months (median, 4 months). Two patients were alive 5 and 3 months after diagnosis of dissemination, respectively. These 11 patients were compared with the other 22 patients who did not have CSF dissemination. The risk factors for dissemination suggested by our data were male sex, ventricular operative entry, multiple resections, and malignant oligodendroglioma. Because of the high incidence (33%) of CSF dissemination, postoperative evaluation of the craniospinal axis with gadolinium-enhanced magnetic resonance imaging should be performed on all children with supratentorial malignant gliomas. Moreover, since the mortality is extremely high once dissemination has occurred, craniospinal irradiation should be considered in children with one or more of the above risk factors, even before symptoms or definite radiological evidence of CSF dissemination emerge.

Methods: Pts with glioblastoma or anaplastic/mixed gliomas receive TMZ 200 mg/m2/day on Days 1–5, and XL765 qd in 28-day cycles. Pts must be on a maintenance TMZ dose of 200 mg/m2/day for at least one 28-day cycle prior to enrollment. Cycle 1 safety data determine dose-limiting toxicities (DLTs). Tumor response is assessed by the modified Macdonald criteria every 8 weeks. Results: As of 24Aug2009, 15 pts (12 with glioblastoma, 2 with mixed glioma and 1 diagnosed with anaplastic oligodendroglioma) have been treated with XL765 in combination with TMZ across 3 dose levels of XL765 (30, 40, and 60 mg qd). The MAD has been identified as 60 mg for the once-daily schedule. Two of 6 pts at the 60 mg XL765 dose level experienced DLTs: one pt experienced DLTs of Grade 3 brain edema and Grade 4 thrombocytopenia (these events were also reported as related SAEs) and the other pt experienced a DLT of Grade 3 diffuse maculopapular rash. Three additional pts experienced SAEs that were not attributed to study treatment. With the exception of the DLTs described above, all AEs reported for 12 pts (as of 03Aug2009) were Grade 1 or Grade 2. Preliminary data suggest no PK interaction between XL765 and TMZ. XL765 PK when given in combination with TMZ are consistent with the PK of single-agent XL765 (Exelixis study XL765-001), and TMZ exposure in this study is similar to that published for single-agent TMZ. At the 30 and 40 mg qd XL765 dose levels, inhibition of PI3K pathway signaling has been demonstrated in paired skin biopsies using immunofluorescent analysis of pAKT-T308, pAKT-S473, and p4EBP1. Based on an initial molecular assessment of archival tumor material the most common molecular alterations detected included MGMT promoter methylation (5 of 12 evaluated pts), PTEN point mutations (8 of 14 evaluated pts), and EGFR gene amplification (7 of 11 evaluated pts). Of the first 12 pts that were enrolled, six pts have remained on study for at least 16 weeks, one of whom continues on study for 50+ weeks (a total of 78+ weeks following chemoradiation). Archival tumor tissue from this pt exhibited MGMT promoter methylation, PTEN mutation, and EGFR amplification. Conclusions: XL765 in combination with TMZ is generally well tolerated at doses up to 40 mg qd. No apparent PK interaction between XL765 and TMZ has been observed. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B265.

Cis-diamminedichloroplatinum (CDDP) was administered by selective continuous internal carotid infusion to nine patients with malignant brain tumors, including five glioblastomas, one mixed glioma, and three metastatic tumors. CDDP was infused through a catheter in the internal carotid artery at 100 mg/hr in all cases, except one glioblastoma case in which the lower rate of 10 mg/hr was used. The results of CDDP concentration measurements were: 1) CDDP in the blood peaked at termination of CDDP infusion and then decreased slowly, 2) CDDP infiltrated intratumoral cysts and accumulated there, 3) CDDP in the cerebrospinal fluid peaked 6-18 hours after infusion, and 4) the tumor/plasma CDDP ratio varied from 2 to 8. The size of tumors decreased moderately in three of the nine cases, but no complete response was achieved. The histological changes due to CDDP were observed in the tumor tissue and were absent in the normal brain parenchyma.

Proliferating cell nuclear antigen (PCNA) is a 36-kDa DNA polymerase-σ auxiliary protein which accumulates in the nucleus during S phase of the cell cycle. Immunohistochemical labeling indices (LI) of PCNA and Ki-67 were compared using an avidin-biotin complex method on frozen sections of 27 nervous system tumors, 3 normal cerebral cortices, and 3 peripheral nerves. In glial tumors, PCNA and Ki-67 LI increased with increasing tumor grade (Daumas-Duport system). In 5 low-grade glial tumors, PCNA and Ki-67 LI were ≤1%, except for one optic nerve glioma (Ki-67 LI=6%). In 7 grade 3 astrocytomas, and 1 mixed glioma, PCNA LI were ≤1–1.5%, while Ki-67 LI were 2%–10%. In 7 grade 4 astrocytomas and 1 metastatic carcinoma, PCNA LI ranged from 6%–15% while Ki-67 LI ranged from 17%–30%. In 5 of 6 schwannomas, focally high PCNA LI (4%–65%) were noted, despite low LI with Ki-67 (≤1.6%). Scattered normal schwann cell nuclei also stained with PCNA, but normal cerebral cortex did not. These data suggest that: (1) in higher-grade gliomas, PCNA may be a more specific S-phase marker, although a less sensitive proliferation marker, than Ki-67; (2) PCNA LI do not distinguish low-grade gliomas from grade 3 astrocytomas; (3) in schwannomas, PCNA may not reflect proliferative activity since it seems to react with an epitope present in normal schwann cells; and (4) the variable PCNA staining pattern introduces greater difficulties in cell counting than with Ki-67. These factors may limit the use of this anti-PCNA antibody in evaluating nervous system tumors.

The expression of epidermal growth factor receptor (EGFR) was determined in cryosections of 42 human gliomas using biotinylated epidermal growth factor (B-EGF) and two monoclonal antibodies (mAb) against EGFR. All gliomas were found to express EGFR when examined with B-EGF, whereas 33 expressed EGFR when examined with the two mAbs. The highly malignant gliomas (glioblastomas and anaplastic astrocytomas) had a more heterogeneous staining pattern and a larger proportion of tumour cells staining strongly with B-EGF than did the low-grade gliomas (astrocytomas, oligodendrogliomas, mixed gliomas, and ependymomas). This indicates that high-grade gliomas contain more tumour cells rich in EGFR than do the low-grade gliomas. Reactive astrocytes, ependymal cells, and many types of nerve cells (cerebral cortical pyramidal cells, pyramidal and granular hippocampal cells, Purkinje cells, cerebellar granular cells and neurons in the molecular layer of the cerebellum) expressed EGFR, whereas small neurons and normal glial cells were not found to express EGFR.

This immunocytochemical study was undertaken to clarify the histogenesis of ethylnitrosourea-induced rat brain tumors. The tumors induced in offspring of Sprague-Dawley rats injected with ethylnitrosourea on day 18 of gestation were used in these experiments. Controls consisted of pregnant Sprague-Dawley rats similarly injected with saline alone. Both microtumors (less than 1 mm) and macrotumors were examined immunocytochemically. The cells present in both macro- and microtumors were reactive with anti-Leu 7, an antibody which recognizes oligodendrocytes. Intermixed with, but distinct from the tumor cells were glial fibrillary acidic protein positive cells morphologically identical to astrocytes found in other areas distant to tumors in the treated animals, and in controls. These data suggest that both early and late tumors are oligodendrogliomas, not astrocytomas or mixed gliomas, and that the cell of origin of the tumor is the oligodendrocyte rather than an uncommitted stem cell as previously suggested.

The ganglioside composition of 15 cases of meningioma, 15 cases of astrocytoma, 5 cases of neurinoma, 4 cases of ependymoma, 3 cases of metastatic brain tumor and 1 case each of mixed glioma, oligodendroglioma, medulloblastoma, embryonal carcinoma, and cultured glioma cell line were analyzed by thin-layer chromatography. The GM2, GD3, and GD2 content of the tumors was determined using specific monoclonal antibodies (MAb). Cases were grouped according to the difference in ganglioside pattern and various clinical features. In meningiomas and astrocytomas, GM3 and GD3 were the major gangliosides. The tumor content of the rather simple gangliosides (GM3, GM2, GD3, GD2) increased or was almost equal to that of normal tissue (leptomeninges tissue in the case of meningiomas, and brain tissue in the case of astrocytomas), while the tumor content of complex gangliosides (GM1, GD1a, GT1a, GT1b) decreased as compared with normal tissue. The GM3 content of meningiomas increased in middle-aged patients, who comprised the majority of the patients with these tumors. The GD2 content decreased in middle-aged patients with initial symptoms of meningioma within a year. The GM3 content of astrocytomas decreased in patients who underwent radiotherapy. The amount of GM3 and GD3 increased in small tumors. GM3 may be related to the early proliferative stage. The ganglioside patterns of brain tumors are shown in this study to differ according to clinical features and also to be changeable in their clinical courses.

Six-month-old Fischer rats (F344) were given the carcinogen methylnitrosourea in their drinking water. Of the induced brain tumors, four were established in culture and propagated as 78FR-G-219 (pleomorphic glioma), 78FR-G-299 (astrocytoma), 78FR-G-284 and 78FR-G-344 (mixed glioma) permanent lines. All cell lines produced S-100 protein and grew as tumors when inoculated s.c. or i.c. in syngeneic hosts. A comparative study of the antigenicity of these lines at different passage levels was carried out using native and chemically modified cells. Syngeneic rats were immunized with cells conjugated with dimethylsulfate and trinitrobenzene sulfonic acid. The immune response was characterized and quantified by an indirect immunofluorescence method and by a complement-dependent microcytotoxicity test. Chemical modification of the tumor cells enhanced antigenicity of the treated cells. The best results were attained with trinitrobenzene sulfonic-acid-treated cells and constituted a two-fold increase in the cytotoxicity index. Cytotoxicity values varied in the different cell lines. Antisera raised with trinitrobenzene sulfonic-acid-modified cells of all lines cross-reacted with cells of all lines. Cytotoxicity values were insignificantly reduced by absorbing the antisera with a variety of syngeneic tissues. Antisera raised against native syngeneic brain cells showed virtually no cytotoxicity for glioma cells. Antisera raised against syngeneic brain cells treated with trinitrobenzene sulfonic acid, however, were slightly cytotoxic for normal brain cells and glioma cells as well. The results of the present studies show that antigenicity of glioma cells can be definitely raised with trinitrobenzene sulfonic acid treatment. Furthermore, it would seem that haptenization of glioma-associated antigens may be a promising approach ot the study of glioma-host interactions.

Ultrastructural concentric laminations have previously been thought to be specific to oligodendroglioma. However, these structures were also recognized in fibrillary astrocytomas, a mixed glioma and a glioblastoma. These laminations continued or closely related to attenuated processes or cytoplasm of astrocytic tumor cells. In addition, some lamellae contained glial filaments. It is considered that the concentric laminations are derived from attenuated astrocytic processes and have no relationship with myelin.

In this review, we try to review concisely the incidence, genetic predilections, classification, and diagnosis of supratentorial gliomas (astrocytomas, oligodendrogliomas, and mixed gliomas) in children. While surgery and irradiation present the most commonly used and valuable modes of treatment, chemotherapy is a valuable adjunctive therapy. Used either with surgery and radiation in primary untreated patients or at recurrence (progression), chemotherapy can increase useful life. The late effects of treatment are primarily endocrine deficiencies and intellectual impairment; nevertheless, they are not of a degree to preclude aggressive therapy. In order to improve therapy, and because of the small number of patients with supratentorial tumors, collaborative multi-institutional trials should be encouraged.

Regional blood flow was measured in experimental brain tumors using iodoantipyrine labeled with carbon 14 and quantitative autoradiography. A total of fifteen oligodendrogliomas, sixteen mixed gliomas, one astrocytoma, one ependymoma, and three malignant schwannomas were studied in 9 rats. The mean tumor blood flows for all glioma classifications were similar, averaging 45 +/- 3 (standard error of the mean) ml . hg-1 . min-1. Flow was fairly uniform within individual oligodendrogliomas and there was no apparent correlation between blood flow and tumor size or location. The mixed gliomas were larger than the oligodendrogliomas and had a wider range of blood flow. Small focal areas of necrosis were observed in 7 mixed gliomas, and low flows were usually measured in these regions; these flows were not always the lowest regional values measured within the mixed gliomas or total group of tumors, however. Small tumor regions with increased vascularity, frequently with endothelial cell proliferation, were observed in oligodendrogliomas and to a greater extent in mixed gliomas; these regions were correlated with small elevations in blood flow (10 to 15 ml . hg-1 . min-1) in comparison with surrounding tumor tissue. Brain adjacent to tumor usually had higher blood flows than that in tumor periphery. Hemispheric differences in blood flow related to the site of primary tumor growth were not observed.

The authors reviewed the clinical information and pathology specimens from 29 children with diencephalic gliomas to determine whether any clinical or histopathologic feature correlated with prognosis. The median survival time for the entire group was 3.96 years. No symptom or sign at the time of diagnosis correlated with outcome. The tumors consisted of 25 astrocytomas or mixed gliomas and 4 malignant astrocytomas-mixed gliomas. Median survival time of the 25 children with astrocytomas-mixed gliomas was 4.8 years, compared with 0.5 years for the 4 children with malignant tumors. The tumor histology was relatively uniform: most tumors were moderately cellular astrocytomas with pleomorphism and hyperchromatism but without mitoses, hemorrhage, or necrosis. High cell density and the presence of mitoses were the two histologic features significantly associated with poor prognosis; no child with mitosis survived longer than 14 months.

The distribution of the glial fibrillary acidic protein (GFAP) was investigated in sections of 131 paraffin-embedded brain neoplasms obtained at surgery or at autopsy. The unlabeled antibody immunoperoxidase (peroxidase-antiperoxidase, PAP) method was used. Equally good results were obtained from 17-year-old material and from recent material derived at surgery or autopsy and fixed with Bouin fluid or phosphate-buffered formalin. The perikaryons and processes of reactive astrocytes showed the most intense stain for GFAP. Positive reaction to antibody against GFAP of varying intensity was demonstrated in astrocytomas of various grades of malignancy (32 of 32), glioblastoma multiforme (10 of 10), subependymal giant cell astrocytoma (1 of 1), ependymoma (2 of 10), subependymoma (4 of 4), and astrocytes in mixed neoplasms (8 of 8). In two neoplasms diagnosed as malignant astrocytomas and in four neoplasms diagnosed as glioblastoma multiforme, GFAP stain was limited to a few neoplastic cells. Usually the stain was more intense over processes than in perikaryons, with the exception of gemistocytic astrocytomas and the giant cells in glioblastoma multiforme, which showed an equally, intense stain over perikaryons and processes. The periphery of Rosenthal fibers was intensely positive for GFAP. In astrocytic neoplasms the number of GFAP-positive cells and the intensity of the stain were inversely proportional to the degree of malignancy. In the following neoplasms the reaction for GFAP was negative: oligodendroglioma (3), oligodendroblastoma (I), medullo-blastoma (3), medulloepithelioma (1), neuroblastoma (1), pineocytoma (1), typical teratoma of the pineal (1), fibrosarcoma (1), pituitary adenoma (2), craniopharyngioma (1), chordoma (1), chemodectoma of globus jugulare (1), metastatic carcinoma (17), and lymphoma (8). In one of 18 meningiomas, endogenous peroxidase activity was seen in mast cells. All meningiomas studied were negative for GFAP. In one of six neurinomas a positive reaction for GFAP was detected over processes. The authors concluded that the immunostain for GFAP is useful in the diagnoses of astrocytic neoplasms and of mixed gliomas.

The aim of this work was to elucidate the direction and time-course of transport processes which may affect the accumulation of oedema associated with experimental brain tumours. Astrocytomas were produced in BD-IX rats by intracerebral injection of cultured neoplastic glial cells. The cell line used was cloned from a culture of a primary mixed glioma induced by transplacental administration of N-ethyl-N-nitrosourea (ENU). At various times after cell injection the protein tracer horseradish peroxidase (HRP) was given to tumour-bearing rats, either intravenously or into the lateral ventricles of the brain. The movement of the HRP into tumours and surrounding brain either from blood or from ventricular cerebrospinal fluid (CSF) was studied by light and electron microscopy at various intervals after the injection of the tracer. The time-course of subsequent clearance of the HRP from the tumours and surrounding brain was also investigated. After intravenous injection, HRP rapidly penetrated all vascularised tumours and became evenly distributed within 10–20 min. The HRP remained present in sufficient quantity within the tumours to maintain this intensity for several hours, after which it gradually disappeared, showing no reaction product after 12 h. After intraventricular injection, HRP penetrated periventricular brain tissue up to a maximal distance 1–2 mm within 2 min, and the reaction product remained visible in this region for at least 20 min. In all tumour-bearing animals, HRP penetrated further into periventricular tumour tissue than into adjacent brain tissue. In large tumours HRP reaction product was seen up to 7 mm from the ventricular ependymal lining, although permeation to this distance took up to 10 min.

The clinicopathologic features of eight new cases of combined intracranial sarcoma and glioma are described. This type of mixed cerebral tumor is histologically characterized by a peripheral distribution of the gliomatous elements in relation to a more centrally situated meningeal or intracerebral sarcoma, and by the frequent presence of gradual transitions from reactive to frankly neoplastic astrocytes. In six of the eight cases, the additional development of either infiltrating astrocytoma or frank glioblastoma in the adjacent brain was demonstrated; this was interpreted as a further expression of malignant glial reaction. It is suggested that these tumors be termed "sarcogliomas" to distinguish them from the type of mixed glioma and sarcoma that has recently been redesignated "gliosarcoma."

In order to clarify the relationship between cellular characteristics of rat brain tumors and the administration time of chemical carcinogens, the incidence and morphology of microtumors in the offspring of five pregnant Sprague-Dawley rats injected with ethylnitrosourea (ENU) intraperitoneally on the 11th day of gestation (Group I) were compared with those of six pregnant rats injected with ENU on the 18th day of gestation (Group II). Twenty-four microtumors and 6 macrotumors were obtained in Group I and 58 microtumors and 5 macrotumors in Group II. Histologically, the macrotumors of Group I showed a poorly differentiated pattern which corresponded to primitive spongioblastomas in comparison with those of Group II which resembled human mature oligodendrogliomas, astrocytomas or mixed gliomas. The constituent cells of the microtumors of both groups were immature and were morphologically similar to each other. Immunohisto-chemically, the cells of microtumors of both groups were negative for Leu 7 and glial fibrillary acidic protein. Microtumors in Group I showed more infiltrative proliferation than those in Group II and had indistinct borders. The 3H-thymidine labeling index of the constituent cells of Group I was significantly higher than that of Group II (p

To study the expression of two different subclasses of intermediate filaments in ethylnitrosourea-induced rat cerebral gliomas, the number of cells immunopositive for each subunit protein, vimentin and astroprotein (GFAP), was quantitatively analyzed. Vimentin is a subunit protein of non-specific intermediate filaments which appear transiently in immature glial cells, while astroprotein (GFAP) is a subunit protein of glial filaments, normally expressed in mature astrocytes. Although most normal astrocytes were negative for vimentin, many tumor cells showed weak to strong immunoreaction for vimentin. The expression of vimentin was more frequent and intense in anaplastic forms of gliomas than in benign forms. Accordingly, the vimentin/GFAP ratio [the number of vimentin-positive cells divided by the number of astroprotein (GFAP)-positive cells] was increased from 0.23 to 1.86, and from 0.26 to 1.85, respectively, as oligodendrogliomas and mixed gliomas become anaplastic. The present study demonstrated that the immunohistochemical study for those two subclasses of intermediate filaments can provide important informations on the cell biological nature of glial tumors.

Four mixed oligodendrogliomas and astrocytomas were investigated by electron microscopy and immunohistochemistry (GFAP, NSE and MBP). GFAP-positive oligodendroglioma cells and their transitional cells to GFAP-negative oligodendroglioma cells were present, suggesting successive morphological changes of astrocytic tumor cells. NSE-positive cells, suggestive of residual neurons, also exhibited round nuclei and perinuclear halos. On electron microscopy, oligodendroglioma cells that showed glial filaments, vascular end-feet and zonulae adherentes were occasionally present. The tumor cells with or without astrocytic characteristics showed common features of cytoplasmic organelles. These findings suggest that most oligodendroglioma cells in mixed gliomas are of an astrocytic nature and that characteristic microscopic features of oligodendroglioma are of a common cellular form that can be taken by various types of cells under certain circumstances.

70 BD-IX rats, in which chemically induced mixed gliomas have been transplanted intracerebrally, were investigated by microangiography. The pattern and the degree of tumor vascularisation of all animals was correlated with the histological findings. Depended on the type of the tumor different localisations of tumor growth could be found: G XII-gliomas preferred the juxtaventricular region and subarachnoid space whereas GL 2.2-gliomas mainly grew as solid intracerebral space occupying lesions. Microangiograms of all tumor stages from the 14th to 42nd day after transplantation revealed a typical vascular pattern consisting of lacunar, glomerulose and netlike vessels. Further, necrosis, bleedings into the tumor, and irregularities of the capillary network could be demonstrated. The volume, age and vascularisation of the tumors are correlated and the results are discussed with regard to the principles of tumor growth and malignancy.

The local use of radionuclides in the management of neoplastic processes was initially considered over 80 yr ago and has enjoyed increasing enthusiasm in the treatment of somatic and central nervous system tumours during the past 30 yr. The marriage of complex neuroimaging techniques and modern stereotactic devices has markedly enhanced the technical precision of interstitial radiobrachytherapy of malignant cerebral neoplasms. In applying these techniques, it is imperative to achieve an optimal placement of radionuclide sources in order to develop a geometrically homogenous, controlled distribution of radiation. Critical considerations include determination of tumour volume and contour, and development of a homogenous dose rate (dependent upon multiple sources at varying intensity) that will not only effect tumour cell kill but do this without excessive production of radionecrosis which necessitates craniotomy because of mass. Using the Brown-Roberts-Wells (BRW) stereotactic guidance system and an image-defined, volumetrically determined target, implants of multiple iridium 192(192Ir) sources were used to establish appropriate isodose envelopes. A methodology for achieving the described objectives is detailed as it applies to a variety of malignant intracerebral neoplasms (glioblastoma multiforme, malignant astrocytoma, malignant mixed glioma, primary cerebral lymphoma, metastatic carcinoma and malignant pineal region tumours). Technical realization of precision implantation relying upon imaging data may be acheived with this method with satisfactory responses that are dependent upon histological tumour type and the morphology of the tumour distribution as related to the image. Early and late complications related to the surgical technique and radionuclide applications were less than 5%. Although encouraging, these techniques require further definition and greater data accrual before uniform application outside major medical centres can be justified. It is anticipated that improvement in results with intrinsic gliomas and other invasive neoplasms will be realized with further definition of tumour boundaries by tract biopsy techniques and concurrent utilization of hyperthermia and brain protective methods.

Five human brain tumours (3 glioblastomas and 2 astrocytomas) and 5 rat brain tumours induced in Sprague--Dawley animals by systemic administration of N-methyl-N-nitrosourea (3 pleomorphic gliomas and 2 mixed gliomas) were studied. The human brain tumours were surgical specimens excised from patients with no cranial surgery prior to their disease. The experimental brain tumour had been adapted to tissue culture, propagated in vitro and then transplanted to immunocompetent and immunodeficient rats of the same stock. The above-described material was selected in consideration of the mononuclear cell infiltrates occurring in these tumours. Frozen sections of human and rat gliomas, the latter both primary and transplanted, were prepared and investigated as to the presence of T-lymphocytes within the mononuclear round cell infiltrates. This was done with the indirect immunofluorescence method using rabbit antisera against man and rat T-lymphocytes. With this technique a variable percentage of T-lymphocytes was demonstrated in the cell infiltrates of human and rat gliomas alike. The tumour transplanted in thymectomized rats showed only isolated, scattered, positive-reacting cells, i.e., cells recognizable as T-lymphocytes by the above method. The results can be interpreted as circumstantial evidence for the occurrence of tumour-specific and/or tumour-associated antigens in the parenchymal cells of spontaneous and chemically-induced gliomas.

The distribution and role of microtubules and filaments in the neoplastic astrocytes of experimental gliomas Neoplasms of the nervous system were induced transplacentally by giving N-ethyl-N-nitrosourea (ENU) to pregnant rats on the 15th day of gestation. Astrocytomas and mixed gliomas with a significant astrocytic component were selected in order to study the distribution of microtubules and filaments in neoplastic fibrillary astrocytes. Electron microscopy of these gliomas revealed a population of pleomorphic astrocytes at various stages of differentiation. Poorly differentiated neoplastic astrocytes showed many microtubules but few filaments. In moderately differentiated cells there was a decrease in the number of microtubules with a concurrent increase of filaments. In well differentiated neoplastic astrocytes filaments dominated the cytoplasm forming thick, tightly packed bundles at the periphery of the cells and in the large processes, while occasional microtubules were intermingled with shorter and looser bundles of filaments. Thus, neoplastic fibrillary astrocytes in ENU-induced gliomas simulate the various stages in the differentiation of normal fibrillary astrocytes. This suggests that the ratio of microtubules to filaments may be one of the more discriminating criteria by which the degree of differentiation of neoplastic astrocytes can be established.

The effects of glia maturation factor (GMF) on cell proliferation and differentiation were investigated with 3 astroglioma cells (GE-12, C6, and GA-1), Schwannoma-like cells (354A), and mixed glioma cells (LRM-55). In the exponentially growing phase the growth rates of all glioma cells were enhanced by GMF regardless of the presence or absence of serum, but the factor failed to make the saturation density surpass the control level observed in the medium without GMF even in the chemically defined medium (N2 medium). GMF markedly lowered the saturation density of Schwannoma-like cells in N2 medium. Although GMF increased the intracellular content of S-100 protein 10-fold and 2′,3′-cyclic nucleotide phosphohydrolase activity 1.5-fold in Schwannoma-like cells, GMF conversely decreased the S-100 contents and glycerol phosphate dehydrogenase activity in astroglioma cells. All the astroglioma cells secreted into the culture medium large quantities of a growth-promoting factor(s) which had similar chemical properties to those of GMF and stimulated the proliferation of normal glioblasts; but Schwannoma-like cells did not, although they produced a small amount of such a factor(s). These findings imply that astroglioma cells are deprived of the differentiation-promoting response to GMF while Schwannoma-like cells still preserve the response in addition to the proliferative response to GMF.