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M. Gazi Yaşargil, Klaus von Ammon, Andreas von Deimling, Anton Valavanis, Werner Wichmann and Otmar D. Wiestler

✓ The central neurocytoma has recently been added to the differential diagnosis of intraventricular tumors. Histopathologically, this tumor is characterized by a uniform neoplastic cell population with features of neuronal differentiation. Central neurocytomas occur in young adults, develop in the area of the foramen of Monro, and are usually associated with the septum pellucidum. Initial reports appeared to indicate that these tumors are benign lesions with a favorable postoperative prognosis. The authors present clinical and neuropathological findings in a series of eight patients with central neurocytoma. An anterior transcallosal microneurosurgical approach yielded good outcomes. Postoperative radiation therapy was restricted to two patients with a malignant variant of central neurocytoma and one patient with a recurrent tumor. Observations of anaplastic variants of this neoplasm in two cases and local tumor recurrences in three indicate that the biological behavior and postoperative prognosis of central neurocytoma may not always be as favorable as previously assumed.

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Florian Stockhammer, Ulrich-Wilhelm Thomale, Michail Plotkin, Christian Hartmann and Andreas von Deimling

Object

Oligodendroglial tumors harboring combined 1p and 19q loss (1p/19q LOH) are characterized by a favorable prognosis and response to chemotherapy and radiotherapy, but detection of 1p/19q LOH relies on postoperative procedures. The authors investigated the potential of fluorine-18–labeled fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) to predict 1p/19q LOH preoperatively in tumors whose appearance on initial magnetic resonance images was consistent with that of low-grade glioma.

Methods

The study population comprised 25 patients who had undergone preoperative FDG-PET followed by tumor resection. Neuronavigation ensured a precise match of FDG uptake wi th the site of biopsy. All tumor specimens were graded according to the World Health Organization (WHO) classification system. Microsatellite analysis was used to identify 1p/19q LOH.

In this series, 16 of 25 gliomas corresponded to WHO Grade II. In eight of these 16, 1p/19q LOH was detected. Raised glucose utilization within the tumor was seen in the six of eight WHO Grade II gliomas with 1p/19q LOH and in none of the WHO Grade II gliomas without this genetic alteration (p = 0.003).

Conclusions

These findings demonstrate the potential of FDG-PET to predict 1p/19q LOH in WHO Grade II gliomas.

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Yutaka Hayashi, Masayuki Iwato, Mitsuhiro Hasegawa, Osamu Tachibana, Andreas von Deimling and Junkoh Yamashita

✓ A gangliocytoma/ganglioglioma with no atypical or malignant features was subtotally resected from the right temporal lobe of a 16-year-old woman. A second resection was performed 8 years later to treat a locally recurrent lesion with increased cellularity that was diagnosed as a World Health Organization Grade II ganglioglioma on the basis of neuropathological examination. Molecular analysis of the recurrent tumor revealed a TP53 gene mutation, but no amplification of the epidermal growth factor receptor (EGFR) gene. Radiotherapy (60 Gy) was administered after the second resection. The patient returned 1 year later with a second focal recurrence. The specimen obtained during the third resection of tumor exhibited exclusively astrocytic differentiation, cellular pleomorphism with multinucleated cells, high mitotic activity, and endothelial proliferation. Therefore, the tumor was diagnosed to be a glioblastoma multiforme (GBM). Molecular analysis of tumor DNA from the second recurrent tumor demonstrated the presence of the TP53 mutation, which previously had been observed in the first recurrent tumor, but again no evidence of EGFR amplification. Findings demonstrate that the presence of TP53 mutation in progressed gangliogliomas should be interpreted as a progression-associated mutation rather than a consequence of treatment. This is the first report to indicate that the molecular pathways of gangliocytomas/gangliogliomas progressing to become GBMs may parallel those of diffuse astrocytomas progressing to become GBMs.

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Andreas Waha, Axel Baumann, Helmut K. Wolf, Rolf Fimmers, Jürgen Neumann, Dietmar Kindermann, Kathy Astrahantseff, Ingmar Blümcke, Andreas von Deimling and Uwe Schlegel

✓ Alterations in the epidermal growth factor receptor (EGFR) and its main ligand, transforming growth factor-α (TGFα), were investigated for a possible prognostic relevance in 125 astrocytic gliomas (44 World Health Organization (WHO) Grade II, 19 WHO Grade III, and 62 WHO Grade IV tumors). The TGFα and EGFR proteins were detected immunohistochemically using monoclonal antibodies. A positive immunoreaction to TGFa was detected in 33 (75%) of 44 WHO Grade II astrocytomas, 18 (95%) of 19 WHO Grade III astrocytoma, and 50 (81%) of 62 WHO Grade IV glioblastomas. No correlation between TGFα immunoreaction and duration of survival could be found. A positive EGFR immunoreaction was detected in seven (16%) of 44 WHO Grade II astrocytomas, five (26%) of 19 WHO Grade III astrocytomas, and 32 (52%) of 62 WHO Grade IV glioblastomas. Of these gliomas, 97 (26 WHO Grade II, 17 WHO Grade III, and 54 WHO Grade IV gliomas) were examined for EGFR gene amplification using a differential polymerase chain reaction assay. Amplification of the EGFR gene was detected in none of the WHO Grade II astrocytomas, one (6%) of 17 WHO Grade III astrocytomas, and 18 (33%) of 54 WHO Grade IV glioblastomas. Twenty-two of the tumors investigated showed a positive EGFR immunoreaction without detectable gene amplification (five WHO Grade II, four WHO Grade III, and 13 WHO Grade IV tumors). Gene amplification was invariably associated with a positive EGFR immunoreaction. For the entire study group, a strong correlation between EGFR alterations (gene amplification and positive immunoreaction) and survival could be found. However, this correlation only reflected the higher percentages of cases with EGFR alterations in malignant gliomas and was not an independent prognostic factor as determined by multifactorial analysis. These data demonstrate that EGFR alterations are frequent events in astrocytic gliomas and are largely restricted to glioblastomas. However, within one tumor grade they do not provide prognostic information.

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Armin P. Stangl, Ruth Wellenreuther, Doris Lenartz, Jürgen A. Kraus, Anil G. Menon, Johannes Schramm, Otmar D. Wiestler and Andreas von Deimling

✓ A significant number of patients with meningiomas develop multiple tumors without anatomical bridges. To understand the mechanism by which multiple meningiomas arise, the authors analyzed DNA from 39 multiple meningiomas in 12 patients to locate alterations in the neurofibromatosis type 2 (NF2) gene. This gene has been shown to be inactivated in meningiomas. No patient in our series had a family history of meningiomas or NF2. All tumors were investigated by single-strand conformation polymorphism analysis of the entire coding region of the NF2 gene and by direct DNA sequencing of altered fragments. The DNA from meningiomas in 10 patients carried NF2 gene mutations. In six of the 10 patients with NF2 mutations, all tumors in the respective individual exhibited the identical DNA alteration in the NF2 gene, thus indicating clonal origin. All four patients with more than two lesions had clonal meningiomas and four patients with two meningiomas each carried different mutations in their tumors. Analysis of constitutional DNA revealed a wild-type NF2 sequence in all 12 patients, thus excluding a forme fruste of NF2 in these cases. Our data demonstrate that the majority of multiple meningiomas with NF2 gene mutations are of somatic and clonal origin. Spread of tumor cells via the cerebrospinal fluid is the most likely mechanism to account for the development of these multiple meningiomas.

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Yasushi Ino, Magdalena C. Zlatescu, Hikaru Sasaki, David R. Macdonald, Anat O. Stemmer-Rachamimov, Sarah Jhung, David A. Ramsay, Andreas von Deimling, David N. Louis and J. Gregory Cairncross

Object. Allelic loss of chromosome 1p is a powerful predictor of tumor chemosensitivity and prolonged survival in patients with anaplastic oligodendrogliomas. Chromosome 1p loss also occurs in astrocytic and oligoastrocytic gliomas, although less commonly than in pure oligodendroglial tumors. This observation raises the possibility investigated in this study that chromosome 1p loss might also provide prognostic information for patients with high-grade gliomas with astrocytic components.

Methods. The authors report on seven patients with high-grade gliomas composed of either pure astrocytic or mixed astrocytic-oligodendroglial phenotypes, who had remarkable neuroradiological responses to therapy or unexpectedly long survivals. All of the tumors from these seven patients demonstrated chromosome 1p loss, whereas other genetic alterations characteristic of high-grade gliomas (p53 gene mutations, EGFR gene amplification, chromosome 10 loss, chromosome 19q loss, or CDKN2A/p16 deletions) were only found in occasional cases. The authors also assessed the frequency of chromosome 1p loss in a series of anonymous high-grade astrocytoma samples obtained from a tumor bank and demonstrate that this genetic change is uncommon, occurring in only 10% of cases.

Conclusions. Although any prognostic importance of chromosome 1p loss in astrocytic or mixed astrocytic—oligodendroglial gliomas can only be determined in larger and prospective series, these findings raise the possibility that some high-grade gliomas with chromosome 1p loss, in addition to pure anaplastic oligodendrogliomas, may follow a more favorable clinical course.

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Andreas von Deimling, David N. Louis, Klaus von Ammon, Iver Petersen, Tomas Hoell, Richard Y. Chung, Robert L. Martuza, David A. Schoenfeld, M. Gazi Yaşargil, Otmar D. Wiestler and Bernd R. Seizinger

✓ Although the loss of tumor suppressor genes and the activation of oncogenes have been established as two of the fundamental mechanisms of tumorigenesis in human cancer, little is known about the possible interactions between these two mechanisms. Loss of genetic material on chromosome 10 and amplification of the epidermal growth factor receptor (EGFR) gene are the most frequently reported genetic abnormalities in glioblastoma multiforme. In order to examine a possible correlation between these two genetic aberrations, the authors studied 106 gliomas (58 glioblastomas, 14 anaplastic astrocytomas, five astrocytomas, nine pilocytic astrocytomas, seven mixed gliomas, six oligodendrogliomas, two ependymomas, one subependymoma, one subependymal giant-cell astrocytoma, and three gangliogliomas) with Southern blot analysis for loss of heterozygosity on both arms of chromosome 10 and for amplification of the EGFR gene. Both the loss of genetic material on chromosome 10 and EGFR gene amplification were restricted to the glioblastomas. Of the 58 glioblastoma patients, 72% showed loss of chromosome 10 and 38% showed EGFR gene amplification. The remaining 28% had neither loss of chromosome 10 nor EGFR gene amplification. Without exception, the glioblastomas that exhibited EGFR gene amplification had also lost genetic material on chromosome 10 (p < 0.001). This invariable association suggests a relationship between the two genetic events. Moreover, the presence of 15 cases of glioblastoma with loss of chromosome 10 but without EGFR gene amplification may further imply that the loss of a tumor suppressor gene (or genes) on chromosome 10 precedes EGFR gene amplification in glioblastoma tumorigenesis.

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Cemaliye B. Akyerli, Şirin Yüksel, Özge Can, E. Zeynep Erson-Omay, Yavuz Oktay, Erdal Coşgun, Ege Ülgen, Yiğit Erdemgil, Aydın Sav, Andreas von Deimling, Murat Günel, M. Cengiz Yakıcıer, M. Necmettin Pamir and Koray Özduman

OBJECTIVE

Recent studies have established that hemispheric diffuse gliomas may be grouped into subsets on the basis of molecular markers; these subsets are loosely correlated with the histopathological diagnosis but are strong predictors of clinical tumor behavior. Based on an analysis of molecular and clinical parameters, the authors hypothesized that mutations of the telomerase promoter (TERTp-mut) mark separate oncogenic programs among isocitrate dehydrogenase 1 and/or 2 (IDH) mutant (IDH-mut) and IDH wild-type (IDH-wt) diffuse gliomas independent of histopathology or WHO grade.

METHODS

Four molecular subsets of the combined statuses of IDH and TERT-promoter mutations (double mutant, IDH only, TERT only, and double negative) were defined. Differences in age, anatomical location, molecular genetics, and survival rates in a surgical cohort of 299 patients with a total of 356 hemispheric diffuse gliomas (WHO Grade II, III, or IV) were analyzed.

RESULTS

TERTp-mut were present in 38.8% of IDH-mut and 70.2% of IDH-wt gliomas. The mutational status was stable in each patient at 57 recurrence events over a 2645-month cumulative follow-up period. Among patients with IDH-mut gliomas, those in the double-mutant subset had better survival and a lower incidence of malignant degeneration than those in the IDH-only subset. Of patients in the double-mutant subset, 96.3% were also positive for 1p/19q codeletions. All patients with 1p/19q codeletions had TERTp-mut. In patients with IDH-mut glioma, epidermal growth factor receptor or phosphatase and tensin homolog mutations were not observed, and copy-number variations were uncommon. Among IDH-wt gliomas, the TERT-only subset was associated with significantly higher age, higher Ki-67 labeling index, primary glioblastoma-specific oncogenic changes, and poor survival. The double-negative subset was genetically and biologically heterogeneous. Survival analyses (Kaplan-Meier, multivariate, and regression-tree analyses) confirmed that patients in the 4 molecular subsets had distinct prognoses.

CONCLUSIONS

Molecular subsets result in different tumor biology and clinical behaviors in hemispheric diffuse gliomas.