Malignant transformation of a gangliocytoma/ganglioglioma into a glioblastoma multiforme: a molecular genetic analysis. Case report.

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.

Homozygous deletion of INK4a/ARF genes and overexpression of bcl-2 in relation with poor prognosis in immunocompetent patients with primary central nervous system lymphoma of the diffuse large B-cell type.

Only a few reports have been published on molecular genetic alterations in primary central nervous system lymphomas (PCNSLs) of the diffuse large B-cell type and no reports have addressed the correlation between the genetic alterations and clinical course of the patients with this neoplasm. Thus, the molecular background of the PCNSL and its importance for the clinical course of the patients are still unclear. We investigated a series of 14 patients with PCNSL to determine structural alterations of the INK4a/ARF, MDM2, and TP53 genes, the status of bcl-2 and bcl-6 protein expression, and the clinical course of the patients (i.e. their survival time after diagnosis). No structural alterations of MDM2 and TP53 genes were found. Only INK4a/ARF genes whose expression affects both the p161NK4a-Rb and p14ARF-mdm2-p53 pathways in the regulation for cell cycle and apoptosis, showed an alteration of the homozygous deletions at a high frequency (nine of 14 patients: 64%). This specific alteration was not related with the bcl-6 expression, but a relation was shown with overexpression of the bcl-2 anti-apoptotic protein (p = 0.036, chi-square test), as well as a shorter patient survival (p = 0.044, Wilcoxon test). There was only a tendency, not a significant correlation, in which the patients with bcl-2 overexpression resulted in poor prognosis (p = 0.149). The present study is the first to suggest that the INK4a/ARF gene homozygous deletions and overexpression of the bcl-2 protein may be correlated with each other and together serve as important predictors for the prognosis of patients with PCNSL.

Alterations of the INK4a/ARF locus in human intracranial germ cell tumors.

Little is known about the molecular mechanisms responsible for the development of intracranial germ cell tumors (ICGTs). Recently, we demonstrated that the balance of the p53-mdm2 interactions is disrupted in ICGTs. The p14ARF product, a tumor suppresser gene located on the INK4a/ARF locus, acts as one of the major factors affecting p53-mdm2 interactions via its binding to mdm2 and the stimulation of mdm2 degradation. To evaluate whether genetic alterations of the INK4a/ARF locus occur in the genesis of ICGTs, we analyzed the INK4a/ARF genes in 21 ICGTs-10 pure germinomas and 11 nongerminomatous germ cell tumors. Fifteen (71%) of the 21 ICGTs displayed genetic alterations, including 14 homozygous deletions and 1 frameshift mutation. Furthermore, the frequency of the alterations was higher in pure germinomas [9 (90%) of the 10] than in nongerminomatous germ cell tumors [6 (55%) of the 11; P = 0.09]. These data suggested that INK4a/ARF gene abnormalities could play an important role in the genesis of ICGTs, especially in pure germinoma.

Molecular analysis for p53 and mdm2 in intracranial germ cell tumors.

Intracranial germ cell tumors (ICGTs) are uncommon neoplasms. The histological appearance of ICGTs is indistinguishable from that of the usual testicular germ cell tumors (TGTs). Recently, several reports have associated molecular abnormalities of p53 and mdm2 in TGTs with their malignancies. However, whether ICGTs are associated with molecular abnormalities is still unknown. We analyzed a series of 16 ICGTs for mutations in the TP53 gene by single-strand conformation polymorphisms, and for amplification of the MDM2 gene using differential PCR. In addition, the same 16 tumors were examined for p53 and mdm2 protein overexpression using antibodies directed against p53 [monoclonal antibodies (mAb) 1801 and DO7] and mdm2 (IF2), respectively. Twelve (75%) and 2 (13%) of the 16 ICGTs reacted with DO7 and PAb1801, respectively, and 1 (6%) carried a TP53 gene mutation. Thirteen (81%) of the 16 ICGTs reacted with IF2, and 3 (19%) carried MDM2 gene amplification. The less frequent TP53 gene mutation compared with MDM2 gene amplification, and the frequently expressed p53 and mdm2 protein, are similar to the case for TGTs. It is tempting to speculate that ICGTs might have the same cellular origins as TGTs with abnormalities in p53 and mdm2, which could play an important role of tumorigenesis.

De novo spinal teratoma after treatment of an intracranial germ cell tumor.

The authors report an extremely rare case of de novo spinal teratoma after treatment for intracranial germ cell tumor. A 17-year-old male developed pain of bilateral lower extremities and urinary retention 18 months after complete remission of intracranial mixed germ cell tumor. Magnetic resonance imaging revealed a huge spinal tumor associated with spina bifida occulta. Total resection was performed, and histogenetical findings led to the diagnosis of a mature teratoma with normal p16 gene, whereas analysis of intracranial tumor showed p16 deletion. The spinal anomaly and genetic analysis strongly suggest that the spinal teratoma was a de novo tumor rather than a metastasis or dissemination of the original intracranial germ cell tumor.

Reversible hyposmia caused by intracranial tumour.

Two patients with hyposmia caused by an intracranial tumour recovered olfactory functions after craniotomy. The first case was a 68-year-old male with a tumour metastasized from the lung to the right frontal lobe. The second case was a 75-year-old male with meningioma of the right frontal lobe. Results of T & T olfactometry and venous olfaction tests also indicated suspected central hyposmia. Magnetic resonance imaging (MRI) indicated compression of the frontal lobe by intracranial tumour. Pressure on the olfactory centre located in the frontal lobe produced hyposmia. Decompression of the frontal lobe by craniotomy improved the sense of smell. Therefore, some cases of olfactory disturbance caused by intracranial tumour may be reversible if they are the result of simple compression of the olfactory centre.

Vibrio sp. strain NM 10, isolated from the intestine of a Japanese coastal fish, has an inhibitory effect against Pasteurella piscicida.

Vibrio sp. strain NM 10 with an inhibitory activity against Pasteurella piscicida K-III was isolated from the intestine of a spotnape ponyfish (Leiognathus nuchalis). This bacterium efficiently produced an antibacterial substance after growth at 20 degrees C for 24 h on 1/5 PYBG agar prepared with 50% seawater at pHs of 7.5 to 9.0. The antibacterial substance was heat labile and proteinaceous, with a molecular mass of less than 5 kDa, possibly a bacteriocin or a bacteriocin-like substance.