Loss of function of the tumor suppressor gene PTEN is more frequently encountered in high-grade malignant gliomas than in low-grade gliomas. High-grade gliomas are characterized by their extremely invasive behavior, suggesting that PTEN is one of the important regulators of cell motility and that alterations of its coding gene contribute to a much more invasive tumor cell phenotype. In order to clarify a role of PTEN in glioma invasion, we introduced the wild-type PTEN gene into human malignant glioma cell lines and investigated their motile and invasive activity in a brain slice model that presents circumstances analogous to normal brain conditions in vivo. In addition, we analyzed biochemical and molecular changes resulting from the transfer of PTEN in the glioma cells. Infection of recombinant replication-defective adenovirus vector containing the wild-type PTEN cDNA (Ad5CMV-PTEN) significantly inhibited the cell migration and invasion activities of PTEN-mutated glioma cell lines in in vitro migration and chemoinvasion assays. In an organotypic brain slice model, co-culture of glioma spheroids and rat brain slices demonstrated that Ad5CMV-PTEN transfected cells failed to invade surrounding normal brain tissues. Ad5CMV-PTEN transfer into the glioma cell lines lacking the wild-type gene product decreased the levels of matrix metalloproteinase (MMP)-2 mRNA and inhibited the enzymatic activities of MMP-2 and MMP-9. In contrast, mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-2 was upregulated by the PTEN gene transfer. Introduction of PTEN gene in glioma cell lines markedly reduced the levels of Rac-GTP and Cdc42-GTP, activated forms of these small GTP-binding proteins, and decreased the phosphorylation levels of focal adhesion kinase. These results suggest that PTEN inhibits glioma cell invasion in two ways: suppressing proteolysis of the extracellular matrix by MMPs and modulating the migratory activity of glioma cells to a less motile nature by inactivating two Rho-family GTP-binding proteins, Rac and Cdc42.

BACKGROUND: Radiation treatment of GCT brain, in particular germinomas which are highly radio-sensitive,over the years has evolved from the cranio-spinal irradiation(CSI) to more conformal treatment like whole ventricle radiation followed by tumor bed boost (WV + TB), without compromising the results. We report our experience of treatment outcome of patients treated consecutively over a period of more than ten years with both the methods. METHOD: Twelve consecutive patients registered and treated in radiotherapy department between 2000 and 2013 after surgery (biopsy/decompression) and chemotherapy, were analysed in December 2013. Total Number (Histo-pathology) 12 (Germinoma-9, Non-Germinoma-2, No histology-1); Median age (Years) 13 (Range 5-24 years); Gender-M/F (%) 10:2(83:17); Co-morbidities None; Pre-Surgery KPS .90 (92%); Surgery (n) Biopsy/Decompression+ VP shunt (11), No Surgery (1); Sub-site Pineal-7(58%), Supra-sellar-5(42%). TREATMENT: Ten patients received 3D-CRT, while two received IMRT. Three received CSI while nine received WV + TB. CSI dose ranged from 23.4 Gy -36 Gy in 13-20 fractions. For WV the intended dose was 36Gy/20 fractions followed by 9Gy/5 fractions to TB. Pre-radiation all received combination chemotherapy, cisplatin or carboplatin + etoposide + irinotecan. RESULTS: All the patients tolerated and completed treatment with no serious adverse effects. Follow-up was done with serial tumor markers, hormonal, visual, auditory assessment and MRI. Two patients,both non-germinomas treated with CSI progressed and died with-in one year of treatment. Ten patients (9-germinomas, 1-no histology) till date are doing fine,without any loco-regional or distant failures. Ten year overall survival is around 80%.Two patients have developed hormonal imbalance and are on treatment,while one of them developed progressive bilateral optic atrophy which was present prior to radiotherapy. CONCLUSION:Our results are comparable with the reported literature.The overall survival in Germinomas is 100%,Treatment related effects are minimal as a result of reduced dose and limited treatment volume,-contributing possibly to better outcome along with various other reasons. BACKGROUND: Intracranial germ cell tumor (ICGCT) represents 3-15% of pediatric brain tumors. According to the current WHO classification, ICGCTs are classified as germinomas and non-germinomatous germ cell tumors. Germinomas are exquisitely radiosensitive, and chemo-radiotherapy is equally effective. Non-germinomatous germ cell tumors, though more aggressive than germinomas, can be treated effectively with intensive chemo-radiotherapy. ICGCTs in infants and very young children are typically mature teratomas which have excellent outcome after gross total resection. ICGCTs excluding mature teratomas, in this young age group, are extremely rare. There is also no published series or reported incidence of ICGCTs which excludes mature teratomas in children younger than 3 years of age. METHODS AND MATERIALS: We describe a series of 15 ICGCTs excluding mature ter...