Randomized trial of chemoradiotherapy and adjuvant chemotherapy with nimustine (ACNU) versus nimustine plus procarbazine for newly diagnosed anaplastic astrocytoma and glioblastoma (JCOG0305).

PURPOSE: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA). METHODS: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108. RESULTS: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone (n = 55) or ACNU + PCZ (n = 56) in the intention-to-treat population were 27.4 and 22.4 months (p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone (n = 40) or ACNU + PCZ (n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events. CONCLUSIONS: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM.

Evaluation of neoadjuvant therapy in patients with nongerminomatous malignant germ cell tumors.

OBJECT: The authors evaluated the effectiveness of a neoadjuvant therapy (NAT) consisting of combined chemo and radiotherapy followed by complete resection of the residual tumor in patients with nongerminomatous malignant germ cell tumors (NGMGCTs). METHODS: The authors treated 14 consecutive patients in whom NGMGCTs were diagnosed based on elevated levels of the tumor markers α-fetoprotein, human chorionic gonadotropin, and the ß-subunit of human chorionic gonadotropin (ß-HCG). Chemotherapy and radiotherapy were performed, and after the serum tumor markers level was in the normal or near-normal range, the residual tumors were completely resected. RESULTS: Residual tumors were confirmed in 11 of the 14 patients after NAT, and total removal was successful in 10 of the 11 patients. In the other patient the residual tumor could not be completely excised because it was attached to a deep vein. The follow-up duration ranged from 1.2 to 22.2 years. The 5-year event-free and total survival rates were 86% and 93%, respectively. Although 3 patients died, 2 of tumor recurrence and 1 of a radiation-induced secondary tumor (glioblastoma), the other 11 are alive and without evidence of tumor recurrence. CONCLUSIONS: The authors consider their NAT protocol for NGMGCT to be highly effective in relation to survival for the patients with NGMGCT, but there are several quality of life issues that need to be resolved.

Successful treatment of neoadjuvant therapy for papillary tumor of the pineal region.

We report a boy who in 1994, at the age of 11, presented with headache and vomiting. The fi nal diagnosis was papillary tumor of the pineal region (PTPR). Magnetic resonance imaging (MRI) revealed a heterogeneous mass. Hydrocephalus was addressed by immediate ventricle drainage; subsequently, we attempted tumor removal. As the intraoperative diagnosis of the hemorrhagic tumor was primitive neuroectodermal tumor (PNET), we did not proceed to total removal. After the delivery of radiotherapy (50.4 Gy) and one course of Nimustine hydrochloride (ACNU) chemotherapy, the residual tumor was completely resected. The diagnosis at that time (1994) was papillary pineocytoma. He was followed on an outpatient basis for 15 years and remained free of recurrence. This type of tumor was later proposed to represent a new distinct tumor subtype, papillary tumor of the pineal region (PTPR). Our data indicate that our patient's tumor should be included in this category.

[Efficacy and safety of monotherapy with temozolomide in patients with anaplastic astrocytoma at first relapse--a phase II clinical study].

The efficacy and safety of temozolomide were evaluated in 32 patients with anaplastic astrocytoma at first relapse. Temozolomide was administered orally once daily for the first five days of a 28-day cycle, at a dose of 150 or 200 mg/m(2)/day. The response rate determined by independent central review of MRI was 34% (95% confidence interval: 18.6%-53.2%), with 3 complete response and 8 partial response. The rate of "no change or better" was 91% (95% confidence interval: 75.0%-98.0%). Progression-free survival (PFS) at 6 months was 40.6%, and the median PFS was 4.1 months. The incidence of constipation (50%) and nausea (25%) was high,but these events were all mild or moderate in severity except in one subject with constipation,and could be managed with standard laxatives and antiemetics. The main laboratory test abnormalities (total incidence and incidence of grade 3/4 change) were lymphocytopenia (50%, 25%), neutropenia (47%, 6%), leukopenia (38%, 3%), thrombocytopenia (31%, 9%), and increased GPT (25%, 3%). Temozolomide was shown to have good efficacy and tolerability in patients with anaplastic astrocytoma at first relapse.

Recurrent intracranial germinoma outside the initial radiation field: a single-institution study.

Between 1975 and 2005, we treated 52 newly diagnosed germinoma patients. Until 1991, patients with pure germinomas or germinomas with syncytiotrophoblastic giant cells (STGCs) received whole-brain radiotherapy only. Of the 52 patients, 30 were treated with a reduced radiation volume and combined chemotherapy; seven of these received local irradiation with 24 Gy, two received whole-brain (30 Gy) plus local irradiation (20 Gy), 16 received extended local irradiation delivered to the whole ventricles (30 Gy) plus local (20 Gy) irradiation, and five received extended local irradiation (24 Gy). Of the 30 patients treated with a reduced radiation volume and combined chemotherapy, four experienced tumor recurrence; three patients had been treated with 24 Gy of local radiotherapy and one had received extended local (30 Gy) plus local (20 Gy) irradiation in addition to chemotherapy. In these patients, the delivered radiotherapy was inadequate and the origin of the recurrent tumors was outside the radiation field. None of the patients who had received at least 24 Gy of whole ventricle radiotherapy combined with chemotherapy experienced tumor recurrence. In combination with chemotherapy, the delivery of irradiation covering the ventricles effectively reduced the incidence of tumor recurrence in patients with germinomas or germinomas with STGCs.

A long-term ventricular drainage for patients with germ cell tumors or medulloblastoma.

BACKGROUND: Hydrocephalus associated with intracranial germ cell tumors or disseminated medulloblastoma has been treated with ventriculoperitoneal shunt. However, this procedure has a potential risk of intraperitoneal metastasis of these brain tumors. To prevent this potential risk and to minimize the risk of infection, we developed a percutaneous long-tunneled ventricular drainage (PLTVD). To confirm the effectiveness, we retrospectively analyzed the results of this procedure. METHODS: From 1979 to 2003, we have treated 96 patients with germ cell tumors and medulloblastoma in our hospital. Of 96 patients, 59 (germ cell tumor, 31; medulloblastoma, 28) had hydrocephalus and 13 needed long-term cerebrospinal fluid drainage to manage the obstructive hydrocephalus due to persistent tumor or communicating hydrocephalus due to dissemination. We performed PLTVD for these cases using a flow-controlled shunt device and percutaneous long-tunneled shunt tube (peritoneal catheter) exiting at the upper abdomen and connecting to a closed drainage system. The occurrence of extraneural metastasis and the incidence of infection were evaluated. RESULTS: The average duration of drainage was 74 days (range, 34-115 days). All 13 cases received full-dose chemotherapy and radiotherapy without infectious complications or extraneural metastasis. CONCLUSIONS: Percutaneous long-tunneled ventricular drainage was an effective method to manage long-lasting obstructive or communicating hydrocephalus with germ cell tumors and medulloblastoma.

Effect of oral colestimide on the elimination of high-dose methotrexate in patients with primary central nervous system lymphoma--case report.

Delayed methotrexate (MTX) elimination occurred in two patients with primary central nervous system lymphoma undergoing high-dose MTX treatment. Oral administration of the anion exchange resin colestimide, which binds MTX effectively in vitro, effectively accelerated MTX elimination. Colestimide probably interrupts the enterohepatic circulation, and is a potential oral antidote to MTX toxicity.

Effect of surgical removal on survival and quality of life in patients with supratentorial glioblastoma.

The relationship between the extent of tumor resection and the progression-free survival, overall survival, and quality of life was evaluated retrospectively in 105 consecutive adult patients with supratentorial hemispheric glioblastoma not primarily involving the basal ganglia, thalamus, or hypothalamus. All patients underwent multidisciplinary treatment including tumor removal and postoperative adjuvant therapy in prospective randomized trials designed to test several chemotherapy regimens. Magnetic resonance imaging with contrast medium was used to determine the extent of tumor resection. Gross total resection (GTR) was performed in 35 patients (33%), partial resection (PR) in 57 (54%), and biopsy in 13 (12%). Univariate and multivariate analysis was performed to assess the prognostic relevance of the extent of resection. The Karnofsky performance status (KPS) improved from 78% to 83% in the GTR group. The difference was not statistically significant. There was no significant change in the PR (from 70% to 72%) and the biopsy groups (from 64% to 62%). Progression- free survival was significantly longer in the GTR group (median survival time [MST] 10.3 months) than in the PR (MST 5.2 months) and the biopsy groups (MST 3.6 months). The overall survival was significantly longer in the GTR group (MST 20 months) than in the PR (MST 14.2 months) and the biopsy groups (MST 8.3 months). The difference in survival between the PR and the biopsy groups was not statistically significant. GTR prolongs the survival of patients with glioblastoma compared to PR or biopsy.

Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence.

BACKGROUND AND PURPOSE: Differentiation between tumor recurrence and treatment-related brain injury is often difficult with conventional MRI. We hypothesized that the diffusion-weighted imaging (DWI) could help differentiate these 2 conditions, because water diffusion may be greater for necrotic tissues in the treatment-related brain injury than for tumor tissues in recurrence. Our aim was to analyze whether DWI findings of recurrent tumor are distinct from those of radiation necrosis. METHODS: Seventeen patients were examined prospectively. Two readers assessed the images by consensus for homogeneity and signal intensity of the lesions. Five regions of interest were drawn within the lesions on trace DWI images and apparent diffusion coefficient (ADC) maps. The minimal, maximal, and mean values of each lesion were compared between the 2 groups. Findings in 12 of 17 patients were verified histologically by surgery or biopsy; the diagnoses in the remaining 5 patients were made on the basis of follow-up MRI findings and clinical follow-up. RESULTS: There were a total of 20 lesions; 12 lesions were due to radiation necrosis and 8 lesions to tumor recurrence. In the radiation necrosis group, 8 lesions had marked hypointensity. In the recurrence group, however, no marked hypointensity was seen. The maximal ADC values within each lesion were significantly smaller for the recurrence group than for the necrosis group (P = .039). CONCLUSION: Radiation necrosis usually showed heterogeneity on DWI images and often included spotty, marked hypointensity. Significant difference was found in the maximal ADC values between radiation necrosis and tumor recurrence. DWI was useful in differentiating recurrent neoplasm from radiation necrosis.

Comparative clinical study of the anti-emetic effects of oral ramosetron and injected granisetron in patients with malignant glioma undergoing ACNU chemotherapy.

The effectiveness of ramosetron tablets and granisetron injection was compared for reducing the frequency of nausea, vomiting, and anorexia in patients with malignant glioma undergoing ACNU chemotherapy. Patients with malignant glioma to be treated with ACNU chemotherapy were randomly assigned to receive oral ramosetron (20 patients) or intravenous granisetron (19 patients) prior to ACNU injection. Gastrointestinal toxicity within 48 hours of ACNU injection was compared to that in patients who had received ACNU chemotherapy with dopamine D2 receptor-blocker as a historical control group. Within 24 hours of the administration of ACNU, 15 of the 20 patients treated with ramosetron and 16 of the 19 treated with granisetron were nausea-free, and 14 of the former and 14 of the latter regained their normal appetite. There was no significant difference in the anti-emetic effects. Ten of the 17 controls experienced no vomiting within 6 hours of the injection of ACNU, five were nausea-free within 24 hours, and two retained their normal appetite within 24 hours. Oral ramosetron has the same anti-anorectic and anti-emetic effects as intravenous granisetron. Ramosetron tablets are less expensive and are easy to take, so should be on the list of first-choice anti-emetic drugs for patients treated with ACNU chemotherapy.

Dephosphorylation of eNOS on Thr495 after transient forebrain ischemia in gerbil hippocampus.

We investigated phosphorylation of endothelial nitric oxide synthase (eNOS) at two major sites, Ser1177 and Thr495, which has a critical role to control its activity, in the gerbil hippocampal microvasculature after transient forebrain ischemia. Ser1177 phosphorylation was unchanged by 24 h after reperfusion, despite post-ischemic up-regulation of eNOS protein. However, Thr495 phosphorylation significantly and persistently decreased by 48 h. We here defined the changes in eNOS phosphorylation in vivo following brain ischemia/reperfusion. (ischemia).

Combination electro-gene therapy using herpes virus thymidine kinase and interleukin-12 expression plasmids is highly efficient against murine carcinomas in vivo.

We report the use of plasmid DNA-mediated combination gene therapy for tumor-bearing mice using in vivo electroporation, also called electro-gene therapy (EGT), that resulted in uncomplicated and complete cures in more than 90% of the mice. Subcutaneously inoculated CT26 tumors in syngeneic BALB/c mice were subjected to repeated EGT treatments consisting of intratumoral co-injection of naked plasmids encoding the cytokine interleukin-12 (IL-12) (p35 and p40 subunits) and the suicide gene herpes simplex virus thymidine kinase (HSV-tk), followed by in vivo electroporation. The early anti-tumor effect was always stronger, and the rate of cure, as seen in the long-term follow-up, was always greater in the groups treated with combination EGT than in those treated with IL-12 or HSV-tk EGT alone. Systemic levels of IL-12 and IFN-gamma increased in both combination and IL-12-alone EGT-treated groups. Moreover, combination EGT for established subcutaneous tumors strongly reduced hematogenous lung metastases and increased survival time when live CT26 tumor cells were injected through the tail vein. Limited experiments on C57/B16 mice with murine melanoma also showed very similar trends. These results suggest that this simple and safe method of plasmid-mediated combination EGT may provide a potentially effective gene therapy for cancer.

Pineal cystic germinoma with syncytiotrophoblastic giant cells mimicking MR imaging findings of a pineal cyst.

We report a case of precocious puberty in a 4-year-old boy. Contrast-enhanced T1-weighted MR imaging suggested a pineal cyst with enhancement of the slightly thickened wall and focal wall irregularity. Three-dimensional constructive interference in a steady-state imaging revealed a focal lobulation and a nodule-like area in the lesion. The lesion mimicking a pineal cyst proved to be a germinoma with syncytiotrophoblastic giant cells, on the basis of biopsy and tumor marker results.

The post-ischemic administration of 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel calmodulin antagonist, prevents delayed neuronal death in gerbil hippocampus.

The novel calmodulin (CaM) antagonist DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate) with an apparent neuroprotective effect in vivo preferentially inhibits neuronal nitric oxide synthase (nNOS), Ca2+/CaM-dependent protein kinase IIalpha (CaMKIIalpha), and calcineurin in vitro. In the present study, we investigated the molecular mechanism underlying its neuroprotective effect with the gerbil transient forebrain ischemia model, by focusing on its inhibition of these Ca2+/CaM-dependent enzymes. Post-ischemic DY-9760e treatment (5 mg/kg, i.p.) immediately after 5-min ischemia significantly reduced the delayed neuronal death in the hippocampal CA1 region. CaMKIIalpha was transiently autophosphorylated immediately after reperfusion with concomitant sustained decrease in its total amounts in the Triton X-100-soluble fractions. Calcineurin activity, accessed by the phosphorylation state of dopamine- and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32) at Thr34, was elevated at 6 h after reperfusion. Post-treatment of DY-9760e had no effects on both CaMKIIalpha and DARPP-32 phosphorylation at 6 h after reperfusion. However, DY-9760e significantly inhibited nitrotyrosine formation, as a biomarker of NO, and in turn, peroxynitrite (ONOO-) production. These results suggest that DY-9760e primarily inhibits Ca2+/CaM-dependent neuronal NOS, without any effects on CaMKII and calcineurin, and the inhibition of NO production possibly accounts for its neuroprotective action in brain ischemic injury.

The influence of sex and the presence of giant cells on postoperative long-term survival in adult patients with supratentorial glioblastoma multiforme.

OBJECT: Glioblastoma multiforme (GBM) remains incurable by conventional treatments, although some patients experience long-term survival. A younger age, a higher Karnofsky Performance Scale (KPS) score, more aggressive treatment, and long progression-free intervals have been reported to be positively associated with long-term postoperative patient survival. The aim of this retrospective study was the identification of additional favorable prognostic factors affecting long-term survival in surgically treated adult patients with supratentorial GBM. METHODS: Of 113 adult patients newly diagnosed with histologically verified supratentorial GBM who were enrolled in Phase III trials during the period between 1987 and 1998, six (5.3%) who survived for longer than 5 years were defined as long-term survivors, whereas the remaining 107 patients served as controls. All six were women and were compared with the controls; they were younger (mean age 44.2 years, range 31-60 years), and their preoperative KPS scores were higher (mean 85, range 60-100). Four of the six patients underwent gross-total resection. In five patients (83.3%) the progression-free interval was longer than 5 years and in three a histopathological diagnosis of giant cell GBM was made. This diagnosis was not made in the other 107 patients. CONCLUSIONS: Among adult patients with supratentorial GBM, female sex and histopathological characteristics consistent with giant cell GBM may be predictive of a better survival rate, as may traditional factors (that is, younger age, good KPS score, more aggressive resection, and a long progression-free interval).

Stereotactic biopsy for multifocal, diffuse, and deep-seated brain tumors using Leksell's system.

Using the Leksell stereotactic system, we selectively performed 91 biopsies for surgically inaccessible brain lesions. There were 25 multiple (27.5%), 15 diffuse (16.5%), and 51 (56.0%) deep-seated lesions. However, we avoided subjecting the patients with lesions adjacent to major vascular trunks or complex vascular structures such as the cavernous sinus, peri-insular regions and the pineal regions to stereotactic biopsy. The diagnosis was histologically confirmed in 84 cases (92.3%). Sixty-nine (75.8%) lesions were primary tumors; 44 (48.4%) were malignant gliomas, 18 (19.8%) malignant lymphomas, and five (5.5%) low-grade gliomas. Thirteen (14.3%) cases had previously undergone radiation and/or chemotherapy for brain tumors, seven had recurrent glioma (five with malignant transformation) and six manifested radiation necrosis. None of the patients died due to the stereotactic procedure; one (1.1%) exhibited morbidity due to complicated hemorrhage. We found asymptomatic minor bleeding occurred in nine (9.9%) patients; the rate of hemorrhage was significantly higher in patients with preoperative angiographic evidence of tumor stain. Two patients (2.2%) suffered seizures, in one case seizure was induced by electric stimulation test at the target site. All five patients younger than 15 years underwent the procedure without complications. The Leksell stereotactic system is useful for diagnostic tissue sampling and contributes effectively to the selection of appropriate therapy in patients with malignant brain tumors. While it carries a low morbidity rate without mortality in our series, care must be taken for selected target sites in highly vascularized lesions exhibiting positive tumor stains.

MR imaging features of a scalp plexiform schwannoma.

Radiologic findings of a case with scalp plexiform schwannoma-an unusual variant of the benign, solitary schwannoma in the skin-are reported. T2-weighted MR imaging exhibited the most specific features: a multinodular pattern and hypointense capsule that separated the tumor from surrounding soft tissue. A surgical specimen was histologically confirmed as schwannoma. The MR imaging findings reported herein may aid in the preoperative diagnosis of this relatively rare scalp tumor.

Correlation between promoter hypermethylation of the O6-methylguanine-deoxyribonucleic acid methyltransferase gene and prognosis in patients with high-grade astrocytic tumors treated with surgery, radiotherapy, and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea-based chemotherapy.

OBJECTIVE: O(6)-Methylguanine-deoxyribonucleic acid methyltransferase (MGMT) is a deoxyribonucleic acid repair protein associated with the chemoresistance of chloroethylnitrosoureas. We investigated whether MGMT promoter hypermethylation is associated with prognosis in patients with high-grade astrocytic tumors treated uniformly with surgery, radiotherapy, and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU)-based chemotherapy. METHODS: Using the methylation-specific polymerase chain reaction, we assayed promoter hypermethylation of the MGMT gene in tumor deoxyribonucleic acid from 116 adult patients with supratentorial high-grade astrocytic tumors (42 anaplastic astrocytomas [AAs] and 74 glioblastomas multiforme [GBMs]). The Cox proportional hazards model was used in forward stepwise regression to assess the relative role of prognostic factors (i.e., age at surgery, sex, Karnofsky Performance Scale score, extent of surgical resection, methylation status of the MGMT promoter, and association between MGMT promoter methylation and survival). RESULTS: MGMT promoter hypermethylation was confirmed in 19 (45.2%) of 42 AA patients and 33 (44.6%) of 74 GBM patients. It was significantly associated with both longer overall and progression-free survival time in AA but not GBM patients. CONCLUSION: Our results demonstrate that MGMT promoter hypermethylation is associated with longer survival time in patients with AA who were treated with surgery, radiotherapy, and ACNU-based chemotherapy but not in patients with GBM.

Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme.

Glioblastoma multiforme (GBM) frequently involves amplification and alteration of the epidermal growth factor receptor (EGFR) gene, resulting in overexpression of varied mutations, including the most common mutation, EGFRvIII, as well as wild-type EGFR (EGFRwt). To test the prognostic value of EGFR, we retrospectively analyzed the relationship between treatment outcomes and the EGFR gene in 87 newly diagnosed adult patients with supratentorial GBM enrolled in clinical trials. The EGFR gene status was assessed by Southern blots and EGFR expression by immunohistochemistry using three monoclonal antibodies (EGFR.25 for EGFR, EGFR.113 for EGFRwt, and DH8.3 for EGFRvIII). EGFR amplification was detected in 40 (46%) of the 87 GBM patients; in 39 (97.5%) of these, EGFR was overexpressed. On the other hand, in 46 of 47 patients without EGFR amplification (97.9%), no EGFR overexpression was present. There was a close correlation between EGFR amplification and EGFR overexpression (P < 0.0001). EGFRwt was overexpressed in 27 of the 40 (67.5%) patients with, and in none without, EGFR amplification (P < 0.0001). Similarly, EGFRvIII was overexpressed in 18 (45.0%) of 40 patients with and in 4 (8.5%) of 47 patients without EGFR amplification (P < 0.0001). The finding that 8 (20%) of the patients with EGFR amplification/EGFR overexpression manifested overexpression of neither EGFRwt nor EGFRvIII indicates that they overexpressed other types of EGFR. Multivariate analysis demonstrated that EGFR amplification was an independent, significant, unfavorable predictor for overall survival (OS) in all patients (P = 0.038, HR = 1.67). With respect to the relationship of age to EGFR prognostication, the EGFR gene status was a more significant prognosticator in younger patients, particularly in those <60 years (P = 0.0003, HR = 3.15), whereas not so in older patients. EGFRvIII overexpression, on the other hand, was not predictive for OS. However, in patients with EGFR amplification, multivariate analysis revealed that EGFRvIII overexpression was an independent, significant, poor prognostic factor for OS (P = 0.0044, HR = 2.71). This finding indicates that EGFRvIII overexpression in the presence of EGFR amplification is the strongest indicator of a poor survival prognosis. In GBM patients, EGFR is of significant prognostic value for predicting survival, and the overexpression of EGFRvIII with amplification plays an important role in enhanced tumorigenicity.

Preliminary observations on genetic alterations in pilocytic astrocytomas associated with neurofibromatosis 1.

Neurofibromatosis 1 (NF1) is an autosomal dominant disorder that predisposes sufferers to various forms of neoplasia. Among affected individuals, 15%-20% develop astrocytomas, especially pilocytic astrocytomas (PA), which are benign and classified as grade I by the World Health Organization. They are generally well circumscribed, and their progression is slow. NF1-associated PAs (NF1-PAs) occasionally behave as aggressive tumors. To elucidate underlying genetic events in clinically progressive NF1-PAs, we performed molecular genetic analysis on 12 PAs, including 3 NF1-PAs, for pS3, p16, and epidermal growth factor receptor genes, as well as loss of heterozygosity (LOH) on chromosome 1p, 10, 17, and 19q. None of the obvious genetic alterations typically seen in higher grade astrocytomas were found in 9 sporadic PAs. However, in 2 of 3 NF1-PAs, microsatellite analysis showed LOH10, including the PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene locus, despite the diagnosis of pilocytic astrocytoma;one of these also manifested homozygous deletion of the p16 gene. The other NF1-PA harbored only LOH of the NF1 gene locus (17q). Our preliminary results support the hypothesis that some NF1-PAs differ genetically from sporadic PAs.