Expression of DNA mismatch repair proteins MLH1, MSH2, and MSH6 in recurrent glioblastoma.

OBJECTIVES: Methylated O6-methylguanin-DNA-methytransferase (MGMT) promoter methylation is associated with survival in patients with glioblastoma. Current evidence suggests that further mismatch repair genes play a pivotal role in the tumor response to treatment. Candidate genes are MLH1, MSH2, and MSH6. Formerly, we found evidence of prognostic impact of MLH1 and MSH6 immunohistochemical expression in a small series of patients with initial glioblastoma. METHODS: Two hundred and eleven patients were included who underwent macroscopically total removal of primary glioblastoma and at least one re-craniotomy for recurrence. Immunohistochemical staining was performed on paraffin-embedded specimens of initial tumors with specific antibodies against MLH1, MSH2, and MSH6. RESULTS were compared to the Ki67 proliferation index and patient survival. Additionally, fresh frozen samples from 16 paired initial and recurrent specimens were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) with specific primers against MLH1, MSH2, and MSH6. RESULTS were compared to MGMT status and survival. RESULTS: (1) Immunohistochemical expression of MSH6 was significantly associated with the Ki67 proliferation index (P<0.001) but not with survival. (2) PCR revealed two patients with increasing expression of MLH1, MLH2, and MSH6 over treatment combined with lacking MGMT methylation. In another two patients, decreased MLH1, MSH2, and MSH6 expression was observed in combination with MGMT promoter methylation. DISCUSSION: Our data indicate that there may be glioblastoma patient subgroups characterized by MMR-expression changes beyond MGMT promoter methylation. The immunohistochemical expression of MLH1, MSH2, and MSH6 in initial glioblastoma is not associated with patient survival.

Glioblastoma multiforme in children: report of 13 cases and review of the literature.

We present clinical and histopathologic data from 13 children who underwent craniotomy for newly diagnosed glioblastoma multiforme. Clinical characteristics were compared to those in adult patients (n = 403). The mean age of the children was 10.4 years. The male/female ratio was 3.3:1. The localization was infratentorial in 6 cases (brainstem, n = 4; cerebellum, n = 2) and supratentorial in 7 cases (frontal, n = 2; parietal, n = 3; temporal, n = 2). Infratentorial localization was observed solely in children from 0-10 years, whereas supratentorial location was found in children between the age of 11 and 21 years. Surgical resection was followed by radiotherapy in 11 cases and additional chemotherapy in 8 cases. Giant cell glioblastoma multiforme was found in 2 cases (15%, vs 1-5% in adults). The mean Ki-67 proliferation index was 29.4% (vs 25.6% in adults). There were no significant differences in histologic morphology between children and adults. The total survival time was 90 weeks (vs 47 weeks in adults). One patient is still alive after 8 years. Predictive factors of prolonged survival were the extent of tumor resection and radio- and/or chemotherapy after resection. Multidisciplinary treatment of glioblastoma in childhood might lead to better median survival than in adults. Infratentorial tumor location was observed exclusively in children younger than 11 years old.

Papillary Ependymoma WHO Grade II of the Aqueduct Treated by Endoscopic Tumor Resection.

Papillary ependymoma is a rare tumor that may be located along the ventricular walls or within the spinal cord. We report the case of a 54-year-old patient with a papillary ependymoma WHO grade II arising at the entrance of the aqueduct. The tumor caused hydrocephalus. The tumor was completely removed via a right-sided endoscopic approach with restoration of the aqueduct. The free cerebrospinal fluid passage through the aqueduct was not only visualized by endoscopy but also controlled by intraoperative high-field magnetic resonance imaging. Therefore, an additional endoscopic third ventriculostomy was unneccessary.

Acute Hydrocephalus due to Secondary Leptomeningeal Dissemination of an Anaplastic Oligodendroglioma.

Secondary leptomeningeal dissemination of oligodendroglioma is very rare. We report the case of a 38-year-old Caucasian male who presented with acute hydrocephalus. 8 months before, the patient had undergone craniotomy for right frontal anaplastic oligodendroglioma, WHO grade III. By that time, there was no evidence of tumor dissemination. MRI now ruled out local tumor progression but revealed meningeal contrast enhancement along the medulla, the myelon, and the cauda equina. Repeated lumbar puncture revealed increased cerebro-spinal fluid (CSF) pressure and protein content. Malignant cells were not detectable. Surgical treatment consisted in (1) placement of an ommaya reservoir for daily CSF puncture, (2) Spinal dural biopsy confirming leptomeningeal oligodendroglioma metastasis, and (3) ventriculo-peritoneal shunt placement after CSF protein has decreased to 1500-2000 mg/l.

p53, BCL-2 and BAX in non-small cell lung cancer brain metastases: a comparison of real-time RT-PCR, ELISA and immunohistochemical techniques.

OBJECTIVES: Metastasis to the brain is a severe and common complication in non-small cell lung cancer (NSCLC). The examination of cell cycle associated genes in these lesions may contribute to the understanding of metastatic growths in the central nervous system. The aim of this study was to evaluate the p53, BCL-2 and BAX mRNA and protein expression in NSCLC brain metastases in comparison with matched primary tumors. METHODS: For quantitative TaqMan real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), fresh frozen tumor specimens from 12 patients with NSCLC brain metastases were available. For immunohistochemical staining, 78 surgically removed NSCLC brain metastases were used. PCR results were analysed using the DeltaDeltaCT method. Staining was analysed using a modified immunoreactive score (IRS). RESULTS: Overall, p53, BCL-2 and BAX expression values in brain metastases and primary tumors showed a wide variety. The comparison of different techniques revealed different findings on the mRNA and protein level. Herein, PCR and ELISA revealed no clear tendencies. In contrast, immunohistochemistry showed significant overexpression of BAX and underexpression of BCL-2 in brain metastases. CONCLUSION: A high variability in the expression of p53, BCL-2 and BAX in NSCLC exists in brain metastases. Immunohistochemistry revealed overexpression of BAX and underexpression of BCL-2 in brain metastases, whereas there were no clear tendencies using PCR and ELISA techniques. More insights into the BAX/BCL-2 interaction are needed before reasonable conclusions can be drawn from the existing data.

Chronic recurrent subarachnoid hemorrhage from a trigeminal nerve malignant peripheral nerve sheath tumor: case report.

OBJECTIVE: Clinically significant intratumoral or peritumoral bleeding from trigeminal nerve tumors is very rare. CLINICAL PRESENTATION: We report the case of a 59-year-old man who presented with recurrent subarachnoid hemorrhage from a left trigeminal nerve malignant peripheral nerve sheath tumor. He presented with decreased consciousness, left facial hypesthesia, and left facial weakness. Trigeminal neuralgia was present for 18 months. Cranial computed tomographic and magnetic resonance imaging scans revealed a left parapontine mass with cystic changes and intratumoral bleeding. Furthermore, signs of hemosiderosis of the subarachnoid space were noted. Lumbar puncture revealed fresh bleeding. Angiography detected no aneurysm or other causes of bleeding. The patient became fully alert within hours, the facial weakness improved within a few days. There was no evidence of vasospasm or persisting hydrocephalus. He underwent left-sided suboccipital craniotomy for macroscopically total tumor removal. INTERVENTION: The patient underwent total tumor removal via a left suboccipital approach. Intraoperatively, evidence of recurrent intratumoral bleeding was noted. Histological examination revealed a malignant peripheral nerve sheath tumor (World Health Organization Grade III). Postoperatively, the hypesthesia improved significantly. The patient was transferred to radiotherapy for external beam radiation. CONCLUSIONS: This is the first report regarding a malignant peripheral nerve sheath tumor of the trigeminal nerve that caused clinically significant subarachnoid hemorrhage caused by intratumoral bleeding.