Two cases of subfrontal schwannoma, including a rare case located between the endosteal and meningeal layers of the dura.

Subfrontal schwannomas arising from the olfactory groove are rare and their origin remains uncertain because olfactory bulbs do not possess Schwann cells. We present two cases of subfrontal schwannomas treated with surgical resection. In one case, the tumor was located between the endosteal and meningeal layers of the dura mater. This rare case suggests that subfrontal schwannomas may originate from the fila olfactoria.

Stitched sling retraction technique for microvascular decompression: procedures and techniques based on an anatomical viewpoint.

The success of microvascular decompression (MVD) depends on the permanent and complete transposition of the offending vessels. This paper describes the stitched sling retraction techniques for treating trigeminal neuralgia (TN), hemifacial spasm (HFS), and glossopharyngeal neuralgia (GPN), focusing on the stitching point for slinging the offending artery in the appropriate direction. Between January 2007 and March 2009, 28 patients with TN, 5 patients with HFS, and 3 patients with GPN underwent MVD with a sling retraction technique. In cases of TN, MVD was performed using the infratentorial lateral supracerebellar approach, and the offending superior cerebellar artery was superomedially transposed with a sling stitched to the tentorium cerebelli. In cases of HFS, MVD was performed using the lateral suboccipital infrafloccular approach, and the offending vertebral artery was superolaterally transposed with a sling stitched to the petrous dura. In cases of GPN, MVD was performed using the transcondylar fossa approach, in which the posterior inferior cerebellar artery was inferolaterally mobilized with a sling secured to the jugular tubercle. No patient suffered recurrence in the follow-up period. For the sling retraction technique to be performed successfully, it is important for a stitch to be placed at a suitable site to sling the offending vessel in the intended direction. An appropriate surgical approach must be used to obtain a sufficient operative field for performing the stitching procedures safely.

Phase I trial of a personalized peptide vaccine for patients positive for human leukocyte antigen--A24 with recurrent or progressive glioblastoma multiforme.

PURPOSE: Personalized selection of suitable peptides for patients could offer a novel approach to developing cancer vaccines that boost anticancer immunity. We present the results of a phase I trial of 14 kinds of vaccine candidates (ITK-1) in patients with recurrent or progressive glioblastoma multiforme (GBM). PATIENTS AND METHODS: From January 2006 to January 2008, 12 patients from eight Japanese hospitals who were positive for human leukocyte antigen-A24, including 10 patients refractory to temozolomide (TMZ), were enrolled. The dose escalation trial included three dose groups (1, 3, and 5 mg) to determine the safety and tolerability of ITK-1 peptides. Immunologic response was monitored by measuring levels of cytotoxic T-lymphocyte precursors and peptide-specific immunoglobulin G. In another ITK-1 phase I trial for advanced prostate cancer, the vaccination schedule was skipped or discontinued in all three patients receiving the highest dose (5 mg/peptide) because of injection site reactions. This trial was therefore ended without enrollment for the highest dose, and data were analyzed by intention to treat. RESULTS: No serious adverse drug reactions were encountered, and treatment was well tolerated. The vaccine induced dose-dependent immune boosting. The recommended dose of ITK-1 peptides is 3 mg/peptide. CONCLUSION: Personalized vaccination with ITK-1 peptides could be recommended in further stages of clinical trials. The safety and increased frequency of immune boosting offers potential clinical benefits in cases of recurrent or progressive GBM, even in TMZ-refractory settings.

Transcondylar fossa (supracondylar transjugular tubercle) approach: anatomic basis for the approach, surgical procedures, and surgical experience.

The authors clarify the anatomic basis and the usefulness of the transcondylar fossa approach (T-C-F A), in which the posterior portion of the jugular tubercle is removed extradurally through the condylar fossa with the atlanto-occipital joint intact. The authors first performed an anatomic study to identify the area to be removed using cadaveric specimens and then applied the T-C-F A to foramen magnum surgeries. The surgeries included clipping a vertebral artery-posterior inferior cerebellar artery aneurysm in 11 cases, microvascular decompression for glossopharyngeal neuralgia in 15 cases, and removing intradural foramen magnum tumors in 17 cases. Only the condylar fossa was removed, but the approach offered very good visualization of the lateral part of the foramen magnum and sufficient working space. These surgeries were performed safely without major complications. This skull base approach is minimally invasive and is not difficult. Therefore, it can be a standard approach for accessing intradural lesions of the foramen magnum. It can be combined with the transcerebellomedullary fissure approach from the lateral side and can also be easily changed to the transcondylar approach, if necessary.

Microvascular decompression for glossopharyngeal neuralgia through the transcondylar fossa (supracondylar transjugular tubercle) approach.

OBJECTIVE: Our surgical results were reviewed to clarify the cause of glossopharyngeal neuralgia (GPN) and the effects of the microvascular decompression (MVD) procedure. METHODS: Fourteen cases of idiopathic GPN were operated on through the transcondylar fossa (supracondylar transjugular tubercle) approach. Their clinical data and operative records were retrospectively reviewed. RESULTS: In every case, vascular compression on the glossopharyngeal nerve was found and MVD was performed without any major complications. In 13 of the 14 cases the neuralgia completely disappeared postoperatively. Recurrence of pain was found in 1 case. Offending vessels were the posterior inferior cerebellar artery (PICA) in 10 cases, the anterior inferior cerebellar artery (AICA) in 2 cases, and both arteries in 2 cases. In 10 of the 14 cases, the high-origin PICA formed an upward loop between the glossopharyngeal and vagus nerves, compressing the glossopharyngeal nerve upward. In those cases, the PICA was transposed and fixed to the dura mater by the stitched sling retraction technique, and MVD was very effective. CONCLUSION: The offending artery was the PICA in most cases. MVD is expected to be very effective, especially when the radiological images show the following 3 findings: 1) high-origin PICA, 2) the PICA making an upward loop, and 3) the PICA coursing the supraolivary fossette. The transcondylar fossa approach is suitable for transposing the PICA by the stitched sling retraction technique, and provides sufficient surgical results.

Thrombosis of the superior petrosal vein mimicking brain tumor. Case report.

A 77-year-old woman was admitted to a local hospital with a 7-day history of vertigo and nausea, followed by gait disturbance. Magnetic resonance imaging showed extensive brain edema with a hemorrhagic component in the right cerebellum. The lesion was heterogeneously enhanced after administration of contrast medium. The presumptive diagnosis was malignant glioma based on these findings, as well as the presence of mass effect and abnormal enhancement. She was referred to our hospital. However, cerebral angiography did not reveal tumor stain or arterial occlusion, but confirmed corkscrew-like venous collaterals and absence of opacification of the superior petrosal vein (SPV) and superior petrosal sinus. Topography of the brain edema was consistent with the drainage territory of the SPV. These findings suggested that the lesion was vasogenic edema caused by thrombosis of the SPV. The patient was conservatively treated without anticoagulation therapy, and the neurological and imaging abnormalities resolved spontaneously. To avoid unnecessary biopsy, thrombosis of the SPV should be considered in the differential diagnosis of infratentorial lesion mimicking brain tumors. Knowledge of the posterior fossa venous anatomy is essential to achieve the correct diagnosis.

Olfactory neuroepithelioma: an immunohistochemical and ultrastructural study.

Three cases of olfactory neuroepithelioma are presented in this report. Histologically, these tumors were composed of small cells with round to oval, relatively hyperchromatic nuclei and scanty cytoplasm. The tumor cells were occasionally observed in tubular formations or rosette-like arrangements. Immunohistochemically, the tumor cells showed a positive reaction for cytokeratin AE1, cytokeratin CAM5.2, Ber-EP4, antisynaptophysin and anti-S100 protein in all cases. In two cases, LH-RH was detected in the tumor cells. Ultrastructurally, the tumor cells had the differentiation features of olfactory epithelium. Olfactory neuroepithelioma is a rare occurrence and it can be very difficult to distinguish olfactory neuroepithelioma from small cell carcinoma, neuroendocrine carcinoma and so-called "olfactory neuroblastoma" on the basis of hematoxylin and eosin stained sections alone. In controversial cases, a diagnosis of olfactory neuroepithelioma must be substantiated by ultrastructural and immunohistochemical findings, particularly regarding the detection of Ber-EP4 and LH-RH immunoreactivity.

Peritoneal shunt tube migration into the stomach--case report--.

A 47-year-old man presented with repeated headache and feverishness 3.5 years after undergoing ventriculoperitoneal shunt surgery for normal pressure hydrocephalus secondary to subarachnoid hemorrhage. Abdominal computed tomography revealed that the peritoneal catheter was encased by fibrous tissue and the distal end of the catheter had migrated into the stomach. The diagnosis was spontaneous gastric perforation by the ventriculoperitoneal shunt. The fibrous tissue was expected to seal the very small gastric perforation, so the catheter was successfully extracted through a scalp incision without abdominal surgical intervention.

Detection of JC virus DNA sequences in brain tumors in pediatric patients.

OBJECT: The JC virus is a human neurotropic polyomavirus that causes progressive multifocal leukoencephalopathy and is closely related to simian virus 40. Several recent reports have indicated a possible association between the JC virus and the development of various human brain tumors. The authors examined the presence of JC virus DNA sequences in primary brain tumors in pediatric patients to evaluate the hypothesis that particular brain tumors can arise in the pediatric population as a consequence of infection with the JC virus. METHODS: Genomic DNA sequences were isolated from 62 brain tumors (32 medulloblastomas, 18 ependymomas, five choroid plexus papillomas, and seven pilocytic astrocytomas) and analyzed for the presence of JC virus DNA by Southern blot hybridization and direct sequencing. The JC virus DNA sequence was detected in five ependymomas and one choroid plexus papilloma. Immunohistochemical studies revealed nuclear expression of the large T-antigen in a choroid plexus papilloma. None of the medulloblastomas or pilocytic astrocytomas contained JC virus DNA. CONCLUSIONS: The results of this study provide molecular evidence of the association between JC virus and the development of certain ependymomas and choroid plexus papillomas.

Induction of the DNA repair gene O6-methylguanine-DNA methyltransferase by dexamethasone in glioblastomas.

OBJECT: The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) inhibits the cytotoxic effect of alkylating agents on tumor cells. The presence of two nonconsensus glucocorticoid-responsive elements in the human MGMT promoter region indicates the potential regulation of MGMT expression by glucocorticoid agents. This study was performed to elucidate whether dexamethasone affects the expression of MGMT in glioblastoma multiforme (GBM) cells, thereby limiting the benefit of chemotherapeutic alkylating agents. METHODS: Four GBM cell lines (A172, T98G, U138MG, and U87MG) were exposed to the alkylating agent 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) with or without dexamethasone. The expression levels of MGMT were correlated with the cytotoxic effects of ACNU in GBM cells. In the presence of ACNU alone, dexamethasone alone, and the combination of both agents, messenger RNA expression of MGMT was induced to varying degrees with the highest increases seen in the later conditions. This dexamethasone-dependent induction of the MGMT gene was even observed in U87MG cells in which the promoter is methylated, although the absolute expression of MGMT mRNA was the lowest in that cell line. The induction of MGMT by dexamethasone was associated with an increased resistance of these cells to ACNU. CONCLUSIONS: These results indicate that dexamethasone-mediated upregulation of MGMT limits the efficiency of alkylating agents in the treatment of malignant gliomas.

Detrended fluctuation analysis of genome-wide copy number profiles of glioblastomas using array-based comparative genomic hybridization.

We examined whole genomic aberrations of biopsied samples from 19 independent glioblastomas by array-based comparative genomic hybridization analysis. The highest frequencies of copy number gains were observed on RFC2 (73.3%), EGFR (63.2%), and FGR, ELN, CDKN1C , FES, TOP2A, and ARSA (57.9% each). The highest frequencies of copy number losses were detected on TBR1 (52.6%), BMI1 (52.6%), EGR2 (47.4%), DMBT1 (47.4%), MTAP (42.1%), and FGFR2 (42.1%). The copy number gains of CDKN1C and INS and the copy number losses of TBR1 were significantly correlated with longer survival of patients. High-level amplifications were identified on EGFR, SAS/CDK4, PDGFRA, MDM2, and ARSA. These genes are assumed to be involved in tumorigenesis or progression of glioblastomas. The first attempts to apply detrended fluctuation analysis to copy number profiles by considering the reading direction as the time axis demonstrated that higher long-term fractal scaling exponents (alpha2) correlated well with longer survival of glioblastoma patients. The present study indicates that array-based comparative genomic hybridization analysis has great potential for assessment of copy number changes and altered chromosomal regions of brain tumors. Furthermore, we show that nonlinear analysis methods of whole genome copy number profiles may provide prognostic information about glioblastoma patients.

Combined proteomic approach with SELDI-TOF-MS and peptide mass fingerprinting identified the rapid increase of monomeric transthyretin in rat cerebrospinal fluid after transient focal cerebral ischemia.

Several proteins are known to be markedly expressed in the brain during cerebral ischemia, however the change in protein profiles within the cerebrospinal fluid (CSF) after an ischemic insult has not been fully elucidated. We studied the changes in the CSF proteome in rat transient middle cerebral artery occlusion model. Surface enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS) was used to detect the time-course changes in CSF protein patterns after transient focal brain ischemia. According to hierarchical cluster analysis by self-organising tree algorism (SOTA), the temporal pattern of protein peaks was divided into four groups: acute increase group, chronic increase group, gradual decrease group and unchanged group. In the acute increase group, the expression of a 13.6-kDa protein was markedly increased during the acute phase. The 13.6-kDa protein was identified as monomeric form of transthyretin using two-dimensional electrophoresis and peptide mass fingerprinting based on matrix-assisted laser desorption/ionization-time of flight mass spectrometry. The monomeric transthyretin may represent an ischemia-specific CSF marker to indicate the sequential changes according to ischemic insults of the brain.

Identification of pleiotrophin in conditioned medium secreted from neural stem cells by SELDI-TOF and SELDI-tandem mass spectrometry.

Neural stem cells (NSCs) are multipotential progenitor cells that have self-renewal activity. Since the fates of the NSCs in situ depend on their niche containing growth factors and cytokines, we performed surface enhanced laser desorption/ionization time-of flight mass spectrometry (SELDI-TOF-MS) to screen for differentially secreted proteins in conditioned medium of neural stem cells and compared with that of NIH3T3 cells. A 15.3-kDa protein detected only in the conditioned medium of neural stem cells was determined as pleiotrophin (PTN) by SELDI-TOF-MS and ProteinChip-tandem MS systems. Identification of pleiotrophin was further confirmed by one-dimensional SDS gel electrophoresis and Edman degradation analysis. The mRNA transcripts of PTN and its receptors [receptor protein tyrosine phosphatase (RPTP) beta/zeta, N-syndecan and anaplastic lymphoma kinase (ALK)] were detected in neurosphere, suggesting that pleiotrophin signaling systems are present in the neural stem cells and are involved in the modulation of fate of neural stem cells.

Increased cytotoxicity of soluble Fas ligand by fusing isoleucine zipper motif.

Fas (CD95) ligand (FasL) has the ability to induce apoptosis in Fas-expressing glioma cells by binding to Fas. Several molecular species have been designed to be soluble Fas ligands for therapeutic purposes. We successfully constructed a chimeric soluble FasL by fusing an isoleucine zipper motif for self-oligomerization and a FLAG sequence to the extracellular domain of the human Fas ligand (FIZ-shFasL). The cytotoxic effect of FIZ-shFasL on Jurkat cells was equivalent to that of membrane-bound FasL and approximately 10-fold stronger than that of agonistic anti-Fas antibody (CH-11). Flow cytometric analysis demonstrated that the differential Fas expression of human brain tumor cell lines partially correlated with levels of apoptosis through FIZ-shFasL. The upper limit of FIZ-shFasL for safe systemic administration to rat is estimated as below 2 microg/ml in plasma concentration. FIZ-shFasL could be applicable as a therapeutic agent for cancer.

Molecular analysis of astrocytoma associated with Turcot syndrome type 1--case report.

A 49-year-old man presented with a brain tumor and colon carcinoma. The patient had been treated under diagnoses of hereditary non-polyposis colorectal cancer syndrome and Muir-Torre syndrome. Magnetic resonance imaging revealed a mass lesion in the right frontal lobe with diffuse high intensity on T2-weighted and fluid-attenuated inversion recovery images. A few small lesions were enhanced by gadolinium on the T1-weighted images. Histological examination revealed the brain neoplasm was astrocytoma grade III according to the World Health Organization classification. Molecular genetic analysis detected microsatellite instability and p53 mutation only in the tumor tissue, indicating a failure of the deoxyribonucleic acid mismatch repair system. These results suggest that inactivation of mismatch repair system and p53 is closely associated with the tumorigenesis of this neoplasm. The final diagnosis was Turcot syndrome type 1.

Report of fogging effect on fast FLAIR magnetic resonance images of cerebral infarctions.

We report a case of multiple small, presumably iatrogenic, cortical infarctions detected incidentally on magnetic resonance imaging (MRI) 5 days after preoperative cerebral angiography but not apparent 12 days after the angiography on noncontrast MRI including a fast fluid-attenuated inversion recovery (FLAIR) sequence. However, the lesions showed marked contrast enhancement with gadolinium on postcontrast T1-weighted images. Cortical laminar necrosis was observed on MRI 35 days after the initial angiographic study. This case shows that the MRI fogging effect may prevent detection of small cortical infarctions in the subacute stage even on fast FLAIR sequences. Postcontrast images should be studied to reduce diagnostic errors associated with this effect.

Expression of the Wilms' tumor gene product WT1 in glioblastomas and medulloblastomas.

The Wilms' tumor gene WT1 was first identified as the gene responsible for a childhood renal tumor, Wilms' tumor. This gene encodes for a zinc finger-containing transcription factor. Although originally identified as a tumor suppressor gene, WT1 is overexpressed in a variety of hematologic malignancies and solid tumors. Recently, WT1 protein has been considered as a new molecular target of cancer immunotherapy for several solid tumors. In the present study, we investigated the expression of WT1 protein and WT1 mRNA in glioblastomas and medulloblastomas. Forty-eight of 51 glioblastoma samples (94%) showed immunohistochemically positive staining of WT1 protein, whereas all 10 medulloblastomas examined were negative. According to the immunohistochemical expression of WT1 protein, WT1 mRNA was also highly expressed in the same glioblastoma tissue. Our results suggest that the WT1 gene may play an important role in the tumorigenesis of glioblastoma, in contrast to medulloblastoma, and be integral in the development of the immunotherapy targeting WT1 protein in patients with glioblastoma.

Biologic characterization of a secondary glioblastoma with extracranial progression and systemic metastasis.

Glioblastomas rarely metastasize outside the CNS. We biologically characterized a case of secondary glioblastoma associated with extracranial progression and distant metastasis. A 42-year-old male patient was subjected to craniotomy for a left temporal tumor (astrocytoma grade II) and subsequently underwent another 3 craniotomies due to tumor recurrences. At the third craniotomy, extracranial progression was noted, and the tumor was classified as a glioblastoma. In order to pinpoint the genes expressed differentially in the intracranial primary tumor and the metastatic tumors, we used cDNA microarray. The patterns of gene expression in these 2 samples were highly similar, suggesting that the mechanism of metastasis was direct infiltration of tumor cells into extracranial blood vessels. Insulin-like growth factor binding protein-2 was overexpressed in both primary and metastatic tumors. Immunohistochemical studies of DNA-dependent protein kinase, which participates in the repair of DNA, was strongly positive in the samples obtained at the first and second operations, but the positive rates were markedly reduced in the specimens obtained at the third and fourth operations. These results suggest that insulin-like growth factor binding protein-2 and deficiency of DNA-dependent protein kinase proteins promoted tumor progression in the present case.