Shinya Nagahisa

Subgrouping of gliomas on the basis of genetic profiles

Management of gliomas depends on histological diagnosis; there are, however, limitations to the systems presently used. Tumors in the same entity can have different clinical courses, especially when they are diagnosed as WHO grade II–III. Previous studies revealed that genetic subgrouping of gliomas provides useful information that could help establishment of treatment procedures on the basis of the genetic background of the tumors. Recently, the authors analyzed the chromosomal copy number aberrations (CNAs) of adult supratentorial gliomas by comparative genomic hybridization using microdissected tissue sections. The tumors were classified into subgroups according to chromosomal CNAs. WHO grade II–III gliomas contained a variety of genetic subgroups that correlated well with the clinical course. Of these, long progression-free survival was observed for tumors with +7q and those with −1p/19q, low-grade tumors of 2 major lineages, and, in our preliminary data, both were closely correlated with mutation of IDH1. Furthermore, in contrast with +7q tumors, the great majority of +7 or +7/−10q groups had wildtype IDH1. Genetic studies suggest that cytogenetic characterization may provide an additional classification system for gliomas, and new criteria could help to establish rational and objective means for analysis of treatment procedures.

Neuroepithelial cyst of the fourth ventricle.

PurposeNeuroepithelial cyst is considered an unusual differential diagnosis for cysts in the posterior fossa. Here, we present a paediatric case with such a pathology and review the pertinent literature.MethodsA 12-year old girl with headache, vertigo and disturbed gait was diagnosed with a cystic lesion in the fourth ventricle after brain MRI study. She was operated with the pre-operative diagnosis of arachnoid cyst.ResultsA transparent, colourless cyst was observed intra-operatively. As frozen sections were consistent with endodermal cyst, total removal of the cyst was attempted. Definite histopathological studies and immunohistochemistry stains were in favour of neuroepithelial cyst. No regrowth of the cyst or recurrence of the symptoms was observed in her 2-year follow-up.ConclusionsAs neuroepithelial cyst is rarely encountered in the posterior fossa, the clinical, radiological and pathological characteristics of our case along with similar cases in the literature were reviewed and discussed.

Treatment of unruptured intracranial aneurysms--a clinicopathological correlation.

Summary Object. Brain check-up is very important for detecting the incidence and prevalence of aneurysms in the population and to get the definite strategy for the treatment of intracranial aneurysms. Methods. This is a retrospective study of 116 aneurysms detected by brain check-up between 1998–1999 which were treated either by clipping or endovascular coiling. In some cases the aneurysmal wall was resected for histopathological examination and compared with five normal autopsy cases. Conclusions. Direct surgery is the primary option for a patient with an aneurysm in the anterior circulation especially in young patients. Intravascular therapy is suitable for aneurysms in the posterior circulation and in intracavernous site.

Study of Changing Intracranial Venous Drainage Patterns in Petroclival Meningioma

OBJECTIVE To elucidate venous drainage patterns to avoid damage to the venous drainage route in the middle cranial fossa and superior petrosal sinus when employing the transpetrosal approach. METHODS Venous drainage patterns were assessed using three-dimensional computed tomography venography in 22 hemispheres of petroclival meningioma (PCM) cases from patients who underwent primary surgery and 40 hemispheres of control cases. Intracranial venous drainage patterns were compared between control cases and PCM cases. RESULTS The proportion of hemispheres with complete and medial superior petrosal sinus drainage patterns was lower in PCM cases. With regard to the superficial middle cerebral vein drainage pattern, the proportion of hemispheres with the cavernous sinus capture type was lower and the proportion with the emissary type was higher in PCM cases. The proportion of hemispheres with multiple greater anastomoses of the superficial middle cerebral vein was higher in PCM cases without the emissary-type and cavernous sinus capture-type patterns. When the venous drainage route of the cavernous sinus capture type and/or emissary type was disturbed, in particular, greater anastomosis via the vein of Labbè and the vein of Trolard was needed to control venous drainage flow. CONCLUSIONS In cases of venous drainage impairment secondary to PCM progression, the drainage route changed to the pterygoid plexus route through the emissary foramen and/or superior sagittal sinus and to the transverse sinus route through the greater anastomosis of the superficial middle cerebral vein. In the anterior transpetrosal approach, peeling off the dura propria of the trigeminal nerve of the foramen rotundum for petrous apex exposure may be associated with the potential risk of pterygoid plexus drainage route impairment.

PCR-Based Simple Subgrouping Is Validated for Classification of Gliomas and Defines Negative Prognostic Copy Number Aberrations in IDH Mutant Gliomas

Genetic subgrouping of gliomas has been emphasized recently, particularly after the finding of isocitrate dehydrogenase 1 (IDH1) mutations. In a previous study, we investigated whole-chromosome copy number aberrations (CNAs) of gliomas and have described genetic subgrouping based on CNAs and IDH1 mutations. Subsequently, we classified gliomas using simple polymerase chain reaction (PCR)-based methods to improve the availability of genetic subgrouping. We selected IDH1/2 and TP53 as markers and analyzed 237 adult supratentorial gliomas using Sanger sequencing. Using these markers, we classified gliomas into three subgroups that were strongly associated with patient prognoses. These included IDH mutant gliomas without TP53 mutations, IDH mutant gliomas with TP53 mutations, and IDH wild-type gliomas. IDH mutant gliomas without TP53 mutations, which mostly corresponded to gliomas carrying 1p19q co-deletions, showed lower recurrence rates than the other 2 groups. In the other high-recurrence groups, the median progression-free survival (PFS) and overall survival (OS) of patients with IDH mutant gliomas with TP53 mutations were significantly longer than those of patients with IDH wild-type gliomas. Notably, most IDH mutant gliomas with TP53 mutations had at least one of the CNAs +7q, +8q, −9p, and −11p. Moreover, IDH mutant gliomas with at least one of these CNAs had a significantly worse prognosis than did other IDH mutant gliomas. PCR-based mutation analyses of IDH and TP53 were sufficient for simple genetic diagnosis of glioma that were strongly associated with prognosis of patients and enabled us to detect negative CNAs in IDH mutant gliomas.

Radiological features of supratentorial gliomas are associated with their genetic aberrations

Gliomas are the most common primary neoplasms of the central nervous system [1]. Histopathological examination of surgically resected tissue is essential for the diagnosis of gliomas, and it forms the basis on which decisions regarding the use of adjuvant therapies are taken. This methodology has several potential difficulties, however. These include the fact that even pathologically identical tumors may have a different prognosis, that occasionally different areas of the same tumor tissue can have different histological characteristics [2], and that there is no entirely objective way of interpreting cellularity, anaplasia, or even cell type. To address these problems, many studies have tried to distinguish tumors on the basis of genetic and protein markers with the aim of standardizing decisions regarding therapeutic strategy based on the tumor subtypes they defined [3, 4]. Of particular note are the allelic losses of chromosomes 1p and 19q (−1p/19q), which have been reported as being positive predictors of chemotherapeutic response for anaplastic oligodendroglial tumors [5, 6]. Moreover, after Parsons et al. demonstrated that some gliomas carry a mutation in the IDH1 gene, genetic investigations have become increasingly important in the study of glioma biology [7]. However, although genetic analysis does provide important information, it requires an invasive surgical procedure. In addition to information provided by genetic analysis, some recent studies have suggested an association between radiological features and tumor type. To better understand the association between the radiological and genetic features of gliomas and to establish prognostic radiological criteria, we designed a study to test whether certain radiological features could be used to predict genetic aberrations in World Health Organization (WHO) grade II–III astrocytic and oligodendroglial tumors.

Surgical navigation-assisted endoscopic biopsy is feasible for safe and reliable diagnosis of unresectable solid brain tumors

Stereotactic biopsy has been validated for tissue sampling of deep-seated lesions that cannot be easily resected via open craniotomy. However, some inherent problems including the inability to directly observe the lesion and difficulty in confirming hemostasis limit its usefulness. To overcome these issues, we used the endoscope in brain tumor biopsy, for not only intraventricular tumors but also intraparenchymal tumors. The rigid scope was used in association with a surgical navigation system for intraparenchymal lesions via a transcortical route. There were no useful anatomical landmarks when the trajectory to the lesions was decided; therefore, surgical navigation system was required for the transcortical procedures. The endoscopic procedure described here was attempted in 21 cases of intraparenchymal lesions between January 2007 and February 2012. A definitive diagnosis was obtained in all cases, and genetic analysis was performed when required. Serious postsurgical hemorrhage or neurological deficits were not observed in any cases. Endoscopic surgery provides a clear view of the target and makes it easier to differentiate tumor tissue from normal brain tissue. Moreover, the endoscope helped to confirm hemostasis during the procedure. Thus, endoscopic biopsy has the potential to contribute toward safe and reliable diagnosis of brain tumors.

Prediction of genetic subgroups in adult supra tentorial gliomas by pre- and intraoperative parameters

Recent progress in neuro-oncology has validated the significance of genetic diagnosis in gliomas. We previously investigated IDH1/2 and TP53 mutations via Sanger sequencing for adult supratentorial gliomas and reported that PCR-based sequence analysis classified gliomas into three genetic subgroups that have a strong association with patient prognosis: IDH mutant gliomas without TP53 mutations, IDH and TP53 mutant gliomas, and IDH wild-type gliomas. Furthermore, this analysis had a strong association with patient prognosis. To predict genetic subgroups prior to initial surgery, we retrospectively investigated preoperative radiological data using CT and MRI, including MR spectroscopy (MRS), and evaluated positive 5-aminolevulinic acid (5-ALA) fluorescence as an intraoperative factor. We subsequently compared these factors to differentiate each genetic subgroup. Multiple factors such as age at diagnosis, tumor location, gadolinium enhancement, 5-ALA fluorescence, and several tumor metabolites according to MRS, such as myo-inositol (myo-inositol/total choline) or lipid20, were statistically significant factors for differentiating IDH mutant and wild-type, suggesting that these two subtypes have totally distinct characteristics. In contrast, only calcification, laterality, and lipid13 (lipid13/total Choline) were statistically significant parameters for differentiating TP53 wild-type and mutant in IDH mutant gliomas. In this study, we detected several pre- and intraoperative factors that enabled us to predict genetic subgroups for adult supratentorial gliomas and clarified that lipid13 quantified by MRS is the key tumor metabolite that differentiates TP53 wild-type and mutant in IDH mutant gliomas. These results suggested that each genetic subtype in gliomas selects the distinct lipid synthesis pathways in the process of tumorigenesis.

A retrospective study of bevacizumab for treatment of brainstem glioma with malignant features

Brainstem glioma is impossible to resect completely, and patients with this type of glioma show a poor prognosis. Therefore, a more effective adjuvant therapy is required to prolong survival. Bevacizumab is an endothelial growth factor monoclonal antibody with strong anti-vascular effects, which may suppress tumor progression. We performed a retrospective study of data from 6 patients with brainstem glioma showing malignant features who were treated with bevacizumab. Tumor-associated lesions, as evaluated by T2 weighted or fluid-attenuated inversion-recovery magnetic resonance imaging, were reduced in all patients, although the timing of the start of bevacizumab administration and pretreatment were not uniform. Clinical symptoms improved in 4 patients and progression was inhibited in 2 patients. The Karnofsky performance status improved from 56.7 to 71.7 on average. The median reduction ratio of tumor-associated lesions was 76.3%, but tumor suppression did not last in any of the cases. Furthermore, 5 patients died of tumor progression, and 1 patient died of a complication of necrotizing colitis. The median progression-free survival after bevacizumab administration was 7 months. The median overall survival after diagnosis was 16.5 months. Bevacizumab might be a potential therapeutic option for progressive brainstem gliomas with malignant features.

Modified Balloon Protection Technique for Preoperative Embolization of Feeder Arteries from Internal Carotid Artery Branches to Skull-Base Tumor: Technical Note.

OBJECTIVE To improve bleeding management during brain tumor surgery, feeder arteries supplying the tumor are often embolized presurgically. However, access to feeder arteries can be limited, and embolization of feeders from internal carotid artery (ICA) branches often causes complications. We evaluated the PercuSurge GuardWire (Medtronic, Minneapolis, Minnesota, United States) system (PGWS) with aspiration catheter as a modification of the embolization technique used to block tumor-supplying branches of the ICA. METHODS Two skull-base tumors were treated with preoperative embolization. One was a meningioma; the other was a hemangiopericytoma. In each case, the microcatheter could not be threaded into the ICA feeder arteries. Therefore, particulate embolic material was injected near the ICA branch while maintaining ICA balloon protection by the PGWS at the orifice of the ophthalmic artery. After embolization, we removed the remaining embolic material in the ICA using an aspiration catheter. In both cases, there were no postembolization complications and no high-intensity areas in the diffusion-weighted magnetic resonance image, and the tumorectomy proceeded as scheduled. CONCLUSION This modified technique may be a promising alternative for reducing embolic complications and improving the success rate, although case accumulation is needed to confirm this result.