Kengo Matsumoto

Proton magnetic resonance spectroscopy reflects cellular proliferative activity in astrocytomas.

Abstract We examined whether proton magnetic resonance spectroscopy (MRS) could provide accurate information on histological grade and cell proliferation in astrocytomas. We studied 23 patients with astrocytomas: five grade II, 10 grade III and eight with grade IV (glioblastoma multiforme). We performed proton MRS and determined the Ki-67 labeling index (LI), a tumour proliferation marker, in the same areas of the astrocytomas, and examined the statistical relationship between proton MRS and Ki-67 LI. The N-acetylaspartate (NAA)/creatine-phosphocreatine (Cr) and NAA/choline (Cho)-containing compound ratios were always significantly lower and the Cho/Cr ratios significantly higher than those for normal brain. The Cho/Cr ratio correlated positively and the NAA/Cho ratio inversely with Ki-67 LI. These findings suggest that the Cho signal in proton MRS reflects cellular proliferation. In Kaplan-Meier survival analysis, there was no significant difference between high (> 2.0, 14 cases) and low (< 2.0, 9 cases) Cho/cr ratio groups.

Peritumoral brain edema in intracranial meningiomas: effects of radiological and histological factors.

OBJECTIVEWe examined the radiological and histological features influencing the development of peritumoral brain edema (PTBE) among patients with meningiomas. METHODSFactors causing PTBE were retrospectively analyzed for 125 patients with primary intracranial meningiomas. These factors included tumor size, tumor location, brain-tumor interface, signal intensity on T2-weighted scans, contrast enhancement, and cyst formation (as observed on magnetic resonance imaging scans), as well as tumor vascularity and blood supply (as observed in digital subtraction angiography studies). We defined the edema/tumor volume ratio as the edema index, and we used this index to evaluate PTBE. RESULTSA relationship between the tumor size and the volume of PTBE was observed. Convexity and middle fossa meningiomas demonstrated the greatest increases in mean edema indices. Meningothelial, anaplastic, microcystic, and angiomatous subtypes exhibited higher edema indices than did other types. Multivariate analysis demonstrated two significant radiological factors: cortical penetration (as defined by the disappearance of the arachnoid layer on magnetic resonance imaging scans) (relative risk, 2.067;P = 0.0148) and vascular supply from the pial-cortical arteries (as observed on angiograms) (relative risk, 2.087;P = 0.0082). CONCLUSIONTumor infiltration into adjacent brain parenchyma and a pial-cortical blood supply are critical factors for the development of PTBE among patients with meningiomas.

Malignant astrocytomas with homozygous CDKN2/p16 gene deletions have higher Ki-67 proliferation indices

p16 is involved in a cell-cycle regulatory cascade that includes cyclin-dependent kinase 4 (cdk4), cyclin D1 and pRb. Alterations of each of these components have been described in primary human glioblastoma multiforme (GBM) or GBM cell lines, and alterations of the individual components of this pathway appear inversely correlated with one another. While this suggests that disruption of any individual component has similar oncogenic effects, homozygous deletions of the CDKN2/p16 gene are the most common genetic alteration. We investigated the relationship between homozygous CDKN2/ p16 deletions and cellular proliferation in 50 primary astrocytomas (2 WHO grade I pilocytic astrocytoma, 15 grade II astrocytomas, 20 grade III anaplastic astrocytomas and 13 grade IV GBMs). Using a comparative multiplex PCR assay, homozygous deletions of the CDKN2/p16 gene were detected in 5 anaplastic astrocytomas (25%) and 6 GBMs (46%), but in none of the lower-grade tumors. Ki-67 immunohistochemistry was used to assess the number of proliferating cells in the same samples used for molecular genetic analysis. In both anaplastic astrocytomas and GBMs, Ki-67 proliferation indices were significantly higher in tumors with CDKN2/p16 deletions (20%) than in those without deletions (10%; p = 0.0001). These results suggest that homozygous CDKN2/p16 deletions in high-grade astrocytomas may have a more deleterious effect on cell cycle control than the other aberrations in the p16-cdk4-cyclin D1-pRb pathway, and may provide one explanation for why homozygous CDKN2/p16 deletions are more common genetic events in high-grade astrocytomas than RB mutations or CDK4 amplification.

In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus.

We evaluated the therapeutic efficacy and neurotoxicity of adenovirus-mediated transduction of the cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) for experimental malignant brain tumors. The 5-FC sensitivity in 9 L cells infected by an adenovirus vector expressing CD (AdexCACD) was increased 1700-fold compared with control cells. Rats bearing 9 L brain tumors were treated with an intratumoral injection of AdexCACD followed by intraperitoneal administration of 5-FC. The rats demonstrated remarkable inhibition of tumor growth by magnetic resonance imaging, and 7 of 10 rats survived for >90 days. To evaluate the potential side-effects of the 5-FC/CD gene therapy, rats were treated with an intracerebral injection of AdexCACD into the right basal ganglia and with 5-FC. The magnetic resonance imaging showed a highly enhanced area on the gadollinium-enhanced T1-weighted image at 18 days postinjection. Pathologically, this corresponded to an area of necrosis with surrounding apoptotic cells. In addition, there was demyelination and gliosis with enlargement of the lateral ventricles. These results suggest that the 5-FC/CD gene therapy may provide an anticancer effect for malignant brain tumors in humans, but also show that there are neurotoxic effects on normal brain tissue.

Metastasis of renal cell carcinoma to central nervous system hemangioblastoma in two patients with von Hippel–Lindau disease

Here we report tumor‐to‐tumor metastases identified in two patients with von Hippel–Lindau (VHL) disease. The first patient had bilateral renal carcinomas and multiple cerebellar hemangioblastomas, and the second patient had a renal carcinoma and multiple hemangioblastomas in the retina, cerebellum and spinal cord. A cerebellar lesion from the first patient and a spinal lesion from the second patient contained two distinct components. The inner part of these tumors consisted of a nested mass of polygonal clear cells that expressed cytokeratin and epithelial membrane antigen, while the outer part of the tumors showed proliferation of capillaries and intervening foamy stromal cells that were negative for cytokeratin and epithelial membrane antigen. The tumors were thus considered to be hemangioblastomas complicated by metastatic lesions of renal cell carcinoma of clear cell type. These cases indicate that tumor‐to‐tumor metastasis should be considered when hemangioblastoma contains a clear cell carcinoma component in the setting of VHL disease, and that immunohistochemical staining for cytokeratin and epithelial membrane antigen is useful for the diagnosis.

Cerebral Gangliogliomas: Clinical Characteristics, CT and MRI

Summary Eight patients with ganglioglioma who received surgical treatment at our institute between January 1989 and January 1997 were reviewed to determine their clinical, CT and MRI characteristics. Tumours were located in the temporal lobe (four patients), trigone of the lateral ventricle (two patients), basal ganglia (one patient) and fronto-temporal lobe (one patient). On imaging, two types of tumours were seen, a solid mass in 5 patients (62.5%) and a cystic mass in three patients (37.5%). Six complete tumours (75%) and all of the solid components of the cystic tumours were enhanced by contrast medium. Seven tumours (88%) had no peripheral oedema. On CT, the tumours being studied appeared as iso-(62.5%) or low density (37.5%) intra-axial tumours. Four tumours (50%) contained calcification. On MRI, the tumours appeared as well-circumscribed, iso- (62.5%) or low intensity (37.5%) intra-axial tumours on T1 weighted images, and as high (75%) on T2 weighted images. Three underwent total resection, 2 subtotal resection and 3 partial resection. No patients had have any further treatment such as radiation therapy or chemotherapy. Postoperative sudies were conducted on all patients with an average follow-up period 56 months (range 4–147 months) after surgery. There was no evidence of recurrence of tumours or of growth of residual tumours. We observed gangliogliomas which were located in unusual regions such as the trigone in two of the patients. To our knowledge, our series is the first report to describe trigonal gangliogliomas. We conclude, therefore, that ganglioglioma should be included as a possibility in the differential diagnosis of intracranial masses, even when they are located in the trigone.

Accumulation of wild-type p53 in astrocytomas is associated with increased p21 expression

Abstract Approximately one quarter of human astrocytomas show immunohistochemical positivity for p53 protein but lack p53 gene mutations, which could reflect either an accumulation of wild-type p53 protein or an inadequate sensitivity of mutation detection. Since wild-type p53 up-regulates p21 expression, increased p21 expression in those astrocytomas with p53 accumulation in the absence of mutations would argue that the protein was wild type in these tumors. We therefore compared p21 expression with p53 gene and protein status in 48 primary human astrocytomas. Single-strand conformation polymorphism analysis and direct sequencing of the p53 gene showed mutations in 11 tumors (22.9%), while immunohistochemistry revealed positive staining in 19 cases (39.6%). Those tumors with p53 immunopositivity in the absence of p53 mutation had significantly increased p21 expression when compared to either mutant p53 or p53-immunonegative cases. Neither p53 nor p21 status correlated with proliferation indices, as assessed by Ki-67 immunohistochemistry. These results support the hypotheses that functionally wild-type p53 accumulates in some astrocytomas, and that alternative cell cycle checkpoints (such as the p16 pathway) may be more important than p21 in regulating proliferation in astrocytomas.

Spinal atypical teratoid/rhabdoid tumor in an infant.

Atypical teratoid/rhabdoid tumor of the central nervous system in infancy and childhood was established as an entity based on histological, immunohistochemical, and cytogenetic studies. We report the case of a 7-month-old girl who presented with progressive paraplegia and hypesthesia of her legs. Imaging studies revealed a spinal cord mass occupying the entire spinal canal below the T7 level. Through a T12-L3 laminectomy, the intramedullary tumor was partially debulked. Histologically, the tumor specimen had rhabdoid cells, and immunostaining showed vimentin and cytokeratin positivity. No abnormality of chromosome 22q was detected with the fluorescence in situ hybridization method.

Hypophysis surgery with or without endoscopy

OBJECTIVE Hardys operation with microscope has long been the standard method for pituitary adenoma. But a new approach via the nasal cavity using an endoscope has been adopted recently. In this study, the postoperative outcome as well as the preoperative evaluation of endoscopic hypophysectomy and non-endoscopic one were compared at our faculty. METHOD We performed the non-endoscopic transnasal hypophysectomy on 18 patients and the endoscopic transnasal hypophysectomy on thirteen patients who had a pituitary lesions from February 1996 to October 1999. As to these patients the situations from preoperation through postoperation such as chief complaints, serum hormone level, final diagnosis, tumor size, as well as operating time or blood loss during the operation were discussed precisely. Then the merits and demerits of endoscopic hypophysectomy were discussed. RESULT Five PRL-producing adenoma, three GH-producing adenoma, nine non-functioning adenoma, and two ACTH or TSH-producing adenoma were included in this discussion as endoscopic group. The age of non-endoscopic group are from 23 to 73 (49.4 in average), and they include ten males and eight females. On the other hand three PRL-producing adenoma, two GH-producing adenoma, two non-functioning adenoma, and one Rathkes cyst were included in this discussion as endoscopic group. The age of endoscopic group are from 19 to 73 (49.1 in average), and they include seven males and six females. As to non-endopscopic group the blood loss during each operation is 568 ml and operating time is 256 min in average. For endoscopic group the blood loss is 296 ml and operating time is 234 min in average. CONCLUSION By microsurgery in the pituitary operation with endoscopy, the minimal invasive surgery becomes possible by reducing blood loss and shortening operating time. During the operation cooperation between neurosurgeon and ENT surgeon is indispensable in order to perform hypophysectomy smoothly. The development of optical better aids and operation instruments for endonasal hypophysectomy is desired in the future. The navigation system was more useful than X-ray fluoroscopy to obtain the detailed information.

Prognostic value of loss of heterozygosity around three candidate tumor suppressor genes on chromosome 10q in astrocytomas

We thoroughly examined loss of heterozygosity (LOH) around three candidate tumor suppressor genes on chromosome 10q to determine whether LOH of each tumor suppressor gene is associated with the previously defined clinical prognostic indices. We also examined whether LOH can help predict prognostic variables in astrocytomas.We selected samples from 40 astrocytomas (grades 2–4), performed Ki-67 immunostaining, and counted positive cells. Using DNA from aliquots of tumor blocks and leukocytes, we investigated LOH around the PTEN, NEURL, and DMBT1 genes (10q23.3–26.1) with the silver staining procedure. We then statistically evaluated the relationship among histological features, regional LOH on chromosome 10q, and survival. The mean survival period for patients with LOH around PTEN was 7.2 months after surgery, while that for patients without LOH around PTEN was 21.4 months. Thus, LOH around PTEN was closely associated with a reduced overall survival (p = 0.0020) but LOH at NEURL or DMBT1 was not (p > 0.05).The combined features of an increase in histological grading and Ki-67-positive cells and the presence of LOH around PTEN significantly correlated with poor prognosis. These factors may be useful predictors of survival, and LOH analysis of tumor suppressor genes on chromosome 10q can contribute greatly to the treatment of patients with astrocytoma.