Satoshi Utsuki

PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas

Gene rearrangement in the form of an intragenic deletion is the primary mechanism of oncogenic mutation of the epidermal growth factor receptor (EGFR) gene in gliomas. However, the incidence of platelet-derived growth factor receptor-α (PDGFRA) gene rearrangement in these tumors is unknown. We investigated the PDGFRA locus in PDGFRA-amplified gliomas and identified two rearrangements, including the first case of a gene fusion between kinase insert domain receptor (KDR) (VEGFRII) and the PDGFRA gene, and six cases of PDGFRA(Δ8, 9), an intragenic deletion rearrangement. The PDGFRA(Δ8, 9) mutant was common, being present in 40% of the glioblastoma multiformes (GBMs) with PDGFRA amplification. Tumors with these two types of PDGFRA rearrangement displayed histologic features of oligodendroglioma, and the gene products of both rearrangements showed constitutively elevated tyrosine kinase activity and transforming potential that was reversed by PDGFR blockade. These results suggest the possibility that these PDGFRA mutants behave as oncogenes in this subset of gliomas, and that the prevalence of such rearrangements may have been considerably underestimated.

Relationship between the expression of E-, N-cadherins and beta-catenin and tumor grade in astrocytomas.

Cadherins are cell-surface glycoproteins that mediate Ca2+-dependent, homophilic cell–cell adhesion. The classical cadherins, E- and N-cadherins, connect to beta-catenin, the lining protein. There appears to be a relationship between their dysfunction and tumor invasion and metastasis. The aim of our study was to examine the possibility of a relationship between alterations in the E- and N-cadherin and catenin expression and malignancy in astrocytomas. Forty-five astrocytomas (18 glioblastomas, 16 anaplastic astrocytomas, and 11 diffuse astrocytomas) were collected and stained immunohistochemically for cadherins and beta-catenin. None of the astrocytomas were immunoreactive for E-cadherin. N-cadherin and beta-catenin were present at cell–cell borders in 61% of glioblastomas and 31% of anaplastic astrocytomas. The incidence of immunoreactivity for N-cadherin and beta-catenin increased significantly with the histological grade of astrocytomas (p=0.001, by Kruskal–Wallis test). Moreover, in anaplastic astrocytomas and glioblastomas, the Ki-67 labeling indices in both N-cadherin-positive and beta-catenin-positive cases were higher than that in negative cases (p=0.05 and 0.03, respectively, by Fishers exact test). These results suggest that the expression of N-cadherin or beta-catenin may be related to the biological behavior of astrocytomas.

Fluorescence-guided resection of metastatic brain tumors using a 5-aminolevulinic acid-induced protoporphyrin IX: pathological study

We performed a pathological study to identify the locus of production of protoporphyrin IX (PPIX) in human metastatic brain tumors. Patients with metastatic brain tumors (n = 11) received 1 g of 5-aminolevulinic acid (5-ALA) perorally 2 h before undergoing surgery. The target region was exposed to laser light with a peak wavelength of 405 ± 1 nm and an output of 40 mW. Tissue samples from the tumor bulk and surrounding areas were examined by histological and fluorescence methods. Of the 11 tumors, 9 manifested PPIX fluorescence in the tumor bulk and peritumoral brain tissue. Our findings indicate that PPIX fluorescence can be observed in peritumoral edematous areas that are free of neoplastic cells, because PPIX produced by neoplastic cells leaks into the surrounding edematous area.

Prognostic value of Ki-67 (MIB-1) and p53 in ependymomas

T a b l e 1 ( P a t h o l o g i c a l d iagnos i s , l oca t ion , o p e r a t i o n , i r r a d i a t i o n , a n d fo l l ow-up o n p a t i e n t s w i t h e p e n d y m o m a s , p. 152), a n d T a b l e 2 ( P e r c e n t e x p r e s s i o n of M I B 1 a n d p53 in e p e n d y m o m a s , p. 153) w e r e in e r ro r . T h e c o r r e c t e d c l in ical d a t a a re s h o w n in t h e f o l l o w i n g tab les .

A nationwide survey of hypertrophic pachymeningitis in Japan

Objectives To clarify the prevalence, frequent causes and distinct features of hypertrophic pachymeningitis (HP) according to background conditions in a nationwide survey in Japan. Methods The study began with a preliminary survey to determine the approximate number of HP patients diagnosed from 1 January 2005 to 31 December 2009, and was followed by a questionnaire survey for clinical and laboratory findings. HP was defined as a condition with thickening of the cranial or spinal dura mater with inflammation, evidenced by MRI or histology. Results Crude HP prevalence was 0.949/100 000 population. The mean age at onset was 58.3±15.8 years. Among 159 cases for whom detailed data were collated, antineutrophil cytoplasmic antibody (ANCA)-related HP was found in 54 cases (34.0%) and IgG4/multifocal fibrosclerosis (MFS)-related HP in 14 cases (8.8%). Seventy cases (44.0%) were classified as ‘idiopathic’ and 21 (13.2%) as ‘others’. ANCA-related HP cases showed a female preponderance, a higher age of onset, and higher frequencies of otological symptoms and elevated systemic inflammatory biomarkers, but lower frequencies of diplopia compared with idiopathic HP. IgG4/MFS-related HP cases showed a marked male predominance; all had cranial HP while none had isolated spinal HP or decreased sensation. Conclusions HP is not extremely rare. ANCA-related HP is the most frequent form, followed by IgG4/MFS-related HP. Both forms have unique features, which may help to differentiate background causes.

O6-methylguanine-DNA methyltranspherase gene expression in gliomas by means of real-time quantitative RT-PCR and clinical response to nitrosoureas

O6‐methylguanine‐DNA methyltransferase (MGMT) mRNA expressions were examined in 100 neuroepithelial tumors by real‐time quantitative reverse transcription‐polymerase chain reaction (RT‐PCR) using SYBR Green I. The mean relative quantitation value of MGMTmRNA normalized to the level of β2‐microglobulin for 100 tumors was 5.3 ± 11.2. The mean value of 41 glioblastomas was significantly higher than that for the other 59 tumors (p = 0.0008 by Students t‐test). In contrast, the means of 19 low‐grade gliomas and 12 medulloblastomas were significantly lower than that of other tumors (p = 0.0282 and p = 0.0456 by Students t‐test). Among the 55 retrospective patients who had been treated with 1‐(4‐amino‐2‐methyl‐5‐pyrimidynyl)methyl‐3‐(2‐chloroethyl)‐ 3‐nitrosourea hydrochloride (ACNU), the value was a significant independent predictor of the effect of initial therapy with ACNU (p = 0.0007 by Mann‐Whitney U‐test) and the survival period (p = 0.0175 by Wald test). The value ≧1 was the most significant factor in predicting the initial effect of treatment by multi‐variant regression analysis (p < 0.0001). These results suggest that our individual adjuvant therapy based on MGMTmRNA expression may be improved by the application of real‐time quantitative RT‐PCR.

Bilateral crossed cerebello-cerebral diaschisis and mutism after surgery for cerebellar medulloblastoma

A 7-year-old boy developed mutism after surgery for cerebellar medulloblastoma. Postoperative magnetic resonance imaging (MRI) whowed atrophy of the cerebellar vermis and both cerebellar hemispheres, predominantly on the right side. Single photon emission computed tomography (SPECT) with technetium-99m-ethyl cysteinate dimer (Tc-99m ECD) revealed decreased cerebral blood flow (CBF) in the bilateral thalami, bilateral medial frontal lobes, and left temporal lobe in addition to the cerebellar vermis and both cerebellar hemispheres when mutism was manifest, indicating the existence of bilateral crossed cerebello-cerebral diaschisis (BCCCD). Circulatory disturbance in both cerebellar hemispheres secondary to tumor resection probably caused BCCCD in both cerebral hemispheres, predominantly in the left, via the dentatothalamocortical pathway (DTCP). With recovery of his mutism, CBF increased in the right thalamus, bilateral medial frontal lobes and left temporal lobe. Thus BCCCD was improved, with only a slight decrease in CBF still persisting in the left thalamus. The mechanism of mutism may have involved damage to the cerebellar vermis (the site of incision at operation), the left dentate nucleus (heavily infiltrated by the tumor) and the right dentate nucleus of the cerebellum (affected by circulatory disturbance secondary to acute postoperative edema). The SPECT findings suggested that mutism was associated with BCCCD-induced cerebral circulatory and metabolic hypofunction in the supplementary motor area mediated via the DTCP.

Long-term functional outcome of suprasellar germinomas: usefulness and limitations of radiotherapy.

We investigated the long-term functional outcome of patients with suprasellar germinoma after radiotherapy to determine the usefulness and limitations of radiotherapy for these tumors. From among 54 cases of intracranial germ cell tumor at Kitasato University Hospital, 12 patients with suprasellar germinoma who were treated with radiotherapy but not chemotherapy retrospectively investigated for mental, hormonal and visual functions. The follow-up period ranged from 63 to 262 months (mean, 161.1 months). The mortality rate was zero and there was no recurrence of tumors. However, three patients treated with local irradiation alone showed metastasis to the ventricles or spinal cord. With regard to mental function, 50% of the patients showed remarkably low mental function after radiotherapy. With regard to pituitary hormonal function, deficiency of ADH, GH, ACTH, and TSH was documented in 75%, 41.7%, 16.7% and 8.3% of the patients, respectively, before radiotherapy. Prolactin was elevated in 50% of the patients. After radiotherapy, 91.7% needed hormone replacement. With regard to visual function, most patients showed an improvement or no change after radiotheray. In conclusion, radiotherapy for suprasellar germinomas gave long-time survival. However, such radiotherapy may cause mental and pituitary hormonal dysfunction. Our results show that while radiotherapy is useful for treating suprasellar germinomas, its dose have some limitations.

Proteomics of tumor‐specific proteins in cerebrospinal fluid of patients with astrocytoma: Usefulness of gelsolin protein

Changes in cerebrospinal fluid (CSF) composition have been shown to accurately reflect pathological processes in the CNS, and are potential indicators of abnormal CNS states, such as tumor growth. To detect biomarkers in high‐grade astrocytomas, the differential expression of proteins in the cerebrospinal fluid was analyzed from two cases each of diffuse astrocytoma (grade II), and glioblastoma (grade IV) using agarose 2‐D gel electrophoresis (2‐DE). It was found that the expression of gelsolin protein decreased with histological grade. To examine whether gelsolin is a useful indicator of tumor aggressiveness or patient outcome, its expression was further studied on immunohistochemistry in 41 formalin‐fixed and paraffin‐embedded astrocytomas. The positive cell rate of gelsolin in tumors was 59.4% in grade II, 30.0% in grade III and 29.4% in grade IV, respectively. Gelsolin expression was significantly lower in high‐grade astrocytomas (grade III or IV) than in low‐grade astrocytomas (grade II; P < 0.05). Moreover, in astrocytomas the overall survival of patients in the low‐expression group was significantly poorer than in the high expression group (P < 0.05). These data suggest that gelsolin is a prognostic factor in astrocytoma.

Pathological and clinical features of cystic and noncystic glioblastomas.

The aim of this study is to review the different histological and clinical characteristics of glioblastoma multiforme (GBM) with and without cysts (cystic and noncystic GBM, respectively). Thirty-seven GBM were collected; these were tumors for which more than 80% of the volume was surgically resected, including a portion of the peripheral parenchyma of the brain. Based on preoperative magnetic resonance (MR) imaging studies, tumors were tentatively classified as cystic GBM if more than 50% of their volume appeared to be liquid; otherwise, they were considered to be noncystic GBM. Tumor volumes were estimated from contrast-enhanced T1-weighted MR images. Edema was deduced from the maximum width of contrast-enhanced edges. Peritumoral pathological analysis showed distinct margins, indicating little or no infiltration of tumor cells into white matter. Five cases were classified as cystic and 32 were noncystic GBMs. There was a statistically significant difference in age (Mann–Whitney U test; P < 0.05) between the patients with cystic tumors (median, 44 years; range, 26–59 years) and those with noncystic tumors (median, 54 years; range, 26–81 years). Four of the cystic tumors and eight of the noncystic tumors were more than 5 cm in maximum diameter. Cystic GBMs had a well-defined tumor interface and less than 2-cm-thick peritumoral edema compared to the noncystic GBMs (Fishers exact test; P < 0.05). For patients with cystic GBMs, median survival time after surgery was 19.8 months and the 2-year survival rate was 50%. Patients with noncystic GBMs had a median survival time of 12.8 months and a 2-year survival rate of only 17%. Median time to tumor recurrence was 13.3 months for patients harboring cystic GBMs and 8.5 months for those with noncystic GBMs (log-rank test; P < 0.05). Thus, the prognosis for cystic GBM was significantly better than that for noncystic GBM, possibly because cystic GBMs showed comparatively little infiltration of the peritumoral brain parenchyma.