Hirohito Yano

Metabolic Assessment of Gliomas Using 11C-Methionine, [18F] Fluorodeoxyglucose, and 11C-Choline Positron-Emission Tomography

BACKGROUND AND PURPOSE: Positron-emission tomography (PET) is a useful tool in oncology. The aim of this study was to assess the metabolic activity of gliomas using 11C-methionine (MET), [18F] fluorodeoxyglucose (FDG), and 11C-choline (CHO) PET and to explore the correlation between the metabolic activity and histopathologic features. MATERIALS AND METHODS: PET examinations were performed for 95 primary gliomas (37 grade II, 37 grade III, and 21 grade IV). We measured the tumor/normal brain uptake ratio (T/N ratio) on each PET and investigated the correlations among the tracer uptake, tumor grade, tumor type, and tumor proliferation activity. In addition, we compared the ease of visual evaluation for tumor detection. RESULTS: All 3 of the tracers showed positive correlations with astrocytic tumor (AT) grades (II/IV and III/IV). The MET T/N ratio of oligodendroglial tumors (OTs) was significantly higher than that of ATs of the same grade. The CHO T/N ratio showed a significant positive correlation with histopathologic grade in OTs. Tumor grade and type influenced MET uptake only. MET T/N ratios of more than 2.0 were seen in 87% of all of the gliomas. All of the tracers showed significantly positive correlations with Mib-1 labeling index in ATs but not in OTs and oligoastrocytic tumors. CONCLUSION: MET PET appears to be useful in evaluating grade, type, and proliferative activity of ATs. CHO PET may be useful in evaluating the potential malignancy of OTs. In terms of visual evaluation of tumor localization, MET PET is superior to FDG and CHO PET in all of the gliomas, due to its straightforward detection of “hot lesions”.

Analysis of 11C-methionine Uptake in Low-Grade Gliomas and Correlation with Proliferative Activity

BACKGROUND AND PURPOSE: The relationship of 11C-methionine (MET) uptake and tumor activity in low-grade gliomas (those meeting the criteria for World Health Organization [WHO] grade II gliomas) remains uncertain. The aim of this study was to compare MET uptake in low-grade gliomas and to analyze whether MET positron-emission tomography (PET) can estimate tumor viability and provide evidence of malignant transformation. MATERIALS AND METHODS: We studied glioma metabolic activity in 49 consecutive patients with newly diagnosed grade II gliomas by using MET PET before surgical resection. On MET PET, we measured tumor/normal brain uptake ratio (T/N ratio) in 21 diffuse astrocytomas (DAs), 12 oligodendrogliomas (ODs), and 16 oligoastrocytomas (OAs). We compared MET T/N ratio among these 3 tumors and investigated possible correlation with proliferative activity, as measured by Mib-1 labeling index (LI). RESULTS: MET T/N ratios of DA, OD, and OA were 2.11 ± 0.87, 3.75 ± 1.43, and 2.76 ± 1.27, respectively. The MET T/N ratio of OD was significantly higher than that of DA (P < .005). In comparison of MET T/N ratios with the Mib-1 LI, a significant correlation was shown in DA (r = 0.63; P < .005) but not in OD and OA. CONCLUSION: MET uptake in DAs may be closely associated with tumor viability, which depends on increased amino acid transport by an activated carrier-mediated system. DAs with lower MET uptake were considered more quiescent lesions, whereas DA with higher MET uptake may act more aggressively.

Selection of eligible patients with supratentorial glioblastoma multiforme for gross total resection.

The purpose of this study is to clarify whether gross total tumor resection can prolong the survival in adult patients with supratentorial glioblastoma multiforme (GBM), and to clarify what subset of these patients obtains a survival advantage by gross total tumor resection without postoperative neurological deterioration.Eighty-two adult patients with supratentorial GBM were retrospectively reviewed. Overall, the median survival time was 13 months, and the 1- and 2-year survival rates were 53.7% and 14.6%, respectively. In a univariate analysis for survival rate by log-rank test, age (>40 years), Karnofsky performance scale (KPS) score (70–100%) and extent of surgery (gross total resection) were revealed to be significant good prognostic factors. A Cox proportional hazard multivariate regression analysis confirmed that the KPS and extent of surgery were independent, significant good prognostic factors. Nine patients (11%) suffered postoperative neurological deterioration.A topographical GBM staging system (Stages I, II and III) with the integration of tumor location, size and eloquence of adjacent brain based on MRI (for explanation of Stages see text) was originally proposed. In Stage I, gross total resection had a strong tendency toward a better prognostic factor in a univariate analysis and was revealed to be a significant independent good prognostic factor in a multivariate analysis. In also Stage II, the survival of patients who underwent gross total resection was better than that of patients with less than gross total resection, although not significant. In Stage III, there were no patients who underwent gross total tumor resection. Risk probabilities of postoperative neurological deterioration, overall, were 0%, 22.2%, and 20% in Stages I, II, and III, respectively, and those after gross total resection were 0% and 16.7% in Stages I and II, respectively.Although gross total tumor resection is associated with prolongation of the survival time of patients with GBM, the risk of postoperative neurological deficit increases with radical tumor resection. To select an eligible subset of patients that benefit in survival from gross total tumor resection without postoperative risk, the following surgical policy for GBM resection is suggested. GBM in Stage I should be resected as radically as possible. Regarding Stage II, risky surgical resection extending to the area adjacent to the critical zone should be avoided and more meticulous and careful surgical planning is needed than that in Stage I. In Stage III, radical gross total tumor resection is not recommended at present.

Impact of [11C]Methionine Positron Emission Tomography for Target Definition of Glioblastoma Multiforme in Radiation Therapy Planning

PURPOSE The purpose of this work was to define the optimal margins for gadolinium-enhanced T(1)-weighted magnetic resonance imaging (Gd-MRI) and T(2)-weighted MRI (T(2)-MRI) for delineating target volumes in planning radiation therapy for postoperative patients with newly diagnosed glioblastoma multiforme (GBM) by comparison to carbon-11-labeled methionine positron emission tomography ([(11)C]MET-PET) findings. METHODS AND MATERIALS Computed tomography (CT), MRI, and [(11)C]MET-PET were separately performed for radiation therapy planning for 32 patients newly diagnosed with GBM within 2 weeks after undergoing surgery. The extent of Gd-MRI (Gd-enhanced clinical target volume [CTV-Gd]) uptake and that of T(2)-MRI of the CTV (CTV-T(2)) were compared with the extent of [(11)C]MET-PET (CTV--[(11)C]MET-PET) uptake by using CT--MRI or CT--[(11)C]MET-PET fusion imaging. We defined CTV-Gd (x mm) and CTV-T(2) (x mm) as the x-mm margins (where x = 0, 2, 5, 10, and 20 mm) outside the CTV-Gd and the CTV-T(2), respectively. We evaluated the relationship between CTV-Gd (x mm) and CTV-- [(11)C]MET-PET and the relationship between CTV-T(2) (x mm) and CTV-- [(11)C]MET-PET. RESULTS The sensitivity of CTV-Gd (20 mm) (86.4%) was significantly higher than that of the other CTV-Gd. The sensitivity of CTV-T(2) (20 mm) (96.4%) was significantly higher than that of the other CTV-T(2) (x = 0, 2, 5, 10 mm). The highest sensitivity and lowest specificity was found with CTV-T(2) (x = 20 mm). CONCLUSIONS It is necessary to use a margin of at least 2 cm for CTV-T(2) for the initial target planning of radiation therapy. However, there is a limit to this setting in defining the optimal margin for Gd-MRI and T(2)-MRI for the precise delineation of target volumes in radiation therapy planning for postoperative patients with GBM.

Venous drainage patterns in perimesencephalic nonaneurysmal subarachnoid hemorrhage

OBJECTIVE The precise etiology of perimesencephalic nonaneurysmal subarachnoid hemorrhage (P-SAH) has not yet been determined. We decided to compare the venograms of patients with P-SAH with those of patients with aneurysmal SAH (A-SAH) to examine the relationship between P-SAH and venous drainage patterns. METHODS We retrospectively studied 18 patients with P-SAH during the past 10 years and 112 patients with ruptured A-SAH during the past 4 years by reevaluating their venograms for possible abnormalities in venous structures, particularly focusing on the basal vein of Rosenthal (BVR). Anatomical variants were classified into three types according to the drainage pathway. RESULTS The location and drainage pathway of the BVR proved to be a significantly more primitive configuration in patients with P-SAH than in those with A-SAH (P<0.05). On the other hand, physical action including components of the Valsalva maneuver were the cause of nine cases of P-SAH (69.2%) in this case profile. The occurrence rate was significantly higher in the P-SAH group than in the A-SAH group (14.3%) (p<0.05). CONCLUSION Our data suggest that failure of longitudinal anastomoses between the primary primitive veins as well as excessive strenuous exertion including components of the Valsalva maneuver plays an important predisposing role in the etiology of P-SAH.

Comparison of (11)C-methionine, (11)C-choline, and (18)F-fluorodeoxyglucose-PET for distinguishing glioma recurrence from radiation necrosis.

The aim of this study is to assess the different metabolic activities characteristic of glioma recurrence and radiation necrosis (RN) and to explore the diagnostic accuracy for differentiation of the two conditions using 11C-methionine (MET), 11C-choline (CHO), and 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). Fifty patients with lesions suggestive of recurrent glioma by magnetic resonance imaging (MRI) underwent MET, CHO, and FDG-PET. All patients who had previously been treated with radiotherapy for malignant glioma were subjected to open surgery and pathological diagnosis (17 recurrent grade 3- gliomas (Gr.3s) comprising 7 anaplastic astrocytomas (AAs) and 10 anaplastic oligodendrogliomas (AOs), 17 recurrent glioblastomas (Gr.4s), and 16 RNs). We measured the PET/Gd volume ratio, the PET/Gd overlap ratio, and the lesion/normal brain uptake ratio (L/N ratio) and determined the optimal index of each PET scan. The PET/Gd volume ratio and the PET/Gd overlap ratio for RN were significantly lower than those of glioma recurrence only with MET-PET (P < 0.05). The L/N ratio of RN was significantly lower than that of Gr.4 with all PET imaging (P < 0.001) and was significantly lower than that of Gr.3, especially for AO, only with MET-PET images (P < 0.005). Receiver operating characteristic (ROC) analysis showed that the area under the curve of MET, CHO, and FDG was 92.5, 81.4, and 77.4, respectively. MET L/N ratio of greater than 2.51 provided the best sensitivity and specificity for establishing glioma recurrence (91.2% and 87.5%, respectively). These results demonstrated that MET-PET was superior to both CHO and FDG-PET for diagnostic accuracy in distinguishing glioma recurrence from RN.

Prognostic factors and therapeutic problems of primary intracranial choriocarcinoma/germ-cell tumors with high levels of HCG.

AbstractObjective: Primary intracranial choriocarcinoma (PICCC)/germ-cell tumors (GCTs) with high levels of human chorionic gonadotropin (HCG) (PICCC/GCTs with HL-HCG) are rare and malignant. The goal of this study was to report our 3 cases of PICCC/GCTs with HL-HCG and to review the literature to elucidate the clinical problems and prognostic factors and to discuss the therapeutic modalities of this rare tumor. Methods: Survival was analyzed in 66 previously reported PICCC/GCTs with HL-HCG including our 3 cases, of which the clinical results have been described in the literature since 1975. In the 66 cases (mean age: 12.1 years; male/female: 45/21), 35 were verified histologically as pure choriocarcinoma, 23 were as mixed GCTs with choriocarcinoma element, and 8 were not verified as including choriocarcinoma element histologically but with very high HCG levels. Significance of the differences among survival curves concerning each parameter (age, sex, tumor location, serum HCG/β-HCG level, precocious puberty, extent of surgery, radiotherapy, chemotherapy, mixture of other non-germinomatous GCT elements and extraneural metastasis) was tested using univariate and multivariate analyses. Results: The median survival time and the 1- and 2-year survival rates were 22 months, 61.2% and 49.8%, respectively. In univariate analysis, male, subtotal removal or more, radiotherapy and chemotherapy were revealed to be significantly good prognostic factors. However, suprasellar region and tumor hemorrhage were poor prognostic factors. Multivariate analysis showed that extent of surgery, radiotherapy and chemotherapy were independent prognostic factors. Conclusions: Although, we should mind the limitations of this study design because of case selection bias, different treatment protocols and incomplete follow-up of patients, this study led the following results and suggestive conclusions. Tumor hemorrhage and progressive extraneural and cerebrospinal fluid metastasis were characteristic clinical problems of PICCC/GCTs with HL-HCG. In the cases with extremely elevated levels of HCG, biopsy for histological diagnosis may be no longer needed. Initial biopsy and radiotherapy may lead to tumor hemorrhage. To prevent tumor hemorrhage, gross tumor removal followed by radiotherapy and chemotherapy should be aimed for. A few courses of chemotherapy before surgery may prevent metastasis. Stereotactic radiotherapy and high dose chemotherapy may be promising options for treatment.

Differential expression of β-catenin in human glioblastoma multiforme and normal brain tissue

Abstract Angiogenesis is considered to play an important role in the development of malignant brain tumors, especially glioblastoma multiforme (GBM). Abnormal vascular construction with a glomeruloid appearance is characteristic of GBM. β-catenin is known as one of the adhesive molecules associated not only with cell adhesion and cell polarity, but also with carcinogenesis. We postulated the relevance of β-catenin to vigorous endothelial proliferation in human GBM because the vascular cells (VCs) are apt to lose their cell polarity. The object of this study is to compare the immunohistochemical localization of β-catenin in VCs between GBMs and normal brain tissues. Immunohistochemical analysis of P-eatenin for VCs in 32 GBMs and 10 normal brain tissues was performed. β-catenin was found concentrated in the areas of vascular cell-cell junction and internal surface of the vascular lumen in all normal brains. In contrast, β-catenin, in proliferating VCs in GBMs, was stained homogeneously and intensely in the cytoplasms of 26 cases (81.3%), in which nuclear staining of β-catenin was also recognized in four cases (12.5%). In conclusion, the intracellular localization of β-catenin in VCs of GBMs was found to be different from that of normal brain tissues. The changes of expression of β-catenin may be associated with the angiogenesis or transformation of the VCs in human GBM. [Neurol Res 2000; 22: 650-656]

Relationship between magnitude of hypothermia during ischemia and preventive effect against post-ischemic DNA fragmentation in the gerbil hippocampus

Protective effect of hypothermia against DNA fragmentation in hippocampal CA1 field after transient forebrain ischemia in gerbils was evaluated by changing the magnitude of hypothermia. Inhibition of DNA fragmentation was proportional to the magnitude of hypothermia. The result indicates that, in terms of susceptibility to ischemia, hippocampal CA1 neurons are sensitive to a relatively small decrement of temperature, with temperatures </=35 degreesC being critical for the prevention of apoptotic process following transient forebrain ischemia.

Target Definition by C11-Methionine-PET for the Radiotherapy of Brain Metastases

PURPOSE To evaluate the ability of 11C-methionine positron emission tomography (MET-PET) to delineate target volumes for brain metastases and to investigate to what extent tumor growth is presented by magnetic resonance imaging (MRI) and MET-PET. MATERIALS AND METHODS Three observers undertook target definition in 19 patients with 95 brain metastases by MRI and MET-PET images. MRI gross target volume (GTV) (GTV-MRI) was defined as the contrast-enhanced area on gadolinium-enhanced T1-weighted MRI. MET-PET GTV (GTV-PET) was defined as the area of an accumulation of MET-PET apparently higher than that of normal tissue on MET-PET images. The size of occupation ratio was determined using the following equation: SOR (%) of MET are within x mm margin outside GTV-MRI = the volume of the GTV-PET within x mm outside the GTV-MRI/the volume of the GTV-PET. RESULTS For GTV-MRI volumes of <or=0.5 mL, the sensitivity of tumor detection by MET-PET was 43%. For GTV-MRI volume of >0.5 mL, GTV-PET volumes were larger than GTV-MRI volumes and a significant correlation was found between these variables by linear regression. For all tumor sizes and tumor characteristics, a 2-mm margin outside the GTV-MRI significantly improved the coverage of the GTV-PET. CONCLUSIONS Although there were some limitations in our study associated with spatial resolution, blurring effect, and image registrations with PET images, MET-PET was supposed to have a potential as a promising tool for the precise delineation of target volumes in radiotherapy planning for brain metastases.