A case of idiopathic hypereosinophilic syndrome with leptomeningeal dissemination and intraventricular mass lesion: an autopsy report.

A 43-year-old female presented with idiopathic hypereosinophilic syndrome (HES) manifesting as an intraventricular mass lesion and leptomeningeal and cerebral parenchymal infiltration by eosinophils, lymphocytes and macrophages. She had no history of either malignancy or allergic disorder. She complained of hearing disturbance caused by eosinophilic otitis media. Eosinophilia was detected in the peripheral blood. Hearing disturbance and eosinophilia improved with corticosteroid treatment. Six months later, she was admitted with disturbances of consciousness. Magnetic resonance imaging revealed a mass lesion in the right lateral ventricle and leptomeningeal involvement around the brain stem. Her symptoms deteriorated rapidly, and she died of brain stem malfunction. Autopsy demonstrated significant infiltration by eosinophils and lymphocytes into the mass lesion in the ventricle, subarachnoid space, perivascular space and parenchyma of the medulla oblongata. Histological examination of the bone marrow and other organs did not detect any evidence of parasites, malignancies, or systemic disorders in any organ. The final diagnosis was idiopathic HES. The present case shows that leptomeningeal dissemination and infiltration by eosinophils into the cerebral ventricles and brain stem should be considered in the course of idiopathic HES.

Protein phosphatase Dusp26 associates with KIF3 motor and promotes N-cadherin-mediated cell-cell adhesion.

Recent studies have demonstrated essential functions for KIF3, a microtubule-directed protein motor, in subcellular transport of several cancer-related proteins, including the beta-catenin-cadherin(s) complex. In this study, we report identification of the protein-phosphatase Dusp26 as a novel regulator of the KIF3 motor. Here we undertake yeast two-hybrid screening and identify Kif3a, a motor subunit of the KIF3 heterotrimeric complex, as a novel Dusp26-binding protein. Co-immunoprecipitation and colocalization experiments revealed that Dusp26 associates not only with Kif3a, but also with Kap3, another subunit of the KIF3 complex. Dephosphorylation experiments in vitro and analysis using mutant forms of Dusp26 in intact cells strongly suggested that Dusp26 is recruited to the KIF3 motor mainly by interaction with Kif3a, and thereby dephosphorylates Kap3. Forced expression of Dusp26, but not its catalytically inactive mutant, promoted distribution of beta-catenin/N-cadherin, an established KIF3 cargo, to cell-cell junction sites, resulting in increased cell-cell adhesiveness. We also showed that Dusp26 mRNA expression was downregulated in human glioblastoma samples. These results suggest previously unidentified functions of Dusp26 in intracellular transport and cell-cell adhesion. Downregulation of Dusp26 may contribute to malignant phenotypes of glioma.

Primary CNS lymphoma treated with combined intra-arterial ACNU and radiotherapy.

OBJECT: To assess whether nimustine (ACNU), a drug that can cross the blood brain barrier, combined with radiotherapy, improved the survival of patients with primary central nervous system lymphoma (PCNSL). CLINICAL MATERIALS AND METHODS: Between 1995 and 2005, we treated 63 immunocompetent PCNSL patients with combination therapy consisting of intra-arterial ACNU (100 mg/m(2)) and whole brain radiotherapy (36-50 Gy). Their median age was 60 years (range 28-81). The median follow-up was 24 months. FINDINGS: With this regimen we achieved a complete response rate of 75% (43 of 57 patients). Kaplan-Meier estimates for median progression-free survival and median overall survival were 26 and 39 months, respectively. The 3- and 5-year survival rates were 51% (95% confidence interval [CI], 36-65%) and 32% (95% CI, 17-47%), respectively. By multivariate analysis, age (<60 vs. > or =60 years) was the only statistically significant prognostic factor; the WBRT dose, sex, and number of tumors were not significant prognostic factors in this study. Myelosuppression was the most frequent side effect, 60% of patients experienced grade 3-4 leukopenia. Late neurotoxicity as a result of treatment was observed in 14 of 43 patients (34%) and higher age (>60) was associated with a high risk of neurotoxicity. CONCLUSION: The intra-arterial administration of ACNU combined with radiation therapy yielded a high response rate at acceptable toxicity levels in younger patients with PCNSL. However, late neurotoxicity was a serious complication in patients above 60 years of age.

Enhancing effect of tumor necrosis factor (TNF)-alpha, but not IFN-gamma, on the tumor-specific cytotoxicity of gammadeltaT cells from glioblastoma patients.

Adoptive immunotherapy using tumor-specific killer cells can be beneficial in inducing regression of advanced cancer. The roles of cytokines on effector cells in inducing maximal killing activity and the accompanying side-effects should be investigated in vitro and fully understood prior to their clinical use. The present study indicates that the gammadeltaT cells involved in autologous tumor-specific killing consist of several populations in terms of their T cell receptor (TCR) repertoire, but predominantly express the products of the Vgamma9/Vdelta2 gene locus of the TCR. We then examined the effect of TNF-alpha and IFN-gamma on these tumor-specific gammadeltaT cells for possible clinical use in cancer patients. TNF-alpha alone, at concentrations of 0.01-1.0 microg/ml, caused increased gammadeltaT cell cytotoxicity against autologous glioblastoma cells, whereas IFN-gamma alone had no effect. The combination of TNF-alpha (1 microg/ml) with IL-2 (50 units/ml) resulted in further enhancement of cytotoxicity. TNF-alpha, but not IFN-gamma, marginally inhibited the proliferative response of gammadeltaT cells; a similar result was seen when the cytokines were combined. TNF-alpha may, therefore, be one cytokine capable of inducing increased autologous tumor-specific activity in gammadeltaT cells, bearing mainly Vgamma9/Vdelta2 chains, which can be enhanced when combined with other cytokines.

Tumor-specific cytocidal and immunopotentiating effects of relatively low molecular weight products derived from the basidiomycete, Agaricus blazei Murill.

Currently, some natural herbal extracts are believed to have a marked tumoricidal effect and low toxicity for normal tissues. We investigated the effect of relatively low molecular weight products extracted from the basidiomycete, Agaricus blazei Murill, on MethA tumor cell growth with the aim of producing synthetic derivatives based on these products. Inoculation of the low molecule fraction (LM) into the primary tumor of a two-tumor model resulted in the marked inhibition of the tumor, not only in the right flank, but also in the non-injected left flank. Chromatographic purification and physicochemical characterization showed the main tumoricidal activity to be located in a low molecule fraction-3 (LM-3), containing alpha-1,4-glucan-beta-1,6-glucan complex with an average molecular weight of 20 kDa. A11 LM fractions and crude ATF showed in vitro selective cytotoxicity for MethA tumor cells, having no effect on normal cells. Serum levels of immunosuppressive acidic protein (IAP) in mice receiving LM fractions, particularly LM-3, significantly increased, indicating the possible activation of granulocytes. We speculate that the inhibition of the distant tumor might be due to the increased migration of granulocytes, enhanced by the effect of extract injections at the primary tumor site.

Injury to autologous normal tissues and tumors mediated by lymphokine-activated killer (LAK) cells generated in vitro from peripheral blood mononuclear cells of glioblastoma patients.

Activation of peripheral blood mononuclear cells (PBMC) with IL-2 generates lymphokine-activated killer (LAK) cells that show a broad target cell range. In adoptive immunotherapy using in vitro-generated LAK cells, the intensity and specificity of their cytotoxic activity affect the prognosis of cancer patients. The present study was designed to examine the tumor-specific spectrum of T lymphocytes generated from the PBMC of patients with recurrent glioblastoma by in vitro propagation with IL-2 plus either soluble or solid-phase anti-CD3 monoclonal antibody (MAb) in short-term or long-term cultures. Both short-term and long-term culturing with solid-phase anti-CD3 MAb plus IL-2 yielded broad-reactivity CD8+ alphabetaT and gammadeltaT lymphocytes, both of which were non-MHC restricted, as shown by the fact that they were able to lyse autologous glioblastoma cells, MHC class I+II- allogeneic glioblastoma cells, and MHC class I-II-NK-sensitive K562 target cells. More importantly, these cells from patients failed to lyse fresh autologous PBMC. These results demonstrate that cells generated using this approach are non-MHC-restricted LAK cells and exhibit marked tumor specificity. In contrast, incubation with soluble anti-CD3 MAb generated T lymphocytes that after long-term culture, were either CD4+ or CD8+. These caused significant lysis of both allogeneic and autologous glioblastoma target cells, the extent of lysis being greater than that using cells produced by culturing with the solid-phase MAb. However, both the CD4+ and CD8+ cells also caused greater lysis of autologous normal PBMC, indicating that cells generated using this approach may cause significant adverse reactions in cancer patients if used for immunotherapy.

Interleukin-15 effectively potentiates the in vitro tumor-specific activity and proliferation of peripheral blood gammadeltaT cells isolated from glioblastoma patients.

GammadeltaT cells play a regulatory role in both primary and metastatic tumor growth in humans. The mechanisms responsible for the activation and proliferation of circulating gammadeltaT cells should be fully understood prior to their adoptive transfer to cancer patients. We have examined in vitro functional effects of interleukin-15 (IL-15) on highly purified gammadeltaT cells isolated from glioblastoma patients. GammadeltaT cells constitutively express the heterotrimeric IL-2 receptor (IL-2R) alpha betagamma, but the levels of IL-2Rbeta or gamma expression were not increased by incubation with saturating amounts of IL-15. IL-15 was shown to induce a maximal gammadeltaT cell proliferation, although at much higher concentrations (at least 2000 U/ml) than IL-2 (100 U/ml). Submaximal concentrations of IL-15 plus low concentrations of IL-2 produced an additive proliferative response. In contrast to the IL-2-induced response, this activity was completely or partially abrogated by anti-IL-2Rbeta, or anti-IL-2Rgamma antibodies, but not by anti-IL-2R alpha antibodies. Incubation of gammadeltaT cells in the presence of IL-15 resulted not only in the appearance of NK and LAK activity, but also in specific autologous tumor cell killing activity, an additive effect being seen with IL-15 and IL-2. This IL-15-induced tumor-specific activity could be significantly blocked by anti-IL-2Rgamma and anti-IL-2R-beta mAb, but not by anti-IL-2R alpha mAb. Thus, in contrast to IL-2, IL-15 activates tumor-specific gammadeltaT cells through the components of IL-2Rbeta and IL-2Rgamma, but not IL-2R alpha. These enhanced in vitro tumor-specific and proliferative responses of gammadeltaT cells seen with IL-15 suggest a rational adjuvant imunotherapeutic use of gammadeltaT cells in cancer patients.

Selective tumoricidal effect of soluble proteoglucan extracted from the basidiomycete, Agaricus blazei Murill, mediated via natural killer cell activation and apoptosis.

We have isolated a novel type of natural tumoricidal product from the basidiomycete strain, Agaricus blazei Murill. Using the double-grafted tumor system in Balb/c mice, treatment of the primary tumor with an acid-treated fraction (ATF) obtained from the fruit bodies resulted in infiltration of the distant tumor by natural killer (NK) cells with marked tumoricidal activity. As shown by electrophoresis and DNA fragmentation assay, the ATF also directly inhibited tumor cell growth in vitro by inducing apoptotic processing; this apoptotic effect was also demonstrated by increased expression of the Apo2.7 antigen on the mitochondrial membranes of tumor cells, as shown by flow-cytometric analysis. The ATF had no effect on normal mouse splenic or interleukin-2-treated splenic mononuclear cells, indicating that it is selectively cytotoxic for the tumor cells. Cell-cycle analysis demonstrated that ATF induced the loss of S phase in MethA tumor cells, but did not affect normal splenic mononuclear cells, which were mainly in the G0G1 phase. Various chromatofocussing purification steps and NMR analysis showed the tumoricidal activity to be chiefly present in fractions containing (1-->4)-alpha-D-glucan and (1-->6)-beta-D-glucan, present in a ratio of approximately 1:2 in the ATF (molecular mass 170 kDa), while the final purified fraction, HM3-G (molecular mass 380 kDa), with the highest tumoricidal activity, consisted of more than 90% glucose, the main component being (1-->4)-alpha-D-glucan with (1-->6)-beta branching, in the ratio of approximately 4:1.

The use of BRM-activated killer cells in adoptive immunotherapy: a pilot study with nine advanced cancer patients.

Adoptive immunotherapy using MHC-nonrestricted-lymphocytes, peripheral blood gammadelta T cells and NK cells was devised. Peripheral blood mononuclear cells (3 x 10(7)) were selected by immobilization to anti-CD3 monoclonal antibody for 4 days and cultured for 2 weeks in the presence of IL-2. Thereafter they were reactivated by 500 U/ml of IFN-alpha and 1000 U/ml of IL-2 for 1 hour. Enhancement of NK and LAK activities was confirmed. Peripheral blood gammadelta T cells proliferated in response to immobilized anti-CD3 antibody (3% to 30%). Approximately 6 x 10(9) BRM-activated killer (BAK) cells composed of CD56+ gammadelta T cells and CD56+ NK cells, were dispensed to cancer patients via intravenous drip infusion. Nine patients were treated with BAK cells every 2 weeks or every month on an outpatient basis. During the course of adoptive immunotherapy, the crossed affinity immunoelectrophoresis (CAIE) pattern of serum immunosuppressive acidic protein (IAP) was analysed. Both the production and glycosylation pattern of IAP is changed in response to tumor enlargement and may therefore act as a marker of the disease progression. During the course of BAK therapy, the glycosylation IAP pattern of 6 patients changed from tumor (T) to normal (N). In addition, the performance status of all patients was maintained at 90-100% of the Karnofsky scale and any side effects including fever were not observed during treatments with BAK cells. Moreover, the overall quality of life (QOL) of the patients, scored at the Face scale was favorable. In addition, blood levels of activated gammadelta T cells producing IFN-gamma were assayed as an indication marker of BAK therapy. The normal range of IFN-gamma producing gammadelta T cells comprised 6.9 +/- 0.9% of peripheral blood mononuclear cells (PBMC), according to a single cell FACScan analyses of PBMCs derived from normal individuals. IFN-gamma producing gammadelta T cells of Patients No. 8 and 9, who received extensive chemotherapy before initiation of BAK therapy, comprised only 0.2% and 2% of PBMC, respectively. These patients died 3 and 6 months after beginning BAK therapy. Peripheral blood gammadelta T cells of Patients Nos. 1-7 proliferated in response to immobilized anti-CD3 antibody and the frequency of IFN-gamma producing gammadelta T cells in PBMC preparation of these patients were over 3% before initiation of BAK therapy. Since our data show a positive correlation between survival time and initial gammadelta T cell counts, a low frequency of these cells may contraindicate BAK therapy.

Supratentorial primary intra-axial tumors in children. MR and CT evaluation.

PURPOSE: To evaluate the MR and CT features of pediatric supratentorial intra-axial tumors with respect to differential diagnosis and the role of each investigation modality. MATERIAL AND METHODS: MR and CT findings in 40 children with 12 types of pathologically proven histological tumors were reviewed. RESULTS: The location of tumors might be one clue to differential diagnosis. In our material, cysts (60%), calcifications (45%), and intratumoral hemorrhages (27%) were found in the tumors. Characteristic features noted in some lesions included: peritumoral hemosiderin deposition in cavernous angiomas; intratumoral flow void in a choroid plexus carcinoma and in glioblastomas; and hemicerebral atrophy in germinomas. A comparison between malignant and benign tumors showed perifocal edema and a mass effect to be significantly more common in malignant lesions. Homogeneous enhancement suggested a benign tumor and an inhomogeneous pattern represented malignancy, while the lack of obvious enhancement did not always suggest benignity. Intratumoral calcium deposition was a not uncommon finding in malignant tumors. CONCLUSION: In most cases, the exact diagnosis should be made by histological examination but it is important for treatment planning that the appropriate depiction of tumor extension and tissue characterization be made by MR and CT.

A simple method for the propagation and purification of gamma delta T cells from the peripheral blood of glioblastoma patients using solid-phase anti-CD3 antibody and soluble IL-2.

Although gamma delta T cells make up no more than 10% of the peripheral blood mononuclear (PBM) cells, they appear to play an important role in host defense against tumor growth. In order to evaluate their functional activity against tumors and their response to various cytokines, large numbers of cells are required. Here, we describe a newly-devised method for the isolation and expansion of gamma delta T cells from the peripheral blood of cancer patients, in particular those with glioblastoma. Using this approach, a 1000-1500-fold increase in total cell numbers was achieved in two weeks, the proportion of gamma delta T cells in the expanded population being, on average, approximately 30% after 14 days of culture. The method therefore gives a yield of approximately 10-15 x 10(8) gamma delta T cells from only 5 ml of peripheral blood from glioblastoma patients and normal controls. The highly purified gamma delta T cells of glioblastoma patients were shown to bear both a high-affinity interleukin-2 receptor (IL-2R) and a low-affinity IL-12 receptor (IL-12R). They also displayed significant cytotoxicity against autologous tumor cells, but not against autologous fresh or IL-2-treated lymphocytes, and proliferated in response to IL-2, both effects being dependent on the dose of IL-2 used for activation. In addition, overnight incubation with 700 U/ml of IL-2 or 50 ng/ml of IL-12 resulted in significant cytotoxic activity of patients' gamma delta T cells against K562 target cells, the level of activity being almost the same as with similarly-treated gamma delta T cells from normal controls (P > 0.05). These results demonstrate that the patients' gamma delta T cells obtained using this method are intact in terms of cytotoxic function. Thus, this method not only makes it possible to produce large numbers of purified gamma delta T cells but also to produce populations containing both gamma delta T cells and NK cells, both active against tumor targets which might be suitable for clinical trials of adoptive-immunotherapy, especially in cancer patients for whom no effective therapy is available.

In vitro interleukin 12 activation of peripheral blood CD3(+)CD56(+) and CD3(+)CD56(-) gammadelta T cells from glioblastoma patients.

Interleukin (IL)-12 has recently been shown to be directly involved in the activation of natural killer and alphabeta T cells via an IL-2-independent pathway. We show here that another type of human cytotoxic cell, gammadelta T cells activated by solid-phase anti-CD3 antibody and expanded using IL-2, obtained, in this case, from the peripheral blood of glioblastoma patients, displays significant tumoricidal activity. In addition, its cytotoxic activity against K562 or Daudi cells or against autologous glioblastoma targets (but not lymphocytes) is significantly enhanced when costimulated with IL-2 and IL-12. To study this synergistic activation by the two interleukins of the patients' gammadelta T cells, we screened the cells for the presence of the IL-2 receptor (IL-2R) and IL-12 receptor (IL-12R) using both flow cytometric analysis and PCR. The patients' gammadelta T cells constitutively expressed the high-affinity IL-2R; when stimulated with IL-12 plus IL-2, the levels of IL-2Ralpha and IL-2Rbeta increased, whereas that of IL-2gamma did not. They also expressed marginal levels of low-affinity IL-12R both immediately after IL-2 expansion and after 24-h incubation, and significantly higher levels after 72-h incubation, consistent with the level of gammadelta T-cell activation. IL-12 alone induced little proliferation of patients' gammadelta T cells in a 24-h assay and none in a 72-h assay; however, it caused a marked inhibition of the IL-2-induced proliferative response in the 72-h assay. The synergistic action of IL-2 and IL-12 was completely abolished by combined pretreatment with anti-IL-2alpha, beta, and gamma mAbs. IL-12-mediated enhancement of gammadelta T cell cytotoxic activity was inhibited by anti-IL-2Rbeta mAb in a dose-dependent manner but not by anti-IL-2Ralpha or anti-IL-2Rgamma mAbs. Thus, the increased expression of the IL-2Rbeta is critical for the synergistic activation of gammadelta T cells by IL-12 plus IL-2; it is also probable that at least the low-affinity IL-12R contributes to the activation of gammadelta T cells mediated by either IL-12 alone or IL-12 plus IL-2. We have, therefore, demonstrated that IL-12 can stimulate the cytotoxic activity of gammadelta T cells from glioblastoma patients, acting via the IL-2Rbeta component of the IL-2R and low-affinity IL-12R. IL-12 activation of patients' gammadelta T cells could possibly be of potential use in the treatment of glioblastoma patients.

Hemorrhage and abnormal veins in acoustic neurinoma: MR findings.

We reviewed the MR imaging findings of 57 acoustic neurinomas which were verified at surgery or diagnosed on the basis of neuroradiological and neurootological data. Two uncommon MR findings of acoustic neurinoma were found. First, hypointense areas were observed on T2-weighted images in five of the 12 tumors larger than 25 mm in diameter. These hypointense areas represented hemosiderin deposition secondary to occult intratumoral hemorrhage. Second, curvilinear or round signal voids were noted at the periphery of 11 large or medium-sized tumors, and these corresponded to "abnormal veins" seen on angiographic studies.

Clinical application of 18F-FUdR in glioma patients--PET study of nucleic acid metabolism.

Positron emission tomography was used to investigate the metabolism of nucleic acids by 18F-fluoro-2'-deoxyuridine (18F-FUdR) in 22 patients with gliomas. Sixteen cases of high grade glioma clearly demonstrated a region of high activity with a differential absorption rate (DAR) of 0.64 +/- 0.34. Six cases of low grade glioma failed to reveal a positive image of the tumor and the DAR in tumor was 0.21 +/- 0.042 (p < 0.01). This PET-18F-FUdR study succeeded in differentiating high and low grade gliomas from the view point of nucleic acid metabolism.

Metabolic changes of glioma following chemotherapy: an experimental study using four PET tracers.

To shed light on the metabolic changes in glioma following therapy, uptake changes among 18F-fluoro-2'-deoxyuridine (18FUdR), 14C-thymidine (dThd), 14C-methionine (Met) and 3H-deoxyglucose (DG) in glioma model after chemotherapy were studied, as a means for interpreting clinical PET results, together with the changes in the bromodeoxyuridine (BUdR) labeling index. 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(-2chloroethyl)-3-nitro sourea hydrochloride (ACNU) was administered intraperitoneally in the tumor-bearing rats and uptake of the tracers or BUdR labeling index in tumor tissue were measured. The metabolic response following chemotherapy was a sharp fall immediately for 14C-dThd and 18FUdR and a moderate fall for 14C-Met whereas there was a fall in 3H-DG from 1 week after chemotherapy. The changes of BUdR labeling index paralleled that in the uptake for dThd and FUdR. These result indicate that PET scans using a variety of tracers in conjunction could be used for clinical diagnosis and evaluation of therapy in glioma cases. 18FUdR is a promising tracer of nucleic acid metabolism to evaluate the proliferative potential of brain gliomas.

[Analysis on combined effect of X-rays with 5-FU on rat subcutaneous gliomas].

In a series of experiments on the combined use of radio- and chemotherapy for malignant glioma, X-rays combined with ACNU or 5-FU treatment caused a supra-additive effect on multicellular spheroids in vitro. In the present experiment, the effect of X-rays combined with 5-FU treatment on subcutaneously transplanted rat gliomas of RGC-6 cells was analyzed. The dose-survival curve for X-rays given to tumors in air-breathing rats was biphasic with a terminal slope (D0 = 4.3 Gy) that was parallel to that for tumors in previously killed rats. The hypoxic cell fraction thus obtained from the ratio of the surviving fraction in two parallel curves at 20 Gy was about 7% in the subcutaneous tumors in air-breathing rats. X-ray-induced, potentially lethal cellular damage recovered within 8 hours in these tumors. The surviving fraction of cells in the tumors decreased to a minimum at 4-6 hours after a 5-FU injection, but increased thereafter. A biphasic dose-response curve for 5-FU was also obtained for cells in these tumors, indicating the presence of 5-FU resistant cells. The effect of X-irradiation given at about 8 hours after a 5-FU injection was greater than the additive effect of both agents acting independently. This was true when an X-ray dose of more than 5 Gy was given.

A case of Rathke's cleft cyst within a pituitary adenoma presenting with acromegaly--do "transitional cell tumors of the pituitary gland" really exist?

A case of multiple large Rathke's cleft cyst within a pituitary adenoma presenting with acromegaly is reported. Rathke's cleft cyst within a pituitary adenoma is rare condition, and this is the first report of such a case presenting with acromegaly. An electron microscopic and an immunohistochemical analysis proved that the cyst within the pituitary adenoma of this case differs from cysts found in the embryonic stage of the pituitary gland.

Dynamic study of methionine uptake in glioma using positron emission tomography.

In order to evaluate the methionine uptake of a glioma with positron emission tomography (PET), the kinetics of carbon-11 methionine was investigated in 11 patients by measuring the free 11C-methionine in plasma as an input function following intravenous administration. When the mean clearance curve of free 11C-methionine in plasma instead of individual 11C-methionine clearance curves was used, mean differences in uptake rate and distribution volume were 4.0% and 4.6% respectively. By applying the mean clearance curve of free 11C-methionine in 18 glioma patients, significant differences in 11C-methionine uptake rate and distribution volume were found according to pathological grading. For the accurate evaluation of the metabolism of 11C-methionine, it is therefore preferable that the actual level of free 11C-methionine in the plasma be measured, especially for the follow-up of individual cases. The study also demonstrated that the mean clearance curve of 11C-methionine in plasma might be employed as an input curve for calculating the uptake rate and distribution volume with small errors.

[A case of glioblastoma in which early diagnosis was difficult by MRI].

The authors report a case of glioblastoma in which MR images with Gd-DTPA enhancement changed rapidly during the early stage. A 61 year-old male presented with sudden right facial spasm and dysarthria. However, both a plain and an enhanced CT failed to demonstrate any abnormal lesions. On the other hand, T2 weighted MR image revealed a well circumscribed high intensity lesion in the left frontal lobe without mass effect. This lesion could not be differentiated from cerebral infarction, since no contrast enhanced lesion was able to be observed in T1 weighted MR image with Gd-DTPA. His symptoms gradually became aggravated and at 3 months from the onset, MR image with Gd-DTPA disclosed a small enhanced lesion in the left frontal lobe near the cortical surface. After 6 months from the onset, he suffered from right hemiparesis and motor aphasia. The MR image with Gd-DTPA at this time showed a large enhanced lesion in the left frontal lobe with mass effect. He was admitted to our hospital, and subtotal removal of the tumor and intraoperative radiation was carried out. The patient did well postoperatively without additional neurological deficit, and then he received additional radiation therapy. It should be noted that Gd-DTPA enhanced MR image might fail to reveal the lesion of glioblastoma in its early stage, while T1 weighted image discloses only the gyral swelling.

[Effect of X-rays combined with ACNU and O6-ethylguanine on rat subcutaneous gliomas].

Rat gliomas of subcutaneously transplanted RGc-6 cells were irradiated with X-ray either alone, or combined with ACNU, and the cell-survival was assayed in vitro. Cell-survival curve composed of two components by X-irradiation alone indicated the presence of a hypoxic cell fraction. We have previously shown that combined treatment with ACNU apparently made the effect of X-ray on spheroids in vitro of the same cell line of RGc-6 more powerful. Although treatment of rat gliomas with ACNU administered at 2 hrs prior to X-irradiation was most effective, it resulted in only the additive effect of the independent action of the two agents. Further treatment by O6-ethylguanine prior to ACNU administration and X-irradiation apparently increased the strength of the effect of ACNU combined with X-ray to the dose-modifying factor for X-ray of 1.8. The result indicated that the combination of O6-ethylguanine prior to ACNU administration and X-irradiation may clinically enhance the effect of X-ray against apparent ACNU-resistant glioma cells such as RGc-6 cells.