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N-myc downstream regulated gene 1 (NDRG1) is a member of the NDRG family, of which four members (NDRG1, NDRG2, NDRG3, and NDRG4) have been identified. NDRG1 is repressed by c-MYC and N-MYC proto-oncogenes. NDRG1 is translated into a 43 kDa protein that is associated with the regulation of cellular stress responses, proliferation, and differentiation. In this study, we aimed to clarify the relationship between progression of glioblastoma (GB) IDH-wildtype and NDRG1 expression in tumor cells. We assessed the expression of NDRG1 in 41 GBs using immunostaining and evaluated its prognostic significance. NDRG1 expression by GBs was evaluated using Histoscore, which showed high and low scores in 23 and 18 cases, respectively. NDRG1-positive cells were strongly expressed in Ki-67 labeled proliferating tumor cells and CD105 positive proliferating microvessels around the area of palisading necrosis. Statistical analyses showed lower survival rates in the high-score group than the low-score group (P < 0.01). This study indicated that overexpression of NDRG1 by GB reflects tumor angiogenesis and poor patient prognosis., (© 2024 Japanese Society of Neuropathology.)

We report a case of pediatric glioma with uncommon imaging, morphological, and genetic features. A one-year-old boy incidentally presented with a tumor in the fourth ventricle. The tumor was completely resected surgically and investigated pathologically. The mostly circumscribed tumor had piloid features but primitive and anaplastic histology, such as increasing cellularity and mitosis. The Ki-67 staining index was 25% at the hotspot. KIAA1549::BRAF fusion and KIAA1549 partial deletions were detected by direct PCR, supported by Sanger sequencing. To the best of our knowledge, this is the first report of a glioma with both deletion of KIAA1549 p.P1771&#95;P1899 and fusion of KIAA1549::BRAF. The tumor could not be classified using DNA methylome analysis. The present tumor fell into the category of pilocytic astrocytoma with histological features of anaplasia (aPA). Further studies are needed to establish pediatric aPA., (© 2023 Japanese Society of Neuropathology.)

Purpose: Intratumoral thrombosis is a specific finding in glioblastomas and considered the origin of palisading necrosis. Its distribution and contribution to the glioblastoma pathophysiology and systemic thrombosis are obscure, although deep vein thrombosis is a common complication in glioblastoma cases., Methods: Clinicopathological and genetic analyses were performed on 97 glioblastoma tissue specimens to elucidate the role of thrombotic events and associated molecular abnormalities., Results: Morphologically, intratumoral thrombosis was observed more frequently in vessels composed of single-layered CD34-positive endothelium and/or αSMA-positive pericytes in the tumor periphery, compared to microvascular proliferation with multi-channeled and pericyte-proliferating vessels in the tumor center. Intratumoral thrombosis was significantly correlated with the female sex, high preoperative D-dimer levels, and epidermal growth factor receptor (EGFR) amplification. The presence of one or more thrombi in 20 high-power fields was a predictive marker of EGFR amplification, with a sensitivity of 81.5% and specificity of 52.6%. RNA sequencing demonstrated that the group with many thrombi had higher EGFR gene expression levels than the group with few thrombi. The tumor cells invading along the vessels in the tumor periphery were positive for wild-type EGFR but negative for EGFRvIII, whereas the cells around the microvascular proliferation (MVP) in the tumor center were positive for both wild-type EGFR and EGFRvIII. Intratumoral thrombosis is an independent poor prognostic factor., Conclusions: Aberrant but exquisitely regulated EGFR can induce thrombosis in non-MVP vessels in the tumor invasion area and then promote palisading necrosis, followed by hypoxia, abnormal angiogenesis, and further tumor cell invasion., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pediatric neoplastic diseases account for about 10% of cases of fever of unknown origin (FUO), and most neoplastic disease cases are leukemia, lymphoma, and neuroblastoma. Brain tumors are rarely reported as the cause of FUO, although craniopharyngioma, metastatic brain tumor, and Castleman's disease have been reported. We report a case of intracranial mesenchymal tumor (IMT) with a FET:CREB fusion gene, which had inflammatory phenotype without neurological signs. A 10-year-old girl was admitted with a 2-month history of intermittent fever and headache, whereas her past history as well as her family history lacked special events. Sepsis work-up showed no pathological organism, and empirical antibiotic therapy was not effective. Bone marrow examination showed a negative result. Cerebrospinal fluid examination showed elevated protein as well as cell counts, and head magnaetic resonance imaging showed a hypervascular mass lesion with contrast enhancement in the left cerebellar hemisphere. The patient underwent tumor excision, which made the intermittent fever disappear. Pathological examinations resembled those of classic angiomatoid fibrous histiocytoma (AFH), but the morphological features were distinct from the AFH myxoid variant; then we performed break-apart fluorescence in situ hybridization and confirmed the tumor harbored the rare EWSR1::CREM fusion gene (Ewing sarcoma breakpoint region 1 gene (EWSR1) and cAMP response element binding (CREB) family gene). Consequently, we diagnosed the condition as IMT with EWSR1::CREM fusion. Elevated serum concentration of interleukin 6 (IL-6) was normalized after tumor resection, which suggested the fever could be caused by tumor-derived IL-6. This is the first case of IMT with EWSR1::CREM fusion that showed paraneoplastic symptoms associated with the IL-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Although brain tumors are rarely diagnosed as a responsible disease for FUO, they should be considered as a cause of unknown fever even in the absence of abnormal neurological findings., (© 2022 Japanese Society of Neuropathology.)

Leucine-rich α-2 glycoprotein 1 (LRG1) is a diagnostic marker candidate for glioblastoma. Although LRG1 has been associated with angiogenesis, it has been suggested that its biomarker role differs depending on the type of tumor. In this study, a clinicopathological examination of LRG1's role as a biomarker for glioblastoma was performed. We used tumor tissues of 155 cases with diffuse gliomas (27 astrocytomas, 14 oligodendrogliomas, 114 glioblastomas). The immunohistochemical LRG1 intensity scoring was classified into 2 groups: low expression and high expression. Mutations of IDH1, IDH2, and TERT promoter were analyzed through the Sanger method. We examined the relationship between LRG1 expression level in glioblastoma and clinical parameters, such as age, preoperative Karnofsky performance status, tumor location, extent of resection, O6-methylguanine DNA methyltransferase promoter, and prognosis. LRG1 high expression rate was 41.2% in glioblastoma, 3.7% in astrocytoma, and 21.4% in oligodendroglioma. Glioblastoma showed a significantly higher LRG1 expression than lower-grade glioma (p = 0.0003). High expression of LRG1 was an independent favorable prognostic factor (p = 0.019) in IDH-wildtype glioblastoma and correlated with gross total resection (p = 0.002) and the tumor location on nonsubventricular zone (p = 0.00007). LRG1 demonstrated multiple potential as a diagnostic, prognostic, and regional biomarker for glioblastoma., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

A subset of central nervous system neuroblastomas (CNS NB), rare primary embryonal CNS tumors, has been encompassed in CNS NB with FOXR2 activation (CNS NB-FOXR2) and usually shows the primitive neuronal architecture and occasional neurocytic differentiation. Here, we report a rare case of 3-year-old female with uncommon morphology of CNS embryonal tumor with FOXR2 activation presenting bidirectional differentiation to neurocytic small primitive cells and astrocytic spindle cells both of which are positive for synaptophysin and GFAP. Ultrastructural study also showed that there were presynaptic structure and intermediate filament in the tumor cells, suggesting glioneuronal differentiation. This case indicates the possibility of CNS neuroblastic tumor to differentiate neuronal and glial lineages.

Glioblastomas are highly aggressive brain tumors with a particularly poor prognosis. Glucose transporter-1 (GLUT1/SLC2A1), a uniporter that is expressed by various carcinomas and may be involved in malignant neoplasm glycometabolism, may also be related to prognosis in glioblastomas. GLUT1 is essential to central nervous system glycometabolism. To clarify the exact role of GLUT1 in glioblastoma, we assessed the expression and localization of GLUT1 in patient samples by immunohistochemistry and in situ RNA hybridization. This revealed that GLUT1 was mainly expressed on perivascular and pseudopalisaded tumor cell membranes. All samples expressed GLUT1 to some degree, with 30.8% showing stronger staining. On the basis of these data, samples were divided into high and low expression groups, although SLC2A1 mRNA expression was also higher in the high GLUT1 expression group. Kaplan-Meier survival curves revealed that high GLUT1 expression associated with lower overall survival (log-rank test, p = 0.001) and worse patient prognoses (p = 0.001). Finally, MIB-1 staining was stronger in high GLUT1 expression samples (p = 0.0004), suggesting a link with proliferation. We therefore hypothesize that GLUT1 expression in glioblastomas may enhance glycolysis, affecting patient prognosis. Examination of GLUT1 in patients with glioblastomas may provide a new prognostic tool to improve outcome., (© 2019 American Association of Neuropathologists, Inc.)

A rare case of extraventricular neurocytoma (EVN) arising from the VIIIth cranial nerve in a 34-year-old woman is reported. The patient had a 20-year history of hearing loss and facial palsy. Computed tomography showed a 3-cm enhancing lesion in the left cerebellopontine angle (CPA). At operation, the tumor was seen to originate from the cochlear and vestibular nerves. The tumor was subtotally resected. Histologically, the tumor consisted of uniform cells with oval to round nuclei and scant cytoplasm. Immunohistochemically, the tumor cells were positive for synaptophysin, but negative for glial fibrillary acid protein and S-100 protein. The Ki-67 labeling index was 0%. Twelve years after the operation, magnetic resonance imaging (MRI) showed tumor recurrence at the left CPA. The tumor was subtotally resected, and radiation therapy was given. Histologically, the tumor consisted of round cells with mild atypia and one mitosis/20 high-power fields (HPF). Immunohistochemically, tumor cells showed the same findings as the first operation sample, except for the Ki-67 labeling index (3%). Twelve years after the second operation, MRI showed a second tumor recurrence at the left CPA and surroundings of the brain stem. The tumor was subtotally resected. Histologically, the tumor consisted of anaplastic short spindle cells and five mitoses/10 HPF. The immunohistochemical findings were almost the same as the earlier operation samples. However, the Ki-67 labeling index was 20%. In addition, tumor cells from the third specimen were more strongly and more diffusely positive for GAB1 (growth factor receptor-bound protein 2-associated binding protein 1) compared to those of the earlier specimens. Electron microscopy showed the presence of numerous cell processes with a dense core and clear vesicles and microtubules. GAB1 immunostaining also indicated that malignant progression might be associated with the sonic hedgehog signaling pathways. To the best of our knowledge, this is the first report of an EVN arising from the VIIIth cranial nerve with malignant progression., (© 2018 Japanese Society of Neuropathology.)

Epithelioid glioblastoma (eGBM) is a rare variant of GBM which was adopted in the 2016 WHO classification. eGBM and pleomorphic xanthoastrocytoma (PXA) sometimes show overlapping features histologically and genetically, such as epithelioid pattern and a highly frequent V600E mutation in the gene for vRAF murine sarcoma viral oncogene homolog B1 (BRAF), respectively. Accurate diagnosis of these rare tumors is challenging according to the new criteria in the revised 2016 WHO classification. It is an urgent task to elucidate the biological properties of the tumors and to select appropriate treatment. Twenty consecutive cases diagnosed as PXA or eGBM histologically were investigated. Twelve of the 20 cases were PXAs and eight were eGBMs. Morphologically, mitotic activity, necrosis and degenerative changes such as intracellular lipid accumulation, eosinophilic granular bodies and reticulin fiber deposits were scored. Immunohistochemical and molecular biological assessment for isocitrate dehydrogenases 1 and 2 (IDH1/2), α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX), p53, BRAF, telomere reverse transcriptase promoter (TERT-p), H3F3A, and integrase interactor 1 (INI1) were performed. eGBM tended to lack the degenerative changes characteristic for PXA. Of the 20 cases tested, Sanger technique showed no mutation in IDH1/2. BRAF mutation at T1799 > A (V600E) was detected in 4/12 (33.3%) PXA and 4/8 (50.0%) eGBM, while TERT-p mutation was detected at C228 > T in 2/12 (16.7%) PXA and at C250 > T in 1/8 (12.5%) eGBM. Retained nuclear ATRX was observed in 12/12 (100%) PXA and 6/7 (85.7%) eGBM while p53 mutation was observed in 2/10 (20%) PXA and 7/7 (100%) eGBM. All tumors retained INI1 expression in their nuclei. None of the tumors harbored H3F3A mutation. One PXA without BRAF mutation acquired TERT-p mutation at recurrence and one eGBM harbored both BRAF and TERT-p mutation. Molecular biological similarity between eGBM and PXA was suggested in our series, while degenerative changes reflected the features of PXA. It was speculated that the common genetic alterations for development and progression of eGBM and PXA might include BRAF and TERT-p mutations., (© 2018 Japanese Society of Neuropathology.)

Ghrelin is a 28-amino-acid peptide that is the endogenous ligand for the pituitary growth hormone secretagogue receptor (GHS-R). Ghrelin is mainly produced from the stomach, but it is also expressed by various other tissues, including the CNS under normal conditions. Physiologically, ghrelin regulates appetite, gut motility, and GH release from the anterior pituitary, as well as cardiovascular and immune systems. Recent studies also indicate that ghrelin and GHS-R may play an important autocrine/paracrine role in neoplastic conditions. In order to clarify the role of ghrelin/GHS-R in gliomas, the present study assessed the expression of ghrelin and its functional receptor, GHS-R1a, in 39 glioblastomas (GBs), 13 anaplastic astrocytomas (AAs) and 11 diffuse astrocytomas (DAs) using immunohistochemical analyses. Immunohistochemical staining was evaluated as follows: no staining; 1+, 0-10% positive cells; 2+, 10-50% positive cells; 3+, >50% positive cells. Ghrelin expression was detected in 52 of 63 cases of which 38, 13 and one were scored as 3+, 2+ and 1+, respectively. GHS-R1a expression was detected in 45 of 63 cases of which 29, 15 and one were scored as 3+, 2+ and 1+, respectively. Ghrelin immunoreactivity was observed in 38 of 39 GBs, 12 of 13 AAs and two of 11 DAs. GHS-R1a immunoreactivity was observed in 39 of 39 GBs, five of 13 AAs, and one of 11 DAs. AAs and GBs showed moderate or strong immunostaining of ghrelin/GHS-R1a in the tumor cells and in proliferating microvessels. Patients were classified into lower to moderate-score, and high-score ghrelin/GHS-R categories according to the principal component and cluster analyses. Multivariate analysis of overall survival indicated that there was a significant difference (P = 0.0001) in the survival rate between these two groups. The combined results indicated that expression of the ghrelin/GHS-R1a axis increases the growth of AAs and GBs through an autocrine/paracrine mechanism., (© 2016 Japanese Society of Neuropathology.)

In order to clarify the role of endothelin B receptors (ETBRs) in gliomas, we analyzed cell cultures and surgical specimens of gliomas using RT-PCR and immunohistochemistry. RT-PCR measured the absolute expression of ETBR mRNA in twelve samples, which included gliomas that were classified using the World Health Organization (WHO) classification system Grade I-IV, as well as two glioblastoma cell lines (CCF-STTG1 and U87-MG). Using immunohistochemistry, 77 glioma specimens were evaluated for their expression of ETBR and infiltrating T lymphocytes, including an analysis of cytotoxic T cells (CTLs) and regulatory T lymphocytes (Tregs). The number of ETBR-positive vessels in the glioblastomas (Grade IV) was significantly higher than in other grades of gliomas (comparisons to Grade IV, Grade I: p = 0.0323, Grade II: p = 0.0009, Grade III: p = 0.0273). The ETBR expression rate (defined as the number of ETBR-positive blood vessels divided by the total number of blood vessels) in the glioblastomas was higher than the ETBR expression rate in the low-grade gliomas (compared to Grade IV, Grade I: p = 0.0132, Grade II: p = 0.0018, Grade III: p = 0.0745). In addition, the cases which had an ETBR expression rate of 50 % or higher exhibited fewer infiltrating CTLs and more infiltrating Tregs compared to the cases with an ETBR expression rate <50 % (CTLs: p = 0.0342; Tregs: p = 0.0175). Isocitrate dehydrogenase 1 (IDH-1) mutations were identified in 21 cases, but there was no correlation between ETBR expression and IDH-1 mutations for any WHO grade. These results suggest that ETBR expression during neo-angiogenesis may interfere with the homing of CTLs around the tumor and be involved in the immune escape mechanism of gliomas.

To study the advantages and pitfalls of intraoperative rapid diagnosis (IRD) of primary central nervous system lymphomas (PCNSL), pathology reports and frozen sections in our institution were reviewed. We examined 27 cases of PCNSL, one case of anaplastic glioma, and one case of metastatic brain tumor that were diagnosed on neuroimaging. Fifteen cases of intraoperative cytological preparations were also reviewed in a correlative manner. Among the 27 cases initially diagnosed as PCNSL, 18 were also diagnosed as PCNSL by IRD. However, IRD identified four of the 27 cases as gliosis, two as demyelination, one as atypical epithelial cells, one as malignant glioma and anaplastic astrocytoma. In addition, the case identified as metastatic brain tumor on neuroimaging was corrected to a diagnosis of PCNSL based on IRD. The final accuracy of IRD in the present study was 89.6% (26/29). After postoperative definitive diagnosis, two cases of anaplastic astrocytoma and one case of PCNSL by IRD were corrected to PCNSL, anaplastic oligodendroglioma and demyelination, respectively. PCNSL were sometimes histologically indistinguishable from malignant gliomas or demyelinating diseases in the present study, particularly in frozen sections. Notably, all cases for which both intraoperative cytology and frozen section were performed concomitantly were correctly diagnosed in the present study. In particular, lymphoglandular bodies were highly characteristic cytological findings of PCNSL. Both intraoperative cytology and frozen sections should therefore be performed concomitantly when PCNSL are suspected., (© 2014 Japanese Society of Neuropathology.)

Background and Purpose: Systematic assessment of brain and head and neck tumors with 4D-CE-MRA at 3T has not been investigated. The purpose of this study was to test the hypothesis that 4D-CE-MRA at 3T can replace DSA in the identification of feeding arteries and tumor stain to plan interventional procedures in hypervascular brain and head and neck tumors., Materials and Methods: Fifteen consecutive patients with brain and head and neck tumors underwent 4D-CE-MRA at 3T and DSA. 4D-CE-MRA combined randomly segmented central k-space ordering, keyhole imaging, SENSE, and half-Fourier imaging. We obtained 30 dynamic scans every 1.9 seconds at an acquired spatial resolution of 0.9 × 0.9 × 1.5 mm; the matrix was 256 × 256. Two independent observers inspected the 4D-CE-MRA images for the main arterial feeders and tumor stain. Interobserver and intermodality agreement was assessed by κ statistics., Results: For 4D-CE-MRA, the interobserver agreement was fair with respect to the main arterial feeders and very good for the degree of tumor stain (κ = 0.28 and 0.87, respectively). Intermodality agreement was moderate for the main arterial feeders (κ = 0.45) and good for the tumor stain (κ = 0.74)., Conclusions: Although 4D-CE-MRA may be useful for evaluating tumor stain in hypervascular brain and head and neck tumors, it is not able to replace DSA in planning interventional procedures.

Background and Purpose: QUASAR is a particular application of the ASL method and facilitates the user-independent quantification of brain perfusion. The purpose of this study was to assess the intermodality agreement of TBF measurements obtained with ASL and DSC MR imaging and the inter- and intraobserver reproducibility of glioma TBF measurements acquired by ASL at 3T., Materials and Methods: Two observers independently measured TBF in 24 patients with histologically proved glioma. ASL MR imaging with QUASAR and DSC MR imaging were performed on 3T scanners. The observers placed 5 regions of interest in the solid tumor on rCBF maps derived from ASL and DSC MR images and 1 region of interest in the contralateral brain and recorded the measured values. Maximum and average sTBF values were calculated. Intermodality and intra- and interobsever agreement were determined by using 95% Bland-Altman limits of agreement and ICCs., Results: The intermodality agreement for maximum sTBF was good to excellent on DSC and ASL images; ICCs ranged from 0.718 to 0.884. The 95% limits of agreement ranged from 59.2% to 65.4% of the mean. ICCs for intra- and interobserver agreement for maximum sTBF ranged from 0.843 to 0.850 and from 0.626 to 0.665, respectively. The reproducibility of maximum sTBF measurements obtained by methods was similar., Conclusions: In the evaluation of sTBF in gliomas, ASL with QUASAR at 3T yielded measurements and reproducibility similar to those of DSC perfusion MR imaging.

Background: A good performance status at diagnosis is a prognostic factor in patients with malignant glioma whose median survival is 24 months. As early diagnosis may improve their poor prognosis, we looked for currently unknown initial symptoms among patients in good performance status., Methods: We chose 17 consecutive patients with malignant glioma in the left frontal and/or temporal lobe whose Karnofsky Performance Status was more than 80. At preoperative evaluation, we administered the Japanese version of the Western Aphasia Battery., Results: The chief complaint was difficulty in speech (n = 6), headache/nausea (n = 4), seizures (n = 5), and uncinate fits (n = 1); one patient was symptom-free. Of the 17 patients, 14 exhibited no motor deficits. In 15 patients, the aphasia quotient exceeded 80, indicating that the overall language deficits were mild. However, in the reading section, their scores on the "spelled kanji (Japanese ideogram) recognition" test (full score = 10) were selectively low (5.3 +/- 1.6 for right-handed individuals with frontal lesions, 6.1 +/- 1.0 for right-handed patients with temporal lesions, 7.2 +/- 2.0 for left-handed/bimanual individuals with frontal/temporal lesions). Their scores on the "spelling kanji" test were 3.0 +/- 1.6, 4.8 +/- 1.2, and 9.4 +/- 0.6, respectively., Conclusions: Our findings point to the importance of recognizing spelling deficits as an initial symptom of left hemisphere glioma in efforts to identify patients in good performance status whose prognosis may be improved. It would be important to determine if the spelling of alphabetic words is also impaired early in the clinical course of left hemisphere glioma.

We report a patient with recurrent glioblastoma, in whom serial magnetic resonance angiography (MRA) demonstrated gradual enlargement of an artery feeding the tumor and the development of an intratumoral aneurysm that led to intratumoral hemorrhage. The literature contains no previous reports that clinically document intratumoral aneurysms arising from these vessels. This is a rare case of glioblastoma in which the association of an intratumoral feeding-artery aneurysm, whose rupture led to intratumoral bleeding, was documented by serial MRA imaging and follow-up.

Background: Hydrocephalus associated with intracranial germ cell tumors or disseminated medulloblastoma has been treated with ventriculoperitoneal shunt. However, this procedure has a potential risk of intraperitoneal metastasis of these brain tumors. To prevent this potential risk and to minimize the risk of infection, we developed a percutaneous long-tunneled ventricular drainage (PLTVD). To confirm the effectiveness, we retrospectively analyzed the results of this procedure., Methods: From 1979 to 2003, we have treated 96 patients with germ cell tumors and medulloblastoma in our hospital. Of 96 patients, 59 (germ cell tumor, 31; medulloblastoma, 28) had hydrocephalus and 13 needed long-term cerebrospinal fluid drainage to manage the obstructive hydrocephalus due to persistent tumor or communicating hydrocephalus due to dissemination. We performed PLTVD for these cases using a flow-controlled shunt device and percutaneous long-tunneled shunt tube (peritoneal catheter) exiting at the upper abdomen and connecting to a closed drainage system. The occurrence of extraneural metastasis and the incidence of infection were evaluated., Results: The average duration of drainage was 74 days (range, 34-115 days). All 13 cases received full-dose chemotherapy and radiotherapy without infectious complications or extraneural metastasis., Conclusions: Percutaneous long-tunneled ventricular drainage was an effective method to manage long-lasting obstructive or communicating hydrocephalus with germ cell tumors and medulloblastoma.

The effectiveness of ramosetron tablets and granisetron injection was compared for reducing the frequency of nausea, vomiting, and anorexia in patients with malignant glioma undergoing ACNU chemotherapy. Patients with malignant glioma to be treated with ACNU chemotherapy were randomly assigned to receive oral ramosetron (20 patients) or intravenous granisetron (19 patients) prior to ACNU injection. Gastrointestinal toxicity within 48 hours of ACNU injection was compared to that in patients who had received ACNU chemotherapy with dopamine D2 receptor-blocker as a historical control group. Within 24 hours of the administration of ACNU, 15 of the 20 patients treated with ramosetron and 16 of the 19 treated with granisetron were nausea-free, and 14 of the former and 14 of the latter regained their normal appetite. There was no significant difference in the anti-emetic effects. Ten of the 17 controls experienced no vomiting within 6 hours of the injection of ACNU, five were nausea-free within 24 hours, and two retained their normal appetite within 24 hours. Oral ramosetron has the same anti-anorectic and anti-emetic effects as intravenous granisetron. Ramosetron tablets are less expensive and are easy to take, so should be on the list of first-choice anti-emetic drugs for patients treated with ACNU chemotherapy.

In highly vascular malignant glioma, glioma cells themselves may express angiogenic factors and induce angiogenesis. Recent studies have shown that novel angiogenic factors, angiopoietin-1 (Ang1) and -2 (Ang2), play important roles in the modulation of vasculogenesis and angiogenesis. In this study, we determined Ang2 mRNA expression in cultured human malignant glioma cells (U105, U251, and U373 MG) by reverse transcriptase-PCR. Western blot analysis and immunocytochemical analysis with antihuman Ang2 antibody revealed that Ang2 protein was expressed and secreted by these cells. Furthermore, hypoxia increased the Ang2 protein level in cultured glioma cells. Serial sections of 32 human glioma tissues (14 glioblastomas, eight anaplastic astrocytomas, seven astrocytomas, and three pilocytic astrocytomas) were immunostained against Ang2, vascular endothelial growth factor, Tie2, von Willebrand factor, and alpha smooth muscle actin. The immunoreactivity of each angiogenic factor was higher in malignant gliomas than in low-grade gliomas. Ang2 protein was detected not only in endothelial cells but also in glioma cells, and its expression was prominent in both the area surrounding the necrosis and the periphery of glioblastomas. In the area surrounding necrosis, Ang2 was highly expressed and tumor vessels showed regression. In the tumor periphery, Ang2 was highly expressed and many small vessels stained positively for von Willebrand factor but not for alpha smooth muscle actin, suggesting angiogenesis. Statistical analysis revealed that the Ang2 expression was negatively correlated with vessel maturation in malignant gliomas and that vascular endothelial growth factor expression was positively correlated with vessel maturation in low-grade gliomas (P < 0.05). These results suggest that glioma cells themselves express Ang2 and that expression may be induced by hypoxic stimulation and may play a crucial role in the vessel maturation, angiogenesis, and vessel regression in malignant glioma.

Trapidil is a PDGF antagonist that can inhibit the proliferation of the PDGF-producing glioma cells, U251MG. As the mechanism of growth-regulation by trapidil remains unclear, we studied its effect on the growth of U251MG cells. We performed a cell cycle analysis and examined the intracellular transduction pathway and oncogene expression in serum-stimulated glioma cells with or without trapidil. After the serum starvation for 3 days, glioma cell proliferation was stimulated by the addition of serum. Cell cycle analysis showed that cell cycle perturbations induced by trapidil included a decreased transition rate from G0-G1 to S phase, suggesting that some metabolic event is required for progress through the G0-G1 phase and that this event is sensitive to trapidil. Internal signal transduction mechanisms are central in the molecular control of cell growth. One such regulator is the protein kinase C(PKC) system and the c-fos gene is likely to be a direct target of intracellular signal transduction pathways. Therefore, we hypothesize that the intracellular PKC activity and c-fos expression of the trapidil-treated cells are suppressed. We posit that trapidil affects the intracellular signal transduction pathway PKC activity and c-fos expression in cells stimulated with serum containing growth factors.

Clinical features of two patients with mixed angiomas are presented. One patient with a cerebral venous angioma with arterial components was successfully treated with radiation therapy; and the other, who had a common draining vein with cerebellar arteriovenous malformation and venous angioma, was treated with surgical removal of the arteriovenous malformation. These two cases suggested that there is a similarity between the pathogenesis of arteriovenous malformation and venous angioma in the brain.

We report two cases with subarachnoid dissemination of medulloblastoma depicted clearly by Gadolinium-DTPA enhanced MRI. We also demonstrate the superiority of Gadolinium-DTPA enhanced MRI over nonenhanced MRI, CT, myelography and postmyelographic CT for diagnosing subarachnoid dissemination and for monitoring the response to therapy.