Clinicopathologic analysis of pineal parenchymal tumors of intermediate differentiation: a multi-institutional cohort study by the Kyushu Neuro-Oncology Study Group.

PURPOSE: Pineal parenchymal tumors of intermediate differentiation (PPTIDs), which were recognized in the 2007 World Health Organization (WHO) classification, are rare, accounting for less than 1% of all central nervous system tumors. This rarity and novelty complicate the diagnosis and treatments of PPTID. We therefore aimed to evaluate the clinicopathological significance of this tumor. METHODS: At 11 institutions participating in the Kyushu Neuro-Oncology Study Group, data for patients diagnosed with PPTID were collected. Central pathology review and KBTBD4 mutation analysis were applied to attain the diagnostically accurate cohort. RESULTS: PPTID was officially diagnosed in 28 patients: 11 (39%) with WHO grade 2 and 17 (61%) with WHO grade 3 tumors. Median age was 49 years, and the male:female ratio was 1:2.1. Surgery was attempted in all 28 patients, and gross total resection (GTR) was achieved in 46% (13/28). Adjuvant radiotherapy and chemotherapy were administered to, respectively, 82% (23/28) and 46% (13/28). The 5-year progression-free survival (PFS) and overall survival rates were 64.9% and 70.4% respectively. Female sex (p = 0.018) and GTR (p < 0.01) were found to be independent prognostic factors for PFS and female sex (p = 0.019) was that for OS. Initial and second recurrences were most often leptomeningeal (67% and 100% respectively). 80% (20/25) of patients harbored a KBTBD4 mutation. CONCLUSIONS: Female sex and GTR were independent prognostic factors in our patients with PPTID. Leptomeningeal recurrence was observed to be particularly characteristic of this tumor. The rate of KBTBD4 mutation observed in our cohort was acceptable and this could prove the accuracy of our PPTID cohort.

Atypical and Fibrous Meningioma with Differential Cerebral Blood Volume on Magnetic Resonance Imaging: A Case Report.

Magnetic resonance imaging (MRI) features of meningiomas typically reveal a well-circumscribed and contrast-enhancing dural mass. Here we discuss the differences in MRI findings between typically benign and atypical meningioma, and their clinical implications. An MRI of a 67-year-old man revealed a substantial homogeneous enhancing tumor nodule. The MRI also showed two components in the tumor, and the regional cerebral blood volume (rCBV) was higher in the lateral than in the medial mass. A pathological examination also revealed features of both benign and atypical meningiomas. The Ki-67 labeling index was 1% on the medial side and 5% on the lateral side. There were clearly two components within the tumor mass, and the MRI revealed differential rCBV in the tumor. The results indicated a nontypical MRI of meningiomas, allowing for predictability of atypical meningiomas using MRI before surgical resection.

5-Aminolevulinic Acid: Pitfalls of Fluorescence-guided Resection for Malignant Gliomas and Application for Malignant Glioma Therapy.

5-Aminolevulinic acid (ALA) has been widely used as an intravital fluorescence marker in the fluorescence-guided resection of malignant gliomas. Although not a photosensitizer itself, 5-ALA is a prodrug that accumulates protoporphyrin IX (PpIX) in the mitochondria of glioma cells; PpIX acts as a photosensitizer. Fluorescence-guided resection for malignant gliomas has some pitfalls. Moreover, 5-ALA is not merely a fluorescence marker but has potential as a mitochondria-targeting drug for malignant glioma therapy. In this article, we review the literature related to 5-ALA, discuss the pitfalls of fluorescence-guided resection using 5-ALA for malignant gliomas, and describe the application of 5-ALA for malignant glioma therapy with personal opinions.

Importance of Finding Embolic Sources for Patients with Embolic Stroke of Undetermined Source.

OBJECTIVE: The concept of embolic stroke of undetermined source refers to cryptogenic strokes caused by either major or minor risks. Although antiplatelet treatments are most often used for secondary prevention of embolic stroke of undetermined source, optimal strategies remain unclear. To determine the ideal treatment strategy for secondary prevention, we investigated embolic sources among patients with embolic stroke of undetermined source. METHODS: The study included 292 consecutive patients (135 men, 157 women; mean age: 74.3 ± 11.6 years) diagnosed with cerebral infarction, 27 of whom were diagnosed with embolic stroke of undetermined source (9.2%; 14 men, 13 women; mean age: 70.7 ± 11.5 years). These 27 patients were examined using contrast-enhanced whole-body computed tomography, transesophageal echocardiography, and Holter electrocardiography. We evaluated whether antiplatelet or anticoagulant treatment was preferred based on the embolic source. RESULTS: Embolic sources among patients with embolic stroke of undetermined source included valve calcification (11.1%), left ventricle diastolic dysfunction (18.5%), cancer-associated stroke (25.9%), covert atrial fibrillation (7.4%), aortic arch atherosclerotic plaques (11.1%), paradoxical embolism (3.7%), and sick sinus syndrome (3.7%). Embolic sources remained unidentified in 5 patients (18.5%). Our analysis revealed that 21 of the 27 patients (77.8%) with embolic stroke of undetermined source required anticoagulant therapy for secondary prevention. CONCLUSION: Although aspirin is the most commonly used antithrombotic drug for embolic stroke of undetermined source, our results suggest that some patients require anticoagulant therapy. Determining embolic sources is important for selecting the appropriate treatment options for this patient population.

Characteristics of Bone Destruction in Cranial Vault Lymphoma Compared with Other Skull Tumors.

Cranial vault lymphomas are rare and challenging to diagnose. We present herein two cases of cranial vault lymphoma. The first patient was a 72-year-old woman who presented with a large mass in the parietal bone found incidentally following a head injury. The second patient was a 63-year-old man who presented with an occipital subcutaneous mass associated with visual disturbance and occipital headaches. The diagnosis of a malignant tumor in the second patient was straightforward due to his symptoms and considerable bone destruction, but the first patient was more difficult to diagnose due to a lack of symptoms and only slight bone destruction detected by computed tomography (CT). Both were histophathologically diagnosed with diffuse large B cell lymphoma (DLBCL) in the cranial vault. We also investigated the clinical features, including initial symptoms and patterns of bone destruction, in 23 patients with other types of skull tumors. This comparison showed that cranial vault lymphomas cause large masses on the scalp and lead to characteristic incomplete bone destruction, indicating that cranial bone is destroyed very slowly despite the expanding subcutaneous mass. This feature is unique compared with other benign and malignant skull tumors. In addition, cranial vault lymphoma can be confirmed via bone window CT.

Pilocytic astrocytoma presenting with atypical features on magnetic resonance imaging.

Pilocytic astrocytoma, which is classified as a grade I astrocytic tumor by the World Health Organization, is the most common type of glioma in children and young adults. Pilocytic astrocytoma generally appears as a well-circumscribed, contrast-enhancing lesion, frequently with cystic components on magnetic resonance imaging (MRI). However, it has been reported that the MRI appearance of pilocytic astrocytoma may be similar to that of high-grade gliomas in some cases. We here report on 6 cases of pilocytic astrocytoma with atypical MRI findings, including small cyst formation, heterogeneously enhancing tumor nodules, irregularly enhancing tumor nodules, and enhancing tumor nodules with internal hemorrhage. All tumors were successfully resected, and the histological diagnoses were pilocytic astrocytoma. When the tumor is located near a cerebral cistern or ventricle, the risk of leptomeningeal dissemination is increased. Furthermore, partial resection has also been associated with a higher risk of recurrence and leptomeningeal dissemination. To date, all but one patient are alive and recurrence-free. Because the preoperative diagnosis influences the decision on the extent of resection and because of the high risk of leptomeningeal dissemination associated with these tumors, careful and correct diagnosis by MRI is important.

Neuroendoscopic cyst fenestration for delayed enlargement of perianeurysmal cyst formation through long-term follow-up after endovascular treatment: A case report and review of literature.

Background: Perianeurysmal cyst formation after endovascular treatment of cerebral aneurysms is a rare complication; however, the number of reports has gradually increased in recent years due to the development of several endovascular treatments. Case Description: We present a case of delayed perianeurysmal cyst enlargement 8 years after endovascular treatment for multiple recurrences of a large cerebral aneurysm in the anterior communicating artery. The patient presented with obstructive hydrocephalus caused by an enlarged perianeurysmal cyst. The patient underwent cyst fenestration using neuroendoscopy and ventriculoperitoneal shunting, recovered from the clinical symptoms, and had a good prognosis. Histopathological findings showed that the cyst wall contained a fibrotic layer under the monoependymal layer with hemosiderosis without evidence of neovascularization or inflammatory cell infiltration. These findings suggest that the origin of the perianeurysmal cyst wall is not the aneurysm itself but the adjacent brain tissue. Conclusion: Perianeurysmal cysts can develop during long-term follow-up, and clinicians should consider surgical treatment, including cyst fenestration, using neuro-endoscopy if the cyst presents with clinical symptoms.

Severe subarachnoid hemorrhage associated with cerebral venous thrombosis in early pregnancy: a case report.

BACKGROUND: Cerebral venous thrombosis (CVT) rarely induces subarachnoid hemorrhage (SAH). During late pregnancy and puerperium, CVT is an uncommon but important cause of stroke. However, severe SAH resulting from CVT is extremely rare during early pregnancy. OBJECTIVE: We report on a rare case of severe SAH due to CVT, and discuss the potential pitfalls of CVT diagnosis in early pregnancy. CASE REPORT: A 32-year-old pregnant woman (9th week of pregnancy) presented with slight head dullness. Initial magnetic resonance imaging (MRI) revealed focal, abnormal signal intensity in the left thalamus. Nine days later, the patient developed a generalized seizure and severe SAH was detected with computed tomography (CT) scan. MRI and cerebral angiography revealed a completely thrombosed superior sagittal sinus, vein of Galen, straight sinus, and right transverse sinus. Transvaginal sonography indicated a missed abortion. The day after admission, the patient presented again with a progressive loss of consciousness and signs of herniation. The patient underwent emergency decompressive craniotomy, followed by intrauterine curettage. Two months later, she made an excellent recovery except for a slight visual field defect. CONCLUSIONS: A rare case of severe SAH due to CVT is reported, with emphasis on the potential pitfalls of CVT diagnosis in early pregnancy.

Primary central nervous system lymphoma of the third ventricle with intra-tumoral hemorrhage: A case report and literature review.

Primary central nervous system lymphoma (PCNSL) is a rare brain tumor that most commonly arises in the cerebral white matter, basal ganglia, peri-ventricle or corpus callosum. Confinement of PCNSL to the third ventricle is extremely rare, and seldom presents with intratumoral hemorrhage (ITH). The present study described the case of a 75-year-old woman who presented with obstructive hydrocephalus due to third-ventricle PCNSL. On magnetic resonance imaging (MRI), the tumor presented ITH on T2*-weighted images and a highly elevated regional cerebral blood volume on dynamic susceptibility contrast-enhanced MRI (DSC-MRI). Due to the high elevation of the regional cerebral blood volume, high-grade glioma was suspected as a preoperative diagnosis. The patient underwent endoscopic tumor biopsy and third ventricle PCNSL was successfully diagnosed. The patient achieved good prognosis at an early stage after the start of treatment initiation. There are many differential considerations for a third-ventricle tumor, and DSC-MRI can help the differential diagnosis of these tumors. Furthermore, the presence of ITH can lead to the inaccurate estimation of regional cerebral blood volume values. Overall, silent or microhemorrhage in PCNSL may be underestimated, and clinicians should therefore carefully evaluate tumor vascularity by MRI.

Preoperative radiological evaluation and surgical strategy for the preservation of visual acuity in patients with skull base meningiomas--two case reports.

Two women aged 48 and 73 years, respectively, presented with unilateral visual disturbance. On admission, magnetic resonance imaging (MRI) showed an extraaxial mass in the parasellar region. Contrast-enhanced fast imaging with steady-state acquisition (CE-FIESTA) showed that the optic nerves were compressed and encased by the tumors. At an early stage of surgery, we performed decompression of the optic nerves to avoid optic nerve injury. Both the patients were relieved of visual disturbances without any postoperative neurological deficit. In conclusion, CE-FIESTA is a useful diagnostic tool for preoperative evaluation of the optic nerves in patients with skull base meningiomas. Decompression of the optic nerves should be performed at an early stage of surgery in meningioma patients presenting with visual disturbance.

Surgical treatment for a ruptured true posterior communicating artery aneurysm arising on the fetal-type posterior communicating artery--two case reports and review of the literature.

Only a small number of aneurysms arising on the posterior communicating artery itself (true Pcom aneurysm) have been reported. We report two cases of ruptured true Pcom aneurysms with some characteristic features of true Pcom aneurysm. A 43 year old man suffering from subarachnoid hemorrhage (SAH) had an aneurysm arising on the fetal-type Pcom artery itself, and underwent surgery for clipping. Most of the aneurysm was buried in the temporal lobe, so retraction of the temporal lobe was mandatory. During the retraction, premature rupture was encountered. After tentative dome clipping and the control of bleeding, complete clipping was achieved. Another patient, a 71 year old woman presenting with consciousness disturbance due to SAH, had an aneurysm on the fetal-type Pcom artery itself, and underwent surgery for clipping. It has been generally considered that hemodynamic factor plays an important role in the formation, the growth, and the rupture of the cerebral aneurysm. This factor is especially significant in true Pcom aneurysm formation and rupture. According to the literature, a combination of fetal type Pcom and formation of the true Pcom aneurysm has been reported in most cases (81.8%). Most of the aneurysm can be buried in the temporal lobe, and the retraction of the temporal lobe during the dissection of the neck would be necessary, which causes premature rupture of the true Pcom aneurysm. In the surgery for a true Pcom aneurysm, we should be aware of possible premature rupture when temporal lobe retraction is necessary.

Primary central nervous system lymphoma presenting with Parkinsonism as an initial manifestation: A case report and literature review.

Primary central nervous system lymphoma (PCNSL) is a rare intracranial neoplasm in older adults. Tumor-associated parkinsonism (TAP) in PCNSL is extremely rare, and its clinical features are unclear. The present report describes the case of a 75-year-old man who presented with parkinsonism due to multiple hyperintense lesions in the thalamus and periventricular white matter as visualized by magnetic resonance imaging (MRI). Due to the rapid progression of parkinsonism and lesion enlargement, the patient underwent stereotaxic biopsy. Subsequently, his condition was diagnosed as TAP in PCNSL at 2 months after onset. The patient completely recovered after treatment and experienced no recurrence of TAP for 8 months. Although it is difficult to distinguish TAP from vascular parkinsonism (VP) at initial consultation, the early diagnosis of PCNSL is important for improving prognosis. In the case of rapidly progressing parkinsonism, one should suspect the possibility of TAP associated with early-stage PCNSL. Early treatment improves the chances of remission and decreases the possibility of recurrence.

Surgical management of primary Ewing's sarcoma of the petroclival bone extend into the sphenoid sinus: A case report and review of literatures.

BACKGROUND: Ewing's sarcoma (ES) is a malignancy that arises from bones or soft tissue, characterized by primitive small and round blue cells. Primary ES typically occurs in the long bones, vertebrae, or pelvis, and is extremely rare in the skull base. CASE DESCRIPTION: A 14-year-old girl presented with posterior cervical pain and dysfunction of multiple cranial nerves (CNs). Radiological investigation revealed a solid mass of the petroclival bone extending into the sphenoid sinus. The patient underwent endoscopic transsphenoidal surgery for diagnosis of the pathology, and partial resection was safely achieved. Histopathological, genetic, and radiological examinations confirmed the diagnosis of primary ES. Subsequently, the patient underwent adjuvant chemotherapy and radiotherapy following which the clinical symptoms resolved. Complete response was achieved after multimodal treatment. Twenty months after treatment, the patient remains in remission without recurrence or metastatic disease. Primary ES of the petroclival bone has been reported in only three cases in the literature. As seen in the present case, dysfunction of multiple CNs is the most common manifestation of petroclival ES. Diagnosis should be confirmed by histopathological and genetic examinations considering the nonspecific clinical symptoms and radiological features. CONCLUSION: Multimodal treatment, including surgery, chemotherapy, and radiotherapy, can result in favorable outcomes. Clinicians should consider safe resection during surgical management to prevent complications that can delay postoperative multimodal treatment.

Intra-arterial Contrast-enhanced Micro-computed Tomography Can Evaluate Intracranial Status in the Ultra-early Phase of Experimental Subarachnoid Hemorrhage in Rats.

The endovascular perforation (EP) model is a common technique for experimental subarachnoid hemorrhage (SAH) in rats, simulating the pathophysiological features observed in the acute phase of SAH. Due to the drawbacks of large variations in the amount of bleeding, the results obtained from this model require severity evaluation. However, no less-invasive procedure could confirm the precise intracranial conditions immediately after establishing the rat EP model. We created a novel method for evaluating SAH immediately after establishing the rat EP model using intra-arterial contrast-enhanced micro-computed tomography (CT). We administered contrast agents continuously via the carotid artery during surgery and performed CT examination immediately after SAH induction. First, bleeding severity was classified by establishing a scoring system based on the CT findings (cSAH scoring system). Subsequently, we determined the actual SAH distribution macroscopically and histologically and compared it with the cSAH scores. Second, we investigated the contrast agent's neurotoxicity in rats. Finally, we confirmed the correlation between cSAH scores and SAH severity, including neurological status, cerebral vasospasm, and hematoma volume 24 hr after SAH. Intra-arterial contrast-enhanced micro-CT could visualize the distribution of SAH proportionally to the bleeding severity immediately after establishing the EP model. Moreover, the contrast agent administration was determined not to be neurotoxic to rats. The cSAH scoring revealed a significant correlation with the SAH severity in the rat EP model (P <0.01). Thus, our minimally invasive method provided precise information on intracranial status in the ultra-early phase of SAH in rats EP model.

Diagnosis and Surgical Management of Exophytic Suprasellar Pituitary Adenoma Extending Over the Diaphragma Sellae and Mimicking Craniopharyngioma: A Case Report.

Pituitary adenomas developing from the lateral surface of the pituitary gland are referred to as exophytic pituitary adenomas. When an exophytic pituitary adenoma extends into the suprasellar region, the tumor exhibits an atypical growth pattern that makes it difficult to distinguish it from craniopharyngiomas or other parasellar lesions on MRI. A 53-year-old woman who presented with general malaise and visual disturbances was diagnosed with a brain tumor. MRI showed a suprasellar tumor presenting as superior lobulation with reticular enhancement and partial calcification. Subsequently, endoscopic transsphenoidal surgery was performed on the patient. The suprasellar tumor was found to originate from the superior surface of the normal pituitary gland and it extended into the supra-diaphragm region. Subtotal tumor resection was achieved, and her clinical symptoms subsequently improved. Exophytic suprasellar pituitary adenomas (SPAs) are extremely rare and may be mistaken for ectopic SPAs in some cases. Contrast-enhanced fast imaging employing steady-state acquisition (CE-FIESTA) can clearly depict the connection between an exophytic SPA and the normal pituitary gland via a diaphragma sellae defect. During surgery, it was seen that the exophytic SPA and anterior lobe of the pituitary gland connected with each other directly. The tumor originated from the superior surface of the pituitary gland and extended into the supra-diaphragm region. These findings clearly confirmed the difference between exophytic SPAs and ectopic SPAs. In surgical management, an exophytic SPA needs careful consideration for resecting the tumor from encased surrounding structures without vascular and nerve injury. Ultrasonic aspiration devices may be useful for safely resecting the tumor from important structures due to tissue selection. Exophytic SPAs are distinguished from ectopic SPAs with respect to the direct connection between the tumor and the normal pituitary gland. These findings can be clearly depicted using CE-FIESTA and should be confirmed during surgery. Clinicians should be aware of the risk that exophytic SPA may extend into the supra-diaphragm region and of the difficulties of resecting the tumor encasing surrounding structures in the suprasellar region.

5-Aminolevulinic Acid Suppresses Prostaglandin E2 Production by Murine Macrophages and Enhances Macrophage Cytotoxicity Against Glioma.

BACKGROUND: 5-Aminolevulinic acid (5-ALA) induces the accumulation of a large amount of protoporphyrin IX (PpIX) in tumors, which has been used in the treatment of several cancers. 5-ALA is commonly used for fluorescence-guided tumor resection in clinical neurosurgery and for photodynamic therapy based on the generation of cytotoxic oxygen. OBJECTIVE: The purpose of this study was to identify the mechanisms of 5-ALA-induced immune response in macrophages in malignant glioma. METHODS: Intracellular levels of 5-ALA-induced PpIX in C3H/HeN murine peritoneal macrophages were measured by the median fluorescence intensity using flow cytometry and confocal laser scanning microscopy. Macrophages were cultured in vitro with or without 0.5 mM 5-ALA, 0.1 µg/mL lipopolysaccharide, and 20% glioma-conditioned medium. Levels of immunosuppressive prostaglandin E2 (PGE2), interleukin-10, and transforming growth factor ß were measured using enzyme immunoassay in the culture supernatant. In addition, macrophages and RSV-M mouse glioma cells were co-cultured in vitro with cell culture inserts with or without 5-ALA (0.1 and 0.5 mM) and lipopolysaccharide (0.1 µg/mL). RESULTS: We found that 5-ALA-induced PpIX accumulated in macrophages and significantly suppressed PGE2 production and expression of both cyclooxygenase-2 and microsomal prostaglandin E synthase-1. 5-ALA treatment also suppressed PGE2 production by glioma-conditioned medium. 5-ALA suppressed RSV-M glioma cell proliferation in a concentration-dependent manner. CONCLUSIONS: These results indicate that 5-ALA suppressed PGE2 production by macrophages via the downregulation of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 expression levels. This is a novel mechanism to induce effective immune response against glioma in macrophages.

Giant Cerebral Aneurysm in a Patient with Cowden Syndrome Treated with Surgical Clipping.

BACKGROUND: Cowden syndrome is characterized by multiple hamartomas and accompanied by a germline mutation of the phosphatase and tensin homolog gene. Cowden syndrome has been described to be associated with vascular anomalies such as arteriovenous malformation and developmental venous anomalies with high frequency. However, the association of cerebral aneurysms with this syndrome has not been reported yet. CASE DESCRIPTION: A 39-year-old Japanese man presented with a subarachnoid hemorrhage due to a ruptured giant fusiform middle cerebral artery aneurysm. We diagnosed him with Cowden syndrome by clinical presentations as outlined in the National Comprehensive Cancer Network's criteria. As the ruptured fusiform aneurysm involved a middle cerebral artery bifurcation, we prepared for extracranial-intracranial bypass surgery. We successfully performed a surgical clipping using multiple tandem clipping techniques and suction decompression techniques. Bypass surgery was not performed as reconstruction of the M2 trunks was successfully completed. CONCLUSIONS: We present this rare case that potentially indicates an association between cerebral aneurysms and Cowden syndrome. Because vascular anomalies are not included in the diagnostic criteria for Cowden syndrome, intracranial vascular anomalies may be underestimated. We therefore recommended a careful search of vascular diseases, including cerebral aneurysms, in cases of Cowden syndrome.

Vessel wall magnetic resonance imaging findings and surgical treatment in nilotinib-associated cerebrovascular disease: A case report.

Nilotinib, a second-generation tyrosine kinase inhibitor, is considered as one of the most effective drugs for the treatment of chronic myeloid leukemia (CML); however, the use of nilotinib has been reported to be associated with vascular adverse events, such as peripheral arterial occlusive disease and ischemic heart disease. Moreover, there are few reports on cerebral vascular disease associated with nilotinib use. We herein describe the case of a 55-year-old male patient with CML, who presented with cerebral infarction and severe cerebrovascular stenosis that developed during nilotinib treatment. The patient was diagnosed with cerebral infarction and severe stenosis of the intracranial arteries associated with nilotinib use. Vessel wall magnetic resonance imaging (VW-MRI) revealed diffuse concentric thickening of the vessel wall, unlike ordinary patterns of atherosclerosis. The patient underwent direct revascularization (superficial temporal artery to middle cerebral artery bypass) and was successfully treated without recurrence. Based on this rare case, VW-MRI may be used to detect the morphological changes of the intracranial arteries that are associated with nilotinib use. Moreover, surgical revascularization may improve the prognosis of nilotinib-associated cerebrovascular diseases, such as severe stenosis or occlusion of the main trunk of the cerebral arteries, that cause brain ischemia.

Induction of prostaglandin E2 synthesis and microsomal prostaglandin E synthase-1 expression in murine microglia by glioma-derived soluble factors. Laboratory investigation.

OBJECT: Microglia are one of the members of monocyte/macrophage lineage in the central nervous system (CNS) and exist as ramified microglia in a normal resting state, but they are activated by various stimuli, such as tumors. Activated microglia induce immune responses in the CNS, but the precise functions of microglia in glioma microenvironments are not clear. It has been reported that glioma cells produce prostaglandin (PG)E2, which promotes the growth of tumor cells and possesses immunosuppressive activity. The authors previously reported that PGE2 production by peritoneal macrophages was enhanced by glioma-derived soluble factors, which induce an immunosuppressive state. In this study, they investigated PGE2 production by microglia treated with glioma cells and assessed the role of microglia in glioma microenvironments in the mouse. METHODS: Microglia and peritoneal macrophages were cultured in vitro with or without lipopolysaccharide, and tumor necrosis factor (TNF) and PGE2 in the culture supernatant were measured using L929 bioassay and enzyme immunoassay. The expression of mRNA was measured using reverse transcriptase polymerase chain reaction, and the protein expression was assayed with Western blotting. In some experiments glioma cells and conditioned glioma medium were added to the microglia cultures. RESULTS: Glioma cells studied in this report did not produce a significant amount of PGE2. However, the coculture of microglia with glioma cells or conditioned glioma medium led to the production of a large amount of PGE2. The enhancement of PGE2 production by microglia was more significant than that by peritoneal macrophages. The expression of cyclooxygenase (COX)-2 and particularly the expression of microsomal PGE synthase (mPGES)-1 (a terminal enzyme of the arachidonate cascade) in microglia were enhanced by conditioned glioma medium. The enhancement of mPGES-1 expression in microglia was more significant than that in peritoneal macrophages. The production of TNF was suppressed when culturing microglia with conditioned glioma medium, but this suppression was abrogated by the addition of a COX inhibitor (NS-398) and a PGE2 receptor (EP4) antagonist. Furthermore, TNF production was not suppressed in microglia from mPGES-1-deficient mice. CONCLUSIONS: These results indicate that PGE2 production by microglia is enhanced by conditioned glioma medium, which induces an immunosuppressive state in the CNS. Therefore, the manipulation of microglia, from the standpoint of PGE2, provides investigators with an important strategy to induce an effective antiglioma immune response.

Cervical intramedullary glioblastoma: report of a long-term survival case and a review of the literature.

Spinal intramedullary glioblastoma has rarely been reported. Among reported cases, the most characteristic features are rapid progression of the disease and very poor prognosis. The mean survival period is 12 months. We report a patient having cervical intramedullary glioblastoma with long-term survival (26 months after the onset). A 21-year-old man presented with weakness in bilateral hands, and the symptoms progressed rapidly. Magnetic resonance imaging (MRI) showed cervical intramedullary tumor. He underwent surgery of debulking of the cervical tumor, fractionated stereotactic irradiation, and repeated chemotherapy using nimustine hydrochloride (ACNU). Although dissemination of the tumor in the intracranial space deteriorated the patient, he survived for 26 months after the initial onset. It has been reported that no treatment is effective for this disease. However, it is also true that some patients respond well to the intensive treatment. It can be emphasized that scheduled intensive treatment for the disease under earlier histological confirmation should be performed.