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.

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.

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.

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.

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.

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: 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.

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.

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.

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.

Intraoperative monitoring of motor-evoked potential for parenchymal brain tumor removal: An analysis of false-negative cases.

Transcranial motor-evoked potential (tc-MEP) monitoring is unreliable for brain tumor removal due to its low sensitivity. According to previous literature, this is because transcranial stimulation seems to reach the deep pyramidal tract beyond the operation point and may thus yield false-negative results, where, although MEP recording is stable, postoperative motor deficits are encountered. Therefore, we aimed to analyze the causes for the false-negative results and investigate whether decreasing the stimulation intensity better reflects the operation point and can improve the sensitivity during parenchymal brain tumor removal. We assessed 122 patients with parenchymal brain and intraventricular tumors, who underwent surgery under tc-MEP monitoring in our hospital between 2011 and 2014. In these patients, the stimulation intensity was fixed at 200 mA. We detected 11 false-negative cases, while the sensitivity of tc-MEP monitoring was 33.9% and the specificity was 99.0%. Between 2015 and 2016, we examined 68 patients with parenchymal brain tumors, in whom the stimulation intensity was reduced to an average of 136.5 mA. Only one case was false-negative, while the sensitivity increased to 83.3% and the specificity was 98.4%. From these results, we conclude that the intensity of tc-MEP stimulation should be minimal to precisely reflect the damage to the operated location. Tc-MEP can be an easy and reliable monitor in brain tumor surgery when used at proper, lower intensity.

Evaluation of Peritumoral Brain Parenchyma Using Contrast-Enhanced 3D Fast Imaging Employing Steady-State Acquisition at 3T for Differentiating Metastatic Brain Tumors and Glioblastomas.

BACKGROUND: Metastatic brain tumors and glioblastomas are the 2 of the most common brain neoplasms in adults. However, distinguishing solitary metastatic brain tumors from glioblastomas on conventional magnetic resonance imaging remains particularly challenging. Thus, we aimed to retrospectively assess the role of contrast-enhanced fast imaging employing steady-state acquisition (CE-FIESTA) imaging in distinguishing between metastatic brain tumors and glioblastomas. MATERIALS AND METHODS: Forty-three patients with metastatic brain tumors and 14 patients with glioblastomas underwent conventional magnetic resonance imaging and CE-FIESTA before surgery. First, 1 neuroradiologist and 1 neurosurgeon classified the CE-FIESTA findings for the peritumoral brain parenchyma by consensus. Next, the 2 neuroradiologists performed an observer performance study comparing tumor shape classification (smooth or irregular margins), a classic imaging finding, with the CE-FIESTA classification of the peritumoral brain parenchyma. RESULTS: The CE-FIESTA findings for the peritumoral brain parenchyma were classified as follows: type A, no hyperintense rim; type B, partial hyperintense rim; and type C, extended hyperintense rim. With regard to the diagnosis of metastatic brain tumors, the observer performance study demonstrated that the mean sensitivity, specificity, and accuracy of an extended hyperintense rim classification (type C) on CE-FIESTA images were 95.3%, 85.7%, and 93.0%, respectively. The accuracy of the CE-FIESTA classification was significantly higher than that of the tumor shape classification. CONCLUSIONS: CE-FIESTA images may provide useful information for distinguishing metastatic brain tumors from glioblastomas, especially when focusing on differences in the peritumoral brain parenchyma.

Clinical features and surgical management of intracranial meningiomas in the elderly.

Meningioma accounts for ~25% of all primary intracranial neoplasms and the incidence increases with age. Prvios population-based studies demonstrated that the annual incidence of intracranial meningiomas was 1.2-3.1/100,000 population. In particular, the incidence of this disease among the elderly is high. Recently, increased life expectancy and greater use of diagnostic radiological imaging led to an increased incidence in the diagnosis of intracranial meningiomas, both symptomatic and asymptomatic, in the elderly. Thus, neurosurgeons may be increasingly confronted with the management of intracranial meningiomas in the elderly. In practice, it is often difficult for physicians to determine whether traditional surgical resection is the optimal management strategy for intracranial meningiomas in the elderly. However, reported clinical studies about the outcome of surgical resection of intracranial meningiomas in the elderly are limited. Increased risk of mortality and morbidity associated with surgical treatment for intracranial meningiomas in the elderly compared with younger patients have been controversial. In the present study, the clinical features of intracranial meningiomas in 70 consecutive intracranial meningioma patients that underwent surgical treatment at the affiliated hospital of University of Occupational and Environmental Health between 2007 and 2013 were assessed. In addition, patient selection and surgical management of intracranial meningioma in elderly patients was discussed. Preoperative factors, including symptoms, tumor location, tumor size, Karnofsky Performance Scale (KPS) score and American Society of Anesthesiology (ASA) score, and postoperative factors, including pathological diagnosis, tumor proliferation index (Ki-67), resection rate (Simpson grade), length of hospital stay and discharge destination were retrospectively analyzed in patients aged ≥75 years (n=16; elderly group) and <75 years (n=54; younger group). Outcomes were assessed 6 months after surgery. Multivariate logistic regression revealed that tumor resection rate (Simpson grade III-V) was an important predictor of surgical complications (odds ratio, 5.662; 95% confidence interval, 1.323-24.236; P=0.0194). Perioperative morbidity was not correlated with age (>75 years), tumor location, tumor size, KPS score or ASA score. Thus, the present study indicated that age is not associated with surgical outcome in elderly meningioma patients. Regardless of patient age, the decision to perform surgical resection should be made on an individual basis wherein tumor characteristics and the general health of the patient are considered.

5-Aminolevulinic acid enhances mitochondrial stress upon ionizing irradiation exposure and increases delayed production of reactive oxygen species and cell death in glioma cells.

5-Aminolevulinic acid (5-ALA) can accumulate protoporphyrin IX (PpIX) in tumour cell mitochondria and is well known for its utility in fluorescence-guided resection of malignant gliomas as a live molecular marker. Previously, we and other authors demonstrated that 5-ALA has a radiosensitizing effect for tumours. In the present study, we aimed to investigate the mechanism underlying the radiosensitizing effect of 5-ALA by focusing on glioma cell mitochondria. Using an enhancer (ciprofloxacin) of 5-ALA-induced PpIX accumulation, we evaluated the influence of ionizing irradiation (IR) and delayed reactive oxygen species (ROS) production 12 h after IR by colony-forming assay and flow cytometry (FCM) with different amounts of PpIX accumulation. The mitochondrial mass and mitochondrial electron transport chain (mtETC) activity were evaluated by FCM and western blot analysis. Cell death and delayed ROS production after IR in glioma cells were increased in proportion to 5-ALA-induced PpIX accumulation. Delayed ROS production enhanced by 5-ALA localized to the glioma cell mitochondria. Mitochondrial mass and mitochondrial complex III activity, among mtETC factors, were also increased 12 h after IR in glioma cells in proportion to 5-ALA-induced PpIX accumulation with some variation. These results suggest that 5-ALA enhances IR-induced mitochondrial oxidative stress and leads to increased cell death with mitochondrial changes, thereby acting as a targeting mitochondrial drug, and so­called radiosensitizer in glioma cells.

Intracranial Neurenteric Cyst with an Enhanced Mural Nodule and Melanin Pigmentation: Radiologic-Pathologic Correlation.

BACKGROUND: An intracranial neurenteric cyst (NC) is a rare congenital benign lesion that usually has a well-demarcated cystic appearance without contrast enhancement on magnetic resonance imaging (MRI). In particular, an intracranial NC with an enhanced mural nodule is extremely rare. CASE DESCRIPTION: A 20-year-old man presented with left-sided hearing disturbance and headache. On MRI, a cystic mass was seen in the prepontine cistern that significantly compressed the brainstem. The lesion was hyperintense on T1-weighted images, and contained a solid component that appeared with marked hypointensity on T2*-weighted images and slight enhancement. The cystic wall was removed via a left transcondylar fossa approach. Histopathologic findings showed an NC with a solid component and melanin pigmentation. The solid component showed xanthogranulomatous changes, with evidence of an old hemorrhage, and was strongly adherent to the brainstem. CONCLUSIONS: We present this rare case and emphasize that an NC should be considered in the differential diagnosis of intracranial cystic lesions with an enhanced mural nodule.

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.

5-Aminolevulinic acid strongly enhances delayed intracellular production of reactive oxygen species (ROS) generated by ionizing irradiation: quantitative analyses and visualization of intracellular ROS production in glioma cells in vitro.

Postoperative adjuvant radiotherapy has important roles in multimodal treatment for highly aggressive malignant gliomas. Previously, we demonstrated that multi-dose ionizing irradiation with repetitive administration of 5-aminolevulinic acid (5-ALA) enhanced the host antitumor response and strongly inhibited tumor growth in experimental glioma. However, the mechanism of the radiosensitizing effect of 5-ALA is not known. Ionizing irradiation not only causes reactive oxygen species (ROS) formation initially by water radiolysis but also induces delayed production of mitochondrial ROS for mediating the long-lasting effects of ionizing irradiation on tumor cells. 5-ALA leads to high accumulation of protoporphyrin IX (PpIX) in the mitochondria of tumor cells, yet can also improve dysfunction of the mitochondrial respiratory chain in tumor cells. Here, we assessed the effect of 5-ALA-induced PpIX synthesis and delayed production of intracellular ROS after ionizing irradiation with 5-ALA in glioma cells in vitro. Temporal changes in intracellular 5-ALA-induced PpIX synthesis after ionizing irradiation in glioma cell lines were evaluated using flow cytometry (FCM). Then, the effect of 5-ALA on delayed production of intracellular ROS 12 h after ionizing irradiation in glioma cells was evaluated by FCM and confocal laser scanning microscopy. Ionizing irradiation had no effect on 5-ALA-induced PpIX synthesis in glioma cells. Delayed intracellular production of ROS was significantly higher than that just after ionizing irradiation, but 5-ALA pretreatment strongly enhanced the delayed intracellular production of ROS, mainly in the cytoplasm of glioma cells. This 5-ALA-induced increase in the delayed production of ROS tended to be higher in the case of 5-ALA treatment before rather than after ionizing irradiation. These results suggest that 5-ALA can affect tumor cells under ionizing irradiation, and greatly increase secondary intracellular production of ROS long after ionizing irradiation, thereby causing a radiosensitizing effect in glioma cells.