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IFN regulatory factor 3 (IRF3) is a transcriptional factor that plays a crucial role in activation of innate immunity and inflammation in response to viral infection, and is also involved in p53-dependent inhibition of cell growth. Although functional activation of IRF3 by viral infection is relatively well documented, the biological role and regulatory mechanism underlying cell growth inhibition by IRF3 are poorly understood. Here, we show a novel regulatory pathway connecting IRF3-promyelocytic leukemia protein (PML)-p53 in primary and cancer cell lines. Overexpression of IRF3 induces p53-dependent cell growth inhibition in cancer cell lines with normal p53 activity. In addition, doxycycline-induced expression of IRF3 in U87MG cells inhibits tumor growth in nude mice in vivo. IRF3 is found to increase expression of PML by a direct transcriptional activation as determined by PML-promoter-luciferase and chromatin immunoprecipitation assays. When PML is depleted by RNA interference–mediated knockdown, IRF3 fails to increase p53 acetylation and its transcriptional activity. Taken together, the results of the present study indicate that direct transcriptional activation of PML by IRF3 results in the p53-dependent growth inhibition of normal and cancer cells in vitro and in vivo, which is suggestive of a novel regulatory network between the innate immune response and tumor suppression. [Cancer Res 2007;67(23):11133–40]

Supplementary Figures 1-4 from Direct Transcriptional Activation of Promyelocytic Leukemia Protein by IFN Regulatory Factor 3 Induces the p53-Dependent Growth Inhibition of Cancer Cells

Background Orbital compartment syndrome (OCS) is a rare but devastating complication following pterional craniotomy. Although the causes of OCS are unclear, external compression of the orbit by a myocutaneous flap is commonly mentioned as a major factor. We evaluated the ocular influence of external compression using an extraocular pressure monitor. Methods We measured extraocular pressure in 86 patients who underwent surgery for cerebral aneurysm via a pterional approach. Clinical information and radiologic parameters, including the area of the medial rectus muscle (MRM) and the craniotomy height from the bottom of the anterior skull base, were collected. As a control group, 117 patients who underwent surgery without pressure monitoring were also evaluated. Results Extraocular pressure reached a maximum during craniotomy (mean, 22.0 mm Hg; range, 18.4–51.0 mm Hg) and decreased after myocutaneous flap adjustment (mean, 7.9 mm Hg; range, 5.4–17.5 mm Hg). Pressure before myocutaneous flap manipulation differed between patients with anterior communicating artery (Acomm) aneurysms and other patients (mean, 16.5 mm Hg vs. 9.4 mm Hg; P = 0.003). Among Acomm aneurysm cases, the monitored group showed a significantly lower MRM swelling ratio (postoperative MRM area/preoperative MRM area) compared with the control group (1.03 ± 0.10 vs. 1.17 ± 0.15; P = 0.036). Conclusions Myocutaneous flaps can produce unnoticed overpressure on the orbit, resulting in OCS-related blindness during aneurysm clipping surgery, especially in cases involving mandatory lower craniotomy. The continuous extraocular compressive pressure monitoring technique is a simple and effective approach to prevent such a serious complication.

BACKGROUND Primary intraventricular hemorrhage (PIVH) is an uncommon type of intracerebral hemorrhage. Owing to its rarity, the clinical and radiological factors affecting outcomes in patients with PIVH have not been widely studied. MATERIAL AND METHODS We retrospectively reviewed 112 patients (mean age 53 years) treated for PIVH at our institution from January 2004 to December 2014. Clinical and radiological parameters were analyzed 3 months after initial presentation to identify factors associated with clinical outcomes, as assessed by the Glasgow Outcome Scale (favorable ≥4, unfavorable

Despite the presence of aggressive treatment strategies, glioblastoma remains intractable, warranting a novel therapeutic modality. An oral antipsychotic agent, penflurido (PFD), used for schizophrenia treatment, has shown an antitumor effect on various types of cancer cells. As glioma sphere-forming cells (GSCs) are known to mediate drug resistance in glioblastoma, and considering that antipsychotics can easily penetrate the blood-brain barrier, we investigated the antitumor effect of PFD on patient-derived GSCs. Using five GSCs, we found that PFD exerts an antiproliferative effect in a time- and dose-dependent manner. At IC50, spheroid size and second-generation spheroid formation were significantly suppressed. Stemness factors, SOX2 and OCT4, were decreased. PFD treatment reduced cancer cell migration and invasion by reducing the Integrin α6 and uPAR levels and suppression of the expression of epithelial-to-mesenchymal transition (EMT) factors, vimentin and Zeb1. GLI1 was found to be involved in PFD-induced EMT inhibition. Furthermore, combinatorial treatment of PFD with temozolomide (TMZ) significantly suppressed tumor growth and prolonged survival in vivo. Immunostaining revealed decreased expression of GLI1, SOX2, and vimentin in the PFD treatment group but not in the TMZ-only treatment group. Therefore, PFD can be effectively repurposed for the treatment of glioblastoma by combining it with TMZ.

When treating childhood acute lymphoblastic leukemia (ALL), secondary neoplasms are a significant long term problem. Radiation is generally accepted to be a major cause of the development of secondary neoplasms. Following treatment for ALL, a variety of secondary tumors, including brain tumors, hematologic malignancies, sarcomas, thyroid cancers, and skin cancers have been reported. However, oligodendroglioma as a secondary neoplasm is extremely rare. Herein we present a case of secondary oligodendroglioma occurring 13 years after the end of ALL treatment.

// Doo-Sik Kong 1,* , Do-Hyun Nam 1,* , Shin-Hyuk Kang 2 , Jae Won Lee 3 , Jong-Hee Chang 4 , Jeong-Hoon Kim 5 , Young-Jin Lim 6 , Young-Cho Koh 7 , Yong-Gu Chung 2 , Jae-Min Kim 8 and Choong-Hyun Kim 8 1 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Department of Neurosurgery, College of Medicine, Korea University, Seoul, Korea 3 Department of Statistics, Korea University, Seoul, Korea 4 Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea 5 Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 6 Department of Neurosurgery, Kyunghee University Hospital, Seoul, Korea 7 Department of Neurosurgery, Konkuk University Medical Center, Seoul, Korea 8 Department of Neurosurgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea * These authors have contributed equally to this work Correspondence to: Choong Hyun Kim, email: // Keywords : immunotherapy, autologous cytokine-induced killer cell, glioblastoma Received : August 05, 2016 Accepted : September 23, 2016 Published : September 27, 2016 Abstract Purpose: Adoptive cell immunotherapy involves an ex vivo expansion of autologous cytokine-induced killer (CIK) cells before their reinfusion into the host. We evaluated the efficacy and safety of CIK cell immunotherapy with radiotherapy-temozolomide (TMZ) for the treatment of newly diagnosed glioblastomas. Experimental design: In this multi-center, open-label, phase 3 study, we randomly assigned patients with newly diagnosed glioblastoma to receive CIK cell immunotherapy combined with standard TMZ chemoradiotherapy (CIK immunotherapy group) or standard TMZ chemoradiotherapy alone (control group). The efficacy endpoints were analyzed in the intention-to-treat set and in the per protocol set. Results: Between December 2008 and October 2012, a total of 180 patients were randomly assigned to the CIK immunotherapy ( n = 91) or control group ( n = 89 ). In the intention-to-treat analysis set, median PFS was 8.1 months (95% confidence interval (CI), 5.8 to 8.5 months) in the CIK immunotherapy group, as compared to 5.4 months (95% CI, 3.3 to 7.9 months) in the control group (one-sided log-rank, p = 0.0401). Overall survival did not differ significantly between two groups. Grade 3 or higher adverse events, health-related quality of life and performance status between two groups did not show a significant difference. Conclusions: The addition of CIK cells immunotherapy to standard chemoradiotherapy with TMZ improved PFS. However, the CIK immunotherapy group did not show evidence of a beneficial effect on overall survival.

Aims Aggressive meningioma remains incurable with neither chemo- nor targeted therapies proven effective, largely due to unidentified genetic alterations and/or aberrant oncogenic pathways driving the disease progression. In this study, we examined the expression and function of Forkhead box M1 (FOXM1) transcription factor during meningioma progression. Methods Human meningioma samples (n = 101) were collected, followed by Western blotting, quantitative PCR, immunohistochemical and progression-free survival (PFS) analyses. For in vitro assays, FOXM1 was overexpressed or knocked-down in benign (SF4433 and SF4068) or malignant (SF3061 and IOMM-Lee) human meningioma cell lines respectively. For in vivo studies, siomycin A (a FOXM1 inhibitor)-pretreated or control IOMM-Lee cells were implanted subcutaneously in nude mice. Results FOXM1 expression was increased in higher grades of meningioma and correlated with the mitotic index in the tumour tissue. Moreover, FOXM1 was increased in recurrent meningioma compared with the matched primary lesions. The patients who had higher FOXM1 expression had shorter PFS. In the subsequent in vitro assays, knockdown of FOXM1 in malignant meningioma cell lines resulted in decreased tumour cell proliferation, angiogenesis and invasion, potentially via regulation of β-catenin, cyclin D1, p21, interleukin-8, vascular endothelial growth factor-A, PLAU, and epithelial-to-mesenchymal transition-related genes, whereas overexpression of FOXM1 in benign meningioma cell lines had the opposite effects. Last, suppression of FOXM1 using a pharmacological inhibitor, siomycin A, decreased tumour growth in an in vivo mouse model. Conclusions Our data demonstrate that FOXM1 is a key transcription factor regulating oncogenic signalling pathways in meningioma progression, and a promising therapeutic target for aggressive meningioma.

Glioblastoma is the most aggressive primary brain tumor with hypoxia-associated morphologic features including pseudopalisading necrosis and endothelial hyperplasia. It has been known that hypoxia can activate signal transducer and activator of transcription 3 (Stat3) and subsequently induce angiogenesis. However, the molecular mechanism underlying hypoxia-induced Stat3 activation has not been defined. In this study, we explored the possible implication of reactive oxygen species (ROS) in hypoxia-driven Stat3 activation in human glioblastoma. We found that hypoxic stress increased ROS production as well as Stat3 activation and that ROS inhibitors (diphenyleneiodonium, rotenone and myxothiazol) and an antioxidant (N-acetyl-L-cysteine) blocked Stat3 activation under hypoxic conditions. To determine a major route of ROS production, we tested whether nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is involved in hypoxia-induced ROS production. Nox4 expression was found to be increased at both mRNA and protein levels in hypoxic glioblastoma cells. In addition, siRNA-mediated knockdown of Nox4 expression abolished hypoxia induced Stat3 activation and vascular endothelial growth factor expression, which is associated with tumor cells' ability to trigger tube formation of endothelial cells in vitro. Our findings indicate that elevated ROS production plays a crucial role for Stat3 activation and angiogenesis in hypoxic glioblastoma cells.

To provide radiobiological information on the inherent response of intracranial meningiomas after three-dimensional conformal radiation therapy. Quantitative tumor volume measurements were generated from 120 magnetic resonance images of a total of 24 patients. Gross tumor volumes were delineated on a series of contrast-enhanced T1-weighted magnetic resonance images by using commercial software. The percentage of tumor volume reduction at each follow-up was determined and compared to the baseline tumor volume. The median follow-up time was 103.5 months (range 30-137 months). The mean pre-radiation therapy tumor volume was 30.0 cm(3) (range 1.3-167.4 cm(3)). Tumor volume reduction was observed in 96 % of the study population. The mean absolute and relative tumor volume reduction were 14.0 cm(3) (range -0.6-84.5 cm(3)) and 40.8 % (range -6.8-82.9 %), respectively. The mean relative tumor volume reduction was 15.9, 28.9, 40.5, 50.3, and 52.6 % at 2, 4, 6, 8, and 10 years after irradiation. The quantitative volumetric analysis of the pattern of tumor volume reduction in response to irradiation gives an insight into the radiobiological nature of intracranial meningiomas after conventionally fractionated radiation therapy.

Romo1 is a mitochondrial protein whose elevated expression is commonly observed in various types of human cancers. However, the expression status of Romo1 and its implication in the pathogenesis of human glioblastoma (GBM) remain largely undefined. To understand the role of Romo1 in the progression of GBM, we explored its expression in a series of GBM tissues and cell lines and determined its effect on ROS production, cell proliferation, and tumor growth. Romo1 was frequently overexpressed at the mRNA level in both primary tumors and cell lines and its elevation was more commonly observed in high grade tumors versus low grade tumors. Romo1 expression was associated with ROS production and its knockdown led to a marked reduction of in vitro cellular growth and anchorage-independent growth of GBM. Consistently, Romo1 depletion induced a G2/M arrest of the cell cycle that was accompanied with accumulation of phospho-cdc2. Furthermore, a mouse xenograft assay revealed that Romo1 depletion significantly decreased tumor formation and growth. Therefore, our data demonstrate that Romo1 upregulation is a common event in human GBMs and contributes to the malignant tumor progression, suggesting that Romo1 could be a new therapeutic target for human GBM.

Astrocyte elevated gene-1 (AEG-1) has recently been proposed to be involved in tumor development, invasion, and metastasis in several human cancers. However, the functional importance of AEG-1 expression in human meningioma has not been determined. We investigate the level of AEG-1 expression by quantitative reverse transcription PCR, immunohistochemistry analysis, and western blotting in various human meningioma tissues and cells. To determine the suppressive effect of AEG-1 on meningioma progression, we inhibited AEG-1 expression using small interfering RNA and examined cell proliferation, apoptosis, colony formation and tumorigenicity in a mouse xenograft model. AEG-1 expression was frequently elevated at both mRNA and protein levels in meningioma tumor tissues and in meningioma-derived cells as well. This elevation was more commonly observed in high-grade tumors than in benign ones. The knockdown of AEG-1 led to a decrease in overall cell proliferation, as well as anchorage-independent growth of malignant meningioma. In addition, apoptotic cell death occurred in AEG-1 depleted meningioma cells through p-Akt and Bcl-2 suppression. Furthermore, a mouse xenograft meningioma model showed that inhibition of AEG-1 expression significantly decreased tumor growth. Altogether, these data show that the elevation of AEG-1 contributes to the malignant progression of meningiomas, suggesting that AEG-1 could be a novel therapeutic target against human meningiomas.

Objective To establish the value of thallium-201 single-photon emission computed tomography ( 201 Tl-SPECT) as a predictor of early progression in low-grade astrocytomas (LGAs). Methods We studied 57 consecutive patients who underwent 201 Tl-SPECT before stereotactic biopsy ( n = 33) or surgical resection ( n = 24). The value of radiologic and histopathological variables ( 201 Tl index and MIB-1 index) in predicting progression free survival (PFS) was examined in each group of patients. Results During a median follow up of 55 months (range, 11–101), progression of the primary lesion was identified in 46 patients (80.7%). Based on Cox's proportional hazards model, the increased thallium uptake was associated with a short PFS in both biopsy and resection groups, whereas the MIB-1 index was significant only in the resection group. Considering the cut-off value, 201 Tl index > 1.7 was statistically significant for reduced PFS in the biopsy group; however, MIB-1 index was not directly related to the PFS at any level. For the surgical resection group, both a 201 Tl index > 1.9 and a MIB-1 index > 6% were associated with short PFS. Conclusion 201 Tl SPECT may play a role in prediction of early tumor progression not only in resected LGAs, but also in biopsy-proven LGAs. Therefore, we suggest that patients with LGAs established from biopsy should be considered as high-risk groups for early progression if the tumor shows a high 201 Tl uptake, even if the tumor demonstrates low proliferative activity on histopathologic examination.

Inflammatory microenvironment signalling plays a crucial role in tumour progression (i.e. cancer cell proliferation, survival, angiogenesis and metastasis) in many types of human malignancies. However, the role of inflammation in brain tumour pathology remains poorly understood. Here, we report that interferon regulatory factor 7 is a crucial regulator of brain tumour progression and heterogeneity. Ectopic expression of interferon regulatory factor 7 in glioma cells promotes tumorigenicity, angiogenesis, microglia recruitment and cancer stemness in vivo and in vitro through induction of interleukin 6, C-X-C motif chemokine 1 and C–C motif chemokine 2. In particular, interferon regulatory factor 7-driven interleukin 6 plays a pivotal role in maintaining glioma stem cell properties via Janus kinase/signal transducer and activator of transcription-mediated activation of Jagged-Notch signalling in glioma cells and glioma stem cells derived from glioma patients. Accordingly, the short hairpin RNA-mediated depletion of interferon regulatory factor 7 in glioma stem cells markedly suppressed interleukin 6-Janus kinase/signal transducer and activator of transcription-mediated Jagged-Notch-signalling pathway, leading to decreases in glioma stem cell marker expression, tumoursphere-forming ability, and tumorigenicity. Furthermore, in a mouse model of wound healing, depletion of interferon regulatory factor 7 suppressed tumour progression and decreased cellular heterogeneity. Finally, interferon regulatory factor 7 was overexpressed in patients with high-grade gliomas, suggesting its potential as an independent prognostic marker for glioma progression. Taken together, our findings indicate that interferon regulatory factor 7-mediated inflammatory signalling acts as a major driver of brain tumour progression and cellular heterogeneity via induction of glioma stem cell genesis and angiogenesis. * Abbreviations : CCL2 : C–C motif chemokine 2 CXCL1 : C-X-C motif chemokine 1 GSC : glioma stem cell IL6 : interleukin 6 IRF7 : interferon regulatory factor 7 JAK : Janus kinase shRNA : short hairpin RNA STAT : signal transducer and activator of transcription TNFα : tumour necrosis factor α

We report here on a rare case of a ruptured basilar tip aneurysm that was successfully treated with coil embolization in the bilateral cervical internal carotid artery (ICA) occlusions with abnormal vascular networks from the posterior circulation. A 43-year old man with a familial history of moyamoya disease presented with subarachnoid hemorrhage. Digital subtraction angiography demonstrated complete occlusion of the bilateral ICAs at the proximal portion and a ruptured aneurysm at the basilar artery bifurcation. Each meningeal artery supplied the anterior cranial base, but most of both hemispheres were supplied with blood from the basilar artery and the posterior cerebral arteries through a large number of collateral vessels to the ICA bifurcation as well as the anterior cerebral and middle cerebral arteries. The perfusion computed tomography (CT) scans with acetazolamide (ACZ) injection revealed no reduction of cerebral blood flow and normal cerebrovascular reactivity to ACZ. An abdominal CT aortogram showed no other extracranial vessel abnormalities. A ruptured basilar tip aneurysm was successfully treated with coil embolization without complications. Endovascular embolization may be a good treatment option with excellent safety for a ruptured basilar tip aneurysm that accompanies proximal ICA occlusion with vulnerable collateral flow.

BACKGROUND: Glioblastoma is the most common primary brain tumor, with typical histopathologic findings, pseudopalisading necrosis, and microvascular proliferation, all of which are associated with a poor prognosis. Hypoxia is known to affect these morphological features, but the underlying molecular mechanism has been poorly understood. OBJECTIVE: To determine the role of signal transducer and activator of transcription 3 (STAT3) in the malignant progression of glioblastoma under hypoxic conditions. METHODS: We studied STAT3 activation by hypoxic stress and its effect on hypoxia-induced angiogenesis and cell migration using U87, A172, T98, and U373 human glioblastoma cell lines. RESULTS: All four glioblastoma cells analyzed expressed detectable levels of STAT3 phosphorylation. Hypoxic stress markedly increased phosphorylated STAT3 level in a time-dependent fashion, and activated STAT3 was translocated into the nucleus. Hypoxic conditions led to a 30-50% increase in angiogenesis and cell migration, but these effects were significantly attenuated by small interfering ribonucleic acid-mediated knockdown of STAT3. Furthermore, STAT3 activation was associated with an elevated expression of hypoxic inducible factor-1, vascular endothelial growth factor, matrix metallaproteinase 2, and TWIST messenger ribonucleic acid and protein, which may play a critical role in hypoxia-induced angiogenesis and migration. CONCLUSION: STAT3 plays an important role in glioblastoma angiogenesis and migration triggered by hypoxia. Therefore, STAT3 might be a target for control of pseudopalisading necrosis and angiogenesis in glioblastoma.

O(6)-methylguanine-DNA methyltransferase (MGMT) is known as a DNA repair protein, and loss of function in MGMT is related to an increase in survival in patients with malignant gliomas treated with alkylating agents. In the present study, we determined the status of MGMT using methylation-specific polymerase chain reaction (PCR) and immunohistochemistry on paraffin-embedded specimens in 12 human gliosarcomas, and these results were then related to overall survival (OS) and response to alkylating agents. The MGMT promoter was methylated in six patients. Immunostaining of MGMT was positive in 58.3% of patients. MGMT methylation status was correlated with immunostaining results in five patients (41.7%). The median OS and progression-free survival (PFS) of the whole population were 13.4 months [95% confidence interval (CI), 12.3-14.5 months] and 8.3 months (95% CI, 7.4-9.2 months), respectively. In patients with methylated MGMT promoter, median OS was 15.0 months, compared with 11.3 months in the unmethylated group. Median PFS of gliosarcoma patients was 10.3 months for the methylated group, whereas it was 7.3 months for the unmethylated group. On multivariate analysis, patients with methylated MGMT promoter had better prognosis than patients with unmethylated MGMT promoter with respect to OS and PFS (P = 0.045 and 0.034, respectively). However, there was no statistical significance between MGMT protein expression and survival. The results show that a significant fraction of gliosarcomas have MGMT promoter methylation and protein expression, and suggest that patient survival is associated with MGMT methylation status.

Spinal cord injury (SCI) develops primary and secondary damage to neural tissue and this often results in permanent disability of the motor and sensory functions. However, there is currently no effective treatment except methylprednisolone, and the use of methylprednisolone has also been questioned due to its moderate efficacy and the drug's downside. Regenerative medicine has remarkably developed since the discovery of stem cells, and many studies have suggested the potential of cell-based therapies for neural injury. Especially, the therapeutic potential of human umbilical cord blood cells (hUCB cells) for intractable neurological disorders has been demonstrated using in vitro and vivo models. The hUCB cells are immune naïve and they are able to differentiate into other phenotypes, including the neural lineage. Their ability to produce several neurotropic factors and to modulate immune and inflammatory reactions has also been noted. Recent evidence has emerged suggesting alternative pathways of graft-mediated neural repair that involve neurotrophic effects. These effects are caused by the release of various growth factors that promote cell survival, angiogenesis and anti-inflammation, and this is all aside from a cell replacement mechanism. In this review, we present the recent findings on the stemness properties and the therapeutic potential of hUCB as a safe, feasible and effective cellular source for transplantation in SCI. These multifaceted protective and restorative effects from hUCB grafts may be interdependent and they act in harmony to promote therapeutic benefits for SCI. Nevertheless, clinical studies with hUCB are still rare because of the concerns about safety and efficiency. Among these concerns, the major histocompatibility in allogeneic transplantation is an important issue to be addressed in future clinical trials for treating SCI.

Irreversible and permanent damage develop immediately adjacent to the region of reduced cerebral blood perfusion in stroke patients. Currently, the proven thrombolytic treatment for stroke, tissue plasminogen activator, is only effective when administered within 3 h after stroke. These disease characteristics should be taken under consideration in developing any therapeutic intervention designed to widen the narrow therapeutic range, especially cell-based therapy. Over the past several years, our group and others have characterized the therapeutic potential of human umbilical cord blood cells for stroke and other neurological disorders using in vitro and vivo models focusing on the cells' ability to differentiate into nonhematopoietic cells including neural lineage, as well as their ability to produce several neurotrophic factors and modulate immune and inflammatory reaction. Rather than the conventional cell replacement mechanism, we advance alternative pathways of graft-mediated brain repair involving neurotrophic effects resulting from release of various growth factors that afford cell survival, angiogenesis, and anti-inflammation. Eventually, these multiple protective and restorative effects from umbilical cord blood cell grafts may be interdependent and act in harmony in promoting therapeutic benefits for stroke.

A 76-year-old man presented with brain stem hemorrhage after burr-hole drainage for bilateral chronic subdural hematomas. Neuroimaging demonstrated resolution of the transtentorial herniation but also detected new brain stem hemorrhage, manifesting as gait disturbance. He recovered after conservative treatment. Asymmetrical and rapid decompression, which leads to vascular disruption and/or sudden increase in cerebral blood flow, was probably responsible for the secondary brain stem hemorrhage. Therefore, simultaneous and bilateral decompression with a slow rate of evacuation of massive bilateral chronic subdural hematomas is recommended to prevent serious complications such as secondary intracranial hematoma.

Objective Understanding the microanatomy of the proximal middle cerebral artery (M1) and its early branches is very important for aneurysm surgery in this region. However, few articles provide detailed descriptions of such aneurysms. We report the angiographic characteristics of a series of M1 aneurysms and our experience with M1 aneurysm surgery. Materials and methods Twenty-three patients with 25 (combined) M1 aneurysms presented to our institution from January 2001 to December 2006. We examined the general characteristics and angiographic features of the M1 aneurysms, such as site, size, direction, and their association with early branches. Results Of the 23 patients with M1 aneurysms, 13 were women and 10 were men. Nineteen of the aneurysms had ruptured prior to presentation. Multiple aneurysms were observed in 10 of the patients. Angiography showed that 14 of the aneurysms were less than 5 mm in size, and most of the aneurysmal projections were superior. Eighteen of the aneurysms involved early frontal branches and three involved the lenticulostriate arteries. Postoperative infarction was seen in eight patients. Five of the eight patients showed either no or slight neurological deficits at the follow-up visit. One patient, however, suffered from hemiparesis and aphasia that corresponded to the vascular territory of the early frontal branches and lenticulostriate arteries. Two patients had a total MCA infarction and a posterior fossa infarction, respectively. Conclusions This study highlights the need for the critical management of M1 aneurysms, taking into consideration the size and number of aneurysms. By performing careful angiographic investigation of the aneurysm and related early arterial branches of M1, postoperative complications may be minimized.

A 13-year-old boy presented with a rare spontaneous spinal chronic subdural hematoma (SCSDH) with no associated trauma or medical problems manifesting as back and bilateral lower extremity pain persisting for 10 days. Neurological examination revealed mild weakness and paresthesia in both lower extremities. Magnetic resonance (MR) imaging performed 1 week after the appearance of symptoms revealed a chronic subdural hematoma at the thoracolumbosacral region. Follow-up MR imaging performed 1 week later showed significant resolution of the hematoma without the need for surgery. The patient was discharged with only conservative management. This case of spontaneous SCSDH with rapid spontaneous remission in a child not associated with coagulopathy indicates that aggressive surgical treatment should be delayed as long as possible in pediatric patients because the spinal structure is still developing.

A 65-year-old woman presented with a thrombosed giant pericallosal artery aneurysm manifesting as headache and memory loss that developed over a 2-year period. Computed tomography (CT), magnetic resonance (MR) imaging, and conventional and CT angiography could not establish the differential diagnosis. Open craniotomy revealed the mass as thrombosed giant aneurysm from the pericallosal artery. Direct clipping with thrombectomy was performed successfully with an uneventful postoperative course. Thrombosed giant aneurysm of the distal anterior cerebral artery should be considered in the differential diagnosis of an unusual mass in the mid-frontal area, particularly in the presence of inconclusive angiographic and MR imaging findings.

We have established several glioma-relevant oncogene-engineered cancer cells to reevaluate the oncogene-selective cytotoxicity of previously well-characterized anticancer drugs, such as etoposide, doxorubicin, staurosporine, and carmustine. Among several glioma-relevant oncogenes (activated epidermal growth factor receptor, Ras, and Akt, as well as Bcl-2 and p53DD used in the present study), the activated epidermal growth factor receptor, Ras, and Akt exerted oncogenic transformation of Ink4a/Arf−/− murine astrocyte cells. We identified that etoposide, a topoisomerase II inhibitor, caused selective killing of myristylated Akt (Akt-myr)–transduced Ink4a/Arf−/− astrocytes and U87MG cells in a dose- and time-dependent manner. Etoposide-selective cytotoxicity in the Akt-myr–transduced cells was shown to be caused by nonapoptotic cell death and occurred in a p53-independent manner. Etoposide caused severe reactive oxygen species (ROS) accumulation preferentially in the Akt-myr–transduced cells, and elevated ROS rendered these cells highly sensitive to cell death. The etoposide-selective cell death of Akt-myr–transduced cells was attenuated by pepstatin A, a lysosomal protease inhibitor. In the present study, we show that etoposide might possess a novel therapeutic activity for oncogenic Akt-transduced cancer cells to kill preferentially through ROS-mediated damage. [Mol Cancer Ther 2007;6(8):2178–87]

Spinal cord injury (SCI) can cause irreversible damage to neural tissues. However, there is currently no effective treatment for SCI. The therapeutic potential of adipose-derived mesenchymal stem cells (ADMSCs) has been emerged.We evaluated the effects and safety of the intrathecal transplantation of autologous ADMSCs in patients with SCI. Participants/Interventions: Fourteen patients with SCI were enrolled (12 for ASIA A, 1 for B, and 1 for D; duration of impairments 3-28 months). Six patients were injured at cervical, 1 at cervico-thoracic, 6 at thoracic, and 1 at lumbar level. Autologous ADMSCs were isolated from lipoaspirates of patients' subcutaneous fat tissue and 9 × 10ASIA motor scores were improved in 5 patients at 8 months follow-up (1-2 grades at some myotomes). Voluntary anal contraction improvement was seen in 2 patients. ASIA sensory score recovery was seen in 10, although degeneration was seen in 1. In somatosensory evoked potential test, one patient showed median nerve improvement. There was no interval change of MRI between baseline and 8 months post-transplantation. Four adverse events were observed in three patients: urinary tract infection, headache, nausea, and vomiting.Over the 8 months of follow-up, intrathecal transplantation of autologous ADMSCs for SCI was free of serious adverse events, and several patients showed mild improvements in neurological function. Patient selection, dosage, and delivery method of ADMSCs should be investigated further.

Genomic instability and apoptosis evasion are hallmarks of cancer, but the molecular mechanisms governing these processes remain elusive. Here, we found that survivin, a member of the apoptosis-inhibiting gene family, and aurora B kinase, a chromosomal passenger protein, were co-overexpressed in the various glioblastoma cell lines and tumors. Notably, exogenous introduction of the aurora B in human BJ cells was shown to decrease cell growth and increase the senescence-associated beta-galactosidase activity by activation of p53 tumor suppressor. However, aurora B overexpression failed to inhibit cell proliferation in BJ and U87MG cells transduced with dominant-negative p53 as well as in p53(-/-) mouse astrocytes. Aurora B was shown to increase centrosome amplification in the p53(-/-) astrocytes. Survivin was shown to induce anchorage-independent growth and inhibit anti-proliferation and drug-sensitive apoptosis caused by aurora B. Overexpression of both survivin and aurora B further accelerated the proliferation of BJ cells. Taken together, the present study indicates that survivin should accelerate tumorigenesis by inhibiting the anti-proliferative effect of p53 tumor suppressor that is activated by aurora B in normal and glioblastoma cells containing intact p53.

A 56-year-old man presented with a meningioma associated with hyperostotic bone containing little tumor cell infiltration. The patient presented with a growing mass on his right forehead and exophthalmos. Computed tomography (CT) taken 4 years previously revealed only hyperostosis without intracranial lesion. Repeat CT revealed an enhanced intracranial mass with overlying diffuse hyperostosis extending extracranially. The tumor and affected bone were widely removed. Histological examination confirmed rhabdoid meningioma in the intracranial and extracranial lesion. However, most of the hyperostotic bone showed no tumor cell infiltration. The cause of hyperostosis associated with meningioma is unclear, but tumor invasion is the generally accepted cause. In this case, hyperostosis occurred without tumor cell infiltration so another mechanism was probably involved. The extracranial extension occurred despite the disproportionately small tumor without global tumor cell infiltration of the bone or bony erosion.

The prognostic factors that contribute to outcome after navigation-assisted drainage in patients with spontaneous intracerebral hemorrhage (ICH) have not been defined. We compared the characteristics and clinical outcomes of patients with spontaneous ICHs who underwent neuronavigation-assisted hematoma drainage.Forty-seven patients were enrolled from January 2004 to August 2013. The patients were divided into two groups according to Glasgow Outcome Scale (GOS) scores: the good- (GOS 4-5) and poor-outcome (GOS 1-3) groups. A variety of factors, characteristics, and clinical outcomes were analyzed.Among the 47 patients, 16 and 31 showed good and poor outcomes, respectively. The mortality rate was 4.3%. Patients' ages, horizontal and vertical diameters and volume of the hematoma on the initial brain computed tomography scan, and the initial Glasgow Coma Scale (GCS) scores were significantly different between the two groups (P0.05). Ages less than 60 years, smaller horizontal and vertical diameters of the hematoma, less initial hematoma volume, higher initial GCS scores, and the absence of intraventricular hemorrhages were significantly associated with good outcome (P0.05). Among these factors, initial hematoma volume was a borderline prognostic factor (odds ratio [OR], 0.951; 95% confidence interval [CI], 0.904-1.001; P=0.054), whereas initial GCS score was a significant prognostic factor (OR, 2.737; 95% CI, 1.371-5.465; P=0.004), in the multivariate analysis.Initial GCS score and hematoma volume were important prognostic factors of clinical outcome in patients with spontaneous ICHs who underwent navigation-assisted drainage. Such factors should be carefully considered before patients are treated with navigation-assisted hematoma drainage.

This case presents a 34-year-old man who had a huge parasagittal meningioma. Initial treatment consisted of preoperative external carotid artery embolization and partial tumor resection. During the resection, we found that the tumor invaded the adjacent calvarium, and due to massive hemorrhage, total removal of the tumor was impossible. The patient was treated with intraoperative radiation therapy (IORT) (25 Gy via 16 MeV) as an adjunctive therapy. Eight months after IORT, we were able to remove the tumor completely without surgical difficulties. IORT can be considered an useful adjunctive therapy for the superficially located, huge, and highly vascular meningioma.

We report the case of a 48-year-old male with iatrogenic arterial cerebral air embolism at the site of a spontaneous pontine hemorrhage. The patient inadvertently received continuous positive pressure ventilation without exhalation for a few minutes, resulting in pneumothorax, interstitial emphysema, pneumoperitoneum, and arterial cerebral air embolism at the site of the intracerebral hemorrhage. This is the first report of pneumocephalus without head trauma or previous surgery in which the air embolism occurs at the site of a spontaneous intracerebral hemorrhage. We hypothesize that air preferentially leaked into the brain parenchyma through the weakened perforating pontine artery that caused the intracerebral bleeding.

Laser-induced autofluorescence measurement of the brain was performed to assess its spectroscopic properties and to distinguish brain tumors from the normal tissues. The excitation-induced emission spectra were plotted on a 2-dimensional map, the excitation-emission matrix, to determine the excitation wavelengths most sensitive for the spectroscopic identification of brain tumors. The excitation-emission matrices of various types of human brain tumors and normal brain samples lead to the selection of three fluorescence peaks at 470, 520, and 630 nm, corresponding excitation light at 360, 440, and 490 nm, respectively for comparing the autofluorescence signatures of brain tissue. The fluorophores most likely related to each of these peaks are NAD(P)H, various flavins, and porphyrins, respectively. In vivo studies of rat gliomas showed that "NAD(P)H", "flavin", and "porphyrin" fluorescence were lower in gliomas than in normal brain. This finding suggests that there are certain relationship between brain tissue autofluorescence intensity and metabolic activity. In vitro human normal brain tissue fluorescence signals were lower in gray matter than in white matter and "NAD(P)H" fluorescence were lower in all measured human brain tumors than in normal brain. "Flavin" and "porphyrin" fluorescence in the neoplastic tissues was lower or higher than normal tissue depending on their nature. In conclusion, the fluorescence spectroscopic diagnostic system might be able to distinguish brain tumors from the normal brain tissue. The results of this study need to be verified and the investigation extended to human brain tumors in the operating room.

Subarachnoid hemorrhage (SAH) is rare in young adults and little is known about aneurysms in this subgroup. The effect of clinical and prognostic factors on the outcome based on the Glasgow Outcome Scale (GOS) scores and the predictors of unfavorable outcomes were analyzed in young adults with aneurysmal SAH. A retrospective review of the clinical parameters, including age, sex, hypertension, smoking status, hyperlipidemia, location of the cerebral aneurysm, size of the aneurysm, multiplicity, perioperative complication such as hydrocephalus, vasospasm, and hematoma, and Hunt and Hess and Fisher grading on presentation, was conducted in 108 young adults (mean age 34.8 years) managed at our institute. The outcome was classified based on GOS grading into unfavorable (GOS scores 1-3) or favorable (GOS scores 4 or 5). The overall mortality rate was 3.7% (4/108 patients). Univariate regression analysis for the outcomes at discharge found that age at the time of presentation, male sex, size of aneurysm, multiple aneurysms, hyperlipidemia, and poor Hunt and Hess and Fischer grades were associated with unfavorable outcome. Multivariate regression analysis found independent effects of sex, multiple aneurysms, size of aneurysm, and Hunt and Hess grade on the outcome at discharge. Size of aneurysm, presence of multiple aneurysms, Hunt and Hess grade, and hypertension were the predictors of outcome at mean 2-year follow up based on multivariate exact regression analysis. The multimodal approach with aggressive medical management, early intervention, and surgical treatment might contribute to favorable long-term outcomes in patients with poor expected outcomes.

Hypothermia and cardiopulmonary bypass has rarely been used for difficult lesions of the brain such as giant aneurysms and hemangioblastoma of the brainstem. We report a case of huge recurrent angioblastic meningioma operated under the profound hypothermia and cardiopulmonary bypass. We reviewed the complications related to hypothermia and cardiopulmonary bypass for brain lesions.

Summary Background We examined the cerebrospinal fluid (CSF) markers of subarachnoid hemorrhage (SAH)-induced and idiopathic normal pressure hydrocephalus (INPH) to investigate the pathophysiology and mechanism of communicating hydrocephalus compared to obstructive hydrocephalus. Material/Methods We obtained CSF samples from 8 INPH, 10 SAH-induced hydrocephalus, and 6 unmatched patients with non-hemorrhagic obstructive hydrocephalus during their ventriculoperitoneal shunt operations. Transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and total tau in the CSF were analyzed via enzyme-linked immunosorbent assay. Results The mean VEGF levels in the CSF of patients with SAH-induced hydrocephalus, INPH, and obstructive hydrocephalus were 239±131, 239±75, and 163±122 pg/mL, respectively. The total tau concentrations in the CSF of the groups were 1139±1900, 325±325, and 1550±2886 pg/mL, respectively. TNF-α values were 114±34, 134±38, and 55±16 pg/mL, respectively. TGF-β1 values were 953±430, 869±447, and 136±63 pg/mL, respectively. A significant difference in TNF-α and TGF-β1 levels was observed only between SAH-induced and chronic obstructive hydrocephalus, and between INPH and chronic obstructive hydrocephalus (p

Dong-Hyuk Park1, Jeong-Hyun Lee2, David J. Eve3, Cesario V. Borlongan3, Paul R. Sanberg3,4, Yong-Gu Chung1 and Tai-Hyoung Cho1 1Department of Neurosurgery, Korea University Medical Center, Korea University College of Medicine, Seoul, 2Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 3Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, 4Office of Research and Innovation, University of South Florida, Tampa, 1,2 Korea 3,4USA

BACKGROUND AND IMPORTANCE: Arachnoid cysts have not been reported to be located within the brain parenchyma. We present a case of an arachnoid cyst that was contained entirely within the right frontal lobe devoid of communication with the subarachnoid space and ventricle. CLINICAL PRESENTATION: A 65-year-old woman presented with a 1-year history of progressive headache and nausea. Computed tomographic and magnetic resonance imagining scans showed a well-defined, nonenhancing mass measuring 5 x 5 x 3.5 cm in the right frontal lobe. The mass appeared to be contained entirely within the brain parenchyma. The patient underwent a right frontal craniotomy, at which time the cystic mass was identified in the brain parenchyma without any communication with the arachnoid space. The cyst contained a clear fluid, and its wall was excised. The fluid contents demonstrated a composition similar to that of normal cerebrospinal fluid. Histological and immunohistochemical examinations of the cyst wall were compatible with the diagnosis of an arachnoid cyst. Postoperatively, the symptoms of the patient resolved, and no recurrence was observed up to 6 months after removal. CONCLUSION: The present case showed an intraparenchymal arachnoid cyst arising in the frontal lobe. Although the etiology is not known, an arachnoid cyst should be included in the differential diagnosis of primary intracerebral cysts.

The annual meeting of the American Society for Neural Therapy and Repair (ASNTR) has always introduced us to top-notch and up-to-date approaches for regenerative medicine related to neuroscience, ranging from stem cell–based therapy to novel drugs. The 16th ASNTR meeting focused on a variety of different topics, including the unknown pathogenesis or mechanisms of specific neurodegenerative diseases, stem cell biology, and development of novel alternative medicines or devices. Newly developed stem cells, such as amniotic epithelial stem cells and induced pluripotent stem cells, as well as well-known traditional stem cells, such as neural, embryonic, bone marrow mesenchymal, and human umbilical cord blood–derived stem cells, were reported. A number of commercialized stem cells were also covered at this meeting. Fetal neural tissues, such as ventral mesencephalon, striatum, and Schwann cells, were investigated for neurodegenerative diseases or spinal cord injury. A number of studies focused on novel methods for drug monitoring or graft tracking, and combination therapy with stem cells and medicine, such as cytokines or trophic factors. Finally, the National Institutes of Health guidelines for human stem cell research, clinical trials of commercialized stem cells without larger animal testing, and prohibition of medical tourism were big controversial issues that led to heated discussion.

We report a case of intracranial dissemination developing approximately 4 months after partial removal of a spinal cord anplastic astrocytoma in a 22-year-old male. He presented with paraplegia on initial admission at a local hospital. Spinal magnetic resonance (MR) images disclosed multiple intramedullary lesions at the T3-11. The tumor was partially removed. The final histologic diagnosis was anaplastic astrocytoma. Four months after the operation, he was admitted with the symptoms of headache and deterioration of consciousness. MR images showed enhanced lesions in the anterior horn of the left lateral ventricle, and septum pellucidum. He underwent computed tomography-guided stereotactic biopsy and histological appearance was consistent with anaplastic astrocytoma. The clinical course indicates that the tumor originated in the spinal cord and extended into the subarachnoid space, first the spinal canal and later intracranial.

Rhino-orbital-cerebral (ROC) mucormycosis is an uncommon, acute and aggressive fungal infection. It remains a challenging problem to clinicians despite aggressive debridement surgery and antifungal therapy. The authors describe a case of ROC mucormycosis with pericranial abscess occurring in a female patient with uncontrolled diabetes mellitus. The infection initially developed in the right-sided nasal sinus and later progressed through the paranasal sinuses with the invasion of the peri-orbital and frontotemporal region, due to the delayed diagnosis and treatment. Numerous non-septate hyphae of the zygomycetes were identified by a punch biopsy from the nasal cavity and by an open biopsy of the involved dura. The patient was treated successfully with extensive debridement of her necrotic skull and surrounding tissues, drainage of her pericranial abscess and antifungal therapy, including intravenous amphotericin B for 61 days and oral posaconazole for the following 26 days. She returned to a normal life and has had no recurrence since the end of her treatment 15 months ago.

A 76-year-old man presented with brain stem hemorrhage after burr-hole drainage for bilateral chronic subdural hematomas. Neuroimaging demonstrated resolution of the transtentorial herniation but also detected new brain stem hemorrhage, manifesting as gait disturbance. He recovered after conservative treatment. Asymmetrical and rapid decompression, which leads to vascular disruption and/or sudden increase in cerebral blood flow, was probably responsible for the secondary brain stem hemorrhage. Therefore, simultaneous and bilateral decompression with a slow rate of evacuation of massive bilateral chronic subdural hematomas is recommended to prevent serious complications such as secondary intracranial hematoma.

Early delayed radiation effects are known to occur within several months after completing radiotherapy for brain tumors. We present marked changes of magnetic resonance imaging (MRI) scan that occurred one month after radiotherapy in a patient with a pleomorphic xanthoastrocytoma, which was eventually diagnosed as an early delayed radiation effect. Such an early development of dramatic MRI change has not been reported in patients treated with radiotherapy for pleomorphic xanthoastrocytomas.

Peritumoral brain edema (PTBE) is associated with perioperative neurological deficits in patients with meningiomas. However, the pathogenesis of meningioma-associated edema remains unclear. In the present study, the authors investigated the expression of interleukin-6 (IL-6) and its relationship with PTBE in resected meningiomas.Thirty-six benign meningiomas obtained in 36 patients were studied retrospectively. Edema volume was assessed on MR images, and an edema index (EI) was calculated. Interleukin-6 mRNA and protein expression were examined by real-time reverse transcriptase polymerase chain reaction and immunohistochemical staining.Peritumoral brain edema was found in 16 patients (44%). Neither age, sex, histological subtype, nor tumor location were related to PTBE. The level of IL-6 mRNA was 7.72 times greater in the edema group (EI0.2) than in the nonedema group (EI0.2; p = 0.011). On immunohistochemical analysis, IL-6 protein was found localized in the cytoplasm of the tumor cells, and was detected in 12 (75%) of 16 cases of edematous meningiomas, but in only 6 (30%) of 20 nonedematous cases. There was a significant correlation between the severity of PTBE and IL-6 expression (p = 0.004).The authors' results in this study indicate that IL-6 expression may contribute to the development of brain edema associated with meningiomas.

To understand the anatomic characteristics of the aortic arch (AA) and its major branches to build a foundation toward performing endovascular surgery safely.A total of 25 formalin fixed Korean adult cadavers were used. The authors investigated : anatomical variations of the AA and its major branches; curvature of the AA; distance from the mid-vertebrae line to the origin of the major branches; distances from the origin of the major branches of AA to the origin of its distal branches; and the angle of the three major branches, the brachiocephalic trunk (BCT), the left common carotid artery (LCCA) and the left subclavian artery (LSCA) arising from AA.The three major branches directly originated from AA in 21 (84%) of the cadavers. In two (8%) of remaining four cadavers, orifice of LCCA was slightly above the stem of BCT. In remaining two (8%) cadavers, the left vertebral artery (LVA) was directly originated from AA. Average angle of AA curvature to the coronal plane was 62.2 degrees. BCT originated 0.92 mm on the right of the mid-vertebrae line. LCCA and LSCA originated from 12.3 mm and 22.8 mm on the left of the mid-vertebrae line. Mean distance from the origin of the BCT to the origin of the RCCA was 32.5 mm. Mean distance from the origin of the LSCA to the origin of the LVA was 33.8 mm. Average angles at which the major branches arise from the AA were 65.3, 46.9 and 63.8 degrees.This study may provides a basic anatomical information to catheterize AA and its branches for safely performing endovascular surgery.

A 13-year-old boy presented with a rare spontaneous spinal chronic subdural hematoma (SCSDH) with no associated trauma or medical problems manifesting as back and bilateral lower extremity pain persisting for 10 days. Neurological examination revealed mild weakness and paresthesia in both lower extremities. Magnetic resonance (MR) imaging performed 1 week after the appearance of symptoms revealed a chronic subdural hematoma at the thoracolumbosacral region. Follow-up MR imaging performed 1 week later showed significant resolution of the hematoma without the need for surgery. The patient was discharged with only conservative management. This case of spontaneous SCSDH with rapid spontaneous remission in a child not associated with coagulopathy indicates that aggressive surgical treatment should be delayed as long as possible in pediatric patients because the spinal structure is still developing.

Olfactory neuroblastoma is extremely rare as a second neoplasm. We report an unusual case of olfactory neuroblastoma in a 59-year-old woman who had undergone two operations and received 54 Gy of irradiation for pituitary adenoma 20 years ago. At the time of admission, the patient presented with nasal obstruction and frequent epistaxis. Imaging studies showed a large mass in the nasal cavities and ethmoid sinus, extending to the intracranial area, with no evidence of any recurrence of the previous pituitary adenoma. The tumor was completely excised via a trans-cranial and trans-nasal approach. A diagnosis of olfactory neuroblastoma was established, and the patient was given postoperative chemotherapy. Although relatively uncommon, second neoplasms are an important consideration in the differential diagnosis of patients with new or recurring symptoms after treatment for pituitary adenoma. Furthermore, it is likely that radiation played a critical role in the development of olfactory neuroblastoma in our patient.