Genetic and Lineage Classification of Glioma-Initiating Cells Identifies a Clinically Relevant Glioblastoma Model.

The Cancer Genome Atlas (TCGA) project described a robust gene expression-based molecular classification of glioblastoma (GBM), but the functional and biological significance of the subclasses has not been determined. The present comprehensive analysis of 25 glioma-initiating cell (GIC) lines classifies GIC lines into four subtypes (classical, mesenchymal, proneural, and neural) that are closely related to the TCGA GBM subclasses and display distinct lineage characteristics and differentiation behavior that recapitulate neural development. More importantly, the GIC subtypes exhibit distinct biological phenotypes in relation to self-renewal capacity, proliferation, invasiveness, and angiogenic potential in vitro and in vivo. In addition, the GIC subtypes exhibit divergent patterns of signaling pathway activation and deactivation of the Wnt, Notch, and TGF-ß pathways. These results will improve drug discovery targeting certain genetic mutation in glioblastoma and improve the development of precision medicine.

The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma.

The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with γ-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH activity. Here we report loss of PTEN function as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of oncogene addiction from the NOTCH pathway to the PI3K pathway. Drug cytotoxicity testing of eight GICs showed a differential growth response to GSI, and the GICs were thus stratified into two groups: sensitive and resistant. In the sensitive group, GICs with loss of PTEN function appeared less sensitive to GSI treatment. Here we show that NOTCH regulates PTEN expression and the activity of the PI3K pathway in GICs, as treatment with GSI attenuated the NOTCH pathway and increased PTEN expression. NOTCH regulates PTEN expression via Hes-1, as knockdown of Notch or Hes1 increased expression of PTEN. This novel observation suggests that both pathways must be simultaneously inhibited in order to improve therapeutic efficacy in human glioblastomas (GBMs).

Investigation and treatment of pulmonary embolism as a potential etiology may be important to improve post-resuscitation prognosis in non-shockable out-of-hospital cardiopulmonary arrest: report on an analysis of the SOS-KANTO 2012 study.

Background: The prognosis of non-shockable out-of-hospital cardiac arrest is worse than that of shockable out-of-hospital cardiac arrest. We investigated the associations between the etiology and prognosis of non-shockable out-of-hospital cardiac arrest patients who experienced the return of spontaneous circulation after arriving at hospital. Methods and Results: All subjects were extracted from the SOS-KANTO 2012 study population. The subjects were 3,031 adults: (i) who had suffered out-of-hospital cardiac arrest, (ii) for whom there were no pre-hospital data on ventricular fibrillation/pulseless ventricular tachycardia until arrival at hospital, (iii) who experienced the return of spontaneous circulation after arriving at hospital. We compared the patients' prognosis after 1 and 3 months between various etiological and presumed cardiac factors. The proportion of the favorable brain function patients that developed pulmonary embolism or incidental hypothermia was significantly higher than that of the patients with presumed cardiac factors (1 month, P < 0.0001 and P < 0.0001, respectively; 3 months, P = 0.0018 and P < 0.0001, respectively). In multiple logistic regression analysis, pulmonary embolism and incidental hypothermia were found to be significant independent prognostic factors for 1- and 3-month survival and the favorable brain function rate. Conclusions: In patients who suffer non-shockable out-of-hospital cardiac arrest, but who experience the return of spontaneous circulation after arriving at hospital, the investigation and treatment of pulmonary embolism as a potential etiology may be important for improving post-resuscitation prognosis.

Effect of Notch expression in glioma stem cells on therapeutic response to chemo-radiotherapy in recurrent glioblastoma.

Glioma stem cells (GSCs) have the capacity to repopulate tumors and mediate resistance to radiotherapy and chemotherapy. The Notch signaling pathway is important in proliferation, stem cell maintenance, cell differentiation, and tumorigenesis in GSCs. In this study, we compared CD133, Notch, and VEGF expressions in histological sections of primary and recurrent glioblastomas after radiotherapy and chemotherapy. In vitro study, the γ-secretase inhibitor inhibited NICD, Hes1 and pVEGFR2 expressions in GSCs. GSCs cultured under endothelial conditions undergo endothelial differentiation. Tumor samples were collected from 27 patients at the time of tumor recurrence. We used immunohistochemical techniques to compare expression of CD133, Notch-1 and VEGF. Expressions of CD133-, Notch-1-, and VEGF-positive glioma cells were higher in recurrent glioblastoma after radiotherapy and chemotherapy. To determine the clinical importance of Notch-1 expression in glioblastoma, we analyzed 15 patients who had received bevacizumab therapy followed by a second surgery at recurrence. OS was significantly longer in cases with Notch-1 negativity (8.8 months) than in those with I Notch-1 positivity (6.8 months). We noted that GSCs have the potential for endothelial differentiation with Notch activity. We believe that Notch-1 is a potential target and/or biomarker for antiangiogenic treatments.

Treatment of moyamoya syndrome associated with systemic lupus erythematosus and hypothyroidism in an adult by encephaloduroarteriosynangiosis: a case report.

A 54-year-old woman presented to our hospital with progressive motor weakness of the right arm. She had a medical history of systemic lupus erythematosus (SLE) and hypothyroidism. Magnetic resonance imaging indicated a watershed infarction of the left hemisphere. Cervical echogram indicated severe stenosis of the internal carotid artery (ICA) without wall thickening. Cerebral angiography indicated left ICA occlusion, development of unilateral moyamoya vessels, and leptomeningeal anastomosis. Encephaloduroarteriosynangiosis (EDAS) was performed after cerebral (99) (m)Technetium-ethyl-cysteinate-dimer single-photon emission computed tomography indicated a decreased cerebral blood flow, diminished cerebrovascular perfusion reserve. Motor weakness finally disappeared 6 months after surgery. Moyamoya syndrome is a rare complication of both SLE and hypothyroidism, and the surgical indication remains controversial. By evaluating the decreased cerebral perfusion reserve capacity and the existence of leptomeningeal anastomosis, EDAS could be an efficient method for the treatment of moyamoya syndrome associated with SLE and hypothyroidism.

Posttraumatic cranial cystic fibrous dysplasia.

A 14-year-old was girl admitted to our hospital with a subcutaneous mass of the occipital head. The mass had grown for 6 years, after she had sustained a head injury at the age of 6, and was located directly under a previous wound. Skull X-ray Photograph (xp), computed tomography (CT), and magnetic resonance imaging (MRI) showed a bony defect and cystic changes in the skull corresponding to a subcutaneous mass. Bone scintigraphy revealed partial accumulation. The patient underwent total removal of the skull mass, and the diagnosis from the pathological findings of the cyst wall was fibrous dysplasia (FD). The radiographic findings for cystic cranial FD can be various. Progressive skull disease has been reported to be associated with head trauma, but the relationship between cranial FD and head trauma has not been previously reported. Previous studies have suggested that c-fos gene expression is a key mechanism in injury-induced FD.

Linezolid treatment for intracranial abscesses caused by methicillin-resistant Staphylococcus aureus--two case reports.

Two patients were treated for intracranial infections involving methicillin-resistant Staphylococcus aureus (MRSA). A 30-year-old woman was admitted to our hospital for intracerebral hemorrhage related to arteriovenous malformation. After decompressive craniectomy, the patient developed an epidural abscess. MRSA was isolated from the pus culture. The infection did not improve after intravenous vancomycin (VCM) administration for 15 days. However, after administration of linezolid (LZD) for 14 days, the infection had improved, and the white blood cell count and C-reactive protein values had normalized. A 53-year-old woman had previously undergone 3 operations for craniopharyngioma before the age of 35 years. She was admitted to our hospital with fever and disturbance of consciousness. Magnetic resonance imaging with contrast medium revealed a brain abscess caused by MRSA. After 14 days of intravenous administration of VCM, the infection had not improved and intravenous administration of LZD was initiated. After administration of LZD for 14 days intravenously and 14 days orally, the infection had improved, and the white blood cell count and C-reactive protein values had normalized. VCM is highly effective against MRSA infection, but penetration into the central nervous system (CNS) is poor. LZD has good CNS penetration, so should be considered for secondline antibiotic therapy for VCM-resistant intracranial MRSA infection.

[A case of encapsulated intracerebral hematoma mimicking metastatic brain tumor].

We report a case of encapsulated intracranial hematoma (EIH) mimicking metastatic brain tumor. A 77-year-old male with a medical history of prostate cancer was admitted to our hospital presenting with progressive left hemiparesis. Previous head CT scan and MRI findings during 3 weeks before admission revealed a subcortical acute to subacute hematoma under the right precentral gyrus with growing perifocal brainedema. The Head DSA showed tumor-stain with vascular compression corresponding to the hemorrhagic mass, and Tl-201 SPECT study revealed high L/N ratio (3.0) and high L/E ratio (0.8). The preoperative diagnosis was metastatic brain tumor originating from prostate cancer, and total removal of the mass was undergone with the postoperative diagnosis of EIH. Neither tumoral component nor vascular malformation was found even by detailed pathological study. EIH is a rare variant of intracranial hemorrhage and most of cases in past reports are preoperatively misdiagnosed as malignant brain tumor. In our case, even Tl-201 SPECT and DSA, which are reported as key studies for distinguishing EIH from other brain tumors, demonstrated brain tumor-like findings. It is necessary to consider the possibility of EIH when we encounter hemorrhagic mass in the brain parenchyma even with brain tumor-like radiographical images.