Nobutaka Kawahara

Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss

Telomere lengthening is one of the key events in most cancers, and depends largely on telomerase activation. Telomerase activation is a well-known phenomenon in gliomas; however, its mechanism remains obscure. In this study, we investigated the presence of mutations in the promoter of the telomerase reverse transcriptase (TERT) gene in a series of 546 gliomas. We found a high incidence of mutually exclusive mutations located at two hot spots, C228T and C250T, in all subtypes of gliomas (55xa0%). The frequency of mutation was particularly high among primary glioblastomas (70xa0%) and pure oligodendroglial tumors (74xa0%), while relatively low in diffuse astrocytomas and anaplastic astrocytomas (19 and 25xa0%, respectively). The expression level of TERT in tumors carrying those mutations was on average 6.1 times higher than that of wild-type tumors, indicating that the mutated promoter leads to upregulation of TERT. TERT promoter mutations were observed in almost all tumors harboring concurrent total 1p19q loss and IDH1/2 mutations (98xa0%). Otherwise TERT promoter mutations were mostly observed among IDH wild-type tumors. Most EGFR amplifications (92xa0%) were also associated with TERT promoter mutations. Our data indicate that mutation of the TERT promoter is one of the major mechanisms of telomerase activation in gliomas. The unique pattern of TERT promoter mutations in relation to other genetic alterations suggests that they play distinct roles in the pathogenesis of oligodendroglial and astrocytic tumors. Our results shed a new light on the role of telomerase activation in the development of adult gliomas.

Stem cell therapy for cerebral ischemia: from basic science to clinical applications

Recent stem cell technology provides a strong therapeutic potential not only for acute ischemic stroke but also for chronic progressive neurodegenerative diseases such as Alzheimers disease, Parkinsons disease, and amyotrophic lateral sclerosis with neuroregenerative neural cell replenishment and replacement. In addition to resident neural stem cell activation in the brain by neurotrophic factors, bone marrow stem cells (BMSCs) can be mobilized by granulocyte-colony stimulating factor for homing into the brain for both neurorepair and neuroregeneration in acute stroke and neurodegenerative diseases in both basic science and clinical settings. Exogenous stem cell transplantation is also emerging into a clinical scene from bench side experiments. Early clinical trials of intravenous transplantation of autologous BMSCs are showing safe and effective results in stroke patients. Further basic sciences of stem cell therapy on a neurovascular unit and neuroregeneration, and further clinical advancements on scaffold technology for supporting stem cells and stem cell tracking technology such as magnetic resonance imaging, single photon emission tomography or optical imaging with near-infrared could allow stem cell therapy to be applied in daily clinical applications in the near future.

Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas

Primary central nervous system lymphoma (PCNSL) manifest aggressive clinical behaviour and have poor prognosis. Although constitutive activation of the nuclear factor‐κB (NF‐κB) pathway has been documented, knowledge about the genetic alterations leading to the impairment of the NF‐κB pathway in PCNSLs is still limited. This study was aimed to unravel the underlying genetic profiles of PCNSL.

A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas

The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients’ treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, nu2009=u2009758; Cohort 2, nu2009=u2009193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (Pu2009<u20090.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (Pu2009=u20090.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type-MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas.

Localized role of CRMP1 and CRMP2 in neurite outgrowth and growth cone steering

Collapsin response mediator protein 1 (CRMP1) and CRMP2 have been known as mediators of extracellular guidance cues such as semaphorin 3A and contribute to cytoskeletal reorganization in the axonal pathfinding process. To date, how CRMP1 and CRMP2 focally regulate axonal pathfinding in the growth cone has not been elucidated. To delineate the local functions of these CRMPs, we carried out microscale‐chromophore‐assisted light inactivation (micro‐CALI), which enables investigation of localized molecular functions with highly spatial and temporal resolutions. Inactivation of either CRMP1 or CRMP2 in the neurite shaft led to arrested neurite outgrowth. Micro‐CALI of CRMP2 in the central domain of the growth cones consistently arrested neurite outgrowth, whereas micro‐CALI of CRMP1 in the same region caused significant lamellipodial retraction, followed by retardation of neurite outgrowth. Focal inactivation of CRMP1 in its half region of the growth cone resulted in the growth cone turning away from the irradiated site. Conversely, focal inactivation of CRMP2 resulted in the growth cone turning toward the irradiated site. These findings suggest different functions for CRMP1 and CRMP2 in growth cone behavior and neurite outgrowth.

Is the nerve origin of the vestibular schwannoma correlated with vestibular evoked myogenic potential, caloric test, and auditory brainstem response?

Conclusions. The results of the caloric test, vestibular evoked myogenic potential (VEMP), and auditory brainstem response (ABR) in patients with vestibular schwannoma (VS) did not show clear correlation with the nerve origin of the tumor but with tumor size. When we focused on patients with VS within the internal acoustic canal (IAC), neither the nerve origin of the tumor nor the tumor size showed clear correlation with the results of these tests. Objectives. This study examined the correlation of the nerve origin of VS, superior or inferior vestibular nerve, with the results of function tests. Subjects and methods. Subjects comprised 109 consecutive patients diagnosed as having unilateral VS. Each test was performed before surgery. Tumor size was measured with preoperative MRI. Results. The nerve origin of the tumor was identified in 63 of the 109 patients. The percentage of patients showing abnormal responses in each test was not different between 37 patients with superior VS and 26 patients with inferior VS. Also, no difference was observed for patients with VS within the IAC. Mean tumor size in patients showing abnormal responses was larger than that in patients showing normal responses on each test. However, this tendency was not observed for patients with VS within the IAC.

Angiographic Classification of Tumor Attachment of Meningiomas at the Cerebellopontine Angle

OBJECTIVEnTo present an angiographic classification of attachment of meningiomas at the cerebellopontine angle (CPA) based on tumor feeding and to validate the utility of this classification in predicting meningioma attachments at the CPA.nnnMETHODSnThe authors retrospectively analyzed 34 consecutive patients with meningioma at the CPA. Based on operative findings, tumors were classified into four types: the petroclival type, in which the trigeminal nerve is displaced laterally; the tentorial type, in which the center of tumor attachment is located at the medial tentorium; the anterior petrous type, in which the center of tumor attachment is located anterior to the meatus; and the posterior petrous type, in which the center of tumor attachment is located posterior to the meatus. Magnetic resonance imaging (MRI) was sufficient to confirm attachment of the posterior petrous type. Another 26 cases were analyzed angiographically and classified into three types: abnormal ipsilateral tentorial artery type (type A); bilateral internal carotid artery (ICA) type (type B); and nontentorial, non-ICA type (type N). This angiographic classification was validated by comparison with the attachment classification.nnnRESULTSnAngiographic types A, B, and N corresponded to tentorial, petroclival, and anterior petrous types of attachment. Observed agreement was very high, particularly for tumors greater than 30 mm in diameter (κ statistic 0.83; 95% confidence interval [CI] 0.62-1.0). Angiographic type in this paired attachment typing offered high sensitivity and specificity greater than 0.80 in tumors larger than 30 mm.nnnCONCLUSIONSnThis angiographic classification seems to be useful in predicting meningioma attachments at the CPA. The existence of an abnormally developed tentorial artery seems highly indicative of tumor attachment to the tentorium.

Tumor hypoxia and microscopic diffusion capacity in brain tumors: A comparison of 62 Cu-Diacetyl-Bis (N4-Methylthiosemicarbazone) PET/CT and diffusion-weighted MR imaging

ObjectivesThe aim of this study was to clarify the relationship between tumor hypoxia and microscopic diffusion capacity in primary brain tumors using 62Cu-Diacetyl-Bis (N4-Methylthiosemicarbazone) (62Cu-ATSM) PET/CT and diffusion-weighted MR imaging (DWI).MethodsThis study was approved by the institutional human research committee and was HIPAA compliant, and informed consent was obtained from all patients. 62Cu-ATSM PET/CT and DWI were performed in a total of 40 primary brain tumors of 34 patients with low grade glioma (LGG, nu2009=u200913), glioblastoma (GBM, nu2009=u200920), and primary central nervous system lymphoma (PCNSL, nu2009=u20097). 62Cu-ATSM PET/CT parameters and apparent diffusion coefficient (ADC) obtained by DWI were compared.ResultsHigh intensity signals by 62Cu-ATSM PET/CT and DWI in patients with GBM and PCNSL, and low intensity signals in LGG patients were observed. An inverse correlation was found between maximum SUV (SUVmax) and minimum ADC (ADCmin) (ru2009=u2009−0.583, pu2009<u20090.0001), and between tumor/brain ratio (T/Bratio) and ADCmin for all tumors (ru2009=u2009−0.532, pu2009<u20090.0001). Both SUVmax and T/Bratio in GBM were higher than LGG (pu2009<u20090.0001 and pu2009<u20090.0001), and those in PCNSL were also higher than GBM (pu2009=u20090.033 and pu2009=u20090.044). The ADCmin was lower in GBM (pu2009=u20090.011) and PCNSL (pu2009=u20090.01) than in LGG, while no significant difference was found between GBM and PCNSL (pu2009=u20090.90).ConclusionTumor hypoxia assessed by 62Cu-ATSM PET/CT correlated with microscopic diffusion capacity obtained by DWI in brain tumors. Both 62Cu-ATSM PET/CT and DWI were considered feasible imaging methods for grading glioma. However, 62Cu-ATSM PET/CT provided additional diagnostic information to differentiate between GBM and PCNSL.

Occipitocervical fusion with relief of odontoid invagination: atlantoaxial distraction method using cylindrical titanium cage for basilar invagination—case report

A 65-year-old woman presented with basilar invagination manifesting as neck pain, dysesthesia around the lips, and truncal ataxia. The radiological findings demonstrated invagination of the odontoid process into the medulla oblongata and vertical atlantoaxial subluxation with C1 assimilation. The clivo-axial angle was 88° and the cervicomedullary angle was 115°, indicating severe basilar invagination. We planned occipitocervical fusion with atlantoaxial distraction using a cylindrical titanium cage. C2 pedicle screws were inserted, and the atlantoaxial joint was opened to translocate the odontoid process downward. A cylindrical titanium cage packed with local bone graft was inserted into the opened facet joint space. Occipital-C2 fusion was completed by fastening the occipital bone plates with pedicle screws using titanium rods. Postoperatively, the apex of the odontoid process descended by 7xa0mm, and the clivo-axial and cervicomedullary angles opened to 112° and 125°, respectively. Invagination of the odontoid process into the medulla oblongata was relieved. The preoperative symptoms improved, and she remained symptom-free without requiring anterior decompression over 2xa0years. Bone fusion of the atlantoaxial joints was completed with sustained facet distraction 12xa0months after the surgery, and adequate relief of the basilar invagination was maintained. The atlantoaxial distraction method using a cylindrical titanium cage can be a useful option in posterior fusion surgery for basilar invagination.

Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy

Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS. The results showed that mutually exclusive mutations of genes involved in the MAPK pathway were most common (48.4xa0%), typically in KIT (27.4xa0%), followed by those in the PI3K pathway (12.9xa0%), particularly in MTOR (6.5xa0%), among the 124 CNS GCTs. Pure germinomas and non-germinomatous germ cell tumors (NGGCTs), as well as CNS and testicular GCTs, showed similar mutational profiles, suggesting that GCTs share a common molecular pathogenesis. Mutated MTOR identified in CNS GCTs upregulated phosphorylation of the AKT pathway proteins including AKT and 4EBP1 in nutrient-deprived conditions and enhanced soft-agar colony formation; both events were suppressed in a dose-dependent manner by addition of the MTOR inhibitor pp242. Our findings indicate that the dominant genetic drivers of GCTs regardless of the site of origin are activation of the MAPK and/or PI3K pathways by somatic point mutations. Mutated MTOR represents a potential target for novel targeted therapies for refractory GCTs.