Ryosuke Ogura

Accumulation of 2-hydroxyglutarate in gliomas correlates with survival: a study by 3.0-tesla magnetic resonance spectroscopy

IntroductionPrevious magnetic resonance spectroscopy (MRS) and mass spectroscopy studies have shown accumulation of 2-hydroxyglutarate (2HG) in mutant isocitrate dehydrogenase (IDH) gliomas. IDH mutation is known to be a powerful positive prognostic marker in malignant gliomas. Hence, 2HG accumulation in gliomas was assumed to be a positive prognostic factor in gliomas, but this has not yet been proven. Here, we analyzed 52 patients harboring World Health Organization (WHO) grade II and III gliomas utilizing 3.0-tesla MRS.ResultsMutant IDH gliomas showed significantly higher accumulation of 2HG (median 5.077 vs. 0.000, p =0.0002, Mann-Whitney test). 2HG was detectable in all mutant IDH gliomas, whereas in 10 out of 27 (37.0%) wild-type IDH gliomas, 2HG was below the detectable range (2HG =0) (p =0.0003, chi-squared test). Screening for IDH mutation by 2HG analysis was highly sensitive (cutoff 2HG =1.489 mM, sensitivity 100.0%, specificity 72.2%). Gliomas with high 2HG accumulation had better overall survival than gliomas with low 2HG accumulation (p =0.0401, Kaplan-Meier analysis).Discussion2HG accumulation detected by 3.0-tesla MRS not only correlates well with IDH status, but also positively correlates with survival in WHO grade II and III gliomas.

Immunohistochemical profiles of IDH1, MGMT and P53: Practical significance for prognostication of patients with diffuse gliomas

Genetic and epigenetic status, including mutations of isocitrate dehydrogenase (IDH) and TP53 and methylation of O6‐methylguanine‐DNA methyltransferase (MGMT), are associated with the development of various types of glioma and are useful for prognostication. Here, using routinely available histology sections from 312 patients with diffuse gliomas, we performed immunohistochemistry using antibodies specific for IDH1 mutation, MGMT methylation status, and aberrant p53 expression to evaluate the possible prognostic significance of these features. With regard to overall survival (OS), univariate analysis indicated that an IDH1‐positive profile in patients with glioblastoma (GBM), anaplastic astrocytoma (AA), anaplastic oligoastrocytoma and oligodendroglioma, or a MGMT‐negative profile in patients with GBM and AA were significantly associated with a favorable outcome. Multivariate analysis revealed that both profiles were independent factors influencing prognosis. The OS of patients with IDH1‐positive/MGMT‐negative profiles was significantly longer than that of patients with negative/negative and negative/positive profiles. A p53 profile was not an independent prognostic factor. However, for GBM/AA patients with IDH1‐negative/MGMT‐negative profiles, p53 overexpression was significantly associated with an unfavorable outcome. Thus, the immunohistochemical profiles of IDH1 and MGMT are of considerable significance in gliomas, and a combination of IDH1, MGMT and p53 profiles may be useful for prognostication of GBM/AA.

Epstein‐Barr virus‐associated primary central nervous system cytotoxic T‐cell lymphoma

Primary central nervous system lymphoma (PCNSL) expressing T‐cell markers is rare, among which nasal‐type extranodal NK/T‐cell lymphoma is an extremely rare subtype associated with Epstein‐Barr virus (EBV) infection. Here we report the clinicopathologic features of a case of EBV‐associated PCNSL showing a cytotoxic T‐cell phenotype. The patient, a 73‐year‐old woman, presented with rapidly progressive mental deterioration. Brain MRI revealed multiple lesions with swelling in the bilateral cerebral hemispheres, which were hypointense on T1‐weighted images, hyperintense on T2‐weighted and fluid‐attenuated inversion recovery images, and slightly hyperintense on diffusion‐weighted images. Biopsy specimens from the temporal region showed many medium‐sized anaplastic lymphocytic cells with perivascular and angio‐invasive patterns in the cortex. Immunohistochemically, the cells were positive for CD3, CD8, T‐cell‐restricted intracellular antigen‐1 (TIA‐1), granzyme B and perforin, but negative for CD56 and CD20. In situ hybridization revealed EBV‐encoded RNAs in the tumor cell nuclei. A rearrangement study showed T‐cell receptor γ–chain gene rearrangement with a clonal appearance. The patient died 6 months after surgery, and a general autopsy revealed no lymphoma cells outside the brain. These cellular profiles are inconsistent with those of extranodal NK/T‐cell lymphoma, and have not been previously described. This case appears to represent an unusual CNS manifestation of EBV‐associated T‐cell lymphoma.

Advantages of Dose-dense Methotrexate Protocol for Primary Central Nervous System Lymphoma: Comparison of Two Different Protocols at a Single Institution

The efficacy and toxicity of high-dose methotrexate (HD-MTX)-based chemotherapy were retrospectively reviewed in patients with primary central nervous system lymphoma (PCNSL). All immunocompetent patients with histologically or radiographically diagnosed PCNSL treated between 2006 and 2012 at Niigata University Hospital were enrolled. Thirty-eight patients with a diagnosis of PCNSL were treated with one of two regimens during different time periods. During the first period, from 2006 to 2009, three 3-week cycles of MPV (MTX + procarbazine + vincristine) were administered (MPV3 group). In the second period, from 2010 to 2012, five 2-week cycles of MTX were administered (MTX5 group). High-dose cytarabine was used in both groups following HD-MTX-based chemotherapy. Whole-brain radiotherapy was used for patients who did not attain a complete response (CR) based on magnetic resonance images. In the MPV3 group, 20 out of 23 patients (87%) completed the planned treatment. The CR rate after chemotherapy was 30%, and 57% after radiation therapy. Thirteen out of 15 patients (87%) in the MTX5 group completed the planned treatment. The CR rates after chemotherapy and radiation therapy were 53% and 93%, respectively. Renal dysfunction was assessed by measuring creatinine clearance rates, which were very similar in both groups. In terms of hematologic toxicity and other adverse reactions, there was no significant difference between the two groups. In conclusion, dose-dense MTX chemotherapy improved outcome with acceptable toxicity compared with the treatment schedule for three cycles of MPV treatment.

Malignant peripheral nerve sheath tumor of the trigeminal nerve: Clinicopathologic features in a young adult patient

Malignant peripheral nerve sheath tumors (MPNSTs) arising from cranial nerves are rare and usually affect adults. Here we report the clinicopathologic features of a young adult patient with a trigeminal nerve MPNST, in whom another tumor involving the oculomotor nerve on the contralateral side was evident. The patient, an 18‐year‐old woman, had suffered recurrent paroxysmal sharp stabbing pain over her cheek and forehead on the right side for 1 month. A brain MRI study disclosed a mass, 35 mm in diameter, in the right Meckels cave, and another mass, 10 mm in diameter, involving the intracranial portion of the left oculomotor nerve. Following gadolinium administration, the former and latter tumors exhibited strong and weak enhancement, respectively. The patient had no clinical stigmata characteristic of neurofibromatosis type 1. Following a tentative diagnosis of schwannoma, total resection of the trigeminal nerve tumor was performed. Histologically, the tumor consisted of highly cellular, spindle‐shaped cells arranged in a fascicular pattern, with occasional mitotic figures, nuclear pleomorphism and necrosis. Immunohistochemically, the tumor cells showed variable intensities and frequencies of reactivity for S‐100 protein, myelin basic protein, CD34, podoplanin and p53, but no reactivity for Smarcb1. Thus, the tumor exhibited features of MPNST. This case appears to provide information that is useful for accurate diagnosis and surgical planning in patients with bilateral or multiple cranial nerve tumors.

Neuronal differentiation associated with Gli3 expression predicts favorable outcome for patients with medulloblastoma

Medulloblastoma (MB) is a malignant cerebellar tumor arising in children, and its ontogenesis is regulated by Sonic Hedgehog (Shh) signaling. No data are available regarding the correlation between expression of Gli3, a protein lying downstream of Shh, and neuronal differentiation of MB cells, or the prognostic significance of these features. We re‐evaluated the histopathological features of surgical specimens of MB taken from 32 patients, and defined 15 of them as MB with neuronal differentiation (ND), three as MB with both glial and neuronal differentiation (GD), and 14 as differentiation‐free (DF) MB. Gli3‐immunoreactivity (IR) was evident as a clear circular stain outlining the nuclei of the tumor cells. The difference in the frequency of IR between the ND+GD (94.4%) and DF (0%) groups was significant (P < 0.001). The tumor cells with ND showed IR for both Gli3 and neuronal nuclei. Ultrastructurally, Gli3‐IR was observed at the nuclear membrane. The overall survival and event‐free survival rates of the patients in the ND group were significantly higher than those in the other groups. The expression profile of Gli3 is of considerable significance, and the association of ND with this feature may be prognostically favorable in patients with MB.

Entrapment of the inferior horns of the lateral ventricle with enlargement of the bilateral choroid plexus.

The patient, a 61-year-old woman, was admitted to a hospital because of a 2-month history of personality alteration, memory disturbance and disorientation. A serological examination revealed a normal CRP value and a normal WBC count, with no detectable antibodies against hepatitis B virus (HBV), HCV or HIV. The CSF showed an increased cell count of 52/μL with predominance of lymphocytes, 547 mg/dL protein, 37 mg/dL glucose and 6397 ng/mL β2 microglobulin. A brain MRI study revealed marked dilatation of the inferior horns of the lateral ventricle on both sides, and enlargement of the bilateral choroid plexus with marked gadolinium enhancement (Fig. 1). A whole-body CT scan disclosed no mass lesions anywhere in the body or visceral organs, and there was no evidence of lymphadenopathy or infectious lesions. The patient had no family history of neurological disorders nor any evidence of contact with bird droppings and never owned any pets. Following a tentative diagnosis of choroid plexus tumor, an endoscopic biopsy of the bilateral masses was performed for histopathological diagnosis. The bilateral choroid plexus observed through the endoscope window was markedly enlarged, constituting a solid, whitish mass (Fig. 2).

Cortico-cortical activity between the primary and supplementary motor cortex: An intraoperative near-infrared spectroscopy study.

Background: The supplementary motor area (SMA) makes multiple reciprocal connections to many areas of the cerebral cortices, such as the primary motor cortex (PMC), anterior cingulate cortex, and various regions in the parietal somatosensory cortex. In patients with SMA seizures, epileptic discharges from the SMA rapidly propagate to the PMC. We sought to determine whether near-infrared spectroscopy (NIRS) is able to intraoperatively display hemodynamic changes in epileptic network activities between the SMA and the PMC. Case Descriptions: In a 60-year-old male with SMA seizures, we intraoperatively delivered a 500 Hz, 5-train stimulation to the medial cortical surface and measured the resulting hemodynamic changes in the PMC by calculating the oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR) concentration changes during stimulation. No hemodynamic changes in the lateral cortex were observed during stimulation of the medial surface corresponding to the foot motor areas. In contrast, both HbO2 and HbR increased in the lateral cortex corresponding to the hand motor areas when the seizure onset zone was stimulated. In the premotor cortex and the lateral cortex corresponding to the trunk motor areas, hemodynamic changes showed a pattern of increased HbO2 with decreased HbR. Conclusions: This is the first reported study using intraoperative NIRS to characterize the epileptic network activities between the SMA and PMC. Our intraoperative NIRS procedure may thus be useful in monitoring the activities of cortico-cortical neural pathways such as the language system.

“Gliomatosis encephali” as a novel category of brain tumors by the first autopsy case report of gliomatosis cerebelli

Gliomatosis cerebri is a rare diffuse glioma that is neither mass‐forming nor necrotic, and does not disrupt existing structures. Gliomatosis occurring in the cerebellum is known as gliomatosis cerebelli, and only three such cases examined by biopsy have been reported. Here we describe the first autopsy findings of a patient who was diagnosed as having gliomatosis in the cerebellum. Neuropathological examination identified the tumor cells as being positive for glial fibrillary acidic protein, vimentin and nestin, with atypical nuclei that were cashew‐nut‐ or dishcloth‐gourd‐shaped. These tumor cells were dense in the right cerebellum, but also spread broadly throughout the brain including the left cerebrum and optic nerve. Mitotic figures were frequently seen in the cerebellum, brain stem and cerebrum. Scherers secondary structures were evident not only in the cerebellum but also the cerebrum. No necrosis, microvascular proliferation or destruction of anatomical structures was detected in the whole brain. Differences in the origin of the tumors of the gliomatoses cerbri and cerebelli suggests these tumors are different types of brain tumors. Thus the findings support that the gliomatosis cerebelli is a novel type of brain tumor classification. Furthermore, by the similarities of the histological features among the tumors, it appears appropriate to establish a novel category of “gliomatosis encephali” which includes both gliomatosis cerebri and gliomatosis cerebelli.

Cerebral amyloid angiopathy‐related leukoencephalopathy: Successful steroid treatment for neurological deficits and subcortical white matter lesions partly involving the cortical gray matter

A 76‐year‐old woman developed subacute cognitive decline, consciousness impairment and right hemiparesis. Magnetic resonance imaging showed asymmetric white matter or cortical gray matter lesions, and multiple cerebral microbleeds. Pathological studies of biopsied brain specimen disclosed amyloid β‐protein deposits in the vessel walls. Repeated steroid‐pulse therapy improved clinical symptoms and resolved the cortico‐subcortical lesions. Steroid therapy should be considered for patients with amyloid β‐protein deposition in cerebral amyloid angiopathy‐related leukoencephalopathy.