Masaya Nagaishi

Radiotherapy plus Concomitant Adjuvant Temozolomide for Glioblastoma: Japanese Mono-Institutional Results

This study was conducted to investigate the feasibility and survival benefits of combined treatment with radiotherapy and temozolomide (TMZ), which has been covered by the national health insurance in Japanese patients with glioblastoma since September 2006. Between September 2006 and December 2011, 47 patients with newly diagnosed and histologically confirmed glioblastoma received radiotherapy for 60 Gy in 30 fractions. Among them, 45 patients (TMZ group) received concomitant TMZ (75 mg/m2/day, every day) and adjuvant TMZ (200 mg/m2/day, 5 days during each 28-days). All 36 of the glioblastoma patients receiving radiotherapy between January 1988 and August 2006 were analyzed as historical controls (control group). All patients were followed for at least 1 year or until they died. The median survival was 15.8 months in the TMZ group and 12.0 months in the control group after a median follow-up of 14.0 months. The hazard ratio for death in the TMZ group relative to the control group was 0.52 (P<0.01); the 2-year survival rate was 27.7% in the TMZ group and 14.6% in the control group. Hematologic toxicity of grade 3 and higher was observed in 20.4% in the TMZ group. Multivariate analysis showed that extent of surgery had the strongest impact on survival (P<0.01), while the use of TMZ had the second largest impact on survival (P = 0.035). The results indicate that combined treatment with radiotherapy and TMZ has a significant survival benefit for Japanese patients with newly diagnosed glioblastoma with slightly higher toxicities than previously reported.

Intratumoral Heterogeneity of Genomic Imbalance in a Case of Epithelioid Glioblastoma with BRAF V600E Mutation

Epithelioid glioblastoma is among the rarest variants of glioblastoma and is not formally recognized in the World Health Organization classification; it is composed of monotonous, discohesive sheets of small, round cells with eccentric nuclei and eosinophilic cytoplasm devoid of cytoplasmic stellate processes, showing the retention of nuclear staining of INI‐1 protein. Here, we report a case involving a 22‐year‐old man with a right occipital lobe tumor, which comprised mainly epithelioid tumor cells with a small area of diffusely infiltrating less atypical astrocytoma cells showing a lower cell density. Array comparative genomic hybridization separately performed for each histologically distinct component demonstrated eight shared copy number alterations (CNAs) and three CNAs observed only in epithelioid cells; one of the latter was a homozygous deletion of a tumor suppressor gene, LSAMP, at 3q13.31. BRAF V600E mutation was observed both in epithelioid tumor cells and in diffusely infiltrating less atypical astrocytoma cells. Our findings suggest that the regional loss of LSAMP led to the aggressive nature of epithelioid cells in the present case of epithelioid glioblastoma.

Tau-positive glial cytoplasmic granules in multiple system atrophy

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease that is pathologically characterized by the filamentous aggregation of α‐synuclein. We report a case of MSA showing unusual neuropathological findings and review six autopsied cases of MSA. The patient progressively developed parkinsonism and ataxia for the 9 years prior to her death at the age of 72 years. Neuropathological examinations revealed neuronal loss restricted to the olivopontocerebellar and striatonigral region, which was more severe in the putamen. Staining with anti‐α‐synuclein antibody demonstrated widespread occurrence of glial cytoplasmic inclusions, which mainly accumulated in oligodendroglial cells and corresponded closely to the degree of disease progression. In addition, tau‐positive granules were detected within the glial cytoplasm in the neurodegenerative region, which was especially prominent in the putamen and internal capsule. Tau accumulation was also clearly recognized by staining with specific antibodies against three‐repeat or four‐repeat tau. The glia that demonstrated deposition of tau‐positive granules were distinguished from α‐synuclein‐positive oligodendroglia by double immunohistochemical staining. These characteristic glial accumulations of tau were also present in all six cases of MSA. These results indicate that tau‐positive granules in glia are common findings in MSA and that tau aggregation might be another pathway to neurodegeneration in MSA.

Clinico-pathological feature of pilomyxoid astrocytomas: three case reports.

Pilomyxoid astrocytoma (PMA) is a newly identified variant of pilocytic astrocytoma (PA). We report three cases of PMA with comparison to seven cases of PA in terms of their clinicopathological features. The three cases occurred at the ages of 2, 36 and 6 years, and their tumors were located in the left basal ganglia, the pineal gland, and the cerebellum, respectively. They were diagnosed PMA by surgical specimens that showed a characteristic monomorphous architecture with an angiocentric growth pattern and myxoid background. One patient developed localized relapse at 6 months after the surgery, but the other patients remained alive without tumor progression more than 5 years after treatment. In analysis of the immunohistochemical association in PMA and PA, no specific staining was found to be useful for differential diagnosis of PMA from PA. The expression of biomarkers including O‐6‐methylguanine‐DNA methyltransferase, p53, MIB‐1, and EGF receptor neither distinguished PMA from PA nor correlated with outcome. But almost all PMA and PA that demonstrated prominent positivity for nestin showed a high MIB‐1 labelling index (LI), and four of these five patients suffered a relapse in the early phase. These results suggest that immunohistochemical expression of nestin and MIB‐1 LI may correlate with the aggressiveness of the tumor in PA and PMA.

Localized overexpression of alpha-internexin within nodules in multinodular and vacuolating neuronal tumors.

Multinodular and vacuolating neuronal tumors (MVNT) have been recently referred to as a distinctive neuronal tumor entity based on histopathological findings. They are characterized by multiple tumor nodules, vacuolar alteration and widespread immunolabeling for human neuronal protein HuC/HuD. Only 13 cases have been reported in the literature to date and little is known about the histopathology of these tumors. Herein, we report a case of MVNT with additional confirmation of immunohistochemical features. A 22‐year‐old woman presented with a continuous headache. MRI showed a subcortical white matter lesion with multiple satellite nodules in the frontal lobe appearing as T2/fluid‐attenuated inversion recovery (FLAIR) hyperintensities. Histological examination of the resected lesion revealed well‐defined multiple nodules composed of predominant vacuolating tumor cells. The tumor cells exhibited consistent immunolabeling for doublecortin, as well as HuC/HuD, both representative neuronal biomarkers associated with earlier stages of neuronal development. Immunopositivity for oligodendrocyte transcription factor 2 (Olig2) and S100 was also detected in tumor cells. Additionally, significant overexpression of alpha‐internexin was observed in the background neuropil limited to tumor nodules. Neuronal nuclear antigen (NeuN), synaptophysin and neurofilament, markers for mature neurons, were either negative or weakly positive. The expression profile of neuronal biomarkers can be distinguished from that of classic neuronal tumors and is the immunohistochemical hallmark of MVNT. In summary, we identified the characteristic tumoral expression of HuC/HuD and doublecortin and the presence of abundant neuropil localized in MVNT tumor nodules, which exhibited widespread alpha‐internexin expression. These results supported the presumption that MVNT is a distinct histopathological entity.

Slug, Twist, and E-Cadherin as Immunohistochemical Biomarkers in Meningeal Tumors

The overexpression of Twist and Slug and subsequent down-regulation of E-cadherin facilitate the acquirement of invasive growth properties in cancer cells. It is unclear which of these molecules are expressed in mesenchymal tumors in the central nervous system. Here, we investigated 10 cases each of hemangiopericytoma, solitary fibrous tumor, meningothelial, fibrous, angiomatous, and atypical meningiomas, and 5 cases of anaplastic meningioma for Slug, Twist, E-cadherin, and N-cadherin immunoexpression. Nuclear Slug expression was observed in 9/10 (90%) hemangiopericytomas and 5/10 (50%) solitary fibrous tumors, but not in any meningiomas, except for 1 case. Similarly, nuclear Twist expression was more extensive in hemangiopericytomas and solitary fibrous tumors than meningiomas. In contrast to Slug and Twist, the positive expression of E-cadherin was observed in 39/45 (87%) meningiomas, but not in any hemangiopericytomas or solitary fibrous tumors (P<0.0001). The fraction of tumor cells expressing E-cadherin in meningeal tumors was negatively correlated to those of Twist (P = 0.004) and Slug (P<0.0001). The overexpression of Slug and Twist with down-regulation of E-cadherin was characteristic findings in hemangiopericytomas and solitary fibrous tumors, but not in meningiomas. The immunohistochemical profiles of the two tumor groups may be useful as diagnostic markers in cases that present a differential diagnosis challenge.

An immunohistochemical finding in glioneuronal lesions associated with epilepsy: The appearance of nestin-positive, CD34-positive and tau-accumulating cells

Several kinds of unusual cells have been pathologically identified in epileptic patients. CD34‐positive, nestin‐positive and tau‐positive cells are some of them. However, no reports have investigated the significance of these cells. We examined 14 cases of seizure‐associated glioneuronal lesions to investigate the incidences and distributions of these cells and the association between their incidence and clinical parameters. CD34‐positive and nestin‐positive cells were seen in 43% and 50% of cases, respectively. In the regions with structural anomalies, there were increased numbers of CD34‐positive cells and nestin‐positive cells, but they were identified as different cells. Both examinations showed many abnormal processes in oligodendroglial‐like cells with round nuclei. In contrast, few reactive astrocytes that demonstrated immunoreactivity for glial fibrillary acidic protein were found in this area. Tau accumulation was present in 37% of cases. There was no correspondence with the regions showing increasing numbers of nestin or CD34‐positive cells. There were no significant associations between epileptic clinical parameters and the incidences of the abovementioned immunopositive cells. CD34‐positive cells and nestin‐positive cells are found as frequently as balloon cells and are associated with abnormal reconstitution of the cortex. These findings support the assertion that increases in the numbers of these cells might contribute to promoting epilepsy. In addition, these immunopositive cells are valuable findings for the pathological identification of epileptogenic lesions.

Genetic mutations in high grade gliomas of the adult spinal cord.

Tumors of the intramedullary spinal cord are a rare entity, accounting for only 4–10 % of all central nervous system tumors [1]. Glial tumors are the most frequent histological type of intramedullary spinal cord tumors, with ependymomas comprising 60–80 % of tumors originating from the glial tissue. While astrocytic tumors are second in prevalence to ependymomas, they represent the most common intramedullary tumor in children, comprising 90 % of all pediatric intramedullary tumors [2]. The most common subtype of intramedullary astrocytic tumors is diffuse astrocytomas, classified as grade II according to the World Health Organization (WHO) criteria, while malignant astrocytomas are less common and account for 25 and 10 % of intramedullary astrocytic tumor cases in adults and children, respectively. Recent genomic studies have attempted to characterize the molecular landscape of gliomas to understand their biology and reliably categorize them into etiologically similar groups. It has been suggested that some new mutations are associated not only with tumor subtype but also with anatomical location and patient age. The mutation of H3F3A K27M has predominantly been detected in malignant astrocytomas arising in structures of the midline including the thalamus, brain stem, and spinal cord and is highly prevalent in pediatric and young adult patients [3]. This recently recognized tumor entity was termed diffuse midline glioma, H3 K27M-mutant, and was included as a separate entity in the 2016 WHO classification [4]. Although several research studies have described malignant diffuse midline glioma, H3 K27M-mutant in the thalamus and brain stem in adults, only a small number of cases have been reported in the spinal cord [5]. In addition, the genetic signatures of this type of tumor remain unknown due to a lack of relevant studies in the published literature. Here we describe the immunohistochemical and genetic features of adult spinal high grade gliomas (HGG) in two newly diagnosed cases. Case 1: A 66-year-old female was diagnosed with an anaplastic astrocytoma, IDH-wildtype when she underwent biopsy for a mass lesion of the thoracic spinal cord at the T6–7 level. She had presented with a 1-month history of rapidly progressive paraplegia. She began radiotherapy with concomitant temozolomide, but she subsequently died of pneumonia caused by severe pancytopenia just 2 months after her initial diagnosis. An autopsy confirmed a diagnosis of anaplastic astrocytoma, IDH-wildtype. Case 2: A 50-year-old male was diagnosed with glioblastoma, IDHwildtype when he underwent biopsy for a mass lesion of the spinal cord at the T11–12 level. He had presented with a 4-month history of paresthesia and weakness in his right leg. Following surgery, the tumor was treated with radiotherapy with concomitant and adjuvant temozolomide. The patient died of tumor growth and cerebrospinal fluid dissemination 11 months after his initial diagnosis. Microscopic analysis of the tumors from these two cases revealed highly cellular tissue composed of astrocytic & Masaya Nagaishi nagaishi-nsu@umin.ac.jp

Treatment of traumatic acute subdural hematoma in adult hydrocephalus patients with cerebrospinal fluid shunt

OBJECTIVE The presence of a cerebrospinal fluid (CSF) shunt is a predisposing factor for the development of subdural hematoma (SDH) in patients with hydrocephalus. However, few reports have addressed how patients with a CSF shunt should be treated in the event of traumatic acute SDH. The purpose of this study was to show how post-traumatic management of CSF shunt affects acute SDH in adult patients with hydrocephalus. METHODS Twelve patients were studied retrospectively. Pressure settings of shunt valve prior to head injury (HI), severity of HI, treatment on admission, changes in SDH thickness and subsequent hydrocephalus were mainly analyzed. RESULTS Ten patients experienced mild HI, with nine showing neurological deterioration until admission. Five patients needed surgical hematoma removal soon after admission. SDH recurred in four cases where shunt pressure levels were kept relatively low. Shunt ligation or raising the pressure level in the programmable valve proved effective for controlling postoperative SDH in such cases. Six of the remaining seven patients underwent only shunt ligation or readjustment of pressure level in the programmable valve on admission. SDH thickness was reduced as ventricles dilated without major neurological complications. Four patients showed delayed development of SDH even though shunts were kept ligated. CONCLUSIONS Hematoma removal alone may result in hematoma recurrence and require a second treatment comprising shunt management to effectively control hematoma. Using shunt management as the only initial treatment can reduce hematoma volume, but some patients may suffer delayed SDH development and require surgery.

Clinicopathological and molecular features of malignant optic pathway glioma in an adult

Malignant gliomas of the optic pathway are rare, and their genetic alterations are poorly understood. We describe a 64-year-old woman with anaplastic astrocytoma originating from the optic pathway, together with the molecular features. She presented with progressive visual field loss, and a biopsy sample was obtained from the lesion in the optic chiasm. She underwent radiosurgery concomitant with temozolomide chemotherapy, and subsequently remained stable for 10 months after initial presentation. Molecular analysis indicated that the mass may have shared common molecular genetic features with conventional primary astrocytic gliomas but not pilocytic gliomas, which supported the morphologic diagnosis of anaplastic astrocytoma. Molecular analysis of malignant optic pathway gliomas in adults is useful for distinguishing between high-grade gliomas and anaplastic pilocytic astrocytomas, and for determining further therapy.