Yoshihiro Tsukamoto

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.

Primary central nervous system lymphomas and related diseases: Pathological characteristics and discussion of the differential diagnosis

Although primary diffuse large B‐cell lymphomas of the CNS are designated as primary CNS lymphomas according to the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue in 2008, a variety of other lymphomas (Burkitt lymphomas, EBV‐positive diffuse large B‐cell lymphoma of the elderly) and related diseases (lymphomatoid granulomatosis) that are also found in the CNS have been spotlighted in recent years. The histopathology of primary CNS Burkitt lymphomas mimics that of primary diffuse large B‐cell lymphomas of the CNS after steroid administration. Therefore, for correct diagnosis of the involved lymphoma, comprehensive fluorescent in situ hybridization analysis for c‐MYC and BCL2 is recommended in all primary CNS lymphoma cases with aggressive clinical course, multifocal involvement of the CNS, and a high proliferation index. The pathological characteristics of primary CNS EBV‐positive diffuse large B‐cell lymphoma of the elderly have similarities with those of the latency phenotype III, EBV lymphoproliferative disorders that arise in the setting of immunodeficiency. These age‐related lymphomas usually occur in elderly immunocompetent patients, and the incidence of this disease was estimated to range from 4.0% to 13.6% of all primary CNS lymphomas. Shorter overall survival has been reported for patients with this disease. Lymphomatoid granulomatosis (LYG) is a systemic, EBV‐driven, angiocentric and angiodestructive lymphoproliferative disorder. Primary LYG that shows distinct clinicopathological features compared with systemic LYG was recently reported. Finally, this review focuses on the relationship between primary CNS lymphomas and demyelinating diseases, and the concomitant use of intraoperative cytology and frozen sections that are helpful in rapid intraoperative diagnosis.

Transarterial embolisation for refractory bilateral chronic subdural hematomas in a case with dentatorubral-pallidoluysian atrophy

A 64-year-old man, receiving treatment for DRPLA, complained of progressive aphasia and right hemiparesis for 1 week, and finally, developed consciousness disturbance. The history of head trauma was unclear. Computed tomography (CT) showed bilateral CSDH (Fig. 1a). After bilateral continuous drainages for 1 day, clinical symptoms resolved completely, and CT showed definite decreases in the hematoma volume, but not complete closure of the subdural space. Three weeks later, we operated for recurrence of CSDH on the left side with aphasia and right hemiparesis. Another 2 weeks later, we performed a third drainage surgery for bilateral recurrences of CSDH with thorough irrigation, with normal saline and steroid administration. A further 2 weeks later, CT showed bilateral CSDH growth persistently (Fig. 1a), and then, we performed angiography to evaluate the underlying specific vascular diseases. Bilateral superselective angiography of the MMA showed diffuse abnormal vascular networks indicating the presence of macrocapillaries in the outer CSDH membrane (Fig. 1c, d). We performed TAE of the bilateral MMAwith polyvinyl alcohol particles, and confirmed that the abnormal vessels were not visible. After 18 months since TAE of the MMA, the CT image still shows bilateral CSDH without enlargement, but the patient has no symptoms.

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.

Successful removal of a huge hypervascular tentorial cavernous angioma after preoperative endovascular embolization

The authors report a rare case of a huge hypervascular tentorial cavernous angioma treated with preoperative endovascular embolization, followed by successful gross-total removal. A 15-year-old girl presented with scintillation, diplopia, and papilledema. Computed tomography and MRI studies revealed a huge irregularly shaped tumor located in the right occipital and suboccipital regions. The tumor, which had both intra- and extradural components, showed marked enhancement and invasion of the overlying occipital bone. Angiography revealed marked tumor stain, with blood supply mainly from a large branch of the left posterior meningeal artery. Therefore, this lesion was diagnosed as a tentorium-based extraaxial tumor. For differential diagnosis, meningioma, hemangiopericytoma, and malignant skull tumor were considered. Tumor feeders were endovascularly embolized with particles of polyvinyl alcohol. On the following day, the tumor was safely gross totally removed with minimum blood loss. Histopathological examination confirmed the diagnosis of cavernous angioma. To date, there have been no reports of tentorium-based cavernous angiomas endovascularly embolized preoperatively. A tentorial cavernous angioma is most likely to show massive intraoperative bleeding. Therefore, preoperative embolization appears to be quite useful for safe maximum resection. Hence, the authors assert that the differential diagnosis of tentorium-based tumors should include tentorial cavernous angioma, for which preoperative endovascular embolization should be considered.

Late relapse of primary central nervous system lymphoma

Ryuya Yamanaka, Ken Morii, Yoshikatsu Shinbo, Masakazu Sano, Jumpei Homma, Naoto Tsuchiya, Naoki Yajima, Yoshihiro Tsukamoto, Ryouske Ogura, Manabu Natsumeda, Hiroshi Aoki, Katsuhiko Akiyama, Takafumi Saitoh, Tetsuro Tamura, Hiroaki Hondoh, Atsushi Kawaguchi, Hitoshi Takahashi and Yukihiko Fujii Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan; Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Neurosurgery, Kitanihon Neurosurgical Hospital, Gosen, Japan; Department of Neurosurgery, Shibata Prefectural Hospital, Shibata, Japan; Department of Neurosurgery, Toyama Prefectural Central Hospital, Toyama, Japan; Department of Neurosurgery, Nagano Red Cross Hospital, Nagano, Japan; Department of Neurosurgery, Uonuma-Kikan Hospital, Minamiuonuma, Japan; Department of Neurosurgery, Niigata Prefectural Central Hospital, Joetsu, Japan; Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga, Japan; Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan

Long-term survivors of primary central nervous system lymphoma

Objective: In this study, we provide long‐term outcome data of patients with primary central nervous system lymphoma Methods: The long‐term outcomes of PCNSL patients diagnosed between 1982 and 2006 were reviewed. Neurological late neurotoxicity symptoms, neuroradiological brain atrophy and leukoencephalopathy were evaluated. Surviving patients completed the Quality of Life Questionnaire‐30 and Brain Cancer Module‐20. The differences in overall survival were assessed using the Kaplan‐Meier method and log‐rank test. The differences between groups in terms of each investigated parameter were analyzed using the Wilcoxon signed‐rank test Results: Among 112 PCNSL patients, there were 33 (29.4%) long‐term (> 5 years) survivors. The median survival of all long‐term survivors was 105.7 months; of these, 8 (7.1%) were alive at the latest follow‐up, with a mean survival time of 170.2 months (range, 121.8‐286.4). Clinical assessment revealed severe neurotoxicity in 14 patients (42.4%), moderate neurotoxicity in 5 (15.1%), and normal status in 14 (42.4%). Correlations were seen between the neuroradiological imaging score changes and neurocognitive condition (P=0.0001), neurocognitive condition and the whole brain irradiation dose (P=0.0004), and atrophy and the whole brain irradiation dose (P=0.0035). Conclusions: A more severe clinical condition was found to be associated with increasing age and whole brain irradiation dose in long‐term survivors with PCNSL.

MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas and MGMT Silencing to Temozolomide Sensitivity in IDH-Mutant Gliomas

Histone H3 mutations are frequently found in diffuse midline gliomas (DMGs), which include diffuse intrinsic pontine gliomas and thalamic gliomas. These tumors have dismal prognoses. Recent evidence suggests that one reason for the poor prognoses is that O6-methylguanine-DNA methyltransferase (MGMT) promoter frequently lacks methylation in DMGs. This review compares the epigenetic changes brought about by histone mutations to those by isocitrate dehydrogenase-mutant gliomas, which frequently have methylated MGMT promoters and are known to be sensitive to temozolomide.

Chemical Screening Identifies EUrd as a Novel Inhibitor Against Temozolomide‐Resistant Glioblastoma‐Initiating Cells

Glioblastoma (GBM), one of the most malignant human cancers, frequently recurs despite multimodal treatment with surgery and chemo/radiotherapies. GBM‐initiating cells (GICs) are the likely cell‐of‐origin in recurrences, as they proliferate indefinitely, form tumors in vivo, and are resistant to chemo/radiotherapies. It is therefore crucial to find chemicals that specifically kill GICs. We established temozolomide (the standard medicine for GBM)‐resistant GICs (GICRs) and used the cells for chemical screening. Here, we identified 1‐(3‐C‐ethynyl‐β‐d‐ribopentofuranosyl) uracil (EUrd) as a selective drug for targeting GICRs. EUrd induced the death in GICRs more effectively than their parental GICs, while it was less toxic to normal neural stem cells. We demonstrate that the cytotoxic effect of EUrd on GICRs partly depended on the increased expression of uridine‐cytidine kinase‐like 1 (UCKL1) and the decreased one of 5′‐nucleotidase cytosolic III (NT5C3), which regulate uridine‐monophosphate synthesis positively and negatively respectively. Together, these findings suggest that EUrd can be used as a new therapeutic drug for GBM with the expression of surrogate markers UCKL1 and NT5C3. Stem Cells 2016;34:2016–2025