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Background Tumor hypoxia and glycolysis have been recognized as determinant factors characterizing tumor aggressiveness in malignant gliomas. To clarify in vivo hypoxia and glucose metabolism in relation to isocitrate dehydrogenase (IDH) mutation and chromosome 1p and 19q (1p/19q) codeletion status, we retrospectively analyzed hypoxia as assessed by positron emission tomography (PET) with [18F]-fluoromisonidazole (FMISO) and glucose metabolism as assessed by PET with [18F]-fluoro-2-deoxy-d-glucose (FDG) in newly diagnosed malignant gliomas. Methods In total, 87 patients with newly diagnosed supratentorial malignant (WHO grade III and IV) gliomas were enrolled in this study. They underwent PET studies with FMISO and FDG before surgery. The molecular features and histopathological diagnoses based on the 2016 WHO classification were determined using surgical specimens. Maximal tumor-to-normal ratio (TNR) was calculated for FDG PET, and maximal tumor-to-blood SUV ratio (TBR) was calculated for FMISO PET. The PET uptake values in relation to IDH mutation and 1p/19q codeletion status were statistically analyzed. Results In all tumors and malignant astrocytomas, the median FMISO TBR in IDH-wildtype tumors was significantly higher than that in IDH-mutant tumors (P P IDH-wildtype tumors tended to be higher than that in IDH-mutant tumors, but the difference was not statistically significant. In WHO grade III anaplastic astrocytomas, there were no significant differences in median FMISO TBR or FDG TNR between IDH-mutant and IDH-wildtype tumors. In IDH-mutant WHO grade III anaplastic gliomas, there were no significant differences in median FMISO TBR or FDG TNR between anaplastic astrocytomas and anaplastic oligodendrogliomas. Conclusions Tumor hypoxia as assessed by FMISO PET was informative for prediction of the IDH mutation status in newly diagnosed malignant gliomas. However, the accuracy of the discrimination was not satisfactory for clinical application. On the other hand, glucose metabolism as assessed by FDG PET could not differentiate the IDH-mutant status. Moreover, PET studies using FMISO and FDG could not predict IDH mutation and 1p/19q codeletion status in WHO grade III tumors.

Background The molecular diagnosis of gliomas such as isocitrate dehydrogenase (IDH) status (wild-type [wt] or mutation [mut]) is especially important in the 2016 World Health Organization (WHO) classification. Positron emission tomography (PET) has afforded molecular and metabolic diagnostic imaging. The present study aimed to define the interrelationship between the 2016 WHO classification of gliomas and the integrated data from PET images using multiple tracers, including 18F-fluorodeoxyglucose (18F-FDG), 11C-methionine (11C-MET), 18F-fluorothymidine (18F-FLT), and 18F-fluoromisonidazole (18F-FMISO). Methods This retrospective, single-center study comprised 113 patients with newly diagnosed glioma based on the 2016 WHO criteria. Patients were divided into 4 glioma subtypes (Mut, Codel, Wt, and glioblastoma multiforme [GBM]). Tumor standardized uptake value (SUV) divided by mean normal cortical SUV (tumor–normal tissue ratio [TNR]) was calculated for 18F-FDG, 11C-MET, and 18F-FLT. Tumor–blood SUV ratio (TBR) was calculated for 18F-FMISO. To assess the diagnostic accuracy of PET tracers in distinguishing glioma subtypes, a comparative analysis of TNRs and TBR as well as the metabolic tumor volume (MTV) were calculated by Scheffe's multiple comparison procedure for each PET tracer following the Kruskal–Wallis test. Results The differences in mean 18F-FLT TNR and 18F-FMISO TBR were significant between GBM and other glioma subtypes (P < .001). Regarding the comparison between Gd-T1WI volumes and 18F-FLT MTVs or 18F-FMISO MTVs, we identified significant differences between Wt and Mut or Codel (P < .01). Conclusion Combined administration of 4 PET tracers might aid in the preoperative differential diagnosis of gliomas according to the 2016 WHO criteria.

Background The molecular features of isocitrate dehydrogenase (IDH) mutation and chromosome 1p and 19q (1p/19q) codeletion status have pivotal role for differentiating gliomas and have been integrated in the World Health Organization (WHO) classification in 2016. Positron emission tomography (PET) with 3′-deoxy-3′-[18F]fluorothymidine (FLT) has been used to evaluate tumour grade and proliferative activity and compared with l-[methyl-11C]-methionine (MET) in glioma patients. Herein, we evaluated tracer uptakes of MET-PET/CT and FLT-PET/CT for differentiating glioma based on the 2016 WHO classification especially in relation to IDH1 mutation status. Methods In total, 81 patients with newly diagnosed supratentorial glioma were enrolled in this study. They underwent PET/CT studies with MET and FLT before surgery. The molecular features and histopathological diagnosis based on the 2016 WHO classification were determined using surgical specimens. The ratios of the maximum standardized uptake value (SUV) of the tumours to the mean SUV of the contralateral cortex (T/N ratios) were calculated on MET-PET/CT and FLT-PET/CT images. Results The mean T/N ratios of MET-PET/CT and FLT-PET/CT in IDH1-wildtype tumours were significantly higher than those in IDH1-mutant tumours (P < 0.001 and P < 0.001, respectively). Receiver operating characteristic analysis for differentiating IDH1 mutation status showed that the area under the curve of the FLT T/N ratio was significantly larger than that of the MET T/N ratio (P < 0.01). The mean T/N ratio of FLT-PET/CT in IDH1-wildtype tumours was significantly higher than that in IDH1-mutant tumours among grade II and III gliomas (P = 0.005), but this was not the case for MET-PET/CT. Both MET-PET/CT and FLT-PET/CT were able to distinguish between grade II and III gliomas in IDH1-mutant tumours (P = 0.002 and P < 0.001, respectively), but only FLT-PET/CT was able to distinguish between grade III and IV gliomas in IDH1-wildtype tumours (P = 0.029). Conclusion This study showed that FLT-PET/CT can be used to determine the IDH1 mutation status and evaluate glioma grade more accurately than MET-PET/CT. FLT-PET/CT can improve glioma differentiation based on the 2016 WHO classification, but caution must be paid for tumours without contrast enhancement and further studies should be conducted with more cases.

The neural circuits responsible for behavior remain largely unknown. Previous efforts have reconstructed the complete circuits of small animals, with hundreds of neurons, and selected circuits for larger animals. Here we (the FlyEM project at Janelia and collaborators at Google) summarize new methods and present the complete circuitry of a large fraction of the brain of a much more complex animal, the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses, and proofread such large data sets; new methods that define cell types based on connectivity in addition to morphology; and new methods to simplify access to a large and evolving data set. From the resulting data we derive a better definition of computational compartments and their connections; an exhaustive atlas of cell examples and types, many of them novel; detailed circuits for most of the central brain; and exploration of the statistics and structure of different brain compartments, and the brain as a whole. We make the data public, with a web site and resources specifically designed to make it easy to explore, for all levels of expertise from the expert to the merely curious. The public availability of these data, and the simplified means to access it, dramatically reduces the effort needed to answer typical circuit questions, such as the identity of upstream and downstream neural partners, the circuitry of brain regions, and to link the neurons defined by our analysis with genetic reagents that can be used to study their functions.Note: In the next few weeks, we will release a series of papers with more involved discussions. One paper will detail the hemibrain reconstruction with more extensive analysis and interpretation made possible by this dense connectome. Another paper will explore the central complex, a brain region involved in navigation, motor control, and sleep. A final paper will present insights from the mushroom body, a center of multimodal associative learning in the fly brain.

The present study investigates the neuroprotective effects of d-allose, a rare sugar, against ischemia/reperfusion injury in a gerbil model. Transient forebrain ischemia was induced by occlusion of the bilateral common carotid arteries for 5 min. D-Allose was intravenously injected before and after ischemia (200 mg/kg). Extracellular glutamate and lactate release from the gerbil brain, and PO₂ profiles were monitored during ischemia and reperfusion. We also examined neuronal death and oxidative damage in the hippocampus one week after ischemia reperfusion, and investigated functional outcome. D-Allose administration suppressed glutamate and lactate release compared to vehicle controls. Brain damage, 8-OHdG levels (a marker of oxidative stress) and locomotor activities were significantly decreased by D-allose treatment. The present results suggest that d-allose reduces delayed neuronal death and behavioral deficits after transient ischemia by changing cerebral metabolism and inhibiting oxidative stress.

The aim of this study was to investigate the neuroprotective effects of yokukansan, a traditional Kampo medicine, on the behavioral dysfunction induced by cerebral ischemia/reperfusion injury in gerbils. Gerbils were treated with yokukasan by oral gavage for 30 days, once per day, until the day before induction of ischemia, which was induced by occluding the bilateral common carotid artery for 5 min. The effects of yokukansan (50, 100 and 300 mg/kg) were examined by measuring neuronal damage and behavioral deficits (locomotor activity, 8-arm radial maze task). The anti-inflammatory and anti-oxidant properties of yokukansan were also examined. Administration of yokukansan at 300 mg/kg significantly reduced hippocampal neuronal death after brain ischemia, inhibited the ischemia-induced inflammatory response and DNA oxidative damage. Yokukansan also reduced ischemia-induced locomotor hyperactivity and improved memory impairment. These findings suggest that yokukansan can inhibit the inflammatory response, oxidative damage and subsequent neuronal death induced by cerebral ischemia/reperfusion injury, and also can contribute to improvement in neurological deficits following such injury.

The authors report on a case of concurrent herpes simplex encephalitis (HSE) and malignant glioma. The co-occurrence of HSE and malignant glioma is very rare, but it can occur during glioma treatment. Both radiotherapy and chemoradiation with temozolomide can induce viral reactivation, leading to HSE relapse. Careful observation for HSE is necessary when administering chemoradiation to patients with a history of HSE. Antiviral therapy for HSE must be initiated immediately, and the chemoradiation for glioma should be stopped; however, it is not clear what antitumor therapy is optimal when HSE co-occurs during the treatment of glioma.

An 11-year-old boy presented with pineal pure germinoma with spinal dissemination manifesting as a 1-month history of ocular motility disturbance and a history of abnormal sensations in the left leg persisting for several months. His past medical history was unremarkable. Craniospinal magnetic resonance imaging showed an enhanced tumor in the pineal gland and widespread leptomeningeal dissemination in the spinal canal. Biopsy of the pineal tumor was performed. Histological examination revealed a pure germinoma. Chemotherapy with carboplatin and etoposide in combination with radiotherapy induced complete remission of the tumors. He regained normal eye movement and sensation in his left leg during the chemotherapy period. Germinomas with dissemination are generally more malignant and refractory than solitary germinomas, but this patient showed a strong response to chemoradiotherapy.

Several biomarkers have been identified as prognostic factors in primary central nervous system lymphoma (PCNSL). However, the correlation between the histogenetic origin of PCNSL and the response to therapy is still unclear. To elucidate the utility of immunophenotypic markers in predicting clinical outcomes, we investigated 27 immunocompetent patients with PCNSL treated with high-dose methotrexate therapy. Of the 27 patients, 25 received whole-brain radiotherapy after high-dose methotrexate. Immunostaining for CD5, CD10, BCL-6, and MUM-1 was used to determine the immunophenotypic profile of diffuse large B-cell lymphoma of PCNSL. We then evaluated whether immunophenotypic markers were associated with the response to therapy or patients' survival. The response to induction high-dose methotrexate therapy was determined by magnetic resonance imaging after three courses of i.v. high-dose methotrexate. We categorized B-cell lymphomas into three known subtypes: germinal center B-cell (GCB), activated-GCB, and post-GCB subtypes according to immunohistochemical profile. All the BCL-6-positive samples were co-positive for MUM-1 and therefore classified into activated-GCB subtype. BCL-6 expression in this study was associated with poor progression-free survival (P = 0.038). No immunophenotypic markers or subtypes had a significant effect on the response to high-dose methotrexate therapy. However, the response itself was a significant predictor for both progression-free survival (P < 0.001) and overall survival (P = 0.003). Further investigation is needed to assess BCL-6 as a potential prognostic factor in PCNSL.

Background The present study investigates the effects of d -allose, a rare sugar, on the inflammatory response after transient forebrain ischemia in the gerbil and whether it reduces oxidative stress (8-hydroxyl-2′-deoxyguanosine levels) and behavioral deficits. Methods Transient forebrain ischemia was induced by occlusion of the bilateral common carotid arteries for 5 minutes. d -Allose was intraperitoneally injected immediately after ischemia (400 mg/kg). Inflammatory cytokines and oxidative damage in the hippocampus and behavioral deficits were examined 3 days after ischemia. Results d -Allose administration reduced ischemia-induced cytokine production, oxidative stress, and behavioral deficits (motor and memory related). Conclusions The present results suggest that d -allose reduces brain injury after transient global ischemia by suppressing inflammation as well as by inhibiting oxidative stress.

OBJECT: Neuroendocrine carcinoma (NEC) is a malignant tumor that usually arises in the lung, pancreas and gastrointestinal tract. Brain metastasis of NEC is merely reported. Herein, we report two cases of NEC in the brain mimicking glioblastoma (GBM). CASES: Both patients were in their 60s, cystic lesions with peritumoral edema affected the temporal lobe. Cyst walls were thin but hyperintense in diffusion weighted images implying increased cellularity. Positron emission tomography (PET) revealed malignant nature by strong uptake of methionine (MET), fluorothymidine (FLT) and fluoromisonidazole likewise GBM. However, fluorodeoxyglucose (FDG) indicated relatively weak uptakes compared as GBM. Both tumors were resected under the preoperative diagnosis of GBM, however, pathological diagnoses were NEC by immunohistochemical finding of negative GFAP and positive markers of neuroendocrine differentiation. Systemic examination failed to reveal the origin. Both cases underwent radiotherapy. One case was lost by spinal dissemination 11 months after the operation. DISCUSSION: FDG-PET of neuroendocrine tumor in the extracranial lesion does not always demonstrate strong uptake. FDG-PET for NEC in the brain could be less accumulated than GBM, while it should be evaluated keeping in mind that the background level of FDG would be high in the brain tissue. In case of malignant tumors endorsed by other tracer such as MET and FLT, inconsistent FDG-PET finding might be useful for the diagnosis of NEC in the brain.

The present study investigates the potential protective effects of granulocyte colony-stimulating factor (G-CSF) and underlying mechanisms in a gerbil model of global cerebral ischemia. We examined neuronal death, inflammatory reaction and neurogenesis in hippocampus 72 h after transient forebrain ischemia and investigated functional deficits. G-CSF was administered intraperitoneally 24 h before ischemia and then daily. Treatment with G-CSF at 25-50 μg/kg significantly reduced neuronal loss in the hippocampus CA1 area but not at 10 ug/kg. G-CSF at 50 μg/kg significantly decreased the level of TNF-α, the number of Iba1 (microglia marker) positive cells and reduced locomotor activity 72 h after transient forebrain ischemia. Furthermore, the number of DCX-positive cells in the hippocampal dentate gyrus increased in with G-CSF treatment. Our findings indicate that G-CSF reduces hippocampal neuronal cell death dose-dependently and attenuates sensorimotor deficits after transient forebrain ischemia. These neuroprotective effects of G-CSF may be linked to inhibition of inflammation and possibly increased neurogenesis in the hippocampus.

The use of positron imaging agents such as FDG, MET, and FLT is expected to lead the way for novel applications toward efficient malignancy grading and treatment of gliomas. In this study, the usefulness of FDG, MET and FLT-PET images was retrospectively reviewed by comparing their histopathological findings. FDG, MET, and FLT-PET were performed in 27 patients with WHO grade IV, 15 patients with WHO grade III, and 12 patients with WHO grade II during 5.5 years. The resulting PET images were compared by measuring SUVs and T/N ratios (tumor to normal tissue ratios). Although there were no significant differences in FDG-PET, there were significant differences in the T/N ratios in the MET-PET between WHO grades II and IV and in the FLT-PET between the WHO grades III and IV. In glioblastoma patients, the SUVs of the areas depicted by MRI in the MET-PET were different from those SUVs in the FLT-PET. Importantly, the areas with high SUVs in both MET-PET and FLT-PET were also high in Ki-67 index and were histologically highly malignant. PET imaging is a noninvasive modality that is useful in determining a tumor area for removal as well as improving preoperative diagnosis for gliomas.

OBJECTIVE: Use of the positron imaging agents, such as 11C-Methionine (MET) and 18F-Fluoromisonidazole (FMISO), is expected to lead the way for novel applications aimed at achieving efficient malignancy grading and treatment of gliomas. The aim of this study was to assess MET and FMISO PET studies to evaluate the biological effects induced by bevacizumab therapy in patients treated for high grade gliomas. METHODS: Twenty-two patients with high grade gliomas were treated biweekly with bevacizumab from July 2013 to May 2015. MR images, as well as MET and FMISO PET scans were obtained at baseline and at follow-up (4 weeks after treatment onset). MRI treatment response was evaluated by T1/T2 volumetry according to the response assessment in neuro-oncology (RANO) criteria. Based on the RANO criteria, we divided the patients into three groups (PR, SD, and PD), and compared changes of MET T/N ratio or FMISO T/B ratio between baseline and follow-up. These PET response assessments were compared in relation to PFS and OS. RESULTS: At the follow-up, MRI showed PR in 6 of 22 patients, SD in 11 of 22 patients, and PD in 5 of 22 patients. The median PFS were 13.1 months, 13.5 months and 2.4 months for PR, SD and PD, respectively. The median OS were 14.6 months, 14.5 months and 5.7 months for each group. MET and FMISO images in the PD group had a tendency to show the increase of changes. FMISO images in the SD group revealed 3 of 11 increased changes (15.1% up) and 8 of 11 decreased changes (11% down). The median PFS were 2.4 months and 16.3 months for each change, and the median OS were 9.8 months and 16.8 months. CONCLUSION: Decreased changes in FMISO-PET after bevacizumab therapy may be a useful biomarker for predicting PFS and OS in high-grade gliomas.

e13028 Background: BCL-6 expression has been reported to be associated with a better prognosis in PCNSL. However, significant differences of B-cell lymphoma subtypes exist in different geographic regions. The objectives of this study were to characterize the immunophenotypes of PCNSL in Japan and to determine their utility in predicting clinical outcomes. Methods: Immunostaining for CD5, CD10, BCL-6, and MUM-1 was done to determine the profile of diffuse large B-cell lymphoma of PCNSL from 27 immunocompetent patients in Japan. Then, the authors evaluated whether clinical and immunophenotypic markers were associated with progression-free or overall survival. Results: Germinal center B-cell (GCB) marker CD10 was positive in 22% of PCNSL samples, while another GCB marker BCL-6 was positive in 48% of samples. Post-GCB marker MUM-1 was positive in 81% of samples. Poor prognostic marker of systemic B-cell lymphoma CD5 was expressed in 15% of samples. In univariate analyses, only BCL-6 expression had a significant effect on progression-free survival (median, 6.1 months in BCL-6-positive patients versus 15.6 months in BCL-6-negative patients; p = 0.037). Patients with BCL-6 expression had a trend towards longer overall survival but nonsignificant. GCB subgroup (CD10-positive or CD10-negative/BCL-6-positive/MUM-1-negative) was not significantly associated with favorable survival. Conclusions: BCL-6 expression is associated with a poor prognosis in patients with PCNSL. The discrepancy between the reports from other groups and our results is potentially due to the racial, geographic or immunophenotypic differences of PCNSL. No significant financial relationships to disclose.