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Ichiro Nakano

Tumor heterogeneity of adult high-grade glioma (HGG) is recognized in 3 major subtypes based on core gene signatures. However, the molecular signatures and clinical implications of glioma stem cells (GSCs) in individual HGG subtypes remain poorly characterized. Recently genome-wide transcriptional analysis identified two mutually exclusive GSC subtypes with distinct dysregulated signaling and metabolic pathways. Analysis of genetic profiles and phenotypic assays distinguished proneural (PN) from mesenchymal (MES) GSCs and revealed a striking correlation with the corresponding PN or MES HGGs. Similar to HGGs with a MES signature, MES GSCs display more aggressive phenotypes both in vitro and in vivo. Furthermore, MES GSCs are markedly resistant to radiation as compared with PN GSCs, consistent with the relative radiation resistance of MES GBM compared with other subtypes. A systems biology approach has identified a set of transcription factors as the master regulators for the MES signature. Metabolic reprogramming in MES GSCs has also been noticed with the prominent activation of the glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes. This review summarizes recent progress in the characterization of the molecular signature in distinct HGG and GSC subtypes and plasticity between different GSC subtypes as well as between GSCs and non-GSCs in HGG tumors. Clinical implications of the translational GSC research are also discussed.

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Ichiro Nakano, Koichi Iwasaki and Akinori Kondo

✓ An unusual case of a metastatic adenocarcinoma located entirely within the trigeminal nerve is reported. The patient, with a history of breast cancer, presented with a pure trigeminal mononeuropathy. The neurological and neuroradiological findings in this patient were quite similar to those of a patient with trigeminal neurinoma. Surgery revealed that the tumor was located within the trigeminal nerve and its appearance was similar to that of a neurinoma. However, histopathological studies proved the tumor to be an adenocarcinoma that was related to the breast cancer treated earlier. A solitary metastatic tumor arising solely in a trigeminal nerve is quite rare; this is the first report of such a case metastasized from breast cancer.

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Nobuhiro Tanaka, Masami Fujii, Hirochika Imoto, Joji Uchiyama, Kimihiko Nakano, Sadahiro Nomura, Hirosuke Fujisawa, Ichiro Kunitsugu, Takashi Saito and Michiyasu Suzuki

Object

The use of focal brain cooling to eliminate epileptic discharges (EDs) has attracted increasing attention in the scientific community. In this study, the inhibitory effect of selective hippocampal cooling on experimental hippocampal seizures was investigated using a newly devised cooling system with a thermoelectric (Peltier) chip.

Methods

A copper needle coated with silicone and attached to the Peltier chip was used for the cooling device. The experiments were performed first in a phantom model with thermography and second in adult male Sprague–Dawley rats in a state of halothane anesthesia. The cooling needle, a thermocouple, and a needle electrode for electroencephalography recording were inserted into the right hippocampus. Kainic acid (KA) was injected into the right hippocampus to provoke the EDs. The animals were divided into hippocampal cooling (10 rats) and noncooling (control, 10 rats) groups.

Results

In the phantom study, the cooling effects (9°C) occurred in the spherical areas around the needle tip. In the rats the temperature of the cooled hippocampus decreased below 20°C within a 1.6-mm radius and below 25°C within a 2.4-mm radius from the cooling center. The temperature at the needle tip decreased below 20°C within 1 minute and was maintained at the same level until the end of the cooling process. The amplitude of the EDs was suppressed to 68.1 ± 4.8% of the precooling value and remained low thereafter. No histological damage due to cooling was observed in the rat hippocampus.

Conclusions

Selective hippocampal cooling effectively suppresses the KA-induced hippocampal EDs. Direct hippocampal cooling with a permanently implantable system is potentially useful as a minimally invasive therapy for temporal lobe epilepsy and therefore could be an alternative to the temporal lobectomy.

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Hirochika Imoto, Masami Fujii, Jouji Uchiyama, Hirosuke Fujisawa, Kimihiko Nakano, Ichiro Kunitsugu, Sadahiro Nomura, Takashi Saito and Michiyasu Suzuki

✓ Local cortical cooling for termination of epileptic discharges (EDs) has recently become a focus of research. The authors report on a newly devised cooling system that uses a thermoelectric (Peltier) chip and examine the system’s performance in experimental neocortical seizures. Experiments were performed in adult male Sprague–Dawley rats after induction of halothane anesthesia. The Peltier chip was attached to a heat sink with a water channel. Two silicon tubes were connected to the heat sink, and water at 37°C was circulated in the channel. The newly designed device was placed on the surface of the cortex. Kainic acid (KA) was injected into the cortex to provoke EDs. In the nonepileptic cortex, the temperature of the cortical surface decreased to 14.8 ± 1.5°C and that 2 mm below the surface to 27.1 ± 3.1°C within 30 seconds after the start of cooling. The temperature of the heated side of the chip was maintained at approximately 36.9°C. Without water circulation, the temperature of the cortical surface decreased to 20°C but soon began to increase, peaking at 30°C. The temperature of the heated side of the chip rose to more than 60°C. The EDs, which appeared within 20 minutes after KA injection, began to decrease in amplitude immediately after cooling began and continued to decrease as the temperature of the cortex was lowered. Sufficient miniaturization and good performance of the cooling device was demonstrated. Further efforts to develop implantable cooling systems and improve existing ones should be continued.

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Ichiro Nakano and E. Antonio Chiocca

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Johan Pallud, Bertrand Devaux, Richard Miles and Gilles Huberfeld