Immunotherapy for cancer began in the 1890s in the form of Coley’s toxin, and in 1950 Burnett proposed the theory on the mechanism of immunological monitoring. In the early 1980s, Rosenberg et al., of the National Cancer Center of the USA (NCI) established lymphokine-activated killer (LAK)/cytotoxic T lymphocyte (CTL) therapy, and a Japanese neurosurgical group joined this field with the introduction of cytokine gene transfer therapy in the 1990s. Until this stage, cancer immunotherapy had generally been looked at skeptically. However, in 1996 Allison showed for the first time that antibody blockade of a T-cell inhibitory molecule (known as CTLA-4) can lead to enhanced antitumor immune response and tumor rejection. On the other hand, in 1992 in the laboratory of Professor Tasuku Honjo, Programmed cell death 1 (PD-1) was isolated and identified as a gene whose expression is strongly induced at the time of death of T lymphocytes (T cells). It was proved to cause autoimmune disease in 1999 and was shown to act as an immunity checkpoint in 2000. Recently, a breakthrough was made in cancer immunotherapy via PD-1-based immunity checkpoint inhibitors, leading to a new era in the field of cancer treatment. However, in the case of glioblastoma and the like, the effect of PD-1 antibody alone is insufficient, and the establishment of combination therapy with other drugs is anticipated.

  Anti-angiogenic therapy, such as bevacizumab, for glioblastoma has several resistance mechanisms. Therefore, the effect of that is limited in point of prolongation of patient survival. Among resistance mechanisms, vessel co-option (normal blood vessel hijack) and vascular mimicry have been well recognized morphologically, but the molecular mechanism of those have not yet well investigated.

  Recent studied demonstrated that IRE1α, angiopoietin2, actin related proteins 2/3 complex, L1CAM, serpin B2 for co-option and PECAM-1, glioma stem cell, HIF-1α for mimicry.

  In future, molecular therapy targeting vessel co-option and mimicry combined with present anti-VEGF therapy is needed for anti-angiogenic therapy of glioblastoma.

  Remarkable invasiveness is one of the major characteristics of glioma. When glioma develops, tumor cells have already reached a remote site in the brain, Therefore, it is impossible to remove all of the glioma cells by surgery alone. In recent years, new findings on glioma invasion have accumulated via advanced basic research. In particular, research on the tumor microenvironment has progressed. Local hypoxia is thought to be the strongest trigger for cell migration. Interaction between microglias and glioma cells positively promotes invasion. Various treatments for glioma change the microenvironment as glioma cells easily invade. These findings indicate that the tumor microenvironment can be a target for glioma invasion.

  Cancer stem cells are a small subpopulation of immature, undifferentiated tumor cells characterized by resistance to therapy/cell death. They are also characterized by their ability to initiate tumors on the one hand and on the other to undergo supposedly irreversible differentiation into mature, non-cancer stem cells that no longer retain therapy resistance or tumor-initiating capacity. As such, cancer stem cells are deemed a major culprit of post-treatment tumor recurrence and therefore a key therapeutic target in the development of curative cancer therapies. Since the publication of our previous review that addressed fundamental issues of cancer stem cell research with particular emphasis on glioma stem cells, a non-negligiable number of key observations have been reported that challenge these classical views of cancer stem cells. Here, in this updated review, we discuss these observations, put forward novel hypotheses to accommodate these observations into the classical views of cancer stem cells, and show how such hypotheses help to evolve our conception of cancer and glioma stem cells.

  Careful examination using an appropriate experimental model is necessary to understand the molecular mechanisms underlying tumorigenesis and to develop new therapies. Cultured cell lines are an essential tools that are currently widely used in cancer research. However, those maintained under non-physiological conditions in vitro cannot necessarily accurately reflect the disease pathology that occurs in patients. Animal models are competent to faithfully recapitulate the biology and pathology of the human disease in vivo ; therefore more useful information can be obtained by selecting the appropriate animal model suitable for a particular experiment. This review outlines the basics, advantages, and limitations of the mouse models commonly used for current cancer research.

  Hyperkinetic seizures (HKS) are characterized by complex movements involving the proximal segment of the limbs and trunk. The proximal predominance of these movements results in large movements, thus the label “hyperkinetic.” Previous reports suggested the orbitofrontal and anterior cingulate cortex are associated with HKS.

  We describe the two male patients with frontal lobe epilepsy who manifest HKS. Both were successfully treated by surgical resection.

  The patients experienced their first seizures at eleven years old and five years old. Both cases exhibited progressive, intractable HKSs and intellectual deterioration. In both, HKS was misdiagnosed as a psychosis. At the ages of nineteen, they were evaluated by a comprehensive epilepsy monitoring unit. FLAIR MR images revealed thickened gray matter and hyperintensity of white matter at right anterior cingulate cortex in one case and that at left frontal lobe involving orbitofrontal area in the other case. Long-term video electroencephalography (EEG) showed interictal spikes in fronto-temporal area in both cases. Ictal EEG was non-localizable in the former, and attenuation in left frontal area in the latter.

  The former was evaluated using intracranial EEG recording, and revealed that the anterior cingulate cortex was the seizure-onset zone. Followed focal cortical resection was performed. The latter was done the extended frontal lobectomy with preservation of the language area since functional mapping is not ideal in patients with mental retardation. Both patients emerged seizure-free.

  This work underscores the importance of considering HKS, which is easily misdiagnosed as a psychiatric disorder, as a manifestation of frontal lobe epilepsy.

  The patient is a 57-year-old female, with a past history of ruptured aneurysm of left MCA bifurcation, treated with coil embolization. One year follow up angiography showed partial recanalization of the aneurysm. She underwent stent-assisted coiling under general anesthesia. Head CT performed on day 4 postoperatively revealed small high density area of left insula. Following MRI showed parenchymal micro-bleeding. Consecutive CT showed no sign of hematoma expansion or re-bleeding. Since the patient was asymptomatic, she was discharged. One month after the procedure, she presented with slight disorientation and weakness of the right hand. Head CT showed diffuse brain edema. Delayed sequence contrast CT revealed white matter change with multi-focal ring enhancement. The diffuse multifocal enhanced lesions were suspected to be the cause of the edema. Head MRI was taken to rule out the possibility of brain infarction. Diffusion weighted image excluded the possibility of brain infarction caused by the stent occlusion. Hydrophilic polymer-induced multiple foreign body granulomas were suspected. The patient was treated with steroids and fully recovered. Since its natural history is still unknown, foreign body granuloma might be underestimated as a complication of endovascular surgery. Micro-bleeding caused by foreign body granuloma in the early stage after surgery is rare, and could be the early sign of foreign body granuloma. We suggest that the delayed sequence contrast CT might be helpful for early detection and diagnosis of foreign body granuloma.