Katsuya Saito

Functional analysis of a novel glioma antigen, EFTUD1

BACKGROUND A cDNA library made from 2 glioma cell lines, U87MG and T98G, was screened by serological identification of antigens by recombinant cDNA expression (SEREX) using serum from a glioblastoma patient. Elongation factor Tu GTP binding domain containing protein 1 (EFTUD1), which is required for ribosome biogenesis, was identified. A cancer microarray database showed overexpression of EFTUD1 in gliomas, suggesting that EFTUD1 is a candidate molecular target for gliomas. METHODS EFTUD1 expression in glioma cell lines and glioma tissue was assessed by Western blot, quantitative PCR, and immunohistochemistry. The effect on ribosome biogenesis, cell growth, cell cycle, and induction of apoptosis and autophagy in glioma cells during the downregulation of EFTUD1 was investigated. To reveal the role of autophagy, the autophagy-blocker, chloroquine (CQ), was used in glioma cells downregulating EFTUD1. The effect of combining CQ with EFTUD1 inhibition in glioma cells was analyzed. RESULTS EFTUD1 expression in glioma cell lines and tissue was higher than in normal brain tissue. Downregulating EFTUD1 induced G1 cell-cycle arrest and apoptosis, leading to reduced glioma cell proliferation. The mechanism underlying this antitumor effect was impaired ribosome biogenesis via EFTUD1 inhibition. Additionally, protective autophagy was induced by glioma cells as an adaptive response to EFTUD1 inhibition. The antitumor effect induced by the combined treatment was significantly higher than that of either EFTUD1 inhibition or CQ alone. CONCLUSION These results suggest that EFTUD1 represents a novel therapeutic target and that the combination of EFTUD1 inhibition with autophagy blockade may be effective in the treatment of gliomas.

Petrous apex cholesterol granuloma: importance of pedicled nasoseptal flap in addition to silicone T-tube for prevention of occlusion of drainage route in transsphenoidal approach--a technical note.

Recently, petrous apex cholesterol granulomas (CGs) have been treated via the endoscopic endonasal transsphenoidal approach (EEA) using a silicone tube, to prevent drainage route occlusion. Occlusion of the drainage route has led to problems with recurrence. The aim of this report is to describe the use of a surgical technique to prevent drainage route occlusion. In surgical technique, the posterolateral wall of the sphenoid sinus was opened by EEA. After cyst debridement, a vascularized nasoseptal flap with a width of approximately 4 cm was inserted into the lumen with a silicone T-tube with a diameter of 7 mm. This technique was used in two patients: the first patient during the second operation after recurrence following occlusion of the drainage route, and the second patient during the first operation. Opening of the cyst wall was confirmed endoscopically in both patients 12–24 months after surgery, even after removal of the T-tube. In conclusion, the use of a pedicled nasoseptal flap with a silicone tube is useful to prevent CG recurrence, by paranasal cavitization of the cystic cavity.

Application of the endoscopic transsphenoidal approach to true type transsellar transsphenoidal meningoencephalocele in an adult: A case report and literature review

Of the transsellar transsphenoidal meningoencephaloceles (TTSMEs), the true type presents with the hernial sac extending from the intracranium to the epipharynx through the sellar floor. The true type is the most serious and difficult to manage, especially when the hernial sac contains vital structures, such as the anterior cerebral artery, pituitary gland, optic nerve, hypothalamus, and third ventricle. Surgical outcome for true type TTSME is reported to be poor. We describe a successful case of endoscopic repair for a 36-year-old man with true type TTSME. Our success with endoscopic repair for true type TTSME in an adult is the first reported case. We believe that the endoscopic transsphenoidal approach allows less invasive surgery and provides an acceptable operative outcome in comparison with other microsurgical approaches.

A pilot study of peptide vaccines for VEGF receptor 1 and 2 in patients with recurrent/progressive high grade glioma

Object Early-phase clinical studies of glioma vaccines have shown feasibility and encouraging preliminary clinical activity. A vaccine that targets tumor angiogenesis factors in glioma microenvironment has not been reported. Therefore, we performed a pilot study to evaluate the safety and immunogenicity of a novel vaccination targeting tumor angiogenesis with synthetic peptides for vascular endothelial growth factor (VEGF) receptor epitopes in patients with recurrent/progressive high grade gliomas. Methods Eight patients received intranodal vaccinations weekly at a dose of 2mg/kg bodyweight 8 times. T-lymphocyte responses against VEGF receptor (VEGFR) epitopes were assessed by enzyme linked immunosorbent spot assays. Results This treatment was well-tolerated in patients. The first four vaccines induced positive immune responses against at least one of the targeted VEGFR epitopes in the peripheral blood mononuclear cells in 87.5% of patients. The median overall survival time in all patients was 15.9 months. Two achieved progression-free status lasting at least 6 months. Two patients with recurrent GBM demonstrated stable disease. Plasma IL-8 level was negatively correlated with overall survival. Conclusion These data demonstrate the safety and immunogenicity of VEGFR peptide vaccines targeting tumor vasculatures in high grade gliomas.

Functional analysis of KIF20A, a potential immunotherapeutic target for glioma

Kinesin family member 20A (KIF20A), an ideal cancer-testis antigen, was reported to be a promising immunotherapeutic target for pancreatic cancers. Clinical trials of KIF20A peptide vaccine immunotherapy have been conducted against pancreatic cancers. To demonstrate the efficacy of KIF20A as a candidate molecular target for gliomas, we analyzed the expression and function of KIF20A in gliomas. Western blot and quantitative PCR analyses showed that KIF20A expression in glioma cell lines and glioma tissues was high compared with that found in a normal brain. KIF20A immunostaining of glioma cells and glioma tissues demonstrated that KIF20A was involved in spindle formation and cytokinesis, and that KIF20A was highly expressed, especially in glioma cells undergoing mitosis. In silico analysis of a cancer microarray database revealed that KIF20A was highly expressed in gliomas depending on the pathological grade, and glioma patients with higher expression of KIF20A showed poorer prognosis. Down-regulating KIF20A reduced cell proliferation in glioma cells due to the failure of cytokinesis and generation of binucleated cells. Additionally, KIF20A inhibition induced significant apoptosis in SF126 glioma cells. Taken together, KIF20A is a tumor-associated antigen involved in the glioma cell growth and cell survival, suggesting that KIF20A is an oncoantigen of gliomas. Thus, KIF20A is a candidate novel immunotherapeutic target for gliomas.

Brain Tumor Stem Cells and Anti-Angiogenic Therapy

The hypothesis that tumor growth may be sustained by a rare subpopulation of cells, termed cancer stem cells, is currently demonstrated in different types of cancer (Al-Hajj et al., 2004; Jordan et al., 2006; Reya et al., 2001). Brain tumor stem cells were isolated from primary brain tumors, such as malignant glioma (Galli et al., 2004; Hide et al., 2008). Glioma stem cells share some characteristics with normal neural stem cells, including the expression of neural stem cell markers, such as CD133 and Nestin (Hadjipanayis and Van Meir, 2009; Singh et al., 2004). Brain tumor stem cells possess the capacity for self-renewal and multipotency (ability to differentiate into neurons, astrocytes, and oligodendrocytes) and the proliferative ability for generation of many progeny. Furthermore, they are able to initiate new tumors in vivo when transplanted into immunocompromised mice even at low cell numbers (Galli et al., 2004). Glioma stem cells play an important role in tumor invasion and therapy resistance (Bao et al., 2006a; Calabrese et al., 2007; Dean et al., 2005; Hirschmann-Jax et al., 2004). Complete surgical resection is almost impossible because of the deep invasion to the normal brain parenchyma. Glioma stem cells have the ability to divide slowly and infinitely, which leads to the resistance to chemotherapy and radiotherapy. These stem cell-like properties allow glioma stem cells to survive selectively and initiate recurrence (Hide et al., 2008). Therapeutic strategy that target glioma stem cells may improve the prognosis of malignant glioma. Recent evidence has revealed that glioma stem cells are located in the highly vascular region, and glioma stem cells’ properties are tightly regulated by the microenvironment, so called vascular niche, similar to normal neural stem cells (Gilbertson and Rich, 2007; Yang and Wechsler-Reya, 2007). The development of new therapeutic strategies that target the glioma stem cells and vascular niche may result in more effective treatment of malignant glioma. In this article, we review the recent evidence on the biology of glioma stem cells associated with vascular endothelial growth factor (VEGF)vascular endothelial growth factor receptor (VEGFR) signalling pathways for anti-angiogenic therapy.

Medulloblastoma in Older Adults: A Case Report and Literature Review

BACKGROUND Medulloblastoma is a malignant tumor of the posterior fossa and is predominantly seen in children younger than 15 years of age. This tumor is uncommon in adults, especially those older than 40 years of age, and reports of cases in patients older than 60 years of age are particularly rare. Although surgery and radiotherapy play important roles in treatment of medulloblastoma in adults, addition of chemotherapy is controversial, especially prior to radiotherapy. CASE DESCRIPTION We present a case of a 63-year-old woman with an atypical medulloblastoma in the cerebellum and a lesion in the suprasellar area that did not appear to be a metastasis of the medulloblastoma. The patient underwent a subtotal resection of the cerebellar medulloblastoma, which was classified histologically as classic subtype and molecularly as non-Wingless/non-Sonic hedgehog subtype in World Health Organization 2016 classification. Then she underwent postoperative chemotherapy followed by radiotherapy. We administered chemotherapy to facilitate therapeutic diagnosis of the suprasellar lesion. The combination treatment resulted in the disappearance of the cerebellar medulloblastoma with treatment toxicity well tolerated. Additionally, the suprasellar lesion remains under control. CONCLUSIONS Even in adults over 60 years of age, medulloblastoma should be included in the differential diagnosis of a cerebellar mass. Chemotherapy for adult medulloblastoma has the potential to be efficacious and tolerable.

A difficult-to-treat Acom aneurysm with the combined vascular anomaly of Acom fenestration and accessory anterior cerebral artery

Background: Vascular anomaly and aneurysmal formation of an anterior communicating artery (Acom) complex has often been reported. Because of such a complicated relationship between the vascular structure and aneurysms, Acom aneurysm is one of the most difficult aneurysms to treat among other common anterior circulation aneurysms. We experienced an extremely rare and difficult-to-treat case of ruptured Acom aneurysm with the combined vascular anomaly of the Acom fenestration and an accessory anterior cerebral artery (ACA). Case Description: A 29-year-old man underwent a clipping surgery for a ruptured Acom aneurysm with an Acom fenestration and an accessory ACA. By reasons of the complicated Acom structure and a posteriorly-projecting aneurysm, the patient was operated via an interhemispheric approach, which is generally reported to provide the best operative view for all types of Acom aneurysms. However, we could not help applying a clip in the narrow working space and the limited operative view, due to the poor mobilization of Acom complex and the interruption by an accessory ACA. Conclusion: The interhemispheric approach may exceptionally have a blind area behind the Acom complex in the case of Acom aneurysms with an accessory ACA. Additionally, the aneurysms arising from the Acom fenestration strongly require neurosurgeons to take a more accurate surgical approach to obtain a direct visualization for an aneurysmal neck.

Isolated Pituitary Tuberculoma

Pituitary tuberculomas are extremely rare, even in the developing countries where tuberculosis is endemic. We report a rare case of isolated pituitary tuberculoma mimicking a pituitary adenoma or a Rathke’s cleft cyst in Japan, a developed country. The patient was a 69-year-old woman presented with visual disturbance. Head magnetic resonance imaging (MRI) with contrast enhancement revealed an isolated intrasellar mass showing central hypointensity with an irregularly enhancing rim. She was operated on via an endoscopic transsphenoidal approach. Histopathological findings and an interferon-gamma release assay were highly suspicious of an isolated tuberculous granuloma. After proper infection control management, she was treated with four-drug antituberculous therapy (ATT). Follow-up MRI showed no recurrence 3 years after the discontinuation of ATT. An isolated pituitary tuberculoma has rarely been reported, especially in developed countries. In conclusion, neurosurgeons should consider an isolated pituitary tuberculoma as one of the differential diagnoses for pituitary tumors, because special management for infection control is required for tuberculosis. An interferon-gamma release assay is helpful for the difficult diagnosis of an isolated pituitary tuberculoma with inactive tuberculosis.