Published papers

A 69-year-old patient with an intramedullary metastasis from colon carcinoma is presented. Total removal of the tumor brought him 3 months of useful life. Although radiation therapy is generally favored, one should consider microsurgical resection of discrete, solitary intramedullary metastases in patients with radioresistant primary tumors. Copyright © 2002 Elsevier Science B.V.

A 21-year-old man presented with bitemporal hemianopia and hyperprolactinemia. Magnetic resonance (MR) imaging showed a suprasellar cystic tumor in contact with the pituitary stalk. The diagnosis was craniopharyngioma. Intraoperatively, there was no clear continuity between the tumor and the tissue of the anterior lobe of the pituitary gland. The pituitary stalk and the diaphragma sellae were intact, and their morphology remained almost completely normal after the tumor was removed. The histological diagnosis was prolactin-producing pituitary adenoma. Postoperatively, the bitemporal hemianopia improved, and the serum prolactin levels returned to normal. The final diagnosis was suprasellar ectopic pituitary adenoma arising in the peri-infundibular region. Follow-up MR imaging at I year showed a normal pituitary stalk and pituitary gland, with no evidence of residual tumor.

Purpose: A variety of cancers, including malignant gliomas, overexpress transforming growth factor-β (TGF-β), which helps tumors evade effective immune surveillance through a variety of mechanisms, including inhibition of CD8+ CTLs and enhancing the generation of regulatory T (Treg) cells. We hypothesized that inhibition of TGF-β would improve the efficacy of vaccines targeting glioma-associated antigen (GAA)-derived CTL epitopes by reversal of immunosuppression. Experimental Design: Mice bearing orthotopic GL261 gliomas were treated systemically with a TGF-β-neutralizing monoclonal antibody, 1D11, with or without s.c. vaccinations of synthetic peptides for GAA-derived CTL epitopes, GARC-1 (77-85) and EphA2 (671-679), emulsified in incomplete Freund's adjuvant. Results: Mice receiving the combination regimen exhibited significantly prolonged survival compared with mice receiving either 1D11 alone, GAA vaccines alone, or mock treatments alone. TGF-β neutralization enhanced the systemic induction of antigen-specific CTLs in glioma-bearing mice. Flow cytometric analyses of brain-infiltrating lymphocytes revealed that 1D11 treatment suppressed phosphorylation of Smad2, increased GAA-reactive/IFN-γ-producing CD8 + T cells, and reduced CD4+/FoxP3+ T reg cells in the glioma microenvironment. Neutralization of TGF-β also upregulated plasma levels of interleukin-12, macrophage inflammatory protein-1α, and IFN-inducible protein-10, suggesting a systemic promotion of type-1 cytokine/chemokine production. Furthermore, 1D11 treatment upregulated plasma interleukin-15 levels and promoted the persistence of GAA-reactive CD8+ T cells in glioma-bearing mice. Conclusions: These data suggest that systemic inhibition of TGF-β by 1D11 can reverse the suppressive immunologic environment of orthotopic tumor-bearing mice both systemically and locally, thereby enhancing the therapeutic efficacy of GAA vaccines. © 2009 American Association for Cancer Research.

Cancer-induced immunosuppression is a major problem as it reduces the anti-tumor effects of immunotherapies. In cancer tissues, cancer cells, immune cells, and other stromal cells interact and create an immunosuppressive microenvironment through a variety of immunosuppressive factors. Some cancer subpopulations such as cancer cells undergoing epithelial-mesenchymal transition and cancer stem-like cells have immunosuppressive and immunoresistant properties. The production of immunosuppressive factors by cancer cells is mechanistically attributed to oncogenic signals frequently activated in cancer cells, including the STAT3, MAPK, NF-κB, and Wnt/β-catenin signals, which are upstream events leading to immunosuppressive cascades. Moreover, some of these signals are also activated in immunosuppressive immune cells stimulated by cancer-derived factors and contribute to their immunosuppressive activities. Therefore, targeting these signals both in cancer cells and immunosuppressive immune cells may result in the restoration of immuno-competence in cancer patients and improve current immunotherapy. © The Japanese Society of Hematology 2011.

Cancer stem cells are relatively resistant to chemotherapy, and cause relapse of cancer. Thus, various strategies to eliminate cancer stem cells have recently been exploited. One of them is immunotherapy. To develop the immunotherapy targeting cancer stem cells, tumor antigens expressed in cancer stem cells have been identified, and their use in the immunotherapy is expected. However, cancer stem cells may have an immunosuppressive ability. Therefore, blockade of the immunosuppressive mechanisms of cancer stem cells may also be required for development of effective immunotherapies against cancer stem cells.

A 62-year-old Japanese male patient presented with right oculomotor, abducens, and trigeminal nerve disturbances. Neuroimaging revealed a right middle cranial fossa mass lesion with the characteristics of trigeminal schwannoma. The patient underwent a right temporal craniotomy for gross total resection. Histological examination confirmed a metastasis of adenoid cystic carcinoma (ACC). After the operation, no evidence of the primary lesion could be found. The patient was treated with radiation therapy. ACC can be difficult to identify before histological confirmation. The incidence of intracranial invasion of ACC is 4-22%, but in this case no evidence of the primary lesion was found.

The RNase III endonuclease Dicer plays a key role in generation of microRNAs (miRs). We hypothesized that Dicer regulates cancer cell susceptibility to immune surveillance through miR processing. Indeed, Dicer disruption up-regulated intercellular cell adhesion molecule (ICAM)-1 and enhanced the susceptibility of tumor cells to antigen-specific lysis by cytotoxic T-lymphocytes (CTLs), while expression of other immunoregulatory proteins examined was not affected. Blockade of ICAM-1 inhibited the specific lysis of CTLs against Dicerdisrupted cells, indicating a pivotal role of ICAM-1 in the interaction between tumor cells and CTL. Both miR-222 and -339 are downregulated in Dicer-disrupted cells and directly interacted with the 3′ untranslated region (UTR) of ICAM-1 mRNA. Modulation of Dicer or these miRs inversely correlated with ICAM-1 protein expression and susceptibility of U87 glioma cells to CTL-mediated cytolysis while ICAM-1 mRNA levels remained stable. Immunohistochemical and in situ hybridization analyses of 30 primary glioblastoma tissues demonstrated that expression of Dicer, miR-222, or miR-339 was inversely associated with ICAM-1 expression. Taken together, Dicer is responsible for the generation of the mature miR-222 and -339, which suppress ICAM-1 expression on tumor cells, thereby down-regulating the susceptibility of tumor cells to CTL-mediated cytolysis. This study suggests development of novel miR-targeted therapy to promote cytolysis of tumor cells.

In an attempt to develop effective vaccines against central nervous system (CNS) tumors, we evaluated the ability of vaccines with standard dendritic cells (DC) versus type 1 polarizing DCs (DC1) to induce glioma-specific type 1 CTLs with CNS tumor-relevant homing properties and the mechanism of their action. C57BL/6 mouse-derived bone marrow cells were cultured with mouse granulocyte/macrophage colony-stimulating factor (GM-CSF) for 6 days, and CD11c + cells were subsequently cultured with GM-CSF, rmIFN-γ, rmIFN-α, rmIL-4, and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for 24 hours to generate DC1s. In analogy to their human counterparts, mouse DC1s exhibited surface marker profiles of mature DCs and produced high levels of IL-12 and CXCL10. Importantly for their application as cancer vaccines, such DC1s stably retained their type 1 phenotype even when exposed to type 2-promoting or regulatory T cell (Treg)-promoting environments. Consistently, mouse DC1s induced antigen-specific type 1 CTLs more efficiently than nonpolarized DCs in vitro. DC1s given s.c. migrated into draining lymph nodes, induced antigen-specific CTLs, and suppressed Treg accumulation. In addition, s.c. immunization with DC1s loaded with glioma-associated antigen (GAA)-derived CTL epitope peptides prolonged the survival of CNS GL261 glioma-bearing mice, which was associated with efficient CNS glioma homing of antigen-specific CTLs. Intratumoral injections of GAA peptideloaded DC1s further enhanced the anti-CNS glioma effects of DC1-based s.c. immunization. Interestingly, the antitumor functions were abrogated with CXCL10 -/- mouse-derived DC1s. Collectively, these findings show the anti-CNS glioma effects of DC1-based therapy and a novel role of CXCL10 in the immunologic and therapeutic activity of DC-based cancer vaccines. © 2009 American Association for Cancer Research.

STAT3 signaling constitutes an important negative feedback mechanism for the maintenance of immune homeostasis, a suppressive signal for the Th1 immune response in murine macrophages, and a cancer immune evasion signal in various immune cells. The strategy for STAT3 signal inhibition should be considered, because these features could impede effective cancer immunotherapy. We have evaluated the effects of STAT3 inactivation in dendritic cells (DCs) on immune responses in mice and humans. DCs derived from LysMcre/STAT3flox/flox mice displayed higher cytokine production in response to TLR stimulation, activated T cells more efficiently, and were more resistant to the suppression of cytokine production by cancer-derived immunosuppressive factors compared with DCs from control littermates. Antitumor activities of STAT3-depleted and control DCs were compared by intratumoral administration of gp70 Ag peptide-pulsed DCs in the therapeutic MC38 tumor model. Intratumoral administration of STAT3-depleted DCs significantly inhibited MC38 tumor growth of both injected and nontreated remote tumors. The inhibition was accompanied by an increase in gp70-specific T cell response as well as in systemic Th1 immune response. STAT3-depleted human DCs with adenoviral STAT3 short hairpin RNAwere also capable of producing more cytokines with TLR stimulation and more resistant to cancer-derived factors, and they induced tumor Ag-specific T cells more efficiently than control DCs. The identified role of DC STAT3 signaling in both in vivo therapeutic tumor models in mice and in vitro-specific T cell induction in humans indicates that STAT3-inactivated DCs may be a promising approach for cancer immunotherapy. Copyright © 2011 by The American Association of Immunologists, Inc.

By screening a human testis cDNA library with glioma patients' sera, we isolated a transcriptional factor, SOX6. Here, we analyzed SOX6 expression in gliomas having a range of malignancy grades using immunostaining. Murine Sox6 is a transcriptional factor that is specifically expressed in the developing central nervous system and in the early stages of chondrogenesis in mouse embryos. The reverse transcription-polymerase chain reaction (RT-PCR) revealed that the SOX6 gene was more highly expressed in glioma tissues and fetal brain than in normal adult brain and other cancer cells, except melanoma cells. Immunohistochemical analysis with the anti-SOX6 antibody showed that all the glioma tissues analyzed (14 glioblastomas, 14 anaplastic astrocytomas, 3 anaplastic oligoastrocytomas, 5 diffuse astrocytomas, 1 oligodendroglioma, and 1 pilocytic astrocytoma) expressed SOX6 in tumor cells, but only a few SOX6-positive cells were detected in nonneoplastic tissues from the cerebral cortex. These results indicate that the developmentally regulated transcription factor SOX6 may be a potential diagnostic marker for gliomas.

Case: A 17-year-old man was brought to our hospital by ambulance due to a severe headache and vomit. The meningeal irritation and right abducens nerve paralysis were found on neurologic examination. Head computed tomography (CT) revealed poor growth of the right mastoid pneumatization and a high absorption area in the sinus sagittalis superior from the right lateral venous sinus. On cerebral angiography, there was no depiction of the right sigmoid sinus, and thrombus was observed in sinus sagittalis superior. Therefore, it was diagnosed as cerebral venous sinus thrombosis. The cause of thrombosis was unknown a blood test. After admission the patient had right otorrhea. After examination, right otitis media cholesteatoma was found. Treatment was commenced with hypothesis thatotitis media cholesteatoma was involved as a cause of cerebral venous sinus thrombosis. Later, the symptoms resolved, and the patient was discharged. In cerebral venous sinus thrombosis, we should consider the possibility of otitis media cholesteatoma as a cause due to poor growth of the mastoid pneumatization as seen on head CT.

© 2019, The Author(s). The anti-VEGF antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Theoretically, vascular endothelial growth factor receptors (VEGFRs)-specific cytotoxic T lymphocytes (CTLs) can kill both tumor vessel cells and tumor cells expressing VEGFRs. Here we show an exploratory clinical study of VEGFRs peptide vaccine in seven patients with progressive NF2-derived schwannomas. Hearing improves in 2/5 assessable patients (40%) as determined by international guidelines, with increases in word recognition scores. Tumor volume reductions of ≥20% are observed in two patients, including one in which bevacizumab had not been effective. There are no severe adverse events related to the vaccine. Both VEGFR1-specific and VEGFR2-specific CTLs are induced in six patients. Surgery is performed after vaccination in two patients, and significant reductions in the expression of VEGFRs in schwannomas are observed. Therefore, this clinical immunotherapy study demonstrates the safety and preliminary efficacy of VEGFRs peptide vaccination in patients with NF2.

© 2020 The Author(s). Background: The expression of vascular endothelial growth factor (VEGF)-A/ VAGF receptors (VEGFRs) signaling plays a pivotal role in the tumor angiogenesis and the development of the immunosuppressive tumor microenvironment in glioblastomas. We have previously conducted exploratory clinical studies investigating VEGFRs peptide vaccination with and without multiple glioma oncoantigens in patients with recurrent high-grade gliomas. Recently, an exploratory clinical investigation of VEGFRs peptide vaccination was conducted in patients with progressive neurofibromatosis type 2. Those studies suggested that cytotoxic T lymphocytes (CTLs) induced by the vaccination can directly kill a wide variety of cells associated with tumor growth, including tumor vessels, tumor cells, and immunosuppressive cells expressing VEGFR1 and/or 2. In the present study, synergistic activity of the combination of VEGFRs peptide vaccination with chemotherapy was evaluated. Methods: We performed the first clinical trial to assess VEGFR1 and 2 vaccination along with temozolomide (TMZ) -based chemoradiotherapy for the patients with primary glioblastomas. Furthermore, histopathological changes after the vaccination were evaluated using paired pre- and post- vaccination specimens. Results: The disappearance of radiographically enhanced lesion was observed in 2 patients after the vaccination, including one in which the methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter was not observed. The histopathological findings of pre- and post-vaccination specimens demonstrated that tumor vessels showed negative or slight VEGFRs expressions after the vaccination and most endothelial cells were covered with PDGFR-β-positive pericytes. Notably, CTLs induced by VEGFRs peptide vaccination attacked not only tumor vessels but also tumor cells and regulatory T cells expressing VEGFRs even in recurrent tumors. Conclusions: VEGFR1 and 2 vaccination may have a preliminary synergistic effect when administered with TMZ. The limitation of the present study was the paucity of the number of the samples. Further studies involving more patients are warranted to confirm the findings of this study. Trial registration: This study was registered as UMIN000013381 (University Hospital Medical Information Network-Clinical Trial Registry: UMIN-CTR) on 5 March, 2014 and with the Japan Registry of Clinical Trials (jRCT) as jRCTs031180170 on 1 March, 2019.

© 2020 Scientific Scholar. All rights reserved. Background: Hemostasis plays an important role in safe brain tumor resection and also reduces the risk for surgical complications. This study aimed to evaluate the efficacy of FLOSEAL®, a topical hemostatic agent that contains thrombin and gelatin granules, in brain tumor resections. Methods: We evaluated the hemostatic effect of FLOSEAL by scoring the intensity of bleeding from 1 (mild) to 4 (life threatening). We assessed the rate of success of hemostasis with 100 patients who underwent intracranial tumor resection. We also investigated the duration of the operation, the amount of intra- and postoperative bleeding, the number of hospital stays, and adverse events in patients who used FLOSEAL compared with those who did not use FLOSEAL. Results: FLOSEAL was applied to a total of 109 bleeding areas in 100 patients. A total of 95 bleeding areas had a score of 1 and 91 (96%) showed successful hemostasis. Thirteen bleeding areas scored 2 and 8 (62%) showed hemostasis with the first application of FLOSEAL. The second application was attempted with five bleeding areas and four showed hemostasis. About 94% (103/109 areas) of bleeding points successfully achieved hemostasis by FLOSEAL. Moreover, FLOSEAL significantly decreased the amount of intraoperative bleeding and postoperative bleeding as assessed with computed tomography on 1 day postoperatively compared with no use of FLOSEAL. There were no adverse events related to FLOSEAL use. Conclusion: Our results indicate that FLOSEAL is a reliable, convenient, and safe topical hemostatic agent for intracranial tumor resection.

© 2018 Vertebrobasilar dolichoectasia sometimes presents with symptoms related to mass effect like cranial nerve palsies, or with ischemia or hemorrhage. Symptomatic hydrocephalus as a complication of vertebrobasilar dolichoectasia is extremely uncommon. Furthermore, there are few cases of vertebrobasilar dolichoectasia, in which cerebrospinal fluid flow disorder mechanisms are clearly demonstrated in neuroimaging findings. Here, we describe a patient with vertebrobasilar dolichoectasia who presented with symptomatic hydrocephalus due to direct compression against the third ventricle, which was immediately relieved by ventriculoperitoneal shunt. This patient exhibited a progressive clinical course of acute hydrocephalus; however, a subclinical ventricular dilatation may have been present before the onset. Therefore, a careful follow-up is warranted to treat symptomatic hydrocephalus that may develop in patients with vertebrobasilar dolichoectasia.