Tatsuhiro Joki

Induction of effective antitumor immunity in a mouse brain tumor model using B7‐1 (CD80) and intercellular adhesive molecule 1 (ICAM‐1; CD54) transfection and recombinant interleukin 12

Although tumor‐specific T lymphocytes recognize tumor‐associated antigens (TAA) present on their cell surface via major histocompatibility complex (MHC) molecules, T cells require other activating signals. These are provided by costimulatory molecules, including B7‐1 (CD80), B7‐2 (CD86) and intercellular adhesive molecule 1 (ICAM‐1; CD54). Transfecting mouse tumor cell lines with the B7 gene can lead to primary tumor rejection and the establishment of protective immunity. However, some studies have shown that the B7 effect upon T‐cell‐dependent tumor immunity is limited. Therefore, we examined the antitumor effects of recombinant interleukin 12 (IL‐12) and genetically engineered glioma cells expressing B7‐1 or both B7‐1 and ICAM‐1. Vaccination of mice with B7‐1‐expressing tumor cells substantially inhibited the growth of subcutaneously inoculated gliomas but not those located in the brain. Vaccination with B7‐1‐expressing tumor cells and systemic recombinant IL‐12 (rIL‐12) was more effective than either B7‐1‐expressing tumor cells or rIL‐12 alone. Our murine brain tumor model also showed that vaccination with tumor cells expressing both B7‐1 and ICAM‐1 combined with rIL‐12 prolonged survival. We have demonstrated the therapeutic potential of vaccination with rIL‐12 and tumor cells expressing both B7‐1 and ICAM‐1 in the control of glioma growth. Int. J. Cancer 82:714–720, 1999.

Robotic digital subtraction angiography systems within the hybrid operating room.

BACKGROUND:Fully equipped high-end digital subtraction angiography (DSA) within the operating room (OR) environment has emerged as a new trend in the fields of neurosurgery and vascular surgery. OBJECTIVE:To describe initial clinical experience with a robotic DSA system in the hybrid OR. METHODS:A newly designed robotic DSA system (Artis zeego; Siemens AG, Forchheim, Germany) was installed in the hybrid OR. The system consists of a multiaxis robotic C arm and surgical OR table. In addition to conventional neuroendovascular procedures, the system was used as an intraoperative imaging tool for various neurosurgical procedures such as aneurysm clipping and spine instrumentation. RESULTS:Five hundred one neurosurgical procedures were successfully conducted in the hybrid OR with the robotic DSA. During surgical procedures such as aneurysm clipping and arteriovenous fistula treatment, intraoperative 2-/3-dimensional angiography and C-arm-based computed tomographic images (DynaCT) were easily performed without moving the OR table. Newly developed virtual navigation software (syngo iGuide; Siemens AG) can be used in frameless navigation and in access to deep-seated intracranial lesions or needle placement. CONCLUSION:This newly developed robotic DSA system provides safe and precise treatment in the fields of endovascular treatment and neurosurgery.

Anti-tumor activity of interleukin-2-producing tumor cells and recombinant interleukin 12 against mouse glioma cells located in the central nervous system

Interleukin 12 (IL‐12) exhibits anti‐tumor activity in a variety of laboratory models. Although IL‐12 itself activates strong anti‐tumor activity, the combination of vaccine therapy with IL‐2‐transduced tumor cells and systemic rIL‐12 has been shown to cure tumor‐bearing mice more effectively than either rIL‐12 or IL‐2‐transduced tumor vaccines alone. In the present study, regression of brain tumors established in naive mice was obtained by combined administration of an intratumoral injection of a single dose of IL‐2‐producing glioma cells (SR/IL‐2 cells) and recombinant IL‐12. Intraperitoneal rIL‐12 administration substantially delayed the growth of s.c. inoculated gliomas, but not of gliomas located in the brain. Although vaccination with SR/IL‐2 cells alone was not effective against s.c. inoculated gliomas, the combination therapy of vaccination with irradiated SR/IL‐2 cells and systemic rIL‐12 was more effective than rIL‐12 alone. In our brain‐tumor model, intratumoral administration of irradiated SR/IL‐2 cells and of rIL‐12 remarkably prolonged survival as compared with untreated mice. Efficacy was reduced when studies were performed in mice depleted of CD8+ cells or NK cells. Mice cured of their intracerebral tumors by combined administration of SR/IL‐2 cells and rIL‐12 demonstrated protective immunity upon rechallenge. In summary, the therapeutic potential for control of tumor growth by intratumoral administration of IL‐2‐producing glioma cells and rIL‐12 may be useful in the development of treatment for patients with glioma. Int. J. Cancer 80:425–430, 1999.

Neuroendoscopic placement of Ommaya reservoir into a cystic craniopharyngioma.

Abstract Introduction. Total removal of the tumor is the most acceptable therapeutic modality in the management of craniopharyngioma; however, there are innumerable factors that can upset treatment plans. Unresectable lesions are often treated with gamma knife surgery (GKS). Reduction of the cystic volume is necessary, to decrease the area to be treated with GKS. An Ommaya reservoir system is usually placed during open surgery or by stereotactic access. Materials and methods. The authors use a neuroendoscope for safer and less invasive placement of the Ommaya reservoir into deep-seated cystic lesions. The cystic component is aspirated, and the Ommaya reservoir tube is precisely guided and placed into the cyst cavity under neuroendoscopic control with a newly developed two-burr-hole technique. This neuroendoscopic procedure could make it easier to reduce cystic volume prior to GKS as the final procedure. This technique may also be used for instillation of chemotherapeutic agents and for repeat aspirations, making the achievement of cystic control more likely. This type of neuroendoscopic management is a safe and effective procedure and could be considered as an alternative management technique for some stubborn cystic craniopharyngiomas.

Antitumor activity of interleukin-18 on mouse glioma cells.

Interleukin-18 (IL-18) exhibits antitumor activity in various laboratory models. In the current study, brain tumors in naive mice regressed after an intratumoral injection of a single dose of recombinant IL-18 (rIL-18). Intraperitoneal rIL-18 substantially delayed the growth of subcutaneously inoculated gliomas but not gliomas located in the brain. Efficacy was reduced when studies were performed in mice depleted of natural killer cells. Although intracerebral administration of rIL-18 increased the serum interferon-&ggr; concentration, the antitumor effect of IL-18 was not mediated by interferon-&ggr;. These data suggest the therapeutic potential for control of tumor growth by intratumoral administration of rIL-18 in patients with glioma.

Neuroendoscopic anatomy and surgery in pineal region tumors

The therapeutic modalities for pineal region tumors in Western countries differ from those in far-eastern countries, that is, Japan and Korea, mainly because of the different patient populations. The majority of pineal region tumors in Japan and Korea are radio sensitive and/or chemosensitive, and adjuvant therapy rather than extensive surgery plays the main part in the treatment of these tumors. The authors have applied minimally-invasive preferential management in pineal region tumors in last 8 years. For the therapeutic regimen, if the tumor markers alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) were not detected in serum and there was significant ventricular dilation visualized on neuroimages, neuroendoscopic surgery was first applied for tumor debulking with tissue diagnosis and gross morphological analysis of the tumor and the intraventricular structures, followed by third-ventriculostomy. In the results, our minimally-invasive preferential regimen clarified the precise indication for neuroendoscopic procedures, and the majority of our patients with dilated ventricles and no evidence of tumor markers were treated satisfactorily with effective neuroendoscopic procedures as the initial procedure. Then avoided unnecessary craniotomy and radiotherapy and promised excellent therapeutic outcomes. Neuroendoscopic procedures have a great advantage in the management of chemo- or radiosensitive tumors, such as germinoma, pineoblastoma, or primitive neuroectodermal tumor. The neuroendoscopic anatomy including the lateral and third ventricles with a pineal region tumor with or without tumor dissemination was described in detail, together with the neuroendoscopic surgical technique.

Clinicopathological Features of Growth Hormone-Producing Pituitary Adenomas in 242 Acromegaly Patients: Classification according to Hormone Production and Cytokeratin Distribution

The aim of this study was to clarify the relationship between the histological features of GH-producing adenomas surgically resected at the Toranomon Hospital and the clinical features of the patients. Histological examinations, including immunohistochemistry for anterior pituitary hormones and cytokeratin (CK), were performed on 242 consecutively excised GH-producing pituitary adenomas. Immunohistochemistry showed 45% of the adenomas to be monohormonal and 55% to be plurihormonal, producing GH-PRL (77%), GH-TSH (13%), and GH-PRL-TSH (10%). One-fourth of the monohormonal GH adenomas had a dot-like pattern of CK immunoreactivity in the majority of the tumor cells (>80%); they were significantly more common in female or younger patients and usually tended to be larger and more invasive than monohormonal GH adenomas with perinuclear CK. Interestingly, CK-immunonegative adenomas were found in only 5% of the patients; they also showed a tendency to be larger, suggesting that they are a distinct type of GH adenoma with clinically aggressive features. Serum hormone levels correlated well with tumor size only in GH-producing adenomas with a perinuclear pattern of CK immunoreactivity. Each histological subtype of adenoma, classified according to the pattern of CK immunoreactivity, was associated with distinct clinical characteristics. This information is useful for understanding the pathophysiology of acromegaly-causing GH-producing adenomas.

Assessment of alterations in gene expression in recurrent malignant glioma after radiotherapy using complementary deoxyribonucleic acid microarrays.

OBJECTIVE We used complementary deoxyribonucleic acid expression microarrays to assess the effects of radiotherapy on gene expression in glioblastoma multiforme. We hypothesized that postradiation recurrent tumors may demonstrate alterations in gene expression from the primary tumor specimen. METHODS Patients were diagnosed with glioblastoma multiforme at resection of the initial tumor, and they received 60 Gy of fractionated radiotherapy before recurrence. Ribonucleic acid samples from both the primary and the postradiation recurrent tumor in each patient were screened and compared using complementary deoxyribonucleic acid expression arrays and Northern blot analysis. RESULTS Messenger ribonucleic acid levels of growth factors participating in paracrine loops, such as vascular endothelial growth factor and platelet-derived growth factor receptor &bgr;, were decreased in postradiation recurrent tumors as compared with primary tumors in three of four patients. However, messenger ribonucleic acid levels of growth factors involved in autocrine loops, such as epidermal growth factor receptor, platelet-derived growth factor &agr;, platelet-derived growth factor A, and basic fibroblast growth factor, were decreased in two of four, two of four, three of four, and three of four patients’ recurrent tumors, respectively. Microvessel counts demonstrated that blood vessel growth was decreased significantly in postradiation recurrent tumor specimens. CONCLUSION After radiotherapy of glioblastoma multiforme, levels of paracrine-acting growth factors are diminished in correspondence with the reduction in vascular density. In contrast, growth factors that participate in autocrine loops demonstrate elevated levels of gene expression. These results suggest that maintenance of autocrine loops may be important in tumor regrowth after radiotherapy.

Induction of antitumor immunity using Intercellular adhesion molecule 1 (ICAM-1) transfection in mouse glioma cells

We investigated the role of intercellular adhesion molecule 1 (ICAM-1) expression in tumorigenicity of gliomas and the antitumor effects of glioma cells genetically engineered to express ICAM- 1. Mouse glioma cells transfected with ICAM-1 grew in T-cell deficient mice but not in syngeneic mice. Vaccination with ICAM-1-transfected tumor cells markedly inhibited the growth of subcutaneously inoculated gliomas but not gliomas located in the brain. In vivo antibody ablation study revealed that CD4+ T, CD8+ T and NK cells were all required to produce the antitumor effect of SR/ICAM- 1. In this study, we demonstrated the therapeutic potential of vaccination with ICAM-1-overexpressing tumor cells for the control of the tumor growth.

A case of sphenoid sinus meningoencephalocele repaired by an image-guided endoscopic endonasal approach

We report a Japanese patient with a complaint of unilateral watery nasal discharge. Analysis of the nasal discharge showed it to contain high levels of sugar and transferrin, which indicated cerebrospinal fluid (CSF) rhinorrhea. A diagnosis of sphenoid sinus meningoencephalocele was easily made on the basis of the CT, MRI and nasal discharge findings. We performed surgery by an image-guided endoscopic endonasal approach (IGEEA). An image guidance system (IGS) was used to confirm the position of the bone defect and the prolapsed brain lobe. We resected the brain lobe, and used fat tissue and fascia to create an extracranial-intracranial blockade. As of 18 months after the operation, there is no evidence of infection or CSF leakage. The IGEEA enabled us to successfully repair the middle skull base using a multi-layer sealing technique, while the IGS allowed us to confirm the anatomical structures and successfully avoid causing collateral damage to the surrounding tissues. This case exemplifies the beneficial effect that of the development of surgical support equipment on the operative approach that is now indicated for sphenoid sinus meningoencephaloceles: the endonasal approach has largely replaced other approaches, such as lateral rhinotomy.