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ABSTRACT: We investigated stereotactic intratumoral microinfusion of nimustine (ACNU) in recurrent brain tumors. Eligibility required
histologic confirmation of glioma recurrence despite standard radiotherapy and chemotherapy as well as enhancement of the
recurrence with gadolinium on magnetic resonance imaging (MRI). A total intratumoral dose of 10 mg of ACNU was administered
continuously with a microinfusion pump over an average of 13h. Fifteen infusions were given in nine patients. All patients
completed the treatment safely. On MRI, necrotic changes surrounded the infusion area in all patients, and tumor progression
was inhibited or performance score was improved in seven of nine patients. No symptomatic systemic toxicity was evident, although
one patient developed permanent left oculomotor palsy locally after treatment of a left medial temporal tumor. It is concluded
that direct microinfusion of ACNU into recurrent gliomas can induce tumor necrosis and inhibit tumor growth.
Brain Tumor Pathology 04/2012; 18(1):23-28. · 1.19 Impact Factor
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ABSTRACT: The retrospective clinicopathological characteristics of oligodendroglial tumors were investigated in patients who underwent
surgery, radiotherapy, and/or chemotherapy. Regarding oligodendroglioma and oligoastrocytoma without malignancy, patients
who had undergone radiation therapy at a total dose of 40–50 Gy had relatively long postoperative survival. Of these 15 patients,
6 showed signs of recurrence, and after additional treatment, 5 patients are still alive. On the other hand, regarding anaplastic
oligodendroglial tumors, patients with anaplastic oligoastrocytoma responded well to combination chemotherapy with interferon
β, nitrosourea derivatives (ACNU/MCNU), and radiation therapy (referred to as IAR/IMR) and survived longer than patients with
anaplastic oligodendroglioma. In conclusion, patients with oligodendroglial tumors could survive longer by treatment involving
surgery and radiotherapy. As for malignancy, cases of anaplastic oligoastrocytoma could be effectively treated by adjuvant
therapy using IAR/IMR after surgery, but in case of anaplastic oligodendroglioma, the response to IAR/IMR was not good, and
another strategy of treatment should be recommended.
Brain Tumor Pathology 04/2012; 17(1):29-33. · 1.19 Impact Factor
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Kenichiro Iwami,
Shinji Shimato,
Masasuke Ohno,
Hideho Okada,
Norimoto Nakahara,
Yuichiro Sato, Jun Yoshida,
Satoshi Suzuki,
Hiroyoshi Nishikawa,
Hiroshi Shiku,
Atsushi Natsume,
Toshihiko Wakabayashi
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ABSTRACT: Dendritic cell (DC)-based vaccination targeting tumor-associated antigens is an attractive approach to overcoming the limitations of current treatments for malignant gliomas (MG). Interleukin-13 receptor α2 chain (IL-13Rα2) is a promising target because of its abundant and specific expression in MG. We conducted a phase I trial of DC vaccination in patients with recurrent MG using two IL-13Rα2-derived peptides restricted to HLA-A*0201 and -A*2402. The objective was to evaluate the safety and clinical and immunologic responses.
Eight recurrent MG patients were enrolled. DC were generated from peripheral blood and pulsed with HLA-matched peptide; 1 × 10(7) DC were administered every 2 weeks for a maximum of six immunizations. The T-cell response in peripheral blood was evaluated by tetramer and ELISPOT assays in HLA-A*2402 patients.
All enrolled patients except one completed at least four DC vaccinations. No severe adverse events were observed. A positive T-cell response was detected in two out of three evaluable HLA-A*2402 patients. One patient achieved stable disease for 16 months and another patient showed a dramatic regression for one lesion for 4 months.
The regimen was feasible and safe, and the HLA-A*24-restricted peptide exhibited a capacity to induce immune responses. These results warrant further studies to evaluate whether add-on regimens to post-operative chemoradiotherapy delays recurrence in newly diagnosed MG patients.
Cytotherapy 03/2012; 14(6):733-42. · 3.63 Impact Factor
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ABSTRACT: We previously reported that cationic multilamellar liposome containing the human interferon-β (huIFN-β) gene (IAB-1) demonstrated significant cytotoxic effect in the NC65 human renal cell carcinoma (RCC) cell line. In this study, we investigated the molecular mechanisms of IAB-1-induced apoptosis and cytotoxicity in RCC cells. Remarkable in vitro cytotoxic and apoptosis-inducing effects of IAB-1 against NC65 cells were observed by a colorimetric method and TUNEL staining, respectively. In contrast, treatment of NC65 cells with exogenously added huIFN-β protein induced low-level cytotoxicity without apoptosis. Neutralizing antibodies against huIFN-β significantly suppressed the cytotoxic effect of huIFN-β protein, but they were unable to block the effect of IAB-1. Cytotoxicity assays using transwell plates revealed that NC65 cells treated with IAB-1 did not secrete cytotoxic soluble factors other than IFN-β. Substantial enhancement of interferon-stimulated response element (ISRE) activity of NC65 cells by IAB-1 was demonstrated by promoter reporter assays. In addition, immunofluorescence using confocal microscopy revealed the intracellular expression of IFN-β and its receptor induced by IAB-1. The induction of c-Myc by IAB-1 was suggested by a cDNA macroarray and was confirmed by western blot analysis. These findings indicate that IAB-1 induces significant cytotoxicity and apoptosis in NC65 cells, possibly through enhanced ISRE activity, that is associated with increased intracellular localization of huIFN-β and IFN-receptor. Our data support the potential clinical application of IAB-1 gene therapy for RCC resistant to IFN.
International Journal of Oncology 02/2012; 40(5):1441-6. · 2.40 Impact Factor
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Jumpei Arata,
Yasunori Tada,
Hiroaki Kozuka,
Tomohiro Wada,
Yoshitaka Saito,
Norio Ikedo,
Yuichiro Hayashi,
Masazumi Fujii,
Yasukazu Kajita,
Masaaki Mizuno,
Toshihiko Wakabayashi, Jun Yoshida,
Hideo Fujimoto
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ABSTRACT: Brain tumor (e.g., glioma) resection surgery, representing the first step for many treatments, is often difficult and time-consuming for neurosurgeons. Thus, intelligent neurosurgical instruments have been developed to improve tumor removal.
The concept and robotic structure of intelligent neurosurgical instruments were introduced. These instruments consist of a surgical robot, a master device and operating software. The robot incorporates a surgical motion base and tool manipulator, including a volume control suction tool. Open Core Control software was developed for connecting intelligent neurosurgical instruments through a network connection and integrating the instruments into a system.
Mechanical evaluation tests on the components and a preliminary system evaluation were performed. A phantom model was fixed on a head frame, and a tumor-removal procedure was successfully performed using prototype intelligent neurosurgical instruments.
Intelligent neurosurgical instruments are feasible and suitable for on-going evaluation in practical tasks, including in-vivo animal testing.
International Journal of Computer Assisted Radiology and Surgery 05/2011; 6(3):375-85. · 1.48 Impact Factor
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Toshihiko Wakabayashi,
Takamasa Kayama,
Ryo Nishikawa,
Hiroshi Takahashi,
Naoya Hashimoto,
Jun Takahashi,
Tomokazu Aoki,
Kazuhiko Sugiyama,
Masatoshi Ogura,
Atsushi Natsume, Jun Yoshida
[show abstract]
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ABSTRACT: Our previous study demonstrated that interferon-β markedly enhanced chemosensitivity to temozolomide; one of the major mechanisms is downregulation of O(6)-methylguanine DNA-methyltransferase transcription via p53 induction. This effect was also observed in an experimental animal model. The results of these studies suggest that compared to temozolomide-based chemotherapy performed concomitantly with radiotherapy, chemotherapy with interferon-β and temozolomide and concomitant radiotherapy might further improve the clinical outcomes of patients with malignant gliomas. A multicenter phase I clinical trial-the Integrated Japanese Multicenter Clinical Trial: a Phase I Study of Interferon-β and Temozolomide for Glioma in Combination with Radiotherapy (INTEGRA Study)-was conducted in patients with high-grade gliomas in order to evaluate the safety, feasibility, and preliminary clinical effectiveness of combination therapy with interferon-β and temozolomide. The primary endpoint was the incidence of adverse events. The exploratory endpoints were progression-free survival time and overall survival time. The study population comprised 16 patients with newly diagnosed and 7 patients with recurrent high-grade gliomas. Grades 3-4 leukocytopenia and neutropenia were observed in 6.7 and 13.3% of patients, respectively. Overall, 40% of patients showed an objective response to therapy. In patients with newly diagnosed glioblastoma, the median overall survival time was 17.1 months and the rate of 1-year progression-free survival was 50%. We conclude that this regimen is safe and well tolerated and may prolong survival of patients with glioblastoma. A phase II clinical study is essential to corroborate our findings.
Journal of Neuro-Oncology 02/2011; 104(2):573-7. · 3.21 Impact Factor
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Masasuke Ohno,
Atsushi Natsume,
Ken Ichiro Iwami,
Hidetaka Iwamizu,
Kana Noritake,
Daiki Ito,
Yuki Toi,
Motokazu Ito,
Kazuya Motomura, Jun Yoshida,
Kazuhiro Yoshikawa,
Toshihiko Wakabayashi
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ABSTRACT: The isotype of epidermal growth factor receptor variant III (EGFRvIII) is often identified in glioblastomas. Previously, we created a mouse monoclonal antibody, 3C10 (IgG2b), that specifically recognized EGFRvIII, and a recombinant single-chain variable fragment of 3C10. The aim of the current study was to develop genetically engineered T cells, termed T-bodies, that express a chimeric receptor consisting of the 3C10 single-chain variable fragment coupled to signaling modules such as the CD3zeta (ζ) chain, for the treatment of tumors expressing mutant EGFR. After successful construction of the chimeric 3C10/CD3ζ T-cell receptor, its expression on the T-body was observed using western blotting and flow cytometry. The specificity of the T-body for EGFRvIII was evaluated using an interferon-gamma Elispot assay and a standard (51) Cr-release cytotoxicity assay. Furthermore, we demonstrated that the systemically delivered T-body infiltrated the intrabrain tumor and significantly delayed tumor growth. These results indicate that the T-body expressing the chimeric 3C10/CD3ζ T-cell receptor specifically recognized glioma cells expressing EGFRvIII. In conclusion, T-body-based immunotherapy appears to be a promising approach for the treatment of glioma.
Cancer Science 09/2010; 101(12):2518-24. · 3.33 Impact Factor
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ABSTRACT: Our goal is to indicate the importance of combining intraoperative tractography with motor-evoked potential (MEP) monitoring for glioma surgery in motor eloquent areas.
Tumor removal was performed in 28 patients with gliomas in and around the corticospinal tract (CST), in an operation theater equipped with an integrated high-field intraoperative magnetic resonance imaging and a neuronavigation system. Diffusion-tensor imaging-based tractography of the CST was implemented preoperatively and intraoperatively. When the surgically manipulated area came close to the corticospinal pathway, MEP responses were elicited by subcortical stimulation. Responsive areas were compared with the locations of fibers traced by preoperative and intraoperative tractography. Imaging and functional outcomes were reviewed.
Intraoperative tractography demonstrated significant inward or outward shift during surgery. MEP responses were observed around the tract at various intensities, and the distance between MEP responsive sites and intraoperative tractography was significantly correlated with the stimulation intensity (P < 0.01). The distance from preoperative tractography was not correlated. A more than subtotal resection was achieved in 24 patients (85.7%). Transient motor deterioration was seen in 12 patients (42.8%), and a permanent deficit was seen in 1 patient (3.5%).
We found that intraoperative tractography demonstrated the location of the CST more accurately than preoperative tractography. The results of the linear regression between distance and stimulation intensity were informative for guiding approaches to tumor remnants without impinging on the CST. The combination of intraoperative tractography and MEP monitoring can enhance the quality of surgery for gliomas in motor eloquent areas.
World Neurosurgery 07/2010; 74(1):153-61. · 0.68 Impact Factor
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ABSTRACT: Almost all cancer cells have multiple epigenetic abnormalities, which combine with genetic changes to affect many cellular processes, including cell proliferation and invasion, by silencing tumor-suppressor genes. In this review, we focus on the epigenetic mechanisms of DNA hypomethylation and CpG island hypermethylation in gliomas. Aberrant hypermethylation in promoter CpG islands has been recognized as a key mechanism involved in the silencing of cancer-associated genes and occurs at genes with diverse functions related to tumorigenesis and tumor progression. Such promoter hypermethylation can modulate the sensitivity of glioblastomas to drugs and radiotherapy. As an example, the methylation of the O6-methylguanine DNA methyltransferase (MGMT) promoter is a specific predictive biomarker of tumor responsiveness to chemotherapy with alkylating agents. Further, we reviewed reports on pyrosequencing - a simple technique for the accurate and quantitative analysis of DNA methylation. We believe that the quantification of MGMT methylation by pyrosequencing might enable the selection of patients who are most likely to benefit from chemotherapy. Finally, we also evaluated the potential of de novo NY-ESO-1, the most immunogenic cancer/testis antigen (CTA) discovered thus far, as an immunotherapy target. The use of potent epigenetics-based therapy for cancer cells might restore the abnormally regulated epigenomes to a more normal state through epigenetic reprogramming. Thus, epigenetic therapy may be a promising and potent treatment for human neoplasia.
Cancer Science 03/2010; 101(6):1331-6. · 3.33 Impact Factor
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ABSTRACT: The purpose of this paper is to describe the newly-established technique in the field of neurological surgery for fusion imaging of three-dimensional magnetic resonance image (3D-MRI) and/or three-dimensional computed tomography (3D-CT) for brain tumor surgery. Combining neuronavigation technology and intraoperative MRI, this method remarkably demonstrates spatial relationships of neurovascular structures and/or skull base landmarks and is very useful for intraoperative evaluation of completed neurosurgical operations. Using the navigation system and intraoperative MRI during surgery, it is possible to resect the brain tumor maximally and preserve essential neurological functions. Furthermore, advanced multimodal neuroradiological images such as functional MRI (fMRI), diffusion tensor imaging (DTI), MR spectroscopy (MRS), and positron emission tomography (PET) clearly demonstrate the dominant cortex including the speech center, primary motor gyrus, primary sensory gyrus, and support high-quality operation with less invasive surgery. In conclusion, multimodal neuroradiological images are very useful for invasive noncircumscribed brain tumors such as glioma and, in combination with such highly technological analyses, advanced neurosurgical procedures are possible.
Nagoya journal of medical science 09/2009; 71(3-4):101-7.
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ABSTRACT: Initial experiences are reviewed in an integrated operation theater equipped with an intraoperative high-field (1.5 T) magnetic resonance (MR) imager and neuro-navigation (BrainSUITE), to evaluate the indications and limitations. One hundred consecutive cases were treated, consisting of 38 gliomas, 49 other tumors, 11 cerebrovascular diseases, and 2 functional diseases. The feasibility and usefulness of the integrated theater were evaluated for individual diseases, focusing on whether intraoperative images (including diffusion tensor imaging) affected the surgical strategy. The extent of resection and outcomes in each histological category of brain tumors were examined. Intraoperative high-field MR imaging frequently affected or modified the surgical strategy in the glioma group (27/38 cases, 71.1%), but less in the other tumor group (13/49 cases, 26.5%). The surgical strategy was not modified in cerebrovascular or functional diseases, but the success of procedures and the absence of complications could be confirmed. In glioma surgery, subtotal or greater resection was achieved in 22 of the 31 patients (71%) excluding biopsies, and intraoperative images revealed tumor remnants resulting in the extension of resection in 21 of the 22 patients (95.4%), the highest rate of extension among all types of pathologies. The integrated neuro-navigation improved workflow. The best indication for intraoperative high-field MR imaging and integrated neuro-navigation is brain tumors, especially gliomas, and is supplementary in assuring quality in surgery for cerebrovascular or functional diseases. Immediate quality assurance is provided in several types of neurosurgical procedures.
Neurologia medico-chirurgica 09/2009; 49(8):340-9; discussion 349-50. · 0.61 Impact Factor
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ABSTRACT: Deoxyribonucleic acid (DNA) methylation of tumor origin can be detected in the serum/plasma of cancer patients. The aim of this study was to detect aberrant p16 promoter methylation as a potential diagnostic marker in the serum of patients with diffuse glioma to differentiate between gliomas and, particularly, to differentiate those in the brainstem from others; this was done by using the modified methylation-specific polymerase chain reaction technique.
The methylation-specific polymerase chain reaction was used to detect p16 methylation in the DNA extracted from 20 astrocytic tumors and 20 oligodendroglial tumors and the corresponding serum samples. Serum samples from 10 healthy individuals were used as controls. The association of p16 hypermethylation in the serum DNA of glioma patients with clinicopathological characteristics was analyzed. In addition, the serum DNA in 7 patients with a brainstem tumor (4 gliomas, 1 schwannoma, 1 cavernous angioma, and 1 ependymoma) was analyzed.
We found p16 methylation in 12 (60%) of the 20 tissues with astrocytoma, but in only 1 of the tissues with oligodendroglioma. Similar methylations were detected in the serum of 9 (75%) of the 12 patients with aberrant methylation in the tumor tissues. No methylated p16 sequences were detected in the peripheral serum of the patients having tumors without these methylation changes or in the 10 healthy controls. Additionally, p16 promoter methylation in the serum was observed in all brainstem astrocytoma cases, but not in other cases.
This assay has potential for use as a serum-based molecular diagnosis technique for diffuse glioma.
Neurosurgery 04/2009; 64(3):455-61; discussion 461-2. · 2.79 Impact Factor
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ABSTRACT: Severe subarachnoid hemorrhage (SAH) induces dysfunction of endothelial nitric oxide synthase (eNOS), resulting in severe vasospasm. Clinically, however, some portions of cerebral arteries may show only mild vasospasm. Although severe vasospastic arteries after SAH have been intensively studied, activity of eNOS associated with the mild form of the disease has received less attention. The purpose of the present study was to clarify molecular mechanisms underlying the regulation of eNOS activity in mild vasospastic arteries after SAH. In a rat single-hemorrhage model, basilar arteries were obtained up to 7 days after SAH. Western blot analysis was used to study the temporal profiles of eNOS, phosphorylated (p)-eNOS at Ser(1177) or Thr(495), inducible NOS (iNOS), AMP-activated protein kinase alpha (AMPK alpha, p-AMPK alpha at Thr(172)Akt, p-Akt at Ser(473), cyclic AMP-dependent protein kinase (PKA), and p-PKA at Thr(197) in basilar arteries. Immunohistochemical studies were performed to examine the spatial expression patterns of p-eNOS at Ser(1177) and p-AMPK alpha at Thr(172). Western blot analysis showed eNOS to be significantly phosphorylated at Ser(1177) from 1 to 2 days after SAH, accompanied by upregulation of iNOS and AMPK, while activation states of Akt and PKA did not show significant change. Immunohistochemistry revealed phosphorylation of eNOS and AMPK alpha in endothelial cells of the basilar artery. SAH might thus induce temporary activation of AMPK alpha, which phosphorylates eNOS at Ser(1177) in endothelial cells of mild vasospastic basilar arteries. This signal transduction may play an important role in controlling cerebral blood flow after SAH.
Journal of neurotrauma 03/2009; 26(7):1157-65. · 4.25 Impact Factor
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ABSTRACT: Comparative investigations were carried out regarding the efficiency of introduction of exogenous genes into cultured cells using a cationic polysaccharide DEAE-dextran-MMA (methyl methacrylate ester) graft copolymer (2-diethylaminoethyl-dextran-methyl methacrylate graft copolymer; DDMC) as a nonviral carrier for gene introduction. The results confirmed that the gene introduction efficiency was improved with DDMC relative to DEAE-dextran. Comparative investigations were carried out using various concentrations of DDMC and DNA in the introduction of DNA encoding luciferase (pGL3 control vector; Promega) into COS-7 cells derived from African green monkey kidney cells. The complex formation reaction is thought to be directly proportional to the transformation rate, but the complex formation reaction between DDMC and DNA is significantly influenced by hydrophobic bonding strength along with hydrogen bonding strength and Coulomb forces due to the hydrophobicity of the grafted MMA sections. It is thought that the reaction is a Michaelis-Menten type complex formation reaction described by the following equation: Complex amount = K1 (DNA concentration)(DDMC concentration). In support of this equation, it was confirmed that the amount of formed complex was proportional to the RLU value.
Molecules 02/2009; 14(7):2669-83. · 2.39 Impact Factor
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ABSTRACT: Formation of a glial scar is one of the major obstacles to axonal growth after injury to the adult CNS. In this study, we have addressed this issue by focusing on reactive astrocytes in a mouse model of spinal cord injury (SCI). First, we attempted to identify profile changes in the expression of astrocytic gliosis 10 days after injury by using gliosis-specific microdissection, genome-wide microarray, and MetaCore(trade mark) pathway analysis. This systematic data processing revealed many intriguing activated pathways. However, considering that proliferation/mitosis is one of the most prominent features of reactive astrocytes, we focused on the functional role of the Ras-MEK-ERK signaling cascades in reactive astrocytes. SCI-induced proliferation of reactive astrocytes in the lesion is in accordance with the increase in the expression and phosphorylation of MEK-ERK. Second, to reduce reactive gliosis after SCI, liposomes containing the interferon-beta (IFN-beta) gene were administered locally 30 min after injury. At 14 days after this treatment, GFAP-positive intensity and MEK-ERK phosphorylation at the lesion were reduced. In the animals receiving the IFN-beta gene, significant recovery of neurobehavior and parameters of electrophysiology following SCI was revealed by assessments of rotarod performance and improvements in the Basso Mouse Scale for locomotion and cortical motor-evoked potentials. SCI resulted in the degeneration of biotinylated dextran amine-labeled descending corticospinal tract axons, but the IFN-beta gene delivery induced regrowth of a large number of corticospinal tract axons. These results suggest that liposome-mediated IFN-beta gene delivery inhibits glial scar formation after SCI and promotes functional recovery.
Journal of neurotrauma 02/2009; 26(1):41-53. · 4.25 Impact Factor
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ABSTRACT: Lymphangioma localized to the bones of the skull base is rare. The authors report herein the case of a 5-year-old boy who presented with lymphangioma of the bone, localized to the skull base and leading to cerebrospinal fluid (CSF) rhinorrhea with meningitis. Neuroimaging demonstrated lytic destruction with a cyst in the right middle skull base. The patient was successfully treated with resection of the tumor and prevention of CSF leakage. Histopathological examination revealed a lymphangioma. An enlarging lymphangioma can lead to bone destruction. A differential diagnosis of a lytic lesion for a cyst at the skull base is important for proper case management.
Journal of Neurosurgery Pediatrics 11/2008; 2(4):273-6. · 1.53 Impact Factor
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Kazuhiko Matsumoto,
Hitomi Kubo,
Hiroshi Murata,
Hisashi Uhara,
Minoru Takata,
Shinichi Shibata,
Satoshi Yasue,
Akihiro Sakakibara,
Yasushi Tomita,
Toshiro Kageshita,
Yutaka Kawakami,
Masaaki Mizuno, Jun Yoshida,
Toshiaki Saida
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ABSTRACT: Cationic liposomes containing the human interferon beta (HuIFNbeta) gene (IAB-1) was used for the clinical trial for glioma patients. HuIFNbeta gene therapy showed much higher anti-tumor activity compared with the administration of HuIFNbeta protein for melanoma. These results suggest that HuIFNbeta gene therapy is an attractive strategy for the treatment of melanoma.
Stage IV or III melanoma patients with cutaneous or subcutaneous metastatic lesions were enrolled in this pilot study. IAB-1 was dissolved by sterile PBS at a concentration of 30 microg DNA/ml and was injected into cutaneous or subcutaneous metastatic nodules three times a week for 2 weeks and the effect on the injected and non-injected metastatic lesions was evaluated.
Clinical responses were as follows (five patients): mixed response (MR) and no change in each one patient, and progressive disease in three patients. In the MR patient, the IAB-1 injected lesion disappeared clinically and histopathologically and one-half of IAB-1 non-injected skin metastases were transiently inflamed and mostly regressed. In the responded non-injected lesions of this patient, histopathologically, infiltration of CD4 positive T cells was observed around the melanoma cells in the dermis, which expressed the HLA-Class II antigen. Adverse events due to this gene therapy were not recognized in any of the patients.
The efficacy of this gene therapy was generally insufficient; however, some immunological responses were recognized in one patient. No adverse events were observed. HuIFNbeta gene therapy could be an attractive strategy for treatment of a variety of malignancies, including melanoma, though some modifications should be required.
Japanese Journal of Clinical Oncology 11/2008; 38(12):849-56. · 1.78 Impact Factor
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Toshihiko Wakabayashi,
Takamasa Kayama,
Ryo Nishikawa,
Hiroshi Takahashi,
Toshiki Yoshimine,
Nobuo Hashimoto,
Tomokazu Aoki,
Kaoru Kurisu,
Atsushi Natsume,
Masatoshi Ogura, Jun Yoshida
[show abstract]
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ABSTRACT: A multicenter phase I clinical trial, namely, Integrated Japanese Multicenter Clinical Trial: A Phase I Study of Interferon-beta and Temozolomide for Glioma in Combination with Radiotherapy (INTEGRA Study), is being conducted for patients with high-grade glioma in order to evaluate the safety, feasibility and preliminary clinical effectiveness of the combination of interferon-beta and temozolomide. The primary endpoint is incidence of adverse events. The secondary endpoints are progression-free survival time and overall survival time. In addition, objective tumor response will be evaluated in a subpopulation of patients with the measurable disease. The reduction rate of tumor will be calculated according to Response Evaluation Criteria In Solid Tumors for measurable tumors as determined by magnetic resonance imaging. Subsequently, the overall response will be evaluated based on the results of measurable and non-measurable tumors. Ten newly diagnosed and 10 recurrent patients will be enrolled in this study.
Japanese Journal of Clinical Oncology 11/2008; 38(10):715-8. · 1.78 Impact Factor
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Kosuke Yamamoto,
Yoichi Mizutani,
Hiroyuki Nakanishi,
Jun Fujiwara,
Hirokazu Ishida,
Daisuke Toiyama,
Koichi Abe,
Issei Hayashi,
Koichi Okada,
Akihiro Kawauchi,
Masaaki Mizuno, Jun Yoshida,
Tsuneharu Miki
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ABSTRACT: Immunotherapy is one of the most effective treatments against metastatic renal cell carcinoma (RCC). However, the response rate is not high. Therefore, more effective therapies are necessary for patients with metastatic RCC. We previously reported on the significant antitumor activity of cationic multilamellar liposome containing human interferon-beta (huIFN-beta) gene (IAB-1) against RCC. We then examined the antitumor effect of IAB-1 in combination with anticancer drugs against RCC. The cytotoxicity of IAB-1 alone, and in combination with anticancer drugs, cisplatin, adriamycin, 5-fluorouracil, gemcitabine, paclitaxel and irinotecan hydrochloride against the human RCC cell line NC65 was examined by the colorimetric method using tetrazolium salt. For the in vivo study, we used NC65 cells inoculated into the severe combined immunodeficiency mouse. The results showed that the in vitro combination therapy with IAB-1 and 5-FU was more cytotoxic than IAB-1 alone. However, synergistic cytotoxicity was not observed when combined with IAB-1 and other anticancer drugs. NC65 tumors transfected with IAB-1 in mice were smaller than those receiving an injection of empty liposome or the recombinant huIFN-beta protein. Treatment with IAB-1 in combination with 5-FU resulted in significant anticancer activity. IAB-1 enhanced the activity of thymidine phosphorylase (TP), which converts 5-FU to the active metabolite, FdUMP. In contrast, IAB-1 decreased the activity of thymidylate synthase (TS), which is a target enzyme of 5-FU. In conclusion, these findings indicate that a combination of IAB-1 and 5-FU may have enhanced antitumor activity against human RCC, suggesting its potential clinical application. The mechanism of enhanced cytotoxicity by combination therapy with IAB-1 and 5-FU may up-regulate TP activity and down-regulate TS activity.
International Journal of Oncology 10/2008; 33(3):565-71. · 2.40 Impact Factor
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ABSTRACT: The treatment of high-grade gliomas remains difficult despite recent advances in surgery, radiotherapy and chemotherapy. True advances may emerge from the increasing understanding in molecular biology and discovery of novel mechanisms for the delivery of tumoricidal agents. In an attempt to overcome this formidable neoplasm, molecular approaches using gene therapy have been investigated clinically since 1992. The clinical trials have mainly been classified into three approaches: suicide gene therapy, immune gene therapy and oncolytic viral therapy. In this article, we review these approaches, which have been studied in previous and ongoing clinical trials.
Cell adhesion & migration 08/2008; 2(3):186-91. · 1.82 Impact Factor
