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Motohiko Maruno

Publications and source records attributed to Motohiko Maruno.

At least 19 recordsLinked to original sources
PubMed2006

A phase I/II trial of a WT1 (Wilms' tumor gene) peptide vaccine in patients with solid malignancy: safety assessment based on the phase I data.

OBJECTIVE: We conducted a phase I study to investigate the safety of a weekly WT1 tumor vaccine therapy in patients with solid tumors that had been refractory to all other anti-cancer therapies. METHODS: Skin-test-negative patients were intradermally injected weekly for 12 weeks with 3.0 mg of an HLA-A*2402-restricted modified 9-mer WT1 peptide emulsified in Montanide ISA51 adjuvant. We estimated the Bayesian posterior probability of the occurrence of grade 3 or 4 toxicity when receiving the weekly WT1 vaccination. This analysis provided the basis for making a decision to terminate the phase I study and switch to phase II. Moreover, we performed an exploratory assessment of the anti-tumor effects of WT1 treatment. RESULTS: Ten patients received 114 vaccinations with WT1 on a weekly schedule. No grade 3 or 4 toxicities were observed. Based on the Bayesian approach, it was highly likely that the probability of grade 3 or 4 toxicity was below 20% (the posterior probability = 0.914). Fifteen grade 2 and two grade 1 toxicities were observed; all of these incidents, however, were determined by the Independent Data and Safety Monitoring Committee to be unrelated to the WT1 treatment. One patient exhibited a partial response; five additional patients had stable disease while receiving weekly WT1 treatment. CONCLUSION: This paper confirms that the potential toxicities of the treatment schedule of weekly WT1 vaccination are acceptable and suggested a potential anti-tumor effect. Consequently, we validated the decision to continue to the phase II trial.

Adolescent↗
PubMed2006

Skull metastases from atypical pulmonary carcinoid tumor in a 19-year-old man.

A 19-year-old man presented with a rare skull metastasis from atypical pulmonary carcinoid tumor (APCT) manifesting as headache, diplopia, and cough. Head magnetic resonance imaging showed a skull base tumor extending from the posterior clinoid process to the clivus, and calvarial tumors in the right temporal and occipital bones. Chest and abdominal computed tomography showed a round tumor, 4 cm in diameter, in the lower lobe of the right lung and multiple small tumors in the liver. Surgery for the calvarial tumor in the right temporal bone was performed on June 27, 2003. The histological diagnosis was skull metastasis of neuroendocrine tumor. Gamma knife radiosurgery was performed for the residual skull metastases. Partial resection of the right lower lobe was performed for the lung tumor on August 22, 2003. The histological diagnosis was atypical carcinoid tumor. Subsequent adjuvant systematic chemotherapy was performed. The patient died of progression of the tumors in the lung and liver on April 19, 2004. We must consider APCT in the differential diagnosis of pulmonary tumors in adolescents, and perform follow-up observation or treatment, including surgery, if APCT is suspected.

Adult↗
PubMed2006

[Efficacy and safety of monotherapy with temozolomide in patients with anaplastic astrocytoma at first relapse--a phase II clinical study].

The efficacy and safety of temozolomide were evaluated in 32 patients with anaplastic astrocytoma at first relapse. Temozolomide was administered orally once daily for the first five days of a 28-day cycle, at a dose of 150 or 200 mg/m(2)/day. The response rate determined by independent central review of MRI was 34% (95% confidence interval: 18.6%-53.2%), with 3 complete response and 8 partial response. The rate of "no change or better" was 91% (95% confidence interval: 75.0%-98.0%). Progression-free survival (PFS) at 6 months was 40.6%, and the median PFS was 4.1 months. The incidence of constipation (50%) and nausea (25%) was high,but these events were all mild or moderate in severity except in one subject with constipation,and could be managed with standard laxatives and antiemetics. The main laboratory test abnormalities (total incidence and incidence of grade 3/4 change) were lymphocytopenia (50%, 25%), neutropenia (47%, 6%), leukopenia (38%, 3%), thrombocytopenia (31%, 9%), and increased GPT (25%, 3%). Temozolomide was shown to have good efficacy and tolerability in patients with anaplastic astrocytoma at first relapse.

Adult↗
PubMed2005

Fiber-tracking does not accurately estimate size of fiber bundle in pathological condition: initial neurosurgical experience using neuronavigation and subcortical white matter stimulation.

The fiber-tracking method enables in vivo visualization of the white matter tracts of the brain using a diffusion tensor MR imaging technique. While this method represents a promising tool in the field of neurosurgery, especially when confronted with brain tumors in eloquent areas, its reliability remains unknown. We present here our preliminary validation of tractography in human subjects harboring brain tumors by comparing the results produced by neuronavigation and electrical white matter stimulation in two patients with gliomas in the eloquent area. Although we were able to visualize the pyramidal tract with the fiber-tracking technique, the images failed to present the actual size of the fiber bundles. Here we discuss the advantages and limitations of fiber-tracking in the field of neurosurgery.

Aged↗
PubMed2005

Inhibition of glioma cell proliferation by neural stem cell factor.

Neural stem cells (NSC) have unique differentiation-, proliferation-, and motility properties. To investigate whether they secrete factors that interfere with the proliferation of glioma cells, we grew glioma cells in conditioned medium (CM) obtained from cultures of neurospheres including neural stem / progenitor cells (NSPC) isolated from embryonic (E14)- or adult mouse brain or fetal human brain. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and BrdU-labeling assays showed that CM from NSPC (NSPC/CM) contained factor(s) that inhibited the proliferation of glioma cells by 28-87%. Filter-fractionation of NSPC/CM revealed that the 50,000-100,000 nominal molecular weight limit (NMWL) fraction contained the inhibitory activity. On the basis of these observations we transplanted 203G glioma cells and/or NSPC into the intrathecal space of the cisterna magna of mice to investigate whether NSPC interfere with the proliferation of glioma cells in vivo. Mice transplanted with both 203G and NSPC survived significantly longer than did mice transplanted only with 203G. We concluded that NSPC secrete factor(s) that may control glioma cell proliferation.

Animals↗
PubMed2005

Ganglioside GM3 inhibits proliferation and invasion of glioma.

GM3, the simplest ganglioside, modulates cell adhesion, proliferation and differentiation in the central nervous system and exogenously added GM3 regulates cell-cell and cell-extracellular matrix adhesion and induces apoptosis. To assess the anti-tumor action of exogenous GM3, we examined its effect on the proliferation and invasion of glioma cells. Its inhibitory effect on cell proliferation was demonstrated in vitro by 3-(4,5-dimethyl-2-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay and in vitro in rats with meningeal gliomatosis whose survival was significantly prolonged by the intrathecal injection of GM3. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assay revealed that GM3 induced glioma cell apoptosis in vitro and in vitro. In rat brain slice cultures, GM3 suppressed the invasion of glioma cells; this effect manifested earlier than the inhibition of cell proliferation and before apoptosis induction. Our results suggest exogenous GM3 as a potential therapeutic agent in patients with glioma requiring adjuvant therapy.

Animals↗
PubMed2005

Immunohistochemical detection of female sex hormone receptors in craniopharyngiomas: correlation with clinical and histologic features.

BACKGROUND: Although craniopharyngiomas have a histologically benign nature, their treatment can be difficult. The correlation among clinical, proliferative, and immunohistologic features of female sex hormone receptors was determined in craniopharyngiomas to analyze whether they influence the growth of the tumor. METHODS: The study subjects were 43 patients with previously untreated craniopharyngioma who underwent surgery at our department over the past 15 years. Serial tissue sections were immunostained with the antibodies against estrogen receptor (ER), progesterone receptor (PR), and Ki-67. RESULTS: The Ki-67 labeling index was significantly higher in patients with regrowth (7.8%) than without regrowth (3.9%). ER and PR were detected in 9 of 30 (30%) craniopharyngiomas, and the incidence of postoperative tumor regrowth was significantly higher in patients negative for ER and PR (29%) than in those positive for both receptors (11%). CONCLUSIONS: A high Ki-67 labeling index suggests a high possibility of tumor regrowth, and the presence of ER and PR is suggestive of a high tissue differentiating potential. ER and PR assay may be useful for determining the indication for additional radiation therapy in craniopharyngioma patients treated by incomplete resection.

Adolescent↗
PubMed2005

Combination gene therapy for glioblastoma involving herpes simplex virus vector-mediated codelivery of mutant IkappaBalpha and HSV thymidine kinase.

To improve the effectiveness of herpes simplex virus (HSV) thymidine kinase/ganciclovir (HSV-tk/GCV) suicide gene therapy, the replication-defective HSV vector TOIkappaB expressing both HSV-TK and a mutant form of the NF-kappaB inhibitor IkappaBalpha (IkappaBalphaM) was developed. TOIkappaB was constructed by recombining the IkappaBalphaM gene into the U(L)41 locus of a replication-defective lacZ expression vector, TOZ.1. Expression of IkappaBalphaM was confirmed by Western blotting, and the ability of the mutant protein to inhibit NF-kappaB nuclear translocation was examined by electrophoretic mobility shift assay. In human glioblastoma U-87MG cells, the p50/p50 dimer of NF-kappaB was already translocated to the nucleus without receptor-dependent signaling by TNF-alpha. Following infection with TOIkappaB, nuclear translocation of NF-kappaB in U-87MG cells was significantly inhibited and caspase-3 activity increased compared with TOZ.1-infected cells. The cytotoxicity of TOIkappaB for U-87MG cells was investigated by colorimetric MTT assay. At an MOI of 3, TOIkappaB infection killed 85% of the cells compared to 20% killed by TOZ.1 infection. In the presence of GCV, these numbers increased to 95-100% for TOIkappaB and 80-85% for TOZ.1. TOIkappaB neurotoxicity measured on cultured murine neurons was relatively low and similar to that of TOZ.1. The survival of nude mice implanted into the brain with U-87MG tumor cells was markedly prolonged by intratumoral TOIkappaB injection and GCV administration. Survival of TOIkappaB+GCV group was significantly longer (P<.02, Wilcoxon test) than for the control groups (TOZ.1 or TOIkappaB only, PBS or PBS+GCV). These results suggest that IkappaBalphaM expression may be a safe enhancement of replication-defective HSV-based suicide gene therapy in vitro and in vivo.

Animals↗
PubMed2005

Overexpressed Skp2 within 5p amplification detected by array-based comparative genomic hybridization is associated with poor prognosis of glioblastomas.

To better understand the pathogenesis of glioblastoma multiforme (GBM) and to increase the accuracy of predicting outcomes for patients with this disease, we performed genome-wide screening for DNA copy-number aberrations in 22 glioma-derived cell lines using a custom-made comparative genomic hybridization-array. Copy-number gains were frequently detected at 3q, 7p, 7q, 20q, Xp and Xq, and losses at 4q, 9p, 10p, 10q, 11q, 13q, 14q, 18q, and 22q. Among several non-random chromosomal aberrations, the gain/amplification of DNA at 5p, which has never been reported before in GBM, was detected with a relatively high ratio (log2 ratio = 0.41-1.19) in four cell lines. Amplification and subsequent overexpression of SKP2, a possible target of amplification within 5p, were detected in four of the 22 cell lines. We also investigated the expression of the gene product in primary GBM by immunohistochemistry, which revealed increased levels of Skp2 in 11 of the 35 tumors examined (31.4%). Heightened expression of Skp2 was associated with shorter overall survival (P = 0.001, logrank test), especially in patients younger than 65 years. These results suggest that overexpression of Skp2 through gene amplification may contribute to the pathogenesis of GBM, and that overabundance of the protein might be a useful prognostic tool in patients with this disease.

Biomarkers, Tumor↗
PubMed2005

Chromosomal and genetic abnormalities in benign and malignant meningiomas using DNA microarray.

BACKGROUND: Meningioma is the commonest brain tumor and many genetic abnormalities, such as the loss of chromosome 22q and the mutation of NF2, have been reported. METHODS: These classical abnormalities were detected using Southern blot, PCR, fluorescence in situ hybridization and comparative genomic hybridization, but these methods examine only very limited regions or limited mapping resolution of the tumor genome. In this study, we used DNA microarray assay, which detects numerous genetic abnormalities simultaneously and analyses a global assessment of molecular events in meningioma cells. We studied 31 meningiomas by GenoSensor Array 300 in order to detect the chromosomal aberrations and genetic abnormalities in the whole genome. RESULTS: This study demonstrated not only classical chromosomal aberration, such as loss of chromosome 22q in 19 meningiomas (61.3%), but also new genetic characteristics of meningiomas, such as amplification of MSH2 in 16 meningiomas (51.6%), deletion of GSCL in 13 meningiomas (41.9%) and deletion of HIRA in seven meningiomas (22.6%). CONCLUSIONS: These results suggest that DNA microarray assay is useful in research for the genetic characters of meningiomas and understanding tumorigenesis.

Adolescent↗
PubMed2004

Genetic analysis of human glioblastomas using a genomic microarray system.

Genomic microarray systems can simultaneously provide substantial genetic and chromosomal information in a relatively short time. We have analyzed genomic DNA from frozen sections of 30 cases of primary glioblastomas by GenoSensor Array 300 in order to characterize gene amplifications, gene deletions, and chromosomal information in the whole genome. Genes that were frequently amplified included RFC2/CYLN2 (63.3%), EGFR (53.3%), IL6 (53.3%), ABCB1 (MDR1) (36.7%), and PDGFRA (26.7%). Genes that were frequently deleted included (56.7%), FGFR2 (66.7%), MTAP (60.0%), DMBT1 CDKN2A (p16)/MTAP (50.0%), PIK3CA (43.3%), and EGR2 (43.3%), but deletion of RB1 or TP53 was rarely detected. Chromosomal gains were observed frequently for 7q (33.3%), 7p (20.0%), and 17q (13.3%). Loss of the 10q was frequently detected in 13 of 30 cases (46.7%). Loss of the entire chromosome 10 was seen in 9 of 30 cases (30.0%), and was often accompanied by EGFR amplification (7 cases, 77.8%). The GenoSensor Array 300 proved to be useful for identification of genome-wide molecular changes in glioblastomas. The obtained microarray profile can also yield valuable insight into the molecular events underlying carcinogenesis of brain tumors and may provide clues about clinical correlations, including response to treatment.

Adult↗
PubMed2004

Chromosomal and genetic aberrations differ with meningioma subtype.

Meningioma is one of the most common brain tumors, and a variety of genetic abnormalities have been detected by the Southern blotting, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), and comparative genomic hybridization (CGH) methods. However, these methods detect only a very limited portion of the tumor genome or have a limited mapping resolution. In this study, we used DNA microarray assay, which detects numerous genetic abnormalities and analyzes a global assessment of molecular events in tumor cells. We analyzed genomic DNA from 26 patients with benign meningiomas by GenoSensor Array 300 in order to characterize gene amplifications, gene deletions, and chromosomal information in the whole genome. Loss of chromosome 22q was found most frequently. This chromosomal aberration was detected in 14 meningiomas (53.8%), particularly in transitional and fibrous meningiomas. In meningothelial meningiomas, amplification of INS and TCL1A was detected more frequently than in other meningioma subtypes. DNA microarray assay revealed new genetic differences among the meningioma subtypes, thus indicating that this novel technique is useful for understanding tumor genesis and for the diagnosis of meningioma subtype.

Adolescent↗
PubMed2004

Meningioma arising from the trigeminal nerve: a case report and literature review.

We report a 69-year-old woman with a meningioma who presented with a 9-month history of progressive facial numbness in the distribution of the left mandibular nerve and left facial palsy. Magnetic resonance imaging revealed a mass in and around the left Meckel's cave (MC). The tumor was totally resected through a lateral suboccipital and subtemporal combined approach. It appeared to be a schwannoma, because it adhered firmly to the cisternal portion of the trigeminal nerve without dural attachment. Histopathological examination revealed that it was a meningothelial meningioma. We concluded that the tumor originated from the arachnoid cap cells within the trigeminal nerve sheath, not from the dura mater in the MC.

Aged↗
PubMed2004

Overexpression of the Wilms' tumor gene W T1 in primary astrocytic tumors.

Expression of the Wilms' tumor gene W T1 in primary astrocytic tumors was examined using a quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) or immunohistochemistry. Real-time RT-PCR showed that W T1 mRNA was expressed at various levels in all of the 25 astrocytic tumors examined. Immunohistochemical analysis showed that W T1 protein was expressed in 5 of 6 low-grade astrocytic tumors (grade I-II) and all of 18 high-grade ones (grade III-IV), and that expression levels of W T1 protein in high-grade tumors were significantly higher than those in low-grade ones. W T1 protein was not detected in the normal glial cells contained in the tumor specimens. Furthermore, treatment with W T1 antisense oligomers specifically inhibited growth of glioblastoma cell lines, U87-MG, A172, and T-98G. These results may indicate that the W T1 gene plays an important role in tumorigenesis of primary astrocytic tumors.

Adolescent↗
PubMed2004

Long-term control of recurrent anaplastic ependymoma with extracranial metastasis: importance of multiple surgery and stereotactic radiosurgery procedures--case report.

An 11-year-old Japanese girl presented with a right frontal lobe anaplastic ependymoma. The tumor was removed surgically. However, she developed a secondary lesion and extracranial metastasis in the cervical lymph node. In total, she underwent eight intracranial tumor removal procedures, five stereotactic radiosurgeries with six targets, and five cervical lymph node removal surgeries during the course of 7 years. She is currently alive with a good quality of life, and has no major neurological deficits except right facial nerve palsy. The combination of surgery and radiosurgery can achieve local control of anaplastic ependymoma. Multiple surgery or radiosurgery procedures can result in good outcome, if the tumor does not involve crucial structures, even if extracranial metastasis occurs.

Brain Neoplasms↗