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Biomedical subjects

Y Sawamura

Publications and source records attributed to Y Sawamura.

At least 91 records · Page 5Linked to original sources
PubMed1998

Rare occurrence of inactivating p53 gene mutations in primary non-astrocytic tumors of the central nervous system: reappraisal by yeast functional assay.

While it is established that p53 mutation plays a critical role in the carcinogenesis of astrocytic brain tumors, its role remains to be clarified for other types of tumors in the central nervous system (CNS). Using a yeast-based assay which tests the ability of human p53 to activate transcription, we analyzed p53 mutations in 85 non-astrocytic CNS tumors, including 4 benign neuronal tumors (3 central neurocytomas and 1 pineocytoma), 12 primitive neuroectodermal tumors, 14 germ cell tumors (7 germinomas, 7 non-germinomatous tumors), 4 craniopharyngiomas, 14 ependymomas, 22 schwannomas, 10 primary brain lymphomas in immunocompetent patients, and 5 bone tumors of the skull. The only tumors found to contain p53 mutations were 3 malignant lymphomas. The presence of mutations in these cases was confirmed by DNA sequencing. Given the high accuracy and sensitivity of the yeast assay and previous negative results using conventional techniques, this indicates that p53 mutation is a rare event in non-astrocytic CNS tumor types examined here.

Adolescent↗
PubMed1998

Expression of oncogenic molecules in primary central nervous system lymphomas in immunocompetent patients.

We studied overexpression of p53, Bcl-2, Bcl-6, c-Myc and Mdm2 proteins by immunohistochemistry for a total of 27 primary central nervous system B cell lymphomas (CNS lymphomas) in immunocompetent patients and one CNS lymphoma in an AIDS patient. The expression of Epstein-Barr (EB) virus-encoded small RNA-1 (EBER-1) was also analysed using in situ hybridisation. Overexpression (more than 20% of cells stained) of p53 protein was detected in 8 of 27 immunocompetent cases (30%); 6 cases showed a nuclear stain and 2 cases showed cytoplasmic stain (nuclear exclusion). Strong Bcl-2 or Bcl-6 immunoreactivity suggestive of overexpression was seen, respectively, in 5 (19%) and 6 (22%) cases; 2 cases were positive for both immunoreactivities. Interestingly, overexpression of Bcl-2 or Bcl-6 was not seen in the cases which showed p53 overexpression (P < 0.03; chi-square test). EBER-1 expression was not detected in any of the 27 immunocompetent cases, but was found in the AIDS-related CNS lymphoma, which also showed an overexpression of Bcl-6, but not Bcl-2. None of the cases showed c-Myc or Mdm2 overexpression. Taken together, it is suggested that CNS lymphoma in immunocompetent hosts is a distinct disease that has a different molecular profile from those of systemic lymphoma and/or AIDS-related CNS lymphoma.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Transsphenoidal-transtuberculum sellae approach for supradiaphragmatic tumours: technical note.

The Classic transsphenoidal approach may not afford sufficient exposure for a supradiaphragmatic tumour adjacent to the pituitary stalk. Various transcranial approaches have been utilized to access such a lesion with adequate results. This report describes a less invasive technique, termed "transsphenoidal-transtuberculum sellae approach". This modified transsphenoidal approach requires a bone ablation of the tuberculum sellae, the limbus sphenoidalis, and a portion of the planum sphenoidale, in addition to an opening of the anterior floor of the sella turcica. The dura mater on the tuberculum sellae and the pituitary fossa is sectioned with a bilateral obliteration of the anterior intercavernous sinus. The anterior pituitary gland is not necessarily resected. The optic chiasm, optic nerves, pituitary stalk, and tuber cinereum can be directly observed, making it possible to safely dissect a lesion from these structures. Utilizing this approach, we have removed 14 supradiaphragmatic tumours without complications and dealt with other lesions such as optic nerve injuries or cerebrospinal fluid rhinorrhea, leaving pituitary function intact. The transsphenoidal-transtuberculum sellae approach for accessing small supradiaphragmatic tumours is a useful procedure requiring only a minor modification of the classic transsphenoidal technique.

Adenoma↗
PubMed1998

Metachronous neurohypophyseal germinoma occurring 8 years after total resection of pineal mature teratoma.

BACKGROUND: Metachronous germ cell tumor in the central nervous system is extremely rare. To our knowledge, only one patient presenting conceivable metachronous intracranial germ cell tumor has been reported. CASE REPORT: A neurohypophyseal germinoma occurring 8 years after total resection of a pineal mature teratoma is presented. The patient underwent total resection of a large pineal mass in 1987. Histologic investigation revealed a mature teratoma without any immature or germinomatous components. In 1995, he developed diabetes insipidus. Magnetic resonance imaging depicted an intrasellar mass extending to the floor of the third ventricle. A transsphenoidal biopsy revealed histologically pure germinoma. CONCLUSION: The second neurohypophyseal germinoma was considered to be a de novo metachronous neoplasm rather than a recurrence of the original mature teratoma.

Adolescent↗
PubMed1998

Audiological assessment before and after fractionated stereotactic irradiation for vestibular schwannoma.

PURPOSE: To find the audiological outcome after LINAC-based fractionated stereotactic irradiation (STI). MATERIALS AND METHODS: Twenty-four patients with vestibular schwannoma treated by fractionated STI between 1991 and 1997 had measurable hearing before STI and were followed audiologically for more than 6 months. The pure tone average (PTA) was measured by averaging the air-conduction threshold for five main frequencies (250-4000 Hz) before and periodically after STI in the 24 patients. Several possible prognostic factors for hearing preservation (defined as a PTA change at the last follow-up of less than 10 dB) were investigated. The median follow-up time was 22 months, ranging from 5 to 69 months. The irradiation schedule was 36 Gy in 20 fractions in 5 weeks to 44 Gy in 22 fractions in 6 weeks followed by 4 Gy/1 fraction boost. RESULTS: The pure tone average before STI was distributed from 7 to 73 dB. Fifty percent of patients showed a change in PTA of less than 10 dB, 79.2% of patients showed a change in PTA of less than 20 dB and 20.8% of patients showed a change in PTA of more than 21 dB at the last follow-up. Only one patient (4%) became deaf. Cases with a sudden loss of hearing were more likely to experience hearing preservation than those with gradual loss of hearing (P<0.05). The mean age was younger in patients whose hearing was preserved (P<0.05). Poor pretreatment PTA appeared to linearly correspond to the changes in PTA (regression coefficient 0.78). The size of the tumor was not related to the change in PTA. No relationship was observed between the maximum or peripheral dose and the PTA change. The real benefit of stereotactic boost after small-field fractionated irradiation was not certain. CONCLUSION: Fractionated STI produced a hearing preservation rate compatible with meticulously collimated multi-spots single fraction irradiation. Further follow-up is required to confirm the long-term benefits of fractionation.

Audiometry↗
PubMed1998

Germ cell tumours of the central nervous system: treatment consideration based on 111 cases and their long-term clinical outcomes.

Germ cell tumours (GCTs) of the central nervous system (CNS) encompass various histological subtypes, and their optimal management has been the subject of debate. To indicate a better management strategy for each subtype, we analysed the records of 111 patients (median age 14 years), who underwent treatment since 1970. With a median follow-up duration of 86 months, the probability of surviving 5 years was: 96% for pure germinoma patients, 100% for mature teratoma, 67% for immature teratoma and 69% immature teratoma mixed with germinoma. The probability of cause-specific progression of germinomas producing human chorionic gonadotropin (HCG) was higher than that of non-producing germinomas (P < 0.01). GCTs that included a highly malignant component, such as embryonal carcinoma or yolk sac tumour, exhibited a poor prognosis with 38% chance of 5-year survival. Late adverse effects of therapy included stroke, secondary malignancy and cognitive, endocrinological, auditory and visual dysfunctions. Of 85 survivors with a median follow-up period of 99 months, 58 patients needed hormone replacement therapy, 26 patients showed poor performance status and, to date, only 1 patient has fathered children. Because the outcomes varied widely for each subtype, the traditional categories, that is, germinoma and non-germinomatous GCT as an extrapolation from the gonadal GCTs, are not suitable for appropriately selecting therapeutic regimen for CNS GCTs.

Activities of Daily Living↗
PubMed1998

Cisplatin/vincristine chemotherapy for hypothalamic/visual pathway astrocytomas in young children.

Hypothalamic/visual pathway astrocytomas in children are usually quiescent, but certain cases contain aggressive neoplasms that cause progressive neurological and visual deterioration. Radiotherapy is not recommended in young children because of its adverse effects later in life. This report describes the efficacy of a chemotherapeutic regimen. Four young children with hypothalamic/visual pathway astrocytoma, with a mean of 18 months of age at diagnosis, were treated with chemotherapy. Three patients had diencephalic syndrome at the disease's onset. Three patients with pilocytic astrocytoma were histologically verified, and another infant was clinically diagnosed. A combination chemotherapy using cisplatin and vincristine was administered in a total of 8 cycles in 3 children and 4 in one child. One patient who demonstrated renal insufficiency after 4 cycles of this regimen was treated with additional 4 cycles using carboplatin instead of cisplatin. The acute and subacute hematologic and otologic toxicities were mild, and a transient renal insufficiency in a child during chemotherapy improved. After chemotherapy, tumor regression was documented in 3 patients, and the disease was observed to be stable in one patient with an evidence of intratumoral necrosis on MRI. Three patients showed neurological and endocrinological improvements. These results suggest that this regimen is feasible in young children and may be useful as a first-line treatment for hypothalamic/visual pathway astrocytomas, which in turn may allow potentially deleterious irradiation on the maturing brain to be deferred until the disease progresses.

Antineoplastic Agents↗
PubMed1998

Human astrocytoma cells are capable of producing macrophage inflammatory protein-1beta.

We investigated expression of macrophage inflammatory protein-1 (MIP-1) alpha and beta in human astrocytoma cell lines and surgical specimens of astrocytic tumors. Enzyme-linked immunosorbent assay (ELISA) showed constitutive secretion of MIP-1alpha protein in only one and MIP-1beta in none of 7 cell lines tested. However, MIP-1alpha production was increased in three cell lines by stimulation with lipopolysaccharide (LPS) and 5 cell lines by stimulation with phorbol-12myristate-13-acetate (PMA). Also, induction of MIP-1beta production was observed in one cell line with LPS stimulation and in two cell lines with PMA stimulation. Reverse-transcription polymerase chain reaction (RT-PCR) showed the increase of MIP-1alpha and beta mRNA expression in these cell lines. The increase of the mRNA with the stimuli was further confirmed by Northern blot analysis. In contrast, RT-PCR analysis revealed that the majority of the tested tumor specimens of high-grade.astrocytomas expressed both MIP-1alpha and MIP-1beta mRNAs. ELISA detected MIP-1beta protein in 1 of 11 cerebrospinal fluid samples from patients with high-grade astrocytoma and in 8 of 9 tumor cyst fluid samples, whereas MIP-1alpha was detected in only 1 cyst fluid somple. Taken together, these results indicate that astrocytic tumor cells are capable of expressing and producing MIPs, and suggest that MIPs may participate in the inflammatory responses commonly seen in astrocytic tumors.

Astrocytoma↗
PubMed1998

Monitoring adenoviral p53 transduction efficiency by yeast functional assay.

Monitoring the transduction efficiency is of paramount importance in gene therapy. To monitor adenovirus-mediated wild-type p53 gene transfer, we have used a quantitative assay which tests the ability of human p53 to activate transcription in yeast. Selective amplification of cellular and viral p53 transcripts followed by quantitative assessment of mutant p53 content with the assay permits measurement of the wild-type p53 transduction efficiency into SF-188, U251MG and HUG31 glioblastoma cells. One reverse transcription primer tracks the wild-type/mutant ratio of endogenous p53 mRNA (P2), and the other the wild-type/mutant ratio of both endogenous and exogenous p53 mRNA (P1). Following infection of cell lines homozygous for mutant p53, the apparent transduction efficiency calculated (tau 0 = [P1-P2]/[1 + P2]) correlated with the level of p21 expression. Transduction efficiency in heterozygous wild-type/mutant HUG31 cells increased linearly with multiplicity of infection (MOI) for tau 0 values between 0.5 and 5.9, and admixture of normal cell-derived RNA produced only a modest reduction in tau 0 value, in keeping with theoretical predictions. These results suggest that the yeast p53 functional assay may be a useful tool for monitoring p53 gene therapy.

Adenoviridae↗
PubMed1998

Pineoblastoma presenting in familial adenomatous polyposis (FAP): random association, FAP variant or Turcot syndrome?

Brain tumours which arise in combination with adenomatous polyposis are usually astrocytic tumours or medulloblastomas. An adult women with a pineoblastoma associated with familial adenomatous polyposis is presented. In regard to the neuro-epithelial origin of this tumour we propose that it should be included in the second category of brain tumour polyposis syndrome.

Adenomatous Polyposis Coli↗
PubMed1998

Twenty-four hour rhythm of melatonin in patients with a history of pineal and/or hypothalamo-neurohypophyseal germinoma.

Melatonin deficiency after a pinealectomy has been investigated in animals; however, in humans, this status can be assessed solely by investigating patients with a tumor originating in the pineal gland. This study analyzes secretion of melatonin and pituitary hormones in 14 patients with germinoma originating in the pineal or the hypothalamic-neurohypophyseal region. Thirteen patients had been successfully treated prior to this study. One patient was included in this study before the initiation of treatments. Plasma sampling was performed every 2 hr for 24 hr and melatonin concentrations were measured by radioimmunoassay. Melatonin secretion was nearly absent in the patients with pineal germinoma regardless of treatment option, even in the patient who had been untreated. In contrast, melatonin secretion and its circadian rhythms were not affected in patients with a hypothalamo-neurohypophyseal germinoma. The circadian rhythms of growth hormone and adrenocorticotropic hormone were not dysregulated in patients with the melatonin deficiency. We conclude that germinoma cells originating the pineal gland impair the production of melatonin by pineocytes and consequently induce a permanent melatonin deficiency in those patients. Since melatonin exerts multiple physiological functions, once a clinical concept of "melatonin deficiency syndrome" is established, melatonin replacement therapy could be investigated in patients who have a pineal germinoma or who have undergone a neurosurgical pinealectomy.

Adolescent↗
PubMed1998

Induction chemotherapy followed by reduced-volume radiation therapy for newly diagnosed central nervous system germinoma.

OBJECT: Although curative, radiation, which is conventionally administered for germinomas, causes significant neurological sequelae. This study aimed at reducing the volume and dose of radiation to a localized level of 24 Gy by pretreating the patient with chemotherapy. METHODS: Seventeen patients were divided into two risk groups based on serological findings and the extent of tumor. They were treated with chemotherapy prior to receiving localized radiation therapy. Six patients with solitary pure germinomas were treated with three or four cycles of cisplatin and etoposide (EP regimen) followed by 24-Gy local radiation therapy. Eleven patients with human chorionic gonadotropin (HCG)-secreting, multifocal, or disseminated germinomas received four to five cycles of ifosfamide, cisplatin, and etoposide (ICE regimen) followed by 24-Gy local radiation therapy. Craniospinal ports were used only in three cases of germinomas with dissemination. Gross-total resection was performed in three patients. Fourteen patients were able to be evaluated for their responses to chemotherapy. All patients achieved a complete response within three cycles. At a median follow-up duration of 24 months, 16 patients (94%) were alive without recurrence. One patient with an HCG-secreting germinoma experienced recurrence 38 months after surgery. That patient underwent successful salvage therapy using the same protocol. Thus, all 17 patients became free of disease with a 70 to 100% Karnofsky Performance Scale status. Toxicities associated with this study's chemotherapy regimen were mostly transient. No patient showed neurological or endocrinological deterioration during the follow-up period. CONCLUSIONS: The EP and ICE regimens were highly effective in treating the central nervous system germinomas and permitted dose and volume reduction of the radiotherapy. Localized 24-Gy irradiation was sufficient for disease control.

Adolescent↗
PubMed1998

Teratomas of the central nervous system: treatment considerations based on 34 cases.

OBJECT: The optimum clinical management of central nervous system (CNS) teratomas, particularly postsurgical adjuvant therapy, is still unclear, partly as a result of the tumors' low incidence. In this study the authors analyze 34 cases of CNS teratomas so that they may adequately indicate management of these lesions. METHODS: The median age of the 34 patients was 13 years. Twenty-seven patients treated between 1970 and 1991 were retrospectively reviewed. Four of these 27 patients died as a result of radical surgery; each of them had a teratoma involving the hypothalamus. After initial treatment, which included radiation therapy, 20 patients (48%) had died. In all seven cases of mature teratomas there was no recurrence. In two cases of immature teratomas in which there was complete surgical resection there was recurrence; however, salvage therapies were effective. Seven of eight patients with highly malignant teratomas died; for these patients salvage therapies, including repeated radiation and chemotherapy, failed. Seven patients who presented with CNS teratomas between 1992 and 1996 received adjuvant chemotherapy and radiation therapy according to a prospective study protocol. All seven patients were free from recurrence with a 70 to 100% Karnofsky Performance Scale score at a median follow-up period of 41 months. Patients with CNS teratomas rarely responded completely to chemotherapy or radiation therapy; an effective adjuvant therapy produced a partial response at best. CONCLUSIONS: Because teratomas show various responses to adjuvant therapy, a misdiagnosis of their histological subtype will lead to inadequate therapy. A diverse therapeutic protocol based on histological diagnosis is necessary to plan appropriate management. Treatment recommendations are discussed in detail in the article.

Adolescent↗
PubMed1997

Nitric oxide as a carcinogen: analysis by yeast functional assay of inactivating p53 mutations induced by nitric oxide.

We have used a yeast p53 functional assay to study induction of mutations in the p53 tumor suppressor gene by nitric oxide and cytosine methylation. The yeast assay identifies only biologically important p53 mutations. p53 cDNA was treated with the nitric oxide donor sydnonimine, PCR-amplified and transfected into yeast. Sydnonimine produced a significant, dose-dependent increase in C:G-->A:T transversions. Many important p53 mutational hotspots are postulated to arise by deamination of methylCpG in tumors. We therefore examined nitric oxide induction of mutations in p53 cDNA methylated by PCR-mediated substitution of 5-methylcytosine for cytosine or by treatment with the SssI CpG methylase. Both methylation procedures increased the baseline mutation rate, and nitric oxide treatment produced a further increase in mutation yield. Sequence analysis showed that methylation alone led to C:G-->T:A transitions, whereas nitric oxide treatment simply produced more C:G-->A:T transversions. Thus the most important factor in C:G-->T:A transition at CpG sites identified in this experimental system is cytosine methylation, consistent with spontaneous conversion of 5-methylcytosine to thymine by deamination.

Carcinogens↗
PubMed1997

Analysis of long-term treatment of intracranial germinoma.

PURPOSE: To determine an appropriate treatment policy for intracranial germinoma. METHODS AND MATERIALS: From 1976 to 1992, 51 patients with germinoma (18 with pathologically verified germinoma and 33 diagnosed as having germinoma by neuroimagings) were treated by radiation therapy. Various radiation doses and treatment fields were used. RESULTS: The 10-year cause-specific survival rate for pathologically verified and unverified germinoma was 100% and 96%, respectively. Relapses were noted in four patients, three of whom died from the disease. Two of the four patients with a tumor larger than 4 cm in gross diameter experienced relapse. Two relapses occurred in a nonirradiated spinal canal and two occurred in the irradiation area treated by 25 Gy in 10 fractions and 30 Gy in 20 fractions. No relapse was noted in patients in whom the whole ventricle field was determined precisely using three-dimensional treatment planning. Five patients who were followed at an outpatient clinic experienced significant late neurocognitive dysfunction, which set in after radiotherapy. CONCLUSION: After pathological confirmation, 40 Gy whole-ventricle irradiation using precise three-dimensional treatment planning is appropriate as a standard treatment for most intracranial germinoma.

Adolescent↗
PubMed1997

Stereotactic irradiation without whole-brain irradiation for single brain metastasis.

PURPOSE: The effectiveness of stereotactic irradiation (STI) alone without whole-brain irradiation (WBI) for a single metastatic brain tumor was analyzed retrospectively. METHODS AND MATERIALS: Forty-four patients with this condition were treated using radiosurgery (RS) alone or fractionated stereotactic radiotherapy (FSR) without WBI. RESULTS: The initial response rate was 92% and the overall local control rate was 84% (37 of 44 patients). A total of 39% (18 of 44) of patients experienced intracranial relapse outside the initial target area. Forty-eight percent (21 of 44) of patients required salvage treatment for intracranial relapse. All 7 patients who received WBI as salvage treatment required no further salvage treatment, but 5 of the 14 patients who received salvage STI without WBI required three to four treatments for brain metastasis. Late radiation damage was not seen with initial treatment but was observed with retreatment. The overall median survival time was 261 days, with a standard error of 64 days. Actuarial survival at 12 and 24 months was 34% and 9%, respectively. The actuarial survival rate was significantly affected by the existence of active extracranial disease (p = 0.041). CONCLUSION: The high response rate and short treatment period of STI alone are advantageous in the treatment of single brain metastasis in patients with active extracranial disease with WBI reserved for relapse. Because of the low complication rate, STI alone may be also useful in patients with good prognosis, without extracranial disease.

Aged↗