Katsuzo Kiya

O6-alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications

SummaryActivity of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) is an important determinant of responsiveness of tumor cells to chloroethylnitrosoureas (CENUs), representative chemotherapeutic agents for primary malignant gliomas. In order to assess the real states of this repair protein in human malignant gliomas, we assayed AGT activity in surgically extirpated 42 malignant glioma samples and studied the distribution of the activity under certain clinical conditions. There were wide variations in AGT activity between individuals. No significant difference in AGT activity on average was seen either between glioblastoma and anaplastic astrocytoma, nor between primary and recurrent tumors. Among 42 malignant gliomas, 7 samples (16.7%) had low AGT activity less than 0.1 pmoles/mg protein. In the case of glioblastoma, tumors possessing higher AGT activity tended to be less responsive to post-operation remission-induction therapy including CENUs. The result of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) chemosensitivity assay by using the corresponding surgical specimens suggested a close relationship between cellular resistance to CENUs and AGT activity. It was found to be unlikely that a short term administration of CENUs had a significant effect on AGT activity of brain tumors in human body. We could detect a bit of definite evidences of the relevance of AGT to resistance to CENUs and need to conduct further investigations for other resistance factors.

Intracranial germ-cell tumor with synchronous lesions in the pineal and suprasellar regions: Report of six cases and review of the literature

The features of intracranial germ-cell tumor with synchronous lesions in the pineal and suprasellar regions (GCTSPS) in six patients were investigated. GCTSPS accounted for 12.8% of all germ-cell tumors (GCT) in our brain tumor study group. In all cases, the initial symptoms were attributable to the suprasellar lesion, and symptoms due to the pineal GCT developed only after admission. Five of the six cases were histologically diagnosed as germinoma. In all cases, tumors of both regions disappeared after irradiation, resulting in no recurrence for an average of 55.3 months. Our experience and reports in the literature suggest that GCTSPS is highly sensitive to radiation in most cases, although some reports indicated that recurrence is frequent after radiation therapy alone. It is suggested that histological diagnosis in one of the GCTSPS lesions is undertaken to make a plan for the following treatment.

Penetration of etoposide into human malignant brain tumors after intravenous and oral administration

SummaryPenetration of etoposide into the cerebrospinal fluid, brain tumor, and brain tissue after intravenous administration was investigated in patients presenting with malignant brain tumors. A relatively low dose (55–65 mg/m2) was used to compare intravenous with oral administration. High-performance liquid chromatography with fluorescence detection was used to evaluate drug levels. Plasma and cerebrospinal fluid levels of etoposide after oral administration (50–150 mg/day) were also studied so as to determine the adequate oral dose for the treatment of malignant brain tumors. The peak plasma concentration after intravenous administration ranged from 7.01 to 10.47 μg/ml, varying in proportion to the injected dose, whereas that after oral administration was lower, namely, 1.44–4.99 μg/ml, and was unstable when the oral dose was 150 mg daily. The peak cerebrospinal fluid level following either intravenous or oral administration was much lower than the plasma concentration and was influenced by the peak plasma level and the sampling site. The etoposide concentration in cerebrospinal fluid taken from the subarachnoid space and ventricle of patients displaying no tumor invasion and of those presenting with meningeal carcinomatosis and in cerebrospinal fluid taken from the dead space after tumor resection was 0.7%±0.5%, 3.4%±1.0%, and 7.2% ± 8.5%, respectively, of the plasma concentration. Serial oral administration did not result in the accumulation of etoposide in cerebrospinal fluid. The tumor concentration (1.04–4.80 μg/g) was 14.0%±2.9% of the plasma level after intravenous administration, was related to the injected dose, and was approximately twice the concentration detected in the brain tissue. Therefore, a relatively low dose of etoposide injected intravenously penetrates the brain tumor at an efficacious concentration. Our results indicate than an oral dose of 100 mg etoposide be given for malignant brain tumors, as limited penetration of the drug into the intracranial region was observed.

Clinical evaluation of 33 patients with histologically verified germinoma

We evaluated 33 patients with histologically verified germinoma between 1978 and 1992. The patients consisted of 23 men and 10 women between 6 and 32 years of age. All patients underwent either biopsy, partial resection, or total resection. All patients received radiotherapy, and all had a complete remission. Recurrence occurred in three patients. Two recurrences were outside of the irradiated area. Though there were four deaths, none were caused by germinoma. Three resulted from the inadequate hormonal replacement. Accurate staging of patients with germinoma using magnetic resonance imaging (MRI), including whole spinal MRI, and development of a radiochemotherapy or chemotherapy method that preserves the hypothalamic-pituitary axis function are needed.

Intracranial metastasis from a spinal cord primitive neuroectodermal tumor: Case report

A patient with intracranial seeding from a spinal cord primitive neuroectodermal tumor with ependymal differentiation is presented. The first and second stages of intracranial dissemination were well controlled by a combination of irradiation and chemotherapy. The authors review previously published cases and discuss the possible mechanism of seeding from the spinal cord to the intracranial region.

Primary malignant rhabdoid tumor of the central nervous system: Case report and review of the literature

Malignant rhabdoid tumor (MRT) is well known as a pediatric malignant tumor of the kidney. Only nine cases of primary MRT of the central nervous system (CNS) have been reported. We are reporting in detail the clinical course and treatment of a patient with primary MRT of the CNS. We cared for a 3-year-old girl with an MRT that extended from the internal auditory canal to the cerebellopontine angle. Despite three surgical attempts at resecting the tumor combined with whole craniospinal axis irradiation, as well as chemotherapy consisting of intravenous nimustine hydrochloride and intrathecal methotrexate injections, the patient died 13 months after her initial hospitalization. The origin of CNS-MRT development is still a question of pathologic debate. Like renal MRT, the prognosis of MRT of the CNS is very poor. The dissemination of MRT of the CNS occurred in most cases.

Cerebral sinovenous thrombosis after closed head injury.

BACKGROUND Cerebral sinovenous thrombosis (CSVT) after closed head injury is an uncommon but potentially serious complication. The aim of this study was to determine whether diffusion weighted imaging (DWI) provide predictive information regarding prognosis. METHODS We retrospectively reviewed a series of 11 patients with CSVT after closed head injury. Each patient underwent computed tomography and magnetic resonance imaging within 24 hours of onset of symptoms, including DWI, magnetic resonance venography, and conventional sequences. Apparent diffusion coefficient (ADC) values were measured in seven regions of interest in 7 of 11 patients using DWI. Follow-up imaging and clinical outcome were assessed 6 months or later after initial presentation. RESULTS The most affected sinus was the posterior portion of the superior sagittal sinus. There was a mean time interval of 4.1 days between subsequent venous stroke and the initial insult. Brain edema improved in 6 of 11 patients on follow-up imaging. Six of 11 patients recovered successfully, although high or mixed DWI intensity associated with moderately decreased ADC (0.53-0.57 x 10(-3) mm2/s). Two other patients with hematomas developed venous infarction, despite mixed DWI with heterogeneous ADC value (0.55-1.11 x 10(-3) mm2/s). The other three patients, with high DWI and strongly decreased ADC values (0.26-0.27 x 10(-3) mm2/s), developed severe brain atrophy after superior sagittal sinus thrombosis. CONCLUSIONS The prospective cutoff point of ADC value may be higher in CSVT after head injury with traumatic hematoma. The territory of venous infarction was found to be larger in infants after treatment failure. In infants, CSVT can demonstrate initially cytotoxic brain edema, which is reversible with anticoagulation therapy.

Brain metastasis of Merkel cell carcinoma. Case report and review of the literature.

Abstract Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumor that is locally aggressive and has potential for metastatic spread. However, brain metastases are rare, and therapy for such tumors has never reported. The authors present a 48-year-old woman with MCC of the left elbow and a right cerebellar metastasis. After the right cerebellar mass was totally resected, radiation treatment and chemotherapy were performed. Eight cases of brain metastasis have been reported in the literature, but only 5 have been presented in sufficient detail for analysis. Therapy for brain metastases has always been palliative whole-brain irradiation and chemotherapy except for our patient, who underwent total removal of the tumor and survived for 11 months without neurological deficit. Except in the case of 1 with a particularly radiosensitive MCC, the patients with brain metastases died within 9 months after detection of the brain lesions. If possible, aggressive excision of brain metastases as well as of the primary lesion should be done.

Spontaneous rupture of craniopharyngioma cysts. A report of five cases and review of the literature.

Reports of spontaneous rupture of a craniopharyngioma cyst are extremely rare. Five cases of spontaneous rupture of a craniopharyngioma cysts are reported. Clinical symptoms included chemical meningitis in three patients, alleviation of headache in one, and improvement in a visual disturbance in one. Reduction in cyst size was confirmed by computed tomography or magnetic resonance imaging in three of five patients, and the histopathological diagnosis was confirmed histologically in four patients. Cerebrospinal fluid findings were abnormal in the three patients with chemical meningitis. Spontaneous rupture of craniopharyngioma cysts tended to occur more frequently in adult males. Computed tomography and magnetic resonance imaging were useful in diagnosing cyst rupture, and cerebrospinal fluid findings, especially the presence of cholesterol crystals and an elevated cholesterol concentration, are suggestive, even when no reduction in cyst size is observed radiologically.

Demonstration of the venous systems with gadolinium-enhanced three-dimensional phase-contrast MR venography

The purpose of this study was to evaluate the usefulness and advantages of gadolinium-enhanced three-dimensional phase-contrast MR venography for demonstrating the venous systems. The three-dimensional phase-contrast MR venography was performed with a velocity encoding gradient settings from 5 to 20 cm/s on 22 normal subjects. In 8 of normal subjects, gadolinium-enhanced phase-contrast MR venography was performed. 22 subjects (100%) had detectable flow in the sphenoparietal sinus, transverse sinus, basal vein, and internal cerebral vein. With a VENC setting at 10 cm/s, venous system was visualized selectively and clearly. Detection ratio in inferior petrosal sinus, superior petrosal sinus, and superior ophthalmic vein increased from 0% to 25%, from 28.6% to 62.5%, and from 28.6% to 37.5%, respectively, after administration of gadopentate dimeglumine. In conclusion, gadolinium-enhanced three-dimensional phase-contrast MR venography was useful for demonstrating the venous systems.