Adenovirus-mediated transfer of p53 augments hyperthermia-induced apoptosis in U251 glioma cells.

PURPOSE: Hyperthermia kills glioma cells by inducing apoptosis and is thereby an effective therapeutic modality for the treatment of malignant gliomas. However, cells harboring mutated p53 are refractory to hyperthermia-induced apoptosis. In this study, we assessed whether or not adenovirus (Adv)-mediated transduction of p53 overrides this resistant mechanism. METHODS AND MATERIALS: We transduced the p53 wild-type tumor suppressor gene into U251 glioma cells harboring mutated p53 using Adv vectors in combination with hyperthermia (43, 44.5 degrees C), and evaluated the degree of cell death and apoptosis. RESULTS: The percentage of cells that had died, as measured by trypan blue staining, among U251 cells infected with the Adv for p53 (Adv-p53) and treated with hyperthermia, was significantly higher than the percentage of cells that had died among U251 cells infected with Adv-p53 and not treated with hyperthermia, or those infected with the control Adv for dE (Adv-dE) and treated with hyperthermia. The degree of apoptosis, measured at 24 h after treatment, in hyperthermia-treated U251 cells infected with Adv-p53 (43 degrees C, 73%; 44.5 degrees C, 92%) was much higher than that infected with Adv-p53 (41%), or that infected with control Adv-dE and treated with hyperthermia (43 degrees C, 1.3%; 44.5 degrees C, 19%). Treatment with combined hyperthermia and Adv-p53 infection induced cleavage of caspase-3 in U251 cells. CONCLUSION: These results indicate that Adv-mediated transduction of p53 would render glioma cells highly sensitive to hyperthermia.

Langerhans cell histiocytosis limited to the pituitary-hypothalamic axis--two case reports.

Langerhans cell histiocytosis rarely presents as a solitary lesion in the pituitary-hypothalamic region, and is indistinguishable from germinoma, which occurs much more frequently, especially in Japanese. A 14-year-old girl and a 9-year-old girl presented with polydipsia and polyuria as the initial symptoms. Magnetic resonance (MR) imaging demonstrated a round mass at the pituitary stalk appearing as isointense on T1-weighted imaging and hyperintense on T2-weighted imaging. Endocrinological examination revealed mild hypopituitarism with central diabetes insipidus. Both patients underwent open craniotomy. Histological examination revealed granulomatous tissue with eosinophil infiltration and frequent Langerhans histiocyte clustering, compatible with the diagnosis of Langerhans cell histiocytosis. Low-dose local irradiation of 20 Gy was administered. First patient was followed up for 8 years, and her hypopituitarism gradually improved to a minimal level with only amenorrhea as the residual symptom. Recent MR imaging showed no residual mass at the region. Second patient was followed up for 15 months, and her diabetes insipidus is stable. MR imaging performed 5 months after the treatment showed marked reduction of the mass. These cases reemphasize the importance of histological diagnosis for lesions with similar neuroimaging appearances. Biopsy and low-dose irradiation are an effective treatment for this rare and essentially benign lesion, as opposed to attempting total removal of the mass.

[Clinical experience of autologous blood transfusion and fibrin glue in neurosurgery].

Clinical experience of autologous blood preservation on 83 patients and transfusion on 43 patients were reported. When drawing blood, 14 patients whose hemoglobin level was below 13 g/dl (body weight < 70 kg) or 14 g/dl (body weight > 70 kg) received subcutaneous recombinant human erythropoietin injection (s.c.) to facilitate erythropoiesis, according to the internal standard protocol. Hemoglobin levels of all the patients recovered to more than 10 g/dl by the time they were admitted to the hospital, which value would not interfere with general neurosurgical procedures. The injection of erythropoietin did not cause any side effects. Autologous blood transfusion was performed in 43 patients but, in 3 patients, additional homologous transfusion was required because of excessive bleeding. Except in cases with meningioma, postoperative hemoglobin values were identical with preoperative values, indicating that autologous blood transfusion was enough to replace intraoperative blood loss. Autologous fibrin glue was applied in 74 patients. In 70 cases including 55 with skull base surgery, the glue was applied to ensure dural closure. The incidence of cerebrospinal fluid leakage was 16.4% (5 patients) in skull base surgery. This incidence was identical to or less than that in previous reports. The glue was also effective in transposing and fixing offending vessels in 4 cases which received microvascular decompression. As a conclusion, procedures for autologous blood preservation and transfusion were safely performed in neurosurgical cases. Review of the literature was also presented to discuss the advantages and problems to be solved in the future.

Arteriovenous malformations in the basal ganglia and thalamus: management and results in 101 cases.

OBJECT: Because arteriovenous malformations (AVMs) in the basal ganglia and thalamus are difficult to treat, the authors conducted a retrospective study to determine the best management strategy for these lesions. METHODS: The authors reviewed the management and outcome in 101 patients with AVMs treated between 1971 and 1995. In 15 conservatively treated patients, hemorrhage occurred in 71.4% (annual rate 11.4%), and the morbidity and mortality rates were 7.1% and 42.9%, respectively, during a mean follow-up period of 6.6 years. Total microsurgical resection was performed in 15 patients with no mortality resulting, but motor function deteriorated permanently in three of them (20%). Postoperative morbidity correlated well with the location of the AVM and with preoperative motor function. In cases of lenticular AVMs without motor weakness, a postoperative decrease in motor function was significantly more common than in the remaining patients. In patients with motor weakness before surgery, AVMs in the thalamus or caudate nucleus were successfully resected. Among 66 patients treated with gamma knife radiosurgery, three had permanent radiation-induced neurological deficits, and three others experienced bleeding (new bleeding in one case and rebleeding in two). The treatment-associated morbidity rate was 6.7%, and the actuarial rate of complete obliteration was 85.7% at 2.5 years. In five patients treated with embolization alone, the morbidity and mortality rates associated with the procedure or bleeding were 40% and 20%, respectively. The morbidity and mortality rates in the pre-gamma knife era were 22.2% and 22.2%, whereas those for the post-gamma knife era are currently 10.4% and 1.5%, respectively. CONCLUSIONS: These results indicate that conservatively treated AVMs are more likely to bleed and thus produce a high incidence of patient mortality. Multimodal treatment including radiosurgery, microsurgery, and embolization improved clinical outcomes by making it possible to treat difficult cases successfully.

Thalamic atrophy following cerebral infarction in the territory of the middle cerebral artery.

We investigated shrinkage of the ipsilateral thalamus following infarction in the territory of the middle cerebral artery in 33 patients who were admitted less than or equal to 2 days after the stroke and who were followed by computed tomography for greater than 1 year with no recurrences. The thalamic area was measured on the computed tomograms, and the ratio of the ipsilateral area to the contralateral area was calculated. All values were compared with values from the initial computed tomogram taken less than or equal to 2 days after the stroke. The values of the ratio on follow-up computed tomograms decreased gradually in 15 patients. In these cases, the area of the ipsilateral thalamus was significantly reduced after 1 year (p less than 0.01) and marked atrophy was observed. These results demonstrate the significance of remote changes over a long period of time after focal cerebral infarction.

Progressive shrinkage of the thalamus following middle cerebral artery occlusion in rats.

Permanent middle cerebral artery occlusion in rats results in infarction in the ipsilateral cortex and caudate nucleus-putamen. In this ischemia model, severe shrinkage of the ipsilateral half of the thalamus was observed several months after surgery. We examined the serial profile of this phenomenon in 40 rats at intervals from 2 weeks to 6 months after the operation. The area of the ipsilateral half of the thalamus as a percentage of the area of the contralateral half was 87% at 2 weeks, 77% at 1 month, 54% at 3 months, and 54% at 6 months. Such severe morphologic change distant from the original ischemic focus has not been reported in models of experimental focal ischemia. Retrograde degeneration is thought to play an important role in this phenomenon.