Targeted therapy for brain metastases: improving the therapeutic ratio.

Brain metastasis is the most common intracranial malignancy in adults. Improvements in modern imaging techniques are detecting previously occult brain metastases, and more effective therapies are extending the survival of patients with invasive cancer who have historically died from extracranial disease before developing brain metastasis. This combination of factors along with increased life expectancy has led to the increased diagnosis of brain metastases. Conventional treatment has been whole brain radiotherapy, which can improve symptoms, but potentially results in neurocognitive deficits. Several strategies to improve the therapeutic ratio are currently under investigation to either enhance the radiation effect, thereby preventing tumor recurrence or progression as well as reducing collateral treatment-related brain injury. In this review article, we discuss new directions in the management of brain metastases, including the role of chemical modifiers, novel systemic agents, and the management and prevention of neurocognitive deficits.     

Chronic ethanol treatment alters the behavioral effects of Ro 15-4513, a partially negative ligand for benzodiazepine binding sites

Pentylenetetrazol (PTZ)-induced convulsion were studied in control, chronic ethanol-maintained, and ethanol-withdrawal rats. The convulsive doses of PTZ varied among the different groups of rats. Ethanol-maintained rats required higher doses of PTZ to produce convulsions, compared to control and ethanol-withdrawal rats. The partially negative ligands for benzodiazepine binding sites, Ro 15-4513 (2 mg/kg, i.p.) and FG 7142 (20 mg/kg, i.p.) produced proconvulsant effect in saline (control) and ethanol-withdrawal rats as they potentiated the effect of subconvulsive dose of PTZ. A higher dose of Ro 15-4513 (4 mg/kg, i.p.), but not FG 7142 (up to 80 mg/kg, i.p.), also produced proconvulsant effect in ethanol-maintained rats. Furthermore, Ro 15-4513 (5, 10 mg/kg, i.p.), but not FG 7142 (up to 80 mg/kg, i.p.), produced clonic-tonic seizures of short duration in ethanol-withdrawal rats. These effects of Ro 15-4513 and FG 7142 were reversed by diazepam (2 mg/kg, i.p.), as well as by the GABA-neutral Ro 15-1788 (10 mg/kg, i.p.), thereby, indicating the involvement of central benzodiazepine receptors in the action of Ro 15-4513 and FG 7142. These observations suggest that chronic ethanol treatment selectively alters the receptor sensitivity to Ro 15-4513, an ethanol antagonist and partially negative ligand for BZ sites, and this observation supports the notion that ethanol effects are more susceptible to reversal by the imidazobenzodiazepine as compared to other negative ligand for BZ binding sites.     

Biopsy excision through a fiberoptic bronchoscope in the palliative management of airway obstruction

Simple biopsy resection through the rigid bronchoscope has been described in the past. We successfully performed such resection through a flexible bronchoscope in six patients with symptomatic and relatively less vascular lesions without complications. In selected patients simple biopsy resection of endobronchial lesion can be safely performed through flexible bronchoscope.     

Ganglioglioma of the spinal cord: report of two cases and review of literature.

Ganglioglioma can involve any part of the central nervous system. Mostly ganglioglioma occur in temporal lobe. Spinal cord ganglioglioma is a very rare entity. We report two cases of cervico-dorsal region ganglioglioma, who underwent complete surgical excision. In the postoperative period they had transient deterioration of their neurological status that gradually recovered with follow-up.     

Subcellular concentrations of estrone, estradiol, androstenedione and 17 beta-hydroxysteroid dehydrogenase (17-beta-OH-SDH) activity in malignant and non-malignant human breast tissues

Total and subcellular (cytosol and nuclear) concentrations of estrone (E1), estradiol (E2), and androstenedione were determined in non-malignant (n = 61) and malignant (n = 65) human breast tissues obtained from post-menopausal women. The 17 beta-hydroxysteroid dehydrogenase (17 beta-OH-SDH) activity was determined in 800g supernatant fraction. Total estrogens, E1 and E2 levels and 17 beta-OH-SDH activity were significantly (p less than 0.005, 0.0005, 0.001, respectively) higher in malignant than in non-malignant breast tissues. We failed to observe significant changes in subcellular steroid concentrations or enzyme activity associated with patients' obesity or tumor estrogen receptor status. When the steroid levels were analyzed in relation to clinical staging of the disease, nuclear contents of estradiol were significantly higher (p less than 0.005) in Stage-IV patients than in those with less advanced disease (Stages I to III). 17 beta-OH-SDH activity was significantly (p less than 0.001) lower in patients with advanced disease than in those with relatively less advanced (Stages I to III) disease and was positively correlated with tissue concentration of androstenedione. Our present data indicate that differential intracellular metabolism of steroid hormones may have some influence on availability of estradiol at nuclear sites. In postmenopausal women, local interconversion of estrogens may provide sufficient estrogenic stimulus to enhance the growth and progression of breast tumors.     

Dominant A1: angiographic and clinical correlations with anterior communicating artery aneurysms.

It has been observed but never proven that anomalies of the anterior communicating artery complex are associated with anterior communicating artery aneurysms (ACAA). Therefore, in an effort to understand the significance of haemodynamic factors in the genesis, as well as the clinical course of ACAA, we evaluated the correlation between certain angiographic patterns of flow in the anterior circulation and the clinical findings of 51 patients with ACAA compared with 50 matched controls. Four significant associations which have never been validated were identified: 1) a dominant A1 (filling both A2's) was found in 57% of ACAA patients versus 14% of controls (p less than 0.001). 2) Unilateral hypoplasia of the opposite A1 was present in 24% of ACAA patients versus 6% of controls (p = 0.01). 3) Exclusive filling of the ACAA from one A1 occurred in 78%. 4) No statistically significant relationship was found between the anatomic flow patterns studied and the patients clinical presentation including age, sex, or grade. We conclude that anterior communicating artery aneurysms are significantly related in a majority of patients with the presence of a dominant A1, probably as the result of enhanced haemodynamic stress caused by this anatomic abnormality in the circulation. However, this association is not constant, and a dominant pattern of flow did not correlate with the clinical course. This is probably a reflection of the differences between factors initiating aneurysm formation and those influencing its growth, as well as of the relative limitations of angiography when pathophysiological extrapolations are attempted.