Endothelial differentiation in intracerebral and subcutaneous experimental gliomas

Blood-brain barrier (BBB) properties of endothelial cells have on impact on brain tumor behavior, diagnosis, and response to therapy. Biochemical BBB properties are expressed by endothelial cells within intracerebral (IC) gliomas but little is known regarding the expression of BBB-associated proteins within gliomas established subcutaneously (SC), a site that is frequently used in experimental glioma models. We compared the expression of two BBB proteins, glucose transporter type-1 (Glut1) and endothelial barrier antigen (EBA), in IC and SC rat 9L and F98 gliomas. The percentage of microvessels with immunohistochemically-detectable Glut1 and EBA in IC 9L tumors (31–98%) contrasted with that found in SC 9L tumors (0–3.9%) (P < 0.0001). Likewise, the percentage of immunohistochemically-positive vessels in IC F98 tumors (35–66%) differed markedly from that in SC F98 tumors (0%) (P < 0.00001). These differences were not explained by effects of tumor location on vessel density or tumor histology. These findings demonstrate that the peritumoral environment influences endothelial differentiation within glial tumors and suggest that glioma cells maintain but do not induce the expression of barrier properties in vessels that infiltrate tumor from surrounding tissue.     

Prevention and reversal of diabetic nephropathy in db/db mice treated with alagebrium (ALT-711)

BACKGROUND: Alagebrium (ALT-711) has been shown to improve renal dysfunction in animal models of diabetes. METHODS: To test its effects in diabetic nephropathy (DN), ALT-711 was administered (1 mg/kg daily i.p.) to 9-week-old female db/db mice (n = 15, group A1) for 3 weeks and to 3-month-old (n = 15, group A2), 7-month-old (n = 7, group A3), and 12-month-old (n = 5, group A4) female db/db mice for 12 weeks, while a similar number of diabetic and nondiabetic mice were used as controls. The epsilonN-carboxymethyllysine (CML) levels in serum, urine, skin, and kidney tissue were measured by enzyme-linked immunosorbent assay. The renal morphometric parameters were assessed by electron and light microscopy. RESULTS: By the 3rd week of treatment, the serum CML level decreased by 41%, and the urinary CML concentration increased by 138% from baseline, while the urinary albumin/creatinine ratio was lower (p < 0.05) in diabetic and nondiabetic group A1 mice. After 3 months of treatment, serum, skin, and kidney CML levels and urinary albumin/creatinine ratio were lower (p < 0.05) and the urinary CML levels higher (p < 0.05) in treated group A2, A3, and A4 animals compared with groups which received phosphate-buffered saline, with a similar pattern observed in nondiabetic mice. The renal morphological parameters characteristic of DN decreased in treated compared with untreated mice. CONCLUSION: Alagebrium may prevent, delay, and/or reverse established DN in db/db mice by reducing the systemic advanced glycation end product pools and facilitating the urinary excretion of advanced glycation end products.     

Effect of chenodeoxycholic acid on 11beta-hydroxysteroid dehydrogenase in various target tissues

Glucocorticoids are metabolized by isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD). There is some controversy concerning the bile acid, chenodeoxycholic acid (CDCA), as a potential endogenously produced inhibitor of 11beta-HSD. The present experiments were designed to determine the relative specificity of CDCA for both isoforms of 11beta-HSD and to assess the biological relevance of inhibition in vascular tissue. IC(50) values (concentrations which inhibit 50% of the enzyme reaction) were calculated using rat liver microsomes as a source of 11beta-HSD1 dehydrogenase, Leydig cells for 11beta-HSD1 dehydrogenase and reductase, aorta for 11beta-HSD1 dehydrogenase and reductase, and sheep kidney for 11beta-HSD2 dehydrogenase. In each case, CDCA functioned as a potent inhibitor of 11beta-HSD1 dehydrogenase with IC(50) values of ranging from 0.2 to 7 micromol/L in contrast to 37 to 200 micromol/L for 11beta-HSD1 reductase. CDCA exhibited relatively weak inhibitory activity against 11beta-HSD2 from sheep kidney with an IC(50) of 70 micromol/L. The effect of CDCA on vascular contraction was studied in aortic rings isolated from Spague-Dawley rats incubated in medium containing corticosterone 10 nmol/L +/- CDCA (1 micromol/L) for 24 hours. Rings were stimulated with graded concentrations of phenylephrine (PE) (10 nmol/L, 100 nmol/L, and 1 micromol/L). Rings exposed to corticosterone and CDCA consistently demonstrated a greater contractile response at lower doses of PE (63% at PE 10 nmol/L, P <.001; 20% at PE 100 nmol/L, P <.025; and 10% at PE 1 micromol/L, not significant [NS]) compared to control preparations incubated with cortiosterone alone. These studies demonstrate (1) that CDCA preferentially affects 11beta-HSD1 dehydrogenase; (2) CDCA does inhibit 11beta-HSD2 dehydrogenase and 11beta-HSD1 reductase but only at high(er) concentrations exceeding 70 micromol/L and 37 micromol/L, respectively; and (3) inhibition of 11beta-HSD1 dehydrogenase in aortic rings by CDCA (1 micromol/L) enhances the contractile response of corticosterone plus PE.     

Intracranial MEMS based temozolomide delivery in a 9L rat gliosarcoma model

Primary malignant brain tumors (BT) are the most common and aggressive malignant brain tumor. Treatment of BTs is a daunting task with median survival just at 21 months. Methods of localized delivery have achieved success in treating BT by circumventing the blood brain barrier and achieving high concentrations of therapeutic within the tumor. The capabilities of localized delivery can be enhanced by utilizing mirco-electro-mechanical systems (MEMS) technology to deliver drugs with precise temporal control over release kinetics. An intracranial MEMS based device was developed to deliver the clinically utilized chemotherapeutic temozolomide (TMZ) in a rodent glioma model. The device is a liquid crystalline polymer reservoir, capped by a MEMS microchip. The microchip contains three nitride membranes that can be independently ruptured at any point during or after implantation. The kinetics of TMZ release were validated and quantified in?vitro. The safety of implanting the device intracranially was confirmed with preliminary in?vivo studies. The impact of TMZ release kinetics was investigated by conducting in?vivo studies that compared the effects of drug release rates and timing on animal survival. TMZ delivered from the device was effective at prolonging animal survival in a 9L rodent glioma model. Immunohistological analysis confirmed that TMZ was released in a viable, cytotoxic form. The results from the in?vivo efficacy studies indicate that early, rapid delivery of TMZ from the device results in the most prolonged animal survival. The ability to actively control the rate and timing of drug(s) release holds tremendous potential for the treatment of BTs and related diseases.     

Predictors of Inpatient Death and Complications among Postoperative Elderly Patients with Metastatic Brain Tumors

Objective

Risks of brain surgery in elderly patients with brain metastases are not well defined. This study was designed to quantify the postoperative risk for these patients after brain surgery for metastatic disease to the brain.

Methods

We performed a retrospective analysis of the Nationwide Inpatient Sample (1998–2005). Patients aged 65 years or older who underwent tumor resection of brain metastases were identified by ICD-9 coding. Primary outcome was inpatient death. Other outcomes included systemic postoperative complications, length of stay (LOS), and total charges.

Results

A total of 4,907 patients (53.6% men) were identified. Mean age was 72.1 years. Mean Charlson comorbidity score was 7.8. Inpatient mortality was 4%. The most common adverse events were pulmonary complications (3.4%). Mean length of stay was 9.2 days. Mean total charges were $57,596.39. In multivariate analysis, patients up to age 80 years had no significantly greater odds of inpatient death, relative to their 65- to 69-year-old counterparts. Each 1-point increase in Charlson score was associated with 12% increased odds of death, 0.52 days increased LOS, and $1,710.61 higher hospital charges. Postoperative pulmonary complications, stroke, or thromboembolic events increased LOS and total charges by up to 9.6 days and $57,664.42, respectively. These associations were statistically significant (P < 0.05).

Conclusions

Surgical resection of brain metastases among the elderly up to the ninth decade of life is feasible. Age older than 80 years and higher Charlson comorbidity scores were found to be important prognostic factors for inpatient outcome. Incorporating these factors into preoperative decision making may help to select appropriately those elderly candidates for neurosurgical intervention.