Effect of human skin-derived stem cells on vessel architecture, tumor growth, and tumor invasion in brain tumor animal models

Glioblastomas represent an important cause of cancer-related mortality with poor survival. Despite many advances, the mean survival time has not significantly improved in the last decades. New experimental approaches have shown tumor regression after the grafting of neural stem cells and human mesenchymal stem cells into experimental intracranial gliomas of adult rodents. However, the cell source seems to be an important limitation for autologous transplantation in glioblastoma. In the present study, we evaluated the tumor targeting and antitumor activity of human skin-derived stem cells (hSDSCs) in human brain tumor models. The hSDSCs exhibit tumor targeting characteristics in vivo when injected into the controlateral hemisphere or into the tail vein of mice. When implanted directly into glioblastomas, hSDSCs distributed themselves extensively throughout the tumor mass, reduced tumor vessel density, and decreased angiogenic sprouts. In addition, transplanted hSDSCs differentiate into pericyte cell and release high amounts of human transforming growth factor-beta1 with low expression of vascular endothelial growth factor, which may contribute to the decreased tumor cell invasion and number of tumor vessels. In long-term experiments, the hSDSCs were also able to significantly inhibit tumor growth and to prolong animal survival. Similar behavior was seen when hSDSCs were implanted into two different tumor models, the chicken embryo experimental glioma model and the transgenic Tyrp1-Tag mice. Taken together, these data validate the use of hSDSCs for targeting human brain tumors. They may represent therapeutically effective cells for the treatment of intracranial tumors after autologous transplantation

Local delivery of a synthetic endostatin fragment for the treatment of experimental gliomas

OBJECTIVE: Endostatin is an anti-angiogenic agent that blocks matrix-metalloproteinase-2 and inhibits endothelial cell proliferation. Currently, endostatin is available through recombinant technology, which limits its broader use. In this study, a synthetic endostatin fragment (EF) was analyzed to determine its anti-angiogenic properties when locally delivered by controlled-release polymers and to establish its effect as a treatment for experimental gliomas. METHODS: Cytotoxicity of EF against 9L gliosarcoma and F98 glioma was determined in vitro. EF was loaded into polyanhydride-poly-(bis- [carboxyphenoxy-propane]-sebacic-acid) (pCPP:SA) polymers at increasing concentrations. Pharmacokinetics of the EF/polymer formulations were defined in vitro. Anti-angiogenic properties of the EF/polymer formulations were evaluated in the rat-cornea micropocket assay. Toxicity and efficacy of locally delivered EF polymers either alone or combined with systemic bischloroethylnitrosourea (carmustine) were determined in rats intracranially challenged with 9L gliosarcoma. RESULTS: EF showed scarce cytotoxicity against 9L and F98 in vitro. EF/pCPP:SA formulations showed sustained release by day 19. Mean corneal angiogenesis index 20 days after tumor implantation was 4.5 (plus or minus) 0.7 for corneas implanted with 40% EF/pCPP:SA compared with controls (8.5 (plus or minus) 1.3, P = 0.02). Intracranial efficacy studies showed that EF polymers alone did not prolong animal survival. Combination of 40% EF/pCPP:SA polymers with systemic bischloroethylnitrosourea (carmustine) prolonged survival (median survival of 44 d, P = 0.001) and generated 33% long-term survivors. CONCLUSION: Controlled-release polymers can effectively deliver a biologically active EF in a sustained fashion. EF inhibits angiogenesis in vitro and in vivo, and even though EF does not prolong survival as a single agent, it exhibits a synergistic effect when combined with systemic bischloroethylnitrosourea (carmustine) in the intracranial 9L gliosarcoma model

Management of 350 aneurysmal subarachnoid hemorrhages in 22 Italian neurosurgical centers

Objective: To collect information on clinical practice and current management strategies in 22 Italian neurosurgical hospitals for patients with aneurysmal subarachnoid hemorrhage. Design and setting: Observational 6-month study for prospective data collection. Patients: 350 cases of aneurysmal subarachnoid hemorrhage. Measurements and results: Each center enrolled from 4-36 patients. Neurological deterioration (24%) was more frequent in patients with higher Fisher classification, and with pretreatment rebleeding and it was associated with an unfavorable outcome (46%, 36/78, vs. 33%, 83/251). Aneurysms were mainly secured by clipping (55%, 191/350). An endovascular approach was utilized in 35% (121/350). The more frequent medical complications were fever, recorded in one-half of cases, pneumonia (18%), sodium disturbances (hyponatremia 22%, hypernatremia 17%), cardiopulmonary events as neurogenic pulmonary edema (4%) and myocardial ischemia (5%). Intracranial hypertension was experienced in one-third of the patients, followed by hydrocephalus (29%) and vasospasm (30%). Cerebral ischemia was found in an about one-quarter of the cohort. To identify the independent predictors of outcome we developed a model in which the dichotomized Glasgow Outcome Scale was tested as function of extracranial and intracranial complications. Only high intracranial pressure and deterioration in neurological status were independent factors related to unfavorable outcome. Conclusions: Our data confirm that in every step of care there is extreme heterogeneity among centers. These patients are complex, with comorbidities, immediate risk of rebleeding, and delayed risk of intracranial and medical complications. Following SAH early treatment and careful intensive care management requires the careful coordination of the various clinical specialties

Microsurgical endoscopic-assisted retrosigmoid intradural suprameatal approach : anatomical considerations

AIM: The aim of this study was to evaluate the feasibility of microscopic endoscopic assisted suprameatal tubercle drilling with a retrosigmoid approach and it focuses on the anatomic structures identified with the endoscope. The advantages of the 30 degrees optic view are also described. METHODS: Fifty dry temporal bones were studied in order to estimate the variability of the prominence of the suprameatal tubercle. Eight fresh cadaveric specimens were prepared for a retrosigmoid approach to allow for microscopic endoscopic assisted suprameatal tubercle drilling. The increase in trigeminal exposure and neurovascular structures visualization with the endoscope, using 0 degrees and 30 degrees optics were then evaluated. RESULTS: Three major types of the suprameatal tubercle were found: 1) a large size tubercle (> 6 mm, 9/50 cases); 2) a medium size tubercle (3-6 mm, 37/50 cases); and 3) an almost absent suprameatal tubercle (< 3 mm, 4/50 cases). Microscopic endoscopic assisted suprameatal tubercle drilling with opening of the Meckel's Cave was found to be technically feasible in all cases. The increase in trigeminal nerve exposition was of 9 mm on average. Endoscopic exploration with 0 degrees and 30 degrees optics made possible the identification of all neurovascular structures in the area. CONCLUSION: Microscopic endoscopic assisted suprameatal tubercle drilling is a feasible procedure that allows the identification of all neurovascular structures in the cerebellopontine angle and petrous apex region. The opening of Meckel's Cave may be particularly useful for lesions located in the cerebellopontine angle having a minor component that extends anteriorly and laterally in the middle cranial fossa

The dysraphic state of the posterior fossa. Clinical review of the Dandy-Walker syndrome and the so-called arachnoid cysts

The Authors report their case material concerning some basic items of the dysraphic pathology of the Posterior Fossa: 22 cases of Dandy Walker syndromes (DWS) and "Arachnoid Cysts" (PFC). The mean clinical findings (predominant involvement of the vestibular structures of the brain stem in the DWS, frequent epileptic seizures and some cases of hypothalamic disturbances in the PFC) are discussed in the light of current embryological theories on Weed's "area membranacea". Finally the results of differential surgical treatments are examined: good or satisfactory results were obtained with shunts, while still debatable seems to be the direct surgical approach