SUMMARY In human glioblastomas (hGBMs), tumor-propagating cells with stem-like characteristics (TPCs) represent a key therapeutic target. We found that the EphA2 receptor tyrosine kinase is overexpressed in hGBM TPCs. Cytofluorimetric sorting into EphA2High and EphA2Low populations demonstrated that EphA2 expression correlates with the size and tumor-propagating ability of the TPC pool in hGBMs. Both, ephrinA1-Fc, which caused EphA2 downregulation in TPCs, and siRNA-mediated knockdown of EPHA2 expression suppressed TPCs self-renewal ex vivo and intracranial tumorigenicity, pointing to EphA2 downregulation as a causal event in the loss of TPCs tumorigenicity. Infusion of ephrinA1-Fc into intracranial xenografts elicited strong tumor-suppressing effects, suggestive of therapeutic applications.

The incidence of post-traumatic hydrocephalus (PTH) has been reported to be 0.7-51.4%, and we have frequently observed the development of PTH in patients undergoing decompressive craniectomy (DC). For this reason we performed a retrospective review of a consecutive series of patients undergoing DC after traumatic brain injury (TBI). From January 2006 to December 2009, 41 patients underwent DC after closed head injury. Study outcomes focused specifically on the development of hydrocephalus after DC. Variables described by other authors to be associated with PTH were studied, including advanced age, the timing of cranioplasty, higher score on the Fisher grading system, low post-resuscitation Glasgow Coma Scale (GCS) score, and cerebrospinal fluid (CSF) infection. We also analyzed the influence of the area of craniotomy and the distance of craniotomy from the midline. Logistic regression was used with hydrocephalus as the primary outcome measure. Of the nine patients who developed hydrocephalus, eight patients (89%) had undergone craniotomy with the superior limit <25 mm from the midline. This association was statistically significant (p = 0.01 - Fisher's exact test). Logistic regression analysis showed that the only factor independently associated with the development of hydrocephalus was the distance from the midline. Patients with craniotomy whose superior limit was <25 mm from the midline had a markedly increased risk of developing hydrocephalus (OR = 17). Craniectomy with a superior limit too close to the midline can predispose patients undergoing DC to the development of hydrocephalus. We therefore suggest performing wide DCs with the superior limit >25 mm from the midline.

The blood brain barrier is a functional barrier allowing the entry into the brain of only essential nutrients, excluding other molecules. Its structure, although essential to keep the harmful entities out, is also a major roadblock for pharmacological treatment of brain diseases. Several alternative invasive drug delivery approaches, such as transcranial drug delivery and disruption of blood brain barrier have been explored, with limited success and several challenges. Intranasal delivery is a non-invasive methodology, which bypasses the systemic circulation, and, through the intra- and extra- neuronal pathways, provides direct brain drug delivery. Colloidal drug delivery systems, particularly lipidic nanoparticles offer several unique advantages for this goal . Areas covered: This review focuses on key brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, and provide a detailed overview of the current lipid nanoparticle based treatment options explored thus far. The review also delves into basic preparation, challenges and evaluation methods of lipid drug delivery systems. Expert opinion: Brain diseases present complex pathophysiology, in addition to the practically inaccessible brain tissues, hence according to the authors, a two-pronged approach utilizing new target discovery coupled with new drug delivery systems such as lipid carriers must be adopted.

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The proposed morphological classification estimates the global ICP wave and its ability to reflect or predict an alteration in CSF hydrodynamics. An ANN can be trained to efficiently recognize four different CSF wave morphologies. This classification seems helpful and accurate for diagnostic use.

Purpose: It has been hypothesized that brain tumors are derived from stem cell or transiently dividing precursor transformation. Furthermore, c-Jun NH 2 -terminal kinases (JNKs) have been involved in gliomagenesis. This study analyzes stem cell marker nestin and JNK expression in glioblastoma multiforme (GBM) and peritumor tissue and assesses their possible prognostic implications. Experimental Design: Nestin and both total JNK (tJNK) and phosphorylated JNK (pJNK) expression was investigated by immunohistochemistry in 20 GBMs. Samples were derived from tumors (first area), from tissues at a distance <1 cm (second area), and between 1 and 3.5 cm (third area) from the macroscopic tumor border. The relationships between patients' age, Karnofsky performance status, gender, protein expression, and survival were analyzed. Results: Nestin cytoplasmic immunoreactivity was observed in the majority of cells in tumor but infrequently in peritumor areas. tJNK, observed in the nucleus and cytoplasm, was widely expressed in the three areas; pJNK, mostly located in the nuclei, was found in a variable percentage of cells in the tumor and peritumor tissue. Nestin and JNK expression in peritumor areas was independent of the presence of neoplastic cells. Univariate analysis indicated that survival was longer (19 versus 12 months; P = 0.01) for patients whose pJNK/nestin and (pJNK/ tJNK)/nestin ratios in the second area were z2.619 and z0.026, respectively. The same variables showed an independent prognostic value in multivariate analysis. Conclusions: Nestin and JNK expression indicates that peritumor tissue, independently of the presence of neoplastic cells, may present signs of transformation. Moreover, pJNK/nestin and (pJNK/tJNK)/nestin ratios in that tissue seem to have some prognostic implications in GBM patients.

In general, cranioplasty is viewed as a straightforward surgical procedure, and for many years the complications associated with the procedure have been underestimated. We reviewed our 5-year experience consisting of 218 cranioplasties. Study outcomes focused specifically on the occurrence of complications after cranioplasty. Autologous bone-assisted and prosthetic cranioplasties were considered. Variables described by other authors to be associated with complications were studied, including history of previous cranioplasty, wider craniectomy size, bifrontal craniectomy, and delayed cranioplasty. We also analyzed the influence of material used for craniectomy on the occurrence of complications. The overall complication rate was 19.7%. Nineteen cases of infection (8.7%), 5 cases of postoperative wound dehiscence (2.3%), 6 cases of epidural hemorrhage (2.8%), and 13 cases of cranioplasty dislocation (5.9%) were observed. Bifrontal cranioplasties were more frequently associated with complications (p=0.01; Fisher's exact test) and infection (p<0.0001; Fisher's exact test). Postoperative wound dehiscence was more frequently observed with hand-made or custom-made cranioplasties compared with autologous cranioplasties (p=0.02). Early cranioplasty (<3 months from craniectomy) was significantly associated with cranioplasty dislocation (p=0.03). Logistical regression analysis showed that the only factor independently associated with complication was the site of cranioplasty (p=0.01). In particular, patients with a bifrontal cranioplasty had a 2-fold increased risk of complication (CI 95 1.1-3.6, p=0.017) and a 2.5-fold increased risk of developing infection (CI 95 1.3-4.9, p=0.009) compared with hemispheric/bihemispheric cranioplasty. Our analysis confirms that cranioplasty is burdened by a significant complication rate. In this context, bifrontal cranioplasty is related to a higher risk of complication and, in particular, infection.

CNS-LYG is a rare disease that should be considered in the differential diagnosis of both diffuse and space-occupying cerebral lesions. Primary cerebral LYG seems not to be associated with EBV and appears to have a better prognosis than systemic LYG with CNS localization, which is frequently EBV positive.