Gerardo Caruso

Time-course of blood-brain barrier permeability changes after experimental subarachnoid haemorrhage.

Summary¶ An increase in blood-brain barrier (BBB) permeability after subarachnoid haemorrhage (SAH) has been described in humans and has been correlated with delayed cerebral ischemia and poor clinical outcome. Few studies examined in the laboratory the relationship between SAH and BBB, with contrasting results due to limitations in experimental probes adopted and in timing of observation. The aim of this study was to quantify the time-course of BBB changes after experimental SAH. Groups of eight rats received injections of 400 μl of autologous arterial blood into the cisterna magna. BBB was assessed 6, 12, 24, 36, 48, 60, and 72 hours after SAH and in sham-operated animals separately for cerebral cortex, i.e. frontal, temporal, parietal, occipital, subcortical gray matter (Caudate-Putamen-Thalamus), cerebellar cortex and nuclei, and brain stem by a spectrophotofluorimetric evaluation of Evans Blue dye extravasation. As compared to sham-operated controls, SAH determined a significant BBB permeability change beginning 36 hours after SAH, peaking at 48 hours, and normalizing on day 3. This study provides a quantitative description of the temporal progression and recovery of BBB dysfunction after SAH. These results have implications for the management of aneurysm patients and for assessing the rationale and the therapeutic window of new pharmacological approaches.

Transverse microincisions of the outer layer of the dura mater combined with foramen magnum decompression as treatment for syringomyelia with Chiari I malformation.

Summary Numerous surgical procedures have been proposed for treatment of syringomyelia associated with Chiari I malformation, but the optimal treatment has not yet been uniformly standardised. The main aim of the surgical treatment of syringomyelia/Chiari I complex is directed toward restoration of physiological cerebrospinal fluid dynamic at the craniovertebral junction. We report the surgical results of eight patients, affected by syringomyelia and Chiari I malformation, age range from 18 to 62 years, treated by bony foramen magnum decompression combined with transverse microincisions of the outer layer of the dura mater. In an average postoperative follow-up period of two years neurological symptoms and signs improved in seven patients. Postoperative Magnetic Resonance showed a decrease in size of the syrinx in seven patients. These results suggest that foramen magnum decompression combined with transverse microincisions of the outer layer of the dura 1) is an effective and safe treatment option for syringomyelia and Chiari I malformation, 2) corrects the circulatory disturbances of cerebrospinal fluid dynamic, 3) leads to a decrease in size of the syrinx and to a significant improvement in neurological signs and symptoms, 4) avoids complications of intradural approaches and syringosubarachnoid shunting.

Reversible cerebral perfusion alterations in children with transient mutism after posterior fossa surgery

Abstract Mutism is an infrequent and transitory complication observed following posterior fossa surgery. Patients become mute in the immediate postoperative period, with restoration of speech within a few weeks in the absence of additional neurological alterations. The anatomical structures thought to be involved are the connections between the cerebellar dentate nucleus, the ventrolateral nucleus of the contralateral thalamus and the supplementary motor area. In an attempt to understand the pathophysiology of this syndrome, and to depict the perfusion of different brain areas semiquantitatively, in two children who had become mute after posterior fossa surgery we performed a Tc99M-HM-PAO SPECT study during the period of mutism and again when normal speech had returned. In one patient, who had a left cerebellar astrocytoma, the SPECT study showed a marked reduction of cerebral perfusion in the right fronto-parietal region, and in the other, who had a medulloblastoma, a left fronto-temporo-parietal perfusion alteration was observed. When the patients regained normal speech, the follow-up SPECT studies revealed normalization of the cerebral perfusion. This study demonstrates the occurrence of a focal dysfunction of cerebral perfusion in children with cerebellar mutism after posterior fossa surgery. These observations are useful in extending our understanding of the pathophysiology of this postoperative clinical syndrome.

Could nanoparticle systems have a role in the treatment of cerebral gliomas

UNLABELLED Malignant brain tumors are difficult to manage clinically and are associated with high rates of morbidity and mortality. Late diagnosis and the limitations of conventional therapies that may result from inefficient delivery of the therapeutic or contrast agent to brain tumors due to the blood-brain barrier and nonspecificity of the agents, are major reasons for this unsolved clinical problem. Nanotechnology involves the design, synthesis, and characterization of materials and devices that have a functional organization in at least one dimension on the nanometer scale. The nanoparticle has emerged as a potential vector for brain delivery, able to overcome the difficulties of modern strategies. Moreover, multifunctionality can be engineered into a single nanoplatform so that it can provide tumor-specific detection, treatment, and follow-up monitoring. This review reports the latest research in nanoparticle-based glioma treatment. FROM THE CLINICAL EDITOR In recent years, nanoparticles have emerged as potential delivery vectors targeting brain tumors, including multifunctional NP-s allowing tumor-specific detection, treatment, and follow-up monitoring. This review summarizes the latest research in nanoparticle-based glioma treatment.

Anomalies of the P1 segment of the posterior cerebral artery: Early bifurcation or duplication, fenestration, common trunk with the superior cerebellar artery

SummaryIn a series of anatomical dissections on 100 fixed human brains, 3% of anomalies of the precommunicating segment of the posterior cerebral artery (P1) were found, among which a case of duplication of the P1 segment. This finding is very unusual and it is much rarer than the many other anatomical patterns reported in the circle of Willis. It is to be considered a very early bifurcation, as reported at the middle cerebral artery level. Another two unusual anatomical patterns were found. One was a large fenestration of the P1 segment, which is rather frequent in the vertebrobasilar system. The other was a bilateral common trunk between the posterior cerebral artery and the superior cerebellar artery, which represents a rare anatomical variation. The existence of such “anomalies” can be explained by the embryological development of the region. Their pathogenic and neurosurgical implications are discussed in the light of the literature.

Does Subarachnoid Blood Extravasation per se Induce Long-Term Neuropsychological and Cognitive Alterations?

Summary Although recent advances in medical and management strategies have reduced the mortality and morbidity rates related to subarachnoid haemorrhage (SAH), patients who survive a SAH may remain nevertheless affected by persistent cognitive and neuropsychological disturbances. The presence of these deficits has been attributed to the neurotoxic effects of the widespread subarachnoid blood. To assess the long-term neuropsychological and cognitive outcome related to subarachnoid blood extravasation per se we evaluated 20 patients affected by an unknown origin subarachnoid haemorrhage, and having SAH characteristics generally considered predictive of a favourable outcome. Patients were enrolled after a one-year interval from the initial insult, and were selected accordingly to a pre-designed protocol. We employed a complete battery of tests, assessing general cognitive and language functions, memory and construction ability, attention and vigilance, anxiety and depression. The results were compared with normal reference values and with performances of a socio-demographically homogenous sample of control volunteers. This study did not evidence any significant long-term cognitive and neuropsychological alteration after subarachnoid blood extravasation. These results indicate that the presence of subarachnoid blood initiate a number of secondary mechanisms of pathology.

Innovative Therapeutic Strategies in the Treatment of Brain Metastases

Brain metastases (BM) are the most common intracranial tumors and their incidence is increasing. Untreated brain metastases are associated with a poor prognosis and a poor performance status. Metastasis development involves the migration of a cancer cell from the bulk tumor into the surrounding tissue, extravasation from the blood into tissue elsewhere in the body, and formation of a secondary tumor. In the recent past, important results have been obtained in the management of patients affected by BM, using surgery, radiation therapy, or both. Conventional chemotherapies have generally produced disappointing results, possibly due to their limited ability to penetrate the blood–brain barrier. The advent of new technologies has led to the discovery of novel molecules and pathways that have better depicted the metastatic process. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review, we will report current data on targeted therapies. A brief review about brain metastatic process will be also presented.

Antisense Oligonucleotides as an Innovative Therapeutic Strategy in the Treatment of High-Grade Gliomas

Despite the intensive recent research in cancer therapy, the prognosis in patients affected by high-grade gliomas is still very unfavorable. The efficacy of classical anti-cancer strategies is seriously limited by lack of specific therapies against malignant cells. The extracellular matrix plays a pivotal role in processes such as differentiation, apoptosis, and migration in both the normal and the pathologic nervous system. Glial tumors seem to be able to create a favorable environment for the invasion of glioma cells in cerebral parenchyma when they combine with the extracellular matrix via cell surface receptors. Glioma cells synthesize matrix proteins, such as tenascin, laminin, fibronectin that facilitate the tumor cells motility. New treatments have shown to hit the acting molecules in the tumor growth and to increase the efficacy and minimize the toxicity. Antisense oligonucleotides are synthetic stretches of DNA which hybridize with specific mRNA strands. The specificity of hybridization makes antisense method an interesting strategy to selectively modulate the expression of genes involved in tumorigenesis. In this review we will focus on the mechanisms of action of antisense oligonucleotides and report clinical and experimental studies on the treatment of high-grade gliomas. We will also report the patents of preclinical and/or clinical studies that adopt the antisense oligonucleotide therapy list in cerebral gliomas.

Nanotechnology Platforms in Diagnosis and Treatment of Primary Brain Tumors

Despite aggressive multimodal strategies, the prognosis in patients affected by primary brain tumors is still very unfavorable. Glial tumors seem to be able to create a favorable environment for the invasion of neoplastic cells into the cerebral parenchyma when they interact with the extracellular matrix via cell surface receptors. The major problem in drug delivery into the brain is due to the presence of the blood brain barrier which limits drug penetration. Nanotechnology involves the design, synthesis and characterization of materials that have a functional organization at least in one dimension on the nanometer scale. Nanoengineered devices in medical applications are designed to interface and interact with cells and tissues at the molecular level. Nanoparticle systems can represent ideal devices for delivery of specific compounds to brain tumors, across the blood brain barrier. In this brief review, we report the results of studies related to the emerging novel applications of nanoparticle systems in diagnosis and treatment of primary brain tumors, and also the patents of studies that adopt nanoparticle systems as drug delivery carriers in brain tumor diagnosis and therapy.

An immunohistochemical study of extracellular matrix proteins laminin, fibronectin and type IV collagen in paediatric glioblastoma multiforme

SummaryAims. In the recent decades many studies have been addressed in the literature to assess specific factors related to glioblastoma multiforme (GBM) invasion. However, few studies have evaluated tumour cell’s interaction with specific extracellular matrix (ECM) components, and, moreover, there is a lack of information regarding the occurrence of these phenomena in paediatric GBM.Methods and results. ECM proteins were evaluated in six cases of paediatric GBM assessing the immunohistochemical expression of laminin, fibronectin, and type IV collagen. We used a semiquantitative scale, ranging from not detected (zero) to marked (3). Laminin expression was minimal in three cases, moderate in one case, marked and generalised in one patient and marked and focal in the last case. Fibronectin expression was minimal in three patients; moderate immunoreactivity was documented in one case. Conversely, one case was classified as marked with generalised distribution and the remaining case as marked with focal immunostaining. Type IV collagen expression was minimal in three cases, moderate in one, marked with focal reaction in one and marked with generalised reaction in the remaining case.Conclusions. This study provides additional insights into tumour invasion features of paediatric GBM, as ECM plays a pivotal role in numerous cellular functions during normal and pathological processes. Although based on a limited number of patients, this investigation may serve as a challenge for the management of paediatric GBM, stimulating trials with larger patient numbers aimed at documenting specific factors influencing GBM prognosis.