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AbstractObjective:To report the first case of mandibular branch haemangioma of the trigeminal nerve causing erosion of the petrous carotid canal. The radiological and histological findings in this case are reviewed.Case report:A 60-year-old woman presented with severe, right-sided facial pain and paraesthesia. There were no associated symptoms of facial weakness or diplopia. A magnetic resonance imaging scan with gadolinium enhancement was performed. This showed a lesion slightly compressing the right Meckel's cave and eroding the right petrous carotid canal, occupying the foramen ovale and extending to the pterygoid muscle. The lesion was removed via a subtemporal approach.Conclusion:Haemangiomas are usually found on the skin and in other soft tissues. However, this rare tumour should also be considered in the differential diagnosis of lesions occupying Meckel's cave and the foramen ovale. [ABSTRACT FROM AUTHOR]

The trafficking of autoreactive leucocytes across the blood-brain barrier endothelium is a hallmark of multiple sclerosis pathogenesis. Although the blood-brain barrier endothelium represents one of the main CNS borders to interact with the infiltrating leucocytes, its exact contribution to neuroinflammation remains understudied. Here, we show that Mcam identifies inflammatory brain endothelial cells with pro-migratory transcriptomic signature during experimental autoimmune encephalomyelitis. In addition, MCAM was preferentially upregulated on blood-brain barrier endothelial cells in multiple sclerosis lesions in situ and at experimental autoimmune encephalomyelitis disease onset by molecular MRI. In vitro and in vivo, we demonstrate that MCAM on blood-brain barrier endothelial cells contributes to experimental autoimmune encephalomyelitis development by promoting the cellular trafficking of TH1 and TH17 lymphocytes across the blood-brain barrier. Last, we showcase ST14 as an immune ligand to brain endothelial MCAM, enriched on CD4+ T lymphocytes that cross the blood-brain barrier in vitro, in vivo and in multiple sclerosis lesions as detected by flow cytometry on rapid autopsy derived brain tissue from multiple sclerosis patients. Collectively, our findings reveal that MCAM is at the centre of a pathological pathway used by brain endothelial cells to recruit pathogenic CD4+ T lymphocyte from circulation early during neuroinflammation. The therapeutic targeting of this mechanism is a promising avenue to treat multiple sclerosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: In multiple sclerosis (MS), peripheral immune cells use various cell trafficking molecules to infiltrate the CNS where they cause damage.The objective of this study was to investigate the involvement of coxsackie and adenovirus receptor-like membrane protein (CLMP) in the migration of immune cells into the CNS of patients with MS., Methods: Expression of CLMP was measured in primary cultures of human brain endothelial cells (HBECs) and human meningeal endothelial cells (HMECs), postmortem brain samples, and peripheral blood mononuclear cells (PBMCs) from patients with MS and controls by RNA sequencing, quantitative PCR, immunohistochemistry, and flow cytometry. In vitro migration assays using HBECs and HMECs were performed to evaluate the function of CLMP., Results: Using bulk RNA sequencing of primary cultures of human brain and meningeal endothelial cells (ECs), we have identified CLMP as a new potential cell trafficking molecule upregulated in inflammatory conditions. We first confirmed the upregulation of CLMP at the protein level on TNFα-activated and IFNγ-activated primary cultures of human brain and meningeal ECs. In autopsy brain specimens from patients with MS, we demonstrated an overexpression of endothelial CLMP in active MS lesions when compared with normal control brain tissue. Flow cytometry of human PBMCs demonstrated an increased frequency of CLMP + B lymphocytes and monocytes in patients with MS, when compared with that in healthy controls. The use of a blocking antibody against CLMP reduced the migration of immune cells across the human brain and meningeal ECs in vitro. Finally, we found CLMP + immune cell infiltrates in the perivascular area of parenchymal lesions and in the meninges of patients with MS., Discussion: Collectively, our data demonstrate that CLMP is an adhesion molecule used by immune cells to access the CNS during neuroinflammatory disorders such as MS. CLMP could represent a target for a new treatment of neuroinflammatory conditions., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The migration of circulating leukocytes into the central nervous system (CNS) is a key driver of multiple sclerosis (MS) pathogenesis. The monoclonal antibody natalizumab proved that pharmaceutically obstructing this process is an effective therapeutic approach for treating relapsing-remitting MS (RRMS). Unfortunately, the clinical efficacy of natalizumab is somewhat offset by its incapacity to control the progressive forms of MS (PMS) and by life-threatening side effects in RRMS rising from the expression of its molecular target, very late antigen 4 (VLA4), on most immune cells and consequent impairment of CNS immunosurveillance. Here, we identified dual immunoglobulin domain containing cell adhesion molecule (DICAM) as a cell trafficking molecule preferentially expressed by T helper 17 (T H 17)–polarized CD4 + T lymphocytes. We found that DICAM expression on circulating CD4 + T cells was increased in patients with active RRMS and PMS disease courses, and expression of DICAM ligands was increased on the blood-brain barrier endothelium upon inflammation and in MS lesions. Last, we demonstrated that pharmaceutically neutralizing DICAM reduced murine and human T H 17 cell trafficking across the blood-brain barrier in vitro and in vivo, and alleviated disease symptoms in four distinct murine autoimmune encephalomyelitis models, including relapsing-remitting and progressive disease models. Collectively, our data highlight DICAM as a candidate therapeutic target to impede the migration of disease-inducing leukocytes into the CNS in both RRMS and PMS and suggest that blocking DICAM with a monoclonal antibody may be a promising therapeutic approach.

Medulloblastoma is an aggressive primary brain tumor that is extremely rare in adults; therefore, prospective studies are limited. We reviewed the information of all MB patients treated at the CHUM between 2006 and 2017. We divided our cohort by age and further divided adult patients (53%) in two groups, those diagnosed between 2006-2012 and 2013-2017. In our adult population, median follow up was 26 months and SHH-activated MB comprised 39% of tumors. Adult 5yOS was 80% and first-line therapy led to a 5yPFS of 77%. The absence of radiosensitizing chemotherapy (100% vs. 50%; p = 0.033) negatively influenced 5yPFS. 96% of adult patients received radiotherapy and 48% of them received concomitant radiosensitizing chemotherapy. Complete surgical resection was performed on 85% of adults, but the extent of resection did not have a discernable impact on survival and did not change with time. Adjuvant chemotherapy did not clearly affect prognosis (5yOS 80% vs. 67%, p = 0.155; 5yPFS 78% vs. 67%, p = 0.114). From 2006-2012, the most common chemotherapy regimen (69%) was Cisplatinum, Lomustine and Vincristine, which was replaced in 2013 by Cisplatinum, Etoposide and Cyclophosphamide (77%) with a trend for worse survival. Nine patients recurred and seven of these (78%) were treated with palliative chemotherapy. In conclusion, we did not identify prognostic demographic or tumor factors in our adult MB population. The presence of radiosensitizing chemotherapy was associated with a more favorable PFS. Cisplatinum, Lomustine and Vincristine regimen might be a better adjuvant chemotherapy regimen.

Objective: To investigate the involvement of interleukin (IL)-26 in neuroinflammatory processes in multiple sclerosis (MS), in particular in blood-brain barrier (BBB) integrity., Methods: Expression of IL-26 was measured in serum, CSF, in vitro differentiated T helper (T H ) cell subsets, and postmortem brain tissue of patients with MS and controls by ELISA, quantitative PCR, and immunohistochemistry. Primary human and mouse BBB endothelial cells (ECs) were treated with IL-26 in vitro and assessed for BBB integrity. RNA sequencing was performed on IL-26-treated human BBB ECs. Myelin oligodendrocyte glycoprotein 35-55 experimental autoimmune encephalomyelitis (EAE) mice were injected IP with IL-26. BBB leakage and immune cell infiltration were assessed in the CNS of these mice using immunohistochemistry and flow cytometry., Results: IL-26 expression was induced in T H lymphocytes by T H 17-inducing cytokines and was upregulated in the blood and CSF of patients with MS. CD4 + IL-26 + T lymphocytes were found in perivascular infiltrates in MS brain lesions, and both receptor chains for IL-26 (IL-10R2 and IL-20R1) were detected on BBB ECs in vitro and in situ. In contrast to IL-17 and IL-22, IL-26 promoted integrity and reduced permeability of BBB ECs in vitro and in vivo. In EAE, IL-26 reduced disease severity and proinflammatory lymphocyte infiltration into the CNS, while increasing infiltration of Tregs., Conclusions: Our study demonstrates that although IL-26 is preferentially expressed by T H 17 lymphocytes, it promotes BBB integrity in vitro and in vivo and is protective in chronic EAE, highlighting the functional diversity of cytokines produced by T H 17 lymphocytes., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The presence of B lymphocyte-associated oligoclonal immunoglobulins in the cerebrospinal fluid is a classic hallmark of multiple sclerosis (MS). The clinical efficacy of anti-CD20 therapies supports a major role for B lymphocytes in MS development. Although activated oligoclonal populations of pathogenic B lymphocytes are able to traffic between the peripheral circulation and the central nervous system (CNS) in patients with MS, molecular players involved in this migration have not yet been elucidated. In this study, we demonstrated that activated leukocyte cell adhesion molecule (ALCAM/CD166) identifies subsets of proinflammatory B lymphocytes and drives their transmigration across different CNS barriers in mouse and human. We also showcased that blocking ALCAM alleviated disease severity in animals affected by a B cell-dependent form of experimental autoimmune encephalomyelitis. Last, we determined that the proportion of ALCAM + B lymphocytes was increased in the peripheral blood and within brain lesions of patients with MS. Our findings indicate that restricting access to the CNS by targeting ALCAM on pathogenic B lymphocytes might represent a promising strategy for the development of next-generation B lymphocyte-targeting therapies for the treatment of MS., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

CD70 is the unique ligand of CD27 and is expressed on immune cells only upon activation. Therefore, engagement of the costimulatory CD27/CD70 pathway is solely dependent on upregulation of CD70. However, the T cell-intrinsic effect and function of human CD70 remain underexplored. Herein, we describe that CD70 expression distinguishes proinflammatory CD4 + T lymphocytes that display an increased potential to migrate into the central nervous system (CNS). Upregulation of CD70 on CD4 + T lymphocytes is induced by TGF-β1 and TGF-β3, which promote a pathogenic phenotype. In addition, CD70 is associated with a T H 1 and T H 17 profile of lymphocytes and is important for T-bet and IFN-γ expression by both T helper subtypes. Moreover, adoptive transfer of CD70 -/- CD4 + T lymphocytes induced less severe experimental autoimmune encephalomyelitis (EAE) disease than transfer of WT CD4 + T lymphocytes. CD70 + CD4 + T lymphocytes are found in the CNS during acute autoimmune inflammation in humans and mice, highlighting CD70 as both an immune marker and an important costimulator of highly pathogenic proinflammatory T H 1/T H 17 lymphocytes infiltrating the CNS.

Background and Objectives: Controversy related to the choice of surgical approach for vestibular schwannoma (VS) resection remains. Whether the retrosigmoid (RS) or translabyrinthine (TL) approach should be performed is a matter of debate. In the context of a lack of clear evidence favoring one approach, we conducted a retrospective study to compare the morbidity rate of both surgical approaches. Subjects and., Methods: 168 patients underwent surgical treatment (2007-2013) for VS at our tertiary care center. There were no exclusion criteria. Patients were separated into two groups according to the surgical approach: TL group and RS group. Signs and symptoms including ataxia, headache, tinnitus, vertigo and cranial nerve injuries were recorded pre- and postoperatively. Surgical complications were analyzed. Perioperative facial nerve function was measured according to House-Brackmann grading system., Results: Tumor resection was similar in both groups. Facial paresis was significantly greater in RS group patients preoperatively, in the immediate postoperative period and at one year follow-up (p<0.05). A constant difference was found between both groups at all three periods (p=0.016). The evolution of proportion was not found to be different between both groups (p=0.942), revealing a similar rate of surgically related facial paresis. Higher rate of ataxic gait (p=0.019), tinnitus (p=0.039) and cranial nerve injuries (p=0.016) was found in RS group patients. The incidence of headache, vertigo, vascular complications, cerebrospinal fluid leak and meningitis was similar in both groups. No reported mortality in this series., Conclusions: Both approaches seem similar in terms of resection efficacy. However, according to our analysis, the TL approach is less morbid. Thus, for VS in which hearing preservation is not considered, TL approach is preferable.

Background: Procarbazine, lomustine, and vincristine (pcv) significantly improve survival outcomes in lgg (low-grade gliomas). Administration of pcv to lgg patients increased tremendously over the past years as it went from 2 patients per year between 2005 and 2012 to 23 patients in 2015 only in our centre. However, serious hematological and non-hematological adverse events may occur. The purpose of this study was to evaluate the toxicity of pcv and its clinical relevance in our practice., Methods: We retrospectively reviewed the charts of 57 patients with lgg who received pcv at the Centre hospitalier de l'Université de Montréal between 1 January 2005 and 27 July 2016., Results: Procarbazine, lomustine, and vincristine were associated with severe hematological toxicity as clinically significant grade 3 anemia, neutropenia, and thrombocytopenia occurred in 7%, 10%, and 28% of patients, respectively. Other frequent adverse events such as the increase of liver enzymes, cutaneous rash, neurotoxicity, and vomiting occurred in 65%, 26%, 60%, and 40% of patients, respectively. Patients with prophylactic trimethoprim/sulfamethoxazole had more grade 3 hematological toxicity with pcv, especially anemia ( p = 0.040) and thrombocytopenia ( p = 0.003) but we found no increase in pcv toxicity in patients on concurrent anticonvulsants. Patients with grade 3 neutropenia had a significantly lower survival (median survival 44.0 months vs. 114.0 months, p = 0.001). Patients who were given pcv at diagnosis had more grade 3 anemia than those who received it at subsequent lines of treatment ( p = 0.042)., Conclusion: Procarbazine, lomustine, and vincristine increase survival in lgg but were also associated with major hematologic, hepatic, neurologic, and cutaneous toxicity. Anti- Pneumocystis jiroveci pneumonia (pjp) prophylaxis, but not anticonvulsants, enhances hematologic toxicity.

Objective: Rhinoliquorrhea is defined as a cerebrospinal fluid leakage from the nose. Our objective in this study is to determine the reduction of rhinoliquorrhea rates by Eustachian tube (ET) obliteration in the context of a translabyrinthine approach performed following vestibular schwannoma (VS) excision., Materials and Methods: This is a prospective study achieved in a tertiary-care center where the chart review revealed 94 VS operated by the translabyrinthine approach between 2009 and 2015. There were 40 males and 54 females aged from 28-76 years. The only exclusion criterion was a previous history of cranial surgery. ET obliteration was systematically executed when the petrous apex pneumatization level was at least 2 of 4. Our main outcome measure was the development of rhinoliquorrhea., Results: Eighty-eight patients underwent ET obliteration and were followed for an average of 2.6±1.2 years. Rhinoliquorrhea was reported in 1.14% of the patients having had an ET obliteration. When compared to our previous sample of patients operated with a translabyrinthine approach, it represents a reduction of 84%., Conclusion: Obliteration of the ET is a fast and simple procedure that reduces the rate of rhinoliquorrhea. We therefore recommend its use, specifically in cases of petrous apex pneumatization levels 2-4.

Background: Twenty percent mannitol is widely used to reduce brain bulk and facilitate the surgical approach in intracranial surgery. However, a dose-response relationship has not yet been established. In this study, we compared the effects of 0.7 and 1.4 g·kg(-1) mannitol on brain relaxation during elective supratentorial brain tumor surgery., Methods: In this prospective, randomized, double-blind study, we enrolled 80 patients undergoing supratentorial craniotomy for tumor resection. Patients were assigned to receive 0.7 g·kg(-1) (group L) or 1.4 g·kg(-1) (group H) of 20% mannitol at surgical incision. Brain relaxation was assessed immediately after opening of the dura on a scale ranging from 1 to 4 (1 = perfectly relaxed, 2 = satisfactorily relaxed, 3 = firm brain, 4 = bulging brain)., Results: There was no significant difference between the 2 groups regarding age, sex, body mass index, and brain tumor localization or size. In group L 52.5% of patients and in group H 77.5% of patients presented a midline shift (P = 0.03). The median scores of brain relaxation (interquantile range) were 2.0 (1.75-3) and 2.0 (1-3) (P = 0.16 for patients in group L and H, respectively). We then used a proportional odds model to adjust for this unbalanced distribution and to assess the group effect (low-dose versus high-dose mannitol) on brain relaxation scores. When adjusted for the presence of midline shift, the use of a higher dose of mannitol resulted in an odds ratio of 2.5 (P = 0.03). This indicates that, considering the effect of a midline shift, the odds of having a 1-level improvement in relaxation score in patients who received a higher dose of mannitol (group H) was 2.5 times as large as the odds for the low-dose group. The odds ratio of 0.29 (P = 0.007) for the midline shift indicates that its occurrence was associated with a higher probability of a lower relaxation score, on average., Conclusion: In this study, we show that 1.4 g·kg(-1) of 20% mannitol results in equivalent brain relaxation scores as 0.7 g·kg(-1) in patients undergoing craniotomy for supratentorial brain tumor. When corrected for the presence of midline shift, this study reveals that patients in the high-dose group had significantly more chances of obtaining a better relaxation score compared with the lower-dose group.

Background: Stereotactic radiosurgery (SRS) is known to safely result in a high obliteration rate for small and medium sized arteriovenous malformations (AVM)., Objective: To evaluate the long-term outcome of patients treated with SRS, with special emphasis given to obliteration and toxicity rates., Methods: We performed a review of 43 cerebral AVM patients, treated from 1998 to 2008 with a single SRS dose ranging from 21-25 Gy. Of these, 37 had a minimal follow-up of one year. Medical files were reviewed to assess patient and AVM characteristics, the SRS treatment, therapy prior to SRS, the obliteration rate and toxicities. Whenever necessary, outcome data was supplemented by telephone interviews with the patient or treating physician., Results: AVM size was ≥3cm in diameter in 21% of patients. Five patients (11.6%) underwent surgery prior to SRS and 31 patients (72.1%) received one or more embolizations prior to SRS. Of the patients followed with angiography ≥1 year post-SRS, 89% (33/37) had a complete obliteration of the nidus, after a median time of 24.7 months post-treatment. Embolization prior to SRS was not predictive of outcome. One patient suffered a non-fatal haemorrhage between treatment and obliteration. The rate of symptomatic radiation-induced radiological changes was 8.1%., Conclusion: Our study shows both obliteration and complication rates in the upper limit of those reported in the literature. SRS seems an attractive treatment option for small AVMs. Unlike other reports, the prior use of embolization did not impact negatively on obliteration rates.

Objective: Blood-derived myeloid antigen-presenting cells (APCs) account for a significant proportion of the leukocytes found within lesions of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). These APCs along with activated microglia are thought to be pivotal in the initiation of the central nervous system (CNS)-targeted immune response in MS and EAE. However, the exact molecules that direct the migration of myeloid cells from the periphery across the blood-brain barrier (BBB) remain largely unknown., Methods: We identified Ninjurin-1 in a proteomic screen of human BBB endothelial cells (ECs). We assessed the expression of Ninjurin-1 by BBB-ECs and immune cells, and we determined the role of Ninjurin-1 in immune cell migration to the CNS in vivo in EAE mice., Results: Ninjurin-1 was found to be weakly expressed in the healthy human and mouse CNS but upregulated on BBB-ECs and on infiltrating APCs during the course of EAE and in active MS lesions. In human peripheral blood, Ninjurin-1 was predominantly expressed by monocytes, whereas it was barely detectable on T and B lymphocytes. Moreover, Ninjurin-1 neutralization specifically abrogated the adhesion and migration of human monocytes across BBB-ECs, without affecting lymphocyte recruitment. Finally, Ninjurin-1 blockade reduced clinical disease activity and histopathological indices of EAE and decreased infiltration of macrophages, dendritic cells, and APCs into the CNS., Interpretation: Our study uncovers an important cell-specific role for Ninjurin-1 in the transmigration of inflammatory APCs across the BBB and further emphasizes the importance of myeloid cell recruitment during the development of neuroinflammatory lesions., (Copyright © 2011 American Neurological Association.)

Objective: Decompressive hemicraniectomy (DH) has been shown to reduce mortality in patients with malignant middle cerebral artery (MCA) territory infarction. However, many patients survive with moderate-to-severe disability and controversy exists as to whether this should be considered good outcome. To answer this question, we assessed the quality of life (QoL) of patients after DH for malignant MCA territory infarction in our milieu., Methods: The outcome of all patients undergoing DH for malignant MCAterritory infarction between 2001 and 2009 was assessed using retrospective chart analysis and telephone follow-up in survivors. Functional outcome was determined using Glasgow outcome scale, modifed Rankin scale (mRS), and Barthel index (BI). The stroke impact scale was used to assess QoL., Results: There were 14 patients, 6 men and 8 women, with a mean age of 44 years (range 27-57). All patients had reduced level of consciousness preoperatively. Five had dominant-hemisphere stroke. Median time to surgery was 45 hours (range 1- 96). Two patients died and one was lost to follow-up. Of 11 survivors, 7 (63.6%) had a favorable functional outcome (mRS<4). No patient was in persistent vegetative state. Despite impaired QoL, particularly in physical domains, the majority of interviewed patients and caregivers (7 of 8), including those with dominant-hemisphere stroke, were satisfied after a median follow-up of 18 months (range 6-43)., Conclusion: Most patients report satisfactory QoL despite significant disability even in the face of moderate-to-severe disability and dominant-hemsiphere stroke. Dominant-hemisphere malignant MCA territory infarction should not be considered a contraindication to DH.

Background: In this study, we compared the quality of transitional analgesia provided by bilateral superficial cervical plexus block (SCPB) or morphine following a remifentanil-based anesthesia for infratentorial or occipital craniotomy., Methods: In this randomized controlled and double-blind study, 30 patients scheduled for infratentorial or occipital craniotomy were divided randomly into two groups: group morphine (morphine 0.1 mg·kg⁻¹ iv after dural closure and a SCPB performed with 20 mL of 0.9% saline at the end of the surgery) or group block (10 mL of 0.9% saline iv instead of morphine after dural closure and a SCPB performed with 20 mL of a 1:1 mixture of 0.5% bupivacaine and 2% lidocaine at the end of the surgery). Postoperative pain was assessed at one, two, four, eight, 12, 16, and 24 hr using an 11-point (0-10) numerical rating scale (NRS). Analgesia was provided with subcutaneous codeine., Results: Average NRS scores were similar between the two groups at each time interval over the study period. The average scores (with 95% confidence interval) were 3.9 (3.4-4.4) and 4.3 (3.8-4.9) for the block and morphine groups, respectively (P = 0.25). The delay before administration of the first dose of codeine was not statistically different between the two groups: 25 min (5-2,880) vs 21.5 min (5-90), median and range for the block and morphine groups, respectively. The incidence of nausea and vomiting was similar between the two groups., Conclusion: Bilateral superficial cervical plexus block provides transitional analgesia that is clinically equivalent to morphine following remifentanil-based anesthesia in patients undergoing occipital or infratentorial craniotomies.

Background: It was recently suggested that communicating hydrocephalus is an almost universal finding after hemicraniectomy and that early cranioplasty may prevent the need for permanent cerebrospinal fluid diversion in these patients., Objective: To conduct a study in an attempt to verify these findings., Methods: The medical records of all patients who underwent decompressive craniectomy for medically refractory elevated intracranial pressure between 2001 and 2009 were retrospectively reviewed. Patients with subarachnoid hemorrhage, intraventricular hemorrhage, or head trauma were excluded. Hydrocephalus was classified as internal or external and as clinically significant or asymptomatic., Results: The patient population consisted of 17 patients, 8 men and 9 women, with a median age of 44 years (range, 27-53 years). Etiologies included malignant middle cerebral artery territory infarction in 12 patients, hemorrhagic transformation of ischemic cerebrovascular accident in 2 patients, dural sinus thrombosis in 2 patients, and hemorrhagic cerebrovascular accident in 1 patient. The extent of craniectomy ranged from a large bone flap in 4 patients to a standard hemicraniectomy in 13 patients. Two patients died and 1 was lost to follow-up during the acute stage. The remaining 14 patients underwent cranioplasty after a median interval of 21 days (range, 3-42 days). In none of these patients did clinically significant hydrocephalus develop requiring cerebrospinal fluid diversion. Asymptomatic extra-axial cerebrospinal fluid collections developed in 2 patients that resolved spontaneously after cranioplasty., Conclusion: Our results suggest that, contrary to some beliefs, hydrocephalus does not frequently occur after decompressive craniectomy.

Among the natural products shown to possess chemopreventive and anticancer properties, curcumin is one of the most potent. In the current study, we investigated the effects of this natural product on the growth of human glioma U-87 cells xenografted into athymic mice. We show here that curcumin administration exerted significant anti-tumor effects on subcutaneous and intracerebral gliomas as demonstrated by the slower tumor growth rate and the increase of animal survival time. While investigating the mechanism of its action in vivo, we observed that curcumin decreased the gelatinolytic activities of matrix metalloproteinase-9. Furthermore, treatment with curcumin inhibited glioma-induced angiogenesis as indicated by the decrease of endothelial cell marker from newly formed vessels and by the diminution of the concentration of hemoglobin in curcumin-treated tumors. We also demonstrate, using an in vitro model of blood-brain barrier, that curcumin can cross the blood-brain barrier to a high level. These are the first results showing that curcumin suppresses tumor growth of gliomas in xenograft models. The mechanisms of the anti-tumor effects of curcumin were related, at least partly, to the inhibition of glioma-induced angiogenesis.

In recent clinical observation, the growth of endothelial tumors, such as hemangiomas of infancy, was repressed by the non-selective beta-adrenergic antagonist propranolol possibly through targeting of the vascular endothelial compartment. As human brain microvascular endothelial cells (HBMEC) play an essential role as structural and functional components in tumor angiogenesis, we assessed whether propranolol could target HBMEC's in vitro angiogenic properties. We found that biopsies from human glioblastoma as well as from experimental brain tumor-associated vasculature expressed high levels of the beta2-adrenergic receptor, suggesting adrenergic adaptative processes could take place during tumor vascularization. We observed that in vitro tubulogenesis was significantly reduced by propranolol when HBMEC were seeded on Matrigel. Propranolol, as much as 100microM, did not reduce cell viability and did not alter HBMEC migration as assessed with Boyden chambers. Secretion of the key angiogenic and extracellular matrix degrading enzymes MMP-2 and MMP-9 was assessed by zymography. Propranolol significantly reduced MMP-9 secretion upon treatment with the tumor-promoting agent phorbol 12-myristate 13-acetate, while secretion of MMP-2 remained unaffected. This was correlated with a decrease in MMP-9 gene expression which is, in part, explained by a decrease in the nucleocytoplasmic export of the mRNA stabilizing factor HuR. Our data are therefore indicative of a selective role for propranolol in inhibiting MMP-9 secretion and HBMEC tubulogenesis which could potentially add to propranolol's anti-angiogenic properties.

Background: In this study, we compared the effect of light sedation with remifentanil versus propofol on intracranial (ICP) and cerebral perfusion pressure (CPP) of patients undergoing stereotactic brain tumor biopsy under regional anesthesia., Methods: This was a prospective, open-label, randomized, and controlled study. Forty patients undergoing stereotactic brain tumor biopsy under regional anesthesia were randomized into two groups to receive remifentanil or propofol titrated to a level of four on the modified Assessment of Alertness/Sedation Scale. ICP was measured via the biopsy needle., Results: At the targeted level of sedation, the rates of infusion for remifentanil and propofol were, respectively, 4.2 +/- 1.8 microg x kg(-1) x h(-1) and 4.3 +/- 2.5 mg x kg(-1) x h(-1). At the time of ICP measurement, patients in the remifentanil group had a slower respiratory rate (11/min +/- 3 vs 15 per min +/- 3, P = 0.0001) and a higher PCO2 (48.3 +/- 6.2 mm Hg vs 43.1 +/- 5.5 mm Hg, P = 0.009) than patients in the propofol group. The mean was similar for both groups, 19.0 +/- 11.9 mm Hg vs 16.4 +/- 11.1 mm Hg for remifentanil and propofol, respectively (P = 0.48). Higher mean arterial blood pressure in the remifentanil group (101.1 +/- 13.7 mm Hg vs 85.8 +/- 12.7 mm Hg, P = 0.0008) resulted in a higher CPP than the propofol group: 82.0 +/- 19.0 mm Hg vs 69.5 +/- 17.0 +/- 19.0 mm Hg (P = 0.03)., Conclusion: Light sedation with remifentanil does not result in a higher ICP than propofol in patients undergoing stereotactic brain tumor biopsy. CPP might be better preserved with remifentanil.

Human brain microvascular endothelial cells (HBMECs) play an essential role as structural and functional components of the blood-brain barrier (BBB). While disruption of the BBB by the brain tumor-secreted matrix metalloproteinase-9 (MMP-9) favors tumor invasion, the role and regulation of MMP-9 secretion by HBMEC themselves in response to carcinogens or brain tumor-derived growth factors has received little attention. Our study delineates a unique brain endothelial phenotype in that MMP-9 secretion is increased upon phorbol 12-myristate 13-acetate (PMA) treatment of HBMEC. Sulforaphane (SFN), an isothiocyanate present in broccoli which exhibits chemopreventive properties, selectively inhibited the secretion of MMP-9 but not that of MMP-2. The decrease in MMP-9 gene expression correlated with a decrease in the expression of the mRNA stabilizing factor HuR protein triggered by SFN. PMA-induced HBMEC migration was also antagonized by SFN. Silencing of the MMP-9 gene inhibited PMA-induced MMP-9 secretion, cell migration, and in vitro tubulogenesis on Matrigel. While SFN inhibited the chemoattractive abilities of brain tumor-derived growth factors, it failed to inhibit PMA-induced tubulogenesis. Our data are indicative of a selective role for SFN to inhibit MMP-9-activated, but not basal, HBMEC migration, and tubulogenesis whose actions could add to SFN's antitumor properties.

Adhesion molecules of the immunoglobulin superfamily are crucial effectors of leukocyte trafficking into the central nervous system. Using a lipid raft-based proteomic approach, we identified ALCAM as an adhesion molecule involved in leukocyte migration across the blood-brain barrier (BBB). ALCAM expressed on BBB endothelium localized together with CD6 on leukocytes and with BBB endothelium transmigratory cups. ALCAM expression on BBB cells was upregulated in active multiple sclerosis and experimental autoimmune encephalomyelitis lesions. Moreover, ALCAM blockade restricted the transmigration of CD4+ lymphocytes and monocytes across BBB endothelium in vitro and in vivo and reduced the severity and delayed the time of onset of experimental autoimmune encephalomyelitis. Our findings indicate an important function for ALCAM in the recruitment of leukocytes into the brain and identify ALCAM as a potential target for the therapeutic dampening of neuroinflammation.

The blood-brain barrier (BBB) restricts molecular and cellular trafficking between the blood and the CNS. Although astrocytes are known to control BBB permeability, the molecular determinants of this effect remain unknown. We show that angiotensinogen (AGT) produced and secreted by astrocytes is cleaved into angiotensin II (AngII) and acts on type 1 angiotensin receptors (AT1) expressed by BBB endothelial cells (ECs). Activation of AT1 restricts the passage of molecular tracers across human BBB-derived ECs through threonine-phosphorylation of the tight junction protein occludin and its mobilization to lipid raft membrane microdomains. We also show that AGT knock-out animals have disorganized occludin strands at the level of the BBB and a diffuse accumulation of the endogenous serum protein plasminogen in the CNS, compared with wild-type animals. Finally, we demonstrate a reduction in the number of AGT-immunopositive perivascular astrocytes in multiple sclerosis (MS) lesions, which correlates with a reduced expression of occludin similarly seen in the CNS of AGT knock-out animals. Such a reduction in astrocyte-expressed AGT and AngII is dependent, in vitro, on the proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma. Our study defines a novel physiological role for AngII in the CNS and suggests that inflammation-induced downregulation of AngII production by astrocytes is involved in BBB dysfunction in MS lesions.

Objective: This retrospective study was designed to assess the intensity of postoperative pain in relation to the location of craniotomy., Methods: After Research Ethics Board approval, data were collected from the charts of all patients who underwent a craniotomy at our institution between January 2004 and December 2005. The severity of post-craniotomy pain was assessed by collecting scores obtained using an 11-point verbal rating scale and calculating the cumulative analgesic requirements for the first 48 hr postoperatively. Data were compared according to the craniotomy location., Results: Data from 299 patients was available for analysis. On average, 76% of patients experienced moderate to severe postoperative pain. Frontal craniotomy was associated with lower pain scores than four of six craniotomy sites analyzed, with 49% of patients reporting mild pain, a significant difference (P < 0.05) compared with all other groups except for parietal craniotomies. Frontal craniotomy patients also had lower opioid analgesic requirements compared to patients who underwent posterior fossa craniotomy (P < 0.05). Logistic regression analysis showed that craniotomy location (P < 0.0001) and age (P = 0.004) were both independent predictors of the intensity of postoperative pain, with lower pain scores as age increased. Postoperative use of steroids, gender and presence of preoperative pain were not statistically linked to postoperative pain intensity. The prevalence of postoperative nausea and vomiting was 56% and it did not vary according to the location of craniotomy., Conclusion: This study shows that the intensity of postoperative pain in neurosurgery is affected by the site of craniotomy. Frontal craniotomy patients experienced the lowest pain scores, and required significantly less opioid than patients undergoing posterior fossa interventions.

We compared transitional analgesia provided by scalp nerve block (SNB) or morphine after remifentanil-based anesthesia in neurosurgery. Fifty craniotomy patients were randomly divided into two groups: morphine (morphine 0.1 mg x kg(-1) IV after dural closure and an SNB performed with 20 mL of 0.9% saline at the end of surgery) and block (10 mL of 0.9% saline instead of morphine after dural closure and an SNB performed with a 1:1 mixture of bupivacaine 0.5% and lidocaine 2% at the end of surgery). Postoperative pain was assessed at 1, 2, 4, 8, 12, 16, and 24 h using a 10-point numerical rating scale. Analgesia consisted of subcutaneous codeine. Average numerical rating scale scores were similar between the two groups at each time interval. Total codeine dosage was also similar, except at 4 h postoperatively when it was higher in the block group. The delay before administration of the first dose of codeine was not statistically different between groups: 45 min (20-2880) vs 30 min (10-2880), median and range for the block and morphine group, respectively. Postoperative hemodynamics were similar for both groups. The incidence of nausea and vomiting was slightly more frequent in the morphine group, but the occurrence of confusion did not differ between groups. In conclusion, SNB provides a quality of transitional analgesia that is similar to that of morphine with the same postoperative hemodynamic profile.

Introduction: Radioresistant brain tumor vasculature is thought to hamper the efficiency of adjuvant cancer therapies. However, little is known regarding the signalling pathways involved in the angiogenic response to brain tumor-derived growth factors in irradiated human brain microvascular endothelial cells (HBMEC). The goal of this study is to assess the effect of ionizing radiation (IR) on HBMEC survival, migration and tubulogenesis., Methods: HBMEC were cultured and irradiated at sublethal single doses. Cell survival was assessed by nuclear cell counting and flow cytometry. HBMEC migration in response to brain tumor-derived growth factors (U-87 GF) and tubulogenesis were assayed using modified Boyden chambers and Matrigel, respectively., Results: We observed that single administration of 3-10 Gy IR doses only reduced cell survival by 30%. Radioresistant HBMEC overexpressed RhoA, a small GTPase protein regulating cellular adhesion and migration, and Rho-kinase (ROK), a serine-threonine protein kinase and one of RhoA's major targets. HBMEC migration was induced by vascular endothelial growth factor (VEGF), but even more so in response to sphingo-sine-1-phosphate (S1P) and to U-87 GF. Following IR exposure, HBMEC basal migration increased more than two-fold, whereas the response to S1P and to U-87 GF was significantly diminished. Similarly, the inhibitor of ROK Y-27632 decreased HBMEC migration in response to S1P and U-87 GF. Overexpression of RhoA decreased tubulogenesis, an effect also observed in irradiated HBMEC., Conclusion: Our results suggest that radioresistant HBMEC migration response to tumor-secreted growth factors and tubulogenesis are altered following IR. The RhoA/ROK signalling pathway is involved in the IR-altered angiogenic functions and may represent a potential molecular target for enhancing the impact of radiotherapy on tumor-associated endothelial cells.

The microvasculature of brain tumors has been proposed as the primary target for ionizing radiation (IR)-induced apoptosis. However, the contribution of low dose IR-induced non-apoptotic cell death pathways has not been investigated. This study aimed to characterize the effect of IR on human brain microvascular endothelial cells (HBMEC) and to assess the combined effect of epigallocatechin-3-gallate (EGCg), a green tea-derived anti-angiogenic molecule. HBMEC were treated with EGCg, irradiated with a sublethal (< or =10 Gy) single dose. Cell survival was assessed 48 h later by nuclear cell counting and Trypan blue exclusion methods. Cell cycle distribution and DNA fragmentation were evaluated by flow cytometry (FC), cell death was assessed by fluorimetric caspase-3 activity, FC and immunoblotting for pro-apoptotic proteins. While low IR doses alone reduced cell survival by 30%, IR treatment was found more effective in EGCg pretreated-cells reaching 70% cell death. Analysis of cell cycle revealed that IR-induced cell accumulation in G2-phase. Expression of cyclin-dependent kinase inhibitors p21(CIP/Waf1) and p27(Kip) were increased by EGCg and IR. Although random DNA fragmentation increased by approximately 40% following combined EGCg/IR treatments, the synergistic reduction of cell survival was not related to increased pro-apoptotic caspase-3, caspase-9 and cytochrome C proteins. Cell necrosis increased 5-fold following combined EGCg/IR treatments while no changes in early or late apoptosis were observed. Our results suggest that the synergistic effects of combined EGCg/IR treatments may be related to necrosis, a non-apoptotic cell death pathway. Strategies sensitizing brain tumor-derived EC to IR may enhance the efficacy of radiotherapy and EGCg may represent such a potential agent.

Objective: Dysregulation of the blood-brain barrier (BBB) and transendothelial migration of immune cells are among the earliest central nervous system changes partaking in lesion formation in both multiple sclerosis (MS) and its early clinical form, the clinically isolated syndrome. Evidence for the anti-inflammatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors within the central nervous system arose from studies demonstrating that statins improve clinical signs in the animal model of MS and reduce the number of gadolinium-enhancing lesions in MS., Methods: We sought to describe the impact of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor treatment on the physiology and immunology of human BBB-derived endothelial cells (ECs)., Results: We demonstrate that lovastatin and simvastatin induce a 50 to 60% reduction in the diffusion rates of bovine serum albumin and [(14)C]-sucrose across human BBB-ECs in vitro through abrogation of isoprenylation processes, but independent of the expression of the tight junction molecules occludin, VE-cadherin, JAM-1, zonula occluden-1, and zonula occluden-2. Simvastatin and lovastatin were equipotent in reducing BBB permeability in vitro, with median effective concentration (EC(50)) of 9.5 x 10(-8) and 1.0 x 10(-7)M, respectively. We further demonstrate that lovastatin and simvastatin treatment of BBB-ECs significantly restricts the migration of clinically isolated syndrome-derived and MS-derived monocytes and lymphocytes across the human BBB in vitro, through a specific reduction in the secretion of the chemokines monocyte chemotactic protein-1/CCL2 and interferon-gamma-inducible protein-10/CXCL10 by BBB-ECs., Interpretation: Our data parallel the previously reported magnetic resonance imaging-based radiological findings and suggest an effect of statins that could be beneficial in early MS, restricting the diffusion of molecular tracers and the migration of immune cells across the human BBB.

Introduction: Glioblastoma multiforme's (GBM) aggressiveness is potentiated in radioresistant tumor cells. The combination of radiotherapy and chemotherapy has been envisioned as a therapeutic approach for GBM. The goal of this study is to determine if epigallocatechin-3-gallate (EGCg), a green tea-derived anti-cancer molecule, can modulate GBMs' response to ionizing radiation (IR) and whether this involves mediators of intracellular signaling and inhibitors of apoptosis proteins., Material and Methods: U-87 human GBM cells were cultured and transfected with cDNAs encoding for Survivin, RhoA or Caveolin-1. Mock and transfected cells were irradiated at sublethal single doses. Cell proliferation was analyzed by nuclear cell counting. Apoptosis was detected using a fluorometric caspase-3 assay. Analysis of protein expression was accomplished by Western immunoblotting., Results: IR (10 Gy) reduced control U-87 cell proliferation by 40% through a caspase-independent mechanism. The overexpression of Survivin induced a cytoprotective effect against IR, while the overexpression of RhoA conferred a cytosensitizing effect upon IR. Control U-87 cells pretreated with EGCg exhibited a dose-dependent decrease in their proliferation rate. The growth inhibitory effect of EGCg was not antagonized by overexpressed Survivin. However, Survivin -transfected cells pretreated with EGCg became sensitive to IR, and their RhoA expression was downregulated. A potential therapeutic effect of EGCg targeting the prosurvival intracellular pathways of cancer cells is suggested to act synergistically with IR., Conclusion: The radioresistance of GBM is possibly mediated by a mechanism dependent on Survivin in conjunction with RhoA. The combination of natural anti-cancerous molecules such as EGCg with radiotherapy could improve the efficacy of IR treatments.

Glioma cell-surface binding to hyaluronan (HA), a major constituent of the brain extracellular matrix (ECM) environment, is regulated through a complex membrane type-1 matrix metalloproteinase (MT1-MMP)/CD44/caveolin interaction that takes place at the leading edges of invading cells. In the present study, intracellular transduction pathways required for the HA-mediated recognition by infiltrating glioma cells in brain was investigated. We show that the overexpression of the GTPase RhoA up-regulated MT1-MMP expression and triggered CD44 shedding from the U-87 glioma cell surface. This potential implication in cerebral metastatic processes was also observed in cells overexpressing the full-length recombinant MT1-MMP, while the overexpression of a cytoplasmic domain truncated from of MT1-MMP failed to do so. This suggests that the cytoplasmic domain of MT1-MMP transduces intracellular signaling leading to RhoA-mediated CD44 shedding. Treatment of glioma cells with the Rho-kinase (ROK) inhibitor Y27632, or with EGCg, a green tea catechin with anti-MMP and anti-angiogenesis activities, antagonized both RhoA- and MT1-MMP-induced CD44 shedding. Conversely, overexpression of recombinant ROK stimulated CD44 release. Taken together, our results suggest that RhoA/ROK intracellular signaling regulates MT1-MMP-mediated CD44 recognition of HA. These molecular processes may partly explain the diffuse brain-infiltrating character of glioma cells within the surrounding parenchyma and thus be a target for new approaches to anti-tumor therapy.

Protein l-isoaspartyl methyltransferase (PIMT) functions as a repair enzyme that acts upon damaged proteins bearing abnormal aspartyl residues. We previously reported that PIMT expression and activity are reduced by half in human epileptic hippocampus. Here we investigated PIMT regulation in astrocytic tumors, which are the most common human brain tumors. PIMT expression and enzyme activity were significantly decreased in all grades of human astrocytic tumors. More precisely, PIMT levels were significantly lower by 76% in pilocytic astrocytomas (grade I), 46% in astrocytomas (grade II), 69% in anaplastic astrocytomas (grade III), and a marked 80% in glioblastomas (grade IV) as compared to normal brains. RT-PCR analysis showed that levels of type I PIMT mRNA were up-regulated while those of type II PIMT mRNA were down-regulated in glioblastomas. Furthermore, the reduced PIMT levels correlated closely with a decrease in the number of neuron cells in astrocytic tumors as assessed by measuring the neuron-specific enolase level. Many proteins with abnormal aspartyl residues accumulated in brain tumors and some were specific to individual grades of astrocytic tumors. Similar results were obtained, either by measuring the reduction in PIMT activity and expression or by measuring the formation of abnormal proteins, in an orthotopic rat brain tumor model implanted with invasive CNS-1 glioma cells. The novelty of these findings was to provide the first evidence for a marked reduction of PIMT expression and activity during stage progression of astrocytic tumors in humans.

The effect of chronic anticonvulsant therapy (CAT) on the maintenance and recovery profiles of cisatracurium-induced neuromuscular blockade has not been adequately studied. In this study, we compared the pharmacokinetics and pharmacodynamics of cisatracurium after a prolonged infusion in patients with or without CAT. Thirty patients undergoing intracranial surgery were enrolled in the study: 15 patients under CAT (carbamazepine and phenytoin, Group A) and 15 controls receiving no anticonvulsant therapy (Group C). Anesthesia was standardized and both groups received a bolus of cisatracurium followed by an infusion to maintain a 95% twitch depression. A steady-state was obtained and the infusion was kept constant for 2 additional hours. Neuromuscular blockade was then allowed to spontaneously recover. Blood samples were taken for measurement of cisatracurium plasma concentration during the steady-state period (Cp(ss)95) and at various times during recovery. Demographic and intraoperative data were similar. CAT resulted in faster 25% and 75% recovery of the first twitch. The rate of infusion of cisatracurium needed to maintain a 95% twitch depression at steady-state was 44% faster in Group A (P < 0.001). The clearance of cisatracurium was significantly faster in Group A when compared with Group C (7.12 +/- 1.87 versus 5.72 +/- 0.70 L . kg(-1) . min(-1), P = 0.01). The Cp(ss)95 was also significantly larger in Group A (191 +/- 45 versus 159 +/- 36 ng/mL, P = 0.04). In addition, patients receiving CAT had a 20% increase in the clearance of cisatracurium that, in turn, resulted in a faster recovery of neuromuscular blockade after an infusion of the drug. Also, patients under CAT had a 20% increase in their Cp(ss)95, indicating an increased resistance to the effect of cisatracurium.

Moyamoya disease is characterized by constrictions of segments of the internal carotid arteries (ICAs) and a resultant abnormal anastomotic network. In the literature, visual disturbances from cerebrovascular accidents in patients with moyamoya disease have been described, but very few reports of intraocular pathological conditions have been published. The authors describe a patient with moyamoya disease who presented with chorioretinal atrophy; an association between these two diseases has not previously been reported in the literature. Findings of a clinical ophthalmological evaluation and angiographic series are presented. During the fundic examination, evidence of chorioretinal atrophy was found in this patient. Choroidal vascular insufficiency was revealed by intravenous fluorescein angiography and occlusion of the ICAs proximal to the origin of the posterior communicating arteries by selective carotid and vertebral arteriography. The vertebrobasilar system provided anastomotic connections via the posterior communicating arteries. This is the first case report of chorioretinal atrophy associated with moyamoya disease. It is believed that the vasoocclusive effects of moyamoya disease may predispose the patient to atrophic changes in the peripheral retina. The development of an anastomotic network precludes the progression of this fundic anomaly.

The fear of producing CO(2) retention and a secondary increase of intracranial pressure (ICP) sometimes precludes the use of sedation for the spontaneously breathing patient in the presence of an intracranial space-occupying lesion. In this study we assessed the effect of moderately deep propofol sedation on the ICP of patients undergoing stereotactic brain tumor biopsy under regional anesthesia. Thirty patients were randomized into 2 groups to receive propofol titrated to a level of 2 on the Observer's Assessment of Alertness/Sedation Scale or no sedation. ICP was measured via the biopsy needle. Preoperative data were similar in both groups. During surgery, patients receiving propofol had a higher arterial Pco(2) (48 +/- 8 mm Hg versus 41 +/- 3 mm Hg; P = 0.005) (95% confidence interval, 43-53 mm Hg and 39-43 mm Hg, respectively), resulting in a lower arterial pH (P = 0.002) than patients in the no-sedation group. The median ICP (95% confidence interval) for both groups was similar-13 mm Hg (8.2-16.2 mm Hg) and 15 mm Hg (8.3-21.7 mm Hg)-for the propofol and no-sedation groups, respectively (P = 0.66). Cerebral perfusion pressure was lower in the propofol group (76 +/- 18 mm Hg versus 89 +/- 18 mm Hg; P = 0.003). Moderately deep propofol sedation does not result in a higher ICP than no sedation in patients undergoing stereotactic brain tumor biopsy. Further studies are needed to assess the effect on ICP of other sedative medications.

Hyaluronan (HA) is a component of the brain extracellular matrix environment that is synthesized and secreted by glioma cells. The primary cell surface receptor for HA is CD44, a membrane glycoprotein that is functionally regulated by a membrane type 1 matrix metalloproteinase (MT1-MMP). Both CD44 and MT1-MMP are partially located in Triton X-100-insoluble domains, but no functional link has yet been established between them. In the present study, we studied the regulation of HA cell surface binding in U-87 glioma cells. We show that an MMP-dependent mechanism regulates the intrinsic cell surface binding of HA as ilomastat, a broad MMP inhibitor, increased HA binding to glioma cells. HA binding was also rapidly and specifically up-regulated by 3-fold by type I collagen in U-87 cells, which also induced a significant morphological reorganization associated with the activation of a latent form of MMP-2 through a MT1-MMP-mediated mechanism. Interestingly, caveolae depletion with a cell surface cholesterol-depleting agent beta-cyclodextrin triggered an additional increase (9-fold) in the binding of HA, in synergy with type I collagen. On the other hand, HA cell surface binding was diminished by the MEK inhibitor PD98059 and by the overexpression of a recombinant, wild type MT1-MMP, whereas its cytoplasmic-deleted form had no effect. Taken together, our results suggest that MT1-MMP regulates, through its cytoplasmic domain, the cell surface functions of CD44 in a collagen-rich pericellular environment. Additionally, we describe a new molecular mechanism regulating the invasive potential of glioma cells involving a MT1-MMP/CD44/caveolin interaction, which could represent a potential target for anti-cancer therapies.

Primary brain tumors, particularly glioblastomas (GB), remain a challenge for oncology. An element of the malignant brain tumors' aggressive behavior is the fact that GB are among the most densely vascularized tumors. To determine some of the molecular regulations occuring at the brain tumor endothelium level during tumoral progression would be an asset in understanding brain tumor biology. Caveolin-1 is an essential structural constituent of caveolae that has been implicated in mitogenic signaling, oncogenesis, and angiogenesis. In this work we investigated regulation of caveolin-1 expression in brain endothelial cells (ECs) under angiogenic conditions. In vitro, brain EC caveolin-1 is down-regulated by angiogenic factors treament and by hypoxia. Coculture of brain ECs with tumoral cells induced a similar down-regulation. In addition, activation of the p42/44 MAP kinase is demonstrated. By using an in vivo brain tumor model, we purified ECs from gliomas as well as from normal brain to investigate possible regulation of caveolin-1 expression in tumoral brain vasculature. We show that caveolin-1 expression is strikingly down-regulated in glioma ECs, whereas an increase of phosphorylated caveolin-1 is observed. Whole-brain radiation treatment, a classical way in which GB is currently being treated, resulted in increased caveolin-1 expression in tumor isolated ECs. The level of tumor cells spreading around newly formed blood vessels was also elevated. The regulation of caveolin-1 expression in tumoral ECs may reflect the tumoral vasculature state and correlates with angiogenesis kinetics., (Copyright 2003 Wiley-Liss, Inc.)

Study Design: A prospective clinical study was conducted to evaluate the efficacy of paraspinous muscle flaps in preventing and managing cerebrospinal fluid fistulas in high-risk neurosurgery patients., Objectives: To evaluate the efficacy of paraspinous muscle flap coverage using a "vest-over-pants" closure in the prevention and treatment of cerebrospinal fluid fistulas., Summary of Background Data: Previous studies have described paraspinous muscle flaps for the closure of complex spinal wounds, but none has addressed their use for the prevention and treatment of cerebrospinal fluid fistulas., Methods: This prospective clinical study evaluated nine consecutive patients with either refractory cerebrospinal fluid fistulas or high risk for cerebrospinal fluid leaks after spinal surgery. Bilateral paraspinous muscle flaps were used as primary flaps and closed using an overlapping vest-over-pants technique in eight of nine cases. The latissimus dorsi and trapezius muscles were recruited as additional muscle flaps for closure of thoracolumbar and high thoracic deficits, respectively., Results: Paraspinous muscle flaps provided immediate wound coverage in seven high-risk patients undergoing spinal surgery and two patients with recurrent cerebrospinal fluid fistulas. Postoperative hospitalization averaged 14.4 days. There was no evidence of a cerebrospinal fluid fistula after an average follow-up of 176.7 days. No wound infections occurred. The only complications were a superficial hematoma, which was drained percutaneously on postoperative day 6, and a seroma, which was drained during the follow-up period and eventually resolved., Conclusions: Paraspinous muscle flaps allow effective treatment and prevention of cerebrospinal fluid fistulas in selected high-risk patients and provide simple durable coverage of complex spinal wounds with minimal morbidity.

Endothelial cells (ECs) are new targets for tumor therapy. In this work, we purified endothelial cells from intracerebral and subcutaneous experimental gliomas as well as from normal brain in order to define some of the phenotypical differences between angiogenic and quiescent brain vasculature. We show that the multidrug resistance genes encoding drug efflux pumps at the brain endothelium are expressed differently in normal and tumoral vasculature. We also show that ECs from gliomas present increased activity of gelatinase B (MMP9), key enzyme in the angiogenic process. Importantly, we observe a different phenotype between ECs in the intracerebral and subcutaneous models. Our results provide molecular evidence of phenotypic distinction between tumoral and normal brain vasculature and indicate that the EC phenotype depends on interactions both with tumor cells and also with the microenvironment.