Long-term follow-up survey reveals a high yield, up to 30% of patients presenting newly detected aneurysms more than 10 years after ruptured intracranial aneurysms clipping.

The need to pursue long-term follow-up in patients treated for a ruptured aneurysm remains debated. New aneurysms development is a crucial element to consider but remains scarcely analyzed especially after a mean follow-up longer than 10 years. Our study was designed to provide rates of newly developed aneurysms in patients who have undergone prior clipping who were not followed with serial imaging. Patients were included if they were (1) treated more than 10 years ago by clipping of a ruptured aneurysm, (2) independent at time of discharge, (3) presently younger than 65 years, and if (4) they agreed to undergo a late digital subtraction angiography (DSA) control or to transmit results of a recent one performed elsewhere. Twenty patients were included with a mean delay between aneurysm treatment and late DSA of 18.0 years (10-26.5 years). Out of these patients, six (30%) harbored new aneurysms. Of these six individuals, four (66.6%) presented multiple aneurysms with a total of 15 newly discovered aneurysms. Aneurysm sizes ranged from 1 to 10 mm. One patient suffered from a de novo aneurysm rupture. Multiple aneurysms at the time of the first hemorrhage were a risk factor in developing de novo aneurysm (p=0.0175). In conclusion, based on a 30% rate of new aneurysm formation in patients clipped more than a decade ago, close screening on a very long-term perspective is encouraged. This study suggests aneurysm formation to be a continuous process.

Clinical, radiological and molecular characterization of intramedullary astrocytomas.

Intramedullary astrocytomas (IMAs) are rare tumors, and few studies specific to the molecular alterations of IMAs have been performed. Recently, KIAA1549-BRAF fusions and the H3F3A p.K27M mutation have been described in low-grade (LG) and high-grade (HG) IMAs, respectively. In the present study, we collected clinico-radiological data and performed targeted next-generation sequencing for 61 IMAs (26 grade I pilocytic, 17 grade II diffuse, 3 LG, 3 grade III and 12 grade IV) to identify KIAA1549-BRAF fusions and mutations in 33 genes commonly implicated in gliomas and the 1p/19q regions. One hundred seventeen brain astrocytomas were analyzed for comparison. While we did not observe a difference in clinico-radiological features between LG and HG IMAs, we observed significantly different overall survival (OS) and event-free survival (EFS). Multivariate analysis showed that the tumor grade was associated with better OS while EFS was strongly impacted by tumor grade and surgery, with higher rates of disease progression in cases in which only biopsy could be performed. For LG IMAs, EFS was only impacted by surgery and not by grade. The most common mutations found in IMAs involved TP53, H3F3A p.K27M and ATRX. As in the brain, grade I pilocytic IMAs frequently harbored KIAA1549-BRAF fusions but with different fusion types. Non-canonical IDH mutations were observed in only 2 grade II diffuse IMAs. No EGFR or TERT promoter alterations were found in IDH wild-type grade II diffuse IMAs. These latter tumors seem to have a good prognosis, and only 2 cases underwent anaplastic evolution. All of the HG IMAs presented at least one molecular alteration, with the most frequent one being the H3F3A p.K27M mutation. The H3F3A p.K27M mutation showed significant associations with OS and EFS after multivariate analysis. This study emphasizes that IMAs have distinct clinico-radiological, natural evolution and molecular landscapes from brain astrocytomas.

Reversible neurochemical changes mediated by delayed intrastriatal glial cell line-derived neurotrophic factor gene delivery in a partial Parkinson's disease rat model.

BACKGROUND: Efficient protection of dopaminergic neurons against a subsequent 6-hydroxydopamine lesion by glial cell line-derived neurotrophic factor (GDNF) gene delivery has been demonstrated. By contrast, the neurorestorative effects of GDNF administered several weeks after the toxin have been less characterized. In particular, whether these were permanent or dependent on the continuous presence of GDNF remains elusive. METHODS: A tetracycline-inducible adeno-associated virus (AAV)-1 vector expressing human GDNF cDNA was administered unilaterally in the rat striatum 5 weeks after 6-hydroxydopamine. Rats were treated with doxycycline (dox) or untreated from the day of vector injection until sacrifice (4 or 14 weeks). A sub-group was dox-treated for 7 weeks then untreated until 14 weeks. The motor behavior was assessed by amphetamine-induced rotations and spontaneous forelimb asymmetry. The amounts of tyrosine hydroxylase (TH), serine-40-phosphorylated TH (S40-TH) and aromatic amino acid decarboxylase (AADC) proteins were compared by western blotting and the dopamine levels quantified by high-performance liquid chromatography. RESULTS: Dox-dependent behavioral improvements were demonstrated 4 weeks post-vector injection. At later time points, spontaneous partial recovery was observed in all rats, but no further improvement was found in dox-treated animals. TH levels were significantly increased in dox-treated rats at all time points. By contrast, striatal dopamine and S40-TH were increased at 4 weeks, but not 14 weeks, and AADC remained unchanged. Dox withdrawal after 7 weeks, resulted in TH levels comparable to the controls at 14 weeks. CONCLUSIONS: Delayed GDNF gene delivery only transiently improved dopaminergic function. Over the long term, TH was more abundant, but not functional, and the increase was lost when GDNF gene expression was switched off.

Brain stem metastases treated with radiosurgery: prognostic factors of survival and life expectancy estimation.

BACKGROUND: The objective of this study is to study prognostic factors of survival and 3 stratification systems for life expectancy estimation in patients with brain stem metastases treated with radiosurgery. METHODS: Between December 1999 and November 2006, 25 patients with 27 brain stem metastases were treated with Gamma Knife radiosurgery. The lesions' mean volume was 0.6 mL (0.013-3.6 mL). The mean marginal dose was 20 Gy (15-24 Gy). Univariate and multivariate studies were done to identify prognostic factors, and 3 patient stratification systems were applied for survival estimation: RPA, SIR, and BSBM. RESULTS: The primary tumor location was in the lungs in 12 patients, breast in 8, and other in 5. Fourteen lesions were located in the pons, 9 in the midbrain, and 4 in the medulla. All patients were followed clinically. Radiologic follow-up was available in 21 lesions (78%). Tumor control was achieved in all but one followed lesion (95%). There were no complications related to treatment. Median survival of patients with brain stem metastases was 11.1 months. In multivariate analysis, KPS of 80 or more, control of the primary tumor, absence of radiotherapy, and a marginal dose higher than 18 Gy were associated with better survival. The BSBM in the univariate and multivariate analyses was the strongest predictor of survival (P < .0001). CONCLUSIONS: The BSBM was the most useful tool for estimating survival. Rather than the brain stem location of an intracranial metastasis, the patient integral clinical status seems to be more important in determining survival.

Recombinant AAV viral vectors serotype 1, 2, and 5 mediate differential gene transfer efficiency in rat striatal fetal grafts.

Intrastriatal grafts of fetal ganglionic eminences (GE) can reverse symptoms of striatal lesions in animal models of Huntington's disease. On the other hand, neurotrophic factors have been shown to protect host striatal neurons from ongoing degeneration. Neurotrophic gene transfer into GE prior to grafting could combine the benefits of striatal neuron replacement and in situ delivery of neurotrophic factors. Here we evaluate the potency of recombinant adeno-associated viruses (rAAV) as vectors for gene delivery into rat embryonic (E15) GE using the eGFP reporter gene under the control of the strong cytomegalovirus (CMV) promoter. We observed a very efficient expression of the eGFP reporter gene in organotypic cultures of GE infected with rAAV serotype 1 from 4 days until at least 4 weeks postinfection. In contrast, transduction was low and absent when using serotype 2 and serotype 5 rAAV, respectively. Two months after transplantation of rAAV2/1-infected embryonic GE in adult rat striatum, more than 20% of grafted cells expressed eGFP. The majority of transduced cells in the graft were neurons as indicated by colabeling of GFP-immunoreactive cells with the NeuN marker. Our study suggests that GE transduced by rAAV-serotype 1 vectors could be an interesting tool to mediate efficient expression of a gene coding a neurotrophic factor in Huntington's disease.

Selective image-guided venous sinus exposure for direct embolization of dural arteriovenous fistula: technical case report.

BACKGROUND: Transcranial approaches for transsinusal endovascular therapy of DAVF have been sporadically reported by large craniectomies. Large craniectomies carry nevertheless a risk of postembolization extradural hematoma, reduced by delaying the endovascular procedure. We report a 1-session technique of SIGC for percutaneous transvenous DAVF embolization. CASE DESCRIPTION: This 58-year-old woman developed a right-sided cerebellar hematoma in relation with a high-grade left transverse and sigmoid sinus DAVF. The DAVF was fed by branches from the left vertebral artery, left internal, and left external carotid arteries, draining into the transverse sinus with retrograde flow in cortical veins. Transvenous retrograde embolization was not feasible either through the left internal jugular vein because of thrombosis, or through the right one because of torcular septa. During the same anaesthetic session, a 5-cm-length selective craniectomy was shaped under magnetic resonance image guidance navigation according to the left transverse sinus with high-speed drill. Thereafter, back in the angiography room, the transverse sinus was taped and coiled resulting in a complete exclusion of the DAVF. CONCLUSION: Selective image-guided craniectomy is efficient and safe for direct percutaneous transvenous embolization of DAVF in a single anesthetic session. Leaving bone beside the sinus prevents a parenchymal traumatic puncture. This bone has nevertheless to be drilled to allow an adequate sharp puncture angle. Doing so, postoperative hematoma is prevented by the small bone opening, the natural adherence of the dura matter and the possibility of direct compression.

Irradiation of cochlear structures during vestibular schwannoma radiosurgery and associated hearing outcome.

OBJECT: The purpose of this study was to measure the dose of radiation delivered to the cochlea during a Gamma knife surgery (GKS) procedure for treatment of patients with vestibular schwannomas (VSs), and to analyze the relationship between cochlear irradiation and the hearing outcome of these patients. METHODS: Eighty-two patients with VSs were treated with GKS using a marginal dose of 12 Gy. No patient had neurofibromatosis Type 2 disease, and all had a Gardner-Robertson hearing class of I to IV before treatment, and a radiological and audiological follow-up of at least 1-year after GKS. The dosimetric data of the volume of the cochlea were retrospectively analyzed and were correlated with the auditory outcome of patients. RESULTS: The mean radiation dose delivered to the cochlear volume ranged from 1.30 to 10.00 Gy (median 4.15 Gy). The cochlea received significantly higher radiation doses in patients with worsening of hearing after GKS. A highly significant association between the cochlear and the intracanalicular dose of radiation delivered during GKS was found. CONCLUSIONS: During GKS for VSs, relatively high doses of radiation can be delivered to the cochlea. Worsening of hearing after GKS can be the consequence of either radiation injury to the cochlea or the irradiation dose delivered into the auditory canal, or both.

Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis.

PURPOSE: The present review aims to emphasize that malignant gliomas are characterized by the diffuse invasion of distant brain tissue by a myriad of single migrating cells that exhibit decreased levels of apoptosis (programmed cell death type I), thus a resistance to cytotoxic insult. METHODS: The present review surveys the molecular mechanisms of migration in malignant gliomas and potential issues arising from treatments, in addition to relationships between glioma cell migration and resistance to apoptosis in terms of the molecular signaling pathways. RESULTS: Clinical and experimental data demonstrate that glioma cell migration is a complex combination of multiple molecular processes, including the alteration of tumor cell adhesion to a modified extracellular matrix, the secretion of proteases by the cells, and modifications to the actin cytoskeleton. Intracellular signaling pathways involved in the acquisition of resistance to apoptosis by migrating glioma cells concern PI3K, Akt, mTOR, NF-kappaB, and autophagy (programmed cell death type II). CONCLUSION: A number of signaling pathways can be constitutively activated in migrating glioma cells, thus rendering these cells resistant to cytotoxic insults. However, these pathways are not all constitutively activated at the same time in any one glioma. Particular inhibitors should therefore only be chosen if the target is present in the tumor tissue, but this is only possible if individual patients are submitted to the molecular profiling of their tumors before undergoing any treatment to combat their migratory glioma cells. Specific antimigratory compounds should be added to conventional radio- and/or chemotherapy.

Role of intracanalicular volumetric and dosimetric parameters on hearing preservation after vestibular schwannoma radiosurgery.

PURPOSE: To analyze the relationship between hearing preservation after gamma knife radiosurgery (GKR) for vestibular schwannoma (VS) and some volumetric and dosimetric parameters of the intracanalicular components of VS. METHODS AND MATERIALS: This study included 82 patients with a VS treated by GKR; all patients had no NF2 disease, a Gardner-Robertson hearing class 1-4 before treatment, a marginal dose of 12 Gy, and a radiologic and audiologic follow-up > or =1 year post-GKR. The volume of both the entire tumor and the intracanalicular part of the tumor and the mean and integrated dose of these two volumes were correlated to the auditory outcomes of patients. RESULTS: At last hearing follow-up, 52 patients had no hearing worsening, and 30 patients had an increase of > or =1 class on Gardner-Robertson classification. We found that hearing preservation after GKR is significantly correlated with the intracanalicular tumor volume, as well as with the integrated dose delivered to the intracanalicular tumor volume. CONCLUSIONS: Some volumetric and dosimetric parameters of the intracanalicular part of the tumor influence hearing preservation after GKR of VS. Consequently, we advise the direct treatment of patients with preserved functional hearing and a VS including a small intracanalicular volume.

Cimetidine, an unexpected anti-tumor agent, and its potential for the treatment of glioblastoma (review).

Cimetidine (CIM), the prototypical histamine H2 receptor antagonist (H2RA), was brought to market based on its ability to accelerate healing of gastrointestinal ulcers through the inhibition of gastric acid secretion. Cimetidine, the most studied H2RA, has been demonstrated to possess anti-tumor activity against colon, gastric and kidney cancers, and melanomas. This activity involves a number of different mechanisms of action: a) CIM antagonizes tumor cell-mediated interleukin-1-induced activation of selectins in liver sinusoids, inhibiting tumor cell binding on liver sinusoids, thereby reducing the development of liver metastasis; b) histamine acts as a growth factor in various tumor cell types via the activation of H2 receptors; CIM therefore may antagonize this effect; c) CIM acts as an immunomodulator by enhancing the host's immune response to tumor cells. With respect to malignant gliomas, CIM added to temozolomide was superior in vivo when compared to temozolomide alone in extending survival of nude mice with human glioblastoma cells orthotopically xenografted into their brain. We review the various mechanisms of action potentially associated with the therapeutic effects of CIM in the case of experimental glioblastomas, observations we hope will encourage clinical investigation of CIM in the management of highly malignant gliomas.

Integrated positron emission tomography and magnetic resonance imaging-guided resection of brain tumors: a report of 103 consecutive procedures.

OBJECT: The aim of this study was to evaluate the integration of positron emission tomography (PET) scanning data into the image-guided resection of brain tumors. METHODS: Positron emission tomography scans obtained using fluorine-18 fluorodeoxyglucose (FDG) and L-[methyl-11C]methionine (MET) were combined with magnetic resonance (MR) images in the navigational planning of 103 resections of brain tumors (63 low-grade gliomas [LGGs] and 40 high-grade gliomas [HGGs]). These procedures were performed in 91 patients (57 males and 34 females) in whom tumor boundaries could not be accurately identified on MR images for navigation-based resection. The level and distribution of PET tracer uptake in the tumor were analyzed to define the lesion contours, which in turn yielded a PET volume. The PET scanning-demonstrated lesion volume was subsequently projected onto MR images and compared with MR imaging data (MR volume) to define a final target volume for navigation-based resection-the tumor contours were displayed in the microscope's eyepiece. Maximal tumor resection was accomplished in each case, with the intention of removing the entire area of abnormal metabolic activity visualized during surgical planning. Early postoperative MR imaging and PET scanning studies were performed to assess the quality of tumor resection. Both pre- and postoperative analyses of MR and PET images revealed whether integrating PET data into the navigational planning contributed to improved tumor volume definition and tumor resection. Metabolic information on tumor heterogeneity or extent was useful in planning the surgery. In 83 (80%) of 103 procedures, PET studies contributed to defining a final target volume different from that obtained with MR imaging alone. Furthermore, FDG-PET scanning, which was performed in a majority of HGG cases, showed that PET volume was less extended than the MR volume in 16 of 21 cases and contributed to targeting the resection to the hypermetabolic (anaplastic) area in 11 (69%) of 16 cases. Performed in 59 LGG cases and 23 HGG cases, MET-PET demonstrated that the PET volume did not match the MR volume and improved the tumor volume definition in 52 (88%) of 59 and 18 (78%) of 23, respectively. Total resection of the area of increased PET tracer uptake was achieved in 54 (52%) of 103 procedures. CONCLUSIONS: Imaging guidance with PET scanning provided independent and complementary information that helped to assess tumor extent and plan tumor resection better than with MR imaging guidance alone. The PET scanning guidance could help increase the amount of tumor removed and target image-guided resection to tumor portions that represent the highest evolving potential.

Comparison of functional MR imaging guidance to electrical cortical mapping for targeting selective motor cortex areas in neuropathic pain: a study based on intraoperative stereotactic navigation.

PURPOSE: To assess the concordance between data from functional MR imaging (fMRI) guidance and the intraoperative electrical cortical mapping (iCM) in targeting selective motor cortex areas in refractory neuropathic pain. METHODS: Twenty-one patients (11 women and 10 men; mean age, 55.6 years) with refractory central (ischemic, 8 cases) and neuropathic pain (trigeminal neuropathy, 6 cases; syrinx/amputation/plexus trauma, 7 cases) underwent surgery for the implantation of an epidural electrode for chronic motor cortex stimulation (MCS) with general anesthesia and a frameless neuronavigation system used for the image-guided targeting procedure. All patients were studied by preoperative fMRI and epidural iCM with somatosensory evoked potentials and motor cortex stimulodetection. fMRI investigated systematically motor tasks of both hands and that related to the somatic area (foot or tongue) affected by pain. fMRI data were analyzed with the Statistical Parametric Mapping99 software (initial analysis threshold [AT] corresponding to P < .001), registered in the neuronavigation system and correlated intraoperatively with iCM. Matching of fMRI and iCM was specifically examined, focusing the study on hand mapping. RESULTS: Concordance between contours of fMRI activation area and iCM in precentral gyrus (mean distance, 3.8 mm) was found in 20/21 patients (95%). Because precision of iCM was suboptimal in 7 patients, concordance for more restrictive values of the AT (P < .0001) was found in only 13 of these 20 patients. Concordance was not found in one patient, as result of image distortion and residual motion artifact. CONCLUSIONS: In this study, fMRI guidance provides information that matches those of an independent functional method. These data illustrate the functional accuracy of fMRI guidance for the operative targeting of selective motor cortex areas in neuropathic pain.

Does gamma knife surgery stimulate cellular immune response to metastatic brain tumors? A histopathological and immunohistochemical study.

OBJECT: The aim of this study was to analyze the cellular immune response and histopathological changes in secondary brain tumors after gamma knife surgery (GKS). METHODS: Two hundred ten patients with cerebral metastases underwent GKS. Seven patients underwent subsequent craniotomy for tumor removal between 1 and 33 months after GKS. Four of these patients had one tumor, two patients had two tumors, and one patient had three. Histological and immunohistochemical investigations were performed. In addition to routine H & E and Mallory trichrome staining, immunohistochemical reactions were conducted to characterize the phenotypic nature of the cell population contributing to the tissue immune response to neoplastic deposits after radiosurgery. Light microscopy revealed an intensive lymphocytic infiltration in the parenchyma and stroma of tumor samples obtained in patients in whom surgery was performed over 6 months after GKS. Contrary to this, extensive areas of tissue necrosis with either an absent or scanty lymphoid population were observed in the poorly controlled neoplastic specimens obtained in cases in which surgery was undertaken in patients less than 6 months after GKS. Immunohistochemical characterization demonstrated the predominance of CD3-positive T cells in the lymphoid infiltration. CONCLUSIONS: Histopathological findings of the present study are consistent with a cellular immune response of natural killer cells against metastatic brain tumors, presumably stimulated by the ionizing energy of focused radiation.

Combined cimetidine and temozolomide, compared with temozolomide alone: significant increases in survival in nude mice bearing U373 human glioblastoma multiforme orthotopic xenografts.

OBJECT: Malignant gliomas consist of both heterogeneous proliferating and migrating cell subpopulations, with migrating glioma cells exhibiting less sensitivity to antiproliferative or proapoptotic drugs than proliferative cells. Therefore, the authors combined cimetidine, an antiinflammatory agent already proven to act against migrating epithelial cancer cells, with temozolomide to determine whether the combination induces antitumor activities in experimental orthotopic human gliomas compared with the effects of temozolomide alone. METHODS: Cimetidine added to temozolomide compared with temozolomide alone induced survival benefits in nude mice with U373 human glioblastoma multiforme (GBM) cells orthotopically xenografted in the brain. Computer-assisted phase-contrast microscopy analyses of 9L rat and U373 human GBM cells showed that cimetidine significantly decreased the migration levels of these tumor cells in vitro at concentrations at which tumor growth levels were not modified (as revealed on monotetrazolium colorimetric assay). Computer-assisted microscope analyses of neoglycoconjugate-based glycohistochemical staining profiles of 9L gliosarcomas grown in vivo revealed that cimetidine significantly decreased expression levels of endogenous receptors for fucose and, to a lesser extent, for N-acetyl-lactosamine moieties. Endogenous receptors of this specificity are known to play important roles in adhesion and migration processes of brain tumor cells. CONCLUSIONS: Cimetidine, acting as an antiadhesive and therefore an antimigratory agent for glioma cells, could be added in complement to the cytotoxic temozolomide compound to combat both migrating and proliferating cells in GBM.

Persistent hydrocephalus after early surgical management of posterior fossa tumors in children: is routine preoperative endoscopic third ventriculostomy justified?

OBJECT: The authors evaluate the incidence of persistent hydrocephalus after early surgical management of pediatric posterior fossa tumors and the indicators for routine preoperative endoscopic third ventriculostomy (ETV). METHODS: Between 1989 and 2004, 160 children with a posterior fossa tumor were treated at Erasme Hospital in Brussels, Belgium. Hydrocephalus was present at admission in 114 of the patients. Thirty-one patients had severe hydrocephalus (Evans index [EI] > 0.4). Twenty-four of these and the 83 patients with mild hydrocephalus (EI between 0.3 and 0.4) were treated with early posterior fossa surgery (Group 1; 107 patients). In this group, 93 patients underwent a total or subtotal tumor resection associated with external ventricular drainage (Group 1A), and 14 underwent a stereotactic biopsy associated with an ETV (Group 1B). The 53 remaining patients underwent elective posterior fossa surgery (Group 2). Early tumor resection (Group 1A) resolved hydrocephalus in 85 (91%) of 93 patients, whereas an ETV resolved intracranial hypertension in 11 patients (Group 1B). In Group 1, persistent hydrocephalus affected 11 (10%) of 107 patients, seven of whom had symptoms and were treated (three with shunts and four with ETVs). Persistent hydrocephalus was more frequent in children with severe preoperative hydrocephalus (p = 0.002) and with medulloblastomas (p = 0.0154). A total of 22 technically successful ETV procedures were performed. The ETV success rate for controlling hydrocephalus was 81% (18 of 22) and the rate of severe complications was 9% (two of 22). CONCLUSIONS: An ETV is an efficient procedure for controlling hydrocephalus associated with posterior fossa tumor. The authors confirm that a routine postoperative ETV is indicated for treating persistent hydrocephalus. For preventing it, however, they recommend early posterior fossa surgery whenever possible. The low rate of persistent hydrocephalus does not justify adopting routine preoperative ETVs.

Characterization of gastrin-induced proangiogenic effects in vivo in orthotopic U373 experimental human glioblastomas and in vitro in human umbilical vein endothelial cells.

PURPOSE: This study aims to investigate the role of gastrin-17 (G17) on angiogenesis features in gliomas both in vitro and in vivo. EXPERIMENTAL DESIGN: The influences of G17 and G17 receptor antagonists were characterized in vitro in terms of angiogenesis on human umbilical vein endothelial cell (HUVEC) tubulogenesis processes on Matrigel and in vivo with respect to U373 orthotopic glioma xenografts. The influence of phosphatidylinositol 3'-kinase, protein kinase C, and nuclear factor-kappaB inhibitors was characterized in vitro on G17-mediated HUVEC tubulogenesis. G17-mediated release of interleukin (IL)-8 from HUVECs and G17-induced modifications in nuclear factor-kappaB DNA binding activity were characterized by means of specific enzyme-linked immunosorbent assays. The influence of G17 on E- and P-selectin expression was determined by means of computer-assisted microscopy, whereas the influence of E- and P-selectin on HUVEC migration was approached by means of antisense oligonucleotides. The chemotactic influence of G17 and IL-8 on HUVEC migration was characterized by means of computer-assisted videomicroscopy with Dunn chambers. RESULTS: Messenger RNAs for cholecystokinin (CCK)A, CCKB, and CCKC receptors were present in HUVECs and microvessels dissected from a human glioblastoma. Whereas G17 significantly increased the levels of angiogenesis in vivo in the U373 experimental glioma model and in vitro in the HUVECs, the CCKB receptor antagonist L365,260 significantly counteracted the G17-mediated proangiogenic effects. G17 chemoattracted HUVECs, whereas IL-8 failed to do so. IL-8 receptor alpha (CXCR1) and IL-8 receptor beta (CXCR2) mRNAs were not detected in these endothelial cells. Gastrin significantly (but only transiently) decreased the level of expression of E-selectin, but not P-selectin, whereas IL-8 increased the expression of E-selectin. Specific antisense oligonucleotides against E- and P-selectin significantly decreased HUVEC tubulogenesis processes in vitro on Matrigel. CONCLUSIONS: The present study shows that gastrin has marked proangiogenic effects in vivo on experimental gliomas and in vitro on HUVECs. This effect depends in part on the level of E-selectin activation, but not on IL-8 expression/release by HUVECs.

Radiosurgery for treatment of brain metastases: estimation of patient eligibility using three stratification systems.

PURPOSE: To compare three patient stratification systems predicting survival: recursive partitioning analysis (RPA), score index for radiosurgery in brain metastases (SIR), and a proposed basic score for brain metastases (BS-BM). METHODS AND MATERIALS: We analyzed the outcome of 110 patients treated with Leksell Gamma Knife radiosurgery between December 1999 and January 2003. The BS-BM was calculated by evaluating three main prognostic factors: Karnofsky performance status, primary tumor control, and presence of extracranial metastases. RESULTS: The median survival was 27.6 months for RPA Class I, 10.7 months for RPA Class II, and 2.8 months for RPA Class III (p <0.0001). Using the SIR, the median survival was 27.7, 10.8, 4.6, and 2.4 months for a score of 8-10, 5-7, 4, and 0-3, respectively (p <0.0001). The median survival was undefined in patients with a BS-BM of 3 (55% at 32 months) and was 13.1 months for a BS-BM of 2, 3.3 months for a BS-BM of 1, and 1.9 months for a BS-BM of 0 (p <0.0001). The backward elimination model in multivariate Cox analysis identified SIR and BS-BM as the only two variables significantly associated with survival (p = 0.031 and p = 0.043, respectively). CONCLUSION: SIR and BS-BM were the most accurate for estimating survival. They were specific enough to identify patients with short survival (SIR 0-3 and BS-BM 0). Because of it simplicity, BS-BM is easier to use.

Comparison of 18F-FDG and 11C-methionine for PET-guided stereotactic brain biopsy of gliomas.

UNLABELLED: We compared the contributions of the labeled tracers (11)C-methionine (Met) and (18)F-FDG for PET-guided stereotactic biopsy of brain gliomas. METHODS: In 32 patients with glioma, stereotactic Met PET and (18)F-FDG PET were integrated in the planning of stereotactic brain biopsy. PET images were analyzed to determine which tracer offered the best information for target definition. The stereotactic coregistration of PET images allowed accurate comparison of the level, distribution, and extent of uptake for both tracers according to tumor location and grade. RESULTS: A histologic diagnosis was obtained for all patients. All gliomas had an area of abnormal Met uptake, and 27 showed abnormal (18)F-FDG uptake. (18)F-FDG was used for target selection when its uptake was higher in tumor than in gray matter (14 gliomas). Seven were in the basal ganglia or brain stem. Met was used for target selection when there was no (18)F-FDG uptake or when (18)F-FDG uptake was equivalent to that in the gray matter (18 gliomas). Thirteen were in the cortex. Sixty-one of the 70 stereotactic trajectories obtained from the 32 patients were based on PET-defined targets and had an area of abnormal Met uptake. These 61 Met-positive trajectories always yielded a diagnosis of tumor. All nondiagnostic trajectories (n = 9) were obtained in areas with no increased uptake of Met. In all patients with increased uptake of both tracers, the focus of highest Met uptake corresponded to the focus of highest (18)F-FDG uptake. However, the extent of uptake of both tracers was variable. CONCLUSION: Distributions of highest Met and (18)F-FDG uptake are similar in brain gliomas. Because Met provides a more sensitive signal, it is the molecule of choice for single-tracer PET-guided neurosurgical procedures in gliomas.

Use of stereotactic PET images in dosimetry planning of radiosurgery for brain tumors: clinical experience and proposed classification.

UNLABELLED: We developed a technique that allows the routine integration of PET in stereotactic neurosurgery, including radiosurgery. We report our clinical experience with the combined use of metabolic (i.e., PET) and anatomic (i.e., MRI and CT) images for the radiosurgical treatment of brain tumors. We propose a classification describing the relative role of the information provided by PET in this multimodality image-guided approach. METHODS: Between December 1999 and March 2003, 57 patients had stereotactic PET as part of their image acquisition for the planning of gamma knife radiosurgery. Together with stereotactic MRI and CT, stereotactic PET images were acquired on the same day using either (18)F-FDG or (11)C-methionine. PET images were imported in the planning software for the radiosurgery dosimetry, and the target volume was defined using the combined information of PET and MRI or CT. To analyze the specific contribution of the PET findings, we propose a classification that reflects the strategy used to define the target volume. RESULTS: The patients were offered radiosurgery with PET guidance when their tumor was ill-defined and we anticipated some limitation of target definition on MRI alone. This represents 10% of the radiosurgery procedures performed in our center during the same period of time. There were 40 primary brain lesions, 7 metastases, and 10 pituitary adenomas. Abnormal PET uptake was found in 62 of 72 targets (86%), and this information altered significantly the MRI-defined tumor in 43 targets (69%). CONCLUSION: The integration of PET in radiosurgery provides additional information that opens new perspectives for the optimization of the treatment of brain tumors.

Granulocyte macrophage-colony stimulating factor gene transfer to induce a protective anti-tumoral immune response against the 9L rat gliosarcoma model.

The injection of irradiated tumor cells genetically engineered to express the granolocyte macrophage-colony stimulating factor (GM-CSF) is reported as stimulating antitumoral immunity in several animal models. We used the 9L gliosarcoma rat model to investigate the potency of this strategy in relation to the central nervous system. After in vitro transduction experiments to generate 9L murine cells producing GM-CSF (9LmGM-CSF cells), we found that with the exception of one rat subcutaneously (s.c.) grafted with 108 9LmGM-CSF cells, syngenic rats s.c. injected (dorsal route) with 106-108 viable 9LmGM-CSF cells did not develop s.c. 9L gliosarcomas, while rats s.c. grafted with the same number of naive 9L cells died between 25 and 45 days postgraft. Intracerebral stereotactic injections of 4.104 naive 9L (without s.c. 9LmGM-CSF treatment) killed all the rats within 18-24 days, while s.c. grafting with 108 9LmGM-CSF cells wholly prevented the development of 9L brain gliosarcomas. These results outline the feasibility of the GM-CSF gene transfer approach in glioma (or at least gliosarcoma) gene therapy and could therefore serve as a basis for the development of an adjuvant treatment of glioblastomas using GM-CSF-producing tumor cell vaccines.