Philippe Métellus

The management of patients with brain metastases has become a major issue due to the increasing frequency and complexity of the diagnostic and therapeutic approaches. In 2014, the European Association of Neuro-Oncology (EANO) created a multidisciplinary Task Force to draw evidence-based guidelines for patients with brain metastases from solid tumors. Here, we present these guidelines, which provide a consensus review of evidence and recommendations for diagnosis by neuroimaging and neuropathology, staging, prognostic factors, and different treatment options. Specifically, we addressed options such as surgery, stereotactic radiosurgery/stereotactic fractionated radiotherapy, whole-brain radiotherapy, chemotherapy and targeted therapy (with particular attention to brain metastases from non-small cell lung cancer, melanoma and breast and renal cancer), and supportive care.

The present joint European Association of Neuro-Oncology (EANO)–European Society for Medical Oncology (ESMO) recommendations for the diagnosis and treatment of parenchymal brain metastasis (BM) from solid cancers complement the first joint EANO–ESMO guideline on leptomeningeal metastasis from solid cancers.1 These recommendations address BMs from solid tumours, but do not address BMs from primary brain tumours or BMs from lymphoma or leukaemia. The recommendations cover prevention, diagnosis, therapy and follow-up, but not differential diagnosis, adverse effects of therapeutic measures or supportive or palliative care.

Brain metastases (BM) are the most common intracranial neoplasm in adults. Initially considered as an essentially terminal stage of advanced cancer, BM are increasingly being recognized as an emerging area of clinical interest. Their epidemiological characteristics have changed significantly, including an increased incidence in tumors frequently associated with BM, such as lung and breast cancer or melanoma, but also a more frequent occurrence with other primary tumor entities such as renal, colorectal and ovarian cancer. BM are more commonly diagnosed in multiple intracerebral sites, but in the context of controlled extracranial disease. Accordingly, progress in the development of systemic treatments, together with the rationalized use of surgical resection, radiosurgery and whole-brain radiotherapy, have led to an increase in the number of long-term survivors and in median survival. The recent emergence of targeted therapies and growing knowledge regarding the specific biology of BM should allow further improvements in prognosis of this devastating disease.

Stereotactic radiosurgery is an alternative to conventional surgery for the treatment of trigeminal neuralgia. The authors conducted a prospective evaluation of the safety and efficacy of this method in a large series of patients.A total of 100 patients presenting with trigeminal neuralgia were treated and followed up for a minimum of 12 months. The mean age was 68.2 years; 54 patients were male, and 46 were female. Seven had a history of multiple sclerosis, and 42 had already received conventional surgical treatment for trigeminal neuralgia. The intervention consisted of gamma knife surgery to the retrogasserian cisternal portion of the fifth cranial nerve. The median dose used at the maximum was 85 Gy (range 70-90 Gy). The number and intensity of pain attacks were recorded by the patient from 3 months before radiosurgery to a minimum of 12 months after treatment. Before and a minimum of 12 months after treatment, the patient completed a quality-of-life questionnaire. Neurological examination and quantitative sensory testing to evaluate sensory perception were performed by an independent neurologist over this same time period. At the last visit 83 of 100 patients were reported to be pain free. Fifty-eight of these 83 patients had stopped taking medication during the study. All quality-of-life parameters were improved (p < 0.001). Six patients reported facial paresthesia, and four patients reported hypesthesia. These symptoms were classified as mild. None of the complications reported for other techniques were observed.Radiosurgery is a safe and effective alternative treatment for trigeminal neuralgia and is associated with a particularly low rate of hypesthesia.

Purpose This phase II study evaluated the efficacy and safety of a 7-day on/7-day off regimen of temozolomide before radiotherapy (RT) in patients with inoperable newly diagnosed glioblastoma. Patients and Methods Patients received temozolomide (150 mg/m 2 /d on days 1 to 7 and days 15 to 21 every 28 days; 7 days on/7 days off) for up to four cycles before conventional RT (2-Gy fractions to a total of 60 Gy) and for four cycles thereafter or until disease progression. The primary end point was tumor response. Tumor tissue from 25 patients was analyzed for O 6 -methylguanine-DNA methyltransferase (MGMT) expression. Results Twenty-nine patients with a median age of 60 years were treated, and 28 were assessable for response. Seven (24%) of 29 patients had a partial response, nine patients (31%) had stable disease, and 12 patients (41%) had progressive disease. Median progression-free survival (PFS) time was 3.8 months, and median overall survival (OS) time was 6.1 months. Patients with low MGMT expression, compared with patients with high MGMT expression, had a significantly higher response rate (55% v 7%, respectively; P = .004) and improved PFS (median, 5.5 v 1.9 months, respectively; P = .009) and OS (median, 16 v 5 months, respectively; P = .003). The most common grade 3 and 4 toxicities were thrombocytopenia (20%) and neutropenia (17%). Conclusion This dose-dense temozolomide regimen resulted in modest antitumor activity with an acceptable safety profile in the neoadjuvant setting, and expression of MGMT correlated with response to temozolomide. However, this treatment approach seems to be inferior to standard concomitant RT plus temozolomide.

Immunostimulating oligodeoxynucleotides containing CpG motifs (CpG-ODN) have shown promising efficacy in cancer models when injected locally. In a phase I clinical trial, intratumoral infusions of CpG-ODN in glioblastoma (GBM) patients were well tolerated at doses up to 20 mg. This phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with recurrent GBMs. Patients with recurrent GBM occurring at least 3 months after radiotherapy, and previously treated with 1 or 2 regimens of chemotherapy received 20 mg of CpG-ODN (CpG-28) by convection-enhanced delivery. The primary endpoint was the percentage of patients without tumor progression 6 months after inclusion. Secondary endpoints were tolerance, survival, and radiological response. Thirty-four patients were enrolled in two centers between November 2004 and March 2006. Thirty-one patients received CpG-ODN treatment. The progression-free survival (PFS) at 6 months was 19%. One partial response and 3 minor responses were observed. The median overall survival was 28 weeks. Eight patients (24%) were alive 1 year after inclusion and 5 patients (15%) were alive after 2 years. Treatment was usually well tolerated. As reported previously, the most common toxicities were lymphopenia, mild fever, seizures, and transient neurological worsening. Despite a few cases showing a radiological response, CpG-28 showed modest activity on the 6-month PFS in this patient population. The molecular or clinical characteristics of a subgroup of patients that could potentially benefit from such an approach remain to be defined.

Whole brain radiation therapy (WBRT) is an effective treatment in brain metastases and, when combined with local treatments such as surgery and stereotactic radiosurgery, gives the best brain control. Nonetheless, WBRT is often omitted after local treatment due to its potential late neurocognitive effects. Publications on radiation-induced neurotoxicity have used different assessment methods, time to assessment, and definition of impairment, thus making it difficult to accurately assess the rate and magnitude of the neurocognitive decline that can be expected. In this context, and to help therapeutic decision making, we have conducted this literature review, with the aim of providing an average incidence, magnitude and time to occurrence of radio-induced neurocognitive decline. We reviewed all English language published articles on neurocognitive effects of WBRT for newly diagnosed brain metastases or with a preventive goal in adult patients, with any methodology (MMSE, battery of neurcognitive tests) with which baseline status was provided. We concluded that neurocognitive decline is predominant at 4 months, strongly dependant on brain metastases control, partially solved at later time, graded 1 on a SOMA-LENT scale (only 8% of grade 2 and more), insufficiently assessed in long-term survivors, thus justifying all efforts to reduce it through irradiation modulation.

Abstract Glioblastomas, like other cancers, harbor small cell populations with the capability of sustaining tumor formation. These cells are referred to as cancer stem cells. We isolated cells expressing the surface marker A2B5 from three human glioblastomas (GBM) and showed that after grafting into nude mice, they generated dense and highly infiltrative tumors. Then, we extensively studied A2B5 + cells isolated from 11 human GBM. These cells display neurosphere‐like, self‐renewal, asymmetrical cell division properties and have multipotency capability. Stereotactic xenografts of dissociated A2B5 + ‐derived secondary spheres revealed that as few as 1000 cells produced a tumor. Moreover, flow cytometry characterization of A2B5 + ‐derived spheres revealed three distinct populations of cells: A2B5 + /CD133 + , A2B5 + /CD133 ‐ and A2B5 ‐ /CD133 ‐ , with striking proportion differences among GBM. Both A2B5 + /CD133 + and A2B5 + /CD133 ‐ cell fractions displayed a high proliferative index, the potential to generate spheres and produced tumors in nude mice. Finally, we generated two green fluorescent protein‐cell lines that display—after serum induction—distinct proliferative and migratory properties, and differ in their CD133 level of expression. Taken together, our results suggest that transformed A2B5 + cells are crucial for the initiation and maintenance of GBM, although CD133 expression is more involved in determining the tumor's behavior.

<h3>Background/objective:</h3> Little is known about the long-term clinical course and management of patients with normal pressure hydrocephalus (NPH) treated by cerebrospinal fluid (CSF) shunting. <h3>Methods:</h3> We retrospectively reviewed records of 55 patients diagnosed with idiopathic NPH (INPH) and treated with CSF shunts, all of whom were followed for more than 3 years after the original shunt surgery. At each annual follow-up visit, the patient was assessed by Folstein Mini Mental State Examination, detailed clinical evaluation of gait and assessment of headache, cognition, gait or urination, as assessed by the patient and relatives. <h3>Results:</h3> The mean duration of follow-up was 5.9±2.5 years. There was an overall sustained improvement among all symptoms. Gait showed the highest maintenance of improvement over baseline (83% at 3 years and 87% at the last analysed follow-up of 7 years), cognition showed intermediary improvement (84% and 86%, respectively), and urinary incontinence showed the least improvement (84% and 80%, respectively). Fifty-three percent of patients required shunt revisions. Indications for revision included shunt malfunction (87%), infection (10%) and change of shunt configuration (3%). Overall, 74% revisions resulted in clinical improvement. <h3>Conclusions:</h3> Clinical improvement of patients with NPH can be sustained for 5–7 years in some patients with NPH, even if shunt revision surgery is needed multiple times. With earlier diagnosis and treatment of NPH and the increasing lifespan of the ageing population, the need for long-term follow-up after shunt surgery for NPH may be greater than it was in the past. Monitoring, identification and treatment of shunt obstruction is a key management principle.

The study design includes prospective evaluation of percutaneous osteosynthesis associated with cement kyphoplasty on 18 patients. The objective of the study is to assess the efficacy of a percutaneous method of treating burst vertebral fractures in patients without neurological deficits. Even if burst fractures are frequent, no therapeutic agreement is available at the moment. We report in this study the results at 2 years with a percutaneous approach for the treatment of burst fractures. 18 patients were included in this study. All the patients had burst vertebral fractures classified type A3 on the Magerl scale, between levels T9 and L2. The patients' mean age was 53 years (range 22–78 years) and the neurological examination was normal. A percutaneous approach was systematically used and a kyphoplasty was performed via the transpedicular pathway associated with percutaneous short-segment pedicle screw osteosynthesis. The patients' follow-up included CT scan analysis, measurement of vertebral height recovery and local kyphosis, and clinical pain assessments. With this surgical approach, the mean vertebral height was improved by 25% and a mean improvement of 11.28° in the local kyphotic angle was obtained. 3 months after the operation, none of the patients were taking class II analgesics. The mean duration of their hospital stay was 4.5 days (range 3–7 days) and the mean follow-up period was 26 months (range 17–30 months). No significant changes in the results obtained were observed at the end of the follow-up period. Minimally invasive methods of treating burst vertebral fractures can be performed via the percutaneous pathway. This approach gives similar vertebral height recovery and kyphosis correction rates to those obtained with open surgery. It provides a short hospital stay, however, and might therefore constitute a useful alternative to open surgical methods.

Ependymomas are rare CNS tumors. Previous studies describing the clinical course of ependymoma patients were restricted to small sample sizes, often with patients at a specific institution.Clinically annotated ependymoma tissue samples from 19 institutions were centrally reviewed. Patients were all adults aged 18 years or older at the time of diagnosis. Potential prognostic clinical factors identified on univariate analysis were included in a multivariate Cox proportional hazards model with backwards selection to model progression-free survival.The 282 adult ependymoma patients were equally male and female with a mean age of 43 years (range, 18-80y) at diagnosis. The majority were grade II (78%) with the tumor grade for 20 cases being reclassified on central review (half to higher grade). Tumor locations were spine (46%), infratentorial (35%), and supratentorial (19%). Tumor recurrence occurred in 26% (n = 74) of patients with a median time to progression of 14 years. A multivariate Cox proportional hazards model identified supratentorial location (P < .01), grade III (anaplastic; P < .01), and subtotal resection, followed or not by radiation (P < .01), as significantly increasing risk of early progression.We report findings from an ongoing, multicenter collaboration from a collection of clinically annotated adult ependymoma tumor samples demonstrating distinct predictors of progression-free survival. This unique resource provides the opportunity to better define the clinical course of ependymoma for clinical and translational studies.

Pretherapeutic determination of tumor grade and genotype in grade II and III oligodendroglial tumors is clinically important but is still challenging. Tumor grade and 1p/19q status are currently the 2 most important factors in therapeutic decision making for patients with these tumors. Histopathology and cMRI studies are still limited in some cases. In the present study, we were interested in determining whether the combination of PWI, DWI, and MR spectroscopy could help distinguish oligodendroglial tumors according to their histopathologic grade and genotype.We retrospectively reviewed 50 adult patients with grade II and III oligodendrogliomas and oligoastrocytomas who had DWI, PWI, and MR spectroscopy at short and long TE data and known 1p/19q status. Univariate analyses and multivariate random forest models were performed to determine which criteria could differentiate between grades and genotypes.ADC, rCBV, rCBF, and rK2 were significantly different between grade II and III oligodendroglial tumors. DWI, PWI, and MR spectroscopy showed no significant difference between tumors with and without 1p/19q loss. Separation between tumor grades and genotypes with cMRI alone showed 31% and 48% misclassification rates, respectively. Multimodal MR imaging helps to determine tumor grade and 1p/19q genotype more accurately (misclassification rates of 17% and 40%, respectively).Although multimodal investigation of oligodendroglial tumors has a lower contribution to 1p/19q genotyping compared with cMRI alone, it greatly improves the accuracy of grading of these neoplasms. Use of multimodal MR imaging could thus provide valuable information that may assist clinicians in patient preoperative management and treatment decision making.

Abstract Brain metastases are devastating complications of cancer. The blood–brain barrier (BBB), which protects the normal brain, morphs into an inadequately characterized blood–tumor barrier (BTB) when brain metastases form, and is surrounded by a neuroinflammatory response. These structures contribute to poor therapeutic efficacy by limiting drug uptake. Here, we report that experimental breast cancer brain metastases of low- and high permeability to a dextran dye exhibit distinct microenvironmental gene expression patterns. Astrocytic sphingosine-1 phosphate receptor 3 (S1P3) is upregulated in the neuroinflammatory response of the highly permeable lesions, and is expressed in patients’ brain metastases. S1P3 inhibition functionally tightens the BTB in vitro and in vivo. S1P3 mediates its effects on BTB permeability through astrocytic secretion of IL-6 and CCL2, which relaxes endothelial cell adhesion. Tumor cell overexpression of S1P3 mimics this pathway, enhancing IL-6 and CCL-2 production and elevating BTB permeability. In conclusion, neuroinflammatory astrocytic S1P3 modulates BTB permeability.

Introduction: Radionecrosis (RN) represents the main complication of stereotactic radiotherapy (SRT) for brain metastases. It may be observed in up to 34% of cases at 24 months after treatment and associated with significant morbidity in 10-17%.Areas covered: Our aim is to discuss the results of original studies on RN related to SRT for brain metastases.Expert commentary: Although the development of RN is unpredictable, larger volume of the lesion, prior whole brain irradiation, and higher dose of radiation represent the major risk factors. RN appears on MRI as contrast-enhancing necrotic lesions, surrounded by edema, occurring at least 3 months after SRT, localized within fields of irradiation. No firm criteria are established. Surgery can provide symptomatic relief but is associated with a risk of complications. Corticosteroids are considered the standard of care treatment, despite limited efficacy and many adverse effects. Bevacizumab represents another interesting option that needs to be validated.

The role of Gamma Knife surgery in the field of functional surgery recently has evolved dramatically. For treatment of trigeminal neuralgia, Gamma Knife surgery is the least invasive procedure, with a low rate of hypesthesia. If a rate of complete relief similar to that of other surgical techniques could be achieved, this approach will become one of the main techniques used to treat the disease initially. The authors present their experience with a group of 16 patients with mesial temporal lobe epilepsy who have been treated successfully (15 completely seizure-free and 1 with rare, nondisabling seizures) without significant complication. After additional follow-up to demonstrate the absence of long-term consequences, this fascinating new approach could change epilepsy surgery practice dramatically.

Ependymomas account for 2% of all intracranial tumours in adults. Considerable controversy continues to exist with regard to their prognostic factors and therapeutic management due to the rarity and the heterogeneity of series reported so far. The authors report a retrospective study of a homogenous population of 152 adult patients harbouring intracranial ependymomas from 24 French Neurosurgical Centres between 1990 and 2004. All clinico-radiological and follow-up data were analysed and a central pathologic review was performed by two confirmed neuropathologists. The 5- and 10-year overall survival rates were 84.8 and 76.5%, respectively; the 5- and 10-year progression-free survival rates were 63.5 and 52.8%, respectively. On multivariate analysis, overall survival rates were associated with histological grade (P < 0.001), extent of surgery (P = 0.006), patient age (P = 0.004) and patient Karnofski performance status (P = 0.03). The multivariate analysis also revealed that the risk of recurrence was associated with high histological grade (P < 0.001), incomplete resection (P < 0.001) and Karnofski performance status < or = 80 (P = 0.04). The impact of radiotherapy was found to be beneficial for incompletely resected low-grade ependymomas and to a lesser extent for completely removed high-grade tumours. In association with Karnofski performance status and extent of surgery, histological grade is a major prognostic factor in adult intracranial ependymomas. The application of a simple and reproducible grading scheme using objective anaplastic criteria seems useful practically and clinically applicable. The role of adjuvant radiotherapy for patients with incompletely resected low-grade ependymomas seems to be beneficial but remains to be addressed for high-grade tumours.

Glioblastoma multiforme (GBM) is the most aggressive and frequent brain tumor, albeit without cure. Although patient survival is limited to one year on average, significant variability in outcome is observed. The assessment of biomarkers is needed to gain better knowledge of this type of tumor, help prognosis, design and evaluate therapies. The neurodevelopmental polysialic acid neural cell adhesion molecule (PSA-NCAM) protein is overexpressed in various cancers. Here, we studied its expression in GBM and evaluated its prognosis value for overall survival (OS) and disease free survival (DFS). We set up a specific and sensitive enzyme linked immunosorbent assay (ELISA) test for PSA-NCAM quantification, which correlated well with PSA-NCAM semi quantitative analysis by immunohistochemistry, and thus provides an accurate quantitative measurement of PSA-NCAM content for the 56 GBM biopsies analyzed. For statistics, the Spearman correlation coefficient was used to evaluate the consistency between the immunohistochemistry and ELISA data. Patients' survival was estimated by using the Kaplan-Meier method, and curves were compared using the log-rank test. On multivariate analysis, the effect of potential risk factors on the DFS and OS were evaluated using the cox regression proportional hazard models. The threshold for statistical significance was p = 0.05. We showed that PSA-NCAM was expressed by approximately two thirds of the GBM at variable levels. On univariate analysis, PSA-NCAM content was an adverse prognosis factor for both OS (p = 0.04) and DFS (p = 0.0017). On multivariate analysis, PSA-NCAM expression was an independent negative predictor of OS (p = 0.046) and DFS (p = 0.007). Furthermore, in glioma cell lines, PSA-NCAM level expression was correlated to the one of olig2, a transcription factor required for gliomagenesis. PSA-NCAM represents a valuable biomarker for the prognosis of GBM patients.

Abstract Meningeal solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) are distinct entities in the World Health Organization (WHO) classification of central nervous system (CNS) tumors while they belong to the same spectrum of tumors in other locations. Well‐defined histological prognostic factors are also lacking for these tumors. In order to clarify the relationship between SFT and HPC and to find histological and immunohistochemical prognostic factors, we carried out a retrospective study in 89 patients. The following histological parameters were recorded: hypercellularity, collagenic areas, cytonuclear atypias, necrosis, mitotic count per 10 high‐power fields, vasculo‐nervous adherences defined by engulfment of vessel or nerve by the tumor, brain infiltration. We found overlapping histological and immunohistochemical features between SFT and HPC. The most relevant histological prognostic factors in the whole cohort for both progression‐free survival (PFS) and overall survival (OS) in univariate analysis were hypercellularity, high mitotic count (&gt;5 per 10 high‐power fields) and necrosis. On the basis of these results, we propose a new grading scheme for these tumors which was of pronostic value for both PFS and OS in uni‐ and multivariate analysis. As extent of surgery was also a prognostic factor for both PFS and OS in univariate analysis, we propose that management of SFT/HPC might be based both on quality of removal and histological grade.

Abstract BACKGROUND: O 6 ‐methylguanine‐DNA methyltransferase (MGMT) is a key enzyme in the DNA repair process after alkylating agent action. Epigenetic silencing of the MGMT gene by promoter methylation has been associated with longer survival in patients with newly diagnosed glioblastoma multiforme (GBM) who receive alkylating agents. In this study, the authors evaluated the prognostic value of different biomarkers in recurrent GBM and analyzed the changes in MGMT status between primary tumors and recurrent tumors. METHODS: Twenty‐two patients who had recurrent GBM and who underwent surgery with carmustine wafer implantation were enrolled prospectively between 2005 and 2007. The authors investigated the correlation between MGMT silencing in the tumor at recurrence and survival taking into account other clinically recognized prognostic factors. MGMT status was determined by using methylation‐specific polymerase chain reaction analysis, a high‐throughput quantitative methylation assay, and immunohistochemistry. In addition, expression analyses of human mutL homolog 1, human mutS homolog 2, and tumor necrosis factor α‐induced protein 3 at recurrence were conducted with regard to their prognostic impact. RESULTS: The median progression‐free survival (PFS) and overall survival (OS) rates after recurrence were 3.6 months and 9.9 months, respectively, and the 6‐month PFS rate after recurrence was 27.2%. On multivariate analysis, only age ( P = .04) and MGMT promoter hypermethylation at recurrence, as determined by MethyLight technology ( P = .0012) and methylation‐specific polymerase chain reaction (MSP) analysis ( P = .004), were correlated with better PFS. On multivariate analysis, only MGMT promoter hypermethylation at recurrence, as determined by using MethyLight technology ( P = .019) and MSP analysis ( P = .046), was associated with better OS. CONCLUSIONS: MGMT methylation status was an important prognostic factor in patients with recurrent GBM who underwent surgery plus carmustine wafer implantation; therefore, it was useful in predicting the outcome of GBM therapy at recurrence. Cancer 2009. © 2009 American Cancer Society.

Prognosis of recurrent high-grade glioma (HGG) is poor, although bevacizumab has been documented in that context. This study aimed to determine the independent prognostic value of fluorodeoxyglucose (FDG)-PET on progression-free survival (PFS) and overall survival (OS) of recurrent HGG after combined treatment with bevacizumab and irinotecan, compared with other documented prognostic variables. Twenty-five adult patients with histologically proven HGG were included at recurrence. Brain FDG-PET imaging was performed within 6 weeks of starting chemotherapy with bevacizumab and irinotecan. Response based on MRI was assessed every 2 months according to revised assessment in Neuro-Oncology (RANO) criteria. Median PFS and OS were 4 months (range, 0.9-10.4 months) and 7.2 months (range, 1.2-41.7 months), respectively. At 6 months, PFS and OS rate were 16.0% and 72.0%. FDG uptake was the most powerful predictor of both PFS and OS, using either univariate or multivariate analysis, among all variables tested: histological grade, Karnofsky performance status, steroid intake, and number of previous treatments. Moreover, FDG uptake was also prognostic of response to bevacizumab-based therapy. This study provides the first evidence that pretreatment FDG-PET can serve as an imaging biomarker in recurrent HGG for predicting survival following anti-angiogenic therapy with bevacizumab.

Clear cell ependymoma is one of the 4 main histological subtypes of ependymomas defined by the World Health Organization (WHO) classification of tumors of the CNS. DNA methylation profiling can distinguish 4 subgroups of intracranial ependymomas, including supratentorial (ST) ependymomas with Yes-associated protein 1 fusion (YAP1), ST ependymomas with fusion of v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), posterior fossa ependymomas with balanced genome, and posterior fossa ependymomas with chromosomal instability. In addition, trisomy 19 is a genomic hallmark of ependymomas with rich branching capillaries. However, the relation of histological and molecular subtypes is unclear.Here, we report a series of 20 ependymomas histologically defined by clear cells and branching capillaries.We observed a strong male predominance. Median age at surgery was 10.4 years (range, 0.8-68.4). All cases were ST, cortical, contrast enhancing, and most often frontal, cystic, and calcified. All tumors qualified as WHO grade III. Some of them exhibited neuronal differentiation. Trisomy 19 was recorded in 13 cases. All samples strongly accumulated p65RelA protein within nuclei, indicating pathological activation of the nuclear factor-kappaB pathway. We identified causative C11ORF95-RELA fusion in almost all cases. Median progression-free survival and overall survival were 11.4 years (95% CI: 5.1-17.8) and not reached, respectively.ST clear cell ependymomas with branching capillaries display characteristic clinicopathological features and are associated with pathological activation of nuclear factor-kappaB signaling, which may indicate a potential novel target for therapy in these patients.

Immunostimulating oligodeoxynucleotides containing unmethylated cytosine-guanosine motifs (CpG-ODN) have shown a promising efficacy in several cancer models when injected locally. A previous phase II study of CpG-ODN in patients with recurrent glioblastoma (GBM) has suggested some activity and has shown a limited toxicity. This multicentre single-blinded randomised phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with de novo glioblastomas.Patients with a newly diagnosed glioblastoma underwent large surgical resection and CpG-ODN was randomly administrated locally around the surgical cavity. The patients were then treated according to standard of care (SOC) with radiotherapy and temozolomide. The primary objective was 2-year survival. Secondary outcomes were progression free survival (PFS), and tolerance.Eighty-one (81) patients were randomly assigned to receive CpG-ODN plus SOC (39 patients) or SOC (42 patients). The 2-year overall survival was 31% (19%; 49%) in the CpG-ODN arm and 26% (16%; 44%) in the SOC arm. The median PFS was 9 months in the CpG-ODN arm and 8.5 months in the SOC arm. The incidence of adverse events was similar in both arms; although fever and post-operative haematoma were more frequent in the CpG-ODN arm.Local immunotherapy with CpG-ODN injected into the surgical cavity after tumour removal and followed by SOC, although well tolerated, does not improve survival of patients with newly diagnosed GBM.

The standard of care for newly diagnosed glioblastoma is maximal safe surgical resection, followed by chemoradiation therapy. We assessed carmustine wafer implantation efficacy and safety when used in combination with standard care.Included were adult patients with (n = 354, implantation group) and without (n = 433, standard group) carmustine wafer implantation during first surgical resection followed by chemoradiation standard protocol. Multivariate and case-matched analyses (controlled propensity-matched cohort, 262 pairs of patients) were conducted.The median progression-free survival was 12.0 months (95% CI: 10.7-12.6) in the implantation group and 10.0 months (9.0-10.0) in the standard group and the median overall survival was 20.4 months (19.0-22.7) and 18.0 months (17.0-19.0), respectively. Carmustine wafer implantation was independently associated with longer progression-free survival in patients with subtotal/total surgical resection in the whole series (adjusted hazard ratio [HR], 0.76 [95% CI: 0.63-0.92], P = .005) and after propensity matching (HR, 0.74 [95% CI: 0.60-0.92], P = .008), whereas no significant difference was found for overall survival (HR, 0.95 [0.80-1.13], P = .574; HR, 1.06 [0.87-1.29], P = .561, respectively). Surgical resection at progression whether alone or combined with carmustine wafer implantation was independently associated with longer overall survival in the whole series (HR, 0.58 [0.44-0.76], P < .0001; HR, 0.54 [0.41-0.70], P < .0001, respectively) and after propensity matching (HR, 0.56 [95% CI: 0.40-0.78], P < .0001; HR, 0.46 [95% CI: 0.33-0.64], P < .0001, respectively). The higher postoperative infection rate in the implantation group did not affect survival.Carmustine wafer implantation during surgical resection followed by the standard chemoradiation protocol for newly diagnosed glioblastoma in adults resulted in a significant progression-free survival benefit.

Background: Lung cancer is the leading cause of brain metastases (BM). The identification of driver oncogenes and matched targeted therapies has improved outcome in non-small cell lung cancer (NSCLC) patients; however, a better understanding of BM molecular biology is needed to further drive the process in this field. Methods: In this observational study, stage IV NSCLC patients tested for EGFR and KRAS mutations were selected, and BM incidence, recurrence and patients' outcome were assessed. Results: A total of 144 patients (142 Caucasian and two Asian) were selected, including 11.27% with EGFR-mutant and 33.10% with KRAS-mutant tumors, and 57.04% patients had developed BM. BM incidence was more frequent in patients with EGFR mutation according to multivariate analyses (MVA) (Odds ratio OR = 8.745 [1.743–43.881], p = 0.008). Among patients with treated BM, recurrence after local treatment was less frequent in patients with KRAS mutation (OR = 0.234 [0.078–0.699], p = 0.009). Among patients with untreated BM, overall survival (OS) was shorter for patients with KRAS mutation according to univariate analysis (OR = 7.130 [1.240–41.012], p = 0.028), but not MVA. Conclusions: EGFR and KRAS mutations have a predictive role on BM incidence, recurrence and outcome in Caucasian NSCLC patients. These results may impact the routine management of disease in these patients. Further studies are required to assess the influence of other biomarkers on NSCLC BM.

Since 2017, we have used IonTorrent NGS platform in our hospital to diagnose and treat cancer. Analyzing variants at each run requires considerable time, and we are still struggling with some variants that appear correct on the metrics at first, but are found to be negative upon further investigation. Can any machine learning algorithm (ML) help us classify NGS variants? This has led us to investigate which ML can fit our NGS data and to develop a tool that can be routinely implemented to help biologists. Currently, one of the greatest challenges in medicine is processing a significant quantity of data. This is particularly true in molecular biology with the advantage of next-generation sequencing (NGS) for profiling and identifying molecular tumors and their treatment. In addition to bioinformatics pipelines, artificial intelligence (AI) can be valuable in helping to analyze mutation variants. Generating sequencing data from patient DNA samples has become easy to perform in clinical trials. However, analyzing the massive quantities of genomic or transcriptomic data and extracting the key biomarkers associated with a clinical response to a specific therapy requires a formidable combination of scientific expertise, biomolecular skills and a panel of bioinformatic and biostatistic tools, in which artificial intelligence is now successful in developing future routine diagnostics. However, cancer genome complexity and technical artifacts make identifying real variants challenging. We present a machine learning method for classifying pathogenic single nucleotide variants (SNVs), single nucleotide polymorphisms (SNPs), multiple nucleotide variants (MNVs), insertions, and deletions detected by NGS from different types of tumor specimens, such as: colorectal, melanoma, lung and glioma cancer. We compared our NGS data to different machine learning algorithms using the k-fold cross-validation method and to neural networks (deep learning) to measure the performance of the different ML algorithms and determine which one is a valid model for confirming NGS variant calls in cancer diagnosis. We trained our machine learning with 70% of our data samples, extracted from our local database (our data structure had 7 parameters: chromosome, position, exon, variant allele frequency, minor allele frequency, coverage and protein description) and validated it with the 30% remaining data. The model offering the best accuracy was chosen and implemented in the NGS analysis routine. Artificial intelligence was developed with the R script language version 3.6.0. We trained our model on 70% of 102,011 variants. Our best error rate (0.22%) was found with random forest machine learning (ntree = 500 and mtry = 4), with an AUC of 0.99. Neural networks achieved some good scores. The final trained model with the neural network achieved an accuracy of 98% and an ROC-AUC of 0.99 with validation data. We tested our RF model to interpret more than 2000 variants from our NGS database: 20 variants were misclassified (error rate < 1%). The errors were nomenclature problems and false positives. After adding false positives to our training database and implementing our RF model routinely, our error rate was always < 0.5%. The RF model shows excellent results for oncosomatic NGS interpretation and can easily be implemented in other molecular biology laboratories. AI is becoming increasingly important in molecular biomedical analysis and can be very helpful in processing medical data. Neural networks show a good capacity in variant classification, and in the future, they may be useful in predicting more complex variants.

OBJECTIVE This is a retrospective study of 18 patients harboring a solitary fibrous tumor of the central nervous system. Therapeutic management and outcome were analyzed. METHODS Between 1999 and 2004, 18 patients harboring central nervous system solitary fibrous tumors were surgically treated at our two institutions. There were nine men and nine women. The patient ages ranged from 33 to 75 years, with a median age of 56.1 years. The locations were spinal in six cases (33.3%), the posterior fossa in six cases (33.3%), supratentorial in four cases (22.2%), and orbital in two cases (11.2%). RESULTS The median follow-up period was 45.3 months. Gross total resection was achieved in 10 cases (55.6%); tumor recurrence or progression occurred in nine cases (50%). Incomplete surgical resection was significantly associated with recurrence (P = 0.018). On univariate analysis, extent of surgery was also associated with a longer progression-free survival (P = 0.05). No statistically significant correlation can be found between histological features and recurrence. CONCLUSION Prognosis of solitary fibrous tumors of the central nervous system remains unclear; consequently, careful and close monitoring of patients and long-term follow-up are mandatory. Radical surgical excision seems to be a significant and reliable prognosis factor, although pathological prognostic features must be defined. In other respects, the role of postoperative radiotherapy in atypical or incompletely resected solitary fibrous tumors of the central nervous system remains to be determined and, therefore, warrants larger series with longer follow-up periods.

Brainstem metastasis is an uncommon complication of systemic cancer, generally considered to have a highly unfavorable prognosis. Surgical risks are high and standard radiation or chemotherapy have little effect. The purpose of this study is to evaluate our experience using Gamma Knife radiosurgery (GKRS) for the management of brainstem metastasis.Between July 1992 and March 2001, we treated 28 patients with brainstem metastasis using GKRS. Lesions were located in the pons in 17 patients, midbrain in nine, and medulla oblongata in two. At time of the radiosurgery, eight patients presented with another supratentorial metastasis. The most frequent primary tumor site was the lung (13 cases) followed by the melanoma in four cases, the kidney in two, and other locations in six. Only six patients underwent fractionated whole-brain radiation therapy. Mean marginal radiation dose for GKRS was 19.6 Gy (range, 11-30). Mean maximum diameter was 17.2 mm (range, 10-30).No GKRS-related morbidity was observed. Local tumor control was achieved in 92% of patients. Twenty-six patients have died. Death was related to the progression of the brainstem lesion in two cases. Mean and median survival after GKRS were 10.2 and 12 months, respectively. Follow-up periods in the two surviving patients were 12 and 13 months.The results of this small series demonstrate that GKRS can be a valuable modality for safe and effective management of brain stem metastasis. Owing to the high risk of surgical resection and low efficacy of medical treatment, radiosurgery can be proposed upfront.

Ependymomas account for 2% of all intracranial tumors in adults. Considerable controversy continues to exist with regard to their prognostic factors and therapeutic management due to the rarity and the heterogeneity of series reported so far. The authors report a retrospective study of a homogenous population of 114 adult patients harboring WHO grade II intracranial ependymomas from 32 French Neurosurgical Centers between 1990 and 2004. All clinico-radiological and follow-up data were analyzed, and a central pathologic review was performed by two confirmed neuropathologists. The 5- and 10-year overall survival (OS) rates were 86.1% and 81.0%, respectively; the 5- and 10-year progression-free survival (PFS) rates were 74.6% and 58.9%, respectively. On multivariate analysis, the OS rates were associated with preoperative KPS score (P = .027), extent of surgery (P = .008), and tumor location (supratentorial vs infratentorial, P = .012). The multivariate analysis also revealed that the risk of recurrence was associated with incomplete resection (P = .001) and supratentotrial location (P = .038). Moreover, adjuvant radiotherapy (RT) for patients with incompletely resected tumors is responsible for a significant improvement of both overall (P = .005) and progression-free (P = .002) survival. This study clearly supports the major prognostic impact of the extent of surgery in WHO grade II. Interestingly, tumor location also seems to have an actual impact on both OS and PFS. Finally, the prognostic impact of RT was found to be beneficial for incompletely resected tumors.

Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through calcitonin receptor-like receptor/receptor activity modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). Previously, we reported on the development of an anti-AM antibody that potently inhibits tumor cell proliferation in vitro and tumor growth in vivo. Here, we report the effect of anti-AM receptor antibodies (alphaAMRs) on angiogenesis and tumor growth. We demonstrate that alphaAMRs decrease in a dose-dependent manner the growth of U87 glioblastoma cells and HT-29 colorectal cancer cells, but not A549 lung cancer cells, in vitro. In vivo, AM in Matrigel plugs induces angiogenesis by promoting recruitment of endothelial cells, pericytes, myeloid precursor cells, and macrophages and by promoting channel formation. Remarkably, systemic administration of alphaAMRs every 3 d markedly reduced neovascularization of Matrigel plugs in a dose-dependent fashion, as demonstrated by reduced numbers of the recruited cells and vessel structures. Several human tumor xenografts in athymic mice were used to examine the effect of alphaAMR treatment on tumor angiogenesis and growth. AlphaAMR treatment significantly suppressed the growth of glioblastoma, lung, and colon tumors. Histological examination of alphaAMR-treated tumors showed evidence of disruption of tumor vascularity with decreased microvessel density, depletion of endothelial and pericyte cells, and increased tumor cell apoptosis. These findings support the conclusion that alphaAMR treatment inhibits tumor growth by suppression of angiogenesis and tumor growth and suggest that AMRs may be useful therapeutic targets.

Identification of new drugs and predicting drug response are major challenges in oncology, especially for brain tumors, because total surgical resection is difficult and radiation therapy or chemotherapy is often ineffective. With the aim of developing a culture system close to in vivo conditions for testing new drugs, we characterized an ex vivo three-dimensional culture system based on a hyaluronic acid-rich hydrogel and compared it with classical two-dimensional culture conditions. U87-MG glioblastoma cells and seven primary cell cultures of human glioblastomas were subjected to radiation therapy and chemotherapy drugs. It appears that 3D hydrogel preserves the original cancer growth behavior and enables assessment of the sensitivity of malignant gliomas to radiation and drugs with regard to inter-tumoral heterogeneity of therapeutic response. It could be used for preclinical assessment of new therapies.

A predictive marker of bevacizumab activity is an unmet medical need. We evaluated the predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent high-grade glioma treated with bevacizumab.Analyzed in plasma were a set of 11 prebiomakers of interest (vascular endothelial growth factor receptor [VEGF]; VEGF receptor 2; basic fibroblast growth factor; stromal cell derived factor 1; placenta growth factor; urokinase-type plasminogen activator; plasminogen activator inhibitor 1; matrix metalloproteinases 2, 7, and 9; and adrenomedulline), using ELISA, at baseline and 2 weeks after bevacizumab initiation in a prospective cohort of 26 patients (Cohort 1). Correlations were validated in a separate retrospective cohort (Cohort 2; n = 50) and tested in cohort patients treated with cytotoxic agents without bevacizumab (Cohort 3; n = 34). Dosages were correlated to objective response, progression-free survival (PFS), and overall survival (OS).In Cohort 1, high MMP2 baseline level was associated with a probability of objective response of 83.3% versus 15.4% for low MMP2 level (P = .001). In multivariate analysis, baseline level of MMP2 correlated with PFS (hazard ratio, 3.92; 95% confidence interval [CI]:1.46-10.52; P = .007) and OS (hazard ratio, 4.62; 95% CI: 1.58-13.53; P = .005), as decrease of VEGF (P = .038 for PFS and P = .013 for OS) and MMP9 (P = .016 for PFS and P = .025 for OS). In Cohort 2, MMP2, but not MMP9, confirmed its predictive significance. In Cohort 3, no association was found between MMP2, MMP9, and outcome.In patients with recurrent high-grade glioma treated with bevacizumab, but not with cytotoxic agent, high MMP2 plasma levels are associated with prolonged tumor control and survival. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role reassessed.

Angiogenesis is one of the key features of glioblastoma (GBM).Our objective was to explore the potential changes of angiogenic factors in GBM between initial diagnosis and recurrence after radiotherapy-temozolomide (RT/TMZ).Paired frozen tumors from both initial and recurrent surgery were available for 29 patients.Screening of genes expressions related to angiogenesis was performed using RT-PCR arrays on 10 first patients.Next, RNA expressions of the selected genes were analyzed on all samples.Protein expression was examined by immunohistochemistry.The anti-tumor effect of AMD3100 (anti-CXCR4) was tested in GBM explants.In the screening step, the initial-recurrence expression changes contributed to a selection of seven genes (VEGFA, VEGFR2, VEGFR1, CXCL12, CXCR4, uPA HIF1α).By quantitative RT-PCR, RNA expressions of CXCR4 (p = 0.029) and CXCL12 (p = 0.107) were increased while expressions of HIF1α (p = 0.009) and VEGFR2 (p = 0.081) were decreased at recurrence.Similarly, CXCL12 protein expression tended to increase (p = 0.096) while VEGFR2 staining was decreased (p = 0.004) at recurrence.An increase of anti-tumoral effect was observed with the combination of AMD3100 and RT/TMZ versus RT/TMZ alone in GB explants.Recurrence of GB after chemoradiation could be associated with a switch of angiogenic pattern from VEGFR2-HIF1α to CXCL12-CXCR4 pathway, leading to new perspectives in angiogenic treatment.

Meningeal solitary fibrous tumors-hemangiopericytomas (SFT-HPC) and meningiomas can be difficult to distinguish on histologic examination. STAT6 immunohistochemistry (IHC) is a reliable diagnostic marker of SFT-HPCs. Recently, GRIA2 has also been reported to be a diagnostic marker of SFT-HPC, although no extensive data are available for meningeal SFT-HPCs yet. The aim of this study was to test their diagnostic performance in a large cohort of SFT-HPCs and meningiomas. IHC analyses for GRIA2 and STAT6 were performed on tissue microarrays containing 76 SFT-HPCs and 181 meningiomas. Results were compared with previous data with ALDH1 and CD34. Two different anti-STAT6 antibodies were tested: SC-20 polyclonal and YE361 monoclonal antibody. Ninety-six percent of meningeal SFT-HPCs but no meningioma displayed nuclear STAT6 positivity. With SC-20 antibody, concomitant cytoplasmic staining for STAT6 was observed in >50% of all cases, including meningiomas. However, using YE361 antibody, cytoplasmic staining was absent, and nuclear signal intensity was stronger leading to better interpretation of STAT6 IHC. GRIA2 was positive in 84% of SFT-HPCs and in 16% of meningiomas. STAT6 had excellent sensitivity (96%) and specificity (100%), ALDH1 and GRIA2 had same sensitivity (84%), but ALDH1 and CD34 had better specificity than GRIA2 (97% and 96% vs. 84%, respectively). For the differential diagnosis of SFT-HPCs versus meningiomas, the best diagnostic approach is to perform STAT6, followed by ALDH1 and CD34 in the case of uncommon STAT6-negative cases. Because of meningioma positivity, GRIA2 seems less useful in this indication.

To specify that postoperative radiotherapy is useful for preventing local recurrence and neuraxis recurrence of surgically treated meningeal hemangiopericytomas.We retrospectively studied 21 patients with meningeal hemangiopericytoma who were followed in our department during a 34-year period. In 17 patients, the meningeal hemangiopericytoma was intracranial, and in 4 there was an intradural extramedullary localization. These groups were studied separately.Of the 17 patients with intracranial hemangiopericytoma, all underwent surgery; 8 also underwent radiotherapy (5,000-6,400 rads) (Group I), and 9 did not (Group II). The mortality rate was zero for Group I patients and 55% for Group II. The mean local recurrence rate was 52% (12.5% in Group I and 88% in Group II; P < 0.05). Neuraxis recurrences occurred in two patients in Group II, and none occurred in Group I (P = 0.4). Peripheral metastasis took place in two patients (22%) in Group II and in one patient (12.5%) in Group I (P = 0.5). Of the four patients with intradural extramedullary hemangiopericytoma, all underwent surgery. Two patients received 4000 rads of radiotherapy after intervention. No patient in this group had a recurrence.For patients with intracranial meningeal hemangiopericytoma, surgical removal followed by external radiotherapy reduced the risk of local recurrence. It was not demonstrated that postoperative radiotherapy protected against neuraxis metastasis. Radiotherapy did not protect against peripheral metastasis, which can occur up to several years after the first operation. It appears that radiotherapy after surgery for local or neuraxis recurrence did not avoid further recurrence. Radiosurgery is indicated for recurrent tumors measuring less than 25 mm in greatest diameter. For intradural extramedullary localizations, the value of postoperative radiotherapy is more questionable.

Abstract OBJECTIVE We report the long-term follow-up of 31 patients with cavernous sinus meningiomas who were treated either with surgery and radiotherapy (RT) or with RT alone. This retrospective review was undertaken to compare long-term efficacy and morbidity of RT with or without previous surgery versus complete, aggressive surgical removal. METHODS Between 1980 and 1997, we performed a retrospective study of 31 patients harboring cavernous sinus meningiomas. The patient group comprised 25 women and 6 men. Patients were divided into two therapeutic categories: patients treated with surgery and RT (Group I, 17 patients) and patients treated with RT alone (Group II, 14 patients). Twenty-five patients (14 in Group I and 11 in Group II) were treated for primary tumors, and 6 patients (3 in Group I and 3 in Group II) were treated for recurrent disease. All three patients who were treated by RT alone at the time of recurrent disease had had previous surgery as initial treatment. Tumor control, treatment morbidity, and functional outcomes were evaluated for all patients. Twenty-eight patients were alive at the time of analysis, with a median follow-up period of 6.1 years. RESULTS The progression-free survival rate was 92.8% at 10-year follow-up. Only two patients exhibited tumor progression after initial treatment. One of the patients who experienced tumor regrowth 4 years after surgery and RT benefited from additional conventional external beam radiation, and this patient exhibited no evidence of tumor progression at the last follow-up examination 6 years later. Two patients experienced cranial nerve impairment after surgery, and no patients developed late radiation toxicity. Follow-up status as measured by the Karnofsky Performance Scale deteriorated in 7% of patients and was the same or improved in 93% of patients. CONCLUSION The results of combined surgery and RT or RT alone indicated a high rate of tumor control and a low risk of complications. Complete aggressive surgical removal of cavernous sinus meningiomas is associated with an increased incidence of morbidity and mortality and does not demonstrate a better rate of tumor control. Conventional external beam radiation seems to be an efficient and safe initial or adjuvant treatment of these lesions, and these findings should serve as a basis for evaluating new alternatives such as radiosurgery or stereotactic RT.

Ependymomas account for 2% of all intracranial tumors in adults. Supratentorial ependymomas are less common than their infratentorial counterparts. To the authors' knowledge to date, the predictive values of surgery, histology, and patient-related prognostic factors for these tumors remain unresolved. The authors report a series of adult patients with supratentorial ependymomas to characterize the roles of surgery and histology in tumor control.The authors retrospectively studied a homogenous population of 46 adult patients who had supratentorial ependymomas from 24 French neurosurgical centers between 1990 and 2004. All clinicoradiologic and follow-up data were analyzed, and a central pathologic review was performed by 2 certified neuropathologists.The mean (+/-standard error) 5- and 10-year overall survival rates for the entire population were 57.1% +/- 8.7% and 41.8% +/- 9.9%, respectively. The 5- and 10-year progression-free survival rates for the entire cohort were of 33.8% +/- 8.1% and 25.4 +/- 8%, respectively. On both univariate and multivariate analysis, age <55 years, greater extent of surgery, and lower histologic grade were associated with longer overall and progression-free survival. However, longer progression-free survival but was not considered a candidate variable for the multivariate model, because data were available for only 34 of 46 patients.In association with age and extent of surgery, histologic grade was identified as a major prognostic factor in adult supratentorial ependymomas. The application of a simple and reproducible grading scheme using objective anaplastic criteria appeared to be both useful practically and clinically applicable. The role of adjuvant radiotherapy for patients with incompletely resected, low-grade ependymomas needs to be investigated further.

Purpose To evaluate long-term outcome of cavernous sinus meningioma (CSM) treated with fractionated conformal radiotherapy (FCR). Patients and Methods Fifty-three patients with CSMs (16 men [30.2%], 37 women [69.8%], aged 53 ± 13.0 years [mean ± SD]) were treated by FCR. In 28 patients (52.8%) FCR was performed as first-line treatment and in 25 patients (47.2%) as adjuvant treatment. All patients received FCR with a dose of 52.9 ± 1.8 Gy in 29.4 ± 1.0 fractions over 6 weeks. Dose per fraction was 1.9 ± 0.1 Gy. Radiotherapy was delivered stereotactically in 47 cases (88.7%) and conformally in 6 (11.3%) Results The median follow-up was 6.9 years (range, 3–19 years). According to Sekhar's classification, 19 patients (35.8%) were Grade 1–2, 30 patients (56.6%) were Grade 3–4, and 4 patients (7.6%) were Grade 5. Pretreatment tumor volume was determined in 46 patients, and tumor volume was 12.6 ± 8.2 cm3. In these patients, the distance between tumor and optic apparatus was 1.62 ± 1.2 mm. Actuarial 5- and 10-year progression-free survival rates were 98.1% and 95.8%, respectively. Clinical improvement was observed in 31 patients (58.5%), and 20 patients (37.7%) remained unchanged. Radiologic response was observed in 18 patients (30.2%), and 35 patients (66.0%) showed stable lesions. Two patients (3.8%) showed tumor progression during follow-up. Transient morbidity was observed in 3 patients (5.7%) and permanent morbidity in 1 (1.9%). Conclusion Fractionated conformal radiotherapy affords satisfactory long-term tumor control and low treatment morbidity. To evaluate long-term outcome of cavernous sinus meningioma (CSM) treated with fractionated conformal radiotherapy (FCR). Fifty-three patients with CSMs (16 men [30.2%], 37 women [69.8%], aged 53 ± 13.0 years [mean ± SD]) were treated by FCR. In 28 patients (52.8%) FCR was performed as first-line treatment and in 25 patients (47.2%) as adjuvant treatment. All patients received FCR with a dose of 52.9 ± 1.8 Gy in 29.4 ± 1.0 fractions over 6 weeks. Dose per fraction was 1.9 ± 0.1 Gy. Radiotherapy was delivered stereotactically in 47 cases (88.7%) and conformally in 6 (11.3%) The median follow-up was 6.9 years (range, 3–19 years). According to Sekhar's classification, 19 patients (35.8%) were Grade 1–2, 30 patients (56.6%) were Grade 3–4, and 4 patients (7.6%) were Grade 5. Pretreatment tumor volume was determined in 46 patients, and tumor volume was 12.6 ± 8.2 cm3. In these patients, the distance between tumor and optic apparatus was 1.62 ± 1.2 mm. Actuarial 5- and 10-year progression-free survival rates were 98.1% and 95.8%, respectively. Clinical improvement was observed in 31 patients (58.5%), and 20 patients (37.7%) remained unchanged. Radiologic response was observed in 18 patients (30.2%), and 35 patients (66.0%) showed stable lesions. Two patients (3.8%) showed tumor progression during follow-up. Transient morbidity was observed in 3 patients (5.7%) and permanent morbidity in 1 (1.9%). Fractionated conformal radiotherapy affords satisfactory long-term tumor control and low treatment morbidity.

Purpose To provide the long-term outcomes of patients treated with fractionated conformal radiotherapy (FCRT) for presumed optic nerve sheath meningiomas (ONSMs). Patients and Methods Between 1995 and 2002, 9 patients with a presumed ONSM were treated with FCRT at our institution. The indications for FCRT were significant visual dysfunction at presentation, progression of visual dysfunction during a period of observation, tumor growth documented by sequential imaging, or a combination of these findings. In 2 patients, FCRT was performed as adjuvant therapy, and in 7, it was the initial and primary treatment. Results Of the 9 patients, 6 were women and 3 were men, with a mean age of 47 years. All 9 patients had evidence of optic nerve dysfunction in the affected eye, characterized by reduced visual acuity, a visual field defect, and a relative afferent pupillary defect. In addition, 2 patients had proptosis and 1 had diplopia. The mean follow-up period was 98 ± 31.7 months (median, 90; range, 61–151). After FCRT, the visual function improved in the 7 patients who had undergone FCRT as the primary treatment. However, 2 patients who were blind in their affected eye at FCRT remained blind. In 4 of the 7 patients with improvement, the improvement was documented within 1–3 months after FCRT. The tumor control rate was 100%. Proptosis and diplopia also regressed in 100% of patients. At 2 years after FCRT, 1 patient had developed radiation retinopathy. Conclusion The results of our study have shown that FCRT is a safe and effective treatment of ONSMs, affording satisfactory long-term tumor control, good functional outcome, and low treatment morbidity. FCRT should be considered the treatment of choice for patients with presumed ONSMs for whom the treatment has been deemed appropriate. To provide the long-term outcomes of patients treated with fractionated conformal radiotherapy (FCRT) for presumed optic nerve sheath meningiomas (ONSMs). Between 1995 and 2002, 9 patients with a presumed ONSM were treated with FCRT at our institution. The indications for FCRT were significant visual dysfunction at presentation, progression of visual dysfunction during a period of observation, tumor growth documented by sequential imaging, or a combination of these findings. In 2 patients, FCRT was performed as adjuvant therapy, and in 7, it was the initial and primary treatment. Of the 9 patients, 6 were women and 3 were men, with a mean age of 47 years. All 9 patients had evidence of optic nerve dysfunction in the affected eye, characterized by reduced visual acuity, a visual field defect, and a relative afferent pupillary defect. In addition, 2 patients had proptosis and 1 had diplopia. The mean follow-up period was 98 ± 31.7 months (median, 90; range, 61–151). After FCRT, the visual function improved in the 7 patients who had undergone FCRT as the primary treatment. However, 2 patients who were blind in their affected eye at FCRT remained blind. In 4 of the 7 patients with improvement, the improvement was documented within 1–3 months after FCRT. The tumor control rate was 100%. Proptosis and diplopia also regressed in 100% of patients. At 2 years after FCRT, 1 patient had developed radiation retinopathy. The results of our study have shown that FCRT is a safe and effective treatment of ONSMs, affording satisfactory long-term tumor control, good functional outcome, and low treatment morbidity. FCRT should be considered the treatment of choice for patients with presumed ONSMs for whom the treatment has been deemed appropriate.

We report 2 cases of suspected low-grade glioma with positive 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET scan, and histological diagnosis of brain inflammation corresponding to an acute disseminated encephalomyelitis (ADEM) and to a neurosarcoidosis. It has been shown that this amino-acid PET radiotracer serves to evaluate tumoral proliferation related to the metabolism of L-amino-acid transporters, and that inflammation may also contribute to the tumoral uptake. This report suggests it may serve to study brain inflammation.

Glioblastoma multiforme (GBM) is the most common primary brain tumor and is among the deadliest of human cancers. Dysregulation of microRNAs (miRNAs) expression is an important step in tumor progression as miRNAs can act as tumor suppressors or oncogenes and may affect cell sensitivity to chemotherapy. Whereas the oncogenic miR21 has been shown to be overexpressed in gliomas, the expression and function of the tumor-supressor miR200a in GBMs remains unknown. In this study, we show that miR21 is upregulated in grade IV (GBMs) vs. grade II–III (LGs) gliomas, confirming that miR21 expression level is correlated with tumor grade, and that it may be considered as a marker of tumor progression. Conversely, miR200a is demonstrated for the first time to be downregulated in GBMs compared with LGs, and overexpression of miR200a in GBM cells is shown to promote TMZ-sensitivity. Interestingly, miR200a but not miR21 expression level is significantly higher in TMZ-responsive vs. -unresponsive tumoral glial cells in primary culture. Furthermore, miR200a appears negatively correlated with the expression of the DNA repair enzyme O6-methylguanine methyltransferase (MGMT), and the inhibition of MGMT activity results in an increase of miR200a expression in GBM cells. Taken together, these data strongly suggest that miR200a is likely to act as a crucial antitumoral factor regarding glioma progression. Interplay between miR200a and MGMT should be considered as potential mechanism involved in therapeutic response.

Object. This study was directed to evaluate the potential role of gamma knife surgery (GKS) in the treatment of secondary trigeminal neuralgia (TN). The authors have identified three anatomicoclinical types of secondary TN requiring different radiosurgical approaches. Methods. Pain control was retrospectively analyzed in a population of patients harboring tumors of the middle or posterior fossa that involved the trigeminal nerve pathway. This series included 53 patients (39 women and 14 men) treated using GKS between July 1992 and June 1997. The median follow-up period was 55 months. Treatment strategies differed according to lesion type, topography, and size, as well as visibility of the fifth cranial nerve in the prepontine cistern. Three different treatment groups were established. When the primary goal was treatment of the lesion (Group IV, 46 patients) we obtained pain cessation in 79.5% of cases. In some patients in whom GKS was not indicated for treatment of the lesion, TN was treated by targeting the fifth nerve directly in the prepontine cistern if visible (Group II, three patients) or in the part of the lesion including this nerve if the nerve root could not be identified (Group III, four patients). No deaths and no radiosurgically induced adverse effects were observed, but in two cases there was slight hypesthesia (Group IV). The neuropathic component of the facial pain appeared to be poorly sensitive to radiosurgery. At the last follow-up examination, six patients (13.3%) exhibited recurrent pain, which was complete in four cases (8.8%) and partial in two (4.4%). Conclusions. The results of GKS regarding facial pain control are very similar to those achieved by microsurgery according to series published in the literature. Nevertheless, the low rate of morbidity and the greater comfort afforded the patient render GKS safer and thus more attractive.

Object The goal of this study was to evaluate the clinical and angiography results in 10 patients with transverse–sigmoid dural arteriovenous fistulas (DAVFs) treated using sinus angioplasty and dural sinus stent insertion. Methods Between 2001 and 2003, 10 consecutive patients (six men and four women, age range 54–79 years) who had presented with transverse and/or sigmoid sinus DAVFs with or without sinus thrombosis underwent self-expanding stent placement and balloon angioplasty. Eight fistulas involved the transverse sinus, three the sigmoid sinus, and one the torcular and occipital sinuses. According to the Djindjian-Merland grading system, there were two Type I, five Type IIa, one Type IIb, and two Type IV DAVFs. The mean clinical follow-up period was 21.1 months. At the last follow-up examination, seven patients were asymptomatic and three were dramatically improved. The mean angiography follow-up period was 7.5 months for the available population: four patients had complete DAVF occlusion, four had significant flow reduction, and two who experienced clinical improvement refused conventional angiography control studies. Delayed computerized tomography angiography scans were obtained to evaluate stent permeability in nine of the 10 patients. Stent permeability was demonstrated in eight of the nine patients with available control studies at a mean follow up of 20.8 months. There were two transient neurological deficits but no severe and permanent complications. Conclusions In this series, sinus stent insertion resulted in a cure or significant clinical improvement in all patients harboring a DAVF, with no severe or permanent complication. Stent placement for transverse and/or sigmoid sinus DAVFs is a promising technique whose viability should be confirmed in larger series with longer follow-up periods.

Solitary Fibrous Tumours (SFT) and haemangiopericytomas (HPC) are rare meningeal tumours that have to be distinguished from meningiomas and more rarely from synovial sarcomas. We recently found that ALDH1A1 was overexpressed in SFT and HPC as compared to soft tissue sarcomas. Using whole-genome DNA microarrays, we defined the gene expression profiles of 16 SFT/HPC (9 HPC and 7 SFT). Expression profiles were compared to publicly available expression profiles of additional SFT or HPC, meningiomas and synovial sarcomas. We also performed an immunohistochemical (IHC) study with anti-ALDH1 and anti-CD34 antibodies on Tissue Micro-Arrays including 38 SFT (25 meningeal and 13 extrameningeal), 55 meningeal haemangiopericytomas (24 grade II, 31 grade III), 163 meningiomas (86 grade I, 62 grade II, 15 grade III) and 98 genetically confirmed synovial sarcomas.ALDH1A1 gene was overexpressed in SFT/HPC, as compared to meningiomas and synovial sarcomas. These findings were confirmed at the protein level. 84% of the SFT and 85.4% of the HPC were positive with anti-ALDH1 antibody, while only 7.1% of synovial sarcomas and 1.2% of meningiomas showed consistent expression. Positivity was usually more diffuse in SFT/HPC compared to other tumours with more than 50% of tumour cells immunostained in 32% of SFT and 50.8% of HPC. ALDH1 was a sensitive and specific marker for the diagnosis of SFT (SE = 84%, SP = 98.8%) and HPC (SE = 84.5%, SP = 98.7%) of the meninges. In association with CD34, ALDH1 expression had a specificity and positive predictive value of 100%.We show that ALDH1, a stem cell marker, is an accurate diagnostic marker for SFT and HPC, which improves the diagnostic value of CD34. ALDH1 could also be a new therapeutic target for these tumours which are not sensitive to conventional chemotherapy.

To assess the influence of the time interval between surgical resection and standard combined chemoradiotherapy on survival in newly diagnosed and homogeneously treated (surgical resection plus standard combined chemoradiotherapy) glioblastoma patients; while controlling confounding factors (extent of resection, carmustine wafer implantation, functional status, neurological deficit, and postoperative complications).From 2005 to 2011, 692 adult patients (434 men; mean of 57.5 ± 10.8 years) with a newly diagnosed glioblastoma were enrolled in this retrospective multicentric study. All patients were treated by surgical resection (65.5% total/subtotal resection, 34.5% partial resection; 36.7% carmustine wafer implantation) followed by standard combined chemoradiotherapy (radiotherapy at a median dose of 60 Gy, with daily concomitant and adjuvant temozolomide). Time interval to standard combined chemoradiotherapy was analyzed as a continuous variable and as a dichotomized variable using median and quartiles thresholds. Multivariate analyses using Cox modeling were conducted.The median progression-free survival was 10.3 months (95% CI, 10.0-11.0). The median overall survival was 19.7 months (95% CI, 18.5-21.0). The median time to initiation of combined chemoradiotherapy was 1.5 months (25% quartile, 1.0; 75% quartile, 2.2; range, 0.1-9.0). On univariate and multivariate analyses, OS and PFS were not significantly influenced by time intervals to adjuvant treatments. On multivariate analysis, female gender, total/subtotal resection and RTOG-RPA classes 3 and 4 were significant independent predictors of improved OS.Delaying standard combined chemoradiotherapy following surgical resection of newly diagnosed glioblastoma in adult patients does not impact survival.

The current first-line treatment of malignant gliomas consists in surgical resection (if possible) as large as possible. The existing tools don’t permit to identify the limits of tumor infiltration, which goes beyond the zone of contrast enhancement on MRI. The fluorescence-guided malignant gliomas surgery was started 15 years ago and had become a standard of care in many countries. The technique is based on fluorescent molecule revelation using the filters, positioned within the surgical microscope. The fluorophore, protoporphyrin IX (PpIX), is converted in tumoral cells from 5-aminolevulinic acid (5-ALA), given orally before surgery. Many studies have shown that the ratio of gross total resections was higher if the fluorescence technique was used. The fluorescence signal intensity is correlated to the cell density and the PpIX concentration. The current method has a very high specificity but still lower sensibility, particularly regarding the zones with poor tumoral infiltration. This book reviews the principles of the technique and the results (extent of resection and survival).

Background Pleomorphic xanthoastrocytoma (PXA) is a rare, low-grade glioma that frequently occurs in pediatric patients. Objective To analyze adult patients diagnosed with PXA and to search for pathological and molecular markers of diagnosis and prognosis. Methods We retrospectively included patients older than 16 years with PXA who were referred to our institution between October 2003 and September 2013. All pathological diagnoses were reviewed by a neuropathologist. Histological characteristics and immunostaining of GFAP, OLIG2, neurofilament, CD34, Ki67, p53, p16, and IDH1 R132H were analyzed. The following molecular alterations were analyzed: mutations of IDH1/2, BRAF and the histone H3.3 and the EGFR amplification. Clinical data, treatment modalities, and patient outcome were recorded. Results We identified 16 adult patients with reviewed PXA diagnosis. No IDH neither histone H3.3 mutations were found; BRAF V600E mutation was recorded in six patients. Ten patients presented with anaplastic features. BRAF mutations were associated with lower Ki67, OLIG2 expression, and lack of p16 expression. Median PFS and OS were 41.5 months (95% CI: 11.4–71.6) and 71.4 months (95% CI: 15.5–127.3), respectively. BRAF mutation tended to be associated with greater PFS (p = 0.051), whereas anaplastic features were associated with minimal PFS (p = 0.042). Conclusion PXA in adults PXA may present features distinct from pediatric PXA. Anaplastic features and BRAF mutation may potentially identify specific subgroups with distinct prognoses.

Anaplastic gangliogliomas (GGGs) are rare tumors whose natural history is poorly documented. We aimed to define their clinical and imaging features and to identify prognostic factors. Consecutive cases of anaplastic GGGs in adults prospectively entered into the French Brain Tumor Database between March 2004 and April 2014 were screened. After diagnosis was confirmed by pathological review, clinical, imaging, therapeutic, and outcome data were collected retrospectively. Forty-three patients with anaplastic GGG (median age, 49.4 y) from 18 centers were included. Presenting symptoms were neurological deficit (37.2%), epileptic seizure (37.2%), or increased intracranial pressure (25.6%). Typical imaging findings were unifocal location (94.7%), contrast enhancement (88.1%), central necrosis (43.2%), and mass effect (47.6%). Therapeutic strategy included surgical resection (95.3%), adjuvant radiochemotherapy (48.8%), or radiotherapy alone (27.9%). Median progression-free survival (PFS) and overall survival (OS) were 8.0 and 24.7 months, respectively. Three- and 5-year tumor recurrence rates were 69% and 100%, respectively. The 5-year survival rate was 24.9%. Considering unadjusted significant prognostic factors, tumor midline crossing and frontal location were associated with shorter OS. Temporal and parietal locations were associated with longer and shorter PFS, respectively. None of these factors remained statistically significant in multivariate analysis. We report a large series providing clinical, imaging, therapeutic, and prognostic features of adult patients treated for an intracerebral anaplastic GGG. Our results show that pathological diagnosis is difficult, that survivals are only slightly better than for glioblastomas, and that complete surgical resection followed with adjuvant chemoradiotherapy offers longer survival.

Improving the systemic treatment of brain metastases (BM) in primary breast cancer (PBC) is impaired by the lack of genomic characterization of BM. To estimate the concordance of DNA copy-number-alterations (CNAs), mutations, and actionable genetic alterations (AGAs) between paired samples, we performed whole-genome array-comparative-genomic-hybridization, and targeted-next-generation-sequencing on 14 clinical PBC–BM pairs. We found more CNAs, more mutations, and higher tumor mutational burden, and more AGAs in BM than in PBC; 92% of the pairs harbored at least one AGA in the BM not observed in the paired PBC. This concerned various therapeutic classes, including tyrosine-kinase-receptor-inhibitors, phosphatidylinositol 3-kinase/AKT/ mammalian Target of Rapamycin (PI3K/AKT/MTOR)-inhibitors, poly ADP ribose polymerase (PARP)-inhibitors, or cyclin-dependent kinase (CDK)-inhibitors. With regards to the PARP-inhibitors, the homologous recombination defect score was positive in 79% of BM, compared to 43% of PBC, discordant in 7 out of 14 pairs, and positive in the BM in 5 out of 14 cases. CDK-inhibitors were associated with the largest percentage of discordant AGA appearing in the BM. When considering the AGA with the highest clinical-evidence level, for each sample, 50% of the pairs harbored an AGA in the BM not detected or not retained from the analysis of the paired PBC. Thus, the profiling of BM provided a more reliable opportunity, than that of PBC, for diagnostic decision-making based on genomic analysis. Patients with BM deserve an investigation of several targeted therapies.

The incidence of brain metastases is increasing because of the use of new therapeutic agents, which allow an improvement of overall survival, but with only a poor penetration into the central nervous system brain barriers. The management of brain metastases has changed due to a better knowledge of immunohistochemical data and molecular biological data, the development of new surgical, radiotherapeutic approaches and improvement of systemic treatments. Most of the time, the prognosis is still limited to several months, nevertheless, prolonged survival may be now observed in some sub-groups of patients. The main prognostic factors include the type and subtype of the primitive, age, general status of the patient, number and location of brain metastases, extracerebral disease. The multidisciplinary discussion should take into account all of these parameters. We should notice also that treatments including surgery or radiotherapy may be proposed in a symptomatic goal in advanced phases of the disease underlying the multidisciplinary approach until late in the evolution of the disease. This article reports on the ANOCEF (French neuro-oncology association) guidelines. The management of brain metastases of breast cancers and lung cancers are discussed in the same chapter, while the management of melanoma brain metastases is reported in a separate chapter due to different responses to the brain radiotherapy.

Advances in drug treatments for brain metastases of breast cancer have improved progression-free survival but new, more efficacious strategies are needed. Most chemotherapeutic drugs infiltrate brain metastases by moving between brain capillary endothelial cells, paracellular distribution, resulting in heterogeneous distribution, lower than that of systemic metastases. Herein, we tested three well-known transcytotic pathways through brain capillary endothelial cells as potential avenues for drug access: transferrin receptor (TfR) peptide, low-density lipoprotein receptor 1 (LRP1) peptide, albumin. Each was far-red labeled, injected into two hematogenous models of brain metastases, circulated for two different times, and their uptake quantified in metastases and uninvolved (nonmetastatic) brain. Surprisingly, all three pathways demonstrated distinct distribution patterns in vivo. Two were suboptimal: TfR distributed to uninvolved brain but poorly in metastases, while LRP1 was poorly distributed. Albumin distributed to virtually all metastases in both model systems, significantly greater than in uninvolved brain (P < 0.0001). Further experiments revealed that albumin entered both macrometastases and micrometastases, the targets of treatment and prevention translational strategies. Albumin uptake into brain metastases was not correlated with the uptake of a paracellular probe (biocytin). We identified a novel mechanism of albumin endocytosis through the endothelia of brain metastases consistent with clathrin-independent endocytosis (CIE), involving the neonatal Fc receptor, galectin-3, and glycosphingolipids. Components of the CIE process were found on metastatic endothelial cells in human craniotomies. The data suggest a reconsideration of albumin as a translational mechanism for improved drug delivery to brain metastases and possibly other central nervous system (CNS) cancers.In conclusion, drug therapy for brain metastasis needs improvement. We surveyed three transcytotic pathways as potential delivery systems in brain-tropic models and found that albumin has optimal properties. Albumin used a novel endocytic mechanism.

Only one phase III prospective randomized study, published in 2006, has assessed the performance of 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery (FGS) for glioblastoma resection. The aim of the RESECT study was to compare the onco-functional results associated with 5-ALA fluorescence and with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care.This was a phase III prospective randomized single-blinded study, involving 21 French neurosurgical centers, comparing 5-ALA FGS with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care, including neuronavigation use and postoperative radiochemotherapy. Randomization was performed in a 1:1 ratio stratified by institution. 5-ALA (20 mg/kg) or placebo (ascorbic acid) was administered orally 3-5 hours before the incision. The primary endpoint was the rate of gross-total resection (GTR) blindly assessed by an independent committee. Patients without a confirmed pathological diagnosis of glioblastoma or with unavailable postoperative MRI studies were excluded from the per-protocol analysis.Between March 2013 and August 2016, a total of 171 patients were assigned to the 5-ALA fluorescence group (n = 88) or to the placebo group (n = 83). Twenty-four cases were excluded because the WHO histological criteria of grade 4 glioma were not met. The proportion of GTR was significantly higher in the 5-ALA fluorescence group (53/67, 79.1%) than in the placebo group (33/69, 47.8%; p = 0.0002). After adjustment for age, preoperative Karnofsky Performance Scale score, and tumor location, GTR was still associated with 5-ALA fluorescence (OR 4.13 [95% CI 1.94-8.79]). The mean 7-day postoperative Karnofsky Performance Scale score (≥ 80% in 49/71, 69.0% [5-ALA group]; 50/71, 70.4% [placebo group], p = 0.86) and the proportion of patients with a worsened neurological status 3 months postoperatively (9/68, 13.2% [5-ALA group]; 9/70, 12.9% [placebo group], p = 0.95) were similar between groups. Adverse events related to 5-ALA intake were rare and consisted of photosensitization in 4/87 (4.6%) patients and hepatic cytolysis in 1/87 (1.1%) patients. The 6-month PFS (70.2% [95% CI 57.7%-79.6%] and 68.4% [95% CI 55.7%-78.1%]; p = 0.39) and 24-month OS (30.1% [95% CI 18.9%-42.0%] and 37.7% [95% CI 25.8%-49.5%]; p = 0.89) did not significantly differ. In multivariate analysis, GTR was an independent predictor of PFS (hazard ratio 0.56 [95% CI 0.36-0.86], p = 0.008) and OS (hazard ratio 0.65 [95% CI 0.42-1.01], p = 0.05). The use of 5-ALA FGS generates a significant extra cost of 2732.36€ (95% CI 1658.40€-3794.11€).The authors found that 5-ALA FGS is an easy-to-use, cost-effective, and minimally time-consuming technique that safely optimizes the extent of resection in patients harboring glioblastoma amenable to a large resection.

To evaluate outcome and potential advantages of a percutaneous posterior approach to burst fractures of the thoraco-lumbar junction without neurological complications by means of a technique combining balloon kyphoplasty and percutaneous pedicule screw fixation. In this preliminary study patients who suffered traumatic of the thoraco-lumbar junction presented a Magerl type A3 fracture. The mean age of the patients was 64 years (54–78 years). All had a normal neurological examination. A combined technique using balloon kyphoplasty, that allows restoration of the vertebral height and fixation by means of cement injection with percutaneous osteosynthesis was performed as a minimal invasive alternative treatment. Mean follow-up (plain radiograph and CT scan, pain assessment) was 12 months (range 5–14 months). All patients experienced an early pain relief, successfully mobilized on day 1 after surgery and discharged after a mean stay of 4.5 days. Immediately postoperatively the mean vertebral height restoration was 11.5% and the reduction of the kyphotic angle was 9°. Those results were maintained over the complete follow-up period. Only one patient required analgesic treatment with weak opioids (step II of the WHO pain ladder) 3 months after surgery. The treatment of burst fractures of the thoraco-lumbar junction with no neurological complication by associating minimally invasive techniques results in good fracture reduction and stabilisation. The main advantage of this approach is to shorten the hospital stay. Cette étude a été proposée pour évaluer une technique chirurgicale mini-invasive dans le traitement de fracture de type burst de la charnière thoracolombaire. La fracture de type burst de la charnière thoracolombaire est le type de fracture du rachis le plus fréquent. La prise en charge des fractures sans troubles neurologiques n'est pas codifiée. Le but de ce travail est de proposer la kyphoplastie associée à une ostéosynthèse percutanée pour traiter les fractures de type A3 de Magerl sans atteinte neurologique. Cette étude préliminaire comporte l'analyse de quatre patients victimes d'un traumatisme de la charnière thoracolombaire responsable d'une fracture de type A3 de Magerl. Les patients étaient âgés en moyenne de 64 ans (54–78 ans). Ils présentaient tous un examen neurologique normal. La durée du suivi est en moyenne de 12 mois (5–14 mois). Le traitement chirurgical a comporté dans un premier temps une kyphoplastie percutanée suivie d'une ostéosynthèse également percutanée sous anesthésie générale et en décubitus ventral. Le suivi des patients a comporté une exploration radiographique par TDM et une analyse de la douleur par EVA. L'augmentation de la hauteur du corps vertébral a été de 11,5 % en moyenne, la réduction de l'angle de cyphose a été lui de 9,5°, la durée moyenne de séjour a été de 4,5 jours. Un seul patient prenait des antalgiques de palier II trois mois après la chirurgie. La prise en charge des fractures de type burst de la charnière thoracolombaire sans trouble neurologique peut bénéficier de cette attitude mini-invasive permettant, une réduction de la fracture, une stabilisation et surtout une réduction de la durée du séjour hospitalier.

To examine effectiveness of standardized occupational therapy and physical therapy assessments in detecting functional changes and predicting clinical improvement in patients with suspected normal pressure hydrocephalus undergoing cerebrospinal fluid drainage.Cohort study.Eighty-seven patients admitted to an inpatient neurology unit for elective cerebrospinal fluid drainage for suspected normal pressure hydrocephalus.Before and after a protocol of continuous cerebrospinal fluid drainage via spinal catheter, patients were administered the Functional Independence Measure (FIMTM), Timed Up and Go (TUG), Tinetti Assessment Tool of Gait and Balance, 9-hole peg test, and Cognitive Assessment of Minnesota (CAM). Following cerebrospinal fluid drainage, changes in functional performance were compared for responders to cerebrospinal fluid drainage and non-responders to cerebrospinal fluid drainage.At baseline, CAM was more sensitive than the Mini Mental State Exam in predicting responders. Post-drainage: responders improved on 52% of tests while non-responders improved on only 11%. Assessments that differentiated magnitude of improvement in responders vs non-responders were: TUG (p<0.05), Tinetti total (p<0.001), Tinetti balance (p<0.001), Tinetti gait (p<0.001), FIM toilet transfer (p<0.001), and FIM lower body dressing (p<0.001).Specific occupational therapy and physical therapy assessments demonstrate sensitivity to change and predictive value with patients with suspected normal pressure hydrocephalus undergoing cerebrospinal fluid drainage.

Introduction: Patients with Pseudotumor Cerebri Syndrome (PTCS) may complain of difficulty in thinking or concentrating; however there has been little formal cognitive evaluation in this population. Objective: To evaluate the characteristics and nature of cognitive impairment in patients with PTCS. Methods: We retrospectively reviewed records of 10 patients diagnosed with PTCS who were cognitively tested at presentation. In each cognitive test, “Borderline deficit” (BD) was defined as a score more than 1 standard deviation (SD) below and “Definite Deficit” (DD) as a score more than 2 SD below the mean for age, sex and education. In each cognitive domain, impairment was defined as a single test score more than 2 SD below the mean, or scores of more than 1 SD below the mean for age, sex and education in &gt; 50% of tests. Results: Mean age of patients was 43.4 ± 13.5 years. 8/10(80%) patients were female. 3/10(30%) had papilledema; 3/10(30%) had significant cerebral venous outflow obstruction. Impairment was most commonly seen and was most severe in the WMS logical memory I (BD44%, DD44%), WMS logical memory II (BD37.5%, DD50%), RAVLT delayed recall (BD30%, DD40%) and RAVLT retention(BD40%, DD30%) tests. Evaluation of cognitive domains revealed impairment in memory and learning (80%), executive function (10%), visuospatial skills (30%), and language (30%). Conclusion: Our results indicate that patients with PTCS can have significant cognitive impairment, particularly in learning and memory. The prevalence needs to be studied in a larger cohort. The relationship of cognitive impairment with chronically elevated intracranial pressures and its role in contributing to patient morbidity needs to be investigated further.

Breast cancer (BC) is the second most common cause of brain metastases (BM). Optimal management of BM from BC is still debated. In an attempt to provide appropriate treatment and to assist with optimal patient selection, several specific prognostic classifications for BM from BC have been established. We evaluated the prognostic value and validity of the 6 proposed scoring systems in an independent population of BC patients with BM.We retrospectively reviewed all consecutive BC patients referred to our institution for newly diagnosed BM between October 1995 and July 2011 (n = 149). Each of the 6 scores proposed for BM from BC (Sperduto, Niwinska, Park, Nieder, Le Scodan, and Claude) was applied to this population. The discriminative ability of each score was assessed using the Brier score and the C-index. Individual prognostic values of clinical and histological factors were analyzed using uni- and multivariate analyses.Median overall survival was 15.1 months (95% CI,11.5-18.7). Sperduto-GPA (P < .001), Nieder (P < .001), Park (P < .001), Claude (P < .001), Niwinska (P < .001), and Le Scodan (P = .034) scores all showed significant prognostic value. The Nieder score showed the best discriminative ability (C-index, 0.672; Brier score error reduction, 16.1%).The majority of prognostic scores were relevant for patients with BM from BC in our independent population, and the Nieder score seems to present the best predictive value but showed a relatively low positive predictive value. Thus, these results remain insufficient and challenge the routine use of these scoring systems.

There is no consensus concerning the management of adult patients with posterior fossa metastasis-associated obstructive hydrocephalus, especially regarding surgical procedures. A literature review was performed to assess the surgical strategy in the management of patients with metastatic brain tumor.A literature search was conducted of PubMed in November 2017 to identify all studies concerning brain metastases and obstructive hydrocephalus in English. All studies (except case reports and pediatric studies) between December 1953 and November 2017 that were about posterior fossa metastasis-associated obstructive hydrocephalus in adult patients were eligible. Eligible studies were classified by level of evidence. We assessed epidemiology, clinical and imaging findings, neurosurgical management, and prognosis of adult patients with posterior fossa metastasis-associated obstructive hydrocephalus. We suggest some practical considerations and a management decision tree on behalf of the Neuro-oncology Club of the French Society of Neurosurgery, with evidence-based analysis.Direct surgical resection could be considered for patients with asymptomatic obstructive hydrocephalus, and endoscopic third ventriculostomy seems to be a reasonable procedure for patients with symptomatic obstructive hydrocephalus. A ventriculoperitoneal or atrial shunt seems to be a valid alternative when patients have a history of central nervous system infection or ventricular hemorrhage, leptomeningeal carcinomatosis, or unfavorable anatomy for an endoscopic third ventriculostomy to be performed.The Neuro-oncology Club of the French Society of Neurosurgery suggests a prospective assessment of these neurosurgical procedures to compare their safety and efficacy.

When feasible, the surgical resection is the standard first step of the management of high-grade gliomas. 5-ALA fluorescence-guided-surgery (5-ALA-FGS) was developed to ease the intra-operative delineation of tumor borders in order to maximize the extent of resection.A Medline electronic database search was conducted. English language studies from January 1998 until July 2018 were included, following the PRISMA guidelines.5-ALA can be considered as a specific tool for the detection of tumor remnant but has a weaker sensibility (level 2). 5-ALA-FGS is associated with a significant increase in the rate of gross total resection reaching more than 90% in some series (level 1). Consistently, 5-ALAFGS improves progression-free survival (level 1). However, the gain in overall survival is more debated. The use of 5-ALA-FGS in eloquent areas is feasible but requires simultaneous intraoperative electrophysiologic functional brain monitoring to precisely locate and preserve eloquent areas (level 2). 5-ALA is usable during the first resection of a glioma but also at recurrence (level 2). From a practical standpoint, 5-ALA is orally administered 3 hours before the induction of anesthesia, the recommended dose being 20 mg/kg. Intra-operatively, the procedure is performed as usually with a central debulking and a peripheral dissection during which the surgeon switches from white to blue light. Provided that some precautions are observed, the technique does not expose the patient to particular complications.Although 5-ALA-FGS contributes to improve gliomas management, there are still some limitations. Future methods will be developed to improve the sensibility of 5-ALA-FGS.

Abstract Penetrating head injury is rare and, their management is nonstandard with persistent cerebrospinal fluid (CSF) leakage being possibly challenging to treat. A 34-year-old man with no past medical history was referred in emergency room for an impressive accidental penetrating craniocerebral wound through which the brain was extruding due to the raised intracranial pressure. Computed tomography scan showed a comminuted frontal fracture extended to the anterior skull base and a severe bifrontal lobe concussion with a diffuse intracranial hemorrhage. A debridement and washout of the craniocerebral wound were achieved with careful hemostasis followed by a decompressive craniectomy. Fortunately, the patient survived but, the CSF continued to leak through the anterior skull base fracture with no endoscopic treatment possibility. Fifteen days after the initial trauma, a surgical sealing was decided using a large fascia lata sheath harvested on the right thigh by a “S”-shaped incision. A significant piece of fascia lata was cut off and meticulously sutured to the remaining dura mater rims in double-layered watertight fashion. Both cranial and right thigh wounds healed uneventfully and the CSF leak never reoccurred. Twenty-two weeks after the initial trauma, a custom-made titanium cranioplasty was inserted without any dissection difficulty. In case of persistent CSF leakage not amenable to endonasal endoscopic treatment, the use of a large piece of facia lata harvested on the thigh using an “S”-shaped incision is a simple, reliable way to efficiently repair a large dura mater defect. It requires neither special skills nor sophisticated instruments.

Effective diagnosis, prognostication, and management of CNS malignancies traditionally involves invasive brain biopsies that pose significant risk to the patient. Sampling and molecular profiling of cerebrospinal fluid (CSF) is a safer, rapid, and noninvasive alternative that offers a snapshot of the intracranial milieu while overcoming the challenge of sampling error that plagues conventional brain biopsy. Although numerous biomarkers have been identified, translational challenges remain, and standardization of protocols is necessary. Here, we systematically reviewed 141 studies (Medline, SCOPUS, and Biosis databases; between January 2000 and September 29, 2022) that molecularly profiled CSF from adults with brain malignancies including glioma, brain metastasis, and primary and secondary CNS lymphomas. We provide an overview of promising CSF biomarkers, propose CSF reporting guidelines, and discuss the various considerations that go into biomarker discovery, including the influence of blood-brain barrier disruption, cell of origin, and site of CSF acquisition (eg, lumbar and ventricular). We also performed a meta-analysis of proteomic data sets, identifying biomarkers in CNS malignancies and establishing a resource for the research community.

Solitary fibrous tumors (SFTs) are rare spindle-cell tumors. Their cell-of-origin and molecular basis are poorly known. They raise several clinical problems. Differential diagnosis may be difficult, prognosis is poorly apprehended by histoclinical features, and no effective therapy exists for advanced stages.We profiled 16 SFT samples using whole-genome DNA microarrays and analyzed their expression profiles with publicly available profiles of 36 additional SFTs and 212 soft tissue sarcomas (STSs). Immunohistochemistry was applied to validate the expression of some discriminating genes.SFTs displayed whole-genome expression profiles more homogeneous and different from STSs, but closer to genetically-simple than genetically-complex STSs. The SFTs/STSs comparison identified a high percentage (∼30%) of genes as differentially expressed, most of them without any DNA copy number alteration. One of the genes most overexpressed in SFTs encoded the ALDH1 stem cell marker. Several upregulated genes and associated ontologies were also related to progenitor/stem cells. SFTs also overexpressed genes encoding therapeutic targets such as kinases (EGFR, ERBB2, FGFR1, JAK2), histone deacetylases, or retinoic acid receptors. Their overexpression was found in all SFTs, regardless the anatomical location. Finally, we identified a 31-gene signature associated with the mitotic count, containing many genes related to cell cycle/mitosis, including AURKA.We established a robust repertoire of genes differentially expressed in SFTs. Certain overexpressed genes could provide new diagnostic (ALDH1A1), prognostic (AURKA) and/or therapeutic targets.

Brain metastases (BMs) from colorectal cancer are rare (2-3%). They usually occur in advanced stages of the disease and their prognosis is poor. The aim of this study was to assess the impact of surgical resection of BMs from colorectal cancer in terms of overall survival.A retrospective bi-centric study included all patients with resected BMs from primary colorectal adenocarcinoma from 1998 to 2009.Twenty-eight patients [13 males, median: 62 (range: 44-86) years old) were included. Fifteen patients presented with other metastatic sites (lung, liver). BMs were metachronous in 16/28 (57%) of patients [median: 19 months (range: 7-97)]. Median overall survival reached 12 months. Brain recurrences occurred in 32% of patients and were treated by curative intent in 5/9 cases.When indicated, an aggressive management based on surgical resection of BMs from colorectal cancer, must be performed, in order to improve overall survival to at least 12 months.

The practical management of cavernous angioma located within eloquent brain area before, during and after surgical resection is poorly documented. We assessed the practical pre-operative, intra-operative, and post-operative management of cavernous angioma located within eloquent brain area.An online survey composed of 61 items was sent to 26 centers to establish a multicenter international retrospective cohort of adult patients who underwent a surgical resection as the first-line treatment of a supratentorial cavernous angioma located within or close to eloquent brain area.272 patients from 19 centers (mean 13.6 ± 16.7 per center) from eight countries were included. The pre-operative management varied significantly between centers and countries regarding the pre-operative functional assessment, the pre-operative epileptological assessment, the first given antiepileptic drug, and the time to surgery. The intra-operative environment varied significantly between centers and countries regarding the use of imaging systems, the use of functional mapping with direct electrostimulations, the extent of resection of the hemosiderin rim, the realization of a post-operative functional assessment, and the time to post-operative functional assessment. The present survey found a post-operative improvement, as compared to pre-operative evaluations, of the functional status, the ability to work, and the seizure control.We observed a variety of practice between centers and countries regarding the management of cavernous angioma located within eloquent regions. Multicentric prospective studies are required to solve relevant questions regarding the management of cavernous angioma-related seizures, the timing of surgery, and the optimal extent of hemosiderin rim resection.

Lung cancer brain metastases (BMs) are frequent and associated with poor prognosis despite a better knowledge of lung cancer biology and the development of targeted therapies.The inconstant intracranial response to systemic treatments is partially due to tumor heterogeneity between the primary lung tumor (PLT) and BMs.There is therefore a need for a better understanding of lung cancer BMs biology to improve treatment strategies for these patients.We conducted a study of whole exome sequencing of paired BM and PLT samples.The number of somatic variants and chromosomal alterations was higher in BM samples.We identified recurrent mutations in BMs not found in PLT.Phylogenic trees and lollipop plots were designed to describe their functional impact.Among the 13 genes mutated in ≥ 1 BM, 7 were previously described to be associated with invasion process, including 3 with recurrent mutations in functional domains which may be future targets for therapy.We provide with some insights about the mechanisms leading to BMs.We found recurrent mutations in BM samples in 13 genes.Among these genes, 7 were previously described to be associated with cancer and 3 of them (CCDC178, RUNX1T1, MUC2) were described to be associated with the metastatic process.

A 30-year old overweight woman was referred for idiopathic intracranial hypertension revealed by worsening headache and, quickly deteriorating visual acuity. Despite acetazolamide treatment and cerebrospinal fluid evacuation by lumbar puncture (54 mmHg), her eyesight continue to worsen. Ventriculoperitoneal shunting was eventfully achieved but, postoperative computed tomography (CT) showed a distal catheter had migrated into the subcutaneous fat. The catheter was reinserted in the peritoneal cavity, confirmed by the postoperative CT.

• Platybasia may be associated with Chiari malformations. • Chiari I malformation is seen in less than 1% of the adult and is usually asymptomatic. • Hydrocephalus is not a common feature of Chiari I malformation. • Cases of sudden death with Chiari I malformation have very rarely reported.

Abstract OBJECTIVE AND IMPORTANCE A Chiari I malformation associated with syringomyelia and hydrocephalus is a rare condition. We report the successful use of endoscopic third ventriculostomy for the treatment of this pathological entity. The successful use of this technique in such a case has not been previously described, and the results allow us to speculate on the pathophysiological mechanism involved. CLINICAL PRESENTATION A 34-year-old woman presented with headaches, a motor deficit of the right upper limb, and gait dyspraxia. Magnetic resonance imaging scans demonstrated dilation of all ventricles, compression of the retrocerebellar cerebrospinal fluid space, downward displacement of the tonsils, and syringomyelia. Syringomyelia involved the cervicodorsal cord below C3, with a syrinx-free segment between C1 and C3 and no enlargement of the rostral part of the central canal. INTERVENTION Endoscopic third ventriculostomy resulted in prompt improvement of the clinical symptoms. Postoperative magnetic resonance imaging scans demonstrated shrinkage of the syrinx and return of the cerebellar tonsils to their physiological positions. CONCLUSION This experience demonstrates that endoscopic third ventriculostomy, which is a simple, safe technique, may be the treatment of choice for associated Chiari I malformations, hydrocephalus, and syringomyelia (even the noncommunicating type).

The authors report their experience using preoperative chest radiography and intraoperative ultrasonography for percutaneous positioning of the distal end of the catheter when placing ventriculoatrial (VA) shunts in patients with hydrocephalus. The distal portion of VA shunt catheters were percutaneously placed into the internal jugular vein with the aid of intraoperative ultrasonography in 14 consecutive adults. In all cases, the technique was easy, there were no postoperative complications, and postoperative chest radiography demonstrated good positioning of the distal catheter tip. One patient presented with a shunt infection and needed a shunt replacement. The authors therefore conclude that percutaneous placement of a VA shunt under preoperative radiographic guidance and ultrasonographic monitoring is a safe, effective, and reliable technique that is simple to learn.

Epidermal growth factor receptor is a transmembrane receptor involved in oncogenesis, including the development of glioblastoma. We studied the prognostic significance of epidermal growth factor receptor amplification as determined by fluorescence in situ hybridization, quantitative polymerase chain reaction, and protein expression by immunohistochemistry. Ninety-nine patients exhibiting glioblastoma were included. Immunohistochemistry was performed on microarray blocks with clone 25, which recognizes both epidermal growth factor receptor wild type and vIII, and scored using a semiquantitative approach. Quantitative polymerase chain reaction and fluorescence in situ hybridization techniques were performed on frozen section: 29.3% of cases had a high epidermal growth factor receptor immunohistochemistry score (score ≥200); and of these cases, 96.5% had gene amplification by fluorescence in situ hybridization and quantitative polymerase chain reaction. Conversely, of cases with a low immunohistochemistry score, 72.9% had normal karyotype or polysomy 7 by fluorescence in situ hybridization technique; but around 25% had gene amplification by fluorescence in situ hybridization and quantitative polymerase chain reaction. In the case of protein overexpression, quantitative polymerase chain reaction and fluorescence in situ hybridization could be avoided in first intention because their positive predictive value for amplification is 97%. In multivariate analysis, there was a trend toward an association between shorter overall survival time and epidermal growth factor receptor amplification as determined by fluorescence in situ hybridization analysis. However, cases with an immunohistochemistry score less 200 require further testing by fluorescence in situ hybridization or quantitative polymerase chain reaction.

Clinical and experimental studies suggest that angiogenesis is a prerequisite for solid tumour growth. Glioblastoma (GBM) and pilocytic astrocytoma (PA), both angiogenic tumours display strong contrast enhancement associated with peripheral oedema in GBM but not in PA indicating differences in vascular permeability in these two types of gliomas. Here we show that expression of adrenomedullin (AM) mRNA is induced in GBM whereas is barely detectable in PA. In situ analysis of tumour specimens undergoing neovascularisation shows that the production of AM is specifically induced in a subset of GBM cells distinguished by their immediate proximity to necrotic foci (presumably hypoxic regions), suggesting a hypoxic induction of AM expression in GBM. Vascular endothelial growth factor (VEGF) mRNA levels are increased in GBM and moderate in PA. Immunohistochemical study showed that cytoplasmic AM, VEGF and HIF-1α nuclear immunoreactivity were recorded in GBM located near large necrotic areas whereas they were not expressed by PA tumour cells. Interestingly, double fluorescence immunostaining demonstrated that 85% of AM immunoreactivity colocalised with VEGF. AM transduces its effects through calcitonin receptor-like receptor/receptor activity modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). Real-time quantitative RT-PCR showed expression of RAMP2, RAMP3 and CLR in PA and GBM, suggesting that AM may function as an autocrine/paracrine growth factor for GBM cells. These observations strongly support the concept that tumour angiogenesis is regulated by paracrine mechanisms and identify beside VEGF, AM as a potential tumour angiogenesis factor in vivo which constitutes a potential interesting molecular target in GBM treatment.

La radiothérapie en conditions stéréotaxiques des métastases cérébrales fait l’objet de débats entre experts et d’indications croissantes au sein des réunions de concertation polydisciplinaires. La définition des techniques de radiothérapie en conditions stéréotaxiques et ses modalités de prescription, ses indications et la balance efficacité contre toxicité sont à discuter. La radiothérapie en conditions stéréotaxiques est une technique d’irradiation dont la précision doit être de l’ordre du millimètre, utilisant différents types de matériels (cadre invasif ou non, photons X ou gamma), permettant de délivrer de fortes doses par séance (de 4 à 25 Gy) en un nombre limité de séances (d’une à cinq habituellement, pouvant aller jusqu’à sept à dix) avec un fort gradient de dose. Le mode de prescription de la dose dépend des matériels utilisés, les contraintes à respecter aux organes à risque variant selon les fractionnements choisis. La radiothérapie en conditions stéréotaxiques peut être proposée : (1) en combinaison avec une irradiation encéphalique totale dans le but d’améliorer la probabilité de survie d’un patient en bon état général, atteint d’une à trois métastases cérébrales, avec maladie extracrânienne contrôlée ; (2) pour ré-évolution d’une métastase cérébrale après irradiation encéphalique totale ; (3) après exérèse « complète » d’une métastase cérébrale volumineuse et/ou symptomatique ; (4) après découverte de trois à cinq métastases cérébrales nouvelles ou progressant malgré les traitements systémiques, peu ou pas symptomatiques. Il s’agit alors de différer l’irradiation encéphalique totale pour éviter sa neurotoxicité potentielle dans un but de contrôle purement focal, un strict suivi clinique et IRM tous les 3 mois permettant de réitérer les radiothérapies en conditions stéréotaxiques sans compromettre la survie. Toute concomitance de radiothérapie en conditions stéréotaxiques et de médicament ciblée doit être soigneusement discutée. Stereotactic radiotherapy of brain metastases is increasingly proposed after polydisciplinary debates among experts. Its definition and modalities of prescription, indications and clinical interest regarding the balance between efficacy versus toxicity need to be discussed. Stereotactic radiotherapy is a ‘high precision’ irradiation technique (within 1 mm), using different machines (with invasive contention or frameless, photons X or gamma) delivering high doses (4 to 25 Gy) in a limited number of fractions (usually 1 to 5, ten maximum) with a high dose gradient. Dose prescription will depend on materials, dose constraints to organs at risk varying with fractionation. Stereotactic radiotherapy may be proposed: (1) in combination with whole brain radiotherapy with the goal of increasing (modestly) overall survival of patients with a good performance status, 1 to 3 brain metastases and a controlled extracranial disease; (2) for recurrence of 1–3 brain metastases after whole brain radiotherapy; (3) after complete resection of a large and/or symptomatic brain metastases; (4) after diagnosis of 3–5 asymptomatic new or progressing brain metastases during systemic therapy, with the aim of delaying whole brain radiotherapy (avoiding its potential neurotoxicity) and maintaining a high focal control rate. Only a strict follow-up with clinical and MRI every 3 months will permit to deliver iterative stereotactic radiotherapies without jeopardizing survival. Simultaneous delivering of stereotactic radiotherapy with targeted medicines should be carefully discussed.

There is a growing body of evidence that carmustine wafer implantation during surgery is an effective therapeutic adjunct to the standard combined radio-chemotherapy regimen using temozolomide in newly diagnosed and recurrent high-grade glioma patient management with a statistically significant survival benefit demonstrated across several randomized clinical trials, as well as prospective and retrospective studies (grade A recommendation). Compelling clinical data also support the safety of carmustine wafer implantation (grade A recommendation) in these patients and suggest that observed adverse events can be avoided in experienced neurosurgeon hands. Furthermore, carmustine wafer implantation does not seem to impact negatively on the quality of life and the completion of adjuvant oncological treatments (grade C recommendation). Moreover, emerging findings support the potential of high-grade gliomas molecular status, especially the O(6)-Methylguanine-DNA Methyltransferase promoter methylation status, in predicting the efficacy of such a surgical strategy, especially at recurrence (grade B recommendation). Finally, carmustine wafer implantation appears to be cost-effective in high-grade glioma patients when performed by an experienced team and when total or subtotal resection can be achieved. Altogether, these data underline the current need for a new randomized clinical trial to assess the impact of a maximal safe resection with carmustine wafer implantation followed by the standard combined chemoradiation protocol stratified by molecular status in high-grade glioma patients.

A 62-year-old woman with severe osteoporosis experienced pulmonary embolism by polymethylmethacrylate after percutaneous vertebroplasty. The patient immediately developed respiratory and cardiac distress, and a computed tomographic scan revealed the presence of cement in the pulmonary circulation. Proper techniques can minimize the risk of pulmonary embolism during percutaneous vertebroplasty: adequate preparation of cement and fluoroscopy during the procedure are recommended.

The majority of osteoporotic, spinal cord compressive, vertebral fractures occurs at the thoracolumbar junction level. When responsible for neurological impairment, these rare lesions require a decompression procedure. We present the results of a new option to treat these lesions: an open balloon kyphoplasty associated with a short-segment posterior internal fixation. Twelve patients, aged a mean 72.3 years, were included in this prospective series; all of them presented osteoporotic burst fractures located between T11 and L2 associated with neurological impairment. The surgical procedure first consisted of a laminectomy, for decompression, followed by an open balloon kyphoplasty. A short-segment posterior internal fixation was subsequently put into place when the local kyphosis was considered severe. A CAT scan study evaluated local vertebral body's height restoration using two pre- and postoperative radiological indices. All of the patients in the series were followed up for a mean 14 months. Local kyphosis improved a mean 10.8 (p < 0.001). Vertebral body height was also substantially restored, with a mean gain of 26% according to the anterior height/adjacent height ratio and 28% according to the Beck Index (p < 0.001). Two cases of cement leakage were recorded, with no adverse clinical side effect. Complete neurological recovery was observed in 10 patients; two retained a minimal neurological deficit but kept a walking capacity. The results presented in this study confirm the data reported in the literature in terms of local kyphosis correction and vertebral body height restoration. The combination of this technique with laminectomy plus osteosynthesis allowed us to effectively treat burst fractures of the thoracolumbar junction and led to stable results 1 year after surgery. This can be advantageous in a population often carrying multiple co-morbidities. With a single operation, we can achieve neurological decompression and spinal column stability in a minimally invasive way; this avoids more substantial surgery in these fragile patients. Level IV. Therapeutic prospective study.

Introduction: To evaluate the feasibility of performing a functional cerebral venous outflow blockage in two large animals species, the swine and the baboon, for elaboration of venous hypertension models. Method: Cerebral venous outflow pathways were identified on angiogram and venography of three swine and two baboons, and potential approaches to access these structures were assessed. Practicability of performing functional intracranial dural outflow blockage was tested. Results: The main cerebral venous outflow route was the internal jugular vein in baboons and the paraspinal venous network in swine. Both animals had an additional venous outflow structure, the petrosquamous sinus. Access to intracranial venous sinuses was achieved through a percutaneous retrograde approach in baboon but not in swine, due to the absence of a direct connection between the dural structures and the internal jugular vein. A transcranial approach allowed to access dural venous structures in swine. In both models, partial and progressive venous sinus occlusion increased intracranial pressure, while preserving the animal's vital status. At 6 months, all animals are alive with no neurological deficits. Conclusion: Functional venous dural outflow blockage for elaboration of intracranial venous hypertension is feasible in both models. To be effective, the sinus blockage must be performed before the origin of the petrosquamous, an additional venous sinus seen in swine and baboon. The baboon has the greatest advantage of resembling human cerebral venous drainage, which enables an intracranial venous retrograde access. However, the transcranial approach remains a valuable option to access intracranial venous sinuses in swine.

Patients with Pseudotumor Cerebri Syndrome (PTCS) may complain of difficulty in thinking or concentrating; however there has been little formal cognitive evaluation in this population.To evaluate the characteristics and nature of cognitive impairment in patients with PTCS.We retrospectively reviewed records of 10 patients diagnosed with PTCS who were cognitively tested at presentation. In each cognitive test, "Borderline deficit" (BD) was defined as a score more than 1 standard deviation (SD) below and "Definite Deficit" (DD) as a score more than 2 SD below the mean for age, sex and education. In each cognitive domain, impairment was defined as a single test score more than 2 SD below the mean, or scores of more than 1 SD below the mean for age, sex and education in > 50% of tests.Mean age of patients was 43.4 ± 13.5 years. 8/10(80%) patients were female. 3/10(30%) had papilledema; 3/10(30%) had significant cerebral venous outflow obstruction. Impairment was most commonly seen and was most severe in the WMS logical memory I (BD-44%, DD-44%), WMS logical memory II (BD-37.5%, DD-50%), RAVLT delayed recall (BD-30%, DD-40%) and RAVLT retention(BD-40%, DD-30%) tests. Evaluation of cognitive domains revealed impairment in memory and learning (80%), executive function (10%), visuo-spatial skills (30%), and language (30%).Our results indicate that patients with PTCS can have significant cognitive impairment, particularly in learning and memory. The prevalence needs to be studied in a larger cohort. The relationship of cognitive impairment with chronically elevated intracranial pressures and its role in contributing to patient morbidity needs to be investigated further.

The cellular and molecular mechanisms by which adrenomedullin (AM) blockade suppresses tumor neovessels are not well defined. Herein, we show that AM blockade using anti-AM and anti-AM receptors antibodies targets vascular endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and induces regression of unstable nascent tumor neovessels. The underlying mechanism involved, and shown in vitro and in vivo in mice, is the disruption of the molecular engagement of the endothelial cell-specific junctional molecules vascular endothelial-cadherin (VE-cadherin)/β-catenin complex. AM blockade increases endothelial cell permeability by inhibiting cell-cell contacts predominantly through disruption of VE-cadherin/β-catenin/Akt signalling pathway, thereby leading to vascular collapse and regression of tumor neovessels. At a molecular level, we show that AM blockade induces tyrosine phosphorylation of VE-cadherin at a critical tyrosine, Tyr731, which is sufficient to prevent the binding of β-catenin to the cytoplasmic tail of VE-cadherin leading to the inhibition of cell barrier function. Furthermore, we demonstrate activation of Src kinase by phosphorylation on Tyr416, supporting a role of Src to phosphorylate Tyr731-VE-cadherin. In this model, Src inhibition impairs αAM and αAMR-induced Tyr731-VE-cadherin phosphorylation in a dose-dependent manner, indicating that Tyr731-VE-cadherin phosphorylation state is dependent on Src activation. We found that AM blockade induces β-catenin phosphorylation on Ser33/Ser37/Thr41 sites in both ECs and VSMCs both in vitro and in vivo in mice. These data suggest that AM blockade selectively induces regression of unstable tumor neovessels, through disruption of VE-cadherin signalling. Targeting AM system may present a novel therapeutic target to selectively disrupt assembly and induce regression of nascent tumor neovessels, without affecting normal stabilized vasculature.

The anterior approach to the thoraco-lumbar junction of the spine allows therapeutic interventions on post-traumatic, infectious, and neoplastic vertebral lesions from T11 to L2 combining spinal cord decompression, corporectomy, and vertebral body fusion. However, this approach also has a reputation for damaging the intervening anatomic structures (lungs, peritoneum, and diaphragm). The objective of this study was to show that both nervous structure decompression and anterior vertebral reconstruction can be achieved via an anterior minimally invasive extrapleural retroperitoneal (AMIER) approach. We describe each of the steps of the AMIER approach to the thoraco-lumbar junction of the spine. The AMIER approach ensures excellent exposure that allows full decompression and satisfactory anterior anatomic reconstruction. The main difficulties and complications relate to the lungs, and a painstaking and rigorous technique limits the complications compared to conventional thoraco-phreno-lumbotomy.

Glioblastomas in adults are highly heterogeneous tumors that can develop throughout the brain.To date no predictive-location marker has been identified.We previously derived two glioblastoma cell lines from cortical and periventricular locations and demonstrated distinct transcriptomic profiles.Based on these preliminary results, the aim of this study was to correlate glioblastoma locations with the expression of ten selected genes (VEGFC, FLT4, MET, HGF, CHI3L1, PROM1, NOTCH1, DLL3, PDGFRA, BCAN).Fifty nine patients with newly diagnosed glioblastomas were retrospectively included.Tumors were classified into cortical and periventricular locations, which were subsequently segregated according to cerebral lobes involved: cortical fronto-parietal (C-FP), cortical temporal (C-T), periventricular fronto-parietal (PV-FP), periventricular temporal (PV-T), and periventricular occipital (PV-O).Gene expression levels were determined using RT-qPCR.Compared to cortical glioblastomas, periventricular glioblastomas were characterized by a higher expression of two mesenchymal genes, VEGFC (p = 0.001) and HGF (p = 0.001).Among cortical locations, gene expressions were homogeneous.In contrast, periventricular locations exhibited distinct expression profiles.PV-T tumors were associated with higher expression of two proneural and cancer stem cell genes, NOTCH1 (p = 0.028) and PROM1 (p = 0.033) while PV-FP tumors were characterized by high expression of a mesenchymal gene, CHI3L1 (p = 0.006).Protein expression of NOTCH1 was correlated with RNA expression levels.PV-O glioblastomas were associated with lower expression of VEGFC (p = 0.032) than other periventricular locations, whereas MET overexpression remained exceptional.These data suggest a differential gene expression profile according to initial glioblastoma location.

Diffusion Tensor Imaging (DTI) is a powerful imaging technique that has led to improvements in the diagnosis and prognosis of cerebral lesions and neurosurgical guidance for tumor resection. Traditional tensor modeling, however, has difficulties in differentiating tumor-infiltrated regions and peritumoral edema. Here, we describe the supertoroidal model, which incorporates an increase in surface genus and a continuum of toroidal shapes to improve upon the characterization of Glioblastoma multiforme (GBM).DTI brain datasets of 18 individuals with GBM and 18 normal subjects were acquired using a 3T scanner. A supertoroidal model of the diffusion tensor and two new diffusion tensor invariants, one to evaluate diffusivity, the toroidal volume (TV), and one to evaluate anisotropy, the toroidal curvature (TC), were applied and evaluated in the characterization of GBM brain tumors. TV and TC were compared with the mean diffusivity (MD) and fractional anisotropy (FA) indices inside the tumor, surrounding edema, as well as contralateral to the lesions, in the white matter (WM) and gray matter (GM).The supertoroidal model enhanced the borders between tumors and surrounding structures, refined the boundaries between WM and GM, and revealed the heterogeneity inherent to tumor-infiltrated tissue. Both MD and TV demonstrated high intensities in the tumor, with lower values in the surrounding edema, which in turn were higher than those of unaffected brain parenchyma. Both TC and FA were effective in revealing the structural degradation of WM tracts.Our findings indicate that the supertoroidal model enables effective tensor visualization as well as quantitative scalar maps that improve the understanding of the underlying tissue structure properties. Hence, this approach has the potential to enhance diagnosis, preoperative planning, and intraoperative image guidance during surgical management of brain lesions.

The following study was conducted to evaluate the results of Gamma Knife stereotactic radiosurgery in the management of secondary trigeminal neuralgia. 53 patients suffering from secondary trigeminal neuralgia were studied and the results reported. We defined four therapeutic groups: group I correspond to essential trigeminal neuralgia. The primary aim was tumor control in group IV and pain cessation in group III and II (visualization of the fifth nerve root was possible in group II but not in group III). The target dose of the radiosurgery used in the current study varied from 20 to 40 Gy in group III and IV and from 70 to 90 Gy in group I and II. At short-term follow-up, 37 patients (74%) were pain-free, 9 patients (18%) were improved (50%–90% relief) and only 4 patients (8%) experienced treatment failure. Among the patients with early treatment success, 10 patients experienced a complete recurrence of pain in the four succeeding years, and 11 initially pain-free patients deteriorated to partial pain relief. The median time to pain relief was three months (range 1 day to 1 year). The mean follow-up was 32 months (range 7 to 60 months). No patient developed increased facial pain or deafferentation pain. Among the 53 patients, only two exhibit a slight facial hypesthesia and one patient described motor fasciculation related to Gamma Knife treatment. In our experience Gamma Knife surgery appears a safe and effective method for the treatment of secondary trigeminal neuralgia.

To assess a surgical technique and the postoperative outcomes of a consecutive series of 22 patients treated for degenerative lumbar spondylolisthesis (DLS) through a minimally invasive unilateral approach associating interbody fusion and percutaneous osteosynthesis. Twenty-two patients were included in this study, with a mean age of 60 years (range, 35–77years). All had low-grade single-level DLS. In all cases, the technique included a posterior unilateral paramedial approach through a tubular retractor that decompressed the vertebral canal and transforaminal intervertebral cage arthrodesis. Osteosynthesis was then systematically put in place. The evaluation criteria were clinical (pain, spinal symptoms, duration of hospital stay) and radiological. The entire series was followed up for a mean of 24 months. In this series, the procedure was performed with no technical problems. The mean hospital stay lasted 4.5days. Postoperative pain assessment showed a mean VAS of 2/10 at discharge and 75% of the patients were asymptomatic at 6 months. The radiological exams showed no extrapedicular screws and the fusion rate was 95% at the last follow-up (with one patient needing surgical revision for malunion). Transforaminal lumbar interbody fusion through a unilateral approach associated with percutaneous osteosynthesis is a reliable and effective technique in DLS surgery. The clinical and radiological results are encouraging, with low morbidity and a fusion rate comparable to conventional techniques. However, a longer follow-up will be necessary so as to assess the long-term results of this surgical strategy. Level IV. Retrospective study.