Early Detection of Underlying Cavernomas in Patients with Spontaneous Acute Intracerebral Hematomas.

BACKGROUND AND PURPOSE: Early identification of the etiology of spontaneous acute intracerebral hemorrhage is essential for appropriate management. This study aimed to develop an imaging model to identify cavernoma-related hematomas. MATERIALS AND METHODS: Patients 1-55 years of age with acute (≤7 days) spontaneous intracerebral hemorrhage were included. Two neuroradiologists reviewed CT and MR imaging data and assessed the characteristics of hematomas, including their shape (spherical/ovoid or not), their regular or irregular margins, and associated abnormalities including extralesional hemorrhage and peripheral rim enhancement. Imaging findings were correlated with etiology. The study population was randomly split to provide a training sample (50%) and a validation sample (50%). From the training sample, univariate and multivariate logistic regression was performed to identify factors predictive of cavernomas, and a decision tree was built. Its performance was assessed using the validation sample. RESULTS: Four hundred seventy-eight patients were included, of whom 85 had hemorrhagic cavernomas. In multivariate analysis, cavernoma-related hematomas were associated with spherical/ovoid shape (P < .001), regular margins (P = .009), absence of extralesional hemorrhage (P = .01), and absence of peripheral rim enhancement (P = .002). These criteria were included in the decision tree model. The validation sample (n = 239) had the following performance: diagnostic accuracy of 96.1% (95% CI, 92.2%-98.4%), sensitivity of 97.95% (95% CI, 95.8%-98.9%), specificity of 89.5% (95% CI, 75.2%-97.0%), positive predictive value of 97.7% (95% CI, 94.3%-99.1%), and negative predictive value of 94.4% (95% CI, 81.0%-98.5%). CONCLUSIONS: An imaging model including ovoid/spherical shape, regular margins, absence of extralesional hemorrhage, and absence of peripheral rim enhancement accurately identifies cavernoma-related acute spontaneous cerebral hematomas in young patients.

Prognostic factors for progression-free survival of the filum terminale ependymomas in adults.

OBJECTIVE: To define the prognostic factors for progression and to determine the impact of the histological grading (according to the World Health Organization) on the progression-free survival (PFS) of filum terminale ependymomas. METHODS: A retrospective chart review of 38 patients with ependymoma of the filum terminale was performed, focusing on demographic data, preoperative symptoms, tumor size, quality of resection, presence of a tumor capsule, and histological grade. RESULTS: Gross total resection (GTR) was achieved in 30 patients (78.9%). Histopathological analysis found 21 (55.3%) myxopapillary grade I ependymoma (MPE), 16 (42.1%) ependymoma grade II (EGII), and 1 (2.6%) ependymoma grade III. There was no significant difference between the mean±SD volume of MPE (5840.5±5244.2mm3) and the one of EGII (7220.3±6305.9mm3, p=0.5). The mean±SD follow-up was 54.1±38.4 months. At last follow-up, 30 (78.9%) patients were free of progression. In multivariate analysis, subtotal resection (p=0.015) and infiltrative tumor (p=0.03) were significantly associated with progression. The PFS was significantly higher in patients with encapsulated tumor than in patients with infiltrative tumor (log-rank p=0.01) and in patients who had a GTR in comparison with those who had an incomplete resection (log-rank p=0.05). There was no difference in PFS between patient with MPE and EGII (p=0.1). CONCLUSION: The progression of ependymoma of the filum terminale highly depends on the quality of resection, and whether the tumor is encapsulated. Except for anaplastic grade, histopathological type does not influence progression.

The TeloDIAG: how telomeric parameters can help in glioma rapid diagnosis and liquid biopsy approaches.

BACKGROUND: In glioma, TERT promoter mutation and loss of ATRX (ATRX loss) are associated with reactivation of telomerase or alternative lengthening of telomeres (ALT), respectively, i.e. the two telomere maintenance mechanisms (TMM). Strangely, 25% of gliomas have been reported to display neither or both of these alterations. MATERIALS AND METHODS: The C-circle (CC) assay was adapted to tumor (formalin-fixed paraffin-embedded and frozen) and blood samples to investigate the TMM. RESULTS: We constructed a CC-based algorithm able to identify the TMM and reported a sensitivity of 100% and a specificity of 97.3% (n = 284 gliomas). By combining the TMM, the mutational status of the isocitrate dehydrogenase 1/2 (IDH) gene (IDHmt), and the histological grading, we propose a new classification tool: TeloDIAG. This classification defined five subtypes: tOD, tLGA, tGBM_IDHmt, tGBM, and tAIV, corresponding to oligodendroglioma, IDHmt low-grade astrocytoma, IDHmt glioblastoma, and IDHwt glioblastoma (GBM), respectively; the last class gathers ALT+ IDHwt gliomas that tend to be related to longer survival (21.2 months) than tGBM (16.5 months). The TeloDIAG was 99% concordant with the World Health Organization classification (n = 312), and further modified the classification of 55 of 144 (38%) gliomas with atypical molecular characteristics. As an example, 14 of 69 (20%) of TERTwt, ATRXwt, and IDHwt GBM were actually tAIV. Outstandingly, CC in blood sampled from IDHmt astrocytoma patients was detected with a sensitivity of 56% and a specificity of 97% (n = 206 gliomas and 30 healthy donors). CONCLUSION: The TeloDIAG is a new, simple, and effective tool helping in glioma diagnosis and a promising option for liquid biopsy.

Medulloblastomas in adolescents and adults - Can the pediatric experience be extrapolated?

Adult medulloblastomas are orphan diseases that differ from their pediatric counterpart. Most are classified as classic or desmoplastic and fall in the SHH subgroup, mainly with loss-of-function mutations in PTCH1 and some by TP53-mutation due to underlying germline mutation. Activation of the WNT pathway is sporadic, although underlying Turcot syndrome may be present. One-third of tumors are issued from group 4. Most adult studies are small non-randomized retrospective heterogeneous studies performed at a single center with short follow-up. Standard craniospinal irradiation followed by maintenance chemotherapy (CCNU, cisplatin-vincristine) results in a 4-year event-free survival (EFS) and overall survival (OS) of 68% and 89% respectively in standard-risk adults, and in a 4-year EFS and OS of 50% and 90%, respectively in high-risk adults. Several pooled analyses point out the potential role of chemotherapy in adults. The feasibility of pediatric protocols in adults is sometimes hampered because of blood and peripheral nerve toxicity. In the near future, subgroups of medulloblastomas may be treated by personalized therapies. With prolonged follow-up, adults fare worse. Long-term sequelae and second line treatment are not well defined in adults. Prospective studies are ongoing to define optimal first-line and relapse treatments.

Characteristics of IDH-mutant gliomas with non-canonical IDH mutation.

BACKGROUND: Approximately 10% of IDH-mutant gliomas harbour non-canonical IDH mutations (non-p.R132H IDH1 and IDH2 mutations). OBJECTIVE: The aim of this study was to analyse the characteristics of non-canonical IDH-mutant gliomas. MATERIALS AND METHODS: We retrospectively analysed the characteristics of 166 patients with non-canonical IDH mutant gliomas and compared them to those of 155 consecutive patients with IDH1 p.R132H mutant gliomas. RESULTS: The median age at diagnosis was 38 years in patients with non-canonical IDH mutant gliomas and 43 years in glioma patients with IDH1 p.R132H-mutant tumours. Family history of cancer was more frequent among glioma patients harbouring non-canonical IDH mutations than in patients with IDH1 p.R132H mutations (22.2% vs 5.1%; P < 0.05). Tumours were predominantly localised in the frontal lobe regardless of the type of IDH mutation. Compared to IDH1 p.R132H-mutant gliomas, tumours with non-canonical IDH mutations were more frequently found in the infratentorial region (5.5% vs 0%; P < 0.05) and were often multicentric (4.8% vs 0.9%; P < 0.05). Compared to IDH1 P.R132H-mutant gliomas, tumours with non-canonical IDH1 mutations were more frequently astrocytomas (65.6% vs 43%, P < 0.05), while those with IDH2 mutations were more frequently oligodendrogliomas (85% vs 48.3%; P < 0.05). The median overall survival was similar in patients with IDH1 p.R132H-mutant gliomas and patients with non-canonical IDH-mutant gliomas. CONCLUSION: Gliomas with non-canonical IDH mutations have distinct radiological and histological characteristics. The presence of such tumours seems to be associated with genetic predisposition to cancer development.

Combined analysis of MGMT methylation and dynamic-susceptibility-contrast MRI for the distinction between early and pseudo-progression in glioblastoma patients.

INTRODUCTION: Currently, no single diagnostic modality allows the distinction between early progression (EP) and pseudo-progression (Psp) in glioblastoma patients. Herein we aimed to identify the characteristics associated with EP and Psp, and to analyze their diagnostic value alone and in combination. MATERIAL AND METHODS: We reviewed the clinical, conventional magnetic resonance imaging (MRI), and molecular characteristics (MGMT promoter methylation, IDH mutation, and EGFR amplification) of glioblastoma patients who presented an EP (n=59) or a Psp (n=24) within six months after temozolomide radiochemotherapy. We analyzed relative cerebral blood volume (rCBV) and relative vessel permeability on K2 maps (rK2) in a subset of 33 patients using dynamic-susceptibility-contrast MRI. RESULTS: In univariate analysis, EP was associated with neurological deterioration, higher doses of dexamethasone, appearance of a new enhanced lesion, subependymal enhancement, higher rCBV and rK2 values. Psp occurred earlier after radiotherapy completion and was associated with IDH1 R132H mutation, and MGMT methylation. In multivariate analysis, rCBV, rK2, and MGMT methylation status were independently associated with EP and Psp. All patients with a methylated MGMT promoter and a low rCBV (<1.75) were classified as Psp while all patients with an unmethylated MGMT promoter and a high rCBV (≥1.75) were classified as EP. Among patients with discordant MGMT methylation and rCBV characteristics, higher rK2 values tended to be associated with EP. CONCLUSION: Combined analysis of MGMT methylation, rCBV and vessel permeability on K2 maps seems helpful to distinguish EP from Psp. A prospective study is warranted to confirm these results.

Spectral complexity of 5-ALA induced PpIX fluorescence in guided surgery: a clinical study towards the discrimination of healthy tissue and margin boundaries in high and low grade gliomas.

Gliomas are diffuse and hard to cure brain tumors. A major reason for their aggressive behavior is their property to infiltrate the brain. The gross appearance of the infiltrative component is comparable to normal brain, constituting an obstacle to extended surgical resection. 5-ALA induced PpIX fluorescence measurements enable gains in sensitivity to detect infiltrated cells, but still lack sensitivity to get accurate discrimination between the tumor margin and healthy tissue. In this fluorescence spectroscopic study, we assume that two states of PpIX contribute to total fluorescence to get better discrimination of healthy tissues against tumor margins. We reveal that fluorescence in low-density margins of high-grade gliomas or in low-grade gliomas is mainly influenced by the second state of PpIX centered at 620 nm. We thus conclude that consideration of the contributions of both states to total fluorescence can help to improve fluorescence-guided resection of gliomas by discriminating healthy tissues from tumor margins.

Thoracic spine intra- and extradural dumbbell-shaped meningioma: Case report and extensive review of the literature with 21 cases.

INTRODUCTION: Spinal dumbbell-shaped meningioma is a rare condition usually mistaken preoperatively for schwannoma. The present study reported a case of dumbbell-shaped meningioma, with an extensive review of literature. METHODS: A documented case of thoracic spine dumbbell-shaped meningioma is reported, followed by an extensive review of the literature to analyze epidemiological features, pathogenesis, histopathological diagnosis, location, Eden classification, surgical treatment and outcome in such tumors. RESULTS: Case report: A 55 year-old woman was admitted with paraparesis and paresthesia of lower limbs. MRI showed a dumbbell-shaped meningioma of the thoracic spine. The tumor was totally removed via a posterolateral approach. REVIEW OF THE LITERATURE: Twenty-one spinal dumbbell-shaped meningiomas were reported in the last twenty years (1997-2017). Mean patient age was 46.57 years, with female predominance. Mean disease progression was 23.11 months. The thoracic spine was the predominant site (38.09%), followed by the cervical spine (33.33%). Eden type-3 was the most frequent tumor type, accounting for 66.67% of cases. In all cases, meningiomas were classified as WHO grade I. Complete removal (Simpson I-II) was achieved in 75% of cases. There was recurrence in 3 patients (14%), including 1 case of malignant transformation leading to death at 12 years post-surgery. CONCLUSION: Spinal dumbbell-shaped meningioma is mainly of the benign subtype. Long-term follow-up shows low rates of morbidity and mortality.

Long-term impact of temozolomide on 1p/19q-codeleted low-grade glioma growth kinetics.

Although upfront temozolomide (TMZ) has been widely-used to treat 1p/19q-codeleted diffuse low-grade gliomas (LGG), its long-term impact on the growth kinetics of these tumors has not been determined. Based on serial magnetic resonance images we retrospectively evaluated the evolution of the mean tumor diameter (MTD) in 36 progressive 1p/19q-codeleted LGG treated with upfront TMZ. After TMZ onset, all but two patients (94.4%) presented a progressive MTD decrease that lasted for a median duration of 23 months (range 3-114). In 10 patients (27%) MTD regrowth occurred during TMZ treatment and in 22 patients (66%) after TMZ discontinuation. In these patients, median time to MTD regrowth after TMZ discontinuation was 12 months (range 1-88). The rate of MTD regrowth at 3 and 5 years after TMZ onset was 77 and 94%, respectively. Time to tumor progression (TTP) based on volumetric analysis was shorter than TTP based on Response Assessment in Neuro-Oncology (RANO) bidimensional criteria (23 vs. 35 months, p = 0.05) and shorter than time to next oncological treatment (23 vs. 46 months, p = 0.001). In 10 patients (27%), absence of volumetric analysis led to continue TMZ for a median of 10 cycles after MTD had started to regrow. Volumetric analysis is important to precisely assess chemotherapy efficacy in 1p/19q-codeleted LGG, identify early tumor progression and avoid futile chemotherapy continuation. In the present series, although some long-lasting volumetric responses were observed, most tumors resumed their growth within 3 years after TMZ onset.

Patterns of care and survival of glioblastoma patients: a comparative study between 2004 and 2008 in Lyon, France.

INTRODUCTION: The treatment of glioblastomas (GBMs) has changed significantly since 2005. However, the extent to which this change has improved overall survival (OS) of patients treated outside clinical trials remains to be determined. METHODS: We compared the patterns of care and OS of all GBM patients diagnosed in 2004 (n=105) and in 2008 (n=130) in our center. RESULTS: Younger patients (aged<70 years) diagnosed in 2008 received temozolomide radiochemotherapy as the initial treatment and bevacizumab at recurrence more frequently than those diagnosed in 2004 (69% vs 26% P<10(-4) and 41% vs 3%, P<10(-4), respectively). Elderly patients (aged≥70 years) diagnosed in 2008 received an oncological treatment (radiotherapy and/or chemotherapy) more frequently than those diagnosed in 2004 (67% vs 38%, P=0.006). The patients diagnosed in 2008 had longer OS than those diagnosed in 2004 (10.5 months vs 5.3 months, P=0.001). This finding was true for both younger and elderly patients (15.3 months vs 8.9 months, P=0.02 and 6.4 months vs 3.2 months, P=0.0002, respectively) and when considering only IDH1 wild-type patients (8.9 months vs 5.3 months, P=0.004). CONCLUSION: In our center, the change in the patterns of care for GBMs between 2004 and 2008 has been associated with a significant improvement in OS.

Rapid screening and confirmatory methods for biochemical diagnosis of human prion disease.

Transmissible spongiform encephalopathies (TSEs) are characterised by accumulation of an abnormal isoform of prion protein (PrP(sc)), mainly in the brain but also in various peripheral tissues. Home-made assays consisting of non-standardised protocols are used currently for laboratory diagnosis of human TSE. The purpose of the present study was to test the ability of two commercial assays, TeSeE™ CJD ELISA and TeSeE™ Western blot, to detect PrPsc in cerebral and lymphoid tissues of TSE patients. Both tests detected a PrPsc-significant signal in the brains of 54 affected patients and not in 51 controls, yielding 100% specificity and 100% sensitivity. Furthermore, three post-mortem spleens and two pre-mortem tonsils from three patients with variant Creutzfeldt-Jakob disease (vCJD) were detected correctly. The expected PrPsc molecular patterns were found in TSE patient brain tissue and in the tonsils and spleens of the three vCJD patients. In conclusion, these rapid and robust in vitro tools were suitable for routine human TSE diagnosis and characterisation. CJD could also be diagnosed during the patient's lifetime by detection of PrPsc in the tonsil. A diagnostic strategy associating TeSeE™ CJD ELISA screening to biochemical confirmation by TeSeE™ Western blot is proposed.

[Structural anatomy of cranial nerves (V, VII, VIII, IX, X)]. / Anatomie structurelle des nerfs crâniens (V, VII, VIII, IX, X).

This study reports a review of the literature on the structural anatomy of the Vth, VIIth, VIIIth, IXth, and Xth cranial nerves, known to harbor dysfunction syndromes in humans. Because these dysfunctions are hypothesized to be caused by neurovascular conflicts at the root entry/exit zone and the transitional zone between central and peripheral myelinization, this investigation focused on the study and description of this junction. All the cranial nerves, except the optic and olfactory nerves, which are considered to be more a direct expansion of the central nervous system, have a transitional zone between central myelin (coming from oligodendrocytes) and peripheral myelin (produced by Schwann cells). The human studies reported in the literature argue in favor of a dome-shaped transitional zone directed to the periphery. It seems that this junctional region is situated more peripherally in sensory nerves than in motor nerves. The transitional zone is situated very peripherally for the cochlear and vestibular nerves, and on the contrary very close to its exit from the brain stem for the facial nerve.

How a neuropsychiatric brain bank should be run: a consensus paper of Brainnet Europe II.

The development of new molecular and neurobiological methods, computer-assisted quantification techniques and neurobiological investigation methods which can be applied to the human brain, all have evoked an increased demand for post-mortem tissue in research. Psychiatric disorders are considered to be of neurobiological origin. Thus far, however, the etiology and pathophysiology of schizophrenia, depression and dementias are not well understood at the cellular and molecular level. The following will outline the consensus of the working group for neuropsychiatric brain banking organized in the Brainnet Europe II, on ethical guidelines for brain banking, clinical diagnostic criteria, the minimal clinical data set of retrospectively analyzed cases as well as neuropathological standard investigations to perform stageing for neurodegenerative disorders in brain tissue. We will list regions of interest for assessments in psychiatric disorder, propose a dissection scheme and describe preservation and storage conditions of tissue. These guidelines may be of value for future implementations of additional neuropsychiatric brain banks world-wide.

[Pulmonary MALT lymphoma revealing AIDS]. / Lymphome pulmonaire du MALT révélant un sida.

INTRODUCTION: We report the case of a patient with an isolated pulmonary mucosa associated lymphoid tissue (MALT) lymphoma that revealed an acquired immune deficiency syndrome (AIDS). CASE REPORT: A 30 year old man from Central Africa was admitted to hospital with cough, dyspnoea and general weakness. A diagnosis of HIV infection was made promptly. The thoracic CT scan revealed diffuse bilateral ground glass opacities as well as consolidation of the right upper lobe. After a non-diagnostic endoscopy the diagnosis of a low grade B cell MALT lymphoma (CD20+) was made by lung biopsy and confirmed by the presence of the t(11;18) translocation. No extrathoracic lymphoma was found. Treatment with rituximab and triple anti-retroviral therapy led to a rapid and complete remission that was maintained for 3 years after the diagnosis. CONCLUSION: Pulmonary MALT lymphoma may reveal AIDS. A combination of rituximab and anti-retroviral therapy led to complete remission in this patient.

Differential MAP kinases activation during semaphorin3A-induced repulsion or apoptosis of neural progenitor cells.

Semaphorins are multifunctional factors implicated in various developmental processes. Little is known about the intracellular pathways ensuring appropriate signal transduction that encode the diverse functions observed. In this study, we investigated whether mitogen-activated protein kinases (MAPK), which are key elements of signal transduction in eukaryotic cells, were activated during semaphorin 3A (Sema3A)-induced repulsion or apoptosis of neural progenitor cells. We found that selective recruitment of the ERK1/2 pathway occurred during Sema3A-induced neural progenitor cell repulsion, whereas p38 MAPK activation was necessary for induction of apoptosis. Moreover, we provide evidence for the involvement of vascular endothelial growth factor receptor 1 (VEGFR1) in the activation of ERK1/2. Additional experiments performed with native cerebellar progenitors confirmed such a selective recruitment of MAPK during Sema3A-dependent migration or apoptosis. Altogether, our results suggest a model to explain how a single factor can exert different functions for a given cell type by the selective recruitment of intracellular pathways.