Multivariate Analysis of RNA Chemistry Marks Uncovers Epitranscriptomics-Based Biomarker Signature for Adult Diffuse Glioma Diagnostics.

One of the main challenges in cancer management relates to the discovery of reliable biomarkers, which could guide decision-making and predict treatment outcome. In particular, the rise and democratization of high-throughput molecular profiling technologies bolstered the discovery of "biomarker signatures" that could maximize the prediction performance. Such an approach was largely employed from diverse OMICs data (i.e., genomics, transcriptomics, proteomics, metabolomics) but not from epitranscriptomics, which encompasses more than 100 biochemical modifications driving the post-transcriptional fate of RNA: stability, splicing, storage, and translation. We and others have studied chemical marks in isolation and associated them with cancer evolution, adaptation, as well as the response to conventional therapy. In this study, we have designed a unique pipeline combining multiplex analysis of the epitranscriptomic landscape by high-performance liquid chromatography coupled to tandem mass spectrometry with statistical multivariate analysis and machine learning approaches in order to identify biomarker signatures that could guide precision medicine and improve disease diagnosis. We applied this approach to analyze a cohort of adult diffuse glioma patients and demonstrate the existence of an "epitranscriptomics-based signature" that permits glioma grades to be discriminated and predicted with unmet accuracy. This study demonstrates that epitranscriptomics (co)evolves along cancer progression and opens new prospects in the field of omics molecular profiling and personalized medicine.

Security and reliability of CUSTOMBONE cranioplasties: A prospective multicentric study.

BACKGROUND: Repairing bone defects generated by craniectomy is a major therapeutic challenge in terms of bone consolidation as well as functional and cognitive recovery. Furthermore, these surgical procedures are often grafted with complications such as infections, breaches, displacements and rejections leading to failure and thus explantation of the prosthesis. OBJECTIVE: To evaluate cumulative explantation and infection rates following the implantation of a tailored cranioplasty CUSTOMBONE prosthesis made of porous hydroxyapatite. One hundred and ten consecutive patients requiring cranial reconstruction for a bone defect were prospectively included in a multicenter study constituted of 21 centres between December 2012 and July 2014. Follow-up lasted 2 years. RESULTS: Mean age of patients included in the study was 42±15 years old (y.o), composed mainly by men (57.27%). Explantations of the CUSTOMBONE prosthesis were performed in 13/110 (11.8%) patients, significantly due to infections: 9/13 (69.2%) (p<0.0001), with 2 (15.4%) implant fracture, 1 (7.7%) skin defect and 1 (7.7%) following the mobilization of the implant. Cumulative explantation rates were successively 4.6% (SD 2.0), 7.4% (SD 2.5), 9.4% (SD 2.8) and 11.8% (SD 2.9%) at 2, 6, 12 and 24 months. Infections were identified in 16/110 (14.5%): 8/16 (50%) superficial and 8/16 (50%) deep. None of the following elements, whether demographic characteristics, indications, size, location of the implant, redo surgery, co-morbidities or medical history, were statistically identified as risk factors for prosthesis explantation or infection. CONCLUSION: Our study provides relevant clinical evidence on the performance and safety of CUSTOMBONE prosthesis in cranial procedures. Complications that are difficulty incompressible mainly occur during the first 6 months, but can appear at a later stage (>1 year). Thus assiduous, regular and long-term surveillances are necessary.

Mis-diagnosed giant ovarian cyst and ventriculoperitoneal shunt malfunction.

Abdominal pseudocysts are common complications of ventriculoperitoneal shunt (VPS). We report the case of a 37-year-old woman treated by VPS for congenital obstructive hydrocephalus, who presented shunt dysfunction related to a voluminous abdominal cyst initially diagnosed as cerebrospinal fluid pseudocyst. The cyst was drained and the VPS was removed after endoscopic third ventriculocisternostomy (ETV). A few months later, a large new abdominal cyst appeared and was operated on. Diagnosis was rectified as massive ovarian mucinous cystadenoma. In any intra-abdominal cyst, differential diagnoses need considering to avoid mis-diagnosis in shunted patients, especially if the cyst is very large. The etiology of the hydrocephalus should also be investigated in case of shunt dysfunction. Even in case of longstanding shunt, ETV can be an alternative to shunt revision surgery in obstructive hydrocephalus, enabling VPS withdrawal and treatment of the hydrocephalus.

Anatomo-radiological correlation between diffusion tensor imaging and histologic analyses of glial tumors: a preliminary study.

BACKGROUND AND PURPOSE: The challenge of the neurosurgical management of gliomas lies in achieving a maximal resection without persistent functional deficit. Diffusion tensor imaging (DTI) allows non-invasive identification of white matter tracts and their interactions with the tumor. Previous DTI validation studies were compared with intraoperative cortical stimulation, but none was performed based on the tumor anatomopathological analysis. This preliminary study evaluates the correlation between the preoperative subcortical DTI tractography and histology in terms of fiber direction as well as potential tumor-related fiber disruption. METHODS: Eleven patients harboring glial tumors underwent preoperative DTI images. Correlations were performed between the visual color-coded anisotropy (FA) map analysis and the tumor histology after "en bloc" resection. Thirty-one tumor areas were classified according to the degree of tumor infiltration, the destruction of myelin fibers and neurofilaments, the presence of organized white matter fibers, and their orientation in space. RESULTS: After histologic comparison, the DTI sensitivity and specificity to predict disrupted fiber tracts were respectively of 89% and 90%. The positive and negative predicted values of DTI were 80% and 95%. The DTI data were in line with the histologic myelin fiber orientation in 90% of patients. In our series, the prevalence of destructed fiber was 31%. Glioblastoma WHO grade IV harbored a higher proportion of destructed white matter tracts. Lower WHO grades were associated with higher preservation of subcortical fiber tracts. CONCLUSION: This DTI/histology study of "en bloc"-resected gliomas reported a high and reproducible concordance of the visual color-coded FA map with the histologic examination to predict subcortical fiber tract disruption. Our series brought consistency to the DTI data that could be performed routinely for glioma surgery to predict the tumor grade and the postoperative clinical outcomes.

Management of multiple tumors in neurofibromatosis type 2 patients.

INTRODUCTION: Neurofibromatosis type 2 is characterized by the presence of bilateral vestibular schwannomas. However, other nervous system tumors may also occur. Therefore, the management of NF2 patients is complex and requires a multidisciplinary discussion in a specialized center. MATERIALS AND METHODS: All recent articles concerning tumors other than vestibular schwannoma in NF2 disease were reviewed, using PubMed databases. RESULTS: Intracranial meningiomas occur in 50% of NF2 patients, and are often multiple. Surgery remains the main treatment and should be performed in cases of growing tumors. The role of antiangiogenic therapy is currently under evaluation and the role of radiosurgery still remains to be defined in NF2 disease. Spinal tumors occur in about half of NF2 patients. Surgery should be discussed when radiological tumor progression is demonstrated, even if spinal tumors are asymptomatic, in order to preserve neurological function and good quality of life. As regards lower cranial nerve schwannomas, radiosurgery appears to be a more appropriate treatment for growing tumor with a small volume in order to avoid post-operative complications, especially swallowing disorders. Facial nerve schwannomas may appear, on MRI, like vestibular schwannomas. The diagnosis should be suspected when the facial palsy is an early symptom during cerebello-pontine tumor progression. Trigeminal schwannomas are frequent in NF2 disease and fortunately they are often asymptomatic. Among major neurofibromatosis types, peripheral nerve sheath schwannomas are only present in patients with NF2 disease and schwannomatosis. Surgical resection is required when the cutaneous schwannomas is painful or when tumor progression is observed and causes symptoms. CONCLUSION: Tumors other than vestibular schwannoma are also associated with a poor prognosis in NF2 patients. Surgery remains the main treatment in most cases. Each treatment decision in NF2 disease requires a complete evaluation of all cranial and spinal locations of the disease in order to establish surgical priorities and strategies.

Engineering thiophene-based nanoparticles to induce phototransduction in live cells under illumination.

We report that nanoparticles prepared from appropriately functionalized polythiophenes once administered to live cells can acquire phototransduction properties under illumination, becoming photoactive sites able to absorb visible light and convert it to an electrical signal through cell membrane polarization. Amine-reactive fluorescent nanoparticles with pendant N-succinimidyl-ester groups (NPs-NHS) are prepared from polythiophenes alternating unsubstituted and 3-(2,5-dioxopyrrolidin-1-yl-8-octanoate)-substituted thiophenes by a nanoprecipitation method. By 1H NMR of nanoparticles prepared using THF-d8/D2O (solvent/non-solvent) we demonstrate that the hydrolysis of the N-succinimidyl-ester group to free N-hydroxysuccinimide takes place slowly over several hours. NPs-NHS reactivity towards primary amine groups is tested towards the NH2 of d- and l-enantiomers of tryptophan. We show that the formation of a tryptophan-nanoparticle amidic bond creates a chiral shell displaying opposite CD signals for the nanoparticles bound to d or l enantiomers. The interaction of NPs-NHS with live HEK-293 cells is monitored via LSCM. We show that the NPs-NHS are not internalized but remain docked on the cell membrane. We assume that this is mainly the result of the reaction of the NHS groups in the external layer with NH2 groups present in cell membrane proteins, although the contribution of alternative mechanisms cannot be excluded. To support this assumption LSCM experiments show that nanoparticles of comparable size obtained from poly(3-hexylthiophene), NPs-P3HT, are rapidly internalized by live HEK-293 cells. Finally, using the whole-cell current clamp technique under light illumination we demonstrate that NPs-NHS can polarize the cell membrane upon light irradiation while NPs-P3HT cannot.

Grade 1 Spetzler and Martin cerebral ruptured arteriovenous malformations treated by microsurgery: Poor functional outcome is related to injury from haemorrhage.

INTRODUCTION: Ruptured arteriovenous malformations (rAVM) are life-threatening diseases. OBJECTIVE: To evaluate the outcome of patients with grade 1 SPM rAVM after microsurgical treatment. MATERIALS AND METHOD: We retrospectively included 64 consecutive operated patients with a grade 1 SPM rAVM in our institution between 2002 and 2012. Complications related to the surgical procedure were recorded. All patients were re-evaluated 3months after treatment using the modified Rankin Scale score (mRS). Persistent neurological disorders were evaluated 1year after bleeding. Conventional cerebral angiography was performed for each patient immediately after surgical treatment and 1year later. RESULTS: The mean age at diagnosis was 30.8 years. Initial WFNS score was grade 1 in 25 patients, grade 2 in 11 patients, grade 3 in 10 patients, grade 4 in 9 patients and grade 5 in 9 patients. No remnant was left and a new surgery was performed only in a single patient who was initially operated-on under emergency conditions with limited preoperative investigations due to a poor clinical grade. Early postoperative complications related to the surgical procedure were recorded in 7 patients. The mRS score 3months after treatment was ≤2 in 53 patients (83%). Persistent neurological disorders were recorded in 40 patients (62.5%). High initial WFNS score (>2) and the hydrocephalus were significantly associated (P<0.05) to a bad functional outcome (mRS>2). CONCLUSION: Grade 1 rAVM is a life-threatening disease concerning in most cases young patients. Long-term morbidity is often related to the hemorrhagic brain damage and rarely to the AVM resection.

[Epidemiology, treatment and follow-up of central nervous system hemangioblastomas in von Hippel-Lindau disease]. / Épidémiologie, traitement et suivi des hémangioblastomes du système nerveux central dans le cadre de la maladie de von Hippel-Lindau.

INTRODUCTION: Central nervous system (CNS) hemangioblastomas (HGB) are rare vascular tumors. The goal of this study was to analyze their epidemiology, treatment and prognosis in association with von Hippel-Lindau (VHL) disease. METHODS: We retrospectively reviewed a series of patients treated in our department for a CNS HGB with VHL disease between 1996 and 2008. We analyzed pre- and postoperative clinical and radiological characteristics, number of visceral lesions (fundoscopy, abdomino-pelvian CT, metanephrines), clinical course (modified Rankin Scale and McCormick scale) and late prognosis (Kaplan-Meier survival curves). RESULTS: We studied 19 cases (sex-ratio 0.9, mean age 36). The mean time to diagnosis was 61days. The main symptom was intracranial hypertension for cerebellar lesions (7/15) and a sensitive-motor deficit for medulla oblongata (2/5) or spinal lesions (5/11). Preferred locations were cerebellum (15/31), often nodulo-cystic appearance, followed by spinal cord (11/31), frequently coming with adjacent syringomyelia. Multiple locations and visceral lesions were found in two-third of the cases. Surgical removal was complete in more than three-quarter of the cases. Mean follow-up duration was 9years. Postoperative mortality rate was 16%. In cerebellar and medulla oblongata locations together, final mRS was ≤1 in 17 of the 20 cases. In spinal cord locations, final McCormick score was ≤2 in all the cases. After delayed follow-up, about two-third of patients experienced recurrence or new progressive CNS lesions. CONCLUSION: HGB are rare CNS tumors. VHL disease should be considered when an HGB is diagnosed before 30, is located at the spinal cord, comes with multiple other CNS lesions or with typical peripheral lesions. Microsurgical removal is the gold standard treatment and can offer good functional results.

Live cell cytoplasm staining and selective labeling of intracellular proteins by non-toxic cell-permeant thiophene fluorophores.

A structurally correlated series of cell-permeant thiophene fluorophores, characterized by intense green or red fluorescence inside live mouse embryonic fibroblasts, was developed. The fluorophores displayed rapid internalization, excellent retention inside the cells, and high optical stability in the cytosolic environment and did not alter cell viability and reproducibility. Depending on the molecular structure, they experienced distinct fate inside the cells: from bright and lasting staining of the cytoplasm to selective tagging of a small set of globular proteins.

Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors.

Glioblastomas are the most aggressive of the brain tumors occurring in adults and children. Currently available chemotherapy prolongs the median survival time of patients by only 4 months. The low efficiency of current treatments is partly owing to the blood-brain barrier, which restricts the penetration of most drugs into the central nervous system. Locoregional treatment strategies thus become mandatory. In this context, viral tools are of great interest for the selective delivery of genes into tumoral cells. Gliomas express high levels of type 2 somatostatin receptors (sstr2A), pinpointing them as suitable targets for the improvement of transduction efficiency in these tumors. We designed a new adenoviral vector based on the introduction of the full-length somatostatin (SRIF (somatotropin release-inhibiting factor)) sequence into the HI loop of the HAdV fiber protein. We demonstrate that (i) HAdV-5-SRIF uptake into cells is mediated by sstr2A, (ii) our vector drives high levels of gene expression in cells expressing endogenous sstr2A, with up to 65-fold enhancement and (iii) low doses of HAdV-5-SRIF are sufficient to infect high-grade human primary glioblastoma cells. Adenoviral vectors targeting SRIF receptors might thus represent a promising therapeutic approach to brain tumors.

[Haemophilia A and intracranial bleedings in infants]. / Hémophilie A et saignements intracrâniens du nourrisson.

BACKGROUND AND PURPOSE: Haemophilia is a well-known X-linked recessive bleeding disorder related to a deficiency of factor VIII. The aim of the paper is to point out the role of an early diagnosis in cases of intracranial bleeding, especially in neonates and to highlight the bad prognosis. METHODS: Three patients were included in the study from our prospective data. All had severe factor VIII deficiency (less than 1%). RESULTS: The first of them was a newborn without familial history of haemophilia which presented with hypotonia and seizures after a delivery with vacuum. CT showed a subdural haematoma and MRI multiple ischemic lesions. Two months later, he died from a new intracranial haemorrhagic episode resistent to infusion of factor VIII related to development of an anti-factor VIII antiboby. The second neonate had no familial history more and experienced hypothermia and areactive mydriasis because of an acute subdural haematoma. He died eight days later of ischemic lesions in spite of a craniotomy. The third was a 5-month-old boy with a familial history. Physical examination revealed lethargy, seizure and a recent cranial perimeter increase. He underwent a craniotomy with a good result. CONCLUSION: The authors stress the need for immediate factor VIII infusion and appropriate neurosurgical work-up. The rapid medical management is mandatory if morbidity and mortality are to be minimized.

[Surgical anatomy of the lateral ventricles]. / Anatomie chirurgicale des ventricules latéraux.

The lateral ventricle is a deep-seated cavity, overlayed by a cortical mantle which contains eloquent areas, especially on the dominant hemisphere, and surrounded by the optic radiations. The surgical approach requires a thorough preoperative reflexion based on magnetic resonance imaging, in order to understand the site of origin and the vascular pedicles of the tumor. Surgical approaches to the frontal horn, temporal horn and atrium are successively described.

[Tumors of the lateral ventricle in child: characteristics and specificities]. / Tumeurs du ventricule latéral de l'enfant: particularités et spécificités.

Tumors of the lateral ventricle are not as rare in children as in adults and present complex problems which are to be dealt with often in a context of emergency, on account of their large size and the risk of life-threatening bleeding in a small child. Their diagnostic features are different in children, especially in infants and even more so in the fetus. The main surgical problems are the risk of bleeding and of hydraulic complications. From an oncological perspective, the main tumor types are choroid plexus tumors, subependymal giant-cell astrocytoma, and low-grade gliomas. The developmental outcome of these patients is often poor, on account of severe intracranial hypertension and young age at diagnosis.

[Subependymomas of lateral ventricle. Analysis of our series and review of literature]. / Les subépendymomes (astrocytomes subépendymaires) du ventricule latéral. Analyse de notre série et revue de la littérature.

Subependymoma is a benign lesion, slow-growing neoplasm, representing 0.2 to 0.7 % of intracranial tumors. They are often clinically silent, incidentally discovered at autopsy. These symptoms are related to big volume. They are attached to the septum pellucidum, leading to hydrocephalus by Monro foramen obstruction. Overall mean age at diagnosis is 39 years with more males than females. At CT-scan, subependymoma shows a slightly low attenuation compared to gray matter. There is no or mild enhancement following contrast injection. On MR T1-weighted imaging, subependymoma is isointense and hyperintense on MR T2-weighted imaging. Intramural calcifications and cystic components are noted in 20 to 30 % of patients. Peritumoral oedema is absent. Immunohistochemicals studies show intense positivity for S-100 and GFAP. The treatment is surgical with an excellent prognosis.

[Meningiomas of the lateral ventricle. A series of 40 cases with analysis of the literature]. / Les méningiomes du ventricule latéral. Analyse d'une série de 40 cas et revue de la littérature.

This series reports 40 cases of meningiomas of the lateral ventricle treated in France between 1995 and 2010. The mean age was 52 years. The revelation was incidental in 23% of cases. 36 patients underwent surgery with uneventful postoperative course in 75% of them. Visual field deficits were the most frequent sequelae. In six cases, recurrences occurred during the follow-up period. The relevant series of the literature were discussed in order to precise the therapeutic strategies and the outcome.

[Rare tumors of the lateral ventricle. Review of the literature]. / Les tumeurs rares du ventricule latéral. Revue de la littérature.

Metastases of lateral ventricle (LV) are attached to choroidal plexus. Primary source is cancer of kidney. Two thirds of patients are male. Oligodendrogliomas occur in young females. Signs of increased intracranial pressure are a constant feature. These tumors are found in anterior portion of the LV with severe enhancement and clumped calcifications. Treatment is surgical. Cavernomas have a preponderance of rapid growth with a bleeding revelation. Seizures are rare. Rebleeding is frequent and justifies a surgical treatment. Schwannomas are a rare entity in which the majority of patients are very young. MRI shows calcifications, cystic components and a strong enhancement. They are limited to sporadic cases, never associated with neurofibromatosis. Arachnoid cysts are located in the atrium and/or in the occipital horn. Patients are young (mean age < 40 years). MRI demonstrates an intracystic lesion with signal intensity similar to the CSF. Best treatment is an endoscopic fenestration. Epidermoid cysts occur in third decade. These pearly tumors appear isointense or a little hyperintense on T1-weighted imaging, very characteristic. They are enhanced after gadolinium injection and appear strongly hyperintense on T2-weighted imaging. An incomplete removal with a thorough long-term follow-up is necessary. Cavernomas of LV are hyperintense on T1- and T2-weighted imaging. They have a bleeding risk of 25 to 45%. Therefore, they must be operated.

[Fundamental embryology and anatomy of the lateral ventricle]. / Embryologie et anatomie fondamentale du ventricule latéral.

The lateral ventricles are the C-shaped cavities of the telencephalon. Embryology of theses cavities is recalled as well as the immediate relationship of the frontal horn, the body, the atrium and the temporal and occipital horns.

[Ependymomas of the lateral ventricle. A series of 27 cases with review of the literature]. / Les épendymomes du ventricule latéral. Analyse de 27 cas et revue de la littérature.

Twenty-seven cases of ependymoma were collected in the French multicentric study dedicated to lateral ventricle tumors. The mean age of patients was 31,5 years. All patients underwent surgery, with complete resection of the tumor in 76% of cases. Histologic examination disclosed 23 grade 2 ependymomas and four grade 3 ependymomas. Postoperative mortality was 7%. Four patients underwent radiotherapy, and five chemotherapy. Local recurrence of the tumor occurred in seven cases, with a mean delay of 48 months. Disseminated disease within the central nervous system was found in only one patient. Median survival in all the 27 patients was 181 months, and median progression-free survival was 106 months. The relevant series of the literature are reviewed in order to precise the prognostic factors of ependymomas and therapeutic strategies.

[Arteries and veins of the lateral ventricle]. / Vascularisation des ventricules latéraux.

Tumors of the frontal horn of the lateral ventricle (LV) are only supplied by the posteromedial choroidal artery. Tumors of the body of the LV are supplied by the same artery. Tumors of the atrium of the LV with anterior extension are supplied by both posteromedial choroidal and posterolateral arteries. Tumors of the atrium with inferior extension are supplied by both anterior choroidal artery and posterolateral choroidal arteries. Tumors of the inferior horn are only supplied by anterior choroidal artery. The tumoral venous drainage is organized with three main groups of veins: a medial group, a lateral group and a choroidal group.

[Tumors of the lateral ventricle. Review of 284 cases]. / Tumeurs du ventricule latéral. Analyse d'une série de 284 cas.

UNLABELLED: The data from 284 cases of lateral ventricle (VL) tumors treated in 18 departments of Neurosurgery in France between 1995 and 2010 were collected in this series. The mean age was 33 years with a large proportion of children (79/284). CLINICAL PRESENTATION: The mean duration of symptoms was short in time (2 months). The revelation was incidental in 10% of the cases; for symptomatic lesions, raised intracranial pressure (ICP, due to hydrocephalus) and neuropsychological signs were the most frequent. Only one third of the patients had no CSF disorder. HISTOPATHOLOGY: The two most frequent tumors were meningiomas (40 cases, 15%) and neurocytomas (35 cases, 13%). The sub-ependymal giant cells astrocytomas, the ependymomas and sub-ependymomas were also common (11, 10 and 9% respectively). THERAPEUTIC MANAGEMENT: A surgical procedure was performed in 258 patients, with the help of neuronavigation in one third of cases. The patients were most frequently operated with a transfrontal approach (40%). The resection was complete in 73%, which was a statistical factor of global survival. The postoperative mortality rate was 4.9%. OUTCOME: Neuropsychological deficits were the most frequent sequelae (22.8%) due to raised ICP. Campimetric deficits (19%), seizures (19%), hemiparesis (15%) and language disorders (12%) were then found. The mean follow-up was 52 months with good evolution for 58% of patients. Fifteen percent of patients had a handicap and, finally, 12.9% will die. At last, two third of living patients had no tumoral residue or re-evolution.