Surgery vs. Radiosurgery for Patients with Localized Metastatic Brain Disease: A Systematic Review with Meta-Analysis of Randomized Controlled Trials.

Purpose: To analyze the efficacy and safety of surgery compared to radiosurgery (RS), combined or not with whole brain radiotherapy (WBRT), for localized metastatic brain disease. Methods: A systematic review with meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The inclusion criteria were limited to randomized controlled trials (RCTs) that compared surgery and RS for patients with up to 3 metastases (median diameter ≤ 4 cm). The primary outcomes were represented by overall survival (OS) and local brain progression-free survival (PFS), with the rate of complications as a secondary outcome. The pooled estimates were calculated using random forest models. The risk of bias was evaluated using the RoB2 revised tool and the certainty of the evidence was assessed according to the GRADE guidelines. Results: In total, 11,256 records were identified through database and register searches. After study selection, 3 RCTs and 353 patients were included in the quantitative synthesis. Surgery and RS represented the main intervention arms in all the included RCTs. Conclusions: A low level of evidence suggests that RS alone and surgery followed by WBRT provide an equal rate of local brain PFS in patients with localized metastatic brain disease. There is a very low level of evidence that surgery and RS as main interventions offer equivalent OS in the population investigated. A reliable assessment of the complication rates among surgery and RS was not achievable. The lack of high-certainty evidence either for superiority or equivalence of these treatments emphasizes the need for further, more accurate, RCTs comparing surgery and RS as local treatment in patients with oligometastatic brain disease.

Prevention of Post-Operative Pain after Elective Brain Surgery: A Meta-Analysis of Randomized Controlled Trials.

Background and Objective: To analyze the effects of several drug for pain prevention in adults undergoing craniotomy for elective brain surgery. Material and Methods: A systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The inclusion criteria were limited to randomized controlled trials (RCTs) that evaluated the effectiveness of pharmacological treatments for preventing post-operative pain in adults (aged 18 years or older) undergoing craniotomies. The main outcome measures were represented by the mean differences in validated pain intensity scales administered at 6 h, 12 h, 24 h and 48 h post-operatively. The pooled estimates were calculated using random forest models. The risk of bias was evaluated using the RoB2 revised tool, and the certainty of evidence was assessed according to the GRADE guidelines. Results: In total, 3359 records were identified through databases and registers' searching. After study selection, 29 studies and 2376 patients were included in the meta-analysis. The overall risk of bias was low in 78.5% of the studies included. The pooled estimates of the following drug classes were provided: NSAIDs, acetaminophen, local anesthetics and steroids for scalp infiltration and scalp block, gabapentinoids and agonists of adrenal receptors. Conclusions: High-certainty evidence suggests that NSAIDs and acetaminophen may have a moderate effect on reducing post-craniotomy pain 24 h after surgery compared to control and that ropivacaine scalp block may have a bigger impact on reducing post-craniotomy pain 6 h after surgery compared to control. Moderate-certainty evidence indicates that NSAIDs may have a more remarkable effect on reducing post-craniotomy pain 12 h after surgery compared to control. No moderate-to-high-certainty evidence indicates effective treatments for post-craniotomy pain prevention 48 h after surgery.

Predicting tumor consistency and extent of resection in non-functioning pituitary tumors.

PURPOSE: To (1) identify a radiological parameter to predict non-functioning pituitary tumor (NFPT) consistency, (2) examine the relationship between NFPT consistency and extent of resection (EOR), (3) investigate if tumor consistency predictors can anticipate EOR. METHODS: The ratio (T2SIR) between the T2 min signal intensity (SI) of the tumor and the T2 mean SI of the CSF was the main radiological parameter, being determined through a radiomic-voxel analysis and calculated using the following formula: T2SIR = [(T2 tumor mean SI - SD)/T2 CSF SI]. The tumor consistency was pathologically estimated as collagen percentage (CP). EOR of NFPTs was evaluated by exploiting a volumetric technique and its relationship with the following explanatory variables was explored: CP, Knosp-grade, tumor volume, inter-carotid distance, sphenoidal sinus morphology, Hardy-grade, suprasellar tumor extension. RESULTS: A statistically significant inverse correlation between T2SIR and CP was demonstrated (p = 0.0001), with high diagnostic power of T2SIR in predicting NFPT consistency (ROC curve analysis' AUC = 0.88; p = 0.0001). The following predictors of EOR were identified in the univariate analysis: CP (p = 0.007), preoperative volume (p = 0.045), Knosp grade (p = 0.0001), tumor suprasellar extension (p = 0.044). The multivariate analysis demonstrated two variables as unique predictors of EOR: CP (p = 0.002) and Knosp grade (p = 0.001). The T2SIR was a significant predictor of EOR both in the univariate (p = 0.01) and multivariate model (p = 0.003). CONCLUSION: This study offers the potential to improve NFPT preoperative surgical planning and patient counseling by employing the T2SIR as a preoperative predictor of tumor consistency and EOR. Meanwhile, tumor consistency and Knosp grade were found to play an important role in predicting EOR.

Magnetic susceptibility as a 1-year predictor of outcome in familial cerebral cavernous malformations: a pilot study.

OBJECTIVES: To test whether quantitative susceptibility mapping (QSM) of cerebral cavernous malformations (CCMs) assessed at baseline may predict the presence or absence of haemorrhagic signs at 1-year follow-up. METHODS: Familial CCM patients were enrolled in the longitudinal multicentre study Treat-CCM. The 3-T MRI scan allowed performing a semi-automatic segmentation of CCMs and computing the maximum susceptibility in each segmented CCM (QSMmax) at baseline. CCMs were classified as haemorrhagic and non-haemorrhagic at baseline and then subclassified according to the 1-year (t1) evolution. Between-group differences were tested, and the diagnostic accuracy of QSMmax in predicting the presence or absence of haemorrhagic signs in CCMs was calculated with ROC analyses. RESULTS: Thirty-three patients were included in the analysis, and a total of 1126 CCMs were segmented. QSMmax was higher in haemorrhagic CCMs than in non-haemorrhagic CCMs (p < 0.001). In haemorrhagic CCMs at baseline, the accuracy of QSMmax in differentiating CCMs that were still haemorrhagic from CCMs that recovered from haemorrhage at t1 calculated as area under the curve (AUC) was 0.78 with sensitivity 62.69%, specificity 82.35%, positive predictive value (PPV) 93.3% and negative predictive value (NPV) 35.9% (QSMmax cut-off ≥ 1462.95 ppb). In non-haemorrhagic CCMs at baseline, AUC was 0.91 in differentiating CCMs that bled at t1 from stable CCMs with sensitivity 100%, specificity 81.9%, PPV 5.1%, and NPV 100% (QSMmax cut-off ≥ 776.29 ppb). CONCLUSIONS: The QSMmax in CCMs at baseline showed high accuracy in predicting the presence or absence of haemorrhagic signs at 1-year follow-up. Further effort is required to test the role of QSM in follow-up assessment and therapeutic trials in multicentre CCM studies. KEY POINTS: • QSM in semi-automatically segmented CCM was feasible. • The maximum magnetic susceptibility in a single CCM at baseline may predict the presence or absence of haemorrhagic signs at 1-year follow-up. • Multicentric studies are needed to enforce the role of QSM in predicting the CCMs' haemorrhagic evolution in patients affected by familial and sporadic forms.

Indication and eligibility of glioma patients for awake surgery: A scoping review by a multidisciplinary perspective.

Background: Awake surgery (AS) permits intraoperative mapping of cognitive and motor functions, allowing neurosurgeons to tailor the resection according to patient functional boundaries thus preserving long-term patient integrity and maximizing extent of resection. Given the increased risks of the awake scenario, the growing importance of AS in surgical practice favored the debate about patient selection concerning both indication and eligibility criteria. Nonetheless, a systematic investigation is lacking in the literature. Objective: To provide a scoping review of the literature concerning indication and eligibility criteria for AS in patients with gliomas to answer the questions:1) "What are the functions mostly tested during AS protocols?" and 2) "When and why should a patient be excluded from AS?". Materials and methods: Pertinent studies were retrieved from PubMed, PsycArticles and Cochrane Central Register of Controlled Trials (CENTRAL), published until April 2021 according to the PRISMA Statement Extension for Scoping Reviews. The retrieved abstracts were checked for the following features being clearly stated: 1) the population described as being composed of glioma(LGG or HGG) patients; 2) the paper had to declare which cognitive or sensorimotor function was tested, or 2bis)the decisional process of inclusion/exclusion for AS had to be described from at least one of the following perspectives: neurosurgical, neurophysiological, anesthesiologic and psychological/neuropsychological. Results: One hundred and seventy-eight studies stated the functions being tested on 8004 patients. Language is the main indication for AS, even if tasks and stimulation techniques changed over the years. It is followed by monitoring of sensorimotor and visuospatial pathways. This review demonstrated an increasing interest in addressing other superior cognitive functions, such as executive functions and emotions. Forty-five studies on 2645 glioma patients stated the inclusion/exclusion criteria for AS eligibility. Inability to cooperate due to psychological disorder(i.e. anxiety),severe language deficits and other medical conditions(i.e.cardiovascular diseases, obesity, etc.)are widely reported as exclusion criteria for AS. However, a very few papers gave scale exact cut-off. Likewise, age and tumor histology are not standardized parameters for patient selection. Conclusion: Given the broad spectrum of functions that might be safely and effectively monitored via AS, neurosurgeons and their teams should tailor intraoperative testing on patient needs and background as well as on tumor location and features. Whenever the aforementioned exclusion criteria are not fulfilled, AS should be strongly considered for glioma patients.

Percutaneous Cement-Augmented Screws Short Fixation for the Treatment of Severe Osteoporotic Vertebral Burst Fractures.

OBJECTIVE: This study aims to evaluate the therapeutic reliability of posterior percutaneous cement-augmented screws short fixation (PASF) in patients with severe osteoporotic vertebral burst fractures (OVBFs). METHODS: Single-level OVBFs with an anterior vertebral body height reduction ≥60% were included. A Frailty Index was used for preoperative frailty assessment. Back pain and related disability were assessed through the visual analog scale (VAS) and Oswestry Low Back Pain Disability Index (ODI), administered at injury time, preoperatively, postoperatively, at 12 months and at last patient follow-up evaluation. The main radiologic outcomes were represented by Cobb angle (CA) and anterior vertebral body compression percentage, measured at injury time, preoperative, postoperatively and at 12-month examination. In addition, the incidence of cement leakages and hardware failures was assessed. RESULTS: Thirty-three patients met the inclusion criteria. All patients were frail (76%) or semi-frail (24%). Significant vertebral body height restoration and segmental kyphosis improvement after PASF were documented (anterior vertebral body compression percentage, -40 [-43 to -37] vs. -67 [-70 to -65], P = 0.0001; CA, 10 [8-12] vs. 24 [23-26], P = 0.0001). The mean VAS and ODI scores documented optimal and long-enduring pain relief and related disability reduction after PASF (VAS score, 2 [2-3] vs. 8 [7-8], P = 0.0001; ODI, 22 [17-26] vs. 64 [60-69], P = 0.0001). Only 1 cement leakage (3%), asymptomatic, occurred. After a mean follow-up of 33 months, no early/late hardware failures were reported. CONCLUSIONS: The clinical and radiologic results of this study suggest that PASF could be a safe and effective treatment option for severe OVBFs when conservative treatments have failed.

Management of patients with cervical spine trauma in the emergency department: a systematic critical appraisal of guidelines with a view to developing standardized strategies for clinical practice.

Several guidelines on the evaluation of patients with suspected cervical spine trauma in the Emergency Department (ED) exist. High heterogeneity between different guidelines has been reported. Aim of this study was to find areas of agreement and disagreement between guidelines, to identify topics in which further research is needed and to provide an evidence-based cervical spine trauma algorithm for ED physicians. The three most relevant guidelines published on cervical spine trauma in the last 10 years were selected screening websites of the main scientific societies and through the comparison of a normalized Google Scholar and SCOPUS citation index. We compared the selected guidelines through seven a-priori defined questions. In case of disagreement between the guidelines or if the quality of evidence appeared low, evidence from published systematic reviews on the topic was added to build an evidence-based algorithm for approach to spinal trauma in the ED. The three selected guidelines were: NICE 2016, Eastern Association for the Surgery of Trauma 2009 and American Association of Neurological Surgeons and Congress of Neurological Surgeons 2013. We found complete agreement on one question, partial agreement for one questions, no agreement for two questions, while agreement was not assessable for 3 questions. The agreement between different guidelines and the evidence on which recommendations are based is low. An attempt to build an evidence-based algorithm has been made. More studies are needed on many topics.

Clinical, neuroradiological and genetic findings in a cohort of patients with multiple Cerebral Cavernous Malformations.

Cerebral cavernous malformations (CCM) consist of clusters of irregular dilated capillaries and represent the second most common type of vascular malformation affecting the central nervous system. CCM might be asymptomatic or cause cerebral hemorrhage, seizures, recurrent headaches and focal neurologic deficits. Causative mutations underlining CCM have been reported in three genes: KRIT1/CCM1, MGC4607/CCM2 and PDCD10/CCM3. Therapeutic avenues are limited to surgery. Here we present clinical, neuroradiological and molecular findings in a cohort of familial and sporadic CCM patients. Thirty subjects underwent full clinical and radiological assessment. Molecular analysis was performed by direct sequencing and MLPA analysis. Twenty-eight of 30 subjects (93%) experienced one or more typical CCM disturbances with cerebral/spinal hemorrhage being the most common (43%) presenting symptom. A molecular diagnosis was achieved in 87% of cases, with three novel mutations identified. KRIT1/CCM1 patients displayed higher risk of de novo CCMs appearance and bleedings. Magnetic Resonance Imaging (MRI) showed that infratentorial region was more frequently affected in mutated subjects while brainstem was often spared in patients with negative genetic testing.

Does COVID-19 Affect Survival and Functional Outcome in Emergency and Urgent Neurosurgical Procedures? A Single-Center Prospective Experience During the Pandemic.

OBJECTIVE: To assess organizational and technical difficulties of neurosurgical procedures during the coronavirus disease 2019 (COVID-19) pandemic and their possible impact on survival and functional outcome and to evaluate virological exposure risk of medical personnel. METHODS: Data for all urgent surgical procedures performed in the COVID-19 operating room were prospectively collected. Preoperative and postoperative variables included demographics, pathology, Karnofsky performance status (KPS) and neurological status at admission, type and duration of surgical procedures, length of stay, postoperative KPS and functional outcome comparison, and destination at discharge. We defined 5 classes of pathologies (traumatic, oncological, vascular, infection, hydrocephalus) and 4 surgical categories (burr hole, craniotomy, cerebrospinal fluid shunting, spine surgery). Postoperative SARS-CoV-2 infection was checked in all the operators. RESULTS: We identified 11 traumatic cases (44%), 4 infections (16%), 6 vascular events (24%), 2 hydrocephalus conditions (8%), and 2 oncological cases (8%). Surgical procedures included 11 burr holes (44%), 7 craniotomies (28%), 6 cerebrospinal fluid shunts (24%), and 1 spine surgery (4%). Mean patient age was 57.8 years. The most frequent clinical presentation was coma (44 cases). Mean KPS score at admission was 20 ± 10, mean surgery duration was 85 ± 63 minutes, and mean length of stay was 27 ± 12 days. Mean KPS score at discharge was 35 ± 25. Outcome comparison showed improvement in 16 patients. Four patients died. Mean follow-up was 6 ± 3 months. None of the operators developed postoperative SARS-CoV-2 infection. CONCLUSIONS: Standardized protocols are mandatory to guarantee a high standard of care for emergency and urgent surgeries during the COVID-19 pandemic. Personal protective equipment affects maneuverability, dexterity, and duration of interventions without affecting survival and functional outcome.

The "Parachute" Technique for the Endoscopic Repair of High-Flow Anterior Skull-Base CSF Leaks.

OBJECTIVE: This study aims to assess the feasibility and reliability of our endoscopic trans-nasal technique for the repair of cribriform and sellar high-flow cerebrospinal fluid (CSF) leaks. METHODS: A comparison between patients suffering from high-flow rhinorrhea and treated through a free grafting endoscopic technique or the "parachute" technique, our nasal packing proposal, was performed. RESULTS: Thirty-three patients were included. The mean age was 52 years (range: 36-68 years). The etiology of the CSF leaks was iatrogenic in 16 cases (48.5%), traumatic in 5 cases (15.2%), spontaneous in 11 cases (33.3%), and related to anterior skull base tumors in 1 case (3%). The bone defect affected the sphenoidal sinus in 20 cases (60.6%), the cribriform plate of the ethmoid in 10 cases (30.3%), and both the sphenoid and ethmoid in 3 cases (9.1%). The mean size of bone defects was 8.5 ± 3.9 mm. The median follow-up was 28 (64) months. A CSF leak recurrence occurred in no cases treated with the parachute technique and in 3 cases that underwent conventional endoscopic treatments. The CSF leak recurrences were associated with 2 iatrogenic and 1 post-traumatic fistula. All the CSF leak recurrences underwent the parachute technique, not showing second recurrences. CONCLUSIONS: Our results suggest that the parachute technique is simple, safe, and effective. We recommend it as an alternative treatment to vascular flaps for the treatment of high-flow and recurrent fistulas.

Insular lobe surgery and cognitive impairment in gliomas operated with intraoperative neurophysiological monitoring.

BACKGROUND: For a long time, surgery of insular gliomas was considered at high risk for postoperative cognitive deficits, but recent studies highlighted the feasibility of the surgical approach. The aims of our study were to investigate the presence of language impairment before and after surgery and the relationship between language impairment and tumor volume preoperatively and extent of resection (EOR) 3 months after surgery. METHODS: Thirty-five patients with insular gliomas underwent an extensive language assessment before and few days after surgery, and after 3 months. Intraoperative neurophysiological monitoring (IOM) and brain mapping with direct electrical stimulation (DES) were used in all the cases; 8 patients underwent awake craniotomy. Statistical analysis was performed on the language tests administered. RESULTS: Patients with pure left insular lesion showed language impairment before and after surgery. Overall, patients with a left lesion showed a drop of performance after surgery followed by a partial recovery. Moreover, when the tumor involved the insula and adjacent networks, we observed a more severe deficit. No correlations were found between tumor volume, EOR, and language impairment. CONCLUSIONS: Left insular lobe is an important hub in language networks; its involvement determines pre- and postsurgical deficits, together with the involvement of white matter connections. Tumor volume and EOR are not risk factors per se directly related to language functioning. Surgery of insular gliomas is possible with a pre- and intraoperative extensive study of the patient with IOM and awake surgery, and encouraged by the trend of cognitive recovery highlighted.

Propranolol for familial cerebral cavernous malformation (Treat_CCM): study protocol for a randomized controlled pilot trial.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular malformations characterized by clusters of enlarged leaky capillaries in the central nervous system. They may result in intracranial haemorrhage, epileptic seizure(s), or focal neurological deficits, and potentially lead to severe disability. Globally, CCMs represent the second most common intracranial vascular malformation in humans, and their familial form (FCCMs) accounts for one-fifth of cases. Neurosurgical excision, and perhaps stereotactic radiosurgery, is the only available therapeutic option. Case reports suggest that propranolol might modify disease progression. METHODS: Treat_CCM is a prospective, randomized, open-label, blinded endpoint (PROBE), parallel-group trial involving six Italian clinical centres with central reading of brain magnetic resonance imaging (MRI) and adverse events. Patients with symptomatic FCCMs are randomized (2:1 ratio) either to propranolol (40-80 mg twice daily) in addition to standard care or to standard care alone (i.e. anti-epileptic drugs or headache treatments). The primary outcome is intracranial haemorrhage or focal neurological deficit attributable to CCMs. The secondary outcomes are MRI changes over time (i.e. de novo CCM lesions, CCM size and signal characteristics, iron deposition, and vascular leakage as assessed by quantitative susceptibility mapping and dynamic contrast enhanced permeability), disability, health-related quality of life, depression severity, and anxiety (SF-36, BDI-II, State-Trait Anxiety Inventory). DISCUSSION: Treat_CCM will evaluate the safety and efficacy of propranolol for CCMs following promising case reports in a randomized controlled trial. The direction of effect on the primary outcome and the consistency of effects on the secondary outcomes (even if none of them yield statistically significant differences) of this external pilot study may lead to a larger sample size in a definitive phase 2 trial. TRIAL REGISTRATION: ClinicalTrails.gov, NCT03589014. Retrospectively registered on 17 July 2018.

Long-term follow-up of neuropsychological functions in patients with high grade gliomas: can cognitive status predict patient's outcome after surgery?

BACKGROUND: Patients affected by a high-grade glioma (HGG) have a poor prognosis with a median survival of 12-16 months. Such poor prognosis affects the perception of the remaining life by patients and the neuropsychological status can strongly affect every-day functioning of these patients. Monitoring changes of neuropsychological functioning (NPF) overtime may provide better clinical information and optimize the neuro-oncological management. The aims of our work were (1) to investigate the feasibility of a complex neuropsychological battery in HGG patients before and during follow-up after surgery; (2) to study the neuropsychological profile of patients affected by HGGs and their relation with the disease status (relapse/death) across time after surgery. METHODS: One hundred two patients who received surgery for HGG between 2011 and 2017 were studied. All clinical data were prospectively recorded. NPF was assessed during the neuro-oncological follow-up through the Milano-Bicocca Battery (MIBIB). Statistical analysis was performed on the neuropsychological results of the tests administered. RESULTS: First, MIBIB proved to be suitable for patients with HGG tumors before and after surgery, and during long-term follow-up; it also showed a cluster structure representative of the principal cognitive domains. Second, we found a steep decline in the neuropsychological profile before death and/or tumor relapse for the 52% of the neuropsychological tests administered. CONCLUSION: Complex neuropsychological batteries can be administered to HGG patients before and during follow-up after surgery. There is a correlation between neuropsychological deterioration and tumor relapse and/or death, which may reflect a progressive damage to cognitive functions due to tumor infiltration and progression.

Constructional Apraxia in Older Patients with Brain Tumors: Considerations with an Up-To-Date Review of the Literature.

BACKGROUND: Constructional apraxia (CA) is a neuropsychological impairment of either basic perceptual and motor abilities or executive functions, in the absence of any kind of motor or perceptual deficit. Considering patients with focal brain tumors, CA is common in left or right parietal and parieto-occipital lesions. In neuropsychology, the Rey-Osterrieth Complex Figure Test (ROCFT; or parallel forms) is commonly used for the assessment of CA. This study stems from a clinical observation of a difficulty with CA tests for the majority of older neurosurgical patients without occipitoparietal lesions. METHODS: Patients were tested at 3 points: before surgery, 3 months after surgery, and 12 months after surgery. Thirty patients (15 meningiomas and 15 glioblastomas) were studied retrospectively. RESULTS: Older patients with focal brain lesions, regardless of the nature of the tumor, performed poorly at CA tests. More than 50% of patients obtained pathologic results at all 3 times considered. CONCLUSIONS: Our findings suggest that as CA complex tests involve multiple domains, poor results in copy task may reflect a global cognitive deficit of older patients with tumors, without a specific constructional praxis deficit. CA complex tests (such as the ROCFT) do not give significant informations about visuo-constructional abilities.

Long-Standing Isolated Autoimmune Hypothalamitis Diagnosed with Endoscopic Transventricular Biopsy.

BACKGROUND: Autoimmune hypothalamitis, which is among the causes of acquired central diabetes insipidus, has seldom been described in the literature. This condition is probably provoked by the production of anti-vasopressin-secreting cell antibodies and antihypothalamus antibodies and is often associated with pituitary or polyendocrine autoimmunity. Correct diagnosis and immediate treatment are essential to avoid the progression of the pathologic process. CASE DESCRIPTION: A woman diagnosed with central diabetes insipidus 12 years ago, who had panhypopituitarism and mild memory deficit, came to our attention. She refused radiologic studies. Magnetic resonance imaging performed in our unit showed a contrast-enhancing hypothalamic lesion. Lumbar puncture was negative for neoplastic markers. We decided to perform a biopsy of the lesion to obtain a histopathologic examination of the tissue and chose an endoscopic transventricular approach to reach the floor of the third ventricle. Autoimmune hypothalamitis was diagnosed and treatment with steroids and azathioprine was started. The lesion size decreased and was stable after 17 months of follow-up. CONCLUSIONS: The endoscopic transventricular approach has proved to be an effective and safe way to obtain tissue samples for histopathologic examination from a region that is usually difficult to reach; it also gives direct visualization of the lesion, which makes sampling easier. The lesion size decreased after treatment but no clinical improvement was detected, either on the cognitive or on the endocrinologic side.

Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition.

BACKGROUND AND PURPOSE: Cerebral cavernous malformation (CCM) is characterized by multiple lumen vascular malformations in the central nervous system that can cause neurological symptoms and brain hemorrhages. About 20% of CCM patients have an inherited form of the disease with ubiquitous loss-of-function mutation in any one of 3 genes CCM1, CCM2, and CCM3. The rest of patients develop sporadic vascular lesions histologically similar to those of the inherited form and likely mediated by a biallelic acquired mutation of CCM genes in the brain vasculature. However, the molecular phenotypic features of endothelial cells in CCM lesions in sporadic patients are still poorly described. This information is crucial for a targeted therapy. METHODS: We used immunofluorescence microscopy and immunohistochemistry to analyze the expression of endothelial-to-mesenchymal transition markers in the cavernoma of sporadic CCM patients in parallel with human familial cavernoma as a reference control. RESULTS: We report here that endothelial cells, a cell type critically involved in CCM development, undergo endothelial-to-mesenchymal transition in the lesions of sporadic patients. This switch in endothelial phenotype has been described only in genetic CCM patients and in murine models of the disease. In addition, TGF-ß/p-Smad- and ß-catenin-dependent signaling pathways seem activated in sporadic cavernomas as in familial ones. CONCLUSIONS: Our findings support the use of common therapeutic strategies for both sporadic and genetic CCM malformations.