The prognostic value of emergency microsurgical clipping of ruptured anterior circulation aneurysms.

BACKGROUND: The treatment of aneurysmal subarachnoid hemorrhage poses a formidable challenge, given the high mortality rate and associated mortality. Current recommendations are for treatment to be initiated within 24 hours of diagnosis. METHODS: In our study, we compared a cohort of 66 patients who received prompt microsurgical treatment within 6 hours of diagnosis with a cohort of 51 patients who received prompt microsurgical treatment within 12 hours of diagnosis. RESULTS: The modified Rankin Scale was utilized to evaluate the follow-up of patients at 30 days, 12 months, and 18 months following surgery. We performed a parametric comparison of the distributions of the means of groups, and our results indicate that treatment within 6 hours of diagnosis results in a lower incidence of obstructive hydrocephalus and a more favorable outcome. CONCLUSIONS: A favorable outcome was observed in patients who were treated within 6 hours. The availability of a specialized vascular team ensures the highest levels of care.

Tuberculum sellae meningiomas: surgical outcomes in 65 patients, review of the literature and proposal for an anatomical and radiological classification.

Tuberculum sellae meningiomas (TSM) are challenging tumors due to their proximity to vital neurovascular structures. We propose a new classification system based on anatomical and radiological parameters. All patients treated for TSM, between January 2003 and December 2016, have been retrospectively reviewed. A systematic research was performed in PubMed database to review all studies comparing the performance of transcranial (TCA) and transphenoidal (ETSA) approaches. Overall, 65 patients were included in the surgical series. Gross total removal (GTR) was achieved in 55 patients (85%) and near total resection in 10 (15%). 54 patients (83%) showed a stability or an improvement of visual functions and 11 (17%) worsened. Postoperative complications were observed in seven patients (11%): CSF leak in one patient (1.5%); diabetes insipidus in two (3%); hypopituitarism in two (3%) third cranial nerve paresis and subdural empyema in one (1.5%). For the literature review, data about 10,833 patients (TCA N.=9159; ETSA N.=1674) were recorded; GTR was achieved in 84.1% (range 68-92%) of TCA and in 79.1% (range 60-92%) of ETSA; visual improvement (VI) occurred in 59.3% of TCA (range 25-84%) and in 79.3% of ETSA (range 46-100%); visual deterioration (VD) was registered in 12.7% of TCA (0-24%) and in 4.1% of ETSA (range 0-17%); a CSF-leak was observed in 3.8% of TCA (range 0-8%) while in ETSA in 18.6% of patients (range 0-62%); vascular injuries was reported in 4% (range 0-15%) of TCA and in 1.5% (range 0-5%) of ETSA. In conclusion, TSMs represent a unique category of midline tumors. The proposed classification system provides an intuitive and reproducible method in the choice of the most suitable approach.

Intracranial Hypotension Syndrome after Lumbar Drainage in Skull Base Surgery: Diagnosis and Correct Management.

Lumbar drainage is commonly used in skull base surgery; however, very few cases of intracranial hypotension syndrome are reported to be caused by this procedure. We present a clinical case of lumbar drainage-assisted orbital and optic canal decompression surgery for a recurrent voluminous spheno-orbital meningioma, together with a literature review. A 49-year-old woman became confused and drowsy on postoperative day 3, after initially experiencing neurologic stability. Computed tomography (CT) scan of the head showed extradural frontotemporal fluid collection with moderate right to left midline shift. Magnetic resonance imaging (MRI) of the brain showed signs of intracranial hypotension, such as brain sagging and diffuse dural contrast enhancement. Conservative treatment with bed rest, aggressive hydration, steroids, and aminophylline led to progressive neurologic improvement. A systematic literature review was also performed, and previous reported cases were analyzed. Overall, neurosurgeons must be aware of the lumbar drainage-induced hypotension syndrome in skull base surgeries, because immediate diagnosis is essential for therapeutic decision-making. In this setting, conservative management is the first-line treatment as surgery may lead to severe complications.

Intracranial Meningiomas in the Elderly: Clinical, Surgical and Economic Evaluation. A Multicentric Experience.

Meningioma is one of the most common intracranial tumors. It is benign and slow growing in the majority of cases. Given the increase in life expectancy and the number of radiological tests performed, the incidence in the elderly population (≥65 years) is continuously increasing. The surgical outcomes and prognostic factors in this age group are unclear. A retrospective analysis of all the patients treated for intracranial meningiomas in two different Italian institutions was performed. The clinical, radiological, surgical and follow-up data were retrospectively reviewed. Statistical analyses were performed to identify relationships between factors and outcomes. We also carried out an economic analysis. We analyzed 321 patients with intracranial meningioma. The mean age was 72.6 years (range, 65-90), with a female predominance (F/M, 1.41). Pre-operative deficits, cognitive impairment and seizures (p < 0.001) were associated with a worse post-operative Karnofsky performance scale (KPS) score (<80). A high pre-operative KPS score was associated with a good clinical and neurological outcome (p < 0.001). Being aged between 65 and 74 years, low surgical timing and Simpson removal grades of I and II were associated with a good outcome (p < 0.001). The length of hospitalization was significantly related to the outcome (p < 0.001). The complication rate was 14.3%. At 6-month follow-up, the mortality rate was 2.5%. The average cost was higher in patients with a pre-operative KPS score lower than 80. The outcome of intracranial-meningioma resection in elderly individuals is favorable when the pre-operative KPS score is >80. Treatment should be patient-specific, and additional factors should be considered. Patients with poor pre-operative clinical conditions might benefit from a combined strategy with partial resection and radiosurgery in order to reduce surgical timing and the complication rate.

Management and Surgical Approaches of Brainstem Cavernous Malformations: Our Experience and Literature Review.

INTRODUCTION: Brainstem cavernous malformations (BSCMs) are clusters of dilated sinusoidal channels. Clinical presentation is characterized by focal neurological deficits and/or hemorrhage. The goal of this study is to analyze surgical indications and approaches in a series of patients with BSCM and review pertinent literature and suggest prognostic factors related to the anatomical, clinical, and surgical data collected. METHODS: We retrospectively reviewed the clinical data of 55 patients with BSCM, treated at three centers, from January 2006 to March 2016. We collected anagraphic data, pre and postoperative neurological status, pre and postradiological images, surgical procedures, and follow-up results. We summarized the anatomical, clinical, and surgical aspects of the lesions and identified two large groups based on the chosen approach: lateral and medial. Clinical and radiological results were then compared. RESULTS: The series comprised 55 patients. Hemorrhagic onset was observed in all patients. Suboccipital, retrosigmoid, anterior, subtentorial, subtemporal, transvermian, telovelar, far lateral and trans, and infratentorial approaches were performed. Neurological status improved postoperatively in 34 cases at last follow-up. Five patients showed clinical neurological worsening. Total resection was achieved in 46 cases and, during a mean follow-up of 63.4 months, no recurrence or re-bleeding occurred in those patients. The mean follow-up was 63.9 months. The mean modified Rankin Scale at final follow-up was used to analyze the results and draw our conclusions. CONCLUSIONS: A reasonable surgical approach, selection, and gentle handling of the surrounding structures are required to prevent impairment of neurologic function and avoid partial resection.

UAIS: Unruptured Aneurysms Italian Study.

BACKGROUND: Unruptured intracranial aneurysms (UIAs) are increasingly identified and are an important health-care burden; in the past they were commonly treated by surgical clipping, but nowadays endovascular coil embolization is increasingly employed as an alternative. METHODS: The Unruptured Aneurysms Italian Study (UAIS) is a multicentric cooperative prospective study aimed to delineate the "State of the Art" of UIAs treatment in Italy. 51 Italian Neurosurgical and Neuroradiological Units, representatives of all 20 Italian regions are involved in the Study. RESULTS: UAIS started on June 2003 and ended on July 2007. 1138 patients were collected by that date, but 181 were ruled-out due to severe violation of the protocol; 957 had complete data and could be statistically evaluated. CONCLUSIONS: UAIS demonstrates that the treatment of UAs, as performed in Italy as a Nation, is effective in improving long-term outcome vs. natural history, particularly in aneurysms larger than 7 mm.

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study.

AIM: To gather data regarding factors predicting responsiveness to pasireotide in acromegaly. PATIENTS AND METHODS: SSTR2a, SSTR3, SSTR5, AIP, Ki-67 and the adenoma subtype were evaluated in somatotroph adenomas from 39 patients treated post-operatively with somatostatin analogues (SSAs). A standardized SSTR scoring system was applied (scores 0-3). All patients received first-generation SSAs, and 11 resistant patients were subsequently treated with pasireotide LAR. RESULTS: None of the patients with negative or cytoplasmic-only SSTR2a expression (scores 0-1) were responsive to first-generation SSAs, as opposed to 20% (score 2) and 50% of patients with a score of 3 (P=0.04). None of the patients with an SSTR5 score of 0-1 were responsive to pasireotide, as opposed to 5/7 cases with a score of 2 or 3 (P=0.02). SSTR3 expression did not influence first-generation SSAs or pasireotide responsiveness. Tumours with low AIP were resistant to first-generation SSAs (100 vs 60%; P=0.02), while they had similar responsiveness to pasireotide compared to tumours with conserved AIP expression (50 vs 40%; P=0.74). Tumours with low AIP displayed reduced SSTR2 (SSTR2a scores 0-1 44.4 vs 6.7%; P=0.006) while no difference was seen in SSTR5 (SSTR5 scores 0-1 33.3 vs 23.3%; P=0.55). Sparsely granulated adenomas responded better to pasireotide compared to densely granulated ones (80 vs 16.7%; P=0.04). CONCLUSION: The expression of SSTR5 might predict responsiveness to pasireotide in acromegaly. AIP deficient and sparsely granulated adenomas may benefit from pasireotide treatment. These results need to be confirmed in larger series of pasireotide-treated patients.

Position statement from the Italian Society of Neurosurgery on the ARUBA Study.

As the conclusions of the ARUBA Study are strongly oriented towards therapeutic abstention, we think it is appropriate to express the concern of the Italian Society of Neurosurgery for the impact that this study might have on the health of patients, if not properly evaluated. The vast majority of patients (76-81%) included in the study was treated with endovascular or radiotherapy treatments, alone or in combination. Only 18 patients (19%) had surgery. It is well known that a partial treatment of arteriovenous malformations (AVMs), as is often the case with endovascular therapy, may increase the risk of bleeding. The primary endpoint (death or symptomatic stroke) in the treated group was reached in 30.7%, i.e. almost one-third of the subjects. This has no comparison in the current surgical literature. Considering permanent and transient neurological deficits along with headaches and seizures all together in the same outcome evaluation parameter may be inappropriate and misleading. The graph with all results from the ARUBA Study, which claims to be the demonstration that natural history is better that treatment, clearly shows that what is assumed to be treated has not actually been treated. If death or stroke occur a few years from treatment, it only means that the disease was not cured and patients received a partial - therefore ineffective, if not dangerous - treatment. An effective treatment, as surgery is, must have a flat follow-up curve. The ARUBA Study shows that incomplete treatment leads to negative outcome, confirming that an integrated multidisciplinary strategy has to be plotted out before starting any treatment and that a complete exclusion of the AVM must be achieved.

The transcriptome and miRNome profiling of glioblastoma tissues and peritumoral regions highlights molecular pathways shared by tumors and surrounding areas and reveals differences between short-term and long-term survivors.

Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor, driving patients to death within 15 months after diagnosis (short term survivors, ST), with the exception of a small fraction of patients (long term survivors, LT) surviving longer than 36 months. Here we present deep sequencing data showing that peritumoral (P) areas differ from healthy white matter, but share with their respective frankly tumoral (C) samples, a number of mRNAs and microRNAs representative of extracellular matrix remodeling, TGFß and signaling, of the involvement of cell types different from tumor cells but contributing to tumor growth, such as microglia or reactive astrocytes. Moreover, we provide evidence about RNAs differentially expressed in ST vs LT samples, suggesting the contribution of TGF-ß signaling in this distinction too. We also show that the edited form of miR-376c-3p is reduced in C vs P samples and in ST tumors compared to LT ones. As a whole, our study provides new insights into the still puzzling distinction between ST and LT tumors, and sheds new light onto that "grey" zone represented by the area surrounding the tumor, which we show to be characterized by the expression of several molecules shared with the proper tumor mass.

Bilateral flow changes after extracranial-intracranial bypass surgery in a complex setting of multiple brain-feeding arteries occlusion: The role of perfusion studies.

We report on a symptomatic case in which the whole intracranial blood supply was provided by a single vertebral artery as both internal carotid arteries were occluded and the contralateral vertebral artery was severely hypoplasic. The patient was treated by a flow-augmentation extracranial-intracranial bypass. Preoperative perfusion studies were essential in tailoring surgical strategy. Keypoints of the paper are contralateral perfusion changes after unilateral bypass surgery. The patient experienced a total recovery from symptoms and a bilateral improvement in brain perfusion, probably as consequence of post-operative hemodynamic rearrangement.

Typical and atypical pituitary adenomas: a single-center analysis of outcome and prognosis.

BACKGROUND AND OBJECTIVE: In 2004, the World Health Organization defined atypical pituitary adenomas as those with a Ki-67 expression > 3%, an excessive p53 expression and increased mitotic activity. As the usefulness of this classification is controversial, we reviewed typical and atypical pituitary adenomas to compare the clinical and prognostic features. PATIENTS AND METHODS: We retrospectively reviewed 343 consecutive pituitary adenomas. Atypical pituitary adenomas represented 18.7% of cases. All patients were operated on at the Department of Neurosurgery of our institution and were followed up at the Hypothalamic-Pituitary Disease Unit of the same institution. The median follow-up time was 75 months (range 7-345). RESULTS: Younger age at diagnosis as well as immunohistochemical positivity for adrenocorticotropic hormone and prolactin correlated with a higher risk of atypical pituitary adenomas, whereas typical and atypical pituitary adenomas did not differ with regard to gender, tumor size, recurrence risk and disease-free survival time (DFST). Among the 219 patients who underwent radical surgery, a Ki-67 expression ≥ 1.5% was associated with a higher risk of recurrence and a worse DFST, even after correction for age at diagnosis, gender, immunohistochemical classification, tumor size, invasiveness and Knosp classification [p = 0.01; hazard ratio (HR) 2.572; 95% confidence interval (CI) 1.251-5.285). Pituitary adenomas with a Ki-67 expression ≥ 1.5% showed a worse DFST as compared to pituitary adenomas with a Ki-67 expression < 1.5% (HR 2.166; 95% CI 1.154-4.064). CONCLUSION: In this series, atypical and typical pituitary adenomas did not differ with regard to recurrence and DFST. Pituitary adenomas with a Ki-67 expression ≥ 1.5% showed a higher recurrence risk and a worse DFST as compared to those with a Ki-67 expression < 1.5%. We suggest that a Ki-67 expression ≥ 1.5% may be useful as a prognostic marker, though this will need to be confirmed by prospective, multicenter data.

Olfactory groove meningioma: report of 99 cases surgically treated at the Catholic University School of Medicine, Rome.

OBJECTIVE: We reviewed our series of olfactory groove meningiomas (OGMs) with the aim to relate the surgical approach with outcome and to define clinical and pathologic predictors of prognosis. METHODS: Ninety-nine patients who underwent 113 craniotomies at our Institution between 1984 and 2010 were entered this study. The relationship between surgical approach (bifrontal, fronto-orbito-basal, and pterional) and either tumor diameter, extent of tumor resection, complication rate, need of reoperation, and Karnofsky Performance Status (KPS) was analyzed. The impact of age (≤ 70 vs. > 70 years), sex, tumor diameter (< 6 vs. ≥ 6 cm), pre- and postoperative KPS (< 80 vs. ≥ 80), Simpson grade (I-II vs. III-IV), and World Health Organization (WHO) histologic grade (I vs. II-III) on survival was assessed. Kaplan-Meier survival curves were plotted and differences in survival between groups of patients were compared. A multivariate analysis adjusted for age, pre- and postoperative KPS, Simpson grade, tumor diameter, and WHO histologic grade also was performed. RESULTS: The fronto-orbito-basal approach (n = 22) allowed a significantly greater percentage of Simpson I-II removals than the bifrontal (n = 70) and pterional approach (n = 21) (P = 0.0354 and P = 0.0485, respectively). The risk of life-threatening complications trended to be lower in patients operated upon either via the fronto-orbito-basal and via the pterional approach than in those treated via the bifrontal approach. Retraction-related brain swelling did not occur in any case after the fronto-orbito-basal approach (P = 0.0384); however, this approach was associated with a greater rate of cerebrospinal fluid leak (P = 0.0011). Among prognostic factors, age ≤ 70 years (P = 0.0044), tumor diameter <6 cm (P = 0.0455), pre- and postoperative KPS ≥ 80 (both P < 0.0001), Simpson grade I-II (P = 0.0096), and WHO histologic grade I (P = 0.0112) were significantly associated with longer overall survival. Age (P = 0.0393) and WHO histologic grade (P = 0.0418) emerged as independent prognostic factors for overall survival on multivariate analysis. CONCLUSION: In the largest series of OGMs published to date, the bifrontal approach was associated with a greater risk of life-threatening complications compared with the lateral pterional and fronto-orbito-basal approaches. The fronto-orbito-basal approach provided greater chances of total tumor removal than the bifrontal and pterional approaches. Two independent factors for overall survival of patients with OGM were identified, namely age and WHO grade.

PDGF receptor alpha inhibition induces apoptosis in glioblastoma cancer stem cells refractory to anti-Notch and anti-EGFR treatment.

BACKGROUND: Cancer stem cells (CSC) represent a rare fraction of cancer cells characterized by resistance to chemotherapy and radiation, therefore nowadays there is great need to develop new targeted therapies for brain tumors and our study aim to target pivotal transmembrane receptors such as Notch, EGFR and PDGFR, which are already under investigation in clinical trials setting for the treatment of Glioblastoma Multiforme (GBM). METHODS: MTS assay was performed to evaluate cells response to pharmacological treatments. Quantitative RT-PCR and Western blots were performed to state the expression of Notch1, EGFR and PDGFRα/ß and the biological effects exerted by either single or combined targeted therapy in GBM CSC. GBM CSC invasive ability was tested in vitro in absence or presence of Notch and/or EGFR signaling inhibitors. RESULTS: In this study, we investigated gene expression and function of Notch1, EGFR and PDGFR to determine their role among GBM tumor core- (c-CSC) vs. peritumor tissue-derived cancer stem cells (p-CSC) of six cases of GBM. Notch inhibition significantly impaired cell growth of c-CSC compared to p-CSC pools, with no effects observed in cell cycle distribution, apoptosis and cell invasion assays. Instead, anti-EGFR therapy induced cell cycle arrest, sometimes associated with apoptosis and reduction of cell invasiveness in GBM CSC. In two cases, c-CSC pools were more sensitive to simultaneous anti-Notch and anti-EGFR treatment than either therapy alone compared to p-CSC, which were mostly resistant to treatment. We reported the overexpression of PDGFRα and its up-regulation following anti-EGFR therapy in GBM p-CSC compared to c-CSC. RNA interference of PDGFRα significantly reduced cell proliferation rate of p-CSC, while its pharmacological inhibition with Crenolanib impaired survival of both CSC pools, whose effects in combination with EGFR inhibition were maximized. CONCLUSIONS: We have used different drugs combination to identify the more effective therapeutic targets for GBM CSC, particularly against GBM peritumor tissue-derived CSC, which are mostly resistant to treatments. Overall, our results provide the rationale for simultaneous targeting of EGFR and PDGFR, which would be beneficial in the treatment of GBM.

Isolation of cancer stem cells from three human glioblastoma cell lines: characterization of two selected clones.

Cancer stem cells (CSC) were isolated via a non-adherent neurosphere assay from three glioma cell lines: LI, U87, and U373. Using a clonal assay, two clones (D2 and F11) were selected from spheres derived from LI cells and were characterized for the: expression of stem cell markers (CD133, Nestin, Musashi-1 and Sox2); proliferation; differentiation capability (determined by the expression of GalC, ßIII-Tubulin and GFAP); Ca(2+) signaling and tumorigenicity in nude mice. Both D2 and F11 clones expressed higher levels of all stem cell markers with respect to the parental cell line. Clones grew more slowly than LI cells with a two-fold increase in duplication time. Markers of differentiation (ßIII-Tubulin and GFAP) were expressed at high levels in both LI cells and in neurospheres. The expression of Nestin, Sox2, and ßIII-Tubulin was down-regulated in D2 and F11 when cultured in serum-containing medium, whereas Musashi-1 was increased. In this condition, duplication time of D2 and F11 increased without reaching that of LI cells. D2, F11 and parental cells did not express voltage-dependent Ca(2+)-channels but they exhibited increased intracellular Ca(2+) levels in response to ATP. These Ca(2+) signals were larger in LI cells and in spheres cultured in serum-containing medium, while they were smaller in serum-free medium. The ATP treatment did not affect cell proliferation. Both D2 and F11 induced the appearance of tumors when ortotopically injected in athymic nude mice at a density 50-fold lower than that of LI cells. All these data indicate that both clones have characteristics of CSC and share the same stemness properties. The findings regarding the expression of differentiation markers and Ca(2+)-channels show that both clones are unable to reach the terminal differentiation. Both D2 and F11 might represent a good model to improve the knowledge on CSC in glioblastoma and to identify new therapeutic approaches.

Association between polymorphisms rs1333040 and rs7865618 of chromosome 9p21 and sporadic brain arteriovenous malformations.

BACKGROUND: The chromosomal locus 9p21 is a novel genetic marker for a variety of cardiovascular and cerebrovascular diseases. In a recent study, we have demonstrated an association between the single nucleotide polymorphism (SNP) rs1333040C>T on chromosome 9p21 and sporadic brain arteriovenous malformations (BAVMs). Here, we extended our analysis to an additional SNP on chromosome 9p21 (rs7865618A>G) and increased our sample size including BAVMs from two different Italian neurosurgical centers. METHODS: We studied 206 patients with sporadic BAVMs and 171 unaffected controls. Genomic DNA was isolated from peripheral blood and the rs1333040C>T and rs7865618A>G polymorphisms were assessed by PCR-RFLP using the BsmI and MspI restriction endonucleases, respectively. For each SNP, we performed dominant, recessive, and additive genetic models. RESULTS: The distribution of the three possible genotypes of rs1333040 (TT, TC and CC) was statistically different between cases and controls (p = 0.0008). The TT genotype was significantly associated with BAVMs both in the dominant (p = 0.013) and recessive (p = 0.012) models. The T allele was significantly associated with BAVMs in the additive model (p = 0.002). Also the distribution of the three possible genotypes of rs7865618 (GG, AG and AA) was statistically different between cases and controls (p = 0.005), and the GG genotype and G allele were significantly associated with BAVMs in the dominant (p = 0.032), recessive (p = 0.007), and additive models (p = 0.009). We also detected a significant association between BAVMs with large nidus size and the GG genotype and G allele of rs7865618 and the TT genotype of rs1333040. A deep venous drainage was instead associated with the TT genotype of the rs1333040 and the GG genotype of the rs7865618. The occurrence of bleeding was associated with the TT genotype and T allele of rs1333040, while the presence of seizures appeared associated with the GG genotype of rs7865618. CONCLUSIONS: SNPs of the 9p21 region, in addition to be genetic markers for coronary artery disease, stroke, and intracranial aneurysms, are associated with sporadic BAVMs. These results extend and strengthen the role of the 9p21 chromosomal region as a common risk factor for cerebrovascular diseases.

Intraorbital and intracanalicular ophthalmic artery aneurysms. Literature review and report of a case.

This paper reviews literature about intraorbital ophthalmic artery aneurysms discussing presentation, aetiology and treatment options. In addition we report on a case of intraorbital ophthalmic artery aneurysm with acute onset of headache, visual loss and right eye ophthalmoplegia.