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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.

To report an unusual case of biopsy-proven autoimmune hypophysitis with predominant hypothalamic involvement associated with empty sella, panhypopituitarism, visual disturbances and antipituitary antibodies positivity. We present the history, physical findings, hormonal assay results, imaging, surgical findings and pathology at presentation, together with a 2-year follow-up. A literature review on the hypothalamic involvement of autoimmune hypophysitis with empty sella was performed. A 48-year-old woman presented with polyuria, polydipsia, asthenia, diarrhea and vomiting. The magnetic resonance imaging (MRI) revealed a clear suprasellar (hypothalamic) mass, while the pituitary gland appeared atrophic. Hormonal testing showed panhypopituitarism and hyperprolactinemia; visual field examination was normal. Pituitary serum antibodies were positive. Two months later an MRI documented a mild increase of the lesion. The patient underwent biopsy of the lesion via a transsphenoidal approach. Histological diagnosis was lymphocytic "hypothalamitis". Despite 6 months of corticosteroid therapy, the patient developed bitemporal hemianopia and blurred vision, without radiological evidence of chiasm compression, suggesting autoimmune optic neuritis with uveitis. Immunosuppressive treatment with azathioprine was then instituted. Two months later, an MRI documented a striking reduction of the hypothalamic lesion and visual field examination showed a significant improvement. The lesion is stable at the 2-year follow-up. For the first time we demonstrated that "hypothalamitis" might be the possible evolution of an autoimmune hypophysitis, resulting in pituitary atrophy, secondary empty sella and panhypopituitarism. Although steroid treatment is advisable as a first line therapy, immunosuppressive therapy with azathioprine might be necessary to achieve disease control.

Background Single nucleotide polymorphisms (SNPs) on chromosome 9p21 have been recently associated with intracranial aneurysms and stroke. In this study, we tested the association between the rs1333040C>T polymorphism on the 9p21 locus and sporadic brain arteriovenous malformations (BAVMs). Methods We studied 78 patients with sporadic BAVMs and 103 unaffected controls. Genomic DNA was isolated from peripheral blood and the rs1333040C>T polymorphism was assessed by PCR–restriction fragment length polymorphism using the BsmI restriction endonuclease. Results We found that the distribution of the three genotypes (TT/TC/CC) of the rs1333040 polymorphism was significantly different between cases and controls (p=0.02). Using dominant, recessive and additive genetic models, we found that the TT genotype and the T allele were significantly more common in the BAVM group than in controls. We also evaluated whether the rs1333040 polymorphism was associated with prototypical angio-architectural features of BAVMs (such as nidus size, venous drainage pattern and Spetzler–Martin grading) and with the occurrence of seizures and bleeding. We detected a significant association between the homozygous T allele in the recessive model and BAVMs with a nidus >4 cm in diameter. Deep venous drainage was significantly more frequent among subjects carrying at least one T allele in the dominant model. Patients with seizures showed a significant association with the TT genotype and the T allele in all genetic models examined whereas those who experienced intracranial bleeding showed a significant association with the T allele in the trend model. Conclusions This is the first study demonstrating an association between an SNP of the 9p21 region and sporadic BAVMs. Our results emphasise the relevance of this chromosomal locus as a common risk factor for various forms of cerebrovascular diseases.

article Although several descriptions of the angioarchitectural features of brain arteriovenous malformations (AVMs) associated with higher hemorrhagic risk have been reported, the prognostic value of the different bleeding pat- terns still needs to be elucidated. This study evaluated the influence on clinical appearance and outcome of the parenchymal and non- parenchymal (subarachnoid hemorrhage—SAH—and intraventricular hemorrhage—IVH) bleedings associated with ruptured AVMs. Clinical records and neuroradiological examinations of 30 patients with hemorrhagic AVMs were reviewed in order to identify their angioarchitectural features and the associated bleeding pattern. These data along with demographic characteristics and treatment modality were dichotomized and their relationship with clinical status at admission and follow-up was tested. IVH as well as parenchymal hematomas larger than 20 cm 3 appeared associated with a severe clinical status at admission, whereas SAH involving basal cisterns was significantly associated with unfavorable outcome. Age, sex and angioarchitectural features did not show significant association with the severity of the prognosis. However, none of these bleeding patterns appeared as an independent risk factor of poor outcome at multi- variate analysis. In conclusion, our data emphasized the possibility that non-parenchymal bleeding may worsen the outcome of patients with hemorrhagic AVMs.

The neuronavigation-assisted anterior subtemporal approach is proposed in this article as an alternative to surgery of posterolateral brainstem cavernomas. Brainstem cavernomas represent a neurosurgical challenge because of the high morbidity and mortality rate related to their surgical removal. Several nerve nuclei, ascending and descending fibers make this region at high risk of serious postoperative deficits. Between 1998 and 2010, 24 patients underwent surgical removal of brainstem cavernomas in our institution. Ten of these patients presented a cavernous malformation in the posterolateral region of the brainstem and underwent surgical removal by means of a neuronavigation-assisted anterior subtemporal approach. Lesion removal was complete for all patients. There were no cases of surgery-related death. Neurological status improved or remained unchanged after surgery in all cases. All patients presented good outcomes at 12 to 154 months' follow-up (mean 70 months; GOS = 5 in 8/10 patients, 4 in 2/10 patients; mRS = 0–1 in all patients). Only one patient presented transient confusion, aphasia and seizures related to temporal lobe swelling, which resolved completely within a few days. One patient developed cranial nerve III palsy and left hemiparesis with gradual recovery. This approach represents a valid alternative to the “more classical” approaches for the surgery of posterolateral cavernomas of the pontomesenchephalic junction reaching the tentorial incisura, reducing the risk of damaging the vein of Labbe, temporal lobe swelling, cerebellar swelling, ophtalmoparesis, fourth ventricle cranial nerve nuclei lesions. Skeletonization of sigmoidal sinus provides with good outcomes, low morbidity and mortality.

The authors evaluated the usefulness of three-dimensional rotational angiography (3DRA) in surgical planning and postoperative evaluation of cerebral aneurysms.A total of 111 consecutive aneurysms in 100 patients (32 emergency referrals due to haemorrhage) were evaluated with 3DRA over a period of 3 years. The rotational study was always performed with a single injection of 20 cc of contrast agent in the afferent vessel after diagnostic cerebral angiography in the two orthogonal projections. Three-dimensional reconstructions were obtained for the pre- and postoperative assessment.Three-dimensional RA provides a virtual view of the surgical field with the same orientation required for the surgical approach and, compared with surgical findings, reliably defined location, orientation, morphology and relationship with parent vessels of the aneurysm in all cases. Postoperatively, it allowed better assessment of any residual lesion and of the relationship between surgical clips and parent vessels, compared with standard 2D angiography.3DRA is a reliable method for preliminary assessment of cerebral aneurysms undergoing surgery. It provides multiple projections with a preview of the surgical field and study of lesion characteristics, which can help achieve faster and safer surgery. Compared with 2D angiography, the 3D model, with its multiple views, allows better assessment of postoperative outcomes. The method also significantly reduces the number of angiographic projections and therefore radiation and contrast-medium dose to the patient.

Combining Gliadel wafers and radiochemotherapy with TMZ may carry the risk of increased adverse events (AE). We analyzed the efficacy and safety in patients with glioblastoma who underwent multimodal treatment with implantation of Gliadel wafers. One hundred sixty-five consecutive patients with newly diagnosed (77 patients) or recurrent (88 patients) glioblastoma were studied. Forty-seven patients underwent surgery + Gliadel. The impact of age (≥65 vs.

Glioblastoma is a highly angiogenetic malignancy, the neoformed vessels of which are thought to arise by sprouting of pre-existing brain capillaries. The recent demonstration that a population of glioblastoma stem-like cells (GSCs) maintains glioblastomas indicates that the progeny of these cells may not be confined to the neural lineage. Normal neural stem cells are able to differentiate into functional endothelial cells. The connection between neural stem cells and the endothelial compartment seems to be critical in glioblastoma, where cancer stem cells closely interact with the vascular niche and promote angiogenesis through the release of vascular endothelial growth factor(VEGF) and stromal-derived factor 1 (refs 5-9). Here we show that a variable number (range 20-90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin. The vascular endothelium contained a subset of tumorigenic cells that produced highly vascularized anaplastic tumours with areas of vasculogenic mimicry in immunocompromised mice. In vitro culture of GSCs in endothelial conditions generated progeny with phenotypic and functional features of endothelial cells. Likewise, orthotopic or subcutaneous injection of GSCs in immunocompromised mice produced tumour xenografts, the vessels of which were primarily composed of human endothelial cells. Selective targeting of endothelial cells generated by GSCs in mouse xenografts resulted in tumour reduction and degeneration, indicating the functional relevance of the GSC-derived endothelial vessels. These findings describe a new mechanism for tumour vasculogenesis and may explain the presence of cancer-derived endothelial-like cells in several malignancies.

Malignant or anaplastic craniopharyngioma, first described in 1987 by Akachi and coworkers, is a rare occurring craniopharyngioma characterized by cytologic atypia and poor prognosis. Fifteen cases have been previously reported, two of which have been defined de novo, i.e. not developing from a previously treated benign craniopharyngioma; both these patients died in the early post-operative period. Herein we describe the case of a 66-year-old female who presented with visual disturbance and radiological evidence of a sellar and suprasellar tumor. The patient underwent trans-sphenoidal biopsy followed by pterional craniotomy with partial tumor removal. Histological diagnosis documented a malignant adamantinomatous type craniopharyngioma. The patient received adjuvant radiotherapy with a significant tumor reduction. She remained in good clinical conditions for 10 months; she deteriorated and died, due to tumor progression, 15 months after diagnosis. Malignant craniopharyngioma is a rare primary malignant tumor of the sellar region. This is the first case of de novo malignant craniopharyngioma with significant follow-up.

Oxidative stress is involved both in metabolic syndrome and male infertility. Hypogonadism is also associated with increased risk for cardiovascular disease. To investigate the role of gonadal steroids in systemic antioxidant regulation, we determined plasma CoenzymeQ(10) (CoQ(10)) and total antioxidant capacity (TAC) in postsurgical hypopituitaric patients. Twenty-six patients aged 28-55 years were studied 6-12 months after surgery. CoQ(10) levels were measured by high-performance liquid chromatography and TAC by spectroscopy with the use of the mioglobin-H(2)O(2) system, which, in interacting with chromogen 2,2(I)-azinobis-(3-ethylbenzothiazoline-6-sulfonate), generates a radical after a latency time (LAG) that is proportional to antioxidant content. Sixteen patients presented low testosterone values; in 10 patients hypogonadism was isolated, and in 6 patients hypothyroidism also was present. CoQ(10) levels were significantly lower in isolated hypogonadism than in normogonadism. Testosterone treatment, performed in those patients with isolated hypogonadism, induced a significant enhancement both in CoQ(10) level and LAG. CoQ(10) and LAG values correlated significantly, suggesting an interrelationship between different antioxidants. Our data suggest that hypogonadism could represent a condition of oxidative stress, in turn related with augmented cardiovascular risk.

Glioblastoma multiforme is a severe form of cancer most likely arising from the transformation of stem or progenitor cells resident in the brain. Although the tumorigenic population in glioblastoma is defined as composed by cancer stem cells (CSCs), the cellular target of the transformation hit remains to be identified. Glioma stem cells (SCs) are thought to have a differentiation potential restricted to the neural lineage. However, using orthotopic versus heterotopic xenograft models and in vitro differentiation assays, we found that a subset of glioblastomas contained CSCs with both neural and mesenchymal potential. Subcutaneous injection of CSCs or single CSC clones from two of seven patients produced tumor xenografts containing osteo-chondrogenic areas in the context of glioblastoma-like tumor lesions. Moreover, CSC clones from four of seven cases generated both neural and chondrogenic cells in vitro. Interestingly, mesenchymal differentiation of the tumor xenografts was associated with reduction of both growth rate and mitotic index. These findings suggest that in a subclass of glioblastomas the tumorigenic hit occurs on a multipotent stem cell, which may reveal its plasticity under specific environmental stimuli. The discovery of such biological properties might provide considerable information to the development of new therapeutic strategies aimed at forcing glioblastoma stem cell differentiation.

Purpose: It has been hypothesized that brain tumors are derived from stem cell or transiently dividing precursor transformation. Furthermore, c-Jun NH2-terminal kinases (JNKs) have been involved in gliomagenesis. This study analyzes stem cell marker nestin and JNK expression in glioblastoma multiforme (GBM) and peritumor tissue and assesses their possible prognostic implications. Experimental Design: Nestin and both total JNK (tJNK) and phosphorylated JNK (pJNK) expression was investigated by immunohistochemistry in 20 GBMs. Samples were derived from tumors (first area), from tissues at a distance Results: Nestin cytoplasmic immunoreactivity was observed in the majority of cells in tumor but infrequently in peritumor areas. tJNK, observed in the nucleus and cytoplasm, was widely expressed in the three areas; pJNK, mostly located in the nuclei, was found in a variable percentage of cells in the tumor and peritumor tissue. Nestin and JNK expression in peritumor areas was independent of the presence of neoplastic cells. Univariate analysis indicated that survival was longer (19 versus 12 months; P = 0.01) for patients whose pJNK/nestin and (pJNK/tJNK)/nestin ratios in the second area were ≥2.619 and ≥0.026, respectively. The same variables showed an independent prognostic value in multivariate analysis. Conclusions: Nestin and JNK expression indicates that peritumor tissue, independently of the presence of neoplastic cells, may present signs of transformation. Moreover, pJNK/nestin and (pJNK/tJNK)/nestin ratios in that tissue seem to have some prognostic implications in GBM patients.

The aim of this longitudinal study was to evaluate the echocardiographic outcome of acromegalic heart disease in patients undergoing different therapeutic approaches, in order to investigate whether SSA could provide therapeutic advantages as compared with neurosurgery. In total of 36, consecutive patients undergoing SSA treatment after neurosurgery were enrolled in this study (Gr.Surg.-SSA). After 12 months of treatment, 21 patients had a controlled disease, while the remaining 15 patients displayed uncontrolled disease. Twelve acromegalic patients who did not undergo SSA treatment due to controlled disease after neurosurgery were enrolled as control group (Gr.Surg). The echocardiographic-Doppler study was performed before neurosurgery and after 12-months of follow-up. After follow-up, a significant reduction in serum GH and IGF-I values, Left Ventricular Mass index (LVMi) and LVH rate with an improvement in diastolic function was observed in both groups of patients. We found a significant reduction of LVMi either in patients with controlled disease or in those with poorly controlled disease undergoing SSA treatment. Diastolic function and of LVH percentage improved in all groups, but significantly so only in controlled patients, no significant difference in any echocardiographic parameters and in the prevalence of the LVH rate were observed between the three groups of patients at the end of follow-up. Therefore, our data appear to show that for echographic parameters medical treatment additive beneficial effects is compared to neurosurgery alone. SSA also appears to contribute to the improvement of acromegalic cardiomyopathy also in patients who did not achieve biochemical control of the disease.

Malignant gliomas represent the most common primary brain tumor: more than 50% of them are glioblastoma multiforme (GBM). Photodynamic therapy may offer a very good chance of targeted destruction of infiltrating GBM cells, thus increasing the survival time and recurrence-free interval of GBM patients. Among photosensitizing agents, meta-tetrahydroxyphenylchlorin (m-THPC) is promising for the treatment of brain tumors. In previous studies, we investigated the transfection activity of dimyristoyl-sn-glycero-phosphatidylcholine (DMPC) liposomes, containing a cationic gemini surfactant, loaded with m-THPC on human colon adenocarcinoma and glioblastoma cell lines. In this paper, the uptake and the intracellular distribution of m-THPC, loaded in several formulations of cationic liposomes, were analyzed, by making a comparison with those obtained using the same chlorin in the pharmaceutical form (Foscan(R)). Moreover, by cloning efficiency assay the potential therapeutic efficiency of chlorin delivered by liposome formulations was compared with that of the pharmaceutical compound, before and after irradiation with laser light at 652 nm. The obtained results indicated that cationic liposomes (i) transferred m-THPC in glioblastoma cells more efficiently than pharmaceutical formulation; (ii) significantly (p < 0.001) increased the m-THPC cytotoxic effect after laser irradiation; (iii) seemed to exert their cytotoxic action in the early phase of interaction with the cells, during adhesion to the plasma membrane.

BACKGROUND AND PURPOSE: Spontaneous transdural spinal cord herniation is no longer a rare cause of myelopathy. The high frequency of diagnoses has led to an increase in the number of surgical procedures. The purpose of this study was to describe the spectrum of postoperative MR imaging findings concerning spontaneous transdural spinal cord herniation and to provide a practical imaging approach for differentiating expected changes and complications after an operation. MATERIALS AND METHODS: We retrospectively reviewed MR images from 12 patients surgically treated for spontaneous transdural spinal cord herniation. Surgery comprised either dural defect enlargement or duraplasty procedures. Postoperative follow-ups included at least 3 (early, intermediate, late) MR imaging studies. MR images were analyzed with respect to 3 spinal compartments: intradural intramedullary, intradural extramedullary, and extradural. The meaning and reliability of changes detected on MR images were related to their radiologic and clinical evolution with time. RESULTS: Spinal cord realignment has been stable since the early study, whereas spinal cord signal and thickness evolved during the following scans. Most extramedullary and extradural changes gradually reduced in later MR images. Three patients treated with dural defect enlargements experienced the onset of new neurologic symptoms. In those patients, late MR images showed extradural fluid collection and the development of pial siderosis. CONCLUSIONS: Our findings demonstrate the spectrum of postoperative imaging findings in spontaneous transdural spinal cord herniation. Spinal cord thickness and signal intensity continued to evolve with time; most extramedullary postsurgical changes became stable. Changes observed in later images may be suggestive of complications.

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.

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 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

Objectives Dural arteriovenous fistulas (DAVFs) are a challenging condition in vascular neurosurgery. Disease natural history and its management is still debated. In the present paper we report our center series on DAVFs over a period of 10 years. Our data were compared with relevant literature. Patient and methods Our series includes 45 cases: 14 cavernous sinus, 11 transverse-sigmoid, 8 patients tentorial, 6 anterior cranial fossa, 5 patients spinal, 1 patient foramen magnum. Results and conclusions DVAFs distribution, clinical presentation and hemorrhagic risk are discussed. Cavernous sinus DAVFs are the most common site in our series. Other locations in order of frequency are transverse-sigmoid sinus, tentorial, anterior cranial fossa, spinal and foramen magnum. The majority of patients presented with non-aggressive symptoms. 18% presented with intracranial hemorrhage: all the hemorrhages occurred in high-grade DAVFs. For most patients, endovascular treatment, transarterial or transvenous, was the first option. Surgery was performed for the anterior cranial fossa DAVFs and other complex lesions draining mostly transverse-sigmoid sinus and tentorium. In 7% of cases a combination of endovascular + surgical treatment was used. Our series has been carefully analyzed in comparison ‘side by side’ with most relevant literature on DVAFs, focusing particularly on management strategies, therapeutic options and risks related to treatment.

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, TGFβ 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-β 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.

The purpose of this study was to characterize mouse neural stem cells (NSC) transduced by a multigenic lentiviral vector (LV) and stably express recombinant human nerve growth factor (rhNGF). We obtained NSC-derived cell lines which express human NGF in relevant amount to exploit their ability for therapeutic applications. METHODS: We constructed advanced multigenic LV vectors which contain a tricistronic cassette to express simultaneously up to three independent genes: (1) rhNGF (beta subunit); (2) EGFP (enhanced green fluorescent protein) and (3) Neo(R) (neomycin antibiotic resistance gene). Lentiviruses were obtained by transfecting LV constructs plus helper plasmids in human embryonic kidney (HEK)-293T packaging cells. Lentiviral virions were released in culture media and subsequent used to infect mouse NSC. Genetycin 418-resistant NSC were obtained after 1 month of selection in the presence of antibiotic (G418). Levels of human NGF secreted by rhNGF-NSC were determined by ELISA (enzyme-linked immunosorbent assay). Features of multipotentiality of engineered NSC-derived cell lines versus naive cells (control-NSC) were assessed by immunocytochemical analysis in differentiation conditions. Self-renewal of NSC was tested by neurospheres assay (NSA). RESULTS: Levels of secreted human NGF, from conditioned media obtained by rhNGF-NSC cultures, were found to be elevated in either proliferation or differentiation conditions as compared with control cells. Moreover, released hNGF demonstrated biologic activity on PC12 cells by a functional test of neurite outgrowth. Immunocytochemical analysis revealed that engineered NSC showed to be all positives for EGFP. After thirty passages in vitro in the presence of G418, engineered cells versus naive NSC cultures maintained their multipotentiality to differentiate into neurons, astrocytes and oligodendrocytes. Furthermore, it was found that rhNGF-NSC-derived neurons expressed choline acetyltransferase (ChAT) and displayed an enhanced axonal growth. NSA showed an altered sphere forming frequency either in rhNGF-NSC or both group of control NSC. DISCUSSION: Lentivirus-mediated rhNGF gene transfer into NSC was achieved using a new version of LV vectors. We obtained rhNGF-NSC-derived cell lines which released hNGF to high levels in the culture medium. The expression of neural differentiation markers, like microtubule associated protein 2 (MAP2) (a/b), glial fibrillary acidic protein (GFAP) and chondroitin sulphate proteoglycan (NG2), was not enhanced in rhNGF-NSC compared with control cells. Secreted hNGF increased axonal sprouting by rhNGF-NSC-derived neurons which was associated with ChAT expression. rhNGF-NSC may prospectively be good candidates for the treatment of either neurodegenerative diseases such as Alzheimer disease or central nervous system injuries.

Object. The primary empty sella syndrome (ESS) represents a heterogeneous clinical picture characterized by endocrine disturbances and signs of intracranial hypertension. An increase in intracranial pressure (ICP) is proposed to be one of the involved pathogenetic factors. Methods. The series included 142 patients who were observed during a period of 20 years. All patients underwent an ICP and cerebrospinal fluid (CSF) dynamics evaluation through the use of a lumbar constant-rate infusion test. Impairment of ICP and CSF dynamics was observed in 109 patients (76.8%). In 35 of the 36 patients affected by severe intracranial hypertension without rhinorrhea, improvement in adverse neurological symptoms was achieved after implanting a CSF shunt. Visual function, already seriously compromised before surgery, remained severely altered in one patient. In the group of 34 patients affected by rhinorrhea, CSF leakage was controlled using different surgical treatments: CSF shunt placement in 16 cases, surgical repair of the sellar floor in three, and both procedures in the remaining 13. Two patients refused any surgical treatment. Conclusions. The role of increased ICP in the pathogenesis and perpetuation of primary ESS has been confirmed. Adverse neurological signs and a CSF leak are correlated with an actual increase in ICP and are relieved after CSF shunt insertion. Cerebrospinal fluid rhinorrhea is more common than generally thought. Its resolution can be achieved using a careful diagnostic protocol and sometimes may require different surgical procedures.

The term primary empty sella (PES) refers to a number of endocrine and/or neurological disturbances that may be caused by the herniation of subarachnoid space within the sella.The records of all patients with a diagnosis of empty sella between 1985 and 2002 seen at the Catholic University of Rome and University of Brescia were examined retrospectively.We have observed 171 female and 42 male patients affected by PES (over 4:1 sex ratio). The mean age at diagnosis in our subjects was 51.8 +/- 2.1 yr. Mean body mass index was 27.3 +/- 3.5 kg/m2.All the patients have been analyzed first either with sellar computed tomography scan or magnetic resonance imaging. All patients underwent neurological, ophthalmological, and baseline endocrine evaluation (appropriate stimulation tests were performed when hypopituitarism was suspected).In the overall population, 40 of 213 patients had documented endocrine abnormalities, specifically 31 females and nine males. Twenty-two patients (10.3% of total patients; 18 women, 10.5% of all women, with a mean age of 38.6 +/- 1.1 yr and four males, with a mean age 46.5 +/- 3.52 yr) presented with hyperprolactinemia. Global anterior hypopituitarism was confirmed in nine patients. Eight patients presented an isolated GH deficiency. One hundred thirty-eight of our patients presented a so-called partial empty sella at computed tomography scan/magnetic resonance imaging, and 75 had total PES.PES may be associated with variable clinical conditions ranging from mild endocrine disturbances to severe intracranial hypertension and rhinorrhea. The need for treatment of hyperprolactinemia as well as for replacement hormone therapy must be assessed in PES. Symptomatic intracranial hypertension makes cerebrospinal fluid shunting procedures necessary.

Chordoid meningioma is a rare meningothelial tumor characterized by chordoma-like histological features with lymphoplasmacellular infiltration. This tumor is often seen in children, but not in adults, with a systemic inflammatory syndrome (iron-resistant microcytic anemia and/or dysgammaglobulinemia) and very rarely with a persistent moderate hyperthermia. In the present report the authors describe a temporal chordoid meningioma in a 30-year-old woman who presented with fever, headache, and a serological inflammatory syndrome. The clinical symptomatology, chiefly the fever, disappeared immediately after removal of the tumor. To the authors' knowledge, only one similar patient with such clinical presentation and response to surgery has been mentioned in the literature. Interestingly, at immunohistochemical examination, the neoplasm showed focal positivity for the pyrogenic cytokine interleukin-6. The capacity of the tumor to produce this pyrogenic cytokine could explain both the patient's clinical presentation and her response to the surgical management.

Object. The optimal approach for the surgical treatment of craniopharyngiomas is still debated. In all cases involving the sella turcica, the authors have exclusively used transsphenoidal surgery (TSS), assuming that this approach is less traumatic than an intracranial one. Moreover, TSS was also performed in some cases of purely suprasellar craniopharyngiomas. In this study the surgical indications and the results obtained in all patients who had undergone TSS were analyzed. Methods. In a series of 92 patients who underwent surgery for craniopharyngiomas, TSS was the first choice of approach in 57 cases (62%) consisting of 29 female and 28 male patients with ages ranging from 12 to 79 years (mean 35 years). The follow-up duration ranged from 2 to 20 years. A standard transsphenoidal approach was used in patients with an exclusively intrasellar (11 patients) or an intrasellar and suprasellar tumor (37 patients); in nine cases of tumors located exclusively above the sella turcica, a transsphenoidal presellar approach (seven patients) or a transsellar—transdiaphragmatic approach (two patients) was used. Total removal was performed in 36 patients (63%). All patients had good clinical results. Postoperative cerebrospinal fluid leakage occurred in 10 cases, but only one case required a surgical repair of the sella. Two patients died of late complications (3.5%). There were eight cases (14%) of tumor regrowth. Conclusions. The authors assert that, when used in appropriately located craniopharyngiomas and by neurosurgeons with extensive experience in pituitary surgery, TSS offers excellent results with minor risks.

To characterize and compare pharmacokinetic parameters in children and adults treated with temozolomide (TMZ) administered for 5 days in three doses daily, and to evaluate the possible relationship between AUC values and hematologic toxicity.TMZ pharmacokinetic parameters were characterized in pediatric and adult patients with primary central nervous system tumors treated with doses ranging from 120 to 200 mg/m2 per day, divided into three doses daily for 5 days. Plasma levels were measured over 8 h following oral administration in a fasting state. A total of 40 courses were studied in 22 children (mean age 10 years, range 3-16 years) and in 8 adults (mean age 30 years, range 19-54 years).In all patients, a linear relationship was found between systemic exposure (AUC) and increasing doses of TMZ. Time to peak concentration, elimination half-life, apparent clearance and volume of distribution were not related to TMZ dose. No differences were seen among TMZ C(max), t(1/2), V(d) or CL/F in children compared with adults. Intra- and interpatient variability of systemic exposure were limited in both children and adults. No statistically significant differences were found between the AUCs of children who experienced grade 4 hematologic toxicity and children who did not.No difference appears to exist between pharmacokinetic parameters in adults and children when TMZ is administered in three doses daily. Hematologic toxicity was not related to TMZ AUC. AUC measurement does not appear to be of any use in optimizing TMZ treatment.

The treatment of cerebrospinal fluid rhinorrhea is a challenge and requires a therapeutic strategy in order to reduce the risk of meningitis. The localization of the fistula is not always easy and direct surgical repair requires major operation with an outcome not always successful. In many patients, an alteration of CSF pressure and/or dynamics may be associated to the rhinorrhea, making its spontaneous or surgical closure difficult. In a series of 81 patients affected by rhinorrhea, we have studied the CSF pressure and dynamics and tried to stop the fistula by using a temporary or permanent CSF drainage. This procedure was able to cure the fistula in 54 cases, while a direct surgical repair was required in 12 patients. In 13 cases both the procedures were required. Two patients refused any treatment. These results indicate that the study of the CSF pressure and dynamics may help to understand physiopathology of the CSF rhinorrhea and that the CSF drain (temporary or permanent) can be a simple way of definitively curing the CSF fistula in the majority of patients suffering from rhinorrhea.

Aims and background. The incidence of pituitary adenomas (PA). in patients aged more than 65 years is relatively low. The goal of this study was to evaluate the growth fraction and the clinical features of PA affecting old patients and to compare the results to those of younger subjects. Methods . We evaluated the Ki-67 LI using the monoclonal antibody MIB-1 in 21 patients of more than 65 years of age affected by PA consecutively operated on and compared the mean LI with that one of 104 patients under 65 operated on in the same period. The clinical behavior of PA was also analyzed in both groups. Results. In older cases PA occurred more frequently with visual disturbances: 17 out of 21 (80.9%) older patients showed pre-operative visual disturbances, versus 43 out of 104 (41.3%) younger patients ( P =0.0009). Fifteen out of 21 (71.4%) older patients had a non-functioning PA, versus 38 out of 66 (36.5%) younger patients ( P =0.003). In relation to surgically verified infiltration of sellar floor dura and bone, we identified non-invasive (12/21 older cases) and invasive (9 cases) adenomas; the wall of the cavernous sinus was infiltrated in 5 cases. The overall mean Ki-67 LI was 4.06±6.73 versus 2.35±2.54% of younger patients ( P =0.04). Conclusions . Our data confirm that Ki-67 LI detected by the MIB-1 monoclonal antibody is a useful marker in the determination of the growth fraction of PA. In relation to our preliminary results, PA in the elderly seem to have a higher growth fraction than in younger patients, are more often non-functioning and occur frequently with visual disturbances. In order to confirm our data further larger studies are necessary.

Primary supratentorial intracerebral hemorrhage can be considered as one of the most devastating forms of cerebrovascular disease. Reduction in intracranial volume buffering capacity and severe intracranial pressure are the most important factors related to a poor prognosis in cases with huge hematoma and altered state of consciousness. The role of surgery in the management of such cases appears still controversial. Nevertheless, it is conceivable that some cases with poor natural outcome might benefit from surgical evacuation. Fifty patients with altered state of consciousness and primary supratentorial intracerebral hemorrhage ranging from 24 to 75 ml were submitted to surgical evacuation of the hematoma. The decision to operate was based on the presence of signs indicating an oncoming severe intracranial hypertension. In 15 patients, in whom a progression in brain swelling was expected to occur after the hematoma evacuation, a decompressive craniectomy, associated with dural enlargement, was performed after the initial surgical procedure. The overall analysis of the clinical results at one year after surgery showed 40% of complete recovery and 38% of improvement. A significant statistical correlation was found between outcome and pre-operative neurological status. The association of decompressive craniectomy and dural enlargement to hematoma evacuation, proved very useful in a group of severely compromised patients. Surgical treatment of patients with primary supratentorial intracerebral hemorrhage and altered state of consciousness can have a positive role, in selected cases, by minimizing the life-threatening progression of intracranial hypertension.

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.

Spontaneous, non traumatic subarachnoid hemorrhage (SAH) is a significant clinical problem that occurs most commonly as a result of aneurysm rupture. In approximately 15 % of cases, nor aneurysm or other vascular malformation can be identified by cerebral angiography as origin of the hemorrhage, and these are commonly defined as idiopathic SAH (ISAH). Because of the negative angiography, limited extension of the bleeding with prevalent prepontine pattern and the benign prognosis, the venous causes has been preferred rather than the arterial ones. In the literature recent studies have suggested a possible contribution by primitive variants of Basal vein of Rosenthal (BVR) in its the pathogenesis of ISAH, commonly grouped according Watanabe classification (type A, B and C). In this paper we evaluated the prevalence of anatomical variants of BVR in ISAH. Venous drainage at angiography was retrospectively analyzed in 40 patients with ISAH and in 40 with unruptured aneurysms as controls. Previous studies displayed a significant prevalence of BVR type C variants in ISAH. Conversely in our study we recognized variant B as prevalent, in which the BVR bifurcates to drain anteriorly into the uncal vein and posteriorly into the Galenic system. Similarly to variant C (in which the BVR drains via perimesencephalic “bridging” veins into cavernous, sphenoparietal, petrosal sinus or directly into transverse sinus) also variant B might be subjected to those stress mechanisms and intrinsic system ‘fragility’ and for reasons yet to determine, sets off a consequent hemorrhage with clinical and radiological features typical of ISAH.

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, βIII-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 (βIII-Tubulin and GFAP) were expressed at high levels in both LI cells and in neurospheres. The expression of Nestin, Sox2, and βIII-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.

In 2003, a 50-year-old woman was admitted to the emergency department of a large hospital for a 2-month history of stabbing epigastric pain radiating backward to the right scapula. The pain was not relieved in any position and was not preceded by fever or trauma. Her history was unremarkable. General examination including temperature, pulse, and blood pressure was normal.

Objective Duraplasty can be performed both by means of autologous tissues (such as galea-pericranium, temporal muscle, fascia lata) or by commercially available dural patches. Nowadays many neurosurgeons consider galea-pericranium duraplasty time-consuming, technically demanding or not adequate, thus dural surrogates are increasingly popular. In this prospective research we compared duraplasty using autologous galea-pericranium vs. dural patches in terms of postoperative long term results, ease/time required and costs. Patients and methods Research has been designed as prospective cohort study, that included 185 patients undergoing supratentorial elective neurosurgery with galea-pericranium or non-autologous duraplasty (minimum follow-up 12 months). Variables taken into account were: wound infection, CSF fistula, subcutaneous CSF collection, bone flap osteitis, brain abscess, empyema and tardive wound dehiscence (particularly after postoperative radiotherapy). Time for galea-pericranium collection, size of galea-pericranium harvest and dural defects were recorded in each case. Costs for non-autologous duroplasty were calculated. Results No statistically significant differences were evident in long term postoperative results between the two groups. Mean time of galea-pericranium collection is less than 2 min and enough galea-pericranium can be harvested in supratentorial approach to cover almost any dural defect. The only difference between the two groups is costs: an average of 268.7€/patient spent just for duraplasty. This figure is surely substantial if considered for the entire amount of surgeries performed in a department. Conclusions Considering that in our study long term results are equivalent, that galea-pericranium duraplasty is feasible and rapid, our indications are in favor of saving a considerable amount of money since an ideal autologous dural substitute is available and “free”.

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/β 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. Electronic supplementary material The online version of this article (doi:10.1186/1476-4598-13-247) contains supplementary material, which is available to authorized users.

Endoscopy represents both an alternative and useful complement to the standard microsurgical approach to the anterior craniovertebral junction (CVJ). Nevertheless, few studies provide an experimental comparison between transnasal and transoral endoscopic control on CVJ. We compared the surgical exposition angle and the working channel volume of both the transnasal and transoral approaches in the cadaver.Eleven fresh non-perfused cadavers were studied. Transnasal and transoral linear and angled exposure of the CVJ were evaluated by means of X-ray and CT scan both in sagittal and lateral planes.The transoral endoscopic surgical exposition was wider compared with the transnasal in anterior and lateral projections:(1)in the sagittal plane, both in vertical exposition (transnasal inferior to transoral from 5.89 % to 76.48 %, average 35.89 %) and in vertical surgical angle (from 22 % to 77.42 %, average 56.53 %); (2)in the coronal plane, both in coronal exposition (transnasal inferior to transoral from 50.77 % to 83.88 %, average 70.34 %) and in coronal surgical angle (from 65.58 % to 86.71 %, average 76.70 %). The sagittal surgical domain was found to spanning from the inferior third of the clivus to C3 with the transoral and from the middle third of the clivus to the nasopalatal line (NPL) with the transnasal approach. The overlapping surgical domain area was found to be the inferior third of the clivus.The endoscope assisted transoral approach allows a better surgical control of the CVJ. It provides a better CVJ exposure, in sagittal and transverse planes, providing a larger working channel and an easier manoeuvrability. The transnasal approach is limited in caudal direction down to the NPL, otherwise the transoral approach is limited in the rostral direction with a maximum to the foramen magnum in normal specimen. In every individual case, pros and cons of the appropriate approach have to be taken into account as well as the choice of a combined transnasal and transoral approaches strategy.

Objective Cerebral vasospasm (VS) is one of the factors that can most significantly worsen the prognosis after aneurysmal subarachnoid hemorrhage (SAH). A substantial body of evidence supports the idea that CSF diversion could prevent VS, even if this issue is still much debated. External ventricular drainage (EVD) is the recommended procedure for post-hemorrhagic hydrocephalus. In this study we analyzed whether EVD, placed for acute hydrocephalus, is effective in reducing the incidence of clinical and radiological cerebral vasospasm in patients who underwent endovascular treatment for aneurysmal SAH. Patients and methods We retrospectively studied the incidence of radiologically confirmed VS in 141 patients treated endovascularly for aneurysmal SAH: 80 underwent EVD for hydrocephalus, 61 did not undergo EVD. Results VS occurred in 8.75% of cases (7 patients) in the first groups, while in 22.95% (14 patients) in the second group. In addition, patients not treated with EVD display a prevalence of VS in lower Fisher grades compared to the other group. Conclusion Our data indicate that CSF drainage reduces the risk of vasospasms in patients with endovascular treatment for aneurysmal SAH.

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.

Object. Evidence from recent in vitro studies indicates that reactivation of telomerase, the enzyme that synthesizes the telomere ends of chromosomes, is a crucial event in the unlimited clonal expansion of endothelial cells that precedes the neoplastic conversion of these cells. It is known that high-grade gliomas express telomerase and that, in these neoplasms, proliferating endothelial cells may undergo transformational changes with development of sarcomatous components within the primitive tumor. To assess whether telomerase is involved in the endothelial cell proliferation that characterizes brain tumor angiogenesis, the authors investigated at the single-cell level the expression of messenger (m)RNA for the human telomerase catalytic subunit human telomerase reverse transcriptase (hTERT) by vascular cells of astrocytic tumors. Methods. The in situ hybridization (ISH) method was performed by processing histological sections with specific riboprobes for hTERT and for c-myc, an oncogene that is known to upregulate hTERT. Results of the ISH studies were compared with proliferative activity, as estimated by Ki-67 immunostaining. The expression of hTERT mRNA by vascular endothelial cells was related to the histological grade of the tumor because it was detected in five (29%) of 17 low-grade astrocytomas, nine (56%) of 16 anaplastic astrocytomas, and 19 (100%) of 19 glioblastomas multiforme (GBMs). Expression of c-myc mRNA was strictly correlated with that of hTERT mRNA. In low-grade astrocytomas and anaplastic astrocytomas, a dissociation was noted between hTERT mRNA expression and the proliferation rate of endothelial cells. Conversely, GBMs displayed a significant correlation between the level of hTERT mRNA expression and endothelial cell proliferation. Data from an in vitro assay in which human umbilical vein endothelial cells were stimulated to proliferate by adding vascular endothelial growth factor and an ISH study of newly formed vessels surrounding brain infarcts confirmed that expression of hTERT mRNA does not merely reflect the proliferative status of endothelial cells but represents a specific feature of brain tumor neovascularization. Conclusions. The results of this study are consistent with a role of telomerase in the angiogenesis of astrocytic tumors. Expression of hTERT mRNA by tumor vascular cells is an early event during the progression of astrocytic tumors, which precedes endothelial cell proliferation and may represent a first sign of dedifferentiation. Other than elucidating the mechanisms of tumor angiogenesis, these results encourage research on antitelomerase drugs for the treatment of malignant gliomas.

Purpose: Cancer stem cells (CSC) are thought to represent the population of tumorigenic cells responsible for tumor development. The stem cell antigen CD133 identifies such a tumorigenic population in a subset of glioblastoma patients. We conducted a prospective study to explore the prognostic potential of CSC analysis in glioblastoma patients. Experimental Design: We investigated the relationship between the in vitro growth potential of glioblastoma CSCs and patient death or disease progression in tumors of 44 consecutive glioblastoma patients treated with complete or partial tumorectomy followed by radiotherapy combined with temozolomide treatment. Moreover, we evaluated by immunohistochemistry and immunofluorescence the prognostic value of the relative presence of CD133+ and CD133+/Ki67+ cells in patient tumors. Results: In vitro CSC generation and the presence of ≥2% CD133+ cells in tumor lesions negatively correlated with overall (P = 0.0001 and 0.02, respectively) and progression-free (P = 0.0002 and 0.01, respectively) survival of patients. A very poor overall (P = 0.007) and progression-free (P = 0.001) survival was observed among patients whose tumors contained CD133+ cells expressing Ki67. Taking into account symptom duration, surgery type, age, O6-methylguanine-DNA methyltransferase promoter methylation, and p53 status, generation of CSCs and CD133/Ki67 coexpression emerged as highly significant independent prognostic factors, with an adjusted hazard ratio of 2.92 (95% confidence interval, 1.37-6.2; P = 0.005) and 4.48 (95% confidence interval, 1.68-11.9; P = 0.003), respectively. Conclusions: The analysis of CSCs may predict the survival of glioblastoma patients. In vitro CSC generation and presence of CD133+/Ki67+ cells are two considerable prognostic factors of disease progression and poor clinical outcome.

OBJECTIVE Craniopharyngiomas usually grow on the cisternal surface of the hypothalamic region; these tumors can also grow from the infundibulum or tuber cinereum on the floor of the third ventricle, developing exclusively into the third ventricle. The aim of the present work was to establish the usefulness of the pterional trans-lamina terminalis approach for the removal of these tumors. METHODS Eight patients who were surgically treated for craniopharyngiomas located exclusively within the third ventricle were considered. The initial symptoms were acute hydrocephalus in two cases, psychological disturbances in two, amenorrhea in two, headaches in one, and hypopituitarism in one. The diagnoses were established, in all cases except one, with magnetic resonance imaging. In all cases, the tumor completely filled the third ventricle. RESULTS Total removal of the lesion was achieved in seven cases. One patient underwent partial removal. In the immediate postoperative period, no major complications were observed. Five patients required replacement hormonal therapy. All patients returned to a normal life. Many months after surgery, two patients exhibited psychological disturbances and died, the first because of voluntary withdrawal of replacement therapy (12 mo after surgery) and the second because of a severe imbalance in body fluids and electrolytes, with a subsequent hyperosmolar coma (27 mo after surgery). Only one patient who underwent initial total removal experienced a small recurrence of the lesion (30 mo after surgery); after 3 years, the lesion exhibited unchanged size. CONCLUSION In our experience, the trans-lamina terminalis approach is a valid choice for the removal of purely intraventricular craniopharyngiomas. These tumors can be removed without significant sequelae related to the surgical approach. The proximity to the hypothalamus requires accurate neuroendocrine and electrolyte control in the postoperative period, in some cases even years after surgery.

Evaluated in this study were the feasibility and the efficacy of concurrent low dose fractionated radiotherapy (LD-FRT) and chemotherapy as palliative treatment for recurrent/progressive glioblastoma multiforme (GBM).Eligible patients had recurrent or progressive GBM, Karnofsky performance status ≥ 70, prior surgery, and standard radiochemotherapy treatment. Recurrence/progression disease during temozolomide (TMZ) received cisplatin (CDDP; 30 mg/m(2) on days 1, 8, 15), fotemustine (FTM; 40 mg/m(2) on days 2, 9, 16), and concurrent LD-FRT (0.3 Gy twice daily); recurrence/progression after 4 months from the end of adjuvant TMZ were treated by TMZ (150/200 mg/m(2) on days 1-5) concomitant with LD-FRT (0.4 Gy twice daily). Primary endpoints were safety and toxicity.A total of 32 patients were enrolled. Hematologic toxicity G1-2 was observed in 18.7 % of patients and G3-4 in 9.4 %. One patient (3.1 %) had complete response, 3 (9.4 %) had partial response, 8 (25 %) had stable disease for at least 8 weeks, while 20 patients (62.5 %) experienced progressive disease. The clinical benefit was 37.5 %. Median progression-free survival (PFS) and overall survival (OS) were 5 and 8 months, respectively. Survival rate at 12 months was of 27.8 %.LD-FRT and chemotherapy for recurrent/progressive GBM have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted.

The adult human olfactory bulb neural stem/progenitor cells (OBNC/PC) are promising candidate for cell-based therapy for traumatic and neurodegenerative insults. Exogenous application of NGF was suggested as a promising therapeutic strategy for traumatic and neurodegenerative diseases, however effective delivery of NGF into the CNS parenchyma is still challenging due mainly to its limited ability to cross the blood–brain barrier, and intolerable side effects if administered into the brain ventricular system. An effective method to ensure delivery of NGF into the parenchyma of CNS is the genetic modification of NSC to overexpress NGF gene. Overexpression of NGF in adult human OBNSC is expected to alter their proliferation and differentiation nature, and thus might enhance their therapeutic potential. In this study, we genetically modified adult human OBNS/PC to overexpress human NGF (hNGF) and green fluorescent protein (GFP) genes to provide insight about the effects of hNGF and GFP genes overexpression in adult human OBNS/PC on their in vitro multipotentiality using DNA microarray, immunophenotyping, and Western blot (WB) protocols. Our analysis revealed that OBNS/PC-GFP and OBNS/PCGFP- hNGF differentiation is a multifaceted process involving changes in major biological processes as reflected in alterations of the gene expression levels of crucial markers such as cell cycle and survival markers, stemness markers, and differentiation markers. The differentiation of both cell classes was also associated with modulations of key signaling pathways such MAPK signaling pathway, ErbB signaling pathway, and neuroactive ligand-receptor interaction pathway for OBNS/PC-GFP, and axon guidance, calcium channel, voltage-dependent, gamma subunit 7 for OBNS/PC-GFP-hNGF as revealed by GO and KEGG. Differentiated OBNS/PC-GFP-hNGF displayed extensively branched cytoplasmic processes, a significant faster growth rate and up modulated the expression of oligodendroglia precursor cells markers (PDGFRα, NG2 and CNPase) respect to OBNS/PC-GFP counterparts. These findings suggest an enhanced proliferation and oligodendrocytic differentiation potential for OBNS/PC-GFP-hNGF as compared to OBNS/PC-GFP. (Egypt (Science and Technology Development Fund, http://www.stdf.org.eg/), Onlus (Associazione per le Terapie Neurochirurgiche Avanzate)

Treatment of glioblastoma recurrence can have a palliative aim, after considering risks and potential benefits. The aim of this study is to verify the impact of surgery and of palliative adjuvant treatments on survival after recurrence.From January 2002 to June 2008, we treated 76 consecutive patients with recurrent glioblastoma. Treatment was: 1-surgery alone--17 patients; 2-adjuvant-therapy alone--24 patients; 3-surgery and adjuvant therapy--16 patients; no treatment--19 patients. The impact on median overall-survival (OS-time between recurrence and death/last follow-up) of age, Karnofsky performance scale (KPS), resection extent and adjuvant treatment scheme (Temozolomide alone vs low-dose fractionated radiotherapy vs others) was determined. Survival curves were obtained through the Kaplan-Meier method. Cox proportional-hazards was used for multivariate analyses. Significance was set at p0.05.Median OS was 7 months. At univariate analysis, patients with a KPS≥70 had a longer OS (9 months vs 5 months--p0.0001). OS was 6 months for patients treated with surgery alone, 5 months for patients that received no treatment, 8 months for patients treated with chemotherapy alone, 14 months for patients treated with surgery and adjuvant therapy--p=0.01. Patients with a KPS70 were significantly at risk for death - HR 2.8 - p=0.001. Subgroup analysis showed no significant differences between patients receiving gross total or partial tumor resection and among patients receiving different adjuvant therapy schemes. Major surgical morbidity at tumor recurrence occurred in 16 out of 33 patients (48%).It is fundamental, before deciding to operate patients for recurrence, to carefully consider the impact of surgical morbidity on outcome.

n this issue of WORLD NEUROSURGERY, de Divitiis and Laws address an important topic of current discussion in skull I base surgery: What is the approach of choice for skull base tumors of the anterior skull base and suprasellar area? Transnasal or transcranial? Endoscopic or microsurgical? An inquiry of the neurosurgical community with these questions most likely would lead to a wide collection of heterogeneous answers. One article (5) documented ample variability in technical neurosurgery decision making by submitting the case of a young patient with a suprasellar, mainly cystic tumor to 40 neurosurgeons; the result was the suggestion of 10 different approaches. The authors commented that “decades into the era of evidence-based medicine, most neurosurgeons are aware that the vast majority of our day-to-day patient care decisions are not guided by class I evidence, especially those related to surgical procedures” (5).

In human glioblastomas (hGBMs), tumor-propagating cells with stem-like characteristics (TPCs) represent a key therapeutic target. We found that the EphA2 receptor tyrosine kinase is overexpressed in hGBM TPCs. Cytofluorimetric sorting into EphA2High and EphA2Low populations demonstrated that EphA2 expression correlates with the size and tumor-propagating ability of the TPC pool in hGBMs. Both ephrinA1-Fc, which caused EphA2 downregulation in TPCs, and siRNA-mediated knockdown of EPHA2 expression suppressed TPCs self-renewal ex vivo and intracranial tumorigenicity, pointing to EphA2 downregulation as a causal event in the loss of TPCs tumorigenicity. Infusion of ephrinA1-Fc into intracranial xenografts elicited strong tumor-suppressing effects, suggestive of therapeutic applications. © 2012 Elsevier Inc.

ccess to the interpeduncular fossa is a surgical challenge, which is documented by the many different A approaches that have been described to expose it. The approaches can be subdivided in two major groups, according to their entry point. Lateral approaches expose the area starting from a lateral entry point, whereas median approaches achieve a midline, symmetric exposure. Each approach has specific limitations, and some approaches have precise indications; all of them are technically demanding, mainly because the interpeduncular fossa remains a narrow, deep, and fragile confined area, regardless of the approach (7). Accessing this region has proved to be a challenge independent of the approach taken (12).