Filippo Flavio Angileri

miR-21 and 221 upregulation and miR-181b downregulation in human grade II–IV astrocytic tumors

MicroRNAs (miRNAs) are small noncoding regulatory RNAs that reduce stability and/or translation of fully or partially sequence-complementary target mRNAs. Recent evidence indicates that miRNAs can function both as tumor suppressors and as oncogenes. It has been demonstrated that in glioblastoma multiforme miR-21 and 221 are upregulated whereas miR-128 and 181 are downregulated. Expression of miR-21, 221, 128a, 128b, 128c, 181a, 181b, 181c was studied using real-time quantitative reverse transcriptase polymerase chain reaction and northern blotting for human astrocytic tumors with different grade of malignancy. miR-21 and 221 were overexpressed in glioma samples, whereas miRNA 181b was downregulated compared with normal brain tissue. miRNA-21 was hyperexpressed in all tumor samples whereas higher levels of miRNA-221 were found in high-grade gliomas. This study is the first analysis of miRNAs in astrocytic tumor at different stages of malignancy. The different expression pattern observed in tumors at different stages of malignancy is probably dependent on the cell-specific repertoire of target genes of tumors sharing different molecular pathways activity and suggests miRNAs may have also a place in diagnosis and staging of brain tumors.

Nuclear factor‐κB activation and differential expression of survivin and Bcl‐2 in human grade 2–4 astrocytomas

Antiapoptotis resulting from hyperactivation of the transcription factor NF‐κB has been described in several cancer types. It is triggered by the interaction of the tumor necrosis factor (TNF) with its receptors and recruitment of the intermediate factor TNF‐receptor associated factor (TRAF) 2. The NF‐κB transcriptional activity could amplify the expression of antiapoptotic genes. The authors investigated the activity of NF‐κB, and the mRNA expression of TNFα, TNFα receptor, TRAF1, TRAF2, and TRAF‐associated NF‐κB activator (TANK), and the antiapoptotic genes Bcl‐2, c‐IAP 1 and 2, and Survivin in human astrocytic tumors.

Microsurgical Anatomic Features of the Olfactory Nerve: Relevance to Olfaction Preservation in the Pterional Approach

OBJECTIVE: The pterional approach represents the standard approach for most lesions of the anterior and middle cranial fossa. It requires some degree of frontal lobe retraction, which may result in temporary or permanent damage of olfaction because of nerve avulsion or mechanical compression. The purpose of this study, based on microanatomic dissection of human cadaveric specimens, was to review the microsurgical anatomic features of the nerve and suggest operative nuances that may contribute to reducing the rate of postoperative olfactory dysfunction. METHODS: Twenty olfactory nerves and tracts were examined in 10 human cadaveric heads obtained from three fresh and seven formalin-fixed adult cadavers. A standard pterional craniotomy was performed. The olfactory nerve was dissected from its arachnoidal envelopes and then mobilized for an average length of 30 mm (range, 25–35 mm). RESULTS: The possible retraction of the frontal lobe was 10 to 15 mm. More retraction invariably resulted in nerve disruption. CONCLUSION: The standard sylvian and basal cistern opening may be insufficient to guarantee preservation of olfactory function. Early identification and arachnoidal dissection of the nerve may reduce the rate of olfaction compromise. The opening of the subarachnoidal space should be performed in a proximal-to-distal manner to allow early visualization of the olfactory bulb and its dissection. The arachnoidal dissection should be performed with sharp instruments, avoiding any traction on the posterior portion of the olfactory tract. Any direct retractor compression should also be avoided to spare the microvasculature lying on the dorsal surface of the nerve.

Post-neurosurgical multidrug-resistant Acinetobacter baumannii meningitis successfully treated with intrathecal colistin. A new case and a systematic review of the literature

INTRODUCTION Post-neurosurgical nosocomial meningitis has become an important subgroup of bacterial meningitis in the hospital setting. The increase in meningitis caused by multidrug-resistant (MDR) Acinetobacter baumannii has resulted in a significant reduction in available treatment options. CASE REPORT AND LITERATURE REVIEW We report the case of a 36-year-old man with a complex craniofacial trauma, who developed a nosocomial meningitis due to MDR A. baumannii that was cured by intrathecal colistin. The case is contextualized among all the published cases of Acinetobacter meningitis treated with topical colistin found through a MEDLINE search of the literature. To date, including the present case, eight reported cases of Acinetobacter meningitis have been treated with colistin administered by an intrathecal route and 24 by an intraventricular route. The daily dose of colistin used ranged from 1.6 mg every 24 h to 20 mg every 24 h in adult patients. The median time necessary to obtain cerebrospinal fluid sterilization was 4.1 days, and treatment was always successful even if in two cases Acinetobacter meningitis relapsed. Toxicity probably or possibly related to the topical administration of colistin was noted in five out of the 32 patients. CONCLUSIONS Topical colistin can be an effective and safe treatment for MDR Acinetobacter meningitis.

PATIENTS WITH MODERATE HEAD INJURY: A PROSPECTIVE MULTICENTER STUDY OF 315 PATIENTS

OBJECTIVETo analyze the risk factors of worst outcome associated with moderate head injury. METHODSData on patients with moderate head injury were collected prospectively in 11 Italian neurosurgical units over a period of 18 months. Patients older than 18 years with blunt head injury and at least one Glasgow Coma Scale (GCS) score between 9 and 13 were enrolled. The outcome was determined at 6 months using the Glasgow Outcome Scale. RESULTSWe analyzed 315 patients. Initial computed tomographic scans showed a diffuse injury type I or II in 63%, a mass lesion in 35%, and traumatic subarachnoid hemorrhage in 42% of the patients. The risk of progression toward a mass lesion was 23% when the admission computed tomographic scan showed diffuse injury type I or II. An emergency craniotomy was performed in 22% of the patients, delayed surgery was performed in 14%, and both were performed in 25%. A favorable outcome was obtained in 74% of the patients. When the GCS score was 9 or 10, the predictor of worst outcome was a motor GCS score of 4 or lower (odds ratio [OR], 8.08; 95% confidence interval [CI], 1.22–67.35; P = 0.008), but when the GCS score was 11 to 13, the factors associated with worst outcome were neuroworsening (OR, 3.43; 95% CI, 1.45–8.17; P = 0.002), seizures (OR, 7.94; 95% CI, 1.18–64.48; P = 0.02), and medical complications (OR, 4.24; 95% CI, 1.74–10.33; P = 0.0006). CONCLUSIONThere is a high percentage of surgery and worsening on computed tomographic scans in patients with moderate head injury. Neuroworsening, seizures, and medical complications as outcome predictors were more strongly associated with a GCS score of 11 to 13, whereas a low motor GCS score was more outcome-related in patients with GCS scores of 9 and 10.

Time-related ultrastructural changes in an experimental model of whole brain irradiation.

To stimulate therapeutic irradiation, we exposed rats to conventional fractionation (200 +/- 4 cGy/d, 5 d/wk; total dose, 4000 cGy). The effects of this regimen were assessed by electron microscopic examinations of brain microvascular and parenchymal cells 15 and 90 days after irradiation. Studies of the transendothelial passage of horseradish peroxidase provided information about the functional status of the blood-brain barrier. At 15 days after irradiation, there was an increased vesicular transport of horseradish peroxidase across the intact endothelium without opening of the tight junctions, and without evidence of structural alterations of neuropil, neuronal bodies, and astrocytes. Ninety days after irradiation, well-defined ultrastructural alterations were observed, involving the microvasculature, the neuropil, the neuronal bodies, and astrocytes. The main ultrastructural feature of cortical microvessels was their collapsed aspect, associated with perivascular edema containing cell debris. Altered neurons and reactive activated astrocytes were also noticeable. These data suggest a possible association, not necessarily causal, between damage of the microvascular/glial unit of tissue injury and development of radiation-induced brain toxicity.

Traumatic intracerebellar hemorrhage: Clinicoradiological analysis of 81 patients

OBJECTIVE We report 81 patients with a traumatic intracerebellar hemorrhagic contusion or hematoma managed between 1996 and 1998 at 13 Italian neurosurgical centers. METHODS Each center provided data about patients’ clinicoradiological findings, management, and outcomes, which were retrospectively reviewed. RESULTS A poor result occurred in 36 patients (44.4%). Forty-five patients (55.6%) had favorable results. For the purpose of data analysis, patients were divided into two groups according to their admission Glasgow Coma Scale (GCS) scores. In Group 1 (39/81 cases; GCS score, ≥8), the outcome was favorable in 95% of cases. In Group 2 (42/81 cases; GCS score, <8), the outcome was poor in 81% of cases. Twenty-seven patients underwent posterior fossa surgery. Factors correlating with outcome were GCS score, status of the basal cisterns and the fourth ventricle, associated supratentorial traumatic lesions, mechanism of injury, and intracerebellar clot size. Multivariate analysis showed significant independent prognostic effect only for GCS score (P = 0.000) and the concomitant presence of supratentorial lesions (P = 0.0035). CONCLUSION This study describes clinicoradiological findings and prognostic factors regarding traumatic cerebellar injury. A general consensus emerged from this analysis that a conservative approach can be considered a viable, safe treatment option for noncomatose patients with intracerebellar clots measuring less than or equal to 3 cm, except when associated with other extradural or subdural posterior fossa focal lesions. Also, a general consensus was reached that surgery should be recommended for all patients with clots larger than 3 cm. The pathogenesis, biomechanics, and optimal management criteria of these rare lesions are still unclear, and larger observational studies are necessary.

Integration of functional neuroimaging in CyberKnife radiosurgery: feasibility and dosimetric results

OBJECT The integration of state-of-the-art neuroimaging into treatment planning may increase the therapeutic potential of stereotactic radiosurgery. Functional neuroimaging, including functional MRI, navigated brain stimulation, and diffusion tensor imaging-based tractography, may guide the orientation of radiation beams to decrease the dose to critical cortical and subcortical areas. The authors describe their method of integrating functional neuroimaging technology into radiosurgical treatment planning using the CyberKnife radiosurgery system. METHODS The records of all patients who had undergone radiosurgery for brain lesions at the CyberKnife Center of the University of Messina, Italy, between July 2010 and July 2012 were analyzed. Among patients with brain lesions in critical areas, treatment planning with the integration of functional neuroimaging was performed in 25 patients. Morphological and functional imaging data sets were coregistered using the Multiplan dedicated treatment planning system. Treatment planning was initially based on morphological data; radiation dose distribution was then corrected in relation to the functionally relevant cortical and subcortical areas. The change in radiation dose distribution was then calculated. RESULTS The data sets could be easily and reliably integrated into the Cyberknife treatment planning. Using an inverse planning algorithm, the authors achieved an average 17% reduction in the radiation dose to functional areas. Further gain in terms of dose sparing compromised other important treatment parameters, including target coverage, conformality index, and number of monitor units. No neurological deficit due to radiation was recorded at the short-term follow-up. CONCLUSIONS Radiosurgery treatments rely on the quality of neuroimaging. The integration of functional data allows a reduction in radiation doses to functional organs at risk, including critical cortical areas, subcortical tracts, and vascular structures. The relative simplicity of integrating functional neuroimaging into radiosurgery warrants further research to implement, standardize, and identify the limits of this procedure.

Giant Olfactory Groove Meningiomas: Extent of Frontal Lobes Damage and Long-Term Outcome After the Pterional Approach

OBJECTIVE The treatment of giant olfactory groove meningiomas (OGMs; maximum diameter ≥ 6 cm) poses special problems and represents a surgical challenge. We discuss the long-term results in a series of 18 patients with giant OGMs and report our experience on a global strategy encompassing the pterional approach to manage the lesion and an extended transbasal approach to treat recurrences. METHODS Between February 1991 and December 2007, 18 patients with giant OGMs were surgically managed via a pterional craniotomy. Postoperative follow-up imaging was obtained at one, six, and 12 months and then yearly. In preoperative images, data from tumor volume were assessed. The volume of the residual right frontal porencephalic cave (ipsilateral to the operative side) was compared with the volume of the porencephalic cave measured in the left frontal lobe (internal control) in each case. Comparison between porencephalic cave and the original tumor volume for each side was also performed. RESULTS At the first operation in 17 of 18 patients (94.4%), the tumor resection was accomplished by a complete macroscopic lesion removal and coagulation of its dural attachment (Simpson grade II). In one patient, a Simpson grade V resection was obtained. The mean follow-up was 93.5 months, ranging from 12 to 214 months. Recurrences were observed in three patients (16.7%) at 103, 102, and 128 months, respectively, from the time of the first operation. These patients were operated on via an extended subfrontal transbasal approach accomplishing a complete (Simpson grade I) resection. No death occurred. The visual deficit improved in seven of 13 patients (53.8%), remained stable in five (38.5%), and worsened in one patient (7.7%). Overall, 17 of 18 patients (94.4%) had a good outcome and returned to their previous occupations. All the tumors presented with a symmetrical growth pattern. The mean meningioma volume was 23.51 ± 1.62 cm(3) for the right portion of the tumor and 23.04 ± 1.35 cm(3) for the left portion. The mean residual porencephalic volume was significantly smaller in the left frontal lobe (mean value 5.7 mL) than in the right frontal lobe (mean value 16.6 mL; P < 0.05). The mean residual porencephalic volume was significantly smaller than the tumor volume both in the left (P < 0.01) and in the right side (P < 0.05). CONCLUSION The pterional-transsylvian approach provides two major advantages: first, it minimizes morbidity and mortality through an early neurovascular control and by limiting parenchymal damage as demonstrated by a quantitative analysis; second it is associated with low recurrence rate at a long-term follow-up.

Role of Inflammation and Oxidative Stress Mediators in Gliomas

Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment.