Alfredo Conti

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.

Does early decompression improve neurological outcome of spinal cord injured patients? Appraisal of the literature using a meta-analytical approach

Study design: Definitive and unequivocal evidence to support the practice of early or late surgery is still lacking in clinical studies. Accordingly, meta-analysis is one of the few methods that offer a rational, statistical approach to management decision. A review of the clinical literature on spinal cord injury with emphasis on the role of early surgical decompression and a meta-analysis of results was performed.Objectives: To determine whether neurological outcome is improved in traumatic spinal cord-injured patients who had surgery within 24 h as compared with those who had late surgery or conservative treatment.Methods: A Medline search covering the period 1966–2000, supplemented with manual search, was used to locate studies containing information on indication, rationale and timing of surgical decompression after spinal cord injuries. The analysis included a total of 1687 eligible patients.Results: Statistically, early decompression resulted in better outcome compared with both conservative (P<0.001) and late management (P<0.001). Nevertheless, analysis of homogeneity showed that only data regarding patients with incomplete neurological deficits who had early surgery were reliable.Conclusions: Although statistically the percentage of patients with incomplete neurological deficits improving after early decompression appear 89.7% (95% confidence interval: 83.9, 95.5%), to be better than with the other modes of treatment when taking into consideration the material available for analysis and the various other factors including clinical limitations; early surgical decompression can only be considered as practice option for all groups of patients.

Anaesthetic-related neuroprotection: intravenous or inhalational agents?

In designing the anaesthetic plan for patients undergoing surgery, the choice of anaesthetic agent may often appear irrelevant and the best results obtained by the use of a technique or a drug with which the anaesthesia care provider is familiar. Nevertheless, in those surgical procedures (cardiopulmonary bypass, carotid surgery and cerebral aneurysm surgery) and clinical situations (subarachnoid haemorrhage, stroke, brain trauma and post-cardiac arrest resuscitation) where protecting the CNS is a priority, the choice of anaesthetic drug assumes a fundamental role. Treating patients with a neuroprotective agent may be a consideration in improving overall neurological outcome. Therefore, a clear understanding of the relative degree of protection provided by various agents becomes essential in deciding on the most appropriate anaesthetic treatment geared to these objectives.This article surveys the current literature on the effects of the most commonly used anaesthetic drugs (volatile and gaseous inhalation, and intravenous agents) with regard to their role in neuroprotection. A systematic search was performed in the MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINHAL®) and Cochrane Library databases using the following keywords: ‘brain’ (with the limits ‘newborn’ or ‘infant’ or ‘child’ or ‘neonate’ or ‘neonatal’ or ‘animals’) AND ‘neurodegeneration’ or ‘apoptosis’ or ‘toxicity’ or ‘neuroprotection’ in combination with individual drug names (‘halothane’, ‘isoflurane’, ‘desflurane’, ‘sevoflurane’, ‘nitrous oxide’, ‘xenon’, ‘barbiturates’, ‘thiopental’, ‘propofol’, ‘ketamine’). Over 600 abstracts for articles published from January 1980 to April 2010, including studies in animals, humans and in vitro, were examined, but just over 100 of them were considered and reviewed for quality.Taken as a whole, the available data appear to indicate that anaesthetic drugs such as barbiturates, propofol, xenon and most volatile anaesthetics (halothane, isoflurane, desflurane, sevoflurane) show neuroprotective effects that protect cerebral tissue from adverse events — such as apoptosis, degeneration, inflammation and energy failure — caused by chronic neurodegenerative diseases, ischaemia, stroke or nervous system trauma. Nevertheless, in several studies, the administration of gaseous, volatile and intravenous anaesthetics (especially isoflurane and ketamine) was also associated with dose-dependent and exposure time-dependent neurodegenerative effects in the developing animal brain. At present, available experimental data do not support the selection of any one anaesthetic agent over the others. Furthermore, the relative benefit of one anaesthetic versus another, with regard to neuroprotective potential, is unlikely to form a rational basis for choice. Each drug has some undesirable adverse effects that, together with the patient’s medical and surgical history, appear to be decisive in choosing the most suitable anaesthetic agent for a specific situation. Moreover, it is important to highlight that many of the studies in the literature have been conducted in animals or in vitro; hence, results and conclusions of most of them may not be directly applied to the clinical setting. For these reasons, and given the serious implications for public health, we believe that further investigation — geared mainly to clarifying the complex interactions between anaesthetic drug actions and specific mechanisms involved in brain injury, within a setting as close as possible to the clinical situation — is imperative.

Role of stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of recurrent glioblastoma multiforme

Glioblastoma multiforme (GBM) is a devastating malignant brain tumor characterized by resistance to available therapeutic approaches and relentless malignant progression that includes widespread intracranial invasion, destruction of normal brain tissue, progressive disability, and death. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) are increasingly used in patients with recurrent GBM to complement traditional treatments such as resection, conventional external beam radiotherapy, and chemotherapy. Both SRS and fSRT are powerful noninvasive therapeutic modalities well suited to treat focal neoplastic lesions through the delivery of precise, highdose radiation. Although no randomized clinical trials have been performed, a variety of retrospective studies have been focused on the use of SRS and fSRT for recurrent GBMs. In addition, state-of-the-art neuroimaging techniques, such as MR spectroscopic imaging, diffusion tensor tractography, and nuclear medicine imaging, have enhanced treatment planning methods leading to potentially improved clinical outcomes. In this paper the authors reviewed the current applications and efficacy of SRS and fSRT in the treatment of GBM, highlighting the value of these therapies for recurrent focal disease.

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.

ENDOSCOPIC TRANSORAL-TRANSCLIVAL APPROACH TO THE BRAINSTEM AND SURROUNDING CISTERNAL SPACE: ANATOMIC STUDY

OBJECTIVEThe purpose of this study was to review the endoscopic anatomic features of the anterior brainstem and surrounding cisternal spaces via a transoral-transclival approach. METHODSFifteen adult human cadaveric heads, obtained from 10 fresh cadavers and 5 formalin-fixed cadavers, were used to demonstrate both the feasibility of an endoscopic transoral-transclival intradural approach and its exposure potential. To analyze the exact extension of a safe entry zone through the clivus, 20 skull bases were used to obtain anatomic measurements. RESULTSThe transoral approach was performed without maxillotomy or mandibulotomy and with a clival opening of 20 by 15 mm. Such a limited clival and dural opening allowed the insertion of the endoscope and instruments, full visualization of the anterolateral brainstem and cisternal spaces around it, and reconstruction of all anatomic layers by means of a paraendoscopic technique. CONCLUSIONThe endoscopic transoral-transclival approach enables full access to the anterolateral brainstem and to the cisternal space around it. The use of the endoscope has the potential to reduce the need for a wider cranial base opening and the danger of postoperative complications.

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.

Navigated transcranial magnetic stimulation for "somatotopic" tractography of the corticospinal tract.

BACKGROUND: Diffusion tensor imaging tractography provides 3-dimensional reconstruction of principal white matter tracts, but its spatial accuracy has been questioned. Navigated transcranial magnetic stimulation (nTMS) enables somatotopic mapping of the motor cortex. OBJECTIVE: We used motor maps to reconstruct the corticospinal tract (CST) by integrating elements of its somatotopic organization. We analyzed the accuracy of this method compared with a standard technique and verified its reliability with intraoperative subcortical stimulation. METHODS: We prospectively collected data from patients who underwent surgery between January 2012 and October 2013 for lesions involving the CST. nTMS-based diffusion tensor imaging tractography was compared with a standard technique. The reliability and accuracy between the 2 techniques were analyzed by comparing the number of fibers, the concordance in size, and the location of the cortical end of the CST and the motor area. The accuracy of the technique was assessed by using direct subcortical stimulation. RESULTS: Twenty patients were enrolled in the study. nTMS-based tractography provided a detailed somatotopic reconstruction of the CST. This nTMS-based reconstruction resulted in a decreased number of fibers (305.1 ± 231.7 vs 1024 ± 193, P < .001) and a significantly greater overlap between the motor cortex and the cortical end-region of the CST compared with the standard technique (90.5 ± 8.8% vs 58.3 ± 16.6%, P < .001). Direct subcortical stimulation confirmed the CST location and the somatotopic reconstruction in all cases. CONCLUSION: These results suggest that nTMS-based tractography of the CST is more accurate and less operator dependent than the standard technique and provides a reliable anatomic and functional characterization of the motor pathway. ABBREVIATIONS: CST, corticospinal tract DSS, direct subcortical stimulation DTI, diffusion tensor imaging DWI, diffusion-weighted imaging FDI, first dorsal interosseous FLAIR, fluid attenuated inversion recovery MEN, mentalis MEP, motor evoked potential nTMS, navigated transcranial magnetic stimulation RMT, resting motor threshold ROI, region of interest TA, tibialis anterior TE, echo time TMS, transcranial magnetic stimulation TR, repetition time

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.