Preliminary experience with 4K ultra-high definition endoscope: analysis of pros and cons in skull base surgery.

During the last two decades endoscopic skull base surgery observed a continuous technical and technological development 3D endoscopy and ultra High Definition (HD) endoscopy have provided great advances in terms of visualisation and spatial resolution. Ultra-high definition (UHD) 4K systems, recently introduced in the clinical practice, will shape next steps forward especially in skull base surgery field. Patients were operated on through transnasal transsphenoidal endoscopic approaches performed using Olympus NBI 4K UHD endoscope with a 4 mm 0° Ultra Telescope, 300 W xenon lamp (CLV-S400) predisposed for narrow band imaging (NBI) technology connected through a camera head to a high-quality control unit (OTV-S400 - VISERA 4K UHD) (Olympus Corporation, Tokyo, Japan). Two screens are used, one 31" Monitor - (LMD-X310S) and one main ultra-HD 55" screen optimised for UHD image reproduction (LMD-X550S). In selected cases, we used a navigation system (Stealthstation S7, Medtronic, Minneapolis, MN, US). We evaluated 22 pituitary adenomas (86.3% macroadenomas; 13.7% microadenomas). 50% were not functional (NF), 22.8% GH, 18.2% ACTH, 9% PRL-secreting. Three of 22 were recurrences. In 91% of cases we achieved total removal, while in 9% near total resection. A mean follow-up of 187 days and average length of hospitalisation was 3.09 ± 0.61 days. Surgical duration was 128.18± 30.74 minutes. We experienced only 1 case of intraoperative low flow fistula with no further complications. None of the cases required any post- or intraoperative blood transfusion. The visualisation and high resolution of the operative field provided a very detailed view of all anatomical structures and pathologies allowing an improvement in safety and efficacy of the surgical procedure. The operative time was similar to the standard 2D HD and 3D procedures and the physical strain was also comparable to others in terms of ergonomics and weight.

Expression of iNOS, CD163 and ARG-1 taken as M1 and M2 markers of microglial polarization in human glioblastoma and the surrounding normal parenchyma.

Microglia and macrophages appear to be the most common cells in the GBM microenvironment. In the present study we investigated the status of macrophages/microglia activation in surgical specimens from 41 patients diagnosed with grade IV GBM. For each patient we analyzed both the center of tumor and the parenchyma surrounding the tumor. The specimens were stained for: i) IBA1, a 17-kDa EF hand protein specifically expressed in microglia/macrophages ii) CD163, a cell surface antigen associated with M2 phenotype; iii) iNOS, taken as a functional marker of M1 phenotype, and iv) ARG-I, taken as a functional marker of M2 phenotype. Staining was scored in a double-blinded score on a scale from 0 to 5. Our results suggest that CD163 expression is higher within the tumor than in surrounding periphery in both male and female patients; while iNOS is higher within the tumor in males, no significant difference was found for ARG-1. In addition, analyzing the data in TGCA database, we found that CD163 expression was significantly and inversely correlated with mean survival times, with average survival times ranging from 448days in patients having low expression, to 319 in mid, and 353 in patients with high CD163 expressing tumors. In contrast, no significant association was found between survival time and ARG-1 or iNOS expression.

Intraventricular versus intravenous colistin for the treatment of extensively drug resistant Acinetobacter baumannii meningitis.

BACKGROUND AND PURPOSE: Reports on the safety and efficacy of intraventricularly administered (IVT) colistin for the treatment of Acinetobacter baumannii ventriculomeningitis in adults are limited and no comparative studies of IVT colistin versus intravenous (IV) therapy alone have been published. This study compared outcomes of patients with postneurosurgical ventriculomeningitis caused by extensively drug-resistant A. baumannii treated with IV colistin or IV plus IVT colistin. METHODS: In an 11-year period, information on 18 consecutive patients with extensively drug-resistant A. baumannii ventriculomeningitis was collected. Infection was defined on the basis of (i) isolation of A. baumannii from the cerebrospinal fluid (CSF); (ii) laboratory evidence of CSF infection; (iii) signs/symptoms of central nervous system (CNS) infection. Patients were divided into group 1 (nine patients, IV colistin alone) and group 2 (nine patients, IV plus IVT colistin). RESULTS: Cerebrospinal fluid sterilization was documented for 12 of 18 patients (66.6%). The CSF sterilization rate was 33.3% in group 1 and 100% in group 2 (P = 0.009). The mean time to CSF sterilization was 21 days (range 8-48). Five patients died due to A. baumannii CNS infection (all in group 1), and five deaths were unrelated to A. baumannii ventriculomeningitis. Intensive care unit mean length of stay was shorter in group 2 (20.7 vs. 41.6 days, P = 0.046). Crude relative risk ratio of cumulative incidence of persistent CNS infection in group 1 versus group 2 was 13. No cases of chemical meningitis due to intrathecal colistin administration were encountered. CONCLUSIONS: Intraventricular colistin administration is much more effective than IV therapy alone and does not seem to add further toxicity.

Concurrent and adjuvant temozolomide-based chemoradiotherapy schedules for glioblastoma. Hypotheses based on two prospective phase II trials.

AIM: To investigate the impact of nonstandard concomitant temozolomide (TMZ) administration in two prospective phase II studies for glioblastoma (GBM). PATIENTS AND METHODS: From October 2000 to June 2008, 104 patients were enrolled in two studies: 25 in RT-TMZ-10.00 and 79 in RT-TMZ-01.04. Adjuvant radiotherapy (RT) was used with a total dose of 59.4 Gy (1.8 Gy/day). Patients received concomitant TMZ (75 mg/m(2)/day) from Monday to Friday during the first and last weeks of RT in the RT-TMZ-10.00 study and from Monday to Friday during all weeks of RT in the RT-TMZ-01.04 trial. Adjuvant TMZ (200 mg/m(2)) was administered for 5 days every 28 days. RESULTS: Median progression-free (PFS) and overall survival (OS) were 9 and 16 months, respectively, with no significant difference between the two groups (p = 0.5 and 0.14, respectively). The 2- and 5-year OS rates were 32 and 3 %, respectively, and similar to those observed with standard treatment regimens. CONCLUSION: Our data support the hypothesis that adjuvant TMZ is more important than concomitant chemotherapy (CH) and that RT is the more important element of the concomitant treatment schedule.

Frataxin participates to the hypoxia-induced response in tumors.

Defective expression of frataxin is responsible for the degenerative disease Friedreich's ataxia. Frataxin is a protein required for cell survival since complete knockout is lethal. Frataxin protects tumor cells against oxidative stress and apoptosis but also acts as a tumor suppressor. The molecular bases of this apparent paradox are missing. We therefore sought to investigate the pathways through which frataxin enhances stress resistance in tumor cells. We found that frataxin expression is upregulated in several tumor cell lines in response to hypoxic stress, a condition often associated with tumor progression. Moreover, frataxin upregulation in response to hypoxia is dependent on hypoxia-inducible factors expression and modulates the activation of the tumor-suppressor p53. Importantly, we show for the first time that frataxin is in fact increased in human tumors in vivo. These results show that frataxin participates to the hypoxia-induced stress response in tumors, thus implying that modulation of its expression could have a critical role in tumor cell survival and/or progression.

Successful treatment of multidrug-resistant Acinetobacter baumannii ventriculitis with intrathecal and intravenous colistin.

Acinetobacter baumannii (AB) nosocomial infections, especially those due to multi-drug resistant (MDR) strains, are increasingly detected. We report a case of a 42-year-old male patient affected by low-grade ependymoma who developed AB-MDR post-neurosurgical ventriculitis. Initially, because of in vitro susceptibility, we used a combination of intravenous colistin and tigecycline. This treatment resulted in the improvement of the patient's initial condition. However, soon after, the infection relapsed; tigecycline was stopped and treatment with intrathecal colistin was initiated. Cure was achieved by continuing this treatment for approximately three weeks, without adverse effects.

Distinct pools of cancer stem-like cells coexist within human glioblastomas and display different tumorigenicity and independent genomic evolution.

Glioblastomas (GBMs) contain transformed, self-maintaining, multipotent, tumour-initiating cancer stem cells, whose identification has radically changed our perspective on the physiology of these tumours. Currently, it is unknown whether multiple types of transformed precursors, which display alternative sets of the complement of properties of true cancer stem cells, can be found in a GBM. If different subsets of such cancer stem-like cells (CSCs) do exist, they might represent distinct cell targets, with a differential therapeutic importance, also depending on their characteristics and lineage relationship. Here, we report the presence of two types of CSCs within different regions of the same human GBM. Cytogenetic and molecular analysis shows that the two types of CSCs bear quite diverse tumorigenic potential and distinct genetic anomalies, and, yet, derive from common ancestor cells. This provides critical information to unravel the development of CSCs and the key molecular/genetic components underpinning tumorigenicity in human GBMs.

Cerebral blood flow autoregulation during intracranial hypertension: a simple, purely hydraulic mechanism?

OBJECTIVE: In this paper, we re-propose the role of a hydraulic mechanism, acting where the bridging veins enter the dural sinuses in cerebral blood flow (CBF) autoregulation. MATERIALS AND METHODS: We carried out an intraventricular infusion in ten albino rabbits and increased intracranial pressure (ICP) up to arterial blood pressure (ABP) levels. We measured CBF velocity by an ultrasound probe applied to a by-pass inserted in a carotid artery and recorded ICP by an intraventricular needle. Diastolic and pulsatile ICP and ABP values were analyzed from basal conditions up to brain tamponade and vice versa. CONCLUSIONS: A biphasic pattern of pulsatile intracranial pressure (pICP) was observed in all trials. Initially, until the CBF velocity remained constant, pICP increased (from 1.2 to 5.4 mmHg) following a rise in diastolic intracranial pressure (dICP); thereafter, in spite of a further rise in dICP, pICP decreased (2.87 mmHg) following CBF velocity reduction until intracranial circulation arrest (pICP=1.2 mmHg). A specular pattern was observed when the intraventricular infusion was stopped and CBF velocity returned to basal levels. These findings can be interpreted as indicating a hydraulic mechanism. Initially, when CBF is still constant, pICP rise is due to an increase in venous outflow resistance; subsequently, when CBF decreases following a further increase in venous outflow resistance, the vascular engorgement produces an arteriolar vasodilation. This vasodilation determines an increase in vascular wall stiffness, thus reducing pulse transmission to surrounding subarachnoid spaces.

Intratumoral vs systemic administration of meta-tetrahydroxyphenylchlorin for photodynamic therapy of malignant gliomas: assessment of uptake and spatial distribution in C6 rat glioma model.

Malignant gliomas, with an incidence of 5 cases per 100,000 population per year, represent the most common primary brain tumour. They have an overall survival length of less than 2 years. Many different adjuvant therapies have been developed. Among them, Photodynamic Therapy (PDT), that is based on photochemical reactions between light and tumoral tissue selectively labelled with exogenous photosensitizing agents. Among photosensitizers, m-THPC (Temoporfin), seems to be the most promising one for the treatment of brain tumors, but, unfortunately, it causes problems of high skin photosensitivity. To by-pass this problem, we devised an intratumoral route of administration of this photosensitizer. The aim of this study is to investigate and compare the uptake of m-THPC in brain tumor and normal tissue after systemic and intratumoral administration of the drug. 30 female Wistar rats received m-THPC 12 days after C6 tumor implantation. Temoporfin was administered intratumorally in 24 rats at two different concentrations. 6 rats constituted the control group and received m-THPC by means of an intraperitoneal injection. The brains were extracted at 4 h, 24 h and 96 h after Temoporfin injection. The samples were examined with a confocal laser scanning microscope. All samples showed high fluorescence emission exclusively in the tumour area, without appreciable differences between the samples taken at the different times of sacrifice and the two routes of administration. No fluorescence whatsoever was detected among normal brain tissue surrounding the tumour. The intratumoral route appears to give comparable results to the systemic one, regarding intracellular uptake efficiency and tumour--normal tissue ratio, with the advantage of a much shorter time needed to reach optimal intratumoural concentration--that is just four hours from m-THPC injection.

Cationic liposomes, loaded with m-THPC, in photodynamic therapy for malignant glioma.

In this study we investigated the feasibility of mixed liposomes formed by dimyristoyl-sn-glycero-phosphatidylcholine (DMPC) and cationic gemini surfactant (Gemini 1) loaded with the chlorin m-tetrahydroxyphenylchlorin (m-THPC), in photodynamic therapy (PDT) for glioma. To this aim, an in vitro study was carried out by employing various human glioblastoma cell lines (A172, DBTRG, LN229, U118). The following liposomal formulations were tested: (i) DMPC and Gemini 1; (ii) m-THPC in DMPC in the absence or (iii) in the presence of Gemini 1 in the molar ratio 8:2; 7:3, and 6:4. The presence of Gemini 1 significantly increased the intracellular uptake of chlorin in all cell tested although with a different extent: LN229>U118>A172>DBTRG. The cytotoxicity of chlorin-loaded liposomes was then tested by cloning efficiency performed on different cultures, before and after irradiation with laser light at 652nm, at a Fluence Rate of 200mW/s for 100s, with a total Fluence of 20J/cm(-2). In the absence of irradiation, the different liposomal formulations induced a cytotoxicity in less than 30% of glioblastoma cells. On the contrary, irradiation induced total destruction of all cultures treated with m-THPC/DMPC+Gemini 1 in the ratios 8:2, or 7:3, or 6:4.

Intracerebral diffusion of paramagnetic cationic liposomes containing Gd(DTPA)2- followed by MRI spectroscopy: assessment of pattern diffusion and time steadiness of a non-viral vector model.

Cationic liposomes are generally considered as the non-viral counterparts of the more common viral vectors used in several gene therapy protocols, but their use as delivery vehicles is limited by their efficiency even if they display a lower toxicity. However, cationic liposomes are promising delivery systems in cell biology due to their ability to incorporate small molecules into their inner aqueous spheres and to deliver them into cells. Additionally, on the external surface they can bind therapeutic molecules such as nucleic acids, oligonucleotides, plasmids, etc. through electrostatic interactions. The aim of this work was to study the diffusion properties of such vehicles in vivo with a non-invasive technique and to monitor their tissue migration in order to collect information to be further used in gene therapy procedures. For this purpose, cationic liposomes containing the paramagnetic contrast agent Gd(DTPA)2- (Gd(III)-diethylenetriamine-N,N,N',N",N"-pentaacetic acid) were investigated because of their extended paramagnetic persistency in vivo, compared to the use of the contrast agent alone, and they were used to monitor the diffusion of such vehicles in an animal model (rat model). In particular, these vectors were injected into the rat brain through a stereotactic frame in a preformed cavity mimicking the lesion which had originated after surgical removal of the primary tumor. For the purpose of comparison, the same injection procedure was also applied to a control series of animals without a preformed brain lesion. Pattern diffusion and steadiness of the reported paramagnetic cationic liposomes were studied by means of Magnetic Resonance Imaging (MRI) which allowed us to monitor their diffusion and assess their intracerebral time availability up to 24 hours.

Spontaneous haematoma of ligamentum flavum. Case report and literature review.

Spontaneous infarction of the ligamentum flavum is a very rare cause of mielo-radicular compression. In the literature only four cases are reported, all characterized by a clinical history of slowly progressive mielo-radiculopathy and good outcome after surgical treatment. A 70 year-old female patient presented with a four months clinical history of spontaneous, sub-continuous, progressive lumbar pain with bilateral irradiation to the L4-L5 dermatomers, right leg monoparesis and hypoaesthesia affecting tactile, thermal and pain sensivity, urinary incontinence and constipation. CT scan and MRI evidenced an extradural ovalar lesion in correspondence of the L1-L2 levels, that exerted compression over the dural sac, dislocating it anteriorly. The patient underwent a L1-L2 laminectomy and the lesion was totally resected. Rapid improvement of the patient's symptomatology has been noticed in the postoperative period, with complete recovery during the following month. Histologic examinations demonstrated that the mass was a haematoma of the ligamentum flavum. It's our opinion, that a picture of ligamentum flavum haematoma should be taken into account in differential diagnosis of posterior mielo-radicular compression. The progressive growth of the haematoma may explain the long clinical history of these patients and surgical treatment, even if delayed, permits an excel-lent clinical outcome.

Glioblastoma multiforme in the elderly: a therapeutic challenge.

INTRODUCTION: Elderly patients with glioblastoma multiforme (GBM) are frequently excluded from cancer therapy trials, treated suboptimally or not treated at all. The average survival in elderly patients is 4-8 months. The goal of the present study was to evaluate the efficacy of different treatment options in terms of survival in an elderly population affected with GBM. MATERIALS AND METHODS: About 34 Patients with primary supratentorial GBM aged 65 or higher were included in this study. All patients underwent craniotomy and tumor mass resection. After surgery they received radiation therapy, chemotherapy and radioimmunotherapy in different combinations. RESULTS: Overall median survival was 10.5 months with one patient still alive at 35 months. Survival was longer for patients who underwent total resection instead of partial (13 months vs 4 months, P=0.006). If total en-bloc resection was used a further survival advantage was obtained (16 months for en-bloc resection, 9 months for inside-out resection, P=0.008). Where a second surgical intervention was performed median survival was 21 months (P=0.05). Survival according to adjuvant therapy has been 21 months (radiotherapy, chemotherapy, radioimmunotheraphy), 18 months (radiotherapy, chemotherapy) and 7 months (radiotherapy) (P=0.0001). CONCLUSIONS: We think that single prognostic factor such as age should be not a reason for undertreatment.

Pure surgical treatment of 109 aneurysms.

AIM: Target of this study was to investigate outcomes after pure surgical treatment of intracranial aneurysms. METHODS: Patients with intracranial supratentorial circle aneurysms were retrospectively reviewed between July 1994 and October 1998. Studied cases were admitted at the Department of Neurosurgery of S. Maria-Hospital, Terni, a Government supported General Hospital. One hundred and nine Hunt and Hess Grade 0 to III patients with supratentorial circle aneurysms was studied in order to determine whether advances in the surgical management of intracranial aneurysms have improved surgical outcomes and which factors may predict outcome. All patients were managed only with standard neurosurgical aneurysms clipping procedures. Outcomes evaluation was made at patients' discharge and classified on the base of the Glasgow Outcome Scale (GOS). Surgical timing, SAH grading, pre and post surgical symptomatic vasospasm, temporary clipping, and intraoperative aneurysm rupture were correlated with outcomes. RESULTS: Surgical results showed a 75% excellent outcome. Mortality rate was 3%. Hunt and Hess grade 0 highly influenced outcome. Differences in outcomes among grades I to III were not significant. No differences in outcomes related to temporary clipping were noted. A low rate of intraoperative aneurysm rupture is reported: 5 out of 109 cases. In all these cases outcome was good, with neither mortality or morbidity. CONCLUSIONS: Results indicate a progressive improvement in surgical outcomes, suggesting that there still exist margins for improvements in pure surgical management of intracranial aneurysms.

Gliomatosis cerebri and pituitary adenoma: case report and literature review.

The diagnosis of Gliomatosis cerebri (GC) is known to be difficult and is still a matter of debate. We describe an in vivo case of GC associated with a pituitary tumor. A 47-year-old woman presented with short-term memory loss. A MRI revealed the presence of a pituitary enhancing tumor and a diffuse lesion involving the brain. A left pterional craniotomy with partial temporal lobectomy and removal of the pituitary lesion were performed in order to obtain diagnosis. The histological analyses showed a pituitary non-functioning tumor and a GC consisting of neoplastic oligodendrocytes and astrocytes. Both lesions showed nuclear immunoreactivity for progesterone receptors (PGr) and estrogen receptors (EGr). This result could suggest there is a common receptor substrate in these tumors. In this case hormones could constitute a common step in tumorigenesis of both lesions.

Extensive modulation of a set of microRNAs in primary glioblastoma.

MicroRNAs (miRNAs) are short non-coding RNA molecules playing regulatory roles in animals and plants by repressing translation or cleaving RNA transcripts. The specific modulation of several microRNAs has been recently associated to some forms of human cancer, suggesting that these short molecules may represent a new class of genes involved in oncogenesis. In our study, we examined by microarray the global expression levels of 245 microRNAs in glioblastoma multiforme, the most frequent and malignant of primary brain tumors. The analysis of both glioblastoma tissues and glioblastoma cell lines allowed us to identify a group of microRNAs whose expression is significantly altered in this tumor. The most interesting results came from miR-221, strongly up-regulated in glioblastoma and from a set of brain-enriched miRNAs, miR-128, miR-181a, miR-181b, and miR-181c, which are down-regulated in glioblastoma.