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Background: Patients with glioblastoma (GBM) inevitably develop recurrent or progressive disease after initial multimodal treatment and have a median survival of 6-9 months from time of progression. To date, there is no accepted standard treatment for GBM relapse or progression. Patupilone (EPO906) is a novel natural microtubule-stabilizing cytotoxic agent that crosses the blood-brain barrier and has been found to have preclinical activity in glioma models. Methods: This is a single-institution, early-phase I/II trial of GBM patients with tumor progression who qualified for second surgery with the goal of evaluating efficacy and safety of the single-agent patupilone (10 mg/m(2), every 3 weeks). Patients received patupilone 1 week prior to second surgery and every 3 weeks thereafter until tumor progression or toxicity. Primary end points were progression-free survival (PFS) and overall survival (OS) at 6 months as well as patupilone concentration in tumor tissue. Secondary end points were toxicity, patupilone concentration in plasma and translational analyses for predictive biomarkers. Results: Nine patients with a mean age of 54.6 ± 8.6 years were recruited between June 2008 and April 2010. Median survival and 1-year OS after second surgery were 11 months (95% CI, 5-17 months) and 45% (95% CI, 14-76), respectively. Median PFS was 1.5 months (95% CI, 1.3-1.7 months) and PFS6 was 22% (95% CI, 0-46), with 2 patients remaining recurrence-free at 9.75 and 22 months. At the time of surgery, the concentration of patupilone in tumor tissue was 30 times higher than in the plasma. Tumor response was not predictable by the tested biomarkers. Treatment was generally well tolerated with no hematological, but cumulative, though reversible sensory neuropathy grade ≤3 was seen in 2 patients (22%) at 8 months and grade 4 diarrhea in the 2nd patient (11%). Non-patupilone-related peri-operative complications occurred in 2 patients resulting in discontinuation of patupilone therapy. Th

Despite the failure of the international extracranial-intracranial (EC-IC) bypass study in showing the benefit of bypass procedure for prevention of stroke recurrence, it has been regarded to be beneficial in a subgroup of well-selected patients with haemodynamic impairment. This report includes the EC-IC bypass experience of a single centre over a period of 14 years. All consecutive 72 patients with atherosclerotic occlusive cerebrovascular lesions associated with haemodynamic compromise treated by EC-IC bypass surgery were retrospectively reviewed. Pre-operatively, 61% of patients presented with minor stroke and the remaining 39% with recurrent transient ischemic attacks (TIAs) despite maximal medical therapy. Angiography revealed a unilateral internal carotid artery (ICA) stenosis/occlusion in 79%, bilateral ICA stenosis/occlusion in 15%, MCA stenosis/occlusion in 3% and other multiple vessel stenosis/occlusion in 3% of the cases. H(2)(15)O positron emission tomography (PET) or 99mTc-HMPAO SPECT with acetazolamide challenge was performed for haemodynamic evaluation of the cerebral blood flow (CBF). All the patients had impaired haemodynamics pre-operatively in terms of reduced regional cerebrovascular reserve capacity and rCBF. Standard STA-MCA bypass procedure was performed in all patients. A total of 68 patients with 82 bypasses were reviewed with a mean follow-up period of 34 months. Stroke recurrence took place in 10 patients (15%) resulting in an annual stroke risk of 5%. Improved cerebral haemodynamics was documented in 81% of revascularised hemispheres. Patients with unchanged or worse haemodynamic parameters had significantly more post-operative TIAs or strokes when compared to those with improved perfusion reserves (30% vs.5% of patients, p<0.05). In conclusion, EC-IC bypass procedure in selected patients with occlusive cerebrovascular lesions associated with haemodynamic impairment has revealed to be effective for prevention of further cerebral ischemia

BACKGROUND: Arterioportal shunts (APS) are well-known critical complications after liver transplantation (OLT). The aims of this study were to assess the frequency and causes of APS after OLT and to analyze APS patients with poor outcomes. PATIENTS: We evaluated 1415 OLT recipients retrospectively investigating APS cases. RESULTS: APS were detected in at least 9 patients (0.6%). All patients with APS had a history of posttransplant invasive procedures; percutaneous transhepatic cholangio drainage (n = 6) or needle biopsy (LNB; n = 3). Two patients with poor outcomes showed proximal APS caused by LNBs. The other 7 patients with distal APSs, showed stable conditions. Imaging findings in the 2 proximal APS patients revealed drastic changes in graft hemodynamics. Although they finally underwent re-OLT, their outcomes were poor, owing to fatal complications associated with advanced collaterals. CONCLUSION: We concluded that even careful LNBs can cause APS at unexpected points. Earlier, more aggressive treatments are required, especially for proximal APS patients.

BACKGROUND: To report the authors' experience with recurrent aneurysms after primarily completely clipped cerebral aneurysms and discuss mechanisms of recurrence and recommended management. METHODS: Data were available for 1016 consecutive patients who underwent clipping of ruptured and unruptured aneurysms in a 15-year period from 1993-2007. RESULTS: Nine patients were treated for recurrent aneurysms after successful complete clipping of the initial aneurysms; six patients had initial surgery before 1992, and three patients underwent surgery during the study period. Mean elapsed time between the first clipping and the recurrence of aneurysm was 13.3 years ± 7.8. Repeat craniotomy was performed in seven patients, and six patients underwent reclipping of aneurysms with or without removal of the old clips. One patient was treated by construction of an extracranial-intracranial (EC-IC) bypass plus coating of the aneurysm. Endovascular occlusion of the parent artery was performed in one patient. One patient died without any intervention. Recurrent aneurysms could be classified into three types according to the relationship of the new aneurysm neck to the old clip. CONCLUSIONS: The incidence of recurrent aneurysms after complete clipping was approximately 0.02% per year; aneurysms recurred after 13.3 years on average with 25 years the longest duration from initial clipping to recurrence. Classification of recurrent aneurysms into three types might be helpful in selecting appropriate surgical management.

Mapping the distribution of GABAA receptor subtypes represents a promising approach to characterize alterations in cortical circuitry associated with neurological disorders. We previously reported subtype-selective changes in GABAA receptor expression in the grey matter of patients with focal epilepsy. In the present follow-up study, we focused on the subcortical white matter in the same tissue specimens obtained at surgery from 9 patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis, 12 patients with TLE associated with neocortical lesions and 5 patients with frontal lobe epilepsy; post-mortem tissue from 4 subjects served as controls. The subunit composition and distribution of three major GABAA receptor subtypes were determined immunohistochemically with subunit-specific antibodies. In all cases, a majority of neurons in the white matter was distinctly labelled, allowing detailed visualization of their dendritic arborization and revealing a differential, cell type-specific expression pattern of alpha-subunit variants. In controls, alpha1-subunit staining was most prominent, displaying a gradient that decreased with depth, in parallel with the density of NeuN-positive cells. Subsets of pyramidal cells were alpha3-subunit-positive, and alpha2-subunit-labelled neurons were rare. In 19 of the 26 patients with focal epilepsy, no changes were detected as compared with controls. In five patients with TLE, striking changes in the dendritic arborization of a subset of white matter neurons were seen with the alpha1-subunit antibody. In two further patients with TLE, we observed a disorganized dendritic network immuno-positive for the alpha1-subunit, cell clusters selectively expressing the alpha2-subunit and small neuronal aggregates that expressed all subunits and appeared to connect to neighbouring white matter neurons. All seven patients with anomalies in the white matter had a selective reduction in alpha3-containing GABAA receptors in the superficial la

Covalent modification of cullins by the ubiquitin-like protein NEDD8 (neddylation) regulates protein ubiquitination by promoting the assembly of cullin-RING ligase E3 complexes. Like ubiquitination, neddylation results from an enzymatic cascade involving the sequential activity of a dedicated E1 (APPBP1/Uba3), E2 (Ubc12), and an ill-defined E3. We show that SCCRO (also known as DCUN1D1) binds to the components of the neddylation pathway (Cullin-ROC1, Ubc12, and CAND1) and augments but is not required for cullin neddylation in reactions using purified recombinant proteins.Wealso show that SCCRO recruits Ubc12∼NEDD8 to the CAND1-Cul1-ROC1 complex but that this is not sufficient to dissociate or overcome the inhibitory effects of CAND1 on cullin neddylation in purified protein assays. In contrast to findings in cellular systems where no binding is seen, we show that SCCRO and CAND1 can bind to the neddylated Cul1-ROC1 complex in assays using purified recombinant proteins. Although neddylated (not unneddylated) Cul1-ROC1 is released from CAND1 upon incubation with testis lysate from SCCRO+/+mice, the addition of recombinant SCCRO is required to achieve the same results in lysate from SCCRO-/-mice. Combined, these results suggest that SCCRO is an important component of the neddylation E3 complex that functions to recruit charged E2 and is involved in the release of inhibitory effects of CAND1 on cullin-RING ligase E3 complex assembly and activity.

Successful removal of a spinal tumor was first reported by Horsely in 1888 [15]. Elsberg proposed a two-stage operation in the case of intramedullary tumors lacking a definitive plane between the spinal cord and tumor in the early part of the twentieth century [12, 13], albeit with high morbidity and mortality. With new technological advances especially the introduction of the bipolar coagulator and microsurgery, starting in the 1950s and 1960s respectively [16, 17, 21], the surgical risks were dramatically reduced.

History of Spinal Disorders.- Basic Science: Biomechanics of the Spine.- Spinal Instrumentation.- Age-Related Changes of the Spine.- Pathways of Spinal Pain.- Epidemiology and Risk Factors of Spinal Disorders.- Predictors of Surgical Outcome.- Patient Assessment: History and Physical Examination.- Imaging Studies.- Spinal Injections.- Neurological Assessment in Spinal Disorders.- Neurophysiological Investigations.- Surgical Approaches.- Peri- and Postoperative Management: Preoperative Assessment.- Intraoperative Anaestesia Management.- Postoperative Care and Pain Management.- Degenerative Disorders: Degenerative Disorders of the Cervical Spine.- Disc Herniation and Radiculopathy.- Lumbar Spinal Stenosis.- Degenerative Lumbar Spondylosis.- Non-specific Low Back Pain.- Postoperative Rehabilitation.- Spinal Deformities and Malformations: Idiopathic Scoliosis.- Neuromuscular Scoliosis.- Congenital Scoliosis.- Degenerative Scoliosis.- Spondylolisthesis.- Juvenile Kyphosis (Scheuermann's Disease).- Malformations of the Spinal Cord.- Fractures: Cervical Spine Injuries.- Thoracolumbar Spinal Injuries.- Osteoporotic Spine Fractures.- Tumor and Inflammation: Primary Tumors of the Spine.- Spinal Metastasis.- Intradural Tumors.- Infections of the Spine.- Rheumatoid Arthritis.- Ankylosing Spondylitis.- Treatment of Postoperative Complications.- Outcome Questionnaires and Tools in Spinal Surgery.

BACKGROUND: Intracranial dermoid cysts are uncommon, and their clinical features as well as surgical management differ from patient to patient. Dermoids are generally benign lesions, but may cause spontaneous complications such as meningitis and/or hydrocephalus due to rupture and epileptic seizures depending on their location. Little has been reported about characteristic imaging findings with resulting therapeutic considerations, and only a few reports exist about associated hydrocephalus. Imaging modalities have changed and can facilitate differential diagnosis and follow-up if applied correctly. In this paper, we attempt to contribute our clinical experience with the management of dermoid cysts. PATIENTS AND METHODS: The charts of five men and two women with intracranial dermoid cysts were retrospectively reviewed. The patients were treated between September 1993 and September 2006. Selected patients are presented in detail. RESULTS: Tumour location, size and radiographic characteristics varied in each patient. Clinical presentations comprised focal neurological deficits as well as epileptic seizures, persistent headache, mental changes and psycho-organic syndromes. One patient underwent delayed ventriculo-peritoneal shunting after ruptured fatty particles caused obstructive hydrocephalus. Despite dermoid rupture into the subarachnoid space, three patients never developed hydrocephalus. Diffuse vascular supra-tentorial lesions were seen in one patient as a result of aseptic meningitis. Diffusion-weighted imaging (DWI) hyperintensity in dermoids is related to decrease of water proton diffusion and should be used for both the diagnosis and follow-up of this lesion. CONCLUSION: Although dermoid cysts are known to be benign entities per se, their rupture can cause a wide range of symptoms including aseptic meningitis and/or hydrocephalus. This may be due to intraventricular obstruction and/or paraventricular compression. While rupture does not necessarily bring abou

We conducted a population-based study on glioblastomas in the Canton of Zurich, Switzerland (population, 1.16 million) to determine the frequency of major genetic alterations and their effect on patient survival. Between 1980 and 1994, 715 glioblastomas were diagnosed. The incidence rate per 100,000 population/year, adjusted to the World Standard Population, was 3.32 in males and 2.24 in females. Observed survival rates were 42.4% at 6 months, 17.7% at 1 year, and 3.3% at 2 years. For all of the age groups, younger patients survived significantly longer, ranging from a median of 8.8 months (<50 years) to 1.6 months (>80 years). Loss of heterozygosity (LOH) 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16(INK4a) deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations and was predictive of shorter survival. Primary (de novo) glioblastomas prevailed (95%), whereas secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hotspot codons 248 and 273, whereas in primary glioblastomas, mutations were more equally distributed. G:C-->A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas (56% versus 30%; P = 0.0208). This suggests that the acquisition of TP53 mutations in these glioblastoma subtypes occurs through different mechanisms.

We report the development of a new subdural probe for combined intracranial pressure (ICP) and cerebral blood flow (CBF) monitoring with near infrared spectroscopy (NIRS) and indocyanine green (ICG) dye dilution. For NIRS a conventional subdural ICP monitoring probe was supplied with two fiber bundles and 90-degree prisms. Injections of 25 mg ICG were performed. Regional values for the mean transit time of ICG (rmtt(ICG)), cerebral blood flow (rCBF) and cerebral blood volume (rCBV) were calculated. With prototypes of the probe in two patients with intracerebral haemorrhage 18 comparative measurements obtained simultaneously with conventional NIRS (optodes placed on the skin) and the subdural NIRS probe were performed. The new subdural NIRS probe allows combined monitoring of ICP and cerebral hemodynamics in the brain directly, without the influence of extracerebral tissue.

We studied the impact of emergency neurosurgery and intensive care on the outcome for patients with severe intracerebral haemorrhage after endovascular treatment of brain arteriovenous malformations (AVMs). We reviewed the case notes of 18 patients with severe haemorrhage after embolisation of a brain AVM between 1986 and 2001. During this period the treatment changed: before 1993, these patients were not surgically treated, and they died, while after 1994, all patients underwent emergency surgery. We established a standardised protocol for emergency treatment and intensive care in May 1998, and emergency surgery was performed as soon as possible after the onset of symptoms of haemorrhage. Postoperative intensive care was according to a standardised regime. During these 15 years, 24 out of 605 patients undergoing 1066 interventions had a haemorrhage during or after the procedure, of which 18 were severe (3% of patients, 1.7% of interventions). All patients had a severe clinical deficit (mean Glasgow coma scale 4.2); eight had uni- or bilateral mydriasis. From 1989 to April 1998 four (31%) of 13 patients died, one (7.5%) remained in a vegetative state and eight (61.5%) made a good recovery. All five patients treated between 1998 and 2001 had a favourable outcome. The mean time from onset of the symptoms of haemorrhage to reaching the operation room was 129 min between 1989 and 1998 and 24 min between 1998 and 2001. Standardised emergency treatment and intensive care with early resuscitation, minimal radiological exploration before rapid surgery improved the outcome. A short time between the onset of the symptoms of haemorrhage and evacuation of the haematoma may be the most important factor for a favourable outcome.

We designed a protocol to improve the immunohistochemical analysis of human brain structures, which overcomes the limited detection sensitivity, high background, and intense autofluorescence commonly associated with human tissue. This procedure was evaluated by using antibodies against major GABAA receptor subunits (alpha1, alpha2, alpha3, gamma2) in autopsy and surgical specimens. Tissue blocks were briefly fixed by immersion and pretreated with microwave irradiation in sodium citrate buffer. Immunoperoxidase staining revealed a marked enhancement of cell surface immunoreactivity and reduction of background in microwave-irradiated tissue, irrespective of its origin. For confocal laser scanning microscopy, immunofluorescence staining was optimized with the tyramide signal amplification (TSA) technique. This procedure not only dramatically increased the sensitivity for antigen detection but also totally suppressed autofluorescence, thus revealing the cellular and subcellular distribution of GABAA receptor subunits. A distinct neuron-specific expression pattern of the alpha-subunit variants was observed in cerebral cortex and hippocampal formation, along with widespread expression of the gamma2-subunit. Of particular interest was the prominent alpha2- and alpha3-subunit staining on the initial axon segment of pyramidal neurons. This protocol represents a major improvement for high-resolution studies of human brain tissue aimed at investigating morphological alterations underlying neurological diseases.