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Background and Aim: Differential diagnosis between Cushing's Disease (CD) and Ectopic ACTH Syndrome (EAS) may be a pitfall for endocrinologists. The increasing use in clinical practice of chromatography and mass spectrometry improves the measurement of urinary free cortisol (UFF) and cortisone (UFE). We have recently observed that cortisol to cortisone ratio (FEr) was higher in a small series of EAS; in this study we collected a larger number of ACTH-dependent Cushing's Syndrome (CS) to study the role of FEr to characterize the source of corticotropin secretion., Materials and Methods: High-pressure liquid chromatography with UV detection (HPLC-UV, n=35) or liquid chromatography-tandem mass spectrometry (LC-MS/MS, n=72) were used to measure UFF, UFE and FEr in 83 patients with CD and 24 with EAS., Results: UFF, UFE and FEr levels were higher in EAS than in CD (UFF: 6671 vs 549 nmol/24 hours; UFE: 2069 vs 464 nmol/24 hours; FEr: 4.13 vs 0.97; all P<.001). FEr >1.15 (the best ROC-based threshold) was able to distinguish CD from EAS with 75% sensitivity (SE) and 75% specificity (SP), AUC 0.811; results were similar between HPLC-UV (SE 73%, SP 79%, AUC 0.708) and LC-MS/MS (SE 77%, SP 73%, AUC 0.834; P=.727). The diagnostic accuracy of FEr was similar to that of CRH test or high-dose dexamethasone suppression test (respectively P=.171 and P=.683), also combined. Finally, FEr was able to increase the number of correct diagnosis in patients with discordant dynamic tests., Conclusions: Urinary FEr >1.15 was able to suggest EAS, with a diagnostic accuracy similar to that of other dynamic tests proposed to study ACTH-dependent CS., (© 2017 John Wiley & Sons Ltd.)

Purpose: In this systematic review, we aim to illustrate the current and safe concepts in the assessment, diagnosis and management of herniated lumbar disc (HLD) during pregnancy., Methods: A systematic review and reporting on the diagnosis, treatment and clinical results of HLD during pregnancy is performed., Results: The MRI represents the first level and safest diagnostic tool for pregnant women affected by spinal problems allowing for a noninvasive and detailed radiological examination of the spine. The initial management of pregnant women affected by HLD is conservative, and primarily aimed to pain therapy. Whenever radicular pain and progressive neurological deficits unresponsive to medical management occur, surgery should be considered. Few case reports regarding the operative management of HLD in pregnant women have been published up to date. Laminectomy and/or microdiscectomy represent the classical and most commonly used techniques that can be safely performed without affecting pregnancy, delivery, or baby's health. Endoscopic discectomy may be an alternative. The most adequate timing and surgical position are chosen based on to the fetal gestational age and site of the pathology., Conclusions: Surgical treatments during pregnancy impose multiple medical and ethical problems. Timely diagnosis by MRI, careful clinical evaluation, and surgical treatment represent safe and effective procedures. Ongoing evolution of surgical, anesthesiological and obstetrical procedures results in favorable outcomes. However, interdisciplinary management and a wide knowledge of pregnancy-related pathologies are crucial for the best outcome for both mother and child.

Background: Changes in hippocampal gray matter volumes are proposed to be involved in pathogenesis, course, and treatment response of major depressive disorder. Converging evidence suggests that reduced neurogenesis may occur in treatment-resistant depression (TRD). Vagus nerve stimulation (VNS) is a well-defined, long-term brain stimulation treatment for TRD. However, its in vivo positive effect on hippocampal modulation as mechanism of action has never been investigated before in clinical studies. In this study, we intended to explore hippocampal volumetric changes and clinical antidepressant responses in patients with TRD after 6 and 12 months of treatment with VNS., Methods: The TRD outpatients were evaluated for VNS implantation. Right and left hippocampal volumes in 6 TRD patients, who met the criteria for VNS treatment, were measured at baseline before the implantation and after 6 and 12 months. The patients were assessed using Beck Depression Inventory and Hamilton Depression Rating Scale at baseline and at follow-up visits., Results: There was a statistically significant and progressive increase in right and left hippocampal volumes during the follow up (P < 0.05). Furthermore, patients showed a significant improvement on Hamilton Depression Rating Scale and Beck Depression Inventory scores (P < 0.05)., Conclusions: Our data suggest a VNS modulatory effect on hippocampal plasticity as measured by hippocampal gray volume increase in TRD patients. These preliminary findings indicate the fundamental role of hippocampal remodeling as a marker of response to VNS in TRD.

Background: Although the diagnosis and treatment of eighth cranial nerve (VIII CN) schwannoma (acoustic neuroma) has improved over the years, no factors capable of predicting tumor growth have been identified as yet. This study is a preliminary investigation of the expression in sporadic VIII CN schwannomas of Yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), and amphiregulin (AREG), a direct target gene of YAP and TAZ. The expression of YAP, TAZ and AREG was correlated with the volumetric dimensions of tumors on contrast-enhanced magnetic resonance imaging (ceMRI)., Methods: YAP, TAZ and AREG expression was assessed immunohistochemically in surgical specimens of 36 consecutive sporadic VIII CN schwannomas. 3D reconstructions of the tumors and their corresponding volumes in cm3 were obtained from measurements on ceMRI images using the OsiriX® software., Results: We found a significant direct correlation between TAZ expression and VIII CN schwannoma volumes on latest preoperative ceMRI (p<0.0003). Mean TAZ expression was also significantly higher in VIII CN schwannomas with a volume ≥2.1 cm3 than in those with a volume <2.1 cm3(p<0.0018). No significant correlations emerged for YAP or AREG expression and VIII CN schwannoma volume., Conclusions: The immunohistochemical expression of TAZ (but not YAP or AREG) correlated significantly with schwannoma volume measured on ceMRI. Further investigations are needed to identify the biological factors influencing tumor proliferation (ideally secreted proteins like AREG) that might be detected using non-invasive approaches (i.e., blood samples).

The diverging evidence for functional localization of response inhibition within the prefrontal cortex might be justified by the still unclear involvement of other intrinsically related cognitive processes like response selection and sustained attention. In this study, the main aim was to understand whether inhibitory impairments, previously found in patients with both left and right frontal lesions, could be better accounted for by assessing these potentially related cognitive processes. We tested 37 brain tumor patients with left prefrontal, right prefrontal and non-prefrontal lesions and a healthy control group on Go/No-Go and Foreperiod tasks. In both types of tasks inhibitory impairments are likely to cause false alarms, although additionally the former task requires response selection and the latter target detection abilities. Irrespective of the task context, patients with right prefrontal damage showed frequent Go and target omissions, probably due to sustained attention lapses. Left prefrontal patients, on the other hand, showed both Go and target omissions and high false alarm rates to No-Go and warning stimuli, suggesting a decisional rather than an inhibitory impairment. An exploratory whole-brain voxel-based lesion-symptom mapping analysis confirmed the association of left ventrolateral and dorsolateral prefrontal lesions with target discrimination failure, and right ventrolateral and medial prefrontal lesions with target detection failure. Results from this study show how left and right prefrontal areas, which previous research has linked to response inhibition, underlie broader cognitive control processes, particularly involved in response selection and target detection. Based on these findings, we suggest that successful inhibitory control relies on more than one functionally distinct process which, if assessed appropriately, might help us to better understand inhibitory impairments across different pathologies., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: glioblastomas are highly vascularized tumors and various antiangiogenic drugs have been investigated in clinical trials showing unclear results. We performed a systematic review and a meta-analysis to clarify and evaluate their effectiveness in glioblastoma patients., Patients and Methods: we searched relevant published and unpublished randomized clinical trials analyzing antiangiogenic drugs versus chemotherapy in glioblastoma patients from January 2006 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases., Results: fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056). Bevacizumab did not improve overall survival. Twelve trials (4113 patients) were analyzed for progression-free survival. Among antiangiogenic drugs, only bevacizumab demonstrated an improvement of progression-free survival (HR=0.63, p<0.001), both alone (HR=0.60, p=0.003) or in combination to chemotherapy (HR=0.63; p<0.001), both as first-line treatment (HR=0.70, p<0.001) or in recurrent disease (HR=0.52, p<0.001)., Conclusions: antiangiogenic drugs did not improve overall survival in glioblastoma patients, either as first or second-line treatment, and either as single agent or in combination with chemotherapy. Among antiangiogenic drugs, only bevacizumab improved progression-free survival regardless of treatment line, both as single agent or in combination with chemotherapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Transnasal endoscopic management of anterior cerebrospinal fluid (CSF) leak: experience from a large case series., Objectives: Anterior cerebrospinal fluid (CSF) leak is a consequence described after head trauma, skull base surgery or inflammatory diseases, but may also occur spontaneously. Prompt recognition and management is crucial in order to avoid complications and to achieve successful surgical repair. The purpose of this study is to present the clinical features of a large group of patients with anterior CSF leak and the results of their surgical management., Methodology: The study approach was a retrospective review of 110 consecutive patients treated by the same surgeon for CSF leak of the anterior skull base via a transnasal endoscopic approach between 2003 and 2013. Patients with anterior skull base surgery due to cancer or pituitary adenoma were excluded from this study. The diagnostic workup included nasal endoscopy, beta2-transferrin and -trace protein assay in the rhinoliquorrhoea and radiological imaging. The intrathecal fluorescein test was performed in selected cases. The surgical techniques used to repair dural defects were primarily middle turbinate placement and fascia lata grafting., Results: Primary endoscopic repair of the CSF fistula was successful in 106/110 (96.4%) patients. Four patients (3.6%) required a revision procedure due to early failure of the repair. After a minimum follow-up of 24 months, no recurrent CSF leaks were observed in the study group. None of the patients developed meningitis as a surgical complication., Conclusions: The endoscopic transnasal approach is a reliable technique for treating CSF leaks. The intrathecal fluorescein test is safe and helpful in locating the defect. The fascia lata proved the best graft available in our experience.

Purpose of Review: The replacement of damaged cells in the central nervous system (CNS) affected by degenerative disorders represents an attractive therapeutic strategy. The advent of stem cell technology may offer the possibility of generating a large number of renewable, specifically differentiated cells to potentially cure large cohorts of patients. In this review, we discuss current knowledge and issues involved in neural cell transplantation. The most important preclinical and clinical results of cellular transplantation applied to Parkinson's, Huntington's disease and amyotrophic lateral sclerosis will be summarized., Recent Findings: Cellular transplantation is emerging as a possible therapy for a variety of incurable neurological disorders. The disorders that will primarily take advantage from neural stem cell grafting are those involving a well defined cell population in a restricted area of the CNS. Several clinical trials have been initiated to assess safety and efficacy of different stem cell-derived products, and promising results have been obtained for disorders such as Parkinson's disease. However, several scientific questions remain unanswered. Among these, the impact of the immunological interaction between host and graft in the particular environment of the CNS still requires additional investigations., Summary: Several chronic neurological disorders appear to be amenable to cell regenerative therapies. However, safety, efficacy and immunological issues will need to be carefully evaluated beforehand.

A remote cerebellar hemorrhage (RCH) is a spontaneous bleeding in the posterior fossa, which may rarely occurs as a complication of supratentorial procedures, and it shows a typical bleeding pattern defined "the zebra sign." However, its pathophysiology still remains unknown. We performed a comprehensive review collecting all cases of RCH after supratentorial craniotomies reported in literature in order to identify the most frequently associated procedures and the possible risk factors. We assessed percentages of incidence and 95 % confidence intervals of all demographic, neuroradiological, and clinical features of the patients. Univariate and multivariate analyses were used to evaluate their association with outcome. We included 49 articles reporting 209 patients with a mean age of 49.09 ± 17.07 years and a male/female ratio 130/77. A RCH was more frequently reported as a complication of supratentorial craniotomies for intracranial aneurysms, tumors debulking, and lobectomies. In the majority of cases, RCH occurrence was associated with impairment of consciousness, although some patients remained asymptomatic or showed only slight cerebellar signs. Coagulation disorders, perioperative cerebrospinal fluid drainage, hypertension, and seizures were the most frequently reported risk factors. Zebra sign was the most common bleeding pattern, being observed in about 65 % out of the cases, followed by parenchymal hematoma and mixed hemorrhage in similar percentages. A multivariate analysis showed that symptomatic onset and intake of antiplatelets/anticoagulants within a week from surgery were independent predictors of poor outcome. However, about 75 % out of patients showed a good outcome and a RCH often appeared as a benign and self-limiting condition, which usually did not require surgical treatment, but only prolonged clinical surveillance, unless in the event of the occurrence of complications.

Introduction: Multiple Myeloma (MM) typically involves the spine and causes bone pain, pathological fractures and spinal cord compression with possible consequent neurological deficits. This retrospective study reports the results of surgery on a selected population of patients who underwent surgery for symptomatic spinal myeloma., Materials and Methods: A total of 26 patients who underwent surgery for spinal myeloma with neurological involvement were studied retrospectively. Neurological evaluation was performed according to the Frankel grade. Characteristics of this population, reconstructive techniques and surgery-related complications were reviewed., Results: The tumours involved the thoracic spine in 13 patients, the lumbar spine in 10 patients, and the cervical spine in three patients. The most common approach was a posterior-only approach (70%), followed by a staged, combined approach (20%), and an anterior-only approach (10%). The mean postoperative survival time was 43 months (range: 8-60 months). A significant improvement in neurological function was observed in the study population after surgery (p=0.001). There were seven early postoperative complications, two late complications and five surgery-related complications., Discussion: Surgery in selected patients affected by spinal myeloma with neurological involvement is associated with good clinical outcomes and neurological recovery and an acceptable rate of complications. Neurological deficit and segmental instability can be treated sufficiently in most cases by the implementation of a posterior-only approach; however, the final treatment should, when possible, include adjuvant chemotherapy and radiotherapy and rigorous bracing., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: The modified Japanese orthopaedic association scale (mJOA) is considered one of the most appropriate outcome measures for the assessment of cervical spondylotic myelopathy (CSM). Moreover, mJOA has been recognised among the key predictors of surgical outcome at a global level. To apply the mJOA successfully at an international level, it should be translated and culturally adapted in the native language of the investigators using this scale. A translated version of the mJOA or any other functional scale has never been studied within an Italian population affected by CSM. The aim of this study has been to describe translation, cultural adaptation and psychometric properties of the Italian version of the mJOA (mJOA-IT)., Methods: The mJOA-IT was developed following a forward-backward translation procedure. Psychometric properties were assessed on a cohort of patients with CSM undergone anterior or posterior decompression associated with stabilisation in lordosis., Results: The mJOA-IT proved to be a reliable outcome measure for CSM (internal consistency 0.60, test-retest stability 0.910, P < 0.001, inter-observer reliability 0.80, P < 0.001). The mJOA-IT was associated with the Nurick scale (r = -0.615) while it was not associated with NDI, SF-36 and SF-36 components. The mJOA-IT was also responsive (d = 0.867)., Conclusions: The mJOA-IT proved to be a reliable and valid tool to assess patients affected by CSM. This form is recommended to be used for clinical and research purposes in Italy, to promote the global standardisation of assessment tools and to compare studies on CSM worldwide.

A remote cerebellar hemorrhage (RCH) is a spontaneous bleeding in the posterior fossa, which can be rarely observed as a complication of spine surgery. As well as for RCH reported after supratentorial procedures, it shows a characteristic bleeding pattern defined "zebra sign". Nowadays, RCH pathophysiology still remains unknown. We performed a comprehensive review, collecting all cases of RCH after spine surgery reported in literature in order to identify the procedures most frequently associated with RCH and the possible risk factors. We assessed percentages of incidence and 95 % confidence interval of all demographic, neuroradiological, and clinical features. Univariate and multivariate analyses were used to evaluate their association with outcome. We included 44 articles reporting 57 patients with mean age of 57.6 ± 13.9 years and a male/female ratio of 23/34. A RCH was more frequently reported as a complication of decompressive procedures for spinal canal stenosis, particularly when associated with instrumented fusion, followed by spinal tumor debulking and disc herniation removal. In the majority of cases, RCH occurrence was characterized by progressive impairment of consciousness, whereas some patients complained non-specific symptoms. Coagulation disorders, hypertension, and placement of postoperative subfascial drainages were the most frequently reported risk factors. The occurrence of intraoperative dural lesions was described in about 93 % of patients. Zebra sign was the most common bleeding pattern (about 43 % of cases) followed by parenchymal hematoma (37.5 %) and mixed hemorrhage (about 20 %). Impairment of consciousness at clinical onset and intake of anticoagulants/antiplatelets appeared associated with poor outcome at univariate analysis. However, more than 75 % of patients showed a good outcome and a RCH often appeared as a benign and self-limiting condition, which usually did not require surgical treatment, but only prolonged clinical surveillance, unless of the occurrence of complications.

Purpose: Surgical management of patients with multilevel CSM aims to decompress the spinal cord and restore the normal sagittal alignment. The literature lacks of high level evidences about the best surgical approach. Posterior decompression and stabilization in lordosis allows spinal cord back shift, leading to indirect decompression of the anterior spinal cord. The purpose of this study was to investigate the efficacy of posterior decompression and stabilization in lordosis for multilevel CSM., Methods: 36 out of 40 patients were clinically assessed at a mean follow-up of 5, 7 years. Outcome measures included EMS, mJOA Score, NDI and SF-12. Patients were asked whether surgery met their expectations and if they would undergo the same surgery again. Bone graft fusion, instrumental failure and cervical curvature were evaluated. Spinal cord back shift was measured and correlation with EMS and mJOA score recovery rate was analyzed., Results: All scores showed a significative improvement (p < 0.001), except the SF12-MCS (p > 0.05). Ninety percent of patients would undergo the same surgery again. There was no deterioration of the cervical alignment, posterior grafted bones had completely fused and there were no instrument failures. The mean spinal cord back shift was 3.9 mm (range 2.5-4.5 mm). EMS and mJOA recovery rates were significantly correlated with the postoperative posterior cord migration (P < 0.05)., Conclusions: Posterior decompression and stabilization in lordosis is a valuable procedure for patients affected by multilevel CSM, leading to significant clinical improvement thanks to the spinal cord back shift. Postoperative lordotic alignment of the cervical spine is a key factor for successful treatment.

Purpose: Spinal cord back shift has been considered the desired end point of posterior decompression procedures for cervical spondylotic myelopathy (CSM). However, the association with postoperative outcomes has not been definitively demonstrated. The aim of this review is to obtain an overview of the current knowledge on the spinal back shift after posterior decompression to clarify the main controversial aspects and provide recommendations for further studies on the subject., Methods: A comprehensive quantitative review of the literature was performed. Bibliographic databases were searched using the following keywords: spinal cord drift, spinal cord shift, CSM, ossification of posterior longitudinal ligament, posterior decompression, laminoplasty, laminectomy and fusion., Results: Twelve eligible studies were included. The authors measured the spinal cord back shift in different ways, using the posterior edge, the center or the anterior margin of the spinal cord as reference points. Six studies analyzed the correlation between the spinal cord back shift and the recovery rate, but their results were discordant. The correlation between the posterior cord migration and cervical alignment was not confirmed in all studies., Conclusions: There is a need for a consensus on the best way to measure the spinal cord back shift. The action of multiple factors on spinal cord back shift can explain the difference in the results collected from the studies. We recommend further studies to clarify the behavior of the spinal cord after posterior decompression and its clinical meaning.

Purpose: The alignment at the cervical spine has been considered a determinant of degeneration at the adjacent disc, but this issue in cervical disc replacement surgery is poorly explored and discussed in this patient population. The aim of this systematic review is to compare anterior cervical fusion and total disc replacement (TDR) in terms of preservation of the overall cervical alignment and complications., Methods: A systematic review of the current literature was performed, together with the evaluation of the methodological quality of all the retrieved studies., Results: In most of the retrieved studies, a tendency towards a more postoperative kyphotic alignment in TDR was reported. The reported mean complication rate was of 12.5 % (0-66.2 %). Complications associated with cervical prosthesis included heterotopic ossification, device migration, mechanical instability, failure, implant removal, reoperations and revision., Conclusions: Even though cervical disc arthroplasty leads to similar outcomes compared to arthrodesis in the middle term follow-up, no evidence of superiority of cervical TDR is available up to date. We understand that the overall cervical alignment after TDR tends towards the loss of lordosis, but only longer follow-up can determine its influence on the clinical results.

Purpose: Cushing's disease (CD) is associated with an increased risk of thrombotic events, particularly after surgery. No guidelines are available on the management of patients with CD undergoing pituitary transsphenoidal surgery (TSS). We aimed to compare the effectiveness of different prophylactic procedures on the prevention of thrombotic events after surgery in CD., Methods: We retrospectively collected data on 78 consecutive patients who underwent TSS for CD between 2001 and 2012 at Padova's Neurosurgical Unit, recording their hemostatic, hormonal and anthropometric parameters. Patients were divided into two groups according to their perioperative management. Group A (34 patients) received fractionated heparin for a maximum of 14 days after surgery. Patients in group B (44 patients) were given no early glucocorticoid replacement therapy, and treated with subcutaneous enoxaparin 4,000-8,000 U/daily (depending on their weight) for 30 days plus graduated elastic stockings until mobilization, and early ambulation., Results: The whole cohort of patients had clotting and anticoagulant factors significantly higher than the normal range. The two groups were comparable for age, BMI, ACTH, urinary free cortisol levels, outcome of surgery, and main clotting parameters. The surgical procedure did not change during the study period. Three venous thrombotic events [venous thromboembolic events (VTE), 2 associated with pulmonary embolism] were recorded in group A, none in group B (p = 0.079). No hemorrhagic events were reported., Conclusions: Provoked thrombotic events pose a major problem in the management of CD patients after surgery, regardless of the procedure's outcome. The prophylactic regimen proposed in this paper afforded an efficacy prophylaxis against postoperative VTE in patients with CD. Due to the rarity of CD, a multicenter study on a larger sample of cases would be warranted in order to collect more thrombotic events.

Introduction: Cerebrospinal fluid (CSF) rhinorrhea can lead to CNS infections, carrying significant morbidity and mortality, especially in the elderly. Endoscopic endonasal surgery is a validated technique in the repair of anterior skull base CSF leaks. The aim of this study is to assess diagnostic management, surgical technique and clinical outcome in a consecutive series of elderly patients., Methods: Patients older than 65 years treated for anterior skull base CSF leaks through endoscopic endonasal surgery between 2003 and 2014 were retrospectively reviewed. All patients underwent preoperative nasal endoscopy, laboratory and radiological assessment. In doubtful cases endoscopic exploration was performed after intrathecal fluorescein (IF) injection. Patients were discharged between 3 and 4 days after surgery, and the endoscopic follow-up ranged from 3 to 24 months., Results: 20 patients (age range 65-92) presented with 10 spontaneous and 10 traumatic/iatrogenic CSF leaks. In 40% of patients formal rhinoscopy and radiological assessment did not localize the CSF leak and IF injection was performed. IF enabled the identification of the skull base defect in all cases, with no adverse effects. In 11 cases the dura was repaired with fascia lata graft. All patients had successful endoscopic repair of the CSF fistula with no complications nor recurrences during follow-up., Conclusion: Endoscopic endonasal surgery is a minimally invasive procedure for CSF leak treatment. In our experience, IF injection proved safe and efficient in detecting skull base defects not identified by preoperative imaging. Endoscopic endonasal surgery proved effective and reliable also in elderly patients, with short hospitalization times and no morbidity., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Aggressive pituitary adenomas (PAs) are clinically challenging for endocrinologists and neurosurgeons due to their locally invasive nature and resistance to standard treatment (surgery, medical or radiotherapy). Two pituitary-directed drugs have recently been proposed: temozolomide (TMZ) for aggressive PA, and pasireotide for ACTH-secreting PA. We describe the experience of our multidisciplinary team of endocrinologists, neurosurgeons, neuroradiologists, oncologists, otolaryngologists and pathologists with TMZ and pasireotide treatment for aggressive PAs in terms of their radiological shrinkage and genetic features. We considered five patients with aggressive PA, three of them non-secreting (two ACTH-silent and one becoming ACTH secreting), and two secreting (one GH and one ACTH). TMZ was administrated orally at 150-200 mg/m(2) daily for 5 days every 28 days to all 5 patients, and 2 of them also received pasireotide 600-900 µg bid sc. We assessed the MRI at the baseline and during TMZ or pasireotide treatment. We also checked for MGMT promoter methylation and IDH, BRAF and kRAS mutations. Considering TMZ, two patients showed PA progression, one stable disease and two achieved radiological and clinical response. Pasireotide was effective in reducing hypercortisolism and mass volume, combined with TMZ in one case. Both treatments were generally well tolerated; one patient developed a grade 2 TMZ-induced thrombocytopenia. None of patients developed hypopituitarism while taking TMZ or pasireotide treatment. No genetic anomalies were identified in the adenoma tissue. TMZ and pasireotide may be important therapies for aggressive PA, alone or in combination.

Cushing's disease (CD) is a rare condition in which hypercortisolemia is secondary to excessive ACTH release from a pituitary corticotroph adenoma. CD is associated with significant morbidity and mortality, and a safe therapy that effectively targets the pituitary tumor is still lacking. Retinoic acid (RA) and dopamine agonists (DAs) have recently been considered as monotherapy in CD patients, and satisfactory results have been reported, albeit in a limited number of patients. Given the permissive role of RA on the dopamine receptor type-2 (DRD2), the aim of the present study was to see whether a combination of 9-cis RA and the DA bromocriptine (Br) might represent a possible treatment for CD. Here we show that 9-cis RA induces a functional DRD2 in the pituitary corticotroph cell line AtT20, and increases cell sensitivity to Br via a mechanism only partially related to corticotroph-to-melanotroph transdifferentiation. In addition, 9-cis RA and Br act synergistically to modulate cell viability, with favorable implications for clinical use. In nearly 45% of corticotropinoma-derived primary cultures, the combined administration of 9-cis RA and Br lowered the steady-state level of the ACTH precursor proopiomelanocortin (POMC) more efficiently than either of the drugs alone. In conclusion, the effects of a combination of 9-cis RA and Br on ACTH synthesis/secretion and cell viability in AtT20, and on POMC transcriptional activity in human corticotropinomas might represent a suitable starting point for assessing the potential of this treatment regimen for ACTH-secreting pituitary adenomas. This study thus has potentially important implications for novel therapeutic approaches to CD.

Background: By implanting electrodes inside peripheral nerves, amputee's intentions are picked up and exploited to control novel dexterous sensorized hand prostheses. Under the pretext of presenting surgical technique and clinical outcomes of the implant of invasive peripheral neural interfaces in a human amputee, this article critically comments, from the point of view of the surgeon, strengths and weaknesses of the procedure., Materials and Methods: Four multielectrodes were implanted in the medial and ulnar nerves of a young volunteer, which, following a car-crash, had a left transradial amputation. Both nerves were approached with a single incision in the medial aspect of the upper arm. Four weeks later, the electrodes were removed., Results: Even if the trauma and the postamputation plastic processes altered the anatomy, electrodes were proficiently implanted with an overall success of 66%. Looking at the procedure from the surgeon's viewpoint unveils few still open issues. Electrodes weaknesses were related to the absence of stabilizing structures, the cable transit through the skin, the implant angle, and the unproven magnetic resonance imaging compatibility. Future investigations are needed to definitely address the better anesthesia, number and sites of incisions, the nerves to implant, and the convenience of performing epineural microdissection., Conclusions: Invasive neural interfaces developmental process almost completely relies on the efforts of bioengineers and neurophysiologists; however, the surgeon is responsible for intra and perioperative factors. Therefore, he deserves to play a major role also at the stage of specifying the requirements, to satisfy the requisites of a safe, stable, and long-lasting implant., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Most pituitary adenomas with FSH- or LH-positive immunohistochemistry are endocrinologically silent, and neurological symptoms due to their large volume are the first clinical signs; they are rarely reported to be secreting gonadotropins, this usually occurring in cases with clinical endocrine findings. Gonadotropinomas are often treated surgically because they are unresponsive to conventional medical therapies. Temozolomide was recently recommended for non-responder aggressive pituitary adenoma management., Case Report: A 43-year-old male with a history of 5 years of erythrocytosis presented with severe headache, orthostatic dizziness, and difficulty walking. MRI documented a giant pituitary adenoma and high uptake of 111In-pentetreotide indicated somatostatin receptor (SSR) expression. Biochemical tests revealed a secreting gonadotropinoma. Therapy with somatostatin analogs and dopamine agonists improved the patient's headache, achieved partial hormone control, slightly reduced the size of the adenoma, and controlled erythrocytosis. Six months after the diagnosis, hormone escape occurred despite therapy, thus neurosurgery was performed. After the procedure the patient died of untreatable intracranial hypertension. The surgical specimen revealed SSR 2 and 3 expression, and temozolomide did not induce apoptosis in primary cell culture., Review of Literature: Among gonadotropinomas, female gender (77%), macroadenoma (84%), young age at diagnosis (28 ± 12 years), delay from first symptoms to diagnosis (up to 15 years), and ovarian cysts/menstrual disorders in females or macro-orchidism in males were the foremost clinical and neuroimaging features., Conclusions: Male gonadotropin-secreting pituitary adenomas may have a variable clinical expression secondary to testosterone excess. Somatostatin analogs, dopamine agonists or temozolomide may have a role that needs to be assessed case by case.

Background: Choroid plexus tumors (CPTs) are intraventricular lesions originating from ventricular neuroepithelium and represent up to 4% of brain neoplasms affecting pediatric population. They are more frequently benign papillomas, but malignant carcinomas can sometimes occur., Method: The authors present a description of surgical approach for CPTs, particularly focusing on the complications related to the cerebrospinal fluid (CSF) circulation, which may affect outcome., Conclusion: Microsurgical resection represents the first line treatment for CPTs. The goal is the complete removal of the tumor and the restoration of a physiological CSF circulation.

Purpose: To characterize in vivo the transpedicular approach (TA) as an alternative route to study intervertebral disc (IVD) regeneration strategies in a sheep model., Methods: 48 IVD of 12 sheep were used. TA was performed under fluoroscopy, followed by nucleotomy (2-mm shaver resector). A polyurethane scaffold was used to repair the end-plate. X-ray and MRI images were acquired pre-, intra- and post-operatively (1, 3, 6 months). Complications were recorded., Results: TA was feasible in all animals; nucleus pulposus (NP) from L1 to L5 was accessible. Nucleotomy followed by end-plate repair was achieved. Loss of NP signal intensity was shown in MRI images of the nucleotomy group., Conclusions: TA is feasible in vivo, repeatable after only a short learning period and safely performed without significant morbidity. This animal model allows the study of IVD degeneration physiopathology and investigation of IVD regeneration techniques in vivo.

Treatment with angiogenesis inhibitors is becoming a cornerstone of modern anticancer therapy. Hypertension (HTN) is a common adverse event during antiangiogenic treatment and might represent a cancer biomarker in patients with recurrent glioblastoma treated with angiogenesis inhibitors. In a retrospective study, we analyzed 53 patients with recurrent glioblastoma treated with antiangiogenic drugs. Thirty patients were treated with sorafenib and 23 patients were treated with bevacizumab. All patients underwent brain gadolinium-enhanced MRI assessments according to the Radiologic Assessment in Neuro-Oncology criteria every 2 months or when clinically indicated. Blood pressure was measured before and during the treatment. We investigated whether treatment-related HTN may be associated with outcome in patients treated with antiangiogenic drugs. After 2 months of treatment, 24 patients (45%) achieved disease control: stable disease (17 patients) or a partial response (seven patients). The median overall survival from the start of antiangiogenic treatment was 7.3 months [95% confidence interval (CI) 6.02-8.5]; the median progression-free survival (PFS) was 2.7 months (95% CI 1.5-3.5); and the 6-month PFS was 32%. Twenty patients (38%) developed grades 2-3 HTN within 2 months of treatment. A significant association was found between HTN and disease control rate, and HTN and 6-month PFS; no significant association was found between HTN and the median PFS. According to univariate and multivariate analyses, HTN was related to a longer survival from antiangiogenic drug administration: 9.8 versus 4.8 months (P=0.001; hazard ratio=3.5, 95% CI 1.6-7.6). Our data indicate that HTN may be an effective biomarker in patients with recurrent glioblastoma treated with antiangiogenic drugs; in particular, it may be associated with a favorable effect on disease control, 6-month PFS, and the median overall survival.

Introduction: Osteoporotic vertebral compression fractures (VCFs) are a growing public health problem with important socio-economic effects in western countries. In the USA, 10 million people over 50 suffer from osteoporosis. In these patients, 1.5 million annual fractures have been registered, and 50% of these are vertebral compression., Sources of Data: We performed a comprehensive search of PubMed, Medline, Cochrane, CINAHL and Embase databases using various combinations of the keywords 'osteoporosis', 'vertebral compression fractures', 'brace', 'bracing', 'orthosis', 'conservative management' and 'rehabilitation' over the years 1966-2011. All articles relevant to the subject were retrieved, and their bibliographies were hand searched for further references in the context of conservative management of osteoporotic vertebral fractures., Areas of Agreement: Conservative management for patients with osteoporotic vertebral fractures includes bed rest, pain medication, physiotherapy and bracing., Areas of Controversy: A conservative management for patients with osteoporotic VCFs s has not been standardized. The utility of vertebral augmentation techniques has been questioned by recent randomized controlled trials., Growing Points: Randomized controlled trials are being performed worldwide on vertebral augmentation techniques., Areas Timely for Developing Research: Although spinal orthoses are commonly used for the management of patients with osteoporotic vertebral fractures, in the literature there is only one randomized controlled trial on bracing for this condition. While the best conservative management for subjects with osteoporotic VCFs s is not defined and standardized, no conclusions on the superiority of vertebral augmentation techniques over conservative management can be drawn.

Gliomas are devastating tumors of the brain resistant to therapies. Although some therapies can prolong the survival time among the affected persons, gliomas are not curable and new therapeutic approaches need to be investigated. Oncolytic viruses seem to represent an interesting alternative, because anticancer agents and new viral agents have to be explored to identify the one with the best characteristics. Bovine herpesvirus type 4 (BoHV-4) is a gammaherpesvirus with a striking tropism and permissive replication toward cancer cells and rat, mouse, and human glioma cells. However, BoHV-4 does not replicate into the normal brain parenchyma. The BoHV-4 genome was cloned as a bacterial artificial chromosome to easily manipulate this large genome and be used as a viral vector platform. In the present study, a herpes simplex virus type 1 thymidine kinase suicide gene-armed BoHV-4 was constructed, characterized, and proven to be highly efficient in killing by apoptosis glioma cells in vitro when co-administered with the pro-drug ganciclovir (GCV). When the armed BoHV-4/GCV therapeutic approach was tested in immunocompetent orthotopic syngenic mouse and rat glioma models in vivo, a significant increase in survival among the treated animals was achieved, and some animals were completely cured. The BoHV-4-based vector represents a promising alternative oncolytic virus for glioma and, perhaps, other types of cancer treatment that merit further investigation. This article represents the result of a mutual interaction between human medical science and veterinary science, a combination of scientific knowledge often neglected.

We recently described a three-layer concentric model of a glioblastoma (GBM) related to a specific distribution of molecular and phenotypic characteristics driven by the intratumoral hypoxic gradient in which the cancer stem cells niche is located in the hypoxic necrotic core of the tumour. The purpose of this study was to investigate the relationship between O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and MGMT expression in GBM samples collected according to the three-layer concentric model. Multiple tissue samples were obtained, by means of image-guided surgery, from the three concentric layers of newly diagnosed GBM. Two samples from each layer were collected from 12 patients (total 72 samples). Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded tissue samples. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. In all tumours, MGMT protein expression decreased progressively from the inner to the outer layer, and methylation of the MGMT promoter was unrelated to tumour layer. In particular, the MGMT promoter was unmethylated in all layers in 41.7% of tumours, methylated in all layers in 25%, and variably methylated in the three layers in 33.3%. We recorded concordance between MGMT expression and MGMT promoter methylation status within the GBM in only 58.8% of the samples collected. Our data suggest that both MGMT expression and promoter methylation data may be variable throughout GBM and that they may, consequently, depend on the site of surgical sample collection, even in the same patient. However, whereas MGMT expression is pre-operatively predictable when sampling is performed according to the three-layer concentric model, MGMT promoter methylation is not. These results must be considered when sample collection is performed for assessment of MGMT data.

Anticonvulsant therapy is usually recommended before surgery in all patients affected by high grade glioma who are planned to be treated with Carmustine 1,3-bis [2 chloroetyl]-1-nitrosurea, or BCNU) wafers. In fact, phase III studies have reported a risk of seizures higher than 30% in this group of patients. The aim of the study was the evaluation of rate type time of occurrence of seizures in BCNU-treated patients in the postoperative period as well as the investigation into possible risk factors for seizure occurrence in this population. From April 2007 to September 2010, 55 patients underwent surgical removal of malignant glioma and BCNU wafers implantation at the Department of Neurosurgery of Padova. All patients were given antiepileptic prophylaxis for 3 months after surgery. Clinical data (including preoperative seizure history), radiological data, surgical treatment, antiepileptic treatment were retrospectively reviewed. Nine percent of the patients treated with BCNU wafers presented seizures in the postoperative course. Seizures were partial in 80% of cases; they occurred within 30 days after surgery and in 80% of cases within the first 7 days. Patients with preoperative seizures presented more frequently postoperative epilepsy than patients who were preoperatively seizure-free [P = 0.0006; OR = 48 (2,4;945)]. Postoperative seizures were more common among patients affected by one or more wafers related adverse event than among patients without adverse events [P = 0.006; OR = 21 (2,06;213)]; however, they did not appear associated to the number of implanted wafers. Patients with a sub-therapeutic level of AED at the seventh day after surgery presented a higher seizure occurrence [P = 0.02; OR = 11 (1,5;79,8)]. In our experience, postoperative seizures in BCNU-treated patients were less frequent than expected. Careful patient selection and postoperative monitoring could probably play a role in order to decrease seizure occurrence.

Insufficient blood supply to the intervertebral disc (IVD) has been proposed to play a role as causative factor in IVD degeneration. There is an association between IVD diseases and increased risk of dying of ischaemic heart disease. Obesity and tobacco are potential risk factors for degenerative IVD disease. High blood cholesterol and triglycerides serum levels are risk factors for atherosclerosis, and could be responsible for a decreased in the blood supply to the already poor vascularized IVD. We performed a frequency-matched case-control study to determine the serum levels of patients with symptomatic herniated lumbar disc. We examined the fasting serum lipid levels in 384 subjects who were operated at our institution. Group 1 included 169 consecutive patients (115 men and 54 women; mean age: 59.1 years, range 29-85) who underwent surgery for symptomatic disc herniation. Group 2 (control group) included 169 patients (115 men and 54 women; mean age: 61 years, range 26-86) who underwent arthroscopic meniscectomy for a meniscal tear in the same period. These patients were frequency-matched by age (within 3 years) and gender with patients of Group 1. Sera were extracted from blood samples and the concentrations of total cholesterol (TC) and triglycerides (TG) were determined. When comparing the two groups, patients with symptomatic herniated lumbar disc showed statistically significant higher triglyceride concentration (P = 0.02) and total cholesterol concentration (P = 0.01). Serum lipid levels may be a risk factor for IVD pathology. An enhanced understanding of these factors holds the promise of new approaches to the prevention and management of IVD pathology.

Background: Implantation of carmustine (1,3-bis (2 chloroetyl)-1-nitrosurea [BCNU]) wafers is an approved local treatment after surgical removal of high-grade gliomas. Safety data have been largely reported by phase III studies. The communication between the final surgical cavity and the ventricular cavities is supposed to be a relative contraindication for positioning of the wafers because of the possible development of hydrocephalus. However, at present there are neither data about this topic published with the exception of a few case reports, nor any proposals for selection criteria for wafer implantation in such circumstances. Furthermore, there are no technical suggestions in literature put forward for the surgical repairing of ventricular defects. Our study was particularly focused on addressing these 3 issues., Methods: Forty-three patients affected by a high-grade glioma underwent surgical removal and BCNU wafer implantation between March 2007 and September 2009 at the Department of Neurosurgery of Padua. Among them, we retrospectively reviewed clinical, surgical, and radiological data of 9 patients who had been treated with carmustine wafers after surgical repair of communication between the surgical cavity and the ventricular cavities. We also focused on the technical details concerning wafers positioning in this particular situation., Results: Ventricular defects were present in the atrium in 4, frontal horn in 3, and temporal horn in 2 cases. The maximum diameter of the defect was between 6 and 10 mm. In all cases, the defect was intraoperatively repaired in the same way, and up to 8 wafers were implanted in the surgical cavity. In the series reported, no cases of hydrocephalus were detected., Conclusions: In our experience, integrity of wafers, size of ventricular wall defect, and accuracy in repairing the defect were crucial issues. Nevertheless, more experience and prospective studies would be helpful to clarify both in what measure ventricular opening affects safety data and the best reliable way of repairing ventricular defects when BCNU wafers are implanted., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Object: Although a rarely reported occurrence, late failure of endoscopic third ventriculostomy (ETV) may occur in children as a result of a variety of factors. Delay in recognition of symptoms can lead to harmful deterioration in the patient's condition. The authors undertook this study to assess the capacity of cine phase-contrast MR imaging to identify late failure in asymptomatic pediatric patients treated with ETV for hydrocephalus., Methods: This study was a retrospective evaluation of cases involving patients who underwent ETV between January 1, 1999, and December 31, 2008, at the pediatric neurological surgery service of the University of Padua. Before 2004, patients were routinely followed up with cine MR imaging at 3, 6, and 12 months after ETV. In 2004, a protocol of annual cine MR follow-up was instituted as a result of a case of fatal late failure. The authors evaluated all cases of late failure identified through cine MR imaging and performed a statistical analysis to investigate the relationship between ETV failure and several variables, including the cause of hydrocephalus for which ETV was originally indicated., Results: In a series of 84 patients (age range 6 days-16 years), 17 patients had early ETV failure. Of the remaining 67 patients, 5 (7%) were found to have no CSF flow through the fenestration and recurrent ventriculomegaly when assessed with cine MR imaging at 1, 2, 3, 4, and 7 years after ETV. The patient in whom ETV failure was identified 1 year postoperatively had Dandy-Walker malformation. The patients in whom ETV failure was identified 2, 3, and 4 years postoperatively all had undergone ETV for treatment of postinfective hydrocephalus. The patient in whom ETV failure was identified 7 years postoperatively had a cystic arachnopathy in the fourth ventricle after cerebellar astrocytoma removal., Conclusions: Patients who undergo ETV for infective hydrocephalus and Dandy-Walker malformation should receive long-term follow-up, because late closure of the stoma may occur progressively and slowly. Intraoperative observation of thickened arachnoid membranes at the level of the interpeduncular cisterns at the first ETV and a progressive decreasing of CSF flow through the stoma on routine cine MR imaging should be considered unfavorable elements entailing a significant risk of deterioration.

Malignant gliomas continue to demand the search for improved chemotherapeutic solutions. In this work the results of a preliminary in vitro screening performed on a small library of compounds are disclosed. As a result 2-(2,4-dihydroxyphenyl)-8-hydroxy-1,4-naphthoquinone emerged as a promising therapeutic lead., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Although many patients with cervical spine metastases are treated surgically, it is unknown whether certain subsets achieve better pain relief and improvement of neurologic function., Questions/purposes: (1) Does tumor removal with reconstruction improve the neurologic status? (2) Is any subset of patients more likely to have neurological recovery from palliative surgery? (3) What is the rate of surgery-related complications?, Patients and Methods: We retrospectively reviewed 46 patients who had palliative surgery for metastatic solid tumor metastases of the subaxial cervical spine. Indications were neurologic deficits, life expectancy longer than 6 months, and a Karnofsky Performance Score of 50 to 70. Surgery consisted of anterior tumor removal and reconstruction with titanium mesh cages and/or tricortical iliac crest allograft plus plate fixation or of a combined procedure with adjunctive posterior decompression and stabilization with lateral mass screw fixation. Postoperatively, neurologic Frankel score grade, Karnofsky Performance Score, and complications were recorded., Results: Five of 18 nonambulatory patients (Frankel B/C) became ambulatory again (Frankel D). No patients were Frankel Grade E preoperatively, whereas 19 of 46 gained Frankel Grade E after surgery. One patient worsened neurologically and died 4 months after surgery. Patients with neoplastic pachymeningitis had less neurologic recovery than those without. Complications included dural tears (three), wound infection (three), and tumor relapse at the same or an adjacent level (four). Two of these four patients had instrumentation-related complications., Conclusions: Surgery improved clinical and neurologic status according to Frankel score; patients with neoplastic pachymeningitis are likely to experience less neurologic recovery., Level of Evidence: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

The application of gene therapy for malignant gliomas is still under study and the use of specific vectors represents an important contribution. Here, we investigated bovine herpesvirus 4 (BoHV-4), which is non-pathogenic if injected into the rodent brain. We show that the vector can infect mouse, rat and human glioma cell lines and primary cultures obtained from human glioblastoma in vitro. BoHV-4 was injected into a tumour grown in rat brain. Although virus expression was scattered across the tumour mass, it was mainly located in the peripheral area of larger gliomas. These data support BoHV-4 as a candidate vector for glioma treatment.

Purpose: Carmustine (1,3-bis[2-chloroetyl]-1-nitrosurea (BCNU)) wafers are approved for the local treatment of newly diagnosed and recurrent malignant glioma. Reassuring data on both safety and efficacy of treatment have been previously reported by phase III studies. Although most of related adverse events are reported in the first few months after surgery, there is a lack in the literature of radiological data regarding this period. Few anecdotal experiences have been reported about surgical bed cyst occurrence. The aim of our study is to analyse the radiological course of patients treated with wafers implantation focusing on the relationship between radiological data, and in particular bed cyst occurrence, and safety data., Methods: Forty-three patients affected by malignant glioma underwent surgical removal and BCNU wafers implantation at the Department of Neurosurgery of Padova from April 2007 to October 2009. Safety data were collected according to previously reported phase III studies. Patients underwent clinical and radiological evaluation (MRI) postoperatively, then before discharge, at 1 month, then every 2 months. In the study were included only patients whose both 1- and 3-month MRIs were available. Finally, 36 out of 43 patients were available for the revision., Findings: Fifty-eight percent of patients treated with BCNU wafers presented a bed cyst of the surgical cave at the 1-month MRI. Forty-eight percent of them were symptomatic. Conversely, among patients who presented one or more adverse event (27%), bed cyst was detected in up to 90% of cases (OR 7.35), being intracranial hypertension more frequently associated (OR 7.35; p value <0.05). In general, cysts presented a benign behaviour in the sense that patients promptly improved with corticosteroid treatment, never required surgery, never reported permanent neurological deficits., Conclusions: Surgical bed cyst occurrence in BCNU wafer-treated patients resulted more frequent than expected. Familiarity with the event is important to correctly handle a possible evolving phenomenon. However, only further larger experiences and prospective studies could reveal how the understanding of such event might be helpful to improve safety data.

Background: The growing teratoma syndrome (GTS) consists of a mature teratoma paradoxically enlarging during or after chemotherapy for malignant nongerminomatous germ cell tumors., Methods and Results: We report two cases of GTS occurring in association with NSGCT of the pineal gland. Although an unusual event, clinicians and radiologists should be aware of its natural history., Conclusions: When normalized tumor markers after chemotherapy are associated with imaging features of a growing mass, the hypothesis of GTS must be taken in consideration. When early diagnosed, GTS can be managed surgically with good results.

Introduction: The integrity of the upper cervical spine is essential for survival and function, because of the neurovascular structures contained within its bony elements. Fractures of the upper cervical spine (C1-C2) are frequent. This systematic review assesses the efficacy and safety of the conservative management in Halo vest for patients with upper cervical spine fractures., Materials and Methods: Two reviewers independently identified studies in English, by a systematic search of CINAHL, Embase, Medline, HealthSTAR, and the Cochrane Central Registry of Controlled Trials, from inception of each database to 28 January 2010, using various combinations of the keywords terms "odontoid fractures", hangman's fractures", "axis fractures", "axis", "atlas", "Jefferson fractures", "C1 arch fractures", "C1 fractures", "C2 fractures", "cervical spine", "injuries", "fracture", "trauma", "neck injury", "surgery"., Results: A total of 43 citations were obtained. An additional 4 papers were obtained from the reference list of the studies included. The 47 studies that were included described a total of 1078 patients with C1-C2 fractures managed by halo fixator., Conclusions: The halo fixator has a well defined place in the management of fractures of the cervical spine. Clearly, studies of higher level of evidence, for instance large randomised trials, should be conducted, even though the available evidences suggest that management of upper cervical spine fracture with halo fixator is safe and effective., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Medulloblastoma (MDB) is the most common brain malignancy of childhood. It is currently thought that MDB arises from aberrantly functioning stem cells in the cerebellum that fail to maintain proper control of self-renewal. Additionally, it has been reported that MDB cells display higher endogenous Notch signaling activation, known to promote the survival and proliferation of neoplastic neural stem cells and to inhibit their differentiation. Although interaction between hypoxia-inducible factor-1α (HIF-1α) and Notch signaling is required to maintain normal neural precursors in an undifferentiated state, an interaction has not been identified in MDB. Here, we investigate whether hypoxia, through HIF-1α stabilization, modulates Notch1 signaling in primary MDB-derived cells. Our results indicate that MDB-derived precursor cells require hypoxic conditions for in vitro expansion, whereas acute exposure to 20% oxygen induces tumor cell differentiation and death through inhibition of Notch signaling. Importantly, stimulating Notch1 activation with its ligand Dll4 under hypoxic conditions leads to expansion of MDB-derived CD133(+) and nestin(+) precursors, suggesting a regulatory effect on stem cells. In contrast, MDB cells undergo neuronal differentiation when treated with γ-secretase inhibitor, which prevents Notch activation. These results suggest that hypoxia, by maintaining Notch1 in its active form, preserves MDB stem cell viability and expansion., (Copyright © 2010 AlphaMed Press.)

We evaluated the morphological features of the newly formed tissue in an experimental model of tibial callotasis lengthening on 24 lambs, aged from 2 to 3 months at the time of operation. A unilateral external fixator prototype Monotube Triax(®) (Stryker Howmedica Osteonics, New Jersey) was applied to the left tibia. A percutaneous osteotomy was performed in a minimally traumatic manner using a chisel. Lengthening was started 7 days after surgery and was continued to 30 mm. The 24 animals were randomly divided into three groups of 8 animals each: in Group 1, lengthening took place at a rate of 1 mm/day for 30 days; in Group 2, at a rate of 2 mm/day for 15 days; in Group 3, at a rate of 3 mm/day for 10 days. In each group, 4 animals were killed 2 weeks after end of lengthening, and the other 4 animals at 4 weeks after end of lengthening. To assess bony formation in the distraction area, radiographs were taken every 2 weeks from the day of surgery. To study the process of vascularization, we used Spalteholz's technique. After killing, the tibia of each animal was harvested, and sections were stained with hematoxylin and eosin, Masson's trichrome, and Safranin-O. Immunohistochemistry was performed, using specific antibodies to detect collagens I and II, S100 protein, and fibronectin. A combination of intramembranous and endochondral ossification occurred together at the site of distraction. Our study provides a detailed structural characterization of the newly formed tissue in an experimental model of tibial lengthening in sheep and may be useful for further investigations on callotasis.

Background: Cervical degenerative pathology produces pain and disability, and if conservative treatment fails, surgery is indicated. The aim of this study was to determined whether anterior decompression and interbody fusion according to Cloward is effective for treating segmental cervical degenerative pathology and whether the results are durable after a 10-year-minimum follow-up., Materials and Methods: Fifty-one patients affected by single-level cervical degenerative pathology between C4 and C7 were surgically treated by the Cloward procedure. Clinical evaluation was rated using the Neck Disability Index (NDI) and the visual analog scale (VAS). At last follow-up, the outcomes were rated according to Odom's criteria. On radiographs, the sagittal segmental alignment (SSA) of the affected level and the sagittal alignment of the cervical spine (SACS) were measured., Results: Average NDI was 34 preoperatively and 11 at last follow-up. Average VAS was 7 preoperatively and 1 at last follow-up. According to Odom's criteria, the outcome was considered excellent in 18 cases, good in 22, and fair in 11. Average SSA was 0.5 +/- 2.1 preoperatively, 1.8 +/- 3.8 at 6 months, and 1.8 +/- 5.7 at last follow-up. Average SACS was 16.5 +/- 4.0 preoperatively, 20.9 +/- 5.8 at 6 months, and 19.9 +/- 6.4 at last follow-up. Degenerative changes at the adjacent levels were observed in 18 patients (35.3%)., Conclusions: The Cloward procedure proved to be a suitable and effective technique for treating segmental cervical degenerative pathology, allowing good clinical and radiographic outcomes even at a long-term follow-up.

Objectives: The principle underlying this project is that, despite nervous reorganization following upper limb amputation, original pathways and CNS relays partially maintain their function and can be exploited for interfacing prostheses. Aim of this study is to evaluate a novel peripheral intraneural multielectrode for multi-movement prosthesis control and for sensory feed-back, while assessing cortical reorganization following the re-acquired stream of data., Methods: Four intrafascicular longitudinal flexible multielectrodes (tf-LIFE4) were implanted in the median and ulnar nerves of an amputee; they reliably recorded output signals for 4 weeks. Artificial intelligence classifiers were used off-line to analyse LIFE signals recorded during three distinct hand movements under voluntary order., Results: Real-time control of motor output was achieved for the three actions. When applied off-line artificial intelligence reached >85% real-time correct classification of trials. Moreover, different types of current stimulation were determined to allow reproducible and localized hand/fingers sensations. Cortical organization was observed via TMS in parallel with partial resolution of symptoms due to the phantom-limb syndrome (PLS)., Conclusions: tf-LIFE4s recorded output signals in human nerves for 4 weeks, though the efficacy of sensory stimulation decayed after 10 days. Recording from a number of fibres permitted a high percentage of distinct actions to be classified correctly. Reversal of plastic changes and alleviation of PLS represent corollary findings of potential therapeutic benefit., Significance: This study represents a breakthrough in robotic hand use in amputees., (Copyright 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Vertebral compression fractures (VCFs) constitute a major health care problem in western countries. Several treatments modalities are available to relieve pain and allow increased activities. Percutaneous vertebroplasty (the injection of bone cement into the fractured vertebral body) is a relatively new procedure to manage patients with these fractures. The aim of this study is to evaluate the efficacy and safety of percutaneous vertebroplasty compared with standard conservative care., Methods/designs: In this double blind, prospective, randomized, controlled study the short- (3 months), medium- (6 months) and long-term (24 months) efficacy and safety of vertebroplasty to alleviate pain and improve function for painful osteoporotic vertebral fractures will be compared to standard conservative therapy. Conservative care will consist of 3 weeks of bed rest, wearing a rigid hyperextension corset, followed by 2-3 months in a Cheneau brace. In each of the two groups, patients will also receive treatment for osteoporosis according to their metabolic profile. Two hundred patients with painful osteoporotic vertebral compression fractures will be recruited over a 3 year period according to inclusion and exclusion criteria. We will randomly assign participants to receive either vertebroplasty or conservative care. Subjects will complete a battery of validated, standardized measures of pain, functional disability, and health related quality of life questionnaires at baseline and at post-randomization time points (1, 3, 6, 12 and 24 months). Each patient will be evaluated for pre-operative MRI, and pre- and post-operative radiographs; all scans will be evaluated independently by 2 orthopaedic surgeons. Laboratory tests to assess their metabolic bone profile will be also performed. Our primary outcome will be change from baseline to 1, 3, 6, 12 and 24 months in the VAS score between the 2 groups., Discussion: To date, vertebroplasty has been not been compared with standard conservative care for the management of patients with painful osteoporotic vertebral fractures in a randomised controlled trial. Therefore, the results of this study will allow to draw firm conclusions on this controversial topic.

The peculiar radiological and pathological findings of four pediatric cases admitted to the University Hospital of Padua between 1990 and 2007 are described. In all cases, the contrast-enhanced head and spine magnetic resonance images revealed thickened and abnormally enhancing subarachnoid spaces particularly at the level of basal cisterns and interhemispheric fissure. Furthermore, small cystic lesions scattered throughout the brain and mainly in the cerebellum were also visible. All patients were missing a well-defined intraparenchymal mass, although during the follow-up a small intramedullary lesion appeared within the cervical spine in two and subsequently in the frontal horn of the left lateral ventricle in one of those. All patients presented an indolent long-term follow-up. Histologically, the tumors were composed by a monotonous population of cells arranged in straight lines or in small lobules. The cells were characterized by round to oval nuclei with finely granular dispersed chromatin, inconspicuous nucleoli with oligodendrocyte-like features. The morphological and immunohistochemical findings suggested in all cases a "glioneuronal commitment" of the tumors. Because of the unique similar clinical and neuroradiological characteristics, we propose this small series of tumors as a new possible distinct pathological and clinical entity.

Introduction: During the past decades several rating scales have been developed to assess the functional status of patients with low back pain., Methods: We performed a search using the keywords 'spine' in combination with 'scoring system', 'scale', 'scores', 'outcome assessment', 'low back pain' and 'clinical evaluation'., Results: Twenty-eight scoring systems are currently available for the evaluation of low back pain. Each of them evaluates low back pain using specific variables. All these scoring systems are presented., Discussion: Although many scoring systems have been used to evaluate the back function, we are still far from a single outcome evaluation system that is reliable, valid and sensitive to clinically relevant changes, taken into account both patients' and physicians' perspective and is short and practical to use., Conclusion: Further studies are required to evaluate the reliability, validity and sensitivity of the low back pain scoring systems used in the common clinical practice.

Two different minimally invasive percutaneous vertebral augmentation methods for cement application into the vertebral body for the management of symptomatic compression fractures without neurologic impairment have been developed, namely, vertebroplasty and kyphoplasty. In vertebroplasty, polymethylmethacrylate cement is injected percutaneously into a collapsed vertebral body. Kyphoplasty involves placing an inflatable bone tamp percutaneously into a vertebral body. The inflation of the bone tamp with fluid allows restoration of vertebral height and correction of the kyphosis. After deflation, the cavity that has been produced is filled by injection of polymethylmethacrylate. This article provides an overview of the state of the art in vertebroplasty and kyphoplasty, discussing the indications, techniques, results, and pitfalls.

Background: Glioblastoma multiforme (GBM) is one of most common and still poorly treated primary brain tumors. In search for new therapeutic approaches, Bone Morphogenetic Proteins (BMPs) induce astroglial commitment in GBM-derived cells in vitro. However, we recently suggested that hypoxia, which is characteristic of the brain niche where GBM reside, strongly counter-acts BMP effects. It seems apparent that a more complete understanding of the biology of GBM cells is needed, in particular considering the role played by hypoxia as a signaling pathways regulator. HIF-1alpha is controlled at the transcriptional and translational level by mTOR and, alike BMP, also mTOR pathway modulates glial differentiation in central nervous system (CNS) stem cells., Methodology/principal Findings: Here, we investigate the role of mTOR signaling in the regulation of HIF-1alpha stability in primary GBM-derived cells maintained under hypoxia (2% oxygen). We found that GBM cells, when acutely exposed to high oxygen tension, undergo Akt/mTOR pathway activation and that BMP2 acts in an analogous way. Importantly, repression of Akt/mTOR signaling is maintained by HIF-1alpha through REDD1 upregulation. On the other hand, BMP2 counter-acts HIF-1alpha stability by modulating intracellular succinate and by controlling proline hydroxylase 2 (PHD2) protein through inhibition of FKBP38, a PHD2 protein regulator., Conclusions/significance: In this study we elucidate the molecular mechanisms by which two pro-differentiating stimuli, BMP2 and acute high oxygen exposure, control HIF-1alpha stability. We previously reported that both these stimuli, by inducing astroglial differentiation, affect GBM cells growth. We also found differences in high oxygen and BMP2 sensitivity between GBM cells and normal cells that should be further investigated to better define tumor cell biology.

Cervical spinal disc replacement is used in the management of degenerative cervical disc disease in an attempt to preserve cervical spinal movement and to prevent adjacent disc overload and subsequent degeneration. A large number of patients have undergone cervical spinal disc replacement, but the effectiveness of these implants is still uncertain. In most instances, degenerative change at adjacent levels represents the physiological progression of the natural history of the arthritic disc, and is unrelated to the surgeon. Complications of cervical disc replacement include loss of movement from periprosthetic ankylosis and ossification, neurological deficit, loosening and failure of the device, and worsening of any cervical kyphosis. Strict selection criteria and adherence to scientific evidence are necessary. Only prospective, randomised clinical trials with long-term follow-up will establish any real advantage of cervical spinal disc replacement over fusion.