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La forma triangular adoptada para el edificio de la Embajada de los EE. UU. en Oslo fue inevitable, ya que el solar disponible (de 600 m2) tenía esta planta con calles por los tres lados y fachada principal (de 58 m) a la de Drammensveien, frente al Palacio Real, el cual está situado en el centro de un espacioso parque-jardín, con ligera pendiente hacia el edificio. La calle de Drammensveien presenta una fisonomía uniforme, con fachadas continuas, por lo que parecía importante continuar este ritmo en la nueva construcción, como en efecto se ha hecho, al igual que en los otros dos alzados.

Introduction: Despite multimodal treatment for high-grade gliomas, prognosis remains grim. Prior Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) reports indicate based on pretreatment and treatment-related factors, a subset of patients experience a significantly improved survival. Since the development of the RTOG-RPA, high-grade gliomas have seen the widespread introduction of temozolomide and tumor oncogenetics. Here we aimed to determine whether the RTOG-RPA retained prognostic significance in the context of modern treatment, as well as generate an updated RPA incorporating both clinical and genetic variables., Methods: Patients with histologically proven glioblastoma, gliosarcoma, anaplastic astrocytoma, and anaplastic oligodendroglioma treated with intensity-modulated radiation therapy (IMRT) between 2004 and 2017 were reviewed. The primary endpoint was overall survival from date of diagnosis. Primary analysis compared actual survival rates to that expected of corresponding RTOG-RPA class. Secondary analysis utilized the rpart function to recursively partition overall survival by numerous clinical and genetic pretreatment and treatment-related variables. A tertiary analysis recursively partitioned a subset of patients in which the status of all genetic markers were known., Results: We identified 878 patients with histologically proven high-grade glioma treated with IMRT and 291 patients in our genetic subset. Median overall survival for the entire cohort was 14.2 months (95% confidence interval, 13.1-15.3). Applying the RTOG-RPA to our cohort validated the relative prognostic ordering of the survival classes except class II. Generating our new RPA created 7 significantly different survival classes (P<0.001, χ=584) with median survival ranging from 96.4 to 2.9 months based on age, histology, O6-methylguanine-DNA methyltransferase methylation status, radiation fractions, tumor location, radiation dose, temozolomide status, and resection status. Our second RPA of our genetic subset generated 5 significantly different survival classes (P<0.001, χ=166) with survival ranging from 65.3 to 5.6 months based on age, isocitrate dehydrogenase 1 mutation status, O6-methylguanine-DNA methyltransferase methylation status, neurological functional classification, hospitalization during IMRT, temozolomide status, and Karnofsky performance status., Conclusions: The RTOG-RPA retains partial prognostic significance, however, should be updated to reflect recent advancements. This series represents a large RPA analyzing both clinical and genetic factors and generated 7 distinct survival classes. Further assessment of patients with fully available genetic markers generated 5 distinct survival classes. These survival classifications need to be validated by a prospective data set and compared against the RTOG-RPA to determine whether they provide improved prognostic power.

Objective: Scheduled early postoperative computed tomography (EPOCT) after craniotomy for brain tumor resection is standard at many institutions. We analyzed utility of preplanned EPOCT after elective craniotomy for brain tumor resection., Methods: We retrospectively analyzed 755 brain tumor resections for which EPOCT was performed within 4 hours of surgery. Postoperative clinical neurologic examination results were classified into expected (baseline or predicted postoperative examination), changed (from baseline examination), and unreliable (sedated or baseline comatose patient). Scans were analyzed for unexpected and/or worrisome findings (e.g., hemorrhagic or ischemic stroke). In cases of unexpected findings, management changes were correlated to patient's neurologic examination. Demographic information, tumor histology, and tumor location were analyzed to determine risk factors for unexpected findings., Results: Rate of unexpected EPOCT findings was 4.1%. Patients with expected postoperative examinations were at significantly lower risk of abnormal findings (odds ratio [OR] = 0.074, P < 0.001). Patients with intraventricular tumors (OR = 5.7, P = 0.001) were at higher risk compared with patients with metastatic tumors (OR = 0.24, P = 0.06). No unexpected EPOCT findings led to management changes in patients with expected postoperative neurologic examinations. All unexpected EPOCT findings in patients with changed postoperative neurologic examinations led to management changes. Patients with nonreliable neurologic examinations were at significantly higher risk for unexpected findings on EPOCT (OR = 6.33, P < 0.001) and subsequent management changes., Conclusions: Routine EPOCT is not indicated for patients undergoing brain tumor resection if postoperative neurologic examination is unchanged, as imaging is unlikely to result in management changes. EPOCT should be obtained in all patients with worrisome changes in examination or nonreliable examinations, as both groups have high rates of unexpected findings on imaging that lead to management changes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Purpose: Intracerebral hemorrhage (ICH) is a devastating disease without a proven therapy to improve long-term outcome. Considerable controversy about the role of surgery remains. Minimally invasive endoscopic surgery for ICH offers the potential of improved neurological outcome., Methods: We tested the hypothesis that intraoperative computerized tomographic image-guided endoscopic surgery is safe and effectively removes the majority of the hematoma rapidly. A prospective randomized controlled study was performed on 20 subjects (14 surgical and 4 medical) with primary ICH of >20 mL volume within 48 hours of ICH onset. We prospectively used a contemporaneous medical control cohort (n=36) from the MISTIE trial (Minimally Invasive Surgery and r-tPA for ICH Evacuation). We evaluated surgical safety and neurological outcomes at 6 months and 1 year., Results: The intraoperative computerized tomographic image-guided endoscopic surgery procedure resulted in immediate reduction of hemorrhagic volume by 68±21.6% (interquartile range 59-84.5) within 29 hours of hemorrhage onset. Surgery was successfully completed in all cases, with a mean operative time of 1.9 hours (interquartile range 1.5-2.2 hours). One surgically related bleed occurred peri-operatively, but no patient met surgical safety stopping threshold end points for intraoperative hemorrhage, infection, or death. The surgical intervention group had a greater percentage of patients with good neurological outcome (modified Rankin scale score 0-3) at 180 and 365 days as compared with medical control subjects (42.9% versus 23.7%; P=0.19)., Conclusions: Early computerized tomographic image-guided endoscopic surgery is a safe and effective method to remove acute intracerebral hematomas, with a potential to enhance neurological recovery., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00224770., (© 2016 American Heart Association, Inc.)

Background: Diffuse gliomas are poorly immunogenic, fatal brain tumors. The basis for insufficient antitumor immunity in diffuse gliomas is unknown. Gain-of-function mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma., Methods: We analyzed the database of The Cancer Genome Atlas for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligand expression levels and NK cell-mediated lysis were measured in IDH mutant and wild-type patient-derived glioma stem cells and genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent 5-aza-2'deoxycytodine (decitabine) as a potential NK cell sensitizing agent in IDH mutant cells., Results: IDH mutant glioma stemlike cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes are resistant to NK cell-mediated lysis. Decitabine increases NKG2D ligand expression and restores NK-mediated lysis of IDH mutant cells in an NKG2D-dependent manner., Conclusions: IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULBP3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell-mediated immune surveillance in patients with IDH mutated diffuse gliomas., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Sinus histiocytosis with massive lymphadenopathy (also known as Rosai-Dorfman disease [RDD]) is a benign but chronic cervical lymphadenopathy associated with systemic inflammation. Although extranodal manifestations of RDD have been described, isolated central nervous system (CNS) involvement is exceedingly rare., Case Description: We present the case of a 66-year-old woman who presented with 3 weeks of intermittent headaches, diplopia, and increasing confusion who was found on work-up to have isolated hypothalamic RDD, evidenced by a dense admixture of large histiocytic cells admixed with numerous small mature lymphocytes and some scattered plasma cells and neutrophils on stereotactic brain biopsy. Over 19 months of follow-up, neurologic examination continues to reveal stable bilateral partial abducens nerve palsies without diplopia, and a new gradual onset short-term memory loss. Interim treatment for the histiocytic lesion consisted of 10 cycles of external-beam radiation therapy along with high-dose steroids. The patient currently experiences minimal functional loss from treatment of her intracranial sinus histiocytosis, with a Karnofsky performance status of 80, and she remains without any disease involvement outside of the CNS., Conclusion: Because misdiagnosis of a hypothalamic contrast-enhancing lesion could potentially lead to therapeutic mismanagement and poor outcomes, it is important to consider RDD in the differential diagnosis., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Postoperative stereotactic radiosurgery for brain metastases potentially offers similar local control rates and fewer long-term neurocognitive sequelae compared to whole brain radiation therapy, although patients remain at risk for distant brain failure (DBF)., Objective: To describe clinical outcomes of adjuvant stereotactic radiosurgery for large brain metastases and identify predictors of intracranial failure and their implications on optimal patient selection criteria., Methods: We performed a retrospective review on 100 large (>3 cm) brain metastases in 99 patients managed by resection followed by postoperative stereotactic radiosurgery to a median dose of 22 Gy (range, 10-28) in 1 to 5 fractions (median, 3). Primary histology was nonsmall cell lung in 40%, breast cancer in 18%, and melanoma in 17%. Forty (40%) patients had uncontrolled systemic disease., Results: With a median follow-up of 12.2 months (range, 0.6-87.4), the 1-year Kaplan-Meier local control was 72%, DBF 64%, and overall survival 55%. Nine patients (9%) developed evidence of radiation injury, and 6 (6%) developed leptomeningeal disease. Uncontrolled systemic disease (P=.03), melanoma histology (P=.04), and increasing number of brain metastases (P<.001) were significant predictors of DBF on Cox multivariate analysis. Patients with <4 metastases, controlled systemic disease, and nonmelanoma primary (n=47) had a 1-year DBF of 48.6% vs 80.1% for all others (P=.01)., Conclusion: Postoperative stereotactic radiosurgery to the resection cavity safely and effectively augments local control of large brain metastases. Patients with <4 metastases and controlled systemic disease have significantly lower rates of DBF and are ideal treatment candidates.

Purpose: WHO grade 2 low-grade gliomas (LGG) with high risk factors for recurrence are mostly lethal despite current treatments. We conducted a phase I study to evaluate the safety and immunogenicity of subcutaneous vaccinations with synthetic peptides for glioma-associated antigen (GAA) epitopes in HLA-A2(+) adults with high-risk LGGs in the following three cohorts: (i) patients without prior progression, chemotherapy, or radiotherapy (RT); (ii) patients without prior progression or chemotherapy but with prior RT; and (iii) recurrent patients., Experimental Design: GAAs were IL13Rα2, EphA2, WT1, and Survivin. Synthetic peptides were emulsified in Montanide-ISA-51 and given every 3 weeks for eight courses with intramuscular injections of poly-ICLC, followed by q12 week booster vaccines., Results: Cohorts 1, 2, and 3 enrolled 12, 1, and 10 patients, respectively. No regimen-limiting toxicity was encountered except for one case with grade 3 fever, fatigue, and mood disturbance (cohort 1). ELISPOT assays demonstrated robust IFNγ responses against at least three of the four GAA epitopes in 10 and 4 cases of cohorts 1 and 3, respectively. Cohort 1 patients demonstrated significantly higher IFNγ responses than cohort 3 patients. Median progression-free survival (PFS) periods since the first vaccine are 17 months in cohort 1 (range, 10-47+) and 12 months in cohort 3 (range, 3-41+). The only patient with large astrocytoma in cohort 2 has been progression-free for more than 67 months since diagnosis., Conclusion: The current regimen is well tolerated and induces robust GAA-specific responses in WHO grade 2 glioma patients. These results warrant further evaluations of this approach. Clin Cancer Res; 21(2); 286-94. ©2014 AACR., (©2014 American Association for Cancer Research.)

Background: Previous research mainly focused on responses to negative affect in relation to depression, and less on responses to positive affect. Cognitive responses to positive affect are interesting in the context of emotion regulation and emotion disorders: positive rumination is associated to hypomania risk and bipolar disorder. There is to date no questionnaire in Swedish that captures the phenomena of cognitive response styles., Aims: The aim of this study was to investigate the replicability of the Responses to Positive Affect questionnaire (RPA) in a newly translated Swedish version and to test its psychometric properties., Methods: Swedish undergraduates (n = 111) completed a set of self-report questionnaires in a fixed order., Results: The hypothesized three-factor model was largely replicated in the subscales Self-focused positive rumination, Emotion-focused positive rumination and Dampening. The two positive rumination subscales were strongly associated with each other and current positive affect. The subscales showed acceptable convergent and incremental validity with concurrent measures of depression, hypomania, anxiety, repetitive negative thinking, and positive and negative affect. The model explained 25% of the variance in hypomania, but fell short in the explanation of depression., Conclusions: The Swedish version of the RPA shows satisfactory reliability and initial findings from a student sample indicate that it is a valid measure comparable with the original RPA questionnaire. RESULTS give emphasis to the importance of further exploration of cognitive response styles in relation to psychopathology.

Background: High-definition fiber tractography (HDFT), an advanced white matter (WM) imaging technique, was evaluated in the management of supratentorial cavernous malformations., Objective: To investigate the relationship of cavernous malformations to the relevant perilesional WM tracts with HDFT and to characterize associated changes first qualitatively and then quantitatively with our novel imaging measure, quantitative anisotropy (QA)., Methods: Imaging analysis was carried out by researchers blinded to the clinical details. Contralateral WM tracts were used for comparison. Mean QA values were obtained for whole WM tracts. Qualitatively affected superior longitudinal fasciculus/arcuate fibers and corticospinal tracts were further analyzed with the use of mean QA values for the perilesional segments., Results: Of 10 patients, HDFT assisted with the decision-making process and the offer of surgical resection in 2 patients, lesion approach and removal in 7 patients, and conservative management in 1 patient. Of 17 analyzed WM tracts, HDFT demonstrated partial disruption in 2 tracts, complete disruption in 2 tracts, a combination of displacement and partial disruption in 1 tract, displacement only in 7 tracts, and no change in 5 tracts. Qualitative changes correlated with clinical symptoms. Mean QA values for the whole WM tracts were similar, with the exception of 1 case demonstrating complete disruption of 2 WM tracts. QA-based perilesional segment analysis was consistent with qualitative data in 5 assessed WM tracts., Conclusion: HDFT illustrated the precise spatial relationship of cavernous malformations to multiple WM tracts in a 3-dimensional fashion, optimizing surgical planning, and demonstrated associated disruption and/or displacement, with both occurring perilesionally. These changes were supported by our quantitative marker, which needs further validation.

Background: Spontaneous intracerebral hemorrhages (ICHs) cause significant morbidity and mortality. Traditional open surgical management strategies offer limited benefit except for the most superficial hemorrhages in select patients. Recent reports suggest that endoscopic approaches may improve outcomes, particularly for deep subcortical hemorrhages. However, the management of these patients remains controversial. We reviewed our experience using endoscopic port surgery to identify characteristics that may predict acceptable outcomes., Materials and Methods: We completed a retrospective chart and imaging review of patients who underwent endoscopic port surgery for evacuation of spontaneous ICH at a single center. Data were gathered regarding patient demographics, hemorrhage locations, operative findings, and clinical outcomes., Results: From 2007 to 2011, 18 patients underwent evacuation of spontaneous intracerebral hematomas using an endoscopic port. The mean age in years was 62 years (range, 43-84 years). Six of 18 patients (33%) died before discharge, and 2 others (11%) died after at least 1 month of survival. Of 12 initial survivors, all were discharged to a rehabilitation or nursing facility. Complete hematoma evacuation was achieved in 7 of 18 patients, with the remaining 11 having a partial evacuation. The patients who died (n = 6) before discharge were statistically more likely to have a left-sided hemorrhage, partial evacuation, or older age than the survivors; death at least 1  month after evacuation was additionally associated with greater preoperative hematoma volumes., Conclusions: Our series demonstrates that endoscopic port surgery for acute intracerebral hematoma evacuation has the ability to achieve significant decompression of large and deep-seated hematomas. Patient age, extent of evacuation, laterality, and preoperative hematoma volume appear to influence patient outcome. Most overall outcomes remain poor. Future studies are necessary to determine if surgical evacuation is in fact superior to best medical treatment and if so, to validate, refute, or further identify characteristics that define surgical candidates., (Georg Thieme Verlag KG Stuttgart · New York.)

Background and Purpose: Intraoperative neurophysiological monitoring (IONM) using upper and lower somatosensory evoked potentials (SSEPs) is an established technique used to predict and prevent neurologic injury during intracranial tumor resections. Endoscopic port surgery (EPS) is a minimally-invasive approach to deep intraparenchymal and intraventricular brain tumors. The authors intended to evaluate the predictive value of SSEP monitoring during resection of intracranial brain tumors using a parallel endoscopic technique., Methods: A retrospective review was conducted of patients operated on from 2007-2010 utilizing IONM in whom endoscopic ports were used to remove either intraparenchymal or intraventricular tumors. Cases were eligible for review if an endoscopic port was used to resect an intracranial tumor and the electronic chart included all intraoperative monitoring data as well as pre- and post-operative neurologic exams., Results: 139 EPS cases met criteria for inclusion. Eighty five patients (61%) had intraparenchymal and fifty four (39%) had intraventricular tumors or colloid cysts. SSEP changes were seen in eleven cases (7.9%), being irreversible in three (2.2%) and reversible in eight cases (5.8%). Seven patients (5.0%) with intraparenchymal tumors had SSEP changes which met our criterea for significant changes while there were four (2.9%) with intraventricular (p-value=0.25). Five patients suffered post operative deficits, two reversible and two irreversible SSEP changes. Only one case exhibited post operative hemiparesis with no SSEP changes. The positive predictive value of SSEP was 45.4% and the negative predictive value was 99.2%., Conclusions: Based on the high negative and low positive predictive values, the utility of SSEP monitoring for cylindrical port resections may be limited. However, the use of SSEP monitoring can be helpful in reducing the impact of endoscopic port manipulation when the tumor is closer to the somatosensory pathway.

Objective: Deep-seated intraventricular and intraparenchymal lesions have traditionally been resected via transcortical routes, often requiring the use of retractors to maintain the corridor created to reach the lesion and proceed with a bimanual microsurgical resection. A transparent cylindrical conduit (port) has been developed to resect deep-seated lesions using the endoscope or, more recently, Video Telescopic Operating Microscopy (VTOM) for visualization. We describe the surgical technique of the port technique and discuss the evolution of the concept of intraaxial brain surgery performed through a conduit., Methods: Detailed description of the ventriculoport and brainport technique with illustrative cases., Results: Results of intraventricular and intraparenchymal port surgery have been published and document the feasibility and safety of this technique. Over the years, the technique has been improved. The port technique offers numerous potential advantages, including: 1) minimizing white matter disruption as the tip design minimizes the risk of fascicles injury during cannulation; 2) ensuring stability as the rigidity prevents inadvertent expansion of the initial diameter of the corticectomy and white fiber tract dissection throughout surgery; 3) protecting the surrounding tissues against iatrogenic injuries caused by instrument entry and reentry; 4) affording constant visualization of the tissue traversed given the transparent conduit design; 5) enabling homogeneous radial dispersion of the pressure on the surrounding tissue to minimize injury., Conclusion: The port technique is an option for resection of intraventricular and intraparenchymal lesions. Additional studies are required to assess its impact on adjacent cerebral tissue morphology, blood flow, and metabolism. Quality-of-life assessments are also needed. High-definition fiber tracking, new visualization techniques (VTOM), and new instrumentation will add to the progress of endoscopic port surgery. We have already seen a significant evolution of the technology even since the preparation of this article., (Copyright © 2013. Published by Elsevier Inc.)

The authors describe the combination of awake craniotomy and minimally invasive endoscopic port surgery to resect a high-grade glioma located near eloquent structures of the temporal lobe. Combined minimally invasive techniques such as these may facilitate deep tumor resection within eloquent regions of the brain, allowing minimum white matter dissection. Technical aspects of this procedure, a case outcome involving this technique, and the direction of further investigations for the utility of these techniques are discussed.

Background: High-definition fiber tracking (HDFT) is a novel combination of processing, reconstruction, and tractography methods that can track white matter fibers from cortex, through complex fiber crossings, to cortical and subcortical targets with subvoxel resolution., Objective: To perform neuroanatomical validation of HDFT and to investigate its neurosurgical applications., Methods: Six neurologically healthy adults and 36 patients with brain lesions were studied. Diffusion spectrum imaging data were reconstructed with a Generalized Q-Ball Imaging approach. Fiber dissection studies were performed in 20 human brains, and selected dissection results were compared with tractography., Results: HDFT provides accurate replication of known neuroanatomical features such as the gyral and sulcal folding patterns, the characteristic shape of the claustrum, the segmentation of the thalamic nuclei, the decussation of the superior cerebellar peduncle, the multiple fiber crossing at the centrum semiovale, the complex angulation of the optic radiations, the terminal arborization of the arcuate tract, and the cortical segmentation of the dorsal Broca area. From a clinical perspective, we show that HDFT provides accurate structural connectivity studies in patients with intracerebral lesions, allowing qualitative and quantitative white matter damage assessment, aiding in understanding lesional patterns of white matter structural injury, and facilitating innovative neurosurgical applications. High-grade gliomas produce significant disruption of fibers, and low-grade gliomas cause fiber displacement. Cavernomas cause both displacement and disruption of fibers., Conclusion: Our HDFT approach provides an accurate reconstruction of white matter fiber tracts with unprecedented detail in both the normal and pathological human brain. Further studies to validate the clinical findings are needed.

Two patients presented with acute subarachnoid hemorrhage from a ruptured intracranial aneurysm. Both patients were treated via endovascular coil embolization, and both developed delayed lower extremity monoparesis without associated symptoms that resolved over the ensuing months. An extensive work-up lead us to propose the following hypothesis: the painless peripheral neuropathy likely resulted from nerve root irritation from abundant subarachnoid blood in the lumbar cistern., ((c) 2010 Elsevier B.V. All rights reserved.)

Objective: The learning curve for endonasal endoscopic and neuroendoscopic port surgery is long and often associated with an increase in complication rates as surgeons gain experience. We present an animal model for laboratory training aiming to encourage the young generation of neurosurgeons to pursue proficiency in endoscopic neurosurgical techniques., Methods: 20 Wistar rats were used as models. The animals were introduced into a physical trainer with multiple ports to carry out fully endoscopic microsurgical procedures. The vertical and horizontal dimensions of the paired ports (simulated nostrils) were: 35×20 mm, 35×15 mm, 25×15 mm, and 25×10 mm. 2 additional single 11.5 mm endoscopic ports were added. Surgical depth varied as desired between 8 and 15 cm. The cervical and abdominal regions were the focus of the endoscopic microsurgical exercises., Results: The different endoscopic neurosurgical techniques were effectively trained at the millimetric dimension. Levels of progressive surgical difficulty depending upon the endoneurosurgical skills set needed for a particular surgical exercise were distinguished. LEVEL 1 is soft-tissue microdissection (exposure of cervical muscular plane and retroperitoneal space); LEVEL 2 is soft-tissue-vascular and vascular-capsule microdissection (aorto-cava exposure, carotid sheath opening, external jugular vein isolation); LEVEL 3 is artery-nerve microdissection (carotid-vagal separation); LEVEL 4 is artery-vein microdissection (aorto-cava separation); LEVEL 5 is vascular repair and microsuturing (aortic rupture), which verified the lack of current proper instrumentation., Conclusion: The animal training model presented here has the potential to shorten the length of the learning curve in endonasal endoscopic and neuroendoscopic port surgery and reduce the incidence of training-related surgical complications., (© Georg Thieme Verlag KG Stuttgart · New York.)

Hypoxia contributes to the progression of a variety of cancers by activating adaptive transcriptional programs that promote cell survival, motility and tumor angiogenesis. Although the importance of hypoxia and subsequent hypoxia-inducible factor-1alpha (HIF-1alpha) activation in tumor angiogenesis is well known, their role in the regulation of glioma-derived stem cells is unclear. In this study, we show that hypoxia (1% oxygen) promotes the self-renewal capacity of CD133-positive human glioma-derived cancer stem cells (CSCs). Propagation of the glioma-derived CSCs in a hypoxic environment also led to the expansion of cells bearing CXCR4 (CD184), CD44(low) and A2B5 surface markers. The enhanced self-renewal activity of the CD133-positive CSCs in hypoxia was preceded by upregulation of HIF-1alpha. Knockdown of HIF-1alpha abrogated the hypoxia-mediated CD133-positive CSC expansion. Inhibition of the phosphatidylinositol 3-kinase(PI3K)-Akt or ERK1/2 pathway reduced the hypoxia-driven CD133 expansion, suggesting that these signaling cascades may modulate the hypoxic response. Finally, CSCs propagated at hypoxia robustly retained the undifferentiated phenotype, whereas CSCs cultured at normoxia did not. These results suggest that response to hypoxia by CSCs involves the activation of HIF-1alpha to enhance the self-renewal activity of CD133-positive cells and to inhibit the induction of CSC differentiation. This study illustrates the importance of the tumor microenvironment in determining cellular behavior.

Object: External ventricular drain (EVD) placement is one of the most common neurosurgical procedures performed. Rates and significance of hemorrhage associated with this procedure have not been well quantified., Methods: All adults who underwent EVD placement at the University of Pittsburgh Medical Center between July 2002 and June 2003 were evaluated for catheter-associated hemorrhage. Patients without postprocedural imaging were excluded., Results: Seventy-seven (41%) of 188 EVDs were associated with imaging evidence of hemorrhage after either placement or removal. Most of these were insignificant, punctate intraparenchymal, or trace subarachnoid hemorrhages (51.9%). Thirty-seven (19.7%) were associated with larger hemorrhages, which were divided into 3 groups according to volume of hemorrhage: 16 patients (8.5%) had < 15 ml of hemorrhage, 20 (10.6%) had hemorrhages of > 15 ml or associated intraventricular hemorrhage, and in 1 case there was a subdural hematoma that required surgical evacuation. No hemorrhages larger than punctate or trace were seen after EVD removal. Hemorrhage was associated with 44.3% of EVDs placed in an intensive care unit compared with 34.8% in EVDs placed in the operating room (p > 0.10)., Conclusions: External ventricular drain placement has a significant risk of associated hemorrhage. However, the hemorrhages are rarely large and almost never require surgical intervention. There is a favorable trend, but no significant risk reduction when EVDs are placed in the operating room rather than the intensive care unit.

Background: Interacting with patients, researchers, and administrators, patient advocates have a unique vantage point. Yet, few prior studies have sought to understand these individuals or to seek their opinions on cancer issues., Methods: A survey to address the foregoing was developed and mailed to advocates within the National Cancer Institute's Prostate Cancer SPORE Program., Results: A total of 10 of 19 advocates responded. All were men, most were retired, and all had faced a diagnosis of prostate cancer. Two major themes emerged: (1) the importance of patient education in promoting informed clinical decision-making and (2) a perceived need for patient-centered research by providers and educators., Conclusions: Prostate cancer patient advocates provide a broad range of opinions on the spectrum of cancer care. Similar studies among advocates involved in other malignancies may be worthwhile.

The present study was performed to determine the histological, ultrastructural, and radiographic changes that occur over time at intramuscular BMP-9 gene therapy treatment sites. Several members of the bone morphogenetic protein (BMP) family have the potential to induce osteochondrogenesis when the protein is delivered to rodents, canines, rabbits, and nonhuman primates. Previous studies have also demonstrated that BMP gene therapy utilizing adenoviral vectors can also stimulate orthotopic and heterotopic bone formation in rodents and rabbits. Athymic nude and Sprague-Dawley rats were injected with Ad-BMP-9 or Ad-beta-Gal (3.75 x 10(9) particles) in their thigh musculature and light microscopic, electron microscopic, and computerized tomography analysis was performed 3, 6, 9, 12, 15, 18, 21, and 100 days later. To assess early mesenchymal cell proliferation, a bromodeoxyuridine (BrdU) immunohistochemical analysis was also performed 48, 60, and 72 hr postinjection in athymic nude rats. All animals demonstrated extensive endochondral bone formation at the Ad-BMP-9 treatment sites within 3 weeks. The Sprague-Dawley rats also exhibited a massive, acute inflammatory infiltrate during the first week. Proliferating mesenchymal stem cells were clearly evident as early as 2 days after treatment, which differentiated into small or hypertrophied chondrocytes during the next week. During the third week, the cartilaginous matrix mineralized and formed woven bone, which converted to lamellar bone by 3 months. No evidence of bone formation was demonstrated at the Ad-beta-Gal injection sites in the athymic nude or Sprague-Dawley rats. In addition, no cellular proliferation was seen at the Ad-beta-Gal treatment sites in the athymic nude animals as assessed by light microscopy and BrdU immunohistochemistry. The extensive bone formation induced by Ad-BMP-9 suggests that BMP gene therapy may have potential utility in the treatment of degenerative, rheumatic, or traumatic bone pathology.