The development of a hiPSC-based platform to identify tissue-dependencies of IDH1 R132H.

The application of patient-derived (PD) in vitro tumor models represents the classical strategy for clinical translational oncology research. Using these cellular heterogeneous cultures for the isolation of cancer stem cells (CSCs), suggested to be the main driver for disease malignancy, relies on the use of surrogate biomarkers or is based on CSC-enriching culture conditions. However, the ability of those strategies to exclusively and efficiently enrich for CSC pool has been questioned. Here we present an alternative in vitro CSC model based on the oncogenic transformation of single clone-derived human induced pluripotent stem cells (hiPSC). Hotspot mutations in the DNA encoding for the R132 codon of the enzyme isocitrate dehydrogenase 1 (IDH1) and codon R175 of p53 are commonly occurring molecular features of different tumors and were selected for our transformation strategy. By choosing p53 mutant glial tumors as our model disease, we show that in vitro therapy discovery tests on IDH1-engineered synthetic CSCs (sCSCs) can identify kinases-targeting chemotherapeutics that preferentially target tumor cells expressing corresponding genetic alteration. In contrast, neural stem cells (NSCs) derived from the IDH1R132H overexpressing hiPSCs increase their resistance to the tested interventions indicating glial-to-neural tissue-dependent differences of IDH1R132H. Taken together, we provide proof for the potential of our sCSC technology as a potent addition to biomarker-driven drug development projects or studies on tumor therapy resistance. Moreover, follow-up projects such as comparing in vitro drug sensitivity profiles of hiPSC-derived tissue progenitors of different lineages, might help to understand a variety of tissue-related functions of IDH1 mutations.

Longitudinal stability of molecular alterations and drug response profiles in tumor spheroid cell lines enables reproducible analyses.

The utility of patient-derived tumor cell lines as experimental models for glioblastoma has been challenged by limited representation of the in vivo tumor biology and low clinical translatability. Here, we report on longitudinal epigenetic and transcriptional profiling of seven glioblastoma spheroid cell line models cultured over an extended period. Molecular profiles were associated with drug response data obtained for 231 clinically used drugs. We show that the glioblastoma spheroid models remained molecularly stable and displayed reproducible drug responses over prolonged culture times of 30 in vitro passages. Integration of gene expression and drug response data identified predictive gene signatures linked to sensitivity to specific drugs, indicating the potential of gene expression-based prediction of glioblastoma therapy response. Our data thus empowers glioblastoma spheroid disease modeling as a useful preclinical assay that may uncover novel therapeutic vulnerabilities and associated molecular alterations.

DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development.

BACKGROUND: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. METHODS: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. RESULTS: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related 'keratinization' methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. CONCLUSIONS: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment.

CBF1 is clinically prognostic and serves as a target to block cellular invasion and chemoresistance of EMT-like glioblastoma cells.

BACKGROUND: Glioblastoma is the most common and most lethal primary brain cancer. CBF1 (also known as Recombination signal Binding Protein for immunoglobulin kappa J, RBPJ) is the cardinal transcriptional regulator of the Notch signalling network and has been shown to promote cancer stem-like cells (CSCs) in glioblastoma. Recent studies suggest that some of the malignant properties of CSCs are mediated through the activation of pro-invasive programme of epithelial-to-mesenchymal transition (EMT). Little is known whether CBF1 is involved in the EMT-like phenotype of glioma cells. METHODS: In a collection of GBM neurosphere lines, we genetically inhibited CBF1 and investigated the consequences on EMT-related properties, including in vitro invasiveness by Boyden chambers assay, chemoresistance using a clinical drug library screen and glycolytic metabolism assessing live-cell extracellular acidification rate. We also compared CBF1 expression in cells exposed to low and high oxygen tension. In silico analysis in large-scale Western and Eastern patient cohorts investigated the clinical prognostic value of CBF1 expression in low- and high-grade glioma as well as medulloblastoma. RESULTS: Mean CBF1 expression is significantly increased in isocitrate dehydrogenase 1 (IDH1) R132H mutant glioblastoma and serves as prognostic marker for prolonged overall survival in brain tumours, particularly after therapy with temozolomide. Hypoxic regions of glioblastoma have higher CBF1 activation and exposure to low oxygen can induce its expression in glioma cells in vitro. CBF1 inhibition blocks EMT activators such as zinc finger E-box-binding homeobox 1 (ZEB1) and significantly reduces cellular invasion and resistance to clinically approved anticancer drugs. Moreover, we indicate that CBF1 inhibition can impede cellular glycolysis. CONCLUSIONS: Mean CBF1 activation in bulk tumour samples serves as a clinical predictive biomarker in brain cancers but its intratumoral and intertumoral expression is highly heterogeneous. Microenvironmental changes such as hypoxia can stimulate the activation of CBF1 in glioblastoma. CBF1 blockade can suppress glioblastoma invasion in vitro in particular in cells undergone EMT such as those found in the hypoxic niche. Targeting CBF1 can be an effective anti-EMT therapy to impede invasive properties and chemosensitivity in those cells.

Minispectrometer with handheld probe for 5-ALA based fluorescence-guided surgery of brain tumors: Preliminary study for clinical applications.

INTRODUCTION: Recently a mini-spectrometer with a handheld probe quantifying 5-aminolevulinic acid (5-ALA) based fluorescence intensity of brain tumors was developped by Kim et al. to improve fluorescence-guided neurosurgery. OBJECTIVE: To evaluate if this new tool is capable to discriminate nuances of fluorescence intensity of strongly fluorescing tumors (glioblastomas (GBM) and meningiomas (MM)). To study different modes of measurement (touch/no-touch). To determine protoporphyrin IX (PPIX) concentration in tumor tissue as compared to a laboratory spectrometer. MATERIAL AND METHODS: The tumor tissue was resected from patients operated in the neurosurgical department of University Hospital Duesseldorf, Germany between 01/2014 and 06/2014. Two spectrometers, one custom-built with a handheld probe ("mini-spectrometer") and one commercial laboratory spectrometer were employed. After calibration they were used to detect and compare fluorescence intensity of human brain tumor samples ex vivo under standardized conditions. The mini-spectrometer was tested at different distances to the tumor. PPIX concentrations of tumor lysates were determined by both spectrometers. RESULTS: In total n=11 tumors (5 MM and 6 GBM) resulting in 17 tumor biopsies were studied. All GBM showed significant higher fluorescence intensity as compared to MM (Z=-3.123, p=0.001). The fluorescence signal was inversely proportional to the square of the distance (GBM: R2=0.226; F=4.683; p<0.5; MM: R2=0255; F=8.042; p<0.01). The mini-spectrometer recorded fluorescence signals up to 2mm ("no-touch"). Determination of PPIX concentration in tumor by the mini-spectrometer did not differ from a laboratory spectrometer. CONCLUSION: The mini-spectrometer was a very sensitive tool for detection of 5-ALA based fluorescence of human brain tumors. Fluorescence intensity of glioblastoma and meningioma were significantly different. A no-touch mode of measurement was possible. PPIX concentration in tumor tissue could be determined as precisely as with a laboratory spectrometer. In future clinical trials the practicability of using such a tool in vivo has to be further evaluated.

Targeting cancer stem-like cells in glioblastoma and colorectal cancer through metabolic pathways.

Cancer stem-like cells (CSCs) are thought to be the main cause of tumor occurrence, progression and therapeutic resistance. Strong research efforts in the last decade have led to the development of several tailored approaches to target CSCs with some very promising clinical trials underway; however, until now no anti-CSC therapy has been approved for clinical use. Given the recent improvement in our understanding of how onco-proteins can manipulate cellular metabolic networks to promote tumorigenesis, cancer metabolism research may well lead to innovative strategies to identify novel regulators and downstream mediators of CSC maintenance. Interfering with distinct stages of CSC-associated metabolics may elucidate novel, more efficient strategies to target this highly malignant cell population. Here recent discoveries regarding the metabolic properties attributed to CSCs in glioblastoma (GBM) and malignant colorectal cancer (CRC) were summarized. The association between stem cell markers, the response to hypoxia and other environmental stresses including therapeutic insults as well as developmentally conserved signaling pathways with alterations in cellular bioenergetic networks were also discussed. The recent developments in metabolic imaging to identify CSCs were also summarized. This summary should comprehensively update basic and clinical scientists on the metabolic traits of CSCs in GBM and malignant CRC.

Impact of 5-aminolevulinic acid fluorescence-guided surgery on the extent of resection of meningiomas--with special regard to high-grade tumors.

BACKGROUND AND OBJECTIVES: In high-grade meningiomas and a subgroup of clinically aggressive benign meningiomas tumor control is still insufficient. Recently 5-ALA fluorescence in meningiomas was reported. The impact of 5-ALA fluorescence-guided surgery (FGS) on surgical decision-making and extent of resection has not yet been systematically analyzed, especially not in high-grade meningiomas. The present study deals with three main questions regarding 5-ALA FGS in meningiomas: to assess the potential for discriminating different WHO grades intra-operatively, to analyze the influence on surgical strategy and to evaluate the impact on extent of resection. METHODS: Data from 31 meningiomas operated with 5-ALA FGS were retrospectively analyzed. Intraoperative fluorescence was graded by the surgeon as "no", "low" or "high". Correlations between semi-quantitative fluorescence and histological features (WHO grade) were analyzed. The influence of 5-ALA fluorescence on surgical strategy and the impact of 5-ALA FGS on degree of resection (Simpson grade and post-operative imaging) were studied. In tumors showing infiltrative growth the extent of resection of fluorescence positive tissue was evaluated. RESULTS: The population comprised 19 WHO grade I, 8 grade II and 4 grade III tumors (61% benign and 39% high-grade meningiomas). 94% of the tumors showed positive fluorescence. Different fluorescence intensities were observed: "no" in two, "high" in 12 and "low" in 17 tumors, respectively. A significant correlation between fluorescence intensity and WHO grade was found (ρ=0.557, p=0.001). 5-ALA improved the extent of resection in 3/16 (19%) of grade I and in 6/8 (75%) of grade II/III meningiomas. This improvement was not measurable by the Simpson grading as rated by the surgeon and controlled on post-operative imaging. CONCLUSIONS: In the present population a strong correlation between fluorescence intensity and WHO grade was observed. 5-ALA FGS improved the extent of resection in meningiomas. Especially in high-grade tumors additional information on brain and neurovascular infiltration was provided. The improved resection was not measurable by Simpson's grading necessitating an additional item, which rates residual fluorescence. Long-term studies are necessary to evaluate a possible impact of FGS on recurrence and overall survival.

The impact of improved treatment strategies on overall survival in glioblastoma patients.

BACKGROUND: The introduction of ALA-Fluorescence-guided surgery (FGS) followed by concomitant radiochemotherapy according to the Stupp-protocol is representative of the major changes in glioblastoma therapy in the past years. We were interested in the impact of this new first-line treatment on the overall survival of patients suffering from newly diagnosed primary glioblastoma in a retrospective single-centre study. METHOD: For this retrospective analysis, data was derived from a prospective single-centre database. Patients were divided into three treatment groups: A (FGS-/radiochemotherapy-), B (FGS-/radiochemotherapy+) and C (FGS+/radiochemotherapy+). Further stratification was applied regarding MGMT-methylation status and degree of resection. Statistical analysis was performed to determine factors (treatment regime, age, gender, performance status, MGMT promoter methylation status) significantly influencing overall survival (OAS). RESULTS: Two hundred and fifty-three patients suffering from primary glioblastoma treated by cytoreductive surgery between 2002 and 2009 were included in this survey. Median OAS differed significantly between the treatment groups (A = 8.8, B = 16.6, C = 20.1, p < 0.01). Resection data was available in all 253 patients. The usage of FGS highly significantly correlated with a complete resection (p < 0.01). Complete resection was positively correlated with an increase in OAS (complete 20.3 months vs. incomplete 9.3 months, p < 0.01). CONCLUSIONS: FGS and radiochemotherapy according to the Stupp protocol have induced an impressive improvement in overall survival in glioblastoma patients. This effect is not limited to clinical trials, but is reproducible in daily routine.

Giant cell tumor of the lumbar spine with intraperitoneal growth: case report and review of literature.

Giant cell tumors of the spine are uncommon. Usually they are benign and solitary, but locally very aggressive. Most of them occur at the sacral spine. There are only 26 reported cases in the literature involving this type of tumor in the lumbar spine, in particular exhibiting an intraperitoneal growth. We present the case of a woman with a primary tumor of the lumbar spine (giant cell tumor) with intraperitoneal growth, the outcome as well as a review of the literature. Furthermore, after reviewing all spinal cases in the literature above the sacral spine, we carefully suggest a management algorithm.

The impact of sequential vs. combined radiochemotherapy with temozolomide, resection and MGMT promoter hypermethylation on survival of patients with primary glioblastoma--a single centre retrospective study.

BACKGROUND: The benefit of the introduction of alkylating chemotherapy in the treatment of glioblastoma multiforme (GBM) patients has been demonstrated by comparing radiotherapy with concomitant plus intermittent temozolomide (iTMZ) to radiation therapy. The isolated impact of the concomitant part of this protocol on survival was not investigated. We were therefore interested in the impact of the effect of the concomitant therapy part on survival. Hence, we compared patients treated with open surgery followed by radiotherapy and iTMZ with patients treated with concomitant plus iTMZ chemotherapy regarding overall (OS) and progression-free survival (PFS). METHODS: We performed a retrospective database search for the period between 2002 and 2007 and aimed at the identification of patients with primary GBM treated by open resection, radiotherapy (only radiotherapy = Group A and plus concomitant TMZ = Group B) and at least two cycles of TMZ. Patients were stratified for established prognostic markers like extent of resection, MGMT promoter methylation, Karnofsky Performance Scale (KPS), and age. RESULTS: Eighty-five patients were analysed, among which 42 patients (49%) were affiliated with Cohort A and 43 patients (51%) with Cohort B. Between both cohorts there was no significant difference regarding MGMT methylation status (p = 0.929), extend of resection (p = 0.102), KPS (p = 0.197) and age (p = 0.327). For the entire patient population, median OS was 18.6 months and PFS was 5.6 months. The extent of resection was significantly correlated with survival (OS: 21.5 vs. 16.1 months (p = 0.001) and PFS: 11.0 vs. 3.9 months (p = 0.044)). MGMT methylation status revealed a significant impact on OS (p = 0.008). Affiliation to Cohort A or B was neither correlated with PFS (p = 0.168) nor with OS (p = 0.343). CONCLUSION: Our study demonstrates that PFS and OS are strongly determined by the MGMT status and the extent of resection. Interestingly, concomitant radiochemotherapy was not superior to radiotherapy followed by iTMZ chemotherapy regarding OS and PFS.

Localization techniques in resection of deep seated cavernous angiomas - review and reevaluation of frame based stereotactic approaches.

BACKGROUND: Providing high accuracy is crucial in neurosurgery especially for resection of deep seated small cerebral pathologies such as cavernous angiomas. The goal of the present series was to reevaluate the feasibility, accuracy, efficacy and safety of frame-based, stereotactically guided resection for patients suffering from small deep-seated cavernous angiomas. Additionally a review of the literature on navigational tools in cavernoma surgery is provided comparing different navigation strategies. METHODS: Ten patients with deep-seated, small intracranial, cavernous angiomas being subject to frame-based, stereotactically aided resection are included in this survey. Based on the stereotactic-fused image, set entry and target point aimed at the rim of the cavernoma were calculated. A minicraniotomy (< 3 cm in diameter) was performed followed by positioning of the stereotactic needle. Following the needle in situ the cavernous angioma was localized and resected. Assets and drawbacks of the stereotactic-aided approach were evaluated, patients were analyzed for surgery-related neurological deficits and completeness of resection. RESULTS: Complete resection was achieved in all ten patients verified by post-surgery MRI imaging. The surgical procedure itself was only slightly aggravated by the stereotactic equipment. No adverse events such as bleedings or infections were observed in our series. CONCLUSIONS: Stereotactically guided, minimally invasive resection of deep seated and small cavernous angiomas is accurate and effective. The frame-based stereotactic guidance requires some additional time and effort which seems justified only for deep seated and small cavernous angiomas. Frameless neuronavigation is a common tool in cavernoma surgery and its spatial resolution is sufficient for the majority of cases.

Meningioangiomatosis in a patient with progressive focal neurological deficit-case report and review of literature.

Meningioangiomatosis (MA) represents a vascular hamartoma accompanied by meningothelial cell proliferation. It generally becomes symptomatic with difficult to control seizures, though in some patients it may be asymptomatic. We present the case of a 41-year-old male patient with a newly developed central distal monoparesis of the left leg. Cranial magnetic resonance imaging (MRI) and further diagnostic characterization via (18)F-Fluoro-Ethyl-Tyrosine positron emission tomography ((18)F-FET-PET) indicated a low-grade glioma. Histopathological diagnosis revealed a meningioangiomatosis. The clinical, radiological and neuropathological findings of this rare constellation are described and discussed with the actual literature.

The impact of brain shift in deep brain stimulation surgery: observation and obviation.

BACKGROUND: The impact of brain shift on deep brain stimulation surgery is considerable. In DBS surgery, brain shift is mainly caused by CSF loss. CSF loss can be estimated by post-surgical intracranial air. Different approaches and techniques exist to minimize CSF loss and hence brain shift. The aim of this survey was to investigate the extent and dynamics of CSF loss during DBS surgery, analyze its impact on final electrode position, and describe a simple and inexpensive method of burr hole closure. METHODS: Sixty-six patients being treated with deep brain stimulation were retrospectively analyzed for this treatise. During surgery, CSF loss was minimized using bone wax as a burr hole closure. Intracranial air volume was calculated based on early post-surgery stereotactic 3D CT and correlated with duration of surgery and electrode deviations derived from post-surgery image fusion. RESULTS: Median early post-surgery intracranial air was 2.1 cm(3) (range 0-35.7 cm(3), SD 8.53 cm(3)). No correlation was found between duration of surgery and CSF-loss (R = 0.078, p = 0.534), indicating that CSF loss mainly occurs early during surgery. Linear regression analysis revealed no significant correlations regarding volume of intracranial air and electrode displacement in any of the three principal axes. No significant difference regarding electrode deviations between first and second side of surgery were observed. CONCLUSIONS: CSF loss mainly occurs during the early phase of DBS surgery. CSF loss during a later phase of surgery can be effectively averted by burr hole closure. Postoperative intracranial air volumes up to 35 cm(3) did not result in significant electrode displacement in our series. Comparing our results to studies previously published on this subject, burr hole closure using bone wax is highly effective.

Traumatic brain injuries in the ancient Egypt: insights from the Edwin Smith Papyrus.

BACKGROUND: Traumatic brain injury (TBI) is probably as old as human beings. The Edwin Smith Papyrus is the first treatise describing the treatment of patients with TBI and allows insights into the medical examination and treatment of head-injured patients in ancient Egypt. METHOD: Clinical, diagnostic, and therapeutic principles in the treatment of TBI in ancient Egypt were analyzed. RESULTS: Methodically, cases and the presentation of each case are neatly classified within the papyrus. The papyrus contains the first description of the brain, pulsations, contusions as the result of TBI, the dura, and cerebrospinal fluid, revealing a more or less sophisticated knowledge of cerebral anatomy. Furthermore, ancient physicians examined wounds, fractures, signs of basal skull fractures, and associated neurological or infectious symptoms, and classified the injury pattern according to their prognosis. Therapeutic options at this time seemed to have been limited. CONCLUSIONS: The Edwin Smith Papyrus reveals astonishing observation skill when considering the methods and limits of ancient times. These physicians were able to recognize many symptoms of TBI and assign them a prognostic value.

A comparative study of perfusion CT and 99m Tc-HMPAO SPECT measurement to assess cerebrovascular reserve capacity in patients with internal carotid artery occlusion.

BACKGROUND AND PURPOSE: Patients with internal carotid artery (ICA) occlusion can demonstrate impaired cerebral vascular reserve (CVR). The detection of CVR using single photon emission CT (SPECT) is nowadays widely accepted as a predictor in the diagnostic pathway in patients considered for cerebral revascularization. Recently perfusion CT (PCT) gained widely acceptance in stroke imaging. The present study was aimed at comparing the results of perfusion CT (PCT) and 99m Tc-HMPAO SPECT with acetazolamide challenge in patients with ICA occlusion. METHODS: 13 patients were included in the prospective evaluation. Both PCT and 99m Tc-HMPAO SPECT were performed before and after the administration of acetazolamide. In detail, regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), adapted time to peak (Tmax) and mean transit times (MTT) were compared with SPECT data. - RESULTS: 99m Tc-HMPAO SPECT demonstrated an impairment of CVR in six patients. A preserved CVR was present in seven patients. All patients with impaired CVR proven by SPECT had a delayed MTT (mean +2.98 s) and a delayed Tmax (mean + 5.9 s), (both p <0.005 compared with the non occluded side). 66% of patients with impaired CVR in SPECT showed a complete correlation of Tmax measurements in PCT with a high positive predictive value (PPV: 88.8%). - CONCLUSION: The prospective study demonstrated a highly significant correlation of perfusion parameters as detected by 99m Tc-HMPAO SPECT and the Tmax as detected by PCT in patients with ICA occlusion. Therefore this easy-to-perform technique seems to be an adequate method for the evaluation of cerebral perfusion in patients with ICA occlusion.

Heat-shock protein 70-dependent dendritic cell activation by 5-aminolevulinic acid-mediated photodynamic treatment of human glioblastoma spheroids in vitro.

BACKGROUND: T-cell responses contribute to the anti-tumoural effect of photodynamic therapy (PDT). For such responses to occur, dendritic cells (DCs) have to migrate to the tumour, take up tumour antigens and respond to danger signals with maturation, before they engage in T-cell activation. Here, we have studied the effect of 5-aminolevulinic acid (ALA)-mediated PDT on DCs in vitro in a human spheroid model of glioblastoma (GB). METHODS: Spheroids of the GB cell lines U87 and U251 were treated with ALA/PDT, and effects on attraction, uptake of tumour antigens and maturation of DCs were studied. To block heat-shock protein-70 (HSP-70) on the spheroids, neutralising antibodies were used. RESULTS: 5-Aminolevulinic acid /PDT-treated GB spheroids attracted DCs that acquired tumour antigens from the spheroids effectively. Moreover, co-culture with ALA/PDT-treated spheroids induced DC maturation as indicated by the upregulation of CD83 and co-stimulatory molecules as well as increased T-cell stimulatory activity of the DCs. Heat-shock protein-70 was upregulated on the spheroids after ALA/PDT treatment. Uptake of tumour antigens and DC maturation induced by the ALA/PDT-treated spheroids were inhibited when HSP-70 was blocked. CONCLUSION: ALA/PDT treatment of glioma spheroids promotes the three initial steps of the afferent phase of adaptive immunity, which is at least partially mediated by HSP-70.

A short review of game theory for neurosurgeons.

Neurosurgery and medicine in general are increasingly dominated by economic factors and considerations. Physicians themselves have partially adopted economic terminology, although they rarely have a profound knowledge of economics. Today game theory is one of the most important factors driving microeconomics, which is the competition for limited resources within a small group of individuals. The purpose of this article is to give a short introduction to game theory and its application to the healthcare system. The Prisoner's Dilemma considers strategies between two persons. In the classic version two burglars are caught. Each could confess and be released from jail if the other does not confess--who will then get a long term in prison. If both confess, both get an intermediate time in jail, and if no one confesses, both get a mild sentence. Wanting to be released from jail, they both confess and get the intermediate term in prison. This remarkable result, initially described by John von Neumann in 1928 and showing that individually rational actions can result in both persons becoming worse off, had a great impact on modern social science. Other scenarios are more complex. The Nash Equilibrium is a wider concept. If there is a set of strategies with the property that no player can benefit by changing his strategy while the other players keep their strategies unchanged, then that set of strategies and the corresponding payoffs constitute the Nash Equilibrium. Another concept particularly important in sociology is the Pareto criterion. If no one can be made better off without making somebody else worse off, then that outcome is Pareto optimal. Respecting these basic principles is a necessary precondition for successful deals and cooperative projects.

Influence of blood pressure variability on short-term outcome in patients with subarachnoid hemorrhage.

OBJECTIVE: Several recent investigations have demonstrated a significant influence of blood pressure variation during the immediate period after stroke. The present study was conducted to evaluate the effect of blood pressure, intracranial pressure and cerebral perfusion pressure variation on short-term outcome in patients after severe subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: 105 patients suffering from severe SAH were included in the study. The Glasgow Coma Scale (GCS) Score and World Federation of Neurological Surgeons (WFNS) grading were used to describe the patients on admission, and the short-term outcome was assessed using the GCS and the Glasgow Outcome Scale (GOS) Score. In all patients, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were continuously recorded. For each recorded parameter (SBP, DBP, MAP, ICP and CPP) the first recorded value was defined as the baseline value (bas). The minimum (min), maximum (max) and average (mean) value was identified from all recorded values for each parameter and the range between minimum and maximum value was calculated (range). Based on the individual parameter range (absolute values) the variability of successive values was determined as the successive variation (sv). Finally, the values obtained were correlated to clinical outcome and analyzed statistically. RESULTS: In 105 patients the database offered an average of 330.4 single readings (median 318). SBPmax, and SBPrange were significantly lower in the group with an improving short-term GCS than in the group with constant or deteriorating GCS ( P=0.0079 and P=0.0006, respectively). SBPmin was significantly higher in the improved GCS group (P=0.0235). With regard to successive variation (SBPsv) we could not demonstrate a significant difference between both groups (mean SBPsv 15.7 vs. 14.7; P=0.1223), and no correlation with either GCS at discharge (P=0.91) or GOS at discharge (P=0.841) was detectable. There was no statistically significant difference in CPP and ICP between both outcome groups. CONCLUSION: Systolic blood pressure levels and range appear to be of importance for the management of patients suffering from SAH and may influence patient outcome.