Meta-topologies define distinct anatomical classes of brain tumours linked to histology and survival.

The current World Health Organization classification integrates histological and molecular features of brain tumours. The aim of this study was to identify generalizable topological patterns with the potential to add an anatomical dimension to the classification of brain tumours. We applied non-negative matrix factorization as an unsupervised pattern discovery strategy to the fine-grained topographic tumour profiles of 936 patients with neuroepithelial tumours and brain metastases. From the anatomical features alone, this machine learning algorithm enabled the extraction of latent topological tumour patterns, termed meta-topologies. The optimal part-based representation was automatically determined in 10 000 split-half iterations. We further characterized each meta-topology's unique histopathologic profile and survival probability, thus linking important biological and clinical information to the underlying anatomical patterns. In neuroepithelial tumours, six meta-topologies were extracted, each detailing a transpallial pattern with distinct parenchymal and ventricular compositions. We identified one infratentorial, one allopallial, three neopallial (parieto-occipital, frontal, temporal) and one unisegmental meta-topology. Each meta-topology mapped to distinct histopathologic and molecular profiles. The unisegmental meta-topology showed the strongest anatomical-clinical link demonstrating a survival advantage in histologically identical tumours. Brain metastases separated to an infra- and supratentorial meta-topology with anatomical patterns highlighting their affinity to the cortico-subcortical boundary of arterial watershed areas.Using a novel data-driven approach, we identified generalizable topological patterns in both neuroepithelial tumours and brain metastases. Differences in the histopathologic profiles and prognosis of these anatomical tumour classes provide insights into the heterogeneity of tumour biology and might add to personalized clinical decision-making.

Dimensionality Reduction: Foundations and Applications in Clinical Neuroscience.

Advancements in population neuroscience are spurred by the availability of large scale, open datasets, such as the Human Connectome Project or recently introduced UK Biobank. With the increasing data availability, analyses of brain imaging data employ more and more sophisticated machine learning algorithms. However, all machine learning algorithms must balance generalization and complexity. As the detail of neuroimaging data leads to high-dimensional data spaces, model complexity and hence the chance of overfitting increases. Different methodological approaches can be applied to alleviate the problems that arise in high-dimensional settings by reducing the original information into meaningful and concise features. One popular approach is dimensionality reduction, which allows to summarize high-dimensional data into low-dimensional representations while retaining relevant trends and patterns. In this paper, principal component analysis (PCA) is discussed as widely used dimensionality reduction method based on current examples of population-based neuroimaging analyses.

Introduction to Machine Learning in Neuroimaging.

Advancements in neuroimaging and the availability of large-scale datasets enable the use of more sophisticated machine learning algorithms. In this chapter, we non-exhaustively discuss relevant analytical steps for the analysis of neuroimaging data using machine learning (ML), while the field of radiomics will be addressed separately (c.f., Chap. 18 -Radiomics). Broadly classified into supervised and unsupervised approaches, we discuss the encoding/decoding framework, which is often applied in cognitive neuroscience, and the use of ML for the analysis of unlabeled data using clustering.

Foundations of Time Series Analysis.

For almost a century, classical statistical methods including exponential smoothing and autoregression integrated moving averages (ARIMA) have been predominant in the analysis of time series (TS) and in the pursuit of forecasting future events from historical data. TS are chronological sequences of observations, and TS data are therefore prevalent in many aspects of clinical medicine and academic neuroscience. With the rise of highly complex and nonlinear datasets, machine learning (ML) methods have become increasingly popular for prediction or pattern detection and within neurosciences, including neurosurgery. ML methods regularly outperform classical methods and have been successfully applied to, inter alia, predict physiological responses in intracranial pressure monitoring or to identify seizures in EEGs. Implementing nonparametric methods for TS analysis in clinical practice can benefit clinical decision making and sharpen our diagnostic armory.

The Artificial Intelligence Doctor: Considerations for the Clinical Implementation of Ethical AI.

The applications of artificial intelligence (AI) and machine learning (ML) in modern medicine are growing exponentially, and new developments are fast-paced. However, the lack of trust and appropriate legislation hinder its clinical implementation. Recently, there is a clear increase of directives and considerations on Ethical AI. However, most literature broadly deals with ethical tensions on a meta-level without offering hands-on advice in practice. In this article, we non-exhaustively cover basic practical guidelines regarding AI-specific ethical aspects, including transparency and explicability, equity and mitigation of biases, and lastly, liability.

Choroidal artery ischemic events after temporal lobe epilepsy surgery: clinical outcome, quality of life, and surgical pitfalls.

OBJECTIVE: Ischemic events within the territory of the choroidal artery are an important cause of morbidity after temporal lobe epilepsy (TLE) surgery. The aim of the present study was to evaluate the rate of these ischemic events, their clinical presentation, and impact on patients' health-related quality of life (HRQoL) after TLE surgery. METHODS: Four hundred twenty-two consecutive patients undergoing temporal resections for drug-resistant TLE were retrospectively analyzed. All patients underwent presurgical multidisciplinary assessment using a standard protocol comprising clinical, neuroradiological, neuropsychological, and EEG data. Postoperative complications with corresponding imaging, neurological deficits, and disease-specific HRQoL questionnaires were evaluated. RESULTS: The overall complication rate was 7.8% (n = 33). Fourteen patients (3.3%) suffered from ischemic events causing 6 permanent motor deficits, 3 with permanent aphasias, and 6 visual field defects that exceeded quadrantanopia. In 8 patients with anterior choroidal artery infarction, accounting for 57% of all ischemic events, infarction volume correlated positively with the occurrence of new permanent neurological deficits (8666 vs 1692 mm3, p = 0.032). Despite the occurrence of ischemic events, HRQoL improved in 71% of patients. However, infarction volume showed a negative correlation trend with HRQoL (Pearson's r = -0.390, p = 0.094). There was a trend toward increased risk for ischemic events in patients who underwent selective amygdalohippocampectomy compared to patients who underwent anterior temporal lobectomy or temporal lesionectomy (RR 0.96, 95% CI 0.93-0.99, p = 0.08). CONCLUSIONS: Choroidal artery infarctions are rare but relevant complications after TLE surgery, presenting with variable clinical courses ranging from devastating neurological deterioration to complete recovery. Despite the occurrence of postoperative infarction, most patients report improvement of HRQoL after TLE surgery. This study showed that the type of surgery appears to modulate the risk for these ischemic events.

18F-FET-PET-guided gross total resection improves overall survival in patients with WHO grade III/IV glioma: moving towards a multimodal imaging-guided resection.

PURPOSE: PET using radiolabeled amino acid [18F]-fluoro-ethyl-L-tyrosine (FET-PET) is a well-established imaging modality for glioma diagnostics. The biological tumor volume (BTV) as depicted by FET-PET often differs in volume and location from tumor volume of contrast enhancement (CE) in MRI. Our aim was to investigate whether a gross total resection of BTVs defined as < 1 cm3 of residual BTV (PET GTR) correlates with better oncological outcome. METHODS: We retrospectively analyzed imaging and survival data from patients with primary and recurrent WHO grade III or IV gliomas who underwent FET-PET before surgical resection. Tumor overlap between FET-PET and CE was evaluated. Completeness of FET-PET resection (PET GTR) was calculated after superimposition and semi-automated segmentation of pre-operative FET-PET and postoperative MRI imaging. Survival analysis was performed using the Kaplan-Meier method and the log-rank test. RESULTS: From 30 included patients, PET GTR was achieved in 20 patients. Patients with PET GTR showed improved median OS with 19.3 compared to 13.7 months for patients with residual FET uptake (p = 0.007; HR 0.3; 95% CI 0.12-0.76). This finding remained as independent prognostic factor after performing multivariate analysis (HR 0.19, 95% CI 0.06-0.62, p = 0.006). Other survival influencing factors such as age, IDH-mutation, MGMT promotor status, and adjuvant treatment modalities were equally distributed between both groups. CONCLUSION: Our results suggest that PET GTR improves the OS in patients with WHO grade III or IV gliomas. A multimodal imaging approach including FET-PET for surgical planning in newly diagnosed and recurrent tumors may improve the oncological outcome in glioma patients.

Adaptation of a semantic picture-word interference paradigm for future language mapping with transcranial magnetic stimulation: A behavioural study.

Neuro-navigated transcranial magnetic stimulation (TMS) helps to identify language-related cortical regions prior to brain tumour surgery. We adapted a semantic picture-word interference (PWI) paradigm from psycholinguistics to high-resolution TMS language mapping which prospectively can be used to specifically address the level of semantic processing. In PWI, pictures are presented along with distractor words which facilitate or inhibit the lexical access to the picture name. These modulatory effects of distractors can be annihilated in language-sensitive areas by the inhibitory effects of TMS on language processing. The rationale here is to observe the distractor effect without active stimulation and then to observe presumably its elimination by interference of the TMS stimulation. The special requirements to use PWI in this setting are (1) identifying word material for accelerating reliably naming latencies, choosing (2) the ideal presentation modality, and (3) the appropriate timing of distractor presentation. These are then controlled in real TMS language mapping. To adapt a semantic PWI naming paradigm for TMS application we employed 30 object-pictures in spoken German language. Part-whole associative semantic related or unrelated distractors were presented in two experiments including 15 healthy volunteers each, once auditorily and once visually. Data analysis across the entire stimulus set revealed a trend for facilitation in the visual condition, whereas no effects were observed for auditory distractors. In a sub-set, we found a significant facilitation effect for visual semantic distractors. Thus, with this study we provide a well-controlled item set for future studies implementing effective TMS language mapping applying visual semantic PWI.

The association of patient age with postoperative morbidity and mortality following resection of intracranial tumors.

Introduction: The postoperative functional status of patients with intracranial tumors is influenced by patient-specific factors, including age. Research question: This study aimed to elucidate the association between age and postoperative morbidity or mortality following the resection of brain tumors. Material and methods: A multicenter database was retrospectively reviewed. Functional status was assessed before and 3-6 months after tumor resection by the Karnofsky Performance Scale (KPS). Uni- and multivariable linear regression were used to estimate the association of age with postoperative change in KPS. Logistic regression models for a ≥10-point decline in KPS or mortality were built for patients ≥75 years. Results: The total sample of 4864 patients had a mean age of 56.4 â€‹± â€‹14.4 years. The mean change in pre-to postoperative KPS was -1.43. For each 1-year increase in patient age, the adjusted change in postoperative KPS was -0.11 (95% CI -0.14 - - 0.07). In multivariable analysis, patients ≥75 years had an odds ratio of 1.51 to experience postoperative functional decline (95%CI 1.21-1.88) and an odds ratio of 2.04 to die (95%CI 1.33-3.13), compared to younger patients. Discussion: Patients with intracranial tumors treated surgically showed a minor decline in their postoperative functional status. Age was associated with this decline in function, but only to a small extent. Conclusion: Patients ≥75 years were more likely to experience a clinically meaningful decline in function and about two times as likely to die within the first 6 months after surgery, compared to younger patients.

Risk of postprocedural intracerebral hemorrhage in patients with ruptured cerebral aneurysms after treatment with antiplatelet agents.

OBJECTIVE: Endovascular treatment of ruptured cerebral aneurysms frequently requires antiplatelet medication to prevent thromboembolism. This might raise concern regarding the risk of postprocedural hemorrhage (pH), e.g. from placement of intracranial probes. We explored the risk of PH associated with standard antiplatelet therapy (sAP: acetylsalicylic acid, and/or clopidogrel) in the context of aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We retrospectively reviewed a total of 146 consecutive cases with cerebral aneurysms treated between 1/2011-12/2015, and distinguished between minor (0.5 cm3) - 4 cm3) or major (> 4 cm3) PH occurring within four weeks after intervention. A separate analysis included hemorrhages related to placement of intracranial probes and drainages in the subgroup of 99 cases with such surgical interventions (pPH). Clinical outcome was assessed via Glasgow Outcome Scale (GOS) twelve months after aSAH. RESULTS: A total of 49 cases (33.6%) in the overall sample sustained PH, there were 19 cases of pPH. Multifactorial analyses yielded sAP as an independent predictor for minor, but not major PH (p < 0.001 vs. p = 0.829), with comparable results for pPH (p = 0.001 vs. p = 0.184). sAP did not influence the clinical outcome in either group. CONCLUSIONS: sAP was associated with a higher rate of minor PH and, more specifically, of minor pPH. However, it was neither accompanied by the occurrence of major hemorrhages nor by unfavorable clinical outcome. Future prospective studies should confirm these observations and hemorrhage risks associated with extended anticoagulation regimes after complex interventions and intra-arterial vasospasm therapy should be explored in order to facilitate interdisciplinary decision-making in aSAH.

Quality of life in elderly patients after surgery for drug-resistant epilepsy - The impact of seizure outcome, neurological deficits and anxiety.

INTRODUCTION: Health related quality of life (HRQoL) has become a pivotal outcome parameter after surgery for drug-resistant epilepsy. The aim of the study was to investigate HRQoL and its relationship to seizure outcome, neurological deficits and anxiety after epilepsy surgery in a specific subpopulation of elderly patients. METHODS: A total of 85 elderly patients (older than 50 years) answered a standardized HRQoL questionnaire one year after epilepsy surgery. The questionnaire addressed the present self-assessed HRQoL in four subdomains (physical function, cognitive function, mood, social interaction). The questionnaire was based on the "Epilepsy Surgery Inventory-55", adapted for use in German speaking patients and validated by the QOLIE -10 and Beck Depression Inventory. RESULTS: A total of 51 patients (60%) were completely seizure free (ILAE1) at last available outcome (LAO). Permanent neurological deficits were observed in 8 patients (7%). Correlation analysis confirmed significant association between seizure outcome and overall HRQoL (r = -0.368, p < .001). New permanent neurological deficits showed impact on both HRQoL and the "cognitive function" subdomain. Anxiety and subjective assessment of postoperative status were strongly correlated with overall HRQoL (r = 0.692, p < .001 and r = 0.591, p < .001 respectively) and remained as independent prognostic factors in a multivariate regression analysis. CONCLUSION: Surgery for drug-resistant epilepsy in elderly improves patients' HRQoL. Both seizure freedom and new neurological deficits influence overall HRQoL. Interestingly, anxiety and patients' subjective assessment of postoperative status showed the highest impact on HRQoL in this subpopulation of epilepsy patients.

Development and external validation of a clinical prediction model for functional impairment after intracranial tumor surgery.

OBJECTIVE: Decision-making for intracranial tumor surgery requires balancing the oncological benefit against the risk for resection-related impairment. Risk estimates are commonly based on subjective experience and generalized numbers from the literature, but even experienced surgeons overestimate functional outcome after surgery. Today, there is no reliable and objective way to preoperatively predict an individual patient's risk of experiencing any functional impairment. METHODS: The authors developed a prediction model for functional impairment at 3 to 6 months after microsurgical resection, defined as a decrease in Karnofsky Performance Status of ≥ 10 points. Two prospective registries in Switzerland and Italy were used for development. External validation was performed in 7 cohorts from Sweden, Norway, Germany, Austria, and the Netherlands. Age, sex, prior surgery, tumor histology and maximum diameter, expected major brain vessel or cranial nerve manipulation, resection in eloquent areas and the posterior fossa, and surgical approach were recorded. Discrimination and calibration metrics were evaluated. RESULTS: In the development (2437 patients, 48.2% male; mean age ± SD: 55 ± 15 years) and external validation (2427 patients, 42.4% male; mean age ± SD: 58 ± 13 years) cohorts, functional impairment rates were 21.5% and 28.5%, respectively. In the development cohort, area under the curve (AUC) values of 0.72 (95% CI 0.69-0.74) were observed. In the pooled external validation cohort, the AUC was 0.72 (95% CI 0.69-0.74), confirming generalizability. Calibration plots indicated fair calibration in both cohorts. The tool has been incorporated into a web-based application available at https://neurosurgery.shinyapps.io/impairment/. CONCLUSIONS: Functional impairment after intracranial tumor surgery remains extraordinarily difficult to predict, although machine learning can help quantify risk. This externally validated prediction tool can serve as the basis for case-by-case discussions and risk-to-benefit estimation of surgical treatment in the individual patient.

Hemispheric Dominance for Language and Side Effects in Mapping the Inferior Frontal Junction Area with Transcranial Magnetic Stimulation.

BACKGROUND AND STUDY AIMS: Language mapping by navigated transcranial magnetic stimulation (TMS) is commonly applied over the left language-dominant hemisphere to indicate the language-related cortex. Detailed language mapping of Broca's region including stimulation targets in the immediate vicinity to the premotor cortex may raise concern about confounding unspecific motor effects. We performed interhemispheric comparisons to delineate such possible unspecific effects from true TMS-induced language inhibition. MATERIAL AND METHODS: Fifteen healthy German speakers named object pictures during navigated TMS over a left- and right-hemispheric target array covering the left inferior frontal junction area. Six mapping repetitions were conducted per hemisphere. Order of stimulation side was randomized between participants. Self-rating of discomfort was assessed after each stimulation; language errors and motor side effects were evaluated offline. RESULTS: Naming errors were observed significantly more frequently during left- than right-hemispheric stimulation. The same pattern was found for the most frequent error category of performance errors. Hierarchical cluster analyses of normalized ratings of error severity revealed a clear focus of TMS susceptibility for language inhibition in object naming at the dorsoposterior target sites only in the left hemisphere. We found no statistical difference in discomfort ratings between both hemispheres and also no interhemispheric difference in motor side effects, but we observed significantly stronger muscle contractions of the eyes as compared with the mouth. CONCLUSION: Our results of (1) unspecific pre-/motor effects similarly induced in both hemispheres, and (2) a specific focus of TMS susceptibility in the language-dominant hemisphere render any substantial contribution of nonlanguage-specific effects in TMS language mapping of the inferior frontal junction area highly unlikely.

Phonological picture-word interference in language mapping with transcranial magnetic stimulation: an objective approach for functional parcellation of Broca's region.

Functional imaging data suggest different regions for semantic, syntactic, and phonological processing in an anterior-to-posterior direction along the inferior frontal gyrus. Language mapping by use of neuro-navigated transcranial magnetic stimulation (TMS) is frequently applied in clinical research to identify language-related cortical regions. Recently, we proposed a high spatial resolution approach for more detailed language mapping of cortical sub-areas such as Broca's region. Here, we employed a phonological picture-word interference paradigm in healthy subjects to reveal functional specialization in Broca's region for phonological processing. The behavioral phonological priming effect is characterized by accelerated naming responses to target pictures accompanied by phonologically related auditory distractor words. We hypothesized that the inhibitory effects of TMS on language processing would reduce phonological priming only at stimulation sites involved in phonological processing. In active as compared to sham TMS, we found reduced phonological facilitation specifically at sites overlapping with the probabilistic cytoarchitectonic area 44. Our findings complemented functional imaging data by revealing structure-function relationship in Broca's region. The introduction of a reaction time based interference paradigm into TMS language mapping increases the objectivity of the method and allows to explore functional specificity with high temporal resolution. Findings may help to interpret results in clinical applications.

Intraindividual comparison of selective intraarterial versus systemic intravenous 68Ga-DOTATATE PET/CT in patients with inoperable meningioma.

AIM: Here we describe the results of superselective intraarterial application of diagnostic Ga-68-DOTA0,Tyr3-octreotate (Ga-68-DOTATATE) in a series of patients with inoperable WHO grade II meningiomas which were no longer amenable to radiotherapy. METHODS: Four patients with inoperable WHO grade II meningioma underwent systemic venous infusion of Ga-68-DOTATATE followed by PET/CT. Ga-68-DOTATATE application was repeated intraarterially via transfemoral catheterization of vessels supplying the meningioma and another PET/CT was performed. RESULTS: Selective arterial infusion of Ga-68-DOTATATE increased the median value for the maximum standardized uptake value (SUV) by 2.6-fold (median venous: 7.1, median arterial: 21.6; range 2.0-5.0) and the median value for mean SUV by 2.7-fold (median venous: 4.3, median arterial: 11.2; range 1.6-5.6) compared to systemic intravenous infusion. Arterial application was well tolerated by all patients without complications. When compared to liver uptake, intravenous tracer uptake was insufficient for PRRT, whereas tracer uptake after superselective intraarterial tracer injection was sufficient to allow for peptide receptor radionuclide therapy (PRRT) in all patients. CONCLUSION: Insufficient tracer uptake in meningiomas after intravenous application of Ga-68-DOTATATE may be safely increased by a factor of 2-5 using transfemoral selective intraarterial tracer application.

Propofol Pharmacodynamics and Bispectral Index During Key Moments of Awake Craniotomy.

BACKGROUND: During awake craniotomy, the patient's language centers are identified by neurological testing requiring a fully awake and cooperative patient. Hence, anesthesia aims for an unconscious patient at the beginning and end of surgery but an awake and responsive patient in between. We investigated the plasma (Cplasma) and effect-site (Ceffect-site) propofol concentration as well as the related Bispectral Index (BIS) required for intraoperative return of consciousness and begin of neurological testing. MATERIALS AND METHODS: In 13 patients, arterial Cplasma were measured by high-pressure liquid chromatography and Ceffect-site was estimated based on the Marsh and Schnider pharmacokinetic/dynamic (pk/pd) models. The BIS, Cplasma and Ceffect-site were compared during the intraoperative awakening period at designated time points such as return of consciousness and start of the Boston Naming Test (neurological test). RESULTS: Return of consciousness occurred at a BIS of 77±7 (mean±SD) and a measured Cplasma of 1.2±0.4 µg/mL. The Marsh model predicted a significantly (P<0.001) higher Cplasma of 1.9±0.4 µg/mL as compared with the Schnider model (Cplasma=1.4±0.4 µg/mL) at return of consciousness. Neurological testing was possible as soon as the BIS had increased to 92±6 and measured Cplasma had decreased to 0.8±0.3 µg/mL. This translated into a time delay of 23±12 minutes between return of consciousness and begin of neurological testing. At begin of neurological testing, Cplasma according to Marsh (Cplasma=1.3±0.5 µg/mL) was significantly (P=0.002) higher as compared with the Schnider model (Cplasma=1.0±0.4 µg/mL). CONCLUSIONS: To perform intraoperative neurological testing, patients are required to be fully awake with plasma propofol concentrations as low as 0.8 µg/mL. Following our clinical setup, the Schnider pk/pd model estimates propofol concentrations significantly more accurate as compared with the Marsh model at this neurologically crucial time point.

High-resolution language mapping of Broca's region with transcranial magnetic stimulation.

Broca's region, corresponding roughly to cytoarchitectonic areas 44 and 45 in the inferior frontal cortex, holds a multifunctional role in language processing, as shown, e.g., by functional imaging data. Neuro-navigated transcranial magnetic stimulation (TMS) enables complementary non-invasive mapping of cortical functions with high spatial resolution. Here, we report on detailed TMS language mapping of Broca's region in 12 healthy participants. The test protocol with an object naming task was adapted for high-resolution and semi-quantitative mapping of TMS-induced effects on speech and language performance. Hierarchical cluster analysis of normalized ratings of error frequency and severity revealed a clear focus of TMS impact at dorso-posterior target sites, close to the inferior frontal junction. Adjacent clusters of moderate and slightly affected stimulation sites yielded a posterosuperior-to-anteroinferior gradient of TMS susceptibility. Our findings indicate that the part of Broca's region most susceptible to TMS-induced language inhibition in object naming is located in the dorsal area 44.

Dissociated Crossed Speech Areas in a Tumour Patient.

In the past, the eloquent areas could be deliberately localised by the invasive Wada test. The very rare cases of dissociated crossed speech areas were accidentally found based on the clinical symptomatology. Today functional magnetic resonance imaging (fMRI)-based imaging can be employed to non-invasively localise the eloquent areas in brain tumour patients for therapy planning. A 41-year-old, left-handed man with a low-grade glioma in the left frontal operculum extending to the insular cortex, tension headaches, and anomic aphasia over 5 months underwent a pre-operative speech area localisation fMRI measurement, which revealed the evidence of the transhemispheric disposition, where the dominant Wernicke speech area is located on the left and the Broca's area is strongly lateralised to the right hemisphere. The outcome of the Wada test and the intraoperative cortico-subcortical stimulation mapping were congruent with this finding. After tumour removal, language area function was fully preserved. Upon the occurrence of brain tumours with a risk of impaired speech function, the rare dissociate crossed speech areas disposition may gain a clinically relevant meaning by allowing for more extended tumour removal. Hence, for its identification, diagnostics which take into account both brain hemispheres, such as fMRI, are recommended.

Comparison of propofol pharmacokinetic and pharmacodynamic models for awake craniotomy: A prospective observational study.

BACKGROUND: Anaesthesia for awake craniotomy aims for an unconscious patient at the beginning and end of surgery but a rapidly awakening and responsive patient during the awake period. Therefore, an accurate pharmacokinetic/pharmacodynamic (PK/PD) model for propofol is required to tailor depth of anaesthesia. OBJECTIVE: To compare the predictive performances of the Marsh and the Schnider PK/PD models during awake craniotomy. DESIGN: A prospective observational study. SETTING: Single university hospital from February 2009 to May 2010. PATIENTS: Twelve patients undergoing elective awake craniotomy for resection of brain tumour or epileptogenic areas. INTERVENTION: Arterial blood samples were drawn at intervals and the propofol plasma concentration was determined. MAIN OUTCOME MEASURES: The prediction error, bias [median prediction error (MDPE)] and inaccuracy [median absolute prediction error (MDAPE)] of the Marsh and the Schnider models were calculated. The secondary endpoint was the prediction probability PK, by which changes in the propofol effect-site concentration (as derived from simultaneous PK/PD modelling) predicted changes in anaesthetic depth (measured by the bispectral index). RESULTS: The Marsh model was associated with a significantly (P = 0.05) higher inaccuracy (MDAPE 28.9 ± 12.0%) than the Schnider model (MDAPE 21.5 ± 7.7%) and tended to reach a higher bias (MDPE Marsh -11.7 ± 14.3%, MDPE Schnider -5.4 ± 20.7%, P = 0.09). MDAPE was outside of accepted limits in six (Marsh model) and two (Schnider model) of 12 patients. The prediction probability was comparable between the Marsh (PK 0.798 ± 0.056) and the Schnider model (PK 0.787 ± 0.055), but after adjusting the models to each individual patient, the Schnider model achieved significantly higher prediction probabilities (PK 0.807 ± 0.056, P = 0.05). CONCLUSION: When using the 'asleep-awake-asleep' anaesthetic technique during awake craniotomy, we advocate using the PK/PD model proposed by Schnider. Due to considerable interindividual variation, additional monitoring of anaesthetic depth is recommended. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT 01128465.

Can in-vitro chemoresponse assays help find new treatment regimens for malignant gliomas?

Various in-vitro chemosensitivity and resistance assays (CSRAs) have been demonstrated to be helpful decision aids for non-neurological tumors. Here, we evaluated the performance characteristics of two CSRAs for glioblastoma (GB) cells. The chemoresponse of fresh GB cells from 30 patients was studied in vitro using the ATP tumor chemoresponse assay and the chemotherapy resistance assay (CTR-Test). Both assay platforms provided comparable results. Of seven different chemotherapeutic drugs and drug combinations tested in vitro, treosulfan plus cytarabine (TARA) was the most effective, followed by nimustine (ACNU) plus teniposide (VM26) and temozolomide (TMZ). Whereas ACNU/VM26 and TMZ have proven their clinical value for malignant gliomas in large randomized studies, TARA has not been successful in newly diagnosed gliomas. This seeming discrepancy between in vitro and clinical result might be explained by the pharmacological behavior of treosulfan. Our results show reasonable agreement between two cell-based CSRAs. They appear to confirm the clinical effectiveness of drugs used in GB treatment as long as pharmacological preconditions such as overcoming the blood-brain barrier are properly considered.