Drug uptake in a rodent sarcoma model after intravenous injection or isolated lung perfusion of free/liposomal doxorubicin.

The distribution of free and liposomal doxorubicin (Liporubicin) administered by intravenous injection (IV) or isolated lung perfusion (ILP) was compared in normal and tumor tissues of sarcoma bearing rodent lungs. A single sarcomatous tumor was generated in the left lung of 35 Fischer rats, followed 10 days later by left-sided ILP (n=20) or IV drug administration (n=12), using 100 microg and 400 microg free or liposomal doxorubicin, respectively. The tumor and lung tissue drug concentration was measured by HPLC. Free doxorubicin administered by ILP resulted in a three-fold (100 microg) and 10-fold (400 microg) increase of the drug concentration in the tumor and normal lung tissue compared to IV administration. In contrast, ILP with Liporubicin resulted in a similar drug uptake in the tumor and lung tissue compared to IV injection. For both drug formulations and dosages, ILP resulted in a higher tumor to lung tissue drug ratio but also in a higher spatial heterogeneity of drug distribution within the lung compared to IV administration. ILP resulted in a higher tumor to lung tissue drug ratio and in a more heterogeneous drug distribution within the lung compared to IV drug administration.

Preliminary regional rockfall hazard mapping using LIDAR-based slope frequency distribution and CONEFALL modeling

A factor limiting preliminary rockfall hazard mapping at regional scale is often the lack of knowledge of potential source areas. Nowadays, high resolution topographic data (LiDAR) can account for realistic landscape details even at large scale. With such fine-scale morphological variability, quantitative geomorphometric analyses become a relevant approach for delineating potential rockfall instabilities. Using digital elevation model (DEM)-based ?slope families? concept over areas of similar lithology and cliffs and screes zones available from the 1:25,000 topographic map, a susceptibility rockfall hazard map was drawn up in the canton of Vaud, Switzerland, in order to provide a relevant hazard overview. Slope surfaces over morphometrically-defined thresholds angles were considered as rockfall source zones. 3D modelling (CONEFALL) was then applied on each of the estimated source zones in order to assess the maximum runout length. Comparison with known events and other rockfall hazard assessments are in good agreement, showing that it is possible to assess rockfall activities over large areas from DEM-based parameters and topographical elements.

Dependence of brain intravoxel incoherent motion perfusion parameters on the cardiac cycle.

Measurement of microvascular perfusion with Intravoxel Incoherent Motion (IVIM) MRI is gaining interest. Yet, the physiological influences on the IVIM perfusion parameters ("pseudo-diffusion" coefficient D*, perfusion fraction f, and flow related parameter fD*) remain insufficiently characterized. In this article, we hypothesize that D* and fD*, which depend on blood speed, should vary during the cardiac cycle. We extended the IVIM model to include time dependence of D* = D*(t), and demonstrate in the healthy human brain that both parameters D* and fD* are significantly larger during systole than diastole, while the diffusion coefficient D and f do not vary significantly. The results non-invasively demonstrate the pulsatility of the brain's microvasculature.

Quantitative integration of geophysical and hydraulic data : from the local towards the regional scale range

Des progrès significatifs ont été réalisés dans le domaine de l'intégration quantitative des données géophysique et hydrologique l'échelle locale. Cependant, l'extension à de plus grandes échelles des approches correspondantes constitue encore un défi majeur. Il est néanmoins extrêmement important de relever ce défi pour développer des modèles fiables de flux des eaux souterraines et de transport de contaminant. Pour résoudre ce problème, j'ai développé une technique d'intégration des données hydrogéophysiques basée sur une procédure bayésienne de simulation séquentielle en deux étapes. Cette procédure vise des problèmes à plus grande échelle. L'objectif est de simuler la distribution d'un paramètre hydraulique cible à partir, d'une part, de mesures d'un paramètre géophysique pertinent qui couvrent l'espace de manière exhaustive, mais avec une faible résolution (spatiale) et, d'autre part, de mesures locales de très haute résolution des mêmes paramètres géophysique et hydraulique. Pour cela, mon algorithme lie dans un premier temps les données géophysiques de faible et de haute résolution à travers une procédure de réduction déchelle. Les données géophysiques régionales réduites sont ensuite reliées au champ du paramètre hydraulique à haute résolution. J'illustre d'abord l'application de cette nouvelle approche dintégration des données à une base de données synthétiques réaliste. Celle-ci est constituée de mesures de conductivité hydraulique et électrique de haute résolution réalisées dans les mêmes forages ainsi que destimations des conductivités électriques obtenues à partir de mesures de tomographic de résistivité électrique (ERT) sur l'ensemble de l'espace. Ces dernières mesures ont une faible résolution spatiale. La viabilité globale de cette méthode est testée en effectuant les simulations de flux et de transport au travers du modèle original du champ de conductivité hydraulique ainsi que du modèle simulé. Les simulations sont alors comparées. Les résultats obtenus indiquent que la procédure dintégration des données proposée permet d'obtenir des estimations de la conductivité en adéquation avec la structure à grande échelle ainsi que des predictions fiables des caractéristiques de transports sur des distances de moyenne à grande échelle. Les résultats correspondant au scénario de terrain indiquent que l'approche d'intégration des données nouvellement mise au point est capable d'appréhender correctement les hétérogénéitées à petite échelle aussi bien que les tendances à gande échelle du champ hydraulique prévalent. Les résultats montrent également une flexibilté remarquable et une robustesse de cette nouvelle approche dintégration des données. De ce fait, elle est susceptible d'être appliquée à un large éventail de données géophysiques et hydrologiques, à toutes les gammes déchelles. Dans la deuxième partie de ma thèse, j'évalue en détail la viabilité du réechantillonnage geostatique séquentiel comme mécanisme de proposition pour les méthodes Markov Chain Monte Carlo (MCMC) appliquées à des probmes inverses géophysiques et hydrologiques de grande dimension . L'objectif est de permettre une quantification plus précise et plus réaliste des incertitudes associées aux modèles obtenus. En considérant une série dexemples de tomographic radar puits à puits, j'étudie deux classes de stratégies de rééchantillonnage spatial en considérant leur habilité à générer efficacement et précisément des réalisations de la distribution postérieure bayésienne. Les résultats obtenus montrent que, malgré sa popularité, le réechantillonnage séquentiel est plutôt inefficace à générer des échantillons postérieurs indépendants pour des études de cas synthétiques réalistes, notamment pour le cas assez communs et importants où il existe de fortes corrélations spatiales entre le modèle et les paramètres. Pour résoudre ce problème, j'ai développé un nouvelle approche de perturbation basée sur une déformation progressive. Cette approche est flexible en ce qui concerne le nombre de paramètres du modèle et lintensité de la perturbation. Par rapport au rééchantillonage séquentiel, cette nouvelle approche s'avère être très efficace pour diminuer le nombre requis d'itérations pour générer des échantillons indépendants à partir de la distribution postérieure bayésienne. - Significant progress has been made with regard to the quantitative integration of geophysical and hydrological data at the local scale. However, extending corresponding approaches beyond the local scale still represents a major challenge, yet is critically important for the development of reliable groundwater flow and contaminant transport models. To address this issue, I have developed a hydrogeophysical data integration technique based on a two-step Bayesian sequential simulation procedure that is specifically targeted towards larger-scale problems. The objective is to simulate the distribution of a target hydraulic parameter based on spatially exhaustive, but poorly resolved, measurements of a pertinent geophysical parameter and locally highly resolved, but spatially sparse, measurements of the considered geophysical and hydraulic parameters. To this end, my algorithm links the low- and high-resolution geophysical data via a downscaling procedure before relating the downscaled regional-scale geophysical data to the high-resolution hydraulic parameter field. I first illustrate the application of this novel data integration approach to a realistic synthetic database consisting of collocated high-resolution borehole measurements of the hydraulic and electrical conductivities and spatially exhaustive, low-resolution electrical conductivity estimates obtained from electrical resistivity tomography (ERT). The overall viability of this method is tested and verified by performing and comparing flow and transport simulations through the original and simulated hydraulic conductivity fields. The corresponding results indicate that the proposed data integration procedure does indeed allow for obtaining faithful estimates of the larger-scale hydraulic conductivity structure and reliable predictions of the transport characteristics over medium- to regional-scale distances. The approach is then applied to a corresponding field scenario consisting of collocated high- resolution measurements of the electrical conductivity, as measured using a cone penetrometer testing (CPT) system, and the hydraulic conductivity, as estimated from electromagnetic flowmeter and slug test measurements, in combination with spatially exhaustive low-resolution electrical conductivity estimates obtained from surface-based electrical resistivity tomography (ERT). The corresponding results indicate that the newly developed data integration approach is indeed capable of adequately capturing both the small-scale heterogeneity as well as the larger-scale trend of the prevailing hydraulic conductivity field. The results also indicate that this novel data integration approach is remarkably flexible and robust and hence can be expected to be applicable to a wide range of geophysical and hydrological data at all scale ranges. In the second part of my thesis, I evaluate in detail the viability of sequential geostatistical resampling as a proposal mechanism for Markov Chain Monte Carlo (MCMC) methods applied to high-dimensional geophysical and hydrological inverse problems in order to allow for a more accurate and realistic quantification of the uncertainty associated with the thus inferred models. Focusing on a series of pertinent crosshole georadar tomographic examples, I investigated two classes of geostatistical resampling strategies with regard to their ability to efficiently and accurately generate independent realizations from the Bayesian posterior distribution. The corresponding results indicate that, despite its popularity, sequential resampling is rather inefficient at drawing independent posterior samples for realistic synthetic case studies, notably for the practically common and important scenario of pronounced spatial correlation between model parameters. To address this issue, I have developed a new gradual-deformation-based perturbation approach, which is flexible with regard to the number of model parameters as well as the perturbation strength. Compared to sequential resampling, this newly proposed approach was proven to be highly effective in decreasing the number of iterations required for drawing independent samples from the Bayesian posterior distribution.

Perfusion-CT guided intravenous thrombolysis in patients with unknown-onset stroke: a randomized, double-blind, placebo-controlled, pilot feasibility trial.

INTRODUCTION: Patients with unknown stroke onset are generally excluded from acute recanalisation treatments. We designed a pilot study to assess feasibility of a trial of perfusion computed tomography (PCT)-guided thrombolysis in patients with ischemic tissue at risk of infarction and unknown stroke onset. METHODS: Patients with a supratentorial stroke of unknown onset in the middle cerebral artery territory and significant volume of at-risk tissue on PCT were randomized to intravenous thrombolysis with alteplase (0.9 mg/kg) or placebo. Feasibility endpoints were randomization and blinded treatment of patients within 2 h after hospital arrival, and the correct application (estimation) of the perfusion imaging criteria. RESULTS: At baseline, there was a trend towards older age [69.5 (57-78) vs. 49 (44-78) years] in the thrombolysis group (n = 6) compared to placebo (n = 6). Regarding feasibility, hospital arrival to treatment delay was above the allowed 2 h in three patients (25%). There were two protocol violations (17%) regarding PCT, both underestimating the predicted infarct in patients randomized in the placebo group. No symptomatic hemorrhage or death occurred during the first 7 days. Three of the four (75%) and one of the five (20%) patients were recanalized in the thrombolysis and placebo group respectively. The volume of non-infarcted at-risk tissue was 84 (44-206) cm(3) in the treatment arm and 29 (8-105) cm(3) in the placebo arm. CONCLUSIONS: This pilot study shows that a randomized PCT-guided thrombolysis trial in patients with stroke of unknown onset may be feasible if issues such as treatment delays and reliable identification of tissue at risk of infarction tissue are resolved. Safety and efficiency of such an approach need to be established.

Evaluation of tumor vascularisation in two rat sarcoma models for studying isolated lung perfusion : Injection route determines the origin of tumour vessels

Résumé Introduction: La perfusion isolée cytostatique du poumon est une technique attractive qui permet l'administration des doses élevées d'un agent cytostatique tout en épargnant dans la mesure du possible la circulation systémique. Cependant, la perfusion de l'artère pulmonaire risque d'épargner le territoire pulmonaire vascularisé par l'intermédiaire des artères bronchiques, ce qui pourrait diminuer l'efficacité de ce traitement au cas où la lésion ciblée est vascularisée par les artères bronchiques. Ce travail est destiné au développement d'un modèle tumoral au niveau des poumons de rongeur (rat) porteur d'un sarcome pulmonaire afin de déterminer si la voie d'injection des cellules tumorales (intraveineuse, versus intratumorale) influencera la vascularisation des tumeurs (provenant du système artères pulmonaires ou artères bronchiques). Méthod: Des tumeurs de sarcomes pulmonaires ont été générées par injection d'une suspension cellulaire de sarcome, soit par injection intraveineuse, soit directement dans le parenchyme pulmonaire par thoracotomie. Ensuite, une perfusion isolée du poumon porteur de la tumeur à l'aide de l'encre a été effectuée, soit par l'artère pulmonaire, soit par le système des artères bronchiques. La distribution de l'encre dans les vaisseaux tumoraux ainsi que dans les vaisseaux non tumoraux du poumon adjacent a été investiguée à l'aide d'une analyse histologique des poumons perfusés. Résultat: L'administration intraveineuse et intratumorale de la suspension de cellules tumorales résulte en des tumeurs similaires sur le plan histologique. Néanmoins, l'injection intra-parenchymateuse démontre des tumeurs plus homogènes et avec un développement plus prédictible, était associée à une survie plus longue qu'après injection intraveineuse. Les analyses histologiques après perfusion isolée à l'aide de l'encre démontre que les tumeurs résultant de l'injection intraveineuse ont développé une vascularisation se basant sur le système d'artères pulmonaires tandis que les tumeurs émergeant après injection intraparenchymateuse ont développé une vascularisation provenant du système des artères bronchiques. Conclusion: Ce travail démontre pour la première fois l'importance du mode de génération de tumeurs pulmonaires en ce qui concerne leur future vascularisation, ce qui pourrait avoir un impact sur leur traitement par perfusion isolée du poumon. Abstract Isolated cytostatic lung perfusion (ILP) is an attractive technique allowing delivery of a high-dose of cytostatic agents to the lungs while limiting systemic toxicity. In developing a rat model of ILP, we have analysed the effect of the route of tumour cell injection on the source of tumour vessels. Pulmonary sarcomas were estab¬lished by injecting a sarcoma cell suspension either by the intravenous (i.v.) route or directly into the lung paren¬chyma. Ink perfusion through either pulmonary artery (PA) or bronchial arteries (BA) was performed and the characteristics of the tumour deposits defined. i.v. and direct injection methods induced pulmonary sarcoma nodules, with similar histological features. The intraparenchymal injection of tumour cells resulted in more reli¬able and reproducible tumour growth and was associat¬ed with a longer survival of the animals. i.v. injected tumours developed a PA-derived vascular tree whereas directly injected tumours developed a BA-derived vasculature.

Standardization of Stroke Perfusion CT for Reperfusion Therapy

With the advances in terms of perfusion imaging, the "time is brain" approach used for acute reperfusion therapy in ischemic stroke patients is slowly being replaced by a "penumbra is brain" or "imaging is brain" approach. But the concept of penumbra-guided reperfusion therapy has not been validated. The lack of standardization in penumbral imaging is one of the main contributing factors for this absence of validation. This article reviews the issues underlying the lack of standardization of perfusion-CT for penumbra imaging, and offers avenues to remedy this situation

Perfusion ct based thrombolysis in acute ischaemic stroke

Background Despite use in clinical practice and trials of thrombolysis, a non-contrast CT is not sensitive for identifying penumbral tissue in acute stroke. This study evaluated how it compares with physiological imaging using CT perfusion.Methods 40 imaging datasets with non-contrast CT (NCCT) and perfusion CT (CTP) were retrospectively identified. 2 sets of observers (n¼6) and a neuroradiologist made a blind evaluation of the images. Inter-observer agreement was calculated for identifying ischaemic change on NCCT, and abnormalities on cerebral blood flow, time to peak and cerebral blood volume maps. A prospective cohort of 73 patients with anterior circulation cortical strokes were thrombolysed based on qualitative assessment of penumbral tissue on CTP within 3 h of stroke onset. Functional outcome was assessed at 3 months.Results Inter-rater agreement was moderate (k¼0.54) for early ischaemic change on NCCT. Perfusion maps improved this to substantial for deficit in cerebral blood volume (k¼0.67) and almost perfect for time to peak and cerebral blood flow (both k¼0.87). In the prospective arm, 58.9% of patients with cortical strokes were thrombolysed. There was no significant difference in attainment of complete recovery (p¼0.184) between the thrombolysed and nonthrombolysed group.Conclusions We demonstrate how perfusion CT aids clinical decision- making in acute stroke. Good functional outcomes from thrombolysis can be safely achieved using this physiologically informed approach.

Postoperative cognitive dysfunction POCD, serum anticholinergic activity and intraoperative cerebral perfusion in geriatric patients

Background: Inadequate intraoperative cerebral perfusion and increased serum anticholinergic activity (SAA) have been suggested as possible causes of postoperative cognitive dysfunction (POCD). Methods: 53 patients aged >65 yrs undergoing elective major surgical procedures under standardized general anaesthesia. Cerebral perfusion was monitored with transcranial Doppler and near-infrared spectroscopy. Mx, an index of cerebral autoregulation was calculated based on the correlation of spontaneous changes inmean arterial blood pressure (MAP) and cerebral blood flow velocity. Cognitive function was measured preoperatively and 7 days postoperatively using the CERAD-Neuropsychological Battery. A postoperative decline >1 z-score in at least 2 cognitive variables was defined as POCD. SAA was measured preoperatively and 7 days postoperatively (data available for 38 patients). CRP was measured at the same time points and 2 days postoperatively. Results: Age was 75_7 yrs (mean_SD). 23 patients (43%) developed POCD. There were no statistical significant differences between patients with POCD and without POCD in age (77_7 vs 73_6 yrs), MAP (74_12 vs 78_11 mmHg), cerebral tissue oxygenation indices (67_6 vs 69_4 %) SAA preoperatively (1.74_1.52 vs 1.74_1.21) and 7 days postoperatively (1.90_1.63 vs 1.84_1.39) and CRP preoperatively (32_72 vs 7_9), 2 days postoperatively (176_129 vs 111_69) and 7days postoperatively (53_43 vs 48_25). Patients with POCD had less efficient autoregulation than patients without POCD (Mx 0.55_0.15 vs 0.45_0.20, p = 0.046). However, the percentage of patients with clearly impaired autoregulation (ie, Mx>0.5) was statistically not different between groups (with POCD: 65%; without POCD: 38%; p = 0.06) but there seems to be a trend. Conclusions: Our data on the association between cerebral perfusion and POCD in elderly patients are inconclusive and more patients need to be investigated. In this small group of patients SAA seems not to be associated with POCD.

Distribution of free and liposomal doxorubicin after isolated lung perfusion in a sarcoma model

Rapport de synthèse : Introduction : La perfusion isolée du poumon à l'aide de Doxorubicine libre et une nouvelle forme de Doxorubicine liposomale pégylée (Liporubicine) est comparé en terme de pénétration et accumulation de Doxorubicine dans le tissu tumoral et pulmonaire dans un modèle de rats porteurs de tumeur sarcomateuse au niveau du poumon gauche. Matériel et méthode : Une tumeur sarcomateuse unique a été générée dans le poumon gauche de 39 Fischer rats, suivi 10 jours plus tard, par une perfusion isolée du poumon gauche (n =36) avec Doxorubicine libre (n=18) et Liporubicine (n=18) à une dose de 100 µg (n=9) et 400 µg (n=9) pour chaque formulation de Doxorubicine. Dans chaque poumon perfusé, la concentration de l'agent cytostatique et sa distribution ont été investiguées dans la tumeur et trois parties du poumon normal par HLPC (n=6) et par microscopie de florescence (n=3). Des analyses histologiques et inmunohistochimiques (facteur von Willebrand) ont été effectuées sur trois animaux non traités. Résultats : Les tumeurs sarcomateuses dans les animaux de contrôle démontraient une bonne vascularisation avec de fines branches capillaires qui étaient présentes partout dans les tumeurs. La perfusion isolée du poumon démontrait une distribution de l'agent cytostatique d'une manière hétérogène dans le poumon perfusé et une concentration de Doxorubicine inférieure dans les tumeurs par rapport au tissu pulmonaire sein pour les deux formulations de Doxorubicine et les deux doses appliquées. La perfusion isolée du poumon avec Doxorubicine libre démontrait une concentration significativement plus élevée que Liporubicine dans la tumeur et le parenchyme pulmonaire pour les deux doses appliquées (p < 0,01). Néanmoins, le coefficient de concentration tumorale et pulmonaire était plus bas pour Doxorubicine libre que pour Liporubicine pour une dose de 100 µg (0.27 ± 0.1 vs 0.53 ± 0.5, p=0.23) tandis qu'il était similaire pour les deux formulations de Doxorubicine à une dose de 400 µg (0.67 ± 0.2 vs 0.54 ± 0.2, p=0.34). Les deux formulations de Doxorubicine émergeaient un signal de fluorescence provenant de tous les compartiments du parenchyme pulmonaire mais seulement un signal sporadique et faible émergeant des tumeurs, provenant de la périphérie de la tumeur et des vaisseaux situés à l'intérieur de la tumeur, pour les deux doses appliquées. Conclusion : La perfusion isolée du poumon démontrait une distribution hétérogène de la Doxorubicine et sa forme liposomale dans le poumon perfusé et une accumulation plus faible dans la tumeur que dans le tissu parenchymateux adjacent pour les deux formulations de Doxorubicine et les deux doses appliquées.

Impact of reduced cerebral perfusion pressure on outcome after severe traumatic brain injury is dependent on brain tissue oxygen pressure

INTRODUCTION. Reduced cerebral perfusion pressure (CPP) may worsen secondary damage and outcome after severe traumatic brain injury (TBI), however the optimal management of CPP is still debated. STUDY HYPOTHESIS: We hypothesized that the impact of CPP on outcome is related to brain tissue oxygen tension (PbtO2) level and that reduced CPP may worsen TBI prognosis when it is associated with brain hypoxia. DESIGN. Retrospective analysis of prospective database. METHODS. We analyzed 103 patients with severe TBI who underwent continuous PbtO2 and CPP monitoring for an average of 5 days. For each patient, duration of reduced CPP (\60 mm Hg) and brain hypoxia (PbtO2\15 mm Hg for[30 min [1]) was calculated with linear interpolation method and the relationship between CPP and PbtO2 was analyzed with Pearson's linear correlation coefficient. Outcome at 30 days was assessed with the Glasgow Outcome Score (GOS), dichotomized as good (GOS 4-5) versus poor (GOS 1-3). Multivariable associations with outcome were analyzed with stepwise forward logistic regression. RESULTS. Reduced CPP (n=790 episodes; mean duration 10.2 ± 12.3 h) was observed in 75 (74%) patients and was frequently associated with brain hypoxia (46/75; 61%). Episodes where reduced CPP were associated with normal brain oxygen did not differ significantly between patients with poor versus those with good outcome (8.2 ± 8.3 vs. 6.5 ± 9.7 h; P=0.35). In contrast, time where reduced CPP occurred simultaneously with brain hypoxia was longer in patients with poor than in those with good outcome (3.3±7.4 vs. 0.8±2.3 h; P=0.02). Outcome was significantly worse in patients who had both reduced CPP and brain hypoxia (61% had GOS 1-3 vs. 17% in those with reduced CPP but no brain hypoxia; P\0.01). Patients in whom a positive CPP-PbtO2 correlation (r[0.3) was found also were more likely to have poor outcome (69 vs. 31% in patients with no CPP-PbtO2 correlation; P\0.01). Brain hypoxia was an independent risk factor of poor prognosis (odds ratio for favorable outcome of 0.89 [95% CI 0.79-1.00] per hour spent with a PbtO2\15 mm Hg; P=0.05, adjusted for CPP, age, GCS, Marshall CT and APACHE II). CONCLUSIONS. Low CPP may significantly worsen outcome after severe TBI when it is associated with brain tissue hypoxia. PbtO2-targeted management of CPP may optimize TBI therapy and improve outcome of head-injured patients.