Flow correlated percolation during vascular network formation in tumors

A theoretical model based on the molecular interactions between a growing tumor and a dynamically evolving blood vessel network describes the transformation of the regular vasculature in normal tissues into a highly inhomogeneous tumor specific capillary network. The emerging morphology, characterized by the compartmentalization of the tumor into several regions differing in vessel density, diameter and necrosis, is in accordance with experimental data for human melanoma. Vessel collapse due to a combination of severely reduced blood flow and solid stress exerted by the tumor, leads to a correlated percolation process that is driven towards criticality by the mechanism of hydrodynamic vessel stabilization.Comment: 4 pages, 3 figures (higher resolution at http://www.uni-saarland.de/fak7/rieger/HOMEPAGE/flow.eps

Fragmentation pathways of nanofractal structures on surface

We present a detailed systematical theoretical analysis of the post-growth processes occurring in nanofractals grown on surface. For this study we developed a method which accounts for the internal dynamics of particles in a fractal. We demonstrate that particle diffusion and detachment controls the shape of the emerging stable islands on surface. We consider different scenarios of fractal post-growth relaxation and analyze the time evolution of the island's morphology. The results of our calculations are compared with available experimental observations, and experiments in which the post-growth relaxation of deposited nanostructures can be probed are suggested.Comment: 34 pages, 11 figure

A Systems Approach for Tumor Pharmacokinetics

Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design.National Institutes of Health (U.S.) (grant T32 CA079443

Simultaneous sleep study and nasoendoscopic investigation in a patient with obstructive sleep apnoea syndrome refractory to continuous positive airway pressure: a case report

<p>Abstract</p> <p>Introduction</p> <p>The standard treatment for obstructive sleep apnoea syndrome is nasal continuous positive airway pressure. In most cases the obstruction is located at the oropharyngeal level, and nasal continuous positive airway pressure is usually effective. In cases of non-response to nasal continuous positive airway pressure other treatments like mandibular advancement devices or upper airway surgery (especially bi-maxillary advancement) may also be considered.</p> <p>Case presentation</p> <p>We report the case of a 38-year-old Caucasian man with severe obstructive sleep apnoea syndrome, initially refractory to nasal continuous positive airway pressure (and subsequently also to a mandibular advancement devices), in which the visualization of the upper airway with sleep endoscopy and the concomitant titration of positive pressure were useful in the investigation and resolution of sleep disordered breathing. In fact, there was a marked reduction in the size of his nasopharynx, and a paresis of his left aryepiglotic fold with hypertrophy of the right aryepiglotic fold. The application of bi-level positive airway pressure and an oral interface successfully managed his obstructive sleep apnoea.</p> <p>Conclusion</p> <p>This is a rare case of obstructive sleep apnoea syndrome refractory to treatment with nocturnal ventilatory support. Visualization of the endoscopic changes, during sleep and under positive pressure, was of great value to understanding the mechanisms of refractoriness. It also oriented the therapeutic option. Refractoriness to obstructive sleep apnoea therapy with continuous positive airway pressure is rare, and each case should be approached individually.</p

High Acute Myeloid Leukemia derived VEGFA levels are associated with a specific vascular morphology in the leukemic bone marrow

Acute Myeloid Leukemia (AML) bone marrow biopsies at diagnosis display enhanced angiogenesis and increased VEGFA expression. In a xenograft mouse model it was described that availability of free VEGFA versus bound VEGFA is related to different vascular morphology. In this study we investigate the relationship between vascular morphology within AML bone marrow biopsies and AML derived VEGFA levels. Vessel count and surface area (Chalkley count) were calculated in AML bone marrow biopsies at diagnosis (n = 32), at remission (n = 8) and Normal Bone Marrow (n = 32) using immunohistochemical staining for FVIII, CD31, CTIV, SMA and VEGFA. VEGFA protein levels were measured. High vessel count was associated with an immature vessel status. Combining vessel count and Chalkley count different vessel morphology patterns were quantified within AML bone marrow biopsies. Three different subgroups could be distinguished. The subgroup (37.5% of the samples) exhibiting a high vessel count and vessels with predominantly large lumen (normal Chalkley count) was associated with high secreted VEGFA protein levels. Different vasculature patterns are seen in AML bone marrow biopsies, defined by combining number and size of vessel. These quantified morphology patterns, combined with VEGFA levels, might be of value in the success of VEGF/VEGFR-signaling interference approaches

Computer-assisted and fractal-based morphometric assessment of microvascularity in histological specimens of gliomas

Fractal analysis is widely applied to investigate the vascular system in physiological as well as pathological states. We propose and examine a computer-aided and fractal-based image analysis technique to quantify the microvascularity in histological specimens of WHO grade II and III gliomas. A computer-aided and fractal-based analysis was used to describe the microvessels and to quantify their geometrical complexity in histological specimens collected from 17 patients. The statistical analysis showed that the fractal-based indexes are the most discriminant parameters to describe the microvessels. The computer-aided quantitative analysis also showed that grade III gliomas are generally more vascularized than grade II gliomas. The fractal parameters are reliable quantitative indicators of the neoplastic microvasculature, making them potential surrogate biomarkers. The qualitative evaluation currently performed by the neuropathologist can be combined with the computer-assisted quantitative analysis of the microvascularity to improve the diagnosis and optimize the treatment of patients with brain cancer

Multimodality Imaging of Abnormal Vascular Perfusion and Morphology in Preclinical 9L Gliosarcoma Model

This study demonstrates that a dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) perfusion parameter may indicate vascular abnormality in a brain tumor model and reflects an effect of dexamethasone treatment. In addition, X-ray computed tomography (CT) measurements of vascular tortuosity and tissue markers of vascular morphology were performed to investigate the underpinnings of tumor response to dexamethasone.One cohort of Fisher 344 rats (N = 13), inoculated intracerebrally with 9L gliosarcoma cells, was treated with dexamethasone (i.p. 3 mg/kg/day) for five consecutive days, and another cohort (N = 11) was treated with equal volume of saline. Longitudinal DSC-MRI studies were performed at the first (baseline), third and fifth day of treatments. Relative cerebral blood volume (rCBV) was significantly reduced on the third day of dexamethasone treatment (0.65 ± .13) as compared to the fifth day during treatment (1.26 ±.19, p < 0.05). In saline treated rats, relative CBV gradually increased during treatment (0.89 ±.13, 1.00 ± .21, 1.13 ± .23) with no significant difference on the third day of treatment (p>0.05). In separate serial studies, microfocal X-ray CT of ex vivo brain specimens (N = 9) and immunohistochemistry for endothelial cell marker anti-CD31 (N = 8) were performed. Vascular morphology of ex vivo rat brains from micro-CT analysis showed hypervascular characteristics in tumors, and both vessel density (41.32 ± 2.34 branches/mm(3), p<0.001) and vessel tortuosity (p<0.05) were significantly reduced in tumors of rats treated with dexamethasone compared to saline (74.29 ± 3.51 branches/mm(3)). The vascular architecture of rat brain tissue was examined with anti-CD31 antibody, and dexamethasone treated tumor regions showed reduced vessel area (16.45 ± 1.36 µm(2)) as compared to saline treated tumor regions (30.83 ± 4.31 µm(2), p<0.001) and non-tumor regions (22.80 ± 1.11 µm(2), p<0.01).Increased vascular density and tortuosity are culprit to abnormal perfusion, which is transiently reduced during dexamethasone treatment

Predicting drug pharmacokinetics and effect in vascularized tumors using computer simulation

In this paper, we investigate the pharmacokinetics and effect of doxorubicin and cisplatin in vascularized tumors through two-dimensional simulations. We take into account especially vascular and morphological heterogeneity as well as cellular and lesion-level pharmacokinetic determinants like P-glycoprotein (Pgp) efflux and cell density. To do this we construct a multi-compartment PKPD model calibrated from published experimental data and simulate 2-h bolus administrations followed by 18-h drug washout. Our results show that lesion-scale drug and nutrient distribution may significantly impact therapeutic efficacy and should be considered as carefully as genetic determinants modulating, for example, the production of multidrug-resistance protein or topoisomerase II. We visualize and rigorously quantify distributions of nutrient, drug, and resulting cell inhibition. A main result is the existence of significant heterogeneity in all three, yielding poor inhibition in a large fraction of the lesion, and commensurately increased serum drug concentration necessary for an average 50% inhibition throughout the lesion (the IC50 concentration). For doxorubicin the effect of hypoxia and hypoglycemia (“nutrient effect”) is isolated and shown to further increase cell inhibition heterogeneity and double the IC50, both undesirable. We also show how the therapeutic effectiveness of doxorubicin penetration therapy depends upon other determinants affecting drug distribution, such as cellular efflux and density, offering some insight into the conditions under which otherwise promising therapies may fail and, more importantly, when they will succeed. Cisplatin is used as a contrast to doxorubicin since both published experimental data and our simulations indicate its lesion distribution is more uniform than that of doxorubicin. Because of this some of the complexity in predicting its therapeutic efficacy is mitigated. Using this advantage, we show results suggesting that in vitro monolayer assays using this drug may more accurately predict in vivo performance than for drugs like doxorubicin. The nonlinear interaction among various determinants representing cell and lesion phenotype as well as therapeutic strategies is a unifying theme of our results. Throughout it can be appreciated that macroscopic environmental conditions, notably drug and nutrient distributions, give rise to considerable variation in lesion response, hence clinical resistance. Moreover, the synergy or antagonism of combined therapeutic strategies depends heavily upon this environment