Noninvasive monitoring of radiotherapy-induced microvascular changes using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in a colorectal tumor model

To examine dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with a macromolecular contrast agent (P792) to visualize effects of radiotherapy (RT) on microvascular leakage in a colorectal cancer model.Journal Articleinfo:eu-repo/semantics/publishe

Pattern recognition and pharmacokinetic methods on DCE-MRI data for tumor hypoxia mapping in sarcoma

The main purpose of this study is to analyze the intrinsic tumor physiologic characteristics in patients with sarcoma through model-free analysis of dynamic contrast enhanced MR imaging data (DCE-MRI). Clinical data were collected from three patients with two different types of histologically proven sarcomas who underwent conventional and advanced MRI examination prior to excision. An advanced matrix factorization algorithm has been applied to the data, resulting in the identification of the principal time-signal uptake curves of DCE-MRI data, which were used to characterize the physiology of the tumor area, described by three different perfusion patterns i.e. hypoxic, well-perfused and necrotic one. The performance of the algorithm was tested by applying different initialization approaches with subsequent comparison of their results. The algorithm was proven to be robust and led to the consistent segmentation of the tumor area in three regions of different perfusion, i.e. well- perfused, hypoxic and necrotic. Results from the model-free approach were compared with a widely used pharmacokinetic (PK) model revealing significant correlations

DCE-MRI perfusion and permeability parameters as predictors of tumor response to CCRT in patients with locally advanced NSCLC

In this prospective study, 36 patients with stage III non-small cell lung cancers (NSCLC), who underwent dynamic contrast-enhanced MRI (DCE-MRI) before concurrent chemo-radiotherapy (CCRT) were enrolled. Pharmacokinetic analysis was carried out after non-rigid motion registration. The perfusion parameters including Blood Flow (BF), Blood Volume (BV), Mean Transit Time (MTT) and permeability parameters including endothelial transfer constant (Ktrans), reflux rate (Kep), fractional extravascular extracellular space volume (Ve), fractional plasma volume (Vp) were calculated, and their relationship with tumor regression was evaluated. The value of these parameters on predicting responders were calculated by receiver operating characteristic (ROC) curve. Multivariate logistic regression analysis was conducted to find the independent variables. Tumor regression rate is negatively correlated with V e and its standard variation V e-SD and positively correlated with K trans and Kep. Significant differences between responders and non-responders existed in Ktrans, Kep, Ve, Ve-SD, MTT, BV-SD and MTT-SD (P < 0.05). ROC indicated that Ve < 0.24 gave the largest area under curve of 0.865 to predict responders. Multivariate logistic regression analysis also showed Ve was a significant predictor. Baseline perfusion and permeability parameters calculated from DCE-MRI were seen to be a viable tool for predicting the early treatment response after CCRT of NSCLC. © 2016 The Author(s)

Oxygen-Enhanced and Dynamic Contrast-Enhanced Optoacoustic Tomography Provide Surrogate Biomarkers of Tumor Vascular Function, Hypoxia, and Necrosis.

Measuring the functional status of tumor vasculature, including blood flow fluctuations and changes in oxygenation, is important in cancer staging and therapy monitoring. Current clinically approved imaging modalities suffer long procedure times and limited spatiotemporal resolution. Optoacoustic tomography (OT) is an emerging clinical imaging modality that may overcome these challenges. By acquiring data at multiple wavelengths, OT can interrogate hemoglobin concentration and oxygenation directly and resolve contributions from injected contrast agents. In this study, we tested whether two dynamic OT techniques, oxygen-enhanced (OE) and dynamic contrast-enhanced (DCE)-OT, could provide surrogate biomarkers of tumor vascular function, hypoxia, and necrosis. We found that vascular maturity led to changes in vascular function that affected tumor perfusion, modulating the DCE-OT signal. Perfusion in turn regulated oxygen availability, driving the OE-OT signal. In particular, we demonstrate for the first time a strong per-tumor and spatial correlation between imaging biomarkers derived from these in vivo techniques and tumor hypoxia quantified ex vivo Our findings indicate that OT may offer a significant advantage for localized imaging of tumor response to vascular-targeted therapies when compared with existing clinical DCE methods.Significance: Imaging biomarkers derived from optoacoustic tomography can be used as surrogate measures of tumor perfusion and hypoxia, potentially yielding rapid, multiparametric, and noninvasive cancer staging and therapeutic response monitoring in the clinic.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5980/F1.large.jpg Cancer Res; 78(20); 5980-91. ©2018 AACR

Emerging Translational Opportunities in Comparative Oncology With Companion Canine Cancers: Radiation Oncology.

It is estimated that more than 6 million pet dogs are diagnosed with cancer annually in the USA. Both primary care and specialist veterinarians are frequently called upon to provide clinical care that improves the quality and/or quantity of life for affected animals. Because these cancers develop spontaneously in animals that often share the same environment as their owners, have intact immune systems and are of similar size to humans, and because the diagnostic tests and treatments for these cancers are similar to those used for management of human cancers, canine cancer provides an opportunity for research that simultaneously helps improve both canine and human health care. This is especially true in the field of radiation oncology, for which there is a rich and continually evolving history of learning from the careful study of pet dogs undergoing various forms of radiotherapy. The purpose of this review article is to inform readers of the potential utility and limitations of using dogs in that manner; the peer-reviewed literature will be critically reviewed, and current research efforts will be discussed. The article concludes with a look toward promising future directions and applications of this pet dog "model.

Advanced signal processing methods in dynamic contrast enhanced magnetic resonance imaging

Tato dizertační práce představuje metodu zobrazování perfúze magnetickou rezonancí, jež je výkonným nástrojem v diagnostice, především v onkologii. Po ukončení sběru časové sekvence T1-váhovaných obrazů zaznamenávajících distribuci kontrastní látky v těle začíná fáze zpracování dat, která je předmětem této dizertace. Je zde představen teoretický základ fyziologických modelů a modelů akvizice pomocí magnetické rezonance a celý řetězec potřebný k vytvoření obrazů odhadu parametrů perfúze a mikrocirkulace v tkáni. Tato dizertační práce je souborem uveřejněných prací autora přispívajícím k rozvoji metodologie perfúzního zobrazování a zmíněného potřebného teoretického rozboru.This dissertation describes quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), which is a powerful tool in diagnostics, mainly in oncology. After a time series of T1-weighted images recording contrast-agent distribution in the body has been acquired, data processing phase follows. It is presented step by step in this dissertation. The theoretical background in physiological and MRI-acquisition modeling is described together with the estimation process leading to parametric maps describing perfusion and microcirculation properties of the investigated tissue on a voxel-by-voxel basis. The dissertation is divided into this theoretical analysis and a set of publications representing particular contributions of the author to DCE-MRI.

A novel in vivo tumor oxygen profiling assay: Combining functional and molecular imaging with multivariate mathematical modeling

Purpose: The objective of this study is to develop and test a novel high spatio-temporal in vivo assay to quantify tumor oxygenation and hypoxia. The assay implements a biophysical model of oxygen transport to fuse parameters acquired from in vivo functional and molecular imaging modalities. ^ Introduction: Tumor hypoxia plays an important role in carcinogenesis. It triggers pathological angiogenesis to supply more oxygen to the tumor cells and promotes cancer cell metastasis. Preclinical and clinical evidence show that anti-angiogenic treatment is capable of normalizing the tumor vasculature both structurally and functionally. The resulting normalized vasculature provides a more efficient and uniform microcirculation that enhances oxygen and drug delivery to the tumor cells and improves second-line treatments such as traditional radiation or chemotherapy. Early studies using the overall or average tumor hypoxia as a prognostic biomarker of anti-angiogenic therapy efficacy was ambivalent; however, recent studies have discovered that the etiology of hypoxia and its heterogeneity could be used as reliable prognostic biomarkers. The capability to longitudinally map tumor hypoxia with high spatial and temporal resolution has the potential to enhance fundamental cancer research and ultimately cancer patient care. ^ Method: A novel methodology to identify and characterize tumor hypoxia by fusing the physiological hemodynamic parametric maps obtained from functional and molecular imaging modalities and technique using a modified Krogh model of oxygen transport (MPO2) was developed. First, simulations studies were performed to validate this technique. Microscopy data of tumor and brain tissue (control) provided both the vasculature and rheology data. A Green\u27s function algorithm was used to solve the ordinary differential equation and calculate the oxygen profile at a microscopic scale (15 μm) (GPO2), which was used as a reference. From this data, simulated physiological maps (perfusion, fractional plasma volume, fractional interstitial volume) and hemoglobin status (oxygen saturation, hemoglobin concentration) was used as input to MPO2 and used to calculate pO2 levels as a function of scanner spatial resolution and noise. Second, MPO2 was compared to pO2 measurements in xenograft breast tumors using OxyLite oxygen sensor as a Gold Standard, where DCE-CT and PCT-S images were acquired to obtain hemodynamic images. Finally, the vascular physiology measurements obtained from an anti-angiogenic therapeutic study in pancreatic tumors was applied to MPO2 and compared to therapeutic response. ^ Results: The simulation results using Green\u27s function pO2 as standard showed that the MPO2 model performance was dependent on the spatial resolution (voxel size) of the images. Sensitivity and error analysis of this model were also investigated in this study. These oxygen transport simulations results suggest the oxygen saturation and hemoglobin concentration were two key factors in tissue oxygenation, and concomitant with blood perfusion and tumor metabolic rate. Comparisons of the pO2 profile obtained from MPO2 and OxyLite probe in MCF7 tumor model demonstrated a significant correlation and approached a slope of one (after accounting for a few outliers). Simulation studies implementing the physiological data obtained from the anti-angiogenic therapeutic study in pancreatic tumors using the MPO2 model agreed with the experimental findings that blood perfusion is a valuable prognostic biomarker in therapeutic efficacy. This model also predicted the oxygenation improvement difference from two vascular renormalization modes (topological normalization and geometrical normalization). ^ Conclusion: The results from the simulation and in vivo studies demonstrated the feasibility of this novel hypoxia assay. Simulation results of the pancreatic tumors provide an example of the impact the MPO2 model in conjunction with imaging can provide when evaluating the therapeutic significance of various normalization modes in anti-angiogenic therapy, and suggests potential approaches to further improve anti-angiogenic therapy efficacy

Dynamic contrast-Enhanced MRI of Pancreatic Islet Transplants

Since its discovery in 1922, insulin has been the life-saving treatment for type 1 diabetes mellitus. As the disease is caused by the loss of insulin-producing pancreatic islets, transplantation of donor islets has the potential to not only supplement insulin replacement therapy but to cure type 1 diabetes. However, long-term insulin independence (\u3e 2 years post-transplant) remains a challenge partly due to low islet blood flow immediately following transplantation leading to hypoxic stress on islets. The goal of our studies is to improve islet engraftment by monitoring and promoting the regrowth and maturation of new islet blood vessels in a clinically applicable manner. The developed technique is based on intravascular injection of a FDA-approved contrast agent which leaks from and accumulates around permeable immature blood vessels. Rapidly acquired MRI scans following contrast administration can then show the location and extent of new vessel formations. Our studies showed dynamic contrast-enhanced MRI to be successful in determining a timeline for islet revascularization as well as evaluating the effectiveness of a hyperbaric oxygen-based engraftment-enhancing therapy. The results are an important step in advancing islet transplantation as a potential cure for type 1 diabetes