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Author: Véronique Fortier Publisher: ISBN: Category : Languages : en Pages :
Book Description
"Hypoxia is a common condition in solid tumors that has been shown to decrease the efficacy of radiotherapy and chemotherapy. Tumor hypoxia would be a very valuable characteristic to monitor during cancer radiotherapy treatments as it could enable the development of personalized treatments. However, there is currently no volumetric technique available to map hypoxia in vivo in a non-invasive way. The aim of this thesis was thus to develop a 3D technique to map hypoxia in tissue.In this work, it was hypothesised that hypoxia can be evaluated reliably using magnetic resonance imaging (MRI). More specifically, two MRI-based biomarkers for tissue oxygenation were investigated in this thesis in the presence of fat; magnetic susceptibility and longitudinal relaxation rate ( 1). Oxygen molecules are paramagnetic, which means that their presence modulates the tissue magnetic susceptibility. Oxygen molecules are also 1 lengthening agents and have a larger solubility in fat than in water. These characteristics of oxygen molecules suggest that fat 1 and susceptibility mapping in the presence of fat could both be sensitive to the presence of dissolved oxygen molecules in interstitial fluid of tissue containing fat, as proposed in previous work.Experiments were performed in this work using two different fat-water emulsions mimicking human soft tissues to investigate the sensitivity of the two biomarkers to oxygen level variations. Results obtained first showed that quantitative susceptibility mapping is unlikely to be sensitive to oxygen variations in tissue in vivo, due to the very small change in magnetic susceptibility that is induced by dissolved oxygen molecules, even in the presence of fat. Second, a detailed study of the longitudinal relaxation of fat molecules and water was performed to provide a more detailed understanding of these relaxation times as a function of the fat fraction. Third, building on the study of the longitudinal relaxation of fat molecules, a volumetric fat 1 mapping technique was proposed based on a variable flip angle approach. Fat 1 estimated with this proposed technique was shown to be highly sensitive in fat-water phantoms to variations in oxygen concentration, more so than water 1, consistent with previous work.The fat 1 mapping technique proposed in this work addresses the main limitations of existing techniques to map fat 1 in the context of tumor hypoxia, which are currently limited to single-slice imaging and require long scan times. This proposed technique is thus a promising tool for mapping hypoxia in vivo"--
Author: Véronique Fortier Publisher: ISBN: Category : Languages : en Pages :
Book Description
"Hypoxia is a common condition in solid tumors that has been shown to decrease the efficacy of radiotherapy and chemotherapy. Tumor hypoxia would be a very valuable characteristic to monitor during cancer radiotherapy treatments as it could enable the development of personalized treatments. However, there is currently no volumetric technique available to map hypoxia in vivo in a non-invasive way. The aim of this thesis was thus to develop a 3D technique to map hypoxia in tissue.In this work, it was hypothesised that hypoxia can be evaluated reliably using magnetic resonance imaging (MRI). More specifically, two MRI-based biomarkers for tissue oxygenation were investigated in this thesis in the presence of fat; magnetic susceptibility and longitudinal relaxation rate ( 1). Oxygen molecules are paramagnetic, which means that their presence modulates the tissue magnetic susceptibility. Oxygen molecules are also 1 lengthening agents and have a larger solubility in fat than in water. These characteristics of oxygen molecules suggest that fat 1 and susceptibility mapping in the presence of fat could both be sensitive to the presence of dissolved oxygen molecules in interstitial fluid of tissue containing fat, as proposed in previous work.Experiments were performed in this work using two different fat-water emulsions mimicking human soft tissues to investigate the sensitivity of the two biomarkers to oxygen level variations. Results obtained first showed that quantitative susceptibility mapping is unlikely to be sensitive to oxygen variations in tissue in vivo, due to the very small change in magnetic susceptibility that is induced by dissolved oxygen molecules, even in the presence of fat. Second, a detailed study of the longitudinal relaxation of fat molecules and water was performed to provide a more detailed understanding of these relaxation times as a function of the fat fraction. Third, building on the study of the longitudinal relaxation of fat molecules, a volumetric fat 1 mapping technique was proposed based on a variable flip angle approach. Fat 1 estimated with this proposed technique was shown to be highly sensitive in fat-water phantoms to variations in oxygen concentration, more so than water 1, consistent with previous work.The fat 1 mapping technique proposed in this work addresses the main limitations of existing techniques to map fat 1 in the context of tumor hypoxia, which are currently limited to single-slice imaging and require long scan times. This proposed technique is thus a promising tool for mapping hypoxia in vivo"--
Author: Publisher: ISBN: Category : Languages : en Pages : 181
Book Description
Hypoxia is a pathophysiologic consequence of structurally and functionally disturbed microcirculation in tumors and is associated with tumor propagation, malignant progression, and resistance to therapy. Nude mice bearing human head and neck squamous cell carcinoma (HNSCC) xenografts A253 and FaDu were treated with combination chemotherapy using irinotecan (CPT-11) and 5-fluorouracil (FUra) or 5-methylselenocysteine (MSC). A253 xenografts were found to consist of 30% well-differentiated avascular and 70% poorly differentiated regions with low microvessel density (MVD, 10/400X), while FaDu xenografts were found to consist of uniformly poorly differentiated regions with higher MVD (19/400X) and were more sensitive to therapy. Studies were performed to test the following hypotheses: (i) Do avascular, differentiated and thus possibly hypoxic regions in A253 hinder drug diffusion and distribution allowing some proliferating tumor cells to escape therapy? and, (ii) Can non-invasive blood oxygen level dependent (BOLD) functional magnetic resonance (fMR) imaging be used as a prognostic tool for determining chemotherapeutic efficacy? Autoradiography results obtained after chemotherapy demonstrated that avascular well-differentiated A253 tumor regions with a hypoxic rim containing few proliferating cells showed five-fold lower 14C labeled CPT-11 concentrations compared to poorly differentiated areas. BOLD fMR imaging can identify regions containing neovasculature and chronic hypoxia and show prognostic differences within different response groups. Tumors that respond with complete remission do not recruit as many neoangiogenic vessels as the non-responders and show an increase in mean fMR signal intensity during therapy. MSC results in tumor vessel maturation as evidenced by increased vessel lumens. This has implications for better intratumoral drug delivery, therapy response and fMR imaging interpretations. (Abstract shortened by UMI.).
Author: Keizō Kaneko Publisher: ISBN: Category : Medicine Languages : en Pages :
Book Description
Measurement of tumor hypoxia is required for the diagnosis of tumor and the evaluation of therapeutic outcome. Currently, invasive and noninvasive techniques being exploited for tumor hypoxia measurement include polarographic needle electrodes, immunohistochemical (IHC) staining, magnetic resonance imaging (MRI), radionuclide imaging (positron emission tomography [PET] and single-photon emission computed tomography [SPECT]), optical imaging (bioluminescence and fluorescence), and hypoxia imaging endoscopy. This review provides a summary of the modalities available for assessment of tissue oxygenation as well as a discussion of current arguments for and against each modality, with a particular focus on noninvasive hypoxia imaging with emerging agents and new imaging technologies intended to detect molecular events associated with tumor hypoxia.
Author: Jingwen Yao Publisher: ISBN: Category : Languages : en Pages : 304
Book Description
The reprogrammed energy metabolism and the dysfunctional vascular network of tumors create a hypoxic and acidic microenvironment, which is related to various malignant properties of cancer and poor patient prognosis. We have developed an amine chemical exchange saturation transfer (CEST) sequence with spin-and-gradient echo (SAGE) echo-planar imaging (EPI) readout to evaluate tumor acidity and hypoxia in human gliomas simultaneously. Amine CEST provided pH-sensitivity through labeling the endogenous amine protons that undergo chemical exchange with water protons, with a pH-dependent exchange rate. On the other hand, the reversible transverse relaxation rate quantified using the multi-echo EPI readout reflects oxygen extraction through sensitivity to paramagnetic deoxyhemoglobin. This dissertation focused on developing and validating this novel dual-function imaging technique, mainly from three aspects: the technical development and validation, the biological validation, and the clinical validation of the proposed pH- and oxygen-sensitive CEST-SAGE-EPI technique in human gliomas. We have developed a new post-processing method for improved $B_0$ correction. A customized CEST physical phantom was designed and developed with validated temporal stability. We also evaluated the CEST contrast variability in healthy volunteers and the normal-appearing contralateral brain regions in glioma patients. The proposed pH- and oxygen-sensitive imaging biomarkers showed significant correlations with the tumor cell metabolomics features and MRI-guided biopsy tissue biomarkers, which validated the biological bases of the imaging biomarkers. Additionally, we have examined the association between tumor acidity with tumor vascularity, as measured by perfusion MRI. Lastly, we investigated the clinical usefulness of the biomarkers to characterize different glioma genotypes, predict patient prognosis, and monitor treatment responses. In summary, this dissertation demonstrated that the novel dual-function pH- and oxygen-sensitive imaging technique reflects the abnormal metabolism in glioma patients and has the potential to provide clinical values for patient diagnosis, prognosis, and treatment efficacy assessment.
Author: Robert John Harris Publisher: ISBN: Category : Languages : en Pages : 184
Book Description
Magnetic resonance imaging is an integral part of medical diagnoses, treatment, and evaluation of patients with brain tumors. While standard anatomical imaging is useful, it does not provide information about molecular-level tumor characteristics that may spatially and temporally vary throughout the tumor. As such, there remains a need for the development of novel MRI techniques that can be used for evaluation of tumor growth and treatment response in patients with glioma undergoing radiochemotherapy. Extracellular acidosis is a hallmark of cancer and is intertwined with other common characteristics of the tumor microenvironment including hypoxia and angiogenesis. Therefore, the central objective of this dissertation was to develop a non-invasive imaging technique for identifying regions of acidosis within glioma and surrounding tissues using MRI. The most common types of glioma are highly aggressive and often require radiochemotherapy, which can result in variable responses across the patient population. Information about the acidity characteristics of these gliomas and the surrounding tissue may allow us to more accurately select targets for biopsy and radiation therapy, identify which patients are responding well to treatment, and predict prognosis. Chemical exchange saturation transfer (CEST) MRI is a molecular imaging technique that generates contrast indirectly from protons on labile functional groups such as amines, amides, and hydroxyls. CEST image contrast is dependent on the exchange rate between bulk water protons and these functional groups, which is in turn dependent upon local pH. Because of this, we hypothesized that we could utilize CEST MRI for pH-weighted imaging in human tissues. By developing simulations of the Bloch-McConnell equations governing chemical exchange, we have shown that the CEST contrast generated by fast-exchanging amino acid amine protons increases with decreasing pH within a physiologically relevant range (6.0-7.4). We have also incorporated experimental scan parameters into these simulations to more accurately simulate the CEST contrast obtained during clinical data acquisition. Data were acquired in amino acid phantoms at varying pH and concentration, verifying our image contrast was dependent on pH. Our pH-weighted MRI sequence was also applied in animal models of glioma, providing evidence it can be used to generate unique contrast within tumors and can serve as a potential biomarker for response to treatment. Our CEST MRI method was then applied serially in a cohort of glioblastoma patients undergoing treatment with standard radiochemotherapy, along with select cases of patients undergoing targeted biopsy. Results showed that tumor acidity characteristics were predictive of progression-free survival in the glioblastoma patient cohort. Acidity of targets selected for biopsy on pH-weighted images was indicative of tumor within those biopsy samples. To improve the imaging time of our sequence, we then upgraded the readout to utilize echo-planar imaging (EPI) rather than the standard gradient echo method. This allowed for whole brain coverage and multiple averages within a reduced scan time. The pH-weighted CEST-EPI sequence was applied in healthy volunteers and in a cohort of glioma patients prior to biopsy, in order to select targets for biopsy in regions of acidic and non-acidic tumor tissue. A subset of these patients also underwent PET imaging using 18F-FDOPA, an amino acid analog, near the time of their their pH-weighted scan. 18F-FDOPA uptake was shown to correlate quantitatively and qualitatively with regions of acidity, although pH-weighted imaging provided unique contrast in some cases. pH-weighted MRI was also acquired in recurrent glioblastoma patients before and after the start of treatment with bevacizumab. Acidity was shown to decrease after bevacizumab treatment, and in some cases acidic regions with no apparent contrast enhancement were shown to develop contrast enhancement on follow-up images, indicating that acidic lesions on pH-weighted MRI may be predictive of further tumor growth. Two additional advanced pH-weighted CEST MRI techniques were also implemented. CEST-EPI with a multi-echo readout was developed and acquired in a small cohort of glioma patients. The short and long echoes can provide sensitivity to more and less restricted water molecules, respectively. Separately, our CEST simulation incorporating T1 and T2 maps was used to quantitatively calculate estimates of pH in each image voxel for a subset of patients and animal models. This allows us to correct for T1 and T2 effects and generate numerical estimates of pH rather than pH-weighted images. Together, these experiments and results present a comprehensive description of pH-weighted molecular MRI in gliomas. This technique has the potential to be implemented clinically for detection of acidosis in gliomas and other brain pathologies.
Author: Praveen Kumar Gulaka Publisher: ISBN: Category : Magnetic resonance imaging Languages : en Pages :
Book Description
The term "tumor microenvironment" usually refers to the description of the physiological and metabolic conditions within solid tumors (primary or metastatic), and is significantly different from that of normal tissues. Assessment of factors like pH, tissue oxygen tension (pO2) and gene expression in the tumor microenvironment and the ability to image them in vivo can provide useful prognostic information. For example, hypoxia (low pO2), typically distributed heterogeneously in solid tumors, is known to affect both radiation sensitivity and the development of metastases thereby influencing the response to treatment. This dissertation research focuses on the evaluation of novel probes to interrogate the tumor microenvironment using proton (1H) magnetic resonance imaging (MRI), specifically hypoxia and gene expression. For the assessment of hypoxia, hexamethyldisiloxane (HMDSO) has been reported as a 1H MR based pO2 reporter molecule by in vivo spectroscopy and imaging using Proton Imaging of Siloxanes to Map Tissue Oxygenation Levels (PISTOL) technique. In further improvement of the technique, I evaluated HMDSO based nanoemulsions and various other siloxanes as quantitative 1H MR pO2 reporter molecules (Chapter 2). These reporter molecules exhibited a linear dependence of the spin lattice relaxation rate (R1) on pO2. HMDSO based nanoemulsions were further used in an in vivo feasibility study showing dynamic changes in rat thigh tissue oxygenation following an intramuscular injection in response to hyperoxic gas (normobaric and hyperbaric oxygen) breathing, thus showing the feasibility for use of these nanoemulsions as pO2 nanoprobes for systemic delivery. Another strategy for hypoxia imaging has been the use of 2-nitroimidazole based agents which selectively accumulated in hypoxic regions. In this dissertation, I report the in vitro and in vivo evaluation of GdDOTA monoamide conjugate of 2-nitroimidazole, GdDO3NI, as a novel hypoxia targeting MRI T1 contrast agent (Chapter 3). A higher uptake of GdDO3NI was observed in cells incubated under hypoxic conditions as well as hypoxic regions of Dunning R3327 AT1 prostate tumors. The MR observations were validated through inductively coupled plasma mass spectroscopic analysis. Further, I demonstrated the ability of GdDO3NI in monitoring the effect of hyperoxic (100% oxygen) gas breathing on modifying hypoxia in AT1 and HI tumors. Thus, GdDO3NI shows promise as a hypoxia targeting small molecular contrast agent, enabling the assessment of hypoxia at very high spatial resolution. For the assessment of gene expression, development of noninvasive imaging based reporter molecules has been an active area of study. In this dissertation, I evaluated a novel platform with enhanced T1 and T2 relaxation properties, for detecting ß-gal activity in lacZ transfected cells using novel analogs of the product of cleavage of commercially available substrate S-Ga ̐(Chapter 4). The synthesized mono and di- galactopyranosides (MGD and GD respectively) showed differential relaxation enhancements in vitro and the molecule C3-GD was identified as the optimal candidate for in vivo studies. Following intra-tumoral injection of C3-GD and ferric ammonium citrate solution in the lacZ transfected tumors, a pronounced shortening of T1 & T2 values was observed when compared to baseline, and persisted over 2 hours. This is attributed to the formation of an iron complex following chelation of aglycones produced by ß- gal activity. Thus C3-GD shows great promise as a 1H MR gene reporter molecule.
Author: Elke Hattingen Publisher: Springer ISBN: 3642450407 Category : Medical Languages : en Pages : 166
Book Description
This book describes the basics, the challenges and the limitations of state of the art brain tumor imaging and examines in detail its impact on diagnosis and treatment monitoring. It opens with an introduction to the clinically relevant physical principles of brain imaging. Since MR methodology plays a crucial role in brain imaging, the fundamental aspects of MR spectroscopy, MR perfusion and diffusion-weighted MR methods are described, focusing on the specific demands of brain tumor imaging. The potential and the limits of new imaging methodology are carefully addressed and compared to conventional MR imaging. In the main part of the book, the most important imaging criteria for the differential diagnosis of solid and necrotic brain tumors are delineated and illustrated in examples. A closing section is devoted to the use of MR methods for the monitoring of brain tumor therapy. The book is intended for radiologists, neurologists, neurosurgeons, oncologists and other scientists in the biomedical field with an interest in neuro-oncology.
Author: Roland N. Pittman Publisher: Biota Publishing ISBN: 1615047212 Category : Medical Languages : en Pages : 117
Book Description
This presentation describes various aspects of the regulation of tissue oxygenation, including the roles of the circulatory system, respiratory system, and blood, the carrier of oxygen within these components of the cardiorespiratory system. The respiratory system takes oxygen from the atmosphere and transports it by diffusion from the air in the alveoli to the blood flowing through the pulmonary capillaries. The cardiovascular system then moves the oxygenated blood from the heart to the microcirculation of the various organs by convection, where oxygen is released from hemoglobin in the red blood cells and moves to the parenchymal cells of each tissue by diffusion. Oxygen that has diffused into cells is then utilized in the mitochondria to produce adenosine triphosphate (ATP), the energy currency of all cells. The mitochondria are able to produce ATP until the oxygen tension or PO2 on the cell surface falls to a critical level of about 4–5 mm Hg. Thus, in order to meet the energetic needs of cells, it is important to maintain a continuous supply of oxygen to the mitochondria at or above the critical PO2 . In order to accomplish this desired outcome, the cardiorespiratory system, including the blood, must be capable of regulation to ensure survival of all tissues under a wide range of circumstances. The purpose of this presentation is to provide basic information about the operation and regulation of the cardiovascular and respiratory systems, as well as the properties of the blood and parenchymal cells, so that a fundamental understanding of the regulation of tissue oxygenation is achieved.
Author: Ulrich Flogel Publisher: CRC Press ISBN: 9814745324 Category : Medical Languages : en Pages : 462
Book Description
Over the past decade, fluorine (19F) magnetic resonance imaging (MRI) has garnered significant scientific interest in the biomedical research community owing to the unique properties of fluorinated materials and the 19F nucleus. Fluorine has an intrinsically sensitive nucleus for MRI. There is negligible endogenous 19F in the body and thus there is no background signal. Fluorine-containing compounds are ideal tracer labels for a wide variety of MRI applications. Moreover, the chemical shift and nuclear relaxation rate can be made responsive to physiology via creative molecular design. This book is an interdisciplinary compendium that details cutting-edge science and medical research in the emerging field of 19F MRI. Edited by Ulrich Flögel and Eric Ahrens, two prominent MRI researchers, this book will appeal to investigators involved in MRI, biomedicine, immunology, pharmacology, probe chemistry, and imaging physics.
Author: Véronique Fortier
Author: Véronique Fortier
Author: Peter Vaupel
Author: 
Author: Keizō Kaneko
Author: Jingwen Yao
Author: Robert John Harris
Author: Praveen Kumar Gulaka
Author: Elke Hattingen
Author: Roland N. Pittman
Author: Ulrich Flogel