36 research outputs found

    Video-Rate Fluorescence Molecular Tomography for Hand-held and Multimodal Molecular Imaging

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    In the United States, cancer is the second leading cause of death following heart disease. Although, a variety of treatment regimens are available, cancer management is complicated by the complexity of the disease and the variability, between people, of disease progression and response to therapy. Therefore, advancements in the methods and technologies for cancer diagnosis, prognosis and therapeutic monitoring are critical to improving the treatment of cancer patients. The development of improved imaging methods for early diagnosis of cancer and of near real-time monitoring of tumor response to therapy may improve outcomes as well as the quality of life of cancer patients. In the last decade, imaging methods including ultrasound, computed tomography: CT), magnetic resonance imaging: MRI), single photon emission computed tomography: SPECT), and positron emission tomography: PET), have revolutionized oncology. More recently optical techniques, that have access to unique molecular reporting strategies and functional contrasts, show promise for oncologic imaging This dissertation focuses on the development and optimization of a fiber-based, video-rate fluorescence molecular tomography: FMT) instrument. Concurrent acquisition of fluorescence and reference signals allowed the efficient generation of ratio-metric data for 3D image reconstruction. Accurate depth localization and high sensitivity to fluorescent targets were established to depths of \u3e10 mm. In vivo accumulation of indocyanine green dye was imaged in the region of the sentinel lymph node: SLN) following intradermal injection into the forepaw of rats. These results suggest that video-rate FMT has potential as a clinical tool for noninvasive mapping of SLN. Spatial and temporal co-registration of nuclear and optical images can enable the fusion of the information from these complementary molecular imaging modalities. A critical challenge is in integrating the optical and nuclear imaging hardware. Flexible fiber-based FMT systems provide a viable solution. The various imaging bore sizes of small animal nuclear imaging systems can potentially accommodate the FMT fiber imaging arrays. In addition FMT imaging facilitates co-registering the nuclear and optical contrasts in time. In this dissertation, the feasibility of integrating the fiber-based, video-rate FMT system with a commercial preclinical NanoSPECT/CT platform was established. Feasibility of in vivo imaging is demonstrated by tracking a monomolecular multimodal-imaging agent: MOMIA) during transport from the forepaw to the axillary lymph nodes region of a rat. These co-registered FMT/SPECT/CT imaging results with MOMIAs may facilitate the development of the next generation preclinical and clinical multimodal optical-nuclear platforms for a broad array of imaging applications, and help elucidate the underlying biological processes relevant to cancer diagnosis and therapy monitoring. Finally, I demonstrated that video-rate FMT is sufficiently fast to enable imaging of cardiac, respiratory and pharmacokinetic induced dynamic fluorescent signals. From these measurements, the image-derived input function and the real-time uptake of injected agents can be deduced for pharmacokinetic analysis of fluorescing agents. In a study comparing normal mice against mice liver disease, we developed anatomically guided dynamic FMT in conjunction with tracer kinetic modeling to quantify uptake rates of fluorescing agents. This work establishes fiber-based, video-rate FMT system as a practical and powerful tool that is well suited to a broad array of potential imaging applications, ranging from early disease detection, quantifying physiology and monitoring progression of disease and therapies

    Novel aspects for methodology and utilization of PET/CT imaging in head and neck cancer

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    Avainsanat: PET, PET/TT, pään ja kaulan alueen syöpä, [18F]EF5, [18F]FDG, hypoksia, molekulaarinen kuvantaminen, sädehoidon suunnittelu Positron emission tomography (PET), combined with computed tomography (CT),plays a key role in the management of head and neck cancer (HNC). In this thesis, novel aspects for PET/CT imaging of HNC regarding low oxygen levels, or hypoxia, and detection of glucose metabolism were evaluated. Hypoxia is a frequently observed hallmark of cancer contributing to radiotherapy resistance and poor prognosis. Enhanced glucose metabolism is characteristic of a malignant tumor, which is exploited in an everyday clinical application of [18F]FDG PET imaging. This study aimed to further investigate the feasibility of a novel hypoxia PET tracer [18F]EF5 and the potential of dynamic [18F]FDG PET/CT imaging in HNC. The first study indicated a favorable human biodistribution and radiation dosimetric profile of the hypoxia tracer [18F]EF5. The second preclinical study showed that the growth rate of human HNC xenografts in nude mice during the exponential growth period correlated with [18F]EF5 uptake in PET/CT images. In the third study, paired [18F]EF5 PET/CT scans performed for untreated HNC patients with a median time interval of seven days presented predominantly highly repeatable results. In the fourth study, advanced mathematical methodology for tracer uptake analysis was evaluated using dynamic [18F]FDG PET/CT in patients who were referred to chemoradiotherapy for oropharyngeal cancer. However, the method showed only a modest performance in the distinction of malignant, inflammatory and healthy tissues. In conclusion, further evaluation of [18F]EF5 PET/CT imaging and dynamic [18F]FDG PET/CT imaging seems important in the development of more effective strategies for the management of HNC

    Advanced radiation therapies for meningioma

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    Radiotherapy has been used to treat meningiomas for decades, both in the primary setting when resection is not possible and as an adjunct to surgery in recurrent/ high grade disease. Newer radiotherapy planning and delivery techniques aim to optimise tumour control and minimise long-term toxicities. The purpose of this thesis was to explore the feasibility and potential for the use of advanced radiation planning and delivery techniques to treat meningiomas. In a prospective observational study of intensity modulated radiotherapy (IMRT) in fifty patients I demonstrated that IMRT is feasible and provided excellent dosimetric parameters. Medium term meningioma control rates were >90% in benign disease. Objective measures of toxicity were low. Visual symptoms improved in 38.5% of patients. In a pilot study of ten patients I showed that simultaneous 68Ga DOTATATE PET/MRI can be utilised in meningioma radiotherapy planning. Baseline levels of interobserver variability in target volume definition between three Observers using CT/MRI alone were very high (mean target volume conformity levels of 0.31-0.34). Levels of agreement improved only 4-5% with the addition of PET and there was negligible difference in contouring between standard PET(CT) and simultaneous PET(MRI). In a planning study of ten meningiomas I did not find a notable advantage for proton therapy (non-intensity modulated) over IMRT. The high quality of the IMRT plans left little room for improvement and range uncertainty restricted exploitation of proton dose deposition characteristics. In my review of the first six patients treated with the radionuclide 177Lutetium DOTATATE for advanced progressive meningioma, tumour growth rates were found to slow, but there was generally disease progression during treatment. In conclusion, advanced radiation techniques for meningioma treatment are feasible and can confer clinical benefit. However, advances in technology do not necessarily translate into therapeutic gains. Careful prospective evaluation is required to ensure their optimal use

    Quantification of tumor heterogeneity using PET/MRI and machine learning

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    Despite a broad understanding that solid tumors exhibit significant tissue heterogeneity, clinical trials have not seen a remarkable development in techniques that aid in characterizing cancer. Needle biopsies often represent only a partial view of the tumor profile, lacking the ability to comprehensively reflect spatiotemporal phenotypic changes. Recent multimodal multiparametric imaging techniques could provide further valuable insights if the complementary imaging information is sufficiently analyzed. Therefore, in this work I developed and applied machine learning methods on multiparametric positron emission tomography (PET) and magnetic resonance imaging (MRI) datasets, acquired using mice bearing subcutaneous tumors, to obtain a precise spatio-temporal characterization of intratumor heterogeneity

    Pulmonary Image Segmentation and Registration Algorithms: Towards Regional Evaluation of Obstructive Lung Disease

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    Pulmonary imaging, including pulmonary magnetic resonance imaging (MRI) and computed tomography (CT), provides a way to sensitively and regionally measure spatially heterogeneous lung structural-functional abnormalities. These unique imaging biomarkers offer the potential for better understanding pulmonary disease mechanisms, monitoring disease progression and response to therapy, and developing novel treatments for improved patient care. To generate these regional lung structure-function measurements and enable broad clinical applications of quantitative pulmonary MRI and CT biomarkers, as a first step, accurate, reproducible and rapid lung segmentation and registration methods are required. In this regard, we first developed a 1H MRI lung segmentation algorithm that employs complementary hyperpolarized 3He MRI functional information for improved lung segmentation. The 1H-3He MRI joint segmentation algorithm was formulated as a coupled continuous min-cut model and solved through convex relaxation, for which a dual coupled continuous max-flow model was proposed and a max-flow-based efficient numerical solver was developed. Experimental results on a clinical dataset of 25 chronic obstructive pulmonary disease (COPD) patients ranging in disease severity demonstrated that the algorithm provided rapid lung segmentation with high accuracy, reproducibility and diminished user interaction. We then developed a general 1H MRI left-right lung segmentation approach by exploring the left-to-right lung volume proportion prior. The challenging volume proportion-constrained multi-region segmentation problem was approximated through convex relaxation and equivalently represented by a max-flow model with bounded flow conservation conditions. This gave rise to a multiplier-based high performance numerical implementation based on convex optimization theories. In 20 patients with mild- to-moderate and severe asthma, the approach demonstrated high agreement with manual segmentation, excellent reproducibility and computational efficiency. Finally, we developed a CT-3He MRI deformable registration approach that coupled the complementary CT-1H MRI registration. The joint registration problem was solved by exploring optical-flow techniques, primal-dual analyses and convex optimization theories. In a diverse group of patients with asthma and COPD, the registration approach demonstrated lower target registration error than single registration and provided fast regional lung structure-function measurements that were strongly correlated with a reference method. Collectively, these lung segmentation and registration algorithms demonstrated accuracy, reproducibility and workflow efficiency that all may be clinically-acceptable. All of this is consistent with the need for broad and large-scale clinical applications of pulmonary MRI and CT

    Biologically conformal radiation therapy and Monte Carlo dose calculations in the clinic

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    The impact of arterial input function determination variations on prostate dynamic contrast-enhanced magnetic resonance imaging pharmacokinetic modeling: a multicenter data analysis challenge, part II

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    This multicenter study evaluated the effect of variations in arterial input function (AIF) determination on pharmacokinetic (PK) analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data using the shutter-speed model (SSM). Data acquired from eleven prostate cancer patients were shared among nine centers. Each center used a site-specific method to measure the individual AIF from each data set and submitted the results to the managing center. These AIFs, their reference tissue-adjusted variants, and a literature population-averaged AIF, were used by the managing center to perform SSM PK analysis to estimate Ktrans (volume transfer rate constant), ve (extravascular, extracellular volume fraction), kep (efflux rate constant), and Ï„i (mean intracellular water lifetime). All other variables, including the definition of the tumor region of interest and precontrast T1 values, were kept the same to evaluate parameter variations caused by variations in only the AIF. Considerable PK parameter variations were observed with within-subject coefficient of variation (wCV) values of 0.58, 0.27, 0.42, and 0.24 for Ktrans, ve, kep, and Ï„i, respectively, using the unadjusted AIFs. Use of the reference tissue-adjusted AIFs reduced variations in Ktrans and ve (wCV = 0.50 and 0.10, respectively), but had smaller effects on kep and Ï„i (wCV = 0.39 and 0.22, respectively). kep is less sensitive to AIF variation than Ktrans, suggesting it may be a more robust imaging biomarker of prostate microvasculature. With low sensitivity to AIF uncertainty, the SSM-unique Ï„i parameter may have advantages over the conventional PK parameters in a longitudinal study

    Magnetic Resonance Imaging (MRI) Biomarkers for Therapeutic Response Prediction in Rectal Cancer

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    Prediction of chemoradiotherapy (CRT) response in rectal cancer would enable stratification of management whereby responders could undergo ‘watch-and-wait’ to avoid surgical morbidity, and non-responders could have early treatment intensification to improve therapeutic outcomes. Functional MRI can assess tumour function and heterogeneity, and may improve therapeutic response prediction. The aims of this PhD were to (i) prospectively evaluate multi-parametric MRI at 3.0 tesla in vivo combining diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE) MRI for prediction of CRT response and 2 year disease-free survival (DFS), and (ii) examine diffusion tensor imaging (DTI) MRI biomarkers of rectal cancer extent and heterogeneity at ultra-high field 11.7 tesla ex vivo in order to establish a pipeline for MRI biomarker discovery from ultra-high field to clinical field. Patients with locally advanced rectal cancer undergoing CRT followed by surgery underwent multi-parametric MRI before, during, and after CRT. A whole tumour voxelwise histogram analysis of apparent diffusion co-efficient (ADC) and Ktrans heterogeneity was performed and correlated with histopathology tumour regression grade. After CRT (before surgery) ADC 75th and 90th quantiles were significantly higher in responders than non-responders. Patients with higher Ktrans values after CRT or greater increase in Ktrans values from before to after CRT had a significantly higher risk of distant metastases, and lower 2 year DFS. Biobank tissue from patients with rectal cancer were examined at 11.7 tesla and DTI-MRI results correlated with histopathology. This work established a discovery framework for screening Biobank cancer tissue for novel MRI biomarkers of tumour extent and heterogeneity, and resulted in good preservation of tissue integrity and MRI-histopathology alignment. DTI-MRI derived fractional anisotropy (FA) was able to differentiate between tumour and desmoplasia, fibrous tissue, and muscularis propria, allowing for more accurate delineation of rectal cancer tumour extent and stromal heterogeneity ex vivo. In conclusion, DWI-MRI was predictive of CRT response, DCE-MRI was predictive of 2 year DFS, and DTI-MRI was able to more accurately define tumour extent and heterogeneity in rectal cancer. These findings could be useful for stratification of patients for individualised treatment based on accurate assessment of tumour extent and therapeutic response prediction

    Phase II Clinical Trial of Concurrent Neoadjuvant Chemotherapy With Radiotherapy in Locally Advanced Breast Cancer

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    Locally advanced breast cancer (LABC) represents 15% of all non-metastatic breast cancers, with an overall poor prognosis, despite current guidelines that recommend neoadjuvant chemotherapy followed by surgery and adjuvant radiation. Therefore, a novel treatment paradigm using concurrent neoadjuvant chemoradiotherapy was proposed. A clinical trial was designed, where 32 LABC patients were treated with q3 weekly 5-fluorouracil, epirubicin and cyclophosphamide for three cycles, followed by weekly docetaxel for 9 weeks with concurrent regional radiation (45+5.4Gy) for the first 6 weeks. Patients subsequently underwent modified radical mastectomies. Pathological complete responses (pCR) and 3 year overall survival rates were compared to a matched concurrent control cohort. The concurrent chemoradiation cohort saw a significant increase in pCR rate and a trend toward 15% improvement in overall survival that failed to reach statistical significance. This regimen was not without toxicity, and 25% of patients experienced grade 3 or greater dermatitis and 25% experienced grade 3 or greater pneumonitis, resulting in one death. Tumour biomarker, plasma osteopontin, prior to chemotherapy was found to significantly predict for overall survival. In conclusion, LABC is an aggressive subset of breast cancer for which novel regimens must continue to be developed, taking advantage of the improved response to treatment with radiosensitivity seen in this concurrent chemoradiation regimen, but using alternative radiosensitizing agents to minimize toxicity

    Clinical Management and Evolving Novel Therapeutic Strategies for Patients with Brain Tumors

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    A dramatic increase in knowledge regarding the molecular biology of brain tumors has been established over the past few years, and this has lead to the development of novel therapeutic strategies for these patients. In this book a review of the options available for the clinical management of patients with these tumors are outlined. In addition advances in radiology both for pre-operative diagnostic purposes along with surgical planning are described. Furthermore a review of newer developments in chemotherapy along with the evolving field of photodynamic therapy both for intra-operative management and subsequent therapy is provided. A discussion of certain surgical management issues along with tumor induced epilepsy is included. Finally a discussion of the management of certain unique problems including brain metastases, brainstem glioma, central nervous system lymphoma along with issues involving patients with a brain tumor and pregnancy is provided
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