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Short, Wesley A. "Evaluating the Dosimetric Accuracy of Small Gating Windows in Radiotherapy." University of Toledo Health Science Campus / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=mco152538625156708.
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Rojas, Callejas Ana Maria. "ARCON in experimental and clinical radiotherapy." Doctoral thesis, Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-207.
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Land, Imke. "The delivery limitations of adaptive radiotherapy systems." Thesis, University of Warwick, 2009. http://wrap.warwick.ac.uk/2276/.
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Organ motion - whether due to respiration, cardiac motion or digestive processes - is one of the major problems in external beam radiotherapy as it limits the achievable precision in dose delivery. Adaptive radiotherapy (ART) is a novel approach for a more precise dose delivery where measured patient-specific variations are used to change the delivery pattern throughout the treatment course. The aim of the work described in this thesis has been to contribute to the progress of ART by developing dynamic phantoms for the simulation of target motion, evaluating adaptive treatment strategies, and providing tools for the assessment of optimal patient-specific treatment parameters. A dynamic, anthropomorphic and tissue equivalent thorax phantom has been developed and assessed. The phantom provides accurate, three-dimensional regular or irregular motion of both a tumour within the lungs and the chest wall independently. It has been designed to investigate the effect of organ motion on the dose delivered to a moving target, to evaluate the potential benefit of adaptive treatment strategies and to assess ART delivery systems. The potential of the phantom has been evaluated through experiments on a respiratory-gated CT system and during tests on a real-time motion tracking system. In addition, the principles used for the thoracic phantom have been used to design dynamic phantoms for the prostate and bladder. An adaptive off-line correction strategy accounting for inter-fractional prostate motion has been evaluated using radiobiological modelling. This work revealed that it is important to consider the normal tissue complication probability of the rectum and the direction of anterior-posterior prostate motion when determining the optimal timing for re-optimisation of the treatment plan. Specifically, relying on calculations of the tumour control probability alone provides misleading results. In general off-line correction based on only a few observations in the early treatment course is shown to improve the probability of uncomplicated tumour control. Target coverage for respiratory-gated radiotherapy has been modelled with simulated and real breathing traces. The results have demonstrated that maximum benefit is achieved with amplitude gating at end of exhalation. The analysis showed that treatment parameters should be adjusted prior to each fraction. As part of this work a model that assists on deciding the most appropriate gating parameters on an individual patient basis has been developed. Finally, a treatment strategy decision support tool has been developed and applied to respiratory data obtained from patients. The tool not only identifies whether tumour mobility justifies implementing an adaptive treatment technique but where it does the tool supports selecting the optimal ART technique to be used together with the appropriate treatment parameters that will provide the greatest benefit to an individual lung cancer patient.
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Abdelhamid, S. "Respiratory motion modelling and predictive tracking for adaptive radiotherapy." Thesis, Coventry University, 2010. http://curve.coventry.ac.uk/open/items/f135cb12-e9f9-1e4f-9c57-6de2fc378069/1.
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External beam radiation therapy (EBRT) is the most common form of radiation therapy (RT) that uses controlled energy sources to eradicate a predefined tumour volume, known as the planning target volume (PTV), whilst at the same time attempting to minimise the dose delivered to the surrounding healthy tissues. Tumours in the thoracic and abdomen regions are susceptible to motion caused mainly by the patient respiration and movement that may occur during the treatment preparation and delivery. Usually, an adaptive approach termed adaptive radiation therapy (ART), which involves feedback from imaging devices to detect organ/surrogate motion, is considered. The feasibility of such techniques is subject to two main problems. First, the exact position of the tumour has to be estimated/detected in real-time and second, the delay that can arise from the tumour position acquisition and the motion tracking compensation. The research work described in this thesis is part of the European project entitled ‘Methods and advanced equipment for simulation and treatment in radiation oncology’ (MAESTRO), see Appendix A. The thesis presents both theoretical and experimental work to model and predict the respiratory surrogate motion. Based on a widely investigated clinical internal and external respiratory surrogate motion data, two new approaches to model respiratory surrogate motion were developed. The first considers the lung as a bilinear model that replicates the motion in response to a virtual input signal that can be seen as a signal generated by the nervous system. This model and a statistical model of the respiratory period and duty cycle were used to generate a set of realistic respiratory data of varying difficulties. The aim of the latter was to overcome the lack of test data for a researcher to evaluate their algorithms. The second approach was based on an online polynomial function that was found to adequately replicate the breathing cycles of regular and irregular data, using the same number of parameters as a benchmark sinusoidal model.
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Curtin-Savard, Arthur. "Dose delivery uncertainty in photon beam radiotherapy." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=22856.
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It is known that slight variations in total dose delivered to the patient in external beam photon radiotherapy can significantly alter the probability of tumour control. For this reason, ICRU has recommended a goal of $ pm$5% precision in the dose delivery to the target volume. Several investigators have analyzed the degree of precision routinely achieved and have come to the conclusion that ICRU's goal can be attained, but in practice this is just barely so.<br>We have measured the degree of precision which exists in our institution by examining each step of the radiotherapy process on a cobalt unit and a 10 MV linear accelerator. Our study finds beam intensity uncertainties of $ pm$3.8% (one standard deviation) and beam positional uncertainties of $ pm$5.5 mm (one standard deviation). The effect of these uncertainties on the dose to the patient is illustrated for a typical case.
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Rhodes, Charles Ray III. "Development of an Automated Program for Calculating Radiation Shielding in a Radiotherapy Vault." University of Toledo Health Science Campus / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=mco1331557547.
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Muirhead, Rebecca. "The optimization of image guided radiotherapy in lung cancer." Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/2711/.
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The hypothesis of this work was whether IGRT could be safely implemented for clinical use in a busy oncology centre. I aimed to study a number of questions that remain unresolved in the current literature regarding safe and optimised implementation of IGRT techniques. The first study undertaken was the calculation of a local set up margin using two widely recognised margin recipes. This involved the assessment and analysis of multiple images belonging to 100 patients. This allowed progression onto the next project which was assessment of the optimal safe method of delineation of 4DCT. The most efficient method was compared to gold standard. At this point a different aspect of the radiation process was assessed, namely verification. A feasibility study of a simple, efficient form of imaging for use in review of a particular error was performed. This also involved the use of a novel tool which required independent assessment. This progressed into a further study of a larger number of patients using this tool and the images assessed previously to verify a novel form of radiation delivery. Lastly a planning study was performed to quantify the clinical benefit of another delivery system. This involved the delineation and planning of a large number of radical lung patients with standard radiation treatment and the novel radiation treatment and an assessment of the potential clinical benefits. The work presented in this thesis has answered some specific questions in IGRT in lung cancer, and contributed both locally and in the wider lung cancer community to increasing the use of IGRT in lung cancer.
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Vos, Andre. "Determination of an optimal treatment margin for intracranial tumours treated with radiotherapy at Groote Schuur Hospital." Master's thesis, Faculty of Health Sciences, 2021. http://hdl.handle.net/11427/33076.
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Background Accurate delivery of radiotherapy is a paramount component of providing safe oncological care. Margins are applied when planning radiotherapy to account for subclinical tumour spread, physiological movement and set-up error. Set-up error is unique to each radiotherapy institution and should be calculated for each organ site to ensure safe delivery of treatment. Aim and setting The aim of this study is to calculate the random and systematic set-up error for a cohort of patients with intracranial tumours treated with 3D Conformal Radiotherapy at the Department of Radiation Oncology, Groote Schuur Hospital, South Africa. After obtaining above mentioned data the ideal CTV-PTV expansion margin was calculated using published CTV-PTV expansion margin recipes. Patients and methods The Electronic Portal Images (EPID) of 20 patients who met the inclusion criteria were compared to their Digitally Reconstructed Radiograph (DRR). The set-up error for each patient was measured after which the random (s) and systematic (S) set-up error for the study group could be calculated. With both these values known the CTV-PTV expansion margin could be determined. Results The largest error was in the Superior/Inferior (SI) direction, followed by the Medial/Lateral (ML) direction and least in the Anterior/Posterior (AP) direction with 87.7%, 76.2% and 91.6% of the errors in the ML, SI and AP directions respectively being less than 3mm. There was no error larger than 5mm in the ML or AP direction with 6.1% of the SI error larger than 5mm. The random and systematic error in all three directions for this patient cohort were less than 2mm conforming to acceptable standards of delivering safe radiotherapy. Using Stroom's margin recipe (2S + 0.7s) a CTV-PTV expansion margin of 5mm can safely be applied for this patient cohort. Conclusion When treating patients with intracranial tumours at Groote Schuur Hospital the CTV-PTV expansion margin can safely be reduced from 1cm to 5mm.
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Vedam, Subrahmanya. "Management of Respiratory Motion in Radiation Oncology." VCU Scholars Compass, 2002. http://scholarscompass.vcu.edu/etd_retro/162.
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Respiratory motion poses significant problems in the radiotherapy of tumors located at sites (lung, liver, pancreas, breast) that are affected by such motion. Effects of respiratory motion on the different stages of the radiotherapy process (imaging, treatment planning and treatment delivery), has formed the focus of significant research over the last decade. Results from such research have revealed that respiratory motion affects the instantaneous position of almost all structures in the thorax and abdomen to different degrees based on their corresponding anatomic location and muscular attachments. As an example, diaphragm motion was found to be of the order of 1.5 cm, predominantly in the superior-inferior (SI) direction during normal breathing. This indicates a similar magnitude of motion for tumors located in the lower lobes of the lung and in the abdomen.The conventional method of accounting for such motion is to add a margin (based on an estimate of the expected range of organ motion) around the clinical target volume (CTV) that is delineated from the image data. This margin also includes errors due beam-bony anatomy alignment during radiation delivery and errors in patient position between simulation and subsequent treatment delivery sessions. Such a margin estimate may or may not encompass the "current" extent of motion exhibited by the tumor, resulting in either a higher dose to the surrounding normal tissue or a potential cold spot in the tumor volume. Several clinical studies have reported the existence of a direct relationship between the reduction in mean dose to the lung and the incidence of radiation induced pneumonitis. Therefore, subjecting additional normal lung tissue to high dose radiation by adding large margins based on organ motion estimates may result in an increased risk of radiation induced lung injury.Monitoring and accounting for respiratory motion can however potentate a reduction in the amount of normal tissue that receives high dose radiation, thereby decreasing the probability of normal tissue complication and also increasing the possibility for dose escalation to the actual tumor volume. The management (monitoring and accounting) of respiratory motion during radiation oncology forms the primary theme of this dissertation.Specific aims of this thesis dissertation include (a) identifying the deleterious effects of respiratory motion on conventional radiation therapy techniques (b) examining the different solutions that have been proposed to counter the deleterious effects of respiratory motion during radiotherapy (c) summarizing the relevant work conducted at our institution as part of this thesis in addressing the issue of respiratory motion and (d) visualizing the future direction of research in the management of respiratory motion in radiation oncology.Among the various techniques available to manage respiratory motion in radiation oncology such as respiratory gated and breath hold based radiotherapy, our research initially focused on respiratory gated radiotherapy, employing a commercially available external marker based real time position monitoring system. Multiple session recordings of simultaneous diaphragm motion and external marker motion revealed a consistent linear relationship between the two signals indicating that the external marker motion (along the anterior-posterior (AP) direction) could be used as a "surrogate" for motion of internal anatomy (along the SI direction). The predictability of diaphragm motion based on such external marker motion both within and between treatment sessions was also determined to be of the order of 0.1 cm.Analysis of the parameters that affected the accuracy and efficacy of respiratory gated radiotherapy revealed a direct relationship between the amount of residual motion and the width of the "gate" window. It also followed therefore that a trade-off existed between the width of the "gate" and the accuracy of gated treatments and also the overall "Beam ON" time. Further, gating during exhale was found to be more reproducible than gating during inhale. Although, it was evident that a reduction in the width of the "gate" implied a reduction in the margins added around the clinical target volume (CTV), such a reduction was limited by setup error.A study of the potential gains that could be derived from respiratory gating (based on motion phantom experimental set up) indicated a potential CTV-PTV margin reduction of 0.2-1.1 cm while employing gating alone in combination with an electronic portal imaging device, thus decreasing the amount of healthy tissue receiving radiation. In addition, gating also improved the quality of images obtained during simulation by reducing the amount of motion artifacts that are typically seen during conventional spiral CT imaging.Imparting some form of training was hypothesized to better enable patients to breathe in a reproducible fashion, which was further thought to increase the accuracy and efficacy of gated radiotherapy, especially when the "gate" was set close to the inhale portion of the breathing cycle. An analysis of breathing patterns recorded from five patients over several sessions under conditions of normal quiet breathing, breathing with audio instructions and breathing with visual feedback indicated that training improved the reproducibility of amplitude or frequency of patient breathing cycles.An initial exploration into respiration synchronized radiotherapy was thought to facilitate realization of reduced margins without having to hold the radiation beam delivery during a breathing cycle (as is the case with gating). A feasibility study based on superimposition of respiratory motion of a tumor (simulated by a sinusoidal motion oscillator) onto the initial beam aperture as formed by the multileaf collimator (MLC) revealed that tumor dose measurements obtained with such a set up were equivalent to those delivered to a static tumor by a static beam.Finally, a feasibility study for a method to acquire respiration synchronized images of a motion phantom and a patient (in order to perform respiration synchronized treatment planning and delivery) yielded success in the form of a 4D CT data set with reduced motion artifacts.In summary, respiratory gated radiotherapy and respiration synchronized are both viable approaches to account for respiratory motion during radiotherapy. While respiratory gated radiotherapy has been successfully implemented in some centers, several technical advances are required to enable similar success in the implementation of respiration synchronized radiotherapy. However, the potential clinical gains that can be obtained from either of the above approaches and their relative contributions to margin reduction will determine their future applicability as routine treatment procedures.
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Sansourekidou, Patricia. "Accessibility of Innovative Services in Radiation Oncology." ScholarWorks, 2019. https://scholarworks.waldenu.edu/dissertations/7738.
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The field of radiation oncology (RO) involves the use of highly advanced techniques to treat cancer and safely spare healthy organs. The discipline has experienced rapid growth in the past 25 years, with technological advancement as the driving force. Available data and an instrument to effectively measure the accessibility of innovation in the field were lacking. The purpose of this study was to investigate the accessibility of innovative services in RO in the United States and assess possible diffusion patterns. Two hundred and forty medical physicists practicing in RO in the United States completed a custom Internet-based survey. The diffusion of innovation theory was used as the theoretical framework for the study. A quantitative cross-sectional analysis was performed to assess how innovation scores may vary depending on individual and organizational factors. ANOVA, Spearman correlation, and multiple linear regression were used to analyze the data. University affiliation, urbanicity, appreciation, and motivation were found to be statistically significant factors affecting accessibility to innovative services. Statistically significant barriers preventing innovation were lack of evidence, increased complexity, staffing constraints, lack of interest from others, lack of interoperability, and lack of reimbursement. Medical physicists are in a leadership position to influence the adoption of innovative services in RO. Encouraging the utilization of innovative and Food and Drug Administration-approved techniques may improve cancer outcomes and consequently have a positive social change effect on public health.
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Tesson, Mathias Christian Stephane. "Copper-dependent enhancement of targeted radiotherapy by combination with the radiosensitiser disulfiram." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4760/.
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The purpose of this research was to enhance the targeted radiotherapy of two metastatic malignant diseases: neuroblastoma and prostatic carcinoma. By virtue of its high affinity for the norepinephrine transporter (NET), [131I]meta-iodobenzylguanidine ([131I]MIBG) has been used for the therapy of tumours of neuroectodermal origin for more than 25 years. Although not yet universally adopted, [131I]MIBG targeted radiotherapy remains a highly promising means of management of neuroblastoma. MIP-1095, a glutamate-urea-lysine dipeptide has high affinity for prostate-specific membrane antigen (PSMA) and has recently demonstrated exquisite specificity for PSMA-expressing, metastatic prostatic carcinoma. Preliminary imaging studies in patients, using [123I]MIP-1095, revealed tumour-selective binding and prolonged retention only in malignant sites. This indicates the therapeutic potential of this agent when labeled with Iodine-131. Our aim is to make the most effective use of [131I]MIBG and [131I]MIP-1095 for the treatment of neuroblastoma and prostatic carcinoma by combining the [131I]-labelled radiopharmaceutical with radiosensitiser drugs. The thiol-containing molecule disulfiram was selected for combination with targeted radiotherapy because of its reported inhibition of the 26S proteasome and NF-kB activity, its ability to chelate copper and its pro-oxidative effects. The copper-dependence of the cytotoxicity and radiosensitising activity of disulfiram was established in neuroblastoma cell models. Radiation dose enhancement values at the 50% toxicity level were 4.24 and 2.00 in SK-N-BE(2c) and UVW/NAT cells, respectively. The radiosensitising mechanism of disulfiram-copper was shown to involve the inhibition of cell cycle arrest in G2. The enhancement of the cytotoxicity of [131I]mIBG and of [131I]MIP-1095 by disulfiram-copper was demonstrated by delay of the growth of multicellular tumour spheroids. Finally, the screening of the enhancing effect of chemotherapeutic agents on the spheroid growth delay induced by [131I]MIP-1095 indicated that combinations with topotecan, nutlin-3, bortezomib or olaparib have good prospects for therapy of metastatic prostate carcinoma. In conclusion, it is expected that DSF:Cu will enhance the outcome of patients undergoing targeted radiotherapy due to its radiosensitising properties.
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Taylor, Carolyn W. "Breast cancer radiotherapy and heart disease." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:c9dda3ca-8cb3-4a38-938d-0b75b4f6471d.
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Introduction: Some past breast cancer radiotherapy regimens led to an increased risk of death from heart disease. Although heart dose from breast cancer radiotherapy has generally reduced over the past few decades, there may still be some cardiac risk. Estimation of future risk for women irradiated today requires both measurement of their cardiac dose and dose-response relationships, which depend on cardiac dosimetry of past regimens, in conjunction with long-term follow-up data. Methods: Virtual simulation and computed tomography 3-dimensional treatment planning on a representative patient were used to estimate mean heart and coronary artery doses for women irradiated since 1950 in 71 randomised trials in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview. Patient-to-patient variability in cardiac dose was assessed. Heart and coronary artery doses were also calculated for breast cancer radiotherapy regimens used since the 1950s in Sweden. Cardiac doses from contemporary (year 2006) radiotherapy were assessed for 55 patients who received tangential breast cancer irradiation at a large UK radiotherapy centre. The maximum heart distance (i.e. the maximum distance between the anterior cardiac contour and the posterior tangential field edges) was measured for the left-sided patients, and its value as a predictor of cardiac doses assessed. Results: Mean heart dose for women irradiated in the EBCTCG trials varied from <1 to 18 Gray, and mean coronary artery dose from <1 to 57 Gray. Patient-to-patient variability was moderate. Mean heart dose for women irradiated in Sweden since the 1950s varied from <1 to 24 Gray, and mean coronary artery dose from <1 to 46 Gray. Heart dose from tangential irradiation has reduced over the past four decades. However, mean heart dose for left-sided patients irradiated in 2006 was 2 Gray and around half of them still received >20 Gray to parts of the heart and left anterior descending coronary artery. For these patients, maximum heart distance was a reliable predictor of cardiac doses. For the other patients, mean heart dose varied little and was usually less than 2 Gray. Conclusions: Cardiac doses from breast cancer radiotherapy can be estimated reliably and are now available for use in deriving dose-response relationships in the EBCTCG data and in a Scandinavian case-control study. Cardiac dose has reduced over the past four decades. Therefore the cardiac risk is also likely to have reduced. Nevertheless, for some patients, parts of the heart still receive >20 Gray in the year 2006.
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Holmqvist, Annica. "Biological and histological factors as predictors in rectal cancer patients : A study in a clinical trial of preoperative radiotherapy." Doctoral thesis, Östergötlands Läns Landsting, Onkologiska kliniken US, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-66207.
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With improved surgical techniques and preoperative radiotherapy (RT) the local recurrence rate in rectal cancer patients has been reduced, however the mortality rate is still high and there is a huge variation in the response to preoperative RT in patients with the same tumour stage. To improve patient’s survival, it is of great importance to identify good prognostic and predictive factors that help us to select the best suited patients for preoperative RT in the future. For many years, studies of neoplastic transformation have mainly focused on tumour cells. In recent years, researchers have realised that the stroma around tumour cells and their extracellular matrix components also play an important role in tumour carcinogensesis. The aim of this thesis was to investigate the biological factors, survivin and particularly interesting new cysteine-histidine rich protein (PINCH), histological factors, inflammatory infiltration, fibrosis, necrosis, mucinous content, angiogenesis and lymphangiogenesis as well as their relationships to preoperative RT and to clinical variables in rectal cancer patients who participated in a Swedish rectal cancer trial of preoperative RT. In paper I, the expression of survivin and its relationship to preoperative RT and clinical factors were investigated in 98 primary rectal tumours and adjacent normal mucosa. In all patients, positive survivin expression was independently related to worse survival compared to negative survivin expression in a multivariate analysis. In paper II, PINCH expression and its relationship to RT, clinical, histological and biological factors were investigated at the invasive margin and inner tumour area in 137 primary rectal tumours and in cell line of fibroblasts. In patients without RT, strong PINCH expression was independently related to worse survival in a multivariate analysis. No survival relationship was found in the patients with RT, and there was no difference in PINCH expression between the subgroups of non-RT and RT at the invasive margin/inner tumour area. In patients with RT, strong PINCH expression at the inner tumour area was related to a high level of lymphatic vessel density (LVD). In paper III, the frequency of LVD/blood vessel density (BVD) was analysed at the periphery, the inner tumour area and the invasive margin of 138/140 primary rectal tumours and correlated to RT, clinical, histological and biological factors. In all patients, LVD at the periphery of the tumour was independently related to better survival compared to LVD at the inner tumour area/invasive margin. In all patients, a higher LVD at the periphery was related to negative (wild type) p53 expression. In paper IV, the inflammatory infiltration, fibrosis, necrosis and mucinous content were studied in relation to RT, clinical and biological parameters in preoperative biopsies (n = 153) and in primary tumours (n = 148). In all patients and in the subgroups of non-RT and RT a higher grade of inflammatory infiltration was independently related to improved survival compared to weak inflammatory infiltration in a multivariate analysis. In this thesis, survivin, PINCH, LVD and inflammatory infiltration are independent prognostic factors in rectal cancer patients who participated in a clinical trial of preoperative RT. This information may help us to improve patient’s survival by selecting the best suited patients for preoperative RT in the future.
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Jadon, Rashmi. "Adaptive image-guided radiotherapy strategies for implementation of IMRT in gynaecological malignancies." Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/98750/.
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Intensity-modulated radiotherapy (IMRT) for gynaecological malignancies aims to reduce toxicity and improve tumour control. However, there are several barriers to its uptake in clinical practice. Amongst these are that of pelvic organ motion, whereby due to motion of the target organs on treatment there is a risk of geographical miss with IMRT. Secondly, although new IMRT techniques may improve bowel toxicity there is limited knowledge about dose-volume constraints for bowel, making it difficult to assess whether new techniques are likely to translate into clinical improvements. The purpose of this thesis is to address these problems. Methods Dose-volume constraints for late bowel toxicity are investigated initially through systematic review, followed by a dose-volume study based on toxicity data from pelvic radiotherapy patients. Pelvic organ motion is assessed in a systematic review examining organ motion patterns and potential strategies to account for this. Population-based and adaptive margin strategies are investigated in modelling studies for both definitive cervical cancer patients and post-hysterectomy patients. Results Initial systematic review of the literature, followed by the analysis of the toxicity and dosevolume data of 203 pelvic radiotherapy patients highlighted anal canal, bowel loops, bowel bag, sigmoid and large bowel as important organs at risk (OARs) for bowel toxicity. Dosevolume constraints were derived for these organs. Pelvic organ motion was found to be a significant problem for gynaecological IMRT. Adaptive margin strategies, such as plan-of-the-day, were demonstrated to achieve both CTV coverage whilst reducing dose to the OARs compared to standard margins and population-based margins. Conclusions Dose-volume constraints derived for late bowel toxicity, if validated with independent data, may be used to reduce bowel toxicity in future patients, and as a benchmark to assess the efficacy of new IMRT techniques. Adaptive strategies for gynaecological cancers appear a promising solution for organ motion management.
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Fakie, Nazia. "Advanced breast cancer: A retrospective review comparing two palliative radiotherapy protocols used at Groote Schuur Hospital between 2010 and 2013." Master's thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/24483.
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Purpose: To retrospectively evaluate and compare the loco-regional progression free survival (PFS), overall survival (OS) and acute effects of the two breast palliative regimes used in patients with locally advanced or metastatic breast cancer between 2010 and 2013 in a single institution. Methods: Compliance to treatment, acute skin reactions, progression free and overall survival were retrospectively evaluated in patients who received palliative breast radiotherapy for locally advanced breast cancer between 2010 and 2013. The radiotherapy regimes were either 4Gy per fraction for 5 fractions treated 4 times a week (20Gy) or 6Gy per fraction for 6 fractions treated once a week (36Gy). They may have received previous chemotherapy with minimal or no clinical response, as well as hormonal treatment. Results: Forty three patients were followed up over a median period of 24 months, 14 of which received 20Gy and 29 received 36Gy. The average age was 64 years old. Compliance was 88% in both groups. Both groups had either grade 1 (71% vs 62%), grade 2 (21% vs 24%) or grade 3 (8% vs 14%) acute skin reactions. No grade 4 skin reactions were documented. The PFS was shorter at 4.5 months in the 20Gy group compared to 7.7 months in the 36Gy group (p=0.27). The OS was also shorter at 25.8 months in the 20Gy group compared to 29.6 months in the 36Gy group (p=0.51) Conclusion: This study did not show a statistically significant difference in terms of PFS and OS between the two radiotherapy regimes. They both remain reasonable options in local palliation in patients with locally advanced breast cancer.
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Ostyn, Mark R. "Reducing Uncertainty in Head and Neck Radiotherapy with Plastic Robotics." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5558.
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One of the greatest challenges in achieving accurate positioning in head and neck radiotherapy is that the anatomy at and above the cervical spine does not act as a single, mechanically rigid body. Current immobilization techniques contain residual uncertainties that are especially present in the lower neck that cannot be reduced by setting up to any single landmark. The work presented describes the development of a radiotherapy friendly mostly-plastic 6D robotic platform for positioning independent landmarks, (i.e., allowing remote, independent positioning of the skull relative to landmarks in the thorax), including analysis of kinematics, stress, radiographic compatibility, trajectory planning, physical construction, and phantom measurements of correction accuracy. No major component of the system within the field of imaging or treatment had a measured attenuation value greater than 250 HU, showing compatibility with x-ray-based imaging techniques. Relative to arbitrary overall setup errors of the head (min = 1.1 mm, max = 5.2 mm vector error) the robotic platform corrected the position down to a residual overall error of 0.75 mm +/- 0.33 mm over 15 cases as measured with optical tracking. This device shows the potential for providing reductions to dose margins in head and neck therapy cases, while also reducing setup time and effort.
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Henson, Katherine Elizabeth. "Heart disease and lung cancer risks after radiotherapy." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:119bdbd9-00a7-484d-96f0-6b1e59dab696.
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Radiotherapy has been shown to increase the subsequent risk of heart disease among survivors of breast cancer, but little is known about factors, other than the dose of radiation delivered to the heart, which determine the magnitude of the risk. In addition, survivors of teenage and young adult cancer are internationally acknowledged as an understudied population, and limited information is available on their late health risks. This thesis sought to utilise the largest observational datasets available to date for these populations: the Collaborative Group on Observational Studies of Breast Cancer Survivors and the Teenage and Young Adult Cancer Survivor Study. These were used to firstly characterise the radiation-related risks of heart disease and lung cancer, and secondly to provide an overview of the long-term risk of heart disease for the entire spectrum of cancers diagnosed in teenagers and young adults aged 15 to 39. Initially, a methodology study and systematic review demonstrated that selection effects and other biases can be very problematic during analyses of observational cohorts, particularly when using a radiotherapy comparison. However, in the case of heart disease and lung cancer, one can take advantage of the breast being a paired organ and use a laterality comparison, particularly when laterality played little effect in treatment selection. This comparison was used throughout the analyses of breast cancer patients. This thesis demonstrated that adjuvant radiotherapy for breast cancer significantly increased the risk of heart disease among women with left-sided breast cancer and those patients with ipsilateral lung cancer. Interestingly, younger women were at the highest risk of heart disease, and a progressive proportional decrease in risk with increasing age at diagnosis was found, which has not been shown before. It also suggested that radiotherapy and chemotherapy combined may further increase the risk of heart disease among breast cancer patients. Survivors of teenage and young adult cancer, particularly Hodgkin lymphoma, were at a significantly raised cardiac mortality risk compared to the matched general population. The findings of this thesis provide evidence to support continued follow-up for cancer patients, as survivors were found to be at a substantial risk into the second or third decade after treatment. It has permitted the detection of groups of individuals at particularly increased risks, for example younger patients and survivors of Hodgkin lymphoma diagnosed in teenagers and young adults, for whom closer monitoring for late effects or measures to reduce the risk, such as adaptations to treatment, may be appropriate. Finally, evidence was also presented to support the development of clinical follow-up guidelines specifically for survivors of teenage and young adult cancer.
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Royle, Georgina. "Towards quantitative intra-nuclear dose mapping of auger emitting radionuclides used for targeted radiotherapy." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:83c94d40-91a2-4175-b208-b5ea1bd5a207.
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Targeted radiotherapy (TRT) is a technique which allows for individual cancer cells to be targeted by radiation. However, there is variation in uptake at the whole body, organ, cellular and subcellular levels. This distribution affects the biological efficacy of the TRT agents. To address this problem, novel techniques have been developed and demonstrated. These aim to provide quantitative information about the spatial distribution of Auger electron (AE) emitting radiopharmaceuticals at the subcellular level. Two methods have been developed. The first, photoresist autoradiography (PAR), uses photoresists as an autoradiography substrate, and the second uses microautoradiography (MAR) and a transmission electron microscope (TEM). The techniques have been demonstrated using the AE emitter indium-111. Firstly, PAR is demonstrated using poly (methyl methacrylate) (PMMA). Photoresists were exposed to indium-111 which had been internalised into cells, and the photoresists were analysed using atomic force microscopy (AFM). The technique has a theoretical resolution in the nanometre range and was able to demonstrate cellular patterns on the micron scale. To gain quantitative information, the photoresist response (depth of pattern) was calibrated as a function of electron fluence and a model of the patterns was created. Combining the calibration data with the point source model allowed the position and intensity of the internalised source terms to be estimated using the PAR method. Secondly, a technique for electron microscope-microautoradiography (EM-MAR) was developed. The processing conditions of the MAR technique were determined and staining techniques developed, to produce high quality TEM micrographs. A time course experiment showed the distribution and variation in the uptake of the radiopharmaceutical at the cellular level. Both techniques are able to provide information about the subcellular distribution of the radioactivity at a higher resolution than current techniques. Both enable the collection of information which can be used in microdosimetric calculations.
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Berthon, Beatrice. "Optimisation of Positron Emission Tomography based target volume delineation in head and neck radiotherapy." Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/69184/.
Full textAbstract:
Automatic segmentation of tumours using Positron Emission Tomography (PET) was recommended for radiotherapy treatment (RT) planning of head and neck (H&N) cancer patients, and investigated in the scientific literature without reaching a consensus on the optimal process. This project aimed at evaluating the performance of PETCbased automatic segmentation (PETCAS) methods and developing an optimal PETC AS process to be used at Velindre Cancer Centre (VCC). For this purpose, ten algorithms were implemented to represent the most promising PETCAS approaches from a systematic review of the literature. The algorithms’ performance was evaluated on filled phantom inserts with variable size, geometry, tumour intensity and image noise. The impact of thick insert plastic walls on both image quantification and segmentation was thoroughly assessed. The PETCAS methods were further applied to realistic H&N tumours, modelled using a printed subresolution sandwich phantom developed and calibrated in house. Results showed that different PETCAS performed best for different types of target objects. An Advanced decision TreeCbased Learning Algorithm for Automatic Segmentation (ATLAAS) was therefore developed and validated for the selection of the optimal PETCAS approach according to the target object characteristics. Finally, a protocol was designed for the use of PETCAS within RT planning at VCC. The protocol was used retrospectively on a group of 10 oropharyngeal cancer patients, and the results highlighted the additional information brought by PET beyond anatomical imaging. In a prospective study on 10 additional patients, PETCAS replaced manual PET/CT delineation, and accounted for up to 33% of the modifications of manually drawn CT/MRI contours to derive the final planning contour. This study demonstrated the usefulness and reliability of the PETCAS method in RT planning, and led to modifying the clinical workflow for H&N patients at VCC. This work has the potential to be extended to other tumour sites and institutions.
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Delaney, Geoffrey Paul SWSAHS Clinical School UNSW. "The Development of a New Measure of Linear Accelerator Throughput in Radiation Oncology Treatment Delivery - The Basic Treatment Equivalent (B.T.E.)." Awarded by:University of New South Wales. SWSAHS Clinical School, 2001. http://handle.unsw.edu.au/1959.4/33381.
Full textAbstract:
The measurement of productivity in health care is difficult. Studies in various specialty disciplines of medicine have identified that the variation in complexities (casemix) between departments or hospitals will vary and therefore will affect any basic productivity statistics that are produced. Radiation oncology is a discipline of medicine where no such studies into radiotherapy casemix variations and the effect that these may have on productivity measures have been performed, despite the high capital expenditure involved in the delivery of radiotherapy. Radiation oncology productivity on linear accelerators is currently measured by the number of patients treated or number of treatment fields treated per unit time (usually per hour). These statistics have been collected for many years and productivity assessments were made on the variations in these statistics that exist between departments. However, these statistics do not consider the variations in casemix that occur between departments. These complexity differences may be quite marked and therefore may strongly influence the ability of a department to achieve a high patient or treatment field throughput. This may be seen as 'reduced productivity' with no consideration of the complexity of the caseload seen in the department. In addition, future technological changes that improve patient outcome may be introduced. These changes may make treatment more complex. Using older measures of productivity such as fields per hour or patients per hour will not consider these technological changes and the subsequent changes in complexity and hence departments may be seen as less productive in the future using current methods of analysis unless a more valid measure of productivity that considers complexity variations is introduced. There have only been 3 previous attempts at developing measures of linear accelerator productivity. Each of these models have been developed empirically and have not been clinically validated. No previous attempts have been made in determining a scientifically-derived complexity model that considers the variations in treatment technique. This thesis describes research performed between 1995 and 2001. This research study???s primary aims were to study the factors that affect radiotherapy treatment time and treatment complexity and to develop a model of linear accelerator productivity that does consider complexity variations in radiotherapy treatment delivery. This model is called the Basic Treatment Equivalent (B.T.E.). This series of trials examines the old models of linear accelerator productivity, describes the derivation and validation of the BTE model both in Australasia and the United Kingdom, identifies the factors that contribute to treatment time and treatment complexity, describes the development of a pilot model of productivity of gynaecological brachytherapy and outpatient chemotherapy using similar BTE methodology, discusses the potential uses of the BTE model, recent independent reviews of BTE by other groups, and the advantages and disadvantages of using such a model. This research has shown that it is possible to identify the various factors that contribute to treatment time and treatment complexity and to derive a model of linear accelerator productivity that considers the variations in complexity. The BTE model has been clinically validated in Australia, New Zealand and a couple of departments in the United Kingdom and Canada and has been adopted as a new measure by various groups. It requires regular updating to maintain currency particularly as there are frequent improvements in radiation treatment technology. Future studies should identify the differences these technological enhancements make to productivity. The BTE derived from outpatient chemotherapy delivery and gynaecological brachytherapy delivery shows promise although these models require further research with the assistance of other departments.
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Johansson, Jonas. "Comparative Treatment Planning in Radiotherapy and Clinical Impact of Proton Relative Biological Effectiveness." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6593.
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Reilly, Andrew James. "Uniform framework for the objective assessment and optimisation of radiotherapy image quality." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5589.
Full textAbstract:
Image guidance has rapidly become central to current radiotherapy practice. A uniform framework is developed for evaluating image quality across all imaging modalities by modelling the ‘universal phantom’: breaking any phantom down into its constituent fundamental test objects and applying appropriate analysis techniques to these through the construction of an automated analysis tree. This is implemented practically through the new software package ‘IQWorks’ and is applicable to both radiotherapy and diagnostic imaging. For electronic portal imaging (EPI), excellent agreement was observed with two commercial solutions: the QC-3V phantom and PIPS Pro software (Standard Imaging) and EPID QC phantom and epidSoft software (PTW). However, PIPS Pro’s noise correction strategy appears unnecessary for all but the highest frequency modulation transfer function (MTF) point and its contrast to noise ratio (CNR) calculation is not as described. Serious flaws identified in epid- Soft included erroneous file handling leading to incorrect MTF and signal to noise ratio (SNR) results, and a sensitivity to phantom alignment resulting in overestimation of MTF points by up to 150% for alignment errors of only ±1 pixel. The ‘QEPI1’ is introduced as a new EPI performance phantom. Being a simple lead square with a central square hole it is inexpensive and straightforward to manufacture yet enables calculation of a wide range of performance metrics at multiple locations across the field of view. Measured MTF curves agree with those of traditional bar pattern phantoms to within the limits of experimental uncertainty. An intercomparison of the Varian aS1000 and aS500-II detectors demonstrated an improvement in MTF for the aS1000 of 50–100% over the clinically relevant range 0.4–1 cycles/mm, yet with a corresponding reduction in CNR by a factor of p 2. Both detectors therefore offer advantages for different clinical applications. Characterisation of cone-beam CT (CBCT) facilities on two Varian On-Board Imaging (OBI) units revealed that only two out of six clinical modes had been calibrated by default, leading to errors of the order of 400 HU for some modes and materials – well outside the ±40 HU tolerance. Following calibration, all curves agreed sufficiently for dose calculation accuracy within 2%. CNR and MTF experiments demonstrated that a boost in MTF f50 of 20–30% is achievable by using a 5122 rather than a 3842 matrix, but with a reduction in CNR of the order of 30%. The MTF f50 of the single-pulse half-resolution radiographic mode of the Varian PaxScan 4030CB detector was measured in the plane of the detector as 1.0±0.1 cycles/mm using both a traditional tungsten edge and the new QEPI1 phantom. For digitally reconstructed radiographs (DRRs), a reduction in CT slice thickness resulted in an expected improvement in MTF in the patient scanning direction but a deterioration in the orthogonal direction, with the optimum slice thickness being 1–2 mm. Two general purposes display devices were calibrated against the DICOM Greyscale Standard Display Function (GSDF) to within the ±20% limit for Class 2 review devices. By providing an approach to image quality evaluation that is uniform across all radiotherapy imaging modalities this work enables consistent end-to-end optimisation of this fundamental part of the radiotherapy process, thereby supporting enhanced use of image-guidance at all relevant stages of radiotherapy and better supporting the clinical decisions based on it.
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Van, Jaarsveld Albert. "The role of adjuvant radiotherapy for breast cancer patients with axillary node negative or limited nodal disease after total mastectomy, axillary nodal clearance and systemic therapy." Master's thesis, University of Cape Town, 2014. http://hdl.handle.net/11427/5931.
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Riddick, Alison. "Clinical symptoms and volumetric radiological responses of acoustic neuroma patients, treated with hypo-fractionated image guided radiotherapy (IGRT) at Groote Schuur hospital between 2013 and 2016." Master's thesis, Faculty of Health Sciences, 2018. http://hdl.handle.net/11427/30174.
Full textAbstract:
Background:
Stereotactic radiosurgery (SRS) is the gold standard for treatment of small and medium
sized tumours, although fractionated regimens are well described. Access is limited in
resource-constrained settings. There are no South African data describing outcomes of AN
patients treated with fractionated stereotactic radiotherapy (SRT) using photons. We
describe clinical and radiological outcomes of AN patients treated with SRT at an academic
centre in Cape Town, South Africa.
Objectives:
To describe patient demographics, tumour characteristics and patients’ symptoms and
changes in symptoms at follow-up. To investigate tumour local control (LC) rates at last
follow up MRI, and compare LC rates described for SRS in the literature. To correlate
radiologists’ serial 2D maximum linear diameter (MLD) measurements with calculated 3D
tumour volume (TV).
Methods:
Fifteen AN patients treated with modified SRT (18.0gy/3fractions, were identified from the
planning database; 13 were included. Patient data and tumour characteristics (size, laterality
and previous surgery) were retrospectively extracted from clinic folders. Initial planning data
was accessed and checked. Tumour volumes were contoured by the author on all
subsequent MRI’s per patient and validated by a second investigator; tumour volume (TV)
was automatically calculated. Radiologist’s 2D MLDs were compared with 3D TV. Sensitivity
and specificity of radiologist reported change of MLD as a measure of actual change in TV
was calculated. LC was calculated, from time of treatment to time of last MRI or time of
progression (defined as ≥20% increase in TV).
Results:
Mean age was 60.4years (range 45-79years), with 4 (30.8%) being female. Seven patients
(53.8%) had left sided tumours and median tumour size was 1.15cm3 (mean 1.59 cm3; range
0.62-3.35 cm3). Nine patients (69.2%) had Koos stage 2 ANs, 3 (23.1%) had stage 3
tumours and 1 (7.7%) had a stage I tumour. Two patients had NF2.Median follow-up time
12 was 29 months (range 0-50 months). Median baseline TV, as was 1.15 cm3 (mean 1.59cm3
with range 0.62-3.35 cm3).
Three patients had no follow-up MRIs: 2 demised and 1 declined further follow-up. In total 5
patients died, 4 of unrelated causes and 1 of unknown cause (median time to death after RT
24 months, range 6 - 36 months). LC was 74% at 36months. Hearing preservation rate was
67%. No new facial or trigeminal nerve symptoms were noted. Radiologists correctly
reported tumour growth in 100% of tumours that grew, and specificity was 77.3% in those
that were stable.
Conclusion:
This is the first local study in hypofractionated SRT using photons. We show lower LC rates
than seen in literature; our numbers are small and short follow up time short, with high
attrition rates. Acute treatment toxicities were absent. Longer term follow-up is needed to
assess late RT effects. A prospective study using this method of treatment would better
define LC.
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Benk, Véronique. "Effect of delay in initiating radiotherapy in patients with early-stage breast cancer : results of a natural experiment." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0020/MQ55038.pdf.
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Mu, Xiangkui. "Clinical application of intensity and energy modulated radiotherapy with photon and electron beams." Doctoral thesis, Umeå : Strålningsvetenskaper, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-443.
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Gyenes, Gábor. "Cardiac side-effects of adjuvant radiotherapy for early breast cancer /." [Budapest] ; Stockholm, 1997. http://diss.kib.ki.se/1997/963-9106-04-6.
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Reddy, Bhiskar. "Dosimetric comparison of volumetric modulated arc therapy and three dimensional conformal radiotherapy in the adjuvant setting for the management of gastric cancer : target volume coverage and normal tissue sparing." Master's thesis, University of Cape Town, 2014. http://hdl.handle.net/11427/12943.
Full textAbstract:
Includes bibliographical references.<br>Whilst the benefit of adjuvant radiotherapy in gastric cancer is known, the optimal means of delivery, including two dimensional conventional, three dimensional conformal radiotherapy, intensity modulated radiotherapy and volumetric modulated arc therapy is less certain. The purpose of this study is to assess and compare volumetric modulated arc therapy (VMAT) and three dimensional conformal radiotherapy (3DCRT) plans in adjuvant radiation of gastric cancer.
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Chandrasekaran, Mekala. "The effect of photon dose calculation algorithms on the clinical outcome of radiotherapy as assessed by radiobiological models." Thesis, University of Liverpool, 2012. http://livrepository.liverpool.ac.uk/9373/.
Full textAbstract:
The accuracy of dose calculation algorithms used for radiotherapy treatment planning play a significant role in the clinical outcome of various treatment regimens. Heterogeneities in human anatomy such as lung, air cavities, bone, soft tissue and fat present challenges to the dose calculation algorithms as they are prone to disrupt the charged-particle equilibrium. Monte Carlo (MC) based dose calculation algorithms are proven to be superior to all the current analytical algorithms owing to their ability to account for all the physical interactions that are involved in radiation transport. Numerous publications have examined the differences in physical doses calculated by analytical algorithms when compared to MC in dealing with heterogeneities. However, before this work the clinical significance of these differences in physical dose has never been investigated in detail. An EGSnrc, BEAMnrc and DOSXYZnrc based MC dose calculation engine was set up in a parallel computing environment to simulate three-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiation therapy (IMRT). A Varian 2100 C/D accelerator head was modeled and validated to match measurements of open and dynamic wedged fields in a homogeneous water phantom which was found to be in good agreement with measurements within 2%/2mm and 3%/3mm respectively. In addition, MC calculated doses in a heterogeneous lung phantom were compared to radiochromic film measurements. Overall, there was good agreement between the two, although large differences of upto 16% were found in some cases. This dose calculation system was used to perform MC simulations on computed tomography (CT) images. The clinical impact of the differences in absolute doses calculated by various photon dose calculation algorithms for two clinical tumour sites was investigated. The tumour control probability (TCP) and normal tissue complication probability (NTCP) were estimated using well established bio-mathematical radiobiological models. This work includes the analysis of 7 convolution (i.e. pencil-beam) and convolution-superposition (CS) based photon dose algorithms available in commercial treatment planning systems (TPSs) as well as MC, in treatment plans of non-small cell lung carcinoma (NSCLC) and nasopharyngeal carcinoma (NPC). In both NSCLC and NPC, the convolution algorithms overestimate the dose to the tumour and hence overestimate the TCP to up to 45%. Some of the CS algorithms were comparable to MC though others exhibit significant differences. In NSCLC, the absolute differences in the NTCP values with radiation pneumonitis and rib fracture as end points were not as large as the differences found in the TCPs. On the other hand, in NPC, the overestimation of probability of occurrence of xerostomia by some TPS algorithms may be preventing dose escalation. Parameters for the TCP model were derived by fitting the TCP predictions to published outcome for four widely varying dose-fractionation regimens for a patient cohort undergoing radical radiotherapy treatment for NSCLC. The derived parameter sets strongly depend on the accuracy of the dose calculation algorithm involved. Parameters derived based on dose-distribution data sets obtained using one particular dose calculation algorithm may not hold good when evaluating treatment plans calculated with a different algorithm. In this sub-study, the influence of dose calculation algorithms on TCP model parameters was evaluated. Significant differences were found in TCPs when calculated with inconsistent parameters. Hence, the choice of dose calculation algorithm is crucial and although some algorithms generally perform close to MC in handling inhomogeneities, it is necessary to understand how the underlying differences affect the predicted clinical outcome.
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Dahrouge, Simone. "Prediction of recurrence in prostate cancer following radiotherapy: Value of biomarkers microvessel density, MIB-1, P-53, BCL2, and Bax." Thesis, University of Ottawa (Canada), 2003. http://hdl.handle.net/10393/26367.
Full textAbstract:
Background. Standard traditional parameters relied on for estimating the risk of disease recurrence after curative radiotherapy in prostate cancer are stage, Gleason score and PSA.
Objectives. To elucidate the prognostic role of biomarkers: P-53, MIB-1, MVD, Bax and BCL2 in prostate cancer.
Method. Cox proportional hazard model was used to estimate the risk of disease progression associated with these biomarkers and develop models based on traditional parameters only or incorporating biomarkers. Models were compared for their predictive potential using Akaike information criteria and concordance index.
Results. Statistically significant associations were found between all biomarkers and risk of progression. MVD, Bax and Bax/BCL2 were independent predictors of outcome. Models incorporating biomarkers were superior to the traditional one in identifying patients at risk of local progression.
Conclusions. Biomarkers may be useful in forecasting the risk of local recurrence following radiotherapy in prostate cancer patients. The results require validation in a separate cohort.
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Nutting, Christopher. "Can intensity-modulated radiotherapy (IMRT) be used to reduce toxicity and improve tumour control in patients with head and neck cancer?" Thesis, City University London, 2012. http://openaccess.city.ac.uk/1128/.
Full textAbstract:
Radiotherapy is commonly used in the treatment of head and neck cancer. For early stage tumours, conventional radiotherapy techniques have a high cure rate and low levels of long-term complications. Patients with more advanced cancers have much lower cure rates and high levels of treatment-related complications. Intensity modulated radiotherapy (IMRT) is a new form of focussed radiation therapy. It has been used to reduce the radiation dose to normal tissue structures and increase the dose delivered to tumour bearing tissues. This potentially allows reduced side effects and increased tumour control compared to conventional radiotherapy. The rationale of this thesis was to test whether these twin goals could be achieved in head and neck cancer patients. The first part of the thesis describes improvements in patient immobilisation, optimisation of techniques for neck irradiation, and evaluation of the technique in a busy radiotherapy department. It includes pre-clinical evaluation of IMRT for different tumour sites, the development of quality assurance programs and the conduct of a national randomised controlled trial of parotid-sparing IMRT. This trial concluded that IMRT significantly reduced patient-reported xerostomia, allowed recovery of saliva production and improved quality of life. The second part of the thesis describes pre-clinical evaluation of techniques to escalate radiation dose in patients with larynx and hypopharynx tumours. A phase I/II clinical trial showed that higher doses of radiation can be delivered at the expense of an increase in acute radiation toxicity but without a measurable increase in late radiation side effects. In the larynx and hypopharynx groups, a possible increase in local control was observed. This thesis describes the process of evaluation of a new radiotherapy technology and could be used as a template for testing other new technologies in the future.
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Cashmore, Jason. "Operation, characterisation & physical modelling of unflattened medical linear accelerator beams and their application to radiotherapy treatment planning." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4616/.
Full textAbstract:
The flattening filter is a conical shaped piece of metal sitting within the treatment head of a linear accelerator, used to produce a flat, uniform beam of X-rays from the forward-peaked distribution exiting the target. Despite their routine use since the introduction of the linac in the 1950’s, however, there are still several unresolved issues surrounding their use. The photon scatter and electron contamination introduced by modifying the fluence are difficult to model, as is the variation in energy spectrum caused by differential absorption across the field. Leakage radiation also causes increased whole body doses to the patient, and the filter itself causes acts as an amplifier for beam bending and steering issues. With advances in tumour imaging, dose optimisation and in-room image-guidance it is now possible to locate a tumour accurately in space and to design radiation fields to conform to its shape, avoiding adjacent normal and critical tissues. This active production of non-flat fields means that the prerequisite for flat fields no longer exists, and the filter is potentially no longer a necessary component. This thesis reports on research to produce a filter-free linear accelerator, from basic operation and optimisation, dosimetric characterisation and beam modelling, through to treatment planning and dose delivery. FFF beams have been shown reduce many of the problems seen with the current generation of linear accelerators, producing beams that are inherently more stable, simple to model and with reduced patient leakage (leading to reduced secondary cancers). The increase in dose rate also translates into shorter treatment times for many treatments, aiding patient comfort and reducing problems associated with intra-fraction motion.
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Belenkov, Alexandre I. "Ku86 antisense oligonucleotides and their delivery : increasing the efficacy of radiotherapy and chemotherapeutic agents in tumor treatment." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85125.
Full textAbstract:
One strategy to overcome intrinsic or acquired resistance of cancer cells to ionizing radiation (IR) and genotoxic chemotherapeutic agents is to modulate DNA repair. IR and some of these agents induce DNA double strand breaks (DSBs) that are primarily repaired in mammalian cell via the nonhomologous end joining (NHEJ) pathway. NHEJ is a crucial process that has been conserved highly throughout eukaryotic evolution. A DNA-dependent protein kinase (DNA-PK) multi-protein complex plays an important role in NHEJ, and its increased level or activity is associated with acquired drug resistance of several human tumors. The core protein of the DNA-PK multi-protein complex is represented by a Mr ~ 460,000 catalytic subunit (DNA-PKcs) which, in itself, is a serine-threonine kinase. Ku86 and Ku70 at an equimolar ratio form the Ku heterodimeric protein, a binding subunit of the DNA-PK complex. The Ku protein binds to DNA ends and other types of discontinuity in double-stranded DNA. Ku86 is well preserved in organisms as evolutionarily disparate as bacteria and humans and its role has also been implicated in a variety of cellular responses such as the regulation of telomere length and the control of transcription.<br>The aim of this thesis was to investigate whether down-regulation of the Ku86 gene, by 2'-O-methoxyethyl/uniform phosphorothioate chimeric antisense oligonucleotides (ASOs), would increase the sensitivity of cancer cells to IR and anticancer drugs. To our expectations, transfection of several cancer cell lines with Ku86 antisense ASOs was associated with a specific decrease in Ku86 mRNA levels (IC50 <25 nM; n = 3) and a concomitant rapid decrease (<10% of control) in Ku86 protein expression. Moreover, a decrease in Ku86 protein levels was associated with a 2-fold increase in cell death after treatment with IR and several chemotherapeutic agents. In our effort to improve the efficacy of antisense in vivo delivery we also evaluated polyethyleneimine (PEI, 2kDa) alone or grafted with non-ionic amphiphilic block copolymer PluronicRTM (P85) as a carrier for Ku86 ASO delivery. In athymic nude mice bearing subcutaneous human HT29 colon adenocarcinoma xenografts, Ku86 ASO - P85-g-PEI (2kDa) administration (15 mg/kg, s.c.) with a Q1D x 7 treatment schedule, when combined with a single dose of ionizing radiation (6Gy), caused a significant inhibition of HT29 tumor growth compared with mismatch- and naked antisense-pretreated control groups (time from 200 to 1,000 mm3, 126.9 vs. 84.18 and 87.76 days, P<0.005). (Abstract shortened by UMI.)
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Chilà, Deborah. "Dose tracking in radiation oncology using daily CBCT: effects of physical parameters on dose calculation accuracy." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2020. http://amslaurea.unibo.it/20587/.
Full textAbstract:
The availability of cone beam computerized tomography (CBCT) images at the time of treatment has opened possibilities for recalculations and tracking of the delivered dose, becoming an effective tool for adaptive radiotherapy. A significant component in the accuracy of dose recalculation on CBCT images is the calibration of the Hounsfield units (HU) to density.
The aim of this thesis, developed at the Policlinic of Modena, is to assert a methodology for the characterization of the HU-to-density calibration curve, and to evaluate the impact of the calibration phantom inserts composition and phantom volume on dose calculation accuracy.
The HU-to-density calibration curves from four different phantoms were measured and compared. The HU output of a kV CBCT scan depends on the physical parameters of the phantom density inserts, with particular reference to the atomic number (Z), due to the photoelectric effect which is the main radiation-matter interaction at kV energies. The phantom radial diameter also influences the HU values on the image. The effect of scattering and beam hardening was examined as a function of phantom diameter, founding a high deviation on the HU value of the same density insert when varying the radial diameter of the phantom, especially for high densities. When we are dealing with CBCTs also the acquisition parameters influence the resulting image, that’s why we will show that a protocol-specific calibration curve is needed. The resulting calibration curves were used to compare the calculated doses against planned ones. The percent difference between recalculated and planned dose was obtained for chosen clinically important dose levels and a box plot analysis was conducted.
Results show that the best calibration curve for dose recalculation on CBCT images has been obtained when a human-tissue-equivalent inserts are used and when the radial diameter of the phantom is close to the dimensions of the real patient.
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Orvehed, Hiltunen Erik. "Robust optimization of radiotherapy treatment plans considering time structures of the delivery." Thesis, Uppsala universitet, Avdelningen för datalogi, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-355628.
Full textAbstract:
Cancer is the second largest mortal disease in Sweden, and high efforts are made to develop the treatment of cancer. One of the main treatment methods is radiotherapy, which uses ionizing radiation to damage the cancerous cells. This has the chance of stopping the cell reproduction, and the goal is to reduce the tumor and stop the tumor growth. The most common forms of radiotherapy uses external beams to irradiate the tumor. In intensity modulated radiotherapy, IMRT, the beam fluences are optimized to give a highly conformal dose, i.e. a dose distribution which is restricted to the tumor and has low dose values outside of the tumor. A conformal dose is necessary to spare healthy tissue and sensitive organs, and thus keep the side-effects of the treatment at an acceptable level. The optimized beam shapes are created using a multileaf collimator, MLC. Finding the leaf positions and dose levels is formulated as a problem in the framework of mathematical optimization. Currently, one of the limitations in delivering conformal dose is due to patient movement during the treatment. In IMRT, the beams are delivered by consecutive segments, and the exact pairing of the segments with the patient position will have an impact on the delivered dose. This is called the interplay effect, and can cause both underdosage of the tumor and overdosage of the surrounding tissue. There are methods of mitigating the interplay effect. For example, the beam could be restricted to a single phase of the motion by repeatedly turning it on and off. This is known as gating. However, gating and many other interplay mitigation techniques lead to prolonged treatment times, which decreases the clinical throughput, causes higher patient discomfort and gives higher uncertainties in the delivered dose. This makes it desirable to find methods which avoid prolonged treatment times, while still giving highly conformal doses. Ideally, the best method would be to have a beam which follows any target movement. This idea is known as target tracking. In this thesis, an optimization method is suggested which includes the interplay effect in the treatment optimization. Two main treatment strategies are proposed. The method which is simplest to implement clinically is to create plans which are robust against uncertainties in the times for the patient motion. The resulting doses are found to give acceptable target covering where similar, conventional plans give a significant target underdose. To further increase the conformality of the doses, a non-robust method paired with gating technology is suggested. This method can effectively be seen as a target tracking method, and has the possibility to give highly conformal doses under acceptable treatment times.
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Jackson, Mark Richard. "The identification and validation of Auger electron-emitting radiopharmaceuticals targeting telomerase for cancer therapy." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:040d10f6-c69b-41d3-b73f-7c47c4053db2.
Full textAbstract:
Telomerase is expressed in the majority (>85%) of tumours but not in differentiated normal tissue. This enzyme catalyses the elongation of telomeres – a process critical for continued cell proliferation. Telomerase is a potential novel target for molecularly-targeted radiotherapy (mRT), due to its nuclear localization and expression profile. The radiolabelling of telomerase inhibitors may accelerate and enhance the cytotoxicity of such molecules, as a result of irradiation of the DNA. An oligonucleotide targeting telomerase RNA (hTR), shown to inhibit enzyme activity in vitro, was selected for study. Complementary and non-targeting control oligonucleotides were conjugated to a metal chelator (DTPA) to allow radiolabelling with indium-111. The radioiodination of MST-312, BIBR-1532 and flavonoid-derived small molecule inhibitors of telomerase was also pursued. The inhibitory activity of the candidate molecules was analysed using the telomeric repeat amplification protocol (TRAP). The internalization of inhibitors was assessed by gamma-counting following cell lysis. The clonogenic assay was employed to measure the effect of modified inhibitors on cell survival. Small molecule telomerase inhibitors were modified for labelling with iodine-123, which led to a modest decrease in inhibitory potency, compared to the parent molecules. Radiolabelled small molecules exhibited poor stability and internalization into cancer cells, so were unsuitable for mRT. Modified oligonucleotides potently inhibited telomerase activity, whereas a non-targeting oligonucleotide exhibited no inhibitory activity. Indium-111 radiolabelled oligonucleotides decreased the clonogenic survival of telomerase-positive breast cancer cells but not telomerase-negative cells, in a sequence-specific manner. Accordingly, complementary radiolabelled oligonucleotides were found to induce the DNA damage marker γH2AX. Oligonucleotides localized to nuclear Cajal bodies, the sites of telomerase assembly, in a proportion of cancer cells. Telomerase inhibitors of different classes were radiolabelled with Auger electron-emitting radionuclides, and delivered to cells. Radiolabelled oligonucleotides targeting telomerase significantly reduced the clonogenicity of cancer cells in vitro. This study represents a novel approach for the mRT of telomerase-positive cancers.
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Somaiah, Navita. "Investigating the role of DNA double strand break repair in determining sensitivity to radiotherapy fraction size." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:8f941f8c-fa0d-4936-aac9-11549aaecb94.
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The dose of curative radiotherapy (RT) for cancer is commonly limited by adverse effects presenting years later. Late reacting normal tissues are, on average, more sensitive to the size of daily doses (fractions) than early reacting normal tissues and cancers. Clinical trials have shown breast cancers to be one exception to this rule, in that they are as sensitive to fraction size as the late reacting normal tissues. This has led to the adoption of hypofractionation (use of fractions >2.0 Gy) in the UK for the adjuvant therapy of women with early breast cancer. An understanding of the molecular basis of fraction size sensitivity is necessary to improve radiotherapy outcome. In this respect, it is relevant that late reacting normal tissues have lower proliferative indices than early reacting normal tissues and most cancers. Here, we test the hypothesis that tissue sensitivity to fraction size is determined by the DNA repair systems activated in response to DNA double strand breaks (DSB), and that these systems vary according to the proliferative status of the tissue. Clinical data suggest that sensitivity of epidermis to fraction size varies over a 5-week course of RT. It resembles a late reacting normal tissue in its sensitivity to fraction size in the first week of RT and loses fractionation sensitivity by weeks 4 & 5. We used this feature of human epidermis to test how fractionation sensitivity and DNA repair changed over 5 weeks of RT. Breast skin biopsies were collected 2 h after the 1st, 5th and last fractions from 30 breast cancer patients prescribed 50 Gy/25fractions/5weeks. Sections of epidermis were co-stained for Ki67, cyclin A, p21, RAD51, 53BP1 and β1-Integrin. After 5 weeks of radiotherapy, the mean basal Ki67 density increased from 5.72 to 15.46 cells per mm of basement membrane (p=0.002), of which the majority were in S/G2 phase as judged by cyclin A staining (p<0.0003). The p21 index rose from 2.8% to 87.4% (p<0.0001) after 25 fractions, indicating cell cycle arrest in the basal epidermis. By week 5, there was a 4-fold increase (p=0.0003) in the proportion of Ki67-positive cells showing RAD51 foci, confirming an association between activation of homologous recombination (HR) and loss of tissue fractionation sensitivity. Subsequently, CHO cell lines deficient in specific DNA repair genes were used to test molecular pathways involved in sensitivity to fraction size. We irradiated AA8 (WT), irs-1SF (XRCC3-), V3-3 (DNA-PK-) and EM9 (XRCC1-) with 16 Gy gamma-rays in 1 Gy daily fractions over 3 weeks or 16 Gy in 4 Gy daily fractions over 4 days, and studied clonogenic survival, DNA double-strand break (DSB) repair kinetics (RAD51 & 53BP1 staining) and cell cycle analysis using flow cytometry. We found that wild-type and DNA repair defective cells acquire resistance to fractionated radiotherapy by accumulation in the late S/G2 phase of the cell cycle and increased use of HR. In contrast, the irs1SF cells, defective in HR, failed to acquire radioresistance and remained equally sensitive to ionizing radiation throughout the 3-week treatment. We also demonstrated that sensitivity to fraction size is associated with functional NHEJ. It was undetectable in V3-3 cells lacking NHEJ and thereby likely relying on HR. The high fidelity of HR, which is independent of induced DNA damage levels and hence, of fraction size, may explain the low fractionation sensitivity of cells using HR to repair radiation induced DSBs. We then wanted to investigate the modifying effects of small molecule inhibitors of DNA repair on fractionation responses. To this end we tested the effects of adding selected ATM, PARP, and DNAPK inhibitors to fractionated radiotherapy in WT CHO cells. Our results showed that the ATM inhibitor had a significant radiosensitising effect when combined with fractionated RT and resulted in loss of sparing effect of fractionation in wild type CHO cells, an observation that may be clinically relevant. We also examined DNA DSB repair kinetics (RAD51 & 53BP1 foci) with these drugs in the context of fractionated IR.
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Wryobeck, John M. "The role of fatigue, positive affect and negative affect in the reporting of quality of life in a group of radiation oncology patients." Virtual Press, 1998. http://liblink.bsu.edu/uhtbin/catkey/1074539.
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The use of quality of life instruments to evaluate the effect of cancer and its treatment on individuals has increased but the process by which the patient comes to make these quality of life evaluations has not been addressed. Earlier studies have shown the reporting of physical symptoms and the evaluation of one's health to be related to negative affect. The purpose of this study was to investigate whether the relationship between negative affect and the evaluation of ones health would remain the same in a group of cancer patients, when a major disease and treatment symptom, fatigue was controlled for. The current study found no relationship between negative affect and the evaluation of health once fatigue was controlled for. Negative affect and fatigue were found to be moderately correlated and fatigue accounted for a large proportion of the variance in the quality of life domains of physical, functional and emotional well-being. Both empirical and theoretical issues are discussed.<br>Department of Counseling Psychology and Guidance Services
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Ovtcharov, Slav. "Impact of TMPRSS2-ERG fusion gene on prostate cancer cell response to chemotherapy, radiotherapy and androgen deprivation therapy." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:f30bf48d-fff5-49e7-8258-107a500c8752.
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Many aspects of the mechanisms by which prostate cancer (PCa) progresses from being a confined tumour to advanced metastatic and castration-resistant disease remain unclear. The aim of this study is to evaluate in vitro the potential role of the fusion gene TMPRSS2-ERG in the response of PCa cells to ionising radiation (IR) and androgen deprivation therapy (ADT). This research focused on assessing the presence of the TMPRSS2-ERG transcript across various PCa cell lines and identifying any correlation between the TMPRSS2-ERG transcript and other genes, particularly genes related to DNA damage repair pathways. Several genes involved in cell metabolism and development were found to correlate with TMPRSS2-ERG but not genes involved in DNA repair. In accordance with previous reports, this research confirmed a proliferative advantage for cells expressing ERG. However this project also tested the role of ERG-status in response to chemotherapy, radiation and ADT. The data showed that VCaP and DuCaP cells exposed to low-dose radiation demonstrated decreased viability irrespective of their ERG-status. Similarly ADT decreased the viability of VCaP cells and seemed to neutralise the proliferative advantage of TMPRSS2-ERG positive cells. Stimulation with dihydrotestosterone caused increased radioresistance of TMPRSS2-ERG positive cells. Treatment with taxanes showed stronger effect on cells with lower ERG expression. This work suggests that the proliferative advantage conferred by ERG overexpression in in vitro models can be neutralised by castration and IR.
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Bham, Saif Ahmed Shahab. "Role of delta-like 4 in solid tumours and response to radiation therapy." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:f977581c-a460-4876-9ce4-dcbe9494aa1e.
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Delta-like ligand 4 (DLL4) is a ligand for the Notch family of receptors. DLL4 is an important regulator of angiogenesis and DLL4 blockade promotes non-productive angiogenesis and delays tumour growth. The aim of this thesis was to investigate the effects of anti-DLL4 therapy in solid tumours in combination with a clinically relevant dose of ionising radiation (5 Gy; IR) and to analyse alterations in the Notch pathway induced by the treatments. Combining both treatments resulted in a greater than additive tumour growth delay in LS174T tumours, compared to either treatment alone. DLL4 blockade dysregulated vasculature and increased necrosis in LS174T and HCT-15 (DLL4-expressing and negative cell lines respectively) tumours within 3 days after treatment, but no changes were observed with IR alone. Additionally, combined IR and anti-DLL4 treatment of FaDu tumours (another DLL4-negative cell line) by our colleagues, also resulted in a supra-additive growth delay. These results show that combining IR with DLL4 blockade is an effective strategy for prolonging tumour growth delay and suggest that the stroma/vasculature provide the main therapeutic target for the anti-DLL4 therapy. Analysis of Notch pathway shows that IR upregulated Jag1 in tumour cells, and may inhibit Notch and downregulate DLL4 in the stroma. These changes may potentially affect tumour vessels and response to anti-DLL4 therapy. In vitro, anti-DLL4 therapy induced proliferation in quiescent contact-inhibited endothelial cells and also appeared to abrogate IR-induced inhibition of migration. These results suggest that DLL4 may be important in maintaining vessel quiescence and that IR may in part decrease migration through Notch signalling. Combining IR and DLL4 blockade to target tumour growth is an effective and well tolerated strategy and warrants further validation and refinement to be translated into clinical practice.
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Thomas, Eloïse. "Développement d’une seconde génération de nanoparticules AGuIX pour des applications théranostiques en oncologie." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1121/document.
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Avec 8,8 millions de morts en 2015, le cancer est la deuxième cause de mortalité dans le monde et le nombre de nouveaux cas ne devrait cesser d'augmenter dans les décennies à venir. Il est donc primordial de développer de nouveaux outils pour le diagnostic et la thérapie de ces maladies. Dans ce contexte, l'Institut Lumière Matière a développé une nanoparticule appelée AGuIX® (Activation et Guidage de l'Irradiation X). De taille inférieure à 5 nm, elle est constituée d'une matrice de polysiloxane, à la surface de laquelle sont greffés de manière covalente des complexes de gadolinium. La présence de ces complexes lui permet d'être utilisée comme agent de contraste en Imagerie par Résonnance Magnétique (IRM) et d'améliorer l'efficacité de la radiothérapie (effet radiosensibilisant).Cette thèse traite du développement d'une deuxième génération de nanoparticules AGuIX® afin de permettre des diagnostics encore plus précis ou des thérapies encore plus performantes. Pour cela, on a cherché : (i) à améliorer l'effet radiosensibilisant de cette nanoplateforme en ajoutant des complexes de bismuth à sa surface ; (ii) à complexer des radiométaux variés pour permettre la détection des particules en scintigraphie ; (iii) à fonctionnaliser les particules pour mettre en place de la photothérapie dynamique guidée par IRM. Dans tous les cas, après avoir optimisé les synthèses, différentes techniques de caractérisation ont été mises en place afin d'obtenir une description précise des particules. L'efficacité de ces nano-objets pour le diagnostic et/ou le traitement des cancers a ensuite été évaluée grâce à de nombreuses collaborations, en France ou à l'international<br>With 8.8 million deaths in 2015, cancer is the second leading cause of death in the world and the number of new cases should continue to increase in the decades to come. It is therefore essential to develop new tools for the diagnosis and therapy of this disease. In this context, the Institute of Light and Matter has developed a nanoparticle called AGuIX® (Activation and Guidance of Irradiation X). With a size below 5 nm, it is made of gadolinium chelates covalently grafted to a polysiloxane core. Thanks to these complexes, the nanoparticle can be used as a contrast agent for Magnetic Resonance Imaging (MRI) and can improve the radiotherapy efficacy (radiosensitizing effect).The goal of this PhD is to develop a second generation of AGuIX® nanoparticles to allow even more precise diagnosis or even more effective therapies. For this, we focused on: (i) improving the radiosensitizing effect of this nanoplateform by adding bismuth complexes to its surface; (ii) complexing various radiometals to enable the NPs detection by scintigraphy; (iii) functionalizing the NPs for MRI-guided photodynamic therapy. In all cases, after optimization of the syntheses, various characterization techniques were put in place to obtain an accurate description of the particles. The effectiveness of these new nano-objects for the diagnosis and/or treatment of cancers was then evaluated thanks to several collaborations, in France or internationally
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Qvarnström, Fredrik. "DNA Damage Response of Normal Epidermis in the Clinical Setting of Fractionated Radiotherapy : Evidence of a preserved low-dose hypersensitivity response." Doctoral thesis, Uppsala universitet, Enheten för onkologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-101075.
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Investigations of DNA damage response (DDR) mechanisms in normal tissues have implications for both cancer prevention and treatments. The accumulating knowledge about protein function and molecular markers makes it possible to directly trace and interpret cellular DDR in a tissue context. Using immunohistochemical techniques and digital image analysis, we have examined several principal DDR events in epidermis from patients undergoing fractionated radiotherapy. Acquiring biopsies from different regions of the skin provides the possibility to determine in vivo dose response at clinically relevant dose levels throughout the treatment. A crucial event in cellular DDR is the repair of DNA double strand breaks (DSBs). These serious lesions can be directly visualised in cells by detecting foci forming markers such as γH2AX and 53BP1. Our results reveal that DSB-signalling foci can be detected and quantified in paraffin-embedded tissues. More importantly, epidermal DSB foci dose response reveals hypersensitivity, detected as elevated foci levels per dose unit, for doses below ~0.3Gy. The low-dose hypersensitive dose response is observed throughout the treatment course and also in between fractions: at 30 minutes, 3 hours and 24 hours following delivered fractions. The dose response at 24 hours further reveals that foci levels do not return to background levels between fractions. Furthermore, a low-dose hypersensitive dose response is also observed for these persistent foci. Investigations of end points further downstream in the DDR pathways confirmed that the low-dose hypersensitivity was preserved for: the checkpoint regulating p21 kinase inhibitor; mitosis suppression; apoptosis induction and basal keratinocyte reduction. Our results reveal preserved low-dose hypersensitivity both early and late in the DDR pathways. A possible link between the dose-response relationships is therefore suggested. The preserved low-dose hypersensitivity is a cause for re-evaluation of the risks associated with low-dose exposure and has implications for cancer treatments, diagnostics and radiation protection.
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Pirovano, Giacomo Maria. "TOPK as a novel determinant of radiosensitivity." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:a2b05e51-7f21-433f-8d28-51ac1a72a503.
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Radiotherapy is the use of ionising radiation to induce localised DNA damage to cancerous tissues, leading to cell death and disease control. In order to maximise tumour growth control and to limit damage of the healthy surrounding tissues and the consequent side effects for the patient, molecular determinants of tumour radioresistance are investigated as potential clinical targets. A high-throughput siRNA colony formation assay screen in HeLa cervical carcinoma cells previously published by our laboratory identified modulators of radiosensitivity. From the list CSF1R, EPHB2, GAK and TOPK, were selected and validated. TOPK (T-LAK cell-originated protein kinase, also known as PDZ-binding kinase, PBK) was selected for further investigation because it is overexpressed in most malignancies but not in normal tissues, apart from testis and placenta. Knockdown of TOPK was shown to induce radiosensitisation in a panel of cancer cell lines with no significant effects on normal cells. A role for TOPK in the cell cycle response to ionising radiation (IR) was discovered in HCT116 colorectal cancer cells, with alterations in the G<sub>1</sub>/S and G<sub>2</sub>/M checkpoints. Furthermore, immunoprecipitation experiments identified a physical interaction between TOPK and CDKN1A (p21) at 8 hours after IR. Apoptosis and the number of multinucleated cells were significantly increased in TOPK depleted cells exposed to IR, suggesting the possibility of aberrant mitosis and mitotic catastrophe in these cells. High TOPK expression in early breast cancer patients was shown to be associated with poor recurrence-free survival. In addition, immunohistochemistry (IHC) analysis on samples from prostate cancer patients identified a strong correlation between high levels of TOPK and poor clinical response to radiotherapy. In order to facilitate future in vivo experiments, an HCT116 shRNA stable knockdown cell line was developed and two commercially available TOPK inhibitors were tested and optimised. Taken together, these data suggest that TOPK is a molecular determinant of radiosensitivity with a great potential for future clinical applications.
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Montay, gruel Pierre-Gabriel. "Réponse du cerveau sain, des cellules souches neuronales et du glioblastome à une nouvelle technique de radiothérapie Flash." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS147.
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De nos jours, plus de 50% des patients porteurs de tumeur bénéficient d’un traitement de radiothérapie. Malgré de récentes avancées technologiques augmentant de la précision des traitements, la radiothérapie encéphalique induit toujours des effets secondaires invalidants et irréversibles. Ce constat justifie le développement de nouvelles techniques de radiothérapie. Des études précliniques réalisées sur l’irradiation FLASH ont montré la possibilité de maintenir un effet anti-tumoral tout en réduisant drastiquement les effets secondaires sur le tissu sain. Cet effet a été appelé « l’effet FLASH ». Cette technologie consistant à délivrer des doses à des débits supérieurs à 40 Gy/s a généré un intérêt important pour l’augmentation de l’index thérapeutique de la radiothérapie.Ce travail de thèse vise à étudier l’effet anti-tumoral de l’irradiation FLASH sur des modèles précliniques de glioblastome, tout en évaluant ses effets sur le tissu cérébral sain. Des modèles murins de glioblastome sous-cutané, orthotopique et transgénique ont été développés et irradiés grâce à un prototype d’accélérateur linéaire d’électrons délivrant une irradiation FLASH ou conventionnelle. De plus, des modèles murins d’irradiation encéphalique ont été mis au point afin d’investiguer les effets cellulaires et les altérations fonctionnelles induites par l’irradiation FLASH. La division cellulaire et la structure neuronale dans l’hippocampe ont été évaluées, ainsi que des aspects plus physiopathologiques comme la neuroinflammation ou l’astrogliose. Un panel de tests cognitifs a également été utilisé afin d’étudier les altérations cognitives induites par l’irradiation encéphalique. Enfin, les évènements physico-chimiques engendrés par l’irradiation FLASH et plus particulièrement le rôle de la consommation de dioxygène lors de l’irradiation, ont été analysés afin d’élucider les mécanismes qui supportent l’effet FLASH.Dans tous les modèles étudiés, l’irradiation FLASH a présenté un effet anti-tumoral au minimum similaire à celui de l’irradiation conventionnelle. Les modèles d’irradiation encéphalique ont montré une innocuité de l’irradiation FLASH sur le tissu cérébral sain, avec une absence de déficits cognitifs pour des débits de dose supérieurs à 100 Gy/s, couplée à une absence d’altération de la division cellulaire et de la structure neuronale dans l’hippocampe, une absence de neuroinflammation et d’astrogliose. De plus, des résultats similaires ont été observés avec l’utilisation de rayons X délivrés à ultra-haut débit par un rayonnement synchrotron. Sur le plan mécanistique, la réversion des effets protecteurs de l’irradiation FLASH par l’induction d’une hyperoxie, l’absence d’effet de l’anoxie sur l’effet anti-tumoral et la production de moins de radicaux libres souligne le rôle primaire du dioxygène dans l’effet FLASH.L’ensemble de ces résultats illustre la possibilité d’augmenter l’index thérapeutique de la radiothérapie en utilisant l’irradiation FLASH. En effet, cette nouvelle technologie permet de préserver le tissu sain contre les toxicités radio-induites lorsque l’irradiation est délivrée à des débits supérieurs à 100 Gy/s, tout en gardant un effet anti-tumoral équivalent à l’irradiation conventionnelle. D’après ces résultats précliniques et un transfert clinique dans un futur proche, l’irradiation FLASH pourrait devenir une technique de choix dans le traitement des tumeurs par radiothérapie<br>Nowadays, more than 50% of cancer patients can benefit from a radiation-therapy treatment. Despite important technological advance and dose delivery precision, encephalic radiation-therapy still induces large and irreversible side effects in pediatric and adult cancer patients, justifying the urge to develop new radiation-therapy techniques. Preclinical studies on FLASH irradiation (FLASH-RT) showed a possibility to efficiently treat the tumors, without inducing drastic side-effects on the normal tissue, by increasing the dose-rate over 40 Gy/s. This so called “FLASH effect” set off an important interest in this new irradiation technology to increase the therapeutic ratio of radiation-therapy.This PhD work aimed at investigating the antitumor effect of FLASH-RT on brain tumor models along with the assessment of the ultra-high dose-rate irradiation effects on the normal brain tissue. In this context, subcutaneous, orthotopic and transgenic glioblastoma murine models were used to investigate the curative effect of FLASH irradiation delivered with an experimental LINAC available at the CHUV, and able to deliver both conventional and FLASH irradiation. Moreover, murine models of whole brain irradiation were developed to investigate the radiation-induced cellular and functional alterations at early and late time-points post-FLASH-RT. These models were used to decipher the cellular effectors involved in the brain’s radiation response including hippocampal cell-division and neuronal responses but also more physio pathological aspects as radiation-induced reactive astrogliosis and neuroinflammation. A panel of well-defined cognitive tests was also developed to investigate the radiation-induced cognitive alterations. Eventually, the physio-chemical primary events induced by FLASH-RT, and particularly the role of dioxygen consumption, were investigated to decipher the mechanisms that underlie the FLASH effect.In all investigated tumor models, FLASH-RT displayed an efficient antitumor effect at least similar to the conventional irradiation. The whole brain irradiation models showed an innocuousness of FLASH-RT on the normal brain tissue, with an absence of cognitive deficit several months after irradiation at dose-rates above 100 Gy/s, coupled with a preservation of hippocampal cell division and neuronal structure. This protection was also observed at the physio pathological level with an absence of astrogliosis and neuroinflammation. Moreover, these results were reproduced with ultra-high dose-rate X-Rays delivered with a synchrotron light source. On the mechanistic side, the reversion of the protective effects of FLASH-RT by hyperoxia, and the absence of effect of anoxia on the antitumor effect, along with a decreased ROS production underlies the primary role of dioxygen consumption during ultra-high dose-rate irradiation.Altogether, these unique results depict the possibility to increase the therapeutic index of radiation-therapy by the use of FLASH-RT. Indeed, this new irradiation technology preserves the normal brain tissue from radiation-induced toxicities by increasing the dose-rate over 100 Gy/s, while keeping an antitumor effect equivalent to the conventional dose-rate irradiation. According to these preclinical results and an upcoming clinical translation, FLASH-RT might become a major contributor to the cancer treatment by radiation therapy
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Cutter, David J. "Radiation-related cardiovascular disease following cancer therapy." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:3f02ca87-530d-4ee7-9382-4b457bec62b5.
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<b><u>Introduction:</b></u> Some cancer survivors are known to have an elevated risk of morbidity and mortality from cardiovascular disease. An important cause of this elevated risk is recognised to be irradiation of normal tissues during radiotherapy received as part of cancer therapy. There are substantial difficulties in studying radiation-related cardiovascular disease (RRCD). The reasons for this include the complexities of measuring radiation normal tissue doses retrospectively and the prolonged latencies of many of the cardiovascular endpoints. A variety of complimentary research methodologies can help provide additional knowledge to guide the appropriate management of patients treated in the past and of new patients in the future. <b><u>Methods:</b></u> 1) A cohort study of mortality from circulatory disease in the nationwide British Childhood Cancer Survivor Study (BCCSS). 2) A case-control study of valvular heart disease (VHD) in Dutch Hodgkin lymphoma (HL) survivors, including retrospective radiation dosimetry to estimate the radiation dose to heart valves. 3) A dosimetric study of cardiovascular radiation doses in patients entered into the UK NCRI Lymphoma Study Group RAPID trial, including predictions of 15-year cardiac mortality using innovative methods. 4) A modelling study to predict mean whole heart dose (MWHD) from involved field radiotherapy (IFRT) for HL using anatomical measures. 5) A prospective study using cardiovascular magnetic resonance (CMR) imaging to characterise the heart in women receiving radiotherapy for breast cancer. <b><u>Results:</b></u> 1) The risks of all types of circulatory mortality are elevated in survivors of childhood cancer. The absolute excess risks continue to increase 40+ years following diagnosis. The risk of death from cardiomyopathy and heart failure increased substantially with the introduction of anthracycline chemotherapy. There is no evidence of a reduction in risk of circulatory mortality in more recent eras of diagnosis. 2) There is a strong relationship between estimated radiation dose to the affected heart valve and the risk of subsequent VHD (p<0.001). This effect was modelled to allow prediction of the risk of VHD. 3) A proportion of patients treated with IFRT received a substantial cardiac radiation dose (MWHD = 8.8 Gy, SD = 5.6) but, on average, the predicted 15-year cardiac mortality following treatment is low (absolute risk 0.2%, range 0.0 to 2.7%). 4) It is possible to estimate the mean whole heart dose from IFRT prior to detailed radiotherapy planning based on pre-treatment diagnostic imaging to an accuracy of 5-6% of the prescribed dose. 5) Although women received low cardiac doses (MWHD = 1.5 Gy, SD = 0.8) and have a low predicted risk of cardiac radiation-related morbidity and mortality, there is some evidence of subclinical effects on strain and strain rate imaging of the anterior portions of the left ventricle that receive the highest radiation dose. <b><u>Conclusions:</b></u> Using a variety of methods these studies have all succeeded in adding to knowledge about the nature, magnitude and timing of RRCD. This knowledge can be used to help the future management of cancer patients. In addition, each of the studies has natural and planned extensions and will continue to contribute further knowledge into the future.
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Sun, Aijun. "Radiolabeled acetate PET in oncology imaging studies on head and neck cancer, prostate cancer and normal distribution /." Doctoral thesis, Umeå : Umeå university, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-32980.
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Khan, Nadeem. "Dosimetric Calculation of a Thermo Brachytherapy Seed: A Monte Carlo Study." Connect to full text in OhioLINK ETD Center, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=mco1228860927.
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Thesis (M.S.)--University of Toledo, 2008.<br>"In partial fulfillment of the requirements for the degree of Master of Science in Biomedical Sciences." Title from title page of PDF document. Bibliography: p. 153-155.
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Brada, Michael. "Contribution to the evolution of treatment and care of oncology patients : technical advances in radiotherapy, introduction of novel systemic therapies and innovative care, their implementation and evaluation with a particular focus on the central nervous system, thoracic, lymphoid and testicular tumours." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.682348.
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The last three decades have seen major advances in oncology. As an active researcher I have been at the forefront of the development and implementation of the changes which included new laboratory tests, the development and implementation of novel radiotherapy technology, technical and clinical evaluation of new techniques of radiotherapy including an interest in late side effects of treatment, systematic reviews of radiotherapy technologies, testing new systemic therapies and developing new methods of care. The dissertation includes the principal work published in peer reviewed literature. While each publication tells an independent story they are linked in a narrative in the initial pages of the dissertation to summarise the critical aspects of each publication and define the context within oncology. The aim has been to generate objective and rigorous research output free of commercial and other potential vested interests to provide sound evidence based framework for patient care and treatment. Optimum management approaches have been defined for a number of tumour types based on distillation of research led by me combined with a critical review of literature published at the time. The goal has always been to come up with treatment and care strategies of real benefit to patients to improve survival, tumour control or quality of life. As would be expected, research activity did not always result in improvement. For ultimate progress it is equally if not more important to discard ineffective treatments that do not live up to expectation not to mislead patients and to avoid research "blind alleys" which divert effort and funds. Many of the studies reported have stood the test of time either as initial reports heralding a change in practice or as benchmark studies of aspects of tumour management some of which are quoted in major oncology texts.
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Baro, Serrano Marta. "Estudio del efecto de dasatinib en combinación con cetuximab en un modelo animal de radioterapia experimental." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/125003.
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La hiperactividad del EGFR (epidermal growth factor receptor) confiere mal pronóstico. El EGFR se encuentra sobreexpresado en distintos tipos de tumores, entre ellos el cáncer de colon, pulmón, páncreas y cabeza y cuello (HNSCC). Además la cooperación con otros miembros de la familia del EGFR podría ampliar esta lista a otras neoplasias. La inhibición del EGFR es una de las vías de investigación más activa contra el cáncer.
La radioterapia consigue, en un elevado porcentaje de casos, una buena respuesta. Sin embargo, la existencia de células resistentes a la radiación reduce el control tumoral. Una de las causas de la radioresistencia es la hiperactividad del EGFR.
En cáncer de cabeza y cuello, el bloqueo del EGFR con el anticuerpo monoclonal anti- EGFR cetuximab aumenta el control local y la supervivencia en pacientes tratados simultáneamente con radioterapia. Sin embargo, no todos los pacientes tratados con cetuximab y radiación se benefician del tratamiento, lo que sugiere que, independientemente de la expresión del EGFR, existen mecanismos de resistencia a la combinación. La ramificación de las vías de señalización que dependen del EGFR sugiere que la topografía de la resistencia puede ser variada y múltiple. Cuanto más arriba de la vía de transmisión de señales se sitúe el by-pass, mayor debería ser la resistencia debido a que un mayor número de funciones citoprotectoras se verían liberadas.
Se han descrito distintas posibilidades de by-pass al bloqueo del EGFR. Una de las oncoproteínas que podría ejercer un by-pass proximal es SRC, cuya actividad se relaciona con la progresión tumoral tanto en fases avanzadas como en lesiones premalignas. Además, SRC y EGFR comparten vías de señalización que promueven la progresión de la célula tumoral. En conjunto estos hechos sugieren que la inhibición de SRC podría aumentar la potencia antitumoral de la combinación de radioterapia y cetuximab.
En este proyecto se han evaluado los efectos del tratamiento concomitante con radioterapia, cetuximab y dasatinib, y mejorado los conocimientos de los mecanismos biológicos involucrados. También se ha determinado si el uso de inhibidores de SRC podía potenciar el efecto antitumoral de la combinación de radioterapia y cetuximab en tumores dependientes del EGFR.
La adición de DST al cetuximab o al cetuximab y radioterapia tuvo un efecto contrario al esperado: produjo un mayor crecimiento de los tumores, un incremento de la angiogénesis y de la síntesis de ADN, un aumento de la fosforilación de las oncoproteínas RAS, ERK1/2, AKT y STAT3; una elevación de la secreción de VEGF, y una hiperactividad del metabolismo glucolítico. El tratamiento combinado con dasatinib e inhibidores de las quinasas JAK, HER2 y MET no inhibió el exceso de fosforilación de ERK inducido por dasatinib, una respuesta reactiva similar a la descrita con C225 y que sugiere la implicación de mecanismos de acción, comunes e independientes de JAK, HER2 y MET.
Por el contrario el bloqueo de EGFR por el inhibidor tirosina quinasa AG1478 dio lugar a una inhibición completa de la fosforilación de ERK y AKT a pesar de la presencia de DST, indicando que la quinasa del EGFR está implicada en el efecto antagónico inducido por dasatinib.
Por último, este trabajo contribuye a la idea que la combinación de terapias moleculares puede dar lugar a antagonismos, que pueden ponerse de manifiesto durante una investigación preclínica antes de ser evaluados en ensayos clínicos.<br>Aberrant epidermal growth factor receptor (EGFR) signalling drives oncogenesis in many carcinomas, including head and neck squamous cell cancer (HNSCC). Irrespective of the mechanism of activation, EGFR overexpression is a major origin of resistance to cancer cell death—and a relevant cause of local failures after radiotherapy.
The blockage of EGFR by the monoclonal antibody cetuximab in combination with radiotherapy has been shown to improve survival and local control in head and neck cancers. However, major responses are limited in part due to the robustness of signalling networking, which grants alternative routes to avoid blockage of EGFR. SRC-family kinases occupy a central position within the cell signal networking, which makes SRC a potential target in cancer treatment.
In this project we evaluated the effects of the concomitant treatment with radiotherapy, cetuximab and dasatinib, and improved the knowledge of the biological mechanisms involved; to determine whether SRC inhibitors could potentiate the antitumor effects of radiotherapy and cetuximab combination in EGFR-dependent tumours. Unexpectedly, the addition of dasatinib to cetuximab or cetuximab and radiotherapy resulted in an antagonistic effect which was characterized by increased tumour growth; an increase in the angiogenesis and DNA synthesis; association with the inhibition of SRC; an increase in cell signalling involving phosphorylation of RAS, ERK1/2, AKT and STAT3 oncoproteins; elevation of VEGF secretion and hyperactivity of glycolytic metabolism. Also, the simultaneous blockade of SRC and JAK kinases, HER2 or MET, induced a similar reaction to that described with cetuximab suggesting the involvement of mechanisms of action, common and independent, of JAK, HER2 and MET.
Conversely, blocking EGFR with the tyrosine kinase inhibitor AG1478 resulted in a complete inhibition of ERK and AKT phosphorylation, despite the presence of dasatinib, indicating that the EGFR kinase is involved in the induced antagonistic effect of dasatinib. Finally, this project contributes to the idea that the combination of molecular therapies can result in antagonism, which may become perceptible during a preclinical research before being evaluated in clinical trials.
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Vouche, Michael. "Radiation Segmentectomy, Radiation Lobectomy and Response Assessment after 90Yttrium Radioembolization for Hepatocellular carcinoma: Imaging and Clinical Implications." Doctoral thesis, Universite Libre de Bruxelles, 2017. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/241979.
Full textAbstract:
Hepatocellular carcinoma is a primary liver cancer.Among treatment options for hepatocellular carcinoma, Yttrium-90 radioembolization is a promising transarterial therapy.This thesis investigates potential clinical applications of radioembolization in the treatment of the hepatocellular carcinoma (techniques of radiation segmentectomy and radiation lobectomy), and adress the problematic of the response Assessment after radioembolization.<br>Doctorat en Sciences médicales (Médecine)<br>info:eu-repo/semantics/nonPublished