The purpose of this thesis was to evaluate and compare the peripheral dose associated with VMAT lung SABR treatments for 10X, 6X, and 10X-FFF beams. Flattening Filter Free (FFF) radiotherapy photon beams exhibit high dose rates as compared to standard flattened photon beams. The high dose rates available with FFF beams make them ideal for high dose treatments, such as Volumetric Modulated Arc Therapy (VMAT)-delivery lung Stereotactic Ablative Radiotherapy (SABR), where treatment delivery is longer than that of standard treatments. They are also known to show reductions in treatment head scatter, multi-leaf collimator (MLC) transmission and treatment head leakage radiation, compared to flattened beams. The use of FFF beams for VMAT lung SABR has been shown to significantly reduce treatment delivery time, while maintaining plan quality and accuracy. Another potential advantage of the use of FFF beams for VMAT lung SABR is the reduction in peripheral (out-of-field) dose, due mainly to the reduction in head scatter and treatment head leakage. The peripheral doses delivered by VMAT Lung SABR treatments using 10X-FFF, 10X and 6X were investigated for the Varian TrueBeam medical linear accelerator. There were three components to this investigation; (1) Ion chamber measurement of peripheral dose for static open, static MLC and dynamic MLC fields, (2) Validation of Monte Carlo, Acuros XB and AAA algorithms for peripheral dose prediction, and (3) Evaluation of peripheral doses for VMAT lung SABR treatments using the validated Monte Carlo model. Measurements of out-of field doses for static open, static MLC and dynamic MLC fields showed that 10X-FFF delivered peripheral doses in the range of 30% to 50%, 3% to 40% and 5% to 20% lower than the peripheral doses for flattened beams. Dose calculation algorithm validation showed that AAA and Acuros XB significantly under predicted the dose in the peripheral region. Monte Carlo was found to be the most accurate dose calculation algorithm for peripheral dose prediction. The VMAT lung SABR dose distributions were calculated for both static gantry delivery and arc delivery using the validated Monte Carlo model. For static gantry Monte Carlo simulation, 10X-FFF was found to show a reduction in peripheral dose in the range of 7% to 21% and 7% to 17% when compared to 6X and 10X. For arc delivery Monte Carlo simulation, 10X-FFF was found to deliver a statistically significant reduction in mean peripheral dose compared to 6X in four of the six cases, and was not found to deliver a statistically significant reduction in mean peripheral dose compared to 10X in any of the six cases. For this type of VMAT lung SABR treatment, 10X-FFF offers a reduction in peripheral dose over 6X. In terms of the benefits of using 10X-FFF for this type of treatment, the reduction in peripheral dose is added to the already-established reduction in treatment times. / Graduate / 0756 / 0574

Ο καρκίνος του πνεύμονα είναι η πιο συχνή αιτία θανάτου από καρκίνο παγκοσμίως. Είναι γνωστό ότι ο καρκίνος του πνεύμονα είναι διαδικασία πολλαπλών σταδίων, στην οποία ενέχονται γενετικοί και επιγενετικοί μηχανισμοί. Ενεργοποίηση ογκογονιδίων συμβαίνει σε όλους τους βρογχοπνευμονικούς καρκίνους με αποτέλεσμα την αύξηση των μιτογόνων σημάτων. Στον καρκίνο του πνεύμονα τα πιο συχνά ενεργοποιημένα ογκογονίδια είναι τα EGFR, ERbB2, MYC, KRAS, MET, CCND1, CDK4, EML4-ALK fusion, και BCL2. Επίσης, η απώλεια ογκοκατασταλτικών γονιδίων είναι ιδιαίτερα σημαντική στην πνευμονική καρκινογένεση και είναι συνήθως αποτέλεσμα απενεργοποίησης και των δυο αλληλόμορφων. Συχνά απενεργοποιημένα ογκοκατασταλτικά γονίδια στον καρκίνο του πνεύμονα είναι TP53, RB1, STK11, CDKN2A, FHIT και PTEN. Οι επιγενετικοί μηχανισμοί περιλαμβάνουν την μεθυλίωση του DNA, την τροποποίηση των ιστονών και τη ρύθμιση της γονιδιακής έκφρασης μέσω των microRNAs. Τα microRNAs είναι μικρά, μη κωδικοποιούντα μόρια RNA που εμπλέκονται στην αρνητική μετα-μεταγραφική ρύθμιση της έκφρασης των γονιδίων. Μελέτες έχουν αποδείξει το ρόλο των miRNAs στην φυσιολογική πνευμονική ανάπτυξη και ομοιόσταση αλλά και τον ενεργό ρολό τους στην παθογένεια πνευμονικών νοσημάτων όπως είναι ο καρκίνος του πνεύμονα. Η δημιουργία ωρίμων, λειτουργικών microRNAs απαιτεί τη συντονισμένη δράση μιας ομάδας πρωτεϊνών που στο σύνολο τους απαρτίζουν το μηχανισμό ρύθμισης των microRNA (microRNA machinery). Ο μηχανισμός ελέγχου των microRNA ρυθμίζει μέσω των παραγομένων microRNAs την έκφραση πολλών ογκοκατασταλτικών γονιδίων και ογκογονιδίων. Κύρια συστατικά του μηχανισμού ρύθμισης των microRNA είναι οι ριβονουκλεάσες Drosha, Dicer και AGO2. Σκοπός της παρούσας διατριβής ήταν η μελέτη της κυτταρικής εντόπισης και έκφρασης των συστατικών του μηχανισμού ρύθμισης των microRNA, Drosha, Dicer και AGO2, στον μη μικροκυτταρικό καρκίνο του πνεύμονα. Συγκεκριμένα, ελέγχθηκε η κυτταρική εντόπιση των Drosha, Dicer και AGO2 στις κυτταρικές σειρές καρκίνου του πνεύμονα A549, H23, H358, H661, HCC827 με τη μέθοδο του ανοσοφθορισμού. Στις ίδιες κυτταρικές σειρές, μελετήθηκαν τα κυτταρικά επίπεδα των πρωτεϊνών Drosha, Dicer και AGO2 με την μέθοδο της SDS-PAGE και του ανοσοαποτυπώματος. H έκφραση των πρωτεϊνών αυτών μελετήθηκε σε ιστολογικές τομές παραφίνης μη μικροκυτταρικού καρκίνου του πνεύμονα NSCLC με την μέθοδο της ανοσοϊστοχημείας. Επιπλέον συσχετίσαμε τα επίπεδα της ανοσοϊστοχημικής χρώσης αυτών των ριβονουκλεασών με κλινικοπαθολογοανατομικές παραμέτρους. Η παρούσα εργασία είναι η πρώτη που μελετά την κυτταρική εντόπιση της Drosha in vitro και σε ιστούς από ανθρώπινο καρκίνο του πνεύμονα. Τα επίπεδα ανοσοέκφρασης της Drosha ήταν στατιστικά χαμηλότερα στα νεοπλασματικά κύτταρα NSCLC, σε σχέση με τα φυσιολογικά. Επίσης, τα κυτταρικά επίπεδα της Drosha ήταν στατιστικά χαμηλότερα στα NSCLC σταδίου Ι σε σχέση με το φυσιολογικό ιστό. Όμως, στατιστικά σημαντική διαφορά δεν προέκυψε από την σύγκριση καρκινικών ιστών μεταξύ τους κατά ιστολογικό τύπο, στάδιο νόσου και βαθμό κακοήθειας. Τα ευρήματα αυτά υποδηλώνουν συμμετοχή της ριβονουκλεάσης Drosha στην πνευμονική κακοήθη εξαλλαγή και στην παθογένεια του NSCLC αλλά όχι στην εξέλιξη της νόσου. Η παρούσα εργασία είναι η πρώτη που μελετά την κυτταρική εντόπιση της Dicer in vitro και σε ιστούς από ανθρώπινο καρκίνο του πνεύμονα. Τα πειράματα ανοσοϊστοχημείας, ανέδειξαν ότι τα επίπεδα ανοσοέκφρασης της Dicer ήταν στατιστικά χαμηλότερα στα NSCLC σταδίου Ι σε σχέση με το φυσιολογικό ιστό (p=0,040). Μάλιστα, παρατηρήθηκε στατιστικά σημαντική διαφορά στην ανοσοέκφραση της Dicer στην σύγκριση των τριών σταδίων μεταξύ τους (p=0,049) και αυτό το εύρημα παρουσιάζεται για πρώτη φορά στη βιβλιογραφία από την παρούσα μελέτη. Όμως, τα κυτταρικά επίπεδα αυτής της πρωτεΐνης δεν σχετίζονται με τον ιστολογικό τύπο αλλά και το βαθμό της κακοήθειας. Τα ευρήματα μας αυτά εισηγούνται τη συμμετοχή της ριβονουκλεάσης Dicer στην πνευμονική καρκινογένεση και στην εξέλιξη της νόσου. Τέλος, τα κυτταρικά επίπεδα της ενδονουκλεάσης AGO2 είναι στατιστικά χαμηλότερα στα πνευμονικά νεοπλασματικά κύτταρα σε σχέση με τα φυσιολογικά. Η πρωτεϊνική έκφραση των κυτταρικών σειρών NSCLC παρουσίασε σχεδόν ομοιόμορφη κατανομή. Μάλιστα, και για την πρωτεΐνη AGO2 τα επίπεδα ανοσοέκφρασης είναι στατιστικά χαμηλότερα στα NSCLC σταδίου Ι σε σχέση με το φυσιολογικό ιστό (p=0,000). Όμως, παρατηρήθηκε ότι τα κυτταρικά επίπεδα αυτής της πρωτεΐνης δεν σχετίζονται με τον ιστολογικό τύπο, το στάδιο της νόσου αλλά και το βαθμό της κακοήθειας. Το γεγονός αυτό ενισχύει την άποψη ότι η AGO2 συμμετέχει στην παθοβιολογία του NSCLC αλλά πιθανά όχι στην εξέλιξη της νόσου. Εάν αποδειχθεί σημαντική η συμμετοχή του μηχανισμού ρύθμισης των microRNA στην παθογένεια της πνευμονικής κακοήθειας, θα υπάρξει η δυνατότητα να χρησιμοποιηθούν για την δημιουργία υποομάδων («μοριακά πορτραίτα») του καρκίνου του πνεύμονα, οι οποίες να έχουν προγνωστική αλλά και θεραπευτική αξία (στοχευμένες θεραπείες). / Lung cancer is the leading cause of cancer related death worldwide. Decades of research have contributed to our understanding that lung cancer is a multistep process involving genetic and epigenetic alterations. Oncogene activation occurs in all lung cancers, resulting in persistent upregulation of mitogenic signals. In lung cancer commonly activated oncogenes are EGFR, ERbB2, MYC, KRAS, MET, CCND1, CDK4, EML4-ALK fusion, and BCL2. Loss of tumor suppressor gene (TSG) function is also important in lung carcinogenesis and usually results from silencing of both alleles. Commonly unactivated TSGs in lung cancer are TP53, RB1, STK11, CDKN2A, FHIT and PTEN. Epigenetic alterations include DNA methylation, histone modification and microRNA regulation of gene expression. MicroRNAs are small non-protein encoding RNAs, responsible for the negative post transcriptional regulation of gene expression. Studies have shown the role of microRNAs in normal pulmonary development and homeostasis but also in the pathogenesis of multiple lung diseases including lung cancer. The biogenesis of mature and functional microRNAs requires the orchestrated action of a group of proteins, collectively refered to as miRNA machinery. The miRNA machinery regulates the expression of many TSGs and oncogenes in a miRNA guided fashion. Drosha, Dicer and AGO2 are main components of the miRNA machinery. Our study adressed the cellular localization and protein levels of Drosha, Dicer and AGO2, components of the miRNA machinery, in NSCLC cell lines, and in NSCLC FFPE tissue sections. We employed immunofluorescence and Western blot analysis in five NSCLC cell lines and immunohistochemistry on FFPE NSCLC tissue sections. Staining intensity of the FFPE tissues was correlated with clinicopathological parameters. Altered Drosha cellular distribution was evident in neoplasia. The staining intensity of Drosha (p=0,03) was significantly lower in neoplastic tissues compared to normal tissues. When we compared neoplastic tissue stage I with normal tissues, Drosha’s staining intensity (p=0,002) was significantly lower. Drosha, protein levels were not significantly associated with age, tumor histology, grade or stage. Altered Dicer nuclear distribution was evident in lung neoplasia. The staining intensity of Dicer was significantly lower in neoplastic tissues stage I compared to normal tissues (p=0,04). Dicer’s protein levels in FFPE tissues were significantly associated with tumor stage (p=0,049). AGO2 excibited physiological cytoplasmic distribution in lung neoplasia. The staining intensity of AGO2 was significantly lower in neoplastic tissues compared to normal tissues (p=0,000). When we compared neoplastic tissue stage I with normal tissues, AGO2 staining intensity (p=0,000) was significantly lower. AGO2 protein levels were not significantly associated with age, tumor histology, grade or stage. Our findings provide evidence that the miRNA machinery components Drosha, Dicer and AGO2 are involved in lung carcinogenesis but only Dicer is implicated in cancer progression. The expression levels of the miRNA processing components might contribute to improved cancerous molecular portraits for achieving personalized medicine, the selection of patient-tailored treatment regimens.

The following thesis describes and analyses the representation of lung cancer in the Canadian print media. The thesis employs a theoretical framework comprised of Giddens’ theory of reflexivity and Goffman’s theory of framing, to understand the social dynamics of negotiation behind the disease’s portrayal in the media, in a late modern context. Late modernity was defined by institutional reflexivity and a focus on understanding and mitigating risk. The research was conducted through a content analysis and examined quantitative trends that contributed to a subsequent qualitative interpretation. The results show that the coverage of lung cancer decreased over time. The analysis shows a discourse of a biomedical institution that has unsuccessfully controlled the disease, a lack of patient advocacy, particularly among celebrities, and a continued conflation of smoking behaviour and lung cancer, all of which contributed to the decreasing coverage. The framing processes point to a society focused on understanding risk through studying the disease’s causes, as well as one concerned with legislative debate and behavioural prevention. The emergence of a frame focused on the patient’s lived experience might contribute to an improved representation of the disease.

Overall, this study enhances our understanding of the role of c-Myc activation in chromosome 11 repositioning in mouse PreB v-abl/myc cells and a possible interaction between telomeres, TRF2, and lamin A/C underlying this phenomenon. Additionally, the importance of human 17q25.3 is confirmed as a potential region involved in NSCLC tumorigenesis. A utilizationof the 3D telomeric organization profiles is demonstrated a tendency to categorize NSCLC patients into different prognostic subgroups, underscoring a potential future value of its clinical application. / February 2017

<p>The developments of highly conformal and precise radiation therapy techniques promote the necessity of more accurate treatment target localization and tracking. On-board imaging techniques, especially the x-ray based techniques, have found a great popularity nowadays for on-board target localization and tracking. With an objective to improve the accuracy of on-board imaging for lung cancer patients, the dissertation work focuses on the investigations of using limited-angle on-board x-ray projections for image guidance. The limited-angle acquisition enables scan time and imaging dose reduction and improves the mechanical clearance of imaging.</p><p>First of all, the dissertation developed a phase-matched digital tomosynthesis (DTS) technique using limited-angle (<=30 deg) projections for lung tumor localization. This technique acquires the same traditional motion-blurred on-board DTS image as the 3D-DTS technique, but uses the planning 4D computed tomography (CT) to synthesize a phase-matched reference DTS to register with the on-board DTS for tumor localization. Of the 324 different scenarios simulated using the extended cardiac torso (XCAT) digital phantom, the phase-matched DTS technique localizes the 3D target position with an localization error of 1.07 mm (± 0.57 mm) (average ± standard deviation (S.D.)). Similarly, for the total 60 scenarios evaluated using the computerized imaging reference system (CIRS) 008A physical phantom, the phase-matched DTS technique localizes the 3D target position with an average localization error of 1.24 mm (± 0.87 mm). In addition to the phantom studies, preliminary clinical cases were also studied using imaging data from three lung cancer patients. Using the localization results of 4D cone beam computed tomography (CBCT) as `gold-standard', the phase-matched DTS techniques localized the tumor to an average localization error of 1.5 mm (± 0.5 mm). </p><p>The phantom and patient study results show that the phase-matched DTS technique substantially improved the accuracy of moving lung target localization, as compared to the 3D-DTS technique. The phase-matched DTS technique can provide accurate lung target localizations like 4D-DTS, but with much reduced imaging dose and scan time. The phase-matched DTS technique is also found more robust, being minimally affected by variations of respiratory cycle lengths, fractions of respiration cycle contained within the DTS scan and the scan directions, which potentially enables quasi-instantaneous (within a sub-breathing cycle) moving target verification during radiation therapy, preferably arc therapy.</p><p>Though the phase-matched DTS technique can provide accurate target localization under normal scenarios, its accuracy is limited when the patient on-board breathing experiences large variations in motion amplitudes. In addition, the limited-angle based acquisition leads to severe structural distortions in DTS images reconstructed by the current clinical gold-standard Feldkamp-Davis-Kress (FDK) reconstruction algorithm, which prohibit accurate target deformation tracking, delineation and dose calculation. </p><p>To solve the above issues, the dissertation further developed a prior knowledge based image estimation technique to fundamentally change the landscape of limited-angle based imaging. The developed motion modeling and free-form deformation (MM-FD) method estimates high quality on-board 4D-CBCT images through applying deformation field maps to existing prior planning 4D-CT images. The deformation field maps are solved using two steps: first, a principal component analysis based motion model is built using the planning 4D-CT (motion modeling). The deformation field map is constructed as an optimized linear combination of the extracted motion modes. Second, with the coarse deformation field maps obtained from motion modeling, a further fine-tuning process called free-form deformation is applied to further correct the residual errors from motion modeling. Using the XCAT phantom, a lung patient with a 30 mm diameter tumor was simulated to have various anatomical and respirational variations from the planning 4D-CT to on-board 4D-CBCTs, including respiration amplitude variations, tumor size variations, tumor average position variations, and phase shift between tumor and body respiratory cycles. The tumors were contoured in both the estimated and the `ground-truth' on-board 4D-CBCTs for comparison. 3D volume percentage error (VPE) and center-of-mass error (COME) were calculated to evaluate the estimation accuracy of the MM-FD technique. For all simulated patient scenarios, the average (± S.D.) VPE / COME of the tumor in the prior image without image estimation was 136.11% (± 42.76%) / 15.5 mm (± 3.9 mm). Using orthogonal-view 30 deg scan angle, the average VPE/COME of the tumors in the MM-FD estimated on-board images was substantially reduced to 5.22% (± 2.12%) / 0.5 mm (± 0.4 mm). </p><p>In addition to XCAT simulation, CIRS phantom measurements and actual patient studies were also performed. For these clinical studies, we used the normalized cross-correlation (NCC) as a new similarity metric and developed an updated MMFD-NCC method, to improve the robustness of the image estimation technique to the intensity mismatches between CT and CBCT imaging systems. Using 4D-CBCT reconstructed from fully-sampled on-board projections as `gold-standard', for the CIRS phantom study, the average (± S.D.) VPE / COME of the tumor in the prior image and the tumors in the MMFD-NCC estimated images was 257.1% (± 60.2%) / 10.1 mm (± 4.5 mm) and 7.7% (± 1.2%) / 1.2 mm (± 0.2mm), respectively. For three patient cases, the average (± S.D.) VPE / COME of tumors in the prior images and tumors in the MMFD-NCC estimated images was 55.6% (± 45.9%) / 3.8 mm (± 1.9 mm) and 9.6% (± 6.1%) / 1.1 mm (± 0.5 mm), respectively. With the combined benefits of motion modeling and free-form deformation, the MMFD-NCC method has achieved highly accurate image estimation under different scenarios. </p><p>Another potential benefit of on-board 4D-CBCT imaging is the on-board dose calculation and verification. Since the MMFD-NCC estimates the on-board 4D-CBCT through deforming prior 4D-CT images, the 4D-CBCT inherently has the same image quality and Hounsfield unit (HU) accuracy as 4D-CT and therefore can potentially improve the accuracy of on-board dose verification. Both XCAT and CIRS phantom studies were performed for the dosimetric study. Various inter-fractional variations featuring patient motion pattern change, tumor size change and tumor average position change were simulated from planning CT to on-board images. The doses calculated on the on-board CBCTs estimated by MMFD-NCC (MMFD-NCC doses) were compared to the doses calculated on the `gold-standard' on-board images (gold-standard doses). The absolute deviations of minimum dose (DDmin), maximum dose (DDmax), mean dose (DDmean) and prescription dose coverage (DV100%) of the planning target volume (PTV) were evaluated. In addition, 4D on-board treatment dose accumulations were performed using 4D-CBCT images estimated by MMFD-NCC in the CIRS phantom study. The accumulated doses were compared to those measured using optically stimulated luminescence (OSL) detectors and radiochromic films. </p><p>The MMFD-NCC doses matched very well with the gold-standard doses. For the XCAT phantom study, the average (± S.D.) DDmin, DDmax, DDmean and DV100% (values normalized by the prescription dose or the total PTV volume) between the MMFD-NCC PTV doses and the gold-standard PTV doses were 0.3% (± 0.2%), 0.9% (± 0.6%), 0.6% (± 0.4%) and 1.0% (± 0.8%), respectively. Similarly, for the CIRS phantom study, the corresponding values between the MMFD-NCC PTV doses and the gold-standard PTV doses were 0.4% (± 0.8%), 0.8% (± 1.0%), 0.5% (± 0.4%) and 0.8% (± 0.8%), respectively. For the 4D dose accumulation study, the average (± S.D.) absolute dose deviation (normalized by local doses) between the accumulated doses and the OSL measured doses was 3.0% (± 2.4%). The average gamma index (3%/3mm) between the accumulated doses and the radiochromic film measured doses was 96.1%. The MMFD-NCC estimated 4D-CBCT enables accurate on-board dose calculation and accumulation for lung radiation therapy under different scenarios. It can potentially be valuable for treatment quality assessment and adaptive radiation therapy.</p><p>However, a major limitation of the estimated 4D-CBCTs above is that they can only capture inter-fractional patient variations as they were acquired prior to each treatment. The intra-treatment patient variations cannot be captured, which can also affect the treatment accuracy. In light of this issue, an aggregated kilo-voltage (kV) and mega-voltage (MV) imaging scheme was developed to enable intra-treatment imaging. Through using the simultaneously acquired kV and MV projections during the treatment, the MMFD-NCC method enabled 4D-CBCT estimation using combined kV and MV projections. </p><p>For all XCAT-simulated patient scenarios, the average (± S.D.) VPE / COME of the tumor in the prior image and tumors in the MMFD-NCC estimated images (using kV + open field MV) was 136.11% (± 42.76%) / 15.5 mm (± 3.9 mm) and 4.5% (± 1.9%) / 0.3 mm (± 0.4 mm), respectively. In contrast, the MMFD-NCC estimation using kV + beam's eye view (BEV) MV projections yielded results of 4.3% (± 1.5%) / 0.3 mm (± 0.3 mm). The kV + BEV MV aggregation can estimate the target as accurately as the kV + open field MV aggregation. The impact of this study is threefold: 1. the kV and MV projections can be acquired at the same time. The imaging time will be cut to half as compared to the cases which use kV projections only. 2. The kV and MV aggregation enables intra-treatment imaging and target tracking, since the MV projections can be the side products of the treatment beams (BEV MV). 3. As the BEV MV projections originate from the treatment beams, there will be no extra MV imaging dose to the patient.</p><p>The above introduced 4D-CBCT estimation techniques were all based on limited-angle acquisition. Though limited-angle acquisition enables substantial scan time and dose reduction as compared to the full-angle scan, it is still not real-time and cannot provide `cine' imaging, which refers to the instantaneous imaging with negligible scan time and imaging dose. Cine imaging is important in image guided radiation therapy practice, considering the respirational variations may occur quickly and frequently during the treatment. For instance, the patient may experience a breathing baseline shift after every respiratory cycle. The limited-angle 4D-CBCT approach still requires a scan time of multiple respiratory cycles, which will not be able to capture the baseline shift in a timely manner. </p><p>In light of this issue, based on the previously developed MMFD-NCC method, an AI-FD-NCC method was further developed to enable quasi-cine CBCT imaging using extremely limited-angle (<=6 deg) projections. Using pre-treatment 4D-CBCTs acquired just before the treatment as prior information, AI-FD-NCC enforces an additional prior adaptive constraint to estimate high quality `quasi-cine' CBCT images. Two on-board patient scenarios: tumor baseline shift and continuous motion amplitude change were simulated through the XCAT phantom. Using orthogonal-view 6 deg projections, for the baseline shift scenario, the average (± S.D.) VPE / COME of the tumors in the AI-FD-NCC estimated images was 1.3% (± 0.5%) / 0.4 mm (± 0.1 mm). For the amplitude variation scenario, the average (± S.D.) VPE / COME of the tumors in the AI-FD-NCC estimated images was 1.9% (± 1.1%) / 0.5 mm (± 0.2 mm). The impact of this study is three-fold: first, the quasi-cine CBCT technique enables actual real-time volumetric tracking of tumor and normal tissues. Second, the method enables real-time tumor and normal tissues dose calculation and accumulation. Third, the high-quality volumetric images obtained can potentially be used for real-time adaptive radiation therapy.</p><p>In summary, the dissertation work uses limited-angle on-board x-ray projections to reconstruct/estimate volumetric images for lung tumor localization, delineation and dose calculation. Limited-angle acquisition reduces imaging dose, scan time and improves imaging mechanical clearance. Using limited-angle projections enables continuous, sub respiratory-cycle tumor localization, as validated in the phase-matched DTS study. The combination of prior information, motion modeling, free-form deformation and limited-angle on-board projections enables high-quality on-board 4D-CBCT estimation, as validated by the MM-FD / MMFD-NCC techniques. The high-quality 4D-CBCT not only can be applied for accurate target localization and delineation, but also can be used for accurate treatment dose verification, as validated in the dosimetric study. Through aggregating the kV and MV projections for image estimation, intra-treatment 4D-CBCT imaging was also proposed and validated for its feasibility. At last, the introduction of more accurate prior information and additional adaptive prior knowledge constraints also enables quasi-cine CBCT imaging using extremely-limited angle projections. The dissertation work contributes to lung on-board imaging in many aspects with various approaches, which can be beneficial to the future lung image guided radiation therapy practice.</p> / Dissertation

To improve relatively poor outcomes for locally-advanced lung cancer patients, many current efforts are dedicated to minimizing uncertainties in radiotherapy. This enables the isotoxic delivery of escalated tumor doses, leading to better local tumor control. The current dissertation specifically addresses inter-fractional uncertainties resulting from patient setup variability. An automatic block-matching registration (BMR) algorithm is implemented and evaluated for the purpose of directly localizing advanced-stage lung tumors during image-guided radiation therapy. In this algorithm, small image sub-volumes, termed “blocks”, are automatically identified on the tumor surface in an initial planning computed tomography (CT) image. Each block is independently and automatically registered to daily images acquired immediately prior to each treatment fraction. To improve the accuracy and robustness of BMR, this algorithm incorporates multi-resolution pyramid registration, regularization with a median filter, and a new multiple-candidate-registrations technique. The result of block-matching is a sparse displacement vector field that models local tissue deformations near the tumor surface. The distribution of displacement vectors is aggregated to obtain the final tumor registration, corresponding to the treatment couch shift for patient setup correction. Compared to existing rigid and deformable registration algorithms, the final BMR algorithm significantly improves the overlap between target volumes from the planning CT and registered daily images. Furthermore, BMR results in the smallest treatment margins for the given study population. However, despite these improvements, large residual target localization errors were noted, indicating that purely rigid couch shifts cannot correct for all sources of inter-fractional variability. Further reductions in treatment uncertainties may require the combination of high-quality target localization and adaptive radiotherapy.

Le but de cette étude a été d’analyser l’intérêt de l’aérosolthérapie d’anticorps monoclonaux (AcM) dans le traitement du cancer broncho-pulmonaire non à petites cellules (CBNPC) en utilisant le cetuximab, un AcM anti-EGFR. L’expression du récepteur FcRn, essentiel dans la pharmacocinétique et la biodistribution des IgGs thérapeutiques a été étudiée dans le CBNPC. Nos résultats montrent que l’AcM peut résister aux contraintes physiques de la nébulisation. Les données de biodistribution et pharmacocinétique, obtenues dans un modèle animal, indiquent que l’Ac administré par aérosol, s’accumule de façon prolongée au niveau pulmonaire. De plus, les tumeurs chez la souris paraissent sensibles à l’aérosolthérapie avec l’AcM. Par ailleurs, le récepteur FcRn est moins exprimé au niveau transcriptionnel et protéique dans le tissu tumoral que dans le tissu sain adjacent à la tumeur dans le CBNPC. Cette altération de l’expression pourrait être due à l’hyperméthylation du promoteur de ce gène. / The project aims at determining whether aerosoltherapy is well suited for monoclonal antibodies (Mab), in Non-Small Cell Lung Cancer (NSCLC). In addition, exploration of the expression of FcRn, an IgG receptor contributing to increased half-life and biodistribution of Mab, has been studied in NSCLC. Using cetuximab, an anti-EGFR Mab, we showed that Mab resist the physical constraints of nebulization. Biodistribution and pharmacokinetic analyses, using a murine model, revealed that cetuximab is highly and durably accumulated within the lungs and slowly and weakly released into the bloodstream following airways delivery. Moreover, animal tumors seem sensitive to cetuximab aerosoltherapy. Expression analysis of FcRn at both the transcript and protein levels showed that the receptor is downregulated in NSCLC. FcRn alteration of expression in the tumor might be due to hypermethylation of the gene promoter as often found in cancer.

A dissertation submitted to the Faculty of Science, University of Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science. March 2015 / Lung cancer is currently the most deadly form of cancer due to the fact that metastasis occurs in the lymph nodes making it difficult to remove by surgical means. Chemotherapy has been the most successful method of treatment, although it has been harmful to human health as a consequence of non-specific cytotoxicity. There has been, therefore, a growing interest in cancer research to develop alternative cancer treatments, which are less toxic. Currently plant-derived drugs are perceived to be more effective as they display both cytotoxic activity and are less harmful to overall human health. Thus the aim of the study was to determine the cytotoxic effects of the plant Lobostemon fruticosus on A549 cells. The IC50 of the methanol and butanol extracts of L. fruticosus were obtained at 40 μg/ml and 50 μg/ml, respectively. DNA fragmentation was observed after 48 hour exposure to treatments, indicating that the plant extracts induced apoptosis. Cell cycle analysis indicated that the plant extracts inhibited cell cycle progression at the sub-G0 phase, which indicated that the cells had undergone apoptosis. RT-PCR showed that the expression of p53 was down-regulated; however, p21 and Bax were up-regulated in all treatments. LC-MS identified that the compounds from the plant extracts are known apoptotic inducers. The results lead to the conclusion that the extracts of L. fruticosus, induce cell death in A549 cells. The plant extracts induced a p53-independent apoptotic mechanism, which was mediated by Bax and p21. Key words: Lobostemon fruticosus, camptothecin, taxol, Non-small cell lung cancer (NSCLC)

Introduction: Environmental pollution is a major human problem since the mid-19th century. This situation is improving in the second half of the 20th century when human recognizes the consequences of industrialization. The issue of air pollution and for example, the negative effects of ionizing radiation, or the release of radon from the geological subsoil and its influence on the diseases as lung carcinoma, all these issues get more important. Purposes: The aim of the work is to find out whether there is an association between elevated radon concentration in buildings and some health indicators (incidence and standardized mortality rate). Using statistical analysis, it is examined if there is a statistically significant relationship among the variables and if these variables should be correlated together. The partial aims of the thesis are also to bring a qualitative view in the form of a professional interview and to visualize the acquired data into maps. Methods: The sources of data were the demographic yearbooks of the Czech Statistical Office, the database on the incidence of lung carcinoma from the National Health Information System and the measured values of the volume activity of radon (OAR) provided by the State Office for Radiation Protection. The data was processed by basic statistical...

Evaluation of dose optimization using the Pencil Beam (PB) and Monte Carlo (MC) algorithms may allow physicists to apply dosimetric offsets to account for inaccuracies of the PB algorithm for lung cancer treatment with Stereotactic Body Radiotherapy (SBRT). 20 cases of Non-Small Cell Lung Cancer (NSCLC) were selected. Treatment plans were created with Brainlab iPlanDose® 4.1.2. The D97 of the Planning Target Volume (PTV) was normalized to 50 Gy on the Average Intensity Projection (AIP) using the fast PB and compared with MC. This exact plan with the same beam Monitor Units (MUs) was recalculated over each respiratory phase. The results show that the PB algorithm has a 2.3-2.4% less overestimation at the maximum exhalation phase than the maximum inhalation phase when compared to MC. Significantly smaller dose difference between PB and MC is also shown in plans for peripheral lesions (7.7 ± 0.7%) versus central lesions (12.7±0.8%)(p< 0.01). / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2014. / FAU Electronic Theses and Dissertations Collection