BACKGROUND:In this study the feasibility of intensity-modulated radiotherapy (IMRT) and tomotherapy-based image-guided radiotherapy (IGRT) for locally advanced esophageal cancer was assessed.METHODS:A retrospective study of ten patients with locally advanced esophageal cancer who underwent concurrent chemotherapy with IMRT (1) and IGRT (9) was conducted. The gross tumor volume was treated to a median dose of 70Gy (62.4-75Gy).RESULTS:At a median follow-up of 14months (1-39 months), three patients developed local failures, six patients developed distant metastases, and complications occurred in two patients (1 tracheoesophageal fistula, 1 esophageal stricture requiring repeated dilatations). No patients developed grade 3-4 pneumonitis or cardiac complications.CONCLUSIONS:IMRT and IGRT may be effective for the treatment of locally advanced esophageal cancer with acceptable complications.

<p>The present thesis is focused on the development and application of dose response models for radiation therapy. Radiobiological models of tissue response to radiation are an integral part of the radiotherapeutic process and a powerful tool to optimize tumor control and minimize damage to healthy tissues for use in clinical trials. Ideally, the models could work as a historical control arm of a clinical trial eliminating the need to randomize patents to suboptimal therapies. In the thesis overview part, some of the basic properties of the dose response relation are reviewed and the most common radiobiological dose-response models are compared with regard to their ability to describe experimental dose response data for rat spinal cord using the maximum likelihood method. For vascular damage the relative seriality model was clearly superior to the other models, whereas for white matter necrosis all models were quite good except possibly the inverse tumor and critical element models. The radiation sensitivity, seriality and steepness of the dose-response relation of the spinal cord is found to vary considerably along its length. The cervical region is more radiation sensitive, more parallel, expressing much steeper dose-response relation and more volume dependent probability of inducing radiation myelitis than the thoracic part. The higher number of functional subunits (FSUs) consistent with a higher amount of white matter close to the brain may be responsible for these phenomena. With strongly heterogeneous dose delivery and due to the random location of FSUs, the effective size of the FSU and the mean dose deposited in it are of key importance and the radiation sensitivity distribution of the FSU may be an even better descriptor for the response of the organ. An individual optimization of a radiation treatment has the potential to increase the therapeutic window and improve cure for a subgroup of patients.</p>

The present thesis is focused on the development and application of dose response models for radiation therapy. Radiobiological models of tissue response to radiation are an integral part of the radiotherapeutic process and a powerful tool to optimize tumor control and minimize damage to healthy tissues for use in clinical trials. Ideally, the models could work as a historical control arm of a clinical trial eliminating the need to randomize patents to suboptimal therapies. In the thesis overview part, some of the basic properties of the dose response relation are reviewed and the most common radiobiological dose-response models are compared with regard to their ability to describe experimental dose response data for rat spinal cord using the maximum likelihood method. For vascular damage the relative seriality model was clearly superior to the other models, whereas for white matter necrosis all models were quite good except possibly the inverse tumor and critical element models. The radiation sensitivity, seriality and steepness of the dose-response relation of the spinal cord is found to vary considerably along its length. The cervical region is more radiation sensitive, more parallel, expressing much steeper dose-response relation and more volume dependent probability of inducing radiation myelitis than the thoracic part. The higher number of functional subunits (FSUs) consistent with a higher amount of white matter close to the brain may be responsible for these phenomena. With strongly heterogeneous dose delivery and due to the random location of FSUs, the effective size of the FSU and the mean dose deposited in it are of key importance and the radiation sensitivity distribution of the FSU may be an even better descriptor for the response of the organ. An individual optimization of a radiation treatment has the potential to increase the therapeutic window and improve cure for a subgroup of patients.

A set of mathematical models, known as radiobiological Dose-Response models, have been developed, to model the biological effects and complications that arise following irradiation. The overall objective is to be able to apply these in clinical practice with confidence, and ensure more successful treatments are given to patients. This investigation serves to assess these models and their predictive power of NTCP following irradiation of the lung. Clinical data, from patients treated for inoperable stage III non-small cell lung cancer is obtained and the consequent biological effect (severity of pneumonitis) observed as a result of this radiation treatment is assessed by the models. By gaining more knowledge about the 3D dose-distribution and the incidence of radiation pneumonitis through the evaluation of the models, the main treatment goal, which is to maximise TCP and minimise NTCP can be achieved. Post treatment data is obtained regarding the clinical outcome or clinical endpoint for each patient, considered to be Radiation Pneumonitis. The clinical endpoint is a specific biological effect that may or may not have occurred,after a certain period, following irradiation. The models are assessed on their ability to predict a NTCP value that corresponds to the resulting clinical endpoint following treatment. Furthermore a software tool for the calculation of NTCP’s by the models is developed, in an attempt to provide an important tool for optimization of radiotherapy treatment planning. With our findings from this study, our aim is to further strengthen, support and challenge already existing literature on dose-response modelling. / -

Somatic Copy Number Alterations (CNAs) are common events in human cancers. Identifying CNAs and Significant Copy number Aberrations (SCAs) in cancer genomes is a critical task in searching for cancer-associated genes. Advanced genome profiling technologies, such as SNP array technology, facilitate copy number study at a genome-wide scale with high resolution. However, due to normal tissue contamination, the observed intensity signals are actually the mixture of copy number signals contributed from both tumor and normal cells. This genetic confounding factor would significantly affect the subsequent copy number analyses. In order to accurately identify significant aberrations in contaminated cancer genome, we develop a Java AISAIC package (Accurate Identification of Significant Aberrations in Cancer) that incorporates recent novel algorithms in the literature, BACOM (Bayesian Analysis of Copy number Mixtures) and SAIC (Significant Aberrations in Cancer). Specifically, BACOM is used to estimate the normal tissue contamination fraction and recover the "true" copy number profiles. And SAIC is used to detect SCAs using large recovered tumor samples. Considering the popularity of modern multi-core computers and clusters, we adopt concurrent computing using Java Fork/Join API to speed up the analysis. We evaluate the performance of the AISAIC package in both empirical family-wise type I error rate and detection power on a large number of simulation data, and get promising results. Finally, we use AISAIC to analyze real cancer data from TCGA portal and detect many SCAs that not only cover majority of reported cancer-associated genes, but also some novel genome regions that may worth further study. / Master of Science

The chief aim in developing radiation treatment plans is to maximise tumour cell kill while minimising the killing of normal cells. The acceptance by a radiation oncologist of a radiation therapy treatment plan devised by the radiation therapist, at present is largely based on the oncologists' previous clinical experience with reference to established patterns of treatment and their clinical interpretation of the dose volume histogram. Some versions of radiotherapy planning computer software now incorporate a function that permits biologically based predictions about the probability of tumour control (TCP) and/or normal tissue complications (NTCP). The biological models used for these probabilities are founded upon statistical and mathematical principles as well as radiobiology concepts. TCP and NTCP potentially offer the capability of being able to better optimise treatments for an individual patient's tumour and normal anatomy. There have been few attempts in the past to correlate NTCPs to actual treatment complications, and the reported complications have generally not shown any significant correlation. Thus determining whether either or both NTCPs and TCPs could be correlated with the observed clinical outcomes of prostate radiotherapy is the central topic of this thesis. In this research, TCPs and NTCPs were prospectively calculated for prostate cancer patients receiving radiation therapy, and subsequently assessed against the clinical results of the delivered treatments. This research was conducted using two different types of NTCP models, which were correlated against observed treatment-induced complications in the rectum and bladder. The two NTCP models were also compared to determine their relative efficacy in predicting the recorded toxicities. As part of this research the refinement of some of the published bladder parameters required for NTCP calculations was undertaken to provide a better fit between predicted and observed complication rates for the bladder wall which was used in this research. TCPs were also calculated for each patient using the best available estimate of the radiosensitivity of the prostate gland from recent research. The TCP/NTCP data was analysed to determine if any correlations existed between the calculated probabilities and the observed clinical data. The results of the analyses showed that a correlation between the NTCP and a limited number of toxicities did occur. Additionally the NTCP predictions were compared to existing parameters and methods for radiotherapy plan evaluation - most notably DVHs. It is shown that NTCPs can provide superior discriminatory power when utilised for prospective plan evaluation. While the TCP could not be correlated with clinical outcomes due to insufficient follow-up data, it is shown that there was a correlation between the TCP and the treatment technique used.

No description available.

<p>As secondary colorectal liver cancer is the most widespread malignancy in patients with colorectal cancer, the main aim of this study is to identify and differentiate between benign and malignant secondary colorectal liver cancer tissue. Low energy X-ray interaction techniques were used. XRF and coherent scattering data were collected for all 24 normal and 24 tumour matched pair tissues. Measurements of these parameters were made using a laboratory experimental set-up comprising a Mo X-ray tube, Si Drift detector and Scintillation (NaI) detector.</p> <p>Twelve elements of interest were statistically explored for normal and tumour samples. Comparing normal and tumour tissues, statistically significant differences have been determined for K, Ca, Cr, Fe, Cu, Zn, Br and Rb. However, for P, S, As and Se, no statistically significant differences have been found.</p> <p>Coherent scatter profiles were collected and fitted for all the samples and three peaks were observed at momentum transfer values: adipose peak: 1.1 nm^-1, fibrous peak: 1.6 nm^-1 and water content peak: 2.2 nm^-1. The Amplitude, FWHM and area under these peaks were statistically analysed. These parameters were found to be significantly higher in secondary colorectal liver tumour compared to surrounding normal liver tissue for both fibrous and water content peaks. However, no significant differences were found for adipose peak parameters.</p> <p>Multivariate analysis was performed using the XRF, coherent scatter and elemental ratios data separately and the accuracy of classification results of 20 unknown samples was found. However when all the variables were combined together, the classification models were improved. This study has shown that the XRF and coherent scatter data of normal and secondary colorectal liver cancer are statistically different and the combination of these variables in multivariate analysis has the potential to be used as a method of distinguishing normal liver tissue from the malignant tumour tissue.</p> / Master of Science (MSc)

Neuroendocrine tumours generally show an overexpression of somatostatin receptors on their cell membranes, mainly subtype 2. This is taken advantage of in diagnosis and therapy by using synthetic somatostatin analogues that can be labelled with radionuclides to visualize and treat tumours with an overexpression of somatostatin receptors. The method traditionally used for visualization is somatostatin receptor scintigraphy (SRS) with 111In-DTPA-octreotide but this method is gradually being substituted by 68Ga-DOTATOC PET/CT. To evaluate patients for peptide receptor radionuclide therapy, it is mandatory for the patient to be examined by both methods. In the evaluation, the tumours are graded according to the Krenning scale on the images from the SRS. Patients with sufficient tumour uptake of somatostatin analogues are eligible for peptide receptor radionuclide therapy (PRRT). The aim of this study was to compare the tumour’s Krenning scores from SRS to the Krenning scores, quantitative indices and TNR-values from the 68Ga-DOTATOC PET/CT images. This was done to investigate if the Krenning scale could be applied to PET/CT enabling the patient to undergo only PET/CT for diagnosis and evaluation prior to PRRT. This study, including 28 patients, found no strong correlation between the Krenning scores from the SRS and the scores from 68Ga-DOTATOC PET/CT. However, a better correlation was shown between the Krenning scores from SRS and TNR-values where the quantitative indices SUVmax and SUVmean were divided with the SUVmean of the spleen. These findings could be worth exploring further in future studies, incorporating larger number of patients.

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.