The goal of radiotherapy is to operate within the therapeutic window - delivering doses of ionizing radiation to achieve locoregional tumour control, while minimizing normal tissue toxicity. A greater therapeutic ratio can be achieved by utilizing radiosensitizing agents designed to enhance the effects of radiation at the tumour. Gold nanoparticles (AuNP) represent a novel radiosensitizer with unique and attractive properties. AuNPs enhance local photon interactions, thereby converting photons into localized damaging electrons. Experimental reports of AuNP radiosensitization reveal this enhancement effect to be highly sensitive to irradiation source energy, cell line, and AuNP size, concentration and intracellular localization. This thesis explored the physics and some of the underlying mechanisms behind AuNP radiosensitization. A Monte Carlo simulation approach was developed to investigate the enhanced photoelectric absorption within AuNPs, and to characterize the escaping energy and range of the photoelectric products. Simulations revealed a 10^3 fold increase in the rate of photoelectric absorption using low-energy brachytherapy sources compared to megavolt sources. For low-energy sources, AuNPs released electrons with ranges of only a few microns in the surrounding tissue. For higher energy sources, longer ranged photoelectric products travelled orders of magnitude farther. A novel radiobiological model called the AuNP radiosensitization predictive (ARP) model was developed based on the unique nanoscale energy deposition pattern around AuNPs. The ARP model incorporated detailed Monte Carlo simulations with experimentally determined parameters to predict AuNP radiosensitization. This model compared well to in vitro experiments involving two cancer cell lines (PC-3 and SK-BR-3), two AuNP sizes (5 and 30 nm) and two source energies (100 and 300 kVp). The ARP model was then used to explore the effects of AuNP intracellular localization using 1.9 and 100 nm AuNPs, and 100 and 300 kVp source energies. The impact of AuNP localization was most significant for low-energy sources. At equal mass concentrations, AuNP size did not impact radiosensitization unless the AuNPs were localized in the nucleus. This novel predictive model of AuNP radiosensitization could help define the optimal use of AuNPs in potential clinical strategies by determining therapeutic AuNP concentrations, and recommending when active approaches to cellular accumulation are most beneficial.

Predictors of response of AIDS-associated Kaposi-Sarcoma to standard chemotherapy Overview: Kaposi Sarcoma is the most common HIV-associated cancer. Its etiology and pathogenesis is not fully understood. Little is known about what predicts prognosis, survival and therapeutic response in HIV-KS. In South Africa given the high seroprevalence rates of HIV-l and human herpes virus 8 (HHV 8), Kaposi's sarcoma is a significant problem. The majority of patients have been treated solely with palliation due to the poor outcome associated with a diagnosis of HIV-KS, more so in the absence of highly active antiretroviral therapy (HAART). Since the national ARV rollout programme and the availability and accessibility of HAART to all patients with a diagnosis of HIV-KS, a new strategy has to be established to enable adequate patient selection for chemotherapy. There have been a few published studies addressing the predictors of response to chemotherapy in the first world. However, this is the first study of these factors in HIV-l infected African patients with Kaposi's sarcoma. Aim: To identify and assess the potential value of several parameters predictive of outcome, survival and therapeutic response in HIV- infected patients with KS. Clinical, hematological, biochemical, immunological and virological variables were evaluated. Methods: We collected data from 25 patients with AIDS-KS who were enrolled in a phase III randomized controlled trial comparing HAART alone with the combination of HAART and chemotherapy. All patients were from the combination therapy arm. The following variables were evaluated as predictors of prognosis and therapeutic response: age, gender, ethnic origin, Haemoglobin (Hb), white blood cells (WBCs), lymphocytes, neutrophils, platelets, S.albumin, ALP, GGT, CD4 count, HIV viral load. These variables were assessed in patients at baseline and month 6 of therapy. Patients were staged into good risk and poor risk according to the AIDS clinical trial group (ACTG) criteria. The outcomes assessed were response to treatment and mortality. Results: A total of 25 patients participated to the study. Of these 16(64%) were males and 9(36%) were females, with male: female ratio of 2.7:1. Median age was 34 years (24-47); all patients were of Black African origin. Of the 21 patients, 15 (71.4%) were of good prognosis and 6(28.6%) were of poor prognosis. At baseline the median values of the different variables were as follows: Hb 10.9 g/dl, WBCs 5.95x109/L, lymphocytes 1.7 x109/L, neutrophils 3 x10 9 /L, platelets 272 x10 9 /L, S.albumin 30 gil, total protein 88 gil, ALP 64 U/L, and GTT 21 U/L, CD4 count was 255 cells/mm 3 , HIV-RNA viral load was 42000( 4.610gs). At month 6, 22 patients remained alive, their median values were: Hb 12.2 g/dl, WBCs 4.65 x109/L, lymphocytes 1.5 x109/L, neutrophils 3 x10 9 /L, platelets 301 x109/L, S.albumin 36.5 gil, total protein 84.5 gil, ALP 78.5 U/L, GTT 44.5 U/L, CD4 count 288 cells/mm3 , HIV-RNA viral load was 50500( 4.6910gs). The baseline median CD4 and HIV-RNA viral load counts for the 3 patients who died before month 6 were 47 cells/mm3 and 31000(4.610gs); respectively. Response to therapy was evaluated in 21(84%) patients as 4(16%) patients were missing, of the 21 patients 3 (14.3%) had complete response and 18(85.7%) had partial response. With respect to sex 2(14.3%) males had complete response and 12(85.7%) had partial response, 1(14.3%) female had complete response and 6 (85.7%) had partial response. Non-parametric statistics were used because of the small sample size and the skewness of the data. Variables were described using medians and ranges, and compared between two independent groups using Mann-Whitney tests. Baseline and month 6 comparisons were done using Wilcoxon signed ranks tests. Receiver Operating Characteristic (ROC) curves were used to analyze cut points to optimize sensitivity and specificity of a quantitative variable for a dichotomous outcome. Discussion In the univariate analysis age and sex didn't influence prognosis and therapeutic response, the influence of ethnic origin couldn't be assessed as all patients were of the same ethnic origin. Baseline WBCs (P= 0.004) and lymphocytes (P=0.026) were significantly associated with complete response. Higher values of GGT (p=O.OOl); ALP (P=0.006) were associated with more deaths. Baseline CD4 count and HIV viral load were not of predictive value, lthough change CD4 (P=002) and VL (p=.OOO) over time was significant and most likely attributed to response to therapy. 90.9 % of patients reached undetectable HIV-l Viral loads at month 6. CONCLUSION: Neither CD4 count nor HIV viral load at baseline predicted prognosis or survival; however there was a borderline significance of CD4 (P=0.058) towards a better survival. / Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2006.

In external electron beam therapy arbitrarily shaped inserts (cutouts) are used to define the contours of the irradiated field. This thesis describes the implementation and verification of a software system to calculate output factors for cutouts using Monte Carlo simulations. The design goals were: (1) A stand-alone software system running on a single workstation. (2) Task oriented graphical user interface with shape input capability. (3) Implementation on Mac OS XRTM (10A.x Tiger). (4) CPU multicore support by job splitting. (5) EGSnrc (Patch level V4-r2-2-5) for particle transport and dose scoring. (6) Validation for clinical use. / The system, called Cutout Manager, can calculate output factors with 1% statistical error in 20 minutes on Mac Pro computer (Intel XeonRTM, 4 cores). When the BEAMnrc linac model correctly reproduces percentage depth doses in the buildup region and around R100, calculated and measured output factors are in good agreement with precision measurements of circular cutouts at 100 cm source-to-surface distance (SSD) and extended SSD. Cutout Manager simulations are consistent with measurements of clinical cutouts within a 2% error margin.

Prostate cancer is frequently diagnosed in elderly men and, despite the largely unproven survival benefits of treatment, the majority receive treatment. Treatment options include surgery, radiation, and/or androgen deprivation therapy (ADT). Risks associated with treatment include hip fracture. Current understanding suggests that hip fracture is a frequent cause of morbidity and mortality in the elderly, and both radiation treatment and ADT can increase the risk of hip fracture. It is important to understand these risks so they can be minimized and the morbidity of treatment reduced. The objectives of this study were to estimate the risk of hip fracture as a major adverse outcome of treatment for prostate cancer among elderly men. The specific objectives include estimating: 1) the risk of hip fracture and the dose-risk relationship among patients receiving curative radiation treatment, and 2) the risk of hip fracture associated with palliative ADT and relapsed ADT compared to curative ADT. The cancer diagnosis and treatment records of 32,673 men were linked to their hospital discharge abstracts. The risk of hip fracture was estimated using Cox regression and the estimates were adjusted for age, comorbidity, income, and year of diagnosis. The risk of hip fracture was 59% higher among men who received curative radiation when compared to men who received curative surgery. The risk of hip fracture fell by 6% with each one Gy increase in radiation dose between 55 and 81 Gy Biological Equivalent Dose to the hip-bone. The risk of hip fracture for subjects in the palliative ADT and relapsed ADT categories was 5.98 and 5.77 times the risk in comparison to men who received curative ADT treatment. Curative radiation treatment is associated with an increased risk of hip fracture when compared to curative surgery. The risk of hip fracture is greater with ADT for palliation and relapsed cancer than with curative treatment. Current treatments for prostate cancer contain significant risk of hip fracture for elderly men and these risks should be considered as part of the treatment decision.

Hadron Therapy is an advanced radiotherapy technique for cancer treatment. It offers a better irradiation ballistic than conventional techniques and therefore requires appropriate quality assurance procedures. In this work, we upgraded the GEANT4-based GATE Monte Carlo platform in order to recalculate the TPS dose distributions in view of further benchmarking. In a first step, we selected an appropriate simulation environment (physics models and parameters) in order to produce accurate and efficient simulations. GATE simulations were validated using measurements and other Monte Carlo codes for depth-dose and transverse profiles. While a good agreement was found for depth-dose profiles, larger discrepancies were pointed out for transverse profiles. In a second step, we developed a modeling method to simulate active scanning beam delivery systems, which does not require to simulate the components of the treatment nozzle. The method has been successfully applied to an IBA proton therapy system and validated against measurements for complex treatment plans. Interfaces have also been developed in order to link DICOM RT ION PLAN and DICOM RT DOSE with GATE. Finally, we compared in a third step the TPS and Monte Carlo dose distributions in homogeneous and heterogeneous configurations. The beam models of both dose engines were in satisfactory agreement, allowing further evaluation of clinical treatment plans. A two-field prostate plan has been evaluated, showing a satisfactory agreement between the TPS and Monte Carlo, and demonstrating the novel capabilities of the platform for the evaluation of the TPS. To summarize, we selected an appropriate simulation environment for proton therapy, proposed a modeling method for active scanning systems and presented a method to compare the TPS and Monte Carlo dose distributions. All tools developed in GATE were or will be publicly released. A detailed validation stage of the system including absolute dosimetry is still necessary, in order to quantitatively evaluate its accuracy in various homogeneous and heterogeneous configurations. In this thesis, we have demonstrated that the GATE Monte Carlo platform is a good candidate for the simulation of active scanning delivery systems, allowing further TPS benchmarking. Moreover, the GATE platform also handles imaging applications, such as PET or prompt-gamma imaging towards online treatment monitoring and paves the way of interdisciplinary research advances.

Objective: The cytotoxic property of anti-EGFR-1 monoclonal-antibody nimotuzumab modified with nuclear localization sequence and radiolabeled with 111In was evaluated in trastuzumab-resistant breast cancer cells. Methods: 111In-nimotuzumab-NLS was constructed and its immunoreactivity was determined. Cellular and nuclear uptake was evaluated by cell fractionation. Finally, the cytotoxicity of conjugates (111In-nimotuzumab/111In-nimotuzumab-NLS) was studied by clonogenic assays. Results: The immunoreactivity of 111In-nimotuzumab-NLS was conserved. 111In-nimotuzumab-NLS exhibited 2-fold higher nuclear translocation as compared to 111In-nimotuzumab in MDA-MB-468 cells. Nuclear importation of 111In-nimotuzumab-NLS in MDA-MB-468 cells was 4-fold and 6-fold higher than moderate and low EGFR expressing cell lines, respectively. Clonogenic survival (CS) for MDA-MB-468 cells showed 111In-nimotuzumab-NLS to be 10-folds and 60-folds more potent than 111In-nimotuzumab and nimotuzumab, respectively. Moderate killing for TrR1 and MDA-MB-231 was observed. 111In-hEGF showed significantly higher cytotoxicity and 2-fold higher γ-H2AX foci integrated density/nuclear-area as compared to 111In-nimotuzumab-NLS. Preserved selectivity of 111In-nimotuzumab-NLS makes it an excellent drug for treating cancers.

The goal of radiotherapy is to operate within the therapeutic window - delivering doses of ionizing radiation to achieve locoregional tumour control, while minimizing normal tissue toxicity. A greater therapeutic ratio can be achieved by utilizing radiosensitizing agents designed to enhance the effects of radiation at the tumour. Gold nanoparticles (AuNP) represent a novel radiosensitizer with unique and attractive properties. AuNPs enhance local photon interactions, thereby converting photons into localized damaging electrons. Experimental reports of AuNP radiosensitization reveal this enhancement effect to be highly sensitive to irradiation source energy, cell line, and AuNP size, concentration and intracellular localization. This thesis explored the physics and some of the underlying mechanisms behind AuNP radiosensitization. A Monte Carlo simulation approach was developed to investigate the enhanced photoelectric absorption within AuNPs, and to characterize the escaping energy and range of the photoelectric products. Simulations revealed a 10^3 fold increase in the rate of photoelectric absorption using low-energy brachytherapy sources compared to megavolt sources. For low-energy sources, AuNPs released electrons with ranges of only a few microns in the surrounding tissue. For higher energy sources, longer ranged photoelectric products travelled orders of magnitude farther. A novel radiobiological model called the AuNP radiosensitization predictive (ARP) model was developed based on the unique nanoscale energy deposition pattern around AuNPs. The ARP model incorporated detailed Monte Carlo simulations with experimentally determined parameters to predict AuNP radiosensitization. This model compared well to in vitro experiments involving two cancer cell lines (PC-3 and SK-BR-3), two AuNP sizes (5 and 30 nm) and two source energies (100 and 300 kVp). The ARP model was then used to explore the effects of AuNP intracellular localization using 1.9 and 100 nm AuNPs, and 100 and 300 kVp source energies. The impact of AuNP localization was most significant for low-energy sources. At equal mass concentrations, AuNP size did not impact radiosensitization unless the AuNPs were localized in the nucleus. This novel predictive model of AuNP radiosensitization could help define the optimal use of AuNPs in potential clinical strategies by determining therapeutic AuNP concentrations, and recommending when active approaches to cellular accumulation are most beneficial.

Breast cancer is a major cause of cancer-related death among women throughout the world. Treatment of breast cancer often fails due to the development of resistance to both chemo- and radiotherapy. The aim of this study was to analyze and compare the response to radiation of MCF-7 breast adenocarcinoma cells and MCF-7 cells that are resistant to doxorubicin (MCF-7/DOX). The results presented in this thesis show that drug-resistant MCF-7/DOX cells survive high doses of radiation exposure better than MCF-7 cells. Moreover, the chemo- and radioresistance of MCF-7/DOX cells share common molecular mechanisms and loss of sensitivity to radiation in chemo-resistant cells may be explained by alterations in their DNA methylation profile. The results of experiments presented in this thesis may, therefore, serve as a first step for future analysis of tumour resistance to radio- and chemotherapy and for the development of novel epigenetic strategies for reversal of breast cancer resistance to cytotoxic treatment regimens. / xi, 98 leaves : ill. (some col.) ; 29 cm

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Thesis (M.Tech.: Radiography) - Dept. of Radiography, Durban Institute of Technology, 2003 1 v. (various pagings) / Cancer is an inexorably progressive disease and a favourable outcome in its management often depends on early intervention (Mackillop, Zhou and Quirt, 1995: 532). Early detection of the disease is therefore important for a favourable outcome to be achieved. When the disease is diagnosed at a late stage, the treatment that is offered is only palliative. Palliative treatment is only offered with the aim to relieve the local symptoms of advanced disease. The treatment intent is therefore not curative but only to give the patient a better quality of life, which sometimes is not possible especially for very advanced disease. In KwaZulu-Natal the incidence of Zulu speaking patients presenting with a late stage disease to the major cancer treatment centres is very high with the result that the majority of these patients can only be offered palliative treatment (Pervan, Cohen and Jaftha, 1995 : 162). Aim of the study is to investigate the factors that contribute to the late presentation of rural Zulu patients with cancer to the two major provincial cancer treatment centers in KwaZulu-Natal (prior to December 2002).