Peritoneal carcinomatosis is a complex clinical-pathological condition and most patients with this disease would die within 6 months. The disadvantage of systemic cancer therapy is that only a small portion of the administered drug can reach the tumor cells, and side effects could occur due to its wide distribution in the body. In recent years, cytoreductive surgery combined with intraperitoneal chemotherapy has been the effective way for the treatment of peritoneal carcinomatosis. But the anticancer agents in aqueous form can be easily absorbed through capillaries below the large serosal surface into the systemic circulation, and it is difficult to retain the drug at a high concentration for a long time in the peritoneal cavity. The ideal drug for intraperitoneal chemotherapy should have a high molecular weight, a prolonged retention in the peritoneal surface, and increase drug exposure to tumor cells, decrease drug absorption and hence reduce systemic toxicity. ABZ (albendazole) with its properties of poor water solubility and strong anticancer effects could be a potential effective agent for the treatment of peritoneal carcinomatosis. The aims of this study are: to compare oral versus i.p administration of ABZ, study pharmacokinetic characteristics of ABZ in i.p administration; to study the efficacy ofABZ on early, middle and later stages of cancer development, to find out the possible antitumor effect of ABZ in suppressing cancer cell proliferation, ascites control and longer survival of mice with peritoneal carcinomatosis; to solve the occurring problems during ABZ i.p administration, reduce side effects and increase the drug efficacy; to investigate possible mechanisms ofABZ suppressing tumor proliferation and ascites formation. A series of experiments were designed in order to achieve the study objectives. The pharmacokinetic study of ABZ gives some dynamic characteristics by oral versus i.p administration in rabbits. Three sets of experiments of ABZ treatment were performed on different stages peritoneal carcinomatosis arising from the OVCAR-3 cancer cells in nude mice, from which the efficacy of ABZ in suppressing tumor growth and ascites formation by i.p administration is clearly demonstrated. The increased solubility of ABZ with three surfactants and in human ascites was carried out in different tests, and the combination of ABZ with Tween 80 has achieved better control of peritoneal carcinomatosis when given by i.p administration. The results from this study have revealed for the first time the capacity of ABZ suppressing VEGF (vascular endothelial growth factor) and ascites formation profoundly, confirmed that ABZ has potent anti-proliferation effects on ovarian cancer cells (OVCAR3); it suppressed tumor growth in early stage of cancer development; and prolonged survival of all ABZ treated mice by i.p administration. The major contributions from this study are: ABZ i.p treatment increases survival, inhibits ascites production, reduces tumor burden at relatively early stage of cancer, changes tumor morphology and reduces vascular density, reduces CA-125 (cancer antigen 125) and VEGF level, decreases in vitro VEGF secretion, and down regulates VEGF mRNA expression. The study results concluded that ABZ could be a potential anticancer agent for the treatment of peritoneal carcinomatosis by i.p administration. The significance of this study is that the fundamental results obtained from all experiments, including the major contributions and other associated works, have provided the scientific foundation for a clinical trial. Currently the maximum tolerated dose of ABZ i.p treatment in mice is on going before clinical trial and studies in related area of ABZ anticancer pathways are continuing in our laboratory.

Introduction Peritoneal metastasis is advanced disease and is usually widely disseminated at the time of discovery. It is crucial to detect peritoneal metastasis at an early stage and to allow precise patient selection for the right treatments. Both fluorodeoxyglucose positron emission tomography/computed tomography (FDGPET/CT) and magnetic resonance imaging (MRI) are used in peritoneal metastasis detection. Standardized uptake value (SUV), derived from FDGPET/ CT can evaluate glucose metabolism in cells, whilst apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI) is used for quantitative analysis of tumour cellularity. Amide proton transfer (APT) MRI is a novel imaging technique based on exchangeable amide protons as endogenous contrast agent and can measure the increased amide proton signal in malignant tissues indirectly through bulk water proton signals. This thesis aims to: 1) compare the diagnostic performance of FDG-PET/CT and MRI in peritoneal metastasis evaluation; 2) study the relationship between SUV and ADC in peritoneal metastasis; 3) investigate the feasibility of APT in peritoneal metastasis evaluation. Materials and Methods Patients with peritoneal metastasis detected on FDG-PET/CT were prospectively recruited for MRI. FDG-PET/CT and MRI images were reviewed independently by two radiologists in separate sessions. Diagnostic characteristics were calculated for both imaging techniques. SUVmax and SUVmean were obtained by placing ROIs on PET, while ADCmin and ADCmean were calculated by contouring lesions on DWI. APT MRI was performed using a single-slice turbo spin echo sequence, with a block of presaturation pulses at 33 frequency offsets. ROIs were placed on peritoneal metastasis and muscle on APT. Mean of integrated asymmetrical magnetic transfer ratio (MTRasym) over 3-4 ppm with respect to water resonance was calculated for peritoneal metastasis and muscle. Results Eight patients were recruited in this study with 128 anatomical sites evaluated. DWI/MRI had good diagnostic performance (sensitivity = 92%, specificity = 99%, accuracy = 98%) compared to that of FDG-PET/CT (sensitivity = 90%, specificity= 100%, accuracy = 98%). Thirty-four peritoneal metastases were selected for quantitative analysis. Significant inverse correlation was found between ADCmean and SUVmax (r = -0.528, p = 0.001) and between ADCmean and SUVmean (r = -0.548, p = 0.001). ADCmin was significantly and negatively correlated with SUVmax (r = -0.508, p = 0.002) and SUVmean (r = -0.513, p = 0.002). In the above study cohort, 6 patients underwent APT imaging with 8 peritoneal metastases evaluated. Seven lesions showed positive APT signal and one had negative APT signal. The mean APT signal for peritoneal metastasis was 2.28%±1.76%, significantly different from that of muscle (-2.79%±0.95%, p < 0.001). Conclusions In conclusion, both DWI/MRI and FDG-PET/CT had good diagnostic performance in peritoneal metastasis evaluation. The negative correlation between SUV and ADC suggested an inverse relationship between tissue metabolism and cellularity. APT MRI is feasible to generate sufficient contrast signal for peritoneal metastasis and has potential to discriminate peritoneal tumours from its surrounding soft tissue using integrated MTRasym as a quantitative marker. These functional indices allow understanding of the biological behaviours of peritoneal tumours and could act as adjuncts in peritoneal metastasis imaging. / published_or_final_version / Diagnostic Radiology / Master / Master of Philosophy

In the past, patients with peritoneal surface malignancy were considered incurable and were only offered palliative treatments. However, in a substantial number of patients, disease progression that is isolated to peritoneum may occur. It has been realised that elimination of peritoneal surface tumours may have an impact on the survival of these cancer patients, in whom a prominent cause of death is peritoneal carcinomatosis. The focus of this PhD. thesis is on the combined treatment of cytoreductive surgery and perioperative intrapersonal chemotherapy for diffuse malignant peritoneal mesothelioma, pseudomyxoma peritonei, colorectal peritoneal carcinomatosis and resectable gastric cancer. Section one describes the major principles of management for peritoneal surface malignancy, covering the historical perspectives, the treatment rationales and the learning curve associated with the combined procedure. Section two is devoted to peritoneal mesothelioma, in trying to examine this disease from its clinical, radiologic and histopathologic aspects. A radiologic classification and a histopathologic staging system for this disease are proposed. In section three, the results of the combined treatment for pseudomyxoma peritonei are presented, including a systematic review of the literature, a case series of 50 patients from our Australian centre and a treatment failure analysis of 402 patients from the Washington Cancer Institute. These studies suggest that a disease-free state is important for long-term survival for patients with pseudomyxoma peritonei. In section four, the current evidence on the combined treatment for colorectaI peritoneal carcinomatosis is demonstrated by conducting a systematic review of the literature and survival and perioperative outcome analyses of two separate patient cohorts. These results suggest that the combined treatment is associated with an improved survival, as compared with historical controls. In the last section, a metaanalysis of the randomised controlled trials on adjuvant intraperitoneal chemotherapy for resectable gastric cancer shows that a significant improvement in survival is associated with hyperthermic intraoperative intraperitoneal chemotherapy alone or in combination with early postoperative intraperitoneal chemotherapy.

Indiana University-Purdue University Indianapolis (IUPUI) / Ovarian cancer (OC) is a lethal disease due to metastasis and chemoresistance. Our laboratory previously reported that tissue transglutaminase (TG2) is overexpressed in OC and enhances OC peritoneal metastasis. TG2 is a multifunctional protein which catalyzes Ca2+-dependent cross-linking of proteins. The purpose of this study was to explore the mechanism by which TG2 is upregulated in OC and its role in OC progression. We demonstrated that transforming growth factor (TGF)-β1 is secreted in the OC milieu and regulates the expression and function of TG2 primarily through the canonical Smad signaling pathway. Increased TG2 expression level correlates with a mesenchymal phenotype of OC cells, suggesting that TGF-β1 induced TG2 promotes epithelial-to-mesenchymal transition (EMT). TG2 induces EMT by negatively regulating E-cadherin expression. TG2 modulates E-cadherin transcriptional suppressor Zeb1 expression by activating NF-κB complex, which leads to increased cell invasiveness in vitro and tumor metastasis in vivo. The N-terminal fibronectin (FN) binding domain of TG2 (tTG 1-140), lacking both enzymatic and GTPase function, induced EMT in OC cells, suggesting the interaction with FN involved in EMT induction. A TGF-β receptor kinase inhibitor, SD-208, blocked TGF-β1 induced TG2 upregulation and EMT in vitro and tumor dissemination in vivo, which confirms the link between TGF-β1 and TG2 in EMT and tumor metastasis. TG2 expression was correlated with the number and size of self-renewing spheroids, the percentage of CD44+CD117+ ovarian cancer stem cells (CSCs) and with the expression level of stem cell specific transcriptional factors Nanog, Oct3/4, and Sox2. These data suggest that TG2 is an important player in the homeostasis of ovarian CSCs, which are critical for OC peritoneal metastasis and chemoresistance. TG2 expression was also increased in CSCs isolated from human ovarian tumors, confirming the implication of TG2 in CSCs homeostasis. Further, we demonstrated that TG2 protects OC cells from cisplatin-induced apoptosis by regulating NF-κB activity. We proposed a model whereby TGF-β-inducible TG2 modulates EMT, metastasis, CSC homeostasis and chemoresistance in OC. These findings contribute to a better understanding of the mechanisms of OC metastasis modulated by TG2.