Source: Dissertation Abstracts International, Volume: 68-11, Section: B, page: 7094. Adviser: Yun-Xin Fu. Includes bibliographical references.

Ecological momentary assessment provides a unique way of studying quality of life factors of colorectal cancer patients. It has yet to be used to study the behavioral expression of distress or depression by colorectal cancer patients. The current study utilized the Electronically Activated Recorder (EAR) technology to capture the daily activities and conversations of forty-eight adults with colorectal cancer. The study had two purposes: 1) to test the feasibility of the EAR with colorectal cancer patients; 2) to examine separate (self-report and behavioral) indicators of physical functioning, coping, and social support for their relationship to depression. Study participants wore the EAR, a portable digital recorder, for two consecutive days as the EAR recorded 30 seconds every 12.5 minutes. The EAR digital data were transcribed and analyzed for behavioral and linguistic indicators of physical functioning, coping, and social support. The acoustic data were analyzed using the standardized coding system Social Environment Coding of Sound Inventory (SECSI) and the Linguistic Inquiry and Word Count (LIWC2007) computer program. The results provided preliminary evidence that the EAR operated as a feasible and non-disruptive tool for gathering naturalistic data about colorectal patients’ lives. The EAR data revealed information about both the colorectal patients’ internal emotional world as well as their external world which was characterized by solitary acts of daily living. Study subjects were more likely to accept and receive tangible support from others than directly discuss their cancer with others. Analysis of language found that personal disclosure to others was associated with coping through emotional support while causation words (e.g., because, effect, hence) were significantly related with self-report cognitive scales. Furthermore, the study found that first-person singular pronouns were associated not only with depression, but with appraisal of social support. Lastly, a predictive model was tested to see whether self-reported tangible and emotional support and behavioral coding of emotional support each contributed uniquely to the prediction of depression. Only self-reported tangible support was found to significantly predict depression. / text

Advances in optical imaging have provided methods for visualizing molecular expression in tumors in vivo, allowing the opportunity to study the complexity of the tumor microenvironment. The development of fluorescent contrast agents targeted to molecules expressed in cancer cells is critical for in vivo imaging of the tumors. Contrast agents emitting in the near infrared (NIR) allow for an increased depth of penetration in tissue due to decreased absorption and scattering. There is also significantly less autofluorescence from tissue in the NIR. Quantum dots are nanoscopic particles of semiconductors whose fluorescent emission wavelength is tunable by the size of the particle with desirable fluorescent qualities such as a wide range of excitation wavelengths, a narrow emission band, high quantum efficiency, high photostablility, and they can be produced to emit throughout the NIR imaging window. It has been shown that vascular endothelial growth factor receptor 2 (VEGFR2) is upregulated in many cancers, including colorectal, as it is important in tumor angiogenesis and is considered a predictor for clinical outcome and, in some instances, is used for targeted therapy with anti-angiogenic drugs. For these reasons, quantum dots bioconjugated to VEGFR2 antibodies have the potential to provide contrast between normal tissue and cancer, as well as a mechanism for evaluating the molecular changes associated with cancer in vivo. In this dissertation, we present on the design of two contrast agents using quantum dots targeted to VEGFR2 for use in the molecular imaging of colon cancer, both ex vivo and in vivo. First, as a preliminary ex vivo investigation into their efficacy, Qdot655® (655nm emission) were bioconjugated to anti-VEGFR2 antibodies through streptavidin/biotin linking. The resulting QD655-VEGFR2 contrast agent was used to label colon adenoma in vivo and imaged ex vivo with significant increase in contrast between diseased and undiseased tissue, allowing for fluorescence based visualization of the VEGFR2 expressing diseased areas of the colon with high sensitivity and specificity. Then, QD655-VEGFR2 was used in a longitudinal in vivo study to investigate ability to correlate fluorescence signal to tumor development over time using optical coherence tomography and laser induced fluorescence spectroscopy (OCT/LIF) dual-modality imaging. The contrast agent was able to target VGEFR2 expressing diseased areas of colon; however, challenges in fully flushing the unbound contrast agent from the colon before imaging arise when moving from ex vivo imaging to in vivo image. Lastly, lead sulfide (PbS) quantum dots were made by colloidal synthesis to emit at a 940 nm (QD940) and conjugated to anti-VEGFR2 primary antibodies through streptavidin/biotin linking. The resulting QD940-VEGFR2 contrast agent was then used to label cells in vitro. The QD940-VEGFR2 molecules were able to positively label VEGFR2 expressing cells and did not label VEGFR2 negative cells. Very low photoluminescence and large amounts of aggregation after conjugation of the quantum dot to streptavidin was detected. Improvements to the quantum dot stability through synthesis, capping and conjugation techniques must be made for this contrast agent to be effective as a contrast agent for cancer imaging.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths around the world. The identification and description of many modifiable and non-modifiable risk factors to CRC has spurred the development of prevention and early detection protocols and recommendations to help reduce CRC incidence and mortality. Measures to manage CRC include diagnostic screenings and lifestyle changes. As rates of screening increase, prevention counseling rates among primary care providers (PCPs) remain low. Barriers to nutrition prevention reported by PCPs are inconsistent across the literature which has led to confusion about the reason for poor nutrition prevention efforts among PCPs. This practice inquiry (PI) addressed the identified practice gap using the Plan-Do-Study-Act (PDSA) quality improvement (QI) model. In the "Plan" phase (Chapter 2), a systematic review of the research literature determined existing nutrition recommendations for CRCs and barriers to implementation by PCPs. Development of several nutrition recommendations for fiber, vitamin D, alcohol, red and processed meats intakes, and dietary patterns were outlined for PCP use in practice. Barriers to nutrition prevention implementation were identified as time, reimbursement, knowledge, and health literacy. To augment findings from the literature, a provider survey was completed (Chapters 3-4). Barriers identified by the participants (n=47) include lack of time, education materials, nutrition knowledge, low health literacy, and lack of patient interest. These findings indicate that several changes are needed to improve the use of CRC prevention guidelines, including additional education and education materials, changes in office policy and additional research to create and analyze the interventions recommended to improve existing nutrition prevention counseling for CRC.

Research has identified a linear relationship between saturated fat intake and colon cancer, and has demonstrated that high fat diets enhance tumorigenesis through elevation of secondary bile acids such as deoxycholic acid (DCA). We and others have shown that DCA can manipulate cell adhesion by decreasing expression of E-cadherin and increasing expression of beta-catenin. We have also shown that DCA significantly reduces EphB2 expression, which regulates cell positioning and segregation. Importantly, vitamin D can reinstate membranous E-cadherin/beta-catenin interactions and increase E-cadherin expression. In the present study, we sought to analyze the effects of DCA and vitamin D (cholecalciferol) treatment on EphB2 in colorectal cancer cells. Pre-treatment with cholecalciferol restored EphB2 expression in a dose-dependent manner, even with combined DCA treatment. This observation may be EGFR-dependent, suggesting that cholecalciferol may antagonize the effects of DCA. Taken together, these results suggest that cholecalciferol may represent an adjuvant therapy for colorectal cancer patients.

Introduction: There is evidence to suggest that common genetic polymorphisms can modify the effect of environmental risk factors on colorectal neoplasia. Methods: Data on 1430 individuals were obtained from two chemoprevention trials, the Wheat Bran Fiber Trial (WBF) (1) and the Effects of Ursodeoxycholic Acid on Adenomatous Polyp Recurrence Trial (URSO) (2). Data were analyzed to test for gene-environment interactions between allelic variation in PPAR-γ (Pro12Ala, C1431T), body mass index (BMI) and waist circumference, and the biochemical biomarkers of metabolic syndrome. Simulated data were then used to determine if the sample size required to formally test the relationship between gene-exposure interactions could be reduced by using a genetically enriched study population. For this simulation aspect of the work, an established gene-drug interaction (i.e.: flavin monooxygenase 3 (FMO3) and sulindac) was used as a model system. Results: There was a borderline significant interaction between BMI and PPAR-γ for the Pro12Ala genotype (p(inter)=0.11) and significant interactions between BMI and the C1431T genotype (p(inter)=0.09). Results from the recursive partition model identified BMI (p = 0.007) and baseline fasting glucose levels (p =0.033) as significant predictors of colorectal adenoma recurrence for carriers of Ala12 and waist circumference as a significant predictor for the Pro12Pro12 carriers (p=0.002). Results from the simulated studies indicated that using genetically pre-screened and enriched populations can result in a 50% savings in the number of subjects required to test the candidate gene-drug interaction. Conclusions: These findings provide evidence that the effect of allelic variation in PPAR-γ on colorectal adenoma recurrence is modified by BMI and that component traits of metabolic syndrome differentially affect the risk of colorectal adenoma recurrence depending on genotype. In addition, using genotype as an inclusion criterion in future studies of adenoma recurrence will result in a smaller sample size required to test gene-environment interactions.

Kolorektale Karzinome sind durch ein spezifisches Muster chromosomaler Aberrationen charakterisiert, die im Verlauf der Tumorprogression akkumulieren. Obwohl die meisten Tumoren Sequenzgewinne oder Amplifikationen von Chromosom 13q aufweisen, sind die Zielgene dieser Aberration nach wie vor unbekannt. Um potentielle Onkogene bzw. therapeutische Zielgene auf Chromosom 13q zu identifizieren, wurde eine hochauflösende Analyse dieser Region durchgeführt. Dazu wurden 25 primäre Kolonkarzinome (UICC-II/III) und 15 kolorektale Zelllinien mittels Array-CGH untersucht. Zusätzlich wurden die Genexpressionsprofile dieser Tumoren und Zelllinien mittels Whole-Genome-Mikroarrays bestimmt. 67 Gene wiesen sowohl eine vermehrte Kopie-Anzahl als auch ein erhöhtes Expressionsniveau auf. Die Expressionsmuster dieser Gene wurden dann in 25 Kolonkarzinom-Zelllinien mittels Real-Time-PCR validiert, wobei 44 der 67 Gene eine deutliche Überexpression auch in den Zelllinien zeigten. Das Ausschalten von 13 dieser 44 Gene in der Kolonkarzinom-Zelllinie SW480 führte zu einer Reduktion der Zellviabilität von 20-60%. Diese 13 Gene könnten somit potentielle Onkogene oder mögliche therapeutische Zielgene darstellen. In Folgeexperimenten versuchen wir daher, die der Viabilitätsreduktion zugrundeliegenden Signalwege zu entschlüsseln.

Tumorerkrankungen stellen in der westlichen Welt eines der wichtigsten Gesundheitsprobleme dar. Das kolorektale Karzinom ist dabei die dritthäufigste Tumorneuerkrankung. Bei fortgeschrittenem Krankheitsverlauf wird zumeist eine kombinierte Radiochemotherapie durchgeführt, bei der zusätzlich zur Bestrahlung Zytostatika wie 5-Fluoruracil oder Oxaliplatin verabreicht werden. Da die eingesetzten Zytostatika nicht ausschließlich gegen Tumorzellen wirken, führt der Einsatz dieser oft zu massiven Nebenwirkungen wie Magen- und Darmproblemen, Myelosuppression und Haarausfall. Neue Therapieansätze versuchen daher Ziele in die Behandlung mit aufzunehmen die stärker karzinomspezifisch sind, wie z.B. verschiedenen Rezeptortyrosinkinasen. Viele Rezeptortyrosinkinasen und deren Liganden liegen im Tumor und umliegenden Gewebe oft dereguliert vor und spielen eine wichtige Rolle bei der Regulierung des Tumorwachstums, der Tumorangiogenese und der Metastasenbildung. In dieser Arbeit konnte für die drei kolorektalen Karzinomzelllinien DLD-1, SW837 und Caco 2 gezeigt werden, dass die gleichzeitige Inhibition des Insulin-like Growth Factor-I Receptor (IGF-IR) und des Epidermal Growth Factor Receptor (EGFR) mit den Tyrosinkinaseinhibitoren AEW-541 (IGF-IR-Inhibitor) und Erlotinib (EGFR-Inhibitor) in vitro zu einem deutlich verstärkten Therapieeffekt der 5-Fluoruracil-basierten Radiochemotherapie führt. Für Xenografttumore der Zelllinie SW837 konnte dieser Effekt auch in vivo bestätigt werden. Mit Hilfe der Co Immunpräzipitation und eines Proximity Ligation Assays konnten in den Kolonkarzinomzelllinien SW480 und DLD-1 Hybridrezeptoren zwischen dem EGFR und dem IGF-IR nachgewiesen werden. Zusätzlich konnte gezeigt werden, dass eine Ligandenstimulation der Rezeptoren zu einer vermehrten EGFR/IGF-IR-Hybridrezeptorbildung führt. Weitere Analysen zeigten, dass für die induzierte Heterodimerisierung beide Liganden notwendig sind und beide Rezeptoren funktionsfähig sein müssen. Mit Hilfe des Proximity Ligation Assays konnten IGF-IR/EGFR-Hybridrezeptoren auch in humanen Rektumtumoren nachgewiesen werden. Im letzten Teil der Arbeit wurde die Bedeutung des Platelet-derived Growth Factor Receptor β (PDGFR-β) in kolorektalen Karzinomzellen untersucht. In SW480- und DLD-1-Zellen führte die Inhibition des PDGFR-β mit Hilfe von spezifischer siRNA zu einer, über den PI3K-Signalweg vermittelten, moderat verminderten Proliferationsrate. Die Verwendung des PDGFR-β-Inhibitors Ki11502 führte in den Zelllinien zu einem starken Rückgang in der Proliferationsrate und zu Veränderungen im Zellzyklus der Zellen. Diese wurden durch eine verminderte Cyclin-B1-Expression hervorgerufen. Weitere Analysen zeigten, dass der Inhibitor Ki11502 neben dem PDGFR-β auch den Rezeptor cKIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) und die Zellmembran-assoziierte zytoplasmatische Tyrosinkinase SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog) inhibiert.

1. INTRODUCTION Colon and rectum cancers (CRC) accounted for about 1 million new cases in 2002 (9.4 % of the world total) with about 529,000 deaths and 2.8 million alive with CRC diagnosed within 5 years of diagnosis [Parkin DM et al, 2005]. Recent estimates indicate that in 2004 CRC among the most common incident form of cancer in the Europe was in the second position with more than 380,000 new cases (13.2% of total). CRC was also one of two most common causes of cancer deaths in Europe (203,700 per year) [Boyle P et al, 2005]. A favourable pattern in CRC mortality for both genders was observed in most of western European countries from the 1990s onwards, but CRC mortality rates were still in the upward direction in some eastern European countries [Fernandez E et al, 2005]. For patients diagnosed with CRC during the early 1990s, the EUROCARE study showed that differences in stage at diagnosis were a key explanation for differences in survival between western European countries, and differences in therapy contributed to survival differences between eastern and western European countries [Gatta G et al, 2000]. The number of new cases of CRC in Lithuania is increasing every year. According to the data of Lithuanian Cancer Registry, there were diagnosed 1442 new colorectal cancer cases and 973 deaths in 2004 in Lithuania [The main results of cancer control in Lithuania. Transitional report 2004. Lithuanian Cancer Registry]. CRC is in the third position according new cancer... [to full text]

Introduction: Despite the public and policy attention on ensuring access to health care for all Canadians, research continues to identify inequities in access to cancer care services. The objectives of this thesis are to define inequity in access to colorectal cancer (CRC), as well as to measure inequity in access to radiotherapy and end-of-life care. Methods: This study examined income-, geography-, sex-, and age-related inequity in access to CRC services along the continuum of care, using the Horizontal Inequity Index. Specifically, we measured and compared inequity in access CRC services in Nova Scotia using linked administrative databases. Results: We have identified that age- and geography-related inequity in access to radiotherapy and end-of-life care are the most consistent for CRC patients in Nova Scotia. Discussion: The clear distinction between inequity and inequality in this study provides indication to policy makers that the variations in access, may be of social concern.