Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Physics, 1980. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Bibliography: leaves 190-193. / by Bruce Robert Rosen. / M.S.

Breast cancer (BC) survivors are at increased risk of cancer recurrence, a second cancer, and non-cancer comorbidities. Previous studies suggest that many women adopt a spontaneous change in lifestyle after a BC diagnosis in hope of achieving a better survival outcome. While this observation has led to the suggestion that a BC diagnosis is a “teachable moment” for improving health behaviors, other conflicting studies report that BC survivors do not make positive changes in health behaviors following a breast cancer diagnosis. Although previous studies suggest that receipt of cancer chemotherapy and hormonal therapy is associated with weight loss or weight gain, the association between post-diagnosis weight change with changes in lifestyle has not been studied in detail. The majority of prior studies of post-diagnosis changes in behavior and weight have examined the mean change between two time points, and therefore may over simplify the trajectory of change over time due to lack of more granular data. New methods are needed to examine the distribution and correlates of behavior/weight trajectories following the BC diagnosis. In my dissertation, a systematic literature review was conducted to evaluate the evidence regarding the frequency, magnitude and pattern of post-diagnosis changes in diet [fruit/vegetable (F/V), dietary fat], physical activity [moderate to vigorous physical activity (MVPA) and sedentary behaviors], alcohol intake, and body weight among BC survivors. A total of 66 studies were included in the systematic review. These studies suggest that after a breast cancer diagnosis, women are less likely to engage in MVPA and more likely to reduce alcohol intake. Previous studies suggested that women may experience weight change after a BC diagnosis, although there were strong evidence showing both weight gain and weight loss were common. The reports of changes in diet and sedentary behavior following a BC diagnosis are limited and inconclusive about the direction of change. The results of the review suggested that there is wide variation in post-diagnosis lifestyle changes among BC survivors. However, very few studies have investigated the variability in multiple behavior trajectories following a BC diagnosis. In this dissertation, I made use of a population of 4,505 women newly diagnosed with a BC and enrolled in the Kaiser Permanente Northern California Pathways Study. I used a combination of statistical methods, including a semi-parametric, group-based trajectory modeling and a non-parametric K-means for longitudinal data analysis, to identify latent trajectories groups that are unobserved clusters of individuals following similar trajectories of a behavior. These analyses tested the hypotheses that in the 24 months following a breast cancer diagnosis, women follow a mixture of lifestyle (F/V, dietary fat, MVPA, sedentary behavior, alcohol) and body mass index (BMI) trajectories, which can be stable, temporarily increase or temporarily decrease. My analysis identified multiple distinct trajectories of lifestyle behaviors and BMI during the first 24 months after a BC diagnosis. The trajectory analysis results suggest that the large majority of women maintained their lifestyles following a BC diagnosis. Socioeconomic status, dispositional optimism, perceived social support, and the severity of CIPN during active treatment were associated with the post-diagnosis trajectories of. Furthermore, the BMI trajectories were stable over the first 24 months following a BC diagnosis. The BMI trajectories were associated with trajectories of F/V, dietary fat intake, MVPA, sedentary behavior and alcohol intake over the same period, independent of demographic characteristics, tumor characteristics and cancer treatment received. In summary, previous studies suggest that women may spent fewer time on MVPA and drink less alcohol after a BC diagnosis, while both weight gain and loss are common post diagnosis. In a trajectory analysis of 4505 BC survivors enrolled in the Pathways Study, I did not observe any latent trajectory of meaningful change in health behavior or BMI in the first 24 months after a BC diagnosis in the Pathways Study. Instead, my analysis suggests that most women maintained their body weight following a BC diagnosis. The BMI trajectories were strongly associated with trajectory of F/V, dietary fat intake, MVPA, sedentary behavior, and alcohol intake over the same period, independent of demographic characteristics, tumor characteristics and receipt of cancer therapies. These results suggest that there is an absence of spontaneous changes in lifestyle behaviors after BC diagnosis and the importance of maintaining a healthy lifestyle in weight management after a BC diagnosis. Future studies should examine the associations of these health behaviors and BMI trajectories and BC prognosis to better understand the effect of post-diagnosis changes in lifestyle and weight on BC-specific and all-cause mortality.

The main strategy for treating solid cancers is based on the very early diagnosis of a malignant tumor, and in general the smaller the tumor, the greater the likelihood of successful treatment. Magnetic Resonance Imaging (MRI), based on the nuclear magnetic resonance phenomenon, provides the possibility of detecting early malignant tumors with the assistance of appropriate contrast agents. Hence, researchers continue to develop novel magnetic materials to achieve this aim. Superparamagnetic nanoparticles have become the focus of these studies because their superparamagnetic, biocompatible and hydrophilic properties would be revealed after modifying the particle surface by suitable surfactants. Considerable research in this area has provided valuable insights; however, suitable magnetic materials that can fulfill all the requirements of MRI application are still under investigation. Surface modification of superparamagnetic nanoparticles towards their use as MRI contrast agents has been the topic for many researchers, but implementation into fully functional in vivo procedures still remains as a challenging task. In the present study, high quality monocrystalline iron oxide nanoparticles have been synthesised and surface-modified with carboxymethylated dextran as well as polyethylene glycol (PEG). Dextran and PEG macromolecules with low and high carboxyl contents were synthesized and grafted onto dopamine-iron oxide nanoparticles. Furthermore, the coating procedure was optimised to prevent aggregation among the nanoparticles. Dextran-coated and PEG-coated nanostructures were characterised by using X- ray Photoelectron Spectroscopy (XPS), Fourier Transformer Infrared Spectroscopy (FTIR), Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS). Consequently, mono-dispersed dextran coated nanoparticles were obtained with an approximate hydrodynamic diameter of 50 nm. The resulting coated nanoparticles exhibited the nanostructures with an excellent colloidal stability in physiological environment even at high salt concentration. The resistance to non-specific protein adsorption was investigated in an in vitro model. Both dextran-coated and PEG-coated nanoparticles displayed low non-specific adsorption. However, the free carboxyl groups could be activated to covalently immobilize proteins. / Thesis (M.Eng.Sc.)--School of Chemical Engineering, 2006.

This study completed the analysis of mutational frequencies and clinicopathological patterns of six EGFR pathway-related genes (EGFR, HER2, HER4, KRAS, BRAF and MET) in 212 resected lung adenocarcinomas (AD) from 98 male and 114 female Chinese patients without prior chemotherapy or tyrosine kinase inhibitor (TKI) therapy. Genomic DNA and cDNA sequencing, quantitative PCR and fluorescence in-situ hybridization (FISH) were employed to investigate mutation and amplification status of the relevant genes. Overall, more than 75% of tumours were detected to harbour mutations or amplification in one of these six genes. The commonest mutation was found to involve EGFR, comprising 60.38% of cases, followed by KRAS (9.43%), HER2 (2.36%), MET (2.36%), BRAF (1.42%) and HER4 (0.47%). Four somatic mutations in MET exon 14 splicing region were found, leading to alternative splicing and a transcript lacking exon 14. Two of the MET mutant tumours and one MET wild-type tumour showed MET amplification of more than 3.5 fold increase in copy number. Mutations of EGFR were significantly more frequent in female (p = 0.0196), non-smokers (p < 0.001) and well differentiated tumours (p = 0.0209). KRAS mutations showed significant association with male (p = 0.0099) and smoking history (p = 0.0011). A novel HER2 D769Y mutation was found and HER2 mutations were associated with smokers (p = 0.0013) and poorly differentiated tumours (p = 0.0147). BRAF, MET mutations and MET amplification were not associated with clinicopathological factors. Mutations were mutually exclusive except for two cases with KRAS and HER4/BRAF. MET amplification was co-existent with MET mutations in two cases. MET amplification was found to negatively correlate with disease-free and cancer-specific survivals. The results suggested that MET amplification may contribute to disease progression and could be a therapeutic target in primary lung AD in Hong Kong Chinese patients. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Background: Human papillomavirus (HPV) DNA test is more sensitive and can detect more high-grade cervical intraepithelial lesions than cytology test in cervical cancer screening. There are studies confirming HPV test being more effective in cervical cancer screening by detecting the persistence of HPV infection that could lead to cancer. However, the costs associated with a HPV test is higher than a cytology test. Moreover, HPV test is less specific which could subject more women to further triage tests or unnecessary invasive diagnostic procedures. Therefore healthcare costs could possibly increase if primary HPV screening is to be adopted. Study objective: The aim of the study is to systematically review the cost-effectiveness of primary HPV testing in cervical cancer screening Method: Electronic search was performed in three biomedical databases (PubMed, Medline, Cochrane Library) and one economic evaluation database to identify relevant studies. Studies were selected according to the explicit inclusion and exclusion criteria defined. Only those studies carried out in high-income countries were included so that result could be better applied to Hong Kong. Results: A total of 19 studies were included in this systematic review. Cytology-only method is generally not cost-effective. To be cost-effective, it has to be performed in a longer screening interval which would reduce not only the screening costs but also a reduction in the health outcomes. Among the different options in HPV-based primary screening, HPV testing with cytology triage is the most cost-effective strategy in many of the studies. Combined HPV/cytology co-screening could achieve the biggest health benefit but is also most costly. HPV-based screening is more cost-effective for those >30 years of age and is usually less cost-effective if applied to young women. From the result in sensitivity analysis, HPV-based screening is sensitive to an increase in the costs of the HPV test, a low HPV test sensitivity and a low screening compliance rate. Conclusion: Primary HPV screening is cost-effective and generally performs better than cytology screening. The result of this systematic review guides the future direction of developing an optimal cervical screening strategy in Hong Kong. Local context has to be considered when examining the cost-effectiveness of primary HPV testing for cervical screening. Good quality local epidemiological data on HPV infection and cervical cancer and screening would be required to aid future research on the application of HPV test for cervical cancer screening in Hong Kong. / published_or_final_version / Public Health / Master / Master of Public Health

In cervical screening programmes, Papanicolaou test (Pap test) is the key screening tool. However Pap test is difficult to implement in low-resource region. Introduction of an economic, cost-effective and less skill demanding equipment is hence a potential direction of advance in cervical screening methodology. 　　Cervical carcinogenesis involves genetic instability which leads to chromosomal aneuploidy. Evaluation of aneuploidy may hence provide information for identifying cancer and precursor cells. An automated DNA-image-cytometry system (DNA-imager) capable of quantitating the DNA content of cells has recently been developed. 　　To evaluate the efficacy of DNA-imager in cervical cancer screening, a total of 483 residual ThinPrep liquid-based cytology (LBC) samples after diagnosis were retrieved and evaluated by the DNA-imager. The high risk human papillomavirus (HPV) status of the atypical squamous cells of undetermined significance (ASC-US) samples has been tested as a parallel study. According to established criteria, 423 out of the 483 samples were satisfactory for downstream analysis. The samples were designated “Normal”, “Suspicious” or “Abnormal” according to their DNA aneuploidy and proliferation activity. 　　Significantly more high grade lesion samples (HSIL and SCC) were designated as “Abnormal” by DNA-imager than were lower grade lesion samples (Negative, ASC-US, AGC, ASC-H, and LSIL) (94.19% vs 51.04%, p<0.0001). For detecting ≥HSIL, DNA-imager achieved high sensitivity and specificity (94.19% and 48.96%) using “Abnormal” as cut off. Adopting a more stringent definition of “Suspicious” or “Abnormal” would increase the sensitivity to 100% but decreased the specificity to 24.33%. 　　 　　Regarding ASC-US triage, DNA-imager achieved a sensitivity and specificity of 80.00% and 71.29% respectively when “Abnormal” was used as test positive to predict cases with ≥HSIL follow-up in the next two year. The sensitivity increased but the specificity decreased to 90.00% and 34.65% respectively if “Suspicious or above” was used as indicator of undesirable follow-up. HR-HPV test, on the other hand, was able to identify all cases with ≥HSIL upon follow-up (sensitivity = 100%) but the specificity was only 15.84%. Among these ASC-US sample, test positivity of the two tests showed poor concordance with each other (Cohen’s κ = 0.062 and 0.074 respectively for “Suspicious or above” or “Abnormal”, respectively). 　　Our findings suggested that DNA-imager may be a useful tool for automated primary screening of cervical cancer 3 / published_or_final_version / Pathology / Master / Master of Medical Sciences

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published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Synovial sarcoma is a soft tissue tumor defined by the presence of t(X;18)(p11.2;q11.2), fusing the SYT (SS18) gene on chromosome 18 and one of three SSX genes on chromosome X. T(X;18) results in production of a fusion protein (SYT-SSX) that is thought to underlie synovial sarcoma pathogenesis through aberrant targeting of both activating (trithorax, SWI/SNF) and repressing (Polycomb) transcription factors when expressed in a stem or progenitor-like cellular background. Clinically, synovial sarcomas present considerable diagnostic and therapeutic challenges. Whereas the classical biphasic histology is distinctive, the more common monophasic histology can be difficult to differentiate from other spindle cell tumors. In these situations, detection of t(X;18) is the gold standard for diagnosis, but it is a specialized and time-consuming process. Immunohistochemistry can be helpful, but no marker that is both highly sensitive and specific is available. Here I describe a fluorescence in situ hybridization based method employing an SYT break-apart probe set that can expedite detection of t(X;18). I also report that TLE1, which was identified in gene expression studies as a good discriminator of synovial sarcoma from other mesenchymal tumors, is a highly sensitive and specific immunohistochemical marker for synovial sarcoma. Both of these novel diagnostic techniques are applicable to small tissue samples such as core needle biopsies and are now being used clinically. The diagnosis of synovial sarcoma carries a poor prognosis and the 10-year overall survival rate is approximately 50%, most of whom are young adults. The addition of chemotherapy to surgical resection (the mainstay of treatment) does not appear to improve overall survival. Thus, there is a strong need for development of a clinically effective systemic therapy to improve patient outcome. I describe preclinical studies that demonstrate the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) inhibits proliferation of synovial sarcoma by inducing apoptosis and that this is associated with degradation of multiple receptor tyrosine kinases and disruption of the SYT-SSX-β-catenin interaction. I also identify a subset of synovial sarcoma cells, typified by expression of CD133, which exhibit stem-like properties and are relatively resistant to doxorubicin but susceptible to 17-AAG at clinically relevant concentrations.