published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Public Health / Master / Master of Public Health

This thesis consisted a series of sentinel node biopsy (SNB) studies in Chinese patients to evaluate its impact on the management of breast cancer. Pilot studies The first SNB pilot study was performed in 30 patients using the blue dye technique. Accuracy was verified by axillary lymph node dissection (ALND). The success rate was 83% and the false-negative rate was 25%. The second pilot study was performed in 50 patients using combined mapping with isotope and dye. The success rate was 94% with no false-negative. SNB is shown to be feasible and accurate in Chinese. The optimal mapping method Combined mapping was superior to the blue dye technique. This could be due to the mapping technique or improved experience. One hundred and twenty-three women were randomly assigned to either the blue dye or combined mapping. Combined mapping had a higher success rate than the blue dye technique (100% versus 86%). False-negative rates were similar (0% versus 4.5%). Combined mapping is the preferred method. Accuracy of frozen section (FS) FS was used intra-operatively to guide the need of ALND. In 260 SNB, FS was compared to serial section and immuno-histochemical staining. FS detected 53 of 86 patients with SN metastases with a false-negative rate of 38.4%. The false-negative rates for macro-, micro-metastases and isolated tumour cells (ITC) were 2.4%, 57.7% and 94.4%. FS was accurate to diagnose macro-metastases but not micro-metastases and ITC. Can we skip ALND in SN metastases? 139 patients with SNB and ALND were studied to identify predictive factors for non-SN metastases. 55 had metastatic SN but 38 (69%) had no residual metastases in non-SN. Tumours <3 cm, a single metastatic SN, micro-metastases and absence of extra-capsular spread were significant factors to predict no residual nodal disease. Non-SN metastases were found in 42%, 19% and 0% when SN contained macro-, micro-metastases and ITC. Based on risk of non-SN involvement, ALND is indicated for macro- and micro-metastases but not for ITC. Extended indication for ductal carcinoma in situ (DCIS) SNB may be useful for staging of patients with a pre-operative diagnosis of DCIS because invasive cancer is not infrequently found on pathological examination of resected specimens after surgical excision. One hundred and seven patients with DCIS on core biopsy underwent SNB. Thirty-two patients (29.9%) were upstaged to invasive cancer and 9 (28.1%) had SN metastases. Performing SNB reduced the re-operation rate from 29.9% to 1.9%. Palpable mass and radiological mass lesion were associated with upstage. Extended indication: Sentinel Node Occult Lesion Localisation (SNOLL) Radioisotope is used to localise non-palpable breast cancer and SN. Seventy-four patients with non-palpable breast cancers underwent SNOLL. Radioisotope was injected into cancer and gamma probe guided breast cancer and SN resection. Primary cancer was removed in 73 patients (99%) after the first-round excision and 82% had complete excision. Gamma probe identified SN in 82% and supplementary blue dye increased SN detection to 97%. SNB modified the practice of breast cancer surgery. It has a major impact on the diagnosis, staging and treatment of breast cancer. / published_or_final_version / Surgery / Master / Master of Surgery

Breast cancer patients consistently reported psychosocial adjustment difficulty in their sense of femininity after breast removal surgery. In view of this, the present study aimed to explore the effects of three femininity-related concepts on emotional reactions towards breast removal surgery – femininity schema, femininity loss appraisals, and femininity contingency of self-worth. 212 women without breast cancer history participated in this study. They completed a questionnaire which included a hypothetical scenario of breast removal. Results showed that women who considered the breast of a high relative importance in femininity schema, and depended their self-worth highly on sense of femininity, reported greater increase in negative emotions after hypothetical breast removal. This effect was mediated by femininity loss appraisals. Implications and future directions were discussed. / published_or_final_version / Clinical Psychology / Master / Master of Social Sciences

Objectives: Forkhead box protein P1 (FOXP1) is a transcription factor, and a member of the P-subfamily of forkhead box transcription factor and regulate transcription of a subset of genes that involved in various cellular events. It plays a critical role in regulating cell growth and proliferation, differentiation, embryogenesis, adult tissue homeostasis, and possibly tumorigenesis. Predominant nuclear localisation of FOXP1 protein is commonly expressed at low level in normal tissues and upregulated in proliferative cells. Studies have demonstrated that the loss of FOXP1 expression and cytoplasmic mis-localisation is significantly associated with various malignant cancers, including breast cancer. FOXP1 can act either as a tumor suppressor or as an oncogenic protein in cell-type specific functions. It has been shown to be a co-regulator of estrogen receptor alpha and can modify a specific subset of forkhead box transcription factor class O (FOXO)-target genes. We hypothesise that there is association between FOXP1 expression and patient survival, and explore the potential role of FOXP1 expression as a prognostic marker in breast cancer. Methods: One hundred and twenty breast cancer samples in tissue microarray blocks were examined for FOXP1 expression by immuno-histochemistry. Nuclear and cytoplasmic FOXP1 expression patterns were analysed with clinico-pathological parameters. Statistical analysis was performed using SPSS software to determine the correlation between FOXP1 expression and clinico-pathological parameters. The correlation between subcellular FOXP1 expression and survival was evaluated by COX regression analysis. Results: Nuclear or cytoplasmic FOXP1 expression showed no association with clinico-pathological parameters. However, our results showed that there was significant association with estrogen receptor and progesterone receptor when nuclear and cytoplasmic scores were combined as total FOXP1 score (p=0.022 and p=0.028 respectively). In univariate analysis, high nuclear and cytoplasmic FOXP1 expression had no significant correlation with poor survival, while high total FOXP1 expression was associated with poor overall and disease-specific survival (p=0.045). Tumor stage and lymph-node involvement were significantly related to poorer overall and disease-specific survival, while other clinico-pathological parameters did not. In breast cancer with advanced tumor grade and lymph-node involvement, overall and disease-specific survival are significantly associated with high FOXP1 expression (p=0.041 and p=0.015 respectively). Conclusion: Unlike previous reports, our findings show that increased nuclear and cytoplasmic FOXP1 expression were both observed and high total FOXP1 expression was associated with poorer survival, particularly in cases of advance tumor grade and with lymph node metastases. These finding are supported by a recent report that showed that FOXP1 can up-regulate its own expression by binding to the promoter of FOXP1 and promote cell survival of breast cancer cells by suppressing FOXO-induced apoptosis. It may be possible that FOXP1 expression is up-regulated in a positive feedback loop in breast cancer cells such that there is both increased nuclear transcriptional activity and cytoplasm localisation of FOXP1. Further investigation is necessary to understand the role of FOXP1 in the progression of breast cancer and determine its potential use as a prognostic marker. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Breast cancer is the most common cancer in females worldwide. RIP140 was one of the first proteins recognized as nuclear receptor transcriptional cofactor which interacts with several nuclear receptors. RIP140 plays a central role in metabolic tissues with multifunctional co-regulation. It is an essential protein required for energy homeostasis and mammary gland development. RIP140 has been found to be involved in development of breast cancer in response to estrogen. RIP140 is recruited by estrogen receptors in the presence of estrogen. Increasing levels of estrogen and RIP140 stimulate their transcription and regulate proliferation and differentiation of mammary glands. We hypothesize that RIP140 may be over expressed in breast cancer and may be correlated with clinicopathological features and may thus serve as a possible new prognostic marker in breast cancer. In our study, the correlation between the RIP140 expression and survival was investigated by immunohistochemistry (IHC), and analyzed by Pearson’s chi-square and Kaplan Meier analysis. Cox regression analysis was performed to examine the relationship between clinic-pathological parameters and the survival. Total of one hundred and eighteen breast cancer samples were examined for the RIP140 staining localization in breast cancer cells. Our results showed that the IHC staining of RIP140 was observed in both cytoplasm and nucleus of breast cancer cells. The ER positive staining was significantly correlated with high nuclear expression of RIP140, but not RIP140 cytoplasmic expression. Thus nuclear RIP140 expression was examined for correlation with other clinic-pathological features and patient survival. The correlation between nuclear RIP140 expression and clinic-pathological features by Pearson’s chi-square test showed that high RIP140 nuclear staining score is associated with ER positive status (p-value=0.041) and tumor stage (p-value=0.008). Kaplan Meier test shown that nuclear RIP140 expression is not significant associated with either overall survival or disease-specific survival. However, a trend of high nuclear RIP140 score was observed with poorer overall and disease-specific survival though not statistically significant. To conclude, our results suggest RIP140 is not a useful prognostic marker for breast cancer. Further investigation with larger sample size is necessary to improve the statistical significance of the test. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Background: Patients with early stage breast cancer having more aggressive surgery have been reported by several studies. Some studies from US also reported that there is an increasing trend in the use of mastectomy. A study even showed that there is 150% increase in bilateral mastectomy rate using data from Surveillance, Epidemiology, and End Results registries (SEER). The increasing use of mastectomy leads to the concerns about reasons behind the decision of surgery type. The objective of this literature review is to identify the factors which would affect the choice of surgery. We will make recommendations on guideline, implementation and the use of appropriate surgery, to prevent the unnecessary mastectomy. Methods: Literature search of articles was conducted using several database including PubMed, MEDLINE and Google Scholar. The keywords used were “Mastectomy rate” AND “breast cancer”, “Breast surgery choice” AND "factor", “Breast conserving surgery” AND “choice”. The periods were limited to 1990-2013. Results: Of 4335 articles identified, 11 studies were found to be relevant to the review. These studies were from different countries with different sample sizes, analysis method and study designs. The rate of mastectomy was widely varied across countries. The rate was clearly lower in western countries, such as Canada, UK and US, while in Asia like Hong Kong and Turkey, the rate is much higher. All of the reviewed studies evaluated different factors, which can influence the choice of treatment. These factors can be broadly categorized as demographics, clinical data, body image and sexuality, surgeon and psychological effects. Factors about age, marital status, family history, tumor size, histological type, nodal status, body image, fears of recurrence, further treatment and dying from cancer and surgeons were included in different studies found to have significant effect on individual in decision of surgery type. Conclusion: Both patient and surgeon play an important role in the selection of surgery. The evidence suggests that reducing unknown bias of surgeons and concerns from patients can help choosing the optimal surgery type. Adequate communication and information are necessary for patient in making the decision on treatment. / published_or_final_version / Public Health / Master / Master of Public Health

Breast cancer is the most common cancer among women worldwide. Millions of new breast cancer cases are diagnosed every year, accounting for one-tenth of all new cancer cases. Because of the proof of equivalent efficacy between breast-conserving therapy (BCT) plus radiotherapy and mastectomy, increasing number of patients received breast irradiation during the past three decades, and radiotherapy plays a more and more important role in managing breast cancer. With the advancement of technology, the radiotherapy treatment techniques changed from conventional wedged technique to intensity modulated radiotherapy (IMRT), resulting in an improvement in the dose homogeneity. Regardless of the treatment techniques, peripheral dose to the contralateral breast is inevitable. The possibility of the peripheral dose causing contralateral breast cancer (CBC) has re-attracted the interest. However, the variation of the peripheral dose with different treatment techniques has not been well identified. Thus this study aims to compare the contralateral breast dose from the primary breast irradiation using various radiotherapy treatment techniques and types of shielding. Six treatment plans by different treatment techniques, including paired physical wedges (PW-P), a lateral physical wedge only(PW-L), paired enhanced dynamic wedges (EDW-P), a lateral enhanced dynamic wedge only(EDW-L), field-in-field tangential opposing (TO-FiF), and inverse-planned intensity modulated radiotherapy (IMRT-IP), were generated using a female Rando phantom. The phantom was treated by all plans, and 15 metal oxide semiconductor field effect transistor(MOSFET)detectors on the surface and inside the contralateral breast were utilized for measuring the contralateral breast dose for each plan. Measurement was repeated with the application of 0.2, 0.3 and 0.5cm lead sheets or 0.5 and 1cm superflab (SF) on the TO-FiF to demonstrate the effect of shielding on the contralateral breast dose. The measured contralateral breast doses were: 2.05Gy for PW-P, 1.44Gyfor PW-L, 1.51Gyfor EDW-P, 1.52Gyfor EDW-L, 1.25Gyfor TO-FiF, and 1.17Gyfor IMRT-IP, corresponding to 2.35% to 4.11% of total dose. PW-P producedthe highest contralateral breast dose while IMRT-IP producedthe lowest. For the addition of shielding, the doses were: 1.25Gy for no shielding, 0.65Gy for 0.2cm lead, 0.61Gy for 0.3cm lead, 0.49Gy for 0.5cm lead, 0.76Gy for 0.5cm SF, and 0.72Gy for 1cm SF. Lead sheet with 0.5cm thickness most effectively reduced the contralateral breast dose by 60%.All techniques showed that the surface dose was much higher than the dose at depth, and the dose dropped exponentially from the surface to the internal. Low energy radiation constitutes a large portion of the contralateral breast dose, so all types of shielding could decrease the surface dose effectively, but not the internal dose. The radiation-induced CBC risks were estimated to be about 0.77% to 1.36%. To conclude, it is important that the contralateral breast dose to patients, especially those under 45, is maintained minimal. Therefore, TO-FiF or IMRT-IP are recommended to be the treatment of choices. The used of shielding, either lead or SF, is also advisable. / published_or_final_version / Diagnostic Radiology / Master / Master of Medical Sciences

Background: Breast cancer is the commonest female cancer. DNA double-strand breaks (DSBs) associated proteins such as BRCA1 have been shown to be involved in tumourigenesis of breast tissue. One of the key regulators of DSBs, the RING Finger Protein 168 (RNF168), controls DNA damage responses (including the manipulation of homologous recombinant and non-homologous end-joining repair) which are responsible for correction of errors that occur during DSBs in order to maintain genomic stability. The nature of this protein suggests that RNF168 may play an important role in development of breast cancer. Material and methods: This study investigated the relationship of RNF168 expression in breast cancer by immunohistochemistry staining of 118 breast cancer samples in tissue microarray. The nuclear stain and cytoplasmic stain of the sections were assessed. Nuclear localization score was obtained and correlated with clinico-pathological features of the patients. Results: Immunohistological staining of RNF168 was successful in 99 cases of the tested breast cancer specimens. The expression of RNF168 was found to be significantly correlated with the occurrence of breast cancer metastasis (p=0.032). Strong expression of the protein was also found to be significantly associated with poorer breast cancer prognosis (p=0.033). In addition, correlation analysis also showed marginal correlation between nuclear localization of RNF168 with the age of patients at their first disease diagnosis (p=0.061). Conclusion: RNF168 might play a critical role in promoting breast cancer metastasis during the advanced stage of breast cancer, which results in poor disease prognosis. Detailed mechanism involved in metastasis promotion remained to be revealed in further study. / published_or_final_version / Pathology / Master / Master of Medical Sciences