Surgery (Austin & Northern Health) - Theses
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ItemConsiderations for surgical intervention in metastatic cancer to the spine: evaluation of risk factors for pathologic fracture and spinal cord compression, and analysis of pre-operative scoring systems for the prognostication and treatment of patients with spinal metastases( 2014)The spine has structural load bearing and neural-protective functions, and tumour growth and bony destruction caused by spinal metastases results in pathologic fracture and cord compression, causing pain, neurological deficit, impaired function and quality of life. Surgery is the only method to immediately stabilise the spine and decompress the spinal cord. Survival prognosis is one of the key factors in selecting patients for surgery, and there are a number of scoring systems aimed at prognostication and treatment decision making for patients with spinal metastases, however these differ in the parameters assessed and prognostic value. The ability to predict those patients with spinal metastases most likely to progress to pathological fracture or develop spinal cord compression may simplify the surgical decision-making process and enable earlier surgical intervention, with the potential to prevent permanent neurological deficit and disability and maintain function and quality of life for the remainder of the patient's life. This thesis considers the complexities of treatment decision making for patients with spinal metastases, with two major aims: 1) An evaluation of patient risk factors and radiological parameters associated with pathological fracture and metastatic epidural spinal cord compression, and 2) Validation of survival prognostication of current pre-operative prognostic scoring systems, in order to optimise the treatment decision-making process. The methodology involved retrospective assessment of clinical and radiological parameters of 72 patients with spinal metastases who had undergone decompressive and/or stabilisation surgery for pathological fracture and/or metastatic epidural spinal cord compression or nerve root compression. The items assessed for association with pathological fracture or metastatic epidural spinal cord compression were: tumour size, location, type and lesion morphology, disease burden, pain and function. Pre-operative scores were calculated for each patient, and the prognostic value of each scoring system evaluated by comparison of predicted and actual survival. The results showed that tumour size within the vertebral body, vertebral endplate and three-column involvement, tumour growth rate, multiple vertebral metastases, and pain were associated with increased risk for pathological fracture. Vertebral posterior element and costovertebral joint involvement by tumour, primary tumour growth rate and presence of visceral metastases were associated with metastatic epidural spinal cord or nerve root compression. All patients with pathological fracture had at least one of three risk factors – pain; >25% tumour occupancy of vertebral body; and endplate or 3-column involvement – and incidence of pathological fracture increased with higher number of risk factors. The Revised Tokuhashi, Bauer, Modified Bauer, and Tomita scoring systems were the most reliable for survival prediction. It is concluded that these risk factors should be considered in the decision-making process for surgery for spinal metastases. Patients with spinal metastases causing pain, greater than 25% occupancy of the vertebral body and involving the vertebral endplate or all three columns should be considered for prophylactic or therapeutic decompressive and stabilization surgery. As a component of comprehensive treatment planning, we recommend the use of Revised Tokuhashi, Modified Bauer, and Tomita scoring systems due to their favourable survival prognostic accuracy and clearly outline of treatment strategy according to prognostic group.
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ItemThe Effect of Co-stimulation Blockade on Survival of Xenogeneic Pancreatic Beta-cells( 2014)Diabetes mellitus is a chronic disease affecting millions of people worldwide. Currently, the only potential cure is through pancreatic transplantation, either as whole organ or with pancreatic islet cells. However, the morbidity associated with immunosuppression and the scarcity of donor organs do not support the common practice of pancreatic transplantation. Both these factors can potentially be addressed by xenotransplantation of genetically modified cells that are capable of attenuating the immune system. The costimulation pathway of the immune system was the focus of this project, in particular blockade of the ICOS (inducible costimulation molecule) and CTLA-4 (cytotoxic T lymphocyte associated antigen 4) pathways to prolong xenograft survival. To address the problem of diabetes as well as investigate the efficacy of costimulation blockade on xenograft survival, rat insulinoma (beta) cell lines (INS-1E) stably expressing either ICOS-Ig or CTLA4-Ig were generated. The secreted proteins were demonstrated to be biologically active in xenogeneic mixed lymphocyte reactions by their ability to inhibit lymphocyte proliferation. Unfortunately, the in vivo effect of these transgenic INS-1E cells on xenograft survival was unable to be determined because of their failure to establish as tumours due to the slow growth rate of these cells following subcutaneous injection into BALB/c mice. The aim of the second part of this project was to assess the effect of rationally mutated ICOS-Ig on xenograft survival. PIEC (pig iliac endothelial cells) stably expressing ICOS-Ig with single (K52/S and S76/E) and combined (K52/S + S76/E) amino acid mutations were generated. In vitro, compared to wild type ICOS-Ig, the mutants with single amino acid substitutions showed stronger binding avidity to ICOS ligand. This increase in binding avidity however did not translate into superior inhibition of lymphocyte proliferation compared to wild type ICOS-Ig in xenogeneic mixed lymphocyte reactions. Similarly in vivo, the PIECs secreting mutated forms of ICOS-Ig did not prolong xenograft survival after subcutaneous injection of these cells into BALB/c mice. These data suggest that despite their higher avidity, the ICOS-Ig mutants are not biologically more superior than wild type ICOS-Ig both in vitro and in vivo.
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ItemIdentification of genetic changes in prostate tissue of men with prostate cancer from multiple breast cancer families( 2013)Introduction: Male BRCA2 mutation carriers are at higher risk of developing aggressive prostate cancer. My research looks at DNA changes in prostate cancer specimens from men positive for a BRCA2 mutation. The first project involves DNA analysis of HG PIN tissue to look for loss of heterozygosity (LOH) in those carriers of a BRCA2 mutation. The purpose of looking for LOH in HG PIN of BRCA2 positive carriers is to ascertain if this tissue is a genomic predictor for tumorigenesis in this population. We also considered that whole exome copy-number analysis (CNA) of prostate cancer tissue, as well as HG PIN and normal prostate tissue from these BRCA2 men, may provide additional insight. Another inheritable mutation associated with prostate cancer is the HOXB13 mutation. We explored our cohort of prostate cancer men from breast cancer-rich families for the incidence of this mutation and impact on survival. We also investigated the incidence of the HOXB13 mutation in breast cancer women from breast cancer-rich families. Patients and Methods: Ten BRCA2 positive participants, from the kConFab cohort of high-risk breast cancer families, were identified , with access to archival prostate tissue specimens. Loss of heterozygosity (LOH) at the BRCA2 gene was examined using mutation specific PCR and sequencing of DNA from laser microdissected HG PIN. We also dispatched 15 DNA samples to Affymetrix for CNA: 9 prostate adenocarcinoma tissue DNA samples with 4 matched normal prostate tissue samples and 2 matched HG PIN samples. This data was analysed using specific software for microarray genetic analysis. For the HOXB13 study, the G84E variant was screened for using high resolution melting analysis in germ-line DNA in the index case or youngest affected member of 898 high-risk breast cancer families and in 1097 population controls. Results: Within this cohort of 10 pathogenic BRCA2 carriers, no patient displayed LOH at the mutation locus within HG PIN, irrespective of whether or not corresponding adenocarcinoma DNA displayed LOH. For the CNA project, our samples showed common sites of amplification at 8q, as well as deletions at 10q and 13q. Six out of 898 multi-case breast cancer families had carriers of the HOXB13 G84E variant: three families had either a single or multi-case family history of prostate cancer (3/99) and three had a personal and family history of breast cancer (3/799). Conclusion: Although HGPIN is considered a precursor to cancer, as no LOH was observed, this assay does not provide a genetic marker that may be considered a positive predictor of tumorigenesis in BRCA2 carriers. Regarding the CNA study, this is the first genomic analysis of this specific patient group, with our results have validated previous results of CNA in prostate cancer, as well as demonstrating the highly heterogenous nature of copy-number changes in this subset of patients. We confirm an association of the HOXB13 G84E variant with good prognosis prostate cancer in non BRCA1 or BRCA2 breast cancer families but we found no evidence for an increased risk of familial breast cancer.
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ItemManagement of young patients with colorectal cancer( 2013)Introduction: Young Patients with Colorectal Cancer (CRC) pose diagnostic and management challenges. A young age denotes an increased risk of a familial syndrome. The thesis aim was to identify how colorectal surgeons manage young colorectal cancer based on the likelihood of hereditary colorectal cancer. We sought to investigate the reliability of endoscopic biopsies, how compliance with post- operative surveillance guidelines influenced the metachronous colorectal cancer rate, and how quality of life was altered by the extent of colectomy. Young CRC patients’ views to varying aspects of colorectal surgery were also tested. Methods: Scenario based electronic surveys were sent to members of the Colorectal surgical society of Australia and New Zealand (CSSANZ), American Society of Colorectal Surgeons (ASCRS) and Association of Coloproctology of Great Britain and Ireland (ACPGBI). DNA mismatch repair protein immunohistochemical testing was compared between matched pairs of preoperative and postoperative samples in patients with known Lynch syndrome. Subsequently, the effect of radiation on the reliability of this technique was tested in a cohort age less than 50. The influence of compliance with post surgical surveillance intervals on metachronous colon cancers was studied in patients with known Lynch syndrome. The influence of an extended colectomy on QOL and bowel function was tested using the Short form- 36 (SF 36) form. Patients’ perspectives and priorities to various aspects of their care including extent of colectomy were tested. Results: A wide spectrum of practices were identified between countries, although the majority would offer an extended colectomy in the presence of known Lynch syndrome, not all would test for this prior to index colectomy. Lynch syndrome could be reliability tested using endoscopic biopsies, and post radiation samples were reliable providing viable tumor was left. Compliance with postoperative surveillance guidelines did not obviate the risk of second primary colorectal cancer, although the stage of disease was less. Short term and medium term quality of life and bowel function were similar between total colectomy and segmental colectomy groups. Young patients would prefer an extended colectomy to reduce the risk of future CRC despite the risk of worsening bowel function. Conclusion: Lynch syndrome can be identified from endoscopic biopsies using DNA MMR immunohistochemical testing and an extended colectomy should be strongly considered in such patients when diagnosed at a young age. Bowel function and quality of life are not dramatically affected by this approach, and young patients are willing to adopt this approach even with the prospect of worse bowel function. Further education among colorectal surgeon society members is required.
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ItemCharacterisation of the remnant foreskin: implications for HIV transmission in circumcised men( 2010)Human Immunodeficiency Virus (HIV) prevention remains one of the world’s top public health and development priorities, and male circumcision is the only biomedical intervention that has achieved level 1 scientific evidence for effectiveness in HIV prevention. Three randomised controlled trials have provided strong evidence that adult male circumcision confers significant protection against HIV infection, with a reduction in the relative risk of at least fifty percent. During surgical circumcision, a sleeve of preputial skin is removed and a cuff of skin around the base of the glans penis remains, forming the remnant foreskin. It is thought that the protective affect of circumcision can be attributable to the surgical removal of the inner foreskin epithelium, the main entry site of HIV into the penis. Current accepted wisdom is that the inner foreskin epithelium is abundantly supplied with HIV-1 target cells, is poorly keratinised, at risk of microscopic tears, exposed to vaginal secretions during intercourse, has a higher degree of susceptibility to HIV infection when compared to the outer foreskin, and provides a moist environment that might sustain the viability of pathogens. The aim of this study was to characterise the remnant foreskin (R), in comparison to the penile shaft skin (S) and the inner foreskin (I), and determine its role in the transmission of HIV. Tissue biopsies were obtained from the remnant foreskin and penile shaft skin of 10 circumcised men undergoing elective vasectomy and from the inner foreskin of 10 uncircumcised men undergoing elective circumcision. Biopsies were stained for Langerhans’ cells and keratin, and the number of Langerhans’ cells/mm2 and the thickness of the epithelium and stratum corneum was measured at each site. This study has shown that what was previously accepted wisdom regarding the keratin thickness of the inner foreskin is incorrect. Instead, our results revealed no significant difference in epithelial (RvS: p=0.38; IvS: p=0.53; RvI: p=0.82) or keratin (RvS: p=0.32; IvS: p=0.15; RvI: p=0.66) thickness between the three sites. In keeping with current evidence, we found that the inner foreskin has a high density of Langerhans’ cells. We found that the remnant foreskin has a significantly smaller amount of Langerhans’ cell within its epithelial, in comparison to both the penile shaft skin and the inner foreskin. In fact, relative to the inner foreskin, there is an astonishing scarcity of Langerhans’ cells in the remnant foreskin. There was significantly fewer Langerhans’ cells in the remnant foreskin compared to the inner foreskin (p=0.00001) and penile shaft skin (p<0.01), and significantly more Langerhans’ cells in the inner foreskin than the penile shaft skin (p<0.02). We believe that the reduced transmission of HIV seen in circumcised men is not because of a difference in keratin thickness between the inner foreskin and other penile skin, as has been previously accepted wisdom, but could be due to the surgical removal of HIV-1 target cells (Langerhans’ cells) in the inner foreskin and the subsequent development of the remnant foreskin, a tissue with a remarkable scarcity of Langerhans’ cells.