Surgery (RMH) - Theses
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ItemNo Preview AvailableReSET Robotics Remodelling Surgical Education and Training in Robotics( 2022)Introduction & Objectives We aimed to develop a urology robotics curriculum that meets the training needs of robotic surgery novices without using live animals. We aimed to design and assess the feasibility of a digital and synthetic organ model curriculum capable of training learners to a level of competency in robotics prior to live surgery. Methods A review of robotic simulation education literature was performed. An online course was designed using Kern’s method for the development of surgical curricula. Learners then progressed to virtual reality simulation training prior to surgeries on a robot assisted radical prostatectomy model fabricated from polyvinyl alcohol, a low-cost hydrogel. Results A complete curriculum was designed and assessed by participants at each stage. This included: A an 11 module online teaching the foundations of robotics. 3 hours of 3D stereoscopic live surgical video. Psychomotor training using virtual reality robotic simulators. Synthetic organ procedural simulation training with objective performance metrics for operative time, blood loss, positive margins, nerve strain, anastomotic leak tests and neurovascular bundle preservation. A system to score live proctored robot assisted radical prostatectomy cases with GEARS and RACE scores which are validated robotic performance scoring systems. Conclusions We have demonstrated the feasibility and preliminary educational validity of a digital training program that includes realistic synthetic human organ models for urological robotic surgery. These surgical models are scalable and offer a viable alternative to live animal surgery without the cost, ethical and accessibility draw backs associated with animal training.
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ItemImpact of polyacrylamide hydrogel (Bulkamid®) in the management of stress urinary incontinence in women( 2021)Stress urinary incontinence (SUI) is a highly prevalent condition among women, with a significant impact on quality of life. Although mid-urethral sling (MUS) is widely considered the reference standard treatment following failure of conservative measures, increasing concern over the risk of mesh morbidity has resulted in it falling out of favour. Instead, more women are choosing to undergo urethral bulking agent treatment as a minimally invasive alternative, despite a lower efficacy rate to open surgery. Despite urethral bulking agents being a well-established treatment in women with SUI, there is a paucity of data to guide its use in clinical practice. Currently marketed urethral bulking agents include polyacrylamide hydrogel (Bulkamid) polydimethylsiloxane (Macroplastique), carbon-coated zirconium oxide (Durasphere), calcium hydroxylapatite (Coaptite) and polymerising polydimethylsiloxane silicone gel (Urolastic). Clinical data comparing the outcomes of these agents are limited. This thesis assesses and compares all available urethral bulking agents used in the treatment of SUI in women. Variable mean success rates of 30%-80% are reported in the short-term. Better long-term success rates were found with Bulkamid, Coaptite and Macroplastique on qualitative review. The majority of urethral bulking agents are reported to be safe, with less frequent adverse events such as urinary tract infection, temporary acute urinary retention and de novo urgency reported. More significant complications such as migration into lymph nodes and erosion have also been reported yet are rare. Despite the common use of polyacrylamide hydrogel urethral bulking agent injections since its introduction in 2006, long-term clinical data are limited. This thesis demonstrates the long-term outcomes of polyacrylamide hydrogel (Bulkamid) transurethral injections in an Australian cohort of women with SUI performed by a single surgeon. 21% of women did not respond to primary polyacrylamide hydrogel (Bulkamid) treatment and proceeded to alternative anti-incontinence surgery. As opposed to the common perception of urethral bulking agents being a short-term therapy, requiring frequent repeat injection, 53% of women at 7-8 years post initial injection self-reported a successful outcome. Polyacrylamide hydrogel (Bulkamid) injection was associated with benefits on other important patient-reported outcomes such as urinary incontinence-related symptom distress and life impact. Short-term adverse events were infrequent and mild and there was no serious long term adverse event. Knowledge of factors associated with superior outcomes in women treated with urethral bulking agents for stress urinary incontinence remains limited yet could help clinicians better select and counsel patients on expected outcomes. This thesis explores factors associated with polyacrylamide hydrogel (Bulkamid) treatment success in women with SUI, and demonstrates that women with type 3 urethral hypermobility, a well-supported urethra, were more likely to report treatment success than women with non-type 3 urethral hypermobility before treatment. Poor bladder compliance before treatment was associated with higher urinary symptom distress, and higher severity and frequency of urinary incontinence post-treatment. Older age was associated with higher levels of self-reported urinary frequency and severity post-treatment. Finally, the severity of pre-treatment incontinence impact was associated with worse incontinence impact post-treatment. Findings from this thesis will assist clinicians in the selection of urethral bulking agents. It will also assist clinicians in the selection of patients most likely to benefit from polyacrylamide hydrogel (Bulkamid) urethral bulking agents injection treatment, and in the counselling of expected long-term efficacy and safety outcomes.
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ItemUse of administrative data to create a colorectal cancer database( 2018)Background: Research into Colorectal cancer (CRC) require maintenance of clinical cancer databases with complex datasets. These are resource intensive, region specific, and compromised by reporting bias [1]. Administrative data are routinely captured for each hospital admission and may serve as an alternative source for populating databases. However, the accuracy of administrative data has not been fully explored and may vary by data item. The aims of this study included identifying a cohort of new CRC patients from administrative data, measuring its accuracy, and deriving coding algorithms to improve the accuracy of diagnoses, procedures and short-term outcomes. There has been much debate that major surgery, in particular for cancer patients, should be concentrated in tertiary centres, based on the premise that high volume centres achieve better outcomes. In this study, we investigated two hypotheses: that the majority of complex colorectal cancer resections are performed in major city hospitals and that the short-term outcomes are better in CSSANZ (Colorectal Surgical Society of Australia and New Zealand) hospitals. Large Inpatient administrative databases are a common source used to identify comorbidities recorded with International Classification of Disease (ICD) diagnostic codes. These data sources may be used to assess the effect of baseline comorbidity status on surgical care outcomes. In this study, we hypothesized that the ASA PS (American Society of Anaesthesiologists physical status) classification can predict short-term outcomes after a colorectal cancer resection when compared to the Elixhauser comorbidity index (ECI). Methods: A retrospective study was conducted to identify all new colorectal cancer resections at The Royal Melbourne Hospital from 1st of January 2008 to 31st of December 2013, using administrative data. Code combinations and algorithms were used to improve the accuracy of administrative data. These algorithms were utilized to identify an accurate cohort of colorectal cancer resection cases from the Victorian Admitted Episodes Dataset (VAED), between July 2008 to June 2013. The short-term outcomes and workloads were compared in public hospitals across the state of Victoria. The algorithms constructed were also utilised to identify an accurate cohort of CRC resection cases from Dr Foster Global Comparators Victorian dataset. ASA PS classification scores were identified from these cases. Multiple linear regression models were constructed to study the association between comorbidity indices and short-term outcomes. Results: It is possible to use administrative data to identify new colorectal cancer patients who have had a surgical resection, using specific coding algorithms. Administrative data has an accuracy of 80-100% for most data fields, and this accuracy can be improved using coding algorithms. An accurate cohort of colorectal cancer resection cases was identified from the VAED dataset. Seventy-three percent of CRC resections in the state were performed in metropolitan city hospitals. There was no significant difference in LOS (length of stay), mortality and reoperation rates between CSSANZ and non-CSSANZ hospitals. This study demonstrates that administrative data is both cost-effective and informative. The ASA PS model was indeed shown to be a strong predictor of the primary outcome: length of stay (LOS). The significant predictors of LOS were emergency operations, rectal cancer resections, ASA3 and patients age. The Elixhauser model was a better predictor than the ASA PS model. However, the full model adjusted for both the ECI and ASA PS grade was the best predictor of outcome. The study indeed showed the ability of the ASA PS classification to identify short-term clinical outcomes. Conclusion: These studies make the possibility of a Victorian CRC registry containing all surgical CRC patients a real possibility. Such a registry would enable outcomes research across the whole state with the possibility of data linkage to international administrative data sets.
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ItemManagement of PET-avid thyroid nodules in cancer patients( 2017)Background and aims: FDG-avid thyroid incidentalomas (TI) are common findings (2.5%) in patients imaged for staging or treatment response and represent thyroid cancer in approximately 35% of cases. Consequently, the 2015 ATA guidelines strongly recommend investigation of such nodules ≥1cm without considering the prognosis of underlying malignancy. In addition, the utility of SUV-max which observes maximum uptake of FDG also has been the described as a potential surrogate marker of thyroid cancer. This study aims to assess the overall and thyroid cancer specific survival in a large cohort of FDG-avid TI; assess the role of SUV-max in predicting thyroid cancer in this cohort; and observe potential confounders of highly avid thyroid nodules – notably benign Hürthle cell adenomas. Methods: A retrospective review was performed on all patients at Peter MacCallum Cancer Centre between 2007 and 2015. 45, 680 consecutive PET/CT scan reports were reviewed, identifying 2588 reports referring to the thyroid. Scan duplicates and normal thyroid reports were excluded. Other exclusions included physiological uptake to the thyroid gland, thyroiditis, patients known thyroid cancer, multi-nodular goitre, focal uptake less than 1mm and nodules identified with non-FDG radiotracers. FDG-avidity parameter data was gathered using MIM imaging software. Variables including age, gender, follow-up time >12 months, primary malignancy, overall survival, thyroid cancer-specific survival, cytology and histopathology were collected until January 2016. Multivariate logistic regression, survival analysis and receiver operator curve (ROC) analysis was performed. Results: The study included 362 patients who met the inclusion criteria with median age 65 years (range 19-96), and median follow-up of 24 months (range 1-103). Lymphoid, lung and colorectal malignancy were the most common indications for staging. The median overall survival was 20 months (IQR 9.5-39). The majority of deaths was due to the primary malignancy (92.2%). One patient (0.6%) died from incidental medullary thyroid cancer. FDG-avidity in primary malignancy, advanced stage and clinician decision to not investigate FDG-avid TI were all predictors of mortality with hazard ratios of 8.5 (95%CI 4.6-15.8), 3.0 (95%CI 2.3-3.9) and 3.3 (95%CI 2.0-5.0) respectively (P<0.001). Receiver operator curve (ROC) analysis demonstrated on optimal SUV-max threshold of 5.33. Sensitivity and specificity of thyroid cancer detected incidentally on PET/CT on ROC analysis was 73.47 and 46.94 respectively, with a broad area under the ROC curve of 0.66 (p = 0.005). Five nodules (20%) necessitated revision of diagnosis on correlative histopathologic-imaging review. Two presumed malignant FDG-avid TI found on imaging were correlated to non-malignant Hürthle cell adenomas on pathology, indicating misclassification by location. Conclusion: The overall survival with FDG-avid TI was poor due to the prognosis associated with underlying malignancy which must be considered prior to investigation of FDG-avid TI. Active surveillance should be considered in this group of patients. SUV-max is not a safe tool to discriminate benign from malignant TI and should remain a theoretical adjunctive tool for predicting thyroid cancer. Benign and malignant oncocytic lesions are a common cause of FDG-avid TI. The incidence of FDG-avid malignancy may be overestimated without careful imaging and histopathologic correlation.
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ItemA study on the use of administrative data to create a colorectal cancer database( 2017)Colorectal cancer (CRC) is a common and life-threatening disease which contributes a significant burden on global health systems. Clinical colorectal cancer registries (CCCRs) are potentially powerful tools in the study of cancer and have the ability to positively impact on the value, efficiency, effectiveness and resource allocation in the management of CRC globally. However, they are resource intensive, region specific, and compromised by reporting and recruiting bias. Hospital administrative data, which are routinely collected, are an obvious source for a more efficient and automated collection pathway of many data fields in CCCRs. They also provide comparable data across many hospitals; these data can be linked and enable comparative studies among hospitals and regions. The first hypothesis of this study was that the research output produced by CCCRs does not provide sufficient value to justify the extensive resources required to maintain these registries. The second hypothesis was that administrative data can be used to autopopulate a Victorian CRC database, and thereby be used to measure and compare clinical outcomes in CRC among health systems. In order to investigate the first hypothesis, a systematic review of CCCRs was performed which aimed to both identify and characterise the existing CCCRs, and also to measure the comparative research impact of each. 18 CCCRs were identified with sample sizes between 104 to 1,400,000 cases. Data fields, published aims and outcomes were similar between registries. The most frequently published outcomes related to anastomotic leak following colorectal surgery. The American National Cancer Database formed the basis of the highest number of publications (66), the British Northern Region Audit had the highest median article citation number (28.5), the British National Bowel Cancer Audit had the highest median impact factor (4.72), and the American National Cancer Database had the highest median Altmetric score (4.5). Overall, we found that there is a significant body of colorectal cancer outcomes research generated from the CCCRs. Given the enormous resources, the overall research output and impact of CCCRs is low in proportion to the size of the data sets. However, these registries hold key oncological and surgical outcomes data; focussing on data linkage and automated data collection will enable international comparisons. The aims of the second part of this study included identifying a cohort of new colorectal cancer patients from administrative data, measuring the accuracy of that administrative data, and deriving coding algorithms to improve the accuracy of diagnoses, procedures and outcomes sourced from administrative data. The study was based on Royal Melbourne Hospital (RMH) administrative data, medical charts and BioGrid Australia data. We found that it is possible to use administrative data to identify new colorectal cancer patients who underwent surgical resection using specific coding algorithms. Further, administrative data has an accuracy of between 80-100% for most data fields, and this accuracy can be improved using coding algorithms. We plan to use these coding algorithms across many hospitals, making the possibility of a Victorian CRC registry containing all surgical CRC patients a real possibility. Such a registry would enable outcomes research across the whole state.
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ItemExosomal regulation of TGF-β signalling( 2015)Exosomes are nanometer-sized vesicles (40-100 nm) secreted by various cells types. They are generated from late endosomes/multivesicular bodies (MVBs) and are released into extracellular space upon the fusion of MVBs outer membrane with plasma membrane. Exosomes exert a broad range of biological effects by transferring different contents (such as DNA, RNA, proteins and lipids). In particular, multiple signalling molecules (such as Wnt proteins) are carried in exosomes which promote tumor aggressiveness. Transforming growth factor-β (TGF-β) is a key player in various biological processes. TGF-β signalling is tightly regulated by multiple molecules at each step of the signalling cascade. Dysregulation of TGF-β signalling has been implicated in the pathogenesis of human diseases, including cancer. TGF-β can signal not only via linear signalling cascade but also through crosstalk with other pathways. Importantly, TGF-β and Ras signallings are found to act in synergy to promote malignant progression. Ras enhances TGF-β signalling by suppressing the SPRY domain and SOCS Box containing protein 1 (SPSB1), a negative regulator of TGF-β type II receptor (TβRII). However, the underlying molecular mechanism is controversial because Ras does not change the poly-ubiquitination levels of SPSB1. Active TGF-β has been discovered in exosomes. Exosomal TGF-β is shown to activate Smad-dependent signalling in recipient cells and drive fibroblast to myofibroblast differentiation. However, it is not clear how exosomes are involved in the regulation of TGF-β signalling. In particular, how exosomal TGF-β may differ from free ligand TGF-β in exerting their biological functions is yet to be answered. Moreover, SPSB1 is detectable in exosomes from Ras-transformed cells, raising the possibility that exosomes participate in Ras-induced up-regulation of TGF-β signalling by exporting SPSB1 from the cell. This thesis demonstrated that highly metastatic tumor cell lines secreted higher levels of exosomal TGF-β in comparison with non-/low- metastatic tumor cell lines, suggesting the potential of exosomal TGF-β as a biomarker for metastatic cancer. Moreover, exosomal TGF-β activated TGF-β signalling in TGF-β receptor-defective cells. This observation will cause a re-evaluation of TGF-β signalling’s role in tumorigenesis of human colon cancer harbouring TβRII inactivating mutation. Importantly, ligand traps were inefficient in blocking exosomal TGF-β-mediated TGF-β signalling. Consequently, strategies have to be developed to target exosomal TGF-β. Next, the intracellular TβRII negative modulator SPSB1 was discharged by exosomes upon Ras overexpression, resulting in a reduction in the cellular pool of SPSB1. Treatments using small molecular inhibitors indicated that Ras-mediated SPSB1’s MVB sorting and exosome secretion were dependent on Ca2+ concentration, ceramide and PI3K. SPSB1’s SOCS box as well as the interaction between Ras and SPSB1’s SPRY domain was required for SPSB1’s co-localization with CD63-positive late endosome and the subsequent release on exosomes. However, exosomal discharge of SPSB1 was independent of the ubiquitination of SOCS box. Furthermore, the SPSB1- and Ras- containing exosomes could be internalized by recipient cells. Collectively, these results highlighted the role of exosomes as vehicles for intracellular protein discharge. Lastly, this thesis revealed that Ras expression resulted in elevated levels of exosomal TGF-β, implying that Ras acts as a pivotal participator in the production of exosomal TGF-β.
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ItemHealth outcomes of delayed union and nonunion of femoral and tibial shaft fractures( 2015)INTRODUCTION: Knowledge about the functional consequences of lower limb long bone fractures is helpful to inform patients, clinicians and employers about their recovery process and prognosis. This study aims to describe the epidemiology and health outcomes of femoral and tibial shaft fractures treated at two level I adult trauma centres, by comparing the differences between patients with delayed union or nonunion and patients with normal union. PATIENTS AND METHODS: An analysis of registry data over two years, supplemented with medical record review, was conducted. Fracture healing was retrospectively assessed by clinical and radiological evidence of union, and the need for surgical intervention. SF-12 scores, and work and pain status were prospectively recorded at 6 and 12 months post injury. RESULTS: 285 fractures progressed to union and 138 fractures developed delayed union or nonunion. There was a significant difference between the two cohorts with regards to the mechanism of injury, association with multitrauma, open fractures, grade of Gustilo classification, patient fund source, smoking status and presence of comorbidities. The SF-12 physical component score was less than 50 in both groups at 6 and 12 months, but significantly better in the union cohort. 72% of patients with union and 59% of patients with delayed union or nonunion had returned to work at 12 months. 54% of patients with union and 72% of patients with delayed union or nonunion continued to have pain at one year. These differences in outcomes were also significant. DISCUSSION: Even patients whose fractures unite in the expectant time frame will have residual physical disability. Patients with delayed union or nonunion have still poorer outcomes, including ongoing problems with returning to work and pain. It is important to educate patients about their injury and prognosis so that they have realistic expectations. This is particularly relevant given that the population most likely to sustain femoral or tibial shaft fractures are working-age healthy adults, and up to one third of these fractures will develop delayed union or nonunion. CONCLUSION: Despite modern treatment, the patient-reported outcomes of lower limb long bone shaft fractures do not return to normal at one year. Patients with delayed union or nonunion can expect poorer health outcomes.
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ItemKey clinical and molecular determinants of biological behavior in glioma: examining the role of the Salvador-Warts-Hippo pathway in glioma stem cells( 2011)Analysis of a landmark genetic sequencing project, identifying likely damaging genetic variants in a series of twenty-one glioma stem cells, reveals the Salvador-Wart-Hippo (SWH) pathway to be a key deregulated pathway. A constitutive tumour suppressor pathway, its down-stream effector yes-associated protein, or “YAP”, is implicated in regulating stem cell and progenitor cell self-renewal. We found that YAP is overexpressed in a group of selected glioma stem cells, in contrast to normal brain, and established glioma cell lines. When we compared YAP and constitutive phosphorylated- YAP (p-YAP) expression between the glioma stem cells and their matched bulk tumours, we found p-YAP was consistently more highly expressed in the bulk “parent” tumour, compared to the corresponding stem cell. These findings are consistent with YAP expression being a molecular marker of “stemness”. YAP expression was shown to correlate with an aggressive phenotype within our stem cell series, with respect to adverse survival outcomes and biological behavior. Tumours associated with YAPexpressing stem cells had worse overall survival than their non-YAP-expressing counterparts (median survival 8 months versus 15 months, HR 1.886, 95% CI 0.224 to 0.8413, p value 0.4727). This favorably contrasts with the only other related published translational research to date, showing that lack of YAP expression in gliomas carries a survival advantage. Within a selected cohort of glioma stem cells, YAP-expression correlated with increased proliferative capacity, assessed by LDH assay. We show new and novel evidence that YAP is an oncogene in glioma, and may be a key glioma stem cell marker, further adding to a shift towards re-conceptualizing high-grade glioma as a disease of molecular-genetic aberrations.
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ItemWeight loss after reoperations for laparoscopic adjustable gastric banding( 2012)Background: Reoperation after laparoscopic adjustable gastric banding occurs with relative frequency and this is often cited as a major weakness of the procedure. There are currently no guidelines for the best reoperative procedure in these cases. Few studies report weight loss after reoperation, especially after band salvage procedures, despite being a critical factor in deciding which reoperative procedure to select. This study aims to assess the impact of major reoperations after laparoscopic adjustable gastric banding on weight loss at 12 and 24 months and on patient satisfaction with the procedure. Methods: An analysis of New York University Langone Medical Centre’s prospectively collected bariatric database was conducted. Adult patients who underwent laparoscopic adjustable gastric banding from 1 January 2001 to 30 June 2009 were identified. Patients who required major reoperation were then studied. Major reoperation included band repositioning, replacement, hiatal hernia repair and band removal. Basic demographic data, weight outcomes and surgical details were recorded. Weights at 12 and 24 months after reoperation were recorded and compared with initial weight and weight at reoperation. Patient satisfaction with the procedure was assessed by a qualitative telephone survey. Results: Of the 4680 patients retrieved, 4652 met inclusion criteria. There were 664 patients who underwent one or more major reoperations. There were no procedure-related deaths in the reoperation group. The 30-day patient complication rate for all reoperations was 1.8%. Patients undergoing 1 reoperation represented the largest subgroup (507 patients). For this subgroup, initial weight and Body Mass Index (BMI) were 122.7±23.3kg and 44.0±6.7kg/m2. At reoperation, weight, BMI and percentage excess weight loss (%EWL) were 91.4±22.7kg, 32.8±7.0kg/m2 and 51±24%. Twelve months after reoperation, weight, BMI and %EWL were 92.7±21.5kg, 33.3±6.8kg/m2 and 49±23% and at 24 months were 91.8±21.0kg, 33.2±6.7kg/m2 and 49±24%. Weight loss was sustained both at 12 months and 24 months after reoperation and did not differ from those without reoperation at the same length of time after primary banding. Patient satisfaction with the band was not affected by reoperation. Conclusion: Reoperation after laparoscopic adjustable gastric banding can be achieved with minimal morbidity. Weight loss is sustained 12 and 24 months after reoperation for laparoscopic adjustable gastric banding.