Surgery (RMH) - Theses
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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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ItemFocused ultrasound as an adjunct to clinical evaluation for patients admitted to general medicine units( 2021)General internal medicine physicians have started to incorporate point-of-care ultrasound (POCUS) into their clinical practices. Limited data is available on POCUS use in internal medicine. This thesis aimed to evaluate the clinical impact of adding POCUS to the initial assessment of patients hospitalised in internal medicine units through three main research projects. First, a systematic review was conducted to investigate POCUS' clinical impact on hospitalised internal medicine patients. Five previous studies have addressed this question differing in their design, intervention, and outcomes reported. Two observational studies described the influence of POCUS on the diagnosis formulation. POCUS use changed in the principal diagnosis and added relevant new diagnoses occurred in up to 18% and 24 % of the cases, respectively. Impact on the management plan was reported in 37% to 52% of the participants as a composite outcome including change in medications, additional testing, change in prognosis or change in discharge time. Two randomised controlled trials (RCTs) addressed the effect of POCUS on the length of hospital stay. One study reported no difference between the groups, and the other study found a reduction of one day using serial lung ultrasound in patients admitted with heart failure. These studies were assessed as having moderate to severe risk of bias, which highlights the need for high-quality studies investigating the effect of POCUS on clinical outcomes. Subsequently, an RCT was conducted at the Royal Melbourne Hospital, Victoria, Australia that tested the impact of adding a multiorgan POCUS exam to the initial assessment of cardiopulmonary admissions on the length of hospital stay, clinical decision-making process, readmissions and health costs. Two hundred fifty participants were enrolled and randomised to intervention or control group. The intervention was a POCUS exam of the heart, lungs, and lower extremities (2-point venous compression) performed in the first 24 hours of admission to the unit. POCUS identified new pathology in 70% and changed the primary diagnosis in 28 %, medical treatment in 28%, and imaging tests in 60% of the subjects. However, there was no significant difference between the POCUS and control groups in the hospital length of stay, (POCUS 113 hours vs. control 125 hours, p=0.53), readmission rates (POCUS 16 % vs. control 12%, p=0.43) and total hospital costs ($7.8K vs. $7.9K, p=0.79). Finally, this thesis reports a prospective observational study assessing the feasibility and effectiveness of a heart and lung POCUS training program delivered to internal medicine physicians. The study identified the potential barriers of implementing POCUS' training programs in Australian hospitals. Moreover, it showed that a combination of electronic learning material, ultrasound simulators and supervised clinical rounds effectively improved participant's knowledge, image acquisition and interpretation skills. Overall, this thesis has generated substantial data on the impact of using POCUS on the clinical decision-making process performed by the treating physician and on patient's outcome, such as the length of hospital stays. Moreover, it has explored a POCUS training program for general internal medicine physicians in Australian hospitals.
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ItemEvaluating the role of invadopodia in glioma invasion and response to therapeutics( 2021)Glioblastoma (GBM) is the most prevalent and aggressive form of glioma, and is associated with an extremely poor prognosis, with a low median patient survival time of just 15 months post-diagnosis with the current therapeutic approach known as the Stupp protocol, consisting of surgical resection, followed by radiotherapy (RT) and concomitant chemotherapy with temozolomide (TMZ). A significant contributing factor that impacts the survival of GBM patients is the highly infiltrative nature of GBM cells, which prevents complete tumour resection and also limits the capacity of targeted therapies to effectively reach the infiltrating tumour cells. Consequently, these tumours can exhibit high rates of recurrence, appearing within months following the completion of the first round of treatment and can also demonstrate minimal response to further rounds of RT/TMZ treatment. Evidence suggests that the efficacy of current therapeutic approach may be compromised by an enhanced invasive phenotype that is displayed by the GBM cells that survive the current treatment protocol (Wild-Bode, Weller et al. 2001, Cordes, Hansmeier et al. 2003, Hegedus, Zach et al. 2004, Trog, Fountoulakis et al. 2006, Trog, Yeghiazaryan et al. 2006, Steinle, Palme et al. 2011). The targeting of the enhanced invasive abilities exhibited by RT/TMZ treated GBM cells could provide a potential therapeutic approach for improving patient outcome, however the mechanisms utilised by invasive GBM cells following the current treatment are not well understood. As GBM cells have been shown to form actin-rich membrane protrusions known as invadopodia that can facilitate invasion by degrading the surrounding ECM via highly localised proteolytic activity (Stylli, Kaye et al. 2008, Mao, Whitehead et al. 2017, Petropoulos, Guichet et al. 2018), it is possible that the enhanced invasive capabilities of GBM cells post- RT/TMZ treatment may be mediated by invadopodia. In this thesis, the role of invadopodia in GBM cell invasion and response to RT/TMZ treatment was investigated. Using clinically relevant doses of RT and TMZ, it was demonstrated that the enhanced invasive capabilities of GBM cells post-RT/TMZ treatment may be attributed to an increase in invadopodia formation and activity. The role of intracellular communication between GBM cells via small extracellular vesicles (sEVs) was also investigated, highlighting the ability of GBM cell line secreted sEVs to transfer a pro-invadopodia phenotype to recipient GBM cells, as well as their potential to facilitate an enhanced pro-invadopodia phenotype following RT/TMZ treatment. Demonstrating the potential to dualistically target invadopodia activity and sEV secretion to overcome RT/TMZ-induced GBM invasion, the addition of the microtubule-targeting agent Vinorelbine Tartrate (VT) alongside RT/TMZ reduced the enhanced secretion of sEVs, in accordance with previous data from our laboratory showing VT also reduces invadopodia activity in GBM cells surviving RT/TMZ (Whitehead, Nguyen et al. 2018). Lastly, GBM cell lines and their corresponding secreted sEVs were subjected to comprehensive proteomic profiling to identify proteins that may facilitate invadopodia formation and activity following exposure to RT/TMZ treatment, thereby contributing to enhanced GBM invasion. Collectively, this work highlights the contributing role of invadopodia and sEVs to the pro-invasive abilities of GBM cells, and provides insight into the dysregulated proteomic landscape of GBM cells and sEVs following exposure to RT/TMZ treatment that may contribute to enhanced invasive capacity, which may ultimately assist in the development of novel adjuvant therapeutic strategies to improve the clinical efficacy of RT and TMZ treatment.