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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ItemThe role of IL-11 signaling in glioblastoma progression( 2022)Glioblastoma is the most common and lethal brain tumour in adults with a mean survival rate of only 12-15 months with current treatment. The microenvironment of a tumour is becoming increasingly more important to current research, with many findings suggesting that the transcription factors driving oncogenic processes are more often due to cytokine stimulation than gene mutation. There have been multiple signalling molecules and corresponding receptors identified as key role-players in the development of glioblastoma, its severity and ability to evade treatment. Cytokines are molecules that initiate and mediate a range of cellular activities essential to the homeostasis of a heathy person but also to tumour growth, invasion and survival. This includes the critical growth factors and cytokines that activate signalling pathways controlling many pro-oncogenic cellular functions. The interleukin-11 (IL-11) cytokine has become increasingly recognised as a driver of the pathogenesis of a wide range of cancers, however, very little is known regarding its role in glioblastoma. Considering this, we hypothesized that IL-11 would contribute to glioblastoma cell viability, migration, invasion and overall tumour progression. We initially identified that IL-11 and its receptor (IL-11RA) inversely correlate with tumour grade and glioblastoma survival. To study the role of IL-11 in glioblastoma, we next determined the expression of endogenous IL-11RA in a range of cell lines and transfected those expressing very little of the gene with the IL-11RA (cell lines #20 and #28). Proteomic analysis was conducted to reveal changes in protein expression after transfection. A large number of proteins involved in proliferation, migration and invasion were seen to be upregulated in the IL-11RA transfected cells. Indeed, the IL-11RA transfected cells displayed significantly greater growth, migration and invasion in proliferation, wound healing, transwell and spheroid invasion assays. This was reversed with IL-11RA knockdown. The proteomic analysis also highlighted the upregulation of proteins involved in metabolism, particularly glutaminolysis and inhibition of apoptosis. Metabolomic analysis revealed the IL-11RA transfected cells displayed increased levels of glutamine oxidation, as well as increased proliferation and survival of these cells in conditions of depleted glucose or glutamine. Similarly, IL-11RA transfected cells displayed no significant difference in invasion rate in the presence or absence of glucose, when glutamine was available. Alternatively, blocking both glucose and glutamine metabolism with a number of drugs significantly reduced the proliferation, migration and invasion of these cells. Our findings suggest that the IL-11RA transfected cells are able to utilise alternative metabolites such as glutamine, in the absence of glucose, in order to proliferate, migrate and survive. Overall, the results of this thesis suggest that the IL-11RA plays an important role in proliferation, migration, invasion, survival and metabolism in glioblastoma.
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ItemCirculating Biomarkers in Glioma( 2022)The identification of accurate circulating biomarkers, otherwise termed “liquid biopsy,” is a major goal in oncology research due to the potential clinical applications in population screening, tumour monitoring and delivery of individualised treatments resulting from tumour genotyping. Recently, large datasets have been made available due to advances in genome sequencing and mass spectrometry, however the difficulty remains in translating these findings to clinically meaningful applications. Gliomas are the most common primary brain cancer and its most aggressive form, glioblastoma (GBM), is rapidly and uniformly lethal.1 Circulating biomarkers have the potential to aid in a number of challenges that are faced in managing these patients. Despite increased efforts in biomarker discovery, currently there is no validated liquid biopsy for glioma. In this thesis, three candidate biomarkers are investigated for use in several clinical applications. Firstly, the small non-coding RNA sequence microRNA, is shown to be able to monitor for glioma progression, assess tumour burden and improve prognostic predictions. Following this, reliable detection of circulating tumour DNA (ctDNA) in plasma of patients is demonstrated using highly sensitive next generation sequencing and PCR techniques. The potential of ctDNA as a diagnostic adjunct for complete molecular tumour characterisation is shown, as well as the ability of ctDNA to monitor an individual tumour’s genomic evolution including identifying early in the blood key gene mutations associated with chemoresistance. Finally, a pilot study is presented using spiral microfluidics, confirming the presence of circulating tumour cells in the blood of glioma patients as a method to increase tumour DNA concentration.
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ItemIdentifying the Risks and Drivers of Aggression in Prostate Cancer( 2022)Prostate cancer is the most commonly diagnosed cancer and the second commonest cause of death in Australian men. The natural history of localised prostate cancer is markedly variable. Most individuals will lead a biologically indolent course where it may never be clinically significant while an unpredictable minority of individuals, approximately 10%, will rapidly progress to metastases and eventually succumb to the disease. Currently there are no adequate methods in determining the difference between an indolent or aggressive course of the disease at an early stage; therefore, leading to significant over-treatment of indolent disease as well as under-treatment of aggressive disease. The identification of potential drivers of aggression in prostate cancer are explored through the compilation of published papers in an integrated thesis by investigating the impacts of obesity, velocity of biochemical recurrence, aggressive ductal adenocarcinoma variant, as well as the molecular comparison between primary and matched metastatic tumours. Obesity is linked with more aggressive prostate cancer and higher rates of disease recurrence post treatment. It is unclear if this is due to specific tumour-promoting effects of obesity or diagnostic bias. The effect of obesity on the accuracy of pre-treatment risk categorisation was determined, and mediation analysis was used to identify the contribution of biologic versus non-biologic mechanisms to the observed increased risk of biochemical recurrence. The analysis included 1587 patients. Despite similar rates of adverse pathological features at prostatectomy, biochemical recurrence rates were significantly higher in very obese patients, which persisted after adjustment for stage, grade and PSA. Tumour volume however correlated significantly with BMI (p = 0.004), and the difference in predicted and observed ‘tumour attributable’ PSA (Delta-PSA) in very obese patients was greater than three times higher than that of healthy patients (p = 0.0067). Regression analysis indicated that the effect of BMI on tumour volume was fully mediated indirectly by its effect on PSA. Inclusion of this diagnostic error as a covariate in the survival analysis attenuated the effect of BMI on recurrence. Being very obese suppresses tumour-associated PSA resulting in a diagnostic bias that is responsible for errors in risk classification, and potentially contributes to a delay in initial presentation. Radical prostatectomy is one of the preferred treatment modalities for localised prostate cancer. Although the majority of patients experience long term disease control, depending on the pre-treatment clinical characteristics of the cohort under study, up to a third of men will develop disease recurrence. The most common manifestation of disease recurrence is a detectable serum PSA in the postoperative period. This thesis characterises the pattern of late disease recurrence in the largest contemporary cohort of localised prostate cancer patients treated with radical prostatectomies in the active surveillance era. Total of 2312 patients were included in the final analysis with up to 12 years of follow up data. The average patient had clinically localised prostate cancer, an elevated PSA, and ISUP grade group 2 on biopsy. 88.7% of patients had ISUP grade group 2 or higher at prostatectomy. A subgroup of 446 patients had undetectable PSA levels at 5 years after prostatectomy; 11.7% of them progressed to experience biochemical recurrence. In this subgroup, late recurrers had significantly higher-grade tumours on ISUP and Gleason sum (p < 0.001 and p = 0.001, respectively), higher rates of extraprostatic extension (p = 0.022), and larger tumour volumes (p = 0.032). Logistic regression demonstrated that prostatectomy ISUP grade group was a significant predictor (OR 2.14, 95% CI 1.43-3.20, p < 0.001). Additionally, the timing of recurrence resides on a continuum of risk and that the potential concept of dormant micrometastatic involvement requires further research and evaluation. Ductal adenocarcinoma is an uncommon prostate cancer variant. Previous studies suggest that ductal variant histology may be associated with worse clinical outcomes, but these are difficult to interpret. Prostatectomy patients with ductal variant histology from two institutional databases were identified and compared to an independent acinar adenocarcinoma cohort. A total of 202 ductal adenocarcinoma and 2037 acinar adenocarcinoma cases were analysed. Deep whole exome sequencing was performed in selected cases (n = 8). Survival analysis after matching demonstrated that patients with ductal variant histology had shorter salvage-free survival (8.1 vs 22.0 months, p = 0.03) and metastasis-free survival (6.7 vs 78.6 months, p < 0.0001). Ductal variant histology was consistently associated with RB1 loss, as well as copy number gains in TAP1, SLC4A2 and EHHADH. The presence of any ductal variant adenocarcinoma at the time of prostatectomy portends a worse clinical outcome than pure acinar cancers, with significantly shorter times to the initiation of salvage therapies and the onset of metastatic disease. The exploration of the impacts of obesity, velocity of biochemical recurrence, aggressive ductal adenocarcinoma variant, as well as the molecular comparison between primary and matched metastatic tumours to provide insights into potential drivers of aggression in prostate cancer.
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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.
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ItemUnderstanding and overcoming resistance to epidermal growth factor receptor therapy( 2020)Colorectal cancer (CRC) is the fourth most common cancer diagnosed in Australia. Current standard treatment includes surgery, chemotherapy, and targeted therapy. Cetuximab is often used as part of the clinical management of unselected patients until a subset of patients were found to harbor KRAS mutations that conferred intrinsic resistance to Cetuximab. In addition, some patients are resistant to Cetuximab despite having wild-type KRAS. Using RNA-sequencing data and differential expression analysis, we discovered five potential biomarkers for predicting resistance to Cetuximab in CRC with wild-type KRAS. After generating 3 CRC models of acquired resistance to Cetuximab, we also employed proteomics analysis to determine potential biomarkers of acquired Cetuximab resistance in CRC cells with wild-type KRAS. In addition, we generated pre-clinical data for the repurposing of Carfilzomib (CFZ) as a novel drug to overcome Cetuximab resistance in metastatic colorectal cancer patients. In conclusion, this study provides a Cetuximab resistant model that can be used for further studies coupled with possible resistance mechanisms as well as a novel drug to overcome Cetuximab resistance.
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ItemColorectal Cancer resection outcomes using administrative data( 2020)Background Colorectal cancer is the second leading cause of cancer death in Australia. If found early, a patient can undergo potentially curative surgery. Even in the third of patients that do recur, there can be palliation or even cure with further surgery with or without chemotherapy. Although surgery remains a vital tool in treating colorectal cancer, it is not without complications. The principal studies of this thesis used administrative data to report on short- and long-term outcomes following resection for colorectal cancer in the state of Victoria over a ten-year period. Methods Administrative data are collected on all patients admitted to Australian Hospitals. Patient demographics, co-morbidities, type of operation, post-operative complications, histopathology and some staging information are recorded. Trained coders review clinical notes and then assign alphanumeric codes to these data based on the International Classification of Diseases Tenth Revision, Australian Modification (ICD-10-AM). These codes were developed for the purpose of billing and therefore may not be focused on reporting data in a clinically relevant fashion. We have previously shown that the use of algorithms of code combinations can increase the accuracy of this data source for clinical research1. This thesis added laparoscopic detail to these coding algorithms. These algorithms were then applied to a central repository of administrative data in Victoria, to report on short-term outcomes following resection for colorectal cancer comparing regional to metropolitan hospitals. Results were adjusted for potential confounding variables using a multivariable logistic regression analysis. This data source was then linked to death data to report on overall long-term survival following colorectal cancer surgery, comparing regional to metropolitan hospitals. Survival results were presented as a rate, adjusted for potential confounders using a multivariable Cox regression analysis. Results These studies found strong evidence for lower odds of prolonged length of stay (OR 0.53, 95% CI 0.48 – 0.58, p=<0.001) and inpatient mortality (OR 0.67, 95%CI 0.49 – 0.91, p=0.01) in inner regional hospital compared with metropolitan hospitals. For outer regional hospitals, there was strong evidence of decreased odds of prolonged LOS (OR 0.64, 95%CI 0.52 – 0.77, p=<0.001) and return to theatre (OR 0.67, 95%CI 0.47 – 0.95, p=0.03). There was no difference in overall survival comparing colorectal cancer resection patients from inner or outer regional hospitals to metropolitan ((HR 1.02, 95%CI 0.95 – 1.09, p=0.59) and (HR 0.97, 95%CI 0.85 – 1.11, p=0.68) respectively). Conclusion These studies demonstrated the strength of administrative data with validated algorithms and data linkage in reporting on outcomes following colorectal cancer resection. This methodology resulted to two of the largest and most detailed studies concerning colorectal cancer resection in Australia. Importantly, they validated current practices in Victoria by revealing similar outcomes in regional and metropolitan centres after resection for colorectal cancer.
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ItemGlioblastoma: Treatment Stagnation and Cellular and Molecular Mechanisms( 2020)Glioblastoma, a WHO grade IV primary brain tumour, remains as one of the most aggressive forms of human cancer. Despite intensive research efforts into understanding the key drivers of tumour progression, few therapeutic advances have been made, with the current standard of care (the Stupp protocol) remaining unchanged for 15 years. The overall improvement to glioblastoma survival in the real-world population has been attributed to the use of the Stupp protocol, yet evidence suggests that survival outcomes were already significantly improving in the years prior to the introduction of this standard of care questioning the overall veracity of this claim. Using the Surveillance, Epidemiology and End Results (SEER) registry data we analysed the survival outcomes for real-world glioblastoma patients diagnosed from 2000 – 2016. Our findings show a consistent incremental survival improvement that preceded the introduction of the Stupp protocol and continued to increase at the same rate till 2009, stagnating afterwards. Significantly, however, this survival improvement is short-term for patients, with no survival improvement observed in patients surviving more than 2 years. Additionally, with the exception of complete tumour resection, all treatment modalities did not improve survival beyond 2 years for glioblastoma. These findings highlight the clinical stagnation of glioblastoma treatment and highlight the inability of current treatments to target the underlying causes of tumour progression. Following the introduction of the Stupp protocol attempts to develop new treatment options have universally been disappointing with a close to 0% success rate for over 1000 phase II and above clinical trials. Conflictingly, many of the therapeutic agents tested have shown promising results in preclinical trials. Current preclinical models, however, test therapies against the primary tumour, which does not recapitulate the biology or targets of tumour recurrence. We therefore developed a highly sensitive luciferase-based glioblastoma mouse model capable of single cell detection in mouse tissue. Analysis of mouse brain tissue implanted with luciferase-labelled human glioblastoma U87MG or MU20 tumours revealed the presence of tumour cells ubiquitously spread across the supratentorial regions of the brain, and distally located from the primary tumour. These tumour cells were observed as single cells in U87MG implanted mice and clusters in MU20 glioblastoma cells. Remarkably, U87MG tumours did not exhibit invasive margins and were contained within an expansive growth phenotype, suggesting invasion-independent dissemination. Our model is consistent with reports of glioblastoma as a systemic brain disease and is capable of sensitive detection of disseminated tumour cells, a model of recurrence potential. Furthermore, this model can be utilised to investigate new mechanisms of glioblastoma infiltration. Targeting aberrant angiogenesis in glioblastoma has been the major focus for glioblastoma treatment since the Stupp protocol. Yet after over a decade of basic research and clinical trials, antiangiogenic inhibitors have failed to translate into improved patient outcome. The discovery of abnormalities in the tumour vasculature suggest that there may be alternate mechanisms driving tumour progression. Vasculogenic mimicry has been observed in glioblastoma and presents as a novel aspect of tumour biology, yet the mechanisms and functional relevance of these structures remain unknown. Our study has confirmed the ability of some glioblastoma cell lines to undergo endothelialisation, forming lattice structures similar to endothelial cells when seeded onto Matrigel in vitro. One lattice forming cell line, U87MG, was also found incorporate into the tumour vasculature in an in vivo orthotopic mouse model. This behaviour was found to be regulated by an expanded TGF-beta-ALK1-Smad1/5 signalling pathway. In vivo inhibition of the Smad1/5 signalling pathway via intracranial treatment with Ad-Smad6 resulted in reduced endothelialisation in the tumour vasculature and inhibited whole brain infiltration in the U87MG mouse model. Since U87MG xenograft tumours are non-invasive, these results suggest that endothelialisation may lead to haematogenous dissemination and distal brain infiltration, providing a novel mechanism for glioblastoma progression.