Surgery (RMH) - Theses
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ItemInvestigation of colorectal cancer outcomes through the use of state-wide administrative data and data linkage( 2023)Background Healthcare administrative data are data that are collected at each encounter with the healthcare system, as part of routine process. Although primarily not for research purposes, administrative data can be utilised as a low-cost source of information for clinical outcomes research, with broader population coverage compared to clinical databases. The use of population-based data linkage to combine various data sources into a linked record has also become an increasingly valuable epidemiology research tool to attempt to address the deficiencies in a single dataset. The current evidence for the effect of socioeconomic disadvantage (SED) on stage at presentation and survival for colorectal cancer in Australia is conflicting, with varying definitions of advanced stage at presentation. The main aim of this thesis was to evaluate the impact of SED (based on area-level measurements) on stage at presentation and survival in patients who had undergone resections for colorectal cancer. Methods The main methodology underpinning the projects in this thesis utilised administrative data and data linkage to construct a more detailed dataset to report on clinical outcomes, and to allow for more adjustments for potentially confounding co-variables. Data linkage services were provided by the Centre for Victorian Data Linkage (CVDL). The Victorian Admitted Episodes Dataset (VAED) was used to identify all patients who had undergone a colorectal cancer resection in Victoria in 2010-2020, and then linked to the Victorian Cancer Registry (VCR) and the Victorian Death Index (VDI) to provide further sociodemographic, pathology, and survival data. SED was measured using the Index of Relative Socioeconomic Disadvantage (IRSD) in quintiles, an area-level composite measure utilising data from the Australian Bureau of Statistics, available from the VCR. Stage at presentation was grouped into specific Tumour Node Metastasis (TNM) stage groupings that were more or less likely to be symptomatic. Multivariable regression analysis was performed to adjust for potentially confounding covariables. Overall survival was analysed using Cox proportional hazards multivariable regression and odds of presenting with an advanced stage tumour were analysed with multivariable logistic regression. Results These studies found that in patients who had undergone resection for colorectal cancer (8,189 patients over a 10-year period in Victoria), there was no evidence of effect of area-level SED on the odds of presenting with a locally advanced stage tumour, which was more likely to be symptomatic (OR=1.08, CI: 0.92 - 1.28; OR=1.09, CI: 0.92 - 1.29; OR=1.00, CI: 0.84 - 1.19; OR=1.11, CI: 0.92 - 1.35 (SED quintiles 2-5 v. SED quintile 1 (most disadvantaged))). Similarly, there was no evidence of effect of SED on the odds of presenting with an early-stage tumour, which was more likely to be asymptomatic. There was no evidence of association between SED and odds of presenting with a more advanced overall stage (Stage III-IV versus Stage I-II). There was no evidence of difference in overall survival comparing patients from different quintiles of SED (HR = 0.96, CI: 0.86 - 1.07; HR = 0.99, CI: 0.88 - 1.11; HR=0.94, CI: 0.84 - 1.06; HR=1.04; CI: 0.91 - 1.18 for SED 2-5 respectively compared to SED 1 (most disadvantaged)). Conclusion The large, detailed studies in this thesis found no evidence that area-level SED was associated with differences in stage at presentation or with poorer overall survival on colorectal cancer resection patients in Victoria. While data regarding symptomatic versus asymptomatic presentations is lacking in registries, these results provide indirect evidence that presentation with less likely symptomatic and more likely symptomatic colorectal cancer may be similar across SED groups in patients undergoing CRC resections.
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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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ItemAn international comparison of outcomes in acute diverticulitis( 2016)Acute diverticulitis is an increasingly common disease but the rate of emergency operative intervention for this condition is decreasing. Despite this decrease, there has been no obvious detriment in outcomes, which suggests that emergency operative intervention may not always improve outcomes. Operative intervention represents higher resource use compared with non-operative intervention. Excessive utilisation of healthcare resources without improvement of outcomes threatens the sustainability of healthcare. Value in healthcare has become a global priority in the developed world. The term ‘value’ represents the optimum use of healthcare resources for quality in outcomes. International variation in surgical practice and outcomes can highlight differences in the value of healthcare systems around the world. The drivers of resource utilisation in healthcare are complex and include financial incentives for surgical activity. The surgical community can improve the value of surgical care by reducing variation through use of the most efficient surgical practices. Administrative data are routinely collected for every inpatient admission in most countries. They are stored as alphanumeric codes for diagnoses and procedures that occur during each inpatient episode. Advances in computing have unlocked the ‘big data’ era and administrative data are currently the only feasible method for international comparisons. Their optimum use as a measurement tool remains undefined. This thesis aimed to explore the limits of administrative data in the context of acute diverticulitis. Specifically, it explored the use of administrative data in performing an international comparison of the emergency operative intervention rate between USA, England and Australia. It also examined their ability to provide meaningful outcomes data about acute diverticulitis admissions in each country. This sets a foundation for their use in surgical audit. Differences in international coding systems require the use of logic algorithms to more clearly define cohorts of uncomplicated and complicated diverticulitis in each country. These algorithms represent combinations of codes that could account for international differences in coding systems as well as predict variations in coding. These logic algorithms were developed after a chart review of Australian coding for diverticular disease. This focussed on how cases that were missed by only searching for diverticular codes, were actually coded. This novel method can be applied to outcomes research in other diseases. Outcomes for unplanned admissions for acute diverticulitis were explored in several hospitals in each of the three countries. The Dr Foster Global Comparators international dataset containing administrative data from hospitals in these countries was used. In addition to providing meaningful outcomes data for a patient with acute diverticulitis in each of these countries, we showed that Hartmann’s procedure remains the most common emergency operation for acute complicated diverticulitis in these countries. Multivariable logistic regression analysis found that Australia had the lowest propensity for emergency operation and that England had the highest inpatient mortality risk for acute diverticulitis. This demonstration of international variation suggests differences in international resource utilisation, their outcomes and therefore healthcare value. This thesis shows how administrative data can be used to measure international variation in the management and outcomes of surgical disease, which is a critical process in addressing healthcare resource utilisation and value.
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ItemImpact of consultant-led care on patient outcomes within an acute care surgical unit( 2016)Background and aims: Healthcare services globally are faced with having to respond to increasing demands of emergency surgery presentations. It is widely recognised that the care and management of emergency patients needs to be prioritised and improved. Consultant-led acute surgical units are being increasingly introduced as a means of addressing this need. To date, improvements in patient outcomes within the acute surgical unit model of care have been reported in the context of prevalent conditions such as acute cholecystitis and acute appendicitis. Studies involving all emergency general surgical conditions have been lacking. The aim of this study was to determine the impact of consultant-led model of care on patient outcomes within an acute care surgical unit at a tertiary centre. In addition to being inclusive of all emergency general surgical conditions, it aimed to report on multiple outcomes including: morbidity and mortality, timeliness of care, elective surgery workload and cancellation rate, as well as impact on surgical training and education. The workforce involved in provision of emergency general surgery at both trainee and consultant level was surveyed to determine current perceptions and future challenges facing consultant-led acute surgical units in Australia. Methods: A retrospective observational study of all consecutive emergency general surgical admissions in 2009-2012 was performed. A 2-year time frame before and after the establishment of the emergency general surgery (EGS) service was used to determine the number of admissions and operations, emergency department and hospital length of stay, as well as complication rates for all emergency general surgery patients. For patients presenting with acute benign biliary disease additional outcomes of time to theatre, rate of definitive surgical management during index admission, conversion from laparoscopic to open cholecystectomy rate, and use of diagnostic radiology in management of biliary disease was determined. On-line questionnaires were used to qualitatively assess the impact on the surgeons and trainees involved in provision of emergency general surgery. Results: The study included 7233 acute admissions. The EGS service managed 4468 patients (61·6 per cent increase) and performed 1804 operations (41·0 per cent increase). The most common diagnoses during the EGS period included acute appendicitis (532, 11·9 per cent), biliary disease (361, 8·1 per cent) and abdominal pain (561, 12·6 per cent). Appendicectomy (536, 29·7 per cent), cholecystectomy (239, 13·2 per cent) and laparotomy (226, 12·5 per cent) were the most commonly performed procedures. In the EGS period, time in the emergency department was reduced (from 8·0 to 6·0 h; P < 0·001), as was length of hospital stay (from 3·0 to 2·0 days; P < 0·001). The number of complications was reduced by 46·8 per cent, from 172 (6·2 per cent) to 147 (3·3 per cent) (P < 0·001), with a 53 per cent reduction in the number of deaths in the EGS period, from 29 (16·9 per cent) to seven (8 per cent) (P = 0·039). A total of 566 patients with benign biliary disease were further analysed (pre-EGS 254 vs. EGS 312). In the EGS period, the number of patients having surgery on index admission increased from 43.7 to 58.7 per cent (p < 0.001) as did use of intra-operative cholangiography from 75.7 to 89.6 per cent (p = 0.003). The conversion to open cholecystectomy rate was reduced from 14.4 to 3.3 per cent (p < 0.001). Overall, a 14 per cent reduction in use of multiple (>1) imaging modalities for diagnosis was noted (p = 0.003). There was a positive trend in reduction of bile leaks but no significant difference in the overall morbidity and mortality. Time to theatre was reduced by 1 day [pre-EGS 2.7 (IQR 1.5-5.0) vs. EGS 1.7 (IQR 1.2-2.6) p < 0.001]. The overall hospital LOS was reduced by 1.5 days [pre-EGS 5.0 (IQR 3-7) vs. EGS 3.5 (IQR 2-5) p < 0.001]. In the EGS period of the study, elective surgery workload increased by 23.7 per cent with a corresponding 16.9 per cent reduction in cancellation rates. Consultant presence in theatre, and surgical trainees’ primary operating role also increased by 12 and 21.5 per cent respectively. The surveys demonstrated overall support for the consultant-led model of acute surgical units. Impact on private practice, remuneration and need for appropriate resource allocation were highlighted as issues needing further consideration. Conclusions: The establishment of a consultant-led emergency surgical service has been associated with improved provision of care, resulting in timely management and improved clinical outcomes.
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ItemBiliary tract injury( 2012)Aim - The aim of the thesis was to examine the causes, mechanisms, recognition and treatment of biliary injury. The hypothesis was that the management principles for biliary injury were similar regardless of the cause. Methods - Biliary injuries secondary to operative damage (iatrogenic), following transplantation or as a result of blunt or penetrating (traumatic) trauma were examined. The following databases were analyzed; A prospective database of biliary injuries in Victoria from 1997 - 1999, a database of iatrogenic biliary injuries from the Royal Infirmary of Edinburgh from 1984 - 2003, a prospective database for all liver transplants performed by the Scottish Liver Transplant Unit (SLTU) until September 2001 and the prospectively gathered trauma registry at The Royal Melbourne Hospital from 1999 - 2011. Retrospective case note review was performed for further data collection. Patient data was entered onto a Microsoft Access database and statistical analysis performed with SSPS versions using Cox regression for multivariate analysis, the Mann Whitney U test for independent variables and the Log rank test when appropriate. Not all data sets were of sufficient size to allow statistical analysis. Management of biliary injury included non-operative, percutaneous, endoscopic and surgical options. Results - Iatrogenic injuries were recorded in 33 patients from the Victorian audit and 123 patients from the Royal Infirmary of Edinburgh. Fifty five (14.6%) of 379 consecutive orthotopic liver transplants at the SLTU had biliary complications. Thirty three patients (0.1%) of 26,014 blunt and penetrating trauma patients had injuries to the biliary tree and gallbladder. Of the 123 iatrogenic injuries from the Royal Infirmary of Edinburgh, 55 (44.7%) had an attempted repair prior to referral, 59 (47.9%) were repaired after referral and 9 (7.3%) were managed without surgery. For the 59 patients repaired after referral a successful repair was possible in 22 (88%) of 25 patients repaired within the first two weeks compared with 20 (91%) of 22 repaired after 6 weeks (p=0.615). Nine patients were considered for hepatic resection. Five patients developed hepatic failure and were considered for liver transplantation with only two reaching transplantation. Of the 55 grafts from the SLTU with biliary complications, 28 biliary leaks occurred with 17 anastomotic leaks successfully treated non-operatively. Of the thirty anastomotic strictures, six (38%) of the 16 early anastomotic strictures required surgery for complete resolution, compared with 12 (86%) of the 14 late anastomotic strictures (p=0.0106). Of the blunt and penetrating biliary injuries there were 10 gallbladder and 23 biliary tree injuries. Fourteen patients had injuries to the intra-hepatic biliary tree and nine to the extra-hepatic biliary tree. Delay in the recognition of biliary injury following iatrogenic injury continues to be prevalent, with the delay often associated with sepsis, jaundice and peritonitis. Injury following liver transplantation is complicated by the association of hepatic arterial thrombosis and immunosuppression, whilst traumatic injury is frequently associated with intra-abdominal organ injury. The timing of repair and utilization of temporizing measures such as biliary drainage depends upon the associated injuries and presence of sepsis or jaundice. For all types of biliary injury, surgical reconstruction with Roux-en-Y hepaticojejunostomy remains the gold standard for repair. Successful long lasting repair is possible in the majority when managed by a specialist hepatobiliary team. Conclusion - The management of biliary injuries is multi-factorial and requires tailoring according to patient variables. However, common management pathways exist regardless of the cause.
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ItemMolecular prognostic and predictive biomarkers in colorectal cancer( 2012)Increasing knowledge of the underlying signalling pathways and molecular defects involved in colorectal cancer (CRC) growth/progression has led to the development of several novel target-based therapeutics along with the discovery of various prognostic and predictive biomarkers. The mitogen-activated protein kinase (MAPK) signalling pathway plays a critical role in colorectal cancer progression. Mutations in BRAF, a principal effector of Ras in this signaling cascade, are found in 10% of CRC. The low frequency of this mutation makes it a challenging target for drug development, unless subsets of patients with higher rates of BRAFV600E can be defined. This thesis first investigates the potential of enriching a CRC patient population for BRAFV600E mutations based on clinical features and KRAS status. The mutational concordance between primary-metastasis pairs, and the impact of BRAFV600E and other molecular changes on patient outcome were also evaluated. This was achieved by analyzing primary CRC from 525 patients evenly matched for age, gender and tumour location, and 81 primary-metastasis pairs. BRAFV600E, KRAS, PIK3CA, NRAS mutations, microsatellite instability (MSI) and loss of heterozygosity (LOH) were determined and correlated with clinical features and patient outcomes. The prevalence of BRAFV600E was found to be considerably higher in older females with KRAS wild-type right-sided colon cancers (50%) compared to the unselected cohort (10%). BRAFV600E was associated with inferior overall survival in metastatic CRC and is independent of MSI status. The previous study suggested that BRAF mutant cancers represent a discrete subset of metastatic CRC defined by poorer survival, right-side tumour location and association with MSI. Whether BRAF mutant CRC is further defined by a distinct pattern of metastatic spread was investigated by using prospective clinical data and molecular analyses from 2 major centers (Royal Melbourne Hospital and The University of Texas MD Anderson Cancer Center). Patients with known BRAF mutation status were analysed for clinical characteristics, survival, and metastatic sites. A distinct pattern of metastatic spread was observed in BRAF mutant tumours, namely higher rates of peritoneal metastases (46% vs 24%, P=0.001), distant lymph node metastases (53% vs 38%, P=0.008), and lower rates of lung metastases (35% vs 49%, P=0.049). To further develop the concept of cancer gene mutations as predictors of site of relapse, CRC metastases from different sites were then examined for oncogene mutation profiles. One-hundred CRC metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analysed for genes with identified mutations. Mutation prevalence was compared between metastases from liver, lung and brain. Differential mutations between metastasis sites were evaluated as predictors for site of relapse in patients from the VICTOR trial. KRAS mutation prevalence differed between metastasis sites, being more common in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P=0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. KRAS mutation was found to be predictive of lung relapse but not liver relapse in patients from the VICTOR trial.
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ItemThe ErbB family of receptor tyrosine kinases in vestibular schwannoma and meningioma( 2004)Neoplastic disease whether benign or malignant, is the aberrant uncontrolled proliferation of cells within any given compartment of the human body, leading to the formation of a tumour. Such proliferation of cells, known as transformation, is due to deregulation of cellular mechanisms that control normal growth and development, so that transformed cells become independent of factors that usually provide constraints for cell growth. Intracranial tumourigenesis essentially results in tumours of the brain, the meninges, the pituitary gland and/or the cranial nerves. (From Chapter 1)