Surgery (RMH) - Theses
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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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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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ItemThe WNT signalling pathway in colorectal cancer( 2015)Alterations in components of the WNT signalling pathway, most commonly adenomatous polyposis coli (APC) gene mutations, are found in the vast majority of colorectal cancers (CRCs). There are many gaps in our understanding of APC mutations and their consequences, particularly in sporadic colorectal tumours. The aim of this study is to improve our understanding of APC mutations and aberrant WNT signalling in colorectal cancer. A cohort of 630 sporadic CRCs is analysed for APC gene mutations and loss of heterozygosity, by Sanger sequencing and single nucleotide polymorphism microarrays, respectively. APC genotypes show evidence of selection for residual APC protein function and a finely tuned ‘just-right’ level of WNT signalling for tumourigenesis. Proximal and distal CRCs appear to have different ‘just-right’ levels. These findings suggest that even subtle perturbation of the WNT pathway by pharmacological means could hinder colorectal tumourigenesis. The prognostic significance of APC mutations in colorectal cancer patients is then examined, controlling for known prognostic markers including BRAF V600E mutation and microsatellite instability. Patients with cancers in the proximal colon that are APC wild type and microsatellite stable are a poor prognosis group, and have features of the sessile serrated neoplasia pathway. This group of patients might warrant more aggressive management. This is the first study to suggest clinical value in the analysis of somatic APC mutations in sporadic CRC. The downstream consequences of APC mutation on gene expression are then investigated. Protein expression by immunohistochemistry is examined in colorectal tumours and normal intestinal mucosa for 83 genes that were previously identified as up- or down-regulated in colorectal tumours using gene expression microarrays. Potential target genes of the WNT pathway are identified, with up-regulated genes predominantly expressed in the basal half of normal crypts. This suggests that the ‘just-right’ level of WNT signalling may correspond to that found in the basal half of normal intestinal crypts, the location where stem cells and transit amplifying cells reside. Expression of PHLDA1, one of the identified potential WNT target genes, is then examined in detail using single- and double-label immunohistochemistry, laser capture microdissection, qRT-PCR, and mRNA in situ hybridisation on human tissue and transgenic mouse models. PHLDA1 is shown to be expressed by LGR5+ crypt base columnar cells, which are the putative human intestinal epithelial stem cells. PHLDA1 is overexpressed in colorectal tumours of all stages, and appears to contribute to tumour cell migration at the invasive front. These findings identify PHLDA1 as a novel protein marker of putative human intestinal stem cells, and a potential functional contributor to colorectal tumourigenesis. In conclusion, APC gene mutations appear to be selected for a ‘just-right’ level of WNT pathway activation, corresponding to the level of WNT signalling in the basal half of normal intestinal crypts. The ‘just-right’ level of WNT signalling appears to drive expression of intestinal stem cell and transit amplifying cell markers, including the novel putative stem cell marker PHLDA1. APC wild type / microsatellite stable cancers in the proximal colon have a poor prognosis, and therefore, testing for somatic APC mutations may have clinical utility for sporadic colorectal cancer patients.
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ItemMolecular profiling of colorectal cancer to inform use of novel drug therapies( 2014)This thesis tests the hypothesis that human colorectal cancers (CRCs) may be profiled for activated signaling pathways and oncogene mutations that determine sensitivity to targeted drug therapies. Genetic alterations that activate the phospho-3-inositide kinase (PI3K) signaling pathway were studied in depth in a large cohort of patients (n=1093) with CRC, and findings analyzed in the context of patient demographics, tumour histopathological findings and other genetic events: microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and mutations in genes KRAS, BRAF and TP53. Colorectal cancers characterized by PI3K pathway activation were found to be enriched in patients of older age and in the proximal colon. Use of meta-analysis to integrate the individual patient data with that of multiple other international cohorts (total n=5594) aided in delineating unique colorectal neoplasia pathways for CRCs with different pathway-activating mutations, however, with potential implications for CRC treatment and chemoprevention. CRCs carrying PTEN or PIK3CA exon 20 mutations demonstrated features of the sessile serrated tumorigenesis pathway and those with PIK3CA exon 9 mutations features of the traditional serrated pathway. The CRCs of a second patient cohort (n=572) were profiled for 19 oncogenes using the Sequenom MassARRAY® OncoCarta v1.0 platform with the aim of efficiently detecting low frequency CRC ‘drug-targetable’ mutations. Reported changes were verified by Sanger sequencing. Detected low frequency events of interest were a 1.1% incidence of AKT1 mutation, one EGFR L858R mutation and mutations in PIK3CA and BRAF outside their known activating mutation ‘hotspots’. CRCs from the same patient cohort were characterized for the oncogenic mutation BRAFV600E using sequencing and then embedded in tissue microrarrays tested for BRAFV600E protein expression using the novel mutation-specific antibody VE1. Results of this study, optimized by repeat immunohistochemistry on whole tissue sections for selected samples, were that VE1 immunohistochemistry is an adequate clinical diagnostic tool for BRAFV600E in CRC due to its demonstrated 100% sensitivity and specificity. Together these findings support the hypothesis that CRCs may be characterized for features relevant to individualized patient therapy with currently available molecular and histopathological technologies.
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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.