Abstract: In genome-wide association studies (GWASs) of colorectal cancer, we have identified two genomic regions in which pairs of tagging-single nucleotide polymorphisms (tagSNPs) are associated with disease; these comprise chromosomes 1q41 (rs6691170, rs6687758) and 12q13.13 (rs7163702, rs11169552). We investigated these regions further, aiming to determine whether they contain more than one independent association signal and/or to identify the SNPs most strongly associated with disease. Genotyping of additional sample sets at the original tagSNPs showed that, for both regions, the two tagSNPs were unlikely to identify a single haplotype on which the functional variation lay. Conversely, one of the pair of SNPs did not fully capture the association signal in each region. We therefore undertook more detailed analyses, using imputation, logistic regression, genealogical analysis using the GENECLUSTER program and haplotype analysis. In the 1q41 region, the SNP rs11118883 emerged as a strong candidate based on all these analyses, sufficient to account for the signals at both rs6691170 and rs6687758. rs11118883 lies within a region with strong evidence of transcriptional regulatory activity and has been associated with expression of PDGFRB mRNA. For 12q13.13, a complex situation was found: SNP rs7972465 showed stronger association than either rs11169552 or rs7136702, and GENECLUSTER found no good evidence for a two-SNP model. However, logistic regression and haplotype analyses supported a two-SNP model, in which a signal at the SNP rs706793 was added to that at rs11169552. Post-GWAS fine-mapping studies are challenging, but the use of multiple tools can assist in identifying candidate functional variants in at least some cases.
Abstract: AIMS: Comprehensive data describing the effect of obesity on type 2 diabetes outcomes is lacking. We sought to address this by analyzing a tertiary hospital clinical database. METHODS: We extracted clinical and biochemical data for patients who attended a tertiary hospital diabetes clinic between 1998 and 2011 and were aged less than 65 years. Body mass index (BMI) was correlated with the prevalence of vascular complications and with cardiovascular risk factors. RESULTS: The means of age and duration of diabetes for the 711 patients (392 men and 319 women) were 53 and 11 years respectively. BMI correlated with the prevalence of ischemic heart disease and, to a lesser degree, albuminuria, but not with the prevalence of cerebrovascular disease, neuropathy, retinopathy or renal function. BMI did not correlate with glycosylated hemoglobin, although obese patients used insulin both more frequently and at higher doses. CONCLUSIONS: In people with long-standing type 2 diabetes who attend a tertiary hospital outpatient clinic, ischemic heart disease, in contrast to other vascular complications, correlates robustly with BMI. These findings indicate that clinical trials of weight loss in type 2 diabetes should use cardiac endpoints as their primary outcomes.
Abstract: Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.
Abstract: Adenoid cystic carcinoma is a tumour of glandular cells responsible for 10% of salivary gland neoplasms. It has a high rate of perineural spread but limited involvement of regional lymphatics even in late stage disease. Early survival is typically good (60-90%) although long term survival is poor with spread to distant sites in 40-60% of cases. The authors performed a retrospective review of clinical and pathological records for 24 patients managed by their institution over a 22-year period. The overall 5, 10 and 20-year survival rates in this study were 92%, 72% and 54%, respectively. Perineural invasion was seen in 63% and close or positive margins seen in 64% of all primary resection specimens although survival was not associated with any clinical factor other than the initial size of lesion. Most patients presented complaining of a lump, whilst a burning neuralgia-type pain was the second most common symptom. The study confirms the conclusion of previous studies that tumour size at diagnosis is the most important predictor of outcome.
Abstract: Background  The complexity and cost of treating cancer patients is escalating rapidly and increasingly difficult decisions are being made regarding which interventions provide value for money. BioGrid Australia supports collection and analysis of comprehensive treatment and outcome data across multiple sites. Here we use preliminary data regarding the National Bowel Cancer Screening Program (NBCSP) and stage-specific treatment costs for colorectal cancer (CRC) to demonstrate the potential value of real world data for cost-effectiveness analyses (CEA). Methods  Data regarding the impact of NBCSP on stage at diagnosis was combined with stage-specific CRC treatment costs and existing literature. An incremental CEA was undertaken from a government healthcare perspective, comparing NBCSP to no-screening. The 2008 invited population (n=681,915) was modelled in both scenarios. Effectiveness was expressed as CRC-related life years saved (LYS). Costs and benefits were discounted at 3% per annum. Results  Over the lifetime and relative to no-screening, NBCSP was predicted to save 1,265 life-years, prevent 225 CRC cases and cost an additional $48.3 million, equivalent to a cost-effectiveness ratio of $38,217 per LYS. A scenario analysis assuming full participation improved this to $23,395. Conclusions  This preliminary CEA based largely on contemporary real world data suggests population-based FOBT screening for CRC is attractive. Planned ongoing data collection will enable repeated analyses over time, using the same methodology in the same patient populations, permitting an accurate analysis of the impact of new therapies and changing practice. Similar CEA using real world data related to other disease types and interventions appears desirable.
Abstract: BioGrid Australia is a federated data linkage and integration infrastructure that uses the Internet to enable patient specific information to be utilized for research in a privacy protected manner, from multiple databases of various data types (e.g. clinical, treatment, genomic, image, histopathology and outcome), from a range of diseases (oncological, neurological, endocrine and respiratory) and across more than 20 health services, universities and medical research institutes. BioGrid has demonstrated an ability to facilitate powerful research into the causation of human disease and the prediction of disease and treatment outcomes. BioGrid has successfully implemented technology and processes that allow researchers to efficiently extract data from multiple sources, without compromising data security and privacy. This article reviews BioGrid's first seven years and how it has overcome 9 of its top 10 challenges.
Abstract: Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse.
Abstract: To report clinical experience with radioembolization (RE) plus systemic chemotherapy as a first-line treatment for liver metastases from colorectal cancer (CRC).
Abstract: Patients who undergo surgical management of oral cancer may greatly benefit from an implant-supported prosthesis. This study reports on the clinical experience of dental implant placement in patients following resection of oral cancer over a 15-year period. Controversies including the use of dental implants in irradiated tissues, and hyperbaric oxygen treatment will also be discussed.
Abstract: Hyperplastic Polyposis Syndrome (HPS) is a condition associated with multiple serrated polyps, and an increased risk of colorectal cancer (CRC). At least half of CRCs arising in HPS show a CpG island methylator phenotype (CIMP), potentially linked to aberrant DNA methyltransferase (DNMT) activity. CIMP is associated with methylation of tumor suppressor genes including regulators of DNA mismatch repair (such as MLH1, MGMT), and negative regulators of Wnt signaling (such as WIF1). In this study, we investigated the potential for interaction of genetic and epigenetic variation in DNMT genes, in the aetiology of HPS.
Abstract: PURPOSE: To assess clinical behavior, response to treatment, and factors affecting survival in maxillofacial osteosarcoma treated at a tertiary referral center. PATIENTS AND METHODS: Ethics-approved retrospective review of clinical and pathological records was undertaken for 15 patients managed by the Royal Melbourne Hospital Head and Neck Oncology Tumor Stream. RESULTS: Treatment was a combination of surgery and chemotherapy. Chemotherapy was given as adjuvant, neoadjuvant, or in combination. The overall 2-, 5-, and 15-year disease-free survival rates in this study were 92%, 74%, and 74%, respectively. Using Kaplan-Meier analysis with log rank tests, increasing T stage (P = .01) and positive margins (P = .003) were found to affect survival significantly. Neoadjuvant chemotherapy was not significantly associated with tumor necrosis or improved survival. CONCLUSIONS: Tumor size and adequacy of local control were found to be the most important predictors of outcome.
Abstract: Regional recurrence is common following surgery for T1/T2 oral tongue squamous cell carcinoma (SCC). Tumor depth >4.0 mm is commonly assigned as an indication for prophylactic neck dissection to improve regional control. Prophylactic neck dissection may detect extracapsular extension, a poor prognostic sign where adjuvant chemotherapy is indicated. The hypothesis in this study is that regional recurrence is a significant problem in 2.1- to 4.0-mm-depth tumors, and detection of extracapsular extension may be important in this group.
Abstract: Cognitive impairment is not uncommon in patients with epilepsy, and may relate to the underlying pathophysiology of epilepsy, the effects of seizures, or epilepsy treatment. Formal neuropsychological testing is not available in many centers, and few cognitive screening tools have been validated in an epilepsy population. We aimed to ascertain the reliability and validity of a multidimensional cognitive screening instrument, the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), in a mixed epilepsy population.
Abstract: Background:  Lymph node yield (LNY) is a measure of quality of care and a strong prognostic factor for outcome from colorectal cancer (CRC). The main aims of this study were to determine LNY across multiple Australian centres and the clinico-pathologic factors that influence yield. Methods:  Analysis of data from prospective CRC databases at 11 Australian centres between January 1988 and May 2008 was undertaken utilizing the linkage and analysis resources of BioGrid Australia. The LNY depending on different clinico-pathologic patient characteristics was evaluated. Results:  In total, 10 082 cases (54.1% men, 45.9% women) were identified. Median LNY was 12 (range 0-174). LNY increased significantly (P < 0.001) over time, from a mean of 8.5 in 1988 to 13 in 2008. LNY also varied significantly between surgical centres. Female gender, younger age, right-sided disease, higher T and N stage, specific operation types and absence of preoperative radiotherapy were all significantly associated with higher LNY. Conclusions:  While varying across centres, the median LNYs in Australia are acceptable and have improved significantly over recent years. Multiple clinico-pathologic factors significantly influence the number of nodes retrieved.
Abstract: The oral cavity is a challenging area for radiological diagnosis. Soft-tissue, glandular structures and osseous relations are in close proximity and a sound understanding of radiological anatomy and common pathways of disease spread is required. In this pictorial review we present the anatomical and pathological concepts of the oral cavity with emphasis on the complementary nature of diagnostic imaging modalities.
Abstract: BRAF(V600E) mutations are found in 10% of colorectal cancers (CRCs). The low frequency of this mutation therefore makes it a challenging target for drug development, unless subsets of patients with higher rates of BRAF(V600E) can be defined. Knowledge of the concordance between primary-metastasis pairs and the impact of BRAF(V600E) on outcome would also assist in optimal drug development. We selected primary CRCs from 525 patients (stages I-IV) evenly matched for age (<70 and ≥70), gender and tumor location (right, left and rectum), and 81 primary-metastasis pairs. BRAF(V600E), KRAS mutation and microsatellite instability (MSI) were determined and correlated with clinical features and patient outcomes. In multivariate analyses, increasing patient age (p = 0.04), female gender (p = 0.0005) and right-sided tumor location (p < 0.0001) were independently associated with BRAF(V600E). The prevalence of BRAF(V600E) was considerably higher in older (age > 70) females with KRAS wild-type right-sided colon cancers (50%) compared to the unselected cohort (10%). BRAF(V600E) was associated with inferior overall survival in metastatic CRC (HR = 2.02; 95% CI 1.26-3.26), particularly evident in patients treated with chemotherapy, and is independent of MSI status. BRAF status was concordant in all primary tumors and matched metastases (79 wild-type pairs and two mutant pairs). Clinicopathological and molecular features can identify CRC patients with a higher prevalence of BRAF(V600E). Patients with BRAF(V600E) wild-type primary tumor do not appear to acquire the mutation in their metastases, and BRAF(V600E) is associated with poorer outcomes in metastatic patients. Our findings are timely and will help inform the rational development of BRAF(V600E) inhibitors in CRC.
Abstract: To test the hypothesis that neuropsychiatric symptomatology is predictive of the success of seizure control in patients newly treated with antiepileptic drugs (AEDs), and that this predictive value adds to that provided by other clinical, imaging, and genomic factors in a multivariate model.
Abstract: To examine baseline clinical features of psychogenic nonepileptic seizures (PNES) in a large cohort and to investigate outcome over a period of up to 10 years. Studies investigating PNES have been limited by differences in diagnostic criteria, short follow-up periods, and the use of limited outcome measures.
Abstract: Rapidly progressing or missed lesions can reduce the effectiveness of colonoscopy-based colorectal cancer surveillance programs. We investigated whether giving fecal immunochemical tests (FITs) for hemoglobin between surveillance colonoscopies resulted in earlier detection of neoplasia.
Abstract: Surgery is recommended for pharmacoresistant temporal lobe epilepsy (TLE), but seizures recur in approximately one third of patients postsurgery. P-glycoprotein is an efflux multidrug transporter that is overexpressed in a range of epileptogenic pathologies. We hypothesized that increased expression of P-glycoprotein in the epileptogenic temporal lobe might be a marker for recurrence of pharmacoresistant seizures postsurgery. We performed immunohistochemistry on temporal lobe tissues resected from 69 patients who underwent anterior temporal lobectomy for pharmacoresistant TLE with histopathological proven hippocampal sclerosis. P-glycoprotein expression was rated by three pathologists independently. Patients with seizure recurrence (n=22) had greater number of positively stained capillaries (p=0.001) and higher P-glycoprotein immunoreactive score in capillaries (p=0.002) in the white matter of resected temporal lobe. The differences remained significant in multivariate analysis (p=0.002 and 0.006, respectively). The results suggest that P-glycoprotein expression in temporal lobe may be associated with seizure recurrence after surgery for pharmacoresistant TLE.
Abstract: This chapter gives an educational overview of: * The clinical research lifecycle * Sources of research data * The need for contextual data standardization to retain meaning * Information management principles for sustainable data * Data linkage technologies used to support collaborative research aimed at improving health outcomes * Making use of identifiers in health.
Abstract: Multidisciplinary Team (MDT) meetings are critical in the management of complex cancer cases. There are limited data regarding the effectiveness of neuro-oncology MDT meetings and the impact of documenting and disseminating the recommended patient management. We established a weekly neuro-oncology MDT meeting and developed a standard electronic communication process. A survey was issued to participating clinicians to assess their level of satisfaction. The survey revealed that 100% felt the meeting and its documentation was very or extremely important, and 94% (n=15) felt the meeting was effective in documentation and communication of plans. There was a mixed response regarding which patients should be discussed: 44% (n=7) thought all patients should be discussed and 56% (n=9) thought only those patients with complex management issues should be discussed. We have developed an efficient method of documenting and disseminating patient information arising from our neuro-oncology MDT meeting. Clinician satisfaction was high.
Abstract: Colorectal cancer is one of the few tumour types, where routine patient follow up has been demonstrated to impact significantly on survival. Patients who fail to attend regular clinic reviews may compromise their outcome, but the frequency at which this occurs is unknown. Identifying the extent of this problem, and the factors that predict non-attendance, may provide opportunities to improve patient outcomes.
Abstract: Varying amounts of data related to cancer diagnosis, treatment and/or outcome are routinely collected by many disparate groups. Routinely combining data from these sources could improve data quality and utility for audit and research purposes. The aim of this study is to demonstrate the benefits of linkage between oncology databases.
Abstract: The aims of this study were to calculate theoretical cost savings of oxaliplatin dose rounding in colorectal cancer (CRC), and to assess clinician attitudes to chemotherapy dose rounding.
Abstract: The optimal strategy for elective distant staging of colorectal carcinoma (CRC) has yet to be defined, with current guidelines based on small and limited series. One specific issue requiring review is the value of routine computerized tomographic (CT) chest examination. Also lacking is data on current routine clinical practice.
Abstract: The National Cancer Institute of Canada Clinical Trials Group CO.17 study showed that patients with advanced colorectal cancer had improved overall survival when cetuximab, an epidermal growth factor receptor-targeting antibody, was given in addition to best supportive care. We conducted a cost-effectiveness analysis using prospectively collected resource utilization and health utility data for patients in the CO.17 study who received cetuximab plus best supportive care (N = 283) or best supportive care alone (N = 274).
Abstract: Most pharmacogenomic studies have attempted to identify single nucleotide polymorphism (SNP) markers that are predictive for treatment outcomes. It is, however, unlikely in complex diseases such as epilepsy, affecting heterogeneous populations, that a single SNP will adequately explain treatment outcomes. This study reports an approach to develop a multi-SNP model to classify treatment outcomes for such a disease and compares this with single-SNP models.
Abstract: The association between a specific polymorphism (3435C>T) in the ABCB1 gene, coding for the membrane drug transporter P-glycoprotein (PgP), and pharmacoresistance to seizure control is controversial. Studies have been limited by multiple drug use, chronic cohorts with varying definitions, and retrospective clinical data. Herein we examine the relationship of this polymorphism with seizure recurrence in three independent international cohorts of patients newly treated for epilepsy.
Abstract: To examine the initial impact of the National Bowel Cancer Screening Program (NBCSP), which was launched in May 2006 and offers faecal occult blood testing to Australians aged 55 or 65 years.
Abstract: PURPOSE: Colorectal cancer prognosis is currently predicted from pathologic staging, providing limited discrimination for Dukes stage B and C disease. Additional markers for outcome are required to help guide therapy selection for individual patients. EXPERIMENTAL DESIGN: A multisite single-platform microarray study was done on 553 colorectal cancers. Gene expression changes were identified between stage A and D tumors (three training sets) and assessed as a prognosis signature in stage B and C tumors (independent test and external validation sets). RESULTS: One hundred twenty-eight genes showed reproducible expression changes between three sets of stage A and D cancers. Using consistent genes, stage B and C cancers clustered into two groups resembling early-stage and metastatic tumors. A Prediction Analysis of Microarray algorithm was developed to classify individual intermediate-stage cancers into stage A-like/good prognosis or stage D-like/poor prognosis types. For stage B patients, the treatment adjusted hazard ratio for 6-year recurrence in individuals with stage D-like cancers was 10.3 (95% confidence interval, 1.3-80.0; P = 0.011). For stage C patients, the adjusted hazard ratio was 2.9 (95% confidence interval, 1.1-7.6; P = 0.016). Similar results were obtained for an external set of stage B and C patients. The prognosis signature was enriched for downregulated immune response genes and upregulated cell signaling and extracellular matrix genes. Accordingly, sparse tumor infiltration with mononuclear chronic inflammatory cells was associated with poor outcome in independent patients. CONCLUSIONS: Metastasis-associated gene expression changes can be used to refine traditional outcome prediction, providing a rational approach for tailoring treatments to subsets of patients. (Clin Cancer Res 2009;15(24):7642-51).
Abstract: DNA-methylation changes in human cancer are complex and vary between the different types of cancer. Capturing this epigenetic variability in an atlas of DNA-methylation changes will be beneficial for basic research as well as translational medicine. Hypothesis-free approaches that interrogate methylation patterns genome-wide have already generated promising results. However, these methods are still limited by their quantitative accuracy and the number of CpG sites that can be assessed individually. Here, we use a unique approach to measure quantitative methylation patterns in a set of >400 candidate genes. In this high-resolution study, we employed a cell-line model consisting of 59 cancer cell lines provided by the National Cancer Institute and six healthy control tissues for discovery of methylation differences in cancer-related genes. To assess the effect of cell culturing, we validated the results from colon cancer cell lines by using clinical colon cancer specimens. Our results show that a large proportion of genes (78 of 400 genes) are epigenetically altered in cancer. Although most genes show methylation changes in only one tumor type (35 genes), we also found a set of genes that changed in many different forms of cancer (seven genes). This dataset can easily be expanded to develop a more comprehensive and ultimately complete map of quantitative methylation changes. Our methylation data also provide an ideal starting point for further translational research where the results can be combined with existing large-scale datasets to develop an approach that integrates epigenetic, transcriptional, and mutational findings.
Abstract: Adjuvant 5-flourouracil-based chemotherapy is standard care for patients with stage III colon cancer. Limited data are available regarding use of adjuvant treatment in routine clinical practice, where patients are often frail and/or elderly.
Abstract: Determining the optimal starting dose of chemotherapy (CHT) presents a considerable challenge when using body-surface area (BSA)-based dosing, particularly in obese, elderly, or thin patients. We sought to document the range of approaches employed when administering CHT to these patients.
Abstract: Intensive follow up after surgery for colorectal cancer is associated with a significant survival advantage and is endorsed by expert panels, but are physicians convinced of the benefit?
Abstract: About 15% of colorectal cancers harbor microsatellite instability (MSI). MSI-associated gene expression changes have been identified in colorectal cancers, but little overlap exists between signatures hindering an assessment of overall consistency. Little is known about the causes and downstream effects of differential gene expression.
Abstract: This study applied decision tree analysis to evaluate the sensitivity, specificity, and cost-effectiveness of clinical algorithms that incorporate 18F-FDG PET.
Abstract: Collecting data regarding treatment and outcomes of patients with cancer, for both audit and research purposes, is a common but challenging goal. Modern technology promises greater ease and sophistication for data collection, linkage and analysis, but many traditional challenges remain.
Abstract: Unique research opportunities are being created in an era of increasingly sophisticated data collection and data linkage. There are Familial Cancer Clinics (FCC) to counsel patients and families about risk reduction strategies and to carry out genetic testing where appropriate. There is currently no objective evidence as to whether appropriate patients are being referred to the FCC.
Abstract: Previous work has identified elevated prevalence rates for psychiatric disorders in individuals with medically refractory focal epilepsy, particularly temporal lobe epilepsy. Many studies were undertaken before the advent of video electroencephalogram monitoring (VEM) and magnetic resonance imaging (MRI).
Abstract: Oral lacerations and urinary incontinence have long been considered useful clinical features for the diagnosis of epileptic seizures; however, both are also reported in patients with psychogenic nonepileptic seizures (PNES). The aims of the study were (1) to investigate whether the presence and nature of oral lacerations or incontinence during convulsive seizures of patients with epilepsy differed from those with PNES, and (2) whether the side of the oral laceration has any correlation with the epilepsy syndrome or lateralization.
Abstract: Treatment options for colorectal cancer have expanded to include multiple oxaliplatin- and irinotecan-based regimens and more biological/targeted therapies.
Abstract: In 2005 a major collaboration in Melbourne, Australia successfully implemented a major medical informatics infrastructure. The convergence of life sciences, healthcare, and information technology is now driving research into the fundamentals of disease causation and toward tailoring individualized treatment. The Molecular Medicine Informatics Model (MMIM) is a 'virtual' research repository of clinical, laboratory and genetic data sets. Integrated data, physically located within independent hospital and research organisations can be searched and queried seamlessly via a federated data integrator. Researchers must gain authorisation to access data, and obtain permission from the data owners before the data can be accessed. The legal and ethical issues surrounding the use of this health data have been addressed so data complies with privacy requirements. The MMIM platform also record links individual cases across multiple institutions and multiple clinical specialties. Significant research outcomes in epilepsy and colorectal cancer have already been enabled by the MMIM research platform. The infrastructure of MMIM enables discovery research to be accessible via the Web with security, intellectual property and privacy addressed.
Abstract: In 2005, a major collaboration in Melbourne Australia successfully completed implementing a major medical informatics infrastructure - this is now being used for discovery research and has won significant expansion funding for 2006 - 2009. The convergence of life sciences, healthcare, and information technology is now driving research into the fundamentals of disease causation. Key to enabling this is collating data in sufficient numbers of patients to ensure studies are adequately powered. The Molecular Medicine Informatics Model (MMIM) is a 'virtual' research repository of clinical, laboratory and genetic data sets. Integrated data, physically located within independent hospital and research organisations can be searched and queried seamlessly via a federated data integrator. Researchers must gain authorisation to access data, and inform/obtain permission from the data owners, before the data can be accessed. The legal and ethical issues surrounding the use of this health data have been addressed so data complies with privacy requirements. The MMIM platform has also solved the issue of record linking individual cases and integrating data sources across multiple institutions and multiple clinical specialties. Significant research outcomes already enabled by the MMIM research platform include epilepsy seizure analyses for responders / non responders to therapy; sensitivity of faecal occult blood testing for asymptomatic colorectal cancer and advanced adenomas over a 25-year experience in colorectal cancer screening; subsite-specific colorectal cancer in diabetic and non diabetic patients; and the influence of language spoken on colorectal cancer diagnosis, management and outcomes. Ultimately the infrastructure of MMIM enables discovery research to be accessible via the Web with security, intellectual property and privacy addressed.
Abstract: A significant minority of patients undergoing surgery for medically refractory non-lesional temporal lobe epilepsy (TLE) continue to have seizures, but the reasons for this are uncertain. Fluorodeoxyglucose (FDG) PET shows hypometabolism in a majority of patients with non-lesional TLE, even in the absence of hippocampal atrophy. We examined whether the extent of resection of the area of FDG-PET hypometabolism influenced outcome following surgery for non-lesional TLE. Twenty-six patients who underwent temporal lobectomy for medically refractory TLE with at least 12 months follow-up were studied. The preoperative FDG-PET was compared with 20 non-epileptic controls using SPM99 to identify regions of significant hypometabolism (P < 0.0005, cluster > 200). This image was then co-registered to the postoperative MRI scan. The volume of the FDG-PET hypometabolism that lay within the area of the resected temporal lobe was calculated. The volume of temporal lobe resected was also calculated. Patients with a good outcome had a greater proportion of the total FDG-PET hypometabolism volume resected than those with a poor outcome (24.1% versus 11.8%, P = 0.02). There was no significant difference between the groups in the volume of temporal lobe resected (P = 0.86). Multivariate regression demonstrated that the extent of resection of the hypometabolism significantly correlated with outcome (P = 0.03), independent of the presence of hippocampal sclerosis (P = 0.03) and total brain volume of hypometabolism (P = 0.45). The extent of resection of the region of hypometabolism on the preoperative FDG-PET is predictive of outcome following surgery for non-lesional TLE. Strategies that tailor resection extent to regional hypometabolism may warrant further evaluation.
Abstract: The Liverpool Adverse Events Profile (LAEP) is used as a systematic measure of adverse effects from antiepileptic drugs (AEDs). This study evaluated LAEP in newly diagnosed seizure patients, and examined the relation between LAEP, anxiety, and depression.
Abstract: Microsatellite instability (MSI) testing of colorectal cancer tumors is used as a screening tool to identify patients most likely to be mismatch repair (MMR) gene mutation carriers. We wanted to examine which microsatellite markers currently used to detect MSI best predict early-onset colorectal cancer caused by germ-line mutations in MMR genes.
Abstract: Familial juvenile polyposis syndrome (JPS) is a rare autosomal dominant condition in which patients develop hamartomatous gastrointestinal polyps with malignant potential. Pathogenic germline mutations in both the SMAD4 and BMPR1A genes involved in the transforming growth factor beta pathway account for 40% of cases of JPS. Genetic heterogeneity remains evident, as the balance of cases is not accounted for by mutations in these genes. The aim of this study was to determine the mutation responsible in a family with juvenile polyposis.
Abstract: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy.
Abstract: The standard management of rectal cancer continues to be defined by the results of randomized, clinical trials exploring the optimal timing and use of adjuvant chemotherapy and radiation therapy in relation to surgery. The patient with rectal cancer who is elderly and/or has significant comorbidities and the patient who refuses surgery are clinical contexts for which there is limited current data to guide decision making.
Abstract: 'MRI negative PET positive temporal lobe epilepsy' represents a substantial minority of temporal lobe epilepsy (TLE). Clinicopathological and qualitative imaging differences from mesial temporal lobe epilepsy are reported. We aimed to compare TLE with hippocampal sclerosis (HS+ve) and non lesional TLE without HS (HS-ve) on MRI, with respect to quantitative FDG-PET and MRI measures.
Abstract: Recent developments in the pharmacogenetics of antiepileptic drugs provide new prospects for predicting the efficacy of treatment and potential side-effects. Epilepsy is a common, serious, and treatable neurological disorder, yet current treatment is limited by high rates of adverse drug reactions and lack of complete seizure control in a significant proportion of patients. The disorder is especially suitable for pharmacogenetic investigation because treatment response can be quantified and side-effects can be assessed with validated measures. Additionally, there is substantial knowledge of the pharmacodynamics and kinetics of antiepileptic drugs, and some candidate genes implicated in the disorder have been identified. However, recent studies of the association of particular genes and their genetic variants with seizure control and adverse drug reactions have not provided unifying conclusions. This article reviews the published work and summarises the state of research in this area. Future directions for research and the application of this technology to the clinical practice of individualising treatment for epilepsy are discussed.
Abstract: Hyperplastic polyposis syndrome (HPS) is defined phenotypically with multiple, large and/or proximal hyperplastic polyps. There is no known germ-line predisposition. We aimed to characterize the clinicopathologic features of 38 patients with HPS and explore the role of germ-line mutations in the base excision repair genes MBD4 and MYH.
Abstract: To examine the validity and reliability of a brief cognitive screen instrument, the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), in patients with dementia, major psychiatric disorders and neurological disorders, and to compare its performance with the Mini-Mental State Examination (MMSE).
Abstract: The study assessed views concerning genetic testing and information and support needs among young adults aged 18 to 35 years with a diagnosis of or at risk of developing familial adenomatous polyposis.
Abstract: The genetic predisposition Peutz-Jeghers Syndrome (PJS) has been shown to be associated with mutations in the serine threonine kinase 11 (STK11) gene but only a proportion of probands have been shown to harbour changes in the gene. The remaining patients were proposed to be either associated with a second PJS gene or they harboured more cryptic mutations within the STK11 gene itself. With the introduction of the multiplex ligation probe amplification (MLPA) assay, large sequence losses or gains can be more readily identified. In this report we have screened 33 PJS patients from unrelated families, employing a combination of denaturing high-performance liquid chromatography, direct DNA sequencing and the MLPA assay to identify deleterious changes in the STK11 gene. The results revealed that 24 (73%) of patients diagnosed with PJS-harboured pathogenic mutations in the STK11 gene, including 10 (36%) with exonic or whole-gene deletions. No phenotypic differences were identified in patients harbouring large deletions in the STK11 gene compared to patients harbouring missense or nonsense mutations. Mutation analysis in PJS should include techniques such as MLPA to identify large exonic or whole-gene deletions and rearrangements. The high proportion of families with identifiable mutations in the STK11 gene using this range of techniques suggests that most, if not all PJS, is attributable to mutations in the STK11 gene, perhaps including as yet undiscovered changes in promoter or enhancer sequences or other cryptic changes.
Abstract: ABSTRACT: Eighteen international cancer centres responded to a questionnaire designed to determine clinic practices regarding the management of Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Areas covered include definition, clinical intakes, pre-genetic testing for microsatellite instability (MSI) or expression of mismatch repair (MMR) genes by immunohistochemistry (IHC), mutational analysis, consent practices, counselling, surveillance planning, and surgical decision making. In the absence of a firm evidence base, some management practices were variable, with local access to funding and other resources being influential. More consistent responses were evident for management practices with a stronger evidence base from previous clinical research. This document provides important information to guide the management of HNPCC patients, allow comparisons to be made between the approaches of various clinics to HNPCC families, and define management issues that need to be addressed in clinical research.
