Nutritional risk of cancer patients receiving chemotherapy in the ambulatory care setting : a prospective study

Background Cancer itself can alter the metabolic and physiologic of the body's nutritional needs. As a result, some patients experience some degree of weight loss before the start of the treatment. Aim The aim of the study was to determine at which chemotherapy treatment cycle patients with cancer begin to exhibit signs and symptoms of malnutrition. Methods A prospective descriptive correlational design was used to assess the nutritional risk of 111 patients with cancer receiving chemotherapy in the ambulatory setting. The data were collected by using a nutritional screening tool. Findings The prevalence of malnutrition risk was 45% in patients undergoing the first cycle of chemotherapy. Patients who received the first three cycles of chemotherapy were 2.62 times more likely to develop malnutrition than those who received seven or more cycles. The risk of developing malnutrition varies depending on the type of cancer, the types of chemotherapy regime, the number of chemotherapy cycles, body mass index and the stage of cancer. Conclusion The study found about half of the patients had developed signs and symptoms of nutritional risk at cycle one. Hence, nutritional support may be required even before the start of chemotherapy.

Changes in disability, physical/mental health states and quality of life during an 8-Week multimodal physiotherapy programme in patients with chronic non-specific neck pain: A prospective cohort study

Aim The aim of this study was to analyse the effect of an 8-week multimodal physiotherapy programme (MPP), integrating physical land-based therapeutic exercise (TE), adapted swimming and health education, as a treatment for patients with chronic non-specific neck pain (CNSNP), on disability, general health/mental states and quality of life. Methods 175 CNSNP patients from a community-based centre were recruited to participate in this prospective study. Intervention: 60-minute session (30 minutes of land-based exercise dedicated to improving mobility, motor control, resistance and strengthening of the neck muscles, and 30 minutes of adapted swimming with aerobic exercise keeping a neutral neck position using a snorkel). Health education was provided using a decalogue on CNSNP and constant repetition of brief advice by the physiotherapist during the supervision of the exercises in each session. Study outcomes: primary: disability (Neck Disability Index); secondary: physical and mental health states and quality of life of patients (SF-12 and EuroQoL-5D respectively). Differences between baseline data and that at the 8-week follow-up were calculated for all outcome variables. Results Disability showed a significant improvement of 24.6% from a mean (SD) of 28.2 (13.08) at baseline to 16.88 (11.62) at the end of the 8-week intervention. All secondary outcome variables were observed to show significant, clinically relevant improvements with increase ranges between 13.0% and 16.3% from a mean of 0.70 (0.2) at baseline to 0.83 (0.2), for EuroQoL-5D, and from a mean of 40.6 (12.7) at baseline to 56.9 (9.5), for mental health state, at the end of the 8-week intervention. Conclusion After 8 weeks of a MPP that integrated land-based physical TE, health education and adapted swimming, clinically-relevant and statistically-significant improvements were observed for disability, physical and mental health states and quality of life in patients who suffer CNSNP. The clinical efficacy requires verification using a randomised controlled study design.

Bahia grass pollen specific IgE is common in seasonal rhinitis patients but has limited cross-reactivity with Ryegrass

Background: Perennial Ryegrass is a major cause of rhinitis in spring and early summer. Bahia grass, Paspalum notatum, flowers late into summer and could account for allergic rhinitis at this time. We determined the frequency of serum immunoglobulin (Ig)E reactivity with Bahia grass in Ryegrass pollen allergic patients and investigated IgE cross-reactivity between Bahia and Ryegrass. Methods: Serum from 33 Ryegrass pollen allergic patients and 12 nonatopic donors were tested for IgE reactivity with Bahia and Ryegrass pollen extracts (PE) by enzyme-linked immunosorbent assay (ELISA), western blotting and inhibition ELISA. Allergen-specific antibodies from a pool of sera from allergic donors were affinity purified and tested for IgE cross-reactivity. Results: Seventy-eight per cent of the sera had IgE reactivity with Bahia grass, but more weakly than with Ryegrass. Antibodies eluted from the major Ryegrass pollen allergens, Lol p 1 and Lol p 5, showed IgE reactivity with allergens of Ryegrass and Canary but not Bahia or Bermuda grasses. Timothy, Canary and Ryegrass inhibited IgE reactivity with Ryegrass and Bahia grass, whereas Bahia, Johnson and Bermuda grass did not inhibit IgE reactivity with Ryegrass. Conclusions: The majority of Ryegrass allergic patients also showed serum IgE reactivity with Bahia grass PE. However, Bahia grass and Ryegrass had only limited IgE cross-reactivity indicating that Bahia grass should be considered in diagnosis and treatment of patients with hay fever late in' the grass pollen season.

Triaging older major trauma patients in the emergency department: An observational study

Background The objective of this study was to compare the triage category assigned to older trauma patients with younger trauma patients upon arrival to the emergency department. The focus was to examine whether older major trauma patients were less likely to be assigned an emergency triage category on arrival to the emergency department after controlling for relevant demographics, injury characteristics and injury severity. Methods This was an observational study using data from the Queensland Trauma Registry. All trauma patients aged 15 years and older who presented to contributing hospitals between 1 January 2005 and 31 December 2009 with an Injury Severity Score (ISS)>15 were included. Logistic regression analysis examined the odds of assignment to emergency (Australasian Triage Scale (ATS) 1 or 2) versus urgent (ATS 3–5) treatment for patients across various age categories after adjustment for relevant demographics, injury characteristics and injury severity. Results The study used data on 6923 patients with a median (IQR) age of 43 (26–62) years and a mortality of 11.4% (95% CI 10.7% to 12.2%). Compared with individuals aged 15–34, the adjusted odds of being assigned an ATS category 1 or 2 were 30% lower (OR=0.68, 95% CI 0.57 to 0.81) for individuals aged 55–75 years and were 50% lower (OR=0.46, 95% CI 0.37 to 0.56) for individuals aged 75 years or older. Conclusions Among patients with an ISS>15, older major trauma patients were less likely to be assigned an emergency triage category compared with younger patients. This suggests that the elderly may be undertriaged and provides a potential area of study for reducing mortality and morbidity in older

First-Line afatinib versus chemotherapy in patients with non–small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases

Introduction Metastatic spread to the brain is common in patients with non–small cell lung cancer (NSCLC), but these patients are generally excluded from prospective clinical trials. The studies, phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations (LUX-Lung 3) and a randomized, open-label, phase III study of BIBW 2992 versus chemotherapy as first-line treatment for patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation (LUX-Lung 6) investigated first-line afatinib versus platinum-based chemotherapy in epidermal growth factor receptor gene (EGFR) mutation-positive patients with NSCLC and included patients with brain metastases; prespecified subgroup analyses are assessed in this article. Methods For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n = 35 and n = 46, respectively). Post hoc analyses of clinical outcomes was undertaken in the combined data set (n = 81). Results In both studies, there was a trend toward improved PFS with afatinib versus chemotherapy in patients with brain metastases (LUX-Lung 3: 11.1 versus 5.4 months, hazard ratio [HR] = 0.54, p = 0.1378; LUX-Lung 6: 8.2 versus 4.7 months, HR = 0.47, p = 0.1060). The magnitude of PFS improvement with afatinib was similar to that observed in patients without brain metastases. In combined analysis, PFS was significantly improved with afatinib versus with chemotherapy in patients with brain metastases (8.2 versus 5.4 months; HR, 0.50; p = 0.0297). Afatinib significantly improved the objective response rate versus chemotherapy in patients with brain metastases. Safety findings were consistent with previous reports. Conclusions These findings lend support to the clinical activity of afatinib in EGFR mutation–positive patients with NSCLC and asymptomatic brain metastases.

Anterior vertebral stapling for the fusionless correction of scoliosis

Fusionless scoliosis surgery is an emerging treatment for idiopathic scoliosis as it offers theoretical advantages over current forms of treatment. Currently the treatment options for idiopathic scoliosis are observation, bracing and fusion. While brace treatment is non-invasive, and preserves the growth, motion, and function of the spine, it does not correct deformity and is only modestly successful in preventing curve progression. In adolescents who fail brace treatment, surgical treatment with an instrumented spinal fusion usually results in better deformity correction but is associated with substantially greater risk. Furthermore in younger patients requiring surgical treatment, fusion procedures are known to adversely effect the future growth of the chest and spine. Fusionless treatments have been developed to allow effective surgical treatment of patients with idiopathic scoliosis who are too young for fusion procedures. Anterior vertebral stapling is one such fusionless treatment which aims to modulate the growth of vertebra to allow correction of scoliosis whilst maintaining normal spinal motion The Mater Misericordiae Hospital in Brisbane has begun to use anterior vertebral stapling to treat patients with idiopathic scoliosis who are too young for fusion procedures. Currently the only staple approved for clinical use is manufactured by Medtronic Sofamor Danek (Memphis, TN). This thesis explains the biomechanical and anatomical changes that occur following anterior vertebral staple insertion using in vitro experiments performed on an immature bovine model. Currently there is a paucity of published information about anterior vertebral stapling so it is hoped that this project will provide information that will aid in our understanding of the clinical effects of staple insertion. The aims of this experimental study were threefold. The first phase was designed to determine the changes in the bending stiffness of the spine following staple insertion. The second phase was designed to measure the forces experienced by the staple during spinal movements. The third and final phase of testing was designed to describe the structural changes that occur to a vertebra as a consequence of staple insertion. The first phase of testing utilised a displacement controlled testing robot to compare the change in stiffness of a single spinal motion segment following staple insertion for the three basic spinal motions of flexion-extension, lateral bending, and axial rotation. For the second phase of testing strain gauges were attached to staples and used to measure staple forces during spinal movement. In the third and final phase the staples were removed and a testing specimen underwent micro-computed tomography (CT) scanning to describe the anatomical changes that occur following staple insertion. The displacement controlled testing showed that there was a significant decrease in bending stiffness in flexion, extension, lateral bending away from the staple, and axial rotation away from the staple following staple insertion. The strain gauge measurements showed that the greatest staple forces occurred in flexion and the least in extension. In addition, a reduction in the baseline staple compressive force was seen with successive loading cycles. Micro-CT scanning demonstrated that significant damage to the vertebral body and endplate occurred as a consequence of staple insertion. The clinical implications of this study are significant. Based on the findings of this project it is likely that the clinical effect of the anterior vertebral staple evaluated in this project is a consequence of growth plate damage (also called hemiepiphysiodesis) causing a partial growth arrest of the vertebra rather than simply compression of the growth plate. The surgical creation of a unilateral growth arrest is a well established treatment used in the management of congenital scoliosis but has not previously been considered for use in idiopathic scoliosis.

Rural and Urban Differentials in Primary Care Management of Chronic Heart Failure: New Data from the CASE Study

Objective: To determine whether primary care management of chronic heart failure (CHF) differed between rural and urban areas in Australia. Design: A cross-sectional survey stratified by Rural, Remote and Metropolitan Areas (RRMA) classification. The primary source of data was the Cardiac Awareness Survey and Evaluation (CASE) study. Setting: Secondary analysis of data obtained from 341 Australian general practitioners and 23 845 adults aged 60 years or more in 1998. Main outcome measures: CHF determined by criteria recommended by the World Health Organization, diagnostic practices, use of pharmacotherapy, and CHF-related hospital admissions in the 12 months before the study. Results: There was a significantly higher prevalence of CHF among general practice patients in large and small rural towns (16.1%) compared with capital city and metropolitan areas (12.4%) (P < 0.001). Echocardiography was used less often for diagnosis in rural towns compared with metropolitan areas (52.0% v 67.3%, P < 0.001). Rates of specialist referral were also significantly lower in rural towns than in metropolitan areas (59.1% v 69.6%, P < 0.001), as were prescribing rates of angiotensin-converting enzyme inhibitors (51.4% v 60.1%, P < 0.001). There was no geographical variation in prescribing rates of β-blockers (12.6% [rural] v 11.8% [metropolitan], P = 0.32). Overall, few survey participants received recommended “evidence-based practice” diagnosis and management for CHF (metropolitan, 4.6%; rural, 3.9%; and remote areas, 3.7%). Conclusions: This study found a higher prevalence of CHF, and significantly lower use of recommended diagnostic methods and pharmacological treatment among patients in rural areas.

Antiretroviral therapy (ART) adherence among people living with HIV/AIDS (PLHIV) in the north of Vietnam : a multi-method approach

The antiretroviral therapy (ART) program for People Living with HIV/AIDS (PLHIV) in Vietnam has been scaled up rapidly in recent years (from 50 clients in 2003 to almost 38,000 in 2009). ART success is highly dependent on the ability of the patients to fully adhere to the prescribed treatment regimen. Despite the remarkable extension of ART programs in Vietnam, HIV/AIDS program managers still have little reliable data on levels of ART adherence and factors that might promote or reduce adherence. Several previous studies in Vietnam estimated extremely high levels of ART adherence among their samples, although there are reasons to question the veracity of the conclusion that adherence is nearly perfect. Further, no study has quantitatively assessed the factors influencing ART adherence. In order to reduce these gaps, this study was designed to include several phases and used a multi-method approach to examine levels of ART non-adherence and its relationship to a range of demographic, clinical, social and psychological factors. The study began with an exploratory qualitative phase employing four focus group discussions and 30 in-depth interviews with PLHIV, peer educators, carers and health care providers (HCPs). Survey interviews were completed with 615 PLHIV in five rural and urban out-patient clinics in northern Vietnam using an Audio Computer Assisted Self-Interview (ACASI) and clinical records extraction. The survey instrument was carefully developed through a systematic procedure to ensure its reliability and validity. Cultural appropriateness was considered in the design and implementation of both the qualitative study and the cross sectional survey. The qualitative study uncovered several contrary perceptions between health care providers and HIV/AIDS patients regarding the true levels of ART adherence. Health care providers often stated that most of their patients closely adhered to their regimens, while PLHIV and their peers reported that “it is not easy” to do so. The quantitative survey findings supported the PLHIV and their peers’ point of view in the qualitative study, because non-adherence to ART was relatively common among the study sample. Using the ACASI technique, the estimated prevalence of onemonth non-adherence measured by the Visual Analogue Scale (VAS) was 24.9% and the prevalence of four-day not-on-time-adherence using the modified Adult AIDS Clinical Trials Group (AACTG) instrument was 29%. Observed agreement between the two measures was 84% and kappa coefficient was 0.60 (SE=0.04 and p<0.0001). The good agreement between the two measures in the current study is consistent with those found in previous research and provides evidence of cross-validation of the estimated adherence levels. The qualitative study was also valuable in suggesting important variables for the survey conceptual framework and instrument development. The survey confirmed significant correlations between two measures of ART adherence (i.e. dose adherence and time adherence) and many factors identified in the qualitative study, but failed to find evidence of significant correlations of some other factors and ART adherence. Non-adherence to ART was significantly associated with untreated depression, heavy alcohol use, illicit drug use, experiences with medication side-effects, chance health locus of control, low quality of information from HCPs, low satisfaction with received support and poor social connectedness. No multivariate association was observed between ART adherence and age, gender, education, duration of ART, the use of adherence aids, disclosure of ART, patients’ ability to initiate communication with HCPs or distance between clinic and patients’ residence. This is the largest study yet reported in Asia to examine non-adherence to ART and its possible determinants. The evidence strongly supports recent calls from other developing nations for HIV/AIDS services to provide screening, counseling and treatment for patients with depressive symptoms, heavy use of alcohol and substance use. Counseling should also address fatalistic beliefs about chance or luck determining health outcomes. The data suggest that adherence could be enhanced by regularly providing information on ART and assisting patients to maintain social connectedness with their family and the community. This study highlights the benefits of using a multi-method approach in examining complex barriers and facilitators of medication adherence. It also demonstrated the utility of the ACASI interview method to enhance open disclosure by people living with HIV/AIDS and thus, increase the veracity of self-reported data.

Serum YKL-40 and Interleukin 6 Levels in Hodgkin Lymphoma

Purpose Serum levels of the inflammatory markers YKL-40 and IL-6 are increased in many conditions, including cancers. We examined serum YKL-40 and IL-6 levels in patients with Hodgkin lymphoma (HL), a tumor with strong immunologic reaction to relatively few tumor cells, especially in nodular sclerosis HL. Experimental Design We analyzed Danish and Swedish patients with incident HL (N=470) and population controls from Denmark (N= 245 for YKL-40; N= 348 for IL-6). Serum YKL-40 and IL-6 levels were determined by ELISA, and log-transformed data were analysed by linear regression, adjusting for age and sex. Results Serum levels of YKL-40 and IL-6 were increased in HL patients compared to controls (YKL-40: 3.6-fold, IL-6: 8.3-fold; both p<0.0001). In samples from pre-treatment HL patients (N=176), levels were correlated with more advanced stages (ptrend 0.0001 for YKL-40 and 0.013 for IL-6) and in those with B symptoms, but levels were similar in nodular sclerosis and mixed cellularity subtypes, by EBV status, and in younger (<45 years old) and older patients. Patients tested soon after treatment onset had significantly lower levels than pre-treatment patients, but even >6 months after treatment onset, serum YKL-40 and IL-6 levels remained significantly increased, compared to controls. In patients who died (N=12), pre-treatment levels for both YKL-40 and IL-6 were higher than in survivors, although not statistically significantly. Conclusions Serum YKL-40 and IL-6 levels were increased in untreated HL patients and those with more advanced stages but did not differ significantly by HL histology. Following treatment, serum levels were significantly lower.

The scalability and the strategy for EMR database encryption techniques

EMR (Electronic Medical Record) is an emerging technology that is highly-blended between non-IT and IT area. One methodology is to link the non-IT and IT area is to construct databases. Nowadays, it supports before and after-treatment for patients and should satisfy all stakeholders such as practitioners, nurses, researchers, administrators and financial departments and so on. In accordance with the database maintenance, DAS (Data as Service) model is one solution for outsourcing. However, there are some scalability and strategy issues when we need to plan to use DAS model properly. We constructed three kinds of databases such as plan-text, MS built-in encryption which is in-house model and custom AES (Advanced Encryption Standard) - DAS model scaling from 5K to 2560K records. To perform custom AES-DAS better, we also devised Bucket Index using Bloom Filter. The simulation showed the response times arithmetically increased in the beginning but after a certain threshold, exponentially increased in the end. In conclusion, if the database model is close to in-house model, then vendor technology is a good way to perform and get query response times in a consistent manner. If the model is DAS model, it is easy to outsource the database, however, some techniques like Bucket Index enhances its utilization. To get faster query response times, designing database such as consideration of the field type is also important. This study suggests cloud computing would be a next DAS model to satisfy the scalability and the security issues.

Ginger (Zingiber officinale) and chemotherapy-induced nausea and vomiting : a systematic literature review

Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of cytotoxic treatment. It continues to affect a significant proportion of patients despite the widespread use of anti-emetic medication. In folk-medicine, ginger (Zingiber officinale) has been used to prevent and treat nausea in many cultures for thousands of years. However, its use has not been validated in the chemotherapy context. To determine the potential use of ginger as a prophylactic or treatment of CINV, a systematic literature review was conducted. Reviewed studies comprised randomised controlled trials or cross-over trials that investigated the anti-CINV effect of ginger as the sole intervention independent variable in chemotherapy patients. Seven studies met the inclusion criteria. All studies were assessed on methodological quality and their limitations were identified. Studies were mixed in their support of ginger as an anti-CINV treatment in patients receiving chemotherapy, with three demonstrating a positive effect, two in favour but with caveats and two showing no effect on measures of CINV. Future studies are required to address the limitations identified before clinical use can be recommended.

The association of single nucleotide polymorphisms with endometrial cancer risk and prognosis

Endometrial cancer is one of the most common female diseases in developed nations and is the most commonly diagnosed gynaecological cancer in Australia. The disease is commonly classified by histology: endometrioid or non-endometrioid endometrial cancer. While non-endometrioid endometrial cancers are accepted to be high-grade, aggressive cancers, endometrioid cancers (comprising 80% of all endometrial cancers diagnosed) generally carry a favourable patient prognosis. However, endometrioid endometrial cancer patients endure significant morbidity due to surgery and radiotherapy used for disease treatment, and patients with recurrent disease have a 5-year survival rate of less than 50%. Genetic analysis of women with endometrial cancer could uncover novel markers associated with disease risk and/or prognosis, which could then be used to identify women at high risk and for the use of specialised treatments. Proteases are widely accepted to play an important role in the development and progression of cancer. This PhD project hypothesised that SNPs from two protease gene families, the matrix metalloproteases (MMPs, including their tissue inhibitors, TIMPs) and the tissue kallikrein-related peptidases (KLKs) would be associated with endometrial cancer susceptibility and/or prognosis. In the first part of this study, optimisation of the genotyping techniques was performed. Results from previously published endometrial cancer genetic association studies were attempted to be validated in a large, multicentre replication set (maximum cases n = 2,888, controls n = 4,483, 3 studies). The rs11224561 progesterone receptor SNP (PGR, A/G) was observed to be associated with increased endometrial cancer risk (per A allele OR 1.31, 95% CI 1.12-1.53; p-trend = 0.001), a result which was initially reported among a Chinese sample set. Previously reported associations for the remaining 8 SNPs investigated for this section of the PhD study were not confirmed, thereby reinforcing the importance of validation of genetic association studies. To examine the effect of SNPs from the MMP and KLK families on endometrial cancer risk, we selected the most significantly associated MMP and KLK SNPs from genome-wide association study analysis (GWAS) to be genotyped in the GWAS replication set (cases n = 4,725, controls n = 9,803, 13 studies). The significance of the MMP24 rs932562 SNP was unchanged after incorporation of the stage 2 samples (Stage 1 per allele OR 1.18, p = 0.002; Combined Stage 1 and 2 OR 1.09, p = 0.002). The rs10426 SNP, located 3' to KLK10 was predicted by bioinformatic analysis to effect miRNA binding. This SNP was observed in the GWAS stage 1 result to exhibit a recessive effect on endometrial cancer risk, a result which was not validated in the stage 2 sample set (Stage 1 OR 1.44, p = 0.007; Combined Stage 1 and 2 OR 1.14, p = 0.08). Investigation of the regions imputed surrounding the MMP, TIMP and KLK genes did not reveal any significant targets for further analysis. Analysis of the case data from the endometrial cancer GWAS to identify genetic variation associated with cancer grade did not reveal SNPs from the MMP, TIMP or KLK genes to be statistically significant. However, the representation of SNPs from the MMP, TIMP and KLK families by the GWAS genotyping platform used in this PhD project was examined and observed to be very low, with the genetic variation of four genes (MMP23A, MMP23B, MMP28 and TIMP1) not captured at all by this technique. This suggests that comprehensive candidate gene association studies will be required to assess the role of SNPs from these genes with endometrial cancer risk and prognosis. Meta-analysis of gene expression microarray datasets curated as part of this PhD study identified a number of MMP, TIMP and KLK genes to display differential expression by endometrial cancer status (MMP2, MMP10, MMP11, MMP13, MMP19, MMP25 and KLK1) and histology (MMP2, MMP11, MMP12, MMP26, MMP28, TIMP2, TIMP3, KLK6, KLK7, KLK11 and KLK12). In light of these findings these genes should be prioritised for future targeted genetic association studies. Two SNPs located 43.5 Mb apart on chromosome 15 were observed from the GWAS analysis to be associated with increased endometrial cancer grade, results that were validated in silico in two independent datasets. One of these SNPs, rs8035725 is located in the 5' untranslated region of a MYC promoter binding protein DENND4A (Stage 1 OR 1.15, p = 9.85 x 10P -5 P, combined Stage 1 and in silico validation OR 1.13, p = 5.24 x 10P -6 P). This SNP has previously been reported to alter the expression of PTPLAD1, a gene involved in the synthesis of very long fatty acid chains and in the Rac1 signaling pathway. Meta-analysis of gene expression microarray data found PTPLAD1 to display increased expression in the aggressive non-endometrioid histology compared with endometrioid endometrial cancer, suggesting that the causal SNP underlying the observed genetic association may influence expression of this gene. Neither rs8035725 nor significant SNPs identified by imputation were predicted bioinformatically to affect transcription factor binding sites, indicating that further studies are required to assess their potential effect on other regulatory elements. The other grade- associated SNP, rs6606792, is located upstream of an inferred pseudogene, ELMO2P1 (Stage 1 OR 1.12, p = 5 x 10P -5 P; combined Stage 1 and in silico validation OR 1.09, p = 3.56 x 10P -5 P). Imputation of the ±1 Mb region surrounding this SNP revealed a cluster of significantly associated variants which are predicted to abolish various transcription factor binding sites, and would be expected to decrease gene expression. ELMO2P1 was not included on the microarray platforms collected for this PhD, and so its expression could not be investigated. However, the high sequence homology of ELMO2P1 with ELMO2, a gene important to cell motility, indicates that ELMO2 could be the parent gene for ELMO2P1 and as such, ELMO2P1 could function to regulate the expression of ELMO2. Increased expression of ELMO2 was seen to be associated with increasing endometrial cancer grade, as well as with aggressive endometrial cancer histological subtypes by microarray meta-analysis. Thus, it is hypothesised that SNPs in linkage disequilibrium with rs6606792 decrease the transcription of ELMO2P1, reducing the regulatory effect of ELMO2P1 on ELMO2 expression. Consequently, ELMO2 expression is increased, cell motility is enhanced leading to an aggressive endometrial cancer phenotype. In summary, these findings have identified several areas of research for further study. The results presented in this thesis provide evidence that a SNP in PGR is associated with risk of developing endometrial cancer. This PhD study also reports two independent loci on chromosome 15 to be associated with increased endometrial cancer grade, and furthermore, genes associated with these SNPs to be differentially expressed according in aggressive subtypes and/or by grade. The studies reported in this thesis support the need for comprehensive SNP association studies on prioritised MMP, TIMP and KLK genes in large sample sets. Until these studies are performed, the role of MMP, TIMP and KLK genetic variation remains unclear. Overall, this PhD study has contributed to the understanding of genetic variation involvement in endometrial cancer susceptibility and prognosis. Importantly, the genetic regions highlighted in this study could lead to the identification of novel gene targets to better understand the biology of endometrial cancer and also aid in the development of therapeutics directed at treating this disease.

Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor

Gemcitabine is indicated in combination with cisplatin as first-line therapy for solid tumours including non-small cell lung cancer (NSCLC), bladder cancer and mesothelioma. Gemcitabine is an analogue of pyrimidine cytosine and functions as an anti-metabolite. Structurally, however, gemcitabine has similarities to 5-aza-2-deoxycytidine (decitabine/Dacogen®), a DNA methyltransferase inhibitor (DNMTi). NSCLC, mesothelioma and prostate cancer cell lines were treated with decitabine and gemcitabine. Reactivation of epigenetically silenced genes was examined by RT-PCR/qPCR. DNA methyltransferase activity in nuclear extracts and recombinant proteins was measured using a DNA methyltransferase assay, and alterations in DNA methylation status were examined using methylation-specific PCR (MS-PCR) and pyrosequencing. We observe a reactivation of several epigenetically silenced genes including GSTP1, IGFBP3 and RASSF1A. Gemcitabine functionally inhibited DNA methyltransferase activity in both nuclear extracts and recombinant proteins. Gemcitabine dramatically destabilised DNMT1 protein. However, DNA CpG methylation was for the most part unaffected by gemcitabine. In conclusion, gemcitabine both inhibits and destabilises DNA methyltransferases and reactivates epigenetically silenced genes having activity equivalent to decitabine at concentrations significantly lower than those achieved in the treatment of patients with solid tumours. This property may contribute to the anticancer activity of gemcitabine.

International hermelin brain tumor symposium on matricellular proteins in normal and cancer cell-matrix interactions

The second of the Hermelin Brain Tumor Center Symposia was held once again at Henry Ford Hospital in Detroit, Michigan on October 24th and 25th, 2003. A public conference was held on the 24th while a closed-door session took place on the 25th. The purpose of these symposia is to bring together experts in a particular field of study with the aim to share information with each other and the public, but then to meet privately to present novel data, hold discussions, and share concepts. While the interaction is intended to benefit all involved, the incentive is the expectation that the shared information will aid researchers at the Hermelin Brain Tumor Center in their quest to identify potential therapeutic targets and explore translational therapeutic strategies for the treatment of patients suffering nervous system tumors...

Measuring patient flow variations : a cross-organisational process mining approach

Variations that exist in the treatment of patients (with similar symptoms) across different hospitals do substantially impact the quality and costs of healthcare. Consequently, it is important to understand the similarities and differences between the practices across different hospitals. This paper presents a case study on the application of process mining techniques to measure and quantify the differences in the treatment of patients presenting with chest pain symptoms across four South Australian hospitals. Our case study focuses on cross-organisational benchmarking of processes and their performance. Techniques such as clustering, process discovery, performance analysis, and scientific workflows were applied to facilitate such comparative analyses. Lessons learned in overcoming unique challenges in cross-organisational process mining, such as ensuring population comparability, data granularity comparability, and experimental repeatability are also presented.