Identification of circulating tumour cells in early stage breast cancer patients using multi marker immunobead RT-PCR

Introduction The ability to screen blood of early stage operable breast cancer patients for circulating tumour cells is of potential importance for identifying patients at risk of developing distant relapse. We present the results of a study of the efficacy of the immunobead RT-PCR method in identifying patients with circulating tumour cells. Results Immunomagnetic enrichment of circulating tumour cells followed by RT-PCR (immunobead RT-PCR) with a panel of five epithelial specific markers (ELF3, EPHB4, EGFR, MGB1 and TACSTD1) was used to screen for circulating tumour cells in the peripheral blood of 56 breast cancer patients. Twenty patients were positive for two or more RT-PCR markers, including seven patients who were node negative by conventional techniques. Significant increases in the frequency of marker positivity was seen in lymph node positive patients, in patients with high grade tumours and in patients with lymphovascular invasion. A strong trend towards improved disease free survival was seen for marker negative patients although it did not reach significance (p = 0.08). Conclusion Multi-marker immunobead RT-PCR analysis of peripheral blood is a robust assay that is capable of detecting circulating tumour cells in early stage breast cancer patients.

Structural and thermal performance of cold-formed steel stud wall systems under fire conditions

Cold-formed steel stud walls are a major component of Light Steel Framing (LSF) building systems used in commercial, industrial and residential buildings. In the conventional LSF stud wall systems, thin steel studs are protected from fire by placing one or two layers of plasterboard on both sides with or without cavity insulation. However, there is very limited data about the structural and thermal performance of stud wall systems while past research showed contradicting results, for example, about the benefits of cavity insulation. This research was therefore conducted to improve the knowledge and understanding of the structural and thermal performance of cold-formed steel stud wall systems (both load bearing and non-load bearing) under fire conditions and to develop new improved stud wall systems including reliable and simple methods to predict their fire resistance rating. Full scale fire tests of cold-formed steel stud wall systems formed the basis of this research. This research proposed an innovative LSF stud wall system in which a composite panel made of two plasterboards with insulation between them was used to improve the fire rating. Hence fire tests included both conventional steel stud walls with and without the use of cavity insulation and the new composite panel system. A propane fired gas furnace was specially designed and constructed first. The furnace was designed to deliver heat in accordance with the standard time temperature curve as proposed by AS 1530.4 (SA, 2005). A compression loading frame capable of loading the individual studs of a full scale steel stud wall system was also designed and built for the load-bearing tests. Fire tests included comprehensive time-temperature measurements across the thickness and along the length of all the specimens using K type thermocouples. They also included the measurements of load-deformation characteristics of stud walls until failure. The first phase of fire tests included 15 small scale fire tests of gypsum plasterboards, and composite panels using different types of insulating material of varying thickness and density. Fire performance of single and multiple layers of gypsum plasterboards was assessed including the effect of interfaces between adjacent plasterboards on the thermal performance. Effects of insulations such as glass fibre, rock fibre and cellulose fibre were also determined while the tests provided important data relating to the temperature at which the fall off of external plasterboards occurred. In the second phase, nine small scale non-load bearing wall specimens were tested to investigate the thermal performance of conventional and innovative steel stud wall systems. Effects of single and multiple layers of plasterboards with and without vertical joints were investigated. The new composite panels were seen to offer greater thermal protection to the studs in comparison to the conventional panels. In the third phase of fire tests, nine full scale load bearing wall specimens were tested to study the thermal and structural performance of the load bearing wall assemblies. A full scale test was also conducted at ambient temperature. These tests showed that the use of cavity insulation led to inferior fire performance of walls, and provided good explanations and supporting research data to overcome the incorrect industry assumptions about cavity insulation. They demonstrated that the use of insulation externally in a composite panel enhanced the thermal and structural performance of stud walls and increased their fire resistance rating significantly. Hence this research recommends the use of the new composite panel system for cold-formed LSF walls. This research also included steady state tensile tests at ambient and elevated temperatures to address the lack of reliable mechanical properties for high grade cold-formed steels at elevated temperatures. Suitable predictive equations were developed for calculating the yield strength and elastic modulus at elevated temperatures. In summary, this research has developed comprehensive experimental thermal and structural performance data for both the conventional and the proposed non-load bearing and load bearing stud wall systems under fire conditions. Idealized hot flange temperature profiles have been developed for non-insulated, cavity insulated and externally insulated load bearing wall models along with suitable equations for predicting their failure times. A graphical method has also been proposed to predict the failure times (fire rating) of non-load bearing and load bearing walls under different load ratios. The results from this research are useful to both fire researchers and engineers working in this field. Most importantly, this research has significantly improved the knowledge and understanding of cold-formed LSF walls under fire conditions, and developed an innovative LSF wall system with increased fire rating. It has clearly demonstrated the detrimental effects of using cavity insulation, and has paved the way for Australian building industries to develop new wall panels with increased fire rating for commercial applications worldwide.

The interactions between insulin and androgens in progression to castrate resistant prostate cancer

An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer.

Human papillomavirus prevalence, viral load and pre-cancerous lesions of the cervix in women initiating highly active antiretroviral therapy in South Africa : a cross-sectional study

Background Cervical cancer and infection with human immunodeficiency virus (HIV) are both important public health problems in South Africa (SA). The aim of this study was to determine the prevalence of cervical squamous intraepithelial lesions (SILs), high-risk human papillomavirus (HR-HPV), HPV viral load and HPV genotypes in HIV positive women initiating anti-retroviral (ARV) therapy. Methods A cross-sectional survey was conducted at an anti-retroviral (ARV) treatment clinic in Cape Town, SA in 2007. Cervical specimens were taken for cytological analysis and HPV testing. The Digene Hybrid Capture 2 (HC2) test was used to detect HR-HPV. Relative light units (RLU) were used as a measure of HPV viral load. HPV types were determined using the Roche Linear Array HPV Genotyping test. Crude associations with abnormal cytology were tested and multiple logistic regression was used to determine independent risk factors for abnormal cytology. Results The median age of the 109 participants was 31 years, the median CD4 count was 125/mm3, 66.3% had an abnormal Pap smear, the HR-HPV prevalence was 78.9% (Digene), the median HPV viral load was 181.1 RLU (HC2 positive samples only) and 78.4% had multiple genotypes. Among women with abnormal smears the most prevalent HR-HPV types were HPV types 16, 58 and 51, all with a prevalence of 28.5%. On univariate analysis HR-HPV, multiple HPV types and HPV viral load were significantly associated with the presence of low and high-grade SILs (LSIL/HSIL). The multivariate logistic regression showed that HPV viral load was associated with an increased odds of LSIL/HSIL, odds ratio of 10.7 (95% CI 2.0 – 57.7) for those that were HC2 positive and had a viral load of ≤ 181.1 RLU (the median HPV viral load), and 33.8 (95% CI 6.4 – 178.9) for those that were HC2 positive with a HPV viral load > 181.1 RLU. Conclusion Women initiating ARVs have a high prevalence of abnormal Pap smears and HR-HPV. Our results underscore the need for locally relevant, rigorous screening protocols for the increasing numbers of women accessing ARV therapy so that the benefits of ARVs are not partially offset by an excess risk in cervical cancer.

Bodyweight and other correlates of symptom detected breast cancers in a population offered screening

Objective: To determine factors associated with symptom detected breast cancers in a population offered screening. Methods We interviewed 1,459 Australian women aged 40–69, 946 with symptom detected and 513 with mammogram detected invasive breast cancers ≥1.1 cm in diameter, about their personal, mammogram and breast histories before diagnosis and reviewed medical records for tumour characteristics and mammogram dates, calculating ORs and 95% confidence intervals (CIs) for symptom- vs mammogram-detected cancers in logistic regression models. Results: Lack of regular mammograms (<2 mammograms in the 4.5 years before diagnosis) was the strongest correlate of symptom detected breast cancer (OR=3.04 for irregular or no mammograms). In women who had regular mammograms (≥2 mammograms in the 4.5 years before diagnosis), the independent correlates of symptom detected cancers were low BMI (OR <25kg/m2 vs ≥30kg/m2=2.18, 95% CI 1.23-3.84; p=0.008), increased breast density (available in 498 women) (OR highest quarter vs lowest =3.50, 95% CI 1.76-6.97; ptrend=0.004), high grade cancer and a larger cancer (each p<0.01). In women who did not have regular mammograms, the independent correlates were age <50 years, a first cancer and a ≥2cm cancer. Smoking appeared to modify the association of symptom detected cancer with low BMI (higher ORs for low BMI in current smokers) and estrogen receptor (ER) status (higher ORs for low BMI in ER− cancers). Conclusion: Women with low BMI may benefit from a tailored approach to breast cancer detection, particularly if they smoke.

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.

Taguchi optimized synthesis of graphene films by copper catalyzed ethanol decomposition

Taguchi method is for the first time applied to optimize the synthesis of graphene films by copper-catalyzed decomposition of ethanol. In order to find the most appropriate experimental conditions for the realization of thin high-grade films, six experiments suitably designed and performed. The influence of temperature (1000–1070 °C) and synthesis duration (1–30 min) and hydrogen flow (0–100 sccm) on the number of graphene layers and defect density in the graphitic lattice was ranked by monitoring the intensity of the 2D- and D-bands relative to the G-band in the Raman spectra. After critical examination and adjusting of the conditions predicted to give optimal results, a continuous film consisting of 2–4 nearly defect-free graphene layers was obtained.

Performance measures for Australian laboratories reporting cervical cytology : a decade of data 1998–2008

Aim Performance measures for Australian laboratories reporting cervical cytology are a set of quantifiable measures relating to the profile and accuracy of reporting. This study reviews aggregate data collected over the ten years in which participation in the performance measures has been mandatory. Methods Laboratories submit annual data on performance measures relating to the profile of reporting, including reporting rates for technically unsatisfactory specimens, high grade or possible high grade abnormalities and abnormal reports. Cytology-histology correlation data and review findings of negative smears reported from women with histological high grade disease are also collected. Suggested acceptable standards are set for each measure. This study reviews the aggregate data submitted by all laboratories for the years 1998-2008 and examines trends in reporting and the performance of laboratories against the suggested standards. Results The performance of Australian laboratories has shown continued improvement over the study period. There has been a fall in the proportion of laboratories with data outside the acceptable standard range in all performance measures. Laboratories are reporting a greater proportion of specimens as definite or possible high grade abnormality. This is partly attributable to an increase in the proportion of abnormal results classified as high grade or possible high grade abnormality. Despite this, the positive predictive value for high grade and possible high grade abnormalities has continued to rise. Conclusion Performance measures for cervical cytology have provided a valuable addition to external quality assurance procedures in Australia. They have documented continued improvements in the aggregate performance, as well as providing benchmarking data and goals for acceptable performance for individual laboratories.

Shortest path and vehicle trajectory aided map-matching for low frequency GPS data

Map-matching algorithms that utilise road segment connectivity along with other data (i.e.position, speed and heading) in the process of map-matching are normally suitable for high frequency (1 Hz or higher) positioning data from GPS. While applying such map-matching algorithms to low frequency data (such as data from a fleet of private cars, buses or light duty vehicles or smartphones), the performance of these algorithms reduces to in the region of 70% in terms of correct link identification, especially in urban and sub-urban road networks. This level of performance may be insufficient for some real-time Intelligent Transport System (ITS) applications and services such as estimating link travel time and speed from low frequency GPS data. Therefore, this paper develops a new weight-based shortest path and vehicle trajectory aided map-matching (stMM) algorithm that enhances the map-matching of low frequency positioning data on a road map. The well-known A* search algorithm is employed to derive the shortest path between two points while taking into account both link connectivity and turn restrictions at junctions. In the developed stMM algorithm, two additional weights related to the shortest path and vehicle trajectory are considered: one shortest path-based weight is related to the distance along the shortest path and the distance along the vehicle trajectory, while the other is associated with the heading difference of the vehicle trajectory. The developed stMM algorithm is tested using a series of real-world datasets of varying frequencies (i.e. 1 s, 5 s, 30 s, 60 s sampling intervals). A high-accuracy integrated navigation system (a high-grade inertial navigation system and a carrier-phase GPS receiver) is used to measure the accuracy of the developed algorithm. The results suggest that the algorithm identifies 98.9% of the links correctly for every 30 s GPS data. Omitting the information from the shortest path and vehicle trajectory, the accuracy of the algorithm reduces to about 73% in terms of correct link identification. The algorithm can process on average 50 positioning fixes per second making it suitable for real-time ITS applications and services.

Cost and outcomes of assessing patients with chest pain in an Australian emergency department

Objectives: We sought to characterise the demographics, length of admission, final diagnoses, long-term outcome and costs associated with the population who presented to an Australian emergency department (ED) with symptoms of possible acute coronary syndrome (ACS). Design, setting and participants: Prospectively collected data on ED patients presenting with suspected ACS between November 2008 and February 2011 was used, including data on presentation and at 30 days after presentation. Information on patient disposition, length of stay and costs incurred was extracted from hospital administration records. Main outcome measures: Primary outcomes were mean and median cost and length of hospital stay. Secondary outcomes were diagnosis of ACS, other cardiovascular conditions or non-cardiovascular conditions within 30 days of presentation. Results: An ACS was diagnosed in 103 (11.1%) of the 926 patients recruited. 193 patients (20.8%) were diagnosed with other cardiovascular-related conditions and 622 patients (67.2%) had non-cardiac-related chest pain. ACS events occurred in 0 and 11 (1.9%) of the low-risk and intermediate-risk groups, respectively. Ninety-two (28.0%) of the 329 high-risk patients had an ACS event. Patients with a proven ACS, high-grade atrioventricular block, pulmonary embolism and other respiratory conditions had the longest length of stay. The mean cost was highest in the ACS group ($13 509; 95% CI, $11 794–$15 223) followed by other cardiovascular conditions ($7283; 95% CI, $6152–$8415) and non-cardiovascular conditions ($3331; 95% CI, $2976–$3685). Conclusions: Most ED patients with symptoms of possible ACS do not have a cardiac cause for their presentation. The current guideline-based process of assessment is lengthy, costly and consumes significant resources. Investigation of strategies to shorten this process or reduce the need for objective cardiac testing in patients at intermediate risk according to the National Heart Foundation and Cardiac Society of Australia and New Zealand guideline is required.

The effects of height and BMI on prostate cancer incidence and mortality: A Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

Background Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality. Methods We conducted a case–control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man’s number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies. Results The genetic risk scores explained 6.31 and 1.46 % of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95 % CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95 % CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneity = 0.03). Conclusions We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with increased mortality (prostate cancer-specific and all-cause, respectively) in men with low-grade disease, a potentially informative but novel finding that requires replication.

Clinical application of biomarkers in prostate cancer in men with metabolic syndrome project: Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) in diagnosing localised prostate cancer

Localised prostate cancer is a heterogenous disease and a multi-modal approach is required to accurately diagnose and stage the disease. Whilst the use of magnetic resonance imaging (MRI) has become more common, small volume and multi-focal disease are oft en diffi cult to characterise. Prostate specifi c membrane antigen is a cell surface protein, which is expressed in nearly all prostate cancer cells. Its expression is signifi cantly higher in high grade prostate cancer cells. In this study, we compare multi-parametric magnetic resonance imaging and 68-Gallinium-PSMA PET with whole-mount pathology of the prostate to evaluate the applicability of multiparameteric (MP) MRI and 68Ga-PSMA PET in detecting and locating tumour foci in patients with localised prostate cancer.

A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma

Background: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5- monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of I mM for six or more hours, significantly enhances the efficacy of 5-FU. Patients and methods: 5-FU/FA was given as follows: days 1 and 2 - FA 250 mg/m 2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m 2 by intravenous bolus (ivb) over 15 minutes and subsequently 5-FU 400 mg/m 2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g ivb over 15 minutes followed by 12 g ivi over 12 hours. Results: Thirty patients were entered into the study. Median survival was nine months (range 1-51 + months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another. Conclusion: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.

Grade A Taipei junior high school principals’ self-reported leadership practices

The principal’s leadership and curriculum development are considered the core elements for creating a high performing junior high school. In Taiwan, mathematics curriculum reform has been an ongoing topic since 1994. The pedagogy, classroom interactions, and the underlying philosophy of mathematics education have varied with different versions of guidelines. These changes inevitably increase the requirement for principals’ leadership in order to effectively implement the curriculum reform. Principals’ leadership is essential to the success of the implementation in their school. This study aimed to explore and identify the leadership of junior high school principals whose schools had been judged by the Taipei City Government as Grade A junior high schools. Principals’ implementations of the reformed mathematics curriculum were used as examples to generate insights of their leadership. This study drew upon a multiple-case study approach. Data were collected from interviews, observations, and documentations. Bass and Avolio’s (1997) full range leadership theory provided a structure for gaining insight into these principals’ leadership practices. Five Grade A Taipei junior high school principals participated and shared their leadership concepts and experiences. Findings revealed that the leadership preferences of the five principles varied considerably. Management by exception-active, contingent reward, individualised consideration, and idealised influence were Grade A Taipei junior high school principals’ preferred leadership practices. In addition, principals’ leadership strategies associated with these practices were identified. These principals had adopted a range of leadership strategies according to the staff and school needs. Results of this study have implications for both Taiwanese principals and education departments. Principals can enhance their leadership by gaining more understanding about the Grade A principals’ leadership practices and strategies. Taiwanese education departments can improve school leadership training programs by focusing on these practices and strategies, which may also lead to more effective strategies for implementing national curriculum reform.