Cohort Of Australian Patients Research Articles

Implications of the LEGACY trial on US Atrial Fibrillation Patients: An NCDR Research to Practice (R2P) Project

The Long-term Effect of Goal Directed Weight Management in an Atrial Fibrillation Cohort: A Long-term Follow-up Study (LEGACY) demonstrated that weight reduction in a cohort of Australian patients with atrial fibrillation (AF) resulted in a reduction in AF burden and improvement in AF symptom severity. The applicability of LEGACY in US cardiovascular practice is not known. A cohort of patients with AF from the National Cardiovascular Data Registry Practice Innovation and Clinical Excellence (PINNACLE) registry of US cardiovascular ambulatory care practices was created. The proportion of PINNACLE AF patients meeting enrollment criteria for LEGACY was assessed. Differences between these patients and LEGACY trial patients were qualitatively compared. Treatment for AF among LEGACY eligible and noneligible patients was compared. Among 349,999 US patients with AF from 179 cardiovascular practices in the PINNACLE registry, 197,255 (56.4%) met enrollment criteria for LEGACY. LEGACY-eligible PINNACLE AF had significantly lower rates of tobacco and alcohol abuse than the LEGACY trial population. There were significant differences in drug therapy comparing LEGACY eligible and LEGACY noneligible PINNACLE AF patients. In this cohort of patients in ambulatory practice in the United States with AF, over 1/2 were potential candidates for a weight management program. Differences between patients in practice and those enrolled in the trial could influence the success and impact of the LEGACY weight management intervention. Our study identifies a potential opportunity to improve AF morbidity and costs to the health care system in the United States by implementing a structured weight reduction program, such as that described in LEGACY.

Validation of the Lupus Impact Tracker in an Australian patient cohort.

The objective of this article is to validate the Lupus Impact Tracker (LIT), a disease-specific patient-reported outcome (PRO) tool, in systemic lupus erythematosus (SLE) patients in a multi-ethnic Australian cohort. Patients attending the Monash Lupus Clinic were asked to complete the LIT, a 10-item PRO. Psychometric testing assessing criterion validity, construct validity, test-retest reliability (TRT) and internal consistency reliability (ICR) were performed. We compared the LIT scores across patient characteristics, and correlations between LIT scores and SLEDAI-2k, PGA, and SLICC-SDI were examined. LIT data were obtained from 73 patients. Patients were 84% female with a median age of 41 years, and 34% were Asian. The cohort had mild-moderate disease activity with a median (IQR) Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2k) of 4 (IQR 2-6). The median LIT score was 32.5 (IQR 17.5-50). LIT demonstrated criterion validity against SLEDAI-2k and SDI. Construct validity assessed by confirmatory factor analysis demonstrated an excellent fit (Goodness of fit index 0.95, Comparative Fit Index 1, Root Mean Square Error of Approximation <0.0001). The LIT demonstrated TRT with an overall intraclass correlation coefficient of 0.986 (95% CI 0.968-0.995). ICR was demonstrated with a Cronbach's alpha of 0.838. Patients with disability, low socioeconomic status, or higher disease activity had significantly worse LIT scores. The LIT demonstrated properties consistent with its being valid in this population. Lower socioeconomic status appears to have a significant impact on patient-reported health-related quality of life in SLE.

Missing Value Imputation Improves Mortality Risk Prediction Following Cardiac Surgery: An Investigation of an Australian Patient Cohort.

The aim of this study was to evaluate the impact of missing values on the prediction performance of the model predicting 30-day mortality following cardiac surgery as an example. Information from 83,309 eligible patients, who underwent cardiac surgery, recorded in the Australia and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) database registry between 2001 and 2014, was used. An existing 30-day mortality risk prediction model developed from ANZSCTS database was re-estimated using the complete cases (CC) analysis and using multiple imputation (MI) analysis. Agreement between the risks generated by the CC and MI analysis approaches was assessed by the Bland-Altman method. Performances of the two models were compared. One or more missing predictor variables were present in 15.8% of the patients in the dataset. The Bland-Altman plot demonstrated significant disagreement between the risk scores (p<0.0001) generated by MI and CC analysis approaches and showed a trend of increasing disagreement for patients with higher risk of mortality. Compared to CC analysis, MI analysis resulted in an average of 8.5% decrease in standard error, a measure of uncertainty. The MI model provided better prediction of mortality risk (observed: 2.69%; MI: 2.63% versus CC: 2.37%, P<0.001). 'Multiple imputation' of missing values improved the 30-day mortality risk prediction following cardiac surgery.

Seasonality of birth patterns in an Australian cohort of patients with biopsy-confirmed idiopathic inflammatory myopathy.

Environmental exposures in the foetal period may predispose to autoimmunity. Aim of this study is to investigate whether seasonality in birth patterns exists in idiopathic inflammatory myopathies (IIM). We used Stata (StataCorp USA, version 13.0) and the user-written routine command 'circsummarise' to assess birth seasonality among South Australian patients with histologically confirmed IIM subsequent to 1980 using their date of birth. There was no evidence for a seasonal birth pattern among IIM patients overall (n = 568), however there were some ethnic variances in birth patterns among non-Caucasian patients. There was evidence for birth seasonality among both Aboriginal (mean = 7 July, Rayleigh P = 0.04) and Asian patients (mean = 12 August, Rayleigh P-value = 0.038). Non-Caucasians born in the third quarter of the calendar year may have an increased risk of developing IIM. Large international studies of IIM patients of diverse ethnicity are required to clarify the role of perinatal exposures in disease susceptibility.

The molecular profile of metastatic melanoma in Australia

Targeted therapy directed at driver oncogenic mutations offers an effective treatment option for select patients with metastatic melanoma. The aim of this study was to assess the prevalence of clinically significant somatic mutations, specifically BRAF, NRAS and KIT, in a large cohort of Australian patients with metastatic melanoma. We performed a cross-sectional cohort study of consecutive patients with American Joint Committee on Cancer (AJCC) stage IIIc unresectable or stage IV melanoma managed at Melanoma Institute Australia, and affiliated sites, that underwent molecular testing between 22 June 2009 and 19 July 2013. Additionally, we examined the change in BRAF testing methodology and patient population over time, and how this influenced the prevalence of mutations. A total of 767 molecular tests were conducted for 733 patients. BRAF V600 mutation testing was performed for 713 patients (97.2%), with an overall mutation prevalence of 37.7% (269/713); 74.3% (200/269) were the V600E genotype and 22.3% (60/269) V600K. The BRAF mutation prevalence and proportion of BRAF V600E and V600K genotypes varied across the study period, as did testing methodology and the median age of the cohorts. Of 222 patients who underwent NRAS testing, 58 (26.1%) had a mutation identified. The overall prevalence of KIT mutations was 3.7% (11/296). In Australia the prevalence of BRAF mutations is lower than initially reported, although this remains the most common mutation identified in metastatic melanoma and an important therapeutic target. NRAS mutations are more prevalent than initially described; however, other mutations reported in melanoma, including KIT, are rare in an unselected population of patients.

Interpretation of an Extended Autoantibody Profile in a Well-Characterized Australian Systemic Sclerosis (Scleroderma) Cohort Using Principal Components Analysis.

To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort. Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.

Malignancy risk in Australian rheumatoid arthritis patients treated with anti-tumour necrosis factor therapy: analysis of the Australian Rheumatology Association Database (ARAD) prospective cohort study.

BackgroundMalignancy risk with tumour necrosis factor inhibitor (TNFi) therapy remains unclear. Our primary aim was to assess malignancy risk with TNFi therapy in a cohort of Australian patients with rheumatoid arthritis (RA). We also assessed risk in a biologic-naïve group.MethodsDemographic data of all RA patients enrolled in the Australian Rheumatology Association Database before 25 October 2010 were matched to national cancer records in July 2010 (linkage complete to 2007). Verified self-reported malignancies occurring between 1 January 2008 and 25 October 2010 were also included in the analysis. Standardised incidence ratios (SIRs) were used to compare malignancy incidence in biologic-naïve and TNFi-exposed ARAD participants to the general population using site-, age- and sex-specific rates by calendar year. Rate ratios (RRs) were used to compare malignancy incidence in TNFi-exposed participants to biologic-naïve RA patients, and a composite RA cohort that included pre-TNFi person years, both adjusted for age, gender, smoking, methotrexate use and prior malignancy.ResultsForty-four malignancies were reported after 5752 person-years in the TNFi-exposed group (N = 2145) and 32 malignancies were reported after 1682 person-years in the biologic-naïve group (N = 803). No overall increased risk of malignancy in TNFi-treated RA patients was found when compared with the general population or with biologic-naïve RA patients. Compared to the biologic naïve group, without the inclusion of pre-TNFi years in the comparator group, the relative risk of female breast cancer was reduced in TNFi-treated patients (RR 0.17 (95 % CI 0.03 to 0.95)). It was no longer significant when adding pre-TNFi years in the comparator group. The risk of melanoma was increased for both biologic naïve and TNFi-treated patients when compared with the general population (SIR 2.72 (95 % CI 1.13 to 6.53) and SIR 2.03 (95 % CI 1.09 to 3.78) respectively). The relative risk of melanoma was not increased in the TNFi-exposed group compared with biologic naïve patients (RR 0.54, 95 % CI 0.12, 2.40). Inclusion of pre-TNFi person years in the comparator group did not change these results.ConclusionsMalignancy incidence was low in this RA cohort and biologic exposure did not increase the risk of malignancy. Melanoma risk was increased in both TNFi-treated and biologic-naïve RA patients compared with the general population suggesting that RA status, and possibly methotrexate exposure, may be responsible.

Patients with Rheumatoid Arthritis in the Australian OPAL Cohort Show Significant Improvement in Disease Activity over 5 Years: A Multicenter Observational Study.

To evaluate disease activity trends in a large cohort of Australian patients with rheumatoid arthritis (RA) from 2009 to 2014. This is a multicenter, cross-sectional, noninterventional study of patients with RA treated in Australia. Patients with RA treated at participating OPAL (Optimising Patient outcome in Australian RheumatoLogy) clinics were included in the study. Data, deidentified by patient, clinic, and clinician, were identified using a purpose-written electronic medical record. Patient demographics, disease onset, medications, and disease measures were analyzed. The Disease Activity Score at 28 joints (DAS28) was used to classify patients into the disease activity states of remission: low disease activity, moderate disease activity (MDA), and high disease activity. Choice of therapy was at the discretion of the treating clinician. At the time of analysis, the database contained 15,679 patients with RA, 8998 of whom fulfilled the inclusion criteria. Mean age was 63.2 years, mean disease duration was 13.8 years, and the majority were women (72.4%). A total of 37,274 individual DAS28-erythrocyte sedimentation rate scores were recorded for the 8998 patients. The frequency of remission increased significantly from 36.7% in 2009 to 53.5% in 2014 (p < 0.001), and that of MDA decreased from 33% (2009) to 22.2% (2014). The use of biologic disease-modifying antirheumatic drugs for the patients in remission increased from 17% in 2009 to 36.9% in 2014. Contemporary management of RA in Australia shows improvements in disease activity toward the target of remission over a 5-year period.

Clinical course and treatment of anti-HMGCR antibody-associated necrotizing autoimmune myopathy.

Objective:We examined a cohort of Australian patients with statin exposure who developed a necrotizing autoimmune myopathy (NAM) associated with a novel autoantibody against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and describe the clinical and therapeutic challenges of managing these patients and an optimal therapeutic strategy.Methods:Clinical, laboratory, EMG, and histopathologic results and response to immunomodulation are reported in 6 Australian patients with previous statin exposure and antibodies targeting HMGCR.Results:All patients presented with painless proximal weakness following statin therapy, which persisted after statin cessation. Serum creatine kinase (CK) levels ranged from 2,700 to 16,200 IU/L. EMG was consistent with a myopathic picture. Muscle biopsies revealed a pauci-immune necrotizing myopathy. Detailed graphical representation of the clinical course of these patients showed a close association with rising CK and an increase in clinical weakness signifying relapses, particularly upon weaning or ceasing steroids. All 6 patients were responsive to initial steroid therapy, with 5 relapsing upon attempts to wean steroids. Both CK and clinical strength improved with the reinstitution of immunotherapy, in particular steroids and IV immunoglobulin (IVIg). All patients required treatment with varying multiagent immunosuppressive regimens to achieve clinical remission, including prednisone (n = 6), IVIg (n = 5), plasmapheresis (n = 2), and additional therapy including methotrexate (n = 6), cyclophosphamide (n = 2), rituximab (n = 2), azathioprine (n = 1), and cyclosporine (n = 1).Conclusions:Recognition of HMGCR antibody–associated NAM is important because these patients are responsive to immunosuppression, and early multiagent therapy and a slow and cautious approach to withdrawing steroids may improve outcomes.

Prospective study of ocular manifestations of pemphigus and bullous pemphigoid identifies a high prevalence of dry eye syndrome.

To study the range of ocular manifestations in an Australian cohort of patients with pemphigus and bullous pemphigoid (BP), including a detailed assessment for dry eye syndrome (DES). Twenty-two patients with pemphigus vulgaris, pemphigus foliaceus, and BP were referred for a detailed ophthalmology review between September 2011 and March 2012. A total of 44 eyes of 22 patients with pemphigus vulgaris, pemphigus foliaceus, and BP were examined. Photophobia was the most common symptom reported. The most common ocular signs found in both groups were blepharitis (68.1%), conjunctival hyperemia (22.7%), and limbal broadening (18.2%). In our DES assessment, 92.9% of patients had a reduced Schirmer test score and an abnormal tear break-up time was recorded in 100% of patients. The ocular surface disease index score ranged from 0 to 47.2, with a median score of 10. The high occurrence of patient-reported ocular symptoms and clinical evidence of dry eye on Schirmer testing and break-up time demonstrate high prevalence of DES in our cohort of pemphigus and BP patients, which is a novel finding. Limbal broadening was another common finding not previously reported.

Characterisation of coronary artery disease in a contemporary cohort of Australian patients with treated HIV, using invasive coronary angiography

Background: Treated HIV has been associated with accelerated vascular disease including a higher incidence of coronary artery disease and myocardial infarction, partly due to metabolic complications of anti-retroviral treatment. We sought to quantify the burden of coronary artery disease in a group of well treated patients with HIV using retrospective data from invasive coronary angiograms in patients presenting for investigation of suspected coronary ischaemia. Methods: Demographic and angiogram data from 160 males who presented acutely with STEMI/NSTEMI or unstable angina (73 patients with HIV and 87 age and clinical presentation matched HIV negative controls) were obtained from St Vincent's Hospital. Coronary vessel patency was calculated using the Gensini Angiographic Scoring System by an experienced cardiologist blinded to HIV status. Results: The two groups were matched for age and there was no difference in cholesterol profiles, rates of smoking or hypertension. Statin use was higher in patients with HIV (59% v's 33% p < 0.001). There was a higher the mean Gensini score in the group with HIV (25.72) compared to controls (25.7 versus 36.6, p=0.034, Fig. 1). Conclusions: Previous studies have shown a higher burden of coronary artery disease in people living with HIV. Our single centre study has demonstrated a lower burden of coronary disease in a group of treated, virally suppressed, matched patients with HIV and similar traditional risk factors. These findings may represent more aggressive risk-factor management in our HIV cohort, including statin use, lowering the burden of coronary disease. Figure 1 Gensini score based on HIV status. * p=0.03

Copy Number Variations of TBK1 in Australian Patients With Primary Open-Angle Glaucoma

To investigate the presence of TBK1 copy number variations in a large, well-characterized Australian cohort of patients with glaucoma comprising both normal-tension glaucoma and high-tension glaucoma cases. A retrospective cohort study. DNA samples from patients with normal-tension glaucoma and high-tension glaucoma and unaffected controls were screened for TBK1 copy number variations using real-time quantitative polymerase chain reaction. Samples with additional copies of the TBK1 gene were further tested using custom comparative genomic hybridization arrays. Four out of 334 normal-tension glaucoma cases (1.2%) were found to carry TBK1 copy number variations using quantitative polymerase chain reaction. One extra dose of the TBK1 gene (duplication) was detected in 3 normal-tension glaucoma patients, while 2 extra doses of the gene (triplication) were detected in a fourth normal-tension glaucoma patient. The results were further confirmed by custom comparative genomic hybridization arrays. Further, the TBK1 copy number variation segregated with normal-tension glaucoma in the family members of the probands, showing an autosomal dominant pattern of inheritance. No TBK1 copy number variations were detected in 1045 Australian patients with high-tension glaucoma or in 254 unaffected controls. We report the presence of TBK1 copy number variations in our Australian normal-tension glaucoma cohort, including the first example of more than 1 extra copy of this gene in glaucoma patients (gene triplication). These results confirm TBK1 to be an important cause of normal-tension glaucoma, but do not suggest common involvement in high-tension glaucoma.

Prolonged impact of home versus clinic-based management of chronic heart failure: Extended follow-up of a pragmatic, multicentre randomized trial cohort

ObjectivesWe compared the longer-term impact of the two most commonly applied forms of post-discharge management designed to minimize recurrent hospitalization and prolong survival in typically older patients with chronic heart failure (CHF). MethodsWe followed a multi-center randomized controlled trial cohort of Australian patients hospitalized with CHF and initially allocated to home-based or specialized CHF clinic-based intervention for 1368±216days. Blinded endpoints included event-free survival from all-cause emergency hospitalization or death, all-cause mortality and rate of all-cause hospitalization and stay. Results280 patients (73% male, aged 71±14years and 73% left ventricular systolic dysfunction) were initially randomized to home-based (n=143) or clinic-based (n=137) intervention. During extended follow-up (complete for 274 patients), 1139 all-cause hospitalizations (7477days of hospital stay) and 121 (43.2%) deaths occurred. There was no difference in the primary endpoint; 20 (14.0%) home-based versus 13 (7.4%) clinic-based patients remained event-free (adjusted HR 0.89, 95% CI 0.70 to 1.15; p=0.378). Significantly fewer home-based (51/143, 35.7%) than clinic-based intervention (71/137, 51.8%) patients died (adjusted HR 0.62, 95% CI 0.42 to 0.90: p=0.012). Home-based versus clinic-based intervention patients accumulated 592 and 547 all-cause hospitalizations (p=0.087) associated with 3067 (median 4.0, IQR 2.0 to 6.8) versus 4410 (6.0, IQR 3.0 to 12.0) days of hospital stay (p<0.01 for rate and duration of hospital stay). ConclusionsRelative to clinic-based intervention, home-based intervention was not associated with prolonged event-free survival. Home-based intervention was, however, associated with significantly fewer all-cause deaths and significantly fewer days of hospital stay in the longer-term. Trial registrationAustralian New Zealand Clinical Trials Registry number 12607000069459 (http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=81803)

Duodenal eosinophilia and early satiety in functional dyspepsia: Confirmation of a positive association in an Australian cohort

Functional dyspepsia (FD), defined by unexplained pain or discomfort centered in the upper abdomen, is common. Diagnosis and treatment of FD based on the symptom-based Rome criteria remains challenging. Recently, eosinophilia in the duodenum has been implicated in the pathophysiology of FD in adults, specifically increased eosinophils in early satiety and postprandial distress, but the association remains controversial. The aim of this study was to characterize upper gastrointestinal (GI) tract pathology, specifically duodenal eosinophilia, in an Australian cohort of patients with FD. Patients prospectively referred for an upper GI endoscopy (n = 55; mean age, 49.6 years; 61.8% female) were stratified to FD cases (n = 33) and controls (n = 22) using Rome II criteria. All subjects completed a validated bowel symptom questionnaire. The eosinophil count per square millimeter in the duodenal bulb (D1) and second part (D2) was assessed and Helicobacter pylori status determined by gastric histology. Associations with clinical symptoms were assessed. Cases and controls were demographically similar. Duodenal eosinophilia was significantly increased in subjects experiencing early satiety (P = 0.01) and postprandial fullness (P = 0.001). This association was seen in D2 but not D1. Abdominal pain was associated with eosinophilia in both D1 (P = 0.02) and D2 (P = 0.005). Smoking was also associated with higher eosinophil counts in D2 (P = 0.007) and symptoms of early satiety (P = 0.02). Duodenal eosinophilia occurs in a subset of FD. The potential role of duodenal eosinophils in FD has implications for diagnosis and therapeutic trials.

Mutations in KCNJ5 determines presentation and likelihood of cure in primary hyperaldosteronism

Primary hyperaldosteronism (PA) is a common cause of secondary hypertension. Two recurrent mutations (G151R and L168R) in the potassium channel gene KCNJ5 have been identified that affect the Kir3.4 potassium channel found in the cells of the zona glomerulosa of the adrenal gland. The aim of this study was to determine the prevalence of KCNJ5 mutations in an Australian cohort of patients and to correlate these findings with clinical outcome data, in order to describe the clinical impact on patients who harbour this mutation. Direct Sanger sequencing for KCNJ5 on DNA from adrenal tumour tissue of 83 patients with PA in a cohort study was undertaken and mutation status correlated with clinical outcome data. Seventy-one of 83 patients (86%) had adrenocortical adenomas and 12 patients (14%) had bilateral adrenal hyperplasia. A total of 34 (41%) patients were found to have heterozygous somatic mutations in KCNJ5, G151R and L168R. No germ line mutations were identified. Patients with mutations were predominately female (68% versus 49%) and significantly younger at presentation (48 versus 55 years). When correlated with clinical data, our results demonstrated that patients with KCNJ5 mutations were more likely to be cured following surgery without the requirement for ongoing medications. Our findings in a large Australian cohort show that patients with mutations in KCNJ5 present earlier with the signs and symptoms of PA benefit from surgical intervention. Moreover, our results highlight the importance of a thorough workup and management plan for younger patients who present with hypertension.

FRI0372 Early mortality in systemic sclerosis: rationale for forming a multinational inception cohort of patients with scleroderma (the insync study)

BackgroundSystemic sclerosis (SSc) has substantial mortality. We hypothesise that survival rates from prevalent cohorts may underestimate mortality early in the disease course, particularly in patients with diffuse disease who may...

Atypical pituitary adenomas – investigation and validation of the 2004 who criteria

Introduction In 2004, the WHO added a new subgroup of pituitary adenoma, ‘atypical’ pituitary adenoma, which may be associated with aggressive behaviour. The features of this subgroup include an elevated mitotic index, Ki-67 index of >3% and extensive nuclear staining for p53. However these criteria have not been validated clinically. Aims To investigate and validate the WHO 2004 criteria on a large Australian cohort of patients who have undergone surgery for a pituitary adenoma. Study Designs We identified 117 patients who had surgery between 2000 and 2009 for which clinical follow-up was available. Of these, archived paraffin embedded tissue was available for 115 cases. Mitotic rate, Ki-67 and p53 expression were scored. Comparison was made with clinical outcome. Results Early results, so far, indicate that the degree of p53 expression is an insensitive marker for aggressive behaviour. We anticipate completing our study of Ki-67 and mitotic index by the end of December 2012. Conclusion In our study, the early indications are that p53 has poor sensitivity to predict aggressive behaviour in pituitary adenomas. The validation of Ki-67 and mitotic index in atypical pituitary adenomas is proceeding and we anticipate completing this analysis during December 2012. In 2004, the WHO added a new subgroup of pituitary adenoma, ‘atypical’ pituitary adenoma, which may be associated with aggressive behaviour. The features of this subgroup include an elevated mitotic index, Ki-67 index of >3% and extensive nuclear staining for p53. However these criteria have not been validated clinically. To investigate and validate the WHO 2004 criteria on a large Australian cohort of patients who have undergone surgery for a pituitary adenoma. We identified 117 patients who had surgery between 2000 and 2009 for which clinical follow-up was available. Of these, archived paraffin embedded tissue was available for 115 cases. Mitotic rate, Ki-67 and p53 expression were scored. Comparison was made with clinical outcome. Early results, so far, indicate that the degree of p53 expression is an insensitive marker for aggressive behaviour. We anticipate completing our study of Ki-67 and mitotic index by the end of December 2012. In our study, the early indications are that p53 has poor sensitivity to predict aggressive behaviour in pituitary adenomas. The validation of Ki-67 and mitotic index in atypical pituitary adenomas is proceeding and we anticipate completing this analysis during December 2012.

The effect of oral anticoagulation on the prevalence and management of haematuria in a contemporary Australian patient cohort

• To examine the effect of oral anticoagulation (OA) on the prevalence and inpatient management of haematuria in a contemporary Australian patient cohort. • Patients across all inpatient units who had diagnosis-related group (DRG) coding for haematuria were identified from April 2010 to September 2011. • A retrospective chart review was performed to identify the type of anticoagulation (if any), requirement for bladder irrigation or blood transfusion, length of stay (LOS) and cause of haematuria. • Patients for whom the anticoagulation status was uncertain were excluded from analysis. • Statistical significance was determined by Pearson's chi-square tests and Student's t-tests. • In all, 335 admissions with DRG coding for haematuria were identified from hospital records, of which 268 admissions had clear documentation of anticoagulation. There were 118 emergency admissions and 150 elective admissions for day case cystoscopy. The mean age of the patients was 66 years and the male:female ratio was 5:1. In all, 123 admissions were for patients on some form of anticoagulation (46%). • Patients were on anticoagulation in 53% of the 118 emergency admissions for gross haematuria. These comprised patients on aspirin (28%), clopidogrel (4%), warfarin (10%), combined aspirin and warfarin (1%) and combined aspirin and clopidogrel (10%). • The use of OA was a significant predictor of the need for intervention among the 118 emergency admissions (86% vs 62%, P = 0.003). • In particular, dual antiplatelet therapy in the form of aspirin and clopidogrel was associated with an increased requirement for bladder irrigation (92%) when compared with patients on other forms of anticoagulation (84%) or none at all (62%, P = 0.01). • The mean LOS for patients admitted to hospital with haematuria was 5.6 days. Patients on warfarin had a statistically significant longer LOS than the other groups (13.7 vs 4.5 days, P < 0.001). A cause for haematuria was identified in 120 of the 234 patients (51%). Of these, the most common was benign prostatic hyperplasia (21%), followed by bladder urothelial carcinoma (17%). • In our cohort of patients, about half of all admissions with haematuria were for patients on some form of OA. • OA use increased the need for intervention, especially for patients on dual antiplatelet therapy.

Mycophenolate Versus Azathioprine for Kidney Transplantation

The use of mycophenolate mofetil (MMF) is associated with less acute rejection than azathioprine (AZA) early after kidney transplantation. However, the long-term impact of MMF versus AZA is less well studied. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study was a double-blind randomized placebo-controlled trial of MMF versus AZA, together with cyclosporine and steroids, first reported in 1996. We analyzed the long-term outcomes of the Australian cohort of patients enrolled in this study using follow-up data from the Australia and New Zealand Dialysis and Transplant Registry. Patient and graft survival, cancer incidence, and estimated kidney function were compared on an intention-to-treat basis. A total of 133 Australian patients participated in the study: 45 were randomized to AZA, 44 were randomized to MMF 2 g/d, and 44 were randomized to MMF 3 g/d. Baseline characteristics were similar between the groups. Median follow-up was 13.8 years, during which there were 97 graft failures, 75 deaths, and 1 lost to follow-up. There were no statistically significant differences between the groups in long-term patient or graft survival, cancer incidence, or kidney function. Death-censored graft survival was best in the group with 3 g/d MMF and worst in the group with 2 g/d MMF. By 5 years, 42% of the MMF group had switched permanently to AZA, whereas crossover from AZA to MMF was rare. This long-term examination, although limited by small numbers, found little evidence for the superiority of MMF over AZA.

Distinguishing Clinicopathologic Features of Patients with V600E and V600K BRAF-Mutant Metastatic Melanoma

Certain clinicopathologic features correlate with BRAF mutation status in melanoma including younger age and primary subtype. This study sought to determine the BRAF mutation status by age-decade and whether BRAF-mutant genotypes correlated with clinicopathologic features and outcome in patients with metastatic melanoma. A prospectively assembled cohort of Australian patients were followed from diagnosis of metastatic melanoma (N = 308). Clinicopathologic variables were correlated with BRAF mutational status, genotype, and survival. Forty-six percent of patients had a BRAF mutation; 73% V600E, 19% V600K, and 8% other genotypes. An inverse relationship existed between BRAF mutation prevalence and age-decade (P < 0.001). All patients <30 years and only 25% ≥ 70 years had BRAF-mutant melanoma. Amongst BRAF-mutant melanoma, the frequency of non-V600E genotypes (including V600K) increased with increasing age. Non-V600E genotypes comprised <20% in patients <50 years and >40% in those ≥ 70 years. A higher degree of cumulative sun-induced damage correlated with V600K but not V600E melanoma (P = 0.002). The disease-free interval from diagnosis of primary melanoma to first distant metastasis was shorter for patients with V600K compared with V600E melanoma (17.4 vs. 39.2 months, P = 0.048), with no difference in survival thereafter. In patients BRAF tested at diagnosis of metastatic melanoma, one year survival from diagnosis of metastasis was significantly longer for patients with BRAF-mutant melanoma treated with an inhibitor (83%), than those not treated with an inhibitor (29%, P < 0.001), or patients with BRAF wild-type melanoma (37%, P < 0.001). Different genotypes exist within BRAF-mutant metastatic melanoma, representing biologically and clinically discrete subtypes, suggesting distinct etiology and behavior.