Clinical School (Royal Melbourne Hospital) - Research Publications
Now showing items 1-12 of 26
Evaluation of the transferability of survival calculators for stage II/III colon cancer across healthcare systems
Adjuvant! Online Inc (A!O), the Memorial Sloan Kettering Cancer Center (MSKCC), MD Anderson (MDA) and Mayo Clinic (MC) provide calculators to predict survival probabilities for patients with resected early-stage colon cancer, trained on data from United States (US) patient cohorts or patients enrolled in international clinical trials. Limited data exist on the transferability of calculators across healthcare systems. Calculator transferability to Australian community practice was evaluated for 1,401 stage II/III patients. Calibration and discrimination were assessed for overall (OS), cancer-specific (CSS) or recurrence-free survival (RFS). The US patient cohort-based calculators, A!O, MSKCC and MDA, significantly overestimated risks of recurrence and death in Australian patients, with 5-year OS, CSS and RFS prediction differences of -6.5% to -9.9%, -9.1% to -14.4% and - 3.8% to -6.8%, respectively (p < 0.001). Significant heterogeneity in calibration was observed for subgroups by tumor stage and treatment, age, gender, tumor location, ECOG and ASA score. Calibration appeared acceptable for the clinical trial patient-based MC calculator, but restricted tool applicability (stage III patients, ≥12 examined lymph nodes, receiving adjuvant treatment) limited the sample size. Compared to AJCC 7th edition tumor staging, calculators showed improved discrimination for OS, but no improvement for CSS and RFS. In conclusion, deficiencies in calibration limited transferability of US patient cohort-based survival calculators for early-stage colon cancer to the setting of Australian community practice. Our results demonstrate the utility for multi-feature survival calculators to improve OS predictions but highlight the importance for performance assessment of tools prior to implementation in an external health care setting.
Robotic-assisted radical cystectomy with intracorporeal urinary diversion versus open: early Australian experience
BACKGROUND: The aim of this study was to describe our initial Australian single surgeon experience with robotic-assisted radical cystectomy (RARC) and intracorporeal urinary diversion (ICUD) and to compare the outcomes with open radical cystectomy (ORC). METHODS: Between January 2014 and June 2016, consecutive patients diagnosed with muscle invasive and high-risk non-muscle invasive bladder cancer undergoing radical cystectomy were included. Treatment modalities included either RARC with ICUD or ORC. ICUD consisted of either intracorporeal ileal conduit or orthotopic neobladder formation. Prospectively collected perioperative and oncological outcomes were analysed. RESULTS: Twenty-six RARC and 13 ORC were performed. Median operating times were 362 and 240 min for RARC and ORC, respectively (P < 0.001). Estimated blood loss for RARC was 300 mL compared with 500 mL for ORC (P = 0.01). Post-operative haemoglobin drop was less in the RARC cohort (20% versus 24%, P = 0.03). There was no statistical difference in overall 90-day complication rates (81% versus 62%, P = 0.25) and 90-day major complication rates (19% versus 23%, P = 0.67) between the RARC and ORC groups, respectively. Positive surgical margins for RARC were 4% and 8% for ORC (P = 1.0). CONCLUSION: Early results demonstrate that the safe introduction of RARC with ICUD in Australia is potentially feasible without compromising perioperative and oncological outcomes. Future randomized trial with larger numbers will be required for further analysis in the Australian setting.
Real-world outcomes for neoadjuvant capecitabine versus infusional 5-fluorouracil in the treatment of locally advanced rectal cancer
BACKGROUND: Neoadjuvant chemoradiation therapy is standard-of-care treatment for locally advanced rectal cancer (LARC). A pathological complete response (pCR) following chemoradiation therapy is an early indicator of treatment benefit and associated with excellent survival outcomes, with capecitabine largely replacing infusional 5-fluorouracil as the choice in routine care of LARC. AIMS: To analyse the uptake of capecitabine usage over time, and on the back of clinical trial data demonstrating equivalence between fluoropyrimidines, confirm that efficacy is maintained in the real-world setting. METHODS: We analysed data from a prospectively maintained colorectal cancer database at three Australian hospitals including patients diagnosed from January 2009 to December 2018. Pathological response was determined as either complete or incomplete and compared for patients receiving 5-FU or capecitabine. RESULTS: A total of 657 patients was analysed, 498 receiving infusional 5-FU and 159 capecitabine. Capecitabine use has markedly increased from approval in 2014 in Australia, now being used in more than 80% of patients. Patient characteristics were similar by treatment, including age, tumour location and pre-treatment stage. pCR was reported in 22/159 (13.8%) of capecitabine-treated patients and 118/380 (23.7%) that received 5-FU (P ≤ 0.01). More capecitabine-treated patients received post-operative oxaliplatin (44.2% vs 6.3%, P < 0.01). Two-year progression-free survival was similar (84.9% vs 88.0%, P = 0.34). CONCLUSIONS: Capecitabine is now the dominantly used neoadjuvant chemotherapy in LARC. Capecitabine use was associated with a lower rate of pCR versus infusional 5-FU, a difference not explained by examined patient or tumour characteristics. Poor treatment compliance with oral therapy in the real-world setting is one possible explanation.
Vertebral fractures following stereotactic body radiotherapy for spine metastases
Stereotactic body radiotherapy has emerged as one of the preferred treatments for patients with spine metastases, with the potential for long-term control from lesion irradiation. Post-treatment vertebral compression fractures are a known complication of this therapy, contributing to worsening pain and reduced quality of life, sometimes requiring surgical intervention. This review explores the current knowledge of post-radiotherapy fractures, in terms of the rates and associated predictive factors. A search of databases including Medline, Embase and the Cochrane Library was conducted using keywords such as 'vertebral compression fracture', 'stereotactic body radiotherapy' and 'spine metastases'. The search was limited to published studies up to March 2019, reporting clinical outcomes including both the post-treatment fracture rate and statistical identification of associated risk factors. Rates of post-treatment fractures ranged from 4 to 39%. A variety of factors were found to increase the risk, including the appearance of lytic vertebral disease, degree of pre-existing compression, spinal malalignment, increased dose per fraction and a Spinal Instability Neoplastic Score >6. This knowledge can enable clinicians to counsel patients when considering management options for spine metastases, maintaining the balance between local tumour control and the risk of subsequent fracture.
Linkage to chromosome 2q32.2-q33.3 in familial serrated neoplasia (Jass syndrome)
Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.
Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A
(OXFORD UNIV PRESS, 2013-10-01)
Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
Mortality in dialysis patients may not be associated with ESA dose: a 2-year prospective observational study
BACKGROUND: Anaemia of chronic kidney disease increases the risk of death and adverse events, but can be managed using erythropoiesis stimulating agents (ESAs). However, recent evidence suggests that targeting a higher haemoglobin concentration ([Hb]) increases mortality risk, and both higher [Hb] targets and ESA doses have been implicated. Nonetheless, a causative role has not been demonstrated, and this potential relationship requires further appraisal in such a complex patient group. METHODS: The relationship between the haematopoietic response to ESAs and patient survival in 302 stable, prevalent dialysis patients was explored in a prospective, single-centre study. Clinical and laboratory parameters influencing mortality and ESA resistance were analysed. Patients were stratified into 5 groups, according to their [Hb] and ESA dosage, and were followed for 2 years. RESULTS: Little difference in co-morbidities between groups was identified. 73 patients died and 36 were transplanted. Initial analysis suggested a direct relationship between mortality and ESA dosage. However, Cox proportional hazards multivariate analysis demonstrated mortality risk was associated only with age (adjusted HR per year: 1.061, 95% CI 1.031-1.092), dialysis duration (adjusted HR: 1.010, 95% CI 1.004-1.016), peripheral vascular disease (adjusted HR: 1.967, 95% CI 1.083-3.576) and CRP (adjusted HR: 1.024, 95% CI 1.011-1.039). Mortality was increased in patients poorly responsive to ESAs (55.5%). CONCLUSION: ESA dose does not appear to contribute substantially to mortality risk in dialysis patients. Instead, age and co-morbidities appear to be the critical determinants. A poor response to ESAs is a marker of overall poor health status.
Investigating the Potential Role of Genetic and Epigenetic Variation of DNA Methyltransferase Genes in Hyperplastic Polyposis Syndrome
(PUBLIC LIBRARY SCIENCE, 2011-02-10)
BACKGROUND: Hyperplastic Polyposis Syndrome (HPS) is a condition associated with multiple serrated polyps, and an increased risk of colorectal cancer (CRC). At least half of CRCs arising in HPS show a CpG island methylator phenotype (CIMP), potentially linked to aberrant DNA methyltransferase (DNMT) activity. CIMP is associated with methylation of tumor suppressor genes including regulators of DNA mismatch repair (such as MLH1, MGMT), and negative regulators of Wnt signaling (such as WIF1). In this study, we investigated the potential for interaction of genetic and epigenetic variation in DNMT genes, in the aetiology of HPS. METHODS: We utilized high resolution melting (HRM) analysis to screen 45 cases with HPS for novel sequence variants in DNMT1, DNMT3A, DNMT3B, and DNMT3L. 21 polyps from 13 patients were screened for BRAF and KRAS mutations, with assessment of promoter methylation in the DNMT1, DNMT3A, DNMT3B, DNMT3L MLH1, MGMT, and WIF1 gene promoters. RESULTS: No pathologic germline mutations were observed in any DNA-methyltransferase gene. However, the T allele of rs62106244 (intron 10 of DNMT1 gene) was over-represented in cases with HPS (p<0.01) compared with population controls. The DNMT1, DNMT3A and DNMT3B promoters were unmethylated in all instances. Interestingly, the DNMT3L promoter showed low levels of methylation in polyps and normal colonic mucosa relative to matched disease free cells with methylation level negatively correlated to expression level in normal colonic tissue. DNMT3L promoter hypomethylation was more often found in polyps harbouring KRAS mutations (p = 0.0053). BRAF mutations were common (11 out of 21 polyps), whilst KRAS mutations were identified in 4 of 21 polyps. CONCLUSIONS: Genetic or epigenetic alterations in DNMT genes do not appear to be associated with HPS, but further investigation of genetic variation at rs62106244 is justified given the high frequency of the minor allele in this case series.
Increased serum kallistatin levels in type 1 diabetes patients with vascular complications.
(Publiverse Online S.R.L, 2010-09-22)
BACKGROUND: Kallistatin, a serpin widely produced throughout the body, has vasodilatory, anti-angiogenic, anti-oxidant, and anti-inflammatory effects. Effects of diabetes and its vascular complications on serum kallistatin levels are unknown. METHODS: Serum kallistatin was quantified by ELISA in a cross-sectional study of 116 Type 1 diabetic patients (including 50 with and 66 without complications) and 29 non-diabetic controls, and related to clinical status and measures of oxidative stress and inflammation. RESULTS: Kallistatin levels (mean(SD)) were increased in diabetic vs. control subjects (12.6(4.2) vs. 10.3(2.8) μg/ml, p = 0.007), and differed between diabetic patients with complications (13.4(4.9) μg/ml), complication-free patients (12.1(3.7) μg/ml), and controls; ANOVA, p = 0.007. Levels were higher in diabetic patients with complications vs. controls, p = 0.01, but did not differ between complication-free diabetic patients and controls, p > 0.05. On univariate analyses, in diabetes, kallistatin correlated with renal dysfunction (cystatin C, r = 0.28, p = 0.004; urinary albumin/creatinine, r = 0.34, p = 0.001; serum creatinine, r = 0.23, p = 0.01; serum urea, r = 0.33, p = 0.001; GFR, r = -0.25, p = 0.009), total cholesterol (r = 0.28, p = 0.004); LDL-cholesterol (r = 0.21, p = 0.03); gamma-glutamyltransferase (GGT) (r = 0.27, p = 0.04), and small artery elasticity, r = -0.23, p = 0.02, but not with HbA1c, other lipids, oxidative stress or inflammation. In diabetes, geometric mean (95%CI) kallistatin levels adjusted for covariates, including renal dysfunction, were higher in those with vs. without hypertension (13.6 (12.3-14.9) vs. 11.8 (10.5-13.0) μg/ml, p = 0.03). Statistically independent determinants of kallistatin levels in diabetes were age, serum urea, total cholesterol, SAE and GGT, adjusted r2 = 0.24, p < 0.00001. CONCLUSIONS: Serum kallistatin levels are increased in Type 1 diabetic patients with microvascular complications and with hypertension, and correlate with renal and vascular dysfunction.
The devil is in the detail - a multifactorial intervention to reduce blood pressure in coexisting diabetes and chronic kidney disease: a single blind, randomized controlled trial
BACKGROUND: About 30-60% of individuals are non-adherent to their prescribed medications and this risk increases as the number of prescribed medications increases. This paper outlines the development of a consumer-centred Medicine Self-Management Intervention (MESMI), designed to improve blood pressure control and medication adherence in consumers with diabetes and chronic kidney disease recruited from specialist outpatients' clinics. METHODS: We developed a multifactorial intervention consisting of Self Blood Pressure Monitoring (SBPM), medication review, a twenty-minute interactive Digital Versatile Disc (DVD), and follow-up support telephone calls to help consumers improve their blood pressure control and take their medications as prescribed. The intervention is novel in that it has been developed from analysis of consumer and health professional views, and includes consumer video exemplars in the DVD. The primary outcome measure was a drop of 3-6 mmHg systolic blood pressure at three months after completion of the intervention. Secondary outcome measures included: assessment of medication adherence, medication self-efficacy and general wellbeing. Consumers' adherence to their prescribed medications was measured by manual pill count, self-report of medication adherence, and surrogate biochemical markers of disease control. DISCUSSION: The management of complex health problems is an increasing component of health care practice, and requires interventions that improve patient outcomes. We describe the preparatory work and baseline data of a single blind, randomized controlled trial involving consumers requiring cross-specialty care with a follow-up period extending to 12 months post-baseline. TRIAL REGISTRATION: The trial was registered with the Australian and New Zealand Clinical Trials Register (ACTRN12607000044426).
Unaccustomed Eccentric Contractions Impair Plasma K+ Regulation in the Absence of Changes in Muscle Na+, K+- ATPase Content
(PUBLIC LIBRARY SCIENCE, 2014-06-24)
The Na+,K+-ATPase (NKA) plays a fundamental role in the regulation of skeletal muscle membrane Na+ and K+ gradients, excitability and fatigue during repeated intense contractions. Many studies have investigated the effects of acute concentric exercise on K+ regulation and skeletal muscle NKA, but almost nothing is known about the effects of repeated eccentric contractions. We therefore investigated the effects of unaccustomed maximal eccentric knee extensor contractions on K+ regulation during exercise, peak knee extensor muscle torque, and vastus lateralis muscle NKA content and 3-O-MFPase activity. Torque measurements, muscle biopsies, and venous blood samples were taken before, during and up to 7 days following the contractions in six healthy adults. Eccentric contractions reduced peak isometric muscle torque immediately post-exercise by 26±11% and serum creatine kinase concentration peaked 24 h post-exercise at 339±90 IU/L. During eccentric contractions, plasma [K+] rose during Set 1 and remained elevated at ∼4.9 mM during sets 4-10; this was despite a decline in work output by Set 4, which fell by 18.9% at set 10. The rise in plasma [K+] x work(-1) ratio was elevated over Set 2 from Set 4- Set 10. Eccentric contractions had no effect on muscle NKA content or maximal in-vitro 3-O-MFPase activity immediately post- or up to 7 d post-exercise. The sustained elevation in plasma [K+] despite a decrease in work performed by the knee extensor muscles suggests an impairment in K+ regulation during maximal eccentric contractions, possibly due to increased plasma membrane permeability or to excitation-contraction uncoupling.
Pooled genome wide association detects association upstream of FCRL3 with Graves' disease
BACKGROUND: Graves' disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves' disease and it is therefore likely that these can be identified by genome wide association studies. This study aimed to determine if a genome wide association study, using a pooling methodology, could detect genomic loci associated with Graves' disease. RESULTS: Nineteen of the top ranking single nucleotide polymorphisms including HLA-DQA1 and C6orf10, were clustered within the Major Histo-compatibility Complex region on chromosome 6p21, with rs1613056 reaching genome wide significance (p = 5 × 10-8). Technical validation of top ranking non-Major Histo-compatablity complex single nucleotide polymorphisms with individual genotyping in the discovery cohort revealed four single nucleotide polymorphisms with p ≤ 10-4. Rs17676303 on chromosome 1q23.1, located upstream of FCRL3, showed evidence of association with Graves' disease across the discovery, replication and combined cohorts. A second single nucleotide polymorphism rs9644119 downstream of DPYSL2 showed some evidence of association supported by finding in the replication cohort that warrants further study. CONCLUSIONS: Pooled genome wide association study identified a genetic variant upstream of FCRL3 as a susceptibility locus for Graves' disease in addition to those identified in the Major Histo-compatibility Complex. A second locus downstream of DPYSL2 is potentially a novel genetic variant in Graves' disease that requires further confirmation.