Sir Charles Gairdner Hospital
Recent publications
The process of tumorigenesis leaves a series of indelible genetic changes in tumor cells, that when expressed, have the potential to be tumor-specific immune targets. Neoantigen vaccines that capitalize on this potential immunogenicity have shown efficacy in preclinical models and have now entered clinical trials. Here we discuss the status of personalized neoantigen vaccines and the current major challenges to this nascent field. In particular, we focus on the types of antigens that can be targeted by vaccination and on the role that preexisting immunosuppression, and in particular T-cell exhaustion, will play in the development of effective cancer vaccines.
Background Participant enrolment, assessment and/or delivery of intervention in many clinical trials during the COVID-19 pandemic were severely impacted by public health measures limiting physical contact. This report describes the lessons learned in completing a repeated measures cohort study involving suspected and confirmed COVID-19 survivors at three sites in Perth, Western Australia. Main body An observational analysis of the conduct and data completeness results of the LATER-19 trial. People with COVID19 symptoms who were tested between February and November 2020 were recruited. In both those who tested positive and those who tested negative (control group) for COVID19, data on physical function and mental health were collected at two time points up to eight months after COVID19 testing. Recruitment of the controls was targeted from hospital records for comparison, it was balanced for age and sex and for the non-hospitalised group also comorbidities. A sample of 344 participants was recruited: 155 (45.1%) COVID-19 positive. Taking the research design and environmental adaptations into account, we recorded > 90% participant engagement during the trial. Of the 637 planned assessments, objective measures were completed on 602 (94.5%) occasions; 543 (90.2%) were on-site and 59 (9.8%) were remote. A total of 577 (90.6%) mental health/symptoms surveys, 569 (89.3%) 1-min sit-to-stand tests, and 520 (81.6%) handgrip strength tests were completed. Conclusion The sample size and high completion rate of planned assessments during the LATER-19 trial potentially increases the contextual, groupwise generalisability of the results. The results demonstrate the effectiveness of a simple, rapid, reproducible and adaptable battery of assessments, leveraging telehealth and digital solutions. Trial registration number Australian and New Zealand Clinical Trial Registration (ANZCTR): ACTRN12621001067864 .
The reported frequency and types of adverse events following initial vaccination and revaccination with Bacille Calmette-Guérin (BCG) varies worldwide. Using active surveillance in a randomised controlled trial of BCG vaccination (the BRACE trial), we determined the incidence and risk factors for the development of BCG injection site abscess and regional lymphadenopathy. Injection site abscess occurred in 3% of 1387 BCG-vaccinated participants; the majority (34/41, 83%) resolved without treatment. The rate was higher in BCG-revaccinated participants (OR 3.6, 95% CI 1.7–7.5), in whom abscess onset was also earlier (median 16 vs. 27 days, p = 0.008). No participant with an abscess had a positive interferon-gamma release assay. Regional lymphadenopathy occurred in 48/1387 (3%) of BCG-vaccinated participants, with a higher rate in revaccinated participants (OR 2.1, 95% CI 1.1–3.9). BCG-associated lymphadenopathy, but not injection site abscess, was influenced by age and sex. A previous positive tuberculin skin test was not associated with local reactions. The increased risk of injection site abscess or lymphadenopathy following BCG revaccination is relevant to BCG vaccination policy in an era when BCG is increasingly being considered for novel applications.
Background: Several million inhalers are used annually by the millions of Australians with respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD). Prescriptions in primary care tend to be for pressurised metered-dose inhalers (pMDIs), and consumers can purchase pMDI salbutamol over the counter. These inhalers contain potent greenhouse gases. Objective: This article briefly summarises the scale of the problem caused by pMDI propellants before discussing options available to general practitioners to mitigate their environmental impact while maintaining high-quality patient care. Discussion: The best inhaler for any patient is one that they can and will use as prescribed. However, for many people with chronic airways diseases, the environmental impact of their inhalers can be considered when doctors make prescribing choices, at least until newer, more climate-friendly propellants are introduced. Other aspects of asthma and COPD management that minimise environmental impact are also important.
The prevalence of keratoconus (Belin/Ambrόsio Enhanced Ectasia Display Score ≥2.6 on Scheimpflug imaging) in a longitudinal, community cohort study from Western Australia was 3.4% (n=26/755). Keratoconus incidence over an 8-year period was 2.2% (n=15/669).
Insulinomas are rare insulin-secreting tumors of pancreatic origin that cause hypoglycemia and can be associated with multiple endocrine neoplasia type 1 (MEN1). Whilst rare, they are the most common cause of hypoglycemia related to endogenous hyperinsulinism. A 28 year old woman with known MEN1 presented with postprandial hypoglycemia in second trimester of pregnancy. Prior to her presentation she was known to have several pancreatic neuroendocrine tumors which had been stable on serial imaging, but no history of hypoglycemia. She was managed with dietary intervention during pregnancy and gave birth to a healthy baby at 37 weeks gestation. After pregnancy, hypoglycemia initially resolved, but then recurred at 8 months postpartum. Magnetic resonance imaging showed several pancreatic neoplasms with the largest lesion measuring 29 mm in the pancreatic tail, unchanged from previous imaging. After localization with a selective arterial calcium stimulation test, she underwent successful distal pancreatectomy with resolution of symptoms. This case is unusual in that her initial presentation was during pregnancy, she had predominantly postprandial rather than fasting hypoglycemia and her symptoms remitted for several months after delivery. Key learning points are to have a low index of suspicion for an insulinoma when there is a history of MEN1 and the need for a pragmatic approach to diagnosis and treatment during pregnancy.
Patients with comorbid asthma-obesity experience greater disease severity and are less responsive to therapy. We have previously reported adipose tissue within the airway wall which positively correlated with body mass index. Accumulation of biologically active adipose tissue may result in the local release of adipokines and disrupt large and small airway function depending on its anatomical distribution. This study therefore characterised airway-associated adipose tissue distribution, lipid composition, and adipokine activity in a porcine model. Airway segments were systematically dissected from different locations of the bronchial tree in inflation-fixed lungs. Cryosections were stained with H&E for airway morphology, oil red O to distinguish adipose tissue and Nile blue A for lipid subtype delineation. Excised airway-associated adipose tissue was cultured for 72 h to quantify adipokine release using immunoassays. Results showed that airway-associated adipose tissue extended throughout the bronchial tree and occupied an area proportionally similar to airway smooth muscle within the wall area. Lipid composition consisted of pure neutral lipids (61.7±3.5 %), a mixture of neutral and acidic lipids (36.3±3.4 %), or pure acidic lipids (2.0±0.8 %). Following tissue culture, there was rapid release of IFN-γ, IL-1β and TNF-α at 12 h. Maximum IL-4 and IL-10 release was at 24 and 48 h, and peak leptin release occurred between 48 and 72 h. These data extend previous findings and demonstrate that airway-associated adipose tissue is prevalent and biologically active within the bronchial tree, providing a local source of adipokines that may be a contributing factor in airway disease.
Waldenström Macroglobulinaemia (WM) is an indolent B‐cell malignancy characterised by the presence of IgM paraprotein, bone marrow infiltration by clonal small B lymphocytes with plasmacytic differentiation, and the MYD88 L265P mutation in >90% of cases. Traditionally, WM has been treated with chemoimmunotherapy. Recent trials have demonstrated the efficacy and safety of Bruton's Tyrosine Kinase inhibitors (BTKi) in WM, both as monotherapy and in combination with other drugs. There is emerging evidence on use of other agents including BCL2 inhibitors and on treatment of rare presentations of WM. In this update, the Medical and Scientific Advisory Group ofMyeloma Australia review available evidence on treatment of WM since the last publication in 2017 and provide specific recommendations to assist Australian clinicians in the management of this disease. This article is protected by copyright. All rights reserved.
Graves' disease and Hashimoto's disease form part of the spectrum of autoimmune thyroid disease (AITD), to which genetic and environmental factors are recognised contributors. Epigenetics provides a potential link between environmental influences, gene expression and thyroid autoimmunity. DNA methylation (DNAm) is the best studied epigenetic process, and global hypomethylation of leucocyte DNA is reported in several autoimmune disorders. This review summarises current understanding of DNAm in AITD. Targeted DNAm studies of blood samples from AITD patients have reported differential DNAm in the promoter regions of several genes implicated in AITD, including TNF, IFNG, IL2RA, IL6, ICAM1 and PTPN22. In many cases, however, the findings await replication and are unsupported by functional studies to support causal roles in AITD pathogenesis. Furthermore, thyroid hormones affect DNAm, and in many studies confounding by reverse causation has not been considered. Recent studies have shown that DNAm patterns in candidate genes including ITGA6, PRKAA2 and DAPK1 differ between AITD patients from regions with different iodine status, providing a potential mechanism for associations between iodine and AITD. Research focus in the field is moving from candidate gene studies to an epigenome-wide approach. Genome-wide methylation studies of AITD patients have demonstrated multiple differentially methylated positions, including some in immunoregulatory genes such as NOTCH1, HLA-DRB1, TNF and ICAM1. Large, epigenome-wide studies are required to elucidate the pathophysiological role of DNAm in AITD, with the potential to provide novel diagnostic and prognostic biomarkers as well as therapeutic targets.
Ibrutinib is a small molecule inhibitor of Bruton's tyrosine kinase indicated for the treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL). The Named Patient Program in Australia and New Zealand (ANZ NPP) provided access to ibrutinib treatment to 1126 R/R CLL/SLL and 330 R/R MCL patients, prior to Pharmaceutical Benefits Scheme listing. This study aimed to assess the duration of treatment for the ANZ NPP patients, as an indicator of efficacy and tolerability of ibrutinib in the real world. Based on the NPP data, ibrutinib provided a median of 47 months clinical benefit for participants with CLL/SLL and 14 months clinical benefit for those with MCL; outcomes that are consistent with the clinical trial results and further support the well-established efficacy and safety profile of ibrutinib in the real world.
Background: Endovascular thrombectomy (EVT) access in remote areas is limited. Preliminary data suggest that long distance transfers for EVT may be beneficial; however, the magnitude and best imaging strategy at the referring center remains uncertain. We hypothesized that patients transferred >300 miles would benefit from EVT, achieving rates of functional independence (modified Rankin Scale [mRS] score of 0-2) at 3 months similar to those patients treated at the comprehensive stroke center in the randomized EVT extended window trials and that the selection of patients with computed tomography perfusion (CTP) at the referring site would be associated with ordinal shift toward better outcomes on the mRS. Methods: This is a retrospective analysis of patients transferred from 31 referring hospitals >300 miles (measured by the most direct road distance) to 9 comprehensive stroke centers in Australia and New Zealand for EVT consideration (April 2016 through May 2021). Results: There were 131 patients; the median age was 64 [53-74] years and the median baseline National Institutes of Health Stroke Scale score was 16 [12-22]. At baseline, 79 patients (60.3%) had noncontrast CT+CT angiography, 52 (39.7%) also had CTP. At the comprehensive stroke center, 114 (87%) patients underwent cerebral angiography, and 96 (73.3%) proceeded to EVT. At 3 months, 62 patients (48.4%) had an mRS score of 0 to 2 and 81 (63.3%) mRS score of 0 to 3. CTP selection at the referring site was not associated with better ordinal scores on the mRS at 3 months (mRS median of 2 [1-3] versus 3 [1-6] in the patients selected with noncontrast CT+CT angiography, P=0.1). Nevertheless, patients selected with CTP were less likely to have an mRS score of 5 to 6 (odds ratio 0.03 [0.01-0.19]; P<0.01). Conclusions: In selected patients transferred >300 miles, there was a benefit for EVT, with outcomes similar to those treated in the comprehensive stroke center in the EVT extended window trials. Remote hospital CTP selection was not associated with ordinal mRS improvement, but was associated with fewer very poor 3-month outcomes.
BACKGROUND Surgical resection of vertebral hemangiomas in the setting of cord compression can be technically difficult and has the potential for life-threatening hemorrhage. The authors report a case of intraoperative direct intralesional n -butyl-cyanoacrylate embolization for intractable vertebral hemangioma bleeding. OBSERVATIONS A 53-year-old woman presented for repeat surgery of a residual vertebral hemangioma after a previous debulking, laminectomy, and fixation that were without problems with bleeding. The second surgery was complicated by intractable hemorrhage. Bleeding was controlled with direct intralesional n -butyl-cyanoacrylate embolization after fluoroscopy without accompanying endovascular embolization. LESSONS Aggressive vertebral hemangiomas should ideally be managed in centers where transarterial embolization is available. If such centers are not available or there is still intractable intraoperative bleeding despite preoperative embolization, direct intralesional embolization may be considered as a potential salvage technique.
Kidney transplantation is the treatment of choice in patients with end‐stage kidney disease because it confers a significant survival advantage compared to dialysis treatment. This chapter discusses the short‐term medical and surgical complications that can potentially cause allograft failure within one year post kidney transplantation, focusing on the practical approach, investigations, and treatment of these complications. The chapter presents the potential surgical and medical complications occurring in the first 12 months after kidney transplantation. The incidence of ureteric complications after kidney transplantation is estimated at between 2% and 12%, predominantly related to urine leak and obstruction. Acute rejection of the kidney allografts following transplantation continues to be a major impediment to long‐term allograft survival. Delayed graft function is a common complication after kidney transplantation, with the highest incidence observed after donation after circulatory death kidney transplants.
Rationale: Ventilatory defects in asthma are heterogeneous and may represent the distribution of airway smooth muscle (ASM) remodelling. Objectives: To determine the distribution of ASM remodelling in mild-severe asthma. Methods: The ASM area was measured in 9 airway levels in 3 bronchial pathways in cases of nonfatal (n=30) and fatal asthma (n=20) and compared with controls without asthma (n=30). Correlations of ASM area within and between bronchial pathways were calculated. Asthma cases with 12 large and 12 small airways available (n=42) were classified based on the presence or absence of ASM remodelling (>2SD of mean ASM area of controls n=86) in the large or small airways or both. Main measurements and results: ASM remodelling varied widely within and between cases of nonfatal asthma and was more widespread and confluent, and more marked, in fatal cases. There were weak correlations of ASM between levels within the same or separate bronchial pathways however, predictable patterns of remodelling were not observed. Using mean data, 44% of all asthma cases were classified as having no ASM remodelling in either the large or small airways, despite a 3-10 fold increase in the number of airways with ASM remodelling and 81% of asthma cases having ASM remodelling in at least 1 large and small airway. Conclusion: ASM remodelling is related to asthma severity but is heterogenous within and between individuals and may contribute to the heterogenous functional defects observed in asthma. These findings support the need for patient-specific targeting of ASM remodelling.
Survival statistics, estimated using data from national cystic fibrosis (CF) registries, inform the CF community and monitor disease progression. This study aimed to estimate survival among people with CF in Australia and to identify factors associated with survival. This population-based cohort study used prospectively collected data from 23 Australian CF centres participating in the Australian CF Data Registry (ACFDR) from 2005–2020. Period survival analysis was used to calculate median age of survival estimates for each 5-year window from 2005–2009 until 2016–2020. The overall median survival was estimated using the Kaplan–Meier method. Between 2005–2020 the ACFDR followed 4,601 people with CF, noting 516 (11.2%) deaths including 195 following lung transplantation. Out of the total sample, more than half (52.5%) were male and 395 (8.6%) had undergone lung transplantation. Two thirds of people with CF (66.1%) were diagnosed before six weeks of age or by newborn/prenatal screening. The overall median age of survival was estimated as 54.0 years (95% CI: 51.0–57.04). Estimated median survival increased from 48.9 years (95% CI: 44.7–53.5) for people with CF born in 2005–2009, to 56.3 years (95% CI: 51.2–60.4) for those born in 2016–2020. Factors independently associated with reduced survival include receiving a lung transplant, having low FEV1pp and BMI. Median survival estimates are increasing in CF in Australia. This likely reflects multiple factors, including newborn screening, improvement in diagnosis, refinements in CF management and centre-based multidisciplinary care.
Background Dementia is a leading cause of death in developed nations. Despite an often distressing and symptom laden end of life, there are systematic barriers to accessing palliative care in older people dying of dementia. Evidence exists that 70% of people living with severe dementia attend an emergency department (ED) in their last year of life. The aim of this trial is to test whether a Carer End of Life Planning Intervention (CELPI), co-designed by consumers, clinicians and content specialists, improves access to end of life care for older people with severe dementia, using an ED visit as a catalyst for recognising unmet needs and specialist palliative care referral where indicated. Methods A randomised controlled trial (RCT) enrolling at six EDs across three states in Australia will be conducted, enrolling four hundred and forty dyads comprising a person with severe dementia aged ≥ 65 years, and their primary carer. Participants will be randomly allocated to CELPI or the control group. CELPI incorporates a structured carer needs assessment and referral to specialist palliative care services where indicated by patient symptom burden and needs assessment. The primary outcome measure is death of the person with dementia in the carer-nominated preferred location. Secondary outcomes include carer reported quality of life of the person dying of dementia, hospital bed day occupancy in the last 12 months of life, and carer stress. An economic evaluation from the perspective of a health funder will be conducted. Discussion CELPI seeks to support carers and provide optimal end of life care for the person dying of dementia. This trial will provide high level evidence as to the clinical and cost effectiveness of this intervention. Trial registration ACTRN12622000611729 registered 22/04/2022.
Introduction Pleural infection causes significant morbidity and mortality. An important aspect in the treatment of pleural infection is the pharmacokinetics of antibiotics, an area often neglected. Areas covered Pathophysiology of pleural infection and the importance of antibiotic therapy in the treatment of pleural infection are discussed. After reviewing all available literature on pharmacokinetics of antibiotics for pleural infection, the scarcity of data and knowledge gaps are highlighted. Expert Opinion This review aims to heighten awareness of the limited pharmacokinetic data of commonly used antibiotics for pleural infection. It serves to remind clinicians that choice of antibiotics for pleural infection should be based not only on bacterial sensitivity but also adequate delivery of antibiotics to the infected pleural cavity. Antibiotic pharmacokinetics may vary with agents used, pleural thickness and individual characteristics. Consideration must be given to insufficient pleural delivery of systemic antibiotics in patients lacking clinical improvement. Pleural infection research has disproportionately focused on fluid drainage. Optimizing delivery of effective antibiotic therapy to the pleural cavity must be regarded a key priority to progress clinical care. Large comprehensive cohort studies on pharmacokinetic variability are the essential next step. The possibility of intrapleural administration is also an area that warrants additional research.
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429 members
Markus Kuster
  • Orthopaedics
Malgorzata Skorska
  • Radiation Oncology
Suki Gill
  • Radiotherapy
Colin I Tang
  • Radiation Oncology
Chan Yoon Cheah
  • Haematology
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Perth, Australia