Surgery (Austin & Northern Health) - Research Publications
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ItemNo Preview AvailableDevelopment of virus-like particles with inbuilt immunostimulatory properties as vaccine candidates(FRONTIERS MEDIA SA, 2023-06-07)The development of virus-like particle (VLP) based vaccines for human papillomavirus, hepatitis B and hepatitis E viruses represented a breakthrough in vaccine development. However, for dengue and COVID-19, technical complications, such as an incomplete understanding of the requirements for protective immunity, but also limitations in processes to manufacture VLP vaccines for enveloped viruses to large scale, have hampered VLP vaccine development. Selecting the right adjuvant is also an important consideration to ensure that a VLP vaccine induces protective antibody and T cell responses. For diseases like COVID-19 and dengue fever caused by RNA viruses that exist as families of viral variants with the potential to escape vaccine-induced immunity, the development of more efficacious vaccines is also necessary. Here, we describe the development and characterisation of novel VLP vaccine candidates using SARS-CoV-2 and dengue virus (DENV), containing the major viral structural proteins, as protypes for a novel approach to produce VLP vaccines. The VLPs were characterised by Western immunoblot, enzyme immunoassay, electron and atomic force microscopy, and in vitro and in vivo immunogenicity studies. Microscopy techniques showed proteins self-assemble to form VLPs authentic to native viruses. The inclusion of the glycolipid adjuvant, α-galactosylceramide (α-GalCer) in the vaccine formulation led to high levels of natural killer T (NKT) cell stimulation in vitro, and strong antibody and memory CD8+ T cell responses in vivo, demonstrated with SARS-CoV-2, hepatitis C virus (HCV) and DEN VLPs. This study shows our unique vaccine formulation presents a promising, and much needed, new vaccine platform in the fight against infections caused by enveloped RNA viruses.
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ItemNo Preview AvailablePoint-of-care detection of fibrosis in liver transplant surgery using near-infrared spectroscopy and machine learning.(Wiley, 2023-11)INTRODUCTION: Visual assessment and imaging of the donor liver are inaccurate in predicting fibrosis and remain surrogates for histopathology. We demonstrate that 3-s scans using a handheld near-infrared-spectroscopy (NIRS) instrument can identify and quantify fibrosis in fresh human liver samples. METHODS: We undertook NIRS scans on 107 samples from 27 patients, 88 from 23 patients with liver disease, and 19 from four organ donors. RESULTS: Liver disease patients had a median immature fibrosis of 40% (interquartile range [IQR] 20-60) and mature fibrosis of 30% (10%-50%) on histopathology. The organ donor livers had a median fibrosis (both mature and immature) of 10% (IQR 5%-15%). Using machine learning, this study detected presence of cirrhosis and METAVIR grade of fibrosis with a classification accuracy of 96.3% and 97.2%, precision of 96.3% and 97.0%, recall of 96.3% and 97.2%, specificity of 95.4% and 98.0% and area under receiver operator curve of 0.977 and 0.999, respectively. Using partial-least square regression machine learning, this study predicted the percentage of both immature (R 2 = 0.842) and mature (R 2 = 0.837) with a low margin of error (root mean square of error of 9.76% and 7.96%, respectively). CONCLUSION: This study demonstrates that a point-of-care NIRS instrument can accurately detect, quantify and classify liver fibrosis using machine learning.
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ItemNo Preview AvailableDetermination of "borderline resectable" pancreatic cancer - A global assessment of 30 shades of grey.(Elsevier BV, 2023-11)BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. Accurate preoperative assessment using computed tomography (CT) to determine resectability is crucial in ensuring patients are offered the most appropriate therapeutic strategy. Despite the use of classification guidelines, any interobserver variability between reviewing surgeons and radiologists may confound decisions influencing patient treatment pathways. METHODS: In this multicentre observational study, an international group of 96 clinicians (42 hepatopancreatobiliary surgeons and 54 radiologists) were surveyed and asked to report 30 pancreatic CT scans of pancreatic cancer deemed borderline at respective multidisciplinary meetings (MDM). The degree of interobserver agreement in resectability among radiologists and surgeons was assessed and subgroup regression analysis was performed. RESULTS: Interobserver variability between reviewers was high with no unanimous agreement. Overall interobserver agreement was fair with a kappa value of 0.32 with a higher rate of agreement among radiologists over surgeons. CONCLUSION: Interobserver variability among radiologists and surgeons globally is high, calling into question the consistency of clinical decision making for patients with PDAC and suggesting that central review may be required for studies of neoadjuvant or adjuvant approaches in future as well as ongoing quality control initiatives, even amongst experts in the field.
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ItemNo Preview AvailableThe Dedicated Imaging Post-Prostatectomy for Enhanced Radiotherapy outcomes (DIPPER) trial protocol: a multicentre, randomised trial of salvage radiotherapy versus surveillance for low-risk biochemical recurrence after radical prostatectomy(WILEY, 2023-08-21)BACKGROUND: Salvage radiation therapy (SRT) and surveillance for low-risk prostate-specific antigen (PSA) recurrence have competing risks and benefits. The efficacy of early SRT to the prostate bed with or without pelvic lymph nodes compared to surveillance in patients with PSA recurrence after radical prostatectomy and no identifiable recurrent disease evident on prostate specific membrane antigen-positron emission tomography/computer tomography (PSMA-PET/CT) is unknown. STUDY DESIGN: The Dedicated Imaging Post-Prostatectomy for Enhanced Radiotherapy outcomes (DIPPER) is an open-label, multicentre, randomised Phase II trial. ENDPOINTS: The primary endpoint is 3-year event-free survival, with events comprising one of PSA recurrence (PSA ≥0.2 ng/mL higher than baseline), radiological evidence of metastatic disease, or initiation of systemic or other salvage treatments. Secondary endpoints include patient-reported outcomes, treatment patterns, participant perceptions, and cost-effectiveness. ELIGIBILITY CRITERIA: Eligible participants have PSA recurrence of prostate cancer after radical prostatectomy, defined by serum PSA level of 0.2-0.5 ng/mL, deemed low risk according to modified European Association of Urology biochemical recurrence risk criteria (International Society for Urological Pathology Grade Group ≤2, PSA doubling time >12 months), with no definite/probable recurrent prostate cancer on PSMA-PET/CT. PATIENTS AND METHODS: A total of 100 participants will be recruited from five Australian centres and randomised 1:1 to SRT or surveillance. Participants will undergo 6-monthly clinical evaluation for up to 36 months. Androgen-deprivation therapy is not permissible. Enrolment commenced May 2023. TRIAL REGISTRATION: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN: ACTRN12622001478707).
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ItemNo Preview AvailableScaphoid, lunate and capitate kinematics in the normal and ligament deficient wrist: A bi-plane X-ray fluoroscopy study(ELSEVIER SCI LTD, 2023-09)The ligamentous structures of the wrist stabilise and constrain the interactions of the carpal bones during active wrist motion; however, the three-dimensional translations and rotations of the scaphoid, lunate and capitate in the normal and ligament deficient wrist during planar and oblique wrist motions remain poorly understood. This study employed a computer-controlled simulator to replicate physiological wrist motion by dynamic muscle force application, while carpal kinematics were simultaneously measured using bi-plane x-ray fluoroscopy. The aim was to quantify carpal kinematics in the native wrist and after sequential sectioning of the scapholunate interosseous ligament (SLIL) and secondary scapholunate ligament structures. Seven fresh-frozen cadaveric wrist specimens were harvested, and cycles of flexion-extension, radial-ulnar deviation and dart-thrower's motion were simulated. The results showed significant rotational and translational changes to these carpal bones in all stages of disruptions to the supporting ligaments (p < 0.05). Specifically, following the disruption of the dorsal SLIL (Stage II), the scaphoid became significantly more flexed, ulnarly deviated, and pronated relative to the radius, whereas the lunate became more extended, supinated and volarly translated (p < 0.05). Sectioning of the dorsal intercarpal (DIC), dorsal radiocarpal (DRC), and scaphotrapeziotrapezoid (STT) ligaments (Stage IV) caused the scaphoid to collapse further into flexion, ulnar deviation, and pronation. These findings highlight the importance of all the ligamentous attachments that relate to the stability of the scapholunate joint, but more importantly, the dorsal SLIL in maintaining scapholunate stability, and the preservation of the attachments of the DIC and DRC ligaments during dorsal surgical approaches. The findings will be useful in diagnosing wrist pathology and in surgical planning.
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ItemNon-beneficial resuscitation during inhospital cardiac arrests in a metropolitan teaching hospital(WILEY, 2023-05)BACKGROUND: There is increasing recognition that a proportion of hospitalised patients receive non-beneficial resuscitation, with the potential to cause harm. AIM: To describe the prevalence of non-beneficial resuscitation attempts in hospitalised patients and identify interventions that could be used to reduce these events. METHODS: A retrospective analysis was conducted of all adult inhospital cardiac arrests (IHCA) receiving cardiopulmonary resuscitation (CPR) in a teaching hospital over 9 years. Demographics and arrest characteristics were obtained from a prospectively collected database. Non-beneficial CPR was defined as CPR being administered to patients who had a current not-for-resuscitation (NFR) order in place or who had a NFR order enacted on a previous hospital admission. Further antecedent factors and resuscitation characteristics were collected for these patients. RESULTS: There were 257 IHCA, of which 115 (44.7%) occurred on general wards, with 19.8% of all patients surviving to discharge home. There were 39 (15.2%) instances of non-beneficial CPR, of which 28 (72%) of 39 occurred in unmonitored patients on the ward comprising nearly one-quarter (28/115) of all arrests in this patient group. A specialist had reviewed 30 (76.9%) of 39 of these patients, and 33.3% (13/39) had a medical emergency team (MET) review prior to their arrest. CONCLUSIONS: Over one in seven resuscitation attempts were non-beneficial. MET reviews and specialist ward rounds provide opportunities to improve the documentation and visibility of NFR status.
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ItemEffects of aromatase inhibitor therapy on visceral adipose tissue area and cardiometabolic health in postmenopausal women with early and locally advanced breast cancer(WILEY, 2023-02)OBJECTIVE: Aromatase inhibitor (AI) therapy provides oncological benefits in postmenopausal women with oestrogen receptor-positive breast cancer. However, AI treatment has been associated with increased cardiovascular risk. In nonbreast cancer populations, experimentally induced low oestrogen states and natural transition to menopause have been associated with increases in visceral adipose tissue (VAT), a known surrogate marker for cardiometabolic risk. Given that AI treatment blocks oestradiol production, we hypothesized that AI treatment would increase VAT. METHODS: We conducted a prospective 12-month cohort study of 52 postmenopausal women newly initiating AI treatment (median age: 64.5 years) and 52 women with breast pathology not requiring endocrine therapy (median age: 63.5 years). VAT area and other body composition parameters were measured at baseline, 6 months and 12 months using dual X-ray absorptiometry. Other risk markers of cardiometabolic health were also assessed. RESULTS: In women initiating AI treatment, there was no statistically significant difference in VAT area after 12 months when compared to controls, with a mean adjusted difference of -5.00 cm2 (-16.9, 6.91), p = .55. Moreover, changes in total fat mass, lean mass, subcutaneous adipose tissue area, hepatic steatosis and measures in endothelial function were also not statistically different between groups after 12 months. Findings were similar after adjustments for activity levels and coronavirus disease 2019 lockdown duration. CONCLUSIONS: These data provide reassurance that over the initial 12 months of AI therapy, AI treatment is not associated with metabolically adverse changes in body composition, hepatic steatosis or vascular reactivity. The impact of extended AI therapy on cardiometabolic health requires further study.
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ItemUse and outcomes from neoadjuvant chemotherapy in borderline resectable pancreatic ductal adenocarcinoma in an Australasian population(WILEY, 2023-02-01)Background: Use of neoadjuvant (NA) chemotherapy is recommended when pancreatic ductal adenocarcinoma (PDAC) is borderline resectable. Method: A retrospective analysis of consecutive patients with localized PDAC between January 2016 and March 2019 within the Australasian Pancreatic Cancer Registry (PURPLE, Pancreatic cancer: Understanding Routine Practice and Lifting End results) was performed. Clinicopathological characteristics, treatment, and outcome were analyzed. Overall survival (OS) comparison was performed using log-rank model and Kaplan–Meier analysis. Results: The PURPLE database included 754 cases with localised PDAC, including 148 (20%) cases with borderline resectable pancreatic cancer (BRPC). Of the 148 BRPC patients, 44 (30%) underwent immediate surgery, 80 (54%) received NA chemotherapy, and 24 (16%) were inoperable. The median age of NA therapy patients was 63 years and FOLFIRINOX (53%) was more often used as NA therapy than gemcitabine/nab-paclitaxel (31%). Patients who received FOLFIRINOX were younger than those who received gemcitabine/nab-paclitaxel (60 years vs. 67 years, p =.01). Surgery was performed in 54% (43 of 80) of BRPC patients receiving NA chemotherapy, with 53% (16 of 30) achieving R0 resections. BRPC patients undergoing surgery had a median OS of 30 months, and 38% (9 of 24) achieved R0 resection. NA chemotherapy patients had a median OS of 20 months, improving to 24 months versus 10 months for patients receiving FOLFIRINOX compared to gemcitabine/nab-paclitaxel (Hazard Ratio (HR).3, p <.0001). Conclusions: NA chemotherapy use in BRPC is increasing in Australia. One half of patients receiving NA chemotherapy proceed to curative resection, with 53% achieving R0 resections. Patients receiving Infusional 5-flurouracil, Irinotecan and Oxaliplatin (FOLIRINOX) had increased survival than gemcitabine/nab-paclitaxel. Treatment strategies are being explored in the MASTERPLAN and DYNAMIC-Pancreas trials.
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ItemTemporal changes in the epidemiology of sepsis-related intensive care admissions from the emergency department in Australia and New Zealand(WILEY, 2022-07-03)OBJECTIVES: The Australasian Resuscitation in Sepsis Evaluation (ARISE) study researched septic shock treatment within EDs. This study aims to evaluate whether: (i) conduct of the ARISE study was associated with changes in epidemiology and care for adults (≥18 years) admitted from EDs to ICUs with sepsis in Australia and New Zealand; and (ii) such changes differed among 45 ARISE trial hospitals compared with 120 non-trial hospitals. METHODS: Retrospective study using interrupted time series analysis in three time periods; 'Pre-ARISE' (January 1997 to December 2007), 'During ARISE' (January 2008 to May 2014) and 'Post-ARISE' (June 2014 to December 2017) using data from the Australian and New Zealand Intensive Care Society Adult Patient Database. RESULTS: Over 21 years there were 54 121 ICU admissions from the ED with sepsis; which increased from 8.1% to 16.4%; 54.6% male, median (interquartile range) age 66 (53-76) years. In the pre-ARISE period, pre-ICU ED length of stay (LOS) decreased in trial hospitals but increased in non-trial hospitals (P = 0.174). During the ARISE study, pre-ICU ED LOS declined more in trial hospitals (P = 0.039) as did the frequency of mechanical ventilation in the first 24 h (P = 0.003). However, ICU and hospital LOS, in-hospital mortality and risk of death declined similarly in both trial and non-trial hospitals. CONCLUSIONS: Sepsis-related admissions increased from 8.1% to 16.4%. During the ARISE study, there was more rapid ICU admission and decreased early ventilation. However, these changes were not sustained nor associated with decreased risk of death or duration of hospitalisation.