Surgery (Austin & Northern Health) - Research Publications

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    Evaluating sex as a predictive marker for response to bevacizumab in metastatic colorectal carcinoma: Pooled analysis of 3,369 patients in the ARCAD database.
    Margalit, O ; Harmsen, WS ; Shacham-Shmueli, E ; Voss, MM ; Boursi, B ; Wagner, AD ; Cohen, R ; Olswold, CL ; Saltz, LB ; Goldstein, DA ; Hurwitz, H ; Tebbutt, NC ; Kabbinavar, FF ; Adams, RA ; Chibaudel, B ; Grothey, A ; Yoshino, T ; Zalcberg, J ; de Gramont, A ; Shi, Q ; Lenz, H-J (Elsevier BV, 2023-01)
    BACKGROUND: Previous studies suggest a possible sex-specific response to bevacizumab in metastatic colorectal carcinoma (mCRC), showing a benefit in males, while the effect in females is less significant. METHODS: Data from 3369 patients with mCRC enrolled on four first-line randomised trials testing chemotherapy with or without bevacizumab (2000-2007) were pooled. Association between sex and progression-free survival and overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction effect between sex and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut point of 60 years to evaluate the possible role of menopausal-related effects. RESULTS: Bevacizumab was associated with an improved median OS in males and females, with a 2.3- and 0.6-months benefit, respectively. Stratified by age, bevacizumab resulted in improved OS in males at both age categories. In females at or above the age of 60 (n = 731), bevacizumab resulted in improved OS. However, in females below the age of 60 (n = 634), OS benefit did not reach statistical significance (adjusted hazard ratio = 0.94, 95% confidence interval 0.74-1.20). CONCLUSIONS: Our results confirmed the OS benefit from the addition of bevacizumab to first-line chemotherapy in mCRC in both sexes. Among females, the benefit was less than 1 month. For females under the age of 60, there was no survival benefit. These findings could be used to relieve financial toxicity or be redistributed within healthcare systems for other health-related purposes.
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    A novel two-stage approach to the treatment of renal cell carcinoma with intra-cardiac tumour extension and Budd-Chiari syndrome
    Perini, MV ; Ischia, J ; Woon, D ; Bhaskar, J ; Starkey, G ; Qi, S ; Wetherell, D ; Ellard, L ; McCall, P ; Miles, LF ; Seevanayagam, S (WILEY, 2023-12-15)
    OBJECTIVE: To present the early results of a new technique for the treatment of renal cell carcinoma with intra-cardiac tumour extension and Budd-Chiari syndrome. PATIENTS AND METHODS: The first stage involves transdiaphragmatic debulking of the right heart, inferior vena cava (IVC) and hepatic veins via median sternotomy, followed by a purse-string suture placed in the IVC below the hepatic veins. The second stage is performed separately and involves en bloc resection of the affected kidney, and IVC and vascular reconstruction via an abdominal incision. RESULTS: Three of five patients presented with clinical Budd-Chiari syndrome; two had radiological features only. The median time between surgical procedures was 12 days (IQR 13 days). Four of the five patients had a R0 resection. While all five patients successfully completed both operative stages, one patient died 22 days after the second stage. Of the remaining four, all survive with no disease recurrence. CONCLUSION: While we continue to compile longer-term data for a larger follow-up series, these preliminary findings show the feasibility of this technique and support the development of this programme of surgery.
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    Breaches of pre-medical emergency team call criteria in an Australian hospital.
    Jones, D ; Kishore, K ; Eastwood, G ; Sprogis, SK ; Glassford, NJ (Elsevier BV, 2023-12)
    OBJECTIVES AND OUTCOMES: To evaluate the 24hrs before medical emergency team (MET) calls to examine: 1) the frequency, nature, and timing of pre-MET criteria breaches; 2) differences in characteristics and outcomes between patients who did and didn't experience pre-MET breaches. DESIGN: Retrospective observational study November 2020-June 2021. SETTING: Tertiary referral Australian hospital. PARTICIPANTS: Adults (≥18 years) experiencing MET calls. RESULTS: Breaches in pre-MET criteria occurred prior to 1886/2255 (83.6%) MET calls, and 1038/1281 (81.0%) of the first MET calls. Patients with pre-MET breaches were older (median [IQR] 72 [57-81] vs 66 [56-77] yrs), more likely to be admitted from home (87.8% vs 81.9%) and via the emergency department (73.0% vs 50.2%), but less likely to be for full resuscitation after (67.3% vs 76.5%) the MET. The three most common pre-MET breaches were low SpO2 (48.0%), high pulse rate (39.8%), and low systolic blood pressure (29.0%) which were present for a median (IQR) of 15.4 (7.5-20.8), 13.2 (4.3-21.0), and 12.6 (3.5-20.1) hrs before the MET call, respectively. Patients with pre-MET breaches were more likely to need intensive care admission within 24 h (15.6 vs 11.9%), have repeat MET calls (33.3 vs 24.7%), and die in hospital (15.8 vs 9.9%). CONCLUSIONS: Four-fifths of MET calls were preceded by pre-MET criteria breaches, which were present for many hours. Such patients were older, had more limits of treatment, and experienced worse outcomes. There is a need to improve goals of care documentation and pre-MET management of clinical deterioration.
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    Development of virus-like particles with inbuilt immunostimulatory properties as vaccine candidates
    Collett, S ; Earnest, L ; Carrera Montoya, J ; Edeling, MAA ; Yap, A ; Wong, CY ; Christiansen, D ; Roberts, J ; Mumford, J ; Lecouturier, V ; Pavot, V ; Marco, S ; Loi, JK ; Simmons, C ; Gulab, SAA ; Mackenzie, JMM ; Elbourne, A ; Ramsland, PAA ; Cameron, G ; Hans, D ; Godfrey, DII ; Torresi, J (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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    Point-of-care detection of fibrosis in liver transplant surgery using near-infrared spectroscopy and machine learning
    Sharma, VJ ; Adegoke, JA ; Fasulakis, M ; Green, A ; Goh, SK ; Peng, X ; Liu, Y ; Jackett, L ; Vago, A ; Poon, EKW ; Starkey, G ; Moshfegh, S ; Muthya, A ; D'Costa, R ; James, F ; Gordon, CL ; Jones, R ; Afara, IO ; Wood, BR ; Raman, J (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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    Determination of "borderline resectable" pancreatic cancer - A global assessment of 30 shades of grey.
    Badgery, HE ; Muhlen-Schulte, T ; Zalcberg, JR ; D'souza, B ; Gerstenmaier, JF ; Pickett, C ; Samra, J ; Croagh, D ; Pancreatic Cancer Image Biobank Authorship Group, (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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    The 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
    Roberts, MJ ; Conduit, C ; Davis, ID ; Effeney, RM ; Williams, S ; Martin, JM ; Hofman, MS ; Hruby, G ; Eapen, R ; Gianacas, C ; Papa, N ; Lourenco, RDA ; Dhillon, HM ; Allen, R ; Fontela, A ; Kaur, B ; Emmett, L (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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    Scaphoid, lunate and capitate kinematics in the normal and ligament deficient wrist: A bi-plane X-ray fluoroscopy study
    Zhang, X ; Tham, S ; Ek, ET ; Mccombe, D ; Ackland, DC (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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    Non-beneficial resuscitation during inhospital cardiac arrests in a metropolitan teaching hospital
    Crosbie, D ; Ghosh, A ; Van Ekeren, N ; Dowling, M ; Hayes, B ; Cross, A ; Jones, D (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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    Effects of aromatase inhibitor therapy on visceral adipose tissue area and cardiometabolic health in postmenopausal women with early and locally advanced breast cancer
    Cheung, Y-MM ; Hoermann, R ; Van, K ; Wu, D ; Healy, J ; Chao, M ; White, S ; Yeo, B ; Zajac, J ; Grossmann, M (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.