Surgery (Austin & Northern Health) - Research Publications
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ItemOnline singing interventions for postnatal depression in times of social isolation: a feasibility study protocol for the SHAPER-PNDO single-arm trial.(Springer Science and Business Media LLC, 2022-07-18)BACKGROUND: Postnatal depression (PND) affects 13% of new mothers, with numbers rising during the COVID-19 pandemic. Despite this prevalence, many women have difficulty with or hesitancy towards accessing pharmacological and/or psychological interventions. Group-based mother-baby activities, however, have a good uptake, with singing improving maternal mental health and the mother-infant relationship. The recent lockdowns highlight the importance of adapting activities to an online platform that is wide-reaching and accessible. AIMS: The SHAPER-PNDO study will primarily analyse the feasibility of a 6-week online singing intervention, Melodies for Mums (M4M), for mothers with PND who are experiencing barriers to treatment. The secondary aim of the SHAPER-PNDO study will be to analyse the clinical efficacy of the 6-week M4M intervention for symptoms of postnatal depression. METHODS: A total of 120 mothers and their babies will be recruited for this single-arm study. All dyads will attend 6 weekly online singing sessions, facilitated by Breathe Arts Health Research. Assessments will be conducted on Zoom at baseline and week 6, with follow-ups at weeks 16 and 32, and will contain interviews for demographics, mental health, and social circumstances, and biological samples will be taken for stress markers. Qualitative interviews will be undertaken to understand the experiences of women attending the sessions and the facilitators delivering them. Finally, data will be collected on recruitment, study uptake and attendance of the programme, participant retention, and acceptability of the intervention. DISCUSSION: The SHAPER-PNDO study will focus on the feasibility, alongside the clinical efficacy, of an online delivery of M4M, available to all mothers with PND. We hope to provide a more accessible, effective treatment option for mothers with PND that can be available both during and outside of the pandemic for mothers who would otherwise struggle to attend in-person sessions, as well as to prepare for a subsequent hybrid RCT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04857593 . Registered retrospectively on 22 April 2021. The first participants were recruited on 27 January 2021, and the trial is ongoing.
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ItemNovel Germline Mutations in a Cohort of Men with Familial Prostate Cancer(MDPI, 2022-08-01)Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4-5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D'Amico intermediate or high risk, comparable to our previously published BRCA2 and BRCAX prostate cancer cohort. HOXB13G84 carriers demonstrated low- to intermediate-risk prostate cancer. In the BRCAX cohort, 53.2% of subjects demonstrated high-risk disease compared with 25% of the PCOR cohort. Conclusions:ATM and CHEK2 germline mutation carriers and the BRCAX (confirmed non-mutation carriers) cohort demonstrated high risk disease compared with the general population. Targeted genetic testing will help identify men at greater risk of prostate-cancer-specific mortality. Data correlating rare variants with clinical phenotype and familial predisposition will strengthen the clinical validity and utility of these results and establish these variants as significant in prostate cancer detection and management.
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ItemModern Cardiac Surgical Outcomes in Nonagenarians: A Multicentre Retrospective Observational Study.(Frontiers Media SA, 2022)Background: There have been multiple recent advancements in the selection, optimisation and management of patients undergoing cardiac surgery. However, there is limited data regarding the outcomes in nonagenarians, despite this cohort being increasingly referred for these interventions. The objective of this study was to describe the patient characteristics, management and outcomes of a cohort of nonagenarians undergoing cardiac surgery receiving contemporary peri-operative care. Methods: After receiving ethics approval, we conducted a retrospective observational study of nonagenarians who had undergone cardiac surgery requiring a classic median sternotomy. All operative indications were included. We excluded patients who underwent transcatheter aortic valve implantation (TAVI), and surgery on the thoracic aorta via an endovascular approach (TEVAR). Patients undergoing TEVAR often have the procedure done under sedation and regional blocks with local anesthetic solution. There is no open incision and these patients do not require cardiopulmonary bypass. We also excluded patients undergoing minimally invasive mitral valve surgery via a videoscope assisted approach. These patients do not have a median sternotomy, have the procedure done via erector spinae block, and often are extubated on table. Data were collected from four hospitals in Victoria, Australia, over an 8-year period (January 2012-December 2019). The primary objective was to assess 6-month mortality in nonagenarian patients undergoing cardiac surgery and to provide a detailed overview of postoperative complications. We hypothesized that cardiac surgery in nonagenarian patients would be associated with a 6-month postoperative mortality <10%. As a secondary outcome, we hypothesized that significant postoperative complications (i.e., Clavien Dindo Grade IIIb or greater) would occur in > 30% of patients. Results: A total of 12,358 adult cardiac surgery patients underwent surgery during the study period, of whom 18 nonagenarians (0.15%) fulfilled inclusion criteria. The median (IQR) [min-max] age was 91.0 years (90.0:91.8) [90-94] and the median body mass index was 25.0 (kg/m2) (22.3:27.0). Comorbidities, polypharmacy, and frailty were common. The median predicted mortality as per EuroSCORE-II was 6.1% (4.1:14.5). There were no cases of intra-operative, in-hospital, or 6-month mortality. One (5.6%) patient experienced two Grade IIIa complications. Three (16.7%) patients experienced Grade IIIb complications. Three (16.7%) patients had an unplanned hospital readmission within 30 days of discharge. The median value for postoperative length of stay was 11.6 days (9.8:17.6). One patient was discharged home and all others were discharged to an inpatient rehabilitation facility. Conclusion: In this selected, contemporary cohort of nonagenarian patients undergoing cardiac surgery, postoperative 6-month mortality was zero. These findings support carefully selected nonagenarian patients being offered cardiac surgery (Trials Registry: https://www.anzctr.org.au/ACTRN12622000058774.aspx).
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ItemTumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes(BMJ PUBLISHING GROUP, 2022-06-01)BACKGROUND: Aberrations in homologous recombination repair (HRR) genes are emerging as important biomarkers for personalized treatment in prostate cancer (PCa). HRR deficiency (HRD) could affect the tumor immune microenvironment (TIME), potentially contributing to differential responses to poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors. Spatial distribution of immune cells in a range of cancers identifies novel disease subtypes and is related to prognosis. In this study we aimed to determine the differences in the TIME of PCa with and without germline (g) HRR mutations. METHODS: We performed gene expression analysis, multiplex immunohistochemistry of T and B cells and quantitative spatial analysis of PCa samples from 36 patients with gHRD and 26 patients with sporadic PCa. Samples were archival tumor tissue from radical prostatectomies with the exception of one biopsy. Results were validated in several independent cohorts. RESULTS: Although the composition of the T cell and B cells was similar in the tumor areas of gHRD-mutated and sporadic tumors, the spatial profiles differed between these cohorts. We describe two T-cell spatial profiles across primary PCa, a clustered immune spatial (CIS) profile characterized by dense clusters of CD4+ T cells closely interacting with PD-L1+ cells, and a free immune spatial (FIS) profile of CD8+ cells in close proximity to tumor cells. gHRD tumors had a more T-cell inflamed microenvironment than sporadic tumors. The CIS profile was mainly observed in sporadic tumors, whereas a FIS profile was enriched in gHRD tumors. A FIS profile was associated with lower Gleason scores, smaller tumors and longer time to biochemical recurrence and metastasis. CONCLUSIONS: gHRD-mutated tumors have a distinct immune microenvironment compared with sporadic tumors. Spatial profiling of T-cells provides additional information beyond T-cell density and is associated with time to biochemical recurrence, time to metastasis, tumor size and Gleason scores.
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ItemProtocol for a feasibility study and process evaluation of a psychosocially modelled diabetes education programme for young people with type 1 diabetes: the Youth Empowerment Skills (YES) programme.(BMJ, 2022-06-09)INTRODUCTION: Adolescence is a challenging period for young people with type 1 diabetes, associated with worsening glycaemia and care disengagement. Educational interventions in this period tend to focus on diabetes-specific skills, with less emphasis on the psychosocial challenges associated with diabetes experienced by young people. To address this limitation, we codesigned with young people a psychosocially modelled programme of diabetes education, named 'Youth Empowerment Skills' (YES). The programme aims to facilitate a positive adaptation to life with diabetes and engagement with diabetes care through peer-based learning, immersive simulations and support from an outreach youth worker. Here, we present a protocol for a feasibility study of the YES programme. METHODS AND ANALYSIS: The study was designed following the Medical Research Council Complex Intervention Evaluation Framework to: test the feasibility (acceptance, implementability, recruitment and completion) of the YES programme; and estimate its efficacy in relation to metabolic and psychosocial outcomes. The study will take place in diabetes centres serving socioculturally diverse populations. We will conduct a feasibility randomised controlled trial (waiting-list design) with integrated process evaluation. Fifty young people with type 1 diabetes (aged 14-19 years) will be randomly allocated to either the YES intervention or a waiting-list control. Randomisation acceptability will be assessed with provision for a preference allocation. Outcomes will be evaluated at 6 months, at which point the waiting list participants will be exposed to the YES programme with further follow-up to 12 months. A simultaneous process evaluation will use a mixed-methods approach collecting qualitative and quantitative data. Study findings will be used to optimise the intervention components, outcome measures and recruitment methods to inform a subsequent definitive trial. ETHICS AND DISSEMINATION: The protocol has ethical approval from the UK Health Research Authority (approval IRAS project ID: 279877). Findings will be disseminated in multiple formats for lay and professional audiences. PROTOCOL DATE AND VERSION: 7 April 2021, V.1.1. TRIAL REGISTRATION NUMBER: NCT04670198.
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ItemExpansion of Liver Transplantation Criteria for Hepatocellular Carcinoma from Milan to UCSF in Australia and New Zealand and Justification for Metroticket 2.0.(MDPI AG, 2022-06-03)BACKGROUND: Expansion in liver transplantation (LT) criteria for HCC from Milan to UCSF has not adversely impacted overall survival, prompting further expansion towards Metroticket 2.0 (MT2). In this study, we compared patient survival post-transplant before and after 2007 and long-term outcomes for LT within Milan versus UCSF criteria (to determine the true benefit of the expansion of criteria) and retrospectively validated the MT2 criteria. METHODS: Retrospective analysis of ANZLITR (including all patients transplanted for HCC since July 1997). The entire cohort was divided based on criteria used at the time of listing, namely, Milan era (1997-2006) and the UCSF era (2007-July 2015). RESULTS: The overall 5- and 10-year cumulative survival rates for the entire cohort of 691 patients were 78% and 69%, respectively. Patients transplanted in UCSF era had significantly higher 5- and 10-year survival rates than in the Milan era (80% vs. 73% and 72% vs. 65%, respectively; p = 0.016). In the UCSF era, the 5-year survival rate for patients transplanted within Milan criteria was significantly better than those transplanted outside Milan but within UCSF criteria (83% vs. 73%; p < 0.024). Patients transplanted within the MT2 criteria had a significantly better 5- and 10-year survival rate as compared to those outside the criteria (81% vs. 64% and 73% vs. 50%, respectively; p = 0.001). CONCLUSION: Overall survival following LT for HCC has significantly improved over time despite expanding criteria from Milan to UCSF. Patients fulfilling the MT2 criteria have a survival comparable to the UCSF cohort. Thus, expansion of criteria to MT2 is justifiable.
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ItemThe Association of Postoperative Complications and Hospital Costs Following Distal Pancreatectomy.(Frontiers Media SA, 2022)Background: Understanding the financial implications associated with the complications post-distal pancreatectomy (DP) may be beneficial for the future optimisation of postoperative care pathways and improved cost-efficiency. The primary outcome of this retrospective study was the characterisation of the additional cost associated with postoperative complications following DP. The secondary outcome was the estimation of the prevalence, type and severity of complications post-DP and the determination of which complications were associated with higher costs. Methods: Postoperative complications were retrospectively examined for 62 adult patients undergoing distal pancreatectomy at an Australian university hospital between January 2012 and July 2021. Complications were defined and graded using the Clavien-Dindo (CVD) classification system. In-hospital cost of index admission was calculated using an activity-based costing methodology and was reported in US dollars at 2021 rates. Regression modelling was used to investigate the relationships among selected perioperative variables, complications and costs. Results: 45 patients (72.6%) experienced one or more postoperative complications. The median (IQR) hospital cost in US dollars was 31.6% greater in patients who experienced complications compared to those who experienced no complications ($40,717.8 [27,358.0-59,834.3] vs. $30,946.9 [23,910.8-46,828.1]). Costs for patients with four or more complications were 43.5% higher than for those with three or fewer complications (p = 0.015). Compared to patients with no complications, the median hospital costs increased by 17.1% in patients with minor complications (CVD grade I/II) and by 252% in patients who developed major complication (i.e., CVD grade III/IV) complications. Conclusion: Postoperative complications are a key target for cost-containment strategies. Our findings demonstrate a high prevalence of postoperative complications following distal pancreatectomy with number and severity of postoperative complications being associated with increased hospital costs. (Registered in the Australian New Zealand Clinical Trials Registry [No. ACTRN12622000202763]).
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ItemSAR131675, a VEGRF3 Inhibitor, Modulates the Immune Response and Reduces the Growth of Colorectal Cancer Liver Metastasis(MDPI, 2022-06-01)Most patients with colorectal cancer (CRC) develop metastases, predominantly in the liver (CLM). Targeted therapies are being investigated to improve current CLM treatments. This study tested the effectiveness of SAR131675, a selective VEGFR-3 tyrosine kinase inhibitor, to inhibit CLM in a murine model. Following intrasplenic induction of CLM, mice were treated daily with SAR131675. Tumor growth and immune infiltrates into tumor and liver tissues were assessed at 10-, 16- and 22-days post tumor induction by stereology, IHC and flow cytometry. SAR151675 treatment significantly reduced tumor burden and F4/80+ macrophages in the liver tissues. Analysis of immune cell infiltrates in liver showed tissue that at day 22, had the proportion of CD45+ leukocytes significantly reduced, particularly myeloid cells. Analysis of myeloid cells (CD11b+ CD45+) indicated that the proportion of F4/80- Ly6Clow was significantly reduced, including a predominate PD-L1+ subset, while CD3+ T cells increased, particularly CD8+ PD1+, reflected by an increase in the CD8+:CD4+ T cell ratio. In the tumor tissue SAR11675 treatment reduced the predominant population of F4/80+ Ly6Clo and increased CD4+ T cells. These results suggest that SAR131675 alters the immune composition within tumor and the surrounding liver in the later stages of development, resulting in a less immunosuppressive environment. This immunomodulation effect may contribute to the suppression of tumor growth.
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ItemPSMA PET-CT Imaging Predicts Treatment Progression in Men with Biochemically Recurrent Prostate Cancer-A Prospective Study of Men with 3 Year Follow Up(MDPI, 2022-06-01)Prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET-CT) is a novel imaging modality used to stage recurrent prostate cancer. It has the potential to improve prognostication and ultimately guide the timing of treatment for men with recurrent prostate cancer. This study aims to assess the clinical impact of PSMA PET-CT by analyzing its predictive value of treatment progression after 3 years of follow-up. In this prospective cohort study of 100 men, patients received a PSMA PET-CT for restaging of their disease which was used by a multi-disciplinary team to make a treatment decision. The primary endpoint was treatment progression. This was defined as the addition or change of any treatment modalities such as androgen deprivation therapy (ADT), radiation therapy or chemotherapy. The median follow-up time was 36 months (IQR 24-40 months). No treatment progression was found in 72 (75%) men and therefore 24 (25%) patients were found to have treatment progression. In men with a negative PSMA PET-CT result, 5/33 (15.1%) had treatment progression and 28/33 (84.8%) had no treatment progression. In conclusion, clinical decisions made with PSMA PET-CT results led to 75% of men having no treatment progression at 3 years of follow-up. In men with negative PSMA PET-CT results, this increased to 85% of men.