Surgery (Austin & Northern Health) - Research Publications

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    Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Tumour Progression in the Regenerating Liver Following Partial Hepatectomy
    Riddiough, GE ; Walsh, KA ; Fifis, T ; Kastrappis, G ; Tran, BM ; Vincan, E ; Muralidharan, V ; Christophi, C ; Gordon, CL ; Perini, MV (MDPI, 2022-05-01)
    (1) Liver regeneration following partial hepatectomy for colorectal liver metastasis (CRLM) has been linked to tumour recurrence. Inhibition of the renin-angiotensin system (RASi) attenuates CRLM growth in the non-regenerating liver. This study investigates whether RASi exerts an antitumour effect within the regenerating liver following partial hepatectomy for CRLM and examines RASi-induced changes in the tumour immune microenvironment; (2) CRLM in mice was induced via intrasplenic injection of mouse colorectal tumour cells, followed by splenectomy on Day 0. Mice were treated with RASi captopril (250 mg/kg/day), or saline (control) from Day 4 to Day 16 (endpoint) and underwent 70% partial hepatectomy on Day 7. Liver and tumour samples were characterised by flow cytometry and immunofluorescence; (3) captopril treatment reduced tumour burden in mice following partial hepatectomy (p < 0.01). Captopril treatment reduced populations of myeloid-derived suppressor cells (MDSCs) (CD11b+Ly6CHi&nbsp;p < 0.05, CD11b+Ly6CLo&nbsp;p < 0.01) and increased PD-1 expression on infiltrating hepatic tissue-resident memory (TRM)-like CD8+ (p < 0.001) and double-negative (CD4-CD8-; p < 0.001) T cells; (4) RASi reduced CRLM growth in the regenerating liver and altered immune cell composition by reducing populations of immunosuppressive MDSCs and boosting populations of PD-1+ hepatic TRMs. Thus, RASi should be explored as an adjunct therapy for patients undergoing partial hepatectomy for CRLM.
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    Stereotactic radiotherapy and the potential role of magnetic resonance-guided adaptive techniques for pancreatic cancer
    Ermongkonchai, T ; Khor, R ; Muralidharan, V ; Tebbutt, N ; Lim, K ; Kutaiba, N ; Ng, SP (BAISHIDENG PUBLISHING GROUP INC, 2022-02-21)
    BACKGROUND: Pancreatic cancer is a malignancy with one of the poorest prognoses amongst all cancers. Patients with unresectable tumours either receive palliative care or undergo various chemoradiotherapy regimens. Conventional techniques are often associated with acute gastrointestinal toxicities, as adjacent critical structures such as the duodenum ultimately limits delivered doses. Stereotactic body radiotherapy (SBRT) is an advanced radiation technique that delivers highly ablative radiation split into several fractions, with a steep dose fall-off outside target volumes. AIM: To discuss the latest data on SBRT and whether there is a role for magnetic resonance-guided techniques in multimodal management of locally advanced, unresectable pancreatic cancer. METHODS: We conducted a search on multiple large databases to collate the latest records on radiotherapy techniques used to treat pancreatic cancer. Out of 1229 total records retrieved from our search, 36 studies were included in this review. RESULTS: Studies indicate that SBRT is associated with improved clinical efficacy and toxicity profiles compared to conventional radiotherapy techniques. Further dose escalation to the tumour with SBRT is limited by the poor soft-tissue visualisation of computed tomography imaging during radiation planning and treatment delivery. Magnetic resonance-guided techniques have been introduced to improve imaging quality, enabling treatment plan adaptation and re-optimisation before delivering each fraction. CONCLUSION: Therefore, SBRT may lead to improved survival outcomes and safer toxicity profiles compared to conventional techniques, and the addition of magnetic resonance-guided techniques potentially allows dose escalation and conversion of unresectable tumours to operable cases.
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    SARS-CoV-2 infection and venous thromboembolism after surgery: an international prospective cohort study
    Li, E (WILEY, 2021-08-24)
    SARS-CoV-2 has been associated with an increased rate of venous thromboembolism in critically ill patients. Since surgical patients are already at higher risk of venous thromboembolism than general populations, this study aimed to determine if patients with peri-operative or prior SARS-CoV-2 were at further increased risk of venous thromboembolism. We conducted a planned sub-study and analysis from an international, multicentre, prospective cohort study of elective and emergency patients undergoing surgery during October 2020. Patients from all surgical specialties were included. The primary outcome measure was venous thromboembolism (pulmonary embolism or deep vein thrombosis) within 30 days of surgery. SARS-CoV-2 diagnosis was defined as peri-operative (7 days before to 30 days after surgery); recent (1-6 weeks before surgery); previous (≥7 weeks before surgery); or none. Information on prophylaxis regimens or pre-operative anti-coagulation for baseline comorbidities was not available. Postoperative venous thromboembolism rate was 0.5% (666/123,591) in patients without SARS-CoV-2; 2.2% (50/2317) in patients with peri-operative SARS-CoV-2; 1.6% (15/953) in patients with recent SARS-CoV-2; and 1.0% (11/1148) in patients with previous SARS-CoV-2. After adjustment for confounding factors, patients with peri-operative (adjusted odds ratio 1.5 (95%CI 1.1-2.0)) and recent SARS-CoV-2 (1.9 (95%CI 1.2-3.3)) remained at higher risk of venous thromboembolism, with a borderline finding in previous SARS-CoV-2 (1.7 (95%CI 0.9-3.0)). Overall, venous thromboembolism was independently associated with 30-day mortality (5.4 (95%CI 4.3-6.7)). In patients with SARS-CoV-2, mortality without venous thromboembolism was 7.4% (319/4342) and with venous thromboembolism was 40.8% (31/76). Patients undergoing surgery with peri-operative or recent SARS-CoV-2 appear to be at increased risk of postoperative venous thromboembolism compared with patients with no history of SARS-CoV-2 infection. Optimal venous thromboembolism prophylaxis and treatment are unknown in this cohort of patients, and these data should be interpreted accordingly.
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    An international pragmatic randomised controlled trial to compare a single use negative pressure dressing versus a surgeon's preference of dressing to reduce the incidence of surgical site infection following emergency laparotomy: the SUNRRISE Trial Protocol.
    SUNRRISE Study Group on behalf of the Northwest Research Collaborative and the West Midlands Research Collaborative, (Wiley, 2020-12-04)
    BACKGROUND: Surgical site infection (SSI) is a common complication following emergency laparotomy occurring in around 25% of patients in UK practice. The use of single use negative pressure dressings (SUNPDs) for these wounds has been proposed as a prophylactic method of reducing the rate of SSI. METHOD: The Single Use Negative pRessure dressing for Reduction In Surgical site infection following Emergency laparotomy (SUNRRISE) study is an international, multicentre, pragmatic, phase III randomised controlled trial (RCT) with internal feasibility phase. The primary aim is to determine if a single use negative pressure dressing (SUNPD) reduces surgical site infection (SSI) at 30 days post-operatively. Patients will be randomised in a 1:1 ratio to either a SUNPD or to receive a dressing of the surgeon's preference. Outcome assessors will be blinded to treatment allocation. The primary outcome measure is SSI within 30 days of surgery as defined by the Centers for Disease Control criteria. A total of 840 patients will be required to detect a relative reduction of 40% in SSI rates (from 25% to 15%) with 90% power accounting for 20% attrition rate. DISCUSSION: SUNRRISE is an international, multicentre RCT evaluating the prophylactic use of SUNPD in primary closed emergency laparotomy wounds for the reduction of SSI. Our hypothesis is that a SUNPD is superior to the surgeon's preference of dressing in reducing surgical site infections at 30 days. These findings may influence dressing choice following emergency abdominal surgery in the future.
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    Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Features of Tumor Invasion and Down-Regulates C-Myc Expression in a Mouse Model of Colorectal Cancer Liver Metastasis
    Riddiough, GE ; Fifis, T ; Walsh, KA ; Muralidharan, V ; Christophi, C ; Tran, BM ; Vincan, E ; Perini, MV (MDPI, 2021-06-01)
    (1) Background: Recent clinical and experimental data suggests that the liver's regenerative response following partial hepatectomy can stimulate tumor recurrence in the liver remnant. The Wnt/β-catenin pathway plays important roles in both colorectal cancer carcinogenesis and liver regeneration. Studies have shown that the Wnt/β-catenin pathway regulates multiple renin-angiotensin system (RAS) genes, whilst RAS inhibition (RASi) reduces tumor burden and progression. This study explores whether RASi attenuates features of tumor progression in the regenerating liver post-hepatectomy by modulating Wnt/β-catenin signaling. (2) Methods: Male CBA mice underwent CRLM induction, followed one week later by 70% partial hepatectomy. Mice were treated daily with captopril, a RASi, at 250 mg/kg/day or vehicle control from experimental Day 4. Tumor and liver samples were analyzed for RAS and Wnt signaling markers using qRT-PCR and immunohistochemistry. (3) Results: Treatment with captopril reduced the expression of down-stream Wnt target genes, including a significant reduction in both c-myc and cyclin-D1, despite activating Wnt signaling. This was a tumor-specific response that was not elicited in corresponding liver samples. (4) Conclusions: We report for the first time decreased c-myc expression in colorectal tumors following RASi treatment in vivo. Decreased c-myc expression was accompanied by an attenuated invasive phenotype, despite increased Wnt signaling.
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    Anaesthesia techniques and advanced monitoring in CANVAS patients -Implications for postoperative morbidity and patient recovery: A case report
    Weinberg, L ; Hungenahally, A ; Meyerov, J ; Miles, LF ; Cox, DRA ; Muralidharan, V (ELSEVIER SCI LTD, 2021-06-05)
    INTRODUCTION: Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a rare multisystem neurodegenerative disorder. We describe our perioperative evaluation and care of a patient with CANVAS undergoing a pancreaticoduodenectomy for an ampullary adenocarcinoma, with a focus on perioperative risk stratification and optimisation, intraoperative advanced haemodynamic monitoring and the postoperative care. CASE PRESENTATION: A 69-year-old female with CANVAS presented with asymptomatic obstructive jaundice, icterus and abdominal pain. She had limited mobility and deconditioning due to severe generalised neuropathy. Computed tomography confirmed a resectable periampullary tumour. Her Duke Activity Status Index was 8.25 points and Edmonton Frailty Scale score was 11, confirming moderate frailty. However, the Charlson Comorbidity Index was five, indicative of a 21% estimated 10-year survival. Further risk stratification including respiratory function testing, echocardiography and cardiopulmonary exercise testing was conducted. The patient proceeded with surgery after multidisciplinary discussions with her treating medical teams. DISCUSSION: CANVAS is a rare and challenging condition requiring careful perioperative planning and management. There is no effective treatment for CANVAS. The management approach focuses on mitigating symptoms and improving quality of life. Given that no specific guidelines for managing these patients in the perioperative period have been provided, this report highlights several critical medical issues and implications that should be considered for the successful management of these patients. We demonstrate the role of specific anaesthesia techniques and advanced haemodynamic monitoring in both preventing postoperative morbidity and optimising patient recovery. CONCLUSION: CANVAS is a rare and challenging condition in anaesthesia requiring careful perioperative planning and management.
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    Perioperative thromboprophylaxis is highly variable in general surgery: results from a multicentre survey
    Liu, DS ; Wong, E ; Fong, J ; Stevens, S ; Mori, K ; Gill, AS ; Crowe, A ; Jain, A ; Chung, C ; Slevin, M ; Fleming, N ; Beh, PS ; Ward, S ; Lee, S ; Bennet, S (WILEY, 2020-12-01)
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    Surgical Outpatient Study: characterizing the educational experience of outpatient clinics for surgical trainees
    Goh, SK ; Dudi-Venkata, NN ; Zhou, B ; Ng, D ; Liu, DS ; Fong, J ; Low, N ; Lau, L ; Mori, K ; Sidhu, A ; Stevens, S ; Muralidharan, V (WILEY, 2020-11-01)
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    Variations in practice of thromboprophylaxis across general surgical subspecialties: a multicentre (PROTECTinG) study of elective major surgeries
    Liu, DS ; Stevens, S ; Wong, E ; Fong, J ; Mori, K ; Fleming, N ; Beh, PS ; Crowe, A ; Howard, T ; Slevin, M ; Jain, A ; Gill, AS ; Lee, S ; Jamel, W ; Bennet, S ; Chung, C ; Ward, S ; Muralidharan, V (WILEY, 2020-12)
    Background Despite guidelines recommending perioperative thromboprophylaxis for patients undergoing general surgery, we have observed significant variations in its practice. This may compromise patient safety. Here, we quantify the heterogeneity of perioperative thromboprophylaxis across all major general surgical operations, and place them in relation to their risk of bleeding and venous thromboembolism. Methods Retrospective review of all elective major general surgeries performed between 1 January 2018 and 30 June 2019 across seven Victorian hospitals was conducted. Results A total of 5912 patients who underwent 6628 procedures were reviewed. Significant heterogeneity was found in the use of chemoprophylaxis, timing of its initiation, type of anticoagulant administered and application of extended chemoprophylaxis. These variations were observed within the same procedure, and between different surgeries and subspecialties. Contrastingly, there was minimal heterogeneity with the use of mechanical thromboprophylaxis. Oesophago‐gastric, liver and colorectal cancer resections had the highest thromboembolic risk. Breast, oesophago‐gastric, liver, pancreas and colon cancer resections had the highest bleeding risk. Conclusion Perioperative chemoprophylaxis across general surgery is highly variable. This study has highlighted key areas of variance. Our findings also enable surgeons to compare their practices, and provide baseline data to inform future efforts towards optimizing thromboprophylaxis for general surgical patients.