Surgery (Austin & Northern Health) - Research Publications

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    SAR131675, a VEGRF3 Inhibitor, Modulates the Immune Response and Reduces the Growth of Colorectal Cancer Liver Metastasis
    Walsh, KA ; Kastrappis, G ; Fifis, T ; Paolini, R ; Christophi, C ; Perini, MV (MDPI, 2022-06)
    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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    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)
    (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 p < 0.05, CD11b+Ly6CLo 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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    Serum carbohydrate antigen 19-9 in pancreatic adenocarcinoma: a mini review for surgeons
    Goh, SK ; Gold, G ; Christophi, C ; Muralidharan, V (WILEY, 2017-12)
    The optimal management of oncological conditions is reflected by the careful interpretation of investigations for screening, diagnosis, staging, prognostication and surveillance. Serum tumour markers are examples of commonly requested tests in conjunction with other imaging and endoscopic tests that are used to help clinicians to stratify therapeutic decisions. Serum carbohydrate antigen 19-9 (CA19-9) is a key biomarker for pancreatic cancers. Although this biomarker is considered clinically useful and informative, clinicians are often challenged by the accurate interpretation of elevated serum CA19-9 levels. Recognizing the pitfalls of normal and abnormal serum CA19-9 concentrations will facilitate its appropriate use. In this review, we appraised the biomarker, serum CA19-9, and highlighted the clinical utility and limitations of serum CA19-9 in the investigation and management of pancreatic cancers.
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    Age 80 years and over is not associated with increased morbidity and mortality following pancreaticoduodenectomy
    Kim, SY ; Fink, MA ; Perini, M ; Houli, N ; Weinberg, L ; Muralidharan, V ; Starkey, G ; Jones, RM ; Christophi, C ; Nikfarjam, M (WILEY, 2018-05)
    BACKGROUND: Pancreaticoduodenectomy (PD) is associated with high morbidity, which is perceived to be increased in the elderly. To our knowledge there have been no Australian series that have compared outcomes of patients over the age of 80 undergoing PD to those who are younger. METHODS: Patients who underwent PD between January 2008 and November 2015 were identified from a prospectively maintained database. RESULTS: A total of 165 patients underwent PD of whom 17 (10.3%) were aged 80 or over. The pre-operative health status, according to American Society of Anesthesiologists class was similar between the groups (P = 0.420). The 90-day mortality rates (5.9% in the elderly and 2% in the younger group; P = 0.355) and the post-operative complication rates (64.7% in the elderly versus 62.8% in the younger group; P = 0.88) were similar. Overall median length of hospital stay was also similar between the groups, but older patients were far more likely to be discharged to a rehabilitation facility than younger patients (47.1 versus 12.8%; P < 0.0001). Older patients with pancreatic adenocarcinoma (n = 10) had significantly lower median survival than the younger group (n = 69) (16.6 versus 22.5 months; P = 0.048). CONCLUSION: No significant differences were seen in the rate of complications following PD in patients aged 80 or over compared to younger patients, although there appears to be a shorter survival in the elderly patients treated for pancreatic cancer. Careful selection of elderly patients and optimal peri-operative care, rather than age should be used to determine whether surgical intervention is indicated in this patient group.
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    Acute cholangitis: current concepts
    Wah, DLC ; Christophi, C ; Muralidharan, V (WILEY, 2017-07)
    BACKGROUND: Acute cholangitis, also known as ascending cholangitis, is a life-threatening systemic condition that results from a biliary tree infection and obstruction. Severe acute cholangitis was reported to have a mortality rate between 11 and 27% in the 1990s. This article is a literature review about acute cholangitis. Its aim is to review the latest literature about acute cholangitis and to discuss its pathogenesis, clinical presentation, diagnosis, prognosis, risk factors and treatment. METHODS: Ovid Medline and PubMed database searches were performed for articles about acute cholangitis published in English from 1877 to 2016. The keyword search headings included 'acute', 'ascending' and 'cholangitis', and a combination of these were used. Only articles with full-text descriptions were chosen for this literature review. RESULTS: Common causes of biliary tree obstruction include choledocholithiasis, benign and malignant biliary strictures. According to the Tokyo Guidelines, clinical presentation, laboratory blood results and diagnostic imaging are important in the diagnosis of acute cholangitis. Treatments consist of intravenous fluids and antibiotics followed by biliary decompression and drainage. Available drainage options include endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, endoscopic ultrasound and open surgical drainage. CONCLUSION: It is important to diagnose acute cholangitis as early as possible to initiate appropriate treatments to reduce mortality and morbidity.
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    Utilizing the gall bladder as a conduit in treating biliary obstruction: a historical perspective
    Raj, M ; Lee, E ; Christophi, C ; Muralidharan, V (WILEY, 2017-03)
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    Peri-operative lidocaine infusion for open radical prostatectomy - a reply
    Weinberg, L ; Story, D ; Gordon, I ; Christophi, C (WILEY-BLACKWELL, 2016-10)
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    Metabolic response evaluation for colorectal liver metastases and correlation to pathologic response and tumour markers
    Lau, LF ; Murone, C ; Williams, DS ; Standish, R ; Lee, ST ; Christophi, C ; Scott, AM ; Muralidharan, V (WILEY, 2018-03)
    BACKGROUND: Tumour metabolic response to chemotherapy is increasingly recognized as a prognostic indicator for colorectal cancer liver metastases (CRCLM). However, its clinical role and the underlying biological mechanism of its prognostic ability are unclear. This study compares metabolic to pathologic response for CRCLM, and correlates metabolic response to tumour expression of six key biomarkers. METHODS: Thirty-seven patients who had positron emission tomography imaging before and after pre-operative chemotherapy prior to liver resection for CRCLM were included. Metabolic response was assessed according to the positron emission tomography response criteria in solid tumours (PERCIST) and correlated to recurrence-free and overall survival. PERCIST was compared to tumour regression grading, computed tomography (CT) response, tumour necrosis and mucin and immunohistochemical expression of Ki-67, hypoxia inducible factor 1α, vascular endothelial growth factor, p53, p16 and vimentin. Area under the receiver operating characteristic curve (AUC), Kaplan-Meier survival, Spearman's correlation (rs ) and multivariate Cox regression analyses were used. RESULTS: PERCIST correlated significantly to 2-year mortality (AUC = 0.162, P < 0.01) and 2-year recurrence (AUC = 0.284, P = 0.03). Metabolically responsive tumours conferred a better overall survival (P = 0.01) and recurrence-free survival (P = 0.03). Tumour regression grading did not stratify for outcome. Metabolic response was significantly correlated to Ki-67 and p16 expression (rs = 0.559 and rs = -0.549, respectively). Multivariate analysis revealed only PERCIST to be correlated to death and recurrence. CONCLUSION: Pre-operative PERCIST assessment of CRCLM was more prognostic than pathologic and CT response assessment. Metabolic non-response correlated with tumour proliferation and loss of tumour suppression.
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    Anatomy of hepatic lymphatics and its implications in hepatic malignancies.
    Yong, TL ; Houli, N ; Christophi, C (Wiley, 2016-11)
    Hepatic malignancy with regional lymph node involvement is generally associated with poor prognosis. Lymphatic drainage from the liver to extrahepatic lymph nodes follows a complex and unpredictable pathway. To add to the complexity of management of regional lymph nodes in hepatic malignancies, not all liver cancers have the same propensity to metastasize through lymphatics. Lymphadenectomy has had mixed results in terms of improving patient survival. Other therapies especially anti-lymphogenic agents might play a role in the near future.
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    Health economic implications of postoperative complications following liver resection surgery: a systematic review
    Cosic, L ; Ma, R ; Churilov, L ; Nikfarjam, M ; Christophi, C ; Weinberg, L (WILEY, 2019-12)
    BACKGROUND: Limited data exists concerning the health economics of liver resection, with even less information on the costs emerging from complications, despite this remaining an important target from a health economic perspective. Our objective was to describe the financial burden of complications following liver resection. METHODS: We conducted a systematic search and included studies reporting resource use of in-hospital complications during the index liver resection admission. All indications for liver resection were considered. All techniques were considered. Data was collected using a data extraction table and a narrative synthesis was performed. RESULTS: We identified 12 eligible articles. There was considerable heterogeneity in study designs, patient populations and outcome definitions. We found weak evidence of increased costs associated with major liver resection compared to minor resections. We found robust evidence supporting the increasing economic burden arising from complications after liver resection. Acceptable evidence for increased cost due to the presence and grade of complication was found. Strong evidence concerning the association of length of stay with costs was demonstrated. CONCLUSIONS: The presence and grade of complications increase hospital cost across diverse settings. The costing methodology should be transparent and complication grading systems should be consistent in future studies.