Surgery (St Vincent's) - Research Publications
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ItemLaminin 521 enhances self-renewal via STAT3 activation and promotes tumor progression in colorectal cancer(ELSEVIER IRELAND LTD, 2020-04-28)Remodeling of basement membrane proteins contributes to tumor progression towards the metastatic stage. One of these proteins, laminin 521 (LN521), sustains embryonic and induced pluripotent stem cell self-renewal, but its putative role in cancer is poorly described. In the present study we found that LN521 promotes colorectal cancer (CRC) cell self-renewal and invasion. siRNA-mediated knockdown of endogenously-produced laminin alpha 5, as well as treatment with neutralizing antibodies against integrin α3β1 and α6β1, were able to reverse the effect of LN521 on self-renewal. Exposure of CRC cells to LN521 enhanced STAT3 phosphorylation, and incubation with STAT3 inhibitors Napabucasin and Stattic was sufficient to block the LN521-driven self-renewal increase. Robust expression of laminin alpha 5 was detected in 7/10 liver metastases tissue sections collected from CRC patients as well as in mouse liver metastasis xenografts, in most cases within areas expressing metastasis cancer stem cell markers such as c-KIT and CD44v6. Finally, retrospective analysis of multiple CRC datasets highlighted the significant association between high LN521 mRNA expression and poor clinical outcome in colorectal cancer patients. Collectively our results indicate that high Laminin 521 expression is a frequent feature of metastatic dissemination in CRC and that it promotes cell invasion and self-renewal, the latter through engagement of integrin isoforms and activation of STAT3 signaling.
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ItemManagement of lateral pelvic lymph nodes by Australasian colorectal surgeons: An insight from the west(WILEY, 2021-12)PURPOSE: Lateral pelvic lymph node dissection (LPLND) for locally advanced low rectal cancer is a common practice in Japan. However, it is not widely performed in western countries. The aim of this survey study is to assess the current practice and management of lateral pelvic lymph nodes by colorectal surgeons in Australasia. METHODS: The authors developed a survey to assess surgeons' assessment and management of lateral pelvic lymph nodes in patients with rectal cancer. The survey was run through the online RedCap® platform in 2019. An electronic link and request to complete the survey was sent to specialist surgeons of the Colorectal Surgical Society of Australia and New Zealand (CSSANZ). RESULTS: Ninety-two colorectal surgeons completed the online survey (32% response rate). Eighty percent of participants consider malignant lateral pelvic lymph nodes to represent locoregional and resectable disease. In patients with clinically malignant lateral pelvic lymph nodes on preoperative imaging the majority of respondents (92%) recommend neoadjuvant chemoradiotherapy and 86% would also recommend LPLND. Over half of the surgeons (57%) had no exposure to LPLND during fellowship training and approximately two thirds (62%) do not perform LPLND in their current practice. CONCLUSION: This study highlights the challenges in the management of the lateral pelvic lymph nodes in a western context. The majority of the participating Australasian colorectal surgeons consider malignant lateral pelvic lymph nodes to represent locoregional and resectable disease. The majority also recommend LPLND for clinically malignant lateral pelvic nodes. However, adequate training and experience with LPLND is limited.
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ItemRobotic colorectal surgery in Australia: evolution over a decade(WILEY, 2021-11)BACKGROUND: Despite reports of increasing adoption of robotics in colorectal surgery worldwide, data regarding its uptake in Australasia are lacking. This study examines the trends of robotic colorectal surgery in Australia during the last 10 years. METHODS: Data from patients undergoing robotic colorectal surgery with the da Vinci robotic platform between 2010 and 2019 were obtained. Overall, numbers of specific colorectal procedures across Australia were obtained from the Medicare Benefit Schedule data over the same period. Pearson's correlation analysis was used to determine the statistical trends of overall and specific robotic colorectal procedures over time. RESULTS: A total of 6110 robotic general surgery procedures were performed across Australia during the study period. Of these, 3522 (57.6%) were robotic colorectal procedures. An increasing trend of overall robotic colorectal procedures was seen over 10 years (Pearson's coefficient of 0.875; P = 0.001). While this applied to both the public and private sectors, 90.7% of the procedures were undertaken in the private sector. Restorative rectal resections, rectopexies, and right hemicolectomies accounted for 82.6% of the robotic colorectal procedures performed during this period with an increasing trend seen over time for each intervention. Moreover, a robotic approach was utilized in 12.5%, 41.0% and 9.0% of all restorative rectal resections, rectopexies and right hemicolectomies undertaken in Australia during 2019, respectively. CONCLUSION: Robotic colorectal surgery has increased dramatically in Australia over the last 10 years, especially in the private sector. Penetration of robotic colorectal surgery in the public healthcare system will require focussed cost-benefit evaluations and governmental investment.
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ItemOncological reasons for performing a complete mesocolic excision: a systematic review and meta-analysis(WILEY, 2021-01)BACKGROUND: While complete mesocolic excision (CME) has been shown to have an oncological benefit as compared to conventional colonic surgery for colon surgery, this benefit must be weighed up against the risk of major intra-abdominal complications. This paper aimed to assess the comparative oncological benefits of CME. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic review of the literature until May 2020 was performed. Comparative studies assessing CME versus conventional colonic surgery for colon cancer were compared, and outcomes were pooled. RESULTS: A total of 700 publications were identified, of which 19 were found to meet the inclusion criteria. A total of 25 886 patients were compared, with 14 431 patients in the CME arm. CME was associated with a significantly higher rate of vascular injury (odds ratio 3, P < 0.001). Rates of local and distant recurrence were lower in the CME group (odds ratio 0.66 and 0.73, respectively, both P < 0.001). CME patients had a significantly higher lymph node yield (P < 0.001). While no significant differences were noted between the two groups in terms of pooled 3- or 5-year disease-free survival, pooled 5-year overall survival was significantly higher in the CME group (relative risk 0.82, P < 0.001). CONCLUSION: Based on the available evidence, CME is associated with improved oncologic outcomes at the expense of higher complication rates, including vascular injury. The oncological benefits need to weighed up against a multitude of factors including the level of hospital support, surgeon experience, patient age, and associated comorbidities.
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ItemAssociation between imaging response and survival following neoadjuvant chemotherapy in patients with resectable colorectal liver metastases: A cohort study(WILEY, 2021-04)BACKGROUND: The association between the imaging response (structural or metabolic) to neoadjuvant chemotherapy (neoCT) before colorectal liver metastasis (CRLM) and survival is unclear. METHOD: A total of 201 patients underwent their first CRLM resection. A total of 94 (47%) patients were treated with neoCT. A multivariable, Cox proportional hazard regression analysis was performed to compare overall survival (OS) and progression-free survival (PFS) between response groups. RESULTS: Multivariable regression analysis of the CT/MRI (n = 94) group showed no difference in survival (OS and PFS) in patients who had stable disease/partial response (SD/PR) or complete response (CR) versus patients who had progressive disease (PD) (OS: HR, 0.36 (95% CI: 0.11-1.19) p = .094, HR, 0.78 (95% CI: 0.13-4.50) p = .780, respectively), (PFS: HR, 0.70 (95% CI: 0.36-1.35) p = .284, HR, 0.51 (0.18-1.45) p = .203, respectively). In the FDG-PET group (n = 60) there was no difference in the hazard of death for patients with SD/PR or CR versus patients with PD for OS or PFS except for the PFS in the small CR subgroup (OS: HR, 0.75 (95% CI: 0.11-4.88) p = .759, HR, 1.21 (95% CI: 0.15-9.43) p = .857), (PFS: HR, 0.34% (95% CI: 0.09-1.22), p = .097, HR, 0.17 (95% CI: 0.04-0.62) p = .008, respectively). CONCLUSION: There was no convincing evidence of association between imaging response to neoCT and survival following CRLM resection.
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ItemSurvival benefit of neoadjuvant chemotherapy and surgery versus surgery first for resectable colorectal liver metastases: a cohort study(WILEY, 2021-06)BACKGROUND: There is continued debate about the survival benefit of neoadjuvant chemotherapy (neoCT) in patients with resectable colorectal liver metastases (CRLM). METHODS: In this retrospective cohort study, we included 201 patients with metastatic colorectal cancer who underwent their first CRLM resection and achieved resection of all sites of disease. We compared the overall survival (OS) and progression-free survival (PFS) between patients who received neoCT prior to CRLM resection with those who underwent CRLM upfront. A multivariable Cox proportional hazard regression analysis was performed to adjust for potential confounders. RESULTS: A total of 101 of 201 (51.2%) patients received chemotherapy prior to CRLM resection and 100 of 201 had surgery upfront. Multivariable Cox proportional hazard regression showed no statistically significant difference in the hazard of death for those given neoCT prior to resection of CRLM compared with surgery first for both OS and PFS (OS: hazard ratio 1.74, 95% confidence interval 0.85-3.55, P = 0.127, PFS: hazard ratio 1.42, 95% confidence interval 0.93-2.19, P = 0.107). CONCLUSION: In our series of patients with metastatic colorectal cancer who achieved surgical resection of all sites of disease, neoCT prior to CRLM resection was not associated with any survival benefit.
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ItemMolecular and genomic characterisation of a panel of human anal cancer cell lines(SPRINGERNATURE, 2021-10-18)Anal cancer is a rare disease that has doubled in incidence over the last four decades. Current treatment and survival of patients with this disease has not changed substantially over this period of time, due, in part, to a paucity of preclinical models to assess new therapeutic options. To address this hiatus, we set-out to establish, validate and characterise a panel of human anal squamous cell carcinoma (ASCC) cell lines by employing an explant technique using fresh human ASCC tumour tissue. The panel of five human ASCC cell lines were validated to confirm their origin, squamous features and tumourigenicity, followed by molecular and genomic (whole-exome sequencing) characterisation. This panel recapitulates the genetic and molecular characteristics previously described in ASCC including phosphoinositide-3-kinase (PI3K) mutations in three of the human papillomavirus (HPV) positive lines and TP53 mutations in the HPV negative line. The cell lines demonstrate the ability to form tumouroids and retain their tumourigenic potential upon xenotransplantation, with varied inducible expression of major histocompatibility complex class I (MHC class I) and Programmed cell death ligand 1 (PD-L1). We observed differential responses to standard chemotherapy, radiotherapy and a PI3K specific molecular targeted agent in vitro, which correlated with the clinical response of the patient tumours from which they were derived. We anticipate this novel panel of human ASCC cell lines will form a valuable resource for future studies into the biology and therapeutics of this rare disease.