Surgery (St Vincent's) - Research Publications

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    Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stem-like Cells
    Paquet-Fifield, S ; Koh, SL ; Cheng, L ; Beyit, LM ; Shembrey, C ; Molck, C ; Behrenbruch, C ; Papin, M ; Gironella, M ; Guelfi, S ; Nasr, R ; Grillet, F ; Prudhomme, M ; Bourgaux, J-F ; Castells, A ; Pascussi, J-M ; Heriot, AG ; Puisieux, A ; Davis, MJ ; Pannequin, J ; Hill, AF ; Sloan, EK ; Hollande, F (American Association for Cancer Research, 2018-06-01)
    Posttreatment recurrence of colorectal cancer, the third most lethal cancer worldwide, is often driven by a subpopulation of cancer stem cells (CSC). The tight junction (TJ) protein claudin-2 is overexpressed in human colorectal cancer, where it enhances cell proliferation, colony formation, and chemoresistance in vitro. While several of these biological processes are features of the CSC phenotype, a role for claudin-2 in the regulation of these has not been identified. Here, we report that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence-free survival following 5-fluorouracil–based chemotherapy, an outcome in which CSCs play an instrumental role. In patient-derived organoids, primary cells, and cell lines, claudin-2 promoted colorectal cancer self-renewal in vitro and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDHHigh CSCs and increased their proportion in colorectal cancer cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSCs toward the ALDHHigh phenotype. Next-generation sequencing in ALDHHigh cells revealed that claudin-2 regulated expression of nine miRNAs known to control stem cell signaling. Among these, miR-222-3p was instrumental for the regulation of self-renewal by claudin-2, and enhancement of this self-renewal required activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of claudin-2 promotes self-renewal within colorectal cancer stem-like cells, suggesting a potential role for this protein as a therapeutic target in colorectal cancer.
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    Colonoscopic surveillance: quality, guidelines and effectiveness
    Chittleborough, TJ ; Kong, JC ; Guerra, GR ; Ramsay, R ; Heriot, AG (WILEY, 2018-01)
    Colonoscopic surveillance in patients with a personal or family history of colorectal carcinoma or colonic polyps represents a significant workload for endoscopy services. Effective colonoscopic surveillance relies on quality endoscopic examination and appropriate surveillance interval. This review will discuss quality in colonoscopy and review guidelines for surveillance.
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    Treatment of peritoneal carcinomatosis with hyperthermic intraperitoneal chemotherapy in colorectal cancer
    Behrenbruch, C ; Hollande, F ; Thomson, B ; Michael, M ; Warrier, SK ; Lynch, C ; Heriot, A (WILEY, 2017-09)
    The peritoneum is the second most common site of metastasis after the liver and the only site of metastatic disease in approximately 25% of patients with colorectal cancer (CRC). In the past, peritoneal carcinomatosis in CRC was thought to be equivalent to distant metastasis; however, the transcoelomic spread of malignant cells is an acknowledged alternative pathway. Metastasectomy with curative intent is well accepted in patients with liver metastasis in CRC despite the paucity of randomized trials. Therefore, there is rationale for local treatment with peritonectomy to eliminate macroscopic disease, followed by hyperthermic intraperitoneal chemotherapy to destroy any residual free tumour cells within the peritoneal cavity. The aim of this paper is to summarize the current evidence for cytoreduction and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis in CRC.
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    Dispelling misconceptions in the management of familial adenomatous polyposis
    Chittleborough, TJ ; Warrier, SK ; Heriot, AG ; Kalady, M ; Church, J (WILEY, 2017-06)
    Patients with familial adenomatous polyposis require surgical intervention at some point in their lives. The diagnosis is often apparent from their phenotype and family history, however, this is not always the case. Many factors can influence the surgical strategy although the polyposis burden and distribution remain the main consideration. While prophylactic removal of the rectum and colon is often required, sparing the rectum at the index surgery is safe in select patients. This article aims to dispel misconceptions in the diagnosis and treatment of patients with familial adenomatous polyposis.
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    A surgical approach: para-aortic nodal recurrence of sigmoid adenocarcinoma
    Britto, MM ; Perera, S ; Alzharani, S ; Heriot, A ; Lynch, C ; Warrier, SK (WILEY, 2017-03)
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    Appendiceal adenocarcinoma masquerading as a primary rectal tumour
    Vu, TM ; Simpson, JA ; Lynch, AC ; Warrier, S ; Heriot, A (WILEY, 2018-06)
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    Rectal adenocarcinoma perforation following palliative colorectal stenting
    Vu, TM ; Simpson, JA ; Alzarhani, S ; Lynch, AC ; Warrier, S ; Heriot, A (WILEY, 2018-06)
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    A case series of anal melanoma including the results of treatment with imatinib in selected patients
    Knowles, J ; Lynch, AC ; Warrier, SK ; Henderson, M ; Heriot, AG (WILEY, 2016-09)
    AIM: Anal melanoma is a rare malignancy with a poor prognosis. METHOD: All patients with a diagnosis of anal melanoma treated at a single institution between 2000 and 2012 were identified and their treatment and outcome were evaluated. RESULTS: Sixteen patients had a median survival of 2.9 years. Fourteen had Stage I or II disease with a median survival of 4.0 years and progression-free survival of 1.5 years. When used for disease staging, whole body positron emission tomography/CT identified an additional three sites of metastasis in five patients compared with CT of the chest, abdomen and pelvis. Surgery involved wide local excision or abdominoperineal excision with respective local recurrence rates of 50% and 66%. Eleven patients underwent testing for c-Kit mutations, of whom five were positive. Four of these were treated with the tyrosine kinase inhibitor imatinib, and showed rapid response of metastases outside the central nervous system. CONCLUSION: The outcome of this malignancy remains poor. PET is the modality of choice for disease staging. Testing tumours for c-Kit mutations may allow selected patients to participate in trials of tyrosine kinase inhibitors.
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    Detection of incidental colorectal pathology on positron emission tomography/computed tomography
    Mui, M ; Akhurst, T ; Warrier, SK ; Lynch, AC ; Heriot, AG (WILEY, 2018-03)
    BACKGROUND: Positron emission tomography/computed tomography (PET/CT) is an important modality in cancer imaging. With its increasing availability and use, it is not uncommon to detect incidental focal colorectal 18 F-FDG uptake which poses a diagnostic challenge, as they may be associated with malignant or pre-malignant colorectal lesions. The aim of our study is to determine the proportion of these findings which represents true pathology. METHODS: Patients with incidental focal colorectal 18 F-FDG uptake on PET/CT who subsequently underwent colonoscopy between January 2002 to September 2013 were identified from a prospective database in a tertiary referral centre. PET/CT results were correlated with colonoscopy and pathology results in these patients. Positive predictive values (PPVs) and 95% confidence intervals (CIs) of PET/CT in the detection of incidental colorectal pathology were calculated. RESULTS: A total of 148 patients (92 men and 56 women), with a mean age 73 years (range of 36 to 93 years) were included in the study. A total of 170 foci of colorectal 18 F-FDG uptake were detected on PET/CT. Of these, 101 foci corresponded to a malignant or pre-malignant lesion (PPV 59%; 95% CI: 52-67%). On a per-patient analysis, 93 patients had at least one focus of colorectal 18 F-FDG uptake which corresponded to a pre-malignant or malignant lesion (PPV 63%; 95% CI: 54-71%). CONCLUSION: Focal colorectal 18 F-FDG uptake on PET/CT is associated with a significant proportion of malignant or pre-malignant lesions. Further evaluation with colonoscopy is recommended.
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    Analysis of mortality in colorectal surgery in the Bi-National Colorectal Cancer Audit.
    Teloken, PE ; Spilsbury, K ; Platell, C ; BCCA Operations Committee, (Wiley, 2016-06)
    BACKGROUND: In the last decade, there has been a significant increase in interest for public reporting of outcome data and performance comparison across institutions and surgeons. This study aims at comparing postoperative mortality after colorectal cancer surgery across units and individual consultants in Australia and New Zealand using funnel plots. METHODS: The Bi-National Colorectal Cancer Audit database was used. Unadjusted and adjusted funnel plots of inpatient mortality were constructed. Risk adjustment was based upon multivariable logistic regression models using purposeful covariate selection. RESULTS: A total of 10 008 patients undergoing surgery for colorectal cancer from 56 surgical units and 90 consultants were identified. Overall inpatient mortality was 1.51%, corresponding to 1.1% for elective and 3.9% for urgent cases. Logistic regression identified age, American Society of Anesthesiologists score, urgent surgery and open surgery to be independently associated with inpatient mortality. Unadjusted and adjusted funnel plot analysis identified three (5.3%) units exceeding the inner limit and none exceeding the outer limit. Six (6.6%) consultants had inpatient mortality between the upper inner and outer limits and one (1.1%) between the inferior inner and outer limits. Upon adjustment, seven (7.7%) consultants had inpatient mortality between the inner and outer limit. Potential limitations of this study include: residual confounding being responsible for the association of open surgery and mortality; incomplete case-mix adjustment resulting in outlier identification; and bias towards inclusion of larger institutions. CONCLUSION: Mortality figures in Australia and New Zealand are comparable to recently reported international data. The vast majority of units and consultants are performing within the expected boundaries.