Anthony Gill

University of Sydney, Sydney, New South Wales, Australia

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Publications (85)434.79 Total impact

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    ABSTRACT: Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme known for its dual function in mediating inflammation and reactive oxygen species production. However, the role of SSAO inhibitors in limiting kidney fibrosis is unclear. We aimed to determine the effectiveness of a SSAO inhibitor (PXS-4728A) as an antifibrotic agent using a 7-day unilateral ureteric obstruction (UUO) model of acute kidney fibrosis in 6-8 week old mice. The experimental groups were: (i) Sham operated; (ii) UUO; (iii) UUO+SSAOi (2mg/kg); (iv) UUO +Telmisartan, an angiotensin receptor blocker (3mg/kg); and (v) UUO + SSAOi + Telmisartan. Kidney tissue was analysed for histological evidence of tubulointerstitial fibrosis, nitrotyrosine staining and mRNA expression of markers associated with fibrosis and inflammation. Kidney SSAO activity was determined by radiometric [(14)C]-benzylamine methodology. Our results show that SSAOi effectively suppresses UUO-mediated SSAO activity. Extracellular matrix markers, namely fibronectin, collagen IV protein and nitrotyrosine staining, were lower in UUO+SSAOi mice compared to untreated UUO mice. This was consistent with the attenuated mRNA expression of collagen-IV and fibronectin. SSAOi effectively inhibited transforming growth factor-beta1 (TGF-β1) and monocyte chemoattractant protein - 1 (MCP-1) expression to a similar extent to that observed with Telmisartan. Individually, SSAOi and Telmistartan induced a reduction in interstitial leukocyte and macrophage accumulation. However, the combination of SSAOi and Telmisartan was more effective at reducing inflammatory cell infiltration. These results demonstrate that SSAO inhibition significantly suppresses profibrotic and proinflammatory cytokine secretion, reduces oxidative stress and limits inflammatory cell accumulation and extracellular matrix expression in an acute model of renal fibrosis.
    American journal of physiology. Renal physiology 08/2014; · 3.61 Impact Factor
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    ABSTRACT: Purpose: PI3K/Akt is over-expressed in 50-70% of pancreatic ductal adenocarcinoma (PDAC). The hypothesis of this study is that PI3K and EGFR co-inhibition may be effective in PDAC with upregulated PI3K/Akt signaling. Experimental Design:Multiple inhibitors were tested on five PDAC cell lines. EGFR inhibitor (EGFRi) resistant cell lines significantly over-expressed AKT2 gene, total Akt and pAkt. In vitro erlotinib-resistant cell models (BxPC-ER, PANC-ER) with highly constitutively active PI3K/Akt were developed. These and their respective parent cell lines were tested for sensitivity to erlotinib, IGF1R inhibitor NVP-AEW541 (AEW), and PI3K-alpha inhibitor NVP-BYL719 (BYL), alone or in combination, by RTK-phosphoarray, western blotting, immunofluorescence, qRT-PCR, cell proliferation, cell cycle, clonogenic, apoptosis, and migration assays. Erlotinib plus BYL was tested in-vivo. Results:Multiple inhibitors were tested on five PDAC cell lines. EGFR inhibitor (EGFRi) resistant cell lines were found to have significantly over-expressed AKT2 gene, total Akt and pAkt. In vitro erlotinib-resistant cell models (BxPC-ER, PANC-ER) with highly constitutively active PI3K/Akt were developed. These and their respective parent cell lines were tested for sensitivity to erlotinib, IGF1R inhibitor NVP-AEW541 (AEW), and PI3K-alpha inhibitor NVP-BYL719 (BYL), alone or in combination, by RTK-phosphoarray, western blotting, immunofluorescence, qRT-PCR, cell proliferation, cell cycle, clonogenic, apoptosis, and migration assays. Erlotinib plus BYL was tested in-vivo. Conclusions:PDAC with increased expression of the PI3K/Akt pathway were susceptible to PI3K/ EGFR co-inhibition suggesting oncogenic dependence. Erlotinib plus BYL should be considered for a clinical study in PDAC; further evaluation of pEGFR and pAkt expression as potential positive and negative predictive biomarkers is warranted.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 06/2014;
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    ABSTRACT: MiR-210 is a key regulator of response to hypoxia. Pheochromocytomas (PCs) and paragangliomas (PGLs) with germline SDHx or VHL mutations have pseudohypoxic gene expression signatures. We hypothesized that PC/PGLs containing SDHx or VHL mutations, and SDH-deficient gastrointestinal stromal tumours (GISTs), would overexpress miR-210 relative to non-SDH or -VHL-mutated counterparts. MiR-210 was analysed by quantitative PCR in: (a) 39 PC/PGLs, according to genotype (1 SDHA, 5 SDHB, 7 VHL, 3 NF1, 7 RET, 15 sporadic, 1 unknown) and pathology (18 benign, 8 atypical, 11 malignant, 2 unknown); (b) 18 gastrointestinal stromal tumours, according to SDHB immunoreactivity (9 SDH-deficient and 9 SDH-proficient); and (c) two novel SDHB-mutant neurosphere cell lines. MiR-210 was higher in SDHx- or VHL-mutated PC/PGLs (7.6 fold) compared to tumours without SDHx or VHL mutations (p=0.0016). MiR-210 was higher in malignant than in unequivocally benign PC/PGLs (p=0.05) but significance was lost when benign and atypical tumours were combined (p=0.08). In multivariate analysis, elevated miR-210 was significantly associated with SDHx or VHL mutation, but not with malignancy. In GISTs, miR-210 was higher in SDH-deficient (median 2.58) compared to SDH-proficient tumours (median 0.60; p=0.0078). MiR-210 was higher in patient-derived neurosphere cell lines containing SDHB mutations (6.5-fold increase) compared to normal controls, in normoxic conditions (p<.01). Furthermore, siRNA-knockdown of SDHB in HEK293 cells increased miR-210 by 2.7-fold (p = 0.001) under normoxia. Overall, our results suggest that SDH deficiency in PC, PGL and GISTs induces miR-210 expression and substantiates the role of aberrant hypoxic-type cellular responses in the development of these tumours.
    Endocrine Related Cancer 03/2014; · 5.26 Impact Factor
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    ABSTRACT: Although pancreatoduodenectomy (PD) with mesenterico-portal vein resection (VR) can be performed safely in patients with resectable pancreatic ductal adenocarcinoma (PDAC), the impact of this approach on long-term survival is controversial. Analyses of a prospectively collected database revealed 122 consecutive patients with PDAC who underwent PD with (PD+VR) or without (PD-VR) VR between January 2004 and May 2012. Clinical data, operative results, and survival outcomes were analysed. Sixty-four (53 %) patients underwent PD+VR. The majority (84 %) of the venous reconstructions were performed with a primary end-to-end anastomosis. Demographic and postoperative outcomes were similar between the two groups. American Society of Anesthesiologists (ASA) score, duration of operation, intraoperative blood loss, and blood transfusion requirement were significantly greater in the PD+VR group compared with the PD-VR group. Furthermore, the tumor size was larger, and the rates of periuncinate neural invasion and positive resection margin were higher in the PD+VR group compared with the PD-VR group. Histological venous involvement occurred in 47 of 62 (76 %) patients in the PD+VR group. At a median follow-up of 29 months, the median overall survival (OS) was 18 months for the PD+VR group, and 31 months for the PD-VR group (p = 0.016). ASA score, lymph node metastasis, neurovascular invasion, and tumor differentiation were predictive of survival. The need for VR in itself was not prognostic of survival. PD with VR has similar morbidity but worse OS compared with a PD-VR. Although VR is not predictive of survival, tumors requiring a PD+VR have more adverse biological features.
    Annals of Surgical Oncology 02/2014; · 4.12 Impact Factor
  • European heart journal cardiovascular Imaging. 02/2014;
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    ABSTRACT: Accurate clinical and pathological data underpins all translational cancer research. Although synoptic reporting has largely replaced free text reporting for the assessment of most major cancer types, much of the historical pathological resources of research institutions were reported in free text format.We sought to assess the accuracy of data mining by relatively unskilled assessors (first year medical students) based on free text reports when compared to less skilled assessors (administrative assistance) based on synoptic reports.Four first year medical students were given formal instruction in the TNM staging system and printed material outlining the 7th edition 2009 AJCC staging system. They were asked to extract basic pathological data from all colon cancers resected over an 18 month period at our institution (group 1). As a control group, administrative assistants without formal training were asked to extract the same data from a consecutive 18 month cohort (group 2).In group 1 there were 417 cases, whereas there were 337 cases in group 2. There were similar numbers of stage py0 (1.9% vs 0%), stage 1 (15.2% vs 15.7%), stage 2A (21.3% vs 24.1%) stage 2C (0.7% to 0.2%), stage 3A (8.2% vs 2.3%), stage 3C (11% vs 11%) and stage 4A (3.5% vs 1.2%). In contrast the number of cases of p3B disease were markedly different between the two cohorts (33.3% compared to 17.3%).We are currently investigating the reason for this discrepancy, but we suspect this is due to incorrect classification of pN1C disease due to the difficulty of those without formal pathology training distinguishing extramural tumour nodules from other findings in the report. In conclusion, quality control processes are vital to ensure correct pathology data is mined from reports.
    Pathology 02/2014; 46 Suppl 1:S113. · 2.66 Impact Factor
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    ABSTRACT: Background Laparoscopic sleeve gastrectomy (SG) is gaining popularity as a revision option following failed laparoscopic adjustable gastric banding (LAGB). Data have shown that single stage revisions may be associated with a higher complication rate. A histological basis for this observation has not been studied. Objectives Document the histological properties of the LAGB capsule across the gastric staple line following SG at various time points after LAGB removal. Setting St George Private Hospital – Sydney, Australia. Royal North Shore Hospital – Sydney, Australia Methods Gastric sleeve specimens of all LAGB to SG revisions were identified from January to May 2013 and underwent histological evaluation of the LAGB capsule. Single blinded pathologist interpretation was performed, with inflammation, fibrosis, neovascularisation, foreign body (FB) reaction and wall thickness assessed semi-quantitatively and scored from 0-3. Based on combined features, an attempt was made to predict the timing of revision surgery. Results The study identified 19 revisions performed for inadequate excess body weight loss or weight regain. The mean age for revision was 44 (19-65). The minimum time to revision was 42 days, the longest 1,188 days. There were no surgical complications. Varying degrees of inflammation and fibrosis were common features at all time periods. Angiogenesis, neovascularisation and FB reaction were prominent in revisions performed before 80 days. The gastric wall was thicker during early revision. The optimal time to perform revision was difficult to determine. Conclusions LAGB caused varying degrees of inflammatory and FB reaction that time did not fully resolve. The lower leak rates observed with delayed revisions do not appear to be attributable to gastric histology.
    Surgery for Obesity and Related Diseases 01/2014; · 4.12 Impact Factor
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    ABSTRACT: This study aimed to investigate whether maternal cigarette smoke exposure can disrupt fetal kidney development by changing the expression of growth and transcription factors essential for renal development, and thereafter predispose the offspring to chronic kidney disease later in life. Female Balb/c mice (6 weeks) were exposed either to cigarette smoke or air under identical conditions, 6 weeks prior to mating, during gestation and during lactation. Male offspring were sacrificed at three time points, postnatal day (P)1, P20 (weaning age), and 13 weeks (mature age). Blood, urine, and kidneys were collected for analysis. At P1, the developmental genes fibroblast growth factor 2, glial cell-line derived neurotrophic factor and paired box 2 were upregulated at mRNA and protein levels; whilst fibroblast growth factor (FGF) 7 and FGF10 were downregulated. At P20, mRNA expression of FGF2, FGF10 and Wingless-type 4 was upregulated by maternal smoke exposure. These changes were normalised in adulthood. Nephron development was delayed, with fewer nephron numbers from P1 persisted to adulthood; while glomerular volume was increased at P20 but reduced in adulthood. Pro-inflammatory marker monocyte chemoatractant protein 1 (MCP1) was increased in the kidney by maternal smoke exposure. These changes were accompanied by an increased albumin/creatinine ratio in adulthood, suggesting reduced renal dysfunction. In conclusion maternal cigarette smoke exposure prior to and during pregnancy, as well as lactation leads to significant renal underdevelopment and functional abnormalities in adulthood. This study confirms the hypothesis that maternal smoking predisposes offspring to chronic kidney disorders.
    PLoS ONE 01/2014; 9(7):e103443. · 3.53 Impact Factor
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    ABSTRACT: Papillary thyroid cancer (PTC) persistence or recurrence and the need for long-term surveillance can cause significant inconvenience and morbidity in patients. Currently, recurrence risk stratification is accomplished by using clinicopathologic factors, and serum thyroglobulin is the only commercially available marker for persistent or recurrent disease. The objective of this study was to determine microRNA (miRNA) expression in PTC and determine whether 1 or more miRNAs could be measured in plasma as a biomarker for recurrence. Patients with recurrent PTC (Rc-PTC) and those without recurrence (NR-PTC) were retrospectively recruited for a comparison of their tumor miRNA profiles. Patients with either newly diagnosed PTC or multinodular goiter who were undergoing total thyroidectomy were prospectively recruited for an analysis of preoperative and postoperative circulating miRNA levels. Healthy volunteers were recruited as the control group. MicroRNA-222 and miR-146b were over-expressed 10.8-fold and 8.9-fold, respectively, in Rc-PTC tumors compared with NR-PTC tumors (P = .014 and P = .038, respectively). In plasma from preoperative PTC patients, levels of miR-222 and miR-146b were higher compared with the levels in plasma from healthy volunteers (P < .01 for both). Reductions of 2.7-fold and 5.1-fold were observed in the plasma levels of miR-222 and miR-146b, respectively, after total thyroidectomy (P = .03 for both). This study demonstrated that tumor levels of miR-222 and miR-146b are associated with PTC recurrence and that miR-222 and miR-146b levels in the circulation correspond to the presence of PTC. The potential of these miRNAs as tumor biomarkers to improve patient stratification according to the risk of recurrence and as circulating biomarkers for PTC surveillance warrants further study. Cancer 2013;119:4358-4365. © 2013 American Cancer Society.
    Cancer 12/2013; 119(24):4358-65. · 5.20 Impact Factor
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    ABSTRACT: Fibroblast activation plays a critical role in diabetic nephropathy (DN). The Ca(2+)-activated K(+) channel KCa3.1 mediates cellular proliferation of many cell types including fibroblasts. KCa3.1 has been reported to be a potential molecular target for pharmacological intervention in a diverse array of clinical conditions. However, the role of KCa3.1 in the activation of myofibroblasts in DN is unknown. These studies assessed the effect of KCa3.1 blockade on renal injury in experimental diabetes. As TGF-β1 plays a central role in the activation of fibroblasts to myofibroblasts in renal interstitial fibrosis, human primary renal interstitial fibroblasts were incubated with TGF-β1 +/- the selective inhibitor of KCa3.1, TRAM34, for 48 h. Two streptozotocin-induced diabetic mouse models were used in this study: wild-type KCa3.1+/+ and KCa3.1-/- mice, and secondly eNOS-/- mice treated with or without a selective inhibitor of KCa3.1 (TRAM34). Then, markers of fibroblast activation and fibrosis were determined. Blockade of KCa3.1 inhibited the upregulation of type I collagen, fibronectin, α-smooth muscle actin, vimentin and fibroblast-specific protein-1 in renal fibroblasts exposed to TGF-β1 and in kidneys from diabetic mice. TRAM34 reduced TGF-β1-induced phosphorylation of Smad2/3 and ERK1/2 but not P38 and JNK MAPK in interstitial fibroblasts. These results suggest that blockade of KCa3.1 attenuates diabetic renal interstitial fibrogenesis through inhibiting activation of fibroblasts and phosphorylation of Smad2/3 and ERK1/2. Therefore, therapeutic interventions to prevent or ameliorate DN through targeted inhibition of KCa3.1 deserve further consideration.
    Nephrology Dialysis Transplantation 10/2013; · 3.37 Impact Factor
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    ABSTRACT: BACKGROUND: Papillary thyroid cancer (PTC) persistence or recurrence and the need for long-term surveillance can cause sig-nificant inconvenience and morbidity in patients. Currently, recurrence risk stratification is accomplished by using clinicopatho-logic factors, and serum thyroglobulin is the only commercially available marker for persistent or recurrent disease. The objective of this study was to determine microRNA (miRNA) expression in PTC and determine whether 1 or more miRNAs could be measured in plasma as a biomarker for recurrence. METHODS: Patients with recurrent PTC (Rc-PTC) and those without recur-rence (NR-PTC) were retrospectively recruited for a comparison of their tumor miRNA profiles. Patients with either newly diagnosed PTC or multinodular goiter who were undergoing total thyroidectomy were prospectively recruited for an analysis of preoperative and postoperative circulating miRNA levels. Healthy volunteers were recruited as the control group. RESULTS: MicroRNA-222 and miR-146b were over-expressed 10.8-fold and 8.9-fold, respectively, in Rc-PTC tumors compared with NR-PTC tumors (P 5.014 and P 5.038, respectively). In plasma from preoperative PTC patients, levels of miR-222 and miR-146b were higher compared with the lev-els in plasma from healthy volunteers (P <.01 for both). Reductions of 2.7-fold and 5.1-fold were observed in the plasma levels of miR-222 and miR-146b, respectively, after total thyroidectomy (P 5.03 for both). CONCLUSIONS: This study demonstrated that tumor lev-els of miR-222 and miR-146b are associated with PTC recurrence and that miR-222 and miR-146b levels in the circulation correspond to the presence of PTC. The potential of these miRNAs as tumor biomarkers to improve patient stratification according to the risk of recurrence and as circulating biomarkers for PTC surveillance warrants further study. Cancer 2013;000:000-000. V C 2013 American Cancer Society.
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    ABSTRACT: Early inferior pancreaticoduodenal artery (IPDA) ligation reduces intraoperative blood loss during pancreatoduodenectomy, but the impact on oncologic and long-term outcomes remains unknown. The aim of this study was to review the impact of complete pancreatic head devascularization during pancreatoduodenectomy on blood loss, transfusion rates, and clinicopathologic outcomes. Clinicopathologic and outcome data were retrieved from a prospective database for all pancreatoduodenectomies performed from April 2004 to November 2010 and compared between early (IPDA+; n = 62) and late (IPDA-; n = 65) IPDA ligation groups. Early IPDA ligation was associated with reduced blood loss (394 ± 21 vs 679 ± 24 ml, P < .001) and perioperative transfusion (P = .031). A trend toward improved R0 resection was seen in patients with pancreatic adenocarcinoma (IPDA+ vs IPDA-, 100% vs 82%; P = .059), but this did not translate to improved 2-year (IPDA+ vs IPDA-, 76% vs 65%; P = .426) or overall (P = .82) survival. Early IPDA ligation reduces blood loss and transfusion requirements. Despite overall survival being unchanged, a trend toward improved R0 resection is encouraging and justifies further studies to ascertain the true oncologic significance of this technique.
    American journal of surgery 06/2013; · 2.36 Impact Factor
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    ABSTRACT: AIM: We assessed the diagnostic accuracy of epidermal growth factor receptor (EGFR) mutant-specific antibodies for detecting two common activating EGFR mutations. METHODS: Immunohistochemical expression of mutation-specific antibodies against EGFR exon 19 deletion E746-A750 ((c.2235_2249del15 or c.2236_2250del15, p. Glu746_Ala750del) and exon 21 L858R point mutation (c.2573T>G, p.Leu858Arg) were assessed in a cohort of 204 resected early stage node negative lung adenocarcinomas, and protein expression was compared with DNA analysis results from mass spectrometry analysis. RESULTS: Of seven cases with L858R point mutation, six were positive by immunohistochemistry (IHC). There were three false positive cases using L858R IHC (sensitivity 85.7%, specificity 98.5%, positive predictive value 66.7%, negative predictive value 99.5%). All seven E746-A750 exon 19 deletions identified by mutation analysis were positive by IHC. Four additional cases were positive for exon 19 IHC but negative by mutation analysis. The sensitivity of exon 19 IHC for E746-A750 was 100%, specificity 98.0%, positive predictive value 63.6% and negative predictive value 100%. CONCLUSIONS: Mutant-specific EGFR IHC has good specificity and sensitivity for identifying targeted activating EGFR mutations. Although inferior to molecular genetic analysis of the EGFR gene, IHC is highly specific and sensitive for the targeted EGFR mutations. The antibodies are likely to be of clinical value in cases where limited tumour material is available, or in situations where molecular genetic analysis is not readily available.
    Journal of clinical pathology 06/2013; · 2.43 Impact Factor
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    ABSTRACT: The Ca(2+)-activated K(+) channel KCa3.1 mediates cellular signaling processes associated with dysfunction of vasculature. However, the role of KCa3.1 in diabetic nephropathy is unknown. We sought to assess whether KCa3.1 mediates the development of renal fibrosis in two animal models of diabetic nephropathy. Wild-type and KCa3.1(-/-) mice, and secondly eNOS(-/-) mice, were induced to diabetes with streptozotocin and then treated with/without a selective inhibitor of KCa3.1 (TRAM34). Our results have shown that the albumin-to-creatinine ratio significantly decreased in diabetic KCa3.1(-/-) mice compared with diabetic wild-type mice and in diabetic eNOS(-/-) mice treated with TRAM34 compared with diabetic mice. The expression of monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), F4/80, plasminogen activator inhibitor type 1 (PAI-1), and type III and IV collagen significantly decreased (P < 0.01) in kidneys of diabetic KCa3.1(-/-) mice compared with diabetic wild-type mice. Similarly, TRAM34 reduced the expression of inflammatory and fibrotic markers described above in diabetic eNOS(-/-) mice. Furthermore, blocking the KCa3.1 channel in both animal models led to a reduction of transforming growth factor-β1 (TGF-β1), TGF-β1 type II receptor (TβRII), and phosphorylation of Smad2/3. Our results provide evidence that KCa3.1 mediates renal fibrosis in diabetic nephropathy through the TGF-β1/Smad signaling pathway. Blockade of KCa3.1 may be a novel target for therapeutic intervention in patients with diabetic nephropathy.
    Diabetes 05/2013; · 7.90 Impact Factor
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    ABSTRACT: While colorectal cancer is increasingly common in western populations, anatomical concepts regarding the anatomy of resection have remained static. In attempting to maximise the chance of surgical cure, surgeons and pathologists are now focussing upon the quality of oncological resection. Amongst pathological indices of interest, lymph node yield and the apical lymph node specifically are increasingly being shown to be reliable markers of the adequacy of oncologic resection. However, the position of the apical node in particular, is highly subjective and may not always correlate with the anatomical boundaries ultimately defining resection. We argue that the present definition of the apical lymph node is overly subjective and requires re-defining based on fixed anatomical landmarks. We propose that this new definition include a block of tissue inferolateral to the Trunk of Henle (the anatomical apical lymph node compartment).
    European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 03/2013; · 2.56 Impact Factor
  • Anthony J Gill
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    ABSTRACT: So the Scottish poet Robert Burns drew an analogy between the suffering of a field mouse whose nest has been overturned by a plough to the unexpected way in which human life can be disrupted by events beyond our control. Burns is saying that mice and humans facing unforseen catastrophes such as cancer have much in common. Unfortunately, whilst it is clear that there are some similarities between mouse models of cancer and cancer as seen in the clinic, the artificial conditions presented by animal models are very different to those found in humans with cancer. It cannot be assumed that even basic pathophysiologic processes found in animal models are anything more than a model (literally a 'likeness') of similar processes found in the clinic. With these caveats, Barone et al's paper published in this edition of Colorectal Disease (REF1) provides important insights into the pathophysiology of cytokeratin positive cells in the bone marrow of patients with colorectal cancer. © 2013 The Authors. Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.
    Colorectal Disease 03/2013; · 2.08 Impact Factor
  • European Heart Journal 03/2013; · 14.72 Impact Factor
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    ABSTRACT: PURPOSEIndividuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. PATIENTS AND METHODS We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ampulla of Vater. RESULTS: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis; two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome; and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. CONCLUSION Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ampulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.
    Journal of Clinical Oncology 02/2013; · 18.04 Impact Factor
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    ABSTRACT: BACKGROUND: Therapeutic central neck dissection (CND) is an accepted part of the management of papillary thyroid carcinoma (PTC), while prophylactic CND remains controversial. Regardless of the indication for CND, the lower anatomic border of the central compartment, specifically the inclusion or otherwise of level VII, is not always clearly defined in the literature. This study aimed to determine if the routine inclusion of level VII lymph node dissection as part of CND confers increased utility in the detection of macrometastatic lymph nodes compared with level VI dissection alone. METHOD: This was a prospective cohort study of patients undergoing CND for PTC at a tertiary referral center. All patients received either a prophylactic or therapeutic CND. The CND specimens were divided by the surgeon into level VI and level VII at the level of the suprasternal notch and submitted separately for histopathology. Criteria for macroscopic lymph node disease were taken from the American Joint Committee on Cancer (AJCC) recommendations for breast cancer. RESULTS: A total of 45 patients with PTC underwent total thyroidectomy and routine CND, at a tertiary referral center; 77 % of the therapeutic CND group had positive level VI lymph nodes, and 38 % had positive level VII lymph nodes. Of the prophylactic CND group, 50 % of patients had positive level VI nodes and 16 % has positive level VII nodes detected. All patients with positive level VII lymph nodes in the prophylactic CND group had macrometastatic disease. Temporary hypocalcemia rate was 31 % in the therapeutic group and 6 % in the prophylactic CND group. One patient experienced permanent hypoparathyroidism. There was no vascular injury or recurrent laryngeal nerve palsy in either group. CONCLUSIONS: CND incorporating both level VI and level VII can be undertaken safely through a cervical incision with no increased risk of permanent complications of hypoparathyroidism or recurrent laryngeal nerve injury. Failure to include level VII as part of CND will leave significant macrometastatic nodal disease behind in both therapeutic and prophylactic dissections. As level VII is in direct anatomic continuity with the pretracheal level VI nodes, it should be routinely included as part of every CND.
    Annals of Surgical Oncology 01/2013; · 4.12 Impact Factor

Publication Stats

783 Citations
434.79 Total Impact Points

Institutions

  • 2007–2014
    • University of Sydney
      • School of Molecular Bioscience
      Sydney, New South Wales, Australia
    • Kolling Institute of Medical Research
      Sydney, New South Wales, Australia
  • 2005–2014
    • Royal North Shore Hospital
      Sydney, New South Wales, Australia