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Background: Previous studies have revealed the role of dysregulated urokinase plasminogen activator (encoded by PLAU) expression and activity in several pathways associated with cancer progression. However, systematic investigation into the association of PLAU expression with factors that modulate PDAC (pancreatic ductal adenocarcinoma) progression is lacking, such as those affecting stromal (pancreatic stellate cell, PSC)-cancer cell interactions, tumour immunity, PDAC subtypes and clinical outcomes from potential PLAU inhibition. Methods: This study used an integrated bioinformatics approach to identify prognostic markers correlated with PLAU expression using different transcriptomics, proteomics, and clinical data sets. We then determined the association of dysregulated PLAU and correlated signatures with oncogenic pathways, metastatic phenotypes, stroma, immunosuppressive tumour microenvironment (TME) and clinical outcome. Finally, using an in vivo orthotopic model of pancreatic cancer, we confirmed the predicted effect of inhibiting PLAU on tumour growth and metastasis. Results: Our analyses revealed that PLAU upregulation is not only associated with numerous other prognostic markers but also associated with the activation of various oncogenic signalling pathways, aggressive phenotypes relevant to PDAC growth and metastasis, such as proliferation, epithelial-mesenchymal transition (EMT), stemness, hypoxia, extracellular cell matrix (ECM) degradation, upregulation of stromal signatures, and immune suppression in the tumour microenvironment (TME). Moreover, the upregulation of PLAU was directly connected with signalling pathways known to mediate PSC-cancer cell interactions. Furthermore, PLAU upregulation was associated with the aggressive basal/squamous phenotype of PDAC and significantly reduced overall survival, indicating that this subset of patients may benefit from therapeutic interventions to inhibit PLAU activity. Our studies with a clinically relevant orthotopic pancreatic model showed that even short-term PLAU inhibition is sufficient to significantly halt tumour growth and, importantly, eliminate visible metastasis. Conclusion: Elevated PLAU correlates with increased aggressive phenotypes, stromal score, and immune suppression in PDAC. PLAU upregulation is also closely associated with the basal subtype type of PDAC; patients with this subtype are at high risk of mortality from the disease and may benefit from therapeutic targeting of PLAU. [ABSTRACT FROM AUTHOR]

Background: Day‐only laparoscopic cholecystectomy (DOLC) has been shown to be safe and feasible yet has not been widely implemented in Australia. This study explores the introduction of routine DOLC to Westmead Hospital, and highlights the barriers to its implementation. Methods: Routine day‐only cholecystectomy protocol was introduced at Westmead Hospital in 2014. A retrospective review of patients who underwent elective laparoscopic cholecystectomy during a 12‐month period in 2014 was compared to a 12‐month period in 2018, to examine the changes in practice after implementation of a unit protocol. Data were collected on patient demographics, admission category, outcomes and re‐presentations. Results: A total of 282 patients were included in the study, of these 169 were booked as day procedures, with 124 (73%) successfully discharged on the same day. There was a significant increase in the proportion of patients booked as day‐only from 2014 to 2018 (48% versus 73%, P < 0.001). Day‐only failure rates (unplanned overnight admissions), readmissions and complication rates were comparable between the two periods. The most common reason for unplanned overnight admissions were due to intraoperative findings (n = 28/45). Conclusion: Routine DOLC can be adopted in Australian hospitals without compromise to patient safety. Unplanned overnight admission is predominantly due to unexpected surgical pathology and can be reduced by protocols for the use of drains and planned outpatient endoscopic retrograde cholangiopancreatography. Unplanned outpatient review can be minimized by optimizing both intra‐ and post‐operative pain management. Individual surgeon and anaesthetist preferences remain an obstacle to a standardized protocol in the Australian setting. [ABSTRACT FROM AUTHOR]

A large right colonic intramural haematoma with contrast extravasation (arrowhead) (indicating ongoing haemorrhage into the haematoma) is demonstrated. The serosa of the right colon has been markedly stretched by the haematoma (arrowhead). gl The right colon and hepatic flexure were mobilized and the intramural haematoma evacuated. Computed tomography scan of the abdomen and pelvis with intravenous contrast was performed which demonstrated a large right colon mural haematoma measuring 11 × 8 × 7 cm, with contrast extravasation into the haematoma indicating active haemorrhage (Figs 1,2). [Extracted from the article]

GLO:HWR/01nov19:ans14858-fig-0001.jpg PHOTO (COLOR): Coronal computed tomography image demonstrating a complex cystic lesion in the left upper quadrant with internal serpiginous hyperdensity, corresponding to the laparotomy pad. gl The patient underwent laparotomy through a left subcostal incision which led directly to the cyst. The most common way of diagnosing gossypiboma is through radiography and the best diagnostic imaging modality is computed tomography scan.[[3], [6], [8]] The risk factors for gossypiboma include emergency surgery, long duration of procedure, unexpected changes during the procedure, disorganized and inexperienced staff, as well as surgery in obese patients.[[2], [7]]. [Extracted from the article]

Simple Summary: Pancreatic cancer (PC) has a poor prognosis. Even though surgical resection and adjuvant chemotherapy is the most effective therapy, recurrence remains common. In this paper, we investigate the effectiveness of dual inhibition of hepatocyte growth factor (HGF) and c-MET when used as treatment after surgical resection of PC in mice. The HGF/c-Met pathway is a major mediator of pancreatic stellate cell (stromal cell)—PC cell interactions. Using single-cell RNA sequencing, we also investigated the existence of co-metastasising cells, circulating pancreatic stellate cells (cPSCs), as facilitators of PC metastasis. We found that HGF/c-Met inhibition reduced both the risk and rate of disease progression after resection and that this effect was associated with reduced cPSC counts. In conclusion, this study is the first to demonstrate the efficacy of adjuvant HGF/c-Met inhibition and is also the first to confirm the existence of cPSCs in PC. Background: Inhibition of hepatocyte growth factor (HGF)/c-MET pathway, a major mediator of pancreatic stellate cell (PSC)−PC cell interactions, retards local and distant cancer progression. This study examines the use of this treatment in preventing PC progression after resection. We further investigate the postulated existence of circulating PSCs (cPSCs) as a mediator of metastatic PC. Methods: Two orthotopic PC mouse models, produced by implantation of a mixture of luciferase-tagged human pancreatic cancer cells (AsPC-1), and human PSCs were used. Model 1 mice underwent distal pancreatectomy 3-weeks post-implantation (n = 62). One-week post-resection, mice were randomised to four treatments of 8 weeks: (i) IgG, (ii) gemcitabine (G), (iii) HGF/c-MET inhibition (HiCi) and (iv) HiCi + G. Tumour burden was assessed longitudinally by bioluminescence. Circulating tumour cells and cPSCs were enriched by filtration. Tumours of Model 2 mice progressed for 8 weeks prior to the collection of primary tumour, metastases and blood for single-cell RNA-sequencing (scRNA-seq). Results: HiCi treatments: (1) reduced both the risk and rate of disease progression after resection; (2) demonstrated an anti-angiogenic effect on immunohistochemistry; (3) reduced cPSC counts. cPSCs were identified using immunocytochemistry (α-smooth muscle actin+, pan-cytokeratin−, CD45−), and by specific PSC markers. scRNA-seq confirmed the existence of cPSCs and identified potential genes associated with development into cPSCs. Conclusions: This study is the first to demonstrate the efficacy of adjuvant HGF/c-Met inhibition for PC and provides the first confirmation of the existence of circulating PSCs. [ABSTRACT FROM AUTHOR]

Background: Previous studies have revealed the role of dysregulated urokinase plasminogen activator (encoded by PLAU ) expression and activity in several pathways associated with cancer progression. However, systematic investigation into the association of PLAU expression with factors that modulate PDAC (pancreatic ductal adenocarcinoma) progression is lacking, such as those affecting stromal (pancreatic stellate cell, PSC)-cancer cell interactions, tumour immunity, PDAC subtypes and clinical outcomes from potential PLAU inhibition., Methods: This study used an integrated bioinformatics approach to identify prognostic markers correlated with PLAU expression using different transcriptomics, proteomics, and clinical data sets. We then determined the association of dysregulated PLAU and correlated signatures with oncogenic pathways, metastatic phenotypes, stroma, immunosuppressive tumour microenvironment (TME) and clinical outcome. Finally, using an in vivo orthotopic model of pancreatic cancer, we confirmed the predicted effect of inhibiting PLAU on tumour growth and metastasis., Results: Our analyses revealed that PLAU upregulation is not only associated with numerous other prognostic markers but also associated with the activation of various oncogenic signalling pathways, aggressive phenotypes relevant to PDAC growth and metastasis, such as proliferation, epithelial-mesenchymal transition (EMT), stemness, hypoxia, extracellular cell matrix (ECM) degradation, upregulation of stromal signatures, and immune suppression in the tumour microenvironment (TME). Moreover, the upregulation of PLAU was directly connected with signalling pathways known to mediate PSC-cancer cell interactions. Furthermore, PLAU upregulation was associated with the aggressive basal/squamous phenotype of PDAC and significantly reduced overall survival, indicating that this subset of patients may benefit from therapeutic interventions to inhibit PLAU activity. Our studies with a clinically relevant orthotopic pancreatic model showed that even short-term PLAU inhibition is sufficient to significantly halt tumour growth and, importantly, eliminate visible metastasis., Conclusion: Elevated PLAU correlates with increased aggressive phenotypes, stromal score, and immune suppression in PDAC. PLAU upregulation is also closely associated with the basal subtype type of PDAC; patients with this subtype are at high risk of mortality from the disease and may benefit from therapeutic targeting of PLAU ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hosen, Uddin, Xu, Buckley, Perera, Pang, Mekapogu, Moni, Notta, Gallinger, Pirola, Wilson, Ranson, Goldstein and Apte.)

Background: The detection and quantification of circulating tumour cells (CTCs) in pancreatic cancer (PC) has the potential to provide prognostic information. The aim of this review was to provide an overview of the literature surrounding CTCs in PC., Methods: A systematic literature review on CTCs in PC between 2005-2020 was performed. Data based on peripheral vein samples were used to determine the positivity rate of CTCs, their prognostic significance and their relative numbers compared to portal vein (PV) samples., Results: The overall CTC detection rate in forty-four articles was 65% (95%CI: 55-75%). Detection rate for CellSearch was 26% (95%CI: 14-38%), which was lower than for both filtration and microfluidic techniques. In nine studies with >50 patients, overall survival was worse with CTC positivity (HR 1.82; 95%CI: 1.61-2.05). Five of seven studies which described PV CTC collection provided patient-level data. PV CTC yield was 7.7-fold (95%CI 1.35-43.9) that of peripheral blood., Conclusions: CTCs were detected in the peripheral circulation of most patients with PC and may be related to prognosis and disease stage. PV blood contains more CTCs than peripheral blood sampling. This review points to the maturation of techniques of CTC enrichment, and its evidence base for eventual clinical deployment., Competing Interests: Declaration of competing interest None., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

There is a lack of satisfactory animal models to study adjuvant and/or neoadjuvant therapy in patients being considered for surgery of pancreatic cancer (PC). To address this deficiency, we describe a mouse model involving orthotopic implantation of PC followed by distal pancreatectomy and splenectomy. The model has been demonstrated to be safe and suitably flexible for the study of various therapeutic approaches in adjuvant and neo adjuvant settings. In this model, a pancreatic tumor is first generated by implanting a mixture of human pancreatic cancer cells (luciferase-tagged AsPC-1) and human cancer associated pancreatic stellate cells into the distal pancreas of Balb/c athymic nude mice. After three weeks, the cancer is resected by re-laparotomy, distal pancreatectomy and splenectomy. In this model, bioluminescence imaging can be used to follow the progress of cancer development and effects of resection/treatments. Following resection, adjuvant therapy can be given. Alternatively, neoadjuvant treatment can be given prior to resection. Representative data from 45 mice are presented. All mice underwent successful distal pancreatectomy/splenectomy with no issues of hemostasis. A macroscopic proximal pancreatic margin greater than 5 mm was achieved in 43 (96%) mice. The technical success rate of pancreatic resection was 100%, with 0% early mortality and morbidity. None of the animals died during the week after resection. In summary, we describe a robust and reproducible technique for a surgical resection model of pancreatic cancer in mice which mimics the clinical scenario. The model may be useful for the testing of both adjuvant and neoadjuvant treatments.

Pancreatic stellate cells (PSCs) are known to play an important role in facilitating pancreatic cancer progression-both in terms of local tumour growth as well as the establishment of metastases. We have previously demonstrated that PSCs from the primary cancer seed to distant metastatic sites. We therefore hypothesise that PSCs circulate along with pancreatic cancer cells (circulating tumour cells-CTCs) to help create a growth permissive microenvironment at distant metastatic sites. This review aims to explore the concept of circulating PSCs in pancreatic cancer and suggests future directions for research in this area., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Adrenocortical carcinoma (ACC) is a rare malignancy that carries a poor prognosis. There has yet to be a large Australian series that documents the characteristics of ACC and there are a paucity of data on management and the long-term outcomes. We sought to provide a unique insight into the management of ACC in Australia as well as to identify factors associated with prognosis and survival., Methods: A multivariate analysis of a cohort of patients identified with ACC between 1998 and 2013 was undertaken. Recurrence-free survival (RFS) and overall survival (OS) were assessed as the main outcome measures and correlated with multiple clinical variables in order to identify prognostic markers., Results: Of the 104 patients identified, a total of 98 patients with complete clinical and outcome data were included in the study. Median OS was 56 months, with the 5-year survival being 48 % (95 % confidence interval 36-59). On multivariate analysis, age ≥50 years, metastases at presentation, and evidence of extra-adrenal invasion were found to be statistically associated with reduced OS. RFS was analyzed in patients without metastases. On multivariate analysis, extra-adrenal invasion and no preoperative endocrine investigations were found to be statistically significant poor prognostic factors, with a non-significant trend for higher individual surgeon volume to be associated with improved resection margins and RFS., Conclusions: We present clinical outcomes and prognostic factors for patients with ACC in a landmark Australian series. We suggest that management in a specialized tertiary endocrine and/or surgical oncology unit is more likely to lead to improved outcomes.

Background: Chemical burns account for a small proportion of total burns in children, but may require specific first aid and different modes of prevention., Methods: A retrospective study between 2006 and 2012 of children ≤16 years treated with chemical burns at a specialist paediatric burn centre. Data were extracted from a prospectively maintained database., Results: 56 episodes of chemical burns occurred during the study period. The majority (54%) occurred in boys. There were 39 (72%) patients <10 years and 17 (39%) ≥10 years. Median total body surface area burnt was 1% with nine (16%) patients requiring skin grafting. Only 24 (45%) had adequate first aid. The majority (n=46, 82%) of chemical burns occurred in the domestic setting, especially in the <10 years age group (P=0.052). Non-intentional exposure of chemicals by an unattended child accounted for half of all (n=22, 49%) chemical burns <10 years of age. Eight (47%) burns in patients ≥10 years resulted from self-harm. The most common aetiological agents were household cleaners and aerosols in the younger and older age groups respectively., Conclusion: Chemical burns remain infrequent but potentially preventable. These burns mainly occur in the domestic setting due to non-intentional exposure of household chemicals in children <10, and due to deliberate self-harm in children ≥10. The use of child-resistant packaging, similar to that used for medications, and improved parental practices could help decrease the incidence of burns in children <10., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Background: Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. The aim of this study was to identify novel protein signatures that would predict clinical outcomes in a large cohort of patients with ACC based on data from previous gene expression microarray studies., Materials and Methods: A tissue microarray was generated from the paraffin tissue blocks of 61 patients with clinical outcomes data. Selected protein biomarkers based on previous gene expression microarray profiling studies were selected, and immunohistochemistry staining was performed. Staining patterns were correlated with clinical outcomes, and a multivariate analysis was undertaken to identify potential biomarkers of prognosis., Results: Median overall survival was 45 months, with a 5-year overall survival rate of 44%. Median disease-free survival was 58 months, with a 5-year disease-free survival rate of 44%. The proliferation marker Ki-67 and DNA topoisomerase TOP2A were associated with significantly poorer overall and disease-free survival. The results also showed strong correlation between the transcriptional repressor EZH2 and TOP2A expression, suggesting a novel role for EZH2 as an additional marker of prognosis. In contrast, increased expression of the BARD1 protein, with its ubiquitin ligase function, was associated with significantly improved overall and disease-free survival, which has yet to be documented for ACC., Conclusion: We present novel biomarkers that assist in determining prognosis for patients with ACC. Ki-67, TOP2A, and EZH2 were all significantly associated with poorer outcomes, whereas BARD1 was associated with improved overall survival. It is hoped that these biomarkers may help tailor additional therapy and be potential targets for directed therapy., (©AlphaMed Press.)

Aim: To describe our own experience with pyogenic liver abscesses over the past 10 years and investigate the risk factors associated with failure of initial percutaneous therapy., Methods: A retrospective study of records of 63 PLA patients presenting between 1998 and 2008 to Australian tertiary referral centre, were reviewed. Amoebic and hydatid abscesses were excluded. Demographic, clinical, radiological, and microbiological characteristics, as well as surgical/radiological interventions, were recorded., Results: Sixty-three patients (42 males, 21 females) aged 65 (± 14) years [mean ± (SD)] had prodromal symptoms for a median (interquartile range; IQR) of 7 (5-14) d. Only 59% of patients were febrile at presentation; however, the serum C-reactive protein was elevated in all 47 in whom it was measured. Liver function tests were non-specifically abnormal. 67% of patients had a solitary abscess, while 32% had > 3 abscesses with a median (IQR) diameter of 6.3 (4-9) cm. Causative organisms were: Streptococcus milleri 25%, Klebsiella pneumoniae 21%, and Escherichia coli 16%. A presumptive cryptogenic cause was most common (34%). Four patients died in this series: one from sepsis, two from advanced cancer, and one from acute myocardial infarction. The initial procedure was radiological aspiration ± drainage in 54 and surgery in two patients. 17% underwent surgical management during their hospitalization. Serum hypoalbuminaemia [mean (95% CI): 32 (29-35) g/L vs 28 (25-31) g/L, P = 0.045] on presentation was found to be the only factor related to failure of initial percutaneous therapy on univariate analysis., Conclusion: PLA is a diagnostic challenge, because the presentation of this condition is non-specific. Intravenous antibiotics and radiological drainage in the first instance allows resolution of most PLAs; However, a small proportion of patients still require surgical drainage.

Background: To determine the extent of discrepancies between ambulatory blood pressure measurement (ABPM) devices and mercury sphygmomanometry in pre-use testing in routine clinical practice and whether such discrepancies are associated with patient characteristics and subsequent 24-h ABPM readings., Methods: A retrospective analysis of a database of 683 prospectively collected records was performed. The study population comprised of patients referred for ABP monitoring at a Sydney teaching hospital. Patients had same-arm sequential measurements with a mercury sphygmomanometer and Spacelabs 90207 or 90217 device before 24-h ABPM. The discrepancy between the test devices and the standard mercury sphygmomanometer were then described by two measures, calculated for both systolic and diastolic pressures for each patient: 1) difference of means (DeltaBP average), and 2) the mean of differences between device measurement and the range of mercury sphygmomanometer readings, analogous to the British Hypertension Society protocol (DeltaBP sequential). The main outcome measures were DeltaBP average and DeltaBP sequential and their relationship to patient characteristics., Results: The median DeltaBP average was 1/2 mm Hg (ABPM device underestimation) and the median DeltaBP sequential was 3/2 mm Hg. Age, gender, arm circumference, body mass index, and degree of hypertension influenced the accuracy of ABPM readings on multivariate analysis. Device accuracy was slightly weaker in patients with higher mercury or ABPM-derived systolic BP., Conclusions: These ABPM devices are accurate enough for routine clinical use in a variety of patients. Factors such as age, weight, gender, and severity of hypertension are statistically associated with greater device error but the differences are small enough to be unlikely to affect clinical practice.