Publications by authors named "Neil D Merrett"

56 Publications

Barriers and enablers to the implementation of protocol-based imaging in pancreatic cancer: A qualitative study using the theoretical domains framework.

PLoS One 2020 17;15(12):e0243312. Epub 2020 Dec 17.

School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.

Background: Accurate pre-operative imaging plays a vital role in patient selection for surgery and in allocating stage-appropriate therapies to patients diagnosed with pancreatic cancer (PC). This study aims to: (1) understand the current diagnosis and staging practices for PC; and (2) explore the factors (barriers and enablers) that influence the use of a pancreatic protocol computed tomography (PPCT) or magnetic resonance imaging (MRI) to confirm diagnosis and/or accurately stage PC.

Methods: Semi-structured interviews were conducted with radiologists, surgeons, gastroenterologists, medical and radiation oncologists from the states of New South Wales (NSW) and Victoria, Australia. Interviews were conducted either in person or via video conferencing. All interviews were recorded, transcribed verbatim, de-identified and data were thematically coded according to the 12 domains explored within the Theoretical Domains Framework (TDF). Common belief statements were generated to compare the variation between participant responses.

Findings: In total, 21 clinicians (5 radiologists, 10 surgeons, 2 gastroenterologists, 4 medical and radiation oncologists) were interviewed over a four-month-period. Belief statements relevant to the TDF domains were generated. Across the 11 relevant domains, 20 themes and 30 specific beliefs were identified. All TDF domains, with the exception of social influences were identified by participants as relevant to protocol-based imaging using either a PPCT or MRI, with the domains of knowledge, skills and environmental context and resources being offered by most participants as being relevant in influencing their decisions.

Conclusions: To maximise outcomes and personalise therapy it is imperative that diagnosis and staging investigations using the most appropriate imaging modalities are conducted in a timely, efficient and effective manner. The results provide an understanding of specialists' opinion and behaviour in relation to a PPCT or MRI and should be used to inform the design of future interventions to improve compliance with this practice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243312PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746147PMC
January 2021

Barriers and enablers to the implementation of multidisciplinary team meetings: a qualitative study using the theoretical domains framework.

BMJ Qual Saf 2020 Nov 27. Epub 2020 Nov 27.

Monash University Faculty of Medicine, Nursing and Health Sciences, Melbourne, Victoria, Australia

Background: Evidence-based clinical practice guidelines recommend discussion by a multidisciplinary team (MDT) to review and plan the management of patients for a variety of cancers. However, not all patients diagnosed with cancer are presented at an MDT.

Objectives: (1) To identify the factors (barriers and enablers) influencing presentation of all patients to, and the perceived value of, MDT meetings in the management of patients with pancreatic cancer and; (2) to identify potential interventions that could overcome modifiable barriers and enhance enablers using the theoretical domains framework (TDF).

Methods: Semistructured interviews were conducted with radiologists, surgeons, medical and radiation oncologists, gastroenterologists, palliative care specialists and nurse specialists based in New South Wales and Victoria, Australia. Interviews were conducted either in person or via videoconferencing. All interviews were recorded, transcribed verbatim, deidentified and data were thematically coded according to the 12 domains explored within the TDF. Common belief statements were generated to compare the variation between participant responses.

Results: In total, 29 specialists were interviewed over a 4-month period. Twenty-two themes and 40 belief statements relevant to all the TDF domains were generated. Key enablers influencing MDT practices included a strong organisational focus (), beliefs about the benefits of an MDT discussion (), the use of technology, for example, videoconferencing (), the motivation to provide good quality care () and collegiality (). Barriers included: absence of palliative care representation (), the number of MDT meetings (), the cumulative cost of staff time (), the lack of capacity to discuss all patients within the allotted time () and reduced confidence to participate in discussions ().

Conclusions: The internal and external organisational structures surrounding MDT meetings ideally need to be strengthened with the development of agreed evidence-based protocols and referral pathways, a focus on resource allocation and capabilities, and a culture that fosters widespread collaboration for all stages of pancreatic cancer.
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http://dx.doi.org/10.1136/bmjqs-2020-011793DOI Listing
November 2020

Determining the CA19-9 concentration that best predicts the presence of CT-occult unresectable features in patients with pancreatic cancer: A population-based analysis.

Pancreatology 2020 Oct 11;20(7):1458-1464. Epub 2020 Aug 11.

Population Health Department, QIMR Berghofer Medical Research Institute, Queensland, Australia; School of Public Health, University of Queensland, Brisbane, Australia; School of Public Health and Social Work, Queensland University of Technology, Brisbane, Australia.

Background: Serum CA19-9 concentration may be useful in triaging patients with pancreatic cancer for more intensive staging investigations. Our aim was to identify the CA19-9 cut-point with the greatest accuracy for detecting unresectable features not identified by CT scan, and to examine the performance of this and other cut-points in predicting the outcome of staging laparoscopy (SL).

Methods: Patients with pancreatic cancer were drawn from two state-wide cancer registries between 2009 and 2011. We used classification and regression tree (CART) analysis to identify the CA19-9 cut-point which best predicted the presence of imaging-occult unresectable features, and compared its performance with that of a number of alternative cut-points. We then used logistic regression to test the association between CA19-9 concentration and detection of unresectable features in patients who underwent SL.

Results: From the CART analysis, the optimal CA19-9 cut-point was 440 U/mL. CA19-9 ≥ 150 U/mL had a similar Youden Index, but greater sensitivity (69% versus 47%). This remained true for those who had obstructive jaundice at the time of CA19-9 sampling. CA19-9 concentration greater than or equal to 110 U/mL, 150 U/mL and 200 U/mL was associated with significantly greater odds of unresectable features being detected during SL.

Conclusion: Elevated serum CA19-9 concentration is a valid marker for CT-occult unresectable features; the most clinically appropriate cut-point appears to be ≥ 150 U/mL irrespective of the presence of jaundice. Clinical trials which evaluate the value of CA19-9 in the staging algorithm for pancreatic cancer are needed before it is routinely used in clinical practice.
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http://dx.doi.org/10.1016/j.pan.2020.07.405DOI Listing
October 2020

Precision Oncology in Surgery: Patient Selection for Operable Pancreatic Cancer.

Ann Surg 2020 08;272(2):366-376

Department of Surgery, Universitätsklinikum Erlangen, Erlangen, Germany.

Objective: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection.

Background: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease.

Method: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram.

Results: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables.

Conclusions: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.
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http://dx.doi.org/10.1097/SLA.0000000000003143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373491PMC
August 2020

The Upper Gastrointestinal Cancer Registry (UGICR): a clinical quality registry to monitor and improve care in upper gastrointestinal cancers.

BMJ Open 2019 09 30;9(9):e031434. Epub 2019 Sep 30.

Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Purpose: The Upper Gastrointestinal Cancer Registry (UGICR) was developed to monitor and improve the quality of care provided to patients with upper gastrointestinal cancers in Australia.

Participants: It supports four cancer modules: pancreatic, oesophagogastric, biliary and primary liver cancer. The pancreatic cancer (PC) module was the first module to be implemented, with others being established in a staged approach. Individuals are recruited to the registry if they are aged 18 years or older, have received care for their cancer at a participating public/private hospital or private clinic in Australia and do not opt out of participation.

Findings To Date: The UGICR is governed by a multidisciplinary steering committee that provides clinical governance and oversees clinical working parties. The role of the working parties is to develop quality indicators based on best practice for each registry module, develop the minimum datasets and provide guidance in analysing and reporting of results. Data are captured from existing data sources (population-based cancer incidence registries, pathology databases and hospital-coded data) and manually from clinical records. Data collectors directly enter information into a secure web-based Research Electronic Data Capture (REDCap) data collection platform. The PC module began with a pilot phase, and subsequently, we used a formal modified Delphi consensus process to establish a core set of quality indicators for PC. The second module developed was the oesophagogastric cancer (OGC) module. Results of the 1 year pilot phases for PC and OGC modules are included in this cohort profile.

Future Plans: The UGICR will provide regular reports of risk-adjusted, benchmarked performance on a range of quality indicators that will highlight variations in care and clinical outcomes at a health service level. The registry has also been developed with the view to collect patient-reported outcomes (PROs), which will further add to our understanding of the care of patients with these cancers.
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http://dx.doi.org/10.1136/bmjopen-2019-031434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773358PMC
September 2019

Migration route of Fasciola into the liver.

JGH Open 2019 Feb 9;3(1):89-90. Epub 2018 Nov 9.

Department of Gastroenterology Liverpool Hospital Sydney New South Wales Australia.

Humans usually acquire Fasciola infection by eating contaminated aquatic vegetation, such as watercress. After ingestion, Fasciola metacercariae excyst in the duodenum. In contrast to other liver flukes (Clonorchis and Opisthorchis) that migrate through the ampulla of Vater and ascend the biliary tree, Fasciola metacercariae penetrate the duodenal wall, migrate through the peritoneal cavity, and enter the liver. After a period of migrating randomly through the liver parenchyma, they eventually reach the larger biliary ducts and mature into adults. We present a case that illustrates this migration route of Fasciola.
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http://dx.doi.org/10.1002/jgh3.12101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386738PMC
February 2019

Chemotherapy in patients with unresected pancreatic cancer in Australia: A population-based study of uptake and survival.

Asia Pac J Clin Oncol 2018 Aug 23;14(4):326-336. Epub 2018 Mar 23.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Aim: Palliative chemotherapy improves symptom control and prolongs survival in patients with unresectable pancreatic cancer, but there is a paucity of data describing its use and effectiveness in everyday practice. We explored patterns of chemotherapy use in patients with unresected pancreatic cancer in Australia and the impact of use on survival.

Methods: We reviewed the medical records of residents of New South Wales or Queensland, Australia, diagnosed with unresectable pancreatic adenocarcinoma between July 2009 and June 2011. Associations between receipt of chemotherapy and sociodemographic, clinical and health service factors were evaluated using logistic regression. We used Cox proportional hazards models to analyze associations between chemotherapy use and survival.

Results: Data were collected for 1173 eligible patients. Chemotherapy was received by 44% (n = 184/414) of patients with localized pancreatic cancer and 53% (n = 406/759) of patients with metastases. Chemotherapy receipt depended on clinical factors, such as performance status and comorbidity burden, and nonclinical factors, such as age, place of residence, multidisciplinary team review and the type of specialist first encountered. Consultation with an oncologist mitigated most of the sociodemographic and service-related disparities in chemotherapy use. The receipt of chemotherapy was associated with prolonged survival in patients with inoperable pancreatic cancer, including after adjusting for common prognostic factors.

Conclusions: These findings highlight the need to establish referral pathways to ensure that all patients have the opportunity to discuss treatment options with a medical oncologist. This is particularly relevant for health care systems covering areas with a geographically dispersed population.
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http://dx.doi.org/10.1111/ajco.12862DOI Listing
August 2018

Biliary Stenting in Patients With Pancreatic Cancer: Results From a Population-Based Cohort Study.

Pancreas 2018 01;47(1):80-86

Objective: We aimed to describe management of biliary obstruction (BO) in the context of pancreatic cancer within a population-based cohort.

Methods: We examined management of BO in 1863 patients diagnosed as having pancreatic cancer in 2010/2011. We used descriptive statistics and logistic regression to describe patterns of biliary stent usage, complications and duration of patency, associations between preoperative stenting and surgical outcomes, and between patient factors and management of jaundice.

Results: Almost half of the people in the cohort (n = 909) were jaundiced within 12 months of diagnosis. Two-thirds of these had at least 1 stent inserted. Preoperative stenting, mostly with plastic stents, occurred for 72% of patients who experienced jaundice prior to an attempted resection but was not associated with surgical outcomes. Seventy percent of the jaundiced patients who did not have an attempted resection were stented. Metal stents were less frequently replaced within 30 days than plastic (9% vs 42%). Living in a rural area was associated with reduced likelihood of having jaundice managed.

Conclusions: Plastic stents were still used frequently, despite guidelines recommending metal in most contexts. Patients living in rural areas were less likely to have BO managed. This work highlights the need to monitor current practice.
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http://dx.doi.org/10.1097/MPA.0000000000000960DOI Listing
January 2018

Ampullary cancer of intestinal origin and duodenal cancer - A logical clinical and therapeutic subgroup in periampullary cancer.

World J Gastrointest Oncol 2017 Oct;9(10):407-415

Department of Upper GI Surgery, Bankstown Hospital, Sydney, New South Wales 2200, Australia.

Periampullary cancers include pancreatic, ampullary, biliary and duodenal cancers. At presentation, the majority of periampullary tumours have grown to involve the pancreas, bile duct, ampulla and duodenum. This can result in difficulty in defining the primary site of origin in all but the smallest tumors due to anatomical proximity and architectural distortion. This has led to variation in the reported proportions of resected periampullary cancers. Pancreatic cancer is the most common cancer resected with a pancreaticoduodenectomy followed by ampullary (16%-50%), bile duct (5%-39%), and duodenal cancer (3%-17%). Patients with resected duodenal and ampullary cancers have a better reported median survival (29-47 mo and 22-54 mo) compared to pancreatic cancer (13-19 mo). The poorer survival with pancreatic cancer relates to differences in tumour characteristics such as a higher incidence of nodal, neural and vascular invasion. While small ampullary cancers can present early with biliary obstruction, pancreatic cancers need to reach a certain size before biliary obstruction ensues. This larger size at presentation contributes to a higher incidence of resection margin involvement in pancreatic cancer. Ampullary cancers can be subdivided into intestinal or pancreatobiliary subtype cancers with histomolecular staining. This avoids relying on histomorphology alone, as even some poorly differentiated cancers preserve the histomolecular profile of their mucosa of origin. Histomolecular profiling is superior to anatomic location in prognosticating survival. Ampullary cancers of intestinal subtype and duodenal cancers are similar in their intestinal origin and form a logical clinical and therapeutic subgroup of periampullary cancers. They respond to 5-FU based chemotherapeutic regimens such as capecitabine-oxaliplatin. Unlike pancreatic cancers, mutation occurs in only approximately a third of ampullary and duodenal cancers. Future clinical trials should group ampullary cancers of intestinal origin and duodenal cancers together given their similarities and their response to fluoropyrimidine therapy in combination with oxaliplatin. The addition of anti-epidermal growth factor receptor therapy in this group warrants study.
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http://dx.doi.org/10.4251/wjgo.v9.i10.407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648984PMC
October 2017

Association between pancreatic cancer patients' perception of their care coordination and patient-reported and survival outcomes.

Palliat Support Care 2018 10 3;16(5):534-543. Epub 2017 Jul 3.

Population Health Department,QIMR Berghofer Medical Research Institute,Brisbane,Queensland,Australia.

Objective: People with pancreatic cancer have poor survival, and management is challenging. Pancreatic cancer patients' perceptions of their care coordination and its association with their outcomes have not been well-studied. Our objective was to determine if perception of care coordination is associated with patient-reported outcomes or survival.

Methods: People with pancreatic cancer who were 1-8 months postdiagnosis (52 with completed resection and 58 with no resection) completed a patient-reported questionnaire that assessed their perceptions of care coordination, quality of life, anxiety, and depression using validated instruments. Mean scores for 15 care-coordination items were calculated and then ranked from highest (best experience) to lowest (worst experience). Associations between care-coordination scores (including communication and navigation domains) and patient-reported outcomes and survival were investigated using general linear regression and Cox regression, respectively. All analyses were stratified by whether or not the tumor had been resected.

Results: In both groups, the highest-ranked care-coordination items were: knowing who was responsible for coordinating care, health professionals being informed about their history, and waiting times. The worst-ranked items related to: how often patients were asked about visits with other health professionals and how well they and their family were coping, knowing the symptoms they should monitor, having sufficient emotional help from staff, and access to additional specialist services. For people who had a resection, better communication and navigation scores were significantly associated with higher quality of life and less anxiety and depression. However, these associations were not statistically significant for those with no resection. Perception of cancer care coordination was not associated with survival in either group.

Significance Of Results: Our results suggest that, while many core clinical aspects of care are perceived to be done well for pancreatic cancer patients, improvements in emotional support, referral to specialist services, and self-management education may improve patient-reported outcomes.
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http://dx.doi.org/10.1017/S1478951517000608DOI Listing
October 2018

Lost in translation: returning germline genetic results in genome-scale cancer research.

Genome Med 2017 04 28;9(1):41. Epub 2017 Apr 28.

Cancer Research Program, Garvan Institute of Medical Research, Kinghorn Cancer Centre, Sydney, Australia.

Background: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies.

Methods: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy.

Results: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR.

Conclusion: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low.
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http://dx.doi.org/10.1186/s13073-017-0430-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408494PMC
April 2017

Whole-genome landscape of pancreatic neuroendocrine tumours.

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
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http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017

Anxiety, depression and quality of life in people with pancreatic cancer and their carers.

Pancreatology 2017 Mar - Apr;17(2):321-327. Epub 2017 Jan 20.

Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia. Electronic address:

Background: People with pancreatic cancer have high levels of anxiety and depression and reduced quality of life (QoL), but few studies have assessed these outcomes for patient-carer dyads. We therefore investigated these issues in an Australian population-based study.

Methods: Patients with pancreatic cancer (n = 136) and many of their carers (n = 84) completed the Hospital Anxiety and Depression Scale (HADS) and Functional Assessment of Cancer Therapy QoL questionnaire at a median of three months after diagnosis. Overall QoL and well-being subscales (physical, social, emotional, functional) were compared with general population norms. Intraclass correlation coefficients were used to compare anxiety, depression and QoL scores of patients and their respective carers.

Results: Fifteen percent of patients and 39% of carers had HADS scores indicative of anxiety and 15% of patients and 14% of carers of depression, respectively. Overall, 70% of patients and 58% of carers had QoL scores below the Queensland population average. Patients' anxiety, depression, overall QoL, social, emotional and functional wellbeing scores were significantly related to those scores in their carers. Among patients and carers, accessing psychological help was associated with elevated anxiety. Not receiving chemotherapy was associated with elevated depression among patients and younger age was associated with poorer outcomes in carers.

Conclusions: More carers had symptoms of anxiety than patients with pancreatic cancer, but symptoms of depression were similarly common in patients and carers. Further research is needed to assess whether interventions to reduce patients' distress could also improve QoL among carers, or whether carer-focussed interventions are required.
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http://dx.doi.org/10.1016/j.pan.2017.01.008DOI Listing
October 2017

Hypermutation In Pancreatic Cancer.

Gastroenterology 2017 01 15;152(1):68-74.e2. Epub 2016 Nov 15.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.
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http://dx.doi.org/10.1053/j.gastro.2016.09.060DOI Listing
January 2017

Determinants of Outcomes Following Resection for Pancreatic Cancer-a Population-Based Study.

J Gastrointest Surg 2016 08 16;20(8):1471-81. Epub 2016 May 16.

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Background: Patient and health system determinants of outcomes following pancreatic cancer resection, particularly the relative importance of hospital and surgeon volume, are unclear. Our objective was to identify patient, tumour and health service factors related to mortality and survival amongst a cohort of patients who underwent completed resection for pancreatic cancer.

Methods: Eligible patients were diagnosed with pancreatic adenocarcinoma between July 2009 and June 2011 and had a completed resection performed in Queensland or New South Wales, Australia, with either tumour-free (R0) or microscopically involved margins (R1) (n = 270). Associations were examined using logistic regression (for binary outcomes) and Cox proportional hazards or stratified Cox models (for time-to-event outcomes).

Results: Patients treated by surgeons who performed <4 resections/year were more likely to die from a surgical complication (versus ≥4 resections/year, P = 0.04), had higher 1-year mortality (P = 0.03), and worse overall survival up to 1.5 years after surgery (adjusted hazard ratio 1.58, 95 % confidence interval 1.07-2.34). Amongst patients who had ≥1 complication within 30 days of surgery, those aged ≥70 years had higher 1-year mortality compared to patients aged <60 years. Adjuvant chemotherapy treatment improved recurrence-free survival (P = 0.01). There were no significant associations between hospital volume and mortality or survival.

Conclusions: Systems should be implemented to ensure that surgeons are completing a sufficient number of resections to optimize patient outcomes. These findings may be particularly relevant for countries with a relatively small and geographically dispersed population.
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http://dx.doi.org/10.1007/s11605-016-3157-4DOI Listing
August 2016

Risk factors for current and future unmet supportive care needs of people with pancreatic cancer. A longitudinal study.

Support Care Cancer 2016 08 16;24(8):3589-99. Epub 2016 Apr 16.

Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Purpose: This study aims to determine if the supportive care needs of people with pancreatic cancer change over time and identify the factors associated with current and future unmet needs.

Methods: Australian pancreatic cancer patients completed a self-administered survey at 0-6 months post-diagnosis (n = 116) then follow-up surveys 2 (n = 82) and 4 months (n = 50) later. The validated survey measured 34 needs across five domains. Weighted generalised estimating equations were used to identify factors associated with having ≥1 current or future moderate-to-high unmet need.

Results: The overall proportion of patients reporting ≥1 moderate-or-high-level need did not significantly change over time (baseline = 70 % to 4 months = 75 %), although there was a non-significant reduction in needs for patients who had a complete resection (71 to 63 %) and an increase in patients with locally advanced (73 to 85 %) or metastatic (66 to 88 %) disease. Higher levels of pain (OR 6.1, CI 2.4-15.3), anxiety (OR 3.3, CI 1.5-7.3) and depression (OR 3.2, CI 1.7-6.0) were significantly associated with current needs. People with pain (OR 4.9, CI 1.5-15.4), metastatic disease (OR 2.7, CI 0.7-10.0) or anxiety (OR 2.5, CI 0.7-8.6) had substantially higher odds of reporting needs at their next survey. The prevalence of needs was highest in the physical/daily living and psychological domains (both 53 % at baseline). Pain and anxiety had respectively the strongest associations with these domains.

Conclusions: Careful and continued attention to pain control and psychological morbidity is paramount in addressing significant unmet needs, particularly for people with metastatic disease. Research on how best to coordinate this is crucial.
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http://dx.doi.org/10.1007/s00520-016-3212-4DOI Listing
August 2016

Genomic analyses identify molecular subtypes of pancreatic cancer.

Nature 2016 Mar 24;531(7592):47-52. Epub 2016 Feb 24.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
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http://dx.doi.org/10.1038/nature16965DOI Listing
March 2016

Using a Delphi process to determine optimal care for patients with pancreatic cancer.

Asia Pac J Clin Oncol 2016 Jun 21;12(2):105-14. Epub 2016 Jan 21.

QIMR Berghofer Medical Research Institute.

Aim: Overall 5-year survival for pancreatic cancer is ∼5%. Optimizing the care that pancreatic cancer patients receive may be one way of improving outcomes. The objective of this study was to establish components of care which Australian health professionals believe important to optimally manage patients with pancreatic cancer.

Methods: Using a Delphi process, a multidisciplinary panel of 250 health professionals were invited to provide a list of factors they considered important for optimal care of pancreatic cancer patients. They were then asked to score and then rescore (from one [no importance/disagree] to 10 [very important/agree]) the factors. The mean and coefficient of variation scores were calculated and categorized into three levels of importance.

Results: Overall, 63 (66% of those sent the final questionnaire; 25% of those initially invited) health professionals from nine disciplines completed the final scoring of 55 statements/factors encompassing themes of presentation/staging, surgery and biliary obstruction, multidisciplinary team details and oncology. Mean scores ranged from 3.7 to 9.7 with the highest related to communication and patient assessment. There was substantial intra- and interdisciplinary variation in views about MDT membership and roles.

Conclusion: Overall, the opinions of Australian health professionals reflect international guideline recommended care; however, they identified a number of additional factors focusing on where patients should be treated, the importance of clear communication and the need for multidisciplinary care which were not included in current clinical practice guidelines. Differences in priorities between specialty groups were also identified.
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http://dx.doi.org/10.1111/ajco.12450DOI Listing
June 2016

Advances in Molecular Pathology and Treatment of Periampullary Cancers.

Pancreas 2016 Jan;45(1):32-9

From the *NHMRC Clinical Trials Centre; †Department of Surgery, The Prince Charles Hospital, Brisbane; ‡Department of Surgery, Flinders Medical Centre; §Queen Elizabeth Hospital, Adelaide; ∥University of Adelaide, South Australia; ¶School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne; #Cancer Care Centre, Department of Medical Oncology, St George Hospital; **Department of Surgery, Bankstown Hospital; and ††Division of Surgery, University of Western Sydney, Sydney, Australia.

Objectives: Periampullary cancers (PACs) include the following 4 traditional anatomic subtypes: pancreatic, ampullary, biliary, or duodenal cancers. This review was performed to highlight recent advances in the genomic and molecular understanding of each PAC subtype and the advances in chemotherapeutic and molecular trials in these cancer subtypes.

Results: Recent advances have highlighted differences in the genomic and molecular features within each PAC subtype. Ampullary cancers can now be further defined accurately into their intestinal and pancreatobiliary subtypes using histomolecular profiling. K-ras mutation, which occurs in most pancreatic cancers, is found to occur less frequently in ampullary (42%-52%), biliary (22%-23%), and duodenal cancers (32%-35%), suggesting crucial differences in targetable mutations in these cancer subtypes.Ampullary cancers of intestinal subtype and duodenal cancers seem to share similarities with colorectal cancer, given that they respond to similar chemotherapeutic regimens. This has potential implications for clinical trials and treatment selection, where PACs are often considered together.

Conclusions: Future trials should be designed in view of our increased understanding of the different anatomic and histomolecularly profiled subtypes of PAC cancers, which respects their individual molecular characteristics, phenotype, and response to treatment.
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http://dx.doi.org/10.1097/MPA.0000000000000385DOI Listing
January 2016

Describing Patterns of Care in Pancreatic Cancer: A Population-Based Study.

Pancreas 2015 Nov;44(8):1259-65

From the *Population Health, QIMR Berghofer Medical Research Institute; †University of Queensland, Brisbane, Queensland; ‡Cancer Research Division, Cancer Council NSW, Sydney; §University of Newcastle, Newcastle; ║Department of Medical Oncology, Prince of Wales Hospital; ¶University of New South Wales; #Sydney Nursing School, University of Sydney, Sydney, New South Wales; **Queensland University of Technology, Brisbane, Queensland; ††School of Medicine, University of Western Sydney, Sydney, New South Wales; and ‡‡Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Queensland.

Objectives: Despite pancreatic cancer being the fifth highest cause of cancer death in developed regions, there is a paucity of population-based management details for patients with pancreatic cancer. The objective of this study was to reflect on current practice and outcomes to facilitate future improvement.

Methods: A comprehensive population-based patterns-of-care study in 2 Australian states was conducted. Patients diagnosed with pancreatic adenocarcinoma between July 2009 and June 2011 were identified by cancer registries, and detailed clinical data were collected from medical records.

Results: Data were collected for 1863 patients, 96% of those eligible. The majority resided in major cities; their median age was 72 years, and 54% were men. Over half of the cases (58%) had metastatic disease at diagnosis. Resection was attempted for 20% of patients but only completed in 15%. The uptake of adjuvant chemotherapy (76%) and the proportion alive at 1-year (22%) were higher than reported in previous population-based reports. Of those with no complete surgical resection, 43% received palliative chemotherapy.

Conclusions: This population-based overview of the management of patients with pancreatic cancer suggests that, despite evidence that the proportion surviving and the use of adjuvant chemotherapy has increased, there may still be underutilization of cancer-directed therapies.
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http://dx.doi.org/10.1097/MPA.0000000000000384DOI Listing
November 2015

A tsunami of unmet needs: pancreatic and ampullary cancer patients' supportive care needs and use of community and allied health services.

Psychooncology 2016 Feb 29;25(2):150-7. Epub 2015 Jun 29.

Cancer Aetiology and Prevention Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Objective: People diagnosed with pancreatic cancer have the worst survival prognosis of any cancer. No previous research has documented the supportive care needs of this population. Our objective was to describe people's needs and use of support services and to examine whether these differed according to whether or not patients had undergone surgical resection.

Methods: Queensland pancreatic or ampullary cancer patients (n = 136, 54% of those eligible) completed a survey, which assessed 34 needs across five domains (Supportive Care Needs Survey-Short Form) and use of health services. Differences by resection were compared with Chi-squared tests.

Results: Overall, 96% of participants reported having some needs. More than half reported moderate-to-high unmet physical (54%) or psychological (52%) needs, whereas health system/information (32%), patient care (21%) and sexuality needs (16%) were described less frequently. The three most frequently reported moderate-to-high needs included 'not being able to do things they used to do' (41%), 'concerns about the worries of those close' (37%) and 'uncertainty about the future' (30%). Patients with non-resectable disease reported greater individual information needs, but their needs were otherwise similar to patients with resectable disease. Self-reported use of support was low; only 35% accessed information, 28%, 18% and 15% consulted a dietician, complementary medicine practitioner or mental health practitioner, respectively. Palliative care access was greater (59% vs 27%) among those with non-resectable disease.

Conclusion: Very high levels of needs were reported by people with pancreatic or ampullary cancer. Future work needs to elucidate why uptake of appropriate supportive care is low and which services are required.
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http://dx.doi.org/10.1002/pon.3887DOI Listing
February 2016

Response to Cheluvappa and Eri: Conjugate products of pyocyanin-glutathione reactions.

Chem Biol Interact 2015 Aug 6;238:40-1. Epub 2015 Jun 6.

Department of Surgery, School of Medicine, University of Western Sydney, Building 30, Goldsmith Avenue, Campbelltown, NSW 2560, Australia.

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http://dx.doi.org/10.1016/j.cbi.2015.06.003DOI Listing
August 2015

Vascular coil erosion into hepaticojejunostomy following hepatic arterial embolisation.

BMC Surg 2015 Apr 29;15:51. Epub 2015 Apr 29.

Upper Gastrointestinal Unit, Bankstown Hospital, Sydney, Australia.

Background: Right hepatic arterial injury (RHAI) is the most common vascular injury sustained during laparoscopic cholecystectomy, occurring in up to 7% of cholecystectomies. RHAI is also the most common vascular injury associated with a bile duct injury (BDI) and is reported to occur in up to 41 - 61% of cases when routine angiography is employed following a BDI. We present an unusual case of erosion of vascular coils from a previously embolised right hepatic artery into bilio-enteric anastomoses causing biliary obstruction. This is on a background of biliary reconstruction following a major BDI.

Case Presentation: A 37-year old man underwent a bile duct reconstruction following a major BDI (Strasberg-Bismuth E4 injury) sustained at laparoscopic cholecystectomy. He had two separate bilio-enteric anastomoses of the right and left hepatic ducts and had a modified Terblanche Roux-en-Y access limb formed. Approximately three weeks later he was admitted for significant gastrointestinal bleeding and was hypotensive and anaemic. Selective computed tomography angiography revealed a 2 x 2 centimetre right hepatic artery pseudoaneurysm, which was urgently embolised with radiological coils. Two months later he developed intermittent fevers, rigors, jaundice, and right upper quadrant pain with evidence of intrahepatic biliary dilatation on magnetic resonance cholangiopancreatography. The degree of intrahepatic biliary dilatation progressively increased on subsequent imaging over several months, suggesting stricturing of the bilio-enteric anastomoses. Several attempts to traverse these strictures with a percutaneous transhepatic approach had failed. Then, approximately ten months after the initial BDI repair, choledochoscopy through the Terblanche access limb revealed multiple radiological coils within the bilio-enteric anastomoses, which had eroded from the previously embolised right hepatic artery. A laparotomy was performed to remove the coils, take down the existing obstructed bilio-enteric anastomoses and revise this. Following this the patient recovered uneventfully.

Conclusion: Obstructive jaundice and cholangitis secondary to erosion of angiographically placed embolisation coils is a rarely described complication. In view of the relative frequency of arterial injury and complications following major bile duct injury, we suggest that these patients be formally assessed for associated arterial injury following a major BDI.
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http://dx.doi.org/10.1186/s12893-015-0039-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423092PMC
April 2015

Large retroperitoneal isolated fibrous cyst in absence of preceding trauma or acute pancreatitis.

BMC Surg 2015 Mar 14;15:25. Epub 2015 Mar 14.

Upper Gastrointestinal Unit, Bankstown Hospital, Sydney, Australia.

Background: Isolated retroperitoneal cystic masses are uncommon with an estimated incidence of 1/5750 to 1/250,000. The majority present with size related symptoms, complications, or a mass. Approximately a third of patients are asymptomatic and are diagnosed incidentally. Aetiologies of retroperitoneal cystic masses (RPC) include mesenteric, omental, splenic and enteric duplication cysts. Neoplastic RPCs can be divided into epithelial (mucinous or serous cystadenoma), mesothelial (mesothelioma), germ cell (cystic teratoma) and cystic changes in a solid neoplasm (paraganglioma, neurilemmoma, sarcoma).

Case Presentation: A 53 year-old man presented to us with abdominal pain related to a large mass in his left upper quadrant with associated anorexia and weight loss. He gave no history of previous trauma and denied having symptoms or a history of pancreatitis. He said he had felt this mass increasing in size over the course of several years. Clinical examination of his abdomen revealed a large firm left sided mass extending to his left upper quadrant. Imaging with computed tomography (CT) and magnetic resonance imaging cholangio-pancreatogram (MRCP) revealed a 13.7 cm × 12.2 cm × 10.9 cm cystic lesion in the retroperitoneum which was separate from the kidney, pancreas, spleen and bowel. At laparotomy, this mass was easily dissected from the surrounding viscera and was excised completely intact. Histopathological assessment found the mass to be a large fibrous pseudocyst with no epithelial lining.

Conclusion: We present a rare case of an isolated large retroperitoneal fibrous pseudocyst unrelated to previous pancreatitis which was successfully managed with surgery.
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http://dx.doi.org/10.1186/s12893-015-0016-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364509PMC
March 2015

Mechanism for glutathione-mediated protection against the Pseudomonas aeruginosa redox toxin, pyocyanin.

Chem Biol Interact 2015 May 17;232:30-7. Epub 2015 Mar 17.

Department of Surgery, School of Medicine, University of Western Sydney, Building 30, Goldsmith Avenue, Campbelltown, NSW 2560, Australia.

Pseudomonas aeruginosa is an important human pathogen associated with several acute and chronic conditions, including diseases of the airways and wounds. The organism produces pyocyanin, an extracellular redox toxin that induces oxidative stress, depletes intracellular glutathione (GSH) and induces proliferative arrest and apoptosis, thus compromising the ability of tissue to repair itself. GSH is an important intra- and extracellular antioxidant, redox buffer and detoxifies xenobiotics by increasing their polarity, which facilitates their elimination. As previous studies have reported exogenous GSH to be protective against pyocyanin toxicity, this study was undertaken to explore the mechanism by which GSH protects host cells from the deleterious effects of the toxin. Co-incubation of pyocyanin with GSH resulted in a time-dependent diminished recovery of the toxin from the incubation medium. Concurrently, a highly polar green-colored metabolite was recovered that exhibited a UV-visible spectrum similar to pyocyanin and which was determined by mass spectrometry to have a major ion (m/z = 516) consistent with a glutathione conjugate. The ability of the conjugate to oxidize NADPH and to reduce molecular oxygen with the production of reactive oxygen species was comparable to pyocyanin yet it no longer demonstrated cytotoxicity towards host cells. These data suggest that GSH forms a cell-impermeant conjugate with pyocyanin and that availability of the thiol may be critical to minimizing the toxicity of this important bacterial virulence factor at infection sites. Our data indicate that for GSH to have a clinically effective role in neutralizing pyocyanin, the thiol needs to be available at millimolar concentrations.
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http://dx.doi.org/10.1016/j.cbi.2015.03.011DOI Listing
May 2015

Whole genomes redefine the mutational landscape of pancreatic cancer.

Nature 2015 Feb;518(7540):495-501

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
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http://dx.doi.org/10.1038/nature14169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523082PMC
February 2015

Multimodality treatment of potentially curative gastric cancer: geographical variations and future prospects.

Authors:
Neil D Merrett

World J Gastroenterol 2014 Sep;20(36):12892-9

Neil D Merrett, Discipline of Surgery, School of Medicine, University Of Western Sydney, Penrith, NSW 2751, Australia.

After much controversy, multimodality therapy is now accepted worldwide as the gold standard for treatment of resectable bulky localized gastric cancer. There is significant regional variation in the style of multimodality treatment with adjuvant chemoradiation the North American standard, neoadjuvant chemotherapy preferred in Europe and Australasia, whilst adjuvant chemotherapy is preferred in Asia. With further standardization of surgery and D1+/D2 resections increasingly accepted world wide, and in particular in the West, as the surgical standard of care for potentially curable disease, it is timely to reassess the multimodality regimes being used. The challenge in the use of multimodality therapy is how current outcomes can be standardized and improved further. Recent studies indicate that mere intensification of the regime in time, dosage or addition of further agents does not improve localized gastric cancer outcomes. More novel strategies including early commencement of adjuvant therapies, intra-peritoneal chemotherapy or assessing neoadjuvant response with positron emission tomography scanning may give improvements in outcomes. The introduction of targeted therapies means that the adjuvant use of biological agents needs to be explored. By proper assessment of the patient's co-morbidities, full tumour staging, and a better understanding of the tumour's molecular pathology, multimodality therapy for gastric adenocarcinoma may be individualized to optimize the likelihood of cure.
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http://dx.doi.org/10.3748/wjg.v20.i36.12892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177471PMC
September 2014

Pyocyanin production by Pseudomonas aeruginosa confers resistance to ionic silver.

Antimicrob Agents Chemother 2014 Sep 7;58(9):5492-9. Epub 2014 Jul 7.

Department of Surgery, School of Medicine, University of Western Sydney, Campbelltown, NSW, Australia.

Silver in its ionic form (Ag+), but not the bulk metal (Ag0), is toxic to microbial life forms and has been used for many years in the treatment of wound infections. The prevalence of bacterial resistance to silver is considered low due to the nonspecific nature of its toxicity. However, the recent increased use of silver as an antimicrobial agent for medical, consumer, and industrial products has raised concern that widespread silver resistance may emerge. Pseudomonas aeruginosa is a common pathogen that produces pyocyanin, a redox toxin and a reductant for molecular oxygen and ferric (Fe3+) ions. The objective of this study was to determine whether pyocyanin reduces Ag+ to Ag0, which may contribute to silver resistance due to lower bioavailability of the cation. Using surface plasmon resonance spectroscopy and scanning electron microscopy, pyocyanin was confirmed to be a reductant for Ag+, forming Ag0 nanoparticles and reducing the bioavailability of free Ag+ by >95% within minutes. Similarly, a pyocyanin-producing strain of P. aeruginosa (PA14) reduced Ag+ but not a pyocyanin-deficient (ΔphzM) strain of the bacterium. Challenge of each strain with Ag+ (as AgNO3) gave MICs of 20 and 5 μg/ml for the PA14 and ΔphzM strains, respectively. Removal of pyocyanin from the medium strain PA14 was grown in or its addition to the medium that ΔphzM mutant was grown in gave MICs of 5 and 20 μg/ml, respectively. Clinical isolates demonstrated similar pyocyanin-dependent resistance to Ag+. We conclude that pseudomonal silver resistance exists independently of previously recognized intracellular mechanisms and may be more prevalent than previously considered.
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http://dx.doi.org/10.1128/AAC.03069-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135871PMC
September 2014