Publications by authors named "Guy Lampe"

18 Publications

  • Page 1 of 1

Fatal Respiratory Diphtheria Caused by ß-Lactam-Resistant Corynebacterium diphtheriae.

Clin Infect Dis 2021 12;73(11):e4531-e4538

School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia.

Background: Diphtheria is a potentially fatal respiratory disease caused by toxigenic Corynebacterium diphtheriae. Although resistance to erythromycin has been recognized, β-lactam resistance in toxigenic diphtheria has not been described. Here, we report a case of fatal respiratory diphtheria caused by toxigenic C. diphtheriae resistant to penicillin and all other β-lactam antibiotics, and describe a novel mechanism of inducible carbapenem resistance associated with the acquisition of a mobile resistance element.

Methods: Long-read whole-genome sequencing was performed using Pacific Biosciences Single Molecule Real-Time sequencing to determine the genome sequence of C. diphtheriae BQ11 and the mechanism of β-lactam resistance. To investigate the phenotypic inducibility of meropenem resistance, short-read sequencing was performed using an Illumina NextSeq500 sequencer on the strain both with and without exposure to meropenem.

Results: BQ11 demonstrated high-level resistance to penicillin (benzylpenicillin minimum inhibitory concentration [MIC] ≥ 256 μg/ml), β-lactam/β-lactamase inhibitors and cephalosporins (amoxicillin/clavulanic acid MIC ≥ 256 μg/mL; ceftriaxone MIC ≥ 8 μg/L). Genomic analysis of BQ11 identified acquisition of a novel transposon carrying the penicillin-binding protein (PBP) Pbp2c, responsible for resistance to penicillin and cephalosporins. When strain BQ11 was exposed to meropenem, selective pressure drove amplification of the transposon in a tandem array and led to a corresponding change from a low-level to a high-level meropenem-resistant phenotype.

Conclusions: We have identified a novel mechanism of inducible antibiotic resistance whereby isolates that appear to be carbapenem susceptible on initial testing can develop in vivo resistance to carbapenems with repeated exposure. This phenomenon could have significant implications for the treatment of C. diphtheriae infection, and may lead to clinical failure.
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http://dx.doi.org/10.1093/cid/ciaa1147DOI Listing
December 2021

Lymphocytic esophagitis: An Australian (Queensland) case series of a newly recognized mimic of eosinophilic esophagitis.

JGH Open 2019 Oct 15;3(5):400-404. Epub 2019 Apr 15.

Department of Anatomical Pathology Princess Alexandra Hospital Brisbane Queensland Australia.

Background And Aim: Lymphocytic esophagitis (LoE) is a recently described upper gastrointestinal tract "disorder" diagnosis of which hinges on histology and is characterized by the excessive infiltration of lymphocytes in the peripapillary fields of the esophageal epithelium, with clinical manifestations similar to those of eosinophilic esophagitis (EoE). In this article, we aim to describe for the first time the clinico-pathological characteristics of a large cohort of Australian (Queensland) cases of LoE.

Methods: Histological data that fulfilled the criteria (predominant lymphocytic infiltration in the peripapillary fields, none or minimal neutrophils or eosinophils, and no infection) were collected between January 2014 and May 2016 from a number of major Queensland Public Hospital anatomical pathology laboratories. Patient presentations were subsequently examined to compile clinical and endoscopic correlates.

Results: A total of 62 cases of LoE were identified. The median age was 55 years, with 59.6% of subjects being male. Major clinical manifestations included dysphagia (32), epigastric or abdominal pain (8), gastro-esophageal reflux (8), association with Crohn's disease (8), and vomiting or diarrhea (6). Endoscopy was normal in 47% of cases; 47% had appearances similar to those of EoE. There were three cases with associated mild monilial esophagitis (6%).

Conclusion: LoE is a relatively recently recognized condition of the esophagus with variable clinical and endoscopic findings. Diagnosis is based on characteristic histological features. Further investigation is needed to ascertain the etiopathology and natural history of the condition and to establish a safe and effective treatment regimen.
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http://dx.doi.org/10.1002/jgh3.12175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788373PMC
October 2019

Complex structural rearrangements are present in high-grade dysplastic Barrett's oesophagus samples.

BMC Med Genomics 2019 02 4;12(1):31. Epub 2019 Feb 4.

Surgical Oncology Group, Diamantina Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia.

Background: Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett's oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic features of BE and EAC may help with the early identification of at-risk individuals.

Methods: In this study, we assessed the genomic features of 16 BE samples using whole-genome sequencing. These included non-dysplastic samples collected at two time-points from two BE patients who had not progressed to EAC over several years. Seven other non-dysplastic samples and five dysplastic BE samples with high-grade dysplasia were also examined. We compared the genome profiles of these 16 BE samples with 22 EAC samples.

Results: We observed that samples from the two non-progressor individuals had low numbers of somatic single nucleotide variants, indels and structural variation events compared to dysplastic and the remaining non-dysplastic BE. EAC had the highest level of somatic genomic variations. Mutational signature 17, which is common in EAC, was also present in non-dysplastic and dysplastic BE, but was not present in the non-progressors. Many dysplastic samples had mutations in genes previously reported in EAC, whereas only mutations in CDKN2A or in the fragile site genes appeared common in non-dysplastic samples. Rearrangement signatures were used to identify a signature associated with localised complex events such as chromothripsis and breakage fusion-bridge that are characteristic of EACs. Two dysplastic BE samples had a high contribution of this signature and contained evidence of localised rearrangements. Two other dysplastic samples also had regions of localised structural rearrangements. There was no evidence for complex events in non-dysplastic samples.

Conclusions: The presence of complex localised rearrangements in dysplastic samples indicates a need for further investigations into the role such events play in the progression from BE to EAC.
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http://dx.doi.org/10.1186/s12920-019-0476-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360790PMC
February 2019

Large frontal osseous hemangioma with dural sinus involvement in a patient with Klippel-Trenaunay syndrome: A rare case report.

Surg Neurol Int 2018 11;9:205. Epub 2018 Oct 11.

Department of Neurosurgery, Princess Alexandra Hospital, Brisbane, QLD, Australia.

Background: We present one of the first documented cases in the literature of an adult with Klippel-Trenaunay syndrome (KTS) with a large frontal osseous hemangioma.

Case Description: A 30-year-old male presented with a rapidly enlarging frontal skull lesion that had developed in only 3 months. Radiological investigation revealed a highly vascular lesion attached to the frontal bone. The lesion was surgically resected with the patient making complete recovery. Histopathology was consistent with an osseous hemangioma.

Conclusion: We report the clinical presentation and surgical management of a rare presentation of osseous hemangioma in a patient with KTS.
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http://dx.doi.org/10.4103/sni.sni_244_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194733PMC
October 2018

A Pragmatic Approach Identifies a High Rate of Nonalcoholic Fatty Liver Disease With Advanced Fibrosis in Diabetes Clinics and At-Risk Populations in Primary Care.

Hepatol Commun 2018 Aug 6;2(8):893-905. Epub 2018 Aug 6.

Department of Gastroenterology and Hepatology Princess Alexandra Hospital Brisbane Australia.

Noninvasive serum biomarkers (nonalcoholic fatty liver disease fibrosis score [NFS], fibrosis 4 score [FIB-4], or enhanced liver fibrosis [ELF] test) are recommended as first-line tools to determine the risk of advanced fibrosis in nonalcoholic fatty liver disease. We aimed to assess the utility of a pragmatic approach to screening for clinically significant fibrosis in primary care and diabetes clinics. We recruited 252 patients from an endocrine clinic or primary care facility. Anthropometric measurements, ELF test, ultrasound, and liver stiffness measurements (LSMs) were performed. Clinically significant fibrosis was defined as LSM ≥8.2 kPa or ELF ≥9.8. A subgroup of patients underwent liver biopsy (n = 48) or had imaging diagnostic of cirrhosis (n = 14). Patients were 57.3 ± 12.3 years old with a high prevalence of metabolic syndrome (84.5%), type 2 diabetes (82.5%), and body mass index (BMI) ≥40 kg/m (21.8%). LSM met quality criteria in 230 (91.3%) patients. NFS and FIB-4 combined had a high negative predictive value (90.0%) for excluding LSM ≥8.2 kPa. However, 84.1% of patients had indeterminate or high NFS or FIB-4 scores requiring further assessment. LSM ≥8.2 kPa and ELF ≥9.8 were present in 31.3% and 28.6% of patients, respectively. Following adjustment for age, BMI, sex, and presence of advanced fibrosis, older age was independently associated with ELF ≥9.8 (adjusted odds ratio, 1.14; 95% confidence interval, 1.06-1.24), whereas increasing BMI was independently associated with LSM ≥8.2 kPa (adjusted odds ratio, 1.15; 95% confidence interval, 1.01-1.30). Concordant LSM <8.2 kPa and ELF <9.8 and concordant LSM ≥8.2 kPa and ELF ≥9.8 had a high negative predictive value (91.7%) and positive predictive value (95.8%) for excluding and identifying clinically significant fibrosis, respectively. Simple scoring tools alone lack accuracy. LSM accuracy is influenced by severe obesity, whereas age impacts the ELF test. Further studies are required to confirm whether combining LSM and ELF may enhance accuracy and confidence in identifying clinically significant fibrosis. ( 2018; 00:000-000).
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http://dx.doi.org/10.1002/hep4.1208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078214PMC
August 2018

Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes.

JCI Insight 2018 07 26;3(14). Epub 2018 Jul 26.

Institute for Molecular Bioscience (IMB) and.

Chronic liver disease (CLD) is associated with tissue-destructive fibrosis. Considering that common mechanisms drive fibrosis across etiologies, and that steatosis is an important cofactor for pathology, we performed RNA sequencing on liver biopsies of patients with different fibrosis stages, resulting from infection with hepatitis C virus (HCV) (with or without steatosis) or fatty liver disease. In combination with enhanced liver fibrosis score correlation analysis, we reveal a common set of genes associated with advanced fibrosis, as exemplified by those encoding the transcription factor ETS-homologous factor (EHF) and the extracellular matrix protein versican (VCAN). We identified 17 fibrosis-associated genes as candidate EHF targets and demonstrated that EHF regulates multiple fibrosis-associated genes, including VCAN, in hepatic stellate cells. Serum VCAN levels were also elevated in advanced fibrosis patients. Comparing biopsies from patients with HCV with or without steatosis, we identified a steatosis-enriched gene set associated with advanced fibrosis, validating follistatin-like protein 1 (FSTL1) as an exemplar of this profile. In patients with advanced fibrosis, serum FSTL1 levels were elevated in those with steatosis (versus those without). Liver Fstl1 mRNA levels were also elevated in murine CLD models. We thus reveal a common gene signature for CLD-associated liver fibrosis and potential biomarkers and/or targets for steatosis-associated liver fibrosis.
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http://dx.doi.org/10.1172/jci.insight.120274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124454PMC
July 2018

HER2 testing in advanced gastric and gastro-oesophageal cancer: analysis of an Australia-wide testing program.

Pathology 2017 Oct 18;49(6):575-581. Epub 2017 Aug 18.

Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia.

This Australian human epidermal growth factor receptor 2 (HER2) testing program aimed to analyse >800 cases tested in a coordinated setting to further evaluate the criteria to establish HER2 status in advanced gastric and gastro-oesophageal junction (GOJ) cancer. Heterogeneity, and minimum number of biopsy fragments for reliable HER2 assessment were also examined in a subset of samples. Five laboratories tested 891 samples referred to determine HER2 status for potential anti-HER2 treatment. Cancer site, specimen type (endoscopic biopsy/resection/metastases), immunohistochemistry (IHC) score, HER2 gene and CEP17 copy number (CN) and HER2:CEP17 ratios were recorded. Samples were derived from stomach (53.1%), GOJ (28.2%) or metastases (18.5%). IHC for HER2 and dual probe HER2:CEP17 in situ hybridisation (ISH) were performed in parallel. A stringent definition (SD) of HER2 positivity was used (IHC2+/3+ plus CN>6 and ratio>2) and compared with other published criteria. HER2 positive rate was 13.9% (114/820) by SD, and 12.9-16.0% using other definitions. There was higher concordance between IHC and HER2 CN by ISH than with ratio. The HER2 positive rate was significantly higher in GOJ samples than others (p = 0.03) and in endoscopic biopsies than resections (p = 0.047). In a subset of 98 positive cases, 39 (39.8%) showed heterogeneity, and in 282 endoscopic biopsies positivity rate plateaued at five tumour fragments, suggesting this is the minimum number of biopsies that should be examined.
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http://dx.doi.org/10.1016/j.pathol.2017.05.009DOI Listing
October 2017

Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers.

PLoS One 2016 18;11(11):e0167001. Epub 2016 Nov 18.

Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, Australia.

Background And Aims: Non-invasive markers of liver fibrosis are urgently required, especially for use in non-specialist settings. The aim of this study was to identify novel serum biomarkers of advanced fibrosis.

Methods: We performed an unbiased screen of 120 serum analytes including cytokines, chemokines and proteases in 70 patients (35 without fibrosis, 35 with cirrhosis on biopsy), and selected a panel of 44 candidate biomarkers, which were subsequently measured in a mixed-etiology cohort of 432 patients with known serum HA, PIIINP and TIMP1 (which comprise the validated Enhanced Liver Fibrosis (ELF) test). Multivariate logistic regression modelling was used to generate models for the prediction of advanced or significant fibrosis (METAVIR ≥F3 and ≥F2, respectively); in addition to identifying biomarkers of disease activity and steatohepatitis.

Results: Seventeen analytes were significantly differentially expressed between patients with no advanced fibrosis and patients with advanced fibrosis, the most significant being hyaluronic acid (HA) and matrix metalloproteinase (MMP) 7 (p = 2.9E-41 and p = 1.0E-26, respectively). The optimal model for the prediction of advanced fibrosis comprised HA, MMP7, MMP1, alphafetoprotein (AFP) and the AST to platelet ratio index (APRI). We demonstrate enhanced diagnostic accuracy (AUROC = 0.938) compared to a model comprising HA, PIIINP and TIMP1 alone (ELF) (AUROC = 0.898, p<0.0001, De Long's test).

Conclusions: We have identified novel serum biomarkers of advanced liver fibrosis, which have the potential to enhance the diagnostic accuracy of established biomarkers. Our data suggest MMP7 is a valuable indicator of advanced fibrosis and may play a role in liver fibrogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167001PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115865PMC
June 2017

Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma.

Carcinogenesis 2016 Apr 10;37(4):356-65. Epub 2016 Feb 10.

Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia, Department of Surgery, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia and.

The incidence of esophageal adenocarcinoma (EAC) has risen significantly over recent decades. Although survival has improved, cure rates remain poor, with <20% of patients surviving 5 years. This is the first study to explore methylome, transcriptome and ENCODE data to characterize the role of methylation in EAC. We investigate the genome-wide methylation profile of 250 samples including 125 EAC, 19 Barrett's esophagus (BE), 85 squamous esophagus and 21 normal stomach. Transcriptome data of 70 samples (48 EAC, 4 BE and 18 squamous esophagus) were used to identify changes in methylation associated with gene expression. BE and EAC showed similar methylation profiles, which differed from squamous tissue. Hypermethylated sites in EAC and BE were mainly located in CpG-rich promoters. A total of 18575 CpG sites associated with 5538 genes were differentially methylated, 63% of these genes showed significant correlation between methylation and mRNA expression levels. Pathways involved in tumorigenesis including cell adhesion, TGF and WNT signaling showed enrichment for genes aberrantly methylated. Genes involved in chromosomal segregation and spindle formation were aberrantly methylated. Given the recent evidence that chromothripsis may be a driver mechanism in EAC, the role of epigenetic perturbation of these pathways should be further investigated. The methylation profiles revealed two EAC subtypes, one associated with widespread CpG island hypermethylation overlapping H3K27me3 marks and binding sites of the Polycomb proteins. These subtypes were supported by an independent set of 89 esophageal cancer samples. The most hypermethylated tumors showed worse patient survival.
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http://dx.doi.org/10.1093/carcin/bgw018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806711PMC
April 2016

The Enhanced liver fibrosis score is associated with clinical outcomes and disease progression in patients with chronic liver disease.

Liver Int 2016 Mar 28;36(3):370-7. Epub 2015 Aug 28.

Centre for Liver Disease Research, School of Medicine, The University of Queensland, Brisbane, QLD, Australia.

Background And Aims: Current tools for risk stratification of chronic liver disease subjects are limited. We aimed to determine whether the serum-based ELF (Enhanced Liver Fibrosis) test predicted liver-related clinical outcomes, or progression to advanced liver disease, and to compare the performance of ELF to liver biopsy and non-invasive algorithms.

Methods: Three hundred patients with ELF scores assayed at the time of liver biopsy were followed up (median 6.1 years) for liver-related clinical outcomes (n = 16) and clear evidence of progression to advanced fibrosis (n = 18), by review of medical records and clinical data.

Results: Fourteen of 73 (19.2%) patients with ELF score indicative of advanced fibrosis (≥9.8, the manufacturer's cut-off) had a liver-related clinical outcome, compared to only two of 227 (<1%) patients with ELF score <9.8. In contrast, the simple scores APRI and FIB-4 would only have predicted subsequent decompensation in six and four patients respectively. A unit increase in ELF score was associated with a 2.53-fold increased risk of a liver-related event (adjusted for age and stage of fibrosis). In patients without advanced fibrosis on biopsy at recruitment, 55% (10/18) with an ELF score ≥9.8 showed clear evidence of progression to advanced fibrosis (after an average 6 years), whereas only 3.5% of those with an ELF score <9.8 (8/207) progressed (average 14 years). In these subjects, a unit increase in ELF score was associated with a 4.34-fold increased risk of progression.

Conclusions: The ELF score is a valuable tool for risk stratification of patients with chronic liver disease.
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http://dx.doi.org/10.1111/liv.12896DOI Listing
March 2016

Human papillomavirus status and p16(INK4A) expression in patients with mucosal squamous cell carcinoma of the head and neck in Queensland, Australia.

Cancer Epidemiol 2015 Apr 9;39(2):174-81. Epub 2015 Feb 9.

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

Background: The last decade has seen changes in the epidemiology of mucosal squamous cell carcinomas of the head and neck (HNSCCs), with increasing numbers of cases attributable to human papillomavirus (HPV) infection. We sought to determine the prevalence of HPV and p16(INK4a) expression in Australian HNSCC patients and to identify predictors of HPV-positivity.

Methods: We recruited 248 HNSCC patients with histologically confirmed primary SCC of the oropharynx, oral cavity, hypopharynx or larynx diagnosed between 2004 and 2010. All patients completed a questionnaire. Clinical data were abstracted from medical records. HPV presence in paraffin-embedded tumours was determined by PCR, and expression of p16(INK4a), p21(WAF1), p53, pRB, cyclin D1, and Ki67 by immunohistochemistry.

Results: Fifty (20%) patients were HPV-positive, 63 (28%) overexpressed p16(INK4a), and 44 (19%) were positive for HPV and p16(INK4a) (high concordance between HPV-positivity and p16(INK4a) status, κ=0.72). HPV-16 was most common (84%), followed by HPV-18 (10%), HPV-33 (4%) and HPV-69 (2%). HPV and p16(INK4a) prevalence was highest for SCCs of the oropharynx, followed by hypopharynx, larynx and oral cavity (HPV and p16(INK4a)p<0.0001). HPV prevalence and p16(INK4a)-overexpression were significantly higher in younger than older patients (HPV p=0.001; p16 (INK4a)p=0.003). Heavy smokers had lower HPV prevalence than non- or moderate smokers (p=0.017). Gender and alcohol consumption were not associated with HPV or p16(INK4a) status. HPV-positive tumours had significantly lower cyclin D1 and higher p21(WAF1) expression than HPV-negative tumours.

Conclusion: HPV prevalence and p16(INK4a)-overexpression were highest in oropharyngeal tumours, younger patients, and non-smokers.
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http://dx.doi.org/10.1016/j.canep.2015.01.010DOI Listing
April 2015

ELF score ≥9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity.

Liver Int 2015 Jun 20;35(6):1673-81. Epub 2015 Jan 20.

Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia.

Background & Aims: There is increasing need to identify individuals with advanced liver fibrosis, who are at risk of complications such as hepatocellular carcinoma. The commercially available enhanced liver fibrosis (ELF) test provides a non-invasive assessment of fibrosis severity. This study was designed to determine the diagnostic accuracy of the manufacturer's cut-off value (≥9.8) in identifying advanced fibrosis.

Methods: The relationship between ELF score and fibrosis was examined using serum collected at time of liver biopsy for investigation of liver disease, particularly viral hepatitis. Fibrosis was staged using a modified METAVIR score. If available, liver tissue was recut and stained with Sirius red to determine collagen proportional area (CPA) and subsinusoidal fibrosis (SSF).

Results: Enhanced liver fibrosis score ≥9.8 had a sensitivity of 74.4% and specificity 92.4% for detecting advanced fibrosis. In the whole cohort (n = 329), ELF score was more likely to incorrectly classify individuals if age was ≥45 years and METAVIR inflammatory grade was 2 or 3 (adjusted OR, odds ratio 3.71 and 2.62 respectively). In contrast, ELF score was less likely to misclassify individuals in the presence of steatosis (OR 0.37). Neither SSF nor CPA explained the discordance in ELF score for patients with or without advanced fibrosis.

Conclusion: Although ELF score ≥9.8 reliably identifies advanced fibrosis in patients with chronic liver disease, both age and inflammatory activity need to be considered when interpreting the result. Importantly, ELF score performed well in the presence of steatosis and could thus be helpful in the assessment of fatty liver disease.
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http://dx.doi.org/10.1111/liv.12760DOI Listing
June 2015

Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.

Nat Commun 2014 Oct 29;5:5224. Epub 2014 Oct 29.

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

Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.
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http://dx.doi.org/10.1038/ncomms6224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596003PMC
October 2014

Genome-wide analysis of esophageal adenocarcinoma yields specific copy number aberrations that correlate with prognosis.

Genes Chromosomes Cancer 2014 Apr 21;53(4):324-38. Epub 2014 Jan 21.

Surgical Oncology Group, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, 4102 Brisbane, QLD 4006, Australia.

The incidence of esophageal adenocarcinoma (EAC) has been increasing rapidly for the past 3 decades in Western (Caucasian) populations. Curative treatment is based around esophagectomy, which has a major impact on quality of life. For those suitable for treatment with curative intent, 5-year survival is ∼30%. More accurate prognostic tools are therefore needed, and copy number aberrations (CNAs) may offer the ability to act as prospective biomarkers in this regard. We performed a genome-wide examination of CNAs in 54 samples of EAC using single-nucleotide polymorphism (SNP) arrays. Our aims were to describe frequent regions of CNA, to define driver CNAs, and to identify CNAs that correlated with survival. Regions of frequent amplification included oncogenes such as EGFR, MYC, KLF12, and ERBB2, while frequently deleted regions included tumor suppressor genes such as CDKN2A/B, PTPRD, FHIT, and SMAD4. The genomic identification of significant targets in cancer (GISTIC) algorithm identified 24 regions of gain and 28 regions of loss that were likely to contain driver changes. We discovered 61 genes in five regions that, when stratified by CNA type (gain or loss), correlated with a statistically significant difference in survival. Pathway analysis of the genes residing in both the GISTIC and prognostic regions showed they were significantly enriched for cancer-related networks. Finally, we discovered that copy-neutral loss of heterozygosity is a frequent mechanism of CNA in genes currently targetable by chemotherapy, potentially leading to under-reporting of cases suitable for such treatment.
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http://dx.doi.org/10.1002/gcc.22143DOI Listing
April 2014

Khat-associated hepatitis.

Med J Aust 2013 Oct;199(7):498-9

Princess Alexandra Hospital, Brisbane, QLD, Australia.

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http://dx.doi.org/10.5694/mja13.10951DOI Listing
October 2013

Is alpha-B crystallin an independent marker for prognosis in lung cancer?

Heart Lung Circ 2013 Sep 10;22(9):759-66. Epub 2013 Apr 10.

Princess Alexandra Hospital, Australia.

Background: Alpha B-crystallin (CRYAB) is an oncogene that increases tumour survival by promoting angiogenesis and preventing apoptosis. CRYAB is an independent prognostic marker in epithelial tumours including head and neck squamous cell carcinoma and breast cancer where it is predictive of nodal status and associated with poor outcome. We explored the role of CRYAB in non-small-cell lung cancer (NSCLC).

Methods: Immunohistochemical analysis was performed on 50 samples. Following staining with anti-alpha-B crystallin antibody, a blinded pathologist scored samples for nuclear (N) and cytoplasmic (C) staining intensity. Analysis was performed using Cox's proportional hazards model.

Results: There were 32 adenocarcinomas and 18 squamous cell carcinomas. The median tumour size was T2, grade 2 moderately differentiated, and 10 patients had nodal spread. Recurrence was seen in 22 patients (46%). Mortality was 48%, with median time to mortality 871 days. N staining was detected in eight samples (16%), and C staining in 20 (40%), with both N and C staining positive in five (10%). Staining for CRYAB predicted neither recurrence (N stain p=0.78, C stain p=0.38) nor mortality (N stain p=0.86, C stain p=0.66).

Conclusion: CRYAB did not predict outcomes in patients treated for NSCLC. Larger studies are required to validate this finding.
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http://dx.doi.org/10.1016/j.hlc.2013.01.014DOI Listing
September 2013

Severe acute liver injury associated with lumiracoxib.

J Gastroenterol Hepatol 2012 Jun;27(6):1102-5

Department of Clinical Pharmacology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.

Background And Aim: Significant elevations in liver transaminases were noted in some patients during pre-marketing clinical trials with lumiracoxib, a selective COX-2 inhibitor. It was withdrawn from the Australian market in August 2007, because of an association with severe liver injury. We describe in detail three cases of severe liver injury in patients taking lumiracoxib

Methods: Three patients admitted to our hospital with severe liver injury and taking lumiracoxib are described in detail, together with information on a further six cases reported to the Australian Therapeutics Goods Administration (TGA), none of whom had pre-existing liver disease or obvious risk factors for liver disease.

Results: Liver histology showed severe hepatic necrosis. One patient required liver transplantation and another died. Autoantibodies were detected in all three patients. As with the other six cases reported to the TGA, all were females who had been taking lumiracoxib 200-400 mg daily, typically for a few months, for osteoarthritis.

Conclusions: Lumiracoxib can be associated with severe liver injury. The presence of a variety of positive auto-antibodies suggests an altered immune response may be contributory.
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http://dx.doi.org/10.1111/j.1440-1746.2011.07036.xDOI Listing
June 2012
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