James Kench

James Kench
Royal Prince Alfred Hospital | RPA · Department of Tissue Pathology and Diagnostic Oncology

MBBS BSc(Med) FRCPA FFSc(RCPA) MIAC

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255
Publications
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Introduction
Skills and Expertise

Publications

Publications (255)
Article
Background While combination therapy with nab-paclitaxel/gemcitabine (nab-gem) is effective in pancreatic ductal adenocarcinoma (PDAC), its efficacy as perioperative chemotherapy is unknown. The primary objective of this multicenter, prospective, single-arm, phase II study was to determine whether neoadjuvant therapy with nab-gem was associated wit...
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Despite advances in antiviral therapy, molecular drivers of Hepatitis C Virus (HCV)-related liver disease remain poorly characterised. Chronic infection with HCV genotypes (1 and 3) differ in presentation of liver steatosis and virological response to therapies, both to interferon and direct acting antivirals. To understand what drives these clinic...
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Introduction: Long-term outcomes from large cohorts are not yet available upon which to base recommended follow-up protocols after prostate focal therapy. This is an updated summary of a 2015 SIU-ICUD review of the best available current evidence and expert consensus on guidelines for surveillance after prostate focal therapy. Methods: We perfor...
Article
Promoter CpG islands are typically unmethylated in normal cells, but in cancer a proportion are subject to hypermethylation. Using methylome sequencing we identified CpG islands that display partial methylation encroachment across the 5′ or 3′ CpG island borders. CpG island methylation encroachment is widespread in prostate and breast cancer and co...
Article
Aims: Ductal adenocarcinoma is a rare variant of prostate cancer, and as such clinical outcomes and best management are not well defined. This series demonstrates the atypical presentation and unusual clinical behaviour of ductal adenocarcinoma and proposes management guidelines to assist clinicians. Materials and methods: A retrospective review...
Article
The International Collaboration on Cancer Reporting (ICCR) is a project which issues datasets and guidelines for international standardisation of cancer reporting. This review summarises the required and recommended elements of the datasets for prostate core needle biopsies and transurethral resection (TURP) and enucleation specimens of the prostat...
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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...
Article
A plethora of individual candidate biomarkers for predicting PSA relapse in localized prostate cancer (PCa) have been proposed. Combined biomarkers may improve prognostication, and ensuring validation against more clinically relevant endpoints are required. The Australian PCa Research Centre NSW has contributed to numerous studies of molecular biom...
Article
Background: Best practise care optimises survival and quality of life in patients with pancreatic cancer (PC), but there is evidence of variability in management and suboptimal care for some patients. Monitoring practise is necessary to underpin improvement initiatives. We aimed to develop a core set of quality indicators that measure quality of c...
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Objective Pancreatic ductal adenocarcinoma (PDAC) is a disease of unmet medical need. While immunotherapy with chimeric antigen receptor T (CAR-T) cells has shown much promise in haematological malignancies, their efficacy for solid tumours is challenged by the lack of tumour-specific antigens required to avoid on-target, off-tumour effects. Switch...
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The urgent unmet need for hepatocellular carcinoma (HCC) therapies is addressed here by characterising a novel mouse model of HCC in the context of ongoing liver damage and overnutrition. Male C57Bl/6J mice were treated with diethylnitrosamine (DEN) and thioacetamide (TAA), and some were provided with an atherogenic high fat diet (HFD). Inflammatio...
Article
Aim Pelvic exenteration surgery remains the only curative option for recurrent rectal cancer. Microscopically involved surgical margins (R1) are associated with a higher risk of local recurrence and decreased survival. Our study aimed to develop a post hoc multidisciplinary case conference review and investigate its potential for identifying areas...
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Background Comprehensive genome-wide DNA methylation profiling is critical to gain insights into epigenetic reprogramming during development and disease processes. Among the different genome-wide DNA methylation technologies, whole genome bisulphite sequencing (WGBS) is considered the gold standard for assaying genome-wide DNA methylation at single...
Article
The growth and progression of solid tumors involves dynamic cross-talk between cancer epithelium and the surrounding microenvironment. To date, molecular profiling has largely been restricted to the epithelial component of tumors; therefore, features underpinning the persistent protumorigenic phenotype of the tumor microenvironment are unknown. Usi...
Article
57 Background: p53 is one of the most common genetic aberrations in human cancer and is associated with poor outcomes with hormone therapy in advanced prostate cancer (PCa). p53 is a well-established predictor of biochemical relapse in PCa, however, increasing evidence from ICECaP has demonstrated that metastatic relapse (MR) not biochemical relaps...
Article
54 Background: Identification of potentially lethal disease at the time of diagnosis with localized prostate cancer (PCa) remains a significant clinical issue despite a plethora of candidate biomarkers. This study evaluates a range of biomarkers previously associated with biochemical relapse (BR) in localized PCa to determine whether a combined exp...
Article
Aims: Despite efforts to standardize grading of prostate cancer, there is still a considerable variation in grading practices even among experts. In this study we describe the use of Pathology Imagebase, a novel reference image library, for setting an international standard in prostate cancer grading. Methods and results: The International Socie...
Article
Background: Docetaxel, the standard chemotherapy for metastatic castration-resistant prostate cancer (CRPC) also enhances the survival of patients with metastatic castration-sensitive prostate cancer (CSPC) when combined with androgen-deprivation therapy. Focal Adhesion Kinase (FAK) activation is a mediator of docetaxel resistance in prostate canc...
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Background: Mitochondrial genome (mtDNA) content is depleted in many cancers. In prostate cancer, there is intra-glandular as well as inter-patient mtDNA copy number variation. In this study, we determine if mtDNA content can be used as a predictor for prostate cancer staging and outcomes. Methods: Fresh prostate cancer biopsies from 115 patient...
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Acetylation of the histone variant H2A.Z (H2A.Zac) occurs at active promoters and is associated with oncogene activation in prostate cancer, but its role in enhancer function is still poorly understood. Here we show that H2A.Zac containing nucleosomes are commonly redistributed to neo-enhancers in cancer resulting in a concomitant gain of chromatin...
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We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-t...
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Aims: Despite efforts to standardize histopathology practice through the development of guidelines, the interpretation of morphology is still hampered by subjectivity. We here describe Pathology Imagebase, a novel mechanism for establishing an international standard for the interpretation of pathology specimens. Methods and results: The Internat...
Article
Background: Prostate cancers with similar characteristics at the time of diagnosis can have very different disease outcomes. Conventional biomarkers of prostate cancer (PC) still lack precision in identifying individuals at high risk of PC recurrence. While many candidate biomarkers are proposed in the literature, few are in clinical practice as th...
Article
Objective: To assess the relationship between the ISUP 2014 grading system, biochemical relapse (BCR) and clinical relapse (CLR) following radical prostatectomy, to determine whether the 2014 ISUP grading system is a better predictor of survival compared to the previous Gleason scoring systems, and to investigate whether incorporation of the terti...
Chapter
Focal therapy represents a new paradigm in the management of prostate cancer. The application of focal therapy results, by definition, in the division of the prostate into two distinct areas: a treated and an untreated zone. Biopsy interrogation of both areas is becoming an integral part of the follow-up of patients treated with focal therapy. Adeq...
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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 signa...
Article
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 re...
Conference Paper
The Upper Gastrointestinal Cancer Registry (UGICR) is a newly formed multi-modular clinical quality registry (CQR) established to measure the quality of care provided to people with newly diagnosed cancer arising from the pancreas, oesophagus, stomach, liver or bile ducts. The UGICR is being piloted with a pancreatic cancer module. A CQR differs to...
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Prostate cancer management is complicated by extreme disease heterogeneity, which is further limited by availability of prognostic biomarkers. Recognition of prostate cancer as a genetic disease has prompted a focus on the nuclear genome for biomarker discovery, with little attention given to the mitochondrial genome. While it is evident that mitoc...
Article
Background: Positive surgical margins (PSMs) in localized prostate cancer (PC) confer a two- to three-fold increased risk of biochemical relapse (BR). Absent/weak AZGP1 expression and Gleason grade ≥4 at the margin are each independent predictors of BR in patients with PSMs. Our study aimed to determine whether the biomarkers AZGP1 expression and...
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A meeting of the Australasian Gastro-Intestinal Trials Group (AGITG) was held to develop a consensus statement defining when a patient with pancreatic cancer has disease that is clearly operable, is borderline, or is locally advanced/inoperable. Key issues included the need for multidisciplinary team consensus for all patients considered for surgic...
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Abdominal actinomycosis (AA) is a rare infection caused by filamentous Gram-positive anaerobic bacteria Actinomyces. We report two cases of adults with AA who initially presented with clinical and radiological features of appendicitis. Both patients underwent appendicectomy with histopathology diagnostic for actinomycosis of the appendix and subseq...
Article
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;...
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Abstract In November, 2014, 65 prostate cancer pathology experts, along with 17 clinicians including urologists, radiation oncologists, and medical oncologists from 19 different countries gathered in a consensus conference to update the grading of prostate cancer, last revised in 2005. The major conclusions were: (1) Cribriform glands should be ass...
Article
The aims of this study were to investigate the immunohistochemical expression and potential prognostic significance of putative cancer stems cell markers ALDH1, EZH2 and SOX2 in prostate cancer.A total of 142 consecutive radical prostatectomies submitted to one laboratory with a diagnosis of prostatic adenocarcinoma between 2008 and 2012 were retri...
Article
Full-text available
In November, 2014, 65 prostate cancer pathology experts, along with 17 clinicians including urologists, radiation oncologists, and medical oncologists from 19 different countries gathered in a consensus conference to update the grading of prostate cancer, last revised in 2005. The major conclusions were: (1) Cribriform glands should be assigned a G...
Article
Background: R0 resection rates (complete tumour removal with negative resection margins) in pancreatic cancer are 70-80 per cent when a 0-mm margin is used, declining to 15-24 per cent with a 1-mm margin. This review evaluated the R0 resection rates according to different margin definitions and techniques. Methods: Three databases (MEDLINE from...
Article
Washout is an important diagnostic imaging feature of hepatocellular carcinoma (HCC) on computed tomography (CT). The primary aim of this study is to evaluate the prevalence and the interobserver variation in the detection of portal venous phase (PVP) washout of HCCs using CT in a transplant population. The secondary aim is to evaluate factors infl...
Conference Paper
Full-text available
The Garvan Query Application (GQA): A Comprehensive Search Engine for a Prostate Cancer Biorepository S. Tiwari, A-M Haynes, Q. Nguyen, G Hammond, JG Kench, LG Horvath, PD Stricker Introduction: CanSto is an in-house bioresource and clinical information database developed by the Garvan Institute of Medical Research, Sydney Australia. It incorporat...
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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 (...
Article
387 Background: Pancreatic cancer (PC) outcomes remain poor, recent series show approximately 37% of patients achieve R0 resection (all margins ≥ 1mm) for resectable disease. Recent data in metastatic disease shows that nab-paclitaxel (nab-PC) and gemcitabine (GEM) chemotherapy (CX) is an active regimen. We aimed to determine the feasibility and R0...
Article
Ipilimumab has been shown to improve overall survival in patients with advanced melanoma. Ipilimumab acts through immune-modulation, and is recognised to cause potentially severe immune-related adverse events (irAEs) including dermatitis, colitis, thyroiditis, hypophysitis and hepatitis. The acceptance of ipilimumab as a treatment for metastatic me...
Article
BACKGROUND Phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in prostate carcinoma due to the loss of tumor suppressor PTEN, which leads to increased Akt activity. Expression of INPP4B, another negative regulator of the PI3K/Akt pathway, is also reduced in prostate carcinoma. However, uncertainty exists regarding the association...
Article
BACKGROUND Inherited predisposition to pancreatic cancer contributes significantly to its incidence and presents an opportunity for the development of early detection strategies. The genetic basis of predisposition remains unexplained in a high proportion of patients with familial PC (FPC).METHODS Clinicopathologic features were assessed in a cohor...
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Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study, we show that ERG overexpression in in vitro and in vivo models of CRPC is associated...
Article
On page 2911 of the 17 October 2013 issue, the byline and author affiliations omit the 7th author, Angelina J. Lay. The byline and author affiliations should have read: Jennifer A. Young,¹ Ka Ka Ting,¹ Jia Li,¹ Thorleif Moller,² Louise Dunn,³ Ying Lu,¹ Angelina J. Lay,¹ Joshua Moses,¹ Leonel Prado-Lourenço,⁴ Levon M. Khachigian,⁴ Martin Ng,³ Philip...
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Background: The promyelocytic leukemia (PML) tumor suppressor plays an important role in the response to a variety of cellular stressors and its expression is downregulated or lost in a range of human tumors. We have previously shown that the E3 ligase E6-associated protein (E6AP) is an important regulator of PML protein stability but the relation...