Malla, S.B.
Fisher, D.J.
Domingo, E.
Blake, A.
Hassanieh, S.
Redmond, K.L.
Richman, S.D.
Youdell, M.
Walker, S.M.
Logan, G.E.
Chatzipli, A.
Amirkhah, R.
Humphries, M.P.
Craig, S.G.
McDermott, U.
Seymour, M.T.
Morton, D.G.
Quirke, P.
West, N.P.
Salto-Tellez, M.
Kennedy, R.D.
Johnston, P.G.
Tomlinson, I.
Koelzer, V.H.
Campo, L.
Kaplan, R.S.
Longley, D.B.
Lawler, M.
Maughan, T.S.
Brown, L.C.
Dunne, P.D.
S:CORT consortium,
(2021). In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer. Clinical cancer research : an official journal of the american association for cancer research,
Vol.27
(1),
pp. 288-300.
show abstract
Purpose The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer.Experimental design Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial ( n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial ( n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer.Results Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer.Conclusions DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status..
Browning, L.
Fryer, E.
Roskell, D.
White, K.
Colling, R.
Rittscher, J.
Verrill, C.
(2021). Role of digital pathology in diagnostic histopathology in the response to COVID-19: results from a survey of experience in a UK tertiary referral hospital. Journal of clinical pathology,
Vol.74
(2),
pp. 129-132.
show abstract
The COVID-19 pandemic has challenged our diagnostic services at a time when many histopathology departments already faced a diminishing workforce and increasing workload. Digital pathology (DP) has been hailed as a potential solution to at least some of the challenges faced. We present a survey of pathologists within a UK National Health Service cellular pathology department with access to DP, in which we ascertain the role of DP in clinical services during this current pandemic and explore challenges encountered. This survey indicates an increase in uptake of diagnostic DP during this period, with increased remote access. Half of respondents agreed that DP had facilitated maintenance of diagnostic practice. While challenges have been encountered, these are remediable, and none have impacted on the uptake of DP during this period. We conclude that in our institution, DP has demonstrated current and future potential to increase resilience in diagnostic practice and have highlighted some of the challenges that need to be considered..
Washington, M.K.
Goldberg, R.M.
Chang, G.J.
Limburg, P.
Lam, A.K.
Salto-Tellez, M.
Arends, M.J.
Nagtegaal, I.D.
Klimstra, D.S.
Rugge, M.
Schirmacher, P.
Lazar, A.J.
Odze, R.D.
Carneiro, F.
Fukayama, M.
Cree, I.A.
WHO Classification of Tumours Editorial Board,
(2021). Diagnosis of digestive system tumours. International journal of cancer,
Vol.148
(5),
pp. 1040-1050.
show abstract
The WHO Classification of Tumours provides the international standards for the classification and diagnosis of tumours. It enables direct comparisons to be made between different countries. In the new fifth edition, the series has gone digital with the launch of a website as well as a series of books, known widely as the WHO Blue Books. The first volume to be produced is on the classification of Digestive System tumours, replacing the successful 2010 version. It has been rewritten and updated accordingly. This article summarises the major diagnostic innovations that have occurred over the last decade and that have now been incorporated in the classification. As an example, it incorporates the recently proposed classification of neuroendocrine tumours, based on the recognition that neuroendocrine tumours and carcinomas differ substantially in the genetic abnormalities that drive their growth, findings relevant to treatment selection and outcome prediction. Several themes have emerged during the production process. One is the importance of the progression from hyperplasia to dysplasia to carcinoma in the evolution of the malignant process. Advances in imaging techniques and endoscopy have resulted in enhanced access to precancerous lesions in the gastrointestinal and biliary tract, necessitating both changes in classification schema and clinical practice. Diagnosis of tumours is no longer the sole purview of pathologists, and some patients now receive treatment before tissue is obtained, based on clinical, radiological and liquid biopsy results. This makes the classification relevant to many disciplines involved in the care of patients with tumours of the digestive system..
Lee, J.W.
Zhu, F.
Srivastava, S.
Tsao, S.K.
Khor, C.
Ho, K.Y.
Fock, K.M.
Lim, W.C.
Ang, T.L.
Chow, W.C.
So, J.B.
Koh, C.J.
Chua, S.J.
Wong, A.S.
Rao, J.
Lim, L.G.
Ling, K.L.
Chia, C.-.
Ooi, C.J.
Rajnakova, A.
Yap, W.M.
Salto-Tellez, M.
Ho, B.
Soong, R.
Chia, K.S.
Teo, Y.Y.
Ming, T.
Yeoh, K.-.
(2021). Severity of gastric intestinal metaplasia predicts the risk of gastric cancer: a prospective multicentre cohort study (GCEP). Gut,
.
show abstract
Objective To investigate the incidence of gastric cancer (GC) attributed to gastric intestinal metaplasia (IM), and validate the Operative Link on Gastric Intestinal Metaplasia (OLGIM) for targeted endoscopic surveillance in regions with low-intermediate incidence of GC.Methods A prospective, longitudinal and multicentre study was carried out in Singapore. The study participants comprised 2980 patients undergoing screening gastroscopy with standardised gastric mucosal sampling, from January 2004 and December 2010, with scheduled surveillance endoscopies at year 3 and 5. Participants were also matched against the National Registry of Diseases Office for missed diagnoses of early gastric neoplasia (EGN).Results There were 21 participants diagnosed with EGN. IM was a significant risk factor for EGN (adjusted-HR 5.36; 95% CI 1.51 to 19.0; p<0.01). The age-adjusted EGN incidence rates for patients with and without IM were 133.9 and 12.5 per 100 000 person-years. Participants with OLGIM stages III-IV were at greatest risk (adjusted-HR 20.7; 95% CI 5.04 to 85.6; p<0.01). More than half of the EGNs (n=4/7) attributed to baseline OLGIM III-IV developed within 2 years (range: 12.7-44.8 months). Serum trefoil factor 3 distinguishes (Area Under the Receiver Operating Characteristics 0.749) patients with OLGIM III-IV if they are negative for H. pylori . Participants with OLGIM II were also at significant risk of EGN (adjusted-HR 7.34; 95% CI 1.60 to 33.7; p=0.02). A significant smoking history further increases the risk of EGN among patients with OLGIM stages II-IV.Conclusions We suggest a risk-stratified approach and recommend that high-risk patients (OLGIM III-IV) have endoscopic surveillance in 2 years, intermediate-risk patients (OLGIM II) in 5 years..
Porter, R.J.
Murray, G.I.
Alnabulsi, A.
Humphries, M.P.
James, J.A.
Salto-Tellez, M.
Craig, S.G.
Wang, J.M.
Yoshimura, T.
McLean, M.H.
(2021). Colonic epithelial cathelicidin (LL-37) expression intensity is associated with progression of colorectal cancer and presence of CD8+ T cell infiltrate. The journal of pathology. clinical research,
.
show abstract
Colorectal cancer (CRC) remains a leading cause of cancer mortality. Here, we define the colonic epithelial expression of cathelicidin (LL-37) in CRC. Cathelicidin exerts pleotropic effects including anti-microbial and immunoregulatory functions. Genetic knockout of cathelicidin led to increased size and number of colorectal tumours in the azoxymethane-induced murine model of CRC. We aimed to translate this to human disease. The expression of LL-37 in a large (n = 650) fully characterised cohort of treatment-naïve primary human colorectal tumours and 50 matched normal mucosa samples with associated clinical and pathological data (patient age, gender, tumour site, tumour stage [UICC], presence or absence of extra-mural vascular invasion, tumour differentiation, mismatch repair protein status, and survival to 18 years) was assessed by immunohistochemistry. The biological consequences of LL-37 expression on the epithelial barrier and immune cell phenotype were assessed using targeted quantitative PCR gene expression of epithelial permeability (CLDN2, CLDN4, OCLN, CDH1, and TJP1) and cytokine (IL-1β, IL-18, IL-33, IL-10, IL-22, and IL-27) genes in a human colon organoid model, and CD3 + , CD4 + , and CD8 + lymphocyte phenotyping by immunohistochemistry, respectively. Our data reveal that loss of cathelicidin is associated with human CRC progression, with a switch in expression intensity an early feature of CRC. LL-37 expression intensity is associated with CD8 + T cell infiltrate, influenced by tumour characteristics including mismatch repair protein status. There was no effect on epithelial barrier gene expression. These data offer novel insights into the contribution of LL-37 to the pathogenesis of CRC and as a therapeutic molecule..
Humphries, M.P.
Maxwell, P.
Salto-Tellez, M.
(2021). QuPath: The global impact of an open source digital pathology system. Computational and structural biotechnology journal,
Vol.19,
pp. 852-859.
show abstract
QuPath, originally created at the Centre for Cancer Research & Cell Biology at Queen's University Belfast as part of a research programme in digital pathology (DP) funded by Invest Northern Ireland and Cancer Research UK, is arguably the most wildly used image analysis software program in the world. On the back of the explosion of DP and a need to comprehensively visualise and analyse whole slides images (WSI), QuPath was developed to address the many needs associated with tissue based image analysis; these were several fold and, predominantly, translational in nature: from the requirement to visualise images containing billions of pixels from files several GBs in size, to the demand for high-throughput reproducible analysis, which the paradigm of routine visual pathological assessment continues to struggle to deliver. Resultantly, large-scale biomarker quantification must increasingly be augmented with DP. Here we highlight the impact of the open source Quantitative Pathology & Bioimage Analysis DP system since its inception, by discussing the scope of scientific research in which QuPath has been cited, as the system of choice for researchers..
Parkes, E.E.
Humphries, M.P.
Gilmore, E.
Sidi, F.A.
Bingham, V.
Phyu, S.M.
Craig, S.
Graham, C.
Miller, J.
Griffin, D.
Salto-Tellez, M.
Madden, S.F.
Kennedy, R.D.
Bakhoum, S.F.
McQuaid, S.
Buckley, N.E.
(2021). The clinical and molecular significance associated with STING signaling in breast cancer. Npj breast cancer,
Vol.7
(1),
pp. 81-?.
show abstract
STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. Currently, there is no robust method of measuring STING activation in cancer. Here, we describe an immunohistochemistry-based assay with digital pathology assessment of STING in tumor cells. Using this novel approach in estrogen receptor-positive (ER+) and ER- breast cancer, we identify perinuclear-localized expression of STING (pnSTING) in ER+ cases as an independent predictor of good prognosis, associated with immune cell infiltration and upregulation of immune checkpoints. Tumors with low pnSTING are immunosuppressed with increased infiltration of "M2"-polarized macrophages. In ER- disease, pnSTING does not appear to have a significant prognostic role with STING uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression is predictive of poor prognosis in independent ER+ datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup..
McCombe, K.D.
Craig, S.G.
Viratham Pulsawatdi, A.
Quezada-Marín, J.I.
Hagan, M.
Rajendran, S.
Humphries, M.P.
Bingham, V.
Salto-Tellez, M.
Gault, R.
James, J.A.
(2021). HistoClean: Open-source software for histological image pre-processing and augmentation to improve development of robust convolutional neural networks. Computational and structural biotechnology journal,
Vol.19,
pp. 4840-4853.
Southwood, M.
Krenz, T.
Cant, N.
Maurya, M.
Gazdova, J.
Maxwell, P.
McGready, C.
Moseley, E.
Hughes, S.
Stewart, P.
Salto-Tellez, M.
Groelz, D.
Rassl, D.
STRATfix Consortium,
(2020). Systematic evaluation of PAXgene® tissue fixation for the histopathological and molecular study of lung cancer. The journal of pathology. clinical research,
Vol.6
(1),
pp. 40-54.
show abstract
Whilst adequate for most existing pathological tests, formalin is generally considered a poor DNA preservative and use of alternative fixatives may prove advantageous for molecular testing of tumour material; an increasingly common approach to identify targetable driver mutations in lung cancer patients. We collected paired PAXgene® tissue-fixed and formalin-fixed samples of block-sized tumour and lung parenchyma, Temno-needle core tumour biopsies and fine needle tumour aspirates (FNAs) from non-small cell lung cancer resection specimens. Traditionally processed formalin fixed paraffin wax embedded (FFPE) samples were compared to paired PAXgene® tissue fixed paraffin-embedded (PFPE) samples. We evaluated suitability for common laboratory tests (H&E staining and immunohistochemistry) and performance for downstream molecular investigations relevant to lung cancer, including RT-PCR and next generation DNA sequencing (NGS). Adequate and comparable H&E staining was seen in all sample types and nuclear staining was preferable in PAXgene® fixed Temno tumour biopsies and tumour FNA samples. Immunohistochemical staining was broadly comparable. PFPE samples enabled greater yields of less-fragmented DNA than FFPE comparators. PFPE samples were also superior for PCR and NGS performance, both in terms of quality control metrics and for variant calling. Critically we identified a greater number of genetic variants in the epidermal growth factor receptor gene when using PFPE samples and the Ingenuity® Variant Analysis pipeline. In summary, PFPE samples are adequate for histopathological diagnosis and suitable for the majority of existing laboratory tests. PAXgene® fixation is superior for DNA and RNA integrity, particularly in low-yield samples and facilitates improved NGS performance, including the detection of actionable lung cancer mutations for precision medicine in lung cancer samples..
Craig, S.G.
Anderson, L.A.
Moran, M.
Graham, L.
Currie, K.
Rooney, K.
Robinson, M.
Bingham, V.
Cuschieri, K.S.
McQuaid, S.
Schache, A.G.
Jones, T.M.
McCance, D.
Salto-Tellez, M.
McDade, S.S.
James, J.A.
(2020). Comparison of Molecular Assays for HPV Testing in Oropharyngeal Squamous Cell Carcinomas: A Population-Based Study in Northern Ireland. Cancer epidemiology, biomarkers & prevention,
Vol.29
(1),
pp. 31-38.
show abstract
Abstract
Background:
Determination of human papillomavirus (HPV) status has become clinically relevant for patient stratification under UICC TNM8 staging. Within the United Kingdom, a combination of p16 IHC and HPV DNA-ISH is recommended for classifying HPV status. This study will assess a series of clinically applicable second-line molecular tests to run in combination with p16 IHC to optimally determine HPV status.
Methods:
The ability of HPV RNA-ISH, HPV DNA-ISH, and HPV DNA-PCR to identify p16-positive/HPV-positive patients was investigated in a population-based oropharyngeal squamous cell carcinoma (OPSCC) cohort of patients diagnosed in Northern Ireland from 2000 to 2011.
Results:
Only 41% of the Northern Irish OPSCC patient population was associated with HPV-driven carcinogenesis. Both ISH assays were more specific than the DNA-PCR assay (100% and 95% vs. 67%) and were less likely to be affected by preanalytic factors such as increasing block age. A pooled HPV genotype probe for RNA-ISH was found to be the most accurate molecular assay assessed (95% accuracy) when compared with p16 positivity.
Conclusions:
Our study demonstrates the advantage of tissue-based molecular assays when determining HPV status in retrospective samples. Specifically, we demonstrate the enhanced sensitivity and specificity of ISH techniques compared with PCR-based methodology when working with formalin-fixed paraffin-embedded tissue, and found HPV RNA-ISH to be the most effective assay for determining HPV status.
Impact:
As p16 IHC is a relatively inexpensive, accessible, and sensitive test for stratifying patients by HPV status, this study finds that more patients would benefit from first-line p16 IHC followed by specific HPV testing using HPV RNA-ISH to confirm HPV status.
.
McCain, R.S.
McManus, D.T.
McQuaid, S.
James, J.A.
Salto-Tellez, M.
Reid, N.B.
Craig, S.
Chisambo, C.
Bingham, V.
McCarron, E.
Parkes, E.
Turkington, R.C.
Coleman, H.G.
(2020). Alcohol intake, tobacco smoking, and esophageal adenocarcinoma survival: a molecular pathology epidemiology cohort study. Cancer causes & control,
Vol.31
(1),
pp. 1-11.
show abstract
Abstract
Purpose
To investigate the association between cigarette smoking, alcohol consumption, and esophageal adenocarcinoma survival, including stratified analysis by selected prognostic biomarkers.
Methods
A population-representative sample of 130 esophageal adenocarcinoma patients (n = 130) treated at the Northern Ireland Cancer Centre between 2004 and 2012. Cox proportional hazards models were applied to evaluate associations between smoking status, alcohol intake, and survival. Secondary analyses investigated these associations across categories of p53, HER2, CD8, and GLUT-1 biomarker expression.
Results
In esophageal adenocarcinoma patients, there was a significantly increased risk of cancer-specific mortality in ever, compared to never, alcohol drinkers in unadjusted (HR 1.96 95% CI 1.13–3.38) but not adjusted (HR 1.70 95% CI 0.95–3.04) analysis. This increased risk of death observed for alcohol consumers was more evident in patients with normal p53 expression, GLUT-1 positive or CD-8 positive tumors. There were no significant associations between survival and smoking status in esophageal adenocarcinoma patients.
Conclusions
In esophageal adenocarcinoma patients, cigarette smoking or alcohol consumption was not associated with a significant difference in survival in comparison with never smokers and never drinkers in fully adjusted analysis. However, in some biomarker-selected subgroups, ever-alcohol consumption was associated with a worsened survival in comparison with never drinkers. Larger studies are needed to investigate these findings, as these lifestyle habits may not only be linked to cancer risk but also cancer survival.
.
Browning, L.
Colling, R.
Rakha, E.
Rajpoot, N.
Rittscher, J.
James, J.A.
Salto-Tellez, M.
Snead, D.R.
Verrill, C.
(2020). Digital pathology and artificial intelligence will be key to supporting clinical and academic cellular pathology through COVID-19 and future crises: the PathLAKE consortium perspective. Journal of clinical pathology,
.
show abstract
The measures to control the COVID-19 outbreak will likely remain a feature of our working lives until a suitable vaccine or treatment is found. The pandemic has had a substantial impact on clinical services, including cancer pathways. Pathologists are working remotely in many circumstances to protect themselves, colleagues, family members and the delivery of clinical services. The effects of COVID-19 on research and clinical trials have also been significant with changes to protocols, suspensions of studies and redeployment of resources to COVID-19. In this article, we explore the specific impact of COVID-19 on clinical and academic pathology and explore how digital pathology and artificial intelligence can play a key role to safeguarding clinical services and pathology-based research in the current climate and in the future..
Humphries, M.P.
Craig, S.G.
Kacprzyk, R.
Fisher, N.C.
Bingham, V.
McQuaid, S.
Murray, G.I.
McManus, D.
Turkington, R.C.
James, J.
Salto-Tellez, M.
(2020). The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation. Bmc cancer,
Vol.20
(1),
pp. 500-?.
show abstract
Background Limited studies examine the immune landscape in Esophageal Adenocarcinoma (EAC). We aim to identify novel associations, which may inform immunotherapy treatment stratification.Methods Three hundred twenty-nine EAC cases were available in Tissue Microarrays (TMA) format. A discovery cohort of 166 EAC cases were stained immunohistochemically for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS, IDO-1, PD-L1, PD-1). A validation cohort of 163 EAC cases was also accessed. A digital pathology analysis approach was used to quantify biomarker density.Results CD3, CD4, CD8, CD45RO, ICOS and PD-1 were individually predictive of better overall survival (OS) (Log rank p = < 0.001; p = 0.014; p = 0.001; p = < 0.001; p = 0.008 and p = 0.026 respectively). Correlation and multivariate analysis identified high CD45RO/ICOS patients with significantly improved OS which was independently prognostic (HR = 0.445, (0.223-0.886), p = 0.021). Assessment of CD45RO and ICOS high cases in the validation cohort revealed an associated with improved OS (HR = 0.601 (0.363-0.996), p = 0.048). Multiplex IHC identified cellular co-expression of high CD45RO/ICOS. High CD45RO/ICOS patients have significantly improved OS.Conclusions Multiplexing identifies true cellular co-expression. These data demonstrate that co-expression of immune biomarkers are associated with better outcome in EAC and may provide evidence for immunotherapy treatment stratification..
McConnell, L.
Houghton, O.
Stewart, P.
Gazdova, J.
Srivastava, S.
Kim, C.
Catherwood, M.
Strobl, A.
Flanagan, A.M.
Oniscu, A.
Kroeze, L.I.
Groenen, P.
Taniere, P.
Salto-Tellez, M.
Gonzalez, D.
(2020). A novel next generation sequencing approach to improve sarcoma diagnosis. Modern pathology,
Vol.33
(7),
pp. 1350-1359.
Quezada-Marín, J.I.
Lam, A.K.
Ochiai, A.
Odze, R.D.
Washington, K.M.
Fukayama, M.
Rugge, M.
Klimstra, D.S.
Nagtegaal, I.D.
Tan, P.-.
Arends, M.J.
Goldblum, J.R.
Cree, I.A.
Salto-Tellez, M.
(2020). Gastrointestinal tissue-based molecular biomarkers: a practical categorisation based on the 2019 World Health Organization classification of epithelial digestive tumours. Histopathology,
Vol.77
(3),
pp. 340-350.
show abstract
Molecular biomarkers have come to constitute one of the cornerstones of oncological pathology. The method of classification not only directly affects the manner in which patients are diagnosed and treated, but also guides the development of drugs and of artificial intelligence tools. The aim of this article is to organise and update gastrointestinal molecular biomarkers in order to produce an easy-to-use guide for routine diagnostics. For this purpose, we have extracted and reorganised the molecular information on epithelial neoplasms included in the 2019 World Health Organization classification of tumours. Digestive system tumours, 5th edn..
Craig, S.G.
Humphries, M.P.
Alderdice, M.
Bingham, V.
Richman, S.D.
Loughrey, M.B.
Coleman, H.G.
Viratham-Pulsawatdi, A.
McCombe, K.
Murray, G.I.
Blake, A.
Domingo, E.
Robineau, J.
Brown, L.
Fisher, D.
Seymour, M.T.
Quirke, P.
Bankhead, P.
McQuaid, S.
Lawler, M.
McArt, D.G.
Maughan, T.S.
James, J.A.
Salto-Tellez, M.
(2020). Immune status is prognostic for poor survival in colorectal cancer patients and is associated with tumour hypoxia. British journal of cancer,
Vol.123
(8),
pp. 1280-1288.
show abstract
Background Immunohistochemical quantification of the immune response is prognostic for colorectal cancer (CRC). Here, we evaluate the suitability of alternative immune classifiers on prognosis and assess whether they relate to biological features amenable to targeted therapy.Methods Overall survival by immune (CD3, CD4, CD8, CD20 and FOXP3) and immune-checkpoint (ICOS, IDO-1 and PD-L1) biomarkers in independent CRC cohorts was evaluated. Matched mutational and transcriptomic data were interrogated to identify associated biology.Results Determination of immune-cold tumours by combined low-density cell counts of CD3, CD4 and CD8 immunohistochemistry constituted the best prognosticator across stage II-IV CRC, particularly in patients with stage IV disease (HR 1.98 [95% CI: 1.47-2.67]). These immune-cold CRCs were associated with tumour hypoxia, confirmed using CAIX immunohistochemistry (P = 0.0009), which may mediate disease progression through common biology (KRAS mutations, CRIS-B subtype and SPP1 mRNA overexpression).Conclusions Given the significantly poorer survival of immune-cold CRC patients, these data illustrate that assessment of CD4-expressing cells complements low CD3 and CD8 immunohistochemical quantification in the tumour bulk, potentially facilitating immunophenotyping of patient biopsies to predict prognosis. In addition, we found immune-cold CRCs to associate with a difficult-to-treat, poor prognosis hypoxia signature, indicating that these patients may benefit from hypoxia-targeting clinical trials..
Viratham Pulsawatdi, A.
Craig, S.G.
Bingham, V.
McCombe, K.
Humphries, M.P.
Senevirathne, S.
Richman, S.D.
Quirke, P.
Campo, L.
Domingo, E.
Maughan, T.S.
James, J.A.
Salto-Tellez, M.
(2020). A robust multiplex immunofluorescence and digital pathology workflow for the characterisation of the tumour immune microenvironment. Molecular oncology,
Vol.14
(10),
pp. 2384-2402.
show abstract
Multiplex immunofluorescence is a powerful tool for the simultaneous detection of tissue-based biomarkers, revolutionising traditional immunohistochemistry. The Opal methodology allows up to eight biomarkers to be measured concomitantly without cross-reactivity, permitting identification of different cell populations within the tumour microenvironment. In this study, we aimed to validate a multiplex immunofluorescence workflow in two complementary multiplex panels and evaluate the tumour immune microenvironment in colorectal cancer (CRC) formalin-fixed paraffin-embedded tissue. We stained CRC and tonsil samples using Opal multiplex immunofluorescence on a Leica BOND RX immunostainer. We then acquired images on an Akoya Vectra Polaris and performed multispectral unmixing using inform. Antibody panels were validated on tissue microarray sections containing cores from six normal tissue types, using qupath for image analysis. Comparisons between chromogenic immunohistochemistry and multiplex immunofluorescence on consecutive sections from the same tissue microarray showed significant correlation (r s > 0.9, P-value < 0.0001), validating both panels. We identified many factors that influenced the quality of the acquired fluorescent images, including biomarker co-expression, staining order, Opal-antibody pairing, sample thickness, multispectral unmixing and biomarker detection order during image analysis. Overall, we report the optimisation and validation of a multiplex immunofluorescence process, from staining to image analysis, ensuring assay robustness. Our multiplex immunofluorescence protocols permit the accurate detection of multiple immune markers in various tissue types, using a workflow that enables rapid processing of samples, above and beyond previous workflows..
Arends, M.J.
Salto-Tellez, M.
(2020). Low-contact and high-interconnectivity pathology (LC&HI Path): post-COVID19-pandemic practice of pathology. Histopathology,
Vol.77
(4),
pp. 518-524.
show abstract
The COVID-19 pandemic situation may be viewed as an opportunity to accelerate some of the ongoing transformations in modern pathology. This refers primarily to the digitalisation of the practice of tissue and cellular pathology diagnostics. However, it is also an opportunity to analyse the modus operandi of a discipline that has been practised in a similar manner for more than 100 years. The challenge is to define the next generation of interconnectivity tools that would be necessary to achieve a new operational model that, while ensuring low face-to-face interaction between the main players of the diagnostic pipeline, allows maximum interconnectivity to serve our patients and the immediate teaching and research needs associated with clinical tissue/cellular samples. This viewpoint aims to describe what this new paradigm, a low-contact and high-interconnectivity pathology (LC&HC Path) operation, may require in the near future..
Loughrey, M.B.
McGrath, J.
Coleman, H.G.
Bankhead, P.
Maxwell, P.
McGready, C.
Bingham, V.
Humphries, M.P.
Craig, S.G.
McQuaid, S.
Salto-Tellez, M.
James, J.A.
(2020). Identifying mismatch repair-deficient colon cancer: near-perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population-based series. Histopathology,
.
show abstract
AIMS:Establishing the mismatch repair (MMR) status of colorectal cancers is important to enable the detection of underlying Lynch syndrome and inform prognosis and therapy. Current testing typically involves either polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing or MMR protein immunohistochemistry (IHC). The aim of this study was to compare these two approaches in a large, population-based cohort of stage 2 and 3 colon cancer cases in Northern Ireland. METHODS AND RESULTS:The study used the Promega pentaplex assay to determine MSI status and a four-antibody MMR IHC panel. IHC was applied to tumour tissue microarrays with triplicate tumour sampling, and assessed manually. Of 593 cases with available MSI and MMR IHC results, 136 (22.9%) were MSI-high (MSI-H) and 135 (22.8%) showed abnormal MMR IHC. Concordance was extremely high, with 97.1% of MSI-H cases showing abnormal MMR IHC, and 97.8% of cases with abnormal IHC showing MSI-H status. Under-representation of tumour epithelial cells in samples from heavily inflamed tumours resulted in misclassification of several cases with abnormal MMR IHC as microsatellite-stable. MMR IHC revealed rare cases with unusual patterns of MMR protein expression, unusual combinations of expression loss, or secondary clonal loss of expression, as further illustrated by repeat immunostaining on whole tissue sections. CONCLUSIONS:MSI PCR testing and MMR IHC can be considered to be equally proficient tests for establishing MMR/MSI status, when there is awareness of the potential pitfalls of either method. The choice of methodology may depend on available services and expertise..
Abdullahi Sidi, F.
Bingham, V.
Craig, S.G.
McQuaid, S.
James, J.
Humphries, M.P.
Salto-Tellez, M.
(2020). PD-L1 Multiplex and Quantitative Image Analysis for Molecular Diagnostics. Cancers,
Vol.13
(1).
show abstract
Multiplex immunofluorescence (mIF) and digital image analysis (DIA) have transformed the ability to analyse multiple biomarkers. We aimed to validate a clinical workflow for quantifying PD-L1 in non-small cell lung cancer (NSCLC). NSCLC samples were stained with a validated mIF panel. Immunohistochemistry (IHC) was conducted and mIF slides were scanned on an Akoya Vectra Polaris. Scans underwent DIA using QuPath. Single channel immunofluorescence was concordant with single-plex IHC. DIA facilitated quantification of cell types expressing single or multiple phenotypic markers. Considerations for analysis included classifier accuracy, macrophage infiltration, spurious staining, threshold sensitivity by DIA, sensitivity of cell identification in the mIF. Alternative sequential detection of biomarkers by DIA potentially impacted final score. Strong concordance was observed between 3,3'-Diaminobenzidine (DAB) IHC slides and mIF slides (R 2 = 0.7323). Comparatively, DIA on DAB IHC was seen to overestimate the PD-L1 score more frequently than on mIF slides. Overall, concordance between DIA on DAB IHC slides and mIF slides was 95%. DIA of mIF slides is rapid, highly comparable to DIA on DAB IHC slides, and enables comprehensive extraction of phenotypic data and specific microenvironmental detail intrinsic to the sample. Exploration of the clinical relevance of mIF in the context of immunotherapy treated cases is warranted..
Li, J.
Duran, M.A.
Dhanota, N.
Chatila, W.K.
Bettigole, S.E.
Kwon, J.
Sriram, R.K.
Humphries, M.P.
Salto-Tellez, M.
James, J.A.
Hanna, M.G.
Melms, J.C.
Vallabhaneni, S.
Litchfield, K.
Usaite, I.
Biswas, D.
Bareja, R.
Li, H.W.
Martin, M.L.
Dorsaint, P.
Cavallo, J.-.
Li, P.
Pauli, C.
Gottesdiener, L.
DiPardo, B.J.
Hollmann, T.J.
Merghoub, T.
Wen, H.Y.
Reis-Filho, J.S.
Riaz, N.
Su, S.-.
Kalbasi, A.
Vasan, N.
Powell, S.N.
Wolchok, J.D.
Elemento, O.
Swanton, C.
Shoushtari, A.N.
Parkes, E.E.
Izar, B.
Bakhoum, S.F.
(2020). Metastasis and immune evasion from extracellular cGAMP hydrolysis. Cancer discovery,
.
show abstract
Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune stimulatory metabolite whose breakdown products include the immune suppressor, adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wildtype ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part, through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune suppressive pathway..
Humphries, M.P.
Bingham, V.
Abdullahi Sidi, F.
Craig, S.G.
McQuaid, S.
James, J.
Salto-Tellez, M.
(2020). Improving the Diagnostic Accuracy of the PD-L1 Test with Image Analysis and Multiplex Hybridization. Cancers,
Vol.12
(5).
show abstract
Targeting of the programmed cell death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis with checkpoint inhibitors has changed clinical practice in non-small cell lung cancer (NSCLC). However, clinical assessment remains complex and ambiguous. We aim to assess whether digital image analysis (DIA) and multiplex immunofluorescence can improve the accuracy of PD-L1 diagnostic testing. A clinical cohort of routine NSCLC patients reflex tested for PD-L1 (SP263) immunohistochemistry (IHC), was assessed using DIA. Samples of varying assessment difficulty were assessed by multiplex immunofluorescence. Sensitivity, specificity, and concordance was evaluated between manual diagnostic evaluation and DIA for chromogenic and multiplex IHC. PD-L1 expression by DIA showed significant concordance (R² = 0.8248) to manual assessment. Sensitivity and specificity was 86.8% and 91.4%, respectively. Evaluation of DIA scores revealed 96.8% concordance to manual assessment. Multiplexing enabled PD-L1+/CD68+ macrophages to be readily identified within PD-L1+/cytokeratin+ or PD-L1-/cytokeratin+ tumor nests. Assessment of multiplex vs. chromogenic IHC had a sensitivity and specificity of 97.8% and 91.8%, respectively. Deployment of DIA for PD-L1 diagnostic assessment is an accurate process of case triage. Multiplex immunofluorescence provided higher confidence in PD-L1 assessment and could be offered for challenging cases by centers with appropriate expertise and specialist equipment..
Humphries, M.P.
McQuaid, S.
Craig, S.G.
Bingham, V.
Maxwell, P.
Maurya, M.
McLean, F.
Sampson, J.
Higgins, P.
Greene, C.
James, J.
Salto-Tellez, M.
(2019). Critical Appraisal of Programmed Death Ligand 1 Reflex Diagnostic Testing: Current Standards and Future Opportunities. Journal of thoracic oncology : official publication of the international association for the study of lung cancer,
Vol.14
(1),
pp. 45-53.
show abstract
Introduction Patient suitability to anti-programmed death ligand 1 (PD-L1) immune checkpoint inhibition is key to the treatment of NSCLC. We present, applied to PD-L1 testing: a comprehensive cross-validation of two immunohistochemistry (IHC) clones; our descriptive experience in diagnostic reflex testing; the concordance of IHC to in situ RNA (RNA-ISH); and application of digital pathology.Methods Eight hundred thirteen NSCLC tumor samples collected from 564 diagnostic samples were analyzed prospectively, and 249 diagnostic samples analyzed retrospectively in tissue microarray format. Validated methods for IHC and RNA-ISH were tested in tissue microarrays and full sections and the QuPath system were used for digital pathology analysis.Results Antibody concordance of clones SP263 and 22C3 validation was 97% to 98% in squamous cell carcinoma and adenocarcinomas, respectively. Clinical NSCLC cases were reported as PD-L1-negative (48%), 1% to 49% (23%), and more than 50% (29%), with differences associated to tissue-type and EGFR status. Comparison of IHC and RNA-ISH was highly concordant in both subgroups. Comparison of digital assessment versus manual assessment was highly concordant. Discrepancies were mostly around the 1% clinical threshold. Challenging IHC interpretation included 1) calculating the total tumor cell denominator and the nature of PD-L1 expressing cell aggregates in cytology samples; 2) peritumoral expression of positive immune cells; 3) calculation of positive tumor percentages around clinical thresholds; and 4) relevance of the 100 malignant cell rule.Conclusions Sample type and EGFR status dictate differences in the expected percentage of PD-L1 expression. Analysis of PD-L1 is challenging, and interpretative guidelines are discussed. PD-L1 evaluations by RNA-ISH and digital pathology appear reliable, particularly in adenocarcinomas..
Salto-Tellez, M.
Maxwell, P.
Hamilton, P.
(2019). Artificial intelligence-the third revolution in pathology. Histopathology,
Vol.74
(3),
pp. 372-376.
Spence, A.D.
Trainor, J.
McMenamin, Ú.
Turkington, R.C.
McQuaid, S.
Bingham, V.
James, J.
Salto-Tellez, M.
McManus, D.T.
Johnston, B.T.
Cardwell, C.R.
Coleman, H.G.
(2019). High PTGS2 expression in post-neoadjuvant chemotherapy-treated oesophageal adenocarcinoma is associated with improved survival: a population-based cohort study. Histopathology,
Vol.74
(4),
pp. 587-596.
Maxwell, P.
Hynes, S.O.
Fuchs, M.
Craig, S.
McGready, C.
McLean, F.
McQuaid, S.
James, J.
Salto-Tellez, M.
(2019). Practical guide for the comparison of two next-generation sequencing systems for solid tumour analysis in a universal healthcare system. Journal of clinical pathology,
Vol.72
(3),
pp. 225-231.
show abstract
AimsAlthough there have been excellent reports in the literature of validating next-generation sequencing, comparisons between two systems are not often published due to cost and time. We set out to establish that targetable mutations could be reliably detected with different gene panels and different chemistries using a common bioinformatics pipeline for meaningful comparisons to be made.MethodsAfter running selected formalin-fixed, paraffin-embedded samples through QPCR, Sanger sequencing and the 50 gene hotspot v2 panel from Life Technologies to determine standard-of-care variants, we compared the Oncomine panel from Life Technologies performed on a Personal Genome Machine (PGM) and the eight-gene actionable panel from Qiagen performed on a MiSeq platform. We used a common bioinformatics program following the creation of respective VCF files.ResultsBoth panels were accurate to above 90%, the actionable panel workflow was easier to perform but the lowest effective starting DNA load was obtained on the Oncomine workflow at 4 ng. Such minimal DNA can help with samples where there is limited material such as those for lung cancer molecular studies. We also discuss gene panel content and propose that increasing the gene profile of a panel will not benefit clinical laboratories where standard-of-care testing is all that is required.ConclusionsOnce recognised, it may be cost-effective for such laboratories to begin validation with an appropriate bioinformatics pipeline for targeted multigene hotspot molecular testing..
Robinson, M.
James, J.
Thomas, G.
West, N.
Jones, L.
Lee, J.
Oien, K.
Freeman, A.
Craig, C.
Sloan, P.
Elliot, P.
Cheang, M.
Rodriguez-Justo, M.
Verrill, C.
UK National Cancer Research Institute (NCRI) Cellular-Molecular Pathology (CM-Path) clinical trials working group,
(2019). Quality assurance guidance for scoring and reporting for pathologists and laboratories undertaking clinical trial work. The journal of pathology. clinical research,
Vol.5
(2),
pp. 91-99.
show abstract
While pathologists have always played a pivotal role in clinical trials ensuring accurate diagnosis and staging, pathology data from prognostic and predictive tests are increasingly being used to enrol, stratify and randomise patients to experimental treatments. The use of pathological parameters as primary and secondary outcome measures, either as standalone classifiers or in combination with clinical data, is also becoming more common. Moreover, reporting of estimates of residual disease, termed 'pathological complete response', have been incorporated into neoadjuvant clinical trials. Pathologists have the expertise to deliver this essential information and they also understand the requirements and limitations of laboratory testing. Quality assurance of pathology-derived data builds confidence around trial-specific findings and is necessarily focused on the reproducibility of pathological data, including 'estimates of uncertainty of measurement', emphasising the importance of pathologist education, training, calibration and demonstration of satisfactory inter-observer agreement. There are also opportunities to validate objective image analysis tools alongside conventional histological assessments. The ever-expanding portfolio of clinical trials will demand more pathologist engagement to deliver the reliable evidence-base required for new treatments. We provide guidance for quality assurance of pathology scoring and reporting in clinical trials..
Pell, R.
Oien, K.
Robinson, M.
Pitman, H.
Rajpoot, N.
Rittscher, J.
Snead, D.
Verrill, C.
UK National Cancer Research Institute (NCRI) Cellular-Molecular Pathology (CM-Path) quality assurance working group,
(2019). The use of digital pathology and image analysis in clinical trials. The journal of pathology. clinical research,
Vol.5
(2),
pp. 81-90.
show abstract
Digital pathology and image analysis potentially provide greater accuracy, reproducibility and standardisation of pathology-based trial entry criteria and endpoints, alongside extracting new insights from both existing and novel features. Image analysis has great potential to identify, extract and quantify features in greater detail in comparison to pathologist assessment, which may produce improved prediction models or perform tasks beyond manual capability. In this article, we provide an overview of the utility of such technologies in clinical trials and provide a discussion of the potential applications, current challenges, limitations and remaining unanswered questions that require addressing prior to routine adoption in such studies. We reiterate the value of central review of pathology in clinical trials, and discuss inherent logistical, cost and performance advantages of using a digital approach. The current and emerging regulatory landscape is outlined. The role of digital platforms and remote learning to improve the training and performance of clinical trial pathologists is discussed. The impact of image analysis on quantitative tissue morphometrics in key areas such as standardisation of immunohistochemical stain interpretation, assessment of tumour cellularity prior to molecular analytical applications and the assessment of novel histological features is described. The standardisation of digital image production, establishment of criteria for digital pathology use in pre-clinical and clinical studies, establishment of performance criteria for image analysis algorithms and liaison with regulatory bodies to facilitate incorporation of image analysis applications into clinical practice are key issues to be addressed to improve digital pathology incorporation into clinical trials..
Craig, S.G.
Anderson, L.A.
Schache, A.G.
Moran, M.
Graham, L.
Currie, K.
Rooney, K.
Robinson, M.
Upile, N.S.
Brooker, R.
Mesri, M.
Bingham, V.
McQuaid, S.
Jones, T.
McCance, D.J.
Salto-Tellez, M.
McDade, S.S.
James, J.A.
(2019). Recommendations for determining HPV status in patients with oropharyngeal cancers under TNM8 guidelines: a two-tier approach. British journal of cancer,
Vol.120
(8),
pp. 827-833.
show abstract
Background TNM8 staging for oropharyngeal squamous cell carcinomas (OPSCC) surrogates p16 immunohistochemistry for HPV testing. Patients with p16+ OPSCC may lack HPV aetiology. Here, we evaluate the suitability of TNM8 staging for guiding prognosis in such patients.Methods HPV status was ascertained using p16 immunohistochemistry and high-risk HPV RNA and DNA in situ hybridisation. Survival by stage in a cohort of OPSCC patients was evaluated using TNM7/TNM8 staging. Survival of p16+/HPV- patients was compared to p16 status.Results TNM8 staging was found to improve on TNM7 (log rank p = 0·0190 for TNM8 compared with p = 0·0530 for TNM7) in p16+ patients. Patients who tested p16+ but were HPV- (n = 20) had significantly reduced five-year survival (33%) compared to p16+ patients (77%) but not p16- patients (35%). Cancer stage was reduced in 95% of p16+/HPV- patients despite having a mortality rate twice (HR 2.66 [95% CI: 1.37-5.15]) that of p16+/HPV+ patients under new TNM8 staging criteria.Conclusion Given the significantly poorer survival of p16+/HPV- OPSCCs, these data provide compelling evidence for use of an HPV-specific test for staging classification. This has particular relevance in light of potential treatment de-escalation that could expose these patients to inappropriately reduced treatment intensity as treatment algorithms evolve..
Salvucci, M.
Rahman, A.
Resler, A.J.
Udupi, G.M.
McNamara, D.A.
Kay, E.W.
Laurent-Puig, P.
Longley, D.B.
Johnston, P.G.
Lawler, M.
Wilson, R.
Salto-Tellez, M.
Van Schaeybroeck, S.
Rafferty, M.
Gallagher, W.M.
Rehm, M.
Prehn, J.H.
(2019). A Machine Learning Platform to Optimize the Translation of Personalized Network Models to the Clinic. Jco clinical cancer informatics,
Vol.3,
pp. 1-17.
show abstract
Purpose Dynamic network models predict clinical prognosis and inform therapeutic intervention by elucidating disease-driven aberrations at the systems level. However, the personalization of model predictions requires the profiling of multiple model inputs, which hampers clinical translation.Patients and methods We applied APOPTO-CELL, a prognostic model of apoptosis signaling, to showcase the establishment of computational platforms that require a reduced set of inputs. We designed two distinct and complementary pipelines: a probabilistic approach to exploit a consistent subpanel of inputs across the whole cohort (Ensemble) and a machine learning approach to identify a reduced protein set tailored for individual patients (Tree). Development was performed on a virtual cohort of 3,200,000 patients, with inputs estimated from clinically relevant protein profiles. Validation was carried out in an in-house stage III colorectal cancer cohort, with inputs profiled in surgical resections by reverse phase protein array (n = 120) and/or immunohistochemistry (n = 117).Results Ensemble and Tree reproduced APOPTO-CELL predictions in the virtual patient cohort with 92% and 99% accuracy while decreasing the number of inputs to a consistent subset of three proteins (40% reduction) or a personalized subset of 2.7 proteins on average (46% reduction), respectively. Ensemble and Tree retained prognostic utility in the in-house colorectal cancer cohort. The association between the Ensemble accuracy and prognostic value (Spearman ρ = 0.43; P = .02) provided a rationale to optimize the input composition for specific clinical settings. Comparison between profiling by reverse phase protein array (gold standard) and immunohistochemistry (clinical routine) revealed that the latter is a suitable technology to quantify model inputs.Conclusion This study provides a generalizable framework to optimize the development of network-based prognostic assays and, ultimately, to facilitate their integration in the routine clinical workflow..
Rees, G.
Salto-Tellez, M.
Lee, J.L.
Oien, K.
Verrill, C.
Freeman, A.
Mirabile, I.
West, N.P.
National Cancer Research Institute (NCRI) Cellular-Molecular Pathology (CM-Path) clinical trials working group,
(2019). Training and accreditation standards for pathologists undertaking clinical trial work. The journal of pathology. clinical research,
Vol.5
(2),
pp. 100-107.
show abstract
Clinical trials rely on multidisciplinary teams for successful delivery. Pathologists should be involved in clinical trial design from the outset to ensure that protocols are optimised to deliver maximum data collection and translational research opportunities. Clinical trials must be performed according to the principles of Good Clinical Practice (GCP) and the trial sponsor has an obligation to ensure that all of the personnel involved in the trial have undergone training relevant to their role. Pathologists who are involved in the delivery of clinical trials are often required to undergo formal GCP training and may additionally undergo Good Clinical Laboratory Practice training if they are involved in the laboratory analysis of trials samples. Further training can be provided via trial-specific investigator meetings, which may be either multidisciplinary or discipline-specific events. Pathologists should also ensure that they undertake External Quality Assurance schemes relevant to the area of diagnostic practice required in the trial. The level of engagement of pathologists in academia and clinical trials research has declined in the United Kingdom over recent years. This paper recommends the optimal training and accreditation for pathologists undertaking clinical trials activities with the aim of facilitating increased engagement. Clinical trials training should ideally be provided to all pathologists through centrally organised educational events, with additional training provided to pathologists in training through local postgraduate teaching. Pathologists in training should also be strongly encouraged to undertake GCP training. It is hoped that these recommendations will increase the number of pathologists who take part in clinical trials research in order to ensure a high level and standard of data collection and to maximise the translational research opportunities..
Roy-Chowdhuri, S.
Pisapia, P.
Salto-Tellez, M.
Savic, S.
Nacchio, M.
de Biase, D.
Tallini, G.
Troncone, G.
Schmitt, F.
(2019). Invited review—next-generation sequencing: a modern tool in cytopathology. Virchows archiv,
Vol.475
(1),
pp. 3-11.
Turkington, R.C.
Knight, L.A.
Blayney, J.K.
Secrier, M.
Douglas, R.
Parkes, E.E.
Sutton, E.K.
Stevenson, L.
McManus, D.
Halliday, S.
McCavigan, A.M.
Logan, G.E.
Walker, S.M.
Steele, C.J.
Perner, J.
Bornschein, J.
MacRae, S.
Miremadi, A.
McCarron, E.
McQuaid, S.
Arthur, K.
James, J.A.
Eatock, M.M.
O'Neill, R.
Noble, F.
Underwood, T.J.
Harkin, D.P.
Salto-Tellez, M.
Fitzgerald, R.C.
Kennedy, R.D.
Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Study Group,
(2019). Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma. Gut,
Vol.68
(11),
pp. 1918-1927.
show abstract
Objective Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC.Design Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS).Results A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025).Conclusion The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC..
Beirne, J.P.
McArt, D.G.
Roddy, A.
McDermott, C.
Ferris, J.
Buckley, N.E.
Coulter, P.
McCabe, N.
Eddie, S.L.
Dunne, P.D.
O'Reilly, P.
Gilmore, A.
Feeney, L.
Ewing, D.L.
Drapkin, R.I.
Salto-Tellez, M.
Kennedy, R.D.
Harley, I.J.
McCluggage, W.G.
Mullan, P.B.
(2019). Defining the molecular evolution of extrauterine high grade serous carcinoma. Gynecologic oncology,
Vol.155
(2),
pp. 305-317.
Roddy, A.C.
Jurek-Loughrey, A.
Souza, J.
Gilmore, A.
O'Reilly, P.G.
Stupnikov, A.
Gonzalez de Castro, D.
Prise, K.M.
Salto-Tellez, M.
McArt, D.G.
(2019). NUQA: Estimating Cancer Spatial and Temporal Heterogeneity and Evolution through Alignment-Free Methods. Molecular biology and evolution,
Vol.36
(12),
pp. 2883-2889.
show abstract
Longitudinal next-generation sequencing of cancer patient samples has enhanced our understanding of the evolution and progression of various cancers. As a result, and due to our increasing knowledge of heterogeneity, such sampling is becoming increasingly common in research and clinical trial sample collections. Traditionally, the evolutionary analysis of these cohorts involves the use of an aligner followed by subsequent stringent downstream analyses. However, this can lead to large levels of information loss due to the vast mutational landscape that characterizes tumor samples. Here, we propose an alignment-free approach for sequence comparison-a well-established approach in a range of biological applications including typical phylogenetic classification. Such methods could be used to compare information collated in raw sequence files to allow an unsupervised assessment of the evolutionary trajectory of patient genomic profiles. In order to highlight this utility in cancer research we have applied our alignment-free approach using a previously established metric, Jensen-Shannon divergence, and a metric novel to this area, Hellinger distance, to two longitudinal cancer patient cohorts in glioma and clear cell renal cell carcinoma using our software, NUQA. We hypothesize that this approach has the potential to reveal novel information about the heterogeneity and evolutionary trajectory of spatiotemporal tumor samples, potentially revealing early events in tumorigenesis and the origins of metastases and recurrences. Key words: alignment-free, Hellinger distance, exome-seq, evolution, phylogenetics, longitudinal..
Bankhead, P.
Fernández, J.A.
McArt, D.G.
Boyle, D.P.
Li, G.
Loughrey, M.B.
Irwin, G.W.
Harkin, D.P.
James, J.A.
McQuaid, S.
Salto-Tellez, M.
Hamilton, P.W.
(2018). Integrated tumor identification and automated scoring minimizes pathologist involvement and provides new insights to key biomarkers in breast cancer. Laboratory investigation,
Vol.98
(1),
pp. 15-26.
Salto-Tellez, M.
(2018). More Than a Decade of Molecular Diagnostic Cytopathology Leading Diagnostic and Therapeutic Decision-Making. Archives of pathology & laboratory medicine,
Vol.142
(4),
pp. 443-445.
Maxwell, P.
Salto-Tellez, M.
(2018). Training in molecular cytopathology testing. Cytopathology,
Vol.29
(1),
pp. 5-9.
Mahyuddin, A.P.
Liu, L.
Zhao, C.
Kothandaraman, N.
Salto-Tellez, M.
Pang, B.N.
Lim, D.G.
Annalamai, L.
Chan, J.K.
Lim, T.Y.
Biswas, A.
Rice, G.
Razvi, K.
Choolani, M.
(2018). Diagnostic accuracy of haptoglobin within ovarian cyst fluid as a potential point-of-care test for epithelial ovarian cancer: an observational study. Bjog: an international journal of obstetrics & gynaecology,
Vol.125
(4),
pp. 421-431.
Bradley, C.A.
Salto-Tellez, M.
Laurent-Puig, P.
Bardelli, A.
Rolfo, C.
Tabernero, J.
Khawaja, H.A.
Lawler, M.
Johnston, P.G.
Van Schaeybroeck, S.
(2018). Erratum: Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges. Nature reviews clinical oncology,
Vol.15
(3),
pp. 150-150.
Ong, C.W.
Maxwell, P.
Alvi, M.A.
McQuaid, S.
Waugh, D.
Mills, I.
Salto-Tellez, M.
(2018). A gene signature associated with PTEN activation defines good prognosis intermediate risk prostate cancer cases. The journal of pathology: clinical research,
Vol.4
(2),
pp. 103-113.
Moore, D.A.
Young, C.A.
Morris, H.T.
Oien, K.A.
Lee, J.L.
Jones, J.L.
Salto-Tellez, M.
(2018). Time for change: a new training programme for morpho-molecular pathologists?. Journal of clinical pathology,
Vol.71
(4),
pp. 285-290.
show abstract
The evolution of cellular pathology as a specialty has always been driven by technological developments and the clinical relevance of incorporating novel investigations into diagnostic practice. In recent years, the molecular characterisation of cancer has become of crucial relevance in patient treatment both for predictive testing and subclassification of certain tumours. Much of this has become possible due to the availability of next-generation sequencing technologies and the whole-genome sequencing of tumours is now being rolled out into clinical practice in England via the 100 000 Genome Project. The effective integration of cellular pathology reporting and genomic characterisation is crucial to ensure the morphological and genomic data are interpreted in the relevant context, though despite this, in many UK centres molecular testing is entirely detached from cellular pathology departments. The CM-Path initiative recognises there is a genomics knowledge and skills gap within cellular pathology that needs to be bridged through an upskilling of the current workforce and a redesign of pathology training. Bridging this gap will allow the development of an integrated ‘morphomolecular pathology’ specialty, which can maintain the relevance of cellular pathology at the centre of cancer patient management and allow the pathology community to continue to be a major influence in cancer discovery as well as playing a driving role in the delivery of precision medicine approaches. Here, several alternative models of pathology training, designed to address this challenge, are presented and appraised..
Wong, N.A.
Amary, F.
Butler, R.
Byers, R.
Gonzalez, D.
Haynes, H.R.
Ilyas, M.
Salto-Tellez, M.
Taniere, P.
(2018). HER2 testing of gastro-oesophageal adenocarcinoma: a commentary and guidance document from the Association of Clinical Pathologists Molecular Pathology and Diagnostics Committee. Journal of clinical pathology,
Vol.71
(5),
pp. 388-394.
show abstract
The use of biologics targeted to the human epidermal growth factor receptor 2 (HER2) protein is the latest addition to the armamentarium used to fight advanced gastric or gastro-oesophageal junction adenocarcinoma. The decision to treat with the biologic trastuzumab is completely dependent on HER2 testing of tumour tissue. In 2017, the College of American Pathologists, American Society for Clinical Pathology and the American Society of Clinical Oncology jointly published guidelines for HER2 testing and clinical decision making in gastro-oesophageal adenocarcinoma. The Association of Clinical Pathologists Molecular Pathology and Diagnostics Committee has issued the following document as a commentary of these guidelines and, in parallel, to provide guidance on HER2 testing in National Health Service pathology departments within the UK. This guidance covers issues related to case selection, preanalytical aspects, analysis and interpretation of such HER2 testing..
Blayney, J.K.
Cairns, L.
Li, G.
McCabe, N.
Stevenson, L.
Peters, C.J.
Reid, N.B.
Spence, V.J.
Chisambo, C.
McManus, D.
James, J.
McQuaid, S.
Craig, S.
Arthur, K.
McArt, D.
Ong, C.-.
Lao-Sirieix, P.
Hamilton, P.
Salto-Tellez, M.
Eatock, M.
Coleman, H.G.
Fitzgerald, R.C.
Kennedy, R.D.
Turkington, R.C.
(2018). Glucose transporter 1 expression as a marker of prognosis in oesophageal adenocarcinoma. Oncotarget,
Vol.9
(26),
pp. 18518-18528.
Loughrey, M.B.
Bankhead, P.
Coleman, H.G.
Hagan, R.S.
Craig, S.
McCorry, A.M.
Gray, R.T.
McQuaid, S.
Dunne, P.D.
Hamilton, P.W.
James, J.A.
Salto-Tellez, M.
(2018). Validation of the systematic scoring of immunohistochemically stained tumour tissue microarrays using QuPath
digital image analysis. Histopathology,
Vol.73
(2),
pp. 327-338.
Stupnikov, A.
O'Reilly, P.G.
McInerney, C.E.
Roddy, A.C.
Dunne, P.D.
Gilmore, A.
Ellis, H.P.
Flannery, T.
Healy, E.
McIntosh, S.A.
Savage, K.
Kurian, K.M.
Emmert-Streib, F.
Prise, K.M.
Salto-Tellez, M.
McArt, D.G.
(2018). Impact of Variable RNA-Sequencing Depth on Gene Expression Signatures and Target Compound Robustness: Case Study Examining Brain Tumor (Glioma) Disease Progression. Jco precision oncology,
Vol.2.
show abstract
Purpose Gene expression profiling can uncover biologic mechanisms underlying disease and is important in drug development. RNA sequencing (RNA-seq) is routinely used to assess gene expression, but costs remain high. Sample multiplexing reduces RNAseq costs; however, multiplexed samples have lower cDNA sequencing depth, which can hinder accurate differential gene expression detection. The impact of sequencing depth alteration on RNA-seq-based downstream analyses such as gene expression connectivity mapping is not known, where this method is used to identify potential therapeutic compounds for repurposing.Methods In this study, published RNA-seq profiles from patients with brain tumor (glioma) were assembled into two disease progression gene signature contrasts for astrocytoma. Available treatments for glioma have limited effectiveness, rendering this a disease of poor clinical outcome. Gene signatures were subsampled to simulate sequencing alterations and analyzed in connectivity mapping to investigate target compound robustness.Results Data loss to gene signatures led to the loss, gain, and consistent identification of significant connections. The most accurate gene signature contrast with consistent patient gene expression profiles was more resilient to data loss and identified robust target compounds. Target compounds lost included candidate compounds of potential clinical utility in glioma (eg, suramin, dasatinib). Lost connections may have been linked to low-abundance genes in the gene signature that closely characterized the disease phenotype. Consistently identified connections may have been related to highly expressed abundant genes that were ever-present in gene signatures, despite data reductions. Potential noise surrounding findings included false-positive connections that were gained as a result of gene signature modification with data loss.Conclusion Findings highlight the necessity for gene signature accuracy for connectivity mapping, which should improve the clinical utility of future target compound discoveries..
Stupnikov, A.
McInerney, C.E.
O’Reilly, P.G.
Roddy, A.C.
Dunne, P.D.
Gilmore, A.
Savage, K.
McIntosh, S.A.
Flannery, T.
Healy, E.
Ellis, H.P.
Kurian, K.M.
Emmert-Streib, F.
Prise, K.M.
Salto-Tellez, M.
McArt, D.G.
(2018). P04 46 Variable RNA sequencing depth impacts gene signatures and target compound robustness - case study examining brain tumour (glioma) disease progression. Neuro-oncology,
Vol.20
(Suppl 3),
pp. iii289-iii289.
show abstract
Abstract
Background
Gene expression profiling can uncover biological mechanisms underlying disease and is important in drug development. RNA-seq is routinely used to assess gene expression but costs remain high. Sample multiplexing reduces RNA-seq costs, however, multiplexed samples have lower cDNA sequencing depth, which can hinder accurate differential gene expression detection. The impact of sequencing depth alteration on RNA-seq-based downstream analyses such as gene expression connectivity mapping is not known, where connectivity mapping can be used to identify potential therapeutic compounds for repurposing.
Material and Methods
In this study, published RNA-seq profiles from brain tumour (glioma) patients were assembled into two disease progression gene signature contrasts for astrocytoma. Available treatments for glioma have limited effectiveness rendering this a disease of poor clinical outcome. Gene signatures were subsampled to simulate sequencing alterations and analysed in connectivity mapping to investigate target compound robustness.
Results
Data loss to gene signatures led to the loss, gain and consistent identification of significant connections. The most accurate gene signature contrast with consistent patient gene expression profiles was more resilient to data loss and identified robust target compounds. Target compounds lost included candidate compounds of potential clinical utility in glioma (e.g. Suramin, Dasatinib). Lost connections may have been linked to low abundance genes in the gene signature that closely characterised the disease phenotype. Consistently identified connections may have been related to highly expressed abundant genes that were ever-present in gene signatures, despite data reductions. Potential noise surrounding findings included false positive connections that were gained as a result of gene signature modification with data loss.
Conclusion
Findings highlight the necessity for gene signature accuracy for connectivity mapping, which should improve the clinical utility of future target compound discoveries..
Cross, W.
Kovac, M.
Mustonen, V.
Temko, D.
Davis, H.
Baker, A.-.
Biswas, S.
Arnold, R.
Chegwidden, L.
Gatenbee, C.
Anderson, A.R.
Koelzer, V.H.
Martinez, P.
Jiang, X.
Domingo, E.
Woodcock, D.J.
Feng, Y.
Kovacova, M.
Maughan, T.
S:CORT Consortium,
Jansen, M.
Rodriguez-Justo, M.
Ashraf, S.
Guy, R.
Cunningham, C.
East, J.E.
Wedge, D.C.
Wang, L.M.
Palles, C.
Heinimann, K.
Sottoriva, A.
Leedham, S.J.
Graham, T.A.
Tomlinson, I.P.
(2018). The evolutionary landscape of colorectal tumorigenesis. Nature ecology & evolution,
Vol.2
(10),
pp. 1661-1672.
show abstract
The evolutionary events that cause colorectal adenomas (benign) to progress to carcinomas (malignant) remain largely undetermined. Using multi-region genome and exome sequencing of 24 benign and malignant colorectal tumours, we investigate the evolutionary fitness landscape occupied by these neoplasms. Unlike carcinomas, advanced adenomas frequently harbour sub-clonal driver mutations-considered to be functionally important in the carcinogenic process-that have not swept to fixation, and have relatively high genetic heterogeneity. Carcinomas are distinguished from adenomas by widespread aneusomies that are usually clonal and often accrue in a 'punctuated' fashion. We conclude that adenomas evolve across an undulating fitness landscape, whereas carcinomas occupy a sharper fitness peak, probably owing to stabilizing selection..
Humphries, M.P.
Hynes, S.
Bingham, V.
Cougot, D.
James, J.
Patel-Socha, F.
Parkes, E.E.
Blayney, J.K.
O’Rorke, M.A.
Irwin, G.W.
McArt, D.G.
Kennedy, R.D.
Mullan, P.B.
McQuaid, S.
Salto-Tellez, M.
Buckley, N.E.
(2018). Automated Tumour Recognition and Digital Pathology Scoring Unravels New Role for PD-L1 in Predicting Good Outcome in ER-/HER2+ Breast Cancer. Journal of oncology,
Vol.2018,
pp. 1-14.
show abstract
The role of PD-L1 as a prognostic and predictive biomarker is an area of great interest. However, there is a lack of consensus on how to deliver PD-L1 as a clinical biomarker. At the heart of this conundrum is the subjective scoring of PD-L1 IHC in most studies to date. Current standard scoring systems involve separation of epithelial and inflammatory cells and find clinical significance in different percentages of expression, e.g., above or below 1%. Clearly, an objective, reproducible and accurate approach to PD-L1 scoring would bring a degree of necessary consistency to this landscape. Using a systematic comparison of technologies and the application of QuPath, a digital pathology platform, we show that high PD-L1 expression is associated with improved clinical outcome in Triple Negative breast cancer in the context of standard of care (SoC) chemotherapy, consistent with previous findings. In addition, we demonstrate for the first time that high PD-L1 expression is also associated with better outcome in ER- disease as a whole including HER2+ breast cancer. We demonstrate the influence of antibody choice on quantification and clinical impact with the Ventana antibody (SP142) providing the most robust assay in our hands. Through sampling different regions of the tumour, we show that tumour rich regions display the greatest range of PD-L1 expression and this has the most clinical significance compared to stroma and lymphoid rich areas. Furthermore, we observe that both inflammatory and epithelial PD-L1 expression are associated with improved survival in the context of chemotherapy. Moreover, as seen with PD-L1 inhibitor studies, a low threshold of PD-L1 expression stratifies patient outcome. This emphasises the importance of using digital pathology and precise biomarker quantitation to achieve accurate and reproducible scores that can discriminate low PD-L1 expression..
McMenamin, Ú.C.
Trainor, J.
Coleman, H.G.
McManus, D.T.
McQuaid, S.
Bingham, V.
James, J.
Salto-Tellez, M.
Johnston, B.T.
Turkington, R.C.
(2018). Sex hormone receptor expression and survival in esophageal adenocarcinoma: a prospective cohort study. Oncotarget,
Vol.9
(82),
pp. 35300-35312.
McCain, S.
Trainor, J.
McManus, D.T.
McMenamin, Ú.C.
McQuaid, S.
Bingham, V.
James, J.A.
Salto-Tellez, M.
Turkington, R.C.
Coleman, H.G.
(2018). Vitamin D receptor as a marker of prognosis in oesophageal adenocarcinoma: a prospective cohort study. Oncotarget,
Vol.9
(76),
pp. 34347-34356.
Salvucci, M.
Würstle, M.L.
Morgan, C.
Curry, S.
Cremona, M.
Lindner, A.U.
Bacon, O.
Resler, A.J.
Murphy, Á.C.
O'Byrne, R.
Flanagan, L.
Dasgupta, S.
Rice, N.
Pilati, C.
Zink, E.
Schöller, L.M.
Toomey, S.
Lawler, M.
Johnston, P.G.
Wilson, R.
Camilleri-Broët, S.
Salto-Tellez, M.
McNamara, D.A.
Kay, E.W.
Laurent-Puig, P.
Van Schaeybroeck, S.
Hennessy, B.T.
Longley, D.B.
Rehm, M.
Prehn, J.H.
(2017). A Stepwise Integrated Approach to Personalized Risk Predictions in Stage III Colorectal Cancer. Clinical cancer research,
Vol.23
(5),
pp. 1200-1212.
show abstract
Abstract
Purpose: Apoptosis is essential for chemotherapy responses. In this discovery and validation study, we evaluated the suitability of a mathematical model of apoptosis execution (APOPTO-CELL) as a stand-alone signature and as a constituent of further refined prognostic stratification tools.
Experimental Design: Apoptosis competency of primary tumor samples from patients with stage III colorectal cancer (n = 120) was calculated by APOPTO-CELL from measured protein concentrations of Procaspase-3, Procaspase-9, SMAC, and XIAP. An enriched APOPTO-CELL signature (APOPTO-CELL-PC3) was synthesized to capture apoptosome-independent effects of Caspase-3. Furthermore, a machine learning Random Forest approach was applied to APOPTO-CELL-PC3 and available molecular and clinicopathologic data to identify a further enhanced signature. Association of the signature with prognosis was evaluated in an independent colon adenocarcinoma cohort (TCGA COAD, n = 136).
Results: We identified 3 prognostic biomarkers (P = 0.04, P = 0.006, and P = 0.0004 for APOPTO-CELL, APOPTO-CELL-PC3, and Random Forest signatures, respectively) with increasing stratification accuracy for patients with stage III colorectal cancer.
The APOPTO-CELL-PC3 signature ranked highest among all features. The prognostic value of the signatures was independently validated in stage III TCGA COAD patients (P = 0.01, P = 0.04, and P = 0.02 for APOPTO-CELL, APOPTO-CELL-PC3, and Random Forest signatures, respectively). The signatures provided further stratification for patients with CMS1-3 molecular subtype.
Conclusions: The integration of a systems-biology–based biomarker for apoptosis competency with machine learning approaches is an appealing and innovative strategy toward refined patient stratification. The prognostic value of apoptosis competency is independent of other available clinicopathologic and molecular factors, with tangible potential of being introduced in the clinical management of patients with stage III colorectal cancer. Clin Cancer Res; 23(5); 1200–12. ©2016 AACR..
Parkes, E.E.
Walker, S.M.
Taggart, L.E.
McCabe, N.
Knight, L.A.
Wilkinson, R.
McCloskey, K.D.
Buckley, N.E.
Savage, K.I.
Salto-Tellez, M.
McQuaid, S.
Harte, M.T.
Mullan, P.B.
Harkin, D.P.
Kennedy, R.D.
(2017). Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer. Journal of the national cancer institute,
Vol.109
(1),
pp. djw199-djw199.
Hynes, S.O.
Pang, B.
James, J.A.
Maxwell, P.
Salto-Tellez, M.
(2017). Tissue-based next generation sequencing: application in a universal healthcare system. British journal of cancer,
Vol.116
(5),
pp. 553-560.
Gray, R.T.
Cantwell, M.M.
Coleman, H.G.
Loughrey, M.B.
Bankhead, P.
McQuaid, S.
O'Neill, R.F.
Arthur, K.
Bingham, V.
McGready, C.
Gavin, A.T.
Cardwell, C.R.
Johnston, B.T.
James, J.A.
Hamilton, P.W.
Salto-Tellez, M.
Murray, L.J.
(2017). Evaluation of PTGS2 Expression, PIK3CA Mutation, Aspirin Use and Colon Cancer Survival in a Population-Based Cohort Study. Clinical and translational gastroenterology,
Vol.8
(4),
pp. e91-e91.
(2017). Annual Trainee Doctors’ Prize Evening, Thursday 5th November 2015 : Centre for Experimental Medicine, Queens University Belfast. The ulster medical journal,
Vol.86
(2),
pp. 127-133.
show abstract
Introduction
Chronic wounds affect around 200 000 people in the UK, costing around £3 billion annually. Wound healing problems are associated with hypoxia of the wound microenvironment. Promoting angiogenesis with autologous cell-based treatments requires both the correct cell and the optimal application method.
Aims
This study has been designed to investigate the use of commercially-available dermal scaffolds in delivering stem cell therapy to wounds.
Methods
Endothelial colony forming cells (ECFCs) were isolated from adult human peripheral blood, and cultured on one of three scaffolds in vitro (Matriderm®, Glyaderm®, Optimaix). The capacity of the cells to form three-dimensional microtubular constructs in scaffolds was determined. Scaffold-cell constructs were implanted into full thickness wounds on the dorsum of athymic nude mice. Wound blood flow was measured using laser Doppler imaging. Wound size was calculated from serial photographs.
Results
ECFCs formed more numerous and more stable microtubular constructs in Matriderm® than in other scaffolds. Preliminary results show that wounds with implanted ECFC-Matriderm® constructs had significantly higher blood flow both 2 and 4 days after wounding than wounds treated with Matriderm® alone.
Discussion
Wound healing problems cause substantial morbidity and considerable costs. Characterising cell delivery methods is essential to translate research into clinical use
Introduction
Smartphones today with their rising popularity and versatile apps have great potential for revolutionising healthcare services. However, this was soon overshadowed by worrying studies over the quality of publically available medical and health apps. These were subject and/or discipline specific, and mostly evaluated partial compliance with information portrayal standards.
Aims
This study aimed to take a broader approach by assessing the most popular medical and health apps in the UK for full compliance with information portrayal standards.
Methods
The top 50 free and paid apps of the “medical” category on both iTunes and Google App stores were evaluated for evidence of compliance with an app-adapted version of the “Health On the Net” foundation principles.
Results
The sample included 64 apps, 34/64 (53%) were on Google Play and 36/64 (56%) were free. None managed to comply with the entire eight principles.
Discussion
Improving the current situation requires raising public awareness, providing tools that would assist in quality evaluation, encouraging developers to use a robust development process, and facilitating collaboration and engagement among the stakeholders.
(2017). Annual Trainee Doctors’ Prize Day, Thursday 10th November 2016 : Postgraduate Centre, Belfast City Hospital. The ulster medical journal,
Vol.86
(2),
pp. 134-142.
show abstract
Background
With increasing age, the processes of functional decline in the immune system that are collectively termed immunosenescence result in an imbalance between inflammatory and anti-inflammatory pathways. The resulting low grade chronic proinflammatory state is associated with the development of age related conditions including Alzheimer’s and cardiovascular disease. The primary aim of the study was to investigate cytokine concentrations change with age in healthy individuals without chronic disease.
Methods
Plasma samples were examined for cytokines IL-1ra, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12(p70), eotaxin-1, GM-CSF, IP-10 and TNF-α. This information was used to compare cytokine levels with average polyphenol intake and increase in age.
Results
63 healthy participants aged 20–84 years were divided into young and old groups. IL4 and IL8 exhibited statistically significant declines in plasma concentrations with age. When comparing cytokine levels between females and males the two anti-inflammatory cytokines IL-4 and IL-10 were higher in women than men and all pro-inflammatory cytokines were decreased. Links between diet, exercise, BMI and plasma cytokine levels were assessed and this identified two associations as significant in young people only: IL-1ra vs. fruit and IP-10 vs. dairy.
Discussion
the results of this study indicate a signal of healthy ageing which differs between genders, with a less inflammatory cytokine milieu observed in females and more substantial proinflammatory changes in men.
Introduction
Trainee-led regional networks can facilitate research through a novel, collaborative approach. We report the establishment and output of the Northern Ireland Surgical Research Collaborative, the first trainee collaborative formed in Northern Ireland.
Aims
To evaluate if a trainee research collaborative could be established in Northern Ireland and if it could deliver good quality research.
Results
After four meetings and a two-month period of research, over a total of six months, the first trainee-led prospective audit has been completed, submitted for presentation and prepared for publication. The strengths of this model were identified as having an enthusiastic cohort of trainees available to gather data, choice of topic acutely relevant to trainees and increase in the profile of research amongst the surgical community. Weaknesses identified included multiple site rotas limiting accurate and timely follow-up, loss of momentum from some members of the collaborative and lack of wider infrastructure to support ongoing research.
Discussion
This process confirms that good quality research can be carried out when initiated and undertaken by trainees, given that trainees can be in frequent contact with each other, are motivated, and require formalised evidence of research and audit.
Gray, R.T.
Loughrey, M.B.
Bankhead, P.
Cardwell, C.R.
McQuaid, S.
O'Neill, R.F.
Arthur, K.
Bingham, V.
McGready, C.
Gavin, A.T.
James, J.A.
Hamilton, P.W.
Salto-Tellez, M.
Murray, L.J.
Coleman, H.G.
(2017). Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study. British journal of cancer,
Vol.116
(12),
pp. 1652-1659.
Alvi, M.A.
Loughrey, M.B.
Dunne, P.
McQuaid, S.
Turkington, R.
Fuchs, M.-.
McGready, C.
Bingham, V.
Pang, B.
Moore, W.
Maxwell, P.
Lawler, M.
James, J.A.
Murray, G.I.
Wilson, R.H.
Salto-Tellez, M.
(2017). Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies. British journal of cancer,
Vol.117
(2),
pp. 203-209.
Hynes, S.O.
Coleman, H.G.
Kelly, P.J.
Irwin, S.
O'Neill, R.F.
Gray, R.T.
McGready, C.
Dunne, P.D.
McQuaid, S.
James, J.A.
Salto-Tellez, M.
Loughrey, M.B.
(2017). Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study. Histopathology,
Vol.71
(1),
pp. 12-26.
Bingham, V.
McIlreavey, L.
Greene, C.
O’Doherty, E.
Clarke, R.
Craig, S.
Salto-Tellez, M.
McQuaid, S.
Lewis, C.
James, J.
(2017). RNAscope in situ hybridization confirms mRNA integrity in formalin-fixed, paraffin-embedded cancer tissue samples. Oncotarget,
Vol.8
(55),
pp. 93392-93403.
Stewart, J.P.
Richman, S.
Maughan, T.
Lawler, M.
Dunne, P.D.
Salto-Tellez, M.
(2017). Standardising RNA profiling based biomarker application in cancer—The need for robust control of technical variables. Biochimica et biophysica acta (bba) - reviews on cancer,
Vol.1868
(1),
pp. 258-272.
Malapelle, U.
Mayo-de-Las-Casas, C.
Molina-Vila, M.A.
Rosell, R.
Savic, S.
Bihl, M.
Bubendorf, L.
Salto-Tellez, M.
de Biase, D.
Tallini, G.
Hwang, D.H.
Sholl, L.M.
Luthra, R.
Weynand, B.
Vander Borght, S.
Missiaglia, E.
Bongiovanni, M.
Stieber, D.
Vielh, P.
Schmitt, F.
Rappa, A.
Barberis, M.
Pepe, F.
Pisapia, P.
Serra, N.
Vigliar, E.
Bellevicine, C.
Fassan, M.
Rugge, M.
de Andrea, C.E.
Lozano, M.D.
Basolo, F.
Fontanini, G.
Nikiforov, Y.E.
Kamel-Reid, S.
da Cunha Santos, G.
Nikiforova, M.N.
Roy-Chowdhuri, S.
Troncone, G.
(2017). Consistency and reproducibility of next-generation sequencing and other multigene mutational assays: A worldwide ring trial study on quantitative cytological molecular reference specimens. Cancer cytopathology,
Vol.125
(8),
pp. 615-626.
Hynes, S.O.
Coleman, H.G.
Kelly, P.J.
Dunne, P.D.
Salto-Tellez, M.
Loughrey, M.B.
(2017). Response to Park et al
reply to ‘Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study’. Histopathology,
Vol.71
(2),
pp. 327-329.
Bradley, C.A.
Salto-Tellez, M.
Laurent-Puig, P.
Bardelli, A.
Rolfo, C.
Tabernero, J.
Khawaja, H.A.
Lawler, M.
Johnston, P.G.
Schaeybroeck, S.V.
(2017). Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges. Nature reviews clinical oncology,
Vol.14
(9),
pp. 562-576.
Alderdice, M.
Dunne, P.D.
Cole, A.J.
O’Reilly, P.G.
McArt, D.G.
Bingham, V.
Fuchs, M.-.
McQuaid, S.
Loughrey, M.B.
Murray, G.I.
Samuel, L.M.
Lawler, M.
Wilson, R.H.
Salto-Tellez, M.
Coyle, V.M.
(2017). Natural killer-like signature observed post therapy in locally advanced rectal cancer is a determinant of pathological response and improved survival. Modern pathology,
Vol.30
(9),
pp. 1287-1298.
Alvi, M.A.
Wilson, R.H.
Salto-Tellez, M.
(2017). Rare cancers: the greatest inequality in cancer research and oncology treatment. British journal of cancer,
Vol.117
(9),
pp. 1255-1257.
Selvarajan, V.
Osato, M.
Nah, G.S.
Yan, J.
Chung, T.-.
Voon, D.C.
Ito, Y.
Ham, M.F.
Salto-Tellez, M.
Shimizu, N.
Choo, S.-.
Fan, S.
Chng, W.-.
Ng, S.-.
(2017). RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC. Leukemia,
Vol.31
(10),
pp. 2219-2227.
Jones, J.L.
Oien, K.A.
Lee, J.L.
Salto-Tellez, M.
(2017). Morphomolecular pathology: setting the framework for a new generation of pathologists. British journal of cancer,
Vol.117
(11),
pp. 1581-1582.
Bankhead, P.
Loughrey, M.B.
Fernández, J.A.
Dombrowski, Y.
McArt, D.G.
Dunne, P.D.
McQuaid, S.
Gray, R.T.
Murray, L.J.
Coleman, H.G.
James, J.A.
Salto-Tellez, M.
Hamilton, P.W.
(2017). QuPath: Open source software for digital pathology image analysis. Scientific reports,
Vol.7
(1).
Lindner, A.U.
Salvucci, M.
Morgan, C.
Monsefi, N.
Resler, A.J.
Cremona, M.
Curry, S.
Toomey, S.
O'Byrne, R.
Bacon, O.
Stühler, M.
Flanagan, L.
Wilson, R.
Johnston, P.G.
Salto-Tellez, M.
Camilleri-Broët, S.
McNamara, D.A.
Kay, E.W.
Hennessy, B.T.
Laurent-Puig, P.
Van Schaeybroeck, S.
Prehn, J.H.
(2017). BCL-2 system analysis identifies high-risk colorectal cancer patients. Gut,
Vol.66
(12),
pp. 2141-2148.
show abstract
ObjectiveThe mitochondrial apoptosis pathway is controlled by an interaction of multiple BCL-2 family proteins, and plays a key role in tumour progression and therapy responses. We assessed the prognostic potential of an experimentally validated, mathematical model of BCL-2 protein interactions (DR_MOMP) in patients with stage III colorectal cancer (CRC).DesignAbsolute protein levels of BCL-2 family proteins were determined in primary CRC tumours collected from n=128 resected and chemotherapy-treated patients with stage III CRC. We applied DR_MOMP to categorise patients as high or low risk based on model outputs, and compared model outputs with known prognostic factors (T-stage, N-stage, lymphovascular invasion). DR_MOMP signatures were validated on protein of n=156 patients with CRC from the Cancer Genome Atlas (TCGA) project.ResultsHigh-risk stage III patients identified by DR_MOMP had an approximately fivefold increased risk of death compared with patients identified as low risk (HR 5.2, 95% CI 1.4 to 17.9, p=0.02). The DR_MOMP signature ranked highest among all molecular and pathological features analysed. The prognostic signature was validated in the TCGA colon adenocarcinoma (COAD) cohort (HR 4.2, 95% CI 1.1 to 15.6, p=0.04). DR_MOMP also further stratified patients identified by supervised gene expression risk scores into low-risk and high-risk categories. BCL-2-dependent signalling critically contributed to treatment responses in consensus molecular subtypes 1 and 3, linking for the first time specific molecular subtypes to apoptosis signalling.ConclusionsDR_MOMP delivers a system-based biomarker with significant potential as a prognostic tool for stage III CRC that significantly improves established histopathological risk factors..
Bankhead, P.
Loughrey, M.B.
Fernández, J.A.
Dombrowski, Y.
McArt, D.G.
Dunne, P.D.
McQuaid, S.
Gray, R.T.
Murray, L.J.
Coleman, H.G.
James, J.A.
Salto-Tellez, M.
Hamilton, P.W.
(2017). QuPath: Open source software for digital pathology image analysis. ,
.
show abstract
AbstractQuPath is new bioimage analysis software designed to meet the growing need for a user-friendly, extensible, open-source solution for digital pathology and whole slide image analysis. In addition to offering a comprehensive panel of tumor identification and high-throughput biomarker evaluation tools, QuPath provides researchers with powerful batch-processing and scripting functionality, and an extensible platform with which to develop and share new algorithms to analyze complex tissue images. Furthermore, QuPath’s flexible design makes it suitable for a wide range of additional image analysis applications across biomedical research..
Lawler, M.
Gavin, A.
Salto-Tellez, M.
Kennedy, R.D.
Van Schaeybroeck, S.
Wilson, R.H.
Harkin, D.P.
Grayson, M.
Boyd, R.E.
Hamilton, P.W.
McArt, D.G.
James, J.
Robson, T.
Ladner, R.D.
Prise, K.M.
O'Sullivan, J.M.
Harrison, T.
Murray, L.
Johnston, P.G.
Waugh, D.J.
(2016). Delivering a research-enabled multistakeholder partnership for enhanced patient care at a population level: The Northern Ireland Comprehensive Cancer Program. Cancer,
Vol.122
(5),
pp. 664-673.
Bingham, V.
Ong, C.W.
James, J.
Maxwell, P.
Waugh, D.
Salto-Tellez, M.
McQuaid, S.
(2016). PTEN mRNA detection by chromogenic, RNA in situ technologies: a reliable alternative to PTEN immunohistochemistry. Human pathology,
Vol.47
(1),
pp. 95-103.
Dunne, P.D.
Dasgupta, S.
Blayney, J.K.
McArt, D.G.
Redmond, K.L.
Weir, J.-.
Bradley, C.A.
Sasazuki, T.
Shirasawa, S.
Wang, T.
Srivastava, S.
Ong, C.W.
Arthur, K.
Salto-Tellez, M.
Wilson, R.H.
Johnston, P.G.
Van Schaeybroeck, S.
(2016). EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer. Clinical cancer research,
Vol.22
(1),
pp. 230-242.
show abstract
Abstract
Purpose: EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.
Experimental Design: EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.
Results: Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.
Conclusions: These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target. Clin Cancer Res; 22(1); 230–42. ©2015 AACR..
Dunne, P.D.
McArt, D.G.
O'Reilly, P.G.
Coleman, H.G.
Allen, W.L.
Loughrey, M.
Van Schaeybroeck, S.
McDade, S.
Salto-Tellez, M.
Longley, D.B.
Lawler, M.
Johnston, P.G.
(2016). Immune-Derived PD-L1 Gene Expression Defines a Subgroup of Stage II/III Colorectal Cancer Patients with Favorable Prognosis Who May Be Harmed by Adjuvant Chemotherapy. Cancer immunology research,
Vol.4
(7),
pp. 582-591.
show abstract
Abstract
A recent phase II study of patients with metastatic colorectal carcinoma showed that mismatch repair gene status was predictive of clinical response to PD-1–targeting immune checkpoint blockade. Further examination revealed strong correlation between PD-L1 protein expression and microsatellite instability (MSI) in stage IV colorectal carcinoma, suggesting that the amount of PD-L1 protein expression could identify late-stage patients who might benefit from immunotherapy. To assess whether the clinical associations between PD-L1 gene expression and MSI identified in metastatic colorectal carcinoma are also present in stage II/III colorectal carcinoma, we used in silico analysis to elucidate the cell types expressing the PD-L1 gene. We found a statistically significant association of PD-L1 gene expression with MSI in early-stage colorectal carcinoma (P < 0.001) and show that, unlike in non–colorectal carcinoma tumors, PD-L1 is derived predominantly from the immune infiltrate. We demonstrate that PD-L1 gene expression has positive prognostic value in the adjuvant disease setting (PD-L1low vs. PD-L1high HR = 9.09; CI, 2.11–39.10). PD-L1 gene expression had predictive value, as patients with high PD-L1 expression appear to be harmed by standard-of-care treatment (HR = 4.95; CI, 1.10–22.35). Building on the promising results from the metastatic colorectal carcinoma PD-1–targeting trial, we provide compelling evidence that patients with PD-L1high/MSI/immunehigh stage II/III colorectal carcinoma should not receive standard chemotherapy. This conclusion supports the rationale to clinically evaluate this patient subgroup for PD-1 blockade treatment. Cancer Immunol Res; 4(7); 582–91. ©2016 AACR..
Stupnikov, A.
Tripathi, S.
de Matos Simoes, R.
McArt, D.
Salto-Tellez, M.
Glazko, G.
Dehmer, M.
Emmert-Streib, F.
(2016). samExploreR: exploring reproducibility and robustness of RNA-seq results based on SAM files. Bioinformatics,
Vol.32
(21),
pp. 3345-3347.
Beirne, J.P.
McArt, D.G.
James, J.A.
Salto-Tellez, M.
Maxwell, P.
McCluggage, W.G.
(2016). p16 as a prognostic indicator in ovarian/tubal high-grade serous carcinoma. Histopathology,
Vol.68
(4),
pp. 615-618.
Huang, B.
Deng, S.
Loo, S.Y.
Datta, A.
Yap, Y.L.
Yan, B.
Ooi, C.H.
Dinh, T.D.
Zhuo, J.
Tochhawng, L.
Gopinadhan, S.
Jegadeesan, T.
Tan, P.
Salto-Tellez, M.
Yong, W.P.
Soong, R.
Yeoh, K.G.
Goh, Y.C.
Lobie, P.E.
Yang, H.
Kumar, A.P.
Maciver, S.K.
So, J.B.
Yap, C.T.
(2016). Gelsolin-mediated activation of PI3K/Akt pathway is crucial for hepatocyte growth factor-induced cell scattering in gastric carcinoma. Oncotarget,
Vol.7
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pp. 25391-25407.
Maxwell, P.
Salto-Tellez, M.
(2016). Validation of immunocytochemistry as a morphomolecular technique. Cancer cytopathology,
Vol.124
(8),
pp. 540-545.
Buckley, N.E.
Forde, C.
McArt, D.G.
Boyle, D.P.
Mullan, P.B.
James, J.A.
Maxwell, P.
McQuaid, S.
Salto-Tellez, M.
(2016). Quantification of HER2 heterogeneity in breast cancer–implications for identification of sub-dominant clones for personalised treatment. Scientific reports,
Vol.6
(1).
Lewis, C.
McQuaid, S.
Hamilton, P.W.
Salto-Tellez, M.
McArt, D.
James, J.A.
(2016). Building a ‘Repository of Science’: The importance of integrating biobanks within molecular pathology programmes. European journal of cancer,
Vol.67,
pp. 191-199.
Dunne, P.D.
O’Reilly, P.G.
Coleman, H.G.
Gray, R.T.
Longley, D.B.
Johnston, P.G.
Salto-Tellez, M.
Lawler, M.
McArt, D.G.
(2016). Stratified analysis reveals chemokine-like factor (CKLF) as a potential prognostic marker in the MSI-immune consensus molecular subtype CMS1 of colorectal cancer. Oncotarget,
Vol.7
(24),
pp. 36632-36644.
Dunne, P.D.
McArt, D.G.
Bradley, C.A.
O'Reilly, P.G.
Barrett, H.L.
Cummins, R.
O'Grady, T.
Arthur, K.
Loughrey, M.B.
Allen, W.L.
McDade, S.S.
Waugh, D.J.
Hamilton, P.W.
Longley, D.B.
Kay, E.W.
Johnston, P.G.
Lawler, M.
Salto-Tellez, M.
Van Schaeybroeck, S.
(2016). Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer. Clinical cancer research,
Vol.22
(16),
pp. 4095-4104.
show abstract
Abstract
Purpose: A number of independent gene expression profiling studies have identified transcriptional subtypes in colorectal cancer with potential diagnostic utility, culminating in publication of a colorectal cancer Consensus Molecular Subtype classification. The worst prognostic subtype has been defined by genes associated with stem-like biology. Recently, it has been shown that the majority of genes associated with this poor prognostic group are stromal derived. We investigated the potential for tumor misclassification into multiple diagnostic subgroups based on tumoral region sampled.
Experimental Design: We performed multiregion tissue RNA extraction/transcriptomic analysis using colorectal-specific arrays on invasive front, central tumor, and lymph node regions selected from tissue samples from 25 colorectal cancer patients.
Results: We identified a consensus 30-gene list, which represents the intratumoral heterogeneity within a cohort of primary colorectal cancer tumors. Using a series of online datasets, we showed that this gene list displays prognostic potential HR = 2.914 (confidence interval 0.9286–9.162) in stage II/III colorectal cancer patients, but in addition, we demonstrated that these genes are stromal derived, challenging the assumption that poor prognosis tumors with stem-like biology have undergone a widespread epithelial–mesenchymal transition. Most importantly, we showed that patients can be simultaneously classified into multiple diagnostically relevant subgroups based purely on the tumoral region analyzed.
Conclusions: Gene expression profiles derived from the nonmalignant stromal region can influence assignment of colorectal cancer transcriptional subtypes, questioning the current molecular classification dogma and highlighting the need to consider pathology sampling region and degree of stromal infiltration when employing transcription-based classifiers to underpin clinical decision making in colorectal cancer. Clin Cancer Res; 22(16); 4095–104. ©2016 AACR.
See related commentary by Morris and Kopetz, p. 3989.
Armstrong, C.W.
Maxwell, P.J.
Ong, C.W.
Redmond, K.M.
McCann, C.
Neisen, J.
Ward, G.A.
Chessari, G.
Johnson, C.
Crawford, N.T.
LaBonte, M.J.
Prise, K.M.
Robson, T.
Salto-Tellez, M.
Longley, D.B.
Waugh, D.J.
(2016). PTEN deficiency promotes macrophage infiltration and hypersensitivity of prostate cancer to IAP antagonist/radiation combination therapy. Oncotarget,
Vol.7
(7),
pp. 7885-7898.
Stewart, J.
James, J.
McCluggage, G.W.
McQuaid, S.
Arthur, K.
Boyle, D.
Mullan, P.
McArt, D.
Yan, B.
Irwin, G.
Harkin, D.P.
Zhengdeng, L.
Ong, C.-.
Yu, J.
Virshup, D.M.
Salto-Tellez, M.
(2015). Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression. Modern pathology,
Vol.28
(3),
pp. 428-436.
Lu, G.
Ang, Y.H.
Zhou, J.
Tamilarasi, J.
Yan, B.
Lim, Y.C.
Srivastava, S.
Salto‐Tellez, M.
Hui, K.M.
Shen, H.
Nguyen, L.N.
Tan, B.C.
Silver, D.L.
Hooi, S.C.
(2015). CCAAT/enhancer binding protein α predicts poorer prognosis and prevents energy starvation–induced cell death in hepatocellular carcinoma. Hepatology,
Vol.61
(3),
pp. 965-978.
Salto-Tellez, M.
(2015). An interview with Manuel Salto-Tellez on diagnostic pathology: the future is morphomolecular. Expert review of molecular diagnostics,
Vol.15
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pp. 585-588.
Srivastava, S.
Thakkar, B.
Yeoh, K.G.
Ho, K.Y.
Teh, M.
Soong, R.
Salto-Tellez, M.
(2015). Expression of proteins associated with hypoxia and Wnt pathway activation is of prognostic significance in hepatocellular carcinoma. Virchows archiv,
Vol.466
(5),
pp. 541-548.
McArt, D.G.
Blayney, J.K.
Boyle, D.P.
Irwin, G.W.
Moran, M.
Hutchinson, R.A.
Bankhead, P.
Kieran, D.
Wang, Y.
Dunne, P.D.
Kennedy, R.D.
Mullan, P.B.
Harkin, D.P.
Catherwood, M.A.
James, J.A.
Salto-Tellez, M.
Hamilton, P.W.
(2015). PICan: An integromics framework for dynamic cancer biomarker discovery. Molecular oncology,
Vol.9
(6),
pp. 1234-1240.
Loughrey, M.B.
Kelly, P.J.
Houghton, O.P.
Coleman, H.G.
Houghton, J.P.
Carson, A.
Salto-Tellez, M.
Hamilton, P.W.
(2015). Digital slide viewing for primary reporting in gastrointestinal pathology: a validation study. Virchows archiv,
Vol.467
(2),
pp. 137-144.
Salto-Tellez, M.
(2015). Diagnostic Molecular Cytopathology - a further decade of progress. Cytopathology,
Vol.26
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pp. 269-270.
Graham, D.M.
Turkington, R.C.
Salto-Tellez, M.
Coyle, V.M.
Wilson, R.H.
(2015). RE: Test of Four Colon Cancer Risk-Scores in Formalin Fixed Paraffin Embedded Microarray Gene Expression Data. Jnci journal of the national cancer institute,
Vol.107
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pp. djv055-djv055.
Elliott, K.
McQuaid, S.
Salto-Tellez, M.
Maxwell, P.
(2015). Immunohistochemistry should undergo robust validation equivalent to that of molecular diagnostics. Journal of clinical pathology,
Vol.68
(10),
pp. 766-770.
show abstract
Immunohistochemistry (IHC) is a widely available and highly utilised tool in diagnostic histopathology and is used to guide treatment options as well as provide prognostic information. IHC is subjected to qualitative and subjective assessment, which has been criticised for a lack of stringency, while PCR-based molecular diagnostic validations by comparison are regarded as very rigorous. It is essential that IHC tests are validated through evidence-based procedures. With the move to ISO15189 (2012), not just of the accuracy, specificity and reproducibility of each test need to be determined and managed, but also the degree of uncertainty and the delivery of such tests. The recent update to ISO 15189 (2012) states that it is appropriate to consider the potential uncertainty of measurement of the value obtained in the laboratory and how that may impact on prognostic or predictive thresholds. In order to highlight the problems surrounding IHC validity, we reviewed the measurement of Ki67and p53 in the literature. Both of these biomarkers have been incorporated into clinical care by pathology laboratories worldwide. The variation seen appears excessive even when measuring centrally stained slides from the same cases. We therefore propose in this paper to establish the basis on which IHC laboratories can bring the same level of robust validation seen in the molecular pathology laboratories and the principles applied to all routine IHC tests..
LER, S.Y.
LEUNG, C.H.
KHIN, L.W.
LU, G.-.
SALTO-TELLEZ, M.
HARTMAN, M.
IAU, P.T.
YAP, C.T.
HOOI, S.C.
(2015). HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population. Oncology reports,
Vol.34
(5),
pp. 2238-2250.
Salto-Tellez, M.
Kennedy, R.D.
(2015). Integrated molecular pathology: the Belfast model. Drug discovery today,
Vol.20
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pp. 1451-1454.
Hutchinson, R.A.
Adams, R.A.
McArt, D.G.
Salto-Tellez, M.
Jasani, B.
Hamilton, P.W.
(2015). Epidermal growth factor receptor immunohistochemistry: new opportunities in metastatic colorectal cancer. Journal of translational medicine,
Vol.13
(1).
Ong, C.W.
Chong, P.Y.
McArt, D.G.
Chan, J.Y.
Tan, H.T.
Kumar, A.P.
Chung, M.C.
Clément, M.-.
Soong, R.
Van Schaeybroeck, S.
Waugh, D.J.
Johnston, P.G.
Dunne, P.D.
Salto-Tellez, M.
(2015). The prognostic value of the stem-like group in colorectal cancer using a panel of immunohistochemistry markers. Oncotarget,
Vol.6
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pp. 12763-12773.
Buckley, N.
Boyle, D.
McArt, D.
Irwin, G.
Harkin, D.P.
Lioe, T.
McQuaid, S.
James, J.A.
Maxwell, P.
Hamilton, P.
Mullan, P.B.
Salto-Tellez, M.
(2015). Molecular classification of non-invasive breast lesions for personalised therapy and chemoprevention. Oncotarget,
Vol.6
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pp. 43244-43254.
Alvi, M.A.
McArt, D.G.
Kelly, P.
Fuchs, M.-.
Alderdice, M.
McCabe, C.M.
Bingham, V.
McGready, C.
Tripathi, S.
Emmert-Streib, F.
Loughrey, M.B.
McQuaid, S.
Maxwell, P.
Hamilton, P.W.
Turkington, R.
James, J.A.
Wilson, R.H.
Salto-Tellez, M.
(2015). Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for clinical utility. Oncotarget,
Vol.6
(25),
pp. 20863-20874.
Hamilton, P.W.
Wang, Y.
Boyd, C.
James, J.A.
Loughrey, M.B.
Hougton, J.P.
Boyle, D.P.
Kelly, P.
Maxwell, P.
McCleary, D.
Diamond, J.
McArt, D.G.
Tunstall, J.
Bankhead, P.
Salto-Tellez, M.
(2015). Automated tumor analysis for molecular profiling in lung cancer. Oncotarget,
Vol.6
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pp. 27938-27952.
Mulligan, J.M.
Hill, L.A.
Deharo, S.
Irwin, G.
Boyle, D.
Keating, K.E.
Raji, O.Y.
McDyer, F.A.
O’Brien, E.
Bylesjo, M.
Quinn, J.E.
Lindor, N.M.
Mullan, P.B.
James, C.R.
Walker, S.M.
Kerr, P.
James, J.
Davison, T.S.
Proutski, V.
Salto-Tellez, M.
Johnston, P.G.
Couch, F.J.
Paul Harkin, D.
Kennedy, R.D.
(2014). Identification and Validation of an Anthracycline/Cyclophosphamide–Based Chemotherapy Response Assay in Breast Cancer. Jnci: journal of the national cancer institute,
Vol.106
(1).
Dunne, P.D.
McArt, D.G.
Blayney, J.K.
Kalimutho, M.
Greer, S.
Wang, T.
Srivastava, S.
Ong, C.W.
Arthur, K.
Loughrey, M.
Redmond, K.
Longley, D.B.
Salto-Tellez, M.
Johnston, P.G.
Van Schaeybroeck, S.
(2014). AXL Is a Key Regulator of Inherent and Chemotherapy-Induced Invasion and Predicts a Poor Clinical Outcome in Early-Stage Colon Cancer. Clinical cancer research,
Vol.20
(1),
pp. 164-175.
show abstract
Abstract
Purpose: Despite the use of 5-fluorouracil (5-FU)–based adjuvant treatments, a large proportion of patients with high-risk stage II/III colorectal cancer will relapse. Thus, novel therapeutic strategies are needed for early-stage colorectal cancer. Residual micrometastatic disease from the primary tumor is a major cause of patient relapse.
Experimental Design: To model colorectal cancer tumor cell invasion/metastasis, we have generated invasive (KRASMT/KRASWT/+chr3/p53-null) colorectal cancer cell subpopulations. Receptor tyrosine kinase (RTK) screens were used to identify novel proteins that underpin the migratory/invasive phenotype. Migration/invasion was assessed using the XCELLigence system. Tumors from patients with early-stage colorectal cancer (N = 336) were examined for AXL expression.
Results: Invasive colorectal cancer cell subpopulations showed a transition from an epithelial-to-mesenchymal like phenotype with significant increases in migration, invasion, colony-forming ability, and an attenuation of EGF receptor (EGFR)/HER2 autocrine signaling. RTK arrays showed significant increases in AXL levels in all invasive sublines. Importantly, 5-FU treatment resulted in significantly increased migration and invasion, and targeting AXL using pharmacologic inhibition or RNA interference (RNAi) approaches suppressed basal and 5-FU–induced migration and invasion. Significantly, high AXL mRNA and protein expression were found to be associated with poor overall survival in early-stage colorectal cancer tissues.
Conclusions: We have identified AXL as a poor prognostic marker and important mediator of cell migration/invasiveness in colorectal cancer. These findings provide support for the further investigation of AXL as a novel prognostic biomarker and therapeutic target in colorectal cancer, in particular in the adjuvant disease in which EGFR/VEGF–targeted therapies have failed. Clin Cancer Res; 20(1); 164–75. ©2013 AACR..
Lau, W.M.
Teng, E.
Chong, H.S.
Lopez, K.A.
Tay, A.Y.
Salto-Tellez, M.
Shabbir, A.
So, J.B.
Chan, S.L.
(2014). CD44v8-10 Is a Cancer-Specific Marker for Gastric Cancer Stem Cells. Cancer research,
Vol.74
(9),
pp. 2630-2641.
show abstract
Abstract
The surface marker CD44 has been identified as one of several markers associated with cancer stem cells (CSC) in solid tumors, but its ubiquitous expression in many cell types, including hematopoietic cells, has hindered its use in targeting CSCs. In this study, 28 paired primary tumor and adjacent nontumor gastric tissue samples were analyzed for cell surface protein expression. Cells that expressed pan-CD44 were found to occur at significantly higher frequency in gastric tumor tissues. We identified CD44v8-10 as the predominant CD44 variant expressed in gastric cancer cells and verified its role as a gastric CSC marker by limiting dilution and serial transplantation assays. Parallel experiments using CD133 failed to enrich for gastric CSCs. Analyses of another 26 primary samples showed significant CD44v8-10 upregulation in gastric tumor sites. Exogenous expression of CD44v8-10 but not CD44 standard (CD44s) increased the frequency of tumor initiation in immunocompromised mice. Reciprocal silencing of total CD44 resulted in reduced tumor-initiating potential of gastric cancer cells that could be rescued by CD44v8-10 but not CD44s expression. Our findings provide important functional evidence that CD44v8-10 marks human gastric CSCs and contributes to tumor initiation, possibly through enhancing oxidative stress defense. In addition, we showed that CD44v8-10 expression is low in normal tissues. Because CD44 also marks CSCs of numerous human cancers, many of which may also overexpress CD44v8-10, CD44v8-10 may provide an avenue to target CSCs in other human cancers. Cancer Res; 74(9); 2630–41. ©2014 AACR..
Subramaniam, M.M.
Loh, M.
Chan, J.Y.
Liem, N.
Lim, P.L.
Peng, Y.W.
Lim, X.Y.
Yeoh, K.G.
Iacopetta, B.
Soong, R.
Salto-Tellez, M.
(2014). The topography of DNA methylation in the non-neoplastic colonic mucosa surrounding colorectal cancers. Molecular carcinogenesis,
Vol.53
(2),
pp. 98-108.
Turkington, R.C.
Longley, D.B.
Allen, W.L.
Stevenson, L.
McLaughlin, K.
Dunne, P.D.
Blayney, J.K.
Salto-Tellez, M.
Van Schaeybroeck, S.
Johnston, P.G.
(2014). Fibroblast growth factor receptor 4 (FGFR4): a targetable regulator of drug resistance in colorectal cancer. Cell death & disease,
Vol.5
(2),
pp. e1046-e1046.
Tan, S.S.
Khin, L.W.
Wong, L.
Yan, B.
Ong, C.W.
Datta, A.
Salto-Tellez, M.
Lam, Y.
Yap, C.T.
(2014). Sphingosine Kinase 1 Promotes Malignant Progression in Colon Cancer and Independently Predicts Survival of Patients With Colon Cancer by Competing Risk Approach in South Asian Population. Clinical and translational gastroenterology,
Vol.5
(2),
pp. e51-e51.
Shin, E.M.
Sin Hay, H.
Lee, M.H.
Goh, J.N.
Tan, T.Z.
Sen, Y.P.
Lim, S.W.
Yousef, E.M.
Ong, H.T.
Thike, A.A.
Kong, X.
Wu, Z.
Mendoz, E.
Sun, W.
Salto-Tellez, M.
Lim, C.T.
Lobie, P.E.
Lim, Y.P.
Yap, C.T.
Zeng, Q.
Sethi, G.
Lee, M.B.
Tan, P.
Goh, B.C.
Miller, L.D.
Thiery, J.P.
Zhu, T.
Gaboury, L.
Tan, P.H.
Hui, K.M.
Yip, G.W.
Miyamoto, S.
Kumar, A.P.
Tergaonkar, V.
(2014). DEAD-box helicase DP103 defines metastatic potential of human breast cancers. Journal of clinical investigation,
Vol.124
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pp. 3807-3824.
Higgins, P.A.
Brady, A.
Dobbs, S.P.
Salto-Tellez, M.
Maxwell, P.
McCluggage, W.G.
(2014). Epidermal growth factor receptor (EGFR), HER2 and insulin-like growth factor-1 receptor (IGF-1R) status in ovarian adult granulosa cell tumours. Histopathology,
Vol.64
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pp. 633-638.
Savage, K.I.
Gorski, J.J.
Barros, E.M.
Irwin, G.W.
Manti, L.
Powell, A.J.
Pellagatti, A.
Lukashchuk, N.
McCance, D.J.
McCluggage, W.G.
Schettino, G.
Salto-Tellez, M.
Boultwood, J.
Richard, D.J.
McDade, S.S.
Harkin, D.P.
(2014). Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability. Molecular cell,
Vol.54
(3),
pp. 445-459.
James, J.A.
Salto-Tellez, M.
(2014). The training of future tissue pathologists in a changing world. Journal of clinical pathology,
Vol.67
(7),
pp. 549-549.
Flynn, C.
James, J.
Maxwell, P.
McQuaid, S.
Ervine, A.
Catherwood, M.
Loughrey, M.B.
McGibben, D.
Somerville, J.
McManus, D.T.
Gray, M.
Herron, B.
Salto-Tellez, M.
(2014). Integrating molecular diagnostics into histopathology training: the Belfast model. Journal of clinical pathology,
Vol.67
(7),
pp. 632-636.
Wong, N.A.
Gonzalez, D.
Salto-Tellez, M.
Butler, R.
Diaz-Cano, S.J.
Ilyas, M.
Newman, W.
Shaw, E.
Taniere, P.
Walsh, S.V.
(2014). RAS testing of colorectal carcinoma—a guidance document from the Association of Clinical Pathologists Molecular Pathology and Diagnostics Group. Journal of clinical pathology,
Vol.67
(9),
pp. 751-757.
show abstract
Analysis of colorectal carcinoma (CRC) tissue for KRAS codon 12 or 13 mutations to guide use of anti-epidermal growth factor receptor (EGFR) therapy is now considered mandatory in the UK. The scope of this practice has been recently extended because of data indicating that NRAS mutations and additional KRAS mutations also predict for poor response to anti-EGFR therapy. The following document provides guidance on RAS (i.e., KRAS and NRAS) testing of CRC tissue in the setting of personalised medicine within the UK and particularly within the NHS. This guidance covers issues related to case selection, preanalytical aspects, analysis and interpretation of such RAS testing..
Salto-Tellez, M.
Gonzalez de Castro, D.
(2014). Next-generation sequencing: a change of paradigm in molecular diagnostic validation. The journal of pathology,
Vol.234
(1),
pp. 5-10.
Boyle, D.P.
McArt, D.G.
Irwin, G.
Wilhelm-Benartzi, C.S.
Lioe, T.F.
Sebastian, E.
McQuaid, S.
Hamilton, P.W.
James, J.A.
Mullan, P.B.
Catherwood, M.A.
Harkin, D.P.
Salto-Tellez, M.
(2014). The prognostic significance of the aberrant extremes of p53 immunophenotypes in breast cancer. Histopathology,
Vol.65
(3),
pp. 340-352.
Salto-Tellez, M.
James, J.A.
Hamilton, P.W.
(2014). Molecular pathology - The value of an integrative approach. Molecular oncology,
Vol.8
(7),
pp. 1163-1168.
Sloan, S.
Maxwell, P.
Salto-Tellez, M.
Loughrey, M.B.
(2014). FOXP3+ regulatory T-cell counts correlate with histological response in Crohn's colitis treated with infliximab. Pathology international,
,
pp. n/a-n/a.
Hamilton, P.W.
Bankhead, P.
Wang, Y.
Hutchinson, R.
Kieran, D.
McArt, D.G.
James, J.
Salto-Tellez, M.
(2014). Digital pathology and image analysis in tissue biomarker research. Methods,
Vol.70
(1),
pp. 59-73.
Cree, I.A.
Deans, Z.
Ligtenberg, M.J.
Normanno, N.
Edsjö, A.
Rouleau, E.
Solé, F.
Thunnissen, E.
Timens, W.
Schuuring, E.
Dequeker, E.
Murray, S.
Dietel, M.
Groenen, P.
Van Krieken, J.H.
(2014). Guidance for laboratories performing molecular pathology for cancer patients. Journal of clinical pathology,
Vol.67
(11),
pp. 923-931.
show abstract
Molecular testing is becoming an important part of the diagnosis of any patient with cancer. The challenge to laboratories is to meet this need, using reliable methods and processes to ensure that patients receive a timely and accurate report on which their treatment will be based. The aim of this paper is to provide minimum requirements for the management of molecular pathology laboratories. This general guidance should be augmented by the specific guidance available for different tumour types and tests. Preanalytical considerations are important, and careful consideration of the way in which specimens are obtained and reach the laboratory is necessary. Sample receipt and handling follow standard operating procedures, but some alterations may be necessary if molecular testing is to be performed, for instance to control tissue fixation. DNA and RNA extraction can be standardised and should be checked for quality and quantity of output on a regular basis. The choice of analytical method(s) depends on clinical requirements, desired turnaround time, and expertise available. Internal quality control, regular internal audit of the whole testing process, laboratory accreditation, and continual participation in external quality assessment schemes are prerequisites for delivery of a reliable service. A molecular pathology report should accurately convey the information the clinician needs to treat the patient with sufficient information to allow for correct interpretation of the result. Molecular pathology is developing rapidly, and further detailed evidence-based recommendations are required for many of the topics covered here..
Loh, M.
Liem, N.
Vaithilingam, A.
Lim, P.L.
Sapari, N.S.
Elahi, E.
Mok, Z.Y.
Cheng, C.L.
Yan, B.
Pang, B.
Salto-Tellez, M.
Yong, W.P.
Iacopetta, B.
Soong, R.
(2014). DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: a comprehensive profiling approach. Bmc gastroenterology,
Vol.14
(1).
show abstract
Abstract
Background
Methylation-induced silencing of promoter CpG islands in tumor suppressor genes plays an important role in human carcinogenesis. In colorectal cancer, the CpG island methylator phenotype (CIMP) is defined as widespread and elevated levels of DNA methylation and CIMP+ tumors have distinctive clinicopathological and molecular features. In contrast, the existence of a comparable CIMP subtype in gastric cancer (GC) has not been clearly established. To further investigate this issue, in the present study we performed comprehensive DNA methylation profiling of a well-characterised series of primary GC.
Methods
The methylation status of 1,421 autosomal CpG sites located within 768 cancer-related genes was investigated using the Illumina GoldenGate Methylation Panel I assay on DNA extracted from 60 gastric tumors and matched tumor-adjacent gastric tissue pairs. Methylation data was analysed using a recursively partitioned mixture model and investigated for associations with clinicopathological and molecular features including age, Helicobacter pylori status, tumor site, patient survival, microsatellite instability and BRAF and KRAS mutations.
Results
A total of 147 genes were differentially methylated between tumor and matched tumor-adjacent gastric tissue, with HOXA5 and hedgehog signalling being the top-ranked gene and signalling pathway, respectively. Unsupervised clustering of methylation data revealed the existence of 6 subgroups under two main clusters, referred to as L (low methylation; 28% of cases) and H (high methylation; 72%). Female patients were over-represented in the H tumor group compared to L group (36% vs 6%; P = 0.024), however no other significant differences in clinicopathological or molecular features were apparent. CpG sites that were hypermethylated in group H were more frequently located in CpG islands and marked for polycomb occupancy.
Conclusions
High-throughput methylation analysis implicates genes involved in embryonic development and hedgehog signaling in gastric tumorigenesis. GC is comprised of two major methylation subtypes, with the highly methylated group showing some features consistent with a CpG island methylator phenotype.
.
Savage, K.I.
Matchett, K.B.
Barros, E.M.
Cooper, K.M.
Irwin, G.W.
Gorski, J.J.
Orr, K.S.
Vohhodina, J.
Kavanagh, J.N.
Madden, A.F.
Powell, A.
Manti, L.
McDade, S.S.
Park, B.H.
Prise, K.M.
McIntosh, S.A.
Salto-Tellez, M.
Richard, D.J.
Elliott, C.T.
Harkin, D.P.
(2014). BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability. Cancer research,
Vol.74
(10),
pp. 2773-2784.
show abstract
Abstract
Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptor-α–negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types. Cancer Res; 74(10); 2773–84. ©2014 AACR..
Kumar, A.P.
Loo, S.Y.
Shin, S.W.
Tan, T.Z.
Eng, C.B.
Singh, R.
Putti, T.C.
Ong, C.W.
Salto-Tellez, M.
Goh, B.C.
Park, J.I.
Thiery, J.P.
Pervaiz, S.
Clement, M.V.
(2014). Manganese Superoxide Dismutase Is a Promising Target for Enhancing Chemosensitivity of Basal-Like Breast Carcinoma. Antioxidants & redox signaling,
Vol.20
(15),
pp. 2326-2346.
D’Costa, Z.C.
Higgins, C.
Ong, C.W.
Irwin, G.W.
Boyle, D.
McArt, D.G.
McCloskey, K.
Buckley, N.E.
Crawford, N.T.
Thiagarajan, L.
Murray, J.T.
Kennedy, R.D.
Mulligan, K.A.
Harkin, D.P.
Waugh, D.J.
Scott, C.J.
Salto-Tellez, M.
Williams, R.
Mullan, P.B.
(2014). TBX2 represses CST6 resulting in uncontrolled legumain activity to sustain breast cancer proliferation: a novel cancer-selective target pathway with therapeutic opportunities. Oncotarget,
Vol.5
(6),
pp. 1609-1620.
Shah, N.
Thakkar, B.
Shen, E.
Loh, M.
Chong, P.Y.
Gan, W.H.
Tu, T.M.
Shen, L.
Soong, R.
Salto-Tellez, M.
(2013). Lymphocytic Follicles and Aggregates Are a Determinant of Mucosal Damage and Duration of Diarrhea. Archives of pathology & laboratory medicine,
Vol.137
(1),
pp. 83-89.
McCourt, C.M.
Boyle, D.
James, J.
Salto-Tellez, M.
(2013). Immunohistochemistry in the era of personalised medicine. Journal of clinical pathology,
Vol.66
(1),
pp. 58-61.
show abstract
BackgroundImmunohistochemistry (IHC) plays a central role in the histopathological classification of diseases, including cancer. More recently, the importance of immunohistochemical staining is increasing. IHC usage in diagnostics is invaluable; however, the genetic and therapeutic significance of biomarker immunostaining has become equally relevant.ContentIn this article, we would like to analyse the three distinct roles of IHC and review their individual impacts on modern diagnostic pathology: (1) diagnostic IHC; (2) genetic IHC and (3) therapeutic IHC.SummaryThus, we will characterise the different analytical processes that are required in the three approaches to IHC usage stated above, as well as the clinical significance and overall importance in patient management. This will allow us to hypothesise on the most appropriate laboratory environment and detection methods for the future..
Srivastava, S.
Salto-Tellez, M.
(2013). Reply: A morpho-molecular prognostic model for hepatocellular carcinoma. British journal of cancer,
Vol.108
(3),
pp. 741-741.
Li, L.
Fox, B.
Keeble, J.
Salto-Tellez, M.
Winyard, P.G.
Wood, M.E.
Moore, P.K.
Whiteman, M.
(2013). The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells. Journal of cellular and molecular medicine,
Vol.17
(3),
pp. 365-376.
Boyle, D.P.
Mullan, P.
Salto-Tellez, M.
(2013). Molecular mapping the presence of druggable targets in preinvasive and precursor breast lesions: A comprehensive review of biomarkers related to therapeutic interventions. Biochimica et biophysica acta (bba) - reviews on cancer,
Vol.1835
(2),
pp. 230-242.
Ilyas, M.
Grabsch, H.
Ellis, I.O.
Womack, C.
Brown, R.
Berney, D.
Fennell, D.
Salto-Tellez, M.
Jenkins, M.
Landberg, G.
Byers, R.
Treanor, D.
Harrison, D.
Green, A.R.
Ball, G.
Hamilton, P.
(2013). Guidelines and considerations for conducting experiments using tissue microarrays. Histopathology,
Vol.62
(6),
pp. 827-839.
Boyle, D.P.
McCourt, C.M.
Matchett, K.B.
Salto-Tellez, M.
(2013). Molecular and clinicopathological markers of prognosis in breast cancer. Expert review of molecular diagnostics,
Vol.13
(5),
pp. 481-498.
van der Deen, M.
Taipaleenmäki, H.
Zhang, Y.
Teplyuk, N.M.
Gupta, A.
Cinghu, S.
Shogren, K.
Maran, A.
Yaszemski, M.J.
Ling, L.
Cool, S.M.
Leong, D.T.
Dierkes, C.
Zustin, J.
Salto-Tellez, M.
Ito, Y.
Bae, S.-.
Zielenska, M.
Squire, J.A.
Lian, J.B.
Stein, J.L.
Zambetti, G.P.
Jones, S.N.
Galindo, M.
Hesse, E.
Stein, G.S.
van Wijnen, A.J.
(2013). MicroRNA-34c Inversely Couples the Biological Functions of the Runt-related Transcription Factor RUNX2 and the Tumor Suppressor p53 in Osteosarcoma. Journal of biological chemistry,
Vol.288
(29),
pp. 21307-21319.
Maxwell, P.J.
Coulter, J.
Walker, S.M.
McKechnie, M.
Neisen, J.
McCabe, N.
Kennedy, R.D.
Salto-Tellez, M.
Albanese, C.
Waugh, D.J.
(2013). Potentiation of Inflammatory CXCL8 Signalling Sustains Cell Survival in PTEN-deficient Prostate Carcinoma. European urology,
Vol.64
(2),
pp. 177-188.
Yan, B.
Lim, M.
Zhou, L.
Kuick, C.H.
Leong, M.Y.
Yong, K.J.
Aung, L.
Salto-Tellez, M.
Chang, K.T.
(2013). Identification of MET genomic amplification, protein expression and alternative splice isoforms in neuroblastomas. Journal of clinical pathology,
Vol.66
(11),
pp. 985-991.
show abstract
BackgroundCrizotinib, a dual anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor, is currently being evaluated for the treatment of neuroblastoma. Its effects are thought to be mediated mainly via its activity against ALK. Although MET genomic/protein expression status might conceivably affect crizotinib efficacy, this issue has hitherto not received attention in neuroblastomas.Aims/MethodsMET genomic and protein expression status was characterised by silver in situ hybridisation and immunohistochemistry (IHC) respectively, in a cohort of 54 neuroblastoma samples. MET splice isoforms were characterised in 15 of these samples by quantitative PCR.ResultsOne case (1/54; prevalence 1.85%) displayed MET genomic amplification, while another case (1/54; prevalence 1.85%) displayed strong membranous MET protein expression (IHC score 3+). Alternative exon 10-deleted and exon 14-deleted MET splice isoforms were identified.ConclusionsMET amplification and protein expression, although low in prevalence, are present in neuroblastomas. This has implications when crizotinib is employed as a therapeutic agent in neuroblastomas. Additionally, the existence of alternatively spliced MET isoforms may have clinical and biological implications in neuroblastomas..
Wang, T.
Buhari, S.A.
Pang, B.
Putti, T.C.
Salto-Tellez, M.
(2013). One-step nucleic acid amplification assay also predicts axillary lymph node status in breast cancer patients: Further molecular diagnostic evidence. European journal of cancer,
Vol.49
(18),
pp. 3945-3946.
McArt, D.G.
Bankhead, P.
Dunne, P.D.
Salto-Tellez, M.
Hamilton, P.
Zhang, S.-.
(2013). cudaMap: a GPU accelerated program for gene expression connectivity mapping. Bmc bioinformatics,
Vol.14
(1).
show abstract
Abstract
Background
Modern cancer research often involves large datasets and the use of sophisticated statistical techniques. Together these add a heavy computational load to the analysis, which is often coupled with issues surrounding data accessibility. Connectivity mapping is an advanced bioinformatic and computational technique dedicated to therapeutics discovery and drug re-purposing around differential gene expression analysis. On a normal desktop PC, it is common for the connectivity mapping task with a single gene signature to take > 2h to complete using sscMap, a popular Java application that runs on standard CPUs (Central Processing Units). Here, we describe new software, cudaMap, which has been implemented using CUDA C/C++ to harness the computational power of NVIDIA GPUs (Graphics Processing Units) to greatly reduce processing times for connectivity mapping.
Results
cudaMap can identify candidate therapeutics from the same signature in just over thirty seconds when using an NVIDIA Tesla C2050 GPU. Results from the analysis of multiple gene signatures, which would previously have taken several days, can now be obtained in as little as 10 minutes, greatly facilitating candidate therapeutics discovery with high throughput. We are able to demonstrate dramatic speed differentials between GPU assisted performance and CPU executions as the computational load increases for high accuracy evaluation of statistical significance.
Conclusion
Emerging ‘omics’ technologies are constantly increasing the volume of data and information to be processed in all areas of biomedical research. Embracing the multicore functionality of GPUs represents a major avenue of local accelerated computing. cudaMap will make a strong contribution in the discovery of candidate therapeutics by enabling speedy execution of heavy duty connectivity mapping tasks, which are increasingly required in modern cancer research. cudaMap is open source and can be freely downloaded from http://purl.oclc.org/NET/cudaMap.
.
So, J.
Rajnakova, A.
Chan, Y.-.
Tay, A.
Shah, N.
Salto-Tellez, M.
Teh, M.
Noriya, U.
(2013). Endoscopic Tri-Modal Imaging Improves Detection of Gastric Intestinal Metaplasia Among a High-Risk Patient Population in Singapore. Digestive diseases and sciences,
Vol.58
(12),
pp. 3566-3575.
Riley, J.S.
Hutchinson, R.
McArt, D.G.
Crawford, N.
Holohan, C.
Paul, I.
Van Schaeybroeck, S.
Salto-Tellez, M.
Johnston, P.G.
Fennell, D.A.
Gately, K.
O'Byrne, K.
Cummins, R.
Kay, E.
Hamilton, P.
Stasik, I.
Longley, D.B.
(2013). Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer. Cell death & disease,
Vol.4
(12),
pp. e951-e951.
Yong, K.J.
Gao, C.
Lim, J.S.
Yan, B.
Yang, H.
Dimitrov, T.
Kawasaki, A.
Ong, C.W.
Wong, K.-.
Lee, S.
Ravikumar, S.
Srivastava, S.
Tian, X.
Poon, R.T.
Fan, S.T.
Luk, J.M.
Dan, Y.Y.
Salto-Tellez, M.
Chai, L.
Tenen, D.G.
(2013). Oncofetal GeneSALL4in Aggressive Hepatocellular Carcinoma. New england journal of medicine,
Vol.368
(24),
pp. 2266-2276.
Nicole Tsang, Y.-.
Wu, X.-.
Lim, J.-.
Wee Ong, C.
Salto-Tellez, M.
Ito, K.
Ito, Y.
Chen, L.-.
(2013). Prolyl isomerase Pin1 downregulates tumor suppressor RUNX3 in breast cancer. Oncogene,
Vol.32
(12),
pp. 1488-1496.
Srivastava, S.
Yan, B.
Chin, S.Y.
Muliana, T.
Salto-Tellez, M.
Teh, M.
(2012). Nuclear p53 Expression Is Associated With Allelic Imbalance (TP53) in Glandular Dysplasia and Typical Cystitis Glandularis: A LCM-Based Molecular Analysis. Clinical genitourinary cancer,
Vol.10
(1),
pp. 57-59.
Tan, H.T.
Wu, W.
Ng, Y.Z.
Zhang, X.
Yan, B.
Ong, C.W.
Tan, S.
Salto-Tellez, M.
Hooi, S.C.
Chung, M.C.
(2012). Proteomic Analysis of Colorectal Cancer Metastasis: Stathmin-1 Revealed as a Player in Cancer Cell Migration and Prognostic Marker. Journal of proteome research,
Vol.11
(2),
pp. 1433-1445.
Yan, B.
Yau, E.X.
Samanta, S.
Ong, C.W.
Yong, K.J.
Ng, L.K.
Bhattacharya, B.
Lim, K.H.
Soong, R.
Yeoh, K.G.
Deng, N.
Tan, P.
Lam, Y.
Salto-Tellez, M.
(2012). Clinical and therapeutic relevance of PIM1 kinase in gastric cancer. Gastric cancer,
Vol.15
(2),
pp. 188-197.
Zang, Z.J.
Cutcutache, I.
Poon, S.L.
Zhang, S.L.
McPherson, J.R.
Tao, J.
Rajasegaran, V.
Heng, H.L.
Deng, N.
Gan, A.
Lim, K.H.
Ong, C.K.
Huang, D.
Chin, S.Y.
Tan, I.B.
Ng, C.C.
Yu, W.
Wu, Y.
Lee, M.
Wu, J.
Poh, D.
Wan, W.K.
Rha, S.Y.
So, J.
Salto-Tellez, M.
Yeoh, K.G.
Wong, W.K.
Zhu, Y.-.
Futreal, P.A.
Pang, B.
Ruan, Y.
Hillmer, A.M.
Bertrand, D.
Nagarajan, N.
Rozen, S.
Teh, B.T.
Tan, P.
(2012). Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nature genetics,
Vol.44
(5),
pp. 570-574.
Wang, T.
Yeoh, K.G.
Salto-Tellez, M.
(2012). Stem cell markers characterise familial adenomatous polyposis. Gut,
Vol.61
(5),
pp. 785-786.
Lee, Y.F.
Miller, L.D.
Chan, X.B.
Black, M.A.
Pang, B.
Ong, C.W.
Salto-Tellez, M.
Liu, E.T.
Desai, K.V.
(2012). JMJD6 is a driver of cellular proliferation and motility and a marker of poor prognosis in breast cancer. Breast cancer research,
Vol.14
(3).
Koo, C.X.
Fang, W.
Salto-Tellez, M.
Leong, D.T.
(2012). Coexpressing shRNA with fluorescence tags for quantification of cell migration studies. Molecular biology reports,
Vol.39
(7),
pp. 7695-7703.
Srivastava, S.
Wong, K.F.
Ong, C.W.
Huak, C.Y.
Yeoh, K.G.
Teh, M.
Luk, J.M.
Salto-Tellez, M.
(2012). A morpho-molecular prognostic model for hepatocellular carcinoma. British journal of cancer,
Vol.107
(2),
pp. 334-339.
Pang, B.
Matthias, D.
Ong, C.W.
Dhewar, A.N.
Gupta, S.
Lim, G.L.
Nga, M.E.
Seet, J.E.
Qasim, A.
Chin, T.M.
Soo, R.
Soong, R.
Salto-Tellez, M.
(2012). The positive impact of cytological specimens for EGFR mutation testing in non-small cell lung cancer: a single South East Asian laboratory’s analysis of 670 cases. Cytopathology,
Vol.23
(4),
pp. 229-236.
Omar, M.F.
Ito, K.
Nga, M.E.
Soo, R.
Peh, B.K.
Ismail, T.M.
Thakkar, B.
Soong, R.
Ito, Y.
Salto-Tellez, M.
(2012). RUNX3 Downregulation in Human Lung Adenocarcinoma is Independent of p53, EGFR or KRAS Status. Pathology & oncology research,
Vol.18
(4),
pp. 783-792.
Catherwood, M.A.
Schmitt, F.
Salto-Tellez, M.
(2012). Molecular diagnostics and the training of future tissue- and cell-based pathologists. Cytopathology,
Vol.23
(5),
pp. 283-285.
Chan, J.Y.
Salto-Tellez, M.
(2012). Opinion. Advances in anatomic pathology,
Vol.19
(6),
pp. 425-426.
Wang, T.
Yeoh, K.G.
Salto-Tellez, M.
(2012). Lgr5 expression is absent in human premalignant lesions of the stomach. Gut,
Vol.61
(12),
pp. 1777-1778.
Pang, B.
Ong, C.-.
Chong, M.-.
Muliana-Ismail, T.
Soong, R.
Salto-Tellez, M.
(2012). KRAS mutation analysis in a complex molecular diagnostic referral practice: the need for test redundancy. Pathology,
Vol.44
(7),
pp. 655-657.
McCourt, C.
Maxwell, P.
Mazzucchelli, R.
Montironi, R.
Scarpelli, M.
Salto-Tellez, M.
O'Sullivan, J.M.
Longley, D.B.
Waugh, D.J.
(2012). Elevation of c-FLIP in Castrate-Resistant Prostate Cancer Antagonizes Therapeutic Response to Androgen Receptor–Targeted Therapy. Clinical cancer research,
Vol.18
(14),
pp. 3822-3833.
show abstract
Abstract
Purpose: To characterize the importance of cellular Fas-associated death domain (FADD)–like interleukin 1β-converting enzyme (FLICE) inhibitory protein (c-FLIP), a key regulator of caspase-8 (FLICE)–promoted apoptosis, in modulating the response of prostate cancer cells to androgen receptor (AR)–targeted therapy.
Experimental Design: c-FLIP expression was characterized by immunohistochemical analysis of prostatectomy tissue. The functional importance of c-FLIP to survival and modulating response to bicalutamide was studied by molecular and pharmacologic interventions.
Results: c-FLIP expression was increased in high-grade prostatic intraepithelial neoplasia and prostate cancer tissue relative to normal prostate epithelium (P < 0.001). Maximal c-FLIP expression was detected in castrate-resistant prostate cancer (CRPC; P < 0.001). In vitro, silencing of c-FLIP induced spontaneous apoptosis and increased 22Rv1 and LNCaP cell sensitivity to bicalutamide, determined by flow cytometry, PARP cleavage, and caspase activity assays. The histone deacetylase inhibitors (HDACi), droxinostat and SAHA, also downregulated c-FLIP expression, induced caspase-8- and caspase-3/7–mediated apoptosis, and increased apoptosis in bicalutamide-treated cells. Conversely, the elevated expression of c-FLIP detected in the CRPC cell line VCaP underpinned their insensitivity to bicalutamide and SAHA in vitro. However, knockdown of c-FLIP induced spontaneous apoptosis in VCaP cells, indicating its relevance to cell survival and therapeutic resistance.
Conclusion: c-FLIP reduces the efficacy of AR-targeted therapy and maintains the viability of prostate cancer cells. A combination of HDACi with androgen deprivation therapy may be effective in early-stage disease, using c-FLIP expression as a predictive biomarker of sensitivity. Direct targeting of c-FLIP, however, may be relevant to enhance the response of existing and novel therapeutics in CRPC. Clin Cancer Res; 18(14); 3822–33. ©2012 AACR..
Pickard, A.
Cichon, A.-.
Barry, A.
Kieran, D.
Patel, D.
Hamilton, P.
Salto-Tellez, M.
James, J.
McCance, D.J.
(2012). Inactivation of Rb in stromal fibroblasts promotes epithelial cell invasion. The embo journal,
Vol.31
(14),
pp. 3092-3103.
Huang, B.
Qu, Z.
Ong, C.W.
Tsang, Y.-.
Xiao, G.
Shapiro, D.
Salto-Tellez, M.
Ito, K.
Ito, Y.
Chen, L.-.
(2012). RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor α. Oncogene,
Vol.31
(4),
pp. 527-534.
Pang, B.
Leong, C.C.
Salto-Tellez, M.
Petersson, F.
(2011). Desmoplastic Small Round Cell Tumor of Major Salivary Glands. Applied immunohistochemistry & molecular morphology,
Vol.19
(1),
pp. 70-75.
Salto-Tellez, M.
Yau, E.X.
Yan, B.
Fox, S.B.
(2011). Where and by Whom Should Gastric Cancer HER2/neu Status Be Assessed?: Lessons From Breast Cancer. Archives of pathology & laboratory medicine,
Vol.135
(6),
pp. 693-695.
Ng, S.-.
Selvarajan, V.
Huang, G.
Zhou, J.
Feldman, A.L.
Law, M.
Kwong, Y.-.
Shimizu, N.
Kagami, Y.
Aozasa, K.
Salto-Tellez, M.
Chng, W.-.
(2011). Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling. The journal of pathology,
Vol.223
(4),
pp. 496-510.
Ito, K.
Chuang, L.S.
Ito, T.
Chang, T.L.
Fukamachi, H.
Salto–Tellez, M.
Ito, Y.
(2011). Loss of Runx3 Is a Key Event in Inducing Precancerous State of the Stomach. Gastroenterology,
Vol.140
(5),
pp. 1536-1546.e8.
Hillmer, A.M.
Yao, F.
Inaki, K.
Lee, W.H.
Ariyaratne, P.N.
Teo, A.S.
Woo, X.Y.
Zhang, Z.
Zhao, H.
Ukil, L.
Chen, J.P.
Zhu, F.
So, J.B.
Salto-Tellez, M.
Poh, W.T.
Zawack, K.F.
Nagarajan, N.
Gao, S.
Li, G.
Kumar, V.
Lim, H.P.
Sia, Y.Y.
Chan, C.S.
Leong, S.T.
Neo, S.C.
Choi, P.S.
Thoreau, H.
Tan, P.B.
Shahab, A.
Ruan, X.
Bergh, J.
Hall, P.
Cacheux-Rataboul, V.
Wei, C.-.
Yeoh, K.G.
Sung, W.-.
Bourque, G.
Liu, E.T.
Ruan, Y.
(2011). Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes. Genome research,
Vol.21
(5),
pp. 665-675.
show abstract
Somatic genome rearrangements are thought to play important roles in cancer development. We optimized a long-span paired-end-tag (PET) sequencing approach using 10-Kb genomic DNA inserts to study human genome structural variations (SVs). The use of a 10-Kb insert size allows the identification of breakpoints within repetitive or homology-containing regions of a few kilobases in size and results in a higher physical coverage compared with small insert libraries with the same sequencing effort. We have applied this approach to comprehensively characterize the SVs of 15 cancer and two noncancer genomes and used a filtering approach to strongly enrich for somatic SVs in the cancer genomes. Our analyses revealed that most inversions, deletions, and insertions are germ-line SVs, whereas tandem duplications, unpaired inversions, interchromosomal translocations, and complex rearrangements are over-represented among somatic rearrangements in cancer genomes. We demonstrate that the quantitative and connective nature of DNA–PET data is precise in delineating the genealogy of complex rearrangement events, we observe signatures that are compatible with breakage-fusion-bridge cycles, and we discover that large duplications are among the initial rearrangements that trigger genome instability for extensive amplification in epithelial cancers..
Lim, L.G.
Yeoh, K.G.
Salto-Tellez, M.
Khor, C.J.
Teh, M.
Chan, Y.H.
So, J.B.
Rajnakova, A.
Shen, E.
Srivastava, S.
Ho, K.Y.
(2011). Experienced versus inexperienced confocal endoscopists in the diagnosis of gastric adenocarcinoma and intestinal metaplasia on confocal images. Gastrointestinal endoscopy,
Vol.73
(6),
pp. 1141-1147.
Srivastava, S.
Subramaniam, M.M.
Guan, Y.K.
Ming, T.
Salto-Tellez, M.
(2011). Gastric pseudolipomatosis: biopsy follow-up and immunohistochemical analysis of a rare condition. Histopathology,
Vol.58
(7),
pp. 1177-1178.
Lee, J.S.
Chiam, L.
Tan, K.B.
Salto-Tellez, M.
Tan, S.H.
Ong, B.H.
Ng, S.K.
(2011). Extensive Hyperpigmented Plaques in a Chinese Singaporean Woman: A Case of Cutaneous Plasmacytosis. The american journal of dermatopathology,
Vol.33
(5),
pp. 498-503.
Wang, T.
Ong, C.W.
Shi, J.
Srivastava, S.
Yan, B.
Cheng, C.L.
Yong, W.P.
Chan, S.L.
Yeoh, K.G.
Iacopetta, B.
Salto-Tellez, M.
(2011). Sequential expression of putative stem cell markers in gastric carcinogenesis. British journal of cancer,
Vol.105
(5),
pp. 658-665.
Yan, B.
Chin, S.Y.
Ismail, T.M.
Salto-Tellez, M.
(2011). KRAS mutation analysis as a diagnostic tool. International journal of colorectal disease,
Vol.26
(8),
pp. 1083-1084.
Soon, W.W.
Miller, L.D.
Black, M.A.
Dalmasso, C.
Chan, X.B.
Pang, B.
Ong, C.W.
Salto‐Tellez, M.
Desai, K.V.
Liu, E.T.
(2011). Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer. Embo molecular medicine,
Vol.3
(8),
pp. 451-464.
Chuah, B.Y.
Putti, T.
Salto-Tellez, M.
Charlton, A.
Iau, P.
Buhari, S.A.
Wong, C.I.
Tan, S.H.
Wong, A.L.
Chan, C.W.
Goh, B.C.
Lee, S.-.
(2011). Serial changes in the expression of breast cancer-related proteins in response to neoadjuvant chemotherapy. Annals of oncology,
Vol.22
(8),
pp. 1748-1754.
Tan, I.B.
Ivanova, T.
Lim, K.H.
Ong, C.W.
Deng, N.
Lee, J.
Tan, S.H.
Wu, J.
Lee, M.H.
Ooi, C.H.
Rha, S.Y.
Wong, W.K.
Boussioutas, A.
Yeoh, K.G.
So, J.
Yong, W.P.
Tsuburaya, A.
Grabsch, H.
Toh, H.C.
Rozen, S.
Cheong, J.H.
Noh, S.H.
Wan, W.K.
Ajani, J.A.
Lee, J.
Salto–Tellez, M.
Tan, P.
(2011). Intrinsic Subtypes of Gastric Cancer, Based on Gene Expression Pattern, Predict Survival and Respond Differently to Chemotherapy. Gastroenterology,
Vol.141
(2),
pp. 476-485.e11.
Lee, C.W.
Chuang, L.S.
Kimura, S.
Lai, S.K.
Ong, C.W.
Yan, B.
Salto-Tellez, M.
Choolani, M.
Ito, Y.
(2011). RUNX3 functions as an oncogene in ovarian cancer. Gynecologic oncology,
Vol.122
(2),
pp. 410-417.
Salto-Tellez, M.
Tsao, M.-.
Shih, J.-.
Thongprasert, S.
Lu, S.
Chang, G.-.
Au, J.S.
Chou, T.-.
Lee, J.-.
Shi, Y.-.
Radzi, A.
Kang, J.-.
Kim, S.-.
Tan, S.-.
Yang, J.C.
(2011). Clinical and Testing Protocols for the Analysis of Epidermal Growth Factor Receptor Mutations in East Asian Patients with Non-small Cell Lung Cancer: A Combined Clinical-Molecular Pathological Approach. Journal of thoracic oncology,
Vol.6
(10),
pp. 1663-1669.
Choong, L.-.
Lim, S.-.
Chen, Y.
Loh, M.-.
Toy, W.
Wong, C.-.
Salto-Tellez, M.
Shah, N.
Lim, Y.-.
(2011). Elevated NRD1 metalloprotease expression plays a role in breast cancer growth and proliferation. Genes, chromosomes and cancer,
Vol.50
(10),
pp. 837-847.
Yan, B.
Yau, E.X.
Choo, S.N.
Ong, C.W.
Yong, K.J.
Pang, B.
Salto-Tellez, M.
(2011). Dual-colour HER2/Chromosome 17 chromogenic in situ hybridisation assay enables accurate assessment of HER2 genomic status in gastric cancer and has potential utility in HER2 testing of biopsy samples. Journal of clinical pathology,
Vol.64
(10),
pp. 880-883.
show abstract
BackgroundDetermination of HER2 protein expression by immunohistochemistry (IHC) and genomic status by fluorescent in situ hybridisation (FISH) are important in identifying a subset of high HER2-expressing gastric cancers that might respond to trastuzumab. Although FISH is considered the standard for determination of HER2 genomic status, brightfield ISH is being increasingly recognised as a viable alternative. Also, the impact of HER2 protein expression/genomic heterogeneity on the accuracy of HER2 testing has not been well studied in the context of gastric biopsy samples.Aims/methodsTo study the utility of brightfield ISH in the evaluation of HER2 genomic status, the correlation coefficient between dual-colour HER2/Chromosome 17 chromogenic in situ hybridisation (CISH) and FISH was ascertained. To study the impact of intratumoral heterogeneity on the accuracy of HER2 testing, the concordance rate of HER2 protein expression/genomic status between matched biopsies and surgical resection specimens of high HER2-expressing gastric cancers was ascertained.ResultsThe dual-colour CISH assay showed a 100% concordance rate with FISH results in 119 samples (Pearson correlation coefficient 0.987, p<0.001). Five of the 11 high-HER2 expressors (defined as IHC 3+ or IHC 2+/FISH-amplified according to Trastuzumab for Gastric Cancer trial criteria) showed an IHC 3+ score on matched biopsies (concordance rate 45.5%). Nine of these 11 cases showed HER2 amplification on matched biopsies (concordance rate 81.8%).ConclusionDual-colour CISH is an excellent alternative for the evaluation of HER2 genomic status in gastric cancers. Determination of HER2 status by HER2 IHC alone in limited gastric biopsy samples results in a high false-negative rate, and diagnostic accuracy appears to be improved if HER2 genomic testing, either alone or concurrently with IHC, is performed for HER2 testing..
Chan, J.Y.
Ong, C.W.
Salto-Tellez, M.
(2011). Overexpression of neurone glial-related cell adhesion molecule is an independent predictor of poor prognosis in advanced colorectal cancer. Cancer science,
Vol.102
(10),
pp. 1855-1861.
Yan, B.
Choo, S.N.
Mulyadi, P.
Srivastava, S.
Ong, C.W.
Yong, K.J.
Putti, T.
Salto-Tellez, M.
Lim, G.S.
(2011). Dual-colour HER2/chromosome 17 chromogenic in situ hybridisation enables accurate assessment of HER2 genomic status in ovarian tumours. Journal of clinical pathology,
Vol.64
(12),
pp. 1097-1101.
show abstract
BackgroundOvarian cancer is a leading cause of gynaecological cancer-related morbidity and mortality. There has been increasing interest in the potential utility of anti-human epidermal growth factor receptor 2 (anti-HER2) agents in the treatment of this disease, with the attendant need to identify suitable predictive biomarkers of response to treatment.Aims/methodsThe authors studied the prevalence of HER2 genomic amplification and overexpression in 85 ovarian tumours in the local patient cohort of this study, as well as the concordance rate between immunohistochemistry, fluorescent in situ hybridisation (FISH) and a dual-colour HER2/chromosome 17 centromere chromogenic in situ hybridisation (CISH) assay.ResultsThe authors identified HER2 genomic amplification and protein overexpression in 35.3% (6/17) and 29.4% (5/17), respectively, of primary ovarian mucinous carcinomas. No other cancer subtypes displayed HER2 amplification or protein overexpression. The authors also found a perfect concordance between FISH and dual-colour CISH analysis (κ coefficient 1.0, p<0.001).ConclusionThe results of this study support existing reports that HER2 genomic amplification and protein overexpression are predominantly found in primary ovarian mucinous carcinomas. Given the perfect concordance between the FISH and dual-colour CISH assays and the advantages of CISH over FISH analysis, future clinical trials investigating the use of anti-HER2 therapeutics in ovarian carcinomas should incorporate dual-colour CISH as part of the HER2 status assessment algorithm..
Pang, N.K.
Nga, M.E.
Chin, S.Y.
Ismail, T.M.
Lim, G.L.
Soong, R.
Salto-Tellez, M.
(2011). KRAS and BRAF mutation analysis can be reliably performed on aspirated cytological specimens of metastatic colorectal carcinoma. Cytopathology,
Vol.22
(6),
pp. 358-364.
Tan, W.L.
Bhattacharya, B.
Loh, M.
Balasubramanian, I.
Akram, M.
Dong, D.
Wong, L.
Thakkar, B.
Salto-Tellez, M.
Soo, R.A.
Fichtner, I.
Iacopetta, B.
Soong, R.
(2011). Low cytosine triphosphate synthase 2 expression renders resistance to 5-fluorouracil in colorectal cancer. Cancer biology & therapy,
Vol.11
(6),
pp. 599-608.
Lauwers, G.Y.
Black-Schaffer, S.
Salto-Tellez, M.
(2010). Molecular Pathology in Contemporary Diagnostic Pathology Laboratory. American journal of surgical pathology,
Vol.34
(1),
pp. 115-117.
Yan, B.
Yau, E.X.
Bte Omar, S.S.
Ong, C.W.
Pang, B.
Yeoh, K.G.
Salto-Tellez, M.
(2010). A study of HER2 gene amplification and protein expression in gastric cancer. Journal of clinical pathology,
Vol.63
(9),
pp. 839-842.
Chang, T.L.
Ito, K.
Ko, T.K.
Liu, Q.
Salto–Tellez, M.
Yeoh, K.G.
Fukamachi, H.
Ito, Y.
(2010). Claudin-1 Has Tumor Suppressive Activity and Is a Direct Target of RUNX3 in Gastric Epithelial Cells. Gastroenterology,
Vol.138
(1),
pp. 255-265.e3.
Yan, B.
Yap, C.T.
Wang, S.
Lee, C.K.
Koh, S.
Omar, M.F.
Salto-Tellez, M.
Kumarasinghe, M.P.
(2010). Cofilin immunolabelling correlates with depth of invasion in gastrointestinal endocrine cell tumors. Acta histochemica,
Vol.112
(1),
pp. 101-106.
Nga, M.E.
Swe, N.N.
Chen, K.T.
Shen, L.
Lilly, M.B.
Chan, S.P.
Salto-Tellez, M.
Das, K.
(2010). PIM-1 kinase expression in adipocytic neoplasms: diagnostic and biological implications. International journal of experimental pathology,
Vol.91
(1),
pp. 34-43.
Ong, C.W.
Kim, L.G.
Kong, H.H.
Low, L.Y.
Iacopetta, B.
Soong, R.
Salto-Tellez, M.
(2010). CD133 expression predicts for non-response to chemotherapy in colorectal cancer. Modern pathology,
Vol.23
(3),
pp. 450-457.
Yixuan, Y.
Kiat, L.S.
Yee, C.L.
Huiyin, L.
Yunhao, C.
Kuan, C.P.
Hassan, A.
Ting, W.T.
Manuel, S.-.
Guan, Y.K.
Pin, L.Y.
(2010). Cathepsin S Mediates Gastric Cancer Cell Migration and Invasion via a Putative Network of Metastasis-Associated Proteins. Journal of proteome research,
Vol.9
(9),
pp. 4767-4778.
Ong, C.W.
Kim, L.G.
Kong, H.H.
Low, L.Y.
Wang, T.T.
Supriya, S.
Kathiresan, M.
Soong, R.
Salto-Tellez, M.
(2010). Computer-assisted pathological immunohistochemistry scoring is more time-effective than conventional scoring, but provides no analytical advantage. Histopathology,
Vol.56
(4),
pp. 523-529.
Lai, K.W.
Koh, K.X.
Loh, M.
Tada, K.
Subramaniam, M.M.
Lim, X.Y.
Vaithilingam, A.
Salto-Tellez, M.
Iacopetta, B.
Ito, Y.
Soong, R.
(2010). MicroRNA-130b regulates the tumour suppressor RUNX3 in gastric cancer. European journal of cancer,
Vol.46
(8),
pp. 1456-1463.
Lai, R.C.
Arslan, F.
Lee, M.M.
Sze, N.S.
Choo, A.
Chen, T.S.
Salto-Tellez, M.
Timmers, L.
Lee, C.N.
El Oakley, R.M.
Pasterkamp, G.
de Kleijn, D.P.
Lim, S.K.
(2010). Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem cell research,
Vol.4
(3),
pp. 214-222.
Lu, G.
Leung, C.H.
Yan, B.
Tan, C.M.
Low, S.Y.
Aung, M.O.
Salto–Tellez, M.
Lim, S.G.
Hooi, S.C.
(2010). C/EBPα Is Up-regulated in a Subset of Hepatocellular Carcinomas and Plays a Role in Cell Growth and Proliferation. Gastroenterology,
Vol.139
(2),
pp. 632-643.e4.
Das, K.
Lorena, P.D.
Ng, L.K.
Lim, D.
Shen, L.
Siow, W.Y.
Teh, M.
Reichardt, J.K.
Salto-Tellez, M.
(2010). Differential expression of steroid 5α-reductase isozymes and association with disease severity and angiogenic genes predict their biological role in prostate cancer. Endocrine-related cancer,
Vol.17
(3),
pp. 757-770.
show abstract
The biological role of steroid 5α-reductase isozymes (encoded by the SRD5A1 and SRD5A2 genes) and angiogenic factors that play important roles in the pathogenesis and vascularization of prostate cancer (PC) is poorly understood. The sub-cellular expression of these isozymes and vascular endothelial growth factor (VEGF) in PC tissue microarrays (n=62) was examined using immunohistochemistry. The effect of SRD5A inhibition on the angiogenesis pathway genes in PC was also examined in prostate cell lines, LNCaP, PC3, and RWPE-1, by treating them with the SRD5A inhibitors finasteride and dutasteride, followed by western blot, quantitative PCR, and ELISA chip array techniques. In PC tissues, nuclear SRD5A1 expression was strongly associated with higher cancer Gleason scores (P=0.02), higher cancer stage (P=0.01), and higher serum prostate specific antigen (PSA) levels (P=0.01), whereas nuclear SRD5A2 expression was correlated with VEGF expression (P=0.01). Prostate tumor cell viability was significantly reduced in dutasteride-treated PC3 and RWPE-1 cells compared with finasteride-treated groups. Expression of the angiogenesis pathway genes transforming growth factor β 1 (TGFB1), endothelin (EDN1), TGFα (TGFA), and VEGFR1 was upregulated in LNCaP cells, and at least 7 out of 21 genes were upregulated in PC3 cells treated with finasteride (25 μM). Our findings suggest that SRD5A1 expression predominates in advanced PC, and that inhibition of SRD5A1 and SRD5A2 together was more effective in reducing cell numbers than inhibition of SRD5A2 alone. However, these inhibitors did not show any significant difference in prostate cell angiogenic response. Interestingly, some angiogenic genes remained activated after treatment, possibly due to the duration of treatment and tumor resistance to inhibitors..
Leong, D.T.
Lim, J.
Goh, X.
Pratap, J.
Pereira, B.P.
Kwok, H.S.
Nathan, S.S.
Dobson, J.R.
Lian, J.B.
Ito, Y.
Voorhoeve, P.M.
Stein, G.S.
Salto-Tellez, M.
Cool, S.M.
van Wijnen, A.J.
(2010). Cancer-related ectopic expression of the bone-related transcription factor RUNX2 in non-osseous metastatic tumor cells is linked to cell proliferation and motility. Breast cancer research,
Vol.12
(5).
Subramaniam, M.M.
Chan, J.Y.
Omar, M.F.
Ito, K.
Ito, Y.
Yeoh, K.G.
Salto-Tellez, M.
Putti, T.C.
(2010). Lack of RUNX3 inactivation in columnar cell lesions of breast. Histopathology,
Vol.57
(4),
pp. 555-563.
Das, K.
Lorena, P.D.
Kuan Ng, L.
Shen, L.
Lim, D.
Siow, W.Y.
Narasimhan, K.
Teh, M.
Choolani, M.
Putti, T.C.
Salto-Tellez, M.
(2010). Aurora-A expression, hormone receptor status and clinical outcome in hormone related cancers. Pathology,
Vol.42
(6),
pp. 540-546.
Mohd Omar, M.F.
Huang, N.
Ou, K.
Yu, K.
Putti, T.C.
Jikuya, H.
Ichikawa, T.
Nishimura, O.
Tan, P.
Salto-Tellez, M.
(2010). Molecular-assisted immunohistochemical optimization. Acta histochemica,
Vol.112
(6),
pp. 519-528.
Loh, M.
Liem, N.
Lim, P.L.
Vaithilingam, A.
Cheng, C.L.
Salto-Tellez, M.
Yong, W.P.
Soong, R.
(2010). Impact of Sample Heterogeneity on Methylation Analysis. Diagnostic molecular pathology,
Vol.19
(4),
pp. 243-247.
Kothandaraman, N.
Bajic, V.B.
Brendan, P.N.
Huak, C.Y.
Keow, P.B.
Razvi, K.
Salto-Tellez, M.
Choolani, M.
(2010). E2F5 status significantly improves malignancy diagnosis of epithelial ovarian cancer. Bmc cancer,
Vol.10
(1).
show abstract
Abstract
Background
Ovarian epithelial cancer (OEC) usually presents in the later stages of the disease. Factors, especially those associated with cell-cycle genes, affecting the genesis and tumour progression for ovarian cancer are largely unknown. We hypothesized that over-expressed transcription factors (TFs), as well as those that are driving the expression of the OEC over-expressed genes, could be the key for OEC genesis and potentially useful tissue and serum markers for malignancy associated with OEC.
Methods
Using a combination of computational (selection of candidate TF markers and malignancy prediction) and experimental approaches (tissue microarray and western blotting on patient samples) we identified and evaluated E2F5 transcription factor involved in cell proliferation, as a promising candidate regulatory target in early stage disease. Our hypothesis was supported by our tissue array experiments that showed E2F5 expression only in OEC samples but not in normal and benign tissues, and by significantly positively biased expression in serum samples done using western blotting studies.
Results
Analysis of clinical cases shows that of the E2F5 status is characteristic for a different population group than one covered by CA125, a conventional OEC biomarker. E2F5 used in different combinations with CA125 for distinguishing malignant cyst from benign cyst shows that the presence of CA125 or E2F5 increases sensitivity of OEC detection to 97.9% (an increase from 87.5% if only CA125 is used) and, more importantly, the presence of both CA125 and E2F5 increases specificity of OEC to 72.5% (an increase from 55% if only CA125 is used). This significantly improved accuracy suggests possibility of an improved diagnostics of OEC. Furthermore, detection of malignancy status in 86 cases (38 benign, 48 early and late OEC) shows that the use of E2F5 status in combination with other clinical characteristics allows for an improved detection of malignant cases with sensitivity, specificity, F-measure and accuracy of 97.92%, 97.37%, 97.92% and 97.67%, respectively.
Conclusions
Overall, our findings, in addition to opening a realistic possibility for improved OEC diagnosis, provide an indirect evidence that a cell-cycle regulatory protein E2F5 might play a significant role in OEC pathogenesis.
.
ZANG, Z.
GUNARATNAM, L.
CHEONG, J.
LAI, L.
HSIAO, L.
OLEARY, E.
SUN, X.
SALTOTELLEZ, M.
BONVENTRE, J.
HSU, S.
(2009). Identification of PP2A as a novel interactor and regulator of TRIP-Br1. Cellular signalling,
Vol.21
(1),
pp. 34-42.
Li, G.
Luo, R.
Zhang, J.
Yeo, K.S.
Lian, Q.
Xie, F.
Tan, E.K.
Caille, D.
Kon, O.L.
Salto-Tellez, M.
Meda, P.
Lim, S.K.
(2009). Generating mESC-derived insulin-producing cell lines through an intermediate lineage-restricted progenitor line. Stem cell research,
Vol.2
(1),
pp. 41-55.
Li, G.D.
Luo, R.
Zhang, J.
Yeo, K.S.
Xie, F.
Way Tan, E.K.
Caille, D.
Que, J.
Kon, O.L.
Salto-Tellez, M.
Meda, P.
Lim, S.K.
(2009). Derivation of functional insulin-producing cell lines from primary mouse embryo culture. Stem cell research,
Vol.2
(1),
pp. 29-40.
Subramaniam, M.M.
Chan, J.Y.
Soong, R.
Ito, K.
Ito, Y.
Yeoh, K.G.
Salto-Tellez, M.
Putti, T.C.
(2009). RUNX3 inactivation by frequent promoter hypermethylation and protein mislocalization constitute an early event in breast cancer progression. Breast cancer research and treatment,
Vol.113
(1),
pp. 113-121.
Nathan, S.S.
Pereira, B.P.
Zhou, Y.-.
Gupta, A.
Dombrowski, C.
Soong, R.
Pho, R.W.
Stein, G.S.
Salto-Tellez, M.
Cool, S.M.
van Wijnen, A.J.
(2009). Elevated expression of Runx2 as a key parameter in the etiology of osteosarcoma. Molecular biology reports,
Vol.36
(1),
pp. 153-158.
Subramaniam, M.M.
Chan, J.Y.
Soong, R.
Ito, K.
Yeoh, K.G.
Wong, R.
Guenther, T.
Will, O.
Chen, C.L.
Kumarasinghe, M.P.
Ito, Y.
Salto-Tellez, M.
(2009). RUNX3 Inactivation in Colorectal Polyps Arising Through Different Pathways of Colonic Carcinogenesis. The american journal of gastroenterology,
Vol.104
(2),
pp. 426-436.
Soong, R.
Shah, N.
Peh, B.K.
Chong, P.Y.
Ng, S.S.
Zeps, N.
Joseph, D.
Salto-Tellez, M.
Iacopetta, B.
Ito, Y.
(2009). The expression of RUNX3 in colorectal cancer is associated with disease stage and patient outcome. British journal of cancer,
Vol.100
(5),
pp. 676-679.
Li, L.
Salto-Tellez, M.
Tan, C.-.
Whiteman, M.
Moore, P.K.
(2009). GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat. Free radical biology and medicine,
Vol.47
(1),
pp. 103-113.
Thamboo, T.P.
Nga, M.-.
Lim, D.G.
Soong, R.
Salto-Tellez, M.
(2009). Thrombomodulin expression in gastrointestinal stromal tumours (GISTs): a novel finding with diagnostic implications. Pathology,
Vol.41
(5),
pp. 488-490.
Das, K.
Leong, D.T.
Gupta, A.
Shen, L.
Putti, T.
Stein, G.S.
van Wijnen, A.J.
Salto-Tellez, M.
(2009). Positive association between nuclear Runx2 and oestrogen-progesterone receptor gene expression characterises a biological subtype of breast cancer. European journal of cancer,
Vol.45
(13),
pp. 2239-2248.
Quek, T.P.
Yan, B.
Yong, W.P.
Salto-Tellez, M.
(2009). Targeted therapeutics-oriented tumor classification: a paradigm shift. Personalized medicine,
Vol.6
(5),
pp. 465-468.
Pang, N.K.
Chin, S.Y.
Nga, M.E.
Chang, A.R.
Ismail, T.-.
Omar, S.-.
Charlton, A.
Salto-Tellez, M.
(2009). Comparative validation ofc-kitexon 11 mutation analysis on cytology samples and corresponding surgical resections of gastrointestinal stromal tumours. Cytopathology,
Vol.20
(5),
pp. 297-303.
Bambang, I.F.
Xu, S.
Zhou, J.
Salto-Tellez, M.
Sethi, S.K.
Zhang, D.
(2009). Overexpression of endoplasmic reticulum protein 29 regulates mesenchymal–epithelial transition and suppresses xenograft tumor growth of invasive breast cancer cells. Laboratory investigation,
Vol.89
(11),
pp. 1229-1242.
Whitehall, V.
Tran, K.
Umapathy, A.
Grieu, F.
Hewitt, C.
Evans, T.-.
Ismail, T.
Li, W.Q.
Collins, P.
Ravetto, P.
Leggett, B.
Salto-Tellez, M.
Soong, R.
Fox, S.
Scott, R.J.
Dobrovic, A.
Iacopetta, B.
(2009). A Multicenter Blinded Study to Evaluate KRAS Mutation Testing Methodologies in the Clinical Setting. The journal of molecular diagnostics,
Vol.11
(6),
pp. 543-552.
Lim, L.-.
Rajnakova, A.
Yan, B.
Salto-Tellez, M.
Lim, L.-.
(2009). Recurrent lower gastrointestinal bleeding secondary to cytomegalovirus-associated colonic ulcer in a non human immunodeficiency virus infected patient: timely diagnosis and treatment averted surgery. Colorectal disease,
Vol.11
(9),
pp. 984-985.
Kong, S.L.
Chui, P.
Lim, B.
Salto-Tellez, M.
(2009). Elucidating the molecular physiopathology of acute respiratory distress syndrome in severe acute respiratory syndrome patients. Virus research,
Vol.145
(2),
pp. 260-269.
Zhu, F.
Loh, M.
Hill, J.
Lee, S.
Koh, K.X.
Lai, K.W.
Salto-Tellez, M.
Iacopetta, B.
Yeoh, K.G.
Soong, R.
(2009). Genetic factors associated with intestinal metaplasia in a high risk Singapore-Chinese population: a cohort study. Bmc gastroenterology,
Vol.9
(1).
show abstract
Abstract
Background
Intestinal metaplasia (IM) is an important precursor lesion in the development of gastric cancer (GC). The aim of this study was to investigate genetic factors previously linked to GC risk for their possible association with IM. A total of 18 polymorphisms in 14 candidate genes were evaluated in a Singapore-Chinese population at high risk of developing GC.
Methods
Genotype frequencies were compared between individuals presenting with (n = 128) or without (n = 246) IM by both univariate and multivariate analysis.
Results
Carriers of the NQO1 609 T allele showed an association with IM in individuals who were seropositive for Helicobacter pylori (HP+; OR = 2.61, 95%CI: 1.18-5.80, P = .018). The IL-10 819 C allele was also associated with IM in HP+ individuals (OR = 2.32, 95%CI: 1.21-4.43, P = 0.011), while the PTPN11 A allele was associated with IM in HP- individuals (OR = 2.51, 95%CI: 1.16-5.40, P = 0.019), but showed an inverse association in HP+ subjects (OR = 0.46, 95%CI: 0.21-0.99, P = 0.048).
Conclusion
Polymorphisms in NQO1, IL-10 and PTPN11, in combination with HP status, could be used to identify individuals who are more likely to develop IM and therefore GC.
.
Subramaniam, M.M.
Chan, J.Y.
Yeoh, K.G.
Quek, T.
Ito, K.
Salto-Tellez, M.
(2009). Molecular pathology of RUNX3 in human carcinogenesis. Biochimica et biophysica acta (bba) - reviews on cancer,
Vol.1796
(2),
pp. 315-331.
Pereira, B.P.
Zhou, Y.
Gupta, A.
Leong, D.T.
Aung, K.Z.
Ling, L.
Pho, R.W.
Galindo, M.
Salto-Tellez, M.
Stein, G.S.
Cool, S.M.
van Wijnen, A.J.
Nathan, S.S.
(2009). Runx2, p53, and pRB status as diagnostic parameters for deregulation of osteoblast growth and differentiation in a new pre-chemotherapeutic osteosarcoma cell line (OS1). Journal of cellular physiology,
Vol.221
(3),
pp. 778-788.
Cheong, J.K.
Gunaratnam, L.
Zang, Z.J.
Yang, C.M.
Sun, X.
Nasr, S.L.
Sim, K.G.
Peh, B.K.
Rashid, S.B.
Bonventre, J.V.
Salto-Tellez, M.
Hsu, S.I.
(2009). TRIP-Br2 promotes oncogenesis in nude mice and is frequently overexpressed in multiple human tumors. Journal of translational medicine,
Vol.7
(1).
show abstract
Abstract
Background
Members of the TRIP-Br/SERTAD family of mammalian transcriptional coregulators have recently been implicated in E2F-mediated cell cycle progression and tumorigenesis. We, herein, focus on the detailed functional characterization of the least understood member of the TRIP-Br/SERTAD protein family, TRIP-Br2 (SERTAD2).
Methods
Oncogenic potential of TRIP-Br2 was demonstrated by (1) inoculation of NIH3T3 fibroblasts, which were engineered to stably overexpress ectopic TRIP-Br2, into athymic nude mice for tumor induction and (2) comprehensive immunohistochemical high-throughput screening of TRIP-Br2 protein expression in multiple human tumor cell lines and human tumor tissue microarrays (TMAs). Clinicopathologic analysis was conducted to assess the potential of TRIP-Br2 as a novel prognostic marker of human cancer. RNA interference of TRIP-Br2 expression in HCT-116 colorectal carcinoma cells was performed to determine the potential of TRIP-Br2 as a novel chemotherapeutic drug target.
Results
Overexpression of TRIP-Br2 is sufficient to transform murine fibroblasts and promotes tumorigenesis in nude mice. The transformed phenotype is characterized by deregulation of the E2F/DP-transcriptional pathway through upregulation of the key E2F-responsive genes CYCLIN E, CYCLIN A2, CDC6 and DHFR. TRIP-Br2 is frequently overexpressed in both cancer cell lines and multiple human tumors. Clinicopathologic correlation indicates that overexpression of TRIP-Br2 in hepatocellular carcinoma is associated with a worse clinical outcome by Kaplan-Meier survival analysis. Small interfering RNA-mediated (siRNA) knockdown of TRIP-Br2 was sufficient to inhibit cell-autonomous growth of HCT-116 cells in vitro.
Conclusion
This study identifies TRIP-Br2 as a bona-fide protooncogene and supports the potential for TRIP-Br2 as a novel prognostic marker and a chemotherapeutic drug target in human cancer.
.
Kumar, A.P.
Quake, A.L.
Chang, M.K.
Zhou, T.
Lim, K.S.
Singh, R.
Hewitt, R.E.
Salto-Tellez, M.
Pervaiz, S.
Clément, M.-.
(2009). Repression of NHE1 Expression by PPARγ Activation Is a Potential New Approach for Specific Inhibition of the Growth of Tumor Cells In vitro and In vivo. Cancer research,
Vol.69
(22),
pp. 8636-8644.
show abstract
Abstract
Ligand-induced activation of peroxisome proliferator-activated receptor γ (PPARγ) inhibits proliferation in cancer cells in vitro and in vivo; however, the downstream targets remain undefined. We report the identification of a peroxisome proliferator response element in the promoter region of the Na+/H+ transporter gene NHE1, the overexpression of which has been associated with carcinogenesis. Exposure of breast cancer cells expressing high levels of PPARγ to its natural and synthetic agonists resulted in downregulation of NHE1 transcription as well as protein expression. Furthermore, the inhibitory effect of activated PPARγ on tumor colony-forming ability was abrogated on overexpression of NHE1, whereas small interfering RNA–mediated gene silencing of NHE1 significantly increased the sensitivity of cancer cells to growth-inhibitory stimuli. Finally, histopathologic analysis of breast cancer biopsies obtained from patients with type II diabetes treated with the synthetic agonist rosiglitazone showed significant repression of NHE1 in the tumor tissue. These data provide evidence for tumor-selective downregulation of NHE1 by activated PPARγ in vitro and in pathologic specimens from breast cancer patients and could have potential implications for the judicious use of low doses of PPARγ ligands in combination chemotherapy regimens for an effective therapeutic response. [Cancer Res 2009;69(22):8636–44].
Hsieh, W.-.
Soo, R.
Peh, B.-.
Loh, T.
Dong, D.
Soh, D.
Wong, L.-.
Green, S.
Chiao, J.
Cui, C.-.
Lai, Y.-.
Lee, S.-.
Mow, B.
Soong, R.
Salto-Tellez, M.
Goh, B.-.
(2009). Pharmacodynamic Effects of Seliciclib, an Orally Administered Cell Cycle Modulator, in Undifferentiated Nasopharyngeal Cancer. Clinical cancer research,
Vol.15
(4),
pp. 1435-1442.
show abstract
Abstract
Purpose: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma.
Experimental Design: Patients with treatment-naïve locally advanced nasopharyngeal carcinoma received seliciclib at 800 mg or 400 mg twice daily on days 1 to 3 and 8 to 12. Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohistochemistry, and transcriptional profiling using real-time PCR low-density array consisting of a panel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation.
Results: At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastoma protein pRB (T821), and significant transcriptional down-regulation of genes related to cellular proliferation and survival were shown in some patients posttreatment, indicative of cell cycle modulation by seliciclib, more specifically inhibition of cdk2/cyclin E, cdk7/cyclin H, and cdk9/cyclin T.
Conclusions: Brief treatment with this regimen of seliciclib in patients with nasopharyngeal carcinoma is tolerable at 400 mg bd and associated with tumor pharmacodynamic changes consistent with cdk inhibition, and warrants further efficacy studies in this tumor..
Yan, B.
Raju, G.C.
Salto-Tellez, M.
(2008). Epithelioid, cytokeratin expressing malignant solitary fibrous tumour of the pleura. Pathology,
Vol.40
(1),
pp. 98-99.
Ou, K.
Yu, K.
Kesuma, D.
Hooi, M.
Huang, N.
Chen, W.
Lee, S.Y.
Goh, X.P.
Tan, L.K.
Liu, J.
Soon, S.Y.
Bin Abdul Rashid, S.
Putti, T.C.
Jikuya, H.
Ichikawa, T.
Nishimura, O.
Salto-Tellez, M.
Tan, P.
(2008). Novel Breast Cancer Biomarkers Identified by Integrative Proteomic and Gene Expression Mapping. Journal of proteome research,
Vol.7
(4),
pp. 1518-1528.
Webb, G.D.
Lim, L.H.
Oh, V.M.
Yeo, S.B.
Cheong, Y.P.
Ali, M.Y.
El Oakley, R.
Lee, C.N.
Wong, P.S.
Caleb, M.G.
Salto-Tellez, M.
Bhatia, M.
Chan, E.S.
Taylor, E.A.
Moore, P.K.
(2008). Contractile and Vasorelaxant Effects of Hydrogen Sulfide and Its Biosynthesis in the Human Internal Mammary Artery. Journal of pharmacology and experimental therapeutics,
Vol.324
(2),
pp. 876-882.
Qiu, G.-.
Salto-Tellez, M.
Ross, J.A.
Yeo, W.
Cui, Y.
Wheelhouse, N.
Chen, G.G.
Harrison, D.
Lai, P.
Tao, Q.
Hooi, S.C.
(2008). The tumor suppressor gene DLEC1 is frequently silenced by DNA methylation in hepatocellular carcinoma and induces G1 arrest in cell cycle. Journal of hepatology,
Vol.48
(3),
pp. 433-441.
Tan, Y.H.
Liu, Y.
Eu, K.W.
Ang, P.W.
Li, W.Q.
Tellez, M.S.
Iacopetta, B.
Soong, R.
(2008). Detection of BRAF V600E mutation by pyrosequencing. Pathology,
Vol.40
(3),
pp. 295-298.
Soong, R.
Shah, N.
Salto-Tellez, M.
Tai, B.C.
Soo, R.A.
Han, H.C.
Ng, S.S.
Tan, W.L.
Zeps, N.
Joseph, D.
Diasio, R.B.
Iacopetta, B.
(2008). Prognostic significance of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase protein expression in colorectal cancer patients treated with or without 5-fluorouracil-based chemotherapy. Annals of oncology,
Vol.19
(5),
pp. 915-919.
Huynh, H.
Chow, P.K.
Palanisamy, N.
Salto-Tellez, M.
Goh, B.C.
Lee, C.K.
Somani, A.
Lee, H.S.
Kalpana, R.
Yu, K.
Tan, P.H.
Wu, J.
Soong, R.
Lee, M.H.
Hor, H.
Soo, K.C.
Toh, H.C.
Tan, P.
(2008). Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. Journal of hepatology,
Vol.49
(1),
pp. 52-60.
Das, K.
Mohd Omar, M.F.
Ong, C.W.
Abdul Rashid, S.B.
Peh, B.K.
Putti, T.C.
Tan, P.H.
Chia, K.S.
Teh, M.
Shah, N.
Soong, R.
Salto-Tellez, M.
(2008). TRARESA: a tissue microarray-based hospital system for biomarker validation and discovery. Pathology,
Vol.40
(5),
pp. 441-449.
Soong, R.
Anuar, D.
Liu, Y.
Eu, K.W.
Han, H.C.
Salto-Tellez, M.
Iacopetta, B.
(2008). Denaturing High Performance Liquid Chromatography for the Detection of Microsatellite Instability Using Bethesda and Pentaplex Marker Panels. Diagnostic molecular pathology,
Vol.17
(3),
pp. 127-133.
Ito, K.
Lim, A.C.
Salto-Tellez, M.
Motoda, L.
Osato, M.
Chuang, L.S.
Lee, C.W.
Voon, D.C.
Koo, J.K.
Wang, H.
Fukamachi, H.
Ito, Y.
(2008). RUNX3 Attenuates β-Catenin/T Cell Factors in Intestinal Tumorigenesis. Cancer cell,
Vol.14
(3),
pp. 226-237.
Yan, B.
Omar, F.M.
Das, K.
Ng, W.H.
Lim, C.
Shiuan, K.
Yap, C.T.
Salto-Tellez, M.
(2008). Characterization of Numb expression in astrocytomas. Neuropathology,
Vol.28
(5),
pp. 479-484.
Shah, N.
Pang, B.
Yeoh, K.-.
Thorn, S.
Chen, C.S.
Lilly, M.B.
Salto-Tellez, M.
(2008). Potential roles for the PIM1 kinase in human cancer – A molecular and therapeutic appraisal. European journal of cancer,
Vol.44
(15),
pp. 2144-2151.
Siok-Bian, N.
Lee, V.
Das, K.
Salto-Tellez, M.
(2008). The relevance of molecular diagnostics in the practice of surgical pathology. Expert opinion on medical diagnostics,
Vol.2
(12),
pp. 1401-1414.
Salto-Tellez, M.
(2007). A Case for Integrated Morphomolecular Diagnostic Pathologists. Clinical chemistry,
Vol.53
(7),
pp. 1188-1190.
Choong, L.-.
Lim, S.
Loh, M.C.
Man, X.
Chen, Y.
Toy, W.
Pan, M.
Chen, C.-.
Poonepalli, A.
Hande, M.P.
Tan, P.-.
Salto-Tellez, M.
Wong, C.-.
Shah, N.
Druker, B.J.
Lim, Y.-.
(2007). Progressive loss of epidermal growth factor receptor in a subpopulation of breast cancers: implications in target-directed therapeutics. Molecular cancer therapeutics,
Vol.6
(11),
pp. 2828-2842.
show abstract
Abstract
Understanding the molecular etiology and heterogeneity of disease has a direct effect on cancer therapeutics. To identify novel molecular changes associated with breast cancer progression, we conducted phosphoproteomics of the MCF10AT model comprising isogenic, ErbB2- and ErbB3-positive, xenograft-derived cell lines that mimic different stages of breast cancer. Using in vitro animal model and clinical breast samples, our study revealed a marked reduction of epidermal growth factor receptor (EGFR) expression with breast cancer progression. Such diminution of EGFR expression was associated with increased resistance to Gefitinib/Iressa in vitro. Fluorescence in situ hybridization showed that loss of EGFR gene copy number was one of the key mechanisms behind the low/null expression of EGFR in clinical breast tumors. Statistical analysis on the immunohistochemistry data of EGFR expression from 93 matched normal and breast tumor samples showed that (a) diminished EGFR expression could be detected as early as in the preneoplastic lesion (ductal carcinoma in situ) and this culminated in invasive carcinomas; (b) EGFR expression levels could distinguish between normal tissue versus carcinoma in situ and invasive carcinoma with high statistical significance (P < 0.001, n = 81). However, no significant correlation of EGFR expression with disease-free survival and overall survival was observed. This is the first time EGFR expression has been tracked meaningfully and developmentally from the normal condition through disease progression using in vitro, xenograft, and matched normal and tumor samples. Thus, our study provides a new insight into the role of EGFR in breast cancer development. Although no value of EGFR expression in prognosis was found, our findings are likely to have implications in the design of clinical trials targeting the EGFR family of proteins in breast cancer. [Mol Cancer Ther 2007;6(11):2828–42].
Lian, Q.
Lye, E.
Suan Yeo, K.
Khia Way Tan, E.
Salto-Tellez, M.
Liu, T.M.
Palanisamy, N.
El Oakley, R.M.
Lee, E.H.
Lim, B.
Lim, S.-.
(2007). Derivation of Clinically Compliant MSCs from CD105+, CD24− Differentiated Human ESCs. Stem cells,
Vol.25
(2),
pp. 425-436.
show abstract
Abstract
Adult tissue-derived mesenchymal stem cells (MSCs) have demonstrated therapeutic efficacy in treating diseases or repairing damaged tissues through mechanisms thought to be mediated by either cell replacement or secretion of paracrine factors. Characterized, self-renewing human ESCs could potentially be an invariable source of consistently uniform MSCs for therapeutic applications. Here we describe a clinically relevant and reproducible manner of generating identical batches of hESC-derived MSC (hESC-MSC) cultures that circumvents exposure to virus, mouse cells, or serum. Trypsinization and propagation of HuES9 or H1 hESCs in feeder- and serum-free selection media generated three polyclonal, karyotypically stable, and phenotypically MSC-like cultures that do not express pluripotency-associated markers but displayed MSC-like surface antigens and gene expression profile. They differentiate into adipocytes, osteocytes, and chondrocytes in vitro. Gene expression and fluorescence-activated cell sorter analysis identified CD105 and CD24 as highly expressed antigens on hESC-MSCs and hESCs, respectively. CD105+, CD24− monoclonal isolates have a typical MSC gene expression profiles and were identical to each other with a highly correlated gene expression profile (r2 > .90). We have developed a protocol to reproducibly generate clinically compliant and identical hESC-MSC cultures..
Chin, T.M.
Anuar, D.
Soo, R.
Salto-Tellez, M.
Li, W.Q.
Ahmad, B.
Lee, S.C.
Goh, B.C.
Kawakami, K.
Segal, A.
Iacopetta, B.
Soong, R.
(2007). Detection of Epidermal Growth Factor Receptor Variations by Partially Denaturing HPLC. Clinical chemistry,
Vol.53
(1),
pp. 62-70.
show abstract
Abstract
Background: Epidermal growth factor receptor gene (EGFR) variants may be useful markers for identifying responders to gefitinib and erlotinib, small-molecule tyrosine kinase inhibitors of EGFR; therefore, sensitive and cost-effective assays are needed to detect EGFR variants in routine clinical samples. We have developed a partially denaturing HPLC (pDHPLC) assay that is superior to direct sequencing with respect to detection limits, costs, and time requirements.
Methods: Primers, temperatures, and buffer conditions were optimized for PCR-pDHPLC analysis of EGFR exons 18–21. We evaluated the detection limits of pDHPLC and direct sequencing by analyzing mixtures of wild-type and variant EGFR DNA and screened 192 lung cancer samples to examine the diversity of pDHPLC-detectable variants. To assess amenability to routine analysis, we tested lung and pleural tissue specimens from 14 lung cancer patients treated with gefitinib.
Results: The detection limits for variant alleles were 1:100 for pDHPLC and 1:5 for direct sequencing. pDHPLC analysis detected 26 unique EGFR variants, including the common deletions in exon 19 and substitutions in codons 787 and 858. Direct sequencing could not identify 30% (18 of 60) of the variant amplicons identified by pDHPLC. We identified these 18 amplicons by fraction collection after pDHPLC analysis. Analysis of a limited series of lung biopsy samples detected EGFR variants more frequently in gefitinib responders than in nonresponders. pDHPLC analysis was 56% less expensive and 39% faster than direct sequencing.
Conclusions: pDHPLC-based analysis detects EGFR variations in routine clinical samples with a better detection limit and lower cost and time requirement than direct sequencing..
Salto-Tellez, M.
Oh, V.M.
Lee, E.H.
(2007). How do we encourage clinician scientists in Singapore?. Annals academy of medicine singapore,
Vol.36
(11),
pp. 879-2.
Salto-Tellez, M.
Nga, M.E.
Han, H.C.
Wong, A.S.
Lee, C.K.
Anuar, D.
Ng, S.S.
Ho, M.
Wee, A.
Chan, Y.H.
Soong, R.
(2007). Tissue microarrays characterise the clinical significance of a VEGF-A protein expression signature in gastrointestinal stromal tumours. British journal of cancer,
Vol.96
(5),
pp. 776-782.
Chen, W.
Salto-Tellez, M.
Palanisamy, N.
Ganesan, K.
Hou, Q.
Tan, L.K.
Sii, L.H.
Ito, K.
Tan, B.
Wu, J.
Tay, A.
Tan, K.C.
Ang, E.
Tan, B.K.
Tan, P.H.
Ito, Y.
Tan, P.
(2007). Targets of genome copy number reduction in primary breast cancers identified by integrative genomics. Genes, chromosomes and cancer,
Vol.46
(3),
pp. 288-301.
Qiu, G.-.
Xie, H.
Wheelhouse, N.
Harrison, D.
Chen, G.G.
Salto-Tellez, M.
Lai, P.
Ross, J.A.
Hooi, S.C.
(2007). Differential expression of hDAB2IPA and hDAB2IPB in normal tissues and promoter methylation of hDAB2IPA in hepatocellular carcinoma. Journal of hepatology,
Vol.46
(4),
pp. 655-663.
Stünkel, W.
Peh, B.K.
Tan, Y.C.
Nayagam, V.M.
Wang, X.
Salto-Tellez, M.
Ni, B.
Entzeroth, M.
Wood, J.
(2007). Function of the SIRT1 protein deacetylase in cancer. Biotechnology journal,
Vol.2
(11),
pp. 1360-1368.
Subramaniam, M.M.
Putti, T.C.
Anuar, D.
Chong, P.Y.
Shah, N.
Salto-Tellez, M.
Soong, R.
(2007). Clonal Characterization of Sporadic Cribriform-Morular Variant of Papillary Thyroid Carcinoma by Laser Microdissection–BasedAPCMutation Analysis. American journal of clinical pathology,
Vol.128
(6),
pp. 994-1001.
Hemandas, A.K.
Salto-Tellez, M.
Maricar, S.H.
Leong, A.F.
Leow, C.K.
(2006). Metastasis-associated protein S100A4—a potential prognostic marker for colorectal cancer. Journal of surgical oncology,
Vol.93
(6),
pp. 498-503.
Lau, Q.C.
Raja, E.
Salto-Tellez, M.
Liu, Q.
Ito, K.
Inoue, M.
Putti, T.C.
Loh, M.
Ko, T.K.
Huang, C.
Bhalla, K.N.
Zhu, T.
Ito, Y.
Sukumar, S.
(2006). RUNX3 Is Frequently Inactivated by Dual Mechanisms of Protein Mislocalization and Promoter Hypermethylation in Breast Cancer. Cancer research,
Vol.66
(13),
pp. 6512-6520.
show abstract
Abstract
A tumor suppressor function has been attributed to RUNX3, a member of the RUNX family of transcription factors. Here, we examined alterations in the expression of three members, RUNX1, RUNX2, and RUNX3, and their interacting partner, CBF-β, in breast cancer. Among them, RUNX3 was consistently underexpressed in breast cancer cell lines and primary tumors. Fifty percent of the breast cancer cell lines (n = 19) showed hypermethylation at the promoter region and displayed significantly lower levels of RUNX3 mRNA expression (P < 0.0001) and protein (P < 0.001). In primary Singaporean breast cancers, 9 of 44 specimens showed undetectable levels of RUNX3 by immunohistochemistry. In 35 of 44 tumors, however, low levels of RUNX3 protein were present. Remarkably, in each case, protein was mislocalized to the cytoplasm. In primary tumors, hypermethylation of RUNX3 was observed in 23 of 44 cases (52%) and was undetectable in matched adjacent normal breast epithelium. Mislocalization of the protein, with or without methylation, seems to account for RUNX3 inactivation in the vast majority of the tumors. In in vitro and in vivo assays, RUNX3 behaved as a growth suppressor in breast cancer cells. Stable expression of RUNX3 in MDA-MB-231 breast cancer cells led to a more cuboidal phenotype, significantly reduced invasiveness in Matrigel invasion assays, and suppressed tumor formation in immunodeficient mice. This study provides biological and mechanistic insights into RUNX3 as the key member of the family that plays a role in breast cancer. Frequent protein mislocalization and methylation could render RUNX3 a valuable marker for early detection and risk assessment. (Cancer Res 2006; 66(13): 6512-20).
Liang, X.
Lau, Q.C.
Salto-Tellez, M.
Putti, T.C.
Loh, M.
Sukumar, S.
(2006). Mutational hotspot in Exon 20 of PIK3CA in breast cancer among singapore chinese. Cancer biology & therapy,
Vol.5
(5),
pp. 544-548.
Vithana, E.N.
Morgan, P.
Sundaresan, P.
Ebenezer, N.D.
Tan, D.T.
Mohamed, M.D.
Anand, S.
Khine, K.O.
Venkataraman, D.
Yong, V.H.
Salto-Tellez, M.
Venkatraman, A.
Guo, K.
Hemadevi, B.
Srinivasan, M.
Prajna, V.
Khine, M.
Casey, J.R.
Inglehearn, C.F.
Aung, T.
(2006). Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2). Nature genetics,
Vol.38
(7),
pp. 755-757.
Salto-Tellez, M.
Peh, B.K.
Ito, K.
Tan, S.H.
Chong, P.Y.
Han, H.C.
Tada, K.
Ong, W.Y.
Soong, R.
Voon, D.C.
Ito, Y.
(2006). RUNX3 protein is overexpressed in human basal cell carcinomas. Oncogene,
Vol.25
(58),
pp. 7646-7649.
Yan, B.
Chour, H.H.
Peh, B.K.
Lim, C.
Salto-Tellez, M.
(2006). RhoA protein expression correlates positively with degree of malignancy in astrocytomas. Neuroscience letters,
Vol.407
(2),
pp. 124-126.
Kong, S.L.
(2005). Discordant quantitative detection of putative biomarkers in nodal micrometastases of colorectal cancer: biological and clinical implications. Journal of clinical pathology,
Vol.58
(8),
pp. 839-844.
Wang, D.Z.
Skinner, S.
Elliot, R.
Escobar, L.
Salto-Tellez, M.
Garkavenko, O.
Khoo, A.
Lee, K.O.
Calne, R.
Isaac, J.R.
(2005). Xenotransplantation of neonatal porcine islets and Sertoli cells into nonimmunosuppressed streptozotocin-induced diabetic rats. Transplantation proceedings,
Vol.37
(1),
pp. 470-471.
Isaac, J.R.
Skinner, S.
Elliot, R.
Salto-Tellez, M.
Garkavenko, O.
Khoo, A.
Lee, K.O.
Calne, R.
Wang, D.Z.
(2005). Transplantation of neonatal porcine islets and sertoli cells into nonimmunosuppressed nonhuman primates. Transplantation proceedings,
Vol.37
(1),
pp. 487-488.
Salto-Tellez, M.
Tan, E.
Lim, B.
(2005). ARDS in SARS: cytokine mediators and treatment implications. Cytokine,
Vol.29
(2),
pp. 92-94.
Ito, K.
Liu, Q.
Salto-Tellez, M.
Yano, T.
Tada, K.
Ida, H.
Huang, C.
Shah, N.
Inoue, M.
Rajnakova, A.
Hiong, K.C.
Peh, B.K.
Han, H.C.
Ito, T.
Teh, M.
Yeoh, K.G.
Ito, Y.
(2005). RUNX3, A Novel Tumor Suppressor, Is Frequently Inactivated in Gastric Cancer by Protein Mislocalization. Cancer research,
Vol.65
(17),
pp. 7743-7750.
show abstract
Abstract
Loss of RUNX3 expression is suggested to be causally related to gastric cancer as 45% to 60% of gastric cancers do not express RUNX3 mainly due to hypermethylation of the RUNX3 promoter. Here, we examined for other defects in the properties of RUNX3 in gastric cancers that express RUNX3. Ninety-seven gastric cancer tumor specimens and 21 gastric cancer cell lines were examined by immunohistochemistry using novel anti-RUNX3 monoclonal antibodies. In normal gastric mucosa, RUNX3 was expressed most strongly in the nuclei of chief cells as well as in surface epithelial cells. In chief cells, a significant portion of the protein was also found in the cytoplasm. RUNX3 was not detectable in 43 of 97 (44%) cases of gastric cancers tested and a further 38% showed exclusive cytoplasmic localization, whereas only 18% showed nuclear localization. Evidence is presented suggesting that transforming growth factor-β is an inducer of nuclear translocation of RUNX3, and RUNX3 in the cytoplasm of cancer cells is inactive as a tumor suppressor. RUNX3 was found to be inactive in 82% of gastric cancers through either gene silencing or protein mislocalization to the cytoplasm. In addition to the deregulation of mechanisms controlling gene expression, there would also seem to be at least one other mechanism controlling nuclear translocation of RUNX3 that is impaired frequently in gastric cancer..
Salto-Tellez, M.
Putti, T.C.
Lee, C.K.
Chiu, L.-.
Koay, E.S.
(2005). Adenomyoepithelioma of the breast: description of allelic imbalance and microsatellite instability. Histopathology,
Vol.46
(2),
pp. 230-231.
Tiong, H.Y.
Kew, C.Y.
Tan, K.B.
Salto-Tellez, M.
Leong, A.F.
(2005). Metastatic Testicular Carcinoma From the Colon With Clinical, Immunophenotypical, and Molecular Characterization: Report of a Case. Diseases of the colon & rectum,
Vol.48
(3),
pp. 582-585.
Huang, B.H.
Laban, M.
Leung, C.H.
Lee, L.
Lee, C.K.
Salto-Tellez, M.
Raju, G.C.
Hooi, S.C.
(2005). Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell death & differentiation,
Vol.12
(4),
pp. 395-404.
Salto-Tellez, M.
(2005). Lewis Carroll versus George Papanicolaou: a case for a unified international classification of cervical cytology. Cytopathology,
Vol.16
(3),
pp. 153-155.
Li, L.
Bhatia, M.
Zhu, Y.Z.
Zhu, Y.C.
Ramnath, R.D.
Wang, Z.J.
Anuar, F.B.
Whiteman, M.
Salto‐Tellez, M.
Moore, P.K.
(2005). Hydrogen sulfide is a novel mediator of lipopolysaccharide‐induced inflammation in the mouse. The faseb journal,
Vol.19
(9),
pp. 1196-1198.
Salto-Tellez, M.
(2005). Dinucleotide microsatellite repeats are essential for the diagnosis of microsatellite instability in colorectal cancer in Asian patients. World journal of gastroenterology,
Vol.11
(18),
pp. 2781-2781.
Nga, M.E.
(2004). Lymphocytic gastritis-like T cell lymphoma: molecular evidence of an unusual recurrence. Journal of clinical pathology,
Vol.57
(11),
pp. 1222-1224.
Lau, L.G.
Tan, L.K.
Salto-Tellez, M.
Koay, E.S.
Liu, T.C.
(2004). T-cell post-transplant lymphoproliferative disorder after hematopoietic stem cell transplantation: another case and a review of the literature. Bone marrow transplantation,
Vol.34
(9),
pp. 821-822.
Salto-Tellez, M.
Siew-Chuan Koay, E.
(2004). The geography of HFE mutations: molecular diagnosis of haemochromatosis and the globalization of genetic testing. European journal of human genetics,
Vol.12
(11),
pp. 877-878.
Salto-Tellez, M.
Lee, S.C.
Chiu, L.L.
Lee, C.K.
Yong, M.C.
Koay, E.S.
(2004). Microsatellite Instability in Colorectal Cancer: Considerations for Molecular Diagnosis and High-Throughput Screening of Archival Tissues. Clinical chemistry,
Vol.50
(6),
pp. 1082-1086.
Salto-Tellez, M.
Yung Lim, S.
El Oakley, R.M.
Tang, T.P.
ALmsherqi, Z.A.
Lim, S.-.
(2004). Myocardial infarction in the C57BL/6J mouse. Cardiovascular pathology,
Vol.13
(2),
pp. 91-97.
Salto-Tellez, M.
Koay, E.S.
(2004). Molecular diagnostic cytopathology: definitions, scope and clinical utility. Cytopathology,
Vol.15
(5),
pp. 252-255.
Low, T.Y.
Leow, C.K.
Salto-Tellez, M.
Chung, M.C.
(2004). A proteomic analysis of thioacetamide-induced hepatotoxicity and cirrhosis in rat livers. Proteomics,
Vol.4
(12),
pp. 3960-3974.
Lim, L.L.
(2004). Effect of biopsies on sensitivity and specificity of ultra-rapid urease test for detection ofHelicobacter pyloriinfection: A prospective evaluation. World journal of gastroenterology,
Vol.10
(13),
pp. 1907-1907.
QUE, J.
EL OAKLEY, R.M.
SALTO-TELLEZ, M.
WONG, N.
de KLEIJN, D.P.
TEH, M.
RETNAM, L.
LIM, S.-.
(2004). GENERATION OF HYBRID CELL LINES WITH ENDOTHELIAL POTENTIAL FROM SPONTANEOUS FUSION OF ADULT BONE MARROW CELLS WITH EMBRYONIC FIBROBLAST FEEDER. In vitro cellular & developmental biology - animal,
Vol.40
(5),
pp. 143-143.
Chang, T.L.
Salto-Tellez, M.
Thamboo, T.P.
Lee, Y.S.
Koay, E.S.
(2003). Diagnostic Validation of Capillary Electrophoresis Analysis of T-Cell Receptor γ-Chain Gene Rearrangements: Prediction of Malignant Transformation of Cutaneous T-Cell Lymphoproliferative Disorders. Clinical chemistry,
Vol.49
(3),
pp. 513-515.
Zhang, D.
Salto-Tellez, M.
Putti, T.C.
Do, E.
Koay, E.S.
(2003). Reliability of Tissue Microarrays in Detecting Protein Expression and Gene Amplification in Breast Cancer. Modern pathology,
Vol.16
(1),
pp. 79-85.
Chang, T.L.
Salto-Tellez, M.
Kueh, Y.K.
Koay, E.S.
(2003). Simplified capillary electrophoresis detection of the Flt-3 internal tandem duplications and D835 point mutations in acute myeloid leukemia. Haematologica,
Vol.88
(2),
p. ELT04.
Zhang, D.
Salto-Tellez, M.
Do, E.
Putti, T.C.
Koay, E.S.
(2003). Evaluation of HER-2/neu oncogene status in breast tumors on tissue microarrays. Human pathology,
Vol.34
(4),
pp. 362-368.
Thamboo, T.P.
Salto-Tellez, M.
Tan, K.B.
Nilsson, B.
Rajwanshi, A.
(2003). Cervical cytology: an audit in a Singapore teaching hospital. Singapore medical journal,
Vol.44
(5),
pp. 256-260.
show abstract
OBJECTIVES: To describe the cervical cytology diagnoses and cyto-histological correlation in the Department of Pathology, National University of Singapore in 1997 and to compare the data with international figures. METHODS: A database search of all cervical cytology cases diagnosed in the department in 1997 as well as follow-up biopsies was carried out. The data was then critically analysed. RESULTS: 10,207 cases were reviewed. 96% of the cases had a diagnosis of "negative". Under 1% of cases were labelled as "inadequate". "Atypia" was diagnosed in 1% and dysplasia and/or malignancy was diagnosed in 1%. These figures correlate well with international data. Of the dysplasia cases, 78% were followed by biopsy. Of the high-grade dysplasia cases that were biopsied, 97% of the biopsy diagnoses were within the acceptable concordance range with the cytology diagnoses and in only 3% was there a significant discrepancy. Of the cases diagnosed as atypia, 39% were subsequently biopsied at the same institution as the next procedure and only one showed high grade dysplasia. A total of six cases showed a significant discrepancy between the cervical cytology result and the subsequent biopsy diagnosis and these were reviewed to elucidate the reasons for the discrepancies. CONCLUSION: The cervical cytology service is of a high diagnostic standard. A subset of patients is probably being prematurely biopsied and may benefit from having a repeat smear instead. Specific clinical protocols regarding subsequent therapy following cytology results and closer cyto-histological correlation are two main areas where the cytology service can be improved..
Salto-Tellez, M.
Kong, S.L.
Leong, A.P.
Koay, E.S.
(2003). Intrinsic variability in the detection of micrometastases in lymph nodes for re-staging of colorectal cancer. European journal of cancer,
Vol.39
(9),
pp. 1234-1241.
Thamboo, T.P.
Tan, K.-.
Wang, S.-.
Salto-Tellez, M.
(2003). Extra-hepatic embolisation of Y-90 microspheres from selective internal radiation therapy (SIRT) of the liver. Pathology,
Vol.35
(4),
pp. 351-353.
Salto-Tellez, M.
Zhang, D.
Chiu, L.L.
Wang, S.C.
Nilsson, B.
Koay, E.S.
(2003). Immunocytochemistry versus molecular fingerprinting of metastases. Cytopathology,
Vol.14
(4),
pp. 186-190.
Zhang, D.H.
Salto-Tellez, M.
Chiu, L.L.
Shen, L.
Koay, E.S.
(2003). Tissue microarray study for classification of breast tumours. Annals of the academy of medicine, singapore,
Vol.32
(5 Suppl),
pp. S75-S76.
Zhang, D.-.
Salto-Tellez, M.
Chiu, L.-.
Shen, L.
Koay, E.S.
(2003). Tissue microarray study for classification of breast tumors. Life sciences,
Vol.73
(25),
pp. 3189-3199.
Salto-Tellez, M.
Shelat, S.G.
Benoit, B.
Rennert, H.
Carroll, M.
Leonard, D.G.
Nowell, P.
Bagg, A.
(2003). Multiplex RT-PCR for the Detection of Leukemia-Associated Translocations. The journal of molecular diagnostics,
Vol.5
(4),
pp. 231-236.
Chiu, L.L.
Koay, E.S.
Chan, N.H.
Salto-Tellez, M.
(2003). Sequence confirmation of theEWS-WT1 fusion gene transcript in the peritoneal effusion of a patient with desmoplastic small round cell tumor. Diagnostic cytopathology,
Vol.29
(6),
pp. 341-343.
Nga, M.E.
Wong, A.S.
Wee, A.
Salto-Tellez, M.
(2002). Lesson of the month. Histopathology,
Vol.40
(5),
pp. 480-481.
Yin, Y.
Lim, Y.K.
Salto‐Tellez, M.
Ng, S.C.
Lin, C.
Lim, S.
(2002). AFP
+
, ESC‐Derived Cells Engraft and Differentiate into Hepatocytes in Vivo. Stem cells,
Vol.20
(4),
pp. 338-346.
Tan, K.B.
Thamboo, T.P.
Wang, S.C.
Nilsson, B.
Rajwanshi, A.
Salto-Tellez, M.
(2002). Audit of transthoracic fine needle aspiration of the lung: cytological subclassification of bronchogenic carcinomas and diagnosis of tuberculosis. Singapore medical journal,
Vol.43
(11),
pp. 570-575.
show abstract
INTRODUCTION: Transthoracic fine-needle aspiration cytology (FNAC) is a useful tool for evaluating neoplastic and inflammatory lung nodules. In view of the relative paucity of published audit studies regionally, such a study was undertaken to assess the use of the technique in our centre. METHODS: One hundred and fourteen FNACs were performed during 1997-1999. Immediate assessment for specimen adequacy was done. Diagnoses were correlated with clinical-pathological information and selective blind review performed. RESULTS: Cytologically, 65.8% of cases were malignant, 1.8% were atypical, 25.4% were inflammatory/non-malignant and 7% were inadequate. Cytological-histological tumour diagnostic concordance was 94.4%. Diagnostic sensitivity for malignancy: 93.4%, specificity: 95.8%, accuracy: 94%. Eight inadequate/ benign cases (7%) proved to be malignant with clinical-pathological follow-up. Tuberculosis was confirmed (acid-fast bacilli detected) in six cases (5.3%) and suggested in a further 10 cases (8.8%). The cytological review showed 96% concordance with the original benign/malignant diagnoses. Pneumothorax rate was 18%. CONCLUSION: FNAC is an accurate and safe method for the evaluation of lung nodules and it enables subclassification of bronchogenic carcinomas in the vast majority of cases. It is also useful for the diagnosis of tuberculous pulmonary nodules. Immediate assessment optimises specimen adequacy; inadequate/non-malignant smears in particular, need clinical correlation, close follow-up and re-biopsy, if necessary..
Salto-Tellez, M.
Saunders, C.
Kocjan, G.
(2000). Correspondence. Cytopathology,
Vol.11
(3),
pp. 191-193.
Salto-Tellez, M.
Price, A.B.
(2000). What is the significance of muciphages in colorectal biopsies?. Histopathology,
Vol.36
(6),
pp. 556-559.
Salto-Tellez, M.
Kocjan, G.
(2000). Lymphocytic mastopathy in a patient with previous breast cancer diagnosed by fine-needle aspirate. Diagnostic cytopathology,
Vol.23
(2),
pp. 141-142.
Lee, S.B.
Kundu, S.
Salto-Tellez, M.
(2000). Plasma cell polyp of the vocal fold. The journal of laryngology & otology,
Vol.114
(8),
pp. 646-648.
show abstract
Plasma cell polyps of the vocal fold (plasma cell granulomas) are rare inflammatory polyps of the larynx. They should be included in the clinical and histological differential diagnosis of laryngeal polyps. Histologically they are polyclonal aggregates of plasma cells. It is essential to distinguish them from monoclonal, neoplastic plasma cell proliferations. The treatment of choice is surgical resection, although radiotherapy, laser ablation, antibiotics and steroids have been used successfully. We present a case of plasma cell granuloma presenting as a vocal fold polyp, treated surgically..
Friedman,
Shah,
Salto-Tellez,
(1999). Ljubljana classification of epithelial hyperplastic laryngeal lesions. Histopathology,
Vol.35
(6),
pp. 579-579.
Molony, N.C.
Salto-Tellez, M.
Grant, W.E.
(1998). KTP laser assisted excision of glomus tympanicum. The journal of laryngology & otology,
Vol.112
(10),
pp. 956-958.
show abstract
AbstractA 39-year-old female with a two-year history of mild hearing loss and discomfort on air flight descent was found to have a pulsatile mass behind an intact tympanic membrane. A suspected diagnosis of glomus tympanicum was confirmed by computed tomography (CT) scan imaging. The lesion filled the mesotympanum and hypotympanum but the jugular bony plate was intact, confirming the tympanic site of the lesion. This very vascular tumour was exposed by a tympanomeatal flap and the KTP laser used to shrink and coagulate the tumour progressively with minimal haemorrhage and blood loss. Complete excision of the lesion was achieved without the need for bony removal, and with minimal blood loss. The use of the KTP laser to coagulate this vascular lesion allowed safe removal of the tumour and avoided the need for extended facial recess or hypotympanotomy surgery..
Carey, F.A.
Gray, E.
OMahony, M.
Craig, S.R.
SaltoTellez, M.
Lamb, D.
(1996). A comparison of flow and image DNA cytometry in prediction of patient prognosis in surgically resected small cell lung cancer. Analytical cellular pathology,
Vol.12
(3),
pp. 137-7.
Carey, F.A.
Gray, E.
Salto-Tellez, M.
Kelly, C.
Dye, R.
Duvall, E.
Lamb, D.
(1995). Interobserver variation in cell selection for DNA image cytometry. Journal of clinical pathology,
Vol.48
(7),
pp. 616-619.
Sampedro, A.
Belderrain, P.
Salto-Téllez, M.
Vijande, M.
Cueto, A.
(1995). Trans-European medical education: experience of the Faculty of Medicine of Oviedo. Medical education,
Vol.29
(3),
pp. 235-241.
Li, G.
Bankhead, P.
Dunne, P.D.
O’Reilly, P.G.
James, J.A.
Salto-Tellez, M.
Hamilton, P.W.
McArt, D.G.
Embracing an integromic approach to tissue biomarker research in cancer: Perspectives and lessons learned. Briefings in bioinformatics,
,
pp. bbw044-bbw044.
Salto-Tellez, M.
More Than a Decade of Molecular Diagnostic Cytopathology Leading Diagnostic and Therapeutic Decision-Making. Archives of pathology & laboratory medicine,
.
Alderdice, M.
Craig, S.G.
Humphries, M.P.
Gilmore, A.
Johnston, N.
Bingham, V.
Coyle, V.
Senevirathne, S.
Longley, D.B.
Loughrey, M.B.
McQuaid, S.
James, J.A.
Salto-Tellez, M.
Lawler, M.
McArt, D.G.
Evolutionary genetic algorithm identifies IL2RB as a potential predictive biomarker for immune-checkpoint therapy in colorectal cancer. Nar genomics and bioinformatics,
Vol.3
(2),
pp. lqab016-?.
show abstract
Identifying robust predictive biomarkers to stratify colorectal cancer (CRC) patients based on their response to immune-checkpoint therapy is an area of unmet clinical need. Our evolutionary algorithm Atlas Correlation Explorer (ACE) represents a novel approach for mining The Cancer Genome Atlas (TCGA) data for clinically relevant associations. We deployed ACE to identify candidate predictive biomarkers of response to immune-checkpoint therapy in CRC. We interrogated the colon adenocarcinoma (COAD) gene expression data across nine immune-checkpoints ( PDL1, PDCD1, CTLA4, LAG3, TIM3, TIGIT, ICOS, IDO1 and BTLA ). IL2RB was identified as the most common gene associated with immune-checkpoint genes in CRC. Using human/murine single-cell RNA-seq data, we demonstrated that IL2RB was expressed predominantly in a subset of T-cells associated with increased immune-checkpoint expression ( P < 0.0001). Confirmatory IL2RB immunohistochemistry (IHC) analysis in a large MSI-H colon cancer tissue microarray (TMA; n = 115) revealed sensitive, specific staining of a subset of lymphocytes and a strong association with FOXP3+ lymphocytes ( P < 0.0001). IL2RB mRNA positively correlated with three previously-published gene signatures of response to immune-checkpoint therapy ( P < 0.0001). Our evolutionary algorithm has identified IL2RB to be extensively linked to immune-checkpoints in CRC; its expression should be investigated for clinical utility as a potential predictive biomarker for CRC patients receiving immune-checkpoint blockade..
McCourt, C.M.
McArt, D.G.
Mills, K.
Catherwood, M.A.
Maxwell, P.
Waugh, D.J.
Hamilton, P.
O'Sullivan, J.M.
Salto-Tellez, M.
Validation of Next Generation Sequencing Technologies in Comparison to Current Diagnostic Gold Standards for BRAF, EGFR and KRAS Mutational Analysis. Plos one,
Vol.8
(7),
pp. e69604-e69604.
McArt, D.G.
Dunne, P.D.
Blayney, J.K.
Salto-Tellez, M.
Van Schaeybroeck, S.
Hamilton, P.W.
Zhang, S.-.
Connectivity Mapping for Candidate Therapeutics Identification Using Next Generation Sequencing RNA-Seq Data. Plos one,
Vol.8
(6),
pp. e66902-e66902.
Zhuo, J.
Tan, E.H.
Yan, B.
Tochhawng, L.
Jayapal, M.
Koh, S.
Tay, H.K.
Maciver, S.K.
Hooi, S.C.
Salto-Tellez, M.
Kumar, A.P.
Goh, Y.C.
Lim, Y.C.
Yap, C.T.
Gelsolin Induces Colorectal Tumor Cell Invasion via Modulation of the Urokinase-Type Plasminogen Activator Cascade. Plos one,
Vol.7
(8),
pp. e43594-e43594.
Lian, Q.
Yeo, K.
Que, J.
Tan, E.
Yu, F.
Yin, Y.
Salto-Tellez, M.
Oakley, R.M.
Lim, S.-.
Establishing Clonal Cell Lines with Endothelial-Like Potential from CD9hi, SSEA-1− Cells in Embryonic Stem Cell-Derived Embryoid Bodies. Plos one,
Vol.1
(1),
pp. e6-e6.
Lee, S.-.
Guo, J.-.
Lim, R.
Soo, R.
Koay, E.
Salto-Tellez, M.
Leong, A.
Goh, B.-.
Clinical and molecular characteristics of hereditary non-polyposis colorectal cancer families in Southeast Asia. Clinical genetics,
Vol.68
(2),
pp. 137-145.
Stupnikov, A.
McInerney, C.E.
Savage, K.I.
McIntosh, S.A.
Emmert-Streib, F.
Kennedy, R.
Salto-Tellez, M.
Prise, K.M.
McArt, D.G.
Robustness of differential gene expression analysis of RNA-seq. Computational and structural biotechnology journal,
Vol.19,
pp. 3470-3481.
show abstract
RNA-sequencing (RNA-seq) is a relatively new technology that lacks standardisation. RNA-seq can be used for Differential Gene Expression (DGE) analysis, however, no consensus exists as to which methodology ensures robust and reproducible results. Indeed, it is broadly acknowledged that DGE methods provide disparate results. Despite obstacles, RNA-seq assays are in advanced development for clinical use but further optimisation will be needed. Herein, five DGE models (DESeq2, voom + limma, edgeR, EBSeq, NOISeq) for gene-level detection were investigated for robustness to sequencing alterations using a controlled analysis of fixed count matrices. Two breast cancer datasets were analysed with full and reduced sample sizes. DGE model robustness was compared between filtering regimes and for different expression levels (high, low) using unbiased metrics. Test sensitivity estimated as relative False Discovery Rate (FDR), concordance between model outputs and comparisons of a 'population' of slopes of relative FDRs across different library sizes, generated using linear regressions, were examined. Patterns of relative DGE model robustness proved dataset-agnostic and reliable for drawing conclusions when sample sizes were sufficiently large. Overall, the non-parametric method NOISeq was the most robust followed by edgeR, voom, EBSeq and DESeq2. Our rigorous appraisal provides information for method selection for molecular diagnostics. Metrics may prove useful towards improving the standardisation of RNA-seq for precision medicine..
Craig, S.G.
Mende, S.
Humphries, M.P.
Bingham, V.
Viratham Pulsawatdi, A.
Loughrey, M.B.
Coleman, H.G.
McQuaid, S.
Wilson, R.H.
Van Schaeybroeck, S.
James, J.A.
Salto-Tellez, M.
Orthogonal MET analysis in a population-representative stage II-III colon cancer cohort: prognostic and potential therapeutic implications. Molecular oncology,
Vol.15
(12),
pp. 3317-3328.
show abstract
Clinical trials for MET inhibitors have demonstrated limited success for their use in colon cancer (CC). However, clinical efficacy may be obscured by a lack of standardisation in MET assessment for patient stratification. In this study, we aimed to determine the molecular context in which MET is deregulated in CC using a series of genomic and proteomic tests to define MET expression and identify patient subgroups that should be considered in future studies with MET-targeted agents. To this aim, orthogonal expression analysis of MET was conducted in a population-representative cohort of stage II/III CC patients (n = 240) diagnosed in Northern Ireland from 2004 to 2008. Targeted sequencing was used to determine the relative incidence of MET R970C and MET T992I mutations within the cohort. MET amplification was assessed using dual-colour dual-hapten brightfield in situ hybridisation (DDISH). Expression of transcribed MET and c-MET protein within the cohort was assessed using digital image analysis on MET RNA in situ hybridisation (ISH) and c-MET immunohistochemistry (IHC) stained slides. We found that less than 2% of the stage II/III CC patient population assessed demonstrated a genetic MET aberration. Determination of a high MET RNA-ISH/low c-MET IHC protein subgroup was found to be associated with poor 5-year cancer-specific outcomes compared to patients with concordant MET RNA-ISH and c-MET IHC protein expression (HR 2.12 [95%CI: 1.27-3.68]). The MET RNA-ISH/c-MET IHC protein biomarker paradigm identified in this study demonstrates that subtyping of MET expression may be required to identify MET-addicted malignancies in CC patients who will truly benefit from MET inhibition..
Alnabulsi, A.
Wang, T.
Pang, W.
Ionescu, M.
Craig, S.G.
Humphries, M.P.
McCombe, K.
Salto Tellez, M.
Alnabulsi, A.
Murray, G.I.
Identification of a prognostic signature in colorectal cancer using combinatorial algorithm-driven analysis. The journal of pathology. clinical research,
Vol.8
(3),
pp. 245-256.
show abstract
Colorectal carcinoma is one of the most common types of malignancy and a leading cause of cancer-related death. Although clinicopathological parameters provide invaluable prognostic information, the accuracy of prognosis can be improved by using molecular biomarker signatures. Using a large dataset of immunohistochemistry-based biomarkers (n = 66), this study has developed an effective methodology for identifying optimal biomarker combinations as a prognostic tool. Biomarkers were screened and assigned to related subsets before being analysed using an iterative algorithm customised for evaluating combinatorial interactions between biomarkers based on their combined statistical power. A signature consisting of six biomarkers was identified as the best combination in terms of prognostic power. The combination of biomarkers (STAT1, UCP1, p-cofilin, LIMK2, FOXP3, and ICOS) was significantly associated with overall survival when computed as a linear variable (χ2 = 53.183, p < 0.001) and as a cluster variable (χ2 = 67.625, p < 0.001). This signature was also significantly independent of age, extramural vascular invasion, tumour stage, and lymph node metastasis (Wald = 32.898, p < 0.001). Assessment of the results in an external cohort showed that the signature was significantly associated with prognosis (χ2 = 14.217, p = 0.007). This study developed and optimised an innovative discovery approach which could be adapted for the discovery of biomarkers and molecular interactions in a range of biological and clinical studies. Furthermore, this study identified a protein signature that can be utilised as an independent prognostic method and for potential therapeutic interventions..
van Asperen, C.J.
Hofland, N.
Moghadasi, S.
Wouts, J.
Wijnen, J.G.
Vreeswijk, M.P.
Selected Abstracts Submitted to the Fourth International Symposium on Hereditary Breast and Ovarian Cancer. Current oncology,
Vol.19
(2),
pp. 84-111.
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Background: Nearly 15% of DNA tests for BRCA1/2 results in the identification of an unclassified variant (UV). In DNA diagnostic laboratories in The Netherlands, a 4-group classification system (class I to IV) is in use (Bell et al.). Aim of this study was to investigate whether the UVs in different classes showed a significant difference in their in silico characteristics and would justify current differences in protocols for counselling with respect to communication to the counselees. Methods: Missense UVs in BRCA1/2 identified between 2002 and 2010 (n = 88) were analyzed. In silico analysis of UVs was performed using SIFT– analysis Grantham score and AGVGD for the predicted severity of amino acid substitutions. Each UV was classified to one of the four classes. Results: More than half of the UVs (n = 50) were predicted to be tolerated using SIFT-analysis. Accordingly, all these variants are scored as neutral (C0) by AGVGD. Of the remaining 38 UVs not tolerated using SIFT-analysis, 19 were scored as C0 (neutral), 8 were scored C15–C25 (intermediate) and 11 were scored C35 or higher (likely to be pathogenic). Although class III UVs more frequently show in silico parameter outcomes that are suspicious for a pathogenic effect, the observed differences are not absolute. Seven UVs classified in class II had similar in silico profiles with 7 UVs in class III. Conclusion: This study showed that, in general, in silico analysis is consistently applied and proved to be able to discriminate between the different classes of UVs. However, additional analyses will be required to classify the UVs with more accuracy. In order to reduce psychological distress in families in which a UV is identified, we propose that communication of a UV should not primarily depend on its class, but also on the possibility to perform additional research in the family..