Publications by authors named "Tony K H Lim"

19 Publications

  • Page 1 of 1

Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma.

Nat Commun 2021 01 11;12(1):227. Epub 2021 Jan 11.

Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore.

The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic immune-ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune-ITH is associated with tumour transcriptomic-ITH, mutational burden and distinct immune microenvironments. Tumours with low immune-ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.
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http://dx.doi.org/10.1038/s41467-020-20171-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801667PMC
January 2021

Neuroblastoma patient-derived cultures are enriched for a mesenchymal gene signature and reflect individual drug response.

Cancer Sci 2020 Oct 28;111(10):3780-3792. Epub 2020 Aug 28.

VIVA-KKH Paediatric Brain and Solid Tumour Programme, KK Women's and Children's Hospital, Singapore, Singapore.

Ex vivo evaluation of personalized models can facilitate individualized treatment selection for patients, and advance the discovery of novel therapeutic options. However, for embryonal malignancies, representative primary cultures have been difficult to establish. We developed patient-derived cell cultures (PDCs) from chemo-naïve and post-treatment neuroblastoma tumors in a consistent and efficient manner, and characterized their in vitro growth dynamics, histomorphology, gene expression, and functional chemo-response. From 34 neuroblastoma tumors, 22 engrafted in vitro to generate 31 individual PDC lines, with higher engraftment seen with metastatic tumors. PDCs displayed characteristic immunohistochemical staining patterns of PHOX2B, TH, and GD2 synthase. Concordance of MYCN amplification, 1p and 11q deletion between PDCs and patient tumors was 83.3%, 72.7%, and 80.0% respectively. PDCs displayed a predominantly mesenchymal-type gene expression signature and showed upregulation of pro-angiogenic factors that were similarly enriched in culture medium and paired patient serum samples. When tested with standard-of-care cytotoxics at human C -equivalent concentrations, MYCN-amplified and non-MYCN-amplified PDCs showed a differential response to cyclophosphamide and topotecan, which mirrored the corresponding patients' responses, and correlated with gene signatures of chemosensitivity. In this translational proof-of-concept study, early-phase neuroblastoma PDCs enriched for the mesenchymal cell subpopulation recapitulated the individual molecular and phenotypic profile of patient tumors, and highlighted their potential as a platform for individualized ex vivo drug-response testing.
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http://dx.doi.org/10.1111/cas.14610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540996PMC
October 2020

Network of clinically-relevant lncRNAs-mRNAs associated with prognosis of hepatocellular carcinoma patients.

Sci Rep 2020 07 7;10(1):11124. Epub 2020 Jul 7.

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Long non-coding RNAs (lncRNAs) are often aberrantly expressed in Hepatocellular Carcinoma (HCC). We hypothesize that lncRNAs modulate HCC prognoses through differential deregulation of key lncRNAs affecting important gene network in key cancer pathways associated with pertinent clinical phenotype. Here, we present a novel approach integrating lncRNA-mRNA expression profiles with clinical characteristics to identify lncRNA signatures in clinically-relevant co-expression lncRNA-mRNA networks residing in pertinent cancer pathways. Notably one network, associated with poorer prognosis, comprises five up-regulated lncRNAs significantly correlated (|Pearson Correlation Coefficient|≥ 0.9) with 91 up-regulated genes in the cell-cycle and Rho-GTPase pathways. All 5 lncRNAs and 85/91 (93.4%) of the correlated genes were significantly associated with higher tumor-grade while 3/5 lncRNAs were also associated with no tumor capsule. Interestingly, 2/5 lncRNAs that are correlated with numerous genes in this oncogenic network were experimentally shown to up-regulate genes involved in cell-cycle and transcriptional regulation. Another network comprising 4 down-regulated lncRNAs and 8 down-regulated metallothionein-family genes are significantly associated with tumor invasion. The identification of these key lncRNAs signatures that deregulate important network of genes in key cancer pathways associated with pertinent clinical phenotype may facilitate the design of novel therapeutic strategies targeting these 'master' regulators for better patient outcome.
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http://dx.doi.org/10.1038/s41598-020-67742-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341759PMC
July 2020

High-Dimensional Characterization of the Systemic Immune Landscape Informs on Synergism Between Radiation Therapy and Immune Checkpoint Blockade.

Int J Radiat Oncol Biol Phys 2020 09 13;108(1):70-80. Epub 2020 Jun 13.

Division of Radiation Oncology, National Cancer Centre Singapore, Singapore; Oncology Academic Programme, Duke-NUS Medical School, Singapore; Division of Medical Sciences, National Cancer Centre Singapore, Singapore. Electronic address:

Purpose: Improved antitumor responses have been observed in patients after combination radiation therapy (RT) and immune checkpoint blockade (ICB). Whether these clinical responses are linked to the host systemic immune system has not been elucidated.

Methods And Materials: In this single-institution prospective observational study, peripheral blood was longitudinally collected from 10 patients with metastatic disease who had responded to anti-PD-1/anti-PD-L1 ICB and received RT (8-50 Gy in 1-5 fractions) upon disease progression at the following timepoints: baseline (pre-RT), 1 to 2 weeks post-RT, and post-ICB (cycle 1) on reintroduction post-RT. To thoroughly characterize the interaction between combined RT-ICB and the host immune system, we performed high-dimensional, mass cytometry-based immunophenotyping of circulating lymphocytes using a 40-marker panel addressing lineage, differentiation, activation, trafficking, cytotoxicity, and costimulatory and inhibitory functions. Phenotypic expression of circulating lymphocytes was compared across patients and time points and correlated with post-RT tumor responses.

Results: Foremost, we demonstrated excellent posttreatment clinical responses, including 4 local responses with >50% reduction in radiated tumor size, 1 out-of-field response, and 4 patients who resumed ICB for >1 year. Baseline and post-RT immune states were highly heterogeneous among patients. Despite this interindividual heterogeneity in baseline immune states, we observed a systemic immune reaction to RT-ICB common across patients, histology, and radiation sites; a subset of pre-existing Ki-67+ CD8+ T cells were increased post-RT and further expanded upon reintroduction of ICB post-RT (2.3-fold increase, P = .02). Importantly, RT did not alter the phenotypic profile of these Ki-67+ CD8+ T cells, which was characterized by a distinct activated and differentiated effector phenotype.

Conclusions: Collectively, these findings point toward a sustained reinvigoration of host antitumor immunity after RT-ICB and suggest an expansion in activated Ki-67+ CD8+ T cells as a possible demonstration of this synergy, thereby providing new insights that may support the development of optimal sequencing strategies.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.007DOI Listing
September 2020

Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome-Wide Association Study in Multiple Cohorts.

Adv Sci (Weinh) 2020 May 20;7(10):1903727. Epub 2020 Mar 20.

Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Guangzhou 510060 P. R. China.

Germline polymorphisms are linked with differential survival outcomes in cancers but are not well studied in nasopharyngeal carcinoma (NPC). Here, a two-phase association study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China. Exome-wide genotypes at 246 173 single nucleotide polymorphisms (SNPs) are determined, followed by survival analysis for each SNP under Cox proportional hazard regression model. Candidate SNP is replicated in another two independent cohorts from Southern China and Singapore. Meta-analysis of all samples ( = 5553) confirms that the presence of rs1131636-T, located in the 3'-UTR of , confers an inferior overall survival (HR = 1.33, 95% CI = 1.20-1.47, = 6.31 × 10). Bioinformatics and biological assays show that rs1131636 has regulatory effects on upstream . Functional studies further demonstrate that RPA1 promotes the growth, invasion, migration, and radioresistance of NPC cells. Additionally, miR-1253 is identified as a suppressor for RPA1 expression, likely through regulation of its binding affinity to rs1131636 locus. Collectively, these findings provide a promising biomarker aiding in stratifying patients with poor survival, as well as a potential drug target for NPC.
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http://dx.doi.org/10.1002/advs.201903727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237860PMC
May 2020

Circulating microRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma.

Sci Rep 2019 07 18;9(1):10464. Epub 2019 Jul 18.

Division of Cellular & Molecular Research, National Cancer Centre Singapore, Singapore, Singapore.

Hepatocellular carcinoma (HCC) is the fifth most common cancer with high mortality, due to late diagnosis and limited treatment options. Blood miRNAs, which circulate in a highly stable, cell-free form, show promise as novel potential biomarkers for early detection of HCC. Whole miRNome profiling was performed to identify deregulated miRNAs between HCC and normal healthy (NH) volunteers. These deregulated miRNAs were validated in an independent cohort of HCC, NH and chronic Hepatitis B (CHB) volunteers and finally in a 3 cohort comprising NH, CHB, cirrhotic and HCC volunteers to evaluate miRNA changes during disease progression. The associations between circulating miRNAs and liver-damage markers, clinicopathological characteristics and survival outcomes were analysed to identify prognostic markers. Twelve miRNAs are differentially expressed between HCC and NH individuals in all three cohorts. Five upregulated miRNAs (miR-122-5p, miR-125b-5p, miR-885-5p, miR-100-5p and miR-148a-3p) in CHB, cirrhosis and HCC patients are potential biomarkers for CHB infection, while miR-34a-5p can be a biomarker for cirrhosis. Notably, four miRNAs (miR-1972, miR-193a-5p, miR-214-3p and miR-365a-3p) can distinguish HCC from other non-HCC individuals. Six miRNAs are potential prognostic markers for overall survival.
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http://dx.doi.org/10.1038/s41598-019-46872-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639394PMC
July 2019

Expanded molecular interrogation for potential actionable targets in non-squamous non-small cell lung cancer.

Ann Transl Med 2017 Sep;5(18):372

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

The advent of targeted therapies has established new standards of care for defined molecular subsets of non-small cell lung cancer (NSCLC). Not only has this led to significant changes in the routine clinical management of lung cancer e.g., multiplexed genomic testing, but it has provided important principles and benchmarks for determining "actionability". At present, the clinical paradigms are most evolved for EGFR mutations and ALK rearrangements, where multiple randomized phase III trials have determined optimal treatment strategies in both treatment naïve and resistant settings. However, this may not always be feasible with low prevalence alterations e.g., ROS1 and BRAF mutations. Another emerging observation is that not all targets are equally "actionable", necessitating a rigorous preclinical, clinical and translational framework to prosecute new targets and drug candidates. In this review, we will cover the role of targeted therapies for NSCLC harbouring BRAF, MET, HER2 and RET alterations, all of which have shown promise in non-squamous non-small cell lung cancer (ns-NSCLC). We further review some early epigenetic targets in NSCLC, an area of emerging interest. With increased molecular segmentation of lung cancer, we discuss the upcoming challenges in drug development and implementation of precision oncology approaches, especially in light of the complex and rapidly evolving therapeutic landscape.
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http://dx.doi.org/10.21037/atm.2017.08.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635263PMC
September 2017

Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma.

Nat Med 2017 Oct 18;23(10):1167-1175. Epub 2017 Sep 18.

Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore.

Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR, c.2361G>A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes. Remarkably, single-copy G>A nucleotide editing in isogenic models conferred a 70-fold increase in sensitivity due to decreased stability of the EGFR-AS1 long noncoding RNA (lncRNA). In the appropriate context, sensitivity could be recapitulated through EGFR-AS1 knockdown in vitro and in vivo, whereas overexpression was sufficient to induce resistance to TKIs. Reduced EGFR-AS1 levels shifted splicing toward EGFR isoform D, leading to ligand-mediated pathway activation. In co-clinical trials involving patients and patient-derived xenograft (PDX) models, tumor shrinkage was most pronounced in the context of the A/A genotype for EGFR-Q787Q, low expression of EGFR-AS1 and high expression of EGFR isoform D. Our study reveals how a 'silent' mutation influences the levels of a lncRNA, resulting in noncanonical EGFR addiction, and delineates a new predictive biomarker suite for response to EGFR TKIs.
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http://dx.doi.org/10.1038/nm.4401DOI Listing
October 2017

A formalin-fixed paraffin-embedded (FFPE)-based prognostic signature to predict metastasis in clinically low risk stage I/II microsatellite stable colorectal cancer.

Cancer Lett 2017 09 15;403:13-20. Epub 2017 Jun 15.

Department of Colorectal Surgery, Singapore General Hospital, 169856, Singapore; SingHealth Duke-NUS Surgery Academic Clinical Programme, Office of Clinical, Academic and Faculty Affairs, Duke-NUS Medical School, National University of Singapore, Singapore; Saw Swee Hock School of Public Health, National University of Singapore, Singapore. Electronic address:

Approximately 20% early-stage (I/II) colorectal cancer (CRC) patients develop metastases despite curative surgery. We aim to develop a formalin-fixed and paraffin-embedded (FFPE)-based predictor of metastases in early-stage, clinically-defined low risk, microsatellite-stable (MSS) CRC patients. We considered genome-wide mRNA and miRNA expression and mutation status of 20 genes assayed in 150 fresh-frozen tumours with known metastasis status. We selected 193 genes for further analysis using NanoString nCounter arrays on corresponding FFPE tumours. Neither mutation status nor miRNA expression improved the estimated prediction. The final predictor, ColoMet19, based on the top 19 genes' mRNA levels trained by Random Forest machine-learning strategy, had an estimated positive-predictive-value (PPV) of 0.66. We tested ColoMet19 on an independent test-set of 131 tumours and obtained a population-adjusted PPV of 0.67 indicating that early-stage CRC patients who tested positive have a 67% risk of developing metastases, substantially higher than the metastasis risk of 40% for node-positive (Stage III) patients who are generally treated with chemotherapy. Predicted-positive patients also had poorer metastasis-free survival (hazard ratios [HR] = 1.92, design-set; HR = 2.05, test-set). Thus, early-stage CRC patients who test positive may be considered for adjuvant therapy after surgery.
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http://dx.doi.org/10.1016/j.canlet.2017.05.031DOI Listing
September 2017

An interesting observation from our experiences with circulating tumour cells.

Lung Cancer 2017 06 28;108:247-249. Epub 2017 Feb 28.

Singapore General Hospital, Department of Anatomical Pathology, Academia, Diagnostics Tower Level 10, 20 College Road, 169856, Singapore.

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http://dx.doi.org/10.1016/j.lungcan.2017.02.015DOI Listing
June 2017

Validation and comparison between current prognostication systems for pancreatic neuroendocrine neoplasms: A single-institution experience with 176 patients.

Surgery 2017 05 19;161(5):1235-1245. Epub 2017 Jan 19.

Duke-National University of Singapore Medical School, Singapore, Republic of Singapore; Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore.

Background: This article aims to validate and compare the performance of 6 prognostication systems-the World Health Organization 2010 grading criteria, the European Neuroendocrine Tumour Society and the American Joint Committee for Cancer staging systems, the Memorial Sloan Kettering Cancer Center staging and grading systems, as well as the Bilimoria criteria in a cohort of patients with pancreatic neuroendocrine neoplasms at a single institution.

Methods: A retrospective review of 176 patients with histologically proven pancreatic neuroendocrine neoplasm was performed. The prognostic ability of the various prognostication systems for pancreatic neuroendocrine neoplasm was assessed by analyzing the homogeneity, discriminatory ability, monotonicity of gradient, and Akaike information criteria.

Results: The 5-year overall survival for the 176 patients was 69% and 5-year recurrence-free survival in 119 patients who underwent curative resection was 78%. Comparison between the 6 prognostication systems demonstrated that the World Health Organization 2010 system had the lowest Akaike information criteria score and was hence the best prognostication system in predicting overall survival and recurrence-free survival rates in our cohort of patients. The European Neuroendocrine Tumour Society was superior to the American Joint Committee for Cancer in prognosticating overall survival rates for pancreatic neuroendocrine neoplasms, as there was a statistically significant difference in overall survival across the different stages when stratified by the European Neuroendocrine Tumour Society, while the use of the American Joint Committee for Cancer was limited to distinguishing between patients in stages I and II versus stages III and IV only.

Conclusion: All 6 prognostication systems were useful in the prognostication of pancreatic neuroendocrine neoplasm. The World Health Organization 2010 grading system was the best prognostication system in predicting both overall survival in our entire cohort of patients and recurrence-free survival in the subset of patients who underwent curative resection.
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http://dx.doi.org/10.1016/j.surg.2016.12.001DOI Listing
May 2017

Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma.

BMC Cancer 2015 Oct 31;15:828. Epub 2015 Oct 31.

Department of Surgical Oncology, National Cancer Centre Singapore, Singapore, 169610, Singapore.

Background: Despite advances in therapeutics, outcomes for hepatocellular carcinoma (HCC) remain poor and there is an urgent need for efficacious systemic therapy. Unfortunately, drugs that are successful in preclinical studies often fail in the clinical setting, and we hypothesize that this is due to functional differences between primary tumors and commonly used preclinical models. In this study, we attempt to answer this question by comparing tumor morphology and gene expression profiles between primary tumors, xenografts and HCC cell lines.

Methods: Hep G2 cell lines and tumor cells from patient tumor explants were subcutaneously (ectopically) injected into the flank and orthotopically into liver parenchyma of Mus Musculus SCID mice. The mice were euthanized after two weeks. RNA was extracted from the tumors, and gene expression profiling was performed using the Gene Chip Human Genome U133 Plus 2.0. Principal component analyses (PCA) and construction of dendrograms were conducted using Partek genomics suite.

Results: PCA showed that the commonly used HepG2 cell line model and its xenograft counterparts were vastly different from all fresh primary tumors. Expression profiles of primary tumors were also significantly divergent from their counterpart patient-derived xenograft (PDX) models, regardless of the site of implantation. Xenografts from the same primary tumors were more likely to cluster together regardless of site of implantation, although heat maps showed distinct differences in gene expression profiles between orthotopic and ectopic models.

Conclusions: The data presented here challenges the utility of routinely used preclinical models. Models using HepG2 were vastly different from primary tumors and PDXs, suggesting that this is not clinically representative. Surprisingly, site of implantation (orthotopic versus ectopic) resulted in limited impact on gene expression profiles, and in both scenarios xenografts differed significantly from the original primary tumors, challenging the long-held notion that orthotopic PDX model is the gold standard preclinical model for HCC.
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http://dx.doi.org/10.1186/s12885-015-1814-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628260PMC
October 2015

Evaluation of the Fukuoka Consensus Guidelines for intraductal papillary mucinous neoplasms of the pancreas: Results from a systematic review of 1,382 surgically resected patients.

Surgery 2015 Nov 29;158(5):1192-202. Epub 2015 May 29.

Department of Hepatopancreatobiliary and Transplantation Surgery, Singapore General Hospital, Singapore.

Background: International consensus guidelines to guide management of intraductal papillary mucinous neoplasms (IPMN) were revised in Fukuoka and published in 2012. However, despite widespread acceptance of the Fukuoka Consensus Guidelines (FCG), the utility of these guidelines have not been well-validated. This systematic review was performed to evaluate the clinical utility of the FCG.

Design: A computerized search of the PubMed and Scopus databases was performed to identify all studies evaluating the utility of the FCG in surgically resected IPMN. IPMN were stratified according to the FCG as high risk (HR), worrisome risk (WR), and low risk (LR). HR and WR IPMN were termed FCG+ve and LR IPMN were termed FCG-ve.

Results: Seven studies analyzing 1,382 patients were included. There were 402 malignant neoplasms (29%), including 242 invasive IPMNs. There were 1,000 IPMN classified as FCG+ve. The FCG+ve group had a positive predictive value (PPV) ranging from 27 to 62% and the FCG-ve group had negative predictive value ranging from 82 to 100%. Pooled analysis demonstrated that there was 362 of 1,000 (36%) malignant FCG+ve IPMN and 342 of 382 (90%) benign FCG-ve IPMN. PPV of the HR group and the WR groups alone were 104 of 158 (66%) and 75 of 261 (29%), respectively. Forty of 382 (11%), including 22 (6%) invasive FCG-ve IPMN, were malignant. Twenty-six malignant including 18 invasive FCG-ve IPMN were reported from a single study. When the results from this study were excluded, there were only 14 of 241 malignant neoplasms (6%), including 4 of 241 (2%) invasive FCG-ve IPMN in the remaining 6 studies.

Conclusion: The FCG+ve criteria had a similarly low PPV compared with the 2006 consensus criteria. Stratification of IPMN into HR and WR groups resulted in a higher PPV in the HR group. Some malignant and even invasive IPMN may be missed by the FCG criteria.
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http://dx.doi.org/10.1016/j.surg.2015.03.021DOI Listing
November 2015

Systematic review and meta-analysis of the spectrum and outcomes of different histologic subtypes of noninvasive and invasive intraductal papillary mucinous neoplasms.

Surgery 2015 Mar 3;157(3):496-509. Epub 2015 Feb 3.

Department of Hepatopancreatobiliary and Transplantation Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore. Electronic address:

Background: Our aim was to review the available evidence to determine the clinical importance of the histologic subtypes of noninvasive and invasive intraductal papillary mucinous neoplasms (IPMNs) on disease characteristics and overall survival.

Methods: We reviewed systematically 14 comparative studies that reported clinicopathologic characteristics and survival of 1,617 patients with IPMN (900 noninvasive and 717 invasive).

Results: The pancreatobiliary subtype was associated with the greatest likelihood of tumor invasion (67.9%; odds ratio [OR], 2.87; 95% CI, 1.90-4.35), harboring an associated mural nodule (56.6%; OR, 2.92; 95% CI, 1.21-7.04), demonstrating tumor recurrence (46.3%; OR, 3.28; 95% CI, 1.41-7.66) and transformation to tubular adenocarcinoma (81.8%; OR, 92.96; 95% CI, 20.76-416.28) among all subtypes. The gastric subtype was associated with the least likelihood of tumor invasion (10.2%; OR, 0.18; 95% CI, 0.13-0.26), association with main duct IPMN (19.2%; OR, 0.12; 95% CI, 0.06-0.26), and tumor recurrence (9.4%; OR, 0.47; 95% CI, 0.26-0.83) among all subtypes. The intestinal subtype had the greatest likelihood of progressing to colloid carcinoma among all subtypes. Tubular adenocarcinoma was associated with an increased risk of vascular invasion (32.9%; OR, 4.86; 95% CI, 1.96-12.01), perineural invasion (54.5%; OR, 2.30; 95% CI, 1.22-4.34), nodal metastasis (52.4%; OR, 3.31; 95% CI, 1.79-6.14), and a positive margin status (17.3%; OR, 8.45; 95% CI, 1.52-46.83). Tubular adenocarcinoma (hazard ratio [HR], 1.90; 95% CI, 1.36-2.67) had a poorer 5-year overall survival compared with colloid carcinoma and was similar to the survival observed in pancreatic ductal adenocarcinoma (HR, 2.00; 95% CI, 1.59-2.52).

Conclusion: The prognosis of IPMN depends on its pathologic subtype. Subtype identification should be considered an essential component in future guidelines for the management of IPMN.
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http://dx.doi.org/10.1016/j.surg.2014.08.098DOI Listing
March 2015

An eleven gene molecular signature for extra-capsular spread in oral squamous cell carcinoma serves as a prognosticator of outcome in patients without nodal metastases.

Oral Oncol 2015 Apr 2;51(4):355-62. Epub 2015 Jan 2.

Department of Surgical Oncology, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore; Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore; Cancer Therapeutics Research Laboratory, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore. Electronic address:

Objectives: Extracapsular spread (ECS) is an important prognostic factor for oral squamous cell carcinoma (OSCC) and is used to guide management. In this study, we aimed to identify an expression profile signature for ECS in node-positive OSCC using data derived from two different sources: a cohort of OSCC patients from our institution (National Cancer Centre Singapore) and The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) cohort. We also sought to determine if this signature could serve as a prognostic factor in node negative cancers.

Materials And Methods: Patients with a histological diagnosis of OSCC were identified from an institutional database and fresh tumor samples were retrieved. RNA was extracted and gene expression profiling was performed using the Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray platform. RNA sequence data and corresponding clinical data for the TCGA HNSCC cohort were downloaded from the TCGA Data Portal. All data analyses were conducted using R package and SPSS.

Results: We identified an 11 gene signature (GGH, MTFR1, CDKN3, PSRC1, SMIM3, CA9, IRX4, CPA3, ZSCAN16, CBX7 and ZFP3) which was robust in segregating tumors by ECS status. In node negative patients, patients harboring this ECS signature had a significantly worse overall survival (p=0.04).

Conclusions: An eleven gene signature for ECS was derived. Our results also suggest that this signature is prognostic in a separate subset of patients with no nodal metastasis Further validation of this signature on other datasets and immunohistochemical studies are required to establish utility of this signature in stratifying early stage OSCC patients.
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http://dx.doi.org/10.1016/j.oraloncology.2014.12.012DOI Listing
April 2015

Tongue carcinoma infrequently harbor common actionable genetic alterations.

BMC Cancer 2014 Sep 19;14:679. Epub 2014 Sep 19.

Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.

Background: Oral tongue squamous cell carcinomas (TSCC) are a unique subset of head and neck cancers with a distinct demographic profile, where up to half of the cases are never smokers. A small proportion of patients with OSCC are known to respond to EGFR TKI. We used a high-sensitivity mass spectrometry-based mutation profiling platform to determine the EGFR mutation status, as well as other actionable alterations in a series of Asian TSCC.

Methods: 66 TSCC patients treated between 1998-2009 with complete clinico-pathologic data were included in this study. Somatic mutation profiling was performed using Sequenom LungCarta v1.0, and correlated with clinical parameters.

Results: Mutations were identified in 20/66(30.3%) of samples and involved TP53, STK11, MET, PIK3CA, BRAF and NRF2. No activating EGFR mutations or KRAS mutations were discovered in our series, where just over a third were never smokers. The most common mutations were in p53 (10.6%; n = 7) and MET (10.6%, n = 11) followed by STK11 (9.1%, n = 6) and PIK3CA (4.5%, n = 3). BRAF and NRF2 mutations, which are novel in TSCC, were demonstrated in one sample each. There was no significant correlation between overall mutation status and smoking history (p = 0.967) or age (p = 0.360). Positive MET alteration was associated with poorer loco-regional recurrence free survival (LRFS) of 11 months [vs 90 months in MET-negative group (p = 0.008)]. None of the other mutations were significantly correlated with LRFS or overall survival. Four of these tumors were propagated as immortalized cell lines and demonstrated the same mutations as the original tumor.

Conclusions: Using the Sequenom multiplexed LungCarta panel, we identified mutations in 6 genes, TP53, STK11, MET, PIK3CA, BRAF and NRF2, with the notable absence of EGFR and HER2 mutations in our series of Asian OSCC. Primary cell line models recapitulated the mutation profiles of the original primary tumours and provide an invaluable resource for experimental cancer therapeutics.
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http://dx.doi.org/10.1186/1471-2407-14-679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177593PMC
September 2014

Utility of the sendai consensus guidelines for branch-duct intraductal papillary mucinous neoplasms: a systematic review.

J Gastrointest Surg 2014 Jul 26;18(7):1350-7. Epub 2014 Mar 26.

Department of Hepatopancreatobiliary and Transplantation Surgery, Singapore General Hospital, 20 College Road, Academia, 169856, Singapore,

Introduction: The Sendai Consensus Guidelines (SCG) was formulated in 2006 to guide the management of intraductal papillary mucinous neoplasms (IPMN). The main area of controversy is the criteria for selection of branch duct (BD)-IPMN for resection. Although these guidelines have gained widespread acceptance, there is limited data to date supporting its use. This systematic review is performed to evaluate the utility of the Sendai Consensus Guidelines (SCG) for BD-IPMN.

Methods: Studies evaluating the clinical utility of the SCG in surgically resected neoplasms were identified. The SCG were retrospectively applied to all resected neoplasms in these studies. BD-IPMNs which met the criteria for resection were termed SCG+ve and those for surveillance were termed SCG-ve.

Results: Twelve studies were included, of which, 9 were suitable for pooled analysis. There were 690 surgically resected BD-IPMNs, of which, 24% were malignant. Five hundred one BD-IPMNs were classified as SCG+ve and 189 were SCG-ve. The positive predictive value (PPV) of SCG+ve neoplasms ranged from 11 to 52% and the NPV of SCG-ve neoplasms ranged from 90 to 100%. Overall, there were 150/501 (29.9%) of malignant BD-IPMNs in the SCG+ve group and 171/189 (90%) of benign BD-IPMNs in the SCG-ve group. Of the 18 reported malignant (11 invasive) BD-IPMNs in the SCG-ve group, 17 (including all 11 invasive) were from a single study. When the results from this single study were excluded, 170/171 (99%) of SCG-ve BD-IPMNs were benign.

Conclusion: The results of this review confirm the limitations of the SCG for BD-IPMN. The PPV of the SCG in predicting a malignant BD-IPMN was low and some malignant lesions may be missed based on these guidelines.
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http://dx.doi.org/10.1007/s11605-014-2510-8DOI Listing
July 2014

Assessment of tumor necrotic fraction by dynamic contrast-enhanced MRI: a preclinical study of human tumor xenografts with histopathologic correlation.

NMR Biomed 2014 Apr 17;27(4):486-94. Epub 2014 Feb 17.

Department of Oncologic Imaging, National Cancer Center, Singapore; Center for Quantitative Biology, Duke-NUS Graduate Medical School, Singapore.

Contrary to the common notion that tumor necrotic regions are non-enhancing after contrast administration, recent evidence has shown that necrotic regions exhibit delayed and slow uptake of gadolinium tracer on dynamic contrast-enhanced MRI (DCE MRI). The purpose of this study is to explore whether the mapping of tumor voxels with delayed and slow enhancement on DCE MRI can be used to derive estimates of tumor necrotic fraction. Patient-derived tumor xenograft lines of seven human cancers were implanted in 26 mice which were subjected to DCE MRI performed using a spoiled gradient recalled sequence. Gadolinium tracer concentration was estimated using the variable flip angle technique. To identify tumor voxels exhibiting delayed and slow uptake of contrast medium, clustering analysis was performed using a k-means clustering algorithm that classified tumor voxels according to their contrast enhancement patterns. Comparison of the percentage of tumor voxels exhibiting delayed and slow enhancement with the tumor necrotic fraction estimated on histology showed a strong correlation (r = 0.962, p < 0.001). The mapping of tumor regions with delayed and slow contrast uptake on DCE MRI correlated strongly with tumor necrotic fraction, and can potentially serve as a non-invasive imaging surrogate for the in vivo assessment of necrotic fraction.
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http://dx.doi.org/10.1002/nbm.3090DOI Listing
April 2014