50 results on '"Alvin Soon Tiong Lim"'
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2. Supplementary Figures 1-6 from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma
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Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul
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Supplementary Figure 1. Unsupervised Clustering on CCA samples. Supplementary Figure 2. Alterations Found in CCA Clusters. Supplementary Figure 3. MAP2K4 Homozygous Deletions and ERBB2 Amplifications. Supplementary Figure 4. Alterations Related to Structural Variations Found in CCAs. Supplementary Figure 5. FIREFLY Analysis of Pathways Systematically Dysregulated by Somatic Promoter Mutations that Alter Transcription Factor Binding. Supplementary Figure 6. Epigenetic Clusters and Mutation Signatures.
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- 2023
3. Supplementary Table 4 from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma
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Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul
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Structural Variations across 71 WGS CCAs.
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- 2023
4. Supplementary Table 3 from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma
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Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul
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Summary of CCA Alterations.
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- 2023
5. Supplementary Methods and Supplementary Figure and Table Legends from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma
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Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul
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Further details of methods, in addition to the supplementary figure and table legends.
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- 2023
6. Supplementary Table 2 from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma
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Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul
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Alterations in CCA Clusters.
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- 2023
7. Supplementary Table 5 from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma
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Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul
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Coverage Statistics and List of Genes for Targeted Sequencing.
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- 2023
8. Individualized Molecular Profiling for Allocation to Clinical Trials Singapore Study—An Asian Tertiary Cancer Center Experience
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Matthew C.H. Ng, Alvin Soon Tiong Lim, Yoon Sim Yap, Justina Yick Ching Lam, Tony Kiat Hon Lim, Chee Keong Toh, Su Pin Choo, N. Gopalakrishna Iyer, Mohamad Farid, Amanda O.L. Seet, Chow Wei Too, Rebecca Dent, Elaine Hsuen Lim, Apoorva Gogna, Angela Takano, Daniel S.W. Tan, Wan-Teck Lim, Tira Jing Ying Tan, Eng Huat Tan, Mei Kim Ang, Gek San Tan, Bien Soo Tan, Aaron Tan, Iain Beehuat Tan, Soon Thye Lim, Tse Hui Lim, David Tai, and Anders Jacobsen Skanderup
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,business.industry ,MEDLINE ,Cancer ,medicine.disease ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Profiling (information science) ,Medicine ,Center (algebra and category theory) ,Medical physics ,business - Abstract
PURPOSE Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center. PATIENTS AND METHODS Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the Individualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made. RESULTS One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors. CONCLUSION Individualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology.
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- 2021
9. Implementation of cytogenomic microarray with plasma cell enrichment enables better abnormality detection and risk stratification in patients with plasma cell neoplasia than conventional cytogenetics and fluorescence in situ hybridization
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Alvin Soon Tiong Lim, Tse Hui Lim, Evelyn Yee Hsieh Heng, Sim Leng Tien, Chuanfei Chen, and Lai Ching Lau
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Male ,Cancer Research ,Microarray ,Plasma Cell Enrichment ,Plasma Cells ,Plasma cell ,Biology ,Loss of heterozygosity ,Cytogenetics ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Neoplasms, Plasma Cell ,Molecular Biology ,In Situ Hybridization, Fluorescence ,Chromothripsis ,medicine.diagnostic_test ,Gold standard (test) ,Prognosis ,Molecular biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Bone marrow ,Fluorescence in situ hybridization - Abstract
The detection of chromosomal abnormalities is important in the diagnosis, prognosis and disease monitoring in plasma cell neoplasia (PCN). However, the gold standard diagnostic techniques of conventional cytogenetics (CC) and fluorescence in situ hybridization (FISH) are hampered by culture difficulties and probe availability. Cytogenomic microarray (CMA), however, is able to surmount such limitations and generate a comprehensive genomic profile with the implementation of plasma cell (PC) enrichment. In this study, we examined 89 bone marrow specimens with CC and FISH without PC enrichment, 35 of which were examined with CMA after PC enrichment. Results revealed that after PC enrichment, CMA was able to detect chromosomal abnormalities in 34 of 35 specimens tested (97.1%), compared to 21 and 32 specimens (60% and 91.4%, respectively) achieved by CC and FISH, respectively, which were similar to the abnormality detection rates among all 89 specimens (59.5% by CC and 92.1% by FISH). In addition, as the only technique capable of detecting copy neutral loss of heterozygosity (CN-LOH) and chromothripsis, CMA appears to be the most powerful tool in risk stratification as it successfully re-stratified 9 (25.7%) and 12 (34.3%) specimens from standard risk (determined by CC and FISH, respectively) to high risk. Based on the encouraging data presented by our study and others, we conclude that implementation of CMA with PC enrichment is of great value in routine clinical workup in achieving a more complete genetic profile of patients with PCN.
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- 2021
10. Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis
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Alvin Soon Tiong Lim, Quan Sing Ng, Anantham Devanand, Daniel S.W. Tan, T. Rajasekaran, Eng Huat Tan, Zaw Win Aung, Chee Keong Toh, G. Lai, Chow Wei Too, Tony Kiat-Hon Lim, Aaron C. Tan, Bien Soo Tan, Tina P.T. Koh, Tse Hui Lim, Mei-Kim Ang, Angela Takano, Wan Ling Tan, Shou Yu Poon, Brett Doble, Apoorva Gogna, Amit Jain, Boon-Hean Ong, Ravindran Kanesvaran, Wan-Teck Lim, and Gek San Tan
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Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Asia ,Lung Neoplasms ,Cost-Benefit Analysis ,medicine.medical_treatment ,Population ,non-small cell lung cancer (NSCLC) ,Adenocarcinoma of Lung ,medicine.disease_cause ,DNA sequencing ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,ROS1 ,Humans ,Molecular Targeted Therapy ,education ,Aged ,Retrospective Studies ,Aged, 80 and over ,education.field_of_study ,business.industry ,High-Throughput Nucleotide Sequencing ,Middle Aged ,Prognosis ,medicine.disease ,ErbB Receptors ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Adenocarcinoma ,Biomarker (medicine) ,Female ,KRAS ,business ,Follow-Up Studies - Abstract
Objectives There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted next-generation sequencing (NGS) panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients. Materials and methods We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue samples were tested using a targeted NGS panel for DNA alterations (29 selected genes including BRAF, EGFR, ERBB2 and TP53) and an RNA fusion panel (ALK, ROS1 and RET). PD-L1 immunohistochemistry was also performed. A cost-effectiveness analysis of NGS compared to standard molecular testing was conducted. Results A total of 174 samples were evaluated: PD-L1 (n = 169), NGS DNA panel (n = 173) and RNA fusion (n = 119) testing. Median age was 68 years, 53 % were male, 58 % were never smokers, 85 % were Chinese, 66 % had stage IV disease and 95 % had adenocarcinoma histology. In patients profiled with NGS on DNA, EGFR (56 %), KRAS (14 %), BRAF (2 %) and ERBB2 (1 %) mutations were found. RNA fusion testing revealed fusions in ALK (6 %), RET (3 %) and ROS1 (1 %). Cost-effectiveness analysis demonstrated that compared to sequential testing in EGFR negative patients, upfront NGS testing would result in an additional 1 % of patients with actionable alterations for targeted therapy being identified without significant increases in testing cost or turnaround time. Conclusions This study demonstrates that even in an EGFR mutant predominant population, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies. Our results support the implementation of diagnostic NGS in non-squamous NSCLC in Asia to allow patients access to the most appropriate personalized therapy.
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- 2020
11. Impact of the updated 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on Human Epidermal Growth Factor Receptor 2 (HER2) gene testing in invasive breast cancers: A single center study
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Tse Hui Lim, Alvin Soon Tiong Lim, Sim Leng Tien, and Puay Hoon Tan
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Pathologists ,Receptor, ErbB-2 ,Practice Guidelines as Topic ,Biomarkers, Tumor ,Humans ,Breast Neoplasms ,Female ,General Medicine ,Medical Oncology ,United States ,Pathology and Forensic Medicine ,Retrospective Studies - Abstract
The study aimed to evaluate the impact of the updated 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on Human Epidermal Growth Factor Receptor 2 (HER2) testing in invasive breast cancer compared with previous 2013 guidelines. Between Jan 2014 and May 2020, 3364 consecutive invasive breast carcinomas with concurrent HER2 immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) results were retrospectively reviewed for HER2 status. Both 2013 and 2018 testing criteria were applied to establish the HER2 status. The testing algorithms involved testing of invasive breast carcinomas by IHC, with equivocal results being reflexed to FISH assays. Concordance rate improved from 92.7% to 94.1% in the non-equivocal IHC cases with the 2018 guidelines. Comparing 2013 versus 2018 criteria, HER2 non-amplified cases increased significantly from 73.7% (n = 2478) to 76.8% (n = 2585), HER2 amplified cases remained similar from 23.4% (n = 789) to 23.2% (n = 779) while equivocal cases decreased from 2.9% (n = 97) to 0% with the new guidelines. Thus, 107 cases (3.2%) were reclassified from HER2 equivocal (n = 97) and amplified (n = 10) to non-amplified with the updated 2018 guidelines. Under the 2018 criteria, a total of 259 cases (7.7%) belonged to the uncommon categories (groups 2 to 4), with group 3 being the most frequent (4.6%), followed by group 4 (2.9%) and group 2 (0.2%). Implementation of 2018 guidelines resulted in a significant increase in HER2 non-amplified cases, mainly due to the abolishment of the equivocal FISH group. This has helped resolve the clinical practice dilemma by providing a more definitive HER2 gene status.
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- 2021
12. Ex Vivo Expansion of CD34+CD90+CD49f+ Hematopoietic Stem and Progenitor Cells from Non-Enriched Umbilical Cord Blood with Azole Compounds
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William Hwang, Zhiyong Poon, Qixing Zhong, Shang Li, Sudipto Bari, Christina L. L. Chai, Alvin Soon Tiong Lim, Niraja Dighe, Tse Hui Lim, Xiubo Fan, and Gigi N.C. Chiu
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0301 basic medicine ,Chemistry ,medicine.medical_treatment ,CD34 ,Cell Biology ,General Medicine ,Hematopoietic stem cell transplantation ,Molecular biology ,Transplantation ,03 medical and health sciences ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,medicine ,CD90 ,Bone marrow ,Stem cell ,Progenitor cell ,Developmental Biology - Abstract
Umbilical cord blood (UCB) transplants in adults have slower hematopoietic recovery compared to bone marrow (BM) or peripheral blood (PB) stem cells mainly due to low number of total nucleated cells and hematopoietic stem and progenitor cells (HSPC). As such in this study, we aimed to perform ex vivo expansion of UCB HSPC from non-enriched mononucleated cells (MNC) using novel azole-based small molecules. Freshly-thawed UCB–MNC were cultured in expansion medium supplemented with small molecules and basal cytokine cocktail. The effects of the expansion protocol were measured based on in vitro and in vivo assays. The proprietary library of >50 small molecules were developed using structure-activity-relationship studies of SB203580, a known p38-MAPK inhibitor. A particular analog, C7, resulted in 1,554.1 ± 27.8-fold increase of absolute viable CD45+CD34+CD38–CD45RA– progenitors which was at least 3.7-fold higher than control cultures (p 600-fold expansion of CD34+/CD90+/CD49f+ rare HSPCs coupled with significant (p
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- 2018
13. Clear cell sarcomas of the kidney are characterised byBCORgene abnormalities, including exon 15 internal tandem duplications andBCOR-CCNB3gene fusion
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Zhongde Zhang, Amos Hong Pheng Loh, Sze Jet Aw, Kenneth Tou En Chang, Minzhi Yin, Vikneswari Rajasegaran, Eva Loh, Jain Sudhanshi, Derrick W. Q. Lian, Jing Ma, Bin Tean Teh, Tse Hui Lim, Shaun Giap Hean Goh, Chik Hong Kuick, Cedric Chuan Young Ng, Jing Quan Lim, Meng Kang Wong, Alwin Hwai Liang Loh, Prasad G. Iyer, Alvin Soon Tiong Lim, Puay Hoon Tan, Angela Goytain, Shi Wang, and Tony Ng
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Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Histology ,Oncogene Proteins, Fusion ,Clone (cell biology) ,Cyclin B ,Biology ,Pathology and Forensic Medicine ,Fusion gene ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Cyclin D1 ,Proto-Oncogene Proteins ,medicine ,Humans ,Child ,Exons ,General Medicine ,medicine.disease ,Kidney Neoplasms ,Repressor Proteins ,030104 developmental biology ,Child, Preschool ,030220 oncology & carcinogenesis ,Immunohistochemistry ,Female ,Sarcoma, Clear Cell ,Clear-cell sarcoma ,Sarcoma ,Clear cell - Abstract
Clear cell sarcoma of the kidney (CCSK) is a rare paediatric renal malignant tumour. The majority of CCSKs have internal tandem duplications (ITDs) of the BCOR gene, whereas a minority have the YWHAE-NUTM2 gene fusion. A third 'double-negative' (DN) category comprises CCSKs with neither BCOR ITDs nor YWHAE-NUTM2 fusion. The aim of this study was to characterise 11 histologically diagnosed CCSKs immunohistochemically (with CCND1, BCOR and CCNB3 stains) and genetically.By next-generation sequencing, 10 cases (90.9%) had BCOR exon 15 ITDs, with positive BCOR immunoreactivity being found in four (36%) or eight (72%) cases, depending on the antibody clone. By reverse transcription polymerase chain reaction, none had the YWHAE-NUTM2 fusion. The DN case had a BCOR-CCNB3 fusion and strong nuclear CCNB3 and BCOR immunoreactivity. Quantitative polymerase chain reaction showed markedly elevated BCOR expression in this case, whereas BCOR ITD cases had lower levels of elevated BCOR expression.The majority of the CCSKs in our cohort had BCOR ITDs, and none had the YWHAE-NUTM2 fusion. We verified the strong, diffuse cyclin D1 (CCND1) immunoreactivity in CCSKs described in recent reports. BCOR immunoreactivity was not consistently positive in all CCSKs with BCOR ITDs, and therefore cannot be used as a diagnostic immunohistochemical stain to identify BCOR ITD cases. The DN case was a BCOR-CCNB3 fusion sarcoma. BCOR-CCNB3 sarcoma is typically a primary bone sarcoma affecting male adolescents, and this is the first report of it presenting in a kidney of a young child as a CCSK. The full spectrum of DN CCSKs awaits more comprehensive characterisation.
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- 2017
14. Chromosomal microarray analysis is superior in identifying cryptic aberrations in patients with acute lymphoblastic leukemia at diagnosis/relapse as a single assay
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Alvin Soon Tiong Lim, Lai Ching Lau, Tse Hui Lim, Evelyn Yee Hsieh Heng, Sim Leng Tien, Gee Chuan Wong, and Chuanfei Chen
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,DNA Copy Number Variations ,Chronic lymphocytic leukemia ,Clinical Biochemistry ,Loss of Heterozygosity ,Chromosomal translocation ,030204 cardiovascular system & hematology ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,CDKN2A ,Recurrence ,Internal medicine ,Complex Karyotype ,medicine ,Humans ,In Situ Hybridization, Fluorescence ,Aged ,Chromosome Aberrations ,medicine.diagnostic_test ,business.industry ,Biochemistry (medical) ,Karyotype ,Hematology ,General Medicine ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,ETV6 ,medicine.anatomical_structure ,Female ,Bone marrow ,business ,030215 immunology ,Fluorescence in situ hybridization - Abstract
Introduction Conventional cytogenetics (CC) is important in diagnosis, therapy, monitoring of post-transplant bone marrow, and prognosis assessment of acute lymphoblastic leukemia (ALL). However, due to the nature of ALL, CC often encounters difficulties of complex karyotype, poor chromosome morphology, low mitotic index, or normal cells dividing only. In contrast, chromosomal microarray analysis (CMA) showed a specificity >99% and a sensitivity of 100% in chronic lymphocytic leukemia (CLL) patients. Here, we report our experience with CMA on adult ALL patients. Methods Thirty-three bone marrow/blood samples from ALL patients (aged 18-79 years, median 44) at diagnosis/relapse, analyzed by CC and/or fluorescence in situ hybridization (FISH), were recruited. Chromosomal microarray analysis results were compared with CC. Fluorescence in situ hybridization analysis, if available, was applied when there was a discrepancy. Results Copy-neutral loss-of-heterozygosity (CN-LOH) was found in 8 cases (24.2%). Only CN-LOH at 9p was recurrent (3 cases, 9.1%). Copy number alterations (CNAs) were detected in 6 of 9 cases (66.7%) with normal karyotypes, in 3 of 5 cases (60.0%) with sole "balanced" translocations, and in 18 of 19 cases (94.7%) with complex karyotypes. Common CNAs involved CDKN2A/2B (30.3%), IKZF1 (27.3%), PAX5 (9.1%), RB1 (9.1%), BTG1 (6.7%), and ETV6 (6.7%), which regulate cell cycle, B lymphopoiesis, or act as tumor suppressors in ALL. Copy number alteration detection rate by CMA was 81.8% (27 of 33 cases) as compared to 57.6% (19 of 33 cases) by CC. Conclusion Incorporation of CMA as a routine clinical test at the time of diagnosis/relapse, in conjunction with CC and/or FISH, is highly recommended.
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- 2019
15. Clonal MET Amplification as a Determinant of Tyrosine Kinase Inhibitor Resistance in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer
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Tony Kiat Hon Lim, Amit Jain, Weiwei Zhai, Angela Takano, Wan-Teck Lim, Mei-Kim Ang, Yin Yeng Lee, Xue Lin Kwang, Daniel Shao-Weng Tan, Gek San Tan, Alvin Soon Tiong Lim, Wai Leong Tam, Chee Keong Toh, Sze Huey Tan, Eng Huat Tan, Perry J R Liew, G. Lai, T. Rajasekaran, Chow Wei Too, Bien Soo Tan, John K.C. Lim, Anantham Devanand, Ju Yuan, Rahul Nahar, Ravindran Kanesvaran, Axel M. Hillmer, Quan Sing Ng, B.H. Ong, Apoorva Gogna, Dawn P. Lau, Zaw Win Aung, N. Gopalakrishna Iyer, Tina P.T. Koh, Wan Ling Tan, and Tse Hui Lim
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0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Databases, Factual ,medicine.drug_class ,Gene Dosage ,Antineoplastic Agents ,In situ hybridization ,medicine.disease_cause ,Gene dosage ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,Genetic Heterogeneity ,0302 clinical medicine ,Predictive Value of Tests ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Humans ,Epidermal growth factor receptor ,Lung cancer ,Protein Kinase Inhibitors ,In Situ Hybridization, Fluorescence ,Retrospective Studies ,Chromosome 7 (human) ,Mutation ,medicine.diagnostic_test ,biology ,business.industry ,Gene Amplification ,Reproducibility of Results ,Proto-Oncogene Proteins c-met ,medicine.disease ,ErbB Receptors ,030104 developmental biology ,Editorial ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,business ,Fluorescence in situ hybridization - Abstract
Purpose Mesenchymal epithelial transition factor ( MET) activation has been implicated as an oncogenic driver in epidermal growth factor receptor ( EGFR)–mutant non–small-cell lung cancer (NSCLC) and can mediate primary and secondary resistance to EGFR tyrosine kinase inhibitors (TKI). High copy number thresholds have been suggested to enrich for response to MET inhibitors. We examined the clinical relevance of MET copy number gain (CNG) in the setting of treatment-naive metastatic EGFR-mutant–positive NSCLC. Patients and Methods MET fluorescence in situ hybridization was performed in 200 consecutive patients identified as metastatic treatment-naïve EGFR-mutant–positive. We defined MET-high as CNG greater than or equal to 5, with an additional criterion of MET/centromeric portion of chromosome 7 ratiο greater than or equal to 2 for amplification. Time-to-treatment failure (TTF) to EGFR TKI in patients identified as MET-high and -low was estimated by Kaplan-Meier method and compared using log-rank test. Multiregion single-nucleotide polymorphism array analysis was performed on 13 early-stage resected EGFR-mutant–positive NSCLC across 59 sectors to investigate intratumoral heterogeneity of MET CNG. Results Fifty-two (26%) of 200 patients in the metastatic cohort were MET-high at diagnosis; 46 (23%) had polysomy and six (3%) had amplification. Median TTF was 12.2 months (95% CI, 5.7 to 22.6 months) versus 13.1 months (95% CI, 10.6 to 15.0 months) for MET-high and -low, respectively ( P = .566), with no significant difference in response rate regardless of copy number thresholds. Loss of MET was observed in three of six patients identified as MET-high who underwent postprogression biopsies, which is consistent with marked intratumoral heterogeneity in MET CNG observed in early-stage tumors. Suboptimal response (TTF, 1.0 to 6.4 months) to EGFR TKI was observed in patients with coexisting MET amplification (five [3.2%] of 154). Conclusion Although up to 26% of TKI-naïve EGFR-mutant–positive NSCLC harbor high MET CNG by fluorescence in situ hybridization, this did not significantly affect response to TKI, except in patients identified as MET-amplified. Our data underscore the limitations of adopting arbitrary copy number thresholds and the need for cross-assay validation to define therapeutically tractable MET pathway dysregulation in EGFR-mutant–positive NSCLC.
- Published
- 2019
16. Concordance of anaplastic lymphoma kinase (ALK) gene rearrangements between circulating tumor cells and tumor in non-small cell lung cancer
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Man Chun Leong, Mei Kim Ang, Tony Kh. Lim, Chwee Teck Lim, Brendan Pang, Alvin Soon Tiong Lim, Angela Takano, Chye Ling Tan, Tse Hui Lim, Yong Wei Chua, Daniel Shao-Weng Tan, and Wan-Teck Lim
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0301 basic medicine ,Adult ,Male ,Pathology ,medicine.medical_specialty ,Lung Neoplasms ,circulating tumor cells ,Adenocarcinoma ,03 medical and health sciences ,0302 clinical medicine ,Circulating tumor cell ,hemic and lymphatic diseases ,Carcinoma, Non-Small-Cell Lung ,Biopsy ,molecular diagnosis ,medicine ,Biomarkers, Tumor ,Anaplastic lymphoma kinase ,Humans ,Anaplastic Lymphoma Kinase ,Lung cancer ,In Situ Hybridization, Fluorescence ,Aged ,Gene Rearrangement ,Crizotinib ,medicine.diagnostic_test ,ALK Gene Rearrangement ,business.industry ,ALK-gene rearrangement ,Receptor Protein-Tyrosine Kinases ,Gene rearrangement ,Middle Aged ,medicine.disease ,Neoplastic Cells, Circulating ,Prognosis ,fluorescent in-situ hybridization ,lung cancer ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Female ,business ,medicine.drug ,Research Paper ,Follow-Up Studies - Abstract
Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC) is routinely evaluated by fluorescent in-situ hybridization (FISH) testing on biopsy tissues. Testing can be challenging however, when suitable tissue samples are unavailable. We examined the relevance of circulating tumor cells (CTC) as a surrogate for biopsy-based FISH testing. We assessed paired tumor and CTC samples from patients with ALK rearranged lung cancer (n = 14), ALK-negative lung cancer (n = 12), and healthy controls (n = 5) to derive discriminant CTC counts, and to compare ALK rearrangement patterns. Blood samples were enriched for CTCs to be used for ALK FISH testing. ALK-positive CTCs counts were higher in ALK-positive NSCLC patients (3-15 cells/1.88 mL of blood) compared with ALK-negative NSCLC patients and healthy donors (0-2 cells/1.88 mL of blood). The latter range was validated as the 'false positive' cutoff for ALK FISH testing of CTCs. ALK FISH signal patterns observed on tumor biopsies were recapitulated in CTCs in all cases. Sequential CTC counts in an index case of lung cancer with no evaluable tumor tissue treated with crizotinib showed six, three and eleven ALK-positive CTCs per 1.88 mL blood at baseline, partial response and post-progression time points, respectively. Furthermore, ALK FISH rearrangement suggestive of gene copy number increase was observed in CTCs following progression. Recapitulation of ALK rearrangement patterns in the tumor on CTCs, suggested that CTCs might be used to complement tissue-based ALK testing in NSCLC to guide ALK-targeted therapy when suitable tissue biopsy samples are unavailable for testing.
- Published
- 2016
17. Clinical outcome of reflex EGFR mutation and ALK fusion testing in patients with non-squamous non-small cell lung cancer
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Chee Keong Toh, Alvin Soon Tiong Lim, Anantham Devanand, Wan-Teck Lim, Tina Puay-Theng Koh, Jonan Zhi-En Tan, Mei-Kim Ang, Daniel Shao-Weng Tan, Whee-Sze Ong, Ravindran Kanesvaran, Quan Sing Ng, Tony Kiat-Hon Lim, Chong-Hee Lim, Amit Jain, Eng Huat Tan, Angela Takano, Anne Ann-Ling Hsu, T.H. Lim, Kian-Sing Chan, and Lynette Oon
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Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Palliative treatment ,Proportional hazards model ,business.industry ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Egfr mutation ,Non squamous ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Reflex ,In patient ,030212 general & internal medicine ,Non small cell ,business ,Lung cancer - Abstract
Introduction Reflex molecular testing plays a critical role in identifying actionable targets and allocating patients to appropriate treatment. We report the clinicopathologic features and treatment outcomes of non-squamous non-small cell lung cancer (NSCLC) patients who underwent reflex testing for EGFR and ALK . Methods We analyzed the data of NSCLC patients diagnosed from 2010 to 2014 who underwent reflex testing for EGFR (from 2010) and ALK (from 2012) alterations and compared the outcome of those positive for the alterations against those who were wild-type (WT). Using multivariate cox regression, we determined the significant prognostic clinical factors that predicted for an improved survival outcome. Results EGFR mutation was more prevalent among females and never-smokers. The median OS (months) for the positive group was 24.8 versus 13.3 for the WT group (p EGFR tyrosine kinase inhibitor (TKI) treatment (all p ALK fusion was more prevalent among Malay patients (p=0.031). There were no significant survival differences in OS between positive and WT groups. Prognostic factors include gender, ethnicity, ECOG status, treatment intent, number of palliative treatment and metastatic sites (all p ALK TKI treatment (p=0.06). Conclusion This study found significant differences in demographic and clinical characteristics, and treatment outcomes between positive and WT patients for EGFR and ALK profiles, reinforcing the importance of reflex testing in patient management.
- Published
- 2016
18. P1.09-19 High-Throughput Next Generation Sequencing of Treatment-Naïve Non-Squamous NSCLC: The Singapore National Lung Profiling Study
- Author
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T. Koh, Daniel Shao Weng Tan, Eng Huat Tan, T. Rajasekaran, Brett Doble, T.H. Lim, Apoorva Gogna, Mei-Kim Ang, Zaw Win Aung, Aaron Tan, Amit Jain, Wan Ling Tan, Kiat Hon Lim, Wan-Teck Lim, Alvin Soon Tiong Lim, Ravindran Kanesvaran, Quan Sing Ng, Gek San Tan, Bien Soo Tan, S.Y. Poon, Angela Takano, Chee Keong Toh, B.H. Ong, Anantham Devanand, G. Lai, and Chow Wei Too
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Pulmonary and Respiratory Medicine ,Therapy naive ,Oncology ,business.industry ,Non squamous ,Medicine ,Profiling (information science) ,Computational biology ,business ,DNA sequencing - Published
- 2019
19. An integrated automated multispectral imaging technique that simultaneously detects and quantitates viral RNA and immune cell protein markers in fixed sections from Epstein-Barr virus-related tumours
- Author
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Alvin Soon Tiong Lim, Rafay Azhar, Josh Jie Hua Loh, Wei Keat Wan, Yu Ting Felicia Wee, Tony Kiat Hon Lim, Amit Jain, Evan W. Newell, Angela Takano, Clara Chong Hui Ong, Joe Yeong, Syed Muhammad Fahmy Alkaff, Maryam Hazly Hilmy, Jeffrey Chun Tatt Lim, and Wen Long Nei
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,CD30 ,Fluorescent Antibody Technique ,Biology ,medicine.disease_cause ,Virus ,Pathology and Forensic Medicine ,Immunophenotyping ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Biomarkers, Tumor ,Humans ,Multiplex ,In Situ Hybridization ,Carcinoma ,RNA ,Cancer ,General Medicine ,medicine.disease ,Epstein–Barr virus ,Hodgkin Disease ,Lymphoma ,030104 developmental biology ,030220 oncology & carcinogenesis ,RNA, Viral ,Oncovirus - Abstract
Background/aim Epstein-Barr virus (EBV) is an oncovirus that is commonly associated with the development of lymphomas and epithelial carcinomas. In the era of immunotherapy, histological evaluation of EBV-related cancers is currently a multi-sample, multi-technique process requiring separate time-consuming detection of EBV-encoded small RNAs by in situ hybridisation (ISH), and parallel labelling of sections for cancer-associated protein markers. Methods Using EBV-associated tumours as proof-of-concept for feasibility, here we developed an approach that allows simultaneous detection of EBV RNAs and multiple protein markers such as PD-L1, EBV-LMP, CD8, CD4, CD20, CD30 and CD15on a single tissue section based on our recently reported automated staining protocol. Results We successfully combined multiplex immunofluorescence (mIF) to detect 3 abovementioned protein markers involved in cancer, with ISH, and applied the protocol to f tissue samples from patients diagnosed with EBV-associated pulmonary lymphoepithelioma-like carcinoma (LELC), gastric carcinoma and Hodgkin's Lymphoma. Empowered by the Vectra 3 Automated Quantitative Pathology Imaging System, we demonstrate the utility and potential of this integrated approach to concurrently detect and quantitate viral RNA and protein biomarkers of immune and tumour cells. Conclusion This study represents an important step forward in the research and diagnosis of EBV-associated cancers, and could be readily modified to include other proteins and RNA markers to apply to other malignancies. More importantly, the novel automated ISH-mIF protocol that we detailly described here could also be readily reproduced by most of the diagnostic and research lab to future projects that aim to look at both RNA and protein markers.
- Published
- 2018
20. TFE3-Expressing Epithelioid Rich Perivascular Epithelioid Cell Neoplasm (PEComa) of the Bladder with Unusual Benign Course
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Xiu Fen, Chen, Joe, Yeong, Kenneth Tou En, Chang, Alvin Soon Tiong, Lim, Chik Hong, Kuick, Tse Hui, Lim, Jain, Sudhanshi, Sathiyamoorthy, Selvarajan, Valerie Huei Li, Gan, and Li Yan, Khor
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Adult ,Gene Rearrangement ,Male ,Oncogene Proteins, Fusion ,Urinary Bladder Neoplasms ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Perivascular Epithelioid Cell Neoplasms ,Humans ,Spectrin ,Receptor, trkC ,PTB-Associated Splicing Factor ,Prognosis ,Translocation, Genetic - Abstract
Perivascular epithelioid cell tumor (PEComa) is an uncommon tumor which presents with epithelioid and spindled cell morphology and is immunoreactive for myogenic and melanocytic markers. Recently, a subset of PEComas has been reported to harbor
- Published
- 2018
21. Ex Vivo Expansion of CD34
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Sudipto, Bari, Qixing, Zhong, Xiubo, Fan, Zhiyong, Poon, Alvin Soon Tiong, Lim, Tse Hui, Lim, Niraja, Dighe, Shang, Li, Gigi Ngar Chee, Chiu, Christina Li Lin, Chai, and William Ying Khee, Hwang
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Azoles ,Pyridines ,Cord Blood ,Azole‐based small molecules ,Hematopoietic stem and progenitor cells ,Ex vivo expansion ,Antigens, CD34 ,Hematopoietic stem cell transplantation ,Mice, SCID ,Xenotransplantation with immunodeficient mouse model ,Integrin alpha6 ,Small Molecule Libraries ,Mice ,Structure-Activity Relationship ,Umbilical cord blood ,Translational Research Articles and Reviews ,Animals ,Cells, Cultured ,Stem Cells ,Imidazoles ,Cord / Cord Blood Stem Cells (WJ-MSCs) ,Fetal Blood ,Hematopoietic Stem Cells ,Small Molecule Based Reprograming ,Hematopoietic Stem/Progenitor Cells ,Thy-1 Antigens ,Hematopoietic Regeneration ,Cell Culture Advances - Abstract
Umbilical cord blood (UCB) transplants in adults have slower hematopoietic recovery compared to bone marrow (BM) or peripheral blood (PB) stem cells mainly due to low number of total nucleated cells and hematopoietic stem and progenitor cells (HSPC). As such in this study, we aimed to perform ex vivo expansion of UCB HSPC from non‐enriched mononucleated cells (MNC) using novel azole‐based small molecules. Freshly‐thawed UCB–MNC were cultured in expansion medium supplemented with small molecules and basal cytokine cocktail. The effects of the expansion protocol were measured based on in vitro and in vivo assays. The proprietary library of >50 small molecules were developed using structure‐activity‐relationship studies of SB203580, a known p38‐MAPK inhibitor. A particular analog, C7, resulted in 1,554.1 ± 27.8‐fold increase of absolute viable CD45+CD34+CD38–CD45RA– progenitors which was at least 3.7‐fold higher than control cultures (p 600‐fold expansion of CD34+/CD90+/CD49f+ rare HSPCs coupled with significant (p
- Published
- 2017
22. Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence
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Panpan Wang, Tse Hui Lim, Henrik J. Ditzel, Min Feng, Soo-Chin Lee, Annette R Kodahl, Suman Sarma, Gokce Oguz, Qiang Yu, Siti Maryam J M Yatim, Wenyu Wang, Ern Yu Tan, Selena Y. Lin, Alvin Soon Tiong Lim, Alexander Lezhava, Jian Yuan Goh, Dave S.B. Hoon, Yoon Sim Yap, Maria Bibi Lyng, Wai Leong Tam, Puay Leng Lee, and Yi Bao
- Subjects
0301 basic medicine ,Oncology ,CA15-3 ,S100A7 ,Bridged-Ring Compounds ,medicine.medical_specialty ,medicine.medical_treatment ,Antineoplastic Agents ,Breast Neoplasms ,Biology ,Bioinformatics ,Polymerase Chain Reaction ,General Biochemistry, Genetics and Molecular Biology ,S100A9 ,03 medical and health sciences ,Mice ,Breast cancer ,Internal medicine ,medicine ,Journal Article ,Biomarkers, Tumor ,Animals ,Humans ,In Situ Hybridization, Fluorescence ,Chemotherapy ,Kinase ,General Medicine ,medicine.disease ,030104 developmental biology ,Pacritinib ,Pyrimidines ,Treatment Outcome ,Chromosomes, Human, Pair 1 ,Disease Progression ,Biomarker (medicine) ,Heterografts ,Female ,Neoplasm Recurrence, Local ,Cell-Free Nucleic Acids - Abstract
Tumor recurrence remains the main reason for breast cancer-associated mortality, and there are unmet clinical demands for the discovery of new biomarkers and development of treatment solutions to benefit patients with breast cancer at high risk of recurrence. Here we report the identification of chromosomal copy-number amplification at 1q21.3 that is enriched in subpopulations of breast cancer cells bearing characteristics of tumor-initiating cells (TICs) and that strongly associates with breast cancer recurrence. Amplification is present in ∼10-30% of primary tumors but in more than 70% of recurrent tumors, regardless of breast cancer subtype. Detection of amplification in cell-free DNA (cfDNA) from blood is strongly associated with early relapse in patients with breast cancer and could also be used to track the emergence of tumor resistance to chemotherapy. We further show that 1q21.3-encoded S100 calcium-binding protein (S100A) family members, mainly S100A7, S100A8, and S100A9 (S100A7/8/9), and IL-1 receptor-associated kinase 1 (IRAK1) establish a reciprocal feedback loop driving tumorsphere growth. Notably, this functional circuitry can be disrupted by the small-molecule kinase inhibitor pacritinib, leading to preferential impairment of the growth of 1q21.3-amplified breast tumors. Our study uncovers the 1q21.3-directed S100A7/8/9-IRAK1 feedback loop as a crucial component of breast cancer recurrence, serving as both a trackable biomarker and an actionable therapeutic target for breast cancer.
- Published
- 2017
23. Amplification of 1q21 and Other Abnormalities in Multiple Myeloma Patients from a Tertiary Hospital in Singapore
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Karen See, Jun Ma, Tse Hui Lim, Alvin Soon Tiong Lim, Natasha Choo, Yit Jun Ng, Yu Min Tan, Sim Leng Tien, Sathish Krishnan, Daryl Tan, Lai Ching Lau, and School of Biological Sciences
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medicine.medical_specialty ,Pathology ,Monosomy ,Hematology ,medicine.diagnostic_test ,business.industry ,Cytogenetics ,Karyotype ,medicine.disease ,Science::Biological sciences [DRNTU] ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Original Article ,Bone marrow ,Hyperdiploidy ,business ,Multiple myeloma ,Fluorescence in situ hybridization - Abstract
Much effort has been made to stratify multiple myeloma patients for targeted therapy. However, responses have been varied and improved patient stratifications are needed. Forty-five diagnostic samples from multiple myeloma patients (median age 65 years) were stratified cytogenetically as 15 having non-hyperdiploidy, 20 having hyperdiploidy and 10 having a normal karyotype. Fluorescence in situ hybridization (FISH) assays with FGFR3/IGH, CCND1/IGH, IGH/MAF, RB1 and TP53 probes on bone marrow samples showed that IGH rearrangements were the most common abnormality in the non-hyperdiploid group but these were also found among hyperdiploid patients and patients with normal cytogenetics. Of these, FGFR3/IGH rearrangements were most frequent. Deletion of RB1/monosomy 13 was the most common genetic abnormality across the three groups and was significantly higher among non-hyperdiploid compared to hyperdiploid patients. On the other hand, the study recorded a low incidence of TP53 deletion/monosomy 17. The FGFR3/IGH fusion was frequently seen with RB1 deletion/monosomy 13. FISH with 1p36/1q21 and 6q21/15q22 probes showed that amplification of 15q22 was seen in all of the hyperdiploid patients while amplification of 1q21, Amp(1q21), characterized non-hyperdiploid patients. In contrast, deletions of 1p36 and 6q21 were very rare events. Amp(1q21), FGFR3/IGH fusion, RB1 deletion/monosomy 13, and even TP53 deletion/monosomy 17 were seen in some hyperdiploid patients, suggesting that they have a less than favorable prognosis and require closer monitoring.
- Published
- 2013
24. Implications of the Updated 2013 American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations on Human Epidermal Growth Factor Receptor 2 Gene Testing Using Immunohistochemistry and Fluorescence In Situ Hybridization for Breast Cancer
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Alvin Soon Tiong Lim, Puay Hoon Tan, Aye Aye Thike, Tse Hui Lim, and Sim Leng Tien
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Pathology ,Receptor, ErbB-2 ,Breast Neoplasms ,In situ hybridization ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Trastuzumab ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Genetic Testing ,In Situ Hybridization, Fluorescence ,Genetic testing ,Retrospective Studies ,Predictive marker ,medicine.diagnostic_test ,business.industry ,Reproducibility of Results ,General Medicine ,Guideline ,medicine.disease ,Immunohistochemistry ,Medical Laboratory Technology ,030104 developmental biology ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Female ,business ,Fluorescence in situ hybridization ,medicine.drug - Abstract
ContextHuman epidermal growth factor receptor 2 (HER2/neu) amplification is used as a predictive marker for trastuzumab treatment in breast cancer. Both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) testing algorithms have been based on the 2007 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. In late 2013, the guidelines were updated with new scoring criteria.Objective—To assess the impact of the revised ASCO/CAP recommendations on both IHC and FISH results by using the dual-color HER2/neu and centromeric FISH probes.DesignRetrospective analysis of 590 invasive carcinomas with concurrent IHC and dual-color HER2/neu and centromeric 17 (CEP17) FISH results, based on 2007 ASCO/CAP guidelines, was conducted from July 2011 to June 2013. With the revised guidelines, patients were recategorized and concordance rates between the 2 assays were recalculated.Results—Overall concordance rates for FISH and IHC decreased from 94.9% to 93.8% with reclassification. Negative FISH cases decreased from 79.1% to 69.3%. However, equivocal FISH cases were significantly increased from 0.7% to 9.5%, leading to more retesting. Both positive IHC and FISH cases were also noted to be increased, leading to more patients being eligible for trastuzumab treatment, especially those patients with concurrent HER2/neu and CEP17 polysomy. Approximately 1% of patients with initial FISH negative results were reclassified as having positive results when both the ratios and average copy number of HER2/neu were considered under the revised guidelines.ConclusionsThe revised 2013 ASCO/CAP guidelines can potentially lead to more patients being eligible for trastuzumab therapy but additional retesting is to be expected owing to an increased number of equivocal FISH cases.
- Published
- 2016
25. TFE3-expressing epithelioid rich perivascular epithelioid cell tumour (PECOMA) of the bladder
- Author
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Alvin Soon Tiong Lim, Xiu Fen Chen, Valerie Huei Li Gan, Jain Sudhanshi, Kenneth Tou En Chang, Li Yan Khor, and Joe Yeong
- Subjects
Pathology ,medicine.medical_specialty ,medicine ,Perivascular epithelioid cell tumour ,TFE3 ,Biology ,medicine.disease ,Pathology and Forensic Medicine - Published
- 2017
26. An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era
- Author
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Lai Ching Lau, T.H. Lim, Alvin Soon Tiong Lim, Y T Goh, Gerrard Teoh, H C Wee, Lai Heng Lee, William Hwang, S Su, K C Yap, Zhentang Lao, Y S Lee, Nelson Wee, P Premalatha, Christine Choo, and Daryl Tan
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Pathology ,medicine.medical_treatment ,Antineoplastic Agents ,Kaplan-Meier Estimate ,Hematopoietic stem cell transplantation ,Biology ,Transplantation, Autologous ,Translocation, Genetic ,Bortezomib ,Cohort Studies ,Bone Marrow ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,In Situ Hybridization, Fluorescence ,Metaphase ,Multiple myeloma ,Aged ,Neoplasm Staging ,Retrospective Studies ,Aged, 80 and over ,Salvage Therapy ,Hematology ,medicine.diagnostic_test ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Middle Aged ,Aneuploidy ,Prognosis ,medicine.disease ,Boronic Acids ,Combined Modality Therapy ,Transplantation ,Treatment Outcome ,Karyotyping ,Pyrazines ,Proteasome inhibitor ,Female ,Multiple Myeloma ,medicine.drug ,Fluorescence in situ hybridization - Abstract
Multiple myeloma is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several high-risk features of myeloma, the validity of conventional risk-stratification and prognostication systems needs to be reevaluated. We study the survival data of 261 previously untreated myeloma patients managed at our institution, where bortezomib became available from 2004 for the treatment of relapse disease. Patient and disease characteristics, and survival data were evaluated overall, and with respect to bortezomib exposure. Overall, the international staging system (ISS), metaphase karyotyping and interphase fluorescence in situ hybridization (FISH) were discerning of survival outcomes, where the median for the entire cohort was 5.2 years. However, when stratified by bortezomib exposure, only metaphase karyotyping was still discriminating of long-term prognosis. The presence of an abnormal nonhyperdiploid karyotype overrides all other clinical and laboratory parameters in predicting for a worse outcome on multivariate analysis (median survival 2.6 years, P = 0.001), suggesting that bortezomib used at relapse is better able to overcome adverse risk related to high tumor burden (as measured by the ISS) than adverse cytogenetics on conventional karyotyping. Metaphase karyotyping provides additional prognostic information on tumor kinetics where the presence of a normal diploid karyotype in the absence of any high-risk FISH markers correlated with superior survival and could act as a surrogate for lower plasma cell proliferation.
- Published
- 2010
27. Ex Vivo Expansion of SCID-Repopulating CD34+CD90+CD49f+Hematopoietic Stem & Progenitor Cells From Non-Enriched Human Umbilical Cord Blood with Novel Azole-Based Small Molecules
- Author
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Gigi N.C. Chiu, Qixing Zhong, William Hwang, Christina L. L. Chai, Shang Li, Sudipto Bari, Alvin Soon Tiong Lim, Niraja Dighe, Xiubo Fan, Tse Hui Lim, and Zhiyong Poon
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Transplantation ,business.industry ,CD34 ,Hematology ,030226 pharmacology & pharmacy ,Small molecule ,Umbilical cord ,03 medical and health sciences ,Haematopoiesis ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,chemistry ,Cancer research ,Azole ,Medicine ,CD90 ,Ex vivo expansion ,Progenitor cell ,business - Published
- 2018
28. MDM2 amplification levels are not correlated to the degree of dedifferentiation and metastatic potential in well differentiated and dedifferentiated liposarcoma
- Author
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Kesavan Sittampalam, Sathiyamoorthy Selvarajan, John Heng Chi Lim, Tse Hui Lim, Fan Foon Cheo, Wei Lin Goh, Mann Hong Tan, Nagavalli Somasundaram, Winston Chew, Jason Yongsheng Chan, Richard Quek, Timothy Kwang Yong Tay, Sze Huey Tan, Eileen Yi Ling Poon, Alvin Soon Tiong Lim, Mohamad Farid, Melissa Ching Ching Teo, and Khee Chee Soo
- Subjects
Dedifferentiated liposarcoma ,biology.protein ,Cancer research ,Mdm2 ,Biology ,Pathology and Forensic Medicine ,Well differentiated ,Degree (temperature) - Published
- 2018
29. ETV6 Disruption Does Not Predict Indolent Clinical Behavior in Secretory Breast Carcinoma
- Author
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Poh Yian Cheok, T.H. Lim, Mabel Wong, Raymond Ng, Puay Hoon Tan, Ana Richelia Jara-Lazaro, Nan Soon Wong, and Alvin Soon Tiong Lim
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Pathology ,medicine.medical_specialty ,MEDLINE ,Breast Neoplasms ,In situ hybridization ,Neoplasm Recurrence ,Biomarkers, Tumor ,Internal Medicine ,Humans ,Medicine ,In Situ Hybridization, Fluorescence ,Aged ,Regulation of gene expression ,Proto-Oncogene Proteins c-ets ,business.industry ,Carcinoma ,Membrane Proteins ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,ETV6 ,Oncology ,Cancer research ,Female ,Surgery ,Neoplasm Recurrence, Local ,business ,Secretory Breast Carcinoma - Published
- 2012
30. Detection of apoptotic alterations in sperm in subfertile patients and their correlations with sperm quality
- Author
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Alvin Soon Tiong Lim, Sin Eng Chia, Han-Ming Shen, Choon Nam Ong, and Jun Dai
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Adult ,Male ,endocrine system ,Cell Survival ,Apoptosis ,DNA Fragmentation ,Phosphatidylserines ,Biology ,Abnormal sperm morphology ,Andrology ,chemistry.chemical_compound ,Humans ,Infertility, Male ,reproductive and urinary physiology ,Sperm motility ,TUNEL assay ,Sperm Count ,urogenital system ,Rehabilitation ,Obstetrics and Gynecology ,Phosphatidylserine ,Middle Aged ,Spermatozoa ,Sperm ,Reproductive Medicine ,chemistry ,Immunology ,Sperm Motility ,DNA fragmentation ,Spermatogenesis - Abstract
BACKGROUND: The aim of the present study was to define the effect of apoptosis on sperm quality and function. METHODS: The apoptotic features in sperm were assessed in 60 subfertile subjects, using Annexin-V staining for phosphatidylserine (PS) externalization and Tdt-mediated dUTP nick end labelling (TUNEL) assay for DNA fragmentation. RESULTS: On average, about 45% of the sperm were found to be apoptotic based on the results from Annexin-V staining, including both early (Annexin-V-positive, PI-negative) and late apoptosis (Annexin-Vpositive, PI-positive). TUNEL-positive cells (median value 15%) significantly correlated to late apoptosis but not early apoptosis, indicating that DNA fragmentation only occurs at the later stage of sperm apoptosis. TUNELpositive and late apoptotic cells (Annexin-V-positive, PI-positive) were found to be inversely correlated to sperm motility and vitality, and positively to abnormal sperm morphology. On the other hand, it is surprising to note that the apoptotic alterations in sperm positively correlated to sperm concentration or total sperm counts. CONCLUSIONS: Overall results from this study support the abortive apoptosis theory; apoptosis in mature sperm is initiated during spermatogenesis, after which some cells earmarked for elimination via apoptosis may escape the removal mechanism and contribute to poor sperm quality.
- Published
- 2002
31. CpG Oligonucleotide and Interleukin 2 stimulation enables higher cytogenetic abnormality detection rates than 12-o-tetradecanolyphorbol-13-acetate in Asian patients with B-cell chronic lymphocytic leukemia (B-CLL)
- Author
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Tse Hui Lim, Geok Yee Lee, Alvin Soon Tiong Lim, Fiona Pui San Liaw, Lai Ching Lau, and Sim Leng Tien
- Subjects
Interleukin 2 ,Male ,medicine.medical_specialty ,Pathology ,Stimulation ,In situ hybridization ,Biology ,Sensitivity and Specificity ,Cytogenetics ,Asian People ,Internal medicine ,medicine ,Humans ,Mitosis ,In Situ Hybridization, Fluorescence ,Aged ,Chromosome Aberrations ,Hematology ,medicine.diagnostic_test ,Middle Aged ,medicine.disease ,Molecular biology ,Leukemia, Lymphocytic, Chronic, B-Cell ,Leukemia ,Oligodeoxyribonucleotides ,Interleukin-2 ,Tetradecanoylphorbol Acetate ,Female ,Detection rate ,Fluorescence in situ hybridization ,medicine.drug - Abstract
The present study was designed to compare abnormality detection rates using DSP30 + IL2 and 12-O-Tetradecanoylphorbol-13-acetate (TPA) in Asian patients with B-CLL. Hematological specimens from 47 patients (29 newly diagnosed, 18 relapsed) were established as 72 h-DSP30 + IL2 and TPA cultures. Standard methods were employed to identify clonal aberrations by conventional cytogenetics (CC). The B-CLL fluorescence in situ hybridization (FISH) panel comprised ATM, CEP12, D13S25, and TP53 probes. DSP30 + IL2 cultures had a higher chromosomal abnormality detection rate (67 %) compared to TPA (44 %, p0.001). The mean number of analyzable metaphases and abnormal metaphases per slide was also higher (p0.005, p0.001, respectively). Culture success rate, percentage of complex karyotype, and percentage of non-clonal abnormal cell were not significantly different (p0.05). Thirteen cases with abnormalities were found exclusively in DSP30 + IL2 cultures compared to one found solely in TPA cultures. DSP30 + IL2 cultures were comparable to the FISH panel in detecting 11q-, +12 and 17p- but not 13q-. It also has a predilection for 11q- bearing leukemic cells compared to TPA. FISH had a higher abnormality detection rate (84.1 %) compared to CC (66.0 %) with borderline significance (p = 0.051), albeit limited by its coverage. In conclusion, DSP30 + IL2 showed a higher abnormality detection rate. However, FISH is indispensable to circumvent low mitotic indices and detect subtle abnormalities.
- Published
- 2014
32. Clinical validation of an ultra high-throughput spiral microfluidics for the detection and enrichment of viable circulating tumor cells
- Author
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Ross A. Soo, Bee Luan Khoo, Daniel Shao-Weng Tan, Alvin Soon Tiong Lim, Majid Ebrahimi Warkiani, Yoon Sim Yap, Wan-Teck Lim, Chwee Teck Lim, Darryl Irwin, Jongyoon Han, Sai Sakktee Krisna, Dawn Pingxi Lau, Kiat Hon Lim, Soo Chin Lee, Ali Asgar S. Bhagat, Wanjin, H, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, and Han, Jongyoon
- Subjects
Pathology ,medicine.medical_specialty ,Lung Neoplasms ,General Science & Technology ,Science ,Bioengineering ,Breast Neoplasms ,Cell Separation ,Lung and Intrathoracic Tumors ,Circulating tumor cell ,Germline mutation ,Breast cancer ,Immunophenotyping ,Cell Line, Tumor ,Breast Tumors ,Breast Cancer ,Basic Cancer Research ,Medicine and Health Sciences ,Cancer Detection and Diagnosis ,medicine ,Humans ,Neoplasm Metastasis ,Liquid biopsy ,Lung cancer ,Multidisciplinary ,Cell-Free System ,biology ,CD44 ,Biology and Life Sciences ,Cancers and Neoplasms ,Microfluidic Analytical Techniques ,Neoplastic Cells, Circulating ,medicine.disease ,Non-Small Cell Lung Cancer ,ErbB Receptors ,Oncology ,Mutation ,Cancer cell ,biology.protein ,Cancer research ,Engineering and Technology ,Medicine ,Cancer Screening ,Research Article ,Biotechnology - Abstract
Background: Circulating tumor cells (CTCs) are cancer cells that can be isolated via liquid biopsy from blood and can be phenotypically and genetically characterized to provide critical information for guiding cancer treatment. Current analysis of CTCs is hindered by the throughput, selectivity and specificity of devices or assays used in CTC detection and isolation. Methodology/Principal Findings: Here, we enriched and characterized putative CTCs from blood samples of patients with both advanced stage metastatic breast and lung cancers using a novel multiplexed spiral microfluidic chip. This system detected putative CTCs under high sensitivity (100%, n = 56) (Breast cancer samples: 12–1275 CTCs/ml; Lung cancer samples: 10–1535 CTCs/ml) rapidly from clinically relevant blood volumes (7.5 ml under 5 min). Blood samples were completely separated into plasma, CTCs and PBMCs components and each fraction were characterized with immunophenotyping (Pan-cytokeratin/CD45, CD44/CD24, EpCAM), fluorescence in-situ hybridization (FISH) (EML4-ALK) or targeted somatic mutation analysis. We used an ultra-sensitive mass spectrometry based system to highlight the presence of an EGFR-activating mutation in both isolated CTCs and plasma cell-free DNA (cf-DNA), and demonstrate concordance with the original tumor-biopsy samples. Conclusions/Significance: We have clinically validated our multiplexed microfluidic chip for the ultra high-throughput, low-cost and label-free enrichment of CTCs. Retrieved cells were unlabeled and viable, enabling potential propagation and real-time downstream analysis using next generation sequencing (NGS) or proteomic analysis., Singapore-MIT Alliance for Research and Technology
- Published
- 2014
33. Ultra-High Throughput Enrichment of Viable Circulating Tumor Cells
- Author
-
Guofeng Guan, Soo-Chin Lee, Ross A. Soo, Bee Luan Khoo, Chwee Teck Lim, Yoon Sim Yap, Jongyoon Han, Wan-Teck Lim, Alvin Soon Tiong Lim, Majid Ebrahimi Warkiani, and Daniel Shao-Weng Tan
- Subjects
Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,Cancer ,Biology ,medicine.disease ,Peripheral blood mononuclear cell ,Transcriptome ,Circulating tumor cell ,Cancer cell ,medicine ,Cancer research ,Lung cancer ,Immunostaining ,Fluorescence in situ hybridization - Abstract
Detection, enumeration and characterization of rare circulating tumor cells (CTCs) from the peripheral blood of cancer patients potentially provide critical insights into tumor biology and is promising for cancer diagnosis and prognosis. Here, we present a novel multiplexed spiral microfluidic device for ultra-high throughput, label-free enrichment of CTCs from clinically relevant blood volumes. The fast processing time of the technique (7.5 mL blood in < 5 min) and high sensitivity of the device lends itself to a broad range of potential genomic and transcriptomic applications. The method can specifically separate and preserve all fractions of blood (i.e., plasma, CTCs and PBMC) for diverse downstream analysis. CTCs were detected from 100% (10/10) of blood samples collected from patients with advanced stage metastatic breast (12-56 CTC/ml) or lung cancer (30-153 CTC/ml). Cancer cells were characterized with immunostaining and fluorescence in situ hybridization (FISH) (HER2/neu). Retrieved cells were unlabelled and hence more viable for propagation and other informative analysis such as the next generation sequencing (NGS) to guide treatment and individualized patient care.
- Published
- 2014
34. Primary nodal follicular lymphoma with spindle cell features: a potential diagnostic pitfall
- Author
-
D G-S Lim, S.S. Ng, Thomas Paulraj Thamboo, A R Chang, Alvin Soon Tiong Lim, L H-C Tan, M-E Nga, and S-L Tien
- Subjects
Pathology ,medicine.medical_specialty ,Histology ,business.industry ,Cell ,Follicular lymphoma ,Cancer ,Anatomical pathology ,General Medicine ,medicine.disease ,Follicular cell ,Pathology and Forensic Medicine ,B-cell neoplasm ,medicine.anatomical_structure ,medicine ,NODAL ,business ,Lymph node - Published
- 2008
35. 461 Individualized molecular profiling for allocation to clinical trials (impact) - experience from an Asian tertiary cancer centre
- Author
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Wan-Teck Lim, A. Seet, T.K.H. Lim, Matthew C.H. Ng, D.S.W. Tan, Apoorva Gogna, G.S. Tan, Alvin Soon Tiong Lim, V.L.L. Wong, D.W.M. Tai, Eng Huat Tan, X.Y. Yew, Zaw Win Aung, Angela Takano, S.S. Krisna, and K.H.T. Lim
- Subjects
Clinical trial ,Cancer Research ,medicine.medical_specialty ,Pathology ,Oncology ,business.industry ,Cancer centre ,Alternative medicine ,Medicine ,Profiling (information science) ,business ,Intensive care medicine - Published
- 2015
36. Dasatinib Induces a Response in Malignant Thymoma
- Author
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Alwin Hwai Liang Loh, Yeow Tee Goh, Richie Soong, Yeh Ching Linn, Alvin Soon Tiong Lim, Chong Hee Lim, Francis Y. Lee, Charles Chuah, Foong Koon Cheah, Sim Leng Tien, and Tse Hui Lim
- Subjects
Dasatinib ,Cancer Research ,Malignant Thymoma ,Oncology ,business.industry ,Cancer research ,Medicine ,business ,medicine.drug - Published
- 2006
37. A novel isoderivative chromosome 20 in a patient with chronic myelomonocytic leukemia
- Author
-
Alvin Soon Tiong Lim, Sim Leng Tien, and Tse Hui Lim
- Subjects
Cancer Research ,Genetics ,medicine ,Cancer research ,Chronic myelomonocytic leukemia ,Biology ,Chromosome 20 ,medicine.disease ,Molecular Biology - Published
- 2006
38. Cytogenetic and molecular aberrations of multiple myeloma patients: a single-center study in Singapore
- Author
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Alvin Soon Tiong, Lim, Tse Hui, Lim, Karen Hsu Shien, See, Yit Jun, Ng, Yu Min, Tan, Natasha Swee Lian, Choo, Sherry Xin Er, Lim, Yenny, Yee, Lai Ching, Lau, Sim Leng, Tien, Kumar, Sathish, and Daryl Chen Lung, Tan
- Subjects
Aged, 80 and over ,Chromosome Aberrations ,Male ,Singapore ,Middle Aged ,Retinoblastoma Protein ,Cytogenetics ,Monosomy ,Karyotyping ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Female ,Immunoglobulin Heavy Chains ,Multiple Myeloma ,In Situ Hybridization, Fluorescence ,Aged - Abstract
Much is known about the cytogenetic lesions that characterize multiple myeloma (MM) patients from the USA, Europe, and East Asia. However, little has been published about the disease among Southeast Asians. The aim of this study was to determine the chromosomal abnormalities of MM patients in our Singapore population.Forty-five newly-diagnosed, morphologically confirmed patients comprising 18 males and 27 females, aged 46 - 84 years (median 65 years) were investigated by karyotyping and fluorescence in situ hybridization (FISH). FISH employing standard panel probes and 1p36/1q21 and 6q21/15q22 probes was performed on diagnostic bone marrow samples.Thirty-four cases (75.6%) had karyotypic abnormalities. Including FISH, a total detection rate of 91.1% was attained. Numerical and complex structural aberrations were common to both hyperdiploid and non-hyperdiploid patients. Numerical gains of several recurring chromosomes were frequent among hyperdiploid patients while structural rearrangements of several chromosomes including 8q24.1 and 14q32 characterized non-hyperdiploid patients. With FISH, immunoglobulin heavy chain (IGH) gene rearrangements, especially fibroblast growth factor receptor 3 (FGFR3)/IGH and RB1 deletion/monosomy 13 were the most common abnormalities (43.4%). Amplification 1q21 was 10 times more frequent (42.5%) than del(1p36) and del(6q21).We have successfully reported the comprehensive cytogenetic profiling of a cohort of newly-diagnosed myeloma patients in our population. This study indicates that the genetic and cytogenetic abnormalities, and their frequencies, in our study group are generally similar to other populations.
- Published
- 2013
39. Chromosomes of oocytes failing in-vitro fertilization
- Author
-
Angela T.N. Ho, Maurine F.H. Tsakok, and Alvin Soon Tiong Lim
- Subjects
Adult ,medicine.medical_specialty ,Aneuploidy ,Trisomy ,Fertilization in Vitro ,Haploidy ,Biology ,Chromosome aberration ,Andrology ,medicine ,Humans ,Chromosome Aberrations ,Rehabilitation ,Cytogenetics ,Obstetrics and Gynecology ,Chromosome ,medicine.disease ,Diploidy ,Molecular biology ,Reproductive Medicine ,Nondisjunction ,Karyotyping ,Oocytes ,Chromosome abnormality ,Female ,Ploidy - Abstract
Of 263 oocytes that failed to fertilize after in-vitro fertilization and were sent for cytogenetic investigation, 179 (68.1%) were analysable. More than 72.0% were normal metaphase II haploids (23,X). Hyperhaploidy, hypohaploidy and complex cases made up a total aneuploidy rate of 12.3%, while 10.1% were diploid. In addition, there were five oocytes with structural aberrations and eight yielded chromatids only. The total chromosome aberration rate was 29.1%. No significant difference was found between the aneuploidy rate and maternal age. Here we present photographic evidence of oocytes with extra whole chromosomes and extra single chromatids. We suggest that both predivision and nondisjunction contribute to the formation of trisomy in man.
- Published
- 1995
40. Abstract 5008: Elucidating HER2 molecular heterogeneity of circulating tumor cells among breast cancer patients
- Author
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Alvin Soon Tiong Lim, Man Chun Leong, Yong Wei Chua, Rebecca Dent, Kiley Wei-Jen Loh, Raymond Ng, Andrew Wu, Chye Ling Tan, Yoon Sim Yap, Guek Eng Lee, Elaine Hsuen Lim, Wan-Teck Lim, and Tse Hui Lim
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Polysomy ,Pathology ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Primary tumor ,Targeted therapy ,Chromosome 17 (human) ,Cytokeratin ,Breast cancer ,Circulating tumor cell ,Internal medicine ,medicine ,skin and connective tissue diseases ,business ,neoplasms - Abstract
Background: HER2-positive tumors are often associated with poor prognosis, chemo-resistances and some patients eventually develop refractory disease during HER2 targeted therapy. While different mechanisms of trastuzumab resistance are being identified in recent years, contribution of confounding factors such as inherent genomic heterogeneity, equivocal HER2 amplifications and presence of chromosome 17 polysomy has been less understood thus far. In this pilot study, we aim to examine HER2 heterogeneity in CTCs obtained from breast cancer patients in the Asian population setting. Methods: CTCs were enriched from blood samples using a label-free spiral microfluidics-based ClearCell® FX system. A total of 26 samples were collected from patients diagnosed with HER2 positive (17/26) and HER2 negative (9/26) breast cancer. The enriched CTCs were analyzed using conventional diagnostic modalities (fluorescence in-situ hybridisation (FISH) and immunocytochemistry) to examine HER2 status. Concordance rate between CTCs and matched primary tumor was evaluated. Results: HER2-positive CTCs were successfully identified in 14 out of 17 HER2+ patients (82.4%); HER2 gene amplification and chromosome 17 polysomy were observed in 10(58.8%) and 13(76.5%) patients respectively. HER2+ CTC counts ranged from 2 to 30 cells from 7.5ml blood (median: 4 HER2+ CTCs/7.5ml). HER2 amplification was not observed in any of the 9 patients with HER2-negative tumors, though 5 out of 9 patients (55.6%) were identified with CTCs harbouring gain in chromosome 17 (median: 2 HER2+ CTCs/7.5ml). A “false positive” cut-off of more than 2 cells/7.5ml blood were established using receiver operating characteristic (ROC) curve analysis and a concordance rate of approximately 70% between paired tumor tissue and CTC among the 26 patients. Immunofluorescence labelling of CTCs with cytokeratin, CD45 and HER2 antibodies further revealed heterogeneity in HER2 expression on CTCs. Conclusion: CTCs capture the heterogeneity of breast cancer, and could potentially overcome limitations of tissue biopsy which are site specific. HER2- patients, as confirmed by tissue biopsy, with HER2+ CTCs pose interesting questions while determining treatment regime. Citation Format: Man Chun Leong, Tse Hui Lim, Chye Ling Tan, Yong Wei Chua, Elaine Hsuen Lim, Kiley Wei Jen Loh, Guek Eng Lee, Rebecca Dent, Raymond Chee Hui Ng, Andrew Wu, Wan-Teck Lim, Alvin Soon-Tiong Lim, Yoon-Sim Yap. Elucidating HER2 molecular heterogeneity of circulating tumor cells among breast cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5008.
- Published
- 2016
41. Synovial sarcoma of the kidney: a report of 4 cases with pathologic appraisal and differential diagnostic review
- Author
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Yia Swam, Tan, Lay Guat, Ng, Sidney Kam-Hung, Yip, Miah-Hiang, Tay, Alvin Soon-Tiong, Lim, Sim Leng, Tien, Liang, Cheng, and Puay Hoon, Tan
- Subjects
Adult ,Diagnosis, Differential ,Male ,Sarcoma, Synovial ,Oncogene Proteins, Fusion ,Humans ,Female ,Carcinoma, Renal Cell ,Kidney Neoplasms - Abstract
Synovial sarcoma of the kidney is rare. It is clinicoradiologically indistinguishable from the more frequently encountered renal cell carcinoma. Histologically it needs to be differentiated from other spindle cell lesions occurring within the kidney, including a spectrum of benign to malignant tumors. Among malignant spindle cell tumors of the kidney, mimics of synovial sarcoma are sarcomatoid renal cell carcinoma, sarcomatoid urothelial carcinoma and other primary sarcomas, such as leiomyosarcoma and malignant fibrous histiocytoma.Four cases of synovial sarcoma originated in the kidney, with this report focusing on clinicopathologic and differential diagnostic features.The correct diagnosis of synovial sarcoma requires support by an immunohistochemical panel as well as adjunctive investigations like polymerase chain reaction and fluorescence in situ hybridization to determine the presence of the SYT-SSX fusion gene and translocation (X,18), respectively.
- Published
- 2011
42. Correlation between semen parameters and the Hamster Egg Penetration Test (HEPT) among fertile and subfertile men in Singapore
- Author
-
T. F. Kruger, Lee Mee Ho, Tse Hui Lim, Alvin Soon Tiong Lim, Siew Chen Hum, and Su Ling Yu
- Subjects
Infertility ,Male ,medicine.medical_specialty ,Urology ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,Population ,Fertility ,Semen ,Biology ,Semen analysis ,In Vitro Techniques ,Andrology ,Endocrinology ,Cricetinae ,medicine ,Animals ,Humans ,education ,Infertility, Male ,media_common ,Retrospective Studies ,Gynecology ,Sperm-Ovum Interactions ,education.field_of_study ,Singapore ,medicine.diagnostic_test ,Receiver operating characteristic ,Mesocricetus ,medicine.disease ,Sperm ,Reproductive Medicine ,Female ,Reproduction - Abstract
The objective of this retrospective study was to distinguish between fertile and subfertile men based on their semen parameters and hamster egg penetration test (HEPT) outcome. This study involved 110 subfertile men recruited from an infertility clinic and 48 fertile men attending an antenatal clinic in Singapore. The men were required to donate a semen specimen for semen analysis and HEPT assay. The results indicated that the subfertile group had significantly lower normal sperm morphology according to the Tygerberg strict criteria, and lower progressive motility (P < .05). Semen volume, density, HEPT decondensation rate, and sperm penetration index were not significantly different between the 2 groups. Receiver operating characteristic curve analysis indicated that sperm morphology had the highest predictive power of 65.7% with a threshold value of 7%, and progressive motility had a predictive power of 61.8% with a threshold value of 50%. Using the tenth percentile of the fertile population as the cutoff, lower adjusted thresholds of 3% for sperm morphology and 28% for progressive motility were obtained, giving higher positive predictive values of 81.8% and 84.4%, respectively. This study shows that these new cutoff values can be used to screen the general population to identify subfertile men. In contrast, the HEPT proved to be an insensitive and unreliable assay in identifying subfertile males. To our knowledge the comparison of HEPT and semen parameters between subfertile and fertile men has not been previously reported in an Asian population.
- Published
- 2006
43. aCGH+SNP as a Promising Analytical Tool for the Detection of Chromosomal Abnormalities in Acute Leukemia
- Author
-
Chuanfei Chen, Li Min Teng, Sim Leng Tien, Lai Ching Lau, Tse Hui Lim, and Alvin Soon Tiong Lim
- Subjects
Cancer Research ,Acute leukemia ,Genetics ,SNP ,Computational biology ,Biology ,Bioinformatics ,Molecular Biology - Published
- 2014
44. Microscopic assessment of pronuclear embryos is not definitive
- Author
-
Victor H.H. Goh, Cai Lan Su, Alvin Soon Tiong Lim, and Su Ling Yu
- Subjects
Adult ,animal structures ,Fertilization in Vitro ,Biology ,Embryo Disposition ,Preimplantation genetic diagnosis ,Andrology ,Genetics ,medicine ,Humans ,Sperm Injections, Intracytoplasmic ,Genetics (clinical) ,In Situ Hybridization, Fluorescence ,Cell Nucleus ,Ploidies ,medicine.diagnostic_test ,Pronucleus ,Karyotype ,Embryo ,Embryo Transfer ,Embryo, Mammalian ,Embryo transfer ,Karyotyping ,embryonic structures ,Female ,Ploidy ,Fluorescence in situ hybridization - Abstract
The microscopic classification of embryos, especially unipronuclear embryos, is not very precise. A number of undocumented and unipronuclear embryos were determined to be diploid following karyotyping and fluorescence in situ hybridization (FISH). Accelerated and asynchronous pronuclear dismantling at the time of checking for embryo fertilization accounts for this disparity. Diploid embryos were also observed among tripronuclear embryos. However, not all embryos ascertained as diploid by FISH were karyotypically normal following full karyotype analysis. By taking into account the "background" abnormality rate, the rate of diploid embryo wastage was estimated to be about 40% among undocumented embryos and about 58% in total. A high percentage of misclassification infers an unintended loss of otherwise transferable embryos. Such a discrepancy is particularly important to older women who have fewer embryos. If these are a woman's only embryos, preimplantation genetic diagnosis might be applicable in determining those that are diploid and suitable for transfer. This could potentially reduce the number of wasted embryos and cycles. The present study has also shown that mosaicism is common but it is still unclear whether mosaicism is indicative of embryonic abnormality or is a fairly common phenomenon among healthy embryos. Bipronuclear embryos that present with abnormal or delayed cleavage are often chaotic in their chromosomal constitution. Such embryos should not be transferred.
- Published
- 2000
45. Analysis of the sex chromosome constitution of sperm in men with a 47, XYY mosaic karyotype by fluorescence in situ hybridization
- Author
-
Yang Fong, Alvin Soon Tiong Lim, and Su Ling Yu
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Aneuploidy ,Semen ,Biology ,Intracytoplasmic sperm injection ,Spermatocytes ,XYY Karyotype ,medicine ,Humans ,Lymphocytes ,In Situ Hybridization, Fluorescence ,Gynecology ,medicine.diagnostic_test ,Mosaicism ,Incidence (epidemiology) ,Obstetrics and Gynecology ,Karyotype ,Oligospermia ,medicine.disease ,Sperm ,Spermatids ,Spermatozoa ,Reproductive Medicine ,Infertility ,Karyotyping ,Hyperdiploidy ,Fluorescence in situ hybridization - Abstract
Objective: To determine the incidence of sex chromosome aneuploidy in the sperm of two men with a 47,XYY/46,XY karyotype. Design: Case report. Setting: Infertility clinic in a teaching hospital. Patient(s): One patient with near normal semen parameters whose wife had a history of miscarriages and one patient with primary infertility and severe oligoasthenozoospermia. Intervention(s): Cytogenetic analysis of peripheral lymphocytes and three-color X/Y/18 fluorescence in situ hybridization analysis of sperm. Main Outcome Measure(s): Analysis of sex chromosome disomy and diploidy rates in sperm. Result(s): Both patients had a 47,XYY/46,XY karyotype. The hyperdiploidy rate of patient 1 was 19% and that of patient 2 was 90%. The incidence of disomy XY was significantly elevated in both patients compared with the controls (0.23% and 1.02%, respectively, versus 0.10%). The incidence of disomy YY (0.44% versus 0.10%) was increased only in patient 2, as was the incidence of disomy 18 (0.49% versus 0.09%) and the rate of diploidy (0.83% versus 0.13%). The rate of 24,XX sperm in both patients was not different from that in the controls. Conclusion(s): Patients with a 47,XYY mosaic karyotype may be at risk of producing offspring with a hyperdiploid sex constitution. These patients should have their sperm investigated by fluorescence in situ hybridization to determine their particular risks before they undergo intracytoplasmic sperm injection.
- Published
- 1999
46. Estimates of sperm sex chromosome disomy and diploidy rates in a 47,XXY/46,XY mosaic Klinefelter patient
- Author
-
Yang Fong, Alvin Soon Tiong Lim, and Su Ling Yu
- Subjects
Adult ,Male ,medicine.medical_specialty ,X Chromosome ,medicine.medical_treatment ,Aneuploidy ,Biology ,Y chromosome ,Intracytoplasmic sperm injection ,Klinefelter Syndrome ,Internal medicine ,Y Chromosome ,Genetics ,medicine ,Humans ,Genetics (clinical) ,X chromosome ,In Situ Hybridization, Fluorescence ,Cell Nucleus ,urogenital system ,Mosaicism ,Karyotype ,medicine.disease ,Sperm ,Diploidy ,Spermatozoa ,Uniparental disomy ,Endocrinology ,Karyotyping ,Klinefelter syndrome - Abstract
A 47,XXY/46,XY male was investigated for the incidence of aneuploidy in sperm sex chromosomes using a three-colour X/Y/18 fluorescence in situ hybridisation (FISH) protocol. A total of 1701 sperm nuclei were analysed. The ratio of X-bearing to Y-bearing sperm did not differ from the expected 1 : 1 ratio although there were more 23,Y sperm than 23,X sperm (844 vs 795). There was a significantly increased proportion of disomy XY and XX sperm compared with normal controls (0.41% vs 0.10%, P < 0.001 and 0.29% vs 0.04%, P < 0.01). However, the incidence of YY sperm was similar to the controls (0.06% vs 0.02%). The diploidy rate was also significantly increased (1.7% vs 0.13%, P < 0.0001), as was disomy 18 (0.71% vs 0.01%) and 25,XXY (0.47% vs 0%). The results support the hypothesis that some 47,XXY cells are able to undergo meiosis and produce mature spermatozoa. Patients with mosaic Klinefelter syndrome with severe oligozoospermia have significantly elevated incidences of disomy XY and XX sperm and may be at a slightly increased risk of producing 47,XXX and 47,XXY offspring. Additionally, they may be at risk of producing offspring with autosomal trisomies. Hence, patients with Klinefelter mosaicism scheduled for intracytoplasmic sperm injection intervention should first undergo FISH analysis of their sperm to determine their risk.
- Published
- 1999
47. Age-related decline in fertility: a link to degenerative oocytes?
- Author
-
Maurine F.H. Tsakok and Alvin Soon Tiong Lim
- Subjects
Infertility ,Adult ,medicine.medical_specialty ,Aging ,Menotropins ,Microinjections ,media_common.quotation_subject ,medicine.medical_treatment ,Population ,Aneuploidy ,Fertility ,Fertilization in Vitro ,Biology ,Intracytoplasmic sperm injection ,Andrology ,Pregnancy ,medicine ,Humans ,education ,media_common ,Gynecology ,Chromosome Aberrations ,education.field_of_study ,Obstetrics and Gynecology ,medicine.disease ,Pregnancy rate ,Reproductive Medicine ,Karyotyping ,Oocytes ,Female ,Follicle Stimulating Hormone ,Embryo quality - Abstract
To determine whether the age-related decline in fertility is due to degenerative oocytes or to aneuploidy.Retrospective.Fertility center of a public and tertiary institution.One hundred fifty-one women (ages 24 to 44 years) undergoing 158 cycles of conventional IVF or IVF with intracytoplasmic sperm injection (ICSI) between January 1993 and December 1995 were divided into three age groups (group 1,or = 34 years; group 2, between 35 and 39 years; and group 3,or = 40 years). They were selected on the basis of available oocytes that remained unfertilized after IVF and that had analyzable chromosomes.Standard pituitary down-regulation and ovarian stimulation with FSH and hMG were done for both IVF and ICSI patients. In addition, all patients were given luteal phase support with P, administered orally, via pessaries, or by IM injections from the day of transfer.Fertilization rates and pregnancy rates (PRs), and cytogenetic analyses of unfertilized oocytes.Although fertilization rates were not different among women in groups 1, 2, and 3 (50.9%, 49.3%, and 37.9%, respectively), PRs were significantly lower between groups 1 and 3 (43.2% versus 14.3%). A total of 383 oocytes were examined, of which 287 (75%) could be karyotyped. Of these, 201 oocytes showed a normal 23,X karyotype (70%), 40 (13.9%) were aneuploid, 24 (8.4%) were diploid, 12 (4.2%) had structural aberrations, and 13 (4.5%) had single chromatids only. No increase in the aneuploidy rate was detected between groups 1 and 2 (14.8% versus 12.4%). However, highly significant differences in the rate of oocyte chromosome degeneration, characterized by chromosomes splitting into unassociated chromatids, were observed with increasing age (group 1, 23.7%; group 2, 52.0%; and group 3, 95.8%).It seems that the age-related decline in fertility may be due more to degenerative oocytes than to aneuploidy. A decline in the number of oocytes retrieved with age may be of less importance than the decline in oocyte quality. Women in the older age group have a higher chance of achieving pregnancy from ovum-donation programs than by persisting in using their own aged oocytes, which have a very poor prognosis for success.The hypothesis that the fertility decline observed in women over 40 years old is linked more to degenerative oocytes than to age-associated aneuploidy was investigated in 151 women 24-44 years old who underwent a total of 158 in vitro fertilization (IVF) cycles at Singapore General Hospital during 1993-95. Fertilization rates were 50.9% in women 34 years or younger, 49.3% in those 35-39 years old, and 37.9% in women 40 years or older. The pregnancy rates were 43.2%, 32.7%, and 14.3%, respectively. 287 (74.9%) of the 383 unfertilized oocytes could be karyotyped fully. The total chromosome abnormality rate was 30.3%; this included aneuploidy (13.9%), diploidy (8.4%), structural aberrations (4.2%), and single chromatids only (4.5%). A relationship between increased maternal age and an increase in the aneuploidy rate could not be assessed because of the small sample size in the oldest age group. The rate of chromatid separation increased significantly from 23.8% in the youngest age group to 95.8% in the oldest age group. This rate did not differ between in vitro fertilization and intracytoplasmic sperm injection. The degeneration evident in the majority of oocytes of older women presumably reflects decades of metabolic arrest at the dictyate stage. These findings suggest that the decline in the number of oocytes retrieved with age may be of less importance than the decline in oocyte quality. Women in the older age group have a greater likelihood of achieving pregnancy from ovum donation programs.
- Published
- 1997
48. A case of pure partial duplication 3q in a fetus due to a maternally inherited der(5)ins(5;3)(q33.1;q26.2q27) delineated by FISH
- Author
-
Tse Hui Lim, Alvin Soon Tiong Lim, D. H. Zaleski, P. Chia, Sim Leng Tien, D. L. Pickering, S. Raman, and Warren G. Sanger
- Subjects
Genetics ,Fetus ,Pediatrics ,medicine.medical_specialty ,business.industry ,Partial duplication ,Obstetrics and Gynecology ,Medicine ,%22">Fish ,business ,Genetics (clinical) - Published
- 2004
49. Mosaic trisomy 18 male with normal intelligence who fathered a normal baby girl
- Author
-
Alvin Soon Tiong Lim and Lan C. Su
- Subjects
Pediatrics ,medicine.medical_specialty ,Normal baby ,business.industry ,media_common.quotation_subject ,Normal intelligence ,Mosaic (geodemography) ,medicine.disease ,medicine ,Girl ,Trisomy ,business ,Genetics (clinical) ,media_common - Published
- 1998
50. Microscopic assessment of pronuclear embryos is not definitive.
- Author
-
Alvin Soon Tiong Lim, Victor Hng Hang Goh, Cai Lan Su, and Su Ling Yu
- Subjects
FERTILIZATION in vitro ,FLUORESCENCE in situ hybridization ,EMBRYOS ,HUMAN genetics ,GENETIC engineering ,OBSTETRICS ,GYNECOLOGY - Abstract
The microscopic classification of embryos, especially unipronuclear embryos, is not very precise. A number of undocumented and unipronuclear embryos were determined to be diploid following karyotyping and fluorescence in situ hybridization (FISH). Accelerated and asynchronous pronuclear dismantling at the time of checking for embryo fertilization accounts for this disparity. Diploid embryos were also observed among tripronuclear embryos. However, not all embryos ascertained as diploid by FISH were karyotypically normal following full karyotype analysis. By taking into account the "background" abnormality rate, the rate of diploid embryo wastage was estimated to be about 40% among undocumented embryos and about 58% in total. A high percentage of misclassification infers an unintended loss of otherwise transferable embryos. Such a discrepancy is particularly important to older women who have fewer embryos. If these are a woman's only embryos, preimplantation genetic diagnosis might be applicable in determining those that are diploid and suitable for transfer. This could potentially reduce the number of wasted embryos and cycles. The present study has also shown that mosaicism is common but it is still unclear whether mosaicism is indicative of embryonic abnormality or is a fairly common phenomenon among healthy embryos. Bipronuclear embryos that present with abnormal or delayed cleavage are often chaotic in their chromosomal constitution. Such embryos should not be transferred. [ABSTRACT FROM AUTHOR]
- Published
- 2000
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