Z. Hugh Fan, PhD, is a professor of the Department of Mechanical and Aerospace Engineering, J. Crayton Pruitt Family Department of Biomedical Engineering, and Department of Chemistry at the University of Florida (UF), USA. Prior to joining UF in 2003, Dr. Fan was a Principal Scientist at ACLARA BioSciences Inc. and was previously a Member of the Technical Staff at Sarnoff Corp. Dr. Fan has been recognized with E.T.S. Walton Award from Science Foundation of Ireland in 2009, Fraunhofer-Bessel Research Award from Alexander von Humboldt Foundation (Germany) in 2010, and UF Research Foundation Professorship in 2014.

• List of Contributors xvForeword xxiPreface xxvPART I INTRODUCTION 11 Circulating Tumor Cells and Historic Perspectives 3Jonathan W. Uhr1.1 Early Studies on Cancer Dormancy Led to the Development of a Sensitive Assay for CTCs (1970–1998) 31.2 Modern Era for Counting CTCs: 1998–2007 61.3 Proof of Malignancy of CTCs 71.4 New Experiments Involving CTCs 71.5 Clinical Cancer Dormancy 81.6 Human Epidermal Growth Factor Receptor 2 (HER2) Gene Amplification can be Acquired as Breast Cancer Progresses 101.7 uPAR and HER2 Co-amplification 111.8 Epithelial–Mesenchymal Transition (EMT) 121.9 New Instruments to Capture CTCs 141.10 Genotypic Analyses 151.11 Conclusions 18References 202 Introduction to Microfluidics 33Kangfu Chen and Z. Hugh Fan2.1 Introduction 332.2 Scaling Law 362.3 Device Fabrication 392.4 Functional Components in Microfluidic Devices 432.5 Concluding Remarks 46References 47PART II ISOLATION METHODS 513 Ensemble-decision Aliquot Ranking (eDAR) for CTC Isolation and Analysis 53Mengxia Zhao, Perry G. Schiro, and Daniel T. Chiu3.1 Overview of eDAR 533.2 Individual Components and Analytical Performance of eDAR 553.3 Application and Downstream Analyses of eDAR 693.4 Conclusion and Perspective 80References 814 Sinusoidal Microchannels with High Aspect Ratios for CTC Selection and Analysis 85Joshua M. Jackson, Małgorzata A. Witek, and Steven A. Soper4.1 Introduction 854.2 Parallel Arrays of High-Aspect-Ratio, Sinusoidal Microchannels for CTC Selection 904.3 Clinical Applications of Sinusoidal CTC Microchip 1144.4 Conclusion 118Acknowledgments 119References 1195 Cell Separation using Inertial Microfluidics 127Nivedita Nivedita and Ian Papautsky5.1 Introduction 1275.2 Device Fabrication and System Setup 1285.3 Inertial Focusing in Microfluidics 1295.4 Cancer Cell Separation in Straight Microchannels 1325.5 Cancer Cell Separation in Spiral Microchannels 1365.6 Conclusions 142References 1426 Morphological Characteristics of CTCs and the Potential for Deformability-Based Separation 147Simon P. Duffy and Hongshen Ma6.1 Introduction 1476.2 Limitations of Antibody-based CTC Separation Methods 1486.3 Morphological and Biophysical Differences Between CTCs and Hematological Cells 1496.4 Historical and Recent Methods in CTC Separation Based on Biophysical Properties 1536.5 Microfluidic Ratchet for Deformability-Based Separation of CTCs 1556.6 Resettable Cell Trap for Deformability-based Separation of CTCs 1606.7 Summary 165References 1667 Microfabricated Filter Membranes for Capture and Characterization of Circulating Tumor Cells (CTCs) 173Zheng Ao, Richard J. Cote, Ram H. Datar, and Anthony Williams7.1 Introduction 1737.2 Size-based Enrichment of Circulating Tumor Cells 1747.3 Comparison Between Size-based CTC Isolation and Affinity-based Isolation 1777.4 Characterization of CTCs Captured by Microfilters 1787.5 Conclusion 180References 1818 Miniaturized Nuclear Magnetic Resonance Platform for Rare Cell Detection and Profiling 183Sangmoo Jeong, Changwook Min, Huilin Shao, Cesar M. Castro,Ralph Weissleder, and Hakho Lee8.1 Introduction 1838.2 μNMR Technology 1848.3 Clinical Application of μNMR for CTC Detection and Profiling 1918.4 Conclusion 196References 1969 Nanovelcro Cell-Affinity Assay for Detecting and Characterizing Circulating Tumor Cells 201Millicent Lin, Anna Fong, Sharon Chen, Yang Zhang, Jie-fu Chen, Paulina Do, Morgan Fong, Shang-Fu Chen, Pauline Yang, An-Jou Liang, Qingyu Li, Min Song, Shuang Hou, and Hsian-Rong Tseng9.1 Introduction 2029.2 Proof-of-Concept Demonstration of NanoVelcro Cell-Affinity Substrates 2079.3 First-Generation NanoVelcro Chips for CTC Enumeration 2099.4 Second-Generation NanoVelcro-LMD Technology for Single CTC Isolation 2149.5 Third-Generation Thermoresponsive NanoVelcro Chips 2199.6 Conclusions and Future Perspectives 220Acknowledgment 221References 22110 Acoustophoresis in Tumor Cell Enrichment 227Per Augustsson, Cecilia Magnusson, Hans Lilja, and Thomas Laurell10.1 Introduction 22710.2 Factors Determining Acoustophoresis Cell Separation 23010.3 Acoustophoresis System for Separating Cells 23410.4 Acoustophoresis Platform for Clinical Sample Processing 23910.5 Unperturbed Cell Survival and Phenotype after Microchip Acoustophoresis 24410.6 Summary 246References 24611 Photoacoustic Flow Cytometry for Detection and Capture of Circulating Melanoma Cells 249John A. Viator, Benjamin S. Goldschmidt, Kiran Bhattacharyya, and Kyle Rood11.1 Introduction 24911.2 Current Methods for Detection and Capture of CMCs 25411.3 Discussion 25911.4 Future Work 261References 26212 Selectin-Mediated Targeting of Circulating Tumor Cells for Isolation and Treatment 267Jocelyn R. Marshall and Michael R. King12.1 Introduction 26712.2 CTC Capture by E-selectin 27112.3 Applications for E-selectin in Cancer Diagnosis and Treatment 27312.4 Conclusions 278References 27913 Aptamer-Enabled Tumor Cell Isolation 287Jinling Zhang and Z. Hugh Fan13.1 Introduction 28713.2 Aptamers and their Biomedical Applications 28813.3 Aptamer-based Tumor Cell Isolation 29013.4 Conclusion and Outlook 297References 29714 Depletion of Normal Cells for CTC Enrichment 301Jeffrey J. Chalmers, Maryam B. Lustberg, Clayton Deighan, Kyoung-Joo Jenny Park, Yongqi Wu, and Peter Amaya14.1 Introduction 30114.2 Estimates of Number and Type of Cells in Blood 30214.3 Summary of Examples of Negative Depletion 30314.4 Types of Cells Observed After Depletion of Normal Cells 30514.5 Incomplete Depletion of Normal Cells 30514.6 Conclusion 310References 311PART III POST-ISOLATION ANALYSIS AND CLINICAL TRANSLATION 31315 Tumor Heterogeneity and Single-cell Analysis of CTCs 315Evelyn K. Sigal and Stefanie S. Jeffrey15.1 Introduction 31515.2 Tumor Heterogeneity 31615.3 Single-Cell Analysis of CTCs and CTC Heterogeneity 31815.4 Gene Expression Analysis 31915.5 Mutational Analysis 32115.6 Conclusion: Clinical Implications and Future Perspectives 323References 32416 Single-Cell Molecular Profiles and Biophysical Assessment of Circulating Tumor Cells 329Devalingam Mahalingam, Pawel Osmulski, Chiou-Miin Wang, Aaron M. Horning, Anna D. Louie, Chun-Lin Lin, Maria E. Gaczynska, and Chun-Liang Chen16.1 Introduction 32916.2 Methods 33116.3 CTC Applications 33616.4 Conclusions 342References 34317 Directing Circulating Tumor Cell Technologies Into Clinical Practice 351Benjamin P. Casavant, David Kosoff, and Joshua M. Lang17.1 Introduction 35117.2 Defining Biomarkers 35217.3 The Technology 35617.4 Translating Technology 35717.5 Conclusions 360References 361PART IV COMMERCIALIZATION 36518 DEPArray™ Technology for Single CTC Analysis 367Farideh Z. Bischoff, Gianni Medoro, and Nicolo Manaresi18.1 Challenges in Molecular Profiling of CTCs 36718.2 DEPArray™ Technology Solution 36818.3 DEPArray™ for Single Tumor Cell Analysis 36918.4 Clinical Significance in Single CTC Profiling 37318.5 Conclusion 374References 37419 CELLSEARCH® Instrument, Features, and Usage 377Denis A. Smirnov, Brad W. Foulk, Mark C. Connelly, and Robert T. McCormack19.1 Introduction 37719.2 Principles of CELLSEARCH® 37919.3 EpCAM Density and CTC Capture 38019.4 Clinical Applications of CELLSEARCH® CTCs 38319.5 Beyond EpCAM Capture 39019.6 Discussion 391References 394PART V GLOSSARY 401Circulating Tumor Cell Glossary 403Jose I. Varillas and Z. Hugh FanIndex 423

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Z. Hugh Fan, PhD, is a professor of the Department of Mechanical and Aerospace Engineering, J. Crayton Pruitt Family Department of Biomedical Engineering, and Department of Chemistry at the University of Florida (UF), USA. Prior to joining UF in 2003, Dr. Fan was a Principal Scientist at ACLARA BioSciences Inc. and was previously a Member of the Technical Staff at Sarnoff Corp. Dr. Fan has been recognized with E.T.S. Walton Award from Science Foundation of Ireland in 2009, Fraunhofer-Bessel Research Award from Alexander von Humboldt Foundation (Germany) in 2010, and UF Research Foundation Professorship in 2014.

• List of Contributors xvForeword xxiPreface xxvPART I INTRODUCTION 11 Circulating Tumor Cells and Historic Perspectives 3Jonathan W. Uhr1.1 Early Studies on Cancer Dormancy Led to the Development of a Sensitive Assay for CTCs (1970–1998) 31.2 Modern Era for Counting CTCs: 1998–2007 61.3 Proof of Malignancy of CTCs 71.4 New Experiments Involving CTCs 71.5 Clinical Cancer Dormancy 81.6 Human Epidermal Growth Factor Receptor 2 (HER2) Gene Amplification can be Acquired as Breast Cancer Progresses 101.7 uPAR and HER2 Co-amplification 111.8 Epithelial–Mesenchymal Transition (EMT) 121.9 New Instruments to Capture CTCs 141.10 Genotypic Analyses 151.11 Conclusions 18References 202 Introduction to Microfluidics 33Kangfu Chen and Z. Hugh Fan2.1 Introduction 332.2 Scaling Law 362.3 Device Fabrication 392.4 Functional Components in Microfluidic Devices 432.5 Concluding Remarks 46References 47PART II ISOLATION METHODS 513 Ensemble-decision Aliquot Ranking (eDAR) for CTC Isolation and Analysis 53Mengxia Zhao, Perry G. Schiro, and Daniel T. Chiu3.1 Overview of eDAR 533.2 Individual Components and Analytical Performance of eDAR 553.3 Application and Downstream Analyses of eDAR 693.4 Conclusion and Perspective 80References 814 Sinusoidal Microchannels with High Aspect Ratios for CTC Selection and Analysis 85Joshua M. Jackson, Małgorzata A. Witek, and Steven A. Soper4.1 Introduction 854.2 Parallel Arrays of High-Aspect-Ratio, Sinusoidal Microchannels for CTC Selection 904.3 Clinical Applications of Sinusoidal CTC Microchip 1144.4 Conclusion 118Acknowledgments 119References 1195 Cell Separation using Inertial Microfluidics 127Nivedita Nivedita and Ian Papautsky5.1 Introduction 1275.2 Device Fabrication and System Setup 1285.3 Inertial Focusing in Microfluidics 1295.4 Cancer Cell Separation in Straight Microchannels 1325.5 Cancer Cell Separation in Spiral Microchannels 1365.6 Conclusions 142References 1426 Morphological Characteristics of CTCs and the Potential for Deformability-Based Separation 147Simon P. Duffy and Hongshen Ma6.1 Introduction 1476.2 Limitations of Antibody-based CTC Separation Methods 1486.3 Morphological and Biophysical Differences Between CTCs and Hematological Cells 1496.4 Historical and Recent Methods in CTC Separation Based on Biophysical Properties 1536.5 Microfluidic Ratchet for Deformability-Based Separation of CTCs 1556.6 Resettable Cell Trap for Deformability-based Separation of CTCs 1606.7 Summary 165References 1667 Microfabricated Filter Membranes for Capture and Characterization of Circulating Tumor Cells (CTCs) 173Zheng Ao, Richard J. Cote, Ram H. Datar, and Anthony Williams7.1 Introduction 1737.2 Size-based Enrichment of Circulating Tumor Cells 1747.3 Comparison Between Size-based CTC Isolation and Affinity-based Isolation 1777.4 Characterization of CTCs Captured by Microfilters 1787.5 Conclusion 180References 1818 Miniaturized Nuclear Magnetic Resonance Platform for Rare Cell Detection and Profiling 183Sangmoo Jeong, Changwook Min, Huilin Shao, Cesar M. Castro,Ralph Weissleder, and Hakho Lee8.1 Introduction 1838.2 μNMR Technology 1848.3 Clinical Application of μNMR for CTC Detection and Profiling 1918.4 Conclusion 196References 1969 Nanovelcro Cell-Affinity Assay for Detecting and Characterizing Circulating Tumor Cells 201Millicent Lin, Anna Fong, Sharon Chen, Yang Zhang, Jie-fu Chen, Paulina Do, Morgan Fong, Shang-Fu Chen, Pauline Yang, An-Jou Liang, Qingyu Li, Min Song, Shuang Hou, and Hsian-Rong Tseng9.1 Introduction 2029.2 Proof-of-Concept Demonstration of NanoVelcro Cell-Affinity Substrates 2079.3 First-Generation NanoVelcro Chips for CTC Enumeration 2099.4 Second-Generation NanoVelcro-LMD Technology for Single CTC Isolation 2149.5 Third-Generation Thermoresponsive NanoVelcro Chips 2199.6 Conclusions and Future Perspectives 220Acknowledgment 221References 22110 Acoustophoresis in Tumor Cell Enrichment 227Per Augustsson, Cecilia Magnusson, Hans Lilja, and Thomas Laurell10.1 Introduction 22710.2 Factors Determining Acoustophoresis Cell Separation 23010.3 Acoustophoresis System for Separating Cells 23410.4 Acoustophoresis Platform for Clinical Sample Processing 23910.5 Unperturbed Cell Survival and Phenotype after Microchip Acoustophoresis 24410.6 Summary 246References 24611 Photoacoustic Flow Cytometry for Detection and Capture of Circulating Melanoma Cells 249John A. Viator, Benjamin S. Goldschmidt, Kiran Bhattacharyya, and Kyle Rood11.1 Introduction 24911.2 Current Methods for Detection and Capture of CMCs 25411.3 Discussion 25911.4 Future Work 261References 26212 Selectin-Mediated Targeting of Circulating Tumor Cells for Isolation and Treatment 267Jocelyn R. Marshall and Michael R. King12.1 Introduction 26712.2 CTC Capture by E-selectin 27112.3 Applications for E-selectin in Cancer Diagnosis and Treatment 27312.4 Conclusions 278References 27913 Aptamer-Enabled Tumor Cell Isolation 287Jinling Zhang and Z. Hugh Fan13.1 Introduction 28713.2 Aptamers and their Biomedical Applications 28813.3 Aptamer-based Tumor Cell Isolation 29013.4 Conclusion and Outlook 297References 29714 Depletion of Normal Cells for CTC Enrichment 301Jeffrey J. Chalmers, Maryam B. Lustberg, Clayton Deighan, Kyoung-Joo Jenny Park, Yongqi Wu, and Peter Amaya14.1 Introduction 30114.2 Estimates of Number and Type of Cells in Blood 30214.3 Summary of Examples of Negative Depletion 30314.4 Types of Cells Observed After Depletion of Normal Cells 30514.5 Incomplete Depletion of Normal Cells 30514.6 Conclusion 310References 311PART III POST-ISOLATION ANALYSIS AND CLINICAL TRANSLATION 31315 Tumor Heterogeneity and Single-cell Analysis of CTCs 315Evelyn K. Sigal and Stefanie S. Jeffrey15.1 Introduction 31515.2 Tumor Heterogeneity 31615.3 Single-Cell Analysis of CTCs and CTC Heterogeneity 31815.4 Gene Expression Analysis 31915.5 Mutational Analysis 32115.6 Conclusion: Clinical Implications and Future Perspectives 323References 32416 Single-Cell Molecular Profiles and Biophysical Assessment of Circulating Tumor Cells 329Devalingam Mahalingam, Pawel Osmulski, Chiou-Miin Wang, Aaron M. Horning, Anna D. Louie, Chun-Lin Lin, Maria E. Gaczynska, and Chun-Liang Chen16.1 Introduction 32916.2 Methods 33116.3 CTC Applications 33616.4 Conclusions 342References 34317 Directing Circulating Tumor Cell Technologies Into Clinical Practice 351Benjamin P. Casavant, David Kosoff, and Joshua M. Lang17.1 Introduction 35117.2 Defining Biomarkers 35217.3 The Technology 35617.4 Translating Technology 35717.5 Conclusions 360References 361PART IV COMMERCIALIZATION 36518 DEPArray™ Technology for Single CTC Analysis 367Farideh Z. Bischoff, Gianni Medoro, and Nicolo Manaresi18.1 Challenges in Molecular Profiling of CTCs 36718.2 DEPArray™ Technology Solution 36818.3 DEPArray™ for Single Tumor Cell Analysis 36918.4 Clinical Significance in Single CTC Profiling 37318.5 Conclusion 374References 37419 CELLSEARCH® Instrument, Features, and Usage 377Denis A. Smirnov, Brad W. Foulk, Mark C. Connelly, and Robert T. McCormack19.1 Introduction 37719.2 Principles of CELLSEARCH® 37919.3 EpCAM Density and CTC Capture 38019.4 Clinical Applications of CELLSEARCH® CTCs 38319.5 Beyond EpCAM Capture 39019.6 Discussion 391References 394PART V GLOSSARY 401Circulating Tumor Cell Glossary 403Jose I. Varillas and Z. Hugh FanIndex 423

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Z. Hugh Fan, PhD, is a professor of the Department of Mechanical and Aerospace Engineering, J. Crayton Pruitt Family Department of Biomedical Engineering, and Department of Chemistry at the University of Florida (UF), USA. Prior to joining UF in 2003, Dr. Fan was a Principal Scientist at ACLARA BioSciences Inc. and was previously a Member of the Technical Staff at Sarnoff Corp. Dr. Fan has been recognized with E.T.S. Walton Award from Science Foundation of Ireland in 2009, Fraunhofer-Bessel Research Award from Alexander von Humboldt Foundation (Germany) in 2010, and UF Research Foundation Professorship in 2014.

• List of Contributors xvForeword xxiPreface xxvPART I INTRODUCTION 11 Circulating Tumor Cells and Historic Perspectives 3Jonathan W. Uhr1.1 Early Studies on Cancer Dormancy Led to the Development of a Sensitive Assay for CTCs (1970–1998) 31.2 Modern Era for Counting CTCs: 1998–2007 61.3 Proof of Malignancy of CTCs 71.4 New Experiments Involving CTCs 71.5 Clinical Cancer Dormancy 81.6 Human Epidermal Growth Factor Receptor 2 (HER2) Gene Amplification can be Acquired as Breast Cancer Progresses 101.7 uPAR and HER2 Co-amplification 111.8 Epithelial–Mesenchymal Transition (EMT) 121.9 New Instruments to Capture CTCs 141.10 Genotypic Analyses 151.11 Conclusions 18References 202 Introduction to Microfluidics 33Kangfu Chen and Z. Hugh Fan2.1 Introduction 332.2 Scaling Law 362.3 Device Fabrication 392.4 Functional Components in Microfluidic Devices 432.5 Concluding Remarks 46References 47PART II ISOLATION METHODS 513 Ensemble-decision Aliquot Ranking (eDAR) for CTC Isolation and Analysis 53Mengxia Zhao, Perry G. Schiro, and Daniel T. Chiu3.1 Overview of eDAR 533.2 Individual Components and Analytical Performance of eDAR 553.3 Application and Downstream Analyses of eDAR 693.4 Conclusion and Perspective 80References 814 Sinusoidal Microchannels with High Aspect Ratios for CTC Selection and Analysis 85Joshua M. Jackson, Małgorzata A. Witek, and Steven A. Soper4.1 Introduction 854.2 Parallel Arrays of High-Aspect-Ratio, Sinusoidal Microchannels for CTC Selection 904.3 Clinical Applications of Sinusoidal CTC Microchip 1144.4 Conclusion 118Acknowledgments 119References 1195 Cell Separation using Inertial Microfluidics 127Nivedita Nivedita and Ian Papautsky5.1 Introduction 1275.2 Device Fabrication and System Setup 1285.3 Inertial Focusing in Microfluidics 1295.4 Cancer Cell Separation in Straight Microchannels 1325.5 Cancer Cell Separation in Spiral Microchannels 1365.6 Conclusions 142References 1426 Morphological Characteristics of CTCs and the Potential for Deformability-Based Separation 147Simon P. Duffy and Hongshen Ma6.1 Introduction 1476.2 Limitations of Antibody-based CTC Separation Methods 1486.3 Morphological and Biophysical Differences Between CTCs and Hematological Cells 1496.4 Historical and Recent Methods in CTC Separation Based on Biophysical Properties 1536.5 Microfluidic Ratchet for Deformability-Based Separation of CTCs 1556.6 Resettable Cell Trap for Deformability-based Separation of CTCs 1606.7 Summary 165References 1667 Microfabricated Filter Membranes for Capture and Characterization of Circulating Tumor Cells (CTCs) 173Zheng Ao, Richard J. Cote, Ram H. Datar, and Anthony Williams7.1 Introduction 1737.2 Size-based Enrichment of Circulating Tumor Cells 1747.3 Comparison Between Size-based CTC Isolation and Affinity-based Isolation 1777.4 Characterization of CTCs Captured by Microfilters 1787.5 Conclusion 180References 1818 Miniaturized Nuclear Magnetic Resonance Platform for Rare Cell Detection and Profiling 183Sangmoo Jeong, Changwook Min, Huilin Shao, Cesar M. Castro,Ralph Weissleder, and Hakho Lee8.1 Introduction 1838.2 μNMR Technology 1848.3 Clinical Application of μNMR for CTC Detection and Profiling 1918.4 Conclusion 196References 1969 Nanovelcro Cell-Affinity Assay for Detecting and Characterizing Circulating Tumor Cells 201Millicent Lin, Anna Fong, Sharon Chen, Yang Zhang, Jie-fu Chen, Paulina Do, Morgan Fong, Shang-Fu Chen, Pauline Yang, An-Jou Liang, Qingyu Li, Min Song, Shuang Hou, and Hsian-Rong Tseng9.1 Introduction 2029.2 Proof-of-Concept Demonstration of NanoVelcro Cell-Affinity Substrates 2079.3 First-Generation NanoVelcro Chips for CTC Enumeration 2099.4 Second-Generation NanoVelcro-LMD Technology for Single CTC Isolation 2149.5 Third-Generation Thermoresponsive NanoVelcro Chips 2199.6 Conclusions and Future Perspectives 220Acknowledgment 221References 22110 Acoustophoresis in Tumor Cell Enrichment 227Per Augustsson, Cecilia Magnusson, Hans Lilja, and Thomas Laurell10.1 Introduction 22710.2 Factors Determining Acoustophoresis Cell Separation 23010.3 Acoustophoresis System for Separating Cells 23410.4 Acoustophoresis Platform for Clinical Sample Processing 23910.5 Unperturbed Cell Survival and Phenotype after Microchip Acoustophoresis 24410.6 Summary 246References 24611 Photoacoustic Flow Cytometry for Detection and Capture of Circulating Melanoma Cells 249John A. Viator, Benjamin S. Goldschmidt, Kiran Bhattacharyya, and Kyle Rood11.1 Introduction 24911.2 Current Methods for Detection and Capture of CMCs 25411.3 Discussion 25911.4 Future Work 261References 26212 Selectin-Mediated Targeting of Circulating Tumor Cells for Isolation and Treatment 267Jocelyn R. Marshall and Michael R. King12.1 Introduction 26712.2 CTC Capture by E-selectin 27112.3 Applications for E-selectin in Cancer Diagnosis and Treatment 27312.4 Conclusions 278References 27913 Aptamer-Enabled Tumor Cell Isolation 287Jinling Zhang and Z. Hugh Fan13.1 Introduction 28713.2 Aptamers and their Biomedical Applications 28813.3 Aptamer-based Tumor Cell Isolation 29013.4 Conclusion and Outlook 297References 29714 Depletion of Normal Cells for CTC Enrichment 301Jeffrey J. Chalmers, Maryam B. Lustberg, Clayton Deighan, Kyoung-Joo Jenny Park, Yongqi Wu, and Peter Amaya14.1 Introduction 30114.2 Estimates of Number and Type of Cells in Blood 30214.3 Summary of Examples of Negative Depletion 30314.4 Types of Cells Observed After Depletion of Normal Cells 30514.5 Incomplete Depletion of Normal Cells 30514.6 Conclusion 310References 311PART III POST-ISOLATION ANALYSIS AND CLINICAL TRANSLATION 31315 Tumor Heterogeneity and Single-cell Analysis of CTCs 315Evelyn K. Sigal and Stefanie S. Jeffrey15.1 Introduction 31515.2 Tumor Heterogeneity 31615.3 Single-Cell Analysis of CTCs and CTC Heterogeneity 31815.4 Gene Expression Analysis 31915.5 Mutational Analysis 32115.6 Conclusion: Clinical Implications and Future Perspectives 323References 32416 Single-Cell Molecular Profiles and Biophysical Assessment of Circulating Tumor Cells 329Devalingam Mahalingam, Pawel Osmulski, Chiou-Miin Wang, Aaron M. Horning, Anna D. Louie, Chun-Lin Lin, Maria E. Gaczynska, and Chun-Liang Chen16.1 Introduction 32916.2 Methods 33116.3 CTC Applications 33616.4 Conclusions 342References 34317 Directing Circulating Tumor Cell Technologies Into Clinical Practice 351Benjamin P. Casavant, David Kosoff, and Joshua M. Lang17.1 Introduction 35117.2 Defining Biomarkers 35217.3 The Technology 35617.4 Translating Technology 35717.5 Conclusions 360References 361PART IV COMMERCIALIZATION 36518 DEPArray™ Technology for Single CTC Analysis 367Farideh Z. Bischoff, Gianni Medoro, and Nicolo Manaresi18.1 Challenges in Molecular Profiling of CTCs 36718.2 DEPArray™ Technology Solution 36818.3 DEPArray™ for Single Tumor Cell Analysis 36918.4 Clinical Significance in Single CTC Profiling 37318.5 Conclusion 374References 37419 CELLSEARCH® Instrument, Features, and Usage 377Denis A. Smirnov, Brad W. Foulk, Mark C. Connelly, and Robert T. McCormack19.1 Introduction 37719.2 Principles of CELLSEARCH® 37919.3 EpCAM Density and CTC Capture 38019.4 Clinical Applications of CELLSEARCH® CTCs 38319.5 Beyond EpCAM Capture 39019.6 Discussion 391References 394PART V GLOSSARY 401Circulating Tumor Cell Glossary 403Jose I. Varillas and Z. Hugh FanIndex 423

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