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Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL

BLOOD 2016年第3期127卷 279-286页

作者： Thompson, Philip A. Wierda, William G. Univ Texas MD Anderson Canc Ctr Dept Leukemia Houston TX 77030 USA

Deep remission and prolonged disease-free survival can be achieved with first-line chemoimmunotherapy (CIT), such as combined fludarabine, cyclophosphamide, and rituximab, in the majority of patients with chronic lymphocytic leukemia (CLL). More modest results are reported with less intense regimens like obinutuzumab plus chlorambucil. Clinical assessment has limited sensitivity indetecting residualdisease responsible for subsequent relapse, even including morphologic bone marrow (BM) evaluation. Multicolor flow cytometry and polymerase chain reaction (PCR)-based methods can detect minimal residual disease (MRD) to a sensitivity of >= 1: 10 000 (10(-4)). Achieving BM MRD-negative complete remission (CR) is associated with superior progression-free survival (PFS) and overall survival;MRD status is the single best posttreatment predictor of long-term outcomes after CIT. Newer oral B-cell receptor signaling pathway inhibitors are highly effective at controlling disease, but best monotherapy responses are typically partial remission, and patients must remain on treatment to maintain disease control. Therapeutic progress is still needed for CLL. We propose that targeting MRD provides opportunity to realize this progress. Achieving BM MRD-negative CR is a prerequisite for long-term unmaintained disease-free survival and potential for cure. We review available methodologies for detecting MRD and correlations with posttreatment outcomes. We discuss the potential utility of MRD to direct individualized therapy. Finally, we discuss the importance of MRD negative status as a surrogate marker for longer PFS in clinical studies to allow more rapid determination of clinical benefit.

关键词： Antineoplastic Combined Chemotherapy Protocols/therapeutic use Clinical Decision-Making flow cytometry/methods flow cytometry/methods Hematopoietic Stem Cell Transplantation Humans Immunotherapy/methods Leukemia, Lymphocytic, Chronic, B-Cell/mortality Leukemia, Lymphocytic, Chronic, B-Cell/pathology Leukemia, Lymphocytic, Chronic, B-Cell/therapy Neoplasm Staging Neoplasm Staging Neoplasm, Residual/diagnosis Neoplasm, Residual/therapy Polymerase Chain Reaction/methods Treatment Outcome

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A tumor deconstruction platform identifies definitive end points in the evaluation of drug responses

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ONCOGENE 2016年第6期35卷 727-737页

作者： Naik, R. R. Singh, A. K. Mali, A. M. Khirade, M. F. Bapat, S. A. Natl Ctr Cell Sci NCCS Complex Pune 411007 Maharashtra India

Tumor heterogeneity and the presence of drug-sensitive and refractory populations within the same tumor are almost never assessed in the drug discovery pipeline. Such incomplete assessment of drugs arising from spatial and temporal tumor cell heterogeneity reflects on their failure in the clinic and considerable wasted costs in the drug discovery pipeline. Here we report the derivation of a flow cytometry-based tumor deconstruction platform for resolution of at least 18 discrete tumor cell fractions. This is achieved through concurrent identification, quantification and analysis of components of cancer stem cell hierarchies, genetically instable clones and differentially cycling populations within a tumor. We also demonstrate such resolution of the tumor cytotype to be a potential value addition in drug screening through definitive cell target identification. Additionally, this real-time definition of intra-tumor heterogeneity provides a convenient, incisive and analytical tool for predicting drug efficacies through profiling perturbations within discrete tumor cell subsets in response to different drugs and candidates. Consequently, possible applications in informed therapeutic monitoring and drug repositioning in personalized cancer therapy would complement rational design of new candidates besides achieving a re-evaluation of existing drugs to derive non-obvious combinations that hold better chances of achieving remission.

关键词： Animals Antineoplastic Agents/isolation & purification Antineoplastic Agents/therapeutic use Cell Fractionation/methods Cell Fractionation/methods Cell Line, Tumor Clone Cells Drug Discovery/methods Drug Screening Assays, Antitumor/methods Drug Screening Assays, Antitumor/methods Endpoint Determination/methods Female flow cytometry/methods flow cytometry/methods Humans Mice Mice, Inbred NOD Mice, SCID Neoplasms/drug therapy Neoplasms/pathology Treatment Outcome Xenograft Model Antitumor Assays

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A novel hematopoietic progenitor cell mobilization and collection algorithm based on preemptive CD34 enumeration

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TRANSFUSION 2015年第8期55卷 2010-2016页

作者： Storch, Emily Mark, Tomer Avecilla, Scott Pagan, Carlos Rhodes, Joanna Shore, Tsiporah van Besien, Koen Cushing, Melissa New York Blood Ctr New York NY 10021 USA New York Presbyterian Hosp Dept Pathol New York NY USA New York Presbyterian Hosp Dept Med New York NY USA

BACKGROUND: The collection of autologous peripheral blood (PB) stem cells can be challenging in the subgroup of patients deemed "poor mobilizers" with granulocyte-colony-stimulating factor. Plerixafor, a CXCR-4 antagonist, is an alternative mobilizing agent, but is costly, and the optimal mobilization algorithm has yet to be determined. STUDY DESIGN AND methods: To address the question we developed a protocol measuring PB CD34 on Day 4 of mobilization. We examined 26 patients before initiating the protocol versus 24 patients after initiation. RESULTS: Significant differences (p <= 0.05) included fewer days of collection (1.25 days vs. 2.42 days), lower total blood volume processed (25.9 L vs. 57.2 L), lower total product volume (324 mL vs. 691 mL), lower RBC content (9 mL vs. 18 mL), and lower granulocyte percentage per collection (35% vs. 11%). There were no significant differences between the two groups in demographics, baseline platelet count, total CD34, or CD34/kg harvested. CONCLUSION: Use of a protocol to assess PB CD34 1 day before collection allows for preemptive administration of plerixafor to augment mobilization. Subsequently, days of collection and processed blood volume are reduced while there is less RBC and granulocyte contamination in the collected stem cell product.

关键词： Adult Aged Algorithms Antigens, CD34/blood Blood Cell Count/instrumentation Blood Cell Count/instrumentation Cell Separation/instrumentation Cell Separation/instrumentation Cell Separation/methods Cell Separation/methods Clinical Protocols Drug Synergism Erythrocytes Female flow cytometry/instrumentation flow cytometry/instrumentation flow cytometry/methods flow cytometry/methods Granulocyte Colony-Stimulating Factor/administration & dosage Granulocyte Colony-Stimulating Factor/pharmacology Granulocytes Hematologic Diseases/blood Hematologic Diseases/therapy Hematopoietic Stem Cell Mobilization/methods Heterocyclic Compounds/administration & dosage Heterocyclic Compounds/pharmacology Humans Male Middle Aged Peripheral Blood Stem Cell Transplantation Retrospective Studies Retrospective Studies Testicular Neoplasms/blood Testicular Neoplasms/therapy Time Factors Transplantation, Autologous Young Adult

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The flow cytometry-defined light chain cytoplasmic immunoglobulin index and an associated 12-gene expression signature are independent prognostic factors in multiple myeloma

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LEUKEMIA 2015年第8期29卷 1713-1720页

作者： Papanikolaou, X. Alapat, D. Rosenthal, A. Stein, C. Epstein, J. Owens, R. Yaccoby, S. Johnson, S. Bailey, C. Heuck, C. Tian, E. Joiner, A. van Rhee, F. Khan, R. Zangari, M. Jethava, Y. Waheed, S. Davies, F. Morgan, G. Barlogie, B. Univ Arkansas Med Sci Myeloma Inst Res & Therapy Little Rock AR 72205 USA Univ Arkansas Med Sci Dept Pathol Little Rock AR 72205 USA Canc Res & Biostat Seattle WA USA

As part of Total Therapy (TT) 3b, baseline marrow aspirates were subjected to two-color flow cytometry of nuclear DNA content and cytoplasmic immunoglobulin (DNA/CIG) as well as plasma cell gene expression profiling (GEP). DNA/CIG-derived parameters, GEP and standard clinical variables were examined for their effects on overall survival (OS) and progression-free survival (PFS). Among DNA/CIG parameters, the percentage of the light chain-restricted (LCR) cells and their cytoplasmic immunoglobulin index (CIg) were linked to poor outcome. In the absence of GEP data, low CIg <2.8, albumin <3.5 g/dl and age >= 65 years were significantly associated with inferior OS and PFS. When GEP information was included, low CIg survived the model along with GEP70-defined high risk and low albumin. Low CIg was linked to beta-2-microglobulin 45.5 mg/l, a percentage of LCR cells exceeding 50%, C-reactive protein >= 8 mg/l and GEP-derived high centrosome index. Further analysis revealed an association of low CIg with 12 gene probes implicated in cell cycle regulation, differentiation and drug transportation from which a risk score was developed in TT3b that held prognostic significance also in TT3a, TT2 and HOVON trials, thus validating its general applicability. Low CIg is a powerful new prognostic variable and has identified potentially drug-able targets.

关键词： Aged Biomarkers, Tumor/genetics Biomarkers, Tumor/metabolism Female flow cytometry/methods flow cytometry/methods Gene Expression Profiling Humans Immunoglobulin Light Chains/metabolism Male Multiple Myeloma/genetics Multiple Myeloma/genetics Multiple Myeloma/immunology Multiple Myeloma/immunology Multiple Myeloma/metabolism Multiple Myeloma/metabolism Multiple Myeloma/mortality Multiple Myeloma/mortality Neoplasm Staging Neoplasm Staging Oligonucleotide Array Sequence Analysis Prognosis Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger/genetics Survival Rate

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Deep profiling of multitube flow cytometry data

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BIOINFORMATICS 2015年第10期31卷 1623-1631页

作者： O'Neill, Kieran Aghaeepour, Nima Parker, Jeremy Hogge, Donna Karsan, Aly Dalal, Bakul Brinkman, Ryan R. British Columbia Canc Agcy Terry Fox Lab Vancouver BC V5Z 1L3 Canada Univ British Columbia Bioinformat Grad Program Vancouver BC V5Z 1M9 Canada Vancouver Gen Hosp Dept Hematopathol Vancouver BC Canada Univ British Columbia Fac Med Genet Vancouver BC V5Z 1M9 Canada

Motivation: Deep profiling the phenotypic landscape of tissues using high-throughput flow cytometry (FCM) can provide important new insights into the interplay of cells in both healthy and diseased tissue. But often, especially in clinical settings, the cytometer cannot measure all the desired markers in a single aliquot. In these cases, tissue is separated into independently analysed samples, leaving a need to electronically recombine these to increase dimensionality. Nearest-neighbour (NN) based imputation fulfils this need but can produce artificial subpopulations. Clustering-based NNs can reduce these, but requires prior domain knowledge to be able to parameterize the clustering, so is unsuited to discovery settings. Results: We present flowBin, a parameterization-free method for combining multitube FCM data into a higher-dimensional form suitable for deep profiling and discovery. flowBin allocates cells to bins defined by the common markers across tubes in a multitube experiment, then computes aggregate expression for each bin within each tube, to create a matrix of expression of all markers assayed in each tube. We show, using simulated multitube data, that flowType analysis of flowBin output reproduces the results of that same analysis on the original data for cell types of >10% abundance. We used flowBin in conjunction with classifiers to distinguish normal from cancerous cells. We used flowBin together with flowType and RchyOptimyx to profile the immunophenotypic landscape of NPM1-mutated acute myeloid leukemia, and present a series of novel cell types associated with that mutation.

关键词： Biomarkers, Tumor/genetics Case-Control Studies Cell Lineage Cell Separation Cell Separation flow cytometry/methods flow cytometry/methods Humans Immunophenotyping Immunophenotyping Leukemia, Myeloid, Acute/genetics Leukemia, Myeloid, Acute/genetics Leukemia, Myeloid, Acute/pathology Leukemia, Myeloid, Acute/pathology Leukocytes, Mononuclear/cytology Leukocytes, Mononuclear/metabolism Mutation/genetics Nuclear Proteins/genetics Software

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flowCL: ontology-based cell population labelling in flow cytometry

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BIOINFORMATICS 2015年第8期31卷 1337-1339页

作者： Courtot, Melanie Meskas, Justin Diehl, Alexander D. Droumeva, Radina Gottardo, Raphael Jalali, Adrin Taghiyar, Mohammad Jafar Maecker, Holden T. McCoy, J. Philip Ruttenberg, Alan Scheuermann, Richard H. Brinkman, Ryan R. Simon Fraser Univ Dept Biochem & Mol Biol Burnaby BC V5A 1S6 Canada British Columbia Canc Agcy Terry Fox Lab Vancouver BC V5Z 1L3 Canada SUNY Buffalo Sch Med & Biomed Sci Dept Neurol Buffalo NY 14203 USA Fred Hutchinson Canc Res Ctr Seattle WA 98109 USA Stanford Univ Sch Med Inst Immun Transplantat & Infect Stanford CA 94305 USA NHLBI NIH Bethesda MD 20892 USA NIH Ctr Human Immunol Autoimmun & Inflammat Bethesda MD 20892 USA SUNY Buffalo Sch Dent Med Buffalo NY 14214 USA J Craig Venter Inst La Jolla CA 92037 USA Univ Calif San Diego Dept Pathol San Diego CA 92093 USA

Motivation: Finding one or more cell populations of interest, such as those correlating to a specific disease, is critical when analysing flow cytometry data. However, labelling of cell populations is not well defined, making it difficult to integrate the output of algorithms to external knowledge sources. Results: We developed flowCL, a software package that performs semantic labelling of cell populations based on their surface markers and applied it to labelling of the Federation of Clinical Immunology Societies Human Immunology Project Consortium lyoplate populations as a use case. Conclusion: By providing automated labelling of cell populations based on their immunopheno-type, flowCL allows for unambiguous and reproducible identification of standardized cell types.

关键词： Algorithms Antigens, CD45/analysis Cell Physiological Phenomena flow cytometry/methods flow cytometry/methods Gene Ontology Humans Immunophenotyping/methods Immunophenotyping/methods Receptors, CCR7/analysis Software

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flowDensity: reproducing manual gating of flow cytometry data by automated density-based cell population identification

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BIOINFORMATICS 2015年第4期31卷 606-607页

作者： Malek, Mehrnoush Taghiyar, Mohammad Jafar Chong, Lauren Finak, Greg Gottardo, Raphael Brinkman, Ryan R. British Columbia Canc Agcy Res Ctr Terry Fox Lab Vancouver BC V5Z 1L3 Canada Fred Hutchinson Canc Res Ctr Vaccine & Infect Dis Div Seattle WA 98109 USA Univ British Columbia Bioinformat Training Program Vancouver BC V5Z 4S6 Canada

flowDensity facilitates reproducible, high-throughput analysis of flow cytometry data by automating a predefined manual gating approach. The algorithm is based on a sequential bivariate gating approach that generates a set of predefined cell populations. It chooses the best cut-off for individual markers using characteristics of the density distribution. The Supplementary Material is linked to the online version of the manuscript.

关键词： Algorithms Biomarkers Cell Physiological Phenomena Cluster Analysis Computational Biology/methods Databases, Factual flow cytometry/methods flow cytometry/methods Humans Software

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Accuracy of flow cytometric perforin screening for detecting patients with FHL due to PRF1 mutations

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BLOOD 2015年第15期126卷 1858-1859页

作者： Abdalgani, Manar Filipovich, Alexandra H. Choo, Sharon Zhang, Kejian Gifford, Carrie Villanueva, Joyce Bleesing, Jack J. Marsh, Rebecca A. Cincinnati Childrens Hosp Med Ctr Div Bone Marrow Transplantat & Immune Deficiency Cincinnati OH 45229 USA Royal Childrens Hosp Dept Allergy & Immunol Melbourne Vic Australia Cincinnati Childrens Hosp Med Ctr Div Human Genet Cincinnati OH 45229 USA

To the editor:

关键词： Adolescent Adult Aged Child Child, Preschool Female flow cytometry/methods flow cytometry/methods Follow-Up Studies High-Throughput Screening Assays Humans Infant Infant, Newborn Lymphohistiocytosis, Hemophagocytic/diagnosis Lymphohistiocytosis, Hemophagocytic/genetics Lymphohistiocytosis, Hemophagocytic/metabolism Male Middle Aged Mutation/genetics Perforin/genetics Perforin/metabolism Prognosis ROC Curve

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Nanowire array chips for molecular typing of rare trafficking leukocytes with application to neurodegenerative pathology

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NANOSCALE 2014年第12期6卷 6537-6550页

作者： Kwak, Minsuk Kim, Dong-Joo Lee, Mi-Ri Wu, Yu Han, Lin Lee, Sang-Kwon Fan, Rong Yale Univ Dept Biomed Engn New Haven CT 06520 USA Chonbuk Natl Univ Dept Semicond Sci & Technol Jeonju 561756 South Korea Chung Ang Univ Dept Phys Seoul 156756 South Korea Yale Comprehens Canc Ctr New Haven CT 06520 USA

Despite the presence of the blood-brain barrier (BBB) that restricts the entry of immune cells and mediators into the central nervous system (CNS), a small number of peripheral leukocytes can traverse the BBB and infiltrate into the CNS. The cerebrospinal fluid (CSF) is one of the major routes through which trafficking leukocytes migrate into the CNS. Therefore, the number of leukocytes and their phenotypic compositions in the CSF may represent important sources to investigate immune-to-brain interactions or diagnose and monitor neurodegenerative diseases. Due to the paucity of trafficking leucocytes in the CSF, a technology capable of efficient isolation, enumeration, and molecular typing of these cells in the clinical settings has not been achieved. In this study, we report on a biofunctionalized silicon nanowire array chip for highly efficient capture and multiplexed phenotyping of rare trafficking leukocytes in small quantities (50 microliters) of clinical CSF specimens collected from neurodegenerative disease patients. The antibody coated 3D nanostructured materials exhibited vastly improved rare cell capture efficiency due to high-affinity binding and enhanced cell-substrate interactions. Moreover, our platform creates multiple cell capture interfaces, each of which can selectively isolate specific leukocyte phenotypes. A comparison with the traditional immunophenotyping using flow cytometry demonstrated that our novel silicon nanowire-based rare cell analysis platform can perform rapid detection and simultaneous molecular characterization of heterogeneous immune cells. Multiplexed molecular typing of rare leukocytes in CSF samples collected from Alzheimer's disease patients revealed the elevation of white blood cell counts and significant alterations in the distribution of major leukocyte phenotypes. Our technology represents a practical tool for potentially diagnosing and monitoring the pathogenesis of neurodegenerative diseases by allowing an effective hema

关键词： Alzheimer Disease/cerebrospinal fluid Alzheimer Disease/immunology Alzheimer Disease/pathology Cells, Cultured Equipment Design Equipment Failure Analysis flow cytometry/instrumentation flow cytometry/instrumentation flow cytometry/methods flow cytometry/methods Humans Leukocytes/immunology Leukocytes/pathology Microfluidic Analytical Techniques/instrumentation Nanowires/chemistry Nanowires/ultrastructure

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Apoptotic pathways of U937 leukemic monocytes investigated by infrared microspectroscopy and flow cytometry

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ANALYST 2014年第12期139卷 3097-3106页

作者： Birarda, Giovanni Bedolla, Diana E. Mitri, Elisa Pacor, Sabrina Grenci, Gianluca Vaccari, Lisa SISSI Beamline Elettra Sincrotrone Trieste I-34149 Trieste Italy Univ Calif Berkeley Lawrence Berkeley Natl Lab Berkeley CA 94720 USA Univ Trieste I-34100 Trieste Italy CNR IOM TASC Lab I-34149 Trieste Italy Natl Univ Singapore Mechanobiol Inst MBI Singapore 117548 Singapore

Apoptosis is a strictly regulated cell death mechanism that plays a pivotal role in the normal evolution of multicellular organisms. Its misregulation has been associated with many diseases, making its early and reliable detection a key point for modern cellular biology. In this paper, we propose the use of infrared microspectroscopy (IRMS) as a label-free methodology for the detection of apoptotic-related biochemical processes induced on U937 leukemic monocytes by serum starvation and CCCP-exposure. The spectroscopic results are in agreement with parallel flow cytometry (FC) experiments, where plasma membrane integrity and mitochondrial activity were assessed. Spectroscopic outcomes complement FC data and allow drawing a more complete picture of the apoptotic pathways. In particular, we established that the two apoptosis-inducing treatments, cell starvation and CCCP exposure, affect the cell cycle in a different way. With the former, cell death is preceded by a cell cycle arrest, whereas the latter causes an increased cell cycle progression. Spectral data demonstrate that for both conditions apoptosis proceeds through the accumulation of lipid droplets within cells. Moreover, we were able to establish a spectral marker for DNA condensation/ fragmentation: the enhancement of the PhI band component centred at similar to 1206 cm(-1), which is more sensitive than the relative intensity of the PhII band to which phospholipids and carbohydrates also contribute significantly. In conclusion, we demonstrate that the intrinsic multi-parametric nature of IRMS and its application on cells under physiological conditions can be well exploited for the investigation of apoptotic pathways.

关键词： Apoptosis flow cytometry/methods flow cytometry/methods Humans Leukemia/pathology Monocytes/pathology Spectrophotometry, Infrared/methods U937 Cells

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