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Journal of Cellular and Molecular... Aug 2021Major advances in the field of genomic technologies have led to an improvement in cancer diagnosis, classification and prognostication. However, many cancers remain... (Review)
Review
Major advances in the field of genomic technologies have led to an improvement in cancer diagnosis, classification and prognostication. However, many cancers remain incurable due to the development of drug resistance, minimal residual disease (MRD) and disease relapse, highlighting an incomplete understanding of the mechanisms underlying these processes. In recent years, the impact of non-genetic factors on neoplastic transformations has increasingly been acknowledged, and growing evidence suggests that low oxygen (O ) levels (ie hypoxia) in the tumour microenvironment play a critical role in the development and treatment of cancer. As a result, there is a growing need to develop research tools capable of reproducing physiologically relevant O conditions encountered by cancer cells in their natural environments in order to gain in-depth insight into tumour cell metabolism and function. In this review, the authors highlight the importance of hypoxia in the pathogenesis of malignant diseases and provide an overview of novel engineering tools that have the potential to further drive this evolving, yet technically challenging, field of cancer research.
Topics: Bioengineering; Humans; Hypoxia; Neoplasm, Residual; Neoplasms; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 34213838
DOI: 10.1111/jcmm.16759 -
Genome Biology Aug 2014DNA fragments released from cancer cells into the blood can be used to generate molecular profiles of tumors. Non-invasive 'liquid biopsies' can be used to monitor... (Review)
Review
DNA fragments released from cancer cells into the blood can be used to generate molecular profiles of tumors. Non-invasive 'liquid biopsies' can be used to monitor minimal residual disease and detect the emergence of drug resistance.
Topics: Cell-Free System; DNA, Neoplasm; Drug Resistance, Neoplasm; Genotype; Humans; Neoplasm, Residual; Neoplasms
PubMed: 25222559
DOI: 10.1186/s13059-014-0449-4 -
Current Oncology Reports Jul 2021Until recently, improvement in terms of survival for patients with acute myeloid leukemia (AML) was achieved mostly in younger patients with dose intensification of... (Review)
Review
PURPOSE OF REVIEW
Until recently, improvement in terms of survival for patients with acute myeloid leukemia (AML) was achieved mostly in younger patients with dose intensification of conventional chemotherapy and a broadening use of allogeneic hematopoietic cell transplantation (allo-HCT) whereas the results remained dismal and very stable in patients older than 60 years. The current review highlights the recent developments in standard intensive post-remission chemotherapy, evidence for the use of recently approved agents, and discusses the relevance of measurable residual disease (MRD) measurement in treatment adaptation.
RECENT FINDINGS
Current approvals of midostaurin, venetoclax, gemtuzumab ozogamicin, VYXEOS, ivosidenib, enasidenib, glasdegib, and CC-486 have changed the structure, aim, and schedule of consolidation therapy, and new, well-tolerated agents are being evaluated as maintenance therapies. Furthermore, MRD assessment has been implemented to guide the duration and type of consolidation and maintenance therapy as well as indicate the optimal timing of allo-HCT. Novel therapies have changed the structure and perspective of post-remission therapy in AML for both young and elderly patients. In addition, MRD assessment could guide the type, duration, and intensity of consolidation and maintenance therapy.
Topics: Acute Disease; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Male; Middle Aged; Neoplasm, Residual; Remission Induction; Survival Analysis; Transplantation, Homologous
PubMed: 34272619
DOI: 10.1007/s11912-021-01092-0 -
Expert Review of Hematology Apr 2019Commonly used scoring systems rely on blood counts, histological and cytological examination of bone marrow and peripheral blood as well as cytogenetic assessments to... (Review)
Review
Commonly used scoring systems rely on blood counts, histological and cytological examination of bone marrow and peripheral blood as well as cytogenetic assessments to estimate prognosis of patients with myelodysplastic syndromes (MDS) and guide therapy decisions. Next-generation sequencing (NGS) has identified recurrent genetic abnormalities in up to 90% of patients with MDS and may provide important information regarding the pathogenesis of the disease, diagnostic and prognostic evaluation, and therapy selection. Areas covered: Herein, the authors review the role of NGS in diagnosis, treatment, and prognosis of MDS at various disease stages, and discuss advantages and caveats of incorporating molecular genetics in routine management of MDS. While a vast majority of patients harbor recurrent mutations implicated in MDS pathogenesis, similar mutations can be detected in otherwise healthy individuals with other hematologic malignancies. Besides establishing a diagnosis, NGS may be used to monitor minimal residual disease following treatment. Expert opinion: As more targeted therapies become available, assessment of genetic mutations will become central to individualized therapy selection and may improve diagnostic accuracy and further guide management for each patient. However, multiple challenges remain before NGS can be incorporated into routine clinical practice.
Topics: Animals; High-Throughput Nucleotide Sequencing; Humans; Mutation; Myelodysplastic Syndromes; Neoplasm, Residual; Prognosis; Stem Cell Transplantation
PubMed: 30977414
DOI: 10.1080/17474086.2019.1592673 -
Leukemia & Lymphoma Aug 2018The primary hurdle in the path to curing multiple myeloma (MM) is defining a validated minimal residual disease (MRD) and its utility in the therapeutic decision making.... (Review)
Review
The primary hurdle in the path to curing multiple myeloma (MM) is defining a validated minimal residual disease (MRD) and its utility in the therapeutic decision making. A better definition of MRD will aid in tailoring MM therapy further to address the clonal heterogeneity and genomic instability and overcome patient's ineffective immune surveillance. MRD analysis can define the logical endpoint for maintenance therapy, in addition also aids in providing a better clinical end point for studies comparing novel agents in myeloma. MRD is a surrogate for the survival in MM. Guidelines for global incorporation of MRD in myeloma are fraught with lack of standardization, universal availability and abridged physicians' understanding of MRD modalities. We aimed at addressing some of the frequently asked questions in the MRD assessment and will also place in perspective some arguments in favor of MRD assessment in routine practice and clinical trial scenario.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Diagnostic Imaging; Disease-Free Survival; Gene Rearrangement; High-Throughput Nucleotide Sequencing; Humans; Multiple Myeloma; Neoplasm, Residual; Prognosis
PubMed: 29019452
DOI: 10.1080/10428194.2017.1386304 -
Seminars in Hematology Jan 2018Circulating tumor DNA faithfully recapitulates somatic mutations detected in bone marrow aspirates from patients with newly diagnosed or relapsed or recurrent myeloma.... (Review)
Review
Circulating tumor DNA faithfully recapitulates somatic mutations detected in bone marrow aspirates from patients with newly diagnosed or relapsed or recurrent myeloma. Extending these methods to enable detection of minimal residual disease will require increased sensitivity and breadth of genomic assays to maximize information content from small quantities of cell-free DNA; as well as definition of a clinically meaningful ctDNA concentration in comparison with conventional bone marrow cell-count thresholds. This review describes the use of cell-free DNA sequencing in myeloma to date, identifies challenges associated with pushing limit of detection of these assays into the realm of detecting minimal residual disease, and describes potential strategies to overcome these challenges.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; Humans; Multiple Myeloma; Neoplasm, Residual
PubMed: 29759151
DOI: 10.1053/j.seminhematol.2018.03.002 -
Archives of Pathology & Laboratory... Apr 2022Measurable (minimal) residual disease (MRD) is an independent prognostic factor for survival outcomes in patients with lymphoid and plasma cell malignancies and has been... (Review)
Review
CONTEXT.—
Measurable (minimal) residual disease (MRD) is an independent prognostic factor for survival outcomes in patients with lymphoid and plasma cell malignancies and has been incorporated into consensus criteria regarding treatment response, strategy, and clinical trial endpoints. clonoSEQ (a next-generation sequencing [NGS]-MRD assay) uses multiplex polymerase chain reaction and NGS to identify clonotypic rearrangements at the immunoglobulin (Ig) H, IgK, IgL, T-cell receptor (TCR)-β, and TCR-γ loci, as well as translocated B-cell lymphoma 1/IgH and 2/IgH sequences for MRD assessment. Additionally, it can be used to confirm diagnoses of cutaneous T-cell lymphoma (CTCL).
OBJECTIVE.—
To review the technical aspects of our experience using the clonoSEQ Assay in routine clinical practice.
DESIGN.—
In this single-center experience, 390 patients with lymphoid and plasma cell malignancies were assessed with the NGS-MRD Assay at a central laboratory.
RESULTS.—
Median time from arrival of the shipment to initiation of the assay (defined as captured in Adaptive's secure tracking system) was 2.1 hours. Overall, 317 patients had 1 or more samples submitted for sequence identification. Of these, 290 (91.5%) had trackable sequences identified. The median calibration rate of samples by malignancy (where n ≥ 10 samples, excluding CTCL samples) was 88.1%, across a variety of fresh and archived sample sources (177 of 201 samples). TCR-β and/or TCR-γ clonotypes were identified in 40 of 95 samples (42.1%) from 66 patients with suspected CTCL.
CONCLUSIONS.—
This NGS-MRD Assay is a valuable and sensitive tool for monitoring MRD in patients with plasma cell and lymphoid malignancies and assisting in the diagnosis of CTCL.
Topics: Gene Rearrangement; High-Throughput Nucleotide Sequencing; Humans; Neoplasm, Residual; Neoplasms, Plasma Cell; Receptors, Antigen, T-Cell
PubMed: 34343238
DOI: 10.5858/arpa.2020-0457-OA -
Nature Reviews. Cancer Apr 2018Therapeutics that block kinases, transcriptional modifiers, immune checkpoints and other biological vulnerabilities are transforming cancer treatment. As a result, many... (Review)
Review
Therapeutics that block kinases, transcriptional modifiers, immune checkpoints and other biological vulnerabilities are transforming cancer treatment. As a result, many patients achieve dramatic responses, including complete radiographical or pathological remission, yet retain minimal residual disease (MRD), which results in relapse. New functional approaches can characterize clonal heterogeneity and predict therapeutic sensitivity of MRD at a single-cell level. Preliminary evidence suggests that iterative detection, profiling and targeting of MRD would meaningfully improve outcomes and may even lead to cure.
Topics: Drug Therapy; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasm, Residual; Precision Medicine; Treatment Outcome
PubMed: 29376520
DOI: 10.1038/nrc.2017.125 -
Recent Results in Cancer Research.... 2012The mechanisms driving dormancy of disseminated tumor cells (DTCs) remain largely unknown. Here, we discuss experimental evidence and theoretical frameworks that support... (Review)
Review
The mechanisms driving dormancy of disseminated tumor cells (DTCs) remain largely unknown. Here, we discuss experimental evidence and theoretical frameworks that support three potential scenarios contributing to tumor cell dormancy. The first scenario proposes that DTCs from invasive cancers activate stress signals in response to the dissemination process and/or a growth suppressive target organ microenvironment inducing dormancy. The second scenario asks whether therapy and/or micro-environmental stress conditions (e.g. hypoxia) acting on primary tumor cells carrying specific gene signatures prime new DTCs to enter dormancy in a matching target organ microenvironment that can also control the timing of DTC dormancy. The third and final scenario proposes that early dissemination contributes a population of DTCs that are unfit for immediate expansion and survive mostly in an arrested state well after primary tumor surgery, until genetic and/or epigenetic mechanisms activate their proliferation. We propose that DTC dormancy is ultimately a survival strategy that when targeted will eradicate dormant DTCs preventing metastasis. For these non-mutually exclusive scenarios we review experimental and clinical evidence in their support.
Topics: Humans; Neoplasm, Residual; Neoplasms; Tumor Microenvironment
PubMed: 22527492
DOI: 10.1007/978-3-642-28160-0_3 -
Nature Reviews. Clinical Oncology Aug 2013Technological advances in the laboratory have led to substantial improvements in clinical decision making through the introduction of pretreatment prognostic risk... (Review)
Review
Technological advances in the laboratory have led to substantial improvements in clinical decision making through the introduction of pretreatment prognostic risk stratification factors in acute myeloid leukaemia (AML). Unfortunately, similar progress has not been made in treatment response criteria, with the definition of 'complete remission' in AML largely unchanged for over half a century. Several clinical trials have demonstrated that high-sensitivity measurements of residual disease burden during or after treatment can be performed, that results are predictive for clinical outcome and can be used to improve outcomes by guiding additional therapeutic intervention to patients in clinical complete remission, but at increased relapse risk. We review these recent trials, the characteristics and challenges of the modalities currently used to detect minimal residual disease (MRD), and outline opportunities to both refine detection and improve clinical use of MRD measurements. MRD measurement is already the standard of care in other myeloid malignancies, such as chronic myelogenous leukaemia and acute promyelocytic leukaemia (APL). It is our belief that response criteria for non-APL AML should be updated to include assessment for molecular complete remission and recommendations for post-consolidation surveillance should include regular monitoring for molecular relapse as standard of care.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Myeloid, Acute; Neoplasm, Residual
PubMed: 23799371
DOI: 10.1038/nrclinonc.2013.100