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Signal Transduction and Targeted Therapy Sep 2021Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other... (Clinical Trial)
Clinical Trial
Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas. In this study, we found that a combined treatment of local radiofrequency ablation (RFA) and melatonin (MLT) greatly improved clinical outcomes for early lung cancer patients with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Mechanically, as demonstrated in an associated mouse lung tumor model, RFA not only effectively remove treated tumors but also stimulate antitumor immunity, which could inhibit tumor growth in non-ablated areas. MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA. Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment, which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT. Analysis of residual tumor further revealed the depressed activity of MAPK, NF-kappa B, Wnt, and Hedgehog pathways and upregulated P53 pathway in tumors, which was in line with the inhibited tumor growth. Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy. These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules. Trial registration: www.chictr.org.cn , identifier ChiCTR2100042695, http://www.chictr.org.cn/showproj.aspx?proj=120931 .
Topics: Adult; Aged; Aged, 80 and over; Animals; Cell Proliferation; Combined Modality Therapy; Female; Hedgehog Proteins; Heterografts; Humans; Kaplan-Meier Estimate; Killer Cells, Natural; Lung Neoplasms; Male; Melatonin; Mice; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Multiple Pulmonary Nodules; NF-kappa B; Neoplasm, Residual; Progression-Free Survival; Radiofrequency Ablation; Treatment Outcome; Wnt Signaling Pathway
PubMed: 34471091
DOI: 10.1038/s41392-021-00745-7 -
Blood May 2024Experts from the European Leukemia Net (ELN) working group for adult acute lymphoblastic leukemia have identified an unmet need for guidance regarding management of... (Review)
Review
Experts from the European Leukemia Net (ELN) working group for adult acute lymphoblastic leukemia have identified an unmet need for guidance regarding management of adult acute lymphoblastic leukemia (ALL) from diagnosis to aftercare. The group has previously summarized their recommendations regarding diagnostic approaches, prognostic factors, and assessment of ALL. The current recommendation summarizes clinical management. It covers treatment approaches, including the use of new immunotherapies, application of minimal residual disease for treatment decisions, management of specific subgroups, and challenging treatment situations as well as late effects and supportive care. The recommendation provides guidance for physicians caring for adult patients with ALL which has to be complemented by regional expertise preferably provided by national academic study groups.
Topics: Humans; Adult; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Europe; Disease Management; Neoplasm, Residual; Prognosis
PubMed: 38306595
DOI: 10.1182/blood.2023023568 -
Clinical Cancer Research : An Official... Jun 2020Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking...
PURPOSE
Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing.
EXPERIMENTAL DESIGN
We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.
RESULTS
Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% ( = 13/16) in newly diagnosed MBC, 23% ( = 7/30) at postoperative and 19% ( = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months).
CONCLUSIONS
Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.
Topics: Adult; Breast Neoplasms; Circulating Tumor DNA; Combined Modality Therapy; Estrogen Receptor alpha; Female; Follow-Up Studies; Humans; Neoplasm Recurrence, Local; Neoplasm, Residual; Prognosis; Prospective Studies; Retrospective Studies; Survival Rate
PubMed: 32170028
DOI: 10.1158/1078-0432.CCR-19-3005 -
Oral Oncology Sep 2023Liquid biopsy has become a significant tool in personalized medicine, enabling real-time monitoring of cancer evolution and patient follow-up. This minimally invasive...
Liquid biopsy has become a significant tool in personalized medicine, enabling real-time monitoring of cancer evolution and patient follow-up. This minimally invasive procedure analyzes circulating tumor cells (CTCs) and circulating tumor-derived materials, such as ctDNA, miRNAs, and EVs. CTC analysis significantly impacts prognosis, detection of minimal residual disease (MRD), treatment selection, and monitoring of cancer patients. Liquid biopsy is an attractive option for mouth cancer detection and treatment progress monitoring in many countries. It is not invasive and requires no surgical expertise, making it an attractive option for mouth cancer detection. Liquid biopsy is a diagnostic repeatable test that can profile cancer genomes in real-time with minimal invasiveness and tailor oncological decision-making. It analyzes different blood-circulating biomarkers, with ctDNA being the preferred one. While tissue biopsy remains the gold standard for molecular evaluation of solid tumors, liquid biopsy is a complementary tool in various clinical settings, including treatment selection, monitoring response, cancer clonal evolution, prognostic evaluation, early disease detection, and minimal residual disease (MRD).
Topics: Humans; Neoplasm, Residual; Early Detection of Cancer; Head and Neck Neoplasms; Liquid Biopsy; Mouth Neoplasms; Biomarkers, Tumor
PubMed: 37399708
DOI: 10.1016/j.oraloncology.2023.106481 -
PLoS Medicine Oct 2021Beryne Odeny discusses PLOS Medicine's Special Issue on early cancer detection and minimal residual disease.
Beryne Odeny discusses PLOS Medicine's Special Issue on early cancer detection and minimal residual disease.
Topics: Cell-Free Nucleic Acids; Colorectal Neoplasms; DNA, Neoplasm; Early Detection of Cancer; Humans; Liquid Biopsy; Liver Neoplasms; Neoplasm Recurrence, Local; Neoplasm, Residual; Risk Factors
PubMed: 34637442
DOI: 10.1371/journal.pmed.1003794 -
Cold Spring Harbor Perspectives in... Apr 2020Recurrent metastasis following extended periods of disease-free survival remains a common cause of morbidity and mortality for many cancer patients. Recurrence is... (Review)
Review
Recurrent metastasis following extended periods of disease-free survival remains a common cause of morbidity and mortality for many cancer patients. Recurrence is thought to be mediated by tumor cells that escaped the primary site early in the disease course and colonize distant organs. In these locations, cells adapt to the local environment, entering a state of long-term dormancy in which they can resist therapy. Then, through mechanisms that are poorly understood, a proportion of these cells are reactivated and become proliferative, forming lethal metastases. Here, we discuss disseminated tumor cell dormancy in recurrent metastasis. We discuss mechanisms known to control entrance of cells into dormancy, highlighting the relevant microenvironments or "niches" in which these cells reside and mechanisms known to be involved in dormant cell reactivation. Finally, we consider emerging therapeutic approaches aimed at eradicating residual disease and preventing metastatic relapse.
Topics: Animals; Disease Progression; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplasms; Tumor Microenvironment
PubMed: 31548220
DOI: 10.1101/cshperspect.a037556 -
Surgical Pathology Clinics Jun 2023Genetic characterization of myeloma at diagnosis by interphase fluorescence in situ hybridization and next-generation sequencing (NGS) can assist with risk... (Review)
Review
Genetic characterization of myeloma at diagnosis by interphase fluorescence in situ hybridization and next-generation sequencing (NGS) can assist with risk stratification and treatment planning. Measurable residual disease (MRD) status after treatment, as evaluated by next-generation flow cytometry or NGS on bone marrow aspirate material, is one of the most important predictors of prognosis. Less-invasive tools for MRD assessment such as liquid biopsy approaches have also recently emerged as potential alternatives.
Topics: Humans; Multiple Myeloma; Pathology, Molecular; In Situ Hybridization, Fluorescence; Plasmacytoma; Prognosis; Neoplasm, Residual; High-Throughput Nucleotide Sequencing; Flow Cytometry
PubMed: 37149365
DOI: 10.1016/j.path.2023.01.005 -
Recent Results in Cancer Research.... 2020An accurate profiling of the genomic landscape is mandatory to establish the best clinical and therapeutic approach for patients with solid malignancies. Moreover, tumor... (Review)
Review
An accurate profiling of the genomic landscape is mandatory to establish the best clinical and therapeutic approach for patients with solid malignancies. Moreover, tumor cells constantly adapt to external pressures-i.e., systemic treatment-with the selection and expansion of resistant subclones and the emergence of heterogeneous overlapping genomic alterations of resistance. The current standard for molecular characterization in cancer is the performance of a tissue tumor biopsy at the time of diagnosis and, when possible, a re-biopsy at the time of progression. However, tissue biopsy is not always feasible or practical and may underestimate tumor heterogeneity and clonal dynamics. Circulating DNA fragments carrying tumor-specific sequence alterations (circulating tumor DNA, ctDNA) are released from cancer cells into the bloodstream, representing a variable and generally small fraction of the total circulating cell-free DNA. Tumor genotyping in ctDNA (liquid biopsy) offers potential advantages versus the standard tumor tissue biopsy, including non-invasiveness and representation of molecular heterogeneity. Technical advances in sequencing platforms have led to dramatic improvements in variant detection sensitivity and specificity that allow for the detection and quantification of low levels of ctDNA. This provides valuable information on both actionable mutations and captures real-time variations in tumor dynamics. Liquid biopsy clinical applications include molecular diagnosis, determination of tumor load as a surrogate marker of early response, monitoring of mutations of resistance to targeted therapy and detection of minimal residual disease after cancer surgery. The aim of this chapter is to provide an overview of the biological rational and technical background of ctDNA analysis, as well as on the main clinical applications of liquid biopsy in dynamic treatment stratification in solid tumors. Special emphasis will be made on the current and potential benefits of the implementation of ctDNA in clinical practice, mainly in melanoma, lung, and colorectal cancer.
Topics: Circulating Tumor DNA; Humans; Liquid Biopsy; Mutation; Neoplasm, Residual; Neoplasms
PubMed: 31605234
DOI: 10.1007/978-3-030-26439-0_14 -
Biomolecules Jan 2021Progression from localized to metastatic disease requires cancer cells spreading to distant organs through the bloodstream. Only a small proportion of these circulating... (Review)
Review
Progression from localized to metastatic disease requires cancer cells spreading to distant organs through the bloodstream. Only a small proportion of these circulating tumor cells (CTCs) survives dissemination due to anoikis, shear forces and elimination by the immune system. However, all metastases originate from CTCs capable of surviving and extravasating into distant tissue to re-initiate a tumor. Metastasis initiation is not always immediate as disseminated tumor cells (DTCs) may enter a non-dividing state of cell dormancy. Cancer dormancy is a reversible condition that can be maintained for many years without being clinically detectable. Subsequently, late disease relapses are thought to be due to cancer cells ultimately escaping from dormant state. Cancer dormancy is usually associated with minimal residual disease (MRD), where DTCs persist after intended curative therapy. Thus, MRD is commonly regarded as an indicator of poor prognosis in all cancers. In this review, we examine the current understanding of MRD and immunity during cancer progression to metastasis and discuss clinical perspectives for oncology.
Topics: Animals; Apoptosis; Clinical Trials as Topic; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Immune System; Immunotherapy; Medical Oncology; Mice; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplasms; Neoplastic Cells, Circulating; Prognosis; Signal Transduction
PubMed: 33498251
DOI: 10.3390/biom11020130 -
Journal For Immunotherapy of Cancer Jun 2023Liquid biopsies using cell-free circulating tumor DNA (ctDNA) are being used frequently in both research and clinical settings. ctDNA can be used to identify actionable... (Review)
Review
Liquid biopsies using cell-free circulating tumor DNA (ctDNA) are being used frequently in both research and clinical settings. ctDNA can be used to identify actionable mutations to personalize systemic therapy, detect post-treatment minimal residual disease (MRD), and predict responses to immunotherapy. ctDNA can also be isolated from a range of different biofluids, with the possibility of detecting locoregional MRD with increased sensitivity if sampling more proximally than blood plasma. However, ctDNA detection remains challenging in early-stage and post-treatment MRD settings where ctDNA levels are minuscule giving a high risk for false negative results, which is balanced with the risk of false positive results from clonal hematopoiesis. To address these challenges, researchers have developed ever-more elegant approaches to lower the limit of detection (LOD) of ctDNA assays toward the part-per-million range and boost assay sensitivity and specificity by reducing sources of low-level technical and biological noise, and by harnessing specific genomic and epigenomic features of ctDNA. In this review, we highlight a range of modern assays for ctDNA analysis, including advancements made to improve the signal-to-noise ratio. We further highlight the challenge of detecting ultra-rare tumor-associated variants, overcoming which will improve the sensitivity of post-treatment MRD detection and open a new frontier of personalized adjuvant treatment decision-making.
Topics: Humans; Circulating Tumor DNA; Neoplasm, Residual; Genomics
PubMed: 37349125
DOI: 10.1136/jitc-2022-006284