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Minimal Residual Disease of Cancers

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 44061

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Dr. Andrei Tchirkov

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Imagerie Moléculaire et Stratégies Théranostiques Faculté de Médecine, Unité INSERM 1240, Université Clermont Auvergne, CHU Clermont-Ferrand, 63003 Clermont Ferrand, France
Interests: minimal residual disease (MRD); hematological malignancies; pediatric tumors; digital PCR; new generation sequencing (NGS); telomere biology
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Special Issue Information

Dear Colleagues,

Minimal residual disease (MRD) is a very small population of cancer cells that persists in a patient in morphologic complete remission (CR) after treatment. The development in the late eighties of highly sensitive molecular tools based on the polymerase chain reaction (PCR) amplification of DNA sequences and mRNA transcripts resulting from tumor-specific chromosomal translocations has created opportunities to study MRD. After the introduction of quantitative real-time PCR, this approach has become a gold-standard method for MRD testing. Alternative approaches have been developed using the detection of tumor cell antigens with sensitive immunological methods. Finally, gene mutations are being increasingly used as biomarkers for MRD detection in liquid biopsies using digital droplet PCR and new generation sequencing.

As a result of these technological advances, there is a growing number of clinical applications of MRD measurement in a variety of hematological and solid tumors. Moreover, the introduction of effective targeted therapies and drug combinations has increased the rate of patients in CR who need MRD monitoring. Accurate measurement of MRD enables specialists to better assess treatment response, patient prognosis, and the risk of relapse. In several cancers, MRD assessment is now a part of routine investigations and a novel endpoint in clinical trials. However, many challenges remain. They concern the clinical significance of MRD in some cancers, the functional assessment of residual tumor cells, and the development of specific MRD-targeting approaches. This Special Issue will give us an excellent opportunity to highlight the most recent MRD applications and concepts, which can ultimately help guide specialists’ treatment decisions in patients with cancer.

Dr. Andrei Tchirkov
Guest Editor

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Keywords

Minimal Residual Disease (MRD)
Hematological malignancies
Solid tumors
MRD biomarkers
Real-time PCR
Digital PCR
NGS
Immunological MRD detection
Functional MRD assays
MRD targeting

Published Papers (11 papers)

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Research

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15 pages, 3515 KiB

Open AccessArticle

Glutamine Availability Controls BCR/Abl Protein Expression and Functional Phenotype of Chronic Myeloid Leukemia Cells Endowed with Stem/Progenitor Cell Potential

by Martina Poteti, Giulio Menegazzi, Silvia Peppicelli, Ignazia Tusa, Giulia Cheloni, Angela Silvano, Caterina Mancini, Alessio Biagioni, Alessandro Tubita, Nathalie M. Mazure, Matteo Lulli, Elisabetta Rovida and Persio Dello Sbarba

Cancers 2021, 13(17), 4372; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174372 - 30 Aug 2021

Cited by 4 | Viewed by 2466

Abstract

This study was directed to characterize the role of glutamine in the modulation of the response of chronic myeloid leukemia (CML) cells to low oxygen, a main condition of hematopoietic stem cell niches of bone marrow. Cells were incubated in atmosphere at 0.2% oxygen in the absence or the presence of glutamine. The absence of glutamine markedly delayed glucose consumption, which had previously been shown to drive the suppression of BCR/Abl oncoprotein (but not of the fusion oncogene BCR/abl) in low oxygen. Glutamine availability thus emerged as a key regulator of the balance between the pools of BCR/Abl protein-expressing and -negative CML cells endowed with stem/progenitor cell potential and capable to stand extremely low oxygen. These findings were confirmed by the effects of the inhibitors of glucose or glutamine metabolism. The BCR/Abl-negative cell phenotype is the best candidate to sustain the treatment-resistant minimal residual disease (MRD) of CML because these cells are devoid of the molecular target of the BCR/Abl-active tyrosine kinase inhibitors (TKi) used for CML therapy. Therefore, the treatments capable of interfering with glutamine action may result in the reduction in the BCR/Abl-negative cell subset sustaining MRD and in the concomitant rescue of the TKi sensitivity of CML stem cell potential. The data obtained with glutaminase inhibitors seem to confirm this perspective. Full article

(This article belongs to the Special Issue Minimal Residual Disease of Cancers)

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15 pages, 3737 KiB

Open AccessArticle

AML/Normal Progenitor Balance Instead of Total Tumor Load (MRD) Accounts for Prognostic Impact of Flowcytometric Residual Disease in AML

by Diana Hanekamp, Jesse M. Tettero, Gert J. Ossenkoppele, Angèle Kelder, Jacqueline Cloos and Gerrit Jan Schuurhuis

Cancers 2021, 13(11), 2597; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112597 - 26 May 2021

Cited by 4 | Viewed by 3145

Abstract

Measurable residual disease (MRD) in AML, assessed by multicolor flow cytometry, is an important prognostic factor. Progenitors are key populations in defining MRD, and cases of MRD involving these progenitors are calculated as percentage of WBC and referred to as white blood cell MRD (WBC-MRD). Two main compartments of WBC-MRD can be defined: (1) the AML part of the total primitive/progenitor (CD34+, CD117+, CD133+) compartment (referred to as primitive marker MRD; PM-MRD) and (2) the total progenitor compartment (% of WBC, referred to as PM%), which is the main quantitative determinant of WBC-MRD. Both are related as follows: WBC-MRD = PM-MRD × PM%. We explored the relative contribution of each parameter to the prognostic impact. In the HOVON/SAKK study H102 (300 patients), based on two objectively assessed cut-off points (2.34% and 10%), PM-MRD was found to offer an independent prognostic parameter that was able to identify three patient groups with different prognoses with larger discriminative power than WBC-MRD. In line with this, the PM% parameter itself showed no prognostic impact, implying that the prognostic impact of WBC-MRD results from the PM-MRD parameter it contains. Moreover, the presence of the PM% parameter in WBC-MRD may cause WBC-MRD false positivity and WBC-MRD false negativity. For the latter, at present, it is clinically relevant that PM-MRD ≥ 10% identifies a patient sub-group with a poor prognosis that is currently classified as good prognosis MRD^negative using the European LeukemiaNet 0.1% consensus MRD cut-off value. These observations suggest that residual disease analysis using PM-MRD should be conducted. Full article

(This article belongs to the Special Issue Minimal Residual Disease of Cancers)

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15 pages, 1547 KiB

Open AccessArticle

Prognostic Impacts of D816V KIT Mutation and Peri-Transplant RUNX1–RUNX1T1 MRD Monitoring on Acute Myeloid Leukemia with RUNX1–RUNX1T1

by Byung-Sik Cho, Gi-June Min, Sung-Soo Park, Silvia Park, Young-Woo Jeon, Seung-Hwan Shin, Seung-Ah Yahng, Jae-Ho Yoon, Sung-Eun Lee, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong Wook-Lee, Myung-Shin Kim, Yong-Goo Kim and Hee-Je Kim

Cancers 2021, 13(2), 336; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13020336 - 18 Jan 2021

Cited by 2 | Viewed by 2246

Abstract

The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, n = 112) or autologous HSCT (Auto-HSCT, n = 54). D816V KIT mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant RUNX1–RUNX1T1 MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V KIT mutation and pre-transplant RUNX1–RUNX1T1 MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V KIT mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V KIT mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V KIT mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V KIT mutation and RUNX1–RUNX1T1 MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches. Full article

(This article belongs to the Special Issue Minimal Residual Disease of Cancers)

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12 pages, 1306 KiB

Open AccessArticle

Specific and Sensitive Detection of Neuroblastoma mRNA Markers by Multiplex RT-qPCR

by Lieke M. J. van Zogchel, Lily Zappeij-Kannegieter, Ahmad Javadi, Marjolein Lugtigheid, Nina U. Gelineau, Nathalie S. M. Lak, Danny A. Zwijnenburg, Jan Koster, Janine Stutterheim, C. Ellen van der Schoot and Godelieve A. M. Tytgat

Cancers 2021, 13(1), 150; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13010150 - 05 Jan 2021

Cited by 12 | Viewed by 3413

Abstract

mRNA RT-qPCR is shown to be a very sensitive technique to detect minimal residual disease (MRD) in patients with neuroblastoma. Multiple mRNA markers are known to detect heterogeneous neuroblastoma cells in bone marrow (BM) or blood from patients. However, the limited volumes of BM and blood available can hamper the detection of multiple markers. To make optimal use of these samples, we developed a multiplex RT-qPCR for the detection of MRD in neuroblastoma. GUSB and PHOX2B were tested as single markers. The adrenergic markers TH, GAP43, CHRNA3 and DBH and mesenchymal markers POSTN, PRRX1 and FMO3 were tested in multiplex. Using control blood and BM, we established new thresholds for positivity. Comparison of multiplex and singleplex RT-qPCR results from 21 blood and 24 BM samples from neuroblastoma patients demonstrated a comparable sensitivity. With this multiplex RT-qPCR, we are able to test seven different neuroblastoma mRNA markers, which overcomes tumor heterogeneity and improves sensitivity of MRD detection, even in those samples of low RNA quantity. With resources and time being saved, reduction in sample volume and consumables can assist in the introduction of MRD by RT-qPCR into clinical practice. Full article

(This article belongs to the Special Issue Minimal Residual Disease of Cancers)

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16 pages, 1700 KiB

Open AccessArticle

Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma: Long Term Results of the International ALCL99 Trial

by Lara Mussolin, Marié-Cecilé Le Deley, Elisa Carraro, Christine Damm-Welk, Andishe Attarbaschi, Denise Williams, Amos Burke, Keizo Horibe, Atsuko Nakazawa, Grazyna Wrobel, Georg Mann, Monika Csóka, Anne Uyttebroeck, Rafael Fernández-Delgado Cerdá, Auke Beishuizen, Karin Mellgren, Birgit Burkhardt, Wolfram Klapper, Suzanne D. Turner, Emanuele S.G. d’Amore, Laurence Lamant, Alfred Reiter, Wilhelm Woessmann, Laurence Brugières, Marta Pillon and on behalf of the European Inter-Group for Childhood Non-Hodgkin lymphoma (EICNHL) Show full author list Hide full author list

Cancers 2020, 12(10), 2747; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102747 - 24 Sep 2020

Cited by 37 | Viewed by 4241

Abstract

With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern; a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern; and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively (p < 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments. Full article

(This article belongs to the Special Issue Minimal Residual Disease of Cancers)

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17 pages, 1733 KiB

Open AccessArticle

Expression Patterns of Coagulation Factor XIII Subunit A on Leukemic Lymphoblasts Correlate with Clinical Outcome and Genetic Subtypes in Childhood B-cell Progenitor Acute Lymphoblastic Leukemia

by Bettina Kárai, Katalin Gyurina, Anikó Ujfalusi, Łukasz Sędek, Gábor Barna, Pál Jáksó, Peter Svec, Eszter Szánthó, Attila Csaba Nagy, Judit Müller, Réka Simon, Ágnes Vojczek, István Szegedi, Lilla Györgyi Tiszlavicz, Jerzy R. Kowalczyk, Alexandra Kolenova, Gábor T. Kovács, Tomasz Szczepański, Michael Dworzak, Angela Schumich, Andishe Attarbaschi, Karin Nebral, Oskar A. Haas, János Kappelmayer, Zsuzsanna Hevessy and Csongor Kiss Show full author list Hide full author list

Cancers 2020, 12(8), 2264; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082264 - 13 Aug 2020

Cited by 2 | Viewed by 2108

Abstract

Background: Based on previous retrospective results, we investigated the association of coagulation FXIII subunit A (FXIII-A) expression pattern on survival and correlations with known prognostic factors of B-cell progenitor (BCP) childhood acute lymphoblastic leukemia (ALL) as a pilot study of the prospective multi-center BFM ALL-IC 2009 clinical trial. Methods: The study included four national centers (n = 408). Immunophenotyping by flow cytometry and cytogenetic analysis were performed by standard methods. Copy number alteration was studied in a subset of patients (n = 59). Survival rates were estimated by Kaplan-Meier analysis. Correlations between FXIII-A expression patterns and risk factors were investigated with Cox and logistic regression models. Results: Three different patterns of FXIII-A expression were observed: negative (<20%), dim (20–79%), and bright (≥80%). The FXIII-A dim expression group had significantly higher 5-year event-free survival (EFS) (93%) than the FXIII-A negative (70%) and FXIII-A bright (61%) groups. Distribution of intermediate genetic risk categories and the “B-other” genetic subgroup differed significantly between the FXIII-A positive and negative groups. Multivariate logistic regression confirmed independent association between the FXIII-A negative expression characteristics and the prevalence of intermediate genetic risk group. Conclusions: FXIII-A negativity is associated with dismal survival in children with BCP-ALL and is an indicator for the presence of unfavorable genetic alterations. Full article

(This article belongs to the Special Issue Minimal Residual Disease of Cancers)

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Review

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22 pages, 1111 KiB

Open AccessReview

Multiparametric Flow Cytometry for MRD Monitoring in Hematologic Malignancies: Clinical Applications and New Challenges

by Giovanni Riva, Vincenzo Nasillo, Anna Maria Ottomano, Giuliano Bergonzini, Ambra Paolini, Fabio Forghieri, Beatrice Lusenti, Patrizia Barozzi, Ivana Lagreca, Stefania Fiorcari, Silvia Martinelli, Rossana Maffei, Roberto Marasca, Leonardo Potenza, Patrizia Comoli, Rossella Manfredini, Enrico Tagliafico, Tommaso Trenti and Mario Luppi

Cancers 2021, 13(18), 4582; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184582 - 12 Sep 2021

Cited by 27 | Viewed by 8742

Abstract

Along with the evolution of immunophenotypic and molecular diagnostics, the assessment of Minimal Residual Disease (MRD) has progressively become a keystone in the clinical management of hematologic malignancies, enabling valuable post-therapy risk stratifications and guiding risk-adapted therapeutic approaches. However, specific prognostic values of MRD in different hematological settings, as well as its appropriate clinical uses (basically, when to measure it and how to deal with different MRD levels), still need further investigations, aiming to improve standardization and harmonization of MRD monitoring protocols and MRD-driven therapeutic strategies. Currently, MRD measurement in hematological neoplasms with bone marrow involvement is based on advanced highly sensitive methods, able to detect either specific genetic abnormalities (by PCR-based techniques and next-generation sequencing) or tumor-associated immunophenotypic profiles (by multiparametric flow cytometry, MFC). In this review, we focus on the growing clinical role for MFC-MRD diagnostics in hematological malignancies—from acute myeloid and lymphoblastic leukemias (AML, B-ALL and T-ALL) to chronic lymphocytic leukemia (CLL) and multiple myeloma (MM)—providing a comparative overview on technical aspects, clinical implications, advantages and pitfalls of MFC-MRD monitoring in different clinical settings. Full article

(This article belongs to the Special Issue Minimal Residual Disease of Cancers)

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22 pages, 764 KiB

Open AccessFeature PaperReview

Eradication of Measurable Residual Disease in AML: A Challenging Clinical Goal

by Paolo Bernasconi and Oscar Borsani

Cancers 2021, 13(13), 3170; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133170 - 25 Jun 2021

Cited by 8 | Viewed by 2345

Abstract

In non-promyelocytic (non-M3) AML measurable residual disease (MRD) detected by multi-parameter flow cytometry and molecular technologies, which are guided by Consensus-based guidelines and discover very low leukemic cell numbers far below the 5% threshold of morphological assessment, has emerged as the most relevant predictor of clinical outcome. Currently, it is well-established that MRD positivity after standard induction and consolidation chemotherapy, as well as during the period preceding an allogeneic hematopoietic stem cell transplant (allo-HSCT), portends to a significantly inferior relapse-free survival (RFS) and overall survival (OS). In addition, it has become absolutely clear that conversion from an MRD-positive to an MRD-negative state provides a favorable clinical outcome similar to that associated with early MRD negativity. Thus, the complete eradication of MRD, i.e., the clearance of the few leukemic stem cells—which, due to their chemo-radiotherapy resistance, might eventually be responsible of disease recurrence—has become an un-met clinical need in AML. Nowadays, this goal might potentially be achieved thanks to the development of novel innovative treatment strategies, including those targeting driver mutations, apoptosis, methylation patterns and leukemic proteins. The aim of this review is to analyze these strategies and to suggest any potential combination able to induce MRD negativity in the pre- and post-HSCT period. Full article

(This article belongs to the Special Issue Minimal Residual Disease of Cancers)

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24 pages, 10416 KiB

Open AccessReview

MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL

by Manuela Tosi, Orietta Spinelli, Matteo Leoncin, Roberta Cavagna, Chiara Pavoni, Federico Lussana, Tamara Intermesoli, Luca Frison, Giulia Perali, Francesca Carobolante, Piera Viero, Cristina Skert, Alessandro Rambaldi and Renato Bassan

Cancers 2021, 13(9), 2108; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092108 - 27 Apr 2021

Cited by 3 | Viewed by 6330

Abstract

In many clinical studies published over the past 20 years, adolescents and young adults (AYA) with Philadelphia chromosome negative acute lymphoblastic leukemia (Ph− ALL) were considered as a rather homogeneous clinico-prognostic group of patients suitable to receive intensive pediatric-like regimens with an improved outcome compared with the use of traditional adult ALL protocols. The AYA group was defined in most studies by an age range of 18–40 years, with some exceptions (up to 45 years). The experience collected in pediatric ALL with the study of post-induction minimal residual disease (MRD) was rapidly duplicated in AYA ALL, making MRD a widely accepted key factor for risk stratification and risk-oriented therapy with or without allogeneic stem cell transplantation and experimental new drugs for patients with MRD detectable after highly intensive chemotherapy. This combined strategy has resulted in long-term survival rates of AYA patients of 60–80%. The present review examines the evidence for MRD-guided therapies in AYA’s Ph− ALL, provides a critical appraisal of current treatment pitfalls and illustrates the ways of achieving further therapeutic improvement according to the massive knowledge recently generated in the field of ALL biology and MRD/risk/subset-specific therapy Full article

(This article belongs to the Special Issue Minimal Residual Disease of Cancers)

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15 pages, 3219 KiB

Open AccessReview

Minimal Disease Monitoring in Pediatric Non-Hodgkin’s Lymphoma: Current Clinical Application and Future Challenges

by Lara Mussolin, Christine Damm-Welk, Marta Pillon and Wilhelm Woessmann

Cancers 2021, 13(8), 1907; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081907 - 15 Apr 2021

Cited by 7 | Viewed by 2609

Abstract

Minimal residual disease (MRD) detection is established routine practice for treatment stratification in leukemia and used for treatment optimization in adult lymphomas. Minimal disease studies in childhood non-Hodgkin lymphomas are challenged by stratified treatment in different subtypes, high cure rates, low patient numbers, limited initial tumor material, and early progression. Current clinical applications differ between the subtypes. A prognostic value of minimal disseminated disease (MDD) could not yet be clearly established for lymphoblastic lymphoma using flow cytometry and PCR-based methods for T-cell receptor (TCR) or immunoglobulin (IG) rearrangements. MYC–IGH fusion sequences or IG rearrangements enable minimal disease detection in Burkitt lymphoma and -leukemia. An additional prognostic value of MDD in Burkitt lymphoma and early MRD in Burkitt leukemia is implicated by single studies with risk-adapted therapy. MDD and MRD determined by PCR for ALK-fusion transcripts are independent prognostic parameters for patients with ALK-positive anaplastic large cell lymphoma (ALCL). They are introduced in routine clinical practice and used for patient stratification in clinical studies. Early MRD might serve as an endpoint for clinical trials and for guiding individual therapy. Validation of MDD and MRD as prognostic parameters is required for all subtypes but ALCL. Next-generation sequencing-based methods may provide new options and applications for minimal disease evaluation in childhood lymphomas. Full article

(This article belongs to the Special Issue Minimal Residual Disease of Cancers)

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18 pages, 1134 KiB

Open AccessReview

Minimal Residual Disease in Acute Lymphoblastic Leukemia: Current Practice and Future Directions

by Gloria Paz Contreras Yametti, Talia H. Ostrow, Sylwia Jasinski, Elizabeth A. Raetz, William L. Carroll and Nikki A. Evensen

Cancers 2021, 13(8), 1847; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081847 - 13 Apr 2021

Cited by 24 | Viewed by 4983

Abstract

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and advances in its clinical and laboratory biology have grown exponentially over the last few decades. Treatment outcome has improved steadily with over 90% of patients surviving 5 years from initial diagnosis. This success can be attributed in part to the development of a risk stratification approach to identify those subsets of patients with an outstanding outcome that might qualify for a reduction in therapy associated with fewer short and long term side effects. Likewise, recognition of patients with an inferior prognosis allows for augmentation of therapy, which has been shown to improve outcome. Among the clinical and biological variables known to impact prognosis, the kinetics of the reduction in tumor burden during initial therapy has emerged as the most important prognostic variable. Specifically, various methods have been used to detect minimal residual disease (MRD) with flow cytometric and molecular detection of antigen receptor gene rearrangements being the most common. However, many questions remain as to the optimal timing of these assays, their sensitivity, integration with other variables and role in treatment allocation of various ALL subgroups. Importantly, the emergence of next generation sequencing assays is likely to broaden the use of these assays to track disease evolution. This review will discuss the biological basis for utilizing MRD in risk assessment, the technical approaches and limitations of MRD detection and its emerging applications. Full article

(This article belongs to the Special Issue Minimal Residual Disease of Cancers)

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