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Expert Review of Hematology 2023Minimal residual disease (MRD) has been an important biomarker for relapse prediction and treatment choice in patients with acute myeloid leukemia (AML). False-positive... (Review)
Review
INTRODUCTION
Minimal residual disease (MRD) has been an important biomarker for relapse prediction and treatment choice in patients with acute myeloid leukemia (AML). False-positive or false-negative MRD results due to the low specificity and sensitivity of techniques such as multiparameter flow cytometry (MFC), real-time quantitative polymerase chain reaction, and next-generation sequencing, as well as the biological characteristics of residual leukemia cells, including antigen shift, clone involution, heterogeneous genome of the blast cells, and lack of specific targets, all restrict the clinical use of MRD.
AREAS COVERED
We summarized the challenges of the techniques for MRD detection, and their application in the clinical setting. We also discussed strategies to overcome these challenges, such as the MFC MRD method based on leukemia stem cells, single-cell DNA sequencing or single-cell RNA sequencing for the investigation of biological characteristics of residual leukemia cells, and the potential of omics techniques for MRD detection. We further noted out that prospective clinical trials are needed to answer clinical questions related to MRD in patients with AML.
EXPERT OPINION
MRD is an important biomarker for individual therapy of patients with AML. In the future, it is important to increase the specificity and sensitivity of the detection techniques.
Topics: Humans; Neoplasm, Residual; Prospective Studies; Leukemia, Myeloid, Acute; Flow Cytometry; Biomarkers
PubMed: 37978882
DOI: 10.1080/17474086.2023.2285985 -
Histopathology Sep 2023The 8th Edition of the American Joint Committee on Cancer Staging System (yAJCC) excludes treatment-related fibrosis from the measurement of residual tumour after...
AIMS
The 8th Edition of the American Joint Committee on Cancer Staging System (yAJCC) excludes treatment-related fibrosis from the measurement of residual tumour after neoadjuvant chemotherapy (NAC) for breast cancer. The impact of the 8th Ed. yAJCC on post-NAC pathologic staging was examined in 188 breast cancer specimens from 183 patients with measurable residual tumour.
METHODS
Tumour size, ypT, and ypN categories were reassessed with the current yACC criteria and compared to the original pathology reports. Histological patterns of response in the breast were categorised as concentric or scattered.
RESULTS
The reassessed breast tumour size or ypT category differed from the original report in 101 (53.7%) cases. Changes in the ypT and/or ypN category resulted in downstaging of 45/185 (24.3%). A smaller reassessed tumour size or lower ypT category occurred more often in hormone receptor-positive/HER2-negative (HR+/HER2-) (68.3%) and HER2-positive (HER2+) tumours (74.0%) than triple-negative breast cancer (TNBC) (37.5%) (P < 0.001). A scattered pattern of response was more frequent in HR+/HER2- (54.9%) and HER2+ (66.0%) tumours than TNBC (35.7%) (P = 0.006). Changes in size, ypT, or multifocality based on the 8th Ed. yAJCC criteria were more frequent in tumours with a scattered pattern of response (P < 0.001).
CONCLUSION
Strict adherence to yAJCC criteria for measurement of the residual breast tumour after NAC resulted in smaller tumour size, lower ypT category, lower yAJCC stage, and more frequent classification of residual tumour as multifocal. Downstaging based on 8th Ed. yAJCC criteria was associated with tumour subtype and histological pattern of response.
Topics: Humans; Female; Breast Neoplasms; Neoadjuvant Therapy; Triple Negative Breast Neoplasms; Neoplasm, Residual; Receptor, ErbB-2; Breast; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Neoplasm Staging; Retrospective Studies
PubMed: 37256703
DOI: 10.1111/his.14966 -
Endocrine Jan 2024Assessment of pituitary adenoma (PA) volume and extent of resection (EOR) through manual segmentation is time-consuming and likely suffers from poor interrater...
PURPOSE
Assessment of pituitary adenoma (PA) volume and extent of resection (EOR) through manual segmentation is time-consuming and likely suffers from poor interrater agreement, especially postoperatively. Automated tumor segmentation and volumetry by use of deep learning techniques may provide more objective and quick volumetry.
METHODS
We developed an automated volumetry pipeline for pituitary adenoma. Preoperative and three-month postoperative T1-weighted, contrast-enhanced magnetic resonance imaging (MRI) with manual segmentations were used for model training. After adequate preprocessing, an ensemble of convolutional neural networks (CNNs) was trained and validated for preoperative and postoperative automated segmentation of tumor tissue. Generalization was evaluated on a separate holdout set.
RESULTS
In total, 193 image sets were used for training and 20 were held out for validation. At validation using the holdout set, our models (preoperative / postoperative) demonstrated a median Dice score of 0.71 (0.27) / 0 (0), a mean Jaccard score of 0.53 ± 0.21/0.030 ± 0.085 and a mean 95 percentile Hausdorff distance of 3.89 ± 1.96./12.199 ± 6.684. Pearson's correlation coefficient for volume correlation was 0.85 / 0.22 and -0.14 for extent of resection. Gross total resection was detected with a sensitivity of 66.67% and specificity of 36.36%.
CONCLUSIONS
Our volumetry pipeline demonstrated its ability to accurately segment pituitary adenomas. This is highly valuable for lesion detection and evaluation of progression of pituitary incidentalomas. Postoperatively, however, objective and precise detection of residual tumor remains less successful. Larger datasets, more diverse data, and more elaborate modeling could potentially improve performance.
Topics: Humans; Pituitary Neoplasms; Magnetic Resonance Imaging; Adenoma; Neoplasm, Residual; Image Processing, Computer-Assisted
PubMed: 37749388
DOI: 10.1007/s12020-023-03529-x -
Cancer Medicine Aug 2023Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection, which can identify disease relapse ahead of radiological imaging, has shown promising...
BACKGROUND
Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection, which can identify disease relapse ahead of radiological imaging, has shown promising performance. The objective of this study was to develop and validate OriMIRACLE S (Minimal Residual Circulating Nucleic Acid Longitudinal Detection in Solid Tumor), a highly sensitive and specific tumor-informed assay for MRD detection.
METHODS
Tumor-specific somatic single nucleotide variants (SNVs) were identified via whole exome sequencing of tumor tissue and matched germline DNA. Clonal SNVs were selected using the OriSelector algorithm for patient-specific, multiplex PCR-based NGS assays in MRD detection. Plasma-free DNA from patients with gastrointestinal tumors prior to and following an operation, and during monitoring, were ultradeep sequenced.
RESULTS
The detection of three positive sites was sufficient to achieve nearly 100% overall sample level sensitivity and specificity and was determined by calculating binomial probability based on customized panels containing 21 to 30 variants. A total of 127 patients with gastrointestinal tumors were enrolled in our study. Preoperatively, MRD was positive in 18 of 26 patients (69.23%). Following surgery, MRD was positive in 24 of 82 patients (29.27%). The positivity rate for MRD was 33.33% (n = 18) for gastric adenocarcinoma and 32.26% (n = 62) for colorectal cancer. Twenty (20) of 59 patients (34.48%) experienced a change in MRD status over the monitoring period. Patients 8 and 31 responded to 3 cycles of systemic therapy, after which levels for all ctDNA dropped below the detection limit. Patient 53 was an example of using MRD to predict tumor metastasis. Patient 55 showed a weak response to treatments first and respond to new systemic therapy after tumor progression.
CONCLUSION
Our study identified a sensitive and specific clinical detection method for low frequency ctDNA, and explored the detection performance of this technology in gastrointestinal tumors.
Topics: Humans; Circulating Tumor DNA; Neoplasm, Residual; Neoplasm Recurrence, Local; Gastrointestinal Neoplasms; Carcinoma
PubMed: 37602656
DOI: 10.1002/cam4.6286 -
Blood Advances Jul 2023Measurable residual disease (MRD) is an adverse prognostic factor in adult patients with acute lymphoblastic leukemia (ALL) undergoing hematopoietic cell transplant...
Measurable residual disease (MRD) is an adverse prognostic factor in adult patients with acute lymphoblastic leukemia (ALL) undergoing hematopoietic cell transplant (HCT). Next-generation sequencing (NGS) can detect MRD with a sensitivity of 10-6, but the prognostic value of NGS-based MRD in adult patients with ALL undergoing HCT remains minimally studied. To evaluate the prognostic value of NGS-based MRD in adult patients with ALL undergoing HCT, patients aged ≥18 years with ALL who underwent allogeneic HCT at Stanford University or Oregon Health & Science University between January 2014 and April 2021 and were evaluated for MRD using the NGS-based clonoSEQ assay were included in this study. MRD was assessed before HCT (MRDpre) and up to 1 year after HCT (MRDpost). Patients were followed up for leukemia relapse and survival for up to 2 years after HCT. In total, 158 patients had a trackable clonotype for MRD monitoring. The cumulative incidence of relapse was increased at all levels of MRDpre, including in patients who had low MRDpre of <10-4 (hazard ratio [HR], 3.56; 95% confidence interval [95% CI], 1.39-9.15). In multivariable analysis, MRDpre level remained significantly prognostic; however, detectable MRDpost was the strongest predictor of relapse (HR, 4.60; 95% CI, 3.01-7.02). In exploratory analyses limited to patients with B-cell ALL, the detection of post-HCT immunoglobulin H (IgH) MRD clonotypes, rather than non-IgH MRD clonotypes, was associated with relapse. In this analysis across 2 large transplant centers, we found that the detection of MRD by NGS at a level of 10-6 offers significant prognostic value in adults with ALL undergoing HCT.
Topics: Adult; Humans; Adolescent; Hematopoietic Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Transplantation, Homologous; Neoplasm, Residual; High-Throughput Nucleotide Sequencing
PubMed: 37196642
DOI: 10.1182/bloodadvances.2023009856 -
Trends in Cell Biology Mar 2024Cytotoxic chemo-, radio-, and targeted therapies frequently elicit apoptotic cancer cell death. Mitochondrial outer membrane permeabilization (MOMP) is a critical,... (Review)
Review
Cytotoxic chemo-, radio-, and targeted therapies frequently elicit apoptotic cancer cell death. Mitochondrial outer membrane permeabilization (MOMP) is a critical, regulated step in this apoptotic pathway. The residual cancer cells that survive treatment serve as the seeds of eventual relapse and are often functionally characterized by their transient tolerance of multiple therapeutic treatments. New studies suggest that, in these cells, a sublethal degree of MOMP, reflective of incomplete apoptotic commitment, is widely observed. Here, we review recent evidence that this sublethal MOMP drives the aggressive features of residual cancer cells while templating a host of unique vulnerabilities, highlighting how failed apoptosis may counterintuitively enable new therapeutic strategies to target residual disease (RD).
Topics: Humans; Mitochondrial Membranes; Mitochondria; Neoplasm, Residual; Apoptosis
PubMed: 37573235
DOI: 10.1016/j.tcb.2023.07.005 -
Journal of Clinical Oncology : Official... Oct 2023There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a...
PURPOSE
There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma.
METHODS
Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index.
RESULTS
In total, 17,930 LNs from 763 patients were examined. LN response classified as (LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%), (LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%), (LNRS 4-5; n = 303, 39.7%), or (no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio [HR], 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%).
CONCLUSION
Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.
Topics: Humans; Adenocarcinoma; Cohort Studies; Esophageal Neoplasms; Esophagectomy; Lymph Nodes; Neoadjuvant Therapy; Neoplasm Staging; Neoplasm, Residual; Prognosis; United Kingdom
PubMed: 37499209
DOI: 10.1200/JCO.23.00139 -
Current Treatment Options in Oncology Aug 2023Mantle cell lymphoma (MCL) treatment advances have significantly improved disease-free remission, with greater focus in clinical trials being placed on measurable... (Review)
Review
Mantle cell lymphoma (MCL) treatment advances have significantly improved disease-free remission, with greater focus in clinical trials being placed on measurable residual disease (MRD) as a marker of subclinical disease assessment. While this concept is used extensively in other haematological neoplasms, there is yet to be a consensus on the threshold for MRD in MCL that demonstrates prognostic and therapeutic significance, and in this context has yet to reach routine clinical practice. The historical long-term method for MCL MRD assessment has been real-time quantitative polymerase chain reaction (PCR), targeting the clonal immunoglobulin heavy locus (IGH) rearrangement or the IGH::CCND1 translocation rearrangement. A significant problem at present relates to identifying alternative assays for patients who do not have a suitable molecular target by this method. This article reviews existing techniques used in MRD assessment for MCL and describes novel methods which may overcome existing limitations, including next-generation sequencing modalities. The use of circulating tumour DNA is explored, with techniques such as CAPP-Seq and PhasED-Seq demonstrating promise in B-lymphoproliferative disorders, though application in MCL requires further study. The other aspect of practice using MRD is identifying therapeutic options which can address a subclinical molecular relapse. Developing suitable interventions that can alter the disease trajectory based on longitudinal MRD kinetics are needed to justify its incorporation into standard care.
Topics: Adult; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Translocation, Genetic; Prognosis; Neoplasm, Residual
PubMed: 37249800
DOI: 10.1007/s11864-023-01102-2 -
Interventional Neuroradiology : Journal... Oct 2023Meningiomas with transosseous extension provide opportunities for extensive preoperative embolization, through conventional trans-arterial approaches, and also through...
Meningiomas with transosseous extension provide opportunities for extensive preoperative embolization, through conventional trans-arterial approaches, and also through less commonly used percutaneous methods. This video demonstrates embolization of a 7.6 × 9.5 × 9.9 cm transosseous WHO grade II meningioma. Trans-arterial embolization was conducted via the left middle meningeal, occipital, and superficial temporal arteries. Only one superficial temporal artery was embolized to preserve vascular supply to the skin flap. To further devascularize the tumor, concomitant percutaneous embolization was performed. Transosseous extension of the tumor facilitated extensive percutaneous embolization of both the intracranial and extracranial components of the mass. Intraoperative bleeding from the scalp and extracranial component of the tumor was minimal. The intracranial tumor was soft and necrotic and was removed with suction and gentle dissection. Residual tumor was left behind within and adjacent to the superior sagittal sinus. The patient recovered without neurological deficit and was referred for radiation of the residual tumor.
Topics: Humans; Meningioma; Meningeal Neoplasms; Neoplasm, Residual; Embolization, Therapeutic; Preoperative Care
PubMed: 35506928
DOI: 10.1177/15910199221095982 -
Seminars in Hematology Jul 2023Large B-cell lymphomas (LBCLs) are a strikingly diverse set of diseases, including clinical, biological, and molecular heterogeneity. Despite a wealth of information...
Large B-cell lymphomas (LBCLs) are a strikingly diverse set of diseases, including clinical, biological, and molecular heterogeneity. Despite a wealth of information resolving this heterogeneity in the research setting, applying molecular features routinely in the clinic remains challenging. The advent of circulating tumor DNA (ctDNA) liquid biopsies promises to unlock additional molecular information in the clinic, including mutational genotyping, molecular classification, and minimal residual disease detection. Here, we examine the technologies, applications, and studies exploring the utility of ctDNA in LBCLs.
Topics: Humans; Cell-Free Nucleic Acids; Neoplasm, Residual; Biomarkers, Tumor; Circulating Tumor DNA; Lymphoma, B-Cell
PubMed: 37474409
DOI: 10.1053/j.seminhematol.2023.06.004