Advances In Liquid Biopsies Research Articles

Advances in liquid biopsy: Computational and artificial intelligence approaches in cancer research

Liquid biopsy analysis has emerged as a promising approach for non-invasive cancer monitoring and diagnosis. This review provides an overview of the current landscape and future potential of liquid biopsy in cancer research, with a particular focus on the computational methodologies and techniques utilized for liquid biopsy data analysis and interpretation. The challenges and opportunities in extracting meaningful insights from the vast array of genomic, epigenomic, transcriptomic, and proteomic data are discussed, as well as the possibilities and current pitfalls of artificial intelligence approaches. In addition, the benefits and limitations of integrating multimodal cancer research data are covered, with a focus on advancing precision oncology and personalized medicine. By providing a critical assessment of the field, this review aims to foster knowledge about the available computational approaches and facilitate the choice of the most appropriate methodology for in silico investigation of liquid biopsy data, ultimately enhancing research endeavors and disease management strategies. Most of the works discussed in this review have emerged within the past 5 years, indicating a rapidly growing interest in this technique.

Circulating tumor DNA predicts venous thromboembolism in patients with cancers

BackgroundDespite rapid advances in liquid biopsy for circulating tumor DNA (ctDNA), its prognostic value for venous thromboembolism (VTE) in patients with cancer is underexplored, particularly in underserved and minoritized populations. Objectives▪. MethodsWe analyzed data from 1038 cancer patients who underwent ctDNA measurement for oncologic care at a large safety-net hospital system in the United States. We investigated the association between ctDNA and VTE after adjusting for cancer type, stage, treatment, and time from initial diagnosis using Fine–Gray models. We further assessed the discrimination of the genetic, clinical-only, and combined models using the area under the time-dependent receiver operating characteristic curve (AUC). ResultsThe presence of pathogenic ctDNA was independently associated with VTE after adjusting for clinical variables. Independent of tumor type, the number of pathogenic ctDNA mutations was predictive of future VTE risk (adjusted subdistribution hazard ratios of 2.75, 1.94, and 1.38 for ≥3, 2, and 1 pathogenic mutation, respectively, compared with none; P < .0001). The association was primarily driven by mutations in KRAS, PTEN, CDKN2A, NF1, and EGFR genes. Compared with the clinical-only model (AUC, 0.71; 95% CI, 0.64-0.76), the combined clinical and ctDNA model had a numerically higher time-dependent AUC (AUC, 0.74; 95% CI, 0.67-0.80). ConclusionctDNA testing may serve as an adjunctive tool to clinical risk assessment models in cancer patients to improve personalized VTE risk assessment and management.

Advances in Liquid Biopsy for Diagnosis of Bladder Cancer.

Bladder cancer (BCa) is the most common malignancy of the urinary system. It has a high recurrence rate and requires longterm follow-up. Significant advances in BCa research have been made in recent years; however, the initial diagnosis and follow-up of BCa relies on cystoscopy, which is an invasive and expensive procedure. Over the past decade, liquid biopsies (e.g., blood and urine) have proven to be highly efficient methods for the discovery of BCa biomarkers. This noninvasive sampling method is used to analyze unique tumor components released into body fluids and enables serial sampling and longitudinal monitoring of tumor progression. Several liquid biopsy biomarkers have been studied extensively and have shown promising results in the clinical applications of BCa, including early detection, microscopic residual disease detection, recurrence prediction, and treatment response. Therefore, this review aims to provide an update on various new liquid biopsy markers and the advantages and current limitations of liquid biopsy in the diagnosis of BCa.

Recent advances in liquid biopsy of central nervous system lymphomas: case presentations and review of the literature.

Surgical biopsy is the gold standard for diagnosing central nervous system (CNS) lymphomas. However, reliable liquid biopsy methods for diagnosing CNS lymphomas have quickly developed and have been implicated in clinical decision-making. In the current report, we introduce two patients for whom liquid biopsy was essential for diagnosing CNS lymphomas and discuss the rapidly growing applications of this technology.

Molecular Biomarkers: Current Advances in Liquid Biopsy in the Diagnosis of Cancer

Molecular Biomarkers: Current Advances in Liquid Biopsy in the Diagnosis of Cancer

Advances in Liquid Biopsy Technology and Implications for Pancreatic Cancer.

Pancreatic cancer is a highly aggressive malignancy with a climbing incidence. The majority of cases are detected late, with incurable locally advanced or metastatic disease. Even in individuals who undergo resection, recurrence is unfortunately very common. There is no universally accepted screening modality for the general population and diagnosis, evaluation of treatment response, and detection of recurrence relies primarily on the use of imaging. Identification of minimally invasive techniques to help diagnose, prognosticate, predict response or resistance to therapy, and detect recurrence are desperately needed. Liquid biopsies represent an emerging group of technologies which allow for non-invasive serial sampling of tumor material. Although not yet approved for routine use in pancreatic cancer, the increasing sensitivity and specificity of contemporary liquid biopsy platforms will likely change clinical practice in the near future. In this review, we discuss the recent technological advances in liquid biopsy, focusing on circulating tumor DNA, exosomes, microRNAs, and circulating tumor cells.

Liquid Biopsy Detecting Circulating Tumor Cells in Patients with Non-Small Cell Lung Cancer: Preliminary Results of a Pilot Study.

Lung cancer is still the leading cause of cancer-related death worldwide. Interest is growing towards early detection and advances in liquid biopsy to isolate circulating tumor cells (CTCs). This pilot study aimed to detect epithelial CTCs in the peripheral blood of early-stage non-small cell lung cancer (NSCLC) patients. We used Smart BioSurface® (SBS) slide, a nanoparticle-coated slide able to immobilize viable nucleated cellular fraction without pre-selection and preserve cell integrity. Forty patients undergoing lung resection for NSCLC were included; they were divided into two groups according to CTC value, with a cut-off of three CTCs/mL. All patients were positive for CTCs. The mean CTC value was 4.7(± 5.8 S.D.) per ml/blood. In one patient, next generation sequencing (NGS) analysis of CTCs revealed v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation, which has also been identified in tissue biopsy. CTCs count affected neither overall survival (OS, p = 0.74) nor progression-free survival (p = 0.829). Multivariable analysis confirmed age (p = 0.020) and pNodal-stage (p = 0.028) as negative predictors of OS. Preliminary results of this pilot study suggest the capability of this method in detecting CTCs in all early-stage NSCLC patients. NGS on single cell, identified as CTC by immunofluorescence staining, is a powerful tool for investigating the molecular landscape of cancer, with the aim of personalized therapies.

Advances in liquid biopsy-based markers in NSCLC.

Lung cancer is the second most-frequently occurring cancer and the leading cause of cancer-associated deaths worldwide. Non-small cell lung cancer (NSCLC), the most common type of lung cancer is often diagnosed in middle or advanced stages and have poor prognosis. Diagnosis of disease at an early stage is a key factor for improving prognosis and reducing mortality, whereas, the currently used diagnostic tools are not sufficiently sensitive for early-stage NSCLC. The emergence of liquid biopsy has ushered in a new era of diagnosis and management of cancers, including NSCLC, since analysis of circulating tumor-derived components, such as cell-free DNA (cfDNA), circulating tumor cells (CTCs), cell-free RNAs (cfRNAs), exosomes, tumor-educated platelets (TEPs), proteins, and metabolites in blood or other biofluids can enable early cancer detection, treatment selection, therapy monitoring and prognosis assessment. There have been great advances in liquid biopsy of NSCLC in the past few years. Hence, this chapter introduces the latest advances on the clinical application of cfDNA, CTCs, cfRNAs and exosomes, with a particular focus on their application as early markers in the diagnosis, treatment and prognosis of NSCLC.

Risk Stratification of Pancreatic Neuroendocrine Neoplasms Based on Clinical, Pathological, and Molecular Characteristics.

Pancreatic neuroendocrine neoplasms consist of heterogeneous diseases. Depending on the novel features detected by various modern technologies, their classification and related prognosis predictions continue to change and develop. The role of traditional clinicopathological prognostic factors, including classification systems, is also being refined, and several attempts have been made to predict a more accurate prognosis through novel serum biomarkers, genetic factors, and epigenetic factors that have been identified through various state-of-the-art molecular techniques with multiomics sequencing. In this review article, the latest research results including the traditional approach to prognostic factors and recent advanced strategies for risk stratification of pancreatic neuroendocrine neoplasms based on clinical, pathological, and molecular characteristics are summarized. Predicting prognosis through multi-factorial assessments seems to be more efficacious, and prognostic factors through noninvasive methods are expected to develop further advances in liquid biopsy in the future.

Liquid biopsy for early detection and therapeutic monitoring of hepatocellular carcinoma.

Advances in our knowledge of the molecular characteristics of hepatocellular carcinoma (HCC) have enabled significant progress in the detection and therapeutic prediction of HCC. As a non-invasive alternative to tissue biopsy, liquid biopsy examines circulating cellular components such as exosomes, nucleic acids, and cell-free DNA found in body fluids (e.g., urine, saliva, ascites, and pleural effusions) and provides information about tumor characteristics. Technical advances in liquid biopsy have led to the increasing adoption of diagnostic and monitoring applications for HCC. This review summarizes the various analytes, ongoing clinical trials, and case studies of United States Food and Drug Administrationapproved in vitro diagnostic applications for liquid biopsy, and provides insight into its implementation in managing HCC.

Recent advances in liquid biopsy in cancers: Diagnosis, disease state and treatment response monitoring

AbstractRecent years have witnessed the development of scientific research and clinical trials of liquid biopsy in various diseases, especially cancers. Liquid biopsy refers to a procedure in which components, including circulating tumour cells (CTCs), cell‐free nucleic acids (cfDNA and cfRNA) and small extracellular vesicles (sEVs), are obtained from blood or other biofluids for analyses. Together with other biocomponents present in liquid biopsies, including CTCs and cell‐free nucleic acids, sEVs are now hotly anticipated as analytical tools and are expected to help identify early‐stage patients and improve cancer patient survival. The independence from tissue availability further confers on liquid biopsy exclusive roles in patient follow‐up and treatment response monitoring. In the past few years, great challenges have been addressed, and remarkable progress has been made in the technologies used for the detection and collection of these biomaterials, enabling liquid biopsy to enter an increasing number of clinical trials and clinical practice. Although problems regarding accuracy and sensitivity remain to be solved, encouraging outcomes have been reported by scientists and clinicians regarding successful applications of liquid biopsy in the prediction of cancer recurrence and responsiveness to specific drugs. Additionally, according to recent reports, this new comprehensive and systematic approach of sampling and analysis shows much potential in non‐tumour fields, such as neurodegenerative and autoimmune diseases. In this review, the current state and latest developments in the applications of different components in liquid biopsy will be discussed, and the use of sEVs in this novel medical strategy will be highlighted.

Isolation of circulating tumor cells to diagnose melanoma and evaluate the efficacy of surgical resection using melanoma-specific microsystem.

Melanoma is one of the most aggressive skin cancers due to its potential to metastasize widely in the body. The risk of metastasis is increased with later detection and increased thickness of the primary lesion, thus early identification and surgical removal is critical for higher survival rates for patients. However, even with appropriate treatment, some patients will develop recurrence which may be difficult to identify until advanced or causing symptoms. Recent advances in liquid biopsy have proposed less-invasive alternatives for cancer diagnosis and monitoring using minimal/zero invasion at sample collection, and circulating tumor cells(CTCs) have been considered a promising blood-based surrogate marker of primary tumors. However, previous CTC technologies relying on epithelial-cell adhesion molecules have limited to epithelial cells, thus hampering use of CTCs for non-epithelial cancers such as melanoma. Here, we used the Melanoma-specific OncoBean platform(MelanoBean) conjugated with melanoma specific antibodies(MCAM and MCSP). The device was used in comprehensive studies for diagnosing melanoma and evaluating surgery efficacy based on change in the number and characteristics of CTCs and CTC-clusters pre- and post-surgical treatment. Our study demonstrated that melanoma patients(n=45) at all stages(I-IV) have a noticeable number of MCTCs as well as MCTC-clusters compared to healthy donors(n=9)(P=0.0011), and surgical treatment leads to a significant decrease in the number of CTCs(P<0.0001). The CTCs recovered from the device underwent molecular profiling for melanoma-associated genes expression using multiplexed qRT-PCR, demonstrating the ability to monitor molecular signature through treatment. The presented MelanoBean and the comprehensive approach will empower prognostic value of CTCs in melanoma in much larger cohort studies.

Expanded knowledge of cell-free DNA biology: potential to broaden the clinical utility

Noninvasive sampling of an individual’s body fluids is an easy means to capture circulating cell-free DNA (cfDNA). These small fragments of DNA carry information on the contributing cell’s genome, epigenome, and nuclease content. Analysis of cfDNA for the assessment of genetic risk has already revolutionized clinical practice, and a compendium of increasingly higher-resolution approaches based on epigenetic and fragmentomic cfDNA signatures continues to expand. Profiling cfDNA has unlocked a wealth of molecular information that can be translated to the clinic. This review covers the biological characteristics of cfDNA, recent advances in liquid biopsy and the clinical utility of cfDNA.

Liquid biopsies in primary and secondary bone cancers.

Liquid biopsies are a powerful tool to non-invasively analyze tumor phenotype and progression as well as drug resistance. In the bone oncology field, liquid biopsies would be particularly important to develop, since standard biopsies can be very painful, dangerous (e.g., when found in proximity to the spinal cord), and hard to collect. In this review, we explore the recent advances in liquid biopsies in both primary (osteosarcoma and Ewing sarcoma) and secondary bone cancers (breast, prostate, and lung cancer-induced bone metastases), presenting their current role and highlighting their unexpressed potential, as well as the barriers limiting their possible adoption, including costs, scalability, reproducibility, and isolation methods. We discuss the use of circulating tumor cells, cell-free circulating tumor DNA, and extracellular vesicles for the purpose of improving diagnosis, prognosis, evaluation of therapy resistance, and driving therapy decisions in both primary and secondary bone malignancies.

Advances in the diagnosis, evaluation, and management of leptomeningeal disease.

Leptomeningeal metastasis (LM) is a devastating complication of cancer with variable clinical presentation and limited benefit from existing treatment options. In this review, we discuss advances in LM diagnostics and therapeutics with the potential to reverse this grim course. Emerging cerebrospinal fluid circulating tumor cell and cell-free tumor DNA analysis technologies will improve diagnosis of LM, while providing crucial genetic information, capturing tumor heterogeneity, and quantifying disease burden. Circulating tumor cells and cell-free tumor DNA have utility as biomarkers to track disease progression and treatment response. Treatment options for LM include ventriculoperitoneal shunting for symptomatic relief, radiation therapy including whole-brain radiation and focal radiation for bulky leptomeningeal involvement, and systemic and intrathecal medical therapies, including targeted and immunotherapies based on tumor mutational profiling. While existing treatments for LM have limited efficacy, recent advances in liquid biopsy together with increasing availability of targeted treatments will lead to rational multimodal individualized treatments and improved patient outcomes.

Multiplexed Liquid Biopsy and Tumor Imaging Using Surface-Enhanced Raman Scattering.

The recent improvements in diagnosis enabled by advances in liquid biopsy and oncological imaging significantly better cancer care. Both these complementary approaches, which are used for early tumor detection, characterization, and monitoring, can benefit from applying techniques based on surface-enhanced Raman scattering (SERS). With a detection sensitivity at the single-molecule level, SERS spectroscopy is widely used in cell and molecular biology, and its capability for the in vitro detection of several types of cancer biomarkers is well established. In the last few years, several intriguing SERS applications have emerged, including in vivo imaging for tumor targeting and the monitoring of drug release. In this paper, selected recent developments and trends in SERS applications in the field of liquid biopsy and tumor imaging are critically reviewed, with a special emphasis on results that demonstrate the clinical utility of SERS.

Recent Advances in Liquid Biopsy of Brain Cancers.

Brain cancers are among the top causes of death worldwide. Although, the survival rates vary widely depending on the type of the tumor, early diagnosis could generally benefit in better prognosis outcomes of the brain cancer patients. Conventionally, neuroimaging and biopsy are the most widely used approaches in diagnosis, subtyping, and prognosis monitoring of brain cancers, while emerging liquid biopsy assays using peripheral blood or cerebrospinal fluid have demonstrated many favorable characteristics in this task, especially due to their minimally invasive and easiness in sampling nature. Here, we review the recent studies in the liquid biopsy of brain cancers. We discuss the methodologies and performances of various assays on diagnosis, tumor subtyping, relapse prediction as well as prognosis monitoring in brain cancers, which approaches have made a big step toward clinical benefits of brain cancer patients.

Biomarkers and Lung Cancer Early Detection: State of the Art.

Simple SummaryLung cancer is the leading cause of cancer death worldwide. Detecting lung malignancies promptly is essential for any anticancer treatment to reduce mortality and morbidity, especially in high-risk individuals. The use of liquid biopsy to detect circulating biomarkers such as RNA, microRNA, DNA, proteins, autoantibodies in the blood, as well as circulating tumor cells (CTCs), can substantially change the way we manage lung cancer patients by improving disease stratification using intrinsic molecular characteristics, identification of therapeutic targets and monitoring molecular residual disease. Here, we made an update on recent developments in liquid biopsy-based biomarkers for lung cancer early diagnosis, and we propose guidelines for an accurate study design, execution, and data interpretation for biomarker development.Lung cancer burden is increasing, with 2 million deaths/year worldwide. Current limitations in early detection impede lung cancer diagnosis when the disease is still localized and thus more curable by surgery or multimodality treatment. Liquid biopsy is emerging as an important tool for lung cancer early detection and for monitoring therapy response. Here, we reviewed recent advances in liquid biopsy for early diagnosis of lung cancer. We summarized DNA- or RNA-based biomarkers, proteins, autoantibodies circulating in the blood, as well as circulating tumor cells (CTCs), and compared the most promising studies in terms of biomarkers prediction performance. While we observed an overall good performance for the proposed biomarkers, we noticed some critical aspects which may complicate the successful translation of these biomarkers into the clinical setting. We, therefore, proposed a roadmap for successful development of lung cancer biomarkers during the discovery, prioritization, and clinical validation phase. The integration of innovative minimally invasive biomarkers in screening programs is highly demanded to augment lung cancer early detection.

Chemo-specific designs for the enumeration of circulating tumor cells: advances in liquid biopsy.

Advanced materials and chemo-specific designs at the nano/micrometer-scale have ensured revolutionary progress in next-generation clinically relevant technologies. For example, isolating a rare population of cells, like circulating tumor cells (CTCs) from the blood amongst billions of other blood cells, is one of the most complex scientific challenges in cancer diagnostics. The chemical tunability for achieving this degree of exceptional specificity for extra-cellular biomarker interactions demands the utility of advanced entities and multistep reactions both in solution and in the insoluble state. Thus, this review delineates the chemo-specific substrates, chemical methods, and structure-activity relationships (SARs) of chemical platforms used for isolation and enumeration of CTCs in advancing the relevance of liquid biopsy in cancer diagnostics and disease management. We highlight the synthesis of cell-specific, tumor biomarker-based, chemo-specific substrates utilizing functionalized linkers through chemistry-based conjugation strategies. The capacity of these nano/micro substrates to enhance the cell interaction specificity and efficiency with the targeted tumor cells is detailed. Furthermore, this review accounts for the importance of CTC capture and other downstream processes involving genotypic and phenotypic CTC analysis in real-time for the detection of the early onset of metastases progression and chemotherapy treatment response, and for monitoring progression free-survival (PFS), disease-free survival (DFS), and eventually overall survival (OS) in cancer patients.

Dual-Isolation and Profiling of Circulating Tumor Cells and Cancer Exosomes from Blood Samples with Melanoma Using Immunoaffinity-Based Microfluidic Interfaces.

Melanoma is among the most aggressive cancers, and its rate of incidence continues to grow. Early detection of melanoma has been hampered due to the lack of promising markers for testing. Recent advances in liquid biopsy have proposed noninvasive alternatives for cancer diagnosis and monitoring. Circulating tumor cells (CTCs) and cancer‐exosomes are gaining influence as promising biomarkers because of their cancer‐associated molecular markers and signatures. However, technologies that offer the dual‐isolation of CTCs and exosomes using a single sample have not been thoroughly developed. The dual‐utilization OncoBean (DUO) device is conjugated with melanoma specific antibodies, MCAM and MCSP, enabling simultaneous CTC and exosome isolations. Using blood samples from patients, CTCs and exosomes are specifically isolated from a single sample and then undergo molecular profiling for comprehensive study. Melanoma patients have 0–17CTCs mL−1 and 299 µg exosomal protein mL−1 while healthy donors display fewer than 2CTCs and 75.6 µg of exosomes mL−1, respectively. It is also demonstrated that both markers express melanoma‐associated genes using multiplex qRT‐PCR to test for expression pattern of a 96 gene panel. The dual isolation and molecular characterization will allow for further research into melanoma to identify viable markers for disease progression and treatment efficacy.