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How to improve the performance of circulating tumor DNA (ctDNA) signal acquisition and the accuracy to authenticate ultra low-frequency mutation are major challenges of minimal residual disease (MRD) detection in solid tumors. In this study, we developed a new MRD bioinformatics algorithm, namely multi-variant joint confidence analysis (MinerVa), and tested this algorithm both in contrived ctDNA standards and plasma DNA samples of patients with early non-small cell lung cancer (NSCLC). Our results showed that the specificity of multi-variant tracking of MinerVa algorithm ranged from 99.62% to 99.70%, and when tracking 30 variants, variant signals could be detected as low as 6.3 × 10 -5 variant abundance. Furthermore, in a cohort of 27 NSCLC patients, the specificity of ctDNA-MRD for recurrence monitoring was 100%, and the sensitivity was 78.6%. These findings indicate that the MinerVa algorithm can efficiently capture ctDNA signals in blood samples and exhibit high accuracy in MRD detection.
Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , Neoplasm, Residual/pathology , Biomarkers, Tumor/genetics , Computational BiologyABSTRACT
Cervical cancer is a leading cause of cancer death in women. There are no reliable noninvasive indicators to predict the recurrence, metastasis and prognosis of cervical cancer. Circulating tumor DNA (ctDNA) is a kind of DNA fragment released from tumor cells into the blood circulation, which has the advantages of being non-invasive, real-time, and of reflecting the genetic characteristics of tumors. With the improvement of ctDNA detection technology and in-depth research on ctDNA, ctDNA has shown more obvious advantages in early diagnosis, tumor molecular typing, treatment monitoring and recurrence prediction of cervical cancer compared with traditional histological, serological and imaging detection methods. This paper reviews the detection methods of ctDNA and its latest research progress of ctDNA in cervical cancer.
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Primary liver cancer includes three types: Hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed hepatocellular carcinoma and cholangiocarcinoma. Among them, hepatocellular carcinoma accounts for 75% to 85%, posing a serious threat to human life and health. The screening and monitoring of high-risk populations for hepatocellular carcinoma is crucial for early detection, diagnosis, and treatment, as well as for improving the prognosis of liver cancer. Serum biomarkers play an important role in monitoring and diagnosing hepatocellular carcinoma. In recent years, new serum biomarkers such as AFP heterogeneity, abnormal prothrombin/de-γ-carboxyprothrombin, Golgi protein 73, Dickkopf-associated protein 1, aldehyde ketone reductase-AKR1B10, gypican 3, liquid biopsies and microRNAs have been recommended for screening and monitoring hepatocellular carcinoma, and some have been included as auxiliary diagnostic measures in liver cell carcinoma guidelines. This article summarizes the progress of relevant basic research and clinical evaluation of these novel biomarkers, which may provide a reference for future clinical application.
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Circulating tumor DNA (ctDNA) has been the most common biomarker in liquid biopsy because of non-invasive detection and overcoming intratumor heterogeneity. Lung cancer remains the leading cause of cancer-related morbidity and mortality all over the world, with non-small cell lung cancer (NSCLC) constituting 85% of the total cases. Radiotherapy plays an important role in phase Ⅰ-Ⅳ NSCLC. It can not only kill tumor cells to eradicate cancer directly, but also increase the release of ctDNA indirectly, which improves the accuracy of liquid biopsy. As a result, ctDNA has the potential to be widely used in radiotherapy for NSCLC. In this review, research progress on ctDNA in the diagnosis, prognosis assessment, recurrence detection and response prediction in NSCLC patients treated with radiotherapy were summarized.
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O carcinoma de células renais (CCR) é o sétimo tipo de câncer mais comum no ocidente e vêm apresentando um aumento em sua prevalência. A classificação histológica dos CCRs é a abordagem mais utilizada para determinar o subtipo da doença, bem como prognosticar o paciente. Cerca de 70-80% dos CCRs é do subtipo células claras (ccRCC), o qual representa o subtipo mais prevalente e agressivo da doença. A escolha do tratamento difere para cada paciente, sendo a ressecção cirúrgica a terapia mais efetiva nos casos de doença localizada. Apesar de ser um tratamento já estabelecido, estudos mostram uma certa heterogeneidade entre massas renais detectadas, onde cerca de 20% apresentam um perfil benigno, 60% são considerados tumores indolentes, sugerindo desta forma que, entender de forma mais detalhada este tumor pode auxiliar na escolha de um tratamento mais direcionado para o paciente. Sendo assim, o presente trabalho buscou selecionar genes potencialmente alterados em CCR com o intuito de customizar um painel multigênico capaz de identificar variantes somáticas, específicas do tumor, e avaliar as variantes específicas do tumor de forma personalizada em amostras de ctDNA (DNA tumoral circulante) extraídas de plasma e dos dois componentes da urina (sedimento e sobrenadante) coletados no momento da cirurgia (baseline). Neste contexto, dentro de nossa proposta, construímos um painel com 28 genes associados com CCR e sequenciamos 89 casos de tumores renais, juntamente com as amostras de leucócitos. Identificamos que dentre os tumores analisados, 59 apresentavam pelo menos uma variante somática, ou seja, o painel customizado apresentou uma sensibilidade para identificar variantes somáticas em 66% dos casos. Com relação aos 45 tumores classificados como ccRCC em 38 casos identificamos pelo menos uma marca tumoral, ou seja, nosso painel foi capaz de detectar variantes somáticas específicas do tumor em 84,4% desses casos. Um total de 105 variantes somáticas foram identificadas, e os genes mais frequentemente mutados nessa coorte de pacientes foram os genes VHL, PBRM1, BAP1, SETD2. Dos 59 casos em que identificamos variante somática, 44 casos foram avaliados as amostras baseline de plasma e 29 casos de urina (sobrenadante e sedimento), e encontramos pelo menos uma marca tumoral em um dos fluidos corpóreos em 11 pacientes, 6 em amostras de plasma e 6 amostras de urina. Através do desenvolvimento deste estudo, confirmamos que o subtipo ccRCC é o CCR mais bem caracterizado genomicamente e que é importante continuar a investigação genômica principalmente nos subtipos não ccRCC. Além disso o estudo demonstra a viabilidade de utilizar biópsia líquida ctDNA tanto no plasma quanto na urina para fins de diagnóstico e prognóstico.
Renal cell carcinoma (RCC) is the seventh most common type of cancer in the West and its prevalence is increasing. The histological classification of RCCs is the most used approach to determine the disease subtype as well as the patient's prognosis. About 70% of RCCs are of the clear cell Renal Cell Carcinoma subtype (ccRCC), which represents the most prevalent and aggressive subtype of the disease. The choice of treatment is different for each patient. Resection is one of the most effective therapies in cases of localized disease. Despite being an established treatment, studies show a certain heterogeneous profile studied. In this profile, up to 20% even present a benign treatment, helping the indolent, thus suggesting that understanding this tumor in detail can help to choose a more targeted treatment for the patient. Therefore, the present work aimed to select potentially altered genes in CCR in order to customize a multigene panel capable of identifying somatic, tumor-specific variants, and to evaluate the tumor-specific variants in a personalized way in ctDNA (circulating tumor DNA) samples extracted from plasma and from two components of urine (sediment and supernatant) collected at the time of surgery (baseline). In this context, within our proposal, we built a panel with 28 genes associated with CCR and sequenced 89 cases of renal tumors, together with leukocyte samples. We identified that among the analyzed tumors, 59 had at least one somatic variant, that is, the customized panel showed sensitivity to identify somatic variants in 66% of cases. Of the 45 classified as ccRCC in 38 cases we identified at least one tumor marker, that is, our panel was able to detect tumor-specific somatic variants in 84.4%. A total of 105 somatic variants were identified, and the genes most frequently mutated in this cohort of patients were the VHL, PBRM1, BAP1, SETD2 genes. Among 59 cases in which we identified somatic variant, 44 cases were evaluated in baseline plasma samples and 29 cases in urine (supernatant and sediment), and we found at least one tumor mark in one of the body fluids in 11 patients, 6 in plasma samples and 6 urine samples. Through the development of this study, we confirm that the ccRCC subtype is the best genomically characterized CCR and that it is important to continue genomic investigation, especially in the non-ccRCC subtypes. Furthermore, the study demonstrates the feasibility of using ctDNA liquid biopsy in both plasma and urine for diagnostic and prognostic purposes.
Subject(s)
Humans , Male , Female , Circulating Tumor DNA , Liquid Biopsy , Kidney Neoplasms , Carcinoma, Renal CellABSTRACT
Early diagnosis of hepatocellular carcinoma (HCC) is of great significance in the management of patients. Liquid biopsy is a promising tool to use for early diagnosis of liver cancer by detecting tumor expressions through analyzing circulating tumor components such as circulating tumor DNA, circulating tumor cells and extracellular vesicles. The advantages of using liquid biopsy include easy collection of specimen samples and its good sensitivity and specificity for HCC detection. In this review, recent research progress on liquid biopsy on HCC is discussed with the aim to provide updated information on early diagnosis of HCC.
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Objective:To investigate the changes of circulating tumor DNA (ctDNA), circulating B cell-specific Moloney leukemia virus insertion site 1 mRNA (Bmi-1 mRNA) and microRNA-21 (miR-21) before and after treatment with epidermal growth factor receptor (EGFR) monoclonal antibody in advanced colorectal cancer, and analyze their association with treatment response.Methods:The clinical data of 98 patients with advanced colorectal cancer from March 2019 to March 2021 in Yantai Yuhuangding Hospital were retrospectively analyzed. After treatment with cetuximab, complete remission was in 4 cases, partial remission in 26 cases, stable disease in 39 cases, and progressive disease in 29 cases. The patients with complete remission and partial remission were classified as remission group (30 cases), the stable disease and progressive disease were classified as non-remission group (68 cases). Before treatment and after 2 cycles of treatment, the plasma level of ctDNA was detected by high-throughput sequencing; the levels of Bmi-1mRNA and miR-21 were detected by real-time fluorescence quantitative polymerase chain reaction. Spearman correlation was used to analyze the relationship between ctDNA, Bmi-1mRNA, miR-21 and treatment responsiveness after 2 cycles of treatment; multivariate Logistic regression was used to analyze the independent risk factors affecting treatment responsiveness; receiver operating characteristic (ROC) curve was drawn to evaluate the value of ctDNA, Bmi-1mRNA and miR-21 in predicting remission after 2 cycles of treatment.Results:There were no significant differences in ctDNA, Bmi-1mRNA and miR-21 before treatment between 2 groups ( P>0.05); the ctDNA, Bmi-1mRNA and miR-21 after 2 cycles of treatment in remission group were significantly lower than those in non-remission group: (10.03 ± 3.32) μg/L vs. (15.33 ± 5.14) μg/L, 0.13 ± 0.04 vs. 0.19 ± 0.05 and 0.81 ± 0.26 vs. 1.08 ± 0.24, and there were statistical differences ( P<0.01). Spearman correlation analysis result showed that ctDNA, Bmi-1mRNA and miR-21 were negatively correlated with treatment response ( r = -0.500, -0.506 and -0.531; P<0.01). Multivariate Logistic regression analysis result showed that, after controlling for the number of distant metastatic organs and clinical stage, ctDNA, Bmi-1mRNA and miR-21 were still independent risk factors for treatment response in patients with advanced colorectal cancer ( OR = 3.342, 2.725 and 1.838; 95% CI 3.116 to 3.584, 2.647 to 2.805 and 1.768 to 1.911; P<0.01). ROC curve analysis result showed that the area under the curve (AUC) of ctDNA, Bmi-1mRNA combined with miR-21 after 2 cycles of treatment to predict the treatment response was the largest with 0.922. Conclusions:The changes of ctDNA, Bmi-1mRNA and miR-21 in patients with advanced colorectal cancer before and after treatment with EGFR monoclonal antibody are related to the treatment response. Combined detection is helpful for screening patients sensitive to EGFR-targeted therapy, and can provide reference for new targets of molecular intervention.
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Neuroblastoma (NB) is the most common extracranial solid tumor in children and has the features of high recurrence rate and low survival rate, and therefore, early diagnosis, treatment response evaluation, and recurrence monitoring are of great significance for NB patients. Liquid biopsy refers to the detection of cells and nucleic acids in fluid specimens, mainly blood. It is noninvasive and can overcome tumor heterogeneity, thus making it possible to achieve the early diagnosis and dynamic detection of NB. This review introduces the latest advances in clinical research on the application of liquid biopsy in NB.
Subject(s)
Child , Humans , Liquid Biopsy , Neuroblastoma/diagnosisABSTRACT
As widely-used immunotherapy has brought therapeutic benefits to cancer patients, some problems begin to come, such as pseudoprogression which has posed a major challenge for clinicians to manage patients receiving novel drugs. If pseudoprogression is mistaken for the progression of the disease, the immunotherapy is stopped, which may lead patients to lose the treatment opportunity. Liquid biopsies based on circulating tumor DNA (ctDNA) play a key role in the evaluation of therapeutic efficacy and drug-resistance mechanism of tumor immunotherapy. This article reviews the potential application of ctDNA in the identification of pseudoprogressio for patients after tumor immunotherapy.
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Lung cancer is the malignant tumor with the highest mortality in the world, of which non-small cell lung cancer (NSCLC) accounts for about 80%. The orderly combination of surgery, radiotherapy, chemotherapy, targeted therapy and immunotherapy is currently the main treatment modality for NSCLC. Liquid biopsy has been increasingly used in clinical practice in recent years due to its advantages of being non-invasive and overcoming tumor heterogeneity, of which circulating tumor DNA (ctDNA) is one of the most commonly used analytical indicators, and ctDNA detection may play a role in the treatment of NSCLC. This article reviews new developments in the use of ctDNA for prognostic assessment, recurrence monitoring and efficacy prediction in NSCLC patients.
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Surgery is recognized as the core treatment for colorectal liver metastasis (CRLM), while its recurrence rate remains relatively high, even for resectable CRLM. This hints that the efficacy of treatment involves not only technological factors of surgery, but also biological behavior of tumor. For resectable CRLM, neoadjuvant therapy is beneficial to eliminate the micro-metastasis, reduce postoperative recurrence rate, screen tumor biological behavior and improve prognosis. However, questions about which kind of CRLM patients fits for neoadjuvant therapy and what regimen should be used are still debatable. This paper reviews stratified management of resectable CRLM, choice of neoadjuvant regimen, especially the application value of targeted therapy, based on the latest guidelines and studies.
Subject(s)
Humans , Colorectal Neoplasms/surgery , Hepatectomy , Liver Neoplasms/surgery , Neoadjuvant Therapy , Neoplasm Recurrence, Local/surgeryABSTRACT
With the improvement of detective sensitivity, the application of circulating tumor DNA (ctDNA) has gradually expanded from advanced tumors to early stage. Recently, the detection of minimal residual disease (MRD) using ctDNA in solid tumors has attracted particular attention. MRD testing has shown an essential role in the risk assessment of solid tumor recurrence and treatment guidance. However, the MRD detection strategies used in each study are different, and the conclusions drawn as well. This paper reviewed the research progress of ctDNA for MRD detection in solid tumor, as well as its challenges of detection technology and application, in order to promote the clinical transformation and standardized application of MRD detection by ctDNA in solid tumors.
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Lung cancer, with the highest incidence in China, is the leading cause of death in cancer patients. Of these, about 85% are patients with non-small cell lung cancer (NSCLC). Therefore, the diagnosis and treatment of patients with lung cancer have always been a top priority nowadays. Fluid biopsy has many advantages, such as safety, convenience, repeatability, low trauma and so on, which are not available in traditional invasive biopsy. In recent years, with the rapid progress of molecular biological detection technology, fluid biopsy, as a new technology, has become the focus of attention. What's more, it contributes to the development of precision treatment and individualized treatment of lung cancer. Liquid biopsy mainly detects circulating tumor DNA (ctDNA), circulating tumor cells (CTCs) and exosomes in peripheral blood. We will make an introduce to the detection and clinical applications of ctDNA, CTCs and exocrine in this article, in order that it can provide insights into future clinical treatment for NSCLC. .
Subject(s)
Humans , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/diagnosis , Circulating Tumor DNA , Liquid Biopsy , Lung Neoplasms/diagnosisABSTRACT
Accurate detection of low frequency mutations from plasma cell-free DNA in blood using targeted next generation sequencing technology has shown promising benefits in clinical settings. Duplex sequencing technology is the most commonly used approach in liquid biopsies. Unique molecular identifiers are attached to each double-stranded DNA template, followed by production of low-error consensus sequences to detect low frequency variants. However, high sequencing costs have hindered application of this approach in clinical practice. Here, we have developed an improved duplex sequencing approach called SinoDuplex, which utilizes a pool of adapters containing pre-defined barcode sequences to generate far fewer barcode combinations than with random sequences, and implemented a novel computational analysis algorithm to generate duplex consensus sequences more precisely. SinoDuplex increased the output of duplex sequencing technology, making it more cost-effective. We evaluated our approach using reference standard samples and cell-free DNA samples from lung cancer patients. Our results showed that SinoDuplex has high sensitivity and specificity in detecting very low allele frequency mutations. The source code for SinoDuplex is freely available at https://github.com/SinOncology/sinoduplex.
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BACKGROUND@#The patients with advanced lung adenocarcinoma should select targeted drugs based on the type of tumor epidermal growth factor receptor (EGFR) gene mutation. However, it is difficult to collect tumor tissue of advanced lung adenocarcinoma, and some experts agree that peripheral blood can be used as a substitute for tumor tissue as a test specimen. This paper aimed to investigate the clinical value of ddPCR and super-amplification refractory mutation system (ARMS) in detecting EGFR gene mutation in peripheral blood of patients with advanced lung adenocarcinoma.@*METHODS@#A total of 119 patients diagnosed in Beijing Chest Hospital Affiliated to Capital Medical University from February 2016 to February 2019 were collected, and the sensitivity and specificity of plasma ctDNA EGFR gene mutation detected by ddPCR and super-arms were compared. Some patients with positive EGFR gene mutations received oral treatment with first-line EGFR tyrosine kinase inhibitors (EGFR-TKI). The patients were divided into subgroups according to the test results. In group 1, both ddPCR and super-arms showed positive EGFR gene mutation results, with 21 cases. In group 2, ddPCR and super-arms detection of EGFR gene mutation were all negative, with 16 cases. In group 3, the ddPCR test was positive and the super-arms test was negative, with 5 cases. In group 4, the ddPCR test result was negative while the super-arms test result was positive. Since the number of patients in group 4 was 0, no statistics were included. Objective response rate (ORR) and disease control rate (DCR) were used to evaluate the short-term outcome, and progression-free survival (PFS) was compared with survival analysis to evaluate the long-term outcome.@*RESULTS@#EGFR mutations were detected in 58 (48.7%) of 119 patients with advanced lung adenocarcinoma. The coincidence rate between ddPCR and EGFR gene mutation in tumor tissues was 82.4% (Kappa=0.647, P0.05). Survival analysis showed that the PFS of the three groups was compared. The difference was not statistically significant (χ²=2.221, P=0.329).@*CONCLUSIONS@#ddPCR, as a high sensitivity and specificity liquid gene detection method, can be used as a reliable method to detect the mutation of plasma ctDNA EGFR gene in patients with advanced lung adenocarcinoma. The results of plasma genetic testing can also be used as the basis for predicting the efficacy of EGFR-TKIs in patients.
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BACKGROUND@#Leptomeningeal metastasis (LM) are a severe complication of non-small cell lung cancer (NSCLC), and normally accompanied by poor prognosis. For the patients with targetable mutations, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment, but the acquired TKI resistance is inextricable. The aim of this study is to analyze the different gene mutation spectrum and mutation frequency of the cerebrospinal fluid (CSF) and plasma in NSCLC patients with LM, and screen out the drug-resistant mutations so as to guide the choice of treatment accurately.@*METHODS@#The paired CSF and plasma samples were collected from the NSCLC-LM patients with acquired TKI resistance. Next generation sequencing (NGS) was used to detect the gene variations of circulating tumor DNA (ctDNA).@*RESULTS@#A total of 18 NSCLC patients with LM were collected. Of the basic mutations, 11 cases (61.11%) were EGFR, 6 cases (33.33%) were anaplastic lymphoma kinase (ALK), and 1 case (5.56%) was ROS proto-oncogene 1, receptor tyrosine kinase (ROS1). Tumor protein p53 gene (TP53) and mesenchymal-epithelial transition factor (MET) were the two most frequently accompanying mutated genes in CSF ctDNA. The detected mutation rate of CSF samples was higher than that of plasma samples (100.00% vs 66.67%, P=0.006), and the maximum allelic fractions were all higher in CSF than in plasma (P<0.001). Abundant single-nucleotide variations (SNV) and copy number variants (CNV) were detected in CSF, the amount of both of which were more than in blood. In addition, the CSF and plasma samples of patients treated with several TKIs had more SNV mutations than patients who received only a single TKI treatment.@*CONCLUSIONS@#For the patients of NSCLC, ctDNA in CSF could reveal genomic alterations of LM more exactly and overally than it in plasma, thus could be an optimal source of liquid biopsy for guiding therapy, monitoring therapeutic effect, and predicting prognosis.
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With the development of precision oncology, a large number of clinical studies have confirmed the great potential of ctDNA in tumor management. However, the effectiveness and versatility of ctDNA detection are still questioned, which hinder the realization of clinical application of ctDNA detection, so there is an urgent need to develop unified quality control standards. The standardized pre-analytical processes for ctDNA analysis are the prerequisite to ensure the subsequent molecular detection. This paper will focus on the factors of quality control of pre-analytical processes for ctDNA analysis, in order to promote the standardized management of ctDNA detection.
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Circulating tumor DNA analysis is the focused issue in clinical research. A few of biomarkers have been used in clinical practice, while some are in the discovery phase. The key challenges for clinical laboratories on the way from discovery to clinical practice of the circulating tumor DNA analysis, including choosing the intended use based on evidence for clinical validity and utility, quality assurance for the testing process, reporting and interpretation for the results will be discussed.
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BACKGROUND@#The mortality rate of lung cancer meningeal metastasis is extremely high. Circulating tumor DNA (ctDNA) has been confirmed to be contain the genomic alterations present in tumors and has been used to monitor tumor progression and response to treatments. Due to the presence of blood-brain barrier and other factors, peripheral blood ctDNA cannot reflect the information of brain lesions for patients with meningeal metastases. However, cerebrospinal fluid ctDNA as a test sample can better reflect the genetic status of intracranial tumors and guide clinical targeted treatment of intracranial lesions. This study explored the feasibility of cerebrospinal fluid ctNDA for evaluating non-small cell lung cancer (NSCLC) meningeal metastasis and the potential clinical value of cerebrospinal fluid ctDNA detection in NSCLC meningeal metastasis.@*METHODS@#A total of 21 patients with NSCLC meningeal metastasis were included. Tumor genomic variation was performed on the cerebrospinal fluid and peripheral blood samples of patients by second-generation gene sequencing technology. The situation was examined, and pathological evaluation of cerebrospinal fluid cytology and head magnetic resonance imaging (MRI) enhanced examination were performed.@*RESULTS@#ctDNA was detected in the cerebrospinal fluid of 21 patients. The sensitivity of cerebrospinal fluid ctDNA detection was superior to cytology in the diagnosis of meningeal metastasis (P<0.001). The detection rate and gene mutation abundance of cerebrospinal fluid were higher than plasma (P<0.001). Cerebro-spinal fluid had a unique genetic profile. In 6 patients with dynamic detection, changes of ctDNA allele fraction occurred at the same time or earlier than clinical disease changes, which could timely monitor drug resistance mechanism and relapse trend.@*CONCLUSIONS@#The detection rate of ctDNA in cerebrospinal fluid is higher than that in cytology and imaging. The detection of ctDNA in cerebrospinal fluid can reveal the specific mutation map of meningeal metastasis lesions. The dynamic monitoring of ctDNA in cerebrospinal fluid has hint significance for clinical response of lung cancer patients.
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Gastric cancer is the fifth most common type of cancer in the world and the third leading cause of cancer death. Conventional treatment for gastric cancer includes surgical resection and adjuvant therapy. More than 50% of patients are reaching the advanced stage when diagnosed, because they do not have typical symptoms at early stage. Researchers continue to investigate more sensitive methods for detecting the occurrence and development of gastric cancer. In addition to new serum tumor biomarkers through proteomics, new concept such as circulating tumor DNA (ctDNA) has also been introduced. This article reviewed the clinical application of ctDNA in diagnosis of gastric cancer.