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@#[摘 要] 恶性黑色素瘤（MM）是一种高侵袭性、高致死率的恶性肿瘤。液体活检由于具有样本易获得和创伤性低等优势，在恶性肿瘤诊断和监测中的重要性日益凸显，循环肿瘤DNA（ctDNA）检测正是其中一项新兴起的检测手段。ctDNA在MM诊断和治疗中的临床应用范围十分广泛，包括早期筛查MM人群、帮助检测MM的可驱动基因、监测和评判肿瘤的复发与转移、预测患者对靶向和免疫治疗的反应等。多项研究表明，无论是肿瘤术后辅助治疗还是晚期治疗的肿瘤患者，ctDNA能更好地反映肿瘤的异质性，提供预后相关信息，更早判断疾病的复发与转移，能准确评估对治疗的反应并确定耐药机制等。虽然目前尚未出现基于ctDNA的MM诊治共识，相关研究结论仍需要在前瞻性临床试验中继续验证，但是ctDNA检测为MM患者的临床管理提供了新的选择，不久或将用于进一步完善MM的诊断和治疗。
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Management and treatment of terminal metastatic castration-resistant prostate cancer (mCRPC) remains heavily debated. We sought to investigate the efficacy of programmed cell death 1 (PD-1) inhibitor plus anlotinib as a potential solution for terminal mCRPC and further evaluate the association of genomic characteristics with efficacy outcomes. We conducted a retrospective real-world study of 25 mCRPC patients who received PD-1 inhibitor plus anlotinib after the progression to standard treatments. The clinical information was extracted from the electronic medical records and 22 patients had targeted circulating tumor DNA (ctDNA) next-generation sequencing. Statistical analysis showed that 6 (24.0%) patients experienced prostate-specific antigen (PSA) response and 11 (44.0%) patients experienced PSA reduction. The relationship between ctDNA findings and outcomes was also analyzed. DNA-damage repair (DDR) pathways and homologous recombination repair (HRR) pathway defects indicated a comparatively longer PSA-progression-free survival (PSA-PFS; 2.5 months vs 1.2 months, P = 0.027; 3.3 months vs 1.2 months, P = 0.017; respectively). This study introduces the PD-1 inhibitor plus anlotinib as a late-line therapeutic strategy for terminal mCRPC. PD-1 inhibitor plus anlotinib may be a new treatment choice for terminal mCRPC patients with DDR or HRR pathway defects and requires further investigation.
Subject(s)
Male , Humans , Prostate-Specific Antigen , Treatment Outcome , Prostatic Neoplasms, Castration-Resistant/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Retrospective StudiesABSTRACT
Precise classification of central nervous system (CNS) malignancies is vital for the treatment and prognostication. Identification of noninvasive markers can be of importance to guide treatment decisions and in monitoring treatment response. CNS tumors are classified based on morphology with an essential complement of molecular changes, including mutations, amplifications, and methylation. Neuroimaging is the mainstay for initial diagnosis and monitoring tumor response with obvious limitations of imprecise tumor typing and no information on diagnostic, predictive and prognostic markers. Liquid biopsy has evolved as a diagnostic tool in body fluids and is being investigated as a surrogate for tissue biopsy in managing primary and metastatic brain tumors. Liquid biopsy refers to analyzing biological fluids such as peripheral blood, urine, pleural effusion, ascites, and cerebrospinal fluid (CSF); however, peripheral blood remains the primary source of fluid biopsy. The analytes include cell-free DNA (cfDNA) circulating tumor cells (CTCs), circulating micro RNAs (miRNAs), circulating proteins and extracellular vesicles (EVs). Analysis of these components is actively used for early cancer detection, auxiliary staging, prognosis assessment, detection of minimal residual disease (MRD), and monitoring drug resistance in various solid tumors. In recent years, liquid biopsy has been studied in CNS tumors, and analysis of CTCs and cfDNA have become relevant research topics. In the current review, we have explained the clinical potential of liquid biopsy in CNS tumors to assist in diagnosing and predicting prognosis and response to treatment.
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Background: Molecular tissue testing in non?small cell lung cancer (NSCLC) is done for the assessment of epidermal growth factor receptor (EGFR) mutation. EGFR mutation status is the basis for deciding the targeted treatment option for patients with metastatic NSCLC. The nonavailability of tissue samples and contraindications for biopsy pose a significant challenge. Hence circulating tumor DNA (ctDNA) by liquid biopsy can be a viable alternative for NSCLC patients. Methods: This study was conducted at 15 sites across India. EGFR mutation testing from plasma was done as part of the study at the central laboratory by the next?generation sequencing (NGS) method and EGFR mutation test results from tissue samples (done as part of routine practice) were recorded for all the patients. Results: Out of the total patients enrolled (N = 245) the majority (64.5% n = 158) were men. The median age of patients was 58.0 (range: 26�) years. The concordance between plasma and tissue testing was found to be 82.9% (95% confidence interval [CI]: 77.55 87.45). The sensitivity and specificity of NGS were 68.4% (95% CI: 56.92 78.37) and 90.1% [95% CI: 84.36 94.21) respectively. Plasma testing detected 1.2% (n = 3) and tissue sample testing detected 2.4% (n = 6) positive status of exon 20 T790M EGFR mutation. Out of the total number of patients enrolled 25 were tissue positive and plasma negative while 16 were plasma positive and tissue negative. Conclusions: This real?world study in Indian patients suggests that plasma testing for EGFR mutation analysis is a viable diagnostic option in newly diagnosed advanced/metastatic NSCLC patients. The noninvasive plasma procedure in patients without available/evaluable tumor sample may enable more patients to receive appropriate targeted therapies by providing clinicians with valuable insights into the patient抯 tumor mutation status. ClinicalTrials.gov Identifier: NCT03562819
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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
Lung cancer is the most common malignant tumor in the world, among which non-small cell lung cancer (NSCLC) accounts for about 85% of the total number of lung cancers. The 5-year overall survial (OS) of radical surgery NSCLC patients ranged from 92% in stage Ia1 to 26% in stage IIIb, and the continuously decreasing survival time made it a strong clinical need for precise adjuvant therapy to eradicate molecular residual disease (MRD). At present, circulating tumor DNA (ctDNA) as a molecular indicator of MRD has gradually moved from the laboratory to the clinic. The latest consensus proposes that ctDNA with abundance ≥0.02% can be stably detected in the peripheral blood of perioperative NSCLC patients, which is based on the possibility of ctDNA as an MRD indicator. MRD detection technology supports the possibility of monitoring after radical treatment of NSCLC, and ctDNA can predict the recurrence of the disease earlier than the imaging monitoring after treatment of NSCLC, providing valuable time for timely adjustment of adjuvant therapy. In the studies on early postoperative adjuvant therapy of NSCLC, different guidelines differ on whether appropriate adjuvant therapy should be carried out, while MRD can be used as a more accurate predictor to guide postoperative adjuvant therapy, so that patients can benefit from the disease treatment. .
Subject(s)
Humans , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/surgery , Circulating Tumor DNA , Lung Neoplasms/surgery , Neoplasm Recurrence, Local , Neoplasm, Residual , Small Cell Lung CarcinomaABSTRACT
Primary central nervous system lymphoma (PCNSL) is a rare and special kind of non-Hodgkin lymphoma. Chemotherapy based on high-dose methotrexate (HD-MTX) is considered a standard therapy for newly diagnosed PCNSL, but the prognosis of PCNSL is poor due to its high invasiveness and recurrence rate. Risk stratification and prognosis assessment of PCNSL in diagnosis is particularly important in clinical treatment. At present, MSKCC (the Memorial Sloan Kettering Cancer Center), the International Extranodal Lymphoma Study Group (IELSG) and Nottingham/Barcelona scoring models are mostly used to classify the risk and evaluate the prognosis of PCNSL. With the further understanding of immunohistochemistry and molecular genetics of PCNSL, potential prognostic factors continue to emerge.
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Objective: To investigate the application of single-molecule PCR (SM-PCR) in the detection of plasma ctDNA for the treat-ment of patients with advanced lung adenocarcinoma. Methods: In total, 30 patients diagnosed with advanced lung adenocarcinoma were enrolled between June 2017 and May 2018. ctDNA fragments of the target genes (EGFR, KRAS, BRAF, ALK, HER2, and TP53) from the blood samples were enriched by SM-PCR, and DNA libraries were prepared. Finally, a high-throughput sequencing was performed. The EGFR detection of tumor tissue samples was performed using real-time fluorescence PCR based on the amplification refractory mutation system (ARMS) and consistency in the results of EGFR mutation detection in the plasma and tissue was compared. Results:The results of both the methods were consistent (Kappa=0.867, P<0.001). The McNemar's test also indicated that the results are not statistically different (P=0.500). Conclusions: SM-PCR can be used for the detection of plasma EGFR mutations. The target detection sites are more comprehensive and multiple mutations can be detected at the same time. Results of the analysis are more precise and can be absolutely quantified.
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Circulating tumor cells (CTC) have become an important biomarker in patients with advanced prostate cancer. CTC count has been demonstrated to be a prognostic factor for overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). In localized prostate cancer, a clear correlation between CTC counts and clinicopathological risk parameters and outcome has not been observed. Currently, the focus of research is shifting from CTC enumeration towards molecular characterization of CTC leading to the discovery of markers predicting treatment response. The role of androgen receptor splice variants expressed by CTC as markers of resistance to abiraterone and enzalutamide has been assessed by various studies. The identification of CTC markers predicting treatment response represents a key step to guide the selection of treatment (e.g., abiraterone/enzalutamide vs taxanes), particularly in patients with mCRPC. As an alternative to CTC, the analysis of circulating tumor DNA has been shown to enable a noninvasive disease characterization having high potential to promote precision oncology.
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Objective To establish a liquid biopsy technique of KRAS gene G12D mutation and to assess its diagnostic value. Methods KRAS G12D mutation was analyzed by ddPCR in plasma DNA from 52 colorectal cancer patients and compared that of to 80 healthy subjects. KRAS gene sequencing in cancerous tissue of colorectal cancer patient being set as a golden standard, we evaluated the accuracy of ddPCR and analyzed the correlation between G12D mutation rate, plasma concentration;and their clinical manifestations in CRC. Results ddPCR indicated that KRAS G12D mutation rate and concentration(26.92％, 81.5 copies/mL) in the plasma samples of colorectal cancer patients were significantly higher than that of healthy subjects (8.75％, 16 copies/mL). Colorectal cancer patients with highly differentiated adenocarcinoma showed a significantly higher number of mutant copies than medium and low differentiated adenocarcinoma(P＜0.05);M2 patients had a significantly higher number of mutant copies than N1 and NO patients (P＜0.05);The concordance rate of KRAS gene mutation between cancerous tissue and plasma ctDNA was 87.50％ in CRC.Conclusions ddPCR is a fast, noninvasive and accurate method for plasma testing of ctDNA, and the test results could be used to monitor the course of the disease and as clinical guidelines.
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Necrosis is a form of cell death, which is related to various serious diseases such as cardiovascular disease, cancer, and neurodegeneration. Necrosis-avid agents (NAAs) selectively accumulated in the necrotic tissues can be used for imaging and/or therapy of related diseases. The aim of this study was to preliminarily investigate necrosis avidity of I-evans blue (I-EB) and its mechanism. The biodistribution of I-EB at 24 h after intravenous administration showed that the radioactivity ratio of necrotic to viable tissue was 3.41 in the liver and 11.82 in the muscle as determined by counting in model rats. Autoradiography and histological staining displayed preferential uptake of I-EB in necrotic tissues. nuclear extracts from necrotic cells exhibited 82.3% of the uptake in nuclei at 15 min, as well as 79.2% of the uptake at 2 h after I-EB incubation. The DNA binding study demonstrated that evans blue (EB) has strong binding affinity with calf-thymus DNA (CT-DNA) (=5.08×10 L/(mol/L)). Furthermore, the accumulation of I-EB in necrotic muscle was efficiently blocked by an excess amount of unlabeled EB. In conclusion, I-EB can not only detect necrosis by binding the DNA released from necrotic cells, but also image necrotic tissues generated from the disease clinically.
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Objective To investigate epidermal growth factor receptor(EGFR)gene T790M mutation in plasmatic ctDNA samples from 171 patients with non-small cell lung cancer and analyze the relationship between EGFR T790M mutation and the clinical factors. Methods The EGFR T790M mutation was detected in 171 cases by super amplification refractory mutation system(Super ARMS)in this paper. Rusults The EGFR gene T790M mutation was identified in 7.60%(13/171)plasmatic ctDNA samples which mostly came from patients withⅢb~Ⅳstages of lung cancer. The EGFR T790M mutation rate was identified in 2.05%(3/146)plasmatic samples of pa-tients who did not received treatment of EGFR-TKIs,which was lower than 40.00%(10/25,P<0.05)plasmatic samples of patients who received treatment of first generational EGFR-TKIs. The EGFR T790M mutation rate was identified in 75.00%(3/4) and 60.00%(6/10) plasmatic samples of patients who have received TKI for 6 to 10 months and more than 10 months,which was higher than 9.10%(1/11,P < 0.05)plasmatic samples of patients who have received TKIs for less than 6 months. Conclusions This article demonstrated that EGFRT790M muta-tion was more common in lately NSCLC patients who have received TKIs treatmentover 6 months,meanwhile the EGFR T790M mutation dynamical detective technology will effectively guide the clinic treatment.
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Objective To investigate epidermal growth factor receptor(EGFR)gene T790M mutation in plasmatic ctDNA samples from 171 patients with non-small cell lung cancer and analyze the relationship between EGFR T790M mutation and the clinical factors. Methods The EGFR T790M mutation was detected in 171 cases by super amplification refractory mutation system(Super ARMS)in this paper. Rusults The EGFR gene T790M mutation was identified in 7.60%(13/171)plasmatic ctDNA samples which mostly came from patients withⅢb~Ⅳstages of lung cancer. The EGFR T790M mutation rate was identified in 2.05%(3/146)plasmatic samples of pa-tients who did not received treatment of EGFR-TKIs,which was lower than 40.00%(10/25,P<0.05)plasmatic samples of patients who received treatment of first generational EGFR-TKIs. The EGFR T790M mutation rate was identified in 75.00%(3/4) and 60.00%(6/10) plasmatic samples of patients who have received TKI for 6 to 10 months and more than 10 months,which was higher than 9.10%(1/11,P < 0.05)plasmatic samples of patients who have received TKIs for less than 6 months. Conclusions This article demonstrated that EGFRT790M muta-tion was more common in lately NSCLC patients who have received TKIs treatmentover 6 months,meanwhile the EGFR T790M mutation dynamical detective technology will effectively guide the clinic treatment.
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Objective To detect the content of plasma ctDNA and the mutation rate of BRAF V600E in plasma of patients with thyroid carcinoma ,and to explore its clinical significance. Methods Plasma ctDNA was extracted from 16 patients with thyroid carcinoma and 59 patients with benign thyroid nodules by using the blood genomic DNA Extraction Kit. The ctDNA content was detected by fluorescence quantitative PCR ,and the mutation of circulating BRAF V600E was detected by PCR and sequencing. Then the clinical significance was analyzed by combined detection analysis. Results The content of ctDNA in thyroid cancer group was significantly higher than that in benign nodule group (P < 0.01). BRAF V600E mutation detection showed that the mutation rate was 43.75%,but benign nodules had no mutation. Parallel combined detection improved the sensitivity and the specific-ity of the combined detection was higher. Conclusion Combined detection of ctDNA and BRAF V600E in plasma is helpful for differential diagnosis of benign and malignant thyroid nodules.
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In physiological condition, the interaction of acteoside and forsythoside B with calf thymus DNA using neutral red (NR) as a fluorescence probe were investigated by fluorescence, UV-visible spectrophotometry, viscosity, DNA melting techniques, and molecular docking. It is observed that acteoside and forsythoside B can react with DNA. The major mode of recognition between drug and DNA is groove binding by hydrogen bonds, and the interaction of acteoside with DNA is stronger than that of forsythoside B.
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Objective To establish a simple method to extract the methylated ctDNA in urine using magnetic beads as solid phase adsorption carri?er with a specific design reagent system and extraction process,and evaluate its application feasibility for methylated gene detection in urine sample . Methods Fourty cases of methylated ctDNA were extracted in urine using magnetic beads. After methylated modification,the concentration and pu?rity of DNA was determined by ultraviolet spectrophotometer. Results The extraction of 50 mL urine can gain 61?200 ng/mL methylated ctDNA, and the OD260/280 was 1.8 ± 0.05. Conclusion There are methylated ctDNA exist in the urine which can be extracted by magnetic beads. The estab?lished extraction method is simple,effective,and with high purity.
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The antibacterial activity, in-silico DNA molecular docking, DNA binding and photo cleavage studies of newly synthesized pyrazole is described. Antibacterial potential of these compounds screened against a wide range of Gram-positive and Gram-negative bacteria showed significant zone of inhibition and MIC with standard drug ciproflaxin is investigated. Among all the orientation of binding, fourth orientation showed significant binding and revealed that the binding and docking energy of 4a was -8.62 and -8.66 and inhibition constant 7.46 X e-6. The absorption spectra showed the dynamic interaction with CT DNA and as proficient DNA intercalator (Kb = 4.5×104 M-1). The viscosity measurements and thermal denaturation affords the positive results towards DNA intercalation in both the studies. The light induced DNA damage was pragmatic in the absence of various ‘‘inhibitors’’ shows in photo cleavage activities at 360 nm.