Pub Date : 2024-02-28eCollection Date: 2024-01-01DOI: 10.1177/11772719241232870
Hiba Al Naji, Jean M Winter, Susanne K Pedersen, Amitesh Roy, Susan E Byrne, Graeme P Young, Erin L Symonds
Background: Colorectal cancer (CRC) has a high rate of recurrence, in particular for advanced disease, but prognosis based on staging and pathology at surgery can have limited efficacy. The presence of circulating tumor DNA (ctDNA) at diagnosis could be used to improve the prediction for disease recurrence.
Objectives: To assess the impact of detecting methylated BCAT1/IKZF1 ctDNA at diagnosis in combination with demographic, lifestyle, clinical factors and tumor pathology, to assess predictive value for recurrence.
Design: A retrospective cohort study.
Methods: The cohort included 180 patients (36 with recurrent CRC), who had undergone complete treatment and surveillance for a minimum of 3 years. Participant clinical details and ctDNA methylated BCAT1/IKZF1 results were compared between those with and without recurrence, and cox regression analysis assessed each factor on disease-free survival.
Results: Clinical factors independently associated with reduced disease-free survival included nodal involvement (HR = 3.83, 95% CI 1.56-9.43, P = .003), M1 stage (HR = 4.41, 95% CI 1.18-16.45, P = .027), a resection margin less than 2 mm (HR = 4.60, 95% CI 1.19-17.76, P = .027), perineural involvement (HR = 2.50, 95% CI 1.01-6.17, P = .047) and distal tumors (HR = 3.13, 95% CI 1.07-9.18, P = .037). Methylated BCAT1/IKZF1 was detected in 51.7% (93/180) of pre-treatment plasma samples. When a positive ctDNA finding was considered in combination with these clinical prognostic factors, there was improved predictive power of recurrence for patients with perineural involvement (HR = 4.44, 95% CI 1.92-10.26, P < .001), and it marginally improved the predictive factor for M1 stage (HR = 7.59, 95% CI 2.30-25.07, P = .001) and distal tumors (HR = 5.04, 95% CI 1.88-13.49, P = .001).
Conclusions: Nodal invasion, metastatic disease, distal tumor site, low resection margins and perineural invasion were associated with disease recurrence. Pre-treatment methylated ctDNA measurement can improve the predictive value for recurrence in a subset of patients, particularly those with perineural involvement.
Registration: Australian and New Zealand Clinical Trials Registry #12611000318987.
背景:结直肠癌(CRC)的复发率很高,尤其是晚期患者,但根据手术分期和病理结果进行预后的效果有限。诊断时出现的循环肿瘤 DNA(ctDNA)可用于改善疾病复发的预测:评估诊断时检测甲基化 BCAT1/IKZF1 ctDNA 与人口统计学、生活方式、临床因素和肿瘤病理学相结合对复发预测价值的影响:设计:一项回顾性队列研究:该队列包括 180 名患者(36 名复发性 CRC 患者),他们接受了至少 3 年的完整治疗和监测。对复发和未复发患者的临床详情和ctDNA甲基化BCAT1/IKZF1结果进行比较,并通过cox回归分析评估各因素对无病生存率的影响:与无病生存率降低独立相关的临床因素包括结节受累(HR = 3.83,95% CI 1.56-9.43,P = .003)、M1 分期(HR = 4.41,95% CI 1.18-16.45,P = .027)、切除边缘小于 2 mm(HR = 4.60,95% CI 1.19-17.76,P = .027)、神经周围受累(HR = 2.50,95% CI 1.01-6.17,P = .047)和远端肿瘤(HR = 3.13,95% CI 1.07-9.18,P = .037)。在51.7%(93/180)的治疗前血浆样本中检测到甲基化的BCAT1/IKZF1。如果将ctDNA阳性结果与这些临床预后因素结合起来考虑,则神经周围受累(HR = 4.44,95% CI 1.92-10.26,P = .001)和远端肿瘤(HR = 5.04,95% CI 1.88-13.49,P = .001)患者的复发预测能力有所提高:结节侵犯、转移性疾病、远端肿瘤部位、切除边缘低和神经周围侵犯与疾病复发有关。治疗前甲基化ctDNA测量可提高对部分患者复发的预测价值,尤其是那些有神经周围受累的患者:澳大利亚和新西兰临床试验注册号:12611000318987。
{"title":"Evaluating the Role of Methylated Circulating Tumor DNA in Combination With Pathological Prognostic Factors for Predicting Recurrence of Colorectal Cancer.","authors":"Hiba Al Naji, Jean M Winter, Susanne K Pedersen, Amitesh Roy, Susan E Byrne, Graeme P Young, Erin L Symonds","doi":"10.1177/11772719241232870","DOIUrl":"10.1177/11772719241232870","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) has a high rate of recurrence, in particular for advanced disease, but prognosis based on staging and pathology at surgery can have limited efficacy. The presence of circulating tumor DNA (ctDNA) at diagnosis could be used to improve the prediction for disease recurrence.</p><p><strong>Objectives: </strong>To assess the impact of detecting methylated <i>BCAT1/IKZF1</i> ctDNA at diagnosis in combination with demographic, lifestyle, clinical factors and tumor pathology, to assess predictive value for recurrence.</p><p><strong>Design: </strong>A retrospective cohort study.</p><p><strong>Methods: </strong>The cohort included 180 patients (36 with recurrent CRC), who had undergone complete treatment and surveillance for a minimum of 3 years. Participant clinical details and ctDNA methylated <i>BCAT1</i>/<i>IKZF1</i> results were compared between those with and without recurrence, and cox regression analysis assessed each factor on disease-free survival.</p><p><strong>Results: </strong>Clinical factors independently associated with reduced disease-free survival included nodal involvement (HR = 3.83, 95% CI 1.56-9.43, <i>P</i> = .003), M1 stage (HR = 4.41, 95% CI 1.18-16.45, <i>P</i> = .027), a resection margin less than 2 mm (HR = 4.60, 95% CI 1.19-17.76, <i>P</i> = .027), perineural involvement (HR = 2.50, 95% CI 1.01-6.17, <i>P</i> = .047) and distal tumors (HR = 3.13, 95% CI 1.07-9.18, <i>P</i> = .037). Methylated <i>BCAT1</i>/<i>IKZF1</i> was detected in 51.7% (93/180) of pre-treatment plasma samples. When a positive ctDNA finding was considered in combination with these clinical prognostic factors, there was improved predictive power of recurrence for patients with perineural involvement (HR = 4.44, 95% CI 1.92-10.26, <i>P</i> < .001), and it marginally improved the predictive factor for M1 stage (HR = 7.59, 95% CI 2.30-25.07, <i>P</i> = .001) and distal tumors (HR = 5.04, 95% CI 1.88-13.49, <i>P</i> = .001).</p><p><strong>Conclusions: </strong>Nodal invasion, metastatic disease, distal tumor site, low resection margins and perineural invasion were associated with disease recurrence. Pre-treatment methylated ctDNA measurement can improve the predictive value for recurrence in a subset of patients, particularly those with perineural involvement.</p><p><strong>Registration: </strong>Australian and New Zealand Clinical Trials Registry #12611000318987.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":"19 ","pages":"11772719241232870"},"PeriodicalIF":3.8,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139997849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-29eCollection Date: 2024-01-01DOI: 10.1177/11772719231225206
Joel Del Bel Pádua, Carolline Fontes Alves Mariano, Alexandre Todorovic Fabro, Fermino Sanches Lizarte Neto, Rogério Lenotti Zuliani, Cláudia Tarcila Gomes Sares, José Sebastião Dos Santos, Ajith Kumar Sankarankutty, Daniela Pretti da Cunha Tirapelli, Vanessa da Silva Silveira, Greice Andreotti de Molfetta, Wilson Araújo da Silva Júnior, Mariângela Ottoboni Brunaldi
Background: Immunohistochemical prognostic significance of the homologous recombination-related proteins RAD51, ATM, BRCA1, and BRCA2 is known in gastric adenocarcinoma, one of the deadliest cancers.
Objective and design: This retrospective cohort study aimed to evaluate mRNA expression and promoter methylation of some homologous recombination-related genes in this neoplasm.
Methods: We evaluated mRNA expression and methylation of RAD51, ATM, ATR, BRCA1, and BRCA2 in tumor and non-tumor frozen samples from gastrectomy specimens by RT-qPCR and MS-HRM, correlating our results with previous immunohistochemistry data and prognostic features.
Results: RAD51, ATR, BRCA1, BRCA2, and ATM mRNA expression was detected in 93.75% (45/48), 93.75% (45/48), 91.67% (44/48), 83.33% (40/48), and 89.58% (43/48) of the tumors; partial or complete methylation, in 94.87% (37/39), 0 (0/42), 97.56% (40/41), 100% (41/41), and 0 (0/40), respectively. Most gene pairs showed significant weak to moderate positive correlations of tumoral mRNA expression with each other: RAD51 with ATR (P = .027), BRCA1 (P < .001), and BRCA2 (P < .001); ATR with BRCA1 (P = .007), and ATM (P = .001); BRCA1 with BRCA2 (P = 0.001). BRCA1 mRNA was reduced in tumors compared with non-neoplastic mucosa (0.345 vs 1.272, P = .015) and, excluding neoadjuvant therapy cases, in T3 to T4 tumors compared with T2 (0.414 vs 0.954, P = .035). Greater tumoral RAD51 mRNA levels correlated with perineural invasion (1.822 vs 0.725, P = .010) and death (1.664 vs 0.929, P = .036), but not with survival time. There was an inverse association between nuclear immunohistochemical positivity for ATR and its mRNA levels (0.487 vs 0.907, P = .032), and no significant correlation for the other markers.
Conclusions: Our results suggest RAD51, BRCA1, and BRCA2 methylation as a frequent epigenetic mechanism in gastric cancer, support the hypothesis that reduced BRCA1 expression participates in disease progression, and show an association between RAD51 mRNA and perineural invasion and mortality that may be considered unexpected, considering the former immunohistochemical studies. The lack of correlation between immunohistochemistry and mRNA, and even the inverse association, for ATR, can be seen as indicative of action of post-transcriptional or post-translational regulatory mechanisms, to be better investigated.
{"title":"mRNA Expression and Methylation of the <i>RAD51</i>, <i>ATM</i>, <i>ATR</i>, <i>BRCA1</i>, and <i>BRCA2</i> Genes in Gastric Adenocarcinoma.","authors":"Joel Del Bel Pádua, Carolline Fontes Alves Mariano, Alexandre Todorovic Fabro, Fermino Sanches Lizarte Neto, Rogério Lenotti Zuliani, Cláudia Tarcila Gomes Sares, José Sebastião Dos Santos, Ajith Kumar Sankarankutty, Daniela Pretti da Cunha Tirapelli, Vanessa da Silva Silveira, Greice Andreotti de Molfetta, Wilson Araújo da Silva Júnior, Mariângela Ottoboni Brunaldi","doi":"10.1177/11772719231225206","DOIUrl":"10.1177/11772719231225206","url":null,"abstract":"<p><strong>Background: </strong>Immunohistochemical prognostic significance of the homologous recombination-related proteins RAD51, ATM, BRCA1, and BRCA2 is known in gastric adenocarcinoma, one of the deadliest cancers.</p><p><strong>Objective and design: </strong>This retrospective cohort study aimed to evaluate mRNA expression and promoter methylation of some homologous recombination-related genes in this neoplasm.</p><p><strong>Methods: </strong>We evaluated mRNA expression and methylation of <i>RAD51</i>, <i>ATM</i>, <i>ATR</i>, <i>BRCA1</i>, and <i>BRCA2</i> in tumor and non-tumor frozen samples from gastrectomy specimens by RT-qPCR and MS-HRM, correlating our results with previous immunohistochemistry data and prognostic features.</p><p><strong>Results: </strong><i>RAD51</i>, <i>ATR</i>, <i>BRCA1</i>, <i>BRCA2</i>, and <i>ATM</i> mRNA expression was detected in 93.75% (45/48), 93.75% (45/48), 91.67% (44/48), 83.33% (40/48), and 89.58% (43/48) of the tumors; partial or complete methylation, in 94.87% (37/39), 0 (0/42), 97.56% (40/41), 100% (41/41), and 0 (0/40), respectively. Most gene pairs showed significant weak to moderate positive correlations of tumoral mRNA expression with each other: <i>RAD51</i> with <i>ATR</i> (<i>P</i> = .027), <i>BRCA1</i> (<i>P</i> < .001), and <i>BRCA2</i> (<i>P</i> < .001); <i>ATR</i> with <i>BRCA1</i> (<i>P</i> = .007), and <i>ATM</i> (<i>P</i> = .001); <i>BRCA1</i> with <i>BRCA2</i> (<i>P</i> = 0.001). <i>BRCA1</i> mRNA was reduced in tumors compared with non-neoplastic mucosa (0.345 vs 1.272, <i>P</i> = .015) and, excluding neoadjuvant therapy cases, in T3 to T4 tumors compared with T2 (0.414 vs 0.954, <i>P</i> = .035). Greater tumoral <i>RAD51</i> mRNA levels correlated with perineural invasion (1.822 vs 0.725, <i>P</i> = .010) and death (1.664 vs 0.929, <i>P</i> = .036), but not with survival time. There was an inverse association between nuclear immunohistochemical positivity for ATR and its mRNA levels (0.487 vs 0.907, <i>P</i> = .032), and no significant correlation for the other markers.</p><p><strong>Conclusions: </strong>Our results suggest <i>RAD51</i>, <i>BRCA1</i>, and <i>BRCA2</i> methylation as a frequent epigenetic mechanism in gastric cancer, support the hypothesis that reduced <i>BRCA1</i> expression participates in disease progression, and show an association between <i>RAD51</i> mRNA and perineural invasion and mortality that may be considered unexpected, considering the former immunohistochemical studies. The lack of correlation between immunohistochemistry and mRNA, and even the inverse association, for <i>ATR</i>, can be seen as indicative of action of post-transcriptional or post-translational regulatory mechanisms, to be better investigated.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":"19 ","pages":"11772719231225206"},"PeriodicalIF":3.4,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10826385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139643125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Inflammation plays a critical role in sepsis. The integration of neutrophil-to-lymphocyte ratio (NLR) and platelets-to-lymphocytes ratio (PLR) from multiple cell types offers a novel approach to rapidly assess inflammation status. However, the predictive role of NLR and PLR in sepsis with lymphopenia remains uncertain.
Objectives: The purpose of this study was to explore the prognostic value of NLR and PLR in sepsis patients with lymphopenia.
Design and methods: In this observational retrospective study, we included 172 sepsis patients with lymphopenia and collected clinical characteristics for analysis. Through binary logistic regression analysis, we identified independent factors. Receiver-operating characteristic curves (ROC) and areas under the curves (AUC) were employed to assess the ability to predict hospital mortality risk.
Results: Our results showed a total hospital mortality rate of 53.49%. Multivariate analysis demonstrated that NLR (OR = 1.11, P < .001) and PLR (OR = 1.01, P = .003) were independent predictors associated with hospital mortality in sepsis patients with lymphopenia. The AUCs of NLR and PLR were 0.750 (95% CI: 0.634-0.788, P < .001) and 0.662 (95% CI: 0.580-0.743, P < .001), respectively. Notably, an optimal cut-off value of 18.93 for NLR displayed a sensitivity of 75.0% and specificity of 63.0% in discriminating hospital mortality in sepsis patients with lymphopenia, while the optimal cut-off value for PLR was 377.50, with a sensitivity of 67.5% and specificity of 64.1%.
Conclusion: NLR and PLR serve as independent predictors of hospital mortality in sepsis patients with lymphopenia.
{"title":"Prognostic Value of Neutrophils-to-Lymphocytes Ratio and Platelets-to-Lymphocytes Ratio in Sepsis Patients With Lymphopenia.","authors":"Xianming Qiu, Quanzhen Wang, Yuke Zhang, Qiannan Zhao, Zhiming Jiang, Lei Zhou","doi":"10.1177/11772719231223156","DOIUrl":"10.1177/11772719231223156","url":null,"abstract":"<p><strong>Background: </strong>Inflammation plays a critical role in sepsis. The integration of neutrophil-to-lymphocyte ratio (NLR) and platelets-to-lymphocytes ratio (PLR) from multiple cell types offers a novel approach to rapidly assess inflammation status. However, the predictive role of NLR and PLR in sepsis with lymphopenia remains uncertain.</p><p><strong>Objectives: </strong>The purpose of this study was to explore the prognostic value of NLR and PLR in sepsis patients with lymphopenia.</p><p><strong>Design and methods: </strong>In this observational retrospective study, we included 172 sepsis patients with lymphopenia and collected clinical characteristics for analysis. Through binary logistic regression analysis, we identified independent factors. Receiver-operating characteristic curves (ROC) and areas under the curves (AUC) were employed to assess the ability to predict hospital mortality risk.</p><p><strong>Results: </strong>Our results showed a total hospital mortality rate of 53.49%. Multivariate analysis demonstrated that NLR (OR = 1.11, <i>P</i> < .001) and PLR (OR = 1.01, <i>P</i> = .003) were independent predictors associated with hospital mortality in sepsis patients with lymphopenia. The AUCs of NLR and PLR were 0.750 (95% CI: 0.634-0.788, <i>P</i> < .001) and 0.662 (95% CI: 0.580-0.743, <i>P</i> < .001), respectively. Notably, an optimal cut-off value of 18.93 for NLR displayed a sensitivity of 75.0% and specificity of 63.0% in discriminating hospital mortality in sepsis patients with lymphopenia, while the optimal cut-off value for PLR was 377.50, with a sensitivity of 67.5% and specificity of 64.1%.</p><p><strong>Conclusion: </strong>NLR and PLR serve as independent predictors of hospital mortality in sepsis patients with lymphopenia.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":"19 ","pages":"11772719231223156"},"PeriodicalIF":3.8,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10768602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139378524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Deregulation in the urokinase-type plasminogen activator receptor (uPA/uPAR) system is reported in many diseases where the immune system is activated. During SARS-CoV-2 infection, a rise in soluble uPAR (suPAR) levels has been detected and its concentration above 6 µg/L predicts worsening to severe respiratory failure 14 days earlier, with a positive predictive value of 85.9%, and was the prerequisite for a treatment with anakinra, a recombinant IL-1 receptor antagonist that blocks the activity of both IL-1α and IL-1β.
Objectives: To compare suPAR concentrations measured by CHORUS suPAR on CHORUS TRIO instrument of DIESSE with the commercially available suPARnostic (ViroGates) ELISA assay.
Design: A single-centre, non-pharmacological, diagnostic study was performed.
Results: A total of 522 serum samples from patients with COVID-19 were tested for suPAR. CHORUS suPAR resulted accurate and reliable, with a high grade of specificity (97.9%), accuracy (97.3%) and sensitivity (96.9%). The median concentration of suPAR, as determined with CHORUS suPAR, was 6.8 µg/L (interquartile range 4.5-9.7) in patients with moderate disease (n = 465) and 8.5 µg/L (interquartile range 5.4-10.6) in patients with severe disease. Among patients with moderate and severe disease, 60.6% and 71.9%, respectively, reached the cut-off concentration of suPAR ⩾6 µg/L, defining their illness severity and suggesting eligibility to anakinra treatment.
Conclusion: CHORUS suPAR kit resulted as sensitive, specific, accurate and able to quantify suPAR concentrations in patients with moderate and severe COVID-19.
{"title":"Detection of Inflammatory Biomarker suPAR in COVID-19 Disease With CHORUS TRIO Instrument.","authors":"Cerutti Helena, Tesi Giulia, Cartocci Alessandra, Guerranti Roberto, Silvestrini Caterina, Gori Sabrina, Bianciardi Simone, Bandini Tommaso, Brogi Alessandra, Leoncini Roberto","doi":"10.1177/11772719231210407","DOIUrl":"10.1177/11772719231210407","url":null,"abstract":"<p><strong>Background: </strong>Deregulation in the urokinase-type plasminogen activator receptor (uPA/uPAR) system is reported in many diseases where the immune system is activated. During SARS-CoV-2 infection, a rise in soluble uPAR (suPAR) levels has been detected and its concentration above 6 µg/L predicts worsening to severe respiratory failure 14 days earlier, with a positive predictive value of 85.9%, and was the prerequisite for a treatment with anakinra, a recombinant IL-1 receptor antagonist that blocks the activity of both IL-1α and IL-1β.</p><p><strong>Objectives: </strong>To compare suPAR concentrations measured by CHORUS suPAR on CHORUS TRIO instrument of DIESSE with the commercially available suPARnostic (ViroGates) ELISA assay.</p><p><strong>Design: </strong>A single-centre, non-pharmacological, diagnostic study was performed.</p><p><strong>Results: </strong>A total of 522 serum samples from patients with COVID-19 were tested for suPAR. CHORUS suPAR resulted accurate and reliable, with a high grade of specificity (97.9%), accuracy (97.3%) and sensitivity (96.9%). The median concentration of suPAR, as determined with CHORUS suPAR, was 6.8 µg/L (interquartile range 4.5-9.7) in patients with moderate disease (n = 465) and 8.5 µg/L (interquartile range 5.4-10.6) in patients with severe disease. Among patients with moderate and severe disease, 60.6% and 71.9%, respectively, reached the cut-off concentration of suPAR ⩾6 µg/L, defining their illness severity and suggesting eligibility to anakinra treatment.</p><p><strong>Conclusion: </strong>CHORUS suPAR kit resulted as sensitive, specific, accurate and able to quantify suPAR concentrations in patients with moderate and severe COVID-19.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":"18 ","pages":"11772719231210407"},"PeriodicalIF":3.8,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10687937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138463551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-14eCollection Date: 2023-01-01DOI: 10.1177/11772719231204508
Paola Monterroso Diaz, Ashton Leehans, Prashanth Ravishankar, Anna Daily
Cancer is a complex and heterogeneous disease that poses a significant threat to global health. Early diagnosis and treatment are critical for improving patient outcomes, and the use of liquid biopsies has emerged as a promising approach for cancer detection and monitoring. Traditionally, cancer diagnosis has relied on invasive tissue biopsies, the collection of which can prove challenging for patients and the results of which may not always provide accurate results due to tumor heterogeneity. Liquid biopsies have gained increasing attention as they provide a non-invasive and accessible source of cancer biomarkers, which can be used to diagnose cancer, monitor treatment response, and detect relapse. The integration of -omics technologies, such as proteomics, genomics, and metabolomics, has further enhanced the capabilities of liquid biopsies by introducing precision oncology and enabling the tailoring of treatment for individual patients based on their unique tumor biology. In this review, we will discuss the challenges and advances in the field of cancer liquid biopsies and the integration of -omics technologies for different types of liquid biopsies, including blood, tear, urine, sweat, saliva, and cerebrospinal fluid.
{"title":"Multiomic Approaches for Cancer Biomarker Discovery in Liquid Biopsies: Advances and Challenges.","authors":"Paola Monterroso Diaz, Ashton Leehans, Prashanth Ravishankar, Anna Daily","doi":"10.1177/11772719231204508","DOIUrl":"10.1177/11772719231204508","url":null,"abstract":"<p><p>Cancer is a complex and heterogeneous disease that poses a significant threat to global health. Early diagnosis and treatment are critical for improving patient outcomes, and the use of liquid biopsies has emerged as a promising approach for cancer detection and monitoring. Traditionally, cancer diagnosis has relied on invasive tissue biopsies, the collection of which can prove challenging for patients and the results of which may not always provide accurate results due to tumor heterogeneity. Liquid biopsies have gained increasing attention as they provide a non-invasive and accessible source of cancer biomarkers, which can be used to diagnose cancer, monitor treatment response, and detect relapse. The integration of -omics technologies, such as proteomics, genomics, and metabolomics, has further enhanced the capabilities of liquid biopsies by introducing precision oncology and enabling the tailoring of treatment for individual patients based on their unique tumor biology. In this review, we will discuss the challenges and advances in the field of cancer liquid biopsies and the integration of -omics technologies for different types of liquid biopsies, including blood, tear, urine, sweat, saliva, and cerebrospinal fluid.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":"18 ","pages":"11772719231204508"},"PeriodicalIF":3.8,"publicationDate":"2023-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/83/d2/10.1177_11772719231204508.PMC10576933.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41239722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Due to diagnostic improvements, medical diagnostics is demanding non-invasive or minimally invasive methods. Non-invasively obtained body fluids (eg., Urine, serum) can replace cerebral fluid, amniotic fluid, synovial fluid, bronchoalveolar lavage fluid, and others for diagnostic reasons. Many illnesses are induced by perturbations of cellular signaling pathways and associated pathway networks as a result of genetic abnormalities. These disturbances are represented by a shift in the protein composition of the fluids surrounding the tissues and organs that is, tissue interstitial fluid (TIF). These variant proteins may serve as diagnostic "signatures" for a variety of disorders. This review provides a concise summary of urine and serum biomarkers that may be used for the diagnosis and prognosis of a variety of disorders, including cancer, brain diseases, kidney diseases, and other system diseases. The studies reviewed in this article suggest that serum and urine biomarkers of various illnesses may be therapeutically useful for future diagnostics. Correct illness management is crucial for disease prognosis, hence non-invasive serum and urine biomarkers have been extensively studied for diagnosis, subclassification, monitoring disease activity, and predicting treatment results and consequences.
{"title":"The Latest Developments in Using Proteomic Biomarkers from Urine and Serum for Non-Invasive Disease Diagnosis and Prognosis.","authors":"Anurag Shama, Thomson Soni, Ishwerpreet Kaur Jawanda, Garima Upadhyay, Anshika Sharma, Vijay Prabha","doi":"10.1177/11772719231190218","DOIUrl":"https://doi.org/10.1177/11772719231190218","url":null,"abstract":"<p><p>Due to diagnostic improvements, medical diagnostics is demanding non-invasive or minimally invasive methods. Non-invasively obtained body fluids (eg., Urine, serum) can replace cerebral fluid, amniotic fluid, synovial fluid, bronchoalveolar lavage fluid, and others for diagnostic reasons. Many illnesses are induced by perturbations of cellular signaling pathways and associated pathway networks as a result of genetic abnormalities. These disturbances are represented by a shift in the protein composition of the fluids surrounding the tissues and organs that is, tissue interstitial fluid (TIF). These variant proteins may serve as diagnostic \"signatures\" for a variety of disorders. This review provides a concise summary of urine and serum biomarkers that may be used for the diagnosis and prognosis of a variety of disorders, including cancer, brain diseases, kidney diseases, and other system diseases. The studies reviewed in this article suggest that serum and urine biomarkers of various illnesses may be therapeutically useful for future diagnostics. Correct illness management is crucial for disease prognosis, hence non-invasive serum and urine biomarkers have been extensively studied for diagnosis, subclassification, monitoring disease activity, and predicting treatment results and consequences.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":"18 ","pages":"11772719231190218"},"PeriodicalIF":3.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1d/f4/10.1177_11772719231190218.PMC10387783.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9916593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1177/11772719231164528
Maribel Salas, Maxine Gossell-Williams, Priyanka Yalamanchili, Sameer Dhingra, Marina A Malikova, Omar Aimer, Toluwalope Junaid
Background The use of biomarkers varies from disease etiognosis and diagnosis to signal detection, risk prediction, and management. Biomarker use has expanded in recent years, however, there are limited reviews on the use of biomarkers in pharmacovigilance and specifically in the monitoring and management of adverse drug reactions (ADRs). Objective The objective of this manuscript is to identify the multiple uses of biomarkers in pharmacovigilance irrespective of the therapeutic area. Design This is a systematic review of the literature. Data Sources and Methods Embase and MEDLINE database searches were conducted for literature published between 2010-March 19, 2021. Scientific articles that described the potential use of biomarkers in pharmacovigilance in sufficient detail were reviewed. Papers that did not fulfill the United States Food and Drug Administration (US FDA) definition of a biomarker were excluded, which is based on the International Conference on Harmonisation (ICH)-E16 guidance. Results Twenty-seven articles were identified for evaluation. Most articles involved predictive biomarkers (41%), followed by safety biomarkers (38%), pharmacodynamic/response biomarkers (14%), and diagnostic biomarkers (7%). Some articles described biomarkers that applied to multiple categories. Conclusion Various categories of biomarkers including safety, predictive, pharmacodynamic/response, and diagnostic biomarkers are being investigated for potential use in pharmacovigilance. The most frequent potential uses of biomarkers in pharmacovigilance in the literature were the prediction of the severity of an ADR, mortality, response, safety, and toxicity. The safety biomarkers identified were used to evaluate patient safety during dose escalation, identify patients who may benefit from further biomarker testing during treatment, and monitor ADRs.
{"title":"The Use of Biomarkers in Pharmacovigilance: A Systematic Review of the Literature.","authors":"Maribel Salas, Maxine Gossell-Williams, Priyanka Yalamanchili, Sameer Dhingra, Marina A Malikova, Omar Aimer, Toluwalope Junaid","doi":"10.1177/11772719231164528","DOIUrl":"https://doi.org/10.1177/11772719231164528","url":null,"abstract":"Background The use of biomarkers varies from disease etiognosis and diagnosis to signal detection, risk prediction, and management. Biomarker use has expanded in recent years, however, there are limited reviews on the use of biomarkers in pharmacovigilance and specifically in the monitoring and management of adverse drug reactions (ADRs). Objective The objective of this manuscript is to identify the multiple uses of biomarkers in pharmacovigilance irrespective of the therapeutic area. Design This is a systematic review of the literature. Data Sources and Methods Embase and MEDLINE database searches were conducted for literature published between 2010-March 19, 2021. Scientific articles that described the potential use of biomarkers in pharmacovigilance in sufficient detail were reviewed. Papers that did not fulfill the United States Food and Drug Administration (US FDA) definition of a biomarker were excluded, which is based on the International Conference on Harmonisation (ICH)-E16 guidance. Results Twenty-seven articles were identified for evaluation. Most articles involved predictive biomarkers (41%), followed by safety biomarkers (38%), pharmacodynamic/response biomarkers (14%), and diagnostic biomarkers (7%). Some articles described biomarkers that applied to multiple categories. Conclusion Various categories of biomarkers including safety, predictive, pharmacodynamic/response, and diagnostic biomarkers are being investigated for potential use in pharmacovigilance. The most frequent potential uses of biomarkers in pharmacovigilance in the literature were the prediction of the severity of an ADR, mortality, response, safety, and toxicity. The safety biomarkers identified were used to evaluate patient safety during dose escalation, identify patients who may benefit from further biomarker testing during treatment, and monitor ADRs.","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":"18 ","pages":"11772719231164528"},"PeriodicalIF":3.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4b/0e/10.1177_11772719231164528.PMC10108426.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9738493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1177/11772719231174746
Ognjen Arandjelović
Background: The focus of the present Letter is on the large and seemingly fertile body of work captured under the umbrella of 'patient stratification'.
Objectives: I identify and explain a fundamental methodological flaw underlying the manner in which the development of an increasingly large number of new stratification strategies is approached.
Design: I show an inherent conflict between the assumptions made, and the very purpose of stratification and its application in practice.
Methods: I analyse the methodological underpinnings of stratification as presently done and draw parallels with conceptually similarly flawed precedents which are now widely recognized.
Results: The highlighted flaw is shown to undermine the overarching ultimate goal of improved patient outcomes by undue fixation on an ill-founded proxy.
Conclusion: I issue a call for a re-think of the problem and the processes leading to the adoption of new stratification strategies in the clinic.
{"title":"Caveat Medicus: It's Time to Re-Think Stratification, You May Not Be Helping.","authors":"Ognjen Arandjelović","doi":"10.1177/11772719231174746","DOIUrl":"https://doi.org/10.1177/11772719231174746","url":null,"abstract":"<p><strong>Background: </strong>The focus of the present Letter is on the large and seemingly fertile body of work captured under the umbrella of 'patient stratification'.</p><p><strong>Objectives: </strong>I identify and explain a fundamental methodological flaw underlying the manner in which the development of an increasingly large number of new stratification strategies is approached.</p><p><strong>Design: </strong>I show an inherent conflict between the assumptions made, and the very purpose of stratification and its application in practice.</p><p><strong>Methods: </strong>I analyse the methodological underpinnings of stratification as presently done and draw parallels with conceptually similarly flawed precedents which are now widely recognized.</p><p><strong>Results: </strong>The highlighted flaw is shown to undermine the overarching ultimate goal of improved patient outcomes by undue fixation on an ill-founded proxy.</p><p><strong>Conclusion: </strong>I issue a call for a re-think of the problem and the processes leading to the adoption of new stratification strategies in the clinic.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":"18 ","pages":"11772719231174746"},"PeriodicalIF":3.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10186568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9495459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1177/11772719231156308
Sultan Almuntashiri, Aaron Chase, Andrea Sikora, Duo Zhang
Background: Club cell secretory protein (CC16) has demonstrated utility as a lung-specific biomarker in predicting mortality in acute respiratory distress syndrome (ARDS). These findings have been observed in pre-clinical trials and a re-analysis of a large, randomized controlled trial of ARDS (Fluid and Catheter Treatment Trial (FACTT)).
Objectives: The purpose of this study was to validate previous findings by evaluating CC16 level as a mortality predictor in patients from the albuterol to treat acute lung injury (ALTA) trial.
Design and method: In this secondary biomarker analysis, plasma CC16 level was measured from 100 ALTA subjects using enzyme-linked immunosorbent assay (ELISA). The rate of mortality was assessed in patients with high (⩾45 ng/mL) versus low CC16 (<45 ng/mL) levels. This cut-off level was applied based on our previous analysis from FACTT trial. Significance was assessed using Kaplan-Meier curves and a log-rank test.
Results: Subjects were an average of 50 years old and 46% of them were females. Patients with high CC16 levels had higher 90-day mortality compared to those with low CC16 levels, (37.73% vs 8.95%, P < .001). Other clinical outcomes including ICU-free days, ventilator-free days, and organ failure free days were significantly different between the groups (All P < .05).
Conclusion: In this validation study, we demonstrated that ARDS patients with high plasma CC16 concentration had a higher mortality rate than those with low CC16 levels, confirming previous findings that CC16 levels are associated with ARDS mortality.
{"title":"Validation of Prognostic Club Cell Secretory Protein (CC16) Cut-point in an Independent ALTA Cohort.","authors":"Sultan Almuntashiri, Aaron Chase, Andrea Sikora, Duo Zhang","doi":"10.1177/11772719231156308","DOIUrl":"https://doi.org/10.1177/11772719231156308","url":null,"abstract":"<p><strong>Background: </strong>Club cell secretory protein (CC16) has demonstrated utility as a lung-specific biomarker in predicting mortality in acute respiratory distress syndrome (ARDS). These findings have been observed in pre-clinical trials and a re-analysis of a large, randomized controlled trial of ARDS (Fluid and Catheter Treatment Trial (FACTT)).</p><p><strong>Objectives: </strong>The purpose of this study was to validate previous findings by evaluating CC16 level as a mortality predictor in patients from the albuterol to treat acute lung injury (ALTA) trial.</p><p><strong>Design and method: </strong>In this secondary biomarker analysis, plasma CC16 level was measured from 100 ALTA subjects using enzyme-linked immunosorbent assay (ELISA). The rate of mortality was assessed in patients with high (⩾45 ng/mL) versus low CC16 (<45 ng/mL) levels. This cut-off level was applied based on our previous analysis from FACTT trial. Significance was assessed using Kaplan-Meier curves and a log-rank test.</p><p><strong>Results: </strong>Subjects were an average of 50 years old and 46% of them were females. Patients with high CC16 levels had higher 90-day mortality compared to those with low CC16 levels, (37.73% vs 8.95%, <i>P</i> < .001). Other clinical outcomes including ICU-free days, ventilator-free days, and organ failure free days were significantly different between the groups (All <i>P</i> < .05).</p><p><strong>Conclusion: </strong>In this validation study, we demonstrated that ARDS patients with high plasma CC16 concentration had a higher mortality rate than those with low CC16 levels, confirming previous findings that CC16 levels are associated with ARDS mortality.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":"18 ","pages":"11772719231156308"},"PeriodicalIF":3.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4b/71/10.1177_11772719231156308.PMC9940244.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9088963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1177/11772719221144459
George Edwards, Anna Seeley, Adam Carter, Maia Patrick Smith, Elizabeth LA Cross, Kathryn Hughes, Ann Van den Bruel, Martin J Llewelyn, Jan Y Verbakel, Gail Hayward
Background: Urinary tract infection (UTI) affects half of women at least once in their lifetime. Current diagnosis involves urinary dipstick and urine culture, yet both methods have modest diagnostic accuracy, and cannot support decision-making in patient populations with high prevalence of asymptomatic bacteriuria, such as older adults. Detecting biomarkers of host response in the urine of hosts has the potential to improve diagnosis.
Objectives: To synthesise the evidence of the diagnostic accuracy of novel biomarkers for UTI, and of their ability to differentiate UTI from asymptomatic bacteriuria.
Design: A systematic review.
Data sources and methods: We searched MEDLINE, EMBASE, CINAHL and Web of Science for studies of novel biomarkers for the diagnosis of UTI. We excluded studies assessing biomarkers included in urine dipsticks as these have been well described previously. We included studies of adult patients (≥16 years) with a suspected or confirmed urinary tract infection using microscopy and culture as the reference standard. We excluded studies using clinical signs and symptoms, or urine dipstick only as a reference standard. Quality appraisal was performed using QUADAS-2. We summarised our data using point estimates and data accuracy statistics.
Results: We included 37 studies on 4009 adults measuring 66 biomarkers. Study quality was limited by case-control design and study size; only 4 included studies had a prospective cohort design. IL-6 and IL-8 were the most studied biomarkers. We found plausible evidence to suggest that IL-8, IL-6, GRO-a, sTNF-1, sTNF-2 and MCR may benefit from more rigorous evaluation of their potential diagnostic value for UTI.
Conclusions: There is insufficient evidence to recommend the use of any novel biomarker for UTI diagnosis at present. Further evaluation of the more promising candidates, is needed before they can be recommended for clinical use.
背景:尿路感染(UTI)影响一半的妇女在其一生中至少一次。目前的诊断包括尿试纸和尿培养,但这两种方法的诊断准确性都不高,不能支持无症状细菌尿高发的患者群体(如老年人)的决策。在宿主尿液中检测宿主反应的生物标志物有可能改善诊断。目的:综合新的UTI生物标志物诊断准确性的证据,以及它们区分UTI和无症状细菌尿的能力。设计:系统回顾。数据来源和方法:检索MEDLINE、EMBASE、CINAHL和Web of Science,寻找诊断UTI的新型生物标志物。我们排除了评估尿试纸中包含的生物标志物的研究,因为这些研究之前已经被很好地描述过。我们纳入了用显微镜和培养作为参考标准的疑似或确诊尿路感染的成人患者(≥16岁)的研究。我们排除了将临床体征和症状或尿液试纸仅作为参考标准的研究。采用QUADAS-2进行质量评价。我们使用点估计和数据准确性统计来总结我们的数据。结果:我们纳入了37项研究,涉及4009名成年人,测量了66种生物标志物。研究质量受到病例对照设计和研究规模的限制;只有4项纳入的研究采用前瞻性队列设计。IL-6和IL-8是研究最多的生物标志物。我们发现可信的证据表明,对IL-8、IL-6、GRO-a、sTNF-1、sTNF-2和MCR的潜在诊断价值进行更严格的评估可能会受益。结论:目前没有足够的证据推荐使用任何新的生物标志物来诊断尿路感染。在推荐临床使用之前,需要对更有希望的候选药物进行进一步评估。
{"title":"What is the Diagnostic Accuracy of Novel Urine Biomarkers for Urinary Tract Infection?","authors":"George Edwards, Anna Seeley, Adam Carter, Maia Patrick Smith, Elizabeth LA Cross, Kathryn Hughes, Ann Van den Bruel, Martin J Llewelyn, Jan Y Verbakel, Gail Hayward","doi":"10.1177/11772719221144459","DOIUrl":"https://doi.org/10.1177/11772719221144459","url":null,"abstract":"<p><strong>Background: </strong>Urinary tract infection (UTI) affects half of women at least once in their lifetime. Current diagnosis involves urinary dipstick and urine culture, yet both methods have modest diagnostic accuracy, and cannot support decision-making in patient populations with high prevalence of asymptomatic bacteriuria, such as older adults. Detecting biomarkers of host response in the urine of hosts has the potential to improve diagnosis.</p><p><strong>Objectives: </strong>To synthesise the evidence of the diagnostic accuracy of novel biomarkers for UTI, and of their ability to differentiate UTI from asymptomatic bacteriuria.</p><p><strong>Design: </strong>A systematic review.</p><p><strong>Data sources and methods: </strong>We searched MEDLINE, EMBASE, CINAHL and Web of Science for studies of novel biomarkers for the diagnosis of UTI. We excluded studies assessing biomarkers included in urine dipsticks as these have been well described previously. We included studies of adult patients (≥16 years) with a suspected or confirmed urinary tract infection using microscopy and culture as the reference standard. We excluded studies using clinical signs and symptoms, or urine dipstick only as a reference standard. Quality appraisal was performed using QUADAS-2. We summarised our data using point estimates and data accuracy statistics.</p><p><strong>Results: </strong>We included 37 studies on 4009 adults measuring 66 biomarkers. Study quality was limited by case-control design and study size; only 4 included studies had a prospective cohort design. IL-6 and IL-8 were the most studied biomarkers. We found plausible evidence to suggest that IL-8, IL-6, GRO-a, sTNF-1, sTNF-2 and MCR may benefit from more rigorous evaluation of their potential diagnostic value for UTI.</p><p><strong>Conclusions: </strong>There is insufficient evidence to recommend the use of any novel biomarker for UTI diagnosis at present. Further evaluation of the more promising candidates, is needed before they can be recommended for clinical use.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":"18 ","pages":"11772719221144459"},"PeriodicalIF":3.8,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9902898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10679738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}