Biomarker-based Screening Research Articles

National Liver Cancer Screening Trial (TRACER) study protocol.

Professional guidelines recommend HCC screening in at-risk patients using semi-annual ultrasound with or without alpha-fetoprotein (AFP); however, this strategy has limited effectiveness due to low adherence and sensitivity. Increasing data support the potential role of blood-based biomarker panels, which could improve both aspects. The biomarker panel GALAD, comprised of sex, age, and 3 blood biomarkers (AFP, AFP-L3, and des-carboxy prothrombin des-carboxy prothrombin), has shown high sensitivity and specificity in biomarker phase II (case-control) and phase III (retrospective cohort) validation studies. However, prospective validation in a large phase IV biomarker clinical utility trial is necessary before its adoption in practice. The National Liver Cancer Screening Trial is an adaptive pragmatic randomized phase IV trial, which began enrollment in January 2024, comparing ultrasound-based versus biomarker-based screening in 5500 patients with chronic hepatitis B infection or cirrhosis from any etiology. Eligible patients are randomly assigned in a 1:1 ratio to semi-annual screening with ultrasound ± alpha-fetoprotein (arm A) or semi-annual screening with GALAD (arm B). Randomization is stratified by enrollment site, liver disease severity (per Child-Pugh class), liver disease etiology (viral, nonviral, and noncirrhotic HBV), and sex. Patients are being recruited from 15 sites (a mix of tertiary care academic referral centers, safety-net health systems, and large community health systems) over a 3-year period, and the primary endpoint, reduction in late-stage HCC, will be assessed at the end of year 5.5. The results of this trial will inform the best strategy for HCC screening and early-stage detection in patients with chronic liver diseases. If GALAD shows superiority, HCC screening would primarily shift from an ultrasound-based strategy to the adoption of the biomarker panel. NCT06084234. The TRACER Study is actively enrolling.

Cost-effectiveness of a biomarker-based screening strategy for hepatocellular carcinoma in patients with cirrhosis

Introduction: Given suboptimal performance of ultrasound-based surveillance for early hepatocellular carcinoma (HCC) detection in patients with cirrhosis, there is interest in alternative surveillance strategies, including blood-based biomarkers. We aimed to evaluate cost-effectiveness of biomarker-based surveillance in patients with cirrhosis. Methods: We constructed a decision-analytic model to compare ultrasound/alpha fetoprotein (AFP) and biomarker-based surveillance strategies in 1,000,000 simulated patients with compensated cirrhosis. Model inputs for adherence, benefits, and harms of each strategy were based on literature review, and costs were derived from the Medicare fee schedule. Primary outcomes were quality-adjusted life-years (QALY) and incremental cost-effectiveness ratio (ICER) of the surveillance strategies, with cost-effectiveness assessed at a threshold of $150,000 per QALY. We performed sensitivity analyses for HCC incidence, test performance characteristics, surveillance adherence, and biomarker costs. Results: In the base case, both ultrasound/AFP and biomarker-based surveillance were cost effective versus no surveillance, with ICERs of $105,620, and $101,295, per QALY, respectively. Biomarker-based surveillance was also cost-effective versus ultrasound/AFP, with an ICER of $14,800 per QALY. Biomarker sensitivity exceeding 80%, cost below $210, or adherence exceeding 58% were necessary for biomarker-based screening to be cost effective versus ultrasound/AFP. In two-way sensitivity analyses, biomarker costs were directly related with test sensitivity and adherence, whereas sensitivity and adherence were inversely related. In a probabilistic sensitivity analysis, biomarker-based screening was the most cost-effective strategy in most (65%) simulations. Conclusion: Biomarker-based screening appears cost-effective for HCC screening, but results are sensitive to test sensitivity, adherence, and costs.

Biomarkers of Brain Dysfunction in Perinatal Iron Deficiency.

Iron deficiency in the fetal and neonatal period (perinatal iron deficiency) bodes poorly for neurodevelopment. Given its common occurrence and the negative impact on brain development, a screening and treatment strategy that is focused on optimizing brain development in perinatal iron deficiency is necessary. Pediatric societies currently recommend a universal iron supplementation strategy for full-term and preterm infants that does not consider individual variation in body iron status and thus could lead to undertreatment or overtreatment. Moreover, the focus is on hematological normalcy and not optimal brain development. Several serum iron indices and hematological parameters in the perinatal period are associated with a risk of abnormal neurodevelopment, suggesting their potential use as biomarkers for screening and monitoring treatment in infants at risk for perinatal iron deficiency. A biomarker-based screening and treatment strategy that is focused on optimizing brain development will likely improve outcomes in perinatal iron deficiency.

Comparing Participation and Interim Effectiveness of Endoscopy and Biomarker-Based Screening for Gastric Cancer: A Cluster Randomized Controlled Trial.

Background: To improve compliance with endoscopic screening for gastric cancer (GC), we assessed five biomarkers-pepsinogen I (PG I), pepsinogen II (PG II), PG I/II ratio, helicobacter pylori antibody (HP-Ab), and gastrin 17 (G17) - for secondary GC screening by comparing participation and effectiveness of traditional endoscopy and biomarker-based screening in a randomized trial with baseline results. Methods: Seventy-four communities were randomly assigned to traditional endoscopy arm (TEA) or biomarker-based endoscopy arm (BEA). TEA uses a questionnaire for risk assessment, and BEA combines a questionnaire with biomarker detection. High-risk individuals in both arms underwent endoscopic screening. Participation and interim screening effectiveness in two arms were reported with baseline analysis. Results: In total, 5,798 participants in TEA and 5,158 in BEA were recruited, with a participation rate of 26.9%. BEA showed a significantly lower high-risk rate than TEA (15.2% vs. 38.9%) and a higher endoscopic participation rate for high-risk individuals (64.9% vs. 53.0%). The endoscopic screening results showed that there was no significant difference in detection rate of GC abnormalities between the two arms. Education level, frequent drinking, hot, rough and hard food consumption, family history of GC, and history of reflux esophagitis or gastropathy influenced participation rates in biomarker-based screening. Age group, sex and regular consumption of meat, eggs and milk products were associated with stomach abnormalities.Cumulative incidence and specific death rates did not significantly differ in intention-to-screen and per-protocol analyses. Conclusions: Biomarker-based screening effectively identifies high-risk individuals and increases endoscopic participation, providing value insights for improving screening efficiency as a secondary procedure.

Biomarkers for Heart Failure Prediction and Prevention.

Heart failure (HF) is a global pandemic affecting over 64 million people worldwide. Its prevalence is on an upward trajectory, with associated increasing healthcare expenditure. Organizations including the American College of Cardiology (ACC) and the American Heart Association (AHA) have identified HF prevention as an important focus. Recently, the ACC/AHA/Heart Failure Society of America (HFSA) Guidelines on heart failure were updated with a new Class IIa, Level of Evidence B recommendation for biomarker-based screening in patients at risk of developing heart failure. In this review, we evaluate the studies that have assessed the various roles and contributions of biomarkers in the prediction and prevention of heart failure. We examined studies that have utilized biomarkers to detect cardiac dysfunction or abnormality for HF risk prediction and screening before patients develop clinical signs and symptoms of HF. We also included studies with biomarkers on prognostication and risk prediction over and above existing HF risk prediction models and studies that address the utility of changes in biomarkers over time for HF risk. We discuss studies of biomarkers to guide management and assess the efficacy of prevention strategies and multi-biomarker and multimodality approaches to improve risk prediction.

Biomarkers for Prediabetes, Type 2 Diabetes, and Associated Complications

Purpose: Diabetes mellitus is a chronic disorder caused by high blood glucose levels due to insulin resistance or insufficient insulin production in pancreatic β-cells. Due to its fastest-growing public health concerns worldwide, it is important to evaluate metabolic profile abnormalities before pre-diabetes or T2DM to anticipate and prevent disease progression. The purpose of the study was to examine the metabolite biomarkers by systematic review and meta-analysis to support early detection of pre-diabetes and T2DM.
 Methodology: Studies published from the earliest online through May 31, 2023, were searched in the Cochrane Library, EMBASE, PubMed, and Scopus. Article titles, abstracts, and complete texts were reviewed after duplicate records were eliminated. Two writers (Long and Yang) created the following inclusion criteria for the publications before literature screening: The study was conducted on humans, did not involve gestational diabetes mellitus (GDM), type 1 diabetes mellitus (T1DM), or subjects under 18 years old, included a diabetic or prediabetes group, and followed international diagnostic guidelines (American Diabetes Association, 2013).
 Findings: The study aimed to review the biomarkers that have been utilized for diabetes in previous research. The comparison of the biomarkers mentioned in the provided information revealed a complex interplay of factors influencing the risk and management of Type 2 Diabetes (T2D). These biomarkers encompass genetic, lifestyle, environmental, and insulin-related factors, each with varying degrees of accuracy and specificity in predicting T2D risk or guiding its management.
 Recommendations: The research will help in spreading awareness among people regarding the identification of diabetes as understanding biomarker-based screening's economic impact can inform healthcare policies. Future studies should validate these biomarkers' diagnostic capacities across varied populations and circumstances. Assessment of these biomarkers' predictive usefulness should be done over time via longitudinal research. Understanding biomarker alterations and diabetes progression improves risk prediction.

Abstract P1-05-18: Orphan non-coding RNAs for early detection of breast cancer with liquid biopsy

Abstract Background: Early detection of breast cancer is crucial for optimal patient outcomes but cannot always be accomplished based on symptoms or screening mammography. Biomarker-based screening could aid early detection of breast cancer by improving sensitivity and specificity. Exai Bio has developed a novel liquid biopsy technology that detects and analyzes small non-coding RNAs that are cancer specific, termed orphan non-coding RNAs (oncRNAs). Previous work in patients with diagnosed breast cancer demonstrated that changes in oncRNAs in serum reflected treatment response and event-free survival. In this study, we developed an assay that measures oncRNAs in serum to detect breast cancer across the range of tumor stages and sizes. Methods: Previously, a library of ~260,000 oncRNAs from 32 different cancers was compiled based on smRNA sequences found in tumor tissues and largely absent in tumor-adjacent normal tissues from The Cancer Genome Atlas (TCGA). To refine this library for applications in serum, we sequenced smRNA in 31 control serum samples. These smRNA sequences were filtered from the larger library, reducing its size to 250,332 oncRNAs. The diagnostic performance of these oncRNAs was then assessed in an independent cohort of archived serum samples from 96 female patients with clinically diagnosed, untreated breast cancer and 95 age- and sex-matched individuals with no known history of cancer. We sequenced smRNAs at an average depth of 17.7 million 50-bp single-end reads per sample. Of the 250,332 oncRNAs in our library, 171,981 (68.7%) were detected in our independent study cohort. An ensemble of logistic regression models was trained with 5-fold cross-validation, using only those oncRNAs yielding an odds ratio >1 and observed in >6% of samples within each training set. Results: The cohort of 96 breast cancer patients and 95 matched controls had mean ages of 59.4 and 56.3 years, respectively. Area under the receiver operating characteristic curve (AUC) for detecting breast cancer was 0.94 (95% CI, 0.85–0.96). Sensitivities for detecting breast cancer at 95% specificity ranged from 0.75 to 0.87 among the four breast cancer stages, including a sensitivity of 0.81 for tumor stage I (Table 1); and from 0.67 to 0.87 among the four main TNM T categories (Table 2). Sensitivities at 95% specificity were relatively high for small tumors, at 0.75 (95% CI, 0.40–0.97) for T1b (>5mm to ≤10mm; n = 9) and 0.80 (0.68–0.94) for T1c (>10mm to ≤20mm; n = 37). Conclusions We have demonstrated the potential value of an oncRNA-based liquid biopsy assay by showing that oncRNAs can be used to detect breast cancer in serum samples with high sensitivity, and that detection requires fewer reads than are needed with other platforms. Moreover, we found that this oncRNA-based assay performed well in detecting early-stage breast cancer and small tumors. This suggests that an oncRNA-based liquid biopsy assay may be beneficial for early detection of breast cancer. Table 1. Model sensitivity by tumor stage. For the indicated numbers of cases (N), sensitivity and Pearson-Clopper 95% confidence intervals are reported for tumor detection by the oncRNA-based model at 95% specificity by tumor stage, as defined by the AJCC 7th Edition breast cancer staging system. Table 2. Model sensitivity by tumor size. For the indicated numbers of cases (N), sensitivity and Pearson-Clopper 95% confidence intervals are reported for tumor detection by the oncRNA-based model at 95% specificity by TNM T category, as defined by the AJCC 7th Edition breast cancer staging system. Citation Format: Taylor B. Cavazos, Jeffrey Wang, Oluwadamilare I. Afolabi, Alice Huang, Dung Ngoc Lam, Seda Kilinc, Jieyang Wang, Lisa Fish, Xuan Zhao, Andy Pohl, Helen Li, Kimberly H. Chau, Patrick A. Arensdorf, Fereydoun Hormozdiari, Hani Goodarzi, Babak Alipanahi. Orphan non-coding RNAs for early detection of breast cancer with liquid biopsy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-18.

Abstract P3-03-21: Biological and Cultural Drivers of Early-Onset Breast Cancer: a mixed-method study

Abstract Background: The incidence of early-onset breast cancer (BC) in adults < 40 years old has increased dramatically in the US over recent decades. The increase in incidence means that identifying higher risk individuals through family-history based guidelines will miss many young adults. As no population-based screening is recommended for adults under 40, so how they detect their BC remains unclear. Using data from a nested case-control study in the Breast Cancer Family Registry, we found that the steroid metabolome may improve risk assessment. If replicated in larger studies, it will be important to know more about the clinical contexts in which this biomarker screening could be implemented from both the provider and patient perspectives. One way to fill these gaps is to identify biocultural drivers of risk that deepen our etiologic understanding and inform risk assessment. We use quantitative and qualitative (mixed) methods to integrate “emics”—the on the ground perspective—from young adults with BC into metabolomic studies. Methods: For the provider perspective, we administered a survey to Obstetricians/gynecologists (OBGYNs) about their knowledge of American College of Obstetrics and Gynecology (ACOG) breast cancer screening guidelines for women under 40 and determined the proportion of correct responses. For the patient perspective, we examined qualitative data from the Young Survival Coalition (YSC). The YSC hosts an online forum where young adults with breast cancer “tell their story” in posts. We reviewed text from posts published between March 2009 and December 2019 and coded text (n=750 posts) according to themes: “first signs and symptoms,” “steps to diagnosis,” “staging type,” and “patient-provider feelings.” Then, we used natural language processing and machine learning with the support vector machine algorithm to build classification models and detect the themes in all posts (n=571,602). We repeated this process for sub-themes. Results: ACOG guidelines recommend that women at “average risk” of breast cancer are counseled about breast self-awareness, and 75% of OBGYN respondents answered this survey question correctly. Our qualitative, “emic” data suggest that the vast majority of young adults find their BC through self-awareness and first seek care from OBGYNs. They first noticed signs (n=3,266) of breast changes through self-detection of lumps (56.5%), self-detected breast and health changes (25.0%), and through a provider (17.2%). The first steps to diagnosis (n=31,640) mainly started with clinic visits (66.5%), others with surgery (23.3%). Stage at diagnoses (n=71,879) were Stage 4 (7.3%), followed by Stage 0 (7.2%), Stage 2-3 (5.5%), and Stage 1 (4.8%), while others mentioned being diagnosed with any invasive cancer (7.3%). Out of 24,648 posts, 70.3% were not satisfied with their providers and felt ignored, their treatment delayed, lacked trust, and felt their providers were not informed. One person said, “My doctor has not had a patient as young as me get diagnosed with cancer and has not suggested ANYONE.” Conclusions: In addition to counseling about breast self-awareness as a means of detection, the OBGYN setting may be a place to implement biomarker-based screening for early-onset BC. These results are derived from our mixed-methods approach, designed to identify biocultural drivers of cancer prevention by incorporating “omics” and “emics”. In the era of “omics,” when molecular markers are incorporated into cancer risk reduction and early detection, “emics” are equally important to identify what is feasible in “real-world” settings. Citation Format: Lauren Houghton, Kathleene T. Ulanday, Maxim Topaz, Desiree Walker, Stacy Lewis, Mary Beth Terry. Biological and Cultural Drivers of Early-Onset Breast Cancer: a mixed-method study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-21.

Natriuretic Peptide Screening for Primary Prevention or Early Detection of Heart Failure: A Pharmacist-Driven Team-Based Approach.

Emerging data indicates that natriuretic peptide biomarker-based screening and early intervention could prevent left ventricular dysfunction or new-onset heart failure (HF). The 2017 update of the American College of Cardiology/ American Heart Association/Heart Failure Society of America guideline for managing HF provides a IIa recommendation for natriuretic peptide biomarker screening followed by a team-based approach for preventing HF. Clinical pharmacists worked collaboratively with a cardiology specialist and primary care practitioners to establish a protocol to identify patients at risk for HF. Patients with hypertension and/or type 2 diabetes mellitus (T2DM) and without a history of HF with N-terminal pro-B-type natriuretic peptide > 125 pg/mL received follow-up from clinical pharmacists, including initiation and/or adjustment of reninangiotensin system inhibitors, discussion of echocardiogram, and comprehensive disease state management of hypertension, T2DM, atherosclerotic cardiovascular disease risk reduction, oral nonsteroidal anti-inflammatory drug reduction, and tobacco cessation. By using natriuretic peptide screening, clinical pharmacists were able to identify patients with hypertension and/or T2DM who were at higher risk for HF and provide comprehensive medication management.

Advances in lung cancer screening and early detection.

Lung cancer is associated with a heavy cancer-related burden in terms of patients’ physical and mental health worldwide. Two randomized controlled trials, the US-National Lung Screening Trial (NLST) and Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON), indicated that low-dose CT (LDCT) screening results in a statistically significant decrease in mortality in patients with lung cancer, LDCT has become the standard approach for lung cancer screening. However, many issues in lung cancer screening remain unresolved, such as the screening criteria, high false-positive rate, and radiation exposure. This review first summarizes recent studies on lung cancer screening from the US, Europe, and Asia, and discusses risk-based selection for screening and the related issues. Second, an overview of novel techniques for the differential diagnosis of pulmonary nodules, including artificial intelligence and molecular biomarker-based screening, is presented. Third, current explorations of strategies for suspected malignancy are summarized. Overall, this review aims to help clinicians understand recent progress in lung cancer screening and alleviate the burden of lung cancer.

Paving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective.

Paving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective.

Opportunistic screening for asymptomatic left ventricular dysfunction in type 2 diabetes mellitus

BackgroundInternational guidelines recommend natriuretic peptide biomarker-based screening for patients at high heart failure (HF) risk to allow early detection. There have been few reports about the incorporation of screening procedure...

Opportunistic screening for asymptomatic left ventricular dysfunction in type 2 diabetes mellitus.

International guidelines recommend natriuretic peptide biomarker-based screening for patients at high heart failure (HF) risk to allow early detection. There have been few reports about the incorporation of screening procedure to existing clinical practice. To implement screening of left ventricular dysfunction in patients with type 2 diabetes mellitus (DM). A prospective screening study at the DM complication screening centre was performed. Between 2018 and 2019, 1043 patients (age: 63.7±12.4 years; male: 56.3%) with mean glycated haemoglobin of 7.25%±1.34% were recruited. 81.8% patients had concomitant hypertension, 31.1% had coronary artery disease, 8.0% had previous stroke, 5.5% had peripheral artery disease and 30.7% had chronic kidney disease (CKD) stages 3-5. 43 patients (4.1%) had an elevated N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration above the age-specific diagnostic thresholds for HF, and 43 patients (4.1%) had newly detected atrial fibrillation (AF). The prevalence of elevated NT-proBNP increased with age from 0.85% in patients aged <50 years to 7.14% in those aged 70-79 years and worsening kidney function from 0.43% in patients with CKD stage 1 to 42.86% in CKD stage 5. In multivariate logistic regression, male gender (OR: 3.67 (1.47-9.16), p = 0.005*), prior stroke (OR: 3.26 (1.38-7.69), p = 0.007*), CKD (p<0.001*) and newly detected AF (OR: 7.02 (2.65-18.57), p<0.001*) were significantly associated with elevated NT-proBNP. Among patients with elevated NT-proBNP, their mean left ventricular ejection fraction (LVEF) was 51.4%±14.7%, and 45% patients had an LVEF <50%. NT-proBNP and ECG screening could be implemented with relative ease to facilitate early detection of cardiovascular complication and improve long-term outcomes.

Screening for Colorectal Cancer Leading into a New Decade: The "Roaring '20s" for Epigenetic Biomarkers?

Colorectal cancer (CRC) has an important bearing (top five) on cancer incidence and mortality in the world. The etiology of sporadic CRC is related to the accumulation of genetic and epigenetic alterations that result in the appearance of cancer hallmarks such as abnormal proliferation, evasion of immune destruction, resistance to apoptosis, replicative immortality, and others, contributing to cancer promotion, invasion, and metastasis. It is estimated that, each year, at least four million people are diagnosed with CRC in the world. Depending on CRC staging at diagnosis, many of these patients die, as CRC is in the top four causes of cancer death in the world. New and improved screening tests for CRC are needed to detect the disease at an early stage and adopt patient management strategies to decrease the death toll. The three pillars of CRC screening are endoscopy, radiological imaging, and molecular assays. Endoscopic procedures comprise traditional colonoscopy, and more recently, capsule-based endoscopy. The main imaging modality remains Computed Tomography (CT) of the colon. Molecular approaches continue to grow in the diversity of biomarkers and the sophistication of the technologies deployed to detect them. What started with simple fecal occult blood tests has expanded to an armamentarium, including mutation detection and identification of aberrant epigenetic signatures known to be oncogenic. Biomarker-based screening methods have critical advantages and are likely to eclipse the classical modalities of imaging and endoscopy in the future. For example, imaging methods are costly and require highly specialized medical personnel. In the case of endoscopy, their invasiveness limits compliance from large swaths of the population, especially those with average CRC risk. Beyond mere discomfort and fear, there are legitimate iatrogenic concerns associated with endoscopy. The risks of perforation and infection make endoscopy best suited for a confirmatory role in cases where there are positive results from other diagnostic tests. Biomarker-based screening methods are largely non-invasive and are growing in scope. Epigenetic biomarkers, in particular, can be detected in feces and blood, are less invasive to the average-risk patient, detect early-stage CRC, and have a demonstrably superior patient follow-up. Given the heterogeneity of CRC as it evolves, optimal screening may require a battery of blood and stool tests, where each can leverage different pathways perturbed during carcinogenesis. What follows is a comprehensive, systematic review of the literature pertaining to the screening and diagnostic protocols used in CRC. Relevant articles were retrieved from the PubMed database using keywords including: “Screening”, “Diagnosis”, and “Biomarkers for CRC”. American and European clinical trials in progress were included as well.

Biomarker-Based Screening of Organ Dysfunction in Patients with MGUS Allows Early Diagnosis of AL Amyloidosis

Introduction. Despite availability of newer effective therapies, approximately 30% of patients with AL amyloidosis still die within 1 year from diagnosis due to advanced, irreversible cardiac involvement at presentation. In 40% of patients the diagnosis is made more than 1 year after the onset of symptoms, and, once amyloid organ involvement becomes symptomatic, organ dysfunction is often already advanced (Kourelis et al. AJH 2014, Lousada et al. Adv Ther 2015). Biomarkers [(N terminal pro natriuretic peptide (NT-proBNP) for the heart, albuminuria for the kidney, and alkaline phosphatase (ALP) for the liver] can detect organ involvement before symptoms appear and can facilitate early diagnosis. Moreover, increased circulating free light chains (FLC) precede the presentation of AL amyloidosis by 4 years or more (Weiss et al. JCO 2014). Thus, we advocated the screening with biomarkers of amyloid organ involvement of all patients with monoclonal gammopathy of undetermined significance (MGUS) and abnormal FLC ratio (Merlini et al. Hematology Am Soc Hematol Educ Program 2012, Merlini et al. Blood 2013). Here we present the clinical features and outcome of patients with MGUS diagnosed with AL amyloidosis while asymptomatic during biomarker-based screening.Methods. The prospectively-maintained database of the Pavia Amyloidosis Research and Treatment Center was systematically searched for patients diagnosed with AL amyloidosis during biomarker-based screening of MGUS. Patients who had amyloid-related symptoms at the time of diagnosis were excluded. The diagnosis of AL amyloidosis was established on abdominal fat or organ biopsy in all cases, and typing by immuno-electron microscopy confirmed that the amyloid fibrils were formed by a light chain of the same isotype as the monoclonal protein.Results. Thirteen patients were identified between January 2012 and December 2016. Six were males and their median age was 67 years (range 38-79 years). The median time from the identification of MGUS to diagnosis of AL amyloidosis was 4.2 years (range 0.7-19.8 years). The monoclonal components were IgAl in 1 patient, IgDl in 1, IgGk in 1, IgGl in 7, and IgMl in 3. The median dFLC value was 67 mg/L (range 21-283 mg/L). The biomarker found abnormal during follow-up was proteinuria (median 1.01 g/24h, range 0.7-1.32 g/24h, predominantly albumin) in 8 patients, elevated NT-proBNP in 8 (median 789 ng/L, range 441-2935 ng/L), and ALP in 1 (509 U/L, upper reference limit 279 U/L). In 4 patients more than 1 biomarker was elevated. Cardiac troponin I was <0.1 ng/mL in all but 1 of the 7 patients with heart involvement, resulting in cardiac stage II in 7 subjects and IIIa in 1. Median left ventricular wall thickness at echocardiography was 13.2 mm (range 10.0-14.4 mm) and median ejection fraction was 62% (range 50-70%) in patients with elevated NT-proBNP. Estimated glomerular filtration rate was >50 mL/min in all patients with proteinuria, resulting in renal stage I in all cases. All the patients are alive and none required dialysis after a median follow-up of 30 months. Eight patients received cyclophosphamide / bortezomib / dexamethasone (CyBorD), 2 (diagnosed in 2009) melphalan / dexamethasone (MDex), and 3 bortezomib / rituximab / dexamethasone. Ten patients obtained complete or very good partial (CR/VGPR) response plus organ response (OR) after upfront treatment. The remaining 3 subjects received second-line therapy, bortezomib /dexamethasone, lenalidomide / dexamethasone, and autologous stem cell transplant and reached CR/VGPR plus OR after rescue treatment.Discussion. Biomarker-based screening for amyloid organ involvement in patients with MGUS allowed pre-symptomatic diagnosis of systemic AL amyloidosis at early stages, resulting in excellent outcomes in all cases, including those who fail to respond to upfront therapy. Larger, prospective studies are warranted to assess the impact of this approach. DisclosuresPalladini:Prothena: Honoraria, Other: Travel grant; Celgene: Other: Travel grants; Jannsen-Cilag: Membership on an entity's Board of Directors or advisory committees. Varettoni:Jannsen: Consultancy, Other: travel expenses.

Nano-scavengers for blood biomarker discovery in ovarian carcinoma

The development and implementation of biomarker-based screening tools for ovarian cancer require novel analytical platforms to enable the discovery of biomarker panels that will overcome the limitations associated with the clinically used CA-125.The systematic discovery of protein biomarkers directly from human plasma using proteomics remains extremely challenging, due to the wide concentration range of plasma proteins. Here, we describe the use of lipid-based nanoparticles (NPs) as an ‘omics’ enrichment tool to amplify cancer signals in the blood and to uncover disease specific signatures. We aimed to exploit the spontaneous interaction of clinically-used liposomes (Caelyx®) with plasma proteins, also known as’ protein corona’ formation, in order to facilitate the discovery of previously unreported differentially abundant molecules. Caelyx® liposomes were incubated with plasma samples obtained from advanced ovarian carcinoma patients and healthy donors and corona-coated liposomes were subsequently recovered. Comprehensive comparison between ‘healthy’ and ‘diseased’ corona samples by label-free proteomics resulted in the identification of multiple differentially abundant proteins. Moreover, immunoassay-based validation of selected proteins demonstrated the potential of nanoparticle-platform proposed to discover novel molecules with great diagnostic potential. This study proposes a nanoparticle-enabled workflow for plasma proteomic analysis in healthy and diseased states and paves the way for further work needed to discover and validate panels of novel biomarkers for disease diagnosis and monitoring.

Refocusing on the Primary Prevention of Heart Failure.

The burden of heart failure (HF) is a significant national and global public health problem, with prevalence rates on the rise. Given the significant morbidity, mortality, and healthcare costs attributable to HF, it is of utmost importance to utilize preventive strategies to prevent the development of HF. Therefore, we sought to address how a multi-modal risk assessment approach can be used to stratify patients for HF risk and guide implementation of therapeutic strategies to prevent HF. New externally validated, multivariate prediction models for incident HF can be applied in the general population and may be used to aide clinicians in assessing individualized HF risk and screening for HF. Recent clinical trial data suggest a natriuretic peptide biomarker-based screening approach coupled with team-based cardiovascular care to focus on optimization of guideline-directed medical therapy may help prevent new-onset HF. However, widespread implementation of clinical risk scores and/or biomarkers is needed. In addition to promoting a heart healthy lifestyle, prevention and management of modifiable risk factors, including intensive blood pressure lowering and use of sodium-glucose cotransporter-2 inhibitors, can prevent incident HF.

Mammography utilization among women with a negative circulating tumor DNA-based early cancer detection test.

1563 Background: Blood-based tests may enable minimally invasive detection of multiple cancer types. One such test, CancerSEEK, employs ctDNA and protein biomarkers for this purpose. Test performance has been evaluated in women without a history of cancer in an ongoing prospective study called DETECT-A. The introduction of such blood tests holds promise, and their future utility lies in augmenting, not displacing, standard-of-care (SOC) cancer screening. One important safety concern is that a negative test result could provide false reassurance that discourages adherence to SOC cancer screening. To investigate this possibility, we studied delivery of mammography to DETECT-A participants before and after receipt of a negative CancerSEEK result. Methods: DETECT-A screened 10,000 women aged 65-75 using CancerSEEK. Participants completed a survey about cancer screening at enrollment and at one-year post-enrollment. We analyzed only those participants who had received a negative CancerSEEK result, were insured by Geisinger Health Plan (GHP), and had completed both surveys. GHP claims data were used to identify mammograms performed within one year prior-to and post-enrollment. Overall utilization was determined by combining claims and survey data at enrollment and one-year post-enrollment. In addition to comparing SOC screening rates pre- versus post-testing, we evaluated the impact of primary care physician (PCP) type (Geisinger versus any other institution), as screening reminder mechanisms differ between institutions. Results: Of the 2,241 participants who met analysis criteria, 73.6% (n = 1,650) had a mammogram in the year before enrollment while a significantly great number (79.3%, n = 1,777) did so during the one-year follow-up (χ2(1) = 59.05, p &lt; 0.001). At enrollment, there were 591 participants who had not had a mammogram completed in the previous year, but 404 (68.4%) of them did have a mammogram during the one-year follow-up. The rate of change in mammography utilization did not differ between those who had a Geisinger versus a non-Geisinger PCP (χ2(2) = 1.83, p = 0.40). Conclusions: Participants in a study using a novel blood test for earlier cancer detection had a significantly higher rate of annual mammography after study enrollment and testing. These results indicate that introduction of a minimally invasive ctDNA and protein biomarker-based cancer screening test may engender greater, not lesser, utilization of SOC cancer screening. Further study is required to understand the root causes of increased utilization in this context.

Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients.

Monogenic diabetes, a young-onset form of diabetes, is often misdiagnosed as type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating type 1 from non-type 1 diabetes, in a biomarker screening pathway for monogenic diabetes. We studied patients diagnosed at age 30 years or younger, currently younger than 50 years, in two U.K. regions with existing high detection of monogenic diabetes. The biomarker screening pathway comprised three stages: 1) assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2) if UCPCR was ≥0.2 nmol/mmol, measurement of GAD and IA2 islet autoantibodies; and 3) if negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes. A total of 1,407 patients participated (1,365 with no known genetic cause, 34 with monogenic diabetes, and 8 with cystic fibrosis-related diabetes). A total of 386 out of 1,365 (28%) patients had a UCPCR ≥0.2 nmol/mmol, and 216 out of 386 (56%) were negative for GAD and IA2 and underwent molecular genetic testing. Seventeen new cases of monogenic diabetes were diagnosed (8 common Maturity Onset Diabetes of the Young [Sanger sequencing] and 9 rarer causes [next-generation sequencing]) in addition to the 34 known cases (estimated prevalence of 3.6% [51/1,407] [95% CI 2.7-4.7%]). The positive predictive value was 20%, suggesting a 1-in-5 detection rate for the pathway. The negative predictive value was 99.9%. The biomarker screening pathway for monogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. The minimum prevalence of monogenic diabetes is 3.6% of patients diagnosed at age 30 years or younger.

Two-Stage Biomarker Protocols for Improving the Precision of Early Detection of Prostate Cancer.

New cancer biomarkers are being discovered at a rapid pace; however, these tests vary in their predictive performance characteristics, and it is unclear how best to use them. We investigated 2-stage biomarker-based screening strategies in the context of prostate cancer using a partially observable Markov model to simulate patients' progression through prostate cancer states to mortality from prostate cancer or other causes. Patients were screened every 2 years from ages 55 to 69. If the patient's serum prostate-specific antigen (PSA) was over a specified threshold in the first stage, a second stage biomarker test was administered. We evaluated design characteristics for these 2-stage strategies using 7 newly discovered biomarkers as examples. Monte Carlo simulation was used to estimate the number of screening biopsies, prostate cancer deaths, and quality-adjusted life-years (QALYs) per 1000 men. The all-cancer biomarkers significantly underperformed the high-grade cancer biomarkers in terms of QALYs. The screening strategy that used a PSA threshold of 2 ng/mL and a second biomarker test with high-grade sensitivity and specificity of 0.86 and 0.62, respectively, maximized QALYs. This strategy resulted in a prostate cancer death rate within 1% of using PSA alone with a threshold of 2 ng/mL, while reducing the number of biopsies by 20%. Sensitivity analysis suggests that the results are robust with respect to variation in model parameters. Two-stage biomarker screening strategies using new biomarkers with risk thresholds optimized for high-grade cancer detection may increase quality-adjusted survival and reduce unnecessary biopsies.