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Instruction-tuned large language models (LLMs) demonstrate exceptional ability to align with human intentions. We present an LLM-based model—instruction-tuned LLM for assessment of cancer (iLLMAC)—that can detect cancer using cell-free deoxyribonucleic acid (cfDNA) end-motif profiles. Developed on plasma cfDNA sequencing data from 1135 cancer patients and 1106 controls across three datasets, iLLMAC achieved area under the receiver operating curve (AUROC) of 0.866 [95% confidence interval (CI), 0.773–0.959] for cancer diagnosis and 0.924 (95% CI, 0.841–1.0) for hepatocellular carcinoma (HCC) detection using 16 end-motifs. Performance increased with more motifs, reaching 0.886 (95% CI, 0.794–0.977) and 0.956 (95% CI, 0.89–1.0) for cancer diagnosis and HCC detection, respectively, with 64 end-motifs. On an external-testing set, iLLMAC achieved AUROC of 0.912 (95% CI, 0.849–0.976) for cancer diagnosis and 0.938 (95% CI, 0.885–0.992) for HCC detection with 64 end-motifs, significantly outperforming benchmarked methods. Furthermore, iLLMAC achieved high classification performance on datasets with bisulfite and 5-hydroxymethylcytosine sequencing. Our study highlights the effectiveness of LLM-based instruction-tuning for cfDNA-based cancer detection. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Screening for early esophageal adenocarcinoma (EAC) may potentially reduce EAC-related mortality and morbidity. This study aimed to examine the Dutch population's intended uptake of 3 hypothetical EAC screening test scenarios and preferences for potential future organization. METHODS: A total of 8,350 Dutch individuals aged 45-75 years were invited, of whom 2,258 completed a web-based survey. Participants were randomly assigned to 1 of 3 hypothetical screening test scenarios (i.e., transnasal endoscopy, ingestible cell collection device, or breath analysis). The primary outcome was intended uptake. Secondary outcomes included acceptance of screening eligibility criteria and preferences regarding invitation, counseling, and diagnostic follow-up. We performed exploratory univariable and multivariable regression analyses to assess which determinants were associated with EAC screening intent. RESULTS: Intended uptake of screening was highest in the breath analysis scenario (95%), followed by conventional upper endoscopy (78%), an ingestible cell collection device (75%), and transnasal endoscopy (68%) (P < 0.001). Anticipating discomfort was most strongly associated with decreased intention to undergo transnasal endoscopy (odds ratio 0.18, 95% confidence interval 0.11-0.29) or swallow a cell collection device (odds ratio 0.20, 95% confidence interval 0.13-0.32). Cancer worry and high acceptance of test sensitivity/specificity were consistently associated with a positive intention to participate in screening. Inviting persons for screening based on gastroesophageal reflux disease symptoms, age, or the output of a risk prediction model was acceptable to 74%, 69%, and 66%, respectively. Inviting only men was acceptable for only 41% of women. The majority (58%) preferred to be invited by a public health organization, and 32% of the participants preferred to discuss their decision to participate with a healthcare professional. DISCUSSION: Participants in this study self-selected through a web-based survey, potentially introducing selection bias. Participants generally intended to participate in EAC screening, although the level of intent depended on the discomfort and performance associated with the offered screening test. Determining eligibility based on gastroesophageal reflux disease symptoms, age, or a risk calculator, but not sex, would be acceptable to most individuals. [ABSTRACT FROM AUTHOR]

The early diagnosis of cancer is vital for effective treatment and improved prognosis. Tumor biomarkers, which can be used for the early diagnosis, treatment, and prognostic evaluation of cancer, have emerged as a topic of intense research interest in recent years. Nucleic acid, as a type of tumor biomarker, contains vital genetic information, which is of great significance for the occurrence and development of cancer. Currently, living cell nucleic acid probes, which enable the in situ imaging and dynamic monitoring of nucleic acids, have become a rapidly developing field. This review focuses on living cell nucleic acid probes that can be used for the early diagnosis of tumors. We describe the fundamental design of the probe in terms of three units and focus on the roles of different nanomaterials in probe delivery. [ABSTRACT FROM AUTHOR]

In this paper, a small antenna is proposed to diagnose skin sarcoma at an embryonic stage. The antenna has an area of 30.54 × 15.27 mm2 and resonates at 1429 MHz with a reflection coefficient of −17.64 dB. The structure consists of a 35 μm copper sheet etched on a 1.6 mm FR-4 substrate. The diagnosis is based on the resonance frequency shift, and the SAR (Specific Absorption Rate) variation when the antenna is positioned on malignant tissue. For the simulations, a three-layer body phantom (skin, fat, muscle), and a half-sphere tumor phantom were considered. Simulations of the antenna performances showed that for a tumor of 100 μm, the resonant frequency, and the SAR decrease by 2 MHz, and 1.09 mW/Kg, respectively. In addition to sarcoma detection, the antenna's 3.6 dBi gain allows for 124.47 m biomedical communication links in a complex environment. [ABSTRACT FROM AUTHOR]

Background: Novel, less-invasive technologies to screen for Barrett's esophagus (BE) may enable a paradigm shift in early detection strategies for esophageal adenocarcinoma (EAC). Understanding professionals' perspectives on screening is important to determine how to proceed. We aimed to explore and compare professionals' perceptions of screening for BE and EAC screening in three countries. Methods: In this study, 29 Dutch, 20 British and 18 American health care professionals (clinicians, researchers and policy makers) participated in concept mapping: a mixed-methods consensus building methodology. Statements on perceived barriers, facilitators, advantages, disadvantages, implications or worries associated with screening for BE and EAC were collected in asynchronous digital brainstorm sessions. Subsequently, participants sorted the statements into groups according to thematic similarity and assessed the relevance of each statement in evaluating the acceptability of BE and EAC screening. Multidimensional scaling and cluster analysis were used to map the associations between generated statements. Results: Professionals across three countries identified eight consistent themes that relate to their perceptions of screening for BE and EAC: (1) Benefits, (2) Harms, (3) Clinical effectiveness concerns, (4) Screening population, (5) Screening modality, (6) Resources, (7) Ownership, and (8) Public communication. Dutch and American professionals prioritized the potential health benefits of screening but also questioned clinical impact. In contrast, British participants prioritized identification of the screening population and suitable test. Conclusions: Most professionals see potential in less-invasive screening tests for BE and EAC but underline the need to define the target screening population and determine benefits and harms before widely employing them. Successful implementation will require thoughtful consideration of the involvement of general practitioners, readiness of endoscopy and pathology services, balanced public communication, and country-specific regulations. [ABSTRACT FROM AUTHOR]

In an era of distinct technological innovations in radiotherapy, a clinically important question has arisen: can the increase of radiotherapy (RT) effectiveness be attributed to these innovations, at least in the case of head and neck (H&N) cancers? In order to answer this question, 133 studies were published, including 21,058 patients who were selected for the present survey with H&N cancer treated within the period of 1970–2010. Three end-points, e.g. 5-year local tumor control (LTC), disease-free survival (DFS) and overall survival (OS) and their average values were evaluated over the consecutive decades. For cancer in the early stage, both LTC and DFS were constantly high (80–90%) through the analyzed decades. For locally advanced cancer, average rates of LTC and an DFS were also constant, but much lower than expected (40–45%). The OS had an increasing tendency: from 45–50% in 1980 to more than 70% in 2010. It may suggest that during the 5-year follow-up period, some proportion (~20%) of advanced tumors gradually progressed from local to chronic disease. Various technical and clinical problems influencing the results of the present review are discussed in detail. Some uncertainties and doubts regarding the RT trials may suggest that “evidence based” recommendations might not be satisfactory, as in the era of combined treatment modalities; it may seem reasonable to replace them with “individually personalized combined therapy”. However, nowadays the only plausible solution to improve H&N cancer curability is to intensify all efforts to detect it in the very early stages of the disease and to increase various activities to convince people to participate in regular prophylactic examinations. [ABSTRACT FROM AUTHOR]

Simple Summary: Blood-based circulating cell-free DNA (cfDNA) biomarkers are important for cancer detection because they can provide a less invasive and more cost-effective way of detecting cancer and offer the possibility of screening large populations at risk for the early detection of multiple cancers. However, highly sensitive techniques are needed to detect circulating tumour DNA (ctDNA), and further optimization and standardization of pre-analytical and analytical steps are required to harness the full potential of cfDNA analysis. Blood-based detection of circulating cell-free DNA (cfDNA) is a non-invasive and easily accessible method for early cancer detection. Despite the extensive utility of cfDNA, there are still many challenges to developing clinical biomarkers. For example, cfDNA with genetic alterations often composes a small portion of the DNA circulating in plasma, which can be confounded by cfDNA contributed by normal cells. Therefore, filtering out the potential false-positive cfDNA mutations from healthy populations will be important for cancer-based biomarkers. Additionally, many low-frequency genetic alterations are easily overlooked in a small number of cfDNA-based cancer tests. We hypothesize that the combination of diverse types of cancer studies on cfDNA will provide us with a new perspective on the identification of low-frequency genetic variants across cancer types for promoting early diagnosis. By building a standardized computational pipeline for 1358 cfDNA samples across seven cancer types, we prioritized 129 shard genetic variants in the major cancer types. Further functional analysis of the 129 variants found that they are mainly enriched in ribosome pathways such as cotranslational protein targeting the membrane, some of which are tumour suppressors, oncogenes, and genes related to cancer initiation. In summary, our integrative analysis revealed the important roles of ribosome proteins as common biomarkers in early cancer diagnosis. [ABSTRACT FROM AUTHOR]

This study aimed to explore the impact of revising suspected-cancer referral guidelines on primary care contacts and costs. Participants had incident cancer (colorectal, n = 2000; ovary, n = 763; and pancreas, n = 597) codes in the Clinical Practice Research Datalink or England cancer registry. Difference-in-differences analyses explored guideline impacts on contact days and nonzero costs between the first cancer feature and diagnosis. Participants were controls ("old National Institute for Health and Care Excellence [NICE]") or "new NICE" if their index feature was introduced during guideline revision. Model assumptions were inspected visually and by falsification tests. Sensitivity analyses reclassified participants who subsequently presented with features in the original guidelines as "old NICE." For colorectal cancer, sensitivity analysis (n = 3481) adjusted for multimorbidity burden. Median contact days and costs were, respectively, 4 (interquartile range [IQR] 2-7) and £117.69 (IQR £53.23-£206.65) for colorectal, 5 (IQR 3-9) and £156.92 (IQR £78.46-£272.29) for ovary, and 7 (IQR 4-13) and £230.64 (IQR £120.78-£408.34) for pancreas. Revising ovary guidelines may have decreased contact days (incidence rate ratio [IRR] 0.74; 95% confidence interval 0.55-1.00; P =.05) with unchanged costs, but parallel trends assumptions were violated. Costs decreased by 13% (equivalent to −£28.05, −£50.43 to −£5.67) after colorectal guidance revision but only in sensitivity analyses adjusting for multimorbidity. Contact days and costs remained unchanged after pancreas guidance revision. The main analyses of symptomatic patients suggested that prediagnosis primary care costs remained unchanged after guidance revision for pancreatic cancer. For colorectal cancer, contact days and costs decreased in analyses adjusting for multimorbidity. Revising ovarian cancer guidelines may have decreased primary care contact days but not costs, suggesting increased resource-use intensity; nevertheless, there is evidence of confounding. • Revising England's National Institute for Health and Care Excellence suspected-cancer referral guidelines shortened the time to diagnosis of colorectal and ovarian cancers. Impacts on healthcare resource use and costs are unknown. • We report weak evidence that revising the guidelines decreased primary care contact days with unchanged costs for symptomatic patients before ovarian cancer diagnosis, suggesting increased resource-use intensity. Contact days and costs remained unchanged for symptomatic patients after pancreas guidance revision and decreased for colorectal cancer but only after adjusting for multimorbidity. • Further research is needed to understand the overall impact of the revised guidelines on the English health system. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, and the currently available techniques for its detection are either invasive or less sensitive. To overcome this limitation, we present here a multiplexed point-of-care test that combines systemic inflammatory response biomarkers, standard laboratory tests, and nanoparticle-based blood tests. This test provides a "risk score" for each individual under investigation, allowing clinicians to distinguish between PDAC patients and healthy subjects accurately and to determine the optimal diagnostic and therapeutic care pathway for each patient. As a result, this work may help advance progress in the early detection of PDAC and contribute to the development of screening programs for high-risk populations. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease, for which mortality closely parallels incidence. So far, the available techniques for PDAC detection are either too invasive or not sensitive enough. To overcome this limitation, here we present a multiplexed point-of-care test that provides a "risk score" for each subject under investigation, by combining systemic inflammatory response biomarkers, standard laboratory tests, and the most recent nanoparticle-enabled blood (NEB) tests. The former parameters are routinely evaluated in clinical practice, whereas NEB tests have been recently proven as promising tools to assist in PDAC diagnosis. Our results revealed that PDAC patients and healthy subjects can be distinguished accurately (i.e., 88.9% specificity, 93.6% sensitivity) by the presented multiplexed point-of-care test, in a quick, non-invasive, and highly cost-efficient way. Furthermore, the test allows for the definition of a "risk threshold", which can help clinicians to trace the optimal diagnostic and therapeutic care pathway for each patient. For these reasons, we envision that this work may accelerate progress in the early detection of PDAC and contribute to the design of screening programs for high-risk populations. [ABSTRACT FROM AUTHOR]

Cu 2 O NP@CuHHTP heterojunction nanoarrays were obtained by partly decomposing the conductive MOF CuHHTP with simple and mild electrochemical reduction. They display super sensing performance for H 2 O 2. [Display omitted] Transition metal oxide/metal–organic framework heterojunctions (TMO@MOF) that combine the large specific surface area of MOFs with TMOs' high catalytic activity and multifunctionality, show excellent performances in various catalytic reactions. Nevertheless, the present preparation approaches of TMO@MOF heterojunctions are too complex to control, stimulating interests in developing simple and highly controllable methods for preparing such heterojunction. In this study, we propose an in situ electrochemical reduction approach to fabricating Cu 2 O nanoparticle (NP)@CuHHTP heterojunction nanoarrays with a graphene-like conductive MOF CuHHTP (HHTP is 2,3,6,7,10,11-hexahydroxytriphenylene). We have discovered that size-controlled Cu 2 O nanoparticles could be in situ grown on CuHHTP by applying different electrochemical reduction potentials. Also, the obtained Cu 2 O NP@CuHHTP heterojunction nanoarrays show high H 2 O 2 sensitivity of 8150.6 μA·mM−1·cm2 and satisfactory detection performances in application of measuring H 2 O 2 concentrations in urine and serum samples. This study offers promising guidance for the synthesis of MOF-based heterojunctions for early cancer diagnosis. [ABSTRACT FROM AUTHOR]

Early diagnosis of cancer is of paramount significance for the therapeutic intervention of cancers. Although the detection of circulating cell-free DNA (cfDNA) has emerged as a promising, minimally invasive approach for early cancer diagnosis, there is an urgent need to develop a highly sensitive and rapid method to precisely identify plasma cfDNA from clinical samples. Herein, we report a robust fluorescent "turn-on" clutch probe based on non-emissive QDs-Ru complexes to rapidly recognize EGFR gene mutation in plasma cfDNA from lung cancer patients. In this system, the initially quenched emission of QDs is recovered while the red emission of Ru(II) complexes is switched on. This is because the Ru(II) complexes can specifically intercalate into the double-stranded DNA (dsDNA) to form Ru-dsDNA complexes and simultaneously liberate free QDs from the QDs-Ru complexes, which leads to the occurrence of an overlaid red fluorescence. In short, the fluorescent "turn-on" clutch probe offers a specific, rapid, and sensitive paradigm for the recognition of plasma cfDNA biomarkers from clinical samples, providing a convenient and low-cost approach for the early diagnosis of cancer and other gene-mutated diseases. [ABSTRACT FROM AUTHOR]

Background: Compared to the rest of Europe, the UK has relatively poor cancer outcomes, with late diagnosis and a slow referral process being major contributors. General practitioners (GPs) are often faced with patients presenting with a multitude of non-specific symptoms that could be cancer. Safety netting can be used to manage diagnostic uncertainty by ensuring patients with vague symptoms are appropriately monitored, which is now even more crucial due to the ongoing COVID-19 pandemic and its major impact on cancer referrals. The ThinkCancer! workshop is an educational behaviour change intervention aimed at the whole general practice team, designed to improve primary care approaches to ensure timely diagnosis of cancer. The workshop will consist of teaching and awareness sessions, the appointment of a Safety Netting Champion and the development of a bespoke Safety Netting Plan and has been adapted so it can be delivered remotely. This study aims to assess the feasibility of the ThinkCancer! intervention for a future definitive randomised controlled trial. Methods: The ThinkCancer! study is a randomised, multisite feasibility trial, with an embedded process evaluation and feasibility economic analysis. Twenty-three to 30 general practices will be recruited across Wales, randomised in a ratio of 2:1 of intervention versus control who will follow usual care. The workshop will be delivered by a GP educator and will be adapted iteratively throughout the trial period. Baseline practice characteristics will be collected via questionnaire. We will also collect primary care intervals (PCI), 2-week wait (2WW) referral rates, conversion rates and detection rates at baseline and 6 months post-randomisation. Participant feedback, researcher reflections and economic costings will be collected following each workshop. A process evaluation will assess implementation using an adapted Normalisation Measure Development (NoMAD) questionnaire and qualitative interviews. An economic feasibility analysis will inform a future economic evaluation. Discussion: This study will allow us to test and further develop a novel evidenced-based complex intervention aimed at general practice teams to expedite the diagnosis of cancer in primary care. The results from this study will inform the future design of a full-scale definitive phase III trial. Trial registration: ClinicalTrials.gov NCT04823559. [ABSTRACT FROM AUTHOR]

Over the last decades, microRNAs (miRNAs) have emerged as important molecules associated with the regulation of gene expression in humans and other organisms, expanding the strategies available to diagnose and handle several diseases. This paper presents a systematic review of literature of miRNAs related to cancer development and explores the main techniques used to quantify these molecules and their limitations as screening strategy. The bibliographic research was conducted using the online databases, PubMed, Google Scholar, Web of Science, and Science Direct searching the terms "microRNA detection", "miRNA detection", "miRNA and prostate cancer", "miRNA and cervical cancer", "miRNA and cervix cancer", "miRNA and breast cancer", and "miRNA and early cancer diagnosis". Along the systematic review over 26,000 published papers were reported, and 252 papers were returned after applying the inclusion and exclusion criteria, which were considered during this review. The aim of this study is to identify potential miRNAs related to cancer development that may be useful for early cancer diagnosis, notably in the breast, prostate, and cervical cancers. In addition, we suggest a preliminary top 20 miRNA panel according to their relevance during the respective cancer development. Considering the progressive number of new cancer cases every year worldwide, the development of new diagnostic tools is critical to refine the accuracy of screening tests, improving the life expectancy and allowing a better prognosis for the affected patients. [ABSTRACT FROM AUTHOR]

In the present study, a sensitive electrochemical aptamer-based biosensing strategy for human non-small cell lung cancer (NSCLC) detection was proposed using nanofiber-modified disposable pencil graphite electrodes (PGEs). The composite nanofiber was comprised of polyacrylonitrile (PAN) and polypyrrole (PPy) polymers, and fabrication of the nanofibers was accomplished using electrospinning process onto PGEs. Development of the nanofibers was confirmed using scanning electron microscopy (SEM). The high-affinity 5′-aminohexyl-linked aptamer was immobilized onto a PAN/PPy composite nanofiber-modified sensor surface via covalent bonding strategy. After incubation with NSCLC living cells (A549 cell line) at 37.5 °C, the recognition between aptamer and target cells was monitored by electrochemical impedance spectroscopy (EIS). The selectivity of the aptasensor was evaluated using nonspecific human cervical cancer cells (HeLa) and a nonspecific aptamer sequence. The proposed electrochemical aptasensor showed high sensitivity toward A549 cells with a detection limit of 1.2 × 103 cells/mL. The results indicate that our label-free electrochemical aptasensor has great potential in the design of aptasensors for the diagnostics of other types of cancer cells with broad detection capability in clinical analysis. [ABSTRACT FROM AUTHOR]

The UK National Health Service has well-developed site-specific referral pathways for patients with suspected cancer, but historically there has been inequality of access for patients with suspected Metastatic malignant disease of Unknown primary Origin (MUO). The Brighton cancer of unknown primary (CUP) clinic covers a population of about 650 000. As well as 'in-house' referrals, direct general practitioner referrals are also accepted (since 2015), aiming to shorten the diagnostic pathway and improve patient support. We present data from the first 3 years of activity. Referrals were screened by an oncologist, ensuring adherence to the strict referral criterion of imaging evidence of a suspected diagnosis of MUO. A standardised data collection form was completed at each clinic appointment by the CUP team. Outcomes were cross-checked against clinic lists, letters and multidisciplinary meeting (MDM) records. A data analysis was carried out of all referrals to the CUP clinic (2015–2018), including general practitioner referrals. In total, 258 patients were seen in the CUP clinic in the first 3 years. The median age was 71 years (range 23–95 years). Source of referral: general practitioner (30%); physician (27%); acute oncology (24%); other MDM (16%); surgeon (3%). A final diagnosis of cancer was made in 83% of referrals, with a primary site identified in 83% of those cancer cases: 19% haematological, 11% lung, 9% urological, 8% upper gastrointestinal, 6% breast, 5% skin, 4% gynaecological, 4% lower gastrointestinal, 0.3% thyroid and 0.3% sarcoma. 10% of referrals remained with a MUO diagnosis (not fit for further investigation) and 7% had confirmed CUP. 17% had a benign diagnosis (of which 56% were general practitioner referrals). Of the general practitioner referrals: 55% were seen in the CUP clinic, 31% did not meet referral criteria and 14% were declined after MDM review of imaging confirmed benign appearances. The development of direct general practitioner referrals to CUP clinics nationally should be encouraged (as supported by the National Institute for Health and Care Excellence) – they are feasible and manageable within a tertiary CUP clinic, resulting in high rates of cancer diagnoses, with attendant early support from specialist nursing teams and oncological review. • Historically there has been inequality of access for patients with suspected MUO. • Direct GP referrals are feasible and manageable within a tertiary CUP clinic. • MUO patients benefit from early specialist nurse support and oncologist input. [ABSTRACT FROM AUTHOR]

Background Cell-free DNA (cf-DNA)-based liquid biopsy is emerging as a revolutionary new method in individualized cancer treatment and prognosis monitoring, although detecting early-stage cancers using cf-DNA remains challenging, partially because of the undefined biological background of cf-DNA. Materials and methods We investigated somatic mutations in the cf-DNA of 259 cancer-free individuals with a median age of 47 years using an endogenous barcoding duplex method with an ultralow base error rate (2 × 10−7) and compared the variant allele frequencies (VAFs) of these mutations between the cf-DNA and the corresponding blood cell DNA. Results Sixty percent (155/259) of the samples showed at least one nonsynonymous mutation on either of two similar target panels covering 508 and 559 cancer-related genes. For individuals older than 50 years of age, the positive rate increased to 76%. Most cf-DNA mutations were also present at similar VAFs in the paired blood cell DNA. The most frequently mutated genes were driver genes of hematologic malignancies, including DNMT3A, TET2, AXSL1, and JAK2. However, the other 58.4% (192/329) of the mutations were likely 'passenger mutations' of clonal hematopoiesis, including mutations in NOTCH2, FAT3, EXT2, ERBB4, and ARID2, which are driver genes of solid tumors. Conclusion Hematopoietic clone-derived mutations, including 'driver mutations' and 'passenger mutations', are prevalent in the cf-DNA of both healthy individuals and cancer patients and may be a potential source of false positives in the liquid biopsy. Our results also suggest the ineffectiveness for distinguishing clonal hematopoietic mutations of low VAF (≤0.1%) from tumor-derived mutations using conventional next-generation sequencing of blood cell DNA. However, an error correction model with an ultralow error rate and high coverage depth is required for blood cell DNA sequencing, which is difficult and costly to achieve with current technologies. [ABSTRACT FROM AUTHOR]

Early cancer detection is critical to control disease progression. Research of high mortality rate cancers is thereby essential although cancer diagnosis is challenging. Mass spectrometry (MS)-based metabolomics is a great technique to support. Despite MS-based metabolomics being a high-throughput technique, it can be inefficient due to the exponentially increased data volume and complexity of MS data. To demonstrate the real power of the MS-based platform, machine learning (ML) can provide insights from the sea of data. As an emerging technology, it is worth reviewing the research work on how ML coupled with MS-based metabolomics in the past decade. An overview of clinical metabolomics studies is presented with respect to cancer type. The primary purpose of this review is to present what data strategy has been applied previously and discuss the challenges and potential solutions when MS-based metabolomics and ML are combined for early cancer diagnosis. • MS-based metabolomics is a high-throughput technique to discover diagnostic biomarkers for early cancer discovery. • Machine learning facilitates clinical metabolomics due to its efficiency in analyzing a high volume of data. • Machine learning is a promising tool to detect cancer, classify cancer subtypes, and predict the risk of cancer occurrence. • Robust machine learning models for early cancer diagnosis boost the data network effect in MS-based clinical metabolomics. [ABSTRACT FROM AUTHOR]

Background: Danish cancer patients have lower survival rates than patients in many other western countries. Half of the patients present with non-alarm symptoms and thus have a long diagnostic pathway. Consequently, an urgent referral pathway for patients with non-specific serious symptoms was implemented throughout Denmark in 2011-2012. As part of the diagnostic workup, a panel of blood tests are performed for all patients referred by their general practitioner (GP) to the urgent referral pathway. In this study, we analysed the probability of being diagnosed with cancer in GP-referred patients with abnormal blood test results.Method: We performed a cohort study that included all patients aged 18 years or older referred by their GP to Silkeborg Regional Hospital for analysis of a panel of blood tests. All patients were followed for 3 months for a cancer diagnosis in the Danish Cancer Registry. The likelihood ratio and post-test probability of subsequently finding cancer were calculated in relation to abnormal blood test results.Results: Among the 1499 patients included in the study, 12.2% were subsequently diagnosed with cancer. The probability of cancer increased with the number of abnormal blood tests. Patients with specific combinations of two abnormal blood tests had a 23-62% probability of cancer. Only a few single abnormal blood tests were linked with a high post-test probability of cancer, and most abnormalities were not specific to cancer.Conclusions: A number of specific abnormal blood tests and combinations of abnormal blood tests markedly increased the probability of cancer being diagnosed. Still, abnormal blood test results should be interpreted cautiously as most are non-specific to cancer. Thus, results from the blood test panel may strengthen the suspicion of cancer, but blood tests cannot be used as a stand-alone tool to rule out cancer. [ABSTRACT FROM AUTHOR]

Social inequality in cancer survival is well known, and within public health promotion enhancing awareness of cancer symptoms is oft en promoted as a way to reduce social differences in stage of cancer at the time of diagnosis. In order to add to our knowledge of what may lie behind social inequalities in cancer survival encountered in many high-income countries, this article explores the situatedness of bodily sensations. Based on comparative ethnographic fieldwork, we argue that the socially and biologically informed body influences how people from lower social classes experience sensations. Overall, we point out how the sensorial is tied to the embodiment of the social situation in the sense that some bodies make more 'noise' than others. It follows that standardised approaches to improving early care seeking by increasing knowledge and awareness may overlook essential explanations of social differences in symptom appraisal. [ABSTRACT FROM AUTHOR]

• A generalized method for effective early diagnosis of pancreatic cancer based on multiple instance learning. • A spatial transformation based on anatomical structures is proposed to reduce the background interference and enhance the detection stability for the learned features. • Instance-level contrastive learning is developed to aggregate different types of tumor features, maintain the tumor feature integrity, and enhance the diagnosis stability. • The method achieves remarkable generalization performance in unseen datasets and is sensitive to tumors smaller than 2 cm in diameter. Pancreatic cancer is a highly malignant cancer type with a high mortality rate. As no obvious symptoms are associated with this cancer type, most of the diagnoses are made when the patients are already in a late stage. In this work, we propose an automated method for effective early diagnosis of pancreatic cancer based on multiple instance learning with contrast-enhanced CT images. In this method, diagnosis stability and generalizability were improved through shape normalization based on anatomical structures as well as instance-level contrastive learning. Specifically, anatomically-guided shape normalization were developed to reconstruct the pancreatic regions of interest by spatial transformations, account for larger tumor parts in these regions, and hence enhance the extraction of pancreatic features. Moreover, instance-level contrastive learning was employed to aggregate different types of tumor features within the multiple instance learning framework. This learning approach can maintain the tumor feature integrity and enhance the diagnosis stability. Finally, a balance-adjustment strategy was designed to alleviate the class imbalance problem caused by the scarcity of tumor samples. Extensive experimental results demonstrated remarkable performance of our method when conducted cross-validation on an in-house dataset with 310 patients and independent test on two unseen datasets (a private test set with 316 and a publicly-available test set with 281). The proposed strategies also led to significant improvements in generalizability. Besides, the clinical significance of the proposed method was further verified through two independent test results in which tumors smaller than 2 cm in diameter were identified at accuracies of 80.9% and 90.1%, respectively. Overall, our method provides a potentially successful tool for early diagnosis of pancreatic cancer. Our source codes will be released at https://github.com/SJTUBME-QianLab/MIL_PAdiagnosis. [Display omitted] [ABSTRACT FROM AUTHOR]

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5′ end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients. • A novel tumor fragment quantification method for the diagnosis of lung cancer. • Machine learning models using ctDNA methylome and fragmentome profiles. • Tumor Originated Fragment (TOF) scoring system to diagnose early-stage lung cancer. [ABSTRACT FROM AUTHOR]

The isolation and analysis of scarce circulating tumor cells (CTCs) with immunomagnetic nanoparticles (IMNs) have shown promising outcomes in noninvasive cancer diagnosis. However, the IMNs adsorb nonspecific proteins after entering into biofluids and the formed protein coronas cover surface targeting ligands, limiting the detection efficiency of IMNs. In addition, the interaction between surface targeting ligands and white blood cells (WBCs) significantly limits the purity of CTCs isolated by IMNs. Furthermore, the interfacial collision of nanoparticles and cells has negative effects on the viability of isolated CTCs. All of these limitations synthetically restrict the isolation and analysis of rare CTCs for early diagnosis and precision medicine. Here, we proposed that surface functionalization of IMNs with neutrophil membranes can simultaneously reduce nonspecific protein adsorption, enhance the interaction with CTCs, reduce the distraction from WBCs, and improve the viability of isolated CTCs. In spiked blood samples, our neutrophil membrane-coated IMNs (Neu-IMNs) exhibited a superior separation efficiency from 41.36% to 96.82% and an improved purity from 40.25% to 90.68% when compared to bare IMNs. Additionally, we successfully isolated CTCs in 19 out of total 20 blood samples from breast cancer patients using Neu-IMNs and further confirmed the feasibility of the isolated CTCs for downstream cell sequencing. Our work provides a new perspective on engineered IMNs for efficient isolation and analysis of CTCs, paving the way for early noninvasive diagnosis of cancer. [ABSTRACT FROM AUTHOR]

Toponome imaging systems (TIS) can yield high-resolution subcellular colocalization images of multiple proteins within single cells and intact tissue sections, giving this technology significant potential for identifying multiplex biomarkers that simultaneously measure several aspects of a cell. The integral role of the microenvironment in malignant progression and the recently appreciated heterogeneity of cancer cells underscore the importance of characterizing complex molecular phenotypes and the large protein network structures of single cells within their preserved anatomical context. Here, we discuss the TIS technique and the potential for developing new sensitive and specific multiplex biomarkers for risk stratification and diagnosis, in addition to its utility for anticancer drug discovery by identifying ‘hub’ proteins that are essential regulators of protein networks. [Copyright &y& Elsevier]

Background Tumor-specific immunity of insulin-like growth factor-binding protein-2 (IGFBP-2) has been reported in several cancers. We aimed to assess the role of serum IGFBP-2 antibodies (IGFBP-2 Abs) in early cancer detection. Patients and methods Glioma and colorectal carcinoma (CRC) were used as models. Serum IGFBP-2 and IGFBP-2 Abs were measured in 260 tumor patients (145 gliomas, 45 colorectal polyps, and 70 CRCs) and 141 controls. Receiver operating characteristic curves were applied. Results Serum IGFBP-2 Ab levels were significantly elevated in tumors (mean: 82 ng/ml, median: 17 ng/ml, range: 0–1387 ng/ml) compared with controls (11, 0, 0–212 ng/ml) (P < 0.0001) and higher in early than advanced cancers opposite of serum IGFBP-2 levels. IGFBP-2 Abs effectively discriminated between controls and grade II and III gliomas [area under the curve (AUC): 0.821–0.864; 95% confidence interval (CI) = 0.762–0.936; P < 0.0001], and CRC I–II (AUC: 0.668; 95% CI = 0.566–0.770; P = 0.002) as well as indicative of advanced polyps at high risk of CRC (AUC: 0.72; 95% CI = 0.630–0.811; P < 0.0001). The sensitivity and specificity for diagnosing grade II–III gliomas reached 66%–84% and 81%. Combined serum IGFBP-2 and IGFBP-2 Abs augmented the discriminative power of all stage tumors (AUC: 0.823), gliomas (AUC: 0.800), and CRCs (AUC = 0.917). Conclusion Our results first demonstrate IGFBP-2 Abs for early cancer detection and in combination of serum IGFBP-2 for improved cancer diagnosis. [ABSTRACT FROM PUBLISHER]

Overexpression of the Bcl-2 protein has emerged as a hallmark of carcinoma cells and can be employed as a biochemical biomarker of these cells. Therefore, some Bcl-2 protein fluorescence probes (BPFPs) were designed for Bcl-2 protein quantification and carcinoma cells labeling. The high Bcl-2 protein binding affinity (K i < 1 nM) and selectivity (over 50,000-fold Bcl-2 protein selectivity against Mcl-1 protein) of BPFP1 endow it with the ability to detect trace amounts of Bcl-2 protein. After being incubated with a range of concentrations of Bcl-2 protein, BPFP1 exhibited the desired fluorescence properties and its fluorescence intensity is proportional to Bcl-2 protein concentration. Therefore, BPFP1 provides a convenient approach for Bcl-2 protein quantification and we could determine the concentration of Bcl-2 protein based on the BPFP1 's fluorescence intensity. Subsequent studies revealed that BPFP1 can fluorescently label carcinoma cells by binding to overexpressed Bcl-2 protein in living cells, and can distinguish carcinoma cells (HL-60 cells and ACHN cells) from normal-tissue cells (HUVECs) according to the different Bcl-2 protein expression levels between carcinoma cells and normal tissue cells. In the present study, BPFP1 represents a new tool for Bcl-2 protein quantification, carcinoma cell visualization and cell sorting. Moreover, BPFP1 can be used in the future for early cancer diagnosis by detecting carcinoma cells in patient tissues. [Display omitted] ● BPFP1 exhibits very high Bcl-2 protein binding affinity (K i < 1 nM) and over 50,000-fold Bcl-2 protein selectivity against Mcl-1 protein; ● BPFP1 provides a convenient approach for Bcl-2 protein quantification and it can detect trace amounts of Bcl-2 protein. ● BPFP1 can be also applied in carcinoma cell visualization and cell sorting. [ABSTRACT FROM AUTHOR]

Colorectal cancer is one of the most common and often fatal cancers in humans, but it has the highest chance of a cure if detected at an early precancerous stage. Carcinogenesis in the colon begins as an uncontrolled growth forming polyps. Some of these polyps can finally be converted to colon cancer. Early diagnosis of adenomatous polyps is the main approach for screening and preventing colorectal cancer, and vibration spectroscopy can be used for this purpose. This work is focused on evaluating FTIR and Raman spectroscopy as a tool in the ex vivo analysis of colorectal polyps, which could be important for the early diagnosis of colorectal carcinoma. Multivariate analyses (PCA and LDA) were used to assist the spectroscopic discrimination of normal colon tissue, as well as benign and malignant colon polyps. The spectra demonstrated evident differences in the characteristic bands of the main tissue constituents, i.e., proteins, nucleic acids, lipids, polysaccharides, etc. Suitable models for discriminating the three mentioned diagnostic groups were proposed based on multivariate analyses of the spectroscopic data. LDA classification was especially successful in the case of a combined set of 55 variables from the FTIR, FT Raman and dispersion Raman spectra. This model can be proposed for ex vivo colorectal cancer diagnostics in combination with the colonoscopic extraction of colon polyps for further testing. This pilot study is a precursor for the further evaluation of the diagnostic potential for the simultaneous in vivo application of colonoscopic Raman probes. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic Ductal Adeno Carcinoma (PDAC) is a highly lethal disease, for which mortality closely parallels incidence. The poor prognosis of PDAC is mainly due to cancer's biological behavior and its advanced stage at the moment of the diagnosis. Despite strong efforts in the scientific community, reaching an effective early diagnosis is still a big challenge. Our research aims to develop highly sensitive and specific technologies for the early diagnosis of PDAC using magnetic levitation (MagLev) of nanoparticles coated by the personalized protein corona, i.e., the protein layer of plasma proteins that bind to nanomaterials exposed to patients' bodily fluids. MagLev does not rely on critical experimental steps (e.g., isolating plasma proteins from nanoparticles) and thus overcomes limitations that propagate biases, hinder reproducibility, and typically impair clinical translation of medical technologies. Pancreatic Ductal Adeno Carcinoma (PDAC) is one of the most lethal malignancies worldwide, and the development of sensitive and specific technologies for its early diagnosis is vital to reduce morbidity and mortality rates. In this proof-of-concept study, we demonstrate the diagnostic ability of magnetic levitation (MagLev) to detect PDAC by using levitation of graphene oxide (GO) nanoparticles (NPs) decorated by a biomolecular corona of human plasma proteins collected from PDAC and non-oncological patients (NOP). Levitation profiles of corona-coated GO NPs injected in a MagLev device filled with a paramagnetic solution of dysprosium(III) nitrate hydrate in water enables to distinguish PDAC patients from NOP with 80% specificity, 100% sensitivity, and global classification accuracy of 90%. Our findings indicate that Maglev could be a robust and instrumental tool for the early detection of PDAC and other cancers. [ABSTRACT FROM AUTHOR]

Nearly one-quarter of all cancer deaths worldwide are due to lung cancer, making this disease the leading cause of cancer death among both men and women. The most important determinant of survival in lung cancer is the disease stage at diagnosis, thus developing an effective screening method for early diagnosis has been a long-term goal in lung cancer care. In the last decade, and based on the results of large clinical trials, lung cancer screening programs using low-dose computer tomography (LDCT) in high-risk individuals have been implemented in some clinical settings, however, this method has various limitations, especially a high false-positive rate which eventually results in a number of unnecessary diagnostic and therapeutic interventions among the screened subjects. By using complex algorithms and software, artificial intelligence (AI) is capable to emulate human cognition in the analysis, interpretation, and comprehension of complicated data and currently, it is being successfully applied in various healthcare settings. Taking advantage of the ability of AI to quantify information from images, and its superior capability in recognizing complex patterns in images compared to humans, AI has the potential to aid clinicians in the interpretation of LDCT images obtained in the setting of lung cancer screening. In the last decade, several AI models aimed to improve lung cancer detection have been reported. Some algorithms performed equal or even outperformed experienced radiologists in distinguishing benign from malign lung nodules and some of those models improved diagnostic accuracy and decreased the false-positive rate. Here, we discuss recent publications in which AI algorithms are utilized to assess chest computer tomography (CT) scans imaging obtaining in the setting of lung cancer screening. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNA) involve in regulating different physiological processes whose dysregulation is associated with a wide range of diseases including cancers, diabetes and cardiovascular problems. Herein, we report a direct, sensitive and highly selective detection assay for circulating microRNA (miRNA). This detection strategy employs magnetic nanoparticles as the reaction platform which can not only allow online pre-concentration and selective separation but also integrates ligation reaction with amplification to enhance the sensitivity of the detection assay. With the presence of the target miRNA, the locked nucleic acid (LNA)-modified molecular beacon (MB) opens up, exposing the binding sites at two ends. The 3'- and 5'-end of the MB responsible for the attachment onto the magnetic nanoparticles, and reporting probe for the attachment of the pair of amplification probes respectively. The ligase ligate RNA to DNA enhance the amplification efficiency. Upon labelled with intercalating fluorophores (YOYO-1) on the hybrids, the quantification of the target miRNA was determined by measuring the fluorescence intensity. A detection limit of 314 fM was achieved with trace amount of sample consumption (~20 μL). As a proof of concept, miRNA-149 was chosen as the target miRNA. This assay is capable of discriminating single-base and reliably quantifying circulating miRNA-149 in both healthy and cancer patient's serums. The result obtained was comparable with that of quantitative reverse transcription polymerase chain reaction (qRT-PCR), suggesting that this direct and sensitive assay can be served as a promising, non-invasive tool for early diagnosis of breast cancer and colorectal cancer. Image 1 • A direct and sensitive detection strategy for circulating miRNAs was developed. • Cancer-specific miR-149 is detected with high sensitivity; detection limit of 314 femto-molar and; discrimination of single-base mismatch. • The developed sensing strategy was applied for the detection of cancer-specific miR-149 in serum samples from cancer patients. [ABSTRACT FROM AUTHOR]

Electrochemical nanobiosensors are ultrasensitive tools used for detection and monitoring of various markers in biofluids. In the absence of reliable techniques for large‐scale production of reproducible nanomaterial structures on the electrodes, they are created individually in batch‐production. This has become a substantial hurdle in the practical implementation of electrochemical nanobiosensors. An automated microfluidic‐based platform (NanoChip) is presented for reproducible and scalable formation of complex nanomaterial constructs with a defined order of nanocomposites and biomaterials to create ultrasensitive nanobiosensors. The automated liquid handling system of the setup delivers reagents to electrodes inserted temporarily into the chip for modifying their surfaces by depositing different nanomaterials. The NanoChip platform is used for the creation of a multilayer nanocomposite structure on the electrode surface. These reproducible nanobiosensors are used for detecting breast cancer cells in the blood. The nanobiosensors offered a dynamic detection range of 10 to 5 × 106 cells mL−1. Performance of sensors produced from NanoChip shows similar selectivity and operational range along with improved sensitivity and reproducibility compared to sensors developed using batch process. These features make automated Nanochip technology a versatile tool for producing nanosensors for the ultrasensitive detection of various markers in biomedical, clinical, energy, and environmental applications. [ABSTRACT FROM AUTHOR]

The article discusses approaches for detecting cancer with circulating cell-free DNA. It mentions diagnosis of cancer through low-depth genomic sequencing of multiple 5-megabase regions in cell-free DNA fragmentation length and position within the genome. It also mentions analysis of tumor through mutant allele fraction.