Strengths and challenges in current lung cancer care: Timeliness and diagnostic procedures in six Dutch hospitals.

OBJECTIVES: Timely diagnosis of lung cancer (LC) is crucial to achieve optimal patient care and outcome. Moreover, the number of procedures required to obtain a definitive diagnosis can have a large influence on the life expectancy of a patient. Here, adherence with existing Dutch guidelines for timeliness and type and number of invasive and imaging procedures was assessed. MATERIALS AND METHODS: 1096 patients with suspected LC were enrolled in this multicenter prospective study (NL9146). The overall survival, time from referral to the first appointment with the pulmonologist, time to diagnosis and treatment, and the number of imaging and invasive procedures were evaluated. Patients were divided into different diagnostic groupsearly- and advanced stage non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), large cell neuroendocrine carcinoma of the lung (LCNEC), patients without LC and patients without a definitive diagnosis. RESULTS: The majority of patients (66 %) received a definitive diagnosis within 5 weeks, although the time to diagnosis of early-stage LC patients and patients without LC was significantly longer comparted to advanced stage LC. An increase in invasive procedures was seen for early-stage LC compared to advanced stage LC and for 13 % of the advanced stage non-squamous NSCLC patients up to three additional invasive procedures were performed solely to obtain sufficient material for NGS. For patients without a definitive diagnosis, 50 % did undergo at least one invasive procedure, while 11 % did not wish to undergo any invasive procedures. CONCLUSION: These insights could aid in improved LC diagnostics and efficient implementation of new techniques like liquid biopsy and artificial intelligence. This may lead to more timely LC care, a decreased number of invasive procedures, less variability between the diagnostic trajectory of different patients and aid in obtaining a definitive diagnosis for all patients.

Postoperative circadian patterns in wearable sensor measured heart rate: a prospective observational study.

PURPOSE: This study aimed to describe the 24-hour cycle of wearable sensor-obtained heart rate in patients with deterioration-free recovery and to compare it with patients experiencing postoperative deterioration. METHODS: A prospective observational trial was performed in patients following bariatric or major abdominal cancer surgery. A wireless accelerometer patch (Healthdot) continuously measured postoperative heart rate, both in the hospital and after discharge, for a period of 14 days. The circadian pattern, or diurnal rhythm, in the wearable sensor-obtained heart rate was described using peak, nadir and peak-nadir excursions. RESULTS: The study population consisted of 137 bariatric and 100 major abdominal cancer surgery patients. In the latter group, 39 experienced postoperative deterioration. Both surgery types showed disrupted diurnal rhythm on the first postoperative days. Thereafter, the bariatric group had significantly lower peak heart rates (days 4, 7-12, 14), lower nadir heart rates (days 3-14) and larger peak-nadir excursions (days 2, 4-14). In cancer surgery patients, significantly higher nadir (days 2-5) and peak heart rates (days 2-3) were observed prior to deterioration. CONCLUSIONS: The postoperative diurnal rhythm of heart rate is disturbed by different types of surgery. Both groups showed recovery of diurnal rhythm but in patients following cancer surgery, both peak and nadir heart rates were higher than in the bariatric surgery group. Especially nadir heart rate was identified as a potential prognostic marker for deterioration after cancer surgery.

Quantification of the lung cancer tumor marker CYFRA 21-1 using protein precipitation, immunoaffinity bottom-up LC-MS/MS.

OBJECTIVES: Numerous studies have proven the potential of cytokeratin 19 fragment 21-1 (CYFRA 21-1) detection in the (early) diagnosis and treatment monitoring of non-small cell lung cancer (NSCLC). Conventional immunoassays for CYFRA 21-1 quantification are however prone to interferences and lack diagnostic sensitivity and standardization. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is an emerging approach based on a different, often superior, detection principle, which may improve the clinical applicability of CYFRA 21-1 in cancer diagnostics. Therefore, we developed and validated a protein precipitation, immunoaffinity (IA) LC-MS/MS assay for quantitative analysis of serum CYFRA 21-1. METHODS: Selective sample preparation was performed using ammonium sulfate (AS) precipitation, IA purification, tryptic digestion and LC-MS/MS quantification using a signature peptide and isotopically labeled internal standard. The workflow was optimized and validated according to EMA guidelines and results were compared to a conventional immunoassay. RESULTS: Significant interference effects were seen during IA purification, which were sufficiently solved by performing AS precipitation prior to IA purification. A linear calibration curve was obtained in the range of 1.0-100 ng/mL (R2=0.98). Accuracy and precision were well within acceptance criteria. In sera of patients suspected of lung cancer, the method showed good correlation with the immunoassay. CONCLUSIONS: A robust AS precipitation-IA LC-MS/MS assay for the quantification of serum CYFRA 21-1 was developed. With this assay, the clinically added value of LC-MS/MS-based detection over immunoassays can be further explored.

Analysis of Neuron-Specific enolase isozymes in human serum using immunoaffinity purification and liquid chromatography-tandem mass spectrometry quantification.

Neuron-specific enolase (NSE) is a promising small-cell lung cancer (SCLC) biomarker composed of αγ and γγ isozyme dimers. As the conventional immunoassays are prone to interferences and cannot differentiate between the isozymes, we developed a multiplex immunoaffinity (IA) liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the quantification of NSEα and NSEγ in human serum. A calibrator was prepared by performing cold denaturation of recombinantly expressed αα and γγ enolase dimers to induce a new dimer equilibrium that was determined to be approximately 1αγ:1γγ:1αα. Selective sample purification was achieved by performing IA extraction using an antibody specific towards NSEγ. The isolated αγ and γγ dimers were denatured and trypsin digested to allow quantification of the selected signature peptides and their corresponding isotopically labelled peptide internal standard. The obtained linear dynamic ranges were determined to be 1.5-56 ng/mL and 0.64-167 ng/mL for NSEα and NSEγ (R2 = 0.88 and 0.97 respectively). Validation of the assay showed acceptable accuracy and precision for NSEα and NSEγ. The method was successfully applied to patient serum in which both isozymes were detected. Compared to the conventional immunoassay, substantially lower total NSE concentrations were measured in IA LC-MS/MS. With this multiplex IA LC-MS/MS assay, the clinical value of quantifying the individual isozymes can be explored. In addition, together with the calibrator described here, it may be applied to standardize NSE immunoassays across different platforms.

Liquid biopsy-based decision support algorithms for diagnosis and subtyping of lung cancer.

OBJECTIVES: Pathologic subtyping of tissue biopsies is the gold standard for the diagnosis of lung cancer (LC), which could be complicated in cases of e.g. inconclusive tissue biopsies or unreachable tumors. The diagnosis of LC could be supported in a minimally invasive manner using protein tumor markers (TMs) and circulating tumor DNA (ctDNA) measured in liquid biopsies (LBx). This study evaluates the performance of LBx-based decision-support algorithms for the diagnosis of LC and subtyping into small- and non-small-cell lung cancer (SCLC and NSCLC) aiming to directly impact clinical practice. MATERIALS AND METHODS: In this multicenter prospective study (NL9146), eight protein TMs (CA125, CA15.3, CEA, CYFRA 21-1, HE4, NSE, proGRP and SCCA) and ctDNA mutations in EGFR, KRAS and BRAF were analyzed in blood of 1096 patients suspected of LC. The performance of individual and combined TMs to identify LC, NSCLC or SCLC was established by evaluating logistic regression models at pre-specified positive predictive values (PPV) of ≥95% or ≥98%. The most informative protein TMs included in the multi-parametric models were selected by recursive feature elimination. RESULTS: Single TMs could identify LC, NSCLC and SCLC patients with 46%, 25% and 40% sensitivity, respectively, at pre-specified PPVs. Multi-parametric models combining TMs and ctDNA significantly improved sensitivities to 65%, 67% and 50%, respectively. CONCLUSION: In patients suspected of LC, the LBx-based decision-support algorithms allowed identification of about two-thirds of all LC and NSCLC patients and half of SCLC patients. These models therefore show clinical value and may support LC diagnostics, especially in patients for whom pathologic subtyping is impossible or incomplete.

The Accuracy of Wrist-Worn Photoplethysmogram-Measured Heart and Respiratory Rates in Abdominal Surgery Patients: Observational Prospective Clinical Validation Study.

BACKGROUND: Postoperative deterioration is often preceded by abnormal vital parameters. Therefore, vital parameters of postoperative patients are routinely measured by nursing staff. Wrist-worn sensors could potentially provide an alternative tool for the measurement of vital parameters in low-acuity settings. These devices would allow more frequent or even continuous measurements of vital parameters without relying on time-consuming manual measurements, provided their accuracy in this clinical population is established. OBJECTIVE: This study aimed to assess the accuracy of heart rate (HR) and respiratory rate (RR) measures obtained via a wearable photoplethysmography (PPG) wristband in a cohort of postoperative patients. METHODS: The accuracy of the wrist-worn PPG sensor was assessed in 62 post-abdominal surgery patients (mean age 55, SD 15 years; median BMI 34, IQR 25-40 kg/m2). The wearable obtained HR and RR measurements were compared to those of the reference monitor in the postanesthesia or intensive care unit. Bland-Altman and Clarke error grid analyses were performed to determine agreement and clinical accuracy. RESULTS: Data were collected for a median of 1.2 hours per patient. With a coverage of 94% for HR and 34% for RR, the device was able to provide accurate measurements for the large majority of the measurements as 98% and 93% of the measurements were within 5 bpm or 3 rpm of the reference signal. Additionally, 100% of the HR and 98% of the RR measurements were clinically acceptable on Clarke error grid analysis. CONCLUSIONS: The wrist-worn PPG device is able to provide measurements of HR and RR that can be seen as sufficiently accurate for clinical applications. Considering the coverage, the device was able to continuously monitor HR and report RR when measurements of sufficient quality were obtained. TRIAL REGISTRATION: ClinicalTrials.gov NCT03923127; https://www.clinicaltrials.gov/ct2/show/NCT03923127.

The Metabolic Health Index Identifies Patients That Will Benefit From Metabolic Surgery.

INTRODUCTION: Metabolic syndrome is a modern world's major health hazard related to comorbidities like type 2 diabetes and cardiovascular disease. Bariatric surgery is well known to lower this health risk in patients with obesity. There is a need for an objective measure to assess the intended reduction in health hazard and indirectly the eligibility for bariatric surgery. The Metabolic Health Index (MHI) quantitatively summarizes the cumulative impact of the metabolic syndrome on health status on a scale from 1 to 6. This study describes the use of the MHI as a supportive tool in the decision for and outcome assessment of bariatric surgery. METHODS: The general usability of the MHI was tested by extending its application to patient data of five other bariatric centers in the Netherlands. Retrospective laboratory and national bariatric quality registry data of 11,501 patients were collected. RESULTS: The quantification of (improvement in) metabolic health burden as measured by the MHI was independent of the dataset that was used to derive the MHI model. Patients with MHI > 2.8 prior to surgery improved significantly more in MHI 12 mo after surgery compared to patients with MHI ≤ 2.8 (1.1 compared to 0.4 MHI points, respectively; P < 0.001). CONCLUSIONS: The MHI is robust between centers and is suitable for general use in clinical decision-making. As changes in MHI over time reflect metabolic health alterations, it is suitable as an outcome measure of surgery. An MHI cut-off value of 2.8 helps to predict the likelihood of significant improvement after surgery, independent of body mass index and known metabolic comorbidities.

Prognostic Value of Combined Biomarkers in Patients With Heart Failure: The Heartmarker Score.

Background: Heart failure (HF) biomarkers have prognostic value. The aim of this study was to combine HF biomarkers into an objective classification system for risk stratification of patients with HF. Methods: HF biomarkers were analyzed in a population of HF outpatients and expressed relative to their cut-off values (N-terminal pro-B-type natriuretic peptide [NT-proBNP] >1,000 pg/mL, soluble suppression of tumorigenesis-2 [ST2] >35 ng/mL, growth differentiation factor-15 [GDF-15] >2,000 pg/mL, and fibroblast growth factor-23 [FGF-23] >95.4 pg/mL). Biomarkers that remained significant in multivariable analysis were combined to devise the Heartmarker score. The performance of the Heartmarker score was compared to the widely used New York Heart Association (NYHA) classification based on symptoms during ordinary activity. Results: HF biomarkers of 245 patients were analyzed, 45 (18%) of whom experienced the composite endpoint of HF hospitalization, appropriate implantable cardioverter-defibrillator shock, or death. HF biomarkers were elevated more often in patients that reached the composite endpoint than in patients that did not reach the endpoint. NT-proBNP, ST2, and GDF-15 were independent predictors of the composite endpoint and were thus combined as the Heartmarker score. The event-free survival and distance covered in 6 minutes of walking decreased with an increasing Heartmarker score. Compared with the NYHA classification, the Heartmarker score was better at discriminating between different risk classes and had a comparable relationship to functional capacity. Conclusions: The Heartmarker score is a reproducible and intuitive model for risk stratification of outpatients with HF, using routine biomarker measurements.

Up-front mutation detection in circulating tumor DNA by droplet digital PCR has added diagnostic value in lung cancer.

Identification of actionable mutations in advanced stage non-squamous non-small-cell lung cancer (NSCLC) patients is recommended by guidelines as it enables treatment with targeted therapies. In current practice, mutations are identified by next-generation sequencing of tumor DNA (tDNA-NGS), which requires tissue biopsies of sufficient quality. Alternatively, circulating tumor DNA (ctDNA) could be used for mutation analysis. This prospective, multicenter study establishes the diagnostic value of ctDNA analysis by droplet digital PCR (ctDNA-ddPCR) in patients with primary lung cancer. CtDNA from 458 primary lung cancer patients was analyzed using a panel of multiplex ddPCRs for EGFR (Ex19Del, G719S, L858R, L861Q and S768I), KRAS G12/G13 and BRAF V600 mutations. For 142 of 175 advanced stage non-squamous NSCLC patients tDNA-NGS results were available to compare to ctDNA-ddPCR. tDNA-NGS identified 98 mutations, of which ctDNA-ddPCR found 53 mutations (54%), including 32 of 45 (71%) targetable driver mutations. In 2 of these 142 patients, a mutation was found by ctDNA-ddPCR only. In 33 advanced stage patients lacking tDNA-NGS results, ctDNA-ddPCR detected 15 additional mutations, of which 7 targetable. Overall, ctDNA-ddPCR detected 70 mutations and tDNA-NGS 98 mutations in 175 advanced NSCLC patients. Using an up-front ctDNA-ddPCR strategy, followed by tDNA-NGS only if ctDNA-ddPCR analysis is negative, increases the number of mutations found from 98 to 115 (17%). At the same time, up-front ctDNA-ddPCR reduces tDNA-NGS analyses by 40%, decreasing the need to perform (additional) biopsies.

A wearable patch based remote early warning score (REWS) in major abdominal cancer surgery patients.

INTRODUCTION: The shift toward remote patient monitoring methods to detect clinical deterioration requires testing of wearable devices in real-life clinical settings. This study aimed to develop a remote early warning scoring (REWS) system based on continuous measurements using a wearable device, and compare its diagnostic performance for the detection of deterioration to the diagnostic performance of the conventional modified early warning score (MEWS). MATERIALS AND METHODS: The study population of this prospective, single center trial consisted of patients who underwent major abdominal cancer surgery and were monitored using routine in-hospital spotcheck measurements of the vital parameters. Heart and respiratory rates were measured continuously using a wireless accelerometer patch (HealthDot). The prediction by MEWS of deterioration toward a complication graded Clavien-Dindo of 2 or higher was compared to the REWS derived from continuous measurements by the wearable patch. MAIN RESULTS: A total of 103 patients and 1909 spot-check measurements were included in the analysis. Postoperative deterioration was observed in 29 patients. For both EWS systems, the sensitivity (MEWS: 0.20 95% CI: [0.13-0.29], REWS: 0.20 95% CI: [0.13-0.29]) and specificity (MEWS: 0.96 95% CI: [0.95-0.97], REWS: 0.96 95% CI: [0.95-0.97]) were assessed. CONCLUSIONS: The diagnostic value of the REWS method, based on continuous measurements of the heart and respiratory rates, is comparable to that of the MEWS in patients following major abdominal cancer surgery. The wearable patch could detect the same amount of deteriorations, without requiring manual spot check measurements.

Quantification of uracil, dihydrouracil, thymine and dihydrothymine for reliable dihydropyrimidine dehydrogenase (DPD) phenotyping critically depend on blood and plasma storage conditions.

Establishing dihydropyrimidine dehydrogenase (DPD) activity is highly important in determining the correct starting dose of fluoropyrimidines such as 5-fluorouracil and capecitabine. The concentration ratio of endogenous uracil with its metabolite dihydrouracil (DHU) is a well-known parameter that is linked to DPD activity. Concentration ratios such as thymine over its DPD-converted metabolite dihydrothymine (DHT) is less described and may serve as an alternative diagnostic biomarker for DPD activity. In this study, we describe the development and validation of an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay for the quantification of uracil, DHU, thymine, and DHT in human plasma. In addition, stability experiments were performed. Uracil and thymine were quantified up to 80.0 ng/mL and DHU and DHT up to 800 ng/mL. Intra- and inter-assay precision were maximum 8.0 % and 7.6 %. respectively. Also, recovery was adequate and significant matrix-effects and carry-over were excluded. Stability experiments showed that uracil concentrations increased with 27-52 % when stored for 1 or 2 h at ambient temperatures compared to cold storage. Thymine, DHU, and DHT concentrations remained stable, thymine after 1 h in plasma excluded, showing the DHT:T ratio might be a more robust marker for DPD activity than DHU:U. In conclusion, we present here a novel assay capable of quantifying uracil, thymine, DHU and DHT in a single analytical run. We provide additional data showing increased stability for DHU, thymine and DHT compared to uracil. This assay may be used as a diagnostic test in future studies, establishing the association of these endogenous biomarker concentrations with DPD activity and safety to treatment with fluoropyrimidines. In addition, future research should also be focused on reducing pre-analytical instability. Standardization in this field is essential to set proper reference values and to allow inter-study comparison on clinical outcomes.

Development and validation of an early warning score to identify COVID-19 in the emergency department based on routine laboratory tests: a multicentre case-control study.

OBJECTIVES: Identifying patients with a possible SARS-CoV-2 infection in the emergency department (ED) is challenging. Symptoms differ, incidence rates vary and test capacity may be limited. As PCR-testing all ED patients is neither feasible nor effective in most centres, a rapid, objective, low-cost early warning score to triage ED patients for a possible infection is developed. DESIGN: Case-control study. SETTING: Secondary and tertiary hospitals in the Netherlands. PARTICIPANTS: The study included patients presenting to the ED with venous blood sampling from July 2019 to July 2020 (n=10 417, 279 SARS-CoV-2-positive). The temporal validation cohort covered the period from July 2020 to October 2021 (n=14 080, 1093 SARS-CoV-2-positive). The external validation cohort consisted of patients presenting to the ED of three hospitals in the Netherlands (n=12 061, 652 SARS-CoV-2-positive). PRIMARY OUTCOME MEASURES: The primary outcome was one or more positive SARS-CoV-2 PCR test results within 1 day prior to or 1 week after ED presentation. RESULTS: The resulting 'CoLab-score' consists of 10 routine laboratory measurements and age. The score showed good discriminative ability (AUC: 0.930, 95% CI 0.909 to 0.945). The lowest CoLab-score had high sensitivity for COVID-19 (0.984, 95% CI 0.970 to 0.991; specificity: 0.411, 95% CI 0.285 to 0.520). Conversely, the highest score had high specificity (0.978, 95% CI 0.973 to 0.983; sensitivity: 0.608, 95% CI 0.522 to 0.685). The results were confirmed in temporal and external validation. CONCLUSIONS: The CoLab-score is based on routine laboratory measurements and is available within 1 hour after presentation. Depending on the prevalence, COVID-19 may be safely ruled out in over one-third of ED presentations. Highly suspect cases can be identified regardless of presenting symptoms. The CoLab-score is continuous, in contrast to the binary outcome of lateral flow testing, and can guide PCR testing and triage ED patients.

Use of an algorithm based on routine blood laboratory tests to exclude COVID-19 in a screening-setting of healthcare workers.

BACKGROUND: COVID-19 is an ongoing pandemic leading to exhaustion of the hospital care system. Our health care system has to deal with a high level of sick leave of health care workers (HCWs) with COVID-19 related complaints, in whom an infection with SARS-CoV-2 has to be ruled out before they can return back to work. The aim of the present study is to investigate if the recently described CoLab-algorithm can be used to exclude COVID-19 in a screening setting of HCWs. METHODS: In the period from January 2021 till March 2021, HCWs with COVID-19-related complaints were prospectively collected and included in this study. Next to the routinely performed SARS-CoV-2 RT-PCR, using a set of naso- and oropharyngeal swab samples, two blood tubes (one EDTA- and one heparin-tube) were drawn for analysing the 10 laboratory parameters required for running the CoLab-algorithm. RESULTS: In total, 726 HCWs with a complete CoLab-laboratory panel were included in this study. In this group, 684 HCWs were tested SARS-CoV-2 RT-PCR negative and 42 cases RT-PCR positive. ROC curve analysis showed an area under the curve (AUC) of 0.853 (95% CI: 0.801-0.904). At a safe cut-off value for excluding COVID-19 of -6.525, the sensitivity was 100% with a specificity of 34% (95% CI: 21 to 49%). No SARS-CoV-2 RT-PCR cases were missed with this cut-off and COVID-19 could be safely ruled out in more than one third of HCWs. CONCLUSION: The CoLab-score is an easy and reliable algorithm that can be used for screening HCWs with COVID-19 related complaints. A major advantage of this approach is that the results of the score are available within 1 hour after collecting the samples. This results in a faster return to labour process of a large part of the COVID-19 negative HCWs (34%), next to a reduction in RT-PCR tests (reagents and labour costs) that can be saved.

Assessment of Comorbidity in Bariatric Patients through a Biomarker-Based Model-A Multicenter Validation of the Metabolic Health Index.

BACKGROUND: The metabolic health index (MHI) is a biomarker-based model that objectively assesses the cumulative impact of comorbidities type 2 diabetes mellitus, hypertension and dyslipidemia on the health state of bariatric patients. The MHI was developed on a single-center cohort using a fully laboratory data-driven approach, resulting in a MHI score on a range from 1 to 6. To show universal applicability in clinical care, the MHI was validated externally and potential laboratory-related shortcomings were evaluated. METHODS: Retrospective laboratory and national bariatric quality registry data were collected from five Dutch renowned bariatric centers (n = 11 501). MHI imprecision was derived from the cumulative effect of biological and analytical variance of the individual input variables of the MHI model. The performance of the MHI (model) was assessed in terms of discrimination and calibration. RESULTS: The cumulative imprecision in MHI was 0.25 MHI points. Calibration of the MHI model diverged over the different centers but was accounted for by misregistration of comorbidity after cross-checking the data. Discriminative performance of the MHI model was consistent across the different centers. CONCLUSIONS: The MHI model can be applied in clinical practice of bariatric centers, regardless of patient mix and analytical platform. Because the MHI is based on objective parameters, it is insensitive to diverging clinical definitions of comorbidities. Therefore, the MHI can be used to objectify severity of metabolic comorbidities in bariatric patients. The MHI can support the patient-selection process for surgery and objectively assessing the effect of surgery on the metabolic health state.

Left atrial reservoir strain as a predictor of cardiac outcome in patients with heart failure: the HaFaC cohort study.

BACKGROUND: The left atrium (LA) is a key player in the pathophysiology of systolic and diastolic heart failure (HF). Speckle tracking derived LA reservoir strain (LASr) can be used as a prognostic surrogate for elevated left ventricular filling pressure similar to NT-proBNP. The aim of the study is to investigate the correlation between LASr and NT-proBNP and its prognostic value with regards to the composite endpoint of HF hospitalization and all-cause mortality within 1 year. METHODS: Outpatients, sent to the echocardiography core lab because of HF, were enrolled into this study. Patients underwent a transthoracic echocardiographic examination, commercially available software was used to measure LASr. Blood samples were collected directly after the echocardiographic examination to determine NT-proBNP. RESULTS: We included 174 HF patients, 43% with reduced, 36% with mildly reduced, and 21% with preserved ejection fraction. The study population showed a strong inverse correlation between LASr and log-transformed NT-proBNP (r = - 0.75, p < 0.01). Compared to NT-proBNP, LASr predicts the endpoint with a comparable specificity (83% vs. 84%), however with a lower sensitivity (70% vs. 61%). CONCLUSION: LASr is inversely correlated with NT-proBNP and a good echocardiographic predictor for the composite endpoint of hospitalization and all-cause mortality in patients with HF. TRIAL REGISTRATION: https://www.trialregister.nl/trial/7268.

Accuracy of vital parameters measured by a wearable patch following major abdominal cancer surgery.

INTRODUCTION: Recent advances in wearable technology allow for the development of wirelessly connected sensors to continuously measure vital parameters in the general ward or even at home. The present study assesses the accuracy of a wearable patch (Healthdot) for continuous monitoring of heartrate (HR) and respiration rate (RR). MATERIALS AND METHODS: The Healthdot measures HR and RR by means of chest accelerometry. The study population consisted of patients following major abdominal oncological surgery. The analysis focused on the agreement between HR and RR measured by the Healthdot and the gold standard patient monitor in the intensive and post-anesthesia care unit. RESULTS: For HR, a total of 112 h of measurements was collected in 26 patients. For RR, a total of 102 h of measurements was collected in 21 patients. On second to second analysis, 97% of the HR and 87% of the RR measurements were within 5 bpm and 3 rpm of the reference monitor. Assessment of 5-min averaged data resulted in 96% of the HR and 95% of the RR measurements within 5 bpm and 3 rpm of the reference monitor. A Clarke error grid analysis showed that 100% of the HR and 99.4% of the 5-min averaged data was clinically acceptable. CONCLUSION: The Healthdot accurately measured HR and RR in a cohort of patients recovering from major abdominal surgery, provided that good quality data was obtained. These results push the Healthdot forward as a clinically acceptable tool in low acuity settings for unobtrusive, automatic, wireless and continuous monitoring.

Validation of Heart Rate Extracted From Wrist-Based Photoplethysmography in the Perioperative Setting: Prospective Observational Study.

BACKGROUND: Measurement of heart rate (HR) through an unobtrusive, wrist-worn optical HR monitor (OHRM) could enable earlier recognition of patient deterioration in low acuity settings and enable timely intervention. OBJECTIVE: The goal of this study was to assess the agreement between the HR extracted from the OHRM and the gold standard 5-lead electrocardiogram (ECG) connected to a patient monitor during surgery and in the recovery period. METHODS: In patients undergoing surgery requiring anesthesia, the HR reported by the patient monitor's ECG module was recorded and stored simultaneously with the photopletysmography (PPG) from the OHRM attached to the patient's wrist. The agreement between the HR reported by the patient's monitor and the HR extracted from the OHRM's PPG signal was assessed using Bland-Altman analysis during the surgical and recovery phase. RESULTS: A total of 271.8 hours of data in 99 patients was recorded simultaneously by the OHRM and patient monitor. The median coverage was 86% (IQR 65%-95%) and did not differ significantly between surgery and recovery (Wilcoxon paired difference test P=.17). Agreement analysis showed the limits of agreement (LoA) of the difference between the OHRM and the ECG HR were within the range of 5 beats per minute (bpm). The mean bias was -0.14 bpm (LoA between -3.08 bpm and 2.79 bpm) and -0.19% (LoA between -5 bpm to 5 bpm) for the PPG- measured HR compared to the ECG-measured HR during surgery; during recovery, it was -0.11 bpm (LoA between -2.79 bpm and 2.59 bpm) and -0.15% (LoA between -3.92% and 3.64%). CONCLUSIONS: This study shows that an OHRM equipped with a PPG sensor can measure HR within the ECG reference standard of -5 bpm to 5 bpm or -10% to 10% in the perioperative setting when the PPG signal is of sufficient quality. This implies that an OHRM can be considered clinically acceptable for HR monitoring in low acuity hospitalized patients.

Sensitive cell-free tumor DNA analysis in supernatant pleural effusions supports therapy selection and disease monitoring of lung cancer patients.

Supernatant pleural effusions (PE) have shown to be a valuable source for the detection of driver mutations in circulating tumor DNA (ctDNA). In this prospective study, the clinical value of ctDNA analysis in supernatant PE to support therapy selection and disease monitoring in lung cancer patients is assessed. Paired PE and plasma samples were collected from lung cancer patients before initiation of therapy (N = 2) and from EGFR positive patients during therapy (N = 3). Supernatant PE and plasma were tested for mutations in EGFR, KRAS and BRAF by droplet digital PCR. In PE of two patients with suspected lung cancer, a KRAS mutation was detected with a 5- and 8-fold higher fractional abundance (FA) compared to plasma. For three patients with progressive disease during therapy, both the EGFR L858R and T790M mutations were detected in PE. However, in plasma only for two of these patients the L858R mutation was detected with a 46- and 14- fold lower FA, and only for one patient the T790M mutation was detected with a 8-fold lower FA. For one patient, longitudinal ctDNA analysis in PE revealed the T790M and L858R mutations already two months prior to detection of progressive disease by CT-scan. In this study, a higher ctDNA concentration and FA was obtained from PE compared to the corresponding blood samples, which enables more sensitive mutation analysis. Thus, PE is a valuable liquid biopsy, complementing plasma, for ctDNA analysis to support therapy selection and disease monitoring in lung cancer patients.

Circulating biomarkers for monitoring therapy response and detection of disease progression in lung cancer patients.

Liquid biopsies have become of interest as minimally invasive ways to monitor treatment response in lung cancer patients. Circulating tumor DNA (ctDNA) and protein biomarkers are evaluated for their added value in monitoring therapy response and early detection of disease progression. Plasma and serum samples of non-small cell or small cell lung cancer patients were analyzed for driver mutations in ctDNA (EGFR, KRAS or BRAF) using droplet digital PCR and protein biomarkers (CA125, CEA, CA15.3, Cyfra 21-1, HE4, NSE, proGRP and SCCA) using electrochemiluminescence immunoassays. Biomarker concentration changes were compared with the outcome of CT-scans during therapy. The median difference of the concentration of ctDNA, CA125 and Cyfra21-1 was significantly lower in patients with partial response (PR) compared to patients with progressive disease (PD) on the first evaluation CT-scan (P<0.001, P=0.042 and P=0.020, respectively). A substantial agreement between ctDNA or CA125 response and radiographic response was observed (k=0.692 and k=0.792, respectively). The median difference of the concentration of ctDNA and Cyfra21-1 was also significantly lower in PR patients compared to PD patients at the last CT-scan during therapy (P<0.001 and P=0.026, respectively). An almost perfect agreement between ctDNA and radiographic response (k=0.827) and a moderate agreement between Cyfra21-1 response and radiographic response was observed (k=0.553). Serial testing of the concentration of ctDNA, Cyfra21-1, and possibly CA125 could be a useful added tool for monitoring therapy response and early detection of disease progression in lung cancer patients.