Combined use of CYFRA 21-1 and CA 125 predicts survival of patients with metastatic NSCLC and stable disease in IMpower150.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) and stable disease (SD) have an unmet clinical need to help guide early treatment adjustments. OBJECTIVE: To evaluate the potential of tumor biomarkers to inform on survival outcomes in NSCLC SD patients. METHODS: This post hoc analysis included 480 patients from the IMpower150 study with metastatic NSCLC, treated with chemotherapy, atezolizumab and bevacizumab combinations, who had SD at first CT scan (post-treatment initiation). Patients were stratified into high- and low-risk groups (overall survival [OS] and progression-free survival [PFS] outcomes) based on serum tumor biomarker levels. RESULTS: The CYFRA 21-1 and CA 125 biomarker combination predicted OS and PFS in patients with SD. Risk of death was ~4-fold higher for the biomarker-stratified high-risk versus low-risk SD patients (hazard ratio [HR] 3.80; 95% confidence interval [CI] 3.02-4.78; p < 0.0001). OS in patients with the low- and high-risk SD was comparable to that in patients with the CT-defined partial response (PR; HR 1.10; 95% CI 0.898-1.34) and progressive disease (PD) (HR 1.05; 95% CI 0.621-1.77), respectively. The findings were similar with PFS, and consistent across treatment arms. CONCLUSIONS: Biomarker testing shows potential for providing prognostic information to help direct treatment in NSCLC patients with SD. Prospective clinical studies are warranted.ClinicalTrials.gov: NCT02366143.

CYFRA 21-1, CA 125 and CEA provide additional prognostic value in NSCLC patients with stable disease at first CT scan.

BACKGROUND: Serum tumor markers (STM) may complement imaging and provide additional clinical information for patients with non-small cell lung cancer (NSCLC). OBJECTIVE: To determine whether STMs can predict outcomes in patients with stable disease (SD) after initial treatment. METHODS: This single-center, prospective, observational trial enrolled 395 patients with stage III/IV treatment-naïve NSCLC; of which 263 patients were included in this analysis. Computed Tomography (CT) scans were performed and STMs measured before and after initial treatment (two cycles of chemotherapy and/or an immune checkpoint inhibitor or tyrosine kinase inhibitor); analyses were based on CT and STM measurements obtained at first CT performed after cycle 2 only PFS and OS were analyzed by Kaplan-Meier curves and Cox-proportional hazard models. RESULTS: When patients with SD (n = 100) were split into high- and low-risk groups based on CYFRA 21-1, CEA and CA 125 measurements using an optimized cut-off, a 4-fold increase risk of progression or death was estimated for high- vs low-risk SD patients (PFS, HR 4.17; OS, 3.99; both p < 0.0001). Outcomes were similar between patients with high-risk SD or progressive disease (n = 35) (OS, HR 1.17) and between patients with low-risk SD or partial response (n = 128) (PFS, HR 0.98; OS, 1.14). CONCLUSIONS: STMs can provide further guidance in patients with indeterminate CT responses by separating them into high- and low-risk groups for future PFS and OS events.

Investigation on core-fucosylated prostate-specific antigen as a refined biomarker for differentiation of benign prostate hyperplasia and prostate cancer of different aggressiveness.

Prostate cancer represents a major cause of cancer death in men worldwide. Novel non-invasive methods are still required for differentiation of non-aggressive from aggressive tumors. Recently, changes in prostate-specific antigen glycosylation pattern, such as core-fucosylation, have been described in prostate cancer. The objective of this study was to evaluate whether the core-fucosylation determinant of serum prostate-specific antigen may serve as refined marker for differentiation between benign prostate hyperplasia and prostate cancer or identification of aggressive prostate cancer. A previously developed liquid chromatography-mass spectrometry/mass spectrometry-based strategy was used for multiplex analysis of core-fucosylated prostate-specific antigen (fuc-PSA) and total prostate-specific antigen levels in sera from 50 benign prostate hyperplasia and 100 prostate cancer patients of different aggressiveness (Gleason scores, 5-10) covering the critical gray area (2-10 ng/mL). For identification of aggressive prostate cancer, the ratio of fuc-PSA to total prostate-specific antigen (%-fuc-PSA) yielded a 5%-8% increase in the area under the curve (0.60) compared to the currently used total prostate-specific antigen (area under the curve = 0.52) and %-free prostate-specific antigen (area under the curve = 0.55) tests. However, our data showed that aggressive prostate cancer (Gleason score > 6) and non-aggressive prostate cancer (Gleason score ≤ 6) could not significantly (p-value = 0.08) be differentiated by usage of %-fuc-PSA. In addition, both non-standardized fuc-PSA and standardized %-fuc-PSA had no diagnostic value for differentiation of benign prostate hyperplasia from prostate cancer. The %-fuc-PSA serum levels could not improve the differentiation of non-aggressive and aggressive prostate cancer compared to conventional diagnostic prostate cancer markers. Still, it is unclear whether these limitations come from the biomarker, the used patient cohort, or the imprecision of the applied method itself. Therefore, %-fuc-PSA should be further investigated, especially by more precise methods whether it could be clinically used in prostate cancer diagnosis.

Diagnostic Performance of Risk of Ovarian Malignancy Algorithm Against CA125 and HE4 in Connection With Ovarian Cancer: A Meta-analysis.

OBJECTIVES: The aim of this study was to determine whether the Risk of Ovarian Malignancy Algorithm (ROMA) is more accurate than the human epididymis 4 (HE4) or carbohydrate antigen 125 (CA125) biomarkers with respect to the differential diagnosis of women with a pelvic mass. The secondary objective is to assess the performance of ROMA in early-stage ovarian cancer (OC) and late-stage OC, as well as premenopausal and postmenopausal patient populations. METHODS/MATERIALS: The PubMed and Google Scholar databases were searched for relevant clinical studies. Eligibility criteria included comparison of ROMA with both HE4 and CA125 levels in OC (unspecified, epithelial, and borderline ovarian tumors), use of only validated ROMA assays, presentation of area under the curve and sensitivity/specificity data, and results from early-stage OC, late-stage OC and premenopausal and postmenopausal women. Area under the curve (AUC), sensitivity/specificity, and the diagnostic odds ratio (DOR) results were summarized. RESULTS: Five studies were selected comprising 1975 patients (premenopausal, n = 1033; postmenopausal, n = 925; benign, n = 1387; early stage, n = 192; and late stage, n = 313). On the basis of the AUC (95% confidence interval) data for all patients, ROMA (0.921 [0.855-0.960]) had a numerically greater diagnostic performance than CA125 (0.883 [0.771-0.950]) and HE4 (0.899 [0.835-0.943]). This was also observed in each of the subgroup populations, in particular, the postmenopausal patients and patients with early OC. The sensitivity and specificity (95% confidence interval) results showed ROMA (sensitivity, 0.873 [0.752-0.940]; specificity, 0.855 [0.719-0.932]) to be numerically superior to CA125 (sensitivity, 0.796 [0.663-0.885]; specificity, 0.825 [0.662-0.919]) and HE4 (sensitivity, 0.817 [0.683-0.902]; specificity, 0.851 [0.716-0.928]) in all patients and for the early- and late-stage OC subgroups. Finally, the ROMA log DOR results were better than HE4 and CA125 log DOR results especially for the early-stage patient group. CONCLUSIONS: The results presented support the use of ROMA to improve clinical decision making, most notably in patients with early OC.

Discovery of a haptoglobin glycopeptides biomarker panel for early diagnosis of hepatocellular carcinoma.

Background: There is a need for new serum biomarkers for early detection of hepatocellular carcinoma (HCC). Haptoglobin (Hp) N-glycosylation is altered in HCC, but the diagnostic value of site-specific Hp glycobiomarkers is rarely reported. We aimed to determine the site-specific glycosylation profile of Hp for early-stage HCC diagnosis. Method: Hp glycosylation was analyzed in the plasma of patients with liver diseases (n=57; controls), early-stage HCC (n=50) and late-stage HCC (n=32). Hp phenotype was determined by immunoblotting. Hp was immunoisolated and digested into peptides. N-glycopeptides were identified and quantified using liquid chromatography-mass spectrometry. Cohort samples were compared using Wilcoxon rank-sum (Mann-Whitney U) tests. Diagnostic performance was assessed using receiver operating characteristic (ROC) curves and area under curve (AUC). Results: Significantly higher fucosylation, branching and sialylation of Hp glycans, and expression of high-mannose glycans, was observed as disease progressed from cirrhosis to early- and late-stage HCC. Several glycopeptides demonstrated high values for early diagnosis of HCC, with an AUC of 93% (n=1), >80% (n=3), >75% (n=13) and >70% (n=11), compared with alpha-fetoprotein (AFP; AUC of 79%). The diagnostic performance of the identified biomarkers was only slightly affected by Hp phenotype. Conclusion: We identified a panel of Hp glycopeptides that are significantly differentially regulated in early- and late-stage HCC. Some glycobiomarkers exceeded the diagnostic value of AFP (the most commonly used biomarker for HCC diagnosis). Our findings provide evidence that glycobiomarkers can be effective in the diagnosis of early HCC - individually, as a panel of glycopeptides or combined with conventional serological biomarkers.

Annoyance and self-reported sleep disturbance due to night-time railway noise examined in the field.

Railway noise interferes with daytime activities and disturbs sleep leading to annoyance of exposed residents. The main objective of this paper was to establish exposure-response relationships between nocturnal railway noise exposure and annoyance and to examine self-reported sleep disturbances as short-term reactions to noise. In a field study 33 residents living close to railway tracks in the Cologne/Bonn area (Germany) were investigated. Railway noise was measured indoors during nine consecutive nights at each site. Questionnaires referring to annoyance and non-acoustical factors were performed. Annoyance ratings increased significantly with the total number of trains and freight trains per night, and non-significantly with rising number of passenger trains and energy equivalent sound pressure level (L(Aeq)), when adjusting the model for non-acoustical variables. The total number of trains and the number of freight trains also significantly affected self-reported awakening frequency, but no other aspects of subjective sleep disturbances. The responses of this subject sample referring to railway noise in the previous night point to rather low impairments of exposed residents.

Effects of aircraft cabin noise on passenger comfort.

The effects of cabin noise on subjective comfort assessments were systematically investigated in order to reveal optimisation potentials for an improved passenger noise acceptance. Two aircraft simulation studies were conducted. An acoustic laboratory test facility provided with loudspeaker systems for realistic sound presentations and an aircraft cabin simulator (Dornier Do 728) with a high degree of ecological validity were used. Subjects were exposed to nine different noise patterns (three noise levels ranging from 66 to 78 dB(A) combined with three different frequency spectra). Regression analysis demonstrated a significant increase of passengers' acceptance with lower noise levels and significant effects of different frequency spectra determined by seat position in the aircraft cabin (front, middle, rear). Acoustic cabin design should therefore consider measures beyond noise level reduction altering noise characteristics to improve passengers' comfort and well-being in the aircraft cabin. PRACTITIONER SUMMARY: To improve passenger comfort in the aircraft with respect to cabin noise, passengers' reactions to specific noise conditions were systematically investigated. Two laboratory studies showed significant dose-response relationships between sound pressure level and subjective comfort ratings which differed due to the noise at specific seat positions in the aircraft.

Performance evaluation of the Elecsys PIVKA-II and Elecsys AFP assays for hepatocellular carcinoma diagnosis.

Background and Aims: Prothrombin induced by vitamin K absence-II (PIVKA-II) is a serum biomarker linked to hepatocellular carcinoma (HCC), showing superiority to alpha-fetoprotein (AFP) for early disease detection. We aimed to assess the clinical and analytical performance of the Elecsys® PIVKA-II immunoassay in diagnosing HCC and evaluate PIVKA-II's technical performance. Methods: Serum samples from adult cases (i.e. patients with a first-time HCC diagnosis; n = 168) and disease controls (i.e. patients without HCC with an at-risk condition; n = 208) were assessed. An AFP cut-off of 20 ng/mL was used to differentiate between HCC cases and disease controls. Clinical performance of the Elecsys PIVKA-II assay was compared with that of comparator assays (Lumipulse G PIVKA-II, µTASWako DCP, ARCHITECT PIVKA-II) using receiver operating characteristic curve analysis to determine the area under the curve (AUC) values. Results: The Elecsys PIVKA-II assay compared favorably with comparator assays. Using a 28.4 ng/mL cut-off, the Elecsys PIVKA-II assay detected HCC with 86.9% sensitivity and 83.7% specificity. Clinical performance of the Elecsys PIVKA-II assay (AUC: 90.8%) was equivalent to that of comparator assays (AUC: 88.3-89.6%). Relatively high PIVKA-II concentrations were observed for cholangiocarcinoma and pancreatic cancer with the Elecsys assay in specificity panel analyses, indicating that high PIVKA-II concentrations should not be used alone in the absence of other clinical data. Conclusions: The Elecsys PIVKA-II assay showed good analytical performance under routine laboratory conditions, comparing favorably with comparator assays. These findings support the suitability of the Elecsys PIVKA-II assay as an aid in HCC diagnosis.

Comprehensive evaluation of microRNA as a biomarker for the diagnosis of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Current guidelines for HCC management recommend surveillance of high-risk patients every 6 mo using ultrasonography. Serum biomarkers, like alpha-fetoprotein (AFP), protein induced by vitamin K absence/antagonist-II (PIVKA-II) and lectin-reactive AFP, show suboptimal performance for detection of HCC, which is crucial for successful resection or treatment. Thus, there is a significant need for new biomarkers to aid early diagnosis of HCC. Studies have shown that the expression level of human microRNAs (miRNAs), a small, non-coding RNA species released into the blood, can serve as an early marker for various diseases, including HCC. AIM: To evaluate the diagnostic role of miRNAs in HCC as single markers, signatures or in combination with known protein biomarkers. METHODS: Our prospective, multicenter, case-control study recruited 660 participants (354 controls with chronic liver disease and 306 participants with HCC) and employed a strategy of initial screening by two independent methods, real-time quantitative PCR (n = 60) and next-generation sequencing (n = 100), to assess a large number of miRNAs. The results from the next-generation sequencing and real-time quantitative PCR screening approaches were then combined to select 26 miRNAs (including two putative novel miRNAs). Those miRNAs were analyzed for their diagnostic potential as single markers or in combination with other miRNAs or established protein biomarkers AFP and PIVKA-II via real-time quantitative PCR in training (n = 200) and validation cohorts (n = 300). RESULTS: We identified 26 miRNAs that differentiated chronic liver disease controls from (early) HCC via two independent discovery approaches. Three miRNAs, miR-21-5p (miR-21), miR-320a and miR-186-5p, were selected by both methods. In the training cohort, only miR-21, miR-320d and miR-423 could significantly distinguish (Q < 0.05) between the HCC and chronic liver disease control groups. In the multivariate setting, miR-21 with PIVKA-II was selected as the best combination, resulting in an area under the curve of 0.87 for diagnosis and area under the curve of 0.74 for early diagnosis of HCC. In the validation cohort, only miR-21 and miR-423 could be confirmed as potential HCC biomarkers. A combination of miRNAs did not perform better than any single miRNA. Improvement of PIVKA-II performance through combination with miRNAs could not be confirmed in the validation panel. Two putative miRs, put-miR-6 and put-miR-99, were tested in the training and validation panels, but their expression could only be detected in very few samples and at a low level (cycle threshold between 31.24 and 34.97). CONCLUSION: miRNAs alone or as a signature in combination with protein biomarkers AFP and PIVKA-II do not improve the diagnostic performance of the protein biomarkers.

Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators.

Background: Several biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation. Methods: Prospective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys® electrochemiluminescence immunoassays on a Cobas e601 instrument. Results: Statistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0-3 vs. 4-6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95-100% specificities. Conclusions: This prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest.

Comparing the Effects of Road, Railway, and Aircraft Noise on Sleep: Exposure⁻Response Relationships from Pooled Data of Three Laboratory Studies.

OBJECTIVES: Air, road, and railway traffic, the three major sources of traffic noise, have been reported to differently impact on annoyance. However, these findings may not be transferable to physiological reactions during sleep which are considered to decrease nighttime recovery and might mediate long-term negative health effects. Studies on awakenings from sleep indicate that railway noise, while having the least impact on annoyance, may have the most disturbing properties on sleep compared to aircraft noise. This study presents a comparison between the three major traffic modes and their probability to cause awakenings. In combining acoustical and polysomnographical data from three laboratory studies sample size and generalizability of the findings were increased. METHODS: Data from three laboratory studies were pooled, conducted at two sites in Germany (German Aerospace Center, Cologne, and Leibniz Research Centre for Working Environment and Human Factors, Dortmund). In total, the impact of 109,836 noise events on polysomnographically assessed awakenings was analyzed in 237 subjects using a random intercept logistic regression model. RESULTS: The best model fit according to the Akaike Information Criterion (AIC) included different acoustical and sleep parameters. After adjusting for these moderators results showed that the probability to wake up from equal maximum A-weighted sound pressure levels (SPL) increased in the order aircraft < road < railway noise, the awakening probability from road and railway noise being not significantly different (p = 0.988). At 70 dB SPL, it was more than 7% less probable to wake up due to aircraft noise than due to railway noise. CONCLUSIONS: The three major traffic noise sources differ in their impact on sleep. The order with which their impact increased was inversed compared to the order that was found in annoyance surveys. It is thus important to choose the correct concept for noise legislation, i.e., physiological sleep metrics in addition to noise annoyance for nighttime noise protection.

Potential for the blood-based biomarkers cytokeratin 19 fragment (CYFRA 21-1) and human epididymal protein 4 (HE4) to detect recurrence during monitoring after surgical resection of adenocarcinoma of the lung.

OBJECTIVES: The biomarkers cytokeratin 19 fragment (CYFRA 21-1) and human epididymis protein 4 (HE4) are useful in the diagnosis, prognosis, and monitoring of non-small cell lung cancer (NSCLC), but their combination has not been investigated yet. The objective of this analysis was to evaluate the ability of CYFRA 21-1 and HE4 to predict recurrence as part of follow-up monitoring in patients with adenocarcinoma (ADC) of the lung. MATERIALS AND METHODS: Serum samples were collected from patients with stage I-IIIA ADC preoperatively and during follow-up at 3, 6, 12, 18, and 24 months and then every 6-12 months up to 5 years post-R0 resection. Samples were analyzed for CYFRA 21-1 and HE4 via electrochemiluminescence immunoassay. All cases of disease recurrence were verified by imaging. The diagnostic performance of CYFRA 21-1, HE4, and their combination to predict recurrence was assessed by Receiver Operating Characteristic (ROC) and corresponding area under the curve (AUC). RESULTS: 115 patients with ADC were included (N = 612 biomarker measurements); median age was 63 years; most had stage I-II disease (n = 97; 84.3%). All patients underwent surgical resection; 44 patients (38%) also received adjuvant chemotherapy and 16 (14%) received radiation therapy. At the median timepoint for the last blood sample collection (37 months), 31 patients (27%) had experienced recurrence. Both CYFRA 21-1 and HE4 were able to detect recurrence (AUC and 95% confidence interval [CI]): 75.9% (66.0-85.8%) and 75.4% (65.9-84.8%), respectively, but this increased with the combination (78.8% [69.0-88.6%]). At a sensitivity of 80%, the respective specificities (95% CI) for CYFRA 21-1, HE4, and the combination were 57.1% (53.0-61.2%), 57.1% (53.0-61.2%), and 69.7% (65.8-73.4%). CONCLUSION: Serial measurements of serum CYFRA 21-1 and HE4 levels could provide a valuable method for follow-up monitoring of patients with ADC to detect recurrence.

The combination of the blood based tumor biomarkers cytokeratin 19 fragments (CYFRA 21-1) and carcinoembryonic antigen (CEA) as a potential predictor of benefit from adjuvant chemotherapy in early stage squamous cell carcinoma of the lung (SCC).

OBJECTIVES: To determine whether the tumor biomarkers cytokeratin 19 fragment (CYFRA 21-1) and carcinoembryonic antigen (CEA), which are prognostic in early-stage non-small cell lung cancer (NSCLC), can predict which patients benefit from adjuvant chemotherapy (CTx). MATERIALS AND METHODS: Serum samples were collected preoperatively from patients with NSCLC who underwent resection. Samples were retrospectively analyzed for CYFRA 21-1 and CEA via electrochemiluminescence immunoassay. Recurrence-free survival (RFS) was compared for patients who received adjuvant CTx versus surgery alone, stratified based on the following prognostic classifications: (1) tumor stage (pT1-2/N0 [stage I] or pT3/N0 or pT1-2/N1 [stage II]), (2) biomarker-based risk score, (3) clinical characteristics. Absolute 2-year RFS rates were calculated via Kaplan-Meier estimations; statistical significance level: 0.05. RESULTS: 227 patients were included (stage I: 69%; male: 67%; median age 65 years); 70 received adjuvant CTx. Median duration of sample collection was 58.8 months. All high-risk patients (by all three prognostic classifications) who received adjuvant CTx had a longer RFS versus those who received surgery alone. In patients with squamous cell carcinoma (SCC) classified as high risk by all three prognostic classifications, there was a benefit from adjuvant CTx versus surgery alone (tumor stage hazard ratio [HR] 4.9, p = 0.004; biomarker levels HR 9.4, p = 0.002; clinical characteristics HR 9.0, p = 0.003). None of the prognostic classifications were able to predict a benefit from adjuvant CTx in patients with adenocarcinoma. CONCLUSION: Baseline CYFRA 21-1 and CEA levels may provide further information to help clinicians decide which patients with SCC should receive adjuvant CTx. Further evaluation of these biomarkers is warranted.

Novel concept to guide systolic heart failure medication by repeated biomarker testing-results from TIME-CHF in context of predictive, preventive, and personalized medicine.

BACKGROUND: It is uncertain whether repeated measurements of a multi-target biomarker panel may help to personalize medical heart failure (HF) therapy to improve outcome in chronic HF. METHODS: This analysis included 499 patients from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF), aged ≥ 60 years, LVEF ≤ 45%, and NYHA ≥ II, who had repeated clinical visits within 19 months follow-up. The interaction between repeated measurements of biomarkers and treatment effects of loop diuretics, spironolactone, ß-blockers, and renin-angiotensin system (RAS) inhibitors on risk of HF hospitalization or death was investigated in a hypothesis-generating analysis. Generalized estimating equation (GEE) models were used to account for the correlation between recurrences of events in a patient. RESULTS: One hundred patients (20%) had just one event (HF hospitalization or death) and 87 (17.4%) had at least two events. Loop diuretic up-titration had a beneficial effect for patients with high interleukin-6 (IL6) or high high-sensitivity C-reactive protein (hsCRP) (interaction, P = 0.013 and P = 0.001), whereas the opposite was the case with low hsCRP (interaction, P = 0.013). Higher dosage of loop diuretics was associated with poor outcome in patients with high blood urea nitrogen (BUN) or prealbumin (interaction, P = 0.006 and P = 0.001), but not in those with low levels of these biomarkers. Spironolactone up-titration was associated with lower risk of HF hospitalization or death in patients with high cystatin C (CysC) (interaction, P = 0.021). ß-Blockers up-titration might have a beneficial effect in patients with low soluble fms-like tyrosine kinase-1 (sFlt) (interaction, P = 0.021). No treatment biomarker interactions were found for RAS inhibition. CONCLUSION: The data of this post hoc analysis suggest that decision-making using repeated biomarker measurements may be very promising in bringing treatment of heart failure to a new level in the context of predictive, preventive, and personalized medicine. Clearly, prospective testing is needed before this novel concept can be adopted. CLINICAL TRIAL REGISTRATION: isrctn.org, identifier: ISRCTN43596477.

Evaluation of a 5-Marker Blood Test for Colorectal Cancer Early Detection in a Colorectal Cancer Screening Setting.

PURPOSE: In initial studies that included colorectal cancer patients undergoing diagnostic colonoscopy, we had identified a serum marker combination able to detect colorectal cancer with similar diagnostic performance as fecal immunochemical test (FIT). In this study, we aimed to validate the results in participants of a large colorectal cancer screening study conducted in the average-risk, asymptomatic screening population. EXPERIMENTAL DESIGN: We tested serum samples from 1,200 controls, 420 advanced adenoma patients, 4 carcinoma in situ patients, and 36 colorectal cancer patients with a 5-marker blood test [carcinoembryonic antigen (CEA)+anti-p53+osteopontin+seprase+ferritin]. The diagnostic performance of individual markers and marker combinations was assessed and compared with stool test results. RESULTS: AUCs for the detection of colorectal cancer and advanced adenomas with the 5-marker blood test were 0.78 [95% confidence interval (CI), 0.68-0.87] and 0.56 (95% CI, 0.53-0.59), respectively, which now is comparable with guaiac-based fecal occult blood test (gFOBT) but inferior to FIT. With cutoffs yielding specificities of 80%, 90%, and 95%, the sensitivities for the detection of colorectal cancer were 64%, 50%, and 42%, and early-stage cancers were detected as well as late-stage cancers. For osteopontin, seprase, and ferritin, the diagnostic performance in the screening setting was reduced compared with previous studies in diagnostic settings while CEA and anti-p53 showed similar diagnostic performance in both settings. CONCLUSIONS: Performance of the 5-marker blood test under screening conditions is inferior to FIT even though it is still comparable with the performance of gFOBT. CEA and anti-p53 could contribute to the development of a multiple marker blood-based test for early detection of colorectal cancer.

Impact of worsening renal function related to medication in heart failure.

AIMS: Renal failure is a major challenge in treating heart failure (HF) patients. HF medication may deteriorate renal function, but the impact thereof on outcome is unknown. We investigated the effects of HF medication on worsening renal function (WRF) and the relationship to outcome. METHODS AND RESULTS: This post-hoc analysis of TIME-CHF (NT-proBNP-guided vs. symptom-guided management in chronic HF) included patients with LVEF ≤45% and ≥1 follow-up visit (n = 462). WRF III was defined as a rise in serum creatinine ≥0.5 mg/dL (i.e. 44.2 µmol/L) at any time during the first 6 months. Four classes of medication were considered: loop diuretics, beta-blockers, renin-angiotensin system (RAS)-blockers, and spironolactone. Functional principal component analysis of daily doses was used to comprehend medication over time. All-cause mortality after 18 months was the primary outcome. Interactions between WRF, medication, and outcome were tested. Patients with WRF III received on average higher loop diuretic doses (P = 0.0002) and more spironolactone (P = 0.02), whereas beta-blockers (P = 0.69) did not differ and lower doses of RAS-blockers were given (P = 0.09). There were significant interactions between WRF III, medicationn and outcome. Thus, WRF III was associated with poor prognosis if high loop diuretic doses were given (P = 0.001), but not with low doses (P = 0.29). The opposite was found for spironolactone (poor prognosis in the case of WRF III with no spironolactone, P <0.0001; but not with spironolactone, P = 0.31). Beta-blockers were protective in all patients (P <0.001), but most in those with WRF III (P <0.05 for interaction). RAS-blockade was associated with improved outcome (P = 0.006), irrespective of WRF III. CONCLUSION: Based on this analysis, it may be hypothesized that high doses of loop diuretics might have detrimental effects, particularly in combination with significant WRF, whereas spironolactone and beta-blockers might be protective in patients with WRF.

Pressure variations on a train - Where is the threshold to railway passenger discomfort?

The implementation of recent guidelines for tunnel construction in Germany leads to extended air pressure variations inside trains and reduces pressure comfort for railway passengers. A questionnaire survey with 262 passengers revealed that pressure variations are rated less important for riding comfort than climatic and spatial aspects (study 1). A laboratory experiment (study 2) in the pressure chamber at the DLR Institute of Aerospace Medicine with 31 subjects (mean age = 37.7, SD = 12.7; 51.6% male) investigated the effects of systematic pressure variations on discomfort. The pressure changes (pressure increases and decreases) ranged from 1 to 100 mbar and were realized within 1-100 s. We derived thresholds for healthy passengers by means of random effects linear and logistic regression analysis. Logistic dose-response curves revealed amplitude/time combinations leading to a certain percentage of passengers perceiving discomfort (e.g. 50% dissatisfied passengers regarding a pressure increase of approximately 30 mbar within 5 s). The findings may help design engineers to meet passengers' comfort requirements.

Continuous assessments of pressure comfort on a train -- a field-laboratory comparison.

Pressure variations on a train predominantly occur while trains are passing through tunnels. These aerodynamic effects may give rise to aural discomfort in railway passengers. We conducted a field study on the high speed railway track Cologne-Frankfurt/Main as well as a simulation study in our pressure chamber TITAN (DLR-Institute of Aerospace Medicine) with 31 subjects (mean age = 37.7, SD = 12.7; 51.6% male) to investigate pressure comfort for passengers. Continuous assessments of pressure events using sliders and retrospective assessments were acquired. Pressure variations were mostly tolerated. A comparison of field and laboratory setting revealed high congruency of continuous as well as retrospective assessments. A generalized estimating equation model identified pressure change attributes contributing to passengers' discomfort. Beside attributes of instantaneous pressure changes (e.g. high amplitudes, short durations), pressure events of the recent past significantly influenced current discomfort. Design engineers may use these findings to improve train and tunnel design.

Examining nocturnal railway noise and aircraft noise in the field: sleep, psychomotor performance, and annoyance.

BACKGROUND: Traffic noise is interfering during day- and nighttime causing distress and adverse physiological reactions in large parts of the population. Railway noise proved less annoying than aircraft noise in surveys which were the bases for a so called 5 dB railway bonus regarding noise protection in many European countries. OBJECTIVES: The present field study investigated railway noise-induced awakenings during sleep, nighttime annoyance and the impact on performance the following day. Comparing these results with those from a field study on aircraft noise allowed for a ranking of traffic modes concerning physiological and psychological reactions. METHODS: 33 participants (mean age 36.2 years ± 10.3 (SD); 22 females) living alongside railway tracks around Cologne/Bonn (Germany) were polysomnographically investigated. These data were pooled with data from a field study on aircraft noise (61 subjects) directly comparing the effects of railway and aircraft noise in one random subject effects logistic regression model. Annoyance was rated in the morning evaluating the previous night. RESULTS: Probability of sleep stage changes to wake/S1 from railway noise increased significantly from 6.5% at 35 dB(A) to 20.5% at 80 dB(A) LAFmax. Rise time of noise events had a significant impact on awakening probability. Nocturnal railway noise led to significantly higher awakening probabilities than aircraft noise, partly explained by the different rise times, whereas the order was inversed for annoyance. Freight train noise compared to passenger train noise proved to have the most impact on awakening probability. Nocturnal railway noise had no effect on psychomotor vigilance. CONCLUSIONS: Nocturnal freight train noise exposure in Germany was associated with increased awakening probabilities exceeding those for aircraft noise and contrasting the findings of many annoyance surveys and annoyance ratings of our study. During nighttime a bonus for railway noise seems not appropriate.