Association between left ventricular global longitudinal strain and natriuretic peptides in outpatients with chronic systolic heart failure.

BACKGROUND: Both impaired left ventricular (LV) global longitudinal strain (GLS) and increased plasma concentrations of natriuretic peptides(NP) are associated with a poor outcome in heart failure (HF). Increased levels of NP reflect increased wall stress of the LV. However, little is known about the relationship between LV GLS and NP. This aim of this study was to evaluate the relationship between the echocardiographic measure LV GLS and plasma levels of NP. METHODS: We prospectively included 149 patients with verified systolic HF at the baseline visit in an outpatient HF clinic. LV GLS was assessed by two dimension speckle tracking and plasma concentrations of N-terminal-pro-brain-natriuretic-peptide (NT-proBNP) and pro-atrial-natriuretic-peptide (proANP) were analysed. RESULTS: The patients had a median age of 70 years, 28.2 % were females, 26.5 % were in functional class III-IV, median left ventricular ejection fraction (LVEF) was 33 % and median LV GLS was -11 %. LV GLS was associated with increased plasma concentrations of NT-proBNP and proANP in multivariate logistic regression (NT-proBNP: Odds RatioGLS: 7.25, 95 %-CI: 2.48-21.1, P < 0.001 and proANP: Odds RatioGLS: 3.26, 95-%-CI: 1.28-8.30, P = 0.013) and linear regression (NT-proBNP: ßGLS: 1.19, 95 %-CI: 0.62-1.76, P < 0.001 and proANP: ßGLS: 0.42, 95-%-CI: 0.11-0.72, P = 0.007) models after adjustment for traditional confounders (age, gender, body-mass-index, atrial fibrillation, renal function) and left atrial volume index. CONCLUSION: Impaired LV GLS is associated with increased plasma concentrations of NP and our data suggest that left ventricular myocardial mechanics estimated by LV GLS reflects myocardial wall stress in chronic systolic HF.

Peripheral venous lactate at admission is associated with in-hospital mortality, a prospective cohort study.

BACKGROUND: The prognostic value of blood lactate as a predictor of adverse outcome in the acutely ill patient is unclear. The aim of this study was to investigate if a peripheral venous lactate measurement, taken at admission, is associated with in-hospital mortality in acutely ill patients with all diagnosis. Furthermore, we wanted to investigate if the test improves a triage model in terms of predicting in-hospital mortality. METHODS: We retrieved a cohort of 2272 adult patients from a prospectively gathered acute admission database. We performed regression analysis to evaluate the association between the relevant covariates and the outcome measure: in-hospital mortality. RESULTS: Lactate as a continuous variable was a risk for in-hospital mortality with an odds ratio (OR) of 1.40 [95% confidence interval (CI) 1.25-1.57, P<0.0001]. OR for in-hospital mortality increased with increasing lactate levels from 2.97 (95% CI 1.55-5.72, P<0.001) for lactate between 2 mmol/l and 4 mmol/l, to 7.77 (95% CI 3.23-18.66, P<0.0001) for lactate>4 mmol/l. If the condition was non-compensated (i.e. pH<7.35), OR for in-hospital mortality increased to 19.99 (7.26-55.06, P<0.0001). Patient with a blood lactate at 4 mmol/l or more had a risk of in-hospital mortality equivalent to the patients in the most urgent triage category. CONCLUSION: We found elevated admission peripheral venous lactate to be independently associated with in-hospital mortality in the acutely ill patient admitted to the emergency department. Patients with a lactate>4 mmol/l at hospital admission should be considered triaged to the most urgent triage category.

CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use.

CA125 is currently the most widely used tumor marker for ovarian epithelial cancer. The aim of this article is to provide guidelines for the routine clinical use of CA125 in patients with ovarian cancer. Due to lack of sensitivity for stage I disease and lack of specificity, CA125 is of little value in the detection of early ovarian cancer. At present, therefore, CA125, either alone or in combination with other modalities, cannot be recommended for screening for ovarian cancer in asymptomatic women outside the context of a randomized controlled trial. Preoperative levels in postmenopausal women, however, may aid the differentiation of benign and malignant pelvic masses. Serial levels during chemotherapy for ovarian cancer are useful for assessing response to treatment. Although serial monitoring following initial chemotherapy can lead to the early detection of recurrent disease, the clinical value of this lead-time is unclear. CA125 is the ovarian cancer marker against which new markers for this malignancy should be judged.

Monitoring different stages of breast cancer using tumour markers CA 15-3, CEA and TPA.

The ability of the tumour markers Cancer Antigen 15-3 (CA 15-3), Carcinoembryonic Antigen (CEA), and Tissue Polypeptide Antigen (TPA) to signal progression in breast cancer patients was investigated in this study. Marker interpretation considered the analytical variation, intra-individual biological variation, and the rate of increase. Patient cohorts were as follows: (A) 90 stage II breast cancer patients who were monitored postoperatively, (B) 204 recurrent breast cancer patients who were monitored during first-line chemotherapy, and (C) 112 patients who were monitored during the time period after first-line chemotherapy. The sensitivity for progression was 44% (cohort A), 69% (cohort B), and 68% (cohort C) without any false progression signals. Marker lead-times exceeded 3 months in 20% (cohort A) and 27% (cohort C) of patients. Marker lead-times were 1-6 months among 33% of the patients receiving first-line chemotherapy (cohort B). Trials are necessary to determine whether tumour marker-guided therapy has any prognostic impact. The data suggest that tumour marker information may be used to stop ineffective treatments and reduce unnecessary adverse effects.

Serum tumor marker CA 125 for monitoring ovarian cancer during follow-up.

CA 125 is currently widely applied in the management of patients with ovarian cancer. However, a change in results of CA 125, which should be considered significant, has not been defined. The aim of this study was to investigate the ability of CA 125 to signal progressive ovarian cancer during follow-up after first-line chemotherapy. The study patients were selected retrospectively among 255 patients with stage IC-IV ovarian cancer. The evaluation of the CA 125 information was based on the analytical imprecision, the normal intra-individual biological variation, the sampling interval, and the cut-off value. Additionally, the utility of a new assessment criterion based upon an increment of 2.5 times the baseline CA 125 concentration confirmed by a third measurement was investigated. The efficiency of CA 125 to identify progression and non-progression during follow-up varied between 76.5 and 79.9%, depending on the applied time limit for an acceptable positive lead time. The median lead time for true positive results was 95-99.5 days. Using the new elaborated criterion, the efficiency of CA 125 for identifying progression and non-progression varied between 75.7 and 78.5%, depending on the applied time limit for an acceptable positive lead time. The median lead time for true positive results was 91-95.5 days. CA 125 provided early and reliable information about progressive disease during follow-up. The applied criteria can therefore be recommended in further studies assessing the clinical utility of serological tumor markers in patients with ovarian cancer.

Interpretation of sequential measurements of cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) based on analytical imprecision and biological variation in the monitoring of ovarian cancer.

The main objective with cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) monitoring of ovarian cancer patients is to detect an early change of disease activity with high reliability. We hypothesized that a monitoring scheme for ovarian cancer patients with serological tumor markers should take into account the stochastic variation, i.e. the probability that observed increases and decreases may solely be due to analytical imprecision and normal intra-individual biological variation. The aim of this study was to provide a detailed characteristic of the within-subject mean steady state concentrations and the associated variability in healthy individuals with an age distribution representative for ovarian cancer patients. Thirty-one healthy women with a median age of 55 years comprised the study population. Sixteen blood samples were collected from each subject in four series, with four samples per series, over a period of approximately 1 year. We found that, i) natural logarithmic-transformed concentrations were more homogeneously distributed between individuals than the original concentrations, ii) the within-subject mean steady state levels, the standard deviations, and the coefficients of variation differed among subjects, and iii) the steady state variability differed among the markers. In conclusion, our data indicate that the assessment of sequential CA 125, CEA, and TPA concentrations is more complex than hitherto recognized. We suggest that it is necessary to adjust the assessment criteria to the type of marker, and that assessment may be facilitated if based on natural logarithmic transformed concentrations.

Serum tumour marker CA 125 in monitoring of ovarian cancer during first-line chemotherapy.

The value of the serum tumour marker CA 125 to date has been in the monitoring of ovarian cancer patients for response to therapy and for recurrence of disease. However, despite the availability of serial data on CA 125, the problem of interpreting a change over time is still unsolved. The aim of this study was to assess the ability of CA 125 to monitor patients with ovarian cancer during postoperative chemotherapy. 255 patients with stage IC-IV ovarian cancer were allocated to the tumour marker monitoring study. The evaluation of CA 125 information was based on the analytical imprecision, the normal intra-individual biological variation, the sampling interval, and the cut-off value. Additionally, a new assessment criterion based upon an increment of 2.5 times the baseline CA 125 concentration confirmed by a third measurement was elaborated and the utility investigated. The efficiency of CA 125 for identifying progression and non-progression during first-line chemotherapy was 91.9%. The median lead time for true positive results was 41 days. Using the new elaborated criterion the efficiency of CA 125 for identifying progression and non-progression during first-line chemotherapy was 90.5%. The median lead time for true positive results was 35 days. CA 125 gave reliable prediction of progressive disease during postoperative chemotherapy. The results indicate a high applicability of the presented progression criteria during CA 125 monitoring of patients with changing activity of ovarian cancer.

Assessment of CA 15.3, CEA and TPA concentrations during monitoring of breast cancer.

The variability of the tumor markers cancer antigen (CA) 15.3, carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA) during steady state concentrations and the rate of increase during progression is described. One hundred and ninety-two patients were monitored during first-line chemotherapy for metastatic breast cancer and during follow-up. Blood specimens were sampled approximately every four weeks. Steady state concentrations were registered for 77 (CA 15.3), 96 (CEA), and 127 (TPA) patients with below cutoff level values and for 28 (CA 15.3), 25 (CEA), and 11 (TPA) patients with above cutoff level values. Clinical and marker progression was registered for 75 (CA 15.3), 62 (CEA), and 57 (TPA) patients. The coefficients of total variation of steady state concentrations (comprising the intra- and interassay analytical imprecision and the within subject biological variation) were higher below (14.9% CA 15.3, 15.4% CEA, 25.9% TPA) than above cutoffs (9.6% CA 15.3,6.0% CEA, 19.9% TPA). The variability was similar for CA 15.3 and CEA but higher for TPA. During progression the rates of increase in concentrations were similar for CA 15.3 (0.0257) and CEA (0.0214) and lower than for TPA (0.0346). Our data indicate that criteria for assessment of sequential tumor marker concentrations should consider the marker in question, the steady state variability, the cutoff value, and the rate of increase during disease progression.

Description of a computer program to assess cancer antigen 15.3, carcinoembryonic antigen, and tissue polypeptide antigen information during monitoring of metastatic breast cancer.

It is time-consuming to process and compare the clinical and marker information registered during monitoring of breast cancer patients. To facilitate the assessment, we developed a computer program for interpreting consecutive measurements. The intraindividual biological variation, the analytical precision profile, the cutoff limit, and the detection limit for each marker are entered and stored in the program. The assessment procedure for marker signals considers the analytical and biological variation of the applied markers. The software package contains a database that can store the interpretation of the measurements as evaluation codes together with patient demographics, information about treatment type, dates for treatment periods, control periods, and evaluation codes for clinical activity of disease. The consecutive concentrations for a patient are imported temporarily into the program from outside sources and presented graphically. Marker concentrations to be compared are selected with the computer mouse and the significance of the difference is calculated by the program. The program has an option for calculating the lead time of marker signals vs clinical information. The program facilitates the monitoring of individual breast cancer patients with tumor marker measurements. It may also be implemented in trials investigating the utility of potential new markers in breast cancer as well as in other malignancies.

Progression criteria for cancer antigen 15.3 and carcinoembryonic antigen in metastatic breast cancer compared by computer simulation of marker data.

BACKGROUND: We investigated the utility of computer simulation models for performance comparisons of different tumor marker assessment criteria to define progression or nonprogression of metastatic breast cancer. METHODS: Clinically relevant values for progressive cancer antigen 15.3 and carcinoembryonic antigen concentrations were combined with representative values for background variations in a computer simulation model. Fifteen criteria for assessment of longitudinal tumor marker data were obtained from the literature and computerized. Altogether, 7200 different patients, each based on 50 measurements, were simulated. With a sampling interval of 4 weeks, the monitoring period for each event was approximately 3.8 years. RESULTS: Modulation of the background variation, the starting concentrations, and the cutoffs enabled identification of criteria that were robust against false-positive signals of progression. CONCLUSIONS: The computer simulation model is a fast, effective, and inexpensive approach for comparing the diagnostic potential of assessment criteria during clinically relevant conditions of steady-state and progressive disease. The model systems can be used to generate tumor marker assessment criteria for a variety of malignancies and to compare and optimize their diagnostic performance.

Biological variation and analytical imprecision of CA 125 in patients with ovarian cancer.

Despite the availability of serial data on CA 125 in ovarian cancer, the problem of interpreting a change over time is still unsolved. Changes in marker concentrations are due not only to patients improving or deteriorating but also to analytical imprecision and normal intra-individual biological variation. The aim of this study was to assess the analytical imprecision (CV(A)) and the intra- and inter-individual biological variation (CV(I) and CV(G), respectively) of CA 125 in a group of 26 patients with clinically stable ovarian cancer. Furthermore, the critical difference for a change between two consecutive CA 125 concentrations calculated as square root(2) x Z x (CV(A)2 + CV(I)2)(1/2) (Z =1.65 for unidirectional and 1.96 for bidirectional changes, p < or = 0.05) and the index of individuality calculated as ((CV(A)2+CV(I)2)/CV(G)2)(1/2) were estimated. After the exclusion of outliers, CV(A) and the average CV(I) and CV(G) were 12.1%, 24.0%, and 43.1%, respectively. The index of individuality was 0.62 and the critical difference calculated for unidirectional changes was 62.6%. CV(A) and CV(I) contribute considerably to the variation in serial results and should, therefore, be included in the criteria for serum tumor marker assessment during monitoring of patients with ovarian cancer. The cut-off value of CA 125 is of minor value in detecting unusual results for an individual subject, when previous measurements from an individual are available. These measurements should be preferred as reference for interpretation of new results.

Assessment of biological variation and analytical imprecision of CA 125, CEA, and TPA in relation to monitoring of ovarian cancer.

OBJECTIVES: Changes in serial tumor marker results during monitoring of patients with ovarian cancer are due not only to deterioration or amelioration of the patient's condition, but also to preanalytical sources of variation (CPP), total random analytical error, and within-subject normal biological variation. The aim of the study was to assess (i) the analytical imprecision (CVA) and the average inherent intra- and interindividual biological variation (CVTI and CVG, respectively) for CA 125, CEA, and TPA in a group of healthy women; (ii) the significance of changes in serial results of each marker; and (iii) the index of individuality. METHODS: The study group consisted of 31 healthy women. Sixteen blood samples from each subject were collected in four series over a period of approximately 1 year. Data analysis was based on ANOVA. The index of individuality was calculated as ((CV2A + CV2TI)/CV2G)1/2 and the critical difference for a change between two consecutive concentrations as radical2xZx(CV2P + CV2A + CV2TI)1/2 (Z = 1.65 for unidirectional and 1.96 for bidirectional changes, P

Carcino-embryonic antigen in monitoring the growth of human colon adenocarcinoma tumour cells SK-CO-1 and HT-29 in vitro and in nude mice.

A set of experimental model systems were designed to investigate (a) the inter-relationship between growth of two human cancer cell lines (SK-CO-1, HT-29) and carcino-embryonic antigen (CEA) kinetics; and (b) whether neoplastic growth or CEA concentration is modulated by human growth hormone (hGH). We found that increasing CEA concentration depended on tumour burden. SK-CO-1 cells had the lowest growth rates but the highest rates of CEA production. The rate of CEA increase exceeded the growth rate of both SK-CO-1 and HT-29. hGH modulated neither neoplastic growth nor CEA production. In conclusion, our results suggest that experimental models may be useful for investigating the role of serological markers as monitors of increasing tumour burden. It will be of interest to investigate the performance of those model systems in examining the effect of cytotoxic agents in neoplastic growth.

Tumor markers cancer antigen 15.3, carcinoembryonic antigen, and tissue polypeptide antigen for monitoring metastatic breast cancer during first-line chemotherapy and follow-up.

We investigated whether model systems integrating stochastic variation into criteria for marker assessment could be used for monitoring metastatic breast cancer. A total of 3989 serum samples was obtained from 204 patients receiving first-line chemotherapy and from 112 of these patients during follow-up. Each sample was analyzed for cancer antigen 15.3, carcinoembryonic antigen, and tissue polypeptide antigen. The efficiency for identifying progression and nonprogression was 94% during therapy and 85% during follow-up, with no false-positive marker results for progressive disease. At clinical progressive disease, the median positive lead time was 35 days during therapy and 76 days during follow-up. Tumor marker assessment may document that a therapy is effective and ought to be continued in spite of adverse toxic effects, and that a treatment is ineffective and should be stopped to prevent unnecessary toxicity. Marker information may also be useful in studies investigating whether early treatment during follow-up will alter the prognosis of metastatic breast cancer.

A novel method for monitoring high-risk breast cancer with tumor markers: CA 15.3 compared to CEA and TPA.

BACKGROUND: An early and reliable diagnosis of metastatic spread has increased interest in serum tumor markers. This study investigated the ability of CA 15.3, CEA, and TPA to identify, predict, and exclude metastases in bone/viscera during adjuvant treatment and follow-up of high-risk breast cancer. METHODS: Ninety females with high-risk breast cancer were included in the study. Response evaluation was based upon clinical examination, x-rays or histology and elaborated marker criteria. RESULTS: During the marker monitoring period, metastases in four patients were confined to skin or lymph nodes, 21 developed metastases to bone/viscera, and 65 females had no evidence of metastases. CA 15.3, CEA, and TPA correctly classified 48%, 10%, and 19% of the patients with metastases in bone/viscera, and 100%, 94%, and 98% without. Following CA 15.3, CEA, and TPA recurrence, 100%, 33%, and 60% of the patients developed metastases in bone/viscera. Metastases in bone/viscera were excluded in 86%, 76%, and 79% of patients without CA 15.3, CEA, and TPA recurrence. CONCLUSION: Only CA 15.3 gave reliable information about recurrence. Metastases in bone/viscera were identified in 10 of the 21 patients with CA 15.3. There was no false-positive CA 15.3 information on the 65 patients without clinical recurrence. The PVneg (86%) indicated that when CA 15.3 did not signal recurrence, metastases to bone/viscera were not likely.