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.

Tissue polypeptide antigen activity in cerebrospinal fluid: a marker of central nervous system metastases of breast cancer.

Tissue polypeptide antigen (TPpA) in the cerebrospinal fluid (CSF) was measured in 59 consecutive breast cancer patients with suspected central nervous system (CNS) metastases. Subsequently, we determined that 13 patients had parenchymal brain metastases, 10 had leptomeningeal carcinomatosis, and 36 had no CNS involvement. The concentration of TPpA, which is a nonspecific marker for cell proliferation, was significantly higher in patients with CNS metastases than in those without it (P less than .0001; Mann-Whitney test). A tentative cutoff value for CNS metastases was set at 95 U/L TPpA; the upper limit of values indicating absence of CNS metastases was 89 U/L. Given these cutoff points, the sensitivity of TPpA as a marker for CNS metastases was 74% and the specificity was 100%; the predictive values of positive and negative tests were 100% and 86%, respectively. In 16 patients with CNS metastases, no correlation was found between TPpA activity in corresponding CSF and blood samples (correlation coefficient, Spearman's rho = .4; P greater than .1). In three patients treated for leptomeningeal carcinomatosis, the measurements of CSF TPpA showed correlation between the presence of tumor cells in the CSF and neurological clinical function. TPpA concentrations decreased in parallel with the clinical response and increased prior to CNS disease progression. As a marker for CNS metastases, the level of TPpA in the CSF in breast cancer patients appears to be superior to the level of protein, lactate dehydrogenase, or glucose, which showed very low sensitivity (41%, 47%, and 8%, respectively). For quantitative evaluation of treatment for leptomeningeal carcinomatosis, the TPpA level appears to be valuable and superior to CSF cytology, because tumor cells are not always present in CSF samples from patients with this condition.

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.

Carbohydrate antigen 549 in metastatic breast cancer during cytostatic treatment and follow-up.

This study was designed to investigate whether the serum tumour marker CA 549 gave early and reliable information about disease activity among metastatic breast cancer patients during cytostatic treatment and follow-up. 50 females with metastatic breast cancer were monitored clinically and with the tumour marker CA 549. Response evaluation was based upon clinical (World Health Organization) and elaborated CA 549 criteria, respectively. In 113 blindly and matched evaluations, concordance appeared in 73/113 and discordance in 40/113 evaluations. In 27, discordance concerned degree of response, in 2 clinical progression followed marker progression after the end of the study, and in 11 progressive disease was established by clinical investigation alone. CA 549 response excluded clinical progression in bone or viscera and reversed. Clinical progression within 2 months in viscera and bone was predicted among 91% by marker progression. Clinical progression was excluded among 93% without marker progression. In conclusion, monitoring of metastatic breast cancer patients could include CA 549 if standardised criteria for marker evaluation are used.

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.

Carcinoembryonic antigen measurement in gastric juice. Discovery and elimination of an inhibitory interference.

In biological fluids containing mucus an inhibitory interference on CEA measurement was found. The interference could be eliminated.

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.

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.

The diagnostic and prognostic value of serum bone Gla protein (osteocalcin) in patients with recurrent breast cancer.

Serum bone Gla protein (S-BGP), a marker of bone metabolism, was measured in 60 patients included in a staging programme for recurrent breast cancer. Other diagnostic procedures comprised S-alkaline phosphatase (S-AP), bone scan (B-scan), bilateral iliac crest bone marrow biopsies, and radiological bone survey. The sites of recurrence were bone (61%), bone marrow (46%), soft tissue (52%), lung (13%), pleura (11%), liver (4%), and brain (2%). Radiology and bone biopsy served as key diagnoses as to the presence or absence of bone metastases. The diagnostic efficiency of B-scan and S-AP was greater than that of S-BGP, and the result of BGP measurement was associated with neither extent nor number of bone metastases. However, the BGP values were significantly lower in patients who had visceral metastases, and the median duration of survival after recurrence was 13 months for patients with low S-BGP levels (= < 2.0 nmol l-1), compared to 18 months for patients with medium S-BGP values (2.0-2.9 nmol l-1), and 25 months for patients with high values (> 3.0 nmol l-1) (p = 0.19). Analyses of the simultaneous effect of univariate prognostic factors were performed using the Cox proportional hazards model. S-alkaline phosphatase (S-AP) and S-BGP were the only significant, independent prognostic factors.

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.

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.

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.

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.

Interpretation of results for tumor markers on the basis of analytical imprecision and biological variation.

Interpretation of results for CA 15.3, carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) during breast cancer monitoring requires data on intra- (CVP) and inter- (CVG) individual biological variation, analytical imprecision (CVA), and indices of individuality. The average CVP and CVG obtained from 22 healthy women were, respectively, 6.2% and 62.9% (CA 15.3), 9.3% and 86.8% (CEA), and 28.3% and 133% (TPA). The indices of individuality were all < 0.6: 0.2 (CA 15.3), 0.15 (CEA), and 0.2 (TPA). CVA depended on the concentration of the analytes. CVP and CVA determine what constitutes a significant difference between sequential results. Assuming a CVA of 11.2% (CA 15.3), 9.5% (CEA), or 11.9% (TPA), results must differ by 30%, 31%, or 72%, respectively, for P < or = 0.05. We found that CVP and CVA contribute considerably to the variation during breast cancer monitoring. Consequently, both CVP and CVA should be considered in criteria for marker evaluation. Because of low indices of individuality, conventional cutoff limits are inappropriate both for initial identification and for follow-up of breast cancer.

Diagnostic value of cerebrospinal fluid cytology in comparison with tumor marker activity in central nervous system metastases secondary to breast cancer.

BACKGROUND: Central nervous system (CNS) metastases occur in approximately 35% of patients with breast cancer. Parenchymal brain metastases (MET) remain undetected in a large proportion of patients, and only 50% of patients with leptomeningeal carcinomatosis (MC) are diagnosed in vivo. METHODS: Cytology and activity of the tumor markers tissue polypeptide antigen (TPA) and creatine kinase-BB isoenzyme (CK-BB) were evaluated in the cerebrospinal fluid (CSF) in 71 consecutive patients with breast cancer suspected for CNS metastases. RESULTS: Forty-three patients had no CNS metastases, 12 patients had MET, 5 patients had both MET and MC, and 11 patients had MC alone. Seven of the patients with MC had an intracerebroventricular (ICV) reservoir inserted, and an additional 70 ICV CSF samples from these patients were obtained. In CSF obtained by lumbar puncture, 11% of the samples were classified as "suspicious for malignancy," but a very limited interobserver variability was demonstrated (Kappa test value, 0.81; 95% confidence limits, 0.67-0.95%). Fifty-one percent of the ICV CSF samples were classified as "suspicious for malignancy" (Kappa test value, 0.58; 95% confidence limits, 0.34-0.82%). TPA and CK-BB were both measured in 101 CSF specimens (61 from lumbar puncture and 40 ICV samples). The differences between patients with and without CNS metastases were significantly different according to TPA (P < 0.00001) and CK-BB (P < 0.00003; Mann-Whitney test). The sensitivity and predictive value of a negative test for having any CNS metastases (in case of elevated values of either TPA or CK-BB or both) were 85% (95% confidence limits, 65-96%) and 90% (95% confidence limits, 76-97%), respectively. In addition, a significant correlation between TPA and CK-BB was demonstrated in CSF from lumbar puncture (Spearmans-Rho, 0.49; P < 0.0001) and ICV (Spearmans-Rho, 0.37; P < 0.02). CONCLUSIONS: Cytologic evaluation of CSF obtained by lumbar punctures is a reliable procedure. In CSF from ICV reservoirs, cytologic evaluation is of limited use, but CK-BB and TPA is of potential value.