Pedro Martínez Hernández

Tumor markers in lung cancer: does the method of obtaining the cut-off point and reference population influence diagnostic yield?

OBJECTIVES The aim of this study was to evaluate the clinical usefulness of the tumor markers CA125, CEA, NSE, SCC, and TPS in a group of patients with lung cancer. We estimated the influence of the method for choosing the cut-off point and of considering as a reference population either healthy controls or patients with some form of non-neoplastic pulmonary disease (NNPD). DESIGN AND METHODS The tumor markers were determined using enzyme immunoassay techniques, and their diagnostic yield was evaluated using ROC curves and their correlation with the percentages between false and true positives. The diagnostic parameters of the tumor markers are presented in 116 patients with lung cancer and compared with a group of 25 healthy controls and another group of 80 patients with some form of NNPD. We determined on the one hand the cut-off points resulting from the best sensitivity-specificity balance in the ROC curves and on the other those resulting from considering a specificity of 95%. With the two cut-offs we studied the different diagnostic parameters: sensitivity, specificity and accuracy or area below the ROC curve. RESULTS Optimum diagnostic yield is obtained when we choose the cut-off point determined by the best balance of sensitivity and specificity in the ROC curves and take a healthy population as a reference group. The cut-off values for CA125, CEA, NSE, SCC, and TPS were 24 U/mL, 2.8 ng/mL, 9.8 ng/mL, 1.6 ng/mL, and 67.8 U/L, respectively. CONCLUSIONS Our results suggest that in future studies on tumor markers, a group of healthy subjects should be used as a reference population and ROC curves should be used to obtain the optimum cut-offs.

Concentración y tamaño de las partículas de LDL tras el tratamiento con rosiglitazona en pacientes con diabetes mellitus tipo 2

BACKGROUND AND OBJECTIVE The effects of rosiglitazone on the lipid profile are controversial, with related increases in the concentration of total and LDL cholesterol. Our objective is to evaluate the evolution of the concentration and size of LDL particles in a group of patients with type 2 diabetes mellitus taking rosiglitazone. PATIENTS AND METHODS We studied 30 patients under treatment with oral antidiabetics to whom rosiglitazone was added to their initial therapy. The following tests were determined before and after 6 months of treatment: glucose, total cholesterol, HDL, LDL, triglycerides, C reactive protein, lipoprotein (a) and glycosylated haemoglobin. The average diameter of the particles LDL was also estimated, as well as the probability of cardiovascular events up to ten years, according to the Framingham and SCORE model. RESULTS Statistically significant reductions of glucose, HbA(1C) and CRP levels, and an increase of total cholesterol, cholesterol LDL and triglycerides concentrations were observed, with statistical significance for total cholesterol. A significant increase in the estimation of cardiovascular risk up to ten years was found. No modifications either in the concentrations of HDL-c and Lp (a) or in the average size of LDL particles were detected. CONCLUSIONS After treatment with rosiglitazone, there is an increase of total cholesterol concentrations without variation in the mean size of LDL particles. Nevertheless, the reduction of CRP, and thus of inflammation is clear, with prevention of the progression of atherosclerosis.

Usefulness of NTproBNP in the Emergency Management of Patients With Severe Dyspnea and an Uncertain Heart Failure Diagnosis

Introduction and objectives. Measurement of N-terminal pro-B-type natriuretic peptide (NTproBNP) helps in diagnosing heart failure (HF). The test’s usefulness may be greatest in patients with severe dyspnea of uncertain origin. However, NTproBNP has not been evaluated specifically in this setting. Patients and method. This prospective emergency department study included 70 patients with shortness of breath at rest as their chief complaint. In the attending physician’s opinion, both HF and a non-cardiac cause were equally probable. Blinded NTproBNP measurement was carried out in blood samples collected on admission. Patients were monitored and their final diagnoses were based on clinical findings, therapeutic responses, and cardiac and noncardiac tests performed during hospitalization. Results. The NTproBNP level was higher in the 49 patients (70%) with a final diagnosis of HF (P=.006); the area under the ROC curve was 0.72 (0.60-0.82). The optimum diagnostic cut-off value was 900 pg/mL, which had an accuracy of 87%, a sensitivity of 98%, and a negative predictive value of 92%. The NTproBNP level was significantly higher in the 6 patients (9%) who died during hospitalization (P=.009); the area under the ROC curve was 0.87 (0.76-0.93) and the optimum cut-off value for predicting death was 5500 pg/mL, which had an accuracy of 77%, a sensitivity of 100%, and a positive likelihood ratio of 4.2. Conclusions. In patients with severe dyspnea and an uncertain diagnosis of HF, an NTproBNP level 5500 pg/mL identifies patients at an increased risk of death.

About the Clinical Performance of the Sysmex XE-500 for Automated Cerebrospinal Fluid Cell Counts

To the Editor We read with interest the article by Sandhaus et al1 in the Journal , and we agree that the cerebrospinal fluid (CSF) cell count—an extremely important test for the diagnosis and follow-up of diseases of the CNS—can benefit from the introduction of automated analyzers. The reference method for cell counting is the manual cytometric chamber technique, although it is labor-intensive, shows important interobserver variability, and can produce errors. Automation of such measurements with a view to standardizing and simplifying these tests would be desirable. In any case, patient classification according to the CSF cell count is a generally accepted practice,2 and any changes in the reference ranges must be contrasted by many studies because the diagnostic and therapeutic decisions made on the basis of these counts are extremely important. Although automated counts can be done with CSF samples with high cell counts, the use of automated systems may be limited by their poor sensitivity …

Marcadores bioquímicos de remodelado en el estudio de la masa ósea en la mujer con menopausia reciente sin osteoporosis

BACKGROUND AND OBJECTIVE: To date, there have not been performed enough studies in Spain to analyze the usefulness of biochemical bone markers in postmenopausal and non-osteoporotic women. POPULATION AND METHOD: We studied several groups of women, ages between 17 and 30 years, 30-45 years, premenopausal and recently postmenopausal in order to know the reference values of some biochemical bone markers along 2 years in premenopausal and postmenopausal women (postmenopausal divided in 2 groups: those under treatment with ordinary hormonal replacement therapy [HRT], and those without it). RESULTS: Values of biochemical bone markers were higher in postmenopausal and in 17-30 years group than in premenopausal and 30-45 years group (p < 0.05). Absolute values and the change in bone markers (%) were higher in postmenopausal and non-osteoporotic women under HRT than in those without HRT (% change: OC, 35,72 vs 4.45 [p < 0.01]; ALPo, 13,13 vs 27.06 [p < 0.01]; NTx, 42.74 vs 10.93 [p < 0.01]; fDPD, 21.07 vs 28.49 [p < 0.05]; betaCrossLaps, 50,17 vs 23.04 [p < 0.01]). CONCLUSIONS: We have defined reference values in our region and have proved that biochemical bone markers (absolute values and their change from the basal value) represent a useful tool in monitoring hormonal replacement therapy in recently postmenopausal and non-osteoporotic women.Fundamento y objetivo En Espana no hay estudios acerca de la utilidad a medio plazo de los marcadores bioquimicos de remodelado oseo en mujeres con menopausia reciente y sin osteoporosis. Poblacion y metodo Constituimos 5 grupos de mujeres de edades comprendidas entre 17-30 anos, 35-45 anos, premenopausicas y posmenopausicas recientes sin osteoporosis, y calculamos los valores de referencia para cada grupo. Posteriormente dividimos el ultimo grupo en dos (sin/con adhesion a tratamiento hormonal sustitutivo [THS] ordinario) para seguir la evolucion de los marcadores y la densidad mineral osea a lo largo de 2 anos. Resultados Constatamos que tanto en el grupo de mujeres de 17-30 anos como en mujeres con menopausia los valores de los marcadores eran superiores a los encontrados en mujeres premenopausicas y el grupo de 35-45 anos (p Conclusiones Los marcadores bioquimicos de remodelado oseo no solo presentan distintos valores de referencia en grupos de distinta edad, sino que son utiles en la evaluacion de la perdida de masa osea ante la aplicacion de un THS ordinario tambien en mujeres con menopausia reciente sin osteoporosis.

DNA aneuploidy, S-phase fraction and nuclear p53 positivity in non-small cell lung carcinoma.

OBJECTIVES Surgical resection currently offers the best option for managing non-small cell lung carcinoma (NSCLC) but its efficiency is limited by subsequent tumor recurrence. We evaluated whether flow cytometric study and the p53 gene staining pattern may be useful in this respect. DESIGN AND METHODS We took biopsy samples of 40 patients with operable NSCLC to study the frequency of aneuploidy, proliferative activity, and alterations in the p53 tumor suppressor gene and compared them with clinicopathological parameters such as age, gender, smoking, histological type, tumor size, and degree of differentiation. To study DNA content, the nuclei were analyzed by flow cytometry using a FACS flow cytometer (Becton-Dickinson) equipped with an argon ion laser, with a propidium iodide excitation of 488 nm. We used the immunohistochemical technique for p53 analysis in samples of paraffin-embedded tissue corresponding to the same patients from whom fresh tissue was taken. RESULTS Nuclear p53 staining was detected in 66.7% of the samples; 69.4% of the cases revealed aneuploid DNA histograms and 59% presented with an S phase fraction of more than 12%. Comparison with clinicopathological parameters showed that p53 protein was associated significantly with histological classification (p = 0.04), gender (p = 0.01), and smoking (p = 0.04). CONCLUSIONS Immunodetection of p53 overexpression and DNA ploidy in the bronchial epithelium may be a useful tool in any future multifactorial analysis in such tumors for identifying previous lesions that may progress to malignancy.

Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical–pathological features in BRCA carriers and non-carriers

This is the first study performed in Murcia (south-eastern Spain) in which 592 families with hereditary breast and ovarian cancer were identified thanks to Genetic Counselling Units from this area over 6 years. Diagnostic performance was 18.1% and 194 different genetic variants were obtained. Variants with uncertain significance accounted for only 5.6% of the total number of reports, so our population has been well characterised. In BRCA1 gene, two novel variants were found (c.1859delT and c.3205C > T) and the most frequently detected mutations were c.68_69delAG, c.212 + 1G > A, c.5123C > A, c.211A > G and c.1918C > T, which together represented 56.67% of total pathogenic mutations. In BRCA2 gene, four recurrent variants were described (deletion of entire exon 2, c.9117G > A, c.3264dupT and c.3455T > G) representing 43.5% of the mutations in this gene. Mutation c.68_69delAG and deletion of entire exon 2 in BRCA1 and BRCA2 genes respectively were the most prevalent variants in our population. Regarding the genotype-phenotype relation, mutation c.212 + 1G > A appeared in an important percentage of breast and ovarian cancer cases, c.5123C > A in bilateral breast cancer and c.9117G > A in bilateral breast cancer and ovarian cancer. With respect to clinical–pathological characteristic, BRCA1/BRCA2 mutation carriers showed earlier onset age of breast tumour and higher risk of developing contra lateral breast cancer than non-informative cases. Moreover, association between either molecular subtype triple negative breast cancer or ovarian cancer and BRCA1 carriers was obtained.This is the first study performed in Murcia (south-eastern Spain) in which 592 families with hereditary breast and ovarian cancer were identified thanks to Genetic Counselling Units from this area over 6 years. Diagnostic performance was 18.1% and 194 different genetic variants were obtained. Variants with uncertain significance accounted for only 5.6% of the total number of reports, so our population has been well characterised. In BRCA1 gene, two novel variants were found (c.1859delT and c.3205C > T) and the most frequently detected mutations were c.68_69delAG, c.212 + 1G > A, c.5123C > A, c.211A > G and c.1918C > T, which together represented 56.67% of total pathogenic mutations. In BRCA2 gene, four recurrent variants were described (deletion of entire exon 2, c.9117G > A, c.3264dupT and c.3455T > G) representing 43.5% of the mutations in this gene. Mutation c.68_69delAG and deletion of entire exon 2 in BRCA1 and BRCA2 genes respectively were the most prevalent variants in our population. Regarding the genotype-phenotype relation, mutation c.212 + 1G > A appeared in an important percentage of breast and ovarian cancer cases, c.5123C > A in bilateral breast cancer and c.9117G > A in bilateral breast cancer and ovarian cancer. With respect to clinical–pathological characteristic, BRCA1/BRCA2 mutation carriers showed earlier onset age of breast tumour and higher risk of developing contra lateral breast cancer than non-informative cases. Moreover, association between either molecular subtype triple negative breast cancer or ovarian cancer and BRCA1 carriers was obtained.