Clinical applicability of diagnostic biomarkers in early-onset cognitive impairment.

BACKGROUND AND PURPOSE: Several diagnostic biomarkers are currently available for clinical use in early-onset cognitive impairment. The decision on which biomarker is used in each patient depends on several factors such as its predictive value or tolerability. METHODS: There were a total of 40 subjects with early-onset cognitive complaints (<65 years of age): 26 with Alzheimer's disease (AD), five with frontotemporal dementia and nine with diagnostic suspicion of non-neurodegenerative disorder. Clinical and neuropsychological evaluation, lumbar puncture for cerebrospinal fluid (CSF) AD core biochemical marker determination, medial temporal atrophy evaluation on magnetic resonance imaging, amyloid-positron emission tomography (PET) and 18 F-fluorodeoxyglucose-PET were performed. Neurologists provided pre- and post-biomarker diagnosis, together with diagnostic confidence and clinical/therapeutic management. Patients scored the tolerability of each procedure. RESULTS: Cerebrospinal fluid biomarkers and amyloid-PET increased diagnostic confidence in AD (77.4%-86.2% after CSF, 92.4% after amyloid-PET, P < 0.01) and non-neurodegenerative conditions (53.6%-75% after CSF, 95% after amyloid-PET, P < 0.05). Biomarker results led to diagnostic (32.5%) and treatment (32.5%) changes. All tests were well tolerated. CONCLUSIONS: Biomarker procedures are well tolerated and have an important diagnostic/therapeutic impact on early-onset cognitive impairment.

Variability of assay methods for total and free PSA after WHO standardization.

The variability of total PSA (tPSA) and free PSA (fPSA) results among commercial assays has been suggested to be decreased by calibration to World Health Organization (WHO) reference materials. To characterize the current situation, it is necessary to know its impact in the critical cutoffs used in clinical practice. In the present study, we tested 167 samples with tPSA concentrations of 0 to 20 µg/L using seven PSA and six fPSA commercial assays, including Access, ARCHITECT i2000, ADVIA Centaur XP, IMMULITE 2000, Elecsys, and Lumipulse G1200, in which we only measured tPSA. tPSA and fPSA were measured in Access using the Hybritech and WHO calibrators. Passing-Bablok analysis was performed for PSA, and percentage of fPSA with the Hybritech-calibrated access comparison assay. For tPSA, relative differences were more than 10 % at 0.2 µg/L for ARCHITECT i2000, and at a critical concentration of 3, 4, and 10 µg/L, the relative difference was exceeded by ADVIA Centaur XP and WHO-calibrated Access. For percent fPSA, at a critical concentration of 10 %, the 10 % relative difference limit was exceeded by IMMULITE 2000 assay. At a critical concentration of 20 and 25 %, ADVIA Centaur XP, ARCHITECT i2000, and IMMULITE 2000 assays exceeded the 10 % relative difference limit. We have shown significant discordances between assays included in this study despite advances in standardization conducted in the last years. Further harmonization efforts are required in order to obtain a complete clinical concordance.

Melanoma inhibiting activity protein (MIA), beta-2 microglobulin and lactate dehydrogenase (LDH) in metastatic melanoma.

BACKGROUND: Serum levels of melanoma markers may have a role in monitoring disease evolution in metastatic melanoma. PATIENTS AND METHODS: Serial measurements of melanoma inhibiting activity protein (MIA), lactate dehydrogenase (LDH), S-100 and beta2-microglubulin were obtained from 42 metastatic melanoma patients during their biochemotherapy treatment. RESULTS: High pre-treatment serum levels of S-100, LDH, MIA and P2-microglobulin were detected in 50%, 57%, 50% and 24% of the patients, respectively. Only S-100 had prognostic significance for both disease-free (p=0.011) and overall survival (p=0.021). In patients who responded to treatment, S-100 levels decreased significantly from pre-treatment to the time of response (p = 0.050). When patients progressed, levels of MIA and P2-microglobulin increased significantly (p =0.028 and p =0.030, respectively). CONCLUSION: Correlation with disease evolution was found for S-100, MIA and P2-microglobulin levels. Despite the small sample size of the study, S-100 was a significant prognostic marker for overall survival and disease-free survival.

S-100beta and MIA in advanced melanoma in relation to prognostic factors.

We compared the sensitivity and specificity of S-100 and MIA in advanced melanoma, in 96 patients with no evidence of disease (NED) and 86 patients with metastatic melanoma. Abnormal S100 (>0.2 microg/l) and MIA (>14 ng/ml) results were found in 1.1% and 3.2% of NED patients and in 59.3% and 54.6% of the patients with active melanoma (p<0.001). Using both tumor markers simultaneously, the sensitivity increased up to 69.8% with the same specificity 96.8%. S100 serum levels were not related to growth patterns. By contrast, MIA levels seemed to be related to the growth pattern, with higher levels in nodular melanoma (60.6+/-87.1 ng/ml) compared with acral-lentigous melanoma (11.9+/-5.4 ng/ml) (p=0.02). Likewise, S100 was related to the metastases site with significantly higher sensitivity and mean concentrations in patients with brain metastases (p=0.01) with the lowest in those with lung MI. MIA was related to the same metastases locations but without statistical significance. In summary, both S100 and ML4 are useful markers related to prognostic factors, being more effective when used in combination.

Serum protein s-100 predicts clinical outcome in patients with melanoma treated with adjuvant interferon--comparison with tyrosinase rt-PCR.

OBJECTIVE: To study the clinical value of the determination of serum S-100 protein as a single tumor marker or in combination with tyrosinase RT-PCR in patients with melanoma receiving adjuvant interferon. PATIENTS AND METHODS: Patients were tested for serum S-100 protein luminoimmunometric assay and for blood tyrosinase mRNA (RT-PCR), before starting interferon and every 2-3 months thereafter. RESULTS: One hundred and six patients (stage IIA, 27; IIB, 19; III, 49; and IV, 11) were included in the study. Median follow-up was 51 months (range 2-76). In the univariate analysis, under treatment S-100 > or =0.15 microg/l and a positive RT-PCR correlated with a lower disease-free survival and overall survival (OS). In the multivariate analysis, clinical stage, under therapy positive RT-PCR and S-100 levels > or =0.15 mug/ml, were independent prognostic factors for OS. The hazard ratio for OS was 3.9 (95% CI, 1.67-9.15; p = 0.004) and 2.2 (95% CI, 1.05-4.6; p = 0.016) for S-100 > or =0.15 microg/l and positive RT-PCR, respectively. When both techniques where combined, a positive RT-PCR indicated a poorer clinical outcome only in patients with S-100 <0.15 microg/l. CONCLUSIONS: S-100 > or =0.15 microg/l and a positive RT-PCR during adjuvant interferon therapy indicate a high risk of death in resected melanoma patients. S-100 determination has a higher positive predictive value than RT-PCR, while tyrosinase RT-PCR adds prognostic information in patients with S-100 <0.15 microg/l.

Tumor markers (CEA, CA 125, CYFRA 21-1, SCC and NSE) in patients with non-small cell lung cancer as an aid in histological diagnosis and prognosis. Comparison with the main clinical and pathological prognostic factors.

CEA, CA 125, SCC, CYFRA 21-1 and NSE were prospectively studied in 211 patients with non-small cell lung cancer and compared with clinical parameters (age, sex, Karnofsky Index, symptoms and smoking status), histopathological parameters (stage, histology, tumor size and nodal involvement), biological parameters (LDH and albumin) and the therapy used (surgery, chemotherapy or radiotherapy). Tumor marker sensitivity was CYFRA 21-1: 76%, CA 125: 55%, CEA: 52%, SCC: 33% and NSE: 22%. One of the tumor markers was abnormally high in 87% of the patients with locoregional disease and in 100% of the patients with metastases. Except for NSE, all tumor markers showed a clear relationship with tumor stage and histology and therefore enabled a better histological diagnosis. Abnormal CEA serum levels were mainly found in adenocarcinomas, CA 125 in large-cell lung cancers (LCLC) and adenocarcinomas and SCC in squamous tumors. Eighty-five percent of the patients with SCC levels >2 ng/ml had squamous tumors. Likewise, CA 125 levels <60 U/ml or CEA <10 ng/ml excluded adenocarcinoma or LCLC with a probability of 82 and 91%, respectively.

Coronary endothelial dysfunction as a predictor of intimal thickening in the long term after heart transplantation.

OBJECTIVES: The mechanisms of cardiac allograft vasculopathy and its predisposing factors are multifactorial and as yet not well established. To determine the influence of endothelial dysfunction on the development of intimal thickening, we prospectively analyzed the vasomotor response to acetylcholine and nitroglycerin, as well as other donor and recipient variables. Findings were correlated with the coronary intimal thickness, which was evaluated by means of intravascular ultrasonography. METHODS: Nineteen patients who had undergone heart transplantation 4.89 +/- 2.35 years previously and who had angiographically normal coronary arteries were included. Endothelial function was analyzed by quantitative coronary analysis of the vasomotor response of the left anterior descending artery to acetylcholine. An intimal thickness index, reflecting the percentage of intima obstructing the coronary lumen, was calculated. RESULTS: Nine (47%) patients showed endothelial dysfunction, and the remaining 10 (53%) patients had a normal response. Four (44%) of 9 patients with a weight gain of greater than 20% after the operation showed endothelial dysfunction compared with none of the 10 patients with normal responses (P <.04). The severity of the intimal thickness correlated with the years after transplant (r = 0.45, P <.05). Patients with endothelial dysfunction had more intimal thickening than those without (32% +/- 17% vs 17% +/- 12%, respectively; P <.05). Furthermore, the degree of intimal thickening correlated with the magnitude of the vasomotor response to acetylcholine (r = -0.60, P =.006). No relationship was found between intimal thickness and the vasodilatory response to nitroglycerin. As independent variables for intimal thickness, multivariate analysis detected the magnitude of the response to acetylcholine (P =.0005), years after transplant (P =.01), and ischemic time (P =.03). CONCLUSIONS: Cardiac allograft vasculopathy is a multifactorial disease the severity of which increases over time. Endothelial dysfunction is a predictive factor of intimal thickening severity. Predisposing factors that provoke endothelial injury, such as perioperative ischemic time and obesity, may contribute to the development of allograft vasculopathy.

[Initial results and 6 month clinical follow-up after implantation of a silicon carbide coated coronary stent]. / Resultados iniciales y seguimiento clínico a 6 meses tras el implante de un stent coronario recubierto de carburo de silicio.

INTRODUCTION AND OBJECTIVES: To present the initial Spanish experience with the Tenax coronary stent, a laser sculpted from high-precision 316L stainless steel coated with hydrogen rich amorphous silicon carbide that reduces thrombogenecity and improves biocompatibility. PATIENTS AND METHODS: From July 1998 to July 1999, 206 patients (62 +/- 5 years) underwent implantation of 231 Tenax stents in 9 centers as the only revascularization procedure. The most frequent clinical indication was unstable angina (66%), and most of the lesions were complex (class B2 and C). The target vessels were the left anterior descending (51%) and right coronary arteries (36%). The ejection fraction was < 0.5 in 19% cases. RESULTS: Revascularization was complete in 70%, elective in 80%, and the implantation was direct in 25% of the cases. The procedure was successful in all the lesions, reducing stenosis from 62 +/- 16 to 16 +/- 10% and increasing the minimal luminal diameter from 0.81 +/- 0.40 to 2.61 +/- 0.59 mm. The TIMI flow was reduced in 30%, but normalized after the stent in all but one case. The incidence of cardiac events was minimal: 1 acute thrombosis (0.5%) resolved by a new angioplasty and 1 non-Q myocardial infarction (0.5%). At the 6-month clinical follow-up 10% of the patients presented complaints of angina greater than class II, and a new angioplasty was carried out in 1.9% of these cases. CONCLUSION: Clinical and angiographic data suggest that the hydrogenated silicon carbide coating of the Tenax coronary stent may indeed play a beneficial role in patient outcome, and should therefore be evaluated by prospective clinical trials.

[Registry of the Activity of the Section of Hemodynamics and Interventional Cardiology of the Spanish Society of Cardiology for the year 2000]. / Registro de Actividad de la Sección de Hemodinámica y Cardiología Intervencionista de la Sociedad Española de Cardiología del año 2000.

The results of the Registry of the Working Group on Hemodynamics and Interventional Cardiology of the Spanish Society of Cardiology for 2000 are presented. Date came from 100 centers representing all the cardiac catheterization laboratories in Spain; 93 centers performed mainly adult catheterization and 7 carried out only pediatric procedures. In 2000, 88,339 diagnostic catheterization procedures were performed (73,382 coronary angiograms), representing a total increase of 12.5% over 1999. The population-adjusted rate was 1,825 coronary angiograms per 106 inhabitants. With a total of 26,993 procedures and a rate of coronary interventions per 106 inhabitants of 671, coronary intervention increased by 17% over figures for 1999. Coronary stents were the devices used most often, with 29,504 implanted in 2000; stenting accounted for 77.2% of procedures, a 30.5% increase over 1999. The increase in direct stenting without predilatation was noteworthy. Direct stenting was done in 8,778 procedures (38.9% of the total), an increase of 131% compared to 1999. IIb-IIIa glycoprotein were used in 4,700 coronary interventions (17%). Angioplasty, performed in 3,128 cases of acute myocardial infarction, accounted for 11.6% of coronary interventions 33.5% more than in 1999. A decrease of 6.5% in valvuloplastics occurred, attributable to the performance of fewer mitral valve repairs (493 vs 525 in 2000 and 1999, respectively). Pediatric procedures increased by 20.5%, from 678 to 817 cases. In conclusion, we would like to underline the high rate of reporting by laboratories, through which the Registry has been able to compile data that are highly representative of the hemodynamic activity in Spain.

Combined therapeutic strategy for multiple coronary thromboemboli.

A female with mitral valvular disease presented an acute myocardial infarction. She suddenly complained of recurrent chest pain with symptoms of pulmonary edema. The angiogram evidenced multiple coronary thromboemboli. A combined strategy using intracoronary thrombolysis, a platelet glycoprotein IIb/IIIa antagonist (abciximab) and percutaneous transluminal coronary angioplasty to help disrupt the thrombus was performed. Clinical and angiographic signs of coronary reperfusion were rapidly achieved. No bleeding complications appeared.

Influence of residual stenosis in determining restenosis after cutting balloon angioplasty.

The cutting balloon is a new device for coronary angioplasty, which, by the combination of incision and dilatation of the plaque, is believed to minimize arterial wall trauma, the neoproliferative response, and subsequent restenosis. In this study, we sought to determine predictors of the restenosis using this technique. Seventy-seven patients underwent successful coronary angioplasty with cutting balloon alone. In 67 of these patients (87%), we performed a control angiogram at 6-month follow-up. Pre-, post-, and late angiographic results were evaluated by quantitative coronary analysis. Clinical and angiographic variables were correlated with restenosis as a binary variable and a continuous variable (late loss and late minimum luminal diameter). Univariate analysis showed that the immediate postprocedure minimum luminal diameter (MLD) was smaller in the restenotic group (defined as MLD > 50% by quantitative coronary angiography) than in the nonrestenotic group (1.90 +/- 0.47 mm vs. 2.19 +/- 0.56 mm, P < 0.05). In addition, the immediate percentage of stenosis was higher in the restenotic group than in the nonrestenotic group (37% +/- 10% vs. 27% +/- 11%, P < 0. 003). Multivariate analysis identified the immediate postcutting balloon percentage of stenosis as an independent determinant of binary restenosis (P < 0.008). When restenosis was defined as a continuous variable, the immediate postprocedure MLD was an independent predictor of late loss (P < 0.02) and of late MLD (P < 0. 0002). No clinical, preprocedure angiographic, or technical variables tested were associated with restenosis. The degree of postprocedural residual stenosis after cutting balloon angioplasty is predictive of late restenosis.

Expanding subintimal coronary dissection under a stent-covered arterial segment: serial intravascular ultrasound observations.

A patient with an angiographically unrecognized minor coronary dissection in a stent-covered coronary segment in which a type D spiral dissection extended submedially to the distal artery is described. This complication occurred 6 months after stent implantation and was ascribed to injury of the stented vessel wall during an intravascular ultrasound study.

Significance of angiographic coronary dissection after cutting balloon angioplasty.

We studied 2 groups of patients with (n = 14) and without (n = 42) minor coronary dissections following cutting balloon angioplasty. Patients with a minor dissection had a longer length of lesion, higher percentage of stenosis, and greater acute gain after angioplasty; at 6-month follow-up both groups had a similar net gain and restenosis rate, suggesting that minor dissection after cutting balloon angioplasty has no influence on restenosis.

[Initial results with the Multi-Link coronary stent]. / Resultados iniciales con el stent coronario multi-link.

INTRODUCTION AND OBJECTIVES: The Multi-Link intracoronary stent is a balloon-expandable stainless steel stent with an interconnected ring structure designed to provide a high degree of compressive resistance while preserving longitudinal flexibility. We present the results of our initial experience with the implantation of this stent. PATIENTS AND METHODS: From May 1996 to April 1997, 124 Multi-link stents were implanted in 97 patients. Mean age 62.2 +/- 11 years. All patients included had a coronary artery diameter > 2.7 mm. Clinical presentation includes stable angina in 20, unstable angina in 72, and myocardial infarction in 5 patients. According to the ACC/AHA classification 6 lesions were type A, 72 type B and 19 type C. The implantation of the stent was for "de novo" lesions in 85 patients and for restenosis in 12. Patients were treated after the procedure with a combination of aspirin and ticlopidine, except six of them who received aspirin and acenocumarol. 16 patients were treated additionally with Abciximab. The degree of stenosis was determined by quantitative angiography. RESULTS: The delivery of the stent was successful in all patients. The degree of stenosis before the procedure was 79.6 +/- 13.1%, and after the stent deployment was 17.7 +/- 11.4%. Three patients presented a non-Q-wave myocardial infarction, two patients had a subacute stent thrombosis, one of them died due to heart failure. During a follow-up of 4.7 +/- 2.6 months five patients were readmitted with recurrent angina (4 due to restenosis and one for vessel occlusion) and one patient with heart failure after myocardial infarction died suddenly three weeks after the dilatation. CONCLUSIONS: The Multi-Link stent was implanted successfully in all patients with a low incidence of complications, showing at the follow-up a reduced rate of clinical restenosis.

[Coronary stent placement for recurrent angina secondary to myocardial bridging]. / Implantación de stent coronario por angina de pecho recurrente secundaria a puente muscular.

Myocardial bridging of the epicardic coronary arteries is not an uncommon finding in angiographic or necropsic studies. Patients who have symptoms usually improve with medical treatment. However, in refractory patients a surgical myotomy of overlying myocardium and/or a coronary bypass may be needed. We report two patients with long myocardial bridges in the mid-left anterior descending coronary artery, who had recurrent angina refractory to conventional treatment. In both patients two consecutive coronary stents were successfully implanted. At five and six months follow-up they are asymptomatic and with good exercise tolerance.

Assessment of the appropriateness of the decision of heart transplantation in idiopathic-dilated cardiomyopathy.

One hundred thirty patients with idiopathic-dilated cardiomyopathy were referred for heart transplantation to our center and followed for 18 months. Heart transplantation was performed on 63 patients, 17 patients died before transplantation due to heart failure, and 50 patients never had transplantation. Clinical, electrocardiographic, echocardiographic, and hemodynamic data of the 50 nontransplanted survivors and the 17 patients who died were used to identify independent risk variables with discriminant analysis. Using a statistical model based on the results of discriminant analysis, each of the remaining 63 transplanted patients were predicted as being alive or dead in absence of transplantation. The discriminant analysis identified right atrial pressure, cardiac index, and the New York Heart Association functional class as the strongest predictors of 18-month outcome. The accuracy of the model in predicting survival without transplantation in the nontransplanted group of patients, based on the concordance between actual and predicted outcome, was 85% (kappa = 0.62). Subsequent application of this model to the transplanted group of patients suggested that the decision for transplantation was appropriate in 41 of the 63 patients, and could have been premature in the remaining 22 patients predicted as alive. These results suggest that two-thirds of patients receiving transplants would have died without intervention, but the decision to transplant could have been premature in the remaining patients.