Psychosocial and biological predictors of resident physician burnout.

BACKGROUND: A high proportion of health professionals in training suffer from work-related stress and may develop a burnout syndrome. OBJECTIVES: To study the incidence of burnout after the first year of residency in a teaching hospital and to identify baseline psychological, psychosocial work conditions, and biological risk factors. METHODOLOGY: We assessed the following in a prospective cohort of residents at baseline (first month residence) and after 1 year: background factors (socio-demographics, psychiatric history), perceived stress score (Perceived Stress Scale), Maslach Burnout Inventory score, and psychosocial factors (Job Content Questionnaire). Blood samples were obtained to study serum cortisol, IL-6, and TNF-α concentrations. The cumulative incidence was modelled by multivariate log-binomial regression analysis. RESULTS: We included 71 participants with a female majority (64.8%), age 26.4 (2.65) years, psychiatric history in 20%, and burnout in 13%. Among those without burnout initially (N = 59), it had developed by 1 year in 22% of residents. Increased job demand (RR = 1.259, 95%CI = 1.019-1.556, p = 0.033) and decreased cortisol levels (RR = 0.877, 95%CI = 0.778-0.989, p = 0.032) predicted burnout after 1 year of residency among medical trainees. CONCLUSION: Burnout syndrome develops in 22% of residents by 1 year of training and can be predicted by increased work demands and decreased cortisol levels.

Low serum osteocalcin levels are associated with diabetes mellitus in glucocorticoid treated patients.

Bone turnover markers are decreased in GC-treated subjects with DM. Decreased OC levels in GC-treated patients were associated with an increased risk of DM. These results suggest the involvement of OC in glucose homeostasis regulation in DM. INTRODUCTION: Osteocalcin (OC) is involved in the regulation of glucose homeostasis. Glucocorticoid (GC) treatment is associated with impaired osteoblast function, decreased OC levels, and the development and/or worsening of pre-existing diabetes mellitus (DM). Whether decreased OC levels in GC-treated subjects contribute to DM is not well known. The aim of this study was to analyse whether OC levels in GC-treated patients are associated with the presence of DM. METHODS: One hundred twenty-seven patients (aged 61.5 ± 17.9 years) on GC treatment were included. GC dose, treatment duration, presence of DM and bone formation (OC, bone ALP, PINP) and resorption markers (urinary NTX, serum CTX) were analysed. The cut-offs of each bone turnover marker (BTM) for the presence of DM were evaluated and optimised with the Youden index and included in the logistic regression analysis. RESULTS: Among the patients, 17.3% presented DM. No differences were observed in GC dose or duration or the presence of fractures. Diabetics showed lower levels of OC (7.57 ± 1.01 vs. 11.56 ± 1; p < 0.001), PINP (21.48 ± 1.01 vs. 28.39 ± 1; p = 0.0048), NTX (24.91 ± 1.01 vs. 31.7 ± 1; p = 0.036) and CTX (0.2 ± 1.01 vs. 0.3 ± 1; p = 0.0016). The discriminating BTM cut-offs for DM presence were < 9.25 ng/mL for OC, < 24 ng/mL for PINP, < 27.5 nMol/mM for NTX and < 0.25 ng/mL for CTX. In a multivariate logistic regression model adjusted for GC dose, BMI, age and the above four BTMs, only OC remained independently associated with DM presence. Thus, in a model adjusted for GC dose, BMI and age, OC was significantly associated with DM (OR: 6.1; 95%CI 1.87-19.89; p = 0.001). CONCLUSION: Decreased OC levels in GC-treated patients are associated with increased odds of DM, and only OC was independently associated with DM in a model including four BTMs.

Development and internal validation of a novel PHI-nomogram to identify aggressive prostate cancer.

BACKGROUND: Prostate Health Index (PHI) is a new test for the detection of prostate cancer (PCa), which improves the performance of total PSA (tPSA) and is related to tumor aggressiveness. The aim of our study was to construct a nomogram based in a multivariate model incorporating PHI to estimate the individual probability of aggressive PCa. METHODS: 276 subjects selected for biopsy were enrolled in our study, including 151 patients with PCa. D'Amico criteria were used to classify these patients in three groups related to risk of progression. Intermediate and high-risk PCa were considered as aggressive PCa. Multivariable models to predict aggressive PCa were constructed using laboratory (tPSA, %fPSA, %p2PSA, PHI) and clinical variables. The best prediction model was graphically presented as a nomogram for clinical use. RESULTS: The highest accuracy (AUC: 0.815) was obtained for a multivariate model including age, digital rectal examination, tPSA, %fPSA, PHI and prostate volume. DCA was performed to confirm the usefulness of this nomogram, showing a higher net clinical benefit (greater than 7%) compared to the base model which included age, digital rectal examination and tPSA. CONCLUSION: PHI-based nomogram is a useful tool for the detection of aggressive PCa.

Cribado del cáncer de próstata mediante antígeno prostático específico: perspectiva del médico en atención primaria y en el laboratorio clínico / Prostate cancer screening using prostate-specific antigen: The views of general and laboratory physicians

Introducción: En el cribado de cáncer de próstata con antígeno prostático específico (PSA) se recomienda ofrecer información individualizada al paciente sobre el balance riesgos-beneficios y compartir la toma de decisiones. Objetivo: Explorar la práctica habitual y la percepción de los médicos de familia y los facultativos de laboratorio sobre el cribado del cáncer de próstata mediante PSA. Material y métodos: Estudio transversal basado en un cuestionario y en las solicitudes de PSA como cribado realizadas desde atención primaria (AP) a hombres mayores de 49 años. Resultados: En 2015, la AP catalana solicitó PSA como cribado oportunista al 15,2% de los hombres. En el cuestionario participaron 114 médicos de familia y 227 facultativos de laboratorio. El 64% fueron mujeres, con 43 años de edad media y 17 de experiencia profesional. Los médicos de familia consideraron que los pacientes inducían el 61% de las solicitudes de PSA. La incertidumbre al solicitar PSA fue de 5 puntos para los médicos de familia y de 5,7 para los del laboratorio. El interés en disponer de recomendaciones clínicas recibió 7,2 puntos en atención primaria y 8,8 en el laboratorio. El conocimiento sobre las diferentes guías de práctica clínica recibió, en global, menos de 5 puntos. Conclusiones: Desde AP se realizó cribado de casi la sexta parte de los hombres mayores de 49 años sin enfermedad prostática, frecuentemente a petición del paciente e informándole de beneficios y riesgos. Los médicos de AP y del laboratorio estaban interesados en disponer de recomendaciones e información, aunque no solían consultar las guías de práctica clínica

Introduction: It is currently recommended to provide individualised information on benefit-risk balance and shared decision-making in prostate cancer screening using prostate-specific antigen (PSA). Aim: To determine the usual practice and the views of general and laboratory practitioners in the screening of prostate cancer using PSA. Material and methods: A cross-sectional study based on a questionnaire and on PSA screening requests from Primary Health Care (PHC) in men older than 49 years with no prostatic symptoms. Results: In 2015, PHC in Catalonia requested PSA on 15.2% of males. A total of 114 general practitioners and 227 laboratory practitioners participated in the questionnaire. The mean age of those who responded was 43 years with a mean of 17 years' experience, and included 64% women. According to general practitioners, 61% of PSA was performed at the patient's request. The uncertainty score when requesting PSA was 5 points for general practitioners and 5.7 for laboratory professionals. Interest in having clinical recommendations received 7.2 points in PHC, and 8.8 in the laboratory. Knowledge about the different clinical practice guidelines received was less than 5 points overall. Conclusions: General practitioners requested PSA screening in almost one-sixth of men over the age of 49 without prostate disease, often at the patient's request, and after informing them of the benefits and risks. PHC and laboratory physicians were interested in having recommendations and information, although they did not usually consult clinical practice guidelines immediately

[Prostate cancer screening using prostate-specific antigen: The views of general and laboratory physicians]. / Cribado del cáncer de próstata mediante antígeno prostático específico: perspectiva del médico en atención primaria y en el laboratorio clínico.

INTRODUCTION: It is currently recommended to provide individualised information on benefit-risk balance and shared decision-making in prostate cancer screening using prostate-specific antigen (PSA). AIM: To determine the usual practice and the views of general and laboratory practitioners in the screening of prostate cancer using PSA. MATERIAL AND METHODS: A cross-sectional study based on a questionnaire and on PSA screening requests from Primary Health Care (PHC) in men older than 49 years with no prostatic symptoms. RESULTS: In 2015, PHC in Catalonia requested PSA on 15.2% of males. A total of 114 general practitioners and 227 laboratory practitioners participated in the questionnaire. The mean age of those who responded was 43 years with a mean of 17 years' experience, and included 64% women. According to general practitioners, 61% of PSA was performed at the patient's request. The uncertainty score when requesting PSA was 5 points for general practitioners and 5.7 for laboratory professionals. Interest in having clinical recommendations received 7.2 points in PHC, and 8.8 in the laboratory. Knowledge about the different clinical practice guidelines received was less than 5 points overall. CONCLUSIONS: General practitioners requested PSA screening in almost one-sixth of men over the age of 49 without prostate disease, often at the patient's request, and after informing them of the benefits and risks. PHC and laboratory physicians were interested in having recommendations and information, although they did not usually consult clinical practice guidelines immediately.

Comparison of total, free and bioavailable 25-OH vitamin D determinations to evaluate its biological activity in healthy adults: the LabOscat study.

Determination of different forms of 25-OHD (total, free and bioavailable) in healthy young women does not offer additional advantages over standard 25-OHDT for evaluating vitamin D deficiency. In these subjects 25-OHDT values <15 ng/ml would be more appropriate for defining this deficiency. INTRODUCTION: Determination of 25-OH vitamin D serum levels (25-OHD) constitutes the method of choice for evaluating vitamin D deficiency. However, vitamin D-binding protein (DBP) may modulate its bioavailability thereby affecting correct evaluation of 25-OHD status. We analysed the impact of the determination of 25-OHD (total, free and bioavailable) on the evaluation its biologic activity (estimated by serum PTH determination) in healthy young women. METHODS: 173 premenopausal women (aged 35-45 yrs.) were included. We analysed serum values of total 25-OHD (25-OHDT), DBP, albumin, PTH and bone formation (PINP,OC) and resorption (NTx,CTx) markers. Free(25-OHDF) and bioavailable (25-OHDB) serum 25-OHD levels were estimated by DBP and albumin determinations and also directly by ELISA (25-OHDF-2). We analysed threshold PTH values for the different forms of 25-OHD and the correlations and differences according to 25-OHDT levels <20 ng/ml. RESULTS: 62% of subjects had 25-OHD values <20 ng/ml and also had significantly lower 25-OHDF and 25-OHDB values, with no significant differences in bone markers and PTH values. The PTH threshold value was similar for all forms of 25-OHD (∼70 pg/ml). Women with PTH values >70 had lower 25-OHDT (15.4 ± 1.4 vs. 18.3 ± 2.7, p < 0.05) and 25OHDB values (1.7 ± 0.2 vs. 2.2 ± 0.09, p < 0.05). The different forms of 25OHD were significantly intercorrelated, with marginal correlations between PTH and 25-OHDT (r = -0.136, p = 0.082). CONCLUSIONS: Determination of different forms of 25-OHD in healthy young women does not offer additional advantages over standard 25-OHDT for evaluating vitamin D deficiency. In these subjects 25-OHDT values <15 ng/ml would be more appropriate for defining this deficiency.

The clinical value of biomarkers in respiratory complications in hematopoietic SCT.

To determine the role of biomarkers in the clinical management of respiratory complications (RC) in hematopoietic stem cell transplantation (HSCT) recipients, we have prospectively evaluated a cohort of 175 patients followed-up for 1 year after HSCT. To avoid misinterpretation, we have excluded both unidentified respiratory infections (RI) and mixed RI. A total of 64 RC were included. Plasma levels of C-reactive protein (CRP), procalcitonin (PCT) and proadrenomedullin (proADM) were measured at diagnosis and on day 3 and 7. Different cytokines were evaluated in serum on the first day. No HSCT recipients without RC were included as a control group. Compared with RI, non-infectious RC showed a significant increase in CRP, proADM and interleukin 6 on day 0 (P=0.005; P=0.03 and P=0.04, respectively). When only RI were considered, we observed that bacterial-fungal PI showed higher levels of CRP (P=0.02), PCT (P=0.04) and proADM (P<0.01). Persistent low levels of proADM biomarkers suggest viral infection (specificity and positive predictive value 100%). Patients dying of RC had PCT and proADM levels higher than survivors (P=0.002 and P=0.03, respectively). In HSCT recipients biomarkers increase in both infectious and non-infectious RC. They may have utility in the assessment of the severity of RC and in suspecting a viral etiology.

Factores relacionados con la respuesta inadecuada al tratamiento osteoformador (teriparatida/PTH 1-84) en pacientes con osteoporosis severa. Resultados preliminares / Factors related to bone forming inadequate response to treatment (teriparatide/PTH 1-84) in patients with severe osteoporosis. Preliminary results

El objetivo de este estudio ha sido analizar la evolución de la masa ósea a largo plazo tras tratamiento osteoformador (teriparatida o PTH 1-84) en pacientes con osteoporosis severa, y determinar la frecuencia y los factores relacionados con una respuesta inadecuada (RI) al tratamiento. Métodos: Se incluyeron 49 pacientes (46 mujeres:3 hombres) con una edad media de 69,5±11,1 años, tratados con teriparatida (41) o PTH1-84 (8) durante 18/24 meses (84% tenían fracturas vertebrales y 84% habían recibido tratamiento previamente). Se analizaron: factores de riesgo y causa de osteoporosis, fracturas y tratamiento antiosteoporótico previo. Se valoraron los marcadores de recambio óseo (MRO), los niveles de 25-OH vitamina D (25OHD) basal y a los 3, 6, 12 y 18/24 meses, radiografías de columna dorso-lumbar y densitometría ósea (DMO) previa, a los 12 y 18/24 meses. Se definió RI cuando el cambio de DMO lumbar era (AU)

The aim of this study was to evaluate the long-term bone mineral density (BMD) response rate to osteoanabolic treatment in patients with severe osteoporosis and the factors related to 'inadequate' response (IR). Methods: 49 patients (46F:3M) with a mean age of 69.5±11.1 years treated with teriparatide (41) or PTH1-84 (8) during 18/24months were included (84% had vertebral fractures and 84% had previously received bisphosphonates). Previous skeletal fractures and antiosteoporotic treatment, risk factors and cause of osteoporosis were recorded in all patients. Bone turnover markers (BTM) and 25-OH vitamin D (25OHD) levels were assessed before and at 3, 6, 12 and 18/24 months. Lumbar and femoral BMD and spinal X-ray were assessed at baseline and at 12 and 18/24 months. IR was defined by a lumbar BMD change (AU)

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.

Effect of glucocorticoid treatment on Wnt signalling antagonists (sclerostin and Dkk-1) and their relationship with bone turnover.

The aim of this study was to analyse the effect of glucocorticoid therapy (GCCT) on Wnt signalling antagonists (sclerostin and Dkk-1) and their relationship with bone turnover. 25 patients (8 M/17 F, aged 48±19yrs) recently initiating GCCT (≥7.5mg/day, ≤6months) were prospectively included. Bone turnover markers (bone formation: P1NP, osteocalcin [OC], bone ALP; bone resorption: sCTx) and Wnt antagonists (serum sclerostin and Dkk-1) were assessed in all patients (short-term and 12months after initiating GCCT). Bone mineral density (BMD) was performed to assess osteoporosis. The results were compared with 60 healthy controls. At short-term patients on GCCT showed a significant decrease in bone formation markers versus controls (P1NP: 19±9 vs. 43±16ng/mL, p<0.001; OC: 7.4±2.4 vs. 18.4±5.2ng/mL, p=0.001) and in Dkk-1 levels (24.5±20.1 vs. 36.8±13.7pmol/L, p=0.008) with similar sclerostin values (41.8±21.8 vs. 42.1±13.9pmol/L, p=0.950). Sclerostin correlated positively with GCCT doses (r=0.449, p=0.024) and lumbar BMD (r=0.424, p=0.035), and negatively with bone ALP (r=-0.398, p=0.049). A progressive decrease in Dkk-1 levels was observed at 12months, (19.1±14.9, p=0.001), whereas sclerostin increased compared to controls (48.9±11.6, p=0.045). In conclusion, the effect of GCCT on the serum levels of the Wnt signalling parameters differs depending on the antagonist evaluated. Whereas sclerostin values increased and showed a relationship with the dose and bone AP, Dkk-1 levels decreased throughout the study suggesting a counter-regulatory mechanism of this factor thereby reducing the deleterious effect of GCCT in the bone.

Factors associated with inflammatory cytokine patterns in community-acquired pneumonia.

Raised systemic levels of interleukin (IL)-6 and IL-10 cytokines have been associated with poorer outcome in community-acquired pneumonia. The aim of our study was to identify potential associated factors with increased levels of IL-6, IL-10, or both cytokines. We performed a prospective study of 685 patients admitted to hospital with community-acquired pneumonia. IL-6 and IL-10 were measured in blood in the first 24 h. 30-day mortality increased from 4.8% to 11.4% (p = 0.003) when both cytokines were higher than the median. Independent associated factors with an excess of IL-6 were neurologic disease, confusion, serum sodium < 130 mEq·L⁻¹, pleural effusion, and bacteraemia. The associated factors for an excess of IL-10 were respiratory rate ≥ 30 breaths·min⁻¹, systolic blood pressure < 90 mmHg and glycaemia ≥ 250 mg·dL⁻¹. The independent associated factors for an excess of both cytokines were confusion, systolic blood pressure < 90 mmHg, pleural effusion and bacteraemia. Protective factors were prior antibiotic treatment and pneumococcal vaccination. Different independent factors are related to an excess of IL-6 and IL-10. Confusion, hypotension, pleural effusion and bacteraemia were associated with the inflammatory profile with the highest mortality rate, whereas anti-pneumococcal vaccination and previous antibiotic treatment appeared to be protective factors.

Stability in community-acquired pneumonia: one step forward with markers?

BACKGROUND: Biological markers as an expression of systemic inflammation have been recognised as useful for evaluating the host response in community-acquired pneumonia (CAP). The objective of this study was to evaluate whether the biological markers procalcitonin (PCT) and C-reactive protein (CRP) might reflect stability after 72 h of treatment and the absence of subsequent severe complications. METHODS: A prospective cohort study was performed in 394 hospitalised patients with CAP. Clinical stability was evaluated using modified Halm's criteria: temperature or=90 mm Hg; oxygen saturation >or=90%; or arterial oxygen tension >or=60 mm Hg. PCT and CRP levels were measured on day 1 and after 72 h. Severe complications were defined as mechanical ventilation, shock and/or intensive care unit (ICU) admission, or death after 72 h of treatment. RESULTS: 220 patients achieved clinical stability at 72 h and had significantly lower levels of CRP (4.2 vs 7 mg/dl) and of PCT (0.33 vs 0.48 ng/ml). Regression logistic analyses were performed to calculate several areas under the ROC curve (AUC) to predict severe complications. The AUC for clinical stability was 0.77, 0.84 when CRP was added (p = 0.059) and 0.77 when PCT was added (p = 0.45). When clinical stability was achieved within 72 h and marker levels were below the cut-off points (0.25 ng/ml for PCT and 3 mg/dl for CRP), no severe complications occurred. CONCLUSIONS: Low levels of CRP and PCT at 72 h in addition to clinical criteria might improve the prediction of absence of severe complications.

Cervical length and gestational age at admission as predictors of intra-amniotic inflammation in preterm labor with intact membranes.

OBJECTIVES: To evaluate cervical length and gestational age as predictors of intra-amniotic inflammation in patients admitted because of preterm labor and intact membranes. METHODS: Ninety-three pregnant women with preterm labor and intact membranes were included in our study. Cervical length was measured on admission by transvaginal sonography and transabdominal amniocentesis was performed within the first 48 h following admission. Positive amniotic fluid cultures defined intra-amniotic infection. Levels of intra-amniotic interleukin-6 (IL-6) were measured, and a receiver-operating characteristics (ROC) curve was constructed to determine the best cut-off point of IL-6 for predicting intra-amniotic infection. This value was then used as a basis for determining a cut-off of IL-6 for defining intra-amniotic inflammation. Considering inflammatory status, perinatal outcomes were evaluated and compared. Logistic regression was used to investigate associations of different explanatory variables with inflammatory status. A non-invasive approach for detection of intra-amniotic inflammation in women admitted because of preterm labor with intact membranes was evaluated. RESULTS: Intra-amniotic infection and inflammation rates were 14% and 28%, respectively. ROC curve analysis showed that the best cut-off value for IL-6 was 13.4 ng/mL for predicting intra-amniotic infection, which was comparable to the cut-off of 11.3 ng/mL reported previously by other authors (which we used to define inflammation). Regardless of the intra-amniotic microbial status, perinatal outcomes in women who developed intra-amniotic inflammation were worse than in those who did not. Cervical length < 15 mm and gestational age at admission < 28 weeks were independently associated with intra-amniotic inflammation. A strategy considering these two non-invasive parameters (either women admitted < 28 weeks or women admitted between >or= 28 and < 32 weeks with a cervical length < 15 mm) could detect 84.0% of women with intra-amniotic inflammation with a positive predictive value of 48.8%, providing improved diagnostic indices compared to either variable considered alone. CONCLUSIONS: Cervical length and gestational age at admission can be used as a non-invasive method to assess the risk of intra-amniotic inflammation in preterm labor and intact membranes.

Biomarkers improve mortality prediction by prognostic scales in community-acquired pneumonia.

BACKGROUND: Prognostic scales provide a useful tool to predict mortality in community-acquired pneumonia (CAP). However, the inflammatory response of the host, crucial in resolution and outcome, is not included in the prognostic scales. METHODS: The aim of this study was to investigate whether information about the initial inflammatory cytokine profile and markers increases the accuracy of prognostic scales to predict 30-day mortality. To this aim, a prospective cohort study in two tertiary care hospitals was designed. Procalcitonin (PCT), C-reactive protein (CRP) and the systemic cytokines tumour necrosis factor alpha (TNFalpha) and interleukins IL6, IL8 and IL10 were measured at admission. Initial severity was assessed by PSI (Pneumonia Severity Index), CURB65 (Confusion, Urea nitrogen, Respiratory rate, Blood pressure, > or = 65 years of age) and CRB65 (Confusion, Respiratory rate, Blood pressure, > or = 65 years of age) scales. A total of 453 hospitalised CAP patients were included. RESULTS: The 36 patients who died (7.8%) had significantly increased levels of IL6, IL8, PCT and CRP. In regression logistic analyses, high levels of CRP and IL6 showed an independent predictive value for predicting 30-day mortality, after adjustment for prognostic scales. Adding CRP to PSI significantly increased the area under the receiver operating characteristic curve (AUC) from 0.80 to 0.85, that of CURB65 from 0.82 to 0.85 and that of CRB65 from 0.79 to 0.85. Adding IL6 or PCT values to CRP did not significantly increase the AUC of any scale. When using two scales (PSI and CURB65/CRB65) and CRP simultaneously the AUC was 0.88. CONCLUSIONS: Adding CRP levels to PSI, CURB65 and CRB65 scales improves the 30-day mortality prediction. The highest predictive value is reached with a combination of two scales and CRP. Further validation of that improvement is needed.

Markers of treatment failure in hospitalised community acquired pneumonia.

BACKGROUND: Lack of response to treatment in community acquired pneumonia (CAP) worsens outcome. We evaluated the systemic cytokine profile (tumour necrosis factor alpha, interleukin (IL)1, IL6, IL8 and IL10), C reactive protein (CRP) and procalcitonin (PCT) in patients with CAP who had treatment failure. METHODS: A prospective study was performed in hospitalised patients with CAP. Cytokines, PCT and CRP measurements were obtained on day 1 and after 72 h of treatment. Treatment failure was the endpoint evaluated, with separation of those with early (< or = 72 h) or late failure. RESULTS: 453 patients were included: 84 (18%) had treatment failure, of whom 38 (8%) were early failures. Median levels of IL6, PCT and CRP on days 1 and 3 and median levels of IL8 on day 1 were significantly higher in patients with any treatment failure. Logistic regression analysis demonstrated that values above the cut-off points for IL6 (> or = 169 pg/ml), IL8 (> or = 14 pg/ml) and CRP (> or = 21.9 mg/dl) on day 1 had independent predictive value for any treatment failure after adjustment for initial severity; relative risks (OR) found were 1.9, 2.2 and 2.6, respectively. Increased levels for CRP and PCT on day 1 were also independent predictors for early failure. Increased levels for IL6 and CRP were the best predictors of late failure. CONCLUSIONS: Serum levels of CRP, IL6 and PCT on days 1 and 3 were independently associated with a higher risk of any treatment failure. Low levels of PCT and CRP on day 1 had a high negative predictive value for early failure.

Serum HER2 extracellular domain predicts an aggressive clinical outcome and biological PSA response in hormone-independent prostate cancer patients treated with docetaxel.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) overexpression has been linked to hormone-independent prostate cancer (HIPC) progression. Its clinical value and correlation with therapy is not defined. PATIENTS AND METHODS: Patients with HIPC treated with docetaxel (Taxotere) were prospectively tested for serum HER2 extracellular domain (ECD) by immunoanalysis. HER2 was determined by immunohistochemistry and fluorescence in situ hybridization (FISH) in tumor samples. RESULTS: Sixty-nine patients were included. Twenty-four (34.8%) patients had high HER2 ECD (>15 ng/ml). Prostate-specific antigen (PSA) response was 58% for patients with low HER2 ECD and 36% for patients with high HER2 ECD (P = 0.046). HER2 ECD levels were an independent prognostic factor for time to PSA progression [hazard ratio (HR) 2.82; 95% confidence interval (CI) 1.22-6.50; P = 0.015] and overall survival (HR 3.24; 95% CI 1.38-7.59; P = 0.007). Tissue samples from 17 patients were tested for HER2. Patients with negative HER2 tissue expression had lower HER2 ECD levels (median 10.5 +/- 2.7 versus 30.5 +/- 24.8 ng/ml; P = 0.016). FISH was negative in all samples. CONCLUSIONS: High HER2 ECD levels in serum are associated with a worst clinical outcome of HIPC patients treated with docetaxel.

TH1/TH2 cytokine release pattern during in vivo cytomegalovirus disease in solid organ transplantation.

BACKGROUND: Cytomegalovirus (CMV) disease is associated with an increased net immunosuppressive state in solid organ transplant recipients, leading to more bacterial and fungal infections. The release of pro- and anti-inflammatory cytokines could be one of the responsible factors. METHODS: We prospectively included all patients undergoing solid organ transplantation between April and November 2004. During follow-up, plasma samples were collected in the immediate postsurgical period, at the first and second months, at the time of maximum antigenemia during CMV disease, and at 6 months posttransplantation. We determine the levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10. Log-transformed data were compared by a nonparametric Wilcoxon test for related variables. RESULTS: During the study period, we monitored 146 recipients of solid organ transplantation: 77 kidneys, 8 kidney-pancreas, 46 liver, 11 heart, 2 liver-kidney, and 2 heart-kidney. No differences were observed between the TNF-alpha and IL-10 levels in the immediate postsurgical period or during CMV disease. TNF-alpha and IL-10 levels during CMV disease were higher than levels during the first month (mean TNF-alpha first month = 12.71 pg/mL vs CMV disease = 22.71 pg/mL, P = .028; mean IL-10 first month = 3.47 pg/mL vs CMV disease = 19.2 pg/mL, P = .018). Th1/Th2 ratio (measured as TNF-alpha/IL-10) was 1.75 in the immediate postsurgical period, 7.5 during the first month, 1.86 at the time of CMV disease, and 4.61 at the sixth month. The difference in Th1/Th2 ratio during CMV disease and in the first month was statistically significant (P = .043). CONCLUSION: During CMV disease, we observed an increase in TNF-alpha and IL-10 release, which was similar to that during the postsurgical period. An imbalance toward an anti-inflammatory pattern was noted in these two periods. This could reflect a cooperative factor increasing the net state of immunosuppression during CMV disease.

Vascular endothelial growth factor serum concentrations in hypercholesterolemic patients.

OBJECTIVE: Vascular endothelial growth factor (VEGF) promotes normal and pathological angiogenesis. VEGF is a chemotactic factor for macrophages and vascular smooth muscle cells, and induces synthesis of metalloproteinases and adhesion molecules. VEGF expression is regulated by hypoxia, cytokines, oncogenes, and oxidized low-density lipoprotein (LDL). The purpose of this study was to determine the relationship between levels of lipid parameters and VEGF, to investigate whether pravastatin treatment influences VEGF serum concentrations, and to examine the relationship between VEGF and the variations in post-treatment lipid and inflammatory parameters. MATERIAL AND METHODS: Eighteen patients aged 48+/-6.8 years with total cholesterol (TC) >6.1 mmol/L comprised the hypercholesterolemic group. The controls included 12 individuals aged 50+/-7.4 years with TC <5.1 mmol/L. TC, high-density lipoprotein cholesterol (HDLC), triglycerides, LDLC, C-reactive protein (CRP), and VEGF were determined in both groups at baseline, and in the hypercholesterolemic group after 4 months of treatment with 20 mg/day pravastatin. RESULTS: A significant correlation was observed between concentrations of VEGF and TC, LDLC and TG, and a significant difference in VEGF concentration was observed between the control group (mean 142 ng/L) and the hypercholesterolemic group (mean 272.9 ng/L). A significant decrease was observed in TC (14.7 %), LDLC (21.5 %), CRP (22.7 %), and VEGF (14.8 %) after 4 months of treatment with pravastatin. CONCLUSIONS: A relationship was found between serum levels of VEGF and most atherogenic lipoproteins. In patients with hypercholesterolemia treated with pravastatin, a reduction in VEGF and CRP was seen in addition to lipid decreases.

Prospective evaluation of procalcitonin in adults with non-neutropenic fever after allogeneic hematopoietic stem cell transplantation.

The aim of this study was to analyze whether procalcitonin (PCT) is a diagnostic marker of infectious diseases during the non-neutropenic period in patients who have received an allogeneic hematopoietic stem cell transplant (HSCT). We included 65 patients in whom an allogeneic HSCT was performed in a 2-year period (April 2002-July 2004). PCT levels were monitored in every febrile episode by an immunoluminometric assay. Febrile episodes were classified according to the final diagnosis in: fever of unknown origin, microbiologically or clinically documented infection and non-infectious fever. Fifty-two febrile episodes in the non-neutropenic period were included in the study. Out of these 52, 26 had an infectious etiology: 11 fulfilled criteria for probable or proven invasive aspergillosis (IA), three were classified as possible invasive fungal infection (IFI) and 12 episodes were caused by other infections. Mean values of PCT on the first day of admission were: 8.0 (+/- 4.9) in probable-proven IA (P = 0.013, Kruskall-Wallis), 4.5 (+/- 3.4) in possible IFI and 1.5 (+/- 0.9) in infections other than IFI. Therefore, we could conclude that during the non-neutropenic phases of allogeneic HSCT, a high PCT value is associated significantly with IA.

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.