Early prediction of endocrine responsiveness in ER+/HER2-negative metastatic breast cancer (MBC): pilot study with 18F-fluoroestradiol (18F-FES) CT/PET.

BACKGROUND: 18F-fluoroestradiol (FES) positron emission tomography (PET)/computed tomography (CT) is considered an accurate diagnostic tool to determine whole-body endocrine responsiveness. In the endocrine therapy (ET)-FES trial, we evaluated 18F-FES PET/CT as a predictive tool in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). PATIENTS AND METHODS: Eligible patients underwent an 18F-FES PET/CT at baseline. Patients with standardized uptake value (SUV) ≥ 2 received single-agent ET until progressive disease; patients with SUV < 2 were randomized to single-agent ET (arm A) or chemotherapy (ChT) (arm B). The primary objective was to compare the activity of first-line ET versus ChT in patients with 18F-FES SUV < 2. RESULTS: Overall, 147 patients were enrolled; 117 presented with 18F-FES SUV ≥ 2 and received ET; 30 patients with SUV < 2 were randomized to ET or ChT. After a median follow-up of 62.4 months, 104 patients (73.2%) had disease progression and 53 died (37.3%). Median progression-free survival (PFS) was 12.4 months [95% confidence interval (CI) 3.1-59.6 months] in patients with SUV < 2 randomized to arm A versus 23.0 months (95% CI 7.7-30.0 months) in arm B, [hazard (HR) = 0.71, 95% CI 0.3-1.7 months]; median PFS was 18.0 months (95% CI 11.2-23.1 months) in patients with SUV ≥ 2 treated with ET. Median overall survival (OS) was 28.2 months (95% CI 14.2 months-not estimable) in patients with SUV < 2 randomized to ET (arm A) versus 52.8 months (95% CI 16.2 months-not estimable) in arm B (ChT). Median OS was not reached in patients with SUV ≥ 2. 60-month OS rate was 41.6% (95% CI 10.4% to 71.1%) in arm A, 42.0% (95% CI 14.0% to 68.2%) in arm B, and 59.6% (95% CI 48.6% to 69.0%) in patients with SUV ≥ 2. In patients with SUV ≥ 2, 60-month OS rate was 72.6% if treated with aromatase inhibitors (AIs) versus 40.6% in case of fulvestrant or tamoxifen (P < 0.005). CONCLUSIONS: The ET-FES trial demonstrated that ER+/HER2- MBC patients are a heterogeneous population, with different levels of endocrine responsiveness based on 18F-FES CT/PET SUV.

Multimorbidity, polypharmacy, and drug-drug-gene interactions following a non-ST elevation acute coronary syndrome: analysis of a multicentre observational study.

BACKGROUND: The number of patients living with co-existing diseases is growing. This study aimed to assess the extent of multimorbidity, medication use, and drug- and gene-based interactions in patients following a non-ST elevation acute coronary syndrome (NSTE-ACS). METHODS: In 1456 patients discharged from hospital for a NSTE-ACS, comorbidities and multimorbidity (≥ 2 chronic conditions) were assessed. Of these, 698 had complete drug use recorded at discharge, and 652 (the 'interaction' cohort) had drug use and actionable genotypes available for CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, F5, SLCO1B1, TPMT, UGT1A1, and VKORC1. The following drug interactions were investigated: pharmacokinetic drug-drug (DDIs) involving CYPs (CYPs above, plus CYP1A2, CYP2C8, CYP3A4), SLCO1B1, and P-glycoprotein; drug-gene (DGIs); drug-drug-gene (DDGIs); and drug-gene-gene (DGGIs). Interactions predicted to be 'substantial' were defined as follows: DDIs due to strong inhibitors/inducers, DGIs due to variant homozygous/compound heterozygous genotypes, and DDGIs/DGGIs where the constituent DDI/DGI(s) both influenced the victim drug in the same direction. RESULTS: In the whole cohort, 727 (49.9%) patients had multimorbidity. Non-linear relationships between age and increasing comorbidities and decreasing coronary intervention were observed. There were 98.1% and 39.8% patients on ≥ 5 and ≥ 10 drugs, respectively (from n = 698); women received more non-cardiovascular drugs than men (median (IQR) 3 (1-5) vs 2 (1-4), p = 0.014). Overall, 98.7% patients had at least one actionable genotype. Within the interaction cohort, 882 interactions were identified in 503 patients (77.1%), of which 346 in 252 patients (38.7%) were substantial: 59.2%, 11.6%, 26.3%, and 2.9% substantial interactions were DDIs, DGIs, DDGIs, and DGGIs, respectively. CYP2C19 (49.5% of all interactions) and SLCO1B1 (18.4%) were involved in the largest number of interactions. Multimorbidity (p = 0.019) and number of drugs (p = 9.8 × 10-10) were both associated with patients having ≥ 1 substantial interaction. Multimorbidity (HR 1.76, 95% CI 1.10-2.82, p = 0.019), number of drugs (HR 1.10, 95% CI 1.04-1.16, p = 1.2 × 10-3), and age (HR 1.05, 95% CI 1.03-1.07, p = 8.9 × 10-7), but not drug interactions, were associated with increased subsequent major adverse cardiovascular events. CONCLUSIONS: Multimorbidity, polypharmacy, and drug interactions are common after a NSTE-ACS. Replication of results is required; however, the high prevalence of DDGIs suggests integrating co-medications with genetic data will improve medicines optimisation.

Hospital admission for complicated diverticulitis is increasing in Italy, especially in younger patients: a national database study.

BACKGROUND: Epidemiological studies show an increasing trend of hospitalization for acute diverticulitis (AD), but data regarding the trend in hospitalization for complicated AD in Italy are scarce. The aim of this study was to analyze the Italian trend in hospitalization for complicated AD, from 2008 to 2015. METHODS: Using the Italian Hospital Information System, we identified all patients with complicated colonic AD as a discharge diagnosis. Age- and sex-specific rates for AD as well as type of hospital admission (emergency/elective), type of complication (peritonitis, obstruction, bleeding, abscess, fistula, perforation, sepsis) and type of treatment (medical/surgical), were analyzed. RESULTS: A total of 41,622 patients with a discharge diagnosis of complicated AD were identified. Over the study period the admission rate grew from 8.8 to 11.8 per 100,000 inhabitants. The hospitalization rate was highest for patients ≥ 70 years, but the increase in the admission rate was higher among patients aged ≤ 60 years. There were more males in the group < 60 years and more females in the group ≥ 60 years old. The rate of emergency admissions associated with surgery showed a significant mean annual increase (+ 3.9% per year) in the rate of emergency admissions associated with surgery, whereas elective admissions for surgery remained stable. Peritonitis was the most frequent complication (35.5%). The rate of surgery increased in AD complicated by peritonitis (+ 5.1% per year), abscess (+ 5.8% per year) and decreased for obstruction (- 1.8% per year). CONCLUSIONS: From 2008 to 2015, we documented an increasing rate of hospitalization for complicated AD, especially for younger patients, with an increase in surgery for peritonitis and abscess. Further studies are needed to clearly assess the risk factors for complications and risk of surgery.

Serum allergen-specific IgE, allergic rhinitis severity, and age.

BACKGROUND: Allergic rhinitis (AR) is characterized by an IgE-mediated reaction. Aging usually induces a progressive decline of immune system function. There is common belief that both allergic symptoms severity and serum IgE production decline during aging. OBJECTIVE: This study aimed to evaluate the possible impact of age on: i) serum allergen-specific IgE levels in a large sample of subjects, and ii) AR symptom severity in a group of mono-allergic patients. METHODS: Serum allergen-specific IgE to birch, Bet v 1, Parietaria, and Dermatophagoides pteronyssinus were measured by immunofluorometric assay (IFMA) in a sample of 8098 subjects. AR symptom severity was assessed by visual analogue scale (VAS) in a sub-group of 531 mono-allergic patients. RESULTS: The analysis of variance showed that IgE to Bet v 1, birch, and Dermatophagoides pteronyssinus significantly decreased considering the age, whereas IgE to Parietaria did not significantly decline in respect of the age. Considering the global sample of mono-allergic patients, elderly subjects (over 65 years old) tended to have lower IgE levels, but had significantly lower VAS rating, and significantly less sensitizations than adult subjects (18-65 years old). In both adult and elderly patients VAS strongly correlated with IgE values. CONCLUSIONS: Allergen-specific IgE levels tend to reduce with aging, but with differences between types of allergy. The IgE decrease is usually associated with reduced AR symptom severity. Elderly AR patients seem to have a different phenotype/endotype in comparison with adult AR ones, characterized by milder symptoms, lower IgE production, and less sensitizations. However, a close positive relationship between IgE values and VAS scores is shared by both adult and elderly AR patients, confirming the close link between allergy and symptoms that persists also in the elderly.

Efficacy of safety catheter devices in the prevention of occupational needlestick injuries: applied research in the Liguria Region (Italy).

Healthcare workers who use or may be exposed to needles are at risk of needlestick injuries, which can lead to serious infections by bloodborne pathogens. These injuries can be avoided by eliminating the unnecessary use of needles and using safety devices. The present study was aimed at evaluating the impact of a safety-engineered device, with passive fully automatic needlestick protection, on the rate of needlestick injuries among healthcare workers. The setting of the study was a network of five public healthcare institutions situated in a Northern Italian Region. Data on the type of device, the number of employees and the number of catheter devices used per year were collected through regular meetings with healthcare workers over a period of five years. The most notable result of this study was the huge risk reduction associated with safety devices. Indeed, the risk of needlestick injuries due to conventional devices was found to be 25-fold higher than that observed for safety devices. However, it is noteworthy that a considerable part of this excess can be explained by the different background number of devices used. Moreover, descriptive analysis suggested that individuals with a poor/moderate training level had a lower risk than those with good/high training, though the difference was not statistically significant. In conclusion, there is convincing evidence of a causal connection between the introduction of safety devices and the reduction in needlestick injuries. This consideration should prompt the introduction of safety devices into daily clinical practice.

Polymorphisms in VEGFA gene affect the antihypertensive responses to enalapril.

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that affects blood pressure by promoting vasodilation mediated by nitric oxide. Angiotensin-converting enzyme inhibitors (ACEi) up-regulate the VEGF expression; thus, genetic polymorphisms in the VEGFA gene could affect the antihypertensive responses to these drugs. METHODS: Hypertensive patients (n = 102) were prospectively treated only with the ACEi enalapril for 60 days. We compared the effect of VEGFA polymorphisms on changes in blood pressure after enalapril treatment. In addition, multiple linear regression analysis was carried out to assess the effect of covariates on blood pressure. Genotypes for g.-2578C>A (rs699947), g.-1154G>A (rs1570360), and g.-634G>C (rs2010963) VEGFA polymorphisms were determined, and haplotype frequencies were estimated. RESULTS: Individuals carrying the CA and AA genotypes for the g.-2578C>A polymorphism and the AGG haplotype showed more intense decrease in blood pressure in response to enalapril 20 mg/day. A multiple linear regression analysis showed that the AA genotype for the g.-2578C>A polymorphism and the AGG haplotype are associated with more intense decrease in blood pressure in response to enalapril 20 mg/day, while the CC genotype for the g.-2578C>A polymorphism and the CGG haplotype are associated with the opposite effect. CONCLUSIONS: These findings suggest that polymorphisms in VEGFA gene may affect the antihypertensive responses to enalapril.

eNOS and BDKRB2 genotypes affect the antihypertensive responses to enalapril.

PURPOSE: The antihypertensive effect of angiotensin-converting enzyme inhibitors (ACEi) is attributed partially to increased nitric oxide bioavailability. It is possible that functional polymorphisms in endothelial nitric oxide synthase (eNOS) and bradykinin receptor B2 (BDKRB2) genes may affect the antihypertensive response to enalapril. METHODS: We evaluated 106 hypertensive patients treated only with enalapril for 60 days. The difference between the mean arterial pressure (MAP) before and after the antihypertensive treatment was defined as ΔMAP. If ΔMAP were below or above the median value, the patients were classified as poor responders (PR) or good responders (GR), respectively. eNOS genotypes for the T(-786)C, G894T and 4b/4a polymorphisms were determined and haplotype frequencies were estimated by PHASE and Haplo.stats programs. The C(-58)T and BE1 +9/-9 polymorphisms of BDKRB2 genes and their haplotypes were determined by DNA sequencing. Robust multifactor dimensionality reduction analysis was used to characterize gene-gene interactions. RESULTS: The TC/CC genotypes and the C allele for the eNOS T(-786)C polymorphism were more frequent in GR than in PR. Furthermore, the TT genotype for the BDKRB2 C(-58)T polymorphism was more frequent in PR than GR. No other significant differences in genotypes or haplotypes were found. However, we found significant gene-gene interactions: the CC genotype for the BDKRB2 C(-58)T polymorphism was associated with response to enalapril depending on eNOS T(-786)C genotypes. CONCLUSIONS: These findings suggest that eNOS T(-786)C and BDKRB2 C(-58)T polymorphisms may synergically affect the antihypertensive response to enalapril.

The predictive and prognostic role of single nucleotide gene variants of PD-1 and PD-L1 in patients with advanced melanoma treated with PD-1 inhibitors.

Background: Despite having revolutionized the treatment paradigm for advanced melanoma, not all patients benefit from immune checkpoint inhibitor therapy. To date, there are no predictive biomarkers for response or the occurrence of immune-related adverse events (irAEs) to programmed cell death protein 1 (PD-1) inhibitors. Our aim was to investigate the predictive and prognostic role of single nucleotide variants (SNVs) of genes involved in the PD-1 axis. Methods: We analysed, in metastatic melanoma patients treated with nivolumab or pembrolizumab, five PD-1 SNVs, namely PD1.3 G>A (rs11568821), PD1.5 C>T (rs2227981), PD1.6 G>A (rs10204525), PD1.7 T>C(rs7421861), PD1.10 C>G (rs5582977) and three programmed death-ligand 1 (PD-L1) SNVs: +8293 C>A (rs2890658), PD-L1 C>T (rs2297136) and PD-L1 G>C (rs4143815). Association of SNV genotypic frequencies with best overall response to PD-1 inhibitors and development of irAEs were estimated through a modified Poisson regression. A Cox regression modelling approach was applied to evaluate the SNV association with OS. Results: A total of 125 patients with advanced melanoma were included in the analysis. A reduction in irAEs risk was observed in patients carrying the PD-L1 +8293 C/A genotype compared with those carrying the C/C genotype (risk ratio = 0.45; 95% CL 0.22-0.93; P = 0.031). A trend for a reduction in irAEs was also observed with the PD1.5 T allele (risk ratio = 0.70, 95% confidence limits 0.48-1.01 versus C allele). None of the SNVs was associated with response to therapy. Finally, a survival benefit was observed in patients harbouring the PD1.7 C/C genotype (hazard ratio = 0.37; 95% confidence limits 0.14-0.96; P = 0.028) in the homozygous model. Conclusions: Our study showed that PD-1.5 and PD-L1 +8293 SNVs may play a role as a predictive biomarker of development of irAEs to PD-1 inhibitors. PD1.7 SNV may also be associated with a reduction of the risk of death, although further translational research is needed to confirm these results.

[The role of the intensive care unit after thoracic surgery]. / Place de la réanimation après chirurgie thoracique.

Lung (bronchial) cancer is the leading cause of cancer-related death in Western countries today. Thoracic surgery represents a major therapeutic strategy and the various advances made in recent years have made it possible to develop less and less invasive techniques. That said, the postoperative period may be lengthy, post-surgical approaches need to be more precisely codified, and it matters that the different interventions involved be supported by sound scientific evidence. To date, however, there exists no evidence that preventive postoperative admission to intensive care is beneficial for patients having undergone lung resection surgery without immediate complications. A stratification of the risk of complications taking into consideration the patient's general state of health (e.g., nutritional status, degree of autonomy, etc.), comorbidities and type of surgery could be a useful predictive tool regarding the need for postoperative intensive care. However, serious post-operative complications remain relatively frequent and post-operative management of these intensive care patients is liable to become complex and long-lasting. In the aftermath of the validation of "enhanced recovery after surgery" (ERAS) in thoracic surgery, new protocols are needed to optimize management of patients having undergone pulmonary resection. This article focuses on the main postoperative complications and more broadly on intensive care patient management following thoracic surgery.

Early effects of low benzene exposure on blood cell counts in Bulgarian petrochemical workers.

OBJECTIVES: Only few studies have examined early hematological effects in human populations exposed to low benzene levels and their findings are controversial. We evaluated hematological outcomes (WBC, neutrophils, lymphocytes, monocytes, eosinophils, basophils, RBC, Hb, HCT MCV, platelets and MPV) in a population of 153 Bulgarian petrochemical workers exposed to benzene (range 0.01-23.9 ppm) and 50 unexposed subjects. METHODS: Written informed consent was obtained and a self-administered questionnaire used to collect information on current smoking habits, lifestyle, and occupational activities. Exposure assessment was based on personal monitoring sampling the day before phlebotomy. Urinary trans-trans-muconic acid (t,t-MA) was determined at the beginning and end of the work shift. Based on individual airborne benzene measurements, study subjects were categorized in three exposure categories (referents, <1 and > or =1 ppm). Mean values of each hematologic outcomes in each exposure category were compared with the referent group using a multiple linear regression model adjusted for age, gender, current smoking habits and environmental toluene level. The influence of the CYP2E1 (RsaI and DraI) and NQO1 609C>T genetic polymorphisms on differential hematological parameters was also investigated. RESULTS: No dose-response effect was observed for most of the examined hematological outcomes (WBC, lymphocytes, neutrophils, monocytes, RBC, Hb, HCT, MCV, platelets and MPV). The eosinophil count was inversely related to benzene exposure only among smokers. Conversely, basophils increased with increasing exposure. No effect on benzene hematotoxicity was found for any of the investigated polymorphisms. CONCLUSION: In our study we did not find a decline in WBC and lymphocytes related to benzene exposure. A myeloproliferative effect of benzene is highly unlikely to explain the observed reduction in eosinophils and increase in basophils as it would lead to a concordant depression in all granulocyte subpopulations. Whether benzene effects at low doses are present in Caucasian populations remains uncertain, thus warranting further investigations.

Allergen-specific IgE: comparison between skin prick test and serum assay in real life.

BACKGROUND: The most common sensitizing allergens in in the area of Liguria region (Northwestern Italy) are pollens, mainly Parietaria and cypress, house dust mites, i.e. Dermatophagoides, and pets. IgE assessment is a crucial step in allergy diagnosis. It may be performed by skin prick test (SPT) or serum IgE (sIgE) assay. Therefore, this study compared these two methods in a real-life setting. METHODS: This retrospective study included 793 subjects, who were referred to the Allergy Department for respiratory allergy during 2014. Inclusion criteria were i) documented diagnosis of allergic rhinitis (AR), and/or allergic asthma, and/or allergic conjunctivitis. SPT and sIgE assay were performed for 5 allergens, such as Dermatophagoides pteronyssinus (D1), cat (E1), Parietaria officinalis (W19), cypress (T23), and dog (E5), as they are the most common in our geographic area. RESULTS: Using a positive SPT result as the target condition, remarkably high and statistically significant values of AUC, ranging from 0.84 to 0.94, were found. On the basis of the Youden index the following optimal classification threshold values were also computed: D1 = 0.22, E1 = 0.26, W19 = 0.61, T23 = 0.25, E5 = 0.34. These values allowed to define a set of sensitivity/specifity estimates ranging from 0.75 to 0.93 and from 0.83 to 0.93, respectively. CONCLUSIONS: The present study shows that SPT and sIgE are two tests that are rather concordant, but with different sensitivity and specificity distinct for each allergen. In clinical practice, both tests should be used depending on clinical history features and obtained findings.

Increased procoagulant cell-derived microparticles (C-MP) in splenectomized patients with ITP.

BACKGROUND: Splenectomy is frequently employed for therapeutic and diagnostic purposes in various clinical disorders. However its long-term safety is not well elucidated. Although risk of infection by encapsulated organisms is widely recognized, less well-known are risks of thrombosis and cardiovascular disease. METHODS: We investigated levels of cell-derived microparticles (C-MP) in 23 splenectomized ITP (ITP-S) and 53 unsplenectomized ITP patients (ITP-nS). Assay of C-MP derived from platelets (PMP), leukocytes (LMP), red cells (RMP) and endothelial cells (EMP) were performed by flow cytometry. Coagulation parameters included PT, aPTT and activities of FVIII, IX and XI. Results of all measures were compared between the two groups, ITP-S vs ITP-nS. RESULTS: Levels of all C-MP were higher in ITP-S than ITP-nS but only RMP and LMP reached statistical significance (p = 0.0035 and p < 0.0001, respectively). The aPTT was significantly shorter in ITP-S (p = 0.029). Interestingly, correlation analysis revealed that RMP, but not other C-MP, were associated with shortening of aPTT (p = 0.024) as well as with increased activities of factors VIII (p = 0.023), IX (p = 0.021) and XI (p = 0.0089). CONCLUSIONS: RMP and LMP were significantly elevated in splenectomized compared to non-splenectomized ITP patients. This suggests that the spleen functions to clear procoagulant C-MP, and that elevation of C-MP might contribute to increased risk of thrombosis, progression of atherosclerosis and cardiovascular disease following splenectomy.

In vitro effects of endosulfan-based insecticides on mammalian sperm.

Endosulfan is an organochloride insecticide extensively used in several countries to protect crops from pests. As several studies indicate that endosulfan can affect human and animal development, the aim of this study was to analyse whether sperm parameters and the process of chromatin decondensation could be altered by endosulfan in mice sperm. Spermatozoa from cauda epididymis were obtained from mature male mice and incubated in the presence of two commercial formulations (CFs) of endosulfan (Master® and Zebra Ciagro®) or the active ingredient (AI) alone. A significant decrease in the percentage motility and viability of spermatozoa with respect to controls was found. In vitro decondensation was performed in the presence of glutathione and heparin. Spermatozoa incubated with the AI, endosulfan Master® and endosulfan Zebra Ciagro® showed an increase in chromatin decondensation. In addition, the TUNEL assay showed that DNA fragmentation was significantly higher when sperm were incubated with either one of the CFs when compared to the AI or controls. The ultrastructure analysis of sperm cells showed evident changes in the structure of the plasma and acrosome membranes of sperm incubated with endosulfan AI or the CFs. These results suggest that endosulfan can affect sperm integrity and in vitro chromatin decondensation as well as DNA fragmentation.

Association between coffee or tea drinking and Barrett's esophagus or esophagitis: an Italian study.

BACKGROUND/OBJECTIVES: Only a few papers have treated of the relationship between Barrett's esophagus (BE) or erosive esophagitis (E) and coffee or tea intake. We evaluated the role of these beverages in BE and E occurrence. SUBJECTS/METHODS: Patients with BE (339), E (462) and controls (619) were recruited. Data on coffee and tea and other individual characteristics were collected using a structured questionnaire. RESULTS: BE risk was higher in former coffee drinkers, irrespective of levels of exposure (cup per day; ⩽1: OR=3.76, 95% CI 1.33-10.6; >1: OR=3.79, 95% CI 1.31-11.0; test for linear trend (TLT) P=0.006) and was higher with duration (>30 years: OR=4.18, 95% CI 1.43-12.3; TLT P=0.004) and for late quitters, respectively (⩽3 years from cessation: OR=5.95, 95% CI 2.19-16.2; TLT P<0.001). The risk of BE was also higher in subjects who started drinking coffee later (age >18 years: OR=6.10, 95% CI 2.15-17.3). No association was found in current drinkers, but for an increased risk of E in light drinkers (<1 cup per day OR =1.85, 95% CI 1.00-3.43).A discernible risk reduction of E (about 20%, not significant) and BE (about 30%, P<0.05) was observed in tea drinkers. CONCLUSIONS: Our data were suggestive of a reduced risk of BE and E with tea intake. An adverse effect of coffee was found among BE patients who had stopped drinking coffee. Coffee or tea intakes could be indicative of other lifestyle habits with protective or adverse impact on esophageal mucosa.

Restricted ROC curves are useful tools to evaluate the performance of tumour markers.

In Clinical Epidemiology, receiver operating characteristic (ROC) analysis is a standard approach for the evaluation of the performance of diagnostic tests for binary classification based on a tumour marker distribution. The area under a ROC curve is a popular indicator of test accuracy, but its use has been questioned when the curve is asymmetric. This situation often happens when the marker concentrations overlap in the two groups under study in the range of low specificity, corresponding to a subset of values useless for classification purposes (non-informative values). The partial area under the curve at a high specificity threshold has been proposed as an alternative, but a method to identify an optimal cut-off that separates informative from non-informative values is not yet available. In this study, a new statistical approach is proposed to perform this task. Furthermore, a statistical test associated with the area under a ROC curve corresponding to informative values only (restricted ROC curve) is provided and its properties are explored by extensive simulations. Finally, the proposed method is applied to a real data set containing peripheral blood levels of six tumour markers proposed for the diagnosis of neuroblastoma. A new approach to combine couples of markers for classification purposes is also illustrated.

Effect of acetazolamide on post-NIV metabolic alkalosis in acute exacerbated COPD patients.

OBJECTIVE: Non-invasive ventilation (NIV) is an effective treatment in patients with acute exacerbation of COPD (AECOPD). However, it may induce post-hypercapnic metabolic alkalosis (MA). This study aims to evaluate the effect of acetazolamide (ACET) in AECOPD patients treated with NIV. PATIENTS AND METHODS: Eleven AECOPD patients, with hypercapnic respiratory failure and MA following NIV, were treated with ACET 500 mg for two consecutive days and compared to a matched control group. Patients and controls were non invasively ventilated in a bilevel positive airway pressure (BiPAP) mode to a standard maximal pressure target of 15-20 cmH2O. RESULTS: ACET intra-group analysis showed a significant improvement for PaCO2 (63.9 ± 9.8 vs. 54.9 ± 8.3 mmHg), HCO3- (43.5 ± 5.9 vs. 36.1 ± 5.4 mmol/L) and both arterial pH (7.46 ± 0.06 vs. 7.41 ± 0.06) and urinary pH (6.94 ± 0.77 vs 5.80 ± 0.82), already at day 1. No significant changes in endpoints considered were observed in the control group at any time-point. Inter-group analysis showed significant differences between changes in PaCO2 and HCO3- (delta), both at day 1 and 2. Furthermore, the length of NIV treatment was significantly reduced in the ACET group compared to controls (6 ± 8 vs. 19 ± 19 days). No adverse events were recorded in the ACET and control groups. CONCLUSIONS: ACET appears to be effective and safe in AECOPD patients with post-NIV MA.

Effect of tamoxifen on endometrial proliferation.

PURPOSE: An increase in the incidence of endometrial cancer and a potential increase in related mortality has been associated with the administration of 20 mg tamoxifen, the dose adopted in breast cancer chemoprevention trials, thus urging studies on intermediate markers of risk. PATIENTS AND METHODS: Thirty-three women who received 20 mg tamoxifen as adjuvant breast cancer treatment underwent endometrial biopsy. Samples were divided for histologic examination, including a quantitative analysis of stromal:epithelial ratio, and an assessment of DNA ploidy and proliferation by flow cytometry. Results were compared with 37 symptomatic subjects. RESULTS: All histograms were DNA diploid. Compared with controls, a significant increase in the risk of proliferation as measured by the hyperdiploid fraction was associated with tamoxifen duration (< or = 36 months: cumulative odds ratio = 16.5, 95% confidence interval, 1.85 to 146.5; > 36 months: cumulative odds ratio = 28.2, 95% confidence interval, 2.56 to 310.6, P for trend < .05). Tamoxifen-induced risk was significantly reduced by the extent of menopausal status. No cases of cancer or epithelial hyperplasia were observed in the tamoxifen group, whereas seven cases of epithelial hyperplasia without atypia were observed in the control group. The effect of tamoxifen on proliferation was associated with an increase in the stromal component. CONCLUSION: Tamoxifen at 20 mg/d exerts a time-dependent proliferative effect on the endometrium, particularly in premenopausal and early postmenopausal women. This effect appears to be mediated by the stromal component, which accounts for the discrepancy between flow cytometry and histology. Our study provides preliminary evidence that the DNA flow cytometric hyperdiploid fraction may be a useful tool for monitoring endometrial cell proliferation in women exposed to tamoxifen.

An update on the pharmacogenetics of treating hypertension.

Hypertension is a leading cause of cardiovascular mortality, but only one third of patients achieve blood pressure goals despite antihypertensive therapy. Genetic polymorphisms may partially account for the interindividual variability and abnormal response to antihypertensive drugs. Candidate gene and genome-wide approaches have identified common genetic variants associated with response to antihypertensive drugs. However, there is no currently available pharmacogenetic test to guide hypertension treatment in clinical practice. In this review, we aimed to summarize the recent findings on pharmacogenetics of the most commonly used antihypertensive drugs in clinical practice, including diuretics, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, beta-blockers and calcium channel blockers. Notably, only a small percentage of the genetic variability on response to antihypertensive drugs has been explained, and the vast majority of the genetic variants associated with antihypertensives efficacy and toxicity remains to be identified. Despite some genetic variants with evidence of association with the variable response related to these most commonly used antihypertensive drug classes, further replication is needed to confirm these associations in different populations. Further studies on epigenetics and regulatory pathways involved in the responsiveness to antihypertensive drugs might provide a deeper understanding of the physiology of hypertension, which may favor the identification of new targets for hypertension treatment and genetic predictors of antihypertensive response.

The insulin-like growth factor axis and plasma lipid levels in the elderly.

The activity of the hypothalamic-GH-insulin-like growth factor (IGF) network declines with age. It has recently been shown that increased cardiovascular mortality occurs in adults with GH deficiency. As hypercholesterolemia is common in GH-deficient adults, and because there is experimental evidence that GH may play a role in regulating plasma cholesterol, we decided to investigate the activity of the GH-IGF axis in an elderly population by measuring serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) levels and to study their relationship with blood lipid levels. One hundred and thirty-two elderly subjects, 52 men and 80 women, were studied (age range, 60-91 yr). Men had significantly lower levels of IGFBP-3, high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) compared to the women, whereas IGF-I and IGF-II were only slightly lower. Using linear regression analysis, we observed an inverse relationship of age with IGF-I (r = -0.35; P < 0.001), IGF-II (r = 0.40; P < 0.001), IGFBP-3 (r = 0.52; P < 0.001), body mass index, and lipid levels. Univariate regression analysis showed a strong and positive correlation of both IGF-I and IGFBP-3 with HDL-C and ApoA1. Partial correlation analysis, after adjustment for age and body mass index, showed that IGFBP-3 and IGF-II were still significantly and positively related to HDL-C and ApoA1. Furthermore, a strong association was documented among IGF-I, IGF-II, and IGFBP-3. These data demonstrate that even in an elderly population, further aging is accompanied by a progressive decline in circulating IGF-I, IGF-II, and IGFBP-3, suggesting a continuing diminution of the GH-IGF axis throughout aging. Moreover, the strong correlation between HDL-C and an index of GH secretion, such as IGFBP-3, suggests that GH might play an important role in lipid metabolism in healthy elderly subjects.

Factors affecting plasma retinol decline during long-term administration of the synthetic retinoid fenretinide in breast cancer patients.

Administration of the synthetic retinoid Fenretinide lowers circulating retinol and may thus affect night vision. We have recently shown that plasma retinol levels below 100 ng/ml are associated with moderate alterations of the dark adaptometry test. To identify which patients are more likely to experience a decrease of plasma retinol under this threshold, we measured plasma levels of retinol, Fenretinide, and its metabolite 4-MPR in a cohort of 28 women receiving Fenretinide at the daily dose of 200 mg and studied their relationship with clinical characteristics such as age, menstrual status, body mass index, and time on treatment. Our results show that patients aged over 55 years with a higher percentage of adipose tissue had higher plasma concentrations of 4-MPR, which turned out to be the major determinant of the retinol decrease. This subgroup may thus deserve careful ophthalmological surveillance.