Abstract: BACKGROUND AND AIMS: Many staging systems for hepatocellular carcinoma (HCC) have been proposed but the best tool for staging of HCC remains controversial. The aim of the present study was to identify the best staging system evaluating the predictive ability for outcome for each of the seven different staging systems applied in a homogeneous group of patients who underwent percutaneous radiofrequency ablation (RFA). METHODS: We analyzed retrospectively 112 patients with HCC and cirrhosis treated with percutaneous RFA from January, 1998 to April, 2005. Response to treatment after 30 days and for long-term follow-up was evaluated with computed tomography (CT) or magnetic resonance imaging (MRI) and serum alpha-fetoprotein level (AFP). All of the 112 patients were grouped according to each one of the seven different staging systems: Okuda, TNM, BCLC, CLIP, GRETCH, CUPI, JIS. RESULTS: The mean follow-up time of the 112 patients submitted to RFA was 24 months (range 3-92 months) with survival rates at 1, 3, and 5 yr of 82%, 40%, and 18%, respectively. Univariate and multivariate analyses showed that factors related to survival were Child-Pugh score (P</= 0.01), serum AFP (P</= 0.01), and the response to treatment (P</= 0.01) with hazard ratios of 2.09 (95% CI 1.21-3.61), 2.79 (95% CI 1.59-4.90), and 2.76 (95% CI 1.25-6.09), respectively. The comparison of the results of the different staging systems in all of the 112 patients and in a subgroup of 96 patients with complete response to treatment showed that BCLC had the best discrimination ability, monotonicity of gradient (linear trend chi(2) 6.07, P= 0.01), and homogeneity ability (LR chi(2) test 10.00, P= 0.008). CONCLUSIONS: The BCLC staging system shows a superior discriminatory power in our cohort of HCC patients who underwent RFA; moreover, it can give important prognostic information after complete response to treatment. Our study confirms the validity of the BCLC staging system in patients with HCC in cirrhosis.
Abstract: This paper considers a measure of variable importance frequently used in variable selection methods based on decision trees and tree-based ensemble models, like CART, Random Forests and Gradient Boosting Machine. It is defined as the total heterogeneity reduction produced by a given covariate on the response variable when the sample space is recursively partitioned. Some authors showed that this measure is affected by a bias that, under certain conditions, may have potentially dangerous effects on variable selection. The aim of our work is to present a simple and effective method for bias correction, focusing on the easily generalizable case of the Gini index as a measure of heterogeneity.
Abstract: BACKGROUND: Relative little attention has been devoted until now to the combined effects of gene polymorphisms of the hemostatic pathway as risk factors for Myocardial Infarction (MI), the main thrombotic complication of Coronary Artery Disease (CAD). The aim of this study was to evaluate the combined effect of ten common prothrombotic polymorphisms as a determinant of MI. METHODOLOGY/PRINCIPAL FINDINGS: We studied a total of 804 subjects, 489 of whom with angiographically proven severe CAD, with or without MI (n = 307; n = 182; respectively). An additive model considering ten common polymorphisms [Prothrombin 20210G>A, PAI-1 4G/5G, Fibrinogen beta -455G>A, FV Leiden and "R2", FVII -402G>A and -323 del/ins, Platelet ADP Receptor P2Y12 -744T>C, Platelet Glycoproteins Ia (873G>A), and IIIa (1565T>C)] was tested. The prevalence of MI increased linearly with an increasing number of unfavorable alleles (chi(2) for trend = 10.68; P = 0.001). In a multiple logistic regression model, the number of unfavorable alleles remained significantly associated with MI after adjustment for classical risk factors. As compared to subjects with 3-7 alleles, those with few (</=2) alleles had a decreased MI risk (OR 0.34, 95%CIs 0.13-0.93), while those with more (>/=8) alleles had an increased MI risk (OR 2.49, 95%CIs 1.03-6.01). The number of procoagulant alleles correlated directly (r = 0.49, P = 0.006) with endogenous thrombin potential. CONCLUSIONS: The combination of prothrombotic polymorphisms may help to predict MI in patients with advanced CAD.
Abstract: The aim of this study was to identify patient characteristics associated with once-only contact with a community-based mental health service (CMHS) and to re-evaluate these patients 3 months after the contact. A 33-month cohort of new episodes of care was followed up to identify and interview once-only contact patients. Of the 1101 patients who met the study criteria, 165 (15%) were discharged after the first contact, 87 (8%) dropped out after the first contact, 440 (40%) were low users and 409 (37%) were high users of the CMHS in the 90 days after the first contact. A higher score on the Global Assessment of Functioning scale, less severe psychiatric diagnoses and lower socioeconomic status were the factors most associated with once-only contact at baseline. At follow-up clinical conditions of patients who had only one contact (both discharged patients and drop-outs) had improved and, in most cases, they were in contact with other services. Drop-out patients, however, were more unwell and less satisfied with the initial contact. This dissatisfaction may have led these patients to seek help elsewhere. It is possible that some of these extremely low users are in need of a different or more specialized clinical treatment approach.
Abstract: OBJECTIVE: The aim of this study was to compare a pure macromolecular contrast agent (Gd-DTPA-albumin) with a new protein-binding blood pool contrast agent (B22956/1) in terms of their capacity to investigate the microvasculature in an experimental model of mammary carcinoma. MATERIALS AND METHODS: Tumors were induced by subcutaneous injection of 5 x 10(5) BB1 cells into the backs of 5-7 week-old female FVB/neuNT233 mice. The animals were observed using DCE-MRI when the longest diameter of the tumor was 10.2+/-2.0 mm. DCE-MRI experiments were carried out using B22956/1 and (24 h later) Gd-DTPA-albumin. RESULTS: DCE-MRI data showed that vasculature in the tumor rim was characterized by greater fractional plasma volume and transendothelial permeability than vasculature in the tumor core as measured by both contrast agents. Permeability to Gd-DTPA-albumin in the tumor core was hardly measurable while permeability to B22956/1 was substantial. Histologically the tumor core showed areas of well vascularized, viable tissue surrounded by necrotic regions. CONCLUSIONS: DCE-MRI experiments performed with B22956/1 are useful in the investigation of vasculature in those tumor regions that are characterized by low permeability to macromolecules.
Abstract: BACKGROUND: Radio frequency ablation (RFA) of hepatocellular carcinoma has proved to be useful in local control of tumor. A few data on survival after treatment are available in literature. The aim of the study was to evaluate factors related to survival and to identify different classes of risk after radio frequency ablation. METHODS: Ninety-eight cirrhotic patients with 145 hepatocellular carcinomas were treated with radio frequency ablation from January 1998 to May 2004. In 55 patients, cirrhosis was in Child-Pugh class A, and in 43, in class B. Tumor was single in 60 and multiple in 38; mean tumor number was 1.5 (range 1-3). Tumor size ranged from 1.5 to 6.0 cm, mean 3.8 cm. Mean follow up period was 24.9 months. Radio frequency ablation was performed with expandable type needle with percutaneous approach under real-time ultrasound guidance. For statistical analysis, univariate and multivariate analysis were performed. RESULTS: Complete ablation of the tumor was achieved in 85.5% of lesions. Survival, 1 and 3 years, was 76.7 and 36.6%, respectively. Univariate analysis showed that Cancer of the Liver Italian Program (CLIP) score, tumor growth pattern, alpha-fetoprotein level, and complete tumor necrosis, were factors significantly related to poor survival. Multivariate analysis identified that factors related to poor survival were alpha-fetoprotein level >100 ng/ml, Child-Pugh class B, and incomplete tumor necrosis with a hazard ratio of 4.0, 2.7, and 3.8, respectively. After complete ablation, median survival was 38 months in patients with Child-Pugh class A cirrhosis and alpha-fetoprotein level < or =100 ng/ml, 22 months for patient with Child-Pugh class B cirrhosis and alpha-fetoprotein < or =100 ng/ml, and 9 months for patient with Child-Pugh class A cirrhosis and alpha-fetoprotein >100 ng/ml (P < 0.01). CONCLUSIONS: Complete necrosis and absence of residual tumor positively affect survival after RFA. In patients with Child-Pugh A cirrhosis and alpha-fetoprotein level < or =100 radio frequency, ablation have results, 55% after 3 years, that are comparable to those of surgical resection. Patients with Child-Pugh B cirrhosis and/or alpha-fetoprotein >100 ng/ml showed less satisfactory results, and in these patients, multimodality treatment or other treatments should be considered.
Abstract: Bronchial asthma is a costly disease: while the role of pharmaceutical strategies was greatly emphasised in order to alleviate its economic burden, the aetiological approach to asthma has received much less attention from this point of view. The impact of gastro-oesophageal reflux (GER)-related asthma was assessed in comparison to atopic asthma in 262 matched patients, and the corresponding direct and indirect annual costs calculated. All subjects were screened by means of a 95-item self-questionnaire. The overall resource utilisation was calculated for the last 12 months. Drug-induced annual costs were euro 290.4 (interquartile range-iqr 32.8) in atopic and euro 438.4 (iqr 27.8) in GER-related asthma (p<0.001); expenditure for medical consultations and diagnostics were euro 166.1 (iqr 14.8) vs. euro 71.6 (iqr 11.0) (p<0.001), and euro 338.4 (20.0) vs. 186.9 (iqr 26.5) (p<0.001), respectively. Direct costs due to hospital admissions and indirect costs due to absenteeism were also higher in GER-related asthmatics: 2.201.7+/-90.0 vs. euro 567.1+/-11.0 (p<0.001), and euro 748.7+/-94.7 vs. euro 103.6+/-33.9 (p<0.001), respectively. The total annual cost per patient was euro 1246.7 (iqr 1979.6) in atopic and euro 3967.1 (iqr 3751.5) in GER-related asthma, p<0.001. In conclusion, GER-induced asthma has a more relevant economic impact on healthcare resources than atopic asthma. Although further studies are needed, present data tend to demonstrate that when facing difficult asthma (GER-related asthma in this case), the aetiological assessment of the disease plays a critical role in optimising the approach to patients' needs.
Abstract: High plasma concentrations of triglycerides (TG) and apolipoprotein C-III (ApoC-III) are well-known risk factors for cardiovascular disease. Two variants of the recently discovered APOA5, 1131 C>T and S19W, have been associated with hypertriglyceridemia, whereas their relation with coronary artery disease (CAD) remains controversial. Nine hundred and thirteen angiografically defined patients (669 CAD and 244 CAD-free) were genotyped for APOA5 -1131 C>T and S19W polymorphisms. Carriership of the APOA5 -1131 C allele was identified, by multiple linear regression models, as a significant independent predictor for both TG (standardized beta-coefficient=0.112; p=0.010) and ApoC-III variability (standardized beta-coefficient=0.113; p=0.013). Similarly, APOA5 19W allele carriership was a significant independent predictor for both TG (standardized beta-coefficient=0.113; p=0.007) and ApoC-III variability (standardized beta-coefficient=0.088; p=0.045). Despite the association with at-risk lipid profile, no significant difference was detected in the distribution of both APOA5 gene polymorphisms between subjects with or without CAD. Moreover, homozygous carriers of the APOC3 -455 C, another TG- and ApoC-III raising variant, showed a significant increased risk for CAD (OR 1.90 with 95% CI 1.002-3.62; p=0.049; by multiple logistic regression). Different genotypes, i.e., APOA5 and APOC3 variants, may lead to similar biochemical phenotypes, namely hypertriglyceridemia, but to contrasting clinical phenotypes such as the presence of angiographically proven CAD.
Abstract: BACKGROUND AND AIM: Subjects with airway obstruction are strongly recommended to monitor their lung function, which is particularly variable in asthma. Unlike PEFR, other personal measurements (such as FEV1) are still difficult to perform. PIKO-1 is the first electronic device for both PEFR and FEV1 personal check, but its precision has not yet been assessed. The aim of this study was to compare PEFR and FEV1 values from PIKO-1 and from a conventional spirometer in subjects with airway obstruction. METHODS: In total, 352 subjects (217 men; 47.6 +/- 19.0 years; 72.6 +/- 15.0 kg; 168.1 +/- 11.9 cm) performed sequential measurements using a PIKO-1 device and a spirometer. Wilcoxon signed-rank test and sign test were used as statistical tests. RESULTS: Mean FEV1 values from the spirometer and PIKO-1, respectively, were 2.9 L +/- 1.1 and 3.0 L +/- 1.1, and mean PEFR values were 466.1 L/min +/- 164.5 SD and 426.3 L/min +/- 151.6 SD. PIKO-1 proved to overestimate FEV1 values by 4% (p<0.0001) and to underestimate PEFR values by 8% (p<0.000) systematically. CONCLUSIONS: The precision of both PIKO-1 measurements (such as FEV1 and PEFR) have been assessed. PEFR and FEV1 measures should be reset by two different constants. Nevertheless, PIKO-1 is a suitable and reliable device for the personal monitoring of obstructive patients in real life.
Abstract: The aims of the study were to explore the importance of macro (patient, physician, consultation) and micro (doctor-patient speech sequences) variables in promoting patient cues (unsolicited new information or expressions of feelings), and to describe the methodological implications related to the study of speech sequences. Patient characteristics, a consultation index of partnership and doctor-patient speech sequences were recorded for 246 primary care consultations in six primary care surgeries in Verona, Italy. Homogeneity and stationarity conditions of speech sequences allowed the creation of a hierarchy of multilevel logit models including micro and macro level variables, with the presence/absence of cues as the dependent variable. We found that emotional distress of the patient increased cues and that cues appeared among other patient expressions and were preceded by physicians' facilitations and handling of emotion. Partnership, in terms of open-ended inquiry, active listening skills and handling of emotion by the physician and active participation by the patient throughout the consultation, reduced cue frequency.
Abstract: OBJECTIVE: Exploring the spectrum of eating disorders (ED) and its sociodemographic correlates in a population of adolescents. METHOD: The sample included 788 adolescent students (384 females and 404 males, 12-14 years old) from Verona, Northern Italy. A two-stage sampling procedure was adopted. Eating Disorder Inventory-2 (EDI-2), Body Image Satisfaction Questionnaire (BISQ) and a socio-demographic questionnaire were applied to the sample in the first stage. The sample was then partitioned in two strata, "below-cutoff" and "above-cutoff", using the threshold DT > or = 14 for the Drive for Thinness (DT) subscale. A second sample of 59+58 subjects was selected from the two strata. The structural interview of the second stage consisted of the Structured Clinical Interview for DSM-IV Axis I Disorders and the Symptom Checklist of EDI-2. RESULTS: Partial syndromes of ED were diagnosed in 9.4% of the interviewed sample with a sex ratio F/M=6. The following factors resulted to be related to partial syndrome of ED: dieting to be thin, body mass index, mother's occupation and being a menstruating girl. CONCLUSION: This study represents one of the few prevalence and association studies about ED in young Italian adolescents. It evidences that partial syndromes of ED, in particular the partial syndrome of binge eating disorder, are the most frequent syndromes in early adolescence. Some social and parental factors resulted to be significantly related to these syndromes.
Abstract: The paper reconsiders and compares some randomized response models in the light of the efficiency/protection criterion. The results show that, despite the assertion of the authors about the superiority of their methods, some procedures are perfectly equivalent to the Warner's or the Simmons’ models. Our work extends and generalizes the results of Bhargava and Singh [2002. On the efficiency comparison of certain randomized response strategies. Metrika 55, 191–197] and other authors.
Abstract: AIM: This cross-sectional study attempted to identify factors associated with clinicians' dispositions of patients after the first visit in an out-patient psychiatric department. METHODS: Over a 33-month period, all new episodes of care with the department were included in the study. For each patient, socio-demographic, clinical information and contact characteristics were prospectively collected in relation to the first visit, as was information on case disposition. Factors associated with clinicians' disposition were analysed. RESULTS: Of the 1,138 patients who met the study criteria, 848 (75%) were followed up by the department, 150 (13%) were referred to other services and 140 (12%) were discharged. Suffering from a major psychiatric disorder, being younger and not living in an institution influenced clinicians' disposition to follow-up patients. Older age increased the chances of being referred to other services rather than discharged. CONCLUSIONS: Examining decision-making behaviour in out-patient psychiatric departments is a worthwhile endeavour because this setting represents the main entry point of modern and accessible community-based systems of care. The findings confirmed the importance of psychiatric determinants in the dispositional process and contribute to make clinicians more aware of other factors related to their decision-making.
Abstract: PURPOSE: To evaluate and compare obliteration rates (OBRs) and treatment-obliteration intervals (TOIs) for cerebral arteriovenous malformations (cAVMs) treated with Gamma Knife radiosurgery in children/adolescents and adults; and to determine factors predicting the OBR and TOI in these two populations. METHODS AND MATERIALS: This study concerned 62 children/adolescents and 193 adults observed for > or = 3 years. Fisher exact two-tailed and Wilcoxon rank-sum tests, multiple logistics, and Cox proportional hazard models were used for statistical analysis. RESULTS: The overall OBR was 85.5% in children/adolescents and 87.6% in adults (p = 0.671), but children/adolescents showed higher 36-month actuarial OBRs (69.35%) and shorter median TOIs (25.7 months) than adults (66.84% and 28.2 months; p = 0.006 and p = 0.017, respectively). In children/adolescents, lower Spetzler-Martin grades (p = 0.043) and younger age (p = 0.019) correlated significantly with OBRs, and lower Spetzler-Martin grades (p = 0.024) and noneloquent cAVM locations (p = 0.046) with TOIs. In adults, low flow through the cAVM and < 6.2-cm3 volume were associated with both OBR and TOI (p = 0.012 and p = 0.002, respectively). CONCLUSIONS: The differences in OBRs within 3 years and TOIs, although slight, seem to show that pediatric cAVMs behave differently from those in adults after Gamma Knife radiosurgery.
Abstract: PURPOSE: To compare the epidemiologic, morphologic, and clinical characteristics of 92 children/adolescents (Group A) and 362 adults (Group B) with cerebral arteriovenous malformations (cAVMs) considered suitable for radiosurgery; to correlate radiosurgery-related permanent complication and post-radiosurgery bleeding rates in the 75 children/adolescents and 297 adults available for follow-up. METHODS AND MATERIALS: Radiosurgery was performed with a model C 201-source Co60 Leksell Gamma Unit (Elekta Instruments, Stockholm, Sweden). Fisher exact two-tailed, Wilcoxon rank-sum, and two-sample binomial exact tests were used for statistical analysis. RESULTS: There were significant differences between the two populations in sex (p = 0.015), clinical presentation (p = 0.001), and location (p = 0.008). The permanent complication rate was lower in younger (1.3%) than in older patients (5.4%), although the difference was not significant (p = 0.213). The postradiosurgery bleeding rate was lower in Group A (1.3%) than in Group B (2.7%) (p = 0.694), with global actuarial bleeding rates of 0.56% per year and 1.15% per year, respectively. CONCLUSIONS: The different characteristics of child/adolescent and adult cAVMs suggest that they should be considered two distinct vascular disorders. The similar rates of radiosurgery-related complications and latency period bleeding in the two populations show that gamma knife radiosurgery does not expose young patients to a higher risk of sequelae than that for older patients.
Abstract: OBJECTIVE: This study examined variables associated with having a once-only contact with the out-patient department of two community mental health services in Italy and Australia. METHOD: Two 8-year cohorts of patients, who had a new episode of care with out-patient psychiatric departments in South Verona and in Western Australia, were followed-up for 3 months after the first contact, to identify those patients who had no further contact with services. Potential determinants of once-only contact were analysed. RESULTS: Thirty percent of new episodes of care for persons who met the inclusion criteria of the study were once-only contacts with the service in South Verona. In Western Australia, the figure was 24%. Moreover, the proportion of once-only contact patients has increased over time in South Verona whereas, in Western Australia, it has remained stable. In Western Australia, once-only contact patients were younger whereas in South Verona they tended to be older. At both research sites, patients who had a once-only contact were more likely to be male and to have a less severe mental illness. CONCLUSIONS: The results of this study suggest that only clinical characteristics were significant determinants of this pattern of contact with services consistently at both sites: the less severe the patient's diagnosis, the more likely the patient is to have a once-only contact. This may well indicate good screening at the initial point of contact by both sets of mental health service providers. Prospective studies are necessary to clarify the problem of 'once-only contact' and to organize a proper psychiatric care.
Abstract: OBJECTS: The authors report their experience of gamma knife radiosurgery (GKR) in a large series of pediatric cerebral arteriovenous malformations (cAVMs). The advantages, risks and failures of this approach are presented and discussed. METHODS: Gamma knife radiosurgery was performed on 63 children aged < or =16 years. Haemorrhage was the clinical onset in 50 out of 63 cases. The mean pre-GK cAVM volume was 3.8 cm(3). Fifty-eight out of 63 cAVMs were Spetzler-Martin grades I-III. Most lesions (47 out of 63) were in eloquent or deep-seated brain regions. CONCLUSION: Gamma knife radiosurgery-related complications occurred in 2 out of 47 cases with an available follow-up (1 had transient and 1 permanent morbidity). No bleeding occurred during the latency period. In 39 children with >36-month follow-up, complete cAVM occlusion was angiographically documented in 31, with a 3- and 4-year actuarial obliteration rate of 72 and 77% respectively. High rates of complete obliteration and very low frequency of permanent morbidity with no bleeding during the latency period encourage widespread application of GKR in the treatment of pediatric cAVMs.
Abstract: BACKGROUND: Apolipoprotein C-III (apo C-III) is a marker of cardiovascular disease risk associated with triglyceride (TG)-rich lipoproteins. The T-455C polymorphism in the insulin-responsive element of the APOC3 gene influences TG and apo C-III concentrations. Long-chain n-3 polyunsaturated fatty acids (PUFAs) contained in fish have well-known apo C-III-lowering properties. METHODS: We investigated the possibility of an interactive effect between the APOC3 gene variant and erythrocyte n-3 PUFAs, suitable markers of dietary intake of fatty acids, on apo C-III concentrations in a population of 848 heart disease patients who had coronary angiography. RESULTS: In the population as a whole, apo C-III concentrations were significantly inversely correlated with total erythrocyte PUFAs, but the correlation was not significant when only -455CC homozygous individuals were taken into account. In the total population and in subgroups with the -455TT and -455CT genotypes, the relative proportions of individuals presenting with increased apo C-III (i.e., above the 75th percentile value calculated on the entire population after exclusion of individuals taking lipids-lowering medications) decreased progressively as the n-3 PUFA and docosahexaenoic acid concentrations increased. The opposite situation was observed in the homozygous -455CC subgroup, in whom increasing erythrocyte n-3 PUFA and docosahexaenoic acid concentrations were associated with higher proportions of individuals with high apo C-III. A formal interactive effect between genotype and n-3 PUFAs was confirmed even after adjustment for possible confounding variables [age, sex, body mass index, smoking, coronary artery disease (CAD)/CAD-free status, or use of lipid-lowering medications] by logistic models. CONCLUSION: Patients homozygous for the -455C APOC3 variant are poorly responsive to the apo C-III-lowering effects of n-3 PUFAs.
Abstract: BACKGROUND: This study examined variables associated with patients who had a once-only contact with the out-patient department of a Community Mental Health Service (CMHS). METHODS: Using the South-Verona Psychiatric Case Register (PCR), an 8-year cohort of patients who had a new episode of care with the out-patient department of the South Verona CMHS was followed up for 3 months after the first contact, to identify those patients who had no further contact with the service. Potential determinants of once-only contact were analysed. RESULTS: A total of 2,446 new episodes of care met the inclusion criteria of the study. Of those, 734 (30%) were once-only contacts with the service. Compared to patients with more than one contact, patients who had a once-only contact were older, more likely to be male, had a lower socio-economic status and less severe psychiatric diagnosis. They were more likely to be referred by consultation/liaison or emergency room. CONCLUSIONS: Multivariate analysis revealed that having a less severe psychiatric diagnosis was the most significant determinant of once-only contact with a CMHS. The results suggest that the behaviour of referring agents in selecting patients and preparing them for treatment merits further investigation.
Abstract: The enzyme serum paraoxonase plays an important role in antioxidant defences and prevention of atherosclerosis. Metabolic syndrome (MS) is a clinical condition associated with increased oxidant stress and cardiovascular mortality. Two common polymorphisms of serum paraoxonase, PON1 Leu(55)Met and Gln(192)Arg, have been postulated to modulate the cardiovascular risk. We studied 915 subjects with angiographic documentation: 642 subjects with coronary atherosclerosis and 273 with normal coronary arteries. Two hundred and twenty-four subjects met the diagnostic criteria of MS. We found a significant interaction between MS and both the PON1 polymorphisms in determining the risk of coronary artery disease (P<0.05 by likelihood-ratio test). The 55Leu and the 192Arg alleles, associated with reduced protection against lipid peroxidation, were associated with coronary artery disease only in the MS subgroup. Subjects with MS and both 55Leu and 192Arg alleles had significantly increased risk (OR=9.38 with 95% CI=3.02-29.13 after adjustment by multiple logistic regression) as compared to subjects without MS and with 55Met/Met-192Gln/Gln genotype. No increased risk was found for subjects with MS and the 55Met/Met-192Gln/Gln genotype. This study highlights a potential example of genetic (paraoxonase polymorphisms)-clinical (MS) interaction influencing cardiovascular risk.
Abstract: PURPOSE: To compare two dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) techniques in terms of their ability in assessing the early antiangiogenic effect of SU11248, a novel selective multitargeted tyrosine kinase inhibitor, that exhibits direct antitumor and antiangiogenic activity via inhibition of the receptor tyrosine kinases platelet-derived growth factor receptor, vascular endothelial growth factor receptor, KIT, and FLT3. EXPERIMENTAL DESIGN: A s.c. tumor model of HT29 human colon carcinoma in athymic mice was used. Two DCE-MRI techniques were used based, respectively, on macromolecular [Gd-diethylenetriaminepentaacetic acid (DTPA)-albumin] and low molecular weight (Gd-DTPA) contrast agents. The first technique provided a quantitative measurement of transendothelial permeability and fractional plasma volume, accepted surrogate markers of tumor angiogenesis. With the second technique, we quantified the initial area under the concentration-time curve, which gives information related to tumor perfusion and vascular permeability. Experiments were done before and 24 hours after a single dose administration of SU11248. RESULTS: The early antiangiogenic effect of SU11248 was detected by DCE-MRI with macromolecular contrast agent as a 42% decrease in vascular permeability measured in the tumor rim. The effect was also detected by DCE-MRI done with Gd-DTPA as a 31% decrease in the initial area under the concentration-time curve. Histologic slices showed a statistically significant difference in mean vessel density between the treated and control groups. CONCLUSIONS: The early antiangiogenic activity of SU11248 was detected in vivo by DCE-MRI techniques using either macromolecular or low molecular weight contrast agents. Because DCE-MRI techniques with low molecular weight contrast agents can be used in clinical studies, these results could be relevant for the design of clinical trials based on new paradigms.
Abstract: OBJECTIVES: The aim of this study was to compare the efficacy of gadoteridol, B22956/1 (a new protein binding blood pool contrast agent), and (Gd-DTPA)37-albumin in detecting, by dynamic contrast-enhanced magnetic resonance imaging (MRI), the effect in vivo of tamoxifen in an experimental model of breast tumor implanted in rats. MATERIALS AND METHODS: Tumors were induced by subcutaneous injection of 10 mammary adenocarcinoma cells (13762 MAT B III). Treatment with tamoxifen (or vehicle) started on day 4 after implantation. On day 10 after implantation, animals were observed by MRI using B22956/1 (or gadoteridol) and, 24 hours later, using (Gd-DTPA)37-albumin. RESULTS: Dynamic contrast-enhanced magnetic resonance imaging data showed that tamoxifen treatment decreased vascular permeability to B22956/1, whereas no difference was detectable in permeability to gadoteridol or to (Gd-DTPA)37-albumin. No effect on fractional plasma volume was detected with either of contrast agents. CONCLUSIONS: B22956/1 is superior to both small Gd chelates and macromolecular contrast agents in the assessment of the effect of tamoxifen treatment on tumor vasculature.
Abstract: Exacerbations often complicate the progressive course of chronic obstructive pulmonary disease (COPD), mainly due to infectious agents. The precise role of bacterial infections in the course and the pathogenesis of COPD has been a source of controversy for decades. Also viruses and other non-infectious causes of exacerbation play a relevant role and also contribute to persisting airway inflammation. Usually, the etiologic identification of the infective causes of COPD require considerable time and costs. The development of more rapid, reliable, and widely applicable methods to promptly define the etiology of COPD exacerbations should represent a relevant issue in devising earlier and more specific strategies for their effective therapeutic control. AIM: Of the study was to assess the predictive role of some pro-inflammatory cytokines measured in spontaneous bronchial secretions in discriminating the main infectious causes of COPD exacerbations. METHODS: 124 subjects with moderate COPD (51-79 y; mean basal FEV1 = 49.6% pred. +/- 4.6 sd; FEV1 reversibility +3.9% from baseline +/- 4.8 sd after salbutamol 200 mcg) were studied during acute exacerbation. Respiratory viruses were isolated from bronchial secretions in 21 cases; common bacteria (CFU > or = 10(6)/ml) in 28 cases; Pseudomonas Aeruginosa (Ps.Ae.; CFU > or = 10(6)/ml) in 20 cases. The cytokines IL1beta, IL8, and TNFalpha (pg/ml; Immulite; Diagnostic Product Corp, Los Angeles, CA, USA), and neutrophils (% total count) were measured in bronchial secretions of all patients. STATISTICS: A two-stage logistic model was chosen for discriminating the different causes of COPD exacerbations (such as: non-infectious, or viral, bacterial, or due to Ps.Ae.). RESULTS: At the first decisional step, the two-stage logistic model proved that TNFalpha levels in bronchial secretions recognise clearly patients belonging to the Ps.Ae. group from those of all other groups (Area under ROC curve = 0.96; 95% CI = 0.91-0.99), and that, at the second decisional step, IL8 + IL10 levels discriminate patients with bacterial causes (such as all bacteria) from the non-infected ones and from those with a viral cause of exacerbation (Area under ROC curve = 0.87; 95% CI = 0.77-0.94). Neutrophil percent count did not support any contribution in discriminating the different subgroups of COPD subjects. CONCLUSIONS: When exacerbated, COPD subjects express different patterns of pro-inflammatory mediators in bronchial secretions, which appear modulated according to the etiological cause of the exacerbation. In particular, TNFalpha concentration per se enables recognition of COPD exacerbations due to Ps.Ae., while IL8 + IL1beta levels prove helpful in discriminating those to common bacteria from those to viral agents and to non-infectious causes. When present data are further confirmed, the use of a decisional rule based on cytokine measurements might be regarded as a helpful predictive tool. As measures of pro-inflammatory cytokines are low-cost, simple, and faster to perform, they could support rapid clinical decision making at the bedside regarding therapeutic strategy for COPD exacerbations, in particular when they are needed for severe COPD patients.
Abstract: BACKGROUND AND STUDY AIMS: The aims of this study were to identify risk factors for recurrence of hemorrhage in bleeding gastroduodenal ulcers after endoscopic injection therapy, and to develop a simple and relevant prognostic score which could be used to assess the early risk of recurrence and the residual risk of rebleeding. PATIENTS AND METHODS: A prospective study was conducted from January 1995 to December 1998, in 738 patients who were admitted to our department for acute bleeding peptic ulcer and who underwent endoscopic examination. Ulcers with active bleeding or signs of recent bleeding were treated with injection therapy using epinephrine (1/10,000) and 1% polidocanol. RESULTS: Multivariate analysis revealed that liver cirrhosis, recent surgery, systolic blood pressure below 100 mmHg, hematemesis, Forrest classification, and ulcer size and site were significantly predictive variables for the recurrence of hemorrhage. Among these, Forrest classification was the most important. The overall accuracy of the predictive model was 71% (95% CI = 63 - 79%). The model showed a better sensitivity of 90% for early rebleeding (< 48 hours) than for late rebleeding (> or = 48 hours) where the sensitivity was 65 %. A prognostic score was obtained and patients were classified into four risk classes: very low (VL), low (L), high (H), and very high (VH). The rebleeding rates for the four classes were 0%, 7.9%, 31.8% and 67.9%, and the mortality rates were 5.9%, 8.6%, 13.9% and 35.7%, respectively. The residual risk of rebleeding after 48 hours was 0%, 3.3%, 10.4%, and 14.3% in the VL, L, H and VH classes, respectively. After 5 days the residual risk was under 4% in all classes. CONCLUSIONS: This study demonstrates that the proposed prognostic score, which is easily obtained after emergency endoscopy, is useful in clinical practice because it can identify patients with different levels of rebleeding risk. It can be helpful in patient management and decision making for discharge.
