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Background: We examined how crossover therapy might affect the association between progression-free survival (PFS) and overall survival (OS) in non-small cell lung cancer (NSCLC). Methods: We extracted PFS- and OS-hazard ratios (HRs) in phase III trials of molecular-targeted agents for advanced NSCLC. Their relationship was modeled in a linear function with the coefficient of determination (R-squared) to assess the correlation between PFS and OS. Results: Thirty-four trials with 35 pairs for the investigational and reference arms were identified (24,158 patients). Overall, there was little correlation between PFS- and OS-HRs (R-squared = 0.14), suggesting PFS-HR could account only for 14% of variation in OS-HR The median proportion of crossover therapy per trial was 20%. If patients seldom crossed over (none or = 1%, however, R-squared declined considerably (>= 1% to = 20% to = 40%, R-squared = 0.27). Conclusions: A PFS advantage seldom is associated with an OS advantage any longer. Our analysis suggests this is due to a high level of crossover now that an increasing number of active agents are available for NSCLC. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

In the course of chronic renal failure, low protein-diets allow better control of metabolic disorders and may delay the start of renal replacement therapy (RRT). However, concerns exist that a very low protein diet supplemented with ketoacids (sVLPD) worsens survival after starting RRT. To evaluate whether a prolonged sVLPD regimen may affect all-cause mortality during the following RRT period, we studied time to all-cause death during RRT in patients previously followed in renal clinics either treated with sVLPD (sVLPD group, n=184, age 67±18 yrs) or not (CKD group, n=334, age 66±14 yrs). A Control group including 9,092 patients (age 66±14 yrs) was selected from the Italian dialysis & transplantation registry (RIDT). In sVLPD, CKD and Control groups, the prevalence of an history of cardiovascular disease was 41, 31, 25% and of diabetes was 18%, 31%, 17%, respectively; the median follow-up time in RRT (36, 32, 36 months) did not differ among groups.Cumulative survival was similar in sVLPD and CKD groups (p=0.638), but significantly higher than in the Control group (Long-rank test, 20,62; p

Evidence of relative effectiveness of local treatments for hepatocellular carcinoma (HCC) is scanty. We investigated, in a retrospective cohort study, whether surgical resection, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), and transarterial embolization with (TACE) or without (TAE) chemotherapy resulted in different survival in clinical practice. All patients first diagnosed with HCC and treated with any locoregional therapy from 1998 to 2002 in twelve Italian hospitals were eligible. Overall survival (OS) was the unique endpoint. Three main comparisons were planned: RFA versus PEI, surgical resection versus RFA/PEI (combined), TACE/TAE versus RFA/PEI (combined). Propensity score method was used to minimize bias related to non random treatment assignment. Overall 425 subjects were analyzed, with 385 (91%) deaths after a median followup of 7.7 years. OS did not significantly differ between RFA and PEI (HR 1.11, 95% CI 0.79–1.57), between surgery and RFA/PEI (HR 0.95, 95% CI 0.64–1.41) and between TACE/TAE and RFA/PEI (HR 0.88, 95% CI 0.66–1.17). 5-year OS probabilities were 0.14 for RFA, 0.18 for PEI, 0.27 for surgery, and 0.15 for TACE/TAE. No locoregional treatment for HCC was found to be more effective than the comparator. Adequately powered randomized clinical trials are still needed to definitely assess relative effectiveness of locoregional HCC treatment.

Purpose Since treatment efficacy of cisplatin- or carboplatin-based chemotherapy in the first-line treatment of small-cell lung cancer (SCLC) remains contentious, a meta-analysis of individual patient data was performed to compare the two treatments. Patients and Methods A systematic review identified randomized trials comparing cisplatin with carboplatin in the first-line treatment of SCLC. Individual patient data were obtained from coordinating centers of all eligible trials. The primary end point was overall survival (OS). All statistical analyses were stratified by trial. Secondary end points were progression-free survival (PFS), objective response rate (ORR), and treatment toxicity. OS and PFS curves were compared by using the log-rank test. ORR was compared by using the Mantel-Haenszel test. Results Four eligible trials with 663 patients (328 assigned to cisplatin and 335 to carboplatin) were included in the analysis. Median OS was 9.6 months for cisplatin and 9.4 months for carboplatin (hazard ratio [HR], 1.08; 95% CI, 0.92 to 1.27; P = .37). There was no evidence of treatment difference between the cisplatin and carboplatin arms according to sex, stage, performance status, or age. Median PFS was 5.5 and 5.3 months for cisplatin and carboplatin, respectively (HR, 1.10; 95% CI, 0.94 to 1.29; P = .25). ORR was 67.1% and 66.0%, respectively (relative risk, 0.98; 95% CI, 0.84 to 1.16; P = .83). Toxicity profile was significantly different for each of the arms: hematologic toxicity was higher with carboplatin, and nonhematologic toxicity was higher with cisplatin. Conclusion Our meta-analysis of individual patient data suggests no differences in efficacy between cisplatin and carboplatin in the first-line treatment of SCLC, but there are differences in the toxicity profile.

The epidemic dimensions of non-dialysis chronic kidney disease (CKD) and the associated elevated cardiovascular risk as well as the high costs of renal replacement therapy have made the identification of CKD patients and the quantification of CKD-related comorbidities a key priority in the strategies of public health agencies worldwide. Information on the CKD prevalence at a national level is still lacking in Italy, although these data are critical for planning preventive strategies and increasing the awareness of CKD as a major chronic disease. In 2008 the CARHES (CArdiovascular risk in Renal Patients of the Italian Health Examination Survey) study was started. The study - a joint venture between the Italian Society of Nephrology, the Italian Society of Cardiologists, and the National Health Institute-Cardiovascular Disease Prevention Project - will integrate the previously collected information on the cardiovascular risk profile of the adult Italian population provided by the Health Examination Survey (HES) with epidemiological data on CKD. The initial results on approximately half of the prospective sample of 9020 subjects aged 35-79 years suggest a lower CKD prevalence than that reported in other countries. The final results will allow to estimate the level of CKD in Italy and hopefully increase the awareness of this high-risk chronic disease among Italian physicians and health authorities.

The hypothesis that fosamprenavir-including highly active antiretroviral therapy (HAART) regimens would be associated with few metabolic and hepatic side-effects was investigated.An observational single-arm retrospective study was set up on a cohort of 139 human immunodeficiency virus (HIV)-infected patients, followed up at A.O.R.N. Cotugno Hospital, Naples, Italy, treated with antiretroviral regimens including fosamprenavir, in order to evaluate the safety of these regimens in relationship to hepatic and metabolic side-effects, also considering co-morbidities and other risk factors.Only seven patients met the criteria to reach the primary end-point (grade ≥ 3 adverse event) and none of them discontinued HAART therapy during the follow-up period. Eighty percent of the patients reached viral load50 cp/μl at 48 weeks of observation. At the end of follow-up, no patient with fasting serum total cholesterol and/or fasting serum triglycerides above grade 3 was found, while 1 out of 114 (0.88%) cases presented aspartate transaminase and alanine transaminase ≥ grade 3 and 1 out of 114 (0.88%) cases had fasting serum glucose ≥ grade 3. One out of 137 patients developed a malignant neoplasm (0.73%) and 4 (2.92%) displayed newly diagnosed hypertension.Fosamprenavir-based regimens caused a low number of serious metabolic adverse events during a 48 week follow-up period, with a low incidence of co-morbidities and satisfying results in terms of viro-immunological response including for patients with already existing co-morbidities requiring other therapies.

PURPOSE: Neuroendocrine differentiation is a hallmark of prostate cancer. The aim of our study was the detection of the parallel expression of neuroendocrine related markers using a prostate tissue microarray (TMA). MATERIALS AND METHODS: Our study was aimed at detecting the parallel expression of NeuroD1, Chromogranin-A (ChrA), Androgen Receptor (AR) and Ki-67 by immunohistochemistry on prostate cancer tissue microarray. The data was analyzed using SAS version 8.2 (SAS Inc, Cary, NC). The relationships between NeuroD1, ChrA and AR expressions and patients' characteristics were investigated by multivariate logistic regression analysis. Progression and Overall Survival (OS) distributions were calculated using Kaplan-Meier method. RESULTS: Tissue reactivity for NeuroD1, ChrA and AR concerned 73%, 49% and 77% of the available cases, respectively. Regarding overall survival, there were 87 deaths and 295 patients alive/censored (6 years of median follow-up). Seventy-seven disease progressions occurred at the median follow-up 5.4y. A significant correlation between NeuroD1, ChrA and AR expression was observed (p < 0.001 and p < 0.03, respectively). Additionally, ChrA was strongly associated in multivariate analysis to Gleason score and Ki67 expression (p < 0.009 and p < 0.0052, respectively). Survival analysis showed no association between markers neither for overall nor for cancer-specific survival. CONCLUSIONS: The results highlight that NeuroD1, Chromogranin-A and Androgen Receptor are strongly associated, however their expression does not correlate with overall survival or disease progression.

Insulin analogues are increasingly used in patients with type 2 diabetes. We performed a systematic review of randomized controlled trials (RCTs) to assess the role of insulin analogues to reach different hemoglobin A1c (HbA1c) targets (from 6.5% to 8%) in type 2 diabetic patients.RCTs involving insulin regimens (basal, prandial, biphasic, and basal-bolus) with insulin analogues in type 2 diabetes were identified through electronic searches (MEDLINE, EMBASE, CINAHL, and The Cochrane Library) through August 2010. We included any study arm of RCTs if they were at least 12 weeks in duration, and reported HbA1c as an outcome and the proportion of diabetic patients reaching the HbA1c target of7%. The proportion of patients with HbA1c6.5%,7.0%,7.5%, and8.0% was estimated using mean and standard deviation of HbA1c at the end of treatment.We identified 53 RCTs, with 92 arms, and 32,689 patients. The proportion of patients at target was highest with the basal-bolus regimen, and ranged from 27.8% (95% CI, 22.2-34%) for the HbA1c target6.5% to 88% (CI 83-92%) for the HbA1c target8%. Biphasic insulin regimen ranked second at any HbA1c target, while prandial and basal regimens alternated across different HbA1c targets.At any HbA1c target, basal-bolus insulin regimens with insulin analogues obtained the best results, which may be useful for detailing the best treatment effect in individual patients.

Experimental studies suggest that oxidative stress and systemic inflammation are involved in the pathogenesis of ischemic stroke. Consuming a diet with a high total antioxidant capacity (TAC) has been related to reduced inflammation and increased circulating antioxidants in cross-sectional and randomized intervention studies. This study investigates the relation between dietary TAC and risk of ischemic and hemorrhagic stroke in 41,620 men and women not previously diagnosed with stroke or myocardial infarction, representing the Italian segment of the European Prospective Investigation into Cancer and Nutrition. Controlling for potential confounders, a diet rich in TAC was associated with a reduction in HR for all types of stroke, but this association was only marginally significant (P-trend = 0.054). When only ischemic stroke cases were considered, data suggest a stronger inverse association with dietary TAC, with HR = 0.41 (95% CI = 0.23-0.74). Regarding single antioxidants, data from subanalyses on stroke types suggest that vitamin C is significantly associated with a decreased risk of ischemic stroke [HR = 0.58 (95% CI = 0.34-0.99)], whereas vitamin E was associated with increased HR of hemorrhagic stroke in the highest tertile of intake [HR = 2.94 (95% CI = 1.13-7.62)]. In conclusion, our findings suggest that antioxidants may play a role in reducing the risk of cerebral infarction but not hemorrhagic stroke. However, a high intake of vitamin E could be positively associated to the risk of brain hemorrhagic events; therefore, more focused investigations about this observation are needed.

The purpose of this paper is to identify immunologic hallmarks of excessive bodyweight. The analysis is based on 176 adults (106 women, 70 men) who participated in a nested case-control study in Italy. All participants were healthy at the time of blood collection and aged between 36 and 75 years. We employed multivariate analysis of variance and a nonparametric Bayesian additive regression tree approach along with a receiver operating characteristic (ROC) curve analysis to determine the immunologic signature of excessive body weight (i.e., obesity and overweight). Interleukin 8 (IL-8), IL-10, interferon γ, and inducible protein 10 were shown to be predictive of excessive body weight with an area under the ROC curve of 71% (p

Stroke is a major cause of death. Several foods and nutrients have been linked to stroke, but their effects may be best investigated considering the entire diet. In the present EPICOR study, we investigated the association between stroke and adherence to 4 a priori-defined dietary patterns: Healthy Eating Index 2005 (HEI-2005), Dietary Approaches to Stop Hypertension (DASH), Greek Mediterranean Index, and Italian Mediterranean Index. We followed 40,681 volunteers and estimated the HR and 95%CI for stroke according to dietary pattern by using multivariate Cox models with adjustment for risk factors. During a mean follow-up of 7.9 y, 178 stroke cases were diagnosed (100 ischemic, 47 hemorrhagic). Scores of 3 dietary patterns (not HEI) were inversely associated with risk of all types of stroke, with the strongest association for the Italian Index [HR = 0.47 (95%CI = 0.30-0.75); third vs. first tertile]. All patterns were significantly inversely associated with ischemic stroke except the Greek Index, with the strongest association for the Italian Index [HR = 0.37 (95%CI = 0.19-0.70); third vs. first tertile]. Only the Italian Index tended to be inversely associated with hemorrhagic stroke [HR = 0.51 (95%CI = 0.22-1.20); P = 0.07)]. These epidemiological findings suggest that adherence to any one dietary pattern investigated would protect against at least one type of stroke. For our Italian population, a diet with a high score on the Italian Index was associated with the greatest risk reduction, probably because it was conceived to capture healthy eating in the context of foods typically available in Italy.

Background/Aims: In chronic kidney disease (CKD), no data on resistant hypertension (RH) are so far available despite the high prevalence of uncontrolled hypertension. We evaluated frequency, correlates and prognosis of RH in 300 consecutive incident hypertensive CKD patients in an academic renal clinic. Methods: RH was defined as office blood pressure (BP) ≧130/80 mm Hg despite ≧3 drugs at full dose including a diuretic, or as BP at goal with ≧4 full-dose drugs. Patients were evaluated at referral and after 6 months of nephrology management; thereafter, they were included in a renal survival analysis lasting 37.6 months. Results: On referral, glomerular filtration rate was 41.3 ± 16.6 ml/min/1.73 m2 and BP 148 ± 23/81 ± 12 mm Hg. After 6 months, BP decreased by 8 ± 23/3 ± 12 mm Hg. From referral to month 6, RH detection increased from 26 to 38% due to the significant increment in full-dose antihypertensive medications (from 2.0, IQR 1.0–3.0 to 2.5, IQR 2.0–3.0). Diabetes and proteinuria predicted the incidence of RH at month 6. Presence of RH at month 6 was associated with greater risk of renal death (HR, 1.85, 95% CI, 1.13–3.03), independent of main clinical features and degree of BP control. Conclusion: In CKD, RH is prevalent and associated with decreased renal survival, independent of BP levels.

BACKGROUND Whether nephrology management improves over time achievement of blood pressure (BP) goal (

Background Ambulatory blood pressure (BP) measurement allows a better risk stratification in essential hypertension compared with office blood pressure measurement, but its prognostic role in nondialysis chronic kidney disease has been poorly investigated. Methods The prognostic role of daytime and nighttime systolic BP (SBP) and diastolic BP (DBP) in comparison with office measurements was evaluated in 436 consecutive patients with chronic kidney disease. Primary end points were time to renal death (end-stage renal disease or death) and time to fatal and nonfatal cardiovascular events. Quintiles of BP were used to classify patients. Results The mean (SD) age of the patients was 65.1 (13.6) years, and the glomerular filtration rate was 42.9 (19.7) mL/min/1.73 m 2 ; 41.7% of the participants were women, 36.5% had diabetes, and 30.5% had cardiovascular disease. Office-measured SBP/DBP values were 146 (19)/82 (12) mm Hg; daytime SBP/DBP was 131 (17)/75 (11) mm Hg, and nighttime SBP/DBP was 122 (20)/66 (10) mm Hg. During follow-up (median, 4.2 years), 155 and 103 patients reached the renal and cardiovascular end points, respectively. Compared with a daytime SBP of 126 to 135 mm Hg, patients with an SBP of 136 to 146 mm Hg and those with an SBP higher than 146 mm Hg had an increased adjusted risk of the cardiovascular end point (hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.13-4.41 and 3.07; 1.54-6.09) and renal death (1.72; 1.02-2.89 and 1.85; 1.11-3.08). Nighttime SBPs of 125 to 137 mm Hg and higher than 137 mm Hg also increased the risk of the cardiovascular end point (HR, 2.52; 95% CI, 1.11-5.71 and 4.00; 1.77-9.02) and renal end point (1.87; 1.03-3.43 and 2.54; 1.41-4.57) with respect to the reference SBP value of 106-114 mm Hg. Office measurement of BP did not predict the risk of the renal or cardiovascular end point. Patients who were nondippers and those who were reverse dippers had a greater risk of both end points. Conclusion In chronic kidney disease, ambulatory BP measurement and, in particular, nighttime BP measurement, allows more accurate prediction of renal and cardiovascular risk; office measurement of BP does not predict any outcome.

Aim: We assessed the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin, sitagliptin, saxagliptin and alogliptin to reach the haemoglobin HbA1c target of

We conducted a systematic review of randomized controlled trials (RCTs) that evaluated the effectiveness of insulin regimens with insulin analogs to reach the glycosylated hemoglobin (HbA1c) target of7% in patients with type 2 diabetes.RCTs involving insulin regimens (basal, prandial, biphasic, and basal-bolus) with insulin analogs in type 2 diabetes were identified through electronic searches [MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and The Cochrane Library] through September, 2010. We included any study arm of RCTs if they were at least 12 weeks in duration and reported HbA1c as an outcome.We identified 55 RCTs, with 96 arms and 33,244 patients, that reported the HbA1c target, and 32 RCTs, with 32 arms and 5,559 patients, that did not report the target. The missing targets were calculated with an algorithm that explained 88% of variability between studies. Overall, the proportion of patients at target (HbA1c7%) was 37.2% [95% confidence interval (CI), 31.5-43.1%] with basal insulin, 35.3% (28.9-42.1%) with biphasic insulin, 37.5% (27.7-47.9%) with prandial insulin, and 51.2% (41.4-61.1%) for basal-bolus insulin, with high heterogeneity (I(2)80% for all).The HbA1c target7% can be achieved in a proportion of patients ranging from 35% to 51%, depending on the particular insulin regimen. At least one half of patients with type 2 diabetes receiving insulin analogs do not reach the HbA1c target.

Background. In chronic kidney disease (CKD), loop diuretics correct volume-dependent hypertension, but their effect on left ventricular mass index (LVMI) is unknown. Methods. Forty hypertensive CKD patients (estimated creatinine clearance 60-15 mL/min/1.73 m 2 ), treated with renin-angiotensin system (RAS) inhibitors, were randomized to receive furosemide or non-diuretic antihypertensive treatment (control group). Office blood pressure (BP) < 130/80 mmHg was pursued in both groups. Primary end point was the reduction of LVMI after 52 weeks. Secondary aims were to verify safety related to furosemide treatment and its effects on ambulatory and clinic BP and body fluid volumes. Results. Office BP similarly declined in the furosemide group (from 161 ± 14/80 ± 10 to 139 ± 14/74 ± 8 mmHg) and in controls (from 159 ± 16/81 ± 10 to 137 ± 16/75 ± 10 mmHg). We detected a greater reduction (P = 0.013) of LVMI in patients receiving furosemide (-7.9, IQR from -15.8 to -1.4 g/h 2.7 ) than in controls (0.0, IQR from -6.2 to +9.5 g/h 2.7 , P = 0.013). Bio-impedance analysis-derived extracellular water (ECW) significantly decreased in furosemide-treated patients (from 18.7 ± 3.9 to 17.7 ± 3.3 L) while remained unchanged in the control group (from 19.5 ± 2.2 to 19.6 ± 1.9 L). Absolute change of LVMI correlated with changes of ECW in furosemide-treated patients (r = 0.458, P = 0.042) but not in controls. In the furosemide group, no patient experienced side effects requiring drug withdrawal. Conclusions. In hypertensive CKD patients treated with RAS inhibitors, add-on furosemide efficaciously reduces LVMI independently from BP changes. The effect is possibly mediated by better control of volume expansion.

The purpose of this study was to perform a meta-analysis of articles to verify the mandibular changes produced by the Frankel-2 (FR-2) appliance during the treatment of growing patients with Class II malocclusions when compared with untreated growing Class II subjects. The literature published from January 1966 to January 2009 was reviewed with search engines. A quality analysis was performed. The effects on primary end points were calculated with random-effect models. Heterogeneity was assessed using Q statistic and investigated using study-level meta-regression. A total of nine articles were identified. The quality of the studies ranged from low to medium. Meta-analysis showed that the FR-2 was associated with enhancement of mandibular body length [0.4 mm/year 95 per cent confidence interval (CI) 0.182-0.618], total mandibular length (1.069 mm/year, 95 per cent CI 0.683-1.455), and mandibular ramus height (0.654 mm/year, 95 per cent CI 0.244-1.064). A consistent heterogeneity among studies was found for all the considered linear measurements. The FR-2 appliance had a statistically significant effect on mandibular growth. Nevertheless, the heterogeneity of the FR-2 effects, the quality of studies, the differences in age, skeletal age, treatment duration, and the inconsistent initial diagnosis seem to overstate the benefits of the FR-2 appliance. An evidence-based approach to the orthodontic outcomes of FR-2 appliance is needed, by selecting and comparing groups of children with the same cephalometric characteristics with and without treatment.

We conducted a systematic review of randomized controlled trials that evaluated the effectiveness of insulin regimens (basal, biphasic, prandial, and basal-bolus) with insulin analogues to reach the haemoglobin A1c target of

Background/Aims: Finding the lowest effective dose of erythropoietin-stimulating agents is critical in the management of renal anemia. We evaluated the efficacy of converting darbepoetin to CERA at doses lower than those usually recommended. Methods: We selected consecutive non-dialysis chronic kidney disease patients treated with darbepoetin doses ≤40 µg/week in absence of iron deficiency, recent blood transfusion, bleeding, neoplasia, myocardial infarction/stroke in the last 3 months. Darbepoetin ≤20 µg/week was shifted to CERA 75 µg/month, while darbepoetin 21–40 µg/week to CERA 100 µg/month. Primary endpoint was the change in hemoglobin (Hb goal, 11–13 g/dl) at month 3, 6, 9 and 12. Results: Studied patients (n = 37) were aged 70 ± 13 years and GFR was 30 ± 12 ml/min/1.73 m2; prevalence of males, diabetes and prior cardiovascular disease was 43, 45 and 40%, respectively. Before switching, efficacy population received darbepoetin 18 ± 10 µg/week with 28 patients receiving ≤20 µg/week. Prevalence of Hb goal at baseline was 75.7% and did not change at months 3 (70.3%), 6 (70.3%), 9 (72.2%), and 12 (80.0%). CERA dose remained unchanged during the study (81 ± 11, 82 ± 16, 91 ± 30, 90 ± 54 and 88 ± 61 µg/month). Out of the 438 visits performed, CERA dose was increased in 52 (11.9%) and reduced in 36 (8.2%) visits. Blood pressure, Hb, GFR, transferrin saturation and ferritin did not change. Conclusions: In chronic kidney disease patients treated with darbepoetin doses ≤40 µg/week, CERA can be efficaciously used at doses lower than those recommended.

Body mass index (BMI), waist circumference (WC), body weight modification, and rate of weight increase over 10 years were evaluated in relation to high-sensitive C-reactive protein (hs-CRP) to assess the association of cross-sectional or longitudinal estimates of obesity/overweight with levels of circulating CRP, a well established and standardized marker of low-grade inflammation, in relation to cardiovascular risk.This study included a subgroup of 390 menopausal women participating in a large currently ongoing epidemiological study (Progetto Atena; N=5062).At the final visit, women in the third tertile of BMI, compared with those in the first tertile, showed the following odds ratio (OR) of having high hs-CRP values: III vs I tertile OR, 3.55; 95% confidence interval, 1.94-6.49, P0.001, adjusted for age, and metabolic syndrome. Similar results were obtained when we evaluated women in the third tertile of WC, or those in the highest group of estimated weight increase, relative to their weight at age 20 years or in the group of highest rate of weight increase over 10 years of observation (weight at the final visit-weight at the baseline visit divided by time in months between visits).The independent relations between different markers of overweight/obesity and elevated hs-CRP consistently indicate that high (above 1.5 mg l(-1), median) hs-CRP is a major biochemical counterpart of cross-sectional or longitudinal estimates of increased adipose tissue mass.

Introduction Mandibular lip-bumper (LB) nonextraction treatment, usually started before complete second molar (M2) eruption, inevitably interacts with the development of the dentition. Yet, its effects on M2 eruption are still unknown. The first aim of this study was to retrospectively investigate whether LB therapy (260 patients) enhances the risk for M2 ectopic eruptions and impactions in comparison with 135 untreated subjects. The second aim was to assess, among treated patients (n = 197), the main potential determinants of M2 impaction and ectopic eruption. Methods M2 eruption and impaction were determined on panoramic radiographs. To assess the predictive role of M2 inclination in relation to the first molar, a panoramic radiograph suitable for this measurement before treatment was required. The data were analyzed by using software (version 8.2, SAS, Cary, NC). Results LB treatment significantly enhanced M2 impaction and ectopic eruption. Negative prognostic factors were found. An initial inclination of the M2 greater than 30° was significantly associated with a higher impaction risk compared with an angulation less than10°. LB treatment duration longer than 2 years increased the risk of ectopic eruptions. Conclusions While gaining space in the anterior arch, unwanted effects might be produced in the posterior arch. To be informed about these unplanned events is necessary to better optimize treatment.

Aims of the study and methods Recent studies suggested the existence of significant regional variations, in Italy, for cancer survival. For most neoplasms, survival rates tended to be lower in Southern regions versus Northern areas; for colorectal tumours, 5-year survival was 60% in Northern regions, but ranged between 40% and 50% in the South. Main purpose of the present study was to find out possible reasons which might explain such differences. To reach this objective, we compared the main epidemiological and clinical data in two areas covered by cancer registration: Modena, in the North, and Naples in the South of Italy. Results The results of the study suggest that differences in colorectal cancer survival can be mainly attributed to a different stage at diagnosis, which was less favourable in a larger fraction of cases diagnosed in Southern Italy. This could be the consequence of an insufficient diffusion of screening procedures. Type of surgery, medical treatment and follow-up seem to play little or no role. The study also shows that incidence rates of colorectal cancer are significantly higher in the North than in the South of the country, and that the excess of cases seen in Modena is limited to the age group 55–75+ years, while age-specific incidence is virtually identical in the younger age classes. Conclusion This high-resolution study confirms the paramount importance of stage at diagnosis in the management of colorectal cancer, and suggests that social and economic factors are of relevance, even in Western countries, for reducing inequalities in cancer care.

Randomised controlled trials (RCT) are considered the best source of scientific evidence--the gold standard--when evaluating the efficacy of orthodontic treatments. Frequently, RCT are planned as multicentre trials, with the intention of increasing statistical power and raising the precision of outcome estimates. The management of large-scale RCT, however, requires even more thorough organisation than conventional RCT. Indeed, the need for high accuracy and standardisation in data collection, research aids, secretarial skills, staff and patient training, and organisational meetings, make these studies time-consuming, expensive and, in general, relatively complex to carry out well. A website was developed to support a large scale-orthodontic RCT which aimed to evaluate the efficacy of a functional appliance(www.ortodonzia.unina.it). Websites such as this can increase the quality of data collection, simplify the randomisation process, speed up data collection, and improve trial monitoring. Web-based RCT have the potential to help globalise orthodontic research and also increase our rate of acquisition of evidence in orthodontics.

Purpose We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone-responsive early breast cancer within an ongoing phase III trial. Patients and Methods Patients were randomly assigned to receive tamoxifen, letrozole, or letrozole plus zoledronic acid. Serum values of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, dehydroepiandrosterone-sulphate (DHEA-S), progesterone, and cortisol were measured at baseline and after 6 and 12 months of treatment. For each hormone, changes from baseline at 6 and 12 months were compared between treatment groups, and differences over time for each group were analyzed. Results Hormonal data were available for 139 postmenopausal patients with a median age of 62 years, with 43 patients assigned to tamoxifen and 96 patients assigned to letrozole alone or combined with zoledronic acid. Baseline values were similar between the two groups for all hormones. Many significant changes were observed between drugs and for each drug over time. Namely, three hormones seemed significantly affected by one drug only: estradiol that decreased and progesterone that increased with letrozole and cortisol that increased with tamoxifen. Both drugs affected FSH (decreasing with tamoxifen and slightly increasing with letrozole), LH (decreasing more with tamoxifen than with letrozole), testosterone (slightly increasing with letrozole but not enough to differ from tamoxifen), and DHEA-S (increasing with both drugs but not differently between them). Zoledronic acid did not have significant impact on hormonal levels. Conclusion Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared with tamoxifen.

BACKGROUND. To the authors' knowledge, calibration of the University of California at Los Angeles (UCLA) Integrated Staging System (UISS) prognostic score in patients nephrectomized for nonmetastatic renal cell carcinoma (RCC) has never been specifically addressed. The objective of the current study was to evaluate the calibration of the UISS prognostic score in a European multicenter retrospective study. METHODS. Six European centers participated in the study. According to the UISS, the endpoint was overall survival (OS). Survival curves were estimated by the Kaplan-Meier method. For calibration assessment, the approach of ‘validation by calibration’ first proposed by Van Houwelingen was used. The original prognostic score is embedded in a ‘calibration model’ that allows testing, in the validation cohort, the baseline hazards function as well the model linear predictor. Estimates of the ‘calibration model’ were used to recalibrate the UISS score. RESULTS. Of the 2471 available subjects, 399 had died of any cause within the first 5 years. The observed OS curves were compared with the corresponding expected model-based curves. The UISS model did not adequately predict OS, particularly in the extreme categories (P < .0001). Patients in the validation sample, indeed, fared systematically better than patients in the developing cohort. There was no evidence, instead, of a change in the relative effect of the prognostic covariates. After recalibration, the UISS score worked well in the validation cohort. CONCLUSIONS. The UISS score has good discrimination accuracy and is based on an adequately developed risk function. However, it systematically underestimates OS. At least in a European cohort of RCC patients, the use of the recalibrated UISS model could improve prediction accuracy. Cancer 2008. © 2008 American Cancer Society.

Objective: To estimate effects of weight change on incidence of major cardiovascular events in the Italian population-based Progetto CUORE. Methods: Prospective observation in 12 Italian population-based cohorts on etiology of cardiovascular disease. Twenty-thousand six-hundred-forty-seven men and women aged 35-69years without previous CVD, examined at baseline between 1984 and 1993 and followed for median time 8.5years, with validated first cardiovascular events. Standardised anthropometric variables, lifestyle and biochemical risk factors for CVD; major cardiovascular events as end-points. Results: Linear regression between BMI and major CVD risk factors was combined with Cox coefficients from a prediction model of CVD, CHD and stroke using major risk factors as dependent variables. Estimated cardiovascular risk reductions with BMI lowered by 1 to 3U were: for men 3.8% to 10.9% for all cardiovascular events, 4.2% to 12.1% for CHD, and 2.3% to 6.9% for stroke; for women 2.8% to 8.1% for all cardiovascular events, 3.4% to 9.8% for CHD, and 2.1% to 6.2% for stroke. Conclusions: Body weight level influences cardiovascular disease risk in the Italian population. © 2008 Elsevier Inc. All rights reserved.

Background and aims Clinical studies suggest that menstrual irregularities are associated with metabolic and hormonal abnormalities, insulin resistance and a hyperestrogenic/hyperandrogenic imbalance, that may influence the risk of cardiovascular disease. Methods and results The association of these abnormalities with the metabolic syndrome suggests that information on lipid patterns at different menstrual cycle length may be of interest in identifying women at higher cardiovascular risk. The association of lipid patterns with menstrual cycle length was evaluated in a cohort of 5062 women participating in the Progetto ATENA Study. Questions were administered to the participants about their cycle lengths at different periods of time over their reproductive life. The period between 20 and 50 years was investigated: normal cycle length was defined as short (≤26 days), medium (between 27 and 29 days) or long (>30 days). Perimenopausal women were excluded and variables adjusted for age, BMI and menopausal status. In 4434 participants serum triglycerides were found to increase with an increased number of days in the menstrual cycle: 106 mg/dl in the short cycle pattern (21–26 days); 113 mg/dl in the medium cycle pattern (27–29 days); and 116 mg/dl in the long cycle pattern (30–31 days), whereas total and LDL cholesterol were found to be higher and HDL was lower in women with longer cycles, but the difference was not statistically significant. The results were very similar when the same adjusted analysis was restricted to a subgroup of 3823 women with a stable cycle length over the fourth and the fifth decade of life. Conclusions These results suggest that cycle length may be a marker of higher cardiovascular risk due to associated metabolic and hormonal patterns.

Background In patients with primary glomerulonephritis (GN), antiproteinuric response to angiotensin-converting enzyme (ACE) inhibitors plus angiotensin receptor blockers (ARBs) versus either monotherapy is undefined because of the small size of studies and high heterogeneity of response. Study Design Meta-analysis/metaregression. Setting & Population Randomized clinical trials (RCTs). Selection Criteria for Studies RCTs published from January 1996 to April 2007. Studies were excluded if information about levels of proteinuria was not available, patients had kidney disease other than primary GN, or if they had end-stage renal disease. Intervention ACE inhibitor plus ARB versus monotherapy with 1 of these drug classes. Outcomes Absolute changes in proteinuria (primary), blood pressure, serum potassium level, and glomerular filtration rate (GFR; secondary). Results We found 13 RCTs including 425 patients with primary GN with proteinuria ranging from 0.8 to 7.9 g/d of protein and age from 25 to 60 years. Combination treatment decreased proteinuria by 0.60 g/d (95% confidence interval, 0.40 to 0.80) versus ACE-inhibitor monotherapy and 0.54 g/d (95% confidence interval, 0.30 to 0.78) versus ARB monotherapy. Baseline levels of proteinuria explained most between-study variability of the antiproteinuric response to combination therapy versus monotherapies. Systolic and diastolic blood pressure, GFR, age, and diagnosis of immunoglobulin A nephropathy did not modify antiproteinuric response. ACE-inhibitor plus ARB therapy did not change GFR, whereas it increased serum potassium levels (by 0.10 mEq/L versus ACE-inhibitor and 0.19 mEq/L versus ARB therapy) and decreased blood pressure. Limitations Only published data are included. Conclusions The antiproteinuric response to ACE-inhibitor plus ARB therapy versus either monotherapy is consistently greater and strictly related to baseline proteinuria, associated with only moderate increase in serum potassium levels, and not peculiar to immunoglobulin A nephropathy.

OBJECTIVE: To evaluate effect of age on hypertensive status in chronic kidney disease (CKD). METHODS: We studied 459 prevalent CKD patients (stages 2-5, no dialysis), grouped by age (< 55, 55-64, 65-74, >or= 75 years), undergoing clinical blood pressure (CBP) and ambulatory blood pressure (ABP) measurement. RESULTS: Prevalence of diabetes, left ventricular hypertrophy and previous cardiovascular disease progressively increased with aging; glomerular filtration rate (GFR) and hemoglobin decreased. Achievement of CBP target decreased from 16% in patients < 55 years to 6% in those >or= 75 years (P = 0.023). ABP 24-h systolic rose while diastolic decreased, with a consequent pulse pressure increase from 45 +/- 8 to 65 +/- 14 mmHg (P < 0.0001). Age, proteinuria, diabetes, cardiovascular disease and anemia but not GFR predicted higher 24-h pulse pressure. CBP overestimated systolic/diastolic daytime ABP by 14 +/- 18/7 +/- 11 mmHg on average, a greater difference in older than younger groups (P < 0.005). Conversely, CBP night-time ABP difference did not vary among groups (24 +/- 20/16 +/- 11 mmHg). These age-dependent differences determined a rising prevalence of white-coat hypertension (from 19 to 40%, P = 0.001) and night/day ratio of at least 0.9 (from 43 to 66%, P = 0.0004). Age, diabetes, left ventricular hypertrophy and anemia but not GFR predicted nondipping status. Among the oldest patients, 13% had diastolic CBP below 70 mmHg, with 48% below the corresponding values of daytime (< 69 mmHg) or night-time ABP (< 60 mmHg). CONCLUSION: In CKD, prevalence of white-coat hypertension, nondipping status and potentially dangerous low diastolic ABP increases with aging. This suggests wider use of ABP monitoring in older patients and need for trials addressing identification of an age-specific blood pressure target.

Purpose Although several randomized trials have been performed comparing weekly docetaxel (wD) with standard docetaxel once every 3 weeks (3wD) as second-line treatment of advanced non–small-cell lung cancer (NSCLC), no single trial had sufficient power to detect clinically relevant differences in survival. Methods We performed a meta-analysis based on individual patient data from all identified randomized trials comparing wD with 3wD as second-line treatment of advanced NSCLC. Baseline characteristics, treatment assigned, and outcome data were collected for each patient. The primary end point was overall survival. All statistical analyses were stratified by trial. Results Five eligible trials were identified for a total of 865 patients: 433 patients had been assigned to 3wD, and 432 patients had been assigned to wD. Median age was 62 years (range, 26 to 80 years). Performance status was 0 in 23%, 1 in 58%, and 2 in 16% of patients; 91% of the patients had received previous platinum, and 14% had received previous paclitaxel. With 733 deaths recorded (85%), median survival was 27.4 weeks for patients treated with 3wD, and 26.1 weeks for patients treated with wD (P = .24, log-rank test). There was no significant heterogeneity among the five trials. No relevant differential effect was detected in subgroup analyses. Significantly less severe and febrile neutropenia was reported with wD (P < .00001 for both), whereas no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxicity. Conclusion wD shows similar efficacy compared with 3wD, and represents an alternative for second-line treatment of advanced NSCLC.

Objectives To summarise the evidence about the efficacy of a Mediterranean diet on the management of type 2 diabetes and prediabetic states. Design A systematic review of all meta-analyses and randomised controlled trials (RCTs) that compared the Mediterranean diet with a control diet on the treatment of type 2 diabetes and prediabetic states was conducted. Electronic searches were carried out up to January 2015. Trials were included for meta-analyses if they had a control group treated with another diet, if they were of sufficient duration (at least 6 months), and if they had at least 30 participants in each arm. A random-effect model was used to pool data. Participants Adults with or at risk for type 2 diabetes. Interventions Dietary patterns that described themselves as using a ‘Mediterranean’ dietary pattern. Outcome measures The outcomes were glycaemic control, cardiovascular risk factors and remission from the metabolic syndrome. Results From 2824 studies, 8 meta-analyses and 5 RCTs were eligible. A ‘de novo’ meta-analysis of 3 long-term (>6 months) RCTs of the Mediterranean diet and glycaemic control of diabetes favoured the Mediterranean diet as compared with lower fat diets. Another ‘de novo’ meta-analysis of two long-term RCTs showed a 49% increased probability of remission from the metabolic syndrome. 5 meta-analyses showed a favourable effect of the Mediterranean diet, as compared with other diets, on body weight, total cholesterol and high-density lipoprotein cholesterol. 2 meta-analyses demonstrated that higher adherence to the Mediterranean diet reduced the risk of future diabetes by 19–23%. Conclusions The Mediterranean diet was associated with better glycaemic control and cardiovascular risk factors than control diets, including a lower fat diet, suggesting that it is suitable for the overall management of type 2 diabetes.

OBJECTIVES: Neuroendocrine differentiation is a common feature of prostate cancer (pCA). NeuroD1 is a neuronal transcription factor able to convert epithelial cells into neurons. The aim of the study is to investigate NeuroD1 expression and compare it with chromogranin-A, synaptophysin, and CD56 staining in human prostate cell lines and surgical specimens. METHODS: We detected NeuroD1 gene expression, by duplex reverse transcriptase-polymerase chain reaction, in primary human prostate fibroblasts, in EPN, LNCaP, DU145, and PC3 cell lines before and after cAMP exposure, in 6 BPH and 11 pCA samples. Thereafter 166 paraffin sections from normal and neoplastic prostates were stained with NeuroD1, chromogranin-A, synaptophysin, and CD56 antibodies. The relationships between chromogranin-A and NeuroD1 and clinicopathologic parameters were evaluated by multivariate logistic regression analysis. RESULTS: NeuroD1 is inactive in baseline prostate cell lines and BPHs, whereas it is actively expressed in cAMP-treated EPN, PC3, and DU145 cells. In our surgical series, positive chromogranin-A, synaptophysin, CD56, and NeuroD1 staining was detected in 26.5%, 4.3%, 3.1%, and 35.5%, respectively (difference between chromogranin-A and NeuroD1: p

The greater antiproteinuric efficacy of converting enzyme inhibitor and angiotensin II receptor blocker combination (CEI+ARB), versus monotherapy with either drug, is not a consistent finding. We evaluated the clinicopathologic predictors of response to CEI+ARB in 43 patients with primary glomerulonephritis (GN), never treated with immunosuppressive drugs, and with persistent proteinuria after CEI alone. Main histological lesions were analyzed by obtaining on 557 glomeruli and 165 arteries formal score of mesangial cellularity, glomerulosclerosis, tubulointerstitial damage, mononuclear cell infiltration, arteriosclerosis, and arteriolar hyalinosis. Duration of CEI and CEI+ARB therapy was similar (4.7+/-2.4 and 5.0+/-1.5 months). Proteinuria (g/day) decreased from 3.5+/-2.9 to 2.4+/-2.3 after CEI, and to 1.5+/-1.3 after CEI+ARB (P

Recently, the focus of research on cardiovascular risk factors has broadened because of new data demonstrating benefits of low risk (i.e., favorable) levels of all major modifiable risk factors. Most data on low risk relate to coronary heart disease, not stroke. This population-based, 12-sample, Italian study (Progetto CUORE, 1983-2002), with 10-year follow-up, assessed the relation of low risk to stroke and implications for prevention. At baseline, women and men were 35-69 years of age. Only 3% were low risk; 80% were high risk. Overall, stroke incidence rates were 20.7 for men and 9.6 for women per 10,000 person-years. No strokes occurred in low risk participants, and stroke incidence was low with borderline elevation of only one risk factor. Four modifiable risk factors--elevated blood pressure, smoking, diabetes, and high total cholesterol/high density lipoprotein cholesterol ratio--related independently to stroke risk. For those at low risk or who had only one unfavorable (but not high) risk factor, the stroke rate was 76% lower than for high risk participants; for all persons not at high risk, the stroke rate was 57% lower than for those at high risk. Results show that favorable risk factor levels assure minimal stroke risk. Population-wide prevention is needed, especially improved lifestyles, to increase the prevalence of low risk.

none 11 no OBJECTIVES: Advanced diabetic nephropathy (DN) is characterized by a marked development of cardiovascular and renal disease. These patients are frequently managed by different health professionals with the consequence that the quality of care may differ substantially. To compare the management of cardiovascular risk factors in patients with type 2 DN and an estimated glomerular filtration rate (GFR) of 15-60 ml/min per 1.73 m2 followed in nephrology, diabetology and primary care. METHODS: This multicentre cross-sectional study verified the control of blood pressure (BP), total cholesterol, triglycerides, glycosylated haemoglobin A1c (HbA1c) and haemoglobin in patients exclusively followed in either nephrology (n = 266), diabetology (n = 246) or primary care (n = 195) of the same metropolitan area for at least 1 year. RESULTS: Primary care patients were older and had a greater prevalence of previous cardiovascular events. The GFR was lower in nephrology than in diabetology and primary care (33 +/- 13 versus 47 +/- 9 and 40 +/- 12 ml/min per 1.73 m2, P < 0.0001). The prevalence of BP target (< 130/80 mmHg) was similarly low in nephrology, diabetology and primary care (14, 13 and 10%, P = 0.421) probably because of insufficient prescription of diuretics and low-salt diet. Whereas the prevalence of the triglycerides target was similar, that of total cholesterol (< 200 mg/dl) was larger in diabetology (63%) than in nephrology and primary care (59 and 46%, P = 0.003) because of greater statin prescription in hypercholesterolemic individuals (70, 50 and 41%, respectively, P = 0.002). The attainment of HbA1c less than 7% was less frequent in diabetology (32%) than in nephrology and primary care (61 and 46%, P = 0.0003) despite a more frequent prescription of insulin/oral agents in diabetology. The control of anaemia was better in diabetology. Multivariate analysis adjusted for the patient case-mix and physician-level clustering confirmed these differences except for anaemia. CONCLUSION: Patients with advanced DN, despite the worst renal and cardiovascular prognosis, are at high risk of being under-treated independently of the type of clinical setting. Il lavoro costituisce una delle tre pubblicazione su riviste internazionale del progetto multicentrico nazionale "NID-2" (Nephropathy in type 2 diabetes), di cui il dott. F.C. Sasso è il coordinatore nazionane. reserved MINUTOLO R; SASSO FC; CHIODINI P; CIANCIARUSO B; CARBONARA O; ZAMBOLI P; TIRINO G; POTA A; TORELLA R; CONTE G; DE NICOLA L Minutolo, Roberto; Sasso, Ferdinando Carlo; Chiodini, Paolo; Cianciaruso, B; Carbonara, O; Zamboli, Pasquale; Tirino, G; Pota, A; Torella, R; Conte, Giuseppe; DE NICOLA, Luca

Many studies confirm that beating heart surgery is an alternative to on-pump myocardial revascularization. However, the clinical conditions of patients are currently considered as a major landmark in the indication for beating heart surgery. This retrospective non-randomized study was carried out to evaluate the efficacy and the advantages of this surgical technique when anatomical criteria are used to choose the surgical strategy.From February to December 2003, 222 consecutive patients underwent isolated myocardial revascularization: 76 (34%) with an off-pump coronary artery bypass (OPCAB) and 146 (66%) with an on-pump coronary artery bypass (ONCAB) procedure. Selection for surgical treatment was based on coronary anatomy. All patients were stratified for mortality risk class according to the EuroSCORE system. Operative and postoperative data were analyzed.Morbidity and mortality did not differ significantly between the two groups but the release of creatine kinase-MB fraction was significantly higher in the ONCAB group (48.7 +/- 55.3 vs 20.8 +/- 16.6 U/ml, p0.001). Patients at high surgical risk were dealt with a more complicated clinical outcome; logistic regression analysis showed that this class was an independent risk factor for postoperative complications in both groups.We did not find any statistical difference in hospital mortality and morbidity either using ONCAB or OPCAB; however a lower release of creatine kinase-MB in beating heart revascularization group suggests that OPCAB reduces myocardial injury and preserves cardiac function when anatomical criteria are considered for patient selection.

Background. As is well known, the use of the immunosuppressive drug cyclosporin A (CsA) is partially restricted by its nephrotoxic effects, which include early changes in haemodynamics followed by irreversible injuries to the renal tubules. Although the mechanisms responsible for these side effects are poorly understood, an involvement of reactive oxygen species (ROS) has been suggested. In this study, we selected three natural antioxidants, resveratrol, hydroxytyrosol and vitamin E, on the basis of their scavenging capabilities, and tested their protective effects against CsA toxicity.Methods. Immortalized rat tubular cells (RPTc) were used as the model system. Cell viability was checked with trypan blue assay, and free radical formation was measured using the fluorescent probe 2,7-dichlorofluorescein (DCF). We evaluated several oxidative stress parameters, including phospholipid peroxidation products, glutathione levels and oxygenase expression.Results. Incubation of RPTc with 25 mu M CsA induced a significant decrease in cell viability paralleled by intracellular ROS formation and alterations in lipid peroxidation. There was also an imbalance of glutathione redox state as well as upregulation of heme oxygenase-1 (HO-1). The three antioxidants, at micromolar concentration, quantitatively prevented the ROS-activated DCF fluorescent signal and membrane lipid peroxidation. Both hydroxytyrosol and resveratrol strengthened the CsA induction of HO-I expression. Moreover, vitamin E and resveratrol counteracted CsA-induced changes in the glutathione redox state via different mechanisms, whereas hydroxytyrosol was completely ineffective. Similarly, CsA-dependent nephrotoxicity was prevented by vitamin E, while resveratrol only exerted partial protection, and hydroxytyrosol showed no protective effects.Conclusion. Our results indicate that the diverse cytoprotective effects of the antioxidants tested in these studies were not directly related to their scavenging capabilities. These findings confirm a key role for glutathione in protecting cells from CsA-induced adverse effects and do not support a direct link between CsA-mediated ROS generation and adverse renal effects.

BACKGROUND The objective of the current study was to compare, in a large multicenter study, the discriminating accuracy of four prognostic models developed to predict the survival of patients undergoing nephrectomy for nonmetastatic renal cell carcinoma (RCC). METHODS A total of 2404 records of patients from 6 European centers were retrospectively reviewed. For each patient, prognostic scores were calculated according to four models: the Kattan model, the University of California at Los Angeles integrated staging system (UISS) model, the Yaycioglu model, and the Cindolo model. Survival curves were estimated by the Kaplan–Meier method and compared by the log-rank test. Discriminating ability was assessed by the Harrell c-index for censored data. The primary end point was overall survival (OS), and the secondary end points were cancer-specific survival (CSS) and disease recurrence-free survival (RFS). RESULTS At last follow-up, 541 subjects had died of any causes, with a 5-year OS rate of 80%. The 5-year CSS and RFS rates were 85% and 78%, respectively. All models discriminated well (P < 0.0001). The c-indexes for OS were 0.706 for the Kattan nomogram, 0.683 for the UISS model, and 0.589 and 0.615 for the Yaycioglu and Cindolo models, respectively. The Kattan nomogram was found to improve discrimination substantially in the UISS intermediate-risk patients. CONCLUSIONS The current study appears to better define the general applicability of prognostic models for predicting survival in patients with nonmetastatic RCC treated with nephrectomy. The results suggest that postoperative models discriminate substantially better than preoperative ones. The Kattan model was consistently found to be the most accurate, although the UISS model was only slightly less well performing. The Kattan model can be useful in the UISS intermediate-risk patients. Cancer 2005. © 2005 American Cancer Society.

Although most patients with moderate chronic kidney disease (CKD) are managed exclusively in primary care (PC), no data on blood pressure (BP) control in this setting are available. We compared hypertension management in patients with CKD followed up in PC and nephrology tertiary care (TC).We studied hypertensive patients with estimated glomerular filtration rates (eGFRs) of 15 to 60 mL/min/1.73 m2 (0.25 to 1.00 mL/s) exclusively followed up for at least 1 year in PC (n = 259) or TC (n = 186).PC compared with TC patients were characterized by older age (73 +/- 10 versus 65 +/- 14 years; P0.0001), greater prevalences of previous cardiovascular events (59% versus 32%; P0.0001) and diabetes (36% versus 23%; P = 0.005), and slightly greater eGFRs (37 +/- 10 versus 34 +/- 11 mL/min/1.73 m2 ; P = 0.005). They showed higher BP levels (143 +/- 15/82 +/- 7 versus 136 +/- 18/78 +/- 11 mm Hg; P0.0001), with a lower prevalence of BP target (5.8% [95% confidence interval (CI), 2.9 to 8.6] versus 21.5% [95% CI, 15.6 to 27.4]; P0.0001). The risk for not achieving BP target in PC was 2.6 times greater, independently from age, sex, diabetes, and eGFR. Fewer antihypertensive drugs were prescribed in PC (1.9 +/- 1.1 versus 2.5 +/- 1.1; P0.0001). In both groups, inhibitors of the renin-angiotensin system were the most frequently prescribed drugs (84%), followed by diuretics (50%). However, family physicians almost exclusively prescribed hydrochlorothiazide, whereas nephrologists preferentially prescribed furosemide, administered at a higher dose than in PC (47 +/- 41 versus 28 +/- 21 mg/d; P = 0.004).Control of CKD-related hypertension is significantly worse in PC despite a greater cardiovascular risk. Barriers to optimal BP control likely are represented by a low number of drugs and inadequate diuretic therapy.

Background The aims of this paper are to derive a 10-year coronary risk predictive equation for adult Italian men, and to assess its accuracy in comparison with the Framingham Heart Study (FHS) and PROCAM study equations. Methods The CUORE study is a prospective fixed-cohort study. Eleven cohorts, from the north and the centre-south of Italy, had been investigated at baseline between 1982 and 1996, adopting MONICA methods to measure risk factors. Among this sample of 6865 men, aged 35-69 years and free of coronary heart disease (CHD) at baseline, 312 first fatal and non-fatal major coronary events occurred in 9.1 years median follow-up. Calibration, as the difference between 10-year predicted and actual risk, and discrimination, as the ability of the risk functions to separate high-risk from low-risk subjects, have been assessed to compare accuracy of the FHS, the PROCAM, and the CUORE study equations. Results The best CUORE equation includes age, total cholesterol, systolic blood pressure, cigarette smoking, HDL-cholesterol, diabetes mellitus, hypertension drug treatment, and family history of CHD (area under the ROC curve = 0.75). The uncalibrated estimates of the 10-year risk in this CUORE follow-up data were 0.093 and 0.109 higher (P < 0.05) from the Framingham and PROCAM risk scores, respectively, than the Kaplan-Meier estimate for CUORE, indicating risk overestimates for both equations. Standard recalibration techniques improved accuracy of the FHS equation only. PROCAM overestimates were prominent in the higher risk deciles. With an alternative method for recalibration better risk estimates were obtained, but a cohort study was needed to obtain a properly calibrated risk equation. Conclusions The CUORE Project predictive equation showed better accuracy of the FHS and PROCAM equations, overcoming frequently reported risk overestimates. The CUORE equation may be adopted to identify men with high coronary risk in Italy.

Summary Background Chemotherapy is the standard treatment for advanced non-small-cell lung cancer, and myelosuppression is a common side-effect. We aimed to assess whether haematological toxic effects could be a biological measure of drug activity and a marker of efficacy. Methods We analysed data for 1265 patients who received chemotherapy (vinorelbine, gemcitabine, gemcitabine and vinorelbine, cisplatin and vinorelbine, or cisplatin and gemcitabine) within three randomised trials. Primary landmark analyses were restricted to 436 patients who received all six planned chemotherapy cycles and who were alive 180 days after randomisation. Neutropenia was categorised on the basis of worst WHO grade during chemotherapy: absent (grade 0), mild (grade 1–2), or severe (grade 3–4). All statistical analyses were stratified by treatment allocation. Analyses were repeated in the out-of-landmark group (829 patients), stratifying by treatment allocation and number of chemotherapy cycles. The primary endpoint was overall survival. Findings In the landmark group, hazard ratios of death were 0·65 (0·46–0·93) for patients with severe neutropenia and 0·74 (0·56–0·98) for those with mild neutropenia. Median survival after the landmark time of 180 days was 31·4 weeks (95% CI 25·7–39·6) for patients without neutropenia compared with 42·0 weeks (32·7–59·7) for patients with severe neutropenia, and with 43·7 weeks (36·6–66·0) for those with mild neutropenia (severe vs mild vs no neutropenia p=0·0118). Findings were much the same for the out-of-landmark group. Interpretation Neutropenia during chemotherapy is associated with increased survival of patients with advanced non-small-cell lung cancer, and its absence might be a result of underdosing. Prospective trials are needed to assess whether drug dosing guided by the occurrence of toxic effects could improve efficacy of standard regimens.

Objective To assess the accuracy and generalizability of the preand postoperative Karakiewicz nomograms for predicting cancer-specific survival (CSS) in patients with renal cell carcinoma (RCC). Patients and Methods This retrospective study included 3231 patients from European and US centres, who were treated by radical or partial nephrectomy for RCC between 1992 and 2010. Prognostic scores for each patient were calculated and the primary endpoint was CSS. Discriminating ability was assessed by Harrell's c-index for censored data. The 'validation by calibration' method proposed by Van Houwelingen was used for checking the calibration of covariate effects. Calibration was graphically explored. Results Local and systemic symptoms were present in 23.2% and 9.1% of the patients, respectively. The median follow-up (FU) was 49 months. At the last FU, 408 cancer-related deaths were recorded, Kaplan-Meier estimates of CSS (with 95% confidence intervals [CIs]) at 5 and 10 years were 0.86 (0.84-0.87) and 0.77 (0.75-0.80), respectively. Both nomograms discriminated well. Stratified c-indices for CSS were 0.784 (95% CI 0.753-0.814) for the preoperative nomogram, and 0.842 (95% CI 0.816-0.867) for the postoperative one, with a significant difference between the two values (P < 0.001). The covariate-based predictions on our data for both nomograms were valid. The calibration plots showed no relevant departures from ideal predictions. Conclusions The results suggest that the postoperative Karakiewicz nomogram discriminates substantially better than the preoperative one. These nomogram-based predictions may be used as benchmark data for pretreatment and postoperative decision-making in patients at various stages of RCC.

Risk charts, built through risk functions deriving from longitudinal studies, are used in order to identify individuals at high risk for cardiovascular disease. For this reason the function has been identified and the global cardiovascular risk chart of the CUORE Project has been prepared, using Italian data coming from different cohorts enrolled between the '80s and the '90s, whose risk factors had been collected by standardized procedures.The following risk factors have been used: age (10-year period, 40-49, 50-59, 60-69 years), gender (men and women), systolic blood pressure (or = 129, 130-149, 150-169,or = 170 mmHg), serum cholesterol (or = 173, 174-212, 213-251, 252-290,or = 291 mg/dl), smoking habit (yes, no) and presence of diabetes (yes, no); the first coronary or cerebrovascular event in people aged 40-69 years with no other previous cardiovascular events was considered as endpoint; survival has been assessed up to December 1998.Out of 18,028 people aged 40-69 years with no previous cardiovascular events, 647 first major cardiovascular events have been identified and validated, 449 coronary and 198 cerebrovascular. Charts are divided according to men and women and to diabetics and non-diabetics respectively; the different colors represent the percent level of risk and go from light green (5% in 10 years for men,1% in 5 years for women), dark green (between 5 and 10% for men, between 1 and 3% for women), yellow (between 10 and 15% for men, between 3 and 5% for women), orange (between 15 and 20% for men, between 5 and 7% for women), red (between 20 and 30% for men, between 7 and 10% for women), violet (30% for men,10% for women).The risk charts were built with data collected in recent years on men and women with a median follow-up of 10 years for men and 5 years for women, considering the first major fatal or non-fatal cardiovascular event as endpoint. Such a tool is easy to be applied by general practitioners and cardiologists in order to achieve a fast and objective evaluation of global cardiovascular risk.