Locally Advanced and Metastatic Prostate Cancer Treated with Intermittent Androgen Monotherapy or Maximal Androgen Blockade: Results from a Randomised Phase 3 Study by the South European Uroncological Group

BACKGROUND: Few randomised studies have compared antiandrogen intermittent hormonal therapy (IHT) with continuous maximal androgen blockade (MAB) therapy for advanced prostate cancer (PCa). OBJECTIVE: To determine whether overall survival (OS) on IHT (cyproterone acetate; CPA) is noninferior to OS on continuous MAB. DESIGN, SETTING, AND PARTICIPANTS: This phase 3 randomised trial compared IHT and continuous MAB in patients with locally advanced or metastatic PCa. INTERVENTION: During induction, patients received CPA 200 mg/d for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH; triptoreline 11.25 mg) analogue plus CPA 200 mg/d. Patients whose prostate-specific antigen (PSA) was <4 ng/ml after 3 mo of induction treatment were randomised to the IHT arm (stopped treatment and restarted on CPA 300 mg/d monotherapy if PSA rose to ≥20 ng/ml or they were symptomatic) or the continuous arm (CPA 200 mg/d plus monthly LHRH analogue). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome measurement was OS. Secondary outcomes included cause-specific survival, time to subjective or objective progression, and quality of life. Time off therapy in the intermittent arm was recorded. RESULTS AND LIMITATIONS: We recruited 1045 patients, of which 918 responded to induction therapy and were randomised (462 to IHT and 456 to continuous MAB). OS was similar between groups (p=0.25), and noninferiority of IHT was demonstrated (hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.76-1.07). There was a trend for an interaction between PSA and treatment (p=0.05), favouring IHT over continuous therapy in patients with PSA ≤1 ng/ml (HR: 0.79; 95% CI, 0.61-1.02). Men treated with IHT reported better sexual function. Among the 462 patients on IHT, 50% and 28% of patients were off therapy for ≥2.5 yr or >5 yr, respectively, after randomisation. The main limitation is that the length of time for the trial to mature means that other therapies are now available. A second limitation is that T3 patients may now profit from watchful waiting instead of androgen-deprivation therapy. CONCLUSIONS: Noninferiority of IHT in terms of survival and its association with better sexual activity than continuous therapy suggest that IHT should be considered for use in routine clinical practice.

Mid-Term Results of EVAR in Severe Proximal Aneurysm Neck Angulation.

OBJECTIVE: To determine if mid-term outcome following endovascular aneurysm repair (EVAR) with the Endurant Stent Graft (Medtronic, Santa Rosa, CA, USA) is influenced by severe proximal neck angulation. METHODS: A retrospective case-control study was performed using data from a prospective multicenter database. All measurements were obtained using dedicated reconstruction software and center-lumen line reconstruction. Patients with neck length >15 mm, infrarenal angle (β) >75°, and/or suprarenal angle (α) >60°, or neck length >10 mm with β >60°, and/or α >45° were compared with a matched control group. Primary endpoint was primary clinical success. Secondary endpoints were freedom from rupture, type 1A endoleak, stent fractures, freedom from neck-related reinterventions, and aneurysm-related adverse events. Morphological neck variation over time was also assessed. RESULTS: Forty-five patients were included in the study group and were compared with a matched control group with 65 patients. Median follow-up time was 49.5 months (range 30.5-58.4). The 4-year primary clinical success estimates were 83% and 80% for the angulated and nonangulated groups (p = .42). Proximal neck angulation did not affect primary clinical success in a multivariate model (hazard ratio 1.56, 95% confidence interval 0.55-4.41). Groups did not differ significantly in regard to freedom from rupture (p = .79), freedom from type 1A endoleak (p = .79), freedom from neck-related adverse events (p = .68), and neck-related reinterventions (p = .68). Neck angle reduction was more pronounced in patients with severe proximal neck angulation (mean Δα -15.6°, mean Δβ -30.6°) than in the control group (mean Δα -0.39°, mean Δβ -5.9°) (p < .001). CONCLUSION: Mid-term outcomes following EVAR with the Endurant Stent Graft were not influenced by severe proximal neck angulation in our population. Despite the conformability of the device, moderate aortic neck remodeling was identified in the group of patients with angulated neck anatomy on the first computed tomography scan after implantation with no important further remodeling afterwards. No device integrity failures were encountered.

Effect of C282Y Genotype on Self-Reported Musculoskeletal Complications in Hereditary Hemochromatosis

OBJECTIVE: Arthropathy that mimics osteoarthritis (OA) and osteoporosis (OP) is considered a complication of hereditary hemochromatosis (HH). We have limited data comparing OA and OP prevalence among HH patients with different hemochromatosis type 1 (HFE) genotypes. We investigated the prevalence of OA and OP in patients with HH by C282Y homozygosity and compound heterozygosity (C282Y/H63D) genotype. METHODS: A total of 306 patients with HH completed a questionnaire. Clinical and demographic characteristics and presence of OA, OP and related complications were compared by genotype, adjusting for age, sex, body mass index (BMI), current smoking and menopausal status. RESULTS: In total, 266 of the 306 patients (87%) were homozygous for C282Y, and 40 (13%) were compound heterozygous. The 2 groups did not differ by median age [60 (interquartile range [IQR] 53 to 68) vs. 61 (55 to 67) years, P=0.8], sex (female: 48.8% vs. 37.5%, P=0.18) or current smoking habits (12.4% vs. 10%, P=0.3). As compared with compound heterozygous patients, C282Y homozygous patients had higher median serum ferritin concentration at diagnosis [1090 (IQR 610 to 2210) vs. 603 (362 to 950) µg/L, P<0.001], higher median transferrin saturation [80% (IQR 66 to 91%) vs. 63% (55 to 72%), P<0.001]) and lower median BMI [24.8 (22.1 to 26.9) vs. 26.2 (23.5 to 30.3) kg/m2, P<0.003]. The overall prevalence of self-reported OA was significantly higher with C282Y homozygosity than compound heterozygosity (53.4% vs. 32.5%; adjusted odds ratio [aOR] 2.4 [95% confidence interval 1.2-5.0]), as was self-reported OP (25.6% vs. 7.5%; aOR 3.5 [1.1-12.1]). CONCLUSION: Patients with C282Y homozygosity may be at increased risk of musculoskeletal complications of HH.

Early Sac Shrinkage Predicts a Low Risk of Late Complications After Endovascular Aortic Aneurysm Repair

BACKGROUND: Aneurysm shrinkage has been proposed as a marker of successful endovascular aneurysm repair (EVAR). Patients with early postoperative shrinkage may experience fewer subsequent complications, and consequently require less intensive surveillance. METHODS: Patients undergoing EVAR from 2000 to 2011 at three vascular centres (in 2 countries), who had two imaging examinations (postoperative and after 6-18 months), were included. Maximum diameter, complications and secondary interventions during follow-up were registered. Patients were categorized according to early sac dynamics. The primary endpoint was freedom from late complications. Secondary endpoints were freedom from secondary intervention, postimplant rupture and direct (type I/III) endoleaks. RESULTS: Some 597 EVARs (71.1 per cent of all EVARs) were included. No shrinkage was observed in 284 patients (47.6 per cent), moderate shrinkage (5-9 mm) in 142 (23.8 per cent) and major shrinkage (at least 10 mm) in 171 patients (28.6 per cent). Four years after the index imaging, the rate of freedom from complications was 84.3 (95 per cent confidence interval 78.7 to 89.8), 88.1 (80.6 to 95.5) and 94.4 (90.1 to 98.7) per cent respectively. No shrinkage was an independent risk factor for late complications compared with major shrinkage (hazard ratio (HR) 3.11; P < 0.001). Moderate compared with major shrinkage (HR 2.10; P = 0.022), early postoperative complications (HR 3.34; P < 0.001) and increasing abdominal aortic aneurysm baseline diameter (HR 1.02; P = 0.001) were also risk factors for late complications. Freedom from secondary interventions and direct endoleaks was greater for patients with major sac shrinkage. CONCLUSION: Early change in aneurysm sac diameter is a strong predictor of late complications after EVAR. Patients with major sac shrinkage have a very low risk of complications for up to 5 years. This parameter may be used to tailor postoperative surveillance.

Clinical Outcome and Morphologic Determinants of Mural Thrombus in Abdominal Aortic Endografts

OBJECTIVE:Endograft mural thrombus has been associated with stent graft or limb thrombosis after endovascular aneurysm repair (EVAR). This study aimed to identify clinical and morphologic determinants of endograft mural thrombus accumulation and its influence on thromboembolic events after EVAR. METHODS: A prospectively maintained database of patients treated by EVAR at a tertiary institution from 2000 to 2012 was analyzed. Patients treated for degenerative infrarenal abdominal aortic aneurysms and with available imaging for thrombus analysis were considered. All measurements were performed on three-dimensional center-lumen line computed tomography angiography (CTA) reconstructions. Patients with thrombus accumulation within the endograft's main body with a thickness >2 mm and an extension >25% of the main body's circumference were included in the study group and compared with a control group that included all remaining patients. Clinical and morphologic variables were assessed for association with significant thrombus accumulation within the endograft's main body by multivariate regression analysis. Estimates for freedom from thromboembolic events were obtained by Kaplan-Meier plots. RESULTS: Sixty-eight patients (16.4%) presented with endograft mural thrombus. Median follow-up time was 3.54 years (interquartile range, 1.99-5.47 years). In-graft mural thrombus was identified on 30-day CTA in 22 patients (32.4% of the study group), on 6-month CTA in 8 patients (11.8%), and on 1-year CTA in 17 patients (25%). Intraprosthetic thrombus progressively accumulated during the study period in 40 patients of the study group (55.8%). Overall, 17 patients (4.1%) presented with endograft or limb occlusions, 3 (4.4%) in the thrombus group and 14 (4.1%) in the control group (P = .89). Thirty-one patients (7.5%) received an aortouni-iliac (AUI) endograft. Two endograft occlusions were identified among AUI devices (6.5%; overall, 0.5%). None of these patients showed thrombotic deposits in the main body, nor were any outflow abnormalities identified on the immediately preceding CTA. Estimated freedom from thromboembolic events at 5 years was 95% in both groups (P = .97). Endograft thrombus accumulation was associated with >25% proximal aneurysm neck thrombus coverage at baseline (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.3), neck length ≤ 15 mm (OR, 2.4; 95% CI, 1.3-4.2), proximal neck diameter ≥ 30 mm (OR, 2.4; 95% CI, 1.3-4.6), AUI (OR, 2.2; 95% CI, 1.8-5.5), or polyester-covered stent grafts (OR, 4.0; 95% CI, 2.2-7.3) and with main component "barrel-like" configuration (OR, 6.9; 95% CI, 1.7-28.3). CONCLUSIONS: Mural thrombus formation within the main body of the endograft is related to different endograft configurations, main body geometry, and device fabric but appears to have no association with the occurrence of thromboembolic events over time.

Coronary Revascularization Induces a Shift From Cardiac Toward Noncardiac Mortality Without Improving Survival in Vascular Surgery Patient

OBJECTIVE: Although evidence has shown that ischemic heart disease (IHD) in vascular surgery patients has a negative impact on the prognosis after surgery, it is unclear whether directed treatment of IHD may influence cause-specific and overall mortality. The objective of this study was to determine the prognostic implication of coronary revascularization (CR) on overall and cause-specific mortality in vascular surgery patients. METHODS: Patients undergoing surgery for abdominal aortic aneurysm, carotid artery stenosis, or peripheral artery disease in a university hospital in The Netherlands between January 2003 and December 2011 were retrospectively included. Survival estimates were obtained by Kaplan-Meier and Cox regression analysis. RESULTS: A total of 1104 patients were included. Adjusted survival analyses showed that IHD significantly increased the risk of overall mortality (hazard ratio [HR], 1.50; 95% confidence interval, 1.21-1.87) and cardiovascular death (HR, 1.93; 95% confidence interval, 1.35-2.76). Compared with those without CR, patients previously undergoing CR had similar overall mortality (HR, 1.38 vs 1.62; P = .274) and cardiovascular mortality (HR, 1.83 vs 2.02; P = .656). Nonrevascularized IHD patients were more likely to die of IHD (6.9% vs 35.7%), whereas revascularized IHD patients more frequently died of cardiovascular causes unrelated to IHD (39.1% vs 64.3%; P = .018). CONCLUSIONS: This study confirms the significance of IHD for postoperative survival of vascular surgery patients. CR was associated with lower IHD-related death rates. However, it failed to provide an overall survival benefit because of an increased rate of cardiovascular mortality unrelated to IHD. Intensification of secondary prevention regimens may be required to prevent this shift toward non-IHD-related death and thereby improve life expectancy.

Predição de Pré-Eclâmpsia no Primeiro Trimestre em Gravidezes de Baixo Risco: Determinação do Cut-Off numa Amostra da População Portuguesa

Objective:We aimed to identify the cut-off for risk of pre-eclampsia (PE) in Portuguese population by applying the first trimester prediction model from Fetal Medicine Foundation (FMF) in a prospective enrolled cohort of low risk pregnant women. Population and methods: A prospective cohort of low risk singleton pregnancies underwent routine first-trimester scree - ning from 2011 through 2013. Maternal characteristics, blood pressure, uterine artery Doppler, levels of pregnancy-associated plasma protein-A (PAPP-A) and free b-human chorionic gonadotropin were evaluated. The prediction of PE in first trimester was calculated through software Astraia, the outcome obtained from medical records and the cutoff value was subse quently calculated. Results:Of the 273 enrolled patients, 7 (2.6%) developed PE. In first trimester women who developed PE presented higher uterine arteries resistance, represented by higher values of lowest and mean uterine pulsatility index, p <0.005. There was no statistical significance among the remaining maternal characteristics, body mass index, blood pressure and PAPP-A. Using the FMF first trimester PE algorithm, an ideal cut-off of 0.045 (1/22) would correctly detect 71% women who developed PE for a 12% false positive rate and a likelihood ratio of 12.98 (area under the curve: 0.69; confidence interval 95%: 0.39-0.99). By applying the reported cutoff to our cohort, we would obtain 71.4% true positives, 88.3% true negatives, 11.4% false positives and 28.6% false negatives. Conclusion: By applying a first trimester PE prediction model to low risk pregnancies derived from a Portuguese population, a significant proportion of patients would have been predicted as high risk. New larger studies are required to confirm the present findings.

Low Socioeconomic Status is an Independent Risk Factor for Survival After Abdominal Aortic Aneurysm Repair and Open Surgery for Peripheral Artery Disease

OBJECTIVE/BACKGROUND: The association between socioeconomic status (SES), presentation, and outcome after vascular surgery is largely unknown. This study aimed to determine the influence of SES on post-operative survival and severity of disease at presentation among vascular surgery patients in the Dutch setting of equal access to and provision of care. METHODS: Patients undergoing surgical treatment for peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), or carotid artery stenosis between January 2003 and December 2011 were retrospectively included. The association between SES, quantified by household income, disease severity at presentation, and survival was studied using logistic and Cox regression analysis adjusted for demographics, and medical and behavioral risk factors. RESULTS: A total of 1,178 patients were included. Low income was associated with worse post-operative survival in the PAD cohort (n = 324, hazard ratio 1.05, 95% confidence interval [CI] 1.00-1.10, per 5,000 Euro decrease) and the AAA cohort (n = 440, quadratic relation, p = .01). AAA patients in the lowest income quartile were more likely to present with a ruptured aneurysm (odds ratio [OR] 2.12, 95% CI 1.08-4.17). Lowest income quartile PAD patients presented more frequently with symptoms of critical limb ischemia, although no significant association could be established (OR 2.02, 95% CI 0.96-4.26). CONCLUSIONS: The increased health hazards observed in this study are caused by patient related factors rather than differences in medical care, considering the equality of care provided by the study setting. Although the exact mechanism driving the association between SES and worse outcome remains elusive, consideration of SES as a risk factor in pre-operative decision making and focus on treatment of known SES related behavioral and psychosocial risk factors may improve the outcome of patients with vascular disease.

The Effect of Long-Chain Polyunsaturated Fatty Acids Intake During Pregnancy on Adiposity of Healthy Full-Term Offspring at Birth

OBJECTIVE: The adjusted effect of long-chain polyunsaturated fatty acid (LCPUFA) intake during pregnancy on adiposity at birth of healthy full-term appropriate-for-gestational age neonates was evaluated. STUDY DESIGN: In a cross-sectional convenience sample of 100 mother and infant dyads, LCPUFA intake during pregnancy was assessed by food frequency questionnaire with nutrient intake calculated using Food Processor Plus. Linear regression models for neonatal body composition measurements, assessed by air displacement plethysmography and anthropometry, were adjusted for maternal LCPUFA intakes, energy and macronutrient intakes, prepregnancy body mass index and gestational weight gain. RESULT: Positive associations between maternal docosahexaenoic acid intake and ponderal index in male offspring (β=0.165; 95% confidence interval (CI): 0.031-0.299; P=0.017), and between n-6:n-3 LCPUFA ratio intake and fat mass (β=0.021; 95% CI: 0.002-0.041; P=0.034) and percentage of fat mass (β=0.636; 95% CI: 0.125-1.147; P=0.016) in female offspring were found. CONCLUSION: Using a reliable validated method to assess body composition, adjusted positive associations between maternal docosahexaenoic acid intake and birth size in male offspring and between n-6:n-3 LCPUFA ratio intake and adiposity in female offspring were found, suggesting that maternal LCPUFA intake strongly influences fetal body composition.

Evaluation of Leishmania antigens preparation and storage for use in enzyme immunoassays

The influence of time and temperature on the storage of an alkaline antigen of L.major-like and L.(V.) braziliensis promastigotes added or not of a proteases inhibitor (PMSF) was evaluted by means of an IgG-ELISA. Antibodies in assays using L. major-like antigen stored at -20oC for 6 monsths had a statistically lower geometric mean titer (GMT) and different 95% confidence interval limits (CL) than antigens stored otherwise, as assessed by the "t" statistic. The PMSF L. major-like antigen after storage for 6 months at a temperature of 4oC had the same GMT and 95% CL displayed at time zero as well as when storage for 4 and 6 months at -20oC. Significant diferences were not found when L.(V.) braziliensis antigens were stored at times and temperatures mentioned; the PMSF antigen stored for 2 months at -70oC resulted in a lower serum GMT and 95% CL than any other, as assessed by the "t" statistic. Antigen performance did not show any statistical difference associated to the addition of PMSF within the same species; the largest difference between antigens was that between PMSF-L. (V.) braziliensis and L. major-like without PMSF.

Erros pré-analíticos em anatomia patológica : prevalência, caracterização e consequências para a segurança do doente

RESUMO - A literatura disponível revela que a maioria dos erros relacionados com os exames anatomopatológicos ocorre na fase pré-analítica. Existem alguns estudos que quantificam e caracterizam estes erros mas, não foram encontrados artigos publicados sobre o tema em hospitais portugueses. Foi objetivo deste estudo determinar qual a prevalência e características dos erros pré-analíticos em amostras anatomopatológicas e as suas consequências para a segurança do doente. Analisaram-se 10574 casos de exames anatomopatológicos, de cinco hospitais da região de Lisboa e Vale do Tejo. Os serviços de anatomia patológica registaram e caracterizaram, durante vinte dias, erros detetados nas amostras anatomopatológicas com origem nos serviços requisitantes. Posteriormente os hospitais foram caracterizados quanto aos procedimentos relativos à fase pré-analítica. A prevalência de erros aferida foi de 3,1% (n=330), com um intervalo de confiança a 95% compreendido entre os valores 2,8% e 3,5%. Para além destes resultados destacam-se os seguintes pontos: i. As amostras histológicas têm 4,1% de prevalentes e as de citologia 0,9%; ii. Foram registados erros em 2,6% das requisições e em 1,5% dos contentores com as amostras; iii. A aceitação dos casos com erro é a ação mais frequente (66,9%), seguida pela devolução (24,4%) e retenção (8,7%); iv. Os hospitais com sistemas de notificação de erros e normas escritas para aceitação de amostras têm menor prevalência de erros; v. O impacte dos erros detetados na segurança dos doentes é difícil de determinar, sendo que os mais críticos relacionam-se com amostras devolvidas a fresco, meio de colheita inadequado ou com amostras danificadas. Este estudo permitiu determinar a prevalência e caracterizar os erros pré-analíticos envolvendo amostras anatomopatológicas em hospitais portugueses. Reflete a dimensão atual do problema e efetua recomendações para a sua mitigação. A prevalência de erros encontrada é inferior às publicadas em estudos semelhantes.

An estimation of the frequency of gestational toxoplasmosis in the Brazilian Federal District

Acute infections by the protozoan Toxoplasma gondii during pregnancy (gestational toxoplasmosis) are known to cause serious health problems to the fetus (congenital toxoplasmosis). In Brasília, there have been few studies on the incidence of toxoplasmosis. This report summarizes a retrospective study performed on 2,636 selected pregnant women attended by the public health system of Guará, a satellite-city of Brasília. In this survey, 17 cases of gestational toxoplasmosis were detected; 15 of which were primary maternal infection and the remaining 2 were consistent with secondary maternal infection. These results suggest an annual seroconversion rate of 0.64 percent (90 percent confidence interval: 0.38, 0.90).

Development of a satellite based PM10 concentration product for urban areas

Dissertação para obtenção do Grau de Doutor em Engenharia do Ambiente

Seroprevalence of Helicobacter pylori infection in chagasic and nonchagasic patients from the same geographical region of Brazil

INTRODUCTION: In this study, we evaluated the seroprevalence of Helicobacter pylori infection among chagasic and non-chagasic subjects as well as among the subgroups of chagasic patients with the indeterminate, cardiac, digestive, and cardiodigestive clinical forms. METHODS: The evaluated subjects were from the Triângulo Mineiro region, Minas Gerais, Brazil. Chagasic patients showed positive reactions to the conventional serological tests used and were classified according to the clinical form of their disease. Immunoglobulin G antibodies specific to H. pylori were measured using a commercial enzyme-linked immunosorbent assay kit. RESULTS: The overall H. pylori prevalence was 77.1% (239/310) in chagasic and 69.1% (168/243) in non-chagasic patients. This difference was statistically significant even after adjustment for age and sex (odds ratio = 1.57; 95% confidence interval, 1.02-2.42; p = 0.04) in multivariate analysis. The prevalence of infection increased with age in the non-chagasic group (p = 0.007, χ2 for trend), but not in the chagasic group (p = 0.15, χ2 for trend). H. pylori infection was not associated with digestive or other clinical forms of Chagas disease (p = 0.27). CONCLUSIONS: Our findings demonstrate that chagasic patients have a higher prevalence of H. pylori compared to non-chagasic subjects; a similar prevalence was found among the diverse clinical forms of the disease. The factors contributing to the frequent co-infection with H. pylori and Trypanosoma cruzi as well as its effects on the clinical outcome deserve further study.

Detection and molecular analysis of Toxoplasma gondii and Neospora caninum from dogs with neurological disorders

INTRODUCTION: Toxoplasma gondii and Neospora caninum are related Apicomplexa parasites responsible for systemic diseases in many species of animals, including dogs. METHODS: This study aimed to determine the occurrence of T. gondii and N. caninum infections in 50 dogs with neurological signs that were admitted to the Veterinary Hospital of Universidade Estadual Paulista, City of Botucatu, Brazil. All animals were screened for antibodies using an immunofluorescent antibody test for both parasites. Tissues of positive animals were bioassayed in mice (T. gondii) and gerbils (N. caninum), and DNA was analyzed using the polymerase chain reaction (PCR). Positive samples for T. gondii by PCR were typed using restriction fragment length polymorphism-PCR for 11 markers: SAG1, SAG2 (5′-3′-SAG2 and alt.SAG2), SAG3, Btub, GRA6, L358, c22-8, c29-6, PK1 and Apico, and CS3 marker for virulence analysis. RESULTS: Specific antibodies were detected in 11/50 (22%; 95% confidence interval (CI95%), 12.8-35.3%) animals for T. gondii and 7/50 (14%; CI95%, 7.02-26.3%) for N. caninum. In the bioassay and PCR, 7/11 (63.6%; CI95%, 34.9-84.8%) samples were positive for T. gondii and 3/7 (42.9%; CI95%I, 15.7-75.5%) samples were positive for N. caninum. Three different genotypes were identified, but only 1 was unique. CONCLUSIONS: These data confirm the presence of T. gondii and N. caninum in dogs from Brazil, indicating the importance of this host as a sentinel of T. gondii for human beings, and the genotypic variation of this parasite in Brazil.