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3.
Sci Rep ; 9(1): 753, 2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679663

RESUMO

The pathogenesis of idiopathic and heritable forms of pulmonary arterial hypertension is still not completely understood, even though several causative genes have been proposed, so that a third of patients remains genetically unresolved. Here we applied a multistep approach to extend identification of the genetic bases of such a disease by searching for novel candidate genes/pathways. Twenty-eight patients belonging to 18 families were screened for BMPR2 mutations and BMPR2-negative samples were tested for 12 additional candidate genes by means of a specific massive parallel sequencing-based assay. Finally, whole exome sequencing was performed on four patients showing no mutations at known disease genes, as well as on their unaffected parents. In addition to EIF2AK4, which has been already suggested to be associated with pulmonary veno-occlusive disease, we identified the novel candidate genes ATP13A3, CD248, EFCAB4B, involved in lung vascular remodeling that represent reliable drivers contributing to the disease according to their biological functions/inheritance patterns. Therefore, our results suggest that combining gene panel and whole exome sequencing provides new insights useful for the genetic diagnosis of familial and idiopathic pulmonary arterial hypertension, as well as for the identification of biological pathways that will be potentially targeted by new therapeutic strategies.

4.
Clin Res Cardiol ; 108(7): 772-778, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30564950

RESUMO

INTRODUCTION: Symptoms and functional limitation are frequently reported by survivors of acute pulmonary embolism (PE). However, current guidelines provide no specific recommendations on which patients should be followed after acute PE, when follow-up should be performed, and which tests it should include. Definition and classification of late PE sequelae are evolving, and their predictors remain to be determined. METHODS: In a post hoc analysis of the Pulmonary Embolism Thrombolysis (PEITHO) trial, we focused on 219 survivors of acute intermediate-risk PE with clinical and echocardiographic follow-up 6 months after randomisation as well as over the long term (median, 3 years after acute PE). The primary outcome was a composite of (1) confirmed chronic thromboembolic pulmonary hypertension (CTEPH) or (2) 'post-PE impairment' (PPEI), defined by echocardiographic findings indicating an intermediate or high probability of pulmonary hypertension along with New York Heart Association functional class II-IV. RESULTS: Confirmed CTEPH or PPEI occurred in 29 (13.2%) patients, (6 with CTEPH and 23 with PPEI). A history of chronic heart failure at baseline and incomplete or absent recovery of echocardiographic parameters at 6 months predicted CTEPH or PPEI at long-term follow-up. CONCLUSIONS: CTEPH or PPEI occurs in almost one out of seven patients after acute intermediate-risk PE. Six-month echocardiographic follow-up may be useful for timely detection of late sequelae.

5.
Eur Respir J ; 53(1)2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30545974

RESUMO

Pulmonary hypertension (PH) is frequent in left heart disease (LHD), as a consequence of the underlying condition. Significant advances have occurred over the past 5 years since the 5th World Symposium on Pulmonary Hypertension in 2013, leading to a better understanding of PH-LHD, challenges and gaps in evidence. PH in heart failure with preserved ejection fraction represents the most complex situation, as it may be misdiagnosed with group 1 PH. Based on the latest evidence, we propose a new haemodynamic definition for PH due to LHD and a three-step pragmatic approach to differential diagnosis. This includes the identification of a specific "left heart" phenotype and a non-invasive probability of PH-LHD. Invasive confirmation of PH-LHD is based on the accurate measurement of pulmonary arterial wedge pressure and, in patients with high probability, provocative testing to clarify the diagnosis. Finally, recent clinical trials did not demonstrate a benefit in treating PH due to LHD with pulmonary arterial hypertension-approved therapies.

9.
Eur J Heart Fail ; 20(2): 248-255, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28464427

RESUMO

AIMS: Pulmonary hypertension (PH) is a relevant complication of left heart disease (LHD). The 2015 ESC/ERS PH guidelines report two different haemodynamic subsets of PH due to LHD (PH-LHD) based on levels of pulmonary vascular resistance (PVR) and diastolic pressure gradient (DPG): isolated post-capillary PH (Ipc-PH) and combined post- and pre-capillary PH (Cpc-PH). The objective of this study is to evaluate the prognostic value of Ipc-PH and Cpc-PH. METHODS AND RESULTS: Data from 276 consecutive incident patients with PH-LHD were included. According to the guidelines, Ipc-PH is defined by DPG <7 mmHg and/or PVR ≤3 Wood units (WU) and Cpc-PH by DPG ≥7 mmHg and/or PVR >3 WU. Using this definition, we identified three patient groups: Ipc-PH with both normal PVR and DPG (108 patients); Cpc-PH with both increased PVR and DPG (66 patients); and an intermediate group with either increased PVR or DPG (102 patients). Survival was estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Patients with Ipc-PH had better survival compared with the group of patients with Cpc-PH (P = 0.026) and the intermediate group (P = 0.025). No survival difference was detected between patients with Cpc-PH and the intermediate group (P = 0.891). Patients with normal PVR had a better survival compared with those with elevated PVR (P = 0.012); while no difference was observed according to the level of DPG (P = 0.253). CONCLUSION: Patients with Ipc-PH have a better prognosis compared with patients with Cpc-PH and with patients with isolated increase of PVR or DPG. Pulmonary vascular resistance has a better predictive value than DPG in patients with PH-LHD.

11.
J Am Coll Cardiol ; 69(23): 2808-2817, 2017 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-28595696

RESUMO

BACKGROUND: Left main coronary artery (LMCA) compression is increasingly recognized as a cause of angina in pulmonary arterial hypertension (PAH). OBJECTIVES: This study aimed to evaluate the prevalence of LMCA extrinsic compression from a dilated pulmonary artery (PA) in patients with PAH and angina or angina-like symptoms, determine the usefulness of screening with computed tomography coronary angiography (CTCA), and assess the safety and efficacy of percutaneous coronary interventions (PCIs). METHODS: All patients with PAH and angina or angina-like symptoms attending the center between May 1, 2008, and December 31, 2013, underwent CTCA. Patients with confirmed LMCA stenosis on selective coronary angiography had PCI. RESULTS: Of 765 patients with PAH, 121 had angina or angina-like symptoms. Ninety-four patients had abnormal CTCA based on the relationship between the PA and the LMCA and underwent selective coronary angiography. LMCA stenosis ≥50% was detected in 48 of the 94 patients. Forty-five patients underwent PCI with stenting, of whom 41 had sustained angina symptom relief. The 3 other patients had surgical PA reduction plasty. Nine months after PCI, 5 patients had LMCA restenosis and PCI was successfully repeated. The best predictor of LMCA stenosis ≥50% was a PA diameter ≥40 mm. Rates for death or double-lung transplant and the composite rates for death, double-lung transplant, or restenosis at 36 months were 5% and 30%, respectively. CONCLUSIONS: The prevalence of LMCA compression in patients with PAH and angina is high. These results suggest that CTCA is indicated in patients with PAH and angina or angina-like symptoms. PCI was well tolerated, improved symptoms, and resulted in favorable long-term outcomes.


Assuntos
Angina Pectoris/etiologia , Estenose Coronária/complicações , Vasos Coronários/diagnóstico por imagem , Hipertensão Pulmonar/etiologia , Artéria Pulmonar/diagnóstico por imagem , Adulto , Angina Pectoris/diagnóstico , Angiografia Coronária , Estenose Coronária/diagnóstico , Estenose Coronária/cirurgia , Vasos Coronários/cirurgia , Feminino , Seguimentos , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Masculino , Intervenção Coronária Percutânea/métodos , Estudos Prospectivos , Tomografia Computadorizada por Raios X
12.
Radiol Med ; 122(7): 495-504, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28316030

RESUMO

PURPOSE: The aim of this study was to retrospectively assess the relationship between radiological and hemodynamic parameters in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We introduced a new CT-score to evaluate hemodynamic changes, only employing CT-pulmonary angiography (CTPA). MATERIALS AND METHODS: 145 patients affected by CTEPH underwent hemodynamic and CTPA evaluation. Among these 145 patients, 69 underwent pulmonary endarterectomy (PEA) and performed a CTPA evaluation even after surgery. Hemodynamic assessment considered the values of mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR), obtained through right heart catheterization (RHC). Radiological evaluation included CTPA signs of pulmonary hypertension. RESULTS: A highly significant statistical correlation was observed between the new CT-score and both mPAP and PVR (p < 0.000) in the whole sample and also in the subgroup who underwent PEA. In addition, mPAP and PVR showed an important association with the severity of mosaic perfusion (p < 0.000). mPAP also correlated with main pulmonary artery diameter (p < 0.01); a significant association was found in both between PVR and tricuspid regurgitation(p < 0.000) and with PVR and presence of unilateral or bilateral pulmonary thromboembolic occlusion (p < 0.05). CONCLUSION: Our results confirm the diagnostic role of CTPA in evaluating patients with CTEPH and in addition open a new horizon in assessing hemodynamic changes in patients with CTEPH, only employing a CTPA, especially when RHC is contraindicated or not possible.


Assuntos
Hemodinâmica/fisiologia , Hipertensão Pulmonar/diagnóstico por imagem , Embolia Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Angiografia , Cateterismo Cardíaco , Doença Crônica , Endarterectomia , Feminino , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/cirurgia , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/complicações , Embolia Pulmonar/fisiopatologia , Embolia Pulmonar/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
13.
Int J Cardiol ; 235: 67-72, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28279499

RESUMO

BACKGROUND: The primary objective of this post hoc analysis was to evaluate clinical outcomes of tadalafil in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD-PAH) compared with patients with idiopathic/heritable PAH (I/H-PAH) for primary and key secondary efficacy endpoints, and safety. This analysis included adult patients with CTD-PAH or I/H-PAH who participated in the PHIRST and PHIRST-2 studies. METHODS: Patients were randomized 1:1:1:1:1 to tadalafil (2.5, 10, 20, or 40mg) or placebo in the PHIRST study and the majority of these patients were subsequently assigned 40mg in PHIRST-2. Patients taking 20mg in PHIRST without demonstrating clinical worsening continued on 20mg in PHIRST-2. Outcomes analyzed included 6MWD, WHO-FC, and incidence and time to first occurrence of clinical worsening. Safety was assessed through evaluation of adverse events (AEs), clinical laboratory data, electrocardiograms, and physical examinations. RESULTS: Increased 6MWD in PHIRST was maintained in both CTD-PAH and I/H-PAH subgroups for 52weeks. Patients with CTD-PAH tended to be older, were more likely female, had lower exercise capacity, were more likely to have clinical worsening, and experienced AEs more frequently than patients with I/H-PAH. CONCLUSION: The effect of tadalafil treatment in patients enrolled in both PHIRST studies was detectable for both I/H-PAH and CTD-PAH subgroups. In general, subgroup differences were modest. Patients with CTD-PAH may perform less well than patients with I/H-PAH in safety and efficacy measures in all treatment groups, which is similar to other studies demonstrating a worse prognosis for patients with CTD-PAH.


Assuntos
Doenças do Tecido Conjuntivo/complicações , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Hipertensão Pulmonar Primária Familiar , Hipertensão Pulmonar , Tadalafila , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Eletrocardiografia/métodos , Hipertensão Pulmonar Primária Familiar/diagnóstico , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Masculino , Pessoa de Meia-Idade , Exame Físico/métodos , Tadalafila/administração & dosagem , Tadalafila/efeitos adversos , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversos
14.
J Am Coll Cardiol ; 69(12): 1536-1544, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28335835

RESUMO

BACKGROUND: The long-term effect of thrombolytic treatment of pulmonary embolism (PE) is unknown. OBJECTIVES: This study investigated the long-term prognosis of patients with intermediate-risk PE and the effect of thrombolytic treatment on the persistence of symptoms or the development of late complications. METHODS: The PEITHO (Pulmonary Embolism Thrombolysis) trial was a randomized (1:1) comparison of thrombolysis with tenecteplase versus placebo in normotensive patients with acute PE, right ventricular (RV) dysfunction on imaging, and a positive cardiac troponin test result. Both treatment arms received standard anticoagulation. Long-term follow-up was included in the third protocol amendment; 28 sites randomizing 709 of the 1,006 patients participated. RESULTS: Long-term (median 37.8 months) survival was assessed in 353 of 359 (98.3%) patients in the thrombolysis arm and in 343 of 350 (98.0%) in the placebo arm. Overall mortality rates were 20.3% and 18.0%, respectively (p = 0.43). Between day 30 and long-term follow-up, 65 deaths occurred in the thrombolysis arm and 53 occurred in the placebo arm. At follow-up examination of survivors, persistent dyspnea (mostly mild) or functional limitation was reported by 36.0% versus 30.1% of the patients (p = 0.23). Echocardiography (performed in 144 and 146 patients randomized to thrombolysis and placebo, respectively) did not reveal significant differences in residual pulmonary hypertension or RV dysfunction. Chronic thromboembolic pulmonary hypertension (CTEPH) was confirmed in 4 (2.1%) versus 6 (3.2%) cases (p = 0.79). CONCLUSIONS: Approximately 33% of patients report some degree of persistent functional limitation after intermediate-risk PE, but CTEPH is infrequent. Thrombolytic treatment did not affect long-term mortality rates, and it did not appear to reduce residual dyspnea or RV dysfunction in these patients. (Pulmonary Embolism Thrombolysis study [PEITHO]; NCT00639743).


Assuntos
Fibrinolíticos/uso terapêutico , Embolia Pulmonar/prevenção & controle , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/diagnóstico por imagem , Embolia Pulmonar/mortalidade , Tenecteplase , Resultado do Tratamento
15.
Radiol Med ; 122(4): 257-264, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28025781

RESUMO

PURPOSE: To test the efficacy of bronchial artery embolization (BAE) to treat haemoptysis in pulmonary hypertension (PH). METHODS: 33 patients were treated by BAE for haemoptysis associated with PH (PH group = 21) or non-associated with PH (control group = 12). The details of procedure, outcome, and rate of relapse were compared between the two groups. Within the PH group, the comparison was operated between subjects with congenital heart disease-associated pulmonary artery hypertension (CHD-APAH subgroup = 12) and non-CHD (non-CHD-APAH subgroup = 9). RESULTS: The rate of relapse at 30 and 90-days was similar between the PH group and control group. BAE in the PH group was more challenging (median 2 arteries embolized per procedure) compared to the control group (median 1 artery embolized per procedure; p = 0.001). Bleeding arteries were more heterogeneous in the PH group, while a single right bronchial artery was the only clinical finding in 66.7% of controls (p = 0.001). Within the PH group, the CHD subgroup showed higher survival rate compared to the non-CHD-APAH group (p = 0.007). CONCLUSION: BAE is effective and safe for the treatment of haemoptysis in PH, yet more challenging than other conditions. In PH-associated haemoptysis, BAE provides higher survival rate for subjects with PH associated with CHD.


Assuntos
Artérias Brônquicas , Embolização Terapêutica/métodos , Hemoptise/etiologia , Hemoptise/terapia , Hipertensão Pulmonar/complicações , Adulto , Feminino , Cardiopatias Congênitas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Taxa de Sobrevida , Resultado do Tratamento
16.
J Heart Lung Transplant ; 36(4): 399-406, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27282418

RESUMO

BACKGROUND: The VOLibris Tracking (VOLT) Study was an open-label, prospective, observational, multicenter, post-marketing registry program designed to more fully characterize the safety profile of ambrisentan for the treatment of pulmonary arterial hypertension (PAH). The key outcome was the incidence of aminotransferase elevations >3× the upper limit of normal (ULN). METHODS: In total, 999 patients from 115 centers in 15 countries, who were prescribed ambrisentan for the treatment of PAH (Functional Class II and III) between 30 June 2008 and 13 May 2011, were enrolled. Of these, 238 had PAH associated with connective tissue disease (PAH-CTD) and 220 had no prior PAH-specific therapy. Routine clinical monitoring data were collected by physicians. RESULTS: The incidence of both alanine and aspartate aminotransferase events (>3× ULN) was 0.02 per patient-year (95% confidence interval 0.015 to 0.027). Similar results were reported for the PAH-CTD and PAH-specific-therapy-naive subgroups. Overall, 514 (52%) patients reported treatment-emergent adverse events of special interest, most commonly edema/fluid retention (249, or 25%) and anemia (143, or 14%). CONCLUSIONS: Data from the VOLT study indicate no new ambrisentan-related safety signals. Ambrisentan was not associated with increases in liver function test abnormalities above the assumed background incidence of 1.5% per year, and the observed safety profile of ambrisentan was consistent with previously published data.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Fenilpropionatos/uso terapêutico , Vigilância de Produtos Comercializados , Piridazinas/uso terapêutico , Sistema de Registros , Adulto , Idoso , Feminino , Hospitalização , Humanos , Hipertensão Pulmonar/enzimologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transaminases/sangue , Resultado do Tratamento
18.
Lancet Respir Med ; 4(2): 129-37, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26795434

RESUMO

BACKGROUND: Mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) are the commonest genetic cause of pulmonary arterial hypertension (PAH). However, the effect of BMPR2 mutations on clinical phenotype and outcomes remains uncertain. METHODS: We analysed individual participant data of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight cohorts that had been systematically tested for BMPR2 mutations. The primary outcome was the composite of death or lung transplantation. All-cause mortality was the secondary outcome. Hazard ratios (HRs) for death or transplantation and all-cause mortality associated with the presence of BMPR2 mutation were calculated using Cox proportional hazards models stratified by cohort. FINDINGS: Overall, 448 (29%) of 1550 patients had a BMPR2 mutation. Mutation carriers were younger at diagnosis (mean age 35·4 [SD 14·8] vs 42·0 [17·8] years), had a higher mean pulmonary artery pressure (60·5 [13·8] vs 56·4 [15·3] mm Hg) and pulmonary vascular resistance (16·6 [8·3] vs 12·9 [8·3] Wood units), and lower cardiac index (2·11 [0·69] vs 2·51 [0·92] L/min per m(2); all p<0·0001). Patients with BMPR2 mutations were less likely to respond to acute vasodilator testing (3% [10 of 380] vs 16% [147 of 907]; p<0·0001). Among the 1164 individuals with available survival data, age-adjusted and sex-adjusted HRs comparing BMPR2 mutation carriers with non-carriers were 1·42 (95% CI 1·15-1·75; p=0·0011) for the composite of death or lung transplantation and 1·27 (1·00-1·60; p=0·046) for all-cause mortality. These HRs were attenuated after adjustment for potential mediators including pulmonary vascular resistance, cardiac index, and vasoreactivity. HRs for death or transplantation and all-cause mortality associated with BMPR2 mutation were similar in men and women, but higher in patients with a younger age at diagnosis (p=0·0030 for death or transplantation, p=0·011 for all-cause mortality). INTERPRETATION: Patients with PAH and BMPR2 mutations present at a younger age with more severe disease, and are at increased risk of death, and death or transplantation, compared with those without BMPR2 mutations. FUNDING: Cambridge NIHR Biomedical Research Centre, Medical Research Council, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, INSERM, Université Paris-Sud, Intermountain Research and Medical Foundation, Vanderbilt University, National Center for Advancing Translational Sciences, National Institutes of Health, National Natural Science Foundation of China, and Beijing Natural Science Foundation.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Hipertensão Pulmonar/genética , Transplante de Pulmão/estatística & dados numéricos , Adulto , Hipertensão Pulmonar Primária Familiar/genética , Hipertensão Pulmonar Primária Familiar/mortalidade , Hipertensão Pulmonar Primária Familiar/cirurgia , Feminino , Humanos , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/cirurgia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Adulto Jovem
20.
Eur Respir Rev ; 24(138): 674-81, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26621981

RESUMO

The diverse challenges associated with diagnosis and management of patients with pulmonary hypertension are illustrated in this case-based review. Case 1 describes a patient diagnosed with pulmonary arterial hypertension (PAH) with right heart failure and active systemic lupus erythematosus who was effectively treated with an up-front triple combination of PAH therapies and immunosuppressive therapy. In case 2, a diagnosis of pulmonary veno-occlusive disease was reached after a combined approach of clinical suspicion, physical examination, and invasive and noninvasive tests. Cautious PAH therapy and high-dose diuretics provided clinical benefit in this patient and served as a bridge to lung transplantation. These cases highlight the need for ongoing follow-up of patients with PAH, comprising frequent assessment of treatment success and continued diagnostic evaluation.


Assuntos
Anti-Hipertensivos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Hipertensão Pulmonar/tratamento farmacológico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Pneumopatia Veno-Oclusiva/terapia , Adulto , Anticoagulantes/uso terapêutico , Cateterismo Cardíaco , Diuréticos/uso terapêutico , Quimioterapia Combinada , Ecocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Transplante de Pulmão , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/fisiopatologia , Pessoa de Meia-Idade , Oxigenoterapia , Pneumopatia Veno-Oclusiva/complicações , Pneumopatia Veno-Oclusiva/diagnóstico , Fatores de Risco , Tomografia Computadorizada por Raios X , Resultado do Tratamento
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