RESUMEN
The impact of host immunity on outcome in nonsmall cell lung cancer (NSCLC) is controversial. We examined the relationship between lymphoid infiltration patterns in NSCLC and prognosis.Tumour- and stroma-infiltrating CD3(+), CD8(+) and forkhead box P3 (Foxp3)(+) T-lymphocytes were identified using immunohistochemistry and a novel image analysis algorithm to assess total, cytotoxic and regulatory T-lymphocyte counts, respectively, in 196 NSCLC cases. The median cell count was selected as a cut-point to define patient subgroups and the ratio of the corresponding tumour islet:stroma (TI/S) counts was determined.There was a positive association between overall survival and increased CD8(+) TI/S ratio (hazard ratio (HR) for death 0.44, p<0.001) but an inverse relationship between Foxp3(+) TI/S ratio and overall survival (HR 4.86, p<0.001). Patients with high CD8(+) islet (HR 0.48, p<0.001) and Foxp3(+) stromal (HR 0.23, p<0.001) counts had better survival, whereas high CD3(+) and CD8(+) stromal counts and high Foxp3(+) islet infiltration conferred a worse survival (HR 1.55, 2.19 and 3.14, respectively). By multivariate analysis, a high CD8(+) TI/S ratio conferred an improved survival (HR 0.48, p=0.002) but a high Foxp3(+) TI/S ratio was associated with worse survival (HR 3.91, p<0.001).Microlocalisation of infiltrating T-lymphocytes is a powerful predictor of outcome in resected NSCLC.
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Adenocarcinoma/inmunología , Linfocitos T CD8-positivos/inmunología , Carcinoma de Células Grandes/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Células Escamosas/inmunología , Neoplasias Pulmonares/inmunología , Linfocitos T Reguladores/inmunología , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Linfocitos T CD8-positivos/metabolismo , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patología , Carcinoma de Células Grandes/cirugía , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Estudios de Cohortes , Receptores ErbB/genética , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Neoplasia Residual , Neumonectomía , Pronóstico , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas p21(ras)/genética , Estudios Retrospectivos , Linfocitos T Reguladores/metabolismo , Carga TumoralRESUMEN
BACKGROUND: The prevalence and characteristics of pulmonary hypertension in adults with sickle cell disease have not been clearly established. METHODS: In this prospective study, we evaluated 398 outpatients with sickle cell disease (mean age, 34 years) at referral centers in France. All patients underwent Doppler echocardiography, with measurement of tricuspid-valve regurgitant jet velocity. Right heart catheterization was performed in 96 patients in whom pulmonary hypertension was suspected on the basis of a tricuspid regurgitant jet velocity of at least 2.5 m per second. Pulmonary hypertension was defined as a mean pulmonary arterial pressure of at least 25 mm Hg. RESULTS: The prevalence of a tricuspid regurgitant jet velocity of at least 2.5 m per second was 27%. In contrast, the prevalence of pulmonary hypertension as confirmed on catheterization was 6%. The positive predictive value of echocardiography for the detection of pulmonary hypertension was 25%. Among the 24 patients with confirmed pulmonary hypertension, the pulmonary-capillary wedge pressure was 15 mm Hg or less (indicating precapillary pulmonary hypertension) in 11 patients. Patients with confirmed pulmonary hypertension were older and had poorer functional capacity and higher levels of N-terminal pro-brain natriuretic peptide than other patients. In contrast, patients who had a tricuspid regurgitant jet velocity of at least 2.5 m per second without pulmonary hypertension and patients with a tricuspid regurgitant jet velocity of less than 2.5 m per second had similar clinical characteristics. CONCLUSIONS: In this study of adults with sickle cell disease, the prevalence of pulmonary hypertension as confirmed on right heart catheterization was 6%. Echocardiographic evaluation alone had a low positive predictive value for pulmonary hypertension. (Funded by the French Ministry of Health and Assistance Publique-Hôpitaux de Paris; ClinicalTrials.gov number, NCT00434902.).
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Anemia de Células Falciformes/complicaciones , Hemodinámica , Hipertensión Pulmonar/etiología , Adulto , Cateterismo Cardíaco/efectos adversos , Ecocardiografía Doppler , Femenino , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/fisiopatología , Masculino , Prevalencia , Estudios ProspectivosRESUMEN
BACKGROUND: The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. METHODS AND RESULTS: This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (≤20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. CONCLUSIONS: Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.
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Antineoplásicos/efectos adversos , Hipertensión Pulmonar/inducido químicamente , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Tiazoles/efectos adversos , Adolescente , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos , Anciano , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Benzamidas , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Bloqueadores de los Canales de Calcio/uso terapéutico , Dasatinib , Utilización de Medicamentos/estadística & datos numéricos , Antagonistas de los Receptores de Endotelina , Femenino , Estudios de Seguimiento , Hemodinámica/efectos de los fármacos , Humanos , Hidroxiurea/uso terapéutico , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/epidemiología , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Sistema de Registros , Tiazoles/farmacología , Tiazoles/uso terapéutico , Resultado del TratamientoRESUMEN
Data on treatment of patients with portopulmonary hypertension (PoPH) are limited, as they are usually excluded from randomised controlled trials with pulmonary arterial hypertension (PAH)-specific therapies. This study investigated the short- and long-term efficacy/safety of bosentan in these patients, as well as its pharmacokinetics. All 34 consecutive patients with PoPH treated with first-line bosentan (December 2002 to July 2009) were retrospectively evaluated. Assessments included the New York Heart Association functional class (NYHA FC), blood tests, haemodynamics, 6-min walk distance (6MWD) and event-free status. The pharmacokinetics of bosentan in five patients with Child-Pugh (C-P) class B cirrhosis were compared with idiopathic PAH patients. Significant improvements from baseline were observed in NYHA FC, 6 MWD and haemodynamics, and were largely maintained during follow-up. Patients with C-P class B cirrhosis (n=9) had significantly larger haemodynamic improvement after mean ± SD 5 ± 2 months. Mean follow-up time was 43 ± 19 months; four patients died and seven patients had significant elevation of liver enzymes (annual rate 5.5%). Plasma concentrations of bosentan were higher in patients with C-P class B cirrhosis than those observed in idiopathic PAH. These data confirm the benefit of bosentan treatment for patients with PoPH. Haemodynamic improvements were particularly pronounced in patients with more severe cirrhosis. The safety profile of bosentan was consistent with previous studies.
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Antihipertensivos/farmacocinética , Antihipertensivos/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Sistema Porta , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéutico , Antihipertensivos/efectos adversos , Bosentán , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sulfonamidas/efectos adversosRESUMEN
Over the past 20 years, great progress has been made in the treatment of pulmonary arterial hypertension (PAH). Available therapies target one of three principal pathways: the endothelin (ET), nitric oxide (NO) or the prostacyclin (PGI2) pathway. Evidence shows that current drugs, used either as monotherapy or in different combinations, can improve exercise capacity, clinical symptoms, hemodynamics and even survival in PAH. Unfortunately, the disease remains incurable and the prognosis of the disease is still poor. However, existing and novel potent antiproliferative therapies are being explored, and new agents targeting different and/or additional pathways are likely to become available to clinicians in the near future. Promising candidates include tyrosine kinase antagonists (e.g. imatinib); soluble guanylate cyclase stimulators (riociguat); an oral analog of prostacyclin (selexipag); and a tissue targeting endothelin receptor antagonist (macitentan). Phase II or III trials have either been completed or are underway to evaluate the safety and efficacy of these various therapies.
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Antihipertensivos/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Vasodilatadores/uso terapéutico , Animales , Ensayos Clínicos como Asunto , Quimioterapia Combinada/métodos , Hipertensión Pulmonar Primaria Familiar , Humanos , Hipertensión Pulmonar/diagnósticoRESUMEN
BACKGROUND: Renal replacement therapy has been suggested as a therapeutic option in the setting of acute right ventricular failure in patients with severe precapillary pulmonary hypertension. However, there are few data supporting this strategy. OBJECTIVES: To describe the clinical course and the prognosis of pulmonary hypertensive patients undergoing renal replacement therapy in the setting of acute right heart failure. METHODS: This was a single-center retrospective study over an 11-year period. Data were collected from all patients with chronic precapillary pulmonary hypertension requiring catecholamine infusions for clinical worsening and acute kidney injury that necessitated renal replacement therapy. RESULTS: Fourteen patients were included. At admission, patients had a blood urea of 28.2 mmol/l (22.3-41.2), a creatinine level of 496 µmol/l (304-590), and a mean urine output in the 24 h preceding hospitalization of 200 ml (0-650). Sixty-eight renal replacement therapy sessions were performed, 36 of which were continuous and 32 of which were intermittent. Systemic hypotension occurred in 16/32 intermittent and 16/36 continuous sessions (p = 0.9). Two patients died during a continuous session. The intensive care unit-related, 1-, and 3-month mortality was 46.7, 66.7, and 73.3%, respectively. CONCLUSION: Renal replacement therapy is feasible in the setting of acute right ventricular failure in patients with severe precapillary pulmonary hypertension but is associated with a poor prognosis. The best modality and timing in this population remain to be defined.
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Insuficiencia Cardíaca/terapia , Hipertensión Pulmonar/complicaciones , Terapia de Reemplazo Renal , Anciano , Femenino , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
RATIONALE: Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a cause of hereditary hemorrhagic telangiectasia (HHT) and/or heritable pulmonary arterial hypertension (PAH). OBJECTIVES: To describe the characteristics of patients with PAH carrying an ACVRL1 mutation. METHODS: We reviewed clinical, functional, and hemodynamic characteristics of 32 patients with PAH carrying an ACVRL1 mutation, corresponding to 9 patients from the French PAH Network and 23 from literature analysis. These cases were compared with 370 patients from the French PAH Network (93 with a bone morphogenetic protein receptor type 2 [BMPR2] mutation and 277 considered as idiopathic cases without identified mutation). Distribution of mutations in the ACVRL1 gene in patients with PAH was compared with the HHT Mutation Database. MEASUREMENTS AND MAIN RESULTS: At diagnosis, ACVRL1 mutation carriers were significantly younger (21.8 +/- 16.7 yr) than BMPR2 mutation carriers and noncarriers (35.7 +/- 14.9 and 47.6 +/- 16.3 yr, respectively; P < 0.0001). In seven of the nine patients from the French PAH Network, PAH diagnosis preceded manifestations of HHT. ACVRL1 mutation carriers had better hemodynamic status at diagnosis, but none responded to acute vasodilator challenge and they had shorter survival when compared with other patients with PAH despite similar use of specific therapies. ACVRL1 mutations in exon 10 were more frequently observed in patients with PAH, as compared with what was observed in the HHT Mutation Database (33.3 vs. 5%; P < 0.0001). CONCLUSIONS: ACVRL1 mutation carriers were characterized by a younger age at PAH diagnosis. Despite less severe initial hemodynamics and similar management, these patients had worse prognosis compared with other patients with PAH, suggesting more rapid disease progression.
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Receptores de Activinas Tipo II/genética , Hipertensión Pulmonar/genética , Adolescente , Adulto , Distribución por Edad , Presión Sanguínea , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Niño , Preescolar , Prueba de Esfuerzo/métodos , Prueba de Esfuerzo/estadística & datos numéricos , Femenino , Francia , Humanos , Hipertensión Pulmonar/fisiopatología , Lactante , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Mutación Puntual/genética , Arteria Pulmonar , Presión Esfenoidal Pulmonar , Sistema de Registros , Eliminación de Secuencia/genética , Análisis de Supervivencia , Resistencia Vascular , Adulto JovenRESUMEN
This review assesses the available evidence supporting the use of drug combinations for the management of the various forms of pulmonary arterial hypertension (PAH). Ongoing and forthcoming randomized trials evaluating this strategy are also highlighted. Furthermore, new types of agents to treat PAH in the future are explored.
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Antihipertensivos/uso terapéutico , Eicosanoides/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Adrenomedulina/fisiología , Angiopoyetina 1/fisiología , Antihipertensivos/farmacología , Benzamidas , Bosentán , Quimioterapia Combinada , Eicosanoides/farmacología , Epoprostenol/análogos & derivados , Epoprostenol/uso terapéutico , Terapia Genética , Humanos , Mesilato de Imatinib , Péptidos y Proteínas de Señalización Intracelular/fisiología , Piperazinas/farmacología , Piperazinas/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Prostaglandinas/uso terapéutico , Proteínas Serina-Treonina Quinasas/fisiología , Purinas/uso terapéutico , Pirimidinas/farmacología , Serotonina/fisiología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/fisiología , Citrato de Sildenafil , Sulfonamidas/uso terapéutico , Sulfonas/uso terapéutico , Péptido Intestinal Vasoactivo/fisiología , Vasodilatadores/uso terapéutico , Quinasas Asociadas a rhoRESUMEN
Intravenous prostacyclins are a valuable treatment for patients with severe pulmonary arterial hypertension, leading to improved exercise capacity, haemodynamics, quality of life and survival. Unfortunately, due to the short half-life of these drugs, they need to be administered continuously through central venous catheters. Despite aseptic technique, regular dressing changes, tunneled central venous catheters and patient education, patients are exposed to central venous catheter associated infections. These infections cause significant morbidity and mortality. The clinical presentation, microbiology, consequences and management of these central venous catheter associated infections in pulmonary arterial hypertension patients treated with intravenous prostacyclins are discussed.
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Antihipertensivos/administración & dosificación , Infecciones Relacionadas con Catéteres/etiología , Catéteres Venosos Centrales/efectos adversos , Epoprostenol/administración & dosificación , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/tratamiento farmacológico , Administración Intravenosa , Infecciones Relacionadas con Catéteres/microbiología , Infecciones Relacionadas con Catéteres/fisiopatología , Infecciones Relacionadas con Catéteres/terapia , Diseño de Equipo , HumanosRESUMEN
Available targeted therapies for pulmonary arterial hypertension are capable only of slowing progression of the disease and a cure remains elusive. However with the improved understanding of the pulmonary vascular remodeling that characterizes the disease, there is optimism that the disconnect between preclinical and clinical studies may be bridged with some of the newer therapies that are now at different stages of clinical evaluation. This article examines the evidence behind these new candidate treatments that may become part of the arsenal available for clinicians managing this devastating disease.
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Antagonistas de los Receptores de Endotelina , Guanilato Ciclasa/antagonistas & inhibidores , Hipertensión Pulmonar/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Receptores de Epoprostenol/agonistas , Sulfonamidas/uso terapéutico , Hipertensión Pulmonar Primaria Familiar , HumanosRESUMEN
BACKGROUND: While up to 50% of patients with severe asthma have no evidence of allergy, IgE has been linked to asthma, irrespective of atopic status. Omalizumab, an anti-IgE monoclonal antibody, is reported to significantly benefit a subset of patients with severe, persistent, allergic asthma. Therefore, we investigated whether omalizumab has biologic and clinical effects in patients with refractory nonatopic asthma. METHODS: Forty-one adult patients who, despite daily treatment with or without maintenance oral corticosteroids, had severe, nonatopic, refractory asthma according to GINA (Global Initiative for Asthma) step 4, were randomized to receive omalizumab or placebo in a 1:1 ratio. The primary end point was the change in expression of high-affinity IgE receptor (FcεRI) on blood basophils and plasmacytoid dendritic cells (pDC2) after 16 weeks. The impact of omalizumab on lung function and clinical variables was also examined. RESULTS: Compared with placebo, omalizumab resulted in a statistically significant reduction in FcεRI expression on basophils and pDC2 (P < .001). The omalizumab group also showed an overall increase in FEV1 compared with baseline (+250 mL, P = .032; +9.9%, P = .029). A trend toward improvement in global evaluation of treatment effectiveness and asthma exacerbation rate was also observed. CONCLUSIONS: Omalizumab negatively regulates FcεRI expression in patients with severe nonatopic asthma, as it does in severe atopic asthma. Omalizumab may have a therapeutic role in severe nonatopic asthma. Nonetheless, our preliminary findings support further investigation to better assess the clinical efficacy of omalizumab. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01007149; URL: www.clinicaltrials.gov and European Clinical Trials Database, EudraCT; No.: 2009-010937-38; URL: https://www.clinicaltrialsregister.eu.
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Antiasmáticos/uso terapéutico , Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Anciano , Asma/inmunología , Asma/fisiopatología , Método Doble Ciego , Femenino , Humanos , Inmunoglobulina E/inmunología , Masculino , Persona de Mediana Edad , Omalizumab , Placebos , Pruebas de Función Respiratoria , Resultado del TratamientoRESUMEN
Pulmonary arterial hypertension (PAH) is a rare disease characterised by a progressive increase in pulmonary vascular resistance, leading to right heart failure and premature death. Over the last two decades, a better understanding of the pathogenesis of PAH has led to the approval of several targeted therapies that confer improvements in patients' clinical and haemodynamic status, quality of life and survival. Analysis of recent survival data in PAH cohorts have been biased by the inclusion of prevalent patients included months or years after PAH diagnosis ("survivors") who have a better prognosis than corresponding incident patients diagnosed at the time of recruitment. A critical analysis of recent multicentre incident cohorts has shown survival improvements in the current management era. However, idiopathic PAH remains a severe disease and still carries a poor prognosis. Modern survival figures also highlight the relevance of lung transplantation in eligible PAH patients who are refractory to current best standard of medical care.
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Presión Arterial , Hipertensión Pulmonar/mortalidad , Arteria Pulmonar/fisiopatología , Progresión de la Enfermedad , Hipertensión Pulmonar Primaria Familiar , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/terapia , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Resistencia VascularRESUMEN
BACKGROUND: Recent guidelines have proposed first-line combination therapy as a potential strategy for the treatment of functional class IV pulmonary arterial hypertension (PAH). METHODS: We analyzed efficacy and safety of upfront epoprostenol and bosentan combination therapy in consecutive patients with idiopathic, heritable, or anorexigen-associated PAH and compared outcomes with matched controls treated by epoprostenol monotherapy. RESULTS: Data for 16 functional class III patients and 7 functional class IV patients were analyzed. Baseline 6-minute walk distance (6MWD) was 287 ± 133 meters, mean pulmonary artery pressure was 65 ± 12 mm Hg, cardiac index was 1.8 ± 0.3 L/min/m(2), and pulmonary vascular resistance (PVR) was 1493 ± 398 dynes/sec/cm(5). After 4 months, 6MWD and PVR significantly improved to 421 ± 100 meters and 784 ± 364 dynes/sec/cm(5), respectively. These improvements were maintained long-term (30 ± 19 months). At 1, 2, 3, and 4 years, overall survival estimates were 100%, 94%, 94%, and 74%, and transplant-free survival estimates were 96%, 85%, 77%, and 60%, respectively. Compared with matched controls started on epoprostenol monotherapy, there was a trend to an improvement in overall survival (p = 0.07). CONCLUSIONS: Initial combination therapy with epoprostenol and bosentan in patients with severe PAH is associated with improvements in important outcomes such as functional class, exercise capacity, and hemodynamics. This combination strategy might also favorably affect overall and transplant-free survival.
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Antihipertensivos/uso terapéutico , Epoprostenol/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Adulto , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Bosentán , Estudios de Casos y Controles , Quimioterapia Combinada , Epoprostenol/administración & dosificación , Epoprostenol/efectos adversos , Hipertensión Pulmonar Primaria Familiar , Femenino , Humanos , Hipertensión Pulmonar/fisiopatología , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Resultado del TratamientoRESUMEN
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension that may develop in patients with connective tissue diseases (CTD). Most cases have been reported in patients with systemic sclerosis, though associations with systemic lupus erythematosis and mixed connective tissue disease have also been described. PVOD is characterised by progressive obstruction of small pulmonary veins and venules that leads to increased pulmonary vascular resistance, right heart failure and premature death. Distinguishing PVOD from pulmonary arterial hypertension (PAH) is often difficult, though use of a diagnostic algorithm may improve diagnostic accuracy and preclude recourse to lung biopsy. The finding of normal left-heart filling pressures in the context of radiological studies suggestive of pulmonary oedema is an important diagnostic clue, particularly if this clinical scenario coincides with the introduction of vasodilator therapy. There are no approved treatments for the disorder, though cautious use of PAH specific therapy may improve short-term outcomes in selected idiopathic PVOD cases. This review summarises the epidemiologic, clinico-pathologic and imaging characteristics of PVOD in the setting of CTD and discusses potential management approaches.
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Enfermedades del Tejido Conjuntivo/complicaciones , Hipertensión Pulmonar/etiología , Enfermedad Veno-Oclusiva Pulmonar/etiología , Humanos , Enfermedad Veno-Oclusiva Pulmonar/diagnóstico , Enfermedad Veno-Oclusiva Pulmonar/epidemiología , Enfermedad Veno-Oclusiva Pulmonar/terapia , Factores de RiesgoRESUMEN
Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of the pulmonary microvasculature that results in elevated pulmonary vascular resistance and premature death. Although no cure exists for PAH, improved understanding of the pathobiological mechanisms of this disease has resulted in the development of effective therapies that target specific aberrant pathways. Agents that modulate abnormalities in the prostacyclin, endothelin, and nitric oxide pathways have been shown in randomized, controlled studies to confer improvements in functional status, pulmonary hemodynamics, and possibly even slow disease progression. Several additional pathways believed to play an important role in the pathogenesis of PAH have been identified as potentially useful therapeutic targets and a number of investigative approaches focusing on these targets are in active development. In this Review, we highlight the pharmacological agents currently available for the treatment of PAH and discuss potential novel strategies.
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Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Drogas en Investigación/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Terapia Molecular Dirigida , Transducción de Señal/efectos de los fármacos , Animales , Hipertensión Pulmonar Primaria Familiar , Humanos , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Resultado del TratamientoRESUMEN
INTRODUCTION: Endothelin is a key mediator in the pathophysiology of pulmonary arterial hypertension (PAH). Its effects are mediated through the activation of two associated receptor subtypes, termed A and B. Therapeutic strategies that modulate the activity of endothelin are, therefore, of interest to improve the functional status of patients with PAH. AREAS COVERED: The rationale for the use of endothelin receptor antagonists as a therapeutic class in PAH and pertinent data from important clinical studies are presented in this review. Areas for future research are also suggested. EXPERT OPINION: The availability of the endothelin receptor antagonist class of agents represents a significant addition to the therapeutic armamentarium which is available for the treatment of PAH. Comparative studies are warranted to establish whether selective endothelin-A receptor antagonism is more advantageous than dual receptor antagonism. Future studies of endothelin receptor antagonists will increasingly focus on the potential of a combination of different PAH therapeutic classes and will employ 'harder' clinical end points. This is of crucial importance to ensure that future developments are both worthwhile and acceptable to patients, physicians, health system payers and regulatory authorities.
Asunto(s)
Antagonistas de los Receptores de la Endotelina A , Antagonistas de los Receptores de la Endotelina B , Hipertensión Pulmonar/tratamiento farmacológico , Animales , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Bosentán , Humanos , Hipertensión Pulmonar/fisiopatología , Fenilpropionatos/farmacología , Fenilpropionatos/uso terapéutico , Piridazinas/farmacología , Piridazinas/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéuticoRESUMEN
Neurofibromatosis type I (NF1) is a rare genetic disease caused by mutations in the NF1 gene, which codes for tumor suppressor neurofibromin. NF1 is transmitted as an autosomal dominant and fully penetrant trait with no sex predominance. Precapillary pulmonary hypertension (PH) is a severe complication of NF1, initially described in patients with advanced parenchymal lung disease, which may complicate the course of NF1. We conducted this study to describe clinical, functional, radiologic, and hemodynamic characteristics and outcome of patients with NF1-associated PH. We identified 8 new cases of NF1-associated PH in patients carrying a NF1 gene mutation. No bone morphogenic protein receptor 2 (BMPR2) point mutation or large size rearrangements were identified. Seven female patients and 1 male patient were reported, suggesting a possible female predominance. PH occurred late in the course of the disease (median age, 62 yr; range, 53-68 yr). Dyspnea and signs of right heart failure were the major symptoms leading to the diagnosis of PH. At diagnosis, patients had severe hemodynamic impairment with low cardiac index (median, 2.3 L/min per m2; range, 1.9-4.7) and elevated indexed pulmonary vascular resistance (median, 15.1 mm Hg/L/min per m2; range, 4.5-25.9). All patients were in New York Heart Association functional class III with severe exercise limitation (median 6-min walk distance, 180 m; range, 60-375 m). Most patients had associated parenchymal lung disease, but some had no or mild lung involvement with disproportionate pulmonary vascular disease. Overall, the impact of PH therapy was limited and outcomes were poor. In conclusion, PH represents a rare but severe complication of NF1, characterized by female predominance, late onset in the course of NF1, and severe functional and hemodynamic impairment. Because of poor outcome and limited impact of specific PH therapy, eligible patients require early referral for lung transplantation. Further studies are needed to better understand the pathophysiology and the role, if any, of neurofibromin in NF1-associated PH.
Asunto(s)
Hipertensión Pulmonar/etiología , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/genética , Anciano , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Endotelio Vascular/metabolismo , Femenino , Humanos , Hipertensión Pulmonar/diagnóstico , Masculino , Persona de Mediana Edad , Mutación/genética , Miocitos del Músculo Liso/metabolismo , Neurofibromatosis 1/diagnóstico , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , PronósticoRESUMEN
The link between chronic immune activation and tumorigenesis is well established. Compelling evidence has accumulated that histologic assessment of infiltration patterns of different host immune response components in non-small cell lung cancer specimens helps identify different prognostic patient subgroups. This review provides an overview of recent insights gained in the understanding of the role played by chronic inflammation in lung carcinogenesis. The usefulness of quantification of different populations of lymphocytes, natural killer cells, macrophages, and mast cells within the tumor microenvironment in non-small cell lung cancer is also discussed. In particular, the importance of assessment of inflammatory cell microlocalization within both the tumor islet and surrounding stromal components is emphasized.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/etiología , Inflamación/complicaciones , Neoplasias Pulmonares/etiología , Inmunidad Adaptativa , Animales , Linfocitos T CD4-Positivos/inmunología , Enfermedad Crónica , Humanos , Inmunidad Celular , Exposición Profesional/efectos adversos , Pronóstico , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Contaminación por Humo de Tabaco/efectos adversosAsunto(s)
Encefalitis Límbica/diagnóstico , Neoplasias Pulmonares/complicaciones , Carcinoma Pulmonar de Células Pequeñas/complicaciones , Femenino , Humanos , Encefalitis Límbica/etiología , Imagen por Resonancia Magnética , Persona de Mediana Edad , Imagen Multimodal , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: At diagnosis of pulmonary arterial hypertension (PAH), some patients are considered to have a "near-normal" 6-min walk distance (6MWD) (ie, > 450 m). Because they are generally excluded from randomized controlled trials, little is known about these patients. METHODS: We analyzed the baseline characteristics and treatment responses of 49 consecutive patients with a 6MWD > 450 m at the time of newly diagnosed PAH. Data from this cohort were then compared with data from hemodynamically matched patients with a 6MWD < or = 450 m. RESULTS: Patients with a 6MWD > 450 m were either in World Health Organization (WHO) functional class (FC) II (n = 23) or III (n = 26) at baseline. Compared with patients in FC II, those in FC III had more severe hemodynamic impairment (ie, a lower cardiac index and higher pulmonary vascular pressures and resistance) but similar 6MWD. At first evaluation after initiation of PAH-specific treatment (3-6 months), FC improved (FC I-II: n = 38; FC III: n = 11, P < .005) and cardiac index increased. However, 6MWD remained unchanged. Compared with matched patients with a 6MWD < or = 450 m (n = 98), individuals with a 6MWD > 450 m were approximately 9 years younger (P = .0006) and had a lower BMI (P = .0009). CONCLUSIONS: Anthropometric characteristics such as younger age and lower BMI may explain higher 6MWD in some PAH patients. In the cohort of patients with a 6MWD > 450 m, hemodynamic indices and WHO FC were more sensitive than 6MWD in detecting changes secondary to PAH-specific treatments.