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1.
Eur Respir J ; 63(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38843916

RESUMO

BACKGROUND: The role of surgery in pleural mesothelioma remains controversial. It may be appropriate in highly selected patients as part of a multimodality treatment including chemotherapy. Recent years have seen a shift from extrapleural pleuropneumonectomy toward extended pleurectomy/decortication. The most optimal sequence of surgery and chemotherapy remains unknown. METHODS: EORTC-1205-LCG was a multicentric, noncomparative phase 2 trial, 1:1 randomising between immediate (arm A) and deferred surgery (arm B), followed or preceded by chemotherapy. Eligible patients (Eastern Cooperative Oncology Group 0-1) had treatment-naïve, borderline resectable T1-3 N0-1 M0 mesothelioma of any histology. Primary outcome was rate of success at 20 weeks, a composite end-point including 1) successfully completing both treatments within 20 weeks; 2) being alive with no signs of progressive disease; and 3) no residual grade 3-4 toxicity. Secondary end-points were toxicity, overall survival, progression-free survival and process indicators of surgical quality. FINDINGS: 69 patients were included in this trial. 56 (81%) patients completed three cycles of chemotherapy and 58 (84%) patients underwent surgery. Of the 64 patients in the primary analysis, 21 out of 30 patients in arm A (70.0%; 80% CI 56.8-81.0%) and 17 out of 34 patients (50.0%; 80% CI 37.8-62.2%) in arm B reached the statistical end-point for rate of success. Median progression-free survival and overall survival were 10.8 (95% CI 8.5-17.2) months and 27.1 (95% CI 22.6-64.3) months in arm A, and 8.0 (95% CI 7.2-21.9) months and 33.8 (95% CI 23.8-44.6) months in arm B. Macroscopic complete resection was obtained in 82.8% of patients. 30- and 90-day mortality were both 1.7%. No new safety signals were found, but treatment-related morbidity was high. INTERPRETATION: EORTC 1205 did not succeed in selecting a preferred sequence of pre- or post-operative chemotherapy. Either procedure is feasible with a low mortality, albeit consistent morbidity. A shared informed decision between surgeon and patient remains essential.


Assuntos
Mesotelioma , Neoplasias Pleurais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Pleurais/cirurgia , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/terapia , Idoso , Mesotelioma/cirurgia , Mesotelioma/tratamento farmacológico , Mesotelioma/mortalidade , Adulto , Mesotelioma Maligno/cirurgia , Mesotelioma Maligno/tratamento farmacológico , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do Tratamento , Terapia Combinada , Pleura/cirurgia , Pneumonectomia/métodos
2.
J Clin Med ; 12(7)2023 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-37048756

RESUMO

In the era of minimally invasive surgery, the role of sublobar resection comprising anatomical segmentectomy and wide wedge excision remains controversial [...].

4.
J Clin Med ; 10(20)2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34682917

RESUMO

Pulmonary ossifications have often been regarded as rare, post-mortem findings without any clinical significance. We have investigated the occurrence of pulmonary ossifications in patients undergoing thoracic procedures, and how this may affect the differential diagnosis of solitary pulmonary nodules. In addition, we have performed a literature search on the occurrence and possible pathogenesis of these ossifications. From January 2008 until August 2019, we identified pulmonary ossifications in 34 patients who underwent elective pulmonary surgery. Pre-operative imaging was unable to differentiate these ossifications from solid tumors. A definitive diagnosis was made by an experienced pathologist (VS, ML). The PubMed database was researched in December 2019 with the search terms "pulmonary ossifications"; "heterotopic ossifications"; and "solitary pulmonary nodule". In total, 27 patients were male, with a mean age of 63 ± 12 years (age 41 to 82 on diagnosis). All lesions were identified on thoracic CT and marked for resection by a multidisciplinary team. A total of 17 patients were diagnosed with malignancy concurrent with ossifications. There was a clear predilection for the right lower lobe (12 cases, 35.3%) and most ossifications had a nodular form (70.6%). We could not identify a clear association with any other pathology, either cancerous or non-cancerous in origin. Oncologic or pulmonary comorbidities did not influence patient survival. Pulmonary ossifications are not as seldom as thought and are not just a curiosity finding by pathologists. These formations may be mistaken for a malignant space-occupying lesion, both pre-and perioperatively, as they are indistinguishable in imaging. We propose these ossifications as an underestimated addition to the differential diagnosis of a solitary pulmonary nodule.

5.
Acta Chir Belg ; 121(3): 184-188, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31750793

RESUMO

OBJECTIVE: There is still no consensus regarding the treatment of empyema in children. Intrapleural combination of tissue plasminogen activator and dornase alfa is a promising treatment for empyema in adults. The aim of this pilot study was to determine whether this combination is safe and successful in pediatric empyema. METHODS: Previous well children diagnosed with empyema as classified by the British Thoracic Society. After chest tube insertion, intrapleurally dornase alfa 2.5 mg for 2 days and tissue plasminogen activator 0.15 mg/kg for 3 days was given after which the chest tube was clamped for 4 h. Primary outcome was safety. RESULTS: Ten consecutive children were included (4 boys, aged 3.2 (1.3-15.0) years old). No serious adverse events were seen. One child developed urticaria but additional intervention or cessation of the trial was not needed. There was no bleeding or mortality and no additional procedures were performed. The median hospital stay after intervention was 7.5 days. CONCLUSIONS: The intrapleural treatment of dornase alfa and tissue plasminogen activator as treatment of empyema was safe in ten children with empyema. If confirmed in further studies, this combination of intrapleural therapy may improve the management of pediatric empyema.


Assuntos
Empiema Pleural , Ativador de Plasminogênio Tecidual , Adolescente , Criança , Pré-Escolar , Desoxirribonuclease I , Empiema Pleural/tratamento farmacológico , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Lactente , Masculino , Projetos Piloto , Proteínas Recombinantes
6.
Interact Cardiovasc Thorac Surg ; 32(2): 270-275, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33257953

RESUMO

OBJECTIVES: The purpose of this study was to assess the quality of video-assisted cervical mediastinoscopy (VACM) in the staging of non-small-cell lung cancer (NSCLC) at the Antwerp University Hospital with a focus on test effectiveness indicators, morbidity and unforeseen pN2 results. METHODS: All consecutive VACM workups of cases of NSCLC performed between January 2010 and December 2015 were included to assess overall test quality and effectiveness. Quality assurance was performed in accordance with the recommendations of the European Society of Gastrointestinal Endoscopy and European Society of Thoracic Surgeons (ESTS) where appropriate. RESULTS: A total of 168 video-assisted cervical mediastinoscopies were included. A total of 91.7% of the procedures were performed in accordance with the ESTS guideline. An unforeseen pN2 staging was identified in 10 anatomical lung resections (8.6%). Statistical analysis showed no significant association between VACM performed in accordance with the ESTS guideline and the presence of pN2 positive lymph nodes [χ2 (1) = 0.61; P = 0.57] and no association between VACM performed in accordance with the ESTS guideline and overall futile thoracotomy [χ2 (1) = 0.76; P = 0.50]. Calculations revealed a sensitivity of 81.8 [95% confidence interval (CI) 69.1-90.9], specificity of 100%, positive predictive value of 100%, negative predictive value of 91.9% (95% CI 86.6-95.2) and diagnostic accuracy of 94.1% (95% CI 89.33-97.11). CONCLUSIONS: Overall, 91.7% of the VACM were performed in accordance with the ESTS guideline. This process resulted in a sensitivity of 81.8%, a negative predictive value of 91.9% and an unforeseen pN2 rate of 8.6%.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Mediastinoscopia/métodos , Idoso , Humanos , Linfonodos/patologia , Masculino , Mediastino/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Procedimentos Cirúrgicos Pulmonares , Toracotomia
7.
Transl Lung Cancer Res ; 7(5): 562-573, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30450295

RESUMO

In spite of recent progress, malignant pleural mesothelioma (MPM) remains synonymous with poor prognosis. A selected minority (<10%) of patients is eligible for a radical treatment with a combination of systemic chemotherapy (CT) and/or surgery and/or radiotherapy (RT), in an effort to maintain locoregional tumor control after achieving a macroscopically complete resection (MCR). However, as of yet there is no standard of care for this so-called multimodality treatment. As its potential gain is still limited (approximately one year added to overall survival), we must balance its efficacy with its cumulative toxicity. Several combined modality treatment trials are currently ongoing using novel techniques in surgery, RT and/or CT in an attempt to reduce the morbidity and mortality associated with older multimodality treatment protocols. Guidelines are following suit and are now including or mentioning this treatment option. In this systematic review, we analyze the available data in order to address the following questions: Is combined modality better than single modality? What is the optimal regimen within each modality? What is the optimal sequence of combined modality?

8.
Transl Lung Cancer Res ; 7(5): 593-598, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30450298

RESUMO

Radical multimodality treatment for malignant pleural mesothelioma (MPM) is controversial, with intense debate (but lack of data) about which surgical procedure to perform [extrapleural pneumonectomy (EPP) or pleurectomy/decortication (PD)], if any. In order to perform a randomized comparison, the most optimal sequence of surgery and chemotherapy should be determined. EORTC 1205 is a clinical trial randomizing between upfront surgery, followed by chemotherapy (cisplatin plus pemetrexed) and deferred surgery, following neoadjuvant chemotherapy in early stage (T1-3 N0-2 M0) MPM (irrespective of histological subtype). The surgical procedure performed is (extended) pleurectomy/decortication (e-PD), which is promoted as an alternative for EPP, but lacks standardization. Primary outcome parameter is successful completion of multimodality treatment; secondary outcome parameters are surgical quality parameters (in order to standardize the procedure), progression free survival (PFS) and overall survival (OS), treatment-failure free survival, operative morbidity and mortality, toxicity and safety.

9.
Eur J Cardiothorac Surg ; 52(2): 256-263, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28481990

RESUMO

OBJECTIVES: Ischaemia-reperfusion injury is a necessary part of organ transplantation and a key determinant of both acute and chronic graft failure. We have assessed the contribution of endothelial nitric oxide synthase (eNOS) and eNOS uncoupling to oxidative and nitrosative stress formation during lung ischaemia-reperfusion injury dependent on ischaemia time. METHODS: Forty eNOS wild-type mice (eNOS +/+ ) and 40 eNOS knock-out mice (eNOS -/- ) received either a sham thoracotomy or 60 or 90 min of ischaemia, followed by 0, 1 or 24 h of reperfusion. Lung tissue was analysed with electron spin resonance for NO production and reactive oxygen species content. Protein nitrosation, eNOS and eNOS uncoupling were determined using western blotting. In peripheral blood, arterial blood gases were taken and reactive oxygen species content was determined. RESULTS: eNOS +/+ mice had lower reactive oxygen species production in their peripheral circulation but worse blood gas values after 1 h of reperfusion. Lung tissue of eNOS -/- mice showed lower reactive oxygen species and NO production and lower protein nitrosation compared with wild-type mice. Longer ischaemia times result in more elaborate oxidative and nitrosative stress dependent on eNOS genotype. Structural eNOS uncoupling was present after 60 min of ischaemia but diminished after 90 min of ischaemia. CONCLUSIONS: eNOS uncoupling may contribute to lung ischaemia-reperfusion injury and inflammation. This ultimately leads to worse clinical outcome. Stabilizing eNOS may therefore be a new approach to extend pulmonary graft survival.


Assuntos
Pulmão/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/fisiologia , Traumatismo por Reperfusão/metabolismo , Animais , Dióxido de Carbono/sangue , Espectroscopia de Ressonância de Spin Eletrônica , Feminino , Concentração de Íons de Hidrogênio , Pulmão/fisiopatologia , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/genética , Estresse Nitrosativo/fisiologia , Oxigênio/sangue , Traumatismo por Reperfusão/fisiopatologia
10.
Eur J Cardiothorac Surg ; 48(4): 622-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25564212

RESUMO

OBJECTIVES: Pulmonary ischaemia-reperfusion injury (IRI) is associated with several life-threatening pulmonary disorders, and may severely compromise the outcome of lung transplantation. Highly reactive molecules such as superoxide, nitric oxide (NO) and peroxynitrite (ONOO(-)) are presumed to contribute to IRI pathogenesis, but this assumption is based on indirect measurements. We use electron spin resonance (ESR) to directly quantify free radical formation after pulmonary ischaemia and reperfusion. METHODS: Five groups of 10 Swiss mice were subjected to left pulmonary hilum clamping for 1 h of ischaemia followed by 0, 1, 4 and 24 h of reperfusion or to sham thoracotomy alone as control procedure. In five mice per group, ESR was used to measure iron-diethyldithio-carbamate trihydrate-trapped NO in the lung. In the other group of 5, reactive oxygen species generation in the lung and in blood was quantified with ESR by detection of ascorbyl radical and CMH spin probe, respectively. Pulmonary ONOO(-) was monitored with nitrotyrosine Western blotting. RESULTS: After 1 h of reperfusion, a pulmonary NO peak (14.69 ± 0.91 × 10(4) Arbitrary Units (A.U.). vs 1.84 ± 0.75 × 10(4) A.U. in sham; P < 0.001) coincided with a significant increase in nitrosated proteins (0.105 ± 0.015 A.U.) compared with sham (0.047 ± 0.006 A.U.); P < 0.005). Peripheral blood showed a significant free radical burst after 1 h of ischaemia (11 774 ± 728 A.U. vs 6660 ± 833 A.U. in sham; P < 0.001). CONCLUSIONS: Longitudinal quantification of free radicals during IRI reveals the occurrence of two major radical bursts. The radical peak in peripheral blood after ischaemia may be related to systemic hypoxia. After 1 h of reperfusion, the lung tissue shows a significant increase of superoxide, NO and their reaction products, which are probably involved in IRI pathogenesis.


Assuntos
Radicais Livres/metabolismo , Pulmão/irrigação sanguínea , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Animais , Modelos Animais de Doenças , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Estudos de Avaliação como Assunto , Feminino , Transplante de Pulmão/efeitos adversos , Camundongos , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo , Sensibilidade e Especificidade , Superóxido Dismutase/metabolismo
11.
J Surg Res ; 194(2): 659-666, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25588947

RESUMO

BACKGROUND: Pulmonary ischemia-reperfusion injury (IRI) causes postoperative morbidity in patients undergoing lung transplantation, isolated lung perfusion, and cardiopulmonary bypass and may lead to potentially lethal pathologies such as respiratory shock. In-depth study of this pathology requires a reliable animal model. Mice are a popular species to develop experimental models because of their logistic advantages and the availability of knock outs. However, their small size warrants microsurgical techniques and a skilled surgeon. MATERIALS AND METHODS: We developed a murine model of pulmonary anoxic IRI through hilar clamping using adult female Swiss mice. After left thoracotomy, we expose the pulmonary hilum keeping the ribs and the muscles of back and forepaw intact. A microvascular clamp is placed over the entire hilum, occluding bronchus, pulmonary artery, and vein. RESULTS: Our model proved to be simple, reliable, and reproducible, showing minimal preoperative and postoperative mortality. Histopathologic analysis indicated all characteristic features of pulmonary IRI, such as an early recruitment of lymphocytes followed by neutrophil influx. CONCLUSIONS: This article presents a murine surgery model for pulmonary IRI based on a muscle-sparing thoracotomy. The minimal approach limits manipulation of lung tissue, minimizing mortality and non-IRI-induced injury.


Assuntos
Lesão Pulmonar Aguda/etiologia , Modelos Animais de Doenças , Traumatismo por Reperfusão/etiologia , Animais , Feminino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microcirurgia/métodos
12.
J Thorac Oncol ; 9(10): 1547-53, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25105436

RESUMO

INTRODUCTION: The 5-year overall survival rate of patients undergoing complete surgical resection of pulmonary metastases (PM) from colorectal cancer (CRC) and sarcoma remains low (20-50%). Local recurrence rate is high (48-66%). Isolated lung perfusion (ILuP) allows the delivery of high-dose locoregional chemotherapy with minimal systemic leakage to improve local control. METHODS: From 2006 to 2011, 50 patients, 28 male, median age 57 years (15-76), with PM from CRC (n = 30) or sarcoma (n = 20) were included in a phase II clinical trial conducted in four cardiothoracic surgical centers. In total, 62 ILuP procedures were performed, 12 bilaterally, with 45 mg of melphalan at 37°C, followed by resection of all palpable PM. Survival was calculated according to the Kaplan-Meier method. RESULTS: Operative mortality was 0%, and 90-day morbidity was mainly respiratory (grade 3: 42%, grade 4: 2%). After a median follow-up of 24 months (3-63 mo), 18 patients died, two without recurrence. Thirty patients had recurrent disease. Median time to local pulmonary progression was not reached. The 3-year overall survival and disease-free survival were 57% ± 9% and 36% ± 8%, respectively. Lung function data showed a decrease in forced expiratory volume in 1 second and diffusing capacity of the alveolocapillary membrane of 21.6% and 25.8% after 1 month, and 10.4% and 11.3% after 12 months, compared with preoperative values. CONCLUSION: Compared with historical series of PM resection without ILuP, favorable results are obtained in terms of local control without long-term adverse effects. These data support the further investigation of ILuP as additional treatment in patients with resectable PM from CRC or sarcoma.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Melfalan/administração & dosagem , Adolescente , Adulto , Idoso , Neoplasias Ósseas/patologia , Quimioterapia do Câncer por Perfusão Regional/métodos , Neoplasias Colorretais/patologia , Terapia Combinada , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Masculino , Metastasectomia/métodos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Osteossarcoma/patologia , Taxa de Sobrevida , Adulto Jovem
14.
Eur J Cardiothorac Surg ; 42(2): 341-7; discussion 347, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22345285

RESUMO

OBJECTIVES: Isolated lung perfusion (ILuP) and selective pulmonary artery perfusion (SPAP) are experimental surgical techniques to deliver high-dose chemotherapy selectively to the lung for the treatment of lung metastases. ILuP with melphalan (MN) has shown to be feasible in clinical studies but can only be used once because it is invasive. SPAP as an endovascular technique can be repeated several times, but no results have been reported so far. Pharmacokinetics and efficacy of SPAP with MN were studied in a rodent lung metastasis model and compared it with ILuP and intravenous (IV) therapy. METHODS: Pharmacokinetics: forty-five Wag-Rij rats were randomized into three groups: IV 0.5 mg MN, ILuP 0.5 mg MN and SPAP 0.5 mg MN. Every treatment group was again randomized in three groups: 15 min treatment, 30 min treatment and 30 min treatment with 30 min reperfusion. Blood and tissue samples were taken for MN concentrations. EFFICACY: twenty-five Wag-Rij rats were randomized into five groups: control, sham thoracotomy, IV 0.5 mg MN, ILuP 0.5 mg MN and SPAP 0.5 mg MN. At day 0, bilateral lung metastases were induced, and treatment followed at day 7. At day 28, rats were sacrificed and pulmonary metastases counted. Survival: thirty Wag-Rij rats were randomized into five groups: control, sham ILuP, IV 0.5 mg MN, ILuP 0.5 mg MN, SPAP 0.5 mg MN. At day 0, left-sided lungmetastases were induced with treatment at day 7. Endpoints were death due to disease or survival up to 90 days. RESULTS: Pharmacokinetics: SPAP and ILuP resulted in significantly higher left lung MN concentrations compared with IV (P = 0.05). EFFICACY: SPAP (30 ± 22 nodules) and ILuP (20 ± 9 nodules) resulted in significantly less nodules compared with IV (113 ± 17 nodules; P < 0.01). Survival: median survival of SPAP (74 ± 8 days) was equal to ILuP MN (71 ± 10 days) but significantly longer compared with IV (54 ± 7 days; P < 0.01 both). CONCLUSIONS: SPAP with MN for the treatment of sarcoma lung metastases in rats is equally effective to ILuP but resulted in a significantly better survival compared with IV MN. As SPAP can be applied as a minimally invasive endovascular procedure, continued research with this technique is warranted.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Melfalan/administração & dosagem , Rabdomiossarcoma/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/farmacocinética , Linhagem Celular Tumoral , Injeções Intra-Arteriais , Injeções Intravenosas , Melfalan/farmacocinética , Transplante de Neoplasias , Artéria Pulmonar , Distribuição Aleatória , Ratos , Ratos Endogâmicos , Rabdomiossarcoma/secundário , Análise de Sobrevida
15.
Innovations (Phila) ; 6(4): 262-4, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22437986

RESUMO

Mediastinal parathyroid glands are often located in a position which is inaccessible through a cervical approach. Because of the significant morbidity of open surgery, the need for minimal invasive approaches is high. More recently, robotic systems have been introduced to refine the dissection and optimize the view in the mediastinal region. We present two cases. The first case is a 34-year-old woman who was diagnosed with primary hyperparathyroidism. Because a bilateral neck dissection disclosed no parathyroid adenoma, we performed a parathyroid sestamibi scan and computed tomographic scan of neck and mediastinum to look for aberrant parathyroid glands. Both showed a parathyroid adenoma in the mediastinum on the left side. The second case is a 66-year-old man. A sestamibi scan showed a parathyroid adenoma of 3 cm in the superior mediastinum which was confirmed by and computed tomographic scan. In both cases, we performed a parathyroidectomy with the da Vinci robotic system through a left-sided approach. Three thoracoports were inserted around the mammary gland for the robot and a fourth auxiliary port was positioned in between. Single-lung ventilation was installed, and the mediastinum was entered by opening the parietal pleura along the left phrenic nerve. The upper margin for dissection was the left brachiocephalic vein that was followed until the right pleura. All the tissue in front of the pericardium was dissected en bloc. The sinking test of the nodule and a preoperative frozen section analysis confirmed the diagnosis of parathyroid adenoma, which was also proven by rapid parathyroid hormone analysis. The resection of a parathyroid adenoma from the aortopulmonary window represents an ideal case for robotic surgery.

16.
Free Radic Biol Med ; 50(7): 765-76, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21172428

RESUMO

The homodimeric flavohemeprotein endothelial nitric oxide synthase (eNOS) oxidizes l-arginine to l-citrulline and nitric oxide (NO), which acutely vasodilates blood vessels and inhibits platelet aggregation. Chronically, eNOS has a major role in the regulation of blood pressure and prevention of atherosclerosis by decreasing leukocyte adhesion and smooth muscle proliferation. However, a disturbed vascular redox balance results in eNOS damage and uncoupling of oxygen activation from l-arginine conversion. Uncoupled eNOS monomerizes and generates reactive oxygen species (ROS) rather than NO. Indeed, eNOS uncoupling has been suggested as one of the main pathomechanisms in a broad range of cardiovascular and pulmonary disorders such as atherosclerosis, ventricular remodeling, and pulmonary hypertension. Therefore, modulating uncoupled eNOS, in particular eNOS-dependent ROS generation, is an attractive therapeutic approach to preventing and/or treating cardiopulmonary disorders, including protective effects during cardiothoracic surgery. This review provides a comprehensive overview of the pathogenetic role of uncoupled eNOS in both cardiovascular and pulmonary disorders. In addition, the related therapeutic possibilities such as supplementation with the eNOS substrate l-arginine, volatile NO, and direct NO donors as well as eNOS modulators such as the eNOS cofactor tetrahydrobiopterin and folic acid are discussed in detail.


Assuntos
Arginina/metabolismo , Óxido Nítrico Sintase Tipo III , Óxido Nítrico/metabolismo , Arginina/farmacologia , Arginina/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Biopterinas/análogos & derivados , Biopterinas/farmacologia , Biopterinas/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Adesão Celular/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Ácido Fólico/farmacologia , Ácido Fólico/uso terapêutico , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Óxido Nítrico/farmacologia , Óxido Nítrico/uso terapêutico , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , Óxido Nítrico Sintase Tipo III/metabolismo , Oxirredução , Oxigênio/metabolismo , Espécies Reativas de Oxigênio/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Vasodilatação/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
17.
Eur J Cardiothorac Surg ; 38(5): 621-7, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20478715

RESUMO

OBJECTIVE: Surgical resection of lung metastases is a widely accepted procedure but 5-year survival rates remain low and vary between 20% and 50%. Isolated lung perfusion (ILuP) is an experimental technique to deliver a high dose of chemotherapy to the lung, without systemic toxicity. Long-term survival of ILuP has not been reported yet and was determined in a phase I clinical trial. METHODS: From May 2001 to December 2004, a phase I clinical trial was conducted to define the maximum tolerated dose (MTD) of ILuP with melphalan. Twenty-nine procedures were performed in 23 patients. The primary tumour was colorectal in 10 patients, renal in eight, sarcoma in four and salivary gland in one. Toxicity results were previously reported and the MTD of melphalan was determined at 45 mg when given at 37°C. Follow-up was updated and long-term survival is reported. RESULTS: Follow-up was complete, except for one patient who was lost to follow-up after 8 months. After a median follow-up of 62 months, 6 out of 23 patients were alive and free of recurrent disease. One patient died after a subsequent operation. Sixteen patients developed recurrent disease, of whom 11 died. Nine patients had intrathoracic recurrent disease only, one intra- and extrathoracic recurrences each and five extrathoracic only. In one patient, the location of recurrence was not known. Overall- and disease-free 5-year survival rates were 54.8 ± 10.6% and 27.5 ± 9.5%, respectively with an overall median survival time (MST) of 84 months (95% confidence interval (CI): 41-128) and disease-free MST of 19 months (95% CI: 4-34). Lung function and diffusion capacity initially dropped 1 month after perfusion, slightly improving afterwards. Radiographic follow-up with chest computed tomography showed no long-term toxicity from ILuP. CONCLUSION: ILuP can be applied without major long-term pulmonary toxicity. Five-year survival rate, overall and disease-free MST in this phase I clinical trial are promising. This is another incentive to perform further studies with ILuP.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Quimioterapia do Câncer por Perfusão Regional/métodos , Neoplasias Pulmonares/tratamento farmacológico , Melfalan/uso terapêutico , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Terapia Combinada , Métodos Epidemiológicos , Feminino , Volume Expiratório Forçado , Humanos , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Reoperação , Capacidade Pulmonar Total , Resultado do Tratamento
19.
Lung Cancer ; 63(3): 400-4, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18657338

RESUMO

INTRODUCTION: Selective pulmonary artery perfusion (SPAP) is an experimental endovascular technique for the treatment of pulmonary malignancies. This study evaluated blood flow occlusion (BFO) after SPAP and dose-escalation in order to delay washout of gemcitabine from the lung tissue, to augment pulmonary drug exposure and to maintain plasma concentrations equivalent to intravenous administration. MATERIAL AND METHODS: Six groups of pigs underwent left-sided SPAP using gemcitabine in a clinically applied dose of 1-1.5g/m(2) after balloon catheterisation. BFO experiment: four groups (n=4, each) were treated with SPAP with 1g/m(2) of gemcitabine during 2 min followed by BFO for 0, 10, 20 and 30 min, respectively. Dose-escalation experiment: two more groups (n=3, each) received SPAP with 1.25 and 1.5 g/m(2) of gemcitabine during 2 min followed by 30 min BFO. All pigs underwent left thoracotomy with sampling of lung, liver and blood. The animals were sacrificed after 1h. The lung and plasma areas under the curve (AUC) were calculated for each group and ANOVA and t-test was used for comparison. RESULTS: Thirty minutes BFO resulted in the highest lung AUC compared to 0, 10 and 20 min BFO (p<0.001), while no significant differences in plasma AUC and liver levels were observed. Gemcitabine dose-escalation up to 1.25 g/m(2) resulted in significantly higher lung AUC (p=0.02) compared to 1g/m(2), while plasma AUC was equivalent with intravenous treatment. Further dose-escalation to 1.5g/m(2) did not result in significantly higher lung levels compared to 1.25 g/m(2). CONCLUSION: BFO after SPAP delays the washout of gemcitabine from lung tissue. Dose-escalation resulted in higher lung concentrations, while plasma levels were equivalent with intravenous administration. We advocate 2 min of SPAP with 1.25 g/m(2) of gemcitabine followed by 30 min of BFO to be investigated as a new treatment modality for pulmonary malignancies.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/análogos & derivados , Embolização Terapêutica/métodos , Neoplasias Pulmonares/terapia , Perfusão/métodos , Artéria Pulmonar , Animais , Cateterismo , Desoxicitidina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Infusões Intra-Arteriais , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Experimentais , Ribonucleotídeo Redutases/antagonistas & inibidores , Suínos , Resultado do Tratamento , Gencitabina
20.
Interact Cardiovasc Thorac Surg ; 7(6): 1191-3, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18682431

RESUMO

A 21-year-old female patient presented with pneumonia and on chest roentgenogram a solitary pulmonary nodule was incidentally found. After an observation period she underwent left upper lobectomy because of documented tumor growth. Pathology showed an intrapulmonary glomus tumor of the proper type, which is a very rare occurrence. Literature review revealed only 11 published cases of this subtype. Radiological investigation is helpful for localization and characterization of the tumor. However, pathological examination is required for definitive diagnosis. Complete surgical excision is the treatment of choice. Although uncommon, glomus and carcinoid tumors should be considered in the differential diagnosis of solitary pulmonary nodules in young patients.


Assuntos
Tumor Glômico/patologia , Achados Incidentais , Neoplasias Pulmonares/patologia , Nódulo Pulmonar Solitário/patologia , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Tumor Glômico/cirurgia , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Pneumonectomia , Nódulo Pulmonar Solitário/cirurgia , Toracotomia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
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