Dysregulation of the renin-angiotensin system during lung ischemia-reperfusion injury.

UNLABELLED: Aim/Purpose of the Study: Activation of the renin-angiotensin system leading to increased angiotensin-(1-7) (Ang-(1-7)) and decreased angiotensin 2 (Ang 2) levels may be a new therapeutic approach to reduce acute lung injury. Prolylcarboxypeptidase (PRCP) and prolyloligopeptidase (PREP) are capable of hydrolyzing Ang 2 into Ang-(1-7). However, their relation with circulating Ang 2 levels after lung ischemia-reperfusion injury (LIRI) has never been explored. This study determines whether the activity and expression of PRCP and PREP in plasma and lung tissue is related to circulating Ang 2 levels in a murine model of LIRI. MATERIALS AND METHODS: LIRI in Swiss mice (6 animals per group) was induced by temporary left lung hilar clamping (1 h) followed by 0, 1 or 24 h of reperfusion. Animals in the sham group received thoracotomy only. PRCP activity was measured via RP-HPLC, PREP activity using a fluorogenic substrate and plasma Ang 2 levels via ELISA. Western blotting was used to determine the PRCP and PREP protein expression profiles in left lung tissue. RESULTS: Plasma Ang 2 levels significantly rise after lung ischemia and remain increased after 1 h and 24 h of reperfusion compared to the sham group. While a significant decrease in plasma PREP activity was found after 24 h of reperfusion, a transient increase in plasma PRCP activity was observed after ischemia. However, no correlation with plasma Ang 2 levels could be demonstrated. The activity profiles of PRCP and PREP and the protein expression of PRCP in the lung tissues remained unchanged after LIRI. CONCLUSIONS: LIRI causes a dysregulation of circulating Ang 2 levels and plasma PREP activity, although no direct link between both phenomena could be shown. The activity profile of pulmonary PRCP and PREP was not significantly changed after LIRI, which implies a minor role for local PRCP and PREP in the ischemic lung itself.

Aortic Dissection Limited to Abdominal Aorta: an Underrecognized Entity?

BACKGROUND: Aortic dissection limited to the abdominal aorta is a rare clinical entity with non-specific clinical features. Optimal treatment, as well as natural history and progression of the disease, remain unclear. In 1992 we -reported 5 cases of isolated abdominal aortic dissection (IAAD) and in the present paper we update our series with 5 additional patients. A concise literature review is also provided. METHODS: Between 1992 and 2014, we diagnosed 5 patients with IAAD (4 men, mean age 60.6 years, range 45-77). No patient presented with acute onset of symptoms. One patient was diagnosed with a periumbilical bruit, and diagnosis was made with magnetic resonance (MR)-angiography. Other diagnoses were incidental findings on computed tomographic (CT) scanning. Dissection was located infrarenally in four cases and at the celiac trunk in one case. RESULTS: All cases were treated conservatively with hypertension control and close follow-up. Follow-up period ranged from 10 months to 20 years and was performed yearly by CT- or MR-angiography and blood pressure monitoring. All patients remained symptom-free, all dissection lengths remained stable. Slowly increasing post-dissection aneurysmal dilatation was encountered in two patients. We combined results of these five new patients with five previously diagnosed and reported patients at our center. Treatment was surgical in only one out of 10 patients. There was no disease-related mortality during follow-up. CONCLUSIONS: Based on our case series, IAAD remains a rare clinical condition with relative benign clinical course. Treatment was almost exclusively conservative. Recent publications state IAAD might be underrecognized and under-diagnosed compared to thoracic aortic dissections.

Preclose Percutaneous Endurant™ Endografting with the Proglide™ Device: a Safe and Feasible Combination.

BACKGROUND: Endovascular repair of abdominal aortic aneurysms has been revolutionized over the last two decades. Opening the doors for a percutaneous approach by avoiding surgical exposure of the vascular access site. The goal of this report is to analyze the feasibility and efficacy of using Perclose Proglide™ through a preclose technique in a percutaneous approach to Endurant™ endografting for Asymptomatisch infrarenal aortic aneurysms in an elective setting. METHODS: Between April 2011 and April 2014, 45 consecutive patients underwent percutaneous endovascular aortic aneurysm repair (PEVAR) for an asymptomatic infrarenal aortic aneurysm. Closure of percutaneous access sites was ensured with Perclose Proglide in a "preclose" technique. Data were collected in a prospective maintained database with a follow-up period of one month. Patient demographics, aneurysmal characteristics, procedural details and complications were recorded. RESULTS: A total of 170 Proglide devices were used to close 85 access sites. Adequate hemostasis was obtained in 96.5 percent (82 of 85 access sites). Conversion to a femoral cutdown was necessary in 2.4% (2 of 85 access sites). The mean hospitalization was 2.6 days and 86.7 percent of patients were discharged within 2 days. The incidence of post-procedural access-related complications was 2.2%. CONCLUSIONS: PEVAR using the Perclose Proglide in preclosing 14Fr to 20Fr access sites for Endurant endografting in the treatment of asymptomatic infrarenal aortic aneurysms is feasible and effective. Moreover, the percutaneous approach allows for procedures to be performed under local anesthesia, while providing a low risk for access-related complications and a relatively short hospitalization.

Malignant Pleural Mesothelioma : Rationale for a New TNM Classification.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with a poor prognosis. In this regard, a well-defined staging system is of utmost importance in order to correctly diagnose and assign an appropriate treatment to the patient. METHODS: The current TNM-staging system (7th edition) enables to either clinically or pathologically stage the severity of the disease according to extension of the tumor (T), number of nodes (N) and presence of metastases (M). Patients with stage I-III are considered for surgery, while palliative treatment is indicated for stage IV patients according to the current classification. RESULTS: Despite its widespread use, the validity of this staging system is questioned due to the low prevalence, histological variety and retrospective nature of the previous study design. In addition, the role of specific treatment modalities including surgery, has yet to be determined, especially for treatment of early-stage disease. In this regard, the International Association for the Study of Lung Cancer (IASLC) initiated the multi-centre, prospective "Mesothelioma Staging Project" in order to address limitations of the 7th edition and to optimize the staging system in accordance to current needs. CONCLUSIONS: An improved staging system will contribute to the design of prospective multi-institutional clinical trials investigating novel treatment strategies for mesothelioma. In this way comparison of outcome between different medical centres also becomes feasible.

Surgical implications of the new IASLC/ATS/ERS adenocarcinoma classification.

A new adenocarcinoma classification was recently introduced by a joint working group of the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS). A distinction is made between pre-invasive lesions, and minimally invasive and invasive adenocarcinoma. The confusing term "bronchioloalveolar carcinoma" is not used any more and new subcategories include adenocarcinoma in situ and minimally invasive adenocarcinoma. Due to a renewed interest in screen-detected nodules and early-stage lung cancers of <2 cm, this classification also has profound implications for thoracic surgeons. In this article, surgical topics are discussed: the role of a minimally invasive approach, especially video-assisted thoracic surgery, limited resection for early-stage lung cancer, the extent of lymph node dissection, the accuracy of intraoperative frozen section analysis, management of multiple lung nodules and prognostic factors in operated patients. Specific key issues are presented based on the current evidence and areas of surgical uncertainty are defined providing a basis for further studies. Thoracic surgeons will play a major role in the application and global introduction of this new adenocarcinoma classification. The remaining controversies regarding the precise diagnosis and management of early-stage lesions will have to be resolved by multidisciplinary and international collaboration.

TNM-classification for lung cancer: from the 7th to the 8th edition.

Most tumors are staged according to the Tumor-Node-Metastasis (TNM) classification. For lung cancer a new edition was introduced in 2009 and generally applied since 2010. This 7th TNM-classification is based on a large, international retrospective database. Important changes were made regarding the T, N, M factors and specific subcategories were added. However, this 7th edition is still purely based on anatomical information. Other prognosticators such as laboratory results, histology, tumor markers and molecular genetic factors are not yet considered. To prepare the 8th TNM classification a prospective database developed by the International Association for the Study of Lung Cancer (IASLC), is currently enrolling patients from all continents. In this way, more precise and reliable data will become available on specific subdivisions of the T, N and M factors. If proven to be prognostically valid, other parameters will be included as histology, demographic data and specific biochemical and molecular predictive and prognostic factors. All centers with a large experience in thoracic oncology are encouraged to participate in this prospective database.

TNM-Classification for Lung Cancer: From the 7(th) to the 8(th) Edition.

Most tumors are staged according to the Tumor-Node-Metastasis (TNM) classification. For lung cancer a new edition was introduced in 2009 and generally applied since 2010. This 7(th) TNM-classification is based on a large, international retrospective database. Important changes were made regarding the T, N, M factors and specific subcategories were added. However, this 7(th) edition is still purely based on anatomical information. Other prognosticators such as laboratory results, histology, tumor markers and molecular genetic factors are not yet considered. To prepare the 8(th) TNM classification a prospective database developed by the International Association for the Study of Lung Cancer (IASLC), is currently enrolling patients from all continents. In this way, more precise and reliable data will become available on specific subdivisions of the T, N and M factors. If proven to be prognostically valid, other parameters will be included as histology, demographic data and specific biochemical and molecular predictive and prognostic factors. All centers with a large experience in thoracic oncology are encouraged to participate in this prospective database.

Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial.

The European Organisation for Research and Treatment of Cancer (EORTC; protocol 08031) phase II trial investigated the feasibility of trimodality therapy consisting of induction chemotherapy followed by extrapleural pneumonectomy and post-operative radiotherapy in patients with malignant pleural mesothelioma (with a severity of cT3N1M0 or less). Induction chemotherapy consisted of three courses of cisplatin 75 mg·m⁻² and pemetrexed 500 mg·m⁻². Nonprogressing patients underwent extrapleural pneumonectomy followed by post-operative radiotherapy (54 Gy, 30 fractions). Our primary end-point was "success of treatment" and our secondary end-points were toxicity, and overall and progression-free survival. 59 patients were registered, one of whom was ineligible. Subjects' median age was 57 yrs. The subjects' TNM scores were as follows: cT1, T2 and T3, 36, 16 and six patients, respectively; cN0 and N1, 57 and one patient, respectively. 55 (93%) patients received three cycles of chemotherapy with only mild toxicity. 46 (79%) patients received surgery and 42 (74%) had extrapleural pneumonectomy with a 90-day mortality of 6.5%. Post-operative radiotherapy was completed in 37 (65%) patients. Grade 3-4 toxicity persisted after 90 days in three (5.3%) patients. Median overall survival time was 18.4 months (95% CI 15.6-32.9) and median progression-free survival was 13.9 months (95% CI 10.9-17.2). Only 24 (42%) patients met the definition of success (one-sided 90% CI 0.36-1.00). Although feasible, trimodality therapy in patients with mesothelioma was not completed within the strictly defined timelines of this protocol and adjustments are necessary.

Emergency endovascular aneurysm repair for ruptured abdominal aortic aneurysms: an institutional experience.

OBJECTIVES: Emergency endovascular aneurysm repair (eEVAR) for ruptured abdominal aortic aneurysms (rAAA) is still under investigation. Since installation of an urgent eEVAR kit in our hospital, all patients with a rAAA or urgent thoracic aortic aneurysm are candidates for eEVAR or eTEVAR (emergency thoracic EVAR), respectively. For this study, we analyzed all rAAA patients treated with eEVAR. METHODS: Data were recorded prospectively. Criteria for an eEVAR were an infrarenal neck > or = 15 mm, acceptable landing zone, angles below 70 degrees and a good femoral approach. We prefer preoperative angio CT-scan but in case of instability, an intra-aortic balloon can stabilize the patient during angiography (in the OR) to decide between open or eEVAR repair. Follow-up was performed on regular intervals by duplex or CT-scan. Thirty-day mortality and overall survival were calculated. RESULTS: Since 2006, nine male rAAA patients with a mean age of 73 years (range : 62-82) had eEVAR repair. Aneurysm diameter was 8 cm (range : 5.8-11). The Hardman index was 1.5 (range : 0-3). In eight patients an aorto-uni-iliac device was placed succesfully followed by a femorofemoral crossover bypass. The 30-day operative mortality was 12.5% (one patient with septic shock). Three patients showed a type 2 endoleak with stable diameter during follow-up but one patient showed expansion 4 years after treatment. CONCLUSIONS: Treating rAAA with eEVAR in selected patients with acceptable anatomy and a kit permanently available in the operating room yielded good results by a surgical team trained for both open and eEVAR repair. The conversion rate was low (11%) and the survival (immediate and 30-days) was excellent (87.5%).

[Early-stage lung cancer: Is there still a role for surgery?] / Tumeurs de petits stades. La chirurgie a-t-elle encore sa place ?

For a patient with stage I or II non-small cell lung cancer (NSCLC) surgical resection remains the treatment of choice on condition that the patient is functionally operable. A complete resection should be obtained. Often lobectomy is feasible by a minimally invasive approach. For patients with compromised cardiopulmonary function stereotactic radiotherapy is an alternative treatment. For patients who are functionally operable, no definite recommendation can be made as no large, randomised studies have been performed with a sufficient number of patients and long-term follow-up. For this reason, it is important to discuss every patient within a multidisciplinary team with participation of thoracic surgeons and radiation oncologists. To provide personalised advice, the primary tumour, its extension, the patient's comorbidities and his respiratory and cardiac function have to be considered.

Red blood cell accumulation in a rat model of pulmonary ischemia/reperfusion injury.

AIM: Red blood cell (RBC) accumulation in lung tissue during ischemia/reperfusion has not been studied extensively. A warm lung ischemia/reperfusion-injury model was developed to determine RBC trapping. METHODS: Twenty-four rats were randomized into 5 groups. In 4 groups, the left lung was submitted to 20 minutes of warm ischemia followed by reperfusion for 3, 10, 30 and 60 minutes. Subsequently, both lungs were flushed. Afterwards the heart-lung block was removed and fixed endoluminally. The fifth group was the sham group, in which lungs were flushed after 20 minutes of perfusion without induction of ischemia. RBC were counted in the hilar sectional plane and expressed in area%. RESULTS: In the left reperfused ischemic lung, already 3 minutes after reperfusion, a significant accumulation of RBC was found in the capillaries. This accumulation was accompanied by a significant vascular congestion of these vessels. After in vivo perfusion, almost all RBC were flushed out the blood vessels of the non-ischemic lung (area%=0.082). In ischemic reperfused lungs, capillaries were densely packed with RBC. Significantly more RBC were counted after 3 (area%=1.572; P=0.002) and 10 minutes (area%=1.240; P=0.011) of reperfusion compared to the sham group. After 30 (area%=0.929; P=0.054) and 60 minutes (area%=0.435; P=0.404) no significant increase in RBC was observed compared to the sham group. In the right non-ischemic lungs, no differences in RBC accumulation were observed between the sham group and ischemia-reperfusion groups. CONCLUSIONS: After warm ischemia/reperfusion, a significant early increase in accumulation of RBC was observed.

Anatomical patterns of the above knee great saphenous vein and its tributaries: implications for endovenous treatment strategy.

OBJECTIVE: The aim of the present study was to analyse the anatomical patterns of the above knee great saphenous vein (GSV) and its tributaries in limbs with varicose veins in view of potential suitability for endovenous treatment. METHODS: Limbs of a consecutive series of new patients with varicose veins presenting at the phlebologic clinic during a 4 month period were studied. In 73 limbs of 56 patients with varicose veins and both saphenofemoral junction and GSV reflux, anatomical patterns of the above knee GSV were defined as: --'complete' GSV: main trunk visualised within the saphenous compartment from the groin to the knee; --'incomplete' GSV: main trunk partially visualised from the groin to mid thigh with a non-refluxing mostly hypoplastic distal GSV and a superficial tributary vein (STV) parallel to the GSV. RESULTS: 51 limbs (70 %) had a 'complete' GSV. In 4 of these 51 limbs reflux passed from the main GSV trunk to a STV at mid thigh level leaving a non-refluxing part of the GSV from mid thigh to the knee. CONCLUSION: In only 64% of limbs with varicose veins the entire above knee GSV was involved in the disease. This may have implications for endovenous treatment strategy.

Surgery: therapeutic indications.

Although never proven to be superior in a large, prospective randomized trial, surgical resection remains the treatment of choice for early stage non-small cell lung cancer (NSCLC). In stages IA, IB, IIA, IIB and resectable IIIA surgical treatment offers the best long-term prognosis when a complete resection can be performed. Standard operations include lobectomy, bilobectomy and pneumonectomy. Whenever possible, lobectomy is the procedure of choice. Lesser resections like segmentectomy or wedge excision are rarely indicated in primary NSCLC. Specific lung parenchyma saving operations include tracheo- and bronchoplastic procedures which are indicated in selected cases of centrally located NSCLC. Extended resections include removal of lung together with another organ or structure as thoracic wall, pericardium, diaphragm or superior sulcus. En bloc excision of the involved structure is advised. Accurate peroperative evaluation will determine the extent of resection and if possible, a pneumonectomy should be avoided because of its high mortality and morbidity rate. Surgical resection after induction therapy for early stage or locally advanced NSCLC is feasible, but is often more complex and carries a higher risk, especially when a right pneumonectomy has to be performed after induction chemoradiotherapy.

Selective pulmonary artery perfusion: a novel method for the treatment of pulmonary malignancies.

Selective pulmonary artery perfusion (SPAP) is a modality of regional chemotherapy first investigated in the 1950's. A number of studies in animal models documented pharmacokinetic superiority with high-dose local cytostatic drug concentrations when compared to intravenous administration. Blood flow occlusion of the pulmonary artery before or after drug injection results in further increase in local drug concentrations. Animal tumor models with sarcoma and coloncarcinoma confirm anti-tumour efficacy in cytostatic SPAP. In human investigations, feasibility and safety of chemotherapeutic SPAP in humans has been documented. Recent encouraging investigations of SPAP with gemcitabine and blood flow occlusion in a porcine model emphasize the need for further investigations in humans with pulmonary malignancies for safety and efficacy assessments.

Asymptomatic pheochromocytoma in the posterior mediastinum.

A 66-year-old female patient was treated for a posterior mediastinal tumour with unknown histology. During thoracotomy, repetitive hypertensive crises had to be treated. The tumour was completely resected. Pathology revealed an extra-adrenal pheochromocytoma. Diagnosis of pheochromocytoma is usually made on the basis of clinical presentation and elevated catecholamine levels in serum or urine. Imaging is used primarily for localizing tumours prior to surgery. Complete surgical excision is the primary treatment. The only absolute indicator of malignancy is the identification of distant metastases to bone, liver, lung or lymph nodes.

Circulating cell-free nucleic acids and platelets as a liquid biopsy in the provision of personalized therapy for lung cancer patients.

Lung cancer is the predominant cause of cancer-related mortality in the world. The majority of patients present with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Treatment for NSCLC is evolving from the use of cytotoxic chemotherapy to personalized treatment based on molecular alterations. Unfortunately, the quality of the available tumor biopsy and/or cytology material is not always adequate to perform the necessary molecular testing, which has prompted the search for alternatives. This review examines the use of circulating cell-free nucleic acids (cfNA), consisting of both circulating cell-free (tumoral) DNA (cfDNA-ctDNA) and RNA (cfRNA), as a liquid biopsy in lung cancer. The development of sensitive and accurate techniques such as Next-Generation Sequencing (NGS); Beads, Emulsion, Amplification, and Magnetics (BEAMing); and Digital PCR (dPCR), have made it possible to detect the specific genetic alterations (e.g. EGFR mutations, MET amplifications, and ALK and ROS1 translocations) for which targeted therapies are already available. Moreover, the ability to detect and quantify these tumor mutations has enabled the follow-up of tumor dynamics in real time. Liquid biopsy offers opportunities to detect resistance mechanisms, such as the EGFR T790M mutation in the case of EGFR TKI use, at an early stage. Several studies have already established the predictive and prognostic value of measuring ctNA concentration in the blood. To conclude, using ctNA analysis as a liquid biopsy has many advantages and allows for a variety of clinical and investigational applications.