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ARTICLE
Lung Transplantation for Cystic Fibrosis in Turkey: First Report

Objectives: Lung transplant is the most important treatment approach that improves the life expectancy and quality of life for patients with cystic fibrosis with end-stage lung disease. In this study, we retros­pectively analyzed patients with cystic fibrosis who were referred to our lung transplant program in Turkey.

Materials and Methods: We evaluated 14 patients with cystic fibrosis who were referred to our lung transplant clinic between December 2016 and December 2019. The characteristics of the patients at the time of referral to our lung transplant clinic, survival, and lung transplant results were recorded.

Results: Four patients died on the wait list, 3 patients were not eligible for lung transplant, and lung transplant was performed in 7 patients. The mean age of all patients was 22.8 years (range, 11-41 years), and the mean age for patients who underwent lung transplant was 27.5 years (range, 21-41 years). The mean time of suitable donor offer or survival life was 140 days in the patients who were referred for lung transplant. The 1-year mortality rate was 28.6% (2 of 7 patients) after lung transplant. One patient died of chronic lung allograft dysfunction at the 25th month after lung transplant. Four patients were alive without any problems.

Conclusions: Lung transplant is the final treatment method for patients with cystic fibrosis with terminal period lung disease. To provide the best benefit, patients should be evaluated for transplant early. Cystic fibrosis care clinics and lung transplant clinics should work in coordination in order to increase the number of lung transplants and improve outcomes.


Key words : Advanced lung disease, Lung transplantation, Referral

Introduction

Cystic fibrosis (CF) is a genetic disease that affects the glands of many organs after birth and leads to dysfunction. Cystic fibrosis frequently involves the lungs, pancreas, liver, intestines, sinuses, and reproductive organs.1 Progressive airway inflam­mation and recurrent respiratory infections lead to bronchiectasis and chronic respiratory failure. Pulmonary damage can cause a decrease in lung function despite bronchodilator treatment, antibiotics, agents that promote improved clearance of secretions, vaccines, and chest physiotherapy. The severity of pulmonary damage determines the patient’s quality of life and duration.2 Recently applied drugs such as ivacaftor, tezacaftor, and lumacaftor, known as cystic fibrosis transmembrane conductance regulator (CFTR) modulators, which act by improving the production, processing, and function of the CFTR protein, improve respiratory function, quality of life, and survival.3,4 A recent large cohort study in Canada showed that the median survival age of 5787 patients with CF increased from 31.9 years in 1990 to years 49.7 in 2012.5 Despite advances in the treatment of CF-related lung disease, disease progression can be slowed but cannot be stopped.

Lung transplant is a treatment method that improves survival and quality of life for patients with CF with end-stage lung disease. Cystic fibrosis is the third most common indication for lung transplant in adults. Patients with CF have better long-term survival than other indications after lung transplant. The median survival is 12.4 years and is increasing with the development of new treatment strategies.6 Lung transplantation has evolved steadily since the first CF transplants in the 1980s with preoperative evaluations, referral criteria, wait-listing strategies, and perioperative and posto­perative management. The number of lung transplant procedures for CF has remained constant over the years, which has been attributed to improvements in CF care. However, many patients with lung transplant eligibility criteria are not referred for lung transplant assessment.7,8 The most important stage for successful lung transplant and long-term survival is the timing of referral. Late referral of patients increases the risks associated with transplant surgery because of insufficient optimal treatment and uncertainty of donor lung offer time.

The aim of this study was to assess patients with CF who were referred to our lung transplant clinic, the suitability of patients as lung transplant candidates, and the outcomes of lung transplant.

Materials and Methods

Between December 2016 and December 2019, 14 patients were evaluated who were referred to the Lung Transplant Program of Kartal Kosuyolu Training Research Hospital for treatment of CF. Lung, heart, kidney, and liver function and nutritional status were evaluated for the suitability for lung transplant. The pretransplant evaluation was performed at the time when there were no adverse conditions such as infection and acute exacerbation. Two patients who were on the active wait list were excluded.

Selection criteria
Patients with CF were listed for lung transplant according to the timing of listing criteria of the International Society for Heart and Lung Transplantation (ISHLT).9 However, in cases for which urgent listing was necessary, for the suitability of lung transplant, we contacted the CF care clinic and considered the patient’s general condition. Patients who worsen unexpectedly as a result of acute exacerbation and have regular follow-up are urgently listed if there is no definite contraindication. Patients in decline from active infection were expected to have the infection stabilized for listing. The patients’ priority for lung transplant was determined according to the general condition of the patient and donor suitability. Recipients and donors were matched according to blood group compatibility, urgency status of the patient, measured and calculated total lung capacity, and height.

The sputum and bronchoalveolar lavage fluid culture results of all lung transplant candidates with CF referred to our clinic from CF care clinics were examined by an infectious disease specialist. In addition, we again obtained sputum and bronc­hoalveolar lavage cultures from the patients in the evaluation period. Antimicrobial therapy was given for at least 14 days and could be extended according to the lavage fluid microbiologic findings. Pseudomonas aeruginosa was the most common organism colonizing/infecting the airways during the CF pretransplant period. Standard antibiotics in both the pretransplant and posttransplant period according to the sensitivity of strains (gentamycin inhaler, piperacillin/tazobactam or colistin inhaler, or intravenous delivery of antibiotics) were implemented. Patients presenting with mild exacerbations are generally not inactivated on the wait list unless there is evidence of new infection.

At least 6 weeks of treatment with intravenous cefoxitin, amikacin, and clarithromycin was admi­nistered in cases of infection with Mycobacterium abscessus before transplant. According to the results of the follow-up microbiologic examination, it was not considered as an absolute contraindication, and the decision was made to consider the general condition of the patient. Deterministic factors in listing for lung transplant were specific cavitary/cystic lesions for M abscessus on thorax computed tomography, frequent hospitalization, and clinical worsening due to M abscessus.

All patients underwent bilateral lung transplant with a clamshell incision. In cases of intense adhesions to the thorax cavity, intraoperative use of extracorpo­real membrane oxygenation (ECMO) was avoided as much as possible because of bleeding. Indications for intraoperative ECMO were hypercapnia, arterial saturation less than 90%, cardiac index less than 2 L/min/m2, and mean pulmonary arterial pressure of 40 mm Hg. After implantation of the first lung, the second assessment was performed by clamping the native pulmonary artery to see whether the new lung could provide adequate oxygenation. Central venoarterial ECMO was used for intraoperative cardiopulmonary support by cannulation of the right atrial auricle and the ascending aorta. A cell saver was used in all patients, to collect blood lost during surgery. The ECMO was gradually reduced and terminated after both lungs were implanted.

In immunosuppressive treatment after transplant, in addition to triple therapy comprising tacrolimus, mycophenolate mofetil, and prednisolone, induction therapy with 20 mg basiliximab was administered on the day of transplant and posttransplant for 4 days. After transplant, tacrolimus was started as a continuous infusion at the dosage of 1 mg/kg/d. It was continued with 0.025 mg/kg oral every 12 hours. The goal trough concentration was 8-12 ng/mL. Mycophenolate mofetil, 1000 mg, was administered in the operating room at the time of transplant. As tolerated, it was given in a dose of 1000 mg twice per day. Methylprednisolone was administered as 250 mg prior to implant, 250 mg postreperfusion, then for the first postoperative days at a dose of 125 mg intravenously 3 times, 1 mg/kg methylprednisolone daily for 1 week, and subsequently tapered to methylprednisolone 0.5 mg/kg/d. Thirty days after lung transplant, methylprednisolone was tapered by 5 mg every 2 weeks to 20 mg/d prednisone by 6 to 8 weeks. The dosage of 5 mg/d prednisone was reduced within 3 months.

Results

Fourteen patients (7 females and 7 males) were evaluated as lung transplant candidates with the diagnosis of CF. The mean age of the patients who were listed for lung transplant was 22.8 years (range, 11-47 years). Eleven patients were listed for lung transplant. Three patients were urgently listed without any pretransplant evaluation. These patients were regularly followed by an external center and worsened because of acute exacerbation. Table 1 shows the characteristic data of the patients at the time of evaluation for lung transplant who were not suitable for lung transplant and died on the wait list.

Three patients were considered unsuitable candidates for lung transplant. A 21-year-old female was not listed because of cachexia and M abscessus growth in the bronchoscopic culture, and she died 7 months after referral despite an intensive treatment program. The second patient, a 19-year-old male, had good functionality in the preoperative evaluation. However, the patient had comorbid factors such as destroyed lung and chest wall deformity. The risks were discussed with the patient and family, and they did not accept lung transplant. He died of progressive respiratory failure on day 165. The third patient was a 21-year-old male. He was consulted when he was treated in the intensive care unit (ICU). The patient did not develop any problems during the follow-up but worsened because of progressive infection. Venovenous ECMO was used. The patient was deemed unsuitable for transplant, and he died of sepsis on day 15 after ICU admission.

Four patients died on the wait list. The mean age of these patients was 16.5 years (11, 14, 19, and 22 years). Two of them were female. Two of the patients were urgently listed. Bridge to lung transplant with ECMO was unsuccessful in these 2 patients.

The mean wait time was 144 days (16, 36, 228, and 295 days).

Lung transplant
Seven patients underwent bilateral lung transplant for CF. This accounted for 9.8% (7/71) of all transplant indications during the same period. The mean age of the patients was 27.5 years (range, 21-41 years). The patients’ characteristics at the time of referral to the lung transplant clinic are given in Table 2. The mean wait time was 146 days (range, 16-208 days). Intraoperative, postoperative, and donor data are given in Table 3.

The patient with M abscessus was listed after 8 weeks of treatment. During this time, the patient needed oxygen and she worsened clinically. In the 6-minute walking test, the distance fell from 440 m to 150 m. Although explanted lung pathology was defined as necrotizing granulomatous inflammation, repetitive postoperative examinations of bronchoscopy specimens showed no evidence of acid-fast bacilli infection in a culture-bronchial lavage. There was bronchial stenosis, but this does not cause lung infection. Hospitalization was indicated to mitigate bronchial dilatation. In the 19th month, she had no other problems and proceeded with her active life.

The 1-year mortality rate was 28.6% (2 of 7 patients) after lung transplant. The first patient was a 24-year-old male who developed a bronchial fistula after lung transplant. A bronchial surgical repair was performed but he died on the postoperative 68th day of sepsis. The second patient was a 23-year-old female who was listed urgently. A suitable donor was found 18 days after venovenous ECMO was used for the bridge to lung transplant. Severe pains started on the 24th day in this patient, who was taken to the clinic from the ICU 10 days after the operation. Unexpectedly, aseptic necrosis of the femoral head was detected in the patient. She died on postoperative day 48.

Long-term survival was achieved in 5 patients. The follow-up of 4 patients continued uneventfully into the 9th, 19th, 28th, and 35th months. A 25-year-old female had an uneventful postoperative period. Unfortunately, she stopped all medication at 20 months; a steady drug regimen was not reestablished despite psychiatric treatment. She died in the 25th month of chronic lung allograft dysfunction.

Discussion

A recent study was published by Hangul and colleagues in which the incidence of CF in the Central Anatolia Region was determined to be 2.9 per 10 000 live births.10 The first results of the Turkish National CF Registry were presented in 2017. There were 1170 patients enrolled, and they are estimated to account for approximately 30% of all patients with CF in Turkey. However, only 4.6% of these patients were over 18 years of age.11 According to the European Cystic Fibrosis Society (ECFS) Patient Registry Annual Data Report, more than half of all patients with CF are aged over 18 years, and 5.6% of all patients with CF are living with lung transplant.12 All these data are estimated to be lacking; however, these are important records for demonstrating the quality life and survival of patients. A small number of patients undergo lung transplant in our country. Lung transplant was performed in 7 patients within 3 years after our lung transplant program started. A total of 14 patients were evaluated for suitability for lung transplant. Our clinic has the largest series of lung transplants for CF in Turkey. According to the data mentioned above, there is a severe deficiency in the number of lung transplant procedures, which is the most critical treatment method in patients with advanced CF.

Advanced CF lung disease is associated with poor quality of life, worsened clinical symptoms, increased acute exacerbations, and increased hospital admissions. Advanced CF lung disease has been defined as forced expiratory volume in 1 second (FEV1) <40% predicted when stable and with 1 or more of the following characteristics or clinical manifestations: ICU admission for respiratory failure, hypercarbia (PaCO2 >50 mm Hg in arterial blood), oxygen requirement at rest, pulmonary hypertension (pulmonary artery systolic pressure >50 mm Hg in echocardiogram), severe functional impairment from respiratory disease (New York Heart Association class IV), 6-minute walk test distance <400 m, worsening malnutrition despite supplementation, frequent pulmonary exacerbations, pneumothorax, hemoptysis requiring ICU admission, or bronchial artery embolization.13 For optimal timing in patients referred to the lung transplant unit, advanced lung disease should be present, but not end-stage lung disease. Although early referral for consideration of lung transplantation is highly desirable, it may be too early for listing. However, early referral is essential for a complete assessment, to inform the patient and the family and to prevent contraindications specific to the lung transplant team. Death on the wait list or postoperative morbidity and mortality may increase as a result of late referral (too sick to undergo routine transplant evaluation). Urgent referral patients may not have sufficient time to undergo evaluation, and such patients may be acceptable without standard evaluation, in selected cases.

Although lung transplant is a viable treatment for patients with advanced CF lung disease, many potential candidates are not referred, even in countries with experienced teams and clinics.7,8 In a retrospective cohort study using the CF Foundation Patient Registry data that included 3340 patients, approximately 37.4% of patients died without referral for a lung transplant program, and 27.5% of the referred patients died on the wait list or were judged unsuitable for lung transplant.14

A Canadian group had the largest series; they performed 364 lung transplant procedures to mitigate CF between 1988 and 2016 and presented the 10-year survival rate as 53%.15 A Swedish group reported a 10-year survival rate of 64.3%.16 Savi and colleagues reported that 31.6% of patients with CF who were followed up after lung transplant had 20 years of survival posttransplant.17 They indicated a median wait time of 17.6 months after 2011. In our study, our patients had transplant or wait list mortality in about 5 months. Compared with experienced clinics, we perform a 1-year late referral and lung transplant operation. The 1-year period is lethal for patients with advanced CF with end-stage lung disease. We think that the reasons for the small number of patients referred for lung transplant are that patients who need lung transplant could not be identified or were referred late, the low number of lung transplant clinics, the low number of lung transplant procedures performed per year, and donor shortage. In order to refer patients with CF for lung transplant, it is vital for pediatric and pulmonologist physicians, who expect transplants to reach a more successful level, and transplant clinics, which want to speed up this process as much as possible, to work closely and in coordination.

In our practice, there were various problems that would increase morbidity and mortality of lung transplant. First, patients were hospitalized for an extended time before transplant, and this created important problems in early rehabilitation. The second problem was intense pleural adhesions caused by frequent infections. Bleeding occurred, especially in patients who required the use of ECMO during surgery. Therefore, the use of erythrocyte suspensions increased. Lung transplant clinics, which have started relatively recently and continue to develop, seek to perform transplants in patients with less risk and a high probability of success. However, unless there is a definite contraindication in urgent patients, our transplant team considers refusal to be unethical. Three patients were accepted for bridge to lung transplant with ECMO, which worsened in the ICU, 2 of whom died on the wait list because of a lack of suitable donors. The remaining patient underwent lung transplant but died of aseptic necrosis at the femoral head. This cause of death was unexpected. In addition, the fact that patients and their relatives have the social and intellectual capacity to conduct their follow-up and treatment regularly over the posttransplant years enables them to perform the processes related to CF and those after lung transplant. One patient who underwent lung transplant died because of a lack of regular medication and poor attention to lifestyle while she had an active business life.

In this study, the average age of the patients was 27.5 years (range, 21-41 years) at the time of lung transplant. This result is close the age documented in international reports. However, the median age during transplant has increased over time as a result of research in areas such as gene therapy, targeted correctors, and ion channel modulators. The ISHLT Thoracic Transplantation Registry analysis of Benden colleagues showed that approximately 90% of patients with CF who underwent lung transplant were over 18 years old and 17.2% were older than 40 years.18 Children diagnosed as having CF grow to older ages with potential for satisfactory quality of life. Therefore, although the age of transplant recipients is increasing, the number of children with CF is likely to decrease.

Especially in patients with CF, Pseudomonas spp. and Aspergillus spp. infections are associated with chronic lung allograft dysfunction. Pseudomonas colonization of allograft is common after lung transplant. Paranasal sinuses can serve as a reservoir for allograft colonization in patients with CF. Previous sinus surgery can be useful.19 Burkholderia cenocepacia and nontuberculosis mycobacteria (NTM) are included among the important strong relative contraindications for lung transplant. Patients infected with M abscessus have a rapid drop in FEV1 and an increase in severe infection attacks compared with NTM.20 Close to one-fifth (18.8%) (3/16) of the patients referred to our clinic were infected with M abscessus. Based on the ECFS Patient Registry Annual Data Report, the rate of patients infected with NTM in Turkey was 0.64% (9/1411). We think that the significant difference in these ratios is attributable to a lack of data, the lack of coordination between transplant clinics and CF care clinics, and the referral of lung transplant clinics after the general condition of the disease has developed (ie, late referral).

Infection by M avium complex before transplant does not cause adverse results, but the presence of M abscessus, which is naturally resistant to many antibiotics, is much more severe. Some authors have reported poor results as a result of reinfection of the lungs as well as surgical wounds and infection of distant sites of infection. In the largest case series (n = 13), Lobo and colleagues showed that there was no difference in survival after transplant compared with other patients with CF.21 There is no definitive recommendation as to how to proceed with lung transplant in patients infected with M abscessus. It is the general belief that a tolerable and effective drug regimen requires evidence of reduced organism load before transplant. If it is not known whether there is a negative smear or culture and how long it takes to continue the transplant safely, then it is important to refer to a lung transplant center early.

Conclusions

This is the first Turkish report describing the short-term survival and outcomes of a single center in lung transplant for CF. Good results were obtained in our center after lung transplant. In the future, we believe that the increase in the donation pool and timely listing in our country may improve our results and increase the number of lung transplant procedures. Coordination of all pediatric and adult CF centers with lung transplant clinics in the country is necessary for the survival of patients with CF and improvement of CF care.


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DOI : 10.6002/ect.2020.0282


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From the 1Department of Thoracic Surgery, Kartal Kosuyolu Training and Research Hospital; the 2Department of Chest Diseases, Kartal Kosuyolu Training and Research Hospital; the 3Department of Infectious Diseases and Clinical Microbiology, Kartal Kosuyolu Training and Research Hospital; and the 4Department of Anesthesia and Reanimation, Kartal Kosuyolu Training and Research Hospital, Istanbul, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Mustafa Vayvada, Thoracic Surgery Department, Kartal Kosuyolu Training And Research Hospital, K blok Cevizli, Kartal, İstanbul, Turkey
Phone: +90 505 556 84 04
E-mail: mustafavayvada@gmail.com