[The start of the Hungarian lung transplantation program and the first results]. / A magyar tüdotranszplantációs program indulása és elso eredményei.

The first lung transplantation in Hungary was performed on 12th of December, 2015. It was a joint effort of the National Institute of Oncology and the Semmelweis University. Hereby we summarise the results and experiences from the first three years. Until August, 2018, 55 lung transplantations were performed in Hungary. This was a retrospective analysis. All patients were listed according to the recommendation of the Lung Transplantation Committee. All implanted lungs have been procured from brain dead donors. Postoperative treatment and rehabilitation of the patients were continued at the Semmelweis University. Between 12. 12. 2015 and 31. 07. 2018, our team performed 76 organ retrievals: out of 45 Hungarian offers, 23 came from Eurotransplant countries and 8 outside of the Eurotransplant region. From these donations, 54 double and 1 single side transplantations were successfully performed. The surgical approach was single side thoracotomy (n = 1), bilateral thoracotomy (n = 1) and in the majority of the cases clamshell incision (n = 53). For the intraoperative veno-arterial extracorporeal membrane oxygenation support was used. The extracorporeal membrane oxygenation support had to be prolonged in 3 patients into the early postoperative period, two other recipients were bridged to transplant with extracorporeal membrane oxygenation. In the same time period, one combined lung-kidney transplantation was also performed. The distribution of recipients according to the underlying disease was: chronic obstructive pulmonary disease (n = 28); idiopathic pulmonary fibrosis (n = 8); cystic fibrosis (n = 12); primary pulmonary hypertension (n = 2); hystiocytosis-X (n = 1); bronchiectasis (n = 2); lymphangioleiomyomatosis (n = 1); and re-transplantation following bronchiolitis obliterans syndrome (n = 1), respectively. The mean age of recipients was 47.5 ± 15.18 years. The youngest recipient was 13 years old. We unfortunately lost 12 patients on our waiting list. The mean intensive care unit stay was 24.6 ± 18.18 days. Two patients were lost in the early postoperative phase. Tracheostomy was necessary in 13 cases due to the need of prolonged ventilation. 1-year survival of the recipients was 82.96% (until 31. 07. 2018). When looking at the first three years of the program, the case numbers elevated quickly throughout the years which is rather unique when compared to other centres in their starting period. Perioperative mortality and morbidity is comparable with high-volume lung transplantation centres. In the future we would like to increase the number of patients on the waiting list, thus increasing the total number of transplantations performed, and we are also planning to implement the use of the ex vivo lung perfusion system (EVLP) in our program. Orv Hetil. 2018; 159(46): 1859-1868.

[Lung transplantation program for Hungarian patients]. / Tüdotranszplantáció magyar betegek számára.

When conservative treatment fails, lung transplantation often remains the only therapeutic option for patients with end stage parenchymal or vascular lung diseases. According to the statistics of the International Society for Heart and Lung Transplantation, in 2010 more than 3500 lung transplantations have been performed worldwide. The Department of Thoracic Surgery at the University of Vienna is considered to be one of the world's leading lung transplantation centres; in the last year 115, since 1989 more than 1500 lung transplantation procedures under the supervision of Prof. Dr. Walter Klepetko. Similar to other Central-European countries, lung transplantation procedures of Hungarian patients have also been performed in Vienna whithin the framework of a twinning aggreement. However, many crucial tasks in the process, such indication and patient selection preoperative rehabilitation organ procurement and long term follow-up care have been stepwise taken over by the Hungarian team. Although the surgery itself is still preformed in Vienna, professional experience is already available in Hungary, since the majority of Hungarian recipients have been transplanted by hungarian surgeons who are authors of this article the professional and personal requirements of performing lung transplantations are already available in Hungary. The demand of performing lung transplantation in Hungary has been raising since 1999 and it soon reaches the extent which justifies launching of an individual national program. Providing the technical requirements is a financial an organisational issue. In order to proceed, a health policy decision has to be made.

[Special considerations in generic substitution of immunosuppressive drugs in transplantation]. / Követokészítmények alkalmazásának lehetoségei a transzplantáció immunszuppresszív terápiájában.

Long-term success in solid organ transplantation strongly depends on the optimal use of maintenance immunosuppressive treatment. Cyclosporin and tacrolimus are the most frequently administered immunosuppressants and they are designed to narrow therapeutic index drugs. The substitution of the branded formulation by their generic counterparts may lead to economic benefit only if equivalent clinical outcomes can be achieved. There is no published evidence to date on the guarantee of their long-term therapeutic equivalence and cases of therapeutic failures have been reported due to inadvertent drug conversion. The disadvantageous clinical consequences of a non medical, mechanistic forced switch from the original to generic formulation of tacrolimus and the estimated loss of the payer's presumed savings are presented in a kidney transplant recipient population. Special problems related to pediatric patients, drug interactions with concurrent medications and the burden of additional therapeutic drug monitoring and follow up visits are also discussed. The authors are convinced that the implementation of the European Society of Organ Transplantation guidelines on generic substitution may provide a safe way for patients and healthcare payers.

Analysis of cytokine pattern in exhaled breath condensate of lung transplant recipients with bronchiolitis obliterans syndrome.

INTRODUCTION: Exhaled breath condensate (EBC) analysis is a promising method for investigating airway pathology. In this pilot study we tested the cytokine pattern of EBC of lung transplant patients with and without clinical evidence of bronchiolitis obliterans syndrome (BOS). MATERIALS AND METHODS: Breath condensates collected from eight BOS patients and eight stable BOS-free lung transplant recipients in three consecutive visits were pooled in order to increase protein concentration and were then used for antibody microarray analysis detecting 120 cytokines simultaneously. RESULTS: Nine cytokines exhibited more than twofold increase and four exhibited more than twofold decrease in BOS patients as compared to stable subjects. CONCLUSION: We conclude that inflammatory cytokines are present in EBC of lung transplant recipients, however the potential benefit of detecting the EBC proteome warrants further studies.

Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses.

INTRODUCTION: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC. METHODS: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. RESULTS: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths. CONCLUSIONS: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.

First 3 Years of the Hungarian Lung Transplantation Program.

In this article we summarize the results of the first 3 years after launching the Hungarian Lung Transplantation Program. PATIENTS AND METHODS: The first lung transplant in Hungary was carried out on December 12, 2015, with the collaboration of the National Institute of Oncology and the Semmelweis University. Up to December 31, 2018, a total of 62 lung transplants were performed. Data were analyzed retrospectively. Patients were listed for lung transplant after the indication was established by the National Lung Transplantation Committee. Donor lungs were procured from brain-dead donors only. RESULTS: Within this period our team was involved in 87 lung procurements, 61 of which resulted in bilateral lung transplant and 1 in single-sided transplant. The operative approach was unilateral thoracotomy (n = 1), bilateral thoracotomy (n = 1), or clamshell incision (n = 60) with venoarterial extracorporeal membrane oxygenation support. The underlying disease of the recipients was obstructive lung disease (n = 30), lung fibrosis (n = 11), cystic fibrosis (n = 18), primary pulmonary hypertension (n = 2), histiocytosis-X syndrome (n = 1), bronchiectasis (n = 2), lymphangioleiomyomatosis (n = 1), and retransplant because of bronchiolitis obliterans syndrome (n = 1). The youngest patient was 13 years of age, while the oldest was 65 years. Three patients died in the early postoperative phase. One-year survival was 80%. DISCUSSION: The number of cases rises steadily in the Hungarian Lung Transplantation Program, which is exceptional compared with the start of other centrums. The incidence of complications and mortality is comparable with those of other experienced centers around the world. Our future goal is to broaden our waiting list, thus increasing the number of lung transplants carried out.

Influence of condensing equipment and temperature on exhaled breath condensate pH, total protein and leukotriene concentrations.

BACKGROUND: Exhaled breath condensate analysis is an attractive but still not fully standardised method for investigating airway pathology. Adherence of biomarkers to various condensing surfaces and changes in condensing temperature has been considered to be responsible for the variability of the results. Our aims were to compare the efficacy of different types of condensers and to test the influence of condensing temperature on condensate composition. METHODS: Breath condensates from 12 healthy persons were collected in two settings: (1) by using three condensers of different type (EcoScreen, R-Tube, Anacon) and (2) by using R-Tube condenser either cooled to -20 or -70 degrees C. Condensate pH at standardised CO(2) level was determined; protein content was measured by the Bradford method and leukotrienes by EIA. RESULTS: Breath condensates collected using EcoScreen were more alkaline (6.45+/-0.20 vs. 6.19+/-0.23, p<0.05 and 6.10+/-0.26, p<0.001) and contained more protein (3.89+/-2.03 vs. 2.65+/-1.98, n.s. and 1.88+/-1.99 microg/ml, p<0.004) as compared to the other devices. Only parameters obtained with R-Tube and Anacon correlated. Condensing temperature affected condensate pH (5.99+/-0.20 at -20 degrees C and 5.82+/-0.07 at -70 degrees C, p<0.05) but not protein content. Leukotriene B(4) was not found in any sample and cysteinyl-leukotriene was not found in condensates collected with R-Tube or Anacon. CONCLUSION: Condenser type influences sample pH, total protein content and cysteinyl-leukotriene concentration. Condensing temperature influences condensate pH but not total protein content. These results suggest that adherence of the biomarkers to condenser surface and condensing temperature may play a role but does not fully explain the variability of EBC biomarker levels.

Variability of exhaled breath condensate pH in lung transplant recipients.

BACKGROUND: Measurement of pH in exhaled breath condensate (EBC) may represent a novel method for investigating airway pathology. OBJECTIVES: The aim of this longitudinal study was to assess the variability of EBC pH in stable lung transplant recipients (LTR). METHODS: During routine clinical visits 74 EBC pH measurements were performed in 17 LTR. EBC pH was also measured in 19 healthy volunteers on four separate occasions. EBC pH was determined at standard CO2 partial pressure by a blood gas analyzer. RESULTS: Mean EBC pH in clinically stable LTR and in controls was similar (6.38 +/- 0.09 vs. 6.44 +/- 0.16; p = nonsignificant). Coefficient of variation for pH in LTR and controls was 2.1 and 2.3%, respectively. The limits of agreement for between-visit variability determined by the Bland-Altman test in LTR and healthy volunteers were also comparable (-0.29 and 0.46 vs. -0.53 and 0.44). CONCLUSIONS: Our data suggest that the variability of EBC pH in stable LTR is relatively small, and it is similar to that in healthy nontransplant subjects.

[Pulmonary infections after lung transplantation]. / Tüdotranszplantált betegek pulmonalis infekciói.

Lung transplantation has become an accepted therapeutic modality for end-stage diseases of the lungs and the pulmonary circulation. In the past two decades more than 20,000 lung transplantations were performed all over the world. Due to improvements in immunosuppressive regimens the mortality rate of severe acute rejections has decreased up to 2% in the first post-transplant year. By contrast, infections became the most common cause of morbidity and mortality after lung transplantation. It was reported that 21.2 and 40% of annual deaths are due to infections in the first 30 days and one year, respectively. In the first month 35-70% of transplant recipients develop bacterial pneumonia caused often by Gram-negative organisms especially by Pseudomonas species. All patients should receive prophylactic antibiotics after the operation, which are to be modified according to the resistance patterns of pathogens isolated from the donor lungs. In the early post-operative period, the frequency of invasive fungal (Aspergillus and Candida) and cytomegalovirus (CMV) infections appears to be less then 10% due to prophylactic amphotericin inhalation and systemic valganciclovir administration for 100 days. After withdrawing these drugs, these infections became more common. In the late post-transplant period, the development of bronchiolitis obliterans syndrome (BOS) may predispose to infections. BOS may be manifested in approximately 50% of patients 5 years post-transplant. Routinely or urgently performed screening tests (laboratory and radiological investigations, lung function tests, sputum culture, bronchoscopy) and specific treatments are of central importance in the management of infections. In this review we discuss the clinical manifestation, the diagnosis and the treatment possibilities of the most common pulmonary infections in lung transplant recipients.

[The first 12 years of Hungarian lung transplantation]. / A tüdôtranszplantáció magyar történetének elsô 12 éve.

12 years have passed since the first Hungarian patient went through lung transplantation. A small but dedicated group of clinicians work to make lung transplantation an easily accessible, accepted therapy for Hungarian patients. Transplantation is recommended for patients suffering from end stage vascular or parenchymal diseases of the lung after conservative therapies are proven unsuccessful. Lung transplantation as a surgical intervention is currently not available in Hungary. In the past 12 years 64 Hungarian patients were transplanted at the Department of Cardiothoracic Surgery, Medical University of Vienna, in Austria by the Vienna Lung Transplant Group led by Prof. Walter Klepetko. Our patients went through lung transplantation for the following indications: cystic fibrosis (22), idiopathic lung fibrosis (18), primer pulmonary hypertonia (8), lymphangioleimyomatosis (5), emphysema (4) and other (7). The 64 patients altogether went through 68 transplantation procedures. In 4 cases re-transplantation was necessary. The surgery techniques employed were as follows: bilateral lung transplantation (33), bilateral lobar transplantation (18), single lung transplantation (13), heart-lung transplantation (2) and split-lung transplantation (2). Bilateral living-donor lung lobar transplantation was performed in one case. The mean age of patients at the time of surgery was 33.3 years (between age 14 and 58). 48 of the 64 patients are still alive.

[Cytomegalovirus infection after solid-organ transplantation, its risk factors, direct and indirect effects and prevention strategies]. / A cytomegalovírus-fertozés rizikófaktorai, hatásai és a megelozés lehetoségei transzplantációt követoen.

The human cytomegalovirus is widely prevalent among human population and it is the most common viral pathogen that affects both the graft's and solid-organ transplant recipient's survival. The risk is highest in donor-seropositive, recipient-seronegative pairing transplantation. These recipients carry increased risk of developing symptomatic primary CMV infection; however, other risk factors may have an impact on cytomegalovirus activation as well: intensity of immunosuppression, type of organ transplanted, rejection and/or treatment for rejection, HLA-mismatch between recipient and donor, certain HLA-types of the recipient, female sex etc. Cytomegalovirus infection in transplant patients has been associated with both direct (symptoms) and indirect effects which are derived from the immunomodulating impact of the virus such as cellular effects and cytokine expression or systemic immune suppression leading to other opportunistic infections. Prevention of the direct and indirect effects of cytomegalovirus infection is the therapeutic goal in transplanted patients. Most transplant centers use either universal prophylaxis or preemptive therapy to prevent the infection. The advantages and disadvantages of these two preventive strategies and current evidence-based recommendations for preventing cytomegalovirus disease in solid-organ transplant recipients are discussed according to others' and the authors' own observations. According to recommendations of the American and Canadian Societies of Transplantation, most of the centers--after analyzing of the CMV-infection risk factors of the recipients--divide them into three groups: high-, moderate- and low-risk groups. The preventive strategy is attached to the risk-group type. In the high-risk group (R-/D+ and lung transplant patients) the use of the universal prophylaxis is necessary. The patients administered anti-lymphocyte antibodies (ATG, ALG or OKT3) need selective (subtype of universal) prophylaxis. Among the moderate-risk patients (R+/D+ or R+/D-) the doctors may choose either universal prophylaxis or preemptive therapy. Selection of a strategy requires consideration of patient-specific factors as well as practical considerations such as available resources. For avoidance of the indirect effects of CMV infection universal prophylaxis is preferred. The use of preventive proceedings in low-risk patients is the matter of the center's decision.

[Bronchiolitis obliterans syndrome in lung transplant recipients]. / Bronchiolitis obliterans szindróma a tüdotranszplantáción átesett betegekben.

Bronchiolitis obliterans syndrome in lung transplant recipients. The leading cause of late graft loss after lung transplantation is bronchiolitis obliterans syndrome. The process is a manifestation of chronic rejection, and is characterized by an excessive fibroproliferation in the small airways, leading progressively to luminal obliteration and graft injury. Both alloantigen-dependent (acute rejection, histocompatibility) and alloantigen-independent (ischaemia-reperfusion injury, cytomegalovirus infection, gastroesophageal reflux disease) risk factors may contribute to the development of the disease. Early in the process, damage to the airway epithelium occurs, which then triggers a massive influx of alloreactive T-cells into the graft tissue. Activated T-cells release a wide range of cytokines and growth factors, which in turn are capable of stimulating cellular proliferation and matrix protein synthesis in fibroblasts as well as in airway smooth muscle cells. Clinically, a decline in lung functions together with nonspecific symptoms can usually be observed in these patients, while later in the disease course recurrent respiratory tract infections are more common. Up till now, no effective therapy is available for bronchiolitis obliterans syndrome, however, certain immunosuppressive regimens may slow down the progression of the disease.

[Lung harvesting in Hungary--results of the first two years]. / Donortüdok kiemelése Magyarországon--az elso két év eredményei.

OBJECTIVE: Hungarian patients undergo lung transplantation within bilateral cooperation in Vienna, Austria since 1995. Lung harvesting was introduced in 2002 in Hungary. Before 2002 Hungarian patients get 16 donor lungs from abroad, and 4 patients died while being on the waiting list for transplantation. METHODS: Between 15/1/2002 and 31/12/2003 Hungarotransplant offered 164 potential lung donors to the Korányi National Institute for Pulmonology. Donor selection was performed according to international guidelines. All operations were performed as part of multiorgan harvesting. Immediately before cross clamping the aorta 500 microg epoprostenol (Flolan) was administered intravenously for opening the pulmonary vascular bed. The lung was perfused through the main pulmonary trunk with a single flush of 6 litre 4 degrees C extra cellular type low potassium dextran solution (Perfadex). During the perfusion both thoraces were cooled topical by 0.9% saline ice slush. After back table separation the donor lungs was packed and transported with topical cooling. RESULTS: The offer was refused in 27 cases due to donor history, in 31 cases due to allograft pathology. In 57 cases the harvesting was not performed due to logistic reasons. Forty three donor lungs have been transplanted, 6 harvested lungs underwent only histopathology. From 43 harvested lungs 41 bilateral and 3 single lung transplant procedures were performed. The mean cold ischaemic time (=CIT) was 3 75 +/- 50 minutes (range: 230-560 min). Forty two donor lungs showed excellent primary graft function. One allograft underwent down-sizing lobectomy, where the histology of the specimen showed multiple microembolization, and signs of fibrosis, bronchiolitis and anthracosis. In this case the cold ischaemic time was 385 min. The patient needed an extracorporeal membrane oxygenation (ECMO) support immediately postoperatively, and died on the 4th postoperative day. After induction of lung harvesting in Hungary the average waiting time of Hungarian citizens dropped within one year from 14 +/- 8 weeks (range: 2-36 weeks) to 2.6 +/- 1.3 weeks (range: 1-4 weeks). In 2002 3 Hungarian patients died while being on the waiting list, their waiting time was 1, 1, and 7 days. In 2003 the waiting list mortality for Hungarian patients was 0%. CONCLUSIONS: After the introduction of lung harvesting both the waiting time and the waiting list mortality for Hungarian patients decreased. The potential yearly lung donor pool of Hungary is in the range of 5/1 million people.

Pulmonary infections increase exhaled nitric oxide in lung transplant recipients: a longitudinal study.

The aim of this longitudinal study was to test whether pulmonary infections influence fractional exhaled nitric oxide levels (FENO) in otherwise clinically-stable lung transplant recipients. Levels of FENO were measured at least on 11 occasions in nine lung transplant recipients who attended for routine or urgent clinical review over 27.0 +/- 3.2 months period. Diagnosis of infection was based on clinical symptoms, functional measurements and radiological findings. Concentrations of FENO were also determined in 12 healthy volunteers. During follow-up, six patients had one, two had three, and one had four episodes of pulmonary infections. Overall, six upper and 10 lower respiratory tract infections were noted. Recipients with active infections developed increased FENO levels as compared with their own baseline levels measured in the clinically well period (10.8 +/- 1.3 vs. 7.6 +/- 1.1 ppb, p < 0.05). After antibiotic treatment, elevated FENO concentrations returned to baseline in association with full clinical recovery. Baseline FENO levels in lung transplant recipients and in healthy volunteers (6.0 +/- 0.5 ppb) were similar. The sensitivity and specificity of FENO measurement in detecting pulmonary infections were 57 and 96%, respectively. Our data suggest that pulmonary infections are associated with increased FENO levels in patients with lung allografts. Nevertheless, the measurement of FENO by itself as a screening tool for infections seems to be limited by its low sensitivity.