Lung transplantation is the only successful treatment option for patients experiencing end-stage lung disease. Results have improved significantly in the last decade; however, the number one limiting ...factor is still the shortage of donor lungs. Due to the discrepancy between available donor lungs and patients awaiting lung transplantation, many centers have reintroduced donation after cardiac death (DCD). According to their results, DCD and donation after brain death (DBD) are comparable in terms of survival and graft function.
Currently in Hungary, donation is only allowed from DBD donors; however, due to the Eurotransplant agreement, non-heart-beating donation (NHBD) organs can be transplanted into Hungarian patients, and in some cases Hungarian transplant teams can also take part in NHBDs within the Eurotransplant region.
The Hungarian experience. A Hungarian patient received a lung from a 15-year-old uncontrolled DCD in Vienna. The donor was reanimated for 54 minutes and after lung procurement the lungs were put on ex vivo lung perfusion and later successfully implanted into the Hungarian recipient. The recovery was very successful and the patient is still alive.
The Hungarian Lung Transplantation Team was involved in a controlled Maastricht III donation in 2017. A 49-year-old female donor was reported from Ghent, Belgium. A multiorgan donation was carried out with 15 minutes of warm ischemic time in the case of the lungs.
DCD is an effective, safe, and available method to increase the donor pool. In the case of controlled donations, the necessary protocols have already been prepared. Although DBD is working very successfully in Hungary, infrastructural developments, education of professionals, and social preparations are all needed to implement a DCD protocol in Hungary.
Abstract Background Donor-specific antibodies (DSAs) are common following lung transplantation (LuTx), yet their role in graft damage is inconclusive. Mean fluorescent intensity (MFI) is the main ...read-out of DSA diagnostics; however its value is often disregarded when analyzing unwanted post-transplant outcomes such as graft loss or chronic lung allograft dysfunction (CLAD). Here we aim to evaluate an MFI stratification method in these outcomes. Methods A cohort of 87 LuTx recipients has been analyzed, in which a cutoff of 8000 MFI has been determined for high MFI based on clinically relevant data. Accordingly, recipients were divided into DSA-negative, DSA-low and DSA-high subgroups. Both graft survival and CLAD-free survival were evaluated. Among factors that may contribute to DSA development we analyzed Pseudomonas aeruginosa (P. aeruginosa) infection in bronchoalveolar lavage (BAL) specimens. Results High MFI DSAs contributed to clinical antibody-mediated rejection (AMR) and were associated with significantly worse graft (HR: 5.77, p < 0.0001) and CLAD-free survival (HR: 6.47, p = 0.019) compared to low or negative MFI DSA levels. Analysis of BAL specimens revealed a strong correlation between DSA status, P. aeruginosa infection and BAL neutrophilia. DSA-high status and clinical AMR were both independent prognosticators for decreased graft and CLAD-free survival in our multivariate Cox-regression models, whereas BAL neutrophilia was associated with worse graft survival. Conclusions P. aeruginosa infection rates are elevated in recipients with a strong DSA response. Our results indicate that the simultaneous interpretation of MFI values and BAL neutrophilia is a feasible approach for risk evaluation and may help clinicians when to initiate DSA desensitization therapy, as early intervention could improve prognosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
OBJECTIVES
For centrally located lung tumours, sleeve lobectomy is preferred over pneumectomy. We report on the surgical practices and perioperative outcomes of sleeve resections based on ...data from the European Society of Thoracic Surgeons database.
METHODS
We retrieved data of patients undergoing sleeve lobectomy or bilobectomy from 2007 to 2021. We evaluated baseline characteristics, surgical approach, neoadjuvant treatments, morbidity and postoperative outcomes of open and video-assisted thoracoscopic surgery (VATS) procedures.
RESULTS
In total, 1652 patients (median age: 63 years; females/males: 446/1206) underwent sleeve lobectomy (n = 1536) or bilobectomy (n = 116) by open thoracotomy (n = 1491; 90.2%) or VATS (n = 161; 9.8%) with a thoracotomy conversion rate of 21.1% (n = 34); 398 (24.1%) patients received neoadjuvant treatment. Overall morbidity and 30-day mortality were 40.6% and 2.2%, respectively. Bronchial anastomotic complications occurred in 29 patients (1.8%) with conservative treatment in 6 cases (20.7%) and operative management in 23 (79.3%). On multivariable analysis, factors related to the elevated risk of cardiopulmonary complications were body mass index < 20 odds ratio (OR): 2.26; P < 0.001 and bilobectomy (OR : 2.28, P < 0.001). Age <60 years (OR: 0.71, P = 0.013), female sex (OR: 0.54, P < 0.001) and VATS (0.64, P < 0.001) were associated with decreased risk. Neoadjuvant treatment was not associated with increased risks of cardiopulmonary complications (OR: 1.05; P = 0.664). Compared to open thoracotomy, VATS was associated with significantly decreased overall morbidity (30.4% vs 41.7%, P = 0.006) and length of stay (median: 5 days vs 8 days; P < 0.001).
CONCLUSIONS
Sleeve lobectomies can be safely performed after neoadjuvant treatment. The VATS approach fosters shorter length of stay and decreased morbidity.
The introduction of the lung allocation score has brought lung transplantation (LTX) of patients on extracorporeal membrane oxygenation (ECMO) bridge into the focus of interest. We reviewed our ...institutional experience with ECMO as a bridge to LTX.
Between 1998 and 2011, 38 patients (median age 30.1 years, range 13-66 years) underwent ECMO support with intention to bridge to primary LTX. The underlying diagnosis was cystic fibrosis (n=17), pulmonary hypertension (n=4), idiopathic pulmonary fibrosis (n=9), adult respiratory distress syndrome (n=4), hemosiderosis (n=1), bronchiolitis obliterans (n=1), sarcoidosis (n=1), and bronchiectasis (n=1). The type of extracorporeal bridge was venovenous (n=18), venoarterial (n=15), interventional lung assist (n=1), or a stepwise combination of them (n=4). The median bridging time was 5.5 days (range 1-63) days. The type of transplantation was double LTX (n=7), size-reduced double LTX (n=8), lobar LTX (n=16), split LTX (n=2), and lobar LTX after ex vivo lung perfusion (n=1).
Four patients died before transplantation. Thirty-four patients underwent LTX, of them eight patients died in the hospital after a median stay of 24.5 days (range 1-180 days). Twenty-six patients left the hospital and returned to normal life (median hospital stay=47.5 days; range 21-90 days). The 1-, 3-, and 5-year survival for all transplanted patients was 60%, 60%, and 48%, respectively. The 1-, 3-, and 5-year survival conditional on 3-month survival for patients bridged with ECMO to LTX (78%, 78%, and 63%) was not worse than for other LTX patients within the same period of time (90%, 80%, and 72%, respectively, P=0.09, 0.505, and 0.344).
Transplantation of patients bridged on ECMO to LTX is feasible and results in acceptable outcome.
•Atypical carcinoids are characterized by high tumor cell CD40 expression.•High CD70 and CD137 expression by tumor cells are characteristic for LCNEC.•SCLC has a high CD47 and ICOS expression in ...tumor and immune cells, respectively.•SCLC and LCNEC tumors have a more immunogenic phenotype than AC.•High tumor cell CD47 and CD40 expressions are associated with improved survival outcomes.
Although immunotherapy has led to a paradigm shift in the treatment of lung cancer, the therapeutic approaches for lung neuroendocrine neoplasms (LNENs) are still limited. Our aim was to explore the immunological landscape and the expression of immune checkpoint markers in LNENs.
Surgically removed tumor samples of 26 atypical carcinoid (AC), 30 large cell neuroendocrine carcinoma (LCNEC) and 29 small cell lung cancer (SCLC) patients were included. The immune phenotype of each tumor type was assessed by using a panel of 15 immune-related markers. As these markers are potentially expressed by immune cells and/or tumor cells, they might serve as putative targets for immunotherapy. Expression patterns were measured by immunohistochemistry and correlated with clinicopathological parameters and prognosis.
Unsupervised hierarchical clustering revealed distinct immunologic profiles across tumor types. Specifically, AC tumors were characterized by high tumor cell CD40 expression and low levels of immune infiltrates whereas SCLC samples had a high CD47 and Inducible T Cell Costimulator (ICOS) expression in tumor cells and immune cells, respectively. High CD70 and CD137 expression by tumor cells as well as elevated expression of CD27, Lymphocyte Activation Gene 3 (LAG3), and CD40 by immune cells were characteristic for LCNEC samples. Overall, SCLC and LCNEC tumors had a more immunogenic phenotype than AC samples. High tumor cell CD47 and CD40 expressions were associated with impaired and improved survival outcomes, respectively.
By providing insights into the widely divergent immunologic profiles of LNENs, our results might serve as a basis for the development of novel immunotherapy-related approaches in these devastating malignancies.
Lung transplant recipients are at risk for life-threatening infections including severe acute respiratory syndrome coronavirus 2-associated COVID-19. Several viral infections have been associated ...with the development of chronic lung allograft dysfunction. Long-term outcomes of COVID-19 on graft function are not known.
A 53-year-old female patient, who underwent bilateral lung transplantation 3 years before because of stage IV sarcoidosis and secondary pulmonary hypertension was admitted in the second wave of the pandemic because of COVID-19 with symptoms including dry cough. Chest computed tomography showed ground glass opacities affecting 25% to 50% of the lung parenchyma. She was admitted to the COVID-19 Unit of our clinic. She received oxygen via nasal cannula, remdesivir, and low-dose methylprednisolone while mycofenolate acid administration was stopped. Her clinical condition improved. The first follow-up visit 1 month after the infection demonstrated deterioration in lung function. Computed tomography scan showed almost complete resolution; transbronchial biopsy was performed and proved acute allograft rejection. During the hospitalization a new onset atrial fibrillation was confirmed. In the background of atrial fibrillation and simultaneous neck pain, severe hyperthyroidism was proven. Because of thyroiditis and lung allograft rejection, high-dose steroid treatment was initiated and everolimus was added to the immunosuppressive therapy. Donor specific antibodies were also detected, hence plasmapheresis was indicated and continued with photoferesis. On the follow-up spirometry the values were stable; however, they did not reach pre-COVID levels.
In lung transplant recipients COVID-19 might trigger allograft rejection in addition to virus-related thyroid disease.
Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and ...cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Advancements in immunotherapeutic approaches only had a modest impact on the therapy of lung neuroendocrine neoplasms (LNENs). Our multicenter study aimed to investigate the expression ...patterns of novel immunotherapy targets in intermediate- and high-grade LNENs.
Methods
The expressions of V-domain Ig suppressor of T cell activation (VISTA), OX40L, Glucocorticoid-induced TNF receptor (GITR), and T cell immunoglobulin and mucin domain 3 (TIM3) proteins were measured by immunohistochemistry in surgically resected tumor samples of 26 atypical carcinoid (AC), 49 large cell neuroendocrine lung cancer (LCNEC), and 66 small cell lung cancer (SCLC) patients. Tumor and immune cells were separately scored.
Results
Tumor cell TIM3 expression was the highest in ACs (
p
< 0.001), whereas elevated tumor cell GITR levels were characteristic for both ACs and SCLCs (
p
< 0.001 and
p
= 0.011, respectively). OX40L expression of tumor cells was considerably lower in ACs (vs. SCLCs;
p
< 0.001). Tumor cell VISTA expression was consistently low in LNENs, with no significant differences across histological subtypes. ACs were the least immunogenic tumors concerning immune cell abundance (
p
< 0.001). Immune cell VISTA and GITR expressions were also significantly lower in these intermediate-grade malignancies than in SCLCs or in LCNECs. Immune cell TIM3 and GITR expressions were associated with borderline prognostic significance in our multivariate model (
p
= 0.057 and
p
= 0.071, respectively).
Conclusions
LNEN subtypes have characteristic and widely divergent VISTA, OX40L, GITR, and TIM3 protein expressions. By shedding light on the different expression patterns of these immunotherapy targets, the current multicenter study provides support for the future implementation of novel immunotherapeutic approaches.
Recombinant human erythropoietins (rHuEPOs) are used to treat cancer-related anemia. Recent preclinical studies and clinical trials, however, have raised concerns about the potential tumor-promoting ...effects of these drugs. Because the clinical significance of erythropoietin receptor (EPOR) signaling in human non-small cell lung cancer (NSCLC) also remains controversial, our aim was to study whether EPO treatment modifies tumor growth and if EPOR expression has an impact on the clinical behavior of this malignancy. A total of 43 patients with stage III-IV adenocarcinoma (ADC) and complete clinicopathological data were included. EPOR expression in human ADC samples and cell lines was measured by quantitative real-time polymerase chain reaction. Effects of exogenous rHuEPOα were studied on human lung ADC cell lines in vitro. In vivo growth of human ADC xenografts treated with rHuEPOα with or without chemotherapy was also assessed. In vivo tumor and endothelial cell (EC) proliferation was determined by 5-bromo-2'-deoxy-uridine (BrdU) incorporation and immunofluorescent labeling. Although EPOR mRNA was expressed in all of the three investigated ADC cell lines, rHuEPOα treatment (either alone or in combination with gemcitabine) did not alter ADC cell proliferation in vitro. However, rHuEPOα significantly decreased tumor cell proliferation and growth of human H1975 lung ADC xenografts. At the same time, rHuEPOα treatment of H1975 tumors resulted in accelerated tumor endothelial cell proliferation. Moreover, in patients with advanced stage lung ADC, high intratumoral EPOR mRNA levels were associated with significantly increased overall survival. This study reveals high EPOR level as a potential novel positive prognostic marker in human lung ADC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hungary joined Eurotransplant International (ET) to improve the chance of transplantation for Hungarian patients and patient outcomes, including access and graft and patient survival. After 5 years ...of full membership, the evaluation of numbers and quality indicators is possible.
A comparison was made between 5 years prior to a preliminary cooperation agreement (2007-2011) and 5 years after full ET membership (2014-2018). During the 2 study periods, we analyzed numbers and circumstances of deceased organ donors, multiorgan donors, donated organs, and transplantations in Hungary and development of waiting lists along with international organ exchanges.
The number of actual organ donors increased by 22.09% (729 vs 890), an additional 823 organ removals represents an increase of 42.71% (1927 vs 2750). There were 46.51% more transplants managed in the selected periods (1561 vs 2287). The number of new patients on the waiting list increased (2305 vs 3247; 40.87%). The mean kidney mismatch number decreased from 3.21 to 2.96.
Joining ET has been an effective and efficient in terms of increasing access to organs and the lives of patients on the Hungarian waiting list posttransplant. It is also a benefit for patients with special needs because the number of organ transplants is greater than the increased number of donors.
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