Expression patterns of novel immunotherapy targets in intermediate- and high-grade lung neuroendocrine neoplasms.

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.

Comparative expression analysis of immune-related markers in surgically resected lung neuroendocrine neoplasms.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 Patients on Kilimanjaro.

BACKGROUND: After its initial difficulties were overcome, lung transplantation became an accepted and effective treatment for end-stage lung disease. Patients can take part in almost all kinds of sports after lung transplantation, including high-altitude mountaineering, which is an extreme sport even for healthy individuals. Several articles have been published about high-altitude tolerance of transplanted patients. However, this was the first high-altitude expedition that included only lung transplant patients. METHODS: The Vienna lung transplantation team organized an expedition in 2017 to conquer the peak of Mount Kilimanjaro, which consisted of 10 lung transplanted patients and 24 accompanying medical personnel. The participants were tested before and several times during the hike to evaluate their general and cardiopulmonary status, the severity of altitude sickness, and radio-morphologic changes. The results of the lung transplanted patients were compared to the results of their healthy companions. RESULTS: The group started at 2360 meters and reached the 5895-meter-high summit of Mount Kilimanjaro after 6 days on June 18, 2017. Eight transplant patients and 24 escorting medical personnel reached the peak. This means that the success rate was 94%, which is significantly higher than the reported 85% for this route. The 2 transplant patients who did not make the summit turned back on the first and second day because they lacked the necessary fitness for the trip. We did not see a significant difference in the results regarding cardiopulmonary status or the severity of altitude sickness, although we observed mildly higher blood pressure and altitude sickness score results in the lung transplant group. CONCLUSION: Based on our experiences, we can state that a stable patient after lung transplantation who attains the necessary physical fitness can achieve similar or even better physical results than an average healthy individual.

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.

Donation After Cardiac Death, a Possibility to Expand the Donor Pool: Review and the Hungarian Experience.

INTRODUCTION: 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. CONCLUSION: 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.

[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.