Tumour immune microenvironment in resected thymic carcinomas as a predictor of clinical outcome.

BACKGROUND: The spatial distribution of tumour-infiltrating lymphocytes (TILs) is a novel descriptor characterising the tumour immune microenvironment (TIME). The aim of our study was to assess whether a specific TIME of surgically resected thymic carcinoma (TC) can predict tumour invasiveness, recurrence or survival. METHODS: Digital microscopy was performed on 39 TCs immunohistochemically stained to investigate the activation of the immune checkpoint pathway (PD-L1/PD-1), along with density and spatial distribution of TILs phenotypes (CD3+, CD4+, CD8+, FOXP3+, CD56+). The impact of PD-L1 and TIL density considering the intratumoural (iTILs) and stromal (sTILs) distribution on pathological characteristics and clinical outcomes were analysed. RESULTS: In early TC stages, we observed a higher total density of CD3+ (p = 0.05) and CD8+ (p = 0.02) TILs. PD-L1 was expressed in 71.8% of TCs. In advanced TC stages, we observed a lower density of CD3+ (p = 0.04) and CD8+ (p = 0.01) iTILs compared to early stages. Serum concentrations of PD-L1 were significantly higher in TCs compared to healthy controls: 134.43 ± 18.51 vs. 82.01 ± 6.34 pg/ml (p = 0.001), respectively. High densities of stromal CD4+ TILs (54 vs. 32%, p = 0.043) and CD8+ TILs (65 vs. 17%, p = 0.048) were associated with improved freedom from recurrence (FFR) and cause-specific survival (CSS). High density of FoxP3+ TILs were associated with improved FFR (p = 0.03) and CSS (p = 0.003). DISCUSSION: Mapping TIL subpopulations complement the armamentarium for prognostication of TC outcomes. The improved outcome in patients with high density of TILs supports the use of immune checkpoint inhibitors in TC patients.

Perioperative Management of Patients With Myasthenia Gravis Undergoing Robotic-Assisted Thymectomy-A Retrospective Analysis and Clinical Evaluation.

OBJECTIVE: Postoperative myasthenic crisis with respiratory failure is a potentially lethal complication, warranting careful perioperative planning and extended postoperative surveillance of patients. Data on the incidence of postoperative respiratory failure and optimal management of patients after robotic-assisted thymectomy are limited. The objective of this study was to evaluate the incidence of respiratory complications and the need for intensive care unit (ICU) capacities after robotic-assisted thymectomy in patients with myasthenia gravis. DESIGN: Retrospective cohort study. SETTING: Single University hospital in Vienna, Austria, from January 2014 to December 2019. PARTICIPANTS: The authors included adult patients who underwent robotic-assisted thymectomy due to myasthenia gravis. MAIN RESULTS: Of 72 patients, 4 patients (5.6%) developed postoperative respiratory failure, needing noninvasive ventilation/intubation. Respiratory failure occurred within the first hours after extubation when patients still were under surveillance in the recovery room or in the ICU. One patient (1.4%) suffered from worsened myasthenic symptoms several days after surgery, and was treated with plasmapheresis. Sixty-five patients (90.3%) were extubated in the operating room, 35 of these (48.6%) were transferred to the ICU, and 30 patients (41.7%) primarily were transferred to the recovery room. Fourteen patients (19.4%) were transferred to the surgical ward after extended observation in the recovery room. Furthermore, after implementation of a standardized perioperative algorithm in 2020, a reduction of ICU admissions was achieved. CONCLUSIONS: After careful patient selection, planning, and postoperative patient evaluation, robotic-assisted thymectomy can be performed safely without postoperative surveillance in an ICU.

Short-term and sustained clinical response following thymectomy in patients with myasthenia gravis.

BACKGROUND AND PURPOSE: This study was undertaken to investigate short- and long-term outcome following thymectomy in patients with acetylcholine receptor antibody (AChR-Ab)-positive myasthenia gravis (MG). METHODS: Rates of clinical response (defined as minimal manifestation, pharmacological remission, or complete stable remission) lasting for at least 1 year were retrospectively analyzed using Cox proportional hazard models. The occurrence of relapses was recorded during follow-up. Clinical factors associated with achieving an initial or a sustained response were analyzed. RESULTS: Ninety-four patients with a median age of 33 years (interquartile range [IQR] = 22-51), 68% with nonthymomatous MG and 32% with thymoma-associated MG, were included. An initial clinical response was reached in 72% (68/94). Neither sex, age at onset, thymus histology, delay to surgery after disease onset, surgical approach, corticosteroid treatment, nor clinical severity before thymectomy was significantly associated with achieving this endpoint. During long-term follow-up (median = 89.5 months, IQR = 46-189.5), only half of the patients with an initial response (34/68) had a sustained response without relapses. No clinical factors predicted whether the response would become sustained. In patients without immunosuppressive treatment before thymectomy (n = 24), a high AChR-Ab reduction rate after thymectomy was associated with a higher likelihood of achieving an initial response (p = 0.03). CONCLUSIONS: Sustained long-term clinical response of MG patients after thymectomy is significantly lower than the initial response rates would suggest. The observation that none of the evaluated clinical factors was associated with a worse outcome supports the current clinical practice of patient selection for thymectomy. The relative decline of AChR-Abs after surgery appears to be a promising prognostic marker.

Outcomes with alemtuzumab induction therapy in lung transplantation: a comprehensive large-scale single-center analysis.

Alemtuzumab is a monoclonal antibody targeting CD52, increasingly used as induction therapy after transplantation. The aim of this study was to analyze the outcomes of alemtuzumab induction therapy followed by a low-dose maintenance immunosuppression in a large single-center cohort of lung transplant recipients. All patients, who received alemtuzumab induction followed by a low-dose maintenance immunosuppression were included in the analysis. Short- and long-term outcomes were analyzed. 721 lung transplant recipients, transplanted between January 2008 and June 2019, were included in this retrospective study. Freedom from higher-grade ACR at 1, 5, and 10 years was 98%, 96%, and 96%, respectively. Thirty-nine patients (5%) developed clinical AMR. Twenty-one percent of patients developed high-grade CKD. A total of 1488 infections were recorded. Sixteen percent were diagnosed within the first 3 months. Sixty-two patients (9%) developed a malignancy during follow-up. Freedom from CLAD at 1, 5, and 10 years was 94%, 72%, and 53%, respectively. Overall survival rates at 1, 5, and 10 years were 85%, 71%, and 61%, respectively. Alemtuzumab induction combined with a low-dose tacrolimus protocol is safe and associated with low rates of acute and chronic rejection, as well as an excellent long-term survival.

Lung Transplantation and Simultaneous Modified Ravitch Procedure.

Lung transplantation is an established treatment for a variety of end-stage lung diseases; however, chest wall deformities such as an asymmetric pectus excavatum are often considered a contraindication for lung transplantation. Consequently, the published experience of lung transplants and simultaneous chest wall reconstruction is limited to a few case reports. This article aims to provide a detailed description of surgical steps as well as technical challenges and pitfalls of lung transplantation with a simultaneous modified Ravitch procedure. Exemplary technical aspects will be discussed for a pediatric patient in whom such a combined procedure resulted in an excellent outcome.

Donor ventilation parameters as predictors for length of mechanical ventilation after lung transplantation: Results of a prospective multicenter study.

BACKGROUND: The evaluation of donor lungs heavily depends on the subjective judgment of the retrieval surgeon. As a consequence, acceptance rates vary significantly among transplant centers. We aimed to determine donor ventilation parameters in a prospective study and test if they could be used as objective quality criteria during organ retrieval. METHODS: A prospective evaluation of lung donors was performed in 3 transplant centers. Ventilation parameters were collected at the time of retrieval using a standardized ventilation protocol. Recipient length of mechanical ventilation (LMV) was defined as the primary end point, and collected data was used to build linear models predicting LMV. RESULTS: In total, 166 donors were included in this study. Median LMV after transplantation was 32 hours (interquartile range: 20-63 hours). Peak inspiratory pressure and dynamic compliance (Cdyn) at the time of retrieval, but not the partial pressure of oxygen/fraction of inspired oxygen (P/F) ratio, correlated with recipient LMV in Spearman correlations (r = 0.280, p = 0.002; r = -0.245, p = 0.003; and r = 0.064, p = 0.432, respectively). Linear models were built to further evaluate the impact of donor ventilation parameters on LMV. The first model was based on donor P/F ratio, donor age, donor intubation time, donor smoking history, donor partial pressure of carbon dioxide, aspiration, chest trauma, and pathologic chest X-ray. This model performed poorly (multiple R-squared = 0.063). In a second model, donor ventilation parameters were included, and Cdyn was identified as the strongest predictor for LMV. The third model was extended by recipient factors, which significantly improved the robustness of the model (multiple R-squared = 0.293). CONCLUSION: In this prospective evaluation of donor lung parameters, currently used donor quality criteria poorly predicted recipient LMV. Our data suggest that Cdyn is a strong donor-bound parameter to predict short-term graft performance; however, recipient factors are similarly relevant.

Ventilation parameters and early graft function in double lung transplantation.

BACKGROUND: Currently, the primary graft dysfunction (PGD) score is used to measure allograft function in the early post-lung transplant period. Although PGD grades at later time points (T48 hours and T72 hours) are useful to predict mid- and long-term outcomes, their predictive value is less relevant within the first 24 hours after transplantation. This study aimed to evaluate the capability of PGD grades to predict prolonged mechanical ventilation (MV) and compare it with a model derived from ventilation parameters measured on arrival at the intensive care unit (ICU). METHODS: A retrospective single-center analysis of 422 double lung transplantations (LTxs) was performed. PGD was assessed 2 hours after arrival at ICU, and grades were associated with length of MV (LMV). In addition, peak inspiratory pressure (PIP), ratio of the arterial partial pressure of oxygen to fraction of inspired oxygen (P/F ratio), and dynamic compliance (cDyn) were collected, and a logistic regression model was created. The predictive capability for prolonged MV was calculated for both (the PGD score and the model). In a second step, the created model was externally validated using a prospective, international multicenter cohort including 102 patients from the lung transplant centers of Vienna, Toronto, and Budapest. RESULTS: In the retrospective cohort, a high percentage of extubated patients was reported at 24 hours (35.1%), 48 hours (68.0%), and 72 hours (80.3%) after transplantation. At T0 (time point defined as 2 hours after arrival at the ICU), patients with PGD grade 0 had a shorter LMV with a median of 26 hours (interquartile range [IQR]: 16-47 hours) than those with PGD grade 1 (median: 42 hours, IQR: 27-50 hours), PGD grade 2 (median: 37.5 hours, IQR: 15.5-78.5 hours), and PGD grade 3 (median: 46 hours, IQR: 27-86 hours). However, IQRs largely overlapped for all grades, and the value of PGD to predict prolonged MV was poor. A total of 3 ventilation parameters (PIP, cDyn, and P/F ratio), determined at T0, were chosen on the basis of clinical reasoning. A logistic regression model including these parameters predicted prolonged MV (>72 hours) with an optimism-corrected area under the curve (AUC) of 0.727. In the prospective validation cohort, the model proved to be stable and achieved an AUC of 0.679. CONCLUSIONS: The prediction model reported in this study combines 3 easily obtainable variables. It can be employed immediately after LTx to quantify the risk of prolonged MV, an important early outcome parameter.

Simultaneous pectus excavatum correction and lung transplantation-A case series.

Severe chest wall deformities are considered an absolute contraindication for lung transplantation. The significantly impaired chest compliance associated with pectus excavatum is thought to result in a high risk of postoperative respiratory complications and significant morbidity and mortality. We herein report our pooled institutional experience consisting of 3 patients who underwent bilateral lung transplantation and simultaneous correction of a pectus excavatum. Two of the patients were children and 1 patient had severe asymmetric pectus. All patients received a size-reduced double lung transplant and the deformity was corrected by a Nuss or modified Ravitch procedure. The perioperative course was complicated by prolonged weaning requiring tracheostomy in 2 of the 3 patients. However, long-term results were good and all 3 patients are alive in excellent clinical condition 72, 60, and 12 months after the transplantation. This case series demonstrates that patients with severe chest wall deformities should not a priori be excluded from lung transplantation, and a combined approach is feasible for selected patients.

New TNM staging in lung cancer (8th edition) and future perspectives.

BACKGROUND: Carrying out a correct anatomical classification of lung cancer is crucial to take clinical and therapeutic decisions in each patient. AIM: TNM staging classification provides an accurate anatomical description about the extension of the disease; however, the anatomical burden of the disease is just one aspect that changes the prognosis. RELEVANCE FOR PATIENTS: TNM staging classification is a tool that predicts survival, but we must consider that TNM is just one of the factors that concern the prognosis. The impact of a factor over the prognosis is complex due to: It depends on the specific environment, the treatment strategy, among others, and our level of certainty makes difficult to include all the factors just in a group of stages. In some groups, there are difficulties to get large series due to the low frequency of cases and the small number of events (metastasis, locoregional recurrence). It does not allow to obtain evidence in a short period of time. On the other hand, in the next years, new markers will be incorporated in the coming years, which are going to be included in the new TNM classification. It could help to improve the classification giving more information about prognosis and risk of recurrence. All these aspects are being used by the International Association for the Study of Lung Cancer (IASLC) to develop a new prognosis model. This continues the evolution of TNM system, allows us to overcome the difficulties, and build a flexible framework enough to continue improving the individual prognosis of the patients.

Chylothorax in a 32-Year-Old Patient With Lymphangioleiomyomatosis After Bilateral Lung Transplant.

We report the case of a 32-year-old woman with persistent chylothorax after double-lung transplant for lymphangioleiomyomatosis. Dietary restrictions failed to decrease chylous effusions, making surgical revision necessary. The choice of an abdominal approach and postoperative treatment with somatostatin proved successful. The patient showed no recurrence of chylothorax at her 2-year follow up.

Lung transplantation for idiopathic pulmonary arterial hypertension on intraoperative and postoperatively prolonged extracorporeal membrane oxygenation provides optimally controlled reperfusion and excellent outcome.

OBJECTIVES: Lung transplantation for idiopathic pulmonary arterial hypertension has the highest reported postoperative mortality of all indications. Reasons lie in the complexity of treatment of these patients and the frequent occurrence of postoperative left ventricular failure. Transplantation on intraoperative extracorporeal membrane oxygenation support instead of cardiopulmonary bypass and even more the prolongation of extracorporeal membrane oxygenation into the postoperative period helps to overcome these problems. We reviewed our experience with this concept. METHODS: All patients undergoing bilateral lung transplantation for idiopathic pulmonary arterial hypertension on intraoperative extracorporeal membrane oxygenation with or without prophylactic extracorporeal membrane oxygenation prolongation into the postoperative period between January 2000 and December 2014 were retrospectively analysed. RESULTS: Forty-one patients entered the study. Venoarterial extracorporeal membrane oxygenation support was prolonged into the postoperative period for a median of 2.5 days (range 1-40). Ninety-day, 1-, 3- and 5-year survival rates for the patient collective were 92.7%, 90.2%, 87.4% and 87.4%, respectively. When compared with 31 patients with idiopathic pulmonary arterial hypertension transplanted in the same period of time without prolongation of extracorporeal membrane oxygenation into the postoperative period, the results compared favourably (83.9%, 77.4%, 77.4%, and 77.4%; P = 0.189). Furthermore, these results are among the best results ever reported for this particularly difficult patient population. CONCLUSIONS: Bilateral lung transplantation for idiopathic pulmonary arterial hypertension with intraoperative venoarterial extracorporeal membrane oxygenation support seems to provide superior outcome compared with the results reported about the use of cardiopulmonary bypass. Prophylactic prolongation of venoarterial extracorporeal membrane oxygenation into the early postoperative period provides stable postoperative conditions and seems to further improve the results.

Surgical treatment of low and intermediate grade lung net.

BACKGROUND: Carcinoids now constitute complex tumours which require a multidisciplinary approach and long-term follow-up. Surgical intervention is nowadays confirmed as the mainstay of treatment. METHODS: From 1980 to 2015, EMETNE-SEPAR collected 1,339 patients treated surgically for bronchial carcinoid (1,154 typical and 185 atypical carcinoids). Standard and conservative procedures were considered with regard to surgical approach. All the patients with carcinoid were pathologically coded following the standards of the 7th edition 2009 TNM lung cancer staging. Statistical analyses were performed in order to determine whether histology, nodal affectation and surgical technique were associated with significant differences in survival, presence of metastases and local recurrence. RESULTS: The influence of the surgical procedure on overall survival, the presence of metastases and local recurrence were demonstrated as no significant in our sample in central tumours (P>0.05). Sublobar resections in peripheral tumours are related to a decrease in survival in typical carcinoids (P=0.008) with nodal involvement and an increased number of recurrences in atypical carcinoids without nodal involvement (P=0.018). CONCLUSIONS: In central typical carcinoid, the use of lung-sparing bronchoplastic techniques could influence local recurrence in some cases. This observation demands the intraoperative pathologic verification of an adequate surgical margin by frozen section. Peripheral typical carcinoids have been surgically treated, occasionally, by sublobar resection. However, in peripheral atypical carcinoid after a limited sublobar resection the observed increase of the probability of local recurrence makes it, in our opinion, not advisable.

Thymic minimally invasive surgery: state of the art across the world-Europe.

In this brief review of selected peer-reviewed literature on thymic minimally-invasive surgery (MIS) we sought to identify if there is a unique approach to thymic MIS on the European continent.

Treatment of primary graft dysfunction after lung transplantation with orally inhaled AP301: A prospective, randomized pilot study.

BACKGROUND: Primary graft dysfunction (PGD) after lung transplantation (LTx) carries significant morbidity and mortality in the early post-operative period and is associated with the development of chronic lung allograft dysfunction. AP301, an activator of epithelial sodium channel-mediated Na+ uptake represents a new concept for prevention and treatment of pulmonary edema and has shown promising results in the pre-clinical setting. This pilot study investigated the clinical effect of inhaled AP301 on patients with development of PGD > 1 according to International Society of Heart and Lung Transplantation criteria after primary LTx in a high-volume center and was conducted as a randomized, placebo-controlled, single-center pilot-study including 20 patients. All consecutive patients fulfilling inclusion criteria were screened for PGD at arrival on the intensive care unit (ICU) after LTx. After randomization, inhaled AP301 or placebo was administered by nebulizer twice daily for 7 days or until extubation. Otherwise, patients were treated according to routine clinical protocol. Partial pressure of arterial oxygen (Pao2)/fraction of inspired oxygen (Fio2) values were obtained until extubation and assessed as a primary outcome parameter. Patients were monitored for 30 days within the study protocol. RESULTS: From July 2013 to August 2014, 20 patients were randomized 1:1 to AP301 (Group 1) or placebo (Group 2). Both groups were comparable with regard to sex (40% women/60% men vs 50% women/50% men), mean age (55 ± 13 vs 54 ± 6 years), comorbidities, and diagnosis leading to LTx. The Pao2/Fio2 ratio at the time of inclusion was comparable in both groups, with a mean 235.65 ± 90.78 vs 214.2 ± 95.84 (p = 0.405), and there was no significant difference in the extravascular lung water index (13.88 ± 5.28 vs 16 ± 6.29 ml/kg, p = 0.476). The primary end point was mean Pao2/Fio2 ratio values between baseline and Day 3. In the AP301 group, only 1 patient was ventilated at Day 4 and no patients were ventilated after Day 4. In the placebo group, 5 patients were ventilated on Day 4 and 2 patients on Days 5, 6, and 7. The mean increase in the Pao2/Fio2 ratio was significantly higher in Group 1 patients, and the mean between baseline and at 72 hours was 365.6 ± 90.4 in Group 1 vs 335.2 ± 42.3 in Group 2 (p = 0.049). The duration of intubation was shorter in Group 1 than in Group 2 patients (2 ± 0.82 vs 3.7 ± 1.95 days; p = 0.02). ICU stay was 7.5 ± 3.13 days in Group 1 vs 10.8 ± 8.65 days in group 2 (p = 0.57). Survival at 30 days was 100%. No severe adverse events were recorded. CONCLUSIONS: This study was designed as a proof-of-concept pilot study. Although it was not powered to achieve statistical significances, the study demonstrated relevant clinical effects of inhaled AP301 on patients with PGD after primary LTx. The improved gas exchange led to a significantly shorter duration of mechanical ventilation and a trend towards a shorter ICU stay. Further investigation of AP301 for treatment of PGD in larger studies is warranted. TRIAL REGISTRATION: The trial is registered at https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000716-21/AT.

Standard donor lung procurement with normothermic ex vivo lung perfusion: A prospective randomized clinical trial.

BACKGROUND: Ex vivo lung perfusion (EVLP) was primarily developed for evaluation of impaired donor lungs. The good clinical results raise the question for its possible impact on lungs meeting standard criteria. Before application of EVLP on such lungs enters routine clinical practice, it must be demonstrated whether EVLP would affect or improve outcome when used in standard donor lungs. We performed a prospective randomized trial to investigate the role of EVLP in standard lung transplantation (Tx). METHODS: This prospective randomized clinical trial compared patients who underwent Tx with ex vivo evaluated donor lungs with an equivalent patient population without previous EVLP. RESULTS: From October 2013 to May 2015, 193 lung Tx were performed at the Medical University of Vienna. During this period, 80 recipient/donor pairs that met the inclusion criteria were included in this trial, 41 pairs in the control group, and 39 in the EVLP group. In the EVLP group, 4 lungs (10.2%) ultimately did not qualify for Tx and were rejected for lung Tx owing to technical reasons (n = 2) and quality criteria (n = 2). Donor and recipient characteristics were comparable in both groups. Total cold ischemic time in the EVLP group was significantly longer for both implanted lungs (first side, 372 minutes vs 291 minutes, p < 0.001; second side, 437 minutes vs 370 minutes, p = 0.001); median duration of surgery showed no differences (277 minutes vs 275 minutes). Median oxygen partial pressure/fraction of inspired oxygen ratio at 24 hours after Tx was 516 (range, 280-557) in the EVLP group and 491 (range, 352-575) in the control group (p = 0.63). Incidence of primary graft dysfunction >1 was lower in the EVLP group at all time points compared with the control group (24 hours, 5.7% vs 19.5%, p = 0.10), and need for post-operative prolonged extracorporeal membrane oxygenation was lower in the EVLP group (5.7% vs 12.2%, p = 0.44). Short-term clinical outcomes did not differ between recipients in the 2 groups. Patients remained intubated (1.6 days vs 1.6 days, p = 0.67), in the intensive care unit (6 days vs 6 days, p = 0.76), and in the hospital (23 days vs 19 days, p = 0.42) for a comparable period of time. The 30-day survival was 97.1% vs 100% (p = 0.46). CONCLUSIONS: This study provides evidence that EVLP can safely be used in standard donor lungs. Functional results and perioperative outcome are comparable to those achieved with standard donor lung preservation techniques. As an evaluation tool, EVLP allows clinicians to identify and to possibly exclude lungs with functional impairment. Finally, EVLP can safely extend total preservation time.