Circulating Vesicular-bound HLA-G as Noninvasive Predictive Biomarker of CLAD After Lung Transplantation.

BACKGROUND: Circulating extracellular vesicles (EVs) have shown promising results as noninvasive biomarkers for predicting disease outcomes in solid organ transplantation. Because in situ graft cell expression of the tolerogenic molecule HLA-G is associated with acceptance after lung transplantation (LTx), we hypothesized that plasma EV-bound HLA-G (HLA-GEV) levels could predict chronic lung allograft dysfunction (CLAD) development. METHODS: We analyzed 78 LTx recipients from the Cohort-for-Lung-Transplantation cohort, all in a stable (STA) state within the first year post-LTx. At 3 y, 41 patients remained STA, and 37 had CLAD (bronchiolitis obliterans syndrome, BOS, [n = 32] or restrictive allograft syndrome [n = 5]). HLA-GEV plasma levels were measured at month 6 (M6) and M12 in 78 patients. CLAD occurrence and graft failure at 3 y post-LTx were assessed according to early HLA-GEV plasma levels. RESULTS: In patients with subsequent BOS, (1) HLA-GEV levels at M12 were significantly lower than those in STA patients (P = 0.013) and (2) also significantly lower than their previous levels at M6 (P = 0.04).A lower incidence of CLAD and BOS and higher graft survival at 3 y were observed in patients with high HLA-GEV plasma levels at M12 (high versus low HLA-GEVs patients [cutoff 21.3 ng/mL]: freedom from CLAD, P = 0.002; freedom from BOS, P < 0.001; and graft survival, P = 0.04, [log-rank]). Furthermore, in multivariate analyses, low HLA-GEV levels at M12 were independently associated with a subsequent risk of CLAD, BOS, and graft failure at 3 y (P = 0.015, P = 0.036, and P = 0.026, respectively [Cox models]). CONCLUSIONS: This exploratory study suggests the potential of EV-bound HLA-G plasma levels as a liquid biopsy in predicting CLAD/BOS onset and subsequent graft failure.

Kidney After Lung Transplants or Combined Kidney-Lung Transplantation: A Single-Center Retrospective Cohort Study.

BACKGROUND End-stage renal disease is a major issue in the management of patients undergoing lung transplantation. Combined kidney-lung transplantation (CKLT) and kidney after lung transplantation (KALT) are the 2 preferred solutions to manage this situation. To evaluate these strategies, we describe kidney and lung graft outcomes and patient survival in patients managed with CKLT and KALT. MATERIAL AND METHODS We conducted a retrospective single-center cohort study. Patients who underwent a CKLT or a KALT were included in this study. Retrospective extraction of data from medical records was performed. RESULTS Seventeen patients underwent CKLT and 9 underwent KALT. Most of the patients had cystic fibrosis and presented renal failure related to anti-calcineurin toxicity. The 30-day and 1-year survival of CKLT recipients were both 75.6%. No patients with KALT died during the follow-up. Kidney graft prognosis was almost exclusively influenced by patient survival in relation to postoperative lung transplant complications. The rate of severe surgical complications was close to 60% for CKLT compared with 30% for KALT. The kidney graft function (estimated kidney graft function) did not differ according to the transplantation strategy. CONCLUSIONS KALT is a safe option, with postoperative morbidity and renal graft function identical to those of kidney transplantation in non-lung-transplanted patients. The results of CKLT depend mainly on the morbidity associated with lung transplantation but remain an attractive option for patients with respiratory failure associated with end-stage renal disease. The choice of transplant strategy must also take into account the most ethical and efficient allocation of kidney grafts.

SARS-CoV2 infection in whole lung primarily targets macrophages that display subset-specific responses.

Deciphering the initial steps of SARS-CoV-2 infection, that influence COVID-19 outcomes, is challenging because animal models do not always reproduce human biological processes and in vitro systems do not recapitulate the histoarchitecture and cellular composition of respiratory tissues. To address this, we developed an innovative ex vivo model of whole human lung infection with SARS-CoV-2, leveraging a lung transplantation technique. Through single-cell RNA-seq, we identified that alveolar and monocyte-derived macrophages (AMs and MoMacs) were initial targets of the virus. Exposure of isolated lung AMs, MoMacs, classical monocytes and non-classical monocytes (ncMos) to SARS-CoV-2 variants revealed that while all subsets responded, MoMacs produced higher levels of inflammatory cytokines than AMs, and ncMos contributed the least. A Wuhan lineage appeared to be more potent than a D614G virus, in a dose-dependent manner. Amidst the ambiguity in the literature regarding the initial SARS-CoV-2 cell target, our study reveals that AMs and MoMacs are dominant primary entry points for the virus, and suggests that their responses may conduct subsequent injury, depending on their abundance, the viral strain and dose. Interfering on virus interaction with lung macrophages should be considered in prophylactic strategies.

Real-world outcomes of lobectomy, segmentectomy and wedge resection for the treatment of stage c-IA lung carcinoma.

OBJECTIVES: To determine safety and survival outcomes associated with lobectomy, segmentectomy and wedge resection for early-stage lung cancer by quiring the French population-based registry EPIdemiology in THORacic surgery (EPITHOR). METHODS: Retrospective analysis of 19 452 patients with stage c IA lung carcinoma who underwent lobectomy, segmentectomy or wedge resection between 2016 and 2022 with curative-intent. Main outcome measures were 90-day mortality and 5-year overall survival estimates. Proportional hazards regression and propensity score matching were used to adjust outcomes for key patient, tumour and practice environment factors. RESULTS: The treatment distribution was 72.2% for lobectomy, 21.5% for segmentectomy and 6.3% for wedge. Unadjusted 90-day mortality rates were 1.6%, 1.2% and 1.1%, respectively (P = 0.10). Unadjusted 5-year overall survival estimates were 80%, 78% and 70%, with significant inter-group survival curves differences (P < 0.0001). Multivariable proportional hazards regression showed that wedge was associated with worse overall survival [adjusted hazard ratio (AHR), 1.23 (95% confidence interval 1.03-1.47); P = 0.021] compared with lobectomy, while no significant difference was disclosed when comparing segmentectomy to lobectomy (1.08 [0.97-1.20]; P = 0.162). The three-way propensity score analyses confirmed similar 90-day mortality rate for wedge resection and segmentectomy compared with lobectomy (hazard ratio: 0.43; 95% confidence interval 0.16-1.11; P = 0.081 and 0.99; 0.48-2.10; P = 0.998, respectively), but poorer overall survival (1.45; 1.13-1.86; P = 0.003 and 1.31; 1-1.71; P = 0.048, respectively). CONCLUSIONS: Wedge resection was associated with comparable 90-day mortality but lower overall survival when compared to lobectomy. Overall, all types of sublobar resections may not offer equivalent oncologic effectiveness in real-world settings.

Prolonged dialysis during ex vivo lung perfusion promotes inflammatory responses.

Ex-vivo lung perfusion (EVLP) has extended the number of transplantable lungs by reconditioning marginal organs. However, EVLP is performed at 37°C without homeostatic regulation leading to metabolic wastes' accumulation in the perfusate and, as a corrective measure, the costly perfusate is repeatedly replaced during the standard of care procedure. As an interesting alternative, a hemodialyzer could be placed on the EVLP circuit, which was previously shown to rebalance the perfusate composition and to maintain lung function and viability without appearing to impact the global gene expression in the lung. Here, we assessed the biological effects of a hemodialyzer during EVLP by performing biochemical and refined functional genomic analyses over a 12h procedure in a pig model. We found that dialysis stabilized electrolytic and metabolic parameters of the perfusate but enhanced the gene expression and protein accumulation of several inflammatory cytokines and promoted a genomic profile predicting higher endothelial activation already at 6h and higher immune cytokine signaling at 12h. Therefore, epuration of EVLP with a dialyzer, while correcting features of the perfusate composition and maintaining the respiratory function, promotes inflammatory responses in the tissue. This finding suggests that modifying the metabolite composition of the perfusate by dialysis during EVLP can have detrimental effects on the tissue response and that this strategy should not be transferred as such to the clinic.

Successful lung transplantation in genetic methionyl-tRNA synthetase-related alveolar proteinosis/lung fibrosis without recurrence under methionine supplementation: Medium-term outcome in 4 cases.

Pulmonary alveolar proteinosis (PAP) results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages, and can be associated with pulmonary fibrosis, with a need for lung transplantation (LTx). Causes of PAP are autoimmune (90%-95%), secondary (5%), or hereditary (<1%). Patients with hereditary PAP are generally not considered for isolated LTx, due to the high probability of recurrence after LTx, and only a challenging scenario with sequential LTx followed by hematopoietic stem cell transplantation (HSCT) was reported as successful. Recently, a new genetic cause of PAP linked to mutations in the methionyl-tRNA synthetase (MARS) gene has been reported, with a highly variable clinical presentation. Because clinical correction of the defective MARS activity with methionine supplementation has been reported in nontransplanted children, we reassessed the feasibility of LTx for candidates with MARS-related PAP/fibrosis. We report 3 cases of LTx performed for MARS-related pulmonary alveolar proteinosis-pulmonary fibrosis without recurrence under methionine supplementation, whereas another fourth case transplanted without supplementation had fatal PAP recurrence. These results suggest the effectiveness of methionine in correcting defective MARS activity and also looking for this very rare diagnosis in case of unclassified PAP/fibrosis. It argues for not excluding the feasibility of isolated LTx in patients with MARS mutation.

Lobar or sublobar resection of peripheral stage I non-small cell lung cancer.

PURPOSE OF REVIEW: We aim to highlight two recent clinical trials that have altered the approach of the management of stage I nonsmall cell lung cancer. RECENT FINDINGS: The JCOG 0802 and CALGB 140503 trials demonstrated that sublobar resection is noninferior to lobectomy for overall and disease-free survival in patients with stage I nonsmall cell lung cancer. SUMMARY: Since 1962, lobectomy has been deemed the gold standard treatment for operable lung cancer. However, two recent clinical trials have demonstrated that, for select patients, sublobar resection is oncologically noninferior; results, which are leading us into a new era for the surgical management of lung cancer. Notwithstanding the progress made by these studies and the opportunities that have been put forth, questions remain. This review aims at reviewing the results of both trials and to discuss future perspectives for the surgical treatment of lung cancer.

Optimizing lung cancer radiation therapy: A systematic review of multifactorial risk assessment for radiation-induced lung toxicity.

BACKGROUND: Radiation therapy (RT) is essential in treating advanced lung cancer, but may lead to radiation pneumonitis (RP). This systematic review investigates the use of pulmonary function tests (PFT) and other parameters to predict and mitigate RP, thereby improving RT planning. METHODS: A systematic review sifted through PubMed and on BioMed Central, targeting articles from September 2005 to December 2022 containing the keywords: Lung Cancer, Radiotherapy, and pulmonary function test. RESULTS: From 1153 articles, 80 were included. RP was assessed using CTCAEv.4 in 30 % of these. Six studies evaluated post-RT quality of life in lung cancer patients, reporting no decline. Patients with RP and chronic obstructive pulmonary disease (COPD) generally exhibited poorer overall survival. Notably, forced expiratory volume in one second (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) declined 24 months post-RT, while forced vital capacity (FVC) stayed stable. In the majority of studies, age over 60, tumors located in the lower part of the lung, and low FEV1 before RT were associated with a higher risk of RP. Dosimetric factors (V5, V20, MLD) and metabolic imaging emerged as significant predictors of RP risk. A clinical checklist blending patient and tumor characteristics, PFT results, and dosimetric criteria was proposed for assessing RP risk before RT. CONCLUSION: The review reveals the multifactorial nature of RP development following RT in lung cancer. This approach should guide individualized management and calls for a prospective study to validate these findings and enhance RP prevention strategies.

Differential early response of monocyte/macrophage subsets to intra-operative corticosteroid administration in lung transplantation.

Introduction: Lung transplantation often results in primary and/or chronic dysfunctions that are related to early perioperative innate allo-responses where myeloid subsets play a major role. Corticosteroids are administered upon surgery as a standard-of-care but their action on the different myeloid cell subsets in that context is not known. Methods: To address this issue, we used a cross-circulatory platform perfusing an extracorporeal lung coupled to cell mapping in the pig model, that enabled us to study the recruited cells in the allogeneic lung over 10 hours. Results: Myeloid cells, i.e. granulocytes and monocytic cells including classical CD14pos and non-classical/intermediate CD16pos cells, were the dominantly recruited subsets, with the latter upregulating the membrane expression of MHC class II and CD80/86 molecules. Whereas corticosteroids did not reduce the different cell subset recruitment, they potently dampened the MHC class II and CD80/86 expression on monocytic cells and not on alveolar macrophages. Besides, corticosteroids induced a temporary and partial anti-inflammatory gene profile depending on cytokines and monocyte/macrophage subsets. Discussion: This work documents the baseline effects of the standard-of-care corticosteroid treatment for early innate allo-responses. These insights will enable further optimization and improvement of lung transplantation outcomes.

Donor/recipient origin of lung cancer after lung transplantation by DNA short tandem repeat analysis.

Background: Lung cancer is more common in posttransplant recipients than in the general population. The objective of this study was to examine the chimerism donor/recipient cell origin of graft cancer in recipients of lung transplant. Methods: A retrospective chart review was conducted at Foch Hospital for all lung transplantations from 1989 to 2020. Short tandem repeat PCR (STR-PCR) analysis, the gold standard technique for chimerism quantification, was used to determine the donor/recipient cell origin of lung cancers in transplant patients. Results: Fourteen (1.4%) of the 1,026 patients were found to have graft lung cancer after lung transplantation, and one developed two different lung tumors in the same lobe. Among the 15 lung tumors, 10 (67%) presented with adenocarcinoma, four (27%) with squamous cell carcinoma and one with small cell lung cancer. STR analysis showed that the origin of the cancer was the donor in 10 patients (71%), the recipient in three patients (21%), and was undetermined in one patient. Median time to diagnosis was 62 months. Conclusion: The prevalence of lung cancer in lung transplant recipients is very low. However, the results of our study showed heterogeneity of genetic alterations, with 21% being of recipient origin. Our results highlight the importance of donor selection and medical supervision after lung transplantation.