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.

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.

Results of Lung Transplantation for Cystic Fibrosis With Selected Donors Over 65 Years Old.

Lung transplantation is limited by the shortage of suitable donors. Many programs have begun to use extended criteria donors. Donors over 65 years old are rarely reported, especially for young cystic fibrosis recipients. This monocentric study was conducted for cystic fibrosis recipients from January 2005 to December 2019, comparing two cohorts according to lung donor age (<65 years or ≥65 years). The primary objective was to assess the survival rate at 3 years using a Cox multivariable model. Of the 356 lung recipients, 326 had donors under 65 years, and 30 had donors over 65 years. Donors' characteristics did not differ significantly in terms of sex, time on mechanical ventilation before retrieval, and partial pressure of arterial oxygen/fraction of inspired oxygen ratio. There were no significant differences in post-operative mechanical ventilation duration and incidence of grade 3 primary graft dysfunction between the two groups. At 1, 3, and 5 years, the percentage of predicted forced expiratory volume in 1 s (p = 0.767) and survival rate did not differ between groups (p = 0.924). The use of lungs from donors over 65 years for cystic fibrosis recipients allows extension of the donor pool without compromising results. Longer follow-up is needed to assess the long-term effects of this practice.

Perioperative Outcomes During Double-Lung Transplantation and Retransplantation in Cystic Fibrosis Patients: A Monocentric Cohort Study.

OBJECTIVE: Life expectancy for lung-transplant patients, especially those with cystic fibrosis (CF), is leading increasingly to more retransplantations. DESIGN: Retrospective monocentric cohort study. SETTING: Foch University Hospital, Suresnes, France. PARTICIPANTS: CF patients having had a primary double-lung transplantation (pLgTx) or a retransplantation (reLgTx) from 2012 to 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors compared the main intraoperative and early postoperative features between pLgTx (n = 258) and reLgTx (n = 24). Demographic characteristics were similar. No patients with retransplantations had a preoperative bridge with extracorporeal membrane oxygenation (ECMO); however, 23 patients had it in the pLgTx group (p = 0.24). Patients with retransplants had longer second graft ischemic time (p = 0.02), larger intraoperative bleeding volume (p = 0.001) and blood transfusion (p = 0.009 for packed red blood cells), increased blood lactate concentrations (p = 0.002), and higher norepinephrine dose at end-surgery (p = 0.001). Extracorporeal membrane oxygenation was used during surgery in 94 patients in the pLgTx group and 12 patients in the reLgTx group (p = 0.39). Extracorporeal membrane oxygenation could not be weaned after surgery in 55 patients in the pLgTx group and 4 in the reLgTx group (p = 0.54). Despite worse preoperative renal function in the reLgTx group (p < 0.001), there was no difference concerning renal replacement therapy in the intensive care unit between groups (p = 0.08). There were no differences between groups concerning the main complications, including primary graft dysfunction. Although the difference was not statistically different (p = 0.17), mortality was 3 times higher in the reLgTx group. CONCLUSIONS: Intraoperative period of retransplantation was more convoluted but had a similar ECMO profile to primary transplantation. In addition, the early postoperative period was similar.

Chronic pain after posterolateral and axillary approaches to lung surgery: a monocentric observational study.

PURPOSE: Post-thoracotomy pain syndrome (PTPS) and chronic postsurgical neuropathic pain (CPNP) were evaluated 4 months after thoracic surgery whether the approach was a posterolateral (PL) incision or the less invasive axillary (AX) one. METHODS: Patients, 79 in each group, undergoing a thoracotomy between July 2014 and November 2015 were analyzed 4 months after surgery in this prospective monocentric cohort study. RESULTS: More PL patients suffered PTPS (60.8% vs. 40.5%; p = 0.017) but CPNP was equally present (45.8% and 46.9% in the PL and AX groups). Patients with PTPS have more limited daily activities (p < 0.001) but a similar psychological disability (i.e., catastrophism). Patients with CPNP have an even greater limitation of daily activities (p = 0.007) and more catastrophism (p = 0.0002). Intensity of pain during mobilization of the homolateral shoulder at postoperative day 6 (OR = 1.40, CI 95% [1.13-1.75], p = 0.002); age (OR = 0.97 [0.94-1.00], p = 0.022), and presence of pain before surgery (OR = 2.22 [1.00-4.92], p = 0.049) are related to the occurrence of PTPS; while, height of hypoesthesia area on the breast line measured 6 days after surgery is the only factor related to that of CPNP (OR = 1.14 [1.01-1.30], p = 0.036). CONCLUSION: Minimally invasive surgery was associated with less frequent PTPS, but with equal risk of CPNP. Pain before surgery and its postoperative intensity are associated with PTPS. This must lead to a more aggressive care of pain patients before surgery and of a better management of postoperative pain. CPNP can be forecasted according to the early postoperative height of hypoesthesia area on the breast line.

Continuous Endogenous Exhaled CO Monitoring by Laser Spectrometer in Human EVLP Before Lung Transplantation.

Endogenous production of carbon monoxide (CO) is affected by inflammatory phenomena and ischemia-reperfusion injury. Precise measurement of exhaled endogenous CO (eCO) is possible thanks to a laser spectrometer (ProCeas® from AP2E company). We assessed eCO levels of human lung grafts during the normothermic Ex-Vivo Lung Perfusion (EVLP). ProCeas® was connected in bypass to the ventilation circuit. The surgical team took the decision to transplant the lungs without knowing eCO values. We compared eCO between accepted and rejected grafts. EVLP parameters and recipient outcomes were also compared with eCO values. Over 7 months, eCO was analyzed in 21 consecutive EVLP grafts. Two pairs of lungs were rejected by the surgical team. In these two cases, there was a tendency for higher eCO values (0.358 ± 0.52 ppm) compared to transplanted lungs (0.240 ± 0.76 ppm). During the EVLP procedure, eCO was correlated with glucose consumption and lactate production. However, there was no association of eCO neither with edema formation nor with the PO2/FiO2 ratio per EVLP. Regarding post-operative data, every patient transplanted with grafts exhaling high eCO levels (>0.235 ppm) during EVLP presented a Primary Graft Dysfunction score of 3 within the 72 h post-transplantation. There was also a tendency for a longer stay in ICU for recipients with grafts exhaling high eCO levels during EVLP. eCO can be continuously monitored during EVLP. It could serve as an additional and early marker in the evaluation of the lung grafts providing relevant information for post-operative resuscitation care.

Prevalence, Characteristics and Preoperative Predictors of Chronic Pain After Double-Lung Transplantation: A Prospective Cohort Study.

OBJECTIVE: Data on chronic pain after lung transplantation are heterogeneous. This study prospectively explored the prevalence, characteristics, consequences, and preoperative predictors of pain in lung transplant recipients. DESIGN: A prospective cohort study. SETTING: The Foch University Hospital, Suresnes, France. PARTICIPANTS: Patients registered on the waiting list for double-lung transplantation in the authors' institution from August 2008 to October 2013 and transplanted. INTERVENTIONS: Database prospectively completed in real time during consultations with a pain-certified anesthesiologist before lung transplantation and six months after surgery. MEASUREMENTS AND MAIN RESULTS: The assessments explored pain in three components: physical (intensity, location, neuropathic and sensory qualifications, treatments), mental (anxiety and depression), and quality of life. Seventy-two patients underwent all assessments. The prevalence of six-month postoperative pain was 68.0%. Among patients with pain, 83.3% reported mild average pain and 26.5% had neuropathic pain. All patients who responded to the questionnaire took analgesics frequently, but only 9.1% took opioids. Patients with pain reported higher levels of anxiety (p = 0.02) and depression (p = 0.01). Additionally, they presented with increased difficulty in ambulation (p = 0.03), work (p = 0.02), and sleep (p = 0.02). The maximum level of preoperative pain was an independent risk factor of six-month postoperative pain (p = 0.03). CONCLUSIONS: The authors report a high prevalence of chronic pain with concomitant psychosocial repercussions despite a reported mild intensity. Perioperative measures, such as personalized and detailed management plans, could improve patient satisfaction.

Feasibility and Usefulness of Self-Hypnosis in Patients Undergoing Double-Lung Transplantation During the Pre- and Postoperative Periods: A Randomized Study.

OBJECTIVE: Hypnosis can reduce pain and anxiety in surgical patients. This study aimed to demonstrate that implementing self-hypnosis in the setting of lung transplantation could improve patients' pain and quality of life. DESIGN: A randomized, single-center study. SETTING: Foch University Hospital, Suresnes, France. PARTICIPANTS: The participants were patients aged 15 years or older who needed a double-lung transplant. Patients were excluded if they participated in only 1 learning self-hypnosis session before transplantation. INTERVENTIONS: Patients were included at the time of their final evaluation before inscription on the waiting list. They were taught self-hypnosis at this time and were asked to perform it by themselves before and after transplantation, as frequently as possible. MEASUREMENTS AND MAIN RESULTS: The main outcome of the study was self-reported pain 1 month after lung transplantation. Secondary outcomes were self-reported pain, anxiety, coping, catastrophism, and self-reported quality of life evaluated at their registration, 7 days and 1 and 4 months after the transplantation. Seventy-eight patients were included, but only 28 patients in the control group and 33 in the self-hypnosis group were evaluated at the fourth postoperative month. Practice of self-hypnosis was high before transplantation (76.6%), lower after, from 32.3% in the intensive care unit to 51.6% during the last 3 months of the study. Group-time interactions were not statistically significant whatever the concerned outcome, especially pain score at 1 month (p = 0.16). CONCLUSION: Implementation of self-hypnosis is possible, but the study failed to demonstrate an improvement in patients' experience, perhaps due to the variable compliance with the technique.

Blood Lactate During Double-Lung Transplantation: A Predictor of Grade-3 Primary Graft Dysfunction.

OBJECTIVE: Many prognostic factors of grade-3 primary graft dysfunction at postoperative day 3 (PGD3-T72) have been reported, but intraoperative blood lactate level has not been studied. The present retrospective study was done to test the hypothesis that intraoperative blood lactate level (BLL) could be a predictor of PGD3-T72 after double-lung transplantation. DESIGN: Retrospective monocentric cohort study. SETTING: Foch University Hospital, Suresnes, France. PARTICIPANTS: Patients having received a double-lung transplantation between 2012 and 2019. Patients transplanted twice during the study period, having undergone a multiorgan transplantation, or cardiopulmonary bypass, and those under preoperative extracorporeal membrane oxygenation, were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Analysis was performed on a cohort of 449 patients. Seventy-two (16%) patients had a PGD3-T72. Blood lactate level increased throughout surgery to reach a median value of 2.2 (1.6-3.2) mmol/L in the No-PGD3-T72 group and 3.4 (2.3-5.0) mmol/L in the PGD3-T72 group after second lung implantation. The best predictive model for PGD3-T72 was obtained adding a lactate threshold of 2.6 mmol/L at the end of surgery to the clinical model, and the area under the curve was 0.867, with a sensitivity = 76.9% and specificity = 85.4%. Repeated-measures mixed model of BLL during surgery remained significant after adjustment for covariates (F ratio= 4.22, p < 0.001 for interaction). CONCLUSIONS: Blood lactate level increases during surgery and reaches a maximum after the second lung implantation. A value below the threshold of 2.6 mmol/L at the end of surgery has a high negative predictive value for the occurrence of a grade-3 primary graft dysfunction at postoperative day 3.

A virtual crossmatch-based strategy for perioperative desensitisation in lung transplant recipients with pre-formed donor-specific antibodies: 3-year outcome.

BACKGROUND: Pre-formed donor-specific antibodies (DSAs) are associated with worse outcome after lung transplantation (LTx) and might limit access to LTx. A virtual crossmatch-based strategy for perioperative desensitisation protocol has been used for immunised LTx candidates since 2012 at Foch Hospital (Suresnes, France). We compared the outcome of desensitised LTx candidates with high DSA mean fluorescence intensity and those with low or no pre-formed DSAs, not desensitised. METHODS: For all consecutive LTx recipients (January 2012 to March 2018), freedom from chronic lung allograft dysfunction (CLAD) and graft survival were assessed using Kaplan-Meier analysis and Cox multivariate analysis. RESULTS: We compared outcomes for desensitised patients with high pre-formed DSAs (n=39) and those with no (n=216) or low pre-formed DSAs (n=66). The desensitisation protocol decreased the level of immunodominant DSA (class I/II) at 1, 3 and 6 months post-LTx (p<0.001, p<0.01 and p<0.001, respectively). Freedom from CLAD and graft survival at 3 years was similar in the desensitised group as a whole and other groups. Nevertheless, incidence of CLAD was higher with persistent high-level DSAs than cleared high-level (p=0.044) or no DSAs (p=0.014). Conversely, graft survival was better with cleared high DSAs than persistent high-level, low-level and no pre-formed DSAs (p=0.019, p=0.025 and p=0.044, respectively). On multivariate analysis, graft survival was associated with cleared high DSAs (hazard ratio 0.12, 95% CI 0.02-0.85 versus no DSAs; p=0.035) and CLAD with persistent DSAs (3.04, 1.02-9.17 versus no pre-formed DSAs; p=0.048). CONCLUSION: The desensitisation protocol in LTx recipients with high pre-formed DSAs was associated with satisfactory outcome, with cleared high pre-formed DSAs after desensitisation identified as an independent predictor of graft survival.

Hanging donor lungs give good short-, mid- and long-term results in lung transplantation.

BACKGROUND: Hanging donors are considered as marginal donors and frequently unsuitable for lung transplantation. However, there is no evidence of higher lung transplantation (LTx) morbidity-mortality with lungs providing by hanging donor. METHODS: Between January 2010 and July 2015, we performed a retrospective study at Foch hospital. We aimed to assess whether hanging donor grafts are suitable for lung transplantation. RESULTS: A total of 299 LTx were performed. Subjects were allocated to a hanging group (HG) (n = 20) and a control group (CG) (n = 279). Donor and recipient characteristics did not differ. Primary graft dysfunction (PGD) at 72 hours was comparable in both groups (P = .75). The median duration of postoperative mechanical ventilation (1 [range, 0-84] vs 1 [range, 0-410] day, P = .35), the hospital length of stay (31 days [20-84] vs 32 days [12-435], P = .36) did not differ between the two groups. No statistically significant difference was found in 1-year and 5-year survival between the HG (83% and 78%) and the CG (86% and 75%), P = .85. CONCLUSION: We believe that hanging donors should be considered as conventional donors with particular caution in the final evaluation of the graft and in perioperative management.

A new technique for intra-abdominal arteries revascularization via extra-anatomic bypass from the brachiocephalic artery with a videoscopic retrosternal tunnel.

Extra-anatomic revascularizations of intra-abdominal or lower limbs arteries, or both, are indicated (1) when the aorta is unsuitable for anatomic bypasses, (2) in patients unfit for aortic surgery, (3) for graft infections, and (4) for visceral debranching during hybrid treatment of a thoracoabdominal aneurysm. We describe a new extra-anatomic bypass from the brachiocephalic artery with video-guided retrosternal tunneling. We discuss the advantages and drawbacks of this technique.

In Situ Fenestration Through the Contralateral Iliac Artery to Convert an Aortouni-iliac Into a Bifurcated Endograft.

PURPOSE: To present a technique of in situ fenestration that allows conversion of an aortouni-iliac endograft into a bifurcated endograft, thereby avoiding crossover femorofemoral bypass and its complications. TECHNIQUE: Following conventional deployment of an aortouni-iliac endograft, in situ fenestration through the contralateral common iliac artery is performed with a transjugular intrahepatic access set. The fabric hole is enlarged using a cutting balloon and a high-pressure noncompliant balloon. Kissing iliac-covered stents are then positioned at the level of the bifurcation to convert the aortouni-iliac endograft into a bifurcated repair. To date, this technique has been successfully used in 4 patients with satisfactory short-term results. CONCLUSION: This technique represents another application of endograft in situ fenestration. This strategy provides a bifurcated repair in cases where bifurcated stent-grafts are usually precluded, such as a narrow distal aorta, ruptured abdominal aortic aneurysm, or combined aortoiliac occlusive disease.

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.

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.

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.

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.

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.