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Night work is frequently associated with sleep deprivation and is associated with greater surgical and medical complications. Lung transplantation (LT) is carried out both at night and during the day and involves many medical healthcare workers. The goal of the study was to compare morbidity and mortality between LT recipients according to LT operative time. We performed a retrospective, observational, single-center study. When the procedure started between 6 AM and 6 PM, the patient was allocated to the Daytime group. If the procedure started between 6 PM and 6 AM, the patient was allocated to the Nighttime group. Between January 2015 and December 2020, 253 patients were included. A total of 168 (66%) patients were classified into the Day group, and 85 (34%) patients were classified into the Night group. Lung Donors’ general characteristics were similar between the groups. The 90-day and one-year mortality rates were similar between the groups (90-days: n = 13 (15%) vs. n = 26 (15%), p = 0.970; 1 year: n = 18 (21%) vs. n = 42 (25%), p = 0.499). Daytime LT was associated with more one-year airway dehiscence (n = 36 (21%) vs. n = 6 (7.1%), p = 0.004). In conclusion, among patients who underwent LT, there was no significant association between operative time and survival.

Introduction Lung transplantation (LTx) aims at improving survival and quality of life for patients with end-stage lung diseases. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is used as intraoperative support for LTx, despite no precise guidelines for its initiation. We aim to evaluate two strategies of VA-ECMO initiation in the perioperative period in patients with obstructive or restrictive lung disease requiring bilateral LTx. In the control ‘on-demand’ arm, high haemodynamic and respiratory needs will dictate VA-ECMO initiation; in the experimental ‘systematic’ arm, VA-ECMO will be pre-emptively initiated. We hypothesise a ‘systematic’ strategy will increase the number of ventilatory-free days at day 28.Methods and analysis We designed a multicentre randomised controlled trial in parallel groups. Adult patients with obstructive or restrictive lung disease requiring bilateral LTx, without a formal indication for pre-emptive VA-ECMO before LTx, will be included. Patients with preoperative pulmonary hypertension with haemodynamic collapse, ECMO as a bridge to transplantation, severe hypoxaemia or hypercarbia will be secondarily excluded. In the systematic group, VA-ECMO will be systematically implanted before the first pulmonary artery cross-clamp. In the on-demand group, VA-ECMO will be implanted intraoperatively if haemodynamic or respiratory indices meet preplanned criteria. Non-inclusion, secondary exclusion and VA-ECMO initiation criteria were validated by a Delphi process among investigators. Postoperative weaning of ECMO and mechanical ventilation will be managed according to best practice guidelines. The number of ventilator-free days at 28 days (primary endpoint) will be compared between the two groups in the intention-to-treat population. Secondary endpoints encompass organ failure occurrence, day 28, day 90 and year 1 vital status, and adverse events.Ethics and dissemination The sponsor is the Assistance Publique–Hôpitaux de Paris. The ECMOToP protocol version 2.1 was approved by Comité de Protection des Personnes Ile de France VIII. Results will be published in international peer-reviewed medical journals.Trial registration number NCT05664204.

We report a case of a 16-year-old man in cardiogenic shock secondary to On-X mitral prosthesis dysfunction due to leaflet embolization through aortic mechanical prosthesis. He underwent an emergency redo mitral valve replacement and, a few days later, leaflet removal by open aortic surgery with full recovery.

Abstract Background Early diagnosis of acute mesenteric ischemia (AMI) is essential for a favorable outcome. Selection of patients requiring a dedicated multiphasic computed tomography (CT) scan remains a clinical challenge. Methods In this cross-sectional diagnostic study conducted from 2016 to 2018, we compared the presentation of AMI patients admitted to an intestinal stroke center to patients with acute abdominal pain of another origin admitted to the emergency room (controls). Results We included 137 patients—52 with AMI and 85 controls. Patients with AMI [median age: 65 years (interquartile range 55–74)] had arterial and venous AMI in 65% and 35% of cases, respectively. Relative to controls, AMI patients were significantly older, more likely to have risk factors or a history of cardiovascular disease, and more likely to present with sudden-onset and morphine-requiring abdominal pain, hematochezia, guarding, organ dysfunction, higher white blood cell and neutrophil counts, and higher plasma C-reactive protein (CRP) and procalcitonin concentrations. On multivariate analysis, two independent factors were associated with the diagnosis of AMI: the sudden-onset (OR = 20, 95%CI 7–60, p

Objective: Implantation of an endovascular device disrupts the homeostatic CD31:CD31 interactions among quiescent endothelial cells (ECs), platelets, and circulating leukocytes. The aim of this study was to design an endothelial-mimetic coating of nitinol and cobalt-chromium (CoCr) surfaces and stents using synthetic CD31 peptides, to promote device endothelialization and pacific integration within the arterial wall. Methods: Peptides mimicking the domains 1 (D1) and 2 (D2) of CD31 were synthetized and immobilized onto experimental nitinol and CoCr surfaces using a three-step, dip-coating, mussel-inspired protocol using copper-free click chemistry. Human aortic EC phenotype and endothelialization assessment using parallel scratch tests were carried out using five synthetic CD31 peptides coated on 4.8-mm nitinol and CoCr flat disks and were compared with control disks. The CD31 peptide exhibiting the best results in vitro was then immobilized on clinical-grade 3 × 40-mm self-expanding nitinol and 2.5 × 20.0-mm balloon-expandable CoCr stents. Such devices were implanted in native arteries of White New Zealand rabbits, and compared with control uncoated bare metal stents (BMS) and drug-eluting stents 7 and 30 days after implantation using resin cross-sections and scanning electron microscopy (n = 2-3 per group at each time point). Results: Membrane-distal CD31 D1 and D2 peptides exhibited a distinct capability to foster a healthy endothelial phenotype and to promote endothelialization in vitro. By day 7 after implantation, CD31 nitinol and CoCr stents were evenly covered by wholesome ECs, devoid of thromboinflammatory signs, in contrast with both BMS and drug-eluting stents. Such results were consistent until day 30. Conclusions: Membrane-distal CD31 biomimetic peptides seem to camouflage the device surface effectively, preventing local reactions and promoting rapid and seamless endovascular integration. : Clinical Relevance: Despite significant technical advancements, the challenge of vascular stent healing persists. In this preclinical study, we developed a novel endothelial-mimetic coating inspired by the trans-homophilic portion of CD31, a glycoprotein predominantly expressed by endothelial cells and pivotal in circulatory homeostasis. After successive peptide design and surface functionalization, both in vitro and in vivo experiments demonstrated the potential of the CD31-coated surface to promote the acquisition of a physiological endothelial cell phenotype, facilitating rapid healing and peaceful integration of stents. Further studies with larger sample sizes, extended follow-up periods, and assessment of the impact on in-stent restenosis are essential before translating this strategy to clinical applications.

Abstract Background Airway complications are frequent after lung transplantation (LT), as they affect up to 23% of recipients. The implication of perioperative extracorporeal membrane oxygenation (ECMO) support and haemodynamic instability has never been specifically assessed. The first aim of this study was to explore the impact of perioperative ECMO support on bronchial anastomotic dehiscence (BAD) at Day 90 after LT. Methods This prospective observational monocentric study analysed BAD in all consecutive patients who underwent LT in the Bichat Claude Bernard Hospital, Paris, France, between January 2016 and May 2019. BAD visible on bronchial endoscopy and/or tomodensitometry was recorded. A univariate analysis was performed (Fisher’s exacts and Mann–Whitney tests), followed by a multivariate analysis to assess independent risk factors for BAD during the first 90 days after LT (p

Key points Reperfusion injury of the bowel occurred in 44% of patients with acute mesenteric ischemia treated by endovascular revascularization. A decreased bowel enhancement on initial CT (HR = 8.2), an occlusion of the superior mesenteric artery (HR = 7.0), an embolic cause (HR = 7.4), and higher initial serum lactate level (HR = 1.4) were identified as predictors of reperfusion injury. Bowel wall hypoattenuation, hyperenhancement of the mucosa, and increase in CRP levels after revascularization were key diagnostic features of reperfusion injury.

Abstract We evaluated the contribution of artificial intelligence in predicting the risk of acute cellular rejection (ACR) using early plasma levels of soluble CD31 (sCD31) in combination with recipient haematosis, which was measured by the ratio of arterial oxygen partial pressure to fractional oxygen inspired (PaO2/FiO2) and respiratory SOFA (Sequential Organ Failure Assessment) within 3 days of lung transplantation (LTx). CD31 is expressed on endothelial cells, leukocytes and platelets and acts as a “peace-maker” at the blood/vessel interface. Upon nonspecific activation, CD31 can be cleaved, released, and detected in the plasma (sCD31). The study included 40 lung transplant recipients, seven (17.5%) of whom experienced ACR. We modelled the plasma levels of sCD31 as a nonlinear dependent variable of the PaO2/FiO2 and respiratory SOFA over time using multivariate and multimodal models. A deep convolutional network classified the time series models of each individual associated with the risk of ACR to each individual in the cohort.

Abstract Introduction The maximum gain in quality of life after lung transplantation (LT) is expected between six months and one year after LT, as the occurrence of chronic lung allograft dysfunction may mask the beneficial effects beyond one year. Thus, the postoperative period could be the cornerstone of graft success. We sought to describe the factors present before postoperative admission to the ICU and associated with favorable, arduous or fatal pathway within 90 days of LT. Materials and methods We conducted a retrospective single-center study between January 2015 and December 2020. Using multinomial regression, we assessed the demographic, preoperative and intraoperative characteristics of patients associated with favorable (duration of postoperative mechanical ventilation

BackgroundRisk factors and the incidence of prolonged mechanical ventilation (PMV) after lung transplantation (LT) have been poorly described. The study assessed predictive factors of PMV after LT.MethodsThis observational, retrospective, monocentric study included all patients who received LT in Bichat Claude Bernard Hospital between January 2016 and December 2020. PMV was defined as a duration of MV > 14 days. Independent risk factors for PMV were studied using multivariate analysis. One-year survival depending on PMV was studied using Kaplan Meier and log-rank tests. A p value 5 red blood cell units (p

Abstract Background In patients receiving single lung transplantation for idiopathic pulmonary fibrosis, worsening of fibrosis of the native lung is usually progressive over time, with no significant effects on gas exchange. Case presentation Here, we describe the cases of two Caucasian male recipients of single lung transplants for idiopathic pulmonary fibrosis, 65 and 62 years of age, who exhibited acute worsening of lung fibrosis after an episode of serious viral infection (cytomegalovirus primo-infection in one case and COVID-19 in the other). In both cases, along with opacification of the native lung over several days, the patients presented acute respiratory failure that required the use of high-flow nasal oxygen therapy. Eventually, hypoxemic respiratory failure resolved, but with rapid progression of fibrosis of the native lung. Conclusion We conclude that acute worsening of fibrosis on the native lung secondary to a severe viral infection should be added to the list of potential complications developing on the native lung after single lung transplantation for idiopathic pulmonary fibrosis.

AimsIgE type immunoglobulins and their specific effector cells, mast cells (MCs), are associated with abdominal aortic aneurysm (AAA) progression. In parallel, immunoglobulin-producing B cells, organised in tertiary lymphoid organs (TLOs) within the aortic wall, have also been linked to aneurysmal progression. We aimed at investigating the potential role and mechanism linking local MCs, TLO B cells, and IgE production in aneurysmal progression.Methods and resultsThrough histological assays conducted on human surgical samples from AAA patients, we uncovered that activated MCs were enriched at sites of unhealed haematomas, due to subclinical aortic wall fissuring, in close proximity to adventitial IgE+ TLO B cells. Remarkably, in vitro the IgEs deriving from these samples enhanced MC production of IL-4, a cytokine which favors IgE class-switching and production by B cells. Finally, the role of MCs in aneurysmal progression was further analysed in vivo in ApoE-/- mice subjected to angiotensin II infusion aneurysm model, through MC-specific depletion after the establishment of dissecting aneurysms. MC-specific depletion improved intramural haematoma healing and reduced aneurysmal progression.ConclusionsOur data suggest that MC located close to aortic wall fissures are activated by adventitial TLO B cell-produced IgEs and participate to their own activation by providing support for further IgE synthesis through IL-4 production. By preventing prompt repair of aortic subclinical fissures, such a runaway MC activation loop could precipitate aneurysmal progression, suggesting that MC-targeting treatments may represent an interesting adjunctive therapy for reducing AAA progression.

Abstract Early diagnosis of acute mesenteric ischemia (AMI) remains a clinical challenge, and no biomarker has been consistently validated. We aimed to assess the accuracy of three promising circulating biomarkers for diagnosing AMI—citrulline, intestinal fatty acid-binding protein (I-FABP), and d-lactate. A cross-sectional diagnostic study enrolled AMI patients admitted to the intestinal stroke center and controls with acute abdominal pain of another origin. We included 129 patients—50 AMI and 79 controls. Plasma citrulline concentrations were significantly lower in AMI patients compared to the controls [15.3 μmol/L (12.0–26.0) vs. 23.3 μmol/L (18.3–29.8), p = 0.001]. However, the area under the receiver operating curves (AUROC) for the diagnosis of AMI by Citrulline was low: 0.68 (95% confidence interval = 0.58–0.78). No statistical difference was found in plasma I-FABP and plasma d-lactate concentrations between the AMI and control groups, with an AUROC of 0.44, and 0.40, respectively. In this large cross-sectional study, citrulline, I-FABP, and d-lactate failed to differentiate patients with AMI from patients with acute abdominal pain of another origin. Further research should focus on the discovery of new biomarkers.

Abstract Extracorporeal membrane oxygenation (ECMO), a relevant technology for patients with acute respiratory distress syndrome (ARDS) or acute cardiac failure (ACF), is a frequent cause of systemic inflammatory response syndrome. During sepsis, HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) concentrations decrease, and an association between low lipoprotein levels and poor outcomes was reported. There are no data from patients undergoing ECMO. The goal of this study was to characterize the lipoprotein profiles of ICU patients requiring ECMO. All consecutive patients admitted for ARDS or ACF requiring ECMO were prospectively included. Daily lipoprotein levels and short-term prognosis outcome were assessed. 25 patients were included. On admission, lipoprotein concentrations were low, under the reference values ([HDL-C] = 0.6[0.4–0.8]mmol/L;[LDL-C] = 1.3[1.0–1.7]mmol/L). A statistically significant rise in lipoproteins overtime was observed during the ICU stay. We found no relationship between lipoproteins concentrations and mortality on Day-28 (p = 0.689 and p = 0.979, respectively). Comparison of surviving patients with non-surviving patients did not reveal any differences in lipoproteins concentrations. Stratification between septic and non-septic patients demonstrated that septic patients had lower lipoproteins concentrations on admission (HDL-C: 0.5[0.3–0.6]mmol/l vs 0.8[0.6–0.9]mmol/l, p = 0.003; LDL-C: 1.1[0.9–1.5]mmol/l vs 1.5[1.3–2.6]mmol/l; p = 0.012), whereas these two groups were comparable in terms of severity and outcomes. HDL-C concentrations during ICU hospitalization were also significantly lower in the septic group than in the non-septic group (p = 0.035). In conclusion, Lipoprotein concentrations are low in patients requiring ECMO but are not associated with poor outcomes. The subpopulation of septic patients had lower lipoprotein levels overtime, which reinforces the potential key-role of these particles during sepsis.

BackgroundIn Marfan syndrome (MFS), an aortic or peripheral arterial dilatation is usually the consequence of aortic dissection. Non-dissecting distal aortic and peripheral aneurysms (DAPA) are barely described. We sought to determine the incidence and prognostic impact of non-dissecting DAPA, requiring a surgical repair in a large population of patients with MFS.MethodsThe patients referred to the French MFS reference center were included in a prospective database, and the patients treated for a non-dissecting DAPA between 2013 and 2020 were retrospectively reviewed. The first-line therapy was open surgery. The patients unfit for open repair or experiencing life-threatening complications underwent endovascular repair.ResultsAmong 1,575 patients with MFS, 19 (1.2%) were operated for 25 non-dissecting DAPA. The mean age was 42.4 ± 11.5 years. Non-dissecting DAPA involved the subclavian or axillary artery (n = 12), the descending or thoracoabdominal aorta (n = 6), the abdominal aorta andiliac arteries (n = 6), and the popliteal artery (n = 1). Open and endovascular repairs were performed in 22 and three cases, respectively. After a median follow-up of 54.2 months, no local recurrence was noticed and no secondary procedure was performed. Eight patients presented a new aortic event, including two aortic dissections and seven new aortic surgeries. Compared to the overall MFS population, the non-dissecting DAPA group presented a significantly higher risk of an aortic event (100 vs. 28%, p < 0.0001), a higher risk of aortic dissection (53 vs. 8%, p < 0.0001), and a higher rate of pejorative genetic mutations (68 vs. 40%, p = 0.011).ConclusionAmong the patients with MFS, the diagnosis of non-dissecting DAPA is infrequent but is associated with a significant adverse outcome, thus, advocating for a specific follow-up.

Abstract Background Some guidelines advocate for managing patients with penetrating thoracic wounds in trauma centres with cardiothoracic surgery. This systematic approach is questionable. Only 15% of these patients require surgery. It is known that clinical examination fails to detect hemopneumothorax in penetrating trauma. However, no studies have evaluated the combined diagnostic performance of vital signs and the clinical evaluation of wounds. The clinical characteristics of wounds have not been investigated. We aimed to evaluate the ability of combinations of pre-hospital signs to rule out invasive chest stab trauma. Methods This was a prospective observational study. All consecutive adult patients hospitalized in the perioperative acute care unit of a tertiary university hospital were included. Injury diagnoses were provided by exploratory surgery and imaging tests. Patients with a final diagnosis of invasive wounds (IWs) and patients with only superficial wounds were compared. Data regarding management and outcome were analysed. Results A total of 153 patients were included. After imaging or surgery, 58 (38%) patients were diagnosed with only superficial wounds, and 95 (62%) were diagnosed with thoracic or abdominal IWs. The false-negative rate of pre-hospital evaluations in the diagnosis of IWs was 42% [31–51]IQR25–75. In stable patients, pre-hospital data could not rule out IWs, with a negative predictive value of 58% and a positive predictive value of 70%. Twenty-nine (19%) patients required early emergent cardiothoracic surgery. Among these patients, 8 (28%) had no evidence of IWs in the pre-hospital period. Among the 59 patients without pre-hospital signs of IWs, 19 (33%) underwent at least one emergent procedure. Conclusions The combination of pre-hospital vital signs, visual evaluation of wounds, and physical examination failed to rule out IWs in patients with chest stab wounds. This implies that caution is needed in triage decision-making.

Abstract Background Respiratory infections are a major threat for lung recipients. We aimed to compare with a monocentric study the impact of late viral and bacterial respiratory infections on the graft function. Methods Patients, who survived 6 months or more following lung transplantation that took place between 2009 and 2014, were classified into three groups: a viral infection group (VIG) (without any respiratory bacteria), a bacterial infection group (BIG) (with or without any respiratory viruses), and a control group (CG) (no documented infection). Chronic lung allograft dysfunction (CLAD) and acute rejection were analysed 6 months after the inclusion in the study. Results Among 99 included lung recipients, 57 (58%) had at least one positive virological respiratory sample during the study period. Patients were classified as follows: 38 in the VIG, 25 in the BIG (among which 19 co-infections with a virus) and 36 in the CG. The BIG presented a higher initial deterioration in lung function (p = 0.05) than the VIG. But 6 months after the infection, only the VIG presented a median decrease of forced expiratory volume in 1 s; − 35 mL (IQR; − 340; + 80) in the VIG, + 140 mL (+ 60;+ 330) in the BIG and + 10 (− 84;+ 160) in the CG, p

We aimed to describe the prevalence, risk factors, morbidity and mortality associated with the occurrence of bacteraemia during the postoperative ICU stay after lung transplantation (LT). We conducted a retrospective single-centre study that included all consecutive patients who underwent LT between January 2015 and October 2021. We analysed all the blood cultures drawn during the postoperative ICU stay, as well as samples from suspected infectious sources in case of bacteraemia. Forty-six bacteria were isolated from 45 bacteraemic patients in 33/303 (10.9%) patients during the postoperative ICU stay. Staphylococcus aureus (17.8%) was the most frequent bacteria, followed by Pseudomonas aeruginosa (15.6%) and Enterococcus faecium (15.6%). Multidrug-resistant bacteria accounted for 8/46 (17.8%) of the isolates. The most common source of bacteraemia was pneumonia (38.3%). No pre- or intraoperative risk factor for bacteraemia was identified. Recipients who experienced bacteraemia required more renal replacement therapy, invasive mechanical ventilation, norepinephrine support, tracheotomy and more days of hospitalization during the ICU stay. After adjustment for age, sex, type of LT procedure and the need for intraoperative ECMO, the occurrence of bacteraemia was associated with a higher mortality rate in the ICU (aOR = 3.55, 95% CI [1.56–8.08], p = 0.003). Bacteraemia is a major source of concern for lung transplant recipients.

Abstract Background Bacterial respiratory infections (BRI) are major complications contributing to increased morbidity and mortality after lung transplantation (LT). This study analyzed epidemiology and outcome of 175 consecutive patients developing BRI in ICU after LT between 2006 and 2012. Methods Three situations were described: colonization determined in donors and recipients, pneumonia and tracheobronchitis during the first 28 postoperative days. Severity score, demographic, bacteriologic and outcome data were collected. Results 26% of donors and 31% of recipients were colonized. 92% of recipients developed BRI, including at least one episode of pneumonia in 19% of recipients. Only 21% of recipients developed BRI with an organism cultured from the donor’s samples, while 40% of recipients developed BRI with their own bacteria cultured before LT. Purulent sputum appears to be an important factor to discriminate tracheobronchitis from pneumonia. When compared to patients with tracheobronchitis, those with pneumonia had longer durations of mechanical ventilation (13 [3–27] vs 3 [29], p = 0.0005) and ICU stay (24 [16–34] vs 14 [9-22], p = 0.002). Pneumonia was associated with higher 28-day (11 (32%) vs 9 (7%), p = 0.0004) and one-year mortality rates (21 (61%) vs 24 (19%), p ≤ 0.0001). Conclusions These data confirm the high frequency of BRI right from the early postoperative period and the poor prognosis of pneumonia after LT.

Aspergillus niger is usually considered to be a low virulence fungus, not commonly reported to cause invasive infections. Invasive pulmonary aspergillosis due to Aspergillus niger was diagnosed in a 43-year-old woman following bilateral lung transplantation. Intravenous voriconazole failed to control progression of the disease. Despite salvage therapy with a combination of voriconazole and caspofungin for 23 days, the patient developed massive hemoptysis leading to death. The authors report the clinical features and treatment of this case.

Abstract Background Primitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS). Methods Thirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group. NGS was performed using an ampliseq panel to analyze hotspots and targeted regions in 22 cancer-associated genes. ALK, ROS1 and PD-L1 expressions were assessed by immunohistochemistry. Results Squamous cell carcinoma was the most frequent histologic subtype in the IPF group (44%), adenocarcinoma was the most frequent subtype in the non-IPF group (62%). Forty-one mutations in 13 genes and one EGFR amplification were identified in 25 samples. Two samples had no mutation in the selected panel. Mutations were identified in TP53 (n = 20), MET (n = 4), BRAF (n = 3), FGFR3, PIK3CA, PTEN, STK11 (n = 2), SMAD4, CTNNB1, DDR2, ERBB4, FBXW7 and KRAS (n = 1) genes. No ALK and ROS1 expressions were identified. PD-L1 was expressed in 10 cases (62%) with only one (6%) case >50%. Conclusions This extensive characterization of lung fibrosis-associated cancers evidenced molecular alterations which could represent either potential therapeutic targets either clues to the pathophysiology of these particular tumors. These findings support the relevance of large molecular characterization of every lung fibrosis-associated cancer.

Aneurysm is associated to a complex remodeling of arteries that affects all their layers. Although events taking place in the intima and the media have received a particular attention, molecular and cellular events taking place in the adventitia have started to be deciphered only recently. In this study, we have precisely described the composition and distribution of stromal and hematopoietic cells in human arterial adventitia, both at steady state and in the setting of aortic aneurysm. Using polychromatic immunofluorescent and flow cytometry analyses, we observed that unlike the medial layer (which comprises mostly macrophages and T cells among leukocytes), the adventitia comprises a much greater variety of leukocytes. We observed an altered balance in macrophages subsets in favor of M2-like macrophages, an increased proliferation of macrophages, a greater number of all stromal cells in aneurysmal aortas. We also confirmed that in this pathological setting, adventitia comprised blood vessels and arterial tertiary lymphoid organs (ATLOs), which contained also M-DC8(+) dendritic cells (slanDCs) that could participate in the induction of T-cell responses. Finally, we showed that lymphatic vessels can be detected in aneurysmal adventitia, the functionality of which will have to be evaluated in future studies. All together, these observations provide an integrative outlook of the stromal and hematopoietic cell network of the human adventitia both at steady state and in the context of aneurysm.

BACKGROUND: Experimental atherosclerosis is characterized by the formation of tertiary lymphoid structures (TLOs) within the adventitial layer, which involves the chemokine-expressing aortic smooth muscle cells (SMCs). TLOs have also been described around human atherothrombotic arteries but the mechanisms of their formation remain poorly investigated. Herein, we tested whether human vascular SMCs play the role of chemokine-expressing cells that would trigger the formation of TLOs in atherothrombotic arteries. RESULTS: We first characterized, by flow cytometry and immunofluorescence analysis, the prevalence and cell composition of TLOs in human abdominal aneurysms of the aorta (AAAs), an evolutive form of atherothrombosis. Chemotaxis experiments revealed that the conditioned medium from AAA tissues recruited significantly more B and T lymphocytes than the conditioned medium from control (N-AAA) tissues. This was associated with an increase in the concentration of CXCL13, CXCL16, CCL19, CCL20, and CCL21 chemokines in the conditioned medium from AAA tissues. Immunofluorescence analysis of AAA cryosections revealed that α-SMA-positive SMCs were the main contributors to the chemokine production. These results were confirmed by RT-qPCR assays where we found that primary vascular SMCs from AAA tissues expressed significantly more chemokines than SMCs from N-AAA. Finally, in vitro experiments demonstrated that the inflammatory cytokines found to be increased in the conditioned medium from AAA were able to trigger the production of chemokines by primary SMCs. CONCLUSION: Together, these results suggest that human vascular SMCs in atherothrombotic arteries, in response to inflammatory signals, are converted into chemokine-expressing cells that trigger the recruitment of immune cells and the formation of aortic TLOs.

BACKGROUND: Abdominal Aortic Aneurysms (AAAs) represent a particular form of atherothrombosis where neutrophil proteolytic activity plays a major role. We postulated that neutrophil recruitment and activation participating in AAA growth may originate in part from repeated episodes of periodontal bacteremia. METHODS AND FINDINGS: Our results show that neutrophil activation in human AAA was associated with Neutrophil Extracellular Trap (NET) formation in the IntraLuminal Thrombus, leading to the release of cell-free DNA. Human AAA samples were shown to contain bacterial DNA with high frequency (11/16), and in particular that of Porphyromonas gingivalis (Pg), the most prevalent pathogen involved in chronic periodontitis, a common form of periodontal disease. Both DNA reflecting the presence of NETs and antibodies to Pg were found to be increased in plasma of patients with AAA. Using a rat model of AAA, we demonstrated that repeated injection of Pg fostered aneurysm development, associated with pathological characteristics similar to those observed in humans, such as the persistence of a neutrophil-rich luminal thrombus, not observed in saline-injected rats in which a healing process was observed. CONCLUSIONS: Thus, the control of periodontal disease may represent a therapeutic target to limit human AAA progression.

BACKGROUND: Preclinical models of non-small cell lung cancer (NSCLC) require better clinical relevance to study disease mechanisms and innovative therapeutics. We sought to compare and refine bioluminescent orthotopic mouse models of human localized NSCLC. METHODS: Athymic nude mice underwent subcutaneous injection (group 1-SC, n = 15, control), percutaneous orthotopic injection (group 2-POI, n = 30), surgical orthotopic implantation of subcutaneously grown tumours (group 3-SOI, n = 25), or transpleural orthotopic injection (group 4-TOI, n = 30) of A549-luciferase cells. Bioluminescent in vivo imaging was then performed weekly. Circulating tumour cells (CTCs) were searched using Cellsearch® system in SC and TOI models. RESULTS: Group 2-POI was associated with unexpected direct pleural spreading of the cellular solution in 53% of the cases, forbidding further evaluation of any localized lung tumour. Group 3-SOI was characterized by high perioperative mortality, initially localized lung tumours, and local evolution. Group 4-TOI was associated with low perioperative mortality, initially localized lung tumours, loco regional extension, and distant metastasis. CTCs were detected in 83% of nude mice bearing subcutaneous or orthotopic NSCLC tumours. CONCLUSIONS: Transpleural orthotopic injection of A549-luc cells in nude mouse lung induces localized tumour, followed by lymphatic extension and specific mortality, and allowed the first time identification of CTCs in a NSCLC mice model.