Case Rep Oncol

The pretreatment detection of an activating mutation of EGFR is now routinely performed in metastatic nonsquamous non-small cell lung cancer (NSCLC). The therapeutic impact of such a detection is major, as patients with advanced NSCLC exhibiting a mutation of exon 19 or 21 will benefit from EGFR-tyrosine kinase inhibitors (TKI). The presence of an EGFR resistance mutation, such as T790M in EGFR-TKI-naïve patients, is seldom looked for and is related either to a germinal mutation or to somatically mutated subclones. It has a negative predictive impact. We present the case of a patient with a lung papillary adenocarcinoma and miliary intrapulmonary metastases whose tumor displays a somatic complex heterozygous EGFR mutation, combining L858R (exon 21) and a primary resistance mutation T790M (exon 20), both detected by direct sequencing

Changes occurring in the bronchial epithelium during chronic lung allograft dysfunction and the role of leukocyte derived microparticles

La dysfonction chronique du greffon pulmonaire (CLAD) est la principale complication limitant la survie à long-terme après une transplantation pulmonaire, avec plusieurs phénotypes décrits. La répétition des agressions inflammatoires contre l’épithélium bronchique contribue à son développement. Au cours de ce travail, nous avons détaillé les différences et similitudes histologiques entre les différents phénotypes de CLAD, à l’aide d’un score semi-quantitatif. Nous avons également montré que la technique d’Imaging mass cytometry, spectrométrie de masse utilisant un marquage avec anticorps conjugués aux métaux lourds, permettait l’identification précise de sous-populations cellulaires dans le tissu du greffon pulmonaire. Enfin, après avoir confirmé la présence d’une transition épithélio-mésenchymateuse (TEM) dans les bronchioles de poumons explantés avec CLAD, nous avons montré que les microparticules membranaires pourraient avoir un rôle comme biomarqueur diagnostique du CLAD et comme bioeffecteur en contribuant à la survenue de la TEM dans des cellules BEAS-2B.Chronic lung graft dysfunction (CLAD) is the main complication limiting long-term survival after lung transplantation, with several phenotypes described. Repeated inflammatory injuries to the bronchial epithelium participate to its development. In this work, we detailed the histological differences and similarities between the different CLAD phenotypes, using a semi-quantitative grading score. We also demonstrated that Imaging mass cytometry, a mass spectrometry technique using a heavy metal-tagged antibodies, enabled a precise identification of cellular subpopulations within the lung allograft tissue. Finally, after confirming the presence of epithelial-mesenchymal transition (EMT) in bronchioles from explanted lungs with CLAD, we showed that membrane microparticles could have a role as a diagnostic biomarker of CLAD and as a bioeffector by contributing to the occurrence of EMT in BEAS-2B cells

Patients Treated for Central Airway Stenosis After Lung Transplantation Have Persistent Airflow Limitation

BACKGROUND: Although central airway stenosis (CAS) is a common complication after lung transplantation, its consequences have been poorly evaluated. The objective of our study was to evaluate the impact of CAS on lung function after lung transplantation. MATERIAL AND METHODS: All lung transplant recipients from June 2009 to August 2014 in a single center (Strasbourg, France) were retrospectively reviewed. RESULTS: A total of 191 lung transplantations were performed: 175 bilateral, 15 single, and 1 heart-lung transplantation. Of the 161 bilateral lung-transplanted patients who survived >3 months, 22 (13.6%) developed CAS requiring endobronchial treatment. All these patients were treated by endoscopic balloon dilatation, and 9 additionally needed endobronchial stents. Respiratory function tests demonstrated persistent obstructive ventilatory pattern despite endoscopic treatment in recipients with CAS compared to those without CAS at 6, 12, and 18 months post-transplant. At 18 months, CAS patients had significantly lower post-transplant FEV1 (1.96±0.60 L versus 2.57±0.76 L, p=0.001) and FEV1/FVC (61±14% versus 81±13%, p<0.001). The percentage of patients hospitalized for respiratory infections and number of hospital days were significantly increased in recipients with CAS (20 [91%] versus 92 [66%] p=0.036, and 144±110 days versus 103±83 days p=0.042, respectively). Survival in transplant recipients did not significantly differ between those with CAS and those without. CONCLUSIONS: CAS after lung transplantation was not associated with worse survival, but it did have a significant and persistent effect on lung function, and was associated with increased rate of respiratory infection

Interferon-stimulated and metallothionein-expressing macrophages are associated with acute and chronic allograft dysfunction after lung transplantation

Background: Lung transplant recipients experience episodes of immune-mediated acute lung allograft dysfunction (ALAD). ALAD episodes are a risk factor for chronic lung allograft dysfunction (CLAD), the major cause of death after lung transplantation. Our objective was to determine key cellular elements in dysfunctional lung allografts, with a focus on macrophages. Methods: We have applied single-cell RNA sequencing (scRNAseq) to bronchoalveolar lavage cells from stable and ALAD patients and to cells from explanted CLAD lung tissue. Results: We identified 2 alveolar macrophage (AM) subsets uniquely represented in ALAD. Using pathway analysis and differentially expressed genes, we annotated these as pro-inflammatory interferon-stimulated gene (ISG) and metallothionein-mediated inflammatory (MT) AMs. Functional analysis of an independent set of AMs in vitro revealed that ALAD AMs exhibited a higher expression of CXCL10, a marker of ISG AMs, and increased secretion of pro-inflammatory cytokines compared to AMs from stable patients. Using publicly available bronchoalveolar lavage scRNAseq datasets, we found that ISG and MT AMs are associated with more severe inflammation in COVID-19 patients. Analysis of cells from 4 explanted CLAD lungs revealed similar macrophage populations. Donor and recipient cells were identified using expressed single nucleotide variations. We demonstrated contributions of donor and recipient cells to all AM subsets early post-transplant, with loss of donor-derived cells over time. Conclusions: Our data reveal extensive heterogeneity among lung macrophages after lung transplantation and indicates that specific sub-populations may be associated with allograft dysfunction, raising the possibility that these cells may represent important therapeutic targets.</p

Primary Hepatic Lymphoma After Lung Transplantation: A Report of 2 Cases

International audienceBackground. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non -Hodgkin lymphoma in the posttransplant setting. Treatment is based on chemotherapy; surgery is still debated and should be performed in very select cases. Methods. We observed 2 patients out of 300 who underwent lung transplantation in the Nouvel Hopital Civil between 2013 and 2019 with primary hepatic lymphoma. Chemotherapy with a rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone protocol was performed in all patients. Mycophenolate mofetil was interrupted before treatment, and everolimus was introduced after chemotherapy by associating tacrolimus withdrawal. Results. One patient showed complete remission; after 7 years, no recurrence has been noticed. The second is still undergoing chemotherapy with no signs of disease progression. Conclusions. DLBCL risk is higher in solid organ transplant recipients than in the general population. Primary hepatic lymphoma diagnosis is often difficult and based on histologic findings after initial clinical and radiological suspicion of primary or secondary liver neoplasia. Diagnosis is challenging because no clinical, radiological, or biological features exist. Biopsy is always indicated for histologic confirmation. Chemotherapy is the mainstay of therapy, but surgery may be indicated in very select patients

Phenotyping CLAD after single lung transplant: limits and prognostic assessment of the 2019 ISHLT classification system

Background: Phenotyping chronic lung allograft dysfunction (CLAD) in single lung transplant (SLTX) is challenging, due to the native lung contribution to pulmonary function test (PFT). We aimed to assess the applicability and prognostic performance of International Society for Heart and Lung Transplantation (ISHLT) classification in SLTX. Methods: In this retrospective study of adult, first, SLTX performed 2009-2017, patients with persistent drop in FEV1≥20% were assessed by 2 independent adjudicators to determine CLAD status and phenotype. Interobserver agreement (IOA) was calculated (Cohen's Kappa) for CLAD, phenotype and presence of RAS (resttrictive allograft syndrome)-like opacities (RLO). Association of CLAD phenotypes with time to death or retransplant (ReTx), adjusted for age at SLTX, sex, CMV mismatch and native lung condition, were assessed using Cox proportional hazards models. Results: Of 172 SLTX recipients, 92 experienced a persistent drop in FEV1&gt;20%. Following adjudication, 67 were diagnosed with CLAD. We noted a moderate IOA for CLAD diagnosis (Kappa 0.69) and poor IOA for phenotype adjudication (Kappa 0.52). The final phenotype adjudication was 31 bronchiolitis obliterans syndrome (BOS) (46.3%), 13 RAS (19.4%), 2 mixed (3%), 2 Undefined (3%), and 19 remained Unclassified (28.3%). Using these adjudicated phenotypes, RAS was significantly associated with a higher risk of death/ReTx compared to other groups (HR 2.98, 95%CI [1.39-6.4]). The adjudication of RLO had the best IOA (Kappa 0.73). The presence of RLO was a strong predictor of death or ReTx (HR 2.37, 95%CI [1.2-4.5]), regardless of the final phenotype. Conclusions: PFT interpretation is challenging in SLTX. A classification essentially relying on imaging, which harbored good IOA, obtained better prognostic performance than a classification using published physiological cut-offs.</p

Efficacy of three COVID-19 vaccine doses in lung transplant recipients: a multicentre cohort study

International audienceQuestion addressed by the study: Do three coronavirus disease 2019 (COVID-19) vaccine doses induce a serological response in lung transplant recipients?Methods: We retrospectively included 1071 adults (551 (52%) males) at nine transplant centres in France. Each had received three COVID-19 vaccine doses in 2021, after lung transplantation. An anti-spike protein IgG response, defined as a titre >264 BAU·mL −1 after the third dose (median (interquartile range (IQR)) 3.0 (1.7–4.1) months), was the primary outcome and adverse events were the secondary outcomes. Median (IQR) age at the first vaccine dose was 54 (40–63) years and median (IQR) time from transplantation to the first dose was 64 (30–110) months.Results: Median (IQR) follow-up after the first dose was 8.3 (6.7–9.3) months. A vaccine response developed in 173 (16%) patients. Factors independently associated with a response were younger age at vaccination, longer time from transplantation to vaccination and absence of corticosteroid or mycophenolate therapy. After vaccination, 51 (5%) patients (47 non-responders (47/898 (5%)) and four (4/173 (2%)) responders) experienced COVID-19, at a median (IQR) of 6.6 (5.1–7.3) months after the third dose. No responders had severe COVID-19 compared with 15 non-responders, including six who died of the disease.Conclusions Few lung transplant recipients achieved a serological response to three COVID-19 vaccine doses, indicating a need for other protective measures. Older age and use of mycophenolate or corticosteroids were associated with absence of a response. The low incidence of COVID-19 might reflect vaccine protection via cellular immunity and/or good adherence to shielding measures

Epithelial-mesenchymal transition and membrane microparticles: potential implications for bronchiolitis obliterans syndrome after lung transplantation

International audienceLong term survival post lung transplantation (LTx) is limited by the occurrence of bronchiolitis obliterans syndrome (BOS). One mechanism involved is the epithelial-mesenchymal transition (EMT). Membrane microparticles (MPs) are known to be involved in some respiratory diseases and in other organs allograft rejection episodes. We hypothesized that leukocyte-derived MPs likely contribute to EMT. To emphasize this physiological concept, our objectives were to: (1) confirm the presence of EMT on explanted lungs from patients who underwent a second LTx for BOS; 2) characterize circulating MPs in transplanted patients, with or without BOS; (3) evaluate in vitro the effect of monocyte-derived MPs in EMT of human bronchial epithelial cells. Our IHC analysis on explanted graft lungs revealed significant pathological signs of EMT with an inhomogeneous destruction of the bronchial epithelium, with decreased expression of the epithelial protein E-cadherin and increased expression of the mesenchymal protein Vimentin. The immunophenotyping of MPs demonstrated that the concentration of MPs carrying E-cadherin was lower in patients affected by BOS (p = .007). In vitro, monocyte-derived MPs produced with LPS were associated with decreased E-cadherin expression (p < .05) along with significant morphological and functional cell modifications. MPs may play a role in EMT onset in bronchial epithelium following LTx