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Chemotherapy; Non–small cell lung cancer; RET inhibitors Quimioteràpia; Càncer de pulmó de cèl·lules no petites; Inhibidors de RET Quimioterapia; Cáncer de pulmón de células no pequeñas; Inhibidores de RET Introduction Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. Methods This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. Results For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1–4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%–55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7–72.1] versus 16.3 mo [12.7–28.8], p < 0.0001). Conclusions Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients. Writing assistance was provided by Mrs. Sarah Mackenzie. Dr. Marinello was the recipient for the grant for DUERTECC/EURONCO (Diplôme Universitaire Européen de Recherche Translationnelle Et Clinique en Cancérologie). Dr. Mezquita received support from the Contrato Juan Rodes 2020 (ISCIII, Ministry of Health); Ayuda de la Acción Estratégica en Salud-ISCIII FIS 2021 (PI21/01653); Ayuda SEOM-Juan Rodés 2020. Dr. Cortellini acknowledges the support from the National Institute for Health Research Imperial Biomedical Research Centre. Dr. Pinato acknowledges the support from the Wellcome Trust Strategic Fund (PS3416), Associazione Italiana per la Ricerca sul Cancro (Associazione Italiana per la Ricerca sul Cancro MFAG Grant ID 25697), National Institute for Health Research Imperial Biomedical Research Centre, Imperial Experimental Cancer Medicine Centre, and the Imperial College Tissue Bank.

Hereditary pulmonary veno-occlusive disease (hPVOD) is a severe form of autosomal recessive pulmonary hypertension and is due to biallelic loss of function of the EIF2AK4 gene (alias GCN2) coding for GCN2. GCN2 is a stress kinase that belongs to the integrated stress response pathway (ISR). Three rat lines carrying biallelic Gcn2 mutation were generated and found phenotypically normal and did not spontaneously develop a PVOD-related disease. We submitted these rats to amino acid deprivation to document the molecular and cellular response of the lungs and to identify phenotypic changes that could be involved in PVOD pathophysiology. Gcn2−/− rat lungs were analyzed under basal conditions and 3 days after a single administration of PEG-asparaginase (ASNase). Lung mRNAs were analyzed by RNAseq and single-cell RNAseq (scRNA-seq), flow cytometry, tissue imaging, and Western blots. The ISR was not activated after ASNase treatment in Gcn2−/− rat lungs, and apoptosis was increased. Several proinflammatory and innate immunity genes were overexpressed, and inflammatory cells infiltration was also observed in the perivascular area. Under basal conditions, scRNA-seq analysis of Gcn2−/− rat lungs revealed increases in two T-cell populations, a LAG3+ T-cell population and a proliferative T-cell population. Following ASNase administration, we observed an increase in calprotectin expression involved in TLR pathway activation and neutrophil infiltration. In conclusion, under basal and asparagine and glutamine deprivation induced by asparaginase administration, Gcn2−/− rats display molecular and cellular signatures in the lungs that may indicate a role for Gcn2 in immune homeostasis and provide further clues to the mechanisms of hPVOD development.

Mutations in

Background: Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca 2+ ) signaling contributes to abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration, and arterial contractility. Store-operated Ca 2+ entry is involved in Ca 2+ homeostasis in PASMCs, but its properties in PAH are unclear. Methods: Using a combination of Ca 2+ imaging, molecular biology, in vitro, ex vivo, and in vivo approaches, we investigated the roles of the Orai1 SOC channel in PA remodeling in PAH and determined the consequences of pharmacological Orai1 inhibition in vivo using experimental models of pulmonary hypertension (PH). Results: Store-operated Ca 2+ entry and Orai1 mRNA and protein were increased in human PASMCs (hPASMCs) from patients with PAH (PAH-hPASMCs). We found that MEK1/2 (mitogen-activated protein kinase kinase 1/2), NFAT (nuclear factor of activated T cells), and NFκB (nuclear factor-kappa B) contribute to the upregulation of Orai1 expression in PAH-hPASMCs. Using small interfering RNA (siRNA) and Orai1 inhibitors, we found that Orai1 inhibition reduced store-operated Ca 2+ entry, mitochondrial Ca 2+ uptake, aberrant proliferation, apoptosis resistance, migration, and excessive calcineurin activity in PAH-hPASMCs. Orai1 inhibitors reduced agonist-evoked constriction in human PAs. In experimental rat models of PH evoked by chronic hypoxia, monocrotaline, or Sugen/hypoxia, administration of Orai1 inhibitors (N-{4-[3,5-bis(Trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide [BTP2], 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline [JPIII], or 5J4) protected against PH. Conclusions: In human PAH and experimental PH, Orai1 expression and activity are increased. Orai1 inhibition normalizes the PAH-hPASMCs phenotype and attenuates PH in rat models. These results suggest that Orai1 should be considered as a relevant therapeutic target for PAH.

International audience; BACKGROUND: Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) predominantly characterized by pulmonary vein and capillary involvement. An association between chemotherapy, in particular mitomycin C (MMC), and PVOD has been reported.RESEARCH QUESTION: What are the characteristics of MMC-induced PVOD, and what is the prognosis for patients with MMC-induced PVOD?STUDY DESIGN AND METHODS: We report the clinical, functional, radiologic, and hemodynamic characteristics at diagnosis and outcomes of patients with PVOD from the French PH Registry after exposure to MMC. The results are expressed as the median (minimum-maximum).RESULTS: From June 2011 to December 2018, 17 incident cases of MMC-induced PVOD were identified. At diagnosis, these patients had severe clinical and functional impairment, with 12 patients having a New York Heart Association (NYHA) functional class of III or IV and a 6-min walk distance of 220 (0-465) m. Right heart catheterization confirmed severe precapillary PH with a mean pulmonary artery pressure of 38 (30-52) mm Hg, a cardiac index of 2.2 (1.5-4) L/(min x m(2)), and pulmonary vascular resistance of 8.3 (5.1-14.5) Wood units. The diffusing capacity of the lungs for carbon monoxide was markedly decreased at 31% (20%-51%) of the theoretical values associated with severe hypoxemia. MMC was withdrawn for all patients, and 14 patients received specific pulmonary arterial hypertension (PAH) therapies. Among these patients, mild but statistically insignificant improvements were observed in NYHA functional class (P = .10), 6-min walk distance (P = .09), and pulmonary vascular resistance (-4.7 Wood units; P = .052) at reassessment (median delay of 4.8 months). Three patients experienced pulmonary edema requiring the cessation or reduction of PAH treatment. The median overall survival was 20 months, and the 6-, 12-, and 24-month survival rates were 76%, 58%, and 18%, respectively.INTERPRETATION: PVOD after MMC treatment is a rare but life-threatening complication associated with a poor prognosis despite MMC withdrawal and PAH-specific therapy.

The phenotype of pulmonary arterial hypertension (PAH) patients carryingWe report the genetic analysis findings, characteristics and outcomes of patients with heritable PAH carryingTwenty patients and eight unaffected relatives were identified. The median (min-max) age at diagnosis was 17 years (2-53), with a female-to-male ratio of 1.5. At diagnosis, most of the patients (74%) were in functional class III or IV with severe hemodynamic compromise, including a median pulmonary vascular resistance (PVR) of 14.0 (4.2-31.5) Wood units (WU). An associated congenital heart disease (CHD) was found in 7 PAH patients (35%). Patients with CHD-associated PAH were significantly younger at diagnosis than PAH patients without CHD. Four patients (20%) suffered from recurrent haemoptysis requiring repeated arterial embolisations. Thirteen out of 16 patients (81%) of whom imaging was available displayed chest computed tomography abnormalities, including dilated, tortuous pulmonary vessels, ground-glass opacities as well as bronchial and non-bronchial arteries anomalies. After a median follow-up of 47 months (1-591 months), 10 patients underwent lung transplantation and one patient benefited from a heart-lung transplantation due to associated CHD. Histopathologic analysis of lung explants showed a congested lung architecture with severe pulmonary arterial remodelling, subpleural vessel dilation and numerous haemorrhagic foci.PAH due to

Pulmonary fibrosis (PF) and pulmonary hypertension (PH) are chronic diseases of the pulmonary parenchyma and circulation, respectively, which may coexist, but underlying mechanisms remain elusive. Mutations in the GCN2 gene (EIF2AK4) were recently associated with pulmonary veno-occlusive disease. This study aims to explore the involvement of the GCN2/eIF2α pathway in the development of PH during PF, in both human disease and in an experimental animal model. Lung tissue from PF patients with or without PH were collected at the time of lung transplantation, and controls were obtained from tumor resection surgery. Experimental lung disease was induced in either male wild-type or EIF2AK4-mutated Sprague-Dawley rats, randomly receiving a single intratracheal instillation of bleomycin or saline. Hemodynamic studies, as well as organ collection were performed 3 weeks post-instillation. Only significant results (p

Busulfan is widely used to treat malignant diseases, particularly for therapeutic intensification prior to an autologous stem cell graft. Numerous side effects consecutive to busulfan are described, but few descriptions of pulmonary hypertension exist, while bronchiolitis obliterans remains a rare complication. We report the clinical observations of four patients from the French Pulmonary Hypertension Registry who experienced subacute pulmonary hypertension after receiving busulfan as preparation regimen before an autologous stem cell graft for malignancies (Hodgkin's disease, Ewing's sarcoma and primary large B cell lymphoma of the brain). Patients experienced severe pulmonary arterial hypertension 2 to 4.5 months after busulfan administration. Pulmonary hypertension improved after treatment with approved drugs for pulmonary arterial hypertension and/or corticosteroids. During the follow-up period, two patients developed chronic respiratory insufficiency due to interstitial lung disease, leading to double lung transplantation. The pathological assessment of explanted lungs revealed interstitial lung fibrosis with advanced bronchiolar lesions and severe pulmonary vascular damage. Three of the four patients were still alive after 36 to 80 months and the fourth died unexpectedly and suddenly after 5 months. In conclusion, PAH is a rare but severe complication associated with busulfan chemotherapy in adults. Histological examinations provide evidence for diffuse pulmonary vascular damage combined with interstitial lung injury in most cases.

Pulmonary endothelial cells play a key role in the pathogenesis of Chronic Thromboembolic Pulmonary Hypertension (CTEPH). Increased synthesis and/or the release of intercellular adhesion molecule-1 (ICAM-1) by pulmonary endothelial cells of patients with CTEPH has been recently reported, suggesting a potential role for ICAM-1 in CTEPH.We studied pulmonary endarterectomy specimens from 172 patients with CTEPH and pulmonary artery specimens from 97 controls undergoing lobectomy for low-stage cancer without metastasis.ICAM-1 was overexpressed in vitro in isolated and cultured endothelial cells from endarterectomy specimens. Endothelial cell growth and apoptosis resistance were significantly higher in CTEPH specimens than in the controls (p0.001). Both abnormalities were abolished by pharmacological inhibition of ICAM-1 synthesis or activity. The overexpression of ICAM-1 contributed to the acquisition and maintenance of abnormal EC growth and apoptosis resistance via the phosphorylation of SRC, p38 and ERK1/2 and the overproduction of survivin. Regarding the ICAM-1 E469K polymorphism, the KE heterozygote genotype was significantly more frequent in CTEPH than in the controls, but it was not associated with disease severity among patients with CTEPH.ICAM-1 contributes to maintaining the abnormal endothelial cell phenotype in CTEPH.

Pulmonary hypertension (PH) is a devastating condition that ultimately leads to right heart failure and death, if untreated. The morphological correlate for clinically relevant PH is pulmonary vascular disease that may concern all vascular compartments of the lung: pulmonary arteries, capillaries and veins, but also systemic lung vessels, commonly known as bronchial arteries and vasa vasorum. The recent diagnostic PH classification at the PH World Symposium in Nice, France, redefined five PH groups based on pathophysiological, histological and clinical differences. This article reviews the rationale of histology/pathology and, partly, pathobiology that has led to these different categories of PH. Even if aetiology and initial pathophysiology discriminate these groups to some extent, it has become clear that several disease-relevant pathomechanisms are shared between the groups, leading to comparable therapeutic molecular targets, such as phosphodiesterase-5 inhibitors for PAH (group 1 in the Nice classification) and soluble guanylate cyclase agonists in CTEPH (group 4 of the Nice classification). When considering PH group 2 (PH due to left heart disease), its histological appearance, with remodelled small pulmonary veins and arteries, and its haemodynamics in some patients suggest an overreacting pre-capillary vasculature in response to left heart failure. Thus the still-used descriptor ‘orphan disease’ might one day no longer be used in relation to PH. Indeed, PH is a condition that represents a global health issue, and hence is worth a closer look and a thorough definition from the perspective of the pathologist.

International audience; Hepatic veno-occlusive disease (HVOD), alias sinusoidal obstruction syndrome, may develop as a complication of chemotherapy in the setting of hematopoietic stem cell transplantation. HVOD is less frequently described after exposure to chemotherapy in the nontransplant setting and can also be a complication after ingestion of toxins, such as pyrrolizidine alkaloids. Veno-occlusive disease may also affect the lungs, and it is therefore termed pulmonary veno-occlusive disease (PVOD). Similarly, PVOD can develop after exposure to chemotherapeutic agents in the treatment of solid and hematological malignancies. In addition, PVOD has also been linked to autoimmune disorders and occupational solvent exposure. Finally, the heritable form of PVOD is due to biallelic mutations of the EIF2AK4 gene. Both HVOD and PVOD share common histopathological features and pathophysiologic mechanisms. Both clinical disorders are rare complications that can appear after exposure to the common inciting trigger of chemotherapeutic agents. The present review aims to summarize the current knowledge of HVOD and PVOD and to describe both similarities as well as differences regarding both conditions.

Objective Lysyl oxidase (LOX) is an extracellular enzyme that cross-links collagen fibrils. LOX was found to be increased in serum of SSc patients and was suggested to be related to skin fibrosis, yet a vascular source of LOX has been demonstrated in idiopathic pulmonary arterial hypertension (iPAH). We aimed to validate elevated LOX serum levels in SSc and to study its correlation with clinical characteristics and investigate its main source at the tissue level. Methods A total of 86 established SSc patients were compared with 86 patients with very early diagnosis of systemic sclerosis (VEDOSS), 110 patients with primary RP (PRP) and 80 healthy controls. LOX serum levels were determined by ELISA. Five lung and 12 skin biopsies from SSc patients were stained for LOX and compared with controls. Results Serum levels of LOX in SSc were significantly higher than in VEDOSS, PRP and healthy controls (P < 0.001). LOX inversely correlated with the diffusing capacity of the lung for carbon monoxide diffusing capacity (DLCO) in diffuse SSc (r = −0.376, P = 0.02). Patients with moderate to severe estimated systolic PAH had higher LOX levels (P < 0.01). Lung biopsies demonstrated intense LOX staining in SSc patients with PAH that was predominantly located in the endothelium of the remodelled pulmonary vessels. Conclusion Serum LOX levels are increased in established SSc and inversely correlate with the DLCO. LOX is elevated in patients with moderate to severe PAH and is located in the proliferating endothelium in lung arterioles, suggesting a possible role for LOX in SSc-associated PAH.

Introduction: RET fusions (RET+) are identified in nearly 1% of advanced NSCLC (aNSCLC). We evaluated characteristics and outcomes of patients (pts) with RET+ aNSCLC. Methods: This is an international, multicenter, retrospective study evaluating clinical, biological, pathological and radiological data of pts with RET+ aNSCLC. Objective response rates (ORR), duration of response (DOR) and progression-free survival (PFS) were evaluated under double or single agent chemotherapy (CT), immunotherapy (ICI), CT-ICI, multityrosine kinase inhibitors (MTKi) and RET inhibitors (RETi). Overall survival (OS) was calculated from the start of first line therapy and compared between pts treated or not by RETi, after stratification by number of treatment lines. Results: A total of 71 pts was included from 11 centers. Median age was 60 [IQR 47-69], 58% were female, 93% had adenocarcinoma, 2 pts (3%) had squamous and 2 (3%) neuroendocrine carcinoma, 38 (53.5%) were tobacco consumers (median 18.5 PY [7.8-31.3]), 50 (70%) had stage IV disease at diagnosis. Fusion partners were KIF5B (35/49, 71%), CCDC6 (9/49, 18%), others (5/49, 10%). Median TMB was 2.76 [2.0-8.5], median PD-L1 5% [0-29]. The most frequent co-mutation was TP53 (18/58 cases, 31%). Median number of metastatic sites was 2 [1-3], most commonly lung (48%), bone (45%), pleura (41%) and nodes (35%). Brain metastases were found in 18% of cases at diagnosis and in 31% at last follow-up or death. Table reports outcomes by treatment. mOS was 50.6 months [95%CI 37.6 - NR]. Fifty-two pts received 1st generation RETi. The use of RETi improved OS in pts treated with ≤2 lines of therapy (NR vs 17.8 months, p=0.024) and in those receiving >2 lines (50.6 vs 12.7 months, p=0.0037). Pts responding to ICI had a median PD-L1 of 85% [15.5-90]. Conclusions: Pts with RET+ aNSCLC have mainly thoracic and bone disease. Despite smoking history, median TMB and PD-L1 expression are low. ICI may have a significant activity in selected cases. RETi improve OS. Outcomes by treatment First use of Doublet CT (N=46) Single agent CT (N=12) CT-ICI (N=9) ICI (N=19) MTKi (N=9) RETi (N=52) Line of treatment (median, range) 1 [1-1] 2 [2-3] 1 [1-2] 2 [2-3] 3 [1.5-3.5] 2 [1-3] ORR (N,%) 25/40 (62.5%) 3/12 (25%) 3/9 (33%) 7/17 (41%) 4/8 (50%) 36/45 (80%) mPFS (months, 95%CI) 7.89 [6.18-14] 2.81 [2.43-NR] 5.62 [2.79-NR] 3.71 [2.99-11.5] 2.76 [1.51-NR] 24.7 [16.2-NR] mDOR (months,95%CI) 11.83 [7.06-15.6] 8.90 [4.21-NR] 14.47 [10.25-NR] 20.47 [11.3-NR] 8.18 [1.64-NR] 24.74 [17.12-NR] Stopped for toxicity (N,%) 7/46 (15%) 1/12 (8%) 2/9 (22%) 4/18 (22%) 1/9 (11%) 14/50 (28%) Citation Format: Mihaela Aldea, Arianna Marinello, Wael Zrafi, Fabrizio Tabbo, Florian Guisier, Damien Vasseur, Vincent Fallet, Clarisse Audigier-Valette, Laura Mezquita, Antonio Calles, Giannis Mountzios, Marco Tagliamento, Judith Raimbourg, Safae Terrisse, Silvia Novello, Maria-Rosa Ghigna, Fabrice Barlesi, David Planchard, Benjamin Besse. RET-MAP: An international multi-center study of patients with advanced non-small cell lung cancer and RET fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4019.

International audience; Heightened pulmonary artery smooth muscle cell (PA-SMC) proliferation and migration and dynamic remodeling of the extracellular matrix are hallmark pathogenic features of pulmonary arterial hypertension (PAH). Pirfenidone (PFD) is an orally bioavailable pyridone derivative with antifibrotic, antiinflammatory, and antioxidative properties currently used in the treatment of idiopathic pulmonary fibrosis. We therefore evaluated the efficacy of curative treatments with PFD in the sugen/hypoxia (SuHx) rat model of severe pulmonary hypertension. Treatment with PFD (30 mg/kg per day by mouth 3 times a day for 3 wk) started 5 wk after sugen injection partially reversed established pulmonary hypertension, reducing total pulmonary vascular resistance and remodeling. Consistent with these observations, we found that continued PFD treatment decreases PA-SMC proliferation and levels of extracellular matrix deposition in lungs and right ventricles in SuHx rats. Importantly, PFD attenuated the proproliferative and promigratory potentials of cultured PA-SMCs from patients with idiopathic PAH and their capacity to produce extracellular matrix components. Finally, we found that PFD dose dependently enhanced forkhead box O1 protein levels and its nuclear translocation in cultured idiopathic PAH PA-SMCs and in PFD-treated SuHx rats. PFD appears to be a potential therapy for PAH worthy of investigation and evaluation for clinical use in conjunction with current PAH treatments.-Poble, P.-B., Phan, C., Quatremare, T., Bordenave, J., Thuillet, R., Cumont, A., Huertas, A., Tu, L., Dorfmüller, P., Humbert, M., Ghigna, M.-R., Savale, L., Guignabert, C. Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension.

Introduction The aim of this study was to study the feasibility of a fully integrated multiparametric imaging framework to characterize non-small cell lung cancer (NSCLC) at 3-T PET/MRI. Patients and methods An 18F-FDG PET/MRI multiparametric imaging framework was developed and prospectively applied to 11 biopsy-proven NSCLC patients. For each tumor, 12 parametric maps were generated, including PET full kinetic modeling, apparent diffusion coefficient, T1/T2 relaxation times, and DCE full kinetic modeling. Gaussian mixture model-based clustering was applied at the whole data set level to define supervoxels of similar multidimensional PET/MRI behaviors. Taking the multidimensional voxel behaviors as input and the supervoxel class as output, machine learning procedure was finally trained and validated voxelwise to reveal the dominant PET/MRI characteristics of these supervoxels at the whole data set and individual tumor levels. Results The Gaussian mixture model-based clustering clustering applied at the whole data set level (17,316 voxels) found 3 main multidimensional behaviors underpinned by the 12 PET/MRI quantitative parameters. Four dominant PET/MRI parameters of clinical relevance (PET: k2, k3 and DCE: ve, vp) predicted the overall supervoxel behavior with 97% of accuracy (SD, 0.7; 10-fold cross-validation). At the individual tumor level, these dimensionality-reduced supervoxel maps showed mean discrepancy of 16.7% compared with the original ones. Conclusions One-stop-shop PET/MRI multiparametric quantitative analysis of NSCLC is clinically feasible. Both PET and MRI parameters are useful to characterize the behavior of tumors at the supervoxel level. In the era of precision medicine, the full capabilities of PET/MRI would give further insight of the characterization of NSCLC behavior, opening new avenues toward image-based personalized medicine in this field.

International audience; Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease that is caused by the progressive occlusion of the distal pulmonary arteries, eventually leading to right heart failure and death. Almost 40% of patients with PAH are iron deficient. Although widely studied, the mechanisms linking between PAH and iron deficiency remain unclear. Here we review the mechanisms regulating iron homeostasis and the preclinical and clinical data available on iron deficiency in PAH. Then we discuss the potential implications of iron deficiency on the development and management of PAH.

Aims Pulmonary hypertension (PH) is a common complication of left heart disease (LHD, Group 2 PH) leading to right ventricular (RV) failure and death. Several loss-of-function (LOF) mutations in KCNK3 were identified in pulmonary arterial hypertension (PAH, Group 1 PH). Additionally, we found that KCNK3 dysfunction is a hallmark of PAH at pulmonary vascular and RV levels. However, the role of KCNK3 in the pathobiology of PH due to LHD is unknown. Methods and results We evaluated the role of KCNK3 on PH induced by ascending aortic constriction (AAC), in WT and Kcnk3-LOF-mutated rats, by echocardiography, RV catheterization, histology analyses, and molecular biology experiments. We found that Kcnk3-LOF-mutation had no consequence on the development of left ventricular (LV) compensated concentric hypertrophy in AAC, while left atrial emptying fraction was impaired in AAC-Kcnk3-mutated rats. AAC-animals (WT and Kcnk3-mutated rats) developed PH secondary to AAC and Kcnk3-mutated rats developed more severe PH than WT. AAC-Kcnk3-mutated rats developed RV and LV fibrosis in association with an increase of Col1a1 mRNA in right ventricle and left ventricle. AAC-Kcnk3-mutated rats developed severe pulmonary vascular (pulmonary artery as well as pulmonary veins) remodelling with intense peri-vascular and peri-bronchial inflammation, perivascular oedema, alveolar wall thickening, and exaggerated lung vascular cell proliferation compared to AAC-WT-rats. Finally, in lung, right ventricle, left ventricle, and left atrium of AAC-Kcnk3-mutated rats, we found a strong increased expression of Il-6 and periostin expression and a reduction of lung Ctnnd1 mRNA (coding for p120 catenin), contributing to the exaggerated pulmonary and heart remodelling and pulmonary vascular oedema in AAC-Kcnk3-mutated rats. Conclusions Our results indicate that Kcnk3-LOF is a key event in the pathobiology of PH due to AAC, suggesting that Kcnk3 channel dysfunction could play a potential key role in the development of PH due to LHD.

The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully understood, but evidence is accumulating that immune dysfunction plays a significant role. We previously reported that 31-week-old Tnfaip3DNGR1-KO mice develop pulmonary hypertension (PH) symptoms. These mice harbor a targeted deletion of the TNFα-induced protein-3 (Tnfaip3) gene, encoding the NF-κB regulatory protein A20, specifically in type I conventional dendritic cells (cDC1s). Here, we studied the involvement of dendritic cells (DCs) in PH in more detail. We found various immune cells, including DCs, in the hearts of Tnfaip3DNGR1-KO mice, particularly in the right ventricle (RV). Secondly, in young Tnfaip3DNGR1-KO mice, innate immune activation through airway exposure to toll-like receptor ligands essentially did not result in elevated RV pressures, although we did observe significant RV hypertrophy. Thirdly, PH symptoms in Tnfaip3DNGR1-KO mice were not enhanced by concomitant mutation of bone morphogenetic protein receptor type 2 (Bmpr2), which is the most affected gene in PAH patients. Finally, in human IPAH lung tissue we found co-localization of DCs and CD8+ T cells, representing the main cell type activated by cDC1s. Taken together, these findings support a unique role of cDC1s in PAH pathogenesis, independent of general immune activation or a mutation in the Bmpr2 gene.

After tobacco, cannabis is the most widely used drug worldwide, and the move to legalise it is growing in more and more countries. The literature about the involvement of cannabis smoking on the development of lung cancer is scarce and most often reassuring [1–3], even though the concentration of carcinogens in cannabis smoke is unquestionably greater than that in tobacco smoke [4]. Moreover, recent studies on cannabis tend to focus on possible therapeutic effects [5]. Studies of the carcinogenic impact of cannabis are indeed limited by its frequent association with tobacco smoking and by its illegal status in most countries [6]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Betser has nothing to disclose. Conflict of interest: Dr. Glorion has nothing to disclose. Conflict of interest: Dr. Mordan has nothing to disclose. Conflict of interest: Dr. Caramella has nothing to disclose. Conflict of interest: Dr. Ghigna has nothing to disclose. Conflict of interest: Dr. Besse has nothing to disclose. Conflict of interest: Dr. planchard has nothing to disclose. Conflict of interest: Dr. Le Pavec has nothing to disclose. Conflict of interest: Dr. Chapelier has nothing to disclose. Conflict of interest: Dr. Friard has nothing to disclose. Conflict of interest: Dr. Gounant has nothing to disclose. Conflict of interest: Dr. Castier has nothing to disclose. Conflict of interest: Dr. Levy has nothing to disclose. Conflict of interest: Dr. Mercier has nothing to disclose. Conflict of interest: Dr. Fabre has nothing to disclose. Conflict of interest: Dr. Fadel has nothing to disclose. Conflict of interest: Dr. pradere has nothing to disclose.

International audience; Pulmonary arterial hypertension (PAH) is a rare and deadly disease affecting roughly 15–60 people per million in Europe with a poorly understood pathology. There are currently no diagnostic tools for early detection nor does a curative treatment exist. The lipid composition of arteries in lung tissue samples from human PAH and control patients were investigated using matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) combined with time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging. Using random forests as an IMS data analysis technique, it was possible to identify the ion at m/z 885.6 as a marker of PAH in human lung tissue. The m/z 885.6 ion intensity was shown to be significantly higher around diseased arteries and was confirmed to be a diacylglycerophosphoinositol PI(C18:0/C20:4) via MS/MS using a novel hybrid SIMS instrument. The discovery of a potential biomarker opens up new research avenues which may finally lead to a better understanding of the PAH pathology and highlights the vital role IMS can play in modern biomedical research.

Objectives To decipher the correlations between PET and DCE kinetic parameters in non-small-cell lung cancer (NSCLC), by using voxel-wise analysis of dynamic simultaneous [18F]FDG PET-MRI. Material and methods Fourteen treatment-naïve patients with biopsy-proven NSCLC prospectively underwent a 1-h dynamic [18F]FDG thoracic PET-MRI scan including DCE. The PET and DCE data were normalized to their corresponding T1-weighted MR morphological space, and tumors were masked semi-automatically. Voxel-wise parametric maps of PET and DCE kinetic parameters were computed by fitting the dynamic PET and DCE tumor data to the Sokoloff and Extended Tofts models respectively, by using in-house developed procedures. Curve-fitting errors were assessed by computing the relative root mean square error (rRMSE) of the estimated PET and DCE signals at the voxel level. For each tumor, Spearman correlation coefficients (rs) between all the pairs of PET and DCE kinetic parameters were estimated on a voxel-wise basis, along with their respective bootstrapped 95% confidence intervals (n = 1000 iterations). Results Curve-fitting metrics provided fit errors under 20% for almost 90% of the PET voxels (median rRMSE = 10.3, interquartile ranges IQR = 8.1; 14.3), whereas 73.3% of the DCE voxels showed fit errors under 45% (median rRMSE = 31.8%, IQR = 22.4; 46.6). The PET-PET, DCE-DCE, and PET-DCE voxel-wise correlations varied according to individual tumor behaviors. Beyond this wide variability, the PET-PET and DCE-DCE correlations were mainly high (absolute rs values > 0.7), whereas the PET-DCE correlations were mainly low to moderate (absolute rs values < 0.7). Half the tumors showed a hypometabolism with low perfused/vascularized profile, a hallmark of hypoxia, and tumor aggressiveness. Conclusion A dynamic “one-stop shop” procedure applied to NSCLC is technically feasible in clinical practice. PET and DCE kinetic parameters assessed simultaneously are not highly correlated in NSCLC, and these correlations showed a wide variability among tumors and patients. These results tend to suggest that PET and DCE kinetic parameters might provide complementary information. In the future, this might make PET-MRI a unique tool to characterize the individual tumor biological behavior in NSCLC.

Pulmonary veno-occlusive disease (PVOD) occurs in humans either as a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2) or as a sporadic form in older age (sPVOD). The chemotherapeutic agent mitomycin C (MMC) is a potent inducer of PVOD in humans and in rats (MMC-PVOD). Here, we compared human hPVOD and sPVOD, and MMC-PVOD pathophysiology at the histological, cellular, and molecular levels to unravel common altered pathomechanisms. MMC exposure in rats was associated primarily with arterial and microvessel remodeling, and secondarily by venous remodeling, when PVOD became symptomatic. In all forms of PVOD tested, there was convergent GCN2-dependent but eIF2α-independent pulmonary protein overexpression of HO-1 (heme oxygenase 1) and CHOP (CCAAT-enhancer-binding protein [C/EBP] homologous protein), two downstream effectors of GCN2 signaling and endoplasmic reticulum stress. In human PVOD samples, CHOP immunohistochemical staining mainly labeled endothelial cells in remodeled veins and arteries. Strong HO-1 staining was observed only within capillary hemangiomatosis foci, where intense microvascular proliferation occurs. HO-1 and CHOP stainings were not observed in control and pulmonary arterial hypertension lung tissues, supporting the specificity for CHOP and HO-1 involvement in PVOD pathobiology. In vivo loss of GCN2 (EIF2AK4 mutations carriers and Eif2ak4-/- rats) or in vitro GCN2 inhibition in cultured pulmonary artery endothelial cells using pharmacological and siRNA approaches demonstrated that GCN2 loss of function negatively regulates BMP (bone morphogenetic protein)-dependent SMAD1/5/9 signaling. Exogenous BMP9 was still able to reverse GCN2 inhibition-induced proliferation of pulmonary artery endothelial cells. In conclusion, we identified CHOP and HO-1 inhibition, and BMP9, as potential therapeutic options for PVOD. ispartof: AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY vol:63 issue:1 pages:118-131 ispartof: location:United States status: published

No prior proteomic screening study has centred on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH. Plasma proteomic profiling was performed using multiplex immunoassay in 121 (discovery cohort) and 76 (validation cohort) PAH patients. The association between proteomic markers and RHMP, defined by the Mayo right heart score (combining RV strain, New York Heart Association (NYHA) class and N-terminal pro-brain natriuretic peptide (NT-proBNP)) and Stanford score (RV end-systolic remodelling index, NYHA class and NT-proBNP), was assessed by partial least squares regression. Biomarker expression was measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice. High levels of hepatocyte growth factor (HGF), stem cell growth factor-β, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant or hospitalisation at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams. High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk of heart failure who warrant closer follow-up and intensified therapy., High plasma HGF levels are associated with right heart maladaptive phenotype and prognosis in PAH. HGF and c-Met RV expression are both increased. Assessing plasma HGF levels might identify patients who warrant closer follow-up and intensified therapy. https://bit.ly/3djiy9O

Objectives: To decipher the interlinks between PET and DCE kinetic parameters in non-small-cell lung cancer (NSCLC), by using voxel-wise analysis of full dynamic simultaneous [18F]FDG PET-MRI. Material and methods: Fourteen treatment-naïve patients with biopsy proven NSCLC prospectively underwent a one-hour dynamic [18F]FDG thoracic PET-MRI scan including DCE. The PET and DCE data were normalized to their corresponding T1-weighted MR morphological space, and tumors were masked semi-automatically. Voxel-wise parametric maps of PET and DCE kinetic parameters were computed by fitting the dynamic PET and DCE tumor data to the Sokoloff and Extended Tofts models respectively, by using in-house developed procedures. Curve fitting errors were assessed by computing the relative root mean square error (rRMSE) of the estimated PET and DCE signals at the voxel level. For each tumor, Spearman correlation coefficients (r s ) between all the pairs of PET and DCE kinetic parameters were estimated on a voxel-wise basis, along with their respective bootstrapped 95% confidence intervals (n = 1000 iterations). Results: Curve fitting metrics provided fit errors under 20% for almost 90% of the PET voxels (median rRMSE,= 10.3, interquartile ranges IQR = 8.1; 14.3), whereas 73.3% of the DCE voxels showed fit errors under 45% (median rRMSE = 31.8%, IQR = 22.4; 46.6). The PET-PET, DCE-DCE and PET-DCE voxel-wise interlinks were heterogeneous, with variations related to individual tumor behaviors. Beyond this wide variability, the PET-PET and DCE-DCE interlinks were mainly high (absolute r s values > 0.7), whereas the PET-DCE interlinks were mainly low to moderate (absolute r s values < 0.7). Half the tumors showed an hypometabolic with low perfused/vascularized profile, a hallmark of hypoxia and tumor aggressiveness. Conclusion: The interlinks between dynamic PET and DCE kinetic parameters assessed simultaneously with [18F]FDG PET-MRI are heterogeneous among NSCLC tumors. In the era of precision medicine, PET-MRI has unique capability to go further insight the individual tumor behavior in NSCLC.

Rationale: Pulmonary hypertension (PH) associated with neurofibromatosis type 1 (NF1) is a rare and largely unknown complication of NF1.Objectives: To describe characteristics and outcomes of PH-NF...

IntroductionTBX4 mutation causes small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown.MethodsWe report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French pulmonary hypertension (PH) network.Results20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0–76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2–41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide (DLCO) was decreased in all patients. High-resolution computed tomography (HRCT) showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients had died and two had undergone lung transplantation. One-year, three-year and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic pulmonary arterial hypertension (IPAH) and accumulation of cholesterol crystals within the lung parenchyma.ConclusionPAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.

Pulmonary capillary haemangiomatosis (PCH) is a rare and incompletely understood histopathological finding characterised by abnormal capillary proliferation within the alveolar interstitium, which has long been noted to share many overlapping features with pulmonary veno-occlusive disease (PVOD). But are PCH and PVOD distinct entities that occur in isolation, or are they closely intertwined manifestations along a spectrum of the same disease? The classic clinical features of both PCH and PVOD include signs and symptoms related to pulmonary hypertension, hypoxaemia, markedly impaired diffusion capacity of the lung and abnormal chest imaging with ground glass opacities, septal lines and lymphadenopathy. In recent years, increasing evidence suggests that the clinical presentation, histopathological features, genetic substrate and pathobiological mechanisms of PCH and PVOD are overlapping and usually indistinguishable. The discovery of biallelic mutations in the eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) gene in heritable PCH and PVOD greatly advanced our understanding of the overlapping nature of these conditions. Furthermore, recognition of PCH and PVOD-like changes in other pulmonary vascular diseases and in conditions that cause chronic pulmonary venous hyper-perfusion or hypertension suggests that PCH/PVOD may develop as a reactive process to various insults or injuries to the pulmonary vasculature, rather than being primary angiogenic disorders.

Objectives: To decipher the metabolism/vascularization regional interlinks in NSCLC, by using full dynamic simultaneous 18F-FDG PET-MRI voxel-wise analysis. Material and methods: Fourteen treatment-naïve patients with biopsy proven NSCLC prospectively underwent a one-hour dynamic 18F-FDG thoracic PET-MRI including DCE. The PET and DCE data were normalized to a reference space, and masked semi-automatically. Full kinetic voxelwise parametric maps were computed by fitting the PET and DCE tumor data to state-of-the-art Sokoloff and Extended Tofts models respectively, by using in-house procedures. Spearman correlation coefficients (rs) between all the tumors kinetic parameters were estimated on a voxelwise basis, both at the whole dataset and tumor levels.Results: At the whole dataset level, the estimated K1, k2, k3, MRGlu and vb median values (IQR) were 0.25ml.min-1.ml-1 (0.17-0.33), 0.68 min-1 (0.48-1.02), 0.11 min-1 (0.07-0.2), 0.20 μmol.ml-1.min-1 (0.13-0.29) and 0.08 a.u (0.05-0.10). The estimated Ktrans, ve, Kep and vp median values (IQR) were 0.44 min-1 (0.14-0.92), 0.64 a.u (0.24-1.0), 0.79 min-1 (0.44-1.3), and 0.04 a.u (0.0007-0.19). At the whole dataset level, all the PET/DCE regional interlinks were weak (|rs

International audience; INTRODUCTION:TBX4 mutation cause small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown.METHODS:We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French PH Network.RESULTS:Twenty patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 (0-76) year-old and a female to male ratio of 3. Most of the patients were in NYHA functional class III or IV (70%) with a severe hemodynamic impairment (median pulmonary vascular resistance of 13.6 [6.2-41.8] Wood Units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity for carbon monoxide was decreased in all patients. High-resolution computed tomography showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients died and two underwent lung transplantation. One-, three- and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic PAH, and accumulation of cholesterol crystals within the lung parenchyma.CONCLUSION:PAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.

International audience; Thymomas are associated with a very high risk of developing Myasthenia Gravis (MG). Our objectives were to identify histological and biological parameters to allow early diagnosis of thymoma patients susceptible to developing MG. We conducted a detailed retrospective analysis from a patient database, searching for differences between patients with thymoma-associated MG (MGT, n = 409) and thymoma without MG (TOMA, n = 111) in comparison with nonthymomatous MG patients (MG, n = 1246). We also performed multiplex and single molecule arrays to measure the serum levels of cytokines in these groups of patients and controls (n = 14-22). We identified a set of parameters associated with MG development in thymoma patients: 1) detection of anti-acetylcholine receptor (AChR) antibodies, 2) development of B1 or B2 thymoma subtypes, 3) presence of ectopic thymic germinal centers (GCs), 4) local invasiveness of thymoma, and 5) being a woman under 50 years old. Among these parameters, 58.8% of MGT patients displayed GCs with a positive correlation between the number of GCs and anti-AChR titers. By immunohistochemistry, we found thymic GCs in the adjacent tissues of thymomas encircled by high endothelial venules (HEVs) that could favor peripheral cell recruitment. We also clearly associated MG symptoms with higher IFN-γ, IL-1β and sCD40L serum levels, specifically in MGT patients compared to TOMA patients. Altogether, these analyses allowed the clear identification of histological, in particular the presence of GCs, and biological parameters that would facilitate the evaluation of the probability of the MG outcome postoperatively in thymoma patients.

We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0-76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2-41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide (PAH due to

International audience; Klippel-Trenaunay syndrome (KTS) is a congenital disorder characterized by cutaneous capillary malformations, soft tissue and bone hypertrophy, and multiple capillary, venous or lymphatic malformations. KTS is associated with recurrent thromboembolic events. We reported herein five cases of chronic thromboembolic pulmonary hypertension (CTEPH) associated with KTS (age minimum-maximum 26-50 years old, 3 males/2 females). Hemodynamics showed severe pulmonary hypertension (PH) with pulmonary vascular resistance ranging from 5.6 to 18.3 Wood units (WU), associated with marked clinical impairment (NYHA functional class III or IV in 4 patients). Computed tomography (CT) of the chest and pulmonary angiography confirmed proximal CTEPH accessible to surgical intervention in one patient and distal forms of CTEPH in 4 patients. Evolution after pulmonary endarterectomy showed hemodynamic normalization, while the patients with distal CTEPH had severe outcomes with 2 early deaths after PH diagnosis (44 and 35 months respectively). One patient with distal CTEPH was still alive 16 years after diagnosis on specific PH therapy and one was transplanted after 15 years because of right heart failure (death after 12 months). Histological analysis of the lung explants showed typical chronic thromboembolic material specific for CTEPH. In conclusion, KTS may be complicated by severe CTEPH requiring careful anticoagulation and multidisciplinary follow-up in expert centers to screen for disease potentially accessible to endarterectomy. In the modern management era of CTEPH, balloon pulmonary angioplasty will certainly be an interesting option in patients with inoperable disease.

Introduction Le cannabis est la drogue la plus consommee au monde, et beaucoup de pays ont depenalise son usage. Malgre une concentration superieure de carcinogenes dans la fumee de cannabis compare au tabac seul [1] , les donnees de la litterature sur les liens entre consommation de cannabis et developpement du cancer bronchique sont pauvres et le plus souvent rassurantes [2] . Les etudes sur l’impact carcinogene de cette drogue sont limitees par la frequente association avec le tabagisme et par le caractere illegal de sa consommation dans encore de nombreux pays. Objectif Decrire la prevalence de la consommation de cannabis parmi de jeunes patients operes pour cancer bronchique et comparer les caracteristiques cliniques, histologiques, et de suivi entre les patients fumeurs de cannabis, fumeurs de tabac seul, et non-fumeurs. Methodes Inclusion de tous les patients de moins de 50 ans operes pour un cancer bronchique primitif au sein des hopitaux Marie-Lannelongue, Foch, et Bichat entre 2018 et 2020. Questionnaire telephonique sur les habitus dont la consommation de cannabis avec chaque patient avec revue retrospective de l’ensemble du dossier medical. Resultats Resultat intermediaires. Au total, 580 patients operes pour cancer bronchique primitif sur la periode, dont 41 de moins de 50 ans. Quatre-vingt-dix pour cent repondent a l’entretien telephonique. Cinquante et un pour cent d’usagers reguliers de cannabis avec mediane de consommation de 150 joints par mois, 27 % de fumeurs de tabac seul, 22 % de non-fumeurs. Plus d’hommes dans le groupe cannabis, plus de femmes dans le groupe non-fumeurs. Duree mediane de consommation de 19 ans. Pour 57 % des fumeurs de cannabis, cette donnee n’est pas notee dans le dossier medical. Plus de T3-T4 dans le groupe cannabis. Conclusion Tres haute prevalence de la consommation reguliere de cannabis dans cette population de patients jeunes operes pour cancer bronchique primitif, surtout chez les hommes, meme si non recherchee systematiquement en pratique clinique courante. Cannabis pourtant non mentionne dans les principales etudes epidemiologiques sur le cancer bronchique, malgre la haute concentration de sa fumee en carcinogenes.

Though commonly used to assess response to therapy, the prognostic value of interim FDG-PET/CT in Primary Mediastinal Large B-cell Lymphoma (PMBCL) is unclear. We conducted a retrospective study on 36 consecutive patients treated at our institution for a PMBCL between 2006 and 2014. All patients with a positive interim FDG-PET/CT had undergone histological restaging consisting either in a surgical debulking of the residual lesion (15 patients) or a CT-guided core needle biopsy (two patients). All FDG-PET/CT were secondarily reviewed according to the more recent Deauville criteria. Interim FDG-PET/CT was considered positive in 17/36 patients using visual evaluation. Among these patients, 14 had a Deauville score of 4. Histological restaging was negative in all but one case, showing inflammation and/or fibrosis. After a median follow-up of 48.5 months, a total of five patients have relapsed, two patients in the positive FDG-PET/CT group, and three patients in the negative FDG-PET/CT group, respectively. These data indicate that a positive interim FDG-PET/CT does not reflect persistence of active disease in the vast majority of PMBCL cases. The relapse rate appears similar regardless of interim FDG-PET/CT results and interpretation criteria. This suggests that interim FDG-PET/CT has a poor positive predictive value, thus kt should be used with caution in PMBCL.

Purpose Transplantation of hearts donated after circulatory death (DCD) remains challenging due to the risk myocardial injuries. These hearts are exposed to hypoxia and prolonged warm ischemic time (WIT). We hypothesize that administration of cardioplegia (CPG) after extended WIT could make DCD hearts suitable for transplantation without severe myocardial injury. Methods A hypoxic cardiac arrest was induced in twelve piglets (40 kg). Since peripheral cannulation could not be considered, a normothermic regional perfusion (NRP) was established between the right atrium and the aortic arch, 5 min. after mechanical asystole. In the CPG group (n=6), a crystalloid solution (40 mL/kg, Celsior, IGL, Lyon, France) was administered after 15 min. of WIT, while no preservation solution was administrated in the control group (n=6). The aortic clamp was released after 35 min. and NRP withdrawal was attempted 60 min. after cardiac reperfusion. Pressure-volume loops were performed before and after cardiac resuscitation. Early ischemic changes were detected on Masson's trichrome staining and incorporated to a composite score. Results Agonal phase was 14 min. in the CPG group (9.5-14) vs. 12 min. (11-13) (P=1.0). Three (50%) piglets could be weaned from NRP in the CPG group, vs. 1 (16.7%) in the CTL group (P=0.55). Troponin I was not different between groups (53 vs. 49 µg/L, P=0.73). All resuscitated hearts had biventricular function impairment with marked decline in left ventricular end-systolic elastance. Left ventricular ischemic changes were less severe in CPG group (P=0.034), while multifocal myocardial injury of the right ventricle was observed in both groups (Figure 1). Conclusion Early administration of crystalloid cardioplegia was associated with a 50% rate of heart resuscitation in our porcine model. The viability of DCD hearts after prolonged WIT was limited by right ventricular severe injury.