[Adipocytes, adipokines and metabolic alterations in pulmonary fibrosis]. / Adipocytes, adipokines et altérations métaboliques dans la fibrose pulmonaire.

Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by severe remodeling of the lung parenchyma, with an accumulation of activated myofibroblasts and extracellular matrix, along with aberrant cellular differentiation. Within the subpleural fibrous zones, ectopic adipocyte deposits often appear. In addition, alterations in lipid homeostasis have been associated with IPF pathophysiology. In this mini-review, we will discuss the potential involvement of the adipocyte secretome and its paracrine or endocrine-based contribution to the pathophysiology of IPF, via protein or lipid mediators in particular.

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future.

BACKGROUND: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. MATERIALS AND METHODS: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. RESULTS: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. CONCLUSIONS: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.

Definitions, outcomes, and management of hyperprogression in patients with non-small-cell lung cancer treated with immune checkpoint inhibitors.

BACKGROUND: The advent of immune checkpoint inhibitors (ICI) has been a breakthrough in the care of patients with non-small-cell lung cancers (NSCLC). However, physicians are now facing a previously unidentified clinical situation called hyperprogression (HP), which presents as a fast and unexpected increase in tumor burden. HP's existence and specificity to ICIs remains controversial because a widely acknowledged definition is currently lacking. Meanwhile, management remains elusive. METHODS: Medical records from all consecutive NSCLC patients who were treated with ICI from 2015 to 2018 were retrospectively analyzed. The HP incidence rate was calculated according to five definitions (tumor growth rate [TGR]ratio, ΔTGR, tumor growth kinetic [TGK], RECIST, and time to treatment failure [TTF]), and the agreement between such definitions was determined. The HP impact on overall survival (OS) was then assessed. The association between HP (defined using the TGRratio definition) and clinical and biological variables was also assessed. Clinical HP management and its impact on outcomes were described. RESULTS: We identified 169 consecutive ICI-treated patients, with potential HP accounting for 11.3 %, 5.7 %, 17.0 %, 9.6 %, and 31.7 % patients, according to TGRratio, ΔTGR, TGK, RECIST, and TTF definitions. Agreement between the different HP definitions was highly heterogeneous (range 29 %-77 %) and globally poor. HP was associated with shorter OS, compared to standard RECIST progressive disease, but this difference only reached statistical significance when using the TTF definition. TGRratio-based HP was significantly associated with hepatic metastases. In TGRratio-based HP patients, neither resuming chemotherapy nor corticosteroids use was associated with statistically significant impact on overall survival. CONCLUSION: We found fairly heterogeneous HP rates using different definitions. TTF was the only definition leading to significantly worsened OS. Further studies are needed to provide consensus recommendations for the assessment, definition, and management of HP, whose existence is likely real.

Multicenter harmonization study for PD-L1 IHC testing in non-small-cell lung cancer.

Background: Various programed death ligand 1 (PD-L1) immunohistochemistry (IHC) assays have been developed and used in clinical trials in association with different drugs. In order to harmonize and make PD-L1 testing in non-small-cell lung cancer (NSCLC) widely available, we conducted a multicenter study comparing PD-L1 standardized assays and laboratory-developed tests (LDTs). Methods: IHC with five anti-PD-L1 monoclonal antibodies (28-8, 22C3, E1L3N, SP142 and SP263) was performed concomitantly on 41 NSCLC surgical specimens in 7 centers using Dako Autostainer Link 48 (3 centers), Leica Bond (2 centers) or Ventana BenchMark Ultra (2 centers) platforms. For each matching platform, 22C3, 28-8 and SP263 assays were performed. For nonmatching platforms and other antibodies, LDTs were developed in each center. A total of 35 stainings were performed for each case across different platforms and antibodies. PD-L1 staining was assessed in tumor cells and immune cells by seven trained thoracic pathologists. For statistical analysis, 1%, 50% and 1%, 5%, 10% expression thresholds were used for tumor cells and immune cells, respectively. Results: 28-8, 22C3 and SP263 assays were highly concordant for tumor cells staining across the five Dako or Ventana platforms. Among 27 LDTs developed in 7 centers on Dako, Ventana and Leica platforms, 14 (51.8%) demonstrated similar concordance when compared with reference assays for tumor cell staining. Clone SP263 achieved the highest concordance rate across all platforms. Lower concordance was observed for immune cells staining when using a four categories scale. Conclusion: 28-8, 22C3 and SP263 assays had close analytical performance for tumor cell staining across seven centers. Some LDTs on Dako, Ventana and Leica platforms achieved similar concordance, but caution is warranted for their validation. These LDTs will be further validated in order to provide recommendations for the use of assays and LDT for PD-L1 testing in NSCLC.

[Idiopathic pulmonary fibrosis: diagnosis and treatment in 2013]. / Fibrose pulmonaire idiopathique : prise en charge diagnostique et thérapeutique en 2013.

Idiopathic pulmonary fibrosis (IPF), the etiopathogeny of which is still unknown, is the most frequent and severe of idiopathic interstitial pneumonias. It progressively leads, sometimes more acutely when exacerbations occur, to a restrictive respiratory insufficiency. Its prognosis is very dark with a median survival of 3-5 years. No treatment so far has been curative. Its diagnostic and therapeutic management has been greatly improved due to the technical progress in terms of high-resolution tomodensitometry, to the availability of new drugs with a real antifibrotic potential and to the production of international recommendations. The diagnosis is reached in 2/3 of IPF patients presenting with a typical usual interstitial pneumonitis (UIP) CT-scan pattern. It requires a videothoracoscopic biopsy in the remaining patients. Multidisciplinary discussions are key to a proper diagnosis of IPF. Pirfenidone is presently the only drug with a real antifibrotic potential in mild to moderate forms of the disease (FVC>50% and DLCO>35% predicted). The other ones have proved either inefficient or toxic. It is highly recommended to include patients in innovative targeted protocols. Non-pharmacological management of these patients comprises long-term oxygen therapy, pulmonary rehabilitation and overall lung transplantation. Pulmonary hypertension, to be detected regularly during the follow-up, is associated to a dark prognosis. No specific treatment is efficient in this context. Several comorbidities, particularly frequent in IPF, should be treated when present: gastro-oesophageal reflux, obstructive sleep apnea, emphysema. The particular high frequency of bronchopulmonary cancer should be highlighted.

[Molecular profiling of non-small cell lung cancer]. / Biologie moléculaire et prise en charge des patients atteints d'adénocarcinomes du poumon.

The management of locally advanced and metastatic non-small cell lung cancer has been revolutionized thanks to recent progress in pathology and molecular biology. The first molecular subgroup is defined by activating mutations of the epidermal growth factor receptor (EGFR), and a dramatic response to specific tyrosine kinase inhibitors. Since then, multiple genetic alterations (KRAS, HER2, BRAF, PIK3CA, ALK, ROS, RET…) have been identified as potential target of novel therapies, and molecular profiling has become common practice. This review focus on the molecular alterations associated with non-small cell lung cancer, including molecular profiling and response to targeted therapies.

[Lymphatic extension and lymphangiogenesis in non-small cell lung cancer]. / Extension lymphatique et lymphangiogenèse dans les cancers pulmonaires non à petites cellules.

Lymph node metastasis is a major adverse prognostic factor of malignant tumors, including non-small cell lung carcinoma (NSCLC). However the characterization of tumor associated lymphatic vessels and lymphangiogenic mediators in NSCLC are recent and their prognostic role is debated. Lymphatic vascular invasion (LVI) appears like a robust adverse prognostic factor when reported in NSCLC. This parameter should be better standardized and could be of use in adjuvant therapy indications. Moreover, anti-lymphangiogenesis therapies are currently under investigation and may become part of the anti-cancer strategy.

Overexpression and promoter mutation of the TERT gene in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a very aggressive tumor with no known curative treatment. Better knowledge of the molecular mechanisms of mesothelial carcinogenesis is required to develop new therapeutic strategies. MPM, like all cancer cells, needs to maintain telomere length to prevent senescence. Previous studies suggested that the telomere lengthening mechanism in MPM is based mainly on telomerase activity. For this reason, we focused on the key catalytic enzyme, TERT (telomerase reverse transcriptase), by analyzing its gene expression in MPM and by studying the mechanism underlying its upregulation. We used our large collection of MPM composed of 61 MPM in culture and 71 frozen MPM tumor samples. Evaluation of TERT mRNA expression by quantitative RT-PCR showed overexpression in MPM in culture compared with normal mesothelial cells, and in MPM tumor samples compared with normal pleura. We identified a 'hot spot' of mutations in the TERT gene core promoter in both MPM in culture and in MPM tumor samples with an overall frequency of 15%. Furthermore, data clearly identified mutation in the TERT promoter as a mechanism of TERT mRNA upregulation in MPM. In contrast, gene copy number amplification was not associated with TERT overexpression. Then, we analyzed the clinicopathological, etiological and genetic characteristics of MPM with mutations in the TERT promoter. TERT promoter mutations were more frequent in MPM with sarcomatoid histologic subtype (P<0.01), and they were frequently associated with CDKN2A gene inactivation (P=0.03). In conclusion, a subgroup of MPM presents TERT promoter mutations, which lead to TERT mRNA upregulation. This is the first recurrent gain-of-function oncogenic mutations identified in MPM.

[Radiofrequency of lung metastases: should initial pneumothorax predict treatment failure?]. / Radiofréquence sur les métastases pulmonaires : un pneumothorax initial pourrait-il prédire un échec thérapeutique ?

In the management of lung metastases originating from colorectal cancer, RFA is particularly indicated in case of major comorbidities contraindicating thoracic surgery or recurrent disease after previous ipsilateral resection. The most frequent complication of RFA is pneumothorax, requiring chest tube insertion in 5% of cases. Interestingly, this proportion is very close to the rate of local recurrence, suggesting a possible association. We report a case of RFA followed by intractable pneumothorax requiring surgical management, and leading to the diagnosis of residual tumour. This case report illustrates this association and questions its relevance.

[Lung volume reduction surgery for emphysema and bullous pulmonary emphysema]. / Chirurgie de réduction volumique et des bulles géantes dans l'emphysème pulmonaire.

The improvement of respiratory symptoms for emphysematous patients by surgery is a concept that has evolved over time. Initially used for giant bullae, this surgery was then applied to patients with diffuse microbullous emphysema. The physiological and pathological concepts underlying these surgical procedures are the same in both cases: improve respiratory performance by reducing the high intrapleural pressure. The functional benefit of lung volume reduction surgery (LVRS) in the severe diffuse emphysema has been validated by the National Emphysema Treatment Trial (NETT) and the later studies which allowed to identify prognostic factors. The quality of the clinical, morphological and functional data made it possible to develop recommendations now widely used in current practice. Surgery for giant bullae occurring on little or moderately emphysematous lung is often a simpler approach but also requires specialised support to optimize its results.

[Lung metastasis surgery, yesterday and now]. / Chirurgie des métastases pulmonaires d'hier à aujourd'hui.

INTRODUCTION: Surgical resection of lung metastases may prolong survival as a part of multimodality treatment. Our aim was to review how the indications and practice of this type of surgery have evolved over time. METHOD: We included in the study all patients who were operated for this indication between 1983 and 2006 in two different surgical departments. A retrospective review was conducted including the following criteria: age, sex, type of primary cancer, type of pulmonary resection, histology of metastases, perioperative chemotherapy. RESULTS: Four hundred and seventy-two operations were performed in 225 men and 145 women: 448 were complete resections (wedge resection: 221, segmentectomy: 47, lobectomy: 148, pneumonectomy: 32), and 24 incomplete resections. Most metastases were from colorectal (n=129), renal (n=73), and sarcoma origin (n=34); the survival rate was 38.5% and 24.3% at 5 and 10 years. The following criteria were markers of poor prognosis: incomplete or large excision (whole lung or lobar excision), size, nodal status, intravascular microemboli. Factors that did not influence prognosis were: disease free interval, location and number of metastases. Prognosis showed a significant improvement since 1998, and with the use of neoadjuvant chemotherapy (77 patients). The survival rate for isolated metastases that were potentially candidates for radiofrequency ablation was 48% at 5 years. CONCLUSION: The prognosis of lung metastases has been notably improved by better understanding of the disease and the adoption of a multidisciplinary approach, integrating recent advances in systemic treatments. The efficacy of other forms of local surgical treatment have yet to be demonstrated.

The constitutive activity of the ALK mutated at positions F1174 or R1275 impairs receptor trafficking.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK), which is transiently expressed during development of the central and peripheral nervous system. ALK has been recently identified as a major neuroblastoma predisposition gene and activating mutations have also been identified in a subset of sporadic neuroblastoma tumors. Two hot spots of ALK mutations have been observed at positions F1174 and R1275. Here, we studied stably transfected cell lines expressing wild-type or F1174L- or R1275Q-mutated ALK in parallel with a neuroblastoma cell line (CLB-GE) in which the allele mutated at position F1174 is amplified. We observed that the mutated ALK variants were essentially intracellular and were largely retained in the reticulum/Golgi compartments. This localization was corroborated by a defect of N-linked glycosylation. Although the mutated receptors exhibited a constitutive activation, the minor pool of receptor addressed to the plasma membrane was much more tyrosine phosphorylated than the intracellular pool. The use of antagonist monoclonal antibodies suggested that the constitutive activity of the mutated receptors did not require the dimerization of the receptor, whereas adequate dimerization triggered by agonist monoclonal antibodies increased this activity. Finally, kinase inactivation of the mutated receptors restored maturation and cell-surface localization. Our results show that constitutive activation of ALK results in its impaired maturation and intracellular retention. Furthermore, they provide a rationale for the potential use of kinase inhibitors and antibodies in ALK-dependent tumors.

[Isolated malignant mediastinal lymphadenopathy]. / Adénopathies médiastinales malignes isolées.

Mediastinal adenopathies without pulmonary disease may be benign, lymphomatous or the metastases from intra- or extrathoracic malignancy or more rarely metastases with unknown primary site. We observed 507 patients with isolated mediastinal adenopathies: benign, lymphomatous and metastatic disease represented 41.4% (210/507), 26.8% (136/507), 31.8% (161/507) of them, respectively. Management of the latter was the most challenging. Surgery was generally diagnostic, restricted to confirming the metastatic process, because of too numerous and disseminated or unresectable lymph nodes in 84% of patients (135/161). However, radical surgery consisting in lymphadenectomy proved effective in case of mediastinal lymph node malignancy without other extra- and intrathoracic disease. We observed long-term good results in such cases, which also was demonstrated by case reports in the literature. We suggest that including surgery in the multimodality treatment of mediastinal metastatic lymph nodes may be advisable in selected patients.

[Mediastinal cysts: clinical approach and treatment]. / Les kystes du médiastin: approche diagnostique et traitement.

Mediastinal cysts (MC), mainly from embryonic origin, are benign and rare malformative lesions, gathering several varieties according to tissue origin. Diagnosis is mostly obtained thanks to tomodensitometry performance and sometimes by magnetic resonance imaging. It may be more difficult in some atypical topographies and in case of bulky MC. The most frequent, springing from division abnormality from embryonic foregut ("foregut cysts" in English literature), are primarily bronchogenic cysts (50 to 60 % of MC), which are symptomatic in 30 to 80 % of cases. Coelomic cysts, lined by a mesothelium, result from embryologic abnormality by incomplete fusion of mesenchymal coelomic lacunae. Rarely symptomatic, excepted in cases of very large cysts, they are mainly pleuropericardic cysts (PPC) that represent 30 % of MC. Thymic cysts, around 15 % of MC, are most often asymptomatic. Cystic lymphangiomas (CL) are congenital lymphatic malformations more frequent and symptomatic in children. Diagnosed in older patients, they are most often acquired and asymptomatic. The only radical and definitive treatment is complete surgical resection of the cyst. It allows suppression of symptoms, procurement of a formal diagnosis and prevention of complications. This resection, generally indicated for all symptomatic cysts, large-sized even asymptomatic and in case of non formal diagnosis, is now recommended for all kinds of cysts except for asymptomatic PPC. This strategy is justified considering morbidity and mortality rising rates in patients treated by surgical resection at time of local complications of the cyst. Surgery is commonly performed by videothoracoscopy or by video-assisted mini-thoracotomy, mainly for PPC and CL. The more conventional thoracotomy is performed in surgery for cysts, which are adhesive to nearby structures. PPC just need a simple follow-up, and surgery is required only in case of symptoms and increasing size. In total, surgical indications for MC are large and accepted because of null postoperative mortality and very low rate of morbidity thanks to mini-invasive surgery. This militates for early surgery, without waiting for cystic complications leading to peroperative difficulties and increasing risks. This review presents the characteristics of those different cysts and the strategies currently acknowledged for the treatment.

[Relevance of surgery in small cell lung cancer]. / Intérêt de la chirurgie dans le cancer bronchique à petites cellules.

Surgery is the most effective treatment of lung cancer provided that there is complete resection. Even though the results in the early stages of small cell lung cancers (SCLC) are encouraging, many oncologists still consider SCLC a contra-indication. The authors report their experience. They retrospectively reviewed the clinical and pathological characteristics and long-term results of 104 patients (mean age: 58.6, male: N=82 and female: N=22) who underwent lung resection with mediastinal lymphadenectomy (lobectomy: N=51 and pneumonectomy: N=53) for small cell lung cancer between 1984 and 2006. The diagnosis was established before the operation in 49 patients (47.1%) of whom 61.2% (N=30) received neoadjuvant therapy. The survival (5-year survival rate 21.7%, median=18 months), postoperative mortality (deaths: N=6) included, depended on the stage: stage I: N=39, 5-year, 34.3%, median=29; stage II: N=23, 5-year, 26.1%, median=12; stage III: N=37, 5-year, 2.7%, median=12 (p=0.000067). There were no 5-year survivors among the N2 patients. The survival did not depend on the diagnostic aspect of the resection, the non-small cell lung cancer histological patterns or perioperative neoadjuvant and adjuvant therapy. The pneumonectomies were more frequent in case of neoadjuvant treatment (23/30 versus 30/47, p=0.00084). The results and the review of the literature indicate that surgery for small cell lung cancer may provide a cure in stages I and II and should not to be ruled out. The only contra-indication is proven pN2. A multicentre, randomised study on surgery versus medical treatment in the early stages should confirm this conclusion.