Cilia and flagella are evolutionarily conserved organelles whose motility relies on the outer and inner dynein arm complexes (ODAs and IDAs). Defects in ODAs and IDAs result in primary ciliary dyskinesia (PCD), a disease characterized by recurrent airway infections and male infertility. PCD mutations in assembly factors have been shown to cause a combined ODA-IDA defect, affecting both cilia and flagella. We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the absence of only IDAs in respiratory cilia. Analyses of both primary cells from individuals carrying TTC12 mutations and human differentiated airway cells invalidated for TTC12 by a CRISPR-Cas9 approach revealed an IDA defect restricted to a subset of single-headed IDAs that are different in flagella and cilia, whereas TTC12 depletion in the ciliate Paramecium tetraurelia recapitulated the sperm phenotype. Overall, our study, which identifies TTC12 as a gene involved in PCD, unveils distinct dynein assembly mechanisms in human motile cilia versus flagella.

Anti-PD-1 antibodies prolong survival of performance status (PS) 0–1 advanced non-small-cell lung cancer (aNSCLC) patients. Their efficacy in PS 3–4 patients is unknown. Conse- cutive PS 3–4 aNSCLC patients receiving compassionate nivolumab were accrued by 12 French thoracic oncology departments, over 24 months. Overall survival (OS) was calculated using the Kaplan-Meier method. Prognostic variables were assessed using Cox proportional hazards models. Overall, 35 PS 3–4 aNSCLC patients (median age 65 years) received a median of 4 nivolumab infusions (interquartile range [IQR], 1–7) as first- (n = 6) or second-line (n = 29) therapy. At a median of 52-month follow-up (95%CI, 41–63), 32 (91%) patients had died. Median progression-free survival was 2.1 months (95%CI, 1.1–3.2). Median OS was 4.4 months (95%CI, 0.5–8.2). Overall, 20% of patients were alive at 1 year, and 14% at 2 years. Treatment-related adverse events occurred in 8/35 patients (23%), mostly of low-grade. After adjustment, brain metastases (HR = 5.2; 95%CI, 9–14.3, p = 0.001) and <20 pack-years (HR = 4.8; 95%CI, 1.7–13.8, p = 0.003) predicted worse survival. PS improvement from 3–4 to 0–1 (n = 9) led to a median 43-month (95%CI, 0–102) OS. Certain patients with very poor general condition could derive long-term benefit from nivolumab salvage therapy.

BACKGROUND: The decision-making on antiplatelet drug withdrawal or continuation before performing a pleural procedure is based on the balance between the risk of bleeding associated with the antiplatelet therapy and the risk of arterial thrombosis due to its interruption. Knowledge on antiplatelet therapy-associated risk of bleeding after pleural procedures is lacking. RESEARCH QUESTION: Is the risk of bleeding associated with antiplatelet drugs increased in patients undergoing pleural procedures? STUDY DESIGN AND METHODS: We conducted a French multicenter cohort study in 19 centers. The main outcome was the occurrence of bleeding, defined as hematoma, hemoptysis, or hemothorax, during the 24 h following a pleural procedure. Serious bleeding events were defined as bleeding requiring blood transfusion, respiratory support, endotracheal intubation, embolization, or surgery, or as death. RESULTS: A total of 1,124 patients was included (men, 66%; median age, 62.6 +/- 27.7 years), of whom 182 were receiving antiplatelet therapy and 942 were not. Fifteen patients experienced a bleeding event, including eight serious bleeding events. The 24-h incidence of bleeding was 3.23% (95% CI, 1.08%-5.91%) in the antiplatelet group and 0.96% (95% CI, 0.43%-1.60%) in the control group. The occurrence of bleeding events was significantly associated with antiplatelet therapy in univariate analysis (OR, 3.44; 95% CI, 1.14-9.66; P = .021) and multivariate analysis (OR, 4.13; 95% CI, 1.01-17.03; P = .044) after adjusting for demographic data and the main risk factors for bleeding. Likewise, antiplatelet therapy was significantly associated with serious bleeding in univariate analysis (OR, 8.61; 95% CI, 2.09-42.3; P = .003) and multivariate analysis (OR, 7.27; 95% CI, 1.18-56.1; P = .032) after adjusting for the number of risk factors for bleeding. INTERPRETATION: Antiplatelet therapy was associated with an increased risk of post-pleural procedure bleeding and serious bleeding. Future guidelines should take into account these results for patient safety. CHEST 2021; 159(4):1621-1629

Background The decision-making on antiplatelet drug withdrawal or continuation before performing a pleural procedure is based on the balance between the risk of bleeding associated with the antiplatelet therapy and the risk of arterial thrombosis due to its interruption. Knowledge on antiplatelet therapy-associated risk of bleeding after pleural procedures is lacking. Research Question Is the risk of bleeding associated with antiplatelet drugs increased in patients undergoing pleural procedures? Study Design and Methods We conducted a French multicenter cohort study in 19 centers. The main outcome was the occurrence of bleeding, defined as hematoma, hemoptysis, or hemothorax, during the 24 h following a pleural procedure. Serious bleeding events were defined as bleeding requiring blood transfusion, respiratory support, endotracheal intubation, embolization, or surgery, or as death. Results A total of 1,124 patients was included (men, 66%; median age, 62.6 ± 27.7 years), of whom 182 were receiving antiplatelet therapy and 942 were not. Fifteen patients experienced a bleeding event, including eight serious bleeding events. The 24-h incidence of bleeding was 3.23% (95% CI, 1.08%-5.91%) in the antiplatelet group and 0.96% (95% CI, 0.43%-1.60%) in the control group. The occurrence of bleeding events was significantly associated with antiplatelet therapy in univariate analysis (OR, 3.44; 95% CI, 1.14-9.66; P = .021) and multivariate analysis (OR, 4.13; 95% CI, 1.01-17.03; P = .044) after adjusting for demographic data and the main risk factors for bleeding. Likewise, antiplatelet therapy was significantly associated with serious bleeding in univariate analysis (OR, 8.61; 95% CI, 2.09-42.3; P = .003) and multivariate analysis (OR, 7.27; 95% CI, 1.18-56.1; P = .032) after adjusting for the number of risk factors for bleeding. Interpretation Antiplatelet therapy was associated with an increased risk of post-pleural procedure bleeding and serious bleeding. Future guidelines should take into account these results for patient safety. The decision-making on antiplatelet drug withdrawal or continuation before performing a pleural procedure is based on the balance between the risk of bleeding associated with the antiplatelet therapy and the risk of arterial thrombosis due to its interruption. Knowledge on antiplatelet therapy-associated risk of bleeding after pleural procedures is lacking. Is the risk of bleeding associated with antiplatelet drugs increased in patients undergoing pleural procedures? We conducted a French multicenter cohort study in 19 centers. The main outcome was the occurrence of bleeding, defined as hematoma, hemoptysis, or hemothorax, during the 24 h following a pleural procedure. Serious bleeding events were defined as bleeding requiring blood transfusion, respiratory support, endotracheal intubation, embolization, or surgery, or as death. A total of 1,124 patients was included (men, 66%; median age, 62.6 ± 27.7 years), of whom 182 were receiving antiplatelet therapy and 942 were not. Fifteen patients experienced a bleeding event, including eight serious bleeding events. The 24-h incidence of bleeding was 3.23% (95% CI, 1.08%-5.91%) in the antiplatelet group and 0.96% (95% CI, 0.43%-1.60%) in the control group. The occurrence of bleeding events was significantly associated with antiplatelet therapy in univariate analysis (OR, 3.44; 95% CI, 1.14-9.66; P = .021) and multivariate analysis (OR, 4.13; 95% CI, 1.01-17.03; P = .044) after adjusting for demographic data and the main risk factors for bleeding. Likewise, antiplatelet therapy was significantly associated with serious bleeding in univariate analysis (OR, 8.61; 95% CI, 2.09-42.3; P = .003) and multivariate analysis (OR, 7.27; 95% CI, 1.18-56.1; P = .032) after adjusting for the number of risk factors for bleeding. Antiplatelet therapy was associated with an increased risk of post-pleural procedure bleeding and serious bleeding. Future guidelines should take into account these results for patient safety.

Introduction: It is not known whether patients with NSCLC who are hospitalized because of cancer-related complications are liable to benefit from salvage immunotherapy. Methods: This is a multicenter observational study including five centers, which involve all patients with advanced-stage NSCLC exhibiting a level of programmed death-ligand 1 (PD-L1) greater than or equal to 1%, having been hospitalized because of complications attributed to the evolution of the NSCLC, and having started pembrolizumab treatment during their hospitalization because of a risk of clinical deterioration in the short term. The analysis measured overall survival (OS) and the rate of discharge to home at 3 months. Results: The study included 33 patients, including 28 (85%) with metastatic NSCLC and 27 (82%) under first-line treatment. The main causes of hospitalization were deterioration of the general condition (52%), acute respiratory failure (18%), and an uncontrolled infection owing to the tumor (15%). A total of 20 patients (60%) had a performance status greater than or equal to 2 and 15 (45%) were under oxygen therapy. A total of 29 patients (88%) had a PD-L1 greater than or equal to 50%. Five patients (15%) started pembrolizumab in the intensive care unit. The median OS was 4.3 months (95% confidence interval [CI]: 0.9–not reached), and the 6-month and 1-year OS rates were 41.5% (95% CI: 27.5%–62.6%) and 32.6% (95% CI: 19.0%–55.9%), respectively. The home discharge rate at 3 months was 39% (95% CI: 23%–58%). Conclusions: Even when initiated in patients hospitalized for a life-threatening clinical deterioration, pembrolizumab seems to prolong the survival of certain patients with high PD-L1 NSCLC. Prospective, controlled data are necessary to confirm these results.

Background: Little data exists regarding the performance of elastography in EBUS-TBNA. The aim of the study was to evaluate the elastography score proposed and previously published by Izumo, in particular its capacity to perfectly identify benign lymph node, and to discriminate malignant ones. Methods: This study included patients undergoing EBUS-TBNA for mediastinal lymph nodes (LN). Before LN needle aspiration, an elastography was performed which allowed a color elastogram to be superimposed on the ultrasound image. Three blinded assessors classified these elastograms into 3 types using the score published by Izumo: type 1 (predominantly not blue), type 2 (partially blue, partially not blue), or type 3 (predominantly blue). These types were then compared with pathology results. Results: A total of 217 LN (114 patients) were analyzed: histologic findings identified 97 benign LN (44.7% of the lymph nodes) and 120 malignant LN (55.3%). There were 44 elastographies (20.2%) that were classified as type 1, 90 elastographies (41.5%) classified as type 2, and 83 elastographies (38.3%) classified as type 3. Considering type 1 as benign and type 3 as malignant, sensitivity, specificity, positive predictive value, and negative predictive value were respectively 87.0%, 68.0% , 80.0% , and 77.0%. Ten (23%) of the 44 lymph nodes with a type 1 elastogram were malignant. Conclusion: Elastography does not preclude performing TBNA of the lymph nodes. It does not preclude EBUS-TBNA when a type 1 elastogram pattern is found. All lymph nodes visualized should be sampled by EBUS-TBNA, regardless of elastography pattern.

Cisplatin-induced acute kidney injury (CIA) is a serious adverse event that affects 20–40% of exposed patients, despite any implemented precaution to avoid it. The aim of this work was therefore to identify a relevant nephroprotective method for CIA. We searched Pubmed, Embase, and Web of Science from 1 January 1978 to 1 June 2018, without language restriction. All studies (observational and interventional) assessing a CIA prevention method for adults receiving at least one course of cisplatin were eligible. The primary outcome was acute nephrotoxicity, as defined by the AKI-KDIGO classification (2012). The odds ratio and corresponding 95% confidence interval were used to assess the associations. We used narrative synthesis in case of heterogeneity regarding intervention, population, or outcome. When possible, a random-effects model was used to pool studies. The heterogeneity between studies was quantified (I2), and multiple meta-regressions were carried out to identify potential confounders. Within 4520 eligible studies, 51 articles fulfilling the selection criteria were included in the review, assessing 21 different prevention methods. A meta-analysis could only be performed on the 15 observational studies concerning magnesium supplementation (1841 patients), and showed a significant nephroprotective effect for all combined grades of CIA (OR 0.24, [0.19–0.32], I2 = 0.0%). This significant nephroprotective effect was also observed for grades 2 and 3 CIA (OR 0.22, [0.14–0.33], I2 = 0.0% and OR 0.25, [0.08–0.76], I2 = 0.0%, respectively). While no method of prevention had so far demonstrated its indisputable efficacy, our results highlight the potential protective effect of magnesium supplementation on cisplatin-induced acute nephrotoxicity. This study is registered in PROSPERO, CRD42018090612.

Journal of Palliative MedicineVol. 22, No. 12 Letters to the EditorCan Studies on Early Palliative Care Be Harmful to Patient Well Being?Licia Touzet, Xavier Dhalluin, Arnaud Scherpereel, Chloé Prod'homme, Alexis Cortot, and Vincent GamblinLicia TouzetAddress correspondence to: Licia Touzet, MD, CHU Lille, Palliative Medicine, Lille 59037, France E-mail Address: licia.touzet@chru-lille.frCHU Lille, Palliative Medicine, Lille, France.Search for more papers by this author, Xavier DhalluinCHU Lille, Pneumology and Thoracic Oncology, Lille, France.Search for more papers by this author, Arnaud ScherpereelCHU Lille, Pneumology and Thoracic Oncology, Lille, France.University Lille, Inserm U1019 Institut National de la Santé et de la Recherche Médicale, Centre d'Infection et d'Immunité de Lille, Lille, France.Search for more papers by this author, Chloé Prod'hommeCHU Lille, Palliative Medicine, Lille, France.ETHICS (Experiment, Transhumanism, Human Interactions, Care, and Society) Lille Catholic University, Lille, France.Search for more papers by this author, Alexis CortotCHU Lille, Pneumology and Thoracic Oncology, Lille, France.Mécanismes de la tumorigénèse et thérapies Ciblées, University Lille, Lille, France.Search for more papers by this author, and Vincent GamblinCentre Oscar Lambret, Palliative Medicine, Lille, France.Search for more papers by this authorPublished Online:27 Nov 2019https://doi.org/10.1089/jpm.2019.0333AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Can Studies on Early Palliative Care Be Harmful to Patient Well Being?." Journal of Palliative Medicine, 22(12), p. 1488FiguresReferencesRelatedDetails Volume 22Issue 12Dec 2019 InformationCopyright 2019, Mary Ann Liebert, Inc., publishersTo cite this article:Licia Touzet, Xavier Dhalluin, Arnaud Scherpereel, Chloé Prod'homme, Alexis Cortot, and Vincent Gamblin.Can Studies on Early Palliative Care Be Harmful to Patient Well Being?.Journal of Palliative Medicine.Dec 2019.1488-1488.http://doi.org/10.1089/jpm.2019.0333Published in Volume: 22 Issue 12: November 27, 2019PDF download

ImmunotherapyVol. 10, No. 2 EditorialFree AccessImmunotherapy in relapsed mesotheliomaSolenn Brosseau, Xavier Dhalluin, Gerard Zalcman & Arnaud ScherpereelSolenn Brosseau Thoracic Oncology Department & Early Trial Clinical Research Center, Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), F-75018 Paris, France University Paris-Diderot, Paris, France, Xavier Dhalluin Pulmonary & Thoracic Oncology, Univ Lille, CHU Lille, INSERM U1019, CIIL, Institut Pasteur de Lille, F59000 Lille, France French National Network of Clinical Expert Centers for Malignant Pleural Mesothelioma Management (MESOCLIN), Lille, France, Gerard Zalcman Thoracic Oncology Department & Early Trial Clinical Research Center, Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), F-75018 Paris, France University Paris-Diderot, Paris, France U830 Inserm, 'Genetics & Biology of Cancers', Research Center-Institut Curie & Arnaud Scherpereel*Author for correspondence: E-mail Address: arnaud.scherpereel@chru-lille.fr Pulmonary & Thoracic Oncology, Univ Lille, CHU Lille, INSERM U1019, CIIL, Institut Pasteur de Lille, F59000 Lille, France French National Network of Clinical Expert Centers for Malignant Pleural Mesothelioma Management (MESOCLIN), Lille, FrancePublished Online:20 Dec 2017https://doi.org/10.2217/imt-2017-0144AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Malignant pleural mesothelioma (MPM) is a rare but aggressive loco-regional cancer arising from the parietal pleura, mainly after occupational asbestos exposure. MPM prognosis remains poor with median OS ranging from 13 to 19 months, in the 2004 pemetrexed registration trial [1], or the 2016 MAPS Phase III when combining anti-VEGF antibodies (bevacizumab) with standard first-line chemotherapy by cisplatin/pemetrexed [2], respectively. Thus, this triple combination may provide a new standard first-line treatment in patients fitted for bevacizumab. Conversely, no second-line strategy has been approved to date, except rechallenging the patients with long-lasting tumor control after first-line treatment with pemetrexed-based chemotherapy [3,4]. In fact, gemcitabine or vinorelbine are often used in this setting, but they exhibited very limited activity [5]. Moreover, almost all experimental therapies tested as second or further line treatment failed to show any substantial activity, with disease control rates (DCR) at 3 months of treatment lower than 30%, and median overall survival (mOS) ranging from 6 to 9 months [3].There is a strong rationale for immunotherapy in patients with MPM, in particular immune checkpoint inhibitors (ICI). The inflammatory phenotype of this tumor hints at the involvement of tumor-infiltrating T cells, while MPM cells express PD-L1 in a substantial proportion of cases [6–9]. Finally, PD-L1 tumor expression is correlated with worse prognosis in MPM patients [10,11].The Phase I trial KEYNOTE-028 investigating anti-PD-1 antibody (Ab) pembrolizumab had yielded promising outcome in 25 patients, with a DCR of 72%, a 5.5-month median progression-free survival (mPFS), and an mOS amounted to 18 months [12]. The Chicago Phase II trial with pembrolizumab had subsequently showed an interim analysis of the first 34 patients accrued (out of 65 planned), with a 6.2 months median PFS, DCR of 80% and mOS of 11.9 months [13]. The NivoMes study yielded very similar encouraging results in 34 patients treated by anti-PD-1 Nivolumab with a 50% 3-month DCR and a 3.6-month mPFS [14]. Finally, the anti-PD-L1 Avelumab (Javelin trial) also exhibited activity in MPM patients (any line of treatment) with DCR of 57% [15]. In contrast, in the multicenter, randomized, double-blind, placebo-controlled Phase IIB DETERMINE trial (n = 571 patients), the anti-CTLA-4 tremelimumab did not significantly improve second- and third-line MPM patients' outcome compared with placebo, yielding a 7.7 months (95%CI [6.8–8.9]) mOS versus 7.3 months (95%CI [5.9–8.7]), respectively (HR = 0.92 [95% CI: 0.76−1.12]; p = 0.41) [16].Therefore, the French Collaborative Thoracic Intergroup (IFCT) launched a randomized, noncomparative, Phase II MAPS-2/IFCT1501 trial evaluating nivolumab (N) 3 mg/kg/2 weeks (n = 63) and the combination of nivolumab and anti-CTLA-4 Ab ipilimumab (N + I) 1 mg/kg/6 weeks (n = 62), until disease progression, unacceptable toxicity or maximum 2 years. The patients with unresectable MPM and documented progression after one or two previous lines of chemotherapy including pemetrexed/platinum doublet were enrolled. In each arm, PD-L1 expression status was available in 79% of patients. The primary end point was the DCR at 12 weeks, targeting DCR ≥ 40% in each arm on the first 108 eligible patients, as centrally assessed by an independent panel. This trial was positive for both arms, with meaningful increases of DCR at 12 weeks in both N + I arm (50.0%) and N arm (44.4%) [17] compared with historical data and previous nonimmunotherapy clinical trials. Updated findings from the MAPS-2 trial were presented at the ESMO 2017 Congress [18]. According to a pooled analysis of patients with available PD-L1 status, centrally assessed PD-L1 expression ≥1% significantly correlated with objective response, and high PD-L1 expression (≥25%) correlated with both objective response and disease control. Median duration of response was 7.9 and 7.4 months in the N + I and N arms, respectively. Long-lasting remissions were observed for all mesothelioma histological subtypes. After a median follow-up of 15 months, median OS was 13.6 months 95% CI (6.7-Not reached) in the monotherapy arm, and not even reached in the combination arm. Mature mPFS results for N + I and N alone arms were 5.6 months 95%CI [3.2–8.4] and 4.0 months 95% CI [2.8–5.7], respectively, after the extended follow-up showing the maturity of such analyses. Toxicity of both regimens was generally manageable. In the combo arm, there were three deaths deemed treatment-related, due to fulminant hepatitis, encephalitis and acute kidney failure, occurring early in the study course, with no more grade 5 event thereafter, suggesting the investigators improved their caring for immune-related AEs during the study proceeding. For the majority of documented immune-related AEs, nonsignificantly higher rates were noted in the N + I arm, but most of these were grades 1 and 2.Thus, results of MAPS-2 support the recent NCCN panel decision to recommend nivolumab monotherapy or the nivolumab plus Ipilimumab combination as options for second- or third-line treatment in relapsing MPM patients. The US FDA also just granted the orphan drug status to nivolumab, and to nivolumab plus ipilimumab combination, in this setting.Based on early trials' results, pembrolizumab started to be used as off-label treatment for relapsed MPM in Switzerland. A Swiss registry assessed the real-life value of pembrolizumab in these patients in 13 cancer centers [19]. Most patients had pembrolizumab at a flat dose of 200 mg every 3 weeks. Among 48 registered patients, one and 11 achieved complete or partial responses, respectively, leading to ORR of 25%. With 13 patients achieving SD, DCR was 52%. Median PFS and OS in this cohort were 3.6 and 7.2 months, respectively. 67% of 37 patients having available tissue samples for of these were PD-L1 expression considered as negative (<5%), while 22 and 11% of these patients had PD-L1 tumor expression of 5–49% and ≥50%, respectively. The PD-L1-positive subgroups showed four- to five-fold higher ORRs compared with the PD-L1-negative cohort. The patients with PD-L1 expression ≥50% achieved a DCR of 100%. Likewise, PFS and OS improved with increasing PD-L1 expression. Seven patients (15%) discontinued pembrolizumab treatment due to AEs.The NIBIT Meso 1 trial assessed the value of anti-PD-L1 Durvalumab combined with Tremelimumab in patients as first (30%) or second (70%) line treatment [20]. Main end point, immune related ORR, was 27.5%; mOS was 15.3 months, consistent with MAPS-2 and other trials [20].Taken all together, the results of these studies accumulating more than 250 patients obviously showed significant activity of ICI, with acceptable toxicity. Thus, one could reasonably question whether the next step should be a placebo-controlled Phase III trial. However, a double-blinded, randomized, Phase III trial comparing nivolumab monotherapy versus placebo has been launched in second-line MPM patients, sponsored by the Southampton University (UK), with OS as primary end point (NCT03063450). It should ultimately confirm the efficacy of nivolumab in such setting, provided the recruitment plan of 336 patients would not be impaired by the spectacular results of MAPS2 trial, which could actually raise some ethical issues on the placebo arm. Alternatively, as previously observed for rare cancer diseases, one could defend a temporary authorization for ICI use, with prospective survey of efficacy and toxicity. A definitive authorization, could then come from the results of the ongoing company-sponsored randomized Phase III trial (Checkmate 743, NCT02890299) comparing first-line combination ICI therapy to pemetrexed–platinum doublet, which should provide enough safety data in 600 patients, as definitively assess the efficacy of ICI in MPM patients. Other clinical research design could also be favored such as anti-PD-1 association with pemetrexed-based chemotherapy, similarly as the ongoing 'Dream' trial in Australia (Cis/Pem/Durvalumab).There are presently other immunotherapies than ICI evaluated in MPM. However, to date, strategies targeting mesothelin did not show significant efficacy. Vaccines and cell or gene therapies are still under investigation after promising preliminary results. Finally, anti-PD-1 or anti-PD-L1 Ab are now evaluated in Phase I trials in combination with a antiangiogenic drugs (bevacizumab or nintedanib), or with epigenetic agents (defactinib), or even with antimesothelin immune-conjugate (Anetumab ravtansine).Although conflicting results arose from PD-L1 biomarker studies, there is currently no ideal biomarker to enable us to define the subset of patients benefiting at best from ICI. As in other cancers, the current search of other potential predictive biomarker for immunotherapy in MPM include assessments of tumor infiltration by immune cells, tumor mutational burden and neo-antigens, whole genome sequencing and gut microbiota evaluation. Finding such biomarkers is a crucial issue to counterbalance the risk of (immune) side effects and the costs of immunotherapy. Thus, malignant pleural mesothelioma research is actually at a crossroad, the breakthrough of immunotherapies and targeted therapies being close to deeply modify therapeutic strategies of this cruel disease.Financial & competing interest disclosureS Brosseau has no relevant affiliation of financial involvement with any organization or entity with a financial interest in or financial conflict with the subject or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony or patents received or pending, or royalties. X Dhalluin was invited by Astra-Zeneca at the 2017 ASCO meeting in Chicago. X Dhalluin, G Zalcman and A Scherpereel are investigators of Checkmate 743 Phase III trial sponsored by BMS. BMS purchased Nivolumab and Ipilimumab in MAPS-2 trial and French Intergroup IFCT perceived a research subvention from BMS for biomarker analyses in MAPS2 trial. G Zalcman perceived reimbursements for AACR Philadelphia meeting 2015 attendance and accommodation from BMS, and the 'Fondation AP-HP pour la Recherche' perceived a financial compensation for G Zalcman's participation to a BMS and MSD advisory boards. A Scherpereel has been also investigator in Phases I, II and III clinical trials in malignant pleural mesothelioma sponsored by Astra-Zeneca/MedImmune, Bayer, Boehringer-Ingelheim, Epizyme and Verastem, with no personal payment, all honoraria being perceived by my Institution (CHU de Lille, Clinical Research Center, France). He was invited at some recent oncology international meetings (AACR, ASCO, WCLC) by Roche, MSD and BMS. He got honoraria for participation to some scientific or advisory Boards, organized by Astra-Zeneca, BMS, Boehringer-Ingelheim, MSD and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J. Clin. Oncol. 21, 2636–2644 (2003).Crossref, Medline, CAS, Google Scholar2 Zalcman G, Mazieres J, Margery J et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, Phase III trial. Lancet 387, 1405–1414 (2016).Crossref, Medline, CAS, Google Scholar3 Scherpereel A, Astoul P, Baas P et al. 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Second or 3rd line nivolumab (nivo) or nivo plus ipilimumab in malignant pleural mesothelioma (MPM) patients: up-dated results of the IFCT-1501 MAPS1 randomized phase 2 trial. ESMO abstract LBA58_PR (2017).Crossref, Google Scholar19 Mauti LA, Klingbiel D, Schmid S et al. Pembrolizumab as second or further line treatment in relapsed malignant pleural mesothelioma; a Swiss registry. ESMO abstract 1615O (2017).Crossref, Google Scholar20 Calabro L, Morra A, Giannarelli D et al. Tremelimumab plus Durvalumab in first-or secondline mesothelioma patients: final analysis of the NIBIT-MESO-1 Study. WCLC, abstract 9202 (2017).Crossref, Google ScholarFiguresReferencesRelatedDetailsCited ByTsunami of immunotherapy reaches mesotheliomaWorld Journal of Clinical Oncology, Vol. 13, No. 4Are circulating microRNAs suitable for the early detection of malignant mesothelioma? Results from a nested case–control study11 February 2019 | BMC Research Notes, Vol. 12, No. 1Prediagnostic detection of mesothelioma by circulating calretinin and mesothelin – a case-control comparison nested into a prospective cohort of asbestos-exposed workers25 September 2018 | Scientific Reports, Vol. 8, No. 1In Silico and In Vitro Analyses of LncRNAs as Potential Regulators in the Transition from the Epithelioid to Sarcomatoid Histotype of Malignant Pleural Mesothelioma (MPM)26 April 2018 | International Journal of Molecular Sciences, Vol. 19, No. 5 Vol. 10, No. 2 Follow us on social media for the latest updates Metrics History Received 11 October 2017 Accepted 26 October 2017 Published online 20 December 2017 Published in print February 2018 Information© 2017 Future Medicine LtdFinancial & competing interest disclosureS Brosseau has no relevant affiliation of financial involvement with any organization or entity with a financial interest in or financial conflict with the subject or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony or patents received or pending, or royalties. X Dhalluin was invited by Astra-Zeneca at the 2017 ASCO meeting in Chicago. X Dhalluin, G Zalcman and A Scherpereel are investigators of Checkmate 743 Phase III trial sponsored by BMS. BMS purchased Nivolumab and Ipilimumab in MAPS-2 trial and French Intergroup IFCT perceived a research subvention from BMS for biomarker analyses in MAPS2 trial. G Zalcman perceived reimbursements for AACR Philadelphia meeting 2015 attendance and accommodation from BMS, and the 'Fondation AP-HP pour la Recherche' perceived a financial compensation for G Zalcman's participation to a BMS and MSD advisory boards. A Scherpereel has been also investigator in Phases I, II and III clinical trials in malignant pleural mesothelioma sponsored by Astra-Zeneca/MedImmune, Bayer, Boehringer-Ingelheim, Epizyme and Verastem, with no personal payment, all honoraria being perceived by my Institution (CHU de Lille, Clinical Research Center, France). He was invited at some recent oncology international meetings (AACR, ASCO, WCLC) by Roche, MSD and BMS. He got honoraria for participation to some scientific or advisory Boards, organized by Astra-Zeneca, BMS, Boehringer-Ingelheim, MSD and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

Pulmonary rehabilitation (PR) is valuable in the peri-operative setting of non-small cell lung cancer (NSCLC) patients, but not established for stage IIIB-IV disease. Previously, we showed that home-based PR is feasible and may significantly improve quality of life (QoL) and functional status of NSCLC patients treated by chemotherapy (submitted). The goal of this study was to assess the feasibility and value of home-based PR in advanced NSCLC patients treated by oral targeted therapies. Advanced NSCLC patients with oral targeted therapy were recruited in a prospective study in 2015-2016 in Lille University Hospital, France. After written informed consent, they benefited from 8 weeks home-based PR including functional exercises, psychological and nutrition support, therapeutic education. Exclusion criteria were cardiovascular contraindication to PR, symptomatic brain metastasis, bone metastasis with high fracture risk, or severe cognitive disorder. Main endpoints were adherence, inclusion rate, and cause of refusal. Secondary endpoints were PR benefits assessed by QoL scales (EORTC QLQ C 30, FACT-L, HAD); functional capacity: 6min walk test, 6 min stepper test, spirometry, respiratory muscle strength; and global condition: nutrition, treatment tolerance. This study was approved by local Ethical Committee. Among 36 screened patients the adhesion rate was 55.6% with 20 patients joining the study. Other patients refused mostly because (a) of “lack of interest for PR and they don’t want to be disturbed” (40% of cases), or (b) they considered “their physical activity already sufficient” (12%), or (c) “family constraints” (12%). Only 15 patients (41.6%) started PR (3 early deaths, 1 exclusion for intraventricular thrombosis, 1 consent withdrawal). No serious adverse event was reported but only grade 1 asthenia or musculoskeletal pain. Significant increases of FACT-L score from 84.7 to 100.2 (p=0.02) and 6 min stepper test from 140 to 195.7 steps (p=0.01) were found after PR, and preservation of patients’ autonomy reflected by stability of 6WT data. Most of other parameters exhibited a positive but not significant trend, likely due to the limited number of participants. Home-based PR is feasible and well-tolerated in patients with advanced NSCLC treated by oral targeted therapies. Significant improvements were obtained with PR based on 6ST and QoL FACT-L data. Moreover, PR was highly appreciated by patients, their relatives, and all medical teams raising our will to be able to propose PR to all our stage III-IV NSCLC patients. Currently, this study is still ongoing and multicentric, aiming at recruiting 50 extra patients.

EGFR TKIs in EGFR-mutated NSCLC patients yield heterogeneous progression-free survivals ranging from <3 months to >3 years. Early identification of lesions that are more likely to progress may provide rationale for aggressive treatment of these lesions. We questioned whether FDG-PET/CT could identify early lesions with higher risk of progression. Eighty-nine lesions from 13 Caucasian EGFR-mutated NSCLC patients treated with TKI were analyzed. Date of progression for each lesion was collected. SUVmax, Metabolic Tumor Volume (MTV), Total Lesion Glycolysis (TLG) were measured on baseline and early follow-up PET/CT performed 2-3 months later. Variations between the 2 PET/CT (ΔSUVmax, ΔMTV, ΔTLG) were calculated. Medians were used as cut-off values for statistical analysis. Risk of progression was analyzed according to PET/CT parameters and Odds Ratios (OR) were calculated. The best metabolic predictors of progression were high SUVmax (>0, i.e. incomplete visual response, OR =9.6, p<0.001), high MTV (>0, OR=8.3, p<0.001) and high TLG (>0, OR=9.6, p<0.001) on the early follow-up PET/CT. ΔSUVmax<97.6% (OR=3.9, p=0.02) was also associated with early progression, whereas ΔMTV (p=0.23) and ΔTLG (p=0.17) were not. Lesions with incomplete visual response on early follow-up FDG-PET/CT upon EGFR TKIs in EGFR-mutated NSCLC show significantly higher risk of progression. Aggressive treatment of these lesions with residual metabolic activity may be further evaluated.

Background When surgery is part of a multimodal treatment for malignant pleural mesothelioma (MPM), it is essential to combine it with a local adjuvant treatment to kill remaining microscopic tumor cells. In this goal, intrapleural photodynamic therapy (iPDT) has recently emerged as a promising technique with major impact on survival and minimum toxicity. Since the success of iPDT depends on complete and uniform illumination of the pleural cavity, we aimed at developing a new light dosimetry method based on imaging. Methods Light dosimetry was performed around the light wand9s tip, made with an endotracheal tube, a cylindrical light diffuser and an electromagnetic sensor. This illumination profile was to be integrated into an electromagnetic tracking system (EMTS), to monitor the motion of the light source inside the thorax. A human-sized intraoperative thorax phantom was created as a template. Results The profile of the light wand showed an ellipse-shaped illumination, with percentage of remaining light according to the distance from the diffuser. EMTS was able to track the wand9s movements inside the cavity with a precision of less than 1mm. The spatial coordinates of the thorax phantom were matched to its CT scan. The light dose delivered on its surfaces was calculated according to the illumination profile and displayed in real time on the CT scan 3D images. Conclusion This study shows the feasibility of this approach, suggesting a complete peroperative dosimetry in real time for iPDT in the future. Clinical validation is ongoing during clinical trials on iPDT for MPM starting in Lille University Hospital. Preliminary results of the clinical trial will be showned at the ERS meeting.

In the surgical multimodal management of malignant pleural mesothelioma, it seems crucial to proceed with an efficient local adjuvant treatment to kill residual tumor cells. Intrapleural photodynamic therapy has recently emerged as a potential candidate in this goal. In this review, we analyzed and classified 16 articles in which patients with malignant pleural mesothelioma received intrapleural photodynamic therapy after maximal surgical resection. The toxicity, effect on survival, and development of the technique were assessed. After two decades of clinical studies, intrapleural photodynamic therapy after surgical resection became a safe treatment that significantly improved the survival of patients.

Introduction: When pleural procedures (PP) are required in patients receiving antiplatelet therapy (APT), the risk of bleeding with APT continuation must be balanced against the risk of arterial thrombosis with APT withdrawal. Currently, the bleeding risk of PP in patients with APT is unknown. Objectives: The study aimed at assessing the incidence of bleeding events (BE) after PP in patients receiving APT in comparison with controls. Methods: A prospective multicentric study was conducted in 18 respiratory care departments and 11 medical intensive care units. The occurrence of BE was considered within the 24 hours following PP performance. Results: 1133 PP were recorded: 130 (12%) blind pleural biopsies, 625 (55%) chest tube insertions, 378 (33%) thoracocentesis in 185 APT+ and 948 APT- subjects. APT+ subjects were more frequently males (89% vs 64%; p=0.02) and were older (73±13 vs 58±19 years; p In the APT+ group, there was a higher prevalence of renal failure (42% vs 23%; p Conclusion: In this study, APT was associated with a 3 folds increase in PP-related bleeding risk.

We prospectively assessed the safety and cost saving of a small-bore drain based procedure for outpatient management of first episodes of primary spontaneous pneumothorax. Patients were managed by observation alone or insertion of an 8.5-F "pig-tail" drain connected to a one-way valve, according to size and clinical tolerance of the pneumothorax. All patients were reassessed after 4 h, on the first working day after discharge and on day 7. Patients still exhibiting air leak on day 4 underwent thoracoscopy. The primary end-point was complete lung re-expansion at day 7. 60 consecutive patients entered the study. 48 (80%) met the definition of large pneumothorax. The success rate was 83%. The 1-year recurrence rate was 17%. 36 (60%) patients were discharged after 4 h and 50% had full outpatient management. No severe complication was observed. The mean ± SD length of hospitalisation was 2.3 ± 3.1 days. This policy resulted in about a 40% reduction in hospital stay-related costs. The present study supports the use of a single system combined with a well-defined management algorithm including safe discharge criteria, as an alternative to manual aspiration or chest tube drainage. This approach participates in healthcare cost-savings.

Background: Combination of bevacizumab and weekly paclitaxel showed synergitic effects, anti-tumor efficacy and a good toxicity profile for patients with breast cancer but has never been evaluated in non small cell lung cancer (NSCLC). We retrospectively reviewed safety and efficacy of this regimen in metastatic non-squamous NSCLC as fourth-line therapy or beyond.Methods: Patients were identified from a prospective database. Treatment consisted in paclitaxel 80 mg/m(2) on days 1, 8 and 15 and bevacizumab 15 mg/kg on day 1, every 3 weeks until progression or unacceptable toxicity.Results: Twenty patients were included in this study. Objective response rate at first evaluation was 40% (8/20), confirmed response rate was 15% (3/20) and disease control rate was 75% (15/20). The median progression-free survival and overall survival were 6.4 months (CI95% 4.1-9) and 9.6 months (CI95% 7-19.7). Grade 3-4 adverse events included neutropenia (4/20), onycholysis (2/20) and infection (2/20). One patient died from a bowel perforation and another one died from unknown cause. Prolonged responses were observed in a patient who had received bevacizumab as part of first-line chemotherapy and in another one who harbored an ALK rearrangement.Conclusions: In our experience, combination of bevacizumab and weekly paclitaxel exhibited acceptable toxicity and had encouraging anti-tumor efficacy as fourth-line treatment or beyond for non-squamous NSCLC patients, supporting further evaluation in larger prospective studies. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

e18066 Background: Paclitaxel (P) and bevacizumab (B) showed synergistic antitumor efficacy in preclinical models. In combination with carboplatin, PB prolonged progression-free survival (PFS) and overall survival (OS) in selected metastatic non-squamous Non Small Cell Lung Cancer (NSCLC) patients compared to carboplatin and paclitaxel. Currently, there are no standard treatments beyond third-line therapy in NSCLC. We sought to determine the efficacy of weekly paclitaxel and bevacizumab (wPB) in non-squamous NSCLC as fourth-line therapy or beyond. Methods: we retrospectively reviewed patients with metastatic non-squamous NSCLC who have been treated with wPB in our institution. Patients were identified from a prospective database. Treatment consisted in P 80mg/m² on days 1, 8, 15 and B 15mg/kg on day 1, every 3 weeks until progression or unacceptable toxicity. Patients were evaluated every 3 cycles. PFS and OS were calculated from the date of initiation of wPB and analyzed using the Kaplan-Meier method. Results: Twenty patients received at least one cycle of wPB between 2008 and 2011. All patients received wPB as fourth-line treatment or beyond. Eight patients (40%) had a partial response, 7 patients (35%) had stable disease and 5 patients (25%) had progressive disease. Grade 3-4 adverse events included neutropenia (20%), onycholysis (10%), infection (10%), pulmonary haemorrhage (5%), neuropathy (5%) and hypertension (5%). One patient died from a bowel perforation following second cycle of wPB. The median PFS was 6.4 months (CI95% 4.1-9) and the median OS was 9.6 months (CI95% 7-19.7). One patient who previously received bevacizumab as part of first-line chemotherapy and another patient harbouring an ALK rearrangement benefited from wPB during more than 8 months and 18 months, respectively. Conclusions: In our experience, wPB exhibited acceptable toxicity and had encouraging anti-tumor efficacy as fourth-line treatment or beyond in non-squamous NSCLC patients, supporting further evaluation in larger prospective studies.

Previously considered to be rare, malignant pleural mesothelioma (MPM) is a highly aggressive tumor with an increasing incidence linked to asbestos exposure, its main etiological factor. MPM is also a very important issue because patients have usually a short survival (median <12 months) despite current treatments. Moreover an optimal treatment for MPM is not defined yet, even if ERS/ESTS experts recently provided clear and up-to-date guidelines on MPM management. These guidelines on chemotherapy and radiotherapy for mesothelioma, as well as new therapeutic developments, are presented in this chapter.