Diagnostic Value of Computed Tomography Imaging Features in Malignant Pleural Mesothelioma.

BACKGROUND: Medical history, thoracentesis, and imaging features are usually the first steps in the investigation of a possible malignant pleural effusion (MPE). Unfortunately, the diagnostic yield of thoracentesis in this situation is suboptimal even if the procedure is repeated, especially in the context of malignant pleural mesothelioma (MPM). The next step for confirming the diagnosis, if clinically appropriate, is thoracoscopy, but not all patients are fit to undergo this procedure, so the diagnosis is then based on the medical history and imaging features only. OBJECTIVES: Our objective was to evaluate the diagnostic value of the medical history and imaging features in MPM. METHODS: We reviewed the imaging and medical charts of 92 patients with a final diagnosis of MPE included in our prospective medical thoracoscopy database. The clinical characteristics and imaging features of patients with primary MPE were compared with those of patients with secondary MPE. RESULTS: Male sex (82 vs. 59%, p = 0.02), asbestos exposure (58 vs. 10%, p < 0.001), and mediastinal (68 vs. 33%, p = 0.04), diaphragmatic (75 vs. 31%, p = 0.001) and circumferential pleural thickening (55 vs. 19% p = 0.001) were significantly more frequent in MPM patients. In a multivariate linear regression model, only asbestos exposure (OR 11.2; 95% CI 3.4-36.9) and circumferential pleural thickening (OR 4.7; 95% CI 1.6-13.9) were significantly associated with a diagnosis of MPM. CONCLUSION: In situations where it is impossible to obtain adequate pleural samples to differentiate MPM from a secondary pleural malignancy, the combination of circumferential pleural thickening and a history of asbestos exposure may be sufficient to make a clinical diagnosis.

Safety and Efficacy of a Fully Covered Self-Expandable Metallic Stent in Benign Airway Stenosis.

BACKGROUND: The use of self-expandable metallic stents (SEMS) in benign airway disease was the object of a boxed warning from the United States Food and Drug Administration in 2005 due to the risk of stent-related complications and difficulties associated with their removal. Third-generation fully covered SEMS have been commercialized since this warning and theoretically should not present the same difficulties associated with removal as they cannot become embedded in the airway mucosa. OBJECTIVES: We aimed to examine the safety and efficacy of a specific third-generation SEMS, the Silmet stent. METHODS: We reviewed the records of all patients treated for benign airway stenosis with third-generation Silmet SEMS from January 2011 to December 2015 at the North Hospital of Marseilles, France. RESULTS: Forty SEMS were inserted in 30 patients over this period. Twenty (50.0%) stents were removed because of stent-related complications after a median of 77.0 ± 96.6 days (migration 32.5%, granulation tissue formation 7.5%, subjective intolerance 5.0%, mucus plugging 2.5%, laryngeal edema 2.5%). There were no cases of stent-related mortality. All complications were managed successfully endoscopically. Thirty-six stents (90.0%) were removed successfully after a median of 122.0 ± 113.2 days without any complications. The clinical success rate of stent treatment was 40.7%. CONCLUSION: Third-generation SEMS are a safe treatment option for complex benign airway stenosis, but complications requiring stent removal are frequent. Further studies are needed to compare the performance of third-generation SEMS and silicone stents in benign airway stenosis.

A phase Ia/Ib clinical trial of metronomic chemotherapy based on a mathematical model of oral vinorelbine in metastatic non-small cell lung cancer and malignant pleural mesothelioma: rationale and study protocol.

BACKGROUND: Metronomic oral vinorelbine is effective in metastatic NSCLC and malignant pleural mesothelioma, but all the studies published thus far were based upon a variety of empirical and possibly suboptimal schedules, with inconsistent results. Mathematical modelling showed by simulation that a new metronomic protocol could lead to a better safety and efficacy profile. DESIGN: This phase Ia/Ib trial was designed to confirm safety (phase Ia) and evaluate efficacy (phase Ib) of a new metronomic oral vinorelbine schedule. Patients with metastatic NSCLC or malignant pleural mesothelioma in whom standard treatments failed and who exhibited ECOG performance status 0-2 and adequate organ function will be eligible. Our mathematical PK-PD model suggested an alternative weekly D1, D2 and D4 schedule (named Vinorelbine Theoretical Protocol) with a respective dose of 60, 30 and 60 mg. Trial recruitment will be two-staged, as 12 patients are planned to participate in phase Ia to confirm safety and consolidate the calibration of the model parameters. Depending on the phase Ia results and after a favourable decision from a consultative committee, the extension phase (phase Ib) will be an efficacy study including 20 patients who will receive the Optimal Vinorelbine Theoretical Protocol. The primary endpoint is the tolerance (assessed by CTC v4.0) for the phase Ia and the objective response according to RECIST 1.1 for phase Ib. An ancillary study on circulating angiogenesis biomarkers will be a subproject of the trial. DISCUSSION: This ongoing trial is the first to prospectively test a mathematically optimized schedule in metronomic chemotherapy. As such, this trial can be considered as a proof-of-concept study demonstrating the feasibility to run a computational-driven protocol to ensure an optimal efficacy/toxicity balance in patients with cancer. TRIAL REGISTRATION: EudraCT N°: 2015-000138-31.

Epidemiology of tobacco use in dialysis patients in France and survey of nephrologists' involvement in counseling on tobacco discontinuation.

BACKGROUND: Tobacco smoking is an independent risk factor for chronic kidney disease (CKD) and increases morbidity and mortality in CKD patients. The primary objective of the study was to investigate the epidemiology of smoking in patients undergoing maintenance dialysis in France. A second objective was to assess the involvement of nephrologists in supporting patients for smoking cessation. METHODS: Data on the smoking history of prevalent patients on maintenance dialysis in France between 2010 and 2020 were obtained from the REIN database (Renal Epidemiology and Information Network), updated by all French nephrology and dialysis centers. As for the support to smoking discontinuation, a questionnaire on smoking cessation assistance was sent to all members of the French Society of Nephrology, Dialysis and Transplantation (SFNDT). RESULTS: The proportion of current smokers among patients on maintenance dialysis was 10.4% in 2010, 11.2% in 2015 and 11.6% in 2020. A total of 228 nephrologists among the 790 members of the SFNDT participated in the survey (28.9%). Most respondents were women (57.3%), worked at a public hospital (61.1%), were under 40 years of age (51.3%) and had no history of smoking (60.8%). The majority reported asking patients about their smoking status and offering brief advice. Among respondents, 72.8% offered help with smoking cessation, 46.3% referred their smoking patients to a tobacco specialist, 51.8% reported prescribing drugs to quit tobacco, and 81.6% requested further training in how to support patients for smoking cessation. CONCLUSION: Smoking cessation training for nephrologists and dedicated programs for patients in nephrology units could improve our practices and decrease the high prevalence of smoking in patients with ESKD.

Awake prone positioning for hypoxaemic respiratory failure: past, COVID-19 and perspectives.

Prone positioning reduces mortality in the management of intubated patients with moderate-to-severe acute respiratory distress syndrome. It allows improvement in oxygenation by improving ventilation/perfusion ratio mismatching.Because of its positive physiological effects, prone positioning has also been tested in non-intubated, spontaneously breathing patients, or "awake" prone positioning. This review provides an update on awake prone positioning for hypoxaemic respiratory failure, in both coronavirus disease 2019 (COVID-19) and non-COVID-19 patients. In non-COVID-19 acute respiratory failure, studies are limited to a few small nonrandomised studies and involved patients with different diseases. However, results have been appealing with regard to oxygenation improvement, especially when combined with noninvasive ventilation or high-flow nasal cannula.The recent COVID-19 pandemic has led to a major increase in hospitalisations for acute respiratory failure. Awake prone positioning has been used with the aim to prevent intensive care unit admission and mechanical ventilation. Prone positioning in conscious, non-intubated COVID-19 patients is used in emergency departments, medical wards and intensive care units.Several trials reported an improvement in oxygenation and respiratory rate during prone positioning, but impacts on clinical outcomes, particularly on intubation rates and survival, remain unclear. Tolerance of prolonged prone positioning is an issue. Larger controlled, randomised studies are underway to provide results concerning clinical benefit and define optimised prone positioning regimens.

[Preventing tobacco sales to minors]. / Pour qu'acheter du tabac ne soit plus un jeu d'enfant !

Preventing tobacco sales to minors. Since 2009, selling tobacco products in France to minors less than 18 years of age is forbidden by law, but this law is poorly enforced even though tobacco use mainly begins at adolescence. The aim of this study was to identify measures implemented by foreign countries leading to a better enforcement of tobacco sale ban to minors. The main measures are: organizing tobacco retailers training programs; using automated age-verification systems; requiring a valid photo ID from anyone who looks under the age of 25; developing communication campaigns directed to the general public in order to explain and promote age control for customers. Furthermore, in all studied countries, the only effective controls rely on "mystery shopping" with underage shoppers accompanied by dedicated inspectors, attempting to purchase tobacco products. In case of non-compliance with the law, these controls must lead to dissuasive financial as well as administrative penalties. In all studied countries, an efficient implementation of these measures has led to reduced tobacco sales to minors, and thus contributed to bring down underage smoking.

Pour qu'acheter du tabac ne soit plus un jeu d'enfant ! En France, la vente de tabac est interdite aux moins de 18 ans depuis 2009, mais la loi est peu respectée alors que la plupart des nouveaux fumeurs commencent leur consommation à l'adolescence. Cette étude a pour objectif d'identifier les mesures mises en œuvre par des pays tiers permettant une meilleure application de l'interdiction de vente de tabac aux mineurs. Parmi ces mesures : la formation des détaillants de tabac ; l'utilisation dans les points de vente de systèmes de vérification automatisée de l'âge ; une vérification de l'âge de toute personne ayant l'apparence d'avoir moins de 25 ans ; le développement de campagnes de communication grand public pour expliquer et promouvoir le contrôle de l'âge des clients. Par ailleurs, les inspections « clients mystères ¼ apparaissent dans tous les pays étudiés comme le seul moyen de contrôle efficace. En cas de non-respect de la loi, ces inspections doivent donner lieu à des sanctions réelles et dissuasives, financières et administratives. Dans les pays étudiés, la mise en place conjointe de ces différentes mesures a permis de réduire la vente de tabac aux mineurs et de contribuer ainsi à diminuer le tabagisme des adolescents.

Nocardiosis in the south of France over a 10-years period, 2004-2014.

BACKGROUND: Nocardiosis is a rare disease with polymorphic presentations. The epidemiology and clinical presentation could change with the increasing number of immunocompromised patients. METHODS: The medical records and microbiological data of patients affected by nocardiosis and treated at the university hospitals of Marseille between 2004 and 2014 were analyzed retrospectively. RESULTS: The cases of 34 patients infected by Nocardia spp during this period were analyzed. The main underlying conditions were transplantation (n=15), malignancy (n=9), cystic fibrosis (n=4), and immune disease (n=3); no immunodeficiency condition was observed for three patients. No case of AIDS was observed. At diagnosis, 61.8% had received steroids for over 3 months. Four clinical presentations were identified, depending on the underlying condition: the disseminated form (50.0%) and the visceral isolated form (26.5%) in severely immunocompromised patients, the bronchial form (14.7%) in patients with chronic lung disease, and the cutaneous isolated form (8.8%) in immunocompetent patients. Nocardia farcinica was the main species identified (26.5%). Trimethoprim-sulfamethoxazole was prescribed in 68.0% of patients, and 38.0% underwent surgery. Mortality was 11.7%, and the patients who died had disseminated or visceral nocardiosis. CONCLUSIONS: The clinical presentation and outcome of nocardiosis depend on the patient's initial immune status and underlying pulmonary condition. Severe forms were all iatrogenic, occurring after treatments altering the immune system.

Mathematical modeling for Phase I cancer trials: A study of metronomic vinorelbine for advanced non-small cell lung cancer (NSCLC) and mesothelioma patients.

INTRODUCTION: Using mathematical modelling allows to select a treatment's regimen across infinite possibilities. Here, we report the phase I assessment of a new schedule for metronomic vinorelbine in treating refractory advanced NSCLC and mesothelioma patients. RESULTS: Overall, 13 patients were screened and 12 were treated (50% male, median age: 68yrs), including 9 NSCLC patients. All patients received at least one week (3 doses) of treatment. At data cut-off, the median length of treatment was 6.5 weeks (1-32+). All the patients presented with at least one adverse event (AE) and six patients with a severe AE (SAE). One partial response and 5 stable diseases were observed. The median OS was 6.4 months (95% CI, 4.8 to 12 months). The median and mean vinorelbine's AUC were 122 ng/ml*h and 159 ng/ml*h, respectively, with the higher plasmatic vinorelbine exposure associated with the best ORR (difference of AUC comparison between responders and non-responders, p-value 0.017). MATERIALS AND METHODS: The mathematical modelling determined the administration of vinorelbine, 60 mg on Day 1, 30 mg on Day 2 and 60 mg on Day 4 weekly until progression, as the best schedule. Advanced NSCLC or mesothelioma patients progressing after standard treatment were eligible for the trial. NCT02555007. CONCLUSIONS: Responses with acceptable safety profile were observed in heavily pretreated NSCLC and mesothelioma patients using oral vinorelbine at this metronomic dosage based on a mathematic modeling. This study demonstrates the feasibility of this new type of approach, as mathematical modeling may help to rationally decide the better regimen to be clinically tested across infinite possibilities.

Metronomics chemotherapy: time for computational decision support.

Over the last decade, metronomic chemotherapy has been increasingly considered as an attractive strategy for treating cancer in a variety of settings. Beside pharmaco-economic considerations making metronomics a unique opportunity in low- or middle-income countries, revisiting dosing schedules using continuous low doses of cytotoxics should theoretically permit to reduce the incidence of treatment-related toxicities, while offering unexpected novel mechanisms of actions such as antiangiogenic or immuno-stimulating properties. Consequently, a number of clinical trials sought to evaluate to what extent switching to metronomic schedules could actually impact indeed on the efficacy/toxicity balance of a variety of anticancer drugs in both adults and pediatric oncology. Vinorelbine is a vinca-alcaloïd that remains the backbone of several regimens to treat patients with metastatic breast cancer or non-small cell lung cancer. Additionally, vinorelbine is widely used to treat a variety of solid tumors in children such as rhabdomyosarcomas and acute leukemia. The recent approval of an oral formulation of vinorelbine has open the way to developing alternative metronomic schedules with this drug. Consequently, a number of clinical trials investigating on metronomic vinorelbine have been performed over the last few years, with seemingly inconsistent results to date. Of note, all the studies published thus far were based upon empirical determination of the metronomic schedule, both in terms of doses, drug-free intervals and repartition of the administrations throughout time. Because the very concept of «low, repeated doses with little or no drug-free interval¼ covers numerous possible combinations, determining the optimal protocol using traditional under-powered empirical design looks like an unreachable goal. In this context, mathematical modeling offers invaluable in silico tools to help determining the optimal metronomic schedule among a variety of possibilities. This review covers the latest clinical trials investigating on metronomic vinorelbine and proposes alternative strategies for developing computational decision support to make metronomics a scientific-grounded strategy, rather than an empirical practice at the bedside. In particular, mathematical simulations using an original pharmacokinetics/pharmacodynamics constraint models provide clues for exploring new paths in the way metronomic vinorelbine could be scheduled in patients with lung cancer.

"Dancing eye syndrome" secondary to opsoclonus-myoclonus syndrome in small-cell lung cancer.

Among paraneoplastic neurologic disorders (PND), opsoclonus-myoclonus syndrome, so-called "dancing eye syndrome," is a rare disorder combining multivectorial eye movements, involuntary multifocal myoclonus, and cerebellar ataxia. Although several paraneoplastic antibodies against postsynaptic or cell-surface antigens have been reported, usually most patients are serum antibody negative. We report a 65-year-old patient with opsoclonus-myoclonus syndrome revealing a small-cell lung carcinoma. If serologic antineuronal anti-body screening was negative, autoantibodies against glutamic acid decarboxylase (anti-GAD) were positive. Despite the specific anticancer treatment and high dose corticosteroids, the patient developed a severe and progressive encephalopathy and died 10 days later.