[Translation into French and republication of: "Recurrent venous thromboembolism in anticoagulated cancer patients: diagnosis and treatment"]. / Traduction et republication de : « Maladie thromboembolique veineuse récidivante chez les patients cancéreux anticoagulés : diagnostic et traitement ¼.

Patients with cancer are at significantly increased risk of venous thromboembolism (VTE), due both to the impact of malignant disease itself and to the impact of certain anticancer drugs on haemostasis. This is true both for first episode venous thromboembolism and recurrence. The diagnosis and management of VTE recurrence in patients with cancer poses particular challenges, and these are reviewed in the present article, based on a systematic review of the relevant scientific literature published over the last decade. Furthermore, it is uncertain whether diagnostic algorithms for venous thromboembolism, validated principally in untreated non-cancer patients, are also valid in anticoagulated cancer patients: the available data suggests that clinical decision rules and D-dimer testing perform less well in this clinical setting. In patients with cancer, computed tomography pulmonary angiography and venous ultrasound appear to be the most reliable diagnostic tools for diagnosis of pulmonary embolism and deep vein thrombosis respectively. Options for treatment of venous thromboembolism include low molecular weight heparins (at a therapeutic dose or an increased dose), fondaparinux or oral direct factor Xa inhibitors. The choice of treatment should take into account the nature (pulmonary embolism or VTE) and severity of the recurrent event, the associated bleeding risk, the current anticoagulant treatment (type, dose, adherence and possible drug-drug interactions) and cancer progression.

[Translation into French and republication of: "Management of cancer-associated thromboembolism in vulnerable population"]. / Traduction et republication de : « Prise en charge de la maladie thromboembolique veineuse associée au cancer chez les populations vulnérables ¼.

Although all patients with cancer-associated thrombosis (CAT) have a high morbidity and mortality risk, certain groups of patients are particularly vulnerable. This may expose the patient to an increased risk of thrombotic recurrence or bleeding (or both), as the benefit-risk ratio of anticoagulant treatment may be modified. Treatment thus needs to be chosen with care. Such vulnerable groups include older patients, patients with renal impairment or thrombocytopenia, and underweight and obese patients. However, these patient groups are poorly represented in clinical trials, limiting the available data on which treatment decisions can be based. Meta-analysis of data from randomised clinical trials suggests that the relative treatment effect of direct oral factor Xa inhibitors (DXIs) and low molecular weight heparin (LMWH) with respect to major bleeding could be affected by advanced age. No evidence was obtained for a change in the relative risk-benefit profile of DXIs compared to LMWH in patients with renal impairment or of low body weight. The available, albeit limited, data do not support restricting the use of DXIs in patients with TAC on the basis of renal impairment or low body weight. In older patients, age is not itself a critical factor for choice of treatment, but frailty is such a factor. Patients over 70 years of age with CAT should undergo a systematic frailty evaluation before choosing treatment and modifiable bleeding risk factors should be addressed. In patients with renal impairment, creatine clearance should be assessed and monitored regularly thereafter. In patients with an eGFR less than 30mL/min/1.72m2, the anticoagulant treatment may need to be adapted. Similarly, platelet count should be assessed prior to treatment and monitored regularly. In patients with grade 3-4, thrombocytopenia (less than 50,000platelets/µL) treatment with a LMWH at a reduced dose should be considered. For patients with CAT and low body weight, standard anticoagulant treatment recommendations are appropriate, whereas in obese patients, apixaban may be preferred.

[Translation into French and republication of: "Anticoagulant treatment of cancer-associated thromboembolism"]. / Traduction et republication de : « Traitement anticoagulant de la maladie veineuse thromboembolique associée au cancer ¼.

Venous thromboembolism (VTE) is a frequent and potentially fatal complication in patients with cancer. During the initial period after the thromboembolic event, a patient receiving anticoagulant treatment is exposed both to a risk of VTE recurrence and also to an elevated bleeding risk conferred by the treatment. For this reason, the choice of anticoagulant is critical. The choice should take into account patient-related factors (such as functional status, age, body mass index, platelet count and renal function), VTE-related factors (such as severity or site), cancer-related factors (such as activity and progression) and treatment related factors (such as drug-drug interactions), which all potentially influence bleeding risk, and patient preference. These should be evaluated carefully for each patient during a multidisciplinary team meeting. For most patients, apixaban or a low molecular-weight heparin is the most appropriate initial choice for anticoagulant treatment. Such treatment should be offered to all patients with active cancer for at least 6months. The patient and treatment should be re-evaluated regularly, and anticoagulant treatment changed when necessary. Continued anticoagulant treatment beyond 6months is justified if the cancer remains active or if the patient experienced recurrence of VTE in the first 6months. In other cases, the interest of continued anticoagulant treatment may be considered on an individual patient basis in collaboration with oncologists.

[Approaching patient experience following pulmonary embolism: A systematic review]. / Approche de l'expérience du patient suite à une embolie pulmonaire : une revue systématique de la littérature.

INTRODUCTION: Pulmonary embolism (PE) is the major complication of thromboembolic disease. While a few qualitative studies have explored patient experience after PE, to our knowledge no literature review is available to date. The aim of this work was to explore patient experience after a PE episode through a systematic review of the literature comprising: patient experience, clinicians' perception of the patients' attitude and knowledge, and the patients' perception of VTE prevention strategies. METHODS: A search of PubMed, Web of science, Cochrane and EMBASE databases. The search was conducted without filters. Search results were combined and duplicates were removed. The selection was blinded by two independent researchers using the Rayyan application. RESULTS: Fifty studies were assessed for quality and 23 were included. Individual semi-structured interviews and focus groups were widely used to explore patient experience after a PE episode. Patients described deterioration in their quality of life, their psychological state and an initial feeling of carer abandonment. The trends observed appear to be more pronounced in patients with an episode characterized as unprovoked. CONCLUSION: These preliminary results call for further longitudinal studies, the objective being to better understand the evolution of these factors in the short and long terms.

Adult breast, lung, pancreatic, upper and lower gastrointestinal cancer patients with hospitalized venous thromboembolism in the national French hospital discharge database.

BACKGROUND: Venous thromboembolism (VTE) and cancer are strongly associated. In France, evidence on patients with pancreatic, upper GI [gastrointestinal], lower GI, lung, or breast cancer-associated VTE and their hospital management is limited. The aims of this study were to provide data on the number of hospitalized VTE events among cancer patients, the patients' characteristics, and their hospital management to estimate the burden of disease and the hospital burden of cancer-related VTE and to provide guidance on research. METHODS: This longitudinal, observational, and retrospective study was based on the comprehensive hospital discharge database (PMSI). Adult patients (≥ 18 years old) hospitalized with a cancer of interest in 2016 and hospitalized (within 2 years with VTE (captured a as a principal, related, or significant associated diagnosis) were included in the study. RESULTS: We identified 340,946 cancer patients, of which 7.2% (24,433 patients) were hospitalized with VTE. The proportions of hospitalized VTE were 14.6% (3,237) for patients with pancreatic cancer, 11.2% (8,339) for lung cancer, 9.9% (2,232) for upper GI cancer, 6.7% (7,011) for lower GI cancer, and 3.1% (3,614) for breast cancer. Around two thirds of cancer patients with a hospitalized VTE had active cancer (with metastases and/or receiving chemotherapy during the six months prior to the index date): from 62% of patients with pancreatic cancer to 72% with breast cancer. Around a third of patients were admitted to the hospital through the emergency room, up to 3% of patients stayed in an intensive care unit. The average length of stay ranged from 10 (breast cancer) to 15 days (upper GI cancer). Nine (lower GI cancer) to 18% (pancreatic cancer) of patients died during the VTE hospital stay. CONCLUSIONS: The burden of cancer-associated VTE is substantial, both in terms of the number of patients affected and in the hospital use. These findings offer guidance on future research on VTE prophylaxis in a very high-risk population, particularly in patients with active cancer.

Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

[Patient expectations in asthma care]. / Attentes des patients asthmatiques vis-à-vis de leur prise en charge.

Asthma, a common chronic disease characterized by variable levels of severity, requires patient-centered management to achieve the best health outcomes. Studies have highlighted the gap between consensus management recommendations and patient goals, which represent a potential source of therapeutic wandering and of poor compliance. Patient expectations are continually evolving and are dependent on knowledge, feelings and individual experience. From this perspective, listening carefully to patients and caregivers makes it easier to exchange views and define common goals. The active participation of patients at all levels of decision-making and transmission of information may improve asthma control and other quality of life parameters.

Comparison of the cardio-respiratory response of a training session on cycloergometer or treadmill versus an Adapted Physical Activity session on Nintendo Wii, in patients with chronic respiratory disease.

OBJECTIVES: During a pulmonary rehabilitation program (PRP), patients frequently report that the classically proposed activities (as cycloergometer or treadmill) are not playful. The goal of adapted physical activities is to maintain physical activity that is more playful for patients. The Nintendo Wii Gaming Console allows a playful physical activity. However, it seems important to know if this tool allows physical activity with an effective cardiorespiratory effect. The objective was to compare the cardiorespiratory response of a 30-minute training session on cycloergometer (C) and treadmill (T) versus a 30-minute training session with Wii. METHODS: Patients admitted to the PR unit of Brest University Hospital (France) were eligible for this randomized study if they had a chronic pulmonary disease. The endpoints were heart rate (HR), pulse oxymetry, dyspnea, lower limb penibility and pleasure felt. RESULTS: Twenty patients were prospectively included. HR was significantly higher at the end of the Wii session in comparison with C session (P=0.001); there was no significant difference in HR between Wii and T. We found no significant difference for dyspnea and lower limb penibility between Wii and C (respectively P=0.8 and P=0.7) and between Wii and T (respectively P=0.96 and P=0.5). The pleasure felt was significantly greater during Wii compared to C and T (respectively P=0.001 and P=0.001). CONCLUSIONS: Exercise training using Wii with identifiable games require higher HR at the end of the session compared to C and a similar cardiorespiratory response compared to T with the same dyspnea and lower limb exertion and with a pleasure felt significantly higher. Wii can be used for exercise training during PRP.

Outcomes in patients with acute pulmonary embolism and patent foramen ovale: Findings from the RIETE registry.

INTRODUCTION: An increased risk of ischemic stroke in patients with acute pulmonary embolism (PE) and patent foramen ovale (PFO) was reported but few data exist regarding prognostic outcomes of those patients. MATERIAL AND METHODS: Using data in the RIETE registry, we compared the characteristics, therapeutic approaches and outcomes of patients with PE according to the presence or absence of PFO. RESULTS: From August 2016 to January 2020, 4148 patients with acute PE were enrolled. Of these, 2775 (67%) had no transthoracic echocardiogram (TTE), 993 (24%) underwent TTE but had no reported results on PFO. Among the remaining 380 patients, 287 (74%) did not have PFO and 93 (26%) had PFO. Patients with PFO were more likely to have chronic heart failure, prior myocardial infarction or ischemic stroke than those without PFO. Patients with PFO had a higher rate of subsequent ischemic stroke than those without PFO (hazard ratio (HR): 9.28; 95% CI: 1.83-69.1), than those with TTE but no data on PFO (HR: 10.1; 95% CI: 2.56-42.4) or without TTE (HR: 9.78; 95% CI: 3.02-28.4). On multivariable analysis, patients with PFO were at increased risk for subsequent ischemic stroke than those without PFO (HR: 8.96; 95% CI: 1.68-47.7). CONCLUSIONS: PFO was searched in a minority of patients with an acute PE in real life setting. Subject to possible selection and measurement biases, our results confirmed a higher risk of ischemic stroke in PE patients with PFO compared to those without PFO. This association warrants further investigation before determining the best therapeutic option in patients with acute PE and concomitant PFO.

Prioritising outcomes for evaluating eosinophil-guided corticosteroid therapy among patients with acute COPD exacerbations requiring hospitalisation: a Delphi consensus study.

OBJECTIVES: Presently, those outcomes that should be prioritised for chronic obstructive pulmonary disease (COPD) exacerbation studies remain unclear. In order to coordinate multicentre studies on eosinophilia-driven corticosteroid therapy for patients hospitalised for acute exacerbation of COPD (AECOPD), we aimed to find consensus among experts in the domain regarding the prioritisation of outcomes. DESIGN: A modified Delphi study was proposed to recognised COPD experts. Two brainstorming questionnaires were used to collect potential outcomes. Four subsequent rounds of questionnaires were used to rank items according to a six-point Likert scale for their importance in the protocol, as well as for being the primary outcome. Priority outcome criteria were predefined as those for which ≥70% of experts indicated that the outcome was essential for interpreting study results. SETTING: COPD exacerbation management in France. PARTICIPANTS: 34 experts recommended by the French Language Pulmonology Society were invited to participate. Of the latter, 21 experts participated in brainstorming, and 19 participated in all four ranking rounds. RESULTS: 105 outcomes were ranked. Two achieved consensus as candidate primary outcomes: (1) treatment failure defined as death from any cause or the need for intubation and mechanical ventilation, readmission because of COPD or intensification of pharmacologic therapy, and (2) the time required to meet predefined discharge criteria. The 10 secondary priority outcomes included survival, time with no sign of improvement, episodes of hospitalisation, exacerbation, pneumonia, mechanical or non-invasive ventilation and oxygen use, as well as comorbidities during the initial hospitalisation. CONCLUSIONS: This Delphi consensus project generated and prioritised a great many outcomes, documenting current expert views concerning a diversity of COPD endpoints. Among the latter, 12 reached consensus as priority outcomes for evaluating the efficacy of eosinophil-driven corticosteroid therapy in AECOPD inpatients. STUDY REGISTRATION: The eo-Delphi project/protocol was registered on 23 January 2018 at https://osf.io/4ahqw/.

[Diagnostic and therapeutic management of venous thromboembolic disease in obese patients]. / Prise en charge diagnostique et thérapeutique de la maladie veineuse thromboembolique chez le patient obèse.

Despite the high proportion of obese patients this population remains understudied in the field of venous thromboembolic disease (VTE). Obesity is a risk factor for pulmonary embolism and/or deep vein thrombosis, especially when it is associated with other risk factors for VTE. Currently there is no validated diagnostic algorithm for VTE in the population of obese patients. Moreover, imaging examinations can be of poor quality and inconclusive. In the prevention of VTE, data concerning obese patients are mainly based on low-level studies. Apart from the context of bariatric surgery, an adjustment of heparin doses according to the weight of the patient is proposed only on a case-by-case basis. According to the current guidelines, therapeutic fixed dose oral anticoagulants should not be prescribed for patients with weights exceeding 120kg or a body mass index>40kg/m2. Heparin doses should be weight adjusted and monitored with anti-Xa activity. Anti vitamin K can be prescribed but require INR monitoring. Therefore, new studies specifically dedicated to obese patients are required in the field of VTE for better diagnostic and therapeutic management.

[Evolution of the costs and management of lung cancer between 2004 and 2014]. / Évolution des coûts et de la prise en charge du cancer pulmonaire entre 2004 et 2014.

BACKGROUND: Given its morbidity and mortality, lung cancer is a major public health issue. In recent years, it has benefited from several therapeutic innovations. The objective of this study was to compare, over two distinct periods of ten years, the impact on survival and the costs of lung cancer management. METHODS: The monocentric study assessed survival and the direct costs of lung cancer management of patients diagnosed in Brest University hospital in 2004 and in 2014. RESULTS: The analysis included 142 patients in 2004 and 156 in 2014. Most patients were smokers (72%), metastatic at diagnosis (60%) both in 2004 and in 2014. Median survival was not significantly improved between the 2 periods (9.7 versus 10.9 months), but there was a significant increase in the average cost of care per patient (€ 17,063 vs. € 29,264, P=<0.0001) between 2004 and 2014. CONCLUSION: The significant increase in treatment costs did not translate into an improvement in the survival of patients with lung cancer between 2004 and 2014.

Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation.

Factor V serves an important role in the regulation of blood coagulation. The rs6025 (R534Q) and rs4524 (K858R) polymorphisms in the F5 gene, are known to influence the risk of venous thrombosis. While the rare Q534 (factor V Leiden) allele is associated with an increased risk of venous thrombosis, the minor R858 allele is associated with a lower risk of disease. However, no study has deeply examined the cumulative impact of these two variations on venous thrombosis risk. We study the association of these polymorphisms with the risk of venous thrombosis in 4 French case-control populations comprising 3719 patients and 4086 controls. We demonstrate that the Q534 allele has a dominant effect over R858. Besides, we show that in individuals not carrying the Q534 allele, the protective effect of the R858 allele acts in a dominant mode. Thrombin generation-based normalized activated protein C sensitivity ratio was lower in the 858R/R homozygotes than in the 858K/K homozygotes (1.92 ± 1.61 vs 2.81 ± 1.57, p = 0.025). We demonstrate that the R858 allele of the F5 rs4524 variant protects from venous thrombosis only in non-carriers of the Q534 allele of the F5 rs6025. Its protective effect is mediated by reduced factor VIII levels and reduced activated protein C resistance.

[Risk factors for thromboembolic disease in young women-the role of hormones]. / Facteurs de risque de maladie veineuse thromboembolique chez les jeunes femmes en contexte hormonal: Risque de survenue d'une maladie thromboembolique veineuse chez les membres de la famille au 1er degré de femmes ayant une maladie veineuse thromboembolique en contexte hormonal : étude « FIT ­ H ¼.

Hormonal exposure in young women increases the risk of venous thromboembolic disease (VTE). Thrombophilia testing is often proposed in women of childbearing age before the initiation of contraception. However, the presence of a familial history of VTE has the potential to be more accurate than the presence of inherited thrombophilia. OBJECTIVE: To demonstrate an association between the risk of VTE in young women with hormonal exposure (pregnancy or oral contraceptive use) and the presence of a previous episode of VTE in their first-degree relatives, according to whether or not a detectable inherited thrombophilia was present. METHODS: We will perform a multicenter case-control cross-sectional study. The main risk factor is defined by the presence of a symptomatic VTE in young women with hormonal exposure. The principle variable is the presence of an objectively diagnosed episode of VTE in first-degree relatives. We will need to include 2,200 family members in 440 cases. EXPECTED RESULTS: We expect to improve understanding of the thrombotic risk in first-degree relatives of patients in hormonal context with or without a past history of VTE.