Significance of aberrant DNA methylation for cancer diagnostics and therapy.

BACKGROUND: Epigenetics is a scientific field that covers changes in gene expression that are not caused by the alteration of the nucleotide sequence in the DNA strand. Together with sequential changes, epigenetic reprogramming is a recognized cancer hallmark driving carcinogenesis. The underlying mechanisms of epigenetically-driven gene expression changes are diverse. However, one of the most extensively studied mechanisms is a change in DNA methylation. Under physiological conditions, DNA methylation ensures tissue-specific gene silencing and helps to maintain genome stability. With malignant transformation, genomic DNA undergoes global hypomethylation as well as locus-specific hypermethylation in promoters of tumor suppressor genes. In the last few decades, specific aberrant DNA methylation changes have emerged as both cancer-associated biomarkers and therapeutic targets and prompted ongoing efforts to enhance both diagnostic and therapeutic means in oncology. PURPOSE: The main purpose of this review is to introduce both established and emerging DNA methylation-based biomarkers for cancer diagnostics with a focus on biomarkers that are either routinely used or have been developed as commercial tests with certification for their use within in vitro diagnostics. Furthermore, therapeutic options for targeting aberrant DNA methylation are described, including both approved compounds and newly developed agents undergoing clinical investigation.

Inflammation and altered metabolism impede efficacy of functional electrical stimulation in critically ill patients.

BACKGROUND: Critically ill patients suffer from acute muscle wasting, which is associated with significant physical functional impairment. We describe data from nested muscle biopsy studies from two trials of functional electrical stimulation (FES) that did not shown improvements in physical function. METHODS: Primary cohort: single-centre randomized controlled trial. Additional healthy volunteer data from patients undergoing elective hip arthroplasty. Validation cohort: Four-centre randomized controlled trial. INTERVENTION: FES cycling for 60-90min/day. ANALYSES: Skeletal muscle mRNA expression of 223 genes underwent hierarchal clustering for targeted analysis and validation. RESULTS: Positively enriched pathways between healthy volunteers and ICU participants were "stress response", "response to stimuli" and "protein metabolism", in keeping with published data. Positively enriched pathways between admission and day 7 ICU participants were "FOXO-mediated transcription" (admission = 0.48 ± 0.94, day 7 = - 0.47 ± 1.04 mean log2 fold change; P = 0.042), "Fatty acid metabolism" (admission = 0.50 ± 0.67, day 7 = 0.07 ± 1.65 mean log2 fold change; P = 0.042) and "Interleukin-1 processing" (admission = 0.88 ± 0.50, day 7 = 0.97 ± 0.76 mean log2 fold change; P = 0.054). Muscle mRNA expression of UCP3 (P = 0.030) and DGKD (P = 0.040) decreased in both cohorts with no between group differences. Changes in IL-18 were not observed in the validation cohort (P = 0.268). Targeted analyses related to intramuscular mitochondrial substrate oxidation, fatty acid oxidation and intramuscular inflammation showed PPARγ-C1α; (P < 0.001), SLC25A20 (P = 0.017) and UCP3 (P < 0.001) decreased between admission and day 7 in both arms. LPIN-1 (P < 0.001) and SPT1 (P = 0.044) decreased between admission and day 7. IL-18 (P = 0.011) and TNFRSF12A (P = 0.009) increased in both arms between admission and day 7. IL-1ß (P = 0.007), its receptor IL-1R1 (P = 0.005) and IL-6R (P = 0.001) decreased in both arms between admission and day 7. No between group differences were seen in any of these (all p > 0.05). CONCLUSIONS: Intramuscular inflammation and altered substrate utilization are persistent in skeletal muscle during first week of critical illness and are not improved by the application of Functional Electrical Stimulation-assisted exercise. Future trials of exercise to prevent muscle wasting and physical impairment are unlikely to be successful unless these processes are addressed by other means than exercise alone.

[Diffuse alveolar hemorrhage in cannabis smokers. A systematic literature review]. / Hémorragies alvéolaires diffuses chez les fumeurs de cannabis. Revue systématique.

Cannabis is the most widely used illicit psychoactive substance in France. It can be responsible for numerous pulmonary complications, including diffuse alveolar hemorrhage (DAH). The objective of this systematic review of the literature was to present data concerning the relationship between cannabis smoking and DAH, which has rarely been reported in the literature. The review was based on a Medline search covering the 1980-2022 period and utilizing data drawn from 10 articles. DAH diagnosis is based on an association of hemoptysis, anemia and diffuse alveolar opacities on chest radiography with siderophages in the Bronchoalveolar Lavage Fluid (BAL). The 11 patients identified in this review were daily or regular cannabis smokers; in 4 cases they presented recent or recurrent hemoptysis with anemia; imaging revealed diffuse alveolar opacities in 10 of them, while BAL endoscopy highlighted a diffuse hemorrhage in the bronchial tree, and siderophages were observed in 6 cases. While evolution was favorable when cannabis consumption was discontinued, resumption occasioned DAH recurrence, and one patient died. Advice to quit should systematically be accompanied by addictological follow-up.

Agreement between isokinetic eccentric hamstring strength, Nordic hamstring strength and Nordic break-point angle in a sample of trained and healthy individuals.

Different eccentric strength assessments are used to identifying the risk of hamstring injury in athletes. However, there is scarce information to determine the association between Nordic-based measurements and the gold standard measurement of eccentric hamstring strength in an isokinetic dynamometer. To investigate the relationship of different measures of eccentric hamstring strength (break-point angle and eccentric strength during Nordic exercise) with eccentric hamstring peak torque measured with an isokinetic dynamometer. Forty-six participants volunteered to participate in this study. Eccentric peak force in the Smart-Nordic System and break-point angle measured as trunk lowering at >20°/s and >150°/s2 during the Nordic exercise via high-frequency video-analysis were compared to eccentric hamstring peak torque in an isokinetic dynamometer set to produce knee extension at 30°/s. There was a moderate association between peak eccentric strength with the Smart-Nordic and isokinetic eccentric hamstring peak torque (r = -0.65, p < 0.001, 95%CI = [-0.76-(-0.50)]). The association between Nordic break-point angle measured at 20°/s (r = 0.49, p < 0.001, 95%CI = [0.30-0.64]) and at 150°/s2 (r = 0.52, p < 0.001, 95%CI = [0.33-0.66]) presented statistically significant but lower associations with isokinetic eccentric hamstring peak torque. All Nordic-based measurements presented acceptable associations with the gold standard isokinetic eccentric hamstring peak torque. However, peak eccentric force measured on the Smart-Nordic device had a better agreement with eccentric peak torque measured with an isokinetic dynamometer than the video-based measurements.Highlights Peak eccentric force measured on the isometric strain-gauges device had a better agreement with eccentric hamstring peak torque measured with an isokinetic dynamometer than the break-point angle.The Nordic-based measurements are an alternative cost-effective method to assess eccentric muscle strength and weakness when the access to isokinetic dynamometry is not feasible.Caution should be taken with certain variables such as participants body mass, hip position and movement speed when interpreting the results of Nordic-based measurements.

[Feminization of the patient in thoracic oncology and experiences of caregivers: An exploratory study]. / Féminisation de la patientèle en oncologie thoracique et vécu des soignantes : recherche exploratoire.

INTRODUCTION: The epidemiology of lung cancer is evolving and caregivers need to address an emerging demographic, women, sometimes presenting at a young age. The effect of this ongoing change on thoracic oncology services and on the nursing population (registered nurses and auxiliary nurses) has not been evaluated. METHODS: A quantitative analysis can help to control the biases that may have an impact on nursing staff identification with female patients. A categorical and automated qualitative study (Tropes software) of speech productions related to "difficult situations" was carried out. RESULTS: Four contexts activating critical situations were identified: disagreement and conflict in care, a constraining situation of care, an overflow situation, particularly related to increased suffering of the patient and a feeling of being isolated in care delivery. Regarding the management of female patients, after the impact of disagreements in management, the feeling of care being constrained in the presence of a female patient with whom caregivers identify themselves is more significant than with regard to male patients. CONCLUSION: Support within the care team is essential, but not sufficient. Only a practice-based training context involving peers outside the team seems to help address the most impactful situations.

[Acute eosinophilic pneumonia and illicit psychoactive substance use]. / Pneumonies aiguës à éosinophiles et usage de substances psychoactives illicites.

Illicit psychoactive substance (IPAS) use can lead to a number of respiratory complications, including acute eosinophilic pneumonia (AEP). Systematic literature review of data on AEP in IPAS users (cannabis, cocaine, heroin and amphetamine). Of two cases of cannabis and tobacco users reported to have developed AEP, one, a teenage15 year old boy presented with acute respiratory distress syndrome (ARSD) which necessitated extracorporeal membrane oxygenation (ECMO). Five cases of AEP in cocaine smokers (crack) are reported, one of which was fatal. The patient presented with acute pulmonary edema and ARDS which progressed to ventricular fibrillation and asystole. A 24-year-old woman presented with AEP after repeated inhalation of heroin. Finally, a case of an amphetamine abuser who developed AEP and ARDS after amphetamine inhalation is reported. The time between the first IPAS use and admission in cases reported ranged from 7 days to 4 years, while time between the last IPAS use and admission was short (less than 15 days). IPAS use must be sought in case of AEP, especially in young adults, and practitioners must advise and help users to stop their consumption.

[Use of time of a nurse involved in breaking the diagnosis of lung cancer and navigating patients in the healthcare system: Experience of an academic thoracic oncology ward]. / Emploi du temps d'une infirmière d'annonce et de coordination du parcours de soins en cancérologie thoracique : expérience du CHU d'Angers.

The Plans cancer 1 and 2 created new nursing posts to improve the way that news about cancer was given to patients and to coordinate their care, helping them to navigate the system. We describe the way a nurse, assuming the role of assisting the doctor when a diagnosis of cancer is revealed and coordinating the care of patients in a teaching hospital, uses her time. One thousand and forty-one patients were supported by the nurse during 6515 procedures over 4.27 years. The median (interquartile range) number of interventions per patient was 3 (7). Helping to break news of cancer and the coordination of care represented approximately 20 and 80% of the working time of the nurse, respectively. The nurse spent 43% of her time without the doctor and more than half of this duration was dedicated to meetings with patients. The nurse timetable analysis shows that her role is very similar to a Canadian 'Pivot' nurse in oncology. In our experience, this combination of the announcement of cancer diagnosis and the coordination of subsequent care seems relevant, but the nurse is not replaced in the case of absence.

[Spontaneous pneumothorax and lung emphysema in cannabis users]. / Pneumothorax spontané et emphysème pulmonaire chez les consommateurs de cannabis.

INTRODUCTION: If pulmonary complications of tobacco smoking are well documented, those associated with cannabis use are less known. OBJECTIVES: Systematic literature review of data on pneumothorax and lung emphysema in cannabis users. DOCUMENTARY SOURCES: Medline, on the period 1980-2018 with the following keywords cannabis or marijuana and pneumothorax or emphysema, limits "title/abstract". Among 97 articles, 42 abstracts have given use to a dual reading to select 20 studies. RESULTS: Eighteen case reports (8 with SP) showed bullae in the upper lobes in combined cannabis and tobacco smokers (CS) and in the 2 cannabis only smokers (COS). The risk of SP was increased in CS, but not in COS. In patients less than 35-years old presenting with SP, the incidence of bullae on thoracic computed tomography (CT) was higher in CS than in tobacco only smokers (TOS). CT in patients with SP showed no significant difference as regards of the prevalence, location and type of emphysema between CS and TOS. Proportion of low lung density areas was higher in CS than in non-smokers (NS), but was similar in TOS and NS. CONCLUSION: These results suggest a cumulative toxic effect of tobacco and cannabis on the risk of SP and lung emphysema.

[Unexpected adverse events of immunotherapies in non-small cell lung cancer: About 2 cases]. / Effets secondaires inhabituels des immunothérapies dans le cancer bronchique non à petites cellules : à propos de deux cas.

Programmed death receptor 1 (PD1) checkpoint inhibitors are known for immune mediated toxicities such as colitis, endocrinopathies and pneumonitis. However, other rare adverse effects are reported in the literature. Nivolumab is an anti-PD1 immunotherapy used in the second line of non-small cell lung cancer (NSCLC). We report two cases of rare toxicities occurring under nivolumab in patients without a history of dysimmunity. A 79-year-old patient with a large-cell carcinoma showed a muscle weakness after the second course, revealing myositis with a CPK grade IV elevation as well as symptoms of myasthenia. The diagnosis of myositis was confirmed by a muscle biopsy. An 82-year-old patient followed for bronchial adenocarcinoma with EGFR mutation, presented with nivolumab shoulder and hip pain with extreme fatigue. After further investigations, the diagnosis of systemic erythematosus lupus was retained. Investigations led to the diagnosis of systemic lupus erythematosus. For both patients treatment was interrupted and systemic corticosteroid therapy was initiated permitting resolution of symptoms. The occurrence of symptoms of dysimmunity should attract the attention of the clinician, leading to discontinuation of anti-PD1 therapy and corticosteroid therapy. Retreatment after symptoms resolution must be collegially discussed if no alternative therapeutic is available.

[Sleep apneas, metabolic syndrome and cardiovascular risk: Data from the Pays de la Loire sleep cohort]. / Apnées du sommeil, syndrome métabolique et risque cardiovasculaire : données de la cohorte sommeil des Pays de la Loire.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a prevalent disease characterized by recurrent episodes of partial or complete obstruction of upper airway during sleep. Untreated moderate to severe OSAHS is recognized as a cardiovascular (CV) risk factor. Data from the Pays de la Loire sleep cohort and other clinic- or population-based cohorts demonstrate a strong association between OSAHS and the different components of the metabolic syndrome including systemic hypertension, diabetes and impaired lipid metabolism. Beside sleep-disordered breathing severity, these factors contribute to increase the risk of CV events in OSAHS patients. Continuous positive airway pressure (CPAP) therapy of OSAHS is associated with a modest but clinically significant blood pressure reduction. Conversely, there is no clear evidence in support of a metabolic impact of CPAP in OSAHS patients. Considering the multifactorial pathophysiology of CV risk in OSAHS patients and the beneficial impact of various lifestyle and pharmacologic interventions on blood pressure and metabolic dysfunction, combined modality therapy is a promising strategy to improve CV outcomes in individuals with OSAHS.

[The fight against smoking. The need to consider behavioral dependence]. / Lutte contre le tabagisme en France. L'indispensable prise en compte de la dépendance comportementale.

The prevalence of smoking in France remains very high compared to other developed Western countries. The management of smoking in smokers is often limited to nicotinic substitution, whether medicated or linked to the use of electronic cigarettes or varenicline and advices more or less reliable or helpful. This strategy of aiding smoking cessation, if isolated, leads to a high number of failures. It is therefore necessary to consider behavioral dependence, in the broad sense in three aspects, "behavioral" (the motor Gestures), cognitive (thoughts) and emotional (emotions). Behaviorists distinguish open (motor) and closed behaviors (cognitions and emotions), the latter two, emotions and cognitions, being quite often related. Practical examples of action in this direction are proposed.

[Cannabis and lung. What we know and everything we don't know yet]. / Cannabis et poumon. Ce que l'on sait et tout ce que l'on ne sait pas.

Cannabis use increased sharply from 2010 to 2014 in France. Cannabis is often consumed with tobacco, although the use of marijuana is developing. Tobacco and cannabis smoke have many common characteristics in terms of irritants, carcinogens and carbon monoxide. They also differentiate by their dependence mechanisms, with nicotine and its receptors for tobacco and tetra-hydro-cannabinol (THC) and its specific receptors for cannabis. Chronic inhalation (700,000 daily users in France) over a long period most likely increases the relative risk of bronchial cancer. But long-term cohort studies targeting this group of strong cannabis users, especially over time, are lacking. Inhalation of cannabis smoke, despite an acute bronchodilator effect, is associated with the risk of chronic bronchitis in the case of regular use. However, the risk of developing COPD in the exclusive marijuana smoker group with no associated tobacco is not yet clear, with studies yielding discordant results. There is also a lack of long-term follow-up studies of respiratory investigations in large cannabis users. Finally, cannabis smoke contains various cannabinoids, for example cannabidiol which also have anti-inflammatory and antifibrotic properties, with the unconfirmed hypothesis that these properties can partially modulate the deleterious action of cannabis smoke.

[Vascular dysfunction in obstructive sleep apnoea: Implication of microparticules]. / Atteinte vasculaire associée au syndrome d'apnées hypopnées obstructives du sommeil : rôle des microparticules.

Obstructive sleep apnea (OSA) is associated with increased cardiovascular diseases, including myocardial infarction and stroke and promotes cardiovascular risk factors including diabetes and hypertension. OSA has also been proposed to have a direct proatherogenic effects. Recent studies have investigated the role of microparticles (MPs) in the atherogenic process. MPs are small plasma membrane vesicles that can be released by a variety of vascular or blood cells and that contain membrane and cytosolic elements. Case-control studies have suggested that OSA is associated with an increase in circulating platelet-, endothelial- and leukocyte-derived MPs. MPs from OSA patients injected to mice have also been shown to induce vascular inflammation and endothelial dysfunction. In this article, we provide an overview of the main characteristics of MPs expressed in OSA and their potential role in the atherogenic process.

[A bronchial mucous gland adenoma resected by endoscopic procedure]. / Un adénome des glandes muqueuses bronchiques réséqué par voie endoscopique.

INTRODUCTION: Surgical resection is usually performed for the treatment of endobronchial tumors. This case describes the use of endoscopic resection as an initial treatment, allowing to spare lung parenchyma. CASE REPORT: A patient was admitted to the emergency unit with right lower lobe pneumonia. A thoracic CT-scan and subsequent bronchoscopy revealed an intrabronchial tumor between the right main and intermediate bronchus. Biopsies were non-diagnostic and a PET-scanner did not find any abnormalities. Surgical resection was initially proposed but would have required a right upper lobectomy. The patient had stage 2 (moderate) chronic obstructive pulmonary disease (GOLD classification). Because of this, we decided to perform an endoscopic resection to obtain further histology and hopefully achieve total removal. Under conscious sedation, the resection by argon plasma coagulation with a flexible bronchoscope was realized without any complication. The histological diagnosis was a bronchial mucous gland adenoma. CONCLUSION: This case emphasizes the role of multidisciplinary discussion when considering suitability of local resection of tumors by an endobronchial procedure rather than a surgical resection.

Practical guidelines on e-cigarettes for practitioners and others health professionals. A French 2016 expert's statement.

A group of 11 French medical experts has developed guidelines through a Delphi progressive consensus about smoking management at the e-cigarette era. The lack of scientific data about e-cigarettes led the experts to set out recommendations, mainly based on clinical practice while waiting for scientific validations. The validated smoking cessation treatments keep the first place in the prevention and the treatment of tobacco-induced damages. The e-cigarette, experimented by a large proportion of smokers, is a safer product than tobacco. The health professional must answer the patients about the e-cigarettes: (1) A smoker who questions about e-cigarettes should receive information. Even if there is a lack of data, e-cigarettes offer much lower risks than tobacco. (2) A dual user is at high risk of returning to exclusive tobacco use; he should also optimize other nicotine intakes by combining nicotine replacement therapy and/or optimizing the nicotine intake through the e-cigarette. (3) A smoker who wish to use the e-cigarette in order to quit with or without associated pharmacological treatment should be accompanied and not discouraged. (4) A vaper who is tired to continuing to vape should be accompanied to quit. Specific guidelines are also provided for adolescents, pregnant women, patients during perioperative periods and also for pulmonary, cardiac and schizophrenic patients.

Corneal graft rejection in a patient treated with nivolumab for primary lung cancer.

We report the case of a 58-year-old woman treated with nivolumab for an unresectable squamous non-small cell lung cancer, after first-line cisplatin and gemcitabine combination chemotherapy. This woman had a history of left corneal graft. After 9 cycles of nivolumab, the patient described decreased visual acuity in the left eye with watering and conjunctival erythema. Ophthalmological examination revealed chronic corneal graft rejection. The patient was then treated with an intravenous bolus of corticosteroids (500mg of methylprednisolone) for 3 days, followed by oral prednisone for 4 weeks and subconjunctival corticosteroid injections every 48h, while treatment with nivolumab was discontinued. No clinical benefit was observed 4 weeks later and the corneal graft became totally unfunctional despite of the therapy. We hypothesise that the treatment was started too late. To our knowledge, this is the first reported case of corneal graft rejection related to nivolumab.