Nathalie Prévôt

Could 99mTc-glucarate be used to evaluate tumour necrosis? In vitro and in vivo studies in leukaemic tumour cell line U937.

PurposeThe aim of this study was to determine whether 99mTc-glucarate (99mTc-GLA) is a powerful and discriminant tumour necrosis marker.Materials and methodsThe induction of apoptosis and secondary necrosis (by a chemotherapeutic agent) and necrosis (by intense hyperthermia) was studied on an in vitro and in vivo leukaemic cell line model (U937). The percentage of apoptosis/necrosis in vitro was determined by flow cytometry after staining cells with annexin-V-fluorescein/propidium iodide. The uptake of 99mTc-GLA was studied after treatments that produce an optimal of necrosis cells or apoptotic cells. Three populations of interest: viable, apoptotic and necrotic cells were sorted by flow cytometry. The uptake and the intracellular distribution of 99mTc-GLA on each population have been studied. We also investigated the influence of necrosis on 99mTc-GLA uptake in a model of U937 xenografts in nude mice.ResultsThe accumulation of 99mTc-GLA in untreated and apoptotic cells was lower than in necrotic cells. Cell sorting discriminated each cellular population and showed a 14% accumulation in necrotic cells and no more than a 3% in apoptotic cells. In apoptotic and viable cells, 99mTc-GLA is distributed between the cytosolic/membrane and the nucleus fractions. In necrotic cells, 99mTc-GLA is mainly found in the nucleus fraction. In vivo investigations showed a higher 99mTc-GLA uptake in necrotic tumour than in apoptotic and control ones.Conclusions99mTc-GLA may be a useful agent to specifically evaluate tumour necrosis and may be helpful for the follow-up of patients with cancer.

Assessing sinus aerosol deposition: Benefits of SPECT–CT imaging

PURPOSE Aerosol inhalation therapy is one of the methods to treat rhinosinusitis. However the topical drug delivery to the posterior nose and paranasal sinuses shows only limited efficiency. A precise sinusal targeting remains a main challenge for aerosol treatment of sinus disorders. This paper proposes a comparative study of the nasal deposition patterns of micron and submicron particles using planar gamma-scintigraphy imaging vs. a new 3-dimensional (3D) imaging approach based on SPECT-CT measurements. METHODS Radiolabelled nebulizations have been performed on a plastinated model of human nasal cast coupled with a respiratory pump. First, the benefits provided by SPECT-CT imaging were compared with 2D gamma-scintigraphy and radioactive quantification of maxillary sinus lavage as reference for the sonic 2.8 μm aerosol sinusal deposition. Then, the impact on nasal deposition of various airborne particle sizes was assessed. RESULTS The 2D methodology overestimates aerosol deposition in the maxillary sinuses by a factor 9 whereas the 3D methodology is in agreement with the maxillary sinus lavage reference methodology. Then with the SPECT-CT approach we highlighted that the higher particle size was mainly deposited in the central nasal cavity contrary to the submicron aerosol particles (33.8 ± 0.6% of total deposition for the 2.8 μm particles vs. 1 ± 0.3% for the 230 nm particles). CONCLUSION Benefits of SPECT/CT for the assessment of radiolabelled aerosol deposition in rhinology are clearly demonstrated. This 3D methodology should be preferentially used for scintigraphic imaging of sinusal deposition in Human.

Lymphoscintigraphy and SPECT/CT using 99mTc filtered sulphur colloid in chylothorax

We present a rare case of a chylothorax in a 60-year-old patient after resection of the thymus (myasthenia gravis and thymus hyperplasia). A left-sided chylothorax developed 20 days after the resection with an estimated daily fluid loss of 1.7 l. Chest lymphoscintigraphy was performed in the anterior and posterior position 60 min after injection of 4×74 MBq Tc filtered sulphur colloid subcutaneously into the first interdigital space and the retromalleolar space of both feet. The images showed abnormal tracer accumulation in the left hemithorax, as seen on the posterior chest lymphoscintigraphic image. SPECT/CT (Symbia T2 Siemens Medical) of the thorax showed abnormal mediastinal tracer accumulation between the left common carotid artery and the left subclavian artery, suggesting rupture of a collateral thoracic lymph duct. Successful ligation of a ruptured ectopic thoracic duct, situated ventral to the left subclavian artery and the phrenic nerve, by video-assisted thoracoscopic surgery was performed and achieved control of the chylothorax. This case clearly illustrates the added value of SPECT/ CT in addition to lymphoscintigraphy for the anatomical location of a traumatic rupture of a thoracic lymph duct. To our knowledge only a few case reports have been published on this subject [1–4].

The value of stress single-photon emission computed tomography imaging performed routinely at 6 months in asymptomatic patients for predicting angiographic restenosis after successful direct percutaneous intervention for acute ST elevation myocardial infarction.

AimsThe authors tested the value of stress single-photon emission computed tomography (SPECT) imaging performed systematically for detecting angiographic restenosis in asymptomatic patients who underwent direct percutaneous coronary intervention (PCI) for acute ST segment elevation myocardial infarction (STEMI). Angiographic restenosis of the infarct-related artery after direct PCI for STEMI is often silent and the strategy for follow-up evaluation of asymptomatic patients remains debated. MethodsA total of 149 patients successfully treated by direct PCI (96% stenting) for STEMI with no symptoms during the follow-up systematically underwent both rest thallium 201/stress Tc 99m setamibi myocardial perfusion imaging and coronary angiogram at 6 months. Patients were followed up for 2.5±0.5 years after 6 months control for cardiac events. ResultsIn the 149 patients, the sensitivity, specificity, positive and negative predictive values and accuracy of SPECT imaging were 48, 61, 35, 72 and 57%, respectively, for detecting binary angiographic restenosis defined as ≥50% diameter stenosis. Whether stress testing was maximal or performed after withheld anti-ischemic drugs did not improve the results. Reversible ischemia at SPECT in the infarct territory did not predict long-term cardiac events. ConclusionThese data suggest a poor correlation between stress SPECT imaging and angiographic restenosis at 6 months in patients treated by direct PCI for STEMI who remain asymptomatic at follow-up. The long-term clinical prognostic value of SPECT reversible ischemia in the infarct territory appears also limited in this peculiar subset of patients. These findings should be taken into account in the strategy of the clinical follow-up of this population.

Nicotine delivery from the refill liquid to the aerosol via high-power e-cigarette device

To offer an enhanced and well-controlled nicotine delivery from the refill liquid to the aerosol is a key point to adequately satisfy nicotine cravings using electronic nicotine delivery systems (ENDS). A recent high-power ENDS, exhibiting higher aerosol nicotine delivery than older technologies, was used. The particle size distribution was measured using a cascade impactor. The effects of the refill liquid composition on the nicotine content of each size-fraction in the submicron range were investigated. Nicotine was quantified by liquid chromatography coupled with tandem mass spectrometry. Particle size distribution of the airborne refill liquid and the aerosol nicotine demonstrated that the nicotine is equally distributed in droplets regardless of their size. Results also proved that the nicotine concentration in aerosol was significantly lower compared to un-puffed refill liquid. A part of the nicotine may be left in the ENDS upon depletion, and consequently a portion of the nicotine may not be transferred to the user. Thus, new generation high-power ENDS associated with propylene glycol/vegetable glycerin (PG/VG) based solvent were very efficient to generate carrier-droplets containing nicotine molecules with a constant concentration. Findings highlighted that a portion of the nicotine in the refill liquid may not be transferred to the user.

Impact of acoustic airflow on intrasinus drug deposition: New insights into the vibrating mode and the optimal acoustic frequency to enhance the delivery of nebulized antibiotic.

AIM We investigated the impact of vibrating acoustic airflow, the high frequency (f≥100 Hz) and the low frequency (f≤45 Hz) sound waves, on the enhancement of intrasinus drug deposition. METHODS (81m)Kr-gas ventilation study was performed in a plastinated human cast with and without the addition of vibrating acoustic airflow. Similarly, intrasinus drug deposition in a nasal replica using gentamicin as a marker was studied with and without the superposition of different modes of acoustic airflow. RESULTS Ventilation experiments demonstrate that no sinus ventilation was observed without acoustic airflow although sinus ventilation occurred whatever the modes of acoustic airflow applied. Intrasinus drug deposition experiments showed that the high frequency acoustic airflow led to 4-fold increase in gentamicin deposition into the left maxillary sinus and to 2-fold deposition increase into the right maxillary sinus. Besides, the low frequency acoustic airflow demonstrated a significant increase of 4-fold and 2-fold in the right and left maxillary sinuses, respectively. CONCLUSION We demonstrated the benefit of different modes of vibrating acoustic airflow for maxillary sinus ventilation and intrasinus drug deposition. The degree of gentamicin deposition varies as a function of frequency of the vibrating acoustic airflow and the geometry of the ostia.

Impact of power level and refill liquid composition on the aerosol output and particle size distribution generated by a new-generation e-cigarette device

ABSTRACT The new high-power Electronic Nicotine Delivery System (ENDS) can generate aerosols with higher nicotine concentrations than older ENDS. Aerosol particle sizes affect deposition patterns and then plasma nicotine levels in vapers. Consequently, understanding the factors influencing particle size distribution of high-power ENDS is relevant to assess their performance in terms of nicotine delivery. The particle size distribution and the aerosol output (aerosol mass) were measured using cascade impactors. The effects of the refill liquid composition (80% PG/20% VG vs. 80% VG/20% PG; PG refers to propylene glycol and VG to vegetable glycerin) and the power level of the battery (from 7 W to 22 W) were investigated. The aerosol output increases significantly with the power level following a logarithmic law. The PG/VG ratio also has an impact on the aerosol output. The higher the VG content in the refill liquid, the higher is the aerosol output. Besides, particle size distribution is positively related to the power level, following linear correlations between the mass median aerodynamic diameter (MMAD) and the power level in the range of 7–22 W. A moderate impact of the PG/VG ratio on size distribution is equally observed. Changes in the power level allow the transition between a dominant mode with MMAD from 613 nm to 949 nm. We demonstrated that the power level can strongly change the aerodynamic properties of high-power ENDS, especially at high voltage. Associated with the aerosol nicotine level assessment, MMAD could be determined as a means for comparing ENDS devices and nicotine delivery. Copyright

Assessment of new-generation high-power electronic nicotine delivery system as thermal aerosol generation device for inhaled bronchodilators

PURPOSE A need remains for alternative devices for aerosol drug delivery that are low cost, convenient and easy to use for the patient, but also capable of producing small-sized aerosol particles. This study investigated the potential of recent high power electronic nicotine delivery systems (ENDS) as aerosol generation devices for inhaled bronchodilators. METHODS The particle size distribution was measured using a cascade impactor. The delivery of terbutaline sulfate, a current bronchodilator used for asthma or COPD therapy by inhalation, was studied. This drug was quantified by liquid chromatography coupled with tandem mass spectrometry. RESULTS The particle size distribution in terms of mass frequency (in two ways, gravimetrically and quantitatively through drug assay on each stage) and the terbutaline sulfate concentration in the aerosol were elucidated. The mass median aerodynamic diameter (MMAD) and the drug delivery rose when the power level increased, to reach 5.6±0.4μg/puff with a MMAD of 0.78±0.03μm at 25W. CONCLUSION New generation high-power ENDS are very efficient to generate carrier-droplets in the submicron range containing drug molecules with a constant drug concentration whatever the size-fractions. ENDS appear to be highly patient-adaptive.

Development of an ex vivo human-porcine respiratory model for preclinical studies

Anatomical models to study aerosol delivery impose huge limitations and extrapolation to humans remains controversial. This study aimed to develop and validate an ex vivo human-like respiratory tract model easy to use and relevant to compare to in vivo human data. A human plastinated head is connected to an ex vivo porcine pulmonary tract ventilated artificially by passive expansion. A physiological study measures “pleural” depressions, tidal volumes, and minute ventilation for the respiratory rates chosen (10, 15, and 20 per minute) with three inspiratory/expiratory ratios (1/1, 1/2, and 1/3). Scintigraphy with 81mKrypton assesses the homogeneity of the ventilation. Forty different experiments were set for validation, with 36 (90%) ventilating successfully. At a respiratory rate of 15/minute with inspiratory/expiratory ratio of 1/2, the tidal volume average was 824 mL (standard deviation, 207 mL). The scintigraphy performed on 16 ex vivo models (44.4%), showed homogenous ventilation with great similarity to human physiological studies. Ratio of the peripheral to central count rates were equally correlated with human data published in the literature. This new model, combining research feasibility and human physiology likeness, provides a realistic approach to human inhalation and therefore can be an interesting tool in aerosol regional deposition studies.

Experimental human-like model to assess the part of viable Legionella reaching the thoracic region after nebulization

The incidence of Legionnaires’ disease (LD) in European countries and the USA has been constantly increasing since 1998. Infection of humans occurs through aerosol inhalation. To bridge the existing gap between the concentration of Legionella in a water network and the deposition of bacteria within the thoracic region (assessment of the number of viable Legionella), we validated a model mimicking realistic exposure through the use of (i) recent technology for aerosol generation and (ii) a 3D replicate of the human upper respiratory tract. The model’s sensitivity was determined by monitoring the deposition of (i) aerosolized water and Tc99m radio-aerosol as controls, and (ii) bioaerosols generated from both Escherichia coli and Legionella pneumophila sg 1 suspensions. The numbers of viable Legionella prior to and after nebulization were provided by culture, flow cytometry and qPCR. This study was designed to obtain more realistic data on aerosol inhalation (vs. animal experimentation) and deposition at the thoracic region in the context of LD. Upon nebulization, 40% and 48% of the initial Legionella inoculum was made of cultivable and non-cultivable cells, respectively; 0.7% of both populations reached the filter holder mimicking the thoracic region in this setup. These results are in agreement with experimental data based on quantitative microbial risk assessment methods and bring new methods that may be useful for preventing LD.