Multimodal imaging for the detection and characterization of liver lesions in a mouse model of neuroendocrine tumor.

BACKGROUND: The aim of this study was to compare in vivo magnetic resonance imaging (MRI) and ex vivo autoradiography with histopathological results for the detection and characterization of liver lesions in an experimental model of human neuroendocrine tumors. MATERIAL AND METHODS: Intestinal STC-1 endocrine tumor cells were injected into 30 nude mice to achieve hepatic dissemination. Seven to 30 days after injection, T2-weighted in vivo images covering the entire liver were acquired with a 7-T system. Autoradiographs were also obtained in 28 mice after injection of fluorodeoxyglucose (18F-FDG). The autoradiographic liver samples were then stained with an antichromogranin antibody before histological analysis. Tumor size and the hepatic tumor fraction were measured using the three imaging modalities. RESULTS: Metastatic tumors visualized on the histological liver sections ranged in size from 50 microm (day 7) to 3 mm (day 30). The hepatic tumor fraction increased with time, reaching 30% of the hepatic surface area on day 30. Visual analysis revealed variable tumor distribution and type (solid and/or cystic). On MRI, lesions were identified from day 12 (about 100 icrom in diameter) and the hepatic tumor fraction was up to 48% at day 30. The smallest lesions (350 microm in diameter) were also detected at day 12 on the autoradiographs. There was good correlation between tumor fractions determined from autoradiographic and histological data. CONCLUSION: In vivo, MRI appears to be well suited to the follow-up of liver lesions in a mouse model of neuroendocrine tumor. Preliminary results using 18F-FDG in this animal model are promising, showing differences in FDG uptake.

A prospective international observational prevalence study on prone positioning of ARDS patients: the APRONET (ARDS Prone Position Network) study.

INTRODUCTION: While prone positioning (PP) has been shown to improve patient survival in moderate to severe acute respiratory distress syndrome (ARDS) patients, the rate of application of PP in clinical practice still appears low. AIM: This study aimed to determine the prevalence of use of PP in ARDS patients (primary endpoint), the physiological effects of PP, and the reasons for not using it (secondary endpoints). METHODS: The APRONET study was a prospective international 1-day prevalence study performed four times in April, July, and October 2016 and January 2017. On each study day, investigators in each ICU had to screen every patient. For patients with ARDS, use of PP, gas exchange, ventilator settings and plateau pressure (Pplat) were recorded before and at the end of the PP session. Complications of PP and reasons for not using PP were also documented. Values are presented as median (1st-3rd quartiles). RESULTS: Over the study period, 6723 patients were screened in 141 ICUs from 20 countries (77% of the ICUs were European), of whom 735 had ARDS and were analyzed. Overall 101 ARDS patients had at least one session of PP (13.7%), with no differences among the 4 study days. The rate of PP use was 5.9% (11/187), 10.3% (41/399) and 32.9% (49/149) in mild, moderate and severe ARDS, respectively (P = 0.0001). The duration of the first PP session was 18 (16-23) hours. Measured with the patient in the supine position before and at the end of the first PP session, PaO2/FIO2 increased from 101 (76-136) to 171 (118-220) mmHg (P = 0.0001) driving pressure decreased from 14 [11-17] to 13 [10-16] cmH2O (P = 0.001), and Pplat decreased from 26 [23-29] to 25 [23-28] cmH2O (P = 0.04). The most prevalent reason for not using PP (64.3%) was that hypoxemia was not considered sufficiently severe. Complications were reported in 12 patients (11.9%) in whom PP was used (pressure sores in five, hypoxemia in two, endotracheal tube-related in two ocular in two, and a transient increase in intracranial pressure in one). CONCLUSIONS: In conclusion, this prospective international prevalence study found that PP was used in 32.9% of patients with severe ARDS, and was associated with low complication rates, significant increase in oxygenation and a significant decrease in driving pressure.

Ventilator-associated pneumonia in ARDS patients: the impact of prone positioning. A secondary analysis of the PROSEVA trial.

BACKGROUND: The goal of this study was to assess the impact of prone positioning on the incidence of ventilator-associated pneumonia (VAP) and the role of VAP in mortality in a recent multicenter trial performed on patients with severe ARDS. METHODS: An ancillary study of a prospective multicenter randomized controlled trial on early prone positioning in patients with severe ARDS. In suspected cases of VAP the diagnosis was based on positive quantitative cultures of bronchoalveolar lavage fluid or tracheal aspirate at the 10(4) and 10(7) CFU/ml thresholds, respectively. The VAP cases were then subject to central, independent adjudication. The cumulative probabilities of VAP were estimated in each position group using the Aalen-Johansen estimator and compared using Gray's test. A univariate and a multivariate Cox model was performed to assess the impact of VAP, used as a time-dependent covariate for mortality hazard during the ICU stay. RESULTS: In the supine and prone position groups, the incidence rate for VAP was 1.18 (0.86-1.60) and 1.54 (1.15-2.02) per 100 days of invasive mechanical ventilation (p = 0.10), respectively. The cumulative probability of VAP at 90 days was estimated at 46.5 % (27-66) in the prone group and at 33.5 % (23-44) in the supine group. The difference between the two cumulative probability curves was not statistically significant (p = 0.11). In the univariate Cox model, VAP was associated with an increase in the mortality rate during the ICU stay [HR 1.65 (1.05-2.61), p = 0.03]. HR increased to 2.2 (1.39-3.52) (p < 0.001) after adjustment for position group, age, SOFA score, McCabe score, and immunodeficiency. CONCLUSIONS: In severe ARDS patients prone positioning did not reduce the incidence of VAP and VAP was associated with higher mortality.

Mechanisms of the effects of prone positioning in acute respiratory distress syndrome.

INTRODUCTION: Prone positioning has been used for many years in patients with acute respiratory distress syndrome (ARDS). The initial reason for prone positioning in ARDS patients was improvement in oxygenation. It was later shown that mechanical ventilation in the prone position can be less injurious to the lung and hence the primary reason to use prone positioning is prevention of ventilator-induced lung injury (VILI). MATERIAL AND METHODS: A large body of physiologic benefits of prone positioning in ARDS patients accumulated but these failed to translate into clinical benefits. More recently, meta-analyses and randomized controlled trial in a specific subgroup of ARDS patients demonstrated that prone positioning can improve survival. This review covers the effects of prone positioning on oxygenation, respiratory mechanics, and VILI. CONCLUSIONS: We conclude with the effects of prone positioning on patient outcome, in particular on survival.

An attempt to validate the modification of the American-European consensus definition of acute lung injury/acute respiratory distress syndrome by the Berlin definition in a university hospital.

PURPOSE: The Berlin definition for acute respiratory distress syndrome (ARDS) is a new proposal for changing the American-European consensus definition but has not been assessed prospectively as yet. In the present study, we aimed to determine (1) the prevalence and incidence of ARDS with both definitions, and (2) the initial characteristics of patients with ARDS and 28-day mortality with the Berlin definition. METHODS: We performed a 6-month prospective observational study in the ten adult ICUs affiliated to the Public University Hospital in Lyon, France, from March to September 2012. Patients under invasive or noninvasive mechanical ventilation, with PaO2/FiO2 <300 mmHg regardless of the positive end-expiratory pressure (PEEP) level, and acute onset of new or increased bilateral infiltrates or opacities on chest X-ray were screened from ICU admission up to discharge. Patients with cardiogenic pulmonary edema were excluded. Patients were further classified into specific categories by using the American-European Consensus Conference and the Berlin definition criteria. The complete data set was measured at the time of inclusion. Patient outcome was measured at day 28 after inclusion. RESULTS: During the study period 3,504 patients were admitted and 278 fulfilled the American-European Consensus Conference criteria. Among them, 18 (6.5 %) did not comply with the Berlin criterion PEEP ≥ 5 cmH2O and 20 (7.2 %) had PaO2/FiO2 ratio ≤200 while on noninvasive ventilation. By using the Berlin definition in the remaining 240 patients (n = 42 mild, n = 123 moderate, n = 75 severe), the overall prevalence was 6.85 % and it was 1.20, 3.51, and 2.14 % for mild, moderate, and severe ARDS, respectively (P > 0.05 between the three groups). The incidence of ARDS amounted to 32 per 100,000 population per year, with values for mild, moderate, and severe ARDS of 5.6, 16.3, and 10 per 100,000 population per year, respectively (P < 0.05 between the three groups). The 28-day mortality was 35.0 %. It amounted to 30.9 % in mild, 27.9 % in moderate, and 49.3 % in severe categories (P < 0.01 between mild or moderate and severe, P = 0.70 between mild and moderate). In the Cox proportional hazard regression analysis ARDS stage was not significantly associated with patient death at day 28. CONCLUSIONS: The present study did not validate the Berlin definition of ARDS. Neither the stratification by severity nor the PaO2/FiO2 at study entry was independently associated with mortality.

Synchronisation strategies in T2-weighted MR imaging for detection of liver lesions: Application on a nude mouse model.

AIM: The objective of this work was to propose original synchronisation strategies based on T2-weighted sequence performed on a small animal MRI spectrometer in order to improve the image contrast and detect mouse liver lesions at high magnetic field. MATERIALS AND METHODS: The experiments were performed in vivo at 7T using a 32 mm inner diameter cylindrical volumetric coil for both RF emission and reception. A sensitive pressure sensor was used to detect external movements due to both respiration and heart beats. The pressure sensor was interfaced with a commercial ECG Trigger Unit to use dedicated functionalities (trigger levels, delays and window). To enable T2-weighted imaging with minimised T1 effects, an acquisition strategy with controlled TR spanning over several respiratory cycles was developed. With this strategy, the slices were acquired over several respiratory periods. RESULTS: The acquisition, performed over several respiratory periods, enables a longer TR than the typical mouse respiratory period. The image contrast is controllable and independent of the respiratory period. The heavily T2-weighted images obtained with the developed strategy allow better visualisation of lesions at high magnetic field. Moreover, double respiratory and cardiac synchronisation, based on a unique sensitive pressure sensor, improves image quality with less motion artifacts, especially in the ventral liver region. The total slice number is independent of respiratory period and thin slices can be acquired to cover the whole liver. CONCLUSION: The developed strategy enables high quality pure T2-weighted imaging with minimal motion artifacts. This strategy improves T2-weighted image contrast and quality, especially at high magnetic field, on animals with short respiratory periods. The strategy was demonstrated using a mouse model of liver lesions at 7T. This protocol could be used to carry out a longitudinal follow-up.

Optical cardiac and respiratory device for synchronized MRI on small animal.

Respiratory and cardiac motion must be overcome if MRI of the thorax or abdomen is to be performed satisfactorily. An optical-based device designed to synchronize MRI acquisition on small animal was developed using a pair of optical fibers. Light from a laser diode was focused into the transmit fiber and impinged upon the moving skin. The reflected light was detected by the receive fiber and then caries to a light-voltage photodiode, were the signal was amplified and filtered. The recorded optical-based signals are well correlated with both respiratory and heart motions. The signal amplitude recorded on both rats and mice were large enough to perform an easy adjustment of gating level with good differentiation between cardiac and respiratory signal. The device developed using thin fibers is simple to use even when space available around the mice is limited (narrow coils). The signal is totally unaffected by radiofrequency impulsions or magnetic field gradients used for imaging. This optical-based trigger system was used successfully for dual cardiac and respiratory synchronization of rat and mice for heart and liver examinations at 4.7T.

Characterization of neuro-endocrine tumors in an athymic nude mouse model using dedicated synchronization strategies for T2-weigted MR imaging at 7T.

Endocrine tumours, with digestive localization, are tumours with variable forecast which are independent of their invasive and metastatic extensions. The experimental model of endocrine tumors with liver dissemination is available for evaluation of new medical therapeutics such as antiangiogenic therapy. MRI is a non invasive modality allowing in vivo examinations and is suitable to follow liver lesion evolution during longitudinal study on animal models. The goal of this study was to assess the detection level and to characterize the liver lesions in an athymic nude mouse model, using a dedicated MRI protocol and an optimized synchronization strategy at high magnetic field strength. The experiments were performed at 7T. To detect liver lesions, respiratory-triggered T2-weighted MR images is the sequence of choice. With conventional acquisition strategies used on small animal MR systems, trigger signal is performed at each respiratory cycle and thus, the T2 contrast is not freely controlled. Additionally, the slice number is limited by the expiration delay. To overcome these drawbacks, we proposed an original strategy enabling true T2-weighted imaging with minimal movement artifacts, regardless of the respiratory period and the number of slices. This protocol was used to carry out a longitudinal follow-up of hepatic lesions in 8 nude mice at stages D7, D12, D17 and D24. The fraction of lesion over the total liver volume was quantified. Moreover, the characterization of cystic or non-cystic type of lesions was achieved using various TE leading to T2 maps. In conclusion, the level of lesion detection and characterization of liver lesions was performed using a devoted protocol with original synchronization strategy dedicated to high field MRI. MR imaging could be used with relevance in the evaluation of new therapeutics protocol for treatment of liver lesions in neuroendocrine tumors using small animal model.