Personalized chemotherapy of lung cancer: What the radiologist should know.

Lung cancer is the leading cause of deaths due to cancer in France. More than half of lung cancers are discovered at an advanced-stage. New anticancer treatment strategies (i.e., the so-called personalized or targeted therapy) have recently been introduced and validated for non-small-cell lung cancer (NSCLC), in addition to or in association with standard chemotherapy. Personalized therapy includes tyrosine kinase inhibitors (TKIs), antiangiogenic treatments and immunotherapy. Because these treatments may be responsible for atypical thoracic adverse effects and responses as compared to standard chemotherapy, RECIST 1.1 criteria may be inadequate to evaluate the responses to these agents. The goal of this article was to review personalized treatment strategies for NSCLC, to consider the therapy-specific responses and thoracic complications induced by these new therapeutic agents and finally to discuss future directions for the personalized assessment of tumor response.

An automated four-point scale scoring of segmental wall motion in echocardiography using quantified parametric images.

The aim of this paper is to develop an automated method which operates on echocardiographic dynamic loops for classifying the left ventricular regional wall motion (RWM) in a four-point scale. A non-selected group of 37 patients (2 and 4 chamber views) was studied. Each view was segmented according to the standardized segmentation using three manually positioned anatomical landmarks (the apex and the angles of the mitral annulus). The segmented data were analyzed by two independent experienced echocardiographists and the consensual RWM scores were used as a reference for comparisons. A fast and automatic parametric imaging method was used to compute and display as static color-coded parametric images both temporal and motion information contained in left ventricular dynamic echocardiograms. The amplitude and time parametric images were provided to a cardiologist for visual analysis of RWM and used for RWM quantification. A cross-validation method was applied to the segmental quantitative indices for classifying RWM in a four-point scale. A total of 518 segments were analyzed. Comparison between visual interpretation of parametric images and the reference reading resulted in an absolute agreement (Aa) of 66% and a relative agreement (Ra) of 96% and kappa (κ) coefficient of 0.61. Comparison of the automated RWM scoring against the same reference provided Aa = 64%, Ra = 96% and κ = 0.64 on the validation subset. Finally, linear regression analysis between the global quantitative index and global reference scores as well as ejection fraction resulted in correlations of 0.85 and 0.79. A new automated four-point scale scoring of RWM was developed and tested in a non-selected database. Its comparison against a consensual visual reading of dynamic echocardiograms showed its ability to classify RWM abnormalities.

Assessment of left ventricular contraction by parametric analysis of main motion (PAMM): theory and application for echocardiography.

The computerized study of the regional contraction of the left ventricle has undergone numerous developments, particularly in relation to echocardiography. A new method, parametric analysis of main motion (PAMM), is proposed in order to synthesize the information contained in a cine loop of images in parametric images. PAMM determines, for the intensity variation time curves (IVTC) observed in each pixel, two amplitude coefficients characterizing the continuous component and the alternating component; the variable component is generated from a mother curve by introducing a time shift coefficient and a scale coefficient. Two approaches, a PAMM data driven and a PAMM model driven (simpler and faster), are proposed. On the basis of the four coefficients, an amplitude image and an image of mean contraction time are synthesized and interpreted by a cardiologist. In all cases, both PAMM methods allow better IVTC adjustment than the other methods of parametric imaging used in echocardiography. A preliminary database comprising 70 segments is scored and compared with the visual analysis, taken from a consensus of two expert interpreters. The levels of absolute and relative concordance are 79% and 97%. PAMM model driven is a promising method for the rapid detection of abnormalities in left ventricle contraction.

[Image analysis in contrast echocardiography]. / Les traitements d'image en échocardiographie de contraste.

The visualization of contrast agents in echocardiography is obtained with complex acquisition sequences and their analysis is dependent on operator experience. In order to be more accessible, images analysis is essential and the main objective is to integrate qualitative and quantitative data in one single image.

[Value of factor analysis in a wall motion study: preliminary application in the detection of left ventricular segmental contraction ischemic disorders by echocardiography]. / Apport d'une analyse factorielle à l'étude de mouvements: application préliminaire à la détection par échocardiographie des troubles de la contraction segmentaire du ventricule gauche ischémique.

PURPOSE: Factor Analysis of Medical Image Sequences (FAMIS) was tested to study the regional wall motion of the left ventricle at echocardiography. MATERIALS AND METHODS: FAMIS analyzed the time signal curves of each pixel. One flat curve and one curve describing the contraction-relaxation of the left ventricle were first estimated. The contributions of the curve of each pixel to the two previous curves were computed, yielding two "factor images". The spatial distribution of positive and negative coefficients of the second factor image was analyzed. The evaluation was carried out on 222 segments (20 patients, 18 parasternal short-axis views, 17 apical four-chamber views, and 15 apical two-chamber views). A first echocardiographer reviewed the factor images and the reading was compared to the conventional reading of the cine-loops by two other echocardiographers. Each segment was scored as normal, hypokinetic, akinetic, or dyskinetic. RESULTS: On normal segments, the positive coefficients of the second factor image were on the inner side, the negative coefficients were on the outer side. Dyskinesis yields the opposite pattern. Hypokinesis and akinesis give intermediate images. An absolute concordance was obtained on 71.2% of all segments between the two types of reading. Larger discrepancies were found for akinetic and hypokinetic segments. CONCLUSION: FAMIS is a promising tool to study regional wall motion of the left ventricle.

In vitro quantification of flow using continuous infusion of Levovist and pairs of harmonic power Doppler images.

To evaluate the potential of harmonic power Doppler to quantify perfusion using a continuous infusion of contrast, two dialysis cartridges were perfused with different flow rates adjusted between 0 to 300 mL/min, corresponding to flow ratios comprised between 300:0 and 150:150. The contrast agent (Levovist, Schering) was injected at constant rates (0.6 to 5 g/h). Sequential pairs of images showing simultaneously the cross-sections of the two filters were acquired with a HDI 5000 (ATL) and the Doppler data were processed with HDI lab software (ATL). The absolute values of the signal in the different regions-of-interest (ROI) were not closely related to flow rate. At the opposite, the rapid signal decrease between the first and the second image of each pair was inversely proportional to the flow rate. An index of perfusion [PerI = image 1/(image 1 -- image 2)] was defined. It correlated closely with the absolute and relative flow rates. For the latter, the slopes of regression were found to be independent of the infusion rate of Levovist. Thus, the use of pairs of images combined with a continuous infusion of Levovist provide a quantification of perfusion.

In vitro validation of a new approach for quantitating regurgitations using proximal isovelocity surface area.

The present work has been designed to validate the calculation of the effective regurgitant orifice (ERO) area with the use of a new formula that takes into account the velocity profile (V(r) vs r) and that is insensitive to errors in the determination of the position of the orifice. Assuming a hemispheric model, ERO = 2 pi r(2). V(r)/V(o) (with V(o) = velocity at the orifice) and (V(o)/V(r))(0.5) = (2 pi/ERO)(0.5) r. Thus, the slope of the corresponding linear regression allows ERO to be calculated as: ERO = 2 pi/slope(2). This approach was tested in vitro in pulsatile conditions on circular, conical, and slit-like orifices. The calculated ERO was compared with the actual jet cross sectional area derived from the transverse velocity profile at the jet origin. For the purpose of comparison, the "classical" ERO was calculated for all the configurations, angulations, and threshold velocities. The relationship between (V(o)/V(r))(0.5) was linear (r > 0.98) over a wide range of velocities. The nonhemispheric components were found to modify the constant and not the slope. The mean variation of the calculated ERO was 6.5%. The correlation between the calculated and the actual ERO was very close (>0.97) with slope equal to 0.96. By comparison with the new method, the classical formula gave an underestimation of the ERO that dramatically increased when studying the flow closer to the orifice or in the case of error on the measurement of r. In conclusion, a method using velocity profiles instead of isolated values improves the accuracy of the proximal isovelocity surface area (PISA) method for measuring the ERO.

Estimation of pressure gradients in pulsatile flow from magnetic resonance acceleration measurements.

A method for estimating pressure gradients from MR images is demonstrated. Making the usual assumption that the flowing medium is a Newtonian fluid, and with appropriate boundary conditions, the inertial forces (or acceleration components of the flow) are proportional to the pressure gradients. The technique shown here is based on an evaluation of the inertial forces from Fourier acceleration encoding. This method provides a direct measurement of the total acceleration defined as the sum of the velocity derivative vs. time and the convective acceleration. The technique was experimentally validated by comparing MR and manometer pressure gradient measurements obtained in a pulsatile flow phantom. The results indicate that the MR determination of pressure gradients from an acceleration measurement is feasible with a good correlation with the true measurements (r = 0.97). The feasibility of the method is demonstrated in the aorta of a normal volunteer. Magn Reson Med 44:66-72, 2000.

Fluid mechanics of regurgitant jets and calculation of the effective regurgitant orifice in free or complex configurations.

The velocity fields of turbulent jets can be described using a single formula which includes two empirical constants: k(core) determining the length of the central core and k(turb) the jet widening. Flow models simulating jet adhesion, confinement and noncircular orifices were studied using laser Doppler anemometer and the modifications of the constants were derived from series of velocity profiles. In circular free jets, k(core) was found equal to 4.1 with a variability of 1.4%. In complex configurations, its variability was equal to 15.2%. For k(turb), the value for free circular jets was of 45.2 with a variability of 6.0% and this variability in complex configurations was significantly higher (30. 1%, p=0.025). The correlation between the actual orifice size and the jet extension was poor (r=0.52). However, the almost constant value of k(core) allowed to define a new algorithm calculating the regurgitant orifice diameter with the use of outlines of the jet image (r=0.89). In conclusion, the fluid mechanics of regurgitant jets is modified in complex configurations but, due to the relative independency of the central core, velocity fields could be used to evaluate the dimensions of the effective regurgitant orifice.

In vitro flow quantification with contrast power Doppler imaging.

To evaluate the effectiveness of contrast harmonic (power Doppler imaging) as an ultrasonic modality to quantify flow, an in vitro model of perfusion was studied using Optison, a second-generation ultrasound (US) contrast agent. The in vitro model was made of two dialysis cartridges placed parallel and allowed absolute and relative flow quantification on both tube (entry lines) and tissue (cartridges) simulations. Video intensity curves were generated using intermittent harmonic power Doppler imaging after bolus injection of contrast. Correlation between flow and different parameters extracted from time-intensity curves and previously defined as indicators of flow was established for both tissue and entry lines, for flow rates ranging from 0 to 400 mL/min. Single-compartment equations were also tested on the model. A good correlation for the tissue model was observed between absolute flow and onset time (O), time to maximal enhancement (TME), peak intensity (P), area under the curve (AUC), and maximal ascending slope (S) parameters, with a r = 0.94, 0.94, 0.91, 0.92 and 0.92, respectively. The correlation for O, TME, P and AUC parameters was r = 0.86, 0.90, 0.78 and 0.82, respectively for entry lines. The correlation for tissue model and entry line was slightly improved when comparing flow ratios with peak ratios (P1/P2) and slope ratios (S1/S2) (r = 0.95 and 0.94). Flow calculation using the gradient-relationship method also showed a good correlation (r = 0.88) with the experimental flow. The results obtained indicated that absolute and relative quantification of flow using PDI is feasible in tube and tissue models. Several clinical applications, namely in myocardial, hepatic and renal artery studies, could be derived from these results.

Acceleration mapping by Fourier acceleration-encoding: in vitro study and initial results in the great thoracic vessels.

Acceleration mapping can be conducted by replacing the bipolar gradient pulse of a velocity mapping sequence by a tripolar pulse. However, since the acceleration encoding pulse is longer, the image quality is altered by the requirement of a long echo time. Since Fourier encoding velocity imaging has been shown to be robust, this velocity mapping method was transformed into an acceleration mapping method. Four steps of the tripolar acceleration encoding gradient pulse were applied successively; acceleration was then obtained by Fourier transform after zero-filling. The accuracy of the method was assessed with a phantom giving a pulsatile flow. Acceleration maps of the ascending aorta and pulmonary artery were obtained in 10 healthy volunteers. The acceleration values measured were in the range of known physiologic values. The feasibility of Fourier encoding acceleration imaging was also demonstrated in four patients.

In vitro flow mapping of regurgitant jets. Systematic description of free jet with laser Doppler velocimetry.

BACKGROUND: Color Doppler and magnetic resonance imaging give pictures of abnormal jets within which the respective contribution of fluid mechanics and image artifacts are difficult to establish because of current technical limitations of these modalities. We conducted the present study to provide numerical descriptions of the velocity fields within regurgitant free jets. METHODS AND RESULTS: Laser Doppler measurements were collected in rigid models with pulsatile flow conditions, giving several series of two-dimensional flow images. The data were studied with the use of two-dimensional or M-mode flow images as well as regular plots. Numerical descriptions validated in steady flow conditions were tested at the various times of the cycle. In these free jets, the momentum was conserved throughout the cycle. The transverse velocity profiles were approximately similar. A central laminar core was found at peak ejection and during the deceleration. Its length (l = 4.08 d-0.036 mm, r = .99) and its diameter (d) were proportional to the orifice diameter. At peak ejection, the velocity decay was hyperbolic, and the transverse velocity profiles were clearly gaussian. The different relations that were tested could be combined in a single formula describing the velocity field: V(x,y,t peak) = V(O,O,t peak).4.(d/x).10(-45(y/x)2) (r = .92). CONCLUSIONS: These in vitro measurements demonstrated the presence of a central laminar core and similar transverse velocity profiles in free turbulent jets. This allowed us to validate a series of numerical relations that can be combined to describe the velocity fields at peak ejection. On the other hand, further studies are needed to describe the various singularities often encountered in pathology.

A new adaptive mean frequency estimator: application to constant variance color flow mapping.

A class of adapted mean frequency estimators is proposed for color flow mapping. These estimators can be fitted to the specific characteristics of a given Doppler signal to optimize the compromise between the range of analysable frequencies and the variance of mean frequency estimation. A sub-optimal estimator is derived for real-time applications, and an adaptive criterion based on the Doppler signal variance is developed for color flow mapping applications. Its performance is compared to that of the usual correlation phase estimator on simulated Doppler signals and on synthetic Doppler images. An improvement in image quality is achieved, mainly for low signal-to-noise ratio Doppler signals.

Smoothed power spectrum estimate applied for analysis of the Doppler signal from blood flow.

A simple method for the improvement of the definition of the instantaneous spectrum estimate of Doppler signal is proposed. A short review of the stochastical properties of FFT spectrum estimates is presented. This review allowed us to develop a concept of the 'estimation noise' as an interpretation of the stochastic uncertainty of the estimation. This, in turn, permitted us to propose a method of adaptive filtering of spectral estimation to minimise the effects of the 'estimation noise'. Proposed filtering in the frequency domain corresponds to a procedure known as smoothing of the estimate. Two different smoothing procedures are presented: classical, linear smoothing and nonlinear, homomorphic smoothing. The performances of the smoothed spectrum estimate are theoretically and experimentally studied, showing that their effectiveness depends mostly on the shape of the Doppler spectrum. Although smoothing always reduces the spectral resolution, the important limitation of the variance of estimation can be achieved without meaningful deterioration of the resolution in our application. Thus, the proposed procedures may sensibly improve the accuracy of the relationship between the shape of the spectrum and the flow parameters. As a result, more exact determination of flow characteristics such as stability or maximum velocity, even in cases of low signal-to-noise power ratio, should be possible.

Velocity profiles and streamlines of a revolution post-stenotic flow.

Velocity fields have been measured in models simulating arterial stenoses for continuous and revolution flows. A pulsed Doppler velocimeter allows for velocity readings in the entire tube and in the wall area. Streamlines are determined by numerical solving of the system of equations defining the current function. Velocity profiles and streamlines are presented and discussed either for steady or for unsteady flows, with different Reynolds numbers and variable degrees of stenosis. There is, in the wall area, a recirculating zone made of a well-defined rouleau. Its length varies increasingly according to the increasing severity of the stenosis. The stability of axial flow depends on the input profile, the degree of stenosis and the Reynolds number. Plotting streamlines allows to describe accurately the flow; its quantitative aspect offers advantages with respect to conventional visualization mode.

Influence of pulsatility on the development of intracardiac jets: an in vitro laser Doppler study.

So far, it has been hypothesized that numerical data obtained in steady flow conditions apply to pulsatile flows. In order to study the modifications of the velocity fields due to pulsatility, jets were produced by 8 orifices (with a diameter "D" of 4.4 to 11.3 mm) included in a chamber of 50 mm. The velocity was measured using laser Doppler anemometry with a pulsatile flow ("pf") and compared to the values obtained in steady ("sf"): at maximum velocity, the longitudinal velocity profile is qualitatively similar to this observed in steady flow: it is made of a plateau followed by an hyperbolic velocity decay in the turbulent area. The length of the core ("Lpf") is strongly related to "D" (Lpf = 3.72 D + 5.49, r = .99) and the velocity decay depends on the ratio between the distance "x" from the orifice and "D" (V/Vo = 2.83D/x + 3.46, r = .85, where V is the velocity at "x" and Vo the initial velocity). During the acceleration and the deceleration, the laminar core is disturbed by turbulences. The comparison of "pf" data with "sf" data demonstrated similar diameters at the origin of the jets (Dpf = 0.96 Dsf + .12, r = .99), but significant (p less than .0001) differences both for "L" and "V/Vo": Lpf = .91Lsf + 6.58, r = .97, V/Vopf = .63 V/Vosf + .34, r = .76. Thus, pulsatility modifies velocity fields and the results obtained in steady flow conditions do not apply to pulsatile jets.

In vitro analysis of a model of intracardiac jet: analysis of the central core of axisymmetric jets.

In order to provide physical information supporting the clinical use of flow mapping, an in vitro model was designed to measure the velocity fields in a pulsatile hydraulic turbulent jet. We used a peak velocity ranging from 2.5 to 5.5 m.s-1, an orifice diameter ranging from 5.8 to 11.3 mm and confined the jet in a receiving tube whose diameter ranged from 16 to 30 mm, thus simulating a large variety of valvular leaks. In steady flow conditions, our results agreed with previously reported descriptions. Under pulsatile conditions, the same structure was found at peak velocity and during the beginning of the deceleration. Below a threshold velocity, the length of the central core was independent of the peak velocity and proportional to about six times the orifice diameter. Above the threshold velocity, this relationship was no longer true, the threshold value being related to the ratio of the orifice diameter to the diameter of the receiving tube.

Doppler imaging of regurgitant jet in aortic insufficiency: experimental validation and preliminary clinical evaluation.

Aortic insufficiency induces the development of a jet within the left ventricular outflow tract. The diameter of a laminar jet is a well-defined hydraulic parameter. This study was designed to evaluate, both experimentally and in patients, the accuracy of its measurement using a Doppler imaging performed with a multigate pulsed Doppler velocimeter. The experimental validation was conducted on a water tank pulsatile model including calibrated orifices. Jet images appeared clearly delineated and were not modified when changing imaging angulation (from 85 degrees to 65 degrees), pump frequency (from 60 to 100 c min-1), pump output (from 0.5 to 3.8 l min-1), wall filtering, orifice shape, or signal-to-noise ratio. The measured jet diameter (jd) correlated closely with the orifice diameter (od): jd (mm) = 1.22 + (0.79 X od), r = 0.98. A preliminary clinical evaluation was performed on jets of aortic insufficiency on a series of 26 patients. Jet cross-section was studied within the left ventricular outflow tract using a parasternal approach. A high setting of wall filters allowed good quality imaging in 24 patients. In the absence of a diastolic jet, jd was taken equal to 0. Measured jet diameters were compared to the angiographic grade (ag): jd (mm) = 2.7 + (3.9 X ag), r = 0.86. In conclusion, jet diameter measurement using M-mode Doppler imaging is experimentally accurate and potentially valuable in patients with aortic insufficiency.

In vitro study of modifications of blood flow patterns induced by a bifurcation.

Velocity profiles obtained with atheromatous and normal bifurcation castings in the presence of various types of flows are proposed. In the atheromatous bifurcation, with steady flow, we observe radial positive or negative velocities at distance to the wall smaller than 1 mm, which may be attributed to small local eddy motions. The maximum of velocity needs a larger distance from the apex than in the case of the "normal" bifurcation to be again located on the axes. With periodical flows, the effects are strongly damped. The wall velocity gradients on several geometries of tubings are investigated to separate the effects of the local rugosity of the wall from those incidental to the geometry of the bifurcation. The alterations caused by the atheroma do not seem to be induced by local modifications or rugosity, but by slow modifications of the local diameter. As a consequence, the variations of the velocity gradient caused by atheroma in the total bifurcation, are more likely due to distance effects of the geometry itself than to local effects of rugosity.