Nothing Special   »   [go: up one dir, main page]

WO2012011872A1 - A method and/or system for determining portal hemodynamics of a subject - Google Patents

A method and/or system for determining portal hemodynamics of a subject Download PDF

Info

Publication number
WO2012011872A1
WO2012011872A1 PCT/SG2011/000258 SG2011000258W WO2012011872A1 WO 2012011872 A1 WO2012011872 A1 WO 2012011872A1 SG 2011000258 W SG2011000258 W SG 2011000258W WO 2012011872 A1 WO2012011872 A1 WO 2012011872A1
Authority
WO
WIPO (PCT)
Prior art keywords
splenic
model
tracer
portal
spleen
Prior art date
Application number
PCT/SG2011/000258
Other languages
French (fr)
Inventor
Tong San Koh
Choon Hua Thng
Original Assignee
National Cancer Centre Singapore
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by National Cancer Centre Singapore filed Critical National Cancer Centre Singapore
Publication of WO2012011872A1 publication Critical patent/WO2012011872A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/02Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/026Measuring blood flow
    • A61B5/0263Measuring blood flow using NMR
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/02Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/026Measuring blood flow
    • A61B5/0275Measuring blood flow using tracers, e.g. dye dilution
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/41Detecting, measuring or recording for evaluating the immune or lymphatic systems
    • A61B5/414Evaluating particular organs or parts of the immune or lymphatic systems
    • A61B5/416Evaluating particular organs or parts of the immune or lymphatic systems the spleen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/42Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
    • A61B5/4222Evaluating particular parts, e.g. particular organs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/02Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03Computed tomography [CT]
    • A61B6/032Transmission computed tomography [CT]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/48Diagnostic techniques
    • A61B6/481Diagnostic techniques involving the use of contrast agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/48Diagnostic techniques
    • A61B6/486Diagnostic techniques involving generating temporal series of image data
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications
    • A61B6/507Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for determination of haemodynamic parameters, e.g. perfusion CT
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/02Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03Computed tomography [CT]
    • A61B6/037Emission tomography
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/48Diagnostic techniques
    • A61B6/488Diagnostic techniques involving pre-scan acquisition

Definitions

  • the present invention relates to a method and/or system for determining portal hemodynamics of a subject.
  • the method and/or system may further determine splenic and splanchnic hemodynamics of the subject.
  • the portal vein receives blood from the spleen and the gastrointestinal tract.
  • Both splenic and splanchnic blood flow and their contributions to portal venous blood flow are important factors involved in disorders such as liver cirrhosis, splenomegaly, portal hypertension and their complications [1].
  • the ability to assess splenic and splanchnic blood flows and their relative contributions to portal venous blood flow thus have important implications in the treatment and management of several liver disorders.
  • a noninvasive imaging method which allows for in-vivo assessment of splenic and portal hemodynamics would be a valuable clinical tool to aid in the understanding and management of these disorders.
  • Quantitative assessment of blood transport within organs and tissues using tracer techniques are typically performed by two approaches (i) arterial-venous sampling approach and (ii) residual tracer analysis approach (or dynamic imaging approach).
  • the arterial-venous sampling approach involves administering one or more tracers (possibly with different transport characteristics) to a subject at an organ inlet, and subsequent sampling at a venous effluent of the organ to analyze outflow curves of the one or more tracers [2].
  • the residual tracer analysis approach involves external monitoring of tissue residual tracer content using dynamic imaging modalities.
  • the residual tracer analysis approach involves administering one or more tracers into an inlet of a tissue of interest in a subject, and subsequently monitoring the concentration of the one or more tracers remaining within the tissue of interest as a function of time. Therefore, the residual tracer analysis approach allows for in-vivo assessment of blood flow in a relatively non-invasive manner.
  • the imaging modalities used for both approaches may comprise dynamic contrast-enhanced computed tomography (DCE CT), dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) and nuclear medicine techniques such as dynamic scintigraphy and dynamic positron emission tomography (PET) [3 - 6].
  • DCE CT dynamic contrast-enhanced computed tomography
  • DCE MRI dynamic contrast-enhanced magnetic resonance imaging
  • PET dynamic positron emission tomography
  • the present invention aims to provide a new and useful method and/or system for determining portal hemodynamics of a subject.
  • the method and/or system may further determine splenic and splanchnic hemodynamics of the subject.
  • the present invention proposes modifying the arterial-venous sampling approach to provide the splanchnic hemodynamics in a non-invasive manner.
  • the modified arterial-venous sampling approach may be based on external data imaging of a tracer.
  • the residual tracer analysis approach may in turn be used in the modified arterial-venous sampling approach together with the tracer data without invasive blood sampling.
  • the subject is administered with a tracer, and the residual tracer analysis approach determines the proportion of the tracer remaining in the spleen and the splenic blood flow.
  • the arterial-venous sampling approach determines the splanchnic blood flow in the portal vein and the splenic and splanchnic contributions to the portal venous blood flow.
  • a first aspect of the present invention is a method for determining portal hemodynamics of a subject administered with a tracer, the method comprising the steps of: (a) determining tracer concentrations in an aorta, spleen and portal vein of the subject over time; (b) fitting a first model to the tracer concentrations in the spleen and aorta over time, wherein the first model relates the tracer concentrations in the spleen and aorta over time and a proportion of the tracer remaining in the spleen; and (c) determining portal hemodynamics of the subject by fitting a second model to the tracer concentrations in the portal vein and aorta over time, wherein the second model relates the tracer concentrations in the portal vein and aorta over time and a tracer concentration emerging from the portal vein, and wherein the fitting of the
  • the invention may alternatively be expressed as a computer system for performing such a method.
  • This computer system may be integrated with a device for capturing input images indicating tracer concentrations in a subject, for example, DCE CT images, DCE MRI images and images from nuclear medicine techniques such as dynamic scintigraphy and dynamic PET.
  • the invention may also be expressed as a computer program product, such as one recorded on a tangible computer medium, containing program instructions operable by a computer system to perform the steps of the method.
  • Fig. 1 illustrates a flow diagram of a method for determining portal hemodynamics of a subject in an embodiment of the present invention
  • Fig. 2 illustrates a schematic diagram of portal circulation
  • Figs. 3(a) and 3(b) illustrate a compartmental model of portal venous blood flow the method of Fig. 1 is based on;
  • Fig. 4 illustrates a block diagram showing examples of the arterial- venous sampling approach and the residual tracer analysis approach of observing an organ or tissue system during a tracer experiment;
  • Fig. 5 illustrates a table tabulating characteristics of patients in a study evaluating the method of Fig. 1 ;
  • Figs. 6(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a first patient;
  • Figs.7(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a second patient;
  • Figs. 8(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a third patient;
  • Figs. 9(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a fourth patient;
  • Figs. 10(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a fifth patient;
  • Figs. 11 (a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a sixth patient;
  • Figs. 12(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a seventh patient;
  • Figs. 13(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for an eighth patient;
  • Fig. 14 illustrates a table tabulating the splenic and splanchnic hemodynamic parameters and blood flow rates, as well as the portal venous parameters and blood flow rate of the patients in the study for evaluating the method of Fig. 1.
  • Method 100 which is an embodiment of the present invention, and which determines portal hemodynamics of a subject administered with a tracer.
  • Method 100 further determines splenic and splanchnic hemodynamics of the subject.
  • the portal hemodynamics of the subject refers to the dynamics of blood flow through the portal vein of the subject. This may comprise the splenic and splanchnic contributions to the portal venous blood flow (i.e. proportion of portal venous blood flow contributed by the splenic and splanchnic circulations) and the portal venous blood flow rate (i.e. rate of blood flow through the portal vein).
  • the splenic and splanchnic hemodynamics of the subject refers to the dynamics of blood flow through the splenic and splanchnic circulations of the subject respectively.
  • the splenic and splanchnic hemodynamics may comprise splenic and splanchnic hemodynamic parameters, and blood flow rates (i.e.
  • the splenic and splanchnic hemodynamic parameters may in turn comprise splenic and splanchnic mean transit times (i.e. average time taken by blood to traverse the splenic and splanchnic circulations respectively).
  • the hemodynamic parameters for each circulation may also comprise exchange rate constants indicating rates at which blood between a vascular space and an interstitial space of the circulation is exchanged - see Figs. 3(a) and (b).
  • the input to method 100 is a plurality of input images acquired from the subject over time. The input images are preferably acquired from one or more sections of the subject comprising both the spleen and aorta.
  • Each input dataset can be a two-(2D) or three-dimensional (3D) image dataset, with each image comprising a plurality of voxels with respective signal values from which tracer concentrations in the subject at each point in time can be deduced.
  • Each input image may be a DCE CT image, DCE MRI image or an image derived from nuclear medicine techniques such as dynamic scintigraphy and dynamic PET.
  • the intensity values of the voxels in each input image may comprise CT numbers with Hounsfield units (HU).
  • Method 100 is based on a model of portal venous blood flow with an analysis of tracer arterial-venous and residual imaging data according to Equations (A.1) - (A.7) as follows.
  • Fig. 2 illustrates a schematic diagram of portal circulation.
  • Fig. 2 illustrates the schematic representation of the relative organ positions and the relationship between portal venous, splenic and splanchnic circulations.
  • the splenic blood flow or splenic contribution to the portal venous blood flow accounts for the venous blood supply to the portal vein from the spleen.
  • the "splenic blood flow” or “splenic contribution to the portal venous blood flow” refers to the portion of the portal venous blood flow that is derived from the spleen alone, i.e. the blood flow through the splenic vein before it mixes with the blood flow from the inferior mesenteric vein.
  • the rest of the portal venous blood flow is accounted for by the splanchnic contribution.
  • the venous blood flow to the portal vein from the gastrointestinal tract forms part of the splanchnic blood flow or splanchnic contribution to the portal blood supply. This includes blood supply through the superior and inferior mesenteric veins.
  • FIGs. 3(a) and 3(b) illustrate a compartmental model of portal venous blood flow.
  • Method 100 is based on this compartmental model.
  • Fig. 3(a) illustrates a block diagram showing splenic and splanchnic contributions to the portal venous blood flow.
  • portal venous blood flow may be resolved into two components represented by a splenic block 302 and a splanchnic block 304.
  • the splenic contribution to portal venous blood flow may be represented by the splenic fraction ⁇ whereas the splanchnic contribution to the portal venous blood flow may be represented by a fraction given by 1— ⁇ .
  • Both the splenic and splanchnic blocks 302, 304 derive their blood supply from the aorta through their respective arteries, namely the splenic artery and the superior mesenteric artery.
  • Fig. 3(b) illustrates a block diagram of a two-compartment exchange model describing each of the splenic and splanchnic blocks 302, 304 of Fig. 3(a).
  • the two-compartment exchange model includes a vascular compartment representing the vascular space and an interstitial compartment representing the interstitial space, with individual blood influx and efflux rates ki, k 2 .
  • F denotes the rate of blood flow that supplies the vascular compartment and k 1 , k 2 denote the exchange rates constants indicating rates at which blood between the vascular and interstitial spaces is exchanged.
  • ki denotes the rate of efflux (backflux) of blood from the vascular space which is assumed to be equal to the rate of influx of blood into the interstitial space
  • k 2 denotes the rate of efflux of blood from the interstitial space which is assumed to be equal to the rate of influx of blood into the vascular space.
  • Each of the splenic and splanchnic blocks 302, 304 of Fig. 3(a) is associated with tracer kinetics equations and these equations can be solved to yield (i) an impulse outflow function h(t) for analysis of the organ arterial-venous tracer data, or (ii) an impulse residue function R(t) for analysis of residual tracer data (to be elaborated below).
  • h(t) and R ⁇ t) for the two- compartment exchange model are also given below.
  • h ⁇ t) and R(t) are two sides of the same coin (or tracer kinetics model). More specifically, both h(t) and R ⁇ t) allow for the estimation of hemodynamic parameters such as the vascular mean transit time MTT (i.e. average time taken by blood to traverse the vascular space), and the vascular-interstitial exchange rate constants, ki and k 2 .
  • Fig. 4 illustrates a block diagram showing the two above-mentioned approaches of observing an organ or tissue system during a tracer experiment: (i) the arterial-venous sampling approach and (ii) the residual tracer analysis approach.
  • the arterial-venous sampling approach monitors the tracer arterial inflow and venous outflow concentrations over time.
  • the function representing a tracer concentration that emerges at the venous exit 404 may be referred to as the impulse outflow response h ⁇ t) since this function represents the system's 406 output response to an impulse input S ⁇ t) .
  • the area under h(t) is unity (i.e. h(t) is normalized).
  • h(t) indicates a probability of the tracer taking time t to traverse the system 406, and can be viewed as a probability density function for traversal times such that the proportion of tracer emerging at the venous exit 404 in an infinitesimal time interval dt is given by h ⁇ t)dt (see Zierler [23]).
  • the dynamic imaging approach monitors the tracer concentration remaining in the organ or tissue of interest as a function of time. Taking the system 406 as the organ or tissue of interest, and following the unit impulse input S ⁇ t) to the system 406, the function that denotes the proportion of tracer remaining in the system 406 may be referred to as the impulse residue response R ⁇ t) since this function is the system residual response to an impulse input ⁇ ( ⁇ .
  • Equation (A.1 ) The relationship between R(t) and h(t) is as follows.
  • the amount of tracer collected in the container 408 at any time t would be the cumulative output J' h(x) dx (here x replaces t as the integration variable to avoid confusion) and the proportion of tracer R(t) remaining in the system 406 can be calculated using Equation (A.1 ) as follows.
  • Equation (A.1 ) the alternative relation between R(t) and h ⁇ t) shown in Equation (A.2) is obtained [23].
  • Equation (A.1 ) R(t) is dimensionless and R(t) ⁇ l . Furthermore h(t) is associated with units of time "1 . However, an impulse tracer input S(t) ' ⁇ s not possible to achieve in practice.
  • Equation (A.3) For an arbitrary input concentration-time curve C Art (f) at the feeding arterial inlet 402, the corresponding venous outflow C v (f) can be given by Equation (A.3) as follows.
  • Convolution is a mathematical operation that treats the input C M (t) as a series of impulses of various strengths and computes the repetitive summation of the corresponding h(t) .
  • Inherent within Equation (A.3) is the assumption of a linear time-invariant system.
  • the assumption of time-invariance (stationarity) implies that each impulse input at a later time would yield the same system response h ⁇ t) , except that the system response h ⁇ t) would be delayed accordingly in time.
  • the assumption of linearity allows the superposition of all the system responses h ⁇ t) , such that the overall output C v (r) is the summation of the individual outputs corresponding to impulse inputs weighted in height and time by C M (t) .
  • Equation (A.4) the system residual tracer concentration C tlss (f) following an arbitrary input of C Art (f) can be given by a convolution integral of the impulse residue response as shown in Equation (A.4).
  • Equation (A.4) the quantity F denotes specific tissue blood flow (i.e. rate of blood flow through the tissue). Since C liss (f) has units of tracer mass per volume of tissue and C Art (f) has units of tracer mass per volume of blood, the quantity F has units of volume of blood (ml) per time (min) per volume of tissue (ml) i.e. ml/min/ml. For simplicity, in formulating Equation (A.4), it is assumed that blood in the tissue consists of only plasma without blood cells i.e. all blood concentration curves are taken to be identical to plasma concentration curves. However, hematocrit corrections may be incorporated into Equation (A.4) if necessary (see Equation (1 ) later).
  • the two-compartment blood-tissue exchange model comprises a vascular compartment and an interstitial compartment, with the vascular compartment supplied by blood at a flow rate F.
  • the tracer kinetics of this two-compartment exchange model can be described by the following pair of mass balance equations (A.5a) and (A.5b). dC, (t)
  • ⁇ and K 2 respectively denote the transfer constants for influx of blood into the interstitial compartment (assumed to be equal to the efflux of blood out of the vascular compartment) and efflux of blood out of the interstitial compartment (assumed to be equal to the influx of blood into the vascular compartment).
  • These transfer constants i and K 2 are related to the exchange rate constants, k 1 and k 2 by Equation (A.5c).
  • the exchange rate constants and k 2 have units of time "1 (min 1 ) whereas the transfer constants ⁇ and K 2 have units of volume of blood (ml) per time (min).
  • the impulse residue response f?(i)for each of the two-compartment systems 302, 304 in Fig. 3(a) can be expressed as a bi-exponential function as shown in Equation (A.6a) [5].
  • Equation (A.2) Using Equation (A.2) and Equation (A.6a), the corresponding impulse outflow response h(t) may be derived as shown in Equation (A.7).
  • h ⁇ t) - x A expfo f) - (l - A) 2 exp(a 2 t) (A.7)
  • Method 100 comprises steps 102 - 1 10.
  • aorta and splenic tracer concentrations i.e. concentrations of the tracer in the aorta and the spleen respectively
  • step 104 splenic hemodynamic parameters and splenic blood flow rate are derived using the aorta and splenic tracer concentrations over time.
  • step 106 portal venous tracer concentrations (i.e. concentrations of the tracer in the portal vein) over time are determined.
  • splanchnic hemodynamic parameters, and splenic and splanchnic contributions to portal venous blood flow are derived using the portal venous and aorta tracer concentrations over time.
  • step 110 portal venous blood flow rate and splanchnic blood flow rate are derived using the splenic and splanchnic contributions to portal venous blood flow.
  • Step 102 Determine aorta and splenic tracer concentrations over time
  • aorta and splenic tracer concentrations in the subject over time are determined.
  • each input image comprises voxels with intensity values indicating tracer concentrations in the subject at one point in time.
  • a region of interest comprising voxels corresponding to the spleen of the subject i.e. splenic region of interest ROI sp ieen
  • a region of interest comprising voxels corresponding to the aorta of the subject i.e. aortic region of interest ROI a0 rta
  • ROI region of interest
  • the identification of the regions of interest (ROIs) may be performed automatically using imaging techniques.
  • the tracer concentrations in the spleen and aorta of the subject at the one point in time corresponding to the input image are determined.
  • the tracer concentration in the spleen is determined based on the intensity values of the voxels in the splenic region of interest ROI sp ieen
  • the tracer concentration in the aorta is determined based on the intensity values of the voxels in the aortic region of interest ROI a0 rta-
  • the tracer concentrations may be determined as the average intensity value of the voxels in the respective ROIs.
  • the tracer concentrations may be determined as the median intensity value of the voxels in the respective ROIs.
  • the average or median of the intensity values of the voxels within each ROI is assumed to be robust to the (usually slight) differences across the ROIs identified in different input images. Therefore, by repeating the above sub-steps for each input image in step 104, tracer concentrations in the spleen of the subject at different points in time (i.e. splenic tracer concentration-time points) and tracer concentrations in the aorta of the subject at different points in time (i.e. aorta tracer concentration-time points) are obtained.
  • These tracer concentration-time points may be viewed as points obtained by sampling the aorta (or splenic) concentration-time curves C Art (f) (or C spleen (f) ).
  • Step 104 Derive splenic hemodynamic parameters and splenic blood flow rate using the aorta and splenic tracer concentrations over time
  • splenic hemodynamic parameters MTT spleen , k 1 spleen and k 2 spleen and splenic blood flow rate F spleen are derived using the aorta and splenic tracer concentrations over time determined in step 102.
  • a first model relating the splenic and aorta tracer concentrations over time may be expressed in the form of Equation (1 ) (which corresponds to Equation (A.4)).
  • the first model relates the tracer concentrations in the spleen and aorta over time and a proportion of the tracer remaining in the spleen.
  • the first model comprises a residual term in the form of a splenic impulse residue function R speen (t) describing the proportion of the tracer remaining in the spleen of the subject at time t .
  • the residual term /? spleen (f) is defined by splenic hemodynamic parameters which comprise a splenic mean transit time (MTT spleen ), and exchange rates constants indicating rates at which blood between a vascular space and an interstitial space of the splenic circulation is exchanged (k 1 spleen and k 2 spleen )) (see Equations (A.6a) - (A.6c)).
  • the first model further comprises a splenic flow rate term F spleen ROI describing a rate of flow through a part of the spleen corresponding to the splenic region of interest ROI sp ieen-
  • F spleen ROI describing a rate of flow through a part of the spleen corresponding to the splenic region of interest ROI sp ieen-
  • a part of the spleen may include the entire spleen.
  • F spleen R0I is a specific quantity indicating the plasma flow through the part of the spleen corresponding to the ROI sp ieen, with units in ml per min per ml of tissue.
  • the first model further implements a hematocrit correction for correcting the tracer concentrations in the aorta to account for red blood cells in the aorta.
  • the hematocrit correction is represented by the constant Hct A which denotes the fractional hematocrit in major blood vessels (which is assumed to be equal to the fraction of blood volume in the aorta occupied by red blood cells).
  • Hct A is 0.4.
  • step 104 the first model is fitted to the tracer concentrations in the spleen and aorta over time (i.e. the splenic and aorta tracer concentration-time points derived from step 102).
  • This fitting is performed by adjusting the residual term fl spleen (f) and the splenic flow rate term F spleen ROI .
  • the adjusting of the residual term ft sp i een (0 is done by adjusting the splenic hemodynamic parameters
  • MTT spleen , spleen and k 2 spleen defining it.
  • splenic hemodynamics of the subject comprising the splenic hemodynamic parameters MTT spleen , k i,s P ieen and k 2, sp ieen defining the resulting residual term R speen (t) is determined.
  • the splenic and aorta tracer concentration-time curves O sp , een ( i) , C Art (f) satisfying Equation (1 ) and comprising the splenic and aorta tracer concentration-time points are also derived through the above fitting.
  • the first model may further comprise an additional delay parameter i " sp i een aorta to account for a difference in tracer arrival times to the spleen and the aorta.
  • the delay parameter T spleen aorta may be adjusted together with the residual term ft spteen (?) and the splenic flow rate term F spleen ROI during the fitting of the first model to the aorta and splenic tracer concentration-time points.
  • the delay parameter r spleen aorta achieving the fit between the first model and the tracer concentration-time points is generally dependent on the relative locations in the input image where the tracer concentration-time points are sampled. This value is not likely to be a characteristic of the spleen two-compartment exchange model shown in Fig. 3(b).
  • the splenic hemodynamics may further comprise a total splenic blood flow rate F spleen (for whole venous blood) that emerges at the splenic vein i.e. a rate of blood flow out of the spleen.
  • F spleen can be calculated based on the resulting splenic flow rate term F spleen ROI (derived from fitting the first model earlier) using
  • the splenic flow rate term F spleen ROI is corrected with a hematocrit correction to account for red blood cells in the splenic vein emerging from the spleen.
  • this hematocrit correction is represented by the constant Hct v which denotes the fractional hematocrit in the venous blood (which is assumed to be equal to the fraction of blood volume in the splenic vein occupied by red blood cells).
  • V spleen denotes the volume of the spleen.
  • l/ spleen is estimated from separate clinical diagnostic scans comprising the entire spleen of the subject.
  • Step 106 Derive portal venous tracer concentrations over time
  • portal venous tracer concentrations in the subject over time are determined.
  • each input image comprises voxels with intensity values indicating tracer concentrations in the subject at one point in time.
  • a region of interest comprising voxels corresponding to the portal vein of the subject (i.e. portal venous region of interest ROW) is identified in the input image.
  • This may be performed manually (for example, a region of interest (ROI) may be manually drawn in each slice of the 3D input image and the regions of interest in all the slices may then be combined to form the final ROIPV).
  • ROI region of interest
  • the identification of ROIpv may be performed automatically using imaging techniques.
  • the tracer concentration in the portal vein at the one point in time corresponding to the input image is determined based on the intensity values of the voxels in the portal venous region of interest ROIpv.
  • the tracer concentration may be determined as the average intensity value of the voxels in the ROIPV. Therefore, by repeating the above sub-steps for each input image in step 106, tracer concentrations in the portal vein of the subject at different points in time (i.e. portal venous tracer concentration-time points) are obtained. These tracer concentration-time points may be viewed as points obtained by sampling the portal venous concentration-time curve C PV (?) .
  • the ROIPV might not contain the entire portal vein and C PV (f) comprising the portal venous tracer concentration-time points could be underestimated due to partial-volume averaging effect. This partial-volume effect may be compensated during the deconvolution fitting of the portal venous tracer concentration-time points in step 108.
  • step 106 may be performed prior to step 104.
  • the portal venous tracer concentrations over time may be determined together with the aorta and splenic tracer concentrations over time in step 102.
  • Step 108 Derive splanchnic hemodynamic parameters, and splenic and splanchnic contributions to portal venous blood flow using the portal venous and aorta tracer concentrations over time
  • anchnic , k ⁇ 2 .sp .lanc .hn .ic , 'and the splenic and sp rlanchnic contributions to p rortal venous blood flow represented by and 1 - ⁇ respectively are derived using the aorta and portal venous tracer concentrations over time as determined in steps 102 and 106.
  • a second model relating portal venous and aorta tracer concentrations over time may be expressed in the form of Equation (3a) (which corresponds to Equation (A.3)).
  • the portal vein concentration-time curve C PV (f) refers to the tracer concentration of the combined output from the splenic and splanchnic blocks 302, 304 (or splenic and splanchnic two-compartment systems 302, 304) as shown in Fig. 3(a).
  • the second model relates the tracer concentrations in the portal vein and aorta over time and the tracer concentration emerging from the portal vein.
  • pC PV (f) C An (t) ® h pw (t) (3a)
  • the second model comprises an outflow term in the form of a portal impulse outflow function /7 PV (f) describing the combined impulse outflow response of the splenic and splanchnic blocks 302, 304 in Fig. 3(a), in other words, the tracer concentration emerging from the portal vein at time t .
  • the second model implements a partial volume correction for correcting the tracer concentrations in the portal vein to account for partial volume effects in the input images from which the portal venous regions of interest are identified.
  • the partial volume correction is in the form of p(> l) which is a scaling factor to correct for partial-volume effects affecting the estimation of the points in C PV (f) (i.e. the portal venous concentration-time points).
  • the portal impulse outflow function ? pv (f) in Equation (3a) is defined by splenic hemodynamics and splanchnic hemodynamics of the subject.
  • the portal impulse outflow function ⁇ ⁇ ( ⁇ ) may be further defined by a weight factor weighting the splenic and splanchnic hemodynamics whereby the weight factor indicates the splenic contribution to portal venous blood flow.
  • the portal impulse outflow function h pv (t) encompasses both splenic and splanchnic components, denoted by and /? splanchnic (f) > respectively. These splenic and splanchnic components are weighted by the weight factor in the form of the splenic fraction ⁇ .
  • the splenic fraction ⁇ represents the fraction of portal venous blood flow contributed by the splenic circulation.
  • 7 spleen (f) comprises the splenic hemodynamic parameters MTT spleen , k, ,spleen , k 2 sp
  • Equation (3b) the parameters defining the residual term R spleen ⁇ t) which achieves the fit between the first model, and the aorta and splenic concentration-time points.
  • the remaining parameters in Equation (3b) are to be determined and these include ⁇ and the splanchnic hemodynamic parameters comprised by
  • the second model is fitted to the tracer concentrations in the portal vein and aorta over time (i.e. the portal venous and aorta tracer concentration- time points). This fitting is performed by adjusting the outflow term (i.e. the portal impulse outflow function h pv ( t) ).
  • the outflow term is defined by h sp een ( t) comprising the splenic hemodynamic parameters, ft sp i anchnic (f) comprising the splanchnic hemodynamic parameters and the splenic fraction ⁇ .
  • the fitting of the second model is based on the fitting of the first model, more specifically, based on the splenic hemodynamics of the subject derived from the fitting of the first model.
  • the adjusting of the outflow term is done by adjusting ⁇ and the splanchnic hemodynamics parameters MTT splancnnic , k 1isplanchnlc , k 2,sp
  • the portal hemodynamics of the subject comprising the resulting splenic fraction ⁇ is determined.
  • the splanchnic contribution (which is also part of the portal hemodynamics) may be obtained based on the resulting splenic fraction ⁇ , in particular, it is calculated as 1 - ⁇ . Furthermore, the splanchnic hemodynamics of the subject comprising the resulting splanchnic hemodynamics parameters MTT splanchnic , k 1 sp
  • the portal venous tracer concentration-time curve C PV (f) satisfying Equation (3a) and comprising the portal venous tracer concentration- time points is also derived.
  • the scaling factor p derived from the fitting can be used to correct for partial-volume effects affecting C pv (f) .
  • the corrected portal venous concentration-time curve is given by Equation (4).
  • C PV,corr (i) pCp V (f) (4)
  • the tracer from the splenic pathway usually arrives earlier at the portal vein, as compared to the tracer from the splanchnic pathway i.e. there is usually a difference in tracer arrival times to the portal vein from the splenic and splanchnic circulations.
  • the second model may further comprise two additional delay parameters r spleen PV and i- splanchnic PV incorporated into /7 spleen (f) and
  • the delay parameters r spleen pv and r splanchnic p V are adjusted with the outflow term h P J ⁇ t) during the fitting of the second model to the aorta and portal venous tracer concentration-time points.
  • the adjustable parameters during the fitting of the second model may comprise p , ⁇ , MTT splanchnic , ic , k 2 nic , r spleer , PV and t- splanchniCiPV .
  • Step 110 Derive portal venous blood flow rate and splanchnic blood flow rate using the splenic and splanchnic contributions to portal venous blood flow
  • the portal hemodynamics of the subject may further comprise a rate of blood flow through the portal vein of the subject i.e. portal venous blood flow rate F pv whereas the splanchnic hemodynamics of the subject may further comprise a rate of blood flow through the splanchnic circulation of the subject i.e. splanchnic blood flow rate F splancnnic .
  • step 110 the portal venous blood flow rate F pv and the splanchnic blood flow rate F splanchnic are derived.
  • the portal venous blood flow rate F pv and the splanchnic blood flow rate F splanchnic may be calculated based on the splenic fraction ⁇ (derived from the fitting in step 108) and the total splenic blood flow rate F leen obtained in step 104 .
  • the total splenic blood flow rate F spleen obtained in step 104 is in turn based on the splenic flow rate term F s P ieen,Roi derived from the fitting in step 104.
  • the portal venous blood flow rate F pv and the splanchnic blood flow rate F splancnnic may be calculated using Equations (5a) and (5b).
  • DCE CT was implemented as part of a trial involving the use of a combination of anti-angiogenic agents for unresectable or metastatic hepatocellular carcinomas (HCCs). DCE CT was performed at baseline and Day 8 or Day 29 of anti-angiogenic therapy to assess the degree of inhibition of angiogenesis. Only the baseline DCE CT scans before therapy were retrospectively analyzed by the current study.
  • Fig. 5 shows a table tabulating the characteristics such as the patient demographics, method for diagnosing cirrhosis and the clinical parameters (e.g. Child's score, and presence of collaterals) of the eight patients.
  • DCE CT was performed using a 64-detector row CT scanner (Lightspeed; General Electric Medical Systems, Milwaukee, Wisconsin).
  • the dynamic CT protocol comprised 27 acquisitions (1 00 kV, 80 mAs, Cine mode with 8 rows of 5 mm collimation, 1 -sec gantry rotation, Field of View 50 x50 cm, Matrix 51 2x51 2) at the following scan and breath-hold timings: 0 (Start of injection at 0 sec), (instruction to breathe and hold, BH) 8, 1 0, 1 2, 1 4, 1 6, 1 8, 20, 22, 24, 26, 28, 32, 36, (BH), 40, 44, 48, 52, 56, (BH), 64, (BH) 76, (BH), 88, (BH), 1 00, (BH), 1 1 2, (BH), 1 24, (BH), 1 36, (BH), and 148 sec.
  • Combined radiation dosage of the scouts and the 27 dynamic scans was estimated to be 62.1 mSv, using an anthropomorphic phantom.
  • a bolus infusion of 70 ml of contrast agent (Omnipaque; General Electric Healthcare, Princeton, NJ) was administered to each patient intravenously at 4 ml/sec using an automatic injector via an antecubital vein.
  • the contrast agent was immediately followed by 30 ml of saline solution at the same flow rate.
  • the ROIs i.e. ROI a0 rta and ROIPV
  • ROIsp ieen An ROI including the whole spleen (ROI sp ieen) as seen on each scan image was also drawn.
  • the ROIs were drawn by a radiologist (CHT with more than 10 years of experience).
  • Intensity values in the form of CT numbers (Hounsfield units HU) of voxels within each ROI were averaged to yield the tracer concentration-time points. The linear relationship between tracer concentration and CT numbers were separately validated using phantom experiments.
  • the splenic and portal vein tracer concentration-time curves C PV (f) derived from the DCE CT images by method 100 can be appropriately described by the portal venous circulatory model.
  • Figs. 6 - 13 show the tracer concentration-time curves C pv (f) .
  • part (a) illustrates a slice of one of the input images showing the outlines of the various ROIs identified for obtaining the tracer concentration-time points.
  • ROIs 602, 702, 802, 902, 1002 are the ROIs comprising voxels corresponding to the aorta i.e. ROI a0 rta
  • ROIs 604, 704, 804, 904, 1004 are the ROIs comprising voxels corresponding to the portal vein i.e. ROIPV
  • ROIs 606, 706, 806, 906, 1006 are the ROIs comprising voxels corresponding to the spleen i.e.
  • ROI sp i e en- Part (b) of Figs. 6 - 13 illustrate the various tracer concentration-time curves obtained from fitting the first and second models to the average intensity values in the ROIs identified in the DCE CT images.
  • Part (c) of Figs. 6 - 13 show the impulse residue function and impulse outflow functions derived from the fittings of the first and second models to the respective tracer concentration-time points.
  • Fig. 14 shows a table tabulating the splenic and splanchnic hemodynamic parameters and blood flow rates, as well as the portal venous parameters and blood flow rate derived in this study.
  • these parameters are derived from parametric deconvolution analysis.
  • the splenic hemodynamics parameters are derived by fitting the first model to the splenic and aorta tracer concentration-time points whereas the splanchnic and portal vein (PV) parameters are derived by fitting the second model to the portal venous and aorta tracer concentration-time points.
  • the splenic component of portal venous blood flow is about 40% (i.e.
  • the splenic fraction ⁇ which specifies the splenic contribution to portal venous blood flow was found to be very close to 1 (i.e. very close to 100%, with negligible splanchnic contribution to portal venous blood flow).
  • the portal venous concentration- time curves C pv (f) for these patients may be predominantly described using splenic parameters.
  • the portal venous concentration-time curve C pv (f) may be completely specified using only the splenic parameters derived from fitting the first model to the splenic and aorta tracer concentration-time points and any adjustment of the splanchnic parameters had no effect on improving the fitting of the second model to the portal venous and aorta tracer concentration-time points.
  • the splenic and portal venous tracer concentration-time curves C spleen (f) and C PV (f) for Patients 4 and 8 are respectively shown in Figs. 9 and 13.
  • Zwiebel et al [8] estimated splenic artery blood flow rate in 17 patients with cirrhosis and portal hypertension to be 599 ⁇ 340 ml/min. This was significantly higher than that in healthy subjects whose estimated splenic artery blood flow rate was found to be about 413 ⁇ 1 10 ml/min. According to Zwiebel et al [8], splenic artery blood flow rate was particularly increased in patients with splenomegaly. The splenic blood flow rate in cirrhotic patients derived using method 100 was 624.41 ⁇ 466.65 ml/min which is similar to the results of Zwiebel et al [8].
  • Zwiebel et al [8] also reported an increase in blood flow rate in the superior mesentery artery (SMA) for patients with cirrhosis and portal hypertension.
  • SMA superior mesentery artery
  • the blood flow rate of these patients with cirrhosis and portal hypertension is approximately 574 ⁇ 220 ml/min whereas the blood flow rate of healthy subjects is approximately 445 ⁇ 63 ml/min.
  • porto-systemic collaterals were present and thus, whether the estimated superior mesenteric arterial blood flow was likely to be largely channeled to the portal vein through the mesenteric veins.
  • the portion of splanchnic blood flow that contributes directly to portal venous flow is calculated.
  • the splanchnic blood flow rate that channels into portal venous flow is found to be 139.4 ⁇ 120.2 ml/min, which is much lower than estimates of blood flow rates in the superior mesenteric artery. This may be due to the presence of portosystemic shunts in some of the patients such that in these patients, only a portion of blood flow in the mesenteric arteries was channeled into the portal vein (note that para-esophageal collaterals were observed in 5 out of the 8 patients examined in the clinical feasibility study).
  • Fine et al [6] studied splenic and splanchnic transit times with tracer kinetics models formulated by a combination of gamma density functions. Their estimates for splenic mean transit time was 5.07 ⁇ 0.701 sec for normal subjects, which is significantly lower than 1 1 .3sec and 29.8 sec for two of their subjects with portal hypertension. Their estimates for blood mean transit time through the gastrointestinal tract was 21 .93 ⁇ 2.88 sec for normal subjects, and 29.0 sec and 17.0 sec for the two subjects with portal hypertension. Referring to Fig.
  • the splenic and splanchnic mean transit times for cirrhotic patients derived using method 100 from the above study are respectively, 15.3 ⁇ 10.1 sec and 23.6 ⁇ 12.1 sec, which are in good agreement with those estimated by Fine et al [6].
  • Partial-volume correction factors p were close to unity (between 1 and 1.04) in 4 cases (Patients 1 , 2, 4, and 8), suggesting that the portal venous concentration-time curve C pv (f) was appropriately sampled in these cases (i.e. the portal venous tracer concentration-time points obtained in step 106 were relatively accurate), ranged between 1.1 and 1 .3 in the other 4 cases.
  • the above study may further include normal subjects as control subjects.
  • the above study may further implement steps to validate the various parameters obtained.
  • DCE CT datasets were used to evaluate method 100 in the above study, method 100 is not limited to using DCE CT images and can similarly be applied on other types of images such as DCE MRI images. However, it is preferable not to use method 100 on images with motion or breathing artifacts or images from techniques which are unable to capture the aorta, portal vein and spleen on a single scan plane.
  • Method 100 employs a combination of deconvolution analysis and portal venous circulatory modeling and allows for separate estimation of splenic and splanchnic components to portal venous blood flow using dynamic contrast- enhanced CT or MR imaging.
  • Method 100 exploits the inventors' observations that major blood vessels such as the aorta or portal vein are usually visible on DCE CT scans and thus, allow for in-vivo monitoring of inlet and outflow tracer concentration-time curves.
  • method 100 uses a novel combination of both arterial-venous and residual tracer analysis approaches to derive quantitative estimates for portal blood flow and to resolve the relative contributions to the portal blood flow from splenic and splanchnic circulation.
  • method 100 first employs the residual tracer analysis approach to determine splenic hemodynamics of the subject, and then by coupling with the arterial-venous approach, further allow the derivation of the splenic fraction ⁇ (i.e. fraction of the portal venous blood flow contributed by the splenic circulation) and other portal hemodynamics parameters.
  • splenic fraction ⁇ i.e. fraction of the portal venous blood flow contributed by the splenic circulation
  • Method 100 is a deconvolution method that can be used to resolve the splenic and splanchnic contributions to portal venous blood flow and derive quantitative estimates describing splenic and portal blood flow.
  • a parametric deconvolution approach is adopted, by first assuming the functional forms of h(t) and R(t) through tracer kinetics modeling, and subsequently fitting models comprising these functional forms by adjusting the model parameters.
  • the method 100 can be implemented using most types of medical images such as DCE CT or MR images. As shown in the above study using DCE CT datasets of 8 cirrhotic patients, method 100 can accurately estimate several portal parameters, and splenic and splanchnic hemodynamic parameters, including splenic and splanchnic mean vascular transit times.
  • Portal venous return from the bowel can take several different routes of which the superior mesenteric vein and the inferior mesenteric vein are the major channels.
  • smaller veins which may drain directly into the portal or splenic veins, such as the short gastric veins, the right and left gastroepiploic veins or pancreaticoduodenal veins.
  • Method 100 is able to account for the blood flow from these smaller veins by simply subtracting the calculated splenic blood flow from the total portal venous blood flow. It does not matter if these smaller veins drain into the splenic vein or the main portal vein branches because they would have been accounted for in method 100 by subtracting the calculated splenic flow from the total portal venous blood flow.
  • Method 100 can be applied on the same DCE imaging dataset for both spleen and portal hemodynamics analysis. Hence, both liver parenchyma perfusion and portal hemodynamics can be concurrently studied using the same set of DCE scans.
  • an accurate C pv (f) is important in liver perfusion assessment using DCE CT or MR imaging.
  • Blood is supplied to the liver by both the hepatic artery and the portal vein, and the hepatic perfusion ratio between the hepatic artery and portal vein has been found to vary in patients with liver tumors and cirrhosis.
  • Reliable assessment of hepatic perfusion and the hepatic perfusion ratio would depend on the accuracy of both input curves, C M (t) and C pv (f) . If C pv (f) was underestimated due to partial-volume effects, the liver parenchyma perfusion parameters subsequently estimated could also be affected.
  • Method 100 corrects for partial-volume effects in C pv (f) before performing liver perfusion analysis. Thus, it can achieve more accurate results.
  • the portal venous impulse outflow response model (which method 100 is based on) can be used in situations where the portal vein cannot be captured during imaging (i.e. when only the aorta tracer concentration-time curve C M (t) can be sampled). If an estimate of C PV (f) is required for further analysis, an approximate C pv (f) function can be derived by convolving the sampled C M ⁇ t) with a model hp V (t) using typical values of splenic and splanchnic parameters pertaining to the particular patient's demographic profile. In addition, quantifying portal venous blood flow and separately identifying the splenic and splanchnic components has potential clinical applications. These include assessing patients with small-for-size liver graft, monitoring the activity of Crohn's disease and monitoring the efficacy of medical therapies for portal hypertension as elaborated below.
  • Small-for-size liver graft is a complication that may occur in liver transplantation [9]. More specifically, small-for-size liver graft refers to the situation in which the transplanted liver is too small to receive the patient's portal blood flow. Barotrauma occurs to the graft and the patient suffers deterioration in liver function. Splenectomy is one possible treatment for this condition. In splenectomy, the portal blood flow from the spleen is reduced by removing the spleen [10-14]. Other strategies for decompressing the portal circulation by shunts have also been considered [15, 16].
  • Method 100 is advantageous as it is able to yield information on the proportion of portal venous blood flow contributed by the splenic and the splanchnic circulation. With this information, a more rational decision on whether to perform splenectomy or a portosystemic shunting procedure may be made. Similar use of method 100 in patients with portal hypertension may also facilitate the selection of patients for splenectomy or shunting procedures.
  • Fine DR Glasser D, Hildebrandt D, Esser J, Lurie RE, Chetty N. An anatomic and physiologic model of hepatic vascular system. Am J Physiol 1995;79(3):1008-1026.
  • Yoshizumi T Taketomi A, Soejima Y, Ikegami T, Uchiyama H, Kayashima H, Harada N, Yamashita Y, Kawanaka H, Nishizak T, Maehara Y. The beneficial role of simultaneous splenectomy in living donor liver transplantation in patients with small-for-size graft. Transpl Int 2008; 21 : 833-42.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Pathology (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Radiology & Medical Imaging (AREA)
  • Optics & Photonics (AREA)
  • Physiology (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Immunology (AREA)
  • Vascular Medicine (AREA)
  • Endocrinology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dentistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Pulmonology (AREA)
  • Theoretical Computer Science (AREA)
  • Measuring Pulse, Heart Rate, Blood Pressure Or Blood Flow (AREA)
  • Apparatus For Radiation Diagnosis (AREA)

Abstract

A method for determining portal hemodynamics of a subject administered with a tracer is disclosed. The method comprises the steps of: (a) determining tracer concentrations in an aorta, spleen and portal vein of the subject over time; (b) fitting a first model to the tracer concentrations in the spleen and aorta over time, wherein the first model relates the tracer concentrations in the spleen and aorta over time and a proportion of the tracer remaining in the spleen; and (c) determining portal hemodynamics of the subject by fitting a second model to the tracer concentrations in the portal vein and aorta over time, wherein the second model relates the tracer concentrations in the portal vein and aorta over time and a tracer concentration emerging from the portal vein, and wherein the fitting of the second model is based on the fitting of the first model.

Description

A Method and/or System for Determining Portal Hemodynamics of a Subject
Field of the invention The present invention relates to a method and/or system for determining portal hemodynamics of a subject. The method and/or system may further determine splenic and splanchnic hemodynamics of the subject.
Background of the Invention
In a human body, the portal vein receives blood from the spleen and the gastrointestinal tract. Both splenic and splanchnic blood flow and their contributions to portal venous blood flow are important factors involved in disorders such as liver cirrhosis, splenomegaly, portal hypertension and their complications [1]. The ability to assess splenic and splanchnic blood flows and their relative contributions to portal venous blood flow thus have important implications in the treatment and management of several liver disorders. A noninvasive imaging method which allows for in-vivo assessment of splenic and portal hemodynamics would be a valuable clinical tool to aid in the understanding and management of these disorders.
Quantitative assessment of blood transport within organs and tissues using tracer techniques are typically performed by two approaches (i) arterial-venous sampling approach and (ii) residual tracer analysis approach (or dynamic imaging approach). The arterial-venous sampling approach involves administering one or more tracers (possibly with different transport characteristics) to a subject at an organ inlet, and subsequent sampling at a venous effluent of the organ to analyze outflow curves of the one or more tracers [2]. The residual tracer analysis approach involves external monitoring of tissue residual tracer content using dynamic imaging modalities. In particular, the residual tracer analysis approach involves administering one or more tracers into an inlet of a tissue of interest in a subject, and subsequently monitoring the concentration of the one or more tracers remaining within the tissue of interest as a function of time. Therefore, the residual tracer analysis approach allows for in-vivo assessment of blood flow in a relatively non-invasive manner. The imaging modalities used for both approaches may comprise dynamic contrast-enhanced computed tomography (DCE CT), dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) and nuclear medicine techniques such as dynamic scintigraphy and dynamic positron emission tomography (PET) [3 - 6]. However since the arterial-venous sampling approach is invasive, this may be less desirable.
Summary of the invention The present invention aims to provide a new and useful method and/or system for determining portal hemodynamics of a subject. The method and/or system may further determine splenic and splanchnic hemodynamics of the subject.
In general terms, the present invention proposes modifying the arterial-venous sampling approach to provide the splanchnic hemodynamics in a non-invasive manner. The modified arterial-venous sampling approach may be based on external data imaging of a tracer. For example the residual tracer analysis approach may in turn be used in the modified arterial-venous sampling approach together with the tracer data without invasive blood sampling. Initially the subject is administered with a tracer, and the residual tracer analysis approach determines the proportion of the tracer remaining in the spleen and the splenic blood flow. Then the arterial-venous sampling approach determines the splanchnic blood flow in the portal vein and the splenic and splanchnic contributions to the portal venous blood flow. A non invasive procedure may have the advantage of reduced risk, reduced cost, faster test procedure, lower chance of infection and/or lower recuperation time. Specifically, a first aspect of the present invention is a method for determining portal hemodynamics of a subject administered with a tracer, the method comprising the steps of: (a) determining tracer concentrations in an aorta, spleen and portal vein of the subject over time; (b) fitting a first model to the tracer concentrations in the spleen and aorta over time, wherein the first model relates the tracer concentrations in the spleen and aorta over time and a proportion of the tracer remaining in the spleen; and (c) determining portal hemodynamics of the subject by fitting a second model to the tracer concentrations in the portal vein and aorta over time, wherein the second model relates the tracer concentrations in the portal vein and aorta over time and a tracer concentration emerging from the portal vein, and wherein the fitting of the second model is based on the fitting of the first model.
The invention may alternatively be expressed as a computer system for performing such a method. This computer system may be integrated with a device for capturing input images indicating tracer concentrations in a subject, for example, DCE CT images, DCE MRI images and images from nuclear medicine techniques such as dynamic scintigraphy and dynamic PET. The invention may also be expressed as a computer program product, such as one recorded on a tangible computer medium, containing program instructions operable by a computer system to perform the steps of the method.
Brief Description of the Figures An embodiment of the invention will now be illustrated for the sake of example only with reference to the following drawings, in which:
Fig. 1 illustrates a flow diagram of a method for determining portal hemodynamics of a subject in an embodiment of the present invention;
Fig. 2 illustrates a schematic diagram of portal circulation;
Figs. 3(a) and 3(b) illustrate a compartmental model of portal venous blood flow the method of Fig. 1 is based on; Fig. 4 illustrates a block diagram showing examples of the arterial- venous sampling approach and the residual tracer analysis approach of observing an organ or tissue system during a tracer experiment;
Fig. 5 illustrates a table tabulating characteristics of patients in a study evaluating the method of Fig. 1 ;
Figs. 6(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a first patient;
Figs.7(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a second patient;
Figs. 8(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a third patient;
Figs. 9(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a fourth patient;
Figs. 10(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a fifth patient;
Figs. 11 (a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a sixth patient;
Figs. 12(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for a seventh patient;
Figs. 13(a) - (c) respectively illustrate a slice of one input image showing outlines of identified regions of interests, tracer concentration-time curves obtained with the method of Fig. 1 , and impulse residue and outflow functions obtained with the method of Fig. 1 for an eighth patient; and
Fig. 14 illustrates a table tabulating the splenic and splanchnic hemodynamic parameters and blood flow rates, as well as the portal venous parameters and blood flow rate of the patients in the study for evaluating the method of Fig. 1.
Detailed Description of the Embodiments
Referring to Fig. 1 , the steps are illustrated of a method 100 which is an embodiment of the present invention, and which determines portal hemodynamics of a subject administered with a tracer. Method 100 further determines splenic and splanchnic hemodynamics of the subject.
The portal hemodynamics of the subject refers to the dynamics of blood flow through the portal vein of the subject. This may comprise the splenic and splanchnic contributions to the portal venous blood flow (i.e. proportion of portal venous blood flow contributed by the splenic and splanchnic circulations) and the portal venous blood flow rate (i.e. rate of blood flow through the portal vein). Similarly, the splenic and splanchnic hemodynamics of the subject refers to the dynamics of blood flow through the splenic and splanchnic circulations of the subject respectively. The splenic and splanchnic hemodynamics may comprise splenic and splanchnic hemodynamic parameters, and blood flow rates (i.e. rates of blood flow through the splenic and splanchnic circulations). The splenic and splanchnic hemodynamic parameters may in turn comprise splenic and splanchnic mean transit times (i.e. average time taken by blood to traverse the splenic and splanchnic circulations respectively). The hemodynamic parameters for each circulation may also comprise exchange rate constants indicating rates at which blood between a vascular space and an interstitial space of the circulation is exchanged - see Figs. 3(a) and (b). The input to method 100 is a plurality of input images acquired from the subject over time. The input images are preferably acquired from one or more sections of the subject comprising both the spleen and aorta. Each input dataset can be a two-(2D) or three-dimensional (3D) image dataset, with each image comprising a plurality of voxels with respective signal values from which tracer concentrations in the subject at each point in time can be deduced. Each input image may be a DCE CT image, DCE MRI image or an image derived from nuclear medicine techniques such as dynamic scintigraphy and dynamic PET. For example, in the case that CT is used, the intensity values of the voxels in each input image may comprise CT numbers with Hounsfield units (HU).
Method 100 is based on a model of portal venous blood flow with an analysis of tracer arterial-venous and residual imaging data according to Equations (A.1) - (A.7) as follows. Model of portal venous blood flow
Fig. 2 illustrates a schematic diagram of portal circulation. In particular, Fig. 2 illustrates the schematic representation of the relative organ positions and the relationship between portal venous, splenic and splanchnic circulations.
The splenic blood flow or splenic contribution to the portal venous blood flow accounts for the venous blood supply to the portal vein from the spleen. Note that although the inferior mesenteric vein joins the splenic vein before reaching the portal vein (see Fig. 2), in this document, the "splenic blood flow" or "splenic contribution to the portal venous blood flow" refers to the portion of the portal venous blood flow that is derived from the spleen alone, i.e. the blood flow through the splenic vein before it mixes with the blood flow from the inferior mesenteric vein. The rest of the portal venous blood flow is accounted for by the splanchnic contribution. Referring to Fig. 2, the venous blood flow to the portal vein from the gastrointestinal tract forms part of the splanchnic blood flow or splanchnic contribution to the portal blood supply. This includes blood supply through the superior and inferior mesenteric veins.
Figs. 3(a) and 3(b) illustrate a compartmental model of portal venous blood flow. Method 100 is based on this compartmental model. In particular, Fig. 3(a) illustrates a block diagram showing splenic and splanchnic contributions to the portal venous blood flow. As illustrated in Fig. 3(a), by specifying a splenic fraction β (note that β need not be a fraction and may be any other measure of a proportion), portal venous blood flow may be resolved into two components represented by a splenic block 302 and a splanchnic block 304. In particular, the splenic contribution to portal venous blood flow may be represented by the splenic fraction β whereas the splanchnic contribution to the portal venous blood flow may be represented by a fraction given by 1— β . Both the splenic and splanchnic blocks 302, 304 derive their blood supply from the aorta through their respective arteries, namely the splenic artery and the superior mesenteric artery.
Fig. 3(b) illustrates a block diagram of a two-compartment exchange model describing each of the splenic and splanchnic blocks 302, 304 of Fig. 3(a). The two-compartment exchange model includes a vascular compartment representing the vascular space and an interstitial compartment representing the interstitial space, with individual blood influx and efflux rates ki, k2. In Fig. 3(b), F denotes the rate of blood flow that supplies the vascular compartment and k1 , k2 denote the exchange rates constants indicating rates at which blood between the vascular and interstitial spaces is exchanged. In particular, ki denotes the rate of efflux (backflux) of blood from the vascular space which is assumed to be equal to the rate of influx of blood into the interstitial space whereas k2 denotes the rate of efflux of blood from the interstitial space which is assumed to be equal to the rate of influx of blood into the vascular space.
Each of the splenic and splanchnic blocks 302, 304 of Fig. 3(a) is associated with tracer kinetics equations and these equations can be solved to yield (i) an impulse outflow function h(t) for analysis of the organ arterial-venous tracer data, or (ii) an impulse residue function R(t) for analysis of residual tracer data (to be elaborated below). Explicit forms of h(t) and R{t) for the two- compartment exchange model are also given below. Note that h{t) and R(t) are two sides of the same coin (or tracer kinetics model). More specifically, both h(t) and R{t) allow for the estimation of hemodynamic parameters such as the vascular mean transit time MTT (i.e. average time taken by blood to traverse the vascular space), and the vascular-interstitial exchange rate constants, ki and k2.
Analysis of tracer arterial-venous and residual imaging data
Fig. 4 illustrates a block diagram showing the two above-mentioned approaches of observing an organ or tissue system during a tracer experiment: (i) the arterial-venous sampling approach and (ii) the residual tracer analysis approach.
The arterial-venous sampling approach monitors the tracer arterial inflow and venous outflow concentrations over time. Referring to Fig. 4, considering a hypothetical unit tracer impulse input S(t) to the system 406 at the arterial inlet 402, the function representing a tracer concentration that emerges at the venous exit 404 may be referred to as the impulse outflow response h{t) since this function represents the system's 406 output response to an impulse input S{t) . Assuming the conservation of tracer mass for this system 406, the area under h(t) is unity (i.e. h(t) is normalized). Statistically, h(t) indicates a probability of the tracer taking time t to traverse the system 406, and can be viewed as a probability density function for traversal times such that the proportion of tracer emerging at the venous exit 404 in an infinitesimal time interval dt is given by h{t)dt (see Zierler [23]). The dynamic imaging approach monitors the tracer concentration remaining in the organ or tissue of interest as a function of time. Taking the system 406 as the organ or tissue of interest, and following the unit impulse input S{t) to the system 406, the function that denotes the proportion of tracer remaining in the system 406 may be referred to as the impulse residue response R{t) since this function is the system residual response to an impulse input δ(ή .
The relationship between R(t) and h(t) is as follows. Consider a hypothetical container 408 placed at the venous end 404 of the system 406 to collect tracer output during the experiment, the amount of tracer collected in the container 408 at any time t would be the cumulative output J' h(x) dx (here x replaces t as the integration variable to avoid confusion) and the proportion of tracer R(t) remaining in the system 406 can be calculated using Equation (A.1 ) as follows.
R(t) = 1 - [ h{x) dx (A.1 )
Differentiating Equation (A.1 ), the alternative relation between R(t) and h{t) shown in Equation (A.2) is obtained [23].
h(t) = - R(t) . (A.2) dt
Note that in Equation (A.1 ), R(t) is dimensionless and R(t)≤l . Furthermore h(t) is associated with units of time"1. However, an impulse tracer input S(t) '\s not possible to achieve in practice. For an arbitrary input concentration-time curve CArt(f) at the feeding arterial inlet 402, the corresponding venous outflow Cv(f) can be given by Equation (A.3) as follows.
Cv (f) = CM (t) ® (t) = Q' CM (x) h(t - x) dx (A.3)
Convolution, as denoted by ® , is a mathematical operation that treats the input CM(t) as a series of impulses of various strengths and computes the repetitive summation of the corresponding h(t) . Inherent within Equation (A.3) is the assumption of a linear time-invariant system. The assumption of time-invariance (stationarity) implies that each impulse input at a later time would yield the same system response h{t) , except that the system response h{t) would be delayed accordingly in time. The assumption of linearity allows the superposition of all the system responses h{t) , such that the overall output Cv(r) is the summation of the individual outputs corresponding to impulse inputs weighted in height and time by CM(t) .
Similarly, the system residual tracer concentration Ctlss(f) following an arbitrary input of CArt(f) can be given by a convolution integral of the impulse residue response as shown in Equation (A.4).
Ctss (t) = F CM.(t) ® R(t) . (A.4) In Equation (A.4), the quantity F denotes specific tissue blood flow (i.e. rate of blood flow through the tissue). Since Cliss(f) has units of tracer mass per volume of tissue and CArt(f) has units of tracer mass per volume of blood, the quantity F has units of volume of blood (ml) per time (min) per volume of tissue (ml) i.e. ml/min/ml. For simplicity, in formulating Equation (A.4), it is assumed that blood in the tissue consists of only plasma without blood cells i.e. all blood concentration curves are taken to be identical to plasma concentration curves. However, hematocrit corrections may be incorporated into Equation (A.4) if necessary (see Equation (1 ) later).
Given CM(t) and Cv (f) , it is possible to estimate h(t) in Equation (A.3) by deconvolution. Similarly, it is possible to estimate F, R(t) in Equation (A.4) given CM(t) and Ctiss(f) . Impulse response functions of the two-compartment exchange model
Referring to Fig. 3(b), the two-compartment blood-tissue exchange model comprises a vascular compartment and an interstitial compartment, with the vascular compartment supplied by blood at a flow rate F. The tracer kinetics of this two-compartment exchange model can be described by the following pair of mass balance equations (A.5a) and (A.5b). dC, (t)
= - F C, (t) - K& (t) + K2C2{t) + S(t) (A.5a) dt dC2 (t)
= K& {t) - K2C2 {t) (A.5b) dt
In Equations (A.5a) and (A.5b), S(t) is an unit impulse input at t = 0 , C{ and C2 respectively denote the tracer concentrations within the vascular and interstitial compartments, and vl and v2 denote the respective fractional volumes. Κ and K2 respectively denote the transfer constants for influx of blood into the interstitial compartment (assumed to be equal to the efflux of blood out of the vascular compartment) and efflux of blood out of the interstitial compartment (assumed to be equal to the influx of blood into the vascular compartment). These transfer constants i and K2 are related to the exchange rate constants, k1 and k2 by Equation (A.5c). The exchange rate constants and k2 have units of time"1 (min 1) whereas the transfer constants Κ and K2 have units of volume of blood (ml) per time (min).
Figure imgf000014_0001
The impulse residue response f?(i)for each of the two-compartment systems 302, 304 in Fig. 3(a) can be expressed as a bi-exponential function as shown in Equation (A.6a) [5].
R{t ) = A exp(<z, t) + (l - A) exp(ar2 t) , (A.6a) where
a2 (A.6b)
Figure imgf000014_0002
and
A = ai + kl + l<2 (A.6c)
Since the vascular mean transit time for each two-compartment system 302, 304 can be expressed as MTT =— , R{t) for the two-compartment system can be completely specified by the parameters MTT, k{ and k2 of the two- compartment system.
Using Equation (A.2) and Equation (A.6a), the corresponding impulse outflow response h(t) may be derived as shown in Equation (A.7). h{t) = - xA expfo f) - (l - A) 2 exp(a2 t) (A.7)
Steps 102 - 110 of method 100
Method 100 comprises steps 102 - 1 10.
In step 102, aorta and splenic tracer concentrations (i.e. concentrations of the tracer in the aorta and the spleen respectively) over time are determined. In step 104, splenic hemodynamic parameters and splenic blood flow rate are derived using the aorta and splenic tracer concentrations over time. Next, in step 106, portal venous tracer concentrations (i.e. concentrations of the tracer in the portal vein) over time are determined. In step 108, splanchnic hemodynamic parameters, and splenic and splanchnic contributions to portal venous blood flow are derived using the portal venous and aorta tracer concentrations over time. Further in step 110, portal venous blood flow rate and splanchnic blood flow rate are derived using the splenic and splanchnic contributions to portal venous blood flow.
These steps 102 - 1 10 will now be described in more detail.
Step 102: Determine aorta and splenic tracer concentrations over time In step 102, aorta and splenic tracer concentrations in the subject over time are determined.
In one example, in step 102, the following sub-steps are performed for each input image. As mentioned before, each input image comprises voxels with intensity values indicating tracer concentrations in the subject at one point in time.
In the first sub-step, a region of interest comprising voxels corresponding to the spleen of the subject (i.e. splenic region of interest ROIspieen) and a region of interest comprising voxels corresponding to the aorta of the subject (i.e. aortic region of interest ROIa0rta) are identified in the input image. This may be performed manually. For example, a region of interest (ROI) may be manually drawn in each slice of the 3D input image and the regions of interest in all the slices may then be combined to form the final ROI. Alternatively, the identification of the regions of interest (ROIs) may be performed automatically using imaging techniques. The identified ROIs usually do not differ by much across the plurality of input images. In the next sub-step, the tracer concentrations in the spleen and aorta of the subject at the one point in time corresponding to the input image are determined. In particular, the tracer concentration in the spleen is determined based on the intensity values of the voxels in the splenic region of interest ROIspieen whereas the tracer concentration in the aorta is determined based on the intensity values of the voxels in the aortic region of interest ROIa0rta- In one example, the tracer concentrations may be determined as the average intensity value of the voxels in the respective ROIs. In another example, the tracer concentrations may be determined as the median intensity value of the voxels in the respective ROIs. The average or median of the intensity values of the voxels within each ROI is assumed to be robust to the (usually slight) differences across the ROIs identified in different input images. Therefore, by repeating the above sub-steps for each input image in step 104, tracer concentrations in the spleen of the subject at different points in time (i.e. splenic tracer concentration-time points) and tracer concentrations in the aorta of the subject at different points in time (i.e. aorta tracer concentration-time points) are obtained. These tracer concentration-time points may be viewed as points obtained by sampling the aorta (or splenic) concentration-time curves CArt(f) (or Cspleen(f) ).
Step 104: Derive splenic hemodynamic parameters and splenic blood flow rate using the aorta and splenic tracer concentrations over time
In step 104, splenic hemodynamic parameters MTTspleen , k1 spleen and k2 spleen and splenic blood flow rate Fspleen are derived using the aorta and splenic tracer concentrations over time determined in step 102.
Referring to Fig. 2, it can be seen that the arterial inlet of the spleen is the inlet of the splenic artery. Furthermore, the splenic artery receives blood from the aorta. Therefore, considering the spleen as the system 406 in Fig. 4 and using the residual tracer analysis approach, a first model relating the splenic and aorta tracer concentrations over time (in other words, the splenic and aorta tracer concentration-time curves Csp,een(i) , CArt(f)) may be expressed in the form of Equation (1 ) (which corresponds to Equation (A.4)). The first model relates the tracer concentrations in the spleen and aorta over time and a proportion of the tracer remaining in the spleen.
^spleen (0 = '"spleen.ROI ^ _ ® ^spleen (0 0)
As shown above, the first model comprises a residual term in the form of a splenic impulse residue function Rspeen(t) describing the proportion of the tracer remaining in the spleen of the subject at time t . The residual term /?spleen(f) is defined by splenic hemodynamic parameters which comprise a splenic mean transit time (MTTspleen ), and exchange rates constants indicating rates at which blood between a vascular space and an interstitial space of the splenic circulation is exchanged (k1 spleen and k2 spleen )) (see Equations (A.6a) - (A.6c)).
The first model further comprises a splenic flow rate term Fspleen ROI describing a rate of flow through a part of the spleen corresponding to the splenic region of interest ROIspieen- Here, "a part of the spleen" may include the entire spleen. In one example, Fspleen R0I is a specific quantity indicating the plasma flow through the part of the spleen corresponding to the ROIspieen, with units in ml per min per ml of tissue.
As shown in Equation (1), the first model further implements a hematocrit correction for correcting the tracer concentrations in the aorta to account for red blood cells in the aorta. The hematocrit correction is represented by the constant HctA which denotes the fractional hematocrit in major blood vessels (which is assumed to be equal to the fraction of blood volume in the aorta occupied by red blood cells). In one example, HctA is 0.4.
In step 104, the first model is fitted to the tracer concentrations in the spleen and aorta over time (i.e. the splenic and aorta tracer concentration-time points derived from step 102). This fitting is performed by adjusting the residual term flspleen(f) and the splenic flow rate term Fspleen ROI . The adjusting of the residual term ftspieen(0 is done by adjusting the splenic hemodynamic parameters
MTTspleen , spleen and k2 spleen defining it.
Resulting residual term flspieen(f) and splenic flow rate term Fspleen ROI achieving the fit between the first model, and the splenic and aorta tracer concentration- time points are therefore achieved. In other words, the splenic hemodynamics of the subject comprising the splenic hemodynamic parameters MTTspleen , ki,sPieen and k2,spieen defining the resulting residual term Rspeen(t) is determined.
The splenic and aorta tracer concentration-time curves Osp,een ( i) , CArt(f) satisfying Equation (1 ) and comprising the splenic and aorta tracer concentration-time points are also derived through the above fitting.
The first model may further comprise an additional delay parameter i" spieen aorta to account for a difference in tracer arrival times to the spleen and the aorta. The delay parameter Tspleen aorta may be adjusted together with the residual term ftspteen (?) and the splenic flow rate term Fspleen ROI during the fitting of the first model to the aorta and splenic tracer concentration-time points. The delay parameter rspleen aorta achieving the fit between the first model and the tracer concentration-time points is generally dependent on the relative locations in the input image where the tracer concentration-time points are sampled. This value is not likely to be a characteristic of the spleen two-compartment exchange model shown in Fig. 3(b).
The splenic hemodynamics may further comprise a total splenic blood flow rate Fspleen (for whole venous blood) that emerges at the splenic vein i.e. a rate of blood flow out of the spleen. Fspleen can be calculated based on the resulting splenic flow rate term Fspleen ROI (derived from fitting the first model earlier) using
Equation (2). p _ ^spleen.ROI
spleen ^ Hd ) sP'een ' ' '
As shown in Equation (2), the splenic flow rate term Fspleen ROI is corrected with a hematocrit correction to account for red blood cells in the splenic vein emerging from the spleen. In particular, this hematocrit correction is represented by the constant Hctv which denotes the fractional hematocrit in the venous blood (which is assumed to be equal to the fraction of blood volume in the splenic vein occupied by red blood cells). In Equation (2), Vspleen denotes the volume of the spleen. In one example, l/spleen is estimated from separate clinical diagnostic scans comprising the entire spleen of the subject.
Step 106: Derive portal venous tracer concentrations over time In step 106, portal venous tracer concentrations in the subject over time are determined.
In one example, in step 106, the following sub-steps are performed for each input image. As mentioned before, each input image comprises voxels with intensity values indicating tracer concentrations in the subject at one point in time.
In the first sub-step, a region of interest comprising voxels corresponding to the portal vein of the subject (i.e. portal venous region of interest ROW) is identified in the input image. This may be performed manually (for example, a region of interest (ROI) may be manually drawn in each slice of the 3D input image and the regions of interest in all the slices may then be combined to form the final ROIPV). Alternatively, the identification of ROIpv may be performed automatically using imaging techniques.
In the next sub-step, the tracer concentration in the portal vein at the one point in time corresponding to the input image is determined based on the intensity values of the voxels in the portal venous region of interest ROIpv. For example, the tracer concentration may be determined as the average intensity value of the voxels in the ROIPV. Therefore, by repeating the above sub-steps for each input image in step 106, tracer concentrations in the portal vein of the subject at different points in time (i.e. portal venous tracer concentration-time points) are obtained. These tracer concentration-time points may be viewed as points obtained by sampling the portal venous concentration-time curve CPV (?) .
In one example, only a portion of the portal vein is visible on certain slices in an input image and the ROIpv is identified in the input image using this portion of the portal vein only. Depending on the size and orientation of the portal vein relative to the imaged section, the ROIPV might not contain the entire portal vein and CPV(f) comprising the portal venous tracer concentration-time points could be underestimated due to partial-volume averaging effect. This partial-volume effect may be compensated during the deconvolution fitting of the portal venous tracer concentration-time points in step 108.
Note that step 106 may be performed prior to step 104. For example, the portal venous tracer concentrations over time may be determined together with the aorta and splenic tracer concentrations over time in step 102. Step 108: Derive splanchnic hemodynamic parameters, and splenic and splanchnic contributions to portal venous blood flow using the portal venous and aorta tracer concentrations over time
In step 108, splanchnic hemodynamic parameters MTTsplanchnic , k1 sp|anchnic , k ^2.sp .lanc .hn .ic , 'and the splenic and sp rlanchnic contributions to p rortal venous blood flow represented by and 1 - β respectively are derived using the aorta and portal venous tracer concentrations over time as determined in steps 102 and 106.
Using the arterial-venous analysis approach [2], a second model relating portal venous and aorta tracer concentrations over time (in other words, the portal venous and aorta tracer concentration-time curves CPV (f) and CArt(f)) may be expressed in the form of Equation (3a) (which corresponds to Equation (A.3)). The portal vein concentration-time curve CPV(f) refers to the tracer concentration of the combined output from the splenic and splanchnic blocks 302, 304 (or splenic and splanchnic two-compartment systems 302, 304) as shown in Fig. 3(a). The second model relates the tracer concentrations in the portal vein and aorta over time and the tracer concentration emerging from the portal vein. pCPV (f) = CAn (t) ® hpw (t) (3a)
As shown above, the second model comprises an outflow term in the form of a portal impulse outflow function /7PV (f) describing the combined impulse outflow response of the splenic and splanchnic blocks 302, 304 in Fig. 3(a), in other words, the tracer concentration emerging from the portal vein at time t .
Furthermore, the second model implements a partial volume correction for correcting the tracer concentrations in the portal vein to account for partial volume effects in the input images from which the portal venous regions of interest are identified. In Equation (3a), the partial volume correction is in the form of p(> l) which is a scaling factor to correct for partial-volume effects affecting the estimation of the points in CPV(f) (i.e. the portal venous concentration-time points). The portal impulse outflow function ?pv (f) in Equation (3a) is defined by splenic hemodynamics and splanchnic hemodynamics of the subject. The portal impulse outflow function Λρν (ί) may be further defined by a weight factor weighting the splenic and splanchnic hemodynamics whereby the weight factor indicates the splenic contribution to portal venous blood flow. In one example, the portal impulse outflow function /7pv(f) may be derived using Equation (3b) as follows. hpv (t) = β Λ-ρΐ8Θη(ί) + (1 - β) ^splanchnic (t) . (3b)
As shown in Equation (3b), the portal impulse outflow function hpv (t) encompasses both splenic and splanchnic components, denoted by and /?splanchnic (f) > respectively. These splenic and splanchnic components are weighted by the weight factor in the form of the splenic fraction β . The splenic fraction β represents the fraction of portal venous blood flow contributed by the splenic circulation. 7spleen(f) comprises the splenic hemodynamic parameters MTTspleen , k, ,spleen , k2 sp|een which have been determined in step 104. More specifically, these are the parameters defining the residual term Rspleen {t) which achieves the fit between the first model, and the aorta and splenic concentration-time points. The remaining parameters in Equation (3b) are to be determined and these include β and the splanchnic hemodynamic parameters comprised by
^splanchnic (0 0·®· "T"T"splanchnic , ^l,sp|anchnic > ^2,Sp|ancnnjC )
In step 108, the second model is fitted to the tracer concentrations in the portal vein and aorta over time (i.e. the portal venous and aorta tracer concentration- time points). This fitting is performed by adjusting the outflow term (i.e. the portal impulse outflow function hpv ( t) ).
As mentioned above, the outflow term is defined by hsp een ( t) comprising the splenic hemodynamic parameters, ftspianchnic (f) comprising the splanchnic hemodynamic parameters and the splenic fraction β . During the fitting of the second model, the splenic hemodynamic parameters MTTspleen , k1 sp|een , k2 n
(determined in step 104) are kept constant. In other words, the fitting of the second model is based on the fitting of the first model, more specifically, based on the splenic hemodynamics of the subject derived from the fitting of the first model. The adjusting of the outflow term is done by adjusting β and the splanchnic hemodynamics parameters MTTsplancnnic , k1isplanchnlc , k2,sp|anchnic . Note that p , the scaling factor to correct for partial-volume effects as shown in Equation (3a), may also be adjusted. Resulting splenic fraction β and splanchnic hemodynamics parameters MTT- snpll_annchhnnii(c. ,' k, i. sp ,lanc .hn .ic ,' k2 z. sp ,lanc .hn .ic defining 53 the outflow term which achieves the fit between the second model and the portal venous and aorta tracer concentration-time points are thus determined. In other words, the portal hemodynamics of the subject comprising the resulting splenic fraction β is determined. The splanchnic contribution (which is also part of the portal hemodynamics) may be obtained based on the resulting splenic fraction β , in particular, it is calculated as 1 - β . Furthermore, the splanchnic hemodynamics of the subject comprising the resulting splanchnic hemodynamics parameters MTTsplanchnic , k1 sp|anchnic , k2,splanchnic are also determined.
From the above fitting, the portal venous tracer concentration-time curve CPV(f) satisfying Equation (3a) and comprising the portal venous tracer concentration- time points is also derived. The scaling factor p derived from the fitting can be used to correct for partial-volume effects affecting Cpv(f) . The corrected portal venous concentration-time curve is given by Equation (4).
CPV,corr(i) = pCpV(f) (4) The tracer from the splenic pathway usually arrives earlier at the portal vein, as compared to the tracer from the splanchnic pathway i.e. there is usually a difference in tracer arrival times to the portal vein from the splenic and splanchnic circulations. The second model may further comprise two additional delay parameters rspleen PV and i-splanchnic PV incorporated into /7spleen(f) and
Splanchnic (0 to account for this difference. The delay parameters rspleen pv and rsplanchnic pV are adjusted with the outflow term hP J{t) during the fitting of the second model to the aorta and portal venous tracer concentration-time points. In other words, the adjustable parameters during the fitting of the second model may comprise p , β , MTTsplanchnic , ic , k2 nic , rspleer,PV and t-splanchniCiPV .
Step 110: Derive portal venous blood flow rate and splanchnic blood flow rate using the splenic and splanchnic contributions to portal venous blood flow The portal hemodynamics of the subject may further comprise a rate of blood flow through the portal vein of the subject i.e. portal venous blood flow rate Fpv whereas the splanchnic hemodynamics of the subject may further comprise a rate of blood flow through the splanchnic circulation of the subject i.e. splanchnic blood flow rate Fsplancnnic .
In step 110, the portal venous blood flow rate Fpv and the splanchnic blood flow rate Fsplanchnic are derived.
Since the splenic blood flow contributes to a fraction of the portal venous blood flow given by the splenic fraction β and the remaining of the portal venous blood flow is contributed by the splanchnic blood flow, the portal venous blood flow rate Fpv and the splanchnic blood flow rate Fsplanchnic may be calculated based on the splenic fraction β (derived from the fitting in step 108) and the total splenic blood flow rate F leen obtained in step 104 . The total splenic blood flow rate Fspleen obtained in step 104 is in turn based on the splenic flow rate term FsPieen,Roi derived from the fitting in step 104.
More specifically, the portal venous blood flow rate Fpv and the splanchnic blood flow rate Fsplancnnic may be calculated using Equations (5a) and (5b).
]_
FPV — n spleen ' (5a) β
^splanchnic n ^spleen (^^)
Clinical Feasibility Study
Patients
To evaluate method 100, DCE CT was implemented as part of a trial involving the use of a combination of anti-angiogenic agents for unresectable or metastatic hepatocellular carcinomas (HCCs). DCE CT was performed at baseline and Day 8 or Day 29 of anti-angiogenic therapy to assess the degree of inhibition of angiogenesis. Only the baseline DCE CT scans before therapy were retrospectively analyzed by the current study.
Images from twenty seven patients 18 years or older with histologically confirmed unresectable HCC were accrued for the trial. Only images satisfying the following criteria are included in the current study: (i) the liver and portal vein are included in the images and (ii) the images show a satisfactory scan quality as evaluated based on the aortic enhancement curves and a lack of severe motion artifacts.
Six patients did not undergo DCE CT and were excluded from this study. DCE CT was not performed for the liver in eight cases and these were excluded from this study as well. The portal vein was not included in one patient's acquired images and this case was also excluded. Of the remaining patients whose images include the liver and portal vein, the scan quality of the images of 4 patients was unsatisfactory due to severe respiratory artifacts and these patients were hence also excluded from this study. Only the images of eight patients satisfied the inclusion criteria. These patients thus formed the study population. All eight patients had HCC previously confirmed by histology. Two of the eight patients were diagnosed with cirrhosis based on histology whereas the remaining six patients were diagnosed with cirrhosis based on CT findings. Fig. 5 shows a table tabulating the characteristics such as the patient demographics, method for diagnosing cirrhosis and the clinical parameters (e.g. Child's score, and presence of collaterals) of the eight patients.
DCE CT protocol In this study, DCE CT was performed using a 64-detector row CT scanner (Lightspeed; General Electric Medical Systems, Milwaukee, Wisconsin). The dynamic CT protocol comprised 27 acquisitions (1 00 kV, 80 mAs, Cine mode with 8 rows of 5 mm collimation, 1 -sec gantry rotation, Field of View 50 x50 cm, Matrix 51 2x51 2) at the following scan and breath-hold timings: 0 (Start of injection at 0 sec), (instruction to breathe and hold, BH) 8, 1 0, 1 2, 1 4, 1 6, 1 8, 20, 22, 24, 26, 28, 32, 36, (BH), 40, 44, 48, 52, 56, (BH), 64, (BH) 76, (BH), 88, (BH), 1 00, (BH), 1 1 2, (BH), 1 24, (BH), 1 36, (BH), and 148 sec. Combined radiation dosage of the scouts and the 27 dynamic scans was estimated to be 62.1 mSv, using an anthropomorphic phantom. A bolus infusion of 70 ml of contrast agent (Omnipaque; General Electric Healthcare, Princeton, NJ) was administered to each patient intravenously at 4 ml/sec using an automatic injector via an antecubital vein. The contrast agent was immediately followed by 30 ml of saline solution at the same flow rate. For each DCE CT scan image, the ROIs (i.e. ROIa0rta and ROIPV) were manually drawn over the aorta and portal vein in the image. An ROI including the whole spleen (ROIspieen) as seen on each scan image was also drawn. The ROIs were drawn by a radiologist (CHT with more than 10 years of experience). Intensity values in the form of CT numbers (Hounsfield units HU) of voxels within each ROI were averaged to yield the tracer concentration-time points. The linear relationship between tracer concentration and CT numbers were separately validated using phantom experiments.
Spleen volume measurement
Routine clinical abdominal CT examinations were performed 2 to 25 days before the DCE CT examinations. Splenic ROIs were manually drawn on all CT sections of the 3D image obtained via the abdominal examination. The cross- sectional areas of these ROIs were computed. Splenic volume was then calculated by summing the consecutive splenic ROIs areas (taking into account the slice thickness as well).
Results
For all the eight patients, the splenic and portal vein tracer concentration-time curves CPV(f) derived from the DCE CT images by method 100 can be appropriately described by the portal venous circulatory model.
Figs. 6 - 13 show the tracer concentration-time curves Cpv(f) ,
Cspleen(f) obtained for the eight patients using method 100. In particular, for each of Figs. 6 - 13, part (a) illustrates a slice of one of the input images showing the outlines of the various ROIs identified for obtaining the tracer concentration-time points. In particular, ROIs 602, 702, 802, 902, 1002 are the ROIs comprising voxels corresponding to the aorta i.e. ROIa0rta, ROIs 604, 704, 804, 904, 1004 are the ROIs comprising voxels corresponding to the portal vein i.e. ROIPV and ROIs 606, 706, 806, 906, 1006 are the ROIs comprising voxels corresponding to the spleen i.e. ROIspieen- Part (b) of Figs. 6 - 13 illustrate the various tracer concentration-time curves obtained from fitting the first and second models to the average intensity values in the ROIs identified in the DCE CT images. Part (c) of Figs. 6 - 13 show the impulse residue function and impulse outflow functions derived from the fittings of the first and second models to the respective tracer concentration-time points.
Fig. 14 shows a table tabulating the splenic and splanchnic hemodynamic parameters and blood flow rates, as well as the portal venous parameters and blood flow rate derived in this study. As mentioned above, these parameters are derived from parametric deconvolution analysis. In particular, the splenic hemodynamics parameters are derived by fitting the first model to the splenic and aorta tracer concentration-time points whereas the splanchnic and portal vein (PV) parameters are derived by fitting the second model to the portal venous and aorta tracer concentration-time points. In normal subjects, the splenic component of portal venous blood flow is about 40% (i.e. β ~ 0.4), whereas in subjects with cirrhosis, the splenic share of portal inflow was previously found to increase markedly, exceeding 50% [1]. In patients with portal hypertension, splanchnic blood flow may be largely shunted from the portal to the systemic circulation through portosystemic collateral vessels, while the spleen actively congests the portal system, contributing to the portal hypertension [1]. In the above clinical feasibility study of cirrhotic patients involving method 100, the mean splenic fraction was also found to be elevated (mean=0.75, std=0.22) with values ranging from 0.42 to 1.0. From Figs. 5 and 14, it can be seen that all patients with elevated splenic fraction β>0.7 except Patient 1 with β =0.77 (i.e. Patients 2, 4, 7 and 8) were previously diagnosed with para-esophageal collaterals. On the other hand, Patients 5 and 6 with relatively lower splenic fraction, β =0.42 and 0.56 respectively, were not previously diagnosed with para-esophageal collaterals. However, Patient 3 who also has a relatively lower splenic fraction β =0.53 was also previously diagnosed with para-esophageal collaterals. Splenic volumes of these eight patients, as estimated using routine abdominal CT scans, varied widely between 48 to 529 ml (see Fig. 5).
Also, as shown in Fig. 14, for Patients 4 and 8, the splenic fraction β which specifies the splenic contribution to portal venous blood flow was found to be very close to 1 (i.e. very close to 100%, with negligible splanchnic contribution to portal venous blood flow). In other words, the portal venous concentration- time curves Cpv(f) for these patients may be predominantly described using splenic parameters. In particular, it was found that for each of Patients 4 and 8, the portal venous concentration-time curve Cpv(f) may be completely specified using only the splenic parameters derived from fitting the first model to the splenic and aorta tracer concentration-time points and any adjustment of the splanchnic parameters had no effect on improving the fitting of the second model to the portal venous and aorta tracer concentration-time points. The splenic and portal venous tracer concentration-time curves Cspleen(f) and CPV(f) for Patients 4 and 8 are respectively shown in Figs. 9 and 13.
Furthermore, para-esophageal collaterals were observed in Patients 4 and 8, implying that the porto-systemic shunting in these patients may be larger than their splanchnic inflow, with the significant efflux via the porto-systemic shunt. This is likely to result in lower than expected values for splanchnic flow. The portal vein concentration-time curves for these patients are thus relatively independent of the splanchnic parameters and therefore it is hard to estimate the splanchnic parameters accurately using method 100. Hence in Fig. 14, splanchnic parameters for Patients 4 and 8 are not included. Note that these cases were not included in the computation of the mean and standard deviation (std) of the splanchnic parameters in Fig. 14.
Using duplex Doppler ultrasound for blood flow measurement, Zwiebel et al [8] estimated splenic artery blood flow rate in 17 patients with cirrhosis and portal hypertension to be 599 ± 340 ml/min. This was significantly higher than that in healthy subjects whose estimated splenic artery blood flow rate was found to be about 413 ± 1 10 ml/min. According to Zwiebel et al [8], splenic artery blood flow rate was particularly increased in patients with splenomegaly. The splenic blood flow rate in cirrhotic patients derived using method 100 was 624.41 ± 466.65 ml/min which is similar to the results of Zwiebel et al [8].
Zwiebel et al [8] also reported an increase in blood flow rate in the superior mesentery artery (SMA) for patients with cirrhosis and portal hypertension. In particular, the blood flow rate of these patients with cirrhosis and portal hypertension is approximately 574± 220 ml/min whereas the blood flow rate of healthy subjects is approximately 445± 63 ml/min. However, it was not indicated in Zwiebel et al [8] whether porto-systemic collaterals were present and thus, whether the estimated superior mesenteric arterial blood flow was likely to be largely channeled to the portal vein through the mesenteric veins. On the other hand, using method 100 in the above study, the portion of splanchnic blood flow that contributes directly to portal venous flow is calculated. Using method 100, the splanchnic blood flow rate that channels into portal venous flow is found to be 139.4 ± 120.2 ml/min, which is much lower than estimates of blood flow rates in the superior mesenteric artery. This may be due to the presence of portosystemic shunts in some of the patients such that in these patients, only a portion of blood flow in the mesenteric arteries was channeled into the portal vein (note that para-esophageal collaterals were observed in 5 out of the 8 patients examined in the clinical feasibility study). Using dynamic scintigraphy, Fine et al [6] studied splenic and splanchnic transit times with tracer kinetics models formulated by a combination of gamma density functions. Their estimates for splenic mean transit time was 5.07 ± 0.701 sec for normal subjects, which is significantly lower than 1 1 .3sec and 29.8 sec for two of their subjects with portal hypertension. Their estimates for blood mean transit time through the gastrointestinal tract was 21 .93 ± 2.88 sec for normal subjects, and 29.0 sec and 17.0 sec for the two subjects with portal hypertension. Referring to Fig. 14, the splenic and splanchnic mean transit times for cirrhotic patients derived using method 100 from the above study are respectively, 15.3± 10.1 sec and 23.6± 12.1 sec, which are in good agreement with those estimated by Fine et al [6]. Partial-volume correction factors p were close to unity (between 1 and 1.04) in 4 cases (Patients 1 , 2, 4, and 8), suggesting that the portal venous concentration-time curve Cpv(f) was appropriately sampled in these cases (i.e. the portal venous tracer concentration-time points obtained in step 106 were relatively accurate), ranged between 1.1 and 1 .3 in the other 4 cases. Although these values are not exceedingly large, their effect on obtaining an accurate fitting of the second model to the tracer concentration-time points, and hence an accurate CPV(f) is not negligible. This is especially since none of the other adjustable parameters can result in the same effect as p in the overall scaling of CPV(i) . Note that in Figs. 9, 1 1 , and 12, the decreasing portion of the partial-volume corrected portal venous concentration-time curve CPV corr(f) is initially above the aorta curve CArt(i) (at about 40 - 50sec for the injection protocol in the above study) and approaches CArt(f) at a later time (about 150 sec for the injection protocol in the above study). This shows that the CPV corr(f) is more accurate since the tracer concentration in the portal vein should, in general, eventually approach that in the artery after a few cardiac cycles of circulatory mixing. However, if the sampled CPV(f) (Le. the portal venous tracer concentration-time points) is affected by partial-volume effects, then the sampled Cpv(f) may be underestimated and a large portion of the sampled Cpv(f) will be lower than CArt(f) (see "CPV(f) " and "Fit using Eq. 3" in Fig. 1 1 (b)).
The above study may further include normal subjects as control subjects. The above study may further implement steps to validate the various parameters obtained. Note that although DCE CT datasets were used to evaluate method 100 in the above study, method 100 is not limited to using DCE CT images and can similarly be applied on other types of images such as DCE MRI images. However, it is preferable not to use method 100 on images with motion or breathing artifacts or images from techniques which are unable to capture the aorta, portal vein and spleen on a single scan plane.
Advantages
The advantages of method 100 are as follows. Method 100 employs a combination of deconvolution analysis and portal venous circulatory modeling and allows for separate estimation of splenic and splanchnic components to portal venous blood flow using dynamic contrast- enhanced CT or MR imaging. Method 100 exploits the inventors' observations that major blood vessels such as the aorta or portal vein are usually visible on DCE CT scans and thus, allow for in-vivo monitoring of inlet and outflow tracer concentration-time curves. In particular, method 100 uses a novel combination of both arterial-venous and residual tracer analysis approaches to derive quantitative estimates for portal blood flow and to resolve the relative contributions to the portal blood flow from splenic and splanchnic circulation. More specifically, method 100 first employs the residual tracer analysis approach to determine splenic hemodynamics of the subject, and then by coupling with the arterial-venous approach, further allow the derivation of the splenic fraction β (i.e. fraction of the portal venous blood flow contributed by the splenic circulation) and other portal hemodynamics parameters.
Method 100 is a deconvolution method that can be used to resolve the splenic and splanchnic contributions to portal venous blood flow and derive quantitative estimates describing splenic and portal blood flow. In particular, in method 100, a parametric deconvolution approach is adopted, by first assuming the functional forms of h(t) and R(t) through tracer kinetics modeling, and subsequently fitting models comprising these functional forms by adjusting the model parameters. The method 100 can be implemented using most types of medical images such as DCE CT or MR images. As shown in the above study using DCE CT datasets of 8 cirrhotic patients, method 100 can accurately estimate several portal parameters, and splenic and splanchnic hemodynamic parameters, including splenic and splanchnic mean vascular transit times.
Portal venous return from the bowel can take several different routes of which the superior mesenteric vein and the inferior mesenteric vein are the major channels. However, there are also smaller veins which may drain directly into the portal or splenic veins, such as the short gastric veins, the right and left gastroepiploic veins or pancreaticoduodenal veins. Method 100 is able to account for the blood flow from these smaller veins by simply subtracting the calculated splenic blood flow from the total portal venous blood flow. It does not matter if these smaller veins drain into the splenic vein or the main portal vein branches because they would have been accounted for in method 100 by subtracting the calculated splenic flow from the total portal venous blood flow.
Method 100 can be applied on the same DCE imaging dataset for both spleen and portal hemodynamics analysis. Hence, both liver parenchyma perfusion and portal hemodynamics can be concurrently studied using the same set of DCE scans.
Furthermore, an accurate Cpv(f) is important in liver perfusion assessment using DCE CT or MR imaging. Blood is supplied to the liver by both the hepatic artery and the portal vein, and the hepatic perfusion ratio between the hepatic artery and portal vein has been found to vary in patients with liver tumors and cirrhosis. Reliable assessment of hepatic perfusion and the hepatic perfusion ratio would depend on the accuracy of both input curves, CM(t) and Cpv(f) . If Cpv(f) was underestimated due to partial-volume effects, the liver parenchyma perfusion parameters subsequently estimated could also be affected. Method 100 corrects for partial-volume effects in Cpv(f) before performing liver perfusion analysis. Thus, it can achieve more accurate results.
Also, the portal venous impulse outflow response model (which method 100 is based on) can be used in situations where the portal vein cannot be captured during imaging (i.e. when only the aorta tracer concentration-time curve CM(t) can be sampled). If an estimate of CPV(f) is required for further analysis, an approximate Cpv(f) function can be derived by convolving the sampled CM{t) with a model hpV (t) using typical values of splenic and splanchnic parameters pertaining to the particular patient's demographic profile. In addition, quantifying portal venous blood flow and separately identifying the splenic and splanchnic components has potential clinical applications. These include assessing patients with small-for-size liver graft, monitoring the activity of Crohn's disease and monitoring the efficacy of medical therapies for portal hypertension as elaborated below.
Small-for-size liver graft is a complication that may occur in liver transplantation [9]. More specifically, small-for-size liver graft refers to the situation in which the transplanted liver is too small to receive the patient's portal blood flow. Barotrauma occurs to the graft and the patient suffers deterioration in liver function. Splenectomy is one possible treatment for this condition. In splenectomy, the portal blood flow from the spleen is reduced by removing the spleen [10-14]. Other strategies for decompressing the portal circulation by shunts have also been considered [15, 16]. Currently, the diagnosis of small- for-size graft is clinical and relies only on portal pressure measurements or clinical effects of back-pressure such as splenic enlargement. Method 100 is advantageous as it is able to yield information on the proportion of portal venous blood flow contributed by the splenic and the splanchnic circulation. With this information, a more rational decision on whether to perform splenectomy or a portosystemic shunting procedure may be made. Similar use of method 100 in patients with portal hypertension may also facilitate the selection of patients for splenectomy or shunting procedures.
In addition, there is currently a need in diagnostics to non-invasively measure portal pressure. This is important in monitoring therapy for portal hypertension and for chronic hepatitis C, as well as for prognostication [17]. Deriving hepatic venous pressure gradient is currently a popular way of measuring portal pressure. In the normal human liver, there is to date no known relationship between portal venous blood flow and portal pressure [18]. However, animal experiments suggest that in a state of increased hepatic resistance, such as cirrhosis, there is an increase in portal venous blood flow which results in an increase in portal pressure [19]. Therefore, method 100 is advantageous as it quantifies portal venous blood flow which may serve as a biomarker for efficacy of therapy for portal hypertension. Furthermore, current concepts of the pathophysiology of cirrhosis and portal hypertension suggest that there is a reversible element of hepatic resistance resulting from contraction of the stellate cell which results in decreased portal venous blood flow. This reversible element can potentially be modulated by pharmacological therapy [20, 21]. It is also known that increased mesenteric blood flow contributes to portal hypertension and there are also potential pharmacological interventions to modulate this effect. Using method 100 to quantify portal venous blood flow, the efficacy of the pharmacological therapies or interventions may also be evaluated. Also, information on splanchnic blood flow is potentially useful in assessing the activity of Crohn's disease. A weak negative correlation has been shown between splanchnic blood flow transit time and disease activity [22]. In general, an increase in splanchnic blood flow correlates with a decrease in splanchnic transit time. Hence, method 100 which derives both splanchnic blood flow and splanchnic transit time is potentially useful for monitoring the activity of the Crohn's disease.
References
1 . Bolognesis M, Merkel C, Sacerdoti D, Nava V, Gatta A. Role of spleen enlargement in cirrhosis with portal hypertension. Digest Liver Dis 2002;34:144- 50.
2. King RB, Deussen A, Raymond GM, Bassingthwaighte JB. A vascular transport operator. Am J Physiol 1993;265:H2196-H2208.
3. Lee TY. Functional CT: physiological models. Trends Biotechnol 2002;20:S3- S10.
4. Tofts P S, Brix G, Buckley D L, et al. Estimating kinetic parameters from dynamic contrast-enhanced T1 -weighted MRI of a diffusible tracer: standardized quantities and symbols. J Magn Reson Imaging 1999;10:223-32.
5. Cheong L H D, Lim C C T and Koh T S. Dynamic contrast-enhanced CT of intracranial meningioma: Comparison of distributed and compartmental tracer kinetic models- Initial results. Radiology 2004;232: 21 -30.
6. Fine DR, Glasser D, Hildebrandt D, Esser J, Lurie RE, Chetty N. An anatomic and physiologic model of hepatic vascular system. Am J Physiol 1995;79(3):1008-1026.
7. Koh TS, Thng CH, Hartono S, Lee PS, Choo SP, Poon DYH, Toh HC, Bisdas S. Dynamic contrast-enhanced CT of hepatocellular carcinoma in cirrhosis:
Feasibility of a prolonged dual-phase imaging protocol with tracer kinetics modeling. Eur Radiol 2009;19:1 184-96.
8. Zwiebel WJ, Mountford RA, Halliwell MJ, Wells PNT. Splanchnic blood flow in patients with cirrhosis and portal hypertension: investigation with duplex Doppler US. Radiology 1995; 194:807-812.
9. Ikegami T, Shimada M, Imura S, Arakawa Y, Nii A, Morine Y, Kanemura H. Current concept of small-for-size grafts in living donor liver transplantation. Surg Today 2008;38: 971 -82.
10. Sato Y, Yamamoto S, Oya H, Nakatsuka H, Tsukahara A, Kobayashi T, Watanabe T, Hatakeyama K. Splenectomy for reduction of excessive portal hypertension after adult living-related donor liver transplantation. Hepatogastroenterology 2002;48:1652-5. 1 1. Shimada M, Ijichi H, Yonemura Y, Harada N, Shiotani S, Ninomiya M, Terashi T, Yoshizumi T, Soejima Y, Suehiro T, Maehara Y. The impact of splenectomy or splenic artery ligation on the outcome of a living donor adult liver transplantation using a left lobe graft. Hepatogastroenterology 2004; 51 :625-9.
12. Gruttadauria S, Mandala' L, Miraglia R, Caruso S, Minervini Ml, Biondo D, Volpes R, Vizzini G, Marsh JW, Luca A, Marcos A, Gridelli B. Successful treatment of small-for-size syndrome in adult-to-adult living-related liver transplantation: single center series. Clin Transplant 2007; 21 :761 -6.
13. Yoshizumi T, Taketomi A, Soejima Y, Ikegami T, Uchiyama H, Kayashima H, Harada N, Yamashita Y, Kawanaka H, Nishizak T, Maehara Y. The beneficial role of simultaneous splenectomy in living donor liver transplantation in patients with small-for-size graft. Transpl Int 2008; 21 : 833-42.
14. Jeng LB, Lee CC, Chiang HC, Chen TH, Hsu CH, Cheng HT, Lai HC. Indication for splenectomy in the era of living-donor liver transplantation.
Transplant Proc 2008;40:2531 -3.
15. Kokai H, Sato Y, Yamamoto S, Oya H, Nakatsuka H, Watanabe T, Takizawa K, Hatakeyama K. Successful super-small-for-size graft liver transplantation by decompression of portal hypertension via splenectomy and construction of a mesocaval shunt: a case report. Transplant Proc 2008; 40:2825-7.
16. Sato Y, Yamamoto S, Takeishi T, Kato T, Nakatsuka H, Kobayashi T, Oya H, Watanabe T, Kokai H, Hatakeyama K. Inferior mesenteric venous left renal vein shunting for decompression of excessive portal hypertension in adult living related liver transplantation. Transplant Proc 2004;36:2234-6.
17. Parikh. Hepatic venous pressure gradient: worth another look? Dig Dis Sci 2009;54:1 178-83.
18. Moreno AH, Burchell AR, Rousselot LM, Panke WF, Slafsky SF, Burke JH. Portal blood flow in cirrhosis of the liver. J Clin Invest 1967;46:436-45.
19. Witte CL, Tobin GR, Clark DS, Witte MH. Relationship of splanchnic blood flow and portal venous resistance to elevated portal pressure in the dog. Gut 1976;17 :122-6. 20. Gupta TK, Chen L, Groszmann RJ.. Pathophysiology of portal hypertension. Clin Liver Dis 1997;1 :1 -12.
21. Groszmann and Abraldes. Portal hypertension: from bedside to bench. J Clin Gastroenterol 2005; 39:S125-30.
22. Kumar P, Domjan J, Bhandari P, Ellis R, Higginson A. Is there an association between intestinal perfusion and Crohn's disease activity? A feasibility study using contrast-enhanced ultrasound. Br J Radiol 2009; 82 :112- 7.
23. Zierler KL. Equations for measuring blood flow by external monitoring of radioisotopes. Circ Res 1965; 16:309-321.

Claims

Claims
1. A method for determining portal hemodynamics of a subject administered with a tracer, the method comprising the steps of:
(a) determining tracer concentrations in an aorta, spleen and portal vein of the subject over time;
(b) fitting a first model to the tracer concentrations in the spleen and aorta over time, wherein the first model relates the tracer concentrations in the spleen and aorta over time and a proportion of the tracer remaining in the spleen; and
(c) determining portal hemodynamics of the subject by fitting a second model to the tracer concentrations in the portal vein and aorta over time, wherein the second model relates the tracer concentrations in the portal vein and aorta over time and a tracer concentration emerging from the portal vein, and wherein the fitting of the second model is based on the fitting of the first model.
2. A method according to claim 1 , wherein in step (b), said fitting of the first model determines splenic hemodynamics of the subject and in step (c), said fitting of the second model further determines splanchnic hemodynamics of the subject.
3. A method according to claim 2, wherein said fitting of the second model is based on the splenic hemodynamics of the subject determined by said fitting of the first model.
4. A method according to any one of the preceding claims, wherein prior to step (a), a plurality of input images is acquired whereby each input image comprises a plurality of voxels with respective intensity values indicating tracer concentrations in the subject at one point in time, and wherein step (a) further comprises the following sub-steps for each input image: identifying aortic, splenic and portal venous region of interests in the input image respectively comprising voxels corresponding to the aorta, spleen and portal vein of the subject; and
determining the tracer concentrations in the aorta, spleen and portal vein at the one point in time corresponding to the input image based on the intensity values of the voxels in the aortic, splenic and portal venous region of interests in the input image respectively.
5. A method according to claim 4, wherein the plurality of input images comprises DCE CT images and the intensity values comprise CT numbers.
6. A method according to any one of the preceding claims, wherein said first model comprises:
a residual term describing the proportion of the tracer remaining in the spleen, the residual term being defined by splenic hemodynamics parameters; and
a splenic flow rate term describing a rate of flow through a part of the spleen corresponding to the splenic region of interest.
7. A method according to claim 6, wherein step (b) further comprises fitting the first model to the tracer concentrations in the spleen and aorta over time by adjusting the residual term and the splenic flow rate term; and
wherein the splenic hemodynamics of the subject comprise the splenic hemodynamics parameters defining the residual term which achieves the fit between the first model and the tracer concentrations in the spleen and aorta over time.
8. A method according to claim 7, wherein the first model further comprises a delay parameter accounting for a difference in tracer arrival times to the spleen and the aorta, said delay parameter being adjusted together with the residual term and the splenic flow rate term during the fitting of the first model to the tracer concentrations in the spleen and aorta over time.
9. A method according to any one of the preceding claims, wherein the first model implements a first hematocrit correction for correcting the tracer concentrations in the aorta to account for red blood cells in the aorta.
10. A method according to claim 9 when dependent on claim 7 or 8, wherein the splenic hemodynamics further comprise a rate of blood flow out of the spleen; and
wherein step (b) further comprises calculating said rate of blood flow out of the spleen based on the splenic flow rate term which achieves the fit between the first model and the tracer concentrations in the spleen and aorta over time, said splenic flow rate term being corrected with a second hematocrit correction to account for red blood cells in a splenic vein emerging from the spleen.
11. A method according to any one of claims 6 - 10, wherein the splenic hemodynamics parameters defining the residual term comprises:
an average time for blood to traverse splenic circulation; and
exchange rates constants indicating rates at which blood between a vascular space and an interstitial space of the splenic circulation is exchanged.
12. A method according to any one of claims 2 - 11 , wherein said second model comprises an outflow term describing the tracer concentration emerging from the portal vein, the outflow term being defined by the splenic hemodynamics and the splanchnic hemodynamics of the subject.
13. A method according to claim 12, wherein the outflow term is further defined by a weight factor weighting the splenic hemodynamics and the splanchnic hemodynamics of the subject, said weight factor indicating splenic contribution to portal venous blood flow.
14. A method according to claim 13, wherein step (c) further comprises fitting the second model to the tracer concentrations in the portal vein and aorta over time by adjusting the outflow term; and wherein the portal hemodynamics of the subject comprise the weight factor defining the outflow term which achieves the fit between the second model and the tracer concentrations in the portal vein and aorta over time.
15. A method according to any one of claims 4 - 14, wherein the second model implements a partial volume correction for correcting the tracer concentrations in the portal vein to account for partial volume effects in the input images from which the portal venous regions of interest are identified.
16. A method according to claim 14 or 15, wherein the second model further comprises at least one delay parameter accounting for:
a difference in tracer arrival times to the portal vein from the splenic circulation and splanchnic circulation; and
wherein said at least one delay parameter of the second model is adjusted together with the outflow term during the fitting of the second model to the tracer concentrations in the portal vein and aorta over time.
17. A method according to any one of claims 14 - 16, wherein step (c) further comprises determining splanchnic contribution to portal venous blood flow based on the weight factor defining the outflow term which achieves the fit between the second model and the tracer concentrations in the portal vein and aorta over time.
18. A method according to any one of claims 14 - 17, wherein the porfal hemodynamics of the subject further comprise a rate of blood flow through the portal vein of the subject and wherein step (c) further comprises calculating said rate of blood flow through the portal vein of the subject based on:
SUBSTITUTE SHEET (RULE 9.2) the weight factor defining the outflow term which achieves the fit between the second model and the tracer concentrations in the portal vein and aorta over time; and
the splenic flow rate term which achieves the fit between the first model and the tracer concentrations in the spleen and aorta over time.
19. A method according to any one of claims 16 - 18, wherein the splanchnic hemodynamics of the subject are described by a rate of blood flow through the splanchnic circulation and wherein step (c) further comprises calculating said rate of blood flow through the splanchnic circulation based on:
the weight factor defining the outflow term which achieves the fit between the second model and the tracer concentrations in the portal vein and aorta over time; and
the splenic flow rate term which achieves the fit between the first model and the tracer concentrations in the spleen and aorta over time.
20. A computer system having a processor arranged to perform a method according to any one of claims 1 to 19.
21. A computer program product such as a tangible data storage device, readable by a computer and containing instructions operable by a processor of a computer system to cause the processor to perform a method according to any one of claims 1 to 19.
PCT/SG2011/000258 2010-07-23 2011-07-19 A method and/or system for determining portal hemodynamics of a subject WO2012011872A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SG201005388-2 2010-07-23
SG201005388 2010-07-23

Publications (1)

Publication Number Publication Date
WO2012011872A1 true WO2012011872A1 (en) 2012-01-26

Family

ID=45497084

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SG2011/000258 WO2012011872A1 (en) 2010-07-23 2011-07-19 A method and/or system for determining portal hemodynamics of a subject

Country Status (1)

Country Link
WO (1) WO2012011872A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106510744A (en) * 2016-04-27 2017-03-22 上海联影医疗科技有限公司 Estimation method for dynamic parameters of multiple tracer agents in PET scanning
WO2019006248A1 (en) * 2017-06-30 2019-01-03 Georgia State University Research Foundation, Inc. Noninvasive methods for detecting liver fibrosis
CN109528196A (en) * 2018-11-14 2019-03-29 北京工业大学 A kind of hepatic vein pressure gradient Noninvasive assessmet method based on multi-modal image and Heuristics
CN109924997A (en) * 2018-05-02 2019-06-25 上海大学 A kind of non-invasive portal venous pressure gradiometry method based on medical image
WO2024128246A1 (en) * 2022-12-14 2024-06-20 北海道公立大学法人 札幌医科大学 X-ray ct device, image capture method, and program

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020103437A1 (en) * 2001-02-01 2002-08-01 Takao Jibiki Blood flow imaging method, blood flow imaging apparatus and ultrasonic diagnostic apparatus
US20080287784A1 (en) * 2007-05-18 2008-11-20 Fujifilm Corporation Image detecting system, image detecting method and computer readable medium
WO2009112538A1 (en) * 2008-03-11 2009-09-17 Karolinska Institutet Innovations Ab A computer-based method and system for imaging-based dynamic function evaluation of an organ

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020103437A1 (en) * 2001-02-01 2002-08-01 Takao Jibiki Blood flow imaging method, blood flow imaging apparatus and ultrasonic diagnostic apparatus
US20080287784A1 (en) * 2007-05-18 2008-11-20 Fujifilm Corporation Image detecting system, image detecting method and computer readable medium
WO2009112538A1 (en) * 2008-03-11 2009-09-17 Karolinska Institutet Innovations Ab A computer-based method and system for imaging-based dynamic function evaluation of an organ

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
CHEN, S. ET AL.: "Noninvasive quantification of the differential portal and arterial contribution to the liver blood supply from pet measurements using the C-Acetate kinetic model", IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, vol. 51, no. 9, September 2004 (2004-09-01), pages 1579 - 1585, XP011117147, DOI: doi:10.1109/TBME.2004.828032 *
DINC, H. ET AL.: "Portal and splanchnic haemodynamics in patients with advanced post- hepatitic cirrhosis and in healthy adults assessment with duplex Doppler ultrasound", ACTA RADIOLOGICA, vol. 39, 1998, pages 152 - 156 *
KOH, T.S. ET AL.: "Dynamic contrast-enhanced CT imaging of hepatocellular carcinoma in cirrhosis: feasibility of a prolonged dual-phase imaging protocol with tracer kinetics modelling", EUR RADIOL., vol. 19, 2009, pages 1184 - 1196, XP019709533 *
KOH, T.S. ET AL.: "Hepatic metastases: in vivo assessment of perfusion parameters at dynamic contrast-enhanced MRI with dual-input two-compartment tracer kinetics model", RADIOLOGY, vol. 249, 2008, pages 307 - 320 *
MATERNE, R. ET AL.: "Non-invasive quantification of liver perfusion with dynamic computed tomography and a dual-input one-compartmental model", CLINICAL SCIENCE, vol. 99, 2000, pages 517 - 525 *
MIYAZAKI, S. ET AL.: "A quantitative method for estimating hepatic blood flow using a dual-input single-compartment model", THE BRITISH JOURNAL OF RADIOLOGY, vol. 81, 2008, pages 790 - 800 *
NORDELL, A. ET AL.: "Liver function test using svd-based deconvolutional analysis in Gd-EOB-DTPA-enhanced MRI", PROC. INTL. SOC. MAG. RESON. MED., vol. 14, - 2006, pages 2204, XP002528515 *
TANIGUCHI, H. ET AL.: "Analysis of Models for Quantification of Arterial and Portal Blood Flow in the Human Liver Using PET", JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY, vol. 20, no. 1, 1996, pages 135 - 144, XP002112961, DOI: doi:10.1097/00004728-199601000-00025 *
TANIGUCHI, H. ET AL.: "Difference in regional hepatic blood flow in liver segments - Non- invasive measurement of regional hepatic arterial and portal blood flow in human by positron emission tomography with H2 15 O", ANNALS OF NUCLEAR MEDICINE, vol. 7, no. 3, 1993, pages 141 - 145 *
TANIGUCHI, H. ET AL.: "Using the spleen for time-delay correction of the input function in measuring hepatic blood flow with oxygen-15 water by dynamic PET", ANNALS OF NUCLEAR MEDICINE, vol. 13, no. 4, 1999, pages 215 - 221 *
THNG, C.H. ET AL.: "Perfusion magnetic resonance imaging of the liver", WORLD JOURNAL OF GASTROENTEROLOGY, vol. 16, no. 13, 7 April 2010 (2010-04-07), pages 1598 - 1609 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106510744A (en) * 2016-04-27 2017-03-22 上海联影医疗科技有限公司 Estimation method for dynamic parameters of multiple tracer agents in PET scanning
CN106510744B (en) * 2016-04-27 2021-01-08 上海联影医疗科技股份有限公司 Method for estimating dynamic parameters of multiple tracers in PET scanning
WO2019006248A1 (en) * 2017-06-30 2019-01-03 Georgia State University Research Foundation, Inc. Noninvasive methods for detecting liver fibrosis
US11576609B2 (en) 2017-06-30 2023-02-14 Georgia State University Research Foundation, Inc. Noninvasive methods for detecting liver fibrosis
CN109924997A (en) * 2018-05-02 2019-06-25 上海大学 A kind of non-invasive portal venous pressure gradiometry method based on medical image
CN109528196A (en) * 2018-11-14 2019-03-29 北京工业大学 A kind of hepatic vein pressure gradient Noninvasive assessmet method based on multi-modal image and Heuristics
CN109528196B (en) * 2018-11-14 2022-07-01 北京工业大学 Hepatic vein pressure gradient non-invasive evaluation method
WO2024128246A1 (en) * 2022-12-14 2024-06-20 北海道公立大学法人 札幌医科大学 X-ray ct device, image capture method, and program

Similar Documents

Publication Publication Date Title
Muzik et al. Assessment of diagnostic performance of quantitative flow measurements in normal subjects and patients with angiographically documented coronary artery disease by means of nitrogen-13 ammonia and positron emission tomography
US9949650B2 (en) Fractional flow reserve estimation
EP2038841B1 (en) Method of perfusion imaging
AU2009224632B2 (en) A computer-based method and system for imaging-based dynamic function evaluation of an organ
EP2271257B1 (en) Imaging technique
US11915361B2 (en) System, method, and computer program product for predicting, anticipating, and/or assessing tissue characteristics
US9232907B2 (en) System, method and computer-accessible medium for utilizing cardiac output to improve measurement of tracer input function in dynamic contrast-enhanced magnetic resonance imaging
WO2012011872A1 (en) A method and/or system for determining portal hemodynamics of a subject
Ohno et al. 3D ECG‐and respiratory‐gated non‐contrast‐enhanced (CE) perfusion MRI for postoperative lung function prediction in non‐small‐cell lung cancer patients: A comparison with thin‐section quantitative computed tomography, dynamic CE‐perfusion MRI, and perfusion scan
Jeong et al. Clinical significance of contrast-enhanced ultrasound in chronic kidney disease: a pilot study
Palmowski et al. Tumor perfusion assessed by dynamic contrast-enhanced MRI correlates to the grading of renal cell carcinoma: initial results
Aramendía‐Vidaurreta et al. Assessment of splenic switch‐off with arterial spin labeling in adenosine perfusion cardiac MRI
Yilmaz et al. Accuracy and feasibility of dynamic contrast-enhanced 3D MR imaging in the assessment of lung perfusion: comparison with Tc-99 MAA perfusion scintigraphy
CN115035208A (en) Lung perfusion and region V/Q non-invasive imaging method, system and equipment
Staub Current and potential methods to assess kidney structure and morphology in term and preterm neonates
Schütz The potential of magnetic particle imaging in the competitive environment of cardiac diagnostics
Cao et al. Response to letter regarding article:“developing dce-ct to quantify intra-tumor heterogeneity in breast tumors with differing angiogenic phenotype”
San Koh et al. Deconvolution assessment of splenic and splanchnic contributions to portal venous blood flow in liver cirrhosis
RU2673384C1 (en) Method for studying kidney function in multispiral computed tomography
Kärcher et al. Two tissue compartment model in DCE-MRI: A Bayesian approach
Seiter Form and Function in the Heart and Placenta: Quantitative Vascular MRI
van Amerom et al. Regional pulmonary blood flow: Comparison of dynamic contrast‐enhanced MR perfusion and phase‐contrast MR
Mousa et al. Role of Cardiac MRI in Diagnosis, Follow Up and Post Management Evaluation of Hypertrophic Cardiomyopathy
CN117242362A (en) Characterization of liver lesions using dynamic contrast enhanced magnetic resonance tomography
Lee et al. Tracer kinetic modeling by morales-smith hypothesis in hepatic perfusion CT

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11809958

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11809958

Country of ref document: EP

Kind code of ref document: A1