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WO2013159111A1 - Méthode et appareil utilisant l'imagerie par résonance magnétique pour la détermination du phénotype et la surveillance de tissus - Google Patents

Méthode et appareil utilisant l'imagerie par résonance magnétique pour la détermination du phénotype et la surveillance de tissus Download PDF

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Publication number
WO2013159111A1
WO2013159111A1 PCT/US2013/037650 US2013037650W WO2013159111A1 WO 2013159111 A1 WO2013159111 A1 WO 2013159111A1 US 2013037650 W US2013037650 W US 2013037650W WO 2013159111 A1 WO2013159111 A1 WO 2013159111A1
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Prior art keywords
mri
dce
trans
region
interest
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Inventor
Charles S. SPRINGER Jr.
Wei Huang
Xin Li
Jr. William D. ROONEY
Ian J. Tagge
James A. BALSCHI
Yajie ZHANG
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Brigham and Womens Hospital Inc
Oregon Health and Science University
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Brigham and Womens Hospital Inc
Oregon Health and Science University
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Priority to US14/395,785 priority Critical patent/US20150087967A1/en
Priority to EP13777980.7A priority patent/EP2838424A1/fr
Publication of WO2013159111A1 publication Critical patent/WO2013159111A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/43—Detecting, measuring or recording for evaluating the reproductive systems
    • A61B5/4306—Detecting, measuring or recording for evaluating the reproductive systems for evaluating the female reproductive systems, e.g. gynaecological evaluations
    • A61B5/4312—Breast evaluation or disorder diagnosis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/563—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution of moving material, e.g. flow contrast angiography
    • G01R33/56366—Perfusion imaging

Definitions

  • Embodiments herein relate to identification of tissue, and, more specifically, to methods and apparatus of using magnetic resonance imaging for tissue identification, phenotyping, and monitoring. Background
  • the method may include receiving a first set of DCE-MRI time-course data for a region, wherein a contrast reagent is administered prior to imaging, identifying a region of interest from the first set of DCE-MRI time-course data for further analysis, and analyzing the data for the region of interest using computer implemented software to produce a first SSM T, value that accounts for
  • the method also may include receiving a second set of DCE-MRI time-course data for the region of interest, wherein the second set of DCE-MRI time-course data is obtained after the region has been treated, analyzing the second set of DCE-MRI time-course data for the region of interest using computer implemented software to produce a second SSM T, value that accounts for transcytolemmal exchange effects, wherein the water exchange between cells or blood and interstitial spaces is assumed to have a finite speed resulting from interaction with the contrast reagent, and wherein T, is indicative of the level of cellular metabolic activity, and determining the difference between the first SSM T, value and the second SSM T, value.
  • the method may include receiving DCE- MRI time-course data for a region, wherein a contrast reagent is administered prior to imaging, identifying a region of interest from the DCE-MRI time-course data for further analysis, analyzing the DCE-MRI time-course data for the region of interest using computer implemented software to produce a SM K trans value, wherein the water exchange between cells or blood and interstitial spaces is assumed to be substantially infinitely fast, analyzing the DCE-MRI time-course data for the region of interest using computer implemented software to produce a SSM K trans value, wherein the water exchange between cells or blood and interstitial spaces is assumed to have a finite speed resulting from interaction with the contrast reagent, analyzing the DCE-MRI time-course data for the region of interest using computer implemented software to produce a SSM T, value that accounts for transcytolemmal exchange effects, and plotting SM K trans and SSM K trans v.
  • SSM T value that accounts for transcytolemmal exchange effects
  • the method may include receiving DCE-MRI time-course data for a region, wherein a contrast reagent is administered prior to imaging, analyzing the DCE-MRI time-course data using computer implemented software to correct for potential 1 H 2 0 signal reduction due to transverse relaxation effects, identifying a region of interest from the DCE-MRI time-course data for further analysis, and analyzing the DCE-MRI time-course data for the region of interest using computer implemented software to produce a first SSM T, value that accounts for transcytolemmal exchange effects, wherein the water exchange between cells or blood and interstitial spaces is assumed to have a finite speed resulting from interaction with the contrast reagent, and wherein T, is indicative of the level of cellular metabolic activity for the region of interest.
  • T is indicative of the level of cellular metabolic activity for the region of interest.
  • Figure 1 illustrates the pharmacokinetic modeling scheme for DCE- MRI in accordance with various embodiments.
  • the three general compartments for contrast reagent (CR) and for water (blood, interstitium, and parenchymal cytoplasmic) are illustrated, though not in relative proportions to their volume fractions (vb, ve, and vi).
  • the pertinent chemical equilibria and their unidirectional rate constants are indicated as well, in accordance with various embodiments.
  • FIG. 2 illustrates a sagittal, fat-suppressed breast DCE-MRI image (panel A) containing a malignant invasive ductal carcinoma (IDC) tumor (circled contrast-enhanced region-of-interest).
  • Pharmacokinetic K trans parametric maps of the tumor generated by the Standard Model (FXL-constrained) and two members of the Shutter-Speed Model family (FXR-allowed) and (SXR-allowed), are shown in panels B, C, and D, in accordance with various embodiments.
  • Figure 3 illustrates 2D scatter plots of the Standard Model (panel A), and the Shutter-Speed Model (Panel B) (FXR-a) results from Table 1 .
  • the ordinates measure the K trans and the abscissae the kep parameters.
  • the black circles mark the positions for ROIs of lesions that were found by biopsy/pathology to have large malignant fractions, while the triangles are those for lesions found to be solely benign.
  • An outlier (Table 1 , patient 5) is plotted in inset panels C and D. Dashed concentric quarter-circles are drawn with radii of 0.19 and 0.23 min "1 .
  • the points for two patients (3 and 7) are marked as gray circles with black cores. These represent lesions with only very small malignant fractions, in accordance with various embodiments.
  • FIG. 4 illustrates a 1 D scatter plot derived from Table 1 .
  • the ordinate, AK trans is [K trans (SSM) - K trans (SM)]: SSM is FXR-a and SM is FXL-c.
  • the values for the lesion ROIs of all 22 subjects are shown. Those proven malignant are given as filled black circles (these include the two Figure 3 gray circles with black cores), while those found solely benign are indicated with triangles.
  • the group mean AK trans values are indicated with open and filled black squares on the right. Error bars represent (SD) values within each category.
  • One malignant lesion outlier is plotted in an inset, and is excluded from the SD calculation.
  • the horizontal cut-off line drawn at 0.024 min "1 cleanly separates the two lesion groups, all in accordance with various embodiments.
  • Figure 5 illustrates how the K trans (volume fraction CR transfer rate constant product, top) and v e (extracellular, extravascular space, EES, volume fraction, bottom) fitting results would change if increasing interstitial 1 H 2 0 T 2 * quenching is assumed, in accordance with various embodiments.
  • Figure 6 panel A shows a transverse pelvic DCE image slice (anterior up/inferior perspective, approximately 34 seconds post CR injection) of a research subject. Two ROIs are indicated within the prostate gland: one in an area of retrospectively-confirmed prostate cancer, left; and the other in contralateral normal- appearing prostate tissue, right.
  • Figure 6, panel A also plots the arterial input function obtained from an ROI in a femoral artery. Its magnitude was adjusted using a custom-written numerical approach and an obturator muscle ROI for reference tissue. The time-course from the first-pass was used to estimate blood volume fraction; in accordance with various embodiments, in accordance with various embodiments.
  • Panel B illustrates color-matched tissue data time-courses (points) and representative fittings, in accordance with various embodiments..
  • Figure 7 illustrates an article of manufacture, in accordance with various embodiments.
  • Figures 8A and 8B show significant inverse correlations between SM K trans and parameters for an entire lesion population (Figure 8A) and malignant lesions (Figure 8B), in accordance with various embodiments.
  • Figure 9 shows an exemplary example of parametric K trans and maps wherein color hot spot maps are overlaid on DCE-MRI images from a malignant (top panel) and a benign (bottom panel) lesion, in accordance with various embodiments.
  • Figure 10 shows spatial, heterogeneous distribution of tumor perfusion/permeability (P), hypoxia (H) and necrosis (N) of a representative tumor slice from an experimental tumor, including K trans and maps of the tumor slice obtained from SSM analysis, in accordance with various embodiments.
  • Figure 1 1 depicts the spatial distribution of DCE-MRI parameters in well-perfused, hypoxic and necrotic areas of a tumor, including corresponding histograms of the regions with mean (variance) demoted, in accordance with various embodiments.
  • Figure 12A and 12B show examples of tumor region of interest (ROI) parameters K trans , AK trans , and % changes plotted against relative changes in tumor density (RCTD; Figure 12A) and residual cancer burden (RCB; Figure 12B) values for three patients receiving neoadjuvant chemotherapy, in accordance with various embodiments.
  • ROI tumor region of interest
  • Figure 13 shows SSM K trans and AK trans maps of a pathologic partial response (pPR) to chemotherapy and a pathologic complete response (pCR) to chemotherapy, in accordance with various embodiments.
  • pPR pathologic partial response
  • pCR pathologic complete response
  • Figure 14 shows DCE-MRI parameters after completion of
  • neoadjuvant chemotherapy that correlate with residual cancer burden (RCB) and may therefore be indicators of residual disease, in accordance with various embodiments.
  • Figure 15 shows SM K trans , SSM K trans , and AK trans maps at two time points (before therapy (TP 0) and after two weeks of Sorafenib only treatment (TP-i ) of a tumor with 95% necrosis and a tumor with 50% necrosis (both necrosis levels determined at a third time point (TP 2 ) - 8 weeks after TP 2 , during which time
  • Sorafenib plus chemotherapy was administered (%)), in accordance with various embodiments.
  • Figure 16 shows a column graph of whole tumor region of interest (ROI) MRI biomarker (parameter) % changes after two weeks of Sorafenib only treatment (TP-i) relative to before therapy (TP 0 ), in accordance with various embodiments.
  • ROI whole tumor region of interest
  • TP-i Sorafenib only treatment
  • Figure 17 show a scatter plot of % changes after two weeks of Sorafenib only treatment (TP-i) in RECIST (tumor size), ROI ADC (apparent diffusion coefficient), ROI AK trans , and histogram median AK trans vs. % necrosis at time of surgery (at TP 2 ), in accordance with various embodiments.
  • the phrase “A/B” means A or B.
  • the phrase “A and/or B” means “(A), (B), or (A and B)”.
  • the phrase “at least one of A, B, and C” means "(A), (B), (C), (A and B), (A and C), (B and C), or (A, B and C)”.
  • the phrase “(A)B” means "(B) or (AB)" that is, A is an optional element.
  • a computing device may be endowed with one or more components of the disclosed apparatuses and/or systems and may be employed to perform one or more methods as disclosed herein.
  • Embodiments herein provide a Magnetic Resonance Imaging (MRI) technique and optionally newly developed software, collectively referred to as the "shutter-speed" model, to analyze image data of cancer patients.
  • MRI Magnetic Resonance Imaging
  • Embodiments provide a minimally invasive, yet precisely accurate, approach to determining whether tumors are malignant or benign.
  • Exemplary embodiments provide MRI measured biomarkers for tumor malignancy determination, effectively solving the false positive riddle from which current MRI techniques suffer.
  • DCE-MRI Dynamic-Contrast-Enhanced Magnetic Resonance Imaging
  • DCE-MRI produces parametric maps of MR, pathophysiological, and/or pharmacokinetic biomarker properties.
  • the DCE-MRI subcategory is particularly significant because it applies to a wide pathology range.
  • the ⁇ -weighted tissue 1 H 2 0 MRI signal intensity is acquired before, during, and after the (usually) bolus injection of a hydrophilic, paramagnetic contrast reagent (CR).
  • CR paramagnetic contrast reagent
  • the CR passage through a tissue region-of-interest (ROI) can cause a transient increase of the longitudinal 1 H 2 0 relaxation rate constant [Ri ⁇ (T-i) "1 ] with consequent elevated MR steady-state signal intensity. This elevation may be identified on the MR image.
  • DCE-MRI In DCE-MRI, the neglect of intercompartmental water exchange kinetics considerations can lead to systematic errors in parameters extracted by quantitative analyses. Examples here are the compartmental water mole fractions defining tissue spaces. Therefore, DCE-MRI is also a sub-category of in vivo MR "molecular imaging," mapping the distribution and/or activity of molecules in living tissues.
  • the CR plays the role of the nuclear medicine radioactive tracer.
  • the tracer is detected directly (by its radioactivity in disintegrations per second (dps), the amount of tracer present in the tissue, but compartmental localization is not intrinsic to the signal).
  • the MRI CR is detected indirectly, via its interaction with water and effect on the nature of tissue 1 H 2 0 relaxation (so the water interaction with the CR is what is directly traced).
  • the CR is not radioactive.
  • MRI involves no ionizing radiation.
  • Affecting the recovery of longitudinal 1 H 2 0 magnetization requires (transient) water CR molecular interaction, as depicted in Figure 1 .
  • the three major loci for tissue water, the cytoplasmae, the interstitium, and the blood, are indicated with subscripts i, o (or e), and b (p, for plasma), respectively.
  • the compartmental volume fractions are designated as v,, v e , and v b , respectively, though the relative areas in Figure 1 are not proportional.
  • the incorporation of equilibrium water exchange MR effects into pharmacokinetic derivation is referred to herein as the Shutter-Speed Model (SSM). This is accomplished by allowing k 0 i + k i0 and k po + k o to be finite.
  • SSM Shutter-Speed Model
  • the SM assumes that water exchange between cells and/or blood and the interstitial spaces is effectively infinitely fast (in the fast exchange limit - FXL).
  • the water exchange systems can depart from this fast exchange limit due to the interaction with the CR (and therefore enter into a fast-exchange regime - FXR).
  • the exchange difference is typically below 0.025 min "1
  • a threshold may be established at an exchange difference of 0.02 to 0.03 min "1 .
  • the shutter-speed model accounts for the FXR (therefore including equilibrium exchange effects when the CR passes through) and thus is better able to pick up the "leaky blood vessel" effect which is common in malignant tumors.
  • FXR equilibrium exchange effects when the CR passes through
  • the shutter-speed model accounts for the FXR (therefore including equilibrium exchange effects when the CR passes through) and thus is better able to pick up the "leaky blood vessel" effect which is common in malignant tumors.
  • FXR equilibrium exchange effects when the CR passes through
  • K trans the volume-weighted CR extravasation rate constant
  • K trans values are greater for malignant tissues than for benign tissues, if K trans is underestimated, then it may make a malignant tumor seem benign (false negative) or vice versa a benign tissue appear to be malignant (false positive).
  • the SSM model accounts for this difference, and by using the delta K trans (change in K trans ) as well as the K trans to k ep comparison, classification of tumors may be accomplished.
  • k ep is the unidirectional CR intravasation rate constant; it is K trans divided by the v e (the extracellular,
  • the difference in K trans returned by SSM offers a very high degree of tumor differentiation (e.g., specificity). It is a measure of the shutter-speed effect, which is disproportionally present and important in malignant tumors, that permits differentiation of benign and malignant tumors.
  • the SM overestimates k ep , particularly for the benign tumors.
  • incorporation of the SSM into the screening protocols may preclude the need for the biopsy/pathology procedures that otherwise would yield benign findings.
  • thresholds may be established with the goal/intention of including all true positives. Thresholds may be established as desired to distinguish/classify the tissues/tumors.
  • further analysis may be conducted via a secondary mapping algorithm (plot of (K trans vs. k ep ) to allow for a second determination with respect to those points that are somewhat unclear or fall below a determined threshold.
  • the radius of the circle may be used as a threshold to distinguish benign from malignant tumors. Such a threshold may be established at
  • an MRI examination aided by SSM analysis may provide a clearer diagnosis and may be an intermediate step between a
  • Adding this intermediate diagnostic step may greatly reduce or eliminate the number of unnecessary (and possibly all) biopsy surgeries and also reduce the pain, stress and expense for most patients.
  • the SSM is a generalization of the SM. That is, the SM is but a special case of the SSM.
  • the program will automatically perform a SM analysis.
  • SSM SSM was employed to analyze MR images of 22 women volunteers who had previously screened positive for breast cancer by mammography and/or clinical examination.
  • the shutter-speed software operates by using a complex mathematical formula to track the passage of injected contrast dye through a tumor area. Contrast dyes are commonly used in medical imaging to increase the visibility of tissue abnormalities.
  • the MRI data suggested that only seven of the 22 women actually had malignant tumors. These projections were later shown to be 100 percent accurate after each of the study participants underwent subsequent biopsies for pathology determinations. Typically, 75 percent of mammographically-indicated biopsies yield negative pathology results, meaning that an intermediate step such as an MRI determination could greatly reduce or eliminate the number of unnecessary biopsy surgeries.
  • This population study has been expanded to include 77 breast tumors (in 74 patients) and, with the mapping provision for one rare type of malignant tumor, maintains 100% specificity.
  • FIG. 2 panel A, shows the DCE pharmacokinetic image of sagittal slice 16 (numbering from lateral to medial) of the left breast of a 52 year-old patient, obtained 2.6 minutes after CR injection. It was acquired with adipose - 1 H 2 C- suppression (required in the institutional protocol). In contrast to those with no fat suppression, this darker image shows glandular regions brighter than fatty tissue.
  • the ROI circumscribes the enhanced lesion evident in this slice, subsequently found to be a malignant invasive ductal carcinoma (IDC) by pathology analysis.
  • IDDC malignant invasive ductal carcinoma
  • IDC invasive ductal carcinoma
  • DCIS ductal carcinoma in situ
  • LCIS lobular carcinoma in situ
  • SF stromal fibrosis
  • FC fibrocystic changes
  • ADH atypical ductal hyperplasia
  • FA fibroadenoma
  • Ri 0 ⁇ R- ⁇ and ⁇ 1 « k.
  • k is finite, and invariant throughout the DCE-MRI study, the system is in the fast-exchange-limit (FXL): the kinetics appear infinitely fast, and the measured tissue 1 H 2 0 Ri is single- valued.
  • the Standard Model assumes that the system remains in the FXL throughout the CR bolus passage, so it is referred to also as the FXL- constrained (FXL-c) model (see Figure 2, panel B).
  • FXL-c FXL- constrained
  • Ri 0 becomes increasingly larger than R-n and ⁇ 1 at least approaches the constant k value.
  • FXR fast-exchange-regime
  • Admitting departure from the FXL for the FXR may be referred to as FXR- allowed (FXR-a) (see Figure 2, panel C).
  • K trans a measure of the rate of passive CR transfer across the vessel wall
  • k ep the unidirectional rate constant for CR intravasation
  • Table 1 indicates that the SM does not completely separate the malignant tumors (top seven entries) from the benign lesions with either the K trans or k ep parameters. However, the SSM significantly increases K for every one of the malignant lesions, and for none of the benign tumors, as compared to the SM.
  • the SSM reduces k ep for both malignant and benign lesions, it does this more for the benign tumors. In embodiments, these changes allow discrimination between the SSM and SM results.
  • the PPV values for the SM K trans , SM k ep , SSM K trans , and SSM k ep dimensions are: 54%, 39%, 70%, and 70%, respectively.
  • the Panel B SSM 2D plot one can draw a dashed quarter- circle of radius 0.19 min "1 , that also allows a 78% PPV.
  • the positions of the Panel A and Panel B insets are placed with constant coordinate aspect ratios. Thus, one can visually include the inset points in the correlations.
  • the slope of a line drawn through the points represents the mean v e value of these lesions.
  • Such a line for Panel B has a slope near 0.5.
  • the first step of such a protocol may be a clinical examination and/or mammography.
  • a positive result (B-4 or B-5), or suspicion of a mammographically occult lesion, may occasion referral for diagnostic MRI that includes DCE.
  • the radiologist may circumscribe an ROI from the DCE image showing the greatest enhancement. Alternatively, this may be automated (e.g., using Jim 4.0 software; Xinapse Systems; Thorpe Waterville, UK).
  • the computer may very quickly (few seconds) conduct SM and SSM analyses on the mean ROI signal time-course data and produce SSM K trans and k ep values, which can be compared with 2D scatter plots such as those in Panel B.
  • a patient's point turns out to be in the annulus between the quarter-circles in Panel B, the radiologist may proceed to read K trans parametric lesion maps made from the same DCR-MRI data, though these require more computational time. Hot spots above 0.1 min "1 may be very suspicious for malignancy.
  • Some oncologists advocate a separate regimen for a malignant ductal carcinoma in situ (DCIS) tumor, possibly simply following it instead of immediate surgery, while others urge excision.
  • DCIS malignant ductal carcinoma in situ
  • Her position in Panel B is the black point closest to the outer quarter-circle. In fact, another concentric quarter-circle of radius 0.3 min "1 would isolate this point.
  • the SSM interpretation is that, during the bolus passage through malignant lesions, the relaxographic ⁇ 1 value for the transcytolemmal water exchange process,
  • Ri 0 increases with CR 0 , while R- ⁇ remains constant. This is a manifestation of the varying equilibrium competition for interstitial water molecules between diamagnetic cytoplasmic spaces and paramagnetic interstitial CR molecules ( Figure 1 ).
  • Informative estimates can be made by comparison of the Table 1 patients 8/4 benign/malignant lesion pair, with SSM K trans 0.034 and 0.254 min "1 , respectively.
  • the ( ⁇ ⁇ , ⁇ ,) parameters returned are similar: (0.60, 0.40 s), and (0.69, 0.39 s) for benign and malignant, respectively.
  • the unidirectional rate constants for water cellular entry [k 0 i ⁇ (v e "1 - 1 ) ⁇ , "1 ] are similar (1 .7 and 1 .2 s "1 , respectively), constant, and not infinitely large.
  • [(CRo)max/(H 2 Oo)]TM "1 values are 104 and 313 s "1 for the benign and malignant lesions, respectively.
  • the interstitial water concentration (H 2 0 0 ) was 50 M and the mean water lifetime on the CR, TM, was 10 "7 s.
  • TM mean water lifetime on the CR
  • an interstitial water molecule in the benign lesion encounters a paramagnetic CR molecule on average 60 times (104/1 .7) before it enters a diamagnetic cell; sufficient, apparently, for the SM 40% v e underestimation. While in the malignant tumor, this happens 260 times (313/1 .2) on average; more than four times as often. This is sufficient to cause significant K trans underestimations if it is neglected.
  • certain steps may be taken, even in the clinical setting, to improve the precision, the accuracy, and/or the diagnostic richness of the SSM DCE-MRI pharmacokinetic parameters.
  • Such modifications may, for example, decrease the random error scatter in the Figures 3 and 4 point clusters. This may allow further discrimination of pathology sub-types.
  • tissue R-io values (the pre-CR 1 H 2 0 longitudinal relaxation rate constants) may be mapped, and not simply assumed as they were herein. Individual AIFs may be used as well. A reference tissue method, or an automated AIF determination (e.g., Jim 4.0 software; Xinapse Systems; Thorpe Waterville, UK) may be used.
  • Increased temporal resolution may be achieved without sacrificing spatial resolution or signal-to-noise.
  • Parallel RF excitation/acquisition may be useful for achieving such increased temporal resolution.
  • the second generation SSM BALDERO (Blood Agent Level Dependent and Extravasation Relaxation Overview)
  • BALDERO Bood Agent Level Dependent and Extravasation Relaxation Overview
  • v b and k b0 are the transendothelial water permeability coefficient surface area product, PwS', where S' is the total capillary bed surface area.
  • the ratio PWS'/PCRS' would be the intensive property PW/PCR-
  • the value of the CR permeability coefficient surface area product (PCRS') may be factored from the K trans parameter using the blood flow value, which may also be determined from DCE-MRI data.
  • the DCE-MRI pharmacokinetic images may also be spatially registered to correct for patient motion.
  • Image acquisition without - 1 H 2 C- suppression may yield signal intensities much more amenable to precision parametric mapping.
  • the maps require sufficient acquisition contrast-to-noise ratio because pixel-by-pixel analytical modeling is more susceptible to noise. However, care must be taken to avoid contamination of 1 H 2 0 by unsuppressed - 1 H 2 C-.
  • the shutter-speed model may be enhanced by adding a factor for putative T 2 * (transverse relaxation) signal quenching.
  • T 2 * transverse relaxation
  • the SXR-a SSM includes T 2 * neglect and therefore underestimates K trans and v e to the extent that there is a disproportionate relaxation of compartmental water signals.
  • Embodiments herein provide a way of testing to see if the blood and interstitial water signals have been edited from the detected signal (that is, SXR-a is inappropriate).
  • DCE-MRI pharmacokinetic modeling usually ignores potential 1 H 2 0 signal reduction due to transverse relaxation (T 2 *) effects.
  • Most clinical DCE-MRI applications employ a contrast reagent (CR) dose of 0.1 mmol/kg which may produce a blood plasma CR concentration above 5.0 mM at its peak during the bolus passage.
  • CR contrast reagent
  • a potential T 2 * effect on DCE-MRI model parameter values is described, by using a water exchange ("shutter-speed") model along with a simplified factor to account for putative T 2 * signal quenching.
  • Prostate 1 H 2 0 MRI data were acquired with a Siemens TIM Trio (3T) system under an IRB approved protocol. RF transmitting was through the whole body coil and RF receiving was with a combination of Spine Matrix and flexible Body Matrix RF coils.
  • the DCE-MRI sequence employed a 3D TurboFLASH sequence with a 256*144*16 matrix size and a 360*203 mm 2 field of view, resulting in an in- plane resolution of 1 .4*1 .4 mm 2 .
  • Other parameters are: slice thickness: 3 mm; TR/TE/FA: 5.42ms/1 .56ms/15°, imaging intersampling interval: 4.16 seconds. Any T 2 *-induced signal reduction is assumed to be proportional to [exp(-(r 2 *(CR) + R 2 o) E)], applying to the 1 H 2 0 signal from the CR-occupied compartment.
  • the most influential CR-containing compartment is the prostate interstitium.
  • r 2 * and CR represent the interstitial CR transverse relaxivity and concentration, respectively. Since susceptibility effects cross compartmental boundaries, surely r 2 * also has a contribution from capillary blood plasma CR.
  • This T 2 *-reduction factor is then directly applied to the interstitial 1 H 2 0 signal in the Ernstian MR steady-state DCE-MRI model expression.
  • Parameter uncertainties were determined with sets of Monte Carlo simulations carried out for each ROI-averaged 1 H 2 0 signal with increasing T 2 * quenching accounted for by choosing an increasing r 2 * value (mM " V 1 ): 0 (no quenching), 5 (a literature value), 20 (an estimated blood plasma value at 3T), or 40.
  • r 2 * value mM " V 1 ): 0 (no quenching), 5 (a literature value), 20 (an estimated blood plasma value at 3T), or 40.
  • SNR signal-to-noise ratio
  • Panel A shows a transverse pelvic DCE image slice (anterior up/inferior perspective, approximately 34 seconds post CR injection) of a research subject.
  • Two ROIs are indicated within the prostate gland: one in an area of retrospectively-confirmed prostate cancer, left; and the other in contralateral normal-appearing prostate tissue, right.
  • Panel A plots the arterial input function obtained from an ROI in a femoral artery. Its magnitude was adjusted using a custom-written numerical approach and an obturator muscle ROI for reference tissue. The time-course from the first-pass (includes the initial peak) was used to estimate blood volume fraction. Color-matched tissue data time-courses (points) and representative fittings (curves) are seen in Panel B.
  • FIG. 5 shows how the K trans (volume fraction CR transfer rate constant product, top) and v e (extracellular, extravascular space, EES, volume fraction, bottom) fitting results would change if increasing interstitial 1 H 2 0 T 2 * quenching is assumed.
  • K trans values this large, the algorithm is effectively a two-site (interstitium/cytoplasmae) exchange model, and the T 2 *-induced signal reduction is applied to only the EES signal.
  • a suitable computing device may include one or more processors for obtaining/receiving data, processing data, etc.
  • One or more of the processors may be adapted to perform methods in accordance with various methods as disclosed herein.
  • a computing device may also include one or more computer readable storage media.
  • an article of manufacture 700 may comprise a computer readable medium 710 (a hard disk, floppy disk, compact disk, etc.) and a plurality of programming instructions 720 stored in computer readable medium 710.
  • programming instructions 720 may be adapted to program an apparatus, such as an MRI device or a processor within or separate from an MRI device, to enable the apparatus to perform one or more of the previously-discussed.
  • Additional embodiments encompass the ability to track cancer growth and demise, as well as can predict cancer therapy response. Such embodiments can allow for MRI detection of two of the major phenotypic properties of cancers, an angiogenic switch and a metabolic switch, which combined can be a very powerful combination. Detecting tumorigenic transformation crucial to cell metastatic potential can be very valuable for therapeutic monitoring.
  • an SSM fitting of DCE-time course data can also return a third parameter, the mean intracellular water molecule lifetime, , which accounts for the transcytolemmal exchange effects.
  • a recent yeast cell suspension study (Zhang et ai. Biophys J 101 :000-000 (201 1 ), hereby incorporated by reference herein, showed that , , is inversely correlation with cell membrane ion ATPase kinetics, a measure of metabolism.
  • measures for both tumor metabolism and perfusion/permeability can be a sensitive DCE-MRI biomarker for evaluation of cancer (e.g., breast cancer) therapeutic response.
  • 157 patients with 172 suspicious breast lesions [89 patients with 92 lesions at institution A (IA); 68 patients with 80 lesions at institution B (IB)] consented to research DCE-MRI studies prior to standard care biopsy procedures.
  • the 92 lesions at IA were mammographically negative, but referred for biopsies following clinical MRI diagnoses.
  • the 80 lesions at IB were referred for biopsies following positive mammography and/or ultrasound diagnoses.
  • the research DCE-MRI acquisitions were performed using 1 .5T GE (IA) and 3T Siemens (IB) instruments with the body transmit and 4- or 7-channel phased-array bilateral breast receive RF coils.
  • a 3D spoiled gradient-recalled-echo (GRE) sequence was used to acquire unilateral sagittal 3 mm-thick DCEMRI images for all 89 IA and 14 IB patients, covering the breast with the suspicious lesion(s).
  • TWIST is a k-space undersampling and data sharing GRE sequence delivering bilateral high patial resolution breast DCE-MRI at uniform 18 s temporal resolution.
  • the DCE-MRI acquisition time was ⁇ 8 (IA) or -10 (IB) min with gadolinium CA (Magnevist®at IA and Prohance®at IB) IV injection through an antecubital vein (0.1 mmol/kg at 2 mL/s) carried out following acquisition of one (IA) or two (IB) baseline image volumes.
  • the lesion ROI and pixel-by-pixel (within ROI) DCE time-course data were subjected to both the SM and the FXR-a (fast exchange-regime-allowed) version SSM
  • Receiver Operating Characteristic (ROC) curve analyses were conducted to assess the diagnostic accuracies of the DCE-MRI biomarkers, while Spearman's correlation analyses were performed to evaluate relationships between Ti and other biomarkers. Biopsy pathology analyses revealed that 46 of the 172 lesions were malignant. Table 2 below lists the mean ⁇ SD lesion ROI DCE-MRI biomarker values for the malignant and benign lesions, as well as the ROC area under the curve (AUC) values with unity indicating perfect diagnostic accuracy.
  • K trans and k ep obtained from either model are good diagnostic markers with the SSM parameters having higher diagnostic accuracies than their SM counterparts.
  • the v e and , parameters show to be poor diagnostic markers.
  • Figure 9 shows parametric K trans and maps wherein color hot spot maps are overlaid on DCE-MRI images from a malignant (top) and a benign (bottom) lesion. In both tumors, areas with "hot” K trans color generally have “cold” color, and vice versa. Consistent with previous studies of smaller cohorts, substantial SM underestimation (relative to SSM) of K trans occurred in only malignant lesions in this larger population. Since the FXL condition assumes ⁇ 0, the fact that malignant lesions have smaller values than benign lesions shows that the greater increase of malignant lesion K trans value by the SSM is not simply because it includes an additional variable ( ), but because of genuine exchange effects.
  • K trans has previously been shown to be a useful biomarker for prediction of breast cancer therapy response.
  • the slope of the K trans / Ti linear regression is -0.13 for the malignant lesions (right side of Fig. 8), which indicates that a small, therapy-induced K change can be reflected by a larger change, making a sensitive DCE-MRI biomarker for evaluation of cancer therapeutic response.
  • FIG. 10 Other embodiments disclosed herein may be used to separate perfused (oxygenated), hypoxic (viable), and necrotic tumor regions, thereby providing tremendous value for treatment since hypoxic cancer cells are more resistant to treatment and thus, tumor hypoxia has been related to treatment outcome and patient survival. Hypoxia imaging and the identification of tumor necrosis early after the start of treatment facilitate the assessment of treatment response before tumor shrinkage occurs. Previous techniques utilizing DCE-MRI have been able to distinguish well-perfused from necrotic tumor tissue, while identification of hypoxic regions still required additional testing using F-Fmiso PET.
  • the arterial input function (AIF) curve shape was taken from a direct measurement in another DCE-MRI study (Li X et al. J Magn Reson 2010. 206: 190, also incorporated by reference herein) and temporally resampled to match the current DCE-MRI data. The AIF amplitude was then adjusted using a muscle ROI within the image field-of-view as reference tissue.
  • K trans lower panel
  • a ke top panel
  • high values bottom panel
  • Figure 1 1 depicts the spatial distribution of DCE-MRI parameters in well-perfused, hypoxic and necrotic areas of a tumor, including corresponding histograms of the regions with mean (variance) demoted.
  • perfused areas P are characterized by high A kep (see left-most columns of Figure 1 1 ) or high K trans and low values (see two right-most columns of Figure 1 1 ), while necrotic areas (N) are characterized by low A kep (see left-most column of Figure 11 A) or low K trans and high values (see two right-most columns of Figure 11 B).
  • Hypoxic areas (H) also have low A kep or K trans , and thus, cannot be separated from necrotic areas (N), using either parameter alone.
  • K trans can be used to separate viable/hypoxic from necrotic or viable/well-perfused areas as K trans values are low and values cover an intermediate range in hypoxic area (see histograms of Figure 11 ).
  • Overlapping values, as seen in the histograms of Figure 11 are to be expected due to volume averaging, especially for pixels containing hypoxic cells located close to well-perfused areas. These, in fact, can be indicative of pixels containing more than one tumor characteristic.
  • results such as those described above show that the successful implementation of SSM analysis of DCE-MRI data can obviate the need for additional imaging studies, such as F-Fmiso PET, to assess tumor microenvironment.
  • SSM DCE-MRI metabolic activity metric parameter is its use as a complimentary biomarker to FDG PET in treatment staging.
  • NACT neoadjuvant chemotherapy
  • SSM DCE-MRI breast tumor functional changes in vascular properties precede size changes in response to NACT.
  • Neoadjuvant chemotherapy (NACT) is increasingly used before surgery to treat locally advanced breast cancer.
  • pathological response is a good indicator of survival, it can be determined only after surgery.
  • accurate assessment of residual disease following NACT completion improves surgery decision making such as lumpectomy vs. mastectomy.
  • DCE dynamic contrast-enhanced
  • the TWIST sequence is a k-space undersampling and data sharing gradient-echo sequence delivering both high spatial and temporal resolution for breast DCE-MRI.
  • Other details of DCE-MRI acquisition included 10 degree flip angle, 2.9/6.2 ms TE/TR, a parallel imaging acceleration factor of two, 30-34 cm FOV, 320x320 matrix size, and 1 .4 mm slice thickness.
  • the total acquisition time was approximately 10 minutes with 18 seconds temporal resolution.
  • Gd contrast agent (Prohance®) IV injection (0.1 mmol/kg at 2 mL/s) was carried out following acquisition of two baseline image volumes. Tumor ROIs were drawn by experienced radiologists who also measured tumor size according to well established (one dimensional) RECIST guidelines.
  • the whole tumor ROI DCE-MRI parameter values were calculated by averaging the ROI values from each of the image slices covering the entire tumor, weighted by the pixel numbers within the ROI in each image slice.
  • novel imaging biomarkers such as AK trans , defined as [K trans (SSM) - K trans (SM)], can be calculated.
  • AK trans is a measure of the exchange effects on K trans quantification.
  • pathological metrics RCTD (relative changes in tumor density) and RCB (residual cancer burden), were computed.
  • Pathologic complete response pCR
  • pathologic non-response pNR
  • pathologic partial response pPR
  • Figure 12 shows examples of tumor region of interest (ROI) parameters K trans , AK trans , and % changes plotted against relative changes in tumor density (RCTD) ( Figure 12A) and residual cancer burden (RCB) ( Figure 12B) values for three patients receiving neoadjuvant chemotherapy.
  • the DEC-MRI parameter changes for the pCR were substantially larger than those of the two pPRs.
  • the RECIST measurement was not a predictor of response at this early stage of the treatment, nor was it at TP 2 ⁇ midpoint of treatment (not shown in Figure 12).
  • the differences in AK trans changes were so significant that even the two pPRs were differentiated from each other, e.g., AK trans changes at TPi predicted RCB after the completion of NACT.
  • Figure 14 shows DCE-MRI parameters after completion of
  • neoadjuvant chemotherapy at time point TP 3 ) that correlate with residual cancer burdern (RCB) and can therefore be indicators of residual disease.
  • RRB residual cancer burdern
  • AK trans DCE-MRI SSM parameter in comparison to other MRI metrics, for evaluation of cancer therapy to response provides for early prediction of soft-tissue sarcoma response to anti-angiogenic therapy.
  • ADC trace maps were generated with manufacturer's DWI data processing software.
  • the DCE-MRI images were processed off-line using the SM and SSM pharmacokinetic models to fit both tumor ROI and pixel-by-pixel (within the ROI) time-course data (2-4).
  • the arterial input functions (AIFs) used for the quantitative analyses were directly measured from ROIs placed in a femoral artery (for thigh, knee, and calf tumors) and an axillary artery(for the shoulder mass).
  • the whole tumor ROI DWI/DCE-MRI parameter values were calculated by averaging the ROI values from each of the image slices covering the entire tumor, weighted by the pixel numbers within the image slice ROIs. Pixel parameter values were analyzed with histograms and the amplitude and median values were obtained.
  • the post- contrast DCE images at or near signal intensity time-course maxima were used to measure tumor size according to the well-established (one dimensional) RECIST guidelines.
  • Figure 15 shows SM K trans , SSM K trans , and AK trans maps at two time points (before therapy (TPo) and after two weeks of Sorafenib only treatment (TP-i ) of a tumor with 95% necrosis (right thigh mass, top portion of Figure 15) and a tumor with 50% necrosis (left thigh mass, bottom portion of Figure 15) (both necrosis levels determined at a third time point (TP 2 ) - 8 weeks after TP 2 , during which time Sorafenib plus chemotherapy was administered).)
  • the optimal responder mass (top portion of Figure 15) had considerable decrease in each of the three markers (SM K trans , SSM K trans , and AK trans ) at TPi with changes in AK trans being the most dramatic, while no substantial K trans / AK trans changes were observed in the sub-optimal responder tumor (bottom portion of Figure 15).
  • Figure 16 shows a column graph of whole tumor region of interest (ROI) MRI biomarker (parameter) % changes after two weeks of Sorafenib only treatment (TP-i) relative to before therapy (TP 0 ).
  • the black columns represent 3 optimal responders, and the gray columns the other 6 sub-optimal responders.
  • the changes in tumor size (RECIST) and ADC were small and indiscriminate for the two groups of responders.
  • ROI K trans (SM),K trans (SSM), and AK trans only % change in AK trans was able to completely separate the optimal and sub-optimal responders.
  • Figure 17 show a scatter plot of % changes after two weeks of
  • Sorafenib only treatment (TP-i) in RECIST tumor size
  • ROI ADC apparatus diffusion coefficient
  • ROI AK trans histogram median AK trans vs. % necrosis at time of surgery (at TP 2 ) for all nine (9) patients.
  • ADC was not a good predictor of response to TPi in this exemplary study, as the tumor size changes were minuscule.
  • AK trans is shown to be more sensitive to therapy-induced tumor vascular changes than K trans itself, and thus a good early predictor of soft-tissue sarcoma pathologic response.
  • AK trans calculation may mitigate or eliminate many common systematic DCE-MRI parameter errors, for example, from AIF uncertainty, since the SM and SSM analyses use the same AIF. Such systematic errors have long been principal challenges in using quantitative DCE-MRI for therapy monitoring.

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Abstract

La présente invention concerne une technique d'imagerie par résonance magnétique (IRM) et éventuellement un logiciel, collectivement désignés sous le nom de modèle de « vitesse d'obturation », permettant d'analyser des données d'image de patients atteints de cancer. Dans certains modes de réalisation, l'invention porte sur une approche minimalement invasive, et néanmoins extrêmement précise, permettant de déterminer si des tumeurs sont malignes ou bénignes par distinction des caractéristiques de l'activité de réactif de contraste dans des tumeurs bénignes et malignes. Des modes de réalisation donnés à titre d'exemple portent sur des biomarqueurs mesurés par IRM pour la détermination et la surveillance de la malignité d'une tumeur, l'élimination efficace ou la limitation des faux positifs qui affectent les techniques d'IRM existantes, tout en améliorant la détermination du phénotype de tissus et la surveillance et la prévision d'interventions thérapeutiques.
PCT/US2013/037650 2008-10-31 2013-04-22 Méthode et appareil utilisant l'imagerie par résonance magnétique pour la détermination du phénotype et la surveillance de tissus Ceased WO2013159111A1 (fr)

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