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DOI: 10.1148/radiol.2451061689
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(Radiology 2007;245:130-139.)
© RSNA, 2007

Experimental Studies

Liver Tumors: Monitoring Embolization in Rabbits with VX2 Tumors—Transcatheter Intraarterial First-Pass Perfusion MR Imaging1

Dingxin Wang, MS, Affaan K. Bangash, DO, Thomas K. Rhee, MD, Gayle E. Woloschak, PhD, Tatjana Paunesku, PhD, Riad Salem, MD, Reed A. Omary, MD, MS, and Andrew C. Larson, PhD

1 From the Departments of Radiology (D.W., A.K.B., T.K.R., R.S., R.A.O., A.C.L.), Biomedical Engineering (D.W., R.A.O., A.C.L.), and Radiation Oncology (G.E.W., T.P.), Feinberg School of Medicine, and the Robert H. Lurie Comprehensive Cancer Center (G.E.W., R.S., R.A.O., A.C.L.), Northwestern University, 448 E Ontario St, Suite 700, Chicago, IL 60611. Received September 29, 2006; revision requested December 8; revision received December 22; final version accepted February 15, 2007. Address correspondence to A.C.L. (e-mail: a-larson{at}northwestern.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively test the hypothesis that transcatheter intraarterial first-pass perfusion (TRIP) magnetic resonance (MR) imaging can depict serial reductions in rabbit liver tumor perfusion during transcatheter arterial embolization (TAE).

Materials and Methods: All experiments had institutional animal care and use committee approval. In four rabbits implanted with eight VX2 liver tumors, catheters were positioned in the hepatic arteries with conventional angiographic guidance. After transfer to the MR imaging suite, serial TAE was performed, with approximately 0.5 million 40–120-µm embolic particles injected at each embolic stage. TRIP MR imaging was performed at baseline and after each subsequent embolic stage (10 minutes between stages). Serial TAE and TRIP MR imaging were repeated until stasis. The first-pass time course of signal enhancement was measured in both tumors and hepatic arteries. Tumor area under the curve (AUC) and maximum upslope (MUS) values, each normalized by arterial input, were measured to assess iterative perfusion reduction. Perfusion measurements across TAE stages were compared with paired t tests and linear regression.

Results: AUC decreased from a pre-TAE baseline of 0.408 (95% confidence interval [CI]: 0.330, 0.486) to 0.065 (95% CI: 0.046, 0.085) (P < .001) after TAE. MUS decreased from a pre-TAE baseline of 0.151 (95% CI: 0.121, 0.181) to 0.027 (95% CI: 0.022, 0.031) (P < .001) after TAE. Reductions to AUC and MUS after each embolic stage were statistically significant (P < .006 for each group of paired comparisons). AUC strongly correlated with MUS (r = 0.966, P < .001).

Conclusion: TRIP MR imaging can depict serial reductions in liver tumor perfusion during TAE. TRIP MR imaging offers the potential to target functional embolic end points during TAE.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Transcatheter arterial embolization (TAE) and transcatheter arterial chemoembolization (TACE) preferentially deliver embolic agents to hepatocellular carcinoma through catheters positioned within the hepatic arteries (1,2). Currently, data supporting optimum embolic end points for TAE and TACE (substasis end points or, alternatively, complete stasis of antegrade blood flow) remain conspicuously lacking. Complete stasis of flow may increase normal liver toxicity and potentially induce release of growth factors promoting tumor growth (3). Embolization to levels beyond therapeutic benefit may accelerate liver decompensation and subsequent failure. However, accurate intraprocedural tumor perfusion measurements are currently not possible with conventional digital subtraction angiography (DSA), thus representing a substantial limitation for evaluating the efficacy of substasis end points.

In recent studies (4), hepatic perfusion measurements were performed by using first-pass magnetic resonance (MR) imaging with intravenous injection of gadolinium-based contrast agents. These perfusion measurements demonstrated good correlation with radiolabeled microsphere measurements in a rabbit model (r = 0.93) (5) and with thermal diffusion probe measurements in a pig model after portal vein occlusion (r = 0.90) (6). Additional studies have used first-pass MR imaging to evaluate alteration to hepatocellular carcinoma perfusion after TACE (7–9) and to fibroid perfusion after uterine fibroid embolization (10). However, in these studies, pre- and posttherapy first-pass MR imaging was performed separately from the interventional procedures.

To use first-pass MR imaging for intraprocedural monitoring of TAE and TACE, perfusion measurements must be performed iteratively at each stage of embolization. The relatively recent development of an interventional radiology MR system (a DSA suite adjacent to a dedicated MR imaging unit) (11) should facilitate acquisition of functional imaging data for intraprocedural guidance. However, with intravenous contrast agent injection, the number of first-pass MR imaging measurements is limited by cumulative dose and the requisite washout times between injections. Transcatheter intraarterial injections permit reductions in contrast agent dose while increasing liver tumor conspicuity and reducing washout times (12). For first-pass studies, targeted delivery of contrast agent to the hepatic artery should simplify evaluation of enhancement curves by requiring consideration of only a single arterial input supply (as opposed to complex dual-supply liver perfusion models [13]). Transcatheter intraarterial first-pass perfusion (TRIP) MR imaging may be ideal for the iterative detection of reductions in perfusion resulting from superselective injection of embolic materials during TAE and TACE. Thus, the purpose of our study was to prospectively test the hypothesis that iterative TRIP MR imaging can depict serial reduction in rabbit liver tumor perfusion during TAE.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Animal Model
Our institutional animal care and use committee approved all experiments. Four New Zealand white rabbits (Covance, Denver, Pa) weighing 4–5 kg were used in these experiments. The rabbit VX2 tumor model was used because the VX2 tumor blood supply is almost entirely from the hepatic artery, similar to that of human hepatocellular carcinoma (14), and rabbit hepatic arteries are large enough to permit hepatic artery catheterization (15). VX2 cells were initially grown in the hind limb of a donor rabbit. Tumor portions approximately 8 mm3 in volume were harvested and implanted in the left liver lobe of the four rabbits in a minilaparotomy procedure (A.K.B. and T.K.R.), inducing liver tumors in 14–28 days. After sterile preparation of the subxiphoid abdominal area, the left lobe of the liver was exposed, a 1–2-cm incision was made on the liver lobe surface by using a number 11 blade, one tumor portion was placed within the incision, and the liver lobe was then sutured with a single stitch by using a 4.0 Vicryl suture. In four rabbits, eight VX2 liver tumors (diameter range, 0.5–3.0 cm) were grown.

Conventional DSA
Each rabbit was successfully catheterized with DSA guidance. Conventional DSA was performed by using a C-arm unit (PowerMobil; Siemens Medical Solutions, Erlangen, Germany). Each rabbit was initially sedated by using a mixture of intramuscular ketamine (80 mg per kilogram of body weight) and xylazine (5 mg/kg). After intubation, inhalational isoflurane (2.0%–3.5%) was administered for anesthesia through an endotracheal tube with a small-animal ventilator. Vascular access was achieved in the femoral artery through surgical cutdown. A 2-F catheter (JB-1; Cook, Bloomington, Ind) was advanced over a 0.014-inch-diameter guidewire into the hepatic arteries. DSA of the hepatic arteries was performed by using 2-mL manual injections of contrast agent (iohexol, Omnipaque 350; Amersham, Princeton, NJ). The catheter was advanced into the left hepatic artery of each rabbit for acquisition of pre-TAE DSA images. Each animal was then transferred to an adjacent MR imaging unit. All subsequent TAE and iterative TRIP MR imaging examinations were performed with rabbits positioned inside the MR imaging unit. All DSA procedures were performed by an attending interventional radiologist (R.A.O., with more than 10 years of experience using DSA guidance for minimally invasive therapies).

Embolization Microspheres
Serial embolization was performed by using 40–120-µm embolization microsphere particles (Embosphere; BioSphere Medical, Rockland, Mass) that are hydrophilic beads made of an acrylic copolymer cross linked with gelatin (16). Although a polyvinyl alcohol embolic agent is more widely used for TAE, the smaller Embosphere microspheres were chosen to avoid occlusion of the small 2-F catheter used for our studies. Embosphere microspheres were supplied in prefilled syringes containing 2 mL of microspheres (16 million spheres) mixed in 6 mL of saline solution (total solution, 8 mL per prefilled syringe). Each syringe was diluted with a saline and iodinated contrast agent (Omnipaque 350) mixture to yield approximately 250 000 microspheres per milliliter. Embosphere microsphere solutions were prepared by one author (A.K.B.) as directed by another (R.A.O.).

MR Imaging and TAE
MR imaging was performed by using a 1.5-T clinical MR imaging unit (Magnetom Sonata; Siemens Medical Solutions). Rabbits were imaged in the supine position by using a clinical head coil. To avoid registration complications, rabbits remained within the magnet bore throughout TRIP MR imaging and TAE procedures.

TRIP MR imaging examinations were performed with manual injections of 3.0 mL of a 5% gadopentetate dimeglumine solution (Magnevist; Berlex, Wayne, NJ) over 6 seconds (A.K.B. and R.O.A.). We used a two-dimensional multisection saturation recovery spoiled gradient-echo pulse sequence with the following parameters: repetition time msec/echo time msec/inversion time msec, 2.7/1.36/104; flip angle, 15°; five contiguous 5-mm-thick transverse sections; field of view, 200 x 100 mm2; matrix, 128 x 64 matrix; bandwidth, 500 Hz/pixel; total imaging time, 100 seconds, with the five-section volume continuously sampled at 1-second intervals after contrast agent injection. On the basis of coverage and temporal sampling requirements, inversion time was minimized and the flip angle was optimized to provide a relatively linear relationship between signal intensity (SI) and tissue R1 over the expected range of R1 values (0.67 sec–1 < R1 < 10 sec–1, 100 msec < T1 < 1500 msec) while simultaneously providing relatively high sensitivity to R1 increases after contrast agent administration (Fig 1). Each contrast agent injection was immediately followed by a 4-mL saline flush injected over 7–10 seconds.


Figure 1
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  		Figure 1: Graph of simulation results shows strong linear relationship between SI of two-dimensional saturation recovery spoiled gradient-echo (GRE) MR imaging sequence and sample R1 over the expected range of R1 values (0.67 sec–1 < R1 < 10 sec–1, 100 msec < T1 < 1500 msec). Limiting sequence flip angle to 15°, as opposed to 20°, reduces unwanted sensitivity to inflow effects while continuing to provide relatively high sensitivity and linear correlation to R1 changes. a.u. = Arbitrary units, TE = echo time, TI = inversion time, TR = repetition time.

 
Baseline TRIP MR imaging was performed before the initial TAE procedure. Next, iterative TAE with intraprocedural TRIP MR imaging was performed, with rabbits remaining inside the imaging unit bore. For each TAE iteration, Embospheres were superselectively delivered by manual injection through the same catheter previously placed during DSA (the same catheter used for intraarterial contrast agent injections). For each iterative stage of embolization, approximately 500 000 microspheres (2 mL of the prepared Embosphere solution) were injected (A.K.B. and R.O.A.). The time interval between iterative stages of TAE was 10 minutes. TRIP MR imaging studies were performed to assess serial reductions in tumor perfusion during each TAE stage. TAE was continued until stasis was suspected (three to four Embosphere injections) on the basis of a qualitative lack of tumor enhancement on MR images after contrast agent injection. After the final TAE iteration, rabbits were returned to the adjacent conventional DSA unit for follow-up angiography and confirmation of complete stasis of antegrade blood flow to the liver tumors. Each animal was then euthanized with a commercial intravenous solution (Beuthanasia; 100 mg/kg) for tumor confirmation at gross necropsy.

MR Data Analysis
Separate regions of interest (ROIs) were drawn to measure the time course of SI within both hepatic arteries and tumor tissues. ROIs containing 5 voxels in hepatic arteries were selected to monitor the arterial input function (AIF). Tumor ROIs were placed in peripheral hypervascular regions to avoid the necrotic core typically present in VX2 tumors (15,17). ROIs were selected by consensus of two observers (D.W. and A.C.L., with more than 8 years of combined experience in MR imaging research). Depending on tumor size and the number of sections required to fully cover each tumor, the number of ROIs for each tumor varied. For tumors 3.0 cm in diameter or larger, four ROIs were drawn; for tumors larger than 1.0 cm but smaller than 3.0 cm, two ROIs were drawn; and for tumors 1.0 cm or smaller, only one ROI was drawn. Identical tumor ROIs were used for each set of first-pass measurements.

SI-time curves (SIcontrast[t]) were generated separately for each ROI. The baseline preprocedural SI (SIbaseline) was measured before the first administration of contrast agent of the study. SIbaseline measurements were used to normalize subsequent SI-time curves. The time course of differential SI changes ({Delta}SI[t]) from the immediate pre–contrast agent injection baseline (SIprecontrast) was calculated for each ROI by using the following equation: {Delta}SI[t] = (SIcontrast[t] – SIprecontrast)/SIbaseline.

The first-pass starting point of the AIF was selected as that time position immediately prior to the initial rapid SI rise. For conventional full-dose intravenous techniques, the second passage of the contrast agent bolus is typically used to establish the first-pass end point (10). However, for the low-dose TRIP MR imaging techniques used in this study, the second pass was not observed. On the basis of conservative estimates from previous VX2 rabbit studies performed by using intraarterial injections with larger contrast agent doses (12), the end point of the first pass was estimated to occur 30 seconds after the first-pass starting point (roughly twice the total contrast agent and saline flush injection time).

Two semiquantitative perfusion parameters, the area under the curve (AUC) and maximum upslope (MUS), were calculated by using the {Delta}SI[t] time curve for each ROI after each TRIP MR imaging measurement. These parameters were measured within the time window between the first-pass start and end points. To correct for potential variations in arterial input, each tumor perfusion parameter was normalized by the corresponding AIF parameter as follows: AUCnorm = AUCtumor/AUCAIF and MUSnorm = MUStumor/MUSAIF (18).

Statistical Analysis
Statistical analysis was performed by using software (Origin, version 7.0; OriginLab, Northampton, Mass). The perfusion parameters AUCnorm and MUSnorm were reported as means and 95% confidence intervals (CIs).

AUCnorm and MUSnorm parameters derived from adjacent intraprocedural embolic stages, as well as from pre-TAE and completion-of-TAE stages, were separately compared by using paired two-tailed t tests. A P value of less than .05 was considered to indicate a significant difference. Linear regression was used to evaluate the correlation between corresponding AUCnorm and MUSnorm measurements (derived from identical {Delta}SI[t] time curves).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Conventional DSA
After iodinated contrast agent injection into the left hepatic artery (Fig 2), post-TAE DSA results confirmed successful stasis of antegrade blood flow in each rabbit.


Figure 2
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  		Figure 2: Coronal images from superselective hepatic artery DSA in two representative rabbits. A, C, Baseline pre-TAE images show peripheral enhancement of VX2 liver tumors (arrowheads). B, D, Corresponding post-TAE images show complete lack of tumor enhancement (arrowheads) and increased definition of proximal vessels (arrows) due to reduced flow to the tumor and subsequent reflux of contrast agent into adjacent vessels.

 
MR Imaging
Baseline pre-TAE images of the VX2 tumors acquired at peak enhancement demonstrated characteristic peripheral rim signal enhancement similar to that on the pre-TAE DSA images (Fig 3). Tumor enhancement was minimal in the corresponding post-TAE images. A total of 16 ROIs were drawn for the eight VX2 tumors (four ROIs for each rabbit). The {Delta}SI[t] curves for a single representative rabbit are shown in Figure 4. Although AIF {Delta}SI[t] remained relatively unchanged, {Delta}SI[t] for each tumor ROI was altered by each stage of embolization.


Figure 3
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  		Figure 3: Representative transverse saturation recovery spoiled gradient-echo MR images in two rabbits with VX2 liver tumors before and after TAE. A, D, Preembolization images acquired before contrast agent injection show preprocedural baseline SI (solid arrows). X = stomach, dashed arrow = gallbladder. B, E, Preembolization images acquired after intraarterial injection at peak enhancement show characteristic peripheral rim signal enhancement for each VX2 tumor (solid arrows). C, F, Postembolization images acquired after intraarterial contrast agent injection show only limited enhancement of the tumors in the corresponding regions (solid arrows). Three tumors of 0.5, 1.0, and 1.5 cm in diameter were embolized in the first rabbit. A single 3.0-cm tumor was embolized in the second rabbit. Peak enhancement images (B and E) also depict the characteristic nonenhancing necrotic core of the VX2 tumors.

 

Figure 4A
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  		Figure 4a: Representative iterative first-pass {Delta}SI[t] curves for single rabbit with VX2 liver tumor (a) before and (b–d) during progressive TAE (separate measurements were obtained after each serial Embosphere injection). Although AIF {Delta}SI[t] remained relatively unchanged, {Delta}SI[t] was altered for each tumor ROI after each TAE stage. a.u. = Arbitrary units.

 

Figure 4B
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  		Figure 4b: Representative iterative first-pass {Delta}SI[t] curves for single rabbit with VX2 liver tumor (a) before and (b–d) during progressive TAE (separate measurements were obtained after each serial Embosphere injection). Although AIF {Delta}SI[t] remained relatively unchanged, {Delta}SI[t] was altered for each tumor ROI after each TAE stage. a.u. = Arbitrary units.

 

Figure 4C
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  		Figure 4c: Representative iterative first-pass {Delta}SI[t] curves for single rabbit with VX2 liver tumor (a) before and (b–d) during progressive TAE (separate measurements were obtained after each serial Embosphere injection). Although AIF {Delta}SI[t] remained relatively unchanged, {Delta}SI[t] was altered for each tumor ROI after each TAE stage. a.u. = Arbitrary units.

 

Figure 4D
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  		Figure 4d: Representative iterative first-pass {Delta}SI[t] curves for single rabbit with VX2 liver tumor (a) before and (b–d) during progressive TAE (separate measurements were obtained after each serial Embosphere injection). Although AIF {Delta}SI[t] remained relatively unchanged, {Delta}SI[t] was altered for each tumor ROI after each TAE stage. a.u. = Arbitrary units.

 
The total number of embolic stages evaluated for each rabbit was dependent on the number of sequential Embosphere injections necessary to achieve stasis (later confirmed at follow-up DSA). Four embolic stages were evaluated in two rabbits, while only three stages were evaluated in the remaining two rabbits. For one rabbit, technical complications with the initial postembolization contrast agent injection precluded {Delta}SI[t] measurement and, therefore, only two embolic stages were evaluated. The semiquantitative perfusion parameters AUCnorm and MUSnorm derived from {Delta}SI[t] curves at each embolic stage revealed serial reduction of tumor perfusion with increasing Embosphere dose (Fig 4) with only two exceptions: MUSnorm for ROI 3 in rabbit 2 after the first embolization and MUSnorm for ROI 2 in rabbit 4 after the third embolization.

AUCnorm decreased from a pre-TAE baseline of 0.408 (95% CI: 0.330, 0.486) to 0.065 (95% CI: 0.046, 0.085) (P < .001) after completion of the final TAE stage. MUSnorm decreased from a pre-TAE baseline of 0.151 (95% CI: 0.121, 0.181) to 0.027 (95% CI: 0.022, 0.031) (P < .001) after completion of the final TAE stage. The reduction of both AUCnorm and MUSnorm perfusion parameters after each embolic stage (Figs 5 and 6, respectively) were statistically significant (P < .006 for each group of paired comparisons). Finally, the AUCnorm measurements demonstrated a strong correlation with corresponding MUSnorm measurements (r = 0.966, P < .001), as shown by results of linear regression analysis (Fig 7).


Figure 5A
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  		Figure 5a: Graphs show reduction in the following semiquantitative tumor perfusion parameters after each Embosphere injection in each rabbit ROI: (a) normalized AUC and (b) normalized MUS. (b) There were only two exceptions to the progressive reduction with TAE stage: normalized MUS for ROI 3 in rabbit 2 after the first embolization and normalized MUS for ROI 2 in rabbit 4 after the third embolization. * = For rabbit 1, technical complications with contrast agent injection after the first TAE stage precluded {Delta}SI[t] measurement.

 

Figure 5B
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  		Figure 5b: Graphs show reduction in the following semiquantitative tumor perfusion parameters after each Embosphere injection in each rabbit ROI: (a) normalized AUC and (b) normalized MUS. (b) There were only two exceptions to the progressive reduction with TAE stage: normalized MUS for ROI 3 in rabbit 2 after the first embolization and normalized MUS for ROI 2 in rabbit 4 after the third embolization. * = For rabbit 1, technical complications with contrast agent injection after the first TAE stage precluded {Delta}SI[t] measurement.

 

Figure 6A
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  		Figure 6a: Box plots show that reductions of both (a) normalized AUC and (b) normalized MUS perfusion parameters after each embolic stage were statistically significant. Boxes represent lower and upper quartiles; line inside each box labels 50th percentile (median); small crossed squares show mean value; whiskers indicate standard deviation; * = extreme points.

 

Figure 6B
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  		Figure 6b: Box plots show that reductions of both (a) normalized AUC and (b) normalized MUS perfusion parameters after each embolic stage were statistically significant. Boxes represent lower and upper quartiles; line inside each box labels 50th percentile (median); small crossed squares show mean value; whiskers indicate standard deviation; * = extreme points.

 

Figure 7
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  		Figure 7: Regression plot demonstrates strong linear relationship between normalized AUC and normalized MUS.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Our study has successfully demonstrated the use of iterative TRIP MR imaging for depicting serial reduction of liver tumor perfusion during TAE. Even with a 90% reduction in contrast agent dose compared with full-dose intravenous strategies, the TRIP MR imaging approach produced tumor enhancement curves that were visibly altered during each stage of TAE. These alterations were reflected in the semiquantitative perfusion parameters derived from these enhancement curves. Two semiquantitative perfusion parameters, AUC and MUS, each demonstrated significant reductions after each embolic stage in the VX2 rabbit liver tumor model.

The selection of optimal embolic end points during TAE (substasis vs complete stasis) remains controversial. Rational arguments can be made in support of either of these different end points, but there currently exist no quantitative data to support such hypotheses. One reason for the lack of such data has been the inability to reproducibly assess substasis end points of tumor perfusion by using conventional DSA. Monitoring of TAE with DSA relies on highly subjective assessment of reductions to antegrade blood flow. Although the spatial resolution of DSA permits superior visualization of vascular anatomy, small or hypovascular tumors can be poorly visualized (19,20). Although the recently introduced three-dimensional conventional angiography system has improved tumor visualization for optimal catheter placement (21), quantitative tumor perfusion measurements have yet to be demonstrated.

Our TRIP MR imaging studies enabled us to derive two semiquantitative parameters (MUS and AUC) to monitor TAE-induced alteration to the tumor enhancement curves. MUS, also described as the wash-in rate, is closely associated with both tissue perfusion and permeability, with perfusion predominating (22). Therefore, MUS should be useful for iterative evaluation of enhancement curves during TAE, which reduces perfusion but has minimal immediate impact on vascular permeability. AUC, however, can be simultaneously dependent on perfusion, permeability, and leakage space. Previous experimental data have indicated that tumor AUC is highly correlated with the volume transfer constant, Ktrans, during the first pass of an extracellular gadolinium contrast agent (23,24). For flow-limited extracranial tumors, Ktrans was primarily dependent on tumor blood flow (22). With the aforementioned assumptions, AUC can be rationalized as a semiquantitative parameter for iterative evaluation of reduction in liver tumor perfusion. Therefore, for our current studies, it was not unexpected that AUC changes were detected with the reductions in tumor perfusion during each stage of TAE. For our studies, a strong linear relationship was demonstrated between MUS and AUC values (r = 0.966), firmly supporting these assumptions.

Which of these semiquantitative perfusion parameters should be most effective for TRIP MR imaging monitoring during TAE? Both the MUS and the AUC parameter are relatively easy to derive from the signal enhancement curves because neither requires complex pharmokinetic modeling. Each was successfully reflective of perfusion changes during progressive stages of TAE. However, because AUC calculation involves integration of a large number of data points along the enhancement curve, the AUC parameter is likely more robust than MUS measurements, which are based on differential comparison of only a few neighboring data points. AUC measurements should be less sensitive to the adverse effects of respiratory motion, which generate artifacts in the enhancement time curves. The increased sensitivity of MUS measurements to motion artifacts may explain the two previously described exceptions to progressive reduction in MUS between TAE stages not demonstrated in the corresponding AUC measurements. However, these assumptions regarding increased motion sensitivity of MUS parameters require further validation.

For our current study we were able to achieve statistical significance (P < .05) for all comparisons. These results are suggestive of the high sensitivity of the TRIP MR imaging technique for depicting perfusion changes during TAE. With the current sample size we have achieved sufficient statistical significance to evaluate our proposed hypothesis. Increasing the sample size of the current study would not be compatible with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals, nor would it be compatible with the policies of our animal care and use committee. Future survival studies are now planned to evaluate the relationship between TRIP MR imaging–monitored functional embolic end points and tumor response in the same VX2 tumor model described in the current study.

The primary limitation our study was the lack of reference validation of substasis reductions in tumor perfusion. Ideally, microspheres would be used to provide reference perfusion measurements at each embolic stage for comparison with our semiquantitative TRIP MR imaging measurements. However, previous studies in the rabbit model have already demonstrated a strong correlation (r = 0.93) between microsphere measurements and intravenous first-pass MR imaging quantitative perfusion measurements performed by using the same saturation recovery spoiled gradient-echo pulse sequence (5). Furthermore, iterative administration of microspheres for hepatic perfusion measurements would require additional invasive procedures, complicating an already relatively time-constrained experiment. Finally, the arterial flow alteration due to hepatic artery catheter placement may complicate interpretation of microsphere results.

Contrast agent washout times and the associated effect on repetitive TRIP MR imaging perfusion measurements were not rigorously evaluated in our studies. Such evaluations were beyond the scope of this initial study to establish the feasibility of detecting progressive perfusion reductions during stages of TAE. Residual contrast agent may adversely alter iterative first-pass measurements. However, by using a small dose for each TRIP MR imaging study with adequate delays between TAE stages, residual tissue and blood pool concentrations should be minimal. Furthermore, each of our studies demonstrated a negligible second passage of the contrast agent bolus. Lack of a second contrast agent passage should limit cumulative dose to targeted tissues. Provided that cumulative tissue concentration remains within a limited range, successive TRIP MR imaging perfusion measurements should remain accurate, particularly if alterations to baseline SI are accounted for.

Translational studies will require additional steps to ensure patient safety and to avoid catheter dislodgment during iterative DSA and MR imaging measurements within an MR–interventional radiology suite. Translational studies will also require rigorous contrast agent dose optimization with respect to targeted lobar and tumor volumes, frequency of iterative TRIP MR imaging perfusion measurements, and contrast agent injection rate. MR-based catheter tracking techniques (25) and the development of MR imaging–visible embolic materials (26,27) may offer the potential to improve the overall efficiency of the proposed procedure by eliminating the need for intraprocedural transport between adjacent DSA and MR imaging units.

Practical application: We have demonstrated that iterative TRIP MR imaging can depict serial reductions in liver tumor perfusion during TAE. Liver tumor perfusion monitoring during TAE should permit standardization of embolization end points to optimize therapy while minimizing toxicity to normal liver tissues. Given that the TRIP MR imaging technique offers the potential to determine functional end points of TAE, our results suggest early clinical translation with hybrid MR–interventional radiology suites (11). In a clinical setting, patients could undergo hepatic artery catheter placement with radiographic guidance, then be transferred between the MR and interventional radiology units during iterative stages of embolization. The interventional radiologist could target functional end points of tumor perfusion reduction, an innovation that cannot be performed by using conventional DSA.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
The authors thank Richard Tang, MD, and Kathy Harris, BS, for expert assistance with animal model preparation and handling during TAE and MR imaging.


   FOOTNOTES
 

Abbreviations: AIF = arterial input function • AUC = area under the curve • CI = confidence interval • DSA = digital subtraction angiography • MUS = maximum upslope • ROI = region of interest • SI = signal intensity • TACE = transcatheter arterial chemoembolization • TAE = transcatheter arterial embolization • TRIP = transcatheter intraarterial first-pass perfusion

Author contributions: Guarantors of integrity of entire study, D.W., A.C.L.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, D.W., A.K.B., A.C.L.; experimental studies, D.W., A.K.B., G.E.W., T.P., R.S., R.A.O., A.C.L.; statistical analysis, D.W., A.C.L.; and manuscript editing, D.W., A.K.B., T.K.R., R.A.O., A.C.L.

Authors stated no financial relationship to disclose.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

  1. Furui S, Otomo K, Itai Y, Iio M. Hepatocellular carcinoma treated by transcatheter arterial embolization: progress evaluated by computed tomography. Radiology 1984;150(3):773–778. [Abstract/Free Full Text]
  2. Konno T. Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium. Cancer 1990;66(9):1897–1903. [CrossRef][Medline]
  3. Guo WJ, Li J, Chen Z, et al. Transient increased expression of VEGF and MMP-1 in a rat liver tumor model after hepatic arterial occlusion. Hepatogastroenterology 2004;51(56):381–386. [Medline]
  4. Pandharipande PV, Krinsky GA, Rusinek H, et al. Perfusion imaging of the liver: current challenges and future goals. Radiology 2005;234(3):661–673. [Abstract/Free Full Text]
  5. Materne R, Smith AM, Peeters F, et al. Assessment of hepatic perfusion parameters with dynamic MRI. Magn Reson Med 2002;47(1):135–142. [CrossRef][Medline]
  6. Scharf J, Zapletal C, Hess T, et al. Assessment of hepatic perfusion in pigs by pharmacokinetic analysis of dynamic MR images. J Magn Reson Imaging 1999;9(4):568–572. [CrossRef][Medline]
  7. Kubota K, Hisa N, Nishikawa T, et al. Evaluation of hepatocellular carcinoma after treatment with transcatheter arterial chemoembolization: comparison of Lipiodol-CT, power Doppler sonography, and dynamic MRI. Abdom Imaging 2001;26(2):184–190. [CrossRef][Medline]
  8. Zhao JG, Feng GS, Kong XQ, Li X, Li MH, Cheng YS. Changes of tumor microcirculation after transcatheter arterial chemoembolization: first pass perfusion MR imaging and Chinese ink casting in a rabbit model. World J Gastroenterol 2004;10(10):1415–1420. [Medline]
  9. Kamel IR, Bluemke DA, Eng J, et al. The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma. J Vasc Interv Radiol 2006;17(3):505–512. [CrossRef][Medline]
  10. Li W, Brophy DP, Chen Q, Edelman RR, Prasad PV. Semiquantitative assessment of uterine perfusion using first pass dynamic contrast-enhanced MR imaging for patients treated with uterine fibroid embolization. J Magn Reson Imaging 2000;12(6):1004–1008. [CrossRef][Medline]
  11. Wilson MW, Kerlan RK, Fidelman NA, et al. Hepatocellular carcinoma: regional therapy with a magnetic targeted carrier bound to doxorubicin in a dual MR imaging/ conventional angiography suite—initial experience with four patients. Radiology 2004;230(1):287–293. [Abstract/Free Full Text]
  12. Larson AC, Rhee TK, Deng J, et al. Comparison between intravenous and intraarterial contrast injection for dynamic 3D MRI of liver tumors in the VX2 rabbit model. J Magn Reson Imaging 2006;24(1):242–247. [CrossRef][Medline]
  13. Materne R, Van Beers BE, Smith AM, et al. Non-invasive quantification of liver perfusion with dynamic computed tomography and a dual-input one-compartmental model. Clin Sci 2000;99(6):517–525. [CrossRef][Medline]
  14. Ramirez LH, Julieron M, Bonnay M, et al. Stimulation of tumor growth in vitro and in vivo by suramin on the VX2 model. Invest New Drugs 1995;13(1):51–53. [CrossRef][Medline]
  15. Geschwind JF, Artemov D, Abraham S, et al. Chemoembolization of liver tumor in a rabbit model: assessment of tumor cell death with diffusion-weighted MR imaging and histologic analysis. J Vasc Interv Radiol 2000;11(10):1245–1255. [Medline]
  16. Laurent A, Wassef M, Chapot R, et al. Partition of calibrated tris-acryl gelatin microspheres in the arterial vasculature of embolized nasopharyngeal angiofibromas and paragangliomas. J Vasc Interv Radiol 2005;16(4):507–513. [Medline]
  17. Deng J, Rhee TK, Sato KT, et al. In vivo diffusion-weighted imaging of liver tumor necrosis in the VX2 rabbit model at 1.5 Tesla. Invest Radiol 2006;41(4):410–414. [CrossRef][Medline]
  18. Fenchel M, Helber U, Simonetti OP, et al. Multislice first-pass myocardial perfusion imaging: comparison of saturation recovery (SR)-TrueFISP-two-dimensional (2D) and SR-TurboFLASH-2D pulse sequences. J Magn Reson Imaging 2004;19(5):555–563. [CrossRef][Medline]
  19. Takayasu K, Maeda T, Iwata R. Sensitivity of superselective arteriography for small hepatocellular carcinoma compared with proximal arteriography and computed tomography during superselective arteriography. Jpn J Clin Oncol 2002;32(6):191–195. [Abstract/Free Full Text]
  20. Yoshimatsu S, Inoue Y, Ibukuro K, Suzuki S. Hypovascular hepatocellular carcinoma undetected at angiography and CT with iodized oil. Radiology 1989;171(2):343–347. [Abstract/Free Full Text]
  21. Liapi E, Hong K, Georgiades CS, Geschwind JF. Three-dimensional rotational angiography: introduction of an adjunctive tool for successful transarterial chemoembolization. J Vasc Interv Radiol 2005;16(9):1241–1245. [Medline]
  22. Collins DJ, Padhani AR. Dynamic magnetic resonance imaging of tumor perfusion. IEEE Eng Med Biol Mag 2004;23(5):65–83. [Medline]
  23. Evelhoch JL. Key factors in the acquisition of contrast kinetic data for oncology. J Magn Reson Imaging 1999;10(3):254–259. [CrossRef][Medline]
  24. Lankester KJ, Taylor NJ, Stirling JJ, et al. Effects of platinum/taxane based chemotherapy on acute perfusion in human pelvic tumours measured by dynamic MRI. Br J Cancer 2005;93(9):979–985. [CrossRef][Medline]
  25. Dumoulin CL, Souza SP, Darrow RD. Real-time position monitoring of invasive devices using magnetic resonance. Magn Reson Med 1993;29(3):411–415. [Medline]
  26. Wilson MW, Fidelman N, Weber OM, et al. Experimental renal artery embolization in a combined MR imaging/angiographic unit. J Vasc Interv Radiol 2003;14(9 pt 1):1169–1175. [Medline]
  27. Fidelman N, Wilson MW, Weber OM et al. Real-time MR properties of particulate embolic agents tested in a dynamic flow model. J Vasc Interv Radiol 2002;13(6):613–618. [Medline]



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A. C. Larson, D. Wang, B. Atassi, K. T. Sato, R. K. Ryu, R. J. Lewandowski, A. A. Nemcek Jr, M. F. Mulcahy, L. M. Kulik, F. H. Miller, et al.
Transcatheter Intraarterial Perfusion: MR Monitoring of Chemoembolization for Hepatocellular Carcinoma--Feasibility of Initial Clinical Translation
Radiology, March 1, 2008; 246(3): 964 - 971.
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