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Published online before print March 18, 2004, 10.1148/radiol.2312030594
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(Radiology 2004;231:491-499.)
© RSNA, 2004

Experimental Studies

Liver Tumors: MR Imaging of Radioactive Holmium Microspheres—Phantom and Rabbit Study1

Johannes F. W. Nijsen, PhD, Jan-Henry Seppenwoolde, MSc, Thomas Havenith, MSc, Clemens Bos, PhD, Chris J. G. Bakker, PhD and Alfred D. van het Schip, PhD

1 From the Department of Nuclear Medicine, University Medical Centre, Heidelberglaan 100, Room E02.222, 3584 CX, Utrecht, the Netherlands (J.F.W.N., T.H., A.D.v.h.S.); and Image Sciences Institute, University Medical Centre, Utrecht, the Netherlands (J.H.S., C.B., C.J.G.B.). Received April 15, 2003; revision requested July 1; revision received August 22; accepted October 8. Address correspondence to J.F.W.N. (e-mail: f.nijsen@azu.nl).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To investigate the use of magnetic resonance (MR) imaging in the administration and biodistribution of holmium-loaded poly(L-lactic acid) microspheres (Ho-PLLA-MS) in liver tumors.

MATERIALS AND METHODS: MR imaging measurements were obtained in phantoms, three ex vivo rabbit livers, and four livers in living rabbits. When applicable, measurements were compared with those on scintigraphic images. The transverse relaxivity R2* of the Ho-PLLA-MS was determined in a phantom study. The in vivo animal experiments were performed by using rabbits with an implanted VX2 tumor. Detection of passing Ho-PLLA-MS to estimate lung shunting was performed in a scaled model of the vena cava.

RESULTS: In the ex vivo liver experiments, the feasibility of real-time MR imaging during administration of microspheres was demonstrated. The in vivo rabbit experiments demonstrated that MR imaging can depict radioactive, nonradioactive, and decayed Ho-PLLA-MS after treatment for as long as they remain in the body. Furthermore, this study showed the ability of dynamic MR imaging to detect single doses of passing Ho-PLLA-MS.

CONCLUSION: Ho-PLLA-MS used for internal radionuclide therapy can be imaged clearly in vivo with MR imaging.

© RSNA, 2004

Index terms: Animals • Liver neoplasms, therapy, 761.12166, 761.1264, 761.1269 • Magnetic resonance (MR), experimental studies • Microspheres • Phantoms


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Primary and metastatic liver tumors are major causes of morbidity and mortality worldwide (1). In the Western world, the incidence of liver metastases is 30–50 per 100,000 people (2,3). The treatment of choice in patients with liver metastases is surgical resection. However, most tumors are inoperable by the time of diagnosis (4,5). Other treatment options, such as conventional chemotherapy and external radiation therapy, have not shown a substantial improvement in patient survival (6). A promising alternative is intraarterial radionuclide therapy with use of radiolabeled microspheres (1,7,8).

An ideal radiolabeled microsphere or particle would have the following characteristics: (a) radionuclide label with high-energy beta particle and intermediate half life to irradiate malignancies; (b) high mechanical and chemical stability to resist elution of radioactive label; (c) near–blood plasma density to minimize risk of backflow—microspheres with low density will be carried with the blood flow into the liver without premature settling due to gravitational forces during administration; and (d) possibility of external imaging of the biodistribution to determine the therapeutic dose and to monitor and evaluate therapy (8,9).

Neutron-activated radioactive holmium 166 (166Ho)–loaded poly(L-lactic acid) microspheres, which emit beta particles (Emax = 1.84 MeV) with radiotherapeutic properties appropriate for therapy, appear to meet these desired qualities. These microspheres also emit photons (81 keV) suitable for imaging with a gamma camera (10,11). An animal study (12) has shown that these microspheres can be targeted to the tumor and that they can be imaged easily with a gamma camera. However, use of a gamma camera does not delineate both the microspheres and the surrounding anatomy.

Since holmium is paramagnetic, it can be viewed with magnetic resonance (MR) imaging whether it is radioactive or not (13–15). The presence of holmium affects the MR signal, and the resultant signal change is dependent on the concentration of holmium. This allows direct visualization of the microspheres and exploitation for dosimetric purposes. This approach of imaging the holmium-loaded poly(L-lactic acid) microspheres (Ho-PLLA-MS) may thus allow quantitative assessment of the Ho-PLLA-MS distribution. MR imaging also provides useful information on the anatomy of the patient and has the soft-tissue contrast to allow detection of tumors.

The possibility of using MR imaging to visualize both nonradioactive and radioactive microspheres opens the way for three additional important features of treatment with Ho-PLLA-MS: (a) preimaging of the distribution of nonradioactive Ho-PLLA-MS to predict tumor targeting and lung shunting, resulting in radiation reduction for patients and medical personnel; (b) guidance and monitoring during administration of the therapeutic radioactive Ho-PLLA-MS, resulting in optimization of the treatment; and (c) postimaging for direct evaluation and follow-up of the distribution of Ho-PLLA-MS in the anatomic environment.

The purpose of this study was to investigate the use of MR imaging in the administration and biodistribution of Ho-PLLA-MS in liver tumors.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Preparation of Microspheres
Radioactive Ho-PLLA-MS were prepared by means of solvent evaporation (10). Holmium acetylacetonate (16) is incorporated into poly(L-lactic acid) by means of solvent evaporation, resulting in microspheres of 20–50 µm after sieving. Particle size distribution was determined at room temperature by using a Coulter Counter Multisizer 3 (Beckman Coulter Nederland, Mijdrecht, the Netherlands) with a 100-µm orifice. The calibration of the instrument was performed by using 20-µm latex beads (Coulter CC size standard L20; Beckman Coulter Nederland). Neutron activation of the microspheres was performed by means of irradiation for 1 hour in the Pneumatic Rabbit System facility of the high-flux nuclear reactor in Petten, the Netherlands. Yttrium-loaded microspheres were prepared as described for Ho-PLLA-MS. No adjustments were made for the lower molecular weight of yttrium (89 g/mol for yttrium vs 165 g/mol for holmium). Prior to administration during the in vivo and ex vivo experiments, microspheres were sonicated for 10 minutes in an ultrasonic cleaner and suspended in Gelofusine (Vifor Medical, Crissier, Switzerland).

Rabbits
All experiments were performed in agreement with the Netherlands Experiments on Animals Act (1977) and the European Convention guidelines (86/609/EC). Approval was obtained from the University Animal Experiments Committee. The experiments were performed by using four female pathogen-free New Zealand White inbred hsdIF rabbits of 3,000–4,000 g (Harlan, Horst, the Netherlands). The rabbits were housed individually in steel cages and provided daily with approximately 100 g of "complete diet" pellets for rabbits. Water was provided ad libitum. The three tumor-bearing rabbits were sacrificed 4 weeks after treatment. The rabbit without tumor was sacrificed directly after administration of Ho-PLLA-MS and acquisition of the scintigraphic and MR images. The overall evaluation of the biodistribution of Ho-PLLA-MS in the phantom and in the ex vivo and in vivo experiments was performed by two authors (J.F.W.N., J.H.S.).

Analgesia, Sedation, and Euthanasia
Analgesia and sedation during laparatomies were achieved with 0.5 mL methadone (10 mg/mL; Veterinary Pharmacy, University of Utrecht, the Netherlands) and 0.5 mL acepromazine (Ventranquil, 10 mg/mL; Sanofi Sante Animale Benelux, Maassluis, the Netherlands). The rabbits were subsequently anesthetized by means of intravenous injection of Hypnomidate (2 mg/mL; B. Braun Melsungen, Germany) and N2O and halothane (Albic, Maassluis, the Netherlands) as inhalation anesthetic. Rabbits were sacrificed with 3 mL pentobarbital (Euthesate, 200 mg/mL; Apharmo, Arnhem, the Netherlands).

Tumor Cells
The VX2 cell line (17) was obtained from the Department of Oral and Maxillofacial Surgery at the University Medical Centre, Utrecht, the Netherlands (18). The VX2 tumor was propagated by means of subcutaneous passage in the hip region of the rabbit. After dissection of the tumor, small portions (2 mm in diameter) were chosen for implantation (J.F.W.N.).

Tumor Implantation
After laparotomy, two or three tumor portions were injected into the left lateral lobe of the liver with an intravenous catheter (Abbocath-T 18G; Abbott, Sligo, Ireland). The injection wound was sealed with tissue glue (Histoacryl, B. Braun Melsungen). All surgical procedures in this study were performed by one author (J.F.W.N.) and a biotechnical assistant. After approximately 12 days, the first ultrasonographic (US) investigation (HDI 3000 ATL, Entos CL10–5 transducer) was performed to check tumor growth and was repeated three times until the animal was sacrificed. All US studies were performed by a US technician. After sacrifice, the dimensions of the tumor were measured with a ruler (J.F.W.N.).

Phantoms
For preparation of an agar gel matrix (T.H.), 20 g of dry agar powder (Life Technologies GIBCO BRL, Paisley, Scotland) was mixed in 1,000 g of cold deionized water with 30 mg of manganese(II) chloride tetrahydrate (Merck, Darmstadt, Germany). The manganese chloride was used to adjust the relaxation properties of the gel and to make them comparable to those of liver tissue (T1 approximately 500 msec, T2 approximately 45 msec). Holmium- or yttrium-loaded poly(L-lactic acid) microspheres were suspended in the agar solution during stirring. The microsphere suspension and agar suspension were heated to 100°C for 10 minutes, resulting in transparent fluid gels. The gels were added to each other in different proportions, which resulted in a rising concentration of Ho-PLLA-MS and yttrium-loaded poly(L-lactic acid) microspheres. To prevent trapping of air bubbles, the mixed gels were sonicated during cooling. Once cooled to room temperature, the gel was optically transparent with visible homogeneously distributed microspheres.

In a perfusion phantom of the abdominal region, the detection of arteriovenous shunting across the liver was evaluated. A tube with an inner diameter of 12 mm was chosen as a scaled model of the human inferior vena cava, which has a diameter of about 24 mm (19). The tube was placed in an acrylic container, which was filled with manganese-doped water as a background to mimic muscle tissue. An air pressure–driven flow pump that generated a constant flow of 17 mL/sec was connected to the phantom, yielding a flow velocity of 15 cm/sec, which is a velocity expected for a typical human vena cava (20). The circulating and background fluid consisted of water with manganese chloride (19.2 mg/L MnCl2. 4H2O). The manganese solution was used to approximate the relaxation times of human blood. For detection of the passage of Ho-PLLA-MS, a holmium-sensitive dynamic sequence (as described in the MR Imaging section) was used. After acquisition of a baseline value, a small injection of Ho-PLLA-MS was given via a 5-F injection catheter, and this was subsequently flushed with approximately 4 mL of the blood-mimicking fluid. The injected doses of Ho-PLLA-MS ranged from 4.4 to 31.0 mg. The shunting experiment was also performed for larger doses injected slowly (40, 48, and 53 mg).

Ex Vivo Experiments
Three livers were obtained from three rabbits used in terminal experiments. No additional rabbits were sacrificed for use in these ex vivo experiments. A needle was inserted in the left ventricle of the heart, and the right atrium was cut away. The animals were perfused with 0.9% NaCl and heparin; 500 mL with 1 mL heparin (5,000 IU/mL; Leo Pharma, Weesp, the Netherlands). The liver was removed, and the hepatic artery was cannulated with an intravenous catheter (Abbocath-T 24 G; Abbott). Again, the liver was flushed with 0.9% NaCl and heparin via the hepatic artery. The livers were stored in 0.9% NaCl at 5°C. Within 24 hours, the suspended microspheres (100 mg Ho-PLLA-MS in 2 mL 0.9% NaCl) were administered via the hepatic artery during the dynamic MR imaging experiments. MR imaging was performed before and after administration as described in the MR Imaging section.

In Vivo Experiments
When the implanted tumor reached a diameter of at least 20 mm, a second laparatomy was performed to administer the Ho-PLLA-MS. The gastroduodenal artery was cannulated with an intravenous catheter (Abbocath-T 24G; Abbott). Backflow was checked with 0.1% methylene blue in 5% glucose. A preflushed administration system similar to that described by Herba et al (21) was connected to the intravenous catheter. The suspended Ho-PLLA-MS were administered, and the syringe was measured for radioactivity before and after injection to calculate the injected dose. The gastroduodenal artery was ligated or, if possible, sealed with tissue glue (Histoacryl, B. Braun Melsungen). MR images were obtained before, 3 days after, and 17 days after administration of the radioactive Ho-PLLA-MS. The rabbits were sacrificed after 4 weeks, and the excised livers were subjected to additional MR imaging. Scintigraphic images were obtained 3 days after administration of Ho-PLLA-MS. To verify the presence and biodistribution of Ho-PLLA-MS in the liver and tumor, the liver was embedded in paraffin, sliced, and evaluated histologically after staining with hematoxylin-eosin. The evaluation was done by one author (J.F.W.N.) and a pathologist.

Scintigraphic Imaging
After administration of the radioactive Ho-PLLA-MS, imaging of the whole rabbit and the abdominal region was performed by using a dual-head gamma camera (Vertex-MCD; ADAC, Milpitas, Calif). Posterior and lateral planar images were acquired with a matrix of 256 x 256 pixels. The energy window was set at the photopeak of 80 keV with a width of 30%, resulting in an accumulation of 1 x 106 counts per image. The gamma camera was equipped with a medium-energy collimator. The acquired images were evaluated by a physicist.

MR Imaging
MR imaging was performed with a whole-body system, operating at 1.5 T (Gyroscan ACS-NT 15; Philips Medical Systems, Best, the Netherlands). Measurement of the relaxation properties of the holmium and yttrium microspheres for different concentrations was performed by using a multiecho spin-echo MR sequence in combination with an inversion-recovery MR sequence (22) with a 25.6-cm field of view, 10-mm section thickness, 256 x 128 matrix, and one signal acquired. The transverse relaxation rate (R2* = 1/T2*) for fast field echo (FFE) MR imaging was determined by using a multi–gradient-echo MR sequence, which was used to acquire 25 echoes with an echo spacing of 0.91 msec. Imaging parameters were 500-msec repetition time with a 25.6-cm field of view, 10-mm section thickness, 256 x 128 matrix, four signals acquired, and 25° flip angle. Evaluation and imaging of the relaxation properties were performed in consensus by two authors (J.H.S., C.B.). All further MR imaging was performed by one author (J.H.S.).

To detect injected boluses of microspheres that passed the modeled vena cava, dynamic transverse T2*-weighted FFE MR imaging was performed. Imaging parameters were 17/15 (repetition time msec/echo time msec) with a 25.0 x 10.2-cm field of view, 256 x 153 matrix, 30-mm transverse section, 10° flip angle, and temporal resolution of 0.352 second per image.

The imaging protocol for both ex vivo and in vivo MR measurements obtained before and after administration of Ho-PLLA-MS included anatomic T1-weighted spin-echo MR imaging (466/13, 25.6 x 15.3-cm field of view, 205 x 256 matrix, 15 adjacent sections with 5.0-mm thickness, four signals acquired, and 90° flip angle), tumor-sensitive T2-weighted turbo spin-echo MR imaging (1,800/90, 25.6 x 15.3-cm field of view, 128 x 128 matrix [reconstruction of 256 x 256], 15 adjacent sections with 5.0-mm thickness, four signals acquired, turbo factor of 12, and 90° flip angle), and holmium-sensitive dual-echo T2*-weighted FFE MR imaging (30/4.6, 9.2; 25.6 x 15.3-cm field of view, 128 x 128 matrix [reconstruction of 256 x 256], 15 adjacent sections with 5.0-mm thickness, eight signals acquired, and 15° flip angle).

For the ex vivo experiments, a dynamic T2*-weighted FFE MR sequence was also used to depict the administration of Ho-PLLA-MS. Imaging parameters were 12/4.6, 9.2 with a 25.6 x 19.2-cm field of view, 256 x 192 matrix, 4.0- or 10.0-mm transverse section thickness, 10° flip angle, and temporal resolution of 1 second per image.

Data Analysis
Longitudinal relaxation rate R1 (1/T1) and transverse relaxation rate R2 (1/T2) of prepared gels were determined by means of least squares exponential fitting of the obtained signal intensities, as implemented with our clinical scanners (Gyroscan Intera NT; Philips Medical Systems). By placing fixed regions of interest with an area of 1.1 cm2 (C.B.), mean relaxation rates were determined for each gel. The transverse relaxation rate R2* (1/T2*) was calculated for each gel by separating even and odd echoes, followed by least squares fitting by using statistical analysis software (SigmaPlot; SPSS, Chicago, Ill). The resultant relaxation rates of even and odd echoes were averaged. Linear least squares fitting (SigmaPlot; SPSS) of the relevant data was used to determine dependency of the relaxation rates on the concentration of the microspheres.

To relate injected and detected boluses of passing Ho-PLLA-MS, the increase of the transverse relaxation rate ({Delta}R2*) was calculated by assuming exponential signal decay relative to a previously acquired baseline value. The baseline value was determined by averaging the signal intensity in the region of interest (placed in fixed position with an area of 2.5 cm2 at the "vessel" [J.H.S.]) of the data points collected before injection of the bolus. The concentration was calculated by using the previously acquired calibration curves, as determined earlier. The summing of all contributions resulted in the total amount of detected microspheres. Finally, the resultant amounts were compared with the injected doses and fitted linearly. All data analysis concerning the shunting experiment was done by using Excel software (Microsoft, Redmond, Wash).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Microspheres
Microspheres prepared by means of solvent evaporation resulted after sieving in 3–5 g of spherical particles with a diameter of 20–40 µm (Fig 1) and a holmium content of 15%–17% (wt/wt) or yttrium content of 6%.



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  		Figure 1. A, Scanning electron micrograph of Ho-PLLA-MS (original magnification, x500). B, Graph shows volume-weight distribution of sieved microspheres, which had a mean diameter of 30 µm. Ninety-six percent of the volume of the particles had a diameter of 20-40 µm.

 
Tumor Implantation and Administration of 166Ho Microspheres
Implantation of the tumor resulted in a 100% acceptance rate. After 16 days, the tumors reached a diameter of approximately 23 mm and were well vascularized, as seen with US. Tumor volume varied from 10 to 17 cm3 (mean ± SD, 12.7 cm3 ± 4.1), as measured with a ruler. A percentage of 6.3% ± 2.0 of the Ho-PLLA-MS adhered to the administration system during application. An amount of 48–50 mg of radioactive Ho-PLLA-MS was effectively administered to the liver and tumor, corresponding to 560–640 MBq of radioactivity.

Phantoms
The longitudinal and transverse relaxation rates (R1 and R2, respectively) of the Ho-PLLA-MS were largely independent of the microsphere concentration. A least squares fit of the data suggests {Delta}R2 = (1.89 ± 0.12) · (Ho-PLLA-MS) · sec–1, where Ho-PLLA-MS is the concentration of holmium-loaded microspheres in milligrams per gram. The transverse relaxivity R2* due to the local field disturbance of the Ho-PLLA-MS was determined to be {Delta}R2* = (86.8 ± 3.5) · (Ho-PLLA-MS) · sec–1, where the concentration Ho-PLLA-MS is given in milligrams per gram (Fig 2). This transverse relaxivity corresponds to that predicted for the static dephasing regime (23). The yttrium 89 microspheres showed only an R1 and R2 dependence on the concentration of microspheres, with no additional relaxation effect of the yttrium: R2* {approx} R2 = (0.8 ± 0.3) · (Y-PLLA-MS) · sec–1, where Y-PLLA-MS is the concentration of yttrium-loaded microspheres in milligrams per gram.



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  		Figure 2. A, Graph shows R1 values versus Ho-PLLA-MS concentration. B, Graph shows R2 values versus Ho-PLLA-MS concentration. C, Graph shows R2* values versus Ho-PLLA-MS concentration. The solid line is a least squares fit to the data points and represents the theoretical result in the static dephasing regime (equation 11 in reference 23) as calculated from the holmium content of the microspheres.

 
Detection of passing Ho-PLLA-MS to allow estimation of lung shunting in a scaled model of a typical human vena cava showed the ability of dynamic MR imaging to demonstrate all single injected doses (Table), which is illustrated in Figure 3 for doses of 6.7 mg and 48.0 mg. The latter dose was injected slowly to simulate shunting of microspheres over time. This figure shows that after acquisition of a baseline value, a dose of a few milligrams is detected easily. For all other injected doses, measured changes in relaxation rates were linearly proportional to the amount of administrated microspheres.


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  		Comparison of Detection of Ho-PLLA-MS with Scintigraphy and MR Imaging

 


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  		Figure 3. Graph shows detection of Ho-PLLA-MS passing a scaled model of a human vena cava. Dashed lines denote the baseline values before injection of the boluses. For the small dose (5.5 mg), a rapid injection was given at point A, whereas the large dose was injected from points B to C. Point D is a rapid flushing of the injection catheter with the circulating fluid. The areas between the baseline values and the curves are proportional to the injected doses. a.u. = arbitrary units.

 
Imaging of Biodistribution in ex Vivo Liver
Administration of Ho-PLLA-MS in three ex vivo rabbit livers showed that the smaller vessels up to the border of the liver were filled with Ho-PLLA-MS (Fig 4, C, numbers 1–4). Thereafter, accumulation of Ho-PLLA-MS appeared in the larger blood vessels and the center of the liver (Fig 4, C, numbers 4–8). After administration of approximately 40 mg of Ho-PLLA-MS (Fig 4, C, number 5), almost no new vessels were embolized.



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  		Figure 4. Images show results of dynamic MR imaging of the administration of Ho-PLLA-MS in an ex vivo rabbit liver (without tumor). A, Photograph of the ex vivo liver. B, Diagram of the ex vivo liver. Microsphere administration was mainly selective for the medial lobe and left lateral lobe. C, Dynamic coronal T2*-weighted FFE MR images (12/4.6, 9.2; 25.6 x 19.2-cm field of view; 256 x 192 matrix; 4.0- or 10.0-mm transverse sections; 10° flip angle; temporal resolution of 1 second per image) show administration of the microspheres in the liver. Images 1-3, section thickness of 4 mm; images 4-8, section thickness of 10 mm. Microspheres first collect in the more peripheral regions of the liver; thereafter, larger central arterial vessels are filled.

 
Imaging of Biodistribution in Tumor-bearing Rabbits
On scintigraphic images, radioactivity was seen in the tumor and the liver (Fig 5). The activity in the liver was distributed heterogeneously. Increased accumulation of microspheres was seen in and around the tumor. MR imaging of the rabbit before administration of Ho-PLLA-MS resulted in good visualization of the VX2 tumor (Fig 6), particularly on the T2-weighted spin-echo MR images (Fig 6, C). The tumor appeared as a homogeneous, round, and sharply marginated lesion. On T1-weighted MR images, the tumors were hypointense, and on T2-weighted MR images, they were hyperintense compared with liver tissue.



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  		Figure 5. Coronal MR and scintigraphic images of one of the treated tumor-bearing rabbits. A, Anatomic T1-weighted spin-echo MR image (466/13, 25.6 x 15.3-cm field of view, 205 x 256 matrix, 15 adjacent sections with 5.0-mm thickness, four signals acquired, and 90° flip angle). B, Holmium-sensitive T2*-weighted FFE MR image (30/4.6, 9.2; 25.6 x 15.3-cm field of view; 128 x 128 matrix [reconstruction, 256 x 256]; 15 adjacent sections with 5.0-mm thickness; eight signals acquired; 15° flip angle). A and B were obtained after Ho-PLLA-MS administration (48 mg, 560 MBq) into the hepatic artery, showing the biodistribution of Ho-PLLA-MS in relation to the surrounding areas. Increased accumulations of paramagnetic holmium are seen on the T2*-weighted MR image (B) as signal voids (small arrows) due to the paramagnetic nature of the holmium. The larger arrow indicates the substantial accumulation of microspheres in and around the tumor. C, Schematic shows the organs and tumor in the rabbit. D, Whole-body scintigraphic image of the rabbit obtained 3 days after injection of radioactive Ho-PLLA-MS. Increased accumulation of radioactivity due to Ho-PLLA-MS is indicated by small arrows. Larger arrow shows increased radioactivity in and around the tumor.

 


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  		Figure 6. A, Schematic shows the rabbit organs, which are seen in the following transverse MR images. B-F, Transverse MR images obtained in a rabbit in prone position. Thick arrows indicate implanted tumor. The gray scale and position of the organs correspond with the small schematics on each MR image. B, Representative anatomic T1-weighted spin-echo MR image obtained before administration of Ho-PLLA-MS (466/13, 25.6 x 15.3-cm field of view, 205 x 256 matrix, 15 adjacent sections with 5.0-mm thickness, four signals acquired, and 90° flip angle). C, T2-weighted spin-echo MR image obtained before administration of Ho-PLLA-MS (1,800/90, 25.6 x 15.3-cm field of view, 128 x 128 matrix [reconstruction, 256 x 256], 15 adjacent sections with 5.0-mm thickness, four signals acquired, turbo factor of 12, and 90° flip angle). D, T2*-weighted FFE MR image obtained before administration of Ho-PLLA-MS (30/4.6, 9.2; 25.6 x 15.3-cm field of view; 128 x 128 matrix [reconstruction, 256 x 256]; 15 adjacent sections with 5.0-mm thickness; eight signals acquired; and 15° flip angle). E, Repeat T1-weighted spin-echo MR image obtained after administration of Ho-PLLA-MS. F, Repeat holmium-sensitive T2*-weighted FFE MR image obtained after administration of Ho-PLLA-MS. Increased holmium accumulation is clearly seen in and around the tumor, as indicated with the thick arrow. Small signal voids (thin arrows) indicate holmium accumulation in liver tissue.

 
After administration of Ho-PLLA-MS, signal voids were seen in the tumor and the liver and were caused by field inhomogeneities created by accumulations of Ho-PLLA-MS (Figs 4–6). The T2*-weighted FFE MR image is more sensitive for holmium, as shown by the increased black areas in the liver, particularly around the tumor.

Follow-up MR images were obtained 17 days after administration of Ho-PLLA-MS. No progression of the tumor was seen. With respect to the biodistribution of Ho-PLLA-MS, no substantial redistribution was seen during the observed period. In two rabbits, MR images showed that the right lateral lobe was increased up to two to four times the original volume.

After excision of the liver and tumor, it appeared that the tumors were completely necrotic. In the right and left medial lobe and the left lateral lobe, damage of the liver tissue was observed. These lobes showed large necrotic areas. No apparent lesions were found in the stomach or duodenum. Histologic findings confirmed the accumulation of Ho-PLLA-MS in and around the tumor (Fig 7). Necrotic liver tissue was also seen close to large blood vessels that contained clusters of Ho-PLLA-MS.



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  		Figure 7. Photomicrograph of large arterial blood vessels (1) filled with Ho-PLLA-MS. Single microspheres are observed in the smaller arterial blood vessels (arrow). Portal veins (2) contain no Ho-PLLA-MS. Tumor (3) and surrounding liver tissue (4) are destroyed by the radioactive Ho-PLLA-MS. Bar = 0.5 mm. (Hematoxylin-eosin stain; original magnification, x40.)

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Without any treatment, the median survival of patients with liver metastases is approximately 9 months (3). Surgical resection is presently the only approach that offers substantial chance of cure in patients with liver metastases, but this is an option for only 10%–20% of patients (1,24,25). An alternative mode of therapy is the use of radioactive yttrium particles (1,26). However, the yttrium microspheres currently used cannot be visualized directly with either scintigraphy or MR imaging.

To overcome this major drawback, radioactive Ho-PLLA-MS are used, which emit both gamma rays for diagnostic scintigraphic imaging and beta particles for therapy (12,27). Since holmium is paramagnetic, it can also be visualized clearly with MR imaging. In our study, the role of MR imaging for selective internal radionuclide therapy was explored and compared with that of traditional scintigraphy.

Phantom experiments with increasing concentrations of Ho-PLLA-MS suspended in agar showed that the longitudinal and transverse relaxation rates of Ho-PLLA-MS were largely independent of the concentration, which is to be expected for stationary paramagnetic perturbers of this size, since the perturbing particles are large compared with the diffusion length of the protons (28). The experiments with increasing Ho-PLLA-MS concentrations showed clear {Delta}R2* effects. These effects were observable for concentrations of Ho-PLLA-MS that corresponded to the quantities that are expected to be necessary for treatment of patients with liver cancer. When compared with Ho-PLLA-MS, the paramagnetic properties of yttrium microspheres are weak. This was to be expected, as the volume magnetic susceptibility of yttrium ({chi}yttrium = 119 ppm) is several orders of magnitude lower than that of holmium ({chi}holmium = 48,851 ppm). Because of this lack of clear paramagnetic dephasing effect, realistic detection of yttrium-loaded microspheres would require administration of an unrealistic amount of microspheres, making yttrium-loaded microspheres useless when combined with MR imaging. Imaging of realistic therapeutic amounts of yttrium-loaded microspheres with MR imaging is therefore not possible.

One of the most important aspects of selective radionuclide therapy of liver malignancies is estimation of the degree of shunting to the lungs. To prevent radiation-induced gastritis or pneumonitis, patients with significant shunting to the lungs and upper gastrointestinal tract must be excluded (29–31). Conventionally, scintigraphy is used for this purpose. Technetium 99m macroaggregated albumin, or 99mTc MAA, has been used to predict the shunting and tumor targeting of yttrium 90 glass- or resin-based microspheres (26,32). Although 99mTc MAA particles give an impression of the biodistribution of the yttrium microspheres, their distribution may deviate greatly from that of the original glass and resin microspheres, since the 99mTc MAA particles are less dense and differ in size, distribution, and shape (8,26). Microspheres that can be used for both diagnostic imaging and therapy are therefore preferable (30). As shown by the described results, Ho-PLLA-MS satisfy these requirements for both MR imaging and scintigraphy.

Furthermore, MR imaging is able to give a survey of the biodistribution, lung shunting, and tumor-to-liver ratio prior to application of the therapeutic dose. The combination of Ho-PLLA-MS and MR imaging offers the opportunity to apply a nonradioactive "tracer dose" with exactly the same composition and physical characteristics as the therapeutic radioactive microspheres. Such a diagnostic tracer dose of microspheres with identical characteristics provides the most accurate prediction of the distribution of the therapeutic microspheres, thereby offering a solution to the major disadvantages (30) of 99mTc MAA, which is used as tracer dose in yttrium therapy (33,34). Nevertheless, quantification of lung shunting of nonradioactive microspheres with MR imaging is complicated, since imaging of the lungs is difficult because of the disturbances of air and motion artifacts (35,36). To overcome this problem, the amount of shunted Ho-PLLA-MS can be measured by detecting the microspheres when they pass the inferior vena cava, with a technique comparable to the determination of cerebral perfusion by means of passage of intravascular contrast agents (37). Phantom studies showed that detection of less than 1% of therapeutic amounts of Ho-PLLA-MS is achievable, possibly allowing estimation of arteriovenous shunting across the liver for in vivo application.

In the ex vivo liver experiments, the feasibility of real-time MR imaging during administration of Ho-PLLA-MS was demonstrated. It was observed that smaller vessels were filled with microspheres first, followed by the larger vessels. Administration of additional Ho-PLLA-MS will only result in undesired filling of the larger vessels and will give risk of "backflow." Generally, these larger vessels are nontumor vessels and therefore will not contribute to tumor treatment after accumulation of Ho-PLLA-MS (Fig 4). Dynamic imaging of the accumulation of Ho-PLLA-MS in the tumor will give the opportunity to stop further administration in that part of the liver at the moment that the tumor is saturated with microspheres. The possibility of real-time imaging during administration of Ho-PLLA-MS will therefore allow for adaptation of the position of the catheter tip and flow and quantity of the microspheres, thereby resulting in customization of the treatment for each individual patient. This approach will result in a decrease in liver damage and an increase in tumor-to-liver ratio.

In our animal studies, high-spatial-resolution imaging of Ho-PLLA-MS and the surrounding anatomy was demonstrated. The tumor was clearly visible as a spherical tissue mass in the left lateral lobe of the liver. Sizes of the tumor measured with US and with a ruler were comparable to the measurements obtained with MR imaging. Accumulation of radioactive Ho-PLLA-MS was seen in and around the tumor, as can be expected because of the hypervascular brim of hepatic arteries around the tumor (38). The rabbit experiments demonstrated that MR imaging can be used to visualize both radioactive and nonradioactive or decayed Ho-PLLA-MS after treatment, for as long as they remain in the body. As expected, no substantial redistribution was observed 17 days or 4 weeks after administration of Ho-PLLA-MS. Since MR imaging can depict the location of accumulations of Ho-PLLA-MS with a straightforward approach, quantitative MR imaging of the microspheres in the target organ containing tumor may provide easy and accurate dosimetric measurement. Complementary studies must be performed to investigate the possibilities of using quantitative MR imaging for accurate and reliable dosimetry.

MR imaging proved to be a useful tool in the direct identification of the anatomic structures of the abdominal region (39), and this (3) facilitates interpretation of the distribution of the spheres. It is generally accepted that MR imaging has superior soft-tissue contrast in comparison to that with spiral computed tomography (CT) and US (39). Nuclear imaging is limited with regard to anatomic information and will therefore require additional information from CT or MR imaging. MR imaging combines the imaging of therapeutic Ho-PLLA-MS with the desired anatomic information.

Limitations of this study include the lack of an animal experiment in which all individual parts of this investigation are combined, such as selective Ho-PLLA-MS administration and lung shunting. However, the feasibility of each individual element is demonstrated in this article and gives a guideline for such combined study. Another limitation is the difference in the size of the liver and body and the quantity of lesions and tumor size in our animal experiment compared with those in human patients with liver malignancies. Extrapolation of the tumor and/or liver volume in our animal model to that in the human liver would likely be the equivalent of a 10–12-cm mass in the human liver. This fact somewhat limits extrapolation of these data to the clinical situation in humans. Real-time imaging possibilities are currently restricted, resulting in suboptimal visualization during MR imaging–guided interventions of the liver. Moreover, the catheters used do not have the most favorable properties necessary for catheterization guided with MR imaging. This limits the practicability of fully MR imaging–guided administration of Ho-PLLA-MS, but a combined radiographic and MR imaging configuration is sufficient at the moment.

MR imaging is relatively expensive when compared with conventional radiography and scintigraphy. During repeat treatment, the MR imaging signals of Ho-PLLA-MS that are still present from a previous administration can interfere with those of the newly administered microspheres. Therefore, a baseline image obtained before treatment is needed for comparison with the image obtained after treatment. We speculate that the high-spatial-resolution imaging, real-time imaging, long-term posttreatment imaging, and additional anatomic detail offered by MR imaging will potentially result in better treatment opportunities and may justify the higher costs of this approach, but more clinical research in this area will be required to support this speculation.

In conclusion, the present study has demonstrated that Ho-PLLA-MS administered in internal radionuclide therapy can be imaged clearly in vivo with MR imaging. It may thus be possible to customize treatment for each individual patient, resulting in the most accurate tumor-to-liver ratio, which will be beneficial for the patient in terms of longevity and palliation. The results warrant further studies to investigate the possibilities of quantitative imaging and direct administration of the microspheres with the use of MR imaging.

Practical application: The results of this study demonstrate that both the biodistribution of Ho-PLLA-MS and the detailed morphology of the liver can be imaged accurately with MR imaging. The possibility of visualization of both radioactive and nonradioactive Ho-PLLA-MS facilitates follow-up of the patient and effectiveness of the treatment. Information about possible redistribution and degradation processes of the microspheres can be obtained with MR imaging. This information will give extra knowledge in the understanding and follow-up of treatment results. However, further work must be performed to optimize MR imaging guidance of this treatment. We believe that MR imaging will provide an opportunity for accurate selective administration of Ho-PLLA-MS during internal radionuclide therapy.


   ACKNOWLEDGMENTS
 
The authors thank Sander Zielhuis, MSc, and Anne Hoekstra, MSc, from the Department of Nuclear Medicine, University Medical Centre, Utrecht, the Netherlands, for preparation of the microspheres and acquisition and evaluation of the scintigraphic images, respectively. The authors acknowledge Mourad El Ouamari from the Department of Radiology, University Medical Centre, for performance of US, and Kees Brandt from the Central Laboratory Animal Institute (GDL), Utrecht University, the Netherlands, for his skilled assistance during the animal studies. Finally, we thank Dr W. A. M. van Maurik from EMSA, Faculty of Biology, Utrecht University, for assistance in scanning electron microscopy acquisition, and Dr Hub Dullens from the Department of Pathology, University Medical Centre, for assistance with histologic analysis.


   FOOTNOTES
 
Abbreviations: FFE = fast field echo, Ho-PLLA-MS = holmium-loaded poly(L-lactic acid) microspheres

Author contributions: Guarantors of integrity of entire study, J.F.W.N., J.H.S., C.J.G.B., A.D.v.h.S.; study concepts, J.F.W.N., J.H.S., C.J.G.B., A.D.v.h.S.; study design, all authors; literature research, J.F.W.N., J.H.S.; experimental studies, J.F.W.N., J.H.S., T.H.; data acquisition, J.F.W.N., J.H.S., T.H., C.B.; data analysis/interpretation, J.F.W.N., J.H.S., C.J.G.B., C.B.; statistical analysis, J.F.W.N., J.H.S., C.B.; manuscript preparation, J.F.W.N., J.H.S., C.B.; manuscript definition of intellectual content, J.F.W.N., J.H.S.; manuscript editing, J.F.W.N., J.H.S., C.J.G.B., A.D.v.h.S.; manuscript revision/review, J.F.W.N., J.H.S., T.H., C.J.G.B., A.D.v.h.S.; manuscript final version approval, all authors


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 MATERIALS AND METHODS
RESULTS
DISCUSSION
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