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(Radiology. 2000;217:827-831.)
© RSNA, 2000

Experimental Studies

Percutaneous Tumor Ablation: Increased Coagulation by Combining Radio-frequency Ablation and Ethanol Instillation in a Rat Breast Tumor Model1

S. Nahum Goldberg, MD, Jonathan B. Kruskal, MD, PhD, Brian S. Oliver, BA, Melvin E. Clouse, MD and G. Scott Gazelle, MD, MPH, PhD

1 From the Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215 (S.N.G., J.B.K., B.S.O., M.E.C.), and the Department of Radiology, Massachusetts General Hospital, Boston (G.S.G.). Received January 17, 2000; revision requested February 13; revision received March 7; accepted April 20. Supported in part by a research grant from Radionics. Address correspondence to S.N.G. (e-mail: sgoldber@caregroup.harvard.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To determine if percutaneously applied radio frequency (RF) combined with percutaneous ethanol instillation (PEI) can increase the extent of ablation in rat breast tumors.

MATERIALS AND METHODS: R3230 mammary adenocarcinoma was implanted bilaterally in the mammary fat pads of 18 female rats. The tumor nodules measured 1.2–1.5 cm. Eight tumors each were treated with (a) conventional, monopolar RF (96 mA ± 28; 70°C for 5 minutes); (b) PEI (250 µL of ethanol infused over 1 minute); (c) combined therapy of PEI immediately followed by RF ablation; or (d) combined therapy of RF ablation immediately followed by PEI. Four tumors were not treated and served as controls. Histopathologic examination included staining for mitochondrial enzyme activity. Resultant coagulation necrosis was compared between treatment groups.

RESULTS: Coagulation necrosis was observed only within treated tumors. Tumors treated with RF alone had 6.7 mm ± 0.6 of coagulation surrounding the electrode, and those treated with PEI alone had 6.4 mm ± 0.6 of coagulation around the instillation needle (not significant). Significantly increased coagulation of 10.1 mm ± 0.9 (P < .001) was observed with the combined therapy of PEI followed by RF. RF followed by PEI did not increase coagulation (6.4 mm ± 0.8 around the needle; not significant).

CONCLUSION: PEI followed by RF ablation therapy increases the extent of induced coagulation necrosis in rat breast tumors, as compared with either therapy alone.

Index terms: Alcohol ablation, **.12692 • Animals • Interventional procedures, experimental studies, **.1269 • Neoplasms, therapy, **.1269 • Radiofrequency (RF) ablation, **.1269


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Potential benefits of minimally invasive, imaging-guided ablation of focal neoplasms over conventional surgical options include the ability to ablate tumor in nonsurgical candidates, reduced morbidity as compared with surgery, and the potential to perform the procedure on an outpatient basis (1). The two main approaches that have been used to induce percutaneous tumor ablation include the direct injection of cytotoxic pharmaceutical agents such as ethanol and the deposition of thermal energy via needlelike applicators to induce coagulation necrosis (1). Initial studies (2–5) focused on direct injection strategies, with the greatest clinical attention given to percutaneous ethanol instillation (PEI), particularly for the treatment of focal liver tumors. Whereas several investigators have achieved results comparable to those of surgical resection (65% 5-year survival rate) for small (<3-cm) focal hepatocellular carcinomas (2,3), the uneven distribution of ethanol throughout the target lesion has dramatically limited therapeutic efficacy for larger tumors and metastatic liver cancer (4,5). An additional limitation of injection therapy has been the necessity of multiple treatment sessions to adequately treat the lesion, which prolongs therapy (1,6).

Recent attempts to improve on the results of ablative injection therapy have included strategies that use thermal energy sources such as radio frequency (RF) (6–10), microwaves (11,12), ultrasound (13), and laser (14,15). Investigators in at least one preliminary clinical study suggest that increased coagulation can be achieved in fewer treatment sessions with these thermal therapies in small liver tumors, as compared with percutaneous injection therapy (6). However, even the most optimistic long-term report for percutaneous RF thermal therapy of colorectal metastases indicates local tumor recurrence in 35% of cases (16), and investigators in a recent study (17) report that a majority of hepatocellular carcinomas greater than 5 cm in diameter are incompletely treated with use of current thermal ablation strategies. Thus, further increases in thermal ablation efficacy are necessary.

One potential strategy for increasing coagulation would be to combine both thermal and pharmacologic injection therapy with the goal of evoking synergy between these two methods. The purpose of this study was to determine whether RF in combination with PEI can increase the extent of ablation in an animal breast tumor model.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Animal Model
Approval of the Institutional Animal Care and Use Committee was obtained prior to the initiation of these studies. All experiments and procedures were performed in fully anesthetized animals. Anesthesia was induced by using ketamine ([50 mg per kilogram of body weight] Ketaject; Phoenix Pharmaceutical, St Joseph, Mo) and xylazine ([5 mg/kg] Xyla-ject; Bayer, Shawnee Mission, Kan) injected into the peritoneum. A booster anesthetic injection at one-tenth the dose was administered every 30–60 minutes as needed.

Experiments were performed by using an established R3230 mammary adenocarcinoma cell line obtained from the laboratory of Ralph Weissleder, MD, PhD (Center for Molecular Imaging, Massachusetts General Hospital, Boston). Fresh tumor was initially harvested from a live carrier. Within 1 hour of this tumor explantation, the tumor was homogenized with a tissue grinder (model 23; Kontes Glass, Vineland, NJ) by using an aseptic technique and was suspended in RPMI 1640 medium (INC Biomedicals, Aurora, Ill) at a concentration of approximately 1 x 107 tumor cells per 0.1 mL. Under direct visualization, 0.2–0.3 mL of the tumor suspension was injected slowly by means of an 18-gauge needle into the mammary fat pad of 18 female Fischer 344 rats (Harlan-Sprague-Dawley, Indianapolis, Ind), the strain of animals most closely associated with this tumor. Two tumors were created in each animal, for a total of 36 tumors. Tumors were grown for 10–20 days until the desired size was achieved. Animals were monitored every 3–4 days to determine tumor growth. Solid nonnecrotic tumors (as determined with ultrasonography [US]) measuring 1.2–1.5 cm in diameter were used for ablation studies.

Experimental and Control Groups
Tumors (n = 32) were divided into four treatment groups of eight tumors each. These treatments included (a) RF alone, (b) PEI alone, (c) combined therapy consisting of PEI immediately followed by RF ablation, or (d) combined therapy consisting of RF ablation immediately followed by PEI. Four tumors were not treated and served as controls. The two tumors on each animal were each assigned to a different treatment group.

RF Application
Conventional monopolar RF was applied by using a 500-kHz RF generator (model 3E; Radionics, Burlington, Mass) (Fig 1). To complete the RF circuit, the animal was placed on a standardized metallic grounding pad (Radionics). Contact was ensured by shaving the animal’s back and by the liberal use of electrolytic contact gel. A coaxial needle system that we built ourselves was used for all treatments to ensure that RF and ethanol were applied to the same region of the tumor. Initially, a 21-gauge partially electrically insulated needle was placed at the center of the tumor by using US guidance. The distal 1-cm tip of this needle was not insulated to permit RF deposition. A 24-gauge monopolar RF electrode was then placed through the needle. RF was applied for 5 minutes with the generator output titrated to maintain a tip temperature of 70°C ± 2° (SD) (95.8 mA ± 28.2; range, 43–153 mA). This standardized method of RF application has been previously demonstrated to provide a reproducible coagulation volume with use of this conventional RF system (18,19). A thermocouple at the tip of the RF electrode constantly measured the local ablation temperature, thereby enabling proper generator manipulation. Parameters of the RF ablation procedure including tip temperature, tissue impedance, and applied current were recorded at baseline and thereafter at 60-second intervals for the duration of RF application.



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  		Figure 1. Experimental setup for RF ablation. An electrically insulated 21-gauge needle containing the RF electrode (arrowhead) has been inserted into a nodule of R3230 rat mammary adenocarcinoma (open arrow). The electrode is attached to an RF generator that deposits sufficient energy to heat the electrode tip to 70°C ± 2. A grounding pad (solid arrow) underneath the rat completes the RF circuit.

 
PEI Technique
For studies in which ethanol was administered, 250 µL of dehydrated 100% ethanol (Bristol Laboratories, Princeton, NJ) was injected into the center of the tumor through the 21-gauge needle. This dose was selected to achieve coagulation over 50% of the tumor diameter by using PEI alone. Injections were performed slowly over 30 seconds without moving the needle, to ensure uniform diffusion of the ethanol. For these injections, no leakage of ethanol around the needle or out of the tumor was observed.

Histopathologic Studies
Within 30 minutes following ablation treatments, the animals were sacrificed with an overdose of pentobarbital (Nembutal 0.2 mL/kg; Abbott Laboratories, North Chicago, Ill). Tumors were excised and sectioned, and the extent of visible coagulation at gross pathology was measured with calipers. Coagulation diameter was determined by consensus of two observers (S.N.G. and B.S.O.). Histopathologic studies included cross-sectional mounting with hematoxylin-eosin staining and staining for mitochondrial enzyme activity by incubating thin representative tissue sections for 30 minutes in 2% 2,3,5-triphenyltetrazolium chloride (Sigma, St Louis, Mo) at room temperature. This latter test is capable of determining irreversible cellular injury during early stages of RF-induced necrosis (20,21).

Statistical Analysis
Measured coagulation necrosis was compared among the four treatment groups. The Student t test was used to determine statistical significance ({alpha} = .05; two-tailed test).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Technical Results
When RF was applied either alone or prior to ethanol instillation, 106.7 mA ± 24.6 of current was required to maintain tissue heating of 70°C ± 2 at the electrode tip. For these procedures, baseline impedance measured 258.5 ohms ± 46.2. For RF procedures performed following ethanol instillation, reduced current (71.1 mA ± 19.2) was required to achieve the 70°C ± 2 tip temperature (P < .003). Additionally, greater tissue impedance (341.0 ohms ± 87.4) was observed during the subsequent RF ablation (P < .01).

Histopathologic Results
Coagulation necrosis was observed only within treated tumors. For all treatments, the region of coagulation surrounded the central needle insertion site, which suggested relatively even distribution of ethanol and RF heating (Fig 2). Tumor nodules treated with RF alone had 6.7 mm ± 0.6 of coagulation that surrounded the electrode, and those treated with PEI alone had 6.4 mm ± 0.6 of coagulation around the instillation needle (the difference was not significant). Significantly increased coagulation was observed with the combined therapy of PEI followed by RF, as 10.1 mm ± 0.9 of coagulation was observed (P < .001). RF application followed by PEI did not increase coagulation, since only 6.4 mm ± 0.8 of coagulation was observed around the instillation needle (not significant).



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  		Figure 2. Tumor ablation from PEI and RF. Three specimens of R3230 rat mammary adenocarcinoma are presented. Specimens (from left to right) were treated with RF alone (solid straight arrow), PEI alone (open arrow), and a combination of ethanol followed by RF (curved arrow). All sections were cut in the transverse plane perpendicular to the needle or electrode inserted into the tumor and stained with 2,3,5-triphenyltetrazolium chloride, a marker for mitochondrial enzymatic activity. Darker peripheral regions represent residual viable tumor, whereas light regions have undergone coagulation necrosis. The arrowheads point to the needle track for cases that underwent RF ablation. Significantly greater coagulation is observed in the specimen treated with PEI administered prior to RF ablation. The fourth treatment group (RF ablation followed by ethanol treatment) produced coagulation similar in size and appearance to the tumor treated with RF alone.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Percutaneous imaging–guided tumor ablation has received much recent attention as a minimally invasive strategy for the treatment of focal malignant diseases in the liver (1–10,16,17), breast (22), and other organs (23–28). However, thus far, technical and biophysical limitations have precluded the induction of sufficient coagulation to adequately destroy most clinically relevant tumors (ie, those greater than 2–3 cm in diameter) (29). The experiments performed in the current study demonstrate that a combined strategy of PEI, another readily accepted method of imaging-guided tumor ablation, followed by RF therapy (2,3) can increase the extent of induced coagulation in an animal breast tumor model, as compared with either therapy alone.

Our results, particularly the fact that increased coagulation was observed only when PEI was administered prior to RF deposition—but not after, suggest that the coagulation induced by the two successive treatments were not simply additive. Rather, ethanol instillation appears to produce immediate changes in the tumor nodules that result in increased tissue heating and coagulation when RF energy is subsequently applied.

Substantial evidence suggests that perfusion-mediated tissue cooling (vascular flow) reduces the extent of coagulation necrosis produced by thermal ablation and is a key determinant of the extent of coagulation observed following RF application (30–34). Computer modeling demonstrates that for a given tissue and power deposition, the effects of tissue blood flow predominate (34). Decreased coagulation has been observed in in vivo liver, as compared with ex vivo and nonperfused liver, with coagulation necrosis in vivo often shaped by hepatic vasculature (30–32). Furthermore, experiments altering hepatic perfusion by mechanical occlusion of the vasculature during RF and laser ablation of normal liver and intrahepatic colorectal tumors strongly support the contention that perfusion-mediated tissue cooling is largely responsible for reduction in observed coagulation (30,31,33). A strong correlation between the diameter of RF-induced coagulation and pharmacologically modulated blood flow in normal liver has also been demonstrated (32). Direct injection of ethanol has been shown to induce coagulation necrosis and coagulate blood vessels, thereby eliminating blood flow in the treatment zone (5,35). Hence, we hypothesize that a likely mechanism for these synergistic effects of PEI prior to RF is the elimination of tumor blood flow and perfusion-mediated tissue cooling prior to RF heating, which in turn leads to improved thermal deposition within the tumor. Thus, PEI therapy may be beneficial in conjunction with other thermal ablation therapies such as laser, microwaves, or ultrasound.

Direct injection of ethanol has major advantages over other currently feasible methods for reducing blood flow during ablation therapy in that it can be readily performed in a minimally invasive manner at the time of RF ablation. Total portal inflow occlusion (Pringle maneuver) has been used at open laparotomy but requires surgery (30). Angiographic balloon occlusion can be used but may not prove adequate for intrahepatic ablation given the dual blood supply with redirection of compensated flow (30,36). However, therapeutic embolization prior to ablation with particulates that occlude sinusoids, such as gelatin sponge or iodized oil, may overcome this limitation (36). Pharmacologic modulation of blood flow and antiangiogenesis therapy are theoretically possible, but to our knowledge clinical implementation of these strategies has yet to be achieved.

When compared with RF application alone, significantly greater tissue impedance was observed for tumors treated first with ethanol and subsequently with RF ablation. This finding is likely due to the presence of ethanol itself and not the ethanol-induced tissue changes, since tissue coagulation has been shown to decrease and not increase impedance (37). Thus, an alternative hypothesis to account for the increased coagulation observed with ethanol pretreatment would be that increased tissue heating was achieved during RF application because of altered tissue electrical conductivity. However, this explanation is unlikely given that the lower current density observed with ethanol pretreatment should, if anything, decrease tissue heating (38). Yet, greater tissue heating in the presence of significantly reduced RF current raises the possibility of improved thermal conduction and diffusivity through previously coagulated tissue. Whether this is due solely to the absence of blood flow requires further study. However, it is unlikely that enhanced ethanol propagation by RF could alone account for the increase in coagulation given known limited RF penetration into the tissue (38), the minimal residual ethanol likely present following coagulation of the central tumor, and the amount of coagulation observed, which translates to a volume (537 mm3) that is double the 250 µL of ethanol instilled.

Key limitations of this study would include the limited generalization of results to clinical practice given the tumor model studied, the size of the ablated foci, and the RF and PEI techniques selected. Although this model was selected given that it is a well-characterized, solid, vascular adenocarcinoma (39,40), it is possible that results will vary with other tumor types (ie, hepatocellular carcinoma) and in other orthotopic tumor sites (ie, the liver). Furthermore, while the 70°C tip temperature for RF and 250 µL of ethanol were optimal in this model to permit the demonstration of synergy between the two methods, alternative PEI and thermal ablation protocols would have been able to destroy the entire 1.5-cm tumor without combined therapy. Hence, the size of our tumor model precluded the detection of differences with higher RF tip temperatures or greater volumes of ethanol. Given these concerns and the relatively small size of the tumors treated in this study, extrapolation to larger, more clinically relevant tumors must be made with caution. Within larger tumors, greater volumes of ethanol will likely need to be injected to achieve a substantial increase in coagulation over RF alone (41). Whereas larger volumes of ethanol have been injected to destroy hepatocellular carcinomas greater than 5 cm (41), it is possible that uniform diffusion of ethanol throughout a larger volume of distribution will prove more difficult. Further, whereas reasonable ethanol deposition was achieved for this tumor model, nonuniform distribution of ethanol has been demonstrated for other tumors such as VX2 rabbit carcinoma (5).

The successful treatment of larger tumors has required modification of the RF technique (1,29). Although in this study the combined PEI–thermal ablation approach was performed only with conventional monopolar RF, the strategy is likely to work with use of the recently described methods that have been devised to increase energy deposition within the tumors to improve tissue heating. One common method has been to simultaneously apply energy by using arrays, a process that has been made technically easier by the development of umbrella RF electrodes with multiple hooks (7,10). Other strategies to increase energy deposited have relied on preferential cooling of tissues nearest the probe in an attempt to increase overall energy deposition; these strategies include the use of single or cluster internally cooled electrodes (8,9,42) and pulsed RF energy deposition (43). With these methods, coagulation diameters of 3.5–5.5 cm have been reported (9,43).

While the combined PEI-RF technique reported herein represents a step forward in that it enables greater tumor coagulation, it is unlikely that this advance will prove sufficient to permit the adequate ablation of all clinically relevant tumors. Nevertheless, the paradigm reported opens the possibility for the study of other percutaneously injected therapies that may further increase tumor destruction. One such agent would be acetic acid, which has been reported to have greater diffusion throughout the tissues (as compared with ethanol), which consequently provides greater destruction of tumor cells and their vasculature (44). In addition, given that acetic acid is an ionic compound, it is less likely to have a potentially detrimental effect on tissue conductivity. Thus, further optimization of this combined injection–thermal ablation strategy may be possible.

Practical application: Methods for increasing the extent of cellular destruction within focal hepatic and other neoplasms are still required for thermal ablation therapies to gain widespread acceptance as reliable methods of therapy for minimally invasive tumors. The experiments performed demonstrate that a combined ablation strategy of PEI followed by RF ablation therapy can increase the extent of induced coagulation necrosis in an animal breast tumor model, as compared with either therapy alone. Although this work focused on a rat model of breast cancer, we believe that this combined approach of PEI followed by RF ablation will be of clinical utility in this and other organ systems, such as the liver, in which the direct injection or systemic administration of pharmaceutical agents can be readily accomplished. Thus, this or similar strategies, if adopted into clinical practice, could potentially improve the efficacy of tumor ablation therapy.


   FOOTNOTES
 
**. Multiple body systems. Back

Abbreviations: PEI = percutaneous ethanol instillation, RF = radio frequency

Author contributions: Guarantors of integrity of entire study, S.N.G., G.S.G.; study concepts, S.N.G., G.S.G., J.B.K.; study design, S.N.G., J.B.K.; definition of intellectual content, S.N.G., J.B.K., G.S.G.; literature research, S.N.G., J.B.K.; experimental studies, S.N.G., J.B.K., B.S.O., G.S.G.; data acquisition, S.N.G., J.B.K., B.S.O.; data analysis, S.N.G., J.B.K., B.S.O., G.S.G.; statistical analysis, S.N.G., G.S.G.; manuscript preparation, S.N.G., J.B.K., G.S.G.; manuscript editing, review, and final version approval, all authors.


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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

  1. Goldberg SN, Livraghi T, Solbiati L, Gazelle GS. In situ ablation of focal hepatic neoplasms. In: Gazelle GS, Saini S, Mueller PR, eds. Hepatobiliary and pancreatic radiology: imaging and intervention. New York, NY: Thieme, 1997; 470-502.
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Combination Radiofrequency Ablation with Intratumoral Liposomal Doxorubicin: Effect on Drug Accumulation and Coagulation in Multiple Tissues and Tumor Types in Animals
Radiology, May 1, 2005; 235(2): 469 - 477.
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 Br. J. Radiol.Home page
J M Lee, J K Han, S H Kim, J Y Lee, S H Choi, and B I Choi
Hepatic bipolar radiofrequency ablation using perfused-cooled electrodes: a comparative study in the ex vivo bovine liver
Br. J. Radiol., November 1, 2004; 77(923): 944 - 949.
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 Am. J. Roentgenol.Home page
S. Shankar, E. vanSonnenberg, P. R. Morrison, K. Tuncali, and S. G. Silverman
Combined Radiofrequency and Alcohol Injection for Percutaneous Hepatic Tumor Ablation
Am. J. Roentgenol., November 1, 2004; 183(5): 1425 - 1429.
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M. Ahmed, W. E. Monsky, G. Girnun, A. Lukyanov, G. D'Ippolito, J. B. Kruskal, K. E. Stuart, V. P. Torchilin, and S. N. Goldberg
Radiofrequency Thermal Ablation Sharply Increases Intratumoral Liposomal Doxorubicin Accumulation and Tumor Coagulation
Cancer Res., October 1, 2003; 63(19): 6327 - 6333.
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G. D'Ippolito, M. Ahmed, G. D. Girnun, K. E. Stuart, J. B. Kruskal, E. F. Halpern, and S. N. Goldberg
Percutaneous Tumor Ablation: Reduced Tumor Growth with Combined Radio-frequency Ablation and Liposomal Doxorubicin in a Rat Breast Tumor Model
Radiology, July 1, 2003; 228(1): 112 - 118.
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W. L. Monsky, J. B. Kruskal, A. N. Lukyanov, G. D. Girnun, M. Ahmed, G. S. Gazelle, J. C. Huertas, K. E. Stuart, V. P. Torchilin, and S. N. Goldberg
Radio-frequency Ablation Increases Intratumoral Liposomal Doxorubicin Accumulation in a Rat Breast Tumor Model
Radiology, September 1, 2002; 224(3): 823 - 829.
[Abstract] [Full Text] [PDF]

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 Am. J. Roentgenol.Home page
S. N. Goldberg, I. R. Kamel, J. B. Kruskal, K. Reynolds, W. L. Monsky, K. E. Stuart, M. Ahmed, and V. Raptopoulos
Radiofrequency Ablation of Hepatic Tumors: Increased Tumor Destruction with Adjuvant Liposomal Doxorubicin Therapy
Am. J. Roentgenol., July 1, 2002; 179(1): 93 - 101.
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G. D. Dodd III, M. S. Frank, M. Aribandi, S. Chopra, and K. N. Chintapalli
Radiofrequency Thermal Ablation: Computer Analysis of the Size of the Thermal Injury Created by Overlapping Ablations
Am. J. Roentgenol., October 1, 2001; 177(4): 777 - 782.
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 RadiologyHome page
S. N. Goldberg, P. F. Saldinger, G. S. Gazelle, J. C. Huertas, K. E. Stuart, T. Jacobs, and J. B. Kruskal
Percutaneous Tumor Ablation: Increased Necrosis with Combined Radio-Frequency Ablation and Intratumoral Doxorubicin Injection in a Rat Breast Tumor Model
Radiology, August 1, 2001; 220(2): 420 - 427.
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S. N. Goldberg, M. Ahmed, G. S. Gazelle, J. B. Kruskal, J. C. Huertas, E. F. Halpern, B. S. Oliver, and R. E. Lenkinski
Radio-Frequency Thermal Ablation with NaCl Solution Injection: Effect of Electrical Conductivity on Tissue Heating and Coagulation--Phantom and Porcine Liver Study
Radiology, April 1, 2001; 219(1): 157 - 165.
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G. S. Gazelle, S. N. Goldberg, L. Solbiati, and T. Livraghi
Tumor Ablation with Radio-frequency Energy
Radiology, December 1, 2000; 217(3): 633 - 646.
[Abstract] [Full Text]

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S. N. Goldberg, G. D. Girnan, A. N. Lukyanov, M. Ahmed, W. L. Monsky, G. S. Gazelle, J. C. Huertas, K. E. Stuart, T. Jacobs, V. P. Torchillin, et al.
Percutaneous Tumor Ablation: Increased Necrosis with Combined Radio-frequency Ablation and Intravenous Liposomal Doxorubicin in a Rat Breast Tumor Model
Radiology, March 1, 2002; 222(3): 797 - 804.
[Abstract] [Full Text] [PDF]

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