J Hepatobiliary Pancreat Sci DOI 10.

1007/s00534-011-0465-7

ORIGINAL ARTICLE

Evaluation of effects of a novel endoscopically applied radiofrequency ablation biliary catheter using an ex-vivo pig liver
Takao Itoi Hiroyuki Isayama Atsushi Sofuni Fumihide Itokawa Miho Tamura Yusuke Watanabe Fuminori Moriyasu Michel Kahaleh Nagy Habib Toshitaka Nagao Tomohisa Yokoyama Kazuhiko Kasuya Hiroshi Kawakami

Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2011

Abstract Background The effects of ablation with various settings of powers and times using a newly developed radiofrequency (RF) ablation device, the HabibTM EndoHPB catheter, are not well known. In the present study, we examined the effects of a novel RF ablation catheter using resected fresh pig livers and evaluated the macroand microscopic effects of RF ablation under various conditions. Materials and methods The RF application was performed step by step at 5, 10, 15, and 20 W power and 60, 90, 120 s, respectively. Macroscopic and microscopic ndings of the ablation area were evaluated at each setting. Results The mean lengths of the short axis of the ablation area at 10 W and 60, 90 and 120 s were 8.0 1.0, 8.3 1.2, and 9.7 0.6 mm, respectively. The mean lengths of the long axis at 10 W power and 60, 90 and

120 s were 20.3 0.6, 21.3 1.6, and 28.3 2.1 mm, respectively. Although the lengths of the short and long axes at 5 and 10 W increased gradually with power, there were no obvious differences in either short or long axis lengths between 15 and 20 W. Of all the settings, only at 5 W and 60 and 90 s did the long axis of the ablation show separate areas around the 2 ring electrodes. Conclusions Although other sequelae including hemorrhage, pancreatitis, acute inammatory changes, perforation and late brosis could not be investigated in our ex-vivo pig model, our study claried the relationship between ablation powers and times and the effects concerning depth and longitudinal spread of ablation. Although the clinical ablation setting at 710 W power and 2 min is suitable, ultimately the ablation power and time should be adjusted according to the size of masses using examples from the present results.

T. Itoi (&) A. Sofuni F. Itokawa F. Moriyasu Department of Gastroenterology and Hepatology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan e-mail: itoi@tokyo-med.ac.jp H. Isayama Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan M. Tamura Y. Watanabe Tokyo Medical University, Tokyo, Japan M. Kahaleh Department of Gastroenterology, Well Cornell Medical Center, New York, NY, USA N. Habib Department of Surgery and Cancer, Imperial College London, London, UK

T. Nagao Department of Pathology, Tokyo Medical University, Tokyo, Japan T. Yokoyama Department of Clinical Oncology, Tokyo Medical University, Tokyo, Japan K. Kasuya Third Department of Surgery, Tokyo Medical University, Tokyo, Japan H. Kawakami Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

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Keywords Endoscopic retrograde cholangiopancreatography Radiofrequency Stent Abbreviations SEMS Self-expandable metallic stent RF Radiofrequency

Introduction Transpapillary endoscopic biliary stenting using plastic stents and self-expandable metallic stents (SEMS) in endoscopic retrograde cholangiopancreatography (ERCP) is a well established palliative treatment for unresectable malignant biliary obstruction [17]. However, plastic stents need to be replaced every 36 months because of obstruction, mainly by biliary sludge [8]. SEMS have longer patency and lower occlusion rates, but their use is limited by tumor ingrowth [6, 7]. Once a SEMS is placed in the bile duct, it is usually difcult or impossible to remove. The stent-in-stent technique using plastic stents or additional SEMS is then used for occluded SEMS [911]. In an effort to achieve longer stent patency for SEMS, we have recently developed a novel endoscopic radiofrequency (RF) catheter for ablating the luminal tumour before stent insertion [12]. However, how the effects of ablation vary with various powers and times when using this catheter is not well known. In the present study, we examined the effects of a novel RF ablation catheter using resected fresh pig livers and evaluated the macro- and microscopic effects of RF ablation under various conditions.
Fig. 1 The HabibTM EndoHPB catheter was advanced into the center of the liver over the guidewire

academic purposes. Briey, the organs were removed within 30 min after the pigs were killed, processed, and transported to our institute while being kept cold with ice. The experiments were started within 8 h after the pigs were killed and were performed at room temperature. Experimental RF application Since the HabibTM EndoHPB catheter is an over-the-wire type device, it was advanced using the over-the-wire technique after a 0.035-inch guidewire (Metro, Cook Endoscopy, Winston-Salem, NC, USA) was passed though the liver (Fig. 1). It was located in the middle of the liver to evaluate correctly the size of the burn effect. Following insertion of the liver, the catheter was connected to a generator and one application of RF power for a set time was performed. The same application was repeated 3 times more than 3 cm apart. The RF application was performed step by step at 5, 10, 15, and 20 W power for times of 60, 90, and 120 s. Macroscopic and microscopic ndings after intervention Immediately after each application, the liver was cut along the catheter using a pathology knife to evaluate the ablation area (Fig. 2). The maximum length of the short axis (a) (i.e. the penetration) and the long axis (b) (i.e. the spreading) were macroscopically measured with a scale (Fig. 3). The resected specimens were xed in formalin and embedded in parafn for hematoxylin and eosin stain and section. The area of necrosis was evaluated microscopically in each specimen in comparison with macroscopic ndings.

Materials and methods RF ablation device The HabibTM EndoHPB (EMcision UK, London, UK) catheter was used in this study. It is a bipolar RFA probe that is 8F (2.6 mm), 1.8 m long, compatible with standard side-viewing endoscopes, and passes over 0.035-inch guidewires. The catheter has 2 ring electrodes 8 mm apart with the distal electrode 5 mm from the leading edge, providing local coagulative necrosis over a 2.5-cm length. Energy was delivered by an RFA generator (Effect 8, VIO300D; ERBE Elektromedizin GmbH, Tubingen, Germany) delivering electrical energy at 450 kHz at 520 W for 30 s to 2 min for this study. Specimens We used 3 resected fresh livers from adult pigs. The specimens were commercially available and provided for The experimental procedure of catheter insertion into the liver and ablation was easily and successfully completed at all settings.

Results

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Fig. 2 Immediately after each application, the liver was cut along the catheter using a pathology knife to evaluate the ablation area

Fig. 4 The specimens were resected for the evaluation of microscopic ndings Table 1 Ablation effects of new radiofrequency catheter No. 1 2 3 4 Ablation power (W) 5 5 5 10 10 10 15 15 15 20 20 20 Ablation time (s) 60 90 120 60 90 120 60 90 120 60 90 120 Length a (mm) 4.3 0.6 5.3 0.6 7.3 0.6 8.0 1.0 8.3 1.2 10.3 0.6 8.3 0.6 10.0 1.0 10.3 0.6 9.3 0.6 11.3 1.2 11.3 1.2 Length b (mm) 11.0 1.0 13.0 1.7 18.0 1.0 20.3 0.6 21.3 1.6 27.7 1.6 23.7 1.2 26.7 0.6 27.7 0.6 29.0 1.0 29.0 1.7 29.0 1.0

Fig. 3 The maximum length of the short axis (a) (the penetration) and the maximum length of the long axis (b) (the spread) were measured macroscopically using a scale

5 6 7 8 9 10 11 12

Macroscopically, RF ablation changed the original liver tissue to a white-yellowish area (Fig. 4). The outcome of ablation area is shown in Table 1. The mean lengths of the short axis at 5 W power and 60, 90 and 120 s were 4.3 0.6, 5.3 0.6, and 7.3 0.6 mm, respectively. On the other hand, the mean lengths of the long axis at 5 W power and 60, 90 and 120 s were 11.0 1.0, 13.0 1.7, and 18.0 1.0 mm, respectively. The mean lengths of the short axis at 10 W and 60, 90 and 120 s were 8.0 1.0, 8.3 1.2, and 9.7 0.6 mm, respectively. The mean lengths of the long axis at 10 W power and 60, 90 and 120 s, were 20.3 0.6, 21.3 1.6, and 28.3 2.1 mm, respectively. Although the lengths of the short and long axes at 5 and 10 W increased gradually according to the power, there were no obvious differences in either short or long axis length between 15 and 20 W. Of all settings, only at 5 W and 60 and 90 s did the long axis of the ablation show separate areas around the 2 ring electrodes (Fig. 5). Microscopically, the necrotic area matched the ablation area in all specimens (Fig. 6). There were no obvious histological differences in necrotic area between various ablation powers and times.

Fig. 5 Ablation by lower power and short time (5 W and 60 s) showed insufcient ablation

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Fig. 6 Specimen of the ablation area showing degenerative and detached hepatic cells

Discussion In this study, we revealed the effects of a novel RF ablation catheter using ex-vivo pig livers. Although an in-vivo experimental study has been published by our institute using a pig model [13, 14], that examined only the normal bile duct which does not involve the pancreas as in human. Thus, it was difcult to evaluate the correct depth of ablation. However, when we use it clinically to ablate an unresectable malignant mass causing biliary obstruction, we need to know how much it can ablate the mass regardless of the presence of the surrounding pancreas. Therefore we used the pig liver as a virtual mass with or without pancreas involvement to measure correctly the effects of depth (short axis length) and longitudinal spread (long axis length) of ablation. To the best of our knowledge, this is the rst ex-vivo report on evaluating the effects of this novel RF catheter for masses according to various ablation powers and times. Theoretically, increasing the ablation power and procedure time leads to larger burn effects. However, actual native extrahepatic bile duct, unlike intrahepatic bile duct or intrahepatic bile duct, is not so thick, less than 2 mm. Furthermore, aside from unresectable large pancreatic cancers or lymph node metastasis, even if the malignant mass is present in the middle to hilar bile duct, the bile duct wall thickness is usually less than 1 mm. Thus, marked ablation causes perforation in not only the tumor portion but also the normal bile duct. On the other hand, inappropriate ablation leads to insufcient effects for therapy. Our present study suggested that at lower power and short ablation time, namely 5 W and 60 or 90 s, it may be possible that the treatment becomes insufcient because of lack of homogeneous longitudinal spread of ablation. On the other hand, higher power and longer procedure time,

namely 15 or 20 W and 120 s, may increase the risk of complications without contributing to the ablation effects. In our rst clinical study [12], the ablation was set at 710 W power, 2 min. Our results suggest that these settings may be suitable for RF ablation using this catheter. The ablation effect depends on the specic organs and surrounding tissues, such as vessels which have a cooling effect during RF ablation. Furthermore, it also depends on the generator; we used a different generator from the previous clinical study [12] but delivering very similar electrical energy. Nevertheless, we believe that our data should be considered before performing RF ablation using this novel catheter. We cannot decide suitable settings for malignant biliary obstructions because these are caused by various diseases, pancreatic cancer, bile duct cancer, lymph node metastasis, prior SEMS placement and so on. Even in bile duct cancer, the size of masses or wall thicknesses are different from case to case: for example, papillary growth and diffusely inltrated growth bile duct cancers. Therefore, before we use this catheter, we should evaluate the size of masses or thickness of wall. Since we use the over-the-wire technique for this catheter, intraductal ultrasonography may be the best technique for evaluating these parameters. There are some limitations to this study. The nature of the experiment is descriptive of a novel endobiliary RF ablation device in pig livers. Other sequelae including hemorrhage, pancreatitis, acute inammatory changes, perforation and late brosis could not be investigated in this ex-vivo pig model. In conclusion, our study claried the relationship between ablation powers and times and the effects concerning depth and longitudinal spread of ablation using pig livers. Although the clinical ablation setting at 710 W power, 2 min is suitable, ultimately the ablation power and time should be adjusted according to the size of masses using examples from the present results.
Conict of interest The following author disclosed nancial relationships relevant to this publication: Dr. Habib: stockholder and board member of EMcision Ltd UK. The other authors disclose no nancial relationship relevant to this publication.

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