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1 Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu
University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
2 Department of Radiology, National Kyushu Cancer Center, Fukuoka 811-1395,
Japan.
Received March 8, 2004;
accepted after revision July 23, 2004.
Address correspondence to T. Tajima
(ttajima{at}dr.hosp.kyushu-u.ac.jp).
Abstract
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SUBJECTS AND METHODS. Sixty-one patients (40 men and 2l women; mean age, 59 years) with advanced liver cancers (primary hepatic or biliary cancer [n = 31] and metastatic liver cancer [n = 30]) underwent percutaneous port-catheter placement with the tip of W-spiral catheter inserted into the right gastroepiploic artery and the side-hole opened at the common hepatic artery after embolization of the right gastric artery, pancreaticoduodenal arteries, or aberrant hepatic arteries. Pericatheter embolization for preventing catheter dislodgement was not performed. The technical success of port-catheter placement, clinical patency of the port-catheter system, and technical success of port-catheter removal were evaluated.
RESULTS. Percutaneous port-catheter placement using this method was successfully performed in 59 (97%) of 61 patients. Subsequently, chemotherapy was successfully performed through the port in 57 (93%) of 61 patients. Complications during and after the procedure were observed in two (3%) of 61 patients and 12 (20.7%) of 58 patients. Hepatic artery thrombosis occurred in two (3.4%) of 58 patients. The port-catheter removal and the catheter replacement were performed in eight and four patients, respectively, who wanted the procedure. It was completed successfully without any complications.
CONCLUSION. This method of implantation of a port-catheter system appeared to offer clinical advantages of safe catheter removal, femoral artery access, and an acceptable complication rate.
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When discussing treatment outcomes of HAIC, it is important to address the issue of how long the intraarterial injection of anticancer drugs by a port-catheter system can proceed without the patient encountering complications. The patency of a port-catheter system is highly correlated with the catheter placement method [4]. Until a few years ago, catheter insertion was performed by straight-forward insertion of the preshaped 5-French indwelling catheters (e.g., hook, RH, or cobra) into the hepatic artery using a right or left femoral approach (i.e., the conventional method) [3]. However, among patients who underwent the conventional method of catheterization, complications occurred with a relatively high incidence; such complications required, for example, reintervention and additional treatment or rendered it difficult to resume chemotherapy [3, 4, 8].
Recently, a fixed catheter insertion method using a left transsubclavian or transbrachial approach has been proposed to prevent hepatic artery occlusion and catheter dislodgement [4–6]. By this method, the indwelling catheter tip is fixed to the wall of the gastroduodenal artery (GDA) using metallic coils or N-butyl cyanoacrylate; infusion is given through the catheter side-hole placed at the confluence of the GDA and the hepatic artery. This technique has been widely used in Japan, and it now has an established reputation of long-term patency and safety. This percutaneous approach thus appears to be superior to the conventional method in terms of both patency and safety.
However, there remain several problems with this method, such as the difficulty of the placement procedure, the possibility of brain infarction [9], the difficulty of catheter removal [5], and the use of unapproved embolic materials [5] or too many embolization coils [8]. The most important issue in this context is the difficulty of removing the implanted catheter either when a problem with the implanted port-catheter system occurs or when the scheduled chemotherapeutic regimen comes to an end.
To solve these problems, we developed a new catheter insertion using a self-retaining indwelling catheter technique (i.e., gastroepiploic method, or GEM), which does not require catheter fixation by embolization of the area around the catheter using embolic materials. It may permit the withdrawal of the implanted catheter when not needed. The purpose of this study was to evaluate the feasibility, safety, and usefulness of GEM.
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Patients with hepatic tumors were included in the study only if there was
no extrahepatic involvement. In addition, patients in whom the GDA was ligated
after gastrectomy or pancreaticoduodenectomy were excluded from the study
sample. Before percutaneous implantation, all patients underwent preliminary
laboratory blood tests (complete blood count, prothrombin time, partial
thromboplastin time, transaminase level, carcinoembryonic antigen level in
patients with metastases from colorectal cancer, and 
-fetoprotein level
in patients with hepatocellular carcinoma).
In 30 patients, the indication for port implantation was liver metastases (colorectal carcinoma [n = 16], pancreatic cancer [n = 3], gastric cancer [n = 6], breast cancer [n = 2], esophageal cancer [n = 1], bladder cancer [n = 1], and uterine cancer [n = 1]), and in the other 31 patients, the indication was the presence of primary hepatic or biliary tumors (hepatocellular carcinoma [n = 29], cholangiocellular carcinoma [n = 1], and gallbladder cancer [n = 1]). All patients were given detailed information about the procedure, and written consent was obtained from all participants in the study. In our series, the vessels in which the catheter tip was positioned were as follows: the right gastroepiploic artery in 59 patients, the GDA in one patient, and the anterior superior pancreaticoduodenal artery in one patient.
Insertion Techniques
Before a patient left for the angiographic room, an intramuscular injection
of a parasympathetic nerve blocker (0.5 mg of atropine sulfate) and a sedative
medication (25–50 mg of hydroxyzine hydrochloride) were given as
premedication. All the procedures were performed under local anesthesia by
percutaneous femoral artery catheterization. The vessels used for percutaneous
access were the right or left femoral artery in all patients. At first, a
4-French hook-shaped catheter was inserted through the femoral artery without
using sheath introducer sets; then, diagnostic celiac or superior mesenteric
arteriography was performed.
Embolization of the replaced or accessory hepatic artery, right gastric artery, accessory left gastric artery, anterior superior pancreaticoduodenal artery, and posterior superior pancreaticoduodenal artery was performed using embolization coils to accomplish the blood flow redistribution. Duodenal arterial branches, anastomotic branches to the dorsal pancreatic artery, and omental branches, in addition, were embolized to prevent gastrointestinal mucosal lesions (e.g., peptic ulcer) in cases in which the vessels were sufficiently dilated to the point that they could be visualized on angiography.
As an indwelling catheter, we used two types of W-spiral catheters: a 5-French nontapered (Figs. 1A and 1B) and 2.7-French tapered catheter (which tapers off to the catheter tip from 5 French to 2.7 French). The W-spiral catheter is a soft spiral catheter whose outer surface is coated with hydrophilic anticoagulant-copolymer called "polyvinylpyrrolidone." Microscopically, 3D shape-memory metals made of nitinol are spirally arranged and concealed within the catheter tip. For these reasons, this catheter is called "W-spiral catheter." After the celiac angiograms were obtained, we decided the types of indwelling catheter, depending on both the caliber of the celiac, hepatic, or GDAs and the branching angle of the celiac trunk and GDA.
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The optimal positions of the side-hole and catheter tip were defined using the micro-guidewire technique: first, a micro guidewire (0.014 inches, Transend EX, Boston Scientific Japan) was advanced to the predetermined position of the catheter tip in the right gastroepiploic artery. Then, under fluoroscopic control, the micro guidewire was pulled to the predetermined position of the side-hole; the movement of the micro guidewire was measured using a disinfected metallic scale, because the distance from the catheter tip to the side-hole can be almost the same as the length of the movement of the micro guidewire. With use of the hole-punch designed for W-spiral catheters, a side-hole of 3.1 mm and 1.1 mm in diameter was created within the W-spiral catheters of the 5-French non-tapered type and the 2.7-French-tapered type, respectively; after the side-hole was created in the catheter, the injected solution flowed primarily out of the side-hole (Figs. 2A, 2B, and 2C).
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After inserting a guidewire deep into the right gastroepiploic artery, the 4-French catheter, formerly inserted within the celiac or common hepatic artery, was exchanged with the indwelling W-spiral catheter. Guidewires with a 0.035- and 0.016-inch diameter are compatible with 5-French nontapered and 2.7-French tapered W-spiral catheters, respectively. The catheters were deeply inserted into the GDA with the tip at the more distal portion of the origin of the right gastroepiploic artery and with the side-hole at the confluence with the hepatic artery. Then, time was allowed to pass (0–60 min) until both the arterial flow distal to the catheter tip and the flow in the GDA spontaneously decelerated. Embolization of the following structures was not performed: the catheter end-hole, the right gastroepiploic artery distal to the catheter tip, and the areas around the indwelling catheter.
After fluoroscopic control of the catheter positioning, we subsequently created a subcutaneous pocket with a 3-cm incision parallel to the short axis of the femur, 4–5 cm caudal to the puncture site. After the catheter hub was cut off, an implantable port (Therdica Port, Clinical Supply) was connected to the tunneled catheter. Then, the port was implanted in the pocket. Immediately after implantation, a 22-gauge Hüber needle (Port-A-Cath Needle, SIMS Deltec) was inserted through the skin and into the port, the blood-flow confirmation was performed via the infusion port, and the port was filled with highly concentrated heparin solution (3,000 IU). Thereafter, serial infusion of heparin solution (3,000 IU) was performed every 10–14 days. No antibiotics were used during or after this procedure. Patients were kept quiet in bed for 6 hr after the procedure. The patients' activities of daily living were permitted the next day after port-catheter placement. In our institutions, however, the first stage of chemotherapy, especially, was performed in the hospital in most patients, whereas the remaining stages of chemotherapy were performed on an outpatient basis after confirming that the port-catheter system was practicable and the first-stage chemotherapy was uneventful. The patients were forbidden to bend their hip joints extensively for 2–3 months after the catheter placement.
Treatment
The chemotherapeutic regimens were determined by radiologists or
oncologists at our institutes. Therefore, the regimens and periods for
chemotherapy varied among patients, although most patients underwent low-dose
cisplatin and continuous infusion of 5-fluorouracil chemotherapy; weekly
high-dose 5-fluorouracil therapy; and 5-fluorouracil, epirubicin, and
mitomycin C; or protocols using gemcitabine. Low-dose cisplatin and continuous
infusion of 5-fluorouracil chemotherapy consisted of 5-fluorouracil (160
mg/m2 per day) and cisplatin (3–7 mg/m2 per day
for 30 min); weekly high-dose 5-fluorouracil therapy consisted of
5-fluorouracil (1,000 mg/m2 per 5 hrs per qw); and 5-fluorouracil,
epirubicin, and mitomycin C therapy consisted of 5-fluorouracil (333 mg
m2 per qw), epirubicin (30 mg m2 per q4w), and mitomycin
C (2.7 mg m2 per q2w).
Follow-Up Criteria and Flow Confirmation
The patients underwent a physical examination before each treatment cycle.
WBC, hemoglobin, and platelets were evaluated before each administration of
chemotherapeutic drugs. Liver function tests were performed before the start
of each intrahepatic treatment cycle. Complete serum biochemistry was
performed at every other complete treatment cycle. Before the initiation of
HAIC, flow confirmation using flow scintigraphy with
99mTc-macroaggregated albumin (MAA), CT angiography, or angiography
via the port was typically obtained within 1 week after placement of the
port-catheter system. After the initiation of HAIC, follow-up flow
scintigraphy or angiography was also performed at intervals of two or three
intrahepatic treatment cycles.
Assessment
Technical success rate.—To evaluate the technical success
rate of this method, we investigated the rates of initial technical success
and therapy initiated. "Initial technical success rate" was
defined as the percentage of catheter placement procedures that was completed
without any technical complications. The "rate of therapy
initiated" was defined as the percentage of HAIC that was initiated
without difficulty following the placement procedure.
Confirmation of the delivery of chemotherapeutic drugs.—To confirm the cessation of blood flow in the GDA and in the right gastroepiploic artery, we performed flow confirmation using angiography via the implanted catheter immediately after placement and every 5 min thereafter. For assessing the cessation of distal catheter flow, the contrast material was injected at the speed of 0.3–0.5 mL/sec. Circumstances permitting, we waited for a more favorable situation (i.e., until cessation of blood flow in both the GDA and the right gastroepiploic artery was confirmed). Flow cessation in the GDA or the right gastroepiploic artery was defined as the state of poor opacification of the GDA and the distal portion of right gastroepiploic artery. As a confirmation of blood flow after catheter placement, a follow-up examination before chemotherapy was performed within a week using flow scintigraphy with 99mTc-MAA, CT angiography, or angiography via the port.
Clinical patency of the port-catheter system.— When HAIC or serial heparin infusion was successfully performed without any difficulty using the port-catheter system, the system was defined as clinically patent. In cases involving any difficulties during the observation period, follow-up angiography or CT angiography was subsequently performed.
Complications during and after the procedure.—Complications that occurred during and after the procedure were recorded when they were encountered. When complications required reintervention, the technical success of subsequent interventions was also assessed.
Removal of the port-catheter system.—When the port-catheter system was removed, the reason for removal, technical success rate, and time required to perform the procedure were evaluated. The system removal technique proceeded as follows: After local anesthesia was administered, the pocket was reopened using electric cautery, and the port-catheter system was exposed. The implantable catheter was disconnected from the port, and a guidewire was inserted into the catheter to straighten the W-spiral catheter. The catheter and the port were removed from the pocket under fluoroscopic control, the subcutaneous tunnel was compressed by manual pressure for 10–20 min, and the subcutaneous pocket was closed using suture thread. After the procedure, patients were hospitalized for 24 hr to watch for potential bleeding.
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As regards the rate of therapy initiated, HAIC was determined to have been feasible in 57 (93%) of 61 patients, and good flow distribution was obtained in all patients. HAIC was unfeasible in four (7%) of 61 patients: In two patients other than the two previously mentioned with initial technical failure, the catheter was successfully inserted once but was removed just after the examination. In one patient, the reinsertion was needed because of angiospasm of the common hepatic artery (i.e., a new indwelling catheter was successfully used for replacement 1 week later), and in the other patient, reinsertion was needed because of hemorrhage at the site of puncture (i.e., the implanted catheter was removed because of the patient's tendency to bleed, and systemic chemotherapy was then introduced).
Confirmation of the Delivery of Chemotherapeutic Drugs
The confirmation of flow was immediately performed after placement of the
catheter. In this study, it was possible to assess blood flow in both the GDA
and the right gastroepiploic artery in 56 of 58 patients, whereby
determination of flow was based on angiograms via the implanted catheter.
Cessation in GDA flow was finally obtained in 49 (88%) of 56 patients during
the procedure (Table 1). In
five (9%) of 56 patients, embolization of the right gastroepiploic artery
distal to the catheter tip was performed. In 46 (90%) of the remaining 51
patients, cessation in the right gastroepiploic artery flow was finally
obtained during the procedure, whereas continuation of the right
gastroepiploic artery flow was observed in five (10%) of 51 patients. In the
last five patients, flow scintigrams obtained 1 week after the procedure
confirmed uniform flow distribution; clinically, there were abnormal findings
at physical examination of the abdomen, from laboratory data (hemocytometry
and biochemistry), or on endoscopy after the initiation of HAIC. In 46
patients whose right gastroepiploic artery flow spontaneously ceased during
the procedure, the GDA and the right gastroepiploic artery ceased flowing at
the following times: mean, 8.6 ± 14.3 (SD) min; range, 0–53 min,
and mean, 12.4 ± 12.3 min; range, 0–40 min, respectively.
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Before the initiation of HAIC, a flow confirmation was performed within 1 week after catheter placement in 50 of 58 patients; the examination consisted of flow scintigraphy with 99mTc-MAA in 22 patients (Figs. 3A, 3B, and 3C), CT angiography in 18 patients (Figs. 4A, 4B, 4C, and 4D), and angiography via the port in 10 patients. A fine flow distribution was shown in 47 (94%) of 50 patients. Inappropriate blood-flow distribution was observed in the other three (6%) of these 50 patients as follows: abnormal accumulation of radionuclide within the right gastroepiploic artery on flow scintigraphy in one patient and catheter dislocation or occlusion on angiography in two patients. Angiography performed in the patient with abnormal radionuclide accumulation showed no abnormal flow distribution; clinically, no adverse reaction was shown after the initiation of HAIC. In the latter two cases, catheter dislocation was corrected, or the occluded catheter was recanalized by urokinase infusion.
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Clinical Patency of the Port-Catheter System
Clinical patency of the port-catheter system was investigated during an
observation period ranging from 14 to 454 days (median, 95 days; mean, 107
± 99 days). Patency of the port-catheter system was confirmed in 55
(95%) of 58 patients. Hepatic artery thrombosis occurred in two patients, at
98 and 150 days after placement. Port-catheter obstruction was found in one
patient at 168 days after the catheter placement, and the system was
recanalized using urokinase.
Complications During and After the Procedure
Complications during and after the procedure were observed in two (3.3%) of
61 patients and 12 (20.7%) of 58 patients, respectively. Complications during
the procedure included embolization coil migration into a segmental hepatic
artery in one patient (without any clinical consequence) and angiospasm of the
common hepatic artery in one patient; in the latter patient, the catheter was
removed and repositioned 1 week later. Complications after placement included
hemorrhage at the puncture site in four patients (6.6%), hepatic artery
thrombosis in two patients (3.3%), catheter dislocation in two patients
(3.3%), peptic ulcer in one patient (1.6%), bone marrow suppression in one
patient (1.6%), infection of port-catheter system in one patient (1.6%), and
subcutaneous leakage of anticancer drugs in one patient (1.6%). Three (25%) of
these 12 patients required reinterventions (e.g., removal and replacement of
the catheter or embolization of an enlarged right gastric artery). The four
patients with hemorrhage at the puncture site included three patients with
persistent oozing around the puncture site and one patient with persistent
bleeding and subcutaneous groin hematomas because of bleeding tendency. In
these cases, after removal of the implanted catheter (n = 3) or port
(n = 1), the bleeding ceased by repeated manual compression of the
puncture site or the pocket or both. In two cases with catheter dislocation,
although the extent of the catheter dislocation was minimal, replacement of
W-spiral catheters was performed because the catheter dislocation caused
displacement of the side-holes from the appropriate site to the celiac
trunk.
Removal of the Port-Catheter System
We tried to remove the port-catheter system in eight patients among the 57
patients in whom HAIC was performed (Table
2); removal was performed because of hemorrhage at the puncture
site in one patient, hepatic artery thrombosis in one patient, dislocation of
the indwelling catheter in two patients, angiospasm of the common hepatic
artery in one patient, subcutaneous leakage of anticancer drugs in one
patient, and completion of the preventive or preoperative chemotherapy in two
patients. The catheter was successfully removed in all eight patients (100%).
The mean time from the placement to the removal of the catheter was 34.0
± 33.2 days (range, 0–98 days; median, 30.5 days). Catheter
replacement was performed in four of these eight patients
(Table 2); the implanted
catheter was successfully replaced with the new W-spiral catheter in all four
patients. The remaining 49 patients are continuing the chemotherapy, scheduled
for catheter removal, or followed up on the outpatient clinic basis.
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As regards the technique for placement of the port-catheter system, several randomized control trials in European countries have been discussed in the literature [10]; these studies have shown low long-term patency and high complication rates. There have been a few randomized control trials from Asian countries, including Japan, showing high long-term patency and low complication rates [4–6]. According to a report by Kerr et al. [24], this issue can be understood from the fact that many patients are missing from the trial because of problems in the port-catheter system or systemic complications in the early stage of HAIC. On the basis of the fixed-cathetertip technique reported by Yamagami et al. [5] and Tanaka et al. [6], an advanced catheter placement technique is needed to obtain good treatment outcomes with HAIC.
GEM is a new insertion technique that uses a W-spiral catheter. The concepts and characteristics of GEM can be summarized as follows: First, the indwelling catheter is self-retaining; therefore, the catheter can be fixed directly to the right gastroepiploic arterial wall, and thus catheter fixation by embolic materials is not necessary. Second, because the blood flow through the GDA and the right gastroepiploic artery spontaneously ceases during catheter placement, neither embolization around the indwelling catheter (for fixation) nor embolization of the end-hole of the catheter and the right gastroepiploic artery distal to the catheter tip is required. Third, if necessary, catheter removal can be achieved simply by pulling the catheter out of the artery.
According to a recent report regarding the technical feasibility of port-catheter systems by a fixed catheter insertion technique using the transsubclavian route, one (3%) of 30 cases was technically unsuccessful because of the tortuosity of the subclavian artery [18]. Compared with the results of that report, the results our study were favorable (the initial technical success rate of catheter placement by GEM was 97%).
Recently, there have been some reports about the use of postoperative HAIC as an adjuvant chemotherapy for curative hepatic resection candidates; in such cases, HAIC was considered as a means of preventing a postoperative recurrence of hepatocellular carcinoma [25–27]. HAIC is also applied for the treatment of metastatic liver tumors from colorectal cancer [28], pancreatic cancer [29], and gastric cancer [30] for preventing a postoperative recurrence; a randomized control trial has shown that HAIC improved the 2-year survival rate after resection of liver metastases from colorectal cancer [30]. On the other hand, Clavien et al. [31] reported that the use of HAIC for 28 patients with advanced liver tumors enabled downstaging, and curative hepatic resection became possible in nine patients. Thus, trials using adjuvant chemotherapy before or after surgery or both have shown improvement in the survival rate of patients with advanced liver tumors.
Especially in patients who receive preventive intraarterial chemotherapy, many can look forward to removal of the redundant port-catheter system as soon as the planned chemotherapy comes to an end. In such situations, the present technique is advantageous so that the removal of the port-catheter system can be performed more easily and safely compared with other placement methods [4–7, 15]. For these reasons, removal of the port-catheter system has shown yearly increases at our institutions.
The feasibility of system removal becomes relevant when a patient or a physician wishes to have the system removed because the liver tumors have disappeared, the treatment has ended, or when there has been some difficulty with the system itself. In our study, system removal was required in eight cases for various reasons (i.e., uncontrollable bleeding at the puncture site, hepatic artery thrombosis, dislocation of the indwelling catheter, angiospasm of the hepatic artery, subcutaneous leakage of anticancer drugs, and completion of chemotherapy). The removal procedure was successfully performed in all eight of these patients (Table 2).
Recently, preventive HAIC has also been introduced for use in postoperative patients with locally advanced gastric or pancreatic cancer; their port-catheter systems were removed from 1 to 3 months after insertion (i.e., as soon as the scheduled chemotherapy ended) [30, 32].
In many Japanese institutions, catheter tips are usually fixed to the GDA wall with metallic coils or by N-butyl cyanoacrylate to prevent catheter dislocation [5]. However, after such a fixed technique is performed, removal of the port-catheter system becomes difficult. Withdrawing the indwelling catheter might be difficult because the catheter tip that is tightly fixed by glues or coils is considered to hinder the withdrawal because of the potential risks of hepatic thrombosis or migration of embolic materials [5]. Moreover, the catheters inserted through the transsubclavian or transbrachial access cannot be removed through the same access route for fear of cerebrovascular diseases, because thrombi formation around the catheter can reportedly occur in 1.1% of the patients who undergo percutaneous implantation of a port-catheter system via the left subclavian artery for HAIC [9]. The most dramatic advantage of GEM is that the catheter can be removed without difficulty, and replacement of the port-catheter system is thus feasible. Catheter removal is accomplished simply by pulling gently on the catheter, and this procedure takes only a few minutes. GEM is thus expected to increase the quality of life in patients with malignant liver tumors.
Our data showed obstruction of the port-catheter system in 2% (1/57) of the patients, and dislocation of the catheter tip occurred in 3.5% (2/57); these complication rates using transfemoral access were favorable compared with those described in recent reports about studies using transsubclavian access [1]. In one case, chemotoxicity, including peptic ulcers, occurred as the result of anticancer drugs flowing into the right gastric artery; in that case, additional embolization of the right gastric artery with a microcatheter via the contralateral femoral approach was performed. With the present method, the incidence of catheter misplacement, migration, and leakage was shown to be lower than that observed with the surgical approach (3.3% vs 5.3% [27]). Furthermore, all these complications were resolved percutaneously. In that study, there were no cases in which the catheter had to be removed after repeated migration.
The following description gives an account of the mechanism by which blood flow into the right gastroepiploic artery and the GDA (i.e., around the catheter and catheter tip) spontaneously ceases. It is proposed that initially, flow-dynamic properties due to the spiral shape of the catheter tip may be of concern—namely, most injected water flows out from the side-hole of the W-spiral catheter, whereas little of the injected fluid flows out from the end-hole, probably because of the resistance of the spiral-shaped flexion of the catheter (Figs. 2A, 2B, and 2C). These characteristics are likely to contribute to the spontaneous cessation of right gastroepiploic artery flow without necessitating embolization of the end-hole. Then, retrograde collateral flow from the left gastroepiploic artery, the left gastric artery, and the short gastric artery may occur. However, reflux of blood into the catheter and subsequent clot formation in the catheter or spasm of GDA might secondarily contribute to the flow cessation.
In conclusion, GEM has many clinical advantages due to the technical feasibility of catheter removal, the general accessibility via the femoral artery, and the relatively acceptable frequency of complications. Our data suggest that the implantation of a port-catheter system by GEM may contribute to an improvement in the quality of life of patients with unresectable malignant liver tumors.
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