Published online before print October 26, 2005, 10.1148/radiol.2373041660
(Radiology 2005;237:1110-1114.)
© RSNA, 2005
Vascular and Interventional Radiology |
Arterial Blood Supply to the Posterior Aspect of Segment IV of the Liver from the Caudate Branch: Demonstration at CT after Iodized Oil Injection1
Shiro Miyayama, MD,
Osamu Matsui, MD,
Keiichi Taki, MD,
Tetsuya Minami, MD,
Yasuji Ryu, MD,
Chiharu Ito, MD,
Koichi Nakamura, MD,
Dai Inoue, MD and
Shigeyuki Takamatsu, MD
1 From the Department of Diagnostic Radiology, Fukuiken Saiseikai Hospital, 7-1, Funabashi, Wadanaka-cho, Fukui 918-8503, Japan (S.M., K.T., T.M., Y.R., C.I., K.N., D.I.); and Department of Radiology, Kanazawa University, Graduate School of Medical Science, Kanazawa, Japan (O.M., S.T.). Received September 30, 2004; revision requested December 7; revision received December 28; accepted January 21, 2005.
Address correspondence to S.M. (e-mail: s-miyayama{at}fukui.saiseikai.or.jp).
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ABSTRACT
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PURPOSE: To retrospectively evaluate the arterial blood supply to the posterior aspect of segment IV of the liver with computed tomography (CT) after transcatheter arterial chemoembolization (TACE) with iodized oil through the caudate arterial branch of the liver for treatment of hepatocellular carcinoma (HCC).
MATERIALS AND METHODS: Institutional review board approval and patient informed consent were not required for this retrospective study. Twenty-four patients (11 men and 13 women; mean age, 68 years) with HCC originating in the caudate lobe (n = 23) or posterior aspect of segment IV (n = 1) were selected. TACE of the caudate arterial branch was performed in all patients, including one patient with HCC in the posterior aspect of segment IV who underwent TACE of the caudate arterial branch after CT helped confirm that iodized oil was not distributed in the tumor after TACE of the medial segmental artery. The distribution of iodized oil in the posterior aspect of segment IV was analyzed with CT 1 week after TACE. The number and origin of all arteries supplying the caudate lobe and the number of arteries embolized were determined.
RESULTS: Thirty-three caudate arterial branches were embolized. Twenty-nine branches were derived from the right hepatic artery and four were derived from the left hepatic artery. A single branch was seen in 17 patients, two branches were seen in five, and three branches were seen in two. Eight patients simultaneously underwent additional TACE of branches of the right hepatic artery (n = 6) or right inferior phrenic artery (n = 2). At CT, iodized oil was seen to be distributed entirely (n = 19) or partially (n = 5) in the caudate lobe. Distribution of iodized oil at the posterior aspect of segment IV was observed in 16 patients (67%), including 13 (54%) whose caudate arterial branches were derived entirely from the right hepatic artery.
CONCLUSION: The results of this study suggest that the caudate arterial branch, which is mainly derived from the right hepatic artery, frequently supplies the posterior aspect of segment IV. This knowledge is important for managing HCC in the posterior aspect of segment IV by means of TACE.
© RSNA, 2005
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INTRODUCTION
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It is well known that the posterior aspect of segment IV of the liver just anterior to the right side of the hepatic hilus is a peculiar area. The aberrant right gastric vein frequently enters there, and focal sparing in the fatty liver, focal fatty changes in the normal liver, and focal hyperplastic changes in the cirrhotic liver are frequently seen (1–4). In addition, one to three tiny portal venules that branch directly from the main right or left portal veins also distribute to the posterior aspect of segment IV in approximately 60% of patients when observed with computed tomography (CT) during arterial portography (5).
In general, arterial blood to the posterior aspect of segment IV is considered to come from the medial segmental artery, which is derived from the left hepatic artery or from the right hepatic artery as the middle hepatic artery. Variation of right arterial supply to the posterior aspect of segment IV, however, was reported on the basis of findings at CT during hepatic arteriography (6). We have also noticed that iodized oil accumulation at the posterior aspect of segment IV was sometimes seen after transcatheter arterial chemoembolization (TACE) of the caudate arterial branch of the liver for the treatment of hepatocellular carcinoma (HCC). Thus, the purpose of our study was to retrospectively evaluate the arterial blood supply to the posterior aspect of segment IV with CT performed after TACE with iodized oil through the caudate arterial branch of the liver for the treatment of HCC.
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MATERIALS AND METHODS
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Patients
Between June 1999 and June 2004, 24 patients with HCC originating in the caudate lobe or posterior aspect of segment IV underwent treatment and imaging. This was a retrospective study in which existing imaging data were used with no change in patient care; institutional review board approval and informed consent are not required at our institution for this type of study. The diagnosis of HCC was clinically made by means of nodular staining at digital subtraction angiography, a nodular perfusion defect at CT during arterial portography, and high serum levels of tumor markers (
-fetoprotein and protein induced by vitamin K absence II). Patients were selected for the study if they (a) had a tumor in the caudate lobe or posterior aspect of segment IV of the liver, (b) underwent initial TACE or had a hepatic arterial circulation that was not attenuated with previous therapies, (c) successfully underwent TACE through all caudate arterial branches that were identified at angiography without overflow of iodized oil, and (d) underwent TACE of only the caudate arterial branch or underwent TACE of a branch other than the caudate arterial branch, and the embolized area of each branch was clearly distinguished at CT. Twenty-four patients satisfied all four criteria. There were 11 men and 13 women aged 53–81 years (mean age, 68 years). All patients had chronic hepatitis or liver cirrhosis. Twenty-two patients had viral hepatitis C, and one had viral hepatitis B. In one patient, the cause of liver cirrhosis was unknown.
Twenty-three patients had a tumor in the caudate lobe. Of these 23 patients, 14 had a solitary tumor in the caudate lobe. Seven patients had one additional tumor in another segment, and one patient had two additional tumors in other segments; one of the two additional tumors was located in the posterior aspect of segment IV and had a viable portion after TACE. One patient with a tumor in the caudate lobe also had multiple tumors in the right lobe of the liver. The remaining patient had a solitary tumor at the posterior aspect of segment IV. Eleven patients had previously undergone TACE for the treatment of HCC in the right lobe of the liver (n = 8), caudate lobe (n = 2), and posterior aspect of segment IV (n = 1). One patient had undergone TACE of the medial segmental artery derived from the left hepatic artery 4 months earlier and had a viable portion in the tumor at the posterior aspect of segment IV. In two patients with a recurrent tumor in the caudate lobe, selective catheterization into the caudate arterial branch derived from the right hepatic artery had resulted in failure at the previous TACE performed 6 and 7 months previously, respectively, and a small amount of embolic material had been injected from the right hepatic artery.
TACE Procedure
Written informed consent was obtained from each patient before the TACE procedure. The caudate arterial branch was identified with selective arteriography. Confirmation of the caudate arterial branch was achieved by means of the distribution of injected iodized oil in the caudate lobe at CT performed after TACE. All patients underwent TACE via all caudate arterial branches when multiple caudate arterial branches were identified.
TACE was performed with gelatin sponge particles (Gelfoam; Upjohn, Kalamazoo, Mich) after the injection of a mixture of 0.5–4.0 mL of iodized oil (Lipiodol; Guerbet, Aulnay-sous-Bois, France), 10–20 mg of epirubicin (Farmorubicin; Kyowa Hakko, Tokyo, Japan), and 2–4 mg of mitomycin C (Mitomycin; Kyowa Hakko). A microcatheter with a 2.4-F tip (Microferret; Cook, Bloomington, Ind) or a 2-F tip (Progreat ; Terumo, Tokyo, Japan) was used to select the target vessels. All TACE procedures were performed by one senior radiologist (S.M., with 14 years of experience in interventional procedures at the beginning of this study) and another radiologist (K.T., T.M., Y.R., C.I., K.N., D.I., or S.T., with 3–11 years experience in interventional procedures).
CT Protocol
CT was performed 1 week after TACE. All patients were scanned with a helical CT unit (Aquilion [n = 4], Aquilion-4 [n = 9], or Aquilion-16 [n = 11]; Toshiba, Tokyo, Japan). Unenhanced scanning (3- or 5-mm collimation, 5-mm-thick sections, 5-mm reconstruction intervals, 135 kVp, and 200 mAs) was performed with a single breath hold. In one patient with a tumor in the posterior aspect of segment IV, CT was also performed during the TACE procedure with the same technique to check iodized oil accumulation in the tumor.
Definition of Posterior Aspect of Segment IV Supply
Three radiologists (S.M., K.T., and T.M., with 19, 11, and 7 years of experience in CT of the liver, respectively) retrospectively evaluated all CT scans in consensus. The distribution of injected iodized oil in the posterior aspect of segment IV was evaluated with CT scans obtained 1 week after TACE. It was determined that the caudate arterial branch supplied the posterior aspect of segment IV when iodized oil was distributed in this area. The location from which the caudate arterial branch supplied the posterior aspect of segment IV was also evaluated. In addition, we determined whether iodized oil was distributed into most of the caudate lobe.
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RESULTS
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Caudate Arterial Branches
Thirty-three caudate arterial branches were identified and embolized in the 24 patients. Twenty-nine caudate arterial branches were derived from the right hepatic artery, and four were derived from the left hepatic artery. One caudate arterial branch was seen in 17 patients (Fig 1), two caudate arterial branches were seen in five patients, and three caudate arterial branches were seen in two patients (Fig 2 ). Fifteen patients underwent TACE of only the caudate arterial branch (Figs 1, 2). Eight patients underwent TACE of branches of the right hepatic artery (n = 6) (Fig 3) or right inferior phrenic artery (n = 2) in addition to TACE of the caudate arterial branch. The remaining patient underwent TACE of the caudate arterial branch after CT helped confirm that iodized oil spared the tumor at the posterior aspect of segment IV just after TACE of the medial segmental artery derived from the left hepatic artery (Fig 4).
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Figure 1a. Images in a 69-year-old woman with a tumor in the caudate lobe of the liver. (a) Posteroanterior celiac arteriogram shows a single caudate arterial branch (arrow) derived from the right hepatic artery. (b) Posteroanterior arteriogram of the caudate arterial branch. The caudate arterial branch was selected, and TACE was performed. (c) Transverse CT image obtained 1 week after TACE shows distribution of the iodized oil not only in the caudate lobe (arrow) but also in the posterior aspect of segment IV (arrowhead). Good iodized oil accumulation in the tumor was seen on another CT image (not shown).
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Figure 1b. Images in a 69-year-old woman with a tumor in the caudate lobe of the liver. (a) Posteroanterior celiac arteriogram shows a single caudate arterial branch (arrow) derived from the right hepatic artery. (b) Posteroanterior arteriogram of the caudate arterial branch. The caudate arterial branch was selected, and TACE was performed. (c) Transverse CT image obtained 1 week after TACE shows distribution of the iodized oil not only in the caudate lobe (arrow) but also in the posterior aspect of segment IV (arrowhead). Good iodized oil accumulation in the tumor was seen on another CT image (not shown).
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Figure 1c. Images in a 69-year-old woman with a tumor in the caudate lobe of the liver. (a) Posteroanterior celiac arteriogram shows a single caudate arterial branch (arrow) derived from the right hepatic artery. (b) Posteroanterior arteriogram of the caudate arterial branch. The caudate arterial branch was selected, and TACE was performed. (c) Transverse CT image obtained 1 week after TACE shows distribution of the iodized oil not only in the caudate lobe (arrow) but also in the posterior aspect of segment IV (arrowhead). Good iodized oil accumulation in the tumor was seen on another CT image (not shown).
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Figure 2a. Images in a 79-year-old woman with a tumor in the caudate lobe of the liver. (a) Posteroanterior proper hepatic arteriogram shows three caudate arterial branches derived from both the anterior (black arrow) and the posterior (arrowhead) segmental branches of the right lobe of the liver and the right hepatic artery (*). Also, note a tumor stain (white arrow). (b) Transverse CT image obtained 1 week after TACE of three caudate arterial branches shows distribution of the iodized oil not only in the caudate lobe (white arrow) but also in the posterior aspect of segment IV (arrowhead). Also, note the accumulation of iodized oil in the tumor (black arrow).
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Figure 2b. Images in a 79-year-old woman with a tumor in the caudate lobe of the liver. (a) Posteroanterior proper hepatic arteriogram shows three caudate arterial branches derived from both the anterior (black arrow) and the posterior (arrowhead) segmental branches of the right lobe of the liver and the right hepatic artery (*). Also, note a tumor stain (white arrow). (b) Transverse CT image obtained 1 week after TACE of three caudate arterial branches shows distribution of the iodized oil not only in the caudate lobe (white arrow) but also in the posterior aspect of segment IV (arrowhead). Also, note the accumulation of iodized oil in the tumor (black arrow).
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Figure 3a. Images in a 78-year-old woman with a tumor in the caudate lobe. (a) Posteroanterior celiac arteriogram shows a tumor stain (arrowhead). The posterior superior subsegmental artery (arrow) partially supplied the tumor, and TACE was performed. (b) Posteroanterior right hepatic arteriogram obtained after TACE of the posterior superior subsegmental artery shows the remaining tumor stain fed by the caudate arterial branch (arrow) derived from the right hepatic artery. Subsequently, this branch was selected and TACE performed. (c) Transverse CT image obtained 1 week after TACE shows iodized oil accumulation in the tumor (arrow), posterior aspect of segment IV (arrowhead), and posterior superior subsegment. The iodized oil is not distributed in the Spiegel lobe of the caudate lobe.
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Figure 3b. Images in a 78-year-old woman with a tumor in the caudate lobe. (a) Posteroanterior celiac arteriogram shows a tumor stain (arrowhead). The posterior superior subsegmental artery (arrow) partially supplied the tumor, and TACE was performed. (b) Posteroanterior right hepatic arteriogram obtained after TACE of the posterior superior subsegmental artery shows the remaining tumor stain fed by the caudate arterial branch (arrow) derived from the right hepatic artery. Subsequently, this branch was selected and TACE performed. (c) Transverse CT image obtained 1 week after TACE shows iodized oil accumulation in the tumor (arrow), posterior aspect of segment IV (arrowhead), and posterior superior subsegment. The iodized oil is not distributed in the Spiegel lobe of the caudate lobe.
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Figure 3c. Images in a 78-year-old woman with a tumor in the caudate lobe. (a) Posteroanterior celiac arteriogram shows a tumor stain (arrowhead). The posterior superior subsegmental artery (arrow) partially supplied the tumor, and TACE was performed. (b) Posteroanterior right hepatic arteriogram obtained after TACE of the posterior superior subsegmental artery shows the remaining tumor stain fed by the caudate arterial branch (arrow) derived from the right hepatic artery. Subsequently, this branch was selected and TACE performed. (c) Transverse CT image obtained 1 week after TACE shows iodized oil accumulation in the tumor (arrow), posterior aspect of segment IV (arrowhead), and posterior superior subsegment. The iodized oil is not distributed in the Spiegel lobe of the caudate lobe.
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Figure 4a. Images obtained in a 71-old-man with a tumor in the posterior aspect of segment IV. (a) Posteroanterior proper hepatic arteriogram shows the medial segmental artery (arrow) derived from the left hepatic artery and the caudate arterial branch (arrowhead) derived from the right hepatic artery. (b) Posteroanterior arteriogram of the medial segmental artery. The medial segmental artery was selected, and TACE was performed. (c) Transverse CT image obtained just after TACE of the medial hepatic artery shows that iodized oil was not injected in the tumor (arrow). (d) Posteroanterior arteriogram of the caudate arterial branch. Subsequently, the caudate arterial branch was selected, and TACE was performed. (e) Transverse CT iamge obtained 1 week after TACE shows the accumulation of iodized oil in the tumor at posterior aspect of segment IV in addition to distribution of the iodized oil in the caudate lobe (arrow).
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Figure 4b. Images obtained in a 71-old-man with a tumor in the posterior aspect of segment IV. (a) Posteroanterior proper hepatic arteriogram shows the medial segmental artery (arrow) derived from the left hepatic artery and the caudate arterial branch (arrowhead) derived from the right hepatic artery. (b) Posteroanterior arteriogram of the medial segmental artery. The medial segmental artery was selected, and TACE was performed. (c) Transverse CT image obtained just after TACE of the medial hepatic artery shows that iodized oil was not injected in the tumor (arrow). (d) Posteroanterior arteriogram of the caudate arterial branch. Subsequently, the caudate arterial branch was selected, and TACE was performed. (e) Transverse CT iamge obtained 1 week after TACE shows the accumulation of iodized oil in the tumor at posterior aspect of segment IV in addition to distribution of the iodized oil in the caudate lobe (arrow).
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Figure 4c. Images obtained in a 71-old-man with a tumor in the posterior aspect of segment IV. (a) Posteroanterior proper hepatic arteriogram shows the medial segmental artery (arrow) derived from the left hepatic artery and the caudate arterial branch (arrowhead) derived from the right hepatic artery. (b) Posteroanterior arteriogram of the medial segmental artery. The medial segmental artery was selected, and TACE was performed. (c) Transverse CT image obtained just after TACE of the medial hepatic artery shows that iodized oil was not injected in the tumor (arrow). (d) Posteroanterior arteriogram of the caudate arterial branch. Subsequently, the caudate arterial branch was selected, and TACE was performed. (e) Transverse CT iamge obtained 1 week after TACE shows the accumulation of iodized oil in the tumor at posterior aspect of segment IV in addition to distribution of the iodized oil in the caudate lobe (arrow).
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Figure 4d. Images obtained in a 71-old-man with a tumor in the posterior aspect of segment IV. (a) Posteroanterior proper hepatic arteriogram shows the medial segmental artery (arrow) derived from the left hepatic artery and the caudate arterial branch (arrowhead) derived from the right hepatic artery. (b) Posteroanterior arteriogram of the medial segmental artery. The medial segmental artery was selected, and TACE was performed. (c) Transverse CT image obtained just after TACE of the medial hepatic artery shows that iodized oil was not injected in the tumor (arrow). (d) Posteroanterior arteriogram of the caudate arterial branch. Subsequently, the caudate arterial branch was selected, and TACE was performed. (e) Transverse CT iamge obtained 1 week after TACE shows the accumulation of iodized oil in the tumor at posterior aspect of segment IV in addition to distribution of the iodized oil in the caudate lobe (arrow).
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Figure 4e. Images obtained in a 71-old-man with a tumor in the posterior aspect of segment IV. (a) Posteroanterior proper hepatic arteriogram shows the medial segmental artery (arrow) derived from the left hepatic artery and the caudate arterial branch (arrowhead) derived from the right hepatic artery. (b) Posteroanterior arteriogram of the medial segmental artery. The medial segmental artery was selected, and TACE was performed. (c) Transverse CT image obtained just after TACE of the medial hepatic artery shows that iodized oil was not injected in the tumor (arrow). (d) Posteroanterior arteriogram of the caudate arterial branch. Subsequently, the caudate arterial branch was selected, and TACE was performed. (e) Transverse CT iamge obtained 1 week after TACE shows the accumulation of iodized oil in the tumor at posterior aspect of segment IV in addition to distribution of the iodized oil in the caudate lobe (arrow).
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Caudate Lobe Distribution
CT scans obtained 1 week after TACE showed that the territory of the embolized artery had high attenuation due to retention of the injected iodized oil in the liver parenchyma. The iodized oil was distributed in most of the caudate lobe in 19 patients (79%). In the remaining five patients (21%), iodized oil did not flow into most of the caudate lobe, and a focal defect was observed (Fig 3).
Distribution of the iodized oil in the posterior aspect of segment IV after TACE of the caudate arterial branch was observed in 16 of the 24 patients (67%), including 13 (54%) in whom all caudate arterial branches were derived from the right hepatic artery (Figs 1–4). In two patients, iodized oil accumulation was seen in the large part of segment IV and the posterior aspect of segment IV at CT. In one patient with a viable portion of the tumor in the posterior aspect of segment IV after TACE of the medial segmental artery, iodized oil accumulation was seen in the viable portion of the tumor after TACE of the caudate arterial branch. In another patient with a tumor in the posterior aspect of segment IV, CT performed just after TACE of the medial segmental artery showed that iodized oil did not accumulate in the tumor at the posterior aspect of segment IV. CT performed 1 week after additional TACE of the caudate arterial branch showed iodized oil accumulation not only in the caudate lobe but also in the tumor at the posterior aspect of segment IV (Fig 4).
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DISCUSSION
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Segment IV of the liver—at least at its anterior portion (the quadrate lobe)—appears rather late during embryologic development, and this explains the great variety in form and the numerous vascular and biliary variations (7). Branches from the neighboring vessels, the left portal vein, and the parabiliary venous system, enter there (7). Analysis with CT during arterial portography has shown that, in addition to aberrant right gastric venous drainage, one to three tiny portal venules that branch directly from the main right or left portal vein similar to a caudate branch distribute to the posterior aspect of segment IV in approximately 60% of patients (5). Couinaud (7) also reported that some caudate portal branches supply the posterior extremity of segment IV.
The arterial blood supply to the posterior aspect of segment IV is not clearly understood. Kobayashi et al (6) reported that arterial blood entered into the posterior aspect of segment IV from the right hepatic artery in 8% of their cases on the basis of findings at CT during hepatic arteriography; however, they did not label the arterial branch arising from the right hepatic artery that supplied the posterior aspect of segment IV.
We analyzed the arterial blood supply of the posterior aspect of segment IV with CT performed 1 week after TACE. Injected iodized oil could demarcate the area supplied by the embolized artery. At CT, iodized oil injected from the caudate arterial branch was distributed into the posterior aspect of segment IV in 67% of our patients. This finding suggests that the caudate arterial branch feeds the posterior aspect of segment IV at high rates, although we could not determine whether the posterior aspect of segment IV was fed only by the caudate arterial branch.
There are some limitations in our study. First, iodized oil may not have been injected adequately into small branches derived from the proximate portion of the caudate arterial branch because it was carefully injected without overflow. Second, it is possible that other caudate arterial branches were not depicted with angiography. It is well known that there are multiple caudate arterial branches derived from both the right and the left hepatic arteries and that they anastomose each other (8). Iodized oil injected into one of the caudate arterial branches may be pushed back by reversed blood flow though the anastomosis with other caudate arterial branches. These technical difficulties of caudate arterial branch TACE may help explain why iodized oil is not distributed in most of the caudate lobe, as was observed in 21% of our patients. Distribution of the injected iodized oil may not correspond with natural arterial blood flow because the iodized oil is injected with little force during the TACE procedure. Some iodized oil injected into one of the caudate arterial branches with little force may pass the anastomosis and flow into areas with other caudate arterial branches. Moreover, it may pass through the anastomosis between caudate arterial branches and neighboring branches. Iodized oil accumulation in the large part of segment IV, in addition to the posterior aspect of segment IV, was seen in two patients. It was speculated that one medial segmental branch and one caudate arterial branch were derived together or connected to each other in these patients. It is impossible to accurately determine whether the iodized oil flows into the posterior aspect of segment IV directly or indirectly through these anastomoses. It seems, however, that this differentiation is not clinically important. Our results suggest that the caudate arterial branch is one of the main arterial sources of the posterior aspect of segment IV, although the posterior aspect of segment IV potentially has multiple feeding branches. This knowledge is clinically very important for managing tumors in the posterior aspect of segment IV with TACE; that is, it may be necessary to perform TACE of the caudate arterial branch in addition to TACE of the medial segmental artery to control tumors originating in the posterior aspect of segment IV.
The frequency of a right arterial supply to the posterior aspect of segment IV was estimated at 54% in our study. This frequency is extremely high compared with the incidence reported by Kobayashi et al (6). The discrepancy between their results and ours may be a result of the different methods used to analyze the arterial blood flow. Kobayashi et al (6) analyzed the arterial flow with images from CT during hepatic arteriography, whereas we used CT scans obtained after TACE. At CT during hepatic arteriography, contrast material may flow into the posterior aspect of segment IV through the branch that is physiologically dominant. Conversely, some iodized oil injected from the caudate arterial branch with little force may pass through the anastomosis between other caudate arterial branches and neighboring branches. We speculate that iodized oil injected from the caudate arterial branch mainly flows into the posterior aspect of segment IV through these anastomoses because the frequency of right arterial supply to the posterior aspect of segment IV in our study was extremely high compared with results obtained with CT during hepatic arteriography, which may reflect physiologic arterial blood flow.
In conclusion, our results suggest that the caudate arterial branch frequently supplies the posterior aspect of segment IV. We believe that this knowledge is very important for managing HCC in the posterior aspect of segment IV with TACE.
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FOOTNOTES
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Abbreviations: HCC = hepatocellular carcinoma • TACE = transcatheter arterial chemoembolization
Authors stated no financial relationship to disclose.
Author contributions: Guarantors of integrity of entire study, S.M., O.M.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, S.M., O.M., K.T., T.M., Y.R., C.I., S.T.; clinical studies, S.M., K.T., T.M., Y.R., C.I., K.N., D.I., S.T.; and manuscript editing, S.M., O.M.
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References
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ABSTRACT
INTRODUCTION
